US4427690A
Expired / Lapsed
US
⏱️ 0.0 years remaining
Esters of clavulanic acid
Assignee: Beecham Group PLC
•
Filing: 1976-09-24
•
Granted: 1984-01-24
•
Expires: 1996-09-24
Abstract
Abstract A new antibacterially active agent has been isolated from Streptomyces clavuligerus. This new compound which is designated clavulanic acid has the formula (I): <IMAGE> (I) 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.
Inventors
- 👤 Martin Cole
- 👤 Thomas T. Howarth
- 👤 Christopher Reading
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-05 14:23
CPC Classifications
C; C12; C12P; C12P17/00; C12P17/18; C12P17/188; A; A61; A61K; A61K31/00; A61K31/33; A61K31/395; A61K31/41; A61K31/42; A61K31/425; A61K31/429; A61K31/43; A61P; A61P31/00; A61P31/04; C07; C07D; C07D498/00; C07D498/02; C07D498/04; C07D503/00; C12N; C12N1/00; C12N1/20; C12N1/205; C12R; C12R2001/00; C12R2001/01; C12R2001/465; Y; Y02; Y02A; Y02A50/00; Y02A50/30
Claims Analysis
Total Claims: 222
Claim 1
Independent Claim
67 words
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.
Claim 2
Dependent Claim
67 words
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.
Claim 3
Dependent Claim
96 words
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.
Claim 4
Dependent Claim
96 words
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.
Claim 5
Independent Claim
113 words
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.
Claim 6
Independent Claim
113 words
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.
Claim 7
Dependent Claim
211 words
A clavulanic acid ester of the formula (V), (VI), (IX) or (X): ##STR18## wherein A 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 2 is hydrogen or methyl; A 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 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 2 R 3 wherein R 2 is hydrogen or lower alkyl, R 3 is hydrogen or lower alkyl or R 3 is linked to R 2 so that NR 2 R 3 is a 5- or 6-membered ring, A 7 is hydrogen or phenyl unsubstituted or mono-substituted by fluorine, chlorine, methyl or methoxyl and A 8 is phenyl unsubstituted or mono-substituted by fluorine, chlorine, methyl or methoxyl.
Claim 8
Dependent Claim
211 words
A clavulanic acid ester of the formula (V), (VI), (IX) or (X): ##STR18## wherein A 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 2 is hydrogen or methyl; A 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 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 2 R 3 wherein R 2 is hydrogen or lower alkyl, R 3 is hydrogen or lower alkyl or R 3 is linked to R 2 so that NR 2 R 3 is a 5- or 6-membered ring, A 7 is hydrogen or phenyl unsubstituted or mono-substituted by fluorine, chlorine, methyl or methoxyl and A 8 is phenyl unsubstituted or mono-substituted by fluorine, chlorine, methyl or methoxyl.
Claim 9
Dependent Claim
36 words
A clavulanic acid ester according to claim 4 wherein A 1 is hydrogen; A 2 is hydrogen or methyl; A 3 is methyl, ethyl, propyl, butyl, benzyl or phenyl; X is oxygen; and Y is oxygen.
Claim 10
Dependent Claim
43 words
A clavulanic acid ester according to claim 4 wherein the ester of clavulanic acid is of the formula (VII) or (VIII): ##STR20## wherein A 4 is hydrogen or methyl, A 5 is methyl, t-butyl or phenyl and A 6 is hydrogen or methoxyl.
Claim 11
Dependent Claim
91 words
A clavulanic acid ester according to claim 4 wherein the ester of clavulanic acid is of the formula (IX): ##STR21## wherein R 1 is a hydrocarbon of 1 to 9 carbon atoms unsubstituted or mono-substituted by halogen, lower alkoxy, lower acyl, hydroxyl, lower alkanoyloxy, a moiety of the formula NR 2 R 3 wherein R 2 is hydrogen or lower alkyl and R 3 is hydrogen or R 3 is linked to R 2 so that NR 2 R 3 is a 5- or 6-membered ring or a non-toxic salt thereof.
Claim 12
Dependent Claim
76 words
A clavulanic acid ester according to claim 7 wherein R 1 is alkyl of 1 to 9 carbon atoms or aralkyl of up to 9 carbon atoms unsubstituted or mono-substituted by halogen, methoxyl, hydroxyl, a group of the formula NR 2 R 3 wherein R 2 is methyl or ethyl and R 3 is methyl or ethyl, or the moiety NR 2 R 3 is a pyrrolidine, piperidine or morpholine ring or a nontoxic salt thereof.
