GB1579531A - Oxazolo-azetidinine antibiotic derivatives - Google Patents

Description

(54) OXAZOLO-AZETIDINE ANTIBIOTIC DERIVATIVES (71) We, GLAXO LABORATORIES LIMITED, a British Company of Greenford, Middlesex, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- This invention relates to novel anitbiotics and ,B-lactamase inhibitors and to processes for their production.

In German OLS No. 2,604,697 we have described the isolation, from fermentations of Streptomyces davuligerus of the carboxylic acid having the formula (I) (clavulanic acid)

and salts thereof in pure form.

The compounds in this specification are named with reference to "clavam"; the name given to the parent heterocycle of formula A

by analogy with the term "cepham" used in the naming of cephalosporin compounds in J. Amer. Chem. Soc., 1962, 84, 3400. Thus, the compound of formula (I) is named (3R,5R,Z) - 2 - (hydroxyethylidene)clavam - 3 - carboxylic acid.

The present invention relates to analogues of the compound of formula (I) above and its salts and esters which carry the residue of a sulphur nucleophile in place of the hydroxy group thereof. These are of use, as detailed below, as antibiotics or as p-lactamase inhibitors, or they may be useful as intermediates in the preparation of further active compounds.

According to one aspect of the invention, we provide compounds of the formula

(where Rd is the residue of a sulphur nucleophile, and Rid is a 4nitrobenzyloxycarbonyl group).

In general, Rd may be represented by -SIl, -SR2, -SO. R2 or -SO2R2 (where R2 is an aliphatic, araliphatic, aromatic or heterocyclic group); or by -SC=Y. R3 (where Y is O or S and R2 is a group as defined above for R2 or a group OR2 or SR2, where R2 is as defined above, or a group NR4R5, where R4 and R5, which may be the same or different, are hydrogen atoms or aliphatic, araliphatic or aromatic groups or together with the nitrogen atom to which they are attached represent a heterocyclic ring); or by groups of the formulae

where R6, R7, Re and R9 which may be the same or different are hydrogen atoms or aliphatic groups, R'O is an aliphatic, araliphatic or aromatic group and M is a cation.

Also included is the compound wherein Rd represents the group

viz: the dimerisation product obtainable by oxidation of a compound of formula (II) wherein Rd represents a thiol (-SH) group.

According to another aspect of the invention, we provide compounds of the formula (II)

in which R represents a group SRX, SO. Rx or SO2. Rx wherein Rx represents an alkyl or alkenyl group or a heterocyclic group containing one or more hetero atoms, which groups may be substituted by a hydroxyl, carboxyl, amino or substituted amino group; a group of the formula . C=Y R3 (where Y is O or S and R3 is an aliphatic, araliphatic, aromatic or heterocyclic group; or a group --OR2 or SR2 wherein R2 is an aliphatic, araliphatic, aromatic or heterocyclic group; or a group -NR4R5 wherein R4 and R5, which may be the same or different, are hydrogen atoms or aliphatic, araliphatic or aromatic groups or together with the nitrogen atoms to which they are attached represent a heterocyclic ring); and Rl represents a carboxyl or esterified carboxyl group and salts of compounds in which Rl is a carboxyl group.

Where, in the group R, the group Ra represents an alkyl group, this preferably contains from 1 to 6 carbon atoms.

We also provide compounds of the formula (IIa)

wherein Ra represents an alkylthio or alkenylthio group or sulphoxide or sulphone derivative thereof substituted by an azido or cyano group; an alkylthio or alkenylthio group or sulphoxide or sulphone derivative thereof substituted by a 4nitrobenzyloxycarbonyl group or a nitro group; an alkylthio or alkenylthio group or sulphoxide or sulphone derivative thereof substituted by a mercapto group, or a heterocyclicthio group containing one or more heteroatoms and substituted by a mercapto group; a group --SRb, --SO.Rb or orSO2Rb wherein Rb is a phenyl or benzyl group substituted by a nitro group; a group SRC wherein Rc is a charged heterocyclic group, or nitrogen-containing heterocyclic group in the form of an Noxide; a fused heterocyclic thio group; one of the groups:

where R6, R7, R8 and R9, which may be the same or different, are hydrogen atoms or aliphatic groups; -SCN; . SO2R1 , where R'O is an aliphatic, araliphatic or aromatic group; --S,O,.M, where M is a cation, and an -SH or

group, and R1 represents a carboxyl or esterified carboxyl group or salts of the compounds in which R1 is a carboxyl group.

Wherein in any of the above groups a positive charge is present, either an anion or a carboxylate (COO) group will also be present.

Alkylthio or alkenylthio groups referred to above will desirably contain from I to 6 carbon atoms.

When any one of the groups R2, R3, R4, R5, R6, R7, Ra, R9 and R10 is an aliphatic group, it may be an alkyl, alkenyl or alkynyl group, which may contain 16 carbon atoms or a cycloalkyl group, which may have 3-7, preferably 5 or 6 carbon atoms; when any of the groups R2, R3, R4, Rs and R10 is an araliphatic or aromatic group, it will desirably be an aralkyl group which may have 1-6 carbon atoms in the alkyl portion or an aryl group, the rings in such aryl and aralkyl groups preferably being monocyclic e.g. phenyl; when either of the groups R2, R3, Ra and Rc is a heterocyclic group, it will desirably contain a carbon-attached 5-7 membered heterocyclic ring containing one or more heteroatoms such as nitrogen, sulphur or oxygen, and may carry one or more alkyl groups which may have 1-6 carbon atoms, e.g. a methyl group.

Such heterocyclic rings may be part of a bicyclic system and in this case may have heteroatoms in both rings. Where a nitrogen atom is present in the heterocyclic ring system, it may be in the form of the N-oxide. Examples of heterocyclic rings R2 and R3 include thiadiazolyl, diazolyl, triazolyl, tetrazolyl, thiazolyl, thiatriazolyl, oxazolyl, oxadiazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, triazolopyridyl, purinyl, pyridyl or pyrimidyl rings.

Such groups identified above may themselves carry substituents such as hydroxyl or substituted hydroxyl, carboxyl or substituted carboxyl, amino or substituted amino groups or azido, mercapto, cyano or nitro groups. Heterocyclic rings carrying hydroxy, mercapto or amino substituents may exist in tautomeric forms. Where NR4Rs represents a heterocyclic ring, this may for example, contain 5-7 ring atoms, including one or more other hetero-atoms e.g. nitrogen, oxygen or sulphur atoms, and may be, for example, a piperidino, piperazino, morpholino or thiamorpholino ring, and may carry one or more alkyl groups which may have 1-6 carbon atoms, e.g. a methyl group.

Substituted hydroxy groups as referred to above include acylated and etherified hydroxy groups. In general, acylated hydroxy groups may have the formula R1lCO2 where R11 is an aliphatic, araliphatic or aromatic group while etherified hydroxy groups may have the formula R11O, where R11 has the above meaning. Substituted carboxyl groups may have the formula COOT", where R11 has the above meaning, while substituted amino groups may have the formula NR4R5 as defined above, one of R4 and R5 being other than hydrogen, or --NR4RSR"A, where R4, R5 and R11 have the above meanings other than hydrogen and A is an anion, for example a halide, e.g. chloride, bromide or iodide; sulphate; phosphate; carboxylate e.g. acetate; or hydrocarbyl-sulphonate e.g. tosylate or mesylate ion. A may also be the group R1, where R1 is COO. Preferred groups R4, R5 and R1l are C 1-4 alkyl groups, e.g. methyl.

The salts according to the invention include salts with inorganic bases, such as alkali metal salts, e.g. sodium, potassium and lithium salts; alkaline earth metal salts, e.g. calcium and magnesium salts; and ammonium salts, as well as salts with organic bases, for example substituted ammonium salts (e.g. salts with amines).

Where more than one acidic group is present, mono- or di-salts are possible.

The cation M may, for example, be an alkali metal, alkaline earth metal, ammonium or substituted ammonium cation, e.g. sodium. Where Rl is esterified carboxyl and R carries a positive charge, for example as in the group

or where Rd or Rx carries a 0 grouping -NR4R5R11 (where R4, R5, R8, R7 R8, R9 and R11 have the above meanings including hydrogen), the associated anions may, for example, be as defined above for A. Where R1 is carboxyl, such compounds may exist as betaines.

Where Rd represents a group -SR2, -SO. R2 or -SO2. R2, R2 is preferably a C14 alkyl group; a C14 alkyl group substituted by an azide, cyano, hydroxy, or C14 alkoxy, e.g. ethoxy, group, or by a carboxyl group or a salt thereof (for example as described above) or a C14 alkyl, e.g. methyl, ester thereof, or by amino group or an amino group substituted by up to three C1.4 alkyl, e.g. methyl, groups; a bicyclic or more preferably monocyclic carbon-attached heterocyclic group, which contains 5-7 atoms in each ring and one to three double bonds in each ring and a total of up to four heteroatoms selected from nitrogen, oxygen and sulphur atoms, and which may be substituted by C1.4 alkyl, e.g. methyl, hydroxy, mercapto or amino groups, and where a nitrogen atom is present in an aromatic ring, the Noxides thereof; a phenyl group; or a phenyl group substituted by an amino or nitro prOUD.

Where Rd or R represents a group C=Y2.R in which Y is O or S,, R3 is preferably a C1.4 alkyl group; a phenyl group; a C1.a alkoxy, e.g. ethoxy, group; a pyridyl group or an Nay1~4) alkyl pyridinio group, e.g. an N - methylpyridinio group; or a group of the fo?rnula -NR4R5, where R4 and R5, which may be the same or different, are hydrogen atoms or C1.4 alkyl, e.g. methyl, groups or together with the nitrogen atom to which they are attached represent a - monocyclic, saturated, 5-7 membered heterocyclic ring which may contain an oxygen, sulphur or nitrogen atom as an additional heteroatom and which may be substituted by one or two C14 alkyl, e.g. methyl, groups.

R6, R7, R8 and R9 are all preferably hydrogen atoms.

R10 is preferably a phenyl group.

Representative groups Rd, R and Ra thus include mercapto, methylthio, ethylthio, propylthio, isopropylthio, butylthio, allylthio, propargylthio, 2aminoethylthio, 2 - azidoethylthio, 2 - hydroxyethylthio, 1 - ethoxyethylthio, cyanomethylthio, carboxymethylthio, methoxycarbonylmethylthio, 4 nitrobenzyloxycarbonylmethylthio, cyclohexylthio, benzylthio, phenethylthio, tetrahydropyranylthio, phenylthio, 4 - nitrophenylthio, 4 - aminophenylthio, 2 pyridylthio, 3 - pyridylthio, 4 - pyridylthio, 1 - oxidopyrid - 2 - ylthio, 1 - oxidopyrid - 4 - ylthio, 1 - methyl - 1,2,3,4 - tetrazol - 5 - ylthio, 5 - methyl 1,3,4 - thiadiazol -2 - ylthio, 1,2,3 - triazol - 4 - ylthio, 1,2,4 - triazol - 3 - ylthio, 2,3 - dihydro - 4 - methyl - 3 - oxo - 1,2,4 - triazol - 5 ylthio, 1 - methyl - 2 pyridiniothio, 1 - methyl - 3 - pyridiniothio, I - methyl - 4 - pyridiniothio, 2 pyrimidylthio, 6 - purinylthio, 4,5 - dihydrothiazol - 2 - ylthio, 5 - amino - 1,3,4 thiadiazol - 2 - ylthio, 5 - mercapto - 1,3,4 - thiadiazol - 2 - ylthio, methylsulphinyl, ethylsulphinyl, phenylsulphinyl, 2- azidoethylsulphinyl, 2aminoethylsulphinyl, 2- hydroxyethylsulphinyl, cyanomethylsulphinyl, methylsulphonyl, ethylsulphonyl, phenylsulphony, methoxycarbonylmethylsulphonyl, 4 - nitrobenzyloxycarbonylmethylsulphonyl, carboxymethylsulphonyl, 4 - nitrophenylsulphonyl, 4 - methylphenylsuiphonyl, 4 - aminophenylsulphonyl, 2 - azidoethylsulphonyl, 2 - aminoethylsulphonyl, ethoxythiocarbonylthio, carbamoylthio, N - methylcarbamoylthio, N,N - dimethylcarbamoylthio, thiocarbamoylthio, 1,3 - dimethylimidazoliothio, 2 - dimethyl aminoethylthio, dimethylaminomethylthio, N - methylthiocarbamoylthio, N,N dimethylthiocarbamoylthio, 4 - methylpiperazin - 1 - ylthiocarbonylthio, 1,1 - dimethyl - 4 - piperaziniothiocarbonylthio, thiobenzoylthio, benzoylthio, thioacetylthio, acetylthio, pyrid - 2 - ylcarbonylthio, pyrid - 3 - ylcarbonylthio, pyrid - 4 - ylcarbonylthio, 1 - methyl - 3 - pyridiniocarbonylthio, phenylsulphonylthio, thiocyanato, thiosulphato, or thiouronium groups. Those compounds wherein R carries a positive charge, e.g. where R is 1 - methylpyridiniothio, may exist as betaines when R1 is carboxyl; when R1 is esterified carboxyl, anions will be present, as set out above. In general these compounds are preferred in the form of the free acids and their salts.

The esters according to the invention may be represented as compounds of formula (II) or (IIa) in which R1 is a group COOR12 where R12 represents an organic group which is conveniently derived from an alcohol (aliphatic or araliphatic), a phenol, a silanol or a stannanol. Such an alcohol, phenol, silanol or stannanol used to esterify the carboxyl group preferably contains not more than 24 carbon atoms.

Thus, the group R12 may represent a straight or branched unsubstituted or substituted alkyl or alkenyl group, preferably having from 1-8 carbon atoms, for example a methyl, ethyl, propyl or isopropyl, butyl, sec-butyl, tert-butyl or allyl group, desirable substituents being for example, alkoxy e.g. methoxy; halogen i.e.

fluorine, chlorine, bromine or iodine' cyano; acyloxy, e.g. alkanoyloxy, such as acetoxy or pivaloyloxy, or alkoxycarbonyloxy, such as ethoxycarbonyloxy; acyl e.g.

p-bromobenzoyl and alkoxycarbonyl e.g. ethoxycarbonyl; an aralkyl group having up to 20 carbon atoms especially an arylmethyl group e.g. a benzyl or substituted benzyl group, suitable substituents being either halo e.g.

chloro; nitro, e.g. o or p-nitro; cyano; alkoxy e.g. p-methoxy or alkyl e.g. p-methyl groups; a diphenylmethyl or triphenylmethyl group or a fur-2-ylmethyl, thien-2- ylmethyl or pyrid-4-ylmethyl group, the hetero-cyclic groups of which may also be substituted e.g. by a C14 alkyl group, preferably methyl; an aryl group having up to 12 carbon atoms e.g. a phenyl or substituted phenyl group, suitable substituents being either halo e.g. chloro; nitro, e.g. o or p-nitro; cyano; alkoxy e.g. p-methoxy or alkyl e.g. p-methyl groups; a cycloalkyl group containing not more than 12 carbon atoms e.g. adamantyl; a heterocyclic group containing not more than 12 carbon atoms, the hetero atom being, for example, oxygen, as in the tetrahydropyranyl or phthalidyl group; a stannyl group having up to 24 carbon atoms for example a stannyl group carrying three substituents which may be the same or different selected from alkyl, alkenyl, aryl, aralkyl, cycloalkyl, alkoxy, or aralkoxy groups. Such groups will include methyl, ethyl, propyl, n-butyl, phenyl and benzyl groups; or a silyl group having up to 24 carbon atoms which may carry three groups which may be the same or different selected from alkyl, alkenyl, cycloalkyl, aralkyl and aryl groups. Such groups will preferably be C, 4 alkyl e.g. methyl, ethyl, npropyl, iso-propyl or t-butyl groups.

The compounds according to the invention generally exhibit p-lactamase inhibitory activity and are of use in the protection of p-lactam antibiotics susceptible to p-lactamase hydrolysis.

The acids, salts and metabolically labile esters of the invention in general also show antibiotic activity against gram-positive organisms and in some cases against gram-negative organisms. The term "salts" in this context includes carboxylate salts where R1 is carboxyl (including internal salts, i.e. betaines, when R or Ra carries a basic group) as well as quaternary ammonium salts and acid addition salts of compounds in which Rd, R or Ra carries a group -NH2 or ~NR4R5 when R1 is esterified carboxyl. Where the 3-carboxylate ester is metabolically labile, the parent acid will be generated in vivo. Examples of such esters include the phthalidyl esters and acyloxymethyl esters, e.g. the alkanoyloxymethyl esters such as the acetoxymethyl and pivaloyloxymethyl esters, and the a-alkoxycarbonyloxyalkyl esters such as l-ethoxycarbonyloxyethyl esters.

The compounds according to the invention for which we have demonstrated antibiotic activity have been active against gram-positive micro-organisms, for example, against strains of Staphylococcus aureus, and also against strains of certain gram-negative organisms such as Haemophilus influenzae. Certain of the compounds, namely those wherein R or Ra in formulae (II) or (lea) represent a methylthio, ethylthio, acetylthio, 5 - methyl - 1,3,4 - thiadiazol - 2 - ylthio, 1 - oxidopyrid -2 - ylthio, 1 - oxido - pyrid .4 - ylthio, ethylsulphinyl, 1 - methyl 4 - pyridiniothio, 2 - hydroxyethylthio, 2 - aminoethylthio, a methylsulphinyl, methylsulphonyl or a carbamoylthio, thiocarbamoylthio, N methylthiocarbamoylthio, 1 - methyl - 3 - pyridiniothio, cyanomethylthio or carboxymethylsulphonyl group and R1 represents a salt of the carboxyl group, have been shown to be active against gram-negative organisms including strains of Escherichia coli, Salmonella typhimurium, Shigella sonnei, Enterobacter cloacae, Klebsiella aerogenes, Proteus mirabilis, Proteus morgan ii, Proteus vulgaris, Serratia marcescens and Pro viden cia species.

The new acids and their salts and esters are stable to the action of p-lactamases produced by gram-positive organisms, for example those produced by Staphylococcus aureus, and to p-lactamases produced by gram-negative organisms.

As indicated above, the new acids and their salts and esters generally also possess the ability to inhibit p-lactamase enzymes for example those produced by gram-positive organisms e.g. those produced by strains of Staphylococcus aureus and enzymes from gram-negative bacteria produced, for example, by strains of Proteus mirabilis, Escherichia coil, Proteus organic, Klebsiella aerogenes, Salmonella typhimurium, Haemophilus influenzae and Neisseria gonorrhoeae. The compounds in which R or Ra is an unsubstituted thiouronium group (betaine form), or a thiobenzoylthio or methylsulphinyl group (sodium salt form) are particularly valuable in inhibiting the p-lactamase from Enterobacter cloacae P99.

Certain of the compounds of the invention, including those compounds of formula (II) or (via) wherein R3 is a carboxyl group and R or Ra represents a pyrid 2 - ylthio, methylthio, ethylthio, 5 - methyl - 1,3,4 - thiadiazol - 2 - ylthio or phenylthio group and salts thereof, are also absorbed when administered orally as shown by studies in mice. Such compounds are of interest for use in conjunction with both injectible and orally absorbed p-lactam antibiotics which show susceptibility to p-lactamases from gram-positive and/or gram-negative organisms.

The new antibiotic acids and their physiologically acceptable salts and metabolically labile esters may be used alone or in conjunction with a p-lactam antibiotic, preferably a broad spectrum p-lactam antibiotic, which may be of a type conventionally administered by the oral or parenteral route. Use of the antibiotic acids and their physiologically acceptable salts is especially preferred.

Examples of orally absorbed broad spectrum B-lactam antibiotics include cephalexin, cephaloglycin, ampicillin and amoxycillin and their orally absorbed esters e.g. the acyloxymethyl and phthalidyl esters, and the orally absorbed esters of carbenicillin and ticarcillin e.g. the indanyl and phenyl esters. Broad spectrum p- lactam antibiotics which are not orally absorbed include carbenicillin, ticarcillin, cephalothin, cephaloridine, cefazolin, cephacetrile and cephapirin. Examples of narrow spectrum p-lactam antibiotics are penicillin G, penicillin V, mecillinam and pivmecillinam. The above antibiotics may also be in the form of their metabolically labile esters, pharmaceutically acceptable salts and/or solvates thereof.

Combinations of the active compounds according to the invention with, for example, ampicillin generally show synergistic activity against p-lactamase producing strains of Staphylococcus aureus. Those compounds which show activity against gram-negative micro-organisms have, when in combination with p- lactamase susceptible p-lactam antibiotics, e.g. penicillins or cephlosporins, generally shown synergistic activity against p-lactamase producing strains of Escherichia coli, Klebsiella aerogenes, Proteus mirabilis, Salmonella trphimurium, Shigella sonnet Proteus morgan ii, and Proteus vulgar is.

The active compounds of the invention may be of use, either alone or in combination with a further p-lactam antibiotic, in treating a variety of diseases of humans and animals caused by pathogenic bacteria, such as respiratory tract or urinary tract infections.

Where the 3-carboxylic ester grouping of a compound of formula (II) or (lea) is readily cleaved, e.g. by hydrolysis or reduction, without significant degradation of the remainder of the molecule, such esters are especially useful as carboxyl protected derivatives of the parent acids. Certain 3-carboxylate esters may be of use either in the purification of characterisation of the acids according to the invention or as carboxyl-protected intermediates for use in preparing further derivatives.

Esters which serve particularly well as carboxyl-protected intermediates and which are primarily of use in this connection include the arylmethyl esters as detailed above, especially the benzyl, p-nitrobenzyl, benzhydryl and trityl esters, as well as stannyl e.g. tri - n - butylstannyl esters.

Especially preferred compounds of formula (II) or (lea) on account of their activity are those where R or Ra represents methylthio, ethylthio, 2 hydroxyethylthio, 1 - methyl - 4 - pyridiniothio, 1 - methyl - 2 - pyridiniothio, 1 - methyl - 3 - pyridiniothio, methylsulphinyl, methylsulphonyl, ethylsulphinyl, 2 aminoethylthio or cyanomethylthio groups and R1 represents a carboxyl group and salts thereof.

According to a further feature of the invention we provide pharmaceutical compositions (including veterinary compositions) containing at least one of the acids, physiologically acceptable salts or metabolically labile esters of a compound of formula (II) according to the invention. In view of the protective action described above, the compositions can advantageously contain further p-lactam antibiotics, orally absorbed p-lactam antibiotics being especially preferred when the compound according to the invention is also orally absorbed. the compositions may normally also contain a pharmaceutical (including veterinary) carrier or excipient.

The compositions may, for example, take the form of powders, tablets, capsules, lozenges, solutions and syrups suitable for oral administration, and may include, for example, starch, lactose, talc, magnesium stearate, gelatin, distilled water and suspending, dispersing, emulsifying, flavouring or colouring agents.

The active compounds may further be formulated in rectal compositions such as suppositories or retention enemas.

The active compounds of the invention may be formulated for injection. The compounds may thus be formulated in ampoules for reconstitution before use, optionally together with a further b-lactam antibiotic.

In general, the weight ratio of the new antibiotic or a salt or ester thereof to the p-lactam antibiotic to be protected will be in the range 10:1 to 1:10, more preferably 5:1 to 1:5, especially 2:1 to 1:2.

The active compounds of the invention will generally be administered at a total daily dosage level of 50 mg to 20 g, preferably from 100 mg to 10 g, which may be in divided doses given from 1-4 times per day. Where the composition contains a further p-lactam antibiotic, the total quantity of p-lactam antibiotic will desirably be from 100 mg to 20 g, which may be given in divided doses from 1--4 times a day.

Dosage units will in general contain 12.5 mg to 5 g, preferably 50 mg to 1 g., of active compound according to the invention when used alone and 25 mg to 5 g, preferably 100 mg to 1 g, of total p-lactam antibiotic where a further antibiotic is present.

