CA1039191A - Antibacterial compositions containing 3-fluoro-d-alanine type compound and n-substituted cycloserine compound - Google Patents
Antibacterial compositions containing 3-fluoro-d-alanine type compound and n-substituted cycloserine compoundInfo
- Publication number
- CA1039191A CA1039191A CA205,968A CA205968A CA1039191A CA 1039191 A CA1039191 A CA 1039191A CA 205968 A CA205968 A CA 205968A CA 1039191 A CA1039191 A CA 1039191A
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- Prior art keywords
- fluoro
- alanine
- methyl
- oxo
- butenyl
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
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- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
PATENT APPLICATION PAPERS
OF
FREDERICK M. KAHAN
for D-ALANINE TYPE COMPOUND AND N-SUBSTITUTED CYCLO-SERINE COMPOUND
ABSTRACT OF THE DISCLOSURE
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 an N-substituted 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.
OF
FREDERICK M. KAHAN
for D-ALANINE TYPE COMPOUND AND N-SUBSTITUTED CYCLO-SERINE COMPOUND
ABSTRACT OF THE DISCLOSURE
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 an N-substituted 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.
Description
~ 15669 il~3~
This invention is concerned generally with novel compositions having antibacterial activity. More particularly, it relates to compositions containing a 3-fluoro-D-alan;ne-type compound in combination with a 3-fluoro-D-alanine auto-antagonist-inhibitor, which compositions are characterized as demonstrating, even at greatly elevated concentrations, the highly effective antibacterial action of 3-fluoro-D-alanine-type compounds, and are further characterized as showing a remarkable synergistic action, the antibacterial potency of the combination being substantially in excess of that con-tributed by the individual components.
The 3-fluoro-D-alanine-type compounds, such as 3-fluoro-D-alanine peY se and its deutero analogs, and lower alkyl esters and pharmacologically acceptable salts thereof, are valuable antibacterial agents showing effective activity ; in inhibiting the growth of pathogenic bacteria of both gram-positive and gram-negative genera, including Streptococcus, Escheriehia, StaphyZoeoeeus, Pseudomonas, DipZoeoecus~
~ZebsieZZa, Proteus, Myeobaeterium, Serratia, Vibrio and PasteureZZa~ and in particular, bacteria belonging to the species Eseheriehia eoZi, Proteus vuZgaris, Proteus mirabiZis, Proteus morganii, Streptomyees pyogenes, Pseudomonas aerugi-nosa, StaphyZoeoceus aureus and Aerobacter aerogenes.
The 3-fluoro-D-alanine-type compounds do, however, possess the unusual characteristic of being autoantagonists at high concentration, which characteristic is disadvantageous where it is desired to employ the antibacterial at elevated ~'.
This invention is concerned generally with novel compositions having antibacterial activity. More particularly, it relates to compositions containing a 3-fluoro-D-alan;ne-type compound in combination with a 3-fluoro-D-alanine auto-antagonist-inhibitor, which compositions are characterized as demonstrating, even at greatly elevated concentrations, the highly effective antibacterial action of 3-fluoro-D-alanine-type compounds, and are further characterized as showing a remarkable synergistic action, the antibacterial potency of the combination being substantially in excess of that con-tributed by the individual components.
The 3-fluoro-D-alanine-type compounds, such as 3-fluoro-D-alanine peY se and its deutero analogs, and lower alkyl esters and pharmacologically acceptable salts thereof, are valuable antibacterial agents showing effective activity ; in inhibiting the growth of pathogenic bacteria of both gram-positive and gram-negative genera, including Streptococcus, Escheriehia, StaphyZoeoeeus, Pseudomonas, DipZoeoecus~
~ZebsieZZa, Proteus, Myeobaeterium, Serratia, Vibrio and PasteureZZa~ and in particular, bacteria belonging to the species Eseheriehia eoZi, Proteus vuZgaris, Proteus mirabiZis, Proteus morganii, Streptomyees pyogenes, Pseudomonas aerugi-nosa, StaphyZoeoceus aureus and Aerobacter aerogenes.
