GB2076801A

GB2076801A - alpha , beta -Disubstituted Acrylamido Cephalosporins

Info

Publication number: GB2076801A
Application number: GB8012212A
Authority: GB
Original assignee: Farmitalia Carlo Erba SRL
Current assignee: Pfizer Italia SRL
Priority date: 1980-04-14
Filing date: 1980-04-14
Publication date: 1981-12-09
Also published as: BE888389A; DE3111159A1; JPS56161394A

Abstract

Compounds having the following general formula (I> <IMAGE> wherein Z is-O-or-S-; A is phenyl or a pentatomic or hexatomic heteromonocyclic ring containing at least a double bond and at least one heteroatom selected from N, S and O, the phenyl and the heteromonocyclic ring being unsubstituted or substituted by one or more specified substituents R is hydrogen, -OCH3 or -SCH3; R1 is hydrogen or a branched or straight chain, saturated or unsaturated C1-C6 aliphatic hydrocarbyl group, which is unsubstituted or substituted by one or more substituents selected from hydroxy, cyano, -COHN2 and -COOR5, wherein R5 is H, C1-6 alkyl, acetoxymethyl or a carboxy-protecting group; Y is: hydrogen or one of various specified substituents M is a carboxylic acid or ester group, and the pharmaceutically and verterinarily acceptable salts thereof are useful as gram-positive and gram- negative antibacterial agents and are useful, inter alia, against Pseudomonas aeruginosa strains which are normally resistant to most cephalosporins.

Description

SPECIFICATION α,ss-Disubstituted Acrylamido Cephalosporins The present invention relates to 7-αss-disubstitued-acrylamido cephalosporins, to a process for their preparation and to pharmaceutical and veterinary compositions containing them.

The compounds of the invention have the following general formula (I)

wherein Z isO- or-S-; A is phenyl or pentatomic or hexatomic heteromonocyclic ring containing at least a double bond and at least one heteroatom selected from N,S and 0, the phenyl and the heteromonocyclic ring being unsubstituted or substituted by one or more substituents selected from:: a) C1-C6 alkyl; b) halogen; c) halo-C1-C8-alkyl; d)

wherein each of the groups R2 and R3, which may be the same or different, is hydrogen, C1-C6 alkyl, C1-C7 acyl or one of R2 and R3 is hydrogen and the other is an amino-protecting group; e) -OR4 wherein R4 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl or a hydroxy-protecting group; or f) a group-O-(CH2)m-COO R5 wherein m is 1, 2 or 3 and R5 is hydrogen, C1-C6 alkyl, acetoxymethyl or a carboxy-protecting group; R is hydrogen, -OCH3 or-SCH3; R, is hydrogen or a branched or straight chain, saturated or unsaturated C1-C6 aliphatic hydrocarbyl group, which is unsubstituted or substituted by one or more substituents selected from hydroxy, cyano, -CONH2 and-COOR5, wherein R5 is as defined above; Y is:: 1 ) hydrogen; 2) halogen; 3) hydroxy; 4) C1-C6 alkoxy; 5) -CH2-OCOCH3; 6)

wherein R6 is hydrogen, C1-C6 alkyl, carboxy, cyano or carbamoyl, or 7)-CH2-S-Het, wherein Het represents a') a pentatomic or hexatomic heteromonocyclic ring containing at least one double bond and at least one heteroatom selected from N,S or 0, the heteromonocyclic ring being unsubstituted or substituted by one or more substituents selected from:: a") hydroxy, C1-C6 alkoxy, halogen, C1-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-R7, wherein R7 is hydrogen or C1-C6 alkyl, or -S-CH2COOR', wherein R' is hydrogen, C1-C6 alkyl or a carboxy-protecting group; e")-9CH2(n-COOR'. -CH=CH-COOR',

or-(CH2)n-CN wherein n is zero, 1,2 or 3 and R', R2 and R3 are as defined above; f") CH2)nSO3H, wherein n is as defined above;; g")

wherein n, R2 and R3 are as defined above; or h") a heterobicyciic ring containing at least two double bonds wherein each of the condensed heteromonocyclic ring which may be the same or different, is a pentatomic or hexatomic heteromonocyclic ring containing at least one heteroatom selected from the group consisting of N, S and 0, the heterobiocyclic ring being unsubstituted or substituted by one or more substituents selected from the groups a"), b"), c"), d"), e"), f"), and g") indicated above;; M is a free or esterified carboxy group, (i.e. carboxylic acid or ester group) and the pharmaceutically and veterinarily acceptable salts of the compounds of formula (i) as well as all the possible isomers, e.g. syn and anti-isomers, cis and trans isomers and optical isomers, and their mixtures, the metabolites provided with antibacterial activity and the metabolic precursors of the comounds of formula (I).

In particular when in the compounds of formula (I) R is hydrogen, the 7chain may be both in the syn and in the anti-configuration: as already said both the single syn and anti isomers of the compounds of formula (I) and their mixtures are included in the scope of the invention. When in the compound of formula (I) A represents, according to one of the preferred features of the invention, a 2amino-thiazol-4-yl group, it may take either or both the two tautomeric forms (la) and (lb)

(thiazoline form) (thiazole form), each of which tautomeric forms is to be regarded as within the scope of formula (I). R3 in formula la and lb is as defined above.

Amino, hydroxy- and carboxy-protecting groups, are the protecting groups usually employed in the chemistry of peptides. Examples of amino-protecting groups are formyl, an optionally halosubstituted C1-C6 aliphatic acyl, preferably chloroacetyl or dichloroacetyl, tert-butoxycarbonyl, pnitrobenzyloxycarbonyl or trityl.

The hydroxy groups, when present, if desired may be protected. Examples of hydroxy-protecting groups are formyl, acetyl, chloroacetyl, dichloroacetyl, trifluoroacetyl, tetrahydropyranyl, trityl or silyl, especially trimethylsilyl or dimethyl-tert-butyl silyl. Examples of carboxy-protecting groups are tertbutyl, benzhydryl, p-methoxy benzyl, p-nitrobenzyl, trityl and trialkylsilyl.

When R1 is C1-C5 aliphatic hydrocarbon group as defined above it is preferably C1-C6 alkyl, most preferably methyl, ethyl, n-propyl or isopropyl, or C2-C3 alkenyl, preferably allyl, optionally substituted as indicated above.

When A is a pentatomic or hexatomic heteromonocyclic ring it is preferably furyl, thienyl, thiazolyl, thiadiazolyl, and imidazolyl, triazolyl, pyridazinyl, most preferably 2-furyl, 2-thienyl or 2amino-4-thiazolyl, all optionally substituted as indicated above.

When Y is a pentatomic or hexatomic heteromonocyclic ring as defined above it is preferably tetrazolyl or thiadiazolyl, most preferably tetrazolyl, optionally substituted as indicated above.

When Y is a heterobicyclic ring as defined above it is preferably tetrazolo-pyridazinyl, tetrazolo pyrazinyl, thiadiazolo-pyridazinyl or triazolo-pyridazinyl, most preferably 6-tetrazolo[ 1 5-hi pyridazinyl, optionally substituted as indicated above.

The alkyl, alkenyl and acyl groups may be branched or straight chain groups. A C1-C6 alkyl group is preferably methyl or ethyl. A C2-C6 alkenyl group is preferably C2-C4 alkenyl most preferably allyl.

A C1-C7 acyl group is preferably C2-C8 alkanoyl, most preferably acetyl or propionyi, or benzoyl. A halogen atom is preferably chlorine, fluorine or bromine. A halo-Ci-Ce alkyl group is preferably a trihalo -C1-C6 alkyl group, most preferably trifluoromethyl. When M is an esterified carboxy group it is preferably a group of formula -COOT, wherein T is one of the radicals

wherein R8 is hydrogen or C1-C6 alkyl: Q is -0- or -NH-; R9 is an alkyl group (e.g.C1-C8 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. R9 is alkyl -NH-CH3, aralkyl-NH-CH3, alkyl

-CH2NH2; R10 is an alkyl group, preferably a C1-C6 alkyl group, e.g. methyl, propyl or isopropyl; an aryl group, preferably phenyl; a cycloalkyl group, preferably cyclopentyl, cyclohexyl or cycloheptyl; a heteromonocyclic ring, e.g. pyridyl, a bicyclic ring, e.g. indanyl; or an aralkyl group, e.g. benzyl.

The pharmaceutically and veterinarily acceptable salts of the compounds of formula (I) include salts formed with inorganic acids, such as hydrochloric acid or sulphuric acid, or with organic acids, such as citric, tartaric, malic, maleic, mandelic, fumaric or methane-sulphonic acid and with inorganic bases such as sodium, potassium, calcium or aluminium hydroxides and alkali metal or alkaline earth metal carbonates or bicarbonates, or vvith organic bases, such as organic amines, e.g., lysine, triethylamine, procaine, dibenzylamine, N-benzyl-p-phenethylamine, N,N'-dibenzyl-ethylenediamine, dehydroabietylamine, N-ethyl-piperidine, diethanolamine, N-methylglucamine, tris-hydromethylaminomethane and the like. Also the internal salts, i.e. zwitterions, are included in the scope of the invention.