Claim 13
Dependent Claim
37 words
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.
Claim 14
Dependent Claim
37 words
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.
Claim 15
Independent Claim
54 words
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.
Claim 16
Independent Claim
54 words
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.
Claim 17
Dependent Claim
7 words
A β-lactamase inhibitory ester of clavulanic acid.
Claim 18
Dependent Claim
7 words
A β-lactamase inhibitory ester of clavulanic acid.
Claim 19
Dependent Claim
7 words
A non-toxic hydrolyzable ester of clavulanic acid.
Claim 20
Dependent Claim
7 words
A non-toxic hydrolyzable ester of clavulanic acid.
Claim 21
Dependent Claim
20 words
An ester of clavulanic acid capable of being converted to clavulanic acid or a salt thereof by hydrolysis or hydrogenolysis.
Claim 22
Dependent Claim
20 words
An ester of clavulanic acid capable of being converted to clavulanic acid or a salt thereof by hydrolysis or hydrogenolysis.
Claim 23
Dependent Claim
13 words
A clavulanic acid ester according to claim 12 which is hydrolyzable in vivo.
Claim 24
Dependent Claim
22 words
A clavulanic acid ester according to claim 12 which hydrolyzes in mammalian tissues to yield clavulanic acid or a non-toxic salt thereof.
Claim 25
Dependent Claim
23 words
A clavulanic acid ester according to claim 12 which hydrolyzes in the human blood to yield clavulanic acid or a non-toxic salt thereof.
Claim 26
Dependent Claim
10 words
A clavulanic acid ester which is a lower alkyl ester.
Claim 27
Dependent Claim
10 words
A clavulanic acid ester which is a lower alkyl ester.
Claim 28
Dependent Claim
36 words
A clavulanic acid ester according to claim 13 which is readily converted to clavulanic acid or a non-toxic salt thereof by chemical or bio-chemical technique sufficiently mild not to degrade the reactive acid labile β-lactam ring.
Claim 29
Dependent Claim
16 words
A clavulanic acid ester according to claim 13 wherein the ester portion is removable by hydrogenolysis.
Claim 30
Dependent Claim
16 words
A clavulanic acid ester which is the benzyl, chlorobenzyl, bromobenzyl, methoxybenzyl, nitrobenzyl, benzhydryl or trityl ester.
Claim 31
Dependent Claim
16 words
A clavulanic acid ester which is the benzyl, chlorobenzyl, bromobenzyl, methoxybenzyl, nitrobenzyl, benzhydryl or trityl ester.
Claim 32
Dependent Claim
13 words
The clavulanic acid ester according to claim 1 which is the methyl ester.
Claim 33
Dependent Claim
13 words
The clavulanic acid ester according to claim 1 which is the p-nitrobenzyl ester.
Claim 34
Dependent Claim
13 words
The clavulanic acid ester according to claim 1 which is the benzyl ester.
Claim 35
Dependent Claim
13 words
The clavulanic acid ester according to claim 1 which is the pivaloyloxymethyl ester.
Claim 36
Dependent Claim
13 words
The clavulanic acid ester according to claim 4 which is the phthalidyl ester.
Claim 37
Dependent Claim
13 words
The clavulanic acid ester according to claim 1 which is the nonyl ester.
Claim 38
Dependent Claim
13 words
The clavulanic acid ester according to claim 1 which is the phenyl ester.
Claim 39
Dependent Claim
13 words
The clavulanic acid ester according to claim 1 which is the 2,2,2-trichloroethyl ester.
Claim 40
Dependent Claim
242 words
A composition according to claim 9 wherein the clavulanic acid ester is of the formula (V), (VI), (IX) or (X): ##STR22## wherein A 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 2 is hydrogen or methyl; A 3 is alkyl of 1 to 6 carbon atoms, phenyl, naphthyl, or phenyl mono-substituted by fluorine, chlorine, 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, X is oxygen or sulphur; Y is oxygen or sulphur and Z is ##STR23## R 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 2 R 3 wherein R 2 is hydrogen or lower alkyl, R 3 is hydrogen or lower alkyl or R 3 is linked to R 2 so that NR 2 R 3 is a 5- or 6-membered ring, or a non-toxic salt thereof, A 7 is hydrogen or phenyl unsubstituted or substituted by fluorine, chlorine, methyl or methoxyl and A 8 is phenyl unsubstituted or substituted by fluorine, chlorine, methyl or methoxyl.