The 3-fluoro-D-alanine-type compounds do, however, possess the unusual characteristic of being autoantagonists at high concentration, which characteristic is disadvantageous where it is desired to employ the antibacterial at elevated ~'.
- 2 - 4~!
lS~ 9~
dosages, or where high, autoantagonist concentrations of the
lS~ 9~
dosages, or where high, autoantagonist concentrations of the
3-fluoro-D-alanine-type compound could result during therapy as, for example, in patients with diminished renal function.
Indeed, since elevated dosages of 3-fluoro-D-alanine-type compounds may be employed with safety, it is advantageous in treatment of infections to utilize the 3-fluoro-D-alanine-type compound at a sufficiently high dosage to provide effective antibacterial action against the most resistant organism by which the infection may be caused, at which high dosage the 3-fluoro-D-alanine-type compound is an autoantagonist with respect to more sensitive microorganisms which may be present.
It is now discovered, in accordance with the present invention, that this autoantagonist action shown by 3-fluoro-D-alanine-type compounds at elevated concentration can be completely suppressed by certain substances which are herein-after referred to as FDA-autoantagonist-inhibitors. As FDA-autoantagonist-inhibitors, it is preferred to employ N-sub-stituted cycloserine compositions which may be represented by the following formula:
~0\
R-CH NH
HC C=0 I
NH
Z O
wherein R is hydrogen or methyl, and X, Y and Z are hydrogen or alkyl, and pharmacologically acceptable salts thereof, and which may be referred to as D-4-(1'-methyl-3'-oxo-1'-butenyl or alkyl-substituted-l'-methyl-3'-oxo-1'-butenyl)amino-3-i(~3~
isoxazolidinones, and their 5-methyl derivatives, as for ex-ample D-4~ methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone, D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-5-methyl-3-isoxazoli-dinone, D-4-(1',2'-dimethyl-3'-oxo-1'-butenyl)amino-3-isoxazol-idinone, D-4-(1',2'-dimethyl-3'-oxo-1'-butenyl)a~ino-5-methyl-3-isoxazolidinone, D-4-(1'-ethyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone, D-4-(1'-ethyl-3'-oxo-1'-butenyl)amino-5-methyl-3-isoxazolidinone, D-4-(1'-ethyl-2'-methyl-3!-oxo-1'-butenyl)amino-3-isoxazolidinone, D-4-(1'-ethyl-2'-methyl-3'-oxo-1'-butenyl)amino-5-methyl-3-isoxazolidinone, D-4-(1'-ethyl-3'-oxo-1'-pentenyl)amino-3-isoxazolidinone, D-4-(1'-ethyl-3'-oxo-l'-pentenyl)amino-5-methyl-3-isoxaziolidinone, D-4-(1'-ethyl-2'-methyl-3'-oxo-1'-pentenyl)amino-3-isoxazolidinone, D-4-(1'-ethyl-2'-methyl-3'-oxo-1'-pentenyl)amino-5-methyl-3-isoxazolidinone, and the likej pharmacologically acceptable ; salts of the foregoing such as alkali metal salts, preferably the sodium and potassium salts; alkaline earth metal salts preferably the calcium and magnesium saltsi ammonium saltsi amine salts, preferably salts with triethylamine, diethylamine, N-methyl-glucamine, diethanolamine, triethanolamine or 2-amino-2-hydroxymethyl-1,3-propanediol, and the like, as for example, the sodium salt of D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone, the calcium salt of D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone, the sodium salt of D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-5-methyl-3-isoxazolidinone, and the like. It is preferred to utilize these N-(l-methyl-3-oxo-l-butenyl or alkyl-substituted-l-methyl-oxo-l-butenyl) deriva-tives of cycloserine and methyl-cycloserine and their pharmaco-logically acceptable salts as FDA-autoantagonist-inhibitors, since these derivatives and, more particularly, D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone and D-4-(1',2'-dimethyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone, and their sodium and potassium salts, are remarkably stable in aqueous solution; when administered clinically, they are extremely effective in releasing cycloserine or methyl-cycloserine in vivo and, at the same time, substantially avoiding the un-wanted dimerization of the cycloserine or methyl-cycloserine.
