US4031231A
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Antibacterial composition comprising 3-fluoro-D-alanine or deutero analog in combination with auto-antagonist inhibitor
Assignee: Merck and Co Inc
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Filing: 1976-01-23
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Granted: 1977-06-21
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Expires: 1996-01-23
Abstract
Abstract Novel antibacterial compositions are prepared by combining 3-fluoro-D-alanine-type compound, such as 3-fluoro-D-alanine and its deutero analogs, and salts and esters thereof, with a 3-fluoro-D-alanine autoantagonist-inhibitor such as cycloserine-type compound. The compositions demonstrate highly effective antibacterial action at high levels of dosage of the 3-fluoro-D-alanine component and, in addition, possess a remarkable synergistic antibacterial action.
Inventors
- 👤 Frederick M. Kahan
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-30 18:29
CPC Classifications
A; A61; A61K; A61K33/00; A61K31/00; A61K31/33; A61K31/395; A61K31/41; A61K31/42; Y; Y02; Y02A; Y02A50/00; Y02A50/30
Claims Analysis
Total Claims: 20
Claim 1
Independent Claim
101 words
An antibacterial composition comprising as active ingredients a combination of 3-fluoro-D-alanine-type compound and 3-fluoro-D-alanine autoantagonist-inhibitor characterized in that the 3-fluoro-D-alanine-type compound is selected from the group consisting of 3-fluoro-D-alanine, 2-deutero-3-fluoro-D-alanine, 2,3-dideutero-3-fluoro-D-alanine, 2,3,3-trideutero-3-fluoro-D-alanine, and their lower alkyl ester or pharmacologically acceptable salt thereof; and the 3-fluoro-D-alanine autoantagonist inhibitor is cycloserine, terizidone, cis-cyclothreonine, transcyclothreonine or an N-substituted cycloserine compound having the formula ##STR4## wherein R is hydrogen or methyl, and X, Y, and Z are hydrogen or loweralkyl, or pharmacologically acceptable salts thereof, the ratio of the 3-fluoro-D-alanine-type compound to the autoantagonist inhibitor being within the range of about 1:120 to about 200:1.
Claim 2
Dependent Claim
101 words
An antibacterial composition comprising as active ingredients a combination of 3-fluoro-D-alanine-type compound and 3-fluoro-D-alanine autoantagonist-inhibitor characterized in that the 3-fluoro-D-alanine-type compound is selected from the group consisting of 3-fluoro-D-alanine, 2-deutero-3-fluoro-D-alanine, 2,3-dideutero-3-fluoro-D-alanine, 2,3,3-trideutero-3-fluoro-D-alanine, and their lower alkyl ester or pharmacologically acceptable salt thereof; and the 3-fluoro-D-alanine autoantagonist inhibitor is cycloserine, terizidone, cis-cyclothreonine, transcyclothreonine or an N-substituted cycloserine compound having the formula ##STR4## wherein R is hydrogen or methyl, and X, Y, and Z are hydrogen or loweralkyl, or pharmacologically acceptable salts thereof, the ratio of the 3-fluoro-D-alanine-type compound to the autoantagonist inhibitor being within the range of about 1:120 to about 200:1.
Claim 3
Dependent Claim
18 words
A composition as defined in claim 1 in which said combination is in admixture with a pharmaceutical carrier.
Claim 4
Dependent Claim
16 words
A composition as defined in claim 2 wherein the pharmaceutical carrier is adapted for oral administration.
Claim 5
Dependent Claim
31 words
A composition as defined in claim 1 in which the 3-fluoro-D-alanine-type compound is 3-fluoro-D-alanine or pharmacologically acceptable salt thereof, and the 3-fluoro-D-alanine autoantagonist-inhibitor is D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone or a pharmacologically acceptable salt thereof.
Claim 6
Dependent Claim
21 words
A composition as defined in claim 1 in which the 3-fluoro-D-alanine-type compound is 2-deutero-3-fluoro-D-alanine, and the 3-fluoro-D-alanine autoantagonist-inhibitor is D-4-(1'-methyl-3'-oxo-1'-butenyl) amino-3-isoxazolidinone.
Claim 7
Dependent Claim
30 words
A composition as defined in claim 1 in which the 3-fluoro-D-alanine-type compound is 2-deutero-3-fluoro-D-alanine or pharmacologically acceptable salt thereof, and the 3-fluoro-D-alanine autoantagonist-inhibitor is D-4-(1',2'-dimethyl-3'-oxo-1'-butenyl)-amino-3-isoxazolidinone or pharmacologically acceptable salt thereof.
Claim 8
Dependent Claim
25 words
A composition as defined in claim 1 in which the 3-fluoro-D-alanine-type compound is 3-fluoro-D-alanine or pharmacologically acceptable salt thereof, and the 3-fluoro-D-alanine autoantagonist-inhibitor is D-cycloserine.
