GB2065098A - N-substituted Thiazolyl Derivatives of 7-amino- cephalosporanic Acid - Google Patents
N-substituted Thiazolyl Derivatives of 7-amino- cephalosporanic Acid Download PDFInfo
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- GB2065098A GB2065098A GB7942241A GB7942241A GB2065098A GB 2065098 A GB2065098 A GB 2065098A GB 7942241 A GB7942241 A GB 7942241A GB 7942241 A GB7942241 A GB 7942241A GB 2065098 A GB2065098 A GB 2065098A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/587—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with aliphatic hydrocarbon radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms, said aliphatic radicals being substituted in the alpha-position to the ring by a hetero atom, e.g. with m >= 0, Z being a singly or a doubly bound hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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Abstract
Compounds of general formula (I> <IMAGE> wherein A is <IMAGE> wherein R2 represents a hydrogen atom or a free or protected hydroxy group; R is 1) -OR3 in which R3 is hydrogen or a branched or straight chain saturated or unsaturated C1-C6 aliphatic hydrocarbon group which is unsubstituted or substituted by one or more substituents selected from a) cyano, b) -COOR' in which R' is hydrogen, C1-C6-alkyl or a carboxy-protecting group; <IMAGE> in which each of the groups R4 and R5, which may be the same or different, represents a hydrogen atom, a C1-C6 alkyl or a C2-C6 aliphatic acyl group, or, when R4 is hydrogen, R5 may be also an amino-protecting group; or <IMAGE> wherein R4 and R5 are as defined above; R1 is hydrogen or an amino- protecting group; n is zero, 1 or 2; Y is a') hydrogen; b') halogen; c') hydroxy; d') C1-C6-alkoxy; e') C1-C6 alkyl; f') -CH2OCOCH3; g') a group <IMAGE> where R'' may be hydrogen, C1-C6 alkyl, carboxy, cyano or carbamoyl; h') a group -CH2-S-Het, wherein Het represents 1) a pentatomic or hexatomic heteromonocyclic ring containing at least one double bond and at least one heteroatom selected from N, S and O, which ring may be unsubstituted or substituted by one or more substituents selected from: a'') hydroxy, C1-C6 alkoxy, halogen, C2-C6 aliphatic acyl; b'') C1-C6 alkyl unsubstituted or substituted by one or more substituents selected from hydroxy and halogen; c'') C2-C6 alkenyl unsubstituted or substituted by one or more substituents selected from hydroxy and halogen; d'') -S-R6 wherein R6 is hydrogen or C1-C6 alkyl -S- CH2COOR' wherein R' is as defined above; e'') -(CH2)m-COOR', -CH=CH-COOR', -(CH2)m- CONH2 or -(CH2)m-CN wherein m is zero, 1, 2 or 3 and R' is as defined above; f'') (CH2)mSO3H wherein m is as defined above; or g''> <IMAGE> wherein m, R4 and R5 are as defined above; or 2) a heterobicyclic ring containing at least two double bonds wherein each of the condensed heteromonocyclic rings thereof is the same or different pentatomic or hexatomic heteromonocyclic ring containing at least a heteroatom selected from N, S and O, the heterobicyclic ring being unsubstituted or substituted by one or more substituents selected from a''), b''), c''), d''), e''), f'') and g'') defined above; X is a free or esterified carboxy group; provided that when A is a -CH2- group, R is not -OH; and the pharmaceutically and veterinarily acceptable salts of compounds of general formula (I) are useful antibacterial agents for treatment of humans and animals.
Description
SPECIFICATiON
N-substituted Thiazolyl Derivatives of Cephalosporanic Acid
The present invention relates to N-substituted thiazolyl derivatives of 7-amino cephalosporanic acid, to a process for their preparation and to pharmaceutical and verterinary compositions containing them.
The compounds of the invention have the following general formula (I)
wherein
A is
or
wherein R2 represents a hydrogen atom or a free or protected hydroxy group;
R is 1)-OR3 in which R3 is hydrogen or a branched or straight chain saturated or unsaturated C1-C6 aliphatic hydrocarbon group which is unsubstituted or substituted by one or more substituents selected from
a) cyano, b) -COOR' in which R' is hydrogen, C1-C6 alkyl or a carboxy-protecting group; c)
in which each of the groups R4 and R5, which may be the same or different, represents a hydrogen atom, a C1-C6 alkyl or a C2-C5 aliphatic acyl group, or, when R4 is hydrogen, R4 may be also an amino-protecting group; or
wherein R4 and R5 are as defined above;
R, is hydrogen or an amino-protecting group;
n is zero, 1 or 2; Y is a') hydrogen; b') halogen; c') hydroxy; d') C1-C6 alkoxy; e') C1-C6 alkyl; f') -CH2OCOCH3; g') a group
where R" may be hydrogen, C1-C6 alkyl, carboxy, cyano or carbamoyl; h') a group -CH2-S-Het, wherein Het represents
1) a pentatomic or hexatomic heteromonocyclic ring containing at least one double bond and at
least one heteroatom selected from N, S and 0, which ring may be unsubstituted or
substituted by one or more substituents selected from::
a") hydroxy, C1-C6 alkoxy, halogen, C2-C6 aliphatic acyl;
b") C1-C6 alkyl unsubstituted or substituted by one or more substituents selected from hydroxy
and halogen;
c") C2-C6 alkenyl unsubstituted or substituted by one or more substituents selected from
hydroxy and halogen;
d")-S-R6 wherein R6 is hydrogen or C1-C6 alkyl -S-CH2COOR' wherein R' is as defined
above;
e")-(CH2)m-COOR'.-CH=CH-COOR', -(CH2)m-CONH2 or -(CH2)m-CNwherein m is
zero, 1, 2 or 3 and R' is as defined above ; f") (CH2)rnS03H wherein m is as defined above; or
wherein m, R4 and R5 are as defined above; or 2) a heterobicyclic ring containing at least two double bonds wherein each of the condensed
heteromonocyclic rings, being the same or different, is a pentatomic or hexatomic
heteromonocyclic ring containing at least a heteroatom selected from
N, S and 0, the heterobicyclic ring being unsubstituted or substituted by one or more substituents
selected from a"), b"), c"), d"), e"), f") and g") indicated above;
X is a free or esterified carboxy group; provided that when R is -OR3 and A is a group
in which R2 is hydrogen, R3 is not hydrogen.
The present invention also includes within its scope the pharmaceutically and verterinarily acceptable salts of the compounds of formula (I) as well as all the possible isomers, e.g. cis and trans isomers and optical isomers and their mixtures, the metabolites provided with antibacterial activity and the metabolic precursors of the compounds of formula (I).
When n is 1 the resulting compounds are sulphoxides and may be in the R or S configuration
When n is 2 the compounds are sulphones. Amino- and carboxy-protecting groups may be, for example, the protecting groups usually employed in the chemistry of peptides. Examples of aminoprotecting groups are formyl, an optionally halo-substituted C2-C6 aliphatic acyl, preferably chloroacetyl or dichloroacetyl, tert-butoxycarbonyl, p-nitrobenzyloxy-carbonyl or trityl.
Examples of carboxy-protecting groups ara tert-butyl, benzhydryl, p-methoxybenzyl p-nitrobenzyl, trityl and trialkylsilyl. When A is
and R2 is hydroxy group, this group may be protected, for example, by a formyl, acetyl, chloroacetyl, dichloroacetyl, trifluoroacetyl, tetrahydropyranyl, trityl or silyl group, especially trimethylsilyl or dimethyl-tert-butyl silyl.
A C2-C6 aliphatic acyl group is preferably a C2-C6 alkanoyl group, most preferably acetyl.
When Xis an esterified carboxy group it is preferably a group of formulaCOOM wherein M is one of the radicals and
wherein R7 is hydrogen or C,--C, alkyl; Q is-0- or -NH-; R8 is an alkyl group (e.g. C1-C6 alkyl) or a basic group, in particular an alkyl (e.g. C1-C6 alkyl) or aralkyl (e.g., benzyl) group substituted by at least an amino group, which in turn, may be unsubstituted or substituted, e.g., R8 is alkyl-NH-CH3, aralkyl-NH-CH3, alkyl
CH2NH2;R9 is an alkyl group, in particular a C1-C6 alkyl group, e.g. methyl, propyl, isopropyl; an aryl group in particular phenyl; a cycloalkyl group, in particular cyclopentyl, cyclohexyl and cycloheptyl; a heteromonocyclic ring, e.g. pyridyl; a bicyclic ring, e.g. indanyl; an aralkyl group e.g. benzyl.