The D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone and its pharmacologically acceptable salts are of particular effectiveness in releasing cycloserine in the blood stream and in the bladder, and are thus of value in providing FDA-auto-antagonist-inhibitor action throughout the vascular system as well as in the urinary tract.
The critical effectiveness of FDA-autoantagonist-inhibitors is exemplified as follows: 3-fluoro-D-alanine per se, at a concentration of 3.2 ~g/ml, completely represses the growth of a virulent culture of Ese~eric~ia coZi~ (Strain 2017), however, at higher concentrations (i.e. at 50 ~g/ml) extensive growth of the organism occurs characteristic of the autoantagonist action of the 3-fluoro-D-alanine. When the 3-fluoro-D-alanine, at this concentration of 50 ~g/ml, is com-bined with an FDA-autoantagonist-inhibitor such as D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone or its sodium salt at 0.72 ~g/ml, growth of the Esc~eric~ia coZi is com-pletely repressed. Surprisingly, the 0.72 ~g/ml D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone concentration, com-1 pletely effective as FnA-autoantagonist-inhibitor~
2 is less than 2% of the minimum concentration which is 3 itself able to completely repress the growth of the
Indeed, since elevated dosages of 3-fluoro-D-alanine-type compounds may be employed with safety, it is advantageous in treatment of infections to utilize the 3-fluoro-D-alanine-type compound at a sufficiently high dosage to provide effective antibacterial action against the most resistant organism by which the infection may be caused, at which high dosage the 3-fluoro-D-alanine-type compound is an autoantagonist with respect to more sensitive microorganisms which may be present.
It is now discovered, in accordance with the present invention, that this autoantagonist action shown by 3-fluoro-D-alanine-type compounds at elevated concentration can be completely suppressed by certain substances which are herein-after referred to as FDA-autoantagonist-inhibitors. As FDA-autoantagonist-inhibitors, it is preferred to employ N-sub-stituted cycloserine compositions which may be represented by the following formula:
~0\
R-CH NH
HC C=0 I
NH
Z O
wherein R is hydrogen or methyl, and X, Y and Z are hydrogen or alkyl, and pharmacologically acceptable salts thereof, and which may be referred to as D-4-(1'-methyl-3'-oxo-1'-butenyl or alkyl-substituted-l'-methyl-3'-oxo-1'-butenyl)amino-3-i(~3~
isoxazolidinones, and their 5-methyl derivatives, as for ex-ample D-4~ methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone, D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-5-methyl-3-isoxazoli-dinone, D-4-(1',2'-dimethyl-3'-oxo-1'-butenyl)amino-3-isoxazol-idinone, D-4-(1',2'-dimethyl-3'-oxo-1'-butenyl)a~ino-5-methyl-3-isoxazolidinone, D-4-(1'-ethyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone, D-4-(1'-ethyl-3'-oxo-1'-butenyl)amino-5-methyl-3-isoxazolidinone, D-4-(1'-ethyl-2'-methyl-3!-oxo-1'-butenyl)amino-3-isoxazolidinone, D-4-(1'-ethyl-2'-methyl-3'-oxo-1'-butenyl)amino-5-methyl-3-isoxazolidinone, D-4-(1'-ethyl-3'-oxo-1'-pentenyl)amino-3-isoxazolidinone, D-4-(1'-ethyl-3'-oxo-l'-pentenyl)amino-5-methyl-3-isoxaziolidinone, D-4-(1'-ethyl-2'-methyl-3'-oxo-1'-pentenyl)amino-3-isoxazolidinone, D-4-(1'-ethyl-2'-methyl-3'-oxo-1'-pentenyl)amino-5-methyl-3-isoxazolidinone, and the likej pharmacologically acceptable ; salts of the foregoing such as alkali metal salts, preferably the sodium and potassium salts; alkaline earth metal salts preferably the calcium and magnesium saltsi ammonium saltsi amine salts, preferably salts with triethylamine, diethylamine, N-methyl-glucamine, diethanolamine, triethanolamine or 2-amino-2-hydroxymethyl-1,3-propanediol, and the like, as for example, the sodium salt of D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone, the