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WO2021261471A1 - Therapeutic agent for obsessive-compulsive disorder - Google Patents

Therapeutic agent for obsessive-compulsive disorder Download PDF

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Publication number
WO2021261471A1
WO2021261471A1 PCT/JP2021/023531 JP2021023531W WO2021261471A1 WO 2021261471 A1 WO2021261471 A1 WO 2021261471A1 JP 2021023531 W JP2021023531 W JP 2021023531W WO 2021261471 A1 WO2021261471 A1 WO 2021261471A1
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Prior art keywords
group
obsessive
optionally substituted
atom
compulsive
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PCT/JP2021/023531
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French (fr)
Japanese (ja)
Inventor
周司 金子
希美 浅岡
輝 幡鎌
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国立大学法人京都大学
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Publication of WO2021261471A1 publication Critical patent/WO2021261471A1/en

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/02—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving viable microorganisms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6844—Nucleic acid amplification reactions

Definitions

  • the present disclosure relates to a therapeutic agent for obsessive-compulsive disorder, a screening method for an active ingredient for treating obsessive-compulsive disorder, and the like.
  • Obsessive-compulsive disorder is a type of mental disorder that repeats irrational acts and thoughts against one's will.
  • OCD Obsessive-compulsive disorder
  • SSRIs selective serotonin reuptake inhibitors
  • the subject of this disclosure is to provide a therapeutic agent for obsessive-compulsive disorder. It is also an object of the present disclosure to provide a method for screening an active ingredient for treating obsessive-compulsive disorder.
  • Item 1 A therapeutic agent for obsessive-compulsive disorder containing a proton pump inhibitor as an active ingredient.
  • Item 2. Proton pump inhibitor, Equation (I) [In the formula, X and Y are the same or different, and the bond or main chain is a spacer having 1 to 20 atoms, and R 1 is a hydrocarbon group which may be substituted or a heterocycle which may be substituted. The groups, R 2 , R 3 and R 4, are the same or different, hydrogen atoms, optionally substituted hydrocarbon groups, optionally substituted thienyl groups, optionally substituted benzo [b].
  • R 5 and R 6 indicate the same or different hydrocarbon atoms or optionally substituted hydrocarbon groups], salts thereof, and prodrugs thereof, and formula (1).
  • R 1 ' is hydrogen, methoxy, difluoromethoxy or trifluoromethyl
  • R 2' and R 3 ' are the same or different, hydrogen, methyl or methoxy
  • R 4' is C 1 -C 5 to 5 lower alkyls which may be fluorinated or alkoxylated, where n'represents 0 or 1, respectively.
  • the therapeutic agent according to Item 1 which is at least one selected from the group consisting of the compound represented by the above, a salt thereof, and a prodrug thereof.
  • Item 3. is at least one selected from the group consisting of the compound represented by the above, a salt thereof, and a prodrug thereof.
  • the proton pump inhibitor is at least one selected from the group consisting of vonoprazan, lansoprazole, pantoprazole, omeprazole, esomeprazole, and rabeprazole.
  • Obsessive-compulsive disorder is a fear of pollution, preservation, suspicion of uncertainty, fear of harm / taboo thinking, obsession with order, obsessive-compulsive cleaning, confirmation, ritualistic behavior to counteract obsessive-compulsive thoughts, sorting and counting, At least one selected from the group consisting of obsessive-compulsive dermatosis, obsessive-compulsive habit, biting cheek habit, obsessive-compulsive purchase, obsessive-compulsive behavior, obsessive-compulsive swelling, obsessive-compulsive lip, obsessive-compulsive ulcer, and obsessive-compulsive wash.
  • Item 3 The therapeutic agent according to any one of Items 1 to 3, which is a disease associated with the symptoms of. Item 5.
  • Item 6. The therapeutic agent according to any one of Items 1 to 4, which is for oral administration or intravenous injection.
  • Item 6. A screening method for active ingredients for treating obsessive-compulsive disorder using proton pump inhibitory activity as an index.
  • B: N 10, * P ⁇ 0.05).
  • the present disclosure includes therapeutic agents for obsessive-compulsive disorder containing a proton pump inhibitor as an active ingredient.
  • the therapeutic agent may be referred to as "therapeutic agent of the present disclosure”.
  • the proton pump inhibitor is not particularly limited as long as it inhibits the enzymatic activity of H + , K + -ATPase, which is a proton pump.
  • proton pump inhibitors examples include Equation (I) [In the formula, X and Y are the same or different, and the bond or main chain is a spacer having 1 to 20 atoms, and R 1 is a hydrocarbon group which may be substituted or a heterocycle which may be substituted.
  • the groups, R 2 , R 3 and R 4, are the same or different, hydrogen atoms, optionally substituted hydrocarbon groups, optionally substituted thienyl groups, optionally substituted benzo [b].
  • R 5 and R 6 indicate the same or different hydrocarbon atoms or hydrocarbon groups which may be substituted], or a salt thereof (hereinafter, may be abbreviated as compound (I)). ), Or its prodrug.
  • the "spacer having 1 to 20 atoms in the main chain” represented by X or Y means a divalent group in which 1 to 20 atoms in the main chain are connected.
  • the "number of atoms in the main chain” is counted so that the atoms in the main chain are minimized.
  • a "spacer having 1 to 20 atoms in the main chain” for example, -O-; -S-; -CO-; -SO-; -SO 2- ; -NR 40- (R 40 is a hydrogen atom, a optionally substituted hydrocarbon group, optionally substituted (eg, halogenated) C 1-6 alkyl-carbonyl, substituted (eg, halogenated).
  • 1 to 5 selected from divalent C 1-6 aliphatic hydrocarbon groups which may have substituents); and may have a C 1-6 alkyl sulfonyl). Examples thereof include a divalent group which can be formed by concatenating the groups of.
  • hydrocarbon group represented by the “optionally substituted hydrocarbon group” in R 40 is, for example, chain or cyclic hydrocarbon group (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, etc. ). Of these, a chain or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferable.
  • alkyl examples include C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and the like.
  • alkenyl examples include C 2-6 alkenyl (eg, vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl). , 2-Methyl-1-propenyl, etc.) and the like.
  • alkynyl examples include C 2-6 alkynyl (eg, ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl, etc.).
  • cycloalkyl examples include C 3-7 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.).
  • aryl examples include C6-14aryl (eg, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthrill, etc.).
  • aralkyl examples include C 7-16 aralkyl (eg, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, etc.
  • Phenyl-C 1-6 alkyl such as 5-phenylpentyl, naphthyl-C 1-6 alkyl or diphenyl-C 1-4 alkyl, etc.
  • hydrocarbon group is alkyl, alkenyl or alkynyl, (1) halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), (2) nitro, (3) cyano, (4) hydroxy, (5) C 1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy) which may have 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom).
  • halogen atom eg, fluorine atom, chlorine atom, bromine atom, iodine atom, etc.
  • Alkyl-carbonyl eg, acetyl, propionyl, etc.
  • C 6-14 aryl-carbonyl eg, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.
  • carboxyl e.g, acetyl, propionyl, etc.
  • C 6-14 aryl-carbonyl eg, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.
  • carboxyl eg, methoxycarbonyl, ethoxycarbonyl
  • C 1-6 alkoxy-carbonyl eg, methoxycarbonyl, ethoxycarbonyl
  • Propoxycarbonyl tert-butoxycarbonyl, etc.
  • C 6-14 aryloxy-carbonyl eg, phenoxycarbonyl, etc.
  • (25) carbamoyl e.g, thiocarbamoyl
  • Alkyl-carbamoyl eg, methylcarbamoyl, ethylcarbamoyl, etc.
  • Di-C 1-6 alkyl-carbamoyl eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.
  • C 6-14aryl- Carbamoyl eg, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.
  • C 1-6 alkylsulfonyl eg, methylsulfonyl, ethylsulfonyl, etc.
  • (31) C 6-14 arylsulfonyl eg, eg, methylsulfonyl, ethylsulfonyl, etc.
  • Phenylsulfonyl
  • Alkylsulfonylamino eg, methylsulfonylamino, ethylsulfonylamino, etc.
  • C 6-14 arylsulfonylamino eg, phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.
  • C 1-6 alkyl-carbonyloxy eg, acetoxy, propionyloxy, etc.
  • (41) C 6-14 aryl-carbonyloxy eg, benzoyloxy, naphthylcarbonyloxy, etc.
  • (42) C 1-6 alkoxy- Carbonyloxy eg, methoxycarbonyloxy, eth) Xycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.
  • mono-C 1-6 alkyl-carbamoyloxy e
  • one or two heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom are 1 to 4 5- to 10-membered aromatic heterocyclic groups including (eg, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indrill, 2-indrill, 3-indrill, 2-benzothiazolyl, 2-benzo [b] thienyl, 3-benzo [b] Thienyl, 2-benzo [b] furanyl, 3-benzo [b] furanyl, etc.), (48) C 1-3 alkyl
  • hydrocarbon group is cycloalkyl, aryl or aralkyl, (1) halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), (2) nitro, (3) cyano, ( 4) hydroxy, (5) C 1-6 alkoxy (eg, methoxy, ethoxy, propoxy, which may have 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom)).
  • halogen atom eg, fluorine atom, chlorine atom, bromine atom, iodine atom, etc.
  • C 1-6 alkyl-carbonyl eg, acetyl, Propionyl, etc.
  • C 6-14 aryl-carbonyl eg, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.
  • carboxyl e.g, methoxycarbonyl, etc.
  • C 1-6 alkoxy-carbonyl e.g, methoxycarbonyl, etc.
  • C 6-14 aryloxy-carbonyl eg, phenoxycarbonyl, etc.
  • (25) carbamoyl, (26) thiocarbamoyl e.g., mono-C 1 -6 alkyl - carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.)
  • C 1-6 alkyl sulfonyl eg, methyl sulfonyl, ethyl sulfonyl, trifluoromethyl sulfonyl, etc.
  • C 6-14 aryl sulfonyl eg, phenyl sulfonyl, 1-naphthyl sulfonyl, 2-naphthyl sulfonyl, etc.
  • C 1-6 alkyl sulfinyl eg, methyl sulfinyl, ethyl sulfinyl, etc.
  • C 6-14 aryl sulfinyl eg, phenyl sulfinyl, 1-naphthyl sulfinyl, 2-naphthyl sulfinyl, etc.
  • Formylamino (35) C 1-6 alkyl-
  • C 1-6 alkoxy-carbonylamino eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, etc.
  • C 1-6 alkylsulfonylamino eg, methylsulfonylamino, ethylsulfonylamino, etc.
  • C 6-14 arylsulfonylamino eg, phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.
  • C 1-6 alkyl-carbonyloxy eg, acetoxy, propionyl, etc.) Oxy, etc.
  • C 6-14 aryl-carbonyl oki Si eg, benzoyloxy, naphthylcarbonyloxy, etc.
  • 5- to 7-membered saturated cyclic aminos may contain 1 to 4 heteroatoms of the above.
  • a 5- to 10-membered aromatic heterocyclic group containing 1 to 4 heteroatoms of 1 or 2 selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom eg, 2-thienyl, 3).
  • oxo group is not included as a substituent in the "hydrocarbon group which may be substituted" in the present specification.
  • Optionally halogenated C 1-6 alkyl - carbonyl represented by R 40 includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine atom, chlorine atom, bromine Examples thereof include C 1-6 alkyl-carbonyl, which may have an atom (atom, iodine atom, etc.) at a substitutable position. Specific examples include acetyl, monochloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, hexanoyl and the like.
  • halogen atoms e.g., fluorine atom, chlorine atom, bromine
  • C 1-6 alkyl-carbonyl which may have an atom (atom, iodine atom, etc.) at a substitutable position. Specific examples include acetyl, monochloroacetyl, trifluor
  • halogenated C 1-6 alkylsulfonyl represented by R 40, for example, 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine atom, chlorine atom, bromine atom , Iodine atom, etc.) may have a substitutable position, such as C 1-6 alkyl sulfonyl.
  • Specific examples include, for example, methyl sulfonyl, difluoromethyl sulfonyl, trifluoromethyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl, butyl sulfonyl, 4,4,4-trifluorobutyl sulfonyl, sec-butyl sulfonyl, tert-butyl.
  • Examples include sulfonyl, pentyl sulfonyl, hexyl sulfonyl and the like.
  • C 1-6 alkylene for example, -CH 2 -,-(CH 2 ) 2 -,-(CH 2 ) 3 -,-(CH 2 ) 4 -,-(CH 2 ) 5 -,-( CH 2 ) 6 -,-CH (CH 3 )-, -C (CH 3 ) 2 -,-(CH (CH 3 )) 2 -,-(CH (CH 3 )) 2 -,-(CH 2 ) 2 C (CH 3 ) 2 -,-( CH 2 ) 3 C (CH 3 ) 2 -etc.);
  • substituents in the "C 1-6 aliphatic hydrocarbon group which may divalent substituted for example, “optionally substituted hydrocarbon group” represented by R 40
  • substituents of alkyl, alkenyl or alkynyl in the above include the same groups as those exemplified, and in particular, halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), hydroxy and the like are preferable.
  • the number of the "substituents" is, for example, 1 to 5, preferably 1 to 3.
  • a suitable example of a "spacer having 1 to 20 atoms in the main chain” is (1) Substituent alkylene group: Specifically, C 1-20 alkylene (for example, -CH 2 -,-(CH 2 ) 2- , which may have 1 to 3 substituents (preferably halogen atom, hydroxy, etc.)).
  • Alquinylene group which may be substituted Specifically, (preferably, a halogen atom, hydroxy, etc.) 1 to 3 substituents which may have a C 2-20 alkynylene (e.g., -C ⁇ C -, - CH 2 -C ⁇ C -, - CH 2 -C ⁇ C-CH 2 -CH 2 - , etc.); (4)-(CH 2 ) w1a O (CH 2 ) w2a -,-(CH 2 )
  • C 1-8 alkylene for example, ⁇ CH 2 ⁇ , ⁇ (CH 2 ) 2 ⁇ , ⁇ (eg, ⁇ CH 2 ⁇ , ⁇ (CH 2) 2 ⁇ , ⁇ (eg, ⁇ CH 2 ⁇ , ⁇ (CH 2) 2 ⁇ , — which may have 1 to 3 substituents (preferably halogen atom, hydroxy, etc.)).
  • the "spacer having 1 to 20 atoms in the main chain” is preferably the following (1) to (6).
  • (1) -SO 2- ; (2) -SO 2- N (R 7 )-(R 7 indicates a hydrogen atom or a optionally substituted hydrocarbon group), here as " optionally substituted hydrocarbon group” in R 7. include the same groups as "optionally substituted hydrocarbon group” in the R 40; (3) -N (R 8 ) -SO 2- (R 8 indicates a hydrogen atom or a optionally substituted hydrocarbon group), here as " optionally substituted hydrocarbon group” in R 8.
  • R 40 include the same groups as "optionally substituted hydrocarbon group” in the R 40; (4) -N (R 9 )-(R 9 indicates a hydrogen atom or a hydrocarbon group which may be substituted), where the "hydrocarbon group which may be substituted” in R 9 is described above. It includes the same groups as the "optionally substituted hydrocarbon group” in R 40; (5) -O-; (6) C 1-8 alkylene (for example, ⁇ CH 2 ) which may have an optionally substituted alkylene group, preferably 1 to 3 substituents (preferably a halogen atom, hydroxy, etc.).
  • Y is a bond or C 1-8 alkylene (for example, -CH 2 -,-(CH 2 ) 2 -,-(CH 2 ) 3 -,-(CH 2 ) 4 -,-(CH 2 ). 5 -,-(CH 2 ) 6- , -CHCH 3- , -C (CH 3 ) 2 -,-(CH (CH 3 )) 2 -,-(CH 2 ) 2 C (CH 3 ) 2- , -(CH 2 ) 3 C (CH 3 ) 2-, etc.) is preferable. Of these, -CH 2- is preferable.
  • R 1 represents a optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
  • an optionally substituted hydrocarbon group include the same groups as “optionally substituted hydrocarbon group” represented by R 40.
  • heterocyclic group of the “optionally substituted heterocyclic group” may be, for example, a nitrogen atom (which may be oxidized), an oxygen atom, or a sulfur atom (which may be mono or dioxidized). ), A 3- to 8-membered heterocyclic group containing 1 to 4 heteroatoms (preferably a 5- to 6-membered heterocyclic group), or a nitrogen atom (which may be oxidized), an oxygen atom, or a sulfur atom (mono).
  • a 3- to 8-membered heterocyclic group (preferably a 5- to 6-membered heterocyclic group) containing 1 to 4 heteroatoms such as (which may be dioxidized) and a benzene ring or nitrogen atom (which may be oxidized). Condensed with a 3-8 membered heterocyclic group (preferably a 5-6 membered heterocyclic group) containing 1 to 4 heteroatoms such as), oxygen atom, sulfur atom (which may be mono or dioxidized).
  • Examples thereof include groups formed by condensation with a 5- to 6-membered ring which may contain 1 to 4 rings. Specifically, aziridinyl (eg, 1- or 2-aziridinyl), azylinyl (eg, 1- or 2-azilinyl), azetyl (eg, 2-, 3- or 4-azetyl), azetidinyl (eg, 1-). , 2- or 3-azetidine), perhydroazepinyl (eg, 1-, 2-, 3- or 4-perhydroazepinyl), perhydroazocinyl (eg, 1-, 2-, 3-).
  • aziridinyl eg, 1- or 2-aziridinyl
  • azylinyl eg, 1- or 2-azilinyl
  • azetyl eg, 2-, 3- or 4-azetyl
  • azetidinyl eg, 1-
  • 2- or 3-azetidine perhydroazepin
  • 4- or 5-perhydroazocinyl pyrrolyl (eg, 1-, 2- or 3-pyrrolyl), pyrazolyl (eg, 1-, 3-, 4- or 5-pyrazolyl), imidazolyl (eg, 1). -, 2-, 4- or 5-imidazolyl), triazolyl (eg, 1,2,3-triazole-1-, 4- or -5-yl, 1,2,4-triazole-1-, 3-, 4- or 5-yl), tetrazolyl (eg, tetrazole-1-, 2- or 5-yl), frills (eg, 2- or 3-frills), thienyl (eg, 2- or 3-thienyl), sulfur.
  • pyrrolyl eg, 1-, 2- or 3-pyrrolyl
  • pyrazolyl eg, 1-, 3-, 4- or 5-pyrazolyl
  • imidazolyl eg, 1).
  • 2-, 4- or 5-imidazolyl triazolyl
  • Atomically oxidized thienyl eg, 2- or 3-thienyl-1,1-dioxide
  • oxazolyl eg, 2-, 4- or 5-oxazolyl
  • isoxazolyl eg, 3-, 4- or 5-
  • Isoxazolyl eg, 1,2,3-oxadiazole-4- or 5-yl, 1,2,4-oxadiazole-3- or 5-yl, 1,2,5-oxadiazole) -3-yl, 1,3,4-oxadiazole-2-yl
  • thiazolyl eg, 2-, 4- or 5-thiazolyl
  • isothiazolyl eg, 3-, 4- or 5-isothiazolyl
  • Thisiazoleyl eg, 1,2,3-thiazole-4- or 5-yl, 1,2,4-thiazole-3- or 5-yl, 1,2,5-thiazole-3-yl, 1,3 4-thiazole-2-yl
  • pyrimidinyl eg, 2-, 4- or 5-pyrimidinyl
  • pyrimidinyl in which one or both of the nitrogen atoms are oxidized eg, 2-, 4-, 5- or 6-pyrimidinyl- N-oxide
  • pyrazi Nyl piperidinyl (eg, 1-, 2-, 3- or 4-piperidinyl), piperazinyl (eg, 1- or 2-piperazinyl), indolyl (eg, 3H-indole-2-, 3-, 4-, 5).
  • pyranyl eg, 2-, 3- or 4-pyranyl
  • thiopyranyl eg, 2-, 3- or 4-thiopyranyl
  • thiopyranyl with oxidized sulfur atom eg, eg) 2-, 3- or 4-thiopyranyl-1,1-dioxide
  • morpholinyl eg, 2-, 3- or 4-morpholinyl
  • thiomorpholinyl quinolyl (eg, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl)
  • isoquinolyl pyrido [2,3-d] pyrimidinyl (eg, pyrido [2,3-d] pyrimidin-2-yl), 1,5-, 1,6-, Naftyridinyl such as 1,7-, 1,8-, 2,6- or 2,7-naphthylidine (eg, 1,5-naphthylidine-2- or 3-yl), thieno [
  • thieno [2,3-d] pyridine-3-yl examples include thieno [2,3-d] pyridine-3-yl), pyrazinoquinolyl (eg, pyrazino [2,3-d] quinoline-2-yl), chromenyl (eg, 2H-chromen-2- or 3-yl).
  • substituted of heterocyclic group
  • substituents include the same substituents as the substituent which may have in the case represented by the R 40 "hydrocarbon group” is cycloalkyl, aryl or aralkyl .
  • the number of the substituents is 1 to 5, preferably 1 to 3.
  • R 1 an optionally substituted alkyl group, an optionally substituted aryl group, preferably a thienyl group which may be the aralkyl group or substituted or optionally substituted, optionally substituted alkyl Groups, optionally substituted aryl groups or optionally substituted aralkyl groups are more preferred, and optionally substituted aryl groups are particularly preferred.
  • R 1 is [1] C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), [2] 1 to 5 (i) halogens (eg, fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) halogens (eg, fluorine, chlorine, bromine, iodine) ( C 1-6 alkyl optionally substituted (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), (v).
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl,
  • C 1-6 alkoxy eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, which may be substituted with 1-5 (preferably 1-3) halogens (eg, fluorine, chlorine, bromine, iodine).
  • a C 6-14 aryl group preferably 1 to 3) which may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from (vi) phenyl and (vi) phenyl (isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.).
  • phenyl, etc.), or [3] (unsubstituted) thienyl groups are preferred, with 1-5 (preferably 1-3) substituents selected from halogens, hydroxys and C 1-6 alkyls.
  • substituents selected from halogens, hydroxys and C 1-6 alkyls.
  • Substituted C 6-14 aryl groups eg, phenyl, etc. are particularly preferred.
  • R 2 , R 3 and R 4 are the same or different, hydrogen atom or optionally substituted hydrocarbon group, optionally substituted thienyl group, optionally substituted.
  • R 2 As “optionally substituted hydrocarbon group” represented by R 2, R 3 and R 4, include the same groups as “optionally substituted hydrocarbon group” represented by R 40.
  • thienyl group of the “optionally substituted thienyl group” represented by R 2, R 3 and R 4 include 2- or 3-thienyl.
  • substituted thienyl group represented by R 40 "hydrocarbon group” is cycloalkyl, it includes the same substituents as the substituents which may have if it is aryl or aralkyl. The number of the substituents is 1 to 3.
  • R 2 "benzo [b] thienyl group” of R 3 and represented by R 4 "optionally substituted benzo [b] thienyl group” includes 2- or 3-benzo [b] thienyl ..
  • R 40 hydrocarbon group
  • the number of the substituents is 1 to 5, preferably 1 to 3.
  • Examples of the "frill group” of the “optionally substituted frill group” represented by R 2 , R 3 and R 4 include 2- or 3-frill.
  • the "substituent" of the furyl group, represented by R 40 "hydrocarbon group” is cycloalkyl, it includes the same substituents as the substituents which may have if it is aryl or aralkyl. The number of the substituents is 1 to 3.
  • R 2, R 3 and represented by R 4 in the "optionally substituted pyridyl group” as “pyridyl group", 2-, include 3- or 4-pyridyl.
  • the "substituent" of the pyridyl group, represented by R 40 "hydrocarbon group" is cycloalkyl, it includes the same substituents as the substituents which may have if it is aryl or aralkyl. The number of the substituents is 1 to 3.
  • R 2, R 3 and represented by R 4 in the "optionally substituted pyrazolyl group” as “pyrazolyl group” include 3- or 4-pyrazolyl.
  • R 40 hydrocarbon group
  • R 40 hydrocarbon group
  • R 2, R 3 and represented by R 4 in the "optionally substituted pyrimidinyl group” as the “pyrimidinyl group", 2-, include 4- or 5-pyrimidinyl.
  • R 40 "hydrocarbon group” is cycloalkyl, it includes the same substituents as the substituents which may have if it is aryl or aralkyl. The number of the substituents is 1 to 3.
  • acyl group represented by R 2, R 3 and R 4, an acyl group having 1 to carbon atoms derived from an organic carboxylic acid 20.
  • C 1-7 alkanoyl groups eg, formyl; C 1-6 alkyl-carbonyls such as acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyyl , etc.
  • C 6-14 aryl-carbonyl groups eg, benzoyl.
  • C 1-6 alkoxy-carbonyl group eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, etc.
  • C 6-14 aryloxy-carbonyl group eg, phenoxycarbonyl group
  • C 7-19 aralkyl-carbonyl group eg, phenyl-C 1-4 alkylcarbonyl, benzhydryl such as benzylcarbonyl, phenethylcarbonyl, phenylpropylcarbonyl
  • Naftyl-C 1-4 alkylcarbonyl such as carbonyl, naphthylethylcarbonyl
  • C 7-19 aralkyloxy-carbonyl group eg, phenyl-C 1-4 alkyloxycarbonyl such as benzy
  • -Tetrazolyl carbonyls such as ylcarbonyl; frill carbonyls such as 2- or 3-furyl carbonyls; thienyl carbonyls such as 2- or 3-thienyl carbonyls; oxazoli such as 2-, 4- or 5-oxazolyl carbonyls.
  • Rucarbonyl isoxazolylcarbonyl such as 3-, 4- or 5-isoxazolylcarbonyl; 1,2,3-oxadiazol-4- or 5-ylcarbonyl, 1,2,4-oxadi Oxadiazolylcarbonyls such as azole-3- or 5-ylcarbonyl, 1,2,5-oxadiazol-3- or 4-ylcarbonyl, 1,3,4-oxadiazol-2-ylcarbonyl; 2 -Thiazolylcarbo such as 4-, 4- or 5-thiazolylcarbonyl Nyl; isothiazolylcarbonyls such as 3-, 4- or 5-isothiazolylcarbonyl; 1,2,3-thiadiazol-4- or 5-ylcarbonyl, 1,2,4-thiadiazol-3- or 5- Thiasiazolylcarbonyl such as ylcarbonyl, 1,2,5-thiadiazol-3- or 4-ylcarbonyl, 1,3,4-thiadiazol-2-ylcarbonyl; pyrrolyl such as
  • the acyl group when the acyl group is an alkanoyl group or an alkoxy-carbonyl group, the acyl group may be 1 to 3 alkylthio groups (eg, methylthio, ethylthio, n-propylthio, isopropylthio and the like. C 1-4 alkylthio, etc.), halogen (eg, fluorine, chlorine, bromine, iodine), alkoxy groups (eg, methoxy, ethoxy, n-propoxy, tert-butoxy, n-hexyloxy, etc., C 1-6 alkoxy, etc.
  • alkylthio groups eg, methylthio, ethylthio, n-propylthio, isopropylthio and the like. C 1-4 alkylthio, etc.
  • halogen eg, fluorine, chlorine, bromine, iodine
  • alkoxy groups
  • an alkoxy - carbonyl group e.g., methoxycarbonyl, ethoxycarbonyl, n- propoxycarbonyl, isopropoxycarbonyl, n- butoxycarbonyl, isobutoxycarbonyl, sec- butoxycarbonyl, etc.
  • alkylamino groups eg, methylamino, ethylamino, n-propylamino, n-butylamino, tert-butylamino, n-pentylamino, n-hexylamino, dimethylamino, diethylamino, methyl Mono- or di-C 1-6 alkylamino such as ethylamino, di- (n-propyl) amino, di- (n-butyl) amino), alkoxyimimino groups (eg, methoxyimino, ethoxyimino, n- It may be substituted with propoxyimino, tert-butoxyimino, C 1-6 alkoxyimino such as n-hexyloxy-imino) or hydroxyimino.
  • alkylamino groups eg, methylamino, ethylamino, n-propylamino, n-buty
  • acyl group is an aryl-carbonyl group, an aryloxy-carbonyl group, an aralkyl-carbonyl group, an aralkyloxycarbonyl group, a 5- or 6-membered heterocyclic-carbonyl group or a 5- or 6-membered heterocyclic-acetyl group, 1 ⁇ 5 (preferably 1-3) alkyl groups (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl) , Neopentyl, n-hexyl, C 1-6 alkyl such as isohexyl, C 3-6 cycloalkyl such as cyclohexyl, etc.), alkenyl groups (eg, allyl, isopropenyl, isobutenyl, 1-
  • alkylthio group such as C 1-4 alkylthio such as methylthio, ethylthio, n-propylthio, isobutylthio, etc.
  • Halogen atom represented by R 2, R 3 and R 4, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom.
  • R 2 examples include a hydrogen atom, a hydrocarbon group which may be substituted, a thienyl group which may be substituted, a benzo [b] thienyl group which may be substituted, a frill group which may be substituted, and a substitution.
  • Pyridyl groups which may be substituted, pyrazolyl groups which may be substituted, or pyrimidinyl groups which may be substituted are preferable, among which a hydrogen atom, a hydrocarbon group which may be substituted, and thienyl which may be substituted may be substituted.
  • Groups optionally substituted benzo [b] thienyl groups, optionally substituted frill groups or optionally substituted pyridyl groups are preferred, and hydrogen atoms or optionally substituted hydrocarbon groups are more preferred. In particular, a hydrogen atom or an optionally substituted aryl group is preferred.
  • Halogen atom eg, fluorine atom, chlorine atom, bromine atom, iodine atom
  • cyano e.g., methyl, ethyl, etc.
  • C 1-6 alkyl eg, methyl, ethyl, etc.
  • Amino e.g., Amino
  • Halogen e.g, fluorine, chlorine, bromine, iodine
  • Halogen eg, fluorine, chlorine, bromine, iodine 1 to 5 (preferably).
  • C 1-6 alkoxy eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.
  • phenoxy which may be substituted.
  • C 1-6 alkylthios eg, methylthio, ethylthio, etc.
  • 1-5 preferably 1-3
  • halogens eg, fluorine, chlorine, bromine, iodine
  • C 6-14 aryl groups eg, phenyl groups
  • 1-5 preferably 1-3
  • substituents preferably 1-3 selected from C 1-6 alkoxy (eg, methoxy, ethoxy, etc.) and C 1-6 alkyl (eg, methyl, ethyl, n-propyl, isobutyl, etc.) C 1-6 alkoxy) may be substituted with a thienyl group, a benzo [b] thienyl group, a fryl group, a pyridyl group, a pyrazolyl group or a pyrimidinyl group [among others, 1 to 3 C 1-6 alkoxys.
  • C 1-6 alkoxy eg, methoxy, ethoxy, etc.
  • C 1-6 alkyl eg, methyl, ethyl, n-propyl, isobutyl, etc.
  • C 1-6 alkoxy may be substituted with a thienyl group, a benzo [b] thienyl group, a fryl group,
  • Substituentally substituted thienyl groups benzo [b] thienyl groups, frills or pyridyl groups are preferred], in particular (i) hydrogen atoms or (ii) halogen atoms (eg, fluorine atoms, chlorine atoms, etc.).
  • a C 6-14 aryl group eg, a phenyl group which may be substituted with 1 to 5 (preferably 1 to 3) with a bromine atom (bromine atom, iodine atom) is preferable.
  • R 3 and R 4 the same or different hydrogen atom or optionally substituted hydrocarbon group, acyl group, halogen atom, cyano group or nitro group is preferable.
  • a hydrogen atom, a C 1-6 alkyl group eg, methyl, ethyl, n-propyl, isobutyl, etc.
  • a C 6-14 aryl group eg, phenyl, etc.
  • a C 1-6 alkyl-carbonyl group eg, eg, phenyl, etc.
  • Acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyle, etc.), halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), cyano group or nitro group are preferable, and hydrogen atom, C 1- 6 Alkyl group (eg, methyl, ethyl, n-propyl, isobutyl, etc.), C 1-6 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyle, etc.), halogen atom (eg, heptanoyle, etc.) Fluorine atom, chlorine atom, bromine atom, iodine atom), cyano group or nitro group are preferable.
  • R 5 and R 6 are the same or different and are each a hydrogen atom or an optionally substituted hydrocarbon group.
  • optionally substituted hydrocarbon group represented by R 5 and R 6 include the same groups as “optionally substituted hydrocarbon group” represented by R 40.
  • R 5 and R 6 hydrogen atoms or C 1-6 alkyl groups (eg, methyl, ethyl, n-propyl, isobutyl, etc.) are particularly preferable independently of each other.
  • a particularly preferable compound is the following [d].
  • [D] Equation (II-d) [In the formula, R 101 represents a monocyclic nitrogen-containing heterocyclic group that may be fused with a benzene ring or a heterocycle, and may be fused with the benzene ring or a heterocycle.
  • the ring group may optionally have a substituent
  • R 102 represents a optionally substituted C 6-14 aryl group or an optionally substituted thienyl group
  • R 103 and R 104 are Each of them represents a hydrogen atom, or one of R 103 and R 104 represents a hydrogen atom and the other represents a lower alkyl group, an acyl group, a halogen atom, a cyano group or a nitro group which may be substituted, where R 105 is , Indicates an alkyl group] or a salt thereof.
  • the "monocyclic nitrogen-containing heterocyclic group which may be condensed with a benzene ring or a heterocycle" represented by R 101 is referred to as "a monocyclic nitrogen-containing heterocyclic group".
  • a monocyclic nitrogen-containing heterocyclic group or equation (2) In the formula, ring A represents a monocyclic nitrogen-containing heterocyclic group, ring B represents a benzene ring or a heterocycle, and a and b are ring-constituting atoms at the bridge head (eg, carbon atom,). (Nitrogen atom, etc.)
  • the ring A may contain at least one nitrogen atom (preferably 1 to 4, more preferably 1 or 2) as an atom (ring atom) constituting the ring A, and the ring of the bridgehead. Only one or both of the constituent atoms a and b may be nitrogen atoms.
  • the "monocyclic nitrogen-containing heterocyclic group that may be condensed with a benzene ring or a heterocycle” may optionally have a substituent, and the substituent is contained in either ring A or ring B. You may.
  • the "monocyclic nitrogen-containing heterocyclic group that may be condensed with a benzene ring or a heterocycle” and the “monocyclic nitrogen-containing heterocyclic group” in the above ring A include, for example, atoms constituting the ring (ring atom). ), An aromatic monocyclic nitrogen-containing heterocyclic group containing at least one nitrogen atom (preferably 1 to 4, more preferably 1 to 2), a saturated or unsaturated non-aromatic monocyclic nitrogen-containing heterocycle. Cyclic (aliphatic monocyclic nitrogen-containing heterocyclic group) and the like can be mentioned.
  • aromatic monocyclic nitrogen-containing heterocyclic group examples include pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl (1H-imidazole-1-yl, 1H-imidazole-4-yl, etc.), pyrazolyl, and the like.
  • the formula nitrogen-containing heterocyclic group is preferable, among which thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl and pyridadinyl are preferable, and pyridyl is particularly preferable.
  • the "saturated or unsaturated non-aromatic monocyclic nitrogen-containing heterocyclic group” includes a partially reduced product of the above-mentioned "aromatic monocyclic nitrogen-containing heterocyclic group” (eg, imidazolinyl, tetrahydropyrimidinyl, etc.).
  • aromatic monocyclic nitrogen-containing heterocyclic group eg, imidazolinyl, tetrahydropyrimidinyl, etc.
  • Cyclic nitrogen-containing heterocyclic groups are preferred.
  • heterocycle that may be condensed with a monocyclic nitrogen-containing heterocyclic group
  • aromatic heterocycles and non-aromatic heterocycles.
