CEPHALOSPORIN DERIVATIVES

Abstract: Compounds of formula (I) or salts thereof: wherein R<1> is hydrogen, methoxy or formamido; R<2> is an acyl group; CO2R<3> is a carboxy group or a carboxylate anion, or R<3> is a readily removable carboxy protecting group or a pharmaceutically acceptable salt-forming group or in vivo hydrolysable ester group; R<4>, R<5>, R<6> and R<7> independently represent hydrogen or a bond or a substituent group or may form a cyclic system. These compounds have antibacterial activity.

Description: 1 CEPHAL0SP0RIN DERIVATIVES This invention relates to novel β-lactam compounds, their preparation and their use, and in particular to a novel class of cephalosporins. These 5 compounds have antibacterial properties, and are therefore of use in the ( treatment of bacterial infections in humans and animals caused by a wide range of organisms. We have now found a particularly advantageous class of polycyclic 10 compounds based upon a cephalosporin nucleus. The present invention provides a compound of formula (I) or a salt thereof: 15 (I) wherein Rl is hydrogen, methoxy or formamido; R2 is an acyl group, in particular that of an antibacterially active 20 cephalosporin; CO2R is a carboxy group or a carboxylate anion, or R3 is a readily removable carboxy protecting group or a pharmaceutically acceptable salt- forming group or in vivo hydrolysable ester group; R , R5, R6 nd R7 independently represent hydrogen or a substituent 25 group; wherein R^ and R? may be absent and be replaced by a chemical bond between the two carbon atoms shown; and wherein R and R^ may be linked together into a cyclic system of formula: 30 wherein X represents - O - or - N 8 _ > wherein each R^ may be the same or different and independently represents hydrogen or a substituent group, or two groups R^ may be linked into a ring system, or any two adjacent - CR^2 - units may be replaced by a - CRβ = CRβ - unit, and wherein n is an integer 1 to 7, m is 0, 1, 2 or 3. In compounds of formula (I) wherein R^- is formamido, the formamido group can exist in conformations wherein the hydrogen atoms of the -NH-CHO moiety are cjt£- or trans-; of these the _as conformation normally predominates. Since the compounds of the present invention are intended for use as therapeutic agents for antibacterial use in pharmaceutical compositions, it will be readily appreciated that preferred compounds within formula (I) are pharmaceutically acceptable, L£_ are compounds of formula (Ia) or pharmaceutically acceptable salts or pharmaceutically acceptable in vivo hydrolysable esters thereof: da) wherein B. R2, R 4 , R5, R6 } nd R? are as defined with respect to formula (I) and the group C02R-----* is CO2R^ where CO2R^ is a carboxy group or a carboxylate anion. Accordingly, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for use as a therapeutic agent, and in particular an in vivo hydrolysable ester thereof for use as an orally administrable therapeutic agent. The present invention further provides a compound of formula (Ia) or a pharmaceutically acceptable salt or in υiυo hydrolysable ester thereof, for use in the treatment of bacterial infections, more particularly an in υiυo hydrolysable ester thereof for use in the oral treatment of bacterial infections. The present invention also includes a method of treating bacterial infections in humans and animals which comprises the administration of a therapeutically effective amount of an antibiotic compound of the formula (Ia) or a pharmaceutically acceptable in υiυo hydrolysable ester thereof, in particular the oral administration of a therapeutically effective amount of an in υiυo hydrolysable ester. In addition, the present invention includes the use of a compound of formula (Ia) or a pharmaceutically acceptable salt or in υiυo hydrolysable ester thereof, for the manufacture of a medicament for the treatment of bacterial infections, in particular the use of an in υiυo hydrolysable ester for the manufacture of a medicament for the oral treatment of bacterial infections. Those compounds of the formula (I) wherein R3 is a readily removable carboxy protecting group other than a pharmaceutically acceptable in υiυo hydrolysable ester or which are in non-pharmaceutically acceptable salt form are primarily useful as intermediates in the preparation of compounds of the formula (Ia) or a pharmaceutically acceptable salt or pharmaceutically acceptable in υiυo hydrolysable ester thereof. Suitable readily removable carboxy protecting groups for the group R3 include groups forming ester derivatives of the carboxylic acid, including in υiυo hydrolysable esters. The derivative is preferably one which may readily be cleaved in υiυo. Also included within the scope of the invention are salts and carboxy-protected derivatives, including in υiυo hydrolysable esters, of any carboxy groups that may be present as optional substituents in compounds of formula (I) or (Ia). Also included within the scope of the invention are acid addition salts of any amino group or substituted amino group that may be present as optional substituents in compounds of formula (I) or (Ia). Suitable ester-forming carboxyl-protecting groups are those which may be removed under conventional conditions. Such groups for R^ include benzyl, p-methoxybenzyl, benzoylmethyl, p-nitrobenzyl, 4-pyridylmethyl, 2,2,2-trichloroethyl, 2,2,2-tribromoethyl, i-butyl, i-amyl, allyl, diphenylmethyl, triphenylmethyl, adamantyl, 2-benzyloxyphenyl, 4-methylthiophenyl, tetrahydrofur-2-yl, tetrahydropyran-2-yl, pentachlorophenyl, acetonyl, ji-toluenesulphonylethyl, methoxymethyl, a silyl, stannyl or phosphorus- containing group, an oxime radical of formula -N=CHR^ where R * - 7 is aryl or heterocyclic, or an in vivo hydrolysable ester radical such as defined below. A carboxyl group may " be regenerated from any of the above esters by usual methods appropriate to the particular B group, for example, aάd- and base- catalysed hydrolysis, or by enzymically-catalysed hydrolysis, or by hydrogenolysis under conditions wherein the remainder of the molecule is substantially unaffected. When used herein the term 'aryl' means phenyl and naphthyl, each optionally substituted with up to five, preferably up to three, groups selected from halogen, mercapto, (C-|_g) alkyl, phenyl, (Ci-g) alkoxy, hydroxy(Cι.g)al_-yl, mercapto(Ci-6)alkyl, halo(Cι_6) alkyl. hydroxy, amino, nitro, carboxy, (Cι_6)al__ylcarbonyloxy, (Cι_6)alkoxycarbonyl, formyl, or (Cι_6)alkylcarbonyl groups. The terms eterocyclyl' and 'htjzroc clic' as used herein mean aromatic and non-aromatic, single and fused, lings suitably containing up to four hetero-atoms in each ring selected from oxygen, nitrogen and sulphur, which rings may be unsubstitutad or substituted by, for example, up to three groups selected from halogen, (C^ g)alkyl, (Cι_6)alkoxy, halo(Cι_ 6)alkyl, hydroxy, carboxy, carboxy salts, carboxy esters such as (C*j_ 6)alkoxycarbonyl, (Cι_6)alkoxycarbonyl(Cι_g)alkyl, aryl, and oxo groups. Each heterocyclic ring suitably has from 4 to 7, preferably 5 or 6, ring atoms. The term neteroaryl' refers to heteroaromatic heterocyclic rings. A fused heterocyclic ring system may include carbocyclic rings and need include only one heterocyclic ring. Compounds within the invention containing a heterocyclyl group may occur in two or more tautometric forms depending on the nature of the heterocyclyl group; all such tautomeric forms are included within the scope of the invention. The term 'heteroaryl' as used herein means a heteroaromatic heterocyclic ring or ring system, suitably having 5 or 6 ring atoms in each ring. When used herein the terms 'alkyl', 'alkenyl', 'alkynyl' and 'alkoxy' include straight and branched chain groups containing from 1 to 6 carbon atoms, such as methyl, ethyl, propyl and butyl. When used herein the term 'halogen' refers to fluorine, chlorine, bromine and iodine. Examples of suitable pharmaceutically acceptable in υiυo hydrolysable ester groups include those which break down readily in the human body to leave the parent acid or its salt. Suitable ester groups of this type include those of part formulae (i), (ii), (iii), (iv) and (v): R, a b -C0 2 CH — O.CO.R (j) d C — R C — N — _ β ^R COjjCHz — OR* wherein R a is hydrogen, (Cι_g) alkyl, (C3.7) cycloalkyl, methyl, or phenyl, R D is (Ci.g) alkyl, (Cj.g) alkoxy, phenyl, benzyl, (C3.7) cycloalkyl, (C3.7) cycloalkyloxy, Cι. ) alkyl (C3.7) cycloalkyl, 1-amino (Cj.g) alkyl, or l-((Cι_g) alkyDamino (Cι_g) alkyl; or R a and R^ together form a 1,2-phenylene group optionally substituted by one or two methoxy groups; RC represents (Cι_g) alkylene optionally substituted with a methyl or ethyl group and R<1 and R e independently represent (Cι_g) alkyl; ' R-^ represents (C^-g) alkyl; RS represents hydrogen or phenyl optionally substituted by up to three groups selected from halogen, (Cι_g) alkyl, or (Ci-g) alkoxy; is oxygen or NH; R is hydrogen or (C]_,g) alkyl; R-* is hydrogen, (Cι_g) alkyl optionally substituted by halogen, (C -g) alkenyl, (Cι_g) alkoxycarbonyl, aryl or heteroaryl; or R-* 1 and R-* together form (Ci. g) alkylene; RJ represents hydrogen, (Cj.g) alkyl or (C^.g) alkoxycarbonyl; and R^ represents (Cι_s) alkyl, (Cχ.8) alkoxy, (C^.g) alkoxy((Cι_ g))alkoxy or aryl. Examples of suitable in vivo hydrolysable ester groups include, for example, acyloxyalkyl groups such as acetoxymethyl, pivaloyloxymethyl, α-acetoxyethyl, α-pivaloyloxyethyl, l-(cyclohexylcarbonyloxy)prop-l- yl, and (l-aminoethyl)carbonyloxymethyl; alkoxycarbonyloxyalkyl groups, such as ethoxycarbonyloxymethyl, α-ethoxycarbonyloxyethyl and propoxycarbonyloxyethyl; dialkylaminoalkyl especially di-loweralkylamino alkyl groups such as dimethylaminomethyl, dimethylaminoethyl, diethylaminomethyl or diethylaminoethyl; 2-(alko_cycarbonyl)-2-a_kenyl groups such as 2-(isobutoxycarbonyl)pent-2-enyl and 2-(ethoxycarbonyl)but-2-enyl; lactone groups such as phthalidyl and dimethoxyphthalidyl; and esters linked to a second β-lactam antibiotic or to a β-lactamase inhibitor. A further suitable pharmaceutically acceptable in υiυo hydrolysable ester group is that of the formula: -CO_CH 2 R m wherein R m is hydrogen, (C^.g) alkyl or phenyl. A preferred in vivo hydrolysable ester group is the pivaloyloxymethyl ester. Suitable pharmaceutically acceptable salts of the carboxy group of the compound of formula (I) include metal salts, eg aluminium, alkali metal salts such as sodium or potassium, especially sodium, alkaline earth metal salts such as calcium or magnesium, and ammonium or substituted ammonium salts, for example those with lower alkylamines such as triethylamine, hydroxy-lower alkylamines such as 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine or tris-(2-hydroxyethyl)- amine, cycloalkylamines such as dicyclohexylamine, or with procaine, dibenzylamine, £ M-dibenzylethylene- diamine, 1-ephenamine, H-methylmorpholine, H-ethylpiperidine, H-benzyl-β-phenethylamine, dehydroabietylamine, ϋ»N'-bisdehydro-abietylamine, ethylenediamine, or bases of the pyridine type such as pyridii e, collidine or quinoline, or other amines which have been used to form salts with known penicillins and cephalosporins. Other useful salts include the lithium salt and silver salt. Salts of formula (I) may be prepared by salt exchange in conventional manner. In compounds of formula (I) or (Ia), the sulphur atom shown may be an oxidised sulphur atom, i.e. a sulphoxide (SO) or sulphone (SO2) group. When the sulphur atom is present as sulphoxide group it will be understood that α- and β-isomers may exist; both such isomers are encompassed within the scope of the present invention. Advantageously, R-1 is hydrogen. Suitable acyl groups R2 include those of formulae (a) - (f): A 2 -X 3 -{CH 2 ) p -CO- (d) A 3 -C-C0- (e) N OΛ, wherein p is 0, 1 or 2; m is 0, 1 or 2; Aj is (Cχ.g) alkyl, substituted (Cχ_g) alkyl wherein the substituents may be as for R 4 above, (C3_ ) cycloalkyl, cyclohexenyl, cyclohexadienyl, an aryl (including heteroaryl) group, such as phenyl, substituted phenyl, thienyl, pyridyl, or