FR2467854A1 - IMIDAZOLIC AND TETRAZOLIC 7- ((2- (AMINO-4-THIAZOLYL) -OXIMINO) CEPHALOSPORIN DERIVATIVES WITH ANTIMICROBIAL AND ANTIBACTERIAL ACTION - Google Patents

Abstract

Compound of formula:

Description

Imidazole and tetrazole derivatives of 7 - [(2-amino)

  The present invention relates to cephalosporins of the formula: (I) 2R4 2R 4 COOR R3 wherein R is a hydrogen or an alkali metal atom

R

D7

  or a radical -CHO-CO-lower alkyl, Si (CH3) 3, para-

  methoxybenzyl, diphenylmethyl, benzyl, trichloroethyl, o0 'or lower alkyl; R1 and R2 and Ret R5 are independently selected from hydrogen and methyl; R4 is a hydrogen atom or a group of formula -OCONH2, R8i -Si R1 0 -9R Uu -Li-u-dL t: L = uL; R6 is a hydrogen atom or a methyl, benzyl or acetyl radical; R7 is a hydrogen atom or a lower alkyl radical; R8 is a hydrogen atom or a -CONH2 radical; R9 is a hydrogen atom, a lower alkyl radical, or a group of formula - (CH2) -C-OR11, 1 - (CH2) pC-ORil, O - (CH2) pS-OR11 or - (CH2) pN- (lower O-alkyl) 2; R10 is a hydrogen atom or a lower alkyl radical; R11 is a hydrogen, sodium or potassium atom; n is 1, 2, 3 or 4; m is 0, 1 or 2;

p is 1, 2, 3 or 4.

  When R4 is a pyridinium or carbamoyl radical

  pyridinium, the compounds may be represented by the following structural formula: (Ia) (O)

COO (-)

  R 6 - in which R 8 is a hydrogen atom or a carbamoyl radical, as well as cephalosporins of formula:> m (II) 0 R16 (O) m

N C-_LN 4f -

N H H2X

O OOR12

  Wherein R12 represents a hydrogen, sodium or potassium atom or a benzyl, paramethoxybenzyl, diphenylmethyl, tert-butyl, trichloroethyl, -CH2-Oalkyl radical;

O O

  lower, -CH-O-C-lower alkyl, or R17 R13 and R14 are independently selected between

  the hydrogen atom and the methyl, ethyl, n-

  propyl, iso-propyl and carboxyl; R15 is a hydrogen atom, a methyl radical or an alkali metal such as sodium or potassium; R16 is in the configuration a and is a hydrogen atom or a methoxy radical; X is a hydrogen atom or a group of formula II -OC-CH 3, -OC-NH 2, -NH 2 -S-R 2 P 2 -C -CHNH 2 SS'-R or NN 8 -SO R 19; is a hydrogen atom or a lower alkyl radical; R 18 is a hydrogen atom or a lower alkyl radical; R19 is a hydrogen atom, a lower alkyl radical or a group of formula - (CH2) p -COOR201 - (CH2) p -SO3R20 or - (CH2) p-N (lower alkyl) 2; n is equal to zero or is an integer of

1 to 4;

  m is zero, one or two; p is an integer from 1 to 4; and R20 is a hydrogen, sodium or potassium atom.

  When X is a pyridinium or carbamoyl radical

  pyridinium, the compounds may be represented by the following structural formula: (IIb)

T 6

H 2 NA N H 2 (C-Z

0

  wherein Z is a hydrogen atom or a carbamoyl radical. The lower alkyl radicals referred to throughout this specification include straight or branched chain hydrocarbon radicals which contain from 1 to 4 carbon atoms, for example, methyl, ethyl, iso-propyl, tert-butyl and the like. The compounds of formulas I, Ia, II and IIb, as well as their intermediates, whose structure comprises the 2-amino-4-thiazolyl group are tautomers and may contain a 2-imino group. Thus, the compounds of formula I can be represented in the following form: (III) m CH 2 R 4 COOR and the compounds of formula II can be represented in the form: (IV) R 16 CH 2 X R 3 -

COOR12

R -N _-N

  The intermediates and end products are structurally represented and are referred to throughout this specification as 2-amino-4-thiazoles, but both forms fall within the scope of the present invention.

  scope of the invention. -

  The compounds of formulas I and II, as well as the intermediates described below, having the oximino-C-substituent can be obtained in the form of the isomer II N or syn- or anti- or in the form of a mixture of these two isomers. All these isomeric forms fall within the scope of the invention. But in general it is

  it is preferable to obtain the final products in the form of

  because it is this isomeric form which has the greatest activity.

  The symbol (O) is used here to represent the sulfide alone or bound to one or two oxygen atoms. When the sulfide is bonded to a single oxygen atom, the sulfoxides of formulas I and II, as well as in the various intermediates described below, can be either in configuration a or in configuration 3. When the sulfoxide is only in configuration B, it will be represented as O, and when it is only in configuration a it will be represented as O. S The cephalosporins of formula I can be prepared by various methods. For example, compounds of formula I wherein R 4 is -OCONH 2, -OC-lower alkyl, -S 2 O and wherein R 9 and R 10 are as defined above can be obtained by acylating an ester of formula :

(V) ()

H2N <<N r H2R4

COOR

  in which R4 and m are as defined above and R is an ester protecting group such as benzyl, diphenylmethyl, tert-butyl, para-methoxybenzyl or trichloroethyl, with a compound of formula: (VI)

C-COOH

52 N R1 (C) n-R2 R -N <R6-

R5 R3

  in which R1, R2, R3, R5, R6 and n are as defined above, to obtain an intermediate of formula:

(VII) (O)

(m C

H2 N XZ_D CH2R4-

COOR O R1- () n-R2

R- "

  6- R5 The acylation reaction is carried out in the presence of a

  condensing agent such as dicyclohexylcarbodiimide.

