DE2617442A1 - BICYCLIC 7-ACYLAMIDO-3-CEPHEM-4-CARBONIC ACID DERIVATIVES, THE PROCESS FOR THEIR PRODUCTION AND THE PHARMACEUTICAL PRODUCTS CONTAINING THEM - Google Patents

Description

The invention relates to new bicyclic derivatives of 7-acylamido-3-cephem-4-carboxylic acid, a process for their preparation and pharmaceutical compositions containing them.

The new compounds forming an object of the invention are characterized by the general formula I.

where mean:

x is the number 0, 1 or 2,

n is the number 0 or 1,

Z 1.) a cyano group, a carbamoyl group or a -COOR- or -COR group, in which R is hydrogen or C [deep] 1-C [deep] 6-alkyl,

2.) a R [deep] 1-SO [deep] 2 group, in which R [deep] 1 C [deep] 1-C [deep] 6-alkyl, amino or salted or not salted Hydroxy means

3.) a phenyl group or a heteromonocyclic ring with 5 or 6 atoms which contains at least one double bond and at least one heteroatom from the group N, S and O, the phenyl group and the heteromonocyclic ring being unsubstituted or by one or more substituents from the group Hydroxy, cyano, carboxy, oxo, halogen, C [deep] 1-C [deep] 6-alkyl, C [deep] 1-C [deep] 6-alkoxy, -SH, C [deep] 1-C [deep ] 6-aliphatic acyl, -CH [deep] 2CN and in which the groups R, which can be the same or different from one another, each have the meanings given above, is substituted,

A is a direct bond or the meanings given below for A [deep] 1,

A [deep] 1 is a branched-chain or straight-chain (unbranched) saturated aliphatic C [deep] 1-C [deep] 8 hydrocarbon radical which is unsubstituted or substituted by one or more substituents from the group OR '' ', where R' '' is hydrogen or is formyl, halogen, cyano, amino, -COOR or -COR, in which R has the meanings given above, and R [deep] 1-SO [deep] 2-, in which R [deep] 1 has the meanings given above, can be substituted,

B is a heterocyclic ring different from triazolophyridyl and purinyl and containing at least two double bonds, each of the fused heteromonocyclic rings, which are the same or different from one another, is a heteromonocyclic ring with 5 or 6 atoms, which is at least one hetero atom from the group N, S and contains O, the heterobicyclic ring being unsubstituted or substituted by one or more substituents from the group: a) hydroxy, cyano, -SH, C [deep] 1-C [deep] 6-alkoxy, halogen, aliphatic C [deep ] 1-C [deep] 6-acyl, -CH [deep] 2CN, -COOR or wherein R has the meanings given above,

b) an unsubstituted or substituted by an aliphatic C [deep] 1-C [deep] 6-acyl group,

c) a C [deep] 1-C [deep] 6-alkyl group which is unsubstituted or substituted by one or more substituents from the group consisting of hydroxy and halogen,

d) where x [deep] 1 is the number 0, 1 or 2 and each of the radicals R 'and R ", which are identical or different from one another, are hydrogen or C [deep] 1-C [deep] 6-alkyl or in which R' and R "together with the nitrogen atom form a morpholino, piperidino or pyridyl ring,

e) -SR [deep] 1 or -SO [deep] 2-R [deep] 1, where R [deep] 1 has the meanings given above, -S-CH [deep] 2CN, where x [deep] 2 is the number 0 or 1 and R has the meanings given above,

M hydrogen or a non-toxic, pharmaceutically acceptable cation,

with the proviso that when B is unsubstituted tetrazolo- (4,5-b) pyridazin-6-yl, A is a direct bond, A [deep] 1 where R '''has the meanings given above and n and x are the number 0, Z is not phenyl or thienyl.

The invention also relates to the salts of the above-mentioned compounds, in particular the pharmaceutically acceptable salts thereof, and all possible cis and trans isomers and the stereoisomers of the formula I and their mixtures, the metabolites (metabolites) which have antibacterial activity, and the metabolic precursors of the compounds of formula I.

Preferred compounds are those in which the side chain in the 7-position contains no asymmetric carbon atoms or only one asymmetric carbon atom. In the latter case, the side chain in the 7-position preferably has either the D configuration (this is indicated by the letter R in the chemical names of the compounds) or the D, L configuration (all compounds whose chemical name does not indicate the Configuration contains are racemic compounds, i.e. D, L derivatives).

The alkyl, alkoxy and aliphatic acyl groups can be branched or straight chain (unbranched).

If R [deep] 1 denotes a hydroxyl group which has been converted into a salt, this is preferably the salt with an alkali metal. If Z is a phenyl group substituted by an oxo group, it has one of the following formulas: wherein any of the above-mentioned substituents for the phenyl group can also be present. If Z is an unsubstituted or substituted heteromonocyclic ring as indicated above, the ring is preferably pyridyl, pyridazinyl, thiadiazolyl, oxadiazolyl, thiazolyl, tetrazolyl,

Thioxadiazolyl, furyl or thienyl.

A and / or A [deep] 1 preferably denote the following aliphatic hydrocarbon radicals: where n [deep] 1 is an integer from 1 to 6, or where n [deep] 2 is the number 0 or an integer from 1 to 5, preferably the number 0 or 1, x [deep] 2 has the meanings given above and R [deep] 2 is hydroxy, halogen, cyano, amino, -COR or -COOR, in which R has the meanings given above, R [deep] 1-SO [deep] 2-, in which R [deep] 1 has the meanings given above, or C [deep] 1-C [deep] 4-Alkyl means that is unsubstituted or substituted by one or more substituents from the group consisting of cyano, hydroxy, carboxy and amino. n [low] 2 preferably denotes the number 0 and at least one of the radicals A and A [low] 1 denotes one

A radical in which n [deep] 1 is preferably an integer from 1 to 3.

For example, the chain means

wherein R has the meanings given above and Hal is halogen:

B preferably denotes tetrazolopyridazinyl, tetrazolopyrimidinyl, tetrazolopyrazinyl, tetrazolotriazinyl, triazolopyridazinyl, triazolopyrimidinyl, triazolopyrazinyl, imidazopyridazinyl, tetrazolopyridyl, furopyridazinyl, thiazolopyridazinyl, as indicated above, furopyridazinyl, thiazolopyridazinyl, thiazolopyridazinyl, thiazolopyridazinyl, thiazolopyridazinyl, thiazolopyridazinyl, thiazolopyridazinyl, thiazolopyridazinyl, thiazolopyridazinyl, thiazolopyridazinyl, thiazolopyridazinyl, thiazolopyridazinyl, thiazolopyridazinyl, thiazolopyridazinyl, thiazolopyridazinyl, may optionally be as indicated above, thiazolopyridazinyl, tetrazolotriazinyl, tetrazolotriazinyl,

The non-toxic, pharmaceutically acceptable cations include both metal cations, such as the cations of sodium, potassium, calcium and aluminum, and the cations of organic amines, such as lysine, triethylamine, procaine, dibenzylamine, N-benzyl-beta phenethylamine, N, N'-dibenzylethylenediamine, dehydroabietylamine, N-ethylpiperidine and the like.

Other salts also falling within the scope of the present invention include those formed by the compounds of formula I wherein M is a cation and one or more of the substituents contains a basic group such as an amino group or an acid group such as a carboxy group. The invention therefore also includes the pharmaceutically acceptable salts of the compounds of the formula I in which M is a cation, both with inorganic acids, such as hydrochloric acid and sulfuric acid, and with organic acids, such as citric acid, tartaric acid, maleic acid, methanesulfonic acid, or with inorganic bases , such as sodium, potassium, calcium and aluminum hydroxides, or with organic bases, such as the organic amines given above. This also includes the inner salts (i.e. the zwitterions).

Preferred compounds are those of the general formula II

where mean:

n the meanings given above,

Z cyano, carbamoyl, acetyl or R [deep] 1-SO [deep] 2-, in which R [deep] 1 has the meanings given above, or if n is the number 0 and A is a direct bond, a phenyl group or a heteromonocyclic ring with 5 or 6 atoms which contains at least one double bond and at least one heteroatom from the group N, S and O, the phenyl group or the heteromonocyclic ring being unsubstituted or by one or more substituents from the group hydroxy, -CH [deep ] 2CN, C [deep] 1-C [deep] 6-alkyl and in which the groups R, which are identical or different from one another, each have the meanings given above, is substituted,

A is a direct bond or the radicals A and A [deep] 1 each represent the group where x [deep] 2 has the meanings given above, and R [deep] 3 is hydrogen, -OR ''', where R''' has the meanings given above, halogen, cyano, amino, R [deep] 1- SO [deep] 2-, in which R [deep] 1 has the meanings given above, or C [deep] 1-C [deep] 6-alkyl which is unsubstituted or substituted by one or more substituents from the group consisting of cyano and carboxy ,

B unsubstituted a heterobicyclic ring selected from the group tetrazolopyridazinyl, Tetrazolopyrimidinyl, Tetrazolotriazinyl, Tetrazolopyrazinyl, tetrazolopyridyl, Triazolopyridazinyl, Triazolopyrimidinyl, Triazolopyrazinyl, Imidazophridazinyl, Furopyridazinyl, Thiazolopyridazinyl, Thiadiazolopyridazinyl, Thienopyridazinyl and thienopyrimidinyl, the or substituted by one or more substituents from the group hydroxy, Cyano, -SH, C [deep] 1-C [deep] 6-alkoxy, halogen, aliphatic C [deep] 1-C [deep] 6-acyl, -CH [deep] 2CN, in which x [deep] 1, R 'and R "have the meanings given above, -SO [deep] 2R [deep] 1, in which R [deep] 1 has the meanings given above, -COR or wherein x [deep] 2 and R have the meanings given above, C [deep] 1-C [deep] 6-alkyl, which is unsubstituted or substituted by one or more substituents from the group consisting of hydroxy and halogen,

M hydrogen or a non-toxic, pharmaceutically acceptable cation,

and the pharmaceutically acceptable salts thereof, with the proviso that when B is simultaneously unsubstituted tetrazolo- (4,5-b) pyridazin-6-yl, A is a direct bond, A [deep] 1 is the group where R '''has the meanings given above, and n is the number 0, Z is not phenyl and thienyl.

