β-Lactam antibiotics, their preparation and use

Claim 1

A compound of the formula (II): ##STR41## a salt thereof or an ester thereof convertible to the free acid or salt thereof by biological or chemical methods wherein R 3 is hydrogen or a group of the formula (i): CR.sup.5 R.sup.6 R.sup.7 (i) wherein R 5 is hydrogen, sulphonato-oxy or a salt or ester thereof, hydroxy, alkoxy of 1 to 4 carbon atoms, OCOR 8 or OCO 2 R 8 wherein R 8 is alkyl of 1 to 4 carbon atoms, phenyl or benzyl unsubstituted or substituted by fluoro, chloro, bromo, alkoxy of 1 to 3 carbon atoms or nitro; R 6 is hydrogen or alkyl of 1 to 4 carbon atoms; and R 7 is hydrogen or alkyl of 1 to 4 carbon atoms, n is zero or one, X is a saturated or unsaturated hydrocarbon unsubstituted or substituted by bromo or chloro, and R 4 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, cyclobutyl, cyclohexyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, phenoxymethyl, phenoxyethyl, hydroxyphenoxymethyl, aminomethyl, aminoethyl, aminopropyl, phenacylmethyl, benzyloxycarbonylmethyl, benozyloxycarbonylethyl, methoxycarbonylmethyl, methoxycarbonylethyl, fluoromethyl, fluoroethyl, cyclopentenyl, cyclohexenyl, benzyl, phenethyl, thienylmethyl, furylmethyl, α-hydroxybenzyl, α-carbonylbenzyl, α-azidobenzyl, α-tetrazolylbenzyl, α-aminobenzyl, p-hydroxybenzyl, α-amino(p-hydroxy)benzyl, α-carboxy(p-hydroxy)benzyl, phenyl, furyl, thienyl, hydroxyphenyl, naphthyl, methoxyphenyl, chlorophenyl or methoxycarbonylphenyl.

Claim 27

A method of treating bacterial infections in humans and animals which comprises administering to a human or animal in need thereof an antibacterially effective amount of a compound of the formula (II): ##STR47## a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof convertible to the free acid or salt thereof by biological or chemical methods wherein R 3 is hydrogen or a group of the formula (i): CR.sup.5 R.sup.6 R.sup.7 (i) wherein R 5 is hydrogen, sulphonato-oxy or a salt or ester thereof, hydroxy, alkoxy of 1 to 4 carbon atoms, OCOR 8 or OCO 2 R 8 wherein R 8 is alkyl of 1 to 4 carbon atoms, phenyl or benzyl unsubstituted or substituted by fluoro, chloro, bromo, alkoxy of 1 to 3 carbon atoms or nitro; R 6 is hydrogen or alkyl of 1 to 4 carbon atoms; and R 7 is hydrogen or alkyl of 1 to 4 carbon atoms n is zero or one, X is a a saturated or unsaturated hydrocarbon unsubstituted or substituted by bromo or chloro, and R 4 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, cyclobutyl, cyclohexyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, phenoxymethyl, phenoxyethyl, hydroxyphenoxymethyl, aminomethyl, aminoethyl, aminopropyl, phenacylmethyl, benzyloxycarbonylmethyl benzoloxycarbonylethyl, methoxycarbonylmethyl, methoxycarbonylethyl, fluoromethyl, fluoroethyl, cyclopentenyl, cyclohexenyl, benzyl, phenethyl, thienylmethyl, furylmethyl, α-hydroxybenzyl, α-carbonylbenzyl, α-azidobenzyl, α-tetrazolylbenzyl, α-aminobenzyl, p-hydroxybenzyl, α-amino(p-hydroxy)benzyl, α-carboxy(p-hydroxy)benzyl, phenyl, furyl, thienyl, hydroxyphenyl, naphthyl, methoxyphenyl, chlorophenyl or methoxycarbonylphenyl, in combination with a pharmaceutically acceptable carrier.