A preferred class of compounds of the invention is those of formula (I), wherein R is hydrogen or-S-CH3; Z is -O- or -S-; R, is hydrogen; C1-C6 alkyl; C2-C4 alkenyl; -(CH2)-COOH; -(CH2)n-CN; -(CH2)N-CONH2 wherein n is as defined above;

A is phenyl, thienyl or

wherein R11 is hydrogen or an amino-protecting group and R12 is hydrogen; hydroxy; -O-C1-C6 alkyl; -O-C2-C4 alkenyl; -O-(CH2)m-COOR2, wherein m and R2 are as defined above; Y is hydrogen, halogen, hydroxy, C1-C3-alkoxy; -CH2-OCOCH3, or -CH2-S-Het, wherein Het is 1) a tetrazolyl radical unsubstituted or substituted by C1-C3 alkyl; C2-C4 alkenyl; (CH2)rn COOR', -CH=CH-COOR', - (CH2)m-CN,-(CH2)m-CONH2, -(CH2)m-SO3H, -(CH2)m

wherein m, R' , R2 and R3 are as defined above; 2) a thiadiazolyl radical unsubstituted or substituted by C1-C4 alkyl; C2-C4 alkenyl; -SH; -SCH3; -SCH2COOH;-(CH2)n-COOH,

wherein each of R2 and R3 is independently hydrogen or C1-C3 alkyl and n is as defined above; or 3) a heterobicyclic ring selected from tetrazolopyridazinyl tetrazolopyrazinyl, thiadiazolopyridazinyl and triazolopyridazinyl, each of which is optionally substituted by hydroxy; -SH;

wherein R2 and R3 are as defined above; C1-C3 alkyl; C2-C4 alkenyl; -COOR', S-CH2COOR', CH2-COOR', -CH=CH-COOR', wherein R' is as defined above; or

wherein R2 and R3 are as defined above, as well as the pharmaceutically or veterinarily acceptable salts thereof. Particularly preferred compounds of the invention are the compounds of formula (I), wherein R is hydrogen or -S-CH3; Z is -O-or-S-.R1 is -CH3 or -CH2COOH; A is phenyl, thienyl or

wherein R11 is as defined above and R13 is hydrogen, hydroxy or methoxy and Y is-CH2OCOCH3 or -CH2-S-Het, wherein Het is tetrazolyl substituted by methyl or is tetrazolopyridazinyl substituted by amino,-COOH or-CH27COOH; as well as the pharmaceutically or veterinarily acceptable salts thereof.

Specific examples of compounds of the invention are the following: 1) 7-[α-phenyl-ss-methoxycrylamido-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4 carboxylic acid (syn-isomer) 2) 7-[α-(2-thienyl)-ss-methoxyacrylamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (synisomer) 3) 7-[α-(2-thienyl)-ss-methoxy acrylamido]-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-3cephem-4-carboxylic acid (syn-isomer) 4) 7-[α-(2-thienyl)-ss-methoxyacrylamido]-3-[(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl]-3- cephem-4-carboxylic acid (syn-isomer) 5) 7-[α;-(2-amino thiazol-4-yl)-ss-methoxyacrylamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid (syn-isomer) 6) 7-kg-(2-aminothiazol-4-yl)-p-methoxyacrylaminoJ-3-Ls 1-methyl-1 ,2,3,4-tetrazol-5 yl)thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer) 7) 7-[α-phenyl-ss-(bis-methylthio)acrylamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid; 8) 7-[α-phenyl-ss-(bis-methylthio)acrylamido]-3-[(1-methyl-1,2,3,4-tetrazo(-5-yl)thiomethyl]-3- cephem-4-carboxylic acid 9) 7-[α-(2-thienyl)-ss-(bis-methylthio)acrylamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid 10) 7-[α-(2-thienyl)-ss-(bis-methylthio)acrylamido]-3-[(1-methyl-1,2,3,4-tetrazol-5- yl)thiomethyl]-3-cephem-4-carboxylic acid 11) 7-[α;-(2-thienyl)-ss-(bis-methylthio)acrylamido]-3-[(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl]- 3-cephem-4-carboxylic acid 12) 7-[α-(2-thienyl)-ss-methylthio-ss-carboxymethylthio-acrylamido]-3-[(tetrazolo[1,5- b]pyridazin-6-ylSthiomethyl]-3-cephem-4-carboxylic acid 13) 7-[α-(2-aminothlazol-4-yl)-ss-(bismethylthio)acrylamido]-3-acetoxymethyl-3-cephem-4- carboxylic acid 14) 7-[α-(2-aminothiazol-4-yl)-ss-(bismethylthio)acrylamido]-3-[(1-methyl-1,2,3,4-tetrazo[5- yl)thiomethyl]-3-cephem-4-carboxylic acid 15) 7-[α-(2-aminothiaol-4-yl)-ss-(bismethylthio)acrylamido]-3-[(tetrazolo[1,5-b]pyridazin -6- yl)thiomethylJ-3-cephem-4-carboxylic acid 16) 7-[α ;-(2-aminothiazol-4-)-ss-(bis-methylthio)acrylamido]-3-[(8-aminotetrazolo[1,5-b]pyridazin- 6-yl)-thiomethyl]-3-cephem-4-carboxyllc acid 17) 7-[α-(2-aminothiazo]-4-yl-[ss-(bis-methylthio)acrylamido]-3-[(8-carboxytetrazolo[1,5- b]pyridazin-6-yl)thiomethyl]-3-cephem-4-carboxylic acid 18) 7-[α-(2-aminothiazol-4-yl)-ss-(bis-methylthio)acrylamido]-3-[(8-carboxymethyltetrazo[1,5- b]pyridazin-6-yl)thiomethyl]-3-cephem-4-carboxylic acid 1 9) 7-rcg-(2-aminothiazol-4yl)-iB-methylthio-iB-carboxY-methylthioacrylamidoJ-3-l(tetrazolol1t5- bSpyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid 20) 7-[α-(2-imino-3-hydroxythiazolin-4-yl)-ss-(bis-methylthio)acrylamido]-3-acetoxymethyl-3- cephem-4-carboxylic acid 21) 7-[α;-(2-imino-3-hydroxythiazolin-4-yl)-ss-(bismethylthio)acrylamido]-3-[(1-methyl-1,2,3,4- tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid 22) 7-[a'-(2-imino-3-hydrnxythiazolin-4-yl)--(bismethyIthio)acrylamido]-3-[(tetrazolo[ 1 ,5- b]pyridazin-6-yl)-thiomethyl-3-cephem-4-carboxylic acid 23) 7-[α-(2-imino-3-hydroxythiazolin-4-yl)-ss-methylthio-ss-carboxymethylthioacrylamido]-3- [(tetrazolot 1 ,5-bJ pyridazin-6-yl)-thiomethyl]-3-cephem-4-carboxylic acid 24) 7-[α-(2-inimo-3-methoxythiazolin-4-yl)-ss-(bis-methylthio)acrylamido]-3-acetoxymethyl-3- cephem-4-carboxylic acid 25) 7-[α;-(2-imino-3-methoxythiazolin-4-yl)-ss-(bis-methylthio)acrylamido]-3-[(1-methyl-1,2,3,4- tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid 26) 7-[α-(2-imino-3-methoxythiazolin-4-yl)-ss-(bis-methylthio)acrylamido]-3-[(tetrazolo[1,5- b]pyridazin-6-yl)thiomethyl]-3-cephem-4-carboxylic acid 27) 7-[α-(2-imino-3-methoxythiazolin-4-yl)-ss-(bis-methylthio)acrylamido]-3-[8- aminotetrazolo[1,5-b]pyridazin-6-yl)thiomethyl]-3-cephem-4-carboxylic acid 28) 7-[α-(2-imino-3-methoxythiazolin-4-yl)-ss-(bis-methylthio)acrylamido]-3-[(8- carboxytetrazolo[1 ,5-b]pyridazin-6-yl)thiomethyl]-3-cephem-4-carboxylic acid as well as the pharmaceutically and veterinarily acceptable salts thereof.

The structural formulae of the above-numbered compounds are shown in the following Table, in which Ph=phenyl, Th=2-thienyl and Ac=-COCH3 (acetyl).

