4-thia-1-aza-bicyclo[4,2,0]oct-2-ene derivatives

• US 5,385,897 A
• Filed: 03/20/1992
• Issued: 01/31/1995
• Est. Priority Date: 08/09/1985
• Status: Expired due to Fees

• Current Assignee: Aventis Pharma SA (Sanofi )
• Original Assignee: Roussel-Uclaf
• Inventors: Aszodi, Jozsef, Bonnet, Alain, Teutsch, Jean-Georges, Gouin d'Ambrieres, Solange
• Primary Examiner(s): RIZZO, NICHOLAS
• Application Number:
  US07/855,324
• Time in Patent Office: 1,047 Days
• Field of Search: 540/225, 540/226, 540/227, 540/214, 514/210
• US Class Current: 514/210.05
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

A compound selected from the group consisting of a compound of the formula ##STR1## wherein R is selected from the group consisting of ##STR2## and R_b --NH--, Ra is an organic radical, Ri and Rj are individually selected from the group consisting of hydrogen, aliphatic hydrocarbon, aromatic hydrocarbon and heterocycle or taken together with the nitrogen atom to which they are attached form an optionally substituted ring, Rb is selected from the group consisting of carbocyclic aryl and heterocyclic aryl, both optionally substituted, R_1A is selected from the group consisting of ##STR3## R_A '"'"' and R_B '"'"' are individually selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms, Z_A is selected from the group consisting of a simple bond, --O-- and optionally oxidize sulfur, R_3A is selected from the group consisting of optionally substituted carbocyclic aryl and heterocyclic aryl, optionally substitute quaternary ammonium, acetyl, carbamoyl, alkoxycarbonyl, alkyl and haloalkyl of 1 to 4 carbon atoms, --CN and azido, R₄ is selected from the group consisting of hydrogen and methoxy, A is selected from the group consisting of hydrogen, alkali metal, alkaline earth metal, magnesium, --NH₄, an organic amine and esterified carboxy or --COOA is --COO.sup.⊖, n₂ is an integer from 0 to 2 and their non-toxic, pharmaceutical acceptable acid addition salts having excellent antibiotic activity.

Claims

1. A compound selected from the group consisting of a compound of the formula ##STR353## wherein R is selected from the group consisting of ##STR354## R_a is selected from the group consisting of ArO--CH₂ --, ArS--CH₂ -- and R_e --NH--, Ar and R_e are individually selected ##STR355## from the group consisting of phenyl and phenyl substituted with at least one member of the group consisting of halogen, alkyl and alkoxy and alkylthio of 1 to 4 carbon atoms, alkylsulfinyl and alkylsulfonyl of 1 to 4 carbon atoms, --NH₂, nitro, --OH, aminoalkyl of 1 to 4 carbon atoms, --CN and --CF₃, R_f is alkyl of 1 to 4 carbon atoms, R_d is selected from the group consisting of a) hydrogen, b) alkyl of 1 to 6 carbon atoms, c) alkenyl and alkynyl of 2 to 6 carbon atoms, d) cycloalkyl of 3 to 8 carbon atoms unsubstituted or substituted with a member of the group consisting of halogen, acyl of 1 to 7 carbon atoms, --CN, carbamoyl, amino, --OH, --SH, alkylthio and alkoxy of 1 to 4 carbon atoms, oxo, carboxyl and salified or esterified carboxyl, R_1A is selected from the group consisting of ##STR356## R_A and R_B are individually selected from the group consisting of hydrogen and alkyl of 1 to 4 carbon atoms, Z_A is selected from the group consisting of a simple bond, --O--, --S-- and oxidized sulfur, R_3A is quaternary ammonium optionally substituted with at least one member of the group consisting of a) alkyl of 1 to 4 carbon atoms unsubstituted or substituted with at least one member of the group consisting of carbocyclic aryl and carbocyclic aryloxy where the carbocyclic aryl is phenyl, diphenyl or naphthyl, alkyl, alkoxy, carbonyl, halogen, --OH, protected, --OH, carboxy, salified or esterified carboxy, --NH₂, acetamido monoalkylamino and dialkylamino, b) alkenyl and alkynyl of 2 to 4 carbon atoms, c) carbocyclic aryl, d) halogen, e) --NH₂, f) --NO₂, g) alkoxy and alkylthio of 1 to 4 carbon atoms, h) --OH or --SH, i) free salified or esterified carboxy, j) carbamoyl and k) cyclopentyl or cyclohexyl, R₄ is selected from the group consisting of hydrogen and methoxy, a is selected from the group consisting of hydrogen, alkali, metal, alkaline earth metal, magnesium, --NH₂, an organic amine selected form the group consisting of methylamine, propylamine, trimethylamine, diethylamine, triethylamine, N, N-dimethylthanolamine, tris(hydroxymethyl)amino methane, ethanolamine, pyridine, picoline, dicyclohexylamine, morpholine, benzylamine, procaine, lysine, arginine, histidine, and N-methylglucamine and esterified carboxy or --COOA is --COO^-, n₂ is an integer from 0 to 2 or a non-toxic, pharmaceutically acceptable acid addition salt.