Claim 41
Dependent Claim
34 words
A composition according to claim 29 wherein A 1 is hydrogen; A 2 is hydrogen or methyl; A 3 is methyl ethyl, propyl, butyl, benzyl or phenyl; X is oxygen; and Y is oxygen.
Claim 42
Dependent Claim
41 words
A composition according to claim 29 wherein the ester of clavulanic acid is of the formula (VII) or (VIII): ##STR24## wherein A 4 is hydrogen or methyl, A 5 is methyl, t-butyl or phenyl and A 6 is hydrogen or methoxyl.
Claim 43
Dependent Claim
93 words
A composition according to claim 29 wherein the ester of clavulanic acid is of the formula (IX): ##STR25## wherein R 1 is a hydrocarbon of 1 to 9 carbon atoms unsubstituted or mono-substituted by halogen, lower alkoxy, lower acyl, hydroxyl, lower alkanoyloxy or a non-toxic salt of a basic moiety of the formula NR 2 R 3 wherein R 2 is hydrogen or lower alkyl and R 3 is hydrogen or lower alkyl or R 3 is linked to R 2 so that NR 2 R 3 is a 5- or 6-membered ring.
Claim 44
Dependent Claim
74 words
A composition according to claim 32 wherein R 1 is alkyl of 1 to 9 carbon atoms or aralkyl of up to 9 carbon atoms unsubstituted or mono-substituted by halogen, methoxyl, hydroxyl or non-toxic salt of a basic group of the formula NR 2 R 3 wherein R 2 is methyl or ethyl and R 3 is methyl or ethyl, or the moiety NR 2 R 3 is a pyrrolidine, piperidine or morpholine ring.
Claim 45
Dependent Claim
64 words
A composition according to claim 32 wherein R 1 is straight chain alkyl of up to 6 carbon atoms unsubstituted or mono-substituted by methoxyl, hydroxyl, a non-toxic salt of a basic moiety of the formula NR 2 R 3 wherein R 2 is methyl or ethyl and R 3 is methyl or ethyl, or by chlorine, bromine, iodine, CCl 3 or CF 3 .
Claim 46
Dependent Claim
25 words
A composition according to claim 2 wherein the ester is the methyl, ethyl, propyl, butyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, benzyl, p-nitrobenzyl, phenyl, acetoxymethyl, pivaloyloxymethyl or 2-dimethylaminoethyl ester.
Claim 47
Dependent Claim
66 words
A clavulanic acid ester according to claim 7 wherein R 1 is straight chain alkyl of up to 6 carbon atoms unsubstituted or mono-substituted by methoxyl, hydroxyl, a nontoxic salt of a basic moiety of the formula NR 2 R 3 wherein R 2 is methyl or ethyl and R 3 is methyl or ethyl, or by chlorine, bromine, iodine, CCl 3 or CF 3 .
Claim 48
Dependent Claim
22 words
A composition according to claim 9 wherein the ester hydrolyzes in mammalian tissues to yield clavulanic acid or a non-toxic salt thereof.
Claim 49
Dependent Claim
23 words
A composition according to claim 9 wherein the ester hydrolyzes in the human blood to yield clavulanic acid or a non-toxic salt thereof.
Claim 50
Dependent Claim
14 words
A composition according to claim 9 wherein the ester is a lower alkyl ester.
Claim 51
Dependent Claim
21 words
A composition according to claim 9 wherein the ester is the benzyl, chlorobenzyl, bromobenzyl, methoxybenzyl or nitrobenzyl, benzhydryl or trityl ester.
Claim 52
Dependent Claim
10 words
A composition according to claim 9 in oral administration form.
Claim 53
Dependent Claim
10 words
A composition according to claim 9 in parenteral administration form.
Claim 54
Dependent Claim
10 words
A composition according to claim 9 in topical application form.
Claim 55
Dependent Claim
14 words
A composition according to claim 9 in a form suitable for administration by injection.
Claim 56
Dependent Claim
14 words
A composition according to claim 9 in a form suitable for administration by infusion.
Claim 57
Dependent Claim
13 words
A composition according to claim 2 wherein the ester is the methyl ester.
Claim 58
Dependent Claim
13 words
A composition according to claim 2 wherein the ester is the p-nitrobenzyl ester.
Claim 59
Dependent Claim
13 words
A composition according to claim 2 wherein the ester is the benzyl ester.
Claim 60
Dependent Claim
13 words
A composition according to claim 2 wherein the ester is the pivaloyloxymethyl ester.