Particularly preferred compounds are those of the general formula III

where mean:

n the meanings given above,

n [deep] 2 the number 0 or 1,

Z Cyano, carbamoyl, acetyl or R [deep] 1-SO [deep] 2-, in which R [deep] 1 has the meanings given above, or when both n and n [deep] 2 are 0, a phenyl group or a tetrazolyl, triazolyl, pyridyl, pyridazinyl, furyl or thienyl group, all of these groups being unsubstituted or by one or more substituents from the group consisting of hydroxy, -CH [deep] 2CN, in which the groups R, which are identical or different, each have the meanings given above, are substituted,

R [deep] 4 hydrogen or C [deep] 1-C [deep] 6-alkyl that is unsubstituted or substituted by one or more substituents from the group consisting of cyano and carboxy,

R [deep] 5 hydrogen, -OR '' ', in which R' '' has the meanings given above, carboxy, amino or R [deep] 1-SO [deep] 2-, in which R [deep] 1 has the meanings given above Has meanings

B is a heterobicyclic ring of the group tetrazolopyridazinyl, Tetrazolopyrimidinyl, Tetrazolopyrazinyl, tetrazolopyridyl, Tetrazolotriazinyl, Triazolopyridazinyl, Triazolopyrimidinyl, Triazolopyrazinyl, Imidazopyridazinyl, Furopyridazinyl, Thiazolopyridazinyl, Thiadiazolopyridazinyl, Thienopyridazinyl and thienopyrimidinyl, which is unsubstitu- ated or substituted by one or more substituents from the group C [deep] 1-C [deep] 3-alkyl, cyano, hydroxy, amino, -SH-, acetyl, -CH [deep] 2CN, -CH [deep] 2OH, in which the groups R, which are identical or different, each have the meanings given above, -SO [deep] 2R [deep] 1, in which R [deep] 1 has the meanings given above, -COOR or -CH [deep] 2COOR or -S-CH [deep] 2-COOR, in which R has the meanings given above,

M hydrogen or a non-toxic, pharmaceutically acceptable cation,

and a pharmaceutically acceptable salt thereof, with the proviso that when B is simultaneously unsubstituted tetrazolo (4,5-b) pyridazin-6-yl, n [deep] 2 and n are 0 and R [deep] 5 -OR '' ', where R' '' is as defined above, Z is not phenyl and thienyl.

In the compounds of the formula III, R [deep] 4 preferably denotes hydrogen, methyl, ethyl or -CH [deep] 2CN, while B is preferably unsubstituted or substituted by one or more substituents from the group consisting of methyl, ethyl, hydroxy, amino, cyano , -CH [deep] 2OH, acetyl, -COOH, -COOCH [deep] 3, -CH [deep] 2COOH, -CH [deep] 2COOCH [deep] 3, in which the groups R, which are identical or different from one another, each have the meanings given above, or -S-CH [deep] 2-COOR, in which R has the meanings given above.

Examples of preferred compounds according to the invention are as follows:

1) 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

2) 7 - {[(Carboxamido) -methyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4- carboxylic acid,

3) 7 - {[(Alpha-Carboxamido) -äthyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

4) 7 - {[(Alpha-Carboxamido) -propyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

5) 7 - {[(Alpha-Cyano) -benzyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

6) 7 - {[(Alpha, Beta-Dicyano) -äthyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

7) 7 - {[(Acetyl) -methyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4- carboxylic acid,

8) 7 - [(1H-1-tetrazolyl) acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid,

9) 7 - [(1-s-Triazolyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

10) 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[triazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

11) 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[triazolo (4,5-b) pyridazin- (6-methyl) -3-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

12) 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-carboxy) -6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

13) 7 - {[(Alpha-Cyano) -benzyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin- (8-carboxy) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

14) 7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin- (8-carboxy) -6-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

15) 7 - [(1H-1-Tetrazolyl) -acetamido] -3 - {[s-triazolo (4,5-b) pyridazin- (6-methyl) -3-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

16) 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin- (5-methyl) -7-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

17) 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-c) pyrimidin-7-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

18) 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-a) pyrazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

19) 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-a) pyridin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

20) 7 - {[(Alpha, Beta-Dicyano) -äthyl-thio] -acetamido} -3 - {[triazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

21) 7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[triazolo (4,5-b) pyridazin- (6-methyl) -3-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

22) 7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[tetrazolo (4,5-a) pyrimidin- (5-methyl) -7-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

23) 7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[tetrazolo (4,5-c) pyrimidin-7-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

24) 7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[tetrazolo (4,5-a) pyrazin-6-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

25) 7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[tetrazolo (4,5-a) pyrid-6-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

26) 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-amino) -6-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

27) 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

28) 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-cyano) -6-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

29) 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyridimidin- (7-methyl) -5-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

30) 7 - {(R) - [2-hydroxy-2- (4-hydroxy) phenyl] acetamido} -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

31) 7 - {(R) - [2-Hydroxy-2- (4-amino) -phenyl] -acetamido} -3 - {[tetrazolo (4,5-c) pyrimidin-5-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

32) 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-6-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

33) 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

34) 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[thiazolo (4,5-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

35) 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

36) 7 - [(R) - (2-Hydroxy-2-phenyl) acetamido] -3 - {[s-triazolo (4,3-b) pyridazin- (3-carboxymethylthio) -6-yl] thiomethyl } -Delta [deep] 3-cephem-4-carboxylic acid,

37) 7 - [(R) - (2-Hydroxy-2-phenyl) acetamido] -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] thiomethyl } -Delta [deep] 3-cephem-4-carboxylic acid,

38) 7 - [(Thien-2-yl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

39) 7 - [(Thien-2-yl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

40) 7 - [(Thien-2-yl) -acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

41) 7 - [(Thien-2-yl) -acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

42) 7 - [(Thien-2-yl) -acetamido] -3 - {[s-triazolo (4,3-b) pyridazin- (3-carboxymethylthio) -6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

43) 7 - [(Thien-2-yl) -acetamido] -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

44) 7 - [(Thien-2-yl) -acetamido] -3 - {[thieno (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

45) 7 - [(R) - (2-Hydroxy-2-thien-2-yl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

46) 7 - [(R) - (2-Hydroxy-2-fur-2-yl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-cyano) -6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

47) 7 - [(R) - (2-Hydroxy-2-fur-2-yl) -acetamido] -3 - {[s-triazolo (4,3-c) pyrimidine- (3-carboxymethylthio) -5- yl] thiomethyl} delta [deep] 3-cephem-4-carboxylic acid,

48) 7 - [(1 H-1-Tetrazolyl) acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-amino) -6-yl] -thiomethyl} -Delta [deep] 3 -cephem-4-carboxylic acid,

49) 7 - [(1 H-1-Tetrazolyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] -thiomethyl} -Delta [deep] 3 -cephem-4-carboxylic acid,

50) 7 - [(1 H-1-tetrazolyl) acetamido] -3 - {[tetrazolo (4,5- a) pyrimidin-5-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid ,

51) 7 - [(1 H-1-tetrazolyl) acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid ,

52) 7 - [(1 H-1-tetrazolyl) acetamido] -3 - {[thiazolo (4,5-d) pyridazin-4-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid ,

53) 7 - [(1 H-1-Tetrazolyl) acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3 -cephem-4-carboxylic acid,

54) 7 - [(1 H-1-tetrazolyl) acetamido] -3 - {[s-triazolo (4,3-b) pyridazin- (3-carboxymethylthio) -6-yl] thiomethyl} delta [deep ] 3-cephem-4-carboxylic acid,

55) 7 - [(1H-1-Tetrazolyl) -acetamido] -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

56) 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-amino) -6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

57) 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

58) 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[s-triazolo (4,3-b) pyridazin- (3-carboxymethylthio) -6-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

59) 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

60) 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

61) 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

62) 7 - {[(Carboxamido-methyl-thio)] - acetamido} -3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

63) 7 - {[(Carboxamido-methyl-thio)] - acetamido} -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

64) 7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin- (8-carboxamido) -6-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

65) 7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl } -Delta [deep] 3-cephem-4-carboxylic acid,

66) 7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

67) 7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[thiazolo (4,5-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

68) 7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

69) 7 - [(R) - (2-Carboxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

70) 7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-carboxymethyl-mercapto) -6-yl] -thiomethyl } -Delta [deep] 3-cephem-4-carboxylic acid,

71) 7 - {[(2,4-Dichloro) -phenyl] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

72) 7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-mercapto) -6-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

73) 7 - {[(Acetyl) -methyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin- (8-cyano) -6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

74) 7 - {[(Acetyl) -methyl-thio] -acetamido} -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [deep] 3-cephem-4- carboxylic acid,

75) 7 - {[(Acetyl) -methyl-thio] -acetamido} -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem-4- carboxylic acid,

76) 7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[thieno (2,3-d) pyrimidin-4-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

77) 7 - [(R) - (2-Sulfo-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

78) 7 - [(R) - (2-Sulfo-2-phenyl) -acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

79) 7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[1,2,3-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

80) 7 - [(R) - (2-Sulfo-2-phenyl) -acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

81) 7 - [(R) - (2-Sulfo-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

82) 7 - [(R) - (2-Sulfo-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

83) 7 - [(R) - (2-Methylsulfonyl-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

84) 7 - [(R) - (2-Methylsulfonyl-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

85) 7 - [(R) - (2-Methylsulfonyl-2-phenyl) -acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

86) 7 - [(R) - (2-Amino-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

87) 7 - [(R) - (2-Amino-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-amino) -6-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

88) 7 - [(R) - (2-Amino-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

89) 7 - [(R) - (2-Amino-2-phenyl) acetamido] -3 - {[s-triazolo (4,3-b) pyridazin- (3-carboxymethylthio) -6-yl] thiomethyl } -Delta [deep] 3-cephem-4-carboxylic acid,

90) 7 - [(R) - (2-Amino-2-phenyl) -acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

and the 2-formyloxy derivatives (instead of the 2-hydroxy derivatives) of compounds No. 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 45, 46 and 47 and the 2-hydroxy derivatives (instead of the 2-formyloxy derivatives) of compounds No. 70, 72, 76 and 79.

The structural formulas of the above-mentioned compounds according to the invention are given in the following table in the same numbering (with increasing numbering):

The compounds according to the invention are prepared by a further object of the invention forming process which is characterized in that

a) a compound of the general formula IV

in which B and M have the meanings given above, E is amino or a group -N = C = W, in which W is an oxygen or sulfur atom,

or a reactive derivative thereof with an acid of the general formula V

where n, x, Z, A and A [deep] 1 have the meanings given above,

or reacts with a reactive derivative thereof;

b) a compound of the general formula VI

wherein A [deep] 1, M and B have the meanings given above and X is a halogen atom,

with a compound of the general formula

Z-A-SH VII

wherein Z and A have the meanings given above, or reacted with a reactive derivative thereof to form compounds of the general formula I in which x is the number 0 and n is the number 1;

c) a compound of the general formula VIII

wherein M, B and A [deep] 1 have the meanings given above,

or reacting a reactive derivative thereof with a compound of the general formula

Z-A-X IX

wherein Z, A and X have the meanings given above,

with formation of compounds of the general formula I in which x is the number 0 and n is the number 1;

d) a compound of the general formula X

where n, x, Z, A, A [deep] 1 and M have the meanings given above,

with a compound of the general formula

H-S-B XI

wherein B has the meanings given above, or reacted with a salt thereof;

and, if desired, the compounds obtained by each of the abovementioned processes (a) and (d), in which A and / or A [deep] 1 is an aliphatic hydrocarbon group as defined above which is replaced by one or more -OR '' 'groups, in which R '' 'is formyl, are substituted, converted into compounds of the general formula I in which A and / or A [deep] 1 is an aliphatic hydrocarbon group as defined above which is substituted by one or more hydroxyl groups, and / or if desired converts the compounds obtained by each of processes (a) to (d) into pharmaceutically acceptable salts and / or, if desired, prepares the free compounds from the salts and / or, if desired, separates an isomer mixture into the individual isomers.

