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WO1998042347A1 - Pharmaceutical composition containing a phosphorylamide and an ayntibiotic - Google Patents

Pharmaceutical composition containing a phosphorylamide and an ayntibiotic Download PDF

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Publication number
WO1998042347A1
WO1998042347A1 PCT/JP1998/001267 JP9801267W WO9842347A1 WO 1998042347 A1 WO1998042347 A1 WO 1998042347A1 JP 9801267 W JP9801267 W JP 9801267W WO 9842347 A1 WO9842347 A1 WO 9842347A1
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WIPO (PCT)
Prior art keywords
group
substituted
groups
halogen
alkyl
Prior art date
Application number
PCT/JP1998/001267
Other languages
French (fr)
Inventor
Satoru Oi
Nobuhiro Inatomi
Original Assignee
Takeda Chemical Industries, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Takeda Chemical Industries, Ltd. filed Critical Takeda Chemical Industries, Ltd.
Priority to AU64222/98A priority Critical patent/AU6422298A/en
Publication of WO1998042347A1 publication Critical patent/WO1998042347A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms
    • C07F9/655345—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having sulfur atoms, with or without selenium or tellurium atoms, as the only ring hetero atoms the sulfur atom being part of a five-membered ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/65515—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a five-membered ring

Definitions

  • the present invention relates to a pharmaceutical composition. More specifically this invention relates to a pharmaceutical composition which comprises a phosphorylamide derivative possessing excellent antibacterial activity based on excellent anti-urease 10 activity, especially potent antibacterial activity against Helicobacter bacteria such as Helicobacter pylori , and an antibiotic.
  • Helicobacter pylori which is a gram-negative , slightly aerobic bacterium belonging to the genus Helicobacter is considered to be a major cause of recurrent gastritis, duodenal ulcer, gastric ulcer etc.
  • Helicobacter bacteria especially Helicobacter pylori , possessing potent urease activity, reportedly survive in the stomach, in which they neutralize strong acidity around them by producing ammonia from urea.
  • Metronidazole an imidazole antibiotic possessing anti- Helicobacter pylori activity, is used in combination with another antibiotic. These bismuth preparations, antibiotics, metronidazole etc. are administered orally.
  • the present invention provides a pharmaceutical composition which comprises a phosphorylamide derivative or a salt thereof possessing excellent antibacterial activity, especially potent antibacterial activity against Helicobacter bacteria such as Helicobacter pylori , and an antibiotic.
  • the present inventors found that a phosphorylamide derivative possessing anti-urease activity exhibits potent antibacterial activity against Helicobacter bacteria in vivo against bacteria (e.g. , Helicobacter bacteria such as Helicobacter pylori ) showing toxic action in the digestive tract .
  • bacteria e.g. , Helicobacter bacteria such as Helicobacter pylori
  • R represents an amino group which may be substituted, or a salt thereof, and an antibiotic
  • R la represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or a salt thereof, and an antibiotic
  • R lb represents a non-cyclic hydrocarbon group substituted by (i) a cyclic hydrocarbon group which may be substituted, (ii) a heterocyclic group which may be substituted, (iii) hydroxyl group substituted by a cyclic hydrocarbon group which may be substituted, (iv) hydroxyl group substituted by a heterocyclic group which may be substituted, (v) thiol group substituted by a cyclic hydrocarbon group which may be substituted, or (vi) thiol group substituted by a heterocyclic group which may be substituted, or a salt thereof, and an antibiotic;
  • a pharmaceutical composition which comprises (i) the compound represented by the formula ( I ) , ( ii) an antibiotic , and (iii) an antacid and/or an acid secretion inhibitor; ( 5 ) a combination preparation which contains the compound represented by the formula (la) or a salt thereof, and antibiotic;
  • a combination preparation which contains (i) the compound represented by the formula (I) or a salt thereof, (ii) an antibiotic, and (iii) an antacid and/or an acid secretion inhibitor;
  • (10) a method for eradicating Helicobacter from a mammal, which comprises administering to said mammal the compound represented by the formula (I) or a salt thereof, in combination with an antibiotic; and (11) a method for eradicating Helicobacter from a mammal, which comprises administering to said mammal the compound represented by the formula (I) or a salt thereof, in combination with an antibiotic and an antacid and/or an acid secretion inhibitor.
  • the substituents in the "amino group which may be substituted" represented by R are exemplified by ( 1 ) acyl groups , ( 2 ) carboxyl groups which may be esterified, and (3) hydrocarbon groups which may be substituted.
  • the amino group may be substituted by 1 or 2, preferably 1 of these substituents, whether identical or not.
  • the substituents are preferably an acyl group or a carboxyl group which may be esterified, more preferably an acyl group.
  • the acyl group as a substituent in the "amino group which may be substituted" represented by R is exemplified by acyl groups derived from carboxylic acids, thiocarboxylic acids, sulfonic acids, sulfinic acids, carbamic acids, thiocarbamic acids etc., specifically those represented by the respective formulas : -COR 1 , -CSR 2 , -S0 2 R 3 , -SOR 4 , -CONHR 5 or -CSNHR 6 , wherein R 1 , R 2 , R 3 , R 4 , R s and R 6 independently represent a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, etc.
  • Preferable acyl groups include those derived from carboxylic acids (-COR 1 ) and those derived from sulfonic acids (-S0 2 R 3 ) , and those derived from carboxylic acids are more preferable
  • the "hydrocarbon group which may be substituted" represented by R 1 , R 2 , R 3 , R 4 , R 5 or R 6 , is exemplified by saturated or unsaturated aliphatic chain hydrocarbon groups , saturated or unsaturated alicyclic hydrocarbon groups and aryl groups .
  • saturated aliphatic hydrocarbon groups include straight-chain or branched saturated aliphatic hydrocarbon groups having 1 to 10 carbon atoms (e.g. , C..
  • alkyl groups such as methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl and octyl), and straight-chain or branched saturated aliphatic hydrocarbon groups having 1 to 6 carbon atoms are preferable.
  • Such unsaturated aliphatic hydrocarbon groups include straight-chain or branched unsaturated aliphatic hydrocarbon groups having 2 to 10 carbon atoms (e.g., C 2 _ 10 alkenyl groups such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3- methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2 , 4-hexadienyl, 5-hexenyl, 1-heptenyl and 1-octenyl; C 2 .
  • C 2 _ 10 alkenyl groups such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pen
  • alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2 , 4-hexadiynyl, 5- hexynyl, 1-heptynyl and 1-octynyl) , and straight-chain or branched unsaturated aliphatic hydrocarbon groups having 2 to 6 carbon atoms are preferable.
  • saturated alicyclic hydrocarbon groups include saturated alicyclic hydrocarbon groups having 3 to 12 carbon atoms (e.g. , monocyclic or bicyclic C 3 . 12 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , cycloheptyl , cyclooctyl , bicyclo [2.2.1]heptyl , bicyclo [2.2.2] octyl , bicyclo [3.2.1] octyl , bicyclo [3.2.2]nonyl , bicyclo[3.3. l]nonyl, bicyclo[ 4.2.1]nonyl and bicyclo[4.3.1]decyl) , and saturated alicyclic hydrocarbon groups having 3 to 6 carbon atoms are preferable.
  • saturated alicyclic hydrocarbon groups having 3 to 6 carbon atoms are preferable.
  • Such unsaturated alicyclic hydrocarbon groups include unsaturated alicyclic hydrocarbon groups having 5 to 12 carbon atoms (e.g., C 5 . 12 cycloalkenyl groups such as 1- cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1- cyclohexenyl , 2-cyclohexenyl, 3-cyclohexenyl, 1- cycloheptenyl , 2-cycloheptenyl, 3-cycloheptenyl, 2- cyclopenten-1-yl, 3-cyclopenten-l-yl, 2-cyclohexen-l-yl and 3-cyclohexen-l-yl; C 5 .
  • cycloalkenyl groups such as 1- cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1- cyclohexenyl , 2-cyclohexenyl, 3-cyclohexenyl, 1- cycloheptenyl , 2-
  • cycloalkadienyl groups such as 2,4-cyclopentadien-l-yl, 2 , 4-cyclohexadien-l-yl and 2,5-cyclohexadien-l-yl and 2 , 4-cycloheptadienyl) .
  • the hydrocarbon group in the "hydrocarbon group which may be substituted” may be a saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms substituted by the above saturated or unsaturated alicyclic hydrocarbon group (e.g., C 3 . 7 cycloalkyl-C ⁇ alkyl groups and C 5 . 7 cycloalkenyl-C x .
  • alkyl groups such as cyclopropylmethyl , cyclopropylethyl , cyclobutylmethyl , cyclopentylmethyl , 2-cyclopentenylmethyl , 3-cyclopentenylmethyl , cyclohexylmethyl , 2-cyclohexenylmethyl, 3- cyclohexenyl ethyl , cyclohexylethyl , cyclohexylpropyl , cycloheptylmethyl and cycloheptylethyl) , or the like.
  • Such aryl groups include monocyclic or fused polycyclic aromatic hydrocarbon ring groups having 6 to 14 carbon atoms .
  • aromatic hydrocarbon ring groups include phenyl, 1- or 2-naphthyl, 1-, 2- or 9-anthryl, 1-, 2-, 3-, 4- or 9-phenanthryl, 1-, 2-, 4-, 5- or 6-azulenyl and acenaphthylenyl , and C 6 .
  • 10 aryl groups such as phenyl, 1-naphthyl and 2-naphthyl are preferable.
  • the "hydrocarbon group which may be substituted” may have 1 to 3 optionally chosen substituents at any possible positions .
  • substituents include ( 1 ) lower alkyl groups which may be substituted, (2) lower alkoxy groups which may be substituted, (3) aryl groups which may be substituted, (4) lower cycloalkyl or lower cycloalkenyl groups which may be substituted, (5) heterocyclic groups which may be substituted, (6) carboxyl groups which may be esterified, (7) carbamoyl groups which may be substituted, (8) amino groups which may be substituted, (9) hydroxyl groups which may be substituted, (10) thiol (mercapto) groups which may be substituted, (11) acyl groups, (12) halogens (e.g., fluorine, chlorine, bromine), (13) nitro, and (14) cyano.
  • the lower alkyl group in the lower alkyl group ( 1 ) which may be substituted is exemplified by C ⁇ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and isohexyl.
  • the lower alkoxy group in the lower alkoxy group ( 2 ) which may be substituted is exemplified by C ⁇ alkoxy groups such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy and isohexyloxy.
  • Said lower alkyl group ( 1 ) and lower alkoxy group ( 2 ) may have 1 to 3 optionally chosen substituents at any possible positions.
  • substituents include halogens (e.g. , fluorine , chlorine , bromine ) and lower ( C 1 .
  • alkoxy groups e.g., methoxy, ethoxy, propoxy.
  • the aryl group in the aryl group (3) which may be substituted is exemplified by C 6 . 14 aryl groups such as phenyl , naphthyl , anthryl , phenanthryl and acenaphthylenyl , and phenyl, 1-naphthyl and 2-naphthyl are preferable among others .
  • the cycloalkyl group in the lower cycloalkyl group (4) which may be substituted, is exemplified by C 3 . 7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
  • the cycloalkenyl group in the lower cycloalkenyl group (4) which may be substituted, is exemplified by C 3 . 6 cycloalkenyl groups such as cyclopropenyl , cyclobutenyl , cyclopentenyl and cyclohexenyl .
  • Said aryl group ( 3 ) , said lower cycloalkyl group ( 4 ) or said lower cycloalkenyl group ( 4 ) may have 1 to 5 , preferably 1 to 3 , optionally chosen substituents at any possible positions, and these substituents include alkoxy groups (e.g. , C ⁇ j alkoxy groups such as methoxy, ethoxy and propoxy) , halogen atoms (e.g. , fluorine, chlorine, bromine, iodine) , alkyl groups (e.g. , C x . 3 alkyl groups such as methyl, ethyl and propyl ) , amino , nitro and cyano .
  • alkoxy groups e.g. , C ⁇ j alkoxy groups such as methoxy, ethoxy and propoxy
  • halogen atoms e.g. , fluorine, chlorine, bromine, iodine
  • the heterocyclic group in the heterocyclic group ( 5 ) which may be substituted is exemplified by aromatic heterocyclic groups and saturated or unsaturated non- aromatic heterocyclic groups (aliphatic heterocyclic groups) having at least 1 hetero atom selected from oxygen, sulfur and nitrogen as a ring-constituting atom (ring atom) , and aromatic heterocyclic groups are preferable.
  • aromatic heterocyclic groups include 5- to 7-membered aromatic heterocyclic groups containing 1 sulfur atom, nitrogen atom or oxygen atom, 5- or 6-membered aromatic heterocyclic groups containing 2 to 4 nitrogen atoms, and 5- or 6-membered aromatic heterocyclic groups containing 1 or 2 nitrogen atoms and 1 sulfur atom or oxygen atom.
  • aromatic heterocyclic groups may be fused with a 6-membered ring containing 2 or fewer nitrogen atoms, a benzene ring, or a 5-membered ring containing 1 sulfur atom.
  • aromatic heterocyclic groups include aromatic monocyclic heterocyclic groups (e.g.
  • the azolyl groups include 5-membered aromatic heterocyclic groups containing 1 to 4 nitrogen atoms (e.g. , pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl) and 5-membered aromatic heterocyclic groups containing 1 or 2 nitrogen atoms and 1 sulfur atom or oxygen atom (e.g. , oxazolyl, isoxazolyl, thiazolyl, isothiazolyl), and the fused azolyl groups include groups formed by fusion of a benzene ring with a 5-membered aromatic heterocyclic ring containing 1 or 2 nitrogen atoms (e.g.
  • benzimidazolyl and groups formed by fusion of a benzene ring with a 5-membered aromatic heterocyclic ring containing 1 nitrogen atom and 1 sulfur atom or oxygen atom (e.g., benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl) .
  • non-aromatic heterocyclic groups include 5- to 7-membered non-aromatic heterocyclic groups containing 1 sulfur atom, nitrogen atom or oxygen atom, and 3- to 7- membered non-aromatic heterocyclic groups containing 1 nitrogen atom and 3 or fewer hetero atoms (e.g.
  • nitrogen, oxygen and sulfur atoms such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl , tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl , morpholinyl, thiomorpholinyl , piperazinyl, homopiperidyl , pyrrolinyl and i idazolidinyl .
  • oxiranyl such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl , tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl , morpholinyl, thiomorpholinyl , piperazinyl, homopiperidyl , pyrrolinyl and i idazolidinyl
  • non-aromatic heterocyclic groups may be fused with a benzene ring, a 6-membered ring containing 2 or fewer nitrogen atoms, a 5-membered ring containing 1 sulfur atom, or the like.
  • fused non- aromatic heterocyclic groups include chromanyl, isochromanyl, indolinyl, isoindolinyl, thiochromanyl and isothiochromanyl .
  • the heterocyclic groups may have 1 to 3 optionally chosen substituents at any possible positions .
  • substituents include alkoxy groups (e.g., C ⁇ ,, alkoxy groups such as methoxy, ethoxy and propoxy) which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine) , halogen atoms (e.g. , fluorine, chlorine, bromine, iodine) , alkyl groups (e.g. , C ⁇ ,, alkyl groups such as methyl , ethyl and propyl) which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), aryl groups (e.g., C 6 . 10 aryl groups such as phenyl, 1-naphthyl and 2-naphthyl), and nitro.
  • alkoxy groups e.
  • the carboxyl group ( 6 ) which may be esterified include carboxyl groups , (lower (C ⁇ ) alkoxy) carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl , isopropoxycarbonyl , butoxycarbonyl , isobutoxycarbonyl , tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl , isopentyloxycarbonyl , neopentyloxycarbonyl , tert-pentyloxycarbonyl, hexyloxycarbonyl) , (C 6 .
  • carboxyl groups e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl , isopropoxycarbonyl , butoxycarbonyl , isobutoxycarbonyl , tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxy
  • aryl ) oxycarbonyl groups e.g., phenoxycarbonyl , 1-naphthoxycarbonyl
  • C 7 . 10 aralkyl oxycarbonyl group e.g., (phenyl-Ci.., alkyl ) oxycarbonyl groups such as benzyloxycarbonyl etc .
  • carboxyl group methoxycarbonyl and ethoxycarbonyl are preferred.
  • the substituents in said carbamoyl group (7) which may be substituted, or in the amino group (8) which may be substituted, are exemplified by lower ( C 1 . 6 ) alkyl groups which may be substituted (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl), C 3 .
  • cycloalkyl groups which may be substituted (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), C 6 . 10 aryl groups which may be substituted (e.g., phenyl, 1-naphthyl, 2- naphthyl), C 7 . 12 aralkyl groups which may be substituted (e.g. , phenyl-C x.4 alkyl groups such as benzyl and phenethyl , and naphthyl-C ⁇ alkyl groups ) , and C 6 .
  • arylsulfonyl groups which may be substituted e.g., benzenesulfonyl, 1- naphthalenesulfonyl , 2-naphthalenesulfonyl
  • substituents in such lower C L alkyl groups which may be substituted, C 3 _ 6 cycloalkyl groups which may be substituted, C 6 . 10 aryl groups which may be substituted, C 7 . 12 aralkyl groups which may be substituted, and C 6 .
  • 10 arylsulfonyl groups which may be substituted include halogens (e.g., fluorine, chlorine, bromine), alkoxy groups (e.g. , C L . 4 alkoxy groups such as methoxy, ethoxy and propoxy) which may be substituted by 1 to 3 halogens, alkyl groups (e.g., C x . 4 alkyl groups such as methyl, ethyl and propyl) which may be substituted by 1 to 3 halogens, and nitro , and 1 to 5 of these substituents may be present .
  • halogens e.g., fluorine, chlorine, bromine
  • alkoxy groups e.g. , C L . 4 alkoxy groups such as methoxy, ethoxy and propoxy
  • alkyl groups e.g., C x . 4 alkyl groups such as methyl, ethyl and propyl
  • the amino group which may be substituted may form a cyclic amino group resulting from binding of two substituents on the nitrogen atom with the nitrogen atom, and such cyclic amino groups include 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino and 1-piperazinyl.
  • the substituents in said hydroxyl group (9) which may be substituted, and the thiol group (10) which may be substituted, are exemplified by hydrocarbon groups which may be substituted, and heterocyclic groups which may be substituted.
  • the "hydrocarbon group which may be substituted” is exemplified by the same groups as those mentioned in the "hydrocarbon group which may be substituted," represented by R 1 , R 2 , R 3 , R » R s or R 6 above, and preferable are lower (C ⁇ ) alkyl groups which may be substituted (e.g.
  • aralkyl groups which may be substituted (e.g., phenyl-Ci.,, alkyl groups such as benzyl and phenethyl, and naphthyl-C.. 2 alkyl groups) .
  • These lower (C ⁇ ) alkyl groups, C 3 - ⁇ cycloalkyl groups, C 6 . 10 aryl groups and C 7 . 12 aralkyl groups may have 1 to 5 optionally chosen substituents at any possible positions, and these substituents include halogens (e.g. , fluorine , chlorine , bromine ) , alkoxy groups (e.g.
  • C._ 4 alkoxy groups such as methoxy, ethoxy and propoxy
  • alkyl groups e.g., C ⁇ ,, alkyl groups such as methyl, ethyl and propyl
  • nitro, amino and cyano alkyl groups
  • the "heterocyclic group which may be substituted” is exemplified by the same groups as those mentioned below in the "heterocyclic group which may be substituted” represented by R 1 , R 2 , R 3 , R 4 , R 5 or R 6 .
  • the acyl group (11) is exemplified by formyl groups, carbonyl groups substituted by a hydrocarbon group which may be substituted, sulfinyl groups substituted by a hydrocarbon group which may be substituted, and sulfonyl groups substituted by a hydrocarbon group which may be substituted.
  • the " hydrocarbon group which may be substituted " is exemplified by the same groups as those mentioned in the " hydrocarbon group which may be substituted " represented by R 1 , R 2 , R 3 , R 4 , R 5 or R 6 above, and preferable are lower ( C 1 . 6 ) alkyl groups which may be substituted, C 3 . 6 cycloalkyl groups which may be substituted, C 6 .
  • aryl groups e.g. , phenyl , naphthyl
  • C 7 . 12 aralkyl groups e.g. , phenyl-C 1 . 4 alkyl groups, naphthyl-C ⁇ alkyl groups
  • Preferable acyl groups include formyl groups, (C ⁇ alkyl)carbonyl groups, (C 3 . 6 cycloalkyl) carbonyl groups, ( c ⁇ - ⁇ o aryl ) carbonyl groups, (C 7 . 12 aralkyl ) carbonyl groups, ( C___ 6 alkyl ) sulfinyl groups ( C 3 .
  • acyl groups may have 1 to 5 optionally chosen substituents at any possible positions , and such substituents include halogens , alkoxy group (e.g.
  • heterocyclic group in the "heterocyclic group which may be substituted" represented by R 1 , R 2 , R 3 , R 4 , R 5 or R 6 is exemplified by aromatic heterocyclic groups and saturated or unsaturated non-aromatic heterocyclic groups (aliphatic heterocyclic groups) having at least 1 hetero atom selected from atoms of oxygen, sulfur and nitrogen as a ring-constituting atom (ring atom), and aromatic heterocyclic groups are preferred.
  • aromatic heterocyclic groups include 5- to 7- membered aromatic heterocyclic groups containing 1 sulfur atom, nitrogen atom or oxygen atom, 5- or 6-membered aromatic heterocyclic groups containing 2 to 4 nitrogen atoms, and 5- or 6-membered aromatic heterocyclic groups containing 1 or 2 nitrogen atoms and 1 sulfur atom or oxygen atom. These aromatic heterocyclic groups may be fused with a 6-membered ring containing 2 or fewer nitrogen atoms, a benzene ring, or a 5-membered ring containing 1 sulfur atom.
  • aromatic heterocyclic groups include aromatic monocyclic heterocyclic groups (e.g.
  • furyl particularly furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, benzofuranyl, benzimidazolyl, benzoxazolyl, 1,2- benzisoxazolyl, benzothiazolyl, benzo[b] thienyl, oxazolyl and isoxazolyl are preferred, and furyl an thienyl are more preferred.
  • non-aromatic heterocyclic groups include 5- to 7-membered non-aromatic heterocyclic groups containing 1 sulfur atom, nitrogen atom or oxygen atom, and 3- to 7- membered non-aromatic heterocyclic groups containing 1 nitrogen atom and 3 or fewer hetero atoms (e.g.
  • nitrogen, oxygen and sulfur atoms such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl , tetrahydrofuryl , thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl , piperazinyl, homopiperidyl , pyrrolinyl and imidazolidinyl.
  • These non-aromatic heterocyclic groups may be fused with a benzene ring, a 6-membered ring containing 2 or fewer nitrogen atoms, a 5-membered ring containing 1 sulfur atom, or the like.
  • fused non- aromatic heterocyclic groups include chromanyl, isochromanyl, indolinyl, isoindolinyl, thiochromanyl and isothiochromanyl .
  • heterocyclic group in the "heterocyclic group which may be substituted" represented by R 1 , R 2 , R 3 , R 4 , R 5 or R 6 above, may have 1 to 4, preferably 1 to 3, optionally chosen substituents at any possible positions .
  • substituents include (i) lower alkyl groups which may be substituted, (ii) lower alkoxy groups which may be substituted, (iii) aryl groups which may be substituted, (iv) lower cycloalkyl or lower cycloalkenyl groups which may be substituted, (v) heterocyclic groups which may be substituted, (vi) carboxyl groups which may be esterified, (vii) carbamoyl groups which may be substituted, (viii) amino groups which may be substituted, (ix) hydroxyl groups which may be substituted, (x) thiol groups which may be substituted, (xi) acyl groups, (xii) halogens (e.g., fluorine, chlorine, bromine), (xiii) nitro, and (xiv) cyano.
  • substituents include (i) lower alkyl groups which may be substituted, (ii) lower alkoxy groups which may be substituted, (iii) aryl groups which may
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are alkyl groups which may be substituted (preferably C x . 4 alkyl groups ) , alkenyl groups which may be substituted (preferably C 2.4 alkenyl groups) , aryl groups which may be substituted (preferably C 6 .
  • aryl groups such as phenyl, 1-naphthyl and 2-naphthyl) , and aromatic heterocyclic groups which may be substituted (preferably furyl, benzofuranyl , thienyl, benzothienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, azolyl, or fused azolyl) .
  • alkyl groups , alkenyl groups and aryl groups may have 1 to 3 (preferably 1 to 2) optionally chosen substituents at any possible positions.
  • Preferable substituents include (1) lower (C ⁇ ) alkyl groups (e.g., methyl, ethyl, propyl, isopropyl) which may be substituted by 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine), (2) lower (C ⁇ ) alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy) , (3) C 6 . 10 aryl groups (e.g., phenyl) which may be substituted by 1 to 3, preferably 1 to 2, substituents selected from halogens (e.g.
  • aryloxy groups e.g. , phenoxy which may be substituted by 1 to 3, preferably 1 to 2 , substituents selected from lower (C ⁇ ) alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), halogens (e.g., fluorine, chlorine, bromine, iodine), nitro, cyano and amino, (5) heterocyclic groups (e.g., thienyl, benzimidazolyl, benzoxazolyl) which may be substituted by 1 to 3 , preferably 1 to 2 , halogens (e.g., fluorine , chlorine , bromine , iodine ) , ( 6 ) amino groups which may be substituted by a p-toluenesulfonyl group etc
  • thiol groups' which may be substituted by a C 6.10 aryl groups (e.g. phenyl) which may have 1 to 3 (preferably 1 to 2) substituents selected from halogens and lower ( C 1 . 3 ) alkoxy groups, or thiol groups which may be substituted by a heterocyclic group (e.g., benzoxazolyl, benzothiazolyl) which may have 1 to 3 (preferably 1 to 2) substituents selected from halogens and lower (C 1 ) alkoxy groups, (9) halogens (e.g., fluorine, chlorine, bromine), (10) nitro, and (11) cyano.
  • halogens e.g., fluorine, chlorine, bromine
  • aromatic heterocyclic groups may have 1 to 3 (preferably 1 to 2) optionally chosen substituents at any possible positions.
  • Preferable substituents include (1) lower (C ⁇ ) alkyl groups which may be substituted by 1 to 3 halogens (e.g., methyl, ethyl, propyl, isopropyl, fluoromethyl , chloromethyl) , (2) C 6 . 10 aryl groups (e.g., phenyl ) , ( 3 ) lower ( C._ 3 ) alkoxy groups which may be substituted by 1 to 3 halogens (e.g., methoxy, ethoxy.
  • propoxy iso-propoxy, fluoromethox , chloromethoxy) , (4) halogens (e.g., fluorine, chlorine, bromine), (5) nitro, ( 6 ) cyano , ( 7 ) ( lower ( C ⁇ ) alkyl ) carbonyl groups and ( 8 ) (Ci.j alkyl ) sulfonyl groups.
  • halogens e.g., fluorine, chlorine, bromine
  • hydrocarbon group is exemplified by the same groups as those mentioned in the "hydrocarbon group which may be substituted" represented by R 1 , R 2 , R 3 , R 4 , R 5 or R 6 above.
  • Said hydrocarbon group may have 1 to 3 optionally chosen substituents at any possible positions .
  • Such substituents include lower alkyl groups which may be substituted, lower alkoxy groups which may be substituted, aryl groups which may be substituted, lower cycloalkyl groups or lower cycloalkenyl groups which may be substituted, heterocyclic groups which may be substituted, carboxyl groups which may be esterified, carbamoyl groups which may be substituted, amino groups which may be substituted, hydroxyl groups which may be substituted, thiol groups which may be substituted, acyl groups, halogens (e.g., fluorine, chlorine , bromine ) , nitro , and cyano .
  • halogens e.g., fluorine, chlorine , bromine
  • Such lower alkyl groups which may be substituted, lower alkoxy groups which may be substituted, aryl groups which may be substituted, lower cycloalkyl groups or lower cycloalkenyl groups which may be substituted, heterocyclic groups which may be substituted, carboxyl groups which may be esterified, carbamoyl groups which may be substituted, amino groups which may be substituted, hydroxyl groups which may be substituted, thiol groups which may be substituted, and acyl groups, are exemplified by the same substituents as those mentioned in the substituent in the "hydrocarbon group which may be substituted" represented by R 1 , R 2 , R 3 , R 4 , R 5 or R 6 above.
  • Said heterocyclic group is exemplified by the same groups as those mentioned in the heterocyclic group in the "heterocyclic group which may be substituted" represented by R 1 , R 2 , R 3 , R 4 , R 5 or R 6 above.
  • Said heterocyclic group may have 1 to 3 optionally chosen substituents at any possible positions .
  • Such substituents include lower alkyl groups which may be substituted, lower alkoxy groups which may be substituted, aryl groups which may be substituted, lower cycloalkyl groups or lower cycloalkenyl groups which may be substituted, heterocyclic groups which may be substituted, carboxyl groups which may be esterified, carbamoyl groups which may be substituted, amino groups which may be substituted, hydroxyl groups which may be substituted, thiol groups which may be substituted, acyl groups, halogens (e.g., fluorine, chlorine, bromine), nitro, and cyano.
  • halogens e.g., fluorine, chlorine, bromine
  • Such lower alkyl groups which may be substituted, lower alkoxy groups which may be substituted, aryl groups which may be substituted, lower cycloalkyl groups or lower cycloalkenyl groups which may be substituted, heterocyclic groups which may be substituted, carboxyl groups which may be esterified, carbamoyl groups which may be substituted, amino groups which may be substituted, hydroxyl groups which may be substituted, thiol groups which may be substituted, and acyl groups, are exemplified by the same substituents as those mentioned in the substituent in the "hydrocarbon group which may be substituted" represented by R 1 , R 2 , R 3 , R 4 , R 5 or R 6 above.
  • groups for R 7 include lower (C ⁇ ) alkyl groups which may be substituted, lower (C 3 . 6 ) cycloalkyl groups, C 6 . 10 aryl groups, and C 7 . 12 aralkyl groups, and lower (C x _ 3 ) alkyl groups are more preferable.
  • Such lower (. C 1 . 6 ) alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and isohexyl.
  • Such lower (C 3 . 6 ) cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Such C 6 . 10 aryl groups include phenyl, 1-naphthyl and 2-naphthyl.
  • Such C 7 . 12 aralkyl groups include phenyl-Ci.,, alkyl groups such as benzyl and phenethyl , and naphthyl-C ⁇ alkyl groups .
  • These lower (C ⁇ alkyl groups, lower (C 3 . 6 ) cycloalkyl groups , C 6 . 10 aryl groups and C 7 . 12 aralkyl groups may have 1 to 3 optionally chosen substituents at any possible positions, and these substituents include halogens (e.g., fluorine , chlorine , bromine ) .
  • hydrocarbon group which may be substituted as a substituent for the "amino group which may be substituted” represented by R, is exemplified by the same groups as those mentioned in the "hydrocarbon group which may be substituted” represented by R 1 , R 2 , R 3 , R , R 5 or R 6 above. Said hydrocarbon group may have 1 to 3 optionally chosen substituents at any possible positions .
  • Such substituents include lower alkyl groups which may be substituted, lower alkoxy groups which may be substituted, aryl groups which may be substituted, lower cycloalkyl groups or lower cycloalkenyl groups which may be substituted, heterocyclic groups which may be substituted, carboxyl groups which may be esterified, carbamoyl groups which may be substituted, amino groups which may be substituted, hydroxyl groups which may be substituted, thiol groups which may be substituted, acyl groups, halogens (e.g., fluorine, chlorine , bromine ) , nitro , and cyano .
  • halogens e.g., fluorine, chlorine , bromine
  • Such lower alkyl groups which may be substituted, lower alkoxy groups which may be substituted, aryl groups which may be substituted, lower cycloalkyl groups or lower cycloalkenyl groups which may be substituted, heterocyclic groups which may be substituted, carboxyl groups which may be esterified, carbamoyl groups which may be substituted, amino groups which may be substituted, hydroxyl groups which may be substituted, thiol groups which may be substituted, and acyl groups, are exemplified by the same substituents as those mentioned in the substituent in the "hydrocarbon group which may be substituted" represented by R 1 , R 2 , R 3 , R 4 , R 5 or R 6 above.
  • R is preferably an amino group which may be substituted by 1 or 2 , preferably 1 substituent selected from the group consisting of (1) an acyl group selected from -COR 1 , -CSR 2 , -S0 2 R 3 , -SOR 4 , -CONHR 5 and -CSNHR 6 wherein each of R 1 , R 2 , R 3 , R 4 , R s and R 6 is (1-1) a hydrogen atom;
  • a hydrocarbon group selected from the group consisting of: (a) an alkyl group having 1 to 10 carbon atom,
  • each of the substituents (a) to (i) may have 1 to 3 substituents selected from the group consisting of:
  • a C 3 . 7 cycloalkyl group or a C 3 . 5 cycloalkenyl group each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C ⁇ alkoxy group, halogen, a C ⁇ alkyl group, amino, nitro and cyano
  • a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C._ 4 alkoxy group which may be substituted by halogen, halogen, a C ⁇ ,, alkyl group which may be substituted by halogen, a C 6 .
  • a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a alkyl group, a C 3 . 6 cycloalkyl group, a C s . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C x . 4 alkoxy group which may be substituted by halogen, C ⁇ alkyl group which may be substituted by halogen, and nitro,
  • each of said C j . 6 alkyl, C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 . 12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ ,, alkoxy group which may be substituted by halogen, a C ⁇ alkyl group which may be substituted by halogen , nitro , amino and cyano
  • said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of
  • (ix-1) a C ⁇ alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C L . 3 alkoxy group,
  • (ix-2) a C x _ 6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ alkoxy group,
  • (ix-3) a C 6 . 14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C ⁇ alkoxy group, halogen, a C ⁇ ., alkyl group, amino, nitro and cyano,
  • (ix-4) a C 3 . 7 cycloalkyl group or a C 3 . 6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C ⁇ -, alkoxy group, halogen, a C ⁇ ., alkyl group, amino, nitro and cyano, (ix-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C._ 4 alkoxy group which may be substituted by halogen, halogen, a C 1.4 alkyl group which may be substituted by halogen, a C 6 .
  • X0 aryl group and nitro, (ix-6) a carboxyl group, a ⁇ C 1 . 6 alkoxy) carbonyl group, a ( C 6 - ⁇ o aryl) oxycarbonyl group or a (C 7 . 10 aralkyl ) oxycarbonyl group ,
  • (ix-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group. a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C 1 . 4 alkoxy group which may be substituted by halogen, C x .
  • aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C.. 4 alkoxy group which may be substituted by halogen, a C ⁇ alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C._ 4 alkoxy group, halogen, a C t . 4 alkyl group and a C 6 . 10 aryl group,
  • (ix-10) a thiol group which may be substituted by a C 1 . 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said C 1-6 alkyl, C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 .
  • aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C 1- alkoxy group which may be substituted by halogen, a C ⁇ alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C x.4 alkoxy group, halogen, a C ⁇ ,, alkyl group and a C 6 . 10 aryl group,
  • an acyl group selected from the group consisting formyl , a ( C ⁇ alkyl ) carbonyl , a ( C 3 . 6 cycloalkyl ) carbonyl , a (C 6 _ 10 aryl ) carbonyl , a (C 7 . 12 aralkyl ) carbonyl , a (C ⁇ alkyl ) sulfinyl , a (C 3 . 6 cycloalkyl) sulfinyl, a (C 6 . 10 aryl) sulfinyl, a (C 7 . 12 aralkyl) sulfinyl, a ( C x .
  • (x) a thiol group which may be substituted by a C l . 6 alkyl group, a C 3.6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group , each of said C ⁇ alkyl , C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 . 12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C : .
  • Ci . ⁇ alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ alkoxy group,
  • Ci .s alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ alkoxy group,
  • (x-3) a C 6 . 14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C._ 3 alkoxy group, halogen, a C ⁇ j alkyl group, amino, nitro and cyano ,
  • (x-4) a C 3 . 7 cycloalkyl group or a C 3 . 6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C ⁇ alkoxy group, halogen, a C x . 3 alkyl group, amino, nitro and cyano,
  • (x-6) a carboxyl group, a ( C 1 , 6 alkoxy) carbonyl group, a (C 6 . 10 aryl ) oxycarbonyl group or a (C 7 . 10 aralkyl ) oxycarbonyl group , (x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C ⁇ alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 .
  • (x-9) a hydroxyl group which may be substituted by a C ⁇ alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said C LJ alkyl, C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ ., alkoxy group which may be substituted by halogen, a C t .
  • (x-10) a thiol group which may be substituted by a C x . 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said alkyl, C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 . 12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C x .
  • an acyl group selected from the group consisting of formyl, a (C ⁇ alkyl ) carbonyl , a (C 3 . 6 cycloalkyl ) carbonyl , a (C 6 . 10 aryl ) carbonyl , a (C 7 . 12 aralkyl) carbonyl , a (C 1-6 alkyl ) sulfinyl , a (C 3 . 6 cycloalkyl ) sulfinyl , a (C 6 . 10 aryl) sulfinyl, a (C 7 .
  • acyl group selected from the group consisting of formyl, a ( C l _ 6 alkyl ) carbonyl , a (C 3 . 6 cycloalkyl) carbonyl, a (C 6 . 10 aryl ) carbonyl , a (C 7 . 12 aralkyl ) carbonyl , a (C x . 6 alkyl) sulfinyl, a (C 3 . 6 cycloalkyl ) sulfinyl , a (C 6 .
  • a heterocyclic group which may be substituted by 1 to 4 substituents selected from the group consisting of (i) a C 1 _ 6 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ alkoxy group, (ii) a C x . 6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ alkoxy group,
  • a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C L . 4 alkoxy group which may be substituted by halogen, halogen, a C 1-4 alkyl group which may be substituted by halogen, a C 6 . 10 aryl group, and nitro, (vi) a carboxyl group, a (C ⁇ alkoxy) carbonyl group, a (C 6 . 10 aryl ) oxycarbonyl group or a (C 7 . 10 aralkyl ) oxycarbonyl group,
  • a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C j . 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ! _ 4 alkoxy group which may be substituted by halogen, C._ 4 alkyl group which may be substituted by halogen, and nitro,
  • substituents selected from the group consisting of a C . 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C x . 4 alkoxy group which may be substituted by halogen, C 1-4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
  • (ix-1) a Ci .j alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ -, alkoxy group
  • (ix-2) a C ⁇ alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C 1 alkoxy group
  • (ix-3) a C 6 . 14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C 1 , 2 alkoxy group, halogen, a C ⁇ ., alkyl group, amino, nitro and cyano,
  • (ix-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C x . 4 alkoxy group which may be substituted by halogen, C._ 4 alkyl group which may be substituted by halogen, and nitro,
  • alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C ⁇ ,, alkoxy group, halogen, a C ⁇ ,, alkyl group and a C 6 . 10 aryl group,
  • (ix-10) a thiol group which may be substituted by a C . 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said Ci. 6 alkyl, C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 . 12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C x . 4 alkoxy group which may be substituted by halogen, a C x .
  • (x) a thiol group which may be substituted by a C ⁇ alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group , each of said C ⁇ alkyl , C 3 - ⁇ cycloalkyl, C 6 . 10 aryl and C 7 .
  • X2 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ ,, alkoxy group which may be substituted by halogen, a C ⁇ ,, alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of (x-1) a C ⁇ _ 6 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ ., alkoxy group,
  • (x-2) a alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C x _ 3 alkoxy group,
  • (x-3) a C 6 . 14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C ⁇ alkoxy group, halogen, a C._ 3 alkyl group, amino, nitro and cyano , (x-4) a C 3 . 7 cycloalkyl group or a C 3 . 6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C ⁇ alkoxy group, halogen, a C 1 alkyl group, amino, nitro and cyano,
  • (x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C x . alkoxy group which may be substituted by halogen, halogen, a C ⁇ ,, alkyl group which may be substituted by halogen, a C 6 . 10 aryl group, and nitro,
  • (x-6) a carboxyl group, a (C._ 6 alkoxy) carbonyl group, a (C 6 . 10 aryl ) oxycarbonyl group or a (C 7 . 10 aralkyl) oxycarbonyl group ,
  • (x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a Cj.j alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C L4 alkoxy group which may be substituted by halogen, a C x . 4 alkyl group which may be substituted by halogen, and nitro ,
  • (x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C ⁇ alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 -i 2 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C x . 4 alkoxy group which may be substituted by halogen, a C 1 .
  • (x-10) a thiol group which may be substituted by a C ⁇ alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said C 1 , 6 alkyl, C 3.6 cycloalkyl, C 6 . 10 aryl and C 7 . 12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C x . 4 alkoxy group which may be substituted by halogen, a C x .
  • alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C 1-4 alkoxy group, halogen, a C ⁇ ,, alkyl group and a C 6 . 10 aryl group,
  • an acyl group selected from the group consisting of formyl, a ( C 1 . 6 alkyl) carbonyl, a (C 3 . 6 cycloalkyl ) carbonyl , a (C 6 . 10 aryl ) carbonyl , a (C 7 . 12 aralkyl)carbonyl , a ( C 1 _ 6 alkyl ) sulfinyl , a (C 3 . 6 cycloalkyl) sulfinyl, a (C 6 . 10 aryl ) sulfinyl , a (C 7 .
  • acyl group selected from the group consisting of formyl, a alkyl)carbonyl, a (C 3 . 6 cycloalkyl) carbonyl, a (C 6 . 10 aryl) carbonyl , a (C 7 . 12 aralkyl)carbonyl , a ( C 1 . 6 alkyl)sulfinyl, a (C 3 . 6 cycloalkyl) sulfinyl, a (C 6 . 10 aryl)sulfinyl , a (C 7 . 12 aralkyl ) sulfinyl , a ( C 1 .
  • each of the substituents (a) to (i) may have 1 to 3 substituents selected from the group consisting of:
  • a Ci. ⁇ alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ ., alkoxy group
  • a C 6 . 14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C ⁇ alkoxy group, halogen, a C x . 3 alkyl group, amino, nitro and cyano ,
  • a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a Ci. 4 alkoxy group which may be substituted by halogen. halogen, a C x . 4 alkyl group which may be substituted by halogen, a C 6 . 10 aryl group, and nitro,
  • a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C 1 , 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C x . 4 alkoxy group which may be substituted by halogen, a C r .
  • aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ ., alkoxy group which may be substituted by halogen, a C ⁇ alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of (ix-1) a C 1 _ & alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ j alkoxy group,
  • (ix-3) a C 6 . 14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C ⁇ 3 alkoxy group, halogen, a C ⁇ ., alkyl group, amino, nitro and cyano, (ix-4 ) a C 3 . 7 cycloalkyl group or a C 3 . 6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C. 3 alkoxy group, halogen, a C x . 3 alkyl group, amino, nitro and cyano,
  • (ix-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C x . 4 alkoxy group which may be substituted by halogen, halogen, a C x . 4 alkyl group which may be substituted by halogen, a C 6 . 10 aryl group, and nitro,
  • (ix-6) a carboxyl group, a (C 1 . 6 alkoxy) carbonyl group, a (C 6 . 10 aryl ) oxycarbonyl group or a (C 7 . 10 aralkyl)oxycarbonyl group ,
  • (ix-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a Cn alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C x . 4 alkoxy group which may be substituted by halogen, a C alkyl group which may be substituted by halogen, and nitro,
  • substituents selected from the group consisting of a C.. 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C L . 4 alkoxy group which may be substituted by halogen, a C x . 4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (ix-9) a hydroxyl group which may be substituted by a C 1 .
  • aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C x.4 alkoxy group which may be substituted by halogen, a C ⁇ .,, alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C ⁇ ,, alkoxy group, halogen, a C x . 4 alkyl group and a C 6 . 10 aryl group,
  • (ix-10) a thiol group which may be substituted by a C ⁇ alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said C j ⁇ j alkyl, C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 .
  • aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ ,, alkoxy group which may be substituted by halogen, a C ⁇ ,, alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C 1 . ⁇ alkoxy group, halogen, a C ⁇ ,, alkyl group and a C 6 . 10 aryl group,
  • an acyl group selected from the group consisting formyl, a ( C 1 . 6 alkyl ) carbonyl , a (C 3 . 6 cycloalkyl) carbonyl, ( C 6 - ⁇ o aryl ) carbonyl , a (C 7 . 12 aralkyl ) carbonyl , a (C,. 6 alkyl ) sulfinyl , a (C 3 . 6 cycloalkyl ) sulfinyl , a (C 6 . 10 aryl) sulfinyl , a (C 7 .
  • (x) a thiol group which may be substituted by a C x _ 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7.12 aralkyl group or a heterocyclic group , each of said C ⁇ alkyl , C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 . 12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C x . 4 alkoxy group which may be substituted by halogen, a C x . 4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of
  • (x-1) a Ci.g alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C.. 3 alkoxy group,
  • (x-2) a Ci. ⁇ alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ alkoxy group,
  • (x-3) a C 6 . 14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C x . 3 alkoxy group , halogen , a C 1-3 alkyl group , amino , nitro and cyano ,
  • (x-4) a C 3 . 7 cycloalkyl group or a C 3 . 6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C ⁇ ., alkoxy group, halogen, a C 1 . 3 alkyl group, amino, nitro and cyano,
  • (x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C ! _ 4 alkoxy group which may be substituted by halogen, halogen, a C x . 4 alkyl group which may be substituted by halogen, a C 6 . 10 aryl group, and nitro,
  • (x-6) a carboxyl group, a (C 1-6 alkoxy) carbonyl group, a (C 6 . 10 aryl)oxycarbonyl group or a (C 7 . 10 aralkyl ) oxycarbonyl group
  • (x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C x _ 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 .
  • (x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a x . 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C 1-4 alkoxy group which may be substituted by halogen, a C x . 4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
  • (x-9) a hydroxyl group which may be substituted by a C ⁇ alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said Ci. ⁇ alkyl, C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 .
  • aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ alkoxy group which may be substituted by halogen, a C x _ 4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C 1- alkoxy group, halogen, a C x . 4 alkyl group and a C 6 . 10 aryl group, (x-10) a thiol group which may be substituted by a C ⁇ alkyl group, a C 3 .
  • alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C ⁇ alkoxy group, halogen, a C ⁇ ,, alkyl group and a C 6 . 10 aryl group,
  • an acyl group selected from the group consisting of formyl, a (C ⁇ alkyl ) carbonyl , a (C 3 . 6 cycloalkyl ) carbonyl , a (C 6 . 10 aryl ) carbonyl , a (C 7 . 12 aralkyl) carbonyl , a ⁇ C 1 . 6 alkyl ) sulfinyl , a (C 3 . 6 cycloalkyl) sulfinyl, a (C 6 . 10 aryl ) sulfinyl , a (C 7 .
  • acyl group selected from the consisting of formyl, a (C 1 , 6 alkyl)carbonyl , a (C 3 . 6 cycloalkyl)carbonyl , a (C 6 . 10 aryl) carbonyl , a (C 7 . 12 aralkyl) carbonyl , a (C ⁇ alkyl) sulfinyl, a (C 3 . 6 cycloalkyl ) sulfinyl , a (C 6 . 10 aryl) sulfinyl , a (C 7 .
  • Ci. s alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ alkoxy group,
  • a C 3 . 7 cycloalkyl group or a C 3 . 6 cycloalkenyl group each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C x . 3 alkoxy group, halogen, a C ⁇ ., alkyl group, amino, nitro and cyano,
  • a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C._ 4 alkoxy group which may be substituted by halogen, halogen, a C L . 4 alkyl group which may be substituted by halogen, a C 6 .
  • a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C x . 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Ci. 4 alkoxy group which may be substituted by halogen, a C 1 . 4 alkyl group which may be substituted by halogen, and nitro,
  • an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C ⁇ alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ! . 4 alkoxy group which may be substituted by halogen, a C l . i alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
  • aralkyl groups being unsubstitued or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ ,, alkoxy group which may be substituted by halogen, a C ⁇ ,, alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of
  • (ix-1) a alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ alkoxy group
  • (ix-2) a C._ 6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ ., alkoxy group
  • (ix-3) a C 6 . 14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C ⁇ alkoxy group, halogen, a C x . 3 alkyl group, amino, nitro and cyano,
  • (ix-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C L6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C x . 4 alkoxy group which may be substituted by halogen, a C x . 4 alkyl group which may be substituted by halogen, and nitro,
  • (ix-9) a hydroxyl group which may be substituted by a alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said C._ 6 alkyl, C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 .
  • aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C 1-4 alkoxy group which may be substituted by halogen, a C 1 , alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C t . 4 alkoxy group, halogen, a C x . 4 alkyl group and a C 6 . 10 aryl group,
  • (ix-10) a thiol group which may be substituted by a C._ 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said Ci.g alkyl, C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 . 12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ ,, alkoxy group which may be substituted by halogen, a C x .
  • an acyl group selected from the group consisting of formyl, a (C ⁇ alkyl ) carbonyl , a (C 3 . 6 cycloalkyl ) carbonyl , a (C 6 . 10 aryl ) carbonyl , a (C 7 . 12 aralkyl) carbonyl , a (C, ⁇ alkyl) sulfinyl, a (C 3 . 6 cycloalkyl ) sulfinyl , a (C 6 _ 10 aryl ) sulfinyl , a (C 7 .
  • a thiol group which may be substituted by a C ⁇ alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group , each of said C 1 . 6 alkyl, 3 - 6 cycloalkyl, C 6 . 10 aryl and C 7 . 12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C 1 .
  • (x-1) a C 1 . 6 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C._ 3 alkoxy group,
  • (x-2) a C 1 . 6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ ., alkoxy group,
  • (x-3) a C 6 . 14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C. .3 alkoxy group, halogen, a C x . 3 alkyl group, amino, nitro and cyano ,
  • (x-4) a C 3 . 7 cycloalkyl group or a C 3 . 6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C ⁇ ., alkoxy group, halogen , a C 1 _ 3 alkyl group , amino , nitro and cyano , (x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C x . 4 alkoxy group which may be substituted by halogen, halogen, a C ⁇ ,, alkyl group which may be substituted by halogen, a C 6 .
  • (x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C _ 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ ,, alkoxy group which may be substituted by halogen, a C ⁇ alkyl group which may be substituted by halogen, and nitro ,
  • (x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C ⁇ alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ ,, alkoxy group which may be substituted by halogen, a Ci. alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
  • (x-9) a hydroxyl group which may be substituted by a C._ 6 alkyl group, a C 3 _ 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said Ci- ⁇ alkyl, C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 . 12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C 1-4 alkoxy group which may be substituted by halogen, a C x .
  • (x-10) a thiol group which may be substituted by a C x . 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said alkyl, C 3.6 cycloalkyl, C 6 . 10 aryl and C 7 . 12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C 1-4 alkoxy group which may be substituted by halogen, a C x .
  • each of the substituents (a) to (i) may have 1 to 3 substituents selected from the group consisting of:
  • Ci. ⁇ alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C 1 alkoxy group,
  • a C 3 . 7 cycloalkyl group or a C 3 . 6 cycloalkenyl group each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C ⁇ alkoxy group, halogen, a C._ 3 alkyl group, amino, nitro and cyano,
  • a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C t . 4 alkoxy group which may be substituted by halogen, halogen, a C._ 4 alkyl group which may be substituted by halogen, a C 6 .
  • a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C LJ alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C x . 4 alkoxy group which may be substituted by halogen, a C x . 4 alkyl group which may be substituted by halogen, and nitro ,
  • (ix-1) a C 1 , 6 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ alkoxy group
  • (ix-2) a C ⁇ alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ ., alkoxy group
  • (ix-3) a C 6 . 14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C 1 . 3 alkoxy group, halogen, a C ⁇ ., alkyl group, amino, nitro and cyano,
  • (ix-4) a C 3 . 7 cycloalkyl group or a C 3 . 6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C l _ 3 alkoxy group, halogen, a C ⁇ ., alkyl group, amino, nitro and cyano.
  • (ix-5) a heterocyclic group which may be substituted by
  • (ix-7) a carbaomoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C ⁇ s alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C L _ 4 alkoxy group which may be substituted by halogen, a C.. 4 alkyl group which may be substituted by halogen, and nitro,
  • (ix-9) a hydroxyl group which may be substituted by a Ci. ⁇ alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said C._ 6 alkyl, a C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 .
  • aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ ,, alkoxy group which may be substituted by halogen, a C x _ 4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C ⁇ ,, alkoxy group, halogen, a C x . 4 alkyl group and a C 6 . 10 aryl group,
  • (ix-10) a thiol group which may be substituted by a C _ 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said C ⁇ s alkyl, C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 . 12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ ., alkoxy group which may be substituted by halogen, a C x .
  • an acyl group selected from the group consisting of formyl, a ( C 1 _ 6 alkyl) carbonyl , a (C 3 . 6 cycloalkyl ) carbonyl , a (C 6 . 10 aryl) carbonyl , a (C 7 . 12 aralkyl ) carbonyl , a ( C 1 _ 6 alkyl) sulfinyl, a (C 3 . 6 cycloalkyl) sulfinyl, a (C 6 . 10 aryl) sulfinyl, a (C 7 . 12 aralkyl ) sulfinyl , a ( C 1 .
  • aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C 1-4 alkoxy group which may be substituted by halogen, a C x . 4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of
  • (x-1) a C x . 6 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C 1 . 3 alkoxy group,
  • Ci. ⁇ alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ alkoxy group,
  • (x-3) a C 5 . 14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C ⁇ alkoxy group, halogen, a C ⁇ ., alkyl group, amino, nitro and cyano ,
  • (x-4) a C 3 . 7 cycloalkyl group or a C 3 . 6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C ⁇ alkoxy group, halogen, a C ⁇ alkyl group, amino, nitro and cyano, (x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C x . 4 alkoxy group which may be substituted by halogen, halogen, a C x . 4 alkyl group which may be substituted by halogen, a C 6 .
  • (x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cj. 4 alkoxy group which may be substituted by halogen, a C x - 4 alkyl group which may be substituted by halogen, and nitro ,
  • (x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C ⁇ alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C 1-4 alkoxy group which may be substituted by halogen, a C ⁇ ,, alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
  • (x-9) a hydroxyl group which may be substituted by a C ⁇ alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said C._ 6 alkyl, C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 .
  • aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ ,, alkoxy group which may be substituted by halogen, a C ⁇ ,, alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C ⁇ ,, alkoxy group, halogen, a C x . 4 alkyl group and a C 6 . 10 aryl group,
  • (x-10) a thiol group which may be substituted by a C ⁇ alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said C 1 _ 6 alkyl, C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 .
  • aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ ,, alkoxy group which may be substituted by halogen, a C ⁇ , alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C 1-4 alkoxy group, halogen, a C x . 4 alkyl group and a C 6 .
  • acyl group selected from the group consisting of formyl, a (C ] ,_ 6 alkyl ) carbonyl , a (C 3 . 6 cycloalkyl) carbonyl, a (C 6 . 10 aryl ) carbonyl , a (C 7 . 12 aralkyl ) carbonyl , a ( C 1 . 6 alkyl) sulfinyl, a (C 3 . 6 cycloalkyl) sulfinyl, a (C 6 . 10 aryl) sulfinyl, a (C 7 .
  • acyl group selected from the group consisting of formyl, a (C ⁇ alkyl) carbonyl , a (C 3 . 6 cycloalkyl ) carbonyl , a (C 6 . 10 aryl ) carbonyl , a (C 7 . 12 aralkyl ) carbonyl , a ⁇ C 1 . 6 alkyl ) sulfinyl , a (C 3 . 6 cycloalkyl) sulfinyl, a (C 6 . 10 aryl ) sulfinyl , a (C 7 .