According to a further feature of the invention, we provide a process for the preparation of a compound of the formula (IId)

wherein Rd and R1 are as defined above which comprises reacting a compound of formula (Ill)

(wherein X is a readily displaceable atom or group and R1 represents an esterified carboxyl group as defined above), with a sulphur nucleophile e.g. a compound of the formula RdH where Rd has the above meaning, or a salt thereof, if required in the presence of an acid binding agent, said reaction being followed, if necessary, where a free acid is required, by cleavage of an esterified carboxyl group R1 and, where a salt is required, by salt formation.

It will be appreciated that the definition of the compound RdH includes compounds RH and RaH, R and R" being as defined above, and so references hereinafter to Rd will also apply to R and Ra where relevant.

The readily displaceable substituent X in the compound of formula (III) may for example, be a halogen (e.g. chlorine, bromine or iodine) atom or an acyloxy group, such as an aliphatic, aromatic or araliphatic carbonyloxy or sulphonyloxy group, containing for example, 1--20 carbon atoms. The aliphatic or aromatic grouping of such a sulphonyloxy group may for example be an alkyl (e.g. C1 8) group, which may be substituted by a halogen atom e.g. fluorine or chlorine, or an aryl (e.g. C6,1) group which may carry alkyl, e.g. methyl, alkoxy e.g. methoxy or halogen e.g. bromine substituents. The aliphatic or aromatic grouping of such a carbonyloxy group may be, for example, an alkyl group (e.g. C, 8) preferably substituted by one or more

In order to prepare a disulphide of formula (II), the thiol may be subjected to mild oxidation e.g. using iodine. In the acid or salt form the thiol may also be oxidised to the disulphide by atmospheric oxygen.

Where the compound RdH is an acid, i.e. of the formula R3 . C=Y. SH or R2 . SO2H, the preferred reagent is a salt thereof, e.g. an alkali metal salt such as a sodium, potassium or lithium salt or an ammonium or substituted ammonium salt.

Where RdH is a thiol, it may be reacted as a salt. Where the reagent RdH which is added is not in salt form, a suitable agent should be present to bind the liberated acid HX e.g. an inorganic base such as an alkali metal carbonate; an organic base such as an alkali metal alkoxide e.g. sodium or potassium t-butoxide, a tertiary nitrogen base such as a trialkylamine, e.g. triethylamine or a heterocyclic base such as pyridine or collidine. Where RdH is a thiol, the presence of a silver salt such as silver nitrate may be advantageous in assisting removal of the substituent X, particularly where this is halogen.

Where Rd is to be a group

the said compound of formula (III) will be reacted with a thiourea of the formula

similarly where Rd is to be a group R2S where R2 is an aromatic heterocyclic group, the reagent of formula R2SH may exist in the tautomeric form as a thione, for example as in the case of pyrid - 4 - thione which reacts to give a pyrid - 4 - ylthio derivative. Where Rd is to be a group -SCN-, S2O2M or . SO2R1 , the said compound of formula (III) will be reacted with an appropriate thiocyanate, thiosulphate or thiosulphonate salt, e.g. an alkali metal salt such as a sodium or potassium salt, or an amine salt. The reaction is preferably effected in a polar solvent e.g. a substituted amide solvent such as dimethylformamide or dimethylacetamide, a nitrile solvent such as acetonitrile, or a sulphoxide such as dimethylsulphoxide. Other solvents which may be used, for example, include esters e.g. ethyl acetate, ethers e.g. tetrahydrofuran, ketones, e.g. acetone and chlorinated hydrocarbons e.g. methylene chloride.

Of value in the preparation of compounds of formula (II) (wherein Rd represents an alkylthio, substituted alkylthio or acylthio group) is the reaction of a compound of formula (II) wherein Rd represents an -SH group with an alkylating or acylating agent. This reaction is especially useful in the preparation of compounds of formula (II) wherein Rd represents an alkylthio or substituted alkylthio group. R1 in this reaction is preferably an esterified carboxyl group. The term "alkylating agents" is used herein also to include reagents serving to introduce substituted alkyl groups such as hydroxyalkyl, azidoalkyl, aminoalkyl, substituted aminoalkyl, cyanoalkyl, alkoxyalkyl and aralkyl groups as well as cycloalkyl groups or heterocyclic groups. Suitable alkylating agents include alkyl halides e.g. methyl or ethyl iodide, or benzyl bromide, or alkyl sulphates e.g.

dimethyl sulphate; these reagents are reacted in the presence of a base. Also useful for introduction of substituted alkyl groups are oxiranes, aziridines, alkyl or substituted alkyl vinyl ethers, e.g. ethyl vinyl ether, as well as cyclic vinyl ethers such as dihydropyran, or alkylenedialkyl ammonium salts such as methylenedimethylammonium iodide.

Suitable acylating agents include compounds of the formula R3 . C=Y. E where E is a readily eliminatable substituent e.g. halogen or acyloxy and R3 and Y are as defined above. This reaction is desirably carried out in the presence of an acid binding agent e.g. pyridine.

Those alkylation reactions requiring a base, e.g. those using halide or sulphate reagents, may be effected as a single liquid-phase or as a two liquid-phase reaction.

Suitable bases for use in the single liquid-phase reaction include alkali metal hydrides, alkoxides, dialkylamides, disilylamides, alkyls and aryls, e.g. sodium, potassium or lithium hydrides; sodium, potassium, or lithium alkoxides, or lithium dialkylamides, disilylamides, alkyls or aryls. In general, it is preferred to use as weak a base as possible which is effective in the reaction. The preferred bases are ones which are of low nucleophilicity under the conditions of the reaction.

The single phase reaction is preferably effected in an aprotic solvent. Such solvents include ethers, e.g. tetrahydrofuran, dioxan or 1,2 - dimethoxyethane; mixtures of ethers and amides (e.g. hexamethylphosphoramide or dimethylformamide), sulphoxides (e.g. dimethyl sulphoxide), or sulphones (e.g.

sulpholane). Single phase alkylation will desirably be effected at from -800C to +20"C, preferably at from -700C to OOC.

A preferred method of alkylation involves the use of a two phase system and a phase-transfer reagent. Preferred solvents are water together with a waterimmiscible solvent such as a halogenated hydrocarbon, e.g. chloroform or dichloromethane. Hydrocarbons such as benzene or toluene may be used in place of halogenated hydrocarbons. The phase-transfer reagent is normally a quaternary ammonium hydroxide, such as tetra - n - butylammoniumhydroxide. Alternatively a water-soluble base such as an alkali metal hydroxide, e.g. sodium or potassium hydroxide, or an alkaline earth metal, e.g. barium, hydroxide, together with a phase-transfer catalyst could be used. The thiol and the water-soluble base are preferably used in approximately stoichiometric ratio. Suitable phase-transfer catalysts include quaternary ammonium halides, sulphates and hydrosulphates and phosphonium salts. It is preferred that the quaternary ammonium or phosphonium cation is quite large, containing, e.g. at least 12 carbon atoms. Suitable catalysts include tetra - n - butylammonium chloride, benzyltriethylammonium bromide or methyltricaprylammonium chloride, or phosphonium salts such as benzyltriphenylphosphonium chloride or bromide. The two phase alkylation is, preferably effected in the temperature range15 to +500C, advantageously 0 to 35"C.

In another type of two phase reaction, the thiol may be reacted with the alkylating agent and a water-soluble base in a halogenated hydrocarbon system using a crown ether to effect phase transfer. A crown ether is a macrocyclic polyether, e.g. a number of ethyleneoxy units joined to form a ring, the internal diameter of the ring being approximately that of a particular metal ion, e.g. sodium or potassium, which is to be transferred across the phase boundary. In general 6 ethyleneoxy units (18-crown-6) are suitable to entrain a potassium ion while 5 ethyleneoxy units (15-crown-5) are suitable for sodium. The ethyleneoxy units may carry substituents e.g. phenyl or cyclohexyl groups. The two most preferred systems are water/dichloromethane with potassium hydroxide/dibenzo- or dicyclohexyl 18-crown-6 or potassium carbonate/18-crown-6. Alternatively when one or more of the reactants, for example the base, is not soluble in the solvent or solvents used in the reaction, the crown ether may be used to effect phase-transfer of the reactant or reactants from the solid phase to the liquid phase. Such solid/liquid phase transfer reactions may be conducted in a water-immiscible solvent as described above in the presence or absence of water as a co-solvent.

Thioethers according to the invention can also be prepared by reaction of an ester of the acid of formula (I) with a disulphide of the formula R2SSR2, where R2 has the above meaning, in the presence of a trivalent phosphorus compound. The trivalent phosphorus compound can be represented as PR13R14R'5 where R13 and R14, which may be the same or different, are hydrocarbyl, hydrocarbyloxy or hydrocarbylamino groups, e.g. alkyl, alkoxy or dialkylamino groups, the alkyl groups preferably having 1-6 carbon atoms such as methyl, ethyl, n-butyl or tbutyl; or aromatic groups, preferably monocyclic groups, such as phenyl, tolyl, phenoxy or tolyloxy groups or diarylamino groups; and R'5 is another group as defined for R'3 and R14 or a hydroxyl group. Particular reagents of this type are the di- and tri-alkyl phosphites, or more preferably the tri-substituted phosphines; convenient reagents are tri-n-butyl, tri-n-octyl and triphenyl phosphines and trimethyl and triethyl phosphite. This reaction is also preferably effected in a polar solvent e.g. a substituted amide solvent such as dimethylformamide or dimethylacetamide, a nitrile solvent such as acetonitrile, or a sulphoxide such as dimethylsulphoxide. Other solvents which may be used, for example, include esters e.g. ethyl acetate, ethers e.g. tetrahydrofuran, ketones e.g. acetone and chlorinated hydrocarbons e.g. methylene chloride and preferably at reduced temperature e.g.

in the range -100 to +100C. This reaction is convenient for the production of aromatic thioethers.

Sulphones and sulphoxides according to the invention may be prepared from the corresponding thioethers by, for example, oxidation with peracids such as peracetic, monoperphthalic, m-chloroperbenzoic or metaperiodic acid. Where a sulphoxide is required oxidation is preferably effected at a temperature not greater than 10"C, and avoiding excess oxidising agent in order to minimise sulphone formation. Where sulphones are required, more peracid may be used.

According to a further feature of the invention we provide a process for the preparation of compounds of formula (lId) wherein Rd carries a secondary, tertiary or quaternary amino group or a tertiary or quaternary heterocyclic nitrogen atom whereby a compound of formula (lId) in which Rd carries a primary, secondary or tertiary amino group or a secondary or tertiary heterocyclic nitrogen atom is subjected to alkylation or aralkylation. In this process, R1 is most preferably an esterified carboxyl group. The reaction is preferably effected using an alkyl or aralkyl halide or a dialkyl sulphate and is conveniently carried out in a ketone solvent such as acetone or an ether solvent such as tetrahydrofuran. Thus, for example, a compound in which Rd is a pyrid - 4 - ylthio or 4 - methylpiperazin 1 - ylthiocarbonylthio group may be reacted with methyl iodide to give compound in which Rd is a 1 - methyl - 4 - pyridinothio or 1,1 - dimethyl - 4 piperaziniothiocarbonylthio group respectively.

Compounds of the invention of formula (lId) wherein Rd contains an azido group may be converted into compounds wherein Rd contains an amino group by reduction. Such reduction may be effected using the methods described below for the reductive cleavage of esters.

Introduction of the group Rd is in general effected on an ester of the acid of formula (III) and where an acid product or salt is required, the ester should subsequently be cleaved. Such esters will generally be esters derived from an alcohol, phenol or stannanol.

For such de-esterification, a stannyl ester may be cleaved by mild solvolysis e.g. by reaction with water, alcohols, phenols or carboxylic acids, e.g. acetic acid.

Alternatively, esters which are subject to facile reduction, for example, arylmethyl esters such as benzyl, benzhydryl, trityl or more preferably, p-nitrobenzyl esters can be cleaved by reduction e.g. hydrogenolysis, for example using a metal catalyst, e.g.

a noble metal such as platinum, palladium or rhodium. the catalyst may be supported e.g. on charcoal or kieselguhr. In the case of p-nitrobenzyl esters, cleavage may be effected by reduction of the nitro group (e.g. using a dissolving metal reducing agent such as zinc in acetic acid or zinc in aqueous tetrahydrofuran or acetone controlled in the pH range 3-6, preferably 4--5.5 by the addition of aqueous HCI; aluminium amalgam in a moist ether, e.g. tetrahydrofuran; or iron and ammonium chloride in an aqueous ether such as aqueous tetrahydrofuran) followed by hydrolysis either under the reduction conditions or by subsequent treatment with acid.

It should be noted that such reductive techniques, e.g. dissolving metals such as zinc in acetic acid or zinc in hydrochloric acid, when applied to esters of the disulphide compound of the invention may cleave both the ester and disulphide bonds to yield the thiol of formula (lid) (Rd=SH) in the free acid form. Reductive cleavage of the ester grouping of a thiol ester will also give the thiol in free acid form. The latter acid may, if desired, be re-oxidised to the more stable disulphide in the free acid form and if desired re-esterified to introduce a different ester grouping. Esterification may be effected by the methods described hereinafter for the esterification of the compound of formula (I). If the latter ester grouping is not cleaved by reduction conditions serving to reduce disulphide to thiol, the disulphide diester can be reduced to the corresponding thiol ester; in this way it is possible to exchange an ester of the thiol which is cleavable by reduction for a different ester grouping which is stable to reduction.

Where it is desired to produce a salt of the compound of formula (lId), an acid initially formed in solution in an appropriate organic solvent may be reacted with an appropriate base, preferably under conditions favouring precipitation of the salt. In the formation of alkali metal salts for example, e.g. sodium salts, an alkanoate is a preferred base e.g. a 2-ethyl hexanoate. Salts may be formed either at the carboxyl group attached to the ring, or any carboxyl group which may be present in Rd.

Compounds of formula (III) in which X is halogen may be obtained by reaction of an ester of a compound of formula (I) with a halogenating agent such as a thionyl halide or with a sulphonylating agent, e.g. a mesylating or tosylating agent, in the presence of halide ions. Compounds of formula (III) in which X is an acyloxy group may be prepared by reacting an ester of a compound of formula (I) with an appropriate acylating agent, e.g. an acyl halide or anhydride. It may be convenient to react the compound of formula III with the sulphur nucleophile without prior isolation.

In the preparation of compounds of formula (lid) some of the corresponding E-isomers may be formed and if desired isolated.

Esters of the compound of formula (I) which may be employed to prepare the compounds of formula (III) may be prepared from the acid or salt of formula (I) by reaction with an alcohol, phenol or stannanol or a reactive derivative thereof to form the desired ester. Reaction will desirably be effected under mild conditions in order to prevent rupture of the bicyclic nucleus. The use of neutral or mild acidic or basic conditions therefore, at temperatures between -70 C and +35"C is preferred.

The alkyl, alkoxyalkyl and aralkyl esters may be prepared by reaction of the acid of formula (I) with the appropriate diazoalkane or diazoaralkane e.g.

diazomethane or diphenyldiazomethane. The reaction will generally be effected in an ether, ester or a halohydrocarbon solvent, e.g. diethyl ether, ethyl acetate or dichloromethane. In general, reduced temperatures are preferred, for example, -15" to +150C.

The esters derived from alcohols may also be produced by reaction of a reactive derivative of the alcohol, for example, a halide such as the chloride, bromide or iodide, or a hydrocarbonylsulphonyl derivative such as a mesyl or tosyl ester, with a salt of the acid of formula (I), e.g. an alkali or alkaline earth metal salt such as a lithium, sodium, potassium, calcium or barium salt or an amine salt, such as a triethylammonium salt. This reaction is preferably carried out in a substituted sulphoxide or amide solvent e.g. dimethyl sulphoxide, dimethylformamide or hexamethylphosphoramide or alternatively, the esters may be prepared by reaction of the acid with the alcohol in the presence of a condensing agent such as dicyclohexylcarbodiimide.

Stannyl esters may conveniently be formed by reaction of the carboxylic acid of formula (I) or a salt thereof with reactive tetravalent tin moieties. Trialkyl tin oxides are preferred for the synthesis of tin compounds in view of their availability and low toxicity.

Esters of formula (lid) may also be prepared by the above esterification procedures.

Silyl esters of the compounds of formula (II) may be formed by reaction of a carboxylic acid of formula (lId) with a reactive tetravalent silicon moiety.

Trialkylsilyl halides and mono- or bis-silylated acetamides are preferred as silylating agents. Proton acceptors e.g. weak bases such as pyridine may often be used with advantage when hydrogen halides are formed during such esterification.

The invention will now be more particularly described in the following nonlimiting Examples.

In the Examples and Preparations which follow, starting materials, reagents and products which occur frequently have been abbreviated for simplicity. Thus, lithium (3R,5R,Z) - 2 - (2 - hydroxyethylidene) - clavam - 3 - carboxylate=LHC; 4 - nitrobenzyl (3R,5R,Z) - 2 - (2 - chloroethylidene)clavam - 3 carboxylate=PCC; 4 - nitrobenzyl (3R,5R,Z) - 2 - (2 - .bromoethylidene) - clavam - 3 - carboxylate=PBC; 4 - nitrobenzyl (3R,5R,Z) - 2 - (2 mercaptoethylidene)clavam - 3 - carboxylate=PMC; 4 - nitrobenzyl (3R,5R,Z) 2 - (2 - hydroxyethylidene)clavam - 3 - carboxylate=PHC; N,N dimethylformamide=DMF; diethyl ether=DE; water=W; ethyl acetate=EA, petroleum ether (b.p. 40-600)=PE; dimethylsulphoxide=DMSO; dichloromethane=DC; acetonitrile=AN; tetrahydrofuran=THF; acetone=AC; ethanol=ET; sodium 2 - ethylhexanoate=SEH; toluene=T; thin layer chromatography=TLC.

Melting points were determined in open capillaries on a Mettler automatic apparatus. All temperatures are in "C.

Preparation 1 4-Nitrobenzyl-(3R,5R,Z)-2-(2-hydroxyethylidene)-clavam- 3-carboxylate A mixture of LHC (10 g.) prepared as described in OLS 2,604,697, 4nitrobenzyl bromide (9.5 g) and hexamethylphosporamide (65 ml) was stirred for 18 hr. at room temperature. The suspension was then partitioned between EA (800 ml.) and 50 /n saturated aqueous NaCI solution (800 ml). the organic layer was separated, washed successively with W, 0.5 M aqueous NaHCO3 solution and W, dried and concentrated to a slurry and the crystals collected to give the title ester (8.39 g) m.p. 117.20 AmTX 264 nm (E 11,000), L'max (CHBr3) 1781 (Cm-t (p-lactam), T (CDCI3) values include 4.30 (d, J 2 Hz, C-S H), 4.61 (s, benzylic protons), 5.09 (t, J, 7 Hz,=CH-) and 5.78 (d, J, 7 Hz, -CH2OH).

Preparation 2 4-Nitrobenzyl-(3R,5R,Z)-2-(2-chloroethylidene)-clavam 3-carboxylate A solution of PHC (1.0 g.) in EA (20 ml) containing pyridine (0.32 ml) was cooled to -600, stirred and treated with a solution of thionyl chloride (0.26 ml) in DE (2.0 ml). The mixture was warmed to -10 and stirred for a further 10 min. at -10 to 0 and then diluted with DE (250 ml). The mixture was washed successively with 0.5 N aqueous HCl, W, saturated aqueous NaHCO3 solution (until the washings were colourless) and W. The DE layer was dried and concentrated to give a slurry of needles which were collected by filtration, washed with DE and dried to give the chloro ester (320 mg.), [ID+30 (c 0.49, DMSO) Amtx 264 nm (E 10,550), smax (CHBr3) 1800 CmP (p-lactam), T (CDCl3) values include 4.25 (d, J 2 Hz, C-S H), 5.08 (t, J 8 Hz, =CH-), 5.82 (d, d J, 8 Hz, CH2CI).

Preparation 3 Diphenylmethyl (3R,5R,Z)-2-(2-hydroxyethylidene)-clavam- 3-carboxylate To a suspension of LHC (3.075 g.) in EA (150 ml) and brine (20 ml) was added 2 N HCl (25 ml). The mixture was quickly shaken and the organic layer separated.

The aqueous layer was extracted once with EA (35 ml). The combined organic extracts were dried (MgSO4) and concentrated in vacuo at below 20 to ca. 30 ml.

To this stirred solution was added dropwise a concentrated solution of diphenyldiazomethane (1.94 g.) in DC (4 ml). The resulting solution was concentrated in vacuo to an oil, which was chromatographed on a column of silica gel and eluted with DE-PE (1:1) followed by DE. The appropriate fractions were combined and the solvent evaporated to yield the title ester as a crystalline solid (3.033 g.) m.p. 82.90 (from DE). vmax (Nujol) 1800 cm-t (p-lactam), ("Nujol" is a Registered Trade Mark), T (CDCI3) values 3.08 (s, -CH(C6H5)2), 4.30 (d, J 3 Hz, C5 H), 4.86 (s C-3 H), 5.14 (t, J 6 Hz=CH--), 5.82 (d, J 6 Hz, -CH2OH), 8.48 (s, -OH).

Preparation 4 Benzyl (3R,5 R,Z)-2-(2-hydroxyethylidene)clavam-3-carboxylate A mixture of LHC (10.25 g) and benzyl bromide (8.55 g) in hexamethylphosphoramide (50 ml) was stirred at room temperature for 22 hrs. The mixture was then diluted with EA (11.) and washed successively with 50 /n saturated brine, W (2x), 5 M NaHCO3 and brine (3x). The organic layer was dried (Na2SO4) and concentrated in vacuo to an oil, which was chromatographed on a column of silica gel (150 g) and eluted with chloroform followed by EA. The appropriate fractions were combined and concentrated in vacuo to yield the title ester (8.8 g) as an oil, Vmax (CHBr3) 1786 cm-t (p-lactam), T (CDCI3) values include 4.38 (d, J, 3 Hz, C-S H), 4.85 (s, CH2Ph), 4.95 (s, C-3 H), 5.16 (t, J 7 Hz,=CH), 5.85 (d J 7 Hz, -CH2OH), 8.29 (s, -CH2OH).

Preparation 5 4-Nitrobenzyl (3R,5R,Z)-2-(2-bromoethylidene)-clavam 3-carboxylate A stirred solution of PHC (10.0 g) in a mixture of THF (40 ml), EA (40 ml), DE (50 ml) and pyridine (4.0 ml), cooled to 600 under nitrogen was treated with a solution of thionyl bromide (3.7 ml) in DE (25 ml). After a rapid rise in temperature to 250, the resulting suspension was cooled to -40 and stirred at this temperature for 10 minutes. The mixture was then poured into a mixture of DE (2 litres) and W (1.5 litres) and, after thorough agitation, a white solid which floated in the aqueous layer was collected by filtration, washed with DE, and dried in vacuo over P205 to afford the title ester as a microcrystalline solid (5.9 g.), #max (Nujol) 1792 cm- (- lactam). This sample contained a small amount of the corresponding E-isomer ( < 10 /n) as indicated by reaction with 4-mercaptopyridine followed by TLC analysis of the isomeric 4-nitrobenzyl (3R,5R) - 2 - [2 - (pyrid - 4 ylthio)ethylidene]clavam - 3 - carboxylates.

The organic layer was washed successively with W (2x), aqueous pH 7 buffer (2x) and brine and then dried (Na2SO4), filtered, and concentrated under reduced pressure to give a slurry of crystalline solid. The solid was collected by filtration, washed with DE, and dried in vacuo to afford a second crop of the title ester (3.0 g), Vmax (Nujol) 1790 cm-' (p-lactam). This sample contained the corresponding Eisomer (ca. 25 /n) as indicated by reaction with 4-mercaptopyridine followed by n.m.r. analysis of the isomeric 4-nitrobenzyl (3R,5R)- 2 - [2 - (pyrid - 4 ylthio)ethylidene]clavam - 3 - carboxylates.

Example 1 4-Nitrobenzyl (3R,5R,Z)-2-(2-acetylthioethylidene)clavam- 3-carboxylate A solution of PCC (2.50 g) in dry DMF (60 ml) was stirred and treated with thioacetic acid (0.605 ml) followed by triethylamine (0.98 ml). The mixture was stirred at room temperature for 1 hour and then partitioned between EA and W.