  The intermediate of formula VII is then treated to remove the ester protecting group and to obtain the compounds of formula I in the form of the acid. Preferably,

  in the above reactions, R is the diphenyl radical

  methyl, and the intermediate of formula VII is treated with

  trifluoroacetic acid to remove the diphenyl radical

  methyl. The compounds of formula VI are obtained by reacting 2-amino-4-thiazole glyoxylic acid, of formula:

(VIII)

XN j -COOH

H2N 1

  with a compound of the formula: ## STR2 ## The compound of formula IX can be prepared by treating the sodium salt of N-hydroxyphthalimide with a

compound of formula: -

  (X) to obtain the compound of formula: (XI) R 3 R 6 R 5 Treatment of the compound of formula XI by the acid

  hydrochloric acid gives the reagent of formula IX.

  The aminocaephalosporanic acid ester α- and β-sulfoxides of formula V (m is equal to one) are prepared by converting the starting 7-aminocephalosporanic acid (7-ACA) (m is zero) to Schiff base ester, of formula: ## STR2 ## which is then oxidized with a percarboxylic acid such as mchloroperbenzoic acid, to obtain a

  Schiff base cephalosporin ester mixture of a-

  and 3-sulfoxides. The side chain of the Schiff base is cut by treatment with toluenesulphonic acid, and

  separates by chromatography the 7-amino acid esters

  cephalosporanic acid of α- and--sulfoxides. Further oxidation of the α-sulfoxide gives the corresponding sulfone (m is two) of formula V. The compounds of formula Ia can be prepared by reacting a compound of formula I wherein R is an atom of hydrogen and R4 is a group of formula -OC-CH3O0 or -OC-NH2, with pyridine or carbamoylpyridine, in a polar solvent such as water and in the presence of a catalyst such as a thiocyanate of alkali metal, according to the procedures taught in US Patent 3,792,047 and in the German patent application published under

N 2.234.280.

  Compounds of formula

  In which R4 is a heterothiocyclic radical (ie

  to say __ or -), by reacting the

S-J-R 10 - O

  R9- compound of formula I wherein R is a hydrogen atom

0 0

  and R4 is a group of formula -O-C-CH3 or -O-C-NH2, with a mercaptan of formula: heterocycle-S-H or with a salt of alkali metal mercaptan (preferably sodium), of formula:

heterocycle-S-alkali metal.

  These methods of introducing a hetero group

  thiocyclic in position 3 are described in various patents

  U.S., including Nos. 3,955,213 and 4,066,762.

  The sulfoxides of formula I (m is equal to one) can also be prepared by direct oxidation of the corresponding sulfide (m is zero). Suitable oxidizing agents are percarboxylic acids such as m-chloroperbenzoic acid, peracetic acid, etc., and this reaction can be carried out at a temperature of about 0 ° C.

 C about.

  The sulfones of formula I (m is equal to two) can also be prepared by direct oxidation of the corresponding α-sulfoxide (m is equal to one). Here again, percarboxylic acids such as mchloroperbenzoic acid and

  peracetic acid are the preferred oxidizing agents.

  The compounds of formula I in which R is a sodium or potassium atom are prepared by reacting the corresponding compound of formula I in which R is a

  hydrogen atom, with the appropriate salt-forming ion.

  Compounds of formula I in which R is a group of formula

R O

  17H-O-C-lower alkyl by treating the corresponding free acid of formula I with a compound of formula:

R O

  Halo-CH-O-C-lower alkyl in which "halo" is a chlorine or bromine atom, in an inert solvent such as dimethylformamide, at

  ambient temperature or below.

  Similarly, the compounds of formula I in which R is a group of formula are prepared by treating the corresponding free acid of formula I with a compound of the formula: LL wherein L is a hydroxy group or a bromine atom, such as taught in US Patent Nos. 3,860,579,

3,951,954 and 4,072,677.

  Preferred compounds of formula I are those wherein: the oximino moiety is in the syn- configuration; n is one or two; m is zero or one, provided that when m is one, the sulfoxide is in configuration 1; R is a hydrogen, sodium or potassium atom; R1, R2, R3 and R5 are independently selected from hydrogen and methyl;

O O

  R4 is a group of the formula -O-C-CH3, -O-C-NH2, N9-R8, S-13LCH3 or -SiX $ W; R9 R6 is benzyl or acetyl R7 is R8 is a formula -C-NH2; R9 is a group of a hydrogen atom or a methyl group, a hydrogen atom; hydrogen atom or a group of hydrogen atom, a methyl radical or

O O

  It contains - (CH2) p-C-OR11, - (CH2) p -S-OR11, or o0 - (CH2) p-N (CH3) 2; R11 is a hydrogen, sodium or

  potassium; and p is 1 or 2.

24678S4

  The best choice among the above compounds is represented by those wherein R 4 is -O-C-CH 3 or N

-S- XCH

  CH3 The cephalosporins of formula II can be prepared by various methods. For example, compounds in which X is a hydrogen atom or

O O

He He

  group -O-C-CH3, -O-C-NH2, or heterothiocyclic (that is,

  ie -S R or -S formula:) by acylating an ester of (XII) CH2X

COOR21

  wherein X, R16 and m are as defined above and R and R21 is an ester protecting group such as benzyl, diphenylmethyl, tert-butyl, para-methoxybenzyl or trichloroethyl, with a compound of the formula:

(XIII) __

  in which R 13, R 14 and n are as defined above and R 15 is a hydrogen atom or a methyl radical, to obtain the intermediate of formula: (XIV) R (O) m

H2N CH X

COOR i 21

R - (C) -R

  13 n 14 The acylation reaction is carried out in the presence of a

  condensing agent such as dicyclohexylcarbodiimide.

  The acid of formula XIII is treated with monosilyl trifluoride.

  acetamide prior to the acylation reaction.

  The intermediate of formula XIV is then treated to remove the ester protecting group R21 and to obtain the compounds of formula II in the form of the acid. Preferably, in the above reactions, R 21 is diphenylmethyl and the intermediate of formula XIV is treated with trifluoroacetic acid and anisole to remove the

diphenylmethyl radical.

  The compounds of formula XIII are obtained in the

  Syn-configuration by reacting a 2-amino-4- acid

  glyoxylic thiazole, optionally protected, of formula:

(XV) N.COOH

  wherein R22 is a hydrogen atom or a conventional amine protecting group such as formyl, trityl or tertbutoxycarbonyl, with a tetrazole of the formula: (XVI) n-NH2N-O- (C) n

14 R3

  R3 wherein R14 is a hydrogen atom or a methyl radical. The optional R22 protecting group can be removed by conventional procedures after the above reaction to obtain the intermediates to

syn-configuration of formula XIII.