  • R is preferably a group represented by the formula:
  • Particularly preferred among the compound represented by the formula (I) is a compound represented by the formula (la):
  • R la represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or a compound represented by the formula (lb) :
  • R lb represents a non-cyclic hydrocarbon group substituted by (i) a cyclic hydrocarbon group which may be substituted, (ii) a heterocyclic group which may be substituted, (iii) hydroxyl group substituted by a cyclic hydrocarbon group which may be substituted, (iv) hydroxyl group substituted by a heterocyclic group which may be substituted, (v) thiol group substituted by a cyclic hydrocarbon group which may be substituted, or (vi) thiol group substituted by a heterocyclic group which may be substituted.
  • R 1 is preferably R l or R lb .
  • R 1 is more preferably R la .
  • the cyclic hydrocarbon group in the "cyclic hydrocarbon group which may be substituted" represented by R la is exemplified by the saturated or unsaturated alicyclic hydocarbon groups and aryl groups (aromatic hydrocarbon groups) mentioned to exemplify the hydrocarbon group in the "hydrocarbon group which may be substituted” represented by R 1 , R 2 , R 3 , R 4 , R 5 or R 6 above, and preferable are C 6 . 10 aryl groups such as phenyl, 1-naphthyl and 2-naphthyl.
  • the heterocyclic group in the "heterocyclic group which may be substituted” represented by R la is exemplified by the same groups as those mentioned in the heterocyclic group in the "heterocyclic group which may be substituted” represented by R 1 , R 2 , R 3 , R 4 , R 5 or R 6 above, and preferable are aromatic heterocyclic groups such as thienyl (e.g. , 2- or 3-thienyl) , furyl (2- or 3-furyl) , pyridyl (e.g.
  • azolyl e.g., oxazolyl (e.g., 2-, 4- or 5- oxazolyl), isoxazolyl (e.g., 3-, 4- or 5-isoxazolyl)
  • fused ring groups of thienyl or azolyl e.g.
  • benzothienyl e.g., 2- or 3-benzo[b] thienyl
  • benzoxazolyl e.g., 2-, 5- or 6 -benz[d] oxazolyl
  • benzothiazolyl e.g., 2- benzo[d] thiazolyl
  • fused furanyl groups e.g., benzofuranyl (e.g., 2- or 3-benzo[b]furanyl)
  • 5- membered aromatic heterocyclic groups such as thienyl and furyl are more preferred.
  • heterocyclic group in the "heterocyclic group which may be substituted” and the cyclic hydrocarbon group in the "cyclic hydrocarbon group which may be substituted” represented by R la may have 1 to 3, preferably 1 to 2 , optionally chosen substituents at any possible positions.
  • substituents are exemplified by the same groups as those mentioned in the substituent to the "heterocyclic group which may be substituted" represented by R 1 , R 2 , R 3 , R 4 , R s or R 6 above, and preferable are lower (C x .
  • alkyl groups e.g., methyl, ethyl, propyl, isopropyl, fluoromethyl, chloro ethyl
  • halogens e.g., fluorine, chlorine, bromine, iodine
  • aryl groups e.g., phenyl
  • lower (C 1 ) alkoxy groups e.g., methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, chloromethoxy
  • 1 to 3 halogens e.g., fluorine, chlorine, bromine, iodine
  • halogens e.g., fluorine, chlorine, bromine
  • heterocyclic group which may be substituted for R la , is exemplified by a heterocyclic group which may have 1 to 4 substituents selected from the group consisting of:
  • a C 3 . 7 cycloalkyl group or a C 3 . 6 cycloalkenyl group each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C._ 3 alkoxy group, halogen, a C ⁇ ., alkyl group, amino, nitro and cyano,
  • a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a Cj. 4 alkoxy group which may be substituted by halogen, halogen, a C L . 4 alkyl group which may be substituted by halogen, a C 6 .
  • a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C._ 6 alkyl group, a C 3 - 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ ,, alkoxy group which may be substituted by halogen, a C x . 4 alkyl group which may be substituted by halogen, and nitro ,
  • an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C L . 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Ci. 4 alkoxy group which may be substituted by halogen, a C x . 4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
  • (ix-1) a C ⁇ j alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ alkoxy group
  • (ix-2) a C._ 6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ alkoxy group
  • (ix-3) a C 6 . 14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C x . 3 alkoxy group, halogen, a C 1 . 3 alkyl group, amino, nitro and cyano,
  • (ix-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C.. 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Ci_ 4 alkoxy group which may be substituted by halogen, a C ⁇ ,, alkyl group which may be substituted by halogen, and nitro ,
  • (ix-9) a hydroxyl group which may be substituted by a Ci.g alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said alkyl, a C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 . 12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C x .
  • (ix-10) a thiol group which may be substituted by a C ⁇ alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said C-.g alkyl, C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 .
  • aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ ., alkoxy group which may be substituted by halogen, a C 1-4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C x . 4 alkoxy group, halogen, a C x . 4 alkyl group and a C 6 . 10 aryl group,
  • an acyl group selected from the group consisting of formyl, a alkyl)carbonyl , a (C 3 . 6 cycloalkyl ) carbonyl , a (C 6 . 10 aryl) carbonyl , a (C 7 . 12 aralkyl ) carbonyl , a alkyl ) sulfinyl , a (C 3 . 6 cycloalkyl ) sulfinyl , C 6 . 10 aryl ) sulfinyl , a (C 7 .
  • aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ ,, alkoxy group which may be substituted by halogen, a C._ 4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of
  • (x-1) a Ci.g alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C x . 3 alkoxy group,
  • (x-2) a alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ alkoxy group,
  • (x-3) a C 6 . 14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C ⁇ .3 alkoxy group, halogen, a C 1 _ 3 alkyl group, amino, nitro and cyano ,
  • (x-4) a C 3 . 7 cycloalkyl group or a C 3 . 6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C ⁇ alkoxy group, halogen, a C ⁇ ., alkyl group, amino, nitro and cyano, (x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a Ci. 4 alkoxy group which may be substituted by halogen, halogen, a C L . 4 alkyl group which may be substituted by halogen, a C 6 .
  • (x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C 1 . 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C x . 4 alkoxy group which may be substituted by halogen, a C._ 4 alkyl group which may be substituted by halogen, and nitro ,
  • (x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C ⁇ g alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Ci. 4 alkoxy group which may be substituted by halogen, a C t . 4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
  • (x-9) a hydroxyl group which may be substituted by a C ⁇ g alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said Ci.g alkyl, C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 .
  • aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ .,, alkoxy group which may be substituted by halogen, a C 1-4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C ⁇ ,, alkoxy group, halogen, a C 1-4 alkyl group and a C 6 . 10 aryl group,
  • (x-10) a thiol group which may be substituted by a alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said C j .g alkyl, C 3.6 cycloalkyl, C 6 . 10 aryl and C 7 .
  • aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C._ 4 alkoxy group which may be substituted by halogen, a C ⁇ alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C ⁇ ,, alkoxy group, halogen, a C x . 4 alkyl group and a C 6 .
  • acyl group selected from the group consisting of formyl, a alkyl ) carbonyl , a (C 3 . 6 cycloalkyl )carbonyl , a (C 6 . 10 aryl )carbonyl , a (C 7 . 12 aralkyl)carbonyl, a alkyl) sulfinyl, a (C 3 . 6 cycloalkyl) sulfinyl, a (C 6 . 10 aryl) sulfinyl, a (C 7 . 12 aralkyl ) sulfinyl , a (C x .
  • an acyl group selected from the group consisting of formyl, a alkyl) carbonyl , a (C 3 . 6 cycloalkyl) carbonyl, a (C 6 . 10 aryl ) carbonyl , a (C 7 . 12 aralkyl)carbonyl , a alkyl) sulfinyl , a (C 3 . 6 cycloalkyl ) sulfinyl , C 6 . 10 aryl) sulfinyl, a (C 7 . 12 aralkyl)sulfinyl , a alkyl) sulfonyl, a (C 3 .
  • the cyclic hydrocarbon group which may be substituted for R la is exemplified by
  • Ci.g alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C 1 . 3 alkoxy group,
  • a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C x . 4 alkoxy group which may be substituted by halogen, halogen, a C ⁇ ,, alkyl group which may be substituted by halogen, a C 6 . 10 aryl group, and nitro,
  • an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C ⁇ g alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Ci. 4 alkoxy group which may be substituted by halogen, a C 1-4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
  • (ix-1) a alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C 1 . 3 alkoxy group,
  • (ix-2) a C x . 6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C j .., alkoxy group, (ix-3) a C 6 . 14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C 1-3 alkoxy group, halogen, a C ⁇ ., alkyl group, amino, nitro and cyano,
  • (ix-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C._ 4 alkoxy group which may be substituted by halogen. halogen, a C x . 4 alkyl group which may be substituted by halogen, a C 6 . 10 aryl group, and nitro,
  • (ix-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C-.g alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 6 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C 1 _ i alkoxy group which may be substituted by halogen, a C x .
  • (ix-9) a hydroxyl group which may be substituted by a alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, 7 . I2 aralkyl group or a heterocyclic group, each of said alkyl, a C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 . 12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C : . 4 alkoxy group which may be substituted by halogen, a C x .
  • alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C 1 . i alkoxy group, halogen, a C ⁇ ,, alkyl group and a C 6 . 10 aryl group. (ix-10) a thiol group which may be substituted by a C ⁇ alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said alkyl, C 3 .
  • an acyl group selected from the group consisting of formyl, a alkyl ) carbonyl , a (C 3 . 6 cycloalkyl ) carbonyl , a (C 6 . 10 aryl ) carbonyl , a (C 7 . 12 aralkyl) carbonyl , a alkyl) sulfinyl, a (C 3 . 6 cycloalkyl) sulfinyl , C 6 . 10 aryl) sulfinyl , a (C 7 . 12 aralkyl) sulfinyl, a alkyl) sulfonyl, a (C 3 .
  • (x) a thiol group which may be substituted by a alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl grou C 7 . 12 aralkyl group or a heterocyclic group , each of said alkyl , C 3 . 6 cycloalkyl, C 6.10 aryl and C 7 . 12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C x .
  • alkoxy group which may be substituted by halogen, a C ⁇ ., alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of
  • (x-1) a alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C 1 alkoxy group,
  • (x-2) a alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C ⁇ alkoxy group,
  • (x-3) a C 6 . 14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C ⁇ alkoxy group, halogen, a C ⁇ j alkyl group, amino, nitro and cyano ,
  • (x-4) a C 3 . 7 cycloalkyl group or a C 3 . 6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C ⁇ alkoxy group, halogen, a C x _ 3 alkyl group, amino, nitro and cyano,
  • (x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C 1-4 alkoxy group which may be substituted by halogen, halogen, a C 1 . 4 alkyl group which may be substituted by halogen, a C 6 . 10 aryl group, and nitro,
  • (x-6) a carboxyl group, a alkoxy)carbonyl group, a (C 6 . 10 aryl ) oxycarbonyl group or a (C 7 . 10 aralkyl)oxycarbonyl group
  • (x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C-.g alkyl group , a C 3 . 6 cycloalkyl group , a C 6 . 10 aryl group , a C 7 . 12 aralkyl group and a C 6 .
  • (x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a alkyl group, a C 3 . 6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 . 12 aralkyl group and a C 5 . 10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Ci.-, alkoxy group which may be substituted by halogen, a C r . 4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
  • (x-9) a hydroxyl group which may be substituted by a C._ 6 alkyl group, a C 3 . 6 cycloalkyl group, a C 6 _. 0 aryl group, a C 7 . 12 aralkyl group or a heterocyclic group, each of said C 1 , 6 alkyl, C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 . 12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C 1 .
  • alkoxy group which may be substituted by halogen
  • a C X _ ⁇ alkyl group which may be substituted by halogen , nitro , amino and cyano
  • said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C ⁇ ,, alkoxy group, halogen, a C ⁇ ,, alkyl group and a C 6 . 10 aryl group, (x-10) a thiol group which may be substituted by a alkyl group, a C 3.6 cycloalkyl group, a C 6 . 10 aryl group, a C 7 .
  • each of said C x . 6 alkyl, C 3 . 6 cycloalkyl, C 6 . 10 aryl and C 7 . 12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C ⁇ ,, alkoxy group which may be substituted by halogen, a C 1 ._ i alkyl group which may be substituted by halogen , nitro , amino and cyano
  • said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C ⁇ alkoxy group, halogen, a C ⁇ ,, alkyl group and a C 6 _. 0 aryl group,
  • acyl group selected from the group consisting of formyl, a alkyl)carbonyl, a (C 3 . 6 cycloalkyl ) carbonyl , a (C 6 . 10 aryl ) carbonyl , a (C 7 . 12 aralkyl)carbonyl , a (Cj.g alkyl) sulfinyl, a (C 3 . 6 cycloalkyl) sulfinyl, a (C 6 . 10 aryl)sulfinyl , a (C 7 .
  • an acyl group selected from the group consisting of formyl, a alkyl ) carbonyl , a (C 3 . 6 cycloalkyl) carbonyl, a (C 6 . 10 aryl) carbonyl , a (C 7 . 12 aralkyl ) carbonyl , a alkyl ) sulfinyl , a (C 3 . 6 cycloalkyl) sulfinyl , C 6 . 10 aryl) sulfinyl , a (C 7 .
  • R la is preferably "an aromaic hydrocarbon group or an aromatic heterocyclic group , each of which may be substituted", more preferably "a 5-membered aromatic heterocyclic group which may be substituted” .
  • groups include a thienyl group or a furyl group, each of which may be substituted by 1 to 3, preferably 1 or 2, substituents selected from the group consisting of a C 1 . 3 alkyl group which may be substituted by 1 to 3 halogen, a C x _ 3 alkoxy group, halogen, nitro, cyano, a (C j.
  • alkyl ) carbonyl and alkyl) sulfonyl, preferably a thienyl group which may be substituted by 1 or 2 C 1 alkyl groups or a furyl group which may be substituted by 1 or 2 C ⁇ _ 3 alkyl groups.
  • R l is particularly preferably a thienyl group or a furyl group each of which is substituted by 1 or 2 C 1 . 3 alkyl groups .
  • the non-cyclic hydrocarbon group in the "non-cyclic hydrocarbon group substituted by is exemplified by the sturated or unsaturated aliphatic chain hydrocarbon groups mentioned to exemplify the hydrocarbon group in the "hydrocarbon group which may be substituted" represented by R 1 , R 2 , R 3 , R 4 , R s or R 6 above.
  • Said non-cyclic hydrocarbon group has , at any possible positions , at least 1 , preferably 1 or 2, of (i) a cyclic hydrocarbon group which may be substituted, (ii) a heterocyclic group which may be substituted, (iii) hydroxyl group substituted by a cyclic hydrocarbon group which may be substituted, (iv) hydroxyl group substituted by a heterocyclic group which may be substituted, (v) thiol group substituted by a cyclic hydrocarbon group which may be substituted, and/or (vi) thiol group substituted by a heterocyclic group which may be substituted.
  • Said "cyclic hydrocarbon group which may be substituted" (i) is exemplified by the "aryl groups which may be substituted” and the "lower cycloalkyl or lower cycloalkenyl groups which may be substituted” mentioned to exemplify the substituents of the hydrocarbon group in the "hydrocarbon group which may be substituted” represented by R 1 , R 2 , R 3 , R 4 , R 5 or R 6 above.
  • heterocyclic group which may be substituted (ii) is exemplified by the same groups as the "heterocyclic group which may be substituted” mentioned to exemplify the substituents in the "hydrocarbon group which may be substituted” represented by R 1 , R 2 , R 3 , R 4 , R 5 or R 6 above.
  • the cyclic hydrocarbon group in said "hydroxyl group substituted by a cyclic hydrocarbon group which may be substituted" (iii) and "thiol group substituted by a cyclic hydrocarbon group which may be substituted” (v) is exemplified by the saturated or unsaturated alicyclic hydrocarbon groups and aryl groups (aromatic hydrocarbon groups ) mentioned to exemplify the hydrocarbon group in the "hydrocarbon group which may be substituted" represented by R 1 , R ⁇ R 3 , R 4 , R 5 or R 6 above.
  • heterocyclic group in said "hydroxyl group substituted by a heterocyclic group which may be substituted” (iv) and "thiol group substituted by a heterocyclic group which may be substituted” (vi) is exemplified by the same groups as the heterocyclic group mentioned to exemplify the "heterocyclic group which may be substituted” represented by R 1 , R 2 , R 3 , R 4 , R 5 or R 6 above.
  • Said "alicyclic hydrocarbon group” may have 1 to 5, preferably 1 to 3, optionally chosen substituents at any possible positions .
  • substituents are exemplified by the same groups as those mentioned to exemplify the substituents of the hydrocarbon group in the "hydrocarbon group which may be substituted" represented by R 1 , R 2 , R 3 , R 4 , R 5 or R 6 above, and preferably exemplified by lower (C 1 ) alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, fluoromethyl , chloromethyl ) which may be substituted by 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine), lower (C._ 3 ) alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, chloromethoxy) which may be substituted by 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine), halogens (e.g., fluorine, chlorine,
  • Said "heterocyclic group” may have 1 to 4, preferably 1 to 3, optionally chosen substituents at any possible positions.
  • substituents are exemplified by the same groups as those mentioned to exemplify the substituents of the heterocyclic group in the "heterocyclic group which may be substituted" represented by R 1 , R 2 , R 3 , R 4 , R 5 or R 6 above, and preferably exemplified by lower ( C 1-4 ) alkyl groups (e.g. , methyl, ethyl, propyl, isopropyl), lower (C x .
  • non-cyclic hydrocarbon group may have optionally chosen substituents at any possible positions, in addition to the above "cyclic hydrocarbon group which may be substituted” , “heterocyclic group which may be substituted", and the like, but the total number of substituents in said non-cyclic hydrocarbon group is preferably 1 to 3 , more preferably 1 to 2.
  • substituents are exemplified by the same groups as those mentioned in the substituent in the "hydrocarbon group which may be substituted" represented by R 1 , R 2 , R 3 , R 4 , R 5 or R 6 above.
  • the cyclic hydrocarbon group in the "non-cyclic hydrocarbon group substituted by a cyclic hydrocarbon group which may be substituted" for R lb is preferably exemplified by aryl groups (C 1 . 4 aryl groups such as phenyl, 1-naphthyl and 2-naphthyl), cycloalkyl groups having 3 to 7 carbon atoms , or cycloalkenyl groups having 3 to 6 carbon atoms .
  • the cyclic hydrocarbon group may have 1 to 5, preferably 1 to 3, substituents. Such substituents are preferably exemplified by C ⁇ alkoxy groups , halogens , C .
  • R b is preferably a non-cyclic hydrocarbon group substituted by a heterocyclic group [e.g., an aromatic heterocyclic group such as thienyl (e.g.
  • 2- or 3-benzo[b]furanyl e.g., benzoxazolyl (e.g., 2-, 5- or 6-benz[d] oxazolyl) , benzisoxazolyl (e.g. , 3-, 4- or 5-benz [d] isoxazolyl ) , benzothiazolyl (e.g., 2-benzo[d] thiazolyl) , benzimidazolyl (e.g., 1- benz [d] imidazolyl) ] ] which may be substituted, more preferably a non-cyclic hydrocarbon group substituted by a thienyl or furyl group which may be substituted.
  • benzoxazolyl e.g., 2-, 5- or 6-benz[d] oxazolyl
  • benzisoxazolyl e.g. , 3-, 4- or 5-benz [d] isoxazolyl
  • benzothiazolyl e.g., 2-benzo[d
  • Said non-cyclic hydrocarbon group is preferably exemplified by C-. 10 alkyl groups (preferably C- ⁇ alkyl groups such as methyl, ethyl and propyl), C 2 . 10 alkenyl groups (preferably C 2 . 4 alkenyl groups such as ethenyl) and C 2 . 10 alkynyl groups (preferably C 2 . 4 alkynyl groups such as ethynyl) .
  • Said aromatic heterocyclic group may have 1 to 3 optionally chosen substituents at any possible positions.
  • substituents are preferably exemplified by lower (C 1 ) alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, fluoromethyl , chloromethyl) which may be substituted by 1 to 3 halogens (e.g. , fluorine, chlorine, bromine, iodine), C 6 - ⁇ o aryl groups (e.g., phenyl), lower (C x . 3 ) alkoxy groups (e.g.
  • R b is preferably exemplified by (a) C ⁇ ,, alkyl groups, (b) C 2 . 10 alkenyl groups and (c) C 2 . 10 alkynyl groups, each of which may have 1 to 3 substituents selected from the group consisting of:
  • a C 6 . 14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C x _ 3 alkoxy group, halogen, a C ⁇ ., alkyl group, amino, nitro and cyano , (ii) a C 3 . 7 cycloalkyl group or a C 3 .
  • a hydroxyl group or a thiol group each of which are substituted by a heterocyclic group which may be substituted by 1 to 4 substituents selected from the group consisting of a C.. 4 alkyl group, a C ⁇ ,, alkoxy group, halogen, and a C 6 . 10 aryl group.
  • Said C.. 10 alkyl groups, C 2 . 10 alkenyl groups and C 2 . 10 alkynyl groups may be substituted by further 1 cyano group.
  • the compound represented by the formula (I) or (la) is preferably exemplified by N- ( diaminophosphinyl) -5-methyl-2-thiophenecarboxamide , N- ( diaminophosphinyl ) -2-methyl-3-furancarboxa ide , N- (diaminophosphinyl) -5-methyl-3-furancarboxamide , N- (diaminophosphinyl) -3 , 5-dimethyl-2-furancarboxamide, and
  • the salt of the compound represented by the formula (I), (la) or (lb) is preferably a pharmaceutically acceptable salt , exemplified by salts formed with inorganic bases , salts formed with organic bases , salts formed with inorganic acids , salts formed with organic acids and salts formed with basic or acidic amino acids.
  • Preferable salts formed with inorganic bases include alkali metal salts such as sodium salt and potassium salt ; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt.
  • Preferable salts formed with organic bases include ammonium salts and salts formed with trimethylamine , triethylamine , pyridine, picoline, ethanolamine , diethanolamine , triethanolamine , dicyclohexylamine and N,N ' -dibenzylethylenediamine .
  • Preferable salts formed with inorganic acids include salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid.
  • Preferable salts formed with organic acids include salts formed with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid.
  • Preferable salts formed with basic amino acids include salts formed with arginine, lysine and ornithine.
  • Preferable salts formed with acidic amino acids include salts formed with aspartic acid and glutamic acid. These salts can be obtained by conventional methods .
  • the salt of the compound represented by the formula (II) or (III) below is exemplified by the same kinds of salts as those mentioned as the salt of the compound represented by the formula ( I ) above .
  • the compound represented by the formula ( I ) can be produced by reacting a compound represented by the formula (II):
  • the desired compound can also be produced by reacting the compound represented by the formula (II) or a salt thereof with phosphorus oxychloride to yield the compound represented by the formula (III) or a salt thereof, and reacting it with ammonia.
  • any solvent can be used, as long as it does not interfere with the reaction, and such a solvent includes halogenated solvents such as carbon tetrachloride, chloroform, dichloromethane and 1 , 2-dichloroethane, ether solvents such as dioxane, tetrahydrofuran and diethyl ether, and hydrocarbon solvents such as benzene and toluene, and the reaction temperature is about -50 to 100 °C , preferably about -20 to 80 °C .
  • halogenated solvents such as carbon tetrachloride, chloroform, dichloromethane and 1 , 2-dichloroethane, ether solvents such as dioxane, tetrahydrofuran and diethyl ether, and hydrocarbon solvents such as benzene and toluene
  • the amount of phosphorus pentachloride or phosphorus oxychloride used is 0.5 to 10 mole equivalents, preferably 1 to 2 mole equivalents , per mole of the compound represented by the formula (II) or salt thereof.
  • halogenated solvents, ether solvents and hydrocarbon solvents as those mentioned above can be use .
  • the reaction temperature is about -50 to 50 "C , preferably about 0 to 30 'C.
  • the amount of formic acid used is 0.5 to 10 mole equivalents , preferably 1 to 3 mole equivalents , per mole of the compound obtained by reacting the compound represented by the formula (II) or its salt with phosphorus pentachloride.
  • the reaction temperature is about -50 to 50 "C , preferably about -20 to lo r .
  • the compound ( I ) or its salt may be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, distillation, fractional distillation, solvent extraction, chromatography, crystallization and recrystallization.
  • a protecting group may be used for an amino group , carboxyl group or hydroxyl group not involved in the reaction. The addition and removal of the protecting group can be achieved by known means .
  • Useful amino group-protecting groups include formyl, and alkylcarbonyl (e.g., acetyl, propionyl), phenylcarbonyl , alkyl-oxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl), phenyloxycarbonyl , C 7 . 10 aralkyloxy-carbonyl (e.g., phenyl-C ⁇ ,, alkyloxy-carbonyl such as benzyloxycarbonyl), trityl, phthaloyl and N,N- dimethylaminomethylene , each of which may have substituents.
  • alkylcarbonyl e.g., acetyl, propionyl
  • phenylcarbonyl alkyl-oxycarbonyl
  • alkyl-oxycarbonyl e.g., methoxycarbonyl, ethoxycarbonyl
  • phenyloxycarbonyl e.g., C
  • substituents include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), formyl, alkyl-carbonyl (e.g., acetyl, propionyl, valeryl) and nitro groups, and the number of substituents is about 1 to 3.
  • Useful carboxyl group-protecting groups include alkyl (e.g. , methyl , ethyl , propyl , isopropyl , butyl , tert-butyl), phenyl, trityl and silyl, each of which may have substituents. These substituents include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), formyl, C-.g alkyl-carbonyls (e.g. , acetyl, propionyl, valeryl) and nitro groups, and the number of substituents is about 1 to 3.
  • alkyl e.g. , methyl , ethyl , propyl , isopropyl , butyl , tert-butyl
  • phenyl, trityl and silyl each of which may have substituents.
  • substituents include halogen atoms (e
  • Useful hydroxyl group-protecting groups include alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl, C 7 . 10 aralkyl (e.g., phenyl-C j .., alkyl such as benzyl) , formyl, alkyl-carbonyl (e.g. , acetyl, propionyl), phenyloxycarbonyl, benzoyl, (C 7 .
  • alkyl e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl
  • phenyl C 7 . 10
  • aralkyl e.g., phenyl-C j .., alkyl such as benzyl
  • formyl alkyl-carbonyl (e.g. , acetyl
  • aralkyloxy) carbonyl e.g., ph-eny!- ⁇ .,, alkyloxy-carbonyl such as benzyloxycarbonyl
  • substituents include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), alkyl (e.g., methyl, ethyl, propyl), phenyl, C 7.10 aralkyl (e.g., phenyl-C ⁇ ,, alkyl such as benzyl) and nitro groups, and the number of substituents is about 1 to 4.
  • Protecting groups can be removed by per se known methods or similar methods thereto, such as treatment with acid, base, reducing agent, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate etc.
  • the anti-Helicobacter agent and the pharmaceutical composition of the present invention are characterized by containing a compound represented by the formula (I) , (la) or (lb) or a pharmaceutically acceptable salt thereof (hereinafter referred to as a compound represented by the formula (I) or salt thereof) and an antibiotic.
  • the above-mentioned pharmaceutical against Helicobacter bacteria characterized by combined use of the compound represented by the formula (I) or its salt with an antibiotic is not limited as to form of use, as long as it comprises a combination of the compound represented by the formula (I) or its salt with an antibiotic.
  • the compound represented by the formula (I) or its salt and (B) an antibiotic may be separately formulated in the respective ordinary dosage forms , or may be a composition prepared by combining both in advance.
  • the pharmaceutical against Helicobacter bacteria of the present invention may be produced as a single preparation prepared by mixing the compound represented by the formula ( I ) or its salt with an antibiotic by a known manufacturing method of pharmaceutical using a pharmaceutically acceptable diluent , excipient etc. when desired, or as separate preparations prepared from the respective components using a pharmaceutically acceptable diluent, excipient etc. when desired, or as a combination preparation (set, kit, pack) by packing the separately prepared preparations into the same container.
  • the pharmaceutical against Helicobacter bacteria of the present invention is used as ( 1 ) a combination preparation in which a pharmaceutical containing the compound represented by the formula ( I ) or its salt and a pharmaceutical containing an antibiotic are packed, or (2) a composition containing the compound represented by the formula ( I ) or its salt and an antibiotic.
  • the pharmaceutical against Helicobacter bacteria of the present invention may also be a combination preparation or composition comprising the compound represented by the formula (I) or its salt and an antibiotic.
  • An antibiotic is exemplified by naturally-occuring substances having antibacterial activity which are extracted from microorganisms such as bacteria, molds and actinomycetes , or plants, substances having antibacterial activity which are obtained by chemically modifying the naturally-occuring substances, and substances having antibacterial activity which are obtained by chemical synthesis .
  • antibiotics include penicillin antibiotics such as amoxicillin, piperacillin, penicillin G and mecillinam; cephalosporin antibiotics such as cefaclor, cefotiam, cefixime, ceftazidime and cefpiro e; carbapenem antibiotics such as imipenem; macrolide antibiotics such as clarithromycin , erythromycin , roxithromycin and azithromycin; lincomycin antibiotics such as clindamycin; chloramphenicol antibiotics such as chloramphenicol; tetracyclin antibiotics such as tetracyclin, minocyclin and doxycyclin; aminoglycoside antibiotics such as streptomycin, gentamycin and amikacin; quinolone antiboitics such as norfloxacin, ofloxacin and ciprofloxacin; indolmycin antibiotics such as indolmycin; nitroimidazole antiboitics (antiprot)
  • penicillin antibiotics such as amoxicillin
  • macrolide antibiotics such as clarithromycin
  • nitroimidazole antiboitics such as metronidazole and tinidazole
  • indolmycin antibiotics such as indolmycin.
  • penicillin antibiotics such as amoxicillin
  • macrolide antibiotics such as clarithromycin
  • nitroimidazole antiboitics such as metronidazole and tinidazole
  • indolmycin antibiotics such as indolmycin.
  • penicillin antibiotics such as amoxicillin
  • macrolide antibiotics such as clarithromycin.
  • One or more (preferably 1 to 3 , more preferably 1 or 2 ) of these antibioitics can be used.
  • the anti--ffelicobacter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria in the present invention can be produced by known preparation methods of pharmaceutical formulation.
  • the anti- Helicobacter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria in the present invention can be used orally or non-orally by inhalation, by rectal administration or by local administration.
  • it can be used in a form of powders, granules, tablets, pills, capsules, injectable preparations, syrups, emulsions, elixirs, suspensions, solutions etc. , and it may contain at least one compound represented by the formula ( I ) or a salt thereof and an antibiotic, or in combination with a pharmaceutically acceptable carrier.
  • the contents of the compound represented by the formula ( I ) or its salt and the antibiotic may be chosen as appropriate depending upon the preparation, but normally are 1 to 99% by weight and 1 to 99% by weight respectively, preferably are 1 to 20% by weight and 1 to 90% by weight respectively.
  • the pharmaceutically acceptable carriers include various organic or inorganic carrier substances commonly used as pharmaceutical materials. And excipients, lubricants, binders and disintegrating agents for solid preparations, and solvents, solubilizers, suspending agents , isotonizing agents , buffers and soothing agents for liquid preparations are used appropriately. Other pharmaceutical additives such as preservatives , antioxidants, coloring agents and sweetening agents may be used appropriately when necessary.
  • Preferable excipients include lactose, sucrose, D- annitol, starch, crystalline cellulose and light silicic anhydride .
  • Preferable lubricants include magnesium stearate, calcium stearate, talc and colloidal silica.
  • Preferable binders include crystallinecellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone .
  • Preferable disintegrating agents include starch, carboxymethylcellulose , carboxymethylcellulose calcium, croscarmellose sodium and carboxymethyl starch sodium.
  • Preferable solvents include water for injection , alcohol , propylene glycol, macrogol, sesame oil and corn oil.
  • Preferable solubilizers include polyethyleneglycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, Tris-aminomethane, cholesterol, triethanolamine , sodium carbonate and sodium citrate.
  • Preferable suspending agents include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl-aminopropionic acid, lecithin, benzalkonium chloride , benzethonium chloride and glycerol monostearate ; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone , carboxymethylcellulose sodium, methylcellulose , hydroxymethylcellulose , hydroxyethylcellulose and hydroxypropylcellulose.
  • Preferable isotonizing agents include sodium chloride, glycerol and D-mannitol.
  • Preferable buffers include buffer solutions of phosphates, acetates, carbonates and citrates.
  • Preferable soothing agents include benzyl alcohol.
  • Preferable preservatives include p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol , dehydroacetic acid and sorbic acid.
  • Preferable antioxidants include sulfites and ascorbic acid.
  • the anti -Helicobacter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria can be prepared as pharmaceutical preparations by ordinary methods.
  • non- oral includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection and drip infusion.
  • injectable preparations e.g., aqueous or oily suspensions for aseptic injection, can be prepared by methods known in relevant fields , using an appropriate dispersing agent or wetting agent and a suspending agent.
  • the aseptic injectable preparation thus obtained may be an aseptically injectable solution or suspension in a diluent or solvent which permits non-toxic non-oral administration, such as an aqueous solution.
  • Acceptable vehicles or solvents include water.
  • Ringer's solution and isotonic saline It is also possible to use aseptic non-volatile oils as solvents or suspending media.
  • any non-volatile oil or fatty acid can be used, including natural, synthetic or semi-synthetic fatty oils or fatty acids, and natural, synthetic or semi- synthetic mono- or di- or tri-glycerides .
  • Suppositories for rectal administration may be produced by mixing the drug with an appropriate non-irritative shaping agent, such as cacao butter or polyethyleneglycol, which is solid at atmospheric temperature and which is liquid at intestinal temperature and melts and releases the drug in the rectum.
  • Solid dosage forms for oral administration include the above-mentioned forms such as powders, granules, tablets, pills and capsules.
  • the active ingredient compound may be mixed with at least one additive such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginate, chitin, chitosan, pectin, gum tragacanth, gum arable, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymer or glyceride .
  • Such dosage forms may additionally contain additives as usual, including inert diluents, lubricants such as magnesium stearate, preservatives such as paraben and sorbic acid, antioxidants such as ascorbic acid, a -tocopherol and cysteine, disintegrating agents, binders , thickening agents , buffers , sweeteners , flavoring agents and perfumes . Tablets and pills may be produced with enteric coating.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions and solutions, and may contain inert diluents, such as water, commonly used in relevant fields .
  • the anti-Helicoba ⁇ ter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria of the present invention may also be an enteric preparation .
  • the compound represented by the formula ( I ) or its salt, and/or an antibiotic can be formulated into a gastrointestinal mucosa-adherent composition according to the methods described in Japanese Patent Unexamined Publication No. 132416/1993, Japanese Patent Unexamined Publication No. 126189/1995, and the like.
  • the dose for a particular patient is determined according to age, body weight, general health status, sex, dietary status, administration time, method of administration, excretion rate, drug combination, severity of the illness being treated and other factors .
  • the compound represented by the formula ( I ) or its salt exhibits antibacterial action (eradication of Helicobacter bacteria), especially against Helicobacter bacteria, based on urease inhibitory activity, it is useful in the prevention or treatment of digestive diseases presumably caused by Helicobacter bacteria, such as gastritis, duodenal ulcer, gastric ulcer and chronic gastritis in mammals (e.g., humans, dogs, cats, monkeys, rats, mice). Since significant correlation between Helico- bacter bacteria, especially Helicobacter pylori , and gastric cancer has recently been suggested, this compound is also expected to be useful in the prevention of gastric cancer. Furthermore, the compound represented by the formula ( I ) or its salt is of low toxicity and can be safely used.
  • the anti-Helicoba ⁇ ter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria of the present invention possesses antibacterial activity against Helicobacter bacteria, it exhibits eradicating and sterilizing effect of Helicobacter bacteria which exhibit toxic action in the digestive tract.
  • the digestive tract is exemplified by the stomach and duodenal.
  • a Helicobacter bacterium exhibiting toxic action in the digestive tract is Helico-bacter pylori .
  • the dose of the anti-Heli ⁇ obacter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria of the present invention is chosen as appropriate, depending on type and symptoms of diseases , but the compound represented by the formula (I) or its salt may be daily administered, per adult patient (50 kg) with gastric ulcer or duodenal ulcer, at about 0.1 to 10 g/day, preferably 0.2 to 2 g/day by oral administration, and about 0.01 to 1 g/day, preferably 0.02 to 0.5 g/day by non-oral administration.
  • the dose per administration is determined taking into consideration such daily doses, dosage forms etc.
  • Administration frequency is not limited, but preferably 1 to 5 times/day, more preferably 1 to 3 times/day.
  • the dose of an antibiotic is chosen as appropriate, depending on type and symptoms of diseases , and kinds of the antibiotic, but the antibiotic, in the case of penicillin antibiotics such as amoxicillin, may be daily administered, per adult patient (50 kg) with gastric ulcer or duodenal ulcer, at about 0.1 to 10 g/day, preferably 0.2 to 2 g/day by oral administration, and about 0.01 to 1 g/day, preferably 0.02 to 0.5 g/day by non-oral administration.
  • the dose per administration is determined taking into consideration such daily doses, dosage forms etc.
  • Administration frequency is not limited, but preferably 1 to 5 times/day, more preferably 1 to 3 times/day.
  • the anti-Helicobacter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria of the present invention may contain antacids and/or acid secretion inhibitors etc. in addition to its active ingredients, i.e. , the compound represented by the formula (I) or its salt and an antibiotic.
  • Such antacids include aluminum hydroxide gel, sodium bicarbonate, aminoacetic acid, aluminum silicate. magnesium metasilicic aluminate, magnesium silicate, magnesium oxide, magnesium hydroxide, magnesium carbonate and calcium carbonate .
  • Such acid secretion inhibitors include drugs which suppress gastric acid secretion, specifically proton pump inhibitors and histamine H 2 blockers .
  • proton pump inhibitor is defined as a drug that suppresses gastric acid secretion by directly or indirectly inhibiting H/K-ATPase, which functions as a proton pump in gastric mucosal membrane acid secreting cells (parietal cells).
  • Examples of such drugs include lansoprazole, omeprazole, pantoprazole, pariprazole sodium (Rabeprazole sodium), leminoprazole, TY-11345, TU-199, FPL-65372, BY-686, tannic acid, ellagic acid, Ebselen, AHR-9294, Cassigarol-A, Bafilomycin, Y- 25942, Xanthoangelol E, SKF-96356, epigallocatechin gallate, WY-27198, T-330 and SK&F-20054.
  • Example of proton pump inhibitors include benzimidazole compounds , which exhibit proton pump inhibiting action and are of low toxicity.
  • Preferable benzimidazole compounds include 2- [ (pyridyl) -methylsulfinyl or - methylthio] benzimidazole, derivatives thereof and salts thereof . More preferable are a compound represented by the following formula ( a ) and a salt thereof :
  • R b represents a hydrogen atom, an alkyl group, an acyl group, a carbalkoxy group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group or an alkylsulfonyl group
  • R°, R ⁇ and R 9 independently represent a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkoxy group
  • R d represents a hydrogen atom, an alkyl group or a group represented by the formula: -OR f or -SR f , wherein R f represents a hydrocarbon group that may be substituted
  • q represents 0 or 1.
  • benzimidazole compounds are described in Japanese Patent Unexamined Publication Nos .62275/1977, 141783/1979, 53406/1982, 135881/1983, 192880/1983, 181277/1984, 50978/1986, 116576/1987, 277322/1987, 258320/1987, 258316/1987, 6270/1989, 79177/1989. 59043/1993, 111980/1987 and 117268/1993, and European Patent Publication Nos. 166287 and 519365, for instance.
  • the substituents to ring A include halogen atoms , alkyl groups that may be substituted, cycloalkyl groups that may be substituted, alkenyl groups that may be substituted, alkoxy groups that may be substituted, cyano group, carboxy group, carbalkoxy groups , carbalkoxyalkyl groups , carbamoyl grou , carbamoylalkyl groups , hydroxy group , hydroxyalkyl groups , acyl groups , carbamoyloxy group , nitro group , acyloxy groups , aryl groups , aryloxy groups , alkylthio groups and alkylsulfinyl groups .
  • Halogen atoms include fluorine, chlorine, bromine and iodine. Of these halogen atoms, fluorine and chlorine are preferred, and fluorine is more preferred.
  • the alkyl group in the alkyl group that may be substituted is exemplified by straight-chain or branched alkyl groups having 1 to 10 carbon atoms (e.g. , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl) .
  • straight-chain or branched alkyl groups having 1 to 10 carbon atoms e.g. , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, hexyl
  • alkyl groups straight-chain or branched alkyl groups having 1 to 6 carbon atoms are preferred, and those having 1 to 3 carbon atoms are more preferred.
  • Substituents of said alkyl group include halogens, nitro. amino groups (which may have 1 to 2 alkyl groups , acyl groups etc. as substituents) , cyano group, hydroxy group, carboxy group , amidino group , guanidino group and carbamoyl group .
  • the cycloalkyl group in the cycloalkyl group that may be substituted is exemplified by cycloalkyl groups having 3 to 7 carbon atoms.
  • such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl .
  • Said cycloalkyl group may have substituents, exemplified by halogens , nitro group, amino groups (which may have 1 to 2 alkyl groups, acyl groups etc. as substituents), cyano group, hydroxyl group, carboxyl group , amidino grou , guanidino group and carbamoyl group .
  • the alkenyl group in the alkenyl group that may be substituted is preferably exemplified by straight-chain or branched alkenyl groups having 2 to 16 carbon atoms.
  • alkenyl groups include allyl, vinyl, crotyl, 2-penten-l-yl, 3-penten-l-yl, 2-hexen-l-yl, 3- hexen-1-yl, 2-methyl-2-propen-l-yl and 3-methyl-2- buten-1-yl.
  • straight-chain or branched alkenyl groups having 2 to 6 carbon atoms are preferred, and those having 2 to 4 carbon atoms are more preferred.
  • Said alkenyl group may have substituents, exemplified by halogens, nitro group, amino groups (which may have 1 to 2 alkyl groups, acyl groups etc. as substituents), cyano group, amidino group and guanidino group.
  • Said alkenyl group include isomers (E- and Z- isomers) with respect to double bond.
  • alkoxy group in the alkoxy group that may be substituted is exemplified by alkoxy groups having 1 to 10 carbon atoms.
  • alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, cyclobutoxy, cyclopentoxy and cyclohexyloxy.
  • those having 1 to 6 carbon atoms are preferred, and those having 1 to 3 carbon atoms are more preferred.
  • Said alkoxy group may have substituents, exemplified by halogens, nitro group, amino groups (which may have 1 to 2 alkyl groups , acyl groups etc . as substituents), amidino group, guanidino group, C x . 4 alkoxy groups and C 6 . 10 aryl groups such as phenyl and naphthyl (which may have 1 to 3 halogens, C t . 4 alkyl groups, C x . 4 alkoxy groups etc. as substituents).
  • substituents exemplified by halogens, nitro group, amino groups (which may have 1 to 2 alkyl groups , acyl groups etc . as substituents), amidino group, guanidino group, C x . 4 alkoxy groups and C 6 . 10 aryl groups such as phenyl and naphthyl (which may have 1 to 3 halogens, C t . 4 alkyl groups, C
  • the halogen as a substituent of the above-mentioned alkyl groups , cycloalkyl groups , alkenyl groups and alkoxy groups includes chlorine, bromine, fluorine and iodine.
  • the alkyl group in the alkylamino group as a substituent of the above-mentioned alkyl groups, cycloalkyl groups, alkenyl groups and alkoxy groups is preferably a straight-chain or branched alkyl group having 1 to 6 carbon atoms.
  • Such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n- pentyl, isopentyl, n-hexyl and isohexyl.
  • straight-chain or branched alkyl groups having 1 to 4 carbon atoms are more preferred.
  • acyl group in the acylamino group as a substituent of the above-mentioned alkyl groups, cycloalkyl groups, alkenyl groups and alkoxy groups is exemplified by acyl groups derived from organic carboxylic acids .
  • acyl groups alkanoyl groups having 1 to 6 carbon atoms are preferred.
  • Such acyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl, and alkanoyl groups having 1 to 4 carbon atoms are more preferred.
  • Substituted alkyl groups include trifluoromethyl, trifluoroethyl , difluoromethyl, trichloromethyl , hydroxymethyl , 1-hydroxyethyl, 2-hydroxyethyl, methoxyethyl, ethoxyethyl, 1-methoxyethyl, 2- methoxyethyl, 2 , 2-dimethoxyethyl, 2 , 2-diethoxyethyl and 2-diethylphosphorylethyl. Of these groups, difluoromethyl , trifluoromethyl and hydroxymethyl are preferred, and trifluoromethyl is more preferred.
  • Substituted cycloalkyl groups include 2- aminocyclopropan-1-yl, 4-hydroxycyclopentan-l-yl and 2 , 2-difluorocyclopentan- 1-yl .
  • Substituted alkenyl groups include 2 , 2-dichlorovinyl, 3-hydroxy-2-propen-l-yl and 2-methoxyvinyl.
  • Substituted alkoxy groups include difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-methoxyethoxy, 4-chlorobenzyloxy and 2- ( 3 , 4-dimethoxypheny1 ) ethoxy. Of these alkoxy groups, difluoromethoxy is preferred.
  • alkoxy group in the carbalkoxy group is exemplified by alkoxy groups having 1 to 7 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy) .
  • alkoxy group in the carbalkoxyalkyl group is exemplified by alkoxy groups having 1 to 4 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy)
  • alkyl group is exemplified by alkyl groups having 1 to 4 carbon atoms (e.g. , methyl , ethyl , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl).
  • carbalkoxyalkyl groups examples include carbomethoxymethyl (methoxycarbonylmethyl ) , 2- carbomethoxyethyl (2-methoxycarbonylethyl) , 2- carbomethoxypropyl ( 2-methoxycarbonylpropyl) , carbethoxymethyl ( ethoxycarbonylmethyl ) , 2- carbethoxyethyl ( 2-ethoxycarbonylethyl) , 1- carbomethoxypropyl ( 1-methoxycarbonylpropyl ) , carbopropoxymethyl (propoxycarbonylmethyl) and carbobutoxymethyl ( butoxycarbonylmethyl ) .
  • the alkyl group in the carbamoylalkyl group is exemplified by alkyl groups having 1 to 4 carbon atoms (e.g. , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl).
  • the alkyl group in the hydroxyalkyl group is exemplified by alkyl groups having 1 to 7 carbon atoms (e.g. , methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl ) .
  • the acyl group and the acyl group in the acyloxy group are exemplified by alkanoyl groups having 1 to 4 carbon atoms , including formyl , acetyl , propionyl , butyryl and isobutyryl .
  • aryl group and the aryl group in the aryloxy group are exemplified by aryl groups having 6 to 12 carbon atoms (e.g. , phenyl , naphthyl ) .
  • alkyl group in the alkylthio group and alkylsulfinyl group is exemplified by alkyl groups having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl).
  • the number of substituents to the substituted ring A is preferably 1 to 4 , and more preferably 1 to 2.
  • the positions of substituents on the benzene ring include 4- and 5- positions (4- and 5-positions of benzimidazole skeleton), and 5-position is preferable.
  • Preferred examples of ring A include benzene ring which may be substituted by a halogen atom, an alkyl group that may be substituted, a cycloalkyl group that may be substituted, an alkenyl group that may be substituted, an alkoxy group that may be substituted, or the like.
  • the alkyl group represented by R b is exemplified by alkyl groups having 1 to 5 carbon atoms (e.g. , methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl);
  • the acyl group is exemplified by acyl groups having 1 to 4 carbon atoms (e.g.
  • alkanoyl groups having 1 to 4 carbon atoms alkanoyl groups having 1 to 4 carbon atoms
  • the alkoxy group in the carbalkoxy group is exemplified by alkoxy groups having 1 to 4 carbon atoms (e.g., methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy)
  • the alkyl group in the alkylcarbamoyl group and the dialkylcarbamoyl group is exemplified by alkyl groups having 1 to 4 carbon atoms (e.g.
  • R b is preferably a hydrogen atom.
  • the alkyl group represented by R c , R ⁇ or R 9 is exemplified by straight-chain or branched alkyl groups having 1 to 10 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl).
  • straight-chain or branched alkyl groups having 1 to 6 carbon atoms are preferred, and straight-chain or branched alkyl groups having 1 to 3 carbon atoms are more preferred.
  • the alkoxy group represented by R°, R ⁇ or R 9 is exemplified by alkoxy groups having 1 to 10 carbon atoms (e.g. , methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy) .
  • alkoxy groups having 1 to 6 carbon atoms are preferred, and alkoxy groups having 1 to 3 carbon atoms are more preferred.
  • Each of the alkoxy groups of the alkoxyalkoxy group represented by R°, R ⁇ or R 9 is exemplified by alkoxy groups having 1 to 4 carbon atoms (e.g. , methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- butoxy) .
  • R° is preferably a hydrogen atom, an alkyl group or an alkoxy group.
  • R ⁇ is preferably a hydrogen atom, an alkyl group or an alkoxy group.
  • R 9 is preferably a hydrogen atom.
  • the alkyl group represented by R d is exemplified by alkyl groups having 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl) .
  • the hydrocarbon group in the hydrocarbon group that may be substituted, represented by R f is exemplified by hydrocarbon groups having 1 to 13 carbon atoms, including straight-chain or branched alkyl groups having 1 to 6 carbon atoms (e.g.
  • alkenyl groups having 2 to 6 carbon atoms e.g., vinyl, allyl, 2-butenyl, methylallyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 5-hexenyl
  • alkynyl groups having 2 to 6 carbon atoms e.g.
  • cycloalkyl groups having 3 to 6 carbon atoms e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl
  • cycloalkenyl groups having 3 to 6 carbon atoms e.g.
  • cyclobutenyl cyclopentenyl, cyclohexenyl, cyclohexadienyl
  • aralkyl groups having 7 to 13 carbon atoms e.g., alkyl groups such as benzyl, 1- phenethyl and 2-phenethyl, naphthyl-C ! .., alkyl groups
  • aryl groups having 6 to 10 carbon atoms e.g., phenyl, naphthyl.
  • straight-chain or branched alkyl groups having 1 to 6 carbon atoms e.g.
  • methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl) are preferred, and straight-chain or branched alkyl groups having 1 to 4 carbon atoms are more preferable.
  • the substituent in the substituted hydrocarbon group is exemplified by C 6 . 10 aryl groups (e.g., phenyl, naphthyl), amino group, C l . 6 alkylamino groups (e.g. , ethylamino, ethylamino, isopropylamino ) , alkylamino groups (e.g., dimethylamino , diethylamino ) , N-C 7 . 14 aralkyl-N-C 3 . 6 cycloalkylamino groups (e.g., N-(C 6 _ 10 aryl-Ci.,, alkyl) -N- C 3 .
  • C 6 . 10 aryl groups e.g., phenyl, naphthyl
  • amino group e.g., C l . 6 alkylamino groups (e.g. , ethylamino, ethyla
  • cycloalkylamino groups such as N-benzyl-N- cyclohexylamino ) , N-C 7 . 14 alkylamino groups (e.g., N-(C 6 . 10 aryl-Ci.,, alkyl) alkylamino such as N-(l-naph-thylmethyl)-N-ethylamino) , azido group, nitro group , halogens (e.g. , fluorine , chlorine , bromine , iodine) , hydroxyl group, C alkoxy groups (e.g. , methoxy, ethoxy, propoxy, butoxy), C 6 .
  • alkylamino groups e.g., N-(C 6 . 10 aryl-Ci.,, alkyl) alkylamino such as N-(l-naph-thylmethyl)-N-ethylamino
  • aryloxy groups e.g., phenoxy, naphthyloxy
  • alkylthio groups e.g., methylthio, ethylthio, propylthio
  • arylthio groups e.g., phenylthio, naphthylthio
  • cyano group carbamoyl group, carboxyl group, C x .
  • alkoxycarbonyl groups e.g., methoxycarbonyl, ethoxycarbonyl
  • C 7 _ u aryloxycarbonyl groups e.g., phenoxycarbonyl , 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl
  • carboxy-Ci. alkoxy groups (e.g., carboxymethoxy, 2-carboxyethoxy)
  • C._ 6 alkanoyl groups e.g., formyl, acetyl, propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl
  • C 7 alkoxycarbonyl groups
  • u aroyl groups e.g., benzoyl, 1-naphthoyl, 2-naphthoyl) , C 6 .
  • arylsulfonyl groups e.g., benzenesulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl
  • alkylsulfinyl groups e.g. , methylsulfinyl , ethylsulfinyl
  • C 6 u aroyl groups
  • arylsulfinyl groups e.g., benzenesulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl
  • alkylsulfonyl groups e.g.
  • the heterocyclic-thio group may be fused with the benzene ring to form a bicyclic fused ring-thio group (e.g., 2- benzothiazolylthio, 8-quinolylthio) .
  • a bicyclic fused ring-thio group e.g., 2- benzothiazolylthio, 8-quinolylthio
  • substituents halogens (e.g. , fluorine, chlorine, bromine, iodine) , hydroxyl group and C ⁇ alkoxy groups (e.g. , methoxy, ethoxy, propoxy, butoxy) are preferred.
  • the number of such substituents is 1 to 5 , preferably 1 to 3.
  • R d is preferably an alkoxy group that may be substituted or an alkoxyalkoxy group that may be substituted.
  • R d is particularly preferably an alkoxy group having 1 to 8 carbon atoms , preferably 1 to 4 carbon atoms , which may be halogenated by 1 to 9 halogens , or an alkoxyalkoxy group which may be halogenated by 1 to 5 halogen atoms .
  • Preferable alkoxy groups which may be halogenated include 2, 2, 2-trifluoroethoxy, 2,2,3,3,3-pentafluoropropoxy, 1- (trifluoromethyl) -2, 2, 2-trifluoroethoxy, 2,2,3,3- tetrafluoropropoxy , 2,2,3,3,4,4, 4 -heptafluorobutoxy , 2,2,3,3, 4, 4,5,5-octafluoropentoxy and methoxy.
  • Preferable alkoxyalkoxy groups which may be halogenated include 3-methoxypropoxy. q is preferably 1.
  • benzimidazole compound is exemplified by a compound represented by the formula ( )3 ) :
  • R w , R ⁇ and R z whether identical or not, represent a hydrogen atom, an alkyl group or an alkoxy group;
  • R x represents a hydrocarbon group that may have substituents; and
  • n represents 0 or 1.
  • ring A is exemplified by the same rings as those mentioned as to ring A in the formula ( ⁇ ) above .
  • the alkyl group represented by R w , R ⁇ or R z is exemplified by straight-chain or branched alkyl groups having 1 to 10 carbon atoms.
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl.
  • straight-chain or branched alkyl groups having 1 to 6 carbon atoms are preferred, and those having 1 to 3 carbon atoms are more preferred.
  • the alkoxy group represented by R w , R* or R z is exemplified by alkoxy groups having 1 to 10 carbon atoms.
  • alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy. isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy.
  • alkoxy groups having 1 to 6 carbon atoms are preferred, and alkoxy groups having 1 to 3 carbon atoms are more preferred.
  • R M is preferably an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms , and more preferably an alkyl group having 1 to 3 carbon atoms.
  • R ⁇ is preferably a hydrogen atom or an alkyl group having
  • R x is preferably an alkyl group having 1 to 6 carbon atoms , that may be substituted by 1 ) 1 to 5 halogens , 2 ) a hydroxyl , or 3 ) an alkoxy group having 1 to 4 carbon atoms , more preferably an alkyl group having 1 to 3 carbon atoms, that may be substituted by 1) 1 to 5 halogens or 2) an alkoxy group having 1 to 4 carbon atoms ,
  • R z is preferably a hydrogen atom.