  • aromatic heterocycle include a furan ring, a thiophene ring, a pyrrole ring, an oxazole ring, an isooxazole ring, a thiazole ring, an isothiazole ring, an imidazole ring, a pyrazole ring, and a 1,2,3-oxadiazole ring.
  • a 12-membered aromatic fused heterocycle (preferably a heterocycle in which the above-mentioned 5- or 6-membered aromatic monocyclic heterocycle is fused with a benzene ring or the above-mentioned 5- or 6-membered aromatic monocyclic heterocycle.
  • a heterocycle in which two identical or different heterocycles are condensed more preferably a heterocycle in which the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group is condensed with a benzene ring, preferably imidazolipyrimidinyl or the like).
  • non-aromatic heterocycle examples include an oxylane ring, an azetidine ring, an oxetane ring, a thietan ring, a pyrrolidine ring, a tetrahydrofuran ring, a thiolan ring, a piperidine ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholin ring, and a piperazine ring.
  • 3-Hexahydrocyclopenta [ c ] 3- to 8-membered saturated or unsaturated non-aromatic heterocycles such as pyrrol ring, homopiperidine ring, homopiperazin ring, etc., or dihydropyridine ring, dihydropyrimidine ring, 1, 2, Part or all of the double bonds of the above-mentioned aromatic monocyclic heterocycle or aromatic fused heterocycle such as 3,4-tetrahydroquinoline ring, 1,2,3,4-tetrahydroisoquinoline ring are saturated.
  • non-aromatic heterocycles include non-aromatic heterocycles.
  • Preferred monocyclic nitrogen-containing heterocyclic groups fused with a benzene ring or a heterocycle include, for example, 2- or 3-indrill, 1- or 3-isoindrill, 1H-indazole-3-yl, 2-benzimidazolyl.
  • the pyridine ring has 1 to 2 (preferably 1) or 1 to 2 benzene rings (preferably) of the above-mentioned 5- or 6-membered aromatic monocyclic nitrogen-containing heterocycle.
  • 1 to 2 preferably 1 to 2 benzene rings (preferably) of the above-mentioned 5- or 6-membered aromatic monocyclic nitrogen-containing heterocycle.
  • fused pyridines condensed with (1) (however, when condensed with a benzene ring, the pyridine ring has a bond) and the pyrimidine ring having the above-mentioned 5 or 6 members.
  • Pyrimidine fused with 1 or 2 (preferably 1) benzene ring (however, when condensed with the benzene ring, the pyrimidine ring has a bond) and the like are preferable.
  • non-aromatic nitrogen-containing heterocycle includes, for example, 3 to 8 members (preferably 5 to 6 members) saturated with azetidine, pyrrolidine, imidazolidine, thiazolidine, oxazolidine, piperidine, morpholin, thiomorpholin, piperazine and the like.
  • an unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocycle aliphatic nitrogen-containing heterocycle or the like, or 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline or the like.
  • examples thereof include the above-mentioned aromatic monocyclic nitrogen-containing heterocycle or non-aromatic nitrogen-containing heterocycle in which a part or all of the double bonds of the aromatic condensed nitrogen-containing heterocycle are saturated.
  • a 5- or 6-membered aromatic monocyclic nitrogen-containing heterocyclic group is preferable, and pyridil is particularly preferable.
  • 6-membered aromatics such as (eg, 2-, 3- or 4-pyridyl, etc.), pyrimidinyl (eg, 2-, 4- or 5-pyrimidinyl, etc.) or pyridadinyl (eg, 3- or 4-pyridazinyl, etc.)
  • Nitrogen heterocyclic groups are preferred, and pyridyl is particularly preferred.
  • Examples of the "benzene ring or heterocyclic ring may be condensed with not monocyclic nitrogen-containing heterocyclic group" substituent which may have a, represented by R 40 "hydrocarbon group” is cycloalkyl, Examples include substituents similar to the substituents that may have if they are aryl or aralkyl.
  • the position of the substituent is not particularly limited as long as it can be substituted, and the number of the substituents is 1 to 5, preferably 1 to 3.
  • Examples of the "C 6-14 aryl group" in the “optionally substituted C 6-14 aryl group” represented by R 102 include phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl and 3-biphenylyl. , 4-Biphenylyl, 2-Anthril and the like.
  • the substituent that the "C 6-14 aryl group” may have the "monocyclic nitrogen-containing heterocyclic group that may be condensed with a benzene ring or a heterocycle” shown in R 101 is used. Examples include groups similar to the substituents that may have. The number of the substituents is 1 to 5, preferably 1 to 3.
  • Examples of the "thienyl group" in the “optionally substituted thienyl group” represented by R 102 include 2- or 3-thienyl.
  • the substituent that the "thienyl group” may have the "monocyclic nitrogen-containing heterocyclic group that may be condensed with a benzene ring or a heterocycle" shown in R 101 is included. Examples are similar to the good substituents.
  • the number of the substituents is 1 to 4, preferably 1 to 3.
  • Examples of the "lower alkyl group" in the “optionally substituted lower alkyl group” represented by R 103 and R 104 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. C 1-4 alkyl group and the like can be mentioned.
  • Examples of the substituent which may have a “lower alkyl group", represented by R 40 "hydrocarbon group” is alkyl, similar to the substituents that may have in the case of alkenyl or alkynyl Substituents can be mentioned. The number of the substituents is 1 to 3.
  • Examples of the "acyl group” represented by R 103 and R 104 include the same groups as the “acyl group” represented by R 2 , R 3 and R 4 above.
  • Examples of the "halogen atom” represented by R 103 and R 104 include fluorine, chlorine, bromine and iodine.
  • alkyl group represented by R 105 examples include C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and the like. Be done.
  • R 101 examples include (i) halogen (eg, fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, and (iv) halogen (eg, fluorine, chlorine, bromine, iodine) from 1 to 5.
  • halogen eg, fluorine, chlorine, bromine, iodine
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • C 1-6 alkoxy eg, methoxy, ethoxy, propoxy, isopropoxy, eg, methoxy, ethoxy, propoxy, isopropoxy, which may be substituted with 1-5 (preferably 1-3) halogens (eg, fluorine, chlorine, bromine, iodine).
  • a “nitrogen heterocyclic group” for example, a 5- to 6-membered aromatic monocyclic nitrogen-containing heterocyclic group such as thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridadinyl, etc.
  • a nitrogen heterocyclic group for example, a 5- to 6-membered aromatic monocyclic nitrogen-containing heterocyclic group such as thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridadinyl, etc.
  • 1 to 5 preferably) of (i) halogen (eg, fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) halogen (eg, fluorine, chlorine, bromine, iodine).
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • halogen which may be substituted.
  • C 1-6 alkoxy eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • a 6-membered nitrogen-containing aromatic heterocyclic group eg, a pyridyl group (eg, 2-, 3- or 4-), which may be substituted with 1 to 3 substituents selected from the optionally substituted amino groups.
  • pyrimidinyl groups eg, 2-, 4- or 5-pyrimidinyl, etc.
  • pyridadinyl groups eg, 3- or 4-pyridazinyl, etc.
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl
  • 1-5 preferably 1-3
  • Halogen eg, fluorine, chlorine, bromine, iodine
  • 1-5 preferably 1-3
  • C 1-6 alkoxy eg, methoxy
  • a pyridyl group which may be substituted with 1 to 3 substituents is particularly preferable.
  • R 102 examples include [1] (i) halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), (ii) cyano, and (iii) halogen (eg, fluorine, chlorine, bromine, iodine).
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • 1 to 5 preferably 1 to 3
  • C 1-6 alkoxy eg, methoxy, ethoxy, propoxy, which may be substituted with 1-5 (preferably 1-3) halogens (eg, fluorine, chlorine, bromine, iodine).
  • C 6 which may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from (v) acetyl (isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.) and (v) acetyl.
  • aryl group eg, phenyl group
  • halogen atom eg, fluorine atom, chlorine atom, bromine atom, iodine atom
  • cyano e.g., halogen
  • fluorine, C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert
  • 1-5 preferably 1-3
  • Halogen eg, fluorine, chlorine, bromine, iodine
  • C 1-6 alkoxy eg.
  • a thienyl group optionally substituted with 1 to 3 substituents selected from acetyl.
  • halogen atoms eg, fluorine atom, chlorine atom, bromine atom, iodine atom
  • halogen eg, fluorine, chlorine, bromine, iodine
  • ⁇ 3) 1-5 selected from C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) which may be substituted.
  • a phenyl group which may be substituted with (preferably 1 to 3) substituents, or [2] (i) halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) and (ii) halogen.
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, which may be substituted 1 to 5 (preferably 1 to 3) with (eg, fluorine, chlorine, bromine, iodine).
  • a thienyl group which may be substituted with 1 to 3 substituents selected from sec-butyl, tert-butyl, pentyl, hexyl, etc. is preferable.
  • R 102 a phenyl group, a 2-fluorophenyl group or a 2-methylphenyl group is particularly preferable.
  • R 103 and R 104 respectively, either indicate a hydrogen atom, or one of R 103 and R 104 is a hydrogen atom and the other is a C 1-6 alkyl group (eg, methyl, ethyl, n-propyl, isobutyl, etc.).
  • C 1-6 alkyl-carbonyl group eg, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl, etc.
  • halogen atom eg, fluorine atom, chlorine atom, bromine atom, iodine atom
  • cyano group or nitro It is preferable to show a group, and it is particularly preferable that both R 103 and R 104 show a hydrogen atom.
  • R 105 methyl or ethyl is preferable, and methyl is particularly preferable.
  • R 101 may be (i) substituted with 1-5 (preferably 1-3) halogens (eg, fluorine, chlorine, bromine, iodine) C 1-6 alkyl (eg, methyl, ethyl, etc.). 1-5 (preferably 1-3) with propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and (ii) halogens (eg, fluorine, chlorine, bromine, iodine).
  • 1-5 preferably 1-3
  • halogens eg, fluorine, chlorine, bromine, iodine
  • R 102 is 1 to 5 (preferably) in [1] (i) halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) and (ii) halogen (eg, fluorine, chlorine, bromine, iodine).
  • halogen atoms eg, fluorine atom, chlorine atom, bromine atom, iodine atom
  • halogen eg, fluorine, chlorine, bromine, iodine
  • C 1-6 alkyl eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.
  • R 103 and R 104 are hydrogen atoms, respectively, It is a compound in which R 105 is methyl.
  • Vonoprazan (1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-yl] -N-methylmethaneamine) or a salt thereof (among others, fumarate). ) Is particularly preferable.
  • the structural formula of Vonoprazan is shown below.
  • Compound (I) can be produced, for example, according to the method described in Patent Document 1 (International Publication No. 2006/036024) or a method similar thereto.
  • R 1 ' is hydrogen, methoxy, difluoromethoxy or trifluoromethyl
  • R 2' and R 3 ' are the same or different, hydrogen, methyl or methoxy
  • R 4' is C 1 -C 5 to 5 lower alkyls which may be fluorinated or alkoxylated, where n'represents 0 or 1, respectively.
  • a salt thereof hereinafter, may be abbreviated as compound (1)), or a prodrug thereof.
  • R 1 ' represents hydrogen, methoxy, difluoromethoxy or trifluoromethyl. Of these, hydrogen, methoxy, or difluoromethoxy is preferable, and hydrogen is more preferable. As the position of R 1 ', 4th and 5th positions are mentioned, and the 5th position is preferable.
  • R 2 'and R 3' are the same or different and represent hydrogen, methyl or methoxy. Among them, it is preferable that R 2 'is methyl or methoxy, and more preferably methyl. Among them, R 3 'is preferably hydrogen or methyl, more preferably hydrogen.
  • the "lower alkyl group 5 having 1 to carbon atoms" represented by R 4 ' for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl , Tert-Pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl group and the like.
  • methyl, ethyl, and propyl are preferable, and methyl is more preferable.
  • the alkoxylation includes, for example, methoxy, ethoxy, propoxy, isopropoxydating and the like having 1 carbon atom. Or 3 alkoxylation and the like.
  • alkoxylated lower alkyl with 1-5 carbon atoms represented by R 4 'are, for example, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, Examples thereof include 5-methoxypentyl, 2-methoxy-1-methylethyl, ethoxymethyl, n-propoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 1-n-propoxyethyl, 1-methylethoxymethyl and the like. Of these, 3-methoxypropyl is preferable.
  • the "number 1 to 5 of the fluorinated or alkoxylated which may be lower alkyl carbon" represented by R 4 ' is 2,2,2-trifluoroethyl, 3-methoxypropyl or methyl, It is preferably present, and more preferably 2,2,2-trifluoroethyl.
  • n' represents 0 or 1, respectively, and is preferably 1.
  • the compound (1) is preferably lansoprazole, pantoprazole, omeprazole, esomeprazole, rabeprazole, or a salt thereof.
  • the structural formulas of these compounds are shown in Table 1.
  • the salt is not particularly limited, and examples thereof include lansoprazole sodium, pantoprazole sodium, omeprazole sodium, esomeprazole magnesium, and rabeprazole sodium.
  • the compound (1) is produced, for example, according to the method described in Patent Document 2 (Japanese Patent Laid-Open No. 61-050978) or Patent Document 3 (Japanese Patent Laid-Open No. 54-141783), or a method similar thereto. be able to.
  • Examples of the salt of the compound (I) and the compound (1) include a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like.
  • a metal salt such as sodium salt and potassium salt
  • alkaline earth metal salts such as calcium salt, magnesium salt and barium salt
  • aluminum salt and the like are examples of the salt of the compound (I) and the compound (1).
  • salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N'-dibenzyl.
  • examples thereof include salts with ethylenediamine and the like.
  • Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene.
  • Examples thereof include salts with sulfonic acid, p-toluene sulfonic acid and the like.
  • Suitable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, etc.
  • suitable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid and the like. Can be mentioned.
  • an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt, etc.) , Ammonium salt, etc.
  • a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumal.
  • examples thereof include salts with organic acids such as acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
  • Compound (I) and compound (1) may be used as a prodrug.
  • the compound (I) or the prodrug of the compound (1) is a compound that is converted into the compound (I) or the compound (1) by a reaction with an enzyme, gastric acid or the like under physiological conditions in the living body, that is, enzymatically oxidized or reduced.
  • the prodrugs of compound (I) and compound (1) include compounds in which the amino group is acylated, alkylated and phosphorylated (eg, the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl).
  • hydroxyl groups are acylated , Alkylated, phosphorylated, borated compounds (eg, hydroxyl group acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.); Compounds in which the carboxy group is esterified or amidated (for example, the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified) , Phtalidyl
  • compound (I) or compound (1) can be produced from compound (I) or compound (1) by a method known per se.
  • compound (I) and the prodrug of compound (1) are prepared under physiological conditions as described in Hirokawa Shoten, 1990, "Drug Development,” Vol. 7, Molecular Design, pp. 163 to 198. It may be changed to compound (I) or compound (1).
  • compound (I) and compound (1) have isomers such as optical isomers, steric isomers, positional isomers, and rotational isomers, either one of the isomers or the mixture is the compound (I) and Each is included in compound (1).
  • the optical isomers are present in the compound (I) and the compound (1), the optical isomers divided from the racemate are also included in the compound (I) and the compound (1), respectively.
  • Each of these isomers can be obtained as a single product by a synthesis method and a separation method (concentration, solvent extraction, column chromatography, recrystallization, etc.) known per se.
  • the compound (I) and the compound (1) may be crystals, and may be included in the compound (I) and the compound (1) regardless of whether they have a single crystal form or a mixture of crystals. Crystals can be produced by crystallization by applying a crystallization method known per se.
  • the compound (I) and the compound (1) may be a solvate (for example, a hydrate or the like) or a non-solvate, and both are the compound (I) and the compound (1), respectively. Be included.
  • Isotope e.g., 3 H, 14 C, 35 S, etc. 125 I
  • compounds labeled with like are also encompassed, respectively compound (I) and compound (1).
  • proton pump inhibitors can be used alone or in combination of two or more.
  • the content of the above-mentioned active ingredient in the therapeutic agent of the present disclosure is not particularly limited, and can be appropriately set in the range of, for example, 1% by mass to 90% by mass.
  • the upper limit or the lower limit of the range may be, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, or 80% by mass. More specifically, it may be, for example, 2% by mass to 80% by mass.
  • the therapeutic agent of the present disclosure contains the above-mentioned active ingredient, and may further contain other ingredients.
  • Other components include pharmaceutically acceptable bases, carriers, and / or additives (eg, solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, binders, disintegrants, glitches, etc.
  • Agents, antioxidants, preservatives, coating agents, colorants, other agents such as gastric mucosa protective agents) and the like can be exemplified.
  • the form of the therapeutic agent of the present disclosure is also not particularly limited, and is not particularly limited. , Suspensions, tinctures, ointments, paps, nasal drops, inhalants, liniments, lotions, aerosols and the like can be exemplified.
  • the therapeutic agent of the present disclosure can be prepared by a conventional method by combining the above-mentioned active ingredient with other ingredients as needed.
  • the therapeutic agent of the present disclosure can be suitably used as a therapeutic agent for obsessive-compulsive disorder.
  • Obsessive-compulsive disorders include, for example, obsessive-compulsive disorder, preservation, doubts about uncertainty, fear of harm / taboo thinking, obsession with order, obsessive-compulsive cleaning, confirmation, ritualistic behavior to counteract obsessive-compulsive thoughts, and sorting.
  • Diseases with symptoms such as counting, obsessive-compulsive dermatosis, biting claw habit, biting cheek habit, obsessive-compulsive purchasing, obsessive-compulsive behavior, obsessive-compulsive swelling, obsessive-compulsive lips, obsessive-compulsive ulcer, and obsessive-compulsive wash. Be done. These symptoms may be one type alone or a combination of two or more types.
  • the administration (ingestion) amount of the therapeutic agent of the present disclosure is not particularly limited, and is determined by the age, gender, degree of symptom, intake method, etc. of the subject to be ingested.
  • Mammals are preferable as the target to which the therapeutic agent of the present disclosure is administered. Not only humans but also non-human mammals may be used. Examples of the target human include a human having obsessive-compulsive disorder or a human suspected to have obsessive-compulsive disorder.
  • an administration method for example, it can be administered by oral administration and parenteral administration (for example, intravenous, arterial, muscle, subcutaneous, abdominal cavity, rectum, transdermal, topical, etc.).
  • parenteral administration for example, intravenous, arterial, muscle, subcutaneous, abdominal cavity, rectum, transdermal, topical, etc.
  • proton pump inhibitors such as lansoprazole and vonoprazan have therapeutic effects on obsessive-compulsive disorder, which are exhibited by suppressing repetitive behavior, reducing the number of nerve firings, and suppressing excessive activation of nerve activity.
  • the decrease in intracellular pH reduces the number of nerve firings.
  • the intracellular pH is lowered by vonoprazan, which is a proton pump inhibitor. Therefore, although not bound by theory, for example, a proton pump inhibitor may suppress the symptoms of obsessive-compulsive disorder by suppressing the excretion of protons and lowering the intracellular pH. It is presumed that it can be done. Therefore, the therapeutic agent of the present disclosure containing a proton pump inhibitor as an active ingredient can be suitably used as a therapeutic agent for obsessive-compulsive disorder.
  • the present disclosure also preferably includes a method for screening an active ingredient for treating obsessive-compulsive disorder, using the proton pump inhibitory activity as an index.
  • the method may be referred to as "the screening method of the present disclosure”.
  • the screening method of the present disclosure it is possible to suppress the symptoms of obsessive-compulsive disorder with a proton pump inhibitor. Therefore, according to the screening method of the present disclosure, obsessive-compulsive disorder using the inhibitory activity of the proton pump as an index.
  • the active ingredient for treating the disease can be screened.
  • the inhibitory activity of the proton pump is, for example, the proton pump inhibitory activity such as adding a test component and ATP to cells expressing a proton pump (H + , K + -ATPase) and measuring the amount of inorganic phosphoric acid produced. It can be measured by a known method that can be measured.
  • an ingredient whose proton pump inhibitory activity has been confirmed when the test ingredient is contained is selected as an active ingredient for treating compulsive disorder as compared with the case where the test ingredient is not contained.
  • the test ingredient may be compared with a known proton pump inhibitor (control), and the test ingredient showing the same level of proton pump inhibitory activity as the control may be used as an active ingredient for treating compulsive disorder. May be selected as.
  • Drugs and Reagents (-)-Kimpilol (dopamine D 2 receptor stimulant) was dissolved in saline (intraperitoneal administration, 1 mg / kg) or water (electrophysiological record).
  • Lansoprazole and vonoprazan were stored in solution in dimethyl sulfoxide and diluted with 1% Tween 80 aqueous solution or saline solution at the time of use.
  • mice Animal male C57BL / 6J mice (6-12 weeks old) were used. The temperature of the animal room was maintained at 22 ⁇ 2 ° C with a 12-hour light-dark cycle, and the experiment was conducted in the light period. Administration of kinpyrol was performed on weekdays. Mice to which kinpyrol (1 mg / kg) was intraperitoneally administered 8 times (once a day) were designated as kinpyrol sensitized mice.
  • the time for chewing behavior was measured for 10 minutes 20 to 30 minutes after the 8th administration of Kinpirol. The results are shown in FIG. In addition, the time of the chewing behavior of the mouse to which the physiological saline was administered instead of the administration of kimpirol is shown in FIG.
  • mice were continuously administered with kinpyrol four times in the same manner, and then lansoprazole (intraperitoneal administration: 10.100 mg / kg) or vonoprazan (intraperitoneal administration: 10.30.100 mg / kg).
  • Lansoprazole or vonoprazan was administered 5 minutes before the 9th to 12th kinpyrol administration, and the time of chewing behavior was measured for 10 minutes 20 to 30 minutes after the 8th, 9th, and 12th quinpirol administration.
  • the administration result of lansoprazole is shown in FIG. 2, and the administration result of vonoprazan is shown in FIG.
  • Pre is the 8th administration of kinpyrol
  • Lpz1 and “Vpz1” are the 9th administration of quinpyrol (that is, the 1st administration of each drug)
  • Lpz4" and “Vpz4" are the 12th administration of quinpillol (that is, , The time of chewing behavior of each drug administration 4th time) is shown.
  • the orbitofrontal cortex (OFC), dorsal striatum (DS), central striatum (CS), and thalamus (TH) were excised from the brain of untreated mice and mRNA was extracted. The gene expression level was compared using the quantitative RT-PCR method from the cDNA sample obtained by the reverse transcription reaction. Each PCR amplification was performed with thermal activation at 95 ° C. for 10 minutes followed by 40 cycles at 95 ° C. for 15 seconds and 60 ° C. for 1 minute.
  • the primer sequences used are as follows.
  • Atp4a is a gene for the ⁇ subunit of the P-type proton pump.
  • FIG. 5 shows relative values quantified with reference to Atp4a / Gapdh in the thalamus.
  • Atp4a As shown in FIG. 5, it was confirmed that the expression level of Atp4a was high in the orbitofrontal cortex.
  • mice were intraperitoneally administered with saline or quinpirol 8 times, and acute brain sections were prepared the day after the 8th administration. Mice were anesthetized with isoflurane, the brain was removed, and a 200 ⁇ m-thick coronal section containing the orbitofrontal cortex was prepared under ice-cooling.
  • the solution composition used during section preparation is as follows: 120 mM N-methyl-D-glucamin Cl, 2.5 mM KCl, 26 mM ⁇ 3 , 1.25 mM NaH 2 PO 4 , 0.5 mM CaCl 2 , 7 mM MgCl 2 , 15 mM D-glucose, 1.3 mM ascorbic acid; pH 7.2.
  • the prepared brain slices were artificial cerebrospinal fluid containing oxygen at 32 ° C (24 mM NaCl, 3 mM KCl, 26 mM ⁇ 3 , 1 mM NaH 2 PO 4 , 2.4 mM CaCl 2 , 1.2 mM MgCl 2 , 10 mM D. -Glucose; stored in pH 7.3) with a recovery period of at least 1 hour.
  • cortical neurons After separating the cerebral cortex from C57BL / 6J mouse embryos on days 14-16 of pregnancy, the cells were treated with trypsin (2.5 mg / mL) to disperse the cells.
  • the obtained cortical neurons were prepared at 37 ° C. using Neurobasal plus medium containing 2% B-27 plus supplement, 2 mM L-glutamine, 100 U / ml penicillin G potassium, and 100 ⁇ g / ml streptomycin sulfate. After culturing for 10-12 days under 5% CO 2 conditions, it was used in the experiment.
  • Electrophysiological studies Acute isolated brain sections and firing responses from primary cultured cortical neurons were recorded by the whole-cell patch clamp method.
  • the recording chamber was filled with artificial cerebrospinal fluid, and a solution having the following composition was used inside the glass electrode: 140 mM potassium gluconate, 5 mM KCl, 10 HEPES, 2 mM Na-ATP, 2 mM MgCl 2 , and 0.2 mM EGTA.
  • the pH of the solution in the electrode was adjusted to 7.3 or 7.0 using potassium hydroxide.
  • Artificial cerebrospinal fluid was perfused at a rate of 1-2 ml / min for recording from acutely isolated brain sections.
  • the fluid temperature in the recording chamber was maintained at 27 ⁇ 1 ° C for acute isolated brain sections and at room temperature for primary cultured cortical neurons.
  • Individual neurons were visualized with a microscope equipped with a 40x water immersion objective and a CCD camera. Nerve activity was evaluated by the number of firings when 0-500 pA was applied under fixed current conditions.
  • the firing response of artificial cerebrospinal fluid containing vonoprazan (10 ⁇ M) before perfusion (QNP Pre) and 5 minutes after the start of perfusion (QNP Post) was compared.
  • FIG. 6 shows the results of measuring the number of firings using an acutely isolated brain section
  • FIG. 7 shows the results of measuring the number of firings using primary cultured cortical neurons.
  • FIG. 6A shows the results of measuring the number of firings when vonoprazan was added to an acute brain section derived from a mouse to which kinpyrol (QNP) was administered. As shown in FIG. 6B, it was found that vonoprazan suppressed the increase in the number of nerve firings due to the administration of kinpyrol.
  • a proton pump inhibitor such as vonoprazan suppresses the excretion of protons, thereby lowering the intracellular pH and suppressing the number of nerve firings.
  • Cannula was implanted in spontaneously active C57BL / 6J mice, and vonoprazan (6 nmol) or solvent (Veh) was intraventricularly administered 7 days later.
  • vonoprazan (6 nmol) or solvent (Veh) was intraventricularly administered 7 days later.
  • open field device 40 x 40 x 30 cm
  • the locomotor activity for 10 minutes 5 to 15 minutes after administration was evaluated. The results are shown in FIG.
  • the composition of the Krebs solution used as a solvent is as follows: 140 mM NaCl, 3 mM KCl, 1 mM MgCl 2 , 2 mM CaCl 2 , 10 mM glucose, 10 mM HEPES.
  • the composition of the high K + Krebs solution is as follows: 5 ⁇ M nigericin, 3 mM NaCl, 140 mM KCl, 1 mM MgCl 2 , 2 mM CaCl 2 , 10 mM glucose, 10 mM HEPES.
  • the pH of the high K + Krebs solution was adjusted to 6.7, 7.0, 7.3, 7.6, and 7.9 using potassium hydroxide.
  • a calibration curve was prepared from the amount of change in intracellular fluorescence intensity when these solvents were refluxed. From the results of the calibration curve, the change in intracellular pH ( ⁇ pH) due to vonoprazan treatment was calculated. The results are shown in FIG. 9 (fluorescence image (A), calibration curve (B), pH change (C) due to administration of vonoprazan).
  • the soaking time for dyeing and the solution composition used are as follows.

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Abstract

Provided are: a therapeutic agent for obsessive-compulsive disorder; and a method for screening an active ingredient for treating obsessive-compulsive disorder. Specifically, provided are: a therapeutic agent for obsessive-compulsive disorder, the therapeutic agent containing a proton pump inhibitor as an active ingredient; and a method for screening an active ingredient for treating obsessive-compulsive disorder, the method using proton pump inhibitory activity as an indicator.

Description

強迫性障害の治療剤Therapeutic agent for obsessive-compulsive disorder
　本開示は、強迫性障害の治療剤、及び強迫性障害を治療するための有効成分のスクリーニング方法等に関する。 The present disclosure relates to a therapeutic agent for obsessive-compulsive disorder, a screening method for an active ingredient for treating obsessive-compulsive disorder, and the like.
　強迫性障害（Obsessive-compulsive disorder；OCD）は不合理な行為や思考を自分の意に反して繰り返してしまう精神障害の一種である。治療としては認知行動療法の他、薬物として選択的セロトニン再取り込み阻害薬（Selective Serotonin Reuptake Inhibitors；SSRI）の大量長期投与が認可されているが、有効率が低く、治療効果が十分ではないため、有効な治療薬の開発が望まれている。 Obsessive-compulsive disorder (OCD) is a type of mental disorder that repeats irrational acts and thoughts against one's will. In addition to cognitive-behavioral therapy, long-term high-dose administration of selective serotonin reuptake inhibitors (SSRIs) has been approved as a treatment, but the efficacy rate is low and the therapeutic effect is not sufficient. The development of effective therapeutic agents is desired.
国際公開第２００６／０３６０２４号International Publication No. 2006/036024 特開昭６１－０５０９７８号公報Japanese Unexamined Patent Publication No. 61-050978 特開昭５４－１４１７８３号公報Japanese Unexamined Patent Publication No. 54-141783
　本開示は、強迫性障害の治療剤を提供することを課題とする。また、本開示は、強迫性障害を治療するための有効成分のスクリーニング方法を提供することを課題とする。 The subject of this disclosure is to provide a therapeutic agent for obsessive-compulsive disorder. It is also an object of the present disclosure to provide a method for screening an active ingredient for treating obsessive-compulsive disorder.
　本発明者らは、プロトンポンプ阻害剤であるボノプラザン等が強迫性障害を抑制することを見出し、さらに改良を重ねた。 The present inventors have found that vonoprazan and the like, which are proton pump inhibitors, suppress obsessive-compulsive disorder, and have made further improvements.
本開示は、例えば以下の項に記載の主題を包含する。
項１．
プロトンポンプ阻害剤を有効成分として含有する、強迫性障害の治療剤。
項２．
プロトンポンプ阻害剤が、
式（Ｉ）
Figure JPOXMLDOC01-appb-C000003
 　［式中、ＸおよびＹは、同一または異なって、結合手または主鎖が原子数１ないし２０のスペーサーを、Ｒ１は置換されていてもよい炭化水素基または置換されていてもよい複素環基を、Ｒ２、Ｒ３およびＲ４は、同一または異なって、水素原子、置換されていてもよい炭化水素基、置換されていてもよいチエニル基、置換されていてもよいベンゾ［ｂ］チエニル基、置換されていてもよいフリル基、置換されていてもよいピリジル基、置換されていてもよいピラゾリル基、置換されていてもよいピリミジニル基、アシル基、ハロゲン原子、シアノ基またはニトロ基を、Ｒ５およびＲ６は、同一または異なって、水素原子または置換されていてもよい炭化水素基を示す］で表される化合物、その塩、及びそのプロドラッグ、並びに
式（１）
Figure JPOXMLDOC01-appb-C000004
 　［式（１）中、Ｒ１’は水素、メトキシ、ジフルオロメトキシまたはトリフルオロメチルを、Ｒ２’およびＲ３’は同一または異なって、水素、メチルまたはメトキシを、Ｒ４’は炭素数１ないし５のフッ素化またはアルコキシ化されていてもよい低級アルキルを、ｎ’は０または１をそれぞれ示す。］で表される化合物、その塩、及びそのプロドラッグからなる群より選択される少なくとも１種である、項１に記載の治療剤。
項３．
プロトンポンプ阻害剤が、ボノプラザン、ランソプラゾール、パントプラゾール、オメプラゾール、エソメプラゾール、及びラベプラゾールからなる群より選択される少なくとも１種である、項１又は２に記載の治療剤。
項４．
強迫性障害が、汚染恐怖、保存、不確実性への疑念、加害恐怖・タブー思考、秩序へのこだわり、強迫性洗浄、確認行為、強迫観念を打ち消すための儀式行為、並び替えや数える行為、自傷性皮膚症、咬爪癖、咬頬癖、強迫性購買、強迫性性行動、強迫的ためこみ、強迫性咬唇、強迫反すう症、及び強迫洗手からなる群より選択される少なくとも１種の症状を伴う疾患である、項１～３のいずれかに記載の治療剤。
項５．
経口投与用、又は静脈注射用である項１～４のいずれかに記載の治療剤。
項６．
プロトンポンプ阻害活性を指標とする、強迫性障害を治療するための有効成分のスクリーニング方法。 The present disclosure includes, for example, the subjects described in the following sections.
Item 1.
A therapeutic agent for obsessive-compulsive disorder containing a proton pump inhibitor as an active ingredient.
Item 2.
Proton pump inhibitor,
Equation (I)
Figure JPOXMLDOC01-appb-C000003
 [In the formula, X and Y are the same or different, and the bond or main chain is a spacer having 1 to 20 atoms, and R 1 is a hydrocarbon group which may be substituted or a heterocycle which may be substituted. The groups, R 2 , R 3 and R 4, are the same or different, hydrogen atoms, optionally substituted hydrocarbon groups, optionally substituted thienyl groups, optionally substituted benzo [b]. Thienyl group, optionally substituted frill group, optionally substituted pyridyl group, optionally substituted pyrazolyl group, optionally substituted pyrimidinyl group, acyl group, halogen atom, cyano group or nitro group. , R 5 and R 6 indicate the same or different hydrocarbon atoms or optionally substituted hydrocarbon groups], salts thereof, and prodrugs thereof, and formula (1).
Figure JPOXMLDOC01-appb-C000004
 Wherein (1), R 1 'is hydrogen, methoxy, difluoromethoxy or trifluoromethyl, R 2' and R 3 'are the same or different, hydrogen, methyl or methoxy, R 4' is C 1 -C 5 to 5 lower alkyls which may be fluorinated or alkoxylated, where n'represents 0 or 1, respectively. ] The therapeutic agent according to Item 1, which is at least one selected from the group consisting of the compound represented by the above, a salt thereof, and a prodrug thereof.
Item 3.
Item 3. The therapeutic agent according to Item 1 or 2, wherein the proton pump inhibitor is at least one selected from the group consisting of vonoprazan, lansoprazole, pantoprazole, omeprazole, esomeprazole, and rabeprazole.
Item 4.
Obsessive-compulsive disorder is a fear of pollution, preservation, suspicion of uncertainty, fear of harm / taboo thinking, obsession with order, obsessive-compulsive cleaning, confirmation, ritualistic behavior to counteract obsessive-compulsive thoughts, sorting and counting, At least one selected from the group consisting of obsessive-compulsive dermatosis, obsessive-compulsive habit, biting cheek habit, obsessive-compulsive purchase, obsessive-compulsive behavior, obsessive-compulsive swelling, obsessive-compulsive lip, obsessive-compulsive ulcer, and obsessive-compulsive wash. Item 3. The therapeutic agent according to any one of Items 1 to 3, which is a disease associated with the symptoms of.
Item 5.
Item 6. The therapeutic agent according to any one of Items 1 to 4, which is for oral administration or intravenous injection.
Item 6.
A screening method for active ingredients for treating obsessive-compulsive disorder using proton pump inhibitory activity as an index.
　強迫性障害の治療剤を提供することができる。また、強迫性障害を治療するための有効成分のスクリーニング方法を提供することができる。 It is possible to provide a therapeutic agent for obsessive-compulsive disorder. It is also possible to provide a method for screening an active ingredient for treating obsessive-compulsive disorder.