an optionally substituted thiazolyl group, a (Cj.g) akylthio group or (C^.g) alkyloxy; X^ is a hydrogen or halogen atom, a carboxylic acid, carboxylic ester, sulphonic acid, azido, tetrazolyl, hydroxy, acyloxy, amino, ureido, acylamino, heterocyclylarαino, guanidino or acylureido group; A2 is an aryl group, for example a phenyl, 2,6-dimethoxyphenyl,2-alkoxy-l-naphthyl, 3-arylisoxazolyl, or a 3-aryl-5-methylisoxazolyl group, such as 3-(2-chloro-6-fluorophenyl)-5-methylisoxazol-4-yl; a substituted alkyl group; or a substituted dithietane; X2 is a -CH2OCH2-, -CH2SCH2- or alkylene group; X3 is an oxygen or sulphur atom; A3 is an aryl or heteroaryl group such as phenyl, substituted phenyl, furyl, aminothiazolyl or aminothiadiazolyl in which the amino group is optionally protected; and A is hydrogen, (Cι_g)alkyl, (C3.8) cycloalkyl, (C3.8) cycloalkyl(Cι.g)alkyl, (Cχ.g) alkoxycarbonyKCx.g) alkyl, (C2- ) alkenyl, carboxy(Cι.g)alkyl, (C2-g) alkynyl, aryl or (Cι.g)alkyl substituted by up to three aryl groups. Suitably when R^ is a group (a), Ai is (Cι_g) alkyl, (C3_g) cycloalkyl, cyclohexenyl, cyclohexadienyl, phenyl, substituted phenyl (eg substituted as for "aryl" above) such as hydroxyphenyl, thienyl or pyridyl; and Xi is a hydrogen or halogen atom, or a carboxy, carboxylic ester, azido, tetrazolyl, hydroxy, acyloxy, optionally protected amino, ureido, guanidino or acylureido group. Suitably when R2 is a group of formula (d), A2 is phenyl, X3 is oxygen and p is O. Alternatively when R2 is a group of formula (e) or (f) suitable values for the group A3 include those commonly found in antibacterially active cephalosporins containing a hydroxyimino, substituted hydroxyimino or vinyl group in the side chain attached to position 7 of the cephalosporin nucleus, for example phenyl, thien-2-yl, thien-3-yl, fur-2-yl, fur-3-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, 5-amino-l,2,4-thiadiazol-3-yl and 2-aminothiazol-4-yl in each of which the amino group is optionally protected. Preferred groups for A3 include phenyl, 2-aminothiazol-4-yl, fur-2-yl, thien-2-yl, 2-(2-chloroacetamido)thiazol-4-yl, 2-tritylamino-thiazol-4-yl, 5-amino-l,2,4-thiadiazol-3-yl and 4-aminopyrimid-2-yl. In compounds of formula (Ia) a preferred acyl group R^ is one of formula (e), having a group, A3 which is 2-aminothiazol-4-yl. Suitable values for the group A4 include hydrogen, methyl, ethyl, cyclopropylmethyl, triphenylmethyl (trityl), cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, phenyl, carboxymethyl, carboxypropyl and i-butoxycarbonylmethyl. Preferred values for A4 in compounds of formula (Ia) include methyl and hydrogen. Suitably the group R2NH may be a 2-(2-aminothiazol-4-yl)-2-(Z)-methoxy- or hydroxy- iminoacetamido group, in which the amino group may be in a protected form. It will be appreciated that compounds of the invention wherein R^ is a group of formula (e) (or (f)) can exist as syn and anti (or J£ and Z) isomers or mixtures thereof. Both isomers are encompassed within the scope of this invention. Preferably the compounds of the invention wherein R2 is a group of formula (e) have the syn configuration (i.e. have the group OA4 svn to the amide linkage) or are enriched in that isomer. Similarly, when R-2 is a group of formula (0, the group A4 is preferably όs to the amide linkage, i.e. when group (f) is 2-amino-thiazol-4-yl, the Z-configuration is preferred. When one or more of R 4 , R , R6 and R * - 7 represent substituent groups they may suitably be selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, thioalkyl, thioaryl, halogen, amino, cyano, alkylamino, acylamino, dialkylamino, CO2R, CONR2, SO2NR2(where R is hydrogen or (Cχ_ g)alkyl), aryl, heterocyclyl, (Cχ_g) alkanoyl, (Cχ.g) alkoxycarbonyl, (Cχ_g) alkoxy (Cχ_g) alkyl, (Cχ.g) alkanoyloxy, (Cχ.g) alkanoyloxy (Cχ.g) alkyl, and trialkylsilyl and where any R 4 , R^, R^ or R * - 7 alkyl substituent may be substituted with any other of the aforementioned groups. Examples of such groups include methyl, butyl, ethoxy, phenyl, hydroxymethyl, acetyl, thiophenyl, methoxymethyl, carbonyloxymethyl and trimethylsilyl. Suitably one, two, three or four of R 4 , R5, R6 and R? may be hydrogen, for example both Εβ and R * - 7 may be hydrogen, and one of R 4 or R5 may be hydrogen/ The compound of formula (I) may suitably have a part formula (EBi) or (IBii): 11 where one or both of R 4 and R5 may be substitutent groups other than hydrogen. When 5 and Bβ are linked together into a cyclic system R 4 and R? may suitably be hydrogen, and the ring system may suitably be a 5- or 6- membered ring system of part formula (IBiii), (IBiv) or (IBv) or (IBvi): -(R )P (IBiii) . where Bβ and n are as defined in formula (I) above and p is zero or an integer up to the number of carbon atoms in the ring. when Bβ represents a substituent group on a ring carbon atom it may be hydrogen or independently selected from the same Hst of substituents from which R 4 , R , R6 and R"* 7 may be selected, and suitably such an R^ may be hydrogen. When ^ represents a substituent on a ring nitrogen atom it may be hydrogen, (Cχ.g) alkyl, or an amino substituting or protecting group such as acyl. Suitably in part formulae (IBiii - IBvi) R8 may be hydrogen, and n may be l or 2. When two groups R^ are linked together to form a ring system, such a ring system may be an aliphatic ring system, for example a cycloalkane or cycloalkene ring system, having from 3 to 7 ring carbon atoms. Such an aliphatic ring system may optionally be substituted by one or more substituents independently selected from the same list of substituents from which R 4 , R5, R6 and R? may be selected. The ring system any alternatively by an aryl or heterocyclyl ring system as defined above. Two groups R8 may be linked together for example to form an optionally substituted phenyl ring system, for example in a compound of part formula (IBvii): (IBvii) wherein the phenyl ring shown in (IBvii) may be substituted with one or more substituents. In the compounds of part formula (IBi-vii) above the ring systems may exist in a number of isomeric forms including stereoisomers, and the present inventions includes all of them as well as mixtures thereof. Certain compounds of the invention include an amino group which may be substituted and/or protected. Suitable amino substituting and protecting groups are those well known in the art which may be removed under conventional conditions without disruption of the remainder of the molecule. Examples of amino substituting and protecting groups include (Cχ.g) alkanoyl; benzoyl; benzyl optionally substituted in the phenyl ring by one or two substituents selected from (Cχ.4) alkyl, (C .4) alkoxy, trifluoromethyl, halogen, or nitro; (C1. ) alkoxycarbonyl; benzyloxycarbonyl or trityl (ie triphenylmethyl) substituted as for benzyl above; allyloxycarbonyl, trichloroethoxycarbonyl or chloroacetyl. Some of the compounds of this invention may be crystallised or recrystallised from solvents such as organic solvents. In such cases solvates may be formed. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. Since the antibiotic compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 95% pure, particularly at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 49% of a compound of the formula (I) or salt thereof. Specific compounds within this invention of formula (Ia) include the pharmaceutically acceptable carboxylic acids listed below, and salts and in-υiυo hydrolysable esters thereof. (5S,6β,8β,9Λ)-9-[2-(2-ammothiazol-4-yl)-2-(Z)-methoxyimmoacetamido]- 5-ethoxy-10-oxo-7-thia-l-azatricyclo[6.2.0.θ3-6]dec-2-ene-2-carboxylic acid, (4β,9ie,10Λ,12_?, 13_?)-13-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxy- iminoacetamido]-14-oxo-8-oxa-ll-thia-l-azatetracyclo[10.2.0.θ3»10.0 4 ''- ) ]- tetra- dec-2-ene-2-carboxylic acid, (5S,6β,8R,9Λ]-5-acetoxy-9-[2-(2-aminothiazol-4-yl)-2-(Z)-methθ--y- iminoa<»tamido]-10-oxo-7-thia-l-azatricyclo[6.2.0.θ3-6]dec-2-ene-2- carboxylic acid, (6S, 8.R, 9_?)-5,5-dimethyl-10-oxo-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.θ3>6]dec-2-ene-2-carboxylic acid, (5S, 6S, 8R, 9Λ)-5-butyl-10-oxo-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.θ3'6]dec-2-ene-2-carboxyHc acid, (6S, 822, 922)-10-oxo-5-phenyl-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.0 3 »6]deca-2,4-c_-ene-2-carboxylic arid, (622, 82?, 922)~10-oxo-5-phenyl-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.θ3>6]deca-2,4-diene-2-carboxylic acid, (6S,8B,92ϊ)-9-[2-(2-an__notMazol-4-yl)-2-(Z>methoxyimmoacetømido]-10- oxo-5-phenyl-7-thia-l-azatricyclo[6.2.0.θ3.6]deca-2,4-diene-2-carboxylic acid, (62-,8H,92?)-9-[2-(2-am otMazol-4-yl)-2-(Z>methoxyimmoacetemido]-10- oxo-5-phenyl-7-tiιia-l-azatricyclo[6.2.0.θ3» β ]deca-2,4-diene-2-carboxylic acid, (62?,822,92-)-10-oxo-9-phenyla(»tamido-5-trimethylsilyl-7-thia- l- azatricyclo[6.2.0.θ3'^]deca-2-4-diene-2-carboxylic acid, (522,6H,82?,922)-9-benzamido-10-oxo-5-phenylthio-7-thia-l- azatricyclo[6.2.0.θ3-6]dec-2-ene-2-carboxylic acid, (5S,6R,82_,9Λ)-9-benzamido-10-oxo-5-phenylthio-7-thia-l- azatricyclo[6.2.0.0 3 >6]- dec-2-ene-2-carboxylic acid, (4S,5S,6S,822,922) -4,5-dimethyl-10-oxo-9-phenylacetamido-7- thia-1- azatricyclo[6.2.0.θ3>6]dec-2-ene-2-carboxylic acid, (6S, 822, 922) -4,5-dinιethyl-10-oxo-9-phenylacetamido-7-thia-l-azatricyclo [6.2.0.0 3 » 6 ]deca-2,4-diene-2-carboxylic acid, (4S, 822, 9S, 1122, 1222)-13-oxo-12-phenylacetamido-5-oxa-10- thia-1-aza- 6,7-benzotetracyclo[9.2.0.0 3 - 9 .0 4 » 8 ]tridec-2-ene-2-carboxylic acid, (4S, 822, 9S, 1122, 1222)-12-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxy- iminoacetamido]-13-oxo-5-oxa-10- thia-l-aza-6,7-benzotetra- <ydo[9.2.0.θ3>9.0 4 »8]tridec-2-ene-carboxylic arid, (4S, 8 , 9S, 1122, 1222)-13-oxo-12-phenylacetamido-10-thia-l-aza-6,7- benzotetracydo[9.2.0.0 3 -9.0 4 -8]tridec-2-ene-2-carboxylic add, (5S, 622„8_5,922)-10-oxo-5-(2-oxopyrrolidin-l-yl)-9-phenylacetamido-7-thia- l-azatricyclo[6.2.0.0 3 »6](iec-2-ene-2-carboxylic add, (522, 65, 822, 922)-5-hydroxymethyl-10-oxo-9-ρhenylacetamido-7-thia-l- azatricyclo[6.2.0.θ3>6]dec-2-ene-2-carboxylic arid, (4S, 922 10S, 1222, 1322)-14-oxo-13-phenylacetamido-ll-thia-l- azatetracydo[10.2.0.θ3»10.0 4 »9]-tetradec-2-ene-2-carboxylic add, * (422,8S,95, 1122, 1222)-13-oxo-12-phenylacetamido-10-thia-l- azatetracydo[9.2.0.