  The tetrazole of formula XVI can be prepared by treating N-hydroxyphthalimide with a nitrile of formula:

(XVII)

  R114Cl- (C) n-CN R13 to obtain the compound of formula:

(XVIII)

O N-O- (C) -CN

  R 13 which is then treated with sodium azide to obtain the compound of formula:

(XIX)

  ## STR5 ## Treatment of the compound of formula XIX with methyl iodide gives a compound of the formula: ## STR5 ##

(XIXA)

R - N-N

- () n I

R14 CH3

  Treatment of the compound of formula XIX or XIXA with hydrochloric acid at the reflux temperature gives

the reagent of formula XVI.

  The compound synthase form can also be obtained

  of formula XIII by reacting a protected 2-amino acid

  a- (oximino) -4-thiazole acetic acid, of formula: (XX) wherein R 22 is as defined above and the alkyl radical is preferably the ethyl radical, with a tetrazole of formula: (XXI)

halo-

halo- (f) n Y A

R14 R23

  wherein "halo" is preferably a chlorine atom and R 23 is a hydrogen atom or a protecting group such as the benzoyl or methyl radical. The possible protecting groups R22 and R23 are removed after the reaction by means of

conventional procedures.

  The anti-form of the compound of formula XIII can be obtained by reacting a 2-amino protected-4-thiazoleglyoxylic acid ester of the formula:

(XXII)

  In which R22 is as defined above and the alkyl radical is preferably the ethyl radical, with the tetrazole of formula XXI. The possible protective groups R22 and R23 are removed after the reaction by means of

classical operations.

  The aminocephalosporanic acid ester α- and α-sulfoxides of Formula XII (n = 1) are prepared by converting the starting 7-aminocephalosporanic acid (n is zero) to the base ester of Schiff, of formula:

(XXIII)

CH = N -

  N2X OOR which is then oxidized with a percarboxylic acid such as m-chloroperbenzoic acid, to obtain a mixture of Schiff base cephalosporin esters of α- and β-sulfoxides. The side chain of the Schiff base is cut by treatment with toluenesulphonic acid, and

  separates by chromatography the 7-amino acid esters

  cephalosporanic acid of α- and--sulfoxides. A new oxidation of the α-sulfoxide gives the corresponding sulfone

  (n is equal to two) of formula XII.

  The compounds of formula IIa can be prepared by reacting a compound of formula II wherein R 12 is hydrogen and X is a group of formula

O O

II He

  -O-C-CH3 or -O-C-NH2, with pyridine or a carbamoyl-

  pyridine, in a polar solvent such as water and in the presence of a catalyst such as an alkali metal thiocyanate, according to the procedures taught in U.S. Patent No. 3,792,047 and in the patent application

  German published as N 2.234.280.

  Compounds of formula

  II in which X is a heterothiocyclic radical (ie

to say v R1 -Stu

R19

  by reacting the compound of formula II wherein R 12 is a hydrogen atom and X is a group of formula

O O

  II -OC-CH3 or -OC-NH2, with a mercaptan of formula: (XXIV) heterocycle -SH or with an alkali metal (preferably sodium) mercaptan salt, of formula: (XXV) heterocycle -S- alkali metal

  Such methods of introducing a heterothio radical

  cyclic in position 3 are described in various U.S. patents,

  including Nos. 3,955,213 and 4,066,762.

  The β-sulfoxides of formula II (m is equal to one) can also be prepared by direct oxidation of the corresponding sulfide (m is zero). Suitable oxidizing agents are percarboxylic acids such as m-chloroperbenzoic acid, peracetic acid, etc., and this reaction can be carried out at a temperature of 0.degree.

about 25 to about.

  The sulfones of formula II (m is equal to two) can also be prepared by direct oxidation of the corresponding α-sulfoxide (m is equal to one). Here again, percarboxylic acids such as mchloroperbenzoic acid and

  peracetic acid are the preferred oxidizing agents.

  The compounds of formula II in which R12, R15 and R20 are sodium or potassium atoms are prepared by reacting the corresponding compound of formula II in which R12, R15 and R20 are hydrogen atoms,

  with a base having the appropriate cation.

  The compounds of formula II in which R is a group of formula -CH-OC-lower alkyl R17 can be obtained by treating the corresponding free acid of formula II with one or two moles of a compound of formula (XXVI) halogen. CH-OC-lower alkyl R17 wherein "halo" is a chlorine or bromine atom, in an inert solvent such as dimethylformamide, at

  ambient temperature or below.

  Similarly, the compounds of formula II in which R12 is a group of formula O are prepared by treating the corresponding free acid of formula II with a compound of formula

(XXVII)

  Wherein L is a hydroxy group or a bromine atom, as taught in U.S. Patent Nos. 3,860,579,

3,951,954 and 4,072,677.

  Preferred compounds of formula II are those wherein R12 is hydrogen, sodium or potassium; R13 and R14 are both hydrogen atoms; n is one; R15 is a hydrogen atom, a methyl radical, or a sodium or potassium atom; R16 is a hydrogen atom; X is a hydrogen atom or a

0 0

  a group of the formula -OC-CH 3, -OC-NH 2, -N, NH 2 S 4 D H 2 O-A; R 19 is a CH 2 or a hydrogen atom, a methyl radical or a group of formula COOR20, -CH2-S-OR20 or - (CH2) 2-N (CH3) 2; and

0

  R20 is a hydrogen, sodium or potassium atom.

  The best choice among the above compounds corresponds to those in which the oximino -C- group is in the syn- configuration; R15 is a hydrogen, sodium or potassium atom; and X is a group of formula -OC-CH 3 or -S H 3 H 3. In particular, these compounds represent the best choice among the compounds of formula II, as defined above, in addition to their broad spectrum of antimicrobial activity, also exhibit outstanding activity against a wide range of Gram-negative microorganisms, for example Serratia, Proteus positive to indole, Enterobacter, and vis-à-vis visions of Klebsiella pneumoniae. These compounds

  have a high degree of stability to lactamases vis-

  against Gram-positive and Gram-negative bacteria.