キンピロール感作マウスの噛み行動の時間を測定した結果を示す（N = 4-5, ***P < 0.001.）。The results of measuring the biting behavior time of the kinpirol sensitized mice are shown (N = 4-5, *** P <0.001.). キンピロール感作マウスにランソプラゾールを腹腔内投与したときの噛み行動の時間を測定した結果を示す（N = 4-10, *P < 0.05, ***P < 0.001）。The results of measuring the chewing behavior time when lansoprazole was intraperitoneally administered to kinpyrol-sensitized mice are shown (N = 4-10, * P <0.05, *** P <0.001). キンピロール感作マウスにボノプラザンを腹腔内投与したときの噛み行動の時間を測定した結果を示す（N = 5-7, ***P < 0.001）。The results of measuring the chewing behavior time when vonoprazan was intraperitoneally administered to kinpyrol-sensitized mice are shown (N = 5-7, *** P <0.001). キンピロール感作マウスにボノプラザンを脳室内投与したときの噛み行動の時間を測定した結果を示す（N = 8, **P < 0.01）。The results of measuring the chewing behavior time when vonoprazan was intraventricularly administered to kinpyrol-sensitized mice are shown (N = 8, ** P <0.01). 眼窩前頭皮質(OFC)、背側線条体(DS)、線条体中央部(CS)、および視床(TH)におけるAtp4aの遺伝子発現量を比較した結果を示す（N = 3）。The results of comparing the gene expression levels of Atp4a in the orbitofrontal cortex (OFC), dorsal striatum (DS), central striatum (CS), and thalamus (TH) are shown (N = 3). 急性単離脳切片を用いて発火回数を測定した結果を示す（Ａ：N = 10-11, *P < 0.05, **P < 0.01、Ｂ：N =11, **P < 0.01, ***P < 0.001）。The results of measuring the number of firings using an acutely isolated brain section are shown (A: N = 10-11, * P <0.05, ** P <0.01, B: N = 11, ** P <0.01, ** * P <0.001). 初代培養皮質神経細胞を用いて発火回数を測定した結果を示す（Ｂ：N = 10, *P < 0.05）。The results of measuring the number of firings using primary cultured cortical neurons are shown (B: N = 10, * P <0.05). ボノプラザンを脳室内投与したときの運動量を測定した結果を示す（N = 3）。The results of measuring the amount of exercise when vonoprazan was administered intraventricularly are shown (N = 3). 初代培養大脳皮質神経細胞におけるボノプラザン投与によるｐＨ変化を測定した結果を示す（Ｂ：N = 4、Ｃ：N = 6-7, *P < 0.05）。The results of measuring the pH change due to vonoprazan administration in primary cultured cerebral cortical neurons are shown (B: N = 4, C: N = 6-7, * P <0.05). ボノプラザンによる側方眼窩前頭皮質のｃ－Ｆｏｓ発現を測定した結果を示す（Ｂ：N = 4-5, *P < 0.05）。The results of measuring c-Fos expression in the lateral orbitofrontal cortex by vonoprazan are shown (B: N = 4-5, * P <0.05). ボノプラザンによる側方眼窩前頭皮質のｓ１００発現を測定した結果を示す（Ｂ：N = 4-5）。The results of measuring the expression of s100 in the lateral orbitofrontal cortex by vonoprazan are shown (B: N = 4-5).
　以下、本開示に包含される各実施形態について、さらに詳細に説明する。 Hereinafter, each embodiment included in the present disclosure will be described in more detail.
　本開示は、プロトンポンプ阻害剤を有効成分として含有する強迫性障害の治療剤を包含する。以下、当該治療剤を「本開示の治療剤」と表記することがある。 The present disclosure includes therapeutic agents for obsessive-compulsive disorder containing a proton pump inhibitor as an active ingredient. Hereinafter, the therapeutic agent may be referred to as "therapeutic agent of the present disclosure".
　本開示において、プロトンポンプ阻害剤とは、プロトンポンプであるＨ＋，Ｋ＋－ＡＴＰａｓｅの酵素活性を阻害するものであれば、特に限定されない。 In the present disclosure, the proton pump inhibitor is not particularly limited as long as it inhibits the enzymatic activity of H + , K + -ATPase, which is a proton pump.
　プロトンポンプ阻害剤としては、例えば、
式（Ｉ）
Figure JPOXMLDOC01-appb-C000005
 ［式中、ＸおよびＹは、同一または異なって、結合手または主鎖が原子数１ないし２０のスペーサーを、Ｒ１は置換されていてもよい炭化水素基または置換されていてもよい複素環基を、Ｒ２、Ｒ３およびＲ４は、同一または異なって、水素原子、置換されていてもよい炭化水素基、置換されていてもよいチエニル基、置換されていてもよいベンゾ［ｂ］チエニル基、置換されていてもよいフリル基、置換されていてもよいピリジル基、置換されていてもよいピラゾリル基、置換されていてもよいピリミジニル基、アシル基、ハロゲン原子、シアノ基またはニトロ基を、Ｒ５およびＲ６は、同一または異なって、水素原子または置換されていてもよい炭化水素基を示す］で表される化合物またはその塩（以下、化合物（Ｉ）と略記することがある）、またはそのプロドラッグが挙げられる。 Examples of proton pump inhibitors include
Equation (I)
Figure JPOXMLDOC01-appb-C000005
 [In the formula, X and Y are the same or different, and the bond or main chain is a spacer having 1 to 20 atoms, and R 1 is a hydrocarbon group which may be substituted or a heterocycle which may be substituted. The groups, R 2 , R 3 and R 4, are the same or different, hydrogen atoms, optionally substituted hydrocarbon groups, optionally substituted thienyl groups, optionally substituted benzo [b]. Thienyl group, optionally substituted frill group, optionally substituted pyridyl group, optionally substituted pyrazolyl group, optionally substituted pyrimidinyl group, acyl group, halogen atom, cyano group or nitro group. , R 5 and R 6 indicate the same or different hydrocarbon atoms or hydrocarbon groups which may be substituted], or a salt thereof (hereinafter, may be abbreviated as compound (I)). ), Or its prodrug.
　式（Ｉ）中、ＸまたはＹで示される「主鎖の原子数１ないし２０のスペーサー」とは、主鎖の原子が１ないし２０個連なっている２価の基を意味する。ここで、「主鎖の原子数」は、主鎖の原子が最小となるように数えるものとする。
　「主鎖の原子数１ないし２０のスペーサー」としては、例えば、
－Ｏ－；
－Ｓ－；
－ＣＯ－；
－ＳＯ－；
－ＳＯ２－；
－ＮＲ４０－（Ｒ４０は水素原子、置換されていてもよい炭化水素基、置換（例えば、ハロゲン化）されていてもよいＣ１－６アルキル－カルボニル、置換（例えば、ハロゲン化）されていてもよいＣ１－６アルキルスルホニルを示す）；および
置換基を有していてもよい２価のＣ１－６脂肪族炭化水素基
から選ばれる１ないし５個（好ましくは１ないし３個）の基を連結して形成し得る２価の基などが挙げられる。 In the formula (I), the "spacer having 1 to 20 atoms in the main chain" represented by X or Y means a divalent group in which 1 to 20 atoms in the main chain are connected. Here, the "number of atoms in the main chain" is counted so that the atoms in the main chain are minimized.
As a "spacer having 1 to 20 atoms in the main chain", for example,
-O-;
-S-;
-CO-;
-SO-;
-SO 2- ;
-NR 40- (R 40 is a hydrogen atom, a optionally substituted hydrocarbon group, optionally substituted (eg, halogenated) C 1-6 alkyl-carbonyl, substituted (eg, halogenated). 1 to 5 (preferably 1 to 3) selected from divalent C 1-6 aliphatic hydrocarbon groups which may have substituents); and may have a C 1-6 alkyl sulfonyl). Examples thereof include a divalent group which can be formed by concatenating the groups of.
　Ｒ４０で示される「置換されていてもよい炭化水素基」の「炭化水素基」としては、例えば、鎖状または環状炭化水素基（例、アルキル、アルケニル、アルキニル、シクロアルキル、アリール、アラルキル等）が挙げられる。このうち、炭素数１ないし１６個の鎖状または環状炭化水素基等が好ましい。 As "hydrocarbon group" represented by the "optionally substituted hydrocarbon group" in R 40 is, for example, chain or cyclic hydrocarbon group (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, etc. ). Of these, a chain or cyclic hydrocarbon group having 1 to 16 carbon atoms is preferable.
　「アルキル」としては、例えば、Ｃ１－６アルキル（例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル等）等が挙げられる。
　「アルケニル」としては、例えば、Ｃ２－６アルケニル（例えば、ビニル、アリル、イソプロペニル、１－ブテニル、２－ブテニル、３－ブテニル、２－メチル－２－プロペニル、１－メチル－２－プロペニル、２－メチル－１－プロペニル等）等が挙げられる。
　「アルキニル」としては、例えば、Ｃ２－６アルキニル（例えば、エチニル、プロパルギル、１－ブチニル、２－ブチニル、３－ブチニル、１－ヘキシニル等）等が挙げられる。
　「シクロアルキル」としては、例えば、Ｃ３－７シクロアルキル（例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル等）等が挙げられる。
　「アリール」としては、例えば、Ｃ６－１４アリール（例えば、フェニル、１－ナフチル、２－ナフチル、２－ビフェニリル、３－ビフェニリル、４－ビフェニリル、２－アンスリル等）等が挙げられる。
　「アラルキル」としては、例えば、Ｃ７－１６アラルキル（例えば、ベンジル、フェネチル、ジフェニルメチル、１－ナフチルメチル、２－ナフチルメチル、２，２－ジフェニルエチル、３－フェニルプロピル、４－フェニルブチル、５－フェニルペンチル等のフェニル－Ｃ１－６アルキル、ナフチル－Ｃ１－６アルキルまたはジフェニル－Ｃ１－４アルキル等）等が挙げられる。 Examples of the "alkyl" include C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and the like.
Examples of the "alkenyl" include C 2-6 alkenyl (eg, vinyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 1-methyl-2-propenyl). , 2-Methyl-1-propenyl, etc.) and the like.
Examples of the "alkynyl" include C 2-6 alkynyl (eg, ethynyl, propargyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-hexynyl, etc.).
Examples of the "cycloalkyl" include C 3-7 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.).
Examples of the "aryl" include C6-14aryl (eg, phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl, 3-biphenylyl, 4-biphenylyl, 2-anthrill, etc.).
Examples of "aralkyl" include C 7-16 aralkyl (eg, benzyl, phenethyl, diphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2,2-diphenylethyl, 3-phenylpropyl, 4-phenylbutyl, etc. Phenyl-C 1-6 alkyl such as 5-phenylpentyl, naphthyl-C 1-6 alkyl or diphenyl-C 1-4 alkyl, etc.) and the like can be mentioned.
　上記炭化水素基がアルキル、アルケニルまたはアルキニルの場合、（１）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子等）、（２）ニトロ、（３）シアノ、（４）ヒドロキシ、（５）１ないし３個のハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）を有していてもよいＣ１－６アルコキシ（例、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ペンチルオキシ、ヘキシルオキシ、フルオロメトキシ等）、（６）Ｃ６－１４アリールオキシ（例、フェニルオキシ、ナフチルオキシ等）、（７）Ｃ７－１６アラルキルオキシ（例、ベンジルオキシ、フェネチルオキシ、ジフェニルメチルオキシ、１－ナフチルメチルオキシ、２－ナフチルメチルオキシ、２，２－ジフェニルエチルオキシ、３－フェニルプロピルオキシ、４－フェニルブチルオキシ、５－フェニルペンチルオキシ等）、（８）メルカプト、（９）１ないし３個のハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）を有していてもよいＣ１－６アルキルチオ（例、メチルチオ、ジフルオロメチルチオ、トリフルオロメチルチオ、エチルチオ、プロピルチオ、イソプロピルチオ、ブチルチオ、４，４，４－トリフルオロブチルチオ、ペンチルチオ、ヘキシルチオ等）、（１０）Ｃ６－１４アリールチオ（例、フェニルチオ、ナフチルチオ等）、（１１）Ｃ７－１６アラルキルチオ（例、ベンジルチオ、フェネチルチオ、ジフェニルメチルチオ、１－ナフチルメチルチオ、２－ナフチルメチルチオ、２，２－ジフェニルエチルチオ、３－フェニルプロピルチオ、４－フェニルブチルチオ、５－フェニルペンチルチオ等）（１２）アミノ、（１３）モノ－Ｃ１－６アルキルアミノ（例、メチルアミノ、エチルアミノ等）、（１４）モノ－Ｃ６－１４アリールアミノ（例、フェニルアミノ、１－ナフチルアミノ、２－ナフチルアミノ等）、（１５）モノ－Ｃ７－１６アラルキルアミノ（例、ベンジルアミノ等）、（１６）ジ－Ｃ１－６アルキルアミノ（例、ジメチルアミノ、ジエチルアミノ等）、（１７）ジ－Ｃ６－１４アリールアミノ（例、ジフェニルアミノ等）、（１８）ジ－Ｃ７－１６アラルキルアミノ（例、ジベンジルアミノ等）、（１９）ホルミル、（２０）Ｃ１－６アルキル－カルボニル（例、アセチル、プロピオニル等）、（２１）Ｃ６－１４アリール－カルボニル（例、ベンゾイル、１－ナフトイル、２－ナフトイル等）、（２２）カルボキシル、（２３）Ｃ１－６アルコキシ－カルボニル（例、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、ｔｅｒｔ－ブトキシカルボニル等）、（２４）Ｃ６－１４アリールオキシ－カルボニル（例、フェノキシカルボニル等）、（２５）カルバモイル、（２６）チオカルバモイル、（２７）モノ－Ｃ１－６アルキル－カルバモイル（例、メチルカルバモイル、エチルカルバモイル等）、（２８）ジ－Ｃ１－６アルキル－カルバモイル（例、ジメチルカルバモイル、ジエチルカルバモイル、エチルメチルカルバモイル等）、（２９）Ｃ６－１４アリール－カルバモイル（例、フェニルカルバモイル、１－ナフチルカルバモイル、２－ナフチルカルバモイル等）、（３０）Ｃ１－６アルキルスルホニル（例、メチルスルホニル、エチルスルホニル等）、（３１）Ｃ６－１４アリールスルホニル（例、フェニルスルホニル、１－ナフチルスルホニル、２－ナフチルスルホニル等）、（３２）Ｃ１－６アルキルスルフィニル（例、メチルスルフィニル、エチルスルフィニル等）、（３３）Ｃ６－１４アリールスルフィニル（例、フェニルスルフィニル、１－ナフチルスルフィニル、２－ナフチルスルフィニル等）、（３４）ホルミルアミノ、（３５）Ｃ１－６アルキル－カルボニルアミノ（例、アセチルアミノ等）、（３６）Ｃ６－１４アリール－カルボニルアミノ（例、ベンゾイルアミノ、ナフトイルアミノ等）、（３７）Ｃ１－６アルコキシ－カルボニルアミノ（例、メトキシカルボニルアミノ、エトキシカルボニルアミノ、プロポキシカルボニルアミノ、ブトキシカルボニルアミノ等）、（３８）Ｃ１－６アルキルスルホニルアミノ（例、メチルスルホニルアミノ、エチルスルホニルアミノ等）、（３９）Ｃ６－１４アリールスルホニルアミノ（例、フェニルスルホニルアミノ、２－ナフチルスルホニルアミノ、１－ナフチルスルホニルアミノ等）、（４０）Ｃ１－６アルキル－カルボニルオキシ（例、アセトキシ、プロピオニルオキシ等）、（４１）Ｃ６－１４アリール－カルボニルオキシ（例、ベンゾイルオキシ、ナフチルカルボニルオキシ等）、（４２）Ｃ１－６アルコキシ－カルボニルオキシ（例、メトキシカルボニルオキシ、エトキシカルボニルオキシ、プロポキシカルボニルオキシ、ブトキシカルボニルオキシ等）、（４３）モノ－Ｃ１－６アルキル－カルバモイルオキシ（例、メチルカルバモイルオキシ、エチルカルバモイルオキシ等）、（４４）ジ－Ｃ１－６アルキル－カルバモイルオキシ（例、ジメチルカルバモイルオキシ、ジエチルカルバモイルオキシ等）、（４５）Ｃ６－１４アリール－カルバモイルオキシ（例、フェニルカルバモイルオキシ、ナフチルカルバモイルオキシ等）、（４６）１個の窒素原子と炭素原子以外に、窒素原子、硫黄原子及び酸素原子から選ばれる１または２種のヘテロ原子を１ないし４個含んでいてもよい５ないし７員飽和環状アミノ（例、ピロリジン－１－イル、ピペリジノ、ピペラジン－１－イル、モルホリノ、チオモルホリノ、ヘキサヒドロアゼピン－１－イル等）、（４７）炭素原子以外に窒素原子、硫黄原子及び酸素原子から選ばれる１または２種のヘテロ原子を１ないし４個含む５ないし１０員芳香族複素環基（例、２－チエニル、３－チエニル、２－ピリジル、３－ピリジル、４－ピリジル、２－キノリル、３－キノリル、４－キノリル、５－キノリル、８－キノリル、１－イソキノリル、３－イソキノリル、４－イソキノリル、５－イソキノリル、１－インドリル、２－インドリル、３－インドリル、２－ベンゾチアゾリル、２－ベンゾ［ｂ］チエニル、３－ベンゾ［ｂ］チエニル、２－ベンゾ［ｂ］フラニル、３－ベンゾ［ｂ］フラニル等）、（４８）Ｃ１－３アルキレンジオキシ（例、メチレンジオキシ、エチレンジオキシ等）、および（４９）Ｃ３－７シクロアルキル（例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル等）等から選ばれる１ないし３個の置換基で置換されていてもよい。 When the hydrocarbon group is alkyl, alkenyl or alkynyl, (1) halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), (2) nitro, (3) cyano, (4) hydroxy, (5) C 1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy) which may have 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom). , Isobutoxy, sec-butoxy, pentyloxy, hexyloxy, fluoromethoxy, etc.), (6) C 6-14 aryloxy (eg, phenyloxy, naphthyloxy, etc.), (7) C 7-16 aralkyloxy (eg,, etc.) Benzyloxy, phenethyloxy, diphenylmethyloxy, 1-naphthylmethyloxy, 2-naphthylmethyloxy, 2,2-diphenylethyloxy, 3-phenylpropyloxy, 4-phenylbutyloxy, 5-phenylpentyloxy, etc.), (8) Mercapto, (9) C 1-6 alkylthio (eg, methylthio, difluoromethylthio, which may have 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom). Trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc.), (10) C 6-14 arylthio (eg, phenylthio, naphthylthio, etc.), (11) C 7-16 Aralkylthio (eg, benzylthio, phenethylthio, diphenylmethylthio, 1-naphthylmethylthio, 2-naphthylmethylthio, 2,2-diphenylethylthio, 3-phenylpropylthio, 4-phenylbutylthio, 5-phenylpenti Lucio, etc.) (12) Amino, (13) Mono-C 1-6 alkylamino (eg, methylamino, ethylamino, etc.), (14) Mono-C 6-14 arylamino (eg, phenylamino, 1-naphthyl, etc.) Amino, 2-naphthylamino, etc.), (15) Mono-C 7-16 aralkylamino (eg, benzylamino, etc.), (16) Di-C 1-6 alkylamino (eg, dimethylamino, diethylamino, etc.), ( 17) Di-C 6-14 arylamino (eg, diphenylamino, etc.), (18) Di-C 7-16 aralkylamino (eg, dibenzylamino, etc.), (19) formyl, (20) C 1-6. Alkyl-carbonyl (eg, acetyl, propionyl, etc.) ), (21) C 6-14 aryl-carbonyl (eg, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), (22) carboxyl, (23) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl, ethoxycarbonyl) , Propoxycarbonyl, tert-butoxycarbonyl, etc.), (24) C 6-14 aryloxy-carbonyl (eg, phenoxycarbonyl, etc.), (25) carbamoyl, (26) thiocarbamoyl, (27) mono-C 1-6. Alkyl-carbamoyl (eg, methylcarbamoyl, ethylcarbamoyl, etc.), (28) Di-C 1-6 alkyl-carbamoyl (eg, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, etc.), (29) C 6-14aryl- Carbamoyl (eg, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), (30) C 1-6 alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.), (31) C 6-14 arylsulfonyl (eg, eg, methylsulfonyl, ethylsulfonyl, etc.) , Phenylsulfonyl, 1-naphthylsulfonyl, 2-naphthylsulfonyl, etc.), (32) C 1-6 alkyl sulfinyl (eg, methylsulfinyl, ethylsulfinyl, etc.), (33) C 6-14 arylsulfinyl (eg, phenylsulfinyl, etc.) , 1-naphthylsulfinyl, 2-naphthylsulfinyl, etc.), (34) formylamino, (35) C 1-6 alkyl-carbonylamino (eg, acetylamino, etc.), (36) C 6-14 aryl-carbonylamino (36) Examples, benzoylamino, naphthoylamino, etc.), (37) C 1-6 alkoxy-carbonylamino (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, etc.), (38) C 1-6. Alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.), (39) C 6-14 arylsulfonylamino (eg, phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.), (40) C 1-6 alkyl-carbonyloxy (eg, acetoxy, propionyloxy, etc.), (41) C 6-14 aryl-carbonyloxy (eg, benzoyloxy, naphthylcarbonyloxy, etc.), (42) C 1-6 alkoxy- Carbonyloxy (eg, methoxycarbonyloxy, eth) Xycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), (43) mono-C 1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), (44) di-C 1-6 alkyl -Carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), (45) C 6-14aryl- carbamoyloxy (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.), (46) One nitrogen atom and carbon In addition to the atom, a 5- to 7-membered saturated cyclic amino (eg, pyrrolidine-1-yl, piperidino, which may contain 1 to 4 heteroatoms of 1 or 2 selected from a nitrogen atom, a sulfur atom and an oxygen atom). Piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepine-1-yl, etc.), (47) In addition to carbon atoms, one or two heteroatoms selected from nitrogen atom, sulfur atom and oxygen atom are 1 to 4 5- to 10-membered aromatic heterocyclic groups including (eg, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 1-indrill, 2-indrill, 3-indrill, 2-benzothiazolyl, 2-benzo [b] thienyl, 3-benzo [b] Thienyl, 2-benzo [b] furanyl, 3-benzo [b] furanyl, etc.), (48) C 1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), and (49) C 3- It may be substituted with 1 to 3 substituents selected from 7 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.) and the like.
　また、上記炭化水素基がシクロアルキル、アリールまたはアラルキルである場合、（１）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子等）、（２）ニトロ、（３）シアノ、（４）ヒドロキシ、（５）１ないし３個のハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）を有していてもよいＣ１－６アルコキシ（例、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ペンチルオキシ、ヘキシルオキシ、フルオロメトキシ等）、（６）Ｃ６－１４アリールオキシ（例、フェニルオキシ、ナフチルオキシ等）、（７）Ｃ７－１６アラルキルオキシ（例、ベンジルオキシ、フェネチルオキシ、ジフェニルメチルオキシ、１－ナフチルメチルオキシ、２－ナフチルメチルオキシ、２，２－ジフェニルエチルオキシ、３－フェニルプロピルオキシ、４－フェニルブチルオキシ、５－フェニルペンチルオキシ等）、（８）メルカプト、（９）１ないし３個のハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）を有していてもよいＣ１－６アルキルチオ（例、メチルチオ、ジフルオロメチルチオ、トリフルオロメチルチオ、エチルチオ、プロピルチオ、イソプロピルチオ、ブチルチオ、４，４，４－トリフルオロブチルチオ、ペンチルチオ、ヘキシルチオ等）、（１０）Ｃ６－１４アリールチオ（例、フェニルチオ、ナフチルチオ等）、（１１）Ｃ７－１６アラルキルチオ（例、ベンジルチオ、フェネチルチオ、ジフェニルメチルチオ、１－ナフチルメチルチオ、２－ナフチルメチルチオ、２，２－ジフェニルエチルチオ、３－フェニルプロピルチオ、４－フェニルブチルチオ、５－フェニルペンチルチオ等）（１２）アミノ、（１３）モノ－Ｃ１－６アルキルアミノ（例、メチルアミノ、エチルアミノ等）、（１４）モノ－Ｃ６－１４アリールアミノ（例、フェニルアミノ、１－ナフチルアミノ、２－ナフチルアミノ等）、（１５）モノ－Ｃ７－１６アラルキルアミノ（例、ベンジルアミノ等）、（１６）ジ－Ｃ１－６アルキルアミノ（例、ジメチルアミノ、ジエチルアミノ等）、（１７）ジ－Ｃ６－１４アリールアミノ（例、ジフェニルアミノ等）、（１８）ジ－Ｃ７－１６アラルキルアミノ（例、ジベンジルアミノ等）、（１９）ホルミル、（２０）Ｃ１－６アルキル－カルボニル（例、アセチル、プロピオニル等）、（２１）Ｃ６－１４アリール－カルボニル（例、ベンゾイル、１－ナフトイル、２－ナフトイル等）、（２２）カルボキシル、（２３）Ｃ１－６アルコキシ－カルボニル（例、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、ｔｅｒｔ－ブトキシカルボニル等）、（２４）Ｃ６－１４アリールオキシ－カルボニル（例、フェノキシカルボニル等）、（２５）カルバモイル、（２６）チオカルバモイル、（２７）モノ－Ｃ１－６アルキル－カルバモイル（例、メチルカルバモイル、エチルカルバモイル等）、（２８）ジ－Ｃ１－６アルキル－カルバモイル（例、ジメチルカルバモイル、ジエチルカルバモイル、エチルメチルカルバモイル等）、（２９）Ｃ６－１４アリール－カルバモイル（例、フェニルカルバモイル、１－ナフチルカルバモイル、２－ナフチルカルバモイル等）、（３０）１ないし３個のハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）を有していてもよいＣ１－６アルキルスルホニル（例、メチルスルホニル、エチルスルホニル、トリフルオロメチルスルホニル等）、（３１）Ｃ６－１４アリールスルホニル（例、フェニルスルホニル、１－ナフチルスルホニル、２－ナフチルスルホニル等）、（３２）Ｃ１－６アルキルスルフィニル（例、メチルスルフィニル、エチルスルフィニル等）、（３３）Ｃ６－１４アリールスルフィニル（例、フェニルスルフィニル、１－ナフチルスルフィニル、２－ナフチルスルフィニル等）、（３４）ホルミルアミノ、（３５）Ｃ１－６アルキル－カルボニルアミノ（例、アセチルアミノ等）、（３６）Ｃ６－１４アリール－カルボニルアミノ（例、ベンゾイルアミノ、ナフトイルアミノ等）、（３７）Ｃ１－６アルコキシ－カルボニルアミノ（例、メトキシカルボニルアミノ、エトキシカルボニルアミノ、プロポキシカルボニルアミノ、ブトキシカルボニルアミノ等）、（３８）Ｃ１－６アルキルスルホニルアミノ（例、メチルスルホニルアミノ、エチルスルホニルアミノ等）、（３９）Ｃ６－１４アリールスルホニルアミノ（例、フェニルスルホニルアミノ、２－ナフチルスルホニルアミノ、１－ナフチルスルホニルアミノ等）、（４０）Ｃ１－６アルキル－カルボニルオキシ（例、アセトキシ、プロピオニルオキシ等）、（４１）Ｃ６－１４アリール－カルボニルオキシ（例、ベンゾイルオキシ、ナフチルカルボニルオキシ等）、（４２）Ｃ１－６アルコキシ－カルボニルオキシ（例、メトキシカルボニルオキシ、エトキシカルボニルオキシ、プロポキシカルボニルオキシ、ブトキシカルボニルオキシ等）、（４３）モノ－Ｃ１－６アルキル－カルバモイルオキシ（例、メチルカルバモイルオキシ、エチルカルバモイルオキシ等）、（４４）ジ－Ｃ１－６アルキル－カルバモイルオキシ（例、ジメチルカルバモイルオキシ、ジエチルカルバモイルオキシ等）、（４５）Ｃ６－１４アリール－カルバモイルオキシ（例、フェニルカルバモイルオキシ、ナフチルカルバモイルオキシ等）、（４６）１個の窒素原子と炭素原子以外に、窒素原子、硫黄原子及び酸素原子から選ばれる１または２種のヘテロ原子を１ないし４個含んでいてもよい５ないし７員飽和環状アミノ（例、ピロリジン－１－イル、ピペリジノ、ピペラジン－１－イル、モルホリノ、チオモルホリノ、ヘキサヒドロアゼピン－１－イル等）、（４７）炭素原子以外に窒素原子、硫黄原子及び酸素原子から選ばれる１または２種のヘテロ原子を１ないし４個含む５ないし１０員芳香族複素環基（例、２－チエニル、３－チエニル、２－ピリジル、３－ピリジル、４－ピリジル、２－キノリル、３－キノリル、４－キノリル、５－キノリル、８－キノリル、１－イソキノリル、３－イソキノリル、４－イソキノリル、５－イソキノリル、１－インドリル、２－インドリル、３－インドリル、２－ベンゾチアゾリル、２－ベンゾ［ｂ］チエニル、３－ベンゾ［ｂ］チエニル、２－ベンゾ［ｂ］フラニル、３－ベンゾ［ｂ］フラニル等）、（４８）Ｃ１－３アルキレンジオキシ（例、メチレンジオキシ、エチレンジオキシ等）、（４９）Ｃ３－７シクロアルキル（例えば、シクロプロピル、シクロブチル、シクロペンチル、シクロヘキシル、シクロヘプチル等）、（５０）１ないし３個のハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）あるいはヒドロキシ基を有していてもよいＣ１－６アルキル基（例、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、ｓｅｃ－ペンチル、イソペンチル、ネオペンチル、ｎ－ヘキシル、イソヘキシル等）、（５１）１ないし３個のハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）を有していてもよいＣ２－６アルケニル基（例、アリル、イソプロペニル、イソブテニル、１－メチルアリル、２－ペンテニル、２－ヘキセニル等）、（５２）Ｃ２－６アルキニル基（例、プロパルギル、２－ブチニル、３－ブチニル、３－ペンチニル、３－ヘキシニル等）、（５３）モノ－Ｃ３－７シクロアルキル－カルバモイル（例、シクロプロピルカルバモイル、シクロブチルカルバモイル等）、および（５４）炭素原子以外に窒素原子、硫黄原子及び酸素原子から選ばれる１または２種のヘテロ原子を１ないし４個含む５ないし１０員複素環－カルボニル（例、４－モルホリノカルボニル等）等から選ばれる１ないし５個（好ましくは１ないし３個）の置換基で置換されていてもよい。 When the hydrocarbon group is cycloalkyl, aryl or aralkyl, (1) halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom, etc.), (2) nitro, (3) cyano, ( 4) hydroxy, (5) C 1-6 alkoxy (eg, methoxy, ethoxy, propoxy, which may have 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom)). Isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, fluoromethoxy, etc.), (6) C 6-14 aryloxy (eg, phenyloxy, naphthyloxy, etc.), (7) C 7-16 aralkyl Oxy (eg, benzyloxy, phenethyloxy, diphenylmethyloxy, 1-naphthylmethyloxy, 2-naphthylmethyloxy, 2,2-diphenylethyloxy, 3-phenylpropyloxy, 4-phenylbutyloxy, 5-phenylpentyl) Oxy, etc.), (8) Mercapto, (9) C 1-6 alkylthio (eg, methylthio) which may have 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom). , Difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio, etc.), (10) C 6-14 arylthio (eg, phenylthio, naphthylthio, etc.) , (11) C 7-16 aralkylthio (eg, benzylthio, phenethylthio, diphenylmethylthio, 1-naphthylmethylthio, 2-naphthylmethylthio, 2,2-diphenylethylthio, 3-phenylpropylthio, 4-phenylbutylthio, 5-Phenylpentylthio, etc.) (12) Amino, (13) Mono-C 1-6 alkylamino (eg, methylamino, ethylamino, etc.), (14) Mono-C 6-14 arylamino (eg, phenylamino, etc.) , 1-naphthylamino, 2-naphthylamino, etc.), (15) Mono-C 7-16 aralkylamino (eg, benzylamino, etc.), (16) Di-C 1-6 alkylamino (eg, dimethylamino, diethylamino, etc.) Etc.), (17) Di-C 6-14 arylamino (eg, diphenylamino, etc.), (18) Di-C 7-16 aralkylamino (eg, dibenzylamino, etc.), (19) Formyl, (20). C 1-6 alkyl-carbonyl (eg, acetyl, Propionyl, etc.), (21) C 6-14 aryl-carbonyl (eg, benzoyl, 1-naphthoyl, 2-naphthoyl, etc.), (22) carboxyl, (23) C 1-6 alkoxy-carbonyl (eg, methoxycarbonyl, etc.) Ethoxycarbonyl, propoxycarbonyl, tert-butoxycarbonyl, etc.), (24) C 6-14 aryloxy-carbonyl (eg, phenoxycarbonyl, etc.), (25) carbamoyl, (26) thiocarbamoyl, (27) mono-C 1 -6 alkyl - carbamoyl (e.g., methylcarbamoyl, ethylcarbamoyl, etc.), (28) di -C 1-6 alkyl - carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl etc.), (29) C 6-14 It has aryl-carbamoyl (eg, phenylcarbamoyl, 1-naphthylcarbamoyl, 2-naphthylcarbamoyl, etc.), (30) 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom). May be C 1-6 alkyl sulfonyl (eg, methyl sulfonyl, ethyl sulfonyl, trifluoromethyl sulfonyl, etc.), (31) C 6-14 aryl sulfonyl (eg, phenyl sulfonyl, 1-naphthyl sulfonyl, 2-naphthyl sulfonyl, etc.) ), (32) C 1-6 alkyl sulfinyl (eg, methyl sulfinyl, ethyl sulfinyl, etc.), (33) C 6-14 aryl sulfinyl (eg, phenyl sulfinyl, 1-naphthyl sulfinyl, 2-naphthyl sulfinyl, etc.), ( 34) Formylamino, (35) C 1-6 alkyl-carbonylamino (eg, acetylamino, etc.), (36) C 6-14 aryl-carbonylamino (eg, benzoylamino, naphthoylamino, etc.), (37). C 1-6 alkoxy-carbonylamino (eg, methoxycarbonylamino, ethoxycarbonylamino, propoxycarbonylamino, butoxycarbonylamino, etc.), (38) C 1-6 alkylsulfonylamino (eg, methylsulfonylamino, ethylsulfonylamino, etc.) ), (39) C 6-14 arylsulfonylamino (eg, phenylsulfonylamino, 2-naphthylsulfonylamino, 1-naphthylsulfonylamino, etc.), (40) C 1-6 alkyl-carbonyloxy (eg, acetoxy, propionyl, etc.) Oxy, etc.), (41) C 6-14 aryl-carbonyl oki Si (eg, benzoyloxy, naphthylcarbonyloxy, etc.), (42) C 1-6 alkoxy-carbonyloxy (eg, methoxycarbonyloxy, ethoxycarbonyloxy, propoxycarbonyloxy, butoxycarbonyloxy, etc.), (43) mono- C 1-6 alkyl-carbamoyloxy (eg, methylcarbamoyloxy, ethylcarbamoyloxy, etc.), (44) Di-C 1-6 alkyl-carbamoyloxy (eg, dimethylcarbamoyloxy, diethylcarbamoyloxy, etc.), (45) C 6-14 aryl-carbamoyloxy (eg, phenylcarbamoyloxy, naphthylcarbamoyloxy, etc.), (46) One or two selected from nitrogen atom, sulfur atom and oxygen atom in addition to one nitrogen atom and carbon atom. 5- to 7-membered saturated cyclic aminos (eg, pyrrolidine-1-yl, piperidino, piperazin-1-yl, morpholino, thiomorpholino, hexahydroazepine-1-yl, etc.) may contain 1 to 4 heteroatoms of the above. ), (47) A 5- to 10-membered aromatic heterocyclic group containing 1 to 4 heteroatoms of 1 or 2 selected from a nitrogen atom, a sulfur atom and an oxygen atom in addition to a carbon atom (eg, 2-thienyl, 3). -Thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 8-quinolyl, 1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl , 1-indrill, 2-indrill, 3-indrill, 2-benzothiazolyl, 2-benzo [b] thienyl, 3-benzo [b] thienyl, 2-benzo [b] furanyl, 3-benzo [b] furanyl, etc.) , (48) C 1-3 alkylenedioxy (eg, methylenedioxy, ethylenedioxy, etc.), (49) C 3-7 cycloalkyl (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.), (50) C 1-6 alkyl group (eg, methyl, ethyl, n-) which may have 1 to 3 halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) or hydroxy group. Propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, etc.), (51) 1 to 3 halogen atoms (eg) , Fluorine atom, chlorine atom, bromine atom, C 2-6 alkenyl group (eg, allyl, isopropenyl, isobutenyl, 1-methylallyl, 2-pentenyl, 2-hexenyl, etc.), which may have an iodine atom) , (52) C 2-6 alkynyl group (52) Examples, propargyl, 2-butynyl, 3-butynyl, 3-pentynyl, 3-hexynyl, etc.), (53) Mono-C 3-7 cycloalkyl-carbamoyl (eg, cyclopropylcarbamoyl, cyclobutylcarbamoyl, etc.), and ( 54) Select from 5- to 10-membered heterocycle-carbonyl (eg, 4-morpholinocarbonyl, etc.) containing 1 to 4 heteroatoms of 1 or 2 selected from nitrogen atom, sulfur atom and oxygen atom in addition to carbon atom. It may be substituted with 1 to 5 (preferably 1 to 3) substituents.