θ3»9.0 4 -8]tridec-2-ene-2-carboxylic add, (4S,82295, 1122, 1222)-13-oxo-12-phenylacetamido-10-thia-l- azatetracydo[9.2.0.0 3 ' 9 .0 4 - 8 9]-tridec-2-ene-2-carboxylic add (55, 6S, 822, 922)-9-benzamido-10-oxo-5-phenyl-7-thia-l- azatricyclo[6.2.0.0 3 -6]dec-2-ene-2-carboxylic add, (522, 6S,822,922)-9-benzamido-10-oxo-5-phenyl-7-thia-l- azatricyclo[6.2.0.0 3 '6]-dec-2-ene-2-carboxylic add, (522, 6S, 822, 922)-5-acetoxymethyl-10-oxo-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.0 3 »6]dec-2-ene-2-carboxylic arid, ( 622, 822, 922)-5-ethoxy-10-oxo-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.0 3 >6]deca-2,4-diene-2-carboxylic add, ( 622 and 65, 822, 922)-5-methoxycarbonyl-10-oxo-9-phenyla∞tamido-7- thia-l-azatricydo[6.2.0.0 3 '6]deca-2,4-diene-2-carboxylic add, (522S, 6S, 822, 922)-5-methoxycarbonyl-10-oxo-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.0 3 »6]dec-2-ene-carboxylic add, (522S, 6S, 75, 822, 922)-7,10-dioxo-5-phenyl-9-phenylacetamido-7-thia-l- azatric3tclo[6.2.0.0 3 »6ldec-2-ene-2-carboxylic add, (522, 6S, 822, 922)-5-phenyl-9-phenylacetamido-7,7,10-trioxo--7-thia-l- azatricyclo[6.2.0.0 3 »6]dec-2-ene-2-carboxylic add, (55, 6S, 822, 922)-5-phenyl-9-phenylacetamido-7,7,10-trioxo-7-thia-l-aza- tricydo[6.2.0.0 3 '6]dec-2-ene-2-carboxylic add, ( 522S, 6S, 822, 922)-5-cyano-10-oxo-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.0 3 »6]dec-2-ene-2-carboxylic add, (522, 65, 822, 3R -5-cyano-10-oxo-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.0 3 >6]dec-2-ene-2-carboxylic add, and (6S, 822, 922)-9-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxy- iminoacetamido] - 10-oxo-7-thia-l-azatricyclo- [6.2.0.0 3 -6]dec-2-ene-2-carboxylic add. The present invention provides a process for the preparation of a compound of formula (I) or (Ia) as defined above in which -CO2 is a carboxy group or carboxylate anion or R 3 is a pharmaceutically acceptable salt-forming group or in-υiυo hydrolysable ester group, wherein a compound of formula (I) as defined above in which R 3 is a carboxy protecting group has its group CO2R 3 replaced by a group CO2R 3 which is a carboxy group or a carboxylate anion, or in which R 3 is a pharmaceutically acceptable salt-forming group or in-υiυo hydrolysable ester group. The present invention further provides a process for the preparation of a compound of formula (D, which process comprises treating a compound of formula (II) or a salt thereof: (ID wherein B CO2R 3 , R^, \ R^, and R * - 7 are as hereinbefore defined, wherein any reactive groups may be protected, and wherein the amino group is optionally substituted with a group which permits acylation to take place; with an add of formula (El) or a N-acylating derivative thereof: R 2 OH (III) wherein R 2 is the acyl group as defined with respect to formula (I) and wherein any reactive groups may be protected; and thereafter, if necessary or desired, carrying out one or more of the following steps: i) removing any protecting groups; ii) converting the group CO2R into a different group CO2R 3 ; iii) converting the group R 2 into a different group R2; iv) converting the sulphur atom into an oxidised sulphur atom; v) converting the product into a salt or ester. Adds of formula (HI) may be prepared by methods known in the art, or methods analogous to such processes. Suitable processes indude those described, for example, in UK Patent 2 107307 B, UK Patent Specification No. 1,536,281, and U.K Patent Specification No. 1,508,064. Suitable groups which permit acylation to take place and which are optionally present on the amino group of the starting material of the formula (H) indude E-silyl, ϋ-stannyl and M-phosphorus groups, for example trialkylsilyl groups such as trimethylsilyl, trialkyltin groups such as tri-n-butyltin, groups of formula -P.R^R 8 wherein R * - 7 is an alkyl, haloalkyl, aryl, aralkyl, alkoxy, haloalkyl, aryl, aralkyl, alkoxy, haloalkoxy, aryloxy, aralkyloxy or dialkylamino group, R 8 is the same as B or is halogen or R? and R 8 together form a ring; suitable such phosphorus groups being -P(OC2H5)2, -P(C2H5)2, A group which may optionally be introduced onto the amino group in the compound of formula (II) is trimethylsilyl. Advantageously the silylation reaction may be carried out in situ, prior to the acylation reaction, with a silylating agent that does not require concomitant addition of base. Suitable silylating agents include, for example, ϋ-(trimethylsilyl)-acetamide, ϋ_Q-bis-(trimethylsilyl)acetamide, H -bis(trimethylsilyl)- trifluoroacetamide, H-methyl-^-trimethylsilylacetamide, K-methyl-H-trimethylsilyl-trifluoroacetamide, H_H'-bis(trimet-iylsilyl)urea, and Hi__-bis(trimethylsilyl)carb_unate. A preferred silylating agent is __ Q.-bis(trimethylsilyl)acetamide. The silylation reaction may suitably be carried out in an inert, anhydrous organic ' solvent such as dichloromethane at room temperature or at an elevated temperature, for example 30 - 60°C, preferably 40 - 50°C. The above process may optionally be carried out in the presence of a small quantity, for example 0.1 equivalents, of a silyl halide, for example a tri(Cχ_g)alkylsilyl halide, espedally trimethylsilyl chloride. A reactive H-acylating derivative of the add (HI) is employed in the above process. The choice of reactive derivative will of course be influenced by the chemical nature of the substituents of the add. Suitable N-acylating derivatives include an add halide, preferably the add chloride or bromide or alternatively a symmetrical or mixed anhydride. The acylation may be effected in the presence of an add binding agent for example, tertiary amine (such as pyridine or dimethylaniline), molecular sieves, an inorganic base (such as caldum carbonate or sodium bicarbonate) or an oxirane, which binds hydrogen halide liberated in the acylation reaction. The oxirane is preferably a (Cχ_ g)-l,2-alkylene oxide - such as ethylene oxide or propylene oxide. The acylation reaction using an add halide may be carried out at a temperature in the range -50°C to +50°C, preferably -20°C to +20°c, in aqueous or non-aqueous media such as water, acetone, tetrahydrofuran, ethyl acetate, dimethylacetamide, dimethylformamide, acetonitrile, dichloromethane, 1,2-dichloroethane, or mixtures thereof. Alternatively, the reaction may be carried out in an unstable emulsion of water-immisdble solvent, espedally an aliphatic ester or ketone, such as methyl isobutyl ketone or butyl acetate. The acylation with add halide or anhydride is suitably carried out in the presence of a basic catalyst such as pyridine or 2,6-lutidine. Add halides may be prepared by reacting the add (IH) or a salt or a reactive derivative thereof with a halogenating (eg chlorinating or brominating) agent such as phosphorus pentachloride, thionyl chloride, oxalyl chloride or phosgene. Suitable mixed anhydrides are anhydrides with, for example, carbonic add monoesters, trimethyl acetic add, thioacetic add, diphenylacetic add, benzoic add, phosphorus adds (such as phosphoric, phosphorous, and phosphinic adds) or aromatic or aliphatic sulphonic adds (such as p-toluenesulphonic add or methanesulphonic add). Alternative H-acylating derivatives of add (HI) are the add azide, or activated esters such as esters with 2-mercaptopyridine, cyanomethanol, n-nitrophenol, 2,4-dinitrophenol, thiophenol, halophenols, including pentachlorophenol, monomethoxyphenol, H-hydroxy succinimide, H-hydroxybenzotriazole, or 8-hydro.rjtqιιinoline; or amides such as M-acylsaccharins, ϋ-acylthiazolidin-2-thione or M-acylphthalimides; or an alkylidene iminoester prepared by reaction of the add (HI) with an oxime. Other reactive H-acylating derivatives of the add (HI) include the reactive intermediates formed by reaction in situ with a condensing agent such as a carbodiimide, for example, H.H-diethyl-, dipropyl- or diisopropylcarbodiimide, HJS'-di-cydohexyl-carbodiimide, or H-ethyl-H'-[3-(dimethylamino)propyl]- carbodiimide; a suitable carbonyl compound, for example, H > H'-carbonylό_umidazole or H.H'-carbonyldi- triazole; an isoxazolinium salt, for example, M-ethyl-5-phenylisoxazolinium-3-sulphonate or H-t-butyl-5- methylisoxazolinium perchlorate; or an H-alkoxycarbonyl 2-alkoxy-l,2-dihydroquinoline, such as H-e hoxycarbonyl 2-ethoxy-l,2-dihydroquinoline. Other condensing agents indude Lewis adds (for example BBr3 - CgHg); or a phosphoric add condensing agent such as diethylphosphorylcyanide. The condensation reaction is preferably carried out in an organic reaction medium, for example, methylene chloride, dimethylformamide, acetonitrile, alcohol, benzene, dioxan or tetrahydrofuran. A further method of forming the H-acylating derivative of the add of formula (HI) is to treat the add of formula (HI) with a solution or suspension preformed by addition of a carbonyl halide, preferably oxalyl chloride, or a phosphoryl halide such as phosphorus oxychloride, to a halogenated hydrocarbon solvent, preferably dichloromethane, containing a lower acyl tertiary amide, preferably H.H-dimethylformamide. The H-acylating derivative of the add of formula (πi) so derived may then be caused to react with a compound of formula (II). The acylation reaction may conveniently be carried out at -40° to +30°C, if desired in the presence of an add binding agent such as pyridine. A catalyst such as 4-dimetEylaminopyridine may optionally also be added. A preferred solvent for the above acylation reaction is dichloromethane. The optional removal of protecting group (i), the optional conversion of CO2R 3 (ii), the optional conversion (iii) of R2 to a different R2, CO2R to a different CO2R 3 and (iv), oxidation of the sulphur, and (v) the optional formation of a salt or ester, may be carried out using methods well known in the art of cephalosporin and penicillin chemistry. For example, the sulphur atom may be oxidised by methods of oxidation or reduction well known in the art of cephalosporin and penicillin synthesis, as described, for example, in European Patent Application Publication No. 0 114752. For example, sulphoxides may be prepared from the corresponding sulphide by oxidation of the sulphur atom with a suitable oxidising agent, for example an organic peradd such as m-chloroperbenzoic add. A reduction step is generally effected by processes well known in the art of β-lactam chemistry, for example using phosphorus trichloride in dimethylformamide. For example, removal of protecting groups may be carried out by any convenient method known in the art such that unwanted side reactions are minimised. When for example R 3 is the protecting group p- methoxybenzyl, this group may suitably be removed by treatment of the protected compound with aluminium chloride in the presence of anisole. Separation of unwanted by-products may be carried out using standard methods. Compounds of formula (II) may be prepared from known (see for example J. Org. Chem (1989), _H, 4 962) starting compounds of formula (IV): (IV) wherein R* and R 3 , are as defined in formula (I), 21 is a group R 2 as hereinbefore defined or is an amino-protecting group or is hydrogen or a group which permits N-acylation to take place and Z is a nudeophilic leaving group, by reaction with a compound of formula (V): 5 6 R R >=< 7 R 4 R (V) wherein R 4 , R , R6 and R7 are as defined with reference to formula (I), R 4 and R * - 7 may be absent and be replaced by a bond to form an alkyne, and wherein R5 and Bβ may be linked together into a cyclic system of formula: wherein X, R 8 , n and m are as defined with respect to formula (I) above. In formula (IV) a suitable group Z is a trifluoromethyl sulphonyloxy or fluorosulphonyloxy group. A suitable group R-^l is phenylacetyl. A suitable group R 3 is p-methoxybenzyl. A suitable group Rl is hydrogen. When in the compound of formula (V) R 4 and B are replaced by a bond between the carbon atoms, the compound of formula (V) is an alkyne, and by the use of such an alkyne compounds of formula (I) may be formed in which a cyclobutene group is present, eg (IBii) above. Suitable values for R 4 , R » R6, R , 8^ y^ m and n in the compound of formula (V) are as defined for formulae (IBi to viii) above. Compounds of formula (V) are known, for example, alkylvinyl ethers, dihydrόfurans, dihydropyrans, vinylalkanoates, pyrrolines, indenes, tetrahydropyridines, alkenes, alkynes, benzofurans, cycloalkenes, etc, and suitable compounds of formula (V) to form a particular compound of formula (H) will be apparent to those skilled in the art. The reaction between compounds of formula (IV) and (V) may be carried out in a solvent suitably an organic solvent such as dichloromethane, and in the presence of a base, suitably an organic amine such as diisopropylethylamine, at a temperature between +40°C and -40°C such as at 0°C. The reaction is facile and may occur simply on stirring the reagents together. The reaction between a compound of formula (IV) and formula (V) to form a compound of formula (II) is novel, and is a further aspect of this invention. The present invention also provides a pharmaceutical composition which comprises a compound of formula (la) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof and a pharmaceutically acceptable carrier. The compositions of the invention indude those in a form adapted for oral, topical or parenteral use and may be used for the treatment of bacterial infection in mammals induding humans. The antibiotic compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibiotics. The composition may be formulated for administration by any route, such as oral, topical or parenteral, espedally oral. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions. The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams. The forinulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation. Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional exdpients such as binding agents, for example syrup, acada, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calάum phosphate, sorbitol or glydne; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehide before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example leάthin, sorbitan monooleate, or acada; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic add, and, if desired, conventional flavouring or colouring agents. Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride. For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the'stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehide. Advantageously, a surfactant or wetting agent is induded in the composition to facilitate uniform distribution of the compound. The compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient. The dosage as employed for adult human treatment will preferably range from 100 to 3000 mg per day, for instance 1500 mg per day depending on the route and frequency of administration. Such a dosage corresponds to 1.5 to 50 mg/kg per day. Suitably the dosage is from 5 to 20 mg kg per day. No unacceptable toxicological effects are expected when a compound of formula (Ia) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof is administered in the above-mentioned dosage range. The compound of formula (Ia) may be the sole therapeutic agent in the compositions of the invention or a combination with other antibiotics or with a β-lactamase inhibitor may be employed. Advantageously, the compositions also comprise a compound of formula (VI) or a pharmaceutically acceptable salt or ester thereof: (VI) 25 wherein A is hydroxyl, substituted hydroxyl, thiol, substituted thiol, amino, mono- or di-hydrocarbyl- substituted amino, or mono- or di-acylamino; an optionally substituted triazolyl group; or an optionally substituted tetrazolyl group as described in EP-A-0 053 893. A further advantageous composition comprises a compound of formula (Ia) or a pharmaceutically acceptable salt or in υiυo hydrolysable ester thereof together with a compound of formula (VII) or a pharmaceutically acceptable salt or in υiυo hydrolysable ester thereof: (VII) wherein B represents hydrogen, halogen or a group of formula: in which D and E are the same or different and each represents hydrogen, (Cχ.g) alkoxycarbonyl or carboxy, or a pharmaceutically acceptable salt thereof. Further suitable β-lactamase inhibitors include 6-alkylidene penems of formula (VHI): (VIH) or a pharmaceutically acceptable salt or in υiυo hydrolysable ester thereof, wherein F and G are the same or different and each represents hydrogen, or a (Cχ_χo) hydrocarbon or heterocyclic group optionally substituted with a functional group; and J represents hydrogen or a group of formula K or -K where K is an optionally substituted (Cχ.χø) hydrocarbon or heterocyclic group, as described in EP-A-0 041768. Further suitable β-lactamase inhibitors include 6β-bromopenirillaι_ic add and pharmaceutically acceptable salts and in υiυo hydrolysable esters thereof and 6β-iodopenicillanic add and pharmaceuticaUy acceptable salts and in vivo hydrolysable esters thereof described in, for example, EP-A-0 041 768 and EP-A-0 154 132 (both Beecham Group). Such compositions of this invention which include a β-lactamase inhibitory amount of a β-lactamase inhibitor are formulated in a conventional manner using techniques and procedures βgr ≤g known in the art. The antibiotic compounds of the present invention are active against a wide range of organisms induding both Gram-negative organisms such as E.coli and Gram-positive organisms such as S.aureus. The following Examples illustrate the preparation of compounds of the invention and intermediates thereto. - EXAMPLE 1 /Step V j?-MethQ χ ybenzyl (δ5,6fl,8fl,92? ) -δ-ethQ χ y-10-o χ o-9-phenylacetamido-7- thia-l-azatricv orβ.2.0.0 3 »6ldec-2-ene-2-carho -- vlate To a mixture of p-methoxybenzyl (6i?,7R)-7-phenylacetamido-3- (1τifluoromethylsulphonyloxy)ceph-3-em-4-carboxylate (IV) (600mg; 1.02mmol), ethyl vinyl ether (V) (0.50ml; 5.23mmol) dichloromethane (20ml) at 0°C was added diisopropylethyl- amine (0.18ml; 1.023mmol). After stirring for 15 min. the mixture was chomato- graphed on silica (20% ethyl acetate in dichloromethane) to give the product (0.392g, 75%) as a white solid (Found: M + - 508J677. C 27 H 28 N 2 0 6 S requires M, 508.1668); u max (CH 2 Cl2), 1787, 1724, 1685cm" 1 ; δ H (CDCI3) 1.20 (3H, t, .77J) 3J7 (IH, dt, 317.2, 2.4), 3.34 (IH, dd, 317.2, 6.4), 3.45 (2H, m), 3.63 (2H, ABq, 316J), 3.80 (3H, s), 4.30 (IH, dd, 36.6, 2.6), 4.40 (IH, dt, 36.5, 2.0), 4.94 (IH, d, 34.9), 5.17 (2H, ABq, 312.0), 5.77 (IH, dd, _79.0, 4.9), 6.06 (IH, d, ^9.0), 6.86 (2H, d, 38.7), 7.30 (7H, m). Step 2 r MethoxvbenzvI f5. .6-?.8-?.9-? 9-a-nino-5-ethoxv-10-oxo-7-thia-l-aza- nicyclor6.2,Q.Q 3 ' 6 ldgc-2-ene-?-carbQxylate To a solution of the product from Step 1 (0.392g, 0.771mmol) in dichloro- methane (7ml), cooled to -30°C, was added N-methylmorpholine (171 μl, 1.54mmol). A solution of phosphorus pentachloride (0.24g, 1 Jόmmol) in dichloromethane (6ml) was added and the mixture stirred at -30°C for 30 min. Methanol (1.55ml) was added and the mixture allowed to warm to room temperature over 30 min. Water (2.08ml) was then added and the mixture stirred vigorously for lh. After concentration the residue was partitioned between water and ethyl acetate, the pH was adjusted to 7 by the addition of 1M aqueous ammonia. The organic phase was washed with water, then brine, dried (MgSO.) and concentrated. The residue (H) was purified by chromatography (50% ethyl acetate in dichloromethane) to give me product (0J84g, 61%) as a foam (Found: M + , 390.1256. C19H22N2O5S requires M, 390.1249); υmax (CH 2 C1 2 ) 1780, 1722cm-l; δH (CDCI3) 1.22 (3H, t, .77.0), 3.21 (IH, dt, 3 17.4, 2.4), 3.37 (IH, dd, 317.3, 6.2), 3.51 (2H, m), 3.81 (3H, s), 4.36 (IH, dd, 36.7, 2.5), 4.44 (IH, dt, .76.5, 2J), 4.71 (IH, d, .75.2), 4.97 (IH, d, j75.2), 5.20 (2H, ABq, 312.0), 6.88 (2H, d, 38.7), 7.33 (2H, d, 38.7). 18044 28 Step 3 - P -Methoxvbenzvi r5*?.6g?.8_?.9_?V9-r2r2-a-ninothiazol-4-vn-2-(ZVmethoxv- iminoacetamido1-5-ethoxv-10-oxo-7-thia-l-azatricvclor6.2.0.0 3 - 6 ldec-2-ene-2- carboxylate A solution of 2(2-aminothiazol-4-yl)-2-(Z)-methoxyiminoacetic acid (HI) (OJOg, 0.50mmol) in N-methylpyrrolidinone (1.5ml) was cooled to -25°C. Diiso- propylethylamine (95μl, 0.54mmol), then methanesulphonyl chloride (42μl, 0.54mmol) were added and the mixture stirred at -25°C for 30 min. A second portion of diisopropylethylamine (79μl, 0.45mmol) was added and the mixture -vas then added to a solution of the product from Step 2 (0.177g, 0.45mmol) in N-methylpyrrolidinone (1.5ml) cooled in an ice bath. After stirring for 30 min. the reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed three times with water, then brine- dried (MgSCλj) and concentrated. Purification by chromatography (ethyl acetate) gave the product (0J31g, 50%) as a white solid; υ max (CH 2 C1 2 ) 1788, 1727- 1686, 1608cm- 1 . Step 4 Sodium r5.?.6_?.8-?.9-?)-9-r2-f2-aminothiazol-4-vn-2-fZVmethoxviminoacet- aτnido1- 5-ethoxv-10-oxo-7-thia-l-azatricvclor6.2.0.0 3 -6ldec-2-ene-2-carboxvlate The product (0.13g, 0.227mmol) from Step 3 was suspended in anisole (1ml) and cooled in an ice bath. Trifluoroacetic acid (2ml) was added and the mixture stirred for 7 min. Toluene (2ml) was added and the mixture was evaporated to dryness. The residue was partitioned between ethyl acetate and water and the pH was adjusted to 7 by the addition of aqueous sodium bicarbonate. The aqueous layer was concentrated and chromatographed on HP20SS (water and THF). The product (I) (69mg, 64%) was obtained as a freeze-dried solid, υ max (KBr) 1759, 1669, 1602, 1532cm' 1 ; δf j (D 2 O) 1J4 (3H, t, .77.0). 3.08 (IH, brd, 316.8), 3.41 (IH, dd, 317.0, 6.0), 3.56 (2H, m), 3.95 (3H, s), 4.55 (2H, m), 5.24 (IH, d, j74.8), 5.74 (IH, d, .74.7), 6.99 (IH, s); m/z476(MH + ). 29 EXAMPLE 2 /Step 1 p-Methoxvbenzvl f4-g.9_?.10-?.12_?. 1 _?V14-oxo-13-Dhenvlacetamido-8-oxa-l 1-thia- 1 -azatetracvclor 10.2.0.Q3, 1 O.O 4 . Q 1tetradec-2-ene-2-carboxvlate To a mixture of p-methoxybenzyl (6_t7_Q-7-phenylacetamido-3-(trifluoro- methylsulphonyloxy)ceph-3-em-4-carboxylate (600mg, 1.02mmol), 3,4- dihydro-2H- pyran (0.28ml, 3.61mmol) and dichloromethane (10ml) at 0°C was added diisopropylethylamine (0J8ml; 1.02mmol). After stirring for 15 min the mixture was chromatographed on silica gel (20% ethyl acetate in dichloromethane) to give the product (0.317g, 58%) as a white solid (Found: M+, 520.1666. C gH 2 gN 2 O fj S requires M, 520.1668); υmax (CH 2 C1 2 ) 1786, 1725, 1684cm' 1 δπ (CDCI3) 1.6 (3H, m) 2.11 (IH, m), 3.6 (4H, m), 3.80 (3H, s), 3.82 (IH, m), 4J0 (IH, dd, .77.3, 6.7), 4.67 (IH, dd, 36.6, 2.8), 4.94 (IH, d, .75.0), 5J7 (2H, ABq, 311.9), 5.76 (IH, dd, 3 9.0, 5.0), 6.09 (IH, d, .79.0), 6.88 (2H, d, 38.8), 7.3 (7H, m), δ c (CDCI3) 22J, 23.5, 42.7, 42.9, 43.4, 55.3, 57.8, 60.0, 62.9, 67.2, 70.0, 114.0 (2C), 122.1, 127.3, 127.8 (2C), 129.2, 129.5 (2C), 130.5 (2C), 133.7, 134.7, 159.9, 160.7, 164.3, 171.3. Step 2 p-Methoxvbenzvl (4g.9- Qg.12_.. 13_?V13-a ino-14-oxo-8-oxa-ll-thia-1. aatgtracyglQri0,2.0.0 3tlo -Ω 4 ' 9 ltgtradgς-2-^n«_-2-carbpχylatg Prepared as in Example 1, Step 2: (76%), (Found: M + 402J250. C 2 ()H 22 N O5S requires 402.1249); υ max (CH 2 C1 2 ) 1781, 1723cm' 1 . Step 3 * p-Methoxybenzyl .4fr9_-J0_?J2g. 13ffM3J2-,2-aminothiazol-4-vn-2-.Z.- τπethoxviminoacetamidoI-14-oxo-8-oxa-ll-thia-l-aza- tet_-tcvcloriQ.2.0.θ340.Cr 4 -9ltetradec-2^ne-2-caτboxvlate Prepared as in Example 1, Step 3: (91%), (Found: M + 585.1346. C 2o H 2 7N5O7S2 requires 585.1352); υ max (CH 2 C1 2 ) 1786, 1724, 1684, 1606, 1516cm' 1 ; δfj (CDCI3) 1.3-212 (4H, m), 3.68-3.88 (3H, m), 3.82 (3H, s), 4.12 (3H, s), 4J8 (IH, t, 3 7.0), 4.73 (IH, dd, 36.6, 2.7), 5.07 (IH, d, 35.0), 5.21 (2H, ABq, 311.9), 5.89 (IH, dd, 38.8, 5.0), 6.90 (2H, d, 38.7), 7.06 (IH, brs), 7.34 (2H, d, 38.7). Stg 4 Sodium r4-?.9_?.10 g.l2-.. 13_?V13-r2-f2-aminothiazol-4-vn-2-(ZVmethoxy- iminoacetamido1-14-oxo-8-oxa-ll-thia-l-azatetracvcloπθ.2.0.θ3- 10.Q4»9l-tetra- dec- 2-ene-2-carboxylate Prepared as in Example 1, Step 4. (80%), υmax (KBr) 1761, 1670, 1603, 1528; δπ (D 2 O) 1.49-1.81 (3H, m), 2.21 (IH, m), 3.66 (IH, m), 3.83 (2H, m), 3.96 (3H, s), 4.20 (IH, t, 37.2), 5.02 (IH, dd, 36.8, 2.5), 5.25 (IH, d, 34.8), 5.73 (IH, d, 34.7), 6.99 (IH, s); m z 488 (MH+), 510 (MNa+)- EXAMPLE /Step 1 r Methoxvbenzvl ('5 .6-?.8-_.9-?)-5-acetoxv-10-oxo-9-phenvlacetamido-7-thia-l- a_atricvclor6.2.0.θ3.6i(iec-2-ene-2-carboxvlate To a mixture of p-methoxybenzyl (όR^RJ-Z-phenylacetamido-S- (trifluoromethylsulphonyloxy)ceph-3-em-4-carboxylate (600mg; 1.02mmol), vinyl acetate (0.47ml, 5.Hmmol) and dichloromethane (20ml) at room temperature was added diisopropylethylamine (0.18ml; 1.02mmol). After stirring for 15min. the mixture was chromatographed on silica gel (20% ethyl acetate in dichloromethane) to give the product (0.396g, 74%); v max (CH 2 C1 2 ) 1789, 1741, 1685cm-ϊ; δ H (CDQ 3 ) 2.06 (3H, s) 3.26 (IH, dt, / 17.3, 2.0), 3.50 (IH, dd, T 17.3, 6.4), 3.65 (2H, ABq, / 16.4), 3.80 (3H, s), 4.51 (IH, dd, / 6.7, 2.5), 4.91 (IH, d, /4.9), 5.19 (2H, ABq, / 11.9), 5.30 (IH, dt, / 6.5, 1.6), 5.81 (IH, dd, / 9.2, 4.9>, 5.91 (IH, d, / 9.3), 6.88 (2H, d, / 8.6), 7.33 (7H, m); m/z 522 (M+). Step 2 p-Methoxybenzyl (5S.6R.8R.9R)-5-acetoxy-9-amino-10-oxo-7-thia-l-aza- tricydor6.2.0.Q3/6l ec-2-ene-2-carboxylate The product was prepared as in Example 1, Step 2: (75%), (Found: M + , 404J040. Cι 9 H 2 ( ) N 2 θ6S requires M, 404.1042); v max (CH 2 C1 2 ) 1783, 1741cm' 1 ; δ H (CDC1 3 ) 2J2 (3H, s), 3.30 (IH, dt, / 17.3, 2.0), 3.53 (IH, dd, / 17.4, 6.4), 3.81 (3H, s), 4.55 (IH, dd, / 6.7, 2.5), 4.74 (IH, d, / 5.2), 4.96 (IH, d, / 5.2), 5.22 (2H, ABq, / 12.0), 5.35 (IH, dt, / 6.5, 1.6), 6.89 (2H, d, / 8.6), 7.34 (2H, d, /8.6). Step 3 p-Methoxybenzyl (5S.6R.8R.9J l-5-acetoxy-9-r2-(2-aminothiazol-4-yl)-2-(Z)- methoxyiminoacetamidol-10-oxo-7-thia-l-azatricyclof6.2.0.0 3 ^ldec-2--ene-2- carboxylate The product was prepared as in Example 1, Step 3: (77%); v max (CH C1 2 ) 1789, 1740, 1684, 1611cm" 1 ; δ H (CDCI3) 2.04 (3H, s), 3.30 (IH, brd, / 17.4), 3.54 (IH, dd, / 17.6, 6.6), 3.81 (3H, s), 4.02 (3H, s), 4.53 (IH, dd, / 6.7, 2.3), 5.04 (IH, d, / 5.1), 5.22 (2H, ABq, / 11.9), 5.32 (IH, dt, / 6.6, 1.4), 5.68 (2H, s), 5.99 (IH, dd, / 9.0, 5.1), 6.80 (IH, s), 6.89 (2H, d, J 8.7), 7.33 (2H, d, } 8.6), 7.63 (IH, d, } 9.0). Step 4 Sodium (5S.6R^R,9R1-5-acetoxy-9-r2-(2-aminothiazol-4-yl)-2-(Z)-methoxy- iminoacetamidoH 0-oxo-7-thia-l -azatricyclo.6.2.0.