If there are groups in the compounds of the formulas IV to XI which have to be protected during one of the reactions (a) to (d), such as, for example, amino, hydroxy, carboxy groups, these groups are protected in the usual way before the reaction .

Examples of protective groups are those as are customarily used for the synthesis of peptides, ie with respect to the hydroxy and amino groups, for example, one of the following groups: carbobenzyloxy, tert-butoxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrophenylsulfenyl, dichloroacetyl , tert-butyl and dimethylsilyl, and with respect to the carboxy group, for example, one of the following groups: tert-butyl, benzhydryl and p-methoxybenzyl.

After the reaction has ended, the protective groups are then removed again in a manner known per se, for example by mild acid hydrolysis or by mild catalytic reduction, for example using Pd / C at atmospheric pressure.

The compounds of the formula I which contain protecting groups also fall within the scope of the present invention.

A reactive derivative of a compound of the formula IV can be, for example, a silyl ester or an amine salt. A reactive derivative of an acid of the formula V is, for example, an acyl halide, an anhydride, an amide, an azide, a reactive ester or a salt, such as a salt with an alkali metal or an alkaline earth metal, with ammonia or an organic base has been formed.

The reaction between the compound of the formula IV and the compound of the formula V can either at room temperature or with cooling in a suitable solvent, for example in acetone, dioxane, tetrahydrofuran, acetonitrile, chloroform, methylene chloride, dimethylformamide, and, if desired, in the presence of a base, such as for example sodium bicarbonate or potassium bicarbonate or a trialkylamine can be carried out. If the compound of the formula V is reacted with a compound of the formula IV, in which E is amino, in the form of a free acid or in the form of a salt, it is advantageous that the reaction is carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide.

The reaction between the compound of the formula VI and the compound of the formula VII or a reactive derivative thereof, such as a salt, preferably an alkali salt, is carried out at temperatures which are within the range between about -30.degree. C. and about + 60.degree lie, preferably at room temperature in the presence of an inorganic or organic base, such as NaOH, KOH, Na [deep] 2CO [deep] 3, triethylamine, in a suitable solvent, which is for example

Acetone, chloroform, methanol, ethanol, methylene chloride and water can act.

When the -SH group in the compound of the formula VII is not converted into a salt, the reaction is preferably carried out in the presence of a base such as an alkali hydroxide, an alkali carbonate or a triethylamine.

The reaction between the compound of the formula VIII or a reactive derivative thereof, such as an alkali metal salt, and the compound of the formula IX can be carried out in an aqueous medium and in the presence of an inorganic base and in an organic, preferably anhydrous, solvent such as, for example, methylene chloride, Chloroform, dioxane, or in the presence of an organic base, the reaction temperature preferably being within the range between about -20 ° C and about + 50 ° C.

The reaction between the compound of the formula X and the compound of the formula XI is preferably carried out in an inert solvent, such as, for example, in ethanol, dimethylformamide, dioxane, acetone, methylene chloride, chloroform, and if a salt of the compound of the formula XI is used is, preferably water or a water-miscible solvent or a mixture of water and a solvent, such as acetone, ethanol, dioxane, tetrahydrofuran, is used. The reaction temperature can vary between about + 5 ° C and about + 70 ° C. The pH is maintained between about 5.0 and about 7.5. If necessary, a buffer such as a phosphate or sodium acetate is used.

The compound of the formula IV in which E is amino can be prepared, for example, by reacting 7-aminocephalosporanic acid or a salt thereof with a compound the formula

H-S-B

using reaction conditions as they are known from the literature.

The compound of the formula IV in which E is the group -N = C = W can be prepared by reacting a compound of the general formula IV in which E is amino with phosgene or thiophosgene in the presence of a hydrochloric acid acceptor using known processes.

The compound of the formula V, in which x is the number 0 and n is the number 1, can be prepared by reacting a compound of the formula ZAX, in which Z, A and X have the meanings given above, with a compound of the formula HS-A [ deep] 1-COOH, in which A [deep] 1 have the meanings given above, using reaction conditions which are analogous to those used for the reaction between the compounds of the formula VIII and the compounds of the formula IX. The compound of the formula V, in which x and n are the number 0, is prepared in an analogous manner by known processes.

The compound of the formula V, in which n is the number 1 and x is the number 1 or 2, can be prepared from the sulfide by treatment with oxidizing agents, such as, for example, H [deep] 2O [deep] 2, preferably in acetic acid, with the formation of a Compound in which x is the number 2, or a salt, preferably an alkali salt, of periodic acid to form a compound in which x is the number 1.

The compound of the formula VI can be prepared, for example, by reacting an acid of the formula

X-A [deep] 1-COOH XII wherein A [deep] 1 has the meanings given above and X is a halogen atom,

or of a reactive derivative of this acid with a compound of the formula IV.

The reaction between the compound of the formula XII and the compound of the formula IV can be carried out in an aqueous or anhydrous solvent in the presence of an organic or inorganic base and at temperatures which are preferably within the range from about -10 to about + 25.degree will. Acyl halides, anhydrides, azides, amides, active esters and salts, for example, can be used as reactive derivatives of the acid of the formula XII.

The compound of the formula VII is known from the literature or can easily be prepared by known processes.

The compound of the formula VIII can be prepared, for example, by reacting the compound of the formula VI with a compound of the formula HS-A [deep] 1-COOH, wherein A [deep] 1 has the meanings given above, or a reactive derivative thereof, such as for example an acid halide, an active ester, an anhydride or a salt, using reaction conditions which are analogous to the conditions used for the reaction between the compound of the formula IV and the compound of the formula V.

The compound of the formula IX, like the compound of the formula XI, can easily be prepared by known processes, starting from known compounds, or these are compounds which are already known from the literature.

The compound of formula X can be prepared, for example are by reacting 7-amino-cephalosporanic acid or a salt thereof with a compound of the formula V or a reactive derivative thereof, as defined above, using reaction conditions which are analogous to the conditions used for the reaction between the compound of Formula IV and the compound of formula V can be used.

The conversion, if carried out, of a compound of the formula I in which A and / or A [deep] 1 is an aliphatic hydrocarbon group as defined above which is substituted by one or more -OR '' 'groups, in which E' '' is formyl , in a compound of the formula I in which A and / or A [deep] 1 is an aliphatic hydrocarbon group as defined above which is substituted by one or more hydroxyl groups, is preferably at room temperature in an alkaline medium, for example by treatment with sodium or potassium bicarbonate. The conversion into a salt step, which may be provided, is carried out using the methods customary in organic chemistry. The reaction to prepare the free compounds from the salts is also carried out in the customary manner. Racemic compounds can be separated into their optical antipodes, e.g. by separation for example by means of fractional crystallization of mixtures of diastereoisomeric salts and, if desired, liberation of the optical antipodes from the salts.

The compounds forming the subject of the invention have a high antibacterial activity in animals and humans against both gram-positive and gram-negative bacteria and are therefore suitable for the treatment of infections caused by these microorganisms, such as, for example, infections of the respiratory tract, such as bronchitis, bronchopneumonia, Pleuritis; Hepatobiliary and abdominal infections such as cholecystitis, peritonitis; Blood and cardiovascular infections ions, e.g., blood poisoning; Urinary tract infections such as pyelonephritis, cystitis; Childbirth and gynecological infections, e.g. cervititis, endometritis; Ear, nose and throat infections such as otitis, sinusitis, parotitis.

The minimum inhibitory concentration (MIC) of these compounds has been found to be within the range of about 0.001 to about 3 gamma / ml, depending on the strains tested.

The compounds of the present invention have been shown to be effectively absorbed either after oral administration or, preferably, parenteral administration. In the latter case, these compounds can be administered to adult humans, for example, in an amount within the range of about 100 to about 200 mg per dose, preferably about 150 mg per dose, dissolved in a suitable solvent such as sterile water or a lidocaine hydrochloride solution for intramuscular injection , and sterile water, a physiological saline solution, a dextrose solution, or in conventional intravenous fluids or electrolytes for intravenous injection.

Determination of the melting points has been somewhat difficult in some cases because the compounds have a tendency to hold on to the solvent. In these cases, the word "decomposition (abbreviated 'Zers.')" Is given after the melting point.

The IR spectra were obtained in solid phase or in a Nujol solution using a Perkin-Elmer 125 spectrophotometer, while the UV spectra were recorded in methanol or in a phosphate buffer solution with a pH of 7.4 using a Bausch- Lomb device were manufactured.

The invention is illustrated in more detail by the following examples, without, however, being restricted thereto.

example 1

To a solution consisting of 0.84 g of cyanomethylmercaptoacetic acid and 0.89 ml of triethylamine in 60 ml of anhydrous tetrahydrofuran, which had been cooled to -5 ° C., 0.78 ml of pivaloyl chloride were added with stirring. After stirring for 15 minutes, the temperature being kept at -5 ° C, a solution cooled to -5 ° C, which consists of 2.32 g of 7-amino-3 - {[tetrazolo (4,5-b) pyridazin-6-yl] thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid and 1.3 ml of triethylamine in 80 ml of 50% tetrahydrofuran. After the addition of the solution, the reaction mixture was stirred at 0 ° C. for 1 hour, then it was stirred at room temperature for 30 minutes. After filtering, the solution was evaporated to low volume in vacuo, brought to pH 2 with 8% HCl and then extracted with ethyl acetate. The organic phase was washed with water, dried over Na [deep] 2SO [deep] 4, concentrated to a small volume and the residue was treated with petroleum ether. Filtration gave a solid product which was then dried to give 1.65 g of 7 - [(cyanomethylthio) acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, mp 70 ° C (dec.);

IR spectrum (KBr): 1780 cm [high] -1 (C = 0): beta-lactam, 1725 cm [high] -1 (C = 0): amide, 1660 cm [high] -1 (C = 0 ): Carboxy, 1625 cm [high] -1 (C = C): double bond delta [low] 3; UV spectrum (phosphate buffer pH 7.4): Lambda [low] max = 241 mµ,

Shoulder lambda = 268 mµ,

TLC analysis: R [deep] f = 0.29 (CHCl [deep] 3: MeOH: HCOOH = 160: 20:20);

Analysis for C [deep] 16H [deep] 14N [deep] 8O [deep] 4S [deep] 3:

Calcd .: C 40.15 H 2.94 N 23.41

found: 39.63 3.04 22.98%.

