GB2132610A - Cephem derivatives - Google Patents

Abstract

The present invention provides a cephem derivative of the general formula II <IMAGE> wherein R<1> denotes an unsubstituted or substituted straight or branched chain aliphatic group, bonded to the ring nitrogen atom via a carbon atom, or an unsubstituted or substituted aryl group; and R<0> denotes a hydrogen atom or a carbonyl esterifying group, and salts thereof. The invention also provides processes for the production of cephem derivatives of the general formula II.

Description

SPECIFICATION Cephem derivatives This invention relates to cephem derivatives, to a process for their preparation, to pharmaceutical preparations comprising them, and to intermediates for use in the preparation of substances having antibacterial activity and/or p-lactamase inhibitory and/or inactivating activity.

The term "cephem" is used herein to denote the following structure

The present invention provides a compound of the general formula II

wherein R1 denotes an unsubstituted or substituted straight or branched chain aliphatic group bonded to the ring nitrogen atom via a carbon atom, or an unsubstituted or substituted aryl group; and R denotes a hydrogen atom or a carboxyl esterifying group.

A compound of formula II may have the R or S configuration at position 6 i.e. a compound may be 6R or 6S. The stereochemistry is preferably that found in naturally occurring penicillins.

The present invention accordingly includes any of the various possible isomers of the compound of formula II, in pure form or in admixture with any one or more other isomer(s). If desired, a mixture of isomers may be separated by a known method.

An aliphatic group R' may have up to 1 8 carbon atoms, for example, up to 12 carbon atoms, preferably up to 8 carbon atoms and especially up to 4 carbon atoms. An aliphatic group R1 may be straight or branched chain alkyl, alkenyl or alkynyl group.

An aryl group R1 may comprise up to 12 carbon atoms and may also comprise two or more fused rings. An aryl group R1 is preferably an unsubstituted or substituted phenyl group.

A group R1 may be substituted, as appropriate and as desired, by one or more substituents, which may be the same or different. Examples of substituents are halogen atoms; oxo groups; hydroxyl and mercapto groups, alkoxy and alkylthio groups; alkylcarbonyl groups; carboxy, alkoxycarbonyl and alkylthiocarbonyl groups; alkanoyloxy and alkanoylthio groups; carbamoyl and carbamoyloxy groups, and carbamoyl and carbamoyloxy groups substituted on the nitrogen atom by one or two groups selected from alkyl and aryl groups, and the corresponding unsubstituted and substituted groups in which the oxygen atom or each or either oxygen atom is replaced by a sulphur atom; nitro, cyano and azido groups; amido and imido groups; imino, amino, mono- and di- alkylamino, mono- and diarylamino groups, and N,N-alkylarylamino groups; acylamino groups; sulphinyl, sulphonyl and sulphonamido groups; cycloalkyl groups; aryl, aryloxy, arylthio, aryloxycarbonyl, arylthiocarbonyl, arylcarbonyloxyl, arylcarbonylthio, aralkoxycarbonyl, aralkylthiocarbonyl, aralkylcarbonyloxy, aralkylcarbonylthio, aralkoxy, and aralkylthio groups; aromatic and non-aromatic heterocyclic groups, for example, having one or more heteroatoms, for example, up to 4 heteroatoms, which may be the same or different, selected from nitrogen, oxygen and sulphur atoms, and preferably up to 14 atoms in total, and the corresponding heterocyclicoxy groups and heterocyclicthio groups.

Examples of aromatic heterocyclic groups are 1 -methyl-imidazol-2-yl, 1 ,3-thiazol-2-yl, 1,3,4thiadiazol-2-yl, 1 ,3,4,5-thiatriazol-2-yl, 1 ,3-oxazol-2-yl, 1 ,3,4,5-oxatriazol-2-yl, 1 ,3,4,5-tetrazol-2-yl, 2-quinolyl, 1 -methylbenzimidazol-2-yl, benzoxazol-2-yl. and benzthiazol-2-yl groups, and the corresponding 2-yl-oxy and 2-yl-thio groups.

Any substituent of R1 that is itself capable of substitution may be substituted for example, by any one or more of the substituents described above. Alkyl groups are preferably lower alkyl groups and aryl groups are especially phenyl groups.

The term "lower" as used herein denotes a molecule, group or radical having up to 8 carbon atoms, and especially up to 4 carbon atoms. Unless stated otherwise, halogen atoms are fluorine, chlorine, bromine, and iodine atoms. The term "known" means in actual use in the art or described in the literature of the art.

R1 preferably represents a methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl or tertbutyl group; a -CH2CH2OH or -CH2CH2SH group in which the hydrogen atom may be replaced by an alkyl, acyl or aryl group; a -CH2 aryl group; a -CH2CO2R group, in which R represents a hydrogen atom or a carboxyl esterifying group, a --CH,CONR'R" group, in which R' and R", which may be the same or different, each represents a hydrogen atom, an alkyl group or an aryl group, or R', R" and the nitrogen atom together form a ring;; or R' represents an unsubstituted phenyl group or a phenyl group substituted by one or two substituents, which may be the same or different in the latter case, for example, selected from alkyl, alkoxy and akylthio groups which may be substituted by one or more halogen atoms; free and esterified carboxy groups; nitrile and nitro groups; and halogen atoms.

Examples of such substituents are methyl, methoxy, nitrile, trifluoromethyl and trifuloromethylthio groups, fluorine and chlorine atoms.

In the above preferred meanings for R', alkyl groups preferably have up to 4 carbon atoms, cycloalkyl groups preferably have up to 8 carbon atoms, for example, cyclopropyl, cyclobutyi, cyclopentyl and cyclohexyl groups, acyl groups preferably have up to 5 carbon atoms, and aryl groups are for example phenyl groups that are unsubstituted or substituted as defined above for phenyl groups R1.

An esterified carboxyl group --COOR is, for example, an ester formed with an unsubstituted or substituted aliphatic, cycloaliphatic, cycloaliphatic-aliphatic, aryl, araliphatic, heterocyclic or heterocyclic-aliphatic alcohol having up to 20 carbon atoms or is, for example, a silyl or stannyl ester.

R may represent, for example, a straight or branched chain substituted or unsubstituted alkyl, alkenyl or alkynyl group having up to 1 8 carbon atoms, preferably up to 8 carbon atoms, and especially up to 4 carbon atoms, for example, a methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, allyl, or vinyl group.

An aliphatic group R, especially a methyl group, may be substituted by a cycloalkyl, aryl or heterocyclic group, or R may itself represent a cycloalkyl, aryl or heterocyclic group.

A cycloaliphatic group R may have up to 1 8 carbon atoms and is, for example, a cyclopentyl, cyclohexyl or adamantyl group. An aryl group may have up to 12 carbon atoms and may have two or more fused rings. An aryl group R is, for example, an unsubstituted or substituted phenyl group, and an unsubstituted or substituted aralkyl group is, for example, a benzyl, p-nitrobenzyl or benzhydryl group.

A heterocyclic group may have one or more heteroatoms, selected from oxygen, nitrogen and sulphur, and up to 14 atoms in total. A heterocyclic group is, for example, an oxygen-containing heterocyclic group, for example, a tetrahydropyranyl or phthalidyl group.

A stannyl group R may have up to 24 carbon atoms, for example, R may represent a stannyl group having three substituents which may be the same or different, selected from alkyl, alkenyl, cycloalkyl, alkyl, aralkyl, alkoxy and aralkoxy groups, for example, alkyl groups having up to 4 carbon atoms, for example, n-butyl groups, phenyl and benzyl groups, especially three n-butyl groups.

A silyl group R may also have up to 24 carbon atoms and three substituents, which may be the same or different, selected from alkyl, alkenyl, cycloalkyl, aryl and aralkyl groups, for example, alkyl groups having up to 4 carbon atoms, for example, methyl and t-butyl groups.

Any group R that is capable of substitution may be substituted. Examples of substituents are given above in relation to R1. Substituents for phenyl groups are, for example, as described above in relation to preferred groups R'.

The group R may be removable by hydrolysis, by reduction or by enzyme action to give the free acid. A group R that may be removed readily without substantial degradation of the rest of the molecule is particularly useful as a carboxyl protecting group. Examples of esters that are readily split by reduction are arylmethyl esters, for example, benzyl, p-nitrobenzyl, benzhydryl and trityl esters.

Reduction of an ester, for example, an arylmethyl ester, may be carried out using hydrogen and a metal catalyst, for example, a noble metal, for example, platinum, palladium or rhodium, which catalyst may be supported, for example, on charcoal or kieselguhr.

A p-nitrobenzyl ester may be split, alternatively, first by reduction of the nitro group, and then by hydrolysis. The nitro group may be reduced, for example, using a metal reducing agent, for example, zinc in acetic acid, aqueous tetrahydrofuran or acetone. The pH should be maintained within the range of from 3 to 6, preferably from 4 to 5.5, preferably by the use of aqueous hydrochloric acid. Other reducing agents are, for example, aluminium amalgam in a moist ether, for example, tetrahydrofuran, and iron and ammonium chloride in an aqueous ether, for example, aqueous tetrahydrofuran.

Reduction of the nitro group is followed by hydrolysis which may occur in situ during reduction of the nitro group or which may be carried out subsequently by treatment with an acid.

A stannyl ester, for example, a tri-n-butyl stannyl ester, may be split readily by hydrolysis, for example, by solvolysis, for example, using water, an alcohol, a phenol or a carboxylic acid, for example, acetic acid.

In some cases it may be preferable if the ester group is removable under physiological conditions, that is to say, the ester group is split off in vivo to give the free acid, for example, an acyloxymethyl ester, e.g. an acetoxymethyl or pivaloyloxymethyl ester, an aminoalkanoyloxymethyl ester, for example, an L-glycyloxymethyl, L-valyloxymethyl or L-leucyloxymethyl ester, or a phthalidyl ester, or an optionally substituted 2-aminoethyl ester, for example, a 2-diethylamino-ethyl or 2-( 1 -morpholino)- ethyl ester.

Preferred esters are the p-nitrobenzyl, phthalidyl and ,pivaloyloxymethyl esters.