calcium salt of D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone, the sodium salt of D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-5-methyl-3-isoxazolidinone, and the like. It is preferred to utilize these N-(l-methyl-3-oxo-l-butenyl or alkyl-substituted-l-methyl-oxo-l-butenyl) deriva-tives of cycloserine and methyl-cycloserine and their pharmaco-logically acceptable salts as FDA-autoantagonist-inhibitors, since these derivatives and, more particularly, D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone and D-4-(1',2'-dimethyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone, and their sodium and potassium salts, are remarkably stable in aqueous solution; when administered clinically, they are extremely effective in releasing cycloserine or methyl-cycloserine in vivo and, at the same time, substantially avoiding the un-wanted dimerization of the cycloserine or methyl-cycloserine.
The D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone and its pharmacologically acceptable salts are of particular effectiveness in releasing cycloserine in the blood stream and in the bladder, and are thus of value in providing FDA-auto-antagonist-inhibitor action throughout the vascular system as well as in the urinary tract.
The critical effectiveness of FDA-autoantagonist-inhibitors is exemplified as follows: 3-fluoro-D-alanine per se, at a concentration of 3.2 ~g/ml, completely represses the growth of a virulent culture of Ese~eric~ia coZi~ (Strain 2017), however, at higher concentrations (i.e. at 50 ~g/ml) extensive growth of the organism occurs characteristic of the autoantagonist action of the 3-fluoro-D-alanine. When the 3-fluoro-D-alanine, at this concentration of 50 ~g/ml, is com-bined with an FDA-autoantagonist-inhibitor such as D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone or its sodium salt at 0.72 ~g/ml, growth of the Esc~eric~ia coZi is com-pletely repressed. Surprisingly, the 0.72 ~g/ml D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone concentration, com-1 pletely effective as FnA-autoantagonist-inhibitor~
2 is less than 2% of the minimum concentration which is 3 itself able to completely repress the growth of the
4 Escherichia coli organisms.
This novel combination is conveniently 6 admministered for antibacterial effectivéness in the form ~ of a pharmaceutical composition containing the 3-fluoro-D-- 8 alanine-type compound in admixture with the FDA-autoantagonist-g inhibitor and a pharmacologically acceptable carrier. r~hen a 3-fluoro-D-alanine-type compound is combined with an N-11 substituted cycloserine-type compound, the ratio of the 3-fluoro-D-alanine-type component to the N-substituted cyclo-serine-type component in the combination ordinarily varies f 14 from about 1:120 to about 200:1 with ratios within the range of about 1:4 to about 4:1 being preferred. As the 3-1uoro-16 D-alanine-type component, it is ordinarily preferred to 17 utilize 3-fluoro-I)-alanine, 2-deutero-3-fluoro-D-alanine, 18 2,3-dideutero-3-fluoro-D-alanine, 2,3,-trideutero-3-fluoro-19 D-alanine, a lower alkyl ester thereof such as the methyl ester, or a pharmacologically acceptable salt such as the 21 sodium, calcium, or hydrochloride salt. As the cycloserine-22 type component, it is ordinarily preferred to utilize N-(l-23 methyl-3-oxo-1-butenyl or alkyl-substituted-1-methyl-3-oxo-24 l-butenyl) derivative of cycloserine or cyclothreonine, or pharmacologically acceptable salts thereof, and it is particu-26 larly preferred to employ D-4-(1'-methyl-3'-oxo-1'-butenyl) 27 amino-3-isoxazolidinone, its sodium or potassium salts such as 2~ D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone 29 sodium salt-~lemihydrate, or D-4-)1,2'-dimethyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone or its sodium or potassium salts.