2. A compound of claim 1 having the formula ##STR357## syn isomer wherein R'"'"' is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl and alkynyl of 2 to 6 carbon atoms and cycloalkyl of 3 to 6 carbon atoms, all unsubstituted or substituted as in claim 1, phenyl, diphenyl, naphthyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyurimidinyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, tetrazinyl, imidazolinyl, benzimidazolyl, benzothiazolyl, benzoxazole, R_3A is selected from the group consisting of, pyridinium, quinolinium, isoquinolinium, cyclopentylpyridinium, and trimethylammonium and Z_A has the definition of claim 1.

3. A compound of claim 2 wherein R'"'"' is selected from the group consisting of hydrogen, allyl, allyl substituted with chlorine of bromine, cyclobutyl and cyclopropyl unsubstituted or substituted with carboxy, phenyl, difluoromethyl, trifluoromethyl and methyl and isopropyl unsubstituted or substituted with carboxy, carbamoyl, nitrile, CH₃ S-- or CH₃ O--.

4. A compound of claim 2 wherein Z_A is a simple bond and R'"'"'_3A is an unsubstituted or substituted pyridinium.

5. A compound of claim 1 selected from the group consisting of the internal salt of (6S, 7S) 7-[3-[7-[[(2-amino-4-thiazolyl)-2-[Z-(difluoromethoxyimino-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-2-(E)-propenyl]thieno-[2,3-b]-pyridinium;

the internal salt of the (6S, 7S) 5-[3-[7-[[(2-amino-4-thiazolyl)-(methoxyiminoacetamidoe]-2-carboxy-8-oxo-4-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2(E)-propenyl]-2-methyl-thiazolo[4,5-c]-pyridinium;

the internal salt of (6S, 7S) 7-[3-[7-[[(2-amino-4-thiazolyl)-2-(Z)-(methoxyiminoacetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-propen-2-(E)-yl]thieno[2,3-b]pyridinium;

the internal salt of the Z isomer of (6S, 7S) 5-[3-[7-[[(2-amino-4-thiazolyl (difluoromethoxy)iminoacetamido]2-carboxy 8-oxo 4-thia 1-azabicyclo[4,2,0]-oct-2-en-3-yl]-2-(E)-propenyl]-2-methyl-thiazolo[4,5-c] pyridinium, 6S,7S,Δ

Z 5-[3-[7-[(2-amino thiazol 4-yl)-(methoxyimino) acetamido] 2-carboxy-8-oxo-4-thia-1-azabyciclo[4,2,0]oct-2-en-3-yl]-2(E)propenyl]-thiazolo[4,5c]pyridinium and 6S,7S syn isomer of 5-[3-[7-[(2-aminothiazol-4-yl) (difluoromethoxyimino) acetamido]2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0] oct-2-en-3-yl]-2 (E)propenyl]-thiazolo[4,5,c]pyridinium and 6S,7S syn isomer of 7-[3-[7-(2-aminothiazol-4-yl)(fluoromethoxuyimino) acetamido]2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]2-(E)propenyl]thieno[2,3-b]pyridinium.

6. An antibacterial composition comprising an antibacterially effective amount of a compound of claim 1 and an inert pharmaceutical carrier.

7. A composition of claim 6 wherein R'"'"' is selected from the group consisting of hydrogen, allyl optionally substituted with chlorine or bromine, cyclobutyl and cyclopropyl optionally substituted with carboxy, phenyl, difluoromethyl, trifluoromethyl and methyl and isopropyl optionally substituted with carboxy, carbamoyl, nitrile CH₃ S-- or CH₃ O--.

8. A composition of claim 6 wherein Z_A is a simple bond and R'"'"'_3A is an unsubstituted or substituted pyridinium.

9. A composition of claim 6 wherein the compound is selected from the group consisting of the internal salt of (6S,7S) 7-[3-[7-[[2-amino-4-thiazolyl)-2-[Z-(difluoromethoxyiminoacetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl 2-(E)-propenyl]thieno[2,3-b]pyridinium;

the internal salt of the syn isomer of (6S,7S) 5-[3-[7-[[(2-amino-4-thiazolyl) (methoxyiminoacetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2(E)-propenyl]-2-methyl thiazolo-[4,5-c]-pyridinium;

the internal salt of (6S,7S) 7-[3-[7-[[(2-amino-4-thiazolyl)-2-(Z)-(methoxyiminoacetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]propen-2-(E)-yl]-thieno-[2,3-b]pyridinium;

the internal salt of the Z isomer of (6S,7S) 5-[3-[7-[ [(2-amino-4-thiazolyl (difluoromethoxy)iminoacetamido]2-carboxy 8-oxo 4-thia 1-azabicyclo[4,2,0]-oct-2-en-3-yl]-2-(E)-propenyl]-2-methyl-thiazolo[4,5-c]pyridinium, 6S,7S,Δ