Particularly preferred compounds are those of formula (I) wherein
R1 is hydrogen or an amino-protecting group;
R is -O-C1-C6-alkyl ; -O-C2-C5-alkenyl ; -O-(CH2)m1-COOR2 wherein R' is as defined above and m1 is 1, 2 or 3; amino; -NHCH3; -N(CH3)2; -NHCOCH3 or NHCOO . tert. butyl; Ais-CH2-,
Y is hydrogen, halogen (preferably chlorine), hydroxy, C1-C6 alkoxy (preferably methoxy), -methyl, -CH2OCOCH3 or CH2-S-Het wherein Het is::
1) a tetrazolyl radical, unsubstituted or substituted by C1-C3-alkyl, C2-C4 alkenyl, (CH2)m1 COOR' wherein m, and R' are as defined above, -CH=CH-COOR1 wherein R' is as defined above, -(CH2)m1-CN,-(CH2)m1-CONH2, -(CH2)m-SO3H wherein m, is as defined above, or
wherein m1, R4 and R5 are as defined above;;
2) a thiadlazolyl radical, unsubstituted or substituted by C1-C4-alkyl, -SH2 -SCH3,-S-CH2COOH,-CH2)m-COOH wherein m is as defined above,
wherein R4 and R5 are hydrogen or C1-C3 alkyl, or
3) a heterobicyclic ring selected from tetrazolopyridazinyl, tetrazolopyrazinyl, thiadiazolopyridazinyl and triazolopyridazinyl, each optionally substituted by hydroxy, -SH,
wherein R4 and R5 are as defined above, -COOR' wherein R' is as defined above, C1-C3 alkyl, C2-C4 alkenyl, -S-CH2COOR', -CH2OOR', or-CH=CH-COOR4 wherein R' is as defined above; or
wherein R4 and RS are as defined above.The pharmaceutically and verterinarily acceptable salts of the
compounds of formula (I) are those either with inorganic acids, such as hydrochloric acid, sulphuric
acid, or with organic acids such as citric, tartaric, malic, maleic, mandelic, fumaric and methanesulphonic acid, or with inorganic bases such as sodium, potassium, calcium or aluminium
hydroxides and alkali metal or alkaline-earth metal carbonates or bicarbonates, or with organic bases,
such as organic amines, e.g. lysine, triethylamine, procaine, dibenzylamine, N-bentyl-ss-
phenethylamine, N,N'-dibenzyl-ethylenediamine, dehydroabietylamine, N-ethyl-piperidine, diethanol
amine, N-methylglucamine, tris-hydroxymethyl-aminomethane and the like.
Specific examples of compounds of the invention are the following:
1)7ss-[2-(2-imino-3-methoxy-4-thiazolinyl) acetamido]-3-cephem-4-carboxylic acid ;
2)7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-2-hydroxy-acetamido]-3-cephem-4-carboxylic acid ;
3) 7ss-[2-(2-imino-3-methoxy-4-thiazolinyl )-2-oxoacetamido)-3-cephem-4-ca rboxylic acid;
4)7ss-[2-(2-imino-3-amino-4-thiazolinyl)-acetamido]-3-cephem-4-carboxylic acid ;
5)7ss-[2-(2-imino-3-amino-4-thiazolinyl)-2-oxoacetamido]-3-cephem-4-carboxylic acid ;
6)7ss-[2-(2-imino-3-amino-4-thiazolinyl)-2-keto-carboxamido]-3-cephem-4-carboxylic acid ;
7)7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-acetoxy-methyl-3-cephem-4carboxylic acid ;
8)7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-2-hydroxy-acetamido]-3-acetoxy-methyl-3-cephem4-carboxylic acid ; ;
9)7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-2-oxoacetamido]-3-acetoxy-methyl-3-cephem-4carboxylic acid;
10) 7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-aceta mido]-1 (S)-oxo-3-acetoxy-methyl-3-cephem4-carboxylic acid;
11) 7 l3-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-1 (R)-oxo-3-acetoxy-methyl-3-cephem4-carboxylic acid;
12) 7,8-[2-(2-imino-8-methoxy-4-thiazolinyl)-acetamido]-1-dioxo-3-acetoxy-methyl-3-cephem- 4-carboxylic acid;
13) 7fi-[2-(2-imino-3-amino-4-thiazolinyl)-acetamido]- 1 -dioxo-3- acetoxy-methyl-3-cephem-4- carboxylic acid;
14) 7fi-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[( 1 -methyl- 1 ,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid;;
1 5) 7,B-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[( 1 -(2-cyanoethyl)- 1 ,2,3,4-tetrazol 5-yl)-thiomethyl]-3-cephem-4-carboxylic acid;
16) 7 -[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(5-methyl-1 ,3,4-thiadiazol-2-yl)- thiomethyl]-3-cephem-4-carboxylic acid;
17) 7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(tetrazolo [1 S-b] pyridazin-6-yl) thiomethyl-3-cephem-4-carboxylic acid:: 1 8) 7p-L2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3- [(8-amino-tetrazolot 1 ,5-b] pyradazin- 6-yl)-thiomethyl]-3-cephem-4-carboxylic acid;
19)7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(-carboxy-tetrazolo[1,5-b]pyridazin6-yl)-thiomethyl]-3cephem-4-carboxylic acid ;
20)7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(8-carboxymethyl-tetrazolo[1,5b]pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid ;
21)7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-2-oxoacetamido]-3-[(1-methyl-1,2,3,4-tetrazol-5yl)-thiomethyl]-3-cephem-4-carboxylic acid;
22)7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-2-hydroxy-acetamido)-3-[(1-methyl-1,2,3,4tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid ;;
23) 7A-[2-(2-imino-3-amino-4-thiazolinyl)-acetamido]-3-[( 1 -methyl- 1 ,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid ;
24) 7ss-[2-(2-imino-3-amino-4-thiazolinyl)-acetamido]-3-[(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl]-3-cephem-4-carboxylic acid ;
25) 7ss-[2-(2-imino-3-amino-4-thiazolinyl)-acetamido]-3-[(8-carboxy-tetrazolo[1,5-b]pyridazin6-yl)-thiomethyl]-3-cephem-4-carboxylic acid;
26) 7ss-[2-(2-imino-3-amino-4-thiazolinyl)-2-oxoacetamido]-3-[( l-methyl-l ,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid ;
27) 7ss-[2-(2-imino-3-amino-4-thiazolinyl)-2-hydroxy-acetamido]-3-[(1-methyl-1,2,3,4-tetrazol5-yl)-thiomethyl]-3-cephem-4-carboxylic acid;;
28) 7-[2-(2-imino-3-amino-4-thiazolinyl)-2-hydrnxy-acetamidoJ-3-[( 1 -(2-cyanoethyl)- 1 ,2,3,4- tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid ;
29) 7ss-[2-(2-imino-3-amino-4-thiazolinyl)-2-hydroxy-acetamido]-3-[(8-amino-tetrazolo[1,5b] pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid;
30) 7ss-[2-(2-imino-3-amino-4-thiazolinyl)-2-hydroxy-acetamido]-3-[(8-carboxy-tetrazolo[1.5b] pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid, as well as their pharmaceutically and veterinarily acceptable salts in particular the hydrochlorides.
The structural formulae of the above-numbered compounds, indicated according to their progressive number, are reported in the following Table.
f=,:,qr- - - = = = = = = = Compd. R R A n X Y ==== == 1 H -OCH3 -CH2 zero -COOH H 2 H -OOH3 OH zero -COOH H 3 H -OCH3 zero -COOH H 4 4 H -NH2 -CH2- zero -COOH H 5 H -NH2 -iOHH- zero -COOH H OH 6 H -NH2 -C- zero -COOH
LCompd.| R1 R | A | n X Y 7 H -OCH3 -CH2 zero -COOH -CH20-COCH3 H H H -9H- zero -COOH zero -CH 00CHO3 OH 9 H -OCH3 zero -COOH -CH20-COCH3 10 H -OCH3 -CH2- 1(S) -COOH -CH20-COCH3 11 H -OCH3 -CH2- 1(R) -COOH -CH2o-COC1J3 12 H -OCH3 -CH2 2 -COOH -CH20-COC113 13 H -NH2 'CH2- 2 -COOH CH,C COCH, 14 H -OCH3 -CH2 - zero -COOH -CH;;S-I' Cll3 15 H -OCH3 -CH2- zero -COOH -CH-S 2 J N-- N 16 H -OCH3 -CH2 - zero -COOH -CH Ss#'cfl3 2 17 H -OCH3 -Cli2- zero -COOH -CII,-S li2 18 II -OCH. zero -COOII Cli2'S-1aNN- ooH 19 H -OCH3 CH zero -COOH -CH2-S 2 - H 2COOH 20 H -OCH3 -CH2- zero -COOH -CH2-S 2 N-N 21 H -OCH3 zero -COOH C2 S-tNvCH 0 'C113 N-N 22 H -OCH3 -COHH- zero -COOH C2 -CH -S CH3 23 H -NH2 -CH2- zerO -COOH -CH2-S CH3 24 H -NH -CH2- zero -C0OH CH2 2
Campd. R1 1R 1 n X V c--tc~ bmne :~h9 25 H -NH2 -CH2- zero -COOH -CH2-SisN, N-N 26 H -!H2 -,CO- zero -COOH -CH -S4tN3k 0 2 'ClI3 N 27 H -19 CsHH zero -COOH CH,-S-N N 'CH3 28 H -hH -NH2 OOH zero -COOH 2 g -CH2-S 9H- 2C112CN 29 H -NH2 -CH- zero -COOH -CH2-S 6H 0011 30 H -llH2 9H zero -COOH -CH2-S 8 ,N-N OH The compounds of the invention may be prepared by a process comprising: a) reacting a compound of formula (II)
wherein
n, X and Y are as defined above and E is an amino or a group -N=C-O or -N=C-S, or a reactive derivative thereof, with a compound of formula (III)
wherein
R, R1 and A are as defined above, or a reactive derivative thereof, and, if desired, removing the protecting groups, where present; or
b) reacting a compound of formula (IV)
wherein
A, n, X and Y are as defined above, or a reactive derivative thereof, with a compound of formula (V) B-NH2 (V) wherein
R is as defined above, or a salt thereof and, if desired, removing the protecting group possibly present; or
c) reacting a compound of formula (VI)
wherein
A, n, X and Y are as defined above, and B is halogen, or a reactive derivative thereof, with a compound of formula (VII)
wherein
R and R, are as defined above, and, if desired, removing the protecting groups where present; or
d) reacting a compound of formula (VIII)
wherein
B, R, A, n, X and Y are as defined above, with thiocyanic acid or a salt thereof, and, if desired, removing the protecting groups, where present, or
e) reacting a compound of formula (IX)
wherein R, 1,A, n and X are as defined above, or a salt thereof, with a compound of formula (X)
HS-Het (X) wherein
Het is as defined above, or a reactive derivative thereof, and, if desired, removing the protecting groups, where present, and/or, if desired, converting a compound of formula (I) where X is carboxy into a pharmaceutically or veterinarily acceptable salt and/or, if desired, obtaining a free compound from a salt and/or, if desired, converting a compound of formula (I) or a salt thereof into another compound of formula (I) or a salt thereof.
