Esters of clavulanic acid
AssigneeBeecham Group Limited
InventorsMartin Cole, Thomas T. Howarth, Christopher Reading
Life of this patent
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Abstract
A new antibacterially active agent has been isolated from Streptomyces clavuligerus. This new compound which is designated clavulanic acid has the formula (I): ##STR1## In addition to being a broad spectrum antibiotic of medium potency, clavulanic acid and its salts and esters have the ability to enhance the effectiveness of .beta.-lactam antibiotics against many .beta.-lactamase producing bacteria.
Claims211
A clavulanic acid ester wherein the ester is the methyl, ethyl, n-propyl, iso-propyl, straight or branched butyl, pentyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, vinyl, allyl, butenyl, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclohexenyl, cyclohexadienyl, methylcyclopentyl, methylcyclohexyl, benzyl, benzhydryl, phenylethyl, naphthylmethyl, phenyl, naphthyl, propynyl, tolyl, 2-chloroethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, acetylmethyl, benzoylmethyl, 2-methoxyethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl, 2-piperidinoethyl, 2-morpholinoethyl, 3-dimethylaminopropyl, p-chlorobenzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, m-chlorobenzyl, 6-methoxynaphthyl-2-methyl, p-chlorophenyl or p-methoxyphenyl ester of clavulanic acid.
A pharmaceutically composition useful for treating bacterial infections in humans and animals which comprises an anti-bacterially effective amount of a pharmaceutically acceptable clavulanic acid ester selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, straight or branched butyl, pentyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, vinyl, allyl, butenyl, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclohexenyl, cyclohexadienyl, methylcyclopentyl, methylcyclohexyl, benzyl, benzhydryl, phenylethyl, naphthylmethyl, phenyl, naphthyl, propynyl, tolyl, 2-chlorenthyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, acetylmethyl, benzoylmethyl, 2-methoxyethyl, 2-dimethylaminoethyl, 2-diethylaminoetihyl, 2-piperidinoethyl, 2-morpholinoethyl, 3-dimethylaminopropyl, p-chlorobenzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, m-chlorobenzyl, 6-methoxynaphthyl-2-methyl, p-chlorophenyl and p-methoxyphenyl ester of clavulanic acid, in combination with a pharmaceutically acceptable carrier.
A method of treating bacterial infections in humans and animals which comprises administering to a human or animal in need thereof an anti-bacterially effective amount of a pharmaceutical composition which comprises an anti-bacterially effective amount of a pharmaceutically acceptable clavulanic acid ester selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl, straight or branched butyl, pentyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, vinyl, allyl, butenyl, cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, cyclohexenyl, cyclohexadienyl, methylcyclopentyl, methylcyclohexyl, benzyl, benzhydryl, phenylethyl, naphthylmethyl, phenyl, naphthyl, propynyl, tolyl, 2-chlorethyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, acetylmethyl, benzoylmethyl, 2-methoxyethyl, 2-dimethylaminoethyl, 2-diethylaminoethyl, 2-piperidinoethyl, 2-morpholinoethyl, 3-dimethylaminopropyl, p-chlorobenzyl, p-methoxybenzyl, p-nitrobenzyl, p-bromobenzyl, m-chlorobenzyl, 6-methoxynaphthyl-2-methyl, p-chlorophenyl and p-methoxyphenyl ester of clavulanic acid, in combination with a pharmaceutically acceptable carrier.
A clavulanic acid ester of the formula (V), (VI), (IX) or (X):
- ##STR18## wherein A.sub.1 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, naphthyl, phenyl mono-substituted by fluorine, chorine, methyl or methoxy or aralkyl wherein the aryl moiety is phenyl, naphthyl, or phenyl mono-substituted by fluorine, chlorine, methyl or methoxy, and the alkyl moiety is of 1 to 6 carbon atoms;
- A.sub.2 is hydrogen or methyl;
- A.sub.3 is alkyl of 1 to 6 carbon atoms, phenyl, naphthyl, or phenyl mono-substituted by fluorine, chlorine, methyl or methoxy and the alkyl moiety is of 1 to 6 carbon atoms;
- X is oxygen os sulphur;
- Y is oxygen or sulphur;
- and Z is ##STR19## R.sup.1 is a hydrocarbon of 1-9 carbon atoms unsubstituted or mono-substituted by halogen, lower alkoxy, lower alkanoyl, hydroxyl, lower alkanoyloxy, a basic group of the formula NR.sup.2 R.sup.3 wherein R.sup.2 is hydrogen or lower alkyl, R.sup.3 is hydrogen or lower alkyl or R.sup.3 is linked to R.sup.2 so that NR.sup.2 R.sup.3 is a 5- or 6-membered ring, A.sub.7 is hydrogen or phenyl unsubstituted or mono-substituted by fluorine, chlorine, methyl or methoxyl and A.sub.8 is phenyl unsubstituted or mono-substituted by fluorine, chlorine, methyl or methoxyl.
A pharmaceutical composition useful for treating bacterial infections in humans and animals which comprises an antibacterially effective amount of a pharmaceutically acceptable clavulanic acid ester which is hydrolyzable in vivo, in combination with a pharmaceutically acceptable carrier.
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 pharmaceutical composition which comprises an antibacterially effective amount of a pharmaceutically acceptable clavulanic acid ester which is hydrolyzable in vivo, in combination with a pharmaceutically acceptable carrier.
A .beta.-lactamase inhibitory ester of clavulanic acid.
A non-toxic hydrolyzable ester of clavulanic acid.
An ester of clavulanic acid capable of being converted to clavulanic acid or a salt thereof by hydrolysis or hydrogenolysis.
A clavulanic acid ester which is a lower alkyl ester.
A clavulanic acid ester which is the benzyl, chlorobenzyl, bromobenzyl, methoxybenzyl, nitrobenzyl, benzhydryl or trityl ester.
Dependencies are inferred from the claim text.