  The compounds of formulas I and II are useful antibacterial agents having activity against various Gram-negative organisms, including Klebsiella, Proteus and Enterobacter species. These compounds are also active against strains of Escherichia coli, Citrobacter freundii, Salmonella typhimurium, etc. They can be used as antibacterial agents to combat

  infections caused by organisms such as those listed above

  above, and in general we can use them in a way

  similar to other Gram-negative antibacterials.

  For example, a compound of formula I or II or a physiologically acceptable salt of one of these compounds may be used in various animal species at a dose of about 1 to 100 mg / kg, daily in parenteral form, in single or in two to four divided doses, to treat infections of bacterial origin, for example at a dose of 5.0 mg / kg in mice. Up to about 600 mg of an acidic compound of formula I or II or a physiologically acceptable salt or ester thereof may be put in an injectable form prepared according to standard pharmaceutical practice. Illustrative manufacturing details can be found in the examples given for the various reactions. All

  the temperatures are expressed in degrees Celsius.

EXAMPLE 1

  Sodium salt of [6R- [6a, 7 (Z)]] - 3 - [(acetyloxy) -

  methyl--7 - [[(2-amino-4-thiazolyl) [(1H-imidazol-2-yl-methoxy) -

  imino] acetyl] amino] -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-

  ene-2-carboxylic acid a) 2- (1H-Imidazol-1-ylmethoxy) -1H-isoindole-11.3 (2H) dione The mixture is stirred at room temperature in methanol.

  dry for two hours 5.1 g of sodium salt of N-hydroxy-

  phthalimide and 1.9 g of 2-chloromethyl imidazole hydrochloride (Journal of Chem Soc., 1965, 4577). The solvent is distilled off in vacuo and the residue is treated with aqueous sodium bicarbonate and extracted three to four times with chloroform. The combined organic layers are dried over sodium sulfate, filtered and

  concentrated to dryness. There remains 1.7 g of 2- (1H-imidazol-1-yl)

  methoxy) -1H-isoindole-1,3 (2H) dione as a solid

  crystalline having a melting point of 158-160 ° C.

  b) 2 - [(Aminoxy) methyl] -1H-imidazole hydrochloride (1: 2)

  1.5 g of 2- (1H-imidazol-1-yl) were refluxed.

  methoxy) -1H-iso-indole-1,3 (2H) dione, with stirring for 4 hours in 20 ml of 17.5% aqueous hydrochloric acid. The mixture is cooled to room temperature and the precipitated phthalic acid is filtered off. The mother liquor is concentrated to dryness. There remains 0.8 g of 2 - [(aminoxy) methyl] -1H-imidazole hydrochloride (1: 2) having a melting point

from 182-183 C.

  c) Hydrochloride (1: 2) (Z) of 2-amino-α - [(1H-imidazole)

  2-yl-methoxy) imino] -4-thiazole acetic acid. Suspended with stirring in 50 ml of water,

  2 g of 2 - [(aminoxy) methyl] -1H- hydrochloride (1: 2)

  imidazole of Example 1 (b) and 2.24 g of 2-amino acid

  thiazole-4-glyoxylic. The pH is adjusted to 6 with potassium carbonate and stirring is continued for 12 hours. The pH is then adjusted to 6.4 with hydrochloric acid. After 2 hours, filtered off

  0.8 g of hydrochloride (1: 2) of 2-amino-α- [(1H-imidazole)

  Crystalline 2-yl-methoxy) imino] -4-thiazole acetic acid having a

  melting point 158-160 ° C (decomposition).

  d) diphenylmethyl ester of [6R- [6a, 7n (Z)] - - 3- acid

  [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-imidazol-2-

  yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo

  [4.2.0] oct-2-ene-2-carboxylic acid is dissolved in 50 ml of dimethylformamide (DMF)

  1.2 g of the hydrochloride (1: 2) of 2-amino-o - [(1H-imidazole)

  2-yl-methoxy) imino] -4-thiazole acetic acid of Example 1 (c),

  1.84 g of 7-ACA benzhydryl ester and 0.54 g of hydroxyl

  benzotriazole. At 0 ° C., 1.1 g of dicyclohexylcarbodiimide in 20 ml of acetonitrile are added to the DMF solution and the mixture is stirred for 24 hours at 0 ° C. At the end of this time, the solvent is removed in vacuo and the solution is dissolved in vacuo. residue in acetone and then filtered. The mother liquor is concentrated to dryness and the oily residue is poured into aqueous sodium bicarbonate at 0 ° C. The crystalline precipitate is filtered off and purified by column chromatography using as eluant silica and magnesium.

  ethyl acetate, to obtain 1.5 g of diphenyl ester

  [6R- [6a, 75 (Z)]] - 3 - [(acetyloxy) methyl] methyl methyl-7-

  [[(2-amino-4-thiazolyl) [(1H-imidazol-2-yl-methoxy) imino] -

  acétyllaminol-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2

  carboxylic acid, having a melting point of 115 C (decomposition). e) Trifluoroacetate of [6R- [6a, 7, '(Z)]] - 3 - [(Acetyl)

  oxy (methyl] -7 - [[(2-amino-4-thiazolyl)] (1H-imidazol-2-

  yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo

  [4.2.0] oct-2-ene-2-carboxylic acid is suspended in 2.5 ml of anisole, stirring at 0 C, 920 mg of diphenylmethyl ester of acid

  [6R- [6-, 7 :( Z)]!] - 3 - [(acetyloxy) methyl] -7 - [[(2-amino-4-

  thiazolyl) [(1H-imidazol-2-yl-methoxy) imino] acetyl] amino] -8

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. 5 ml of trifluoroacetic acid are added and the mixture is stirred for a further hour at 0 ° C. At the end of this time, the solution is poured into 100 ml of a 1: 1 mixture of ether and petroleum ether. . The precipitated acid is filtered and washed

  to ether and dried to obtain 850 mg of trifluoro-

  acid acetate [6R- [6,?, 7, (Z)]] - 3 - [(acetyloxy (methyl) -7-

* [[2-amino-4-thiazolyl) [(1H-imidazol-2-ylmethoxy) imino] -

  acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2

carboxylic acid.