Claim 61
Dependent Claim
13 words
A composition according to claim 2 wherein the ester is the phthalidyl ester.
Claim 62
Dependent Claim
13 words
A composition according to claim 2 wherein the ester is the nonyl ester.
Claim 63
Dependent Claim
13 words
A composition according to claim 2 wherein the ester is the phenyl ester.
Claim 64
Dependent Claim
13 words
A composition according to claim 2 wherein the ester is the 2,2,2-trichloroethyl ester.
Claim 65
Dependent Claim
242 words
A method according to claim 10 wherein the clavulanic acid ester is of the formula (V), (VI), (IX) or (X): ##STR26## wherein A 1 is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, naphthyl, phenyl mono-substituted by fluorine, chlorine, 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 2 is hydrogen or methyl; A 3 is alkyl of 1 to 6 carbon atoms, phenyl, naphthyl, or phenyl mono-substituted by fluorine, chlorine, 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, X is oxygen or sulphur; Y is oxygen or sulphur and Z is ##STR27## ,R 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 2 R 3 wherein R 2 is hydrogen or lower alkyl, R 3 is hydrogen or lower alkyl or R 3 is linked to R 2 so that NR 2 R 3 is a 5- or 6-membered ring, or a non-toxic salt thereof, A 7 is hydrogen or phenyl unsubstituted or substituted by fluorine, chlorine, methyl or methoxyl and A 8 is phenyl unsubstituted or substituted by fluorine, chlorine, methyl or methoxyl.
Claim 66
Dependent Claim
34 words
A method according to claim 54 wherein A 1 is hydrogen; A 2 is hydrogen or methyl; A 3 is methyl, ethyl, propyl, butyl, benzyl or phenyl; X is oxygen and Y is oxygen.
Claim 67
Dependent Claim
41 words
A method according to claim 54 wherein the ester of clavulanic acid is of the formula (VII) or (VIII): ##STR28## wherein A 4 is hydrogen or methyl, A 5 is methyl, t-butyl or phenyl and A 6 is hydrogen or methoxyl.
Claim 68
Dependent Claim
93 words
A method according to claim 54 wherein the ester of clavulanic acid is of the formula (IX): ##STR29## wherein R 1 is a hydrocarbon of 1 to 9 carbon atoms unsubstituted or mono-substituted by halogen, lower alkoxy, lower acyl, hydroxyl, lower alkanoyloxy or a non-toxic salt of a basic moiety of the formula NR 2 R 3 wherein R 2 is hydrogen or lower alkyl and R 3 is hydrogen or lower alkyl of R 3 is linked to R 2 so that NR 2 R 3 is a 5- or 6-membered ring.
Claim 69
Dependent Claim
75 words
A method according to claim 57 wherein R 1 is alkyl of 1 to 9 carbon atoms or aralkyl of up to 9 carbon atoms unsubstituted or mono-substituted by halogen, methoxyl, hydroxyl or a non-toxic salt of a basic group of the formula NR 2 R 3 wherein R 2 is methyl or ethyl and R 3 is methyl or ethyl, or the moiety NR 2 R 3 is a pyrrolidine, piperidine or morpholine ring.
Claim 70
Dependent Claim
64 words
A method according to claim 57 wherein R 1 is straight chain alkyl of up to 6 carbon atoms unsubstituted or mono-substituted by methoxyl, hydroxyl, a non-toxic salt of a basic moiety of the formula NR 2 R 3 wherein R 2 is methyl or ethyl and R 3 is methyl or ethyl, or by chlorine, bromine, iodine, CCl 3 or CF 3 .
Claim 71
Dependent Claim
27 words
A clavulanic acid ester according to claim 4 wherein the ester is the methyl, ethyl, propyl, butyl, 2,2,2-trichloroethyl, 2,2,2-trifluoroethyl, benzyl, p-nitrobenzyl, phenyl, acetoxymethyl, pivaloyloxymethyl or 2-dimethylaminoethyl ester.
Claim 72
Dependent Claim
23 words
A method according to claim 10 wherein the ester hydrolyzes in the human blood to yield clavulanic acid or a non-toxic salt thereof.
Claim 73
Dependent Claim
14 words
A method according to claim 10 wherein the ester is a lower alkyl ester.
Claim 74
Dependent Claim
20 words
A method according to claim 10 wherein the ester is benzyl, chlorobenzyl, bromobenzyl, methoxybenzyl or nitrobenzyl, benzhydryl, or trityl ester.
Claim 75
Dependent Claim
11 words
A method according to claim 10 wherein the administration is oral.
