US4962097A
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Method of treating bacterial infection with phosphorus containing DHP enzyme inhibitors
Assignee: Merck and Co Inc
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Filing: 1989-08-17
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Granted: 1990-10-09
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Expires: 2009-08-17
Abstract
Abstract Dipeptide mimics which contain phosphorus and their pharmaceutical use and preparation are disclosed. The compounds have dehydropeptidase (DHP) enzyme inhibitor activity.
Inventors
- 👤 William H. Parsons
- 👤 William R. Schoen
- 👤 Arthur A. Patchett
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-11-07 14:01
CPC Classifications
C; C07; C07F; C07F9/00; C07F9/02; C07F9/28; C07F9/30; C07F9/306; A; A61; A61K; A61K31/00; A61K31/33; A61K31/395; A61K31/40; C07F9/301; C07F9/302; C07F9/303; C07F9/547; C07F9/553; C07F9/576; C07F9/58
Claims Analysis
Total Claims: 6
Claim 1
Independent Claim
370 words
A method of treatment for bacterial infections which comprises administering to a host a therapeutically effective amount of a DHP-inhibiting compound of Formula II, in combination with a therapeutically effective amount of a carbapenem or penem antibiotic: ##STR53## wherein: R 1 is (a) C 2 -C 12 linear or branched unsubstituted alkyl; (b) C 1 -C 12 linear or branched substituted alkyl; (c) C 2 -C 12 linear or branched monoalkenyl; (d) C 2 -C 12 linear or branched alkynyl; (e) C 7 -C 20 aralkyl, wherein the alkyl chain is linear or branched C 1 -C 8 and the aryl moiety is C 6 -C 12 ; (f) C 4 -C 10 cycloalkylalkyl; (g) C 3 -C 7 cycloalkyl; wherein said above values for R 1 , excluding (a), can be substituted by one or more: C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyloxy, C 3 j-C 6 cycloalkylthio, C 6 -C 12 aryloxy, C 1 -C 4 alkylthio, C 6 -C 12 arylthio, C 7 -C 10 aralkyloxy, C 7 -C 16 aralkylthio; R 5 is (a) H or C 1 -C 12 linear or branched alkyl; (b) C 2 -C 12 linear or branched monoalkenyl; (c) C 7 -C 20 aralkyl, wherein the alkyl chain is linear or branched C 1 -C 8 and the aryl moiety is C 6 -C 12 ; (d) C 4 -C 10 cycloalkylalkyl (e) C 3 -C 7 cycloalkyl (f) heterocyclic alkyl, wherein the alkyl chain is linear or branched C 1 -C 8 and the heterocyclic ring is 5-6 membered, optionally fused benzene ring, fully aromatic, containing 1-2 O, N or S heteroatoms; wherein said above value for R 5 can be substituted by one or more: halo, hydroxy, carboxy, C 1 -C 4 alkoxycarbonyl, C 7 -C 16 arylalkoxycarbonyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxy, C 6 -C 12 aryloxy, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkylthio, amino, mono- or di-C 1 -C 8 alkylamino, thio, C 1 -C 4 alkylthio, C 6 -C 12 arylthio, C 7 -C 16 aralkylthio, or the radical --S--(CH 2 )n--CH(NH 2 )COOH, where n=1-2; and including DHP-inhibiting stereoisomers and racemates thereof Structure II.