The EA layer was washed with W, saturated aqueous NaHCO2 solution (x2) and W, and then dried over sodium sulphate and evaporated to leave an oil.

Trituration of the oil with DE gave a crystalline solid which was collected by filtration, washed with DE, and then dried in vacuo to give the title ester (1.25 g) m.p. 86.60, [&alpha;]D+8.7 (c 1.04, DMSO), imtax 236, 264 nm (E 11,890, 11,030), Vmax (Nujol) 1782 cm-l (p-lactam), T (CDCl3) values include 4.29 (d, J 2 Hz, =CH-), 4.91 (s, C-3 H), 5.24 (t, J 8 Hz, =CH-), 6.42 (d, J 8 Hz,-CH2-S-) and 7.70 (s, -S. COCH3).

Example 2 4-Nitrobenzyl (3R,5R,Z)-2-(2-phenylthioethylidene)clavam- 3-carboxylate PCC (0.900 g) was added to a stirred solution of thiophenol (0.39 ml) and triethylamine (0.35 ml) in DMF (13 ml). The temperature was kept between 20 and 25". After 2 minutes, the resulting suspension was diluted with DE (ca. 500 ml) and washed with 0.2 M aqueous HCL, W (x2), saturated aqueous NaHCO2 solution, and W. The DE solution was dried and evaporated to leave an oil which was chromatographed on silica gel eluting with DE-PE (2:1) to afford the title ester as an oil (0.695 g), [&alpha;]D+6 , (c 0.98, DMSO), AmtaX 257.5 nm (e 14,370), Vmax (CHBr3) 1798 cm-' (p-lactam), T (CDCI3) values include 4.42 (d, J 2 Hz, C-S H), 4.95 (s, C-3 H), 5.23 (t, J 7 Hz, =CH-) and 6.40 (d, J 7 Hz, -CH2-S-).

Example 3 4-Nitrobenzyl (3R,5R,Z)-2-(2-thioacetylthioethylidene)-clavam- 3-carboxylate PCC (0.500 g) was added to a stirred solution of dithioacetic acid (0.144 g) and triethylamine (0.196 ml) in DMF (15 ml). The mixture was stirred for 0.5 hr at room temperature and then diluted with EA (50 ml) and washed with W (x2), saturated aqueous NaHCO2, and W. The EA layer was then dried and evaporated to give the title ester as an oil (0.52 g), AmtaX 264 nm, 305 nm (E 9,900, 12,450), Vmax (CHBr3) 1800 cm-' (p-lactam), T (CDCl3) values include 4.25 (d, J 2 Hz, C-S H), 4.88 (s, C-3 H), 5.16 (t, J 8 Hz, =CH-), 6.08 (d, J 8 Hz, CH2-S) and 7.18 (s, -CH2).

Example 4 4-Nitrobenzyl (3R,5R,Z)-2-[2-(pyrid-2-ylcarbonylthi ester as a microcrystalline solid (1.16 g), m.p. 129.10, AmETax 265 nm (E 11,000), may (Nujol) 1790 cm-l (p-lactam), T (DMSO-d6) values include 4.27 (d, J 2 Hz, C-S H), 4.88 (s, C-3 H), 5.17 (t, J, 8 Hz, =CH-) and 6.40 (d, J 8 Hz, CH2-S). An analytical sample (crystallised from EA-DE) had m.p. 143.9 Example 6 4-Nitrobenzyl (3R,5R,Z)-2-[2-(pyrid-3-ylcarbonylthio)ethylidene]- clavam-3-carboxylate Reaction of PCC (3.00 g) with pyridine - 3 - thiocarboxylic acid (1.18 g) and triethylamine (1.18 ml) in DMF (60 ml) at 200 for 15 minutes followed by workup as in Example 4 gave the title ester as a crystalline solid (3.31 g), Amtx 270 nm (E 18,100), vmax (Nujol) 1788 cm-l (p-lactam), T (DMSO-d6) values include 4.18 (d, J 2 Hz, C-S H), 4.51 (s, C-3 H), 5.12 (t, J 8 Hz, -CH=) and 6.18 (d, J 8 Hz, CH2-S).

Example 7 4-Nitrobenzyl (3 R, 5 R,Z)-2-[2-( 1-methyl- 1,2,3 ,4-tetrazol-5-ylthio) ethylidene]clavam-3-carboxylate 5 - Mercapto - I - methyl - 1,2,3,4 - tetrazole (0.877 g) was dissolved in a solution of potassium t-butoxide (0.753 g) in dry DMSO (ca. 25 ml) and the resulting solution made up to 50 ml with DMSO. A portion of this solution (42 ml) was added dropwise with stirring over 10 minutes to a partial solution of PCC (2.00 g) in DMSO (30 ml) at 20 . The resulting solution was kept at 20 for 7 minutes, and then partitioned between EA and W. The EA layer was separated, washed successively with W (x3), saturated aqueous NaHCO3 and W, and then dried and evaporated. The residue was chromatographed on silica gel eluting with DE and then with EA-DE (1:9) to afford the title ester as a foam (1.695 g), AmTX 260 nm (E 4,900), Vmax (CHBr3) 1792 cm (p-lactam), T (CDCl2) values include 4.24 (d, J 2 Hz, C-S H), 4.86 (s, C-3 H), 4.96 (t, J 8 Hz, -CH=) and 6.04 (s, N-CH2).

Example 8 4-Nitrobenzyl (3 R,5 R,Z)-3-[2-(5-methyl- 1 ,3,4-thiadiazol- 2-ylthio)ethylidene] clavam-3-carboxylate The reaction of PCC (1.30 g) with the potassium salt of 2 - mercapto - 5 methyl - 1,3,4 - thiazole in DMSO using the procedure described in Example 7 gave the title ester as a gum (0.291 g), AmaTX (266 nm (E 6,680), vmax (CHBr3) 1798 cm-l (plactam), T (CDCI3) values include 4.25 (d, J 2 Hz, C-S H), 4.84 (s, C-3 H), 4.96 (t, J 7 Hz, CH-) and 7.25 (s, Me).

Example 9 4-Nitrobenzyl (3 R,5 R,Z)-2-[2-(2,3-dihydro-4-methyl-3-oxo- 1,2,4- triazol-5-ylthio)ethylidene] clavam-3-carboxylate The reaction of PCC (2.40 g) with the potassium salt of 5 - mercapto - 2,3 dihydro - 4 - methyl - 3 - oxo - 1,2,4 - triazole in DMSO for 10 minutes at 200 using the procedure described in Example 7 gave the title ester as crystals from EA DE (2.05 g), [a]D+6.4 (c 0.78, DMSO), Amtx 260,263 nm (E 14,600, 14,700), vmax (Nujol) 1800 cm-' (p-lactam), T (CDCI3) values include 4.28 (d, J 2 Hz, C-S H), 4.84 (s, Cr3 H), 5.09 (t, J 8 Hz, --CH=), 6.28 (d, J 8 Hz, CH2-S) and 6.78 (s, N--CH,).

Example 10 4-Nitrobenzyl (3R,5R,Z)-2-l2(pyrid-4-ylthio)ethylidenelclavam- 3-carboxylate PBC (1.0 g) was added to a stirred solution of 4-mercaptopyridine (1.12 g) in DMF (20 ml) and pyridine (0.41 ml). The resulting solution was kept at 200 for 15 minutes and then partitioned between EA and W. The EA layer was separated, washed with W (3x), dried, treated with charcoal, and filtered through Kieselguhr.

The filtrate was evaporated to leave a viscous oil which was chromatographed on silica gel, eluting with EA. Appropriate fractions were combined and evaporated to leave the title ester as a gum (0.58 g), vmax (CHBr3) 1800 cm-' (p-lactam), T (CDCI3) values include 4.25 (d, J 3 Hz, C-S H), 4.90 (s, C-3 H), 5.26 (t, J 7 Hz, =CH).

Example 11 4-Nitrobenzyl (3 R,5 R,Z)-2- [2-(4-nitrobenzyloxycarbonyl- methylthio)ethylidene] clavam-3-carboxylate To a stirred solution of 4-nitrobenzyl mercaptoacetate (1.672 g) in DMF (50 ml) containing triethylamine (0.757 g) was added PCC (2.6 g). The resulting solution was stirred for 5 minutes at room temperature, diluted with DE (850 ml) and washed successively with W, 0.1 M HCI, pH 7 buffer solution and finally with W and dried (MgSO4) and concentrated in vacuo to yield an oil. The oil was chromatographed on a column of silica gel and eluted with DE. The appropriate fractions were combined and concentrated in vacuo to yield the title ester as an oil (2 g) Vmax 1802 cm-l (ss-lactam), #(CDCl3) values include 4.32 (d, J 3 Hz, C-S H), 4.91 (s, C-3 H), 5.26 (t, J 8 Hz, =CH), 6.76 (s, -SCH2CO-2).

Example 12 4-Nitrobenzyl (3R,5R,Z)-2-[2-(4-nitrophenyl)thioethylidene]clavam- 3-carboxylate To a solution of DMF (12 ml) containing 4-nitrothiophenol (790 mg) and pyridine (505 mg.) was added PBC (1.98 g). After stirring at room temperature for 2 minutes and then in an ice-bath for another 5 minutes, the solution was diluted with DE (I litre) and washed with 0.1 M HCl, W (2x), dried (MgSO4) and concentrated in vacuo to yield the title ester as a foam (2.2 g) may (CHBr3), 1802 cm-l (p-lactam), T (CDCl3) values include 4.24 (d, J 3 Hz, C-S H), 4.88 (s, C-3 H), 5.23 (t, J 8 Hz, =CH), 6.26 (dd, J 4 and 8 Hz, -CH2S).

Example 13 4-Nitrobenzyl (3R,5R,Z)-2-(2-methoxycarbonylmethylthio ethylidene)clavam-3-carboxylate The reaction between PCC (353 mg) and methyl mercaptoacetate (0.1 ml) in DMF (5 ml) containing triethylamine (0.14 ml) for 5 min. at ambient temperature gave, after work-up as described in Example 11, the title ester (442 mg); #max (CHBr3) 1800 cm-1 (p-lactam), T values (CDCl3) include 4.23 (d, J 2 Hz, C-S H), 4.80 (s, C-3 H), 5.17 (t, J 7 Hz, =CH-), 6.23 (s, -OCH3), 6.58 (d, J 7 Hz, =C-CH2-S) and 6.78 (s, -SCH2CO).

Example 14 (3R,SR,Z)-4-[2-(3{4-Nitrobenzoyloxycarbonylclavam-2- ylidene)-ethylthio]pyridine I-oxide PBC (1.50 g) was added to a stirred mixture of 4-mercaptopyridine oxide (0.72 g), DC (20 ml) and triethylamine (0.53 ml) at 20 . The resulting solution was kept at 20C for 10 minutes and then diluted with DC (500 ml) and washed successively with W, saturated aqueous NaHCO3 and W. The solution was then dried and evaporated to leave the title ester as a foam (1.54 g), AmETxx 302.5 nm (E 19,100), #max (CHBr3) 1800 cm-l (p-lactam), T (DMSO-d6) values include, 1.89, 2.73 (ABq, J 7 Hz, pyridine ring protons), 4.17 (d, J 2 Hz, C-S H), 4.51 (s, C-3 H), 5.21 (t, J 8 Hz, =CH--), and 6.21 (d, J 8 Hz, -CH2-S).

Example 15 4-Nitrobenzyl (3R,5R,Z)-2-[2-(5-amino-1,3,4-thiadiazol- 2-ylthio)-ethylidene] clavam-3-carboxylate Reaction of PBC (3.81 g) with 5 - amino - 2 - mercapto - 1,3,4 - thiadiazole (2.53 g) and pyridine (1.61 ml) in DMF (60 ml) at 20C followed by work-up and chromatography as in Example 10 gave the title ester (1.29 g), ,,ax (CHBr) 1798 cm-l (p-lactam), T (CDCl3) values include 4.34 (d, J 3 Hz, C-S H), 4.88 (s, C-3 H), 5.08 (t, J 8 Hz, =CH-), 6.14-6.30 (m, S-CH2-).

Example 16 4-Nitrobenzyl (3R,5R,Z)-2-(2-phenylsulphonylethylidene)- clavam-3-carboxylate A mixture of PCC (1.095 g), sodium benzenesulphinate (0.512 g) and dry DMF (25 ml) was stirred at room temperature for 40 minutes and then partitioned between DE and W. The DE layer was washed with W (3x) and then filtered to collect a crystalline solid which had separated. The solid was dissolved in EA and the solution, after drying (Na2SO4), was concentrated to give a slurry of colourless crystals which were collected by filtration, washed with DE and dried in vacuo to afford the title ester (0.351 g), m.p. 165.4, [&alpha;]D+38 (c, 1.01, DMSO), AmETxx 266, 271.5 nm ( 13,840, 13,800), Vmax (CHBr3) 1796 cm-l (p-lactam), T (CDCl3) values include 4.64 (d, J 2 Hz, C-S H), 5.20 (t, J 7 Hz, =CH-) and 6.12 (d, J 7 Hz, -C)I2-SO2).

Example 17 4-Nitrobenzyl (3R,5R,Z)-2-(2-benzoylthioethylidene)clavam- 3-carboxylate Sodium thiobenzoate (0.908 g) was added to a solution of PCC (2.00 g) in dry DMF (25 ml) and the mixture stirred at room temperature for 2.5 hours, and then partitioned between EA and W. The EA layer was washed with W, dried, charcoaled and concentrated to ca. 10 ml. A crystalline solid which separated was triturated with PE-DE (1:1) and then collected by filtration, washed with DE and dried in vacuo to give the title ester (1.86 g), m.p. 111.30 la]-260 (c, 1.07, DMSO), #maxET 238.5, 265.5 nm (E 15,820, 15,680), small (Nujol) 1800 cm-l (ss-lactam), T (CDCl3) values include 4.24 (d, 2 Hz, C-S H), 4.85 (s, C-3 H), 5.12 (t, 3 7 Hz, =CH-), and 6.24 (d, 7 Hz, -CH2-S-).

Example 18 4-Nitrobenzyl (3 R,5R,Z)-2-(2-N,N-dimethylthiocarbamoylthio- ethylidene)clavam-3-carboxylate Sodium dimethyldithiocarbamate (0.716 g) was reacted with a solution of PCC (1.764 g) in dry DMF (20 ml) at room temperature for 0.5 hour as described in Example 17 to afford the title ester (0.900 g) [&alpha;]D-4.6 (c, 1.1, DMSO), Vmax (Nujol) 1794 cm-l (plactam), T (CDCl3) values include 4.30 (d, 52 Hz, C-S H), 4.90 (s, C-3 H), 6.02 (d, J 8 Hz, -CH2-S-), 6.48, 6.67 (broad s's, NMe's).

Example 19 4-Nitrobenzyl (3R,5R,Z)-2-(2-thiobenzoylthioethylidene)- clavam-3-carboxylate A mixture of PCC (1.00 g), sodium dithiobenzoate (0.549 g) and DMF (14 ml) was stirred at 1018 for 10 min. and then diluted with DE (500 ml) and washed successively with W (x3), saturated aqueous NaHCO3, and W. The DE solution was dried and concentrated to give a slurry of a solid which was collected by filtration, washed with PE, and dried in vacuo to afford the title ester (1.23 g), AmtaX (285 nm (E 19,400), Vmxx (Nujol) 1798 cm-1 (ss-lactam), # (CDCl3) values include 2.02.3 and 2.5-2.9 (m's, -Ph), 4.28 (d, J 2 Hz, C-S H), 4.88 (s, C-3 H), 5.08 (t, J 7 Hz, =CH--), and 5.90 (d, J 7 Hz, -CH2-S).

Example 20 4-Nitrobenzyl (3R,5R,Z)-2-(2-thiocarbamoylthioethylidene)- clavam-3-carboxylate A mixture of PCC (1.50 g), ammonium dithiocarbamate (0.515 g) and DMF (21 ml) was stirred at 200 for 7 mins. and then diluted with EA (600 ml) and washed with W (x4). The EA solution was dried and evaporated to leave the title ester as a foam (1.88 g) #maxET 246, 274 nm ( 4,350, 4,660) Vmax (CHBr3) 1796 cm-l (p-lactam), T (CDCI3) values include 4.26 (d, J 2 Hz, C-S H), 4.88 (s, C-3 H), 5.08 (t, J 8 Hz, =CH-), and 6.09 (d, J 8 Hz, -CH 2-S-).

Example 21 4-Nitrobenzyl (3 R,5R,Z)-2-(2-ethoxythiocarbonylthioethylidene)- clavam-3-carboxylate A mixture of PCC (2.00 g), potassium ethylxanthate (1.00 g) and DMF (30 ml) was stirred at room temperature for 0.5 hr and then partitioned between EA and W.

The EA layer was washed with W (x3), dried and concentrated to a small volume.

The residue was triturated with DE to give a solid which was collected by filtration, washed with DE and dried in vacuo to afford the title ester (2.15 g), m.p. 84.1 [&alpha;]D-16 (c, 0.95, DMSO), #maxET 277 nm (E 17,300), small (Nujol) 1792 cm 1 (ss- lactam), T (CDCl3) values include 4.28 (d, J 2 Hz, C-S H), 4.89 (s, C-3 H), 5.11 (t, J 8 Hz, =CH-), 5.36 (q, J 7 Hz, O-CH2-CH,i), 6.17 (d, J 8 Hz, -CH2-S), 8.60 (t, J, 7 Hz, O-CH2-CH3).

Example 22 4-Nitrobenzyl (3R,5R,Z)-2-[2-(4-methylpiperazin- 1- ylthiocarbonylthio)ethylidene] clavam-3-carboxylate The reaction of sodium 4 - methylpiperazin - 1 - yldithio - carboxylate (0.828 g) with PCC (1.50 g) in DMF (30 ml) for 7 minutes at 200 followed by work-up as in Example 4 gave the title ester as a foam (2.074 g), #maxET 276 nm (E 18,100), Vmax 1802 cm-l (ss-lactam), T (CDCl3) values include 4.21 (d, J 2 Hz, C-S H), 4.80 (s, C-3 H), 4.94 (t, J 8 Hz, -CH=), and 7.64 (s, N-Me).

Example 23 4-Nitrobenzyl (3R,5R,Z)-2-[2-(N-methylthiocarbamoyl)- thioethylidene]clavam-3-carboxylate The reaction of methylammonium N-methyldithiocarbamate (0.584 g) with PCC (1.5 g) in DMF (30 ml) at 20 for 30 minutes followed by work-up as in Example 4 gave the title ester as a foam (1.97 g), #maxET 254.5, 268.5 nm (18,500, 18,300), Vmax (Nu jol) 1798 cm-l (p-lactam), t (CDCl3) values include 4.28 (d, J 3 Hz, C-S H), 4.78 (s, C-3 H), 5.08 (t, J 8 Hz, -CH=), 6.04 (d, J 8 Hz, CH2-S) and 6.76 (d, J 5 Hz, N-CH3).

Example 24 4-Nitrobenzyl (3 R,5 R,Z)-2-(2-thiocyanatoethylidene)clavam- 3-carboxylate The reaction of PCC (1.0 g) with potassium thiocyanate (0.303 g) in DMF (20 ml) for 15 minutes at 200 gave the title ester as crystals from EA-DE (0.804 g), [a]D+14.3 (c 1.05, DMSO), AmTaX 267 nm (E 12,000), Vmax (Nujol) 2158 (SCN), 1792 cm-l (p-lactam), T (CDCl3) values include 4.18 (d, J 3 Hz, C-S H), 4.76 (s, C-3 H), 5.05 (t, J 8 Hz, -CH=) and 6.22 (d, J 8 Hz, CH2-S).

Example 25 4-Nitrobenzyl (3R,SR,Z)-2-[2-(phenylsulphonylthio)ethylidene]- clavam-3-carboxylate A solution of sodium benzenethiosulphonate (0.816 g) and PCC (1.466 g) in DMF (50 ml) was stirred at room temperature for 1.5 hr., then worked up as described in Example 11 to give, after chromatography on silica gel and elution with DE, the title ester (0.179 g) as an oil; T values (CDCl3) include 2.10, 2.40 (m, SO2Ph), 4.29 (d, J, 2 Hz, C-S H), 4.97 (s, C-3 H), 5.24 (t, J 7 Hz, -CH=), and 6.24 (d, J 7 Hz, -CH2-S-).

Example 26 4-Nitrobenzyl (3R,SR,Z)-2-(2-phenylthioethylidene)clavam- 3-carboxylate A solution of PHC (167 mg) in dry DMF (0.5 ml), was cooled to 00, stirred, and treated dropwise with a solution of tri-n-butylphosphine (121 mg) and diphenyl disulphide (131 mg) in DMF (0.5 ml). After stirring for 0.5 hour at 00, the mixture was diluted with DE and washed three times with W. Examination of the DE solution by TLC showed that the major product had an R, identical to that of the product of Example 2.

Example 27 4-Nitrobenzyl (3 R,5 R,Z)-2-[2-(pyrid-2-ylthio)ethylidene] - clavam-3-carboxylate A solution of PHC (2.34 g) in dry DMF (7.0 ml) was cooled to 00, stirred, and treated dropwise over 20 minutes with a solution of tri-n-butylphosphine (3.39 g) and di-(2-pyridyl) disulphide (4.78 g) in DMF (14 ml). After stirring for 50 minutes at 0 , the mixture was diluted with DE (ca. 600 ml), and washed with W (4x). The DE solution was then dried and evaporated to leave an oil which was chromatographed on silica gel eluting with DE-PE (2:1) to afford a mixture of di-(2pyridyl) disulphide and the title ester (2.00 g), t (CDCI3) values include 4.28 (d, J 2 Hz, C-S H), 5.04 (t, J 7 Hz, =CH-), and 6.12 (d, J 7 Hz, -CH -S). The sample contained ca. 66 /n by weight of di-(2-pyridyl) disulphide as determined by integration of the n.m.r. spectrum.

Example 28 4-Nitrobenzyl (3R,5R,Z)-2-(2-methylthioethylidene)clavam- 3-carboxylate A suspension of PCC (2.12 g) in a 38 /n w/w solution of methanethiol in AN (70 ml) was stirred at room temperature and treated with a 1.0 M solution of pyridine in AN (6.6 ml) followed by finely powdered silver nitrate (4.08 g). The mixture was stirred rapidly at room temperature for 2.25 hours, and then filtered through Kieselguhr. The filtrate was diluted to ca 800 ml with EA and washed with W (3x), 0.5 N aqueous HCI, and finally W (2x).

The solution was then dried and evaporated to leave an oil which was chromatographed on silica gel eluting with DE-PE (2:1) to give the title ester as an oil (0.457 g), ArnETax 262 nm ( 9.140), Vrnax (CHBr3) 1798 cm-' (plactam), T (CDCl3) values include 4.30 (d, J 2 Hz, C-S H), 4.84 (s, C-3 H), 5.25 (t, J 7 Hz, =CH-), 6.80 (d, J 7 Hz, -CH2-S-) and 8.00 (s, S-Me).

Example 29 4-Nitrobenzyl (3 R,5 R,Z)-2-(2-ethylthioethylidene)clavam- 3-carboxylate PCC (4.00 g) was reacted with ethanethiol in AN for 55 minutes using the procedure described in Example 28 to yield title ester as a gum (0.497 g), #maxET 263.5 nm (E 10,300), Vrnxx (CHBr3) 1794 cm-l (p-lactam), T (CDCl3) values include 4.33 (d.

J 2 Hz, C-S H), 4.88 (s, C-3 H), 5.26 (t, J 8 Hz, -CH=) and 8.79 (t, J 7 Hz, -CH3).