Pharmaceutically acceptable carriers for the afore-said compositions include convenient vehicles adapted for oral administration such as capsules, tablets, or liquid solutions or suspensions, or the combination may be dissolved in a vehi-cle adapted for administration by injection. Suitable formu-lations for oral use may include diluents, granulating agents, preservatives, binders, flavoring agents and coating agents which are well known to those skilled in the art, and the dosage of the products may be varied over a wide range. A
composition for oral use comprising the combination of 3-fluoro-D-alanine-type compound and N-substituted-cycloserine-type compGund is conveniently prepared by intermixing the individual components in a dry, pulverulent state with gelatin, starch, magnesium stearate and alginic acid, pressed into a tablet. The 3-fluoro-D-alanine-type compound and the N-substituted-cycloserine-type compound may also be incorporated together in aqueous solution, and the solution evaporated to provide the combination in the form of an intimate mixture of the components.
Alternatively, in accordance with a further embodi-ment of this invention, the components of the combination may be separately administered, particularly where it is desired for maintenance of blood levels of the more rapidly excreted 3-fluoro-D-alanine-type component.
The N-(l-methyl-3-oxo-1-butenyl or alkyl-substituted-l-methyl-3-oxo-1-butenyl) cycloserine or methyl-cycloserine 3-FDA-autoantagonist inhibitors may be prepared by stirring together, at room temperature for a period of about two days, cycloserine or methyl-cycloserine with an excess of a 2,4-pentanedione compound having the following formula:
O O
Il 11 wherein X, Y and Z are hydrogen or alkyl, such as 2,4-pentane-dione, under which conditions, the cycloserine compound gradu-ally goes into solution, with formation of the corresponding N-substituted-cycloserine compound of the formula:
R C/ 0 ~ NH
HC C=0 X-CH2-C= lC- ICI-CH2 Y
wherein R is hydrogen or methyl, and X, Y and Z are hydrogen or alkyl, which, as the reaction proceeds, crystallizes from the resulting reaction solution, and is recovered by fil-tration, washed with ether and dried. For example, D-4-(l'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone is con-veniently prepared by stirring a mixture of about 3.0 g. of D-4-amino-3-isoxazolidinone and 30 ml. of 2,4-pentanedione in a dry atmosphere at approximately room temperature for ~a~ lsl 1 about two days. The D-4-amino-3-isoxazolidinone gradually 2 goes into solution, and the reaction product, which 3 crystallizes from the reaction solution, is recovered by 4 Eil~ration, washed with three 20 ml.-portions of ether, and dried at room temperature ln vacuo to give about 3~5 g.
6 o~ D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone.
7 The latter is convenlently converted to its 3 pharmacologically acceptahie salts, e.g. the sodium or 9 calcium salts as follows: 0.143 g. of D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone is dissolved in 0.8 ml.
11 of methanol,and 1~56 ml. of an O.OS molar solution of 12 sodium hydroxide in methanol, is added to give a pH of 13 approximately 7Ø The methanol is evaporated from the re-14 sulting solution under a stream of nitrogen until crystals form; the crystalline slurry is further evaporated to dryness 16 in vacuo. The residual material is washed with 2.5 ml. of 17 acetone, and redissolved in 0.55 ml. of methanol; the solution 18 i5 filtered and the filtrate diluted with 0.45 ml. of methanol.
19 To the resulting solution is added 4 ml. of ether, and the crystalline precipitate which forms is recovered by filtration, 21 washed with ether and dried co give substantially pure D-4~
22 (1'-methyl-3'-oxo-1' butenyl)amino-3-isoxazolidinone sodium 23 salt-hemihydrate.