θ3/6ldec-2-ene-2- carb "o ■ xylate The product was prepared as in Example 1, Step 4. (82%), v max (KBr) 1762, 1669, 1602, 1528cm' 1 ; δ H (D 2 0) 2.07 (3H, s), 3.26 (IH, dt, } 16.8, 1.8), 3.55 (IH, dd, J 16.9, 6.2), 3.94 (3H, s), 4.78 (IH, obscured by HOD), 5.22 (IH, d, J 4.7), 5.31 (IH, dt, 6.2, 1.2), 5.71 (IH, d, J 4.7), 6.95 (IH, s); m/z 490 (MH+), 512 (MNa+). Example 4/ Step 1 p-Methoxybenzyl (6S, 8R, 9R)-5,5-dimethyl-10-oxo-9-phenylacetamido-7-thia- l-azatricydor6.2.0.θ3/^ldec-2-ene-2-carboxylate A solution of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3-(trifluoro- methylsulphonyloxy)ceph-3-em-4-carboxylate (20mg, 0.0341mmol) in dichloro- methane (2.0ml) was cooled to -15°C Isobutylene (ca. 1ml) was condensed into the solution. Diisopropylethylamine (6μl, 0.034mmol) was added and th^mixture allowed to warm to room temperature over 30 minutes. The mixture was chromatographed (10% ethyl acetate in dichloromethane) to give the product (15 mg, 90%), (Found: M + 492.1715. C27H 28 N 2 0 5 S requires M, 492.1719); v max (CH 2 C1 2 ) 1786, 1723, 1686cm' 1 ; δfi (CDCI3) 1.04 (3H, s), 1.33 (3H, s), 2.85 (IH, d, } 15.7), 2.97 (IH, dd, J 15.6, 2.5), 3.64 (2H, ABq, J 16.1), 3.80 (3H, s), 4.02 (IH, dd, J 2.4, 1.2), 4.92 (IH, d, / 4.9), 5.17 (2H, ABq, J 12.0), 5.75 (IH, dd, J 8.9, .9), 6.04 (IH, d, } 9.0), 6.87 (2H, d, 78.7), 7.29 (7H, m); BQ (CE 3) 23.4, 29.5, 37.7, 43.4, 44.3, 50.8, 55.3, 58.3, 59.6, 67.0, 114.0 (2C), 120.9, 127.5, 127.7, 129.2 (2C), 129.6 (2C), 130.3 (2C), 133.8, 136.4, 159.8, 161.0, 164.0, 171.2. Example 5/ Step 1 p-Methoxybenzyl (5S.6S.8R.9K)-5-butyl-10-oxo-9-phenylacetamido-7-thia-l- azatricydor6.2.0.0 3 ^1dec-2-ene-2-carboxylate To a mixture of p-methoxybenzyl (6R,7J0-7-phenylacetamido-3- (trifluoromethylsulphonyloxy)ceph-3-em-4-carboxylate (20mg, 0.0341mmol), 1-hexene (21μl, 0J68mmol) and dichloromethane (2ml) at room temperature was added diisopropylethylamine (6μl, 0.034mmol). After stirring for 5 minutes the mixture was chromatographed on silica gel to give the product (9-5mg, 54%), (Found: M+, 520.2023. C 29 H3 2 N 2 θ5S requires M, 520.2032); v max (CH 2 C1 2 ) 1785, 1722, 1686cm '1 ; δ H (CDCl 3 ) 0.92 (3H, t,76.8), 1.18-1.50 (6H, m), 2.66 (IH, m), 2.84 (IH, dt, f 16.2, 3.1), 3.22 (IH, dd, J 16.3, 9.2), 3.65 (2H, ABq, J 16.D, 3.80 (3H, s), 4.40 (IH, br d, } 9.3), 4.92 (IH, d, f 4.9), 5.17 (2H, ABq, 711.9), 5.76 (IH, dd, J 9J, 4.9), 5.97 (IH, d, J 9.1), 6.87 (2H, d, J 8.6), 7.31 (7H, ). Example 6 /Step 1 p-Methoxybenzyl (6S.8R, 9R)-10-oxo-5-phenyl-9-phenylacetamido-7-thia-l- azatricyclof6.2.0.θ3/6]deca-2,4-diene-2-carboxylate and p-methoxybenzyl (6R.8R.9R)-10-oxo-5-phenyl-9-phenylacetamido-7-thia-l- a-atricyclof6.2.0.θ3^1deca-2,4-diene-2-carboxylate To a solution of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3-(trifluoro- methylsulphonyloxy)ceph-3-em-4-carboxylate (600mg, 1.023mmol) and phenylacetylene, (3.4ml, 31mmol) in dichloromethane (15ml) with added dϋso- propylethylamine (0J78ml, 1.023mmol). After stirring for 15 min the mixture was chromatographed on silica gel. The (6S) product was eluted first (154mg, 28%), m.p.240° dec (EtOAc) (Found: C, 69.0; H, 4.6; N, 5.3; S, 6.0. C 3 ιH 26 N 2 0 5 S requires C, 69J; H, 4.9; N, 5.2; S, 5.95%); υ max (CH 2 C1 2 ) 1787, 1720, 1688cm' 1 ; δ H (CDC1 3 ) 3.64 (2H, ABq, J 16.2), 3.82 (3H, s), 4.61 (IH, d, J 0.9), 4.99 (IH, d, J 4.6), 5.25 (2H, ABq, J 11.9), 5.91 (IH, dd, J 8.3, 4.7), 5.98 (IH, d, 78.5), 6.89 (IH, s), 6.90 (2H, d, J 8.7), 7.34 (12H, m). The later eluting product was the (6R) isomer (0.369g, 67%), m.p.98-101°C (Found: C, 69.3; H, 4.9; N, 5.1; S, 5.8%); υ max (CH 2 C1 2 ) 1782, 1718, 1684cm' 1 ; δ (CDCI3) 3.73 (2H, s), 3.81 (3H, s), 4.59 (IH, s), 5.00 (2H, ABq, J 12J), 5.33 (IH, dd, } 8.0, 4.2), 5.62 (IH, d, 74.2), 6.59 (IH, s), 6.61 (IH, d, J 7.9), 6.89 (2H, d, } 8.6), 7.2-7.5 (12H, m). Step 2a Sodium ( 6S.8R- 9R ) -10-oxo-5-phenyl-9-phenylacetamido-7-thia-l- azatricyclof6.2.0.0 3 ^1deca-2-4-diene-2-carboxylate The (6S) product from Step 1 (14mg, 0.026mmol) was dissolved in anisole (1ml, and cooled in an ice-bath. Trifluoroacetic acid (2.0ml) was added and the mixture stirred for 7 min. Toluene (2ml) was added and the mixture was evaporated to dryness. The residual solid was dissolved in THF (0.5ml) and water (0.5ml), the pH was adjusted to 7.0 by addition of aqueous sodium bicarbonate, and the mixture chromatographed on HP20SS using water and THF mixtures as the elutant. The product was obtained as a freeze-dried solid (8.0mg, 76%); υ max (KBr) 1753, 1657, 1600, 1537cm' 1 ; δ jj (d 6 -DMSO) 3.50 (2H, s), 4.64 (IH, s), 5.00 (IH, s), 5.00 (IH, d, } 4.8), 5.65 (IH, dd, J 8.4, 4.9), 7.15 (IH, s), 7.25-7.52 (10H, m), 9.04 (IH, d, J 8.4); m/z 441 (MH+). Step 2b Sodium (6R, 8R.9R)-10-oxo-5-phenyl-9-ρhenylacetamido-7-thia-l- a-atricyclor6.2.0.θ3/6ldeca-2,4-diene-2-carboxylate The (6R) product from Step 1 (35mg, 0.060mmol) was hydrolysed as in Step 2a to give the product (20mg, 76%); υ max (KBr) 1765, 1744, 1669, 1576cm' 1 ; δ H (c-6- DMSO + D 2 0) 3.62 (2H, ABq, J 13.8), 4.86 (IH, s), 5.06 (IH, d, J 3.9), 5.55 (IH, d, 73.9), 6.91 (IH, s), 7.28-7.49 (10H, m); m/z 441 (MH+), 463 (MNa+). Example 7/Step 1 p-Methoxybenzyl (65, 8R, 9R)-9-amino-10-oxo-5-phenyl-7-thia-l-azatricydo- r6.2.0.0 3 / 6 ldeca-2.4-diene-2-carboxylate The (6S) product from Example 6, Step 1 was treated with phosphorus penta- chloride as in Example 1, Step 2 to give the title compound; (52%), (Found: M + , 420.H43. C23H20N2O4S requires M, 420.H44); δji (CDCI3) 3.83 (3H, s), 4.65 (IH, d,71.2), 4.93 and 4.98 (2H, ABq, J 5.2), 5.28 (2H, ABq, J 12.0), 6.91 (IH, d, 71.2), 6.92 (IH, d, J ~8Hz), 7.41 (5H, m), 7.52 (2H, m). Step 2 p-Methoxybenzyl (65.8R, 9R)-9-r2-(2-aminothiazol-4-yl)-2-(Z)- methoxyimino- acetamidol-10-oxo-5-phenyl-7-thia-l- azatricydor6.2.0.0 3 /6ldeca-2,4-diene-2-carboxylate The product was prepared as in Example 1, Step 3: (67%); υ m ax (KBr) 1774, 1706, 1664, 1611cm' 1 ; δ H (CDCI3) 3.83 (3H, s), 4.03 (3H, s), 4.68 (IH, s), 5J0 (IH, d, 74.8), 5.11 (2H, s), 5.29 (2H, ABq, J 11.9), 6.09 (IH, dd, J 8.4, 4.9), 6.92 (2H, d, 78.4), 6.98 (IH, s), 7.07 (IH, d, f 8.5), 7.39 (5H, m), 7.51 (2H, m); m/z 604 (MH+). Step 3 * Sodium (65^R.9R)-9-r2-(2-aminothiazol-4-yl)-2-(Z)- me oxyiminoacetamido1-10-oxo-5-phenyl-7-thia-l- azatricyclor6.2.0.0^/6]deca-2,4-diene-2-carboxylate The product was prepared as in Example 1, Step 4: (70%); υ max (KBr) 1752, 1663, 1602, 1528cm' 1 ; δ H (D2θ) 3.90 (3H, s), 5.26 (IH, d, J 4.8), 5.92 (IH, d, } 4.7), 6.94 (IH, s), 7.07 (IH, s), 7.43 (3H, m), 7.60 (2H, m); m/z 506 (MH+), 528 (MNa+). Example 8 /Step 1 p-Methoxybenzyl (6R.8R, 9R)-9-amino-10-oxo-5-phenyl-7-thia-l-azatricydo- r6.2.0.0 3 / 6 1deca-2.4-diene-2-carboxylate The (6R) product from Example 6, Step 1 was treated with phosphorus penta- chloride as in Example 1, Step 2 to give the title compound (40%), (Found: M + , 420.1143. C23H 2 o 2 θ4S requires M, 420.1144); υ max (CH 2 Q 2 ) 1775, 1716cm" 1 . Step 2 p-Methoxybenzyl (6R.8R.9R)-9-r2-(2-aminothiazol-4-yl)-2-(Z)- methoxyimino- acetamidol-10-oxo-5-phenyl-7-thia-l- azatricyclo.6.2.0.0 3 '6ldeca-2.4-diene-2-carboxylate The product was prepared as in Example 1, Step 3: (64%); υ max (KBr) 1774, 1708, 1674, 1611cm- 1 ; δπ (CDC1 3 ) 3.83 (3H, s), 4.12 (3H, s), 4.96 (IH, s), 5.19 (2H, ABq, J 12.0), 5.24 (2H, brs), 5.61 (IH, dd, J 7.6, 4.3), 5.81 (IH, d, } 4.3), 6.63 (IH, s), 6.92 (2H, d, ] 8.7), 7.11 (IH, s), 7.34 (2H, d, ] 8.6), 7.42 (5H, m), 7.64 (IH, brd, J 7.1); m/z 626 (MNa+). Step 3 * Sodium (6R.8R.9R)-9-r2-(2-aminothiazol-4-yl)-2-(Z)- memoxyiminoacetamidol-10-oxo-5-phenyl-7-thia-l- azatricyclor6.2.0.0 3 /6]deca-2,4-diene-2-carboxylate The product was prepared as in Example 1, Step 4: (64%); υ max (KBr) 1753, 1671, 1586, 1533cm- 1 ; δ H (D 6 -DMSO) 3.90 (3H, s), 4.82 (IH, s), 5.24 (IH, dd, J 8.2, 4.0), 5.66 (IH, d, } 4.0), 6.89 (IH, s), 7J9 (IH, s), 7.30 (2H, brs), 7.43 (5H, m), 9.51 (IH, d, J 8.3); m/z 506 (MH+). Example 9 /Step 1 p-Memo>ybenzyl (6R.8R.9R)-10-oxc>-9-phenylaretamido-5-trimethylsilyl-7- thia- l-azatricydor6.2.0.θ3/^ldeca-2-4-diene-2-carboxylate To a solution of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3- (trifluromethyl-sulphonyloxy)ceph-3-em-4-carboxylate (20mg, 0.0341mmol) and trimethylsilyl- acetylene (24μl, 0J7mmol) in dichloromethane (1ml) was added dϋsopropyl- ethylamine (6μl, 0.034mmol). After stirring for 30 minutes the mixture was chromatographed on silica gel to give the product (9.6mg, 53%), (Found: M+, 534.1650. C 2 8H 30 N 2 O5SSi requires 534.1645); υ-nax (CH 2 C1 2 ) 1787, 720, 1687cm" 1 ; δ H (CDCI3) 0. 8 (9H, s), 3.63 (2H, ABq, 716.D, 3.80 (3H, s), 4.23 (IH, s), 4.80 (IH, d, J 4.2), 5.22 (2H, ABq, J 12.0), 5.93 (2H, s + d) 6.88 (2H, d, } 8.5), 7.05 (IH, s), 7.25-7.35 (7H, m). Example 10 /Step 1 p-Methoxybenzyl ( 5R.6R.8R.9R ) -9-benzamido-10-oxo-5-phenylthio-7-thia-l- azatricydor6.2.0.0 3 /^ldec-2-ene-2-carboxylate and p-Methoxybenzyl (5S.6R.8R.9R)-9-benzamido-10-oxo-5-phenylthio-7-thia-l- a_atr-cyclo.6.2.0.θ3/6l- dec-2-ene-2-carboxylate To a solution of p-methoxybenzyl (6R,7R)-7-benzamido-3-(trifluoromethyl- sulphonyloxy)ceph-3-em-4-carboxylate (75mg, 0J31mmol), and phenyl vinyl sulphide (19ml, 0J45mmol) in dichloromethane (3ml) was added diisopropylethylamine (23μl, 0J3mmol). After stirring for 15 minutes the mixture was chromatographed on silica gel. The (5R) product was eluted first (13.1mg, 18%). (Found: M+), 558.1281. C 30 H 26 N 2°5 S 2 rec l uires M ' 558J283); υmaχ (CH 2 C1-,) 1788, 1725, 1677cm-l; δ H (CDCI3) 3J6 (IH, m, J 15.5, 8.5, 1.3), 3.68 (IH, m, J 8.5, 7.9, 7.2), 3.76 (IH, m, J 15.5, 7.9, 2.7), 3.81 (3H, s), 4.28 (IH, m, J 7.2, 2.7, 1.3), 5.05 (IH, d, ] 4.9), 5.21 (2H, s), 5.95 (IH, dd, J 8.4, 4.9), 6.70 (IH, d, J 8.4), 6.90 (2H, d, 8.7), 7.26-7.78 (12H, m); δ c (CDC13) 39.4, 43.6, 48.9, 55.3, 58.9, 60.5, 67.3, 114J (2C), 120.4, 127.3 (3C), 128.2, 128.8 (2C), 129.4 (2C), 130.5 (2C), 132.4, 132.6 (2C), 132.8, 132.9, 133.1, 159.9, 160.8, 164.3. 167.4. The later eluting product was the (5S) isomer, (36.4mg, 50%), (Found: M + , 558.1293); Vmax (CH 2 C1 2 ) 1788, 1725, 1677cm' 1 ; δ H (CDCI3) 3.31 (IH, dt, } 16.9, 3.0), 3.72 (IH, dd, J 16.9, 8.4), 3.81 (3H, s), 4.30 (IH, dt, J 8.4, 3.0), 4.86 (IH, dd, 78.4, 3.0), 5.H (IH, d, J 5.0), 5.23 (2H, ABq, J 12.0), 6.00 (IH, dd, 78.6, 5.0), 6.77 (IH, d, J 8.6), 6.88 (2H, d, J 8.7), 7.19-7.77 (12H, m); δc (CDCI3) 39.0, 42.3, 46.3, 55.3, 58.9, 60.6, 67.2, 114.0 (2C), 122.2, 126.9, 127.3, 127.4 (2C), 128.7 (2C), 129.2 (2C), 129.4 (2C), 130.3 (2C), 132.3, 132.9, 134.9, 136.0, 159.8, 160.8, 163.8. 