  (f) Sodium salt of [6R- [6a, 7B (Z)]] - 3 - [(acetyloxy) -

  methyl] -7 - [[(2-amino-4-thiazolyl) [(lH-imidazol-2-yl-

  methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo

  [4.2.0] oct-2-ene-2-carboxylic acid Dissolve in 15 ml of a 1: 1 mixture of acetone

  dried methanol 850 mg of acid trifluoroacetate [6R-

  [6a, 75 (Z)]] - 3 - [(acetyloxy (methyl] -7 - [[(2-amino-4-thiazolyl) -

  [(1H-imidazol-2-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-

  1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, and the solution is treated at 0 ° C. with 765 mg of sodium ethylhexanoate in ml of butanol. After stirring for 10 minutes, the mixture is poured into 100 ml of ether and separated by filtration.

  630 mg of sodium salt of [6R- [6a, 7 (Z)]] I-3 - [(Acetyl)

  oxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-imidazol-2-yl-

  methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] -

  precipitated oct-2-ene-2-carboxylic acid having a melting point

from 163-165C.

EXAMPLE 2

  Sodium salt of 5S [5S, 6q, 7a (Z)] - 5-oxide acid

  [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-imidazol

  2-Methoxy-iminolacetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid a) Benzhydryl ester of 5S [5S] -5-oxide [ 5a, 6F, 7a)

  (Z)]] - 3 [(acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(l1H-

  imidazol-2-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-

  1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid is dissolved in 80 ml of cooled dimethylformamide

  at 0 ° C. 2 g of the hydrochloride (1: 2) of 2-amino-α - [(1H-

  imidazol-2-yl-methoxy) imino] -4-thiazole acetic acid of Example 1 (c), 2.95 g of 7-ACA benzhydryl ester g-sulfoxide and 1.2 g of hydroxybenzotriazole, and 1.8 g of dicyclohexylcarbodiimide are added. The solution is stirred at 0 ° C. overnight. The solvent is removed in vacuo and the oily residue is stirred at 0 ° C. with an aqueous solution of sodium bicarbonate. The precipitated compound is filtered off and purified by column chromatography using silica and magnesium as the eluent.

  acetone, to obtain 2.2 g of benzhydryl ester of 5-

  5S [5a, 63,7a (Z)]] - [[acetyloxy) methyl] -7 -

  amino-4-thiazolyl) [(1H-imidazol-2-yl-methoxy) imino] acetyl] -

  amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2

carboxylic acid.

  b) trifluoroacetate of 5S [5S, 65,7a (Z)] 5-oxide

  3 [(acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl [(1H-imidazol

  2-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo

[4.2.0] oct-2-ene-2-carboxylic acid

  A suspension of 2 g of benzene ester is stirred at 0 ° C.

  5S [5a, 65,7a (Z)]] - 3 - [(Acetyl)

  oxy) methyl--7 - [[(2-amino-4-thiazolyl) [(1H-imidazol-2-yl-

  methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] -

  oct-2-ene-2-carboxylic acid and 6 g of anisole, at the same time as 8 ml of trifluoroacetic acid. Stirring is continued for 45 minutes and then the solution is poured into 200 ml of ether. The precipitate is filtered off and washed with ether to give 1.8 g of 5-oxide trifluoroacetate.

  of [5S [5a, 6r, 7a (Z)]] - 3 - [(acetyloxy) methyl] -7 - [[(2-amino)]

  4-thiazolyl) [(1H-imidazol-2-yl-methoxy) imino] acetyl] amino] -8

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

  (c) Sodium salt of 5S [5S, 63,7a (Z)] - 3- [5S] oxide

  [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-imidazol

  2-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo

[4.2.0] oct-2-ene-2-carboxylic

  1.9 g of [5S] [5a] trifluoroacetate are treated.

  , 7 (Z)]] - 3 - [(acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) -

  [(1H-imidazol-2-yl-methoxy) imino] acetyl] amino] -8-oxo-5-

  thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid of Example 2 (b) in 5 ml of a 1: 1 mixture of dimethylformamide and methanol for 5 minutes with stirring. 200 ml of ether are added and the precipitated sodium salt is filtered off to give 1.1 g of sodium 5-oxide salt.

  of [5S [5a, 6r, 7a (Z)]] - 3 - [(acetyloxy) methyl] -7 - [[(2-

  amino-4-thiazolyl) [(l1H-imidazol-2-yl-methoxy) imino] acetyl] -

  amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2

  carboxylic acid having a melting point of 140-145 ° C

(decomposition).

EXAMPLE 3

  Sodium salt of [6R- [6a, 7I (Z)]] - 7 - [[(2-amino-4-)

  thiazolyl) [(1H-imidazol-2-yl-methoxy) imino] acetyl] amino] -3-

  [[(1-methyl-lH-tetrazol-5-yl) thio] methyl] -8-oxo-5-thia-1-

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid When 2-amino-α - [(1H-imidazol-2-yl-methoxy) imino] hydrochloride (1: 2) is reacted 4thiazole acetic acid of Example 1 (c) with benzhydryl ester of 3- (1-methyl-1H-tetrazolyl) -7-ACA according to the procedure

  given in Example 1 (d), the diphenyl ester is obtained.

  [6R- [6a, 73 (Z)]] - 7 - [[(amino-4-) methyl)

  thiazolyl) [(1H-imidazol-2-yl-methoxy) imino] acetyl] amino] -3-

  [[(1-methyl-lH-tetrazol-5-yl) thio] methyl] -8-oxo-5-thia-1-

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. We then treat

  this compound as described in Example 1 (e) and 1 (f), that is,

  that is, the benzhydryl part is cut off by treatment with trifluoroacetic acid and subsequent formation of the sodium salt. By this process, the sodium salt of the acid is obtained

  [6R- [6a, 7 (Z)?]] - 7 - [[(2-amino-4-thiazolyl) [(1H-imidazol-2-yl-

  methoxy) imino] acetyl] amino] -3 - [[(1-methyl-1H-tetrazol-5-yl)]

  thio] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2

  carboxylic acid having a melting point of 198-200 ° C (decomposition).

