1-dethia-2-thia-cephalosporanic acids

• US 4,908,359 A
• Filed: 02/08/1988
• Issued: 03/13/1990
• Est. Priority Date: 02/06/1987
• Status: Expired due to Fees

• Current Assignee: Aventis Pharma SA (Sanofi )
• Original Assignee: Roussel Uclaf
• Inventors: Teutsch, Jean-Georges, Gouin d'Ambrieres, Solange, Costerousse, Germain
• Primary Examiner(s): RIZZO, NICHOLAS
• Application Number:
  US07/153,148
• Time in Patent Office: 764 Days
• Field of Search: 540/214, 540/215, 514/210
• US Class Current: 514/210.05
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07D 513/04 Ortho-condensed systems

Abstract

1-dethia-2-thia-cephalosporanic acids of the formula ##STR1## wherein R is selected from the group consisting of ##STR2## R_b --NH--and ##STR3## R_a is an organic radical R_i and R_j are individually selected from the group consisting of hydrogen, aliphatic, aromatic and heterocycle or taken together with the nitrogen atom form an optionally substituted heterocycle, R_b is optionally substituted carbocyclic or heterocyclic aryl, R_1B is --[CH═CH]_n1 --CH₂ --S--R_m, n₁ is 0, 1 or 2, Rm is an unsaturated radical including a positively charged and doubly bonded nitrogen atom and bonded to the sulfur atom through a carbon atom, R₄ is hydrogen or methoxy, n₂ is 0, 1 or 2 and A is selected from the group consisting of hydrogen, alkali metal ion, or alkaline earth metal ion, magnesium ion, ammonium ion, an organic amine base and an ester group or --COOA is --COO^- and their non-toxic, pharmaceutically acceptable acid addition salts, having antibiotic activity.

Claims

1. A compound selected from the group consisting of 1-dethia-2-thia-cephalosporanic acids of the formula ##STR37## 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 substituted or unsubstituted with at least one member of the group consisting of halogen, carboxy, salified carboxy, esterified carboxy, alkoxy, oxo, alkylthio, mercapto, hydroxy, amino, nitro, carbamoyl and cyano, n₂ is 0, 1 or 2, R₄ is hydrogen or methoxy, R_1B is --(CH═

CH)_n1 --CH₂ --S--R_m, n₁ is 0, 1 or 2, R_m is an unsaturated group including a positively charged and double bonded nitrogen atom, the said group being bonded to the sulfur atom through a carbon atom and selected from the group consisting of pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, quinoleinyl, isoquinoleinyl, cinnolinyl, quanazolinyl, pyridino pyrimidinyl, dihydro- or tetrahydro-pyridyl, unsubstituted or substituted by at least one member selected from the group of alkyl of 1 to 4 carbon atoms, methoxy, ethoxy, halogen, carboxyalkyl, esterified carboxyalkyl, carbamoyl, thioacetylalkyl, thiocarbamoylalkyl, haloalkyl, cyanoalkyl and alkenyl of 2 to 4 carbon atoms Y is methine or nitrogen and A is selected from the group consisting of hydrogen, alkali metal ion, or alkaline earth metal ion, magnesium ion, ammonium ion, an organic amine base and an ester group or --COOA is --COO^- and their non-toxic, pharmaceutically acceptable acid addition salts.

2. A compound of claim 1 selected from the group consisting of compounds of the formula ##STR38## syn isomer, wherein R'"'"' is hydrogen or alkyl, alkenyl, alkynyl or cycloalkyl of up to 6 carbon atoms or aryl, R_m is pyridinium unsubstituted or substituted as in claim 1 or, partially hydrogenated and bonded to the sulfur atom through a carbon atom, Y is methine or nitrogen and A has the definition of claim 1 and its non-toxic, pharmaceutically acceptable acid addition salts.