The cyanomethyl mercaptoacetic acid used as the starting material was prepared as follows:

15.85 g (0.21 mol) of chloroacetonitrile were added to a solution of 18.4 g (0.2 mol) of mercaptoacetic acid in 400 ml of 1N NaOH over a period of 20 minutes. After stirring at room temperature for 24 hours and heating at 50 ° C. for 1 hour, the reaction mixture was extracted with 2 × 100 ml of ethyl ester, then the ethereal extracts were removed. After acidifying the aqueous solution with 50% sulfuric acid until a pH value of 2.5 was reached and after extracting it with ethyl ether (3 x 150 ml), the ethereal solution was washed with water over Na [deep] 2SO [deep ] 4 dried and evaporated to give 21.50 g of a yellow oil (yield 82%). The 7-amino-3 - {[tetrazolo (4,5-b) pyridazin-6-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid also used as starting material were prepared by known processes, as described in have already been described in the introduction to the description.

Example 2

To a solution consisting of 0.897 g of alpha-carboxamidoethylmercaptoacetic acid and 0.772 ml of triethylamine in 50 ml of anhydrous tetrahydrofuran, which had been cooled to -5 ° C., 0.676 ml of pivaloyl chloride were added with stirring. After stirring for 15 minutes at -5 ° C., a solution of 1.84 g of 7-amino-3 - {[tetrazolo (4,5-b) pyridazin-6-yl] thiomethyl} -Delta [deep] 3-cephem was obtained -4-carboxylic acid and 1.2 ml of triethylamine in 50 ml of 50% tetrahydrofuran, which had been cooled to -5 ° C., were added. The reaction mixture was stirred for 1 hour at 5 ° C, then it was stirred for 30 minutes at room temperature. After filtering, the solution was concentrated to a small volume, brought to pH 2 with 1N H [deep] 2SO [deep] 4 and extracted with ethyl acetate. The organic phase, washed with water and dried over Na [deep] 2SO [deep] 4, was evaporated to dryness and the residue was redissolved in tetrahydrofuran and an insoluble residue was filtered off.

A solid precipitated from the solution treated with petroleum ether, which was filtered off and dried, 1.25 g of 7 - {[(alpha-carboxamido) ethylthio] acetamido} -3 - {[tetrazolo (4,5-b) pyridazine being obtained -6-yl] thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, mp 99 ° C (dec.).

IR spectrum (KBr): 1780 cm [high] -1 (C = 0) beta-lactam, 1710 cm [high] -1 (C = 0) amide, 1680 cm [high] -1 (C = 0) Carboxy, 1610 cm [high] -1 (C = C), double bond delta [low] 3; UV spectrum (phosphate buffer pH 7.4) Lambda [deep] max 240 mµ,

Shoulder lambda 265 mµ,

TLC analysis: R [deep] f = 0.24 (CHCl [deep] 3: MeOH: HCOOH = 160: 20:20);

Analysis for C [deep] 17H [deep] 18N [deep] 8O [deep] 4S [deep] 3

calc .: C 41.28 H 3.66 N 22.65

found: 40.91 3.81 22.26%.

The (alpha-carboxamido) ethyl mercaptoacetic acid used as starting material was prepared as follows:

To a solution of sodium methylate prepared by dissolving 2.3 g of sodium in 100 ml of anhydrous methanol, 4.6 thioglycolic acid was added and then, after stirring for 30 minutes at room temperature, 5.38 g of alpha-chloropropionamide were added. After stirring for 18 hours at room temperature, after cooling, filtering and evaporating to dryness, the product was dissolved in water, washed with ethyl acetate, the pH was brought to 2.5 with 20% sulfuric acid and it was extracted with ethyl acetate. The dried organic phase was evaporated to dryness, 5.7 g of a white solid being obtained (yield 70%), mp 108-110 ° C. Using the same procedure, the following compounds were made:

7 - {[(Alpha-Carboxamido) -propyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4- carboxylic acid, m.p. 98 ° C (dec.).

IR spectrum (KBr): 1780 cm [high] -1 (C = 0) beta-lactam; 1720 cm [high] -1 (C = 0) amide;

1670 cm [high] -1 (C = 0) carboxy; 1615 cm [high] -1 (C = C) double bond delta [deep] 3; UV spectrum (phosphate buffer pH 7.4) Lambda [deep] max 241 mµ,

Shoulder lambda = 266 mµ,

TLC analysis: R [deep] f = 0.24 (CHCl [deep] 3: MeOH: HCOOH = 160: 20:20).

Analysis for C [deep] 18H [deep] 20N [deep] 8S [deep] 3O [deep] 5

Calcd .: C 41.20 H 3.84 N 21.36

found: 41.09 3.98 21.00%

7 - {[(Carboxamido) methylthio] acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

7 - {[(Alpha-Cyano) -benzylthio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

F. 180 ° C (destruction)

UV spectrum (phosphate buffer pH 7.4): Lambda [low] max = 240 mµ,

Shoulder lambda = 265 mµ,

TLC: R [deep] f = 0.40 (CHCl [deep] 3: MeOH: HCOOH = 160: 20:20).

Analysis for C [deep] 22H [deep] 18N [deep] 8O [deep] 4S [deep] 3

calc .: C 47.63 H 3.27 N 20.20

found: 47.42 3.41 20.01%

7 - {[(Acetyl) methylthio] acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid

UV spectrum (phosphate buffer pH 7.4): Lambda [low] max = 241 mµ,

Shoulder lambda = 270 mµ,

TLC R [deep] f = 0.64 (CHCl [deep] 3: MeOH: HCOOH = 160: 40:20).

Analysis for C [deep] 17H [deep] 17N [deep] 7O [deep] 5S [deep] 3

Calcd .: C 41.19 H 3.45 N 19.78

found: 40.91 3.64 19.52%

7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-a) pyrazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

7 - [(Cyanomethylthio) acetamido] -3 - {[tetrazolo (4,5-a) pyridin-6-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid.

Example 3

A solution of 1.36 ml of isobutyl chloroformate in 20 ml of anhydrous tetrahydrofuran was added to a solution consisting of 1.32 g of cyanomethylmercaptoacetic acid and 1.4 ml of triethylamine in 100 ml of anhydrous tetrahydrofuran, which had been cooled to -20 ° C. After stirring for 15 minutes at a temperature of -20 ° C., a solution of 2.64 g of 7-amino-3 - {[s-triazol (4,5-b) pyridazin-6-yl] thiomethyl} -delta [ deep] 3-cephem-4-carboxylic acid and 1.43 ml of triethylamine in 120 ml of 50% tetrahydrofuran were added with cooling so that the temperature was kept at -20.degree. Then the reaction mixture was stirred for 1 hour at -20 ° C, for 1 hour at -5 ° C and at 0 ° C and for 1 hour at room temperature. After filtering off a residue and after evaporating the tetrahydrofuran in vacuo, the residue was extracted with ethyl acetate after dilution with water. The aqueous phase was brought to pH 2 to 2.5 with 1N sulfuric acid and then extracted with ethyl acetate. After drying over Na [deep] 2SO [deep] 4, the organic phase was evaporated to dryness and, after dissolving in tetrahydrofuran with petroleum ether, 1.48 g of 7 - [(cyanomethylthio) acetamido] -3 - {[ s-triazol (4,5-b) pyridazin-6-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid, mp 105 ° C. (decomp.), precipitated;

IR spectrum (KBr): 1775 cm [high] -1 (C = 0) beta-lactam, 1710 cm [high] -1 (C = 0) amide, 1670 cm [high] -1 (C = 0) Carboxy, 1630 cm [high] -1 (C = C) double bond delta [low] 3; UV spectrum (phosphate buffer pH 7.4): Lambda [low] max = 234 mµ,

Shoulder lambda = 265 mµ,

TLC analysis: R [deep] f = 0.15 (CHCl [deep] 3: MeOH: HCOOH = 160: 20:20);

Analysis for C [deep] 17H [deep] 15N [deep] 7O [deep] 4S [deep] 3:

Calcd .: C 42.75 H 3.16 N 20.53

found: 42.81 3.32 19.68%.

The 7-amino-3 - {[s-triazolo (4,5-b) pyridazin-6-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid used as a starting material in the above reaction was prepared as follows :

6.84 g were added in portions to a solution of 7.46 g of 7-aminocephalosporanic acid and 5.04 g of NaHCO [deep] 3 in 200 ml of 50% aqueous acetone, with stirring and at a temperature of 45 to 50 ° C 6-mercapto-s-triazole (4,5-b) pyridazine was added. The mixture was heated to the boil for 2 1/2 hours, during which time the pH was kept at 7.4 by adding NaHCO [low] 3 if necessary. After cooling and filtering, the reaction mixture was acidified to pH 5 with 8% HCl, then it was kept at 0 ° C for 30 minutes and the resulting solid was filtered off, then twice with 150 ml of 50% aqueous acetone and finally with 2 x 150 ml of acetone washed. This gave 5.8 g of the desired product, mp 202 ° C. (decomp.);

Analysis for C [deep] 13H [deep] 12N [deep] 6O [deep] 3S [deep] 2:

calc .: C 42.84 H 3.32 N 23.06

found: 42.08 3.37 22.38%.

Using the same procedure, the following compounds were made:

7 - [(Cyanomethyl-thio) -acetamido] -3 - {[s-triazolo (4,5-b) pyridazin- (6-methyl) -3-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, m.p. 98 ° C (dec.).

IR spectrum: (KBR) 1780 cm [high] -1 (C = 0) beta-lactam; 1720 cm [high] -1 (C = 0) amide, 1680 cm [high] -1 (C = 0) carboxy, 1625 cm [high] -1 (C = C) double bond Delta [deep] 3.

UV spectrum (phosphate buffer pH 7.4): Lambda [low] max = 272 mµ,

TLC: R [deep] f = 0.20 (CHCl [deep] 3: MeOH: HCOOH = 160: 20:20).

Analysis for C [deep] 18H [deep] 17N [deep] 7O [deep] 4S [deep] 3

calc .: C 43.97 H 3.48 N 19.94

found: 43.58 3.61 19.46%

7 - [(Cyanomethylthio) acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin- (5-methyl) -7-yl] thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-c) pyrimidin-7-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

7 - {[(Alpha, Beta-Dicyano) -äthyl-thio] -acetamido} -3 - {[tetrazolo (4,5-a) pyrazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[tetrazolo (4,5-) pyrid-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4 -carboxylic acid.