　なお、本明細書において「置換されていてもよい炭化水素基」における置換基としてオキソ基は包含しない。 It should be noted that the oxo group is not included as a substituent in the "hydrocarbon group which may be substituted" in the present specification.
　Ｒ４０で示される「ハロゲン化されていてもよいＣ１－６アルキル－カルボニル」としては、例えば、１ないし５個、好ましくは１ないし３個のハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子など）を置換可能な位置に有していてもよいＣ１－６アルキル－カルボニルなどが挙げられる。具体例としては、例えば、アセチル、モノクロロアセチル、トリフルオロアセチル、トリクロロアセチル、プロパノイル、ブタノイル、ペンタノイル、ヘキサノイルなどが挙げられる。 "Optionally halogenated C 1-6 alkyl - carbonyl" represented by R 40 includes, for example, 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine atom, chlorine atom, bromine Examples thereof include C 1-6 alkyl-carbonyl, which may have an atom (atom, iodine atom, etc.) at a substitutable position. Specific examples include acetyl, monochloroacetyl, trifluoroacetyl, trichloroacetyl, propanoyl, butanoyl, pentanoyl, hexanoyl and the like.
　Ｒ４０で示される「ハロゲン化されていてもよいＣ１－６アルキルスルホニル」としては、例えば、１ないし５個、好ましくは１ないし３個のハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子など）を置換可能な位置に有していてもよいＣ１－６アルキルスルホニルなどが挙げられる。具体例としては、例えば、メチルスルホニル、ジフルオロメチルスルホニル、トリフルオロメチルスルホニル、エチルスルホニル、プロピルスルホニル、イソプロピルスルホニル、ブチルスルホニル、４，４，４－トリフルオロブチルスルホニル、ｓｅｃ－ブチルスルホニル、ｔｅｒｔ－ブチルスルホニル、ペンチルスルホニル、ヘキシルスルホニルなどが挙げられる。 As "optionally halogenated C 1-6 alkylsulfonyl" represented by R 40, for example, 1 to 5, preferably 1 to 3 halogen atoms (e.g., fluorine atom, chlorine atom, bromine atom , Iodine atom, etc.) may have a substitutable position, such as C 1-6 alkyl sulfonyl. Specific examples include, for example, methyl sulfonyl, difluoromethyl sulfonyl, trifluoromethyl sulfonyl, ethyl sulfonyl, propyl sulfonyl, isopropyl sulfonyl, butyl sulfonyl, 4,4,4-trifluorobutyl sulfonyl, sec-butyl sulfonyl, tert-butyl. Examples include sulfonyl, pentyl sulfonyl, hexyl sulfonyl and the like.
　前記「置換基を有していてもよい２価のＣ１－６脂肪族炭化水素基」における「２価のＣ１－６脂肪族炭化水素基」としては、アルキレン基、アルケニレン基、アルキニレン基が挙げられ、例えば、
（１）Ｃ１－６アルキレン（例えば、－ＣＨ２－、－（ＣＨ２）２－、－（ＣＨ２）３－、－（ＣＨ２）４－、－（ＣＨ２）５－、－（ＣＨ２）６－、－ＣＨ（ＣＨ３）－、－Ｃ（ＣＨ３）２－、－（ＣＨ（ＣＨ３））２－、－（ＣＨ２）２Ｃ（ＣＨ３）２－、－（ＣＨ２）３Ｃ（ＣＨ３）２－など）；
（２）Ｃ２－６アルケニレン（例えば、－ＣＨ＝ＣＨ－、－ＣＨ２－ＣＨ＝ＣＨ－、－ＣＨ＝ＣＨ－ＣＨ２－、－ＣＨ＝ＣＨ－ＣＨ２－ＣＨ２－、－Ｃ（ＣＨ３）２－ＣＨ＝ＣＨ－、－ＣＨ２－ＣＨ＝ＣＨ－ＣＨ２－、－ＣＨ２－ＣＨ２－ＣＨ＝ＣＨ－、－ＣＨ＝ＣＨ－ＣＨ＝ＣＨ－、－ＣＨ＝ＣＨ－ＣＨ２－ＣＨ２－ＣＨ２－など）；
（３）Ｃ２－６アルキニレン（例えば、－Ｃ≡Ｃ－、－ＣＨ２－Ｃ≡Ｃ－、－ＣＨ２－Ｃ≡Ｃ－ＣＨ２－ＣＨ２－など）などが挙げられる。 Examples of the "divalent C 1-6 aliphatic hydrocarbon group" of the "C 1-6 aliphatic hydrocarbon group which may divalent substituted", the alkylene group, alkenylene group, alkynylene group For example,
(1) C 1-6 alkylene (for example, -CH 2 -,-(CH 2 ) 2 -,-(CH 2 ) 3 -,-(CH 2 ) 4 -,-(CH 2 ) 5 -,-( CH 2 ) 6 -,-CH (CH 3 )-, -C (CH 3 ) 2 -,-(CH (CH 3 )) 2 -,-(CH 2 ) 2 C (CH 3 ) 2 -,-( CH 2 ) 3 C (CH 3 ) 2 -etc.);
(2) C 2-6 alkenylene (e.g., -CH = CH -, - CH 2 -CH = CH -, - CH = CH-CH 2 -, - CH = CH-CH 2 -CH 2 -, - C ( CH 3) 2 -CH = CH - , - CH 2 -CH = CH-CH 2 -, - CH 2 -CH 2 -CH = CH -, - CH = CH-CH = CH -, - CH = CH-CH 2- CH 2- CH 2 -etc.);
(3) C 2-6 alkynylene (e.g., -C≡C -, - CH 2 -C≡C -, - CH 2 -C≡C-CH 2 -CH 2 - , etc.) and the like.
　「置換基を有していてもよい２価のＣ１－６脂肪族炭化水素基」における「置換基」としては、例えば、前記Ｒ４０で示される「置換されていてもよい炭化水素基」におけるアルキル、アルケニルまたはアルキニルの置換基として例示した置換基と同様の基が挙げられ、特に、ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、ヒドロキシなどが好ましい。該「置換基」の数は、例えば、１ないし５個、好ましくは１ないし３個である。 As the "substituent" in the "C 1-6 aliphatic hydrocarbon group which may divalent substituted", for example, "optionally substituted hydrocarbon group" represented by R 40 Examples of the substituent of alkyl, alkenyl or alkynyl in the above include the same groups as those exemplified, and in particular, halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), hydroxy and the like are preferable. The number of the "substituents" is, for example, 1 to 5, preferably 1 to 3.
　「主鎖の原子数１ないし２０のスペーサー」の好適な例としては、
（１）置換されていてもよいアルキレン基：
具体的には、１ないし３個の置換基（好ましくは、ハロゲン原子、ヒドロキシなど）を有していてもよいＣ１－２０アルキレン（例えば、－ＣＨ２－、－（ＣＨ２）２－、－（ＣＨ２）３－、－ＣＨ（ＯＨ）－（ＣＨ２）２－、－（ＣＨ２）４－、－（ＣＨ２）５－、－（ＣＨ２）６－、－ＣＨＣＨ３－、－Ｃ（ＣＨ３）２－、－ＣＨ（ＣＦ３）－、－（ＣＨ（ＣＨ３））２－、－（ＣＦ２）２－、－（ＣＨ２）２Ｃ（ＣＨ３）２－、－（ＣＨ２）３Ｃ（ＣＨ３）２－、－（ＣＨ２）７－、－（ＣＨ２）８－、－（ＣＨ２）９－、－（ＣＨ２）１０－、－（ＣＨ２）１１－、－（ＣＨ２）１２－、－（ＣＨ２）１３－、－（ＣＨ２）１４－、－（ＣＨ２）１５－、－（ＣＨ２）１６－、－（ＣＨ２）１７－、－（ＣＨ２）１８－、－（ＣＨ２）１９－、－（ＣＨ２）２０－など）；
（２）置換されていてもよいアルケニレン基：
具体的には、１ないし３個の置換基（好ましくは、ハロゲン原子、ヒドロキシなど）を有していてもよいＣ２－２０アルケニレン（例えば、－ＣＨ＝ＣＨ－、－ＣＨ２－ＣＨ＝ＣＨ－、－ＣＨ＝ＣＨ－ＣＨ２－、－ＣＨ＝ＣＨ－ＣＨ２－ＣＨ２－、－ＣＨ２－ＣＦ＝ＣＨ－、－Ｃ（ＣＨ３）２－ＣＨ＝ＣＨ－、－ＣＨ２－ＣＨ＝ＣＨ－ＣＨ２－、－ＣＨ２－ＣＨ２－ＣＨ＝ＣＨ－、－ＣＨ＝ＣＨ－ＣＨ＝ＣＨ－、－ＣＨ＝ＣＨ－ＣＨ２－ＣＨ２－ＣＨ２－など）；
（３）置換されていてもよいアルキニレン基：
具体的には、１ないし３個の置換基（好ましくは、ハロゲン原子、ヒドロキシなど）を有していてもよいＣ２－２０アルキニレン（例えば、－Ｃ≡Ｃ－、－ＣＨ２－Ｃ≡Ｃ－、－ＣＨ２－Ｃ≡Ｃ－ＣＨ２－ＣＨ２－など）；
（４）－（ＣＨ２）ｗ１ａＯ（ＣＨ２）ｗ２ａ－、－（ＣＨ２）ｗ１ａＳ（ＣＨ２）ｗ２ａ－、－（ＣＨ２）ｗ１ａＣＯ（ＣＨ２）ｗ２ａ－、－（ＣＨ２）ｗ１ａＳＯ（ＣＨ２）ｗ２ａ－、－（ＣＨ２）ｗ１ａＳＯ２（ＣＨ２）ｗ２ａ－、－（ＣＨ２）ｗ１ａＮＲ４０（ＣＨ２）ｗ２ａ－；
（５）－（ＣＨ２）ｗ３ａＣＯ－、－（ＣＨ２）ｗ３ａＣＯＮＲ４０（ＣＨ２）ｗ４ａ－、－（ＣＨ２）ｗ３ａＮＲ４０ＣＯ（ＣＨ２）ｗ４ａ－、－（ＣＨ２）ｗ３ａＳＯ２ＮＲ４０（ＣＨ２）ｗ４ａ－、－（ＣＨ２）ｗ３ａＮＲ４０ＳＯ２（ＣＨ２）ｗ４ａ－、－（ＣＨ２）ｗ３ａＣＯＯ（ＣＨ２）ｗ４ａ－；
（６）－（ＣＨ２）ｗ５ａＮＲ４０ＣＯＮＲ４０ｂ（ＣＨ２）ｗ６ａ－；
（Ｒ４０は前記と同意義を；Ｒ４０ｂはＲ４０と同意義を；ｗ１ａおよびｗ２ａは０ないし１９の整数を、かつｗ１ａ＋ｗ２ａが０ないし１９を；ｗ３ａおよびｗ４ａは０ないし１８の整数を、かつｗ３ａ＋ｗ４ａが０ないし１８を；ｗ５ａおよびｗ６ａは０ないし１７の整数を、かつｗ５ａ＋ｗ６ａが０ないし１７を示す）などが挙げられる。 A suitable example of a "spacer having 1 to 20 atoms in the main chain" is
(1) Substituent alkylene group:
Specifically, C 1-20 alkylene (for example, -CH 2 -,-(CH 2 ) 2- , which may have 1 to 3 substituents (preferably halogen atom, hydroxy, etc.)). -(CH 2 ) 3 -,-CH (OH)-(CH 2 ) 2 -,-(CH 2 ) 4 -,-(CH 2 ) 5 -,-(CH 2 ) 6- , -CHCH 3- , -C (CH 3 ) 2- , -CH (CF 3 )-,-(CH (CH 3 )) 2 -,-(CF 2 ) 2 -,-(CH 2 ) 2 C (CH 3 ) 2- , -(CH 2 ) 3 C (CH 3 ) 2 -,-(CH 2 ) 7 -,-(CH 2 ) 8 -,-(CH 2 ) 9 -,-(CH 2 ) 10 -,-(CH 2) ) 11 -,-(CH 2 ) 12 -,-(CH 2 ) 13 -,-(CH 2 ) 14 -,-(CH 2 ) 15 -,-(CH 2 ) 16 -,-(CH 2 ) 17 -,-(CH 2 ) 18 -,-(CH 2 ) 19 -,-(CH 2 ) 20 -etc.);
(2) Alkenylene group which may be substituted:
Specifically, C 2-20 alkenylene (eg, -CH = CH-, -CH 2 -CH = CH) which may have 1 to 3 substituents (preferably halogen atom, hydroxy, etc.). -, - CH = CH-CH 2 -, - CH = CH-CH 2 -CH 2 -, - CH 2 -CF = CH -, - C (CH 3) 2 -CH = CH -, - CH 2 -CH = CH-CH 2 -, - CH 2 -CH 2 -CH = CH -, - CH = CH-CH = CH -, - CH = CH-CH 2 -CH 2 -CH 2 - , etc.);
(3) Alquinylene group which may be substituted:
Specifically, (preferably, a halogen atom, hydroxy, etc.) 1 to 3 substituents which may have a C 2-20 alkynylene (e.g., -C≡C -, - CH 2 -C≡C -, - CH 2 -C≡C-CH 2 -CH 2 - , etc.);
(4)-(CH 2 ) w1a O (CH 2 ) w2a -,-(CH 2 ) w1a S (CH 2 ) w2a -,-(CH 2 ) w1a CO (CH 2 ) w2a -,-(CH 2 ) w1a SO (CH 2 ) w2a -,-(CH 2 ) w1a SO 2 (CH 2 ) w2a -,-(CH 2 ) w1a NR 40 (CH 2 ) w2a- ;
(5)-(CH 2 ) w3a CO-,-(CH 2 ) w3a CONR 40 (CH 2 ) w4a -,-(CH 2 ) w3a NR 40 CO (CH 2 ) w4a -,-(CH 2 ) w3a SO 2 NR 40 (CH 2 ) w4a -,-(CH 2 ) w3a NR 40 SO 2 (CH 2 ) w4a -,-(CH 2 ) w3a COO (CH 2 ) w4a- ;
(6) - (CH 2) w5a NR 40 CONR 40b (CH 2) w6a -;
(R 40 has the same meaning as above; R 40b has the same meaning as R 40 ; w1a and w2a have integers of 0 to 19, and w1a + w2a have 0 to 19; w3a and w4a have integers of 0 to 18. And w3a + w4a indicates 0 to 18; w5a and w6a indicate an integer of 0 to 17, and w5a + w6a indicates 0 to 17) and the like.
　前記した「主鎖の原子数１ないし２０のスペーサー」のなかでも、以下のような「主鎖の原子数１ないし８のスペーサー」が好ましい。
（１）１ないし３個の置換基（好ましくは、ハロゲン原子、ヒドロキシなど）を有していてもよいＣ１－８アルキレン（例えば、－ＣＨ２－、－（ＣＨ２）２－、－（ＣＨ２）３－、－ＣＨ（ＯＨ）－（ＣＨ２）２－、－（ＣＨ２）４－、－（ＣＨ２）５－、－（ＣＨ２）６－、－ＣＨＣＨ３－、－Ｃ（ＣＨ３）２－、－ＣＨ（ＣＦ３）－、－（ＣＨ（ＣＨ３））２－、－（ＣＦ２）２－、－（ＣＨ２）２Ｃ（ＣＨ３）２－、－（ＣＨ２）３Ｃ（ＣＨ３）２－など）；
（２）１ないし３個の置換基（好ましくは、ハロゲン原子、ヒドロキシなど）を有していてもよいＣ２－８アルケニレン（例えば、－ＣＨ＝ＣＨ－、－ＣＨ２－ＣＨ＝ＣＨ－、－ＣＨ＝ＣＨ－ＣＨ２－、－ＣＨ＝ＣＨ－ＣＨ２－ＣＨ２－、－ＣＨ２－ＣＦ＝ＣＨ－、－Ｃ（ＣＨ３）２－ＣＨ＝ＣＨ－、－ＣＨ２－ＣＨ＝ＣＨ－ＣＨ２－、－ＣＨ２－ＣＨ２－ＣＨ＝ＣＨ－、－ＣＨ＝ＣＨ－ＣＨ＝ＣＨ－、－ＣＨ＝ＣＨ－ＣＨ２－ＣＨ２－ＣＨ２－など）；
（３）１ないし３個の置換基（好ましくは、ハロゲン原子、ヒドロキシなど）を有していてもよいＣ２－８アルキニレン（例えば、－Ｃ≡Ｃ－、－ＣＨ２－Ｃ≡Ｃ－、－ＣＨ２－Ｃ≡Ｃ－ＣＨ２－ＣＨ２－など）；
（４）－（ＣＨ２）ｗ１Ｏ（ＣＨ２）ｗ２－、－（ＣＨ２）ｗ１Ｓ（ＣＨ２）ｗ２－、－（ＣＨ２）ｗ１ＣＯ（ＣＨ２）ｗ２－、－（ＣＨ２）ｗ１ＳＯ（ＣＨ２）ｗ２－、－（ＣＨ２）ｗ１ＳＯ２（ＣＨ２）ｗ２－、－（ＣＨ２）ｗ１ＮＲ４０（ＣＨ２）ｗ２－；
（５）－（ＣＨ２）ｗ３ＣＯ－、－（ＣＨ２）ｗ３ＣＯＮＲ４０（ＣＨ２）ｗ４－、－（ＣＨ２）ｗ３ＮＲ４０ＣＯ（ＣＨ２）ｗ４－、－（ＣＨ２）Ｗ３ＳＯ２ＮＲ４０（ＣＨ２）ｗ４－、－（ＣＨ２）ｗ３ＮＲ４０ＳＯ２ＣＨ２）ｗ４－、－（ＣＨ２）ｗ３ＣＯＯ（ＣＨ２）ｗ４－；
（６）－（ＣＨ２）ｗ５ＮＲ４０ＣＯＮＲ４０ｂ（ＣＨ２）ｗ６－；
（Ｒ４０は前記と同意義を；Ｒ４０ｂはＲ４０と同意義を；ｗ１およびｗ２は０ないし５の整数を、かつｗ１＋ｗ２が０ないし７を；ｗ３およびｗ４は０ないし４の整数を、かつｗ３＋ｗ４が０ないし６を；ｗ５およびｗ６は０ないし３の整数を、かつｗ５＋ｗ６が０ないし５を示す）などが挙げられる。 Among the above-mentioned "spacers having 1 to 20 atoms in the main chain", the following "spacers having 1 to 8 atoms in the main chain" are preferable.
(1) C 1-8 alkylene (for example, −CH 2 −, − (CH 2 ) 2 −, − (eg, −CH 2 −, − (CH 2) 2 −, − (eg, −CH 2 −, − (CH 2) 2 −, — which may have 1 to 3 substituents (preferably halogen atom, hydroxy, etc.)). CH 2 ) 3- , -CH (OH)-(CH 2 ) 2 -,-(CH 2 ) 4 -,-(CH 2 ) 5 -,-(CH 2 ) 6- , -CHCH 3- , -C (CH 3 ) 2 -,-CH (CF 3 )-,-(CH (CH 3 )) 2 -,-(CF 2 ) 2 -,-(CH 2 ) 2 C (CH 3 ) 2 -,-( CH 2 ) 3 C (CH 3 ) 2 -etc.);
(2) C 2-8 alkenylene (eg, -CH = CH-, -CH 2- CH = CH-, which may have 1 to 3 substituents (preferably halogen atom, hydroxy, etc.). -CH = CH-CH 2 -, - CH = CH-CH 2 -CH 2 -, - CH 2 -CF = CH -, - C (CH 3) 2 -CH = CH -, - CH 2 -CH = CH -CH 2 -, - CH 2 -CH 2 -CH = CH -, - CH = CH-CH = CH -, - CH = CH-CH 2 -CH 2 -CH 2 - , etc.);
(3) 1 to (preferably, halogen atom, hydroxy, etc.) three substituents optionally C 2-8 alkynylene optionally having (e.g., -C≡C -, - CH 2 -C≡C- , -CH 2 -C≡C-CH 2 -CH 2 - , etc.);
(4)-(CH 2 ) w1 O (CH 2 ) w2 -,-(CH 2 ) w1 S (CH 2 ) w2 -,-(CH 2 ) w1 CO (CH 2 ) w2 -,-(CH 2 ) w1 SO (CH 2 ) w2 -,-(CH 2 ) w1 SO 2 (CH 2 ) w2 -,-(CH 2 ) w1 NR 40 (CH 2 ) w2- ;
(5)-(CH 2 ) w3 CO-,-(CH 2 ) w3 CONR 40 (CH 2 ) w4 -,-(CH 2 ) w3 NR 40 CO (CH 2 ) w4 -,-(CH 2 ) W3 SO 2 NR 40 (CH 2 ) w4 -,-(CH 2 ) w3 NR 40 SO 2 CH 2 ) w4 -,-(CH 2 ) w3 COO (CH 2 ) w4- ;
(6)-(CH 2 ) w5 NR 40 CONR 40b (CH 2 ) w6- ;
(R 40 has the same meaning as above; R 40b has the same meaning as R 40 ; w1 and w2 have integers of 0 to 5, and w1 + w2 have 0 to 7; w3 and w4 have integers of 0 to 4. And w3 + w4 indicates 0 to 6; w5 and w6 indicate an integer of 0 to 3, and w5 + w6 indicates 0 to 5) and the like.
　「主鎖の原子数１ないし２０のスペーサー」は、好ましくは下記（１）～（６）である。
（１）－ＳＯ２－；
（２）－ＳＯ２－Ｎ（Ｒ７）－（Ｒ７は水素原子または置換されていてもよい炭化水素基を示す）、ここでＲ７における「置換されていてもよい炭化水素基」としては、前記Ｒ４０における「置換されていてもよい炭化水素基」と同様の基が挙げられる；
（３）－Ｎ（Ｒ８）－ＳＯ２－（Ｒ８は水素原子または置換されていてもよい炭化水素基を示す）、ここでＲ８における「置換されていてもよい炭化水素基」としては、前記Ｒ４０における「置換されていてもよい炭化水素基」と同様の基が挙げられる；
（４）－Ｎ（Ｒ９）－（Ｒ９は水素原子または置換されていてもよい炭化水素基を示す）、ここでＲ９における「置換されていてもよい炭化水素基」としては、前記Ｒ４０における「置換されていてもよい炭化水素基」と同様の基が挙げられる；
（５）－Ｏ－；
（６）置換されていてもよいアルキレン基、好ましくは、１ないし３個の置換基（好ましくは、ハロゲン原子、ヒドロキシなど）を有していてもよいＣ１－８アルキレン（例えば、－ＣＨ２－、－（ＣＨ２）２－、－（ＣＨ２）３－、－ＣＨ（ＯＨ）－（ＣＨ２）２－、－（ＣＨ２）４－、－（ＣＨ２）５－、－（ＣＨ２）６－、－ＣＨＣＨ３－、－Ｃ（ＣＨ３）２－、－ＣＨ（ＣＦ３）－、－（ＣＨ（ＣＨ３））２－、－（ＣＦ２）２－、－（ＣＨ２）２Ｃ（ＣＨ３）２－、－（ＣＨ２）３Ｃ（ＣＨ３）２－など）。 The "spacer having 1 to 20 atoms in the main chain" is preferably the following (1) to (6).
(1) -SO 2- ;
(2) -SO 2- N (R 7 )-(R 7 indicates a hydrogen atom or a optionally substituted hydrocarbon group), here as " optionally substituted hydrocarbon group" in R 7. include the same groups as "optionally substituted hydrocarbon group" in the R 40;
(3) -N (R 8 ) -SO 2- (R 8 indicates a hydrogen atom or a optionally substituted hydrocarbon group), here as " optionally substituted hydrocarbon group" in R 8. include the same groups as "optionally substituted hydrocarbon group" in the R 40;
(4) -N (R 9 )-(R 9 indicates a hydrogen atom or a hydrocarbon group which may be substituted), where the "hydrocarbon group which may be substituted" in R 9 is described above. It includes the same groups as the "optionally substituted hydrocarbon group" in R 40;
(5) -O-;
(6) C 1-8 alkylene (for example, −CH 2 ) which may have an optionally substituted alkylene group, preferably 1 to 3 substituents (preferably a halogen atom, hydroxy, etc.). -,-(CH 2 ) 2 -,-(CH 2 ) 3- , -CH (OH)-(CH 2 ) 2 -,-(CH 2 ) 4 -,-(CH 2 ) 5 -,-(CH 2) 2 ) 6- , -CHCH 3- , -C (CH 3 ) 2- , -CH (CF 3 )-,-(CH (CH 3 )) 2 -,-(CF 2 ) 2 -,-(CH 2) ) 2 C (CH 3 ) 2 -,-(CH 2 ) 3 C (CH 3 ) 2-, etc.).
　式（Ｉ）において、Ｘは、－ＳＯ２－、－ＳＯ２－Ｎ（Ｒ７）－（Ｒ７は前記と同意義を示す）、－Ｎ（Ｒ８）－ＳＯ２－（Ｒ８は前記と同意義を示す）、－Ｎ（Ｒ９）－（Ｒ９は前記と同意義を示す）または－Ｏ－が好ましい。とりわけ－ＳＯ２－が好ましい。 In formula (I), X, -SO 2 -, - SO 2 -N (R 7) - (R 7 is as defined above), - N (R 8) -SO 2 - (R 8 is (Same meaning as above), -N (R 9 )-(R 9 has the same meaning as above) or -O- is preferable. In particular, -SO 2- is preferable.
　一方、Ｙは、結合手またはＣ１－８アルキレン（例えば、－ＣＨ２－、－（ＣＨ２）２－、－（ＣＨ２）３－、－（ＣＨ２）４－、－（ＣＨ２）５－、－（ＣＨ２）６－、－ＣＨＣＨ３－、－Ｃ（ＣＨ３）２－、－（ＣＨ（ＣＨ３））２－、－（ＣＨ２）２Ｃ（ＣＨ３）２－、－（ＣＨ２）３Ｃ（ＣＨ３）２－など）が好ましい。中でも、－ＣＨ２－、が好ましい。 On the other hand, Y is a bond or C 1-8 alkylene (for example, -CH 2 -,-(CH 2 ) 2 -,-(CH 2 ) 3 -,-(CH 2 ) 4 -,-(CH 2 ). 5 -,-(CH 2 ) 6- , -CHCH 3- , -C (CH 3 ) 2 -,-(CH (CH 3 )) 2 -,-(CH 2 ) 2 C (CH 3 ) 2- , -(CH 2 ) 3 C (CH 3 ) 2-, etc.) is preferable. Of these, -CH 2- is preferable.
　前記式（Ｉ）中、Ｒ１は、置換されていてもよい炭化水素基または置換されていてもよい複素環基を示す。 In the formula (I), R 1 represents a optionally substituted hydrocarbon group or an optionally substituted heterocyclic group.
　該「置換されていてもよい炭化水素基」としては、前記Ｒ４０で示される「置換されていてもよい炭化水素基」と同様の基が挙げられる。 As the "an optionally substituted hydrocarbon group" include the same groups as "optionally substituted hydrocarbon group" represented by R 40.
　該「置換されていてもよい複素環基」の「複素環基」としては、例えば、窒素原子（オキシド化されていてもよい）、酸素原子、硫黄原子（モノまたはジオキシド化されていてもよい）などのヘテロ原子を１ないし４個含む３～８員複素環基（好ましくは５～６員複素環基）、または窒素原子（オキシド化されていてもよい）、酸素原子、硫黄原子（モノまたはジオキシド化されていてもよい）などのヘテロ原子を１ないし４個含む３～８員複素環基（好ましくは５～６員複素環基）とベンゼン環または窒素原子（オキシド化されていてもよい）、酸素原子、硫黄原子（モノまたはジオキシド化されていてもよい）などのヘテロ原子を１ないし４個含む３～８員複素環基（好ましくは５～６員複素環基）とが縮合して形成する基、好ましくは該５～６員複素環基と窒素原子（オキシド化されていてもよい）、酸素原子、硫黄原子（モノまたはジオキシド化されていてもよい）などのヘテロ原子を１ないし４個含んでいてもよい５～６員環とが縮合して形成する基が挙げられる。　具体的には、アジリジニル（例、１－または２－アジリジニル）、アジリニル（例、１－または２－アジリニル）、アゼチル（例、２－、３－または４－アゼチル）、アゼチジニル（例、１－、２－または３－アゼチジニル）、パーヒドロアゼピニル（例、１－、２－、３－または４－パーヒドロアゼピニル）、パーヒドロアゾシニル（例、１－、２－、３－、４－または５－パーヒドロアゾシニル）、ピロリル（例、１－、２－または３－ピロリル）、ピラゾリル（例、１－、３－、４－または５－ピラゾリル）、イミダゾリル（例、１－、２－、４－または５－イミダゾリル）、トリアゾリル（例、１，２，３－トリアゾール－１－、４－または－５－イル、１，２，４－トリアゾール－１－、３－、４－または５－イル）、テトラゾリル（例、テトラゾール－１－、２－または５－イル）、フリル（例、２－または３－フリル）、チエニル（例、２－または３－チエニル）、硫黄原子が酸化されたチエニル（例、２－または３－チエニル－１，１－ジオキシド）、オキサゾリル（例、２－、４－または５－オキサゾリル）、イソキサゾリル（例、３－、４－または５－イソキサゾリル）、オキサジアゾリル（例、１，２，３－オキサジアゾール－４－または５－イル、１，２，４－オキサジアゾール－３－または５－イル、１，２，５－オキサジアゾール－３－イル、１，３，４－オキサジアゾール－２－イル）、チアゾリル（例、２－、４－または５－チアゾリル）、イソチアゾリル（例、３－、４－または５－イソチアゾリル）、チアジアゾリル（例、１，２，３－チアジアゾール－４－または５－イル、１，２，４－チアジアゾール－３－または５－イル、１，２，５－チアジアゾール－３－イル、１，３，４－チアジアゾール－２－イル）、ピロリジニル（例、１－、２－または３－ピロリジニル）、ピリジル（例、２－、３－または４－ピリジル）、窒素原子が酸化されたピリジル（例、２－、３－または４－ピリジル－Ｎ－オキシド）、ピリダジニル（例、３－または４－ピリダジニル）、窒素原子の一方または両方が酸化されたピリダジニル（例、３－、４－、５－または６－ピリダジニル－Ｎ－オキシド）、ピリミジニル（例、２－、４－または５－ピリミジニル）、窒素原子の一方または両方が酸化されたピリミジニル（例、２－、４－、５－または６－ピリミジニル－Ｎ－オキシド）、ピラジニル、ピペリジニル（例、１－、２－、３－または４－ピペリジニル）、ピペラジニル（例、１－または２－ピペラジニル）、インドリル（例、３Ｈ－インドール－２－、３－、４－、５－、６－または７－イル）、ピラニル（例、２－、３－または４－ピラニル）、チオピラニル（例、２－、３－または４－チオピラニル）、硫黄原子が酸化されたチオピラニル（例、２－、３－または４－チオピラニル－１，１－ジオキシド）、モルホリニル（例、２－、３－または４－モルホリニル）、チオモルホリニル、キノリル（例、２－、３－、４－、５－、６－、７－または８－キノリル）、イソキノリル、ピリド〔２，３－ｄ〕ピリミジニル（例、ピリド〔２，３－ｄ〕ピリミジン－２－イル）、１，５－、１，６－、１，７－、１，８－、２，６－または２，７－ナフチリジニルなどのナフチリジニル（例、１，５－ナフチリジン－２－または３－イル）、チエノ〔２，３－ｄ〕ピリジル（例、チエノ〔２，３－ｄ〕ピリジン－３－イル）、ピラジノキノリル（例、ピラジノ〔２，３－ｄ〕キノリン－２－イル）、クロメニル（例、２Ｈ－クロメン－２－または３－イル）、２－ベンゾ［ｂ］チエニル、３－ベンゾ［ｂ］チエニル、２－ベンゾ［ｂ］フラニル、３－ベンゾ［ｂ］フラニル、２，３－ジヒドロ－１－ベンゾフラニル、２，１，３－ベンゾチアジアゾリル、２，３－ジヒドロ－１，４－ベンゾジオキシン－５－または－６－イル、１，３－ベンゾチアゾール－６－イル、１，１－ジオキシド－２，３－ジヒドロ－１－ベンゾチエン－６－イル、１－ベンゾチエニルなどが用いられる。中でも、ピリジル（例、２－、３－または４－ピリジル）が好ましい。 The "heterocyclic group" of the "optionally substituted heterocyclic group" may be, for example, a nitrogen atom (which may be oxidized), an oxygen atom, or a sulfur atom (which may be mono or dioxidized). ), A 3- to 8-membered heterocyclic group containing 1 to 4 heteroatoms (preferably a 5- to 6-membered heterocyclic group), or a nitrogen atom (which may be oxidized), an oxygen atom, or a sulfur atom (mono). A 3- to 8-membered heterocyclic group (preferably a 5- to 6-membered heterocyclic group) containing 1 to 4 heteroatoms such as (which may be dioxidized) and a benzene ring or nitrogen atom (which may be oxidized). Condensed with a 3-8 membered heterocyclic group (preferably a 5-6 membered heterocyclic group) containing 1 to 4 heteroatoms such as), oxygen atom, sulfur atom (which may be mono or dioxidized). A group formed in the above, preferably the 5- to 6-membered heterocyclic group and a heteroatom such as a nitrogen atom (which may be oxidized), an oxygen atom, and a sulfur atom (which may be mono or dioxidized). Examples thereof include groups formed by condensation with a 5- to 6-membered ring which may contain 1 to 4 rings. Specifically, aziridinyl (eg, 1- or 2-aziridinyl), azylinyl (eg, 1- or 2-azilinyl), azetyl (eg, 2-, 3- or 4-azetyl), azetidinyl (eg, 1-). , 2- or 3-azetidine), perhydroazepinyl (eg, 1-, 2-, 3- or 4-perhydroazepinyl), perhydroazocinyl (eg, 1-, 2-, 3-). , 4- or 5-perhydroazocinyl), pyrrolyl (eg, 1-, 2- or 3-pyrrolyl), pyrazolyl (eg, 1-, 3-, 4- or 5-pyrazolyl), imidazolyl (eg, 1). -, 2-, 4- or 5-imidazolyl), triazolyl (eg, 1,2,3-triazole-1-, 4- or -5-yl, 1,2,4-triazole-1-, 3-, 4- or 5-yl), tetrazolyl (eg, tetrazole-1-, 2- or 5-yl), frills (eg, 2- or 3-frills), thienyl (eg, 2- or 3-thienyl), sulfur. Atomically oxidized thienyl (eg, 2- or 3-thienyl-1,1-dioxide), oxazolyl (eg, 2-, 4- or 5-oxazolyl), isoxazolyl (eg, 3-, 4- or 5-) Isoxazolyl), oxadiazolyl (eg, 1,2,3-oxadiazole-4- or 5-yl, 1,2,4-oxadiazole-3- or 5-yl, 1,2,5-oxadiazole) -3-yl, 1,3,4-oxadiazole-2-yl), thiazolyl (eg, 2-, 4- or 5-thiazolyl), isothiazolyl (eg, 3-, 4- or 5-isothiazolyl), Thisiazoleyl (eg, 1,2,3-thiazole-4- or 5-yl, 1,2,4-thiazole-3- or 5-yl, 1,2,5-thiazole-3-yl, 1,3 4-thiazole-2-yl), pyrrolidinyl (eg, 1-, 2- or 3-pyrrolidinyl), pyridyl (eg, 2-, 3- or 4-pyridyl), nitrogen atom oxidized pyridyl (eg, 2). -, 3- or 4-pyridyl-N-oxide), pyridadinyl (eg, 3- or 4-pyridazinyl), pyridadinyl in which one or both of the nitrogen atoms are oxidized (eg, 3-, 4-, 5- or 6). -Pyridadinyl-N-oxide), pyrimidinyl (eg, 2-, 4- or 5-pyrimidinyl), pyrimidinyl in which one or both of the nitrogen atoms are oxidized (eg, 2-, 4-, 5- or 6-pyrimidinyl- N-oxide), pyrazi Nyl, piperidinyl (eg, 1-, 2-, 3- or 4-piperidinyl), piperazinyl (eg, 1- or 2-piperazinyl), indolyl (eg, 3H-indole-2-, 3-, 4-, 5). -, 6- or 7-yl), pyranyl (eg, 2-, 3- or 4-pyranyl), thiopyranyl (eg, 2-, 3- or 4-thiopyranyl), thiopyranyl with oxidized sulfur atom (eg, eg) 2-, 3- or 4-thiopyranyl-1,1-dioxide), morpholinyl (eg, 2-, 3- or 4-morpholinyl), thiomorpholinyl, quinolyl (eg, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl), isoquinolyl, pyrido [2,3-d] pyrimidinyl (eg, pyrido [2,3-d] pyrimidin-2-yl), 1,5-, 1,6-, Naftyridinyl such as 1,7-, 1,8-, 2,6- or 2,7-naphthylidine (eg, 1,5-naphthylidine-2- or 3-yl), thieno [2,3-d] pyridyl (eg, 1,5-naphthylidine-2- or 3-yl). Examples, thieno [2,3-d] pyridine-3-yl), pyrazinoquinolyl (eg, pyrazino [2,3-d] quinoline-2-yl), chromenyl (eg, 2H-chromen-2- or 3-yl). ), 2-Benzo [b] thienyl, 3-benzo [b] thienyl, 2-benzo [b] flanil, 3-benzo [b] flanyl, 2,3-dihydro-1-benzofuranyl, 2,1,3- Benzothiasiazolyl, 2,3-dihydro-1,4-benzodioxin-5- or -6-yl, 1,3-benzothiazole-6-yl, 1,1-dioxide-2,3-dihydro-1 -Benzothione-6-yl, 1-benzothienyl and the like are used. Of these, pyridil (eg, 2-, 3- or 4-pyridyl) is preferred.