An ester of formula li, or of any other free acid described herein, may be prepared by reaction with an alcohol, phenol or stannanol or a reactive derivative thereof. The reaction is preferably carried out under mild conditions in order to prevent rupture of the ring or ring system, for example, under neutral or mild acidic or basic conditions, and at temperatures within the range of from --700 to +350C.

An alkyl, alkoxyalkyl or aralkyl ester may be prepared by reaction of an acid of formula ll or any other free acid with the appropriate diazoalkane or diazoaralkane for example, diazomethane or diphenyldiazomethane. The reaction is preferably carried out in an ether, ester or halogenohydrocarbon as solvent, for example, in diethyl ether, ethyl acetate, or dichloromethane. In general, temperatures below room temperature are preferred, for example, from --150 to +1 50C.

An ester derived from an alcohol may also be produced by reaction of a reactive derivative of the alcohol, for example, a halide, for example a chloride, bromide or iodide, or a hydrocarbonsulphonyl derivative, for example, a mesyl or tosyl ester, with a salt of an acid of formula I or another free acid described herein for example, an alkali or alkaline earth metal salt, for example, a lithium, sodium, potassium, calcium or barium salt or an amine salt, for examle, a triethylammonium salt. This reaction is preferably carried out in a substituted sulphoxide or amide solvent for example, in dimethyl sulphoxide, dimethylformamide or hexamethylphosphoramide or, alternatively, an ester may be prepared by reaction of the acid with the alcohol in the presence of a condensing agent, for example, dicyclohexylcarbodiimide.

A stannyl ester may be formed by reaction of a carboxylic acid of formula II or another free acid described herein, or a salt thereof with a reactive tetravalent tin compound, especially a trialkyl tin oxide.

The present invention also provides the salts of those compounds of the invention that have salt forming groups, especially the salts of free acids of formula II and the acid addition salts of compounds of formula II having a basic group The salts are especially physiologically tolerable salts, for example, alkali metal and alkaline earth metal salts, for example, sodium, potassium, lithium, calcium and magnesium salts, ammonium salts and salts with an appropriate organic amine; also physiologically tolerable acid addition salts, where appropriate, with suitable inorganic and organic acids, for example, hydrochloric acid, sulphuric acid, carboxylic and organic sulphonic acids, for example, trifluoroacetic acid and p-toluene sulphonic acid. Some compounds of formula I which contain a basic centre may exist as Zwitterions; such salts are also part of this invention.

A salt of a free acid of formula I may be produced by reacting the free acid with the appropriate base in a solvent, preferably under conditions under which the salt precipitates. In the case of an alkali metal salt, for example, a sodium or potassium salt, the preferred base is an alkoxide.

A salt may be produced directly from an ester by splitting off the ester group under suitable reaction conditions, for example, catalytic reduction of an ester, for example, a p-nitrobenzyl ester, in an aqueous/organic solvent, for example, comprising water and ethyl acetate, dioxane, or tetrahydrofuran, in the presence of an appropriate metal salt, especially a bicarbonate, for example, in an equivalent amount or in a slight excess, yields a salt directly.

The invention also provides a process for the production of a compound of the general formula II, wherein (i) a compound of formula II is obtained, by treatment with a base, from a compound of the general formula IV via a compound of the general formula III

in which formulae R and R' are as defined above, and Y represents a group that is capable of being removed by a nucleophilic group, and denotes that a group may be cis or trans to the group CO2R; or (ii) a compound of the general formula VII

in which R and R' are as defined above, and Z represents an unsubstituted or substituted aromatic heterocyclic radical with up to 1 5 carbon atoms and at least one ring nitrogen atom and optionally a further ring heteroatom, which radical is bonded to the dithio group by one of its ring carbon atoms, which is bonded to a ring nitrogen atom by a double bond, or Z represents an acyl radical derived from an organic carboxylic or thiocarboxylic acid, is treated with a thiophilic agent.

The following reaction scheme shows various ways of producing a compound of formula II.

in which denotes that a group may be cis or trans to the group --COOR, R and R1 are as defined above, Z represents an unsubstituted or substituted aromatic heterocyclic radical with up to 15, preferably up to 9, carbon atoms and at least one ring nitrogen atom and optionally a further ring heteroatom, which radical is bonded to the dithio group by one of its ring carbon atoms, which is bonded to a ring nitrogen atom by a double bond, or Z represents an acyl radical derived from an organic carboxylic or thiocarboxylic acid, and Y represents a group that is capable of being replaced by a nucleophilic group and is, for example, a sulphonyloxy or phosphinyloxy group or a halogen atom, for example, a radical of the formula

in which R5 represents an aliphatic, cycloaliphatic, aryl or araliphatic group having up to 20 carbon atoms, which may be substituted or unsubstituted, for example, as described above for R'. An aliphatic group R5 is, for example, an alkyl group having up to 8 carbon atoms which may be substituted by one or more halogen atoms, for example, chlorine and bromine atoms. An aryl group R5 has, for example, up to 1 5 carbon atoms, and may be substituted by one or more substituents, which may be the same or different, selected from alkyl and alkoxy groups, for example, methyl and methoxy groups, and halogen atoms, especially bromine atoms. R5 preferably represents an unsubstituted or substituted aryl group having up to 1 5 carbon atoms, for example, a phenyl p-tolyl, p-bromophenyl or p-nitrophenyl .

group, or an unsubstituted or substituted alkyl group, especially with 1 to 4 carbon atoms, and preferably a methyl or trifluoromethyl group.

In the radical

R6 and R7, which may be the same or different, each represents an unsubstituted or substituted alkyl, aryl or aralkyl group, or R6 and R7 together with the phosphorus atom may form a 5or 6-membered ring, or either or both R6 and R7 may represent a group OP6a or OP7a respectively, in which P6a and P7a are as defined above for R6 and R7 respectively and, in the case when R6 represents ORa5 and R7 represents -OR7 R6a and P7a may together represent a 5- or 6-membered ring.

A preferred phosphinyloxy group Y is a dimethylphosphinyloxy group.

-Hal represents, for example, a chlorine, bromine or iodine radical.

An aromatic heterocyclic radical Z may be monocyclic or bicyclic and may be substituted, for example, by a lower alkyl group, for example, a methyl or ethyl group, a lower alkoxy group, for example, a methoxy or ethoxy group, a halogen atom, for example, a fluorine or chlorine atom, or an aryl group, for example, a phenyl group.

A heterocyclic radical Z is, for examle, a monocyclic five-membered thiadiazacyclic, thiatriazacyclic, oxadiazacyclic or oxatriazacyclic radical of aromatic character, especially a monocyclic five-membered diazacyclic, oxazacyclic or thiazacyclic radical of aromatic character and above all, the corresponding benzdiazacyclic, benzoxazacyclic or benzthiazacyclic radicals, wherein the heterocyclic part is five-membered and is of aromatic character.

In radicals Z a substitutable ring nitrogen atom can be substituted, for example, by a lower alkyl group. Examples of such groups Z are 1 -methyl- imidazol-2-yl, 1 ,3-thiazol-2-yl, 1 ,3,4-thiadiazol-2-yl, 1 ,3,4,5-thiatriazol-2-yl, 1,3-oxazol-2-yl, 1 ,3,4-oxadiazol-2-yl, 1 ,3,4,5-oxatriazol-2-yl, 2-quinolyl, 1 - methyl-benzimidazol-2-yl, benzoxazol-2-yl and especially benzthioazol-2-yl groups.Z may also represent an acyl radical of an organic carboxylic or thiocarboxylic acid, for example, an unsubstituted or substituted aliphatic, cycloaliphatic, araliphatic or aromatic acyl or thioacyl group having up to 18, preferably up to 10, carbon atoms, for example, lower alkanoyl groups, for example, acetyl and propionyl groups, lower thioalkanoyl groups, for example thioacetyl and thiopropionyl groups, cycloalkanecarbonyl groups, for example a cyclohexa necarbonyl group, cycloalkanethiocarbonyl groups, for example, a cyclohexanethiocarbonyl group, benzoyi, thiobenzyl, naphthylcarbonyl, and naphthylthiocarbonyl groups, heterocyclic carbonyl and thiocarbonyl groups, for example, 2-, 3- or 4pyridylcarbonyl, 2- or 3-thenoyl, 2- or 3-furoyl, 2-, 3- or 4-pyridylthiocarbonyl, 2- or 3-thiothenoyl, and 2- or 3-thiofuroyl groups, and corresponding substituted acyl and thioacyl groups, for example, acyl and thioacyl groups monosubstituted or polysubstituted by lower alkyl groups, for example, methyl groups, halogen atoms, for example, fluorine and chlorine atoms, lower alkoxy groups, for example, methoxy groups, aryl groups for example phenyl groups, and aryloxy groups, for example phenyloxy groups.

Z preferably represents a

group.

As shown above, a compound of formula II may be produced from a compound VI via compounds V, IV and Ill, via compounds V and VII, or via compound VII.

Taking the first of these routes, a compound of formula VI may be converted into a compound of formula V by reaction with a compound capable of introducing the group Y at the hydroxyl group of the enol.

Y is a group that can be replaced by a nucelophilic group, especially one that can be replaced readily by a nucelophilic group, for example, a compound capable of yielding a sulphonyloxy or phosphinyloxy group or a halogen atom. Examples of compounds capable of introducing the group Y are the following: R5SO2X Vllla R5SQOSQR5 Vlllb

SOX2 Vlile PX3 Vlllf PX6 Vlllg in which R5, R6 and R7 are defined as above and X represents a fluorine, chlorine or bromine atom, especially a fluorine or chlorine atom.

The reaction is generally carried out in the presence of an inert non-nucelophilic base to neutralise any acid formed.

The base may be organic, for example, a primary, secondary or teritary amine, for example, a trialkyl amine, for example, triethylamine, dabco (diazabicyclo-(2,2,2)-octane) or Nmethyldiisopropylamine, an N,N-dialkylarylamine, for example, N,N-dialkylanaline, or a pyridine which may be unsubstituted or substituted for example, by one or more alkyl groups, for example,

in which Ra and Rb represent the same or different alkyl groups, or lutidine or collidine; or the base may be inorganic, for example, an alkali metal carbonate, bicarbonate or hydroxide, for example, NaHCO3, Na2CO3 or NaOH.

The reaction is preferably carried out in an inert solvent or diluent, for example, as described above, and the reaction temperature may be within the range of from -20 to +6O0C, preferably from -20 to OOC.

