1-dethia-2-thia-cephalosporanic acids

• US 5,663,164 A
• Filed: 04/27/1995
• Issued: 09/02/1997
• Est. Priority Date: 02/13/1984
• Status: Expired due to Fees

• Current Assignee: Aventis Pharma SA (Sanofi )
• Original Assignee: Roussel Uclaf
• Inventors: Aszodi, Jozsef, Bonnet, Alain, Costerousse, Germain, d'Ambrieres, Solange Gouin, Teutsch, Jean-Georges
• Primary Examiner(s): Grumbling, Matthew V.
• Assistant Examiner(s): WONG, KING
• Application Number:
  US08/429,600
• Time in Patent Office: 859 Days
• Field of Search: 540/214, 540/210
• US Class Current: 514/210.05
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: C07C 323/00 Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
• CPC Class Codes: C07C 391/02 having selenium atoms bound to carbon atoms of six-membered aromatic rings
• CPC Class Codes: C07C 45/515 the singly bound functional group being an acetalised, ketalised hemi-acetalised, or hemi-ketalised hydroxyl group cyclic acetals or ketals C07C45/59, C07C45/60
• CPC Class Codes: C07C 47/198 containing ether groups, groups, groups, or groups
• CPC Class Codes: C07C 59/21 containing halogen
• CPC Class Codes: C07C 59/88 containing halogen
• CPC Class Codes: C07D 205/085 with a nitrogen atom directly attached in position 3
• CPC Class Codes: C07D 213/71 to which a second hetero atom is attached
• CPC Class Codes: C07D 257/04 Five-membered rings
• CPC Class Codes: C07D 285/125 with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 303/48 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 containing three or more hetero rings
• CPC Class Codes: C07D 513/04 Ortho-condensed systems
• CPC Class Codes: C07D 513/14 Ortho-condensed systems
• CPC Class Codes: C07F 7/1804 Compounds having Si-O-C linkages Si-O-acyl linkages C07F7/1896
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Novel 1-dethia-2-thia-cephalosporanic acid derivatives of the formula ##STR1## wherein R is selected from the group consisting of ##STR2## Ra 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 to which they are attached form an optionally substituted cycle or R_b NH--, R_b is optionally substituted carbocyclic or heterocyclic aryl, R₁ and --COM are as defined in the specification, R₄ is hydrogen or methoxy, n₂ is 0, 1 or 2 and their non-toxic, pharmaceutically acceptable acid addition salts in racemic or optically active form having antibiotic activity and their preparation and novel intermediates.

Claims

1. A compound selected from the group consisting of a compound of the formula ##STR2235## wherein R_a is selected from the group consisting of ##STR2236## R_c is selected from the group consisting of 2-amino-4-thiazolyl, 2-amino-5-chloro-thiazolyl, 5-amino-1,2,4-thiadiazolyl, 4-thiazolyl, 2-thienyl and 2-furyl, R_d is selected from the group consisting of hydrogen, alkyl of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms and phenyl, all optionally substituted with at least one member of the group consisting of halogen, --CN, carbamoyl, --NO₂, --NH₂, --OH, --SH, ═

O and carboxyl free, esterified or salified, ##STR2237## R₁ is selected from the group consisting ##STR2238## R₂ is selected from the group consisting of alkyl, alkenyl and alkynyl all optionally substituted with at least one member of the group consisting of nitro, carboxy free, esterified or salified, amino, --OH, azido, sulfo free or salified, halogen, carbamoyl, methyltetrazolylcarbamoyl, aryl selected from the group consisting of phenyl, diphenyl, naphthyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, pyrannyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, trazinyl, thiadiazinyl, oxadiazinyl, tetrazinyl, imidazolinyl, benzimidazolyl, benzothiazolyl and benzoxazol, all optionally substituted with at least one member of the group consisting of acetyl, nitrophenyl, 1-methyl-pyrrolidinium, methylpyridinium, trimethyl ammonium, pyridinium, methylthio-pyridinium, trifluoromethylphenyl and cyano-phenyl and R₂ can be optionally interrupted with optionally oxidized --S-- or --O-- or --NH-- or --Se--, Z is selected from the group consisting of optionally oxidized --S-- or --O-- or --Se-- or --NH--, Za is selected from the group consisting of -CH₂ --, --O--, --S--, --Se--, --NH--, --CH₂ S-- and a simple bond, R₃ is selected from the group consisting of phenyl, diphenyl, naphthyl, heterocyclearyl selected from the group consisting of thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, tetrazinyl, imidazolinyl, benzimidazolyl, benzothiazolyl, and benzoxazol, a quaternary ammonium pyridinium, quinolinium, isoquinolinium, 2,3-cyclopenteno pyridinium, thienopyridinium, cyclohexylpyridinium and trimethylammonium and optionally substituted with at least one member of the group consisting of alkyl optionally substituted with at least one member of the group consisting of phenyl, thienyl, phenoxy, alkoxycarbonyl, halogen, hydroxy, carboxy free, esterified or salified, amino, alkylamino, and dialkylamino;