Example 30 4-Nitrobenzyl (3 R,5 R,Z)-2-(2-methylsulphinylethylidene)clavam- 3-carboxylate A stirred and ice-cooled solution of 4-nitrobenzyl (3R,5R,Z)- 2 - (2 methylthioethylidene)clavam - 3 - carboxylate (1.092 g) in dry DC (35 ml) was treated with dropwise addition of a solution of m-chloroperbenzoic acid (516 mg) in DC (20 ml). After stirring at 0-5 C for 3 hrs and at room temperature for 2 hrs, the resulting solution was diluted with DC and washed with saturated aqueous NaHCO3 (x2), dried (MgSO4) and concentrated in vacuo to give a foam. This was chromatographed on a column of silica gel and eluted with EA followed by AC.

The appropriate fractions were combined and concentrated in vacuo to yield the title ester as a foam. (800 mg.) AmtaX 264 nm, Vmax (CHBr3) 1800(ss-lactam), 1038 cm-l (S- > O). T (CDCI3) values include 4.23 (d, J 3 Hz, C-S H), 4.75 (s, C-3 H), 5.12 (t, J 8 Hz, =CH), 6.44 (d, J 8 Hz, -CH2SOCH3) and two singlets at 7.48 and 7.52 for the methyl group indicating the presence of a 50:50 mixture of R,S sulphoxides.

Example 31 4-Nitrobenzyl (3R,5R,Z)-2-(2-methylsulphonylethylidene)- clavam-3-carboxylate To a stirred, ice-cooled solution of 4-nitrobenzyl (3R,5R,Z) - 2 - (2 methylthioethylidene)clavam - 3 - carboxylate (91 mg) in dry DC (5 ml) was added dropwise a solution of m-chloroperbenzoic acid (126 mg) in dry DC (5 ml). The resulting solution was stirred at 0-5 C for 2+ hours, diluted with DC, washed with saturated aqueous NaHCO3 (x2) and dried (MgSO4). Evaporation of the solvent yielded the title ester as a foam (96 mg). AmtaX 266 nm L'rnax 1802 cm-' (ss-lactam), t (CDCl3) values include 4.23 (d, J 3 Hz, C-S H), 4.7 (s, C-3 H), 5.15 (t, J 8 Hz, =CH), 6.18 (d, J 8 Hz, CH2SO2CH3), 7.2 (s, -CH2SO2CH3).

Example 32 4-Nitrobenzyl (3R,5R,Z)-2-(2-phenylsulphinylethylidene)- clavam-3-carboxylate The reaction of 4 - nitrobenzyl (3R,5R,Z) - 2 - (2 phenylthioethylidene)clavam - 3 - carboxylate(1.917g)with m-chlorobenzoic acid (774 mg) and work up was carried out as described in Example 30. This afforded the title ester as a foam as a 50:50 mixture of R,S sulphoxides, Amtx 255 nm; t'rnax (Nujol) 1800 (p-lactam), 1040 cm-' (S- > O), T (CDCl3) values include 2.48 (s, phenyl) 4.49 to 4.56 (dd, i 3-Hz, C-5 H), 4.9 (s, C-3 H), 5.15 to 5.5 (m, =CH), 6.1 to 6.5 (m, -CH2SOPh).

Example 33 4-Nitrobenzyl (3 R,5R,Z)-2-(2-ethylsulphinylethylidene) clavam-3-carboxylate The reaction of 4-nitrobenzyl (3R,5R,Z) - 2 - (2 ethylthioethylidene)clavam - 3 - carboxylate (1.85 g) in dry DC (40 ml) with mchloroperbenzoic acid (722 mg) in dry DC (15 ml) and work-up, was carried out as described in Example 30 to afford the title ester as a foam (736 mg) Vmax 1800 (A- lactam), 1040 cm-' (S- > O), t (CDCl3) values include 4.29 (d, J 3 Hz, C-S H), 4.81 (s, C-3 H), 5.16 (d, J 8 Hz, =CH), 6.51 (d, J 8 Hz, -CH2SOC2H5), 7.36 (m, SOCH2CH3), 8.73 (m, -SOCH2CH3).

Example 34 4-Nitrobenzyl (3R,5R,Z)-2-[2-(4-nitrobenzyloxy-carbonyl- methylsulphonyl)ethylidene] clavam-3-carboxylate The reaction of 4-nitrobenzyl (3R,SR,Z) - 2 - [2 - (4 nitrobenzyloxycarbonylmethylthio)ethylidene]clavam - 3 - carboxylate (3.8 g) in dry DC (40 ml) with m-chloroperbenzoic acid (3.61 g) in dry DC (40 ml) and the work-up was carried out as described in Example 31. Chromatography on a silica gel column and elution with EA:T (1:1) yielded the title ester as a foam (1.92 g) #maxET 266 nm (E' 407); Vmxx (CHBr3) 1802 cm (ss-lactam), T (CDCl3) values include 4.25 (d, J 3 Hz, C-S H), 4.70 and 4.72 (two singlets -CH2C6H4NO2), 4.84 (s, C-3 H), 5.19 (t, J 8 Hz, =CH), 5.98 (d, J 8 Hz, -CH2SO2), 6.05 (s, -SO2CH2).

Example 35 4-Nitrobenzyl (3R,5R,Z)-2-[2-(4-nitrophenyl)sulphonylethylidene]- clavam-3-carboxylate The oxidation of 4-nitrobenzyl (3R,5R,Z) - 2 - [2 - (4 nitrophenyl)thioethylidene]clavam - 3 - carboxylate (471 mg) with mchloroperbenzoic acid (519 mg) and the work-up was carried out as described in Example 31 to yield the title ester as a foam (491 mg), imHCx'3 258.5 nm (E' 331), t'ma,x (Nujol) 1800 cm-t (plactam), t values (CDCl3) include 4.56 (d, J 3 Hz, C-S H), 4.68 (s, -CH2C6H4NO2), 4.88 (s, C-3 H), 5.21 (t, J 8 Hz, =CH), 6.04 (d, J 8 Hz, -CH2SO,-).

Example 36 (3R,5R,Z)-1-Methyl-3-[2-(3-(4-nitrobenzyloxycarbonyl]clavam- 2-ylidene)ethylthio]carbonyl-pyridinium Iodide A solution of 4-nitrobenzyl (3R,5R,Z)- 2 - [2 - (pyrid - 3 ylcarbonylthio)ethylidene]clavam - 3 - carboxylate (2.50 g) in THF (20 ml) was stirred with a large excess of iodomethane for 24 hours. The resulting precipitated solid was collected by filtration, washed with DE, and dried in vacuo to afford the title salt (2.41 g), [&alpha;]D-6 (c, 1.04, DMSO), ArnETxx 266 nm (E 16,300), small (Nujol) 1788 cm-l (plactam), T (DMSO-d6) values include 4.16 (d, J 2 Hz, C-S H), 4.50 (s, C-3 H), 5.09 (t, 3 8 Hz, =CH-), 5.55 (s, N±CH3) and 6.07 (d, J 8 Hz, S-CH2-).

Example 37 (3R,5R,Z)-1,1-Dimethyl-4-[2-(3-{4-nitrobenzyloxycarbonyl}- clavam-2-ylidene)ethylthio]thiocarbonyl piperazinium Iodide Reaction of 4-nitrobenzyl (3R,5R,Z) - 2 - [2 - (4 - methylpiperazine - 1 thiocarbonylthio)ethylidene]clavam - 3 - carboxylate (3.049 g) with iodomethane (6 ml) in THF (30 ml) as in Example 36 and precipitation of the product from EA gave the title salt (1.265 g), #maxET 260, 294.5 nm (E 23,800, 19,800), #max (Nujol) 1798 cm-' (p-lactam) t (DMSO-d5) values include 4.15 (d, J 3 Hz, C-S H), 4.52 (s, C-3 H), 5.07 (t, J 8 Hz, -CH=) and 6.71 (s, =N+Me2).

Example 38 (3R,5R,Z)- 1-Methyl-4-[2-(3-14-nitrobenzyloxycarbon clavam-2-ylidene)ethylthio]pyridinium Iodide The reaction of 4-nitrobenzyl (3R,5R,Z) - 2 - [2 - (pyrid - 4 - ylthio) ethylidene]clavam - 3 - carboxylate (0.757 g) with iodomethane (3.1 ml) in AC (15.5 ml) for 16 hours at 200 as in Example 36 and precipitation of the product from DE gave the title salt (0.699 g), ArnETax 269,306, ID was added with stirring to DE (600 ml). A solid was formed, which was collected by filtration, washed with DE, and dried in vacuo to give the title salt (1.462 g), lal+S5 70 AmETX 243.5, 265, 290 nm (E 17,366, 9615, 6863), smax (Nujol) 1800 cm (plactam), T values (DMSO-d6) include 0.88 (s, NH2 =N+H2),-4.13-(d, J 3 Hz, C-S H), 4.42 (s, C-3 H), 5.09 (t, J 8 Hz, =CH-), 6.02 (d, J 8 Hz, CH2-S).

Example 41 4-Nitrobenzyl (3R,5R,Z)-2-(2-mercaptoethylidene)clavam 3-carboxylate PCC (2.094 g) was added to a stirred ice-cold mixture of 1.84 M aqueous sodium trithiocarbonate (3.95 ml) and DMF (25 ml) under nitrogen. After stirring for 2 mins, the reaction flask was immersed in a water bath at 200 and stirring continued for 12 mins. The resulting solution was poured into a rapidlv stirred mixture of EA (800 ml), W (600 ml) and 1 M aqueous HC1 (25 ml) under nitrogen.

The EA layer was separated, washed with W (x4j, dried and filtered, all operations being conducted under nitrogen. The filtrate was concentrated to give a slurry of crystals of volume ca, 5 ml. The slurry was diluted slowly with DE and the solid collected by filtration, washed with DE, and dried in vacuo to afford the title ester (1.073 g), m.p. 136.00,[a],+230 (c, 1.06, DMSO), Amax 262.5 nm (E 9,950), t'rnax (CHBr3) 1798 cm-' (p-lactam), T (CDCl3) values include 4.30 (d, J 2 Hz, C-S H), 4.88 (s, C-3 H), 5.16 (t, J 8 Hz, =CH-), 6.74 (t, J 7 Hz, -CH2-S), 8.42 (t, J 7 Hz, SH).

Example 42 4-Nitrobenzyl (3 R,5 R,Z)-2-(2-methylthioethylidene)clavam- 3-carboxylate A solution of PMC (1.044 g) and iodomethane (0.4 ml) in dry THF (25 ml) was cooled to 0 under nitrogen, stirred rapidly and treated with a 57% dispersion of sodium hydride in oil (127 mg). After 5 mins. the solution was diluted with EA (400 ml) and washed successively with 0.5 M aqueous HCl and W (x3), dried and evaporated to leave a viscous oil which was chromatographed on silica gel to afford the title ester as an oil (181 mg), AmtaX 262.5 nm (E 10,600), Vrnxx (CHBr3) 1798 cm-' (v5- lactam), T (CDCl3) values include 4.32 (d, J 2 Hz, C-S H), 4.86 (s, C-3 H), 5.27 (t, J 7 Hz, =CH-), 6.81 (d, J 7 Hz, -CH2-S) and 8.01 (s, S-Me).

Example 43 4-Nitrobenzyl (3 R,5 R,Z)-2-(2-methylthioethylidene)clavam- 3-carboxylate A solution of PMC (42 mg) in a 0.4 M DC solution of iodomethane (1.0 ml) was stirred rapidly under nitrogen at room temperature and treated with a 0.12 M aqueous solution of tetrabutyl-ammonium hydroxide (1.0 ml). Stirring was continued for 20 mins. and then the mixture was diluted with EA (50 ml) washed with W (3x), dried and evaporated to leave the title ester as an oil (44 mg) which had physical characteristics corresponding to those of the product of Example 42.

Example 44 4-Nitrobenzyl (3R,5R,Z)-2-(2-mercaptoethylidene)clavam 3-carboxylate A 1.00 M solution of triethylamine in DMF (1.50 ml) was diluted with DMF (3 ml) and saturated with hydrogen sulphide at 200. The solution was stirred under nitrogen and treated with carbon disulphide (0.1 ml), cooled to 0 and treated with PCC (250 mg). The mixture was stirred at 0 for 2 minutes and at 200 for 10 minutes and then poured into a rapidly stirred mixture of EA (100 ml), W (75 ml) and 1 N aqueous HCI (3.5 ml) under nitrogen. The EA layer was separated, washed with W, (x4), dried, and concentrated to a viscous oil which crystallised on standing. The crystals were triturated with EA-DE, washed with DE, and dried in vacuo to afford the title ester (85 mg), identical with the product of Example 41 by TLC and n.m.r. spectroscopy.

Example 45 4-Nitrobenzyl (3 R,5R,Z)-2-(2-mercaptoethylidene)clavam- 3-carboxylate PCC (353 mg) was added to a stirred solution of ammonium trithiocarbonate (158 mg) in DMF (4 ml) at 20O under nitrogen. The mixture was stirred at 200 for 10 minutes, and then poured into a rapidly stirred mixture of EA (100 ml), W (80 ml) and 1 N aqueous HCl (2 ml) under nitrogen. The EA layer was separated, washed with W (x4), dried, and evaporated to leave a foam (380 mg) which was crystallised from EA-DE to afford the title ester (141 mg), identical with the product of Example 41 by TLC and n.m.r. spectroscopy.

Example 46 4-Nitrobenzyl (3R,5R,Z)-2-(2-mercaptoethylidene)clavam 3-carboxylate A solution of 3-azabicyclo[3.2.2]nonane (0.710 g) in DMF (30 ml) was saturated with hydrogen sulphide at 200. The resulting suspension was cooled to 0 under hydrogen sulphide and treated with PCC (2.00 g). The mixture was stirred at 0 for 1 minute and at 200 for 5 minutes, and then diluted with EA (600 ml). The diluted solution was washed with 0.5 N aqueous HCI, W, aqueous pH 7 buffer and W, and then dried and concentrated to leave a viscous oil which crystallised. The crystals were collected, washed with EA-DE (1:1) and DE, and dried in vacuo to afford the title ester (0.735 g), identical with the product of Example 41 by TLC and n.m.r. spectroscopy.

Example 47 4-Nitrobenzyl (3R,5R,Z)-2-(2-ethylthioethylidene)clavam- 3-carboxylate A solution of PMC (114 mg) in DC (2.7 ml) containing iodoethane (0.08 ml) was stirred rapidly under nitrogen, and treated with 0.12 M aqueous tetrabutylammonium hydroxide (2.7 ml). After 15 minutes at 200, the mixture was partitioned between EA and W. The EA layer was washed with W (3x), dried and evaporated to leave the title ester as a gum (109 mg), T (CDCl3) values include 4.32 (d, J 2 Hz, C-S H), 4.88 (s, C-3 H), 5.26 (t, J 8 Hz, =CH), 6.74 (d, J 8 Hz, =CH- CH2-S-), 7.56 (q, J 7 Hz, S-CH2CH3), and 8.76 (t, J 7 Hz, S-CH2-CH).

Example 48 Di-1(3R,SR,Z)-2-[3-(4-nitrobenzyloxycarbonyl)clavam-2- ylidene]ethylldisulphide A solution of PMC (1.60 g) in a 0.2 M solution of pyridine in DC (27 ml) was stirred rapidly at 150 and treated dropwise with a 0.1 M solution of iodine in DC until a permanent yellow colouration was produced. The resulting suspension was filtered and the filtrate washed successively with 0.5 N aqueous HCI, W, and 1% aqueous sodium thiosulphate. The DC solution was then dried and evaporated to leave the title ester as a foam (1.62 g), AmTaX 262 nm (E 20,800), t'rnax (Nujol) 1798 cm-' (plactam), t (CDCI3) values include 4.32 (d, J 2 Hz, C-S H), 4.87 (s, C-3 H), 6.62 (d, J 8 Hz, S-CH2).

Example 49 4-Nitrobenzyl (3R,SR,Z)-2-[2-(2-hydroxyethylthio)ethylidenej- clavam-3-carboxylate A solution of PMC (114 mg) and 2-iodoethanol (168 mg) in DC (2.7 ml) was stirred under nitrogen at 200 and treated dropwise with 0.12 M aqueous tetrabutylammonium hydroxide (2.7 ml). The mixture was stirred for 15 minutes and then partitioned between EA and W. The EA layer was washed with W (4x), dried, and evaporated to leave a gum which was chromatographed on silica gel, eluting with DE and then EA-DE to afford the title ester (20 mg), Vmxx (CHBr3) 1800 cm-' (p-lactam), T (CDCl3) values include 4.30 (d, J 2 Hz, C-S H), 4.86 (s, C-3 H), 5.26 (t, J 8 Hz, -CH=), 6.31 (t, J 7 Hz, CH2OH), 6.76 (d, J 8 Hz, CH2-S), and 7.39 (t, J 7 Hz, S-CH2CH2OH).

Example 50 4-Nitrobenzyl (3R,5R,Z)-2-[2-(1-ethoxyethylthio)ethylidene]- clavam-3-carboxylate A solution of PMC (200 mg), ethyl vinyl ether (0.165 ml) and ptoluenesulphonic acid (10 mg) in THF (6 ml) was kept at 200 for 15 minutes and then diluted with EA (100 ml) was washed successively with W, saturated aqueous NaHCO3, and W. The EA solution was then dried and evaporated to leave the title ester as an oil (248 mg), AmTaX 264 nm (E 9,800) #max (CHBr3) 1800 cm-t (p-lactam), T (CDCI3) values include 4.34 (d, J 2 Hz, C-S H), 4.93 (s, C-3 H), 5.25 (t, J 8 Hz, =CH--), 5.38 (q, J 7 Hz, -S-CH(CH3O).

Example 51 (3R,5R,Z)-Dimethyl-[2-(3-{4-nitrobenzyloxycarbonyliclavam- 2-ylidene)ethyl]thiomethylammonium Iodide A solution of PMC (1.20 g) in DC (30 ml) was stirred under nitrogen at 200 and treated with dimethylmethylene-ammonium iodide (0.655 g). After 15 minutes the solvent was removed in vacuo to leave the title salt as a foam (1.93 g), AmTX 262.5 nm (E 9,900), Vmax (CHBr3) 1800 cm-' (p-lactam), T(DMSO-d6) values include 4.18 (d, J 2 Hz, C-S H), 4.52 (s, C-3 H), 5.16 (t, J 8 Hz, -CH=), 5.65 (s, S-CH2-N), and 7.16 (s, NMe2).

Example 52 4-Nitrobenzyl (3R,5R,Z)-2-[2-(2-azidoethylthio)ethylidene]- clavam-3-carboxylate A solution of PMC (42 mg) and 1 - azido - 2 - iodoethane (71 mg) in DC (1 ml) was stirred under nitrogen at 200 and treated dropwise with 0.12 M aqueous tetrabutyl-ammonium hydroxide (1.0 ml). The mixture was stirred for 15 minutes and then partitioned between EA and W. The EA layer was washed with W (x4), dried, charcoaled, filtered through Kieselguhr and evaporated to leave a gum (33 mg) which was chromatographed on silica gel eluting with PE and then DE-PE (3:1) to afford the title ester (11 mg), Vrnax (CHBr3) 1800 cm-t (p-lactam), T (CDCl3) values include 4.28 (d, J 2 Hz, C-S H), 4.85 (s, C-3 H), 5.26 (t, J 8 Hz, -CH=), 6.60 (d, J 8 Hz, -CH2-S), 6.64 (t, J 7 Hz, S-CH2Cll2N3) and 7.39 (t, 7 Hz, S-CH2-CH2N2).

Example 53 Diphenylmethyl (3R,5R,Z)-2-(2-thiocarbamoylthioethylidene)- clavam-3-carboxylate A stirred solution of diphenylmethyl (3R,5R,Z) - 2 - (2 hydroxyethylidene) - clavam - 3 - carboxylate (730 mg) and pyridine (237 mg) in dry THF (12 ml) was cooled to -35 to 40a and treated with a solution of thionyl chloride (238 mg) in DE (10 ml). The temperature of the reaction rose to -150 and was then raised to 00. The reaction mixture was stirred at this temperature for 10 minutes, and filtered to yield diphenylmethyl (3R,5R,Z) - 2 - (2 - chloroethylidene) clavam - 3 - carboxylate in the filtrate. Ammonium dithiocarbamate (220 mg) was added to the filtrate and the mixture stirred under nitrogen at room temperature for 5 minutes, then poured into DE (400 ml) and washed with W (2x) and pH 7 buffer solution. The organic layer was dried (MgSO4) and the solvent evaporated in vacuo to yield title ester as a crystalline solid (808 mg) Vrnax (CHBr3) 1800 cm (p lactam), T (CDCI3) values (Z-isomer) include 3.12 (s, -CH(C6H)2), 4.29 (d, J 3 Hz, C-S H), 4.84 (s, C-3 H), 5.07 (t, J 7 Hz, =CH-), 6.08 (d, J 7 Hz), -CH2-S-).

Additional closely associated resonances indicated the presence of the corresponding E-isomer (ca. 20).

Example 54 B enzyl (3R,5R,Z)-2-(2-thiocarbamoylthioethylidene)- clavam-3-carboxylate To a solution of benzyl (3R,5R,Z) - 2 - (2 - hydroxyethylidene) - clavam - 3 carboxylate (1.45 g) in dry THF (20 ml) containing 0.474 g of pyridine, cooled to -40 and stirred under nitrogen, was added thionyl chloride (0.708 g) in DE (15 ml).

The temperature of the reaction rose to -100C and this was adjusted to OOC. The mixture was stirred for 10 minutes then filtered to yield benzyl (3R,SR,Z) - 2 - (2 chloroethylidene)- clavam - 3 - carboxylate in the filtrate. Ammonium dithiocarbamate (0.550 g) was added to the filtrate and the reaction mixture was stirred in an ice-bath for 7 minutes, diluted with DE (750 ml) and washed with W and brine and dried (MgSO4), Evaporation of the solvent yielded a foam (1.677 g).

200 mg of the crude product was purifed by preparative TLC on silica gel plates using EA:PE (1:1) as eluant. The appropriate band was extracted with EA and the solvent evaporated to yield the title ester as an oil (62 mg), vm 1800 cm-' (B- lactam), t values (CDCI3) include 2.96 (s, -NH2), 4.27 (d, J 3 Hz, C-S H), 4.79 (s, CH2Ph), 4.86 (s, C-3 H), 5.08 (t, J 7 Hz, =CH), 6.09 (d, J 7 Hz, -CH2S-).

Additional closely associated resonances indicated the presence of the corresponding E-isomer (ca. 25 /").

Example 55 Sodium (3R,5R,Z)-2-(2-phenylsulphonylethylidene)- clavam-3-carboxylate A partial solution of 4-nitrobenzyl (3R,5R,Z) - 2 - (2 phenylsulphonylethylidene)clavam - 3 - carboxylate (0.681 g) in EA (70 ml) was stirred with a 10 /O palladium on carbon catalyst (0.70 g) under one atmosphere of hydrogen at room temperature. After 10 minutes, when hydrogen uptake had ceased, the suspension was degassed and filtered through Kieselguhr. The filtrate was concentrated in vacuo to ca. 20 ml. stirred, and treated with a 1.0 M solution of SEH in EA (1.3 ml). The resulting suspension was diluted with De (ca. 15 ml) and the precipitated solid collected by filtration, washed with DE and dried in vacuo to afford the title salt (0.306 g), [&alpha;]D+91 (c 0.444, DMSO), Vrnxx (Nujol) 1788 cm ( - lactam), T (D2O) values include 2.02.6 (m, pH-), 4.71 (d, J2 Hz, C-S H), 5.14 (s, C-3 H) and 5.91 (d, J 7 Hz, -CH2-SO2-).

Example 56 Sodium (3R,5R,Z)-2-(2-methylsulphinylethylidene)- clavam-3-carboxylate 4-Nitrobenzyl (3R,5R,Z)- 2 - (2 - methylsulphinylethylidene)clavam - 3 carboxylate (236 mg) dissolved in EA (20 ml) and ET (8 ml) was hydrogenated by shaking with hydrogen in the presence of 10% Pd C catalyst (354 mg). 50 ml of hydrogen was taken up in 17 minutes. The solution was filtered through a bed of Kieselguhr. To the filtrate was added dropwise a solution of SEH (83 mg) in EA (4 ml). The solution was concentrated to ca. 7 ml and diluted with dropwise addition of DE (150 ml). The precipitated solid was filtered, washed with EA and DE, and dried in vacuo to yield the title salt as an amorphous powder (102 mg), Vmxx 1788 cm-' (plactam), T (D2O) 4.28 (d, J, 3 Hz, C-S H), 5.0 (s, C-3 H), 5.24 (t, J 8 Hz, =CH), 6.36 (d, J 8 Hz, CH2 SO CH3), and two overlapping singlets at 7.43 for the methyl group indicating a 50:50 mixture of R,S sulphoxides.