TABLE

Compound A R Z R1 . 1 Ph H- -O- -CH3 N-N 2 'CH3 2 Th H- -O- -CH3 -CH2-0-Ac N-N 3 Th H- -O- -CH3 -CH2-S4N > CNH 'CH3 4 Th H- -O- -CH3 -CH2-S CN- h 5 HNHNt E H- -O- -CH3 -CH2-0-Ac H s, N~ N 6 Hli < H- -O- -CH3 -cH,-s -s -cH, 7 Ph H3C-S- -S- -CH3 -CH2-0-Ac N-N -sii 8 Ph H,C-S- -S- -CH3 -CH -S 4 9 Th H3C-S- -S- -CH3 -CH2-0-Ac N-N 10 1 Th H3C-S- -S- -CH3 -CH2-S2tN N 3 11 Th H3C-S- -S- -CH3 -CH2-S " ,N- N 12 Th H3C-S- -S- -CH2C H -CH2-S- 2 - NCOOH COOll 2

Cc?ound A R Z R1 y Hs HC-S- S- CU3 CH2-O-Ac HN N-N 14 HX H3C-S- -S- -CH3 -CH2-S-tN 3 HN vS 15 HNHNt > H3C-S- -S- -CH3 J 2 16 H H3C-S- -S- -CH3 COÓH . 17 HN;;7fi H C-S- -S- -CH3 CH2S()lNHo 17 HNH S S) H3C-S- -S- -CH3 -cH2~s~ > N-N~ | 2 H C-S- 18 HN 3 -S- -CH3 ~ -CH2-S -N- BN HN 19 s~ H,C-S- -S- CH,COOH H3 2 C-S- -S- -CH COOH -CH2-S HN )AL 20 HON H C-S- -S- -CH3 -CH2-ON-Ac 3 3 20 N 21 L H3C-S- -S- -CH3 -CH2 CH3 HN t S) ) ,NN I 22 HON H C-S- -S- -CH3 CH2 S > NN N 3 3 HN N%N 23 HOHtN II H3C-S- -S- -CH2COOH -CH2 eNN - 1N COOH - N HN 24 H CON H3C-S- -S- -CH3 -CH2N- NAc 3 3 HMi N-N N--N 25 H3CON ) H3C-S- -S- -CH3 -CH2-S CH3 CH3 NN 26 |H3CHOaa 51 H3CON " H3C-S- | -S- | -CH | -CH2-S A HN CH NH2 27 3 H3C-S- -S- -CH3 2,-'k d, COOH -CH,-S 28 H3CON -S- -CII3 CH2-N"N%NI

The compounds of the invention may be prepared by a process comprising: a) reacting a compound of formula (II)

wherein Y and M are as defined above and E is amino or a group --N=C=Q), wherein is oxygen or sulphur, or a reactive derivative thereof, with a compound of formula (Ill)

wherein A, R, Z and R, are as defined above, or with a reactive derivative thereof and, if desired, removing the protecting groups, where present; or b) reacting a compound of formula (IV)

wherein A, R, Z, R1 and M are as defined above, or a reactive derivative thereof, with a compound of formula (V) HS-Het (V) wherein Het is as defined above, or a reactive derivative thereof and, if desired, removing the protecting groups where present, so obtaining a compound of formula (I), wherein A, R, Z, R1 and Mare so defined above and Y is -CH2-S-Het wherein Het is as defined above; or c) methylating a compound of formula (Vl)

wherein A, M, R1 and Y are as defined above and each of the symbols Z is, independently, oxygen or sulphur, or a salt thereof, and, if desired, removing the protecting groups, where present, to give a compound of formula (I) wherein A, M, Y and Z are as defined above and R is -OCH3 or -S-CH3 and wherein R1 is either methyl, when starting from a compound (VI) where R1 is hydrogen, or any branched or straight chain saturated or unsaturated C1-C6 aliphatic hydrocarbon groups as defined above in formula (I), when starting from a compound (VI) wherein R1 is other than hydrogen; or d) reacting a compound of formula (VII)

wherein A, M and Y are as defined above, with a compound of formula (VIII)

wherein R" is C1-C6 alkyl and Z is as defined above and if desired, removing the protecting groups where present, to give compounds of formula (I) wherein R and R, are both hydrogen and Z, A, M and Y are as defined above, and if desired, etherifying a compound of formula (I) wherein R1 is hydrogen and R, Z, A, M and Y are as defined above or a salt thereof, to give compounds of formula (I), wherein R1 has the meanings reported above except hydrogen and R, Z, A, M and Y are as defined above, and or if desired, converting a compound of formula (I) where M 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 and or, if desired, resolving a mixture of isomers into the single isomers. In the compounds having the formulae (if), (III), (IV), (V), (VI) and (VII) the carboxy, amino and hydroxy groups, when present, 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, such as, for instance, those indicated above. The carboxy-protecting groups can be 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. The amino-protecting groups, can be removed at the end of the reaction in a known manner, for example the monochloroacetyl group may be removed by treatment with thiourea. The formyl and trifluoroacetyl groups may be removed by treatment with potassium carbonate in aqueous methanol and the trityl group by treatment with formic or trifluoroacetic acid. The hydroxy protecting groups may be removed in a known analogous way.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 d), when one or more asymmetric carbon atoms are present, may be either optically active or racemic compounds.

Furthermore, the starting materials may be syn- or anti-isomers and their mixtures, as well as cis- or trans-isomers and their mixtures.

A reactive derivative of a compound of formula (II) may be for example, an amine salt, a silyl ester of a metal salt when M is carboxy.

A reactive derivative of a compound of formula (III) may be for example, an acyl halide, an anhydride or a mixed anhydride, an amide, an azide, a reactive ester or a salt, for instance a salt formed with an alkali metal or alkaline earth metal, ammonia or an organic base.

A reactive ester may be, for example, a p-nitrophenyl ester, 2,4-dinitrophenyl ester, pentachlorophenyl ester, N-hydroxysuccinimide ester or N-hydroxyphthalimide ester.

The reaction between a compound of formula (II) or a reactive derivative thereof and a compound of formula (III) or a reactive derivative thereof may be performed either at room temperature or under cooling, preferably from about --500 to about +400C in a suitable solvent, e.g. acetone, dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, N,N-dimethylformamide or 1,2chloroethane 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 a compound of formula (III) is reacted with a 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'-dicylcohexylcarbodiimide. The optional removal of the protecting groups at the end of the reaction, may be performed in a known manner as stated above.

The reaction between a compound of formula (IV) our a salt thereof and a compound of formula (V), 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 (V). The subsequent optional removal of the protecting groups may be performed by known methods e.g. those indicated above.

A salt of a compound of formula (VI) may be e.g. a salt with an alkali metal or alkaline earth metal.

The methylation of a compound of formula (VI) or a salt thereof, may be carried out by treatment with a methylhalide, e.g. bromide, chloride, iodide, preferably iodide in an organic solvent, e.g. benzene, toluene, xylene, dioxane, acetone or chloroform, preferably benzene, at temperatures ranging from about 200C to about 800C, preferably from 500C to 700C, and for reaction times varying from 30 mins. to 2 hours.The reaction of a compound of formula (VII) with a compound of formula (VIII), may be performed in the presence of a strong base, such as an alkali metal e.g. sodium in a suitable an hydros organic solvent, e.g. diethyl ether, N,N-dimethylformamide, dioxane, tetrahydrofuran or similar, preferably diethyl ether, at temperatures ranging from about 50C to about 400 C, preferably at room temperature and for reaction times varying from 12 to 36 hours, preferably 24 hours.

The etherification of a compound of formula (I) wherein R1 is hydrogen, or a salt thereof, e.g. the salt with an alkali metal or alkaline earth metal, may be carried out by reaction with an appropriate compound of formula (R")2 SO4,wherein R" is as defined above, in an inert aqueous or organic solvent, e.g. ethanol, dioxane, N,N-dimethylformamide or a mixture of these solvents with water, in the presence of a base, e.g. NaOH or KOH, preferably NaOH, at temperatures ranging from about OOC to the reflux temperature and for reaction times varying approximately from 2 to 8 hours, thus giving a compound of formula (I) wherein R1 is -C1-C6 alkyl.

The same etherification may also be performed by reaction with the suitable optionally substituted halide of formula R1,, wherein R1, has the meanings reported above for R1 except hydrogen and Xis halogen, preferably chlorine or bromine, thus giving a compound of formula (I) wherein R, has the meanings reported above except hydrogen. The reaction may be carried out by using approximately the same reaction conditions indicated above for the methylation of a compound of formula (VI).

The optional salification of the compounds 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 known perse 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. Optional conversions include the esterification of a compound of formula (I), wherein M 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 an appropriate halide, in an organic solvent, e.g. acetone, tetrahydrofuran, chloroform, methylene chloride, N,N-dimethylformamide, dimethylsulphoxide, 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 M is an esterified carboxy group, may be saponified using, for example, an inorganic acid, such as hydrochloric acid or an inorganic basis, such as sodium or potassium hydroxide, by methods known per se in organic chemistry.

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 fractionated crystallization of mixtures of diastereoisomeric salts, and, if desired, liberating the optical antipodes from the salts.

Cis and trans-isomers or syn and anti-isomers may be separated from their mixtures by fractional crystallization or by chromatography, either column chromatography, or high pressure liquid chromatography (HPLC). The compounds 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 compounds of formula (II), wherein E is -N=C 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 compounds of formula (III)

may be prepared according to one of the same methods c) and d) set out above for the preparation of the compounds of formula (I), for example, a') by methylating a compound of formula (IX)

wherein Z, A, R1 and R" are as defined above, thus giving a C1-C6 alkyl ester of a formula (III) wherein R is -OCH3 or -S-CH3, A and Z are as defined above and R1 is either methyl, when starting from a compound (IX) R1 is hydrogen or a C1-C6 aliphatic group as defined in formula (I), when starting from a compound (IX) where R, is such an aliphatic group. The obtained C1-C6 alkyl ester of the compound of formula (III) may be, if desired, saponified and subsequently acidified to give the free acid or converted into any other reactive derivative thereof by a method known per se, or b') by reacting a compound of formula (X) A-CH2-COOR" (X) wherein A and R" are as defined above with a compound of formula (VIII),

thus giving a compound of formula (ill)

wherein A, Z and R" are as defined above which may be-transformed either into the corresponding free acid or into another reactive derivative thereof, by a method known per se; or c') by etherifying a compound of formula (Illa) or any other compound of formula (III) wherein R is hydrogen, to give a compound of formula (III) wherein R1 has the meanings given above except hydrogen.