  • Examples of the above-described benzimidazole compound include 2- [ 2- [ 3-methyl-4-(2, 2,3,3- tetrafluoropropoxy)pyridyl]methylthio]benzimidazole, 2- [2-[3-methyl-4-(2,2,2- trifluoroethoxy)pyridyl ]methylsulfinyl]benzimidazole (lansoprazole) , 2-[(2- pyridyl)methylsulfinyl]benzimidazole ( timoprazole) , 2- [ 2- ( 3 , 5-dimethyl-4-methoxypyridyl )methylsulfinyl] -5- methoxy- lH-benzimidazole ( omeprazole ) , 2-[2-[4-(3- methoxypropoxy) -3-methylpyridyl]methylsulfinyl] -1H- benzimidazole sodium salt (Pariprazole sodium, Rabeprazol
  • the salt of a benzimidazole compound is used as a pharmaceutically acceptable salt .
  • Useful pharmaceutically acceptable salts include salts formed with inorganic bases , salts formed with organic bases and salts formed with basic amino acids .
  • Useful inorganic bases include alkali metals (e.g., sodium, potassium); alkaline earth metals (e.g., calcium, magnesium).
  • Useful organic bases include trimethylamine , triethylamine , pyridine, picoline, N,N-dibenzylethylenediamine, ethanolamine , diethanolamine , trishydroxymethylaminomethane and dicyclohexylamine .
  • Useful basic amino acids include arginine and lysine.
  • salts are produced by per se known methods, e.g. , those described in Japanese Patent Unexamined Publication Nos. 79177/1989 and 167587/1984, or similar methods thereto .
  • histamine H 2 blockers as the acid secretion inhibitors include 2-cyano-1-methyl-3- [2- [ [ (5- methylimidazol-4-yl)methyl] thio ]ethyl] guanidine (cimetidine) , N-[2-[[5-
  • an antacid and an acid secretion inhibitor for use in the Helicobacter agent , pharmaceutical composition, and pharmaceutical against Helicobacter bacteria of the present invention one or more (preferably 3 or fewer) of antacids and/or acid secretion inhibitors selected among them, preferaby 1 or 2 of antacids and/or acid secretion inhibitors are used.
  • an acid secretion inhibitor is preferable, and a proton pump inhibitor is more preferable.
  • the Helicobacter agent and pharmaceutical composition of the present invention may contain antacids and/or acid secretion inhibitors etc. in addition to its active ingredients, i.e.. the compound represented by the formula (I) and an antibiotic.
  • active ingredients i.e.. the compound represented by the formula (I) and an antibiotic.
  • containing covers both simultaneous use and use at a time interval of 2 or more active substances after admixing or without admixing, and further covers combined use and use in combination.
  • the above-mentioned pharmaceutical against Helicobacterbacteria characterized by combined use of the compound represented by the formula ( I ) or its salt and an antibiotic with an antacid and/or an acid secretion inhibitor, is not limited as to form of use, as long as it comprises a combination of the compound represented by the formula (I) or its salt, an antibiotic, and an antacid and/or an acid secretion inhibitor.
  • the compound represented by the formula (I) or its salt, (B) an antibiotic, and (C) an antacid and/or an acid secretion inhibitor may be separately formulated in the respective ordinary dosage forms , or may be a composition prepared by combining them in advance.
  • the anti-Helicobacter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria in the present invention may be produced as a single preparation prepared by mixing the compound represented by the formula (I) or its salt, an antibiotic, and an antacid and/or an acid secretion inhibitor by a known manufacturing method of pharmaceutical using a pharmaceutically acceptable diluent , excipient etc . when desired; as separate preparations prepared from the respective components using a pharmaceutically acceptable diluent, excipient etc. when desired; as separate preparations comprising a preparation prepared from two ingredients among the compound represented by the formula (I) or its salt, an antibiotic, and an antacid and/or an acid secretion inhibitor using a pharmaceutically acceptable diluent, excipient etc.
  • the pharmaceutical against Helicobacter bacteria of the present invention is used as ( 1 ) a combination preparation in which a pharmaceutical containing the compound represented by the formula ( I ) or its salt , a pharmaceutical containing an antibiotic, and a pharmaceutical containing an antacid and/or an acid secretion inhibitor are packed, or (2) a composition containing the compound represented by the formula (I) or its salt, an antibiotic, and an antacid and/or an acid secretion inhibitor.
  • the pharmaceutical against Helicobacter bacteria of the present invention may also be a combination preparation or composition consisting of the compound represented by the formula (I) or its salt, an antibiotic and an antacid and/or an acid secretion inhibitor.
  • both oral and non-oral administrations e.g., intravenous administration, subcutaneous administration, intramuscular administration
  • the route is determined in consideration of the site of target ulcer etc.
  • an antibiotic When the compound represented by the formula (I) or its salt , an antibiotic , and an antacid and/or an acid secretion inhibitor are prepared as separate preparations , they may be administered to the same subject simultaneously or at a time interval via the same route or different routes .
  • the compound represented by the formula (I) or its salt, an antibiotic, and an antacid or an acid secretion inhibitor can be administered in dosage forms prepared by conventional methods in the same manner as the above- described anti-Helicobacter agent.
  • tablets and capsules are prepared using pharmaceutically acceptable carriers (e.g., lactose, corn starch, light silicic anhydride, microcrystalline cellulose, sucrose), binders (e.g., alpha starch, methylcellulose, carboxymethylcellulose , hydroxypropylcellulose , hydroxypropylmethylcellulose , polyvinylpyrrolidone) , disintegrating agents (e.g., carboxymethylcellulose, starch, low-substituted hydroxypropylcellulose), surfactants [e.g., Tween 80 (Kao-Atlas), Pluronic F68 (Asahi Denka, Japan), polyoxyethylene-polyoxypropylene copolymer] , antioxidants (e.g.
  • pharmaceutically acceptable carriers e.g., lactose, corn starch, light silicic anhydride, microcrystalline cellulose, sucrose
  • binders e.g., alpha starch, methylcellulose, carboxymethylcellulose , hydroxyprop
  • a solution for injection is produced by a conventional method using an aqueous solvent (e.g., distilled water, physiological saline. Ringer's solution) or an oily solvent (e.g., sesame oil, olive oil).
  • aqueous solvent e.g., distilled water, physiological saline. Ringer's solution
  • oily solvent e.g., sesame oil, olive oil.
  • One or more additives can be used if necessary.
  • Such additives include solubilizers (e.g., sodium salicylate, sodium acetate) , buffers (e.g., sodium citrate, glycerol), isotonizing agents (e.g., glucose, invert sugar), stabilizers (e.g., human serum albumin, polyethylene glycol), antiseptics (e.g., benzyl alcohol, phenol) and analgesics (e.g., benzalkonium chloride, procaine hydrochloride) .
  • solubilizers e.g., sodium salicylate, sodium acetate
  • buffers e.g., sodium citrate, glycerol
  • isotonizing agents e.g., glucose, invert sugar
  • stabilizers e.g., human serum albumin, polyethylene glycol
  • antiseptics e.g., benzyl alcohol, phenol
  • analgesics e.g., benzalkonium chloride, proca
  • a solid preparation for injection can be produced by a conventional method using diluents (e.g., distilled water, physiological saline, glucose), activators (e.g., carboxymethylcellulose, sodium alginate), antiseptics (e.g., benzyl alcohol, phenol) and analgesics (e.g., benzalkonium chloride, procaine hydrochloride).
  • diluents e.g., distilled water, physiological saline, glucose
  • activators e.g., carboxymethylcellulose, sodium alginate
  • antiseptics e.g., benzyl alcohol, phenol
  • analgesics e.g., benzalkonium chloride, procaine hydrochloride
  • the acid secretion inhibitor is a proton pump inhibitor
  • the same methods as those described above are generally applicable, but it is preferable that the inhibitor be administered as granules with core coated with a dusting powder consisting of the inhibitor and low- substituted hydroxypropylcellulose by the method described in Japanese Patent Unexamined Publication No.301816/1988, or a solid composition stabilized by the method described in Japanese Patent Unexamined Publication No.163018/1991, i.e. , by using a stabilizer consisting of a basic inorganic salt of magnesium and/or calcium.
  • compositions for oral administration of the anti- Helicobacter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria of the present invention include tablets, pills, granules, powders , capsules , syrups , emulsions and suspensions , in the same manner as the above-described anti-Helicobacter agent.
  • Such compositions are produced by per se known methods, and lactose, starch, sucrose, magnesium stearate etc. are used as carriers or excipients.
  • compositions for non-oral administration can be prepared as suppositories, externally applied preparations etc.
  • suppositories include rectal suppositories and vaginal suppositories
  • externally applied preparations include ointments (including creams ) , vaginal preparations , nasal preparations and transdermal preparations .
  • suppositories can be obtained by preparing the composition of the present invention as oily or aqueous solid, semisolid or liquid suppositories.
  • the contents of the compound represented by the formula (I) or its salt, an antibiotic, and an antacid and/or an acid secretion inhibitor in the anti-Helicobacter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria of the present invention may be chosen as appropriate depending upon formulation, but the content of the compound represented by the formula (I) or its salt, for example, is about 1 to 20% by weight, preferably about 2 to 10% by weight .
  • the antibiotic content varying depending on the kinds of the antiboitic, is about 1 to 95% by weight, preferably about 5 to 90% by weight.
  • the antacid content is about 20 to 90% by weight, preferably about 30 to 80% by weight, more preferably about 50 to 70% by weight
  • the acid secretion inhibitor content is about 0.3 to 15% by weight, preferably about 1 to 10% by weight, more preferably about 2 to 5% by weight.
  • the content ratio of the compound represented by the formula (I) or its salt used, relative to the antacid and acid secretion inhibitor varies among individual combinations .
  • its content ratio is about 0.01 to 0.5 times (weight ratio) , preferably about 0.1 to 0.3 times (weight ratio), that of the antacid;
  • its content ratio is about 3 to 70 times (weight ratio), preferably about 7 to 30 times (weight ratio) , that of the acid secretion inhibitor.
  • the content ratio of the compound represented by the formula (I) or its salt used, relative to the antibiotic varies depending on the kinds of the antibiotic.
  • the content ratio of the compound represented by the formula ( I ) or its salt is about 0.01 to 10 times (weight ratio), preferably about 0.1 to 5 times (weight ratio), that of the antibiotic.
  • the compound represented by formula (I) or its salt, an antibiotic, and an antacid or acid secretion inhibitor prepared as separate preparations can be administered to the same subject simultaneously. They can also administered to the same subject at a time interval.
  • the administration frequencies of respective components may differ mutually.
  • the administration frequency of the acid secretion inhibitor is preferably 1 to 2 times/day, more preferably 1 time/day
  • the administration frequency of the compound represented by the formula (I) or its salt is preferably 1 to 5 times/day, more preferably 1 to 3 times/day.
  • the administration frequency of the antacid is preferably 1 to 5 times/day, more preferably 1 to 3 times/day.
  • the administration frequency of the antibiotic is preferably 1 to 6 times/day, more preferably 1 to 4 times/day.
  • the compound represented by the formula ( I ) or its salt be administered in a state in which acid secretion is suppressed by administration of acid secretion inhibitor (normally after 30 to 60 minutes following oral or non- oral administration of an acid secretion inhibitor) .
  • acid secretion is continuously suppressed by administration of an acid secretion inhibitor for consecutive days
  • the compound represented by the formula (I) or its salt can be administered simultaneously with the administration of an acid secretion inhibitor.
  • the dose of the anti-Helicobacter agent , pharmaceutical composition and pharmaceutical against Helicobacter bacteria of the present invention is chosen as appropriate, depending on type and symptoms of diseases , but the compound represented by the formula ( I ) or its salt is administered, per adult patient (50 kg) with gastric ulcer or duodenal ulcer, at about 0.1 to 10 g/day, preferably about 0.2 to 2 g/day for oral administration, and about 0.01 to 1 g/day, preferably about 0.02 to 0.5 g/day for non-oral administration.
  • the antibiotic is administered, per adult patient (50 kg) , at about 0.1 to 10 g/day, preferably about 0.2 to 2 g/day for oral administration, and about 0.01 to 1 g/day, preferably about 0.02 to 0.5 g/day for non-oral administration.
  • the antacid is administered, per adult patient (50 kg), at about 1 to 30 g/day, preferably about 2 to 5 g/day for oral administration
  • the acid secretion inhibitor is administered, per adult patient (50 kg), at about 10 to 200 mg/day, preferably about 30 to 60 mg/day for oral administration, and about 10 to 200 mg/day, preferably about 30 to 60 mg/day for non-oral administration.
  • the dose per administration of each component is determined in consideration of such daily doses, dosage forms etc.
  • the administration frequency is not limited, but preferably 1 to 5 times/day, more preferably 1 to 3 times/day.
  • the anti-Helicobacter agent. pharmaceutical composition and pharmaceutical against Helicobacter bacteria of the present invention are effective in the prevention or treatment of various digestive tract diseases (e.g., gastritis, duodenal ulcer, gastric ulcer, chronic gastritis) caused by bacteria showing toxic action in the digestive tract , particularly Helicobacter pylori .
  • various digestive tract diseases e.g., gastritis, duodenal ulcer, gastric ulcer, chronic gastritis
  • the anti-Helicobacter agent, pharmaceutical composition and pharmaceutical against Helicobacter bacteria of the present invention are applicable to the prevention or treatment of ulcers in animals (e.g. , mammals such as humans, dogs and cats) and particularly effective in the prevention or treatment of digestive ulcers in mammals, including humans.
  • Such digestive ulcers include gastric ulcer, duodenal ulcer, reflux esophagitis , stomal ulcer and acute and chronic gastritis .
  • the anti-Helicobacter agent, pharmaceutical composition and pharmaceutical against Helicobacter bacteria of the present invention may further contain mucosa-protecting antiulcer drugs etc.
  • Such mucosa-protecting antiulcer drugs include ( z ) - 7-[ (lR,2R,3R)-2-[ (E ) - ( 3R) -3-hydroxy-4 , 4-dimethyl-l- octenyl] -3-methyl-5-oxocyclopentyl] -5-heptenoic acid (trimoprostil, ulstar) , 1-butyric acid-7- (L-2- aminobutyric acid) -26-L-aspartic acid-27-L-valine-29-L- alanine calcitonin (Elcatonin) and 3-ethyl-7-isopropyl- 1-azurenesulfonate sodium (egualen sodium).
  • Such phosphorylamide derivatives include N- (diaminophosphinyl) -5-methyl-3- furancarboxamide or its salt, N- (diaminophosphinyl) - 3, 5-dimethyl-2-furancarboxamide or its salt, and N- ( diaminophosphinyl ) -3 , 5-dimethyl-2-thiophenecarboxamide or its salt.
  • These phosphorylamide derivatives possessing antibacterial activity based on anti-urease activity, especially antibacterial activity against Helicobacter bacteria, are effective in the prevention or treatment of digestive tract diseases of mammals such as gastritis, duodenal ulcer, gastric ulcer, and chronic gastritis, which are considered to be caused by Helicobacter bacteria, in the same manner as the compounds represented by the formula (I), (la) or (lb), or their salts.
  • room temperature means about 15 to 30 'C.
  • N- ( Diaminophosphinyl ) -3-pyridinecarboxamide 3-Pyridinecarboxamide (5 g) was suspended in chloroform (55 ml), and phosphorus pentachaloride (8.5 g) was added portionwise. The mixture was heated under reflux for 2 hours, and cooled to room temperature, and then formic acid (1.9 g) was added dropwise. The resulting mixture was stirred at room temperature for 20 hours, and then ammonia gas was introduced into the mixture for 1 hour. After the introduction, the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration, washed with water and dried. The resulting solid was recrystallized from water to give N-
  • Cinnamamide (10 g) was suspended in toluene (50 ml) , and phosphorus pentachloride (15.6 g) was added portionwise. The mixture was stirred at 70 " for 25 minutes, and cooled to room temperature and then formic acid (3.1 g) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours, and precipitated crystals were collected by filtration. The crystals were washed with toluene and dried to give 4.8 g of crystals . The crystals were dissolved in tetrahydrofuran ( 150 ml) , and ammonia gas was introduced under ice-cooling for 30 minutes . After the introduction, the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration. washed with water and dried. The resulting solid was recrystallized from methanol to give N- ( diaminophosphinyl ) cinnamamide (0.8 g) as colorless crystals . mp 176-178 .
  • N-(Diaminophosphinyl)cinnamamide (1 g) was dissolved in methanol (200 ml), and 10% Pd-C (wet) (0.4 g) was added. The mixture was hydrogenated at room temperature under atmospheric pressure for 30 minutes, and the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with diethyl ether and recrystallized from methanol to give the titled compound
  • the compound of Reference Example 80 was synthesized by the following method.
  • the compound of Reference Example 98 was synthesized by the following method. 3-Thiophenecarboxyalic acid ethyl ester (1.98 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.5 ml) was added under ice-cooling. The mixture was stirred at 10 °C for 30 minutes, and then 10% aqueous sodium thiosulfate (100 ml) was added. The resulting mixture was stirred at room temperature for 2 hours, and then extracted with diethyl ether .
  • the extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a mixture of 5-chloro-3-thiophenecarboxylic acid ethyl ester and 2 , 5-dichloro-3-thiophenecarboxylic acid ethyl ester.
  • This mixture was dissolved in a mixture of ethanol (15 ml) and tetrahydrofuran (15 ml) , and IN aqueous sodium hydroxide (20 ml) was added. The resulting mixture was stirred at room temperature for 2 hours , and then washed with diethyl ether.
  • the aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate .
  • the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of 5-chloro-3-thiophenecarboxylic acid and 2, 5-dichloro-3- thiophenecarboxylic acid (1.7 g) .
  • This mixture was suspended in toluene (15 ml) , and oxalyl chloride (1.56 ml) was added dropwise. Further, N,N- imethylformamide (1 drop) was added, and the reaction mixture was stirred at room temperature for 1 hour.
  • the reaction mixture was concentrated under reduce pressure , and the concentrate was dissolved in ethyl acetate ( 10 ml) .
  • the resulting solution was added dropwise to a mixture of 25% aqueous ammonia (16 ml) and ethyl acetate (70 ml) with stirring under ice- cooling.
  • the resulting mixture was stirred at room temperature for 10 minutes, and the organic layer was collected.
  • the aqueous layer was extracted with ethyl acetate.
  • the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography to give 5-chloro-3-thiophenecarboxamide (0.76 g). mp 138-139 * .
  • the extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product of 5-chloro-2-methyl-3- thiophenecarboxylic acid ethyl ester.
  • This crude product was dissolved in a mixture of ethanol (25 ml) and tetrahydrofuran (25 ml), and IN aqueous sodium hydroxide (50 ml) was added. The resulting mixture was stirred at 65 * C for 2 hours, and then washed with diethyl ether.
  • the aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate.
  • the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 5-chloro-2-methyl- 3-thiophenecarboxylic acid.
  • This crude product of 5- chloro-2-methyl-3-thiophenecarboxylic acid was suspended in toluene (50 ml) , and oxalyl chloride (4.6 ml) was added dropwise. Further, N,N-dimethylformamide (3 drops) was added, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the concentrate was dissolved in ethyl acetate (20 ml).
  • 2-Thiophenecarboxylic acid (3.84 g) was added to bromine (9.3 ml), and the mixture was stirred at room temperature for 15 hours. An excess amount of bromine was neutralized with aqueous ammonium carbonate, and then the mixture was acidified with IN hydrochloric acid. The precipitated crystals were collected by filtration, and dissolved in IN sodium hydroxide. The mixture was acidified with IN hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4,5- dibromo-2-thiophenecarboxylic acid (7.48 g) as crystals, mp 225-227 , .
  • Silver nitrate (1.7 g) was dissolved in water (40 ml), and sodium hydroxide (0.44 g) in water (1 ml) was added. Precipitated silver oxide was collected by filtration and suspended in 10% aqueous sodium hydroxide (20 ml). The resulting suspension was heated at 60 to 65 * C , and 4- bromo-2-thiophenecarbaldehyde (1.91 g) was added dropwise . The mixture was stirred for 30 minutes, and precipitates were removed by filtration. The filtrate was washed with diethyl ether, and IN hydrochloric acid was added to the aqueous layer to adjust the pH to 4.
  • 5-Nitro-2-thiophenecarbaldehyde (7.86 g) was dissolved in acetonitrile (50 ml), and sodium dihydrogen phosphate (1.6 g) in water (20 ml) and 30% aqueous hydrogen peroxide (5.9 ml) were added. Further, sodium chlorite (8.0 g) in water (70 ml) was added dropwise under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours , and then sodium thiosulfate was added to remove an excess amount of hydrogen peroxide . The mixture was alkalifled with IN sodium hydroxide and extracted with diethyl ether.
  • the aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate.
  • the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-nitro-2-thiophenecarboxylic acid (7.83 g) as crystals, mp 158-159 °C .
  • the aqueous layer was acidified with IN hydrochloric acid and extracted with diethyl ether.
  • the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-difluoromethyl-2-thiophenecarboxylic acid (2.13 g) as crystals, mp 111-112 V .
  • 3-Thiophenecarboxylic acid (3.84 g) was dissolved in tetrahydrofuran (50 ml) , and the mixture was cooled to -78 'C.
  • n-Butyllithium ( 1.6M in hexane, 41.3 ml) was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes.
  • Iodomethane (3.7 ml) in tetrahydrofuran (10 ml) was added dropwise.
  • the resulting mixture was heated to room temperature and stirred for 15 hours .
  • the mixture was poured into water and washed with diethyl ether.
  • the aqueous layer was acidified with IN hydrochloric acid, and extracted with ethyl acetate.
  • the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-methyl-3- thiophenecarboxylic acid (3.98 g) as crystals. p 71
  • 3-Bromo-2-thiophenecarboxylic acid methyl ester (7.74 g) was dissolved in a mixture of methanol (35 ml) and tetrahydrofuran (35 ml), and IN aqueous sodium hydroxide (53 ml) was added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-bromo-2-thiophenecarboxylic acid (7.05 g) as crystals, mp 200-201 °C .
  • the aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate.
  • the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the residue was recrystallized from ethyl acetate-diisopropyl ether to give 5- methanesulfonyl-2-thiphenecarboxylic acid (1.73 g) as crystals . mp 190-194 " (decmop.).
  • 3-Thiophenecarbaldehyde (22.43 g) was dissolved in toluene (200 ml) and N,N' -dimethylethylenediamine (22.3 ml) was added. The mixture was stirred for 16 hours with removing azeotropic water under reflux by Dean-stark trap. The reaction mixture was concentrated under reduced pressure and the residue was distilled under reduced pressure to give 1, 3-dimethyl-2- ( 3-thienyl)imidazolidine (5.88 g). bp 63-64 'C/O. ⁇ mmHg, mp 112-113 .
  • the reaction mixture was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a mixture of 2-formyl-3-thiophenecarboxylic acid and 5- formyl-3-thiophenecarboxylic acid (2.11 g) . This mixture was dissolved in N,N-dimethyIformamide (30 ml), and iodoethane (0.95 ml) and potassium carbonate (1.66 g) were added. The reaction mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether.
  • Difluoromethyl-3-thiophenecarboxylic acid ethyl ester was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml), and IN aqueous sodium hydroxide (7.8 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-difluoromethyl-3-thiophenecarboxylic acid (0.88 g) as crystals, mp 127-128 * .
  • the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of 3-methoxy-2- thiophenecarboxylic acid and 4-methoxy-2- thiophenecarboxylic acid (6.0 g) .
  • This mixture was dissolved in N,N-dimethylformamide (50 ml), and iodoethane (3.0 ml) and potassium carbonate (5.25 g) were added.
  • the mixture was stirred at room temperature for 15 hours , poured into water and extracted with diethyl ether.
  • the extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate .
  • the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methoxy-2-thiophenecarboxylaic acid (2.11 g) as crystals, mp 172-173 °C .
  • 3-Thiophenecarboxylic acid ethyl ester (1.56 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (5.36 g) was added. The mixture was stirred at room temperature for 4 hours, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred for 15 minutes and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2, 5-dichloro-3-thiophenecarboxylic acid ethyl ester (2.3 g) .
  • the filtrate was concentrated under reduced pressure to give a crude product of 2-bromo-3- thiophenecarbaldehyde (3.92 g) .
  • the crude product of 2-bromo-3-thiophenecarbaldehyde was dissolved in acetonitrile (50 ml) , and sodium dihydrogen phosphate (1.0 g) in water (15 ml) and 30% aqueous hydrogen peroxide (2.5 ml) were added. Further, sodium chlorite (2.7 g) in water (30 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours , alkalified with IN aqueous sodium hydroxide and washed with diethyl ether.
  • 3-Acetyl-2-thiophenecarboxylic acid (3.0 g) was dissolved in N,N-dimethylformamide (50 ml), and iodomethane (4.0 ml) and potassium carbonate (6.0 g) were added. The mixture was stirred at room temperature for 3 hours, poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-acetyl-2- thiophenecarboxylic acid methyl ester (3.07 g) as crystals . mp 59-60 C .
  • 5-Bromo-4-methyl-2-thiophenecarboxylic acid (3.33 g) was dissolved in dimethylformamide (50 ml) , and potassium carbonate (4.0 g) and iodomethane (4.0 ml) were added. The mixture was stirred at room temperature for 2 hours , diluted with ethyl acetate (200 ml), washed with IN hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-bromo-4- methyl-2-thiophenecarboxylic acid methyl ester (3.47 g) .
  • 5-Bromo-4-methyl-2- thiophenecarbaldehyde (6.18 g) was dissolved in acetonitrile ( 100 ml) , and sodium dihydrogen phosphate (1.3 g) in water (20 ml) and 30% aqueous hydrogen peroxide (3.8 ml) were added. Further sodium chlorite (4.07 g) in water (50 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours , alkalified with IN aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-bromo-4-methyl-2- thiophenecarboxylic acid (6.01 g) as crystals. mp 159 - 161 * C .
  • 5-Difluoromethyl-3-thiophenecarboxylic acid 5-Bromo-3-thiophenecarboxylic acid (4.14 g) was dissolved in tetrahydrofuran (50 ml) , and the mixture was cooled to -78 °C .
  • n-Butyllithium 1.6M in hexane , 27.5 ml was slowly added dropwise. The resulting mixture was stirred at the same temperature for 1 hour, and N,N- dimethylformamide (3.1 ml) was added. The mixture was warmed slowly to room temperature and concentrated under reduced pressure. The concentrate was acidified with IN hydrochloric acid and extracted with ethyl acetate.
  • the aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate.
  • the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5- difluoromethyl-3-thiophenecarboxylic acid (0.58 g) as crystals, mp 131-132 °C .
  • 5-Chloro-2-thiophenecarboxylic acid (6.50 g) was dissolved in N,N-dimethylformamide (30 ml), and ethyl iodide (3.2ml) and potassium carbonate (5.52 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-chloro-2- thiophenecarboxylic acid ethyl ester (5.27 g) .
  • the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 4-acetoxymethyl-3- bromothiophene .
  • This crude product was dissolved in tetrahydrofuran (50 ml), and IN aqueous sodium hydroxide (50 ml) and ethanol (20 ml) were added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhdrous magnesium sulfate and concentrated under reduced pressure.
  • 2-Methyl-3-furancarboxylic acid ethyl ester (10.5 g) was dissolved in acetonitrile (50 ml), and sulfuryl chloride (5.6 ml) was added under ice-cooling. The mixture was stirred at 10 "C for 30 minutes, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours , and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure.
  • the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of ethyl 5-chloro-4-methyl-3-thiophenecarboxylate and ethyl 2,5-dichloro-4-methyl-3-thiophenecarboxylate .
  • the mixture of ethyl 5-chloro-4-methyl-3- thiophenecarboxylate and ethyl 2, 5-dichloro-4-methyl-3- thiophenecarboxylate was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml) , and IN aqueous sodium hydroxide (20 ml) was added.
  • 5-Bromo-2-chloro-3-thiophenecarboxylic acid A mixture of 2-chloro-3-thiophenecarboxylic acid (2.44 g) , pyridinium bromide perbromide (5.33 g) and acetic acid (15 ml) was stirred at 40 * C for 4 hours and poured into ice water. Precipitated crystals were collected by filtration, dissolved in ethyl acetate and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to give 5-bromo-2- chloro-3-thiophenecarboxylic acid (2.81 g) as crystals, mp 159-160 " .
  • 3-Thiophenecarboxamide (3.18 g) was suspended in toluene (25 ml), and phosphorus pentachloride (5.21 g) was added portionwise. The mixture was heated to 65 'C and stirred for 3 hours and then cooled to room temperature. Formic acid (1.15 g) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Precipitated crystals were collected by filtration, washed with toluene and dried to give 5.43 g of crystals. The crystals were dissolved in tetrahydrofuran (100 ml) , and ammonia gas was introduced under ice-cooling for 30 minutes. The mixture was stirred at room temperature for 1 hour, and precipitate was collected by filtration, washed with water and dried. The obtained solid was recrystallized from methanol to give
  • N- (diaminophosphinyl) -3-thiophenecarboxamide (1.05 g) as colorless crystals. mp 269-278 "C- .
  • Example 4 N- (Diaminophosphinyl) -3-methyl-2-thiophenecarboxamide 3-Methyl-2-thiophenecarboxamide (4.24 g) was suspended in toluene (25 ml), and phosphorus pentachloride (6.25 g) was added portionwise. The mixture was heated to 65 * and stirred for 1 hour, and then cooled to room temperature.
  • Formic acid (1.38 g) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Hexane was added, and the resulting mixture was stirred for 30 minutes .
  • Precipitated crystals were collected by filtration, washed with toluene and dried to give 7.10 g of crystals.
  • the crystals were dissolved in tetrahydrofuran (100 ml), and ammonia gas was introduced under ice-cooling for 30 minutes .

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Abstract

A pharmaceutical composition comprising a compound represented by formula (I), wherein R represents an amino group which may be substituted, or a salt thereof, and an antibiotic, possesses excellent antibacterial activity, especially potent antibacterial activity against Helicobacter bacteria such as Helicobacter pylori, and is useful for prevention or treatment of digestive diseases caused by Helicobacter bacteria, solely or in combination with an antacid and/or an acid secretion inhibitor.

Description

DESCRIPTION PHARMACEUTICAL COMPOSITION CONTAINING A PHOSPHORYLAMIDE AND AN AYNTIBIOTIC
Technical Field 5 The present invention relates to a pharmaceutical composition. More specifically this invention relates to a pharmaceutical composition which comprises a phosphorylamide derivative possessing excellent antibacterial activity based on excellent anti-urease 10 activity, especially potent antibacterial activity against Helicobacter bacteria such as Helicobacter pylori , and an antibiotic.
Background Art
15 Among the bacteria showing toxic action, Helicobacter pylori which is a gram-negative , slightly aerobic bacterium belonging to the genus Helicobacter is considered to be a major cause of recurrent gastritis, duodenal ulcer, gastric ulcer etc.
20 Helicobacter bacteria, especially Helicobacter pylori , possessing potent urease activity, reportedly survive in the stomach, in which they neutralize strong acidity around them by producing ammonia from urea.
Various diseases caused by Helicobacter pylori are now
25 treated by double chemotherapy with a bismuth preparation and another antibiotic, or by triple chemotherapy with a bismuth preparation, metronidazole (US Patent No. 2,944,061) and either tetracycline (e.g., US Patent No. 2,712,517) or amoxicillin (US Patent No. 3,192,198). The
30 above Metronidazole, an imidazole antibiotic possessing anti- Helicobacter pylori activity, is used in combination with another antibiotic. These bismuth preparations, antibiotics, metronidazole etc. are administered orally.
However, these antibiotics must be administered at high
35 daily doses to maintain sufficient concentrations to inhibit Helicobacter pylori proliferation at the sites of their proliferatio , and this produces in many problems , including adverse effects such as vomiting and diarrhea. On the other hand, some phosphorylamide derivatives are known to possess anti-urease activity (e.g. , US Patent No. 3,317,637, USPatentNo.4,517,003, USPatentNo.4,528,020, EP-A 210703, US Patent No. 4,182,881, US Patent No. 4,221,730, Japanese Patent Unexamined Publication No. 99490/1983, Japanese Patent Examined Publication No. 7379/1967, USPatentNo.4 , 629 , 491 and J. Pharm. Sci., 189. 57 (1968)), but there is no disclosure that these phoaphorylamide derivatives exhibit antibacterial action, especially anti-J-Teli.cobacte.r pylori action, in vivo.
Disclosure of Invention
The present invention provides a pharmaceutical composition which comprises a phosphorylamide derivative or a salt thereof possessing excellent antibacterial activity, especially potent antibacterial activity against Helicobacter bacteria such as Helicobacter pylori , and an antibiotic.
After extensive investigation in view of the above problem, the present inventors found that a phosphorylamide derivative possessing anti-urease activity exhibits potent antibacterial activity against Helicobacter bacteria in vivo against bacteria (e.g. , Helicobacter bacteria such as Helicobacter pylori ) showing toxic action in the digestive tract . The inventors conducted further research based on this finding, and completed the present invention. Accordingly, the present invention relates to:
( 1 ) an anti-Helicobacter agent which comprises a compound represented by the formula ( I ) :
0
R—P—NH, (I)
NH, wherein R represents an amino group which may be substituted, or a salt thereof, and an antibiotic;
(2) a pharmaceutical composition which comprises a compound represented by the formula (la):
0 R,a—CONH—p-NH2 (la)
NH. wherein Rla represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or a salt thereof, and an antibiotic;
(3) a pharmaceutical composition which comprises a compound represented by the formula (lb):
0 Rlb—CONH—p-NH2 (lb) NH2 wherein Rlb represents a non-cyclic hydrocarbon group substituted by (i) a cyclic hydrocarbon group which may be substituted, (ii) a heterocyclic group which may be substituted, (iii) hydroxyl group substituted by a cyclic hydrocarbon group which may be substituted, (iv) hydroxyl group substituted by a heterocyclic group which may be substituted, (v) thiol group substituted by a cyclic hydrocarbon group which may be substituted, or (vi) thiol group substituted by a heterocyclic group which may be substituted, or a salt thereof, and an antibiotic;
(4) a pharmaceutical composition which comprises (i) the compound represented by the formula ( I ) , ( ii) an antibiotic , and (iii) an antacid and/or an acid secretion inhibitor; ( 5 ) a combination preparation which contains the compound represented by the formula (la) or a salt thereof, and antibiotic;
(6) a combination preparation which contains the compound represented by the formula (lb) or a salt thereof, and an antibiotic;
(7) a combination preparation which contains (i) the compound represented by the formula (I) or a salt thereof, (ii) an antibiotic, and (iii) an antacid and/or an acid secretion inhibitor;
(8) use of the compound represented by the formula (I) or a salt thereof, for the preparation of an anti -Helicobacter agent which is used in combination with an antibiotic;
(9) use of the compound represented by the formula (I) or a salt thereof, for the preparation of an anti -Helicobacter agent in combination with an antibiotic and an antacid and/or an acid secretion inhibitor;
(10) a method for eradicating Helicobacter from a mammal, which comprises administering to said mammal the compound represented by the formula (I) or a salt thereof, in combination with an antibiotic; and (11) a method for eradicating Helicobacter from a mammal, which comprises administering to said mammal the compound represented by the formula (I) or a salt thereof, in combination with an antibiotic and an antacid and/or an acid secretion inhibitor.
With respect to the above formulas , the substituents in the "amino group which may be substituted" represented by R are exemplified by ( 1 ) acyl groups , ( 2 ) carboxyl groups which may be esterified, and (3) hydrocarbon groups which may be substituted. The amino group may be substituted by 1 or 2, preferably 1 of these substituents, whether identical or not. The substituents are preferably an acyl group or a carboxyl group which may be esterified, more preferably an acyl group. (1) The acyl group as a substituent in the "amino group which may be substituted" represented by R, is exemplified by acyl groups derived from carboxylic acids, thiocarboxylic acids, sulfonic acids, sulfinic acids, carbamic acids, thiocarbamic acids etc., specifically those represented by the respective formulas : -COR1, -CSR2, -S02R3, -SOR4, -CONHR5 or -CSNHR6, wherein R1, R2, R3, R4, Rs and R6 independently represent a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, etc. Preferable acyl groups include those derived from carboxylic acids (-COR1) and those derived from sulfonic acids (-S02R3) , and those derived from carboxylic acids are more preferable.
The "hydrocarbon group which may be substituted" represented by R1, R2, R3, R4, R5 or R6, is exemplified by saturated or unsaturated aliphatic chain hydrocarbon groups , saturated or unsaturated alicyclic hydrocarbon groups and aryl groups . Such saturated aliphatic hydrocarbon groups include straight-chain or branched saturated aliphatic hydrocarbon groups having 1 to 10 carbon atoms (e.g. , C..10 alkyl groups such as methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, isohexyl, heptyl and octyl), and straight-chain or branched saturated aliphatic hydrocarbon groups having 1 to 6 carbon atoms are preferable.
Such unsaturated aliphatic hydrocarbon groups include straight-chain or branched unsaturated aliphatic hydrocarbon groups having 2 to 10 carbon atoms (e.g., C2_10 alkenyl groups such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3- methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2 , 4-hexadienyl, 5-hexenyl, 1-heptenyl and 1-octenyl; C2.10 alkynyl groups such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2- butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2 , 4-hexadiynyl, 5- hexynyl, 1-heptynyl and 1-octynyl) , and straight-chain or branched unsaturated aliphatic hydrocarbon groups having 2 to 6 carbon atoms are preferable.
Such saturated alicyclic hydrocarbon groups include saturated alicyclic hydrocarbon groups having 3 to 12 carbon atoms (e.g. , monocyclic or bicyclic C3.12 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , cycloheptyl , cyclooctyl , bicyclo [2.2.1]heptyl , bicyclo [2.2.2] octyl , bicyclo [3.2.1] octyl , bicyclo [3.2.2]nonyl , bicyclo[3.3. l]nonyl, bicyclo[ 4.2.1]nonyl and bicyclo[4.3.1]decyl) , and saturated alicyclic hydrocarbon groups having 3 to 6 carbon atoms are preferable.
Such unsaturated alicyclic hydrocarbon groups include unsaturated alicyclic hydrocarbon groups having 5 to 12 carbon atoms (e.g., C5.12 cycloalkenyl groups such as 1- cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1- cyclohexenyl , 2-cyclohexenyl, 3-cyclohexenyl, 1- cycloheptenyl , 2-cycloheptenyl, 3-cycloheptenyl, 2- cyclopenten-1-yl, 3-cyclopenten-l-yl, 2-cyclohexen-l-yl and 3-cyclohexen-l-yl; C5.12 cycloalkadienyl groups such as 2,4-cyclopentadien-l-yl, 2 , 4-cyclohexadien-l-yl and 2,5-cyclohexadien-l-yl and 2 , 4-cycloheptadienyl) .
The hydrocarbon group in the "hydrocarbon group which may be substituted" may be a saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms substituted by the above saturated or unsaturated alicyclic hydrocarbon group (e.g., C3.7 cycloalkyl-C^ alkyl groups and C5.7 cycloalkenyl-Cx.8 alkyl groups, such as cyclopropylmethyl , cyclopropylethyl , cyclobutylmethyl , cyclopentylmethyl , 2-cyclopentenylmethyl , 3-cyclopentenylmethyl , cyclohexylmethyl , 2-cyclohexenylmethyl, 3- cyclohexenyl ethyl , cyclohexylethyl , cyclohexylpropyl , cycloheptylmethyl and cycloheptylethyl) , or the like.
Such aryl groups include monocyclic or fused polycyclic aromatic hydrocarbon ring groups having 6 to 14 carbon atoms . Such aromatic hydrocarbon ring groups include phenyl, 1- or 2-naphthyl, 1-, 2- or 9-anthryl, 1-, 2-, 3-, 4- or 9-phenanthryl, 1-, 2-, 4-, 5- or 6-azulenyl and acenaphthylenyl , and C6.10 aryl groups such as phenyl, 1-naphthyl and 2-naphthyl are preferable.
The "hydrocarbon group which may be substituted" may have 1 to 3 optionally chosen substituents at any possible positions . Such substituents include ( 1 ) lower alkyl groups which may be substituted, (2) lower alkoxy groups which may be substituted, (3) aryl groups which may be substituted, (4) lower cycloalkyl or lower cycloalkenyl groups which may be substituted, (5) heterocyclic groups which may be substituted, (6) carboxyl groups which may be esterified, (7) carbamoyl groups which may be substituted, (8) amino groups which may be substituted, (9) hydroxyl groups which may be substituted, (10) thiol (mercapto) groups which may be substituted, (11) acyl groups, (12) halogens (e.g., fluorine, chlorine, bromine), (13) nitro, and (14) cyano. The lower alkyl group in the lower alkyl group ( 1 ) which may be substituted, is exemplified by C^ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and isohexyl. The lower alkoxy group in the lower alkoxy group ( 2 ) which may be substituted, is exemplified by C^ alkoxy groups such asmethoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy and isohexyloxy. Said lower alkyl group ( 1 ) and lower alkoxy group ( 2 ) may have 1 to 3 optionally chosen substituents at any possible positions. Such substituents include halogens (e.g. , fluorine , chlorine , bromine ) and lower ( C1.3 ) alkoxy groups (e.g., methoxy, ethoxy, propoxy). The aryl group in the aryl group (3) which may be substituted, is exemplified by C6.14 aryl groups such as phenyl , naphthyl , anthryl , phenanthryl and acenaphthylenyl , and phenyl, 1-naphthyl and 2-naphthyl are preferable among others . The cycloalkyl group in the lower cycloalkyl group (4) which may be substituted, is exemplified by C3.7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The cycloalkenyl group in the lower cycloalkenyl group (4) which may be substituted, is exemplified by C3.6 cycloalkenyl groups such as cyclopropenyl , cyclobutenyl , cyclopentenyl and cyclohexenyl .
Said aryl group ( 3 ) , said lower cycloalkyl group ( 4 ) or said lower cycloalkenyl group ( 4 ) may have 1 to 5 , preferably 1 to 3 , optionally chosen substituents at any possible positions, and these substituents include alkoxy groups (e.g. , C^j alkoxy groups such as methoxy, ethoxy and propoxy) , halogen atoms (e.g. , fluorine, chlorine, bromine, iodine) , alkyl groups (e.g. , Cx.3 alkyl groups such as methyl, ethyl and propyl ) , amino , nitro and cyano .
The heterocyclic group in the heterocyclic group ( 5 ) which may be substituted, is exemplified by aromatic heterocyclic groups and saturated or unsaturated non- aromatic heterocyclic groups (aliphatic heterocyclic groups) having at least 1 hetero atom selected from oxygen, sulfur and nitrogen as a ring-constituting atom (ring atom) , and aromatic heterocyclic groups are preferable. Such aromatic heterocyclic groups include 5- to 7-membered aromatic heterocyclic groups containing 1 sulfur atom, nitrogen atom or oxygen atom, 5- or 6-membered aromatic heterocyclic groups containing 2 to 4 nitrogen atoms, and 5- or 6-membered aromatic heterocyclic groups containing 1 or 2 nitrogen atoms and 1 sulfur atom or oxygen atom. These aromatic heterocyclic groups may be fused with a 6-membered ring containing 2 or fewer nitrogen atoms, a benzene ring, or a 5-membered ring containing 1 sulfur atom. Such aromatic heterocyclic groups include aromatic monocyclic heterocyclic groups (e.g. , furyl , thienyl , pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1 ,2,3-oxadiazolyl, 1,2,4- oxadiazolyl, 1,3, 4-oxadiazolyl, furazanyl, 1,2,3- thiadiazolyl, 1, 2,4-thiadiazolyl, 1 , 3 , 4-thiadiazolyl, 1,2, 3-triazolyl, 1 , 2 , 4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl) and aromatic fused heterocyclic groups (e.g., benzofuranyl, isobenzofuranyl, benzo[b] thienyl, indolyl, isoindolyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, 1,2- benzisoxazolyl, benzothiazolyl, 1 , 2-benzisothiazolyl, lH-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl , phthalazinyl, naphthyridinyl , purinyl, pteridinyl, carbazolyl, α -carbolinyl, β - carbolinyl, r -carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl , thianthrenyl , phenanthridinyl , phenanthrolinyl , indolizinyl, pyrrolo [1,2-b]pyridazinyl , pyrazolo [1,5-a] pyridyl , imidazo [ 1 , 2-a]pyridyl , imidazo [ 1 , 5-a] yridyl , imidazo [ 1 , 2-b]pyridaziny1 , imidazo [ 1 , 2-a]pyrimidinyl , l,2,4-triazolo[4,3-a]pyridyl and 1 , 2, 4-triazolo[ 4 , 3- b]pyridazinyl) , and preferable are furyl, fused furyl, thienyl, fused thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, azolyl and fused azolyl groups thereof. The azolyl groups include 5-membered aromatic heterocyclic groups containing 1 to 4 nitrogen atoms (e.g. , pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl) and 5-membered aromatic heterocyclic groups containing 1 or 2 nitrogen atoms and 1 sulfur atom or oxygen atom (e.g. , oxazolyl, isoxazolyl, thiazolyl, isothiazolyl), and the fused azolyl groups include groups formed by fusion of a benzene ring with a 5-membered aromatic heterocyclic ring containing 1 or 2 nitrogen atoms (e.g. , benzimidazolyl) and groups formed by fusion of a benzene ring with a 5-membered aromatic heterocyclic ring containing 1 nitrogen atom and 1 sulfur atom or oxygen atom (e.g., benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl) . Particular preferred are furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, benzofuranyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, benzo[b] thienyl, oxazolyl and isoxazolyl , and furyl and thienyl are more preferred.
Such non-aromatic heterocyclic groups include 5- to 7-membered non-aromatic heterocyclic groups containing 1 sulfur atom, nitrogen atom or oxygen atom, and 3- to 7- membered non-aromatic heterocyclic groups containing 1 nitrogen atom and 3 or fewer hetero atoms (e.g. , nitrogen, oxygen and sulfur atoms), such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl , tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl , morpholinyl, thiomorpholinyl , piperazinyl, homopiperidyl , pyrrolinyl and i idazolidinyl . These non-aromatic heterocyclic groups may be fused with a benzene ring, a 6-membered ring containing 2 or fewer nitrogen atoms, a 5-membered ring containing 1 sulfur atom, or the like. Such fused non- aromatic heterocyclic groups include chromanyl, isochromanyl, indolinyl, isoindolinyl, thiochromanyl and isothiochromanyl .
The heterocyclic groups may have 1 to 3 optionally chosen substituents at any possible positions . Such substituents include alkoxy groups (e.g., C^,, alkoxy groups such as methoxy, ethoxy and propoxy) which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine) , halogen atoms (e.g. , fluorine, chlorine, bromine, iodine) , alkyl groups (e.g. , C^,, alkyl groups such as methyl , ethyl and propyl) which may be substituted by 1 to 3 halogen atoms (e.g. fluorine, chlorine, bromine, iodine), aryl groups (e.g., C6.10 aryl groups such as phenyl, 1-naphthyl and 2-naphthyl), and nitro.
The carboxyl group ( 6 ) which may be esterified include carboxyl groups , (lower (C^) alkoxy) carbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl , isopropoxycarbonyl , butoxycarbonyl , isobutoxycarbonyl , tert-butoxycarbonyl, sec-butoxycarbonyl, pentyloxycarbonyl , isopentyloxycarbonyl , neopentyloxycarbonyl , tert-pentyloxycarbonyl, hexyloxycarbonyl) , (C6.10 aryl ) oxycarbonyl groups (e.g., phenoxycarbonyl , 1-naphthoxycarbonyl) and (C7.10 aralkyl ) oxycarbonyl group (e.g., (phenyl-Ci.., alkyl ) oxycarbonyl groups such as benzyloxycarbonyl etc . ) , and the carboxyl group , methoxycarbonyl and ethoxycarbonyl are preferred.
The substituents in said carbamoyl group (7) which may be substituted, or in the amino group (8) which may be substituted, are exemplified by lower ( C1.6 ) alkyl groups which may be substituted (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl), C3.β cycloalkyl groups which may be substituted (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), C6.10 aryl groups which may be substituted (e.g., phenyl, 1-naphthyl, 2- naphthyl), C7.12 aralkyl groups which may be substituted (e.g. , phenyl-Cx.4 alkyl groups such as benzyl and phenethyl , and naphthyl-C^ alkyl groups ) , and C6.10 arylsulfonyl groups which may be substituted (e.g., benzenesulfonyl, 1- naphthalenesulfonyl , 2-naphthalenesulfonyl) , and 1 or 2 of these substituents, whether identical or not, may be present. The substituents in such lower (CL alkyl groups which may be substituted, C3_6 cycloalkyl groups which may be substituted, C6.10 aryl groups which may be substituted, C7.12 aralkyl groups which may be substituted, and C6.10 arylsulfonyl groups which may be substituted, include halogens (e.g., fluorine, chlorine, bromine), alkoxy groups (e.g. , CL.4 alkoxy groups such as methoxy, ethoxy and propoxy) which may be substituted by 1 to 3 halogens, alkyl groups (e.g., Cx.4 alkyl groups such as methyl, ethyl and propyl) which may be substituted by 1 to 3 halogens, and nitro , and 1 to 5 of these substituents may be present . Also , the amino group which may be substituted, may form a cyclic amino group resulting from binding of two substituents on the nitrogen atom with the nitrogen atom, and such cyclic amino groups include 1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino and 1-piperazinyl.
The substituents in said hydroxyl group (9) which may be substituted, and the thiol group (10) which may be substituted, are exemplified by hydrocarbon groups which may be substituted, and heterocyclic groups which may be substituted. The "hydrocarbon group which may be substituted" is exemplified by the same groups as those mentioned in the "hydrocarbon group which may be substituted," represented by R1, R2, R3, R » Rs or R6 above, and preferable are lower (C^) alkyl groups which may be substituted (e.g. , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl , hexyl , isohexyl ) , C3.6 cycloalkyl groups which may be substituted (e.g., cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl ) , C6.10 aryl groups which may be substituted (e.g., phenyl, 1-naphthyl, 2-naphthyl), and C7.12 aralkyl groups which may be substituted (e.g., phenyl-Ci.,, alkyl groups such as benzyl and phenethyl, and naphthyl-C..2 alkyl groups) . These lower (C^) alkyl groups, C 3-β cycloalkyl groups, C6.10 aryl groups and C7.12 aralkyl groups may have 1 to 5 optionally chosen substituents at any possible positions, and these substituents include halogens (e.g. , fluorine , chlorine , bromine ) , alkoxy groups (e.g. , C._4 alkoxy groups such as methoxy, ethoxy and propoxy) which may be substituted by 1 to 3 halogens, alkyl groups (e.g., C^,, alkyl groups such as methyl, ethyl and propyl) which may be substituted by 1 to 3 halogens, nitro, amino and cyano. The "heterocyclic group which may be substituted" is exemplified by the same groups as those mentioned below in the "heterocyclic group which may be substituted" represented by R1, R2, R3, R4, R5 or R6. The acyl group (11) is exemplified by formyl groups, carbonyl groups substituted by a hydrocarbon group which may be substituted, sulfinyl groups substituted by a hydrocarbon group which may be substituted, and sulfonyl groups substituted by a hydrocarbon group which may be substituted. The " hydrocarbon group which may be substituted" is exemplified by the same groups as those mentioned in the " hydrocarbon group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above, and preferable are lower ( C1.6 ) alkyl groups which may be substituted, C3.6 cycloalkyl groups which may be substituted, C6.10 aryl groups (e.g. , phenyl , naphthyl ) which may be substituted, and C7.12 aralkyl groups (e.g. , phenyl-C1.4 alkyl groups, naphthyl-C^ alkyl groups) which may be substituted. Preferable acyl groups include formyl groups, (C^ alkyl)carbonyl groups, (C3.6 cycloalkyl) carbonyl groups, (cβ-ιo aryl ) carbonyl groups, (C7.12 aralkyl ) carbonyl groups, ( C___6 alkyl ) sulfinyl groups ( C3.6 cycloalkyl) sulfinyl groups , (C 6-ιo aryl)sulfinyl groups, (C7.12 aralkyl) sulfinyl groups, alkyl) sulfonyl groups, (C3.6 cycloalkyl ) sulfonyl groups, (C6.10 aryl ) sulfonyl groups and (C7.12 aralkyl ) sulfonyl groups. These acyl groups may have 1 to 5 optionally chosen substituents at any possible positions , and such substituents include halogens , alkoxy group (e.g. , C^,, alkoxy groups ) and alkyl groups (e.g. , C^ alkyl groups ) . The heterocyclic group in the "heterocyclic group which may be substituted" represented by R1, R2, R3, R4, R5 or R6, is exemplified by aromatic heterocyclic groups and saturated or unsaturated non-aromatic heterocyclic groups (aliphatic heterocyclic groups) having at least 1 hetero atom selected from atoms of oxygen, sulfur and nitrogen as a ring-constituting atom (ring atom), and aromatic heterocyclic groups are preferred.
Such aromatic heterocyclic groups include 5- to 7- membered aromatic heterocyclic groups containing 1 sulfur atom, nitrogen atom or oxygen atom, 5- or 6-membered aromatic heterocyclic groups containing 2 to 4 nitrogen atoms, and 5- or 6-membered aromatic heterocyclic groups containing 1 or 2 nitrogen atoms and 1 sulfur atom or oxygen atom. These aromatic heterocyclic groups may be fused with a 6-membered ring containing 2 or fewer nitrogen atoms, a benzene ring, or a 5-membered ring containing 1 sulfur atom. Such aromatic heterocyclic groups include aromatic monocyclic heterocyclic groups (e.g. , furyl , thienyl , pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2, 3-oxadiazolyl, 1,2,4- oxadiazolyl, 1 , 3 , 4-oxadiazolyl, furazanyl, 1,2,3- thiadiazolyl, 1 , 2 , 4-thiadiazolyl, 1 , 3 , 4-thiadiazolyl, 1,2, 3-triazolyl, 1 , 2 , 4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl) and aromatic fused heterocyclic groups (e.g., benzofuranyl , isobenzofuranyl , benzo[b] thienyl, indolyl, isoindolyl, lH-indazolyl, benzimidazolyl, benzoxazolyl, 1,2- benzisoxazolyl, benzothiazolyl, 1, 2-benzisothiazolyl, lH-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, a -carbolinyl, β - carbolinyl, r -carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl , thianthrenyl , phenanthridinyl , phenanthrolinyl , indolizinyl, pyrrolofl, 2-b]pyridazinyl, pyrazolof 1 , 5-a]pyridyl. imidazo [ 1 , 2-a]pyridyl, imidazo [ 1 , 5-a]pyridyl, imidazo [ 1 , 2-b] yridazinyl, imidazo [ 1, 2-a]pyrimidinyl, l,2,4-triazolo[4, 3-a]pyridyl and 1 , 2 , 4-triazolo[4 , 3- b]pyridazinyl ) , and furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, azolyl and fused ring groups thereof are preferred. Particularly furyl, thienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, benzofuranyl, benzimidazolyl, benzoxazolyl, 1,2- benzisoxazolyl, benzothiazolyl, benzo[b] thienyl, oxazolyl and isoxazolyl are preferred, and furyl an thienyl are more preferred.
Such non-aromatic heterocyclic groups include 5- to 7-membered non-aromatic heterocyclic groups containing 1 sulfur atom, nitrogen atom or oxygen atom, and 3- to 7- membered non-aromatic heterocyclic groups containing 1 nitrogen atom and 3 or fewer hetero atoms (e.g. , nitrogen, oxygen and sulfur atoms), such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl , tetrahydrofuryl , thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl , piperazinyl, homopiperidyl , pyrrolinyl and imidazolidinyl. These non-aromatic heterocyclic groups may be fused with a benzene ring, a 6-membered ring containing 2 or fewer nitrogen atoms, a 5-membered ring containing 1 sulfur atom, or the like. Such fused non- aromatic heterocyclic groups include chromanyl, isochromanyl, indolinyl, isoindolinyl, thiochromanyl and isothiochromanyl .