　該複素環基の「置換基」としては、上記Ｒ４０で示される「炭化水素基」がシクロアルキル、アリールまたはアラルキルである場合に有していてもよい置換基と同様の置換基が挙げられる。該置換基の数は１ないし５個、好ましくは１ないし３個である。 Examples of the "substituent" of heterocyclic group, include the same substituents as the substituent which may have in the case represented by the R 40 "hydrocarbon group" is cycloalkyl, aryl or aralkyl .. The number of the substituents is 1 to 5, preferably 1 to 3.
　Ｒ１としては、置換されていてもよいアルキル基、置換されていてもよいアリール基、置換されていてもよいアラルキル基または置換されていてもよいチエニル基が好ましく、置換されていてもよいアルキル基、置換されていてもよいアリール基または置換されていてもよいアラルキル基がより好ましく、置換されていてもよいアリール基が特に好ましい。具体的には、Ｒ１は、
［１］Ｃ１－６アルキル（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル等）、
［２］（ｉ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）、（ｉｉ）ヒドロキシ、（ｉｉｉ）シアノ、（ｉｖ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルキル（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル等）、（ｖ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルコキシ（例、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ペンチルオキシ、ヘキシルオキシ等）および（ｖｉ）フェニルから選ばれる１～５個（好ましくは１～３個）の置換基で置換されていてもよいＣ６－１４アリール基（例、フェニル等）、または
［３］（無置換の）チエニル基
が好ましく、中でも、ハロゲン、ヒドロキシおよびＣ１－６アルキルから選ばれる１～５個（好ましくは１～３個）の置換基で置換されていてもよいＣ６－１４アリール基（例、フェニル等）が特に好ましい。 The R 1, an optionally substituted alkyl group, an optionally substituted aryl group, preferably a thienyl group which may be the aralkyl group or substituted or optionally substituted, optionally substituted alkyl Groups, optionally substituted aryl groups or optionally substituted aralkyl groups are more preferred, and optionally substituted aryl groups are particularly preferred. Specifically, R 1 is
[1] C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.),
[2] 1 to 5 (i) halogens (eg, fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) halogens (eg, fluorine, chlorine, bromine, iodine) ( C 1-6 alkyl optionally substituted (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), (v). C 1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, which may be substituted with 1-5 (preferably 1-3) halogens (eg, fluorine, chlorine, bromine, iodine). A C 6-14 aryl group (preferably 1 to 3) which may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from (vi) phenyl and (vi) phenyl (isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.). For example, phenyl, etc.), or [3] (unsubstituted) thienyl groups are preferred, with 1-5 (preferably 1-3) substituents selected from halogens, hydroxys and C 1-6 alkyls. Substituted C 6-14 aryl groups (eg, phenyl, etc.) are particularly preferred.
　前記式（Ｉ）中、Ｒ２、Ｒ３およびＲ４は、同一または異なって、水素原子または置換されていてもよい炭化水素基、置換されていてもよいチエニル基、置換されていてもよいベンゾ［ｂ］チエニル基、置換されていてもよいフリル基、置換されていてもよいピリジル基、置換されていてもよいピラゾリル基、置換されていてもよいピリミジニル基、アシル基、ハロゲン原子、シアノ基またはニトロ基を示すが、好ましくは、水素原子または置換されていてもよい炭化水素基、置換されていてもよいチエニル基、置換されていてもよいベンゾ［ｂ］チエニル基、置換されていてもよいフリル基、置換されていてもよいピリジル基、アシル基、ハロゲン原子、シアノ基またはニトロ基である。 In the formula (I), R 2 , R 3 and R 4 are the same or different, hydrogen atom or optionally substituted hydrocarbon group, optionally substituted thienyl group, optionally substituted. Benzo [b] thienyl group, optionally substituted frill group, optionally substituted pyridyl group, optionally substituted pyrazolyl group, optionally substituted pyrimidinyl group, acyl group, halogen atom, cyano It indicates a group or a nitro group, but preferably a hydrogen atom or a optionally substituted hydrocarbon group, an optionally substituted thienyl group, an optionally substituted benzo [b] thienyl group, substituted. It may be a frill group, an optionally substituted pyridyl group, an acyl group, a halogen atom, a cyano group or a nitro group.
　Ｒ２、Ｒ３およびＲ４で示される「置換されていてもよい炭化水素基」としては、前記Ｒ４０で示される「置換されていてもよい炭化水素基」と同様の基が挙げられる。 As "optionally substituted hydrocarbon group" represented by R 2, R 3 and R 4, include the same groups as "optionally substituted hydrocarbon group" represented by R 40.
　Ｒ２、Ｒ３およびＲ４で示される「置換されていてもよいチエニル基」の「チエニル基」としては、２－または３－チエニルが挙げられる。
　該チエニル基の「置換基」としては、上記Ｒ４０で示される「炭化水素基」がシクロアルキル、アリールまたはアラルキルである場合に有していてもよい置換基と同様の置換基が挙げられる。該置換基の数は１ないし３個である。 As "thienyl group" of the "optionally substituted thienyl group" represented by R 2, R 3 and R 4, include 2- or 3-thienyl.
As the "substituent" of the thienyl group, represented by R 40 "hydrocarbon group" is cycloalkyl, it includes the same substituents as the substituents which may have if it is aryl or aralkyl. The number of the substituents is 1 to 3.
　Ｒ２、Ｒ３およびＲ４で示される「置換されていてもよいベンゾ［ｂ］チエニル基」の「ベンゾ［ｂ］チエニル基」としては、２－または３－ベンゾ［ｂ］チエニルが挙げられる。
　該ベンゾ［ｂ］チエニル基の「置換基」としては、上記Ｒ４０で示される「炭化水素基」がシクロアルキル、アリールまたはアラルキルである場合に有していてもよい置換基と同様の置換基が挙げられる。該置換基の数は１ないし５個、好ましくは１ないし３個である。 The R 2, "benzo [b] thienyl group" of R 3 and represented by R 4 "optionally substituted benzo [b] thienyl group" includes 2- or 3-benzo [b] thienyl ..
As the "substituent" of the benzo [b] thienyl group, represented by R 40 "hydrocarbon group" is cycloalkyl, aryl or same substituents as the substituents which may have in the case of aralkyl Can be mentioned. The number of the substituents is 1 to 5, preferably 1 to 3.
　Ｒ２、Ｒ３およびＲ４で示される「置換されていてもよいフリル基」の「フリル基」としては、２－または３－フリルが挙げられる。
　該フリル基の「置換基」としては、上記Ｒ４０で示される「炭化水素基」がシクロアルキル、アリールまたはアラルキルである場合に有していてもよい置換基と同様の置換基が挙げられる。該置換基の数は１ないし３個である。 Examples of the "frill group" of the "optionally substituted frill group" represented by R 2 , R 3 and R 4 include 2- or 3-frill.
As the "substituent" of the furyl group, represented by R 40 "hydrocarbon group" is cycloalkyl, it includes the same substituents as the substituents which may have if it is aryl or aralkyl. The number of the substituents is 1 to 3.
　Ｒ２、Ｒ３およびＲ４で示される「置換されていてもよいピリジル基」の「ピリジル基」としては、２－，３－または４－ピリジルが挙げられる。
　該ピリジル基の「置換基」としては、上記Ｒ４０で示される「炭化水素基」がシクロアルキル、アリールまたはアラルキルである場合に有していてもよい置換基と同様の置換基が挙げられる。該置換基の数は１ないし３個である。 R 2, R 3 and represented by R 4 in the "optionally substituted pyridyl group" as "pyridyl group", 2-, include 3- or 4-pyridyl.
As the "substituent" of the pyridyl group, represented by R 40 "hydrocarbon group" is cycloalkyl, it includes the same substituents as the substituents which may have if it is aryl or aralkyl. The number of the substituents is 1 to 3.
　Ｒ２、Ｒ３およびＲ４で示される「置換されていてもよいピラゾリル基」の「ピラゾリル基」としては、３－または４－ピラゾリルが挙げられる。
　該ピラゾリル基の「置換基」としては、上記Ｒ４０で示される「炭化水素基」がシクロアルキル、アリールまたはアラルキルである場合に有していてもよい置換基と同様の置換基が挙げられる。該置換基の数は１ないし３個である。 R 2, R 3 and represented by R 4 in the "optionally substituted pyrazolyl group" as "pyrazolyl group" include 3- or 4-pyrazolyl.
As the "substituent" of the pyrazolyl group, represented by R 40 "hydrocarbon group" is cycloalkyl, it includes the same substituents as the substituents which may have if it is aryl or aralkyl. The number of the substituents is 1 to 3.
　Ｒ２、Ｒ３およびＲ４で示される「置換されていてもよいピリミジニル基」の「ピリミジニル基」としては、２－，４－または５－ピリミジニルが挙げられる。
　該ピリミジニル基の「置換基」としては、上記Ｒ４０で示される「炭化水素基」がシクロアルキル、アリールまたはアラルキルである場合に有していてもよい置換基と同様の置換基が挙げられる。該置換基の数は１ないし３個である。 R 2, R 3 and represented by R 4 in the "optionally substituted pyrimidinyl group" as the "pyrimidinyl group", 2-, include 4- or 5-pyrimidinyl.
As the "substituent" of the pyrimidinyl group, represented by R 40 "hydrocarbon group" is cycloalkyl, it includes the same substituents as the substituents which may have if it is aryl or aralkyl. The number of the substituents is 1 to 3.
　Ｒ２、Ｒ３およびＲ４で示される「アシル基」としては、有機カルボン酸から誘導される炭素数１ないし２０のアシル基が挙げられる。例えば、Ｃ１－７アルカノイル基（例、ホルミル；アセチル、プロピオニル、ブチリル、イソブチリル、ペンタノイル、ヘキサノイル、ヘプタノイル等のＣ１－６アルキル－カルボニル等）、Ｃ６－１４アリール－カルボニル基（例、ベンゾイル、ナフタレンカルボニル等）、Ｃ１－６アルコキシ－カルボニル基（例、メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、イソブトキシカルボニル、ｓｅｃ－ブトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル等）、Ｃ６－１４アリールオキシ－カルボニル基（例、フェノキシカルボニル基）、Ｃ７－１９アラルキル－カルボニル基（例、ベンジルカルボニル、フェネチルカルボニル、フェニルプロピルカルボニルなどのフェニル－Ｃ１－４アルキルカルボニル、ベンズヒドリルカルボニル、ナフチルエチルカルボニルなどのナフチル－Ｃ１－４アルキルカルボニル等）、Ｃ７－１９アラルキルオキシ－カルボニル基（例、ベンジルオキシカルボニルなどのフェニル－Ｃ１－４アルキルオキシカルボニル等）、５もしくは６員複素環カルボニル基またはその縮合した複素環カルボニル基（例、２－または３－ピロリルカルボニルなどのピロリルカルボニル；３－、４－または５－ピラゾリルカルボニルなどのピラゾリルカルボニル；２－、４－または５－イミダゾリルカルボニルなどのイミダゾリルカルボニル；１，２，３－トリアゾール－４－イルカルボニル、１，２，４－トリアゾール－３－イルカルボニルなどのトリアゾリルカルボニル；１Ｈ－または２Ｈ－テトラゾール－５－イルカルボニルなどのテトラゾリルカルボニル；２－または３－フリルカルボニルなどのフリルカルボニル；２－または３－チエニルカルボニルなどのチエニルカルボニル；２－、４－または５－オキサゾリルカルボニルなどのオキサゾリルカルボニル；３－、４－または５－イソキサゾリルカルボニルなどのイソキサゾリルカルボニル；１，２，３－オキサジアゾール－４－または５－イルカルボニル、１，２，４－オキサジアゾール－３－または５－イルカルボニル、１，２，５－オキサジアゾール－３－または４－イルカルボニル、１，３，４－オキサジアゾール－２－イルカルボニルなどのオキサジアゾリルカルボニル；２－、４－または５－チアゾリルカルボニルなどのチアゾリルカルボニル；３－、４－または５－イソチアゾリルカルボニルなどのイソチアゾリルカルボニル；１，２，３－チアジアゾール－４－または５－イルカルボニル、１，２，４－チアジアゾール－３－または５－イルカルボニル、１，２，５－チアジアゾール－３－または４－イルカルボニル、１，３，４－チアジアゾール－２－イルカルボニルなどのチアジアゾリルカルボニル；２－または３－ピロリジニルカルボニルなどのピロリジニルカルボニル；２－、３－または４－ピリジルカルボニルなどのピリジルカルボニル；２－、３－または４－ピリジル－Ｎ－オキシドカルボニルなどの窒素原子が酸化されたピリジルカルボニル；３－または４－ピリダジニルカルボニルなどのピリダジニルカルボニル；３－、４－、５－または６－ピリダジニル－Ｎ－オキシドカルボニルなどの１個または両方の窒素原子が酸化されたピリダジニル；２－、４－または５－ピリミジニルカルボニルなどのピリミジニルカルボニル；２－、４－、５－または６－ピリミジニル－Ｎ－オキシドカルボニルなどの１個または両方の窒素原子が酸化されたピリミジニルカルボニル；ピラジニルカルボニル；２－、３－または４－ピペリジニルカルボニルなどのピペリジニルカルボニル；ピペラジニルカルボニル；３Ｈ－インドール－２－または３－イルカルボニルなどのインドリルカルボニル；２－、３－または４－ピラニルカルボニルなどのピラニルカルボニル；２－、３－または４－チオピラニルカルボニルなどのチオピラニルカルボニル；３－、４－、５－、６－、７－または８－キノリルカルボニルなどのキノリルカルボニル；イソキノリルカルボニル；ピリド〔２，３－ｄ〕ピリミジニルカルボニル（例、ピリド〔２，３－ｄ〕ピリミジン－２－イルカルボニル）；１，５－、１，６－、１，７－、１，８－、２，６－または２，７－ナフチリジニルカルボニルなどのナフチリジニルカルボニル（例、１，５－ナフチリジン－２－または３－イルカルボニル）；チエノ〔２，３－ｄ〕ピリジルカルボニル（例、チエノ〔２，３－ｄ〕ピリジン－３－イルカルボニル）；ピラジノキノリルカルボニル（例、ピラジノ〔２，３－ｂ〕キノリン－２－イルカルボニル）；クロメニルカルボニル（例、２Ｈ－クロメン－２－または３－イルカルボニル等）等の窒素原子（オキシド化されていてもよい）、酸素原子、硫黄原子（モノまたはジオキシド化されていてもよい）などのヘテロ原子を１ないし４個含む５もしくは６員複素環－カルボニル基）、５もしくは６員複素環－アセチル基（例、２－ピロリルアセチル、３－イミダゾリルアセチル、５－イソオキサゾリルアセチル等の窒素原子（オキシド化されていてもよい）、酸素原子、硫黄原子（モノまたはジオキシド化されていてもよい）などのヘテロ原子を１ないし４個含む５もしくは６員複素環－アセチル基）等が用いられる。 As "acyl group" represented by R 2, R 3 and R 4, an acyl group having 1 to carbon atoms derived from an organic carboxylic acid 20. For example, C 1-7 alkanoyl groups (eg, formyl; C 1-6 alkyl-carbonyls such as acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyyl , etc.), C 6-14 aryl-carbonyl groups (eg, benzoyl). , Naphthalenecarbonyl, etc.), C 1-6 alkoxy-carbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, etc.), C 6-14 aryloxy-carbonyl group (eg, phenoxycarbonyl group), C 7-19 aralkyl-carbonyl group (eg, phenyl-C 1-4 alkylcarbonyl, benzhydryl such as benzylcarbonyl, phenethylcarbonyl, phenylpropylcarbonyl) Naftyl-C 1-4 alkylcarbonyl such as carbonyl, naphthylethylcarbonyl), C 7-19 aralkyloxy-carbonyl group (eg, phenyl-C 1-4 alkyloxycarbonyl such as benzyloxycarbonyl), 5 or 6 A member heterocyclic carbonyl group or a fused heterocyclic carbonyl group thereof (eg, pyrrolylcarbonyl such as 2- or 3-pyrrolylcarbonyl; pyrazolylcarbonyl such as 3-, 4- or 5-pyrazolylcarbonyl; 2-, 4- Or imidazolylcarbonyl such as 5-imidazolylcarbonyl; triazolylcarbonyl such as 1,2,3-triazole-4-ylcarbonyl, 1,2,4-triazole-3-ylcarbonyl; 1H- or 2H-tetrazole-5. -Tetrazolyl carbonyls such as ylcarbonyl; frill carbonyls such as 2- or 3-furyl carbonyls; thienyl carbonyls such as 2- or 3-thienyl carbonyls; oxazoli such as 2-, 4- or 5-oxazolyl carbonyls. Rucarbonyl; isoxazolylcarbonyl such as 3-, 4- or 5-isoxazolylcarbonyl; 1,2,3-oxadiazol-4- or 5-ylcarbonyl, 1,2,4-oxadi Oxadiazolylcarbonyls such as azole-3- or 5-ylcarbonyl, 1,2,5-oxadiazol-3- or 4-ylcarbonyl, 1,3,4-oxadiazol-2-ylcarbonyl; 2 -Thiazolylcarbo such as 4-, 4- or 5-thiazolylcarbonyl Nyl; isothiazolylcarbonyls such as 3-, 4- or 5-isothiazolylcarbonyl; 1,2,3-thiadiazol-4- or 5-ylcarbonyl, 1,2,4-thiadiazol-3- or 5- Thiasiazolylcarbonyl such as ylcarbonyl, 1,2,5-thiadiazol-3- or 4-ylcarbonyl, 1,3,4-thiadiazol-2-ylcarbonyl; pyrrolyl such as 2- or 3-pyrrolidinylcarbonyl Dinylcarbonyl; pyridylcarbonyl such as 2-,3- or 4-pyridylcarbonyl; pyridylcarbonyl with oxidized nitrogen atoms such as 2-,3- or 4-pyridyl-N-oxidecarbonyl; 3- or 4-pyridyl Pyridadinyl carbonyls such as dazinyl carbonyls; pyridadinyls in which one or both nitrogen atoms such as 3-, 4-, 5- or 6-pyridaddinyl-N-oxide carbonyls are oxidized; 2-, 4- or Pyrimidinylcarbonyls such as 5-pyrimidinylcarbonyl; pyrimidinylcarbonyls in which one or both nitrogen atoms such as 2-,4-,5- or 6-pyrimidinyl-N-oxidecarbonyl are oxidized; pyramidinylcarbonyl; 2-, Piperidinyl carbonyls such as 3- or 4-piperidinyl carbonyls; piperazinyl carbonyls; indolyl carbonyls such as 3H-indole-2- or 3-ylcarbonyl; 2-, 3- or 4-pyranyl carbonyls and the like. Pyranylcarbonyls; thiopyranylcarbonyls such as 2-, 3- or 4-thiopyranylcarbonyls; quinolylcarbonyls such as 3-, 4-, 5-, 6-, 7- or 8-quinolylcarbonyls; Isoquinolylcarbonyl; pyrido [2,3-d] pyrimidinylcarbonyl (eg, pyrido [2,3-d] pyrimidin-2-ylcarbonyl); 1,5-, 1,6-, 1,7-1, , 8-, 2,6- or 2,7-naphthylidineylcarbonyl (eg, 1,5-naphthylidine-2- or 3-ylcarbonyl); thieno [2,3-d] pyridyl Carbonyl (eg, thieno [2,3-d] pyridine-3-ylcarbonyl); pyradinoquinolylcarbonyl (eg, pyrazino [2,3-b] quinoline-2-ylcarbonyl); chromenylcarbonyl (eg, eg) Nitrogen atoms (which may be oxidized) such as 2H-chromen-2- or 3-ylcarbonyl), oxygen atoms, sulfur atoms (mono or dioxidized) A 5- or 6-membered heterocyclic-carbonyl group containing 1 to 4 heteroatoms such as (may be)), a 5- or 6-membered heterocyclic-acetyl group (eg, 2-pyrrolylacetyl, 3-imidazolylacetyl, 5 or 6 containing 1 to 4 heteroatoms such as nitrogen atom (which may be oxidized) such as 5-isooxazolylacetyl, oxygen atom, sulfur atom (which may be mono or dioxidized). A member heterocycle-acetyl group) or the like is used.
　アシル基の置換基に関し、例えば、上記アシル基が、アルカノイル基またはアルコキシ－カルボニル基の場合、該アシル基は１～３個のアルキルチオ基（例、メチルチオ、エチルチオ、ｎ－プロピルチオ、イソプロピルチオ等のＣ１－４アルキルチオなど）、ハロゲン（例、フッ素、塩素、臭素、ヨウ素）、アルコキシ基（例、メトキシ、エトキシ、ｎ－プロポキシ、ｔｅｒｔ－ブトキシ、ｎ－ヘキシルオキシ等のＣ１－６アルコキシなど）、ニトロ基、アルコキシ－カルボニル基（例、メトキシカルボニル、エトキシカルボニル、ｎ－プロポキシカルボニル、イソプロポキシカルボニル、ｎ－ブトキシカルボニル、イソブトキシカルボニル、ｓｅｃ－ブトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル等のＣ１－６アルコキシ－カルボニルなど）、アルキルアミノ基（例、メチルアミノ、エチルアミノ、ｎ－プロピルアミノ、ｎ－ブチルアミノ、ｔｅｒｔ－ブチルアミノ、ｎ－ペンチルアミノ、ｎ－ヘキシルアミノ、ジメチルアミノ、ジエチルアミノ、メチルエチルアミノ、ジ－（ｎ－プロピル）アミノ、ジ－（ｎ－ブチル）アミノ等のモノ－もしくはジ－Ｃ１－６アルキルアミノなど）、アルコキシイミノ基（例、メトキシイミノ、エトキシイミノ、ｎ－プロポキシイミノ、ｔｅｒｔ－ブトキシイミノ、ｎ－ヘキシルオキシ－イミノ等のＣ１－６アルコキシイミノなど）またはヒドロキシイミノで置換されていてもよい。 Regarding the substituent of the acyl group, for example, when the acyl group is an alkanoyl group or an alkoxy-carbonyl group, the acyl group may be 1 to 3 alkylthio groups (eg, methylthio, ethylthio, n-propylthio, isopropylthio and the like. C 1-4 alkylthio, etc.), halogen (eg, fluorine, chlorine, bromine, iodine), alkoxy groups (eg, methoxy, ethoxy, n-propoxy, tert-butoxy, n-hexyloxy, etc., C 1-6 alkoxy, etc. ), a nitro group, an alkoxy - carbonyl group (e.g., methoxycarbonyl, ethoxycarbonyl, n- propoxycarbonyl, isopropoxycarbonyl, n- butoxycarbonyl, isobutoxycarbonyl, sec- butoxycarbonyl, etc. tert- butoxycarbonyl C 1- 6 alkoxy-carbonyl, etc.), alkylamino groups (eg, methylamino, ethylamino, n-propylamino, n-butylamino, tert-butylamino, n-pentylamino, n-hexylamino, dimethylamino, diethylamino, methyl Mono- or di-C 1-6 alkylamino such as ethylamino, di- (n-propyl) amino, di- (n-butyl) amino), alkoxyimimino groups (eg, methoxyimino, ethoxyimino, n- It may be substituted with propoxyimino, tert-butoxyimino, C 1-6 alkoxyimino such as n-hexyloxy-imino) or hydroxyimino.
　また、上記アシル基がアリール－カルボニル基、アリールオキシ－カルボニル基、アラルキル－カルボニル基、アラルキルオキシカルボニル基、５もしくは６員複素環－カルボニル基または５もしくは６員複素環－アセチル基の場合、１～５個（好ましくは１～３個）のアルキル基（例、メチル、エチル、ｎ－プロピル、イソプロピル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ｎ－ペンチル、ｓｅｃ－ペンチル、イソペンチル、ネオペンチル、ｎ－ヘキシル、イソヘキシルなどのＣ１－６アルキル、シクロヘキシルなどのＣ３－６シクロアルキルなど）、アルケニル基（例、アリル、イソプロペニル、イソブテニル、１－メチルアリル、２－ペンテニル、２－ヘキセニルなどのＣ２－６アルケニルなど）、アルキニル基（例、プロパルギル、２－ブチニル、３－ブチニル、３－ペンチニル、３－ヘキシニルなどのＣ２－６アルキニルなど）、アルコキシ基（例、メトキシ、エトキシ、ｎ－プロポキシ、ｔｅｒｔ－ブトキシ、ｎ－ヘキシルオキシなどのＣ１－６アルコキシなど）、アシル基［例、ホルミル、アセチル、プロピオニル、ブチリル、イソブチリル、ペンタノイル、ヘキサノイル、ヘプタノイルなどのＣ１－７アルカノイル；ベンゾイル、ナフタレンカルボニルなどのＣ６－１４アリール－カルボニル；メトキシカルボニル、エトキシカルボニル、プロポキシカルボニル、イソプロポキシカルボニル、ブトキシカルボニル、イソブトキシカルボニル、ｓｅｃ－ブトキシカルボニル、ｔｅｒｔ－ブトキシカルボニルなどのＣ１－６アルコキシ－カルボニル；フェノキシカルボニルなどの、Ｃ６－１４アリールオキシ－カルボニル；フェニル－Ｃ１－４アルキル－カルボニル（例、ベンジルカルボニル、フェネチルカルボニル、フェニルプロピルカルボニルなど）などのＣ７－１９アラルキル－カルボニル；フェニル－Ｃ１－４アルキルオキシ－カルボニル（例、ベンジルオキシカルボニルなど）などのＣ７－１９アラルキルオキシ－カルボニルなど］、ニトロ、アミノ、ヒドロキシ、シアノ、スルファモイル、メルカプト、ハロゲン（例、フッ素、塩素、臭素、ヨウ素）、またはアルキルチオ基（メチルチオ、エチルチオ、ｎ－プロピルチオ、イソブチルチオなどのＣ１－４アルキルチオなど）で置換されていてもよい。 When the acyl group is an aryl-carbonyl group, an aryloxy-carbonyl group, an aralkyl-carbonyl group, an aralkyloxycarbonyl group, a 5- or 6-membered heterocyclic-carbonyl group or a 5- or 6-membered heterocyclic-acetyl group, 1 ~ 5 (preferably 1-3) alkyl groups (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl) , Neopentyl, n-hexyl, C 1-6 alkyl such as isohexyl, C 3-6 cycloalkyl such as cyclohexyl, etc.), alkenyl groups (eg, allyl, isopropenyl, isobutenyl, 1-methylallyl, 2-pentenyl, 2- C 2-6 alkenyl such as hexenyl ), alkynyl group (eg, C 2-6 alkynyl such as propargyl, 2-butynyl, 3-butynyl, 3-pentynyl, 3-hexynyl), alkoxy group (eg, methoxy, etc.) C 1-6 alkoxy such as ethoxy, n-propoxy, tert-butoxy, n-hexyloxy, etc.), acyl group [eg, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyyl, etc. C 1-7 alkanoyl; benzoyl, C 6-14 aryl, such as naphthalene carbonyl - carbonyl; methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec- butoxycarbonyl, such as tert- butoxycarbonyl C 1- 6 Alkoxy-carbonyl; C 6-14 aryloxy-carbonyl such as phenoxycarbonyl; C 7-19 aralkyl-such as phenyl-C 1-4 alkyl-carbonyl (eg, benzylcarbonyl, phenethylcarbonyl, phenylpropylcarbonyl, etc.) Carbonyl; C 7-19 aralkyloxy-carbonyl such as phenyl-C 1-4 alkyloxy-carbonyl (eg, benzyloxycarbonyl, etc.)], nitro, amino, hydroxy, cyano, sulfamoyl, mercapto, halogen (eg, fluorine). , Chlorine, bromine, iodine), or an alkylthio group (such as C 1-4 alkylthio such as methylthio, ethylthio, n-propylthio, isobutylthio, etc.).
　Ｒ２、Ｒ３およびＲ４で示される「ハロゲン原子」としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子が挙げられる。 "Halogen atom" represented by R 2, R 3 and R 4, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom.
　Ｒ２としては、水素原子、置換されていてもよい炭化水素基、置換されていてもよいチエニル基、置換されていてもよいベンゾ［ｂ］チエニル基、置換されていてもよいフリル基、置換されていてもよいピリジル基、置換されていてもよいピラゾリル基または置換されていてもよいピリミジニル基が好ましく、なかでも水素原子、置換されていてもよい炭化水素基、置換されていてもよいチエニル基、置換されていてもよいベンゾ［ｂ］チエニル基、置換されていてもよいフリル基または置換されていてもよいピリジル基が好ましく、水素原子または置換されていてもよい炭化水素基がより好ましく、特に、水素原子または置換されていてもよいアリール基が好ましい。 Examples of R 2 include a hydrogen atom, a hydrocarbon group which may be substituted, a thienyl group which may be substituted, a benzo [b] thienyl group which may be substituted, a frill group which may be substituted, and a substitution. Pyridyl groups which may be substituted, pyrazolyl groups which may be substituted, or pyrimidinyl groups which may be substituted are preferable, among which a hydrogen atom, a hydrocarbon group which may be substituted, and thienyl which may be substituted may be substituted. Groups, optionally substituted benzo [b] thienyl groups, optionally substituted frill groups or optionally substituted pyridyl groups are preferred, and hydrogen atoms or optionally substituted hydrocarbon groups are more preferred. In particular, a hydrogen atom or an optionally substituted aryl group is preferred.
　具体的には、Ｒ２としては、
［１］水素原子、
［２］（ｉ）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、（ｉｉ）シアノ、（ｉｉｉ）Ｃ１－６アルキル（例えば、メチル、エチル等）またはアセチルで１または２個置換されていてもよいアミノ、（ｉｖ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルキル（例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル等）、（ｖ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルコキシ（例、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ペンチルオキシ、ヘキシルオキシ等）、（ｖｉ）フェノキシ、（ｖｉｉ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルキルチオ（例、メチルチオ、エチルチオ等）、（ｖｉｉｉ）アセチルおよび（ｉｘ）アミノカルボニルから選ばれる１～５個（好ましくは１～３個）の置換基で置換されていてもよいＣ６－１４アリール基（例、フェニル基）、または
［３］Ｃ１－６アルコキシ（例、メトキシ、エトキシ等）およびＣ１－６アルキル（例、メチル、エチル、ｎ－プロピル、イソブチル等）から選ばれる１～３個の置換基（好ましくは１～３個のＣ１－６アルコキシ）で置換されていてもよい、チエニル基、ベンゾ［ｂ］チエニル基、フリル基、ピリジル基、ピラゾリル基またはピリミジニル基〔なかでも１～３個のＣ１－６アルコキシで置換されていてもよい、チエニル基、ベンゾ［ｂ］チエニル基、フリル基またはピリジル基が好ましい〕が好ましく、特に、（ｉ）水素原子または（ｉｉ）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）で１～５個（好ましくは１～３個）置換されていてもよいＣ６－１４アリール基（例、フェニル基）が好ましい。 Specifically, as R 2,
[1] Hydrogen atom,
[2] (i) Halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), (ii) cyano, (iii) C 1-6 alkyl (eg, methyl, ethyl, etc.) or 1 or acetyl. 2 may be substituted Amino, (iv) Halogen (eg, fluorine, chlorine, bromine, iodine) may be substituted 1 to 5 (preferably 1 to 3) C 1-6 alkyl (preferably 1 to 3). For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), (v) Halogen (eg, fluorine, chlorine, bromine, iodine) 1 to 5 (preferably). C 1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.), (vi) phenoxy, which may be substituted. (Vii) C 1-6 alkylthios (eg, methylthio, ethylthio, etc.), which may be substituted with 1-5 (preferably 1-3) halogens (eg, fluorine, chlorine, bromine, iodine), (viii). C 6-14 aryl groups (eg, phenyl groups), which may be substituted with 1-5 (preferably 1-3) substituents selected from acetyl and (ix) aminocarbonyl, or [3]. 1-3 substituents (preferably 1-3) selected from C 1-6 alkoxy (eg, methoxy, ethoxy, etc.) and C 1-6 alkyl (eg, methyl, ethyl, n-propyl, isobutyl, etc.) C 1-6 alkoxy) may be substituted with a thienyl group, a benzo [b] thienyl group, a fryl group, a pyridyl group, a pyrazolyl group or a pyrimidinyl group [among others, 1 to 3 C 1-6 alkoxys. Substituentally substituted thienyl groups, benzo [b] thienyl groups, frills or pyridyl groups are preferred], in particular (i) hydrogen atoms or (ii) halogen atoms (eg, fluorine atoms, chlorine atoms, etc.). A C 6-14 aryl group (eg, a phenyl group) which may be substituted with 1 to 5 (preferably 1 to 3) with a bromine atom (bromine atom, iodine atom) is preferable.