Example 4

60 ml of a solution of 2.5 g of 7- [1H-1-tetrazolylacetamido] cephalosporanic acid, 0.5 g of NaHCO [deep] 3 and 0.92 g of 6-mercaptotetrazole- (4,5-b) pyridazine in a phosphate buffer Stirred for 6 hours at 50 ° C. After cooling, the reaction mixture was acidified to pH 2.5 with 1N H [deep] 2SO [deep] 4 and extracted with ethyl acetate. The organic phase was washed with a solution saturated with NaCl, dried over Na [deep] 2SO [deep] 4 and then evaporated to dryness. The residue was dissolved in tetrahydrofuran, then petroleum ether was added, whereby 1.9 g of 7 - [(1H-1-tetrazolyl) acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] thiomethyl } -Delta [deep] 3-cephem-4-carboxylic acid, mp 145 ° C. (decomp.), Precipitated;

IR spectrum (Nujol): 1770 cm [high] -1 (C = 0) beta-lactam, 1710 cm [high] -1 (C = 0) amide, 1680 cm [high] -1 (C = 0) carboxy , 1620 cm [high] -1 (C = C) double bond delta [deep] 3;

UV analysis (phosphate buffer pH 7.4): Lambda [deep] max = 241 mµ,

Shoulder lambda = 265 mµ

TLC analysis: R [deep] f = 0.59 [(CH [deep] 3) [deep] 2CO: H [deep] 2O: CH [deep] 3COOH = 180: 20:10)];

Analysis for C [deep] 15H [deep] 13N [deep] 10O [deep] 4S [deep] 2

Calc .: C 39.03 H 2.83 N 30.35

found: 39.32 3.02 29.95%

The 7- [1H-1-tetrazolylacetamido] cephalosporanic acid used as the starting material was prepared from 1-tetrazolylacetic acid and 7-aminocephalosporanic acid by a known method, as has already been described in the introduction to the description.

Using the same procedure, the following compounds were made:

7 - [(1-s-Triazolyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

7 - [(Cyanomethylthio) acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-carboxy) -6-yl] thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

7 - {[(Alpha-Cyano) -benzylthio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin- (8-carboxy) -6-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin- (8-carboxy) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid.

Example 5

1.8 g of dicyclohexylcarbodiimide were added to a solution consisting of 0.935 g of (alpha, beta-dicyano) ethyl mercaptoacetic acid in 30 ml of anhydrous tetrahydrofuran, while stirring and while cooling with ice. After 15 minutes, a solution of 1.84 g of 7-amino-3 - {[tetrazolo (4,5-b) pyridazin-6-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid and 0 , 5 g of NaHCO [deep] 3 in 60 ml of 50% aqueous tetrahydrofuran were added. After stirring for 4 hours at room temperature, after filtering and after removing the tetrahydrofuran under reduced pressure, 150 ml of water were added. After covering with ethyl acetate, the pH was brought to 2.5 with 40% phosphoric acid. The organic phase was separated off and the aqueous phase was extracted again with ethyl acetate. The collected and dried organic phases were evaporated to dryness and the residue was dissolved in tetrahydrofuran. By adding 1.94 g of 7 - {[(alpha, beta-dicyano) ethylthio] acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] thiomethyl} -delta [deep] 3 were obtained from petroleum ether -cephem-4-carboxylic acid, mp 86 ° C (decomp.), precipitated;

IR spectrum (KBr): 1780 cm [high] -1 (C = 0) beta-lactam, 1710 cm [high] -1 (C = 0) amide, 1680 cm [high] -1 (C = 0) carboxy , 1630 cm [high] -1 (C = C) double bond delta [deep] 3.

UV spectrum (phosphate buffer pH 7.4): Lambda [low] max = 241 mµ,

Shoulder lambda = 265 mµ

TLC: R [deep] f = 0.15 (CHCl [deep] 3: MeOH: HCOOH = 160: 20:20).

Analysis for C [deep] 18H [deep] 15N [deep] 9O [deep] 4S [deep] 3

Calcd .: C 41.76 H 2.92 N 24.35

found: 42.12 3.06 23.78%

The alpha, beta-dicyanoethyl mercaptoacetic acid used as the starting material was prepared as follows:

11.5 g of maleic acid dinitrile and 9.8 ml of thioglycolic acid were heated to 90 ° C. in 70 ml of water for 2 hours. After cooling, extraction with ethyl acetate and drying over Na [deep] 2SO [deep] 4 and evaporation to dryness, an oil was obtained which was pure enough for the subsequent reaction.

Using the same procedure, the following compounds were made:

7 - {[(Alpha, Beta-Dicyano) ethylthio] acetamido} -3 - {[triazolo (4,5-b) pyridazin-6-yl] thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid ,

7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[triazolo (4,5-b) pyridazin- (6-methyl) -3-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[tetrazolo (4,5-a) pyrimidin- (5-methyl) -7-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

7 - {[(Alpha, Beta-Dicyano) -äthyl-thio] -acetamido} -3 - {[tetrazolo (4,5-c) pyrimidin-7-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

Example 6

To a solution of 3.78 g of 7-amino-3 - {[s-triazolo (4,5-b) pyridazin- (6-methyl) -3-yl] thiomethyl} -Delta [deep] 3-cephem-4 carboxylic acid and 2.7 g of NaHCO [deep] 3 in 100 ml of 50% aqueous acetone were added dropwise with stirring at about 0 ° C., a solution of 2.2 g of (1-tetrazolyl) acetyl chloride in 20 ml of acetone. The reaction mixture, which was kept at 7.8 with NaHCO 3 [deep] 3, was stirred for 1 hour at 0 ° C and for 2 hours at room temperature, after which it was washed repeatedly with ether, filtered and the pH value became 5 Brought to about 2% HCl. After extraction with ethyl acetate, which was dried and evaporated to dryness, the residue was dissolved in tetrahydrofuran, then 3.15 g of 7 - [(1H-1-tetrazolyl) acetamido] -3 - {[s- Triazolo (4,5-b) pyridazin- (6-methyl) -3-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid precipitated;

IR spectrum (KBr) 1770 cm [high] -1 (C = 0) beta-lactam, 1715 cm [high] -1 (C = 0) amide, 1680 cm [high] -1 (C = 0) carboxy, 1630 cm [high] -1 (C = C) double bond delta [deep] 3. UV spectrum (phosphate buffer pH 7.4): Lambda [low] max 268,

Analysis for C [deep] 17H [deep] 16N [deep] 10O [deep] 4S [deep] 2

Calcd .: C 41.79 H 3.30 N 28.67

found: 41.53 3.46 28.05%

The (1-tetrazolyl) acetyl chloride used as the starting compound was prepared from 1-tetrazolyl acetic acid and PCl [deep] 5 by a known method. The 7-amino-3 - {[s-triazol (4,5-b) pyridazin- (6-methyl) -3-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid (F. 212 ° C., decomposition) was prepared using the same method as specified in Example 3.

Using the same procedure as indicated above, the following was prepared:

7 - [(1H-1-tetrazolyl) acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid,

IR spectrum (Nujol) 1770 cm [high] -1 (C = 0) beta-lactam, 1710 cm [high] -1 (C = 0) amide, 1680 cm [high] -1 (C = 0) carboxy, 1620 cm [high] -1 (C = C) double bond Delta [deep] 3.

UV spectrum (phosphate buffer pH 7.4): Lambda [low] max = 241,

Shoulder lambda = 265 mµ

TLC: R [low] f = 0.59

Analysis for C [deep] 15H [deep] 13N [deep] 10O [deep] 4S [deep] 2

calc .: C 39.03 H 2.83 N 30.35 S 13.85

found: 39.35 3.02 30.12 13.43%

Example 7

To a solution cooled to 0 ° C., the 1.36 g of 7-amino-3 - {[tetrazolo (1,5-a) pyrimidin- (7-methyl) -5-yl] thiomethyl} -Delta [deep] 3 -cephem-4-carboxylic acid and 0.91 g of NaHCO [deep] 3 in 60 ml of 50% acetone, the chloride of (R) -alpha-formyloxy-alpha-phenylacetic acid (1.44 g), dissolved in 40 ml of acetone was added. After the addition, the pH of the solution was brought to about 6.4 with NaHCl [deep] 3 and the solution was then stirred for 11/2 hours at room temperature. After acidification with 2N H [deep] 2SO [deep] 4 to reach the pH value of 3 and after extraction with ethyl acetate, the organic solution was dried over Na [deep] 2SO [deep] 4 and then evaporated to dryness. The solid obtained was suspended in 100 ml of ethyl ether and stirred for 30 minutes. The product was filtered and dried to give 1.4 g of 7 - [(R) -2-formyloxy-2-phenylacetamido] -3 - {[tetrazolo (4,5-a) pyrimidine- (7-methyl) -5 -yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid.

1.36 g of 7 - [(R) - (2-formyloxy-2-phenyl) acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin- (7-methyl) -5-yl] thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid were dissolved in 100 ml of water and 2 g of NaHCO [deep] 3 and stirred for 4 hours at room temperature. The solution then became acidified with 2N H [deep] 2SO [deep] 4 and extracted with ethyl acetate.

The organic solution was dried over Na [deep] 2SO [deep] 4 and evaporated to dryness. The residue obtained was treated with ethyl ether and then filtered, giving 1.1 g of 7 - [(R) - (2-Hydroxy-2-phenyl) acetamido] -3 - {[tetrazolo (4,5-a) pyrimidine - (7-methyl) -5-ethyl] thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, mp 148 ° C. (decomp.).

UV spectrum (phosphate buffer pH 7.4): Lambda [low] max = 244 mµ,

Shoulder lambda at 265 mµ and at 296 mµ

TLC: R [deep] f = 0.36 (CHCl [deep] 3: MeOH: HCOOH = 160: 20:20).

Analysis for C [deep] 21H [deep] 19N [deep] 7O [deep] 5S [deep] 2

calc .: C 49.11 H 3.72 N 19.09 S 12.48

found: 48.86 3.78 18.84 12.36%.

The following compounds were prepared in an analogous manner:

7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-cyano) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

7 - {(R) - [2-Hydroxy-2- (4-hydroxy) phenyl] acetamido} -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] thiomethyl} delta [ deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[thiazolo (4,5-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[s-triazolo (4,3-b) pyridazin- (3-carboxymethylthio) -6-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Hydroxy-2-fur-2-yl) acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-cyano) -6-yl] thiomethyl } -Delta [deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Hydroxy-2-fur-2-yl) -acetamido] -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-mercapto) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-carboxymethylmercapto) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[ethieno (2,3-d) pyrimidin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[1,2,3-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-cyano) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

7 - {(R) - [2-Formyloxy-2- (4-hydroxy) -phenyl] -acetamido} -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[thiazolo (4,5-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[s-triazolo (4,3-b) pyridazin- (3-carboxymethylthio) -6-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Formyloxy-2-fur-2-yl) acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-cyano) -6-yl] thiomethyl } -Delta [deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Formyloxy-2-fur-2-yl) -acetamido] -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-mercapto) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-carboxymethyl-mercapto) -6-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[thieno (2,3-d) pyrimidin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[1,2,3-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid.

