2-Amino-4-thiazolyl-2-oxyimino-acetamido-bicyclooctene-carboxylic acids

• US 4,476,124 A
• Filed: 05/12/1982
• Issued: 10/09/1984
• Est. Priority Date: 05/13/1981
• Status: Expired due to Fees

• Current Assignee: Roussel Uclaf
• Original Assignee: Roussel Uclaf
• Inventors: Bonnet, Alain, Heymes, Rene, Pronine, Didier
• Primary Examiner(s): Ford, John M.
• Application Number:
  US06/377,597
• Time in Patent Office: 881 Days
• Field of Search: 544/47, 424/246
• US Class Current: 514/210.05
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

Novel syn isomers of optically active isomers and racemates of 7-[2-(2-amino-4-thiazolyl)-2-oxyimino-acetamido]-bicyclooctene-carboxylic acid derivatives of the formula ##STR1## wherein R is selected from the group consisting of hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms and optionally substituted alkenyl and alkynyl of 2 to 6 carbon atoms, R₁ is selected from the group consisting of hydrogen, methyl, halomethyl, hydroxymethyl and acyloxymethyl, X is selected from the group consisting of oxygen and optionally oxidized sulfur, A is selected from the group consisting of hydrogen, an alkali metal, --NH₄, alkaline earth metal equivalent, a non-toxic, pharmaceutically acceptable organic amine and an easily cleavable ester group and their non-toxic, pharmaceutically acceptable acid addition salts having antibiotic activity and their preparation.

Claims

1. A compound selected from the group consisting of syn isomers of optically active isomers and racemates of 7-[2-(2-amino-4-thiazolyl)-2-oxyimino-acetamido]-bicyclooctene-carboxylic acid derivatives of the formula ##STR97## wherein R is selected from the group consisting of hydrogen, optionally substituted alkyl of 1 to 6 carbon atoms and optionally substituted alkenyl and alkynyl of 2 to 6 carbon atoms, R₁ is selected from the group consisting of hydrogen, methyl, halomethyl, hydroxymethyl and acyloxymethyl of an organic carboxylic acid of 1 to 7 carbon atoms, X is optionally oxidized sulfur, A is selected from the group consisting of hydrogen, an alkali metal, --NH₄, alkaline earth metal equivalent, a non-toxic, pharmaceutically acceptable organic amine and an easily cleavable ester group and their non-toxic, pharmaceutically acceptable acid addition salts, the optional substituents being selected from the group consisting of optionally salified or esterified carboxyl, alkoxycarbonyl, carbamoyl, dimethylcarbamoyl, amino, dialkylamino of 1 to 6 alkyl carbons, alkylamino of 1 to 6 alkyl carbons, halogens, alkoxy and alkylthio of 1 to 6 carbon atoms, tetrazolyl, optionally alkyl substituted phenylthio, optionally alkyl substituted tetrazolylthio and thiadiazolylthio wherein the alkyl is 1 to 6 carbon atoms.

2. A compound of claim 1 wherein R is selected from the group consisting of hydrogen, amino and alkyl of 1 to 3 carbon atoms optionally substituted with a free, salified or esterified carboxyl, X is sulfur and R₁ is hydrogen.

3. A compound of claim 1 which is selected from the group consisting of optically active isomers and racemic mixtures of syn isomer of 7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-8 -oxo-4-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid and its alkali metal, alkaline earth metal, ammonium, magnesium and organic amine salts and easily cleavable esters, and salts with acids.

4. A compound of claim 1 which is selected from the group consisting of optically active isomers and racemic mixtures of syn isomer of 7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-8-oxo-4-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid and its alkali metal, alkaline earth metal, ammonium, magnesium and organic amine salts and easily clevable esters, and salts with acids.

5. A compound of claim 1 which is selected from the group consisting of optically active isomers and racemic mixtures of syn isomer of 7-[2-(2-amino-4-thiazolyl)-2-carboxymethoxyimino-acetamido]-8-oxo-4-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid and its alkali metal, alkaline earth metal, ammonium, magnesium and organic amine salts and easily clevable esters, and salts with acids.

6. A syn isomer of a compound of the formula ##STR98## wherein R₁ , A and X have the definitions of claim 1, R'"'"'₁ is an amino protective group and R"₁ is selected from the group consisting of hydroxyl protective group and R as defined in claim 1 or R'"'"'₁ is hydrogen and R"₁ is a hydroxyl protective group in its optically active isomeric form or racemic mixtures thereof.

7. An antibacterial composition comprising an antibacterially effective amount of at least one compound of claim 1 and an inert pharmaceutical carrier.

8. A composition of claim 7 wherein R is selected from the group consisting of hydrogen, amino and alkyl of 1 to 3 carbon atoms optionally substituted with a free, salified and esterified carboxyl, X is sulfur and R₁ is hydrogen.

9. A composition of claim 7 wherein the compound is selected from the group consisting of optically active isomers and racemic mixtures of syn isomers of 7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-8-oxo-4-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid and its alkali metal, alkaline earth metal, ammonium, magnesium and organic amine salts and easily cleavable esters, and salts with acids.

10. A composition of claim 7 wherein the compound is selected from the group consisting of optically active isomers and racemic mixtures of syn isomers of 7-[2-(2-amino-4-thiazolyl)-2-hydroxyimino-acetamido]-8-oxo-4-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid and its alkali metal, alkaline earth metal, ammonium, magnesium and organic amine salts and easily cleavable esters, and salts with acids.

11. A composition of claim 7 wherein the compound is selected from the group consisting of optically active isomers and racemic mixtures of syn isomers of 7-[2-(amino-4-thiazolyl)-2-carboxymethoxyimino-acetamido]-8-oxo-4-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid and its alkali metal, alkaline earth metal, ammonium, magnesium, and organic amine salts and easily cleavable esters, and salts with acids.

12. A method of combatting bacterial infections in warm-blooded animals comprising administering to warm-blooded animals an antibacterially effective amount of at least one compound of claim 1.

13. A method of claim 12 wherein R is selected from the group consisting of hydrogen, amino and alkyl of 1 to 3 carbon atoms optionally substituted with a free, salified and esterified carboxyl, X is sulfur and R₁ is hydrogen.

14. A method of claim 12 wherein the compound is selected from the group consisting of optically active and racemic mixtures of syn isomers of 7-[2-(2-amino-4-thiazolyl)-2-methoxyimino-acetamido]-8-oxo-4-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid and its alkali metal, alkaline earth metal, ammonium, magnesium and organic amine salts and easily cleavable esters, and salts with acids.

15. A method of claim 12 wherein the compound is selected from the group consisting of optically active and racemic mixtures of syn isomers of 7-[2-(2-amino-4-thiazolyl) -2-hydroxy-imino-acetamido] -8-oxo-4-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid and its alkali metal, alkaline earth metal, ammonium, magnesium and organic amine salts and easily cleavable esters, and salts with acids.

16. A method of claim 12 wherein the compound is selected from the group consisting of optically active and racemic mixtures of syn isomers of 7-[2-(2-amino-4-thiazolyl)-2-carboxymethoxyimino-acetamido]-8-oxo-4-thia-1-azabicyclo [4,2,0] oct-2-ene-2-carboxylic acid and its alkali metal, alkaline earth metal, ammonium, magnesium and organic amine salts and easily cleavable esters, and salts with acids.