The heterocyclic group in the "heterocyclic group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above, may have 1 to 4, preferably 1 to 3, optionally chosen substituents at any possible positions . Such substituents include (i) lower alkyl groups which may be substituted, (ii) lower alkoxy groups which may be substituted, (iii) aryl groups which may be substituted, (iv) lower cycloalkyl or lower cycloalkenyl groups which may be substituted, (v) heterocyclic groups which may be substituted, (vi) carboxyl groups which may be esterified, (vii) carbamoyl groups which may be substituted, (viii) amino groups which may be substituted, (ix) hydroxyl groups which may be substituted, (x) thiol groups which may be substituted, (xi) acyl groups, (xii) halogens (e.g., fluorine, chlorine, bromine), (xiii) nitro, and (xiv) cyano. The lower alkyl group (i) which may be substituted, the lower alkoxy group (ii) which may be substituted, the aryl group (iii) which may be substituted, the lower cycloalkyl group or lower cycloalkenyl group (iv) which may be substituted, the heterocyclic group (v) which may be substituted, the carboxyl group (vi) which may be esterified, the carbamoyl group (vii) which may be substituted, the amino group (viii) which may be substituted, the hydroxyl group (ix) which may be substituted, the thiol group (x) which may be substituted, and the acyl group (xi), are exemplified by the same substituents as those mentioned in the substituents in the "heterocyclic group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above.
Particularly preferable for R1, R2, R3, R4, R5 and R6 are alkyl groups which may be substituted (preferably Cx.4 alkyl groups ) , alkenyl groups which may be substituted (preferably C2.4 alkenyl groups) , aryl groups which may be substituted (preferably C6.10 aryl groups such as phenyl, 1-naphthyl and 2-naphthyl) , and aromatic heterocyclic groups which may be substituted (preferably furyl, benzofuranyl , thienyl, benzothienyl, indolyl, isoindolyl, pyrazinyl, pyridyl, pyrimidinyl, azolyl, or fused azolyl) . These alkyl groups , alkenyl groups and aryl groups may have 1 to 3 (preferably 1 to 2) optionally chosen substituents at any possible positions. Preferable substituents include (1) lower (C^) alkyl groups (e.g., methyl, ethyl, propyl, isopropyl) which may be substituted by 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine), (2) lower (C^) alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy) , (3) C6.10 aryl groups (e.g., phenyl) which may be substituted by 1 to 3, preferably 1 to 2, substituents selected from halogens (e.g. fluorine, chlorine , bromine , iodine ) , amino , nitro and cyano , ( 4 ) C6.10 aryloxy groups (e.g. , phenoxy) which may be substituted by 1 to 3, preferably 1 to 2 , substituents selected from lower (C^) alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), halogens (e.g., fluorine, chlorine, bromine, iodine), nitro, cyano and amino, (5) heterocyclic groups (e.g., thienyl, benzimidazolyl, benzoxazolyl) which may be substituted by 1 to 3 , preferably 1 to 2 , halogens (e.g., fluorine , chlorine , bromine , iodine ) , ( 6 ) amino groups which may be substituted by a p-toluenesulfonyl group etc. , (7) hydroxyl groups, (8) thiol groups' which may be substituted by a C6.10 aryl groups (e.g. phenyl) which may have 1 to 3 (preferably 1 to 2) substituents selected from halogens and lower ( C1.3 ) alkoxy groups, or thiol groups which may be substituted by a heterocyclic group (e.g., benzoxazolyl, benzothiazolyl) which may have 1 to 3 (preferably 1 to 2) substituents selected from halogens and lower (C1 ) alkoxy groups, (9) halogens (e.g., fluorine, chlorine, bromine), (10) nitro, and (11) cyano.
These aromatic heterocyclic groups may have 1 to 3 (preferably 1 to 2) optionally chosen substituents at any possible positions. Preferable substituents include (1) lower (C^) alkyl groups which may be substituted by 1 to 3 halogens (e.g., methyl, ethyl, propyl, isopropyl, fluoromethyl , chloromethyl) , (2) C6.10 aryl groups (e.g., phenyl ) , ( 3 ) lower ( C._3 ) alkoxy groups which may be substituted by 1 to 3 halogens (e.g., methoxy, ethoxy. propoxy, iso-propoxy, fluoromethox , chloromethoxy) , (4) halogens (e.g., fluorine, chlorine, bromine), (5) nitro, ( 6 ) cyano , ( 7 ) ( lower ( C^ ) alkyl ) carbonyl groups and ( 8 ) (Ci.j alkyl ) sulfonyl groups.
(2) The "carboxyl group which may be esterified" as a substituent in the "amino group which may be substituted" represented by R, is exemplified by groups represented by the formula: -COOR7, wherein R7 represents a hydrogen atom, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted.
Said hydrocarbon group is exemplified by the same groups as those mentioned in the "hydrocarbon group which may be substituted" represented by R1, R2, R3, R4 , R5 or R6 above. Said hydrocarbon group may have 1 to 3 optionally chosen substituents at any possible positions . Such substituents include lower alkyl groups which may be substituted, lower alkoxy groups which may be substituted, aryl groups which may be substituted, lower cycloalkyl groups or lower cycloalkenyl groups which may be substituted, heterocyclic groups which may be substituted, carboxyl groups which may be esterified, carbamoyl groups which may be substituted, amino groups which may be substituted, hydroxyl groups which may be substituted, thiol groups which may be substituted, acyl groups, halogens (e.g., fluorine, chlorine , bromine ) , nitro , and cyano .
Such lower alkyl groups which may be substituted, lower alkoxy groups which may be substituted, aryl groups which may be substituted, lower cycloalkyl groups or lower cycloalkenyl groups which may be substituted, heterocyclic groups which may be substituted, carboxyl groups which may be esterified, carbamoyl groups which may be substituted, amino groups which may be substituted, hydroxyl groups which may be substituted, thiol groups which may be substituted, and acyl groups, are exemplified by the same substituents as those mentioned in the substituent in the "hydrocarbon group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above.
Said heterocyclic group is exemplified by the same groups as those mentioned in the heterocyclic group in the "heterocyclic group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above. Said heterocyclic group may have 1 to 3 optionally chosen substituents at any possible positions . Such substituents include lower alkyl groups which may be substituted, lower alkoxy groups which may be substituted, aryl groups which may be substituted, lower cycloalkyl groups or lower cycloalkenyl groups which may be substituted, heterocyclic groups which may be substituted, carboxyl groups which may be esterified, carbamoyl groups which may be substituted, amino groups which may be substituted, hydroxyl groups which may be substituted, thiol groups which may be substituted, acyl groups, halogens (e.g., fluorine, chlorine, bromine), nitro, and cyano.
Such lower alkyl groups which may be substituted, lower alkoxy groups which may be substituted, aryl groups which may be substituted, lower cycloalkyl groups or lower cycloalkenyl groups which may be substituted, heterocyclic groups which may be substituted, carboxyl groups which may be esterified, carbamoyl groups which may be substituted, amino groups which may be substituted, hydroxyl groups which may be substituted, thiol groups which may be substituted, and acyl groups, are exemplified by the same substituents as those mentioned in the substituent in the "hydrocarbon group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above.
Preferably groups for R7 include lower (C^) alkyl groups which may be substituted, lower (C3.6) cycloalkyl groups, C6.10 aryl groups, and C7.12 aralkyl groups, and lower (Cx_ 3) alkyl groups are more preferable.
Such lower (. C1.6 ) alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl and isohexyl. Such lower (C3.6) cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Such C6.10 aryl groups include phenyl, 1-naphthyl and 2-naphthyl.
Such C7.12 aralkyl groups include phenyl-Ci.,, alkyl groups such as benzyl and phenethyl , and naphthyl-C^ alkyl groups .
These lower (C^ alkyl groups, lower (C3.6) cycloalkyl groups , C6.10 aryl groups and C7.12 aralkyl groups may have 1 to 3 optionally chosen substituents at any possible positions, and these substituents include halogens (e.g., fluorine , chlorine , bromine ) .
(3) The "hydrocarbon group which may be substituted" as a substituent for the "amino group which may be substituted" represented by R, is exemplified by the same groups as those mentioned in the "hydrocarbon group which may be substituted" represented by R1, R2, R3, R , R5 or R6 above. Said hydrocarbon group may have 1 to 3 optionally chosen substituents at any possible positions . Such substituents include lower alkyl groups which may be substituted, lower alkoxy groups which may be substituted, aryl groups which may be substituted, lower cycloalkyl groups or lower cycloalkenyl groups which may be substituted, heterocyclic groups which may be substituted, carboxyl groups which may be esterified, carbamoyl groups which may be substituted, amino groups which may be substituted, hydroxyl groups which may be substituted, thiol groups which may be substituted, acyl groups, halogens (e.g., fluorine, chlorine , bromine ) , nitro , and cyano .
Such lower alkyl groups which may be substituted, lower alkoxy groups which may be substituted, aryl groups which may be substituted, lower cycloalkyl groups or lower cycloalkenyl groups which may be substituted, heterocyclic groups which may be substituted, carboxyl groups which may be esterified, carbamoyl groups which may be substituted, amino groups which may be substituted, hydroxyl groups which may be substituted, thiol groups which may be substituted, and acyl groups, are exemplified by the same substituents as those mentioned in the substituent in the "hydrocarbon group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above.
With respect to the formula (I) above, R is preferably an amino group which may be substituted by 1 or 2 , preferably 1 substituent selected from the group consisting of (1) an acyl group selected from -COR1, -CSR2, -S02R3, -SOR4, -CONHR5 and -CSNHR6 wherein each of R1, R2, R3, R4, Rs and R6 is (1-1) a hydrogen atom;
(1-2) a hydrocarbon group selected from the group consisting of: (a) an alkyl group having 1 to 10 carbon atom,
(b) an alkenyl group having 2 to 10 carbon atoms,
(c) an alkynyl group having 2 to 10 carbon atoms,
(d) a cycloalkyl group having 3 to 12 carbon atoms,
(e) a cycloalkenyl group having 5 to 12 carbon atoms, (f) a cycloalkadienyl group having 5 to 12 carbon atoms,
(g) a C3.7 cycloalkyl-Ci-a alkyl group, (h) a C5.7 cycloalkenyl-Ci.8 alkyl group, and (i) an aryl group having 6 to 10 carbon atoms, each of the substituents (a) to (i) may have 1 to 3 substituents selected from the group consisting of:
(i) a C1.6 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1-3 alkoxy group,
(ii) a C1_6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a Cx,3 alkoxy group,
(iii) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1.3 alkoxy group, halogen, a Cx.3 alkyl group, amino, nitro and cyano ,
(iv) a C3.7 cycloalkyl group or a C3.5 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C^ alkoxy group, halogen, a C^ alkyl group, amino, nitro and cyano, (v) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C._4 alkoxy group which may be substituted by halogen, halogen, a C^,, alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro, (vi) a carboxyl group, a (C^ alkoxy) carbonyl group, a (C6.10 aryl) oxycarbonyl group or a (C7.10 aralkyl) oxycarbonyl group ,
(vii) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a alkyl group, a C3.6 cycloalkyl group, a Cs.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, C^ alkyl group which may be substituted by halogen, and nitro,
(viii) an amino group which may be substituted by 1 or
2 substituents selected from the group consisting of a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a
C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C._4 alkoxy group which may be substituted by halogen, C^,, alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (ix) a hydroxyl group which may be substituted by a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said Cj.6 alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group which may be substituted by halogen, a C^ alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of
(ix-1) a C^ alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a CL.3 alkoxy group,
(ix-2) a Cx_6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^ alkoxy group,
(ix-3) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C^ alkoxy group, halogen, a C^., alkyl group, amino, nitro and cyano,
(ix-4) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C^-, alkoxy group, halogen, a C^., alkyl group, amino, nitro and cyano, (ix-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C._4 alkoxy group which may be substituted by halogen, halogen, a C1.4 alkyl group which may be substituted by halogen, a C6.X0 aryl group, and nitro, (ix-6) a carboxyl group, a { C1.6 alkoxy) carbonyl group, a (C 6-ιo aryl) oxycarbonyl group or a (C7.10 aralkyl ) oxycarbonyl group ,
(ix-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group. a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1.4 alkoxy group which may be substituted by halogen, Cx.4 alkyl group which may be substituted by halogen, and nitro, (ix-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a Cx.6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, C1- alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group , (ix-9) a hydroxyl group which may be substituted by a C..6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group , each of said alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C..4 alkoxy group which may be substituted by halogen, a C^ alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C._4 alkoxy group, halogen, a Ct.4 alkyl group and a C6.10 aryl group,
(ix-10) a thiol group which may be substituted by a C1.6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said C1-6 alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1- alkoxy group which may be substituted by halogen, a C^ alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a Cx.4 alkoxy group, halogen, a C^,, alkyl group and a C6.10 aryl group,
(ix-11) an acyl group selected from the group consisting formyl , a ( C^ alkyl ) carbonyl , a ( C3.6 cycloalkyl ) carbonyl , a (C6_10 aryl ) carbonyl , a (C7.12 aralkyl ) carbonyl , a (C^ alkyl ) sulfinyl , a (C3.6 cycloalkyl) sulfinyl, a (C6.10 aryl) sulfinyl, a (C7.12 aralkyl) sulfinyl, a ( Cx.6 alkyl ) sulfonyl , a (C3.6 cycloalkyl) sulfonyl, a (C6.10 aryl ) sulfonyl , and a (C7.12 aralkyl ) sulfonyl , each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C._4 alkoxy group and a CL.4 alkyl group,
(ix-12) halogen, (ix-13) nitro, and
(ix-14) cyano,
(x) a thiol group which may be substituted by a Cl.6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group , each of said C^ alkyl , C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C:.4 alkoxy group which may be substituted by halogen, a C^,, alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of
(x-1) a Ci.β alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^ alkoxy group,
(x-2) a Ci.s alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^ alkoxy group,
(x-3) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C._3 alkoxy group, halogen, a C^j alkyl group, amino, nitro and cyano ,
(x-4) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C^ alkoxy group, halogen, a Cx.3 alkyl group, amino, nitro and cyano,
(x-5) a heterocyclic group which may be substituted by
1 to 3 substituents selected from the group consisting of a Cx.4 alkoxy group which may be substituted by halogen, halogen, a Cx.4 alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro,
(x-6) a carboxyl group, a ( C1,6 alkoxy) carbonyl group, a (C6.10 aryl ) oxycarbonyl group or a (C7.10 aralkyl ) oxycarbonyl group , (x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, C^,, alkyl group which may be substituted by halogen, and nitro,
(x-8) an amino group which may be substituted by 1 or
2 substituents selected from the group consisting of a C._6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a
C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, Cx.4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino gorup,
(x-9) a hydroxyl group which may be substituted by a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said CLJ alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^., alkoxy group which may be substituted by halogen, a Ct.4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a Ct.4 alkoxy group, halogen, a C^,, alkyl group and a C6.10 aryl group,
(x-10) a thiol group which may be substituted by a Cx.6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a C._4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a Cx.4 alkoxy group, halogen, a C1_i alkyl group and a C6.10 aryl group,
(x-11) an acyl group selected from the group consisting of formyl, a (C^ alkyl ) carbonyl , a (C3.6 cycloalkyl ) carbonyl , a (C6.10 aryl ) carbonyl , a (C7.12 aralkyl) carbonyl , a (C1-6 alkyl ) sulfinyl , a (C3.6 cycloalkyl ) sulfinyl , a (C6.10 aryl) sulfinyl, a (C7.12 aralkyl ) sulfinyl , a (C^ alkyl ) sulfonyl , a (C3.6 cycloalkyl ) sulfonyl , a (C6_10 aryl ) sulfonyl , and a (C7.12 aralkyl ) sulfonyl , each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group and a C1-4 alkyl group,
(x-12) halogen, (x-13) nitro, and (x-14) cyano, (xi) an acyl group selected from the group consisting of formyl, a ( Cl_6 alkyl ) carbonyl , a (C3.6 cycloalkyl) carbonyl, a (C6.10 aryl ) carbonyl , a (C7.12 aralkyl ) carbonyl , a (Cx.6 alkyl) sulfinyl, a (C3.6 cycloalkyl ) sulfinyl , a (C6.10 aryl ) sulfinyl , a (C7.12 aralkyl ) sulfinyl , a (C^ alkyl) sulfonyl, a (C3.6 cycloalkyl) sulfonyl, a (C6.10 aryl ) sulfonyl , and a (C7_12 aralkyl ) sulfonyl , each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1_t alkoxy group and a Cx.4 alkyl group,
(xii) halogen,
(xiii) nitro, and
(xiv) cyano , or
(1-3) a heterocyclic group which may be substituted by 1 to 4 substituents selected from the group consisting of (i) a C1_6 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^ alkoxy group, (ii) a Cx.6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^ alkoxy group,
(iii) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a Cx.3 alkoxy group, halogen, a C..3 alkyl group, amino, nitro and cyano ,
(iv) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C^., alkoxy group, halogen , a C^., alkyl group , amino , nitro and cyano ,
(v) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a CL.4 alkoxy group which may be substituted by halogen, halogen, a C1-4 alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro, (vi) a carboxyl group, a (C^ alkoxy) carbonyl group, a (C6.10 aryl ) oxycarbonyl group or a (C7.10 aralkyl ) oxycarbonyl group,
(vii) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a Cj.6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C!_4 alkoxy group which may be substituted by halogen, C._4 alkyl group which may be substituted by halogen, and nitro,
(viii) an amino group which may be substituted by 1 or
2 substituents selected from the group consisting of a C .6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, C1-4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
(ix) a hydroxyl group which may be substituted by a C..6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said C1.6 alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1.4 alkoxy group which may be substituted by halogen, a C._4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of
(ix-1) a Ci.j alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^-, alkoxy group, (ix-2) a C^ alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1 alkoxy group,
(ix-3) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1,2 alkoxy group, halogen, a C^., alkyl group, amino, nitro and cyano,
(ix-4 ) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C._3 alkoxy group, halogen, a C^., alkyl group, amino, nitro and cyano,
(ix-5) a heterocyclic group which may be substituted by
1 to 3 substituents selected from the group consisting of a CL.4 alkoxy group which may be substituted by halogen, halogen, a Cx.4 alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro,
(ix-6) a carboxyl group, a (C._6 alkoxy) carbonyl group, a (C6.10 aryl ) oxycarbonyl group or a (C7.10 aralkyl )oxycarbonyl group ,
(ix-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, C._4 alkyl group which may be substituted by halogen, and nitro,
(ix-8) an amino group which may be substituted by 1 or
2 substituents selected from the group consisting of a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, C1_i alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group. (ix-9) a hydroxyl group which may be substituted by a Cx.6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said Cl.6 alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C^,, alkoxy group, halogen, a C^,, alkyl group and a C6.10 aryl group,
(ix-10) a thiol group which may be substituted by a C .6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said Ci.6 alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a Cx.4 alkoxy group, halogen, a C^,, alkyl group and a C6.10 aryl group, (ix-11) an acyl group selected from the group consisting of formyl, a { Cx.6 alkyl) carbonyl , a (C3.6 cycloalkyl) carbonyl , a (C6.10 aryl ) carbonyl , a (C7_12 aralkyl ) carbonyl , a (C^ alkyl) sulfinyl, a (C3.6 cycloalkyl ) sulfinyl , a (C6.10 aryl ) sulfinyl , a (C7.12 aralkyl ) sulfinyl , a (C..6 alkyl ) sulfonyl , a (C3.6 cycloalkyl ) sulfonyl , a (C6.10 aryl ) sulfonyl , and a (C7.12 aralkyl) sulfonyl , each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group and a C^,, alkyl group. (ix-12) halogen,
(ix-13) nitro, and
(ix-14) cyano,
(x) a thiol group which may be substituted by a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group , each of said C^ alkyl , C 3-β cycloalkyl, C6.10 aryl and C7.X2 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group which may be substituted by halogen, a C^,, alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of (x-1) a Cλ_6 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^., alkoxy group,
(x-2) a
Figure imgf000034_0001
alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a Cx_3 alkoxy group,
(x-3) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C^ alkoxy group, halogen, a C._3 alkyl group, amino, nitro and cyano , (x-4) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C^ alkoxy group, halogen, a C1 alkyl group, amino, nitro and cyano,
(x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a Cx. alkoxy group which may be substituted by halogen, halogen, a C^,, alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro,
(x-6) a carboxyl group, a (C._6 alkoxy) carbonyl group, a (C6.10 aryl ) oxycarbonyl group or a (C7.10 aralkyl) oxycarbonyl group ,
(x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a Cj.j alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a CL4 alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen, and nitro ,
(x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C 7-i2 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a C1.4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (x-9) a hydroxyl group which may be substituted by a C1,6 alkyl group, a C3„6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said alkyl, C3.6 cycloalky, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Ct.4 alkoxy group which may be substituted by halogen, a C^ alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstitruted or substituted by 1 to 3 substituents selected from the group consisting of a Cx.4 alkoxy group, halogen, a CL.4 alkyl group and a C6.10 aryl group,
(x-10) a thiol group which may be substituted by a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said C1,6 alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a C^,, alkyl group and a C6.10 aryl group,
(x-11) an acyl group selected from the group consisting of formyl, a ( C1.6 alkyl) carbonyl, a (C3.6 cycloalkyl ) carbonyl , a (C6.10 aryl ) carbonyl , a (C7.12 aralkyl)carbonyl , a ( C1_6 alkyl ) sulfinyl , a (C3.6 cycloalkyl) sulfinyl, a (C6.10 aryl ) sulfinyl , a (C7.12 aralkyl) sulfinyl, a (C^ alkyl) sulfonyl , a (C3.6 cycloalkyl) sulfonyl, a (C6.10 aryl ) sulfonyl , and a (C7.12 aralkyl) sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group and a Cx.4 alkyl group, (x-12) halogen,
(x-13) nitro, and (x-14) cyano,
(xi) an acyl group selected from the group consisting of formyl, a
Figure imgf000036_0001
alkyl)carbonyl, a (C3.6 cycloalkyl) carbonyl, a (C6.10 aryl) carbonyl , a (C7.12 aralkyl)carbonyl , a ( C1.6 alkyl)sulfinyl, a (C3.6 cycloalkyl) sulfinyl, a (C6.10 aryl)sulfinyl , a (C7.12 aralkyl ) sulfinyl , a ( C1.6 alkyl) sulfonyl, a (C3.6 cycloalkyl ) sulfonyl , a (C6.10 aryl ) sulfonyl , and a (C7.12 aralkyl) sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^., alkoxy group and a C1-4 alkyl group,
(xii) halogen, (xiii) nitro, and ( xiv ) cyano ,
( 2 ) an optionally esterified carboxyl group represented by the formula: -COOR7 wherein R7 is (2-1) a hydrogen atom;
(2-2) a hydrocarbon group selected from the group consisting of:
(a) an alkyl group having 1 to 10 carbon atoms,
(b) an alkenyl group having 2 to 10 carbon atoms, (c) an alkynyl group having 2 to 10 carbon atoms,
(d) a cycloalkyl group having 3 to 12 carbon atoms,
(e) a cycloalkenyl group having 5 to 12 carbon atoms,
(f ) a cycloalkadienyl group having 5 to 12 carbon atoms,
(g) a C3.7 cycloalkyl-C-L.g alkyl group, (h) a C5.7 cycloalkenyl-Ci.g alkyl group, and
(i) an aryl group having 6 to 10 carbon atoms, each of the substituents (a) to (i) may have 1 to 3 substituents selected from the group consisting of:
(i) a C1.6 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^., alkoxy group ,
(ii) a Ci.β alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^., alkoxy group, (iii) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C^ alkoxy group, halogen, a Cx.3 alkyl group, amino, nitro and cyano ,
(iv) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C^ alkoxy group, halogen, a Cx.3 alkyl group, amino, nitro and cyano,
(v) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a Ci.4 alkoxy group which may be substituted by halogen. halogen, a Cx.4 alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro,
(vi) a carboxyl group, a (C^ alkoxy) carbonyl group, a (C6.10 aryl ) oxycarbonyl group or a (C7.10 aralkyl ) oxycarbonyl grou ,
(vii) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1,6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a Cr.4 alkyl group which may be substituted by halogen, and nitro, (viii) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1.6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a C1→i alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
(ix) a hydroxyl group which may be substituted by a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said Ci.s alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^., alkoxy group which may be substituted by halogen, a C^ alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of (ix-1) a C1_& alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^j alkoxy group,
(ix-2) a Ci.6 alkoxy group which may be substituted by
1 to 3 substituents selected from the group consisting of halogen and a Cx_.3 alkoxy group,
(ix-3) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C^3 alkoxy group, halogen, a C^., alkyl group, amino, nitro and cyano, (ix-4 ) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C.3 alkoxy group, halogen, a Cx.3 alkyl group, amino, nitro and cyano,
(ix-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a Cx.4 alkoxy group which may be substituted by halogen, halogen, a Cx.4 alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro,
(ix-6) a carboxyl group, a (C1.6 alkoxy) carbonyl group, a (C6.10 aryl ) oxycarbonyl group or a (C7.10 aralkyl)oxycarbonyl group ,
(ix-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a Cn alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a C alkyl group which may be substituted by halogen, and nitro,
(ix-8) an amino group which may be substituted by 1 or
2 substituents selected from the group consisting of a C..6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a CL.4 alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group, (ix-9) a hydroxyl group which may be substituted by a C1.6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said C1.6 alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a C^.,, alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C^,, alkoxy group, halogen, a Cx.4 alkyl group and a C6.10 aryl group,
(ix-10) a thiol group which may be substituted by a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said Cj^j alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group which may be substituted by halogen, a C^,, alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1.Λ alkoxy group, halogen, a C^,, alkyl group and a C6.10 aryl group,
(ix-11) an acyl group selected from the group consisting formyl, a ( C1.6 alkyl ) carbonyl , a (C3.6 cycloalkyl) carbonyl, (C 6-ιo aryl ) carbonyl , a (C7.12 aralkyl ) carbonyl , a (C,.6 alkyl ) sulfinyl , a (C3.6 cycloalkyl ) sulfinyl , a (C6.10 aryl) sulfinyl , a (C7.12 aralkyl) sulfinyl, a (C^ alkyl) sulfonyl , a (C3.6 cycloalkyl ) sulfonyl , a (C6.10 aryl) sulfonyl , and a (C7.12 aralkyl ) sulfonyl , each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group and a Cx.4 alkyl group,
(ix-12) halogen, (ix-13) nitro, and
(ix-14) cyano,
(x) a thiol group which may be substituted by a Cx_6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group , each of said C^ alkyl , C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of
(x-1) a Ci.g alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C..3 alkoxy group,
(x-2) a Ci.β alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^ alkoxy group,
(x-3) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a Cx.3 alkoxy group , halogen , a C1-3 alkyl group , amino , nitro and cyano ,
(x-4) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C^., alkoxy group, halogen, a C1.3 alkyl group, amino, nitro and cyano,
(x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C!_4 alkoxy group which may be substituted by halogen, halogen, a Cx.4 alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro,
(x-6) a carboxyl group, a (C1-6 alkoxy) carbonyl group, a (C6.10 aryl)oxycarbonyl group or a (C7.10 aralkyl ) oxycarbonyl group , (x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a Cx_6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^__, alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen, and nitro,
(x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a x.6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
(x-9) a hydroxyl group which may be substituted by a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said Ci.β alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^ alkoxy group which may be substituted by halogen, a Cx_4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1- alkoxy group, halogen, a Cx.4 alkyl group and a C6.10 aryl group, (x-10) a thiol group which may be substituted by a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7-12 aralkyl group or a heterocyclic group, each of said C1.6 alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^ alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C^ alkoxy group, halogen, a C^,, alkyl group and a C6.10 aryl group,
(x-11) an acyl group selected from the group consisting of formyl, a (C^ alkyl ) carbonyl , a (C3.6 cycloalkyl ) carbonyl , a (C6.10 aryl ) carbonyl , a (C7.12 aralkyl) carbonyl , a { C1.6 alkyl ) sulfinyl , a (C3.6 cycloalkyl) sulfinyl, a (C6.10 aryl ) sulfinyl , a (C7.12 aralkyl) sulfinyl, a (C1-6 alkyl ) sulfonyl , a (C3.6 cycloalkyl) sulfonyl , a (C6.10 aryl) sulfonyl , and a (C7.12 aralkyl) sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group and a Cx.4 alkyl group,
(x-12) halogen, (x-13) nitro, and (x-14) cyano,
(xi) an acyl group selected from the consisting of formyl, a (C1,6 alkyl)carbonyl , a (C3.6 cycloalkyl)carbonyl , a (C6.10 aryl) carbonyl , a (C7.12 aralkyl) carbonyl , a (C^ alkyl) sulfinyl, a (C3.6 cycloalkyl ) sulfinyl , a (C6.10 aryl) sulfinyl , a (C7.12 aralkyl ) sulfinyl , a (C._6 alkyl ) sulfonyl , a (C3.6 cycloalkyl ) sulfonyl , a (C6.10 aryl) sulfonyl , and a (C7.12 aralkyl ) sulfonyl , each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Ci.4 alkoxy group and a C1-4 alkyl group. (xii) halogen,
(xiii) nitro, and
(xiv) cyano, or (2-3) a heterocyclic group which may be substituted by 1 to 4 substituents selected from the group consisting of
(i) a Ci.s alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^ alkoxy group,
(ii) a Cx_6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^ alkoxy group,
(iii) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a Cj_.3 alkoxy group, halogen, a C..., alkyl group, amino, nitro and cyano ,
(iv) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a Cx.3 alkoxy group, halogen, a C^., alkyl group, amino, nitro and cyano, (v) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C._4 alkoxy group which may be substituted by halogen, halogen, a CL.4 alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro, (vi) a carboxyl group, a ( C1.6 alkoxy)carbonyl group, a (C6.10 aryl ) oxycarbonyl group or a (C7_10 aralkyl ) oxycarbonyl group ,
(vii) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a Cx.6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Ci.4 alkoxy group which may be substituted by halogen, a C1.4 alkyl group which may be substituted by halogen, and nitro,
(viii) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C!.4 alkoxy group which may be substituted by halogen, a Cl.i alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
(ix) a hydroxyl group which may be substituted by a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said Cλ_6 alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstitued or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group which may be substituted by halogen, a C^,, alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of
(ix-1) a
Figure imgf000045_0001
alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^ alkoxy group, (ix-2) a C._6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^., alkoxy group,
(ix-3) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C^ alkoxy group, halogen, a Cx.3 alkyl group, amino, nitro and cyano,
(ix-4 ) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C^ alkoxy group, halogen, a C^., alkyl group, amino, nitro and cyano. (ix-5) a heterocyclic group which may be substituted by
1 to 3 substituents selected from the group consisting of a Cx.4 alkoxy group which may be substituted by halogen, halogen, a C^,, alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro,
(ix-6) a carboxyl group, a { C1_6 alkoxy) carbonyl group, a (C6.10 aryl ) oxycarbonyl group or a (C7.10 aralkyl )oxycarbonyl group ,
(ix-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a CL6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen, and nitro,
(ix-8) an amino group which may be substituted by 1 or
2 substituents selected from the group consisting of a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a
C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a CL4 alkoxy group which may be substituted by halogen, a C^,, alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
(ix-9) a hydroxyl group which may be substituted by a alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said C._6 alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C1, alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a Ct.4 alkoxy group, halogen, a Cx.4 alkyl group and a C6.10 aryl group,
(ix-10) a thiol group which may be substituted by a C._6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said Ci.g alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a Cx.4 alkoxy group, halogen, a C^,, alkyl group and a C6.10 aryl group,
(ix-11) an acyl group selected from the group consisting of formyl, a (C^ alkyl ) carbonyl , a (C3.6 cycloalkyl ) carbonyl , a (C6.10 aryl ) carbonyl , a (C7.12 aralkyl) carbonyl , a (C,^ alkyl) sulfinyl, a (C3.6 cycloalkyl ) sulfinyl , a (C6_10 aryl ) sulfinyl , a (C7.12 aralkyl) sulfinyl , a
Figure imgf000047_0001
alkyl) sulfonyl , a (C3.6 cycloalkyl ) sulfonyl , a (C6.10 aryl ) sulfonyl , and a (C7.12 aralkyl) sulfonyl , each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group and a Cx.4 alkyl group,
(ix-12) halogen, (ix-13) nitro, and (ix-14) cyano, (x) a thiol group which may be substituted by a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group , each of said C1.6 alkyl, 3-6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1.4 alkoxy group which may be substituted by halogen, a C1._l alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of
(x-1) a C1.6 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C._3 alkoxy group,
(x-2) a C1.6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^., alkoxy group,
(x-3) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C..3 alkoxy group, halogen, a Cx.3 alkyl group, amino, nitro and cyano ,
(x-4) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C^., alkoxy group, halogen , a C1_3 alkyl group , amino , nitro and cyano , (x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a Cx.4 alkoxy group which may be substituted by halogen, halogen, a C^,, alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro, (x-6) a carboxyl group, a (C._6 alkoxy) carbonyl group, a (C 6-ιo aryl)oxycarbonyl group or a (C7.10 aralkyl) oxycarbonyl group ,
(x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C _6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group which may be substituted by halogen, a C^ alkyl group which may be substituted by halogen, and nitro ,
(x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group which may be substituted by halogen, a Ci. alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
(x-9) a hydroxyl group which may be substituted by a C._6 alkyl group, a C3_6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said Ci-β alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a Cx.4 alkoxy group, halogen, a CL_4 alkyl group and a C6.10 aryl group,
(x-10) a thiol group which may be substituted by a Cx.6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a Cx.4 alkoxy group, halogen, a C1.4 alkyl group and a C6.10 aryl group, (x-11) an acyl group selected from the group consisting of formyl, a ( C1.6 alkyl ) carbonyl , a (C3.6 cycloalkyl ) carbonyl , a (C6.10 aryl ) carbonyl , a (C7_12 aralkyl) carbonyl , a { C1_e alkyl) sulfinyl, a (C.6 cycloalkyl) sulfinyl, a (C6.10 aryl) sulfinyl, a (C7.12 aralkyl ) sulfinyl , a (Ct.6 alkyl ) sulfonyl , a (C3.6 cycloalkyl) sulfonyl, a (C6.10 aryl) sulfonyl, and a (C7.12 aralkyl ) sulfonyl , each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group and a C1-4 alkyl group,
(x-12) halogen,
(x-13) nitro, and
(x-14) cyano,
(xi) an acyl group selected from the group consisting of formyl, a (C^ alkyl ) carbonyl , a (C3.6 cycloalkyl ) carbonyl , a (C6.xo aryl ) carbonyl , a (C7.X2 aralkyl ) carbonyl , a (C^ alkyl ) sulfinyl , a (C3.6 cycloalkyl) sulfinyl, a (C6.10 aryl ) sulfinyl , a (C7.12 aralkyl ) sulfinyl , a ( Cx_6 alkyl ) sulfonyl , a (C3.6 cycloalkyl) sulfonyl, a (C6.10 aryl) sulfonyl, a (C7.12 aralkyl ) sulfonyl , each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen , a Cx.4 alkoxy group and a C.„ alkyl group, (xii) halogen,
(xiii) nitro, and
(xiv) cyano, and (3) a hydrocarbon group selected from the group consisting of (a) an alkyl group having 1 to 10 carbon atoms,
(b) an alkenyl group having 2 to 10 carbon atoms,
(c) an alkynyl group having 2 to 10 carbon atoms,
(d) a cycloalkyl group having 3 to 12 carbon atoms,
(e) a cycloalkenyl group having 5 to 12 carbon atoms, (f) a cycloalkadienyl group having 5 to 12 carbon atoms. (g) a C3.7 cycloalkyl-Ci.g alkyl group, (h) a C5.7
Figure imgf000051_0001
alkyl group, and (i) an aryl group having 6 to 10 carbon atoms, each of the substituents (a) to (i) may have 1 to 3 substituents selected from the group consisting of:
(i) a Ci.β alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1 alkoxy group,
(ii) a C._6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a Cl.3 alkoxy group,
(iii) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C^ alkoxy group, halogen, a C^., alkyl group, amino, nitro and cyano ,
(iv) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C^ alkoxy group, halogen, a C._3 alkyl group, amino, nitro and cyano, (v) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a Ct.4 alkoxy group which may be substituted by halogen, halogen, a C._4 alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro, (vi) a carboxyl group, a (C._6 alkoxy) carbonyl group, a (C 6-ιo aryl)oxycarbonyl group or a (C7.10 aralkyl)oxycarbonyl group,
(vii) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a CLJ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen, and nitro ,
(viii) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a Cx.6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C._4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
(ix) a hydroxyl group which may be substituted by a C._6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said C^s alkyl, C3.6 cycloalkyl, C6,10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a C^,, alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of
(ix-1) a C1,6 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^ alkoxy group, (ix-2) a C^ alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^., alkoxy group,
(ix-3) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1.3 alkoxy group, halogen, a C^., alkyl group, amino, nitro and cyano,
(ix-4) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a Cl_3 alkoxy group, halogen, a C^., alkyl group, amino, nitro and cyano. (ix-5) a heterocyclic group which may be substituted by
1 to 3 substituents selected from the group consisting of a Cx.4 alkoxy group which may be substituted by halogen, halogen, a CL.4 alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro,
(ix-6) a carboxyl group, a (C^ alkoxy) carbonyl group, (C 6-ιo aryl ) oxycarbonyl group or a (C7.10 aralkyl) oxycarbonyl group ,
(ix-7) a carbaomoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C^s alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a CL_4 alkoxy group which may be substituted by halogen, a C..4 alkyl group which may be substituted by halogen, and nitro,
(ix-8) an amino group which may be substituted by 1 or
2 substituents selected from the group consisting of a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a
C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C._4 alkoxy group which may be substituted by halogen, a C._4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
(ix-9) a hydroxyl group which may be substituted by a Ci.β alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said C._6 alkyl, a C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group which may be substituted by halogen, a Cx_4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C^,, alkoxy group, halogen, a Cx.4 alkyl group and a C6.10 aryl group,
(ix-10) a thiol group which may be substituted by a C _6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said C^s alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^., alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a Cx.4 alkoxy group, halogen, a Cx.4 alkyl group and a C6.10 aryl group,
(ix-11) an acyl group selected from the group consisting of formyl, a ( C1_6 alkyl) carbonyl , a (C3.6 cycloalkyl ) carbonyl , a (C6.10 aryl) carbonyl , a (C7.12 aralkyl ) carbonyl , a ( C1_6 alkyl) sulfinyl, a (C3.6 cycloalkyl) sulfinyl, a (C6.10 aryl) sulfinyl, a (C7.12 aralkyl ) sulfinyl , a ( C1.6 alkyl) sulfonyl, a (C3.6 cycloalkyl) sulfonyl, a (C6.10 aryl ) sulfonyl , a (C7.12 aralkyl ) sulfonyl , each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group and a C^., alkyl group,
(ix-12) halogen, (ix-13) nitro, and (ix-14) cyano, (x) a thiol group which may be substituted by a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group , each of said C^ alkyl , C 3-6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of
(x-1) a Cx.6 alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1.3 alkoxy group,
(x-2) a Ci.β alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^ alkoxy group,
(x-3) a C5.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C^ alkoxy group, halogen, a C^., alkyl group, amino, nitro and cyano ,
(x-4) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C^ alkoxy group, halogen, a C^ alkyl group, amino, nitro and cyano, (x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a Cx.4 alkoxy group which may be substituted by halogen, halogen, a Cx.4 alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro, (x-6) a carboxyl group, a { C1.6 alkoxy)carbonyl group, a (C 6-ιo aryl )oxycarbonyl group or a (C7.10 aralkyl)oxycarbonyl group ,
(x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cj.4 alkoxy group which may be substituted by halogen, a Cx-4 alkyl group which may be substituted by halogen, and nitro ,
(x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a C^,, alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
(x-9) a hydroxyl group which may be substituted by a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said C._6 alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group which may be substituted by halogen, a C^,, alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C^,, alkoxy group, halogen, a Cx.4 alkyl group and a C6.10 aryl group,
(x-10) a thiol group which may be substituted by a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said C1_6 alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group which may be substituted by halogen, a C^, alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group, halogen, a Cx.4 alkyl group and a C6.10 aryl group, (x-11) an acyl group selected from the group consisting of formyl, a (C],_6 alkyl ) carbonyl , a (C3.6 cycloalkyl) carbonyl, a (C6.10 aryl ) carbonyl , a (C7.12 aralkyl ) carbonyl , a ( C1.6 alkyl) sulfinyl, a (C3.6 cycloalkyl) sulfinyl, a (C6.10 aryl) sulfinyl, a (C7.12 aralkyl ) sulfinyl , a (C^ alkyl) sulfonyl, a (C3.6 cycloalkyl) sulfonyl, a (C5.10 aryl) sulfonyl, a (C7.12 aralkyl ) sulfonyl , each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group and a Cx.4 alkyl group,
(x-12) halogen,
(x-13) nitro, and
(x-14) cyano,
(xi) an acyl group selected from the group consisting of formyl, a (C^ alkyl) carbonyl , a (C3.6 cycloalkyl ) carbonyl , a (C6.10 aryl ) carbonyl , a (C7.12 aralkyl ) carbonyl , a { C1.6 alkyl ) sulfinyl , a (C3.6 cycloalkyl) sulfinyl, a (C6.10 aryl ) sulfinyl , a (C7.12 aralkyl ) sulfinyl , a (C^ alkyl ) sulfonyl , a (C3.6 cycloalkyl ) sulfonyl , a (C6.10 aryl ) sulfonyl , and a (C7.12 aralkyl) sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx_4 alkoxy group and a C^,, alkyl group, (xii) halogen,
(xiii) nitro, and
(xiv) cyano .
With respect to the formula ( I ) above , R is preferably a group represented by the formula:
R^CO-NH- or
R3-S02-NH- wherein R1 and R3 have the same meanings as defined above, and the former (R^CO-NH-) is more preferable. Particularly preferred among the compound represented by the formula (I)is a compound represented by the formula (la):
0 R ,a—CONH—p-NH2 (la) NH2 wherein Rla represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or a compound represented by the formula (lb) :
0
R,—CONH—p-NH2 (1b) NH2 wherein Rlb represents a non-cyclic hydrocarbon group substituted by (i) a cyclic hydrocarbon group which may be substituted, (ii) a heterocyclic group which may be substituted, (iii) hydroxyl group substituted by a cyclic hydrocarbon group which may be substituted, (iv) hydroxyl group substituted by a heterocyclic group which may be substituted, (v) thiol group substituted by a cyclic hydrocarbon group which may be substituted, or (vi) thiol group substituted by a heterocyclic group which may be substituted.
Namely, R1 is preferably Rl or Rlb. R1 is more preferably Rla.
With respect to the formula (la), the cyclic hydrocarbon group in the "cyclic hydrocarbon group which may be substituted" represented by Rla, is exemplified by the saturated or unsaturated alicyclic hydocarbon groups and aryl groups (aromatic hydrocarbon groups) mentioned to exemplify the hydrocarbon group in the "hydrocarbon group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above, and preferable are C6.10 aryl groups such as phenyl, 1-naphthyl and 2-naphthyl. With respect to the formula (la) , the heterocyclic group in the "heterocyclic group which may be substituted" represented by Rla, is exemplified by the same groups as those mentioned in the heterocyclic group in the "heterocyclic group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above, and preferable are aromatic heterocyclic groups such as thienyl (e.g. , 2- or 3-thienyl) , furyl (2- or 3-furyl) , pyridyl (e.g. , 2-pyridyl, 3-pyridyl, 4-pyridyl) , azolyl [e.g., oxazolyl (e.g., 2-, 4- or 5- oxazolyl), isoxazolyl (e.g., 3-, 4- or 5-isoxazolyl) ] , fused ring groups of thienyl or azolyl [e.g. , benzothienyl (e.g., 2- or 3-benzo[b] thienyl) , benzoxazolyl (e.g., 2-, 5- or 6 -benz[d] oxazolyl ) , benzothiazolyl (e.g., 2- benzo[d] thiazolyl) ] and fused furanyl groups [e.g., benzofuranyl (e.g., 2- or 3-benzo[b]furanyl) ] , and 5- membered aromatic heterocyclic groups such as thienyl and furyl are more preferred.
The heterocyclic group in the "heterocyclic group which may be substituted" and the cyclic hydrocarbon group in the "cyclic hydrocarbon group which may be substituted" represented by Rla, may have 1 to 3, preferably 1 to 2 , optionally chosen substituents at any possible positions. These substituents are exemplified by the same groups as those mentioned in the substituent to the "heterocyclic group which may be substituted" represented by R1, R2, R3, R4, Rs or R6 above, and preferable are lower (Cx.3) alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, fluoromethyl, chloro ethyl) which may be substituted by 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine), C6.10 aryl groups (e.g., phenyl), lower (C1 ) alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, chloromethoxy) which may be substituted by 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine), halogens (e.g., fluorine, chlorine, bromine), nitro, cyano, ( l.6 alkyl ) carbonyl groups and (C^ alkyl ) sulfonyl groups.
The heterocyclic group which may be substituted for Rla, is exemplified by a heterocyclic group which may have 1 to 4 substituents selected from the group consisting of:
(i) a C^s alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C _3 alkoxy group,
(ii) a
Figure imgf000060_0001
alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^ alkoxy group,
(iii) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C^ alkoxy group, halogen, a C^., alkyl group, amino, nitro and cyano ,
(iv) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C._3 alkoxy group, halogen, a C^., alkyl group, amino, nitro and cyano, (v) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a Cj.4 alkoxy group which may be substituted by halogen, halogen, a CL.4 alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro, (vi) a carboxyl group, a ( C1.6 alkoxy) carbonyl group, a (C6.10 aryl ) oxycarbonyl group or a (C7.10 aralkyl )oxycarbonyl group ,
(vii) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C._6 alkyl group, a C3-6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen, and nitro ,
(viii) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a CL.6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Ci.4 alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
(ix) a hydroxyl group which may be substituted by a
Figure imgf000061_0001
alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of
(ix-1) a C^j alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^ alkoxy group, (ix-2) a C._6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^ alkoxy group,
(ix-3) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a Cx.3 alkoxy group, halogen, a C1.3 alkyl group, amino, nitro and cyano,
(ix-4 ) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a Cx.3 alkoxy group, halogen, a C._3 alkyl group, amino, nitro and cyano. (ix-5) a heterocyclic group which may be substituted by
1 to 3 substituents selected from the group consisting of a Cx.4 alkoxy group which may be substituted by halogen, halogen, a C^,, alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro,
(ix-6) a carboxyl group, a
Figure imgf000062_0001
alkoxy) carbonyl group, a (C6.10 aryl ) oxycarbonyl group or a (C7.10 aralkyl ) oxycarbonyl group ,
(ix-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C..6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Ci_4 alkoxy group which may be substituted by halogen, a C^,, alkyl group which may be substituted by halogen, and nitro ,
(ix-8) an amino group which may be substituted by 1 or
2 substituents selected from the group consisting of a
Figure imgf000062_0002
alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a
C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Ci.4 alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
(ix-9) a hydroxyl group which may be substituted by a Ci.g alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said alkyl, a C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a C1.4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a CL.4 alkoxy group, halogen, a Cx.4 alkyl group and a C6_10 aryl group,
(ix-10) a thiol group which may be substituted by a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said C-.g alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^., alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a Cx.4 alkoxy group, halogen, a Cx.4 alkyl group and a C6.10 aryl group,
(ix-11) an acyl group selected from the group consisting of formyl, a
Figure imgf000063_0001
alkyl)carbonyl , a (C3.6 cycloalkyl ) carbonyl , a (C6.10 aryl) carbonyl , a (C7.12 aralkyl ) carbonyl , a alkyl ) sulfinyl , a (C3.6 cycloalkyl ) sulfinyl , C6.10 aryl ) sulfinyl , a (C7.12 aralkyl) sulfinyl, a
Figure imgf000063_0002
alkyl ) sulfonyl , a (C3_6 cycloalkyl) sulfonyl, a (C6.10 aryl ) sulfonyl , a (C7.12 aralkyl) sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C._4 alkoxy group and a C..4 alkyl group,
(ix-12) halogen, (ix-13) nitro, and (ix-14) cyano, (x) a thiol group which may be substituted by a
Figure imgf000063_0003
alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said C._6 alkyl, C 3-6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group which may be substituted by halogen, a C._4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of
(x-1) a Ci.g alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a Cx.3 alkoxy group,
(x-2) a
Figure imgf000064_0001
alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^ alkoxy group,
(x-3) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a Cτ.3 alkoxy group, halogen, a C1_3 alkyl group, amino, nitro and cyano ,
(x-4) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C^ alkoxy group, halogen, a C^., alkyl group, amino, nitro and cyano, (x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a Ci.4 alkoxy group which may be substituted by halogen, halogen, a CL.4 alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro, (x-6) a carboxyl group, a (C..6 alkoxy) carbonyl group, a (C6.10 aryl)oxycarbonyl group or a (C7.10 aralkyl )oxycarbonyl group ,
(x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1.6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a C._4 alkyl group which may be substituted by halogen, and nitro ,
(x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C^g alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Ci.4 alkoxy group which may be substituted by halogen, a Ct.4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
(x-9) a hydroxyl group which may be substituted by a C^g alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said Ci.g alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^.,, alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C^,, alkoxy group, halogen, a C1-4 alkyl group and a C6.10 aryl group,
(x-10) a thiol group which may be substituted by a
Figure imgf000065_0001
alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said Cj.g alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C._4 alkoxy group which may be substituted by halogen, a C^ alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C^,, alkoxy group, halogen, a Cx.4 alkyl group and a C6.10 aryl group, (x-11) an acyl group selected from the group consisting of formyl, a
Figure imgf000066_0001
alkyl ) carbonyl , a (C3.6 cycloalkyl )carbonyl , a (C6.10 aryl )carbonyl , a (C7.12 aralkyl)carbonyl, a
Figure imgf000066_0002
alkyl) sulfinyl, a (C3.6 cycloalkyl) sulfinyl, a (C6.10 aryl) sulfinyl, a (C7.12 aralkyl ) sulfinyl , a (Cx.6 alkyl) sulfonyl, a (C3.6 cycloalkyl) sulfonyl, a (C6.10 aryl ) sulfonyl , a (C7.12 aralkyl ) sulfonyl , each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group and a Cx.4 alkyl group,
(x-12) halogen,
(x-13) nitro, and
(x-14) cyano,
(xi) an acyl group selected from the group consisting of formyl, a
Figure imgf000066_0003
alkyl) carbonyl , a (C3.6 cycloalkyl) carbonyl, a (C6.10 aryl ) carbonyl , a (C7.12 aralkyl)carbonyl , a alkyl) sulfinyl , a (C3.6 cycloalkyl ) sulfinyl , C6.10 aryl) sulfinyl, a (C7.12 aralkyl)sulfinyl , a
Figure imgf000066_0004
alkyl) sulfonyl, a (C3.6 cycloalkyl ) sulfonyl , a (C6.10 aryl ) sulfonyl , and a (C7.12 aralkyl) sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a CL.4 alkoxy group and a C^,, alkyl group, (xii) halogen,
(xiii) nitro, and
(xiv) cyano .
The cyclic hydrocarbon group which may be substituted for Rla, is exemplified by
(a) a cycloalkyl group having 3 to 12 carbon atoms,
(b) a cycloalkenyl group having 5 to 12 carbon atoms,
(c) a cycloalkadienyl group having 5 to 12 carbon atoms, or (d) an aryl group having 6 to 10 carbon atoms. each of which may have 1 to 3 substituents selected from the group consisting of:
(i) a
Figure imgf000067_0001
alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^ alkoxy group,
(ii) a Ci.g alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1.3 alkoxy group,
(iii) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a Cj^ alkoxy group, halogen, a C^ alkyl group, amino, nitro and cyano ,
(iv) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C^-j alkoxy group, halogen, a C^., alkyl group, amino, nitro and cyano,
(v) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a Cx.4 alkoxy group which may be substituted by halogen, halogen, a C^,, alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro,
(vi) a carboxyl group, a
Figure imgf000067_0002
alkoxy) carbonyl group, a (C6.10 aryl ) oxycarbonyl group or a (C7.10 aralkyl ) oxycarbonyl group , (vii) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a CL4 alkoxy group which may be substituted by halogen, a Ci.4 alkyl group which may be substituted by halogen, and nitro ,
(viii) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C^g alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Ci.4 alkoxy group which may be substituted by halogen, a C1-4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
(ix) a hydroxyl group which may be substituted by a
Figure imgf000068_0001
alkyl group, a C3.6 cycloalkyl group, a C5.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of
(ix-1) a
Figure imgf000068_0002
alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1.3 alkoxy group,
(ix-2) a Cx.6 alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a Cj.., alkoxy group, (ix-3) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C1-3 alkoxy group, halogen, a C^., alkyl group, amino, nitro and cyano,
(ix-4 ) a C3.7 cycloalkyl group or a C3,6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C^ alkoxy group, halogen, a C1.3 alkyl group, amino, nitro and cyano,
(ix-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C._4 alkoxy group which may be substituted by halogen. halogen, a Cx.4 alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro,
(ix-6) a carboxyl group, a
Figure imgf000069_0001
alkoxy) carbonyl group, a (C6.10 aryl ) oxycarbonyl group or a (C7.10 aralkyl ) oxycarbonyl group,
(ix-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C-.g alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1_i alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen, and nitro , (ix-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a C1.6 alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7_12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a Cj.4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
(ix-9) a hydroxyl group which may be substituted by a alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, 7.I2 aralkyl group or a heterocyclic group, each of said
Figure imgf000069_0002
alkyl, a C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C:.4 alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1.i alkoxy group, halogen, a C^,, alkyl group and a C6.10 aryl group. (ix-10) a thiol group which may be substituted by a C^ alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^.,, alkoxy group which may be substituted by halogen, a Cx_4 alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C1._i alkoxy group, halogen, a Cx.4 alkyl group and a C6.10 aryl group,
(ix-11) an acyl group selected from the group consisting of formyl, a
Figure imgf000070_0001
alkyl ) carbonyl , a (C3.6 cycloalkyl ) carbonyl , a (C6.10 aryl ) carbonyl , a (C7.12 aralkyl) carbonyl , a alkyl) sulfinyl, a (C3.6 cycloalkyl) sulfinyl , C6.10 aryl) sulfinyl , a (C7.12 aralkyl) sulfinyl, a
Figure imgf000070_0002
alkyl) sulfonyl, a (C3.6 cycloalkyl) sulfonyl, a (C6.10 aryl ) sulfonyl , a (C7.12 aralkyl) sulfonyl, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group and a C._4 alkyl group,
(ix-12) halogen, (ix-13) nitro, and (ix-14) cyano,
(x) a thiol group which may be substituted by a alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl grou C7.12 aralkyl group or a heterocyclic group , each of said
Figure imgf000070_0003
alkyl , C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a C^., alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 4 substituents selected from the group consisting of
(x-1) a
Figure imgf000071_0001
alkyl group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C1 alkoxy group,
(x-2) a
Figure imgf000071_0002
alkoxy group which may be substituted by 1 to 3 substituents selected from the group consisting of halogen and a C^ alkoxy group,
(x-3) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C^ alkoxy group, halogen, a C^j alkyl group, amino, nitro and cyano ,
(x-4) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C^ alkoxy group, halogen, a Cx_3 alkyl group, amino, nitro and cyano,
(x-5) a heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C1-4 alkoxy group which may be substituted by halogen, halogen, a C1.4 alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro,
(x-6) a carboxyl group, a
Figure imgf000071_0003
alkoxy)carbonyl group, a (C6.10 aryl ) oxycarbonyl group or a (C7.10 aralkyl)oxycarbonyl group , (x-7) a carbamoyl group which may be substituted by 1 or 2 substituents selected from the group consisting of a C-.g alkyl group , a C3.6 cycloalkyl group , a C6.10 aryl group , a C7.12 aralkyl group and a C6.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Cx.4 alkoxy group which may be substituted by halogen, a Cx.4 alkyl group which may be substituted by halogen, and nitro,
(x-8) an amino group which may be substituted by 1 or 2 substituents selected from the group consisting of a alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group and a C5.10 arylsulfonyl group, each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a Ci.-, alkoxy group which may be substituted by halogen, a Cr.4 alkyl group which may be substituted by halogen, and nitro, or a cyclic amino group,
(x-9) a hydroxyl group which may be substituted by a C._6 alkyl group, a C3.6 cycloalkyl group, a C6_.0 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said C1,6 alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1. alkoxy group which may be substituted by halogen, a CX_Λ alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C^,, alkoxy group, halogen, a C^,, alkyl group and a C6.10 aryl group, (x-10) a thiol group which may be substituted by a
Figure imgf000072_0001
alkyl group, a C3.6 cycloalkyl group, a C6.10 aryl group, a C7.12 aralkyl group or a heterocyclic group, each of said Cx.6 alkyl, C3.6 cycloalkyl, C6.10 aryl and C7.12 aralkyl groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group which may be substituted by halogen, a C1._i alkyl group which may be substituted by halogen , nitro , amino and cyano , and said heterocyclic group being unsubstituted or substituted by 1 to 3 substituents selected from the group consisting of a C^ alkoxy group, halogen, a C^,, alkyl group and a C6_.0 aryl group,
(x-11) an acyl group selected from the group consisting of formyl, a
Figure imgf000072_0002
alkyl)carbonyl, a (C3.6 cycloalkyl ) carbonyl , a (C6.10 aryl ) carbonyl , a (C7.12 aralkyl)carbonyl , a (Cj.g alkyl) sulfinyl, a (C3.6 cycloalkyl) sulfinyl, a (C6.10 aryl)sulfinyl , a (C7.12 aralkyl) sulfinyl, a
Figure imgf000073_0001
alkyl) sulfonyl, a (C3.6 cycloalkyl) sulfonyl, a (C6.10 aryl ) sulfonyl , a (C7.12 aralkyl ) sulfonyl , each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C^,, alkoxy group and a C^., alkyl group,
(x-12) halogen, (x-13) nitro, and (x-14) cyano,
(xi) an acyl group selected from the group consisting of formyl, a
Figure imgf000073_0002
alkyl ) carbonyl , a (C3.6 cycloalkyl) carbonyl, a (C6.10 aryl) carbonyl , a (C7.12 aralkyl ) carbonyl , a alkyl ) sulfinyl , a (C3.6 cycloalkyl) sulfinyl , C6.10 aryl) sulfinyl , a (C7.12 aralkyl ) sulfinyl , a
Figure imgf000073_0003
alkyl ) sulfonyl , a (C3.6 cycloalkyl ) sulfonyl , a (C6.xo aryl ) sulfonyl , and a (C7_12 aralkyl ) sulfonyl , each of said groups being unsubstituted or substituted by 1 to 5 substituents selected from the group consisting of halogen, a C1-4 alkoxy group and a Cj.4 alkyl group,
(xii) halogen, (xiii) nitro, and (xiv) cyano .