The reactions indicated above as a'), b') and c') may be carried out by using the same reaction conditions described above for the analogous reactions used to prepare the compound of formula (I). In particular a compound of formula (III) wherein A is the radical

wherein R11 and R12 are as defined above, may be prepared according to one of the following methods: a") reacting a compound of formula (XI)

wherein X is halogen preferably chlorine, R, Z, R1 and R" are as defined above or a reactive derivative thereof with a compound of formula (XII)

wherein R11 and R12 are as defined above; or b") reacting a compound of formula (XIII)

wherein ZR, R1 and R" are as defined above or a reactive derivative thereof, with a compound of formula (XIV) R12-NH2 (XIV) wherein R12 is as defined above, or a salt thereof, to give a C1-C6 alkyl ester of a compound of formula (III) wherein A is

where R11 is hydrogen.

The reaction between a compound of formula (XI) or a reactive derivative thereof which may be, for instance a salt, or an ester thereof, and a compound of formula (XII) 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 ranges from about OOC to about +900C.

The reaction between a compound of formula (XIII) or a reactive derivative thereof which may be, for instance, a salt or an ester, with a compound of formula (XIV) or a salt thereof may be performed in a suitable solvent e.g. water, methanol, ethanol, dioxane, acetonitrile, N,N-dimethylformamide N,Ndimethylacetamide, or methylenechloride. A salt of a compound of formula (XIV) may be a salt with an inorganic acid such as hydrochloric acid or sulphuric acid, or with an organic acid, such as citric, tartaric, oxalic orp-toluenesulphonic acid.

The reaction temperature preferably ranges from about 0 C to about 900C and the pH is preferably maintained from about 1 to about 7.5.

A C1-C6 alkyl ester of the compounds of formula (III) obtained by the above two steps a") and b") may be, if desired, converted into the corresponding free-acid or into a reactive derivative thereof by known methods. A compound of formula (III) wherein A is

in which R,2 is hydrogen and R" is as defined above, may be transformed into the corresponding compound wherein R,2 is hydroxy and R,1 is as defined above by methods known peruse, for example by treatment with an oxidizing agent especially a peracid, e.g. perbenzoic acid, m-chloroperbenzoic acid, permaleic acid, pertrifluoroacetic acid, sodium periodate, hydrogen peroxide or a mixture thereof with an inorganic or organic acid, e.g. formic, acetic or trifluoroacetic acid.The reaction may be performed in a solvent, e.g. dioxane, methylene chloride, chloroform or methanol, at temperatures ranging from -30 to +90C.

A resultant compound wherein R12 is hydroxy may be, if desired, etherified by known methods to give the corresponding compound wherein R12 is -O-C1-C6 alkyl, -O-C2-C4 alkenyl or -0- (CH2)mCOOR2 wherein m and R2 are as defined above.

The compounds of formula (IV) are a particular class of compounds of formula (I) and may be obtained by the same methods a), d) and the following methods, reported above for the preparation of the compounds of formula (I). For example the compounds of formula (IV) wherein R1 is hydrogen, may be obtained by reacting a compound of formula (all), wherein Y is -CH2OCOCH3,with a a compound of formula (VII I) or a salt thereof and following approximately the same reaction conditions reported above for the process step d). The compounds of formula (IV), wherein R1 is as defined above, except hydrogen, may be obtained by etherifying the corresponding compounds of formula (IV), wherein R1 is hydrogen, by following the same reaction conditions used to etherify a compound of formula (I), wherein R1 is hydrogen, set out above.

Alternatively the compounds of formula (IV) may be obtained by reacting a compound of formula (Il), wherein Y is -CH2OCOCH3, or a derivative thereof with a compound of formula (III) or with a derivative thereof, following the same reaction conditions set out above for process step a).

The compounds of formula (V) are known or may be prepared by known methods from known compounds. The compounds of formula (VI) may be prepared by reacting a compound of formula (II) with a compound of formula (IX) or the corresponding free acid or another reactive derivative thereof, using the same reaction conditions reported above for the process step a). The compounds of formula (VII) may be obtained by reacting a compound of formula (II), or a reactive derivative thereof, with a compound of formula (X) or the corresponding free acid or a reactive derivative thereof, following approximately the same reaction conditions used for the reaction indicated above for process step a).

The compounds of formula (VIII) and (IX) are known or may be obtained by known methods. In particular, for example, the compounds of formula (IX) wherein R1 is hydrogen may be obtained by reacting a compound of formula (X) with CS2 or CO2 in the presence of an appropriate base, e.g.

potassium tert-butoxide, to give a compound of formula (IX) wherein Z and Z1, being the same, are sulphur or oxygen. The reaction may be carried out in a suitable anhydrous organic solvent e.g.

benzene, toluene or xylene at temperatures varying from about -i 00C to about 400C and for reaction times ranging approximately from 30 mins to 4 hours. The compounds of formula (X) are known or may be obtained by known methods. The compounds of formula (XI) and (XIII) may be obtained by known methods, for example, starting from the corresponding unsubstituted carboxylic esters which are known compounds and using approximately the same methods indicated above for the synthesis of the compounds of formula (Ill), starting from compounds of formula (X). The compounds of formula (XII) and (XIV) are known or may be obtained by known methods from known compounds.

The compounds of the present invention have a high antibacterial activity both in animals and in humans against Gram-Positive and Gram-negative bacteria normally susceptible to cephalosporins such as staphylococci, streptococci, diplococci, Klebsiella, Escherichia coli, Proteus mirabilis, Salmonella, Shigella, Haemophilus and Neisseria. The compound of the invention show also a high activity against the strong beta-lactamase producer micro-organisms, for example, Klebsiella aerogenes 1082 E, Escherichia coli Tem, Entembecter cloacae P99, and indole-posive Proteus and the like, as well as against Pseudomonas aeruginosa strains, which are normally resistant to most cephalosporins.

Owing to their high antibacterial activity either in animals or in humans against both Grampositive and Gram-negative bacteria the compounds of the present invention are 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, 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. For example, the approximate acute toxicity in the mouse determined with single intravenous administrations of increasing doses and measured on the seventh day of treatment is greater than 2000 mg/kg.

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 invention includes pharmaceutical and veterinary compositions comprising a compound of the invention, in association with a pharmaceutically or veterinarily acceptable excipient e.g. a diluent or carrier. These pharmaceutical or veterinary compositions may be prepared in a conventional way by employing the conventional carriers 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 of the conventional intravenous fluids or electrolytes, for intravenous injections.

Furthermore, the compounds of the invention may be used as anti-bacterial 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 a nutritional supplement in animai feeds.

The following Examples illustrate the present invention. Assessment of melting points 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 "decomposition" was added.

The l.R. spectra were determined in a solid phase or in Nujol on a Perkin-Elmer 125 spectrophotometer.

N.M.R. spectra were determined with a Perkin-Elmer R-24 B(6OMH z) spectrometer in appropriate solvents as specified hereinafter. Shifts in ppm are given with reference to (CH3)4 SI as internal standard.

Preparations of Starting Materials Preparation 1 -(2-thienyl)'p-methoxyacrylic Acid A solution of methyl 2-thienyl acetate (51.5 g; 0.33 mol) and methyl formate (22.5 g; 0.375 mol) in anhydrous diethyl ether (50 ml) was added to a suspension of sodium wire (7.84 g; 0.34 mol) in anhydrous diethyl ether (150 ml). The temperature of the mildly exothermic reaction was controlled by means of a water bath kept near room temperature. After stirring for 24 hours at room temperature, the mixture was cooled, diluted carefully with water and acidified with 8% HCI.The ethereal solution was separated, washed with a saturated aqueous sodium chloride solution, separated, dried and evaporated to dryness giving a residue, which was triturated with petroleum ether and filtered, thus giving 48.5 g (yield 80%) of methyl -(2-thienyl)-p-hydroxyacrylate m.p. 102-1 040C; Elemental Analysis Found:C 52.02; H 4.29; S 17.46 Calculated for C8H8O3S: C 52.16; H 4.37; S 17.40 N.M.R., a ppm (CDCI3): 3.8 (3 H.s.-CH3) 7.1 (3H, m, hydrogen on thienyl ring) 7.45 (1 H, d, =CH-) 12.1 (iH,d,-OH) To a solution of the above prepared compound 11.04 g; 0.06 mol) in 2N NaOH (40 ml; 0.08 mol), cooled at 5"C, dimethyl sulfate (5.70 ml; 0.06 mol) was added. The reaction mixture was stirred for 1 hour under cooling and then for 6 hours at room temperature.

The reaction mixture was extracted twice with diethyl ether, dried, evaporated and distilled. The major fraction was collected at 1 1 0--1 1 30C (0.2 mm Hg), thus giving 9.0 g (yield 75%) of colorless oil) Elemental Analysis Found: C 54.35; H 5.01; S 1 5.92 Calculated for C9H10O3S: C 54.53; H 5.08; S 16.17 N.M.R., 3 ppm (CDCI3): 3.6 (3H, s -COOCH30 3.85 (3H, s, -OCH3) 7.0 (3H, m, hydrogen on thienyl ring) 7.4 ( 1 H, s=CH-) A solution of the above-prepared ester (10.2 g; 0.051 mol) and 2N NaOH (82 ml; 0.164 mol) was stirred for 20 hours at room temperature. The reaction mixture was washed with ethyl acetate, the aqueous layer was acidified with dilute H2SO4 and extracted with ethyl acetate.The organic layer was evaporated to dryness. The oily residue obtained was crystallized from ethyl ether/petroleum ether, thus giving 6.48 g (yield 70%) of α-(2-thienyl)-ss-methoxycarylic acid, m.p. 1 34-60C.