2~ rrhree grams of calcium o~ide ~re slurried in 40 ml. of water, and the slurry cooled to 0-5C. Five grams 26 of D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone 27 is added to the cooled slurry, the resulting mixture is heated 28 with slurry to room temperature alld stirred at that temperature 29 for 5 minutes. r~e mixture is filtered, and the insoluble material is washed with 10 ml. of water. To the combined solution and washings (having a p~ of about 11.0 - 11.5) is added sufficient D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone to give a final pH of about 9.5. Activated carbon (0.5 9.) is added to the resulting solution, and the mixture is stirred for about 15 minutes and filtered. The filtered solution is diluted with six times its volume of ethanol, and the crystalline precipitate which forms is recovered by filtration, washed with ethanol and dried in va~uo to give, in substantially pure form, the calcium salt of D-4-(1'-methyl~3'-oxo-1'-butenyl)amino-3-isoxazolidinone.
This novel combination is conveniently 6 admministered for antibacterial effectivéness in the form ~ of a pharmaceutical composition containing the 3-fluoro-D-- 8 alanine-type compound in admixture with the FDA-autoantagonist-g inhibitor and a pharmacologically acceptable carrier. r~hen a 3-fluoro-D-alanine-type compound is combined with an N-11 substituted cycloserine-type compound, the ratio of the 3-fluoro-D-alanine-type component to the N-substituted cyclo-serine-type component in the combination ordinarily varies f 14 from about 1:120 to about 200:1 with ratios within the range of about 1:4 to about 4:1 being preferred. As the 3-1uoro-16 D-alanine-type component, it is ordinarily preferred to 17 utilize 3-fluoro-I)-alanine, 2-deutero-3-fluoro-D-alanine, 18 2,3-dideutero-3-fluoro-D-alanine, 2,3,-trideutero-3-fluoro-19 D-alanine, a lower alkyl ester thereof such as the methyl ester, or a pharmacologically acceptable salt such as the 21 sodium, calcium, or hydrochloride salt. As the cycloserine-22 type component, it is ordinarily preferred to utilize N-(l-23 methyl-3-oxo-1-butenyl or alkyl-substituted-1-methyl-3-oxo-24 l-butenyl) derivative of cycloserine or cyclothreonine, or pharmacologically acceptable salts thereof, and it is particu-26 larly preferred to employ D-4-(1'-methyl-3'-oxo-1'-butenyl) 27 amino-3-isoxazolidinone, its sodium or potassium salts such as 2~ D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone 29 sodium salt-~lemihydrate, or D-4-)1,2'-dimethyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone or its sodium or potassium salts.
Pharmaceutically acceptable carriers for the afore-said compositions include convenient vehicles adapted for oral administration such as capsules, tablets, or liquid solutions or suspensions, or the combination may be dissolved in a vehi-cle adapted for administration by injection. Suitable formu-lations for oral use may include diluents, granulating agents, preservatives, binders, flavoring agents and coating agents which are well known to those skilled in the art, and the dosage of the products may be varied over a wide range. A
composition for oral use comprising the combination of 3-fluoro-D-alanine-type compound and N-substituted-cycloserine-type compGund is conveniently prepared by intermixing the individual components in a dry, pulverulent state with gelatin, starch, magnesium stearate and alginic acid, pressed into a tablet. The 3-fluoro-D-alanine-type compound and the N-substituted-cycloserine-type compound may also be incorporated together in aqueous solution, and the solution evaporated to provide the combination in the form of an intimate mixture of the components.
Alternatively, in accordance with a further embodi-ment of this invention, the components of the combination may be separately administered, particularly where it is desired for maintenance of blood levels of the more rapidly excreted 3-fluoro-D-alanine-type component.