Z 5-[3-[7-[(2-amino thiazol 4-yl)-(methoxyimino) acetamido]2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2(E)propenyl]thiazolo[4,5-c]pyridinium, 6S,7S syn isomer of 5-[3-[7-[(2-aminothiazol-4-yl) (difluoromethoxyimino) acetamido]2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2(E)propenyl]-thiazolo[4,5,c]pyridinium and 6S,7S syn isomer of 7-[3-[7-(2-aminothiazol-4-yl)(fluoromethoxyimino)acetamido]2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]2-(E)propenyl]thieno[2,3-b]pyridinium.

10. A method of treating or preventing bacterial infections in warm-blooded animals comprising administering to warm-blooded animals an antibacterioidally effective amount of a compound of claim 1.

11. A method of claim 10 wherein R'"'"' is selected from the group consisting of hydrogen, allyl unsubstituted or substituted with chlorine or bromine, cyclobutyl and cyclopropyl unsubstituted or substituted with carboxy, phenyl, difluoromethyl, trifluoromethyl and methyl and isopropyl unsubstituted or substituted with carboxy, carbamoyl, nitrile, CH₃ S-- or CH₃ O--.

12. A method of claim 10 wherein Z_A is a simple bond and R'"'"'_3A is an unsubstituted or substituted pyridinium.

13. A method of claim 10 wherein the compound is selected from the group consisting of the internal salt (6S,7S) of 7-[3-[7-[[2-amino-4-thiazolyl)-2-[Z-(difluoromethoxyimino-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl-2-(E)-propenyl]thieno[2,3-b]pyridinium;

the internal salt of the syn isomer of (6S,7S) 5-[3-[7-[[(2-amino-4-thiazolyl)-(methoxyiminoacetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2-(E)-propenyl]-2-methyl-thiazolo[4,5-c]pyridinium;

the internal salt of (6S,7S) 7-[3-[7-[[(2-amino-4-thiazolyl)-2-(Z)-(methoxyiminoacetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-propen-2-(E)-yl]-thieno-[2,3-b]pyridinium;

the internal salt of the Z isomer of (6S,7S) 5-[3-[7-[[(2-amino-4-thiazolyl) (difluoromethoxy) iminoacetamido]2-carboxy 8-oxo 4-thia 1-azabicyclo-[4,2,0]-oct-2-en-3-yl]-2-(E)-propenyl]-2-methyl-thiazolo[4,5-c]pyridinium, 6S,7S,Δ

Z 5-[3-[7-[(2-amino thiazol 4-yl)-(methoxyimino) acetamido]2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2(E)propenyl]thiazolo[4,5-c]pyridinium, 6S,7S syn isomer of 5-[3-[7-[(2-aminothiazol-4-yl) (difluoromethoxyimino) acetamido]2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-2(E)propenyl]-thiazolo[4,5,c]pyridinium and 6S,7S syn isomer of 7-[3-[7-(2-aminothiazol-4-yl)(fluoromethoxyimino)acetamido]2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]2-(E)propenyl]thieno[2,3-b]pyridinium.

14. A composition of claim 6 wherein the active compound has the formula ##STR358## syn isomer, wherein R'"'"' is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl and alkynyl of 2 to 6 carbon atoms all unsubstituted or substituted as in claim 1, phenyl, diphenyl, naphthyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridinyl pyimidinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, tetrazinyl, imidazolinyl, benzimidazolyl, benzothiazolyl, benzoxazole, R_3A is selected from the group consisting of pyridinium, quinolinium, isoquinolinium cyclopentylpyridinium, and trimethylammonium and Z_A has the definition of claim 1.

15. A method of claim 10 wherein the active compound has the formula ##STR359## syn isomer, wherein R'"'"' is selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl and alkynyl of 2 to 6 carbon atoms and cycloalkyl of 3 to 6 carbon atoms and cycloalkyl of 3 to 6 carbon atoms, all unsubstituted or substituted as in claim 2, phenyl, diphenyl, naphthyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, tetrazinyl, imidazolinyl, benzimidazolyl, benzothiazolyl, benzoxazole, R_3A is selected from the group consisting of pyridinium, quinolinium, isoquinolium, cyclopentyl pyridinium, trimethylammonium and Z_A has the definition of claim 1.