3. A compound of claim 1 selected from the group consisting of compound of the formula ##STR39## in which R" is methyl, fluoromethyl or difluoromethyl, R_m " is ##STR40## in which Alk is alkyl of 1 to 4 carbon atoms, R₅ is hydrogen, alkyl or alkythio of 1 to 4 carbon atoms, R_m " is bonded to the sulfur atom by the positions 2 or 4 and A has the definition of claim 1 and its non-toxic, pharmaceutically acceptable acid addition salts.

4. A compound of claim 1 selected from the group consisting of (6S) (7S) (Z) 4-[[[7-[(2-amino-4-thiazolyl)[(difluoromethoxy)-imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]-thio]-1-methyl pyridinium, (6S) (7S) (Z) 4-[[[7-[(2-amino-4-thiazolyl)-[(fluoromethoxy)imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]-thio]-1-methyl pyridinium, (6S) (7S) (Z) 2-[[[7-[2-amino-4-thiazolyl)-(fluoromethoxy)imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]-thio]-1-methyl pyridinium, 4-[[[7-[[2-(2-amino-4-thiazolyl)-2-(methoxy)imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]thio]-1-ethyl-3-methyl pyridinium, (6S) (7S) (Z), 4-[[[7-[[2-(2-amino-4-thiazolyl)-2-(methoxy)imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]methyl]-thio]-1,3-dimethyl pyridinium, (6S) (7S) (Z), 4-[[[7-[[2-(2-amino-4-thiazolyl)(methoxy)-imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]-thio]-1-methyl pyridinium, (6S) (7S) (Z), 4-[[[7-[[2-(2-amino-4-thiazolyl) (methoxy)imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]thio]-1-methyl-5,6-dihydro pyridinium, (6S) (7S) (Z), in the form of an internal salt and their non-toxic, pharmaceutically acceptable acid addition salts.

5. A compound of claim 1 selected from the group consisting of (6S) (7S) (Z) 4-[[[7-[(2-amino-4-thiazolyl)[(difluoromethoxy)imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]-thio]-1-methyl pyridinium in the form of an internal salt and its non-toxic, pharmaceutically acceptable acid addition salts.

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

7. A composition of claim 6 wherein the active compound is selected from the group consisting of compounds of the formula ##STR41## syn isomer wherein R'"'"' is hydrogen or alkyl, alkenyl, alkynyl or cycloalkyl of up to 6 carbon atoms or aryl, R_m '"'"' is pyridinium unsubstituted or substituted as in claim 1 or partially hydrogenated and bonded to the sulfur atom through a carbon atom, Y is methine or nitrogen and A has the definition of claim 1 and its non-toxic, pharmaceutically acceptable acid addition salts.

8. A composition of claim 6 wherein the active compound is selected from the group consisting of compounds of the formula ##STR42## in which R" is methyl, fluoromethyl or difluoromethyl, R_m " is ##STR43## in which Alk is alkyl of 1 to 4 carbon atoms, R₅ is hydrogen, alkyl or alkylthio of 1 to 4 carbon atoms, R_m " is bonded to the sulfur atom by the positions 2 or 4 and A has the definition of claim 1 and its non-toxic, pharmaceutically acceptable acid addition salts.

9. A composition of claim 6 wherein the active compound is selected from the group consisting of (6S) (7S) (Z) 4-[[[7-[(2-amino-4-thiazolyl)-[(difluoromethoxy)imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]-thio]-1-methyl pyridinium, (6S) (7S) (Z) 4-[[[7-[(2-amino-4-thiazolyl)-[(fluoromethoxy)imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]-thio]-1-methyl pyridinium, (6S) (7S) (Z) 2-[[[7-[[(2-amino-4-thiazolyl)-(fluoromethoxy)imino]acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]-thio]-1-methyl pyridinium, 4-[[[7-[[2-(2-amino-4-thiazolyl)-2-(methoxy)imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicylco[4,2,0]oct-2-en-3-yl]-methyl]thio]-1-ethyl-3-methyl pyridinium, (6S) (7S) (Z), 4-[[[7-[[2-(2-amino-4-thiazolyl)-2-(methoxy)imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]thio]-1,3-dimethyl pyridinium, (6S) (7S) (Z) 4-[[[7-[[2-(2-amino-4-thiazolyl) (methoxy)imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]thio]-1-methyl pyridinium, (6S) (7S) (Z), 4-[[[7-[[2-(2-amino-4-thiazolyl) (methoxy)imino]acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]thio]-1-methyl-5,6-dihydro pyridinium, (6S) (7S) (Z), in the form of an internal salt and their non-toxic, pharmaceutically acceptable acid addition salts.