The resulting compound of formula V may then be converted to a compound of formula IV or of formula VII.

A compound of formula V may be converted to a compound of formula IV by reaction with an amine of the formula R'NH2, in which R1 is as defined above, in the presence of a thiophilic agent.

The thiophilic agent is especially a thiophilic metal salt, for example, a salt of an element of Group Ib, llb or VIII of the Periodiic Table of the Elements (cf. Advanced Inorganic Chemistry, F. A. Cotton and G. Wilkinson, Interscience), for example a silver, copper, zinc, nickel, iron, cadmium, mercury or cobalt thiophilic salt, silver and copper salts being preferred.Examples of preferred thiophilic salts are (i) AgNO3, AgOSO2CF3, AgOSO2Me, AgB, AgPF68, CuCI, CuBr, Cut12, CuBr2, CuOSO2Me, CuOSO2CF3, CuSO4, Cu(NO3)2 and the corresponding nickel, zinc, iron and cobalt salts; and (ii) AgOCOCH3, Ag2CO3, AgO, Cu(acac)2, Cu(CO3)2, Cu2CO3, and CuOR7 in which R7 represents an alkyl group or cycloalkyl group for example, comprising up to 8 carbon atoms, preferably CH3, C2H5, or t-butyl. Silver acetate is particularly preferred.

As a proton is liberated in the course of the reaction with the thiophilic agent, it is desirable that this is removed by a base so the reaction can go to completion. The base preferably has a pK > 4, so if the metal salt is itself sufficiently basic, for example, the salts of group (ii) above, it is not necessary to incorporate a further base in the reaction mixture. If, however, the metal salt is only weakly basic, for example, the salts of group (i) above, then it is preferable to use a further base; having a pK > 4. The term "thiophilic agent" is used herein to mean a thiophilic metal salt alone, or a thiophilic metal salt plus base, as appropriate.

The base may be inorganic or organic, and preferred organic bases are pyridine, lower alkyl substituted pyridines, alkylamine substituted pyridines, and lower alkyl substituted piperidines e.g.

2,2,6,6-tetramethylpiperidine, and trisubstituted amines, for example, trialkylamines, for example triethylamine and ethyldiisopropylamine, and N-alkyl-arylamines, for example 1 ,8-bis-(dimethylamino) naphthalene, or N,N-dimethylphenylamine. Examples of preferred inorganic bases are metal hydrides, e.g. sodium hydride, and metal carbonates, for example, sodium carbonate.

The reaction is preferably carried out in an inert solvent or diluent, which is preferably highly purified. Any solvent or diluent maybe used provided it is not hydroxylic. Examples of solvents and diluents are given above in relation to the conversion of compound II to compound I, chlorinated hydrocarbons, for example, methylene chloride and chloroform, being preferred. The reaction temperature is, for example, within the range of from -20 to +600 C, preferably from 0 to 200 C.

The amine is preferably used in an amount equivalent to the amount of compound V and is preferably added to a stirred solution of the compound V and the thiophilic agent.

The group Y may be removed from a compound of formula IV by treatment with a base to give an allene III as a transient intermediate which then dyclises, in the presence of the base, to give a compound of formula 11. The base should have a pKa sufficient to cause the elimination of the group Y as a suitable rate, for example, the pKa is preferably greater than 7 when Y represents a mesylate group. Examples of bases are tertiary amines, for example, triethylamine and preferably dabco.

An inert non-protic solvent or diluent is preferably used, especially chloroform or toluene, and the reaction temperature is, for example, from -20 to +1 000 C, preferably from 20 to 400 C.

As indicated above, compound V may be converted into compound Vl! in another route for the production of compound II: A compound of formula V is reacted with a primary amine of the formula R'NH2 in which R' is as defined above. No thiophilic agent need be present in this case as the amine replaces the group Y rather than the group -SZ as in the previous case.

The amine and compound V may be used in equimolar amounts. It is generally preferable, however, to carry out the reaction in the presence of a base to neutralise any acid iiberated, so excess amine for example, two equivalents or more may be used. Alternatively, another base may be provided in addition to the amine.

The base may be organic, for example, a primary, secondary or tertiary amine, for example, a trialkylamine, for example, triethylamine, dabco, (diazabicyclo-(2,2,2)octane) or Nmethyldiisopropylamine, an N,N-dialkylamine for example, N,N-dialkylanaline, or

in which R8 and R9 represent the same or different alkyl groups; or the base may be inorganic, for example, an alkali metal carbonate or bicarbonate or hydroxide, for example NaHCO3, Na2CO3, or NaOH.

If the pK of the amine R'NH2 is equal to or less than 7, the reaction tends to be slow, so it is preferable to carry out the reaction in the presence of a base that is inert to the reaction and which has a pK greater than 7 to accelerate the reaction. It will be appreciated that one base may act as both catalyst and acid acceptor.

The reaction is preferably carried out in a dry, inert solvent, for example, as described above in relation to the conversion of compound II to compound I, especially in methylene chloride. The reaction temperature is, for example, from -20 to 600 C, preferably from -20 to +200 C.

The resulting compound of formula VII is generally produced as a mixture of E and Z isomers.

Either the E- or Z-isomer or a mixture of E and Z-isomers may then be converted to a compound of formula II by treatment with a thiophilic agent, preferably in an inert solvent or diluent. (It will be appreciated that the E-isomer must be converted to the Z-isomer before cyclisation can occur. This isomerisation occurs in situ under the reaction conditions for the conversion of compound VII to compound II).

Thiophilic agents are as described above for the conversion of compound V to compound IV, and may be used in equimolar amount or in an excess, preferably a molar excess, over compound VII. The reaction temperature is, for example, from 0 to 1000C, preferably from 60 to 800 C, and it will be appreciated that the thiophilic agent must be chosen with the proposed reaction temperature in mind, so there is not substantial decomposition of the thiophilic agent during the reaction. Silver acetate is the preferred thiophilic agent.

Solvents and diluents are also as described above for the conversion of compound V to IV; benzene is the preferred solvent or diluent. Vigorous stirring is required if the thiophilic agent is partially insoluble in the reaction mixture.

Yields are improved by using the reactants in dilute solution, and the preferred concentration range for the thiophilic agent and for compound VII is from 0.1 g to 1 g in 1000 ml. It is also preferable to use a highly purified and dried solvent, and a finely divided thiophilic agent.

The reaction is preferably carried out by refluxing a mixture of 1 g of compound VII in 1 litre of dry benzene containing finely ground silver acetate. The mixture is preferably refluxed under an inert gas, for example, argon or nitrogen, with vigorous stirring.

A compound of formula VII may be produced directly from a compound of formula Vl by treatment with a salt of an amine of the formula R1NH2, in which R1 is as defined above, for example, an acid addition salt, especially a hydrogen halide addition salt, for example, the hydrochloride addition salt. The reaction is generally carried out in the presence of a tertiary amine, for example pyridine, in a solvent or diluent for example, an alcohol, for example, ethanol or methanol. The reaction temperature is, for example, from 20 to 'i1 000C, preferably from 40 to 6O0C.

A compound of formula VI which has the R-configuration at position 4 may be produced from 6amino penicillanic acid, a relatively inexpensive and readily available product, for example, as shown below:

In the above scheme R is as defined above and X' and X2 both represent halogen atoms, or one represents a halogen atom and the other a hydrogen atom. A halogen atom is preferably a bromine or iodine atom. ~ is also as defined above.

A compound of formula VI may be produced by converting a compound of formula IX

in which R and Z are as defined above, into the corresponding enol.

This is preferably carried out by ozonolysis, generally via an intermediate ozonide of the general formula

Ozone is usually employed in the presence of a solvent, for example, an alcohol, for example a lower alkanol, for example methanol or ethanol, a ketone, for example a lower alkanone, for example acetone, an optionally halogenated aliphatic, cycloaliphatic or aromatic hydrocarbon, for example a halogeno-lower alkane, for example methylene chloride or carbon tetrachloride, an ester, for example methyl acetate or ethyl acetate, or a mixture of two or more solvents, including an aqueous mixture, and with cooling or slight warming, for example at temperatures of from -900C to +400 C, preferably from -600C to +00.

An ozonide intermediate Via can be split by reduction to give a compound of the formula VI for which it is possible to use catalytically activated hydrogen, for example hydrogen in the presence of a heavy metal hydrogenation catalyst, for example a nickel catalyst, or a palladium catalyst, preferably on a suitable carrier, for example, calcium carbonate or charcoal; or a chemical reducing agent, for example, a reducing heavy metal, including a heavy metal alloy or amalgam, for example zinc, in the presence of a hydrogen donor, for example, an acid, for example acetic acid, or an alcohol, for example a lower alkanol, a reducing inorganic salt, for example an alkali metal iodide, for example sodium iodide, in the presence of a hydrogen donor, for example, an acid, for example acetic acid, a reducing sulphide compound for example, sulphur dioxide or a di-lower alkyl sulphide, for example dimethyl sulphide, a reducing organic phosphorus compound, for example a phosphine, which can optionally contain substituted aliphatic or aromatic hydrocarbon radicals as substituents, for example tri-lower alkylphosphines, for example tri-n-butylphosphine, or triarylphosphines, for example triphenylphosphine, also phosphites which contain optionally substituted aliphatic hydrocarbon radicals as substituents, for example tri-lower alkyl phosphites, usually in the form of the corresponding alcohol adduct compounds, for example trimethylphosphite, or phosphorus acid triamides which contain optionally substituted aliphatic hydrocarbon radicals as substituents, for example hexa-lower alkyl phosphorus acid triamides, for example hexamethyl-phosphorus acid triamide, the latter preferably in the form of a methanol adduct, or tetracyanoethylene. The splitting of the ozonide, which is usually not isolated, is normally carried out under the conditions which are employed for its manfuacture, that is to say in the presence of a suitable solvent or solvent mixture, and with cooling or slight warming.

The ozonolysis is preferably carried out in ethyl acetate or dichloromethane which comprises from 0 to 50% by volume of methanol. A mixture of 75% dichloromethane and 25% methanol is particularly preferred. The preferred reducing agents are dimethyl sulphide and sulphur dioxide.

The ozonolysis may result, inter alia, in a mixture of isomers Vlb and Vlc about the double bond i.e.