167.5. Example 11 /Step 1 p-Methoxybenzyl (45 5.6S.8R.9R)-4 -dimethyl-l 0-oxo-9-phenylacetamido- 7- thia-l-azatricydof6.2.0.0 3 /^ldec-2-ene-2-carboxylate A solution of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3- (trifluoromethyl- sulphonyloxy)ceph-3-em-4-carboxylate (40mg, 0.0682mmol) in dichloromethane (5.0ml) was cooled to -20°C. Trans-2-butene (ca.5ml) was condensed into the solution. Diisopropylethylamine (12 μl, 0.068mmol) was added and the mixture allowed to warm to room temperature over lh. The mixture was chromatographed to give the title compound (29.7mg, 88%), m.p. 172-173°C (EtOAc) (Found: C, 65.6; H, 5.5; N, 5.6; S, 6.2; M+, 492.1724. C 2 7H 2 8N 2 C>5S requires C, 65.8; H, 5.7; N, 5.7; S, 6.5%; M, 492.1719; υ max (CH 2 C1 2 ) 1786, 1721, 1687cm" 1 ; δ H (CDCI3) 1.03 (3H, d, J 7.1), 1.25 (3H, d, } 7.3), 2.41 (IH, ddq, J 9.5, 7.1, 3.0), 3.04 (IH, ddq, J 7.3, 3.2, 3.0), 3.63 (2H, ABq, 716.0), 3.79 (3H, s), 4.47 (IH, dd, J 9.5, 3.2), 4.90 (IH, d, } 4.9), 5.08 (IH, d, J 11.9), 5.26 (IH, d, 711.9), 5.76 (IH, dd, J 9.0, 4.9), 6.07 (IH, d, J .9.0), 6.87 (2H, d, 78.7), 7.30 (7H, m); δ c (CDCI3) 15.9, 17.9, 37.2, 43J, 43.4, 47.0, 55.3, 58.3, 59.8, 67.0, 114.0 (2c), 130.5 (2c) 121.7, 127.4, 127.7, 129J (2c), 129.5 (2c), 130.5 (2c), 133.8, 142.9, 159.8, 160.8, 164.2, 171.2 Step 2 Sodium (4R.5S-65.8R.9R) -4 -dimethyl-10-oxo-9-phenylacetamido-7- thia-1- azatricydor6.2.0.0 3 /^ldec-2-ene-2-carboxylate The product from Step 1 (21mg, 0.0426mmol) was hydrolysed as in Example 6, Step 2a to give the title compound (lOmg, 60%); υmax (KBr) 1754, 1659, 1600cm-l; δH (D20) 1.08 (3H, d, J 7.1), 1.29 (3H, d, J 7.3), 2.43 (IH, m), 3.04 (IH, m), 3.66 (2H, ABq, J 14.8), 4.64 (IH, dd, J 9.2, 2.9), 5.01 (IH, d, J 4.7), 5.56 (IH, d, 74.7), 7.36 (5H, m); m/z 373 [(M-Na + 2H)+], 395 (MH+). Example 12 /Step 1 p-Methoxybenzyl (6S.8R.9R)-45-dimethyl-10-oxo-9-phenylacetamido-7-thia- 1-azatricydo r6.2.0.0 3 ^ldeca-2.4-diene-2-carboxylate A solution of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3- (trifluoromethyl- sulphonyloxy)ceph-3-em-4-carboxylate (60mg, 0.102mmol) in dichloromethane (10ml) was cooled to 0°C, 2-Butyne (1.2ml, 153mmol) was added followed by diisopropylethylamine (18 μl, 0.102mmol). The mixture was stirred and allowed to warm to room temperature over 15 min. Chromatography gave the title compound (28.4mg, 57%), (Found: M + , 490.1562. C 27 H 26 N 2 0 5 S requires M, 490.1562); υ max (CH 2 C1 2 ) 1783, 1716, 1684cm" 1 ; δ H (CDCI3) 1.79 (3H, s), 1.97 (3H, s), 3.62 (2H, ABq, J 16Λ), 3.79 (3H,s),4.07(IH,brs),4.79(IH,d, }4.8),5.21 (2H,ABq, J11.8),5.89(IH,dd, } 8.6,4.8),6.06(IH,d, J8.6),6.86(2H,d, J.8.6),7.30(7H,m);δ c (CDC1 3 ) 12.5, 13.2,43.3,45.6,55.3,59.8,62.3,67.1,111.8,113.9(2c),127.4,127.7,129.2(2c) 129.5(2c),130.8(2c),133.7,135.4,142.5,149.1,159.9,161.4,164,4,171.2. Steρ 2 * Sodium (65.8R.9R) -4,5-dimethyl-10-oxo-9-phenylacetamido-7-thia-l- azatricyclo f6.2.0.θ3/6ideca-2,4-diene-2-carboxylate The product from Step 1 (23mg, 0.047mmol) was hydrolysed as in Example 6, Step 2a to give the title compound (12mg, 65%); υ max (KBr) 1745, 1654, 1612cm" 1 δ (D 2 0) 1.85 (3H, s), 1.94 (3H, s), 3.64 (2H, ABq, ] 14.7), 4.20 (IH, s), 4.93 (IH, d, 74.7), 5.70 (IH, d, J 4.7), 7.34 (5H, m); m/z 393 (MH+). Example 13/Step 1 p-Methoxybenzyl (45. 8R.95. 11R. 12R)-13-oxo-12-phenylacetamido-5-oxa-10- tMa-l-aza-67-benzotetracyclof9.2.0.θ3^.Q4,8]- τ idec-2-ene-2-carboxylate To a solution of p-Methoxybenzyl (6R,7R)-7-phenylacetamido-3-(trifluoro- methylsulphonyloxy)ceph-3-em-4-carboxylate (60mg, 0J02mmol) and 2,3- benzo- furan (1.5ml, 13.6mmol) in dichloromethane (2.0ml) at 0°C was added dϋso- propylethylamine (18 μl, 0J02mmol) After stirring at room temperature for 10 min the mixture was chromatographed to give the title compound (30.8mg, 54%) as a white solid. υ max (CH 2 Q 2 ) 1795, 1729, 1687cm" δ H (CDCI3) 3.66 (2H, ABq, J 16.3), 3.80 (3H, s), 4.07 (IH, bit, J -5.5) 4.24 (IH, dd, 74.7, 1.7), 4.88 (IH, d, J 5.0), 5.26 (2H, ABq, J 11.9), 5.83 (IH, dd, } 8.7, 5.0), 5.93 (IH, d, J 8.9), 6.05 (IH, dd, J 6.3, 1.7), 6.91 (4H, m), 7.17-7.39 (9H, m); m/z 554 (M + ). Step 2 Sodium (45.8R.95.11R. 12R)-13-oxo-12-phenylacetamido-5-oxa-10- thia-1- aza-^.7-benzotetracydor9.2.0.0 3 9.o4,8i ridec-2-ene-2-carboxylate The product from Step 1 (15mg, 0.027mmol) was hydrolysed as in Example 6, Step 2a to give the title compound (8mg, 65%); υ max (KBr) 1764, 1642, 1618cm" 1 ; δ H (D 2 O) 3.77 (2H, ABq), 4.36-4.42 (2H, m), 5.18 (IH, d, .75.0), 5.72 (IH, d, .75.0), 6.14 (IH, d, :75.7), 7.01 (IH, d, .78.0), 7.08 (IH, t, .77.6), 7.31-7.53 (7H, m); m/z 435 [(M-Na+2H)+], 457 (MH+). Example g 14. Step 1 p-Methoxybenzyl (4S.8R.95JlRJ2R)-12-amino-13-oxo-5-oxa-10-thia-l-aza- 6.7-ben_«)tetracydor9.2.0.0 3 / 9 .0 48 1tridec-2-ene-2-carboxylate The product from Example 13, Step 1 was treated with phosphorus penta- chloride as in Example 1, Step 2 to give the title compound; (46%), (Found: M+ 436.1092. C23H20N2Q5S requires M, 436.1093); υmax (KBr) 1786, 1513cm" 1 ; δ H (CDCI3) 3.80 (3H, s), 4J2 (IH, m), 4.28 (IH, dd, J 4.8, 1.9), 4.79 (lH,d, 75.4), 4.89 (IH, d, 75.4), 5.82 (2H, ABq), 6.10 (IH, dd, J 6.3, 1.9), 6.82- 7.00 (4H, m), 7.14-7.43 (4H, m). Step 2 p-Methoxybenzyl (4S.8R.95.HRJ2R)-12-r2-(2-aminothiazol-4-yl)-2-(Z)- memoxy- iminoacetamidol-13-oxo-5-oxa-10-thia-l-aza-6.7-benzotetracydo- r9.2.0.0 3 / 9 .0 8 ltridec-2-ene-2-carboxylate The product was prepared as in Example 1, Step 3: υ max (KBr) 1764, 1733, 1684, 1518cm" 1 ; δ H (CDCI3) 3.82 (3H, s), 4.H (3H, s), 4J6 (IH, t, ^6.4), 4.31 (IH, dd, .74.7, 2.0), 5.01 (IH, d, 35.3), 5J9 (2H, s), 5.30 (2H, ABq), 6.00 (IH, dd, 3 8.6, 5.1), 6.10 (IH, dd, 36.2, 1.9Hz), 6.78-7.00 (4H, m), 7.H (IH, d, .78.6), 7.23 (2H, d, 38.7), 7.27 (IH, s), 7.41 (2H, d, 38.7); m/z 620 (MH+). Stgp 3 Sodium (45.8R.95.11R.12R)-12-r2-(2-aminothiazol-4-yl)-2-(Z)-methoxy- iminoaostamido1-13-oxo-5-oxa-10- thia-l-aza-6.7-benzotetra- cydor9.2.0.0 3 / 9 .0 4 / 8 ltridec-2-ene-carboxylate The product was prepared as in Example 1, Step 4; υ m ax (KBr) 1772, 1671, 1611, 1529, δ H (D 2 O) 4.00 (3H, s), 4.27-4.35 (2H, m), 5.20 (IH, d, .75.1), 5.83 (IH, d, .75.0), 6.04-6J2 (IH, m), 6.90-7.05 (3H, m), 7.22-7.40 (2H, m); m/z 500 [(M- Na+2H) + ], 522 (MH + ). Example 15. Step 1 p-Methoxybenzyl (45.85.95.HRJ2R)-13-oxo-12-phenylacetamido-10-thia-l- a_-a- 6,7-benzotetracyclof9.2.0.0 3 / 9 .0 4 ^ltridec-2-ene-2-carboxylate To a solution of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3- (trifluoromethyl- sulphonyloxy)ceph-3-em-4-carboxylate (40mg, 0.0682mmol) and indene (0.40μl, 0.341mmol) in dichloromethane (2.0ml) was added diisopropylethylamine (12 μl, 0.068mmol). After stirring at room temperature for 15 min the mixture was chromatographed to give the title compound (34mg, 90%), (Found: M + , 552.1730. C3 H 8N 2 OsS requires M, 552.1719); υ max (KBr) 1781, 1730, 1650cm' 1 ; δfj (D6-DMSO) 3J8 (IH, dd, ] 17.6, 4.9), 330 (IH, dd, 7, 17.4, 10.3), 3.54 (2H, ABq, J 14.0), 3.76 (3H, s), 3.95 (IH, dd, 76.8, 5.7), 4.24 (2H, m), 5.04 (IH, d, J 5.0), 5.22 (2H, ABq, ] 11.9), 5.67- (IH, dd, 78.3, 5.0), 6.96 (2H, d, J 8.6), 7.28 (9H, m), 7.40 (2H, d, J 8.6), 9.08 (_H, d, 78.3). Step 2 Sodium (45.85 .95. 11R. 12R)-13-oxo-12-phenylacetamido-10-thia-l-aza-6.7- benzotetracydof9.2.0.0 3 / 9 .0 4 /8ltridec-2-ene-2-carboxylate The product from Step 1 (8mg, 0.014mmol) was hydrolysed as in Example 6, Step 2a to give the title compound (6mg, 91%), υ max (KBr) 1751, 1650, 1602, 1532cm '1 ; fa (D6-DMSO) 3.10 (IH, dd, } 17.3, 4.5), 3.31 (IH, dd, J 17.3, 10.3) 3.53 (2H, ABq, J 13.8), 3.84 (IH, dd, J 7.2, 5.5), 4.02 (IH, dd, J 5J, 2.4), 4.36 (IH, m), 4.89 (IH, d, J 4.9), 5.41 (IH, dd, J 8.4, 4.9) 7J8-7.28 (9H, m), 8.98 (IH, d,78.5); m/z 455 (MH+). Example 16 /Step 1 p-Methoxybenzyl (55.6R.8R.9R)-10-oxo-5-(2-oxopyrrolidin-l-yl)-9-phenyl- acetamido-7-thia-l-azatricydor6.2.0.θ3^1dec-2-ene-2-carboxylate To a mixture of p-methoxybenzyl (6R,7R)-phenylacetamido-3- (trifluoromethyl- sulphonyloxy)ceph-3-em-4-carboxylate (80mg, 0J36mmol), freshly distilled l-vinyl-2-pyrτolidinone (OJOml, 0.94mmol) and dichloromethane (5ml) was added diisopropylethylamine (24 μl 0J38mmol) 164.2, After stirring at room temperature for 10 min the mixture was chromatographed to give the title compound (74mg, 99%), (Found: M + , 547.1788. C 2 9H29N 3 0 6 S requires M, 54.7.1777); υ max (CH 2 C1 2 ) 1789, 1724, 1686cm" 1 ; δ H (CDC1 3 ) 1.85 (IH, m), 1.94 (IH, m), 2.36 (2H, m), 3.36 (2H, m), 3.42 (IH, dt, 717.4, 2.8), 3.53 (IH, dd, J 17.2, 8.6), 3.64 (2H, ABq, } 16.4), 3.80 (3H, s), 4.52 (IH, dd, J 8.0, 2.2), 4.98 (IH, d, J 4.9), 5.07 (IH, dt, } 8.4, 2.7), 5.19 (2H, ABq, 712.0), 5.81 (IH, dd, J 9J, 4.9), 5.91 (IH, d, J 9J), 6.87 (2H, d, J 8.5), 7.23-7.35 (7H, m). Step 2 Sodium (55.6R..8R.9R)-10-oxo-5-(2-oxopyrrolidin-l-yl)-9-phenylacetamido-7- mia-l-azatricyclor6.2.0.o3/6ldec-2-ene-2-carboxylate The product from Step 1 (21mg, 0.038mmol) was hydrolysed as in Example 6, Step 2a to give the title compound (llmg, 64%); υ ma χ (KBr) 1764, 1664, 1604cm" 1 ; δ H ( D 2θ) 1-97 (2H, m), 2.42 (2H, m), 3.43-3.64 (6H, m), 4.8 obscured by HOD (2H, m), 5J3 (IH, ά f J4.7), 5.49 (IH, d, 74.6), 7.34 (5H, m); m/z 450 (MH + ), 472 (MNa + ). Example 17/Step 1 p-Methoxybenzyl (5R.6S.8R.9R)-5-hydroxymethyl-10oxo-9- phenylacetamido- 7-thia-l-azatricydor6.2.0.0 3 /6ldec-2-ene-2-carboxylate To a mixture of p-methoxybenzyl (6R, 7R)-7-phenylacetamido-3-(trifluoro- methylsulphonyloxy)ceph-3-em-4-carboxylate (20mg, 0.0341mmol), allyl alcohol (11.6μl, 0.171mmol) and dichloromethane (0.5ml) was added diisopropylethyl- amine (6μl, 0.034mmol). After stirring at room temperature for 30 min the mixture was chromatographed to give the title compound (12mg, 71%), (Found: M+, 494.1528. C26H26N2O6S requires M, 494.1512); υmax (CH 2 C1 2 ) 1787, 1722, 1687cm '1 . δ H (CDCI3) 2.89 (IH, m), 2.96 (IH, dt 16.8, 3.0), 3.22 (IH, ddd, J 16.2, 8.9, 1.2), 3.62 (2H, ABq, } 15.7), 3.65 (2H, d, } 7.2), 3.79 (3H, s), 4.44 (IH, m), 4.92 (IH, d, J 5.0), 5J7 (2H, ABq, } 12.0), 5.76 (IH, dd, 78.9, 5.0), 6.32 (IH, d, J 8.9), 6.86 (2H, d, J 8.6), 7.28 (7H, m). Step 2 - Sodium (5R, 65.8R.9R)-5-hydroxymethyl-10-oxo-9-phenylacetamido-7-thia- l-azatricyclof6.2.0.θ3/6]dec-2-ene-2-carboxylate The produd from Step 1 (27mg, 0.055mmol) was hydrolysed as in Example 6, Step 2a to give the title compound (17mg, 79%); υ ma χ ( KBr ) 1759 / 1 6 4, 1597cm" 1 ; δ H (D 2 0) 2.85 (2H, m), 3.21 (IH, dd, J 16, 8.6), 3.66 (4H, m), 4.57 (IH, dd, 77.7, 2.6), 5.07 (IH, d, J 4.7), 5.56 (IH, d, J 4.7), 7.34 (5H, m); m/z 397 (MH+). Example 18/Step 1 p-Methoxybenzyl (4S.9R. 105. 12R. 13R)-14-oxo-13-phenylacetamido-ll-thia- 1- azatetracyclott 0.2.0.0 3 ' 10 .0 4 ' 9 l-tetradec-2-ene-2-carboxylate Potassium carbonate (9.5mg, 0.068mmol) was added to a solution of p- methoxy- benzyl (6R,7R)-7-phenylacetamido-3- (trifluoromethylsulphonyloxy)ceph-3-em-4- carboxylate (20mg, 0.034mmol) and cydohexene (17.3μl 0J7mmol) in dichloro- methane (1.5ml). The mixture was stirred for 16h, then chromatographed to give the title compound (7.8mg, 44%) as a cream solid, mp.234-236°C (EtOAc) (Found: M+, 518.1882. C29H30N2O5S requires M, 518.1875); υ ma χ (CH 2 C1 2 ) 1784, 1718, 1685cm" 1 ; δ (CDCI3) 1.00-1.99 (8H, m), 2.39 (IH, br q, ] 8.2), 3.47 (IH, tdd, } 9.3, 8.4, 2.6), 3.63 (2H, ABq, J 16.3), 3.80 (3H, s), 4.26 (IH, dd, } 8.7, 2.6), 4.90 (IH, d, J 4.9), 5.17 (2H, ABq, J 11.9), 5.75 (IH, dd, J 8.9, 4.9), 5.98 (IH, d, ] 8.8), 6.86 (2H, d, 78.7), 7.25-7.37 (7H, m). Example 19/Step 1 p-Methoxybenzyl (4R.8S.9S.11R.12R)-13-oxo-12-phenylacetamido-10-thia-l- azatetracydor9.2.0.0 3 / 9 .0 4 3 1tridec-2-ene-2-carboxylate and p-Methoxybenzyl (4S.8R95. 11R. 12R)-13-oxo-12-phenylacetamido-10-thia-l- azatetracyclof9.2.0.θ3/9.o4,89i- tr idec-2-ene-2-carboxylate To a solution of p-methoxybenzyl (6R,7R)-phenylacetamido-3- (trifluoromethyl- sulphonyloxy)ceph-3-em-4-carboxylate (70mg, 0J2mmol) and cydopentene (0J7ml) in dichloromethane (3.0ml) was added diisopropylethylamine (21μl, 0J2mmol). After stirring at room temperature for 30 min the mixture was chromatographed to give the title compounds. The (4R, 8S) isomer eluted first (12mg, 20%). (Found: M+, 504.1729. C 2 8H 28 N 2 θ5S requires M, 504.1719); υ ma χ (CH 2 C1 2 ) 1785, 1719, 1685cm' 1 ; δ H (CE 3) 1.39 (IH, m), 1.60 (2H, m), 1.69 (2H, m), 2.27 (IH, m), 3J3 (IH, dtd, 79.8, 6.8, 2.7), 3.63 (2H, ABq, J 16.0), 3.79 (3H, s), 3.86 (IH, t, J 6.8), 4.31 (IH, d, 79.8), 4.98 (IH, d, } 4.9), 5J6 (2H, ABq, J 12.0), 5.74 (IH, dd, J 9.0, 4.9), 6.0 (IH, d 8.7), 6.87 (2H, d, J 8.6), 7.30 (7H, m); δ c (CDCI3) 26.8, 28.7, 31.9, 39.6, 42.6, 3.4, 50.5, 55.3, 58.3, 60.9, 67J, 114.0 (2c), 12U, 127.4, 127.7, 129J (2c), 129.5 (2c), 130.5 (2c), 133.8, 144.8, 159.8, 160.3, 164J, 171.1. The later eluting isomer was (45, 8ϋQ (21mg, 35%), (Found: M + , 504.1719); υ ma χ (CH2 Q 2) 1785, 1720, 1687cm' 1 ; fa (CDCI3) 1.60 (IH, ), 1.65 (IH, m), 1.77 (IH, m), 1.80 (IH, m), 1.81 (IH, m), 1.91 (IH, m), 2.85 (IH, q, .76.0), 3.62 (2H, ABq, 316J), 3.77 (IH, dd, .75.0, 3.3), 3.79 (3H, s), 3.89 (IH, m), 4.88 (IH, d, .75.0), 5.11 (IH, d, 311.9), 5.23 (IH, d, 3 H.9), 5.74 (IH, dd, 38.8, 5.0), 6.06 (IH, d, 38.8), 6.86 (2H, d, .78.6), 7.30 (7H, m); δc (CDCI3) 25.7, 30.7, 32.9, 43.4, 43.5, 43.7, 9.4, 55.3, 58.4, 61.4, 67.0, 114.0(2c), 120.7, 127.5, 127.7, 129.2 (2c), 129.5 (2c), 130.5 (2c), 133.8, 140.7, 159.8, 160.9, 164.3, 171.2. Example 20/Step 1 p-Methoxybenzyl (5.9. 