Claim 28

A method of treating bacterial infections in humans and animals which comprises administering to a human or animal in need thereof an antibacterially effective amount of a compound of the formula (II): ##STR47## a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable ester thereof convertible to the free acid or salt thereof by biological or chemical methods wherein R 3 is hydrogen or a group of the formula (i): CR.sup.5 R.sup.6 R.sup.7 (i) wherein R 5 is hydrogen, sulphonato-oxy or a salt or ester thereof, hydroxy, alkoxy of 1 to 4 carbon atoms, OCOR 8 or OCO 2 R 8 wherein R 8 is alkyl of 1 to 4 carbon atoms, phenyl or benzyl unsubstituted or substituted by fluoro, chloro, bromo, alkoxy of 1 to 3 carbon atoms or nitro; R 6 is hydrogen or alkyl of 1 to 4 carbon atoms; and R 7 is hydrogen or alkyl of 1 to 4 carbon atoms n is zero or one, X is a a saturated or unsaturated hydrocarbon unsubstituted or substituted by bromo or chloro, and R 4 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, cyclobutyl, cyclohexyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, phenoxymethyl, phenoxyethyl, hydroxyphenoxymethyl, aminomethyl, aminoethyl, aminopropyl, phenacylmethyl, benzyloxycarbonylmethyl benzoloxycarbonylethyl, methoxycarbonylmethyl, methoxycarbonylethyl, fluoromethyl, fluoroethyl, cyclopentenyl, cyclohexenyl, benzyl, phenethyl, thienylmethyl, furylmethyl, α-hydroxybenzyl, α-carbonylbenzyl, α-azidobenzyl, α-tetrazolylbenzyl, α-aminobenzyl, p-hydroxybenzyl, α-amino(p-hydroxy)benzyl, α-carboxy(p-hydroxy)benzyl, phenyl, furyl, thienyl, hydroxyphenyl, naphthyl, methoxyphenyl, chlorophenyl or methoxycarbonylphenyl, in combination with a pharmaceutically acceptable carrier.