Example 57 Sodium (3R,5R,Z)-2-(2-benzoylthioethylidene) clavam-3-carboxylate The hydrogenolysis of 4-nitrobenzyl (3R,5R,Z) - 2 - (2 benzoylthioethylidene)clavam - 3 - carboxylate (1.60 g) in EA (150 ml) containing a 10% Pd-C (3.2 g) and the precipitation of the sodium salt with SEH was carried out as described in Example 56 which afforded the title salt (0.60 g), [a]0+ 120 (c 1.00 DMSO), AmPHxGx 234.5, 270 nm (E 11,195, 8,430), #max (Nujol) 1782 cm-' (p-lactam), T (DMSO-d6) values include 2.02.8 (m, -Pb), 4.34 (d, J 2 Hz, C-S H), 5.30 (t, J 7 Hz, =CH--) and 5.45 (s, C-3 H).

Example 58 Sodium (3R,5R,Z)-2-(2-methylsulphonylethylidene)- clavam-3-carboxylate The hydrogenolysis of 4-nitrobenzyl (3R,5R,Z) - 2 - (2 methylsulphonylethylidene)clavam - 3 - carboxylate (792 mg) dissolved in EA (30 ml) containing 10% Pd-C (792 mg) and the precipitation of the sodium salt with SEH (288 mg) was carried out as described in Example 56, which afford the title salt as an amorphous powder (328 mg), Vmxx (Nujol) 1788 cm-' (plactam). T (D2O) values include 4.22 (d, J 4 Hz, C-S H), 4.92 (s, C-3 H), 5.19 (t, J 8 Hz, =CH), 6.0 (d, J 8 Hz, -CH2SO2), 7.0 (s, -CH2SO2CH2).

Example 59 Sodium (3R,5R,Z)-2-(2-phenylsulphinylethylidene)- clavam-3-carboxylate The hydrogenolysis of 4-nitrobenzyl (3R,5R,Z) - 2 - (2 phenylsulphinylethylidene)clavam - 3 - carboxylate (221 mg) dissolved in EA (5 ml) and ET (20 ml) containing 10% Pd-C (331 mg) and the work-up was carried out as described in Example 56, which affords the title salt as an amorphous solid (67 mg). Vrnxx (Nujol) 1780 cm-' (plactam), t (D2O) values include 2.36 (s, aromatic), 4.60 and 4.68 (br.d. C-S H), 5.15 (C-3 H and =CH), 6.15 (br.d, J 7 Hz, CH2SOPh).

Example 60 Sodium (3R,5R,Z)-2-(2-ethylsulphinylethylidene)- clavam-3-carboxylate The hydrogenolysis of 4-nitrobenzyl (3R,5R,Z) - 2 - (2 ethylsulphinylethylidene)clavam - 3 - carboxylate (788 mg) dissolved in EA (75 ml) and ET (50 ml) containing 10% Pd-C and the precipitation of the sodium salt with SEH (166 mg) was carried out as described in Example 56, to give the title salt as an amorphous solid (171 mg), Vmax (Nujol) 1790 cm-' (p-lactam), T (D2O) values include 4.23 (d, J 3 Hz, C-S H), 4.96 (s, C-3 H), 5.19 (t, J 8 Hz, =CH), 6.29 (d, J 8 Hz, CH2SOC2Hs), 7.0 to 7.3 (m, -SOCH2CH3), 8.72 (t, J 7 Hz, SOCH2CH3).

Example 61 Disodium (3R,5R,Z)-2-[2-(carboxymethylsulphonyl) ethylidene] clavam- 3-carboxylate The hydrogenolysis of 4-nitrobenzyl (3R,5R,Z) - 2 - [2 - (4 nitrobenzyloxycarbonylmethylsulphonyl)ethylideneiclavam - 3 - carboxylate (228 mg) dissolved in EA (12 ml) and ET (12 ml) containing 10% Pd-C (228 mg) and the precipitation of the sodium salt was carried out as described in Example 56. This afforded the title salt as an amorphous powder (61 mg), Vrnxx (Nujol) 1786 cm-' (p- lactam), T (D2O) values include 4.18 (d, J 3 Hz, C-S Hz), 4.9 (s, C-3 H), 5.13 (t, J 8 Hz, =CH), 5.8 (dd, J 8 Hz, -CH2SO2-), 5.96 (s, SO2CH2).

Example 62 Sodium (3R,5R,Z)-2-(2-phenylthioethylidene)clavam- 3-carboxylate A solution of 4-nitrobenzyl (3R,5R,Z)- 2 - (2 - phenylthioethylidene) clavam - 3 - carboxylate (0.829 g) in THF (24 ml) was diluted with 1 M aqueous NH4Cl solution (24 ml) and stirred rapidly with iron powder (3.16 g). After 20 minutes, a second portion of iron powder (3.16 g) was added, followed by 1 M aqueous NH4Cl solution (8 ml). After 50 minutes, the mixture was diluted with EA to ca. 600 ml and H2S gas was passed through it for 10 minutes with rapid stirring.

The resulting black suspension was filtered through Kieselguhr and the filter pad washed with W. The aqueous layer of the filtrate was saturated with NaCI and refiltered through Kieselguhr. The organic and aqueous layers were combined, acidified with 2 N aqueous HCl (6 ml) and immediately shaken. The EA layer was then separated dried (Na2SO4) and filtered through Kiesulguhr. The filtrate was extracted with pH 7 buffer (100 ml; 3x50 ml) and the combined extracts were saturated with NaCI, covered with EA, acidified with 2 N aquoeus HCI (6 ml) and immediately shaken. The EA layer was separated, dried, concentrated to ca. 10 ml and treated with a 1.02 M solution of SEH in EA (1.35 ml). The resulting solution was further concentrated to ca. 2 ml and then stirred and diluted slowly with DE to ca. 50 ml. An amorphous solid which separated was collected by filtration, washed with DE, and dried in vacuo to give the title salt (0.381 g), [a]D+47.5 (c, 0.96, W), Vrnax (Nujol) 1786 cm-' (p-lactam), T (D2O) values include 2.5-2.9 (rn-Pb), 4.53 (d, J 2 Hz, C-S H), 5.20 (s, C-3 H), 6.28 and 6.54 (AB quartet, J 16 Hz, -CH2S-).

* Example 63 Sodium (3R,5R,Z)-2-(2-acetylthioethylidene)clavam- 3-carboxylate 4-Nitrobenzyl (3R,5R,Z) - 2 - (2 - acetylthioethylidene)clavam - 3 carboxylate (0.800 g) was deprotected using the method described in Example 62 to give the title salt as a powder (0.300 g), [&alpha;]D+25 (c 0.50, W), Arnax 228 nm (E 8,850), #max (Nujol) 1782 cm-' ( -lactam), t (DMSO-d6) values include 4.39 (d, 52 Hz, C-S H), 5.45 (t, J 8 Hz, =CH-), 5.53 (s, C-3 H), 6.49 (d, J 8 Hz, -CH2-S) and 7.70 (s, SCOCH3).

Example 64 Sodium (3 R,5 R,Z)-2-(2-N,N-dimethylthiocarbamoylthio- ethylidene)-clavam-3-carboxylate 4-Nitrobenzyl (3R,5R,Z) - 2 - (2 - N,N dimethylthiocarbamoylthioethylidene)clavam - 3 - carboxylate (0.700 g) was deprotected using the method described in Example 62 to give the title salt (0.350 g), [a]000 (c 0.49, W), #maxpHS 253, 266.5 nm (10,300, 10,200) Vxxxx (Nujol) 1780 cm-' (/3- lactam), T (D,O) values include 4.26 (d, J 3 Hz, C-S H), 5.08 (s, C-3 H), 6.03 (d, J 8 Hz, -CH2S-), 6.52, 6.64 (broad s's, N-Me's).

Example 65 Sodium (3 R,5R,Z)-2-[2-(pyrid-2-ylthio)ethylidene] clavam- 3-carboxylate A solution of a 2:1 mixture of di-(2-pyridyl) disulphide and 4-nitrobenzyl (3R,5R,Z) - 2 - [2 - (pyrid - 2 - ylthio)ethylidene]clavam - 3 - carboxylate (1.95 g) was deprotected using the method described in Example 62 to give the title salt (0.300 g), [&alpha;]D+30 (c, 1.025, W), ArnPHaGx 224, 289 nm (E 9,870, 7,540, 3,930), #max (Nujol) 1798 cm-' ( -lactam), T (D2O) values include 1.63 (d, J 4 Hz, 6-pyridyl proton), 2.2-2.5 (m, 4-pyridyl proton), 2.64 (d, J 8 Hz, 3-pyridyl proton), 2.7-2.9 (m, 5-pyridyl proton), 4.36 (d, J 2 Hz, C-S H), and 5.13 (s, C-3 H).

Example 66 Sodium (3R,5R,Z)-2-(2-methylthioethylidene)clavam- 3-carboxylate 4-Nitrobenzyl (3R,5R,Z)- 2 - (2 - methylthioethylidene)clavam - 3 carboxylate (0.964 g) was deprotected using the method described in Example 62 to give the title salt as a powder (0.458 g), [a]0+ 160 (c, 0.99, W), VmaX (Nujol) 1786 cm-' (plactam), T (D2O) values include 4.30 (d, J 2 Hz, C-S H), 5.06 (s, C-3 H), 5.20 (t, J 8 Hz, =CH-), 6.76 (d, J 8 Hz, -CH2-S), and 7.97 (s, S-Me).

Example 67 Sodium (3R,5R,Z)-2-(2-thiobenzoylthioethylidene)clavam 3-carboxylate 4-Nitrobenzyl (3R,5R,Z)- 2 - (2 - thiobenzoylthioethylidene)clavam - 3 carboxylate (1.05 g) was deprotected using the method described in Example 62 to give the title salt as a powder (0.282 g), AmPHx 304 nm (E 9,620), #max (Nujol) 1782 cm-' (plactam), T (DMSO-d6) values include 2.0, 2.4 (m's, -Ph), 4.26 (d, J 2 Hz, C-S H), 5.16 (t, J 7 Hz, =CH-), 5.36 (s, C-3 H), and 5.92 (d, J 7 Hz, -CH2-S-).

Example 68 Sodium (3R,5R,Z)-2-(2-thiocarbamoylthioethylidene)- clavam-3-carboxylate 4-Nitrobenzyl (3R,5R,Z) - 2 - (2 - thiocarbamoylthioethylidene)clavam - 3 carboxylate (1.77 g) was deprotected using the method described in Example 62 to give the title salt as a powder (0.664 g), [&alpha;]D+14 (c, 0.93, W), #maxpHE279 nm (E 8,770), #max (Nujol) 1780 cm-1 (plactam), t (D2O) values include 4.21 (d, J 2 Hz, C-5H), 5.00 (s, C-3 H), 5.05 (t, J 8 Hz, =CH-), and 6.10 (d, J 8 Hz, CH2-S).

Example 69 Sodium (3R,5R,Z)-2-(2-ethoxythiocarbonylthioethylidene)- clavam-3-carboxylate 4 - Nitrobenzyl (3R,5R,Z) - 2 - (2 - ethoxythiocarbonyl thioethylidene)clavam - 3 - carboxylate (2.00 g) was deprotected using the method described in Example 62 to give the title salt as a powder (0.381 g), [a]0+60 (c, 0.98, W), #maxPH6 285 nm (E 9,250), #max (Nujol) 1782 cm ( -lactam) T (D2O) values include 4.28 (d, J 2 Hz, C-S H), 5.10 (s, C-3 H), 5.13 (t, J 8 Hz, =CH-), 6.16 (d, J 8 Hz, CH2-S), and 8.62 (t, J 7 Hz, O-CH2CH3).

Example 70 Sodium (3R,SR,Z)-2-(2-thioacetylthioethylidene)clavam- 3-carboxylate 4-Nitrobenzyl (3R,5R,Z)- 2 - (2 - thioacetylthioethylidene)clavam - 3 carboxylate (2.00 g) was deprotected using the method described in Example 62 to give the title salt (0.372 g), [&alpha;]D+17 (c, 0.81, W), AmPHx 308.5 nm ( 6,880), #max (Nujol) 1788 cm-' (plactam), T (D2O) values include 4.25 (d, 32Hz, C-S H), 5.10 (s, C-3 H), 6.05 (d, J 8 Hz, CH,-S), and 7.16 (s, -CH3).

Example 71 Sodium (3R,5R,Z)-2-[2-(5-methyl-1,3,4-thiadiazol-2- ylthio)-ethylidene]clavam-3-carboxylate 4-Nitrobenzyl (3R,5R,Z)- 2 - [2 - (5 - methyl - 1,3,4 - thiadiazol - 2 ylthio)ethylidene]clavam - 3 - carboxylate (1.14 g) was deprotected using the method described in Example 62 to give the title salt as a powder (0.284 g), [&alpha;]D+15 (c, 0.975, W), ID= afford the title salt (390 mg), [&alpha;]D+13.5 (c, 0.965, W), Vmax (Nujol) 1782 cm-' (ss- lactam), T (D2O) values include 4.28 (d, J 2 Hz, C-S H), 5.09 (s, C-3 H), 5.19 (t, J 8 Hz, -CH=), and 8.86 (t, J 7 Hz, CH3).

Example 73 Sodium (3R,5R,Z)-2-[2-(pyrid-2-ylcarbonylthio)ethylidene]- clavam-3-carboxylate 4-Nitrobenzyl (3R,5R,Z) - 2- [2 - (pyrid - 2 - ylcarbonylthio) ethylidene]clavam - 3 - carboxylate (1.50 g) was deprotected by the method described in Example 62 to afford the title salt (345 mg), [&alpha;]D+7 (c, 1.00, W), AmPHxOx 226.5, 277.5 nm (E 12,200, 6,710), Vmax 1782 cm1 (plactam), T (D2O) values include 4.23 (d, J 2 Hz, C-S H), 5.08 (s, C-3 H), 5.10 (t, J 8 Hz, -CH=), 6.26 (d, J 8 Hz, CH2-S).

Example 74 Sodium (3 R,5 R,Z)-2-(2-carbamoylthioethylidene)clavam- 3-carboxylate 4-Nitrobenzyl (3R,5R,Z) - 2 - (2 - carbamoylthioethylidene)clavam - 3 carboxylate (1.20 g) was deprotected by the method described in Example 62 to afford the title salt (0.54 g), [&alpha;]D+29 (c, 0.925; W), #max (Nujol) 1782 cm-' (ss- lactam), t (D2O) values include 4.24 (d, J 2 Hz), C-S H), 5.04 (s, C-3 H), 5.12 (t, J 7 Hz, =CH--), and 6.42 (d, J 7 Hz), -CII2S-).

Example 75 Sodium (3R,5R,Z)-2-[2-(N-methylthiocarbamoyl-thio- ethylidene]-clavam-3-carboxylate 4 - Nitrobenzyl (3R,5R,Z) - 2 - [2 - (N - methylthiocarbamoyl)thioethylidene]clavam - 3 - carboxylate (1.50 g), was deprotected by the method described in Example 62 to afford the title salt (0.365 g), [&alpha;]D-23.5 (c, 1.00, W), A PH8x 270.5 nm (E 8,550), Vrnax (Nujol) 1780 cm-' (plactam), T (D2O) values include 4.18 (d, J 3 Hz), (C-5 H), 5.00 (s, C-3 H), 5.05 (t, J 8 Hz, -CH=), 6.04 (d, J 8 Hz), CH2-S), 6.7-9 (s, N-CH3).

Example 76 Sodium (3 R,5 R,Z)-2-(2-methoxycarbonylmethylthioethylidene) clavam-3-carboxylate 4 - Nitrobenzyl (3R,5R,Z) - 2 - (2 - methoxycarbonyl methylthioethylidene)clavam - 3 - carboxylate (2.21 g) was deprotected as described in Example 62 to give the title salt (125 mg); [a]0+390 (c 0.93, W); #maxpH6 289 nm; #max (Nujol) 1788 cm-' (plactam), t values (D2O) include 4.24 (d, J 2 Hz, C-S H), 5.02 (s, C-3 H), 6.20 (s, OCH3), 6.60 (s, SCH2CO).

Example 77 (3 R, S R,Z)-2-[2-(4-Methylpiperazin- 1 -ylthiocarbonylthio)- ethylidene]clavam-3-carboxylic acid A solution of 4-nitrobenzyl (3R,5R,Z) - 2 - [2 - (4 - methylpiperazin - I ylthiocarbonylthio)ethylidene]clavam - 3 - carboxylate (0.996 g) in THF (20 ml) and W (20 ml) was stirred in an ice-bath. Zinc dust (1.35 g) was added in portions, keeping pH of the solution between 4.5 and 5.5 by the addition of 1 N aqueous HCI.

When reaction was complete (as indicated by a steady pH and failure to detect starting material by TLC) the solution was decanted from unreacted zinc, diluted with EA (100 ml) and water (50 ml), and saturated with H2S. The mixture was basified to pH 4 by the addition of 1 N aqueous NaOH, and then filtered through Kieselguhr. The aqueous layer of the filtrate was separated, washed with DE (200 ml) acidified to pH 6 by the addition of 1 N aqueous HCI, and freeze-dried to give an amorphous powder (0.92 g). The crude product was chromatographed on Amberlite XAD-2 resin (500 g) eluting with W and then with ET-W (3:7).

Appropriate fractions were combined, concentrated in vacuo and freeze-dried to afford the title acid (144 mg), AWmax 285 nm (E 10,400), #max (Nujol) 1784 cm-' (ss- lactam), T (DMSO-d6) values include 4.29 (C-5 H), 5.07 (C-3 H), 5.20 (-CH=), 6.14 (CH2S) 7.67 (N-Me).

Example 78 (3R,5R,Z)-2-[2-(1,1-Dimethyl-4-piperaziniothiocarbonylthio)- ethylidene]-clavam-3-carboxylate (3R,5R,Z) - 1,1 - Dimethyl - 4 - [2 - (3 - (4' - nitrobenzyloxycarbonyl) clavam - 2 - ylidene)ethylthio]thiocarbonylpiperazinium iodide (1.18 g) was deprotected in aqueous AC solution with zinc dust by the method described in Example 77 to afford the title betaine (315 mg), [&alpha;]D-13 (c 0.98, W), AWmxx 257, 276 nm (E 11,700, 10,700) #max(Nujol) 1774 cm-1(ss-lactam), T (DMSO-d6) values include 4.38 (C-5 H), 5.56, 6.40 (piperazine ring protons), 6.08 (CH2-S) and 6.76 (=N+Me).

Example 79 (3R,5R,Z)-2-[2-(1 -Methyl-4-pyridinio)thioethylidene] clavam-3-carboxylate (3R,5R,Z) - 1 - Methyl - 4 - [2 - (3 - (4 - nitrobenzyloxycarbonylclavaml 2 - ylidene)ethylthio]pyridinium iodide (1.20 g) was deprotected by the method described in Example 77 to afford the title betaine (188 mg), #max 1780 cm-' (ss- lactam), T (D2O) values include 1.62 2.27 (ABq, J 7 Hz, pyridine ring protons), 4.16 (d, J 3 Hz, C-S H), 5.07 (s, C-3 H), 5.13 (t, J 8 Hz, -CH=), and 5.79 (s, N±CH3).

Example 80 (3R,5R,Z)-2-[2-(1-Methyl-3-pyridiniocarbonylthio)- ethylidene]clavam-3-carboxylate (3R,5R,Z) - 1 - Methyl - 3 - [2 - (3 - 14 - nitrobenzyloxycarbonyl) clavam - 2 - ylidene)ethylthio]carbonyl - pyridinium iodide (2.20 g) was deprotected by the method described in Example 77 to afford the title betaine (242 mg), [a]0-240 (c 0.95, W), AmPHa6 224, 264.5 nm (E 15,100, 3,480), #max (Nujol) 1782 cm-1 (p-lactam), T (D2O) values include 0.61, 0.95, 1.76 (complex, pyridine ring protons), 4.20 (d, J 2 Hz, C-S H), 5.49 (s, N-CH3) and 6.01 (d, J 8 Hz, CII 2-S).

Example 81 (3R,5R,Z)-2-(2-amidinothioethylidene)clavam-3- carboxylic Acid (3R,5R,Z), - 2 - (2 - [3 - (4 - Nitrobenzyloxycarbonyl)clavam - 2 ylidene]ethylthiouronium bromide (1.3 g) was deprotected by the method described in Example 77 to afford the title acid as an amorphous powder (319 mg), L'rnax (Nujol) 1788 cm-' (plactam), T (DMSO-d6) values include 4.28 (d, J 2 Hz, C-S H), 5.28 (t, J 7 Hz, =CH-), 5.35 (s, C-3 H), 6.17 (d, J 7 Hz, -CH2S-).

Example 82 Sodium (3R,5R,Z)-2-[2-(1 -oxidopyridinio-4-thio)ethylidene]- clavam-3-carboxylate (3R,5R,Z)- 4 - [2 - (3 - (4 - Nitrobenzyloxycarbonyl}clavam - 2 ylidene)ethylthio]pyridine - 1 - oxide (1.43 g) was deprotected by the method described in Example 77 to afford the title salt (0.473 g), APH6 302.5 nm (E 16,270), #max (Nujol) 1782 cm-' (p-lactam), T (D2O) values include 1.92, 2.58 (ABq, J 6 Hz, aromatic protons) 4.27 (d, J 2 Hz, C-S H), 5.10 (s, C-3 H), 6.18 (d, J 8 Hz, CII 2-S).

Example 83 Sodium (3R,5R,Z)-2-(2-mercaptoethylidene)clavam 3-carboxylate' 4-Nitrobenzyl (3R,5R,Z) - 2- (2 - mercaptoethylidene)clavam - 3 carboxylate (1.35 g) was deprotected under nitrogen by the method described in Example 77 to afford the title salt (219 mg), Vrnax (Nujol) 1784 cm-' (plactam), (DMSO-d6) values include 4.32 (d, J 2 Hz, C-S H), 5.27 (t, J 8 Hz, =CH-), 5.43 (s, C-3 II).

Example 84 Disodium 2,2'-dithiodi-[(3R,SR,Z)-2-ethylideneclavam- 3-carboxylate] A solution of di-((3R,SR,Z) - 2 - [3 - (4 - nitrobenzyloxycarbonyl)clavam 2 - ylidene - ethyl}disulphide (1.545 g) in TIIF (40 ml) and W (20 ml) was stirred under nitrogen at 0 and treated with zinc dust (2.23 g) added in portions whilst maintaining the pH at 4.5 by addition of 2 N aqueous HCl. When reduction was complete, the solution was decanted and made up to ca. 350 ml with EA. The aqueous layer was saturated with NaCI, and the mixture stirred rapidly and treated with a 1% solution of iodine in EA until a permanent brown colouration was produced. The brown colouration was then discharged with 10% aqueous sodium thiosulphate and the mixture acidified with 1 N aqueous IICl (10 ml). The resulting suspension was filtered through keiselguhr and the organic layer of the filtrate separated, dried, and re-filtered. The filtrate was repeatedly extracted with portions (4x50 ml) of a 1% solution of ethylenediaminetetracetic acid disodium salt in aqueous pH 7 buffer to which saturated aqueous NaHCO3 had been added to a pH of 6.9. The combined aqueous extracts were covered with EA (400 ml), saturated with NaCI, stirred rapidly, and acidified with 2 N aqueous HC1 (ca. 15 ml). The EA layer was separated, dried, filtered, concentrated to ca. 50 ml and treated with a 1.0 M solution of SEH in EA (1.25 ml). The resulting precipitate was washed with DE and dried in vacuo over P205 to afford the title salt (0.27 g), Vrnxx (Nujol) 1784 cm-' (plactam), T (DMSO-d6) values include 4.37 (d, J 2 Hz, C-S H), 5.32 (t, J 8 Hz, =CH-), 5.41 (s, C-3 H), 6.50 (d, J 8 Hz, CH2-S).