When in the compounds having the formulae (II), (IV), (Vl), (VIII) and (IX) X is a free carboxy group, the carboxy group may be protected, if necessary, in a conventional manner, before the reaction takes place. Examples of protecting groups are those usually employed in the synthesis of peptides, for example, tert. butyl, benzhydryl, p-methoxybenzyl, p-nitrobenzyl, trityl and trialkylsilyl.
The protecting groups are then removed, at the end of the reaction, in a known manner, e.g. by mild acid hydrolysis or by catalytic hydrogenation, for example, with Pd/C at room pressure.
Since, however, compounds of formula (I) containing the said protecting groups are included in the present invention, removal of the protecting groups is not an essential process step.
The starting materials used in each of the above-mentioned processes a) to e), when one or more asymmetric carbon atoms are present, may be either optically active or racemic compounds.
A reactive derivative of the compound of formula (II) may be, for example, an amine salt, a silyl ester or a metal salt when X is carboxy.
A reactive derivative of the compound of formula (III) is, for example, an acyl halide, an anhydride or a mixed anhydride, an amide, an azide, a reactive ester or a salt, such as, for instance, the salts formed with alkali or alkaline-earth metals, ammonia or an organic base.
A reactive ester may be, for example,p-nitrophenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, N-hydroxy succinimide ester and N-hydroxy phthalimide ester.
The reaction between the compound of formula (II) or a reactive derivative thereof and the compound of formula (III) or a reactive derivative thereof may be performed either at room temperature or under cooling, preferably from about -500C to about +400C in a suitable solvent, e.g. acetone, dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, dimethylformamide, 1 2-chloro- ethane or in a mixture of water and a solvent miscible with water and, if necessary, in the presence of a base, for example sodium bicarbonate, potassium bicarbonate or a trialkylamine, or in the presence of another acid acceptor, such as an alkylene oxide, e.g. propylene oxide.
When the compound of formula (III) is reacted with the compound of formula (II) wherein E is amino, as a free acid or as a salt, it is desirable that the reaction be performed in the presence of a condensing agent, such as, for instance, N,N'-dicyclohexylcarbodiimide. The optional removal of the protecting groups at the end of the reaction, may be performed in a known manner.
For example, the tert. butoxycarbonyl group may be removed by treatment with an aqueous solution of an acid (for example CF3COOH or HCOOH) and the monochloroacetyl group may be removed by treatment with thiourea. The formyl and the trifluoroacetyl groups may be removed by treatment with potassium carbonate in aqueous methanol; the tetrahydropyranyl group by treatment with dilute hydrochloric acid and the trityl group by treatment with formic or trifluoroacetic acid.
The reaction between the compound of formula (IV) or a reactive derivative thereof which may be, for instance, a salt or an ester, with a compound of formula (V) or a salt thereof may be performed in a suitable solvent, e.g., water, methanol, ethanol, dioxane, acetonitrile, dimethylformamide, dimethyl acetamide, or methylene chloride.
A salt of the compound of formula (V) may be either a salt with inorganic acids e.g. hydrochloric acid or sulphuric acid, or with organic acids, e.g. citric, tartaric, oxalic or p-toluenesulphonic acid.
The reaction temperature preferably ranges from about OOC to about 900C and the pH is preferably maintained from about 1 to about 7.5. The subsequent optional removal of the protecting groups may be performed by known methods e.g. those indicated above.
In the compounds of formula (VI) and (VIII) B is preferably chlorine or bromine.
The reaction between the compound of formula (Vl) or a reactive derivative thereof which may be, for instance, a salt, or an ester thereof, and the compound of formula (ill) is preferably carried out in an aprotic solvent, e.g. N,N'-dimethylformamide, N,N'-dimethylacetamide, dimethylsulphoxide, acetonitrile, hexamethylphosphorotriamide or in a mixture of these solvents. The reaction temperature preferably ranqes from about OOC to about +900C. The subsequent optional removal of the protecting groups possibly present may be carried out as indicated above.
The reaction between a compound of formula (VIII) with thiocyanic acid or a salt thereof, for instance an alkali metal e.g., potassium, thiocyanate, may be performed in an inert solvent preferably a dipolar aprotic solvent, like acetonitrile or dimethylacetamide. A salt of a compound of formula (IX) is, for example, a salt, especially an alkali metal salt, of a compound (IX) where X is carboxy. A salt of a compound of formula (X) may be, for example, the salt with an alkali metal, e.g. sodium.
The reaction between the compound of formula (IX) or a salt thereof and the compound of formula (X) or a reactive derivative thereof, for example, an alkali metal salt, may be carried out in water or in a mixture of water and an organic solvent, e.g. acetone, ethanol, dioxane or tetrahydrofuran, in the presence of about 2 equivalents of a base, for example, sodium bicarbonate.
The reaction temperature preferably ranges from about 50C to about 900C and the pH is preferably maintained from about 5 to about 7.5. If desired a buffer may be used, for example, sodium phosphate or acetate. In a different way, the same reaction may be performed without any base and in a strictly anhydrous solvent, at temperatures ranging from about 500C to about 1200 C, and for reaction times ranging from a few hours to a few days. The preferred solvent is acetonitrile and an inert atmosphere (e.g. nitrogen) may be advisable in order to prevent the oxidation of the heterocyclic thiol (X). The subsequent optional removal of the protecting groups may be performed by known methods e.g. those indicated above.
The optional salification of the compound of formula (I) as well as the optional conversion of a salt into a free compound, may be carried out according to conventional methods, i.e. methods already known in organic chemistry.
As stated above, a compound of formula (I) or a salt thereof, may be converted into another compound of formula (I) or a salt thereof; also these optional conversions may be performed by conventional methods.
Thus for example a compound of formula (I) where R is -OH may be converted into the
corresponding compound of formula (I) wherein R is -OR3, with R3 other than hydrogen, by the usual
etherification reactions.
Other optional conversions may be also the esterification of a compound of formula (I), wherein X
is carboxy, which may be carried out by reacting the compound of formula (I), wherein the carboxy
group is free or salified, for example in the form of a sodium, potassium, calcium or triethylammonium
salt, with the suitable halide, in an organic solvent, such as acetone, tetrahydrofuran, chloroform,
methylene chloride, dimethylformamide, diemthylsuphoxide, or in a mixture of water and an organic
solvent, e.g. dioxane and acetone; the reaction temperature ranges from about -200C to about
+800C. Furthermore a compound of formula (I), wherein X is an esterified carboxy group, may be saponified using, for example, an inorganic acid, such as hydrochloric acid or an inorganic base, such as sodium or potassium hydroxide, as is known in organic chemistry.
The compounds of formula (I) wherein n is 1 and wherein the sulphoxide is in the S configuration, may be preferably obtained from the corresponding compounds of formula (I) wherein n is zero by treatment with an oxidizing agent especially a peracid, for example perbenzoic acid, mchloroperbenzoic acid, permaleic acid, sodium periodate, hydrogen peroxide or a mixture of these, with an inorganic acid e.g., formic acid, acetic acid or trifluoroacetic acid.
The reaction may be performed in a solvent, e.g. dioxane, tetrahydrofuran, chloroform, methylene chloride, formic acid, acetic acid, benzene, N,N-dimethyl formamide, N,N-dimethylacetamide or the like. The reaction temperature is preferably from about -300C to about +90"C.
To obtain the sulphoxide with the R-configuration it is preferable to carry out the same oxidation reaction on the intermediate products, preferably on the compounds of formula (II) wherein E is amino, after first protecting this amino group by formation of a Schiff base.
The Schiff base may be performed by known methods e.g. by treatment of the amine of formula (II) with an aldehyde, e.g. as benzaldehyde, salicylaldehyde or p-nitrobenzaldehyde; at the end of the oxidation reaction the free amino group may be obtained for example by treatment with a hydrazine derivative, for instance phenylhydrazine, 2,4-dinitrophenyl hydrazine or a Girard reagent. The carboxy group is preferably protected during the oxidation reaction using e.g. as protecting groups those mentioned above.
The conversion of sulphide to sulphoxide, i.e. the conversion of a compound of formula (I) wherein n is zero into the corresponding compound wherein n is 1, may be effected by using 1-1.2 molar equivalents of the oxidizing agent for each mole of the compound to be oxidized.
The conversion of sulphide to sulphone, i.e. the conversion of a compound of formula (I) wherein
n is zero into the corresponding compound of formula (I) wherein n is 2, may be performed by the same
oxidizing agents used to obtain the sulphoxides, using in this case at least two molar equivalents of the
oxidizing agent for each mole of the compound to be oxidized.
Also the optional resolution of a mixture of isomers into the single isomers may be carried out by
conventional methods. Thus, racemic compounds may be resolved into the optical antipodes, for
example, by resolution, e.g. by means of fractional crystallization of mixtures of diastereoisomeric salts, and, if desired, liberating the optical antipodes from the salts.
The compound of formula (II) wherein E is amino and Y is hydrogen, halogen, hydroxy, C1-C6 alkyl or C1-C6 alkoxy are known compounds or may be prepared by known methods.
The compound of formula (II), wherein E is -N=C=O or N=C=S may be prepared e.g., by reacting a compound of formula (II), wherein E is amino, with phosgene or thiophosgene, in the presence of a hydrochloric acid acceptor, using known methods.
The compound of formula (III) may be prepared according to one of the following methods:
1 ) by reaction of a compound of formula (Xl)
wherein A and R' are as defined above, with a compound of formula (V) using reaction conditions analogous to those indicated for the reaction between the compound of formula (IV) and the compound of formula (V).