Claim 76
Dependent Claim
11 words
A method according to claim 10 wherein the administration is parenteral.
Claim 77
Dependent Claim
13 words
A method according to claim 10 wherein the administration is by topical application.
Claim 78
Dependent Claim
12 words
A method according to claim 10 wherein the administration is by injection.
Claim 79
Dependent Claim
12 words
A method according to claim 10 wherein the administration is by infusion.
Claim 80
Dependent Claim
13 words
A method according to claim 3 wherein the ester is the methyl ester.
Claim 81
Dependent Claim
13 words
A method according to claim 3 wherein the ester is the p-nitrobenzyl ester.
Claim 82
Dependent Claim
13 words
A method according to claim 3 wherein the ester is the benzyl ester.
Claim 83
Dependent Claim
13 words
A method according to claim 3 wherein the ester is the pivaloyloxymethyl ester.
Claim 84
Dependent Claim
13 words
A method according to claim 3 wherein the ester is the phthalidyl ester.
Claim 85
Dependent Claim
13 words
A method according to claim 3 wherein the ester is the nonyl ester.
Claim 86
Dependent Claim
13 words
A method according to claim 3 wherein the ester is the phenyl ester.
Claim 87
Dependent Claim
13 words
A method according to claim 3 wherein the ester is the 2,2,2-trichloroethyl ester.
Claim 88
Dependent Claim
22 words
A method according to claim 10 wherein the ester hydrolyzes in mammalian tissues to yield clavulanic acid or a non-toxic salt thereof.
Claim 89
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the ethyl ester.
Claim 90
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the n-propyl ester.
Claim 91
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the iso-propyl ester.
Claim 92
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the n-butyl ester.
Claim 93
Dependent Claim
14 words
The clavulanic ester according to claim 1 which is a branched chain butyl ester.
Claim 94
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the pentyl ester.
Claim 95
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the heptyl ester.
Claim 96
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the octyl ester.
Claim 97
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the decyl ester.
Claim 98
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the undecyl ester.
Claim 99
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the dodecyl ester.
Claim 100
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the vinyl ester.
Claim 101
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the allyl ester.
Claim 102
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the butenyl ester.
Claim 103
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the cyclopropyl ester.
Claim 104
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the cyclobutyl ester.
Claim 105
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the cyclohexyl ester.
Claim 106
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the cycloheptyl ester.
Claim 107
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the cyclohexenyl ester.
Claim 108
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the cyclohexadienyl ester.
Claim 109
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the methylcyclopentyl ester.
Claim 110
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the methylcyclohexyl ester.
Claim 111
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the benzhydryl ester.
Claim 112
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the phenylethyl ester.
Claim 113
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the naphthylmethyl ester.
Claim 114
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the naphthyl ester.
Claim 115
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the propynyl ester.
Claim 116
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the tolyl ester.
Claim 117
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the 2-chloroethyl ester.
Claim 118
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the 2,2,2-trifluoroethyl ester.
Claim 119
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the acetylmethyl ester.
Claim 120
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the benzoylmethyl ester.
Claim 121
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the 2-methoxyethyl ester.
Claim 122
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the 2-dimethylaminoethyl ester.
Claim 123
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the 2-diethylaminoethyl ester.
Claim 124
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the 2-piperidinoethyl ester.
Claim 125
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the 2-morpholinoethyl ester.
Claim 126
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the 3-dimethylaminopropyl ester.
Claim 127
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the p-chlorobenzyl ester.
Claim 128
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the p-methoxybenzyl ester.
Claim 129
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the p-bromobenzyl ester.
Claim 130
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the m-chlorobenzyl ester.
Claim 131
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the 6-methoxynaphthyl-2-methyl ester.
Claim 132
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the p-chlorophenyl ester.
Claim 133
Dependent Claim
12 words
The clavulanic ester according to claim 1 which is the p-methoxyphenyl ester.
Claim 134
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the ethyl ester.
Claim 135
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the n-propyl ester.
Claim 136
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the iso-propyl ester.
Claim 137
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the n-butyl ester.
Claim 138
Dependent Claim
17 words
A composition according to claim 2 wherein the clavulanic acid ester is a branched chain butyl ester.
Claim 139
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the pentyl ester.
Claim 140
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the heptyl ester.
Claim 141
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the octyl ester.
Claim 142
Dependent Claim
15 words
A composition according to claim 2 wherein the clabulanic acid ester is the decyl ester.
Claim 143
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the undecyl ester.
Claim 144
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the dodecyl ester.