Example 85 4-Nitrobenzyl (3R,5R)-2-(2-(pyrid-4-ylthio)ethylidene)- clavam-3-carboxylate A solution of 4-mercaptopyridine (133 mg) in DMF (3.0 ml) containing pyridine (47.5 mg) was added with stirring at room temperature to PBC (119 mg; a mixture of E- and Z-isomers obtained as the second crop in Preparation 5). The resulting solution was allowed to stand for 15 minutes, and then partitioned between EA and W. The EA layer was washed with W (3x), dried (Na2SO4), treated with charcoal, filtered through Kieselguhr and evaporated in vacuo to afford a mixture of Z- and E-isomers of title ester as a gum (130 mg), Vrnxx 1800 cm-' (A- lactam), T (CDCl3) values (Z-isomer) include 4.18 (d, J 3 Hz, C-S H), 5.19 (t, J 7 Hz, =CH), 6.24 (d, J 7 Hz, CH2-S). Additional closely associated resonances indicated the presence of the corresponding E-isomer (ca. 25 /"). TLC [silica gel, developed with EA-T(l:l)] showed two spots, Rf 0.5 and 0.4, of intensity ratio 1:3 respectively.

Example 86 4-Nitrobenzyl (3R,5R,Z)-2-(2-methylthioethylidene)- clavam-3-carboxylate PBC (2.8 g) was added to a stirred ice-cold 10% w/w solution of methanethiol in AN (110 ml), and the resulting solution treated immediately with pyridine (1.2 ml), and then finely powdered silver nitrate (5.5 g). The mixture was stirred rapidly at 0 for 25 minutes, and then filtered through Kieselguhr, washing the filter pad through with EA. The filtrate and washings were concentrated under reduced pressure to ca. 300 ml. and then diluted to ca. 1 litre with EA and washed with W.

The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to ca. 20 ml. The concentrated solution was diluted to ca. 100 ml with DE and chromatographed on a short column of silica gel (200 g) eluting with DE. The eluate was evaporated in vacuo to leave the title ester as a gum (2.3 g) T (CDCI3) values include 4.26 (d, J 2 Hz, C-S H), 4.80 (s, C-3 H), 5.20 (t, J 7 Hz, =CH--) 6.76 (d, J 7 Hz, CII2-S) and 8.00 (s, S--CH,).

Example 87 Sodium (3 R,5 R,Z)-2-[2-(2-hydroxyethyl)thioethylidene] - clavam-3-carboxylate 4-Nitrobenzyl (3R,5R,Z) - 2 - [2 - (2 - hydroxyethyl)thioethylidene]clavam 3 - carboxylate (1.26 g) was deprotected as described in Example 77. The freezedried amorphous powder was suspended in EA (250 ml) and saturated brine (80 ml). To this was added 25 ml of 0.1 N aqueous HCI, quickly shaken and the organic layer separated. The aqueous layer was once again quickly extracted with EA. The combined organic extracts were dried (MgSO4), filtered and treated with SEH (198 mg) in EA (10 ml). The resultant cloudy solution was concentrated in vacuo to ca 20 ml. and diluted with a dropwise addition of DE (150 ml). The precipitated solid was filtered, washed with EA and DE, and dried in vacuo to yield the title salt (286 mg) Vrnxx (Nujol) 1782 cm-' (p-lactam); T values (D2O) include 4.32 (d, J 3 Hz, C-S H), 5.08 (s, C-3 H), 5.22 (t, J 8 Hz, =CH), 6.7 (d, J 8 Hz, =CH-CH2).

Example 88 4-Nitrobenzyl (3 R,5R)-2- [2-(6-Purinyl)thioethylidene] - clavam-3-carboxylate The reaction of PBC (1.071 g) with 6-mercaptopurine monohydrate (0.484 g) in DMF containing pyridine (0.217 g) was carried out as described in Example 10.

Evaporation of the organic extract yielded the title ester as a foam (930 mg). #max (CHBr3) 1800 cm-' (p-lactam). T (CDCl3) values include 1.32, 1.72 (heterocyclic protons) 4.26 (C-5 H), 4.86 (C-3 H), 5.9 (=CH-CH2). The compound was a 50:50 mixture of E and Z isomers as deduced from n.m.r. spectroscopy.

Example 89 Sodium (3R,5R)-2-[2-(6-purinyl)thioethylidene]clavam- 3-carboxylate 4-Nitrobenzyl (3R,5R)- 2 - [2 - (6 - purinyl)thioethylidene]clavam - 3 carboxylate (1.22 g) was deprotected as described in Example 77 to afford the title salt (172 mg); #max (Nujol) 1780 cm-' (p-lactam). T (D2O) values include 1.53, 1.76 (heterocyclic protons), 4.22 (C-5 H), 5.98 (-CH2-S). The compound was a 50:50 mixture of E- and Z-isomers.

Example 90 4-Nitrobenzyl (3R,5R)-2-[2-(2-pyrimidyl)thioethylidene]- clavam-3-carboxylate The reaction of PBC (1.588 g) with 2-mercaptopyrimidine (0.459 g) in DMF (15 ml) containing pyridine (0.323 g) was carried out as described in Example 10.

Evaporation of the organic extract yielded the title ester as a foam (867 mg). Vmax (CHBr3) 1796 cm-l (p-lactam). T (CDCI3) values include 1.5 (heterocyclic protons), 4.26 (C-5 H), 5.03 (=CH) 6.12 (-CH2S). The compound was a 50:50 mixture of E and Z isomers.

Example 91 Sodium (3R,5R,Z)-2-[2-(2-pyrimidyl)thioethylidene]- clavam-3-carboxylate 4-Nitrobenzyl (3R,5R) - 2 - [2 - (2 - pyrimidyl)thioethylidene]clavam - 3 carboxylate (1.797 g) was deprotected as described in Example 77 to afford the title salt (151 mg) Vrnxx (Nujol) 1774 cmz (plactam), T (D2O) values include 1.41 and 2.76 (heterocyclic protons), 4.23 (C-5 H), 5.04 (=CH), 5.09 (C-3 H), 6.1 (-CH2S).

Additional closely associated resonances showed the presence of the E-isomer ca.

25.

Example 92 4-Nitrobenzyl (3R,5R,Z)-2-[2-cyanomethylthioethylidene]- clavam-3-carboxylate PMC (1.51 g) was alkylated with chloroacetonitrile (0.5 ml) in DC in the presence of 0.123 N aqueous tetrabutylammonium hydroxide solution (35 ml) as described in Example 47. Chromatography on silica gel, elution with DE, and concentration of the appropriate fraction gave the title compound as colourless crystals (1.01 g), #max (CHBr3) 1798 cm (plactam), T values (CDCl3) include 4.28 (d, J 3 Hz, C-S H), 4.86 (s, C-3 H), 5.27 (t, J 7 Hz, =CH), 6.56 (d, J 7 Hz, =CH- CH2S), 6.80 (s, S-CH2CN).

Example 93 Sodium (3R,5R,Z)-2-[2-(cyanomethyl)thioethylidene]- clavam-3-carboxylate 4-Nitrobenzyl (3R,5R,Z) - 2 - [2 - (cyanometbyl)thioethylidenel - clavam 3 - carboxylate (900 mg) was deprotected as described in Example 77 to give the title salt (203 mg); #max (Nujol), 1786 cm-' (p-lactam); T values (D2O) include 4.23 (d, J 3 Hz, C-S H), 5.01 (s, C-3 H), 5.16 (t, J 7 Hz, =CH-), 6.49 (d, J 7 Hz, =CH- CH2S), 6.52 (s, -SCH2CN).

Example 94 4-Nitrobenzyl (3R,5R,Z)-2-[2-(1 ,2,4-triazol-3-yl) thioethylidene]-clavam-3-carboxylate PBC (1.527 g) was reacted with 3 - mercapto - 1,2,4 - triazole (0.5 g) in DMF (20 ml) containing pyridine (0.5 ml) as described in Example 10. Chromatography of the organic extract on silica gel, elution with AC, and concentration of the appropriate fraction gave the title ester (0.448 g); #max (CHBr3) 1800 cm-' (p- lactam), T values (CDCl3) include 1.84 (s, triazole C-H), 4.31 (d, J 3 Hz, C-S H), 4.88 (s, C-3 H), 5.06 (t, J 8 Hz, =CH), 6.16 (d, J 8 Hz, =CH-CH2S).

Example 95 (3R,5R,Z)-2-[2-(2-Aminoethylthio)ethylidene]clavam- 3-carboxylic Acid A solution of 4-nitrobenzyl (3R,5R,Z) - 2- [2 - (2 - azidoethylthio) ethylidene]clavam - 3 - carboxylate (1.65 g) in TIIF (62 ml) and W (32 ml) was stirred at 0 with zinc dust (5.25 g), added in portions over 0.75 hours. The pH of the mixture was kept at 4.3 by addition of 1 N aqueous HCI in Example 77 to afford the title acid (0.389 g), #max (Nujol) 1780 cm-' (plactam), T values (D2O) include 4.25 (d, J 2 Hz, C-S H), 5.03 (s, C-3 H), 5.18 (t, J 8 Hz, =CH-), 6.74 (d, J 8 Hz, =CH- CH2-S), 6.76 (t, J 6 Hz, -S-CII2CH2-N+II3), 7.20 (t, J 6 Hz, S-CH2-CH2 N+II3).

Example 96 (3R,5R,Z)-2-[2-(1-Methyl-3-pyridinio)thioethylidene]- clavam-3-carboxylate (3R,5R,Z) - 1 - Methyl - 3 - [2 - (3 - (4 - nitrobenzyloxycarbonyl)clavam 2 - ylidene)ethylthio]pyridinium iodide (1.24 g) was deprotected by the method described in Example 77 to afford the title betaine (0.35 g), Vrnxx (Nujol) 1780 cm-' (p- lactam), t (D2O) values include 4.33 (d, J 2 Hz, C-S H), 5.10 (s, C-3 H).

Example 97 (3R,5R,Z)-2-[2-(3-(4-Nitrobenzyloxycarbonyl(clavam-2- ylidene)ethylthio]pyridine-l-oxide PBC (1.50 g) was added to a stirred solution of 2-mercaptopyridine oxide (0.72 g) in DC (20 ml) and triethylamine (0.53 ml) at 200. The resulting solution was kept at 20 for 10 minutes, and then diluted with DC (500 ml) and washed successively with W, saturated aqueous NaHCO3 and W. The solution was then dried and evaporated to leave the title ester as a foam (1.522 g), ArnETax, 248 nm, 278.5 nm (E 23,500, 20,400), #max (CHBr3) 1802 cm-' (p-lactam), T (DMSO-d6) values include 4.11 (d, J 2 Hz, C-S H), 4.47 (s, C-3 H), 5.12 (t, J 7 Hz, =CH-), and 6.24 (d, J 7 Hz, -CH2-S).

Example 98 Sodium (3R,5R,Z)-2-[2-(1 -oxidopyrid-2-ylthio)ethylidene] - clavam-3-carboxylate (3R,SR,Z) - 2 - [2 - (3 - (4 - Nitrobenzyloxycarbonyl)clavam - 2 - ylidene) ethylthio]pyridine - 1 - oxide (1.43 g) was deprotected by the method described in Example 77 to afford the title salt (0.11 g), #maxpH6 238.5, 308 nm (E 22,200, 6,100), #max (Nujol) 1786 cm-', T (D2O) values include 4.20 (d, J 2 Hz, C-S H), 5.06 (s, C-3 H), 6.18 (d, J 8 Hz), CH2-S).

Example 99 4-Nitrobenzyl (3 R,5 R,Z)-2- [2-(pyrid-3-ylthio)ethylidene] - clavam-3-carboxylate PBC (1.7 g) was added to a stirred solution of 3-mercaptopyridine (0.714 g) and pyridine (0.735 ml) in DMF (30 ml). the resulting solution was kept at 200 for 15 minutesa nd then partitioned between EA and W. The EA layer was separated, washed with W (3x) dried and evaporated to leave the title ester as a gum (1.39 g); #maxET 273 nm (E 17,100), small (Nujol) 1800 cm-' (p-lactam), T (CDCl3) values include (4.41 (d, J 3 Hz, C-S H), 4.94 (s, C-3 H), 5.26 (t, J 8 Hz, =CH-), 6.37 (d, J 8 Hz, -CH2-S).

Example 100 (3R,5R,Z)-1,3-Dimethyl-2-[2-(3-{4-nitrobenzyloxycarbonyl} clavam-2-ylidene)ethylthio]imidazolium Bromide PBC (1.32 g) was added to a stirred solution of 1,2 - dihydro - 1,3 dimethylimidazole - 2 - thione (0.427 g) in DC (50 ml) at 200. After 15 minutes, the solvent was removed in vacuo to leave the title salt as a foam (1.92 g), #max (Nujol) 1798 cm-1 (p-lactam), T (DMSO-d6) values include 4.33 (d, J 3 Hz, C-S H), 4.54 (s, C-3 H), 5.10 (t, J 8 Hz, =CH-), 6.08 (s, N-CH3's), 6.18 (d, J 8 Hz, -CH2S).

Example 101 (3R,5R,Z)-1 -Methyl-3-[2-(3-I4-nitrobenzyloxycarbony clavam-2-ylidene)ethylthio]pyridinium Iodide The reaction of 4-nitrobenzyl (3R,5R,Z)- 2 - [2 - (pyrid - 3 - ylthio)ethylidene]clavam - 3 - carboxylate (1.30 g) with iodomethane (5.6 ml) in AC (50 ml) for 18 hours at 20C as in Example 36 and precipitation of the product from DE gave the title salt (1.41 g), #maxET 306 nm (E 19,300), #max (Nujol) 1792 cm-' (p-lactam), (DMSO-d6) values include 4.15 (d, J 2 Hz, C-S H), 4.49 (s, C-3 H), 5.12 (t, J 8 Hz, =CH-), 5.64 (s, N-CH3) and 6.03 (d, J 8 Hz, CH2-S).

Example 102 4-Nitrobenzyl (3R,5R,Z)-2-[2-(4,5-dihydrothiazol-2-yl) thioethylidene]clavam-3-carboxylate The reaction of PBC (2.38 g) with 2-mercaptothiazoline (833 mg) in DMF containing pyridine (632 mg) was carried out as described in Example 10. The crude product was chromatographed on a silicagel column and eluted with EA:T (1:1). The first few fractions yielded the E isomer. The later fractions yielded the title ester as an oil (398 mg). Vmax (CHBr3) 1800 cm-' ( -lactam) T values (CDCl3) include 4.28 (d, J 3 Hz, C-S H), 4.88 (s, C-3 H), 5.09 (t, J 8 Hz,=CH), 5.81 (t, J 8 Hz, 2 heterocyclic protons) 6.18 (d, J, 8 Hz, =CH-CH2), 6.62 (t, J 8 Hz, 2 heterocyclic protons.

Example 103 4-Nitrobenzyl (3R,5R,Z)-2-[2-(5-mercapto-1,3,4-thiadiazol- 2-yl)thioethylidene]clavam-3-carboxylate The reaction of PBC (198 mg) with 2,5 - dimercapto - 1,3,4 - thiadiazole (150 mg) in DMF containing pyridine (0.047 g) was carried out as described in Example 10. Chromatography on silica gel, elution with EA:T (1:1), concentration of the appropriate fractions yielded the title ester as a foam (166 mg), #maxET 261.5 (El 299) and 325 nm (E11 235). small 1800 cm-' (plactam), T values (CDCl3) include 4.25 (d, J 3 Hz, C-S H), 4.82 (s, C-3 H), 5.12 (d, J 8 Hz, =CH), 6.19 (d, J 8 Hz, =CH-CH2).

Example 104 4-Nitrobenzyl (3R,5R,Z)-2-[2-(1 ,2,3-triazol-4-yl)- thioethylidene]clavam-3-carboxylate PBC (1.5 g) was reacted with 4 - mercapto - 1,2,3 - triazole (0.5 g) in DMF (20 ml) containing pyridine (0.5 ml) as described in Example 10. Chromatography of the organic extract on silica gel, elution with EA, and concentration of the appropriate fraction gave the title ester (0.903 g); #max (CHBr3) 1800 cm-' (p- lactam); T values include 4.40 (d, J 3 Hz), 4.66 (s, C-3 H), 5.23 (t, J 7 Hz, =CH).

Example 105 Sodium (3R,5R,Z)-2-[2-(5-mercapto-1,3,4-thiadiazol-2- yl)thioethylidene] clavam-3-carboxylate 4-Nitrobenzyl (3R,SR,Z) - 2 - [2 - (5 - mercapto - 1,3,4 - thiadiazol - 2 yl)thioethylidene]clavam - 3 - carboxylate (2.097 g) was deprotected as described in Example 77, to afford the title salt (119 mg) VmaX (Nujol) 1782 cm-' (/3-lactam), values (D,O) include 4.29 (C-5 H), 5.32 (t, =CH), 5.37 (s, C-3 H).

Example 106 Sodium (3R,5R,Z)-2-[2-(pyrid-3-ylthio)ethyliden]clavam 3-carboxylate 4-Nitrobenzyl (3R,5R,Z) - 2 - [2 - (pyrid - 3 - ylthio)ethylidene]clavam - 3 - carboxylate (1.21 g) was deprotected by the method described in Example 77 to afford the title salt (0.21 g), VmaX (Nujol) 1784 cm-', T (DMSO-d6) values include 4.30 (C-5 H), 5.24 (=CH-), 5.34 (C-3 H).

Example 107 Sodium (3R,5R,Z)-2-[2-(5-amino-1,3,4-thiadiazol-2- ylthio)-ethylidene]clavam-3-carboxylate 4-Nitrobenzyl (3R,5R,Z)- 2 - [2 - (5 - amino- 1,3,4 - thiadiazol - 2 ylthio)ethylidene]clavam - 3 - carboxylate (1.238 g) was deprotected by the method described in Example 77 to afford the title salt (0.317 g), ArnPHx 283, 222 nm (E 6,100, 9,250), #max (Nujol) 3300, 3160 (NH2), 1782 cm-' (p-lactam), T (D2O) values include 4.36 (d, J 2 Hz, C-S H), 5.05 (s

Example 109 Acetoxymethyl (3R,SR,Z)-2-(2-phenylsulphonylethylidene) clavam-3-carboxylate A solution of sodium (3R,SR,Z) - 2 - (2 phenylsulphonylethylidene)clavam - 3 - carboxylate (345 mg) and acetoxymethyl bromide (152 mg) in DMF (6 ml) was stirred at room temperature for 18 hr. The solution was diluted with EA, washed with 50% saturated brine (x2) and W (x2), dried and filtered through silica gel. Concentration of the filtrate gave the title ester (80 mg); ArnEaTa 258, 265, 272 nm (E, 58, 59, 54), vmax (CHBr3) 1801 cm-1 (p-lactam); T (CDCl3) values include 4.18 (ABq, -OCH2O-), 4.71 (d, J 2 Hz, C-S H), 4.96 (s, C3 H), 5.20 (t, J 8 Hz, =CH), and 7.84 (s, -COCH3).

Examples A-C In Example A sodium (3R,SR,Z) - 2 - (2 - methylthioethylidene)clavam - 3 carboxylate is used as densified granules containing 1% magnesium stearate, which are prepared as follows: Blend sodium (3R,SR,Z) - 2 - (2 - methylthioethylidene)clavam - 3 carboxylate with 1% magnesium stearate and prepare tablet slugs by direct compression on a tablet machine. Break down the slugs through a senses of screens (12 mesh, 16 mesh and 20 mesh) on a rotary granulator to produce free flowing densified granules with an apparent bulk density of about 0.7 gms per ml (BSS method).

Ampicillin trihydrate granules and sodium (3R,SR,Z) - 2 - (2 ethylthioethylidene)clavam - 3 - carboxylate (used in Example B) may be prepared in a similar manner.

Example A Formula per Tablet Densified sodium (3R,SR,Z) - 2 - (2 methylthioethylidene)clavam - 3 - carboxylate granules containing 1% magnesium stearate. 252.5 mg Avicel PH 101 grade of microcrystalline cellulose to tablet core weight of 325 mg ("Avicel" is a Registered Trade Mark).

Method of Preparation Blend together the granules of the salt and Avicel and compress them on deep concave punches, 9.5 mm in diameter. Take precautions to avoid unnecessary exposure to light and conditions of high humidity.

Example B Formula per capsule Densified sodium (3R,5R,Z) - 2 - (2 ethylthioethylidene)clavam - 3 - carboxylate granules containing 1% magnesium stearate 252.5 mg Densified ampicillin trihydrate granules containing 1% magnesium stearate equal to 250 mg ampicillin (approx.) 300.0 mg Sodium starch glycollate (Primojel) 11.5 mg Target capsule fill weight 564.0 mg Method of Preparation Remove a proportion of fine granules passing 40 mesh equal to the weight of Primojel from the bulk densified granules of the sodium salt and blend with Primojel. Add the blend to the bulk and re-blend. Blend with the ampicillin granules. Fill the composite granules into size 0 hard gelatin capsules (lock fitting type) on an automatic capsule filling machine. Take precautions to avoid unnecessary exposure to light and conditions of high humidity.

Example C Dry Powder for Injection Fill sterile sodium (3R,5R,Z) - 2 - (2 - methylsulphinylethylidene)clavam 3 - carboxylate (500 mg) into glass vials, carry out the filling aseptically, in an area of controlled low humidity, under a blanket of nitrogen. Close the vials under rubber discs or plugs held in position by aluminium sealing rings, thereby preventing gaseous exchange or ingress of micro-organisms. Constitute the product by dissolving in Water for Injections shortly before administration. Other suitable sterile vehicles can be used in place of Water for Injections.

WHAT WE CLAIM IS: 1. Compounds of the formula (II)

wherein R represents a group SR, -SO. . or -SO2. RX where Rx represents an alkyl or alkenyl group or a heterocyclic group containing one or more hetero atoms, which groups may be substituted by a hydroxyl, carboxyl, amino or substituted amino group; and R1 is a carboxyl or esterified carboxyl group and salts of compounds of formula II containing a carboxyl group.

2. Compounds of the formula (II) as shown in Claim 1, wherein R represents a group of the formula -S. C=Y. R3 (where Y is O or S and R3 is an aliphatic, araliphatic, aromatic or heterocyclic group; or agroup-OR2 or -SR2 wherein R2 is an aliphatic, araliphatic, aromatic or heterocyclic group; or a group -NR4R6 wherein R4 and R6, which may be the same or different, are hydrogen atoms or aliphatic, araliphatic or aromatic groups or together with the nitrogen atom to which they are attached represents a heterocyclic ring); and R1 is a carboxyl or esterified carboxyl group and salts of the compounds in which R' is a carboxyl group.

3. Compounds as claimed in Claim 1, wherein R represents a group -SRx wherein RX represents a C,-6 alkyl group substituted by a hydroxy group.

4. Compounds as claimed in Claim 1, wherein R represents a group -SRx wherein RX represents a C16 alkyl group substituted by an amino group.

5. Compounds as claimed in Claim 1, wherein R represents a group SRX wherein Rx represents a C16 alkyl group substituted by a substituted amino group of the formula -NR4R6 wherein R4 and R5 are as defined in Claim 2, one of them being other than hydrogen, or a group -NR4R5RA wherein R4 and R6 are as defined above, R" is a group as defined for R4 and R5 and A is an anion, none of R4, R6 and R" being hydrogen.

6. Compounds as claimedin Claim 5, wherein R4, R5 and where applicable R" represents a C14 alkyl group.

7. Compounds as claimed in Claim 2, wherein one or more of R2, R3, R4 and R5 represents a C16 alkyl, alkenyl or alkynyl group; an aralkyl group having 1-6 carbon atoms in the alkyl portion; an aryl group; a cycloalkyl group having from 3-7 carbon atoms, or a carbon-attached 5-7 membered heterocyclic ring containing one or more heteroatoms optionally carrying one or more C16 alkyl groups, all of which groups are unsubstituted or substituted by a hydroxyl, substituted hydroxy, carboxyl, substituted carboxyl, amino or substituted amino group.