Elemental Analysis Found: C 51.86; H4.28; S 17.46 Calculated for C8H8O3S: C52.16; H 4.37; S 17.40 I.R. (Nujol) cm-1 # 1660 ( > C=O) 2550 (-OCH3) N.M.R., a ppm (CDCI3): 3.8 (3H, s, -OCH3) 7.1 (3H, m, hydrogen on thienyl ring) 7.4(1 H, s, =CH-) 11.5 (1 H, br-s, -COOH).

Preparation 2 α-(2-thienyl)-ss-methoxyacryloyl Chloride To a solution of the acid described in preparation 1 (1.84 g; 0.01 mol) and triethylamine (1.4 ml; 0.01 mol in an hydros methylene chloride (CH2 Cl2) (50 ml), cooled at OOC, a few drops of anhydrous N,N-dimethylformamide (DMF) and oxalyl chloride (1 ml; 0.0117 mol) were added.

The mixture was stirred for 1 hour at OOC; the CH2 Cl2 was evaporated under vacuum, the residue was taken up with anhydrous benzene and then evaporated, thus giving an oily residue, which was used for the next step without further purification.

Preparation 3 α-(2-phenyl)-ss-methoxyacrylic Acid was prepared by the method reported in preparation 1, m.p. 170-173 C, I.R. (Nujol) cm-1 # 1660 ( > C-O) N.M.R., a ppm (CDCI3): 3.75 (3H, s, -OCH3) 7.2 (5H, m, H on benzene) 7.5 (1 H, s, > CH-O) 10.6 (1 H, br-s, -COOH).

Preparation 4 Potassium α-(2-thienyl)-ss-(bis-methylthio)acrylate To a suspension of potassium-t-butoxide (28.05 g; 0.25 mol) in anhydrous benzene (400 ml), cooled at OOC, was added under stirring a mixture of methyl 2-thienylacetate (19.5 g; 0.125 mol) and CS2 (7.51 ml; 0.125 mol). The mixture was stirred for 2 hours room temperature (the progress of the reaction can be monitored by thin layer chromatography). Methyl iodide (15.5 ml; 0.25 mol) was then added to the suspension and the mixture was heated for 1 hour at 600C with stirring.After cooling the mixture to 50C, 1 50 ml of water was added, the organic layer was separated, washed with water, dried and evaporated to dryness, and the oily residue was then distilled, b.p. 145-147 C (0.15 mm Hg), thus giving 23.29 g (yield 71.5%) of ethyl α-(2-thienyl)-ss-(bis-methylthio) acrylate.

Elemental Analysis Found: C 46.60; H 4.62; S 35.51 Calculated for C,,H,,O,S,: C46.12; H4.64; S35.94 I.R. (film) v 1720 cm-1 ( > C=O) N.M.R., # ppm (CCI4): 2.23 (3H, s, -SCH3) 2.27 (3H, s, -SCH3) 3.7 (3H, s, -OCH3) 6.8-7.2 (3H, m, hydrogen on thienyl ring) A mixture of this ester (7.81 g; 0.03 mol) and 2N ethanolic KOH (60 ml) was heated for 5 hours under reflux. The reaction mixture was taken up with a mixture of hexane-ethyl acetate the supernatant mother iiquors were discarded and the residue was triturated with the mixture of hexane-ethyl acetate until a solid was obtained.The solid material was filtered and washed with petroleum ether, thus giving 6.5 g (yield 76%) of potassium α-(2-thienyl)-ss-(bis-methylthio)acrylate, which was pure enough for the next step.

Preparation 5 α-(2-thienyl)-ss-(bis-methylthio)acryloylchloride An aqueous solution of potassium α-(2-thienyl)-ss-(bis-methylthio)acrylate (1.42 g; 0.005 mol) was stratified with ethyl acetate and brought to pH 2 with 20% H2 SO4. After stirring for 15 minutes, the organic layer was separated, dried (Na2SO4) and evaporated to dryness under vacuum. The free acid so obtained was dissolved in anhydrous methylene chloride (40 ml), two drops of anhydrous N,Ndimethylformamide was added, the mixture was cooled at 0 C and then triethylamine (0.7 ml) and oxalyl chloride (0.43 ml; 0.005 mol) were added. After stirring for 1 hour at OOC, the reaction mixture was evaporated to dryness under vacuum.The oily residue was triturated with anhydrous benzene and the solid was filtered off and then taken up in ethyl acetate to yield α-(2-thienyl)-ss-(bis- methylthio)acryloylchlorsae, which was used for the next step without further purification.

Preparation 6 Potassium α-phenyl-ss-(bis-methylthio)acrylate This compound was prepared by following the method reported in preparation 4, m.p. 264- 265 C.

N.M.R., S ppm (CCI4) 2.10 (3H s, -SCH3) 2.30 (3H, 5 -SCH3) 7.2 (5H, m, H on benzene ring).

The corresponding acyl chloride was prepared as reported in preparation 5.

Preparation 7 Ethyl α-(2aminothiazol-4-yl)-ss-methoxyacrylate A mixture of ethyl-ar-bromoacetoacetate (20.9 g; 0.1 mol), methyl orthoformate (10.6 g; 0.1 mol) and acetic anhydride (20.4 g; 0.2 mol) was refluxed for 1 hour under stirring. The reaction mixture was evaporated to dryness under vacuum, thus giving ethyl α-methoxymethylene-α-bromoacetoacetate, as oily residue, which was used for the next step without further purification.

To an ice-cold solution of this ester (0.1 mol) in methanol (100 ml), thiquerea (7.6 g, 0.1 mol) was added and the mixture was stirred for 3 hours at room temperature. After cooling the precipitate was collected by filtration.

The solid was stirred with an aqueous solution of NaHCO3 and filtered again, thus giving 16 g (yield 70%) of ethyl α-(2-aminothiazol-4-yl)-ss-methoxyacrylate, m.p. 107-i 090C.

Elemental Analysis Found: C 47.10; H 5.13; N 12.29; S 14.18 Calculated for C9Ht2N203S: C 47.37; H 5.30; N 12.27; S 14.04 N.M.R. ô ppm (d6-DMSO, i.e. fully deuterium-substituted dimethyl sulfoxide: 1.2 (3H, t -OCH2-C113) 3.8 (3H, s, -OCH2) 4.1 (2H q, -OCK2CH3) 6.35 (1 H, s, 5-H on thiazole ring) 6.7 (2H, br-s, -NH2) 7.35 (1 H, s, =CH-) Preparation 8 Ethyl α-(2-tritylaminothiazol-4-yl)-ss-methoxyacrylate To an ice-cold solution of ethyl α-(2-amino-thiazol-4-yl)-ss-methoxyacrylate (1 g; 4.38 m mol) and triethylamine (0.58 g; 5.7 m mol) in methylene chloride (25 ml) trityl chloride (1.47 g; 5.27 m mol) was added portionwise. After stirring for 4 hours at room temperature, the solution was shaken with water, the organic layer was separated, dried (Na2SO4) and evaporated to dryness under vacuum. The foamy residue was triturated with petroleum ether, this giving ethyl -(2-tritylaminothiazol-4-yl-B- methoxyacrylate (1.88 g;yield 72%), m.p. 68 -70 C, N.M.R. a ppm (d6 -DM50):: 1.2 (3H, t, -OCH2CH3) 3.8 (3H, 5 -OCH3) 4.1 (2H, q,-OCH2CH3) 6.35 (1 H, s, 5-H on thiazole ring) 7.3 (16H, br-s, Ph and =CH-) 8.2(1H, br-s, -NH-) Preparation 9 a-(2-trityla minothiazol-4-yl)-p-(bis-methylthio)acrylic Acid To an ice-cold suspension of potassium tert-butoxide (5.6 g; 0.05 mol) in anhydrous benzene (100 ml) was added, under stirring, a solution of ethyl-(2-tritylaminothiazol-4-yl)-acetate (10.7 g, 0.025 mol) and CS2 (1.51 ml; 0.025 mol) in anhydrous benzene (30 ml). The mixture was stirred for 4 hours at room temperature (the progress of the reaction can be monitored by TLC).Methyl iodide (3.12 ml; 0.05 mol) was added to the suspension and the mixture was heated for 1 hour at 600C under stirring.

After cooling OOC, 100 ml of water was added, the organic layer was separated, washed with water, dried (Na2SO4) and evaporated to dryness.

The oily residue was purified through a column of silica gel using (CH2CI2:EtOAC=1 96:4) as eluent to yield ethyl α-(2-tritylamino-thiazol-4-yl)-ss-(bismethylthio) acrylate (lOg; 75%) m.p. 1400C.

Elemental Analysis Found: C65.86; H 5.43; N 5.12; S 17.70 Calculated for C29H28N202S3: C 65.38; H 5.29; N 5.26; S 18.06 IR (Nujol) cm-1# (171 5 > C=O) N.M.R. a ppm (CCI4): 1.1 (3H, s, -OCH2CH3) 2.1 (6H, s, - s CH3) 4.0 (2H, q, -OCH2C H3) 6.6 (1 H, s, 5-H on thiazole ring) 7.1 (15H,s,Ph).