6-9. 8ff. 9-?V9-benzajnido-10-oxo-5-phenyl-7-thia-^- azatricvclor6.2.0.θ3.6idec-2-ene-2-carboxvlate and p-Methoxvbenzvl (5X. 6.9.8_?.9_?V 9-benzamido-10-oxo-5-phenyl-7-thia-l-azatricyclor6.2.0.θ3/6l-dec-2-ene-2- carboxylate To a solution of p-methoxybenzyl (6R-7R)-7-benzamido-3-(trifluoro- sulphonyloxy)ceph-3-em-4-carboxylate (0.20g, 0.347mmol) and styrene (0.12ml, 1.04mmol) in dichloromethane (10ml) at 0°C was added diisopropylethylamine (60μl, 0.344mmol). After stirring for 10 min the mixture was chromatographed to give the title compounds. The (5S) isomer was eluted first (75.6mg, 41%) (Found: C, 68.4; H, 5.0; N, 5.5; S, 6.1; M+, 526.1578. C3θH 26 N 2 θ5S requires C, 68.4; H, 5.0; N, 5.3; S, 6.1%; M, 526.1562); ax (CH 2 C1 2 ) 1787, 1724, 1677; δ H (CDCI3) 3.33 (IH, ddd, } 15.0, 9.2, -1.4), 3.56 (IH, brq, 7~8.4), 3.80 (3H, s + IH, ddd, f 15.0, 8.0, 2.5), 4.41 (IH, ddd, / 7.9, 2.3, 1.4), 5J2 (IH, d, J 4.9), 5.24 (2H, ABq, 711.9), 5.98 (IH, dd, J 8.4, 4.9), 6.89 (2H, d, J 8.6), 7.20-7.56 (12H, m), 7.81 (IH, d, J 7.0). The later eluting isomer was the (5R) (59.2mg, 32%), (Found: M + , 526.1583); υ max (CH 2 C1 2 ) 1786, 1724, 1676cm' 1 ; δ H (CDC1 3 ) 3.56 (IH, dt, } 16.8, 3.3), 3.65 (IH, dd, J 16.9, 9.2), 3.80 (3H, s), 4.01 (IH, td, J 9.4, 4.0), 4.76 (IH, ddd, } 9.8, 2.5, 1.2)„5.08 (IH, d, 75.0), 5.28 (2H, ABq, J 12.0), 5.96 (IH, dd, J 8.9, 5.0), 6.59 (IH, d, J 8.7), 6.90 (2H, d, 78.5), 7J6-7.51 (10H, m), 7.65 (2H, d, J 8.5). Example 21/Step 1 p-MgΦoxybgnzyl (g_?, fc 8%, 9^)-5-acgtQ χ yrngthyl-lQ-p χ o-9-p gnyl- acgtømidp-7- thia-l-azatricvclor6.2.0.Q3-6ldec-2-ene-2-carboxvlate To a mixture of p-methoxybenyl (6R,7R)-7-phenylacetamido-3-trifluoro- methanesulphonyloxy ceph-3-em-4-carboxylate (57mg, 0.097mmol) and allyl acetate (30μl, 0.278mmol) in dichloromethane (3ml) was added diisopropyl¬ ethylamine (17 μl, 0.095mmol). After stirring and room temperature for 30 min the mixture was chromatographed to give the title compound (8mg, 15%), (Found: M + , 536.1615. C 2 gH 2 8N 2 OτS requires 536.1617), υ ma χ (CH 2 C1 2 ) 1782, 1745, 1686cm" 1 ; fa (CDCI3) 7.37-7.27 (7H, m), 6.88 (2H, d, J 8.7Hz), 5.99 (IH, br d, } 8.9Hz), 5.79 (IH, dd, J 8.9, 5.0Hz), 5.24 (IH, d, 7=11.9Hz), 5.13 (IH, d, 7=12.0Hz), 4.93 (IH, d, J 5.0Hz), 4.47 (IH, br dd, 7=8.7, 2.8Hz), 4.08 (2H, d, j 7.5Hz), 3.81 (3H, s), 3.69 (IH, d, } 16.1Hz), 3.60 (IH, d, J 16JHz), 3.30 (IH, dd, J 16.7, 9.3Hz), 3.07-2.94 (2H, m). Example 22 /Step 1 p-Methoxybenzyl ( 6R.8R.9R)-5-ethoxy-10-oxo-9-phenylacetamido-7-thia-l- azartcyclof6.2.0.θ3/6ldeca-2,4-diene-2-carboxylate To a mixture of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3-trifluoro- methanesulphonyloxy ceph-3-em-4-carboxylate (57mg, 0.097mmol) and ethyl- ethynylether (200 μl, 50% in hexane, 0.97mmol) in dichloromethane (3ml) was added diisopropylethylamine (17 μl, 0.097mmol). After stirring at room temperature for lh the mixture was chromatographed to give the title compound (17.5mg, 36%), (Found: M + , 506.1513. C 2 7H 2 gN 06S requires 506.1512); υ ma χ (CH 2 C1 2 ) 1782, 1733, 1685cm' 1 ; δ H (CDCI3) 7.39-7.24 (7H, m), 6.87 (2H, d, J 8.7Hz), 6.02 (IH, d, } 8.5Hz), 5.88 (IH, dd, J 8.5, 4.6Hz), 5.54 (IH, d, 71Hz), 5.24 (IH, d, J 12.0Hz), 5.15 (IH, d, J 12.0Hz), 4.82 (IH, d, J 4.6Hz), 4.37 (IH, d, J 1.2Hz), 4.10 (2H, q, } 7.2Hz), 3.80 (3H, s), 3.67 (IH, d, } 16JHz), 3.59 (IH, d, J 16JHz), 1.41 (3H, t, } 7.2Hz). Example 23 /Step 1 p-Methoxybenzyl ( 6R and 6S, 8R, 9R)-5-methoxycarbonyl-10-oxo-9- phenylacetamidcr-7-thia-l-azatricyclor6.2.0.θ3/6ldeca-2.4-diene-2-carboxylate To a mixture of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3-trifluoro- methanesulphonyloxy-ceph-3-em-4-carboxylate (57mg, 0.097mmol) and methyl- propiolate (90 μl, l.Olmmol) in dichloromethane (3ml) was added dϋsopropyl- ethylamine (17 μl, 0.097mmol). After stirring at room temperture for lh the mixture was chromatographed to give firstly the 6R isomer (12.5mg, 25%), (Found: M + , 520.1310. C 2 7H 2 4N 2 θ7S requires 520.1304); Umax (CH 2 C1 2 ) 1792, 1721, 1684cm' 1 ; δ H (CDC1 3 ) 735-7.24 (7H, m), 7.20 (IH, s), 6.89 (2H, d, f 8.4Hz), 5.99 (2H, m), 5.26 (IH, d, ] 11.9Hz), 5.20 (IH, d, 711.9Hz), 4.88 (IH, d, f 4.4Hz), 4.39 (IH, s), 3.82 (3H, s), 3.81 (3H, s), 3.66 (IH, d, 16.3Hz), 3.60 (IH, d, J 16.3Hz); followed by the 6S isomer (5Jmg, 10%), (Found: M+, 520.1310); ma χ (CH 2 C1 2 ) 1783, 1724, 1678cm' 1 ; δ H (CDCI3), 7.41-7.26 (7H, m), 6.90 (2H, d, J 8.7Hz), 6.86 (IH, s), 6.17 (IH, d, J 7.8Hz), 5.67 (IH, d, J 4JHz), 5.20 (IH, d, J 11.3Hz), 5.19 (IH, m), 5.13 (IH, d, J 11.3Hz), 4.43 (IH, s), 3.86 (3H, s), 3.82 (3H, s), 3.74 (IH, d, } 16.5Hz), 3.67 (IH, d,/ 16.5Hz). Example 24/Step 1 p-Methoxybenzyl (5RS.65.8R.9R)-5-methoxycarbonyl-10-oxo-9- phenylacetamidc>-7-thia-l- azaτricyclor6.2.0.θ36χdec-2-ene-carboxylate To a mixture of p-methoxybenzyl (6R, 7R)-7-phenylacetamido-3-trifluoro- methanesulphonyloxy ceph-3-em-4-carboxylate (57mg, 0.097mmol) and methyl acrylate (440 μl, 4.9mmol) in dichloromethane (3ml) was added dϋsopropyl- ethylamine (17 μl, 0.097mmol). After stirring at room temperature for 20 min the mixture was chromatographed to give the tide compound (39mg, 76%), (Found: M + , 522.1482. C 2 7H 2 6N 2 OτS requires 522.1461); Umax (CH 2 C1 2 ) 1786, 1728, 1686cm' 1 ; δ H (CDCI3), 739-7.22 (7H, m), 6.87 (2H, d, J 8.6Hz), 6.06 (IH, d, J 8.9Hz), 5.77 (IH, m), 5J9 (1.2H, ABq, J 11.9Hz), 5J7 (0.8H, ABq, J 12.0Hz) 4.97 (0.4H, d, J 5.0Hz), 4.94 (0.6H, d, J 5.0Hz), 4.58 (IH, m), 3.79 (3H, s), 3.75 (1.2H, s), 3.70 (4H, m), 3.67 (1.8H,s), 3.33 (0.6H, m), 3J0 (0.4H, m). Example 25/Step 1 p-Methoxybenzyl (5R5.65.75.8R, 9R)-7J0-dioxo-5-phenyl-9- phenylacetamido-7-thia-l-azatricyclor6.2.0.θ3/6]dec-2-ene-2-carboxylate To a suspension of p-methoxybenzyl (lS,6R,7R)-l-oxo-7-phenylacetamido- 3- trifluoromethanesulphonyloxyceph-3-em-4-carboxylate (30mg, 0.05mmol) and styrene (300 μl, 2.62mmol) in dichloromethane (3ml), was added diisopropyl- ethylamine (10 μl, 0.057mmol). After stirring at room temperature for 30 min the mixture was chromatographed to give the title compounds (14.7mg, 53%), υ max (CH 2 C1 2 ), 1790, 1728, 1689cm '1 ; δjj (CDC1 3 ) 7.41-7J6 (12H, m) 6.89 (2H, m) 6.67 (0.4H, d, 79.7Hz), 6.52 (0.6H, d, J 9.8Hz), 5.98 (0.4H, dd, J 9.7, 4.9Hz), 5.86 (0.6H, dd, J 9.8, 4.9Hz), 5.28 (ABq, J 11.9Hz), 5.23 (0.8H, ABq, J 11.8Hz), 438 (IH, m), 4.31 (0.6H, m), 4.0 (1.4H, m), 3.80 (3H, s), 3.73-3.82 (4H, m). Intermediate preparation 1 p-Methoxybenzyl (15.6R.7R)-l-oxo-7-phenylacetamido-3-(trifluoromethane- sulphonyloxy)ceph-3-em-4-carboxylate A solution of p-methoxybenzyl (6R,7R)-7-phenylacetamido-3-(trifluoro- methanesulphonyloxy)ceph-3-em-4-carboxylate (l.Og, 1.7mmol) in dichloro- methane (25ml) was treated with a solution of m-chloroperbenzoic add (70%) (0.45, l.δmmol) in dichloromethane (15ml). After stirring at room temperature for 30 min the solvent was evaported and the residue crystallised from dichloro- methane/hexane to give the title compound (775mg, 75%); m/z (3-NOBA sodium) 625 (MNa + ); υ ma χ (KBr) 1793, 1736, 1649cm' 1 ; fa (CDCI3) 3.47 (IH, dd, J 18.4, 1.4Hz), 3.63 (IH, d, } 15.6Hz), 3.66 (IH, d, 715.6Hz), 3.81 (3H, s), 3.87 (IH, d, 718.4Hz), 4.53 (IH, dd, J 4.8, 1.4Hz), 5.20 (IH, d, 711.7Hz), 5.36 (IH, d, J 11.7Hz), 6.07 (IH, dd, J 4.9, 9.8Hz), 6.75 (IH, d, 79.8Hz), 6.89 (2H, d, J 8.6Hz), 7.25-736 (7H, m). Intermediate preparation 2 p-Methoxybenzyl ( 6_?. 7_?VlJ-dioxo-7-phenvIacetamido-3-( ' trifluoro- methanesuIphonvIoχvteeph-3-em-4-carboxvlate A mixture of p-methoxybenzyl(lS, 6R, 7R)-l-oxo-7-phenylacetamido-3- (trifluoro- methanesulphonyloxy)ceph-3-em-4-carboxylate (767mg, 1.27mmol) and m-chloroperbenzoic add (939mg, 3.81mmol) in chloroform (60ml) was heated to reflux. After refluxing for 7 hours the mixture was chromatographed to give the title compound (560mg, 71%); υmax (KBr) 1819, 1740, 1697cm '1 ; δ H (CDC1 3 ) 3.60 (2H, m), 3.81 (3H, s), 3.87 (IH, d, J 18JHz), 4.17 (IH, d, 718.1Hz), 4.53 (IH, d, J 4.9), 5.20 (IH, d, ] 11.8Hz), 5.37 (IH, d, 711.8Hz), 6.08 (IH, dd, J 4.9, 9.9Hz), 6.55 (IH, d, J 9.8Hz), 6.89 (2H, d, J 8.7Hz), 7.18-737 (7H, m). Example 26 p-Methoxvbenzvl ( 5_ . 6-9. 83?. 9-?V5-phenvl-9-phenvlacetamido-7.7.10-trioxo-7- thia-l-azatricvclor6.2.0.0 3 -6ldec-2-ene-2-carboxvlate and p-methoxvbenzvl (5.9. 6.9. 8-?. 9-?V5-phenvl-9-phenvlacetamido-7.7J0-trioxo-7-thia-l-aza- tricvclor6.2.0.θ3-6idec-2-ene-2-carboxvlate To a mixture p-Methoxybenzyl (6R,7R)-l,l-dioxo-7-phenylacetamido-3-(tri- fluoromethane sulphonyloxy)ceph-3-em-4-carboxylate (88mg, 0J4mmol) and styrene (80.2 μl, 0.70mmol) in dichloromethane (9ml) was diisopropylethylamine (26.8 μl, 0.15mmol). After stirring at room temperature for 50 min the mixture was chromatographed to give the 5R isomer (12mg, 15%); m/z ( H3DCI) 573 (MH+); υ ma χ (CH 2 C1 2 ) 1805, 1730, 1690cm" 1 ; δπ (CDCI3) 3.26 (IH, ddd, J 2.2, 9.6, 15.4Hz), 3.63 (IH, d, J 16.3Hz), 3.68 (IH, d, 716.3Hz), 3.69 (IH, ddd, } 2.5, 8.5, 15.5Hz), 3.81 (3H, s), 4.22 (IH, q, 78.7), 4.51 (IH, dd, J 8.4, .5Hz), 4.84 (IH, dd, } 1.3, 5JHz), 5.19 (IH, d, J 11.9Hz), 5.23 (IH, d, 711.8Hz), 6.07 (IH, dd, J 5.0, 10.5Hz), 6.65 (IH, d, J 10.7Hz), 6.89 (2H, d, J 8.6Hz), 7.20-7.40 (12H, m); followed by the 5S isomer (5mg, 7%); m/z (NH3DCI), 573 (MH+); υ max (CH 2 C1 2 ) 1805, 1729, 1686cm" 1 ; δ H (CDCI3) 3.35 (IH, ddd, J 1.6, 8.8, 17.2Hz), 3.53 (IH, ddd, J 3.1, 8.7, 17.2Hz), 3.61-3.66 (2H, m), 3.81 (3H, s), 4.21 (IH, q, } 8.5Hz), 4.45 (IH, d, J 4.9Hz), 4.77 (IH, m), 5.16 (IH, d, J 12.0Hz), 5.25 (IH, d, f 11.9Hz), 5.50 (IH, dd, 74.9, 8.6Hz), 6.46 (IH, d, J 8.5Hz), 6.89 (2H, d, } 8.7Hz), 7.20-7.40 (12H, m). Example 27 Step 1 p-Methoxvbenzvl ( _?.9. 6S. 8ff. 9-?V5-cvano-10-oxo-9-phenvlacetamido-7-thia-l- azatricvclor6.2.0.θ3>6idec-2-ene-2-carboxvlate To a mixture of p-methoxybenzyl (6R, 7R)-7-phenylacetamido-3-(trifluoro methanesulphonyloxy)ceph-3-em-4-carboxylate (lOOmg, 0J7mmol) and aαylonitrile (500 μl, 7.6mmol) in dichloromethane (5ml) was added diisopropyl- ethylamine (31 μl, OJδmmol). After stirring at room temperature for 20 min the mixture was chromatographed to give the 55 isomer (21.6mg, 26.6%); υ ma χ (KBr) 2243, 1787, 1724, 1674cm" 1 ; δji (CDC1 3 ) 3.09 (IH, q, 78.6Hz), 3.54 (IH, ddd, ] 16.0, 8.9, 1.7Hz), 3.61 (IH, d, J 16.3Hz), 3.68 (IH, d, 716.3Hz), 3.72 (IH, ddd, J 15.9, 8.6, 2.7Hz), 3.81 (3H, s), 4.64 (IH, ddd, 71.6, 2.6, 8.0Hz), 4.99 (IH, d, J 4.9Hz), 5J6 (IH, d, J 12.0Hz), 5.20 (IH, d, 712.0Hz), 5.80 (IH, dd, J 4.9, 8.7Hz), 5.90 (IH, d, J 8.7Hz), 6.88 (2H, d, } 8.7Hz), 7.24-7.41 (7H, m); followed by the 5R isomer (10.2mg, 12.6%); δπ (CDCI3) 3.53-3.72 (5H, m) 3.81 (3H, s), 4.57 (IH, m), 5.02 (IH, d, J 5.0Hz), 5J6 (IH, d, 711.9Hz), 5.25 (IH, d, J 11.9Hz), 5.82 (IH, dd, } 5.0, 8.8Hz), 6.16 (IH, d, 78.7Hz), 6.88 (2H, d, ] 8.7Hz), 7.24-7.41 (7H, m). Step 2 Sodium (53?. 6.9. 8-?, _>R^5-cvano-10-oxo-9-phenvlacetamido-7-thia-l- azatricyclor6,2.Q,Q 3<6 ]dgc-2-gpg-2-cart>p χ ylatg The 5S isomer from step 1 (693mg, 0J5mmol) was hydrolysed as in Example 6, Step 2a to give the title compound (33mg, 58%); m/z (glycerol) 414 (MNa+), 392 (MH+); υ ma χ (KBr) 2242, 1763, 1666, 1607cm" 1 ; δ H (D 2 0) 3.38 (IH, q, 78.6Hz), 3.5-3.8 (4H, m), 5.14 (IH, d, J 4.7Hz), 5.62 (IH, d, } 4.7Hz), 7.35 (5H, m). Example 28 Step 1 o-Methoxvbenzvl ( 6S. 8R. 9_-2)-10-oxo-9-Dhenvlacetamido-7-thia-l- azatricvclor6.2.0.0 3 » 6 1dec-2-ene-2-carboxvlate Ethylene was bubbled into a solution of p-methoxybenzyl (6R,7R)-7-phenyl- acetamido-3-(trifluoromethanesulphonyloxy)ceph-3-em-4-carboxylate (0.50g, 0.852mmol) in ethyl acetate (500ml) whilst a solution of " diisopropylethylamine (0J5ml, 0.852mmol) in ethyl acetate (100ml) was added dropwise over 2h. After completion of the addition the mixture was left to stand for 18h then the solvent was evaporated under reduced pressure. The residue was chromatographed to give the title compoimd (0.24g, 61%), (Found: M+, 464.1411. C 25 H 24 2 θ5S requires M, 464.1406); ~ o ma (CH 2 C_2) 1786, 1722, 1686, 1604cm' 1 ; δH (CDCI3) 2.08 (IH, m), 2.46 (IH, dtd, J 10.4, 9.3, 3.2), 3.16 (IH, dtd, J 15.8, 9.4, 1.6), 3.28 (IH, ddt, J 15.8, 8.8, 3.0). 