Claim 2
Independent Claim
370 words
A method of treatment for bacterial infections which comprises administering to a host a therapeutically effective amount of a DHP-inhibiting compound of Formula II, in combination with a therapeutically effective amount of a carbapenem or penem antibiotic: ##STR53## wherein: R 1 is (a) C 2 -C 12 linear or branched unsubstituted alkyl; (b) C 1 -C 12 linear or branched substituted alkyl; (c) C 2 -C 12 linear or branched monoalkenyl; (d) C 2 -C 12 linear or branched alkynyl; (e) C 7 -C 20 aralkyl, wherein the alkyl chain is linear or branched C 1 -C 8 and the aryl moiety is C 6 -C 12 ; (f) C 4 -C 10 cycloalkylalkyl; (g) C 3 -C 7 cycloalkyl; wherein said above values for R 1 , excluding (a), can be substituted by one or more: C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyloxy, C 3 j-C 6 cycloalkylthio, C 6 -C 12 aryloxy, C 1 -C 4 alkylthio, C 6 -C 12 arylthio, C 7 -C 10 aralkyloxy, C 7 -C 16 aralkylthio; R 5 is (a) H or C 1 -C 12 linear or branched alkyl; (b) C 2 -C 12 linear or branched monoalkenyl; (c) C 7 -C 20 aralkyl, wherein the alkyl chain is linear or branched C 1 -C 8 and the aryl moiety is C 6 -C 12 ; (d) C 4 -C 10 cycloalkylalkyl (e) C 3 -C 7 cycloalkyl (f) heterocyclic alkyl, wherein the alkyl chain is linear or branched C 1 -C 8 and the heterocyclic ring is 5-6 membered, optionally fused benzene ring, fully aromatic, containing 1-2 O, N or S heteroatoms; wherein said above value for R 5 can be substituted by one or more: halo, hydroxy, carboxy, C 1 -C 4 alkoxycarbonyl, C 7 -C 16 arylalkoxycarbonyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxy, C 6 -C 12 aryloxy, C 3 -C 6 cycloalkyloxy, C 3 -C 6 cycloalkylthio, amino, mono- or di-C 1 -C 8 alkylamino, thio, C 1 -C 4 alkylthio, C 6 -C 12 arylthio, C 7 -C 16 aralkylthio, or the radical --S--(CH 2 )n--CH(NH 2 )COOH, where n=1-2; and including DHP-inhibiting stereoisomers and racemates thereof Structure II.
Claim 3
Dependent Claim
15 words
The method of claim 1 wherein R 1 is cyclohexylmethyl, isobutyl, ethyl, benzyl, or n-pentyl.
Claim 4
Dependent Claim
140 words
The method of claim 1 wherein: R 5 is (a) C 1 -C 12 linear or branched alkyl; (b) C 2 -C 12 linear or branched monoalkenyl; (c) C 7 -C 20 aralkyl, wherein the alkyl chain is linear or branched C 1 -C 8 and the aryl moiety is C 6 -C 12 ; wherein said above values for R 5 can be substituted by one or more: halo, hydroxy, carboxy, C 1 -C 4 alkoxycarbonyl, C 7 -C 16 arylalkoxycarbonyl, C 3 -C 7 cycloalkyl, C 1 -C 4 alkoxy, C 6 -C 12 aryloxy, amino, mono- or di-C 1 -C 8 alkylamino, thio, C 1 -C 4 alkylthio, C 6 -C 12 arylthio, C 7 -C 16 aralkylthio, or the radical --S--(CH 2 ) n --CH(NH 2 )COOH, and including DHP-inhibiting stereoisomers and racemates thereof Structure II.
Claim 5
Dependent Claim
29 words
The method of claim 1 in which the stereochemical configuration of the carbon attached to R 1 is (R) or (SR) and R 5 is in the "Z" configuration.
Claim 6
Dependent Claim
50 words
The method of claim 1 with said DHP-inhibiting compound being: (1-amino-2-cyclohexylethyl) 2-carboxy-4-methyl (E & Z)-2-butenyl phosphinic acids; (1-amino-2-cyclohexylethyl) 2-carboxy-3(Z)-cyclohexyl2-butenyl phosphinic acid; (1-aminohexyl) 2-carboxy-2(Z)-octenyl phosphinic acid; (1-aminohexyl) 2-carboxy-4-cyclopentyl-2(Z)-butenyl phosphinic acid; (1-amino-2-cyclohexylethyl) 2-carboxy-2(Z)-octenyl phosphinic acid; (1-amino-2-cyclohexylethyl) 2-carboxy-4-cyclopentyl2 (Z)-butenyl phosphinic acid; (1-aminohexyl) 2-carboxy-3-cyclohexyl-2(Z)-butenyl phosphinic acid; [1(R)-amino-2-cyclohexylethyl]-2-carboxy-4-methyl-2 (Z)-butenylphosphinic acid; [1(R)-amino-2-cyclohexylethyl]-2-carboxy-3(Z)-cyclohexyl-2-propenyl phosphinic acid; [1(R)-amino-2-cyclohexylethyl]-2-carboxy-4-cyclopentyl-2(Z)-butenylphosphinic acid.
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