Europaisches Patentamt European Patent Office © Publication number: 0 008 899 A1 Office europeen des brevets © EUROPEAN PATENT APPLICATION © Application number. 79301684.1 © int ci.3: C 07 D 498/04 A 61 K 31/42, A 61 K 31/43 © Date of filing: 17.08.79 A 61 K 31/545 //(C07D498K>4, 263/00, 205/00), (A61K31/43, 31/42) © Priority: 05.09.78 GB 3564278 © Applicant: BEECHAM GROUP LIMITED B.eecham House Great West Road Brentford, Middlesex(GB) © Date of publication of application: 19.03.80 Bulletin 80/6 © Inventor: Zomaya, Iskander Ishu 19 Purdey Court The Avenue © Designated Contracting States: Worcester Park, Surrey(GB) AT BE CH DE FR GB IT LU NL SE © Inventor: Davies, John Sydney 17 Beaufort Road Reigate, Surrey(GB) © Representative: Cole, William Gwyn, Dr. et al, Beecham Pharmaceutical Research Centre Yew Tree Bottom Road Epsom, Surrey KT18 5XQ(GB) © Clavuianic acid derivatives, their preparation and use. The compounds of-the formula (I): and salts and esters thereof wherein R1 is a hydrogen atom or a lower alkyl, aryl or aralkyl group, R2 and R3 are indepen- dantly hydrogen, aryl, aralkyl, lower alkyl or substituted lower alkyl, or R3 is joined to R, to form a 5- or 6- membered ring and X is S, SO or SO2; have been found to be β-lactamase inhibitors and antibacterial agents. Their prep- aration and use is described. The present invention relates to new derivatives of clavulanic acid, to pharmaceutical compositions containing them and to a process for their preparation. In Belgian Patent No. 850779, it was disclosed that thioethers of clavulanic acid could be prepared by the reaction of an ester of clavulanic acid with a thiol or other thioetherifying agent. The later published French Patent No. 2342292 also related to thioethers of clavulanic acid. It has now been found that certain novel thiol derivatives can be prepared that offer a useful range of S-lactamase inhibitory properties and so serve to enhance the spectrum or penicillins and cephalosporins. In addition these compounds have antibacterial properties. The present invention provides the compounds of the formula (I): and salts and esters thereof wherein R1 is a hydrogen atom or a lower alkyl, aryl or aralkyl group, R2 and R3 are independantly hydrogen, aryl, aralkyl, lower alkyl or substituted lower alkyl, or R3 is joined to R1 to form a 4-, 5- or 6- membered ring or is joined to R2 to form a 5- or 6- membered ring and X is S, SO or SO2. When used herein the term "lower" means that the group contains not more than 6 carbon atoms and more suitably not more than 4 carbon atoms. When used herein the term "aryl" means a phenyl, thienyl or furyl group or a phenyl group substitute by a fluorine or chlorine atom or a lower alkyl or lower alkoxy group. When used herein the term "aralkyl" means a lower alkyl group substituted by an aryl group. When used herein the term "substituted alkyl" means a lower alkyl group substituted by a lower alkoxy group, an aryloxy group, a carboxylic acid group or a salt or lower alkyl or aralkyl ester of said carboxylic acid group or by an amino group or an aryl group. When used herein the term "aryloxyalkyl" mean a lower alkyl group substituted by an O-aryl group. Suitably the compound of this invention is of the formula (II): or a salt thereof wherein R1 is a hydrogen atom and R3 is a hydrogen atom or an aryl, aralkyl, lower alkyl or substituted lower alkyl group or R1 and R3 are joined sc that the CHR1NH.CO.R3 moiety forms a group of the sub- formula (a): wherein R4 is a hydrogen atom or a NH.CO.R5 group wherein R5 is a lower alkyl, lower alkoxy lower alkyl, aryl, aralkyl, aryloxyalkyl, lower alkoxy or aryloxy group and X is S, SO or SO2. One suitable sub-group of compounds of the formula (II) are those of the formula (III): and salts and esters thereof wherein R6 is a hydrogen atom or an aryl, aralkyl, lower alkyl or substituted lower alkyl group and X is S, SO or SO2. Suitably R6 is a hydrogen atom; an alkyl group of up to 4 carbon atoms; an alkyl group of up to 4 carbon atoms substituted by an alkoxy group of up to 4 carbon atoms; a phenyl group; a phenyl group substituted by a fluorine or chlorine atom or a methyl or methoxyl group; a benzyl group; or a benzyl group substituted by a fluorine or chlorine atom or a methyl or methoxyl group. Favoured values for R6 include