Example 8

A few drops of N-methylmorpholine were added to a solution containing 2.56 g of 1-tetrazolylacetic acid and 2.8 ml of triethylamine in 120 ml of anhydrous acetone. After cooling to -10 ° C., 2.44 ml of pivaloyl chloride, dissolved in 30 ml of anhydrous acetone, were added. After stirring for 30 minutes at a temperature of -10 ° C, a solution of 7.62 g of 7-amino-3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] thiomethyl } -Delta [deep] 3-cephem-4-carboxylic acid and 2.8 ml of triethylamine in 240 ml of 50% strength acetone, which had been cooled to -20 ° C., were added over a period of 30 minutes. After stirring at -20 ° C. for 1 hour and stirring at room temperature for 2 hours, the solution was filtered and the acetone was evaporated in vacuo. After dilution with water and after layering with ethyl acetate, the pH was brought to 2.5 with 40% H [deep] 3PO [deep] 4. After filtering off the residue, the ethyl acetate was separated off; the organic phase was then washed with water, dried over Na [deep] 2SO [deep] 4 and reduced to a low volume constricted. By adding ethyl ether a solid was formed, which was then filtered off, then stirred with ethyl ether, filtered off again; this gave 5.4 g of 7 - [(1H-1-tetrazolyl) acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] thiomethyl} -Delta [deep ] 3-cephem-4-carboxylic acid.

The following connections were made in a corresponding manner:

7 - [(1H-1-tetrazolyl) acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid,

7 - [(1H-1-Tetrazolyl) -acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

7 - {[(Alpha, Beta-Dicyano) ethylthio] acetamido} -3 - {[tetrazolo (4,5-b) pyridazin- (8-carboxamido) -6-yl] thiomethyl} delta [deep] 3 -cephem-4-carboxylic acid,

7 - {[(Alpha, Beta-Dicyano) -äthylthio] -acetamido} -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

7 - {[(Alpha, Beta-Dicyano) -äthylthio] -acetamido} -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem-4- carboxylic acid,

7 - {[(Alpha, Beta-Dicyano) -äthyl-thio] -acetamido} -3 - {[thiazolo (4,5-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - {[(Alpha, Beta-Dicyano) -äthylthio] -acetamido} -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

7 - {[(2,4-dichloro) phenyl] acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] thiomethyl} -Delta [deep] 3-cephem-4- carboxylic acid,

7 - [(R) - (2-methylsulfonyl-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - [(R) - (2-Methylsulfonyl-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - [(R) - (2-Methylsulfonyl-2-phenyl) -acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid.

Example 9

1.7 ml of isobutyl chloroformate dissolved in 16 ml of anhydrous acetone were added to a solution, cooled from 10 ° C., of 0.97 g of 1-tetrazolylacetic acid in 60 ml of anhydrous acetone and 1.24 ml of triethylamine. After stirring for 30 minutes at -10 ° C and subsequent cooling to -30 ° C, a solution of 3.3 g of 7-amino-3 - {[1,2,5-thiadiazolo (3,4-d) pyridazine- 4-yl] thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid and 4 ml of triethylamine in 120 ml of 50% acetone were added. After 1 hour of stirring at a temperature between -20 and -30 ° C and then 1 hour of stirring at a temperature between -5 and 0 ° C and subsequent 3 hours of stirring at room temperature and filtration, the acetone was evaporated under vacuum and the The residue was then diluted with 200 ml of water and extracted with 2 × 100 ml of ethyl ether. After separation, the aqueous solution was brought to pH 2.5 with 10% HCl and extracted with ethyl acetate. The organic phase was washed with water, dried over Na [deep] 2SO [deep] 4, concentrated to a small volume and poured into ethyl ether, 2.2 g of 7 - [(1H-1-tetrazolyl) acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid.

The following compounds were prepared in an analogous manner:

7 - [(1H-1-Tetrazolyl) -acetamido] -3 - {[thiazolo (4,5-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

7 - [(1H-1-tetrazolyl) acetamido] -3 - {[s-triazolo (4,3-b) pyridazin- (3-carboxymethylthio) -6-yl] thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

7 - [(1H-1-tetrazolyl) -acetamido] -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid.

Example 10

To a solution, cooled to 0 ° C., of 1.49 h of carboxyamidomethyl mercaptoacetic acid in 20 ml of anhydrous dimethylformamide 2.1 g of dicyclohexylcarbodiimide were added, then a solution of 3.81 g of 7-amino-3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] thiomethyl} delta was added [deep] 3-cephem-4-carboxylic acid in 30 ml of anhydrous dimethylformamide and 3 ml of triethylamine were added. After stirring for 4 hours at room temperature and after evaporation in vacuo, the residue was covered with a layer of ethyl acetate, treated with a NaHCO [deep] 3 solution and washed with ethyl acetate; After separation, the aqueous solution was covered with a layer of ethyl acetate and then acidified with 2N H [deep] 2SO [deep] 4. The organic solution was separated off, washed with water, dried over Na [deep] 2SO [deep] 4 and evaporated to dryness. The residue was dissolved in a small amount of acetone and the 7 - {[(carboxamido) methylthio] acetamido} -3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl was made with petroleum ether ] thiomethyl} delta [deep] 3-cephem-4-carboxylic acid precipitated.

The following compounds were prepared in an analogous manner:

7 - {[(Carboxamido) -methyl-thio] -acetamido} -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

7 - [(R) - (2-Carboxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid.

Example 11

1.425 g of 6-mercaptotetrazolo (4.5-b) pyridazine and 0.9 g NaHCO [deep] 3 added. The mixture was stirred at 60 ° C. for 8 hours, with 1N H [deep] 2SO [deep] 4 being added from time to time to keep the pH at 7.4. After completion of the reaction and after cooling, acidification with 2N H [deep] 2SO [deep] 4 and extraction with ethyl acetate, the organic solution was dried and then evaporated to dryness. The residue obtained was dissolved in a small amount of ethyl acetate, then precipitated with ethyl ether.

The solid obtained was filtered off, taken up in 300 ml of ethyl ether and stirred for 30 minutes. After this

Filtering, after suspending in a mixture of ethyl acetate and ethyl ether (1: 3) and stirring and again filtering, 1.7 g of 7- (thien-2-yl-acetamido) -3 - {[tetrazolo (4, 5-b) pyridazin-6-yl] thiomethyl} delta [deep] 3-cephem-4-carboxylic acid, mp 125 ° C (dec.);

IR spectrum (KBr) 1785 cm [high] -1 (C = 0) beta-lactam; 1730 cm [high] -1 (C = 0) amide, 1670 cm [high] -1 (C = 0) carboxy, 1620 cm [high] -1 (C = C) double bond Delta [deep] 3. UV spectrum (phosphate buffer pH 7.4): Lambda [deep] max 238 mµ,

TLC: R [deep] f = 0.45 (CHCl [deep] 3: MeOH: HCOOH = 160: 20:20).

Analysis for C [deep] 18H [deep] 15N [deep] 7O [deep] 4S [deep] 3

calc .: C 44.15 H 3.08 N 20.02 S 19.65

found: 44.24 3.33 19.72 19.24%

The following compounds were prepared in an analogous manner:

7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-amino) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

7 - [(Thien-2-yl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

7 - [(Thien-2-yl) -acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

7 - [(Thien-2-yl) acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - [(Thien-2-yl) -acetamido] -3 - {[s-triazolo (4,3-b) pyridazin- (3-carboxymethylthio) -6-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

7 - [(Thien-2-yl) -acetamido] -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

7 - [(Thien-2-yl) -acetamido] -3 - {[thieno (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Hydroxy-2-thien-2-yl) acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] thiomethyl } -Delta [deep] 3-cephem-4-carboxylic acid,

7 - [(1H-1-tetrazolyl) acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-amino) -6-yl] thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-amino) -6-yl] -thiomethyl} -Delta [deep] 3-cephem-4- carboxylic acid.

Example 12

To a suspension of 4.86 g of 7- (bromoacetamido) -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid in 50 ml of CH [deep] 2Cl [deep] 2 2.8 ml of triethylamine were added. After stirring for 30 minutes at room temperature, 0.73 g of 2-mercaptoacetonitrile were added. After stirring for 6 hours at room temperature, the precipitate formed was filtered off, the organic solution was washed with water, then dried and evaporated to dryness in vacuo. The residue was taken up in ethyl ether, where 2.2 g of 7 - [(cyanomethylthio) acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid were obtained.

The following compounds were prepared in an analogous manner:

7 - [(Cyanomethyl-thio) -acetamido] -3 - {[s-triazolo (4,3-b) pyridazin- (3-carboxymethylthio) -6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - [(Cyanomethyl-thio) -acetamido] -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - [(Cyanomethyl-thio) -acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem-4- carboxylic acid,

7 - [(Cyanomethyl-thio) -acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid.

Example 13

To a suspension of 4.39 g of 7- (mercaptoacetamido) -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid in 70 ml of CH [deep] 2Cl [deep] 2 2.8 ml of triethylamine were added; After stirring for 30 minutes at room temperature, 0.92 g of monochloroacetone, dissolved in 15 ml of CH [deep] 2Cl [deep] 2, were added. After stirring for 4 hours at 60 ° C., the precipitate formed was filtered off, then the organic solution was washed with water, dried and evaporated to dryness in vacuo. The residue obtained was taken up in ethyl ether, 2.5 g of 7 - {[(acetyl) - methylthio] acetamido} -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid.

The following compounds were prepared in an analogous manner:

7 - {[(Acetyl) -methyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin- (8-cyano) -6-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid,

7 - {[(Acetyl) -methyl-thio] -acetamido} -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid.

Example 14

To a solution of 3.58 g of 7-amino-3 - {[1,2,5-thiazolo (3,4-d) pyridazin-4-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid , 0.4 g of NaOH and 2 g of NaHCO [deep] 3 in 60 ml of water and 60 ml of acetone, which had been cooled to 0 ° C., was a solution of 3.6 g of (R) -2-sulfophenylacetyl chloride in 60 ml Acetone added with stirring. The mixture was then stirred for 20 minutes at a temperature within the range of 0 to 5 ° C. The acetone was evaporated and ethyl acetate was added to the aqueous solution, then acidified with 8% HCl to reach pH 2. The organic phase was then washed with water, dried and evaporated to dryness in vacuo. The residue was taken up in ethyl ether and filtered, 3.5 g of 7 - [(R) - (2-sulfo-2-phenyl) acetamido] -3 - {[1,2,5-thiadiazolo (3,4 -d) pyridazin-4-yl] thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid.