These isomers are readily interconvertible, and compounds of the formulae Vlb and VIc can also exist in the tautomeric keto form.

A compound of formula IX is preferably produced by reacting a compound of formula

in which R is as defined above with a compound of formula H--SS-Z (Xl) in which Z is as defined above.

This reaction may be carried out by merely heating the compound of formula X with the compound of formula Xl preferably in a nitrogen or argon atmosphere, in an inert solvent or diluent at a temperature from 50 to 1500 especially from 80 to 1200. Suitable solvents are those which possess a sufficiently elevated boiling point to achieve the necessary reaction temperature and in which the starting materials and product are stable at the temperature of the reaction. Examples of solvents are benzene, toluene, ethylacetate, acetonitrile, dioxane, N,N-dimethyl formamide and N,Ndimethylacetamide.

The compound of formula X is preferably produced from a compound of formula XII

in which R is defined as above, by means of oxidation.

The oxidation may be carried out by any method suitable for oxidising sulphides to the corresponding suiphoxides. Oxidising agents are, for example, hydrogen peroxide, periodates e.g., sodium periodate, ozone, peracids e.g. peracetic acid, perbenzoic acid, substituted perbenzoic acids e.g. m-chloroperbenzoic acid, and permanganate salts,.e.g potassium permanganate. Preferred oxidising agents are hydrogen peroxide and m-chloroperbenzoic acid.

The oxidation is preferably conducted in an inert solvent at a preferred temperature of from 200 to +300. Preferred solvents are ethyl acetate, methylene chloride, chloroform, acetonitrile, and lower aicohols, for example, methanol and ethanol.

A compound of formula XII may be prepared by catalytically hydrogenating a compound of the general formula XIII

in which X' and X2 are the same and each represents a halogen atom, or X1 represents a hydrogen atom and X2 represents a halogen atom, and R represents a hydrogen atom or a carboxyl esterifying group.

An example of such a process in which R represents a hydrogen atom is given in J. Chem. Soc.

2623(1969).

Some compounds of formula XIII are known and can be prepared according to known procedures. One such procedure which is described in J. Chem. Soc., 2623 (1969) involves the treatment of 6-amino penicillanic acid simultaneously with nitrous acid and a halogenating agent. The use of sodium bromide as the halogenating agent results in a compound uf foi-mula XIII in which X represents a hydrogen atom, Y represents a bromine atom and R represents a free carboxyl group, with sodium iodide giving the corresponding compound in which Y represents an iodine atom, and bromine giving the dibromo anaiogue.

A compound of formula XIII in which R represents-CH2Ph, X represents a hydrogen atom and Y represents an iodine atom, and the dibromo analogue thereof, may both be prepared by the process described in J. Org. Chem., 43, 2960 (1977).

Other compounds of formula XIII may be prepared analogously.

6-Aminopenicillanic is an advantageous starting material as it is readily available and relatively inexpensive. It will be appreciated that the use of a compound analogous to 6-aminopenicillanic acid but having a different stereochemical configuration will result in the production of a compound of formula Vl having the corresponding stereochemical configuration.

It is advisable to esterify a free carboxyl group in a compound of formula Ill or VII prior to cyclisation. Although an ester group may be introduced immediately prior to cyclisation, it is preferably to esterify the carboxyl group, at an earlier stage in the preferred reaction sequence, for example, to esterify a free carboxyl group in a compound of formula XII, XII, XIV or X to ensure that the carboxyl group does not take part in any of the subsequent reactions.

At each stage of the preferred reaction sequence, the desired compound may be isolated from the reaction mixture and, if desired, purified by appropriate techniques generally used for the purification of organic compounds, for example, chromatography or crystallisation.

As indicated above, various intermediates may be produced in the form of mixture of isomers of various kinds. Such a mixture may be separated or resolved at any stage, or the isomeric mixture may be used per se for subsequent reactions.

All of the compounds that are provided by the invention may exist in any appropriate isomeric form, as discussed above, either as a pure isomer or as a mixture of any two or more isomers.

A compound of the general formula II may be converted into a compound of the general formula I

in which R and R' are as defined above, by treatment with a tertiary organophosphorus compound.

Compounds of formula I have antibacterial activity and/or p-lactamase inhibitory and/or inactivating activity, and are described and claimed in our specification No. 2 066 249.

The following table gives examples of compounds of the general formula I:

R1 R 7 7 phenyl H 2 o-cyanophenyl H 3 m-cyanophenyl H 4 p-cyanophenyl H 5 o-trifluoromethylphenyl H 6 m-trifluromethylphenyl H 7 p-trifluromethylphenyl H 8 o-nitrophenyl H 9 m-nitrophenyl H 10 p-nitrophenyl H 11 o-flurophenyl H 12 m-fluorophenyl H 13 p-flurophenyl H 14 2,3-diflurophenyl H 1 5 2,4-diflurophenyl H 16 2,5-diflurophenyl H 17 2,6-diflurophenyl H 18 3,5-diflurophenyl H 19 - 3,4-difiurophenyl H 20 methyl H 21 ethyl H 22 -CH2CF3 H 23 -CH2CN H 24 benzyl H 25 -CH2CO2H H 26 -CH2CO2CH3 H 27 -CH2CO2C2H5 H 28 -CH2CO2-n-C3H7 H 29 -CH2CO24so-C3H7 H 30 --CH,CO,-n-C,H, H 31 -CH2CO2-sec-C4H9 H 32 -CH2CO24so-C4H9 H 33 -CH2CO2-tert-C4H9 H 34 -CH2CO2CH=CH2 H 35 -CH2CONH2 H 36 -CH2CONHCH3 H 37 -CH2CONHC2H5 H 38 -CH2CONH-n-C3H7 H 39 -CH2CONH4so-C3H7 H 40 -CH2CONH-n-C4H9 H 41 -CH2CONH4so-C4H9 H 42 -CH2CONH-sec-C4H9 H 43 -CH2CONH-tert-QH9 H 44 -CH2CON(CH3)2 H 45 -CH2CON(C2H5)2 H 46 | -CH2CON(n-C3H7)2 H 47 -CH2CON(iso-C3H7)2 H 48 -CH2CON(n-C4H9)2 H 49 -CH2CON(iso-C4H9)2 H 50 -CH2CON(sec-C4H9)2 H 51 -CH2CON(tert-C4H9)2 H 52 -CH2CO"3 H

R1 R 53 -cR2CON H 54 -cH2CON H -Q coy 55 | 2 3 H 56 1 CH2CONHCeH6 H 57 to 12 ! as compounds 1 to 56 respectively p-nitrobenzyl 113 to 1 68 as compounds 1 to 56 respectively phthalidyl Compounds 1 to 56 may be in the form of a salt, especially a physiologically tolerable salt.

These compounds are prepared from the corresponding compounds of formula II.

The following examples illustrate the invention In them, temperatures are expressed in degrees Celcius and ratios of solvents for chromatography are by volume.

Example 1 (a) 4'Nitrobenzyl-2-[4R-(2benzthiazolyIdithio).2-oxo-1 -azetidi nylj-3-ethylamino crotonate (VII)

A solution of 5.0 g of 4'-nitrobenzyl-2-[4R-(2-benzthiazolyldithio)-2-oxo-1-azetidinyl]-3- methylsulphonyloxy crotonate in 105 ml dry dichloromethane was cooled to --200 under an argon atmosphere, and to this was added 1.23 ml ethylamine. After stirring for one hour, the solution was filtered through Hyflo (Trade Mark), evaporated in vacuo and chromatographed on silica gel eluting with hexane/ethyl acetate (1:1). 4.04 g of 4'-nitrobenzyl-2-[4R-(2-benzthiazolyldithio)-2-oxo-1- azetidinyl]-3-ethylamino crotonate (88% of the theoretical yield), were obtained as 7 pale yellow solid.

mp 149.5--150.50 Vmax (film) 1770, 1660 cm-'.

s ppm (CDCl3) 1.23 (3H, t, J=7.5 Hz, CH2CH3), 2.11 (3H, S, CH3) 2.90-3.73 (4H, M, CH2CH3, H-3) 5.22 (3H, m, CH2Ph, H-4) 7.20-8.38 (8H, m, aromatics) 9.10 (1 H, m, NH).

(b) 2-Ethyl-3-methyl-4-(4-nitrobenzyloxycarbonyl)-2-azacephem (II)

To a solution of 4.7 g of 4'-nitrobenzyl-2-[4R-(2-benzthiazolyidithio)-2-oXo-1 -azetidinyl]-3-ethylamino crotonate in 3000 ml dry benzene under an argon atmosphere, was added 5 g of finely divided silver acetate. The vigourously stirred solution was refluxed until the reaction was shown by thin layer chromatography to be essentially complete. The suspension was filtered through Hyflo then evaporated in vacuo, and the residue was chromatograhped on silica gel eluting with hexane/ethyl acetate (1 :1) 1.46 g of 2-ethyl-3-methyl-4-(4-nitrobenzyloxycarbonyl)-6R-2-azacephem (50.6% of the theoretical yield) was obtained as a white crystalline solid.

mp 110112 Vmax (CHCI3) 1775, 1706 cm-1 a ppm (CDCl3) 1.77 (3H, t, J=7Hz, CH2CH3), 2.43 (3H, S, CH3) 2.77 (1 H, dd, Jab=1 5.5 Hz, Jax=2Hz, H-7) 3.13-3.87 (2H, m, CH2CH3) 3.80 (1 H, dd, Jab=1 5.5 Hz, Jbx=5 Hz, H-7) 4.38 (1 H, dd, Jax=2 Hz, Jbx=5 Hz, H-6) 5.35 (2H, S, CH2Ph) 7.43-8.47 (4H, m, aromatics).

m/e found 363.0837; C16H'7 N305S requires 363.0888.