alkenyl;

alkyl;

phenyl;

tolyl;

halogen;

nitro;

alkoxy of 1 to 4 carbon atoms;

alkylthio;

hydroxy;

mercapto;

carboxyl free, esterified or salified;

carbamoyl;

##STR2239## pyridinium substituted with cyano, --CF₃ or acetyl;

(2-chloro-2-propenyl)-1,4,5,6-tetrahydro, 5,6-dioxo-1,2,4-triazin-3-yl and 1,2, 5,6-tetrahydro-2-methy-5,6-dioxo-1,2,4-triazin-3-yl, d) alkyl, alkenyl or alkynyl of 2 to 4 carbon atoms optionally substituted with a member selected from the group consisting of phenyl, carboxy free, esterified or salified, cyano, amino, acyl, halogen and --CF₃ and optionally interrupted with optionally oxidized --S--, --O-- or --NH--, e) halogen, nitrile, caboxy, free, esterified or salified, azide, thiocyanato, isothiocyanato and f) azidomethyl, amino, mono or dialkylaminomethyl, thiocyanatomethyl, isothiocyanatomethyl, carbamoyloxymethyl, semicarbazonomethine, arylhydrazonomethine optionally substituted with nitro, nitromethyl, di or trihalomethyl, --CH₂ --ONO₂, --CH⁺₂ P(alk₃), ##STR2240## alk is alkyl of 1 to 4 carbon atoms, R₄ is hydrogen, COM is CO₂ A or A is hydrogen, an equivalent of alkali metal, alkaline earth metal, magnesium, ammonium or an organic amine or A is an ester or CO₂ A is CO^-₂, or R₁ and CO₂ A form with the carbon to which they are attached ##STR2241## or COM is carbamoyl and their non-toxic, pharmaceutically acceptable acid addition salts.

2. A compound of claim 1 wherein Rd is selected from the group consisting of hydrogen, methyl and allyl and R₁ is selected from the group consisting of methoxymethyl, pyridinylthio, pyridinyl, phenyl or phenylthio optionally substituted by methyl, cyclopropyl, nitro, chloro or methoxy, phenyl-selenyl, methylthio or ethylthio optionally substituted by carboxy, ethoxy-carbonyl or amino, ethyl, isopropyl, methyltetrazolylthio, methyl or thiomethylthiadiazolylthio, trimethylammonium methyl and pyridinium optionally substituted with at least one member of the group consisting of dialkylamino of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxy, alkoxyalkyl and alkylthio of 1 to 4 carbon atoms, cyano, acetyl, carboxy, phenyl, benzoyl, alkoxycarbonyl, acylamino, halogen, hydroxyalkyl, thiocyanate, phenylthio, hydroxy, amino, phenoxy, methylimidazolinium, pyrazinium, alkyl thienopyridinium, benzopyridinium, vinylimidazolinium, thiazolinium, methyl methylthio imidazolinium and cyclohexyl pyridinium or dihydro-pyridinium.

3. A compound of claim 1, wherein R₁ is Z'"'"'_a --R'"'"'₃ in which Z'"'"'_a is sulfur and R'"'"'₃ is a heterocyclic aryl with 5 to 6 links optionally substituted, or Z'"'"'_a is methylene and R'"'"'₃ is selected from the group consisting of pyridinium, thienopyridinium, quinolinium, isoquinolinium, cyclohexylpyridinium and phenyl optionally substituted with --NO₂, chlorine or CH₃ O-- and its non-toxic, pharmaceutically acceptable salts.

4. A compound of claim 1 selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-(3-nitro-phenylthio)-8-oxo-4-thia-1-azabicyclo[4,2,0]-oct-2-ene-2-carboxylic acid and its non-toxic, pharmaceutically acceptable salts.