the methyl group, the ethyl group and the phenyl group. A further suitable sub-group of compounds of the formula (II) are those of the formula (IV) and salts and esters thereof wherein R4 is as defined in relation to sub-formula (a) and X is S, SO or S02. Suitably R4 is a hydrogen atom. Suitably R4 is a NH.CO.R7 group where R7 is an alkyl group of up to 4 carbon atoms; an alkyl group of up to 4 carbon atoms substituted by an alkoxy group of up to 4 carbon atoms; an aryl group; an aralkyl group; or an aryloxyalkyl group. Similarly R7 may be an alkoxy group of up to 4 carbon atoms or an aryloxy group. Favoured values for R7 include the methyl, ethyl, phenyl, benzyl, phenoxymethyl, p-methoxyphenyl, p-methoxyphenoxymethyl, ethoxyethyl and like groups. A further suitable sub-group of compounds of the formula (I) is that of the formula (V): and salts and esters thereof wherein Ra is a lower alkyl, aryl or aralkyl group, R9 is a hydrogen atom or an aryl, aralkyl, lower alkyl or substituted lower alkyl group and X is S, SO or SO2. Suitable values for R8 include methyl, ethyl, n-propyl, n-butyl and phenyl. A favoured value for R8 is the methyl group. Suitably R9 is a hydrogen atom; an alkyl group of up to 4 carbon atoms; an alkyl group of up to 4 carbon atoms substituted by an alkoxy group of up to 4 carbon atoms; a phenyl group; a phenyl group substituted by a fluorine or chlorine atom or a methyl or methoxyl group; a benzyl group; or a benzyl group substituted by a fluorine or chlorine atom or a methyl or methoxyl group. Favoured values for R9 include the methyl group, the ethyl group and the phenyl group. Another suitable sub-group of compounds of the formula (I) is that of the formula (VI): and salts and esters thereof wherein R is a hydrogen 10 atom lower or a alkyl group and R11 is a lower alkyl group substituted by an amino group and optionally by an aryl group or R10 and R11 are joined so that the CHR10-NH-CO-R11 moiety forms a group of the sub-formula (b): and X is S, SO or SO2. Suitably R10 is a hydrogen atom. Suitably R10 is a methyl, ethyl, n-propyl or n-butyl group of which methyl and ethyl are preferred. One suitable sub-group of compounds of the formula (VI) is that of the formula (VII): and salts and esters thereof wherein R11 is an alkyl group of up to 4 carbon atoms substituted by an amino group or R11 is an alkyl group of up to 4 carbon atoms substituted by an amino group and by an aryl group and X is S, SO or SO2. Favoured values for R11 include those groups wherein the amino substituent is on the a-carbon atom , for example the aminomethyl, @-aminoethyl, a-aminobenzyl and like groups. A further suitable sub-group of compounds of the formula (VI) are the compound of the formula (VIII) and salts and esters thereof wherein X is S, SO or S02. The compound of the formula (VIII) may have the cis- or trans- stereochemistry about the monocyclic ß-lactam or may be in the form of mixtures of such compounds. Another suitable sub-group of compounds of the formula (I) are those of the formula (IX): and salts and esters thereof wherein R12 is a hydrogen atom or a lower alkyl, aryl or aralkyl group, R13 is an aryl, aralkyl, lower alkyl or substituted lower alkyl group and R14 is a lower alkyl group or is joined to R12 to form a 4-, 5- or 6- membered ring or is joined to R13 to form a 5- or 6- membered ring and X is S, SO or SO2. Suitable acyclic values for R12 include the hydrogen atom and the methyl, ethyl, n-propyl, n-butyl and phenyl groups. The hydrogen atom is a particularly suitable acyclic value for R12, as is the methyl group. Suitable acyclic values for R13 include an alkyl group of up to 4 carbon atoms; an alkyl group of up to 4 carbon atoms substituted by an alkoxy group of up to 4 carbon atoms; a phenyl group; a phenyl group substi- tuted by a fluorine or chlorine atom or a methyl or methoxyl group; a benzyl group; or a benzyl group substituted by a fluorine or chlorine atom or a methyl or methoxyl group. Favoured acyclic values for R13 include the methyl group, the ethyl group and the phenyl group and the optionally salted or esterified carboxymethyl group. Suitable values for -CHR12-N(R13)COR14 when R12 and R14 are linked include those of the sub-formula (c): wherein n is 1, 2 or 3 and R13is an acylic moiety as defined in relation to formula (VII).