With respect to the formula (la), Rla is preferably "an aromaic hydrocarbon group or an aromatic heterocyclic group , each of which may be substituted", more preferably "a 5-membered aromatic heterocyclic group which may be substituted" . Examples of such groups include a thienyl group or a furyl group, each of which may be substituted by 1 to 3, preferably 1 or 2, substituents selected from the group consisting of a C1.3 alkyl group which may be substituted by 1 to 3 halogen, a Cx_3 alkoxy group, halogen, nitro, cyano, a (Cj.g alkyl ) carbonyl , and
Figure imgf000073_0004
alkyl) sulfonyl, preferably a thienyl group which may be substituted by 1 or 2 C1 alkyl groups or a furyl group which may be substituted by 1 or 2 Cλ_3 alkyl groups.
Rl is particularly preferably a thienyl group or a furyl group each of which is substituted by 1 or 2 C1.3 alkyl groups .
The non-cyclic hydrocarbon group in the "non-cyclic hydrocarbon group substituted by (i) a cyclic hydrocarbon group which may be substituted, (ii) a heterocyclic group which may be substituted, (iii) hydroxyl group substituted by a cyclic hydrocarbon group which may be substituted, (iv) hydroxyl group substituted by a heterocyclic group which may be substituted, (v) thiol group substituted by a cyclic hydrocarbon group which may be substituted, or (vi) thiol group substituted by a heterocyclic group which may be substituted" represented by Rlb above, is exemplified by the sturated or unsaturated aliphatic chain hydrocarbon groups mentioned to exemplify the hydrocarbon group in the "hydrocarbon group which may be substituted" represented by R1, R2, R3, R4, Rs or R6 above. Said non-cyclic hydrocarbon group has , at any possible positions , at least 1 , preferably 1 or 2, of (i) a cyclic hydrocarbon group which may be substituted, (ii) a heterocyclic group which may be substituted, (iii) hydroxyl group substituted by a cyclic hydrocarbon group which may be substituted, (iv) hydroxyl group substituted by a heterocyclic group which may be substituted, (v) thiol group substituted by a cyclic hydrocarbon group which may be substituted, and/or (vi) thiol group substituted by a heterocyclic group which may be substituted.
Said "cyclic hydrocarbon group which may be substituted" (i) is exemplified by the "aryl groups which may be substituted" and the "lower cycloalkyl or lower cycloalkenyl groups which may be substituted" mentioned to exemplify the substituents of the hydrocarbon group in the "hydrocarbon group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above.
Said "heterocyclic group which may be substituted" (ii) is exemplified by the same groups as the "heterocyclic group which may be substituted" mentioned to exemplify the substituents in the "hydrocarbon group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above. The cyclic hydrocarbon group in said "hydroxyl group substituted by a cyclic hydrocarbon group which may be substituted" (iii) and "thiol group substituted by a cyclic hydrocarbon group which may be substituted" (v) is exemplified by the saturated or unsaturated alicyclic hydrocarbon groups and aryl groups (aromatic hydrocarbon groups ) mentioned to exemplify the hydrocarbon group in the "hydrocarbon group which may be substituted" represented by R1, R\ R3, R4, R5 or R6 above.
The heterocyclic group in said "hydroxyl group substituted by a heterocyclic group which may be substituted" (iv) and "thiol group substituted by a heterocyclic group which may be substituted" (vi) is exemplified by the same groups as the heterocyclic group mentioned to exemplify the "heterocyclic group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above. Said "alicyclic hydrocarbon group" may have 1 to 5, preferably 1 to 3, optionally chosen substituents at any possible positions . Such substituents are exemplified by the same groups as those mentioned to exemplify the substituents of the hydrocarbon group in the "hydrocarbon group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above, and preferably exemplified by lower (C1 ) alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, fluoromethyl , chloromethyl ) which may be substituted by 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine), lower (C._3) alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, chloromethoxy) which may be substituted by 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine), halogens (e.g., fluorine, chlorine, bromine ) , nitro , amino and cyano .
Said "heterocyclic group" may have 1 to 4, preferably 1 to 3, optionally chosen substituents at any possible positions. Such substituents are exemplified by the same groups as those mentioned to exemplify the substituents of the heterocyclic group in the "heterocyclic group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above, and preferably exemplified by lower ( C1-4 ) alkyl groups (e.g. , methyl, ethyl, propyl, isopropyl), lower (Cx.4) alkoxy groups (e.g., methoxy, ethoxy, propoxy, isopropoxy), halogens (e.g., fluorine, chlorine, bromine) and C6.10 aryl groups (e.g. , phenyl) . Said non-cyclic hydrocarbon group may have optionally chosen substituents at any possible positions, in addition to the above "cyclic hydrocarbon group which may be substituted" , "heterocyclic group which may be substituted", and the like, but the total number of substituents in said non-cyclic hydrocarbon group is preferably 1 to 3 , more preferably 1 to 2. Such substituents are exemplified by the same groups as those mentioned in the substituent in the "hydrocarbon group which may be substituted" represented by R1, R2, R3, R4, R5 or R6 above.
The cyclic hydrocarbon group in the "non-cyclic hydrocarbon group substituted by a cyclic hydrocarbon group which may be substituted" for Rlb, is preferably exemplified by aryl groups (C1.4aryl groups such as phenyl, 1-naphthyl and 2-naphthyl), cycloalkyl groups having 3 to 7 carbon atoms , or cycloalkenyl groups having 3 to 6 carbon atoms . The cyclic hydrocarbon group may have 1 to 5, preferably 1 to 3, substituents. Such substituents are preferably exemplified by C^ alkoxy groups , halogens , C .3 alkyl groups , amino, nitro and cyano. Rb is preferably a non-cyclic hydrocarbon group substituted by a heterocyclic group [e.g., an aromatic heterocyclic group such as thienyl (e.g. , 2- or 3-thienyl) , furyl (e.g., 2- or 3-furyl) , azolyl [e.g., oxazolyl (e.g., 2-, 4- or 5-oxazolyl), isoxazolyl (e.g., 3-, 4- or 5- isoxazolyl) ] , fused ring groups of thienyl, furyl or azolyl [benzothienyl (e.g., 2- or 3-benzo[b] thienyl) , benzofuranyl (e.g. , 2- or 3-benzo[b]furanyl) , benzoxazolyl (e.g., 2-, 5- or 6-benz[d] oxazolyl) , benzisoxazolyl (e.g. , 3-, 4- or 5-benz [d] isoxazolyl ) , benzothiazolyl (e.g., 2-benzo[d] thiazolyl) , benzimidazolyl (e.g., 1- benz [d] imidazolyl) ] ] which may be substituted, more preferably a non-cyclic hydrocarbon group substituted by a thienyl or furyl group which may be substituted. Said non-cyclic hydrocarbon group is preferably exemplified by C-.10 alkyl groups (preferably C-^ alkyl groups such as methyl, ethyl and propyl), C2.10 alkenyl groups (preferably C2.4 alkenyl groups such as ethenyl) and C2.10 alkynyl groups (preferably C2.4 alkynyl groups such as ethynyl) . Said aromatic heterocyclic group may have 1 to 3 optionally chosen substituents at any possible positions. Such substituents are preferably exemplified by lower (C1 ) alkyl groups (e.g., methyl, ethyl, propyl, isopropyl, fluoromethyl , chloromethyl) which may be substituted by 1 to 3 halogens (e.g. , fluorine, chlorine, bromine, iodine), C 6-ιo aryl groups (e.g., phenyl), lower (Cx.3) alkoxy groups (e.g. , methoxy, ethoxy, propoxy, isopropoxy, fluoromethoxy, chloromethoxy) which may be substituted by 1 to 3 halogens (e.g., fluorine, chlorine, bromine, iodine), halogens (e.g., fluorine, chlorine, bromine, iodine), and nitro. The non-cyclic hydrocarbon group may have a substituent such as a cyano group in addition to the "cyclic hydrocarbon group which may be substituted" , "heterocyclic group which may be substituted", and the like. Rb is preferably exemplified by (a) C^,, alkyl groups, (b) C2.10 alkenyl groups and (c) C2.10 alkynyl groups, each of which may have 1 to 3 substituents selected from the group consisting of:
(i) a C6.14 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a Cx_3 alkoxy group, halogen, a C^., alkyl group, amino, nitro and cyano , (ii) a C3.7 cycloalkyl group or a C3.6 cycloalkenyl group, each of which may be substituted by 1 to 5 substituents selected from the group consisting of a C^- alkoxy group, halogen, a Cx_3 alkyl group, amino, nitro and cyano, (iii) an aromatic heterocyclic group which may be substituted by 1 to 3 substituents selected from the group consisting of a C^., alkoxy group which may be substituted by halogen, halogen, a Cx_3 alkyl group which may be substituted by halogen, a C6.10 aryl group, and nitro, (iv) a hydroxyl group or a thiol group, each of which are substituted by a C3.6 cycloalkyl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C^., alkyl group which may be substituted by halogen, a C^ alkoxy group which may be substituted by halogen, halogen, nitro, amino and cyano, (v) a hydroxyl group or a thiol group, each of which are substituted by a C6.10 aryl group which may be substituted by 1 to 5 substituents selected from the group consisting of a C..3 alkyl group which may be substituted by halogen, a C..3 alkoxy group which may be substituted by halogen, halogen, nitro, amino and cyano, and
(vi) a hydroxyl group or a thiol group, each of which are substituted by a heterocyclic group which may be substituted by 1 to 4 substituents selected from the group consisting of a C..4 alkyl group, a C^,, alkoxy group, halogen, and a C6.10 aryl group. Said C..10 alkyl groups, C2.10 alkenyl groups and C2.10 alkynyl groups may be substituted by further 1 cyano group.
In the present invention, the compound represented by the formula (I) or (la) is preferably exemplified by N- ( diaminophosphinyl) -5-methyl-2-thiophenecarboxamide , N- ( diaminophosphinyl ) -2-methyl-3-furancarboxa ide , N- (diaminophosphinyl) -5-methyl-3-furancarboxamide , N- (diaminophosphinyl) -3 , 5-dimethyl-2-furancarboxamide, and
N- (diaminophosphinyl) -3 , 5-dimethyl-2- thiophenecarboxamide .
In the present invention, the salt of the compound represented by the formula (I), (la) or (lb) is preferably a pharmaceutically acceptable salt , exemplified by salts formed with inorganic bases , salts formed with organic bases , salts formed with inorganic acids , salts formed with organic acids and salts formed with basic or acidic amino acids. Preferable salts formed with inorganic bases include alkali metal salts such as sodium salt and potassium salt ; alkaline earth metal salts such as calcium salt and magnesium salt; and aluminum salt. Preferable salts formed with organic bases include ammonium salts and salts formed with trimethylamine , triethylamine , pyridine, picoline, ethanolamine , diethanolamine , triethanolamine , dicyclohexylamine and N,N ' -dibenzylethylenediamine . Preferable salts formed with inorganic acids include salts formed with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid. Preferable salts formed with organic acids include salts formed with formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. Preferable salts formed with basic amino acids include salts formed with arginine, lysine and ornithine. Preferable salts formed with acidic amino acids include salts formed with aspartic acid and glutamic acid. These salts can be obtained by conventional methods .
Hydrates and non-hydrates of the compound represented by the formula (I), (la) or (lb) are included in the scope of the present invention.
The salt of the compound represented by the formula (II) or (III) below is exemplified by the same kinds of salts as those mentioned as the salt of the compound represented by the formula ( I ) above .
Production method for the compound represented by the formula (I) is hereinafter described. Both the compound represented by the formula (la) and the compound represented by the formula (lb) are within the scope of the formula ( I ) .
The compound represented by the formula ( I ) can be produced by reacting a compound represented by the formula (II):
R-H (II) wherein the symbol has the same meanings as defined above, or a salt thereof, with phosphorus pentachloride, then reacting the resulting compound or a salt thereof with formic acid to yield a compound represented by the formula
(III):
0
R—P—Cl (IN) I Cl wherein the symbol has the same meanings as defined above, or a salt thereof, and then reacting it with ammonia.
The desired compound can also be produced by reacting the compound represented by the formula (II) or a salt thereof with phosphorus oxychloride to yield the compound represented by the formula (III) or a salt thereof, and reacting it with ammonia.
In the reaction of the compound represented by the formula (II) or a salt thereof with phosphorus pentachloride or phosphorus oxychloride, any solvent can be used, as long as it does not interfere with the reaction, and such a solvent includes halogenated solvents such as carbon tetrachloride, chloroform, dichloromethane and 1 , 2-dichloroethane, ether solvents such as dioxane, tetrahydrofuran and diethyl ether, and hydrocarbon solvents such as benzene and toluene, and the reaction temperature is about -50 to 100 °C , preferably about -20 to 80 °C . The amount of phosphorus pentachloride or phosphorus oxychloride used is 0.5 to 10 mole equivalents, preferably 1 to 2 mole equivalents , per mole of the compound represented by the formula (II) or salt thereof. In the reaction with formic acid of the compound or its salt obtained by reacting the compound represented by the formula (II) or its salt with phosphorus pentachloride, halogenated solvents, ether solvents and hydrocarbon solvents as those mentioned above can be use . The reaction temperature is about -50 to 50 "C , preferably about 0 to 30 'C. The amount of formic acid used is 0.5 to 10 mole equivalents , preferably 1 to 3 mole equivalents , per mole of the compound obtained by reacting the compound represented by the formula (II) or its salt with phosphorus pentachloride. In the reaction of the compound represented by the formula (III) or its salt with ammonia, halogenated solvents , ether solvents and hydrocarbon solvents as those mentioned above can be used. The reaction temperature is about -50 to 50 "C , preferably about -20 to lo r .
The compound ( I ) or its salt may be isolated and purified by known separation and purification methods such as concentration, concentration under reduced pressure, distillation, fractional distillation, solvent extraction, chromatography, crystallization and recrystallization. In the compounds or salts thereof to be used for the above reactions , a protecting group may be used for an amino group , carboxyl group or hydroxyl group not involved in the reaction. The addition and removal of the protecting group can be achieved by known means . Useful amino group-protecting groups include formyl, and alkylcarbonyl (e.g., acetyl, propionyl), phenylcarbonyl ,
Figure imgf000082_0001
alkyl-oxycarbonyl (e.g., methoxycarbonyl, ethoxycarbonyl), phenyloxycarbonyl , C7.10 aralkyloxy-carbonyl (e.g., phenyl-C^,, alkyloxy-carbonyl such as benzyloxycarbonyl), trityl, phthaloyl and N,N- dimethylaminomethylene , each of which may have substituents. These substituents include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), formyl,
Figure imgf000082_0002
alkyl-carbonyl (e.g., acetyl, propionyl, valeryl) and nitro groups, and the number of substituents is about 1 to 3.
Useful carboxyl group-protecting groups include
Figure imgf000082_0003
alkyl (e.g. , methyl , ethyl , propyl , isopropyl , butyl , tert-butyl), phenyl, trityl and silyl, each of which may have substituents. These substituents include halogen atoms (e.g., fluorine, chlorine, bromine, iodine), formyl, C-.g alkyl-carbonyls (e.g. , acetyl, propionyl, valeryl) and nitro groups, and the number of substituents is about 1 to 3. Useful hydroxyl group-protecting groups include
Figure imgf000082_0004
alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, tert-butyl), phenyl, C7.10 aralkyl (e.g., phenyl-Cj.., alkyl such as benzyl) , formyl, alkyl-carbonyl (e.g. , acetyl, propionyl), phenyloxycarbonyl, benzoyl, (C7.10 aralkyloxy) carbonyl (e.g., ph-eny!-^.,, alkyloxy-carbonyl such as benzyloxycarbonyl), pyranyl, furanyl and silyl, each of which may have substituents . These substituents include halogen atoms (e.g., fluorine, chlorine, bromine, iodine),
Figure imgf000083_0001
alkyl (e.g., methyl, ethyl, propyl), phenyl, C7.10 aralkyl (e.g., phenyl-C^,, alkyl such as benzyl) and nitro groups, and the number of substituents is about 1 to 4.
Protecting groups can be removed by per se known methods or similar methods thereto, such as treatment with acid, base, reducing agent, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride, palladium acetate etc.
The anti-Helicobacter agent and the pharmaceutical composition of the present invention are characterized by containing a compound represented by the formula (I) , (la) or (lb) or a pharmaceutically acceptable salt thereof (hereinafter referred to as a compound represented by the formula (I) or salt thereof) and an antibiotic.
The above-mentioned pharmaceutical against Helicobacter bacteria characterized by combined use of the compound represented by the formula (I) or its salt with an antibiotic, is not limited as to form of use, as long as it comprises a combination of the compound represented by the formula (I) or its salt with an antibiotic. For example, (A) the compound represented by the formula (I) or its salt and (B) an antibiotic may be separately formulated in the respective ordinary dosage forms , or may be a composition prepared by combining both in advance.
For example, the pharmaceutical against Helicobacter bacteria of the present invention may be produced as a single preparation prepared by mixing the compound represented by the formula ( I ) or its salt with an antibiotic by a known manufacturing method of pharmaceutical using a pharmaceutically acceptable diluent , excipient etc. when desired, or as separate preparations prepared from the respective components using a pharmaceutically acceptable diluent, excipient etc. when desired, or as a combination preparation (set, kit, pack) by packing the separately prepared preparations into the same container. For example, the pharmaceutical against Helicobacter bacteria of the present invention is used as ( 1 ) a combination preparation in which a pharmaceutical containing the compound represented by the formula ( I ) or its salt and a pharmaceutical containing an antibiotic are packed, or (2) a composition containing the compound represented by the formula ( I ) or its salt and an antibiotic.
The pharmaceutical against Helicobacter bacteria of the present invention may also be a combination preparation or composition comprising the compound represented by the formula (I) or its salt and an antibiotic.
An antibiotic is exemplified by naturally-occuring substances having antibacterial activity which are extracted from microorganisms such as bacteria, molds and actinomycetes , or plants, substances having antibacterial activity which are obtained by chemically modifying the naturally-occuring substances, and substances having antibacterial activity which are obtained by chemical synthesis .
Preferable antibiotics include penicillin antibiotics such as amoxicillin, piperacillin, penicillin G and mecillinam; cephalosporin antibiotics such as cefaclor, cefotiam, cefixime, ceftazidime and cefpiro e; carbapenem antibiotics such as imipenem; macrolide antibiotics such as clarithromycin , erythromycin , roxithromycin and azithromycin; lincomycin antibiotics such as clindamycin; chloramphenicol antibiotics such as chloramphenicol; tetracyclin antibiotics such as tetracyclin, minocyclin and doxycyclin; aminoglycoside antibiotics such as streptomycin, gentamycin and amikacin; quinolone antiboitics such as norfloxacin, ofloxacin and ciprofloxacin; indolmycin antibiotics such as indolmycin; nitroimidazole antiboitics (antiprotozoa agent) such as metronidazole and tinidazole; bismuth compounds such as colloidal bismuth subcitrate and bismuth subsalicylate; fosfomycin, rifampicin, nitrofurantoin and furazolidone. Among these, preferred are penicillin antibiotics such as amoxicillin; macrolide antibiotics such as clarithromycin; nitroimidazole antiboitics such as metronidazole and tinidazole; and indolmycin antibiotics such as indolmycin. More preferred are penicillin antibiotics , macrolide antibiotics and nitroimidazole antiboitics. Especially preferred are penicillin antibiotics such as amoxicillin; and macrolide antibiotics such as clarithromycin.
One or more (preferably 1 to 3 , more preferably 1 or 2 ) of these antibioitics can be used.
The anti--ffelicobacter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria in the present invention can be produced by known preparation methods of pharmaceutical formulation. The anti- Helicobacter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria in the present invention can be used orally or non-orally by inhalation, by rectal administration or by local administration. For example, it can be used in a form of powders, granules, tablets, pills, capsules, injectable preparations, syrups, emulsions, elixirs, suspensions, solutions etc. , and it may contain at least one compound represented by the formula ( I ) or a salt thereof and an antibiotic, or in combination with a pharmaceutically acceptable carrier. When such a carrier is used, the contents of the compound represented by the formula ( I ) or its salt and the antibiotic may be chosen as appropriate depending upon the preparation, but normally are 1 to 99% by weight and 1 to 99% by weight respectively, preferably are 1 to 20% by weight and 1 to 90% by weight respectively.
The pharmaceutically acceptable carriers include various organic or inorganic carrier substances commonly used as pharmaceutical materials. And excipients, lubricants, binders and disintegrating agents for solid preparations, and solvents, solubilizers, suspending agents , isotonizing agents , buffers and soothing agents for liquid preparations are used appropriately. Other pharmaceutical additives such as preservatives , antioxidants, coloring agents and sweetening agents may be used appropriately when necessary.
Preferable excipients include lactose, sucrose, D- annitol, starch, crystalline cellulose and light silicic anhydride . Preferable lubricants include magnesium stearate, calcium stearate, talc and colloidal silica.
Preferable binders include crystallinecellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose and polyvinylpyrrolidone . Preferable disintegrating agents include starch, carboxymethylcellulose , carboxymethylcellulose calcium, croscarmellose sodium and carboxymethyl starch sodium.
Preferable solvents include water for injection , alcohol , propylene glycol, macrogol, sesame oil and corn oil.
Preferable solubilizers include polyethyleneglycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, Tris-aminomethane, cholesterol, triethanolamine , sodium carbonate and sodium citrate. Preferable suspending agents include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, lauryl-aminopropionic acid, lecithin, benzalkonium chloride , benzethonium chloride and glycerol monostearate ; and hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone , carboxymethylcellulose sodium, methylcellulose , hydroxymethylcellulose , hydroxyethylcellulose and hydroxypropylcellulose.
Preferable isotonizing agents include sodium chloride, glycerol and D-mannitol. Preferable buffers include buffer solutions of phosphates, acetates, carbonates and citrates.
Preferable soothing agents include benzyl alcohol.
Preferable preservatives include p-oxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol , dehydroacetic acid and sorbic acid.
Preferable antioxidants include sulfites and ascorbic acid.
The anti -Helicobacter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria can be prepared as pharmaceutical preparations by ordinary methods. In the present specification, "non- oral" includes subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection and drip infusion. Injectable preparations, e.g., aqueous or oily suspensions for aseptic injection, can be prepared by methods known in relevant fields , using an appropriate dispersing agent or wetting agent and a suspending agent. The aseptic injectable preparation thus obtained may be an aseptically injectable solution or suspension in a diluent or solvent which permits non-toxic non-oral administration, such as an aqueous solution. Acceptable vehicles or solvents include water. Ringer's solution and isotonic saline. It is also possible to use aseptic non-volatile oils as solvents or suspending media. For this purpose any non-volatile oil or fatty acid can be used, including natural, synthetic or semi-synthetic fatty oils or fatty acids, and natural, synthetic or semi- synthetic mono- or di- or tri-glycerides . Suppositories for rectal administration may be produced by mixing the drug with an appropriate non-irritative shaping agent, such as cacao butter or polyethyleneglycol, which is solid at atmospheric temperature and which is liquid at intestinal temperature and melts and releases the drug in the rectum.
Solid dosage forms for oral administration include the above-mentioned forms such as powders, granules, tablets, pills and capsules. In these dosage forms, the active ingredient compound may be mixed with at least one additive such as sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginate, chitin, chitosan, pectin, gum tragacanth, gum arable, gelatin, collagen, casein, albumin, synthetic or semi-synthetic polymer or glyceride . Such dosage forms may additionally contain additives as usual, including inert diluents, lubricants such as magnesium stearate, preservatives such as paraben and sorbic acid, antioxidants such as ascorbic acid, a -tocopherol and cysteine, disintegrating agents, binders , thickening agents , buffers , sweeteners , flavoring agents and perfumes . Tablets and pills may be produced with enteric coating. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, syrups, elixirs, suspensions and solutions, and may contain inert diluents, such as water, commonly used in relevant fields .
The anti-Helicobaσter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria of the present invention may also be an enteric preparation . The compound represented by the formula ( I ) or its salt, and/or an antibiotic can be formulated into a gastrointestinal mucosa-adherent composition according to the methods described in Japanese Patent Unexamined Publication No. 132416/1993, Japanese Patent Unexamined Publication No. 126189/1995, and the like.
The dose for a particular patient is determined according to age, body weight, general health status, sex, dietary status, administration time, method of administration, excretion rate, drug combination, severity of the illness being treated and other factors .
Since the compound represented by the formula ( I ) or its salt exhibits antibacterial action (eradication of Helicobacter bacteria), especially against Helicobacter bacteria, based on urease inhibitory activity, it is useful in the prevention or treatment of digestive diseases presumably caused by Helicobacter bacteria, such as gastritis, duodenal ulcer, gastric ulcer and chronic gastritis in mammals (e.g., humans, dogs, cats, monkeys, rats, mice). Since significant correlation between Helico- bacter bacteria, especially Helicobacter pylori , and gastric cancer has recently been suggested, this compound is also expected to be useful in the prevention of gastric cancer. Furthermore, the compound represented by the formula ( I ) or its salt is of low toxicity and can be safely used.
Because the anti-Helicobaσter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria of the present invention possesses antibacterial activity against Helicobacter bacteria, it exhibits eradicating and sterilizing effect of Helicobacter bacteria which exhibit toxic action in the digestive tract. The digestive tract is exemplified by the stomach and duodenal. A Helicobacter bacterium exhibiting toxic action in the digestive tract is Helico-bacter pylori .
The dose of the anti-Heliσobacter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria of the present invention is chosen as appropriate, depending on type and symptoms of diseases , but the compound represented by the formula (I) or its salt may be daily administered, per adult patient (50 kg) with gastric ulcer or duodenal ulcer, at about 0.1 to 10 g/day, preferably 0.2 to 2 g/day by oral administration, and about 0.01 to 1 g/day, preferably 0.02 to 0.5 g/day by non-oral administration. The dose per administration is determined taking into consideration such daily doses, dosage forms etc. Administration frequency is not limited, but preferably 1 to 5 times/day, more preferably 1 to 3 times/day. The dose of an antibiotic is chosen as appropriate, depending on type and symptoms of diseases , and kinds of the antibiotic, but the antibiotic, in the case of penicillin antibiotics such as amoxicillin, may be daily administered, per adult patient (50 kg) with gastric ulcer or duodenal ulcer, at about 0.1 to 10 g/day, preferably 0.2 to 2 g/day by oral administration, and about 0.01 to 1 g/day, preferably 0.02 to 0.5 g/day by non-oral administration. The dose per administration is determined taking into consideration such daily doses, dosage forms etc. Administration frequency is not limited, but preferably 1 to 5 times/day, more preferably 1 to 3 times/day.
The anti-Helicobacter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria of the present invention may contain antacids and/or acid secretion inhibitors etc. in addition to its active ingredients, i.e. , the compound represented by the formula (I) or its salt and an antibiotic.
Such antacids include aluminum hydroxide gel, sodium bicarbonate, aminoacetic acid, aluminum silicate. magnesium metasilicic aluminate, magnesium silicate, magnesium oxide, magnesium hydroxide, magnesium carbonate and calcium carbonate .
Such acid secretion inhibitors include drugs which suppress gastric acid secretion, specifically proton pump inhibitors and histamine H2 blockers . The term proton pump inhibitor is defined as a drug that suppresses gastric acid secretion by directly or indirectly inhibiting H/K-ATPase, which functions as a proton pump in gastric mucosal membrane acid secreting cells (parietal cells). Examples of such drugs include lansoprazole, omeprazole, pantoprazole, pariprazole sodium (Rabeprazole sodium), leminoprazole, TY-11345, TU-199, FPL-65372, BY-686, tannic acid, ellagic acid, Ebselen, AHR-9294, Cassigarol-A, Bafilomycin, Y- 25942, Xanthoangelol E, SKF-96356, epigallocatechin gallate, WY-27198, T-330 and SK&F-20054.
Example of proton pump inhibitors include benzimidazole compounds , which exhibit proton pump inhibiting action and are of low toxicity. Preferable benzimidazole compounds include 2- [ (pyridyl) -methylsulfinyl or - methylthio] benzimidazole, derivatives thereof and salts thereof . More preferable are a compound represented by the following formula ( a ) and a salt thereof :
Figure imgf000091_0001
wherein ring A may be substituted; Rb represents a hydrogen atom, an alkyl group, an acyl group, a carbalkoxy group, a carbamoyl group, an alkylcarbamoyl group, a dialkylcarbamoyl group or an alkylsulfonyl group; R°, Rβ and R9 independently represent a hydrogen atom, an alkyl group, an alkoxy group or an alkoxyalkoxy group; Rd represents a hydrogen atom, an alkyl group or a group represented by the formula: -ORf or -SRf, wherein Rf represents a hydrocarbon group that may be substituted; and q represents 0 or 1. The benzimidazole compounds are described in Japanese Patent Unexamined Publication Nos .62275/1977, 141783/1979, 53406/1982, 135881/1983, 192880/1983, 181277/1984, 50978/1986, 116576/1987, 277322/1987, 258320/1987, 258316/1987, 6270/1989, 79177/1989. 59043/1993, 111980/1987 and 117268/1993, and European Patent Publication Nos. 166287 and 519365, for instance.
With respect to formula ( a ) above, the substituents to ring A include halogen atoms , alkyl groups that may be substituted, cycloalkyl groups that may be substituted, alkenyl groups that may be substituted, alkoxy groups that may be substituted, cyano group, carboxy group, carbalkoxy groups , carbalkoxyalkyl groups , carbamoyl grou , carbamoylalkyl groups , hydroxy group , hydroxyalkyl groups , acyl groups , carbamoyloxy group , nitro group , acyloxy groups , aryl groups , aryloxy groups , alkylthio groups and alkylsulfinyl groups .
The above-mentioned substituents are described below. Halogen atoms include fluorine, chlorine, bromine and iodine. Of these halogen atoms, fluorine and chlorine are preferred, and fluorine is more preferred.
The alkyl group in the alkyl group that may be substituted is exemplified by straight-chain or branched alkyl groups having 1 to 10 carbon atoms (e.g. , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n- pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl) . Of these alkyl groups, straight-chain or branched alkyl groups having 1 to 6 carbon atoms are preferred, and those having 1 to 3 carbon atoms are more preferred. Substituents of said alkyl group include halogens, nitro. amino groups (which may have 1 to 2 alkyl groups , acyl groups etc. as substituents) , cyano group, hydroxy group, carboxy group , amidino group , guanidino group and carbamoyl group .
The cycloalkyl group in the cycloalkyl group that may be substituted is exemplified by cycloalkyl groups having 3 to 7 carbon atoms. Specifically, such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl . Said cycloalkyl group may have substituents, exemplified by halogens , nitro group, amino groups (which may have 1 to 2 alkyl groups, acyl groups etc. as substituents), cyano group, hydroxyl group, carboxyl group , amidino grou , guanidino group and carbamoyl group .
The alkenyl group in the alkenyl group that may be substituted is preferably exemplified by straight-chain or branched alkenyl groups having 2 to 16 carbon atoms. Specifically, such alkenyl groups include allyl, vinyl, crotyl, 2-penten-l-yl, 3-penten-l-yl, 2-hexen-l-yl, 3- hexen-1-yl, 2-methyl-2-propen-l-yl and 3-methyl-2- buten-1-yl. Of these alkenyl groups, straight-chain or branched alkenyl groups having 2 to 6 carbon atoms are preferred, and those having 2 to 4 carbon atoms are more preferred. Said alkenyl group may have substituents, exemplified by halogens, nitro group, amino groups (which may have 1 to 2 alkyl groups, acyl groups etc. as substituents), cyano group, amidino group and guanidino group. Said alkenyl group include isomers (E- and Z- isomers) with respect to double bond.
The alkoxy group in the alkoxy group that may be substituted is exemplified by alkoxy groups having 1 to 10 carbon atoms. Specifically, such alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, cyclobutoxy, cyclopentoxy and cyclohexyloxy. Of these alkoxy groups , those having 1 to 6 carbon atoms are preferred, and those having 1 to 3 carbon atoms are more preferred. Said alkoxy group may have substituents, exemplified by halogens, nitro group, amino groups (which may have 1 to 2 alkyl groups , acyl groups etc . as substituents), amidino group, guanidino group, Cx.4 alkoxy groups and C6.10 aryl groups such as phenyl and naphthyl (which may have 1 to 3 halogens, Ct.4 alkyl groups, Cx.4 alkoxy groups etc. as substituents).
The halogen as a substituent of the above-mentioned alkyl groups , cycloalkyl groups , alkenyl groups and alkoxy groups includes chlorine, bromine, fluorine and iodine.
The alkyl group in the alkylamino group as a substituent of the above-mentioned alkyl groups, cycloalkyl groups, alkenyl groups and alkoxy groups is preferably a straight-chain or branched alkyl group having 1 to 6 carbon atoms. Such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n- pentyl, isopentyl, n-hexyl and isohexyl. Of these alkyl groups, straight-chain or branched alkyl groups having 1 to 4 carbon atoms are more preferred.
The acyl group in the acylamino group as a substituent of the above-mentioned alkyl groups, cycloalkyl groups, alkenyl groups and alkoxy groups is exemplified by acyl groups derived from organic carboxylic acids . Of these acyl groups , alkanoyl groups having 1 to 6 carbon atoms are preferred. Such acyl groups include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl and hexanoyl, and alkanoyl groups having 1 to 4 carbon atoms are more preferred.
The number of substituents to the above-mentioned alkyl groups , cycloalkyl groups , alkenyl groups and alkoxy groups is 1 to 6 , preferably 1 to 3. Substituted alkyl groups include trifluoromethyl, trifluoroethyl , difluoromethyl, trichloromethyl , hydroxymethyl , 1-hydroxyethyl, 2-hydroxyethyl, methoxyethyl, ethoxyethyl, 1-methoxyethyl, 2- methoxyethyl, 2 , 2-dimethoxyethyl, 2 , 2-diethoxyethyl and 2-diethylphosphorylethyl. Of these groups, difluoromethyl , trifluoromethyl and hydroxymethyl are preferred, and trifluoromethyl is more preferred.
Substituted cycloalkyl groups include 2- aminocyclopropan-1-yl, 4-hydroxycyclopentan-l-yl and 2 , 2-difluorocyclopentan- 1-yl .
Substituted alkenyl groups include 2 , 2-dichlorovinyl, 3-hydroxy-2-propen-l-yl and 2-methoxyvinyl.
Substituted alkoxy groups include difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, 2-methoxyethoxy, 4-chlorobenzyloxy and 2- ( 3 , 4-dimethoxypheny1 ) ethoxy. Of these alkoxy groups, difluoromethoxy is preferred.
The alkoxy group in the carbalkoxy group ( alkoxycarbonyl group) is exemplified by alkoxy groups having 1 to 7 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n- butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy) . The alkoxy group in the carbalkoxyalkyl group ( alkoxycarbonylalkyl group) is exemplified by alkoxy groups having 1 to 4 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy) , and the alkyl group is exemplified by alkyl groups having 1 to 4 carbon atoms (e.g. , methyl , ethyl , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl). Examples of such carbalkoxyalkyl groups include carbomethoxymethyl (methoxycarbonylmethyl ) , 2- carbomethoxyethyl (2-methoxycarbonylethyl) , 2- carbomethoxypropyl ( 2-methoxycarbonylpropyl) , carbethoxymethyl ( ethoxycarbonylmethyl ) , 2- carbethoxyethyl ( 2-ethoxycarbonylethyl) , 1- carbomethoxypropyl ( 1-methoxycarbonylpropyl ) , carbopropoxymethyl (propoxycarbonylmethyl) and carbobutoxymethyl ( butoxycarbonylmethyl ) . The alkyl group in the carbamoylalkyl group is exemplified by alkyl groups having 1 to 4 carbon atoms (e.g. , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl).
The alkyl group in the hydroxyalkyl group is exemplified by alkyl groups having 1 to 7 carbon atoms (e.g. , methyl , ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl ) . The acyl group and the acyl group in the acyloxy group are exemplified by alkanoyl groups having 1 to 4 carbon atoms , including formyl , acetyl , propionyl , butyryl and isobutyryl .
The aryl group and the aryl group in the aryloxy group are exemplified by aryl groups having 6 to 12 carbon atoms (e.g. , phenyl , naphthyl ) .
The alkyl group in the alkylthio group and alkylsulfinyl group is exemplified by alkyl groups having 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl).
The number of substituents to the substituted ring A is preferably 1 to 4 , and more preferably 1 to 2. The positions of substituents on the benzene ring include 4- and 5- positions (4- and 5-positions of benzimidazole skeleton), and 5-position is preferable.
Preferred examples of ring A include benzene ring which may be substituted by a halogen atom, an alkyl group that may be substituted, a cycloalkyl group that may be substituted, an alkenyl group that may be substituted, an alkoxy group that may be substituted, or the like.
The alkyl group represented by Rb is exemplified by alkyl groups having 1 to 5 carbon atoms (e.g. , methyl, ethyl , n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl); the acyl group is exemplified by acyl groups having 1 to 4 carbon atoms (e.g. , alkanoyl groups having 1 to 4 carbon atoms ) ; the alkoxy group in the carbalkoxy group (alkoxycarbonyl group) is exemplified by alkoxy groups having 1 to 4 carbon atoms (e.g., methoxy, ethoxy, propoxy, butoxy, isobutoxy, sec-butoxy) ; the alkyl group in the alkylcarbamoyl group and the dialkylcarbamoyl group is exemplified by alkyl groups having 1 to 4 carbon atoms (e.g. , methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl) ; and the alkyl group of the alkylsulfonyl group is exemplified by the above-mentioned alkyl groups having 1 to 4 carbon atoms. Rb is preferably a hydrogen atom.
The alkyl group represented by Rc, Rβ or R9 is exemplified by straight-chain or branched alkyl groups having 1 to 10 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl). Of these alkyl groups, straight-chain or branched alkyl groups having 1 to 6 carbon atoms are preferred, and straight-chain or branched alkyl groups having 1 to 3 carbon atoms are more preferred.
The alkoxy group represented by R°, Rβ or R9 is exemplified by alkoxy groups having 1 to 10 carbon atoms (e.g. , methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy) . Of these alkoxy groups, alkoxy groups having 1 to 6 carbon atoms are preferred, and alkoxy groups having 1 to 3 carbon atoms are more preferred. Each of the alkoxy groups of the alkoxyalkoxy group represented by R°, Rθ or R9 is exemplified by alkoxy groups having 1 to 4 carbon atoms (e.g. , methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert- butoxy) .
R° is preferably a hydrogen atom, an alkyl group or an alkoxy group. Rβ is preferably a hydrogen atom, an alkyl group or an alkoxy group. R9 is preferably a hydrogen atom.
The alkyl group represented by Rd is exemplified by alkyl groups having 1 to 4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl) .
The hydrocarbon group in the hydrocarbon group that may be substituted, represented by Rf, is exemplified by hydrocarbon groups having 1 to 13 carbon atoms, including straight-chain or branched alkyl groups having 1 to 6 carbon atoms (e.g. , methyl, ethyl , propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl); alkenyl groups having 2 to 6 carbon atoms (e.g., vinyl, allyl, 2-butenyl, methylallyl, 3-butenyl, 2-pentenyl, 4-pentenyl, 5-hexenyl) ; alkynyl groups having 2 to 6 carbon atoms (e.g. , ethynyl, propargyl, 2-butyn-l-yl, 3-butyn-2-yl, 1- pentyn-3-yl, 3-pentyn-l-yl, 4-pentyn-2-yl, 3-hexyn-l- yl); cycloalkyl groups having 3 to 6 carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl); cycloalkenyl groups having 3 to 6 carbon atoms (e.g. , cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl) ; aralkyl groups having 7 to 13 carbon atoms (e.g.,
Figure imgf000098_0001
alkyl groups such as benzyl, 1- phenethyl and 2-phenethyl, naphthyl-C!.., alkyl groups) ; and aryl groups having 6 to 10 carbon atoms (e.g., phenyl, naphthyl). Of these groups, straight-chain or branched alkyl groups having 1 to 6 carbon atoms (e.g. , methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, isopentyl, hexyl) are preferred, and straight-chain or branched alkyl groups having 1 to 4 carbon atoms are more preferable.
The substituent in the substituted hydrocarbon group is exemplified by C6.10 aryl groups (e.g., phenyl, naphthyl), amino group, Cl.6 alkylamino groups (e.g. , ethylamino, ethylamino, isopropylamino ) ,
Figure imgf000099_0001
alkylamino groups (e.g., dimethylamino , diethylamino ) , N-C7.14 aralkyl-N-C3.6 cycloalkylamino groups (e.g., N-(C6_10 aryl-Ci.,, alkyl) -N- C3.6 cycloalkylamino groups such as N-benzyl-N- cyclohexylamino ) , N-C7.14
Figure imgf000099_0002
alkylamino groups (e.g., N-(C6.10 aryl-Ci.,, alkyl)
Figure imgf000099_0003
alkylamino such as N-(l-naph-thylmethyl)-N-ethylamino) , azido group, nitro group , halogens (e.g. , fluorine , chlorine , bromine , iodine) , hydroxyl group, C alkoxy groups (e.g. , methoxy, ethoxy, propoxy, butoxy), C6.10 aryloxy groups (e.g., phenoxy, naphthyloxy) ,
Figure imgf000099_0004
alkylthio groups (e.g., methylthio, ethylthio, propylthio), C6.10 arylthio groups (e.g., phenylthio, naphthylthio ) , cyano group, carbamoyl group, carboxyl group, Cx.4 alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl), C7_u aryloxycarbonyl groups (e.g., phenoxycarbonyl , 1-naphthyloxycarbonyl, 2-naphthyloxycarbonyl) , carboxy-Ci.,, alkoxy groups (e.g., carboxymethoxy, 2-carboxyethoxy) , C._6 alkanoyl groups (e.g., formyl, acetyl, propionyl, isopropionyl, butyryl, pentanoyl, hexanoyl), C7.u aroyl groups (e.g., benzoyl, 1-naphthoyl, 2-naphthoyl) , C6.10 arylsulfonyl groups (e.g., benzenesulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl) , alkylsulfinyl groups (e.g. , methylsulfinyl , ethylsulfinyl ) , C6.10 arylsulfinyl groups (e.g., benzenesulfinyl, 1-naphthylsulfinyl, 2-naphthylsulfinyl) , alkylsulfonyl groups (e.g. , methylsulfonyl , ethylsulfonyl) , 5- or 6-membered heterocyclic groups containing 1 to 4 hetero atoms (e.g., nitrogen, oxygen, sulfur) (e.g., 2-furyl, 2-thienyl, 4-thiazolyl, 4- imidazolyl, 4-pyridyl, 1, 3, 4-thiadiazol-2-yl, 1-methyl- 5-tetrazolyl) , 5- or 6-membered heterocyclic-carbonyl groups containing 1 to 4 hetero atoms (e.g., nitrogen, oxygen, sulfur) (e.g., 2-furoyl, 2-thenoyl, nicotinoyl, isonicotinoyl), and 5- or 6-membered heterocyclic-thio groups containing 1 to 4 hetero atoms (e.g., nitrogen, oxygen, sulfur) (e.g., 4-pyridylthio, 2-pyrimidylthio, l,3,4-thiadiazol-2-ylthio, 1-methyl-5-tetrazolylthio) . The heterocyclic-thio group may be fused with the benzene ring to form a bicyclic fused ring-thio group (e.g., 2- benzothiazolylthio, 8-quinolylthio) . Of these substituents, halogens (e.g. , fluorine, chlorine, bromine, iodine) , hydroxyl group and C^ alkoxy groups (e.g. , methoxy, ethoxy, propoxy, butoxy) are preferred. The number of such substituents is 1 to 5 , preferably 1 to 3.
Rd is preferably an alkoxy group that may be substituted or an alkoxyalkoxy group that may be substituted. The alkoxy group in said alkoxy group that may be substituted is exemplified by alkoxy groups having 1 to 8 carbon atoms (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy) ; each of the alkoxy groups in said alkoxyalkoxy group that may be substituted is exemplified by alkoxy groups having 1 to 4 carbon atoms (e.g. , methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy) . Rd is particularly preferably an alkoxy group having 1 to 8 carbon atoms , preferably 1 to 4 carbon atoms , which may be halogenated by 1 to 9 halogens , or an alkoxyalkoxy group which may be halogenated by 1 to 5 halogen atoms . Preferable alkoxy groups which may be halogenated include 2, 2, 2-trifluoroethoxy, 2,2,3,3,3-pentafluoropropoxy, 1- (trifluoromethyl) -2, 2, 2-trifluoroethoxy, 2,2,3,3- tetrafluoropropoxy , 2,2,3,3,4,4, 4 -heptafluorobutoxy , 2,2,3,3, 4, 4,5,5-octafluoropentoxy and methoxy. Preferable alkoxyalkoxy groups which may be halogenated include 3-methoxypropoxy. q is preferably 1.
More specifically, the above-described benzimidazole compound is exemplified by a compound represented by the formula ( )3 ) :
Figure imgf000101_0001
wherein ring A may be substituted; Rw, Rγ and Rz, whether identical or not, represent a hydrogen atom, an alkyl group or an alkoxy group; Rx represents a hydrocarbon group that may have substituents; and n represents 0 or 1.
With respect to the formula ( β ) above, ring A is exemplified by the same rings as those mentioned as to ring A in the formula ( α ) above .
The alkyl group represented by Rw, Rγ or Rz is exemplified by straight-chain or branched alkyl groups having 1 to 10 carbon atoms. Such alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl, and decyl. Of these alkyl groups, straight-chain or branched alkyl groups having 1 to 6 carbon atoms are preferred, and those having 1 to 3 carbon atoms are more preferred.
The alkoxy group represented by Rw, R* or Rz is exemplified by alkoxy groups having 1 to 10 carbon atoms. Such alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy. isopentoxy, neopentoxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, cyclobutoxy, cyclopentoxy, and cyclohexyloxy. Of these alkoxy groups , alkoxy groups having 1 to 6 carbon atoms are preferred, and alkoxy groups having 1 to 3 carbon atoms are more preferred.
The hydrocarbon group that may be substituted, represented by Rx, is exemplified by the same groups mentioned as to the hydrocarbon group represented by Rf above . RM is preferably an alkyl group having 1 to 6 carbon atoms or an alkoxy group having 1 to 6 carbon atoms , and more preferably an alkyl group having 1 to 3 carbon atoms.
Rγ is preferably a hydrogen atom or an alkyl group having
1 to 6 carbon atoms, more preferably a hydrogen atom. Rx is preferably an alkyl group having 1 to 6 carbon atoms , that may be substituted by 1 ) 1 to 5 halogens , 2 ) a hydroxyl , or 3 ) an alkoxy group having 1 to 4 carbon atoms , more preferably an alkyl group having 1 to 3 carbon atoms, that may be substituted by 1) 1 to 5 halogens or 2) an alkoxy group having 1 to 4 carbon atoms ,
Rz is preferably a hydrogen atom.
Examples of the above-described benzimidazole compound include 2- [ 2- [ 3-methyl-4-(2, 2,3,3- tetrafluoropropoxy)pyridyl]methylthio]benzimidazole, 2- [2-[3-methyl-4-(2,2,2- trifluoroethoxy)pyridyl ]methylsulfinyl]benzimidazole (lansoprazole) , 2-[(2- pyridyl)methylsulfinyl]benzimidazole ( timoprazole) , 2- [ 2- ( 3 , 5-dimethyl-4-methoxypyridyl )methylsulfinyl] -5- methoxy- lH-benzimidazole ( omeprazole ) , 2-[2-[4-(3- methoxypropoxy) -3-methylpyridyl]methylsulfinyl] -1H- benzimidazole sodium salt (Pariprazole sodium, Rabeprazole sodium) and 2- [ 2- ( 3 , 4-dimethoxy)pyridyl ]methylsulfinyl] - 5-difluoromethoxy-lH-benzimidazole (panthoprazole) . The above-described benzimidazole compounds or their salts can be produced by, for example, the above-mentioned known methods described in Japanese and European Patent Publications, or similar methods thereto.
Preferably, the salt of a benzimidazole compound is used as a pharmaceutically acceptable salt . Useful pharmaceutically acceptable salts include salts formed with inorganic bases , salts formed with organic bases and salts formed with basic amino acids . Useful inorganic bases include alkali metals (e.g., sodium, potassium); alkaline earth metals (e.g., calcium, magnesium). Useful organic bases include trimethylamine , triethylamine , pyridine, picoline, N,N-dibenzylethylenediamine, ethanolamine , diethanolamine , trishydroxymethylaminomethane and dicyclohexylamine . Useful basic amino acids include arginine and lysine.
These salts are produced by per se known methods, e.g. , those described in Japanese Patent Unexamined Publication Nos. 79177/1989 and 167587/1984, or similar methods thereto .
Such histamine H2 blockers as the acid secretion inhibitors include 2-cyano-1-methyl-3- [2- [ [ (5- methylimidazol-4-yl)methyl] thio ]ethyl] guanidine (cimetidine) , N-[2-[[5-
[ ( dimethylamino) ethyl] furfuryl ] thio ] ethyl] -N ' -methyl- 2-nitro-1, 1-ethenediamine (ranitidine) and (±)-2- ( furfurylsulfinyl ) -N- [ 4- [ 4- (piperidinylmethyl) -2- pyridyl]oxy-(z)-2-butenyl]acetamide (loctidine) .
With respect to an antacid and an acid secretion inhibitor for use in the Helicobacter agent , pharmaceutical composition, and pharmaceutical against Helicobacter bacteria of the present invention, one or more (preferably 3 or fewer) of antacids and/or acid secretion inhibitors selected among them, preferaby 1 or 2 of antacids and/or acid secretion inhibitors are used.
Among an antacid and an acid secretion inhibitor, an acid secretion inhibitor is preferable, and a proton pump inhibitor is more preferable.
As stated above, the Helicobacter agent and pharmaceutical composition of the present invention, may contain antacids and/or acid secretion inhibitors etc. in addition to its active ingredients, i.e.. the compound represented by the formula (I) and an antibiotic. The present specification holds that the term "containing" covers both simultaneous use and use at a time interval of 2 or more active substances after admixing or without admixing, and further covers combined use and use in combination.
The above-mentioned pharmaceutical against Helicobacterbacteria, characterized by combined use of the compound represented by the formula ( I ) or its salt and an antibiotic with an antacid and/or an acid secretion inhibitor, is not limited as to form of use, as long as it comprises a combination of the compound represented by the formula (I) or its salt, an antibiotic, and an antacid and/or an acid secretion inhibitor. For example, (A) the compound represented by the formula (I) or its salt, (B) an antibiotic, and (C) an antacid and/or an acid secretion inhibitor may be separately formulated in the respective ordinary dosage forms , or may be a composition prepared by combining them in advance.
For example, the anti-Helicobacter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria in the present invention may be produced as a single preparation prepared by mixing the compound represented by the formula (I) or its salt, an antibiotic, and an antacid and/or an acid secretion inhibitor by a known manufacturing method of pharmaceutical using a pharmaceutically acceptable diluent , excipient etc . when desired; as separate preparations prepared from the respective components using a pharmaceutically acceptable diluent, excipient etc. when desired; as separate preparations comprising a preparation prepared from two ingredients among the compound represented by the formula (I) or its salt, an antibiotic, and an antacid and/or an acid secretion inhibitor using a pharmaceutically acceptable diluent, excipient etc. when desired, and a preparation prepared from the remaining active ingredient using a pharmaceutically acceptable diluent , excipient etc. when desired; or as a combination preparation (set, kit, pack) by packing the separately prepared preparations into the same container . For example , the pharmaceutical against Helicobacter bacteria of the present invention is used as ( 1 ) a combination preparation in which a pharmaceutical containing the compound represented by the formula ( I ) or its salt , a pharmaceutical containing an antibiotic, and a pharmaceutical containing an antacid and/or an acid secretion inhibitor are packed, or (2) a composition containing the compound represented by the formula (I) or its salt, an antibiotic, and an antacid and/or an acid secretion inhibitor.
The pharmaceutical against Helicobacter bacteria of the present invention may also be a combination preparation or composition consisting of the compound represented by the formula (I) or its salt, an antibiotic and an antacid and/or an acid secretion inhibitor.
Regarding the route of administration of the anti- Helicobacter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria of the present invention, both oral and non-oral administrations (e.g., intravenous administration, subcutaneous administration, intramuscular administration) are applicable, in the same way as the above-described anti-Helicobacter agent , pharmaceutical composition, and pharmaceutical against Helicobacter bacteria. Specifically, the route is determined in consideration of the site of target ulcer etc.