5. A compound of claim 1 selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-(4-nitro-phenyl)-8-oxo-4-thia-1-azabicyclo[4,2,0]-oct-2-ene-2-carboxylic acid and its non-toxic, pharmaceutically acceptable salts.

6. A compound of claim 1 selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-[1-methyl-(1H)-tetrazol-5-yl)-thio]-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid and its non-toxic, pharmaceutically acceptable salts.

7. A compound of claim 1 selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-[1-methyl-(1H)-tetrazol-5-yl)-thiomethyl)-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid and its non-toxic, pharmaceutically acceptable salts.

8. A compound of claim 1 selected from the group consisting of racemic or optically active forms of the syn isomer of 1-[7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methyl-pyridinium and its non-toxic, pharmaceutically acceptable salts.

9. A compound of claim 1 selected from the group consisting of racemic or optically active forms of the syn isomer of 1-[7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methyl-(6,7,-dihydro)-5H-1-pyrindinium and its non-toxic, pharmaceutically acceptable salts.

10. A compound of claim 1 selected from the group consisting of racemic or optically active forms of the syn isomer of 6-[7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methyl-thieno[2,3-c]pyridinium and its non-toxic, pharmaceutically acceptable salts.

11. A compound of claim 1 selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-8-oxo-2-carboxy-4-thia-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methyl-trimethyl ammonium and its non-toxic, pharmaceutically acceptable salts.

12. A compound of claim 1 selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-8-oxo-4-thia-2-carboxy-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methyl-4-cyclopropylpyridinium and its non-toxic, pharmaceutically acceptable salts.

13. A compound of claim 1 selected from the group consisting of racemic or optically active forms of the syn isomer of 6-[7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-8-oxo-4-thia-2-carboxy-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methyl-7-methylthieno[2,3-c]pyridinium and its non-toxic, pharmaceutically acceptable salts.

14. A compound of claim 1 selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-8-oxo-4-thia-2-carboxy-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methylthieno[2,3-b]pyridinium and its non-toxic, pharmaceutically acceptable salts.

15. A compound of claim 1 selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-(2-propenyloxy)-imino-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methyl pyridinium and its non-toxic, pharmaceutically acceptable salts.

16. A compound of claim 1 selected from the group consisting of racemic or optically active forms of the syn isomer of 1-[(7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methyl-(2-methylthio]-pyridinium and its non-toxic, pharmaceutically acceptable salts.

17. A compound of claim 1 selected from the group consisting of racemic or optically active forms of the syn isomer of 5-[7-[2-(2-aminothiazol-4-yl)-[(difluoromethoxy)-imino-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methylthieno[2,3-b]pyridinium and its non-toxic, pharmaceutically acceptable salts.

18. A compound of claim 1 selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[7-[2-(2-aminothiazol-4-yl-[(propenyloxy-imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methyl]-thieno[2,3-b]pyridinium (6RS,7RS) and its non-toxic, pharmaceutically acceptable salts.

19. An antibiotic composition comprising an antibiotically effective amount of at least one compound of claim 1 and an excipient.

20. A composition of claim 19 wherein Rd is selected from the group consisting of hydrogen, methyl and allyl and R₁ is selected from the group consisting of methoxymethyl, pyridiniylthio, pyridinyl, phenyl or phenylthio optionally substituted by methyl, cyclopropyl, nitro, chloro or methoxy, phenylselenyl, methylthio or ethylthio optionally substituted by carboxy, ethoxy-carbonyl or amino radical, ethyl, isopropyl, methyltetrazolylthio, methyl or thiomethylthiadiazolylthio, trimethylammonium methyl, pyridinium optionally substituted with at least one member of the group consisting of dialkylamino of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxy, alkoxyalkyl and alkylthio of 1 to 4 carbon atoms, cyano, acetyl, carboxy, phenyl, benzoyl, alkoxycarbonxyl, acylamino, halogen, hydroxyalkyl, thiocyanato, phenylthio, hydroxy, amino, phenoxy, methylimidazolinium, pyrazinium, alkyl thienopyridinium, benzopyridinium, vinylimidazolinium, thiazolinium, methyl methylthio imidazolinium, cyclohexylpyridinium and dihydropyridinium.

21. A composition of claim 19 wherein R₁ is --Z'"'"'_a --R'"'"'₃ in which Z'"'"'_a is sulfur and R'"'"'₃ is a heterocyclic aryl with 5 to 6 links optionally substituted, or Z'"'"'_a is methylene and R'"'"'₃ is selected from the group consisting of pyridinium, thienopyridinium, quinolinium, isoquinolinium and phenyl optionally substituted with --NO₂, chlorine or CH₃ O.