Claim 38

A method of treating bacterial infections in humans and animals which comprises administering to a human or animal in need thereof, an antibacterially effective amount of a compound of the formula (III): ##STR49## or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof wherein: (A) R 3 is hydrogen or a group of the sub-formula (a): CR.sup.5 R.sup.6 R.sup.7 (a) wherein R 5 is hydrogen, hydroxy, alkoxy of 1 to 4 carbon atoms, OCO 2 R 8 wherein R 8 is alkyl of 1 to 4 carbon atoms, phenyl, benzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, alkoxybenzyl or nitrobenzyl; R 6 is hydrogen or alkyl of 1 to 4 carbon atoms; R 7 is hydrogen or alkyl of 1 to 4 carbon atoms; X 1 is a group of the sub-formula (b) or (c): --S(O).sub.n --C.sub.2-6 -- (b) --S--CR.sup.9 ═CR.sup.10 -- (c) wherein n is zero or 1; R 9 is hydrogen or alkyl of 1 to 4 carbon atoms; R 10 is hydrogen or alkyl of 1 to 4 carbon atoms; and R 4 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, cyclobutyl, cyclohexyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, phenoxymethyl, phenoxyethyl, hydroxyphenoxymethyl, aminomethyl, aminoethyl, aminopropyl, phenacylmethyl, benzyloxycarbonylmethyl benzoloxycarbonylethyl, methoxycarbonylmethyl, methoxycarbonylethyl, fluoromethyl, fluoroethyl, cyclopentenyl, cyclohexenyl, benzyl, phenethyl, thienylmethyl, furylmethyl, α-hydroxybenzyl, α-carbonylbenzyl, α-azidobenzyl, α-tetrazolylbenzyl, α-aminobenzyl, p-hydroxybenzyl, α-amino(p-hydroxy)benzyl, α-carboxy (p-hydroxy)benzyl, phenyl, furyl, thienyl, hydroxyphenyl, naphthyl, methoxyphenyl, chlorophenyl or methoxycarbonylphenyl, or (B) R 3 is CH 3 CH(OH)O, R 4 is methyl, and X 1 is a group of the sub-formula (d) or (e): --S(O)--CH═CH-- (d) --S--C(Y)═CH-- (e) wherein Y is a bromine or chlorine atom; (C) R 3 is CH 3 CH(OSO 3 H)-- or a methyl or ethyl ester thereof; R 4 is methyl; and X 1 is a group of the sub-formula (f) or (g): --S(O).sub.n --CH.sub.2 --CH.sub.2 -- (f) --S(O).sub.n --C(Z)═CH-- (g) wherein n is zero or 1; and Z is a hyrogen, chlorine or bromine atom; or (D) R 3 is CH 3 CH(OSO 3 H)--or a methyl or ethyl ester thereof; R 4 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, cyclobutyl, cyclohexyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, phenoxymethyl, phenoxyethyl, hydroxyphenoxymethyl, aminomethyl, aminoethyl, aminopropyl, phenacylmethyl, benzyloxycarbonylmethyl, benzoloxycarbonylethyl, methoxycarbonylmethyl, methoxycarbonylethyl, fluoromethyl, fluoroethyl, cyclopentenyl, cyclohexenyl, benzyl, phenethyl, thienylmethyl, furylmethyl, α-hydroxybenzyl, α-carbonylbenzyl, α-azidobenzyl, α-tetrazolylbenzyl, α-aminobenzyl, p-hydroxybenzyl, α-amino(p-hydroxy)benzyl, α-carboxy (p-hydroxy)benzyl, phenyl, furyl, thienyl, hydroxyphenyl, naphthyl, methoxyphenyl, chlorophenyl or methoxycarbonylphenyl; and X 1 is --S--CH 2 --CH 2 --; or (E) R 3 is CH 3 CH(OSO) 3 H-- or a methyl or ethyl ester thereof; R 4 is ethyl; and X 1 is --S--CH═CH--; or (F) R 3 is CH 3 CH(SR o )-- wherein R o is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, cyclobutyl, cyclohexyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, phenoxymethyl, phenoxyethyl, hydroxyphenoxymethyl, aminomethyl, aminoethyl, aminopropyl, phenacylmethyl, benzyloxycarbonylmethyl benzoloxycarbonylethyl, methoxycarbonylmethyl, methoxycarbonylethyl, fluoromethyl, fluoroethyl, cyclopentenyl, cyclohexenyl, benzyl, phenethyl, thienylmethyl, furylmethyl, α-hydroxybenzyl, α-carbonylbenzyl, α-azidobenzyl, α-tetrazolylbenzyl, α-aminobenzyl, p-hydroxybenzyl, α-amino(p-hyroxy)benzyl, α-carboxy (p-hydroxy)benzyl, phenyl, furyl, thienyl, hydroxyphenyl, naphthyl, methoxyphenyl, chlorophenyl or methoxycarbonylphenyl, R 4 is methyl; and X 1 is --S--CH 2 CH 2 -- or a group of the sub-formula (h): --S(O).sub.n --CH═CH-- (h) wherein n is zero or 1: with the proviso that when R 3 is CH 3 CH(OSO 3 H)-- or a methyl or ethyl ester thereof, the C-5 and C-6 protons are cis, in combination with a pharmaceutically acceptable carrier.