EXAMPLE 4

  Sodium salt of 5,5- [5a, 6f, 7a (Z)] 5,5-dioxide acid] -

  3 - [(acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-

  imidazol-2-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

  a) Diphenylmethyl ester of [5S- [5a] 5-oxide,

  6, 7a]] - 3 - [(acetyloxy) methyl] -7-amino-8-oxo-5-thia-1-aza;

  bicyclo [4.2.0] oct-2-ene-2-carboxylic acid (i.e.

  sulfoxide) and diphenylmethyl ester of 5-oxide of the acid

  [5R- [5a, 6a, 7-1]] - 3 - [(acetyloxy) methyl] -7-amino-8-oxo-5-

  thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (i.e.

  say a-sulfoxide) A suspension of 50 g of 7-aminocephalosporanic acid (7-ACA) in a liter of water is magnetically stirred,

  at the same time as one adds drop by drop of

  octylamine, which has the effect of maintaining the pH between 7 and 8. After one hour, the undissolved solid is filtered on "CELITE" and the filtrate is treated with a solution prepared by adjusting to pH 8.0, using 6N hydrochloric acid, a mixture of 10 ml of 5-octylamine and 20 ml of water. We

  then treat the resulting solution with 10 ml of salicylate.

  aldehyde. After two minutes, a solid forms, and

  after five minutes another 10 ml of salicylate is added.

  aldehyde. The suspension is stirred for a further 10 minutes, cooled to 0 for 4.5 hours and filtered. The filter cake is stirred twice with 300 ml of cold water and filtered. The wet cake was dried under vacuum over a large amount of phosphoric anhydride to give 66 g of 7-salicylaldiminococephalosporanic acid tert-octylamine salt as a

solid beige color.

  A suspension of 25.25 g (0.05 mole) of the above tert-octylamine salt (pulverized with a mortar and pestle) is treated in 250 ml of dry acetonitrile,

  9.5 g (0.05 mole) of para-toluenesulphonic acid mono-

  hydrate. After 10 minutes, a solution of 9.7 g (0.05 mol) of diphenyldiazomethane in 50 ml of acetonitrile is added over 15 minutes. After one hour, the suspension is filtered, the solid is washed with acetonitrile, and the combined filtrate and washings are concentrated under vacuum. The resulting oil is chromatographed in a column of 300 g of silica gel, which is eluted with methylene chloride. Fractions 2 and 3 (500 ml) contain 7.5 g of the desired diphenylmethyl ester plus a higher Rf impurity (which is monitored by TLC on silica gel with development with a 3: 1 mixture of chloroform and ethyl acetate). The

  Fractions 4 to 1il contain 12.3 g of diphenyl ester

  pure 7-salicylaldiminocéphalosporanique acid methyl; NMR (CDCl3) δ 1.97 (s, 3H, CH3CO); 3.23 and 3.60 (AB q, J = 19 Hz, 2H, C-2); 4.67 and 5.01 (AB q, J = 14 Hz, 2H, C-3 '); 4.99 (d, J = 5Hz, 1H, C-6); 5.20 (broadened d, J = 5 Hz, 1H, C-7); 6.62 - 7.60 (m, about 15H); 9.07 (broad s, 1H,

-CH = N-).

  A solution of 12.3 g (0.023 mole) of the diphenylmethyl ester obtained above in ml of methylene chloride is cooled to 0, and a solution of 4.6 g (0.023 mol) of toluene is added over 15 minutes. 85% benzoic chloroacetic acid in 70 ml of methylene chloride. After one hour, the suspension is washed with a mixture of 5% sodium bicarbonate and 50 ml of 6% sodium sulphite solution. The organic layer is dried and concentrated in vacuo. The resulting oil crystallized from 70 ml of ethyl acetate to give 8.7 g of a mixture of α- and β-sulfoxides. We also obtain

  a second harvest of 1.5 g of a mixture of a- and j-

  sulfoxides. The major isomer (a-) has a methyl acetate (2.02 ppm) and a C-2 quartet (3.57 and 4.10 ppm) lower field than those of the minor isomer (3) ( 1.97, 3.26 and

3.94 ppm, respectively).

  A suspension of 10 g (0.018 mol) of

  above mixture of α- and β-diphenyl ester-3-sulfoxides

  7-salicylaldiminococephalosporanic acid methyl ester in ml of ethyl acetate, by 3.42 g (0.018 mole) of para-toluenesulphonic acid monohydrate. After 3.5 hours, 300 ml of ether are added and the rubbery solid is triturated, filtered and washed twice with ether. The remaining wet solid is dissolved in 200 ml of ethyl acetate and the solution is washed with 100 ml of 5% sodium bicarbonate solution, dried and concentrated to give 8.0 g of residue. Chromatography in a column of 300 g of silica gel eluted with a 3: 1 mixture of chloroform and ethyl acetate gives (500 ml fractions): fraction 3, 1.0 g of ester recovered 7-salicylaldiminococephalosporanic acid diphenylmethyl; Fractions 6 to 16, 4.5 g of diphenylmethyl ester

  5R- [5a, 6a, 7f]] - 3 - [(acetyloxy) methyl] 5-oxide oxide

  amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2

  carboxylic acid (i.e., isomer α-sulfoxide): NMR (CDCl3) δ 2.00 (CH3COO-); 3.43 and 4.06 ppm (AB q, C-2); fractions 22-30 (the eluent for ethyl acetate is changed after fraction 16): 1.5 g of diphenylmethyl ester

  5S- [5a, 6,7a]] - 3 - [(acetyloxy) methyl] -5

  amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2

  carboxylic acid (i.e. isomer 3-sulfoxide): NMR

  (CD 13) δ 2.10 (CH 3 COO-); 2.97 and 3.54 ppm (AB q, C-2).

  (b) Diphenylmethyl ester of 5,5-dioxide [6R-

  [6a, 71]] - 3E - [(actyloxy) methyl] -7-amino-8-oxo-5-thia-1-

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid -

  Methylene chloride is added and the diphenylmethyl ester of the 5-oxide is cooled to 0.degree.

  [5R- [5a, 6a, 73]] - 3 - [(acetyloxy) methyl] -7-amino-8-

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid of Example 4 (a). An equimolar amount of meta-chloroperbenzoic acid in methylene chloride is added. Once the reaction is complete, the suspension is treated with

  5% sodium bicarbonate and 5% sodium sulfite.