Claim 145
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the vinyl ester.
Claim 146
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the allyl ester.
Claim 147
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the butenyl ester.
Claim 148
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the cyclopropyl ester.
Claim 149
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the cyclobutyl ester.
Claim 150
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the cyclohexyl ester.
Claim 151
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the cycloheptyl ester.
Claim 152
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the cyclohexenyl ester.
Claim 153
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the cyclohexadienyl ester.
Claim 154
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the methylcyclopentyl ester.
Claim 155
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the methylcyclohexyl ester.
Claim 156
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the benzhydryl ester.
Claim 157
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the phenylethyl ester.
Claim 158
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the naphthylmethyl ester.
Claim 159
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the naphthyl ester.
Claim 160
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the propynyl ester.
Claim 161
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the tolyl ester.
Claim 162
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the 2-chloroethyl ester.
Claim 163
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the 2,2,2-trifluoroethyl ester.
Claim 164
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the acetylmethyl ester.
Claim 165
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the benzoylmethyl ester.
Claim 166
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the 2-methoxyethyl ester.
Claim 167
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the 2-dimethylaminoethyl ester.
Claim 168
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the 2-diethylaminoethyl ester.
Claim 169
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the 2-piperidinoethyl ester.
Claim 170
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the 2-morpholinoethyl ester.
Claim 171
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the 3-dimethylaminopropyl ester.
Claim 172
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the p-chlorobenzyl ester.
Claim 173
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the p-methoxybenzyl ester.
Claim 174
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the p-bromobenzyl ester.
Claim 175
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the m-chlorobenzyl ester.
Claim 176
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the 6-methoxynaphthyl-2-methyl ester.
Claim 177
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the p-chlorophenyl ester.
Claim 178
Dependent Claim
15 words
A composition according to claim 2 wherein the clavulanic acid ester is the p-methoxyphenyl ester.
Claim 179
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the ethyl ester.
Claim 180
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the n-propyl ester.
Claim 181
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the iso-propyl ester.
Claim 182
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the n-butyl ester.
Claim 183
Dependent Claim
17 words
A method according to claim 3 wherein the clavulanic acid ester is a branched chain butyl ester.
Claim 184
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the pentyl ester.
Claim 185
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the heptyl ester.
Claim 186
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the octyl ester.
Claim 187
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the decyl ester.
Claim 188
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the undecyl ester.
Claim 189
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the dodecyl ester.
Claim 190
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the vinyl ester.
Claim 191
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the allyl ester.
Claim 192
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the butenyl ester.
Claim 193
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the cyclopropyl ester.
Claim 194
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the cyclobutyl ester.
Claim 195
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the cyclohexyl ester.
Claim 196
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the cycloheptyl ester.
Claim 197
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the cyclohexenyl ester.
Claim 198
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the cyclohexadienyl ester.
Claim 199
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the methylcyclopentyl ester.
Claim 200
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the methylcyclohexyl ester.
Claim 201
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the benzhydryl ester.
Claim 202
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the phenylethyl ester.
Claim 203
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the naphthylmethyl ester.
Claim 204
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the naphthyl ester.
Claim 205
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the propynyl ester.
Claim 206
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the tolyl ester.
Claim 207
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the 2-chloroethyl ester.
Claim 208
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the 2,2,2-trifluoroethyl ester.
Claim 209
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the acetylmethyl ester.
Claim 210
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the benzoylmethyl ester.
Claim 211
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the 2-methoxyethyl ester.
Claim 212
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the 2-dimethylaminoethyl ester.
Claim 213
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the 2-diethylaminoethyl ester.
Claim 214
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the 2-piperidinoethyl ester.
Claim 215
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the 2-morpholinoethyl ester.
Claim 216
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the 3-dimethylaminopropyl ester.
Claim 217
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the p-chlorobenzyl ester.
Claim 218
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the p-bromobenzyl ester.
Claim 219
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the m-chlorobenzyl ester.
Claim 220
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the 6-methoxynaphthyl-2-methyl ester.
Claim 221
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the p-chlorophenyl ester.
Claim 222
Dependent Claim
15 words
A method according to claim 3 wherein the clavulanic acid ester is the p-methoxyphenyl ester.
References Cited (Backward Citations)
US3801464A
Cited
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1987-01-23 | 1987-07-25 | 1988-01-24 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1991-01-23 | 1991-07-25 | 1992-01-24 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1995-01-23 | 1995-07-25 | 1996-01-24 | $7700.00 | Window Closed / Lapsed |