Example 2 (a) 4'-Nitrobenzyl-2-[4R-(2-benzthiazolyldithio)-2-oxo-1 -azetidinyl]-3-anilino crotonate (VII)

To a stirred solution of 2.274 g of 4'-n itrobenzyl-2-[4R-(2-benzthiazolyldithio)-2-oxo- 1 -azetidinyl]-3- methylsulphonyloxy crotonate in 60 ml dry dichloromethane was added 0.7 ml of purified aniline followed by a solution of 0.438 g of diazabicyclo[2,2,2]-octane in 6 ml dry dichloromethane. After having been stirred for one hour the solution was evaporated in vacuo and chromatographed on silica gel eluting with hexane/ethyl acetate (1:1) 1.59 g (70% of the theoretical yield) of 4'-nitrobenzyl-2 [4R-(2-benzthiazolyldithio)-2-oxo- 1 -azetidinyl]-3-anilino crotonate were obtained.

Vmax (film) 1 765, 1 664 cm-1.

a ppm (CDCl3) 2.13 (3H, S, CH3) 3.10 (1 H, dd, Jab=1 6 Hz, Jax=2.5 Hz, H-3) 3.49 (1 H, dd, Jab=1 6 Hz, Jbx=4.5 Hz, H-3) 5.27 (3H, m, H-4, PhCH2) 6.86-8.33 (13H, m, aromatics) 10.80 (1H, S, NH).

(b) 2-Phenyl-3-methyl-4-(4-nitrobenzyloxycarbonyl)-2-azacephem (II)

To a vigorously stirred solution of 1.59 g of 4'-nitrobenzyl-2-[4R-(2-benzthiazolyldithio)-2-oxo-1 - azetidinyl]-3-anilino crotonate in 1000 ml dry benzene under an argon atmosphere was added 1.59 g of finely divided silver acetate. The solution was brought to reflux and stirring was continued until the reaction was shown by thin layer chromatography to be complete. The solution was then filtered through Hyflo and concentrated in vacuo. Chromatography on silica gel using hexane/ethyl acetate (1:1) as eluant afforded 0.76 g (62% of the theoretical yield) of 2-phenyl-3-methyl-4-(4 nitrobenzyloxycarbonyl)-6R-2-azacephem as a colourless foam.

Vmax (film) 1782, 1715 cm~1.

a ppm (CDCl3) 2.20 (3H, S, CH3), 2.83 (1 H, dd, Jab=1 6 Hz, Jax=2 Hz, H-7) 3.80 (1 H, dd, Jab=1 6 Hz, Jbx=5 Hz, H-7) 4.50 (1 H, dd, Jax=2 Hz, Jbx=5 Hz, H-6) 5.37 (2H, S, PhCH2) 6.90-8.42 (9H, m, aromatics).

m/e Found 411.0880. C20H,7N3OsS requires 411.0888.

Example 3 (a) 4'-nitrobenzyI-2[4R-ethyIsuIphenamoyI-2-oxo-1 -azetidinyl]-3-methylsulphonyloxy crotonate.

To a solution of 0.329 g of 4'-nitrobenzyl-2-[4R-(2-benzthiazolyidithio)-2-oXo-1 -azetidinyl]-3methylsulphonyloxy crotonate in 4 ml dry chloroform was added 0.094 g silver acetate, followed by 37 yl ethylamine. When the reaction was shown by thin layer chromatography to be complete, the solution was filtered through Hyflo, evaporated in vacuo, and chromatographed on silica gel, eluting with ethyl acetate/hexane (1:1)0.194 g (75% of the theoretical yield), of 4'-nitrobenzyl-2-[4Rethylsulphenamoyl-2-oxo-1 -azetidinyl]-3-methylsulphonyloxy crotonate was obtained, as a mixture of E- and Z-isomers as a pale yellow syrup.

Major isomer a ppm (CDCl3) 1.07 (3H, t, J=7.5 Hz, CH2CK3), 2.65 (3H, S, Cos), 2.90 (2H, q, J=7.5 Hz, CH2CH3) 3.03-3.43 (2H, m, H-3), 3.30 (3H, S, SO2CH3), 5.00 (1 H, t, J=4 Hz H-4), 5.38 (2H, S, CH2P) 7.43-8.47 (4H, m, aromatics).

Minor isomer 1.07, (3H, t, J=7.5 Hz, CH2CH3) 2.37 (3H, S, CH3) 2.90 (2H, q, J=7.5 Hz, CH2CH3) 3.03-3.43 (2H, m, H-3) 3.23 (3H, S, SO2CH3), 5.03 (1 H, t, J=4 Hz, H-4) 5.38 (2H, S, CH2Ph) 7.43- 8.47 (4H, m, aromatics).

(b) 2-Ethyl-3-methyl-4-(4-nitrobenzyloxycarbonyl)-2-azacephem

A solution of 0.065 g of 4'-nitrobenzyl-2-[4R-ethyisulphenamoyl-2-oxo-1-azetidinyl]-3- methylsulphonyloxy crotonate in 0.4 ml deuteriochloroform was treated with a solution of 0.01 6 g of diazabicyclo(2,2,2)octane in 0.1 ml deuteriochloroform and the course of the reaction was observed using n.m.r. spectroscopy.

A singlet at (S 5.68) corresponding to the allene of formula Ill shown above was observed to appear, to increase and then to decay with the simultaneous growth of absorption due to the azacephem derivative of formula II indicated above.

When the reaction was shown by n.m.r. to be complete, the solution was concentrated in vacuo and chromatographed on silica gel using ethyl acetate/hexane (1:1) as eluant to give 2-ethyl-3-methyl 4-(4-nitrobenzyloxy-carbonyl)-6R-2-azacephem (0.012 g, 3 3% of the theoretical yield). This compound was identified by comparison with an authentic sample.

Example 4 a) Phthal idyl-2-[(2-benzthiazolyldithio)-2-oxo-1 -azatidinyl]-3-ethylamino crotonate

1.18 g of ethylamine was added dropwise to a solution of 6.90 g of phthalidyl 2-[4-(2benzthiazolyldithio)-2-oxo-1 -azetidinyl]-3-methylsulphonyl crotonate in 100 ml of dry dichloromethane at 200. When the reaction was complete, the reaction mixture was filtered through Hyflo, evaporated in vacuo and chromatographed on silica gel, eluting with ethyl acetate/hexane, to give 3.4 g of the title compound as a mixture of isomers.

v(film) 1 780, 1 670, 1 590 cm~1 ô (CDCl3) 1.23 (t, J=7 Hz, 3H, CH2CH3), 1.95-2.1 6 (m, 3H, CH3) 2.60-3.86 (m, 4H, CH2CH3, H3), 4.86-5.1 6 (m, 1 H, H4) 7.06-8.00 (M, 9H, Phthalidyl CH, Aromatics) 9.06 (bs, 1 H, NH).

(b) 2-Ethyl-3-methyl-4-phthalidyloxycarbonyl-2-azacephem

To a solution of 3.4 g of phthalidyl-2-[4-(2-benzthiazolyidithio)-2-oxo-1-azetidinyl]-3-ethylamino crotonate in 3000 ml of purified benzene under an argon atmosphere, was added 3.4 g of silver acetate. The solution was stirred rapidly and refluxed. When the reaction was complete, the solution was filtered through Hyflo and evaporated in vacuo. Chromatography on silica gel gave the title compound (phthalidyl 4-ethyl-3-methyl-8-oxo-5,4,1-thiadiazodicyclo[4,2,0]oct-2-ene-2-carboxylate) as two optically pure isomers in non-equivalent yield.

Less polar isomer (0.38 g).

m.p. 174.5--1750 D (film) 1780, 1712 cm-' [a]D CHCl3 3580 ô CDCI3 1.17 (t, J=7 Hz, 3H, CH3CH2) 2.46 (S, 3H, CH3), 2.66 (dd, Jab=1 6 Hz, Jax=2 Hz, 1 H, H7), 3.60 (dd, Jab=1 6 Hz, Jbx=5 Hz, 1 H, H7), 3.0-4.0 (m, 2H, CH2CH3) 4.33 (dd. Jxa=2 Hz, Jxb=5 Hz, 1 H, H6) 7.43 (s, 1 H, Phthalidyl CH) 7.33-8.10 (m, 4H, Aromatics).

The more polar isomer (0.213 g) m.p. 165-166 .

V (film) 1780,1712 cm- [&alpha;]D CHCl3 289o # (CDCl3) 1.15 (t, J=7 Hz, 3H, CH2CH3) 2.36 (S, 3H, CH3) 2.67 (dd, Jab=1 5 Hz, Jax=2 Hz, 1 H, H7), 3.08-4.00 (M, 3H, H7, CH2CH 3) 4.33 (dd, Jxa=2 Hz, Jxb=5 Hz, 1 H, H6), 7.20-8.06 (M, 5H, Phthalidyl CH, Aromatics).

Example 5 a) Phthal idyl 2-[4-(2-benzthiazolyldithio)-2-oxo-1 -azetidi nyl]-3-phenyla mi no crotonate

To a solution of 5.6 g of phthalidyl-2-[4-(2-benzthiazolyidithio)-2-oxo-1-azetidinyl]-3- methylsulphonyl crotonate in 50 ml of dichloromethane was added 1.76 g of aniline followed by a solution of 1.08 g of dabco (diazabicyclo(2,2,2)octane) in 10 ml of dichloromethane. The reaction mixture was stirred for 30 minutes, then diluted with dichloromethane, washed with water, dilute hydrochloric acid (0.5 M) and water, dried and evaporated in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate/hexane mixtures to give 4.5 g of the title compound as a light brown foam.

# (film) 1780, 1670 cm-1 # (CDCl3) 2.13(S, 3H, CH3), 2.90-3.48 (M, 2H, H3), 4.96-5.20 (m, 1 H, H4) 6.83-8.05 (M, 1 4H, Phthalidyl CH, Aromatics) 10.76 (S, 1 H, NHPh).

(b) 2-Phenyl-3-ethyl-4-phthalidyloxycarbonyl-2-azacephem

To a solution of 4.5 g of phthalidyl 2-[4-(2-benzthiazolyldithio)-2-oxo-1-azetidinyl] 3phenylamino crotonate in 2000 mls of purified benzene was added 4.5 g of finely divided silver acetate. The reaction and purification were carried out as described in Example 4b. The title compound (phtha lidyl 3-methyl-8-oxo-4-phenyl-5,4, 1 -triazabicyclo[4,2,0]oct-2-ene-2-carboxylate) was obtained in the form of two optically pure isomers.