The N-(l-methyl-3-oxo-1-butenyl or alkyl-substituted-l-methyl-3-oxo-1-butenyl) cycloserine or methyl-cycloserine 3-FDA-autoantagonist inhibitors may be prepared by stirring together, at room temperature for a period of about two days, cycloserine or methyl-cycloserine with an excess of a 2,4-pentanedione compound having the following formula:
O O
Il 11 wherein X, Y and Z are hydrogen or alkyl, such as 2,4-pentane-dione, under which conditions, the cycloserine compound gradu-ally goes into solution, with formation of the corresponding N-substituted-cycloserine compound of the formula:
R C/ 0 ~ NH
HC C=0 X-CH2-C= lC- ICI-CH2 Y
wherein R is hydrogen or methyl, and X, Y and Z are hydrogen or alkyl, which, as the reaction proceeds, crystallizes from the resulting reaction solution, and is recovered by fil-tration, washed with ether and dried. For example, D-4-(l'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone is con-veniently prepared by stirring a mixture of about 3.0 g. of D-4-amino-3-isoxazolidinone and 30 ml. of 2,4-pentanedione in a dry atmosphere at approximately room temperature for ~a~ lsl 1 about two days. The D-4-amino-3-isoxazolidinone gradually 2 goes into solution, and the reaction product, which 3 crystallizes from the reaction solution, is recovered by 4 Eil~ration, washed with three 20 ml.-portions of ether, and dried at room temperature ln vacuo to give about 3~5 g.
6 o~ D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone.
7 The latter is convenlently converted to its 3 pharmacologically acceptahie salts, e.g. the sodium or 9 calcium salts as follows: 0.143 g. of D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone is dissolved in 0.8 ml.
11 of methanol,and 1~56 ml. of an O.OS molar solution of 12 sodium hydroxide in methanol, is added to give a pH of 13 approximately 7Ø The methanol is evaporated from the re-14 sulting solution under a stream of nitrogen until crystals form; the crystalline slurry is further evaporated to dryness 16 in vacuo. The residual material is washed with 2.5 ml. of 17 acetone, and redissolved in 0.55 ml. of methanol; the solution 18 i5 filtered and the filtrate diluted with 0.45 ml. of methanol.
19 To the resulting solution is added 4 ml. of ether, and the crystalline precipitate which forms is recovered by filtration, 21 washed with ether and dried co give substantially pure D-4~
22 (1'-methyl-3'-oxo-1' butenyl)amino-3-isoxazolidinone sodium 23 salt-hemihydrate.
2~ rrhree grams of calcium o~ide ~re slurried in 40 ml. of water, and the slurry cooled to 0-5C. Five grams 26 of D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone 27 is added to the cooled slurry, the resulting mixture is heated 28 with slurry to room temperature alld stirred at that temperature 29 for 5 minutes. r~e mixture is filtered, and the insoluble material is washed with 10 ml. of water. To the combined solution and washings (having a p~ of about 11.0 - 11.5) is added sufficient D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone to give a final pH of about 9.5. Activated carbon (0.5 9.) is added to the resulting solution, and the mixture is stirred for about 15 minutes and filtered. The filtered solution is diluted with six times its volume of ethanol, and the crystalline precipitate which forms is recovered by filtration, washed with ethanol and dried in va~uo to give, in substantially pure form, the calcium salt of D-4-(1'-methyl~3'-oxo-1'-butenyl)amino-3-isoxazolidinone.
Claims (7)
1. An antibacterial composition comprising as active ingredients a combination of 3-fluoro-D-alanine or its 2-deutero analog, or pharmacologically acceptable salt thereof, and a 3-fluoro-D-alanine autoantagonist-inhibitor which is an N-substituted cycloserine compound having the formula:
wherein R is hydrogen or methyl, and X, Y and Z are hydrogen or alkyl, or pharmacologically acceptable salt thereof, the ratio of the 3-fluoro-D-alanine type compound to the autoantagonist inhibitor being in the range of from 1:120 to about 200:1.
wherein R is hydrogen or methyl, and X, Y and Z are hydrogen or alkyl, or pharmacologically acceptable salt thereof, the ratio of the 3-fluoro-D-alanine type compound to the autoantagonist inhibitor being in the range of from 1:120 to about 200:1.
