US5147867A
Expired / Lapsed
US
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Phosphorus containing enzyme inhibitors
Assignee: Merck and Co Inc
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Filing: 1992-01-21
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Granted: 1992-09-15
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Expires: 2012-01-21
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
2026-11-08 05:03
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: 8
Claim 1
Independent Claim
372 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 I, 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 -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 2 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 heterocyclyl ring is 5-6 membered, optionally fused with a benzene ring, fully aromatic, containing 1-2: O, N or S heteroatoms; wherein said above values for R 2 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, and including DHP-inhibiting stereoisomers and racemates thereof Structure I.
Claim 2
Independent Claim
372 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 I, 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 -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 2 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 heterocyclyl ring is 5-6 membered, optionally fused with a benzene ring, fully aromatic, containing 1-2: O, N or S heteroatoms; wherein said above values for R 2 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, and including DHP-inhibiting stereoisomers and racemates thereof Structure I.
Claim 3
Dependent Claim
14 words
The method of claim 1 wherein R 1 is cyclohexylmethyl, isobutyl, ethyl, benzyl, or
Claim 4
Dependent Claim
129 words
The method of claim 1 wherein: R 2 is C 1 -C 10 linear or branched alkyl; C 7 -C 14 aralkyl; wherein both groups can be substituted with halo, amino, mono- or di-C 1 -C 4 linear or branched alkylamino, carboxyl, C 1 -C 4 alkoxycarbonyl, hydroxy, C 1 -C 4 alkoxy, C 5 -C 6 cycloalkyl, C 6 -C 10 aryloxy, thio, C 1 -C 4 linear or branched alkylthio, C 6 -C 10 arylthio, C 7 -C 14 aralkylthio, --S--(CH 2 ) n --CH(NH 2 )CO 2 H, and wherein the aryl groups can further be substituted by linear or branched C 1 -C 4 alkyl; R 3 and R 4 are hydrogen, C 1 -C 4 linear or branched alkyl, C 7 -C 14 aralkyl.
Claim 5
Dependent Claim
33 words
The method of claim 1 in which the stereochemical configurations of the carbon attached to R 1 is (R) or (SR), and the carbon attached to R 2 is (R), (RS), or (S).
Claim 6
Dependent Claim
27 words
The method of claim 4 in which the stereochemical configurations of the carbon attached to R 1 is (R) and to R 2 is (S) or (RS).
Claim 7
Dependent Claim
48 words
The method of claim 1 in which the specific compound of Formula I is: 1-amino-3-methylbutyl-[2-carboxy-1-hexyl]phosphinic acid; 1-aminopropyl-[2-carboxy-4-phenyl-1-butyl]-phosphinic; 1-aminopropyl-[2-carboxy-1-butyl]phosphinic acid; 1-aminopropyl-[2-carboxy-1-hexyl]phosphinic acid; 1-aminopropyl-2-phenylethyl-[2-carboxy-1-hexyl]-phosphinic acid; (1-amino-2-cyclohexylethyl)-2-carboxy-5-(4-pyridyl)-pentyl phosphinic acid; 1-amino-2-cyclohexylethyl-[2-carboxy-5-(4-methyl)-1-pentyl phosphinic acid; (1-amino-2-cyclohexylethyl)-2-carboxy-3-cyclohexyl-1-propyl phosphinic acid; (1-amino-1-hexyl)-2-carboxy-1-octyl phosphinic acid; (1-amino-1-hexyl)-2-carboxy-4-cyclopentyl-1-butyl phosphinic acid; (1-amino-2-cyclohexylethyl)-2-carboxy-1-octyl phosphinic acid; (1-amino-2-cyclohexylethyl)-2-carboxy-4-cyclopentyl-1-butyl phosphinic acid; (1-amino-1-hexyl)-2-carboxy-3-cyclohexyl-1- propyl phosphinic acid.
Claim 8
Dependent Claim
34 words
A pharmaceutical composition for treatment of bacterial infections which comprises a therapeutically effective amount of a DHP-inhibiting compound of claim 1, in combination with a therapeutically effective amount of a carbapenem or penem antibiotic.
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