The compound of formula (Xl) are known compounds or may be prepared by known methods.
2) by reaction of a compound of formula (XII)
wherein B, A and R' are as defined above, with a compound of formula (VII) using reaction conditions analogous to those indicated for the reaction between the compound of formula (VI) and the compound of formula (VII) 3) by reaction of a compound of formula (XIII)
wherein B, R, A and R' are as defined above, with thiocyanic acid or a salt thereof using reaction conditions analogous to those indicated for the reaction between the compound of formula (VIII) and thiocyanic acid.
4) by treatment of a compound of formula (III) wherein R is H and the carboxy group is a free or esterified or protected carboxy group with a N-aminating agent, such as O-mesitylene-sulphonyl hydroxylamine, thus giving the ammonium mesitylene sulfonate salt of a compound (Ill) where R is -NH2 from which the free base can be obtained in a conventional manner.
The reaction may be performed in an inert solvent e.g. chloroform, methylene chloride, at temperature ranging from -300C to +400 C.
5) by treatment of a compound of formula (III) wherein R is hydrogen with an oxidizing agent, especially a peracid, for example, perbenzoic acid, m-chloro-perbenzoic acid, permaleic, pertrifluoroacetic acid, sodium periodate, hydrogen peroxide or a mixture of these with an inorganic or organic acid e.g. formic acid, acetic acid or trifluoroacetic acid, thus giving a compound of formula (III) wherein R is hydroxy which in turn may be etherified to give a compound of formula (III) where R is -OR3 in which R3 has the meanings reported above except hydrogen.
The oxidation reaction may be performed in a solvent e.g., dioxane methylene chloride, chloroform or methanol at a temperature preferably between about -300C and about 900C.
The etherification reaction may be performed in a conventional manner by known methods, e.g., by treatment with the appropiate alkyl halides or diazoalkanes.
6) by rearrangement of a compound of formula (XIV)
wherein A and R3 are as defined above, thus giving a compound of formula (III) where R is amino and
R1 is hydrogen.
The reaction may be performed by heating the compound (XIV) in acid medium, for instance hydrochloric acid, sulfuric acid, formic acid and the like. During this reaction the removal of the carboxy protecting groups possibly present may occur.
The compounds of formula (XIV) are known compounds.
The compound of formula (IV) may be prepared from a compound of formula (VI) by reaction with thiocyanic acid or a salt thereof, e.g., potassium thiocyanate in an inert solvent, preferably a dipolar solvent e.g. acetonitrile or N,N-dimethylacetamide.
The compounds of formula (V) are known or may be prepared by known methods.
The compounds of formula (VI) and (ill) are known compounds or may be prepared by known
methods.
The compounds of formula (VIII) may be prepared from compounds of formula iVI) by reaction with a compound of formula (V) using reaction conditions analogous to those indicated for the reaction
between the compound of formula (IV) and the compound of formula (V).
The compounds of formula (IX) wherein n is zero may be prepared, for example, by reacting 7
amino-cephalosporanic acid or a salt thereof with a compound of formula (III) or a reactive derivative
thereof using reaction conditions analogous to those described above for the reaction between the
compound of formula (II) and the compound of formula (III).
The compounds of formula (X) are known compounds or may be prepared by known methods.
The compounds of formulae (II), (it), (VI), (VIII), (IX) wherein n is 1 or 2 may be obtained by
oxidizing the corresponding compounds wherein n is zero as described above for the analogous
conversions on the compounds of formula (I).
The compounds of the present invention have a high antibacterial activity either in animals or in humans against gram-positive and gram-negative bacteria normally susceptible to cephalosporins such as staphylococci, streptococci, diplococci, Klebsiella, Escherichia coli, Proteus mirabilis, Salmonella, Shighella, Haemophilus and Neisseria.
The compounds of the invention are therefore useful in the treatment of the infections caused by said microorganisms, such as, respiratory tract infections, for example, bronchitis, bronchopneumonia, pleurisy, hepatobiliary and abdominal infections, for example, cholecistitis, peritonitis; blood and cardiovascular infections for example, septicemia; urinary tract infections, for example, pyelonephritis, cystitis; obstetrical and gynecological infections, for instance, cervicitis, endometritis; ear, nose and throat infections, for instance, otitis, sinusitis, parotitis.
The toxicity of the compounds of the invention is quite negligible and therefore they can be safely used in therapy.
The compounds of the invention may be administered, either to humans or to animals, in a variety of dosage forms, e.g., orally in the form of tablets, capsules, drops or syrups; rectally in the form of suppositories; parenterally, e.g., intravenously or intramuscularly (as solutions or suspensions), with intravenous administration being preferred in emergency situation; by inhalation in the form of aerosols or solutions for. nebulizers; intravaginally in the form e.g., of bougies; or topically in the form of lotions, creams and ointments. The pharmaceutical or veterinary compositions containing the compounds of the invention may be prepared in a conventional way by employing the conventional carriers and/or diluents used for the other cephalosporins.
Conventional carriers or diluents are, for example, water, gelatine, lactose, starches, magnesium stearate, talc, vegetable oils, cellulose and the like. Daily doses in the range of about 1 to about 100 mg per Kg of body weight may be used, in various animal species, the exact dose depending on the age, weight and condition of the subject to be treated and on the frequency and route of administration.
A preferred way of administration of the compounds of the invention is the parenteral one: in this
case the compounds may be administered for example, to adult humans, in an amount ranging from
about 100 mg to about 200 mg pro dose, preferably about 150 mg pro dose, 1-4 times a day,
dissolved in a suitable solvent, such as, for example sterile water or lidocaine hydrochloride solution for
intramuscular injections, and sterile water, physiological saline solution, dextrose solution or the
conventional intravenous fluids or electrolytes, for intravenous injections.
Furthermore, the compounds of the invention may be used as antibacterial agents in a
prophylactic manner, e.g. in cleaning or as surface disinfecting compositions, for example, at a
concentration of about 0.2 to 1% by weight of such compounds admixed with, suspended or dissolved
in conventional inert dry or aqueous carriers for application by washing or spraying.
They are also useful as nutritional supplements in animal feeds.
Assessment of melting point was somewhat difficult in some cases, as the compounds tend to
retain the solvent. In these cases, after the indication of the melting point, the word "dec."
(decomposition) was added.
The l.R. spectra were determined in a solid phase on a Perkin-Elmer 125 spectrophotometer.
N.M.R. spectra were determined in DMSO (dimethylsulphoxide) with a Perkin-Elmer R24-B (60
MHz) spectrometer with (CH3)4Si as internal standard.
The following examples iilustrate but do not limit the present invention.
Preparation 1
Ethyl 2-im ino-3-hydroxy-thiazoline-4-acetate Hydrochloride
To a solution of ethyl chloroacetoacetate (4.94 g) in acetonitrile (30 ml), potassium thiocyanate
(2.91 g) was added and the mixture was stirred for 12 hours at room temperature. The KCI precipitated
was filtered off and the solution was evaporated to dryness under vacuum. To the residue, dissolved in N,N-dimethylacetamide (10 ml), hydroxylamine hydrochloride (2.085 g) was added and the solution
was stirred overnight at room temperature. Ethyl ether (40 ml) was added to the solution, the solid
precipitated was filtered off, thus giving 6.0 g (83.5%) of the title compound, m.p. 1 68-1 700C (dec.).
N.M.R. (DMSO-d6): 1.27 (3H, t, -OCH2CH3) 3.89 (2H, s, -CH2-) 4.64 (2H, q, -OCH2-CH3) 6.85 (1H, s, 5-H on thiazoline ring)
9.5 (3H, br-s, -NH+2 and -OH).
By the same procedure the tert.butyl-2-imino-3-hydroxy-thiazoline-l4-acetate. Hydrochloride and
the benzhydryl-2-imino-3-hydroxy-thiazoline-4-acetate hydrochloride were obtained.
Preparation 2 2-imino-3-a mino-thiazoline-4-acetic Acid Hydrochloride
A mixture of ethyl-2-amino-6H-1 ,3,4-thiadiazine-5-acetate . hydrochloride (2.3 g) in 37% HCI (7
ml) was heated for 20 minutes at 60--700C. After cooling the obtained precipitate was filtered off and
then crystallized from methanol, thus giving 1.75 g (86%) of the title compound, m.p. 213-21 50C (dec.).
N.M.R. (DMSO-d6):
3.82 (2H,s, -CH2-) 6.12 (2H,s-N-NH2) 6.85 (1H, s, 5-H on thiazoline ring)
9.7 (3H, br-s, -OH and =NH+2)
The free base was obtained by treatment of the hydrochloride with sodium hydroxide, m.p.
205-2070C (dec.).
Preparation 3 2-imino-3-amino-thiazoline-4-acetic Acid Hydrochloride
A mixture of thiosemicarbazide (2 g) and ethyl chloroacetoacetate (3.6 g) in 37% HCI (15 ml) was heated for 3 hours at 600C; the white hydrochloride precipitated upon cooling. The product was filtered off and crystallized from methanol so obtaining 2.64 g (58%) of the title compound which was identical to that described in preparation 2.
Preparation 4 2-(N-chloroacetyl)-imino-3-hydroxy-thiazoline-4-acetic Acid
To a suspension of 2-(N-chloroacetyl)-imino-thiazoline-4-acetic acid (1.7 g) in acetonitrile (20 ml) a solution of diphenyldiazomethane (1.41 g) in acetonitrile (20 ml) was added dropwise under cooling at OOC. The reaction mixture was stirred for 3 hours at room temperature. The solution was then evaporated to dryness under vacuum; the residue was taken up with ethyl acetate, the solution was washed with aqueous sodium bicarbonate, and then dried.