　Ｒ３およびＲ４としては、同一または異なって、水素原子または置換されていてもよい炭化水素基、アシル基、ハロゲン原子、シアノ基またはニトロ基が好ましい。
　中でも、水素原子、Ｃ１－６アルキル基（例、メチル、エチル、ｎ－プロピル、イソブチル等）、Ｃ６－１４アリール基（例、フェニル等）、Ｃ１－６アルキル－カルボニル基（例、アセチル、プロピオニル、ブチリル、イソブチリル、ペンタノイル、ヘキサノイル、ヘプタノイル等）、ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、シアノ基またはニトロ基が好ましく、特に、水素原子、Ｃ１－６アルキル基（例、メチル、エチル、ｎ－プロピル、イソブチル等）、Ｃ１－６アルキル－カルボニル基（例、アセチル、プロピオニル、ブチリル、イソブチリル、ペンタノイル、ヘキサノイル、ヘプタノイル等）、ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、シアノ基またはニトロ基が好ましい。 As R 3 and R 4 , the same or different hydrogen atom or optionally substituted hydrocarbon group, acyl group, halogen atom, cyano group or nitro group is preferable.
Among them, a hydrogen atom, a C 1-6 alkyl group (eg, methyl, ethyl, n-propyl, isobutyl, etc.), a C 6-14 aryl group (eg, phenyl, etc.), a C 1-6 alkyl-carbonyl group (eg, eg, phenyl, etc.). Acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyle, etc.), halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), cyano group or nitro group are preferable, and hydrogen atom, C 1- 6 Alkyl group (eg, methyl, ethyl, n-propyl, isobutyl, etc.), C 1-6 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyle, etc.), halogen atom (eg, heptanoyle, etc.) Fluorine atom, chlorine atom, bromine atom, iodine atom), cyano group or nitro group are preferable.
　前記式（Ｉ）中、Ｒ５およびＲ６は、同一または異なって、水素原子または置換されていてもよい炭化水素基を示す。 In the above formula (I), R 5 and R 6 are the same or different and are each a hydrogen atom or an optionally substituted hydrocarbon group.
　Ｒ５およびＲ６で示される「置換されていてもよい炭化水素基」としては、前記Ｒ４０で示される「置換されていてもよい炭化水素基」と同様の基が挙げられる。
　Ｒ５およびＲ６としては、特に、それぞれ独立して水素原子またはＣ１－６アルキル基（例、メチル、エチル、ｎ－プロピル、イソブチル等）が好ましい。 As "optionally substituted hydrocarbon group" represented by R 5 and R 6, include the same groups as "optionally substituted hydrocarbon group" represented by R 40.
As R 5 and R 6 , hydrogen atoms or C 1-6 alkyl groups (eg, methyl, ethyl, n-propyl, isobutyl, etc.) are particularly preferable independently of each other.
　また別の態様として、化合物（Ｉ）に含まれる化合物の中でも特に好ましい化合物は次の〔ｄ〕である。
　〔ｄ〕式（ＩＩ－ｄ）
Figure JPOXMLDOC01-appb-C000006
 ［式中、Ｒ１０１は、ベンゼン環もしくは複素環と縮合していてもよい単環式含窒素複素環基を示し、該ベンゼン環もしくは複素環と縮合していてもよい単環式含窒素複素環基は任意に置換基を有していてもよく、Ｒ１０２は、置換されていてもよいＣ６－１４アリール基または置換されていてもよいチエニル基を示し、Ｒ１０３およびＲ１０４は、それぞれ水素原子を示すか、あるいはＲ１０３およびＲ１０４の一方が水素原子を示し、他方が置換されていてもよい低級アルキル基、アシル基、ハロゲン原子、シアノ基またはニトロ基を示し、Ｒ１０５は、アルキル基を示す］で表される化合物またはその塩。 As another aspect, among the compounds contained in the compound (I), a particularly preferable compound is the following [d].
[D] Equation (II-d)
Figure JPOXMLDOC01-appb-C000006
 [In the formula, R 101 represents a monocyclic nitrogen-containing heterocyclic group that may be fused with a benzene ring or a heterocycle, and may be fused with the benzene ring or a heterocycle. The ring group may optionally have a substituent, R 102 represents a optionally substituted C 6-14 aryl group or an optionally substituted thienyl group, and R 103 and R 104 are Each of them represents a hydrogen atom, or one of R 103 and R 104 represents a hydrogen atom and the other represents a lower alkyl group, an acyl group, a halogen atom, a cyano group or a nitro group which may be substituted, where R 105 is , Indicates an alkyl group] or a salt thereof.
　式（ＩＩ－ｄ）中、Ｒ１０１で示される「ベンゼン環もしくは複素環と縮合していてもよい単環式含窒素複素環基」としては、
（１）単環式含窒素複素環基、または
（２）式
Figure JPOXMLDOC01-appb-C000007
 で表される縮合環基（式中、環Ａは単環式含窒素複素環基を、環Ｂはベンゼン環もしくは複素環を示し、ａおよびｂは橋頭の環構成原子（例、炭素原子、窒素原子など）を示し、
Figure JPOXMLDOC01-appb-C000008
 In the formula (II-d), the "monocyclic nitrogen-containing heterocyclic group which may be condensed with a benzene ring or a heterocycle" represented by R 101 is referred to as "a monocyclic nitrogen-containing heterocyclic group".
(1) Monocyclic nitrogen-containing heterocyclic group or equation (2)
Figure JPOXMLDOC01-appb-C000007
 (In the formula, ring A represents a monocyclic nitrogen-containing heterocyclic group, ring B represents a benzene ring or a heterocycle, and a and b are ring-constituting atoms at the bridge head (eg, carbon atom,). (Nitrogen atom, etc.)
Figure JPOXMLDOC01-appb-C000008
は単結合または二重結合を示す。なお、式（ＩＩ―ｄ）における－ＳＯ２－基への結合手は、橋頭の環構成原子ａおよびｂ以外の環Ａを構成する原子（環原子）に有する。）が挙げられる。 Indicates a single bond or a double bond. It should be noted that the bond to the -SO 2 -group in the formula (II-d) is possessed by the atoms (ring atoms) constituting the ring A other than the ring-constituting atoms a and b of the bridge head. ).
　ここで、環Ａは、環Ａを構成する原子（環原子）として、窒素原子を少なくとも１個（好ましくは１ないし４個、さらに好ましくは１ないし２個）含んでいればよく、橋頭の環構成原子ａおよびｂの一方または両方だけが窒素原子であってもよい。 Here, the ring A may contain at least one nitrogen atom (preferably 1 to 4, more preferably 1 or 2) as an atom (ring atom) constituting the ring A, and the ring of the bridgehead. Only one or both of the constituent atoms a and b may be nitrogen atoms.
　「ベンゼン環もしくは複素環と縮合していてもよい単環式含窒素複素環基」は任意に置換基を有していてもよく、該置換基は環Ａおよび環Ｂのいずれに有していてもよい。 The "monocyclic nitrogen-containing heterocyclic group that may be condensed with a benzene ring or a heterocycle" may optionally have a substituent, and the substituent is contained in either ring A or ring B. You may.
　「ベンゼン環もしくは複素環と縮合していてもよい単環式含窒素複素環基」および上記環Ａにおける「単環式含窒素複素環基」としては、例えば、環を構成する原子（環原子）として窒素原子を少なくとも１個（好ましくは１ないし４個、さらに好ましくは１ないし２個）含む芳香族単環式含窒素複素環基、飽和あるいは不飽和の非芳香族単環式含窒素複素環基（脂肪族単環式含窒素複素環基）等が挙げられる。 The "monocyclic nitrogen-containing heterocyclic group that may be condensed with a benzene ring or a heterocycle" and the "monocyclic nitrogen-containing heterocyclic group" in the above ring A include, for example, atoms constituting the ring (ring atom). ), An aromatic monocyclic nitrogen-containing heterocyclic group containing at least one nitrogen atom (preferably 1 to 4, more preferably 1 to 2), a saturated or unsaturated non-aromatic monocyclic nitrogen-containing heterocycle. Cyclic (aliphatic monocyclic nitrogen-containing heterocyclic group) and the like can be mentioned.
　該「芳香族単環式含窒素複素環基」としては、例えば、ピロリル、オキサゾリル、イソオキサゾリル、チアゾリル、イソチアゾリル、イミダゾリル（１Ｈ－イミダゾール－１－イル、１Ｈ－イミダゾール－４－イル等）、ピラゾリル、１，２，３－オキサジアゾリル、１，２，４－オキサジアゾリル、１，３，４－オキサジアゾリル、フラザニル、１，２，３－チアジアゾリル、１，２，４－チアジアゾリル、１，３，４－チアジアゾリル、１，２，３－トリアゾリル、１，２，４－トリアゾリル（１，２，４－トリアゾリル－１－イル、１，２，４－トリアゾリル－４－イル等）、テトラゾリル、ピリジル（２－、３－又は４－ピリジル等）、ピリダジニル、ピリミジニル、ピラジニル、トリアジニル等の芳香族単環式含窒素複素環基およびそのＮ－オキシド体等が挙げられ、なかでも、５～６員の芳香族単環式含窒素複素環基が好ましく、中でもチアゾリル、イミダゾリル、ピラゾリル、ピリジル、ピリミジニル、ピリダジニルが好ましく、とりわけ、ピリジルが好ましい。 Examples of the "aromatic monocyclic nitrogen-containing heterocyclic group" include pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl (1H-imidazole-1-yl, 1H-imidazole-4-yl, etc.), pyrazolyl, and the like. 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, frazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl (1,2,4-triazolyl-1-yl, 1,2,4-triazolyl-4-yl, etc.), tetrazolyl, pyridyl (2,3) -Or 4-pyridyl, etc.), aromatic monocyclic nitrogen-containing heterocyclic groups such as pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, and N-oxides thereof, among which 5 to 6-membered aromatic monocycles are mentioned. The formula nitrogen-containing heterocyclic group is preferable, among which thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl and pyridadinyl are preferable, and pyridyl is particularly preferable.
　「飽和あるいは不飽和の非芳香族単環式含窒素複素環基」としては、上記した「芳香族単環式含窒素複素環基」の部分還元体（例、イミダゾリニル、テトラヒドロピリミジニルなど）の他、例えば、アゼチジニル、ピロリジニル、ピペリジル（２－、３－又は４－ピペリジル）、モルホリニル、チオモルホリニル、ピペラジニル（１－ピペラジニル等）、ホモピペラジニル等が挙げられ、なかでも、５～６員の非芳香族単環式含窒素複素環基が好ましい。 The "saturated or unsaturated non-aromatic monocyclic nitrogen-containing heterocyclic group" includes a partially reduced product of the above-mentioned "aromatic monocyclic nitrogen-containing heterocyclic group" (eg, imidazolinyl, tetrahydropyrimidinyl, etc.). For example, azetidinyl, pyrrolidinyl, piperidyl (2-, 3- or 4-piperidyl), morpholinyl, thiomorpholinyl, piperazinyl (1-piperazinyl, etc.), homopiperazinyl, etc., among which 5 to 6 members of non-aromatic singles are mentioned. Cyclic nitrogen-containing heterocyclic groups are preferred.
　単環式含窒素複素環基と縮合していてもよい「複素環」としては、例えば、芳香族複素環または非芳香族複素環が挙げられる。
　「芳香族複素環」としては、例えば、フラン環、チオフェン環、ピロール環、オキサゾール環、イソオキサゾール環、チアゾール環、イソチアゾール環、イミダゾール環、ピラゾール環、１，２，３－オキサジアゾール環、１，２，４－オキサジアゾール環、１，３，４－オキサジアゾール環、フラザン環、１，２，３－チアジアゾール環、１，２，４－チアジアゾール環、１，３，４－チアジアゾール環、１，２，３－トリアゾール環、１，２，４－トリアゾール環、テトラゾール環、ピリジン環、ピリダジン環、ピリミジン環、ピラジン環、トリアジン環等の５または６員の芳香族単環式複素環、および、例えば、ベンゾフラン環、イソベンゾフラン環、ベンゾ〔ｂ〕チオフェン環、インドール環、イソインドール環、１Ｈ－インダゾール環、ベンズインダゾール環、ベンゾオキサゾール環、１，２－ベンゾイソオキサゾール環、ベンゾチアゾール環、ベンゾピラン環、１，２－ベンゾイソチアゾール環、１Ｈ－ベンゾトリアゾール環、キノリン環、イソキノリン環、シンノリン環、キナゾリン環、キノキサリン環、フタラジン環、ナフチリジン環、プリン環、プテリジン環、カルバゾール環、α－カルボリン環、β－カルボリン環、γ－カルボリン環、アクリジン環、フェノキサジン環、フェノチアジン環、フェナジン環、フェノキサチイン環、チアントレン環、フェナトリジン環、フェナトロン環、インドリジン環、ピロロ〔１，２－ｂ〕ピリダジン環、ピラゾロ〔１，５－ａ〕ピリジン環、イミダゾ〔１，２－ａ〕ピリジン環、イミダゾ〔１，５－ａ〕ピリジン環、イミダゾ〔１，２－ｂ〕ピリダジン環、イミダゾ〔１，２－ａ〕ピリミジン環、１，２，４－トリアゾロ〔４，３－ａ〕ピリジン環、１，２，４－トリアゾロ〔４，３－ｂ〕ピリダジン環等の８ないし１２員の芳香族縮合複素環（好ましくは、前記した５または６員の芳香族単環式複素環がベンゼン環と縮合した複素環または前記した５または６員の芳香族単環式複素環の同一または異なった複素環２個が縮合した複素環、より好ましくは前記した５または６員の芳香族単環式複素環基がベンゼン環と縮合した複素環、好ましくはイミダゾピリミジニル等）等が挙げられる。
　「非芳香族複素環」としては、例えば、オキシラン環、アゼチジン環、オキセタン環、チエタン環、ピロリジン環、テトラヒドロフラン環、チオラン環、ピペリジン環、テトラヒドロピラン環、モルホリン環、チオモルホリン環、ピペラジン環、３－ヘキサヒドロシクロペンタ〔ｃ〕ピロール環、ホモピペリジン環、ホモピペラジン環等の３ないし８員の飽和あるいは不飽和の非芳香族複素環等、あるいはジヒドロピリジン環、ジヒドロピリミジン環、１，２，３，４－テトラヒドロキノリン環、１，２，３，４－テトラヒドロイソキノリン環などのように前記した芳香族単環式複素環又は芳香族縮合複素環の一部又は全部の二重結合が飽和した非芳香族複素環等が挙げられる。 Examples of the "heterocycle" that may be condensed with a monocyclic nitrogen-containing heterocyclic group include aromatic heterocycles and non-aromatic heterocycles.
Examples of the "aromatic heterocycle" include a furan ring, a thiophene ring, a pyrrole ring, an oxazole ring, an isooxazole ring, a thiazole ring, an isothiazole ring, an imidazole ring, a pyrazole ring, and a 1,2,3-oxadiazole ring. , 1,2,4-oxadiazole ring, 1,3,4-oxadiazole ring, frazan ring, 1,2,3-thiadiazole ring, 1,2,4-thiadiazole ring, 1,3,4- 5- or 6-membered aromatic monocyclic type such as thiadiazole ring, 1,2,3-triazole ring, 1,2,4-triazole ring, tetrazole ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, etc. Heterocycles and, for example, benzofuran ring, isobenzofuran ring, benzo [ b ] thiophene ring, indole ring, isoindole ring, 1H-indazole ring, benzindazole ring, benzoxazole ring, 1,2-benzoisoxazole ring, Heterothiazole ring, benzopyran ring, 1,2-benzoisothiazole ring, 1H-benzotriazole ring, quinoline ring, isoquinoline ring, cinnoline ring, quinazoline ring, quinoxalin ring, phthalazine ring, naphthylidine ring, purine ring, pteridine ring, carbazole. Ring, α-carbolin ring, β-carbolin ring, γ-carbolin ring, aclysine ring, phenoxazine ring, phenothiazine ring, phenazine ring, phenoxatiin ring, thiantolen ring, phenatridine ring, phenatron ring, indridin ring, pyroro [ 1,2- b ] pyridazine ring, pyrazolo [1,5- a ] pyridine ring, imidazo [1,2- a ] pyridine ring, imidazo [1,5- a ] pyridine ring, imidazo [1,2- b ] 8 such as pyridazine ring, imidazo [1,2- a ] pyrimidine ring, 1,2,4-triazolo [4,3- a ] pyridine ring, 1,2,4-triazolo [4,3- b ] pyridazine ring, etc. Or a 12-membered aromatic fused heterocycle (preferably a heterocycle in which the above-mentioned 5- or 6-membered aromatic monocyclic heterocycle is fused with a benzene ring or the above-mentioned 5- or 6-membered aromatic monocyclic heterocycle. A heterocycle in which two identical or different heterocycles are condensed, more preferably a heterocycle in which the above-mentioned 5- or 6-membered aromatic monocyclic heterocyclic group is condensed with a benzene ring, preferably imidazolipyrimidinyl or the like). Can be mentioned.
Examples of the "non-aromatic heterocycle" include an oxylane ring, an azetidine ring, an oxetane ring, a thietan ring, a pyrrolidine ring, a tetrahydrofuran ring, a thiolan ring, a piperidine ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholin ring, and a piperazine ring. 3-Hexahydrocyclopenta [ c ] 3- to 8-membered saturated or unsaturated non-aromatic heterocycles such as pyrrol ring, homopiperidine ring, homopiperazin ring, etc., or dihydropyridine ring, dihydropyrimidine ring, 1, 2, Part or all of the double bonds of the above-mentioned aromatic monocyclic heterocycle or aromatic fused heterocycle such as 3,4-tetrahydroquinoline ring, 1,2,3,4-tetrahydroisoquinoline ring are saturated. Examples include non-aromatic heterocycles.
　ベンゼン環もしくは複素環と縮合した単環式含窒素複素環基として好ましいものとしては、例えば、２－または３－インドリル、１－または３－イソインドリル、１Ｈ－インダゾール－３－イル、２－ベンズイミダゾリル、２－ベンゾオキサゾリル、３－ベンゾイソオキサゾリル、２－ベンゾチアゾリル、３－ベンゾイソチアゾリル、２－、３－または４－キノリル、１－、３－または４－イソキノリル、３－または４－シンノリニル、２－または４－キナゾリニル、２－または３－キノキサリニル、１－または４－フタラジニル、ナフチリジニル、プリニル、プテリジニル、１，７－フェナントロリン－２－、３－または４－イル、１－、２－または３－インドリジニル、ピロロ〔１，２－ｂ〕ピリダジニル、ピラゾロ〔１，５－ａ〕ピリジル、イミダゾ〔１，２－ａ〕ピリジル、イミダゾ〔１，２－ｂ〕ピラゾリル、イミダゾ〔１，５－ａ〕ピリジル、イミダゾ〔４，５－ｃ〕ピリジル、ピラゾロ〔１，５－ａ〕ピリミジニル、ピラゾロ〔１，５－ｃ〕ピリミジニル、ピラゾロ〔３，４－ｄ〕ピリミジニル、イミダゾ〔１，２－ｂ〕ピリダジニル、イミダゾ〔１，５－ｂ〕ピリダジニル、ピラゾロ〔３，４－ｂ〕ピリジル、イミダゾ〔１，２－ａ〕ピリミジニル、１，２，４－トリアゾロ〔４，３－ａ〕ピリジル、１，２，４－トリアゾロ〔４，３－ｂ〕ピリダジニル、〔１，２，４〕トリアゾロ〔１，２－ａ〕ピリダジニル、〔１，２，３〕トリアゾロ〔１，５－ａ〕ピリミジニル、〔１，２，４〕トリアゾロ〔１，５－ｃ〕ピリミジニル、〔１，２，４〕トリアゾロ〔１，５－ａ〕ピリジル、〔１，２，４〕トリアゾロ〔４，３－ａ〕ピリジル、ピラゾロ〔５，１－ｂ〕チアゾリル、ピロロ〔２，１－ｆ〕〔１，２，４〕トリアジニル、ピロロ〔１，２－ｂ〕ピリダジニル、ピロロ〔２，３－ｄ〕ピリミジニル、ピロロ〔２，３－ｂ〕ピリジル、チエノ〔３，２－ｂ〕ピリミジニル、チエノ〔２，３－ｂ〕ピリジル、チエノ〔２，３－ｃ〕ピリジル、チエノ〔３，２－ｂ〕ピリジル、チエノ〔３，２－ｃ〕ピリジル、ピリド〔２，３－ｂ〕ピラジル、ピリド〔３，４－ｂ〕ピラジル、ピリド〔２，３－ｄ〕ピリミジニル、ピリド〔３，２－ｄ〕ピリミジニル、ピリド〔４，３－ｄ〕ピリミジニル等の８～１６員（好ましくは、８～１２員）の芳香族二環性縮合含窒素複素環基などの芳香族縮合含窒素複素環基などが挙げられる。該芳香族縮合含窒素複素環としては、ピリジン環が前記した５または６員の芳香族単環式含窒素複素環１～２個（好ましくは、１個）またはベンゼン環１～２個（好ましくは、１個）と縮合した縮合ピリジン（ただし、ベンゼン環と縮合する場合、ピリジン環に結合手を有する。）、およびピリミジン環が前記した５または６員の１～２個（好ましくは、１個）またはベンゼン環１～２個（好ましくは、１個）と縮合した縮合ピリミジン（ただし、ベンゼン環と縮合する場合、ピリミジン環に結合手を有する。）等が好ましい。 Preferred monocyclic nitrogen-containing heterocyclic groups fused with a benzene ring or a heterocycle include, for example, 2- or 3-indrill, 1- or 3-isoindrill, 1H-indazole-3-yl, 2-benzimidazolyl. , 2-benzoxazolyl, 3-benzoisoxazolyl, 2-benzothiazolyl, 3-benzoisothiazolyl, 2-, 3- or 4-quinolyl, 1-, 3- or 4-isoquinolyl, 3-or 4-Synnolinyl, 2- or 4-quinazolinyl, 2- or 3-quinoxalinyl, 1-or 4-phthalazinyl, naphthyldinyl, prynyl, pteridinyl, 1,7-phenanthroline-2-, 3- or 4-yl, 1-, 2- or 3-Indridinyl, Pyrrolo [1,2-b] Pyridadinyl, Pyrazolo [1,5-a] Pyridyl, Imidazo [1,2-a] Pyridyl, Imidazo [1,2-b] Pyrazolyl, Imidazo [1] , 5-a] pyridyl, imidazole [4,5-c] pyridyl, pyrazolo [1,5-a] pyrimidinyl, pyrazolo [1,5-c] pyrimidinyl, pyrazolo [3,4-d] pyrimidinyl, imidazole [1] , 2-b] pyridadinyl, imidazole [1,5-b] pyridadinyl, pyrazolo [3,4-b] pyridyl, imidazole [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] ] Pyridil, 1,2,4-triazolo [4,3-b] pyridadinyl, [1,2,4] triazolo [1,2-a] pyridadinyl, [1,2,3] triazolo [1,5-a] ] Pyrimidinyl, [1,2,4] triazolo [1,5-c] pyrimidinyl, [1,2,4] triazolo [1,5-a] pyridyl, [1,2,4] triazolo [4,3-] a] Pyridyl, Pyrazolo [5,1-b] Thiazolyl, Pyrrolo [2,1-f] [1,2,4] Triazinyl, Pyrrolo [1,2-b] Pyridadinyl, Pyrrolo [2,3-d] Pyrimidinyl , Pyrrolo [2,3-b] pyridyl, thieno [3,2-b] pyrimidinyl, thieno [2,3-b] pyridil, thieno [2,3-c] pyridyl, thieno [3,2-b] pyridyl , Thieno [3,2-c] pyridyl, pyrido [2,3-b] pyrazil, pyrido [3,4-b] pyrazil, pyrido [2,3-d] pyrimidinyl, pyrido [3,2-d] pyrimidinyl , Pyrido [4,3-d] pyrimidinyl and the like with 8 to 16 members (preferably 8 to 12 members), aromatic bicyclic condensed nitrogen-containing heterocyclic groups and the like, aromatic condensed nitrogen-containing heterocyclic groups and the like. Can be mentioned. As the aromatic condensed nitrogen-containing heterocycle, the pyridine ring has 1 to 2 (preferably 1) or 1 to 2 benzene rings (preferably) of the above-mentioned 5- or 6-membered aromatic monocyclic nitrogen-containing heterocycle. Is one or two (preferably 1) fused pyridines condensed with (1) (however, when condensed with a benzene ring, the pyridine ring has a bond) and the pyrimidine ring having the above-mentioned 5 or 6 members. Pyrimidine fused with 1 or 2 (preferably 1) benzene ring (however, when condensed with the benzene ring, the pyrimidine ring has a bond) and the like are preferable.
　該「非芳香族含窒素複素環」としては、例えば、アゼチジン、ピロリジン、イミダゾリジン、チアゾリジン、オキサゾリジン、ピペリジン、モルホリン、チオモルホリン、ピペラジン等の３～８員（好ましくは５～６員）の飽和あるいは不飽和（好ましくは飽和）の非芳香族含窒素複素環（脂肪族含窒素複素環）等、あるいは１，２，３，４－テトラヒドロキノリン、１，２，３，４－テトラヒドロイソキノリンなどのように前記した芳香族単環式含窒素複素環又は芳香族縮合含窒素複素環の一部又は全部の二重結合が飽和した非芳香族含窒素複素環等が挙げられる。 The "non-aromatic nitrogen-containing heterocycle" includes, for example, 3 to 8 members (preferably 5 to 6 members) saturated with azetidine, pyrrolidine, imidazolidine, thiazolidine, oxazolidine, piperidine, morpholin, thiomorpholin, piperazine and the like. Alternatively, an unsaturated (preferably saturated) non-aromatic nitrogen-containing heterocycle (aliphatic nitrogen-containing heterocycle) or the like, or 1,2,3,4-tetrahydroquinoline, 1,2,3,4-tetrahydroisoquinoline or the like. Examples thereof include the above-mentioned aromatic monocyclic nitrogen-containing heterocycle or non-aromatic nitrogen-containing heterocycle in which a part or all of the double bonds of the aromatic condensed nitrogen-containing heterocycle are saturated.
　「ベンゼン環もしくは複素環と縮合していてもよい単環式含窒素複素環基」としては、上記したものの中でも、５または６員の芳香族単環式含窒素複素環基が好ましく、中でもピリジル（例、２－、３－または４－ピリジル等）、ピリミジニル（例、２－、４－または５－ピリミジニル等）またはピリダジニル（例、３－または４－ピリダジニル等）などの６員芳香族含窒素複素環基が好ましく、ピリジルが特に好ましい。 As the "monocyclic nitrogen-containing heterocyclic group which may be condensed with a benzene ring or a heterocycle", among the above-mentioned ones, a 5- or 6-membered aromatic monocyclic nitrogen-containing heterocyclic group is preferable, and pyridil is particularly preferable. Includes 6-membered aromatics such as (eg, 2-, 3- or 4-pyridyl, etc.), pyrimidinyl (eg, 2-, 4- or 5-pyrimidinyl, etc.) or pyridadinyl (eg, 3- or 4-pyridazinyl, etc.) Nitrogen heterocyclic groups are preferred, and pyridyl is particularly preferred.
　該「ベンゼン環もしくは複素環と縮合していてもよい単環式含窒素複素環基」の有していてもよい置換基としては、上記Ｒ４０で示される「炭化水素基」がシクロアルキル、アリールまたはアラルキルである場合に有していてもよい置換基と同様の置換基が挙げられる。該置換基の位置は、置換可能な位置であれば特に限定されるものではなく、また、該置換基の数は１ないし５個、好ましくは１ないし３個である。 Examples of the "benzene ring or heterocyclic ring may be condensed with not monocyclic nitrogen-containing heterocyclic group" substituent which may have a, represented by R 40 "hydrocarbon group" is cycloalkyl, Examples include substituents similar to the substituents that may have if they are aryl or aralkyl. The position of the substituent is not particularly limited as long as it can be substituted, and the number of the substituents is 1 to 5, preferably 1 to 3.
　Ｒ１０２で示される「置換されていてもよいＣ６－１４アリール基」における「Ｃ６－１４アリール基」としては、例えば、フェニル、１－ナフチル、２－ナフチル、２－ビフェニリル、３－ビフェニリル、４－ビフェニリル、２－アンスリル等が挙げられる。
　該「Ｃ６－１４アリール基」の有していてもよい置換基としては、前記Ｒ１０１で示される「ベンゼン環もしくは複素環と縮合していてもよい単環式含窒素複素環基」が有していてもよい置換基と同様の基が挙げられる。該置換基の数は１ないし５個、好ましくは１ないし３個である。
　Ｒ１０２で示される「置換されていてもよいチエニル基」における「チエニル基」としては、２－または３－チエニルが挙げられる。
　該「チエニル基」の有していてもよい置換基としては、前記Ｒ１０１で示される「ベンゼン環もしくは複素環と縮合していてもよい単環式含窒素複素環基」が有していてもよい置換基と同様の基が挙げられる。該置換基の数は１ないし４個、好ましくは１ないし３個である。 Examples of the "C 6-14 aryl group" in the "optionally substituted C 6-14 aryl group" represented by R 102 include phenyl, 1-naphthyl, 2-naphthyl, 2-biphenylyl and 3-biphenylyl. , 4-Biphenylyl, 2-Anthril and the like.
As the substituent that the "C 6-14 aryl group" may have, the "monocyclic nitrogen-containing heterocyclic group that may be condensed with a benzene ring or a heterocycle" shown in R 101 is used. Examples include groups similar to the substituents that may have. The number of the substituents is 1 to 5, preferably 1 to 3.
Examples of the "thienyl group" in the "optionally substituted thienyl group" represented by R 102 include 2- or 3-thienyl.
As the substituent that the "thienyl group" may have, the "monocyclic nitrogen-containing heterocyclic group that may be condensed with a benzene ring or a heterocycle" shown in R 101 is included. Examples are similar to the good substituents. The number of the substituents is 1 to 4, preferably 1 to 3.
　Ｒ１０３およびＲ１０４で示される「置換されていてもよい低級アルキル基」における「低級アルキル基」としては、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチルなどのＣ１－４アルキル基等が挙げられる。
　該「低級アルキル基」の有していてもよい置換基としては、上記Ｒ４０で示される「炭化水素基」がアルキル、アルケニルまたはアルキニルである場合に有していてもよい置換基と同様の置換基が挙げられる。該置換基の数は１ないし３個である。
　Ｒ１０３およびＲ１０４で示される「アシル基」としては、上記Ｒ２、Ｒ３およびＲ４で示される「アシル基」と同様の基が挙げられる。
　Ｒ１０３およびＲ１０４で示される「ハロゲン原子」としては、フッ素、塩素、臭素、ヨウ素が挙げられる。 Examples of the "lower alkyl group" in the "optionally substituted lower alkyl group" represented by R 103 and R 104 include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. C 1-4 alkyl group and the like can be mentioned.
Examples of the substituent which may have a "lower alkyl group", represented by R 40 "hydrocarbon group" is alkyl, similar to the substituents that may have in the case of alkenyl or alkynyl Substituents can be mentioned. The number of the substituents is 1 to 3.
Examples of the "acyl group" represented by R 103 and R 104 include the same groups as the "acyl group" represented by R 2 , R 3 and R 4 above.
Examples of the "halogen atom" represented by R 103 and R 104 include fluorine, chlorine, bromine and iodine.
　Ｒ１０５で示される「アルキル基」としては、例えば、Ｃ１－６アルキル（例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル等）等が挙げられる。 Examples of the "alkyl group" represented by R 105 include C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and the like. Be done.
　Ｒ１０１としては、（ｉ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）、（ｉｉ）ヒドロキシ、（ｉｉｉ）シアノ、（ｉｖ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルキル（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル等）、（ｖ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルコキシ（例、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ペンチルオキシ、ヘキシルオキシ等）、（ｖｉ）Ｃ１－６アルキル（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル等）で置換されていてもよいアミノ基および（ｖｉｉ）オキソから選ばれる１～３個の置換基で置換されていてもよい「ベンゼン環もしくは複素環と縮合していてもよい単環式含窒素複素環基」（例えば、チアゾリル、イミダゾリル、ピラゾリル、ピリジル、ピリミジニル、ピリダジニルなどの５～６員の芳香族単環式含窒素複素環基など）が好ましい。
　中でも、（ｉ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）、（ｉｉ）ヒドロキシ、（ｉｉｉ）シアノ、（ｉｖ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルキル（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル等）、（ｖ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルコキシ（例、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ペンチルオキシ、ヘキシルオキシ等）および（ｖｉ）Ｃ１－６アルキル（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル等）で置換されていてもよいアミノ基から選ばれる１～３個の置換基で置換されていてもよい６員含窒素芳香族複素環基（例えば、ピリジル基（例、２－、３－または４－ピリジル等）、ピリミジニル基（例、２－、４－または５－ピリミジニル等）、ピリダジニル基（例、３－または４－ピリダジニル等）等）が好ましく、（ｉ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルキル（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル等）および（ｉｉ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルコキシ（例、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ペンチルオキシ、ヘキシルオキシ等）から選ばれる１～３個の置換基で置換されていてもよいピリジル基が特に好ましい。 Examples of R 101 include (i) halogen (eg, fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, and (iv) halogen (eg, fluorine, chlorine, bromine, iodine) from 1 to 5. C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), which may be substituted (preferably 1 to 3), (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), ( v) C 1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, eg, methoxy, ethoxy, propoxy, isopropoxy, which may be substituted with 1-5 (preferably 1-3) halogens (eg, fluorine, chlorine, bromine, iodine). Butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.), (vi) C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) Etc.) and may be substituted with 1 to 3 substituents selected from (vii) oxo, which may be substituted with "a monocyclic type which may be condensed with a benzene ring or a heterocycle". A "nitrogen heterocyclic group" (for example, a 5- to 6-membered aromatic monocyclic nitrogen-containing heterocyclic group such as thiazolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridadinyl, etc.) is preferable.
Among them, 1 to 5 (preferably) of (i) halogen (eg, fluorine, chlorine, bromine, iodine), (ii) hydroxy, (iii) cyano, (iv) halogen (eg, fluorine, chlorine, bromine, iodine). C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.), (v) halogen which may be substituted. C 1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy) may be substituted with 1-5 (preferably 1-3) with (eg, fluorine, chlorine, bromine, iodine). , Sc-butoxy, pentyloxy, hexyloxy, etc.) and (vi) C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) A 6-membered nitrogen-containing aromatic heterocyclic group (eg, a pyridyl group (eg, 2-, 3- or 4-), which may be substituted with 1 to 3 substituents selected from the optionally substituted amino groups. Pyridyl, etc.), pyrimidinyl groups (eg, 2-, 4- or 5-pyrimidinyl, etc.), pyridadinyl groups (eg, 3- or 4-pyridazinyl, etc.), etc.) are preferred, (i) halogens (eg, fluorine, chlorine, etc.). C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl) may be substituted with 1-5 (preferably 1-3) with (bromine, iodine). , Pentyl, hexyl, etc.) and (ii) Halogen (eg, fluorine, chlorine, bromine, iodine) may be substituted with 1-5 (preferably 1-3) C 1-6 alkoxy (eg, methoxy). , Ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.), and a pyridyl group which may be substituted with 1 to 3 substituents is particularly preferable.