Less polar isomer m.p. 177-178 # (CHCl3) 1 780, 1 726 cm-1 # (CDCl3) 2.28 (S, 3H, OH3) 2.81 (dd, Jab=16 Hz, Jax=2 Hz, 1 H, H7) 3.76 (dd, Jba=16 Hz, Jbx=6 Hz, 1 H, H7) 4.48 (dd, Jxa=2 Hz, Jxb=5 Hz, 1 H, H6) 6.90-8.06 (M, 1 OH, Phthalidyl CH, Aromatics).

More polar isomer V (film) 1782, 1727 cm-' [&alpha;]D (CHCI3) 200.50 ot (CDCl3) 2.15 (S, 3H, CH3) 2.83 (dd, Jab=1 6 Hz, Jax=2 Hz, 1 H, H7) 3.79 (dd, Jba=1 6 Hz, Jbx=5 Hz, 1 H, H7) 4.47 (dd, Jxa=2 Hz, Jxb=5 Hz, 1 H, H6) 6.90-8.06 (M, 1 OH, Phthalidyl CH, Aromatics).

Example 6 a) Phthalidyl 2-[4-(2-benzthiazolyldithio)-2-oxo-1-azetidinyl]-3-cyanomethyl crotonate

To a suspension of 0.1 54 g of cyanomethylamine hydrochloride in 10 ml of dry dichloromethane was added 0.33 g of triethylamine. When the solution became homogeneous, a solution of 0.96 g phthalidyl-2-[4-(2-benzthiazolyldithio)-2-oxo-1-azetidinyl]-3-methylsulphonyl crotonate in 8 ml of dichloromethane was added in one batch. The reaction was carried out and the mixture worked up as described in Example 5a, giving 0.7 g of the title compound.

v (film) 1 780, 1 680 cm-' # (CDCl3) 2.26 (S, 3H, CH3) 2.73-3.90 (M, 2H, H3), 4.24 (d, J=6 Hz, 2H, CH2CN), 4.96-5.23 (M, 1 H, H45) 7.16-8.10 (M, 5H, Phthalidyl CH, Aromatics). 9.06-9.56 (M, 1 H, NH).

(b) 2-Cya nomethyl-3-methyl-4-phthalidyloxycarbonyl-2-azacephem

To a solution of 0.323 g of cyanomethyl enamine in 1 50 ml of purified benzene, held under an argon atmosphere, was added 0.323 g of silver acetate. The reaction and purification were carried out as described in Example 4(b), giving the title compound (phthalidyl 4-cyanomethyl-8-oxo-5,4,1 thiadiazabicyclo[4,2,0]oct-2-ene-2-carboxylate) as two optically pure isomers.

Less polar isomer (0.083 g) m.p.2010 DEC V #(film) 1783, 1731 cm-1 ot (CDCl3) 2.46 (S, 3H, CH3), 2.80 (dd, Jab=1 6 Hz, Jax=2 Hz, 1 H, H7) 3.79 (dd, Jba=1 6 Hz, Jbx=4.5 Hz, 1 H, H7) 4.06 (d, Jab=1 8.6 Hz, 1 H, CH2CN), 4.62 (d, Jba=1 8.6 Hz, CH2CN) 4.75 (dd, Jxa=2 Hz, Jxb=4.5 Hz, 1H, H6), 7.23-8.06 (M, 5H, Phthalidyl CH, Aromatics).

More polar isomer (0.075 g) V (film) 1783, 1 730 cm-' ot (CDCl3) 2.36 (S, 3H, CH3), 2.76 (dd, Jab=1 6 Hz, Jax=2 Hz, 1 H, H7) 3.79 (dd, Jba=1 6 Hz, Jbx=5 Hz, 1 H, H7) 4.03 (d, Jab=18 Hz, 1H, CH2CN), 4.57 (d, Jba=18 Hz, 1 H, CH2CN) 4.74 (dd, Jxa=2 Hx, Jxb=5 Hz, 1H, H6) 7.20-8.00 (M, 5H, Phthalidyl CH, Aromatics).

Example 7 a) Phthalidyl 2-[4-(2-benzthiazolyidithio)-2-oxo-1-azetidinyl]-3-(4-cyanophenyl) crotonate

To a solution of 1.5 g of phthalidyl 2-[4-(2-benzthiazolyldithio)-2-oxo-1-azetidinyl]-3- methylsulphonyl crotonate in 10 ml of dry dichloromethane was added 0.614 g of aminobenzonitrile followed by 0.313 g of triethylamine. The solution was stirred for 0.5 hour, then diluted and washed with water and brine, dried, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexane to give 0.78 g of the title compound.

#(film) 1781, cm-1 # (CDCl3) 2.23 (S, 3H, CH3) 2.73-3.60 (M, 2H, H3) 5.06-5.33 (M, 1 H, H4) 6.90-8.13 (M, 9H, Phthalidyl CH, Aromatics), 11.03(d, J=3H, 1 H, NH).

(b) 2-(4-Cyanophenyl)-3-methyl-4-phthalidyloxywarbonyl-2-azacephem

To a solution of 0.78 g of 4-cyanophenyl enamine in 300 ml of purified benzene, held under an argon atmosphere, was added 0.78 g of silver acetate. The reaction and purification were carried out as described in Example 4b, giving the title compound (phthalidyl 4-(4 cyanophenyl)-3-methyl-8-oxo- 5,4,1-thiadiazabicyclo[4,2,0]oct-2-ene-2-carboxylate) in the form of two optically pure isomers.

Less polar isomer (0.199 g) #(film) 1785, 1735cm1 # (CDCl3) 2.31 (S, 3H, CH3) 2.92 (dd, J=1 6 Hz, Jxa=2.5 Hz, 1 H, H7), 3.78 (dd, Jba=1 6 Hz, Jbx=5 Hz, 1 H, H7), 4.48 (dd, Jxa=2.5 Hz, Jxb=5 Hz, 1 H, H6), 7.03-8.03 (M, 9H, Phthalidyl CH, Aromatics).

More polar isomer (0.14 g) #(film) 1785, 1730 cm-1 (CDCl3) 2.20 (S, 3H, CH3), 2.90 (dd, Jab=16 Hz, Jax=2 Hz, 1 H, H7), 3.80 (dd, Jba=1 6 Hz, Jbx=5 Hz, 1 H, H7), 4.50 (dd, Jxa=2 Hz, Jxb=5 Hz, 1 H, H 6)' 6.96-8.10 (M, 9H, Phthalidyl CH, Aromatics).

Example 8 a) Phthalidyl 3,3-dimethyl-7-oxo-4,1 -thiazabicyclo-[3,2,O] heptan-2-carboxylate

To a solution of 7.4 g of penicillanic acid (3,3-dimethyl-7-oxo-4,1-thiazabicyclo[3,2,0]heptan-2- carboxylate in 30 ml of dimethylacetamide was added 5.53 ml of diisopropylamine. After 5 minutes 8.4 g of phthalidyl bromide were added and the reaction mixture was stirred until the reaction was shown to be complete by thin layer chromatography. The solution was diluted with ethyl acetate and washed six times with water, then dried and evaporated to afford the title compound in crude form as a dark oil. Chromatography over silica gel, eluting with ethyl acetate/hexane mixtures gave the title compound (9.1 1 g, 74%) as a mixture of phthalidyl isomers which could be partially separated by crystallisation.

Crystalline isomer.

m.p. 165-166 V (CHCl3) 1785 (shoulders at 1792 and 1775) cm-1.

# (CDCl3) 1.56 (S, 3H, CH3), 1.67 (S, 3H, CH3), 3.03 (dd, Jax=2 Hz, Jab=16 Hz, 1 H, H 3.60 (dd, Jbx=4 Hz, Jba=1 6 Hz, 1 H, H6) 4.56 (S, 1 H, H3), 5.26 (dd, Jxa=2 Hz, Jxb=4 Hz, 1 H, H6), 7.50 (S, 1 H, Phthalidyl CH) 7.50-8.20 (M, 4H, Aromatics).

Second isomer (by subtraction) V (film) 1785 (shoulder 1792 and 1775) cm-' # (CDCl3) 1.58 (S, 3H, CH3), 1.63 (S, 3H, CH3), 3.03 (dd, Jab=1 6 Hz, Jax=2.5 Hz, 1 H, H6), 3.62 (dd, Jba=1 6 Hz, Jbx=4 Hz, 1 H, H6), 4.56 (S, 1 H, H3), 5.23 (dd, Jxa=2 Hz, Jxb=4 Hz, 1 H, H5) 7.45 (S, 1 H, Phthalidyl CH), 7.50-8.2 (M, 4H, Aromatics).

b) Phthalidyl 3,3-dimethyl-4,7-dioxo-4, I -thiazabicyclo-[3,2,0] heptan-2-carboxylata

A solution of 9.0 g of phthalidyl 3,3-dimethyl-7-oxo-4,1-thiazabicyclo[3,2,0]heptan-2- carboxylate in 100 ml of acetic acid was cooled to 0 and to it was added dropwise a solution of 5.8 g of m-chloroperbenzoic acid in 55 ml of ethyl acetate. The reaction was monitored using thin layer chromatography. The resulting gelatinous solution was diluted with chloroform (300 ml), washed with saturated aqueous sodium bicarbonate (400 ml), dried over magnesium sulphate and evaporated in vacuo to give the mixed sulphoxides as a gelatinous solid. A sample of the crude product was chromatographed on silica gel, eluting with ethyl acetate/hexane mixtures.The less polar isomer was obtained as an oil, and the more polar isomer as a gelatinous solid.

Less polar isomer V (film) 1788 cm- # (CDCl3) 1.35 (S, 3H, CH3), 1.63 (S, 3H, CH3), 3.40 (d, J=4 Hz, 2H, H6) 4.63 (S, 1 H, H3), 5.06 (t, J=4Hz, H, H 3), 7.56 (S, 1 H, Phthalidyl CH) 7.50-8.23 (M, 4H, Aromatics).