After evaporating we obtained 2.2 g of the benzhydryl ester. To a solution of the above mentioned ester(1.6 g) in chloroform (10 ml) a solution of m-chloroperbenzoic acid (0.97 g) in chloroform (20 ml) was added under cooling at OOC. The reaction was then stirred for 3 hours at room temperature. Ethyl ether was then added, the solid precipitated was filtered off and washed with ethyl ether, thus giving 1.2 g of the benzhydryl ester of 2' (N-chloroacetyl)-imino-3-hydroxy-thiazoline-4acetic acid. A solution of this ester (1 g) in trifluoroacetic acid (TFA) (25 ml) was stirred for 1 hour at 0 C and then evaporated to dryness under vacuum. The residue was taken up with ethyl ether, and then filtered off, thus giving 0.6 g of 2-(N-chloroacetyl)-imino-3-hydroxy-thiazoline-4-acetic acid, m.p.
185-1 870C (dec.).
N.M.R. (DMSO-d6):
3.82 (211,s, -CH2-) 4.5 (2H,s,
7.1 (1H, s.5-H on thiazoline ring)
8.2 (2H, br-s, -OH and -COOH).
Preparation 5 2-(N-chloroacetyl)-imino-3-methoxy-thiazolirie-4-acetic Acid
To a suspension of benzhydryl ester of 2-(N-chloroacetyl)-imino-3-hydroxy-thiazoline-4-acetic acid (2.25 g) in dimethylformamide (25 ml) and water (2.5 ml), NaHCO3 (0.450 g) was added and the mixture was stirred for 2 hours at room temperature; then CH3l (1.5 ml) was added and the mixture was stirred for 6 hours at room temperature. The reaction mixture was diluted with water and extracted with ethyl acetate; the organic layer was washed with water, dried and evaporated to dryness under vacuum, thus giving 2.0 g of the benzhydryl ester of 2-(N-chloroacetyl)-imino-3 methoxy-thiazoline-4-acetic acid.
The ester was then hydrolyzed with TFA as reported in preparation 4, thus giving the title compound.
N.M.R. (DMSO-d6): 3.8 (2H, -CH2-)
4.15 (3H, s,OMe) 4.5(2H,s,-CO-CH2-CI)
6.7 (1H, s, 5-H on thiazoline ring).
Preparation 6
Ethyl 2-imino-3-amino-thiazoline-4-acetate Hydrochloride
To a solution of ethyl chloroacetoacetate (4.94 g) in acetonitrile (30 ml) potassium thiocyanate (2.91 g) was added and the mixture was stirred for 12 hours at room temperature. The KCI precipitated was filtered off and the solution was evaporated to dryness under vacuum. To the residue dissolved in
N,N-dimethylacetamide (10 ml), N2H4. HCI (2.09 g) was added, and the solution was stirred overnight at room temperature. Ethyl ether (40 ml) was added to the solution, the solid precipitated was filtered off so obtaining 5.0 g of the title compound.
N.M.R. (DMSO-d6):
1.27 (3H, t, -0-C112-CH3) 3.89 (2H, 5, -C112-) 4.64 (2H, q, -O-CH2-CH3) 8.12 (2H,s,-N-NH2)
6.85 (1H, s, 5-H on thiazoline ring)
9.7 (2H, br-s, -N11+2).
By the same procedure the tert. butyl-2-imino-3-amino-thiazoline-4-acetate hydrochloride and the benzhydryl-2-imino-3-amino-thiazoline-4-acetate hydrochloride were obtained.
Example 1 7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic
Acid (7)
To a suspension of 2-(N-chloroacetyl)-imino-3-methoxy-thiazoline-4-acetic acid (2.4 g) in anhydrous tetrahydrofuran (150 ml), 7-amino-cephalosporanic acid tert.butyl ester (2.91 g) was added under cooling at 50C and afterwards, dropwise, a solution of dicyclohexylcarbodiimide (1.92 g) in anhydrous tetrahydrofuran (30 ml) was added too. The reaction mixture was stirred for 3 hours at room temperature, then was filtered and the filtrate was evaporated to dryness under vacuum.The residue was taken up with ethyl acetate, the solid was filtered off, the filtrate was evaporated, the residue was taken up with ethyl ether, the precipitated product was filtered and washed with ethyl ether, thus giving 4.65 g of tert.butyl ester of 7ss-[2-(2-N-chloroacetyl-imino- 3-methoxy-4-thiazolinyl)-acetamido]3-acetoxy-methyl-3-cephem-4-carboxylic acid. A solution of this ester (1.495 g) and thiourea (0.188 g) in N,N-dimethylacetamide (10 ml) was stirred for 2 hours at room temperature. The solution was then diluted with ethyl acetate; a gummy material precipitated, the supernatant solvent was discarded and the residue was carefully triturated with fresh ethyl acetate until a powder was obtained.The product was collected by filtration, thus giving the tert.butyl ester of 7p-[2-(2-imino-3-methoxy-4- thiazoli nyl)-aceta mido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (1.1 g).
A solution of this compound (0.8 g) in trifluoroacetic acid (15 ml) was stirred for 70 minutes at room temperature. The solvent was then evaporated to dryness under reduced pressure; the residue was taken up with acetone, filtered off from undissolved material, the filtrate was evaporated to dryness, and the residue triturated with ethyl ether, thus giving 0.50 g of the title compound.
I.R. (KBr):
3320-3180 cm-1 NH
(ss-lactam) 1520 cm-1-CONH (secamide)
N.M.R. (DMSO-d6) ppm: 2.00 (3H, s,
3.74 (2H, d.d, -C112-in-2) 3.89 (2H, s, -C112-) 4.15 (3H,s,-OCH3)
4.8 (2H, q, -CH2-O-C0) 5.20 (111, d, 6-H)
5.83 (1H, d.d, 7-H)
6.82 (1H, s, 5-H on thiazoline ring)
9.4 (1H, br-s,=NH)
9.69 (1 d, -CONH).
Example 2
By proceeding according to Example 1 , the following compounds were obtained:
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-cephem-4-carboxylic acid ;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-2-hydroxy-acetamido]-3-cephem-4-carboxylic acid ;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-2-oxoacetamido]-3-cephem-4-carboxylic acid ;
7p-[2-(2-imino-3-methoxy-4-thiazoli nyl)-2-hydroxy-acetamido]-3-acetoxy-methyl-3-cephem-4carboxylic acid; 7p-[2-(2-imino-3-methoxy-4-thiazolinyi)-2-oxoacetamido]-3-acetoxy-methyl-3-cephem-4- carboxylic acid; 7p-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-1 (S)-oxo-3-acetoxy-methyl-3-cephem-4carboxylic acid:: 7fi-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-1 (R)-oxo-3-acetoxy-methyl-3-cephem-4carboxylic acid; 7P-[2-(2-imino-3-methoxy-4- thiazolinyl)-acetamido]- 1 -oxo-3-acetoxy-methyi-3-cephem-4carboxylic acid; 7,B-[2-(2-imino-3-amino-4-thiazolinyl)-acetamido]- 1 -dioxo-3-acetoxy-methyl-3-cephem-4carboxylic acid; 7p-[2-(2-imino-3-methoxy-4-thiazoli nyl)-acetamido]-3-[(1 -methyl-l ,2,3,4-tetrazol-5-yl)- thiomethyl]-3-cephem-4-carboxylic acid;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(1-(2-cyano-ethyl)-1-2,3,4-tetrazol-5yl)-thiomethyl]-3-cephem-4-carboxylic acid
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(5-methyl-1,3,4-thiadiazol-2-yl) thiomethylS-3-cephem-4-carboxylic acid;;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(tetrazolo[1,5-b]pyridazin-6-ylthiomethyl]-3-cephem-4-carboxylic acid ;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(8-carboxy-tetrazolo[1,5-b]pyridazin-6yl)-thlomethyl]-3-cephem-4-carboxylic acid ;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(8-carboxy-tetrazolo[1,5-b]pyridazin-6yl)-thiomethyl]-3-cephem-4-carboxylic acid ;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(8-carboxymethyl-tetrazolo[1,5b]pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid ;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-2-oxoacetamido]-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid ;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-2-hydroxy-acetamido]-3-[(1-methyl-1,2,3,4-tetrazol-5yl)-thiomethyl]-3-cephem-4-carboxylic acid.
Example 3 7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic Acid (14)
To a solution containing 2-(N-chloroacetyl)-imino-3-methoxy-thiazoline-4-acetic acid (5.48 g) and triethylamine (2.8 g) in anhydrous acetone (120 ml) some drops of N-methylmorpholine were added.
The mixture was cooled at - 10 C and then pivaloyl chloride (2.44 ml) dissolved in anhydrous acetone (30 ml) was added under stirring and then, after stirring for 30 minutes at - 10 C, a solution containing 7-amino-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-3-carboxylic acid (6.56 g) and triethylamine (2.8 ml) in 50% acetone (240 ml), cooled at - 20 C, was added after 30 minutes. The mixture was then stirred at -200C for 1 hour and afterwards at room temperature for 2 hours. The acetone was evaporated under vacuum. The residue was taken up with water, separated into layers with ethyl acetate and the pH of the mixture was brought to 2.5 with 40% H3PO4. After filtration, the ethyl acetate was separated and the organic phase was washed with water, dried on NazSO4 and evaporated to small volume.Ethyl ether was added to give a solid, which was filtered and stirred with ethyl ether. The solld was filtered again, thus giving 7.4 g of 7ss-[2-(2-N-chloroacetyl-imino-3methoxy-4-thiazolinyl)-acetamido]-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4carboxylic acid.
By treating the product with thiourea as reported in Example 1, the imino-protecting group was removed, thus giving the title compound.