  The organic layer is dried and concentrated in vacuo.

  Thin-layer chromatography preparation of the residue gives the diphenylmethyl ester of 5,5-dioxide acid

  [6R- [6α, 7]] - 3 - [(acetyloxy) methyl] -7-amino-8-oxo-5-thia-1

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

  (c) Diphenylmethyl ester of 5,5-dioxide of [5S-

  [5a, 63,7a (Z)]] - 3 - [(acetyloxy) methyl] -7 - [[(2-amino-4-

  thiazolyl) [(1H-imidazol-2-ylmethoxy) imino] acetyl] amino] -8-oxo-5-thia-1azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid Following the procedure of Example 1 (d) but replacing the 7-ACA diphenylmethyl ester with the ester

  diphenylmethyl of 5,5- [5a, 6p, 7a] 5,5-dioxide

  3- [(Acetyloxy) methyl] -7-amino-8-oxo-5-thia-1-azabicyclo

  [4.2.0] oct-2-ene-2-carboxylic acid, the ester is obtained

  diphenylmethyl of 5,5- [5S, 6f, 7a]

  (Z)]] - 3 - [(acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl [(1H-

  imidazol-2-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

  d) Trifluoroacetate of 5,5- (5a, 6,7a) 5,5-dioxide

  3 - [(Acetyloxy) methyl] -7 - [(2-amino-4-thiazolyl)] - (1H-imidazole)

  2-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-l-azabicyclo

  [4.2.0] oct-2-ene-2-carboxylic acid Following the procedure of Example 1 (e) but

  by replacing the diphenylmethyl ester of [6R- [6a] acid,

  (Z)]] - 3 - [(acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-

  imidazol-2-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid by the ester

  diphenylmethyl of 5,5- [5S- [5a, 65,7-

  (Z)]] - 3 - [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl)] [1H-

  imidazol-2-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, the

  trifluoroacetate of 5,5- (5a, 6p, 7a)] -5,5-dioxide

  [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) (1H-imidazol-2-

  yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo

[4.2.0] oct-2-ene-2-carboxylic acid.

  (e) Sodium salt of [5S- [5a] 5,5-dioxide,

  (Z)]] - 3 - [(acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-

  imidazol-2-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid Following the procedure of Example 1 (f) but

  replacing the trifluoroacetate of the acid [6R- [6a, 7p (Z)]] -

  3- [(acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl)] (1H-imidazol);

  2-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo

  [4.2.0] oct-2-ene-2-carboxylic acid by trifluoroacetate of 5S- (5a, 61,7x)] - [3-acetyloxy] -5-dioxide

  methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-imidazol-2-yl-methoxy) -

  imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-

  ene-2-carboxylic acid, the sodium salt of 5,5-

  [5S- [5a, 6j, 7 (Z)]] - 3 - [(acetyloxy) methyl) acid dioxide

  7 - [[(2-amino-4-thiazolyl) [(1H-imidazol-2-yl-methoxy) imino] -

  acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2

carboxylic acid.

EXAMPLE 5

  Sodium salt of [5R- [5a, 6a, 7P]] -3-acid 5-oxide

  [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-imidazol

  2-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo

  [4.2.0] oct-2-ene-2-carboxylic acid (i.e., α-sulfoxide)

  a) Diphenylmethyl ester of [5R- [5o] 5-oxide,

  6a, 7]] - 3 - [(ac6tyloxy) methyl] -7 - [[(2-amino-4-thiazolyl [(LH-

  imidazol-2-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid Following the procedure of Example 1 (d) but replacing the diphenylmethyl ester of 7-ACA with the ester

  Diphenylmethylic acid 5-oxide [5R- [5a, 6a, 71]] - 3-

  [(Acetyloxy) methyl] -7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] -

  oct-2-ene-2-carboxylic acid (i.e., α-sulfoxide) (prepared as in Example 4 (a)), the ester is obtained

  [5R- [5a, 6a, 7e]] - 5-oxide diphenylmethyl

  [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl [(1H-imidazol-2-

  yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo

[4.2.0] OCCT-2-ene-2-carboxylic acid.

  b) Trifluoroacetate of 5-r- [5a, 6a, 7j]] 3- [5R-]

  [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-imidazol

  2-yl-methoxy) imino] acetyl] amino] 8-oxo-5-thia-1-azabicyclo

  [4.2.0] oct-2-ene-2-carboxylic acid Following the procedure of Example 1 (e) but using the diphenylmethyl ester of 5-oxide of the acid

  [5R- [5a, 6a, 7]] - 3 - [(acetyloxy) methyl] -7 - [[(2-amino-4-

  thiazolyl [(1H-imidazol-2-yl-methoxy) imino] acetyl] amino] -8

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic

  instead of the diphenylmethyl ester of [6R- [6a, 7n, (Z)] -

  3-1 (acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl)] - (1H-imidazol)

  2-yl-methoxy) iminol] acetyl] amino] -8-oxo-5-thia-l-azabicyclo

  [4.2.0] oct-2-ene-2-carboxylic acid, the trifluoride is obtained

  acetate of [5R- [5a, 6a, 71]] - [- acetyl-

  oxy) methyl-7 - [[(2-amino-4-thiazolyl)] - (1H-imidazol-2-yl)

  methoxy) iminol] acetyl] laminol-8-oxo-5-thia-1-azabicyclo

[4.2.0] oct-2-ene-2-carboxylic acid.

  c) Sodium salt of [5R- [5n, 6a, 73]] 3- [5R-]

  [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl)] - (1H-imidazol)

  2-yl-methoxy) iminol] acetyl] amino] -8-oxo-5-thia-l-azabicyclo

  [4.2.0] oct-2-ene-2-carboxylic acid (i.e., α-sulfoxide) Following the procedure of Example 1 (f) but using 5-oxide trifluoroacetate. 'acid

  [5R- [5c, 6.7. 11] -3- (acetyloxy) methyl] -7 - [[(2-amino-4-

  thiazolyl) [(11H-imidazol-2-yl-methoxy) iminolacetyll] -amino] -8

  oxo-5-tri-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid instead of [6R- [6d, 7p (Z)]] - 3 - [(acetyloxy) trifluoroacetate methyl] -7- [C (2-amino-4-thiazolyl)] (1H-imidazol-2-yl-methoxy)

  iminolacetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0O oct-2-

  ene-2-carboxylic acid, the sodium salt of [5R [5c, 6c, 71j] -3 - [(acetyloxy) methyl] -7-LX (2-amino-4-thiazolyl) 5-oxide ) [(1H-imidazol-2-ylmethoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2. 0] oct-2-ene-2-carboxylic

(i.e., α-sulfoxide).