A solution of the above mentioned ester (2.5 g; 4.7 m mol) and 2N NaOH (7.05 ml; 14.1 m mol) in 95% ethanol (50 ml) was refluxed for 4 hours. The ethanol was evaporated under vacuum, 20 ml of water was added and the solution was stratified with ethyl acetate (20 ml) and acidified with 8% of HCI.

After stirring for 1 hour at room temperature, the undissolved material was filtered off and the collected precipitate was washed with ethyl acetate and dried under vacuum at 600C to yield -(2tritylaminothiazol-4-yl)-ss-(bis-methylthio)acrylic acid (1.88 g; 79.5%) m.p. 198200 C.

Elemental Analysis Found: C 63.99; H 4.73; N 5.36; S 18.81 Calculated for C27H24N2O2S3: C 64.25; H 4.80; N 5.55; S 19.06 I.R. (Nujol) cm-1 v 1660 (C=O) N.M.R., # ppm 9ds-DMSO): 1.92 (3H, s, -SCH3) 2.05 (3H, s, -SCH3) 6.5 (1 H, s, 5-H on thiazole ring) 7.1 (15H,s,-Ph).

Preparations of Compounds of Formula (I) Example 1 7-[α-(2-thienyl)-ss-methoxyacrylamido]-3-[(methyl-1,2,3,4-tetrazol-5-yl(thiomethyl]-3-cephem- 4-carboxylic Acid (syn-isomer), Compound 3 A suspension of 7-amino-3-[( 1-methyl-1 ,2,3,4-tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid (1.31 g; 0.004 mol) and N,O-bis-(trimethylsilyl)acetamide (3.25 g; 0.016 mol) in anhydrous ethyl acetate (80 ml) and anhydrous acetonitrile (20 ml) was stirred for 2 hours at 50 C, until all the solid materal was dissolved. Into this solution, cooled with an ice bath, a solution of α-(2-thienyl)-ss- methoxyacryloyl chloride (0.002 mol) in anhydrous ethyl acetate (25 ml) was added under stirring.The mixture was stirred for 20 hours at room temperature and then a solution of NaHCO3 in water was added, the organic layer was separated, the aqueous solution was acidified with dilute H2SO4, extracted with ethyl acetate, the organic phase was washed with water, dried and evaporated to a small volume and diluted with diethyl ether. The precipitated solid was collected thus giving 7-[a-(2- thienyl)-ss-methoxyacrylamido]-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (syn-isomer) m.p. 143-147 (decomposition) Elemental Analysis Found: C43.38; H 3.76; N 16.63; S 19.24 Calculated for C18Ha8N605S3: C 43.71; H 3.67; N 16.99; S 19.45 I.R. (KBr) cm-' v 1780 ( > C=O ,B-lactam) 1680 ( > C=O sec.amide) 3350 (-NH- sec.amide), N.M.R., #(d6-DMSO): 3.85 (3H, s, > N-CH3 on tetrazole ring) 3.9 (3H, s, -OCH3) 7.1 (3H, m, hydrogen on thienyl ring).

Example 2 7-[α-(2-thienyl)-ss-methoxyacrylamido]-3-acetoxymethyl-3-cephem-4-carboxyl ic Acid (synisomer), Compound 2 was prepared using a method similar to that of Example 1 m.p. 130-1 31 0 (decomposition), Elemental Analysis Found: C49.05; H4.11; N6.57; S 14.15 Calculated for C18H18N2O7S2: C49.3; H4.14; N 6.39; S14.63.

I.R. (KBr): cm-1 D 1 780 ( > C=0 lactam) 3300 (-NH- sec.amide) N.M.R., a ppm (d6-DMSO): 2 (3H, s,-O-CO-CH3) 3.90 (3H, s, -OCH3) 7.1 (3H, m, H on thiophene ring).

Example 3 7-[α-ss-methoxyacrylamido]-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4- carboxylic Acid (syn-isomer), Compound 1 To a suspension of ct-phenyl-P-methoxyacnllic acid (0.55 g, 3.1 m mol) in anhydrous acetone (25 ml) was added under cooling at 50C N,N'-dicyclohexylcarbodiimide (0.64 g; 3.1 m mol). After stirring the suspension for 40 minutes at 50C a cooled solution of 7-amino-3-[(1 -methyl-1,2,3,4,-tetrazol-5- yl)-thiomethyl]-3-cephem-4-carboxylic acid (1.01 g; 3.1 m mol) and NaHCO3 (0.26 g; 3.1 m mol) in acetone (10 ml) and water (15 ml) was added dropwise. The reaction mixture was stirred for 1 hour at 50C and afterwards for 20 hours at room temperature. The acetone was evaporated under vacuum and the separated solid dicylcohexylurea filtered off.The filtrate was washed with ethyl acetate, the aqueous phase was acidified with 10% H2SO4 and extracted with ethylacetate. The organic layer was separated, washed with saturated NaCI solution, dried (Na2SO4) and evaporated to dryness under vacuum.

The residue was taken up with diethyl ether, the solid was filtered off, the solid was dissolved in a small amount of ethyl acetate, the undissolved material was filtered off, the filtrate was evaporated to a small volume and a precipitate obtained by adding diethyl ether, thus yielding 7-[α-phenyl-ss- methoxyacry[amido]-3-[(methyl-1,2,3,4-tetrazol-5-yl)thlomethyl]-3-cephem-4-carboxylic acid (synisomer), m.p. 1500 (decomposition) I.R. (Nujol) cm-1 # 1780 ( > C=O ss-lactam) 1660 (-COHN- sec.amide) 3300 (-NH-), N.M.R., # ppm (CD3COCD3):: 3.7 (3H, s,-NCH3) 3.85 (3H, x, -OCH3) 7.2 (5H, m, H on benzene ring) 7.3 (1 H, s, =CH-O) By the same procedure compounds 4, 5 and 6 were obtained.

Example 4 7-[α-(2-thienyl)-ss-(bis-methylthio)acrylamido]-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiorhnethyl]-3- cephem-4-carboxylic Acid, Compound 10 To an ice-cold suspension of 7-amino-3-[(1-methyl-1,2,3,4-tetrazo]-5-yl)thiomethyl]-3-cephem-4- carboxylic acid (1.64 g; 0.005 mol) in anhydrous ethyl acetate (80 ml) and anhydrous acetonitrile (20 ml) was added, under stirring, N,O-bis(trimethylsilyl)acetamide (4.95 ml; 0.02 mol). After stirring for 3 hours at 500C, the reaction mixture was cooled at 0 C and then a solution of α-(2-thienyl)-ss- (bismethylthio)acryloyl chloride (1.32 g; 0.005 mol) in anhydrous ethyl acetate (30 ml) was added. The mixture was stirred for 1 hour at 0 C and then for 16 hours at room temperature.After cooling at 0 C the reaction mixture was diluted with water and brought to neutrality with an aqueous solution of NaHCO3. The organic layer was discarded, the aqueous phase was stratified with ethyl acetate and brought to pH 2 with 20% H2 S 04. The mixture was stirred for 1 5 minutes and the undissolved material was filtered off.Afterwards the organic layer was separated, the aqueous phase was extracted again with ethyl acetate, the combined organic extracts were dried (Na2SO4) and evaporated to a small volume under vacuum; after adding diethyl ether a solid product was obtained, which was filtered and dried under vacuum at 600C to yield 7-[-(2-thienyl)-,B-(bismethylthio)acrylamido]-3-L(1 methyl 1,2,3,4-tetrazol-5-yl)-thiomethyl]-3-cephem-4-carboxylic acid m.p. 125-i 290 (decomposition) Elemental Analysis Found: C40.72; H3,89; N 14.99; S28.53 Calculated for C19H20N8O4S5: C40.99; H 3.62; N 15.09; S 28.79.

TLC (CHCI3: CH3OH:HCOOH=1 80:20:10) R0.54, I.R. (Nujol) cm-' v 3300 (-NH-) 1780 ( > C=O p-iactam) 1715 ( > C=O acid) 1660 ( > C=O sec.-amlde), N.M.R., # ppm (d6-DMSO): 2.35 (3H, s, -SCH3) 2.4 (3H, s, -SCH3) 3.9 (3H, s, -NCH3) 6.9-7.2 (3H, s, m, H on thiophene ring).

Example 5 Using the procedure of Example 4 the following compounds were prepared: 7-[α-phenyl-ss-(bis-methylthio)acrylamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid, compound 7, m.p. 88-90 (decomposition).

Elemental Analysis Found: C 50.64; H 4.66; N 5.49; S 18.99 Calculated for C21H22N2O6S3: C 50.99; H 4.48; N 5.66; S 19.45 i.R. (Nujol) cm-1 # 3300 (-NH-) 1780 ( > CH=O p-lactam) N.M.R. # ppm (CDCl3): 1.87 (3H, s, -COCH3) 2.0 (3H, s, -SCH3) 2.20 (3H, s, -SCH3) 7.15 (5H, m, H on benzene ring); and 7-[α-ss-(bis-methylthio)acrylamido]-3-[(1-methyl-1,2,3,4-tetrazol-5-yl)thiomethyl]-3-cephem-4- carboxylic acid, compound 8, m.p. 115-120 (decomposition).