I.R. (KBr): 1760cm-1
(ss-lactam)
1520 cm-l sec.amide
N.M.R. (DMSO-d6):
3.68 (2H, q, -CH2-in-2) 3.89 (211,s, -CH2) 3.94 (311,s, -CH3-N) 4.15 (3H, s, - OCH3)
4.31 (2H, q, -CH2-S) 5.10(111,d,-6-H) 5.63 (1 H, d-d, 7-H) 6.82 (111,5, 5-H on thiazoline ring) 9.2 (1H, d, - CONH)
9.4 (2H, br-s, =NH}.
Example 4
By proceeding according to Example 3, the following compounds were obtained:
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-cephem-4-carboxylic acid ;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-2-hydroxy-acetamido]-3-cephem-4-carboxylic acid ;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-2-oxoacetamido]-3-cephem-4-carboxylic acid ;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-acetoxy-methyl-3-cephem-4-carboxylic acid; 7,B-[2-(2-imino-3-methoxy-4-thiazolinyl)-2-hydroxy-aceta mido]-3-acetoxy-methyl-3-cephem4-carboxylic acid;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-2-oxoacetamido]-3-acetoxy-methyl-3-cephem-4carboxylic acid ;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-1(S)-oxo-3-acetoxy-methyl-3-cephem-4carboxylic acid ; ; 7,B-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]- 1 (R)-oxo-3-acetoxy-methyl-3-cephem-4carboxylic acid;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-1-dioxo-3-acetoxy-methyl-3-cephem-4carboxylic acid; 7,B-[2-(2-i mino-3-a mi no-4-thiazolinyl)-acetamido]- 1 -dioxo-3-acetoxy-methyl-3-cephem-4carboxylic acid;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(1-(2-cyano-ethyl)-1,2,3,4-tetrazol-5yl)-thiomethyl]-3-cephem-4-carboxylic acid ;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(tetrazolo[1,5-b]pyridazin-6-yl) thiomethyl]-3-cephem-4-ca rboxylic acid;;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(8-amino-tetrazolo[1,5-b]pyridazin-6yl)-thiomethyl]-3-cephem-4-carboxylic acid;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(8-amino-tetrazolo[1,5-b]pyridazin-6yl)-thiomethyl]-3-cephem-4-carboxylic acid;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(8-carboxy-methyl-tetrazolo[1,5b]pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid ;
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-2-oxoacetamido]-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid; 7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-2-hydroxy-aceta mido]-3-[(1 1-methyl-i 2,3,4-tetrazol- 5-yl)-thiomethyl]-3-cephem-4-carboxylic acid.
Example 5 7ss-[2-(2-imino-3-amino-4-thiazolinyl)-acetamido]-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic Acid Hydrochloride (a Salt of Compounds (23)
To a solution containing 2-(N-chloroacetyl)-imino-3-(N-chloroacetyl)-amino-thiazoline-4-acetic acid (3 g) in anhydrous acetone (60 ml) and triethylamine (1.24 ml) cooled at 0 C. isobutyl chloroformate (1.7 ml) dissolved in anhydrous acetone (16 ml) was added understirring.The stirring was continued for 30 minutes at-10 C. then the mixture was cooled at 300 C. A solution containing 7-amino-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (2.8 g) and triethylamine (4 ml) in 50% acetone (120 ml) was then added and the resulting mixture was stirred for 1 hour at a temperature between -200C and -300C, subsequently for 1 hour at a temperature between -50C to 0 C and afterwards for 3 hours at room temperature. The acetone was filtered and evaporated under vacuum; the residue was taken up with water (200 ml) and extracted with ethyl ether (2 x 100 ml). After separation the aqueous solution was brought to pH 2.5 with 10% hydrochloric acid and extracted with ethyl acetate.The organic phase was washed with water, dried on Na2SO4, concentrated to small volume and poured into cyclohexane so obtaining 7p-[2-(2-N-chloroacetyl- imino-3-N-chloroacetylamino-4-thiazolinyl)-acetamido]-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid. By treating this compound with thiourea as reported in
Example 1, the protecting groups were removed thus giving the title compound.
I.R. (KBr): 1760 cm-t
(p-lactam)
1520 cm-' sec.amide
N.M.R. (DMSO-d6):
3.68 (2H, q, -C112-in-2) 3.89 (2H, s -C112-) 3.94 (3H, s, -C113-N) 4.31 q, -C112-S) 5.10 (1H, d, 6-H)
5.63 (1H, d-d, 7-H)
6.12 (2H, s, -N-NH2)
6.82 (1H,s,-5-H) on thiazoline ring)
9.2 (2H, broad, -CONH and =NH).
Example 6
By proceeding according to Example 5, the following compounds were obtained:
7ss-[2-(2-imino-3-amino-4-thiazolinyl)-acetamido]-3-cephem-4-carboxylic acid ;
7ss-[2-(2-imino-3-amino-4-thiazolinyl)-2-hydroxy-acetamido]-3-cephem-4-carboxylic acid ;
7ss-[2-(2-imino-3-amino-4-thiazolinyl)-2-oxoacetamido]-3-cephem-4-carboxylic acid ;
7ss-[2-(2-imino-3-amino-4-thiazolinyl)-acetamido]-3-[(tetrazolo[1,5-b]pyridazin-6-yl) thiomethyl]-3-cephem-4-carboxylic acid;
7ss-[2-(2-imino-3-amino-4-thiazolinyl)-acetamido]-3-[(8-carboxy[1,5-b]pyridazin-6-yl)
thiomethyl]-3-cephem-4-carboxylic acid ; 7/3-[2-(2-imino-3-amino-4-thiazolinyl)-2-oxoacetamido]-3-[(1 i-methyl-i ,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid;;
7ss-[2-(2-imino-3-amino-4-thiazolinyl)-2-hydroxy-acetamido]-3-[(1-methyl-1,2,3,4-tetrazol-5yl)-thiomethyl]-3-cephem-4-carboxylic acid;
7ss-[2-(2-imino-3-amino-4-thiazolinyl)-2-hydroxy-acetamido]-3-[(1-(2-cyanoethyl)-1,2,3,4tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid;
7ss-[2-(2-imino-3-amino-4-thiazolinyl)-2-hydroxy-acetamido]-3-[(8-amino-tetrazolo[1,5 b]pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid;
7ss-[2-(2-imino-3-amino-4-thiazolinyl)-2-hydroxy-acetamido]-3-[(8-carboxy-tetrazolo[1,5b]pyridazin-8-yl)-thiomethyl]-3-cephem-4-carboxylic acid.
Example 7 7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(8-amino-tetrazolo[1,5-b]pyridain-8yl)-thiomethyl]-3-cephem-4-carboxylic Acid (18)
To a solution of 7-a mino-3-[(tetrazolo [1,5-b]pyridazin-8-amino-6-yl)-thiomethyl]-3-cephem-4- carboxylic acid (3.80 g) and NaHCO3 (2 g) in 50% aqueous acetone (60 ml), cooled at OOC, a solution of 2-(N-chloroacetyl)-imino-3-methoxy-thiazolinyl-4-acetic acid chloride (obtained from the acid by reaction with oxalyl chloride in dimethylformamide at 0 C in acetone (30 ml) was added under stirring. The mixture was stirred for 20 minutes at a temperature between 0 C and 50C. The acetone was evaporated; ethyl acetate was added to the resulting aqueous solution which was then acidified with 8% hydrochloric acid to pH 2.The organic phase was washed with water, dried and evaporated under vacuum. The residue was treated with ethyl ether and filtered. The product so obtained was dissolved in N,N-dimethylacetamide and then treated with thiourea as reported in Example 1, to give the title compound.
I.R. (KBr):
(p-lactam) 1520 cm-1 sec.amide
N.M.R. (DMSO-d6): 3.74 (2H, q,-C112-in-2) 3.89 (211,s, -C112-) 4.15 (3H, 5, s,OCH3) 4.36 (2H, d-d, -C112-S) 5.20 (2H, d, 6-H)
5.83 (1H, d-d, 7-H) 6.41(111, s, 7-H on pyridazine ring)
6.82 (111,s, 5-H on thiazoline ring)
8,02 (2H, broad s,-NH2 on pyridazine ring)
9.4-9.69 (2H, broad,- CONH and=nh).
Example 8
7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(8-amino-tetrazolo[1,5-b]pyridazin-6
yl)-thiomethyl]-3-cephem-4-carboxylic Acid (18)
To a solution containing the sodium salt of the 7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)- acetamido]-3-acetoxy-methyl-3-cephem-4-carboxylic acid (5.1 g) in acetone (40 ml) and buffer phosphate (pH 7) (200 ml), 6-mercapto-8-amino-tetrazolo[1 ,5-b]pyridazine (1.9 g) and NaHCO3 (1.84 g) were added and the mixture was stirred for 6 hours at 600C. Then it was cooled, separated into layers with ethyl acetate and acidifed with 10% HCI until the pH was brought to 2. The two phases system was filtered, the organic phase was separated; the aqueous phase was brought to pH 4.5 with
10% NH3 and extracted with ethyl acetate.The organic phase was washed with water, dried and evaporated to dryness, thus yiving the title compound, which was identical to that already reported in
Example 7.
By proceeding analogously, also the other 3-heterocyclylthiomethyl compounds of the invention listed above were prepared.
Example 9 7ss-[2-(2-imino-3-amino-4-thiazolinyl)-acetamido]-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)-] thiomethyl]-3-cephem-4-carboxylic Acid (14)
To a suspension containing 2-(N-chloroacetyl)-imino-3-methoxy-thiazoline-4-acetic acid (2.9 g) in anhydrous tetrahydrofuran (200 ml), cooled to OOC, dicyclohexylcarbodiimide (2.1 g) was added.
The reaction mixture was stirred for 10 minutes at 0 C and then for 40 minutes at room temperature.
This solution was then added to a solution, cooled to -50C, containing 7-amino-3-[(1 -methyl-1,2,3,4 tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (3.7 g) and N,0-bis-trimethylsilylacetamide (9 g) in a mixture of anhydrous tetrahydrofuran (260 ml), dimethylformamide (4 ml) and CH3CN (100 ml).