　Ｒ１０２としては、［１］（ｉ）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、（ｉｉ）シアノ、（ｉｉｉ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルキル（例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル等）、（ｉｖ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルコキシ（例、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ペンチルオキシ、ヘキシルオキシ等）および（ｖ）アセチルから選ばれる１～５個（好ましくは１～３個）の置換基で置換されていてもよいＣ６－１４アリール基（例、フェニル基）、または
　［２］（ｉ）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、（ｉｉ）シアノ、（ｉｉｉ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルキル（例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル等）、（ｉｖ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルコキシ（例、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ペンチルオキシ、ヘキシルオキシ等）および（ｖ）アセチルから選ばれる１～３個の置換基で置換されていてもよいチエニル基が好ましく、
　特に、［１］（ｉ）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）および（ｉｉ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルキル（例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル等）から選ばれる１～５個（好ましくは１～３個）の置換基で置換されていてもよいフェニル基、または
　［２］（ｉ）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）および（ｉｉ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルキル（例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル等）から選ばれる１～３個の置換基で置換されていてもよいチエニル基が好ましい。　Ｒ１０２としては、フェニル基、２－フルオロフェニル基または２－メチルフェニル基が特に好ましい。 Examples of R 102 include [1] (i) halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), (ii) cyano, and (iii) halogen (eg, fluorine, chlorine, bromine, iodine). C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) may be substituted from 1 to 5 (preferably 1 to 3). ), (Iv) C 1-6 alkoxy (eg, methoxy, ethoxy, propoxy, which may be substituted with 1-5 (preferably 1-3) halogens (eg, fluorine, chlorine, bromine, iodine). C 6 which may be substituted with 1 to 5 (preferably 1 to 3) substituents selected from (v) acetyl (isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.) and (v) acetyl. -14 aryl group (eg, phenyl group), or [2] (i) halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), (ii) cyano, (iii) halogen (eg, fluorine, C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert) may be substituted with 1-5 (preferably 1-3) with (chlorine, bromine, iodine). -Butyl, pentyl, hexyl, etc.), (iv) Halogen (eg, fluorine, chlorine, bromine, iodine) may be substituted with 1-5 (preferably 1-3) C 1-6 alkoxy (eg). , Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.) and (v) a thienyl group optionally substituted with 1 to 3 substituents selected from acetyl. Preferably
In particular, [1] (i) halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) and (ii) halogen (eg, fluorine, chlorine, bromine, iodine) have 1 to 5 (preferably 1). ~ 3) 1-5 selected from C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) which may be substituted. A phenyl group which may be substituted with (preferably 1 to 3) substituents, or [2] (i) halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) and (ii) halogen. C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, which may be substituted 1 to 5 (preferably 1 to 3) with (eg, fluorine, chlorine, bromine, iodine). A thienyl group which may be substituted with 1 to 3 substituents selected from sec-butyl, tert-butyl, pentyl, hexyl, etc.) is preferable. As R 102 , a phenyl group, a 2-fluorophenyl group or a 2-methylphenyl group is particularly preferable.
　Ｒ１０３およびＲ１０４については、それぞれ水素原子を示すか、あるいはＲ１０３およびＲ１０４の一方が水素原子を、他方がＣ１－６アルキル基（例、メチル、エチル、ｎ－プロピル、イソブチル等）、Ｃ１－６アルキル－カルボニル基（例、アセチル、プロピオニル、ブチリル、イソブチリル、ペンタノイル、ヘキサノイル、ヘプタノイル等）、ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）、シアノ基またはニトロ基を示す場合が好ましく、特に、Ｒ１０３およびＲ１０４の両者がともに水素原子を示す場合が好ましい。 For R 103 and R 104 , respectively, either indicate a hydrogen atom, or one of R 103 and R 104 is a hydrogen atom and the other is a C 1-6 alkyl group (eg, methyl, ethyl, n-propyl, isobutyl, etc.). , C 1-6 alkyl-carbonyl group (eg, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl, heptanoyl, etc.), halogen atom (eg, fluorine atom, chlorine atom, bromine atom, iodine atom), cyano group or nitro It is preferable to show a group, and it is particularly preferable that both R 103 and R 104 show a hydrogen atom.
　Ｒ１０５としては、メチルまたはエチルが好ましく、特に、メチルが好ましい。 As R 105 , methyl or ethyl is preferable, and methyl is particularly preferable.
　式（ＩＩ－ｄ）で表される化合物の中で特に好ましい化合物は、例えば、
　Ｒ１０１が、（ｉ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルキル（例、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル等）および（ｉｉ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルコキシ（例、メトキシ、エトキシ、プロポキシ、イソプロポキシ、ブトキシ、イソブトキシ、ｓｅｃ－ブトキシ、ペンチルオキシ、ヘキシルオキシ等）から選ばれる１～３個の置換基で置換されていてもよいピリジル基であり、
　Ｒ１０２が、［１］（ｉ）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）および（ｉｉ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルキル（例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル等）から選ばれる１～５個（好ましくは１～３個）の置換基で置換されていてもよいフェニル基、または、
　［２］（ｉ）ハロゲン原子（例、フッ素原子、塩素原子、臭素原子、ヨウ素原子）および（ｉｉ）ハロゲン（例、フッ素、塩素、臭素、ヨウ素）で１～５個（好ましくは１～３個）置換されていてもよいＣ１－６アルキル（例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル等）から選ばれる１～３個の置換基で置換されていてもよいチエニル基であり、
　Ｒ１０３およびＲ１０４がそれぞれ水素原子であり、
　Ｒ１０５がメチルである、化合物である。 Among the compounds represented by the formula (II-d), particularly preferable compounds are, for example, for example.
R 101 may be (i) substituted with 1-5 (preferably 1-3) halogens (eg, fluorine, chlorine, bromine, iodine) C 1-6 alkyl (eg, methyl, ethyl, etc.). 1-5 (preferably 1-3) with propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) and (ii) halogens (eg, fluorine, chlorine, bromine, iodine). Substituted with 1 to 3 substituents selected from optionally substituted C 1-6 alkoxy (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, pentyloxy, hexyloxy, etc.) It is a pyridyl group that may be
The number of R 102 is 1 to 5 (preferably) in [1] (i) halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) and (ii) halogen (eg, fluorine, chlorine, bromine, iodine). 1 to 3 selected from C 1-6 alkyl (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) which may be substituted. A phenyl group that may be substituted with 5 (preferably 1 to 3) substituents, or
[2] 1 to 5 (preferably 1 to 3) halogen atoms (eg, fluorine atom, chlorine atom, bromine atom, iodine atom) and (ii) halogen (eg, fluorine, chlorine, bromine, iodine). 1 to 3 substitutions selected from C 1-6 alkyls which may be substituted (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, etc.) A thienyl group that may be substituted with a group,
R 103 and R 104 are hydrogen atoms, respectively,
It is a compound in which R 105 is methyl.
　化合物（Ｉ）としては、
Ｎ－メチル－１－［１－（フェニルスルホニル）－５－（３－チエニル）－１Ｈ－ピロール－３－イル］メタンアミン、Ｎ－メチル－１－［５－フェニル－１－（３－チエニルスルホニル）－１Ｈ－ピロール－３－イル］メタンアミン、Ｎ－メチル－１－（１－｛［３－（メチルスルホニル）フェニル］スルホニル｝－５－フェニル－１Ｈ－ピロール－３－イル）メタンアミン、１－［１－（１－ベンゾチエン－２－イルスルホニル）－５－フェニル－１Ｈ－ピロール－３－イル］－Ｎ－メチルメタンアミン、１－［５－（２－フルオロフェニル）－１－｛［３－（メチルスルホニル）フェニル］スルホニル｝－１Ｈ－ピロール－３－イル］－Ｎ－メチルメタンアミン、１－｛５－（２－フルオロフェニル）－１－［（２－フルオロフェニル）スルホニル］－１Ｈ－ピロール－３－イル｝－Ｎ－メチルメタンアミン、Ｎ－メチル－３－（｛４－［（メチルアミノ）メチル］－２－フェニル－１Ｈ－ピロール－１－イル｝スルホニル）ベンズアミド、またはそれらの塩が特に好ましく、
とりわけ、式（ＩＩ－ｄ）で表される化合物としては、
Ｎ－メチル－１－［５－フェニル－１－（ピリジン－３－イルスルホニル）－１Ｈ－ピロール－３－イル］メタンアミン、１－［５－（２－フルオロフェニル）－１－（ピリジン－３－イルスルホニル）－１Ｈ－ピロール－３－イル］－Ｎ－メチルメタンアミン（ボノプラザンとも言う）、Ｎ－メチル－１－［４－メチル－１－（ピリジン－３－イルスルホニル）－５－フェニル－１Ｈ－ピロール－３－イル］メタンアミン、Ｎ－メチル－１－［１－（ピリジン－３－イルスルホニル）－５－（３－チエニル）－１Ｈ－ピロール－３－イル］メタンアミン、Ｎ－メチル－１－［５－（２－メチルフェニル）－１－（ピリジン－３－イルスルホニル）－１Ｈ－ピロール－３－イル］メタンアミン、１－［５－（２，４－ジフルオロフェニル）－１－（ピリジン－３－イルスルホニル）－１Ｈ－ピロール－３－イル］－Ｎ－メチルメタンアミン、またはそれらの塩が特に好ましい。
　中でも、ボノプラザン（１－［５－（２－フルオロフェニル）－１－（ピリジン－３－イルスルホニル）－１Ｈ－ピロール－３－イル］－Ｎ－メチルメタンアミン）又はその塩（中でもフマル酸塩）が特に好ましい。ボノプラザンの構造式を以下に示す。
Figure JPOXMLDOC01-appb-C000009
 As compound (I),
N-methyl-1- [1- (phenylsulfonyl) -5- (3-thienyl) -1H-pyrrole-3-yl] methaneamine, N-methyl-1- [5-phenyl-1- (3-thienylsulfonyl) ) -1H-Pyrrole-3-yl] methaneamine, N-methyl-1- (1-{[3- (methylsulfonyl) phenyl] sulfonyl} -5-phenyl-1H-pyrrole-3-yl) methaneamine, 1- [1- (1-benzothien-2-ylsulfonyl) -5-phenyl-1H-pyrrole-3-yl] -N-methylmethaneamine, 1- [5- (2-fluorophenyl) -1-{[3 -(Methylsulfonyl) phenyl] sulfonyl} -1H-pyrrole-3-yl] -N-methylmethaneamine, 1- {5- (2-fluorophenyl) -1-[(2-fluorophenyl) sulfonyl] -1H -Pyrrole-3-yl} -N-methylmethaneamine, N-methyl-3-({4-[(methylamino) methyl] -2-phenyl-1H-pyrrole-1-yl} sulfonyl) benzamide, or them. Salt is especially preferred,
In particular, as the compound represented by the formula (II-d),
N-Methyl-1- [5-phenyl-1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-yl] methaneamine, 1- [5- (2-fluorophenyl) -1- (pyridine-3) -Ilsulfonyl) -1H-pyrrole-3-yl] -N-methylmethaneamine (also called bonoplazan), N-methyl-1- [4-methyl-1- (pyridine-3-ylsulfonyl) -5-phenyl -1H-pyrrole-3-yl] methaneamine, N-methyl-1- [1- (pyridine-3-ylsulfonyl) -5- (3-thienyl) -1H-pyrrole-3-yl] methaneamine, N-methyl -1- [5- (2-Methylphenyl) -1- (pyridine-3-ylsulfonyl) -1H-pyrrole-3-yl] methaneamine, 1- [5- (2,4-difluorophenyl) -1- (Pyrid-3-ylsulfonyl) -1H-pyrrole-3-yl] -N-methylmethaneamine, or salts thereof, are particularly preferred.
Among them, vonoprazan (1- [5- (2-fluorophenyl) -1- (pyridin-3-ylsulfonyl) -1H-pyrrole-3-yl] -N-methylmethaneamine) or a salt thereof (among others, fumarate). ) Is particularly preferable. The structural formula of Vonoprazan is shown below.
Figure JPOXMLDOC01-appb-C000009
　化合物（Ｉ）は、例えば、特許文献１（国際公開第２００６／０３６０２４号）に記載の方法、またはこれらに準じた方法に従って製造することができる。 Compound (I) can be produced, for example, according to the method described in Patent Document 1 (International Publication No. 2006/036024) or a method similar thereto.
　また、プロトンポンプ阻害剤としては、例えば、式（１）
Figure JPOXMLDOC01-appb-C000010
 　［式（１）中、Ｒ１’は水素、メトキシ、ジフルオロメトキシまたはトリフルオロメチルを、Ｒ２’およびＲ３’は同一または異なって、水素、メチルまたはメトキシを、Ｒ４’は炭素数１ないし５のフッ素化またはアルコキシ化されていてもよい低級アルキルを、ｎ’は０または１をそれぞれ示す。］で表される化合物またはその塩（以下、化合物（１）と略記することがある）、またはそのプロドラッグが挙げられる。 Further, as a proton pump inhibitor, for example, the formula (1)
Figure JPOXMLDOC01-appb-C000010
 Wherein (1), R 1 'is hydrogen, methoxy, difluoromethoxy or trifluoromethyl, R 2' and R 3 'are the same or different, hydrogen, methyl or methoxy, R 4' is C 1 -C 5 to 5 lower alkyls which may be fluorinated or alkoxylated, where n'represents 0 or 1, respectively. ], Or a salt thereof (hereinafter, may be abbreviated as compound (1)), or a prodrug thereof.
　式（１）中、Ｒ１’は水素、メトキシ、ジフルオロメトキシまたはトリフルオロメチルを示す。中でも、水素、メトキシ、またはジフルオロメトキシであることが好ましく、水素であることがより好ましい。Ｒ１’の位置としては、４位および５位が挙げられそのうち、５位が好ましい。 Wherein (1), R 1 'represents hydrogen, methoxy, difluoromethoxy or trifluoromethyl. Of these, hydrogen, methoxy, or difluoromethoxy is preferable, and hydrogen is more preferable. As the position of R 1 ', 4th and 5th positions are mentioned, and the 5th position is preferable.
　式（１）中、Ｒ２’およびＲ３’は同一または異なって、水素、メチルまたはメトキシを示す。中でも、Ｒ２’はメチルまたはメトキシであることが好ましく、メチルであることがより好ましい。中でも、Ｒ３’は水素またはメチルであることが好ましく、水素であることがより好ましい。 Wherein (1), R 2 'and R 3' are the same or different and represent hydrogen, methyl or methoxy. Among them, it is preferable that R 2 'is methyl or methoxy, and more preferably methyl. Among them, R 3 'is preferably hydrogen or methyl, more preferably hydrogen.
　式（１）中、Ｒ４’で表される「炭素数１ないし５の低級アルキル基」としては、例えば、メチル、エチル、プロピル、イソプロピル、ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ｔｅｒｔ－ペンチル、ネオペンチル、イソペンチル、ｓｅｃ－ペンチル、３－ペンチル基等が挙げられる。中でも、メチル、エチル、プロピルであることが好ましく、メチルであることがより好ましい。 In the formula (1), the "lower alkyl group 5 having 1 to carbon atoms" represented by R 4 ', for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl, pentyl , Tert-Pentyl, neopentyl, isopentyl, sec-pentyl, 3-pentyl group and the like. Of these, methyl, ethyl, and propyl are preferable, and methyl is more preferable.
　式（１）中、Ｒ４’で表される「炭素数１ないし５のフッ素化された低級アルキル」としては、例えば、トリフルオロメチル、２，２，２－トリフルオロエチル、２，２，３，３，３－ペンタフルオロプロピル、２，２，３，３－テトラフルオロプロピル、１，１，１－トリフルオロメチル－２，２，２－トリフルオロエチル、２，２，３，３，４，４，４－ヘプタフルオロブチル、２，２，３，３，４，４，５，５－オクタフルオロペンチルなどが挙げられる。中でも、２，２，２－トリフルオロエチルであることが好ましい。 In the formula (1), as "1 -C 5 fluorinated lower alkyl" represented by R 4 'are, for example, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2, 3,3,3-Pentafluoropropyl, 2,2,3,3-tetrafluoropropyl, 1,1,1-trifluoromethyl-2,2,2-trifluoroethyl, 2,2,3,3 4,4,4-Heptafluorobutyl, 2,2,3,3,4,5,5-octafluoropentyl and the like can be mentioned. Of these, 2,2,2-trifluoroethyl is preferable.
　式（１）中、Ｒ４’で表される「炭素数１ないし５のアルコキシ化された低級アルキル」において、アルコキシ化としては、例えば、メトキシ、エトキシ、プロポキシ、イソプロポキシ化などの炭素数１ないし３のアルコキシ化等が挙げられる。
　式（１）中、Ｒ４’で表される「炭素数１ないし５のアルコキシ化された低級アルキル」としては、例えば、メトキシメチル、２－メトキシエチル、３－メトキシプロピル、４－メトキシブチル、５－メトキシペンチル、２－メトキシ－１－メチルエチル、エトキシメチル、ｎ－プロポキシメチル、１－メトキシエチル、１－エトキシエチル、１－ｎ－プロポキシエチル、および１－メチルエトキシメチル等が挙げられる。中でも、３－メトキシプロピルであることが好ましい。 In the formula (1), in the "alkoxylated lower alkyl having 1 to 5 carbon atoms" represented by R 4 ', the alkoxylation includes, for example, methoxy, ethoxy, propoxy, isopropoxydating and the like having 1 carbon atom. Or 3 alkoxylation and the like.
In the formula (1), as "alkoxylated lower alkyl with 1-5 carbon atoms" represented by R 4 'are, for example, methoxymethyl, 2-methoxyethyl, 3-methoxypropyl, 4-methoxybutyl, Examples thereof include 5-methoxypentyl, 2-methoxy-1-methylethyl, ethoxymethyl, n-propoxymethyl, 1-methoxyethyl, 1-ethoxyethyl, 1-n-propoxyethyl, 1-methylethoxymethyl and the like. Of these, 3-methoxypropyl is preferable.
　中でも、Ｒ４’で表される「炭素数１ないし５のフッ素化またはアルコキシ化されていてもよい低級アルキル」としては、２，２，２－トリフルオロエチル、３－メトキシプロピル、またはメチルであることが好ましく、２，２，２－トリフルオロエチルであることがより好ましい。 Among them, the "number 1 to 5 of the fluorinated or alkoxylated which may be lower alkyl carbon" represented by R 4 'is 2,2,2-trifluoroethyl, 3-methoxypropyl or methyl, It is preferably present, and more preferably 2,2,2-trifluoroethyl.
　式（１）中、ｎ’は０または１をそれぞれ示し、１であることが好ましい。 In the formula (1), n'represents 0 or 1, respectively, and is preferably 1.
　化合物（１）としては、より具体的には、ランソプラゾール、パントプラゾール、オメプラゾール、エソメプラゾール、ラベプラゾール、またはそれらの塩が好ましい。これらの化合物の構造式を表１に示す。なお、当該塩としては、特に限定はされないが、例えばランソプラゾールナトリウム、パントプラゾールナトリウム、オメプラゾールナトリウム、エソメプラゾールマグネシウム、ラベプラゾールナトリウムなどが例示される。 More specifically, the compound (1) is preferably lansoprazole, pantoprazole, omeprazole, esomeprazole, rabeprazole, or a salt thereof. The structural formulas of these compounds are shown in Table 1. The salt is not particularly limited, and examples thereof include lansoprazole sodium, pantoprazole sodium, omeprazole sodium, esomeprazole magnesium, and rabeprazole sodium.
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
　化合物（１）は、例えば、特許文献２（特開昭６１－０５０９７８号公報）、若しくは特許文献３（特開昭５４－１４１７８３号公報）に記載の方法、またはこれらに準じた方法に従って製造することができる。 The compound (1) is produced, for example, according to the method described in Patent Document 2 (Japanese Patent Laid-Open No. 61-050978) or Patent Document 3 (Japanese Patent Laid-Open No. 54-141783), or a method similar thereto. be able to.
　化合物（Ｉ）及び化合物（１）の塩としては、例えば、金属塩、アンモニウム塩、有機塩基との塩、無機酸との塩、有機酸との塩、塩基性または酸性アミノ酸との塩等が挙げられる。金属塩の好適な例としては、例えば、ナトリウム塩、カリウム塩等のアルカリ金属塩；カルシウム塩、マグネシウム塩、バリウム塩等のアルカリ土類金属塩；アルミニウム塩等が挙げられる。有機塩基との塩の好適な例としては、例えば、トリメチルアミン、トリエチルアミン、ピリジン、ピコリン、２，６－ルチジン、エタノールアミン、ジエタノールアミン、トリエタノールアミン、シクロヘキシルアミン、ジシクロヘキシルアミン、Ｎ，Ｎ’－ジベンジルエチレンジアミン等との塩が挙げられる。無機酸との塩の好適な例としては、例えば、塩酸、臭化水素酸、硝酸、硫酸、リン酸等との塩が挙げられる。有機酸との塩の好適な例としては、例えば、ギ酸、酢酸、トリフルオロ酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、リンゴ酸、メタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸等との塩が挙げられる。塩基性アミノ酸との塩の好適な例としては、例えば、アルギニン、リジン、オルニチン等との塩が挙げられ、酸性アミノ酸との塩の好適な例としては、例えば、アスパラギン酸、グルタミン酸等との塩が挙げられる。
　このうち、薬学的に許容し得る塩が好ましい。例えば、化合物内に酸性官能基を有する場合には、アルカリ金属塩（例、ナトリウム塩、カリウム塩等）、アルカリ土類金属塩（例、カルシウム塩、マグネシウム塩、バリウム塩等）等の無機塩、アンモニウム塩等、また、化合物内に塩基性官能基を有する場合には、例えば、塩酸、臭化水素酸、硝酸、硫酸、リン酸等の無機酸との塩、または酢酸、フタル酸、フマル酸、シュウ酸、酒石酸、マレイン酸、クエン酸、コハク酸、メタンスルホン酸、ｐ－トルエンスルホン酸等の有機酸との塩が挙げられる。 Examples of the salt of the compound (I) and the compound (1) include a metal salt, an ammonium salt, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid, and the like. Can be mentioned. Preferable examples of the metal salt include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt, magnesium salt and barium salt; aluminum salt and the like. Suitable examples of salts with organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, 2,6-lutidine, ethanolamine, diethanolamine, triethanolamine, cyclohexylamine, dicyclohexylamine, N, N'-dibenzyl. Examples thereof include salts with ethylenediamine and the like. Preferable examples of the salt with an inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Preferable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, phthalic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzene. Examples thereof include salts with sulfonic acid, p-toluene sulfonic acid and the like. Suitable examples of salts with basic amino acids include, for example, salts with arginine, lysine, ornithine, etc., and suitable examples of salts with acidic amino acids include, for example, salts with aspartic acid, glutamic acid and the like. Can be mentioned.
Of these, pharmaceutically acceptable salts are preferable. For example, when the compound has an acidic functional group, an inorganic salt such as an alkali metal salt (eg, sodium salt, potassium salt, etc.), an alkaline earth metal salt (eg, calcium salt, magnesium salt, barium salt, etc.) , Ammonium salt, etc., and if the compound has a basic functional group, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, or acetic acid, phthalic acid, fumal. Examples thereof include salts with organic acids such as acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid and p-toluenesulfonic acid.
　化合物（Ｉ）及び化合物（１）は、プロドラッグとして用いてもよい。化合物（Ｉ）又は化合物（１）のプロドラッグは、生体内における生理条件下で酵素や胃酸等による反応により化合物（Ｉ）又は化合物（１）に変換する化合物、すなわち酵素的に酸化、還元、加水分解等を起こして化合物（Ｉ）又は化合物（１）に変化する化合物、胃酸等により加水分解等を起こして化合物（Ｉ）又は化合物（１）に変化する化合物をいう。 Compound (I) and compound (1) may be used as a prodrug. The compound (I) or the prodrug of the compound (1) is a compound that is converted into the compound (I) or the compound (1) by a reaction with an enzyme, gastric acid or the like under physiological conditions in the living body, that is, enzymatically oxidized or reduced. A compound that changes to compound (I) or compound (1) by causing hydrolysis or the like, or a compound that changes to compound (I) or compound (1) by causing hydrolysis or the like due to gastric acid or the like.
　化合物（Ｉ）及び化合物（１）のプロドラッグとしては、アミノ基がアシル化、アルキル化、リン酸化された化合物（例えば、アミノ基がエイコサノイル化、アラニル化、ペンチルアミノカルボニル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メトキシカルボニル化、テトラヒドロフラニル化、ピロリジルメチル化、ピバロイルオキシメチル化、ｔ－ブチル化された化合物等）；ヒドロキシル基がアシル化、アルキル化、リン酸化、ホウ酸化された化合物（例えば、ヒドロキシル基がアセチル化、パルミトイル化、プロパノイル化、ピバロイル化、スクシニル化、フマリル化、アラニル化、ジメチルアミノメチルカルボニル化された化合物等）；カルボキシ基がエステル化、アミド化された化合物（例えば、カルボキシ基がエチルエステル化、フェニルエステル化、カルボキシメチルエステル化、ジメチルアミノメチルエステル化、ピバロイルオキシメチルエステル化、エトキシカルボニルオキシエチルエステル化、フタリジルエステル化、（５－メチル－２－オキソ－１，３－ジオキソレン－４－イル）メチルエステル化、シクロヘキシルオキシカルボニルエチルエステル化、メチルアミド化された化合物等）；等が挙げられる。これらの化合物は、自体公知の方法によって化合物（Ｉ）又は化合物（１）から製造することができる。
　また、化合物（Ｉ）及び化合物（１）のプロドラッグは、広川書店、１９９０年刊、「医薬品の開発」第７巻、分子設計、１６３頁から１９８頁に記載されているような生理的条件で化合物（Ｉ）又は化合物（１）に変化するものであってもよい。 The prodrugs of compound (I) and compound (1) include compounds in which the amino group is acylated, alkylated and phosphorylated (eg, the amino group is eicosanoylated, alanylated, pentylaminocarbonylated, (5-methyl). -2-oxo-1,3-dioxolen-4-yl) methoxycarbonylation, tetrahydrofuranylation, pyrrolidylmethylation, pivaloyloxymethylation, t-butylated compounds, etc.); hydroxyl groups are acylated , Alkylated, phosphorylated, borated compounds (eg, hydroxyl group acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumarylated, alanylated, dimethylaminomethylcarbonylated compounds, etc.); Compounds in which the carboxy group is esterified or amidated (for example, the carboxy group is ethyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified) , Phtalidyl esterification, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl esterification, cyclohexyloxycarbonylethyl esterification, methylamided compounds, etc.); and the like. These compounds can be produced from compound (I) or compound (1) by a method known per se.
In addition, compound (I) and the prodrug of compound (1) are prepared under physiological conditions as described in Hirokawa Shoten, 1990, "Drug Development," Vol. 7, Molecular Design, pp. 163 to 198. It may be changed to compound (I) or compound (1).
　化合物（Ｉ）及び化合物（１）が、光学異性体、立体異性体、位置異性体、回転異性体等の異性体を有する場合には、いずれか一方の異性体も混合物も化合物（Ｉ）及び化合物（１）にそれぞれ包含される。例えば、化合物（Ｉ）及び化合物（１）に光学異性体が存在する場合には、ラセミ体から分割された光学異性体も化合物（Ｉ）及び化合物（１）にそれぞれ包含される。これらの異性体は、自体公知の合成手法、分離手法（濃縮、溶媒抽出、カラムクロマトグラフィー、再結晶など）によりそれぞれを単品として得ることができる。 When compound (I) and compound (1) have isomers such as optical isomers, steric isomers, positional isomers, and rotational isomers, either one of the isomers or the mixture is the compound (I) and Each is included in compound (1). For example, when the optical isomers are present in the compound (I) and the compound (1), the optical isomers divided from the racemate are also included in the compound (I) and the compound (1), respectively. Each of these isomers can be obtained as a single product by a synthesis method and a separation method (concentration, solvent extraction, column chromatography, recrystallization, etc.) known per se.
　化合物（Ｉ）及び化合物（１）は、結晶であってもよく、結晶形が単一であっても結晶形混合物であっても化合物（Ｉ）及び化合物（１）にそれぞれ包含される。結晶は、自体公知の結晶化法を適用して、結晶化することによって製造することができる。 The compound (I) and the compound (1) may be crystals, and may be included in the compound (I) and the compound (1) regardless of whether they have a single crystal form or a mixture of crystals. Crystals can be produced by crystallization by applying a crystallization method known per se.
　化合物（Ｉ）及び化合物（１）は、溶媒和物（例えば、水和物等）であっても、無溶媒和物であってもよく、いずれも化合物（Ｉ）及び化合物（１）にそれぞれ包含される。 The compound (I) and the compound (1) may be a solvate (for example, a hydrate or the like) or a non-solvate, and both are the compound (I) and the compound (1), respectively. Be included.
　同位元素（例、３Ｈ、１４Ｃ、３５Ｓ、１２５Ｉなど）などで標識された化合物も、化合物（Ｉ）及び化合物（１）にそれぞれ包含される。 Isotope (e.g., 3 H, 14 C, 35 S, etc. 125 I) compounds labeled with like are also encompassed, respectively compound (I) and compound (1).
　これらのプロトンポンプ阻害剤は一種単独で、又は２種以上を組み合わせて用いることができる。 These proton pump inhibitors can be used alone or in combination of two or more.
　本開示の治療剤における、上述した有効成分の含有量は、特に限定されず、例えば、１質量％～９０質量％の範囲において、適宜設定することができる。当該範囲の上限若しくは下限は、例えば２、３、４、５、６、７、８、９、１０、２０、３０、４０、５０、６０、７０、又は８０質量％であってもよい。より具体的には、例えば、２質量％～８０質量％であってもよい。 The content of the above-mentioned active ingredient in the therapeutic agent of the present disclosure is not particularly limited, and can be appropriately set in the range of, for example, 1% by mass to 90% by mass. The upper limit or the lower limit of the range may be, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 70, or 80% by mass. More specifically, it may be, for example, 2% by mass to 80% by mass.
　本開示の治療剤は、上述した有効成分を含み、さらに他の成分を含むことができる。当該他の成分としては、薬学的に許容される基剤、担体、及び／又は添加剤（例えば溶剤、分散剤、乳化剤、緩衝剤、安定剤、賦形剤、結合剤、崩壊剤、滑沢剤、抗酸化剤、保存剤、コーティング剤、着色料、胃粘膜保護剤などのその他の薬剤等）等が例示できる。
　本開示の治療剤の形態も、特に限定されず、錠剤、丸剤、カプセル剤、散剤、細粒剤、顆粒剤、液剤、トローチ剤、ゼリー剤、注射剤、硬膏剤、エキス剤、坐剤、懸濁剤、チンキ剤、軟膏剤、パップ剤、点鼻剤、吸入剤、リニメント剤、ローション剤、エアゾール剤等が例示できる。 The therapeutic agent of the present disclosure contains the above-mentioned active ingredient, and may further contain other ingredients. Other components include pharmaceutically acceptable bases, carriers, and / or additives (eg, solvents, dispersants, emulsifiers, buffers, stabilizers, excipients, binders, disintegrants, glitches, etc. Agents, antioxidants, preservatives, coating agents, colorants, other agents such as gastric mucosa protective agents) and the like can be exemplified.
The form of the therapeutic agent of the present disclosure is also not particularly limited, and is not particularly limited. , Suspensions, tinctures, ointments, paps, nasal drops, inhalants, liniments, lotions, aerosols and the like can be exemplified.
　本開示の治療剤は、上述した有効成分と、必要に応じて他の成分とを組み合わせて常法により調製することができる。 The therapeutic agent of the present disclosure can be prepared by a conventional method by combining the above-mentioned active ingredient with other ingredients as needed.
　本開示の治療剤は、強迫性障害の治療剤として好適に用いることができる。 The therapeutic agent of the present disclosure can be suitably used as a therapeutic agent for obsessive-compulsive disorder.
　強迫性障害としては、例えば、汚染恐怖、保存、不確実性への疑念、加害恐怖・タブー思考、秩序へのこだわり、強迫性洗浄、確認行為、強迫観念を打ち消すための儀式行為、並び替えや数える行為、自傷性皮膚症、咬爪癖、咬頬癖、強迫性購買、強迫性性行動、強迫的ためこみ、強迫性咬唇、強迫反すう症、強迫洗手等の症状を伴う疾患が挙げられる。これらの症状は、一種単独であってもよく、２種以上の組み合わせであってもよい。 Obsessive-compulsive disorders include, for example, obsessive-compulsive disorder, preservation, doubts about uncertainty, fear of harm / taboo thinking, obsession with order, obsessive-compulsive cleaning, confirmation, ritualistic behavior to counteract obsessive-compulsive thoughts, and sorting. Diseases with symptoms such as counting, obsessive-compulsive dermatosis, biting claw habit, biting cheek habit, obsessive-compulsive purchasing, obsessive-compulsive behavior, obsessive-compulsive swelling, obsessive-compulsive lips, obsessive-compulsive ulcer, and obsessive-compulsive wash. Be done. These symptoms may be one type alone or a combination of two or more types.
　本開示の治療剤の投与（摂取）量は、特に限定されず、摂取する対象の年齢、性別、症状の程度、摂取方法等により決定される。 The administration (ingestion) amount of the therapeutic agent of the present disclosure is not particularly limited, and is determined by the age, gender, degree of symptom, intake method, etc. of the subject to be ingested.
　本開示の治療剤を投与される対象としては、哺乳動物が好ましい。ヒトのみならず、非ヒト哺乳動物であってもよい。対象となるヒトとしては、例えば、強迫性障害を有するヒト、又はその疑いがあるヒトなどが挙げられる。 Mammals are preferable as the target to which the therapeutic agent of the present disclosure is administered. Not only humans but also non-human mammals may be used. Examples of the target human include a human having obsessive-compulsive disorder or a human suspected to have obsessive-compulsive disorder.
　投与方法としては、例えば、経口投与、及び非経口（例えば静脈、動脈、筋肉、皮下、腹腔、直腸、経皮、局所など）投与により、投与することができる。 As an administration method, for example, it can be administered by oral administration and parenteral administration (for example, intravenous, arterial, muscle, subcutaneous, abdominal cavity, rectum, transdermal, topical, etc.).
　後述の実施例に示す通り、ランソプラゾール、ボノプラザンなどのプロトンポンプ阻害剤は、反復行動の抑制や神経発火回数の低下、神経活動の過剰な活性化の抑制などにより示される強迫性障害の治療効果を有する。また、後述の実施例に示す通り、細胞内のｐＨが低下することによって、神経発火回数が低下する。また、後述の実施例に示す通り、プロトンポンプ阻害剤であるボノプラザンにより、細胞内のｐＨが低下する。よって、理論に拘束されることを望むものではないが、例えば、プロトンポンプ阻害剤が、プロトンの排出を抑制し、細胞内のｐＨが低下することによって、強迫性障害の症状を抑制することができると推察される。このため、プロトンポンプ阻害剤を有効成分として含有する本開示の治療剤は、強迫性障害の治療剤として好適に用いることができる。 As shown in Examples described later, proton pump inhibitors such as lansoprazole and vonoprazan have therapeutic effects on obsessive-compulsive disorder, which are exhibited by suppressing repetitive behavior, reducing the number of nerve firings, and suppressing excessive activation of nerve activity. Have. Further, as shown in Examples described later, the decrease in intracellular pH reduces the number of nerve firings. In addition, as shown in Examples described later, the intracellular pH is lowered by vonoprazan, which is a proton pump inhibitor. Therefore, although not bound by theory, for example, a proton pump inhibitor may suppress the symptoms of obsessive-compulsive disorder by suppressing the excretion of protons and lowering the intracellular pH. It is presumed that it can be done. Therefore, the therapeutic agent of the present disclosure containing a proton pump inhibitor as an active ingredient can be suitably used as a therapeutic agent for obsessive-compulsive disorder.