11. A method of combatting bacterial infections in warm-blooded animals comprising administering to warm-blooded animals a bactericidally effective amount of at least one compound of claim 1.

12. A method of claim 11 wherein the active compound is selected from the group consisting of compounds of the formula ##STR44## syn isomer wherein R'"'"' is hydrogen or alkyl, alkenyl, alkynyl or cycloalkyl of up to 6 carbon atoms or aryl, R_m is pyridinium unsubstituted or substituted as in claim 1 or partially hydrogenated and bonded to the sulfur atom through a carbon atom, Y is methine or nitrogen and A has the definition of claim 1 and its non-toxic, pharmaceutically acceptable acid addition salts.

13. A method of claim 11 wherein the active compound is selected from the group consisting of compounds of the formula ##STR45## in which R" is methyl, fluoromethyl or difluoromethyl R_m " is ##STR46## in which Alk is alkylof 1 to 4 carbon atoms, R₅ is hydrogen, alkyl or alkylthio of 1 to 4 carbon atoms, R_m " is bonded to the sulfur atom by the positions 2 or 4 and A has the defintion of claim 1 and its non-toxic, pharmaceutically acceptable acid addition salts.

14. A method of claim 11 selected from the group consisting of (6S) (7S) (Z) 4-[[[7-[(2-amino-4-thiazolyl)-[(difluoromethoxy)imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]-thio]-1-methyl pyridinium, (6S) (7S) (Z) 4-[[[7-[(2-amino-4-thiazolyl)-[(fluoromethoxy)imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]-thio]-1-methyl pyridinium (6S) (7S) (Z) 2-[[[7-[(2-amino-4-thiazolyl)-(fluoromethoxy) imino]-acetamido]-2-carboxy-8-ox-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]-thio]-1-methyl pyridinium, 4-[[[7-[2-(2-amino-4-thiazolyl)-2-(methoxy)imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]methyl]-thio]-1-ethyl-3-methyl pyridinium, (6S) (7S) (Z) 4-[[[7-[2-(2-amino-4-thiazolyl)-2-(methoxy)imino]-acetamido]2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]methyl]-thio]-1,3-dimethyl pyridinium, (6S) (7S) (Z) 4-[[[7-[2-amino-4-thiazolyl)(methoxy)imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]methyl]-thio]-1-methyl pyridinium (6S) (7S) (Z) 4-[[[7-[2-(2-amino-4-thiazolyl) (methoxy)imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]methyl]-thio]-1-methyl-5,6-dihydro pyridinium (6S) (7S) (Z), in the form of an internal salt and their non-toxic, pharmaceutically acceptable acid addition salts.

15. A method of claim 11 wherein the active compound is selected from the group consisting of (6S) (7S) (Z) 4-[[[7-[(2-amino-4-thiazolyl)[(difluoromethoxy)imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]-thio]-1-methyl pyridinium in the form of an internal salt and its non-toxic, pharmaceutically acceptable acid addition salts.

10. A composition of 6 claim wherein the active compound is selected from group consisting of (6S) (7S) (Z) 4-[[[7-[(2-amino-4-thiazolyl)-[(difluoromethoxy)imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]-thio]-1-methyl pyridinium in the form of an internal salt and its non-toxic, pharmaceutically acceptable acid addition salts.