The mixture was stirred for 20 minutes at OOC and then for 30 minutes at room temperature. After evaporating to dryness under reduced pressure, the residue was treated with water (300 ml) and ethyl acetate (400 ml). The organic layer was separated, the undissolved material was filtered off and treated again with ethyl acetate (400 ml). The combined organic layers were evaporated to small volume thus giving a product which, after dissolving in N,N-dimethylacetamide, was treated with thiourea as reported in Example I, to give the title compound, which is identical to that described in
Example 3.
Example 10 Pivaloyloxymethyl 7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido-3-[8-amino- tetrazolo[1,5-b]pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic Acid (an Ester of Compound (18))
To a suspension of sodium salt of 7ss-[2-(2-imino-3-methoxy-4-thiazolinyl-acetamido]-3-[(8- amino-tetrazolo[1,5-b]pyridazin-6-yl)-thiomothyl]-3-cephem-4-carboxylic acid (2.74 g) in acetone (40 ml), a 10% solution of sodium iodide in water (0.4 ml) and chloromethyl pivalate (0.72 ml) was added.
The suspension was heated for 3 hours under reflux and after cooling at 50C, the solid was filtered off and the resulting solution evaporated under vacuum. The oily residue was dissolved in ethyl acetate (50 ml), the resulting solution washed with a 5% solution of NaHCO3 in water and then with water, dried and evaporated to dryness so obtaining the pivaloyloxymethyl ester of 7B-[2-(2-imino-3- methoxy-4-thiazolinyl)-acetamido]-3-[(8-a mino-tetrazolo 1 ,5-b] pyridazin-6-yl)-thiomethyl]-3-cephem4-carboxylic acid.
Analogously, the pivaloyloxymethyl esters of the compounds described in the preceding
examples were obtained.
Claims (41)
1. Compounds of general formula (I)
wherein
A is or
wherein R2 represents a hydrogen atom or a free or protected hydroxy group;
R is 1)--OR, in which R3 is hydrogen or a branched or straight chain saturated or unsaturated C1-C8 aliphatic hydrocarbon group which is unsubstituted or substituted by one or more substituents selected from
a) cyano, b) -COOR' in which R' is hydrogen, C,C-alkyl or a carboxy-protecting group; c)
in which each of the groups R4 and R5, which may be the same or different, represents a hydrogen atom, a C1-C6 alkyl or a C2-C6 aliphatic acyl group, or, when R4 is hydrogen, B5 may be also an amino-protecting group; or
wherein R4 and R5 are as defined above;
R, is hydrogen or an amino-protecting group;
n is zero, 1 or 2;
Y is a') hydrogen; b') halogen; c') hydroxy; d') C1-C5 alkoxy; e') C1-C6 alkyl; f')-CH2OCOCH3 g') a group
where R" may be hydrogen, C1-C8 alkyl, carboxy, cyano or carbamoyl; h') a group -CH2-S-Het, wherein Het represents
1) a pentatomic or hexatomic heteromonocyclic ring containing at least one double bond and at least one heteroatom selected from N, S and 0, which ring may be unsubstituted or substituted by one or more substituents selected from::
a") hydroxy, C1-C6 alkoxy, halogen, C2-C6 aliphatic acyl;
b") C1-C5 alkyl unsubstituted or substituted by one or more substituents selected from hydroxy
and and halogen;
c')C2-C8 alkenyl unsubstitued or substituted by one or more substituents selected from
hydroxy and halogen;
d8)-S-R6 wherein R6 is hydrogen or C1-C8 alkyl -S-CH2COOB' wherein R' is as defined
above;
e")-(CH2)m-COOR1,-CH=CH-COOR',-(CH2)m-CONH2 or-(CH2)m-CN wherein m is zero, 1, 2 or 3 and R' is as defined above;
f")-(CH2)mSO3H wherein m is as defined above; or
wherein m, R4 and R5 are as defined above; or
2) a heterobicyclic ring containing at least two double bonds wherein each of the condensed heteromonocyclic rings thereof is the same or different pentatomic or hexatomic heteromonocyclic ring containing at least a heteroatom selected from N, S and 0, the heterobicyclic ring being unsubstituted or substituted by one or more substituents selected from a"), b"), c"), d"), e"), f") and g") defined above; X is a free or esterified carboxy group; provided that when A is a -CH2- group, R is not -OH; and the pharmaceutically and veterinarily acceptable salts of compounds of general formula (I).
2. Compounds according to Claim 1, wherein
R1 is hydrogen or an amino-protecting group ;
Ris -O-C1-C6-alkyl ; -o-C2-C8-alkenyl; -O-(CH2)m1-COOR',R' being as defined in
Claim 1 and m1 is 1,2 or 3; NH2,-NHCH3-N9CH3)2;-NHCOCH3 or NHCOO-C(C113)3; Ais-C112-,
Y is hydrogen, halogen, hydroxy, C1-C6 alkoxy, -methyl, -CH2OCOCH3 or C112-S-Het wherein Het is::
1) a tetrazolyl radical, unsubstituted or substituted by C1-C3-alkyl, C2-C4 alkenyl,-(CH2)m1-
COOR' wherein m1 is as defined above and R' is as defined in Claim 1, -CH=CH-COOR' wherein R is as defined in Claim 1.-(CH2)m1-CN,-(CH2)m1-CONH2,-(CH2)m1-SO3H wherein m1 is as defined above, or
wherein m, is as defined above and Rd and Rs are as defined in Claim 1;;
2) a thiadiazolyl radical, unsubstituted or substituted by C1-C4-alkyl, C2-C4 alkenyl, -SH, -SCH3,-S-CH2COOH, -(CH2)m-COOH wherein m is as defined in Claim 1,
wherein R4 and R5 are hydrogen or C1-C3 alkyl, or
3) a heterobicyclic ring selected from tetrazolopyridazinyl, tetrazolopyrazinyl, thiadiazolopyridazinyl and triazolopyridazinyl, each of which is unsubstituted or substituted by hydroxy, --SH,
R4 and Rs being as defined above, -COOR' wherein R' as as defined in Claim 1, C1-C3 alkyl, kyl,C2-C4 alkenyl, -S-CH2COOR', -C11=CH-COOR' R' being as defined in Claim 1, or
3,7ss-[2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-cephem-4-carboxylic acid.
4,7ss-[2-imino-3-methoxy-4-thiazolinyl)-2-hydroxy-acetamido]-3-cephem-4-carboxylic acid.
5,7ss-[2-imino-3-methoxy-4-thiazolinyl)-2-oxoacetamido]-3-cephem-4-carboxylic acid.
6,7ss-[2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid.
7,7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-2-hydroxy-acetamido]-3-acetoxy-methyl-3-cephem4-carboxylic acid.
8. 7P-[2-(2-i mino-3-methoxy-4- thiazolinyl)-2-oxoacetamido]-3-acetoxy-methyl-3-cephem-4- carboxylic acid.
9.7ss-[2-imino-3-methoxy-4-thiazolinyl)-acetamido]-1(S)-oxo-3-acetoxy methyl-3-cephem-4carboxylic acid.
10.7ss-[2-imino-3-methoxy-4-thiazolinyl)-acetamido]-1(R)-oxo-3-acetoxy-methyl-3-cephem4-carboxylic acid;
11. 7P-[2-(2-imino-3-methoxy- 4-thiazolinyl)-acetamido]- 1 -dioxo-3-acetoxy-methyl-3-cephem- 4-carboxylic acid;
12.7ss-[2-(2-1 mino-3-methoxy-4-thiazolinyl)-acetamido]-3-[( i-methyl- 1,2 ,3,4-tetrazol-5-yl)- thiomethyl]-3-cephem-4-carboxylic acid;
13. 7-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[( 1 -(2-cyanoethyl)- 1 ,2,3,4-tetrazol- 5-yl)-thiomethyl]-3-cephem-4-carboxylic acid;
14. -[2-(2-imino-3-methoxy-4-thiazolinyl)-acetam jdo]-3-[(5-methyl- 1 ,3,4-thiadiazol-2-yl)thiomethyl]-3-cephem-4-carboxylic acid;
15.7ss-[2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(tetrazolo[1,5-bipyridazin-6-yl)thiomethyl]-3-cephem-4-ca rboxylic acid;;
16.7ss-[2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3[(8-amino-tetrazolo[1,5-b]pyridazin6-yl)-thiomethyl]-3-cephem-4-carboxylic acid;
17.7ss-[2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(8-carboxy-tetrazolo[1,5 bi pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid.
18.7ss-[2-(2-imino-3-methoxy-4-thiazolinyl)-acetamido]-3-[(8-carboxymethyltetrazolo[1,5-b]pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid.
1 9. 7-[2-(2-imino-3-methoxy-4-thiazolinyl)-2-oxoacetamido]-3-[( i-methyl-i ,2,3,4-tetrazol-5- yl)-thiomethyl]-3-cephem-4-carboxylic acid.
20.7ss-[2-imino-3-methoxy-4-thiazolinyl)-acetamido]-2-hydroxy-acetamido]-3-[(1-methyl-1,2,3,4tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid;
21. Pharmaceutically and verterinarily acceptable salts of a compound claimed in any one of
Claims 3 to 20.
22.7ss-[2-imino-3-amino-4-thiazolinyl)-acetamido]-3-cephem-4-carboxylic acid.
23.7ss-[2-imino-3-amino-4-thiazolinyl)-acetamido]-2-hydroxy-acetamido]-3-cephem-4-carboxylic acid
24.7ss-[2-imino-3-amino-4-thiazolinyl)-acetamido]-2-oxoacetamido]-3-cephem-4-carboxylic acid.