　本開示は、プロトンポンプ阻害活性を指標とする、強迫性障害を治療するための有効成分のスクリーニング方法をも好ましく包含する。以下、当該方法を「本開示のスクリーニング方法」と表記することがある。後述の実施例に示す通り、プロトンポンプ阻害剤によって、強迫性障害の症状を抑制することが可能であるため、本開示のスクリーニング方法によれば、プロトンポンプの阻害活性を指標として、強迫性障害を治療するための有効成分をスクリーニングすることができる。 The present disclosure also preferably includes a method for screening an active ingredient for treating obsessive-compulsive disorder, using the proton pump inhibitory activity as an index. Hereinafter, the method may be referred to as "the screening method of the present disclosure". As shown in Examples described later, it is possible to suppress the symptoms of obsessive-compulsive disorder with a proton pump inhibitor. Therefore, according to the screening method of the present disclosure, obsessive-compulsive disorder using the inhibitory activity of the proton pump as an index. The active ingredient for treating the disease can be screened.
　プロトンポンプの阻害活性は、例えば、プロトンポンプ（Ｈ＋，Ｋ＋－ＡＴＰａｓｅ）を発現する細胞に、被験成分及びＡＴＰを添加し、生成した無機リン酸量を測定するなどのプロトンポンプ阻害活性を測定できる公知の方法によって測定することができる。 The inhibitory activity of the proton pump is, for example, the proton pump inhibitory activity such as adding a test component and ATP to cells expressing a proton pump (H + , K + -ATPase) and measuring the amount of inorganic phosphoric acid produced. It can be measured by a known method that can be measured.
　有効成分のスクリーニング方法としては、被験成分を含有しない場合と比較して、被験成分を含有する場合に、プロトンポンプ阻害活性が確認された成分を、強迫性障害を治療するための有効成分として選択してもよく、被験成分と、公知のプロトンポンプ阻害剤（対照）とを比較して、対照と同程度のプロトンポンプ阻害活性を示した被験成分を、強迫性障害を治療するための有効成分として選択してもよい。 As a method for screening the active ingredient, an ingredient whose proton pump inhibitory activity has been confirmed when the test ingredient is contained is selected as an active ingredient for treating compulsive disorder as compared with the case where the test ingredient is not contained. The test ingredient may be compared with a known proton pump inhibitor (control), and the test ingredient showing the same level of proton pump inhibitory activity as the control may be used as an active ingredient for treating compulsive disorder. May be selected as.
　なお、本明細書において「含む」とは、「本質的にからなる」と、「からなる」をも包含する（The term "comprising" includes "consisting essentially of” and "consisting of."）。また、本開示は、本明細書に説明した構成要件を任意の組み合わせを全て包含する。 In addition, in this specification, "includes" also includes "consisting of" and "consisting of" (The term "comprising" includes "consisting essentially of" and "consisting of."). In addition, the present disclosure includes all combinations of the constituent elements described herein.
　また、上述した本開示の各実施形態について説明した各種特性（性質、構造、機能等）は、本開示に包含される主題を特定するにあたり、どのように組み合わせられてもよい。すなわち、本開示には、本明細書に記載される組み合わせ可能な各特性のあらゆる組み合わせからなる主題が全て包含される。 Further, the various characteristics (property, structure, function, etc.) described for each embodiment of the present disclosure described above may be combined in any way in specifying the subject matter included in the present disclosure. That is, the present disclosure includes all subjects consisting of any combination of the combinable properties described herein.
　本開示の内容を以下の実施例を用いて具体的に説明する。しかし、本開示はこれらに何ら限定されるものではない。下記において、特に言及する場合を除いて、実験は大気圧及び常温条件下で行っている。また特に言及する場合を除いて、「％」は「質量％」を意味する。なお、本明細書及び図面において、キンピロールをQNP、生理食塩水をSal、溶媒をVeh、ランソプラゾールをLpz、ボノプラザンをVpzと表記することがある。また、in vivoおよびin vitro実験の統計分析は、GraphPad Prism 5およびPrism 7を使用し行った。 The contents of this disclosure will be specifically described using the following examples. However, this disclosure is not limited to these. In the following, the experiments are conducted under atmospheric pressure and normal temperature conditions, unless otherwise specified. Also, unless otherwise specified, "%" means "mass%". In the present specification and drawings, quinpyrrole may be referred to as QNP, saline may be referred to as Sal, solvent may be referred to as Veh, lansoprazole may be referred to as Lpz, and vonoprazan may be referred to as Vpz. In addition, GraphPad Prism 5 and Prism 7 were used for statistical analysis of in vivo and in vitro experiments.
薬物および試薬
　（-）-キンピロール（ドパミンD2受容体刺激薬）は生理食塩水（腹腔内投与、1 mg/kg）または水（電気生理学的記録）に溶解した。
　ランソプラゾールとボノプラザンはジメチルスルホキシドに溶解した状態で保存し、使用時に1％ Tween80水溶液または生理食塩水にて希釈した。 Drugs and Reagents (-)-Kimpilol (dopamine D 2 receptor stimulant) was dissolved in saline (intraperitoneal administration, 1 mg / kg) or water (electrophysiological record).
Lansoprazole and vonoprazan were stored in solution in dimethyl sulfoxide and diluted with 1% Tween 80 aqueous solution or saline solution at the time of use.
動物
　雄性C57BL/6J マウス（6-12週齢）を用いた。動物室は気温を22 ± 2℃、12時間の明暗周期で保たれており、実験は明期に行った。キンピロールの投与は、平日に行った。また、キンピロール（1 mg/kg）を8回（1日につき1回）腹腔内投与したマウスを、キンピロール感作マウスとした。 Animal male C57BL / 6J mice (6-12 weeks old) were used. The temperature of the animal room was maintained at 22 ± 2 ° C with a 12-hour light-dark cycle, and the experiment was conducted in the light period. Administration of kinpyrol was performed on weekdays. Mice to which kinpyrol (1 mg / kg) was intraperitoneally administered 8 times (once a day) were designated as kinpyrol sensitized mice.
反復行動の記録
　マウスは単独で飼育し、飼育ケージにおける自発行動をビデオ記録した。強迫性障害の症状の1つである反復行動や儀式的な行動の指標として、自発的に反復する噛み行動を解析した。噛み行動はケージの床敷きを前肢で持ち上げて噛むもしくはくわえて引っ張る行動とした。 Recording of repetitive behavior Mice were bred independently and video-recorded their self-issued behavior in a rearing cage. We analyzed spontaneously repetitive chewing behavior as an index of repetitive behavior and ritual behavior, which are one of the symptoms of obsessive-compulsive disorder. The chewing behavior was the behavior of lifting the floor of the cage with the forelimbs and chewing or pulling it in addition.
　8回目のキンピロール投与20分後から30分後の10分間の噛み行動の時間を測定した。結果を図１に示す。なお、キンピロールの投与に代えて、生理食塩水を投与したマウスの噛み行動の時間を図１に合わせて示す。 The time for chewing behavior was measured for 10 minutes 20 to 30 minutes after the 8th administration of Kinpirol. The results are shown in FIG. In addition, the time of the chewing behavior of the mouse to which the physiological saline was administered instead of the administration of kimpirol is shown in FIG.
　図１に示す通り、キンピロールの反復投与により反復行動を示すことを確認した。 As shown in FIG. 1, it was confirmed that repeated administration of kinpyrol showed repetitive behavior.
　上述したキンピロール感作マウスに、続けて4回同様にキンピロールを投与し、さらにランソプラゾール（腹腔内投与：10・100 mg/kg）、又はボノプラザン（腹腔内投与：10・30・100 mg/kg）を投与した。ランソプラゾール又はボノプラザンは、9～12回目のキンピロール投与の5分前に投与し、8、9、及び12回目のキンピロール投与20分後から30分後の10分間の噛み行動の時間を測定した。ランソプラゾールの投与結果を図２に、ボノプラザンの投与結果を図３に示す。なお、図中、「Pre」はキンピロール投与8回目、「Lpz1」及び「Vpz1」はキンピロール投与9回目（すなわち、各薬剤投与1回目）、「Lpz4」及び「Vpz4」はキンピロール投与12回目（すなわち、各薬剤投与4回目）の噛み行動の時間を示す。 The above-mentioned kinpyrol-sensitized mice were continuously administered with kinpyrol four times in the same manner, and then lansoprazole (intraperitoneal administration: 10.100 mg / kg) or vonoprazan (intraperitoneal administration: 10.30.100 mg / kg). Was administered. Lansoprazole or vonoprazan was administered 5 minutes before the 9th to 12th kinpyrol administration, and the time of chewing behavior was measured for 10 minutes 20 to 30 minutes after the 8th, 9th, and 12th quinpirol administration. The administration result of lansoprazole is shown in FIG. 2, and the administration result of vonoprazan is shown in FIG. In the figure, "Pre" is the 8th administration of kinpyrol, "Lpz1" and "Vpz1" are the 9th administration of quinpyrol (that is, the 1st administration of each drug), and "Lpz4" and "Vpz4" are the 12th administration of quinpillol (that is, , The time of chewing behavior of each drug administration 4th time) is shown.
　図２及び３に示す通り、ランソプラゾール又はボノプラザンの投与によって、噛み行動の時間が減少し、異常な反復行動が抑制されることが分かった。 As shown in FIGS. 2 and 3, it was found that administration of lansoprazole or vonoprazan reduced the time for chewing behavior and suppressed abnormal repetitive behavior.
　上述したキンピロール感作マウスに、続けて2回同様にキンピロールを投与し、さらにボノプラザン（脳室内投与： 1 μg/μl,3μl）を投与した。ボノプラザン又は溶媒を9又は10回目のキンピロール投与の5分前に投与し、9、10回目のキンピロール投与20分後から30分後の10分間の噛み行動の時間を測定した。結果を図４に示す。 The above-mentioned kinpyrol-sensitized mice were continuously administered with kinpyrol twice in the same manner, and then vonoprazan (intracerebroventricular administration: 1 μg / μl, 3 μl). Vonoprazan or solvent was administered 5 minutes before the 9th or 10th kinpyrol administration, and the time of chewing behavior for 10 minutes 20 to 30 minutes after the 9th and 10th quinpirol administration was measured. The results are shown in FIG.
　図４に示す通り、脳室内に投与した場合にも、ボノプラザンの投与によって、噛み行動の時間が減少し、異常な反復行動が抑制されることが分かった。 As shown in FIG. 4, it was found that administration of vonoprazan reduced the time for chewing behavior and suppressed abnormal repetitive behavior even when administered intraventricularly.
定量的RT-PCR
　薬物処置のないマウスの脳から眼窩前頭皮質(OFC)、背側線条体(DS)、線条体中央部(CS)、および視床(TH)を切り出し、mRNAを抽出した。遺伝子発現量の比較は、逆転写反応で得たcDNAサンプルより定量的RT-PCR法を用いて行った。各PCR増幅は、95℃で10分間の熱活性化と、それに続く95℃で15秒間および60℃で1分間の40サイクルで行った。使用したプライマー配列は以下のとおりである。
Gapdh 5’- CTTACTAATTGGAGGCCATGTAG -3’ および 5’- TGTCAAGCTCATTTCCTGGT -3’, Atp4a 5’- GCTGGTTCCCTCTGTTGTGT -3’ and 5’- TACAGGCGCTGACCAAATGT -3’ 
　なお、Atp4a はP型プロトンポンプのαサブユニットの遺伝子である。視床におけるAtp4a/Gapdhを基準として定量した相対値を図５に示す。 Quantitative RT-PCR
The orbitofrontal cortex (OFC), dorsal striatum (DS), central striatum (CS), and thalamus (TH) were excised from the brain of untreated mice and mRNA was extracted. The gene expression level was compared using the quantitative RT-PCR method from the cDNA sample obtained by the reverse transcription reaction. Each PCR amplification was performed with thermal activation at 95 ° C. for 10 minutes followed by 40 cycles at 95 ° C. for 15 seconds and 60 ° C. for 1 minute. The primer sequences used are as follows.
Gapdh 5'-CTTACTAATTGGAGGCCATGTAG -3'and 5'- TGTCAAGCTCATTTCCTGGT -3', Atp4a 5'-GCTGGTTCCCTCTGTTGTGT -3' and 5'-TACAGGCGCTGACCAAATGT -3'
Atp4a is a gene for the α subunit of the P-type proton pump. FIG. 5 shows relative values quantified with reference to Atp4a / Gapdh in the thalamus.
　図５に示す通り、眼窩前頭皮質において、Atp4a 発現量が高いことが確認された。 As shown in FIG. 5, it was confirmed that the expression level of Atp4a was high in the orbitofrontal cortex.
脳スライスの準備
　マウスに生理食塩水またはキンピロールを8回腹腔内投与し、8回目の投与の次の日に急性脳切片を作製した。マウスはイソフルランで麻酔し、脳を摘出し、氷冷下で眼窩前頭皮質を含む厚さ200 μmの冠状切片を作製した。切片作成時に使用した溶液組成は以下のとおりである：120 mM N-methyl-D-glucamin Cl、2.5 mM KCl、26 mM NaHCO3、1.25 mM NaH2PO4、0.5 mM CaCl2、7 mM MgCl2、15 mM D-glucose、1.3 mM ascorbic acid；pH 7.2。作製した脳スライスは32℃の酸素を含んだ人工脳脊髄液（24 mM NaCl、3 mM KCl、26 mM NaHCO3、1 mM NaH2PO4、2.4 mM CaCl2、1.2 mM MgCl2、10 mM D-glucose；pH 7.3)中にて保管し、最低1時間の回復期を設けた。 Preparation of Brain Slices Mice were intraperitoneally administered with saline or quinpirol 8 times, and acute brain sections were prepared the day after the 8th administration. Mice were anesthetized with isoflurane, the brain was removed, and a 200 μm-thick coronal section containing the orbitofrontal cortex was prepared under ice-cooling. The solution composition used during section preparation is as follows: 120 mM N-methyl-D-glucamin Cl, 2.5 mM KCl, 26 mM י 3 , 1.25 mM NaH 2 PO 4 , 0.5 mM CaCl 2 , 7 mM MgCl 2 , 15 mM D-glucose, 1.3 mM ascorbic acid; pH 7.2. The prepared brain slices were artificial cerebrospinal fluid containing oxygen at 32 ° C (24 mM NaCl, 3 mM KCl, 26 mM י 3 , 1 mM NaH 2 PO 4 , 2.4 mM CaCl 2 , 1.2 mM MgCl 2 , 10 mM D. -Glucose; stored in pH 7.3) with a recovery period of at least 1 hour.
皮質神経細胞の初代培養
　妊娠14-16日目のC57BL/6Jマウス胎仔より大脳皮質を分離した後、細胞をトリプシン（2.5 mg / mL）で処理して細胞を分散させた。得られた皮質神経細胞は、2％B-27 plus supplement、2 mM L-グルタミン、100 U / ml ペニシリンGカリウム、および100 μg/ ml硫酸ストレプトマイシンを加えたNeurobasal plus培地を用いて、37℃・5％CO2条件下で10-12日間培養したのち、実験に用いた。 Primary culture of cortical neurons After separating the cerebral cortex from C57BL / 6J mouse embryos on days 14-16 of pregnancy, the cells were treated with trypsin (2.5 mg / mL) to disperse the cells. The obtained cortical neurons were prepared at 37 ° C. using Neurobasal plus medium containing 2% B-27 plus supplement, 2 mM L-glutamine, 100 U / ml penicillin G potassium, and 100 μg / ml streptomycin sulfate. After culturing for 10-12 days under 5% CO 2 conditions, it was used in the experiment.
電気生理学的検討
　急性単離脳切片、および初代培養皮質神経細胞からの発火応答の記録は、whole-cell patch clamp法にて行った。記録チャンバーは人工脳脊髄液で満たし、ガラス電極の内部には以下の組成の溶液を用いた：140 mMグルコン酸カリウム、5 mM KCl、10 HEPES、2 mM Na-ATP、2 mM MgCl2、および0.2 mM EGTA。
　なお、初代培養皮質神経細胞を用いた検討においては、電極内液のpHは、水酸化カリウムを用いて7.3または7.0に調整した。
　急性単離脳切片からの記録の際は、人工脳脊髄液を1-2 ml/minの速度で灌流した。
　記録チャンバー内の液温は急性単離脳切片の場合は27±1℃、初代培養皮質神経細胞の場合は室温に維持した。個々のニューロンは、40倍の水浸対物レンズとCCDカメラを備えた顕微鏡で可視化した。神経活動性の評価は、電流固定条件下で0-500 pAの通電を行った際の発火回数により評価した。
　ボノプラザンの効果を検討する場合、ボノプラザン(10 μM)を含む人工脳脊髄液の灌流前（QNP Pre）と灌流開始5分後（QNP Post）の発火応答を比較した。
　急性単離脳切片を用いて発火回数を測定した結果を図６に、初代培養皮質神経細胞を用いて発火回数を測定した結果を図７に示す。 Electrophysiological studies Acute isolated brain sections and firing responses from primary cultured cortical neurons were recorded by the whole-cell patch clamp method. The recording chamber was filled with artificial cerebrospinal fluid, and a solution having the following composition was used inside the glass electrode: 140 mM potassium gluconate, 5 mM KCl, 10 HEPES, 2 mM Na-ATP, 2 mM MgCl 2 , and 0.2 mM EGTA.
In the study using primary cultured cortical neurons, the pH of the solution in the electrode was adjusted to 7.3 or 7.0 using potassium hydroxide.
Artificial cerebrospinal fluid was perfused at a rate of 1-2 ml / min for recording from acutely isolated brain sections.
The fluid temperature in the recording chamber was maintained at 27 ± 1 ° C for acute isolated brain sections and at room temperature for primary cultured cortical neurons. Individual neurons were visualized with a microscope equipped with a 40x water immersion objective and a CCD camera. Nerve activity was evaluated by the number of firings when 0-500 pA was applied under fixed current conditions.
When examining the effect of vonoprazan, the firing response of artificial cerebrospinal fluid containing vonoprazan (10 μM) before perfusion (QNP Pre) and 5 minutes after the start of perfusion (QNP Post) was compared.
FIG. 6 shows the results of measuring the number of firings using an acutely isolated brain section, and FIG. 7 shows the results of measuring the number of firings using primary cultured cortical neurons.
　図６のＡに示す通り、生理食塩水（Saline）を投与したマウス由来の急性脳切片を用いた場合と比較して、キンピロール（QNP）を投与したマウス由来の急性脳切片を用いた場合に、神経発火回数が増加することが確認された。
　図６のＢは、キンピロール（QNP）を投与したマウス由来の急性脳切片にボノプラザンを添加した場合の発火回数を測定した結果を示す。図６のＢに示す通り、キンピロール投与による神経発火回数の増加が、ボノプラザンによって抑制されることが分かった。 As shown in FIG. 6A, when the acute brain section derived from the mouse to which quinpirol (QNP) was administered was used as compared with the case where the acute brain section derived from the mouse to which saline (Saline) was administered was used. , It was confirmed that the number of nerve firings increased.
FIG. 6B shows the results of measuring the number of firings when vonoprazan was added to an acute brain section derived from a mouse to which kinpyrol (QNP) was administered. As shown in FIG. 6B, it was found that vonoprazan suppressed the increase in the number of nerve firings due to the administration of kinpyrol.
　図７に示す通り、電極内液のpHにより、静止膜電位には変化が見られなかった（図７Ａ）。一方、pHが7.3の場合と比較して、7.0の場合に神経発火回数が低下することが分かった。 As shown in FIG. 7, no change was observed in the resting membrane potential depending on the pH of the liquid in the electrode (FIG. 7A). On the other hand, it was found that the number of nerve firings decreased when the pH was 7.0 compared to when the pH was 7.3.
　以上のことから、ボノプラザンなどのプロトンポンプ阻害剤がプロトンの排出を抑制することによって、細胞内のpHが低下し、神経発火回数を抑制することが示唆された。 From the above, it was suggested that a proton pump inhibitor such as vonoprazan suppresses the excretion of protons, thereby lowering the intracellular pH and suppressing the number of nerve firings.
自発運動活性
　C57BL/6Jマウスにカニューレを埋め込み、７日後にボノプラザン（6nmol）又は溶媒（Ｖｅｈ）を脳室内投与した。オープンフィールド装置（40 × 40 × 30 cm）を用い、投与5分後から15分後の10分間の自発運動量を評価した。結果を図８に示す。 Cannula was implanted in spontaneously active C57BL / 6J mice, and vonoprazan (6 nmol) or solvent (Veh) was intraventricularly administered 7 days later. Using an open field device (40 x 40 x 30 cm), the locomotor activity for 10 minutes 5 to 15 minutes after administration was evaluated. The results are shown in FIG.
　図８に示す通り、ボノプラザン又は溶媒の投与によって、運動量に差は見られなかった。つまり、ボノプラザンは、運動機能全般に作用するものではないことが確認された。 As shown in FIG. 8, no difference in the amount of exercise was observed by administration of vonoprazan or a solvent. In other words, it was confirmed that vonoprazan does not affect motor function in general.
ボノプラザンの細胞内ｐＨに対する影響
　C57BL/6Jマウスより大脳皮質を分離した後、組織をトリプシン（2.5 mg / mL）で処理して細胞を分散させ培養した。２日後、得られた初代培養大脳皮質神経細胞にｐＨ感受性蛍光タンパク質SEpHluorinを含むアデノ随伴ウイルスベクター（AAV-hSyn-SEpHluorin-mCherry）をトランスフェクトし、大脳皮質神経細胞にSEpHluorinを発現させた。大脳皮質の分離後、１２、１３、１４、及び１５日目にボノプラザン（10 μM）又は溶媒処置5分後の細胞内蛍光強度の変化（ΔF/F０）を測定した。溶媒として用いたクレブス液の組成は以下の通りである：140 mM NaCl、 3 mM KCl、 1 mM MgCl2、 2 mM CaCl2、 10 mM glucose、10 mM HEPES。nigericin を含む高K+クレブス液に置換することで、細胞内外のpHは等しくなる。高K+クレブス液の組成は以下のとおりである：5 μM nigericin、 3 mM NaCl、 140 mM KCl、 1 mM MgCl2、 2 mM CaCl2、 10 mM glucose、10 mM HEPES。
　水酸化カリウムを用いて高K+クレブス液のpHが6.7、 7.0、 7.3、 7.6、 7.9となるように調整した。これらの溶媒を還流させた際の細胞内蛍光強度変化量から検量線を作成した。検量線の結果から、ボノプラザン処置による細胞内ｐＨの変化（ΔｐＨ）を算出した。結果を図９（蛍光画像（Ａ）、検量線（Ｂ）、ボノプラザンの投与によるｐＨ変化（Ｃ））に示す。 Effect of vonoprazan on intracellular pH After separating the cerebral cortex from C57BL / 6J mice, the tissues were treated with trypsin (2.5 mg / mL) to disperse and culture the cells. Two days later, the obtained primary cultured cerebral cortical neurons were transfected with an adeno-associated virus vector (AAV-hSyn-SEpHluorin-mCherry) containing the pH-sensitive fluorescent protein SEP Fluorin to express SEP Fluorin in the cerebral cortical neurons. Changes in intracellular fluorescence intensity (ΔF / F 0 ) were measured on days 12, 13, 14, and 15 days after separation of the cerebral cortex after vonoprazan (10 μM) or solvent treatment 5 minutes. The composition of the Krebs solution used as a solvent is as follows: 140 mM NaCl, 3 mM KCl, 1 mM MgCl 2 , 2 mM CaCl 2 , 10 mM glucose, 10 mM HEPES. By substituting with a high K + Krebs solution containing nigericin, the pH inside and outside the cell becomes equal. The composition of the high K + Krebs solution is as follows: 5 μM nigericin, 3 mM NaCl, 140 mM KCl, 1 mM MgCl 2 , 2 mM CaCl 2 , 10 mM glucose, 10 mM HEPES.
The pH of the high K + Krebs solution was adjusted to 6.7, 7.0, 7.3, 7.6, and 7.9 using potassium hydroxide. A calibration curve was prepared from the amount of change in intracellular fluorescence intensity when these solvents were refluxed. From the results of the calibration curve, the change in intracellular pH (ΔpH) due to vonoprazan treatment was calculated. The results are shown in FIG. 9 (fluorescence image (A), calibration curve (B), pH change (C) due to administration of vonoprazan).
　図９に示す通り、初代培養大脳皮質神経細胞では、細胞内の酸性化により蛍光強度が低下することが確認された（Ｂ）。また、ボノプラザン処理により、初代培養大脳皮質神経細胞の細胞内ｐＨが低下することが確認された（Ｃ）。 As shown in FIG. 9, in primary cultured cerebral cortical neurons, it was confirmed that the fluorescence intensity decreased due to intracellular acidification (B). It was also confirmed that the intracellular pH of the primary cultured cerebral cortical neurons was lowered by the vonoprazan treatment (C).
免疫組織学的検討
　キンピロールの繰り返し投与は、側方眼窩前頭皮質の過活動を引き起こすことが知られている（Asaoka et al., eNeuro, 2019）。そこで、ボノプラザンの側方眼窩前頭皮質に対する影響を調べた。
　また、ｃ－Ｆｏｓの発現は、神経細胞からの興奮性アミノ酸（グルタミン酸）の遊離により増加すること、及びグルタミン酸はアストロサイトにより取り込まれ消去されることが知られていることから、後述する（図１０）ｃ－Ｆｏｓの発現増加抑制（神経細胞の過活動の抑制）が、アストロサイトの活性化によるものであるかを確認するため、アストロサイトのマーカーであるｓ１００を染色した。
　12回目のキンピロール投与120分後に脳を回収し、1.5時間4%PFA/0.1 Mリン酸緩衝液を用いて後固定を行なった。その後、一晩15 %スクロースで置換した脳を凍結させ、30 μmの切片を作製した。染色の浸漬時間と使用した溶液組成は以下のとおりである。
ブロッキング（1時間）：0.3 % トリトンX 100、 5 %　ウマ血清
一次抗体（一晩）：0.3 % トリトンX 100、 ウサギポリクローナルc-Fos抗体（1:2000）またはウサギポリクローナルS100抗体（1:200）
二次抗体（2時間）：Alexa Fluor 594 標識ロバ抗ウサギ抗体（1:200）
　DAPIで封入した後、共焦点顕微鏡による蛍光観察から、lOFCのc-Fos陽性細胞またはs100陽性細胞数を計測した。
　また、キンピロールに代えて、生理食塩水（Ｓａｌ）を投与したマウスにおいて同様の試験を行った。結果を図１０及び１１（蛍光画像（Ａ）、染色された細胞数（Ｂ））に示す。 Immunohistological study Repeated administration of kinpyrol is known to cause overactivity of the lateral orbitofrontal cortex (Asaoka et al., ENeuro, 2019). Therefore, we investigated the effect of vonoprazan on the lateral orbitofrontal cortex.
Further, it is known that the expression of c-Fos is increased by the release of excitatory amino acid (glutamic acid) from nerve cells, and that glutamic acid is taken up and eliminated by astrocytes, which will be described later (Fig.). 10) In order to confirm whether the suppression of increased expression of c-Fos (suppression of overactivity of nerve cells) was due to the activation of astrocytes, s100, which is a marker of astrocytes, was stained.
Brains were harvested 120 minutes after the 12th administration of quinpirol and post-fixed with 4% PFA / 0.1 M phosphate buffer for 1.5 hours. Then, the brain replaced with 15% sucrose overnight was frozen to prepare 30 μm sections. The soaking time for dyeing and the solution composition used are as follows.
Blocking (1 hour): 0.3 % Triton X 100, 5% Horse serum primary antibody (overnight): 0.3% Triton X 100, Rabbit polyclonal c-Fos antibody (1: 2000) or Rabbit polyclonal S100 antibody (1: 200)
Secondary antibody (2 hours): Alexa Fluor 594 labeled donkey anti-rabbit antibody (1: 200)
After encapsulation with DAPI, the number of c-Fos-positive cells or s100-positive cells of lOFC was counted from fluorescence observation with a confocal microscope.
A similar test was also performed on mice treated with saline (Sal) instead of quinpyrol. The results are shown in FIGS. 10 and 11 (fluorescent image (A), number of stained cells (B)).
　図１０に示す通り、キンピロールを投与することにより、ｃ－Ｆｏｓの発現が増加し、さらにボノプラザンを投与することにより、ｃ－Ｆｏｓの発現増加が抑制されることが確認された。つまり、ボノプラザンは、側方眼窩前頭皮質の過活動を抑制した。 As shown in FIG. 10, it was confirmed that administration of kinpyrol increased the expression of c-Fos, and administration of vonoprazan suppressed the increase of expression of c-Fos. That is, vonoprazan suppressed overactivity in the lateral orbitofrontal cortex.
　図１１に示す通り、ボノプラザンは、ｓ１００の発現には影響を与えないことが確認された。つまり、ボノプラザンによるｃ－Ｆｏｓの発現増加抑制（神経細胞の過活動の抑制）は、アストロサイトの活性化によるものではないことが明らかとなった。 As shown in FIG. 11, it was confirmed that vonoprazan did not affect the expression of s100. That is, it was clarified that the suppression of the increase in c-Fos expression (suppression of nerve cell overactivity) by vonoprazan was not due to the activation of astrocytes.

Claims (6)

  1. プロトンポンプ阻害剤を有効成分として含有する、強迫性障害の治療剤。 A therapeutic agent for obsessive-compulsive disorder containing a proton pump inhibitor as an active ingredient.
  2. プロトンポンプ阻害剤が、
    式（Ｉ）
    Figure JPOXMLDOC01-appb-C000001
     　［式中、ＸおよびＹは、同一または異なって、結合手または主鎖が原子数１ないし２０のスペーサーを、Ｒ１は置換されていてもよい炭化水素基または置換されていてもよい複素環基を、Ｒ２、Ｒ３およびＲ４は、同一または異なって、水素原子、置換されていてもよい炭化水素基、置換されていてもよいチエニル基、置換されていてもよいベンゾ［ｂ］チエニル基、置換されていてもよいフリル基、置換されていてもよいピリジル基、置換されていてもよいピラゾリル基、置換されていてもよいピリミジニル基、アシル基、ハロゲン原子、シアノ基またはニトロ基を、Ｒ５およびＲ６は、同一または異なって、水素原子または置換されていてもよい炭化水素基を示す］で表される化合物、その塩、及びそのプロドラッグ、並びに
    式（１）
    Figure JPOXMLDOC01-appb-C000002
     　［式（１）中、Ｒ１’は水素、メトキシ、ジフルオロメトキシまたはトリフルオロメチルを、Ｒ２’およびＲ３’は同一または異なって、水素、メチルまたはメトキシを、Ｒ４’は炭素数１ないし５のフッ素化またはアルコキシ化されていてもよい低級アルキルを、ｎ’は０または１をそれぞれ示す。］で表される化合物、その塩、及びそのプロドラッグからなる群より選択される少なくとも１種である、請求項１に記載の治療剤。     Proton pump inhibitor,
    Equation (I)
    Figure JPOXMLDOC01-appb-C000001
     [In the formula, X and Y are the same or different, and the bond or main chain is a spacer having 1 to 20 atoms, and R 1 is a hydrocarbon group which may be substituted or a heterocycle which may be substituted. The groups, R 2 , R 3 and R 4, are the same or different, hydrogen atoms, optionally substituted hydrocarbon groups, optionally substituted thienyl groups, optionally substituted benzo [b]. Thienyl group, optionally substituted frill group, optionally substituted pyridyl group, optionally substituted pyrazolyl group, optionally substituted pyrimidinyl group, acyl group, halogen atom, cyano group or nitro group. , R 5 and R 6 indicate the same or different hydrocarbon atoms or optionally substituted hydrocarbon groups], salts thereof, and prodrugs thereof, and formula (1).
    Figure JPOXMLDOC01-appb-C000002
     Wherein (1), R 1 'is hydrogen, methoxy, difluoromethoxy or trifluoromethyl, R 2' and R 3 'are the same or different, hydrogen, methyl or methoxy, R 4' is C 1 -C 5 to 5 lower alkyls which may be fluorinated or alkoxylated, where n'represents 0 or 1, respectively. ] The therapeutic agent according to claim 1, which is at least one selected from the group consisting of the compound represented by the above, a salt thereof, and a prodrug thereof.
  3. プロトンポンプ阻害剤が、ボノプラザン、ランソプラゾール、パントプラゾール、オメプラゾール、エソメプラゾール、及びラベプラゾールからなる群より選択される少なくとも１種である、請求項１又は２に記載の治療剤。 The therapeutic agent according to claim 1 or 2, wherein the proton pump inhibitor is at least one selected from the group consisting of vonoprazan, lansoprazole, pantoprazole, omeprazole, esomeprazole, and rabeprazole.
  4. 強迫性障害が、汚染恐怖、保存、不確実性への疑念、加害恐怖・タブー思考、秩序へのこだわり、強迫性洗浄、確認行為、強迫観念を打ち消すための儀式行為、並び替えや数える行為、自傷性皮膚症、咬爪癖、咬頬癖、強迫性購買、強迫性性行動、強迫的ためこみ、強迫性咬唇、強迫反すう症、及び強迫洗手からなる群より選択される少なくとも１種の症状を伴う疾患である、請求項１～３のいずれかに記載の治療剤。 Obsessive-compulsive disorder is a fear of pollution, preservation, suspicion of uncertainty, fear of harm / taboo thinking, obsession with order, obsessive-compulsive cleaning, confirmation, ritualistic behavior to counteract obsessive-compulsive thoughts, sorting and counting, At least one selected from the group consisting of obsessive-compulsive dermatosis, obsessive-compulsive habit, biting cheek habit, obsessive-compulsive purchase, obsessive-compulsive behavior, obsessive-compulsive stagnation, obsessive-compulsive lip, obsessive-compulsive ulcer, and obsessive-compulsive wash. The therapeutic agent according to any one of claims 1 to 3, which is a disease associated with the symptoms of.
  5. 経口投与用、又は静脈注射用である請求項１～４のいずれかに記載の治療剤。 The therapeutic agent according to any one of claims 1 to 4, which is for oral administration or intravenous injection.
  6. プロトンポンプ阻害活性を指標とする、強迫性障害を治療するための有効成分のスクリーニング方法。 A screening method for active ingredients for treating obsessive-compulsive disorder using proton pump inhibitory activity as an index.
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09510441A (en) * 1994-03-09 1997-10-21 メレル ファーマスーティカルズ インコーポレーテッド Treatment of obsessive-compulsive disease with N-aralkylpiperidine derivatives
WO2008016002A1 (en) * 2006-07-31 2008-02-07 Osaka University AMYLOID β PRODUCTION REGULATOR CONTAINING PROTON PUMP INHIBITOR
JP2015145343A (en) * 2014-01-31 2015-08-13 公立大学法人和歌山県立医科大学 Novel pharmaceutical use of lansoprazole

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09510441A (en) * 1994-03-09 1997-10-21 メレル ファーマスーティカルズ インコーポレーテッド Treatment of obsessive-compulsive disease with N-aralkylpiperidine derivatives
WO2008016002A1 (en) * 2006-07-31 2008-02-07 Osaka University AMYLOID β PRODUCTION REGULATOR CONTAINING PROTON PUMP INHIBITOR
JP2015145343A (en) * 2014-01-31 2015-08-13 公立大学法人和歌山県立医科大学 Novel pharmaceutical use of lansoprazole

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Title
KELLNER, M.: "Drug treatment of obsessive- compulsive disorder", DIALOGUES CLIN NEUROSCI., vol. 12, 2010, pages 187 - 197, XP055055291 *

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