2. 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 pharmacologically acceptable salt thereof.
3. A composition as defined in Claim 1 in which the 3-fluoro-D-alanine-type compound is 3-fluoro-D-alanine, and the 3-fluoro-D-alanine autoantagonist-inhibitor is D-4-(1'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone.
4. 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'-methyl-3'-oxo-1'-butenyl)amino-3-isoxazolidinone or pharmacologically acceptable salt thereof.
5. 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.
6. 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 the sodium salt of D-4-(1'-meth-1-3'-oxo-1'-butenyl)amino-3-isoxazolidinone.
7. 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 pharmaco-logically acceptable salt thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US38757173A | 1973-08-10 | 1973-08-10 | |
| US47879374A | 1974-06-13 | 1974-06-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1039191A true CA1039191A (en) | 1978-09-26 |
Family
ID=27011935
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA205,968A Expired CA1039191A (en) | 1973-08-10 | 1974-07-30 | Antibacterial compositions containing 3-fluoro-d-alanine type compound and n-substituted cycloserine compound |
Country Status (11)
| Country | Link |
|---|---|
| CA (1) | CA1039191A (en) |
| CY (1) | CY1054A (en) |
| DE (1) | DE2436959C2 (en) |
| FR (1) | FR2240000B2 (en) |
| GB (1) | GB1457950A (en) |
| HK (1) | HK23280A (en) |
| IE (1) | IE39587B1 (en) |
| IL (1) | IL45174A (en) |
| KE (1) | KE3042A (en) |
| MY (1) | MY8100050A (en) |
| NL (1) | NL181407C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4034713A1 (en) * | 1990-11-01 | 1992-05-07 | Bayer Ag | 3-OXY-SUBSTITUTED ISOXAZOLINES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE FOR THE CONTROL OF ENDOPARASITES |
| AU2436600A (en) * | 1999-01-13 | 2000-08-01 | Jomaa Pharmaka Gmbh | Use of 3-isoxazolidinones and hydroxylamine acids for the treatment of infections |
-
1974
- 1974-07-02 IL IL45174A patent/IL45174A/en unknown
- 1974-07-03 IE IE1408/74A patent/IE39587B1/en unknown
- 1974-07-15 NL NLAANVRAGE7409574,A patent/NL181407C/en active Search and Examination
- 1974-07-22 CY CY1054A patent/CY1054A/en unknown
- 1974-07-22 GB GB3236074A patent/GB1457950A/en not_active Expired
- 1974-07-30 CA CA205,968A patent/CA1039191A/en not_active Expired
- 1974-07-31 DE DE2436959A patent/DE2436959C2/en not_active Expired
- 1974-08-08 FR FR7427593A patent/FR2240000B2/en not_active Expired
-
1980
- 1980-04-18 KE KE3042A patent/KE3042A/en unknown
- 1980-05-01 HK HK232/80A patent/HK23280A/en unknown
-
1981
- 1981-12-30 MY MY50/81A patent/MY8100050A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| CY1054A (en) | 1980-08-01 |
| GB1457950A (en) | 1976-12-08 |
| NL7409574A (en) | 1975-02-12 |
| DE2436959A1 (en) | 1975-02-20 |
| HK23280A (en) | 1980-05-09 |
| IE39587B1 (en) | 1978-11-08 |
| FR2240000B2 (en) | 1977-10-28 |
| AU7125074A (en) | 1976-01-15 |
| NL181407C (en) | 1987-08-17 |
| DE2436959C2 (en) | 1987-03-05 |
| KE3042A (en) | 1980-05-09 |
| FR2240000A2 (en) | 1975-03-07 |
| MY8100050A (en) | 1981-12-31 |
| IL45174A (en) | 1976-12-31 |
| IE39587L (en) | 1975-02-10 |
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