22. A composition of claim 19 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxy-imino-acetamido]-3-(3-nitrophenylthio)-8-oxo-4-thia-1-azabicyclo (4,2,0]oct-2-ene-2-carboxylic acid and its non-toxic, pharmaceutically acceptable salts.

23. A composition of claim 21 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxy-imino-acetamido]-3-(4-nitrophenyl)-8-oxo-4-thia-1-azabicyclo [4,2,0]oct-2-ene-2-carboxylic acid and its non-toxic, pharmaceutically acceptable salts.

24. A composition of claim 19 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxy-imino-acetamido]-3-[(1-methyl-(1H)-tetrazol-5-yl)-thio]-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid and its non-toxic, pharmaceutically acceptable salts.

25. A composition of claim 19 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of7-[2-(2-aminothiazol-4-yl)-2-methoxy-imino-acetamido]-3-[(1-methyl-(1H)-tetrazol-5-yl)-thiomethy]-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid and its non-toxic, pharmaceutically acceptable salts.

26. A composition of claim 19 wherein the active compound is selected from the group consisting of racemic or optically active forms, of the syn isomer of 1-[7-[(2-aminothiazol-4-yl)-2-methoxy-imino-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methylpyridiniuim and its non-toxic, pharmaceutically acceptable salts.

27. A composition of claim 19 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of 1-[7-[(2-aminothiazol-4-yl)-2-methoxy-imino-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl(6,7-dihydro)-5H-1-pyrindinium and its non-toxic, pharmaceutically acceptable salts.

28. A composition of claim 19 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of 6-[7-[(2-(2-aminothiazol-4-yl)-2-methoxy-imino-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-methylthieno[2,3-c]pyridinium and its non-toxic, pharmaceutically acceptable salts.

29. A composition of claim 19 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxy-imino-acetamido]-8-oxo-2-carboxy-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl)-methyl-trimethyl ammonium and its non-toxic, pharmaceutically acceptable salts.

30. A composition of claim 19 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-aminothiazol-4-y)-2-methoxy-imino-acetamido]-8-oxo-4-thia-2-carboxy-1-azabicyclo[4,2,0]oct-2-en-3-yl)-methyl-4-cyclopropyl-pyridinium and its non-toxic, pharmaceutically acceptable salts.

31. A composition of claim 19 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of 6-[7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-8-oxo-4-thia-2-carboxy-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl-7-methylthieno[2,3-c]pyridinium and its non-toxic, pharmaceutically acceptable salts.

32. A composition of claim 19 wherein the active compound is selected from the group consisting of racemic or optically forms of the syn isomer of 7-[7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-8-oxo-4-thia-2-carboxy-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methylthieno[2,3-b]pyridinium and its non-toxic, pharmaceutically acceptable salts.

33. A composition of claim 19 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-propenyloxy)-imino-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methyl pyridinium and its non-toxic, pharmaceutically acceptable salts.

34. A composition of claim 19 wherein the active compound is selected from the group consisting of racemic or optically forms of the syn isomer of 1-[(7-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl-(2-methylthio)-pyridinium and its non-toxic, pharmaceutically acceptable salts.

35. A composition of claim 19 wherein the active compound is selected from the group consisting of racemic or optically forms of the syn isomer of 5-[7-(2-aminothiazol-4-yl)-[(difluoromethoxy)-imino]-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methylthieno[2,3-b]pyridinium and its non-toxic, pharmaceutically acceptable salts.

36. A composition of claim 19 wherein the active compound is selected from the group consisting of racemic or optically forms of the syn isomer of 7-[7-[2-(2-aminothiazol-4-yl)-2-[(propenyloxy)-imino]-acetamido-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-en-3-yl]-methyl]-thieno[2,3-b]-pyridinium (6RS,7RS) and its non-toxic, pharmaceutically acceptable salts.

37. A method of treating bacterial infections in warm-blooded animals comprising administering to warm-blooded animals an anti-bactericidally effective amount of at least one compound of claim 1.