8. Compounds as claimed in Claim 7, wherein the substituted hydroxyl group has the formula RCO2- or -OR, the substituted carboxyl group has the formula --COOR" and the substituted amino group has the formula -NR4R6 or --NR4RSR"A, wherein R4, R5, R11 and A are as defined in Claim 5.

9. Compounds as claimed in Claim 8, wherein R4, R5 and R" each represents a C14 alkyl group.

10. Compounds as claimed in Claim 2, wherein R represents a benzoylthio, thiobenzoylthio, acetylthio, dimethylthiocarbamoylthio, thiocarbamoylthio, ethoxythiocarbonylthio, or thioacetylthio group.

11. Compounds as claimed in any of Claims 1 to 10, wherein R' represents an esterified carboxyl group --COOR'2 wherein R'2 is an organic group derived from an aliphatic or araliphatic alcohol, a phenol, a silanol or a stannanol.

12. Compounds as claimed in Claim 11, wherein R'2 represents a straight or branched substituted or unsubstituted alkyl or alkenyl group having up to 8 carbon atoms; an aralkyl group having up to 20 carbon atoms; an aryl group having up to 12 carbon atoms; a cycloalkyl group containing up to 12 carbon atoms, optionally

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (1)

1. **WARNING** start of CLMS field may overlap end of DESC **.

   of controlled low humidity, under a blanket of nitrogen. Close the vials under rubber discs or plugs held in position by aluminium sealing rings, thereby preventing gaseous exchange or ingress of micro-organisms. Constitute the product by dissolving in Water for Injections shortly before administration. Other suitable sterile vehicles can be used in place of Water for Injections.

   WHAT WE CLAIM IS: 1. Compounds of the formula (II)

   wherein R represents a group SR, -SO. . or -SO2. RX where Rx represents an alkyl or alkenyl group or a heterocyclic group containing one or more hetero atoms, which groups may be substituted by a hydroxyl, carboxyl, amino or substituted amino group; and R1 is a carboxyl or esterified carboxyl group and salts of compounds of formula II containing a carboxyl group.

   2. Compounds of the formula (II) as shown in Claim 1, wherein R represents a group of the formula -S. C=Y. R3 (where Y is O or S and R3 is an aliphatic, araliphatic, aromatic or heterocyclic group; or agroup-OR2 or -SR2 wherein R2 is an aliphatic, araliphatic, aromatic or heterocyclic group; or a group -NR4R6 wherein R4 and R6, which may be the same or different, are hydrogen atoms or aliphatic, araliphatic or aromatic groups or together with the nitrogen atom to which they are attached represents a heterocyclic ring); and R1 is a carboxyl or esterified carboxyl group and salts of the compounds in which R' is a carboxyl group.

   3. Compounds as claimed in Claim 1, wherein R represents a group -SRx wherein RX represents a C,-6 alkyl group substituted by a hydroxy group.

   4. Compounds as claimed in Claim 1, wherein R represents a group -SRx wherein RX represents a C16 alkyl group substituted by an amino group.

   5. Compounds as claimed in Claim 1, wherein R represents a group SRX wherein Rx represents a C16 alkyl group substituted by a substituted amino group of the formula -NR4R6 wherein R4 and R5 are as defined in Claim 2, one of them being other than hydrogen, or a group -NR4R5RA wherein R4 and R6 are as defined above, R" is a group as defined for R4 and R5 and A is an anion, none of R4, R6 and R" being hydrogen.

   6. Compounds as claimedin Claim 5, wherein R4, R5 and where applicable R" represents a C14 alkyl group.

   7. Compounds as claimed in Claim 2, wherein one or more of R2, R3, R4 and R5 represents a C16 alkyl, alkenyl or alkynyl group; an aralkyl group having 1-6 carbon atoms in the alkyl portion; an aryl group; a cycloalkyl group having from 3-7 carbon atoms, or a carbon-attached 5-7 membered heterocyclic ring containing one or more heteroatoms optionally carrying one or more C16 alkyl groups, all of which groups are unsubstituted or substituted by a hydroxyl, substituted hydroxy, carboxyl, substituted carboxyl, amino or substituted amino group.

   8. Compounds as claimed in Claim 7, wherein the substituted hydroxyl group has the formula RCO2- or -OR, the substituted carboxyl group has the formula --COOR" and the substituted amino group has the formula -NR4R6 or --NR4RSR"A, wherein R4, R5, R11 and A are as defined in Claim 5.

   9. Compounds as claimed in Claim 8, wherein R4, R5 and R" each represents a C14 alkyl group.

   10. Compounds as claimed in Claim 2, wherein R represents a benzoylthio, thiobenzoylthio, acetylthio, dimethylthiocarbamoylthio, thiocarbamoylthio, ethoxythiocarbonylthio, or thioacetylthio group.

   11. Compounds as claimed in any of Claims 1 to 10, wherein R' represents an esterified carboxyl group --COOR'2 wherein R'2 is an organic group derived from an aliphatic or araliphatic alcohol, a phenol, a silanol or a stannanol.

   12. Compounds as claimed in Claim 11, wherein R'2 represents a straight or branched substituted or unsubstituted alkyl or alkenyl group having up to 8 carbon atoms; an aralkyl group having up to 20 carbon atoms; an aryl group having up to 12 carbon atoms; a cycloalkyl group containing up to 12 carbon atoms, optionally

   containing one or more heteroatoms in the ring system; a silyl group having up to 24 carbon atoms or a stannyl group having up to 24 carbon atoms.

   13. Compounds as claimed in Claim 12, wherein -COOR12 is a metabolically labile ester group.

   14. A compound as claimed in any of Claims 11 to 13 in which R12 is a C14 alkyl group which may carry an acyloxy group, an alkoxy group, a cyano group, an acyl group or a halogen atom.

   15. A compound as claimed in Claim 14 in which R12 is a C1.4 alkyl group which may carry an acetoxy, pivaloyloxy, methoxy, fluorine, chlorine, bromine, iodine, cyano, p-bromobenzoyl or ethoxycarbonyl group.

   16. A compound as claimed in Claim 14 or Claim 15 in which R12 is a methyl, ethyl, propyl, butyl, acetoxymethyl or pivaloyloxymethyl group.

   17. A compound as claimed in any of Claims 11 to 13, wherein R12 is a phthalidyl group.

   18. Compounds as claimed in Claim 12, wherein R12 is a diphenylmethyl group, a benzyl group or a benzyl group substituted by an o- or p-nitro, p-methoxy or p-methyl group.

   19. Compounds as claimed in Claim 12, wherein R12 represents ap-nitrobenzyl group.

   20. An alkali metal, alkaline earth metal, or ammonium salt or a salt with an organic base of any carboxylic acid compound as claimed in any of Claims I to 10.

   21. A sodium, potassium, lithium, calcium or magnesium salt as claimed in Claim 20.

   22. Compounds of the formula (IIa)

   wherein Ra represents an alkylthio or alkenylthio group or a sulphoxide or sulphone derivative thereof substituted by an azido or cyano group and R1 is as defined in any of Claims 1 and 11 to 21.

   23. Compounds of the formula (ill) as shown in Claim 22, wherein Ra represents an alkylthio or alkenylthio group or sulphoxide or sulphone derivative thereof substituted by a 4-nitrobenzyloxycarbonyl or nitro group and R' is as defined in any of Claims 1 and 11 to 21.

   24. Compounds of the formula (Ila) as shown in Claim 22, wherein Ra represents an alkylthio or alkenylthio group or a sulphoxide or sulphone derivative thereof substituted by a mercapto group, or Ra represents a heterocyclicthio group containing one or more heteroatoms and substituted by a mercapto group and R1 is as defined in any of Claims 1 and 11 to 21.

   25. Compounds of the formula (IIa) as shown in Claim 22, wherein Ra represents a group --SRb, --SO . Rb or SO2. Rb wherein Rb is a phenyl or benzyl group substituted by a nitro group, and R1 is as defined in any of Claims 1 and 11 to 21.

   26. Compounds of formula (IIa) as shown in Claim 22, wherein Ra represents a group SRC wherein Rc is a charged heterocyclic group, or nitrogen-containing heterocyclic group in the form of an N-oxide and R' is as defined in any of Claims 1 and 11 to 21 and where Rc is a charged heterocyclic group an anion is present except when R is COO'.

   27. Compounds of formula (IIa) as shown in Claim 22, wherein Ra represents a fused heterocyclicthio group and R1 is as defined in any of Claims 1 and 11 to 21

   28. Compounds as claimed in Claim 22, wherein R" represents a C16 alkylthio group substituted by an azido or cyano group.

   29. Compounds as claimed in Claim 23, wherein Ra represents a C16 alkylthio group substituted by a 4-nitrobenzyloxycarbonyl or nitro group.

   30. Compounds as claimed in Claim 24, wherein Ra represents a C1.6 alkylthio group substituted by a mercapto group.

   31. Compounds as claimed in Claim 26, wherein, when Rc is charged heterocyclic group, it represents a carbon attached 5 to 7 membered heterocyclic ring containing at least one nitrogen atom, which nitrogen atom carries a C14 alkyl group.

   32. Compounds as claimed in Claim 31, wherein Rc represents a pyridine ring carrying a C, 4 alkyl group on the nitrogen atom.

   33. Compounds as claimed in Claim 27, wherein Ra is a (bicyclic carbonattached heterocyclic) thio group, containing 5 to 7 atoms in each ring, one to three double bonds in each ring and a total of up to four heteroatoms selected from nitrogen, oxygen and sulphur atoms, and optionally substituted by one or more C, 4 alkyl, hydroxy, mercapto or amino groups.

   34. Compounds as claimed in Claim 27, wherein Ra is a benzimidazolylthio, benzoxazolylthio, triazolopyridylthio or purinylthio group.

   35. Compounds as claimed in Claim 2 in which, when R represents a group --S.C=Y.R3, R3 represents a C14 alkyl group; a phenyl group; a C,~4 alkoxy group; a pyridyl group; an N--(C,,) alkyl pyridinio group, or a group of formula -NR4R5 where R4 and R5 which may be the same or different, are hydrogen atoms or C14 alkyl or together with the nitrogen atom to which they are attached, represent a saturated monocyclic 5-7 membered heterocyclic ring which may contain an oxygen, sulphur or nitrogen atom as an additional heteroatom, which ring may also be substituted by one or two C14 alkyl groups and an anion being present or R' representing COOS when R3 represents an N(C, 4)alkyl pyridinio group.

   36. Compounds of the formula (IIa) as shown in Claim 22, wherein Ra represents one of the groups:

   where R6, R7, R8 and R9, which may be the same or different, are hydrogen atoms or aliphatic groups; -SCN; . SO2R' , where R'O is an aliphatic, araliphatic or aromatic group; S2O2 .' M, where M is a cation, and R' is as defined in any of Claims I and 11 to 21 and an anion being present or R' representing COOO when Ra represents a thiozoronium group.

   37. Compounds as claimed in Claim 36, wherein R'O represents a phenyl group.

   38. Compounds as claimed in Claim 36, wherein the cation M is an alkali metal, alkaline earth metal, ammonium or substituted ammonium ion.

   39. Compounds as claimed in Claim 36, wherein R6, R7, R8 and R9 are all hydrogen.

   40. Compounds as claimed in any of Claims 26, 27, 31 to 33, 35, 36 and 39 wherein, if the group Ra contains a positive charge, the associated anion is a halide, sulphate, phosphate or hydrocarbylsulphonate ion.

   41. Compounds as claimed in Claim 26, wherein Ra represents a 1 - oxidopyrid - 4 - ylthio, 1 - methyl - 2 - pyridiniothio, or 1 - methyl - 4 pyridiniothio group.

   42. Compounds as claimed in Claim 25, wherein Ra represents a 4nitrophenylthio or 4 - nitrophenylsulphonyl group.

   43. Compounds as claimed in Claim 1, wherein R represents a 2,3 - dihydro 4 - methyl - 3 - oxo - 1,2,4 - triazol - 5 - ylthio group or a carboxymethylsulphonyl group.

   44. Compounds as claimed in Claim 2, wherein R represents a pyrid - 2 ylcarbonylthio, pyrid - 3 - ylcarbonylthio, 1 - methyl - 3 - pyridiniocarbonylthio, 4 - methylpiperazin - 1 - ylthiocarbonylthio, N - methylthiocarbamoylthio, or 1,1 - dimethyl - 4 - piperaziniothiocarbonylthio group.

   45. Compounds as claimed in Claim 36, wherein Ra represents a thiocyanato, thiosulphato, or thiouronium group.

   46. Compounds as claimed in any of Claims 41 to 45 in which R' is a carboxyl group or salt thereof or a metabolically labile ester thereof.

   47. Compounds of the formula (IIa) as shown in Claim 22, wherein Ra represents an -SH or

   group, wherein R' is as defined in any of Claims 1 and 11 to 21.

   48. Compounds as claimed in any of Claims 1, 11 to 17, 20 and 21, wherein R represents a 2 - hydroxyethylthio or 2 - aminoethylthio group, and R' represents a carboxyl group, or a salt thereof or a metabolically labile ester thereof.

   49. Compounds as claimed in any of Claims 2, 11 to 17, 20 and 21, wherein R represents a carbamoylthio or N - methylcarbamoylthio group and R' represents a carboxyl group, or a salt thereof or a metabolically labile ester thereof.

   50. Compounds as claimed in Claim 22, wherein R" represents a cyanomethylthis group and R' represents a carboxyl group, or a salt thereof or a metabolically labile ester thereof.

   51. Compounds of the formula

   wherein Rd is the residue of a sulphur nucleophile and R'd is a 4nitrobenzyloxycarbonyl group.

   52. Compounds as claimed in Claim 51, wherein Rd represents one of the groups: -SH; -SR2, -SO. R2 or SO2. R2 (where R2 is an aliphatic, araliphatic, aromatic or heterocyclic group); -S. C=Y . R3, (where Y is O or S and R3 is a group as defined above for R2, or a groupOR2 or -SR2 where R2 is as defined above, or a group -NR4R6, where R4 and R5, which may be the same or different, are hydrogen atoms or aliphatic, araliphatic or aromatic groups or together with the nitrogen atoms to which they are attached represent a heterocyclic ring);

   where R6, R7, R6 and R9, which may be the same or different, are hydrogen atoms or aliphatic groups; -SCN; S . SO2R' , where R'O is an aliphatic, araliphatic or aromatic group; 520S M, where M is a cation, or

   wherein R' is as defined in Claim 1 and an anion being present or R' representing COOs when Rd represents a thiouronium group.

   53. Compounds as claimed in Claim 51 or Claim 52 in which, when Rd represents one of the groups: -SR2; -SO. R2 or 502. R2 wherein R2 is as defined in Claim 52; or a group . C=Y. R3 (where Y is O or S and R3 is as defined in Claim 52); one or more of R2, R3, R4 and R6 represents a C1.6 alkyl, alkenyl or alkynyl group; an aralkyl group having I to 6 carbon atoms in the alkyl portion; an aryl group; a cycloalkyl group having from 3 to 7 carbon atoms, or a carbon-attached 5-7 membered heterocyclic ring containing one or more heteroatoms optionally carrying one or more C1.6 alkyl groups, all of which groups are unsubstituted or substituted by a hydroxyl, substituted hydroxyl, carboxyl, substituted carboxyl, amino or substituted amino group.

   54. 4-Nitrobenzyl (3R,5R,Z) - 2 - (2 - phenylsulphonylethylidene)clavam 3 - carboxylate.

   55. (3R,5R,Z) - 2 - (2 - Phenylsulphonylethylidene)clavam - 3 - carboxylic acid and the alkali metal or alkaline earth metal salts thereof.

   56. Sodium (3R,5R,Z) - 2 - (2 - phenylsulphonylethylidene)clavam - 3 carboxylate.

   57. 4-Nitrobenzyl (3R,5R,Z) - 2 - (2 - benzoylthioethylidene)clavam - 3 carboxylate.

   58. (3R,SR,Z) - 2 - (2 - Benzoylthioethylidene)clavam - 3 - carboxylic acid and the alkali metal or alkaline earth metal salts thereof.

   59. 4-Nitrobenzyl (3R,5R,Z) - 2 - (2 - acetylthioethylidene)clavam - 3 carboxylate.

   60. (3R,5R,Z) - 2 - (2 - Acetylthioethylidene)clavam - 3 - carboxylic acid and the alkali metal or alkaline earth metal salts thereof.

   61. 4-Nitrobenzyl (3R,SR,Z) - 2 - (2 - N,N dimethylthiocarbamoylthioethylidene)clavam - 3 - carboxylate.

   62. (3R,5R,Z) - 2 - - (2 - N,N - Dimethylthiocarbamoylthioethylidene)clavam - 3 - carboxylic acid and the alkali metal or alkaline earth metal salts thereof.

   63. 4-Nitrobenzyl (3R,5R,Z) - 2 - (2 - phenylthioethylidene)clavam - 3 carboxylate.

   64. (3R,SR,Z) - 2 - (2 - Phenylthioethylidene)clavam - 3 - carboxylic acid and the alkali metal and alkaline earth metal salts thereof.

   65. Sodium (3R,5R,Z)- 2 - (2 - phenylthioethylidene)clavam - 3 carboxylate.

   66. 4-Nitrobenzyl (3R,5R,Z) - 2 - [2 - (pyrid - 2 - ylthio)ethylidene]clavam 3 - carboxylate.

   67. (3R,5R,Z) - 2 -[2 - (Pyrid - 2 - ylthio)ethylidene]clavam - 3 - carboxylic acid and the alkali metal and alkaline earth metal salts thereof.

   68. Sodium (3R,5R,Z) - 2 - [2 - (pyrid - 2 - ylthio)ethylidene]clavam - 3 carboxylate.

   69. 4-Nitrobenzyl (3R,5R,Z) - 2 - [2 - (5 - methyl - 1,3,4 - thiadiazol - 2 ylthio)ethylidene]clavam - 3 - carboxylate.

   70. (3R,5R,Z)- 2- [2 - (5 - Methyl - 1,3,4 - thiadiazol - 2ylthio)ethylidene]clavam - 3 - carboxylic acid and the alkali metal and alkaline earth metal salts thereof.

   71. Sodium (3R,5R,Z) - 2 - [2 - (5 - methyl - 1,3,4 - thiadiazol - 2 ylthio)ethylidene]clavam - 3 - carboxylate.

   72. 4-Nitrobenzyl (3R,5R,Z) - 2 - (2 - methylthioethylidene)clavam - 3 carboxylate.

   73. (3R,5R,Z) - 2 - (2 - Methylthioethylidene)clavam - 3 - carboxylic acid and the alkali metal and alkaline earth metal salts thereof.

   74. Sodium (3R,5R,Z)- 2 - (2 - methylthioethylidene)clavam - 3 carboxylate.

   75. 4-Nitrobenzyl (3R,5R,Z) - 2 - (2 - thiobenzoylthioethylidene)clavam - 3 carboxylate.

   76. (3R,5R,Z) - 2 - (2 - Thiobenzoylthioethylidene)clavam - 3 - carboxylic acid and the alkali metal and alkaline earth metal salts thereof.

   77. 4-Nitrobenzyl (3R,5R,Z) - 2 - (2 - thiocarbamoylthioethylidene)clavam 3 - carboxylate.

   78. (3R,5R,Z) - 2 - (2 - Thiocarbamoylthioethylidene)clavam - 3 - carboxylic acid and the alkali metal and alkaline earth metal salts thereof.

   79. 4 - Nitrobenzyl (3R,5R,Z) - 2 - (2 - ethoxythio carbonylthioethylidene)clavam - 3 - carboxylate.

   80. (3R,5R,Z)- 2 - (2 - Ethoxythiocarbonylthioethylidene)clavam - 3 carboxylic acid and the alkali metal and alkaline earth metal salts thereof.

   81. 4-Nitrobenzyl (3R,5R,Z) - 2 - (2 - thioacetylthioethylidene)clavam - 3 carboxylate.

   82. (3R,SR,Z) - 2 - (2 - Thioacetylthioethylidene)clavam - 3 - carboxylic acid and the alkali metal and alkaline earth metal salts thereof.

   83. 4-Nitrobenzyl (3R,5R,Z) - 2 - (2 - methylsulphinylethylidene)clavam - 3 carboxylate.

   84. (3R,5R,Z) - 2 - (2 - Methylsulphinylethylidene)clavam - 3 - carboxylic acid and the alkali metal and alkaline earth metal salts thereof.

   85. Sodium (3R,SR,Z) - 2 - (2 - methylsulphinylethylidene)clavam - 3 carboxylate.

   86. 4-Nitrobenzyl (3R,SR,Z) - 2 - (2 - methylsulphonylethylidene)clavam 3 - carboxylate.

   87. (3R,SR,Z) - 2 - (2 - Methylsulphonylethylidene)clavam - 3 - carboxylic acid and the alkali metal and alkaline earth metal salts thereof.

   88. Sodiury(3R,SR,Z) - 2 - (2 - methylsulphonylethylidene) - clavam - 3 carboxylate.

   89. 4-Nitrobenzyl (3R,5R,Z) - 2 - (2 - ethylsulphinylethylidene)clavam - 3 carboxylate.

   90. (3R,SR,Z) - 2 - (2 - Ethylsulphinylethylidene)clavam - 3 - carboxylic acid and the alkali metal and alkaline earth metal salts thereof.

   91. Sodium (3R,5R,Z)- 2 - (2 - ethylsulphinylethylidene)clavam - 3 carboxylate.

   92. 4-Nitrobenzyl (3R,5R,Z) - 2 - [2 - (4 - nitrobenzyloxycarbonyl methylsulphonyl)ethylidene] clavam - 3 - carboxylate.

   93. (3R,5R,Z) - 2 - [2 - (Carboxymethylsulphonyl)ethylidene]clavam - 3 carboxylic acid and the alkali metal and alkaline earth metal salts thereof.

   94. 4-Nitrobenzyl (3R,5R,Z) - 2 - (2 - carbamoylthioethylidene)clavam - 3 carboxylate.

   95. (3R,5R,Z)- 2 - (2 - Carbamoylthioethylidene)clavam - 3 - carboxylic acid and alkali metal and alkaline earth metal salts thereof.

   96. Sodium (3R,5R,Z) - 2 - (2 - carbamoylthioethylidene)clavam - 3 - carboxylate.

   97. (3R,5R,Z)- 1 - Methyl - 4- [2 - (3 - (4 - nitrobenzyloxy carbonylclavam) - 2 - ylidene)ethylthio]pyridinium iodide.

   98. (3R,5R,Z) - 2 - [2 - (1 - Methyl - 4 - pyridinio)thioethylidene]clavam 3 - carboxylate.

   99. (3R,5R,Z) - 4 - [2 - (3 - 14 - Nitrobenzyloxycarbonyllclavam - 2 ylidene)ethylthio]pyridine oxide.

   100. (3R,5R,Z) - 2 - [2 - (1 - Oxidopyridinio - 4 - thio)ethylidene]clavam 3 - carboxylic acid and alkali metal and alkaline earth metal salts thereof.

   101. 4-Nitrobenzyl (3R,5R,Z) - 2 - [2 - (2 - hydroxyethyl)thioethylidene]clavam - 3 - carboxylate.

   102. (3R,5R,Z) - 2 - [2 - (2 - hydroxyethyl)thioethylidene]clavam - 3 - carboxylic acid and the alkali metal and alkaline earth metal salts thereof.

   103. Sodium (3R,5R,Z) - 2 - [2 - (2 - hydroxyethyl)thioethylidene]clavam 3 - carboxylate.

   104. 4-Nitrobenzyl (3R,5R,Z) - 2 - [2 - (cyanomethyl)thio ethylidene]clavam - 3 - carboxylate.

   105. (3R,5R,Z)- 2 - [2 - (Cyanomethyl)thioethylidene]clavam - 3 - carboxylic acid and alkali metal and alkaline earth metal salts thereof.