25.7ss-[2-imino-3-amino-4-thiazolinyl)-acetamido]-1-dioxo-3-acetoxymethyl-3-cephem-4carboxylic acid.
26.7ss-[2-imino-3-amino-4-thiazolinyl)-acetamido]-3-[(1-methyl-1,2,3,4-tetrazol-5-yl) thiomethyl]-3-cephem-4-carboxylic acid.
27.7ss-[2-imino-3-amino-4-thiazolinyl)-acetamido]-3-[(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl]-3-cephem-4-carboxylic acid.
28.7ss-[2-imino-3-amino-4-thiazolinyl)-acetamido]-3-[(8-carboxytetrazolo[1,b-b]pyridazin-byl)-thiomethyl]-3-cephem-4-carboxylic acid.
29.7ss-[2-(2-imino-3-amino-4-thiazolinyl)-2-oxoacetamido]-3-[(1 i-methyl-i ,2,3,4-tetrazol-5-yl)- thiomethyl]-3-cephem-4-carboxylic acid.
30.7ss-[2-(2-imino-3-amino-4-thiazolinyl)-2-hydroxy-acetamido]-3-[(1-methyl-1,2,3,4- tetrazol-5-yl)-thiomethyl-3-cephem-4-carboxylic acid.
31.7ss-[2-imino-3-amino-4-thiazolinyl)-2-hydroxy-acetamido]-3-[(1-(2-cyanoethyl)-1,2,3,4tetrazol- 5-yl)-thiomethyl]-3-cephem-4-carboxylic acid.
32.7ss-[2-imino-3-amino-4-thiazolinyl)-2-cetamido]-3-[(8-amino-tetrazolo[1,5 b]pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid.
33. 7-[2-(2-imino-3-amino-4-thiazolinyl)-2-hydrnxy-acetamido]-3-[(8-carboxy-tetrazolo[ 1,5- b]pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid.
34.7ss-[2-imino-3-amino-4-thiazolinyl)-2-hydroxy-acetamido]-3-[(8-carboxytetrazolo[1,5-b]pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid.
35. Pharmaceutically and verterinarily acceptable salts of a compound claimed in any one of
Claims 22 to 34.
36. Compounds according to Claim 1 specifically hereinbefore named and their pharmaceutically and verterinarily acceptable salts, excluding compounds claimed in Claims 3 to 35.
37. A process for the preparation of a compound claimed in Claim 1, said process comprising:
a) reacting a compound of formula (II)
wherein
n, X and Y are as defined in Claim 1, and E is amino, --N=C=O or -N=C=S or a reactive derivative thereof, with a compound of formula (III)
wherein
R, R, and A are as defined in Claim 1, or a reactive derivative thereof, and, if desired, removing the protecting groups, where present; or
b) reacting a compound of formula (IV)
wherein
A, n, X and Y are as defined in Claim 1, or a reactive derivative thereof, with a compound of formula (V) B-NH2 (V) wherein
R is as defined in Claim 1, or a salt thereof and, if desired, removing the protecting group possibly present, or
c) reacting a compound of formula (VI)
wherein
A, n, X and Y are as defined in Claim 1, and B is halogen, or a reactive derivative thereof, with a compound of formula (VII)
wherein R and R, are as defined in Claim 1, and, if desired, removing the protecting groups where present; or
d) reacting a compound of formula (VIII)
wherein
B, R, A, n, X and Y are as defined in Claim 1, with thiocyanic acid or a salt thereof, and, if desired, removing the protecting groups, where present, or
e) reacting a compound of formula (IX)
wherein
R, R,, A, n and X are as defined in Claim 1, or a salt thereof, with a compound of formula (X) 115-Het (X) wherein
Het is as defined above, or a reactive derivative thereof, and if desired, removing the protecting groups, where present, and/or, if desired, converting a compound of formula (I) where X is carboxy into a pharmaceutically or verterinarily acceptable salt and/or, if desired, obtaining a free compound from a salt and/or, if desired, converting a compound of formula (I) or a salt thereof into another compound of formula. (I) or a salt thereof.
38. A process according to Claim 37, substantially as hereinbefore described with reference to any one of the Examples.
39. Compounds according to Claim 1 when obtained by a process claimed in Claim 36 or 37.
40. A pharmaceutical or veterinary composition containing a compound according to any one of
Claims 1 to 35 or Claim 39 and a pharmaceutically or verterinarily acceptable carrier and/or diluent.
New Claims or Amendments to Claims filed on 16.1.81.
Superseded Claim 2
New or Amended Claims:
2. Compounds according to Claim 1, wherein
R1 is hydrogen or an amino-protecting group:
R is-O-C1-C6-alkyl ; -O-C2-C6-alkenyl ; -O-(CH2)m1-COOR', R' being as defined in
Claim 1 and m1 is 1,2 or 3 ; NH2-NH2, -NHCH3,-N(CH3)2; -NHCOCH3 or NHCOO-C(CH3)3 Ais-C112-,
Y is hydrogen, halogen, hydroxy, C1-C6 alkoxy, -methyl2-CH2OCOCH3 or CH2-S-Het wherein Het is::
1) a tetrazolyl radical, unsubstituted or substituted by C1-C3-alkyl, C2-C4 alkenyl, (CH2)mi COOR' wherein m, is as defined above and R' is as defined in Claim 1, -CH=CH-COOR' wherein R' is as defined in Claim 1,-(CH2)m1-CN-(CH2)m1-CONH2,-(CH2)m1-SO3H wherein m, is as defined above, or
wherein m, is as defined above and R4 and R5 are as defined in Claim 1;;
2) a thiadiazolyl radical, unsubstituted or substituted by C1-C4-alkyl, C2-C4 alkenyl,-SH, -SCH3, -S-CH2COOH,-(CH2)m-COOH wherein m is as defined in Claim 1,
wherein R4 and R5 are hydrogen or C1-C3 alkyl, or
3) a heterobicyclic ring selected from tetrazolopyridazinyl, tetrazolopyrazinyl, thiadiazolopyridazinyl and triazolopyridazinyl, each of which is unsubstituted or substituted by hydroxy, -SH,
R4 and R5 being as defined above, -COOR' wherein R' is as defined in Claim 1, C1-C3 alkyl, C2-C4 alkenyl,-S-CH2COOR',-CH2COOR',-CH=CH-COOR' R' being as defined in Claim 1, or
41. A compound or salt according to any one of Claims 1 to 36 or 39 or a composition according to Claim 40 for use in a method of treatment of the human or animal body by surgery or therapy or of diagnosis practised on the human or animal body.
Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7942241A GB2065098A (en) | 1979-12-07 | 1979-12-07 | N-substituted Thiazolyl Derivatives of 7-amino- cephalosporanic Acid |
| DE19803045343 DE3045343A1 (en) | 1979-12-07 | 1980-12-02 | N-SUBSTITUTED THIAZOLYL DERIVATIVES OF 7-AMINO-CEPHALSOSPORANIC ACID, METHOD FOR THE PRODUCTION THEREOF AND THEIR CONTAINING PHARMACEUTICAL AND VETERINE MEDICAL AGENTS |
| JP17253480A JPS5692292A (en) | 1979-12-07 | 1980-12-05 | Nnsubstituted thiazolyl derivative of 77aminocephalosporanic acid |
| BE0/203084A BE886545A (en) | 1979-12-07 | 1980-12-08 | N-SUBSTITUTED THIAZOLYL DERIVATIVES OF 7-AMINO-CEPHALOSPORANIC ACID |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB7942241A GB2065098A (en) | 1979-12-07 | 1979-12-07 | N-substituted Thiazolyl Derivatives of 7-amino- cephalosporanic Acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| GB2065098A true GB2065098A (en) | 1981-06-24 |
Family
ID=10509687
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB7942241A Withdrawn GB2065098A (en) | 1979-12-07 | 1979-12-07 | N-substituted Thiazolyl Derivatives of 7-amino- cephalosporanic Acid |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JPS5692292A (en) |
| BE (1) | BE886545A (en) |
| DE (1) | DE3045343A1 (en) |
| GB (1) | GB2065098A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITPI20090140A1 (en) * | 2009-11-09 | 2011-05-10 | Univ Pisa | COMPOUND INHIBITOR OF THE ENZYME LACTATE DEHYDROGENASE (LDH) AND PHARMACEUTICAL COMPOSITION INCLUDING SUCH COMPOUND |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5877886A (en) * | 1981-11-02 | 1983-05-11 | Toyama Chem Co Ltd | Novel cephalosporin |
| US4502988A (en) * | 1983-08-08 | 1985-03-05 | Eli Lilly And Company | Oxidation process |
-
1979
- 1979-12-07 GB GB7942241A patent/GB2065098A/en not_active Withdrawn
-
1980
- 1980-12-02 DE DE19803045343 patent/DE3045343A1/en not_active Withdrawn
- 1980-12-05 JP JP17253480A patent/JPS5692292A/en active Pending
- 1980-12-08 BE BE0/203084A patent/BE886545A/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ITPI20090140A1 (en) * | 2009-11-09 | 2011-05-10 | Univ Pisa | COMPOUND INHIBITOR OF THE ENZYME LACTATE DEHYDROGENASE (LDH) AND PHARMACEUTICAL COMPOSITION INCLUDING SUCH COMPOUND |
| WO2011054525A1 (en) * | 2009-11-09 | 2011-05-12 | Universita' Di Pisa | Compounds inhibitors of enzyme lactate dehydrogenase (ldh) and pharmaceutical compositions containing these compounds |
Also Published As
| Publication number | Publication date |
|---|---|
| BE886545A (en) | 1981-06-09 |
| DE3045343A1 (en) | 1981-08-27 |
| JPS5692292A (en) | 1981-07-25 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| WAP | Application withdrawn, taken to be withdrawn or refused ** after publication under section 16(1) |