Claim 9
Dependent Claim
25 words
A composition as defined in claim 1 in which the 3-fluoro-D-alanine-type compound is 2-deutero-3-fluoro-D-alanine or pharmaceutically acceptable salt thereof, and the 3-fluoro-D-alanine autoantagonist-inhibitor is D-cycloserine.
Claim 10
Dependent Claim
25 words
A composition as defined in claim 1 in which the 3-fluoro-D-alanine-type compound is 3-fluoro-D-alanine or pharmacologically acceptable salt thereof, and the 3-fluoro-D-alanine autoantagonist-inhibitor is terizidone.
Claim 11
Dependent Claim
97 words
An antibacterial composition comprising as active ingredients a combination of 3-fluoro-D-alanine-type compound and 3-fluoro-D-alanine autoantagonist-inhibitor characterized in that the 3-fluoro-D-alanine-type compound is selected from the group consisting of 3-fluoro-D-alanine, 2-deutero-3-fluoro-D-alanine, 2,3-dideutero-3-fluoro-D-alanine, 2,3,3-trideutero-3-fluoro-D-alanine and their loweralkyl ester and pharmacologically acceptable salt thereof; and the 3-fluoro-D-alanine autoantagonist inhibitor is an isoxazolidinone compound which, in vivo or upon solution is aqueous media, has the ability to inhibit the action of the D-alanyl-D-alanine synthetase or D-alanine: α-keto-glutarate transaminase enzymes of microorganisms, the ratio of the 3-fluoro-D-alanine-type compound to the autoantagonist inhibitor being within the range of about 1:120 to about 200:1.
Claim 12
Dependent Claim
97 words
An antibacterial composition comprising as active ingredients a combination of 3-fluoro-D-alanine-type compound and 3-fluoro-D-alanine autoantagonist-inhibitor characterized in that the 3-fluoro-D-alanine-type compound is selected from the group consisting of 3-fluoro-D-alanine, 2-deutero-3-fluoro-D-alanine, 2,3-dideutero-3-fluoro-D-alanine, 2,3,3-trideutero-3-fluoro-D-alanine and their loweralkyl ester and pharmacologically acceptable salt thereof; and the 3-fluoro-D-alanine autoantagonist inhibitor is an isoxazolidinone compound which, in vivo or upon solution is aqueous media, has the ability to inhibit the action of the D-alanyl-D-alanine synthetase or D-alanine: α-keto-glutarate transaminase enzymes of microorganisms, the ratio of the 3-fluoro-D-alanine-type compound to the autoantagonist inhibitor being within the range of about 1:120 to about 200:1.
Claim 13
Dependent Claim
16 words
The composition of claim 10 in which said combination is in admixture with a pharmaceutical carrier.
Claim 14
Dependent Claim
15 words
The composition of claim 11 in which the pharmaceutical carrier is adapted for oral administration.
Claim 15
Dependent Claim
28 words
An antibacterial composition comprising 2-deutero-3-fluoro-D-alanine and D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone, sodium salt, the ratio of the alanine compound to the isoxazolidinone compound being within the range of about 1:4 to 4:1.
Claim 16
Dependent Claim
28 words
An antibacterial composition comprising 2-deutero-3-fluoro-D-alanine and D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone, sodium salt, the ratio of the alanine compound to the isoxazolidinone compound being within the range of about 1:4 to 4:1.
Claim 17
Dependent Claim
28 words
An antibacterial composition comprising 3-fluoro-D-alanine and D-4-(1'-methyl-3'-oxo-1'-butenyl)-amino-3-isoxazolidinone, sodium salt, the ratio of the alanine compound to the isoxazolidinone compound being within the range of about 1:4 to 4:1.
Claim 18
Dependent Claim
28 words
An antibacterial composition comprising 3-fluoro-D-alanine and D-4-(1'-methyl-3'-oxo-1'-butenyl)-amino-3-isoxazolidinone, sodium salt, the ratio of the alanine compound to the isoxazolidinone compound being within the range of about 1:4 to 4:1.
Claim 19
Dependent Claim
35 words
An antibacterial composition comprising either 2-deutero-3-fluoro-D-alanine or 3-fluoro-D-alanine and D-cycloserine or a pharmacologically acceptable salt thereof, the ratio of the alanine compound to the cycloserine compound being within the range of about 1:4 to 4:1.
Claim 20
Dependent Claim
35 words
An antibacterial composition comprising either 2-deutero-3-fluoro-D-alanine or 3-fluoro-D-alanine and D-cycloserine or a pharmacologically acceptable salt thereof, the ratio of the alanine compound to the cycloserine compound being within the range of about 1:4 to 4:1.
References Cited (Backward Citations)
No citation records indexed.
USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1980-06-20 | 1980-12-20 | 1981-06-21 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1984-06-20 | 1984-12-20 | 1985-06-21 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 1988-06-20 | 1988-12-20 | 1989-06-21 | $7700.00 | Window Closed / Lapsed |