The following compounds were prepared in an analogous manner:

7 - [(R) - (2-Sulfo-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - [(R) - (2-Sulfo-2-phenyl) -acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - [(R) - (2-Sulfo-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Sulfo-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid.

Example 15

A few drops of N-methylmorpholine were added to a solution of 5.02 g of [(R) -2-tert-butoxy-carbonyl-amino-2-phenyl] -acetic acid and 2.8 ml of triethylamine in 120 ml of anhydrous acetone. After cooling to -10 ° C., 2.44 ml of pivaloyl chloride, dissolved in 30 ml of anhydrous acetone, were added with stirring. After stirring for 30 minutes at a temperature of -10 ° C, a solution of 7.3 g of 7-amino-3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid and 2.8 ml of triethylamine in 240 ml of 50% strength acetone, which had been cooled to -20 ° C., were added over a period of 30 minutes. After stirring for 1 hour at -20 ° C. and then stirring for 2 hours at room temperature, the solution was filtered. After evaporation of the acetone in vacuo, the mixture was diluted with water, covered with a layer of ethyl acetate and the pH was brought to 2.5 with 40% H [deep] 3PO [deep] 4. After filtering off the residue, the ethyl acetate was separated off and the organic phase was washed with water, dried over Na [deep] 2SO [deep] 4 and evaporated to a small volume. After the addition of ethyl ether a solid was obtained which was then filtered off, whereby the 7 - [(R) -2- (tert-butoxycarbonyl-aminophenyl) -acetamido] -3 - {[tetrazolo (4.5 -a) pyrimidin-5-yl] thiomethyl} delta [deep] 3-cephem-4-carboxylic acid. 4 g of 7 - [(R) -2- (tert-butoxycarbonylaminophenyl) acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] thiomethyl} delta [deep] 3 -cephem-4-carboxylic acid were stirred with 50 ml of CF [deep] 3COOH at room temperature and saturated with nitrogen. After removing the trifluoroacetic acid in vacuo and after dissolving the residue in ethyl acetate after extraction with a NaHCO [deep] 3 solution, the aqueous phase was covered with ethyl acetate and brought to pH 4.5 with CH [deep] 3COH. The organic phase was washed with water, dried over Na [deep] 2SO [deep] 4 and evaporated to dryness, then it was taken up in ethyl ether, 5.1 g of 7 - [(R) - (2-amino-2 -phenyl) acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid.

The following compounds were prepared in an analogous manner:

7 - {(R) - [2-Hydroxy-2- (4-amino) -phenyl] -acetamido} -3 - {[tetrazolo (4,5-c) pyrimidin-5-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Amino-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid,

7 - [(R) - (2-Amino-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-amino) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Amino-2-phenyl) -acetamido] -3 - {[s-triazolo (4,3-b) pyridazin- (3-carboxymethylthio) -6-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid,

7 - [(R) - (2-Amino-2-phenyl) -acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid.

Claims (6)