38. A method of claim 37 wherein Rd is selected from the group consisting hydrogen, methyl and allyl and R₁ is selected from the group consisting of methoxymethyl, pyridinylthio, pyridinyl, phenyl or, phenylthio optionally substituted by methyl, cyclopropyl, nitro, chloro or methoxy, phenyl-selenyl, methylthio optionally substituted by carboxy, ethoxycarbonyl, or amino radical, ethyl, isopropyl, methyltetrazolylthio, methyl or thiomethyl-thiadiazolylthio, trimethyl-ammonium methyl, pyridinium optionally substituted with at least one member of the group consisting of dialkylamino of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, alkoxy, alkoxyalkyl and alkylthio of 1 to 4 carbon atoms, cyano, acetyl, carboxy, phenyl, benzoyl, alkoxycarbonyl, acylamino, halogen, hydroxyalkyl, thiocyanate, phenylthio, hydroxy, amino, phenoxy, methylimidazolinium, pyrazinium, alkyl thienopyridinium, benzopyridinium, vinylimidazolinium, thiazolinium, methyl methylthio imidiazolinium and cyclohexyl-pyridinium or dihydropyridinium.

39. A method of claim 37 wherein R₁ is Z_a --R₃ in which Z_a is sulfur and R₃ is a heterocyclic aryl with 5 to 6 links optionally substituted, or Z_a is methylene and R₃ is selected from the group consisting of pyridinium, thienopyridinium, quinolinium, isoquinolinium and phenyl optionally substituted with --NO₂, chlorine or CH₃ O--.

40. A method of claim 35 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-amino-thiazol-4-yl)-2-methoxy-imino-acetamido]-3-(3-nitrophenylthio)-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid and its non-toxic, pharmaceutically acceptable salts.

41. A method of claim 35 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-amino-thiazol-4-yl)-2-methoxy-imino-acetamido]-3-(4-nitrophenyl)-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid and its non-toxic, pharmaceutically acceptable salts.

42. A method of claim 37 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxy-imino-acetamido]-3-[(1-methyl-(1H)-tetrazol-5-yl)-thio]-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid and its non-toxic, pharmaceutically acceptable salts.

43. A method of claim 37 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxy-imino-acetamido]-3-[(1-methyl-(1H)-tetrazol-5-yl)-thiomethyl]-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-2-carboxylic acid and its non-toxic, pharmaceutically acceptable salts.

44. A method of claim 37 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of 1-[7-[(2-aminothiazol-4-yl)-2-methoxy-imino-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methylpyridinium and its non-toxic, pharmaceutically acceptable salts.

45. A method of claim 37 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of 1-[7-[(2-aminothiazol-4-yl)-2-methoxy-imino-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methyl-(6,7-dihydro)-5H-1-pyrindinium and its non-toxic, pharmaceutically acceptable salts.

46. A method of claim 37 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of 6-(7-[2-(2-aminothiazol-4-yl)-2-methoxy-imino-acetamido]-2-carboxy-8-oxo-4-thia-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methylthieno[2,3-c]pyridinium and its non-toxic, pharmaceutically acceptable salts.

47. A method of claim 37 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxy-imino-acetamido]-8-oxo-2-carboxy-4-thia-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methyl-trimethyl ammonium and its non-toxic, pharmaceutically acceptable salts.

48. A method of claim 13 wherein the active compound is selected from the group consisting of racemic or optically active forms of the syn isomer of 7-[2-(2-aminothiazol-4-yl)-2-methoxy-imino-acetamido]-8-oxo-4-thia-2-carboxy-1-azabicyclo[4,2,0]oct-2-ene-3-yl]-methyl-4-cyclopropyl-pyridinium and its non-toxic, pharmaceutically acceptable salts.

49. A method of treating bacterial infections in warm-blooded animals comprising administering to warm-blooded animals an anti-bactericidally effective amount of at least one compound of claim 13.

50. A method of treating bacterial infections in warm-blooded animals comprising administering to warm-blooded animals an anti-bactericidally effective amount of at least one compound of claim 14.

51. A method of treating bacterial infections in warm-blooded animals comprising administering to warm-blooded animals an anti-bactericidally effective amount of at least one compound of claim 15.

52. A method of treating bacterial infections in warm-blooded animals comprising administering to warm-blooded animals an anti-bactericidally effective amount of at least one compound of claim 16.

53. A method of treating bacterial infections in warm-blooded animals comprising administering to warm-blooded animals an anti-bactericidally effective amount of at least one compound of claim 17.

54. A method of treating bacterial infections in warm-blooded animals comprising administering to warm-blooded animals an anti-bactericidally effective amount of at least one compound of claim 18.