Elemental Analysis Found: C45.94; H4.25; N 15.01; S22.91 Calculated for C21H22N8O4S4: C 45.8; H 4.02; N 15.26; S 23.29 I.R. (Nujol) cm-1 V 3300 (-NH-) 1780 ( > C=O p-lactam) 1715 (-CO- acid) 1 660 (-CO- sec.-amide) N.M.R., # ppm (d6-DMSO): 1.9 (3H, s, -SCH3) 2.1 (3H,s,-SCH3) 3.7 (3H, s, -NCH3) 7.1 (5 H, m, H on benzene ring); 7-[α-(2-thienyl)-ss-(bis-methylthio)acrylamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid, compound 9, m.p. 105-110 (decomposition).

Elemental Analysis Found: C 45.35; H 4.22; N 5.73; S 25.11 Calculated for C15H20N2O6S4: C 45.58; H 4.03; N 5.59; S 25.62.

TLC (CH Cl3: CH3OH: HCOOH=180:20:10) R0.62, I.R. (Nujol) cm-1 v 3300 (-NH-) 1780 ( > C=O ss-lactam) 1715 (-CO-acid) 1660 (-CO-sec.-amide), N.M.R., # ppm (d6-DMSO) 1.7 (3H, s, -OCOCH3) 2.22 (3H, s, -SCH3) 2.28 (3H, s, -SCH3) 6.8-7.2 (3H, m H on thiophene ring); and 7-[α-(2-thienyl)-ss-(bis-methylthio)acry(amido)-3-[(tetrazolo[1,5-blpyridazin-6-yl)-thiomethyl]-3- cephem-4-carboxylic acid, compound 11, m.p. 135-140 C (decomposition).

Elemental Analysis Found: C 42.20; H 3.33; N 16.23; S 26.74 Calculated for C21H19N7O4S5: C42.48; H3.22; N 16.51; S27.00.

TLC (CHCI3: CH3 OH: HCOOH=1 80:20:10) R4=0.55, I.R. (Nujol) cm-1 V 3300 (-NH-) 1780 ( > C=O ss-lactam) V 1 720 (-CO- acid) 1660 (-CO- sec.amide), N.M.R., # S ppm (d5-DMSO): 2.15 (3H,2,-SCH3) 2.20 (3H, 5, -SCH3) 6.8-7 (3H, m, H on thiophene ring) 7.75 (1 H, d, 8-H on the pyridazine ring) 8.57 (1 H, d, 7-H on the pyridazine ring).

Example 6 7-[α-(2-aminothiazo]-4-yl)-ss-(bis-methylthio]acrylamido]-3-[(tetrazolo[1,5-b))pyridazin-6-yl)- thiomethyl]-3-cephem-4-carboxylic Acid, Compound 15 To an ice-cold solution of α-(2-tritylaminothiazol-4-yl)-ss-(bis-methylthio)acrylic acid (4.04 g; 80 m mol) and triethylamine (1.12 ml; 80 m mol) in anhydrous tetrahydrofuran (THF) (300 ml), was added, under stirring, isobutyi chloroformate (1.05 ml; 80 m mol). After stirring for 30 minutes at 0 C, a solution of 7-amino-3-[(tetrazolo[1,5-b]pyridazin-6-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.93 g; 80 m mol) and triethylamine (1.120 ml; 80 m mol) in 50% THF (200 ml) was added dropwise.

After stirring for 1 hour at 0 C and then for 18 hours at room temperature, the solvent was evaporated under vacuum, the residue was diluted with water, then stratified with ethyl acetate and acidified with dilute hydrochloric acid. After stirring for half an hour, the undissolved material was filtered off, the organic layer was separated, dried (Na2SO4), evaporated to a small volume under vacuum, and taken up in diethylether. The collected precipitate was filtered off and washed several times with diethyl ether.

The resultant solid was dissolved in 30 ml of 99% formic acid and stirred for 90 minutes at room temperature. The formic acid was eliminated under vacuum, the residue was taken up in diethyl ether and stirred for 30 minutes and the solid was filtered and dried at 600C under vacuum to give 7-La-(2- aminothiazoi-4yl)-/3-(bis-methylthio)acrylamido]-3-[(tetrazoloL 1,5-b] pyridazin-6-yl)thiom ethylj-3- cephem-4-carboxylic acid, compound 15, m.p. 171-175 C (decomposition).

Elemental Analysis Found: C 39.61; H 3.20; N 29.31; S 25.97 Calculated for C20H19N9O4S5: C39.39; H3.14; N20.67; S26.29 I.R. (Nujol) cm-1 V 1780 ( > C=O ss-lactam) 1650 ( > C=O sec.-amide), N.M.R., # ppm (d6-DMSO): 2.35 (3H, 5, -SCH3) 2.4 (3H, 5, -SCH3) - 6.6 (1 H, s, 5-H on thiazole ring) 7.30 (2H, br-s, NH2 on thiazole ring) 7.75 (1 H, d, 8-H on the pyridazine ring) 8.57 (1 H, d, 7-H on the pyridazine ring) Example 7 By the procedure of Example 6 the following compounds were obtained: 7-[α-(2-aminothiazo]-4-yl)-ss-(bis-methylthio)acrylamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid, compound 13.

Elemental Analysis Found: C41.53; H4.05; N 10.63; S24.61 Calculated for C18H20N4O6S4: C41.84; H 3.90; N 10.84; S 24.83, I.R. (Nujol) cm-1 # 1780 > C=O ss-lactam) 1650 ( > C=0 sec.-amide), N.M.R., # ppm (d6-DMSO): 2.0 (3H, s, -OCOCH3) 2.35 (3H, s, -SCH3) 2.4 (3H, 5, -SCH3) 6.4 (1 H, s, 5-H on thiazole ring) 7.3 (2H, br-s, -NH2 on thiazole ring) 7-[α-(2-aminothiazol-4-yl)-ss-bis-methylthio)acrylamido]-3-[(1-methyl-1,2,3,4-tetrazol-5- yl)thiomethyl]-3-cephem-4-carboxylic acid, compound 14.

Elemental Analysis Found: C37.91; H3.61; N19.31; S27.63 Calculated for C15H20N8O4S5: C 37.75; H 3.52; N 19.57; S 27.99 I.R. (Nujol) cm-' 1780 ( > C=O lactam) 1650 ( > C=O sec.-amide) N.M.R., # ppm (d6-DMSO): 2.35 (3H, s,-SCH3) 2.4 (3H, 5, -SCH3) 3.85 (3H, s, > N-CH3) 6.4 (1 H, s, 5-H on thiazole ring) 7.3 (2H, br-s, -NH2 on thiazole ring); 7-[a-(2-aminothiazol-4-yl)-,6-(bis-methylthio)acrylamido]-3-[(8-amino-tetrazolo[i ,5-h]pyridazin-6- yl)thiomethyl]-3-cephem-4-carboxylic acid, compound 16.

Elemental Anaylsis Found: C38.61; H3.31; N22.21; S25.36 Calculated for C20H20N10O4S5: C 38.45; H 3.23; N 22.42; S 25.66, I.R. (Nujol) cm-' V 1780 ( > C=O p-lactam) 1650 ( > C=O sec.-amide), N.M.R., # ppm (d6-DMSO): 2.35 (3H, s,-SCH3) 2.4 (3H, 5, -SCH3) 6.41(1 H, s, 7-H on pyridazine ring) 7.12 (1 H, s, 5-H on thiazole ring) 7.30 (2H, br-s, -NH2 on thiazole ring) 8.02 (2H, br-s, -NH2 on pyridazine ring) 7-[α-(2-aminothiazol-4-yl)-ss-(bis-methylthio)acrylamldo]-3-[(8-carboxytetrazolo[1,5-b]pyridazin-6- yl)thiomethyl]-3-cephem-4-carboxylic acid, compound 17.

Elemental Analysis Fond: C 38.77; H 3.02; N 19.11; S 24.23 Calculated for C21H19N9O6S5: C 38.58; H 2.93; N 19.28; S 24.52 I.R. (Nujol) cm-1 V 1780 ( > C=O ss-lactam) 1650 ( > C=O sec.-amide) N.M.R., a ppm (d5-DMSO): 2.35 (3H, s,-SCH3) 2.4 (3H, 5, -SCH3) 6.83 (1 H, s, 5-H on thiazole ring) 7.30 (2H, br-s, -NH2 on thiazole ring) 8.02 (1 H, s, 7-H on pyridazine ring); and compounds 18,20,21,22,24,25,26,27 and 28.

Example 8 7-[α-(2-aminothiazol-4-yl)-ss-(bis-methylthio)acrylamido]-3-[(tetrazolo[1,5-b[pyridazin-6- yl)thiomethyl]-3-cephem-4-carboxylic acid, compound 15.

To a mixture of 7-[α-(2-amino-thiazol-4-yl)-ss-(bis-methylthio)-acrylamido]3-acetoxymethyl-3- cephem-4-carboxylic acid (2.58 g; 0.005 mol) (prepared as described in Example 7) and 6 mercaptotetrazololl ,5-b]-pyridazine (0.91 g; 0.006 mol) in distilled water (150 ml), NaHCO3 was added in small portions with stirring until a clear solution was obtained and a pH of 6.5 to 7 was reached. This solution was heated for 6.5 hours in an oil bath at 670C; the progress of the reaction can be monitored by TLC (CHCI3: CH3CH:HCOOH = 160:10:30).