When the compound represented by the formula (I) or its salt , an antibiotic , and an antacid and/or an acid secretion inhibitor are prepared as separate preparations , they may be administered to the same subject simultaneously or at a time interval via the same route or different routes .
In administering the anti-Helicobacter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria of the present invention, the compound represented by the formula (I) or its salt, an antibiotic, and an antacid or an acid secretion inhibitor can be administered in dosage forms prepared by conventional methods in the same manner as the above- described anti-Helicobacter agent. For example, tablets and capsules are prepared using pharmaceutically acceptable carriers (e.g., lactose, corn starch, light silicic anhydride, microcrystalline cellulose, sucrose), binders (e.g., alpha starch, methylcellulose, carboxymethylcellulose , hydroxypropylcellulose , hydroxypropylmethylcellulose , polyvinylpyrrolidone) , disintegrating agents (e.g., carboxymethylcellulose, starch, low-substituted hydroxypropylcellulose), surfactants [e.g., Tween 80 (Kao-Atlas), Pluronic F68 (Asahi Denka, Japan), polyoxyethylene-polyoxypropylene copolymer] , antioxidants (e.g. , L-cysteine, sodium sulfite, sodium ascorbate), lubricants (e.g., magnesium stearate, talc) and substances similar thereto. A solution for injection is produced by a conventional method using an aqueous solvent (e.g., distilled water, physiological saline. Ringer's solution) or an oily solvent (e.g., sesame oil, olive oil). One or more additives can be used if necessary. Such additives include solubilizers (e.g., sodium salicylate, sodium acetate) , buffers (e.g., sodium citrate, glycerol), isotonizing agents (e.g., glucose, invert sugar), stabilizers (e.g., human serum albumin, polyethylene glycol), antiseptics (e.g., benzyl alcohol, phenol) and analgesics (e.g., benzalkonium chloride, procaine hydrochloride) . A solid preparation for injection can be produced by a conventional method using diluents (e.g., distilled water, physiological saline, glucose), activators (e.g., carboxymethylcellulose, sodium alginate), antiseptics (e.g., benzyl alcohol, phenol) and analgesics (e.g., benzalkonium chloride, procaine hydrochloride).
When the acid secretion inhibitor is a proton pump inhibitor, the same methods as those described above are generally applicable, but it is preferable that the inhibitor be administered as granules with core coated with a dusting powder consisting of the inhibitor and low- substituted hydroxypropylcellulose by the method described in Japanese Patent Unexamined Publication No.301816/1988, or a solid composition stabilized by the method described in Japanese Patent Unexamined Publication No.163018/1991, i.e. , by using a stabilizer consisting of a basic inorganic salt of magnesium and/or calcium.
The compound represented by the formula ( I ) or its salt , and/or an antibiotic can be formulated into a gastrointestinal (gastric) mucosa-adherent composition according to the methods described in Japanese Patent Unexamined Publication No. 132416/1993, Japanese Patent Unexamined Publication No. 126189/1995, and the like. Compositions for oral administration of the anti- Helicobacter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria of the present invention include tablets, pills, granules, powders , capsules , syrups , emulsions and suspensions , in the same manner as the above-described anti-Helicobacter agent. Such compositions are produced by per se known methods, and lactose, starch, sucrose, magnesium stearate etc. are used as carriers or excipients.
Compositions for non-oral administration can be prepared as suppositories, externally applied preparations etc.
Examples of suppositories include rectal suppositories and vaginal suppositories , and examples of externally applied preparations include ointments ( including creams ) , vaginal preparations , nasal preparations and transdermal preparations .
For example, suppositories can be obtained by preparing the composition of the present invention as oily or aqueous solid, semisolid or liquid suppositories.
The contents of the compound represented by the formula (I) or its salt, an antibiotic, and an antacid and/or an acid secretion inhibitor in the anti-Helicobacter agent, pharmaceutical composition, and pharmaceutical against Helicobacter bacteria of the present invention may be chosen as appropriate depending upon formulation, but the content of the compound represented by the formula (I) or its salt, for example, is about 1 to 20% by weight, preferably about 2 to 10% by weight . The antibiotic content , varying depending on the kinds of the antiboitic, is about 1 to 95% by weight, preferably about 5 to 90% by weight. The antacid content is about 20 to 90% by weight, preferably about 30 to 80% by weight, more preferably about 50 to 70% by weight , and the acid secretion inhibitor content is about 0.3 to 15% by weight, preferably about 1 to 10% by weight, more preferably about 2 to 5% by weight.
The content ratio of the compound represented by the formula (I) or its salt used, relative to the antacid and acid secretion inhibitor, varies among individual combinations . For example , when the compound represented by the formula (I) or its salt is combined with an antacid, its content ratio is about 0.01 to 0.5 times (weight ratio) , preferably about 0.1 to 0.3 times (weight ratio), that of the antacid; when the compound represented by the formula ( I ) or its salt is combinedwith an acid secretion inhibitor, its content ratio is about 3 to 70 times (weight ratio), preferably about 7 to 30 times (weight ratio) , that of the acid secretion inhibitor. The content ratio of the compound represented by the formula (I) or its salt used, relative to the antibiotic, varies depending on the kinds of the antibiotic. For example, the content ratio of the compound represented by the formula ( I ) or its salt is about 0.01 to 10 times (weight ratio), preferably about 0.1 to 5 times (weight ratio), that of the antibiotic.
In the anti-Helicobacter agent and pharmaceutical against Helicobacterbacteria of the present invention, the compound represented by formula (I) or its salt, an antibiotic, and an antacid or acid secretion inhibitor prepared as separate preparations can be administered to the same subject simultaneously. They can also administered to the same subject at a time interval. The administration frequencies of respective components may differ mutually. For example, the administration frequency of the acid secretion inhibitor is preferably 1 to 2 times/day, more preferably 1 time/day, and the administration frequency of the compound represented by the formula (I) or its salt is preferably 1 to 5 times/day, more preferably 1 to 3 times/day. The administration frequency of the antacid is preferably 1 to 5 times/day, more preferably 1 to 3 times/day. The administration frequency of the antibiotic is preferably 1 to 6 times/day, more preferably 1 to 4 times/day.
In administering the pharmaceutical composition of the present invention, it is normally preferable that the compound represented by the formula ( I ) or its salt be administered in a state in which acid secretion is suppressed by administration of acid secretion inhibitor (normally after 30 to 60 minutes following oral or non- oral administration of an acid secretion inhibitor) . When acid secretion is continuously suppressed by administration of an acid secretion inhibitor for consecutive days , the compound represented by the formula (I) or its salt can be administered simultaneously with the administration of an acid secretion inhibitor.
The dose of the anti-Helicobacter agent , pharmaceutical composition and pharmaceutical against Helicobacter bacteria of the present invention is chosen as appropriate, depending on type and symptoms of diseases , but the compound represented by the formula ( I ) or its salt is administered, per adult patient (50 kg) with gastric ulcer or duodenal ulcer, at about 0.1 to 10 g/day, preferably about 0.2 to 2 g/day for oral administration, and about 0.01 to 1 g/day, preferably about 0.02 to 0.5 g/day for non-oral administration. The antibiotic is administered, per adult patient (50 kg) , at about 0.1 to 10 g/day, preferably about 0.2 to 2 g/day for oral administration, and about 0.01 to 1 g/day, preferably about 0.02 to 0.5 g/day for non-oral administration. The antacid is administered, per adult patient (50 kg), at about 1 to 30 g/day, preferably about 2 to 5 g/day for oral administration, and the acid secretion inhibitor is administered, per adult patient (50 kg), at about 10 to 200 mg/day, preferably about 30 to 60 mg/day for oral administration, and about 10 to 200 mg/day, preferably about 30 to 60 mg/day for non-oral administration. The dose per administration of each component is determined in consideration of such daily doses, dosage forms etc. The administration frequency is not limited, but preferably 1 to 5 times/day, more preferably 1 to 3 times/day.
As stated above, the anti-Helicobacter agent. pharmaceutical composition and pharmaceutical against Helicobacter bacteria of the present invention are effective in the prevention or treatment of various digestive tract diseases (e.g., gastritis, duodenal ulcer, gastric ulcer, chronic gastritis) caused by bacteria showing toxic action in the digestive tract , particularly Helicobacter pylori .
The anti-Helicobacter agent, pharmaceutical composition and pharmaceutical against Helicobacter bacteria of the present invention are applicable to the prevention or treatment of ulcers in animals (e.g. , mammals such as humans, dogs and cats) and particularly effective in the prevention or treatment of digestive ulcers in mammals, including humans. Such digestive ulcers include gastric ulcer, duodenal ulcer, reflux esophagitis , stomal ulcer and acute and chronic gastritis .
The anti-Helicobacter agent, pharmaceutical composition and pharmaceutical against Helicobacter bacteria of the present invention may further contain mucosa-protecting antiulcer drugs etc.
Such mucosa-protecting antiulcer drugs include ( z ) - 7-[ (lR,2R,3R)-2-[ (E ) - ( 3R) -3-hydroxy-4 , 4-dimethyl-l- octenyl] -3-methyl-5-oxocyclopentyl] -5-heptenoic acid (trimoprostil, ulstar) , 1-butyric acid-7- (L-2- aminobutyric acid) -26-L-aspartic acid-27-L-valine-29-L- alanine calcitonin (Elcatonin) and 3-ethyl-7-isopropyl- 1-azurenesulfonate sodium (egualen sodium).
Further, the present invention relates to novel phosphorylamide derivatives . Such phosphorylamide derivatives include N- (diaminophosphinyl) -5-methyl-3- furancarboxamide or its salt, N- (diaminophosphinyl) - 3, 5-dimethyl-2-furancarboxamide or its salt, and N- ( diaminophosphinyl ) -3 , 5-dimethyl-2-thiophenecarboxamide or its salt.
These phosphorylamide derivatives possessing antibacterial activity based on anti-urease activity, especially antibacterial activity against Helicobacter bacteria, are effective in the prevention or treatment of digestive tract diseases of mammals such as gastritis, duodenal ulcer, gastric ulcer, and chronic gastritis, which are considered to be caused by Helicobacter bacteria, in the same manner as the compounds represented by the formula (I), (la) or (lb), or their salts.
Best Mode for Carrying Out the Invention
The present invention is hereinafter described in more detail by means of, but not limited to, the following Reference Examples , Examples , Experimental Examples and Preparation Examples. In the description below, "room temperature" means about 15 to 30 'C.
Reference Example 1
N- (Diaminophosphinyl) -4-fluorobenzamide ( Flurofamide ) 4-Fluorobenzamide (5 g) was suspended in chloroform (55 ml), and phosphorus pentachloride (7.5 g) was portionwise added. The mixture was heated under reflux for 2 hours, and cooled to room temperature , and then formic acid (1.7 g) was dropwise added. The resulting mixture was stirred at room temperature for 20 hours, and then ammonia gas was introduced into the mixture for 1 hour under ice-cooling. After the introduction, the mixture was stirred for 1 hour at room temperature. The precipitate was collected by filtration, washed with water and dried. The resulting solid was recrystallized from water to give N-
( diaminophosphinyl) -4-fluorobenzamide (0.46 g) as colorless crystals, mp 255-257 'C .
Elemental Analysis for C7H9N302FP Calcd : C, 38.72; H, 4.18; N, 19.35. Found : C, 38.65; H, 4.08; N, 19.31.
Reference Example 2
N- ( Diaminophosphinyl ) -3-pyridinecarboxamide 3-Pyridinecarboxamide (5 g) was suspended in chloroform (55 ml), and phosphorus pentachaloride (8.5 g) was added portionwise. The mixture was heated under reflux for 2 hours, and cooled to room temperature, and then formic acid (1.9 g) was added dropwise. The resulting mixture was stirred at room temperature for 20 hours, and then ammonia gas was introduced into the mixture for 1 hour. After the introduction, the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration, washed with water and dried. The resulting solid was recrystallized from water to give N-
( iaminophosphinyl ) -3-pyridinecarboxamide (0.46 g) as colorless crystals. mp 280-283 t) .
Elemental Analysis for C6H9N402P Calcd : C, 36.01; H, 4.53; N, 27.99. Found : C, 35.71; H, 4.55; N, 27.91.
Reference Example 3
N-( Diaminophosphinyl) -4-nitrobenzamide 4-Nitrobenzamide (25.4 g) was suspended in carbon tetrachloride (150 ml) , and phosphorus pentachloride (32.9 g) was added portionwise at 40 to 50 °C . The mixture was stirred under heating at 65 to 70 °C for about 50 minutes, and cooled to room temperature, and then formic acid (7 g) was added dropwise. The mixture was stirred at room temperature for 4 hours , and precipitated crystals were collected by filtration. The crystals were washed with carbon tetrachloride, and dried to give 40 g of crystals. The crystals (14.2 g) was suspended in chloroform (150 ml) , and ammonia gas was introduced under ice-cooling for 30 minutes. After the introduction, the mixture was stirred at room temperature for 1.5 hour The precipitate was collected by filtration, washed with water and dried. The resulting solid was recrystallized from water to give N- (diaminophosphinyl) -4-nitrobenzamide (7 g) as colorless crystals . mp 279-285 °C (decomp. ) . Elemental Analysis for C7H9N404P
Calcd : C, 34.44; H, 3.72; N, 22.95. Found : C, 34.33; H, 3.81; N, 22.63.
Reference Example 4
N- (Diaminophosphinyl) cinnamamide
Cinnamamide (10 g) was suspended in toluene (50 ml) , and phosphorus pentachloride (15.6 g) was added portionwise. The mixture was stirred at 70 " for 25 minutes, and cooled to room temperature and then formic acid (3.1 g) was added dropwise. The resulting mixture was stirred at room temperature for 2 hours, and precipitated crystals were collected by filtration. The crystals were washed with toluene and dried to give 4.8 g of crystals . The crystals were dissolved in tetrahydrofuran ( 150 ml) , and ammonia gas was introduced under ice-cooling for 30 minutes . After the introduction, the mixture was stirred at room temperature for 1 hour. The precipitate was collected by filtration. washed with water and dried. The resulting solid was recrystallized from methanol to give N- ( diaminophosphinyl ) cinnamamide (0.8 g) as colorless crystals . mp 176-178 .
Elemental Analysis for C9H12N302P
Calcd : C, 48.00; H, 5.37; N, 18.66. Found : C, 47.94; H, 5.31; N, 18.62.
Reference Example 5 to 36
In the same manner as Reference Example 4 , the following compounds were synthesized.
Reference Example Compound mp ( °C ) 5 N-( Diaminophosphinyl)- 187-189 4-methylbenzenesulfonamide N- ( Diaminophosphinyl) - 255-257 phenylacetamide
N- ( Diaminophosphinyl) - 185-189 4-chlorobenzamide
N- (Diaminophosphinyl) - 260-265 3-fluorobenzamide
N- (Diaminophosphinyl ) - 279-296 2 , 6-difluorobenzamide
10 N- (Diaminophosphinyl ) - 167-169 2 , 4-difluorobenzamide
11 N- (Diaminophosphinyl) - 167-169 4-chlorobenzenesulfonamide
12 N- ( diaminophosphinyl ) - 290-295 4-methoxybenzamide
13 N- (Diaminophosphinyl ) - 161-163 benzenesulfonamide
14 N- (Diaminophosphinyl) - 164-166 4-fluorobenzenesulfonamide 15 N- ( Diaminophosphinyl ) - 245-250 4-methylbenzamide
16 N- ( Diaminophosphinyl ) - 264-267 2-fluorobenzamide 17 N-( Diaminophosphinyl)- 264-269
4-cyanobenzamide
18 N-(Diaminophosphinyl)- 287-296 2-nitrobenzamide
19 N-(Diaminophosphinyl)- 185-190 4-trifluoromethylbenzamide
20 N-( Diaminophosphinyl)- 288-290 4-fluorocinnamamide
21 N- (Diaminophosphinyl) - 217-218 3 , 5-difluorobenzamide 22 N- (Diaminophosphinyl) - 200 (decomp.)
4-bromobenzamide
23 N-( Diaminophosphinyl)- 168-171 3-nitrobenzamide
24 N-(Diaminophosphinyl)- 183-187 2-trifluoromethylbenzamide
25 N- (Diaminophosphinyl ) - 171-173 2-furancarboxamide
26 N-(Diaminophosphinyl)- 201-213 1-naphthalenecarboxamide 27 N-(Diaminophosphinyl)- 178-181
3-chlorobenzamide
28 N-(Diaminophosphinyl)- 202-208 2-naphthalenecarboxamide
29 N- ( Diaminophosphinyl ) - 285-295 3-furancarboxamide
30 N-( Diaminophosphinyl)- 176-178 5-nitro-2-furancarboxamide
31 N-(Diaminophosphinyl)- 183-194 4-chlorocinnamamide 32 N-(Diaminophosphinyl)- 182-186 4-cyanocinnamamide
33 N-(Diaminophosphinyl)- 169-173 2-nitrocinnamamide
34 N-( Diaminophosphinyl)- 174-179 2 , 4-difluorocinnamamide
35 N- ( Diaminophosphinyl ) - 162-166 3-fluorocinnamamide
36 N- ( Diaminophosphinyl ) - 159-163 3 , 4-dichlorocinnamamide
Reference Example 37
N- (Diaminophosphinyl) -3-phenylpropionamide
N-(Diaminophosphinyl)cinnamamide (1 g) was dissolved in methanol (200 ml), and 10% Pd-C (wet) (0.4 g) was added. The mixture was hydrogenated at room temperature under atmospheric pressure for 30 minutes, and the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The precipitated crystals were collected by filtration, washed with diethyl ether and recrystallized from methanol to give the titled compound
(0.63 g) as colorless crystals. mp >300 "C
Elemental Analysis for C9H14N302P
Calcd : C, 47.58; H, 6.21; N, 18.49. Found : C, 47.39; H, 6.14; N, 18.28.
Reference Example 38 to 44
In the same manner as Reference Example 37 , the following compounds were synthesized.
Reference
Example Compound mp (*C )
38 N-( Diaminophosphinyl)- 160-162
3- ( 4-fluorophenyl )propionamide 39 N-( Diaminophosphinyl)- 151-157 3- ( 4-chlorophenyl)propionamide
40 N- (Diaminophosphinyl) - 162-165 3- ( 4-cyanophenyl)propionamide
41 N-( Diaminophosphinyl)- 170-175 3- ( 2 , 4-difluorophenyl )propionamide
42 N- (Diaminophosphinyl) - 149-153 3- ( 3-fluorophenyl )propionamide
43 N-(Diaminophosphinyl)- 183-187 3- ( 2-aminophenyl )propionamide 44 N- (Diaminophosphinyl)- 158-165
4-aminophenoxyacetamide
Reference Example 45 4-Nitrophenoxyacetamide A mixture of 4-nitrophenol (7.5 g) , iodoacetamide (10 g) , potassium carbonate (7.5 g) and dimethylformamide (50 ml) was stirred at 50 "C for 15 hours. The mixture was poured into ice-water, and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride , and dried over anhydrous magnesium sulfate , and then concentrated under reduced pressure. The residue was recrystallized from acetone-diisopropyl ether to give the titled compound (7.9 g) as colorless crystals, m.p. 160-161 *C
Reference Examples 46 to 59
In the same manner as Reference Example 45, the following compounds were synthesized.
Reference
Example Compound mp (* )
46 4-Methoxyphenoxyacetamide 116-117
47 4-Fluorophenoxyacetamide 111-112
48 4-Chlorophenoxyacetamide 142-143 49 2,3,5-Trimethylphenoxyacetamide 138-139 50 4-Cyanophenoxyacetamide 154-156
51 3-Chlorophenoxyacetamide 128-129
52 2-Chlorophenoxyacetamide 153-155
53 3-Fluorophenoxyacetamide 112-113 54 Phenylthioacetamide 112-113
55 4-Fluorophenylthioacetamide 122-123
56 2-Benzoxazolylthioacetamide 162-164
57 2-Benzothiazolylthioacetamide 144-147
58 5-Chloro-2-benzothiazolylthio- 180-183 acetamide
59 5-Ethoxy-2-benzothiazolylthio- 132-137 acetamide
Reference Example 60 2-Benzofurancarboxamide
2-Benzofurancarboxylic acid (6.0 g) was dissolved in tetrahydrofuran (50 ml), and N,N-dimethylformamide (3 drops) was added. Oxalyl chloride (4.9 g) was added dropwise at room temperature, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (20 ml). The resulting solution was added dropwise to a mixture of 25% aqueous ammonia (30 ml) and ethyl acetate (100 ml) with stirring under ice-cooling. The resulting mixture was stirred at room temperature for 3 hours, and then the organic layer was collected. The organic layer was washed with water and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The precipitated crystals were collected by filtration and washed with isopropyl ether to give 2- benzofurancarboxamide (4.5 g) . mp 165-166 "C .
Reference Examples 61-119 In the seune manner as Reference Example 60, the following compounds were synthesized.
Reference Example Compound mp ("C )
61 2-Methyl-5-benzoxazolecarboxamide 236-238
62 3-(5-Chloro-2-benzoxazolyl)- 230 propenamide (decomp. )
63 5-Methyl-3-phenyl-4-isoxazole- 215-216 carboxamide
64 3- ( 4-Bromo-2-thienyl ) propenamide 187-188 65 3- (2-Thienyl) propenamide 158-159 66 2-Cyano-3- ( 2-thienyl )propenamide 159-163 67 2-Thienylacetamide 150-152 68 3-Thienylacetamide 155-157 69 2-Thiophenecarboxamide 181-183 70 3-Thiophenecarboxamide 186-189 71 5-Chloro-2-thiophenecarboxamide 102-104 72 5-Bromo-2-thiophenecarboxamide 112-113 73 5-Methyl-2-thiophenecarboxamide 125-128 74 4, 5-Dibromo-2-thiophenecarboxamide 172-175 75 4-Bromo-2-thiophenecarboxamide 153-157 76 3-Methyl-2-thiophenecarboxamide 124-127 77 5-Ethyl-2-thiophenecarboxamide 145-147 78 5-Nitro-2-thiophenecarboxamide 191-192 79 5-Bromo-3-thiophenecarboxamide 100-101 80 5-Cyano-2-thiophenecarboxamide 222-2231' 81 5-Difluoromethyl-2-thiophene- 137-138 carboxamide
82 3-Chloro-2-thiophenecarboxamide 102-104 83 2-Methyl-3-thiophenecarboxamide 137-138 84 3-Bromo-2-thiophenecarboxamide 112-113 85 5-Acetyl-2-thiophenecarboxamide 233-236 ( decomp . )
86 5-Methanesulfonyl-2-thiophene- 165-169 carboxamide
87 3-Difluoromethyl-2-thiophene- 143-144 carboxamide
88 2-Difluoromethyl-3-thiophene- 119-120 carboxamide
89 5-Nitro-3-thiophenecarboxamide 163-165
90 5-Methoxy-2-thiophenecarboxamide 158-160
91 3-Cyano-2-thiophenecarboxamide 174-176
92 4-Methoxy-2-thiophenecarboxamide 163-165 93 2,5-Dichloro-3-thiophene- 98-100 carboxamide
94 2-Bromo-3-thiophenecarboxamide 141-142
95 3-Ethyl-2-thiophenecarboxamide 146-149
96 4-Methyl-2-thiophenecarboxamide 109-114 97 5-Bromo-4-methyl-2-thiophene- 162-164 carboxamide
98 5-Chloro-3-thiophenecarboxamide 138-1392)
99 5-Difluoromethyl-3-thiophene- 83-84 carboxamide 100 2,5-Dimethyl-3-thiphenecarboxamide 137-138
101 5-Chloro-2-methyl-3-thiophene- 125-1273' carboxamide
102 4-Chloro-5-methyl-3-thiophene- 136-137 carboxamide 103 5-Chloro-4-methyl-3-thiophene- 144-145 carboxamide
104 4,5-Dichloro-2-thiophene- 163-164 carboxamide
105 4-Bromo-3-thiophenecarboxamide 151-153 106 2-Chloro-3-thiophenecarboxamide 131-132
107 5-Bromo-2-furancarboxamide 149-150
108 5-Chloro-2-furancarboxamide 160-161
109 5-Bromo-3-furancarboxamide 174-176
110 5-Methyl-2-furancarboxamide 135-136 111 5-Ethyl-2-furancarboxamide 107-109 112 2-Methyl-3-furancarboxamide 87-88
113 2-Chloro-3-furancarboxamide 104-105
114 5-Chloro-3-furancarboxamide 180-181
115 5-Difluoromethyl-2 -furan- 80-81 carboxamide
116 2-Trifluoromethyl-5-methyl-3- 127-128 furancarboxamide
117 2, 5-Dimethyl-3-furancarboxamide 128-129
118 5-Chloro-2-methyl-3-furan- 132-133 carboxamide
119 2-Ethyl-3-f rancarboxamide 67-69
1) 5-Cyano-2-thiophenecarboxamide
The compound of Reference Example 80 was synthesized by the following method.
5-Formyl-2-thiophenecarboxylic acid (2.64 g) (synthesized in accordance with the method described in Tetrahedron, 41, 3803 (1985)) was dissolved in tetrahydrofuran (30 ml), and N,N-dimethylformamide (3 drops ) was added. Oxalyl chloride (2.2 ml ) was added dropwise at room temperature, and the mixture was stirred for 2 hours . The reaction mixture was concentrated under reduced pressure and the concentrate was dissolved in ethyl acetate ( 50 ml) . The resulting solution was added dropwise to a mixture of 25% aqueous ammonia ( 50 ml) and ethyl acetate (200 ml) with stirring under ice-cooling. The resulting mixture was stirred at room temperature for 1 hour, and then the organic layer was collected. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure to give 5-formyl-2- thiophenecarboxamide (1.77 g). A mixture of 5-formyl- 2-thiophenecarboxamide (1.55 g), N,0- bis(trifluoroacetyl)hydroxyamine (3.5 g), pyridine (2ml) and toluene (110 ml) was stirred under reflux for 1 hour. and then cooled, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-cyano-2-thiophenecarboxamide (0.6 g). mp 222-223 C .
2) 5-Chloro-3-thiophenecarboxamide
The compound of Reference Example 98 was synthesized by the following method. 3-Thiophenecarboxyalic acid ethyl ester (1.98 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.5 ml) was added under ice-cooling. The mixture was stirred at 10 °C for 30 minutes, and then 10% aqueous sodium thiosulfate (100 ml) was added. The resulting mixture was stirred at room temperature for 2 hours, and then extracted with diethyl ether . The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a mixture of 5-chloro-3-thiophenecarboxylic acid ethyl ester and 2 , 5-dichloro-3-thiophenecarboxylic acid ethyl ester. This mixture was dissolved in a mixture of ethanol (15 ml) and tetrahydrofuran (15 ml) , and IN aqueous sodium hydroxide (20 ml) was added. The resulting mixture was stirred at room temperature for 2 hours , and then washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate . The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of 5-chloro-3-thiophenecarboxylic acid and 2, 5-dichloro-3- thiophenecarboxylic acid (1.7 g) . This mixture was suspended in toluene (15 ml) , and oxalyl chloride (1.56 ml) was added dropwise. Further, N,N- imethylformamide (1 drop) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduce pressure , and the concentrate was dissolved in ethyl acetate ( 10 ml) . The resulting solution was added dropwise to a mixture of 25% aqueous ammonia (16 ml) and ethyl acetate (70 ml) with stirring under ice- cooling. The resulting mixture was stirred at room temperature for 10 minutes, and the organic layer was collected. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-chloro-3-thiophenecarboxamide (0.76 g). mp 138-139 * .
3) 5-Chloro-2-methyl-3-thiophenecarboxamide The compound of Reference Example 101 was synthesized by the following method.
2-Methyl-3-thiophenecarboxylic acid (5.69 g) synthesized in the same manner as Reference Example 127 was dissolved in N,N-dimethylformamide (50 ml) , and iodoethane (3.2 ml) and potassium carbonate (5.52 g) were added. The reaction mixture was stirred at room temperature for 15 hours, and poured into water, and then extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a crude product of 2-methyl-3-thiophenecarboxylic acid ethyl ester. This crude product of 2-methyl-3- thiophenecarboxyliσ acid ethyl ester was dissolved in acetonitrile (50 ml), and sulfuryl chloride (3.0 ml) in acetonitrile (20 ml) was added dropwise. The mixture was stirred for 1 hour under cooling over a water bath, and then 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours, and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give a crude product of 5-chloro-2-methyl-3- thiophenecarboxylic acid ethyl ester. This crude product was dissolved in a mixture of ethanol (25 ml) and tetrahydrofuran (25 ml), and IN aqueous sodium hydroxide (50 ml) was added. The resulting mixture was stirred at 65 *C for 2 hours, and then washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 5-chloro-2-methyl- 3-thiophenecarboxylic acid. This crude product of 5- chloro-2-methyl-3-thiophenecarboxylic acid was suspended in toluene (50 ml) , and oxalyl chloride (4.6 ml) was added dropwise. Further, N,N-dimethylformamide (3 drops) was added, and the reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure, and the concentrate was dissolved in ethyl acetate (20 ml). The resulting solution was added dropwise to a mixture of 25% aqueous ammonia (56 ml) and ethyl acetate (150 ml) with stirring under ice-cooling. The mixture was stirred at room temperature for 10 minutes, and then the organic layer was collected. The aqueous layer was extracted with ethyl acetate . The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5- chloro-2-methyl-3-thiophenecarboxamide (1.6 g) mp 125-127 "C .
Reference Example 120
4,5-Dibromo-2-thiophenecarboxylie acid
2-Thiophenecarboxylic acid (3.84 g) was added to bromine (9.3 ml), and the mixture was stirred at room temperature for 15 hours. An excess amount of bromine was neutralized with aqueous ammonium carbonate, and then the mixture was acidified with IN hydrochloric acid. The precipitated crystals were collected by filtration, and dissolved in IN sodium hydroxide. The mixture was acidified with IN hydrochloric acid, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give 4,5- dibromo-2-thiophenecarboxylic acid (7.48 g) as crystals, mp 225-227 , .
Reference Example 121
4-Bromo-2-thiophenecarboxylic acid
Silver nitrate (1.7 g) was dissolved in water (40 ml), and sodium hydroxide (0.44 g) in water (1 ml) was added. Precipitated silver oxide was collected by filtration and suspended in 10% aqueous sodium hydroxide (20 ml). The resulting suspension was heated at 60 to 65 *C , and 4- bromo-2-thiophenecarbaldehyde (1.91 g) was added dropwise . The mixture was stirred for 30 minutes, and precipitates were removed by filtration. The filtrate was washed with diethyl ether, and IN hydrochloric acid was added to the aqueous layer to adjust the pH to 4. The aqueous layer was extracted with ethyl acetate , and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-bromo-2-thiophenecarboxylic acid (1.39 g) as crystals, mp 124-126 T..
Reference Example 122
5-Ethyl-2-thiophenecarboxylic acid l,3-Dimethyl-2-(2-thienyl)imidazolidine (5.46 g)
(synthesized in accordance with the method described in Tetrahedron, 41, 3803 (1985)) and N,N,N' ,N' - tetramethylethylenediamine (4.7 ml) were dissolved in tetrahydrofuran (150 ml). The mixture was cooled to -78 , and n-butyllithium ( 1.6M in hexane, 19.5 ml) was slowly added dropwise. The mixture was stirred at the same temperature for 2 hours, and iodoethane (2.4 ml) was added. The mixture was slowly heated to room temperature and then stirred for 15 hours. The reaction mixture was concentrated under reduced pressure, and 10% sulfuric acid (200 ml) was added to the residue. The mixture was stirred for 24 hours and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-ethyl-2-thiophenecarbaldehyde (1.68 g) as oil. 5-Ethyl-2-thiophenecarbaldehyde (1.68 g) was dissolved in acetonitrile ( 20 ml ) , and sodium dihydrogen phosphate (0.54 g) in water (10 ml) and 30% hydrogen peroxide (2.0 ml) were added. Sodium chlorite (3.0 g) in water (20 ml) was then added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours , alkalifled with IN sodium hydroxide and washed with diethyl ether . The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-ethyl-2-thiophenecarboxylic acid (1.48 g) as crystals, mp 65-66 "C .
Reference Example 123
5-Nitro-2-thiophenecarboxylic acid
5-Nitro-2-thiophenecarbaldehyde (7.86 g) was dissolved in acetonitrile (50 ml), and sodium dihydrogen phosphate (1.6 g) in water (20 ml) and 30% aqueous hydrogen peroxide (5.9 ml) were added. Further, sodium chlorite (8.0 g) in water (70 ml) was added dropwise under ice-cooling. The reaction mixture was stirred at room temperature for 2 hours , and then sodium thiosulfate was added to remove an excess amount of hydrogen peroxide . The mixture was alkalifled with IN sodium hydroxide and extracted with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-nitro-2-thiophenecarboxylic acid (7.83 g) as crystals, mp 158-159 °C .
Reference Example 124 5-Bromo-3-thiophenecarboxylic acid
A mixture of 3-thiophenecarboxylic acid (12.81 g) , pyridinium bromide perbromide (35.54 g) and acetic acid (50 ml) was stirred at 45 -. for 48 hours. The mixture was poured into ice-water and precipitated crystals were collected by filtration. The crystals were dissolved in ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-bromo-3- thiophenecarboxylic acid (19.78 g) as crystals, mp 137-138 *C .
Reference Example 125
5-Difluoromethyl-2-thiophenecarboxylic acid
5-Formyl-2-thiophenecarboxylic acid methyl ester (1.7 g) (synthesized in accordance with the method described in J. Heterocyclic Chem. , 28, 17 (1991)) in methylene chloride (10 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.6 g) in methylene chloride (20 ml) at room temperature. The mixture was stirred at room temperature for 2 hours , and then diethylaminosulfur trifluoride (DAST) (0.5 g) was further added. The resulting mixture was stirred at room temperature for 1 hour, and water (10 ml) and saturated aqueous sodium bicarbonate (10 ml) were added. The resulting mixture was allowed to stand overnight. The organic layer was collected, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5- difluoromethyl-2-thiophenecarboxylic acid methyl ester (0.81 g). 5-Difluoromethyl-2-thiophenecarboxylic acid methyl ester (2.58 g) synthesized in this manner was dissolved in methanol (50 ml) , and IN sodium hydroxide (30 ml) was added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-difluoromethyl-2-thiophenecarboxylic acid (2.13 g) as crystals, mp 111-112 V .
Reference Example 126
3-Chloro-2-thiophenecarboxylic acid
This compound was synthesized in accordance with the method described in Heterocycles , 23, 1431 (1985).
Reference Example 127
2-Methyl-3-thiophenecarboxylic acid
3-Thiophenecarboxylic acid (3.84 g) was dissolved in tetrahydrofuran (50 ml) , and the mixture was cooled to -78 'C. n-Butyllithium ( 1.6M in hexane, 41.3 ml) was slowly added dropwise, and the mixture was stirred at the same temperature for 30 minutes. Iodomethane (3.7 ml) in tetrahydrofuran (10 ml) was added dropwise. The resulting mixture was heated to room temperature and stirred for 15 hours . The mixture was poured into water and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-methyl-3- thiophenecarboxylic acid (3.98 g) as crystals. p 71 - 73 °C .
Reference Example 128 3-Bromo-2-thiophenecarboxylic acid 3-Amino-2-thiophenecarboxylic acid methyl ester (9.4 g) was suspended in hydrobromic acid (20 ml) , and the mixture was stirred at room temperature for 30 minutes . The mixture was cooled to 0 "C , and sodium nitrite (4.2 g) in water (10 ml) was added dropwise below 10 'C . The mixture was stirred for 1 hour, and then poured into copper (I) bromide (9.06 g) in hydrobromic acid (25 ml) . The resulting mixture was stirred at 60 °C for 1 hour and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure and distilled under reduced pressure to give 3-bromo-2-thiophenecarboxylic acid methyl ester (7.99 g) as crystals, bp 101 /8 mmHg, mp 47-48 C.
3-Bromo-2-thiophenecarboxylic acid methyl ester (7.74 g) was dissolved in a mixture of methanol (35 ml) and tetrahydrofuran (35 ml), and IN aqueous sodium hydroxide (53 ml) was added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-bromo-2-thiophenecarboxylic acid (7.05 g) as crystals, mp 200-201 °C .
Reference Example 129
5-Acetyl-2-thiophenecarboxylic acid
2-Methyl-2-(2-thienyl)-l,3-dioxolan (6.6 g) (synthesized in accordance with the method described in Tetrahedron, 41, 3803 (1985)) was dissolved in tetrahydrofuran (200 ml), and N,N,N' ,N' - tetramethylethylenediamine (5.87 ml) was added. The mixture was cooled to -78 " , and n-butyllithium (1.6M in hexane, 25 ml) was slowly added dropwise. The mixture was stirred at the same temperature for 2 hours, and warmed slowly to room temperature for a period of 2 hours with introducing carbon dioxide gas . The reaction mixture was concentrated under reduced pressure, and 2N hydrochloric acid ( 200 ml) was added. The mixture was stirred for 3 hours , and precipitated crystals were collected by filtration, washed with water and dried to give 5-acetyl-2- thiophenecarboxylic acid (3.87 g) as crystals, mp 283 °C .
Reference Example 130 5-Methanesulfonyl-2-thiophenecarboxylic acid
5-Methylthio-2-thiophenecarbaldehyde (4.48 g) (synthesized in accordance with the method described in Tetrahydron, 41, 3803 (1985)) was dissolved in acetonitrile (20 ml), and sodium dihydrogen phosphate (1.2 g) in water (10 ml) and 30% aqueous hydrogen peroxide (3.5 ml) were added. Further sodium chlorite (3.85 g) in water (10 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 15 hours , and sodium sulfite (1 g) was added. The mixture was alkalifled with IN aqueous sodium hydroxide and extracted with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-diisopropyl ether to give 5- methanesulfonyl-2-thiphenecarboxylic acid (1.73 g) as crystals . mp 190-194 " (decmop.).
Reference Example 131 3-Difluoromethyl-2-thiophenecarboxylic acid
3-Thiophenecarbaldehyde (22.43 g) was dissolved in toluene (200 ml) and N,N' -dimethylethylenediamine (22.3 ml) was added. The mixture was stirred for 16 hours with removing azeotropic water under reflux by Dean-stark trap. The reaction mixture was concentrated under reduced pressure and the residue was distilled under reduced pressure to give 1, 3-dimethyl-2- ( 3-thienyl)imidazolidine (5.88 g). bp 63-64 'C/O.β mmHg, mp 112-113 . l,3-Dimethyl-2-( 3-thienyl) imidazolidine (9.06 g) synthesized in this manner was dissolved in tetrahydrofuran ( 100 ml) , andN,N,N' ,N' -tetramethylethylenediamine ( 7.85 ml) was added. The mixture was cooled to -78 "C , and n-butyllithium ( 1.6M in hexane, 32.5 ml) was slowly added dropwise. The mixture was stirred at the same temperature for 2 hours and poured into a mixture of dry ice and diethyl ether. The resulting mixture was warmed to room temperature with stirring, and concentrated under reduced pressure. 10% Sulfuric acid (100 ml) was added to the residue, and the mixture was stirred for 15 hours and extracted with diethyl ether . The diethyl ether layer was extracted with IN aqueous sodium hydroxide, and the aqueous layer was washed with diethyl ether, acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-formyl-2- thiophenecarboxylic acid (5.92 g) as crystals, mp 119-120 "C . 3-Formyl-2-thiophenecarboxylic acid (3.12 g) was dissolved in N,N-dimethylformamide ( 30 ml) , and iodoethane (1.76 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours and poured into water. The mixture was extracted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate. dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 3- formyl-2-thiophenecarboxylic acid ethyl ester (2.91 g). 3-Formyl-2-thiphenecarboxylic acid ethyl ester (1.84 g) in methylene chloride (10 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.45 ml) in methylene chloride (10 ml) at room temperature. The mixture was stirred at room temperature for 3 hours , and saturated aqueous sodium bicarbonate was added. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-difluoromethyl-2-thiophenecarboxylic acid ethyl ester (1.58 g) . 3-Difluoromethyl-2-thiophenecarboxylic acid ethyl ester was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml), and IN aqueous sodium hydroxide (11 ml) was added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-difluoromethyl-2- thiophenecarboxylic acid (1.12 g) as crystals, mp 119-120 *C .
Reference Example 132
2-Difluoromethyl-3-thiphenecarboxylic acid 3-Thiophenecarboxylic acid (3.48 g) was dissolved in tetrahydrofuran (50 ml), and N,N,N' ,N' - tetramethylethylenediamine ( 10 ml) was added. The mixture was cooled to -78 *C , and n-butyllithium ( 1.6M in hexane, 41.3 ml) was slowly added dropwise . The mixture was stirred at the same temperature for 1 hour, and N,N- dimethylformamide (4.6 ml ) was added dropwise . The mixture was warmed to room temperature and stirred for 15 hours. The reaction mixture was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give a mixture of 2-formyl-3-thiophenecarboxylic acid and 5- formyl-3-thiophenecarboxylic acid (2.11 g) . This mixture was dissolved in N,N-dimethyIformamide (30 ml), and iodoethane (0.95 ml) and potassium carbonate (1.66 g) were added. The reaction mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 2-formyl-3-thiophenecarboxylic acid ethyl ester (1.75 g) . 2-Formyl-3-thiophenecarboxylic acid ethyl ester (1.66 g) in methylene chloride (20 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.32 ml) in methylene chloride (10 ml) at room temperature. The mixture was stirred at room temperature for 15 hours, and saturated aqueous sodium bicarbonate was added. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-difluoromethyl-3- thiophenecarboxylic acid ethyl ester (1.08 g) . 2-
Difluoromethyl-3-thiophenecarboxylic acid ethyl ester was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml), and IN aqueous sodium hydroxide (7.8 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-difluoromethyl-3-thiophenecarboxylic acid (0.88 g) as crystals, mp 127-128 * .
Reference Example 133
5-Nitro-3-thiophenecarboxylic acid 3-Thiophenecarboxylic acid (5.12 g) was added portionwise to a mixture of nitric acid (20 ml) and sulfuric acid (11.5 ml) below 5 "C . The mixture was stirred at the same temperature for 30 minutes, and poured into ice water. The mixture was alkalified with IN sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure . The residue was recrystallized from ethyl acetate to give 5-nitro-3- thiophenecarboxylic acid (4.45 g) as crystals, mp 117-118 *C .
Reference Example 134
5-Methoxy-2-thiophenecarboxylic acid 2-Methoxythiophene (4.0 ml) was dissolved in tetrahydrofuran (50 ml) , and the mixture was cooled to -78 *C . n-Butyllithium ( 1.6M in hexane , 31 ml) was slowly added dropwise, and the mixture was stirred at the same temperature for 1 hour. The mixture was poured into a mixture of dry ice and diethyl ether, and warmed to room temperature with stirring. The solvent was distilled off, and the residue was acidified with IN hydrochloric acid. The mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-methoxy-2- thiophenecarboxylic acid (5.62 g) . mp 167-168 *C .
Reference Example 135 3-Cyano-2-thiophenecarboxylic acid
3-Formyl-2-thiophenecarboxylic acid (4.68 g) was dissolved in N,N-dimethylformamide (30 ml), and benzyl bromide (3.9 ml) and potassium carbonate (4.15 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water, and then extracted with diethyl ether. The extract was washed with 5% potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 3- formyl-2-thiophenecarboxylic acid benzyl ester (2.65 g) . 3-Formyl-2-thiophenecarboxylic acid benzyl ester (2.46 g) was dissolved in ethanol (50 ml), and hydroxylamine hydrochloride (0.83 g) and pyridine (0.97 ml) were added. The mixture was stirred under reflux for 3 hours , and concentrated under reduced pressure. The residue was poured into water, and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-aldoxime- 2-thiophenecarboxylic acid benzyl ester (2.61 g) . This product was dissolved in acetic anhydride (20 ml) , and the mixture was stirred at 160 "C for 10 hours . The mixture was cooled, poured into water (100 ml) and extracted with diethyl ether. The extract was washed with saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3-cyano-2-thiophenecarboxylic acid benzyl ester (2.01 g). This product was dissolved in tetrahydrofuran (40 ml), and 5% Pd-C (wet) (0.25 g) was added. The mixture was hydrogenated at room temperature under atmospheric pressure for 72 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give 3-cyano-2-thiophenecarboxylic acid (0.98 g) as crystals, mp 204-205 °C .
Reference Example 136
4-Methoxy-2-thiophenecarboxylic acid 3-Methoxythiophene (4.0 ml) was dissolved in tetrahydrofuran (50 ml) , and the mixture was cooled to -78 °C . n-Butyllithium ( 1.6M in hexane, 19.5 ml) was slowly added dropwise, and the mixture was stirred at the same temperature for 1 hour. The mixture was poured into a mixture of dry ice and diethyl ether, and warmed to room temperature with stirring. The solvent was distilled off, and the residue was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of 3-methoxy-2- thiophenecarboxylic acid and 4-methoxy-2- thiophenecarboxylic acid (6.0 g) . This mixture was dissolved in N,N-dimethylformamide (50 ml), and iodoethane (3.0 ml) and potassium carbonate (5.25 g) were added. The mixture was stirred at room temperature for 15 hours , poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 4- methoxy-2-thiophenecarboxylic acid ethyl ester (2.69 g) and 3-methoxy-2-thiophenecarboxylic acid ethyl ester (3.98 g). 4-Methoxy-2-thiophenecarboxylic acid ethyl ester (2.69 g) was dissolved in a mixture of ethanol (25 ml) and tetrahydrofuran (25 ml), and IN aqueous sodium hydroxide (22 ml) was added. The mixture was stirred at room temperature for 3 hours and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate . The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methoxy-2-thiophenecarboxylaic acid (2.11 g) as crystals, mp 172-173 °C .
Reference Example 137
2, 5-Dichloro-3-thiophenecarboxylic acid
3-Thiophenecarboxylic acid ethyl ester (1.56 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (5.36 g) was added. The mixture was stirred at room temperature for 4 hours, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred for 15 minutes and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2, 5-dichloro-3-thiophenecarboxylic acid ethyl ester (2.3 g) . 2 , 5-Dichloro-3-thiophenecarboxylic acid ethyl ester (2.25 g) was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml) , and IN aqueous sodium hydroxide ( 20 ml) was added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and and concentrated under reduced pressure to give 2,5- dichloro-3-thiophenecarboxylic acid (1.89 g) as crystals, mp 140-141 *C .
Reference Example 138 2-Bromo-3-thiophenecarboxylic acid A mixture of 2-bromo-3-methylthiophene (17.7 g) , N- bromosuccinimide (17.7 g) , 2,2' -azobis(isobutyronitrile) (0.32 g) and carbon tetrachloride (200 ml) was stirred for 4 hours under reflux. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to give 3-bromomethyl-2- bromothiophene (12.56 g) . A suspension of 3- bromomethyl-2-bromothiophene (6.30 g) , potassium acetate (9.8 g) in acetone (100 ml) was stirred at room temperature for 3 hours. The mixture was poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 3-acetoxymethyl-2- bromothiophene (5.8 g) . This crude product was dissolved in tetrahydrofuran ( 50 ml) , and IN aqueous sodium hydroxide (50 ml) and ethanol (20 ml) were added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 3-hydroxymethyl-2-bromothiophene (4.6 g) . This crude product of 3-hydroxymethyl-2-bromothiophene was dissolved in methylene chloride (100 ml), and manganese dioxide (15 g) was added. The mixture was stirred at room temperature for 6 hours, and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of 2-bromo-3- thiophenecarbaldehyde (3.92 g) . The crude product of 2-bromo-3-thiophenecarbaldehyde was dissolved in acetonitrile (50 ml) , and sodium dihydrogen phosphate (1.0 g) in water (15 ml) and 30% aqueous hydrogen peroxide (2.5 ml) were added. Further, sodium chlorite (2.7 g) in water (30 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours , alkalified with IN aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-bromo-3-thiophenecarboxylic acid (2.89 g) as crystals, mp 151-154 °C .
Reference Example 139 3-Ethyl-2-thiophenecarboxylic acid
A mixture of 3-acetylthiophene (20 g) , ethyleneglycol (10.54 g) , p-toluenesulfonic acid (0.15 g) and toluene (200 ml) was stirred for 16 hours under reflux with removing azeotropic water by Dean-Stark trap. The mixture was cooled, washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2-methyl-2-( 3-thienyl) -1 , 3-dioxolan (12.6 g) . 2-Methyl-2-( 3-thienyl) -1 , 3-dioxolan (12.0 g) was dissolved in tetrahydrofuran (200 ml), and N,N,N' ,N* - tetramethylethylenediamine (1.3 ml) was added. The mixture was cooled to -78 °C , and n-butyllithium ( 1.6M in hexane, 49 ml) was slowly added dropwise. The mixture was stirred at the same temperature for 2 hours , and then warmed slowly to room temperature for a period of 2 hours with introducing carbon dioxide gas . The reaction mixture was concentrated under reduced pressure, and 2N hydrochloric acid ( 200 ml) was added. The mixture was stirred for 3 hours , and precipitated crystals were collected by filtration, washed with water and dried to give 3-acetyl-2- thiophenecarboxylic acid (10 g) as crystals, mp 155-156 t .
3-Acetyl-2-thiophenecarboxylic acid (3.0 g) was dissolved in N,N-dimethylformamide (50 ml), and iodomethane (4.0 ml) and potassium carbonate (6.0 g) were added. The mixture was stirred at room temperature for 3 hours, poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-acetyl-2- thiophenecarboxylic acid methyl ester (3.07 g) as crystals . mp 59-60 C .
3-Acetyl-2-thiophenecarboxylic acid methyl ester (3.87 g) synthesized in this manner was dissolved in methanol (50 ml), and sodium borohydride (0.95 g) was added under ice-cooling. The mixture was stirred at room temperature for 1 hour, and IN hydrochloric acid (50 ml) was added. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3- ( 1-hydroxyethyl) -2- thiophenecarboxylic acid methyl ester (3.77 g) . This product was dissolved in ethyl acetate (100 ml), and methanesulfonyl chloride (2.86 g) , triethylamine (3.5 g) and dimethylaminopyridine (0.2 g) were added. The mixture was stirred at room temperature for 2 hours, and IN hydrochloric acid (50 ml) was added. The mixture was extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in acetone (100 ml), and sodium iodide ( 10 g) was added. The mixture was stirred at room temperature for 2 hours , and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The desired fractions were concentrated under reduced pressure to give 3-(l- iodoethyl) -2-thiophenecarboxylic acid methyl ester (3.0 g). 3- (1-iodoethyl) -2-thiophenecarboxylic acid methyl ester was dissolved in dimethylsulfoxide (10 ml), and sodium borohydride (0.4 g) was added at room temperature . The mixture was stirred for 1 hour, and IN hydrochloric acid was added. The mixture was extracted with ethyl acetate. and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3- ethyl-2-thiophenecarboxylic acid methyl ester (1.0 g) . A mixture of 3-ethyl-2-thiophenecarboxylic acid methyl ester (1.0 g), IN aqueous sodium hydroxide (15 ml), tetrahydrofuran (30 ml) and methanol (10 ml) was stirred at room temperature for 1 hour . The mixture was washed with diethyl ether, and the aqueous layer was acidified with IN hydrochloric acid and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3-ethyl-2- thiophenecarboxylic acid (0.9 g) as crystals, mp 106-109 °C .
Reference Example 140
4-Methyl-2-thiophenecarboxylic acid
5-Bromo-4-methyl-2-thiophenecarboxylic acid (3.33 g) was dissolved in dimethylformamide (50 ml) , and potassium carbonate (4.0 g) and iodomethane (4.0 ml) were added. The mixture was stirred at room temperature for 2 hours , diluted with ethyl acetate (200 ml), washed with IN hydrochloric acid, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-bromo-4- methyl-2-thiophenecarboxylic acid methyl ester (3.47 g) . A mixture of 5-bromo-4-methyl-2-thiophenecarboxylic acid methyl ester (2.36 g) , zinc powder (1.65 g), acetic acid (10 ml) and water (10 ml) was stirred under reflux for 3 hours. Zinc powder (1 g) and acetic acid (10 ml) were further added. The mixture was stirred under reflux for 1 day, cooled, poured into concentrated aqueous ammonia and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methyl-2-thiophenecarboxylic acid methyl ester (1.42 g). 4-Methyl-2-thiophenecarboxylic acid methyl ester (1.42 g) was dissolved in a mixture of methanol ( 10 ml) and tetrahydrofuran ( 30 ml) , and IN aqueous sodium hydroxide ( 15 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-methyl-2-thiophenecarboxylic acid (1.16 g) .
Reference Example 141
5-Bromo-4-methyl-2-thiophenecarboxylic acid
Aluminum chloride (14.6 g) was added portionwise to 2-bromo-3-methylthiophene (8.85 g) and dichloromethyl methyl ether (6.27 g) in dichloromethane (100 ml) under ice-cooling. The mixture was stirred at room temperature for 1 hour and poured into ice water, acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was washed with aqueous sodium chloride , dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-bromo-4-methyl-2- thiophenecarbaldehyde (8.0 g). 5-Bromo-4-methyl-2- thiophenecarbaldehyde (6.18 g) was dissolved in acetonitrile ( 100 ml) , and sodium dihydrogen phosphate (1.3 g) in water (20 ml) and 30% aqueous hydrogen peroxide (3.8 ml) were added. Further sodium chlorite (4.07 g) in water (50 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours , alkalified with IN aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-bromo-4-methyl-2- thiophenecarboxylic acid (6.01 g) as crystals. mp 159 - 161 *C .
Reference Example 142
5-Difluoromethyl-3-thiophenecarboxylic acid 5-Bromo-3-thiophenecarboxylic acid (4.14 g) was dissolved in tetrahydrofuran (50 ml) , and the mixture was cooled to -78 °C . n-Butyllithium ( 1.6M in hexane , 27.5 ml) was slowly added dropwise. The resulting mixture was stirred at the same temperature for 1 hour, and N,N- dimethylformamide (3.1 ml) was added. The mixture was warmed slowly to room temperature and concentrated under reduced pressure. The concentrate was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 5-formyl-3-thiophenecarboxylic acid (3.12 g) . 5- Formyl-3-thiophenecarboxylic acid (3.12 g) was dissolved in N,N-dimethylformamide (50 ml) , and iodoethane (1.58 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with ethyl acetate. The extract was washed with 5 % potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-formyl-3- thiophenecarboxylic acid ethyl ester (0.71 g). 5- Formyl-3-thiophenecarboxylic acid ethyl ester (1.47 g) synthesized in this manner in methylene chloride (10 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.2 ml) in methylene chloride (10 ml) at room temperature . The mixture was stirred at room temperature for 15 hours, and saturated aqueous sodium bicarbonate was added. The organic layer was collected, dried over anhydrous magnesium sulfate and concentrated under reduced pressure . The residue was purified by silica gel column chromatography to give 5-difluoromethyl-3- thiophenecarboxylic acid ethyl ester (0.7 g) . 5- Difluoromethyl-3-thiophenecarboxylic acid ethyl ester was dissolved in a mixture of ethanol ( 5 ml) and tetrahydrofuran (5 ml), and IN aqueous sodium hydroxide (5 ml) was added. The mixture was stirred at room temperature for 1 hour and washed with diethyl ether . The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5- difluoromethyl-3-thiophenecarboxylic acid (0.58 g) as crystals, mp 131-132 °C .