Claim 39

A method of treating bacterial infections in humans and animals which comprises administering to a human or animal in need thereof, an antibacterially effective amount of a compound of the formula (III): ##STR49## or a pharmaceutically acceptable salt or in-vivo hydrolysable ester thereof wherein: (A) R 3 is hydrogen or a group of the sub-formula (a): CR.sup.5 R.sup.6 R.sup.7 (a) wherein R 5 is hydrogen, hydroxy, alkoxy of 1 to 4 carbon atoms, OCO 2 R 8 wherein R 8 is alkyl of 1 to 4 carbon atoms, phenyl, benzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, alkoxybenzyl or nitrobenzyl; R 6 is hydrogen or alkyl of 1 to 4 carbon atoms; R 7 is hydrogen or alkyl of 1 to 4 carbon atoms; X 1 is a group of the sub-formula (b) or (c): --S(O).sub.n --C.sub.2-6 -- (b) --S--CR.sup.9 ═CR.sup.10 -- (c) wherein n is zero or 1; R 9 is hydrogen or alkyl of 1 to 4 carbon atoms; R 10 is hydrogen or alkyl of 1 to 4 carbon atoms; and R 4 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, cyclobutyl, cyclohexyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, phenoxymethyl, phenoxyethyl, hydroxyphenoxymethyl, aminomethyl, aminoethyl, aminopropyl, phenacylmethyl, benzyloxycarbonylmethyl benzoloxycarbonylethyl, methoxycarbonylmethyl, methoxycarbonylethyl, fluoromethyl, fluoroethyl, cyclopentenyl, cyclohexenyl, benzyl, phenethyl, thienylmethyl, furylmethyl, α-hydroxybenzyl, α-carbonylbenzyl, α-azidobenzyl, α-tetrazolylbenzyl, α-aminobenzyl, p-hydroxybenzyl, α-amino(p-hydroxy)benzyl, α-carboxy (p-hydroxy)benzyl, phenyl, furyl, thienyl, hydroxyphenyl, naphthyl, methoxyphenyl, chlorophenyl or methoxycarbonylphenyl, or (B) R 3 is CH 3 CH(OH)O, R 4 is methyl, and X 1 is a group of the sub-formula (d) or (e): --S(O)--CH═CH-- (d) --S--C(Y)═CH-- (e) wherein Y is a bromine or chlorine atom; (C) R 3 is CH 3 CH(OSO 3 H)-- or a methyl or ethyl ester thereof; R 4 is methyl; and X 1 is a group of the sub-formula (f) or (g): --S(O).sub.n --CH.sub.2 --CH.sub.2 -- (f) --S(O).sub.n --C(Z)═CH-- (g) wherein n is zero or 1; and Z is a hyrogen, chlorine or bromine atom; or (D) R 3 is CH 3 CH(OSO 3 H)--or a methyl or ethyl ester thereof; R 4 is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, cyclobutyl, cyclohexyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, phenoxymethyl, phenoxyethyl, hydroxyphenoxymethyl, aminomethyl, aminoethyl, aminopropyl, phenacylmethyl, benzyloxycarbonylmethyl, benzoloxycarbonylethyl, methoxycarbonylmethyl, methoxycarbonylethyl, fluoromethyl, fluoroethyl, cyclopentenyl, cyclohexenyl, benzyl, phenethyl, thienylmethyl, furylmethyl, α-hydroxybenzyl, α-carbonylbenzyl, α-azidobenzyl, α-tetrazolylbenzyl, α-aminobenzyl, p-hydroxybenzyl, α-amino(p-hydroxy)benzyl, α-carboxy (p-hydroxy)benzyl, phenyl, furyl, thienyl, hydroxyphenyl, naphthyl, methoxyphenyl, chlorophenyl or methoxycarbonylphenyl; and X 1 is --S--CH 2 --CH 2 --; or (E) R 3 is CH 3 CH(OSO) 3 H-- or a methyl or ethyl ester thereof; R 4 is ethyl; and X 1 is --S--CH═CH--; or (F) R 3 is CH 3 CH(SR o )-- wherein R o is alkyl of 1 to 6 carbon atoms, alkenyl of 2 to 6 carbon atoms, cyclobutyl, cyclohexyl, hydroxymethyl, hydroxyethyl, hydroxypropyl, methoxymethyl, methoxyethyl, ethoxymethyl, ethoxyethyl, phenoxymethyl, phenoxyethyl, hydroxyphenoxymethyl, aminomethyl, aminoethyl, aminopropyl, phenacylmethyl, benzyloxycarbonylmethyl benzoloxycarbonylethyl, methoxycarbonylmethyl, methoxycarbonylethyl, fluoromethyl, fluoroethyl, cyclopentenyl, cyclohexenyl, benzyl, phenethyl, thienylmethyl, furylmethyl, α-hydroxybenzyl, α-carbonylbenzyl, α-azidobenzyl, α-tetrazolylbenzyl, α-aminobenzyl, p-hydroxybenzyl, α-amino(p-hyroxy)benzyl, α-carboxy (p-hydroxy)benzyl, phenyl, furyl, thienyl, hydroxyphenyl, naphthyl, methoxyphenyl, chlorophenyl or methoxycarbonylphenyl, R 4 is methyl; and X 1 is --S--CH 2 CH 2 -- or a group of the sub-formula (h): --S(O).sub.n --CH═CH-- (h) wherein n is zero or 1: with the proviso that when R 3 is CH 3 CH(OSO 3 H)-- or a methyl or ethyl ester thereof, the C-5 and C-6 protons are cis, in combination with a pharmaceutically acceptable carrier.