More polar isomer V (film) 1788 cm-1 ot (CDCN) 1.33 (S, 3H, CH3), 1.61 (S, 3H, CH3), 3.08 (dd, Jab=1 6 Hz, Jax=2 Hz, 1 H, H6), 3.44 (dd, Jba=1 6 Hz, Jbx=4 Hz, 1 H, H6) 4.50 (S, 1 H, H3), 5.10 (dd, Jax=2 Hz, Jbx=4Hz, 1 H, H5), 7.48 (S, 1 H, Phthalidyl CH), 7.55-8.13 (M, 4H, Aromatics).

c) Phthalidyl 2-[4-(benzthiazolyidithio)-2-oxo-1 -azetidinyl]-2-(1 -propen-2-yl)-acetate

To a solution of 8.1 g of crude phthalidyl 3,3-dimethyl-4,7-dioxo-4,1-thiazabicyclo [3,2,0]heptan2-carboxylate in 200 ml of dry toluene was added 3.83 g of mercaptobenzthiazole. The solution was refluxed until all of the starting material had been consumed, then cooled, and washed twice with sodium bicarbonate and once with water, dried and evaporated in vacuo to give the title compound (14 g). An aliquot was chromatographed on silica gel eluting with ethyl acetate/hexane mixtures to afford the title compound as a colourless foam.

V (CHCl3) 1780, (shoulder at 1770) cm-' or (CDCl3) 1.92 (S, 3H, CH3), 2.96-3.73 (m, 2H, H3) 4.90 (d, J=4 Hz, H3) 5.00-5.43 (M, 3H, H4=CH2) 7.10-8.10 (M, 9H, Phthalidyl, Aromatics).

d) Phthalidyl 2-[4-(2-benzthiazolyidithio)-2-oxo-1-azetidinyl]-3-hydroxy crotonate

Through a solution of 1 49 of crude phthalidyl 2-[4-(2-benzthiazolyldithio)-2-oxo-1 -azetidinyi]-2- (1 -propen-2-yl)-acetate in a mixture of 200 ml of dichloromethane and 65 ml of methanol cooled to --780 was bubbled ozone. When the starting material had been consumed the reaction was quenched by the addition of dimethyl sulphide (30 ml) in one batch. The reaction was warmed to room temperature and evaporated in vacuo.The residue was dissolved in ethyl acetate, washed twice with water and twice with brine, then dried (MgSO4) and evaporated to yield the title compound as a colourless foam. (10.2 g) V (film) 1788, 1675 cm-' (CDCl3) 2.18 (S, 3H, CH3), 3.O5-3.55(m, 2H, H3), 5.0-5.30 (M, 1 H, H4) 7.2-8.06 (m, 9H, Phthalidyl CH, Aromatics), 11.1 (bs, 1 H, OH).

e) Phthalidyl 2-[4-(2-benzthiazolyl)-2-oxo-1 -azetidinyl]-3-O-methylsulphonyl crotonate

To a solution of 10.0 g of phthalidyl 2-[4-(2-benzthiazolyldithio)-2-oxo-1 -azatidinyl]-3-hydroxy crotonate in 80 ml of dry dichloromethane, cooled to --200, was added 2.018 g of triethylamine followed by 2.39 g of methanesulphonyl chloride. The reaction mixture was diluted with dichloromethane, and washed three times with water, then dried and evaporated in vacuo. The resulting oil was chromatographed on silica gel eluting with ethyl acetate/hexane mixtures to give the title product (5.6 g) as mixture of E and Z isomers.

V (film) 1 786 cm-' ot (CDCl3) 2.48 and 2.52 (S, 3H, CH3), 3.03-3.66 (m, 2H, H3), 3.28 (S, 3H, CH3SO2) 5.20-5.50 (m, 1 H, H4), 7.00-7.93 (m, 9H, Phthalidyl CH, Aromatics).

Claims (64)

Claims

1. A cephem derivative of the general formula II

wherein R' denotes an unsubstituted or substituted straight or branched chain aliphatic group, bonded to the ring nitrogen atom via a carbon atom, or an unsubstituted or substituted aryl group; and R denotes a hydrogen atom or a carboxyl esterifying group.

2. A compound as claimed in Claim 1, wherein R' represents an unsubstituted or substituted, straight or branched chain aliphatic group having up to 1 8 carbon atoms.

3. A compound as claimed in Claim 2, wherein an aliphatic group R1 has up to 12 carbon atoms.

4. A compound as claimed in Claim 3, wherein an aliphatic group R1 has up to 8 carbon atoms.

5. A compound as claimed in Claim 4, wherein an aliphatic group R' has up to 4 carbon atoms.

6. A compound as claimed in Claim 1, wherein R' represents an aryl group having up to 12 carbon atoms.

7. A compound as claimed in Claim 6, wherein R1 represents an unsubstituted or substituted phenyl group.

8. A compound as claimed in any one of Claims 1 to 7, wherein an aliphatic group R' or an aryl group R1 is substituted by one or more sub'stituents, which may be the same or different, selected from halogen atoms; oxo groups; hydroxyl and mercapto groups, alkoxy and alkylthio groups; alkylcarbonyl groups; carboxy, alkoxycarbonyl and alkylthiocarbonyl groups; alkanoyloxy and alkanoylthio groups; carbamoyl and carbamoyloxy groups, and carbamoyl and carbamoyloxy groups substituted on the nitrogen atom by one or two groups selected from alkyl and aryl groups, and the corresponding unsubstituted and substituted groups in which the oxygen atom or each or either oxygen atom is replaced by a sulphur atom; nitro, cyano and azido groups; amido and imido groups; imino; amino, mono- and di-alkylamino, mono- and di-arylamino groups, and N,N-alkylarylamino groups; acylamino groups; suiphinyl, sulphonyl and sulphonamido groups; cycloalkyl groups; aryl, aryloxy, arylthio, aryloxycarbonyl, arylthiocarbonyl, arylcarbonyloxyl, arylcarbonylthio, aralkoxycarbonyl, aralkylthiocarbonyl, aralkylcarbonyloxy, aralkylcarbonylthio, aralkoxy, and aralkylthio groups; aromatic and non-aromatic heterocyclic groups having one or more hetero atoms, which may be the same or different, selected from nitrogen, oxygen and sulphur atoms, and up to 14 atoms in total, and the corresponding heterocyclicoxy groups and heterocyclicthio groups.

9. A compound as claimed in Claim 8, wherein an aromatic hetercyclic group is a 1-methyl imidazol-2-yl, 1 ,3-thiazol-2-yl, 1 ,3,4-thiadiazol-2-yl, 1 ,3,4,5-thiatriazol-2-yl, 1 ,3-oxazol-2-yl, 1 ,3,4,5- oxatriazol-2-yl, 1 ,3,4,5-tetrazol-2-yl, 2-quinolyl, 1 -methyl-benzimidazol-2-yl, benzoxazol-2-yl or a benzthiazol-2-yl group.

10. A compound as claimed in Claim 8 or Claim 9, wherein any substituent of R' is itself substituted.

11. A compound as claimed in Claim 10, wherein a substituent of R1 is substituted as defined for R' in Claim 8 or Claim 9.

12. A compound as claimed in Claim 1, wherein R' represents a methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl or tert-butyl group; a -CH2CH2OH or-CH2CH2SH group in which the hydrogen atom may be replaced by an acyl, alkyl or aryl group; a -CH2 aryl group; a -CH2 cycloalkyl group; a -CH2CO2R group, in which R represents a hydrogen atom or a carboxyl esterifying group; a -CH2CONR'R" group, in which R' and R", which may be the same or different, each represents a hydrogen atom, an alkyl group or an aryl group, or R', R" and the nitrogen atom together form a ring; or an unsubstituted phenyl group or a phenyl group having 1 or 2 substituents.

13. A compound as claimed in Claim 12, wherein, in the definitions of R', an alkyl group has up to 4 carbon atoms, a cycloalkyl group, is a cyclopentyl or cyclohexyl group, an acyl group has up to 5 carbon atoms, and an aryl group is an unsubstituted or substituted phenyl group.

14. A compound as claimed in Claim 12 or Claim 13, wherein a substituted phenyl group has one or two substituents, which may be the same or different, selected from alkyl, alkoxy and alkylthio groups, which are unsubstituted or are substituted by one or more halogen atoms; free and esterified carboxy groups; nitrile and nitro groups; and halogen atoms.

1 5. A compound as claimed in any one of Claims 1 to 14, wherein an esterified carboxyl group rOOR is an ester formed with an unsubstituted or substituted aliphatic, cycloaliphatic, cycloaliphaticaliphatic, aryl, araliphatic, heterocyclic or heterocyclic-aliphatic alcohol having up to 20 carbon atoms.

1 6. A compound as claimed in Claim 15, wherein an alkyl, alkenyl, alkynyl or cycloaliphatic group has up to 18 carbon atoms, an aryl group has up to 12 carbon atoms, and a heterocyclic group has one or more hetero atoms selected from oxygen, nitrogen and sulphur atoms, and has up to 14 atoms in total.

1 7. A compound as claimed in Claim 16, wherein R represents an unsubstituted or substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl, allyl, vinyl, cyclopentyl, cyclohexyl, adamantyl, phenyl, benzyl, tetrahydropyranyl or phthalidyl group.

18. A compound as claimed in any one of Claims 1 to 14, wherein an esterified group --COOR is a silyl or stannyl ester.

19. A compound as claimed in Claim 18, wherein R represents a stannyl group having up to 24 carbon atoms and three substituents, which may be the same or different, selected from alkyl, alkenyl, cycloalkyl, aryl, aralkyl, alkoxy and aralkoxy groups, or a silyl group having up to 24 carbon atoms and three substituents, which may be the same or different, selected from alkyl, alkenyl, cycloalkyl, aryl and aralkyl groups.

20. A compound as claimed in any one of Claims 1 to 14, wherein R represents a group removable under physiological conditions.

21. A compound as claimed in Claim 20, wherein R represents an acyloxymethyl, aminoalkanoyloxymethyl, or unsubstituted or substituted 2-aminoethyl group.

22. A compound as claimed in any one of Claims 1 to 14, wherein R represents a p-nitrobenzyl, or pivoloyloxymethyl group.

23. A salt of a compound as claimed in any one of Claims 1 to 14 wherein R represents a hydrogen atom.

24. An acid addition salt of a compound as claimed in any one of Claims 1 to 23 having a basic group.

25. A compound as claimed in any one of Claims 1 to 22, in Zwitterionic form.

26. A physiololgically tolerable salt as claimed in Claim 23 or Claim 24.

27. A compound of the general formula II as claimed in Claim 1, substantially as described in any one of the examples herein or in the Table herein, or a salt thereof.