1. Bicyclic 7-acylamido-3-cephem-4-carboxylic acid derivatives, characterized by the general formula (I) where mean: x is the number 0, 1 or 2, n is the number 0 or 1, Z 1.) a cyano group, a carbamoyl group or a -COOR- or -COR group, in which R is hydrogen or C [deep] 1-C [deep] 6-alkyl, 2.) a R [deep] 1-SO [deep] 2 group, in which R [deep] 1 C [deep] 1-C [deep] 6-alkyl, amino or salted or not salted Hydroxy means 3.) a phenyl group or a heteromonocyclic ring with 5 or 6 atoms, which has at least one double bond and contains at least one heteroatom from the group N, S and O, the phenyl group and the heteromonocyclic ring being unsubstituted or substituted by one or more substituents from the group hydroxy, cyano, carboxy, oxo, halogen, C [deep] 1-C [deep] 6-alkyl, C [deep] 1-C [deep] 6-alkoxy, -SH, aliphatic C [deep] 1 -C [deep] 6-acyl, -CH [deep] 2CN and in which the groups R, which are identical or different from one another, each have the meanings given above, A is a direct bond or the meanings given below for A [deep] 1, A [deep] 1 is a branched or straight-chain (unbranched) saturated aliphatic C [deep] 1-C [deep] 8 hydrocarbon radical which is unsubstituted or substituted by one or more substituents from the group OR '' ', where R' ' 'Is hydrogen or formyl, halogen, cyano, amino, -COOR or -COR, in which R has the meanings given above, and R [deep] 1-SO [deep] 2-, in which R [deep] 1 has the meanings given above Has, B is a heterobicyclic ring different from triazolophyridyl and purinyl and containing at least two double bonds, each of the fused heteromonocyclic rings, which are the same or different from one another, is a heteromonocyclic ring with 5 or 6 atoms, which is at least one hetero atom from the group N, S and contains O, the heterobicyclic ring being unsubstituted or substituted by one or more substituents from the group: a) Hydroxy, cyano, -SH, C [deep] 1-C [deep] 6-alkoxy, halogen, aliphatic C [deep] 1-C [deep] 6-acyl, -CH [deep] 2CN, -COOR or wherein R has the meanings given above, b) an unsubstituted or substituted by an aliphatic C [deep] 1-C [deep] 6-acyl group, c) a C [deep] 1-C [deep] 6-alkyl group which is unsubstituted or substituted by one or more substituents from the group consisting of hydroxy and halogen, d) the group where x [deep] 1 is the number 0, 1 or 2 and each of the radicals R 'and R ", which are identical or different from one another, are hydrogen or C [deep] 1-C [deep] 6-alkyl or in which R' and R "together with the nitrogen atom form a morpholino, piperidino or pyridyl ring, e) -SR [deep] 1 or -SO [deep] 2-R [deep] 1, where R [deep] 1 has the meanings given above, -S-CH [deep] 2CN, where x [deep] 2 denotes the number 0 or 1 and R has the meanings given above, M hydrogen or a non-toxic pharmaceutically acceptable cation, as well as the salts, in particular the pharmaceutically acceptable salts thereof, with the proviso that, if at the same time B is unsubstituted tetrazolo (4,5-b) pyridazin-6-yl, A is a direct bond, A [deep] 1 where R '''has the meanings given above, and n and x are the number 0, Z is not phenyl and thienyl. 2. Compounds according to claim 1, characterized by the general formula (II) where mean: n the meanings given in claim 1, Z cyano, carbamoyl, acetyl or R [deep] 1-SO [deep] 2-, in which R [deep] 1 has the meanings given in claim 1, or when n is the number 0 and A is a direct bond, Z a phenyl group or a heteromonocyclic ring with 5 or 6 atoms, which has at least one double bond and contains at least one heteroatom from the group N, S and O, the phenyl group or the heteromonocyclic ring being unsubstituted or substituted by one or more substituents from the group Hydroxy, -CH [deep] 2CN, C [deep] 1-C [deep] 6-alkyl and wherein the groups R, which are identical or different from one another, each have the meanings given in claim 1, A is a direct bond or each of the radicals A and A [deep] 1 is the group wherein x [deep] 2 has the meanings given in claim 1, and R [deep] 3 is hydrogen, -OR ''', where R''' has the meanings given in claim 1, halogen, cyano, amino, R [ deep] 1-SO [deep] 2-, wherein R [deep] 1 has the meanings given in claim 1, or C [deep] 1-C [deep] 6-alkyl, which is unsubstituted or selected by one or more substituents Group is substituted by cyano and carboxy, B is a heterobicyclic ring of the group tetrazolopyridazinyl, Tetrazolopyrimidinyl, Tetrazolotriazinyl, Tetrazolopyrazinyl, tetrazolopyridyl, Triazolopyridazinyl, Triazolopyrimidinyl, Triazolopyrazinyl, Imidazophridazinyl, Furopyridazinyl, Thiazolopyridazinyl, Thiadiazolopyridazinyl, Thienopyridazinyl and thienopyrimidinyl, which is unsubstituted or substituted by one or more substituents from the group hydroxy Cyano, -SH, C [deep] 1-C [deep] 6-alkoxy, halogen, aliphatic C [deep] 1-C [deep] 6-acyl, -CH [deep] 2CN, wherein x [deep] 1, R 'and R "have the meanings given in claim 1, -SO [deep] 2R [deep] 1, in which R [deep] 1 has the meanings given in claim 1, -COOR or wherein x [deep] 2 and R have the meanings given in claim 1, C [deep] 1-C [deep] 6-alkyl which is unsubstituted or substituted by one or more substituents from the group consisting of hydroxy and halogen, M hydrogen or a non-toxic, pharmaceutically acceptable cation as well as the salts, in particular the pharmaceutically acceptable salts thereof, with the proviso that when B is simultaneously unsubstituted tetrazolo (4,5-b) pyridazin-6-yl, A is a direct bond, wherein R '''has the meanings given in claim 1, and n is the number 0, Z is not phenyl and thienyl. 3. Compounds according to claim 1, characterized by the general formula (III) where mean: n the meanings given in claim 1, n [deep] 2 the number 0 or 1, Z Cyano, carbamoyl, acetyl or R [deep] 1-SO [deep] 2-, in which R [deep] 1 has the meanings given in claim 1, or when both n and n [deep] 2 are the number 0 denote a phenyl group or a tetrazolyl, triazolyl, pyridyl, pyridazinyl, furyl or thienyl group, all of these groups being unsubstituted or by one or more substituents from the group consisting of hydroxy, -CH [deep] 2CN, wherein the groups R, which are identical or different from one another, each have the meanings given in claim 1, are substituted, R [deep] 4 hydrogen or C [deep] 1-C [deep] 6-alkyl that is unsubstituted or substituted by one or more substituents from the group consisting of cyano and carboxy, R [deep] 5 hydrogen, -OR '' ', in which R' '' has the meanings given in claim 1, carboxy, amino or R [deep] 1-SO [deep] 2-, in which R [deep] 1 is the has the meanings given in claim 1, B is a heterobicyclic ring of the group tetrazolopyridazinyl, Tetrazolopyrimidinyl, Tetrazolopyrazinyl, tetrazolopyridyl, Tetrazolotriazinyl, Triazolopyridazinyl, Triazolopyrimidinyl, Triazolopyrazinyl, Imidazopyridazinyl, Furopyridazinyl, Thiazolopyridazinyl, Thiadiazolopyridazinyl, Thienopyridazinyl and thienopyrimidinyl, which is unsubstituted or substituted by one or more substituents from the group C [ deep] 1-C [deep] 3-alkyl, cyano, hydroxy, amino, -SH-, acetyl, -CH [deep] 2CN, -CH [deep] 2OH, wherein the groups R, which are identical or different from one another, each have the meanings given in claim 1, -SO [deep] 2R [deep] 1, in which R [deep] 1 has the meanings given in claim 1, -COOR or - CH [deep] 2COOR or -S-CH [deep] 2-COOR, in which R has the meanings given in claim 1, M hydrogen or a non-toxic, pharmaceutically acceptable cation, and the salts, in particular the pharmaceutically acceptable salts thereof, with the proviso that when B is simultaneously unsubstituted tetrazolo (4,5-b) pyridazin-6-yl, n [deep] 2 and n is the number 0 and R [deep] 5-OR '' ', where R' '' has the meanings given in claim 1, Z is not phenyl and thienyl. 4. Compound, characterized by one of the following formulas: 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - {[(Carboxamido) -methyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - {[(Alpha-Carboxamido) -äthyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4- carboxylic acid, 7 - {[(Alpha-Carboxamido) -propyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4- carboxylic acid, 7 - {[(Alpha-Cyano) -benzyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4- carboxylic acid, 7 - {[(Alpha, Beta-Dicyano) -äthyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - {[(Acetyl) -methyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(1H-1-tetrazolyl) acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid, 7 - [(1-s-Triazolyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[triazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[triazolo (4,5-b) pyridazin- (6-methyl) -3-yl] -thiomethyl} -Delta [deep] 3-cephem-4- carboxylic acid, 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-carboxy) -6-yl] -thiomethyl} -Delta [deep] 3-cephem-4- carboxylic acid, 7 - {[(Alpha-Cyano) -benzyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin- (8-carboxy) -6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin- (8-carboxy) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - [(1H-1-tetrazolyl) acetamido] -3 - {[s-triazolo (4,5-b) pyridazin- (6-methyl) -3-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid, 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin- (5-methyl) -7-yl] -thiomethyl} -Delta [deep] 3-cephem-4- carboxylic acid, 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-c) pyrimidin-7-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-a) pyrazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-a) pyridin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - {[(Alpha, Beta-Dicyano) -äthyl-thio] -acetamido} -3 - {[triazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[triazolo (4,5-b) pyridazin- (6-methyl) -3-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[tetrazolo (4,5-a) pyrimidin- (5-methyl) -7-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - {[(Alpha, Beta-Dicyano) -äthyl-thio] -acetamido} -3 - {[tetrazolo (4,5-c) pyrimidin-7-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - {[(Alpha, Beta-Dicyano) -äthyl-thio] -acetamido} -3 - {[tetrazolo (4,5-a) pyrazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - {[(Alpha, Beta-Dicyano) -äthyl-thio] -acetamido} -3 - {[tetrazolo (4,5-a) pyrid-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-amino) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-cyano) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyridimidin- (7-methyl) -5-yl] -thiomethyl} -delta [ deep] 3-cephem-4-carboxylic acid, 7 - {(R) - [2-Hydroxy-2- (4-hydroxy) phenyl] acetamido} -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] thiomethyl} delta [ deep] 3-cephem-4-carboxylic acid, 7 - {(R) - [2-Hydroxy-2- (4-amino) -phenyl] -acetamido} -3 - {[tetrazolo (4,5-c) pyrimidin-5-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[thiazolo (4,5-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[s-triazolo (4,3-b) pyridazin- (3-carboxymethylthio) -6-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(Thien-2-yl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(Thien-2-yl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(Thien-2-yl) -acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(Thien-2-yl) acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(Thien-2-yl) -acetamido] -3 - {[s-triazolo (4,3-b) pyridazin- (3-carboxymethylthio) -6-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid, 7 - [(Thien-2-yl) -acetamido] -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid, 7 - [(Thien-2-yl) -acetamido] -3 - {[thieno (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Hydroxy-2-thien-2-yl) acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] thiomethyl } -Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Hydroxy-2-fur-2-yl) acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-cyano) -6-yl] thiomethyl } -Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Hydroxy-2-fur-2-yl) -acetamido] -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(1 H-1-Tetrazolyl) acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-amino) -6-yl] thiomethyl} -Delta [deep] 3-cephem -4-carboxylic acid, 7 - [(1 H-1-Tetrazolyl) acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] thiomethyl} -Delta [deep] 3-cephem -4-carboxylic acid, 7 - [(1 H-1-tetrazolyl) acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid, 7 - [(1 H-1-tetrazolyl) acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid, 7 - [(1 H-1-tetrazolyl) acetamido] -3 - {[thiazolo (4,5-d) pyridazin-4-yl] thiomethyl} -delta [deep] 3-cephem-4-carboxylic acid, 7 - [(1 H-1-tetrazolyl) acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] thiomethyl} -Delta [deep] 3-cephem -4-carboxylic acid, 7 - [(1 H-1-Tetrazolyl) -acetamido] -3 - {[s-triazolo (4,3-b) pyridazin- (3-carboxymethylthio) -6-yl] -thiomethyl} -Delta [deep] 3 -cephem-4-carboxylic acid, 7 - [(1H-1-tetrazolyl) -acetamido] -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid, 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-amino) -6-yl] -thiomethyl} -Delta [deep] 3-cephem-4- carboxylic acid, 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[s-triazolo (4,3-b) pyridazin- (3-carboxymethylthio) -6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem-4- carboxylic acid, 7 - [(Cyanomethyl-thio) -acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - {[(Carboxamido-methyl-thio)] - acetamido} -3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid, 7 - {[(Carboxamido-methyl-thio)] - acetamido} -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid, 7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin- (8-carboxamido) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid, 7 - {[(Alpha, Beta-Dicyano) -äthyl-thio] -acetamido} -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - {[(Alpha, Beta-Dicyano) -äthyl-thio] -acetamido} -3 - {[thiazolo (4,5-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - {[(Alpha, Beta-Dicyano) -ethyl-thio] -acetamido} -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid. 7 - [(R) - (2-Carboxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-carboxymethyl-mercapto) -6-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid, 7 - {[(2,4-Dichloro) -phenyl] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem-4- carboxylic acid, 7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-mercapto) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - {[(Acetyl) -methyl-thio] -acetamido} -3 - {[tetrazolo (4,5-b) pyridazin- (8-cyano) -6-yl] -thiomethyl} -Delta [deep] 3- cephem-4-carboxylic acid, 7 - {[(Acetyl) -methyl-thio] -acetamido} -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - {[(Acetyl) -methyl-thio] -acetamido} -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[thieno (2,3-d) pyrimidin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(R) - (2-Sulfo-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(R) - (2-Sulfo-2-phenyl) -acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[1,2,3-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Sulfo-2-phenyl) -acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(R) - (2-Sulfo-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Sulfo-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(R) - (2-methylsulfonyl-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(R) - (2-Methylsulfonyl-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(R) - (2-Methylsulfonyl-2-phenyl) -acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Amino-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(R) - (2-Amino-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-amino) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Amino-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(R) - (2-Amino-2-phenyl) -acetamido] -3 - {[s-triazolo (4,3-b) pyridazin- (3-carboxymethylthio) -6-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Amino-2-phenyl) -acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-cyano) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - {(R) - [2-Formyloxy-2- (4-hydroxy) -phenyl] -acetamido} -3 - {[tetrazolo (4,5-a) pyrimidin-5-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin-6-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[furo (2,3-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[thiazolo (4,5-d) pyridazin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[1,2,5-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[s-triazolo (4,3-b) pyridazin- (3-carboxymethylthio) -6-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} - Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Formyloxy-2-fur-2-yl) acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-cyano) -6-yl] thiomethyl } -Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Formyloxy-2-fur-2-yl) -acetamido] -3 - {[s-triazolo (4,3-c) pyrimidin- (3-carboxymethylthio) -5-yl] -thiomethyl} -Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-amino) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Formyloxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-a) pyrimidin- (7-methyl) -5-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - {(R) - [2-Formyloxy-2- (4-amino) -phenyl] -acetamido} -3 - {[tetrazolo (4,5-c) pyrimidin-5-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Formyloxy-2-thien-2-yl) acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-hydroxy) -6-yl] thiomethyl } -Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-carboxy-methyl-mercapto) -6-yl] -thiomethyl } -Delta [deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[tetrazolo (4,5-b) pyridazin- (8-mercapto) -6-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid, 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[thieno (2,3-d) pyrimidin-4-yl] -thiomethyl} -Delta [deep] 3-cephem- 4-carboxylic acid, 7 - [(R) - (2-Hydroxy-2-phenyl) -acetamido] -3 - {[1,2,3-thiadiazolo (3,4-d) pyridazin-4-yl] -thiomethyl} -Delta [ deep] 3-cephem-4-carboxylic acid and a salt, especially a pharmaceutically acceptable salt, thereof. 5. A process for the preparation of a bicyclic 7-acylamido-3-cephem-4-carboxylic acid derivative according to any one of claims 1 to 4, characterized in that one a) a compound of the general formula (IV) in which B and M have the meanings given in claim 1, E is amino or the group -N = C = W, in which W is an oxygen or sulfur atom, or a reactive derivative thereof with an acid of the general formula (V) wherein n, x, Z, A and A [deep] 1 have the meanings given in claim 1, or a reactive derivative thereof; b) a compound of the general formula (VI) wherein A [deep] 1, M and B have the meanings given in claim 1, and X denotes a halogen atom, with a compound of the general formula Z-A-SH (VII) wherein Z and A have the meanings given in claim 1, or reacted with a reactive derivative thereof to form compounds of the general formula I given in claim 1, in which x is the number 0 and n is the number 1; c) a compound of the general formula (VIII) wherein M, B and A [deep] 1 have the meanings given in claim 1, or a reactive derivative thereof with a compound of the general formula Z-A-X (IX) wherein Z, A and X have the meanings given in claim 1, reacts to form compounds of the general formula I given in claim 1, in which x is the number 0 and n is the number 1; d) a compound of the general formula (X) where n, x, Z, A, A [deep] 1 and M have the values given in claim 1 have interpretations with a compound of the general formula H-S-B (XI) wherein B has the meanings given in claim 1, or reacted with a salt thereof and, if desired, the compounds obtained by each of processes (a) and (d), in which A and / or A [deep] 1 is an aliphatic hydrocarbon group as defined above which is replaced by one or more -OR '' 'groups, in which R '' 'Formyl, is substituted, converted into compounds of the formula I in which A and / or A [deep] 1 mean an aliphatic hydrocarbon group as defined above which is substituted by one or more hydroxyl groups, and / or, if desired, after each the compounds obtained in processes (a) to (d) are converted into salts, in particular pharmaceutically acceptable salts, and / or, if desired, prepares the free compounds from the salts and / or, if desired, separates an isomer mixture into the individual isomers. 6. Pharmaceutical agent, characterized in that it contains at least one compound according to any one of claims 1 to 4, optionally in combination with a pharmaceutically acceptable carrier or excipient.