Derivatives of clavulanic acid, their preparation and their use

A method of treating bscterial infections in humans and animals which comprises administering to a human or animal in need thereof a synergistically effective amount of a compound of the formula (II):

• ##STR16## a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof wherein X is tetrazolyl attached via a nitrogen atom, said tetrazolyl moiety being unsubstituted or substituted by a non-toxic carboxyl salt, an in-vivo hydrolyzable carboxyl ester of the formula (b), (C), (d) or (e):
• --CO--O--CHR.sup.3 --O--CO--R.sup.4 (b)
• --CO--O--R.sup.5 --NR.sup.6 R.sup.7 (c)
• CO--OA.sup.1 (d)
• or
• CO--O--CHA.sup.2 A.sup.3 (e)
• wherein R.sup.3 is hydrogen, methyl or phenyl;
• R.sup.4 is alkyl of 1 to 6 carbon atoms, phenyl, phenylalkyl of 1 to 3 carbon atoms in the alkyl moiety, alkoxy of 1 to 6 carbon atoms, phenoxy or phenylalkoxy of 1 to 3 carbon atoms in the alkyl moiety;
• or R.sup.3 and R.sup.4 are joined to form a 1,2-diphenylene or 3,4-dimethoxy-1,2-diphenylene moiety;
• R.sup.5 is methylene or ethylene;
• R.sup.6 and R.sup.7 are each methyl or ethyl;
• A.sup.1 is alkyl of 1 to 6 carbon atoms unsubstituted or substituted by alkoxy of 1 to 7 carbon atoms;
• A.sup.2 is alkenyl of 2 to 7 carbon atoms unsubstituted or substituted by phenyl;
• phenyl unsubstituted or substituted by fluoro, chloro, bromo, nitro, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms, and A.sup.3 is hydrogen;
• alkyl of 1 to 4 carbon atoms or phenyl unsubstituted or substituted by fluoro, chloro, bromo, nitro, alkyl of 1 to 4 carbon atoms or alkoxy of 1 to 4 carbon atoms;
• alkoxy of 1 to 6 carbon atoms, alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms or aryl unsubstituted or substituted by hydroxy, halo, aryl, carboxy, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms, arylalkoxy of 1 to 6 carbon atoms in the alkyl moiety, arylcarbonyl, alkylthio of 1 to 6 carbon atoms in the alkyl moiety, arylthio, amino, azido, mono-alkylamino of 1 to 6 carbon atoms in the alkyl moiety or di-alkylamino of 1 to 6 carbon atoms in each alkyl moiety;
• azido;
• isocyani;
• cyano;
• nitro;
• bromo;
• chloro;
• or is a group of the sub-formula (a):
• --(CO).sub.n --NR.sup.1 R.sup.2 (a)
• wherein n is zero or one;
• R.sup.1 is hydrogen or alkyl of 1 to 6 carbon atoms, alkanoyl of 1 to 6 carbon atoms or arylcarbonyl unsubstituted or substituted by one or more hydroxy, halo, carboxy, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms in the alkoxy moiety, aralkoxy of 1 to 10 carbon atoms in the alkoxy moiety, arylcarbonyl, alkylthio of 1 to 6 carbon atoms in the alkyl moiety, arylthio, amino, alkylamino of 1 to 6 carbon atoms in the alkyl moiety or di-alkylamino of 1 to 6 carbon atoms in each alkyl moiety;
• and R.sup.2 is hydrogen, alkyl of 1 to 6 carbon atoms, or alkanoyl of 1 to 6 carbon atoms, or R.sup.1 or R.sup.2 is methyl substituted by carboxy, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms or arylcarbonyl;
• or R.sup.2 is not methyl, the R.sup.2 moiety is substituted by hydroxy, halo, carboxy, alkanoyl of 1 to 6 carbon atoms, alkanoyloxy of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkoxycarbonyl of 1 to 6 carbon atoms in the alkoxy moiety, arylalkoxy of 1 to 6 carbon atoms in the alkoxy moiety, arylcarbonyl, alkylthio of 1 to 6 carbon atoms, arylthio, amino, alkylamino of 1 to 6 carbon atoms or di-alkylamino of 1 to 6 carbon atoms;
• or R.sup.1 and R.sup.2 are joined to form with the nitrogen atom to which they are attached, a 4-, 5- or 6-membered ring wherein the nitrogen atom is the only heteroatom and wherein aryl as used herein is phenyl, pyrrolyl, furyl, thienyl, indolyl, benzofuryl, or thionaphthyl, and an antibacterially effective amount of a penicillin, in combination with a pharmaceutically acceptable carrier.