3.63 (2H, ABq, J 16.1), 3.80 (3H, s), 4.32 (IH, dddd, J9.3, 8.2, 2.8, 1.5), 4.94 (IH, d, J ' 5.0), 5.18 (2H, ABq, J 11.9), 5.76 (IH, d, J 8.8, 5.0), 5.97 (IH, d, J " 8.8), 6.87 (2H, d, 8.7), 7.26 (7H, m). p-Methoxvbenzvl ( 6S. 8R. 9_?V9-amino-10-oxo-7-thia-l-azatricvclo- r6.2.0.0 3 » β ldec-2-ene-2-carboxylate The product was prepared as in Example 1, Step 2: (91%), (Found: M + 346.0984. Cχ7H 18 N 2 θ4S requires 346.0987); υ ma χ (CH2CI2) 1780, 1723, 1603cm" 1 ; δ H (CDCI3) 2.11 (IH, m), 2.51 (IH, m), 3.16 (IH, m), 3.30 (IH, m), 3.80 (3H, s), 4.35 (IH, m), 4.71 (IH, m), 4.95 (IH, d, J 5.2), 5.20 (2H, ABq, J 12.0), 6.88 (2H, d, J 8.7), 7.34 (2H, d, J 8.7). p-Methoxybenzyl (fig. 8R. 9-2)-9-r2-(2-aminothiazol-4-vlV2-(Z)-methoxv- ι-mιnnanflta-mιdn1-10-oxo-7-thia-l-aza-ricvclo- r6.2.0.0 3 - 6 ldec-2-ene-2- carboxylate The product was prepared as in Example 1, Step 3: (91%); υ m ax (CH2CI2) 1787, 1723, 1687cm' 1 ; δ H (CDCI3) 2.16 (IH, m), 2.49 (IH, m), 3.24 (2H, m), 3.81 (3H, s), 4.05 (3H, s), 4.37 (IH, m), 5.07 (IH, d, J 5.0), 5.22 (2H, ABq, J 11.9), 5.54 (2H, s), 5.96 (IH, dd, J 8.7, 5.0), 6.78 (IH, s), 6.89 (2H, d, J 8.7), 7.33 (2H, d, J 8.7), 7.72 (IH, d, J 8.7); m/z 530 (MH+). Ste Sodium (6S. 8R. 9_?)-9-r2-(2-aminothiazol-4-ylV2-(Z)-methoxy- iminoacet__midol-10-oxo-7-thia-l-azatricvclo- r6.2.0.0 3 »6ldec-2-ene-2- carboxylate The product was prepared as in Example 1, Step 4: (85%); υ m ax (KBr) 1758, 1671, 1604, 1530, 1442cm' 1 ; δ H (CDCI3) 2.10 (IH, m), 2.45 (IH, m), 3.15 (2H, m), 3.96 (3H, s), 4.50 (IH, bit, J -8.7), 5.22 (IH, d, 4.8), 5.71 (IH, d, 4.8), 7.00 (IH, s); m/z 432 (MH+), 454 (MNa+). In Vitro Biological Data Compound of Example 14

Claims: Claims: 1. A compound of formula (I) or a salt thereof: (I) wherein R 1 is hydrogen, methoxy or formamido; R2 is an acyl group, in particular that of an antibacterially active cephalosporin; CO2R 3 is a carboxy group or a carboxylate anion, or R 3 is a readily removable carboxy protecting group or a pharmaceutically acceptable salt- forming group or in υiυo hydrolysable ester group; R4, R5, R6 a d B? independently represent hydrogen or a substituent group; wherein R^ and R? may be absent and be replaced by a chemical bond between the two carbon atoms shown; and wherein R5 and Bβ may be linked together into a cyclic system of formula: wherein X represents - O - or - NR 3 -, wherein each R 3 may be the same or different and independently represents hydrogen or a substituent group, or two groups R 3 may be linked into a ring system, or any two adjacent - CR 2 - units may be replaced by a - CR 3 = CR 3 - unit, and wherein n is an integer 1 to 7, m is 0, 1, 2 or 3. 2. A compound of formula (I) as claimed in claim 1 having a formula (Ia) or pharmaceutically acceptable salts or pharmaceutically acceptable in υiυo hydrolysable esters thereof: (la) wherein R , R^, R^, R5, 6, and l are as defined with respect to formula (I) and the group CO2 is CO2 where CO2 is a carboxy group or a carboxylate anion. 3. A compound as claimed in claim 1 or 2 in which R is hydrogen. 4. ' A compound as claimed in claim 1 wherein R^NH is a 2-(2- aminothiazol-4-yl)-2-(Z)-methoxy- or hydroxy- iminoacetamido group in which the amino group may be in a substituted or protected form. 5. A compound of formula (I) as claimed in daim 1 having a part formula (IBi) or (IBii): where one or both of R^ and 5 may be substitutent groups other than hydrogen. 6. A compound of formula (I) as claimed in claim 1 wherein R and R6 are linked together into a cyclic ring system, R^ and R? being hydrogen, and the ring system being a 5- or 6- membered ring system of part formula (IBiii), (IBiv) or (IBv) or (IBvi): (IBiii) where R 3 and n are as defined in formula (I) and p is zero or an integer up to the number of carbon atoms in the ring. 7. A compoimd according to claim 6 in which in part formulae (IBiii IBvi) R 3 is hydrogen, and n is 1 or 2. 8. A compound of formula (I) as daimed in claim 1 wherein two groups R 3 are linked together to form an optionally substituted phenyl ring system in a compound of formula (I) having a part formula (IBvii): (IBvii) wherein the phenyl ring shown in (IBvii) may be substituted with one or more substituents. 9. A compound of formula (IA) as claimed in claim 2, being selected from the carboxylic adds Hsted below, and salts and in-υiυo hydrolysable esters thereof: (5S,6i2,8B,9i2)-9-[2-(2-aιr_mothiazol-4-yl)-2- 5-etho3cy-10-oxo-7-thia-l-azatricydo[6.2.0.0 3 » 6 ]dec-2-ene-2-carboxylic add, (422,972,1012,1222, 1322)-13-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxy- iminoacetamido]-14-oxo-8-oxa-ll-thia-l-azatetra(yclo[10.2.0.0 3 ' 0.θ4-9]- tetra- dec-2-ene-2-carboxylic add, (5S,622,8R,9_3]-5-aceto--y-9-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxy- immoa∞tamidol-10-oxo-7-thia-l-azatricydo[6.2.0.0 3 »6]dec-2-ene-2- carboxylic add, (6S, 822, 922)-5,5-dimethyl-10-oxo-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.0 3 »6]dec-2-ene-2-carboxylic add, (5S, 6S, 822, 922)-5-butyl-10-oxo-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.0 3 » 3 ]dec-2-ene-2-carboxylic add, (6S, 822, 922)-10-oxo-5-phenyl-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.0 3 » 3 ]deca-2,4-diene-2-carboxylic add, (622, 822, 922)~10-oxo-5-phenyl-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.0 3 » 3 ldeca-2,4-diene-2-carbθ5_ylic add, (6S,822,922)-9-[2-(2-am otMazol-4-yl)-2-(Z)-methoxyimmoacetamido]-10- oxo-5-phenyl-7-thia-l-azatricydo[6.2.0.0 3 ' 3 ]deca-2,4-diene-2-carboxylic add, (622, 822, 922)-9-[2-(2-ammothiazol-4-yl)-2-(Z methoxyinήnoa(»tamido]-10- oxo-5-phenyl-7-thia-l-azatricyclo[6.2.0.0 3 « 3 ]deca-2,4-diene-2-carboxylic add, (622,822,922)-10-oxo-9-phenylacetamido-5-trimethylsilyl-7-thia- l- azatricyclo[6.2.0.0 3 ' 3 ]deca-2-4-diene-2-carboxylic add, (522,622,822,922)-9-benzamido-10-oxo-5-phenylthio-7-thia-l- azatricycIo_6.2.0.0 3 » 3 ]dec-2-ene-2-carboxylic add, (5S,622,822,922)-9-benzamido-10-oxo-5-phenylthio-7-thia-l- azatricyclo[6.2.0.0 3 ' 3 ]- dec-2-ene-2-carboxylic add, (4S,5S,6S,822,922) -4,5-dimethyl-10-oxo-9-phenylacetamido-7- thia-1- azatricyclo[6.2.0.0 3 -6]dec-2-ene-2-carboxylic add, (6S, 822, 922) -4,5-dimethyl-10-oxo-9-phenylacetamido-7-thia-l-azatricyclo _6.2.0.0 >6]deca-2,4-diene-2-carboxylic add, (4S, 822, 9S, 1122, 1222)-13-oxo-12-phenylacetamido-5-oxa-10- thia-1-aza- 6,7-benzotetracyclo[9.2.0.0 3 ' 9 .0 4 ' 3 ]tridec-2-ene-2-carboxylic add, (4S, 822, 9S, 1122, 1222)-12-[2-(2-aminothiazol-4-yl)-2-(Z)-methoxy- iminoacetamido]- 13-oxo-5-oxa- 10- thia-l-aza-6,7-benzotetra- cyclo[9.2.0.0 3 »9.θ4»8]t r idec-2-ene-carboxylic add, (4S, 8S , 9S, 1122, 1222)-13-oxo-12-phenylacetamido-10-thia-l-aza-6,7- benzotetracydo[9.2.0.0 3 * 9 .θ4» ]tridec-2-ene-2-carboxylic add, (5S, 622,,822,922)-10-oxo-5-(2-oxopyrrolidin-l-yl)-9-phenylacetamido-7-thia- l-azatricyclo[6.2.0.0 3 '6]dec-2-ene-2-carboxylic add, (522, 6S, 822, 922)-5-hydroxymethyl-10-oxo-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.0 » 3 ]dec-2-ene-2-carboxylic add, (4S, 922, 10S, 1222, 1322)-14-oxo-13-phenylacetamido-ll-thia-l- azatetracydo[10.2.0.0 3 » 1 0.θ4»9]-tetradec-2-ene-2-carboxylic add, (422,85,9S, 1122, 1222)-13-oxo-12-phenylacetamido-10-thia-l- azatetracydo[9.2.0.0 3 »9.θ4» 3 ]tridec-2-ene-2-carboxylic add, (4S,8229S, 1122, 1222)-13-oxo-12-phenylacetamido-10-thia-l- azatetracydo[9.2.0.0 3 »9-θ4» 3 9]-tridec-2-ene-2-carboxylic add (5S, 6S, 822, 922)-9-benzamido-10-oxo-5-phenyl-7-thia-l- azatricyclo[6.2.0.0 3 » 3 ]dec-2-ene-2-carboxylic add, (522, 6S,822,922)-9-benzamido-10-oxo-5-phenyl-7-thia-l- azatricyclo[6.2.0.0 3 '6]-dec-2-ene-2-carboxyhc add, (522, 6S, 822, 922)-5-acetoxymethyl-10-oxo-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.0 3 » 3 ]dec-2-ene-2-carboxylic add, ( 622, 822, 922)-5-ethoxy-10-oxo-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.0 3 '6]deca-2,4-diene-2-carboxyHc add, ( 622 and 6S, 822, 922)-5-methoxycarbonyl-10-oxo-9-phenylacetamido-7- thia-l-azatricydo[6.2.0.0 3 »6]deca-2,4-diene-2-carboxylic add, (522S, 6S, 822, 922)-5-methoxycarbonyl-10-oxo-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.0 3 »6]dec-2-ene-carboxylic add, (522S, 6S, 7S, 822, 922)-7,10-dioxo-5-phenyl-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.0 - β ]dec-2-ene-2-carboxylic add, (522, 6S, 822, 922)-5-phenyl-9-phenylacetamido-7,7,10-trioxo-7-thia-l- azatricyclo[6.2.0.0 3 -6]dec-2-ene-2-carboxylic aάd, (5S, 6S, 822, 922)-5-phenyl-9-phenylacetamido-7,7,10-trioxo-7-thia-l-aza- tricydo[6.2.0.0 3 '6]dec-2-ene-2-carboxylic add, ( 522S, 6S, 822, 922)-5-cyano-10-oxo-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.0 3 '6]dec-2-ene-2-carboxylic add, (522, 6S, 822, 9R,-5-cyano-10-oxo-9-phenylacetamido-7-thia-l- azatricyclo[6.2.0.0 3 -6]dec-2-ene-2-carboxylic add, and (6S, 822, 922)-9-[2-(2-aminothiazol-4-yl 2-(Z)-methoxy- iminoacetamido]- 10-oxo-7-thia-l-azatricyclo- [6.2.0.0 3 » 3 ]dec-2-ene-2-carboxylic add. 10. A process for the preparation of a compound of formula (I) as daimed in daim 1, which process comprises treating a compound of formula (II) or a salt thereof: (ID wherein R , CO2 3 , R 4 , R^, R*\ and R^ are as hereinbefore defined, wherein any reactive groups may be protected, and wherein the amino group is optionally substituted with a group which permits acylation to take place; with an add of formula (UI) or a N-acylating derivative thereof: R 2 OH (HI) wherein R 2 is the acyl group as defined with respect to formula (I) and wherein any reactive groups may be protected; and thereafter, if necessary or desired, carrying out one or more of the following steps: i) removing any protecting groups; ii) converting the group CO2R into a different group CO2R 3 ; iii) converting the group R 2 into a different group R 2 ; iv) converting the sulphur atom into an oxidised sulphur atom; v) converting the product into a salt or ester. 11. A process for the preparation of a compound of formula (II) as defined in claim 10, which indudes the step of reaction between a compound of formula (TV): (TV) wherein R 1 and R 3 , are as defined in formula (I), R 21 is a group R 2 as defined in formula (I) or is an amino-protecting group or is hydrogen or a group which permits N-acylation to take place and Z is a nucleophilic leaving group, with a compound of formula (V): (V) wherein R 4 , R5, R6 and R? are as defined with reference to formula (I), R4 and B may be absent and be replaced by a bond to form an alkyne, and wherein and R 3 may be linked together into a cyclic system of formula: wherein X, R 3 , n and m are as defined with respect to formula (I). 12. A pharmaceutical composition which comprises a compound of formula (Ia) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof and a pharmaceutically acceptable carrier. 13. A compound of formula (Ia) or a pharmaceutically acceptable salt or in υiυo hydrolysable ester thereof. 14. A compoimd of formula (Ia) or a pharmaceutically acceptable salt or in υiυo hydrolysable ester thereof, for use in the treatment of bacterial infections. 15. A method of treating bacterial infections in humans and animals which comprises the administration of a therapeutically effective amount of an antibiotic compound of the formula (Ia) or a pharmaceutically acceptable in υiυo hydrolysable ester thereof. 16. The use of a compound of formula (Ia) or a pharmaceutically acceptable salt or in υiυo hydrolysable ester thereof, for the manufacture of a medicament for the treatment of bacterial infections.

Inventors: BURTON GEORGE, ELLIOT RICHARD LEONARD, BURTON, GEORGE, ELLIOT, RICHARD, LEONARD
Applicants: SMITHKLINE BEECHAM PLC
Application year: 1993
Main classification: C07D501
IPC codes: A61K31, A61P31, C07D501