28. A process for the production of a cephem derivative of the general formula II as claimed in Claim 1, wherein (i) a compound of formula li is obtained, by treatment with a base, from a coinpound of the general formula IV via a compound of the general formula III

in which formulae R' is as defined in any one of Claims 1 to 14 and R is as defined in any one of Claims 15 to 22, and Y represents a group that is capable of being removed by a nucleophilic group, and denotes that a group may be cis or trans to the group CO2R; or (ii) a compound of the general formula VII

in which R is as defined in Claim 1 or any one of Claims 1 5 to 22, R' is as defined in any one of Claims 1 to 14, and Z represents an unsubstituted or substituted aromatic heterocyclic radical with up to 1 5 carbon atoms and at least one ring nitrogen atom and optionally a further ring heteroatom, which radical is bonded to the dithio group by one of its ring carbon atoms, which is bonded to a ring nitrogen atom by a double bond, or Z represents an acyl radical derived from an organic carboxylic or thiocarboxylic acid, is treated with a thiophilic agent.

29. A process as claimed in Claim 28, wherein Y represents a sulphonyloxy or phosphinyloxy group or a halogen atom.

30. A process as claimed in Claim 29, wherein Y represents a radical of the formula

in which R5 represents an unsubstituted or substituted aliphatic, cycloaliphatic, aryl or araliphatic group having up to 20 carbon atoms, P6 and R7, which may be the same or different, each represents an unsubstituted or substituted alkyl, aryl or aralkyl group, or R6 and R7 together with the phosphorus atom may form a 5- or 6-membered ring, or either or both of R6 and R7 may represent a group OR6a or OP7a respectively, in which Ra5 and Ra are as defined above for R6 and R7 respectively and, in the case when Re rnpresents-OR6a and R7 represents -0 P7a, P6a and Pa7 may together represent a 5- or 6-membered ring, and -Hal represents a chlorine, bromine or iodine radical.

31. A process as claimed in Claim 30, wherein a substituted group R5 is substituted as defined for R1 in any one of Claims 8 to 11.

32. A process as claimed in Claim 30 or Claim 31, wherein an aliphatic group R5 is an unsubstituted alkyl group having up to 8 carbon atoms, or an alkyl group having up to 8 carbon atoms which is substituted by one or more halogen atoms, and an aryl group R5 has up to 1 5 carbon atoms and is unsubstituted or is substituted by one or more substituents, which may be the same or different, selected from alkyl and alkoxy groups and halogen atoms.

33. A process as claimed in Claim 30, wherein Y represents the group R5SO2O- in which R5 represents an unsubstituted or substituted aryl group having up to 1 5 carbon atoms or an unsubstituted or substituted alkyl group having up to 4 carbon atoms.

34. A process as claimed in Claim 33, wherein R5 represents a phenyl, p-tolyl, p-bromophenyl, pnitrophenyl, methyl or trifluoromethyl group.

35. A process as claimed in any one of Claims 28 to 34, wherein the base is a tertiary amine.

36. A process as claimed in Claim 35, wherein a tertiary amine is triethylamine or diazabicyclo(2,2,2)octane.

37. A process as claimed in any one of Claims 28 to 36, wherein a compound of formula IV is produced by reacting a compound of the general formula V

in which R is as defined in Claim 1 or any one of Claims 1 5 to 22, Y is as defined in any one of Claims 28 to 34, and Z is as defined in Claim 28, with an amine of the formula R'NH2, in which R' is as defined in any one of Claims 1 to 14, in the presence of a thiophilic agent.

38. A process as claimed in Claim 37, wherein Z represents a monocyclic or bicyclic aromatic heterocyclic radical, unsubstituted or substituted by a lower alkyl or alkoxy group, a halogen atom or an aryl group, a halgoen atom or an aryl group.

39. A process as claimed in Claim 37 or Claim 38, wherein Z represents a monocyclic, fivemembered thiadiazacyclic, thiatriazacyclic, oxadiazacyclic, oxatriazacyclic, diazacyclic, oxazacyclic or thiazacyclic radical of aromatic character, or a benzdiazacyclic, benzoxazacyclic or benzthiacyclic radical, wherein the heterocyclic moiety is five membered and of aromatic character, a substitutable ring nitrogen atom being optionally substituted.

40. A process as claimed in Claim 39, wherein Z represents 1 -methyl-imidazol-2-yl, 1 ,3-thiazol- 2-yl, 1 ,3,4-thiadiazol-2-yl, 1,3,4,5-thiatriazol-2-yl, 1,3-oxazol-2-yl, 1 ,3,4-oxadiazol-2-yl, 1,3,4,5- oxatriazol-2-yl, 2-quinolyl, 1-methyl-benzimidazol-2-yl, benzoxazol-2-yl or benzthiazol-2-yl group.

41. A process as claimed in Claim 37, wherein Z represents an acyl radical having up to 1 8 carbon atoms derived from an unsubstituted or substituted aliphatic, cycloaliphatic, araliphatic or aromatic carboxylic or thiocarboxylic acid.

42. A process as claimed in Claim 37, wherein Z represents the group

43. A process as claimed in any one of Claims 37 to 42, wherein the thiophilic agent is a thiophilic silver, copper, zinc, nickel, iron, cadmium, mercury or cobalt salt.

44. A process as claimed in Claim 43, wherein the thiophilic agent is AgOCOCH3, Ag2CO3, AgO, Cu(acac)2, Cu(CO3)2, Cu2CO3, CuOR7 in which R7 represents an alkyl group or cycloalkyl group.

45. A process as claimed in Claim 43, wherein the thiophilic agent is (i) AgO,, AgOSO2CF3, AgOSO2Me, AgBF4e, A9PF6E, CuCI, Cu Br, CuCI2, Cubs,, CuOSO2Me, CUOSO2CF3, CuSO4, Cu(NO3)2 or the corresponding nickel, zinc, iron or cobalt salt, and (ii) a base.

46. A process as claimed in any one of Claims 37 to 42, wherein the thiophilic agent is silver acetate.

47. A process as claimed in any one of Claims 37 to 46, wherein a compound of formula V is produced by reacting a compound of the general formula VI

in which R is as defined in Claim 1 or any one of Claims 1 5 to 22, and Z is as defined in Claim 28 or in any one of Claims 38 to 42 with a compound capable of introducing the group Y at the hydroxyl group of the enol, Y being as defined in any one of Claims 28 to 34.

48. A process as claimed in Claim 47, wherein a compound capable of introducing the group Y has the general formula Vllla, Vlllb, Vlllc, Vllld, Vllle, Vlllf or Vlllg R5SO2X Vllla R5SO20SO2R5 Vlllb

SOX2 Vlile PX3 Vlllf PX6 Vlilg in which R5 is as defined in any one of Claims 30 to 34, R6 and R7 are as defined in Claim 30, and X represents a fluorine, chlorine or bromine atom.

49. A process as claimed in Claim 47 or Claim 48, carried out in the presence of an inert nonnucleophilic base.

50. A process as claimed in Claim 28 (ii), wherein the thiophilic agent is as defined in any one of Claims 43 to 46.

51. A process as claimed in Claim 28 (ii) or Claim 50, wherein the thiophilic agent is used in an equimolar amount or in a molar excess, calculated on compound VII.

52. A process as claimed in Claim 28 (ii), Claim 50 or Claim 51, wherein the thiophilic agent and compound VII are each used in an inert solvent or diluent in an amount of from 0.1 g to 1 g in 1000 ml.

53. A process as claimed in Claim 28 (ii) or in any one of Claims 50 to 52, wherein a compound of formula VII is produced by treating a compound of formula VI as defined in Claim 47 with a salt of an amine of formula P1 NH2, in which R' is as defined in any one of Claims 1 to 14.

54. A process as claimed in Claim 53, carried out in the presence of a tertiary amine.

55. A process as claimed in Claim 53 or Claim 54, wherein the salt is a hydrogen halide addition salt.

56. A process as claimed in Claim 28 (ii) or in any one of Claims 50 to 55, wherein a compound of formula VII is produced by treating a compound of formula V as defined in Claim 37 with an amine of formula R'NH2 in which R' is as defined in any one of Claims 1 to 14.

57. A process as claimed in Claim 56, wherein two or more equivalents of the amine R'NH2 are used, calculated on compound V, or a further base is also present.

58. A process as claimed in Claim 56 or Claim 57, wherein, if the amine R'NH2 has a pK of less than 7, there is also present a base that is inert to the reaction and that has a pK greater than 7.

59. A process as claimed in any one of Claims 47 to 49 or 53 to 55, wherein the compound of formula VI is produced by converting a compound of formula IX

in which R is as defined in Claim 1 or any one of Claims 1 5 to 22, and Z is as defined in Claim 28 (ii) or in any one of Claims 38 to 42, into the corresponding enol of formula VI by ozonolysis.

60. A process as claimed in Claim 59, wherein a compound of formula IX is produced by reacting a compound of formula X

in which R is as defined in Claim 59, with a compound of formula Xl H-S-Z (Xl) in which Z is as defined in Claim 59.

61. A process as claimed in Claim 60, wherein a compound of formula X is produced by oxidising a compound of formula (XII)

in which R is as defined in Claim 59.

62. A process as claimed in Claim 61, wherein a compound of formula XII is prepared from a compound of the general formula XIII

in which X' and X2 are the same and each represents a halogen atom, or X' represents a hydrogen atom and X2 represents a halogen atom, and R is as defined in Claim 59, by catalytic hydrogenation.

63. A process as claimed in Claim 62, wherein a compound of formula XIII in which R represents a hydrogen atom is produced from 6-amino-penicillanic acid by treatment with nitrous acid and a halogenating agent.

64. A process as claimed in Claim 28, carried out substantially as described in any one of Examples 1 to 7 herein.

64. A process as claimed in claim 28, carried out substantially as described in any one of the Examples herein.

65. A compound as claimed in Claim 1, whenever produced by a process as claimed in any one of Claims 28 to 64.

New claims or amendments to claims filed on 1/2/84 Superseded claims 27 and 64 New or Amended Claims:

27. A compound of the general formula II as claimed in Claim 1, substantially as described in any one of Examples 1 to 7 herein or in the Table herein, or a salt thereof.