Reference Example 143
2 , 5-Dimethyl-3-thiophenecarboxylic acid
Phosphorus oxychloride (10 ml) was slowly added dropwise to dimethylformamide (30 g) under ice-cooling, and 2,5- dimethylthiophene (11.2 g) was added. The mixture was stirred at 100 °C for 15 hours, poured into water and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 2, 5-dimethyl-3- thiophenecarbaldehyde (1.41 g) . 2, 5-Dimethyl-3- thiophenecarbaldehyde (3.89 g) synthesized in this manner was dissolved in acetonitrile (30 ml), and sodium dihydrogen phosphate (1.2 g) in water (15 ml) and 30% aqueous hydrogen peroxide (3.5 ml ) were added dropwise . Further, sodium chlorite (3.75 g) in water (20 ml) was added dropwise under ice-cooling. Then the mixture was stirred at room temperature for 2 hours , alkalified with IN aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2 , 5-dimethyl-3-thiophenecarboxylic acid (4.09 g) as crystals. mp 113-114 * .
Reference Example 144
4-Chloro-5-methyl-2-thiophenecarboxylic acid
5-Methyl-2-thiophenecarboxylic acid (2.84 g) was dissolved in N,N-dimethylformamide (30 ml), and iodoethane (1.68 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours , poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-methyl-2- thiophenecarboxyliσ acid ethyl ester (1.84 g) . 5- Methyl-2-thiophenecarboxylic acid ethyl ester (1.84 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.31 ml) in acetonitrile (20 ml) was added dropwise. The mixture was stirred for 1.5 hour under cooling over a water bath, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether . The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 4-chloro-5- methyl-2-thiophenecarboxylic acid ethyl ester (1.67 g). 4-Chloro-5-methyl-2-thiophenecarboxylic acid ethyl ester (1.67 g) was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml), and IN aqueous sodium hydroxide (16 ml) was added. The mixture was stirred at 60 , for 2 hours and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-chloro-5-methyl-2-thiophenecarboxylic acid (0.98 g) as crystals, mp 164-165 IC.
Reference Example 145
5-Chloro-4-methyl-2-thiophenecarboxylic acid 4-Methyl-2-thiophenecarboxylic acid ethyl ester (3.4 g) synthesized in accordance with the method of Reference Example 140 was dissolved in acetonitrile (30 ml), and sulfuryl chloride ( 2.4 ml ) in acetonitrile ( 20 ml ) was added dropwise. The mixture was stirred at room temperature for 30 minutes, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-chloro-4- methyl-2-thiophenecarboxylic acid ethyl ester (4.09 g) . 5-Chloro-4-methyl-2-thiophenecarboxylic acid ethyl ester (4.09 g) was dissolved in a mixture of ethanol (20 ml) and tetrahydrofuran (20 ml), and IN aqueous sodium hydroxide (40 ml) was added. The mixture was stirred at 60 " for 2 hours and washed with diethyl ether . The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-chloro-4-methyl-2-thiophenecarboxylic acid (2.37 g) as crystals, mp 144-145 *C . Reference Example 146
4,5-Dichloro-2-thiophenecarboxylic acid
5-Chloro-2-thiophenecarboxylic acid (6.50 g) was dissolved in N,N-dimethylformamide (30 ml), and ethyl iodide (3.2ml) and potassium carbonate (5.52 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 5-chloro-2- thiophenecarboxylic acid ethyl ester (5.27 g) . 5- Chloro-2-thiophenecarboxylic acid ethyl ester (2.23 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.4 ml) in acetonitrile (20 ml) was added dropwise. The mixture was stirred at room temperature for 48 hours, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The desired fractions were concentrated under reduced pressure to give 4, 5-dichloro-2-thiophenecarboxylic acid ethyl ester (6.21 g). 4 , 5-Dichloro-2-thiophenecarboxylic acid ethyl ester (6.21 g) was dissolved in a mixture of ethanol (25 ml) and tetrahydrofuran (25 ml) , and IN aqueous sodium hydroxide (50 ml) was added. The mixture was stirred at 60 *C for 15 hours and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4 , 5-dichloro-2-thiophenecarboxylic acid (2.14 g) as crystals, mp 162-163 *C . Reference Example 147
4-Bromo-3-thiophenecarboxylic acid
A mixture of 3-bromo-4-methylthiophene (8.85 g) , N- bromosuccini ide (8.85 g) , 2,2* -azobis (isobutyronitrile) ( 0.16 g ) and carbon tetrachloride ( 100 ml ) was stirred under reflux for 6 hours . The mixture was concentrated under reduced pressure to give a crude product of 3-bromo-4- bromomethylthiophene . A suspension of this crude product of 3-bromo-4-bromomethylthiophene and potassium acetate (30 g) in acetone (100 ml) was stirred at room temperature for 5 hours . The mixture was poured into water and extracted with ethyl acetate . The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 4-acetoxymethyl-3- bromothiophene . This crude product was dissolved in tetrahydrofuran (50 ml), and IN aqueous sodium hydroxide (50 ml) and ethanol (20 ml) were added. The mixture was stirred at room temperature for 2 hours and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhdrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 3- bromo-4-hydroxymethylthiophene (5.33 g) as oil. 3- Bromo-4-hydroxymethylthiophene was dissolved in methylene chloride (100 ml), and manganese dioxide (15 g) was added. The mixture was stirred at room temperature for 6 hours , and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of 4-bromo-3-thiophenecarbaldehyde. The crude product of 4-bromo-3-thiophenecarbaldehyde was dissolved in acetonitrile (50 ml), and sodium dihydrogen phosphate (1.2 g) in water (15 ml) and 30% aqueous hydrogen peroxide (3.5 ml) were added. Further, sodium chlorite (3.7 g) in water (40 ml) was added dropwise under ice- cooling. The mixture was stirred at room temperature for 2 hours , alkalified with IN aqueous sodium hydroxide and washed with diethyl ether . The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-bromo-3- thiophenecarboxylic acid (3.40 g) as crystals, mp 161-162 °C .
Reference Example 148
2-Chloro-3-thiophenecarboxylic acid
3-Methylthiophene (19.63 g) was dissolved in acetonitrile (100 ml) , and sulfuryl chloride (16.64 ml) was added dropwise. The mixture was stirred at room temperature for 1 hour, stirred under reflux for another 1 hour, then cooled to room temperature, and 10% aqueous sodium thiosulfate (200 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-chloro-3-methylthiophene (21.52 g) . A mixture of 2- chloro-3-methylthiophene (3.53 g) , N-bromosuccinimide (4.73 g) , 2,2' -azobis(isobutyronitrile) (0.87 g) and carbon tetrachloride (25 ml) was stirred under reflux for 4 hours. The mixture was cooled to room temperature and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of 2-chloro-3-bromomethylthiophene. A suspension of the crude product of 2-chloro-3- bromomethylthiophene and potassium acetate (9.82 g) in acetone ( 50 ml ) was stirred at room temperature for 48 hours . The mixture was poured into water and extracted with diethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a crude product of 3-acetoxymethyl-2-chlorothiophene. This crude product was dissolved in a mixture of ethanol (25 ml) and tetrahydrofuran (25 ml), and IN aqueous sodium hydroxide (50 ml) was added. The mixture was stirred at room temperature for 30 minutes. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography. The desired fractions were concentrated under reduced pressure to give 3-hydroxymethyl-2-chlorothiophene (3.22 g) . 3- Hydroxymethyl-2-chlorothiophene (3.16 g) was dissolved in methylene chloride (50 ml) , and manganese dioxide (9.66 g) was added. The mixture was stirred at room temperature for 15 hours, and insoluble substances were removed by filtration. The filtrate was concentrated under reduced pressure to give a crude product of 2-chloro-3- thiophenecarbaldehyde (3.16 g) . The crude product of 2-chloro-3-thiophenecarbaldehyde was dissolved in acetonitrile ( 20 ml) , and sodium dihydrogen phosphate (0.67 g) in water (10 ml) and 30% aqueous hydrogen peroxide (2.6 ml) were added. Further, sodium chlorite (3.41 g) in water (30 ml) was added dropwise under ice-cooling. The mixture was stirred at room temperature for 2 hours , alkalified with IN aqueous sodium hydroxide and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhdrous magnesium sulfate and concentrated under reduced pressure to give 2-chloro-3-thiophenecarboxylic acid (1.92 g) as crystals, mp 166-167 t .
Reference Example 149 2-Methyl-3-furancarboxylic acid 2-Methyl-3-furancarboxylic acid ethyl ester (10 g) was dissolved in ethanol (70 ml), and IN aqueous sodium hydroxide (78 ml) was added. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate . The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were collected by filtration with diisopropyl ether to give 2-methyl-3-furancarboxylic acid (5.5 g) as crystals, mp 101-102 °C.
Reference Example 150
5-Bromo-3-furancarboxylic acid
This compound was synthesized in accordance with the method described in J. Org. Chem., 41, 2350 (1976).
Reference Example 151
5-Chloro-2-furancarboxylic acid
5-Chloro-2-furancarboxyliσ acid ethyl ester (8 g) (synthesized in accordance with the method described in Chem. Pharm. Bull., 40, 1966 (1992)) was dissolved in ethanol (50 ml), and IN aqueous sodium hydroxide (50 ml) was added. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure . Precipitated crystals were collected by filtration and washed with diethyl ether-hexane to give 5-chloro-2-furancarboxylic acid (5.3 g) as crystals. p 182-183 °C (decomp.).
Reference Example 152 5-Methyl-2-furancarboxylic acid This compound was synthesized in accordance with the method described in J.C.S. Perkin, 1, 1125 (1981).
Reference Example 153 5-Ethyl-2-furancarboxylic acid 2-Ethylfuran (9.1 g) was dissolved in diethyl ether, and the mixture was cooled to -70 under nitrogen atmosphere. n-Butyllithium ( 1.6M in hexane, 60 ml) was slowly added dropwise. The mixture was stirred at room temperature for 2 hours, and then cooled to -70 °C . The mixture was stirred for 30 minutes with introducing carbon dioxide gas , and then warmed to room temperature . The mixture was stirred at room temperature for 30 minutes, poured into ice water, acidified with concentrated hydrochloric acid and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride and concentrated under reduced pressure. The residue was crystallized from water and collected by filtration to give 5-ethyl-2- furancarboxylic acid (9 g). mp 92-94 V, .
Reference Example 154 2-Chloro-3-furancarboxylic acid
2-Trimethylsilyl-3-furancarboxylic acid (16.4 g) (synthesized in accordance with the method described in J.C.S. Perkin, 1, 1125 (1981)) was dissolved in N,N- dimethyIformamide (50 ml), and potassium carbonate (12.3 g) and iodoethane (13.9 g) were added. The mixture was stirred at room temperature for 15 hours, poured into ice water and extracted with diethyl ether. The extract was washed with water and saturated aqueous sodium chloride. dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 2- trimethylsilyl-3-furancarboxylic acid ethyl ester (16.3 g) as oil. 2-Trimethylsilyl-3-furancarboxylic acid ethyl ester (16.3 g) was dissolved in acetonitrile (75 ml), and sulfuryl chloride ( 10.9 g) in acetonitrile (25 ml) was added dropwise. The mixture was stirred at room temperature for 1 hour, poured into ice water and extracted with diethyl ether. The extract was washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 2-chloro-3- furancarboxylic acid ethyl ester (3.5 g) as oil. 2- Chloro-3-furancarboxylic acid ethyl ester (3.5 g) was dissolved in ethanol (25 ml), and IN aqueous sodium hydroxide (25 ml) was added. The mixture was stirred at room temperature for 1.5 hour and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were collected by filtration and washed with diisopropyl ether-hexane to give 2-chloro-3- furancarboxylic acid (2.2 g) as crystals, mp 138-141 .
Reference Example 155 5-Chloro-3-furancarboxylic acid 5-Trimethylsilyl-3-furancarboxylic acid (4.1 g) (synthesized in accordance with the method described in Tetrahedron Lett., 25, 4451 (1984)) was dissolved in tetrahydrofuran (100 ml), and N,N-dimethylformamide (3 drops) was added. Oxalyl chloride (3.0 g) was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Ethanol (100 ml) and triethylamine (4.7 g) were added, and the resulting mixture was stirred at room temperature for 15 hours. The mixture was concentrated under reduced pressure, and water was added to the residue. The mixture was extracted with ethyl acetate , and the extract was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-trimethylsilyl-3-furancarboxylic acid ethyl ester (3 g) as oil. 5-Trimethylsilyl-3-furancarboxylic acid ethyl ester (3.0 g) was dissolved in acetonitrile (15 ml), and sulfuryl chloride (2.0 g) in acetonitrile (5 ml) was added dropwise. The mixture was stirred at room temperature for 30 minutes, poured into ice water and extracted with diethyl ether. The extract was washed with 10% aqueous sodium thiosulfate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-chloro-3-furancarboxylic acid ethyl ester (1.9 g) as oil. 5-Chloro-3-furancarboxylic acid ethyl ester (1.9 g) was dissolved in ethanol (15 ml), and IN aqueous sodium hydroxide ( 12 ml) was added. The mixture was stirred at room temperature for 1.5 hour and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate . The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magensium sulfate and concentrated under reduced pressure. Precipaitated crystals were collected by filtration and washed with hexane to give 5-chloro-3-furancarboxylic acid (1.1 g) as crystals, mp 124-125 °C .
Reference Example 156 5-Difluoromethyl-2-furancarboxylic acid
5-Formyl-2-furancarboxylic acid (2.9 g) was dissolved in N,N-dimethylformamide (30 ml) , and potassium carbonate (2.9 g) and iodoethane (3.6 g) were added. The mixture was stirred at room temperature for 12 hours, poured into ice water and extracted with diethyl ether. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5- formyl-2-furancarboxylic acid ethyl ester (1.3 g). 5- Formyl-2-furancarboxylic acid ethyl ester (1.3 g) in methylene chloride (5 ml) was slowly added dropwise to diethylaminosulfur trifluoride (DAST) (1.3 g) in methylene chloride (5 ml) at room temperature. The mixture was stirred at room temprature for 30 minutes, and water was added to the mixture . The resulting mixture was extracted with diethyl ether, and the extract was washed with water and saturated aqueous sodium chloride , dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5- difluoromethyl-2-furancarboxylic acid ethyl ester ( 0.7 g) . 5-Difluoromethyl-2-furancarboxylic acid ethyl ester (2.3 g) synthesized in this manner was dissolved in ethanol (20 ml) , and IN aqueous sodium hydroxide ( 15 ml) was added. The mixture was stirred at room temperature and concentrated under reduced pressure . The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were collected by filtration and washed with hexane-isopropyl ether to give 5- difluoromethyl-2-furancarboxylic acid (1.2 g) as crystals, mp 112-113 2 .
Reference Example 157
5-Methyl-2-trifluoromethyl-3-furancarboxylic acid
This compound was synthesized in accordance with the method described in J. Heterocycl. Chem., 5, 95 (1968).
Reference Example 158
2, 5-Dimethyl-3-furancarboxylic acid
2, 5-Dimethyl-3-furancarboxylic acid ethyl ester (14.6 g) (synthesized in accordance with the method described in J.A.C.S., 59, 2525 (1937)) was dissolved in ethanol (100 ml), and IN aqueous sodium hydroxide (100 ml) was added. The mixture was stirred at room temperature for 1 hour, and then stirred under reflux for 30 minutes. The mixture was concentrated under reduced pressure, and the residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were recrystallized from acetone-hexane to give 2 , 5-dimethyl-3-furancarboxylic acid (7.3 g) as crystals, mp 139-140 °C .
Reference Example 159 5-Chloro-2-methyl-3-furancarboxylic acid
2-Methyl-3-furancarboxylic acid ethyl ester (10.5 g) was dissolved in acetonitrile (50 ml), and sulfuryl chloride (5.6 ml) was added under ice-cooling. The mixture was stirred at 10 "C for 30 minutes, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours , and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 5-chloro-2-methyl-3-furancarboxylic acid ethyl ester (10 g) as oil. 5-Chloro-2-methyl-3-furancarboxylic acid ethyl ester (10 g) was dissolved in ethanol (100 ml), and IN aqueous sodium hydroxide (60 ml) was added. The mixture was stirred under reflux for 30 minutes and concentrated under reduced pressure. The residue was dissolved in water and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were recrystallized from acetone-hexane to give 5-chloro-2-methyl-3- furancarboxylic acid (5.5 g) as crystals, mp 126-127 V. .
Reference Example 160 2-Ethyl-3-furancarboxylic acid This compound was synthesized in accordance with the method described in J.C.S. Perkin, 1. 1125 (1981).
Reference Example 161 to 169
The following compounds were synthesized in the same manner as Reference Example 60.
Reference Example Compound mp (C )
161 4-Chloro-2-thiophenecarboxamide 150-151
162 4-Methyl-3-thiophenecarboxamide 140-142
163 5-Bromo-2-chloro-3- 130-131 thiophenecarboxamide
164 5-Chloro-4-methyl-3- 172-173 4) thiophenecarboxamide 165 2, 5-Dichloro-4-methyl-3- 181-182ό*> thiophenecarboxamide 166 2-Chloro-5-methyl-3- 107-108 thiophenecarboxamide
167 3-Chloro-4-methyl-2- 158-160 thiophenecarboxamide
168 3, 5-Dimethyl-2-thiophene- 114-116 carboxamide
169 3-Methyl-2-furancarboxamide 66-68
4) These compounds were synthesized in the following manner.
5-Chloro-4-methyl-3-thiophenecarboxamide and 2,5- dichloro-4-methyl-3-thiophenecarboxamide
4-Methyl-3-thiophenecarboxylic acid (1.42 g) synthesized in the same manner as Reference Example 171 was dissolved in N,N-dimethylformamide (30 ml) , and iodoethane (0.8 ml) and potassium carbonate (1.38 g) were added. The mixture was stirred at room temperature for 15 hours , poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 4-methyl-3- thiophenecarboxylate (1.7 g) . Ethyl 4-methyl-3- thiophenecarboxylate (1.70 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.2 ml) in acetonitrile (20 ml) was added. The mixture was stirred at room temperature for 1 hour, and then 10% aqueous sodium thiosulfate (100 ml) was added and stirred at room temperature for 2 hours . The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of ethyl 5-chloro-4-methyl-3-thiophenecarboxylate and ethyl 2,5-dichloro-4-methyl-3-thiophenecarboxylate . The mixture of ethyl 5-chloro-4-methyl-3- thiophenecarboxylate and ethyl 2, 5-dichloro-4-methyl-3- thiophenecarboxylate was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml) , and IN aqueous sodium hydroxide (20 ml) was added. The mixture was stirred at room temperature for 2 hours , and washed with diethyl ether. The aqueous layer was acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give a mixture of 5-chloro-4- methyl-3-thiophenecarboxylic acid and 2, 5-dichloro-4- methyl-3-thiophenecarboxylic acid. The mixture was suspended in toluene (15 ml). Oxalyl chloride (1.31 ml) was added dropwise and then N,N-dimethylformamide (1 drop) was added. The mixture was stirred at room temperature for 1 hour and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (5 ml) and added dropwise into a mixture of 25% aqueous ammonia solution (16 ml) and ethyl acetate (50 ml) with stirring under ice- cooling. The resulting mixture was stirred at room temperature for 10 minutes. The organic layer was collected and the aqueous layer was extracted with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 5-chloro-4-methyl-3- thiophenecarboxamide (0.83 g) and 2 , 5-dichloro-4- methyl-3-thiophenecarboxamide (0.61 g) .
Reference Example 170 4-Chloro-2-thiophenecarboxylic acid This compound was synthesized in accordance with the method described in J. Heterocyclic Chem. , 13, 393 (1976) .
Reference Example 171 4-Methyl-3-thiophenecarboxylic acid This compound was synthesized in accordance with the method described in J. Org. Chem., 51, 230 (1986).
Reference Example 172
5-Bromo-2-chloro-3-thiophenecarboxylic acid A mixture of 2-chloro-3-thiophenecarboxylic acid (2.44 g) , pyridinium bromide perbromide (5.33 g) and acetic acid (15 ml) was stirred at 40 *C for 4 hours and poured into ice water. Precipitated crystals were collected by filtration, dissolved in ethyl acetate and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to give 5-bromo-2- chloro-3-thiophenecarboxylic acid (2.81 g) as crystals, mp 159-160 " .
Reference Example 173
2-Chloro-5-methyl-3-thiophenecarboxylic acid
5-Bromo-2-chloro-3-thiophenecarboxylic acid (2.41 g) was dissolved in tetrahydrofuran (50 ml), and the mixture was cooled to -78 *C . N-Butyllithium (1.6 M in hexane, 14 ml) was slowly added dropwise. The mixture was stirred at the same temperature for 1 hour, and iodomethane (1.4 ml) was added dropwise . The reaction mixture was warmed to room temperature and stirred for 15 hours, poured into water, acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-chloro-5-methyl-3-thiophenecarboxylic acid (1.7 g) as crystals.
Reference Example 174
3 , 5-Dimethyl-2-thiophenecarboxylic acid
3-Methyl-2-thiophenecarboxylic acid (7.11 g) was dissolved in tetrahydrofuran (100 ml) , and the mixture was cooled to -78 O . n-Butyllithium (1.6 M in hexane, 69 ml) was slowly added dropwise. The mixture was stirred at the same temperature for 1 hour, and iodomethane (6.2 ml) was added dropwise. The reaction mixture was warmed to room temperature, stirred for 15 hours, poured into water, acidified with IN hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 3 , 5-dimethyl-2-thiophenecarboxylic acid (4.97 g) as crystals . mp 153-155 °C .
Reference Example 175
3-Methyl-2-furancarboxylic acid
This compound was synthesized in accordance with the method described in Org. Synth., IV, 628.
Reference Example 176
5-Methyl-2-thiophenecarboxamide
2.6 g(0.1 M) of 5-methyl-2-thiophenecarbaldehyde, 8.3 g(0.12 M) of hydroxylamine hydrochloride and 9.8 g(0.12 M) of sodium acetate were added to 50 ml of acetic acid, which was allowed to react under reflux for 13-15 hours. After the starting compound (retention time: about 13 min.) ceased to be detected by liquid chromatography (HPLC) , the reaction mixture was concentrated under reduced pressure to about half its initial volume. To this concentrate was added 100 ml of concentrated hydrochloric acid, which was allowed to react at 60 °C for 4 hours. After completion of the reaction, 100 ml of water was added to the reaction mixture , which was stirred under ice-cooling for 30 minutes . Precipitated crystals were collected by filtration and washed with 100 ml of ice water to give 11.6 g (82 %) of 5-methyl-2-thiophenecarboxamide (HPLC retention time: about 4 min . ) . HPLC analysis conditions Column: GL Science's Inertsil ODS-3, 5 U m, 4.6 x 150 mm
Eluent : acetonitrile: 0.05 M aqueous potassium dihydrogen phosphate = 30 : 70 Detection wavelength: 231 nm Flow rate: 1.0 ml/min.
XH-NMR (DMS0-d6) <5 : 2.54 (3H, d, CH3) , 7.01 (1H, dd, thiophene-4-H) , 7.78 (1H, dd, thiophene-3-H) .
Reference Example 177 to 182 The following compounds were synthesized in the same manner as Reference Example 60.
Reference
Example Compound mp ("C) 177 5-Methyl-3-f rancarboxamide 123-124
178 3-Methyl-2-furancarboxamide 66-68
179 3, 5-Dimethyl-2-furancarboxamide 141-142
180 5-Methyl-3-thiophenecarboxamide 123-124
181 3, 5-Dimethyl-2-thiophene- 114-116 carboxamide
182 2-Ethyl-3-thiophenecarboxamide 116-117
Example 1
N- ( Diaminophosphinyl ) -2- thiophenecarboxamide 2 -Thiophenecarboxamide ( 3 .82 g) was suspended in toluene (25 ml), and phosphorus pentachloride (6.25 g) was added portionwise. The mixture was heated to 65 *C and stirred for 3 hours and then cooled to room temperature. Formic acid (1.38 g) was added dropwise. The mixture was stirred at room temperature for 1 hour, and precipitated crystals were collected by filtration, washed with toluene and dried to give 6.67 g of crystals. The crystals were dissolved in tetrahydrofuran (100 ml) , and ammonia gas was introduced under ice-cooling for 30 minutes. The mixture was stirred at room temperature for 1 hour. Precipitate was collected by filtration, washed with water and dried. The obtained solid was recrystallized from water to give N- ( diaminophosphinyl ) -2-thiophenecarboxamide (1.56 g) as colorless crystals. mp 272-280 °C .
Elemental Analysis for C5H8N302SP
Calcd : C, 29.27; H, 3.93; N, 20.48. Found : C, 29.42; H, 4.00; N, 20.40. Hl-NMR (DMSO-d6) (5 : 4.23(4H,br s), 7.14-7.18 ( lH,m) , 7.83-8.15(lH,d, J=5.2Hz) , 8.13(lH,m), 9.16( lH,br s) .
Exampale 2
N- (Diaminophosphinyl) -3-thiophenecarboxamide
3-Thiophenecarboxamide (3.18 g) was suspended in toluene (25 ml), and phosphorus pentachloride (5.21 g) was added portionwise. The mixture was heated to 65 'C and stirred for 3 hours and then cooled to room temperature. Formic acid (1.15 g) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Precipitated crystals were collected by filtration, washed with toluene and dried to give 5.43 g of crystals. The crystals were dissolved in tetrahydrofuran (100 ml) , and ammonia gas was introduced under ice-cooling for 30 minutes. The mixture was stirred at room temperature for 1 hour, and precipitate was collected by filtration, washed with water and dried. The obtained solid was recrystallized from methanol to give
N- (diaminophosphinyl) -3-thiophenecarboxamide (1.05 g) as colorless crystals. mp 269-278 "C- .
Elemental Analysis for C5H8N3θ2SP
Calcd : C, 29.27; H, 3.93; N, 20.48.
Found : C, 29.12; H, 3.78; N, 20.62. XH-NMR (DMSO-d6) 6 : 4.20( 4H,br s ) , 7.57-7.64( 2H,m) , 8.48-8.50(lH,m) , 9.13( lH,br s ) .
Example 3
N- ( Diaminophosphinyl ) -5-methyl-2-thiophenecarboxamide
5-Methyl-2-thiophenecarboxamide (4.24 g) was suspended in toluene (25 ml), and phosphorus pentachloride (6.25 g) was added portionwise. The mixture was heated to 65 *C and stirred for 1 hour, and then cooled to room temperature. Formic acid (1.38 g) was added dropwise, and the mixture was stirred at room temperature for 2 hours . Precipitated crystals were collected by filtration, washed with toluene and dried to give 6.93 g of crystals. The crystals were dissolved in tetrahydrofuran (100 ml) , and ammonia gas was introduced under ice-cooling for 30 minutes. The mixture was stirred at room temperature for 1 hour, and precipitate was collected by filtration, washed with water and dried. The obtained solid was recrystallized from water-methanol to give N- (diaminophosphinyl) -5-methyl-2- thiophenecarboxamide (3.86 g) as colorless crystals, mp 284-293 *C . Elemental Analysis for C6HιoN302SP Calcd : C, 32.88; H, 4.60; N, 19.17. Found : C, 32.68; H, 4.67; N, 19.17. XH-NMR (DMSO-d6) δ : 2.49(3H.s), 4.20(4H,br s), 6.87(lH,d,J=3.6Hz), 7.94( lH,d, J=3.6Hz ) , 9.27 ( lH.br s ) .
Example 4 N- (Diaminophosphinyl) -3-methyl-2-thiophenecarboxamide 3-Methyl-2-thiophenecarboxamide (4.24 g) was suspended in toluene (25 ml), and phosphorus pentachloride (6.25 g) was added portionwise. The mixture was heated to 65 * and stirred for 1 hour, and then cooled to room temperature.
Formic acid (1.38 g) was added dropwise, and the mixture was stirred at room temperature for 1 hour. Hexane was added, and the resulting mixture was stirred for 30 minutes .
Precipitated crystals were collected by filtration, washed with toluene and dried to give 7.10 g of crystals. The crystals were dissolved in tetrahydrofuran (100 ml), and ammonia gas was introduced under ice-cooling for 30 minutes .
The mixture was stirred at room temperature for 1 hour, and precipitate was collected by filtration and washed with water to give N- (diaminophosphinyl) -3-methyl-2- thiophenecarboxamide (2.50 g) as colorless crystals. mp 267-275 "C.
Elemental Analysis for C6Hι0N3O2SP
Calcd : C, 32.88; H, 4.60; N, 19.17. Found : C, 33.26; H, 4.55; N, 19.35.
^-NMR (DMSO-dβ) <5 : 2.47(3H,s), 4.20 ( 4H,br s ) ,
6.84(lH,d, J=3.7Hz) , 7.94 ( 1H, d, J=3.7Hz ) ,
9.50(lH.d, J=7.2Hz) .
Exampales 5 to 38
The following compounds were synthesized in the same manner as Example 1.
Example 5 N- (Diaminophosphinyl) -5-chloro-2-thiophenecarboxamide mp 273-279 . Elemental Analysis for C5H7N3O2SCIP
Calcd : C, 25.06; H, 2.94; N, 17.54. Found : C, 25.10; H, 2.88; N, 17.55. ^-NMR (DMSO-dβ) <5 : 4.25(4H,br s), 7.22( lH,d, J=4.0Hz) . 8.01(lH,d,J=4.0Hz) , 9.48(lH,br s).
Exampale 6
N- (Diaminophosphinyl) -5-bromo-2-thiophenecarboxamide mp 238-244 'C.
Elemental Analysis for C5H7N302SBrP
Calcd : C, 21.14; H, 2.48; N, 14.79. Found : C, 21.22; H, 2.45; N, 14.88. XH-NMR (DMSO-d6) 6 -. 4.25(4H,br s), 7.32 ( 1H, d, J=4. OHz) , 7.95(lH,d, J=4.0Hz) , 9.47( lH,d, J=7.4Hz ) .
Example 7
N-( Diaminophosphinyl) -4 , 5-dibromo-2- thiophenecarboxamide mp 257-266 °C .
Elemental Analysis for C5H6N3θ2SBr2P
Calcd : C, 16.55; H, 1.67; N, 11.58. Found : C, 16.70; H, 1.55; N, 11.46. XH-NMR (DMSO-d6) <5 : 4.28(4H,br s), 8.14(lH,s), 9.65(lH,d, J=6.4Hz) .
Example 8
N- (Diaminophosphinyl) -4-bromo-thiophenecarboxamide mp 263-268 t. Elemental Analysis for C5H7N3θ2SBrP
Calcd : C, 21.14; H, 2.48; N, 14.79. Found : C, 21.27; H, 2.39; N, 14.75.
XH-NMR (DMSO-d6) δ . 4.24(4H,br s), 7.96( lH,d, J=l .4Hz) ,
8.13(lH,d,J=1.4Hz) , 9.58(lH,br s).
Example 9
N- (Diaminophosphinyl) -5-ethyl-2-thiophenecarboxamide mp 167-174 O.
Elemental Analysis for C7Hι2N302SP Calcd : C, 36.05; H, 5.19; N, 18.02. Found : C, 35.97; H, 5.02; N, 18.16. ^-NMR (DMSO-dβ) 6 : 1.24 ( 3H, t . J=7.0Hz ) , 2.82(2H,q, J=7.0Hz) , 4.16 ( 4H,br s ) , 6.88( lH,d, J=4. OHz) , 7.91(lH.d, J=4.0Hz) , 9.35(lH,br d, J=7.0Hz).
Example 10
N- (Diaminophosphinyl) -5 -nitro- thiophenecarboxamide mp 183-187 V, .
Elemental Analysis for C5H7N404SP Calcd : C, 24.01; H, 2.82; N, 22.40.
Found : C, 24.44; H, 2.92; N, 22.35. XH-NMR (DMSO-dβ) <5 : 4.36(4H,br s), 8.04-8.32 ( 2H,m) , 10.01(lH,br s) .
Example 11
N- (Diaminophosphinyl) -5-bromo-3-thiophenecarboxamide mp 193-196 ) .
Elemental Analysis for C5H7N3θ2SBrP
Calcd : C, 21.14; H, 2.48; N, 14.79. Found : C, 21.38; H, 2.23; N, 15.04.
XH-NMR (DMSO-dβ) <5 : 4.17(4H,br s), 7.68( 1H, d, J=l .6Hz) ,
8.40(lH,d, J=1.6Hz) , 9.28 ( lH,d, J=6.8Hz) .
Example 12 N- (Diaminophosphinyl) -5-cyano-2-thiophenecarboxamide mp 200-205 °C (decomp.). Elemental Analysis for C6H7N402SP
Calcd : C, 31.31; H, 3.07; N, 24.34. Found : C, 31.42; H, 3.03; N, 24.17. ^-NMR (DMSO-dβ) δ : 4.28(4H,s), 7.98 ( 1H, d, J=4. OHz ) , 8.17(lH,d,J=4.0Hz) , 9.84(lH,br d,J=7.0Hz).
Example 13
N- (Diaminophosphinyl) -5-difluoromethyl-2- thiophenecarboxamide mp 165-169 C .
Elemental Analysis for C6H8N302SF2P
Calcd : C, 28.24; H, 3.16; N, 16.47. Found : C, 28.24; H, 2.92; N, 16.55. XH-NMR (DMSO-dβ) δ : 4.23(4H,br s), 7.31 ( 1H, t , J=56Hz ) , 7.47(lH,m), 8.07(lH,m), 9.64 ( lH,br d, J=7. OHz) .
Example 14
N- (Diaminophosphinyl) -3-chloro-2-thiophenecarboxamide mp 154-164 "€ .
Elemental Analysis for C5H7N302SC1P
Calcd : C, 25.06; H, 2.97; N, 17.54. Found : C, 25.15; H, 2.70; N, 17.62. Hl-NMR (DMSO-dβ) δ : 4.33 ( 4H,br s ) , 7.20( lH,d, J=5.3Hz ) , 7.93(lH.d, J=5.3Hz) , 8.45 ( 1H, d, J=6. OHz ) .
Example 15
N- (Diaminophosphinyl) -2-methyl-3-thiophenecarboxamide mp 155-157 "C . Elemental Analysis for C6HιoN302SP-l/5H2θ Calcd : C, 32.34; H, 4.63; N, 19.13. Found : C, 32.15; H, 4.63; N, 19.39.
^-NMR (DMSO-dβ) δ : 2.62(3H,s), 4.13( 4H,br s ) ,
7.35(lH,d, J=5.4Hz) , 7.54( lH,d, J=5.4Hz ) , 8.98( lH.br s ) .
Example 16
N- (Diaminophosphinyl ) -3-bromo-2-thiophenecarboxamide mp 160-167 ° .
Elemental Analysis for C5H7N302SBrP Calcd : C. 21.14; H, 2.48; N, 14.79.
Found : C, 21.38; H, 2.44; N, 14.85.
XH-NMR (DMSO-dβ) : 4.31(4H,br s), 7.22 ( 1H. d, J=5.2Hz ) ,
7.90(lH,d, J=5.2Hz) , 8.55 ( lH,d, J=6.6Hz ) .
Example 17 N- (Diaminophosphinyl) - 5-acetyl-2-thiophenecarboxamide mp 185 °C (decomp.).
Elemental Analysis for C7H10N3O3SP
Calcd : C, 34.01; H, 4.08; N, 17.00. Found : C, 34.34; H, 4.12; N, 17.03.
XH-NMR (DMSO-d5) δ : 2.56(3H,s), 4.28 ( 4H,br s ) , 7.92(lH,d,J=4.0Hz), 8.12( lH,d, J=4. OHz ) , 9.68( lH,br m) .
Example 18 N- (Diaminophosphinyl) -5-methanesulfonyl-2- thiophenecarboxamide mp 180-185 °C (decomp.).
Elemental Analysis for CeH1.0N3O.4S2P
Calcd : C, 25.44; H, 3.56; N, 14.83. Found : C, 25.90; H, 3.31; N, 14.56.
^-NMR (DMSO-d6) δ : 3.39(3H,s), 4.28( 4H,br d, J=3. OHz ) ,
7.81(lH,d, J=4.0Hz) , 8.13 ( lH,d, J=4. OHz ) ,
9.78(lH,d, J=7.0Hz) .
Example 19
N- (Diaminophosphinyl) -3-difluoromethyl-2- thiophenecarboxamide mp 158-162 .
Elemental Analysis for C6H8N3θ2SF2P Calcd : C, 28.24; H, 3.16; N, 16.47. Found : C, 28.43; H, 2.98; N, 16.58.
^-NMR (DMSO-d6) <5 : 4.25 ( 4H,br s ) , 7.37( lH,d, J=5. OHz) ,
7.38(lH,t, J=55Hz) , 7.87( IH, d, J=5.0Hz ) , 9.35( lH,br s) .
Example 20
N- (Diaminophosphinyl) -2-difluoromethyl-3- thiophenecarboxamide mp 168-173 °C .
Elemental Analysis for C6H8N3θ2SF2P Calcd : C, 28.24; H, 3.16; N, 16.47. Found : C, 28.56; H, 2.93; N, 16.61. ^-NMR (DMSO-dβ) <5 : 4.22(4H,br s), 7.67( IH. t , J=55Hz) , 7.78(lH,d, J=5.3Hz) , 7.84 ( IH, d, J=5.3Hz ) , 9.42(lH,d, J=6.6Hz) .
Example 21
N- (Diaminophosphinyl) -5-nitro-3-thiophenecarboxamide mp 181-184 *C .
Elemental Analysis for C5H N404SP Calcd : C, 24.01; H, 2.82; N, 22.40.
Found : C, 23.97; H, 2.76; N, 22.14. XH-NMR (DMSO-dβ) δ : 4.24(4H,br s), 8.57 ( lH,d, J=l .5Hz) , 8.72(lH,d, J=1.5Hz) , 9.60 ( lH,d, J=6.6Hz) .
Example 22
N- (Diaminophosphinyl) -5-methoxy-2-thiophenecarboxamide mp 209-216 "C .
Elemental Analysis for C6HιoN3θ3SP
Calcd : C, 30.64; H, 4.29; N, 17.87. Found : C, 30.77; H, 4.17; N, 18.04.
XH-NMR (DMSO-dβ) δ : 3.90(3H,s), 4.14(4H,br s),
6.35(lH,d, J=4.2Hz) , 7.86( lH,d, J=4.2Hz ) , 9.25 ( lH,br s ) .
Example 23 N- ( Diaminophosphinyl ) - 3 - cyano - 2 - thiophenecarboxamide mp 211-219 " . Elemental Analysis for C6H7N402SP
Calcd : C, 31.31; H, 3.07; N, 24.34. Found : C, 31.27; H, 3.21; N, 23.99. XH-NMR (DMSO-d6) δ : 4.29(4H,br s), 7.57 ( lH,d, J=5.2Hz) , 7.98(lH,d, J=5.2Hz) , 9.49(lH,br s).
Example 24
N- (Diaminophosphinyl) -4-methoxy-2-thiophenecarboxamide mp 206-215 "C. Elemental Analysis for C6H10N3O3SP
Calcd : C, 30.64; H, 4.29; N, 17.87.
Found : C. 30.65; H, 4.42; N, 17.70. ^-NMR (DMSO-dβ) δ : 3.75(3H,s), 4.20 ( 4H,br s ) , 6.91(lH,d, J=1.8Hz) , 7.82( lH.d, J=l .8Hz) , 9.44(lH,d,J=7.0Hz) .
Example 25
N- ( Diaminophosphinyl ) -2 , 5- ichloro-3- thiophenecarboxamide mp 168-172 C . Elemental Analysis for CSH6N3O2SCI2P
Calcd : C, 21.91; H, 2.21; N, 15.33. Found : C, 21.81; H, 2.38; N, 15.44. ^-NMR (DMSO-dβ) δ : 4.19 ( 4H, br s ) , 7.51 ( IH, s ) , 9.15 ( lH,br s).
Example 26
N- (Diaminophosphinyl ) -2-bromo-3-thiophenecarboxamide mp 160-162 V .
Elemental Analysis for C5H7N3θ2SBrP
Calcd : C, 21.14; H, 2.48; N, 14.79. Found : C, 21.19; H, 2.53; N, 14.86. ^-N R (DMSO-dβ) <5 : 4.17(4H,br s), 7.45( lH,d, J=5.OHz) , 7.60(lH,d, J=5.0Hz) , 9.11(lH,m).
Example 27
N- (Diaminophosphinyl) -3-ethyl-2-thiophenecarboxamide mp 130-135 "C. Elemental Analysis for C7Hi2N302SP
Calcd : C, 36.05; H, 5.19; N, 18.02. Found : C, 35.80; H, 5.17; N, 17.81. XH-NMR (DMSO-dβ) <5 : 1.16 ( 3H, t , J=7. OHz ) , 2.89(2H,q, J=7.0Hz) , 4.15( 4H,br s ) , 7.05( lH,d, J=5. OHz ) , 7.63(lH,d, J=5.0Hz) , 8.65( lH,br d, J=9.OHz) . Exampale 28
N- (Diaminophosphinyl) -4-methyl-2-thiophenecarboxamide mp 160-163 °C .
Elemental Analysis for CβHι0N3θ2SP
Calcd : C, 32.88; H, 4.60; N, 19.17.
Found : C, 32.73; H, 4.60; N, 18.76. ^-NMR (DMSO-d6) <5 : 2.21( 3H, s ) , 4.14 ( 4H,br s ) , 7.40( IH, s) , 7.89(lH,s), 9.30(lH,br m) .
Example 29
N- (Diaminophosphinyl) -5-bromo-4-methyl-2- thiophenecarboxamide mp 170-175 °C . Elemental Analysis for C6H9N3θ2SBrP
Calcd : C, 24.18; H, 3.04; N, 14.10. Found : C, 24.39; H, 3.13; N, 14.22.
XH-NMR (DMSO-d6) <5 : 2.14 ( 3H, s ) , 4.19 ( 4H,br s ) , 7.89 ( IH, s ) ,
9.44(lH,br m) .
Example 30
N- (Diaminophosphinyl ) -5-chloro-3-thiophenecarboxamide mp 177-184 "C .
Elemental Analysis for C5H7N3O2SCIP Calcd : C, 25.06; H, 2.94; N, 17.54. Found : C, 25.08; H, 3.08; N, 17.64.
^- MR (DMSO-dβ) <5 : 4.17 ( 4H,br s ) , 7.59( lH.d, J=l .OHz ) ,
8.31(lH,d, J=1.0Hz) , 9.30( lH,d, J=6.8Hz) .
Example 31
N- ( Diaminophosphinyl ) -5-difluoromethyl-3- thiophenecarboxamide mp 149-153 t .
Elemental Analysis for C6H8N3θ2SF2P Calcd : C, 28.24; H, 3.16; N, 16.47. Found : C, 28.19; H, 3.11; N, 16.42. ^-NMR (DMSO-dβ) δ : 4.17(4H,br s), 7.31( IH, t , J=55Hz) , 7.90(lH,s), 8.65(lH,s), 9.38 ( IH, d, J=6.6Hz ) .
Example 32
N- (Diaminophosphinyl) -2 , 5-dimethyl-3- thiophenecarboxamide mp 159-162 °C .
Elemental Analysis for C7H12N3O2SP Calcd : C, 36.05; H, 5.19; N, 18.02.
Found : C, 35.90; H, 5.04; N, 17.75.
XH-NMR (DMSO-d6) δ : 2.34 ( 3H , s ) , 2.57 ( 3H, s ) , 4.08 ( 4H,br s ) ,
7.19(lH,s), 8.76(lH,br d,J=7.0Hz).
Example 33
N- (Diaminophosphinyl) -5-chloro-2-methyl-3- thiophenecarboxamide mp 218-225 C .
Elemental Analysis for C6H9N302SC1P Calcd : C, 28.41; H, 3.58; N, 16.57. Found : C, 28.13; H, 3.58; N, 16.68.
XH-NMR (DMS0-d6) δ ■ 2.60( 3H, s ) , 4.13 ( 4H, br s ) , 7.54 ( IH, s ) ,
9.01(lH,br s) .
Example 34
N- (Diaminophosphinyl) -4-chloro-5-methyl-2- thiophenecarboxamide mp 225-233 °C .
Elemental Analysis for C6H9N3θ2SClP Calcd : C, 28.41; H, 3.58; N, 16.57.
Found : C, 28.58; H, 3.72; N, 16.69.
XH-NMR (DMSO-dβ) <5 : 2.39 ( 3H, s ) , 4.19 ( 4H,br s ) , 8.02 ( IH, s ) ,
9.44(lH,br s).
Example 35 N- ( Diaminophosphinyl ) -5-chloro-4-methyl-2- thiophenecarboxamide mp 182-184 °C .
Elemental Analysis for C6H9 3θ2SClP Calcd : C, 28.41; H, 3.58; N, 16.57. Found : C, 28.02; H, 3.54; N, 16.47. ^-NMR (DMSO-dβ) δ : 2.15( 3H, s ) , 4.19( 4H,br s) , 7.92( IH, s) , 9.19(lH,br s) .
Example 36
N-(Diaminophosphinyl) -4 , 5-dichloro-2- thiophenecarboxamide mp 276-278 °C .
Elemental Analysis for C5H6N3θ2SCl2P Calcd : C, 21.91; H, 2.21; N, 15.33.
Found : C, 22.08; H, 2.29; N, 15.45.
XH-NMR (DMSO-dβ) <5 : 4.26 ( 4H ,br s ) , 8.16 ( IH, s ) , 9.43 ( lH,br s).
Example 37
N- (Diaminophosphinyl) -4-bromo-3-thiophenecarboxamide mp. 149-153 T..
Elemental Analysis for C5H7N302SBrP
Calcd : C, 21.14; H, 2.48; N, 14.79. Found : C, 21.40; H, 2.56; N, 14.42.
^-NMR (DMSO-d6) 5 : 4.18( 4H,br s ) , 7.72( lH,m) , 8.28( lH,m) ,
9.29(lH,br m) .
Example 38 N- ( Diaminophosphinyl ) - 2 -chloro - 3 - thiophenecarboxamide mp 153-155 .
Elemental Analysis for C5H7N3θ2SClP-l/4H20 Calcd : C, 24.60; H, 3.10; N, 17.21. Found : C, 24.70; H, 3.21; N, 17.04. XH-NMR (DMSO-d6) <5 : 4.17 ( 4H,br s ) , 7.40-7.50( 2H,m) , 9.03(lH,br s) .
Example 39
N- (Diaminophosphinyl) -5-bromo-2-furancarboxamide 5-Bromo-2-furancarboxamide (5.0 g) was suspended in toluene (30 ml), and phosphorus pentachloride (5.8 g) was added portionwise . The mixture was heated to 70 °C , stirred for 30 minutes and then cooled to room temperature. Formic acid (1.2 g) was added dropwise , and the mixture was stirred at room temperature for 30 minutes. Precipitated crystals were collected by filtration, washed with toluene and hexane, and dried to give 7.9 g of crystals. The crystals were dissolved in tetrahydrofuran ( 150 ml) , and ammonia gas was introduced under ice-cooling for 30 minutes. The mixture was stirred at room temperature for 1 hour, and precipitate was collected by filtration, washed with water and dried. The obtained solid was recrystallized from methanol to give N- (diaminophosphinyl) -5-bromo-2- furancarboxamide (2.0 g) as colorless crystals. mp 175-176 t) .
Elemental Analysis for C5H7N3θ3SBrP
Calcd : C, 22.41; H, 2.63; N, 15.68. Found : C, 22.44; H, 2.76; N, 15.71. ^-N R (DMSO-d6) δ : 4.22(4H,s), 6.77 ( IH, d, J=3.6Hz ) , 7.55(lH,d, J=3.6Hz) , 9.28( lH,d, J=5.8Hz ) .
Example 40
N- (Diaminophosphinyl) -2-methyl-3-furancarboxamide
2-Methyl-3-furancarboxamide (2.0 g) was suspended in toluene (30 ml), and phosphorus pentachloride (3.5 g) was added portionwise . The mixture was heated to 70 °C , stirred for 30 minutes , and then cooled to room temperature . Formic acid (0.74 g) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. Hexane (20 ml) was added, and the resulting mixture was stirred for 10 minutes . Precipitated crystals were collected by filtration, washed with hexane and dried to give 3.3 g of crystals. The crystals were dissolved in tetrahydrofuran (100 ml) , and ammonia gas was introduced under ice-cooling for 30 minutes . The mixture was stirred at room temperature for 1 hour, and diethyl ether (100 ml) was added. The resulting mixture was stirred for 10 minutes, and precipitate was collected by filtration, washed with water and dried. The obtained solid was recrystallized from methanol to give N- (diaminophosphinyl) -2-methyl-3- furancarboxamide (0.85 g) as colorless crystals, mp 249-253 °C (decomp.). Elemental Analysis for C6Hι0N3O3P
Calcd : C, 35.48; H, 4.96; N, 20.69. Found : C, 35.41; H, 4.86; N, 20.68.
^-NMR (DMSO-dβ) δ : 2.52(3H,s), 4.13(4H,s), 7.17(lH,d, J=2.0Hz) , 7.50 ( IH, d, J=2. OHz ) , 9.00(lH,d, J=7.4Hz) .
Example 41
N- (Diaminophosphinyl) -5-bromo-3-furancarboxamide
5-Bromo-3-furancarboxamide (2.0 g) was suspended in toluene (30 ml), and phosphorus pentachloride (2.3 g) was added portionwise . The mixture was heated to 70 *C , stirred for 30 minutes , and then cooled to room temperature . Formic acid (0.48 g) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. Hexane (20 ml) was added, and the mixture was stirred for 10 minutes. Precipitated crystals were collected by filtration, washed with hexane and dried to give 2.3 g of crystals . The crystals were dissolved in tetrahydrofuran (100 ml), and ammonia gas was introduced under ice-cooling for 30 minutes . The resulting mixture was stirred at room temperature for 1 hour, and precipitate was collected by filtration, washed with water and dried. The obtained solid was recrystallized from methanol to give N-
( diaminophosphinyl ) -5-bromo-3-furancarboxamide (1.0 g) as colorless crystals. mp 181-183 V.
Elemental Analysis for C5H7N3θ3BrP
Calcd : C, 22.41; H, 2.63; N, 15.68.
Found : C, 22.46; H, 2.40; N, 15.76. LH-NMR (DMSO-d6) δ : 4.18(4H,s), 7.03 ( IH, d, J=l . OHz ) , 8.46(lH,d, J=1.0Hz) , 9.25 ( lH,d, J=7. OHz) .
Examples 42 to 51
The following compounds were synthesized in the same manner as Example 39.
Example 42
N- (Diaminophosphinyl) -5-chloro-2-furancarboxamide mp 242-244 °C.
Elemental Analysis for C5H7N3O3CIP
Calcd : C, 26.86; H, 3.16; N, 18.80. Found : C, 26.82; H, 2.96; N, 18.85.
XH-NMR (DMSO-d6) <5 : 4.22 ( 4H, d, J=2.6Hz ) ,
6.68(lH,d, J=3.5Hz) , 7.58 ( IH, d, J=3.5Hz ) ,
9.26(lH,d, J=7.0Hz)
Example 43
N- (Diaminophosphinyl) -5-methyl-2-furancarboxamide mp 281-285 TD (decomp.).
Elemental Analysis for C6HιoN303P
Calcd : C, 35.48; H, 4.96; N, 20.69. Found : C, 35.56; H, 4.94; N, 20.68.
XH-NMR (DMSO-dβ) δ : 2.33(3H,s), 4.16(4H,s),
6.25(lH,d, J=3.0Hz) , 7.37 ( lH,d, J=3. OHz) ,
8.94(lH,d, J=7.0Hz) .
Example 44 N- ( Diaminophosphinyl ) -5-ethyl- 2-furancarboxamide mp 151-153 °C .
Elemental Analysis for C7H12N303P-1/4H20 Calcd : C, 37.93; H, 5.68; N, 18.96. Found : C, 37.96; H, 5.56; N, 18.77. XH-NMR (DMSO-dβ) <5 : 1.20 ( 3H, t , J=7.6Hz ) , 2.70(2H,q, J=7.6Hz) , 4.16(4H,s), 6.26 ( IH, d, J=3.3Hz) , 7.37(lH,d, J=3.3Hz) , 8.91(lH,br s).
Example 45
N- ( Diaminophosphinyl ) -2-chloro-3-furancarboxamide mp 153-155 "C .
Elemental Analysis for C5H7N303C1P
Calcd : C, 26.86; H, 3.16; N, 18.80. Found : C, 27.13; H, 3.14; N, 18.61.
^-NMR (DMSO-d6) <5 : 4.20 (4H,s), 7.33 ( IH, d, J=2.2Hz ) ,
7.74(lH,d, J=2.2Hz) , 9.14 ( IH, d, J=7. OHz ) .
Example 46 N- (Diaminophosphinyl) -5-chloro-3-furancarboxamide mp 170-171 °C . Elemental Analysis for C5H7N303C1P
Calcd : C, 26.86; H, 3.16; N, 18.80. Found : C, 26.76; H, 3.00; N, 18.70. ^-NMR (DMSO-dβ) δ : 4.18(4H,s), 6.94(lH,s), 8.39(lH,s), 9.23(lH,d,J=7.4Hz) .
Example 47
N- ( Diaminophosphinyl ) - 5 -dif luoromethyl- 2 - furancarboxamide mp 156-158 "C. Elemental Analysis for C6H8N303F2P
Calcd : C, 30.14; H, 3.37; N, 17.57. Found : C, 30.06; H, 3.14; N, 17.60. Hl-NMR (DMSO-d6) <5 : 4.23(4H,s), 7.01-7.05 ( lH,m) , 7 . 15 ( lH , t , J=53Hz ) , 7 . 57 ( IH , d , J=3 . 6Hz ) , 9 . 35 ( lH , d , J=6 . 0Hz ) .
Example 48 N- (Diaminophosphinyl) -2-trifluoromethyl-5-methyl-3- furancarboxamide mp 158-160 *C . Elemental Analysis for C7H9N3θ3F3P
Calcd : C, 31.01; H, 3.35; N, 15.50. Found : C, 31.28; H, 3.40; N, 15.62.
^-NMR (DMSO-dβ) δ : 2.35(3H,s), 4.19(4H,s), 6.85(lH,s), 9.37(lH,d, J=6.8Hz) .
Example 49 N- (Diaminophosphinyl) -2 , 5-dimethyl-2-furancarboxamide mp 167-169 °C . Elemental Analysis for C7H12N3O3P
Calcd : C, 38.72; H, 5.57; N, 19.35. Found : C, 38.95; H, 5.33; N, 19.29. XH-NMR (DMSO-dβ) <5 : 2.20(3H,s), 2.47(3H,s), 4.09(4H,s), 6.71(lH,s), 8.80(lH,br s) .
Example 50
N- (Diaminophosphinyl ) -5-chloro-2-methyl-3- furancarboxamide mp 270-275 "C (decomp.). Elemental Analysis for C6H9N303C1P
Calcd : C, 30.33; H, 3.82; N, 17.69. Found : C, 30.32; H, 3.96; N, 17.78. ^-NMR (DMSO-dβ) <5 : 2.52(3H,s), 4.15(4H,s), 7.13(lH,s), 9.04(lH,d,J=7.4Hz) .
Example 51
N- (Diaminophosphinyl) -2-ethyl-3-furancarboxamide mp 277-280 "C (decomp.). Elemental Analysis for C7H12N3O3P
Calcd : C, 38.72; H, 5.57; N, 19.35.
Found : C, 38.68; H, 5.67; N, 19.42. XH-NMR (DMSO-dβ) δ : 1.15 ( 3H, t , J=7.6Hz ) , 2.98(2H,q, J=7.6Hz) , 4.09(4H,s), 7.14 ( IH, d, J=2.2Hz ) , 7.51(lH,d, J=2.2Hz) , 8.90 ( lH,d, J=7. OHz ) .