After cooling to 50C a few drops of 8% HCI were carefully added under stirring, causing the separation of a precipitate (at about pH 3). This was collected, washed with acetone and dried to give 7-[α-(2-aminothiazol-4-yl)-ss-(bis-methylthio)acrylamido]-3-[(tetrazolo[1,5-b]pyridazin-6- yl)thiomethyl]-3-cephem-4-carboxylic acid identical to that prepared in Example 6.

By proceeding analogousiy compounds 8, 10, 1 1, 12, 14, 16, 17, 18, 19, 21,22, 23, 25, 26, 27 and 28 were obtained.

Example 9 To an aqueous suspension of 7-[-(2-aminothiazol-4-yl)-/3-(bis-methylthio)acrylamido]-3- [(tetrazolo[1,5-b]pyridzin-6-yl)thiomethyl]-3-cephem-4-carboxylic acid, (3.5 g) in water (80 ml) the stoichiometric amount of NaHCO3 was added, thus giving a complete solution of the compound. This solution was then lyophilized, to give the sodium salt of the above-mentioned acid.

Preparation of Pharmaceutical Compositions Example 10 Injectable pharmaceutical compositions were prepared by dissolving 100-500 mg of sodium 7 [α-(2-aminothiazol-4-yl)-ss-(bis-methylthio)acrylamido]-3-[(tetrazolo[1,5-b] pyridazin-6-yl)thiomethyl]- 3-cephem-4-carboxylate in sterile water or sterile normal saline solution (1-2 ml).

Claims

1. Compounds having the following general formula (I)

wherein Z is -O- or -S-; A is phenyl or a pentatomic or hexatomic heteromonocyclic ring containing at least a double bond and at least one heteroatom selected from N, S and 0, the phenyl and the heteromonocyclic ring being unsubstituted or substituted by one or more substituents selected from: a) C1-C6 alkyl; b) halogen; c) halo-C1-C6-alkyl; d)

wherein each of the groups R2 and R3, which may be the same or different, is hydrogen, C1-C6 alkyl, C1-C7 acyl or one of R2 and R3 is hydrogen and the other is an amino-protecting group; e) -OR4 wherein R4 is hydrogen, C1-C5 alkyl, C2-C6 alkenyl or a hydroxy-protecting group; or f) a group -O-(CH2)m-COO R5 wherein m is 1,2 or 3 and R5 is hydrogen, C1-C6 alkyl, acetoxymethyl or a carboxy-protecting group; R is hydrogen, -OCH3 or -SCH3; R, is hydrogen or a branched or straight chain, saturated or unsaturated C1-C6 aliphatic hydrocarbyl group, which is unsubstituted or substituted by one or more substituents selected from hydroxy, cyano,-CONH2 and -COOR5, wherein R5 is as defined above; Y is:: 1) hydrogen; 2) halogen; 3) hydroxy; 4) C1-C6 alkoxy; 5) -CH2-OCOCH3; 6)

wherein R6 is hydrogen, C1-C6 alkyl, carboxy, cyano or carbamoyl, or 7) -CH2-S-Het, wherein Het represents a') a pentatomic or hexatomic heteromonocyclic ring containing at least one double bond and at least one heteroatom selected from N, S or 0, the heteromonocyclic ring being unsubstituted or substituted by one or more substituents selected from:: a") hydroxy, C1-C6 alkoxy, halogen, C1-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-R7, wherein R7 is hydrogen or C1-C6 alkyl, or -S-CH2COOR', wherein R' is hydrogen, C1-C6 alkyl, or a carboxy-protecting group; e") -(CH2)n-COOR', -CH=CH-COOR',

or -(CH2)n-CN wherein n is zero, 1,2 or 3 and R', R2 and R3 are as defined above; (")-(CH2)n-SO3H, wherein n is as defined above; 9")

wherein n, R2 and R3 are as defined above; or h") a heterobicyclic ring containing at least two double bonds wherein each of the condensed heteromonocyclic ring which may be the same or different, is a pentatomic or hexatomic heteromonocyclic ring containing at least one heteroatom selected from the group consisting of N, S and 0, the heterobicyclic ring being unsubstituted or substituted by one or more substituents selected from the groups a"), b"), c"), d"), e"), f"), and g") indicated above; M is a carboxylic acid or ester group, and the pharmaceutically and veterinarily acceptable salts thereof.

2. Compounds having the formula (I) given in Claim 1 wherein: R is hydrogen or-S-CH3; Z is -O- or -S-; R1 is hydrogen; C1-C8 alkyl; C2-C4 alkenyl; -(CH2)n-COOH;-(CH2)n-CN;-(CH2)n CONH2, wherein n is 0,1,2 or 3;

A is phenyl; thienyl or

wherein R" is hydrogen or an amino-protecting group and R12 is hydrogen; hydroxy; -O-C1-C6- alkyl; -O-C2-C4 alkenyl-O-(CH2)m -COOR2, wherein m is 1,2 or 3 and R2 is as defined in claim 1;Y is hydrogen, halogen, hydroxy, C1-C3 alkoxy; -CH2-OCOCH3, or -CH2-S-Het, Het representing 1) a tetrazolyl radical unsubstituted or substituted by C1-C3 alkyl; C2-C4 alkenyl; -(CH2)m- COOR', -CH=CH-COOR', -(CH2)m-CN,-(CH2)m-CONH2,-(CH2)m-SO3H

wherein m is 1,2 or 3 and R', R2 and R3 are as defined in claim 1; 2) a thiadiazolyl radical and unsubstituted or substituted by C1-C4 alkyl; C2-C4 alkenyl; -SH; -SCH3;-SCH2COOH; -(CH2)n-COOH,-N R3' R3' wherein each R2, and R3, is independently hydrogen or C1-C3 alkyl and n is 0, 1,2 or 3; or 3) a heterobicyclic ring selected from tetrazolopyridazinyl, tetrazolopyrazinyl, thiadiazolopyridazinyl and triazolopyridazinyl, each of which is unsubstituted or substituted by hydroxy; -SH;

wherein R2 and R3 are as defined in claim 1; C1-C3 alkyl; C2-C4 alkenyl; -COOR', -S-CH2COOR', -CH2-COOR', -CH=CH-COOR', wherein R' is as defined in claim 1; or

wherein R2 and R3 are as defined in claim 1 and the pharmaceutically and veterinarily acceptable salts thereof.

3. Compounds having the formula (I) given in Claim 1 wherein R is hydrogen or-S-CH3; Z is -O- or -S-: R, is -CH3 or -CH2COOH; A is phenyl, thienyl or

wherein R" is as defined in claim 1 and R,3 is hydrogen, hydroxy or methoxy and Y is -CH2OCOCH3 or -CH2-S-Het, wherein Het is tetrazolyl substituted by methyl or tetrazolopyridazinyl substituted by amino, -COOH or -CH2-COOH; as well as the pharmaceutically and veterinarily acceptable salts thereof.

4. Each of the compounds (1) to (28) hereinbefore set forth and their pharmaceutically and veterinarily acceptable salts.

5. A process for the preparation of a compound of formula (I) the process comprising: a) reacting a compound of formula (II)

wherein Y and M are as defined in claim 1 and E is amino or a group -N=C, wherein # is oxygen or sulphur, our a reactive derivative thereof, with a compound of formula (III)

wherein A, R, Z and R, are as defined in Claim 1, or with a reactive derivative thereof, and if desired, removing the protecting groups, where present; or b) reacting a compound of formula (IV)

wherein A, R, Z, R, and M are as defined in Claim 1, or a reactive derivative thereof, with a compound of formula (V) HS-Het (V) wherein Het is as defined in claim 1, or a reactive derivative thereof and, if desired, removing the protecting groups where present, to give a compound of formula (I), wherein A, R, Z, R, and Mare so defined in Claim 1 and Y is -CH2-S-Het wherein Het is as defined in Claim 1; or c) methylating a compound of formula (VI)

wherein A, M, R, and Y are as defined in Claim 1 and each of the symbols Z is, independently, oxygen or sulphur, or a salt thereof, and, if desired, removing the protecting groups, where present, to give a compound of formula (I) wherein A, M, Y and Z are as defined in Claim 1 and R is -OCH3or -S-CH3 and wherein R is either methyl, when starting from a compound (VI) where R, is hydrogen, or any branched or straight chain saturated or unsaturated C1-C6 aliphatic hydrocarbon group as defined above in formula (I), when starting from a compound (VI) wherein R, is other than hydrogen; or d) reacting a compound of formula (VII)

wherein A, M and Y are as defined in Claim 1 with a compound of formula (VIII)

wherein R" is C1-C5 alkyl and Z is as defined in Claim 1 and, if desired, removing the protecting groups where present, to give compounds of formula (I) wherein R and R1 are both hydrogen and Z, A, M and Y are as defined in Claim 1 and, if desired, etherifying a compound of formula (I) wherein R, is hydrogen and R, Z, A, M and Y are as defined in Claim 1 or a salt thereof, to give a compound of formula (I), wherein R, has the meanings reported in Claim 1 except hydrogen and R, Z, A, M and Y are as defined in Claim 1, and or, if desired, converting a compound of formula (1) wherein M 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 and or, if desired, resolving a mixture of isomers into the single isomers.

6. A process according to Claim 5 substantially as described in any one of Examples 1 to 9.

7. Compounds claimed in claim 1 when obtained by a process claimed in claim 5 or 6.

8. A pharmaceutical or veterinary composition containing a compound according to anyone of claims 1 to 4 or claim 7 and a pharmaceutically and verterinarily acceptable carrier and/or diluent.