   106. Sodium (3R,5R,Z) - 2 - [2 - (cyanomethyl)thioethylidene]clavam - 3 carboxylate.

   107. (3R,5R,Z)- 2 - [2 - (2 - Aminoethylthio)ethylidene]clavam - 3 carboxylic acid.

   108. The physiologically acceptable salts of the acid as claimed in Claim 107.

   109. (3R,5R,Z) - [2 - (I - Methyl - 3 - pyridinio)thioethylidene]clavam - 3 carboxylate.

   110. The physiologically acceptable salts of the compounds as claimed in either of Claims 98 and 109.

   111. (3R,5R,Z) - 1 - Methyl - 3 - [2 - (3 - 14 - nitrobenzyloxy carbonyliclavam - 2 - ylidene)ethylthio]pyridinium iodide.

   112. The sodium salt of a compound as claimed in any of Claims 58, 60, 62, 76, 78, 80 and 82.

   113. The sodium salt of a compound as claimed in any of Claims 93 and 100.

   114. A pharmaceutical composition (including a veterinary composition) comprising at least one acid, physiologically acceptable salt or metabolically labile ester as claimed in any of Claims 1 to 17, 20, 21, 26, 27, 48, 49, 55, 56, 58, 60, 62, 64, 65, 67, 68, 70, 71, 73, 74, 76, 78, 80, 82, 102, 103 and 112 in admixture with a pharmaceutically acceptable carrier or diluent and/or a further plactam antibiotic.

   115. A pharmaceutical composition (including a veterinary composition) comprising at least one acid, physiologically acceptable salt or metabolically labile ester as claimed in any of Claims 24, 35, 50 and 105 to 110 in admixture with a pharmaceutically acceptable carrier or diluent and/or a further plactam antibiotic.

   116. A pharmaceutical composition (including a veterinary composition) comprising at least one acid, physiologically acceptable salt or metabolically labile ester as claimed in any of Claims 23, 25, 36, 84, 85, 87, 88, 90, 91, 93, 95, 96, 98, 100 and 113 in admixture with a pharmaceutically acceptable carrier or diluent and/or a further plactam antibiotic.

   117. A pharmaceutical composition (including a veterinary composition) comprising at least one acid, physiologically acceptable salt or metabolically labile ester as claimed in either of Claims 22 and 47 in admixture with a pharmaceutically acceptable carrier or diluent and/or a further plactam antibiotic.

   118. A composition as claimed in Claim 114, wherein the weight ratio of the compound of formula (II) to the further plactam antibiotic is in the range from 10:1 to 1:10.

   119. A composition as claimed in Claim 115, wherein the weight ratio of the compound of formula (lea) to the further plactam antibiotic is in the range from 10:1 to 1:10.

   120. A composition as claimed in Claim 116, wherein the weight ratio of the compound of formula (lea) to the further plactam antibiotic is in the range from 10:1 to 1:10.

   121. A composition as claimed in Claim 117, wherein the weight ratio of the compound of formula (IIa) to the further p-lactam antibiotic is in the range from 10:1 to 1:10.

   122. A composition as claimed in either of Claims 114 and 118 which is in the form of dosage units containing from 50 mg to 1 g of active compound of the invention when this is employed alone and from 100 mg to 1 g of plactam antibiotic when an active compound of the invention and a further plactam antibiotic are present.

   123. A composition as claimed in either of Claim 115 and 119 which is in the form of dosage units containing from 50 mg to 1 g of active compound of the invention when this is employed alone and from 100 mg to 1 g of plactam antibiotic when an active compound of the invention and a further plactam antibiotic are present.

   124. A composition as claimed in either of Claims 116 and 120 which is in the form of dosage units containing from 50 mg to 1 g of active compound of the invention when this is employed alone and from 100 mg to 1 g of plactam antibiotic when an active compound of the invention and a further plactam antibiotic are present.

   125. A composition as claimed in either of Claims 117 and 121 which is in the form of dosage units containing from 50 mg to 1 g of active compound of the invention when this is employed alone and from 100 mg to 1 g of plactam antibiotic when an active compound of the invention and a further p-lactam antibiotic are present.

   126. A composition as claimed in any of Claims 114, 118 and 122, wherein the further p-lactam antibiotic is selected from cephalexin, cephaloglycin, ampicillin, amoxycillin, carbenicillin and ticarcillin and their orally absorbed esters; cephalothin, cephaloridine, cefazolin, cephacetrile, and cephapirin, penicillin G a

   130. A composition as claimed in Claim 126, wherein the further plactam antibiotic is ampicillin or amoxycillin.

   131. A composition as claimed in Claim 127, wherein the further plactam antibiotic is ampicillin or amoxycillin.

   132. A composition as claimed in Claim 128, wherein the further plactam antibiotic is ampicillin or amoxycillin.

   133. A composition as claimed in Claim 129, wherein the further plactam antibiotic is ampicillin or amoxycillin.

   134. A composition as claimed in Claim 114 substantially as hereinbefore described.

   135. A composition as claimed in Claim 115 substantially as hereinbefore described.

   136. A composition as claimed in Claim 116 substantially as hereinbefore described.

   137. A composition as claimed in Claim 117 substantially as hereinbefore described.

   138. A process for the preparation of compounds of formula

   wherein Rd is as defined in Claim 51 and R' is as defined in Claim 1 which comprises reacting a compound of formula (III)

   (wherein X is a readily displaceable atom or group and R' is an esterified carboxyl group) with a sulphur nucleophile, if required in the presence of an acid binding agent, followed by cleavage of the esterified carboxyl group R', when a free acid is required, and subsequent salt formation when a salt is required.

   139. A process as claimed in Claim 138 for the production of a compound of formula (lId) in which R1 represents a carboxyl group or a salt thereof wherein a compound of formula (lId) in which R' represents a group --COOR'2, wherein R'2 represents a stannyl group containing up to 24 carbon atoms or an arylmethyl group containing up to 24 carbon atoms is initially produced, and cleavage of the ester group is effected by solvolysis or hydrogenolysis respectively followed by subsequent salt formation if desired.

   140. A process as claimed in Claim 139 for the production of an ester of formula (lId) wherein the compound of formula (lId) formed is esterified by reaction of a free acid of formula (IId) or a salt thereof with an alcohol, phenol, silanol or stannanol or a reactive derivative thereof.

   141. A process as claimed in any of Claims 138 to 140, wherein the readily displaceable substituent is a halogen atom or an acyloxy group.

   142. A process as claimed in Claim 141, wherein the readily displaceable substituent is an iodine atom or an aliphatic, araliphatic or aromatic carbonyloxy or sulphonyloxy group having up to 20 carbon atoms.

   143. A process as claimed in Claim 141, wherein the readily displaceable substituent is a chlorine or bromine atom.

   144. A process as claimed in any of Claims 138-143, wherein R' represents a 4-nitrobenzyloxycarbonyl group.

   145. A process as claimed in any of Claims 138-144, wherein the reagent providing the sulphur nucleophile is a compound of formula RdH or a salt thereof wherein Rd is as defined for the group R in Claim 1 or 2.

   146. A process as claimed in Claim 145, wherein the compound RdH is employed in the presence of an acid binding agent.

   147. A process as claimed in Claim 146, wherein the acid binding agent is an alkali metal alkoxide, a tertiary nitrogen base or a heterocyclic base.

   148. A process as claimed in Claim 145, wherein the compound RdH is employed, X is halogen and silver nitrate is present to assist reaction.

   149. A process as claimed in Claim 145, wherein, when Rd represents a group -S. C=Y. R3 orSO2. R2 wherein R3 and R2 are as defined in Claim 52, and the reagent R3. C=Y . SH or R2. SO2. H is employed in the form of a salt.

   150. A process as claimed in either of Claims 145 and 149, wherein the salt of the compound RdH is an alkali metal salt or an ammonium salt or substituted ammonium salt.

   151. A process for the production of compounds of formula (tri) as defined in Claim 1, wherein R is a group -SO. Ra or -SO2. R", RX being as defined in Claim 1, wherein a compound of formula (II) wherein R is a group . Ra is oxidised by a peracid, followed, in the case where R' represents an esterified carboxyl group, by cleavage of the esterified carboxyl group where a free acid is required, and subsequent salt formation if desired.

   152. A process as claimed in Claim 151, wherein, to prepare a compound of formula (II) in which R represents a group -SO. R", reaction is effected at below 10"C in the absence of excess peracid.

   153. A process as claimed in Claim 151, wherein, to prepare a compound of formula (11) in which R represents a group SO2 . Ra, reaction is effected at above 10"C in the presence of excess peracid.

   154. A process for the preparation of compounds of formula (lla) as claimed in Claim 22, wherein reaction is carried out in a manner as defined in any of Claims 138 to 144 and 146 to 148 and the reagent providing the sulphur nucleophile is a compound RaH or a salt thereof wherein Ra is as defined in Claim 22.

   155. A process for the production of compounds of formula (lea) as defined in Claim 22, wherein Ra represents a sulphoxide or sulphone wherein a compound of formula (IIa) wherein Ra represents a thio compound is oxidised by a peracid, followed, in the case where R' represents an esterified carboxyl group, by cleavage of the esterified carboxyl group where a free acid is required, and subsequent salt formation if desired.

   156. A process as claimed in Claim 155, wherein, to prepare the sulphoxide compound, reaction is effected at below 10 C in the absence of excess peracid.

   157. A process as claimed in Claim 155, wherein, to prepare the sulphone compound, reaction is effected at above 10 C in the presence of excess peracid.

   158. A process for the preparation of compounds of formula (lla) as claimed in Claim 23, wherein reaction is carried out in a manner as defined in any of Claims 138 to 144 and 146 to 148 and the reagent providing the sulphur nucleophile is a compound RaH or a salt thereof wherein Ra is as defined in Claim 23.

   159. A process for the production of compounds of formula (lea) as defined in Claim 23, wherein Ra represents a sulphoxide or sulphone wherein a compound of formula (lea) wherein Ra represents a thio compound is oxidised by a peracid, followed, in the case where R' represents an esterified carboxyl group, by cleavage of the esterified carboxyl group where a free acid is required, and subsequent salt formation if desired.

   160. A process as claimed in Claim 159, wherein, to prepare the sulphoxide compound, reaction is effected at below 10 C in the absence of excess peracid.

   161. A process as claimed in Claim 159, wherein, to prepare the sulphone compound, reaction is effected at above 10 C in the presence of excess peracid.

   162. A process for the preparation of compounds of formula (IIa) as claimed in Claim 24, wherein reaction is carried out in a manner as defined in any of Claims 138 to 144 and 146 to 148 and the reagent providing the sulphur nucleophile is a compound RaH or a salt thereof wherein Ra is as defined in Claim 24.

   163. A process for the production of compounds of formula (IIa) as defined in Claim 24, wherein Ra represents a sulphoxide or sulphone wherein a compound of formula (Ila) wherein Ra represents a thio compound is oxidised by a peracid, followed, in the case where R' represents an esterified carboxyl group, by cleavage of the esterified carboxyl group where a free acid is required, and subsequent salt formation is desired.

   164. A process as claimed in Claim 163, wherein, to prepare the sulphoxide compound, reaction is effected at below 10"C in the absence of excess peracid.

   165. A process as claimed in Claim 163, wherein, to prepare the sulphone compound, reaction is effected at above 10 C in the presence of excess peracid.

   166. A process for the preparation of compounds of formula (IIa) as claimed in Claim 25, wherein reaction is carried out in a manner as defined in any of Claims 138 to 144 and 146 to 148 and the reagent providing the sulphur nucleophile is a compound RaH or a salt thereof wherein Ra is as defined in Claim 25.

   167. A process for the production of compounds of formula (IIa) as defined in Claim 25, wherein Ra represents a sulphoxide or sulphone wherein a compound of formula (lla) wherein Ra represents a thio compound is oxidised by a peracid, followed, in the case where R' represents an esterified carboxyl group, by cleavage of the esterified carboxyl group where a free acid is required, and subsequent salt formation if desired.

   168. A process as claimed in Claim 167, wherein, to prepare the sulphoxide compound, reaction is effected at below 10"C in the absence of excess peracid.

   169. A process as claimed in Claim 167, wherein, to prepare the sulphone compound, reaction is effected at above 10 C in the presence of excess peracid.

   170. A process for the preparation of compounds of formula (IIa) as claimed in Claim 26, wherein reaction is carried out in a manner as defined in any of Claims 138 to 144 and 146 to 148 and the reagent providing the sulphur nucleophile is a compound R"H or a salt thereof wherein Ra is as defined in Claim 26.

   171..A process for the preparation of compounds of formula (IIa) as claimed in Claim 27, wherein reaction is carried out in a manner as defined in any of Claims 138 to 144 and,146 to 148 and the reagent providing the sulphur nucleophile is a compound R"H or a salt thereof wherein Ra is as defined in Claim 27.

   172. A process for the preparation of compounds as claimed in Claim 36, wherein reaction is carried out in a manner as defined in any of Claims 138 to 144, and 146 to 148 and the reagent providing the sulphur nucleophile is a compound of formula

   wherein Rp, R', R8 and R9 are as defined in Claim 36 or is a thiocyanate, thiosulphate or thiosulphonate salt.

   173. A process as claimed in Claim 172, wherein the salt is an alkali metal or amine salt.

   174. A process for the preparation of compounds as claimed in Claim 47, wherein reaction is carried out in a manner as defined in any of Claims 138 to 144 and 146 to 148 and the reagent providing the sulphur nucleophile is a hydrosulphide salt; a compound wherein R6 representsSH being produced, or the sulphur nucleophile is a trithiocarbonate salt and the trithiocarbonate product is decomposed by protonation to yield a compound in which Ra represents -SH.

   175. A process as claimed in Claim 174, wherein the displaceable substituent X is a halogen atom.

   176. A process wherein the compound of formula (lId) as defined in Claim 138 in which Rd is -SH is subjected to mild oxidation to produce the compound wherein Rd in the compound of formula (IId) represents the group

   wherein R' is as defined in Claim 1.

   177. A process as claimed in Claim 176, wherein oxidation is effected using iodine or atmospheric oxygen.

   178. A process wherein the compound of formula (IId) as defined in Claim 138 in which Rd is -SH may be obtained from the compound of formula (IId) wherein Rd represents the group

   wherein R1 is as defined in Claim 1 by mild reduction.

   179. A process as claimed in Claim 178, wherein reduction is effected using a dissolving metal reducing agent.

   180. A process for the preparation of a compound of formula (lId) as defined in Claim 138, wherein Rd represents an alkylthio, substituted alkylthio or acylthio group which comprises reacting a compound of formula (IId) wherein R' is an esterified carboxyl group and Rd represents an -SH group with an alkylating or acylating agent followed by cleavage of the esterified carboxyl group R' when a free acid is required, and subsequent salt formation when a salt is required.

   181. A process as claimed in Claim 180, wherein alkylation or acylation is effected in the presence of base.

   182. A process as claimed in Claim 180 or Claim 181, wherein the alkylating agent is an alkyl or aralkyl halide, an alkyl sulphate, an oxirane, an aziridine, a vinyl ether or an alkylenedialkylammonium salt.

   183. A process as claimed in Claim 180 or Claim 181, wherein the acylating agent has the formula R3 . C=Y . E wherein R3 and Y are as defined in Claim 52 and E is a halogen atom or acyloxy group.

   184. A process as claimed in any of Claims 180 to 182, wherein alkylation is effected using a two phase system and a phase transfer reagent or catalyst.

   185. A process as claimed in Claim 184, wherein the phase transfer reagent is a quaternary ammonium hydroxide or a crown ether.

   186. A process as claimed in Claim 184 in which the phase transfer catalyst is a quaternary ammonium halide, sulphate or hydrosulphate or a phosphonium salt.

   187. A process as claimed in Claim 186, wherein the phase transfer catalyst is tetra-n-butylammonium chloride, benzyltriethylammonium bromide, methyltricaprylammonium chloride or benzyltriphenylphosphonium chloride or bromide.

   188. A process for the preparation of a compound of formula (IId) as defined in Claim 138, wherein Rd represents a group -SR2 in which R2 is as defined in Claim 52 which comprises reaction of a compound of formula (IV)

   wherein R' represents an esterified carboxyl group with a djsulphide of formula R2S . SR2 in the presence of a trivalent phosphorus compound followed by cleavage of the esterified carboxyl group R' when a free acid is required and subsequent salt formation when a salt is required.

   189. A process as claimed in Claim 188, wherein the trivalent phosphorus compound has the formula PR'3R'4R'5 wherein R'3 and R14, which may be the same or different are hydrocarbyl, hydrocarbyloxy or hydrocarbylamino groups, and R15 is either as defined for R13 and R'4 or is a hydroxyl group.

   190. A process as claimed in Claim 189, wherein R'3, R14 and R15 are selected from alkyl, alkoxy, dialkylamino, or monocyclic aromatic groups or diarylamino groups.

   191. A process as claimed in any of Claims 188 to 190, wherein R2 represents an aromatic group.

   192. A process for the preparation of compounds of formula II as defined in Claim 138, wherein Rd carries a secondary, tertiary or quaternary amino group or a tertiary or quaternary heterocyclic nitrogen atom whereby a compound as defined in Claim 138 in which Rd carries a primary, secondary or tertiary amino group or a heterocyclic nitrogen atom is subjected to alkylation or aralkylation followed, by cleavage of the esterified carboxyl group R' when a free acid is required, and subsequent salt formation when a salt is required.

   193. A process as claimed in Claim 192 in which alkylation or aralkylation is effected by reaction with an alkyl or aralkyl halide or a dialkyl sulphate.

   194. A process as claimed in Claim 192 or Claim 193 in which alkylation is effected using iodomethane.

   195. A process for the preparation of compounds of formula (IId) as defined in Claim 138, wherein Rd contains an amino group which comprises reducing a compound of formula (IId) wherein Rd contains an azido group.

   196. A process as claimed in Claim 138 substantially as hereinbefore described.

   197. A process as claimed in Claim 145 substantially as hereinbefore described.

   198. A process as claimed in Claim 138 substantially as hereinbefore described with reference to any one of Examples 2, 8, 16, 28, 55, 66 and 71.

   199. A process as claimed in Claim 138 substantially as hereinbefore described with reference to any one of Examples 7, 10,13, 25, 29, 72 and 76.

   200. A process as claimed in Claim 138 substantially as hereinbefore described with reference to any of Examples 90, 91, 94, 99, 102, 104, 106 and 108.

   201. A process as claimed in Claim 138 substantially as hereinbefore described with reference to Example 85.

   202. A process as claimed in Claim 138 substantially as hereinbefore described, with reference to Example 86.

   203. A process as claimed in Claim 145 substantially as hereinbefore described with reference to any of Examples 1, 3, 17 to 21, 57, 63, 64 and 67 to 70.

   204. A process as claimed in Claim 145 substantially as hereinbefore described with reference to any of Examples 4, 5, 6, 9, 15, 22, 23, 73, 74, 75 and 77.

   205. A process as claimed in Claim 145 substantially as hereinbefore described with reference to Example 107.

   206. A process as claimed in Claim 145 substantially as hereinbefore described with reference to either of Examples 53 and 54.

   207. A process as claimed in Claim 154 substantially as hereinbefore described.

   208. A process as claimed in Claim 154 substantially as hereinbefore described with reference to Example 24.

   209. A process as claimed in Claim 151 substantially as hereinbefore described.

   210. A process as claimed in Claim 155 substantially as hereinbefore described.

   211. A process as claimed in Claim 158 substantially as hereinbefore described.

   212. A process as claimed in Claim 158 substantially as hereinbefore described with reference to Example 11.

   213. A process as claimed in Claim 159 substantially as hereinbefore described.

   214. A process as claimed in Claim 159 substantially as hereinbefore described with reference to either of Examples 34 and 61.

   215. A process as claimed in Claim 162 substantially as hereinbefore described.

   216. A process as claimed in Claim 162 substantially as hereinbefore described with reference to either of Examples 103 and 105.

   217. A process as claimed in Claim 163 substantially as hereinbefore described.

   218. A process as claimed in Claim 166 substantially as hereinbefore described.

   219. A process as claimed in Claim 166 substantially as hereinbefore described with reference to Example 12.

   * 220. A process as claimed in Claim 167 substantially as hereinbefore described.

   221. A process as claimed in Claim 167 substantially as hereinbefore described with reference to Example 35.

   222. A process as claimed in Claim 170 substantially as hereinbefore described.

   223. A process as claimed in Claim 170 substantially as hereinbefore described with reference to any of Examples 14, 39 and 82.

   224. A process as claimed in Claim 170 substantially as hereinbefore described with reference to any of Examples 97, 98 and 100.

   225. A process as claimed in Claim 171 substantially as hereinbefore described.

   226. A process as claimed in Claim 171 substantially as hereinbefore described with reference to either of Examples 88 and 89.

   227. A process as claimed in Claim 172 substantially as hereinbefore described.

   228. A process as claimed in Claim 172 substantially as hereinbefore described with reference to either of Examples 40 and 81.

   229. A process as claimed in Claim 174 substantially as hereinbefore described.

   230. A process as claimed in Claim 174 substantially as hereinbefore described with reference to any of Examples 41, 44, 45, 46 and 83.

   231. A process as claimed in Claim 176 substantially as hereinbefore described.

   232. A process as claimed in Claim 176 substantially as hereinbefore described with reference to either of Examples 48 and 84.

   233. A process as claimed in Claim 178 substantially as hereinbefore described.

   234. A process as claimed in Claim 180 substantially as hereinbefore described.

   235. A process as claimed in Claim 180 substantially as hereinbefore described with reference to any of Examples 42, 43, 47 and 49 to 52.

   236. A process as claimed in Claim 180 substantially as hereinbefore described with reference to any of Examples 87, 92 and 93.

   237. A process as claimed in Claim 188 substantially as hereinbefore described.

   238. A process as claimed in Claim 188 substantially as hereinbefore described with reference to any of Examples 26, 27, 62 and 65.

   239. A process as claimed in Claim 192 substantially as hereinbefore described.

   240. A process as claimed in Claim 192 substantially as hereinbefore described with reference to any of Examples 36, 37, 38, 78, 79 and 80.

   241. A process as claimed in Claim 192 substantially as hereinbefore described with reference to either of Examples 96 or 101.

   242. A process as claimed in Claim 195 substantially as hereinbefore described.

   243. A process as claimed in Claim 195 substantially as hereinbefore described with reference to Example 95.

   244. Compounds of formula (lId) as defined in Claim 138 whenever prepared by a process as claimed in Claim 138.

   245. Compounds as claimed in Claim 244, wherein in formula (lId), the group Rd is as defined in Claim 52.

   246. Compounds as claimed in Claim 245, wherein in formula (lId), the group Rd is a group -SR2, -SO. R2 or -SO2. R2 wherein R2 represents a C1.6 alkyl, alkenyl or alkynyl group; an aralkyl group having 1-6 carbon atoms in the alkyl portion; an aryl group; a cycloalkyl group having from 3-7 carbon atoms, or a carbon-attached 5-7 membered heterocyclic ring containing one or more heteroatoms optionally carrying one or more C1.6 alkyl groups, all of which groups are unsubstituted or substituted by a hydroxyl, substituted hydroxyl, carboxyl, substituted carboxyl, amino or substituted amino group.

   247. Compounds as claimed in Claim 246, wherein in formula (lId), the group Rd is a methylthio, ethylthio, propylthio, isopropylthio, butylthio, allylthio, propargylthio, phenylthio, benzylthio, phenethylthio, cyclohexylthio, pyridylthio, tetrahydropyranylthio and 5 - methyl - 1,3,4 - thiadiazol - 2 - ylthio group.

   248. Compounds of formula (lId) as shown in Claim 138, wherein R' is as defined in Claim 138 and Rd is a methylsulphonyl, methylsulphinyl, ethylsulphonyl or ethylsulphinyl group whenever prepared by a process as described either in Claim 138 or Claim 151.

   249. Compounds as claimed in Claim 247 or Claim 248 in the form of their acids, salts or metabolically labile esters.