Example 52
N- (Diaminophosphinyl ) -4-nitrophenoxyacetamide 4-Nitrophenoxyacetamide ( 3.5 g) was suspended in toluene (30 ml), and phosphorus pentachloride (3.9 g) was added portionwise. The mixture was heated to 70 °C , stirred for 3 hours , and then cooled to room temperature . Formic acid (0.83 g) was added dropwise, and the mixture was stirred at room temperature for 2 hours . Precipitated crystals were collected by filtration, washed with toluene and dried to give 3.5 g of crystals. The crystals were dissolved in tetrahydrofuran (150 ml), and ammonia gas was introduced under ice-cooling for 30 minutes. The mixture was stirred at room temperature for 1 hour, and precipitate was collected by filtration, washed with water and dried. The obtained solid was recrystallized from water to give N- ( diaminophosphinyl ) -4-nitrophenoxyacetamide (0.5 g) as colorless crystals. mp 174-176 °C .
Elemental Analysis for C8HnN405P
Calcd : C, 35.05; H,4.04 ; N, 20.43. Found : C, 34.84; H, 3.97; N, 20.14. Hl-NMR (DMSO-dβ) δ : 4.19(4H,s), 4.79(2H,s), 7.10- 7.14(2H,m), 8.18-8.23( 2H,m) , 9.08( lH,d, J=8. OHz ) .
Example 53 to 81
The following compounds were synthesized in the same manner as Example 52. Example 53
N- ( Diaminophosphinyl ) -4 -methoxyphenoxyacetamide mp 154-156 °C .
Elemental Analysis for C9Hι4N304P Calcd : C, 41.70; H, 5.41; N, 16.21. Found : C, 41.59; H, 5.21; N, 16.14. XH-NMR (DMSO-dβ) <5 : 3.70(3H,s), 4.16(4H,s), 4.49(2H,s), 6.86(4H,s), 8.75(lH,d, J=8.0Hz) .
Example 54
N- (Diaminophosphinyl) -4-fluorophenoxyacetamide mp 156-158 °C .
Elemental Analysis for C8HiiN303FP
Calcd : C, 38.88; H. 4.49; N, 17.00. Found : C, 38.81; H, 4.42; N, 17.01.
^-NMR (DMSO-d6) <5 : 4.18(4H,s), 4.56(2H,s). 6.90-
6.97(2H,m), 7.07-7.16(2H,m) , 8.87( lH.d, J=7. OHz ) .
Example 55 N- ( Diaminophosphinyl ) - 4 -chlorophenoxyacetamide mp 155-157 °C . Elemental Analysis for C8HuN303ClP
Calcd : C, 36.45; H, 4.21; N, 15.94. Found : C, 36.54; H. 4.17; N, 15.72. XH-NMR (DMSO-dβ) : 4.18(4H,s), 4.59(2H,s), 6.92- 6.98(2H,m), 7.31-7.35( 2H,m) , 8.91( lH,d, J=7.8Hz) .
Example 56
N- (Diaminophosphinyl) -2,3, 5-trimethylphenoxyacetamide mp 171-173 .
Elemental Analysis for CιιHι8N303P
Calcd : C, 48.71; H, 6.69; N, 15.49. Found : C, 48.54; H, 6.63; N, 15.12. XH-NMR (DMSO-dβ) δ ■ 2.07(3H,s), 2.17(3H,s), 2.21(3H,s), 4.19(4H,s), 4.53(2H,s), 6.48(lH,s), 6.60(1H,S), 8.69(lH,d, J=8.2Hz) .
Example 57
N- (Diaminophosphinyl) -4-cyanophenoxyacetamide mp 173-178 °C .
Elemental Analysis for C9HuN403P
Calcd : C, 42.53; H, 4.36; N, 22.04. Found : C, 42.76; H, 4.38; N, 21.97. XH-NMR (DMSO-dβ) <5 : 4.22(4H,br s), 4.73(2H,s), 7.08(2H,d, J=8.6Hz) , 7.77 ( 2H, d, J=8.6Hz ) , 9.06 ( lH,br s ) .
Example 58
N- ( Diaminophosphinyl ) - 3 -chlorophenoxyacetamide mp 143-148 °C . Elemental Analysis for C8H11N3O3CIP
Calcd : C, 36.45; H, 4.21; N, 15.94. Found : C, 36.12; H, 4.30; N, 16.08. XH-NMR (DMSO-dβ) <5 : 4.21(4H,br s), 4.63(2H,s), 6.87- 6.93(lH,m), 6.99-7.03( 2H,m) , 7.33( lH,d, J=8.4Hz) , 8.93(lH,br s) .
Example 59
N- (Diaminophosphinyl) -2 -chlorophenoxyacetamide mp 141-148 . Elemental Analysis for C8HιιN3θ3ClP-l/4H20 Calcd : C, 35.84; H, 4.32; N, 15.67. Found : C, 35.44; H, 4.15; N, 16.03. XH-NMR (DMSO-dβ) <5 : 4.21(4H,br s), 4.71(2H,s), 6.97- 7.01(2H,m), 7.23-7.32(lH,m), 7.41-7.46( lH,m) , 8.84(lH,br s).
Example 60
N-(Diaminophosphinyl) -3-fluorophenoxyacetamide mp 144-149 °C . Elemental Analysis for C8HιιN303FP Calcd : C, 38.88; H, 4.49; N, 17.00.
Found : C, 38.97; H, 4.58; N, 17.04. ^-NMR (DMSO-dβ) δ : 4.22(4H,br s), 4.62(2H,s), 6.74- 6.82(3H.m), 7.26-7.38( lH,m) , 8.95 ( lH,d, J=8.4Hz ) .
Example 61
N- ( Diaminophosphinyl ) phenyl thioacetamide mp 156-162 °C .
Elemental Analysis for C8Hι2N3θ2SP Calcd : C, 39.18; H, 4.93; N, 17.13.
Found : C, 39.30; H, 4.97; N, 17.21. XH-NMR (DMSO-d6) <5 : 3.76(2H,s), 4.13 ( 4H,br s ) , 7.17- 7.46(5H,m), 9.15( lH,br s) .
Example 62
N-( Diaminophosphinyl) -4-fluorophenylthioacetamide mp 155-160 T .
Elemental Analysis for C8HιιN302SFP
Calcd : C, 36.50; H, 4.21; N, 15.96. Found : C, 36.42; H, 3.96; N, 15.98.
^-NMR (DMSO-d6) δ : 3.71 (2H,s), 4.12(4H,br s),
7.15(lH,d, J=8.8Hz) , 7.19 ( lH,d, J=9. OHz ) ,
7.42(lH,dd, J=9.0Hz & 5.4Hz ) , 7.44( lH,dd, J=8.8Hz & 5.2Hz ) ,
9.11(lH,br s) .
Example 63
N- (Diaminophosphinyl) -2-benzoxazolylthioacetamide mp 160-164 * .
Elemental Analysis for C9HuN403SP Calcd : C, 37.76; H, 3.87; N, 19.57.
Found : C, 37.63; H, 3.78; N, 19.48.
XH-NMR (DMSO-dβ) <5 : 4.16(4H,br s), 4.27(2H,s), 7.30-
7.37(2H,m), 7.61-7.66( 2H,m) , 9.34 ( lH,br s ) .
Example 64 N- ( Diaminophosphinyl ) -2-benzothiazolylthioacetamide mp 166-170 * .
Elemental Analysis for C9HιιN402S2P
Calcd : C, 35.76; H, 3.67; N, 18.53. Found : C, 35.75; H, 3.77; N, 18.58.
^Η-NMR (DMSO-dβ) <5 : 4.17(4H,br s), 4.28(2H,s), 7.34- 7.53(2H,m), 7.84-7.88( lH,m) , 8.01-8.05( lH,m) , 9.35(lH,br s).
Example 65
N- (Diaminophosphinyl ) -5-chloro-2- benzothiazolylthioacetamide mp 165-171 °C .
Elemental Analysis for C9Hι0N4O2S2ClP Calcd : C, 32.10; H, 2.99; N, 16.64.
Found : C, 32.18; H, 2.94; N, 16.58.
XH-NMR (DMSO-dβ) <5 : 4.19(4H,br s), 4.29(2H,s),
7.44(lH,dd, J=8.6Hz & 2.0Hz), 7.94( IH, d, J=2. OHz ) ,
8.07(lH,d, J=8.6Hz) , 9.38(lH,br s).
Example 66
N- (Diaminophosphinyl ) -5-ethoxy-2- benzothiazolylthioacetamide mp 169-174 tl. Elemental Analysis for CιιHi5N403S2P-H20 Calcd.: C, 36.25; H, 4.70; N, 15.38. Found : C, 36.20; H, 4.54; N, 15.78.
XH-NMR (DMSO-dβ) δ : 1.33 ( IH, t , J=7. OHz ) ,
4.04(2H,q, J=7.0Hz) , 4.16(4H,br s), 7.02( lH.dd, J=9.OHz & 2.6Hz), 7.56(lH,d, J=2.6Hz) , 7.71 ( lH,d, J=9. OHz) ,
8.32(lH,br s) .
Example 67
N-( Diaminophosphinyl) - 2 -benzof urancarboxamide mp 172-174 *C . Elemental Analysis for C9Hι0N3O3P
Calcd.: C, 45.20; H, 4.21; N, 17.57.
Found : C, 45.05; H, 4.24; N, 17.50. XH-NMR (DMSO-dβ) δ : 4.27(4H,s), 7.34 ( IH, t , J=7.4Hz) , 7.68(lH,d, J=8.4Hz) , 7.79 ( IH, d, J=7.6Hz ) ,
7.84(lH,t, J=7.0Hz) , 7.90(lH,s), 9.40( IH, d, J=7. OHz ) .
Example 68
N- (Diaminophosphinyl) -2-methyl-5-benzoxazolecarboxamide mp 250 *C (decomp.).
Elemental Analysis for C9HuN403P-H20 Calcd : C, 39.71; H, 4.81; N, 20.58. Found : C, 39.48; H, 4.09; N, 20.45. ^-NMR (DMSO-dβ) <5 : 2.66(3H,s), 4.19(4H,br s), 7.68(2H,d, J=9.0Hz) , 8.03( IH, dd, J=9. OHz & 2.0Hz), 8.34(lH,d,J=2.0Hz) , 9.52(lH,br d,J=7.0Hz).
Example 69
N- (Diaminophosphinyl ) -3- ( 2-benzoxazolyl ) propenamide mp 180 (decomp.).
Elemental Analysis for Cι0HιιN4O3P
Calcd : C, 45.12; H, 4.17; N, 21.05. Found : C, 45.00; H, 3.98; N, 20.97. XH-NMR (DMSO-d6) <5 : 4.24 ( 4H,br s ) , 7.35-7.52( 4H,m) , 7.74-7.83(2H,m) , 9.61( lH.d, J=6. OHz) .
Example 70
N- (Diaminophosphinyl ) -2-benzothiazolecarboxamide mp 169-174 * . Elemental Analysis for C8H9N402SP
Calcd : C, 37.50; H, 3.54; N, 21.87. Found : C, 37.42; H, 3.38; N, 21.86. XH-NMR (DMSO-d6) δ : 4.44(4H,br s), 7.61-7.67( 2H,m) , 8.17-8.28(2H,m) , 8.90( lH,br s) . Example 71
N- (Diaminophosphinyl) -3-chloro-6-methyl-2- benzothiophenecarboxamide mp 173-178 °C . Elemental Analysis for C10HHN3O2SCIP-I/5CH3OH
Calcd : C, 39.51; H, 3.71; N, 13.55.
Found : C, 39.30; H, 3.64; N, 13.15. XH-NMR (DMSO-d6) <5 : 2.48(3H,s), 4.39(4H,br s), 7.43(lH,dd, J=8.2Hz & 1. OHz ) , 7.81( lH,d, J=8.2Hz ) , 7.92(lH,s), 8.38(lH,br s) .
Example 72
N-( Diaminophosphinyl) -3- ( 5 -chloro- 2- benzoxazolyl )propenamide mp 210-211 °C (decomp.).
Elemental Analysis for CιoH10N4θ3ClP
Calcd : C, 39.95; H, 3.35; N, 18.64. Found : C, 39.79; H, 3.42; N, 18.49.
^-NMR (DMSO-dβ) δ : 4.23(4H,br d,J=2.0Hz), 7.35(2H,m), 7.52(lH,dd, J=9.0Hz & 2.0Hz), 7.83( IH, d, J=9. OHz ) ,
7.93(lH,d, J=2.0Hz) , 9.55(lH,br m) .
Example 73
N- ( Diaminophosphinyl ) -5-methyl- 3-phenyl-4- isoxazolecarboxamide mp 230 * (decomp.).
Elemental Analysis for CιιH13N4O3P-0.2H0 Calcd : C, 46.55; H, 4.76; N, 19.74. Found : C, 46.42; H, 4.78; N, 20.10. XH-NMR (DMSO-dβ) δ : 2.56(3H, s ) , 4.24( 4H,br s ) , 7.49( 3H,m) , 7.70(2H,m), 9.34 ( lH.br m) .
Example 74
N- ( Diaminophosphinyl ) -3 -chloro-2 - benzothiophenecarboxamide mp 261-271 X2.
Elemental Analysis for C9H9N302SC1P
Calcd : C, 37.27; H, 3.13; N, 14.51.
Found : C, 36.92; H, 3.18; N, 14.59. XH-NMR (DMSO-d6) <5 : 4.38(4H,br s), 7.56-7.64( 2H,m) , 7.88-7.93(lH,m) , 8.09-8.13( lH,m) , 8.68( lH,br s) .
Example 75
N- ( Diaminophosphinyl ) - 3 -benzisoxazolylacetamide mp 157-164 " .
Elemental Analysis for C9HuN403P
Calcd : C, 42.53; H, 4.36; N, 22.04. Found : C, 42.30; H, 4.31; N, 21.49. ^-NMR (DMSO-dβ) δ : 4.06(2H,s) , 4.15(4H,br s) , 7.38(lH,m) , 7.67(2H,m), 7.87( lH,d, J=8. OHz ) , 9.43( lH,br m) .
Example 76
N- ( Diaminophosphinyl ) -N' -(4- methylbenzenesulfonyl ) glycinamide mp 161-169 * .
Elemental Analysis for C9Hι5N4O4SP-l/10H2O Calcd : C, 35.09; H, 4.97; N, 18.19. Found : C, 34.76; H, 4.94; N, 18.10.
^-NMR (DMSO-dβ) δ : 2.38( 3H, s) , 3.52(2H,s ) , 4.08(4H,br s) . 7.39(2H,d,J=8.0Hz), 7.68(2H,d, J=8. OHz ) , 7.77( lH,br s) ,
8.77(lH,br s) .
Example 77
N- ( Diaminophosphinyl ) -3- ( 4 -bromo- 2 - thienyl ) propenamide mp 176-184 °C .
Elemental Analysis for C7H9 3θ2BrP
Calcd : C, 27.11; H, 2.93; N, 13.55. Found : C, 26.91; H, 2.86; N, 13.71. XH-NMR (DMSO-dβ) δ : 4.16 ( 4H,br s ) , 6.59 ( lH,d, J=15.7Hz) , 7.47(lH,s), 7.63( IH, d, J=15.7Hz ) , 7.76(lH,s), 9.14(lH,d,J=7.4Hz).
Example 78
N- ( Diaminophosphinyl ) - 3 - ( 2 - thienyl ) propenamide mp 173-177 °C .
Elemental Analysis for C7HιoN302SP
Calcd : C, 36.36; H, 4.36; N, 18.17. Found : C, 36.16; H, 4.21; N, 18.16. XH-NMR (DMSO-dβ) δ : 4.08 ( 4H,br s ) , 6.55( lH,d, J=15.6Hz) , 7.13(lH,dd, J=5.0Hz & 3.6Hz ) , 7.43 ( lH,d, J=3.6Hz) ,
7.60(lH,d, J=5.0Hz) , 7.67 ( IH, d, J=15.6Hz ) , 9.06 ( lH.br s ) .
Example 79
N- (Diaminophosphinyl) -2-cyano-3- ( 2-thienyl)propenamide mp 190-196 °C .
Elemental Analysis for C8H9N402SP
Calcd : C, 37.50; H, 3.54; N, 21.87. Found : C, 37.14; H, 3.56; N, 21.78. XH-NMR (DMSO-d6) δ : 4.26(4H,br s), 7.32-7.37( lH,m) , 7.85(lH,d, J=4.3Hz) , 8.15 ( IH, d, J=4.3Hz ) , 8.61(lH,s), 9.08(lH,br s) .
Example 80
N- (Diaminophosphinyl ) -2-thienylacetamide mp 179-184 °C .
Elemental Analysis for C6H1oN302SP
Calcd : C, 32.88; H, 4.60; N, 19.17. Found : C, 32.81; H, 4.48; N, 19.14. XH-NMR (DMSO-d6) δ : 3.77(2H,s), 4.11(4H,br s), 6.93- 6.99(2H,m), 7.38 ( lH,dd, J=5. OHz & 1.4Hz), 9.16 ( lH,br s ) .
Example 81
N- (Diaminophosphinyl ) -3-thienylacetamide mp 174-181 °C . Elemental Analysis for C6HιoN3θ2SP Calcd : C , 32 . 88 ; H , 4 . 60 ; N , 19 . 17 .
Found : C, 32.55; H, 4.50; N, 18.92. ^-NMR (DMSO-d6) δ : 3.54 (2H,s), 4.08(4H,br s), 7.04(lH,d, J=4.8Hz) , 7.27 ( IH, d, J=2.8Hz ) , 7.46(lH,dd, J=4.8Hz & 2.8Hz ) , 9.12(lH,br s).
Example 82
N- (Diaminophosphinyl) -3- ( 2-benzoxazolyl)propionamide N- ( Diaminophosphinyl ) -3- ( 2-benzoxazolyl )propenamide (0.25 g) was dissolved in methanol (30 ml) with heating, and 10% Pd-C (wet) (0.05 g) was added. The mixture was hydrogenated at room temaperature under atmospheric pressure for 1 hour . The catalyst was removed by filtration , and the filtrate was concentrated under reduced pressure. Precipitated crystals were collected by filtration to give
N- ( diaminophosphinyl ) -3- ( 2-benzoxazolyl )propinonamide
(0.17 g) as colorless crystals. mp 176-178 °C (decomp.).
Elemental Analysis for C10H13N4O3P Calcd : C, 44.78; H, 4.89; N, 20.89. Found : C, 44.71; H, 4.90; N, 20.82.
XH-NMR (DMSO-dβ) δ : 2.83( 2H,m) , 3.13 ( 2H,m) , 4.00(4H,br s) ,
7.35(2H,m), 7.67(2H,m), 9.05(lH,m).
Example 83
N- (Diaminophosphinyl) -1-benzimidazolylacetamide
A mixture of benzimidazole (10 g), ethyl bromoacetate (15.5 g), potassium carbonate (12.9 g) and N,N- dimethylformamide (50 ml) was stirred at 50 °C for 15 hours. The mixture was poured into water and extracted with diethyl ether. The extract was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give ethyl 1-benzimidazolylacetate (12 g) as oil. Ethyl 1-benzimidazolylacetate (12 g) was dissolved in ethanol (200 ml) , and ammonia gas was introduced under ice-cooling for 30 minutes . The mixture was stirred at room temperature for 65 hours. Precipitated crystals were collected by filtration, washed with ethanol to give 1- benzimidazolylaceta ide (4.3 g) as colorless crystals, mp 204-205 .
1-Benzimidazolylacetamide (2.0 g) was suspended in toluene (30 ml), and phosphorus pentachloride (2.5 g) was added portionwise. The mixture was heated to 70 "C , stirred for 1 hour and then cooled to room temperature . Formic acid (0.52 g) was added dropwise, and then tetrahydrofuran (30 ml) was added. The mixture was stirred at room temperature for 1 hour. Precipitate was collected by filtration, washed with toluene and hexane, and dried to give powder. The powder was suspended in tetrahydrofuran (150 ml) and ammonia gas was introduced under ice-cooling for 50 minutes . The mixture was stirred at room temperature for 1 hour. Diethyl ether was added and precipitate was collected by filtration, washed with diethyl ether. The obtained solid was purified by column chromatography on XAD-II using water as an eluent . The desired fractions were concentrated under reduced pressure and the residue was crystallized from ethanol. The crystals were recrystallized from water-ethanol to give N- (diaminophosphinyl) -1- benzimidazolylacetamide (0.19 g) as colorless crystals, mp 186-188 "C .
Elemental analysis for C9Hi2 5θ2P-l/4H20 Calcd : C, 41.95; H, 4.89; N, 27.18. Found : C, 42.14; H, 4.84; N, 26.99.
^-NMR (DMSO-d6) <5 : 4.17(4H,s), 5.04 (2H,s), 7.16- 7.29(2H,m), 7.43-7.47( lH,m) , 7.63-7.67( lH,m) , 8.15(lH,s), 9.32(lH,s).
Examples 84 to 91 The following compounds were synthesized in the same manner as Example 1.
Example 84 N- (Diaminophosphinyl) -4-chloro-2-thiophenecarboxamide mp 278-280 °C . Elemental analysis for C5H7N3O2SCIP
Calcd : C, 25.06; H, 2.94; N, 17.54. Found : C, 24.95; H, 2.87; N, 17.57. XH-NMR (DMSO-dβ) δ : 4.23(4H,br s), 7.86( lH,d, J=l .4Hz) , 8.11(lH,d, J=1.4Hz) , 9.51(lH,br s).
Example 85
N- ( Diaminophosphinyl ) - 4 -methyl- 3 - thiophenecarboxamide mp 145-147 *C .
Elemental analysis for C6HιoN302SP-l/4H2θ Calcd : C, 31.94; H, 4.88; N, 18.64. Found : C, 32.21; H, 4.73; N, 18.78. XH-NMR (DMSO-dβ) δ : 2.36 (3H,s), 4.13(4H,br s), 7.19(lH,d, J=3.2Hz) , 8.32 ( IH, d, J=3.2Hz ) , 9.12 ( lH,br s ) .
Example 86
N- (Diaminophosphinyl) -2-bromo-5-chloro-3- thiophenecarboxamide mp 181-183 .
Elemental analysis for C5H6N3θ2SBrClP Calcd : C, 18.95; H, 1.90; N, 13.19. Found : C, 19.05; H, 1.91; N, 13.37. ^-NMR (DMSO-dβ) <5 : 4.19 ( 4H,br s ) , 7.16 ( IH, s ) , 9.15 ( lH,br s).
Example 87
N- (Diaminophosphinyl) -5-chloro-4-methyl-3- thiophenecarboxamide mp 159-161 X2. Elemental analysis for C6H9N302SC1P-1/4H20
Calcd : C, 27.91; H, 3.71; N, 16.28.
Found : C, 27.82; H, 3.57; N, 16.24. XH-NMR (DMSO-dβ) <5 : 2.29( 3H, s) , 4.14( 4H,br s ) , 7.18( lH,s) , 8.92(lH,br s) .
Example 88
N- ( Diaminophosphinyl ) - 2 , 5 - dichloro - 4 -methyl - 3 - thiophenecarboxamide mp 178-180 * .
Elemental analysis for C6H8N302SC12P
Calcd : C, 25.01; H, 2.80; N, 14.59. Found : C, 24.89; H, 2.81; N, 14.62. XH-NMR (DMSO-d6) : 2.12( 3H, s ) , 4.21( 4H,br s) , 9.42( lH,br s).
Example 89
N- (Diaminophosphinyl) -2-chloro-5-methyl-3- thiophenecarboxamide mp 180-183 "C .
Elemental analysis for C6H9N302SC1P
Calcd : C, 28.41; H, 3.58; N, 16.57. Found : C, 28.34; H, 3.39; N, 16.64. XH-NMR (DMSO-dβ) <5 : 2.38( 3H, s ) , 4.17 ( 4H,br s ) , 7.16 ( IH, s ) . 8.92(lH,br s) .
Example 90
N- (Diaminophosphinyl) -3-chloro-4-methyl-2- thiophenecarboxamide mp 288-291 °C .
Elemental analysis for C6H9N302SC1P
Calcd : C, 28.41; H, 3.58; N, 16.57. Found : C, 28.35; H, 3.45; N, 16.57. ^-NMR (DMSO-dβ) δ : 2.18 ( 3H, d, J=0.8Hz ) , 4.31 ( 4H,br s ) , 7.65(lH,q, J=0.8Hz) , 8.37( lH,d, J=6.6Hz ) . Example 91
N- (Diaminophosphinyl) -3 , 5-dimethyl-2- thiophenecarboxamide mp 160-162 °C .
Elemental analysis for C7H12N3O2SP
Calcd : C, 36.05; H, 5.19; N, 18.02. Found : C, 35.86; H, 5.16; N, 17.97. ^-NMR (DMSO-dβ) <5 : 2.37( 3H, s ) , 2.41( 3H, s) , 4.13( 4H,br s) , 6.68(lH,s), 8.37(lH,d,J=6.6Hz) .
Example 92
The following compound was synthesized in the same manner as Example 39. N- (Diaminophosphinyl ) -3-methyl-2-furancarboxamide mp 157-158 °C . Elemental analysis for CβHιoN303P-l/4H20
Calcd : C, 34.71; H, 5.10; N, 20.24.
Found : C, 34.75; H, 5.09; N, 20.38. ^-NMR (DMSO-d6) 0 : 2.30 (3H,s), 4.16(4H,br s),
6.53(lH,d, J=1.4Hz) , 7.70( IH, d, J=l .4Hz ) , 8.31 ( lH,br s ) .
Example 93
N- (Diaminophosphinyl) -5-methyl-2-thiophenecarboxamide 7.6 g (47 mM) of 5-methyl-2-thiophenecarboxamide obtained in Reference Example 176 was suspended in 50 ml of toluene, and 10.9 g (50 mM) of phosphorus pentachloride was added at room temperature with vigorous stirring. The mixture was stirred at 65 for 30 minutes and ice-cooled. Then, 2.0 ml of formic acid was added dropwise, and the mixture was stirred at 25 °C for 30 minutes. Toluene was removed under reduced pressure. The residue was dissolved in 100 ml of tetrahydrofuran (THF) , which was added to 17.1 ml of 25% aqueous ammonia under ice-cooling. The mixture was stirred at 25 X for 30 minutes . Then, 100 ml of toluene was added. Precipitated crystals were collected by filtration. The crystals were washed with 50 ml of THF and 50 ml of water, which was subjected to vacuum drying to give give 6.78 g (64 %) of N- (diaminophosphinyl) -5-methyl-2- thiophenecarboxamide . mp 285-297 °C (decomp.).
Example 94
N- ( Diaminophosphinyl) - 5-methyl-3-furancarboxamide 5-Methyl-3-furancarboxamide (0.94 g) was suspended in toluene (10 ml), and phosphorus pentachloride (1.6 g) was added portionwise . The mixture was heated to 70 X2 , stirred for 30 minutes and then cooled to room temperature. Formic acid (0.35 g) was added dropwise, and the mixture was stirred at room temperature for 20 minutes. Then, hexane
( 30 ml) was added, and the mixture was stirred for 15 minutes .
Precipitated crystals were collected by filtration, washed with hexane, and dried to give 1.1 g of crystals. The crystals were dissolved in tetrahydrofuran (50 ml) and ammonia gas was introduced under ice-cooling for 30 minutes .
The mixture was stirred at room temperature for 50 minutes.
Ethyl ether (50 ml) was added and stirred for 20 minutes.
Precipitate was collected by filtration, washed with water, and dried. The obtained solid was recrystallized from methanol-ethyl ether to give N- (diaminophosphinyl) -5- methyl-3-furancarboxamide (0.39 g) as colorless crystals. mp 168-170 * .
Elemental analysis for C6H10N3O3P
Calcd : C, 35.48; H, 4.96; N, 20.69. Found : C, 35.42; H, 4.90; N, 20.42.
^-NMR (DMSO-dβ) δ : 2.12( 3H, s ) , 4.12 ( 4H,br s ) , 7.48( IH, s) ,
8.44(1H,S), 9.07(lH,d, J=7.6Hz) .
Examples 95 to 99 The following compounds were synthesized in the same manner as Example 94.
Example 95
N- ( Diaminophosphinyl ) -3-methyl-2-furancarboxamide mp 157-158 X2.
Elemental analysis for C6HιoN3θ3P-l/4H20 Calcd : C, 35.48; H, 4.96; N, 20.69. Found : C, 34.75; H, 5.09; N, 20.38. XH-NMR (DMSO-d6) δ : 2.30(3H,s), 4.16 ( 4H,br s ) , 6.53(lH,d, J=1.4Hz) , 7.70 ( IH, , J=l .4Hz ) , 8.31 ( lH.br s ) .
Example 96
N- (Diaminophosphinyl) -3 , 5-dimethyl-2-furancarboxamide mp 189-191 T . Elemental analysis for C7Hι2N3θ3P
Calcd : C, 38.72; H, 5.57; N, 19.35. Found : C, 38.36; H, 5.31; N, 19.24.
^-NMR (DMSO-dβ) δ : 2.24(2H,s) , 2.28 (3H,S) , 4.15 (4H,brs) ,
6.17(lH.s), 8.09(lH,d, J=7.8Hz) .
Example 97
N- ( Diaminophosphinyl ) -5-methyl-3-thiophenecarboxamide mp 178-181 X2.
Elemental analysis for C6H10N3O2SP-l/2H2O Calcd : C, 32.61; H, 4.65; N, 19.01.
Found : C, 32.37; H, 4.66; N, 19.28.
XH-NMR (DMSO-dβ) δ : 2.44 ( 3H, d, J=l .2Hz ) , 4.15(4H,br s),
7.26(1H,S), β.OKlH.m). 9.12( lH,d, J=7.4Hz) .
Example 98
N- (Diaminophosphinyl) -3 , 5-dimethyl-2- thiophenecarboxamide mp 160-162 *C .
Elemental analysis for C7H12N3O2SP Calcd : C, 36.05; H, 5.91; N, 18.02. Found : C, 35.86; H, 5.16; N, 17.97. XH-NMR (DMSO-dβ) δ : 2.37 ( 3H, s ) , 2.41 ( 3H, s ) , 4.13 ( 4H,br s ) , 6.68(lH,s), 8.31(lH,br s) .
Example 99
N- ( Diaminophosphinyl ) -2-ethyl-3-thiophenecarboxamide mp 154-155 "C .
Elemental analysis for C7Hi2N3θ2SP-2/5H20 Calcd : C, 34.96; H, 5.31; N, 17.49. Found : C, 35.36; H, 5.17; N, 17.10.
^-N R (DMSO-dβ) δ : 1.23 ( 3H, t , J=7.3Hz ) , 3.13 ( 2H, q, J=7Hz ) , 4.11(4H,br s) , 7.28( lH.d, J=5.2Hz ) , 7.53( lH,d, J=5.2Hz) , 8.97(lH,br s) .
Experimental Example 1
Bacteria Eradication effect of urease inhibitor (in vivo)
To 5 male ICR mice, a bacterial suspension (1 ml) containing 1 x 107 CFU Helicobacter pylori (CPY-433 F4 ) was orally administered to cause infection. Starting at 10 days after the bacterial inoculation, a test compound (10 mg/kg), which was suspended in 0.5% methylcellulose solution containing 1% NaHC03, was orally administered twice daily for 2 to 4 days. Separately, lansoprazole (30 mg/kg), which was suspended in 0.5% methylcellulose solution, was subcutaneously administered 10 minutes before the first administration on each day. On the next day after the final administration, mice were sacrificed and stomachs were excised, washed with physiological saline (5 ml) and homogenized in Brucella medium (2 ml) . A series of 10-fold dilutions of the gastric homogenate in Brucella medium (0.1 ml ) were spread over a modified Brucella agar medium and incubated at 37 for 4 days under microaerobic conditions, and the CFU per stomach was determined. The results were shown in Table 7. Table 7
Compound Eradication Rate Days for therapy
Example 94 3/5 2
Example 96 1/5 2
Example 98 1/4 2
Eradication rate: (Number of mice in which bacteria was eradicated) /(Number of mice used in Experiment)
Experimental Example 2
Screening of urease inhibitors
One hundred (100) p 1 of 100 mM Bis-Tris buffer (pH 6.5) and 60 p 1 of an urease solution prepared from Helicobacter pylori were added to 20 P 1 of a test drug dissolved in 0.1% N,N-dimethylformamide solution. The mixture was incubated at room temperature for 30 minutes, and then 20 p 1 of 100 mM urea was added. The mixture was kept at room temperature for 10 minutes, and then the yielded ammonia in the incubation mixture was measured using a commercial test kit (Ammonia Test Wako™ ; Wako Pure Chemical) . The percent inhibition against the yield of ammonia in the solvent addition group was calculated to obtain the IC5o value. The results are shown in Tables 8-1, 8-2 and 8- 3.
Table 8- 1
Inhibitory effect against Helicobacter pylori-derived urease ( ICso : nM)
Example No . ICso Example No . ICn
1 1.2 31 7.1
2 4.7 32 8.7
3 5.5 33 1.9
4 6.8 34 12
5 3.0 35 11
6 3.5 36 7.4
7 4.3 37 1.8
8 4.3 38 1.7
9 13 39 2.2
10 3.6 40 7.9
11 4.2 41 7.7
12 3.6 42 2.3
13 5.2 43 6.2
14 1.1 44 14
15 1.7 45 1.4
16 0.8 46 5.7
17 8.2 47 1.9
18 11 48 8.3
19 4.6 49 27
20 2.5 50 7.5
21 4.3 51 22
22 12 52 12
23 2.2 53 7.9
24 9.1 54 3.3
25 1.1 55 3.0
26 1.3 56 41
27 4.1 57 7.5
28 1.5 58 3.0
29 8.1 59 5.4
30 4.3 60 3.6 Table 8-2
Inhibitory effect against Helicobacter pylori-derived urease (IC50 :nM)
Example No . IC.50 Example No . IC-,0
61 2.8 91 6.3
62 2.8 92 6.0
63 5.6 94 1.9
64 2.9 95 6.0
65 2.3 96 7.8
66 10 97 5.9
67 6.1 98 7.8
68 18 99 2.4
69 9.7
70 13
71 1.9
72 3.6
73 55
74 5.1
75 22
77 8.1
78 4.7
79 6.0
80 4.4
81 7.9
82 27
83 7.0
84 2.5
85 2.2
86 0.9
87 2.5
88 3.3
89 2.6
90 6.3 Table 8 - 3
Inhibitory effect against Helicobacter pylori-derived urease (IC50 :nM)
Reference Reference
Example No . IC™ Example No . IC50
1 5.0 31 71
2 9.6 32 14
3 6.6 33 83
4 10 34 22
6 15 35 17
7 6.9 36 8.9
8 4.5 37 17
9 9.7 38 9.7
10 7.8 39 5.9
12 44 40 18
15 17 41 10
16 2.7 42 22
17 5.4 43 71
18 5.1 44 11
19 12
20 6.5
21 7.9
22 9.3
23 5.7
24 8.0
25 1.9
26 13
27 3.9
28 35
29 5.9
30 4.3 Experimental Example 3
To 5 male ICR mice, a bacterial suspension (1 ml) containing 1 x 107 CFU Helicobacter pylori (CPY-433 F4 ) was orally administered to cause infection. Then, 0.5% methylcellulose solution or a drug (LPZ: Lansoprazole) suspended in the solution was subcutaneously administered. Twenty minutes after this administration, 0.5% methylcellulose solution containing 1% NaHC03 or a drug suspended in the solution was orally administered. The drug administration was conducted twice daily for 2 days . On the next day after the final administration, mice were sacrificed and stomachs were excised, washed with physiological saline (5 ml) and homogenized in Brucella medium (2 ml) . A series of 10-fold dilutions of the gastric homogenate in Brucella medium (0.1 ml ) were spread over a modified Brucella agar medium and incubated at 37 t for 4 days under microaerobic conditions , and the CFU per stomach was determined. The results were shown in Table 9.
Table 9
Drug Drug Number of Eradication administered administered bacteria rate subcutaneously orally in stomach (loσ CFU)
- (Control) - (Control) 4.62+ 0.12 0/5
LPZ(10mg/kg) Compound of 1.78±0.30** 3/5 Working Ex.3 (lOmg/kg) + clarithromycin (30mg/kg)
LPZ(10mg/kg) Compound of 1.63 + 0.20** 1/5 Working Ex.3 (lOmg/kg) + amoxicillin (3mg/kg)
LPZ(10mg/kg) Compound of 2.09±0.28** 1/5 Working Ex.3 (lOmg/kg) + metronidazole (3 mq/kq)
Data about Number of bacteria in stomach shows mean ± standard error of 5 examples .
Eradication rate means (number of mice in which bacteria was eradicated) /(number of mice used in the experiment). **: p<0.01 (compared with control group, Dunnett's test)
Preparation Examples
The anti-Helicobacter agent and pharmaceutical against Helicobacter bacteria of the present invention can, for example, be produced with the following formulations: 1. Capsules (1) Compound of Working Example 3 100 mg
(2) Amoxicillin 500 mg
(3) Microcrystalline cellulose 70 mg
(4) Magnesium stearate 10 mg
Total 680 mg per capsule Ingredients (1), (2) and (3) and a half portion of ingredient ( 4 ) are mixed and granulated. To these granules , the remaining portion of component (4) is added, and the whole mixture is packed in a gelatin capsule.
2. Tablets
(1) Compound of Working Example 3 100 mg
(2) Amoxicillin 500 mg
(3) Microcrystalline cellulose 30 mg (4) Magnesium stearate 5 mg
Total 635 mg per tablet Ingredients (1), (2) and a two-third portion of ingredient (3) and a half portion of ingredient (4) are mixed and granulated. To these granules, the remaining portions of ingredients (3) and (4) are added, and the whole mixture is tableted by compressive tableting.
3. Capsules
(1) Compound of Working Example 3 100 mg (2) Lansoprazole 10 mg
(3) Amoxicillin 500 mg
(4) Microcrystalline cellulose 70 mg
(5) Magnesium stearate 10 mg
Total 690 mg per capsule Ingredients (1), (2), (3) and (4) and a half portion of ingredient ( 5 ) are mixed and granulated. To these granules , the remaining portion of ingredient (5) is added, and the whole mixture is packed in a gelatin capsule.
4. Tablets (1) Compound of Working Example 3 100 mg
(2) Lansoprazole 10 mg
(3) Amoxicillin 500 mg
(4) Microcrystalline cellulose 30 mg (5) Magnesium stearate 5 mg
Total 645 mg per tablet Ingredients (1), (2) and (3). a two-third portion of ingredient (4) and a half portion of ingredient (5) are mixed and granulated. To these granules, the remaining portions of ingredients (4) and (5) are added, and the whole mixture is tableted by compressive tableting.
5. Combination preparation (kit)
Capsules A and B, each of which contains an active ingredient, are prepared separately, and packed into a box.
(a) Capsule A
(1) Lansoprazole 10 mg
(2) Lactose 90 mg
(3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg
Total 180 mg per capsule Ingredients (1), (2) and (3) and a half portion of ingredient ( 4 ) are mixed and granulated . To these granules , the remaining portion of ingredient (4) is added, and the whole mixture is packed in a gelatin capsule.
(b) Capsule B
(1) Compound of Working Example 3 100 mg
(2) Amoxicillin 500 mg
(3) Microcrystalline cellulose 70 mg (4) Magnesium stearate 10 mg
Total 680 mg per capsule Ingredients (1), (2) and (3) and a half portion of ingredient ( 4 ) are mixed and granulated . To these granules , the remaining portion of ingredient (4) is added, and the whole mixture is packed in a gelatin capsule. 6. Phosphorylamide derivative-containing gastric mucosa-adherent dosage form
Behenic acid hexa(tetra)glyceride (HB-310™, Sakamoto Yakuhin Kogyo Co. , Ltd. ) , 86.0 g, is weighed and melted at 84°C . To this molten glyceride, 4 g of compound of Working Example 3 and 10.0 g of acrylic polymer (HIVISWAKO™ 104, Wako Pure Chemical Industries) are serially added and the mixture is stirred for dispersion at a constant temperature of 84°C for 15 minutes. This molten mixture is dripped at a flow rate of 10 g/min. onto a 15 cm (dia. ) aluminum disk revolving at 1950 rpm to provide spherical 42/60 mesh (under 42 mesh sieve/on 60 mesh sieve) fine granules.
7. Phosphorylamide derivative-containing gastric mucosa-adherent dosage form
Hydrogenated castor oil (Lubriwax™ 101, Freund Industrial Co.), 63 g, and behenic acid hexa(tetra) glyceride (HB-310™, Sakamoto Yakuhin Kogyo Co . , Ltd. ) , 5.0 g, are respectively weighed and melted together at 84*0. To this molten mixture, 4 g of compound of Working Example 3, 8.0 g of acrylic polymer (HIVISWAKO™ 104, Wako Pure Chemical Industries), and 20 g of Curdlan (Takeda Chemical Industries ) are serially added and the mixture is stirred for dispersion at a constant temperature of 84 "C for 15 minutes. This molten mixture is dripped at a flow rate of 10 g/min. onto a 15 cm (dia. ) aluminum disk revolving at 1950 rpm to provide spherical 42/60 mesh fine granules.
8. Phosphorylamide derivative-containing gastric mucosa-adherent dosage form
Hydrogenated castor oil (Lubriwax™ 101, Freund Industrial), 63 g, and behenic acid hexa(tetra) glyceride (HB-310™, Sakamoto Yakuhin Kogyo Co., Ltd.), 5.0 g, are respectively weighed and melted together at 84C . To this molten mixture , 4 g of compound of Working Example 3 , 8.0 g of acrylic polymer (HIVISWAKO™ 104, Wako Pure Chemical Industries), and 20 g of low substituted hydroxypropylcellulose (L-HPC™, Shin-Etsu Chemical) are serially added and the mixture is stirred for dispersion at a constant temperature of 84°C for 15 minutes. This molten mixture is dripped at a flow rate of 10 g/min. onto a 15 cm (dia. ) aluminum disk revolving at 1950 rpm to provide spherical 42/60 mesh fine granules.
9. Phosphorylamide derivative-containing gastric mucosa-adherent dosage form
Behenic acid hexa( tetra) glyceride (HB-310™, Sakamoto Yakuhin Kogyo Co. , Ltd. ) , 81.5 g, is weighed and melted at 84X . To this molten glyceride , 0.5 g of compound of Working Example 3, 8.0 g of acrylic polymer (HIVISWAKO™ 104, Wako Pure Chemical Industries), and 10 g of Curdlan (Takeda Chemical Industries) are serially added and the mixture is stirred for dispersion at a constant temperature of 84 * for 15 minutes . This molten mixture is dripped at a flow rate of 10 g/min. onto a 15 cm (dia. ) aluminum disk revolving at 1950 rpm to provide spherical 42/60 mesh fine granules.
10. Phosphorylamide derivative-containing gastric mucosa-adherent dosage form
Hydrogenated castor oil (Lubriwax™ 101, Freund Industrial), 54 g, and behenic acid hexa( tetra) glyceride (HB-310™, Sakamoto Yakuhin Kogyo Co., Ltd.), 1.0 g, are respectively weighed and melted together at 84^ . To this molten mixture, 35 g of compound of Working Example 3, 5.0 g of acrylic polymer (HIVISWAKO™ 104, Wako Pure Chemical Industries), and 5.0 g of Curdlan (Takeda Chemical Industries) are serially added and the mixture is stirred for dispersion at a constant temperature of 84 for 15 minutes . This molten mixture is dripped at a flow rate of 10 g/min. onto a 15 cm (dia.) aluminum disk revolving at 1950 rpm to provide spherical 42/60 mesh fine granules.
11. Phosphorylamide derivative-containing gastric mucosa-adherent dosage form
Hydrogenated castor oil (Lubriwax™ 101, Freund Industrial), 35 g, and behenic acid hexa( tetra)glyceride (HB-310™, Sakamoto Yakuhin Kogyo Co., Ltd.), 1 g, are respectively weighed and melted together at 84X3. To this molten mixture, 35 g of compound of Working Example 3, 5.0 g of acrylic polymer (HIVISWAKO™ 104, Wako Pure Chemical Industries), and 5.0 g of low substituted hydroxypropylcellulose (L-HPC™, Shin-Etsu Chemical) are serially added and the mixture is stirred for dispersion at a constant temperature of 84 3 for 15 minutes. This molten dispersion is dripped at a flow rate of 10 g/min. onto a 15 cm (dia. ) aluminum disk revolving at 1950 rpm to provide spherical 42/60 mesh fine granules.
12. Phosphorylamide derivative-containing gastric mucosa-adherent dosage form
Hydrogenated castor oil (Lubriwax TM 101, Freund Industrial) , 76 g, is weighed and melted at 84X3. To this molten glyceride, 4.0 g of compound of Working Example 3, 10.0 g of acrylic polymer (HIVISWAKO™ 104, Wako Pure Chemical Industries), and 10.0 g of low substituted hydroxypropylcellulose (L-HPC™, Shin-Etsu Chemical) are serially added and the mixture is stirred for dispersion at a constant temperature of 84X3 for 15 minutes. This molten dispersion is dripped at a flow rate of 10 g/min. onto a 15 cm (dia. ) aluminum disk revolving at 1950 rpm to provide spherical 42/60 mesh fine granules.
13. Antibiotic-containing gastric mucosa-adherent dosage form Hydrogenated castor oil (Lubriwax TM 101, Freund Industrial) , 75 g, is weighed and melted at 95X3. To this molten glyceride, 1.5 g of amoxicillin, 10.0 g of acrylic polymer (HIVISWAKO™ 104, Wako Pure Chemical Industries), and 13.5 g of Curdlan (Takeda Chemical Industries) are serially added and the mixture is stirred for dispersion at a constant temperature of 95X3 for 15 minutes. This molten mixture is dripped at a flow rate of 10 g/min. onto a 15 cm (dia. ) aluminum disk revolving at 1950 rpm to provide spherical 42/60 mesh fine granules.
14. Antibiotic-containing gastric mucosa-adherent dosage form
Carnauba wax ( Polishingwax™ 103, Freund Industrial), 88.5 g, is weighed and melted at 95X3. To this molten glyceride, 1.5 g of amoxicillin and 10.0 g of acrylic polymer (HIVISWAKO™ 104, Wako Pure Chemical Industries) are serially added and the mixture is stirred for dispersion at a constant temperature of 95X3 for 15 minutes. This molten mixture is dripped at a flow rate of 10 g/min. onto a 15 cm (dia. ) aluminum disk revolving at 1950 rpm to provide spherical 42/60 mesh fine granules.
15. Phosphorylamide derivative-containing gastric mucosa-adherent dosage form
Hydrogenated castor oil (Lubriwax™ 101, Freund Industrial) , 78 g. is weighed and melted at 84X3. To this molten glyceride , 4 g of compound of Working Example 3 , 8.0 g of acrylic polymer (HIVISWAKO™ 104, Wako Pure Chemical Industries), and 10.0 g of Curdlan (Takeda Chemical
Industries) are serially added and the mixture is stirred for dispersion at a constant temperature of 84X3 for 15 minutes . This molten mixture is dripped at a flow rate of 10 g/min. onto a 15 cm (dia.) aluminum disk revolving at 1950 rpm to provide spherical 42/60 mesh fine granules. Industrial Applicability
The the anti-Helicobacter agent, the pharmaceutical composition and the pharmaceutical against Helicobacter bacteria of the present invention possess antibacterial activity against Helicobacter bacteria, and they exhibit anti-Helicobacter action against Helicobacter bacteria which exhibit toxic action in the digestive tract. The anti-Helicobacter agent, the pharmaceutical composition and the pharmaceutical against Helicobacterbacteria of the present invention are therefore useful for prevention or treatment of digestive diseases presumably caused by Helicobacter bacteria, such as gastritis, duodenal ulcer, gastric ulcer and chronic gastritis. Since significant correlation between Helicobacter bacteria, especially Helicobacter pylori , and gastric cancer has recently been suggested, the phosphorylamide derivative, the anti- Helicobacter agent , the pharmaceutical composition and the pharmaceutical against Helicobacter bacteria of the present invention are also expected to be useful in the prevention of gastric cancer.

Claims

1. An anti-Helicobacter agent which comprises a compound represented by the formula:
0
II RΓÇöPΓÇöNH, I 2 NH2 wherein R represents an amino group which may be substituted, or a salt thereof, and an antibiotic.
2. An anti-Helicobacter agent according to claim 1, wherein R is a group represented by the formula:
-NHCOR1 wherein R1 represents hydrogen, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted.
3. An anti-Helicobacter agent according to claim 1, wherein the antibiotic is a penicillin antibiotic, a macrolide antibiotic or a nitroimidazole antibiotic.
4. A pharmaceutical composition which comprises a compound represented by the formula:
0 ,aΓÇöCONHΓÇöP-NH? NH2 wherein Rla represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or a salt thereof, and an antibiotic.
5. A composition according to claim 4, wherein Rl╬▓ represents an aromatic hydrocarbon group or an aromatic heterocyclic group each of which may be substituted.
6. A composition according to claim 4 , wherein Rla represents a 5-membered aromatic heterocyclic group which may be substituted.
7. A composition according to claim 4 , wherein Rla represents thienyl group or furyl group each of which is substituted by one or two C^ alkyl group.
8. A composition according to claim 4, wherein the compound is N- (diaminophosphinyl) -5-methyl-2- thiophenecarboxamide .
9. A composition according to claim 4 , wherein the compound is N- (diaminophosphinyl) -2-methyl-3- furancarboxamide .
10. A composition according to claim 4 , wherein the antibiotic is a penicillin antibiotic, a macrolide antibiotic or a nitroimidazole antibiotic.
11. A composition according to claim 4 which is an anti-Helicobacter agent.
12. A composition according to claim 4 which is for prophylaxis of recurrence of an ulcer.
13. A pharmaceutical composition which comprises a compound represented by the formula:
0 R,bΓÇöCONHΓÇöp-NH7 NH2 wherein Rl represents a non-cyclic hydrocarbon group substituted by ( i) a cyclic hydrocarbon group which may be substituted, (ii) a heterocyclic group which may be substituted, (iii) hydroxyl group substituted by a cyclic hydrocarbon group which may be substituted, (iv) hydroxyl group substituted by a heterocyclic group which may be substituted, (v) thiol group substituted by a cyclic hydrocarbon group which may be substituted, or (vi) thiol group substituted by a heterocyclic group which may be substituted, or a salt thereof, and an antibiotic.
14. A pharmaceutical composition according to claim 13, wherein the antibiotic is a penicillin antibiotic, a macrolide antibiotic or a nitroimidazole antibiotic.
15. A pharmaceutical composition which comprises (1) a compound represented by the formula:
0
II RΓÇöPΓÇö H, I 2 NH2 wherein R represents an amino group which may be substituted, or a salt thereof, (2) an antibiotic, and (3) an antacid and/or an acid secretion inhibitor.
16. A composition according to claim 15, wherein R is a group represented by the formula:
-NHCOR1 wherein R1 represents hydrogen, a hydrocarbon group which may be substituted or a heterocyclic group which may be substituted.
17. A composition according to claim 16, wherein R1 represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted.
18. A composition according to claim 16, wherein R1 represents a non-cyclic hydrocarbon group substituted by (i) a cyclic hydrocarbon group which may be substituted, (ii) a heterocyclic group which may be substituted, (iii) hydroxyl group substituted by a cyclic hydrocarbon group which may be substituted, (iv) hydroxyl group substituted by a heterocyclic group which may be substituted, (v) thiol group substituted by a cyclic hydrocarbon group which may be substituted, or (vi) thiol group substituted by a heterocyclic group which may be substituted.
19. A composition according to claim 16, wherein R1 represents an aromatic hydrocarbon group or an aromatic heterocyclic group each of which may be substituted.
20. A composition according to claim 16, wherein R1 represents a 5-membered aromatic heterocyclic group which may be substituted.
21. A composition according to claim 16, wherein R1 represents thienyl group or furyl group each of which is substituted by one or two C^ alkyl group.
22. A composition according to claim 15, wherein the compound is N- (diaminophosphinyl) -5-methyl-2- thiophenecarboxamide .
23. A composition according to claim 15, wherein the compound is N- (diaminophosphinyl) -2-meth╬│l-3- furancarboxamide .
24. A composition according to claim 15, wherein the antibiotic is a penicillin antibiotic, a macrolide antibiotic or a nitroimidazole antibiotic.
25. A composition according to claim 15, wherein the acid secretion enhancer is a proton pump inhibitor.
26. A composition according to claim 25, wherein the proton pump inhibitor is a benzimidazole compound.
27. A composition according to claim 15 which is an anti-Helicobacter agent.
28. A composition according to claim 15 which is for prophylaxis of recurrence of an ulcer.
29. A combination preparation which contains a compound represented by the formula:
Figure imgf000216_0001
wherein Rla represents a cyclic hydrocarbon group which may be substituted or a heterocyclic group which may be substituted, or a salt thereof, and an antibiotic.
30. A combination preparation which contains a compound represented by the formula:
0
R1bΓÇöCONHΓÇöp-NH, NH2 wherein Rl represents a non-cyclic hydrocarbon group substituted by (i) a cyclic hydrocarbon group which may be substituted, (ii) a heterocyclic group which may be substituted, (iii) hydroxyl group substituted by a cyclic hydrocarbon group which may be substituted, (iv) hydroxyl group substituted by a heterocyclic group which may be substituted, (v) thiol group substituted by a cyclic hydrocarbon group which may be substituted, or (vi) thiol group substituted by a heterocyclic group which may be substituted, or a salt thereof, and an antibiotic.
31. A combination preparation which contains (1) a compound represented by the formula: 0
I I RΓÇö PΓÇö H, I 2
NH2 wherein R represents an amino group which may be substituted, or a salt thereof, (2) an antibiotic, and (3) an antacid and/or an acid secretion inhibitor.
32. Use of a compound represented by the formula:
0
II RΓÇöPΓÇöNH, I 2 NH2 wherein R represents an amino group which may be substituted, or a salt thereof, for the preparation of an anti- Helicobacter agent which is used in combination with an antibiotic.
33. Use of a compound represented by the formula:
0
II RΓÇöPΓÇöNH, I 2 NH2 wherein R represents an amino group which may be substituted, or a salt thereof, for the preparation of an anti- Helicobacter agent in combination with an antibiotic and an antacid and/or an acid secretion inhibitor.
34. A compound which is N- (diaminophosphinyl) -5- methyl-2-furancarboxamide or a salt thereof.
35. A compound which is N- (diaminophosphinyl) -3 , 5- dimethyl-2-furancarboxamide or a salt thereof.
36. A compound which is N- (diaminophosphinyl) -3,5- dimethyl-2-thiophenecarboxamide or a salt thereof.
37. A method for eradicating Helicobacter from a mammal, which comprises administering to said mammal a compound represented by the formula:
0 II RΓÇöPΓÇöNH, I 2 NH2 wherein R represents an amino group which may be substituted, or a salt thereof, in combination with an antibiotic.
38. A method for eradicating Helicobacter from a mammal, which comprises administering to said mammal a compound represented by the formula:
0
II RΓÇöPΓÇöNH, I 2 NH2 wherein R represents an amino group which may be substituted, or a salt thereof, in combination with an antibiotic and an antacid and/or an acid secretion inhibitor.
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WO2004035560A1 (en) * 2002-10-16 2004-04-29 Nippon Soda Co.,Ltd. Pyrrole derivative, intermediate, and agricultural or horticultural bactericide
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US9035044B2 (en) 2011-05-09 2015-05-19 Janssen Pharmaceutica Nv L-proline and citric acid co-crystals of (2S, 3R, 4R, 5S,6R)-2-(3-((5-(4-fluorophenyl)thiopen-2-yl)methyl)4-methylphenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol
US11207337B2 (en) 2015-09-15 2021-12-28 Janssen Pharmaceutica Nv Co-therapy comprising canagliflozin and phentermine for the treatment of obesity and obesity related disorders
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WO2021123051A1 (en) 2019-12-20 2021-06-24 Bayer Aktiengesellschaft Substituted thiophene carboxamides, thiophene carboxylic acids and derivatives thereof

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