EXAMPLES 6 to 31

  By following the procedure of Examples 1 to 5

  but using the ester indicated in column I above

  below and the acid indicated in column II below,

  the ester indicated in column III below is obtained.

  Removal of the ester protecting group gives as

  produces the acid indicated in column IV below.

  Collar. I (O) H N 2 CH2R4 COOR Col. II Col. III m

H 2N S X

  Collar. IV CH2R4 COOH R4 -O-CHl3O-O-C-ClH3O-O-C -C13 O

-O-C-CH3

O -O-C-Cli 3

-O-C-CH3

O - C2H5

-H

R R1

-i2 -H -CH-) 2 -t -H

-C (CH3) 3 -H

-CH12- - OCH3 -CH3

-H

-CH-) -H

-H

-CI I) 2 -H

-Cit-H;) 2 -CH3 -CH-4>) 2 -l

-CH4>) 2 -H

R2 R

-IH -Hi -iH -CEI3

-CH3 -CH

CH3

-H -CH3

-Hl -CH3

-CH3 -CH3

-H -C

-I -CH3

-H -CH3

  R5 -H1 -H1 -H -H -H -H -H1 -H R6 -CiI3 -CH3 -CH3-CH3 m one two ero one zero zero zero -Hl two -H zero -CilH3 zero -l3 zero -CH3 zero

-CH-E!) 2,

-CH3 -H -CH 3

-H -Hi zero

Example

a one a

14 -01-C2H5

  w one a one a "I o 'Co us n ze an il-H_ an oxaz a c a c a c a x an oz 0 ua o) Daz úl;) zaaz úHO_ an EHO_

* a úEH-

UT

-az úHD-

  ú iii iii iii iii iii iii iii iii iii iii iii iii iii iii iii iii iii iii iii iii iii iii iii iii iii iii iii iii iii

H- H- (<) HD-

l- Hl- (&H;

il- úHO- (i-

H- H- (H-

úE, úCID- Zg (<- IHD-

he- he- Z (-ID-

he- 1-1 Z (FI 1D-

1- - (H;

Z (<Y1 -

ZI Is kI

úHD -'- VS- EZ

  HN-D-OsS-6Z eHO-DSO-OZ gZHIN-D: -O- 6 1 EZIN-D-O- si

_HN-D-O- 91

  z 91 He zHN-D-O-SI v U oldmuoxz u. % o ",, i'M r)

EOz úHD-

an Ei) D-

an EtlD-

ur o.jazúEHD-

9u H

H-

E: HD (HDHD-

H- úHD- úHD- (H-

H4- EHD- E HD- (W D

H-il- i- z (HD-

H- H- H- z (H D-

ú 7dEI Tu -

HúOS ZH

úHD t úHD I <S-EHD

NÀ 's

  I s-- úHD t s OidTuox I * or a Co a o.xz or a _ _i

R3 R5

R6

29 -J

CH2 COOil H

31 (C 2 N (CH 3

(C112) 2N (CH3)

-CH29>

-CH-2 D) 2

-H -H -H

  -Hi -H -il -il -H -H -H -H -H -CH3 -CH3 -CIl3 zero one one one zero

Example

R4 R

R1 R2

  The acids obtained in Examples 6 to 31 can be converted into their sodium or potassium salts in accordance with the methods described in US Pat.

known operating procedures.

  The products of Examples 6 to 31 are obtained in the form of the syn- or anti-isomer following the configuration of the acid indicated in column II above. Moreover, when R1 and R2 are not identical, the products are obtained in the form of dextrorotatory (D-), levorotatory (L-) or racemate (D, L) depending on the optical activity of the acid.

  indicated in column II above.

EXAMPLE 32

  [6R- [6a, 7 (Z)] - [- [[4- (aminocarbonyl) pyridino] methyl acid] -

  7 - [[(2-amino-4-thiazolyl) [imino] (H-imidazol-2-yi-methoxy!) -

  acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene

  2-carboxylic acid (syn-isomer) A mixture of 0.005 mol of the sodium salt obtained in Example 1, 0.0075 mol of 4-pyridinecarboxamide, 12 g of potassium thiocyanate 7.5 ml of water. The resulting solution was passed through a chromatography column packed with Amberlite XAD-2 ion exchange resin. The column is washed with water and the title compound is eluted with an 8: 2 mixture of water and methanol. The methanol is evaporated from the eluate and the aqueous solution is lyophilized. The amorphous residue is triturated with ether and filtered under suction for

  obtain the acid [6R- [6a, 7p (Z)]] - [- 4- (aminocarbonyl) -

  pyridino] methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-imidazol-2-yl)

  methoxy) iminolacétyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] -

oct-2-ene-2-carboxylic acid.

EXAMPLES 33 to 40

  Following the procedure of Example 32 but using the cephalosporanic acid sodium salt indicated in column I below and the pyridine derivative indicated in column II below, the indicated product is obtained.

in column III below.

Collar. I O II

H2N S - N

1 1-,

2 \

  R 1 - (C) n -R 2 -N R <3 - o -i CH 2 -O-9-CH 3 COONa Col. II Col. IIIR Col. III

H2 NQ!

COO CH2-

-) 9

/ N / - R3

(7) ZHIND-

He o R-

I zIND-

he It- o H- I! ND-

(i) aIiN9;

  I at 6 o'clock oaz a oloz a u oaGz op uig

o0az H-

o0az H-

o0az H-

a H-

ILOgZ it-

oaaz úHD-

xnúp HD-

  an alwi 9tU * r oe us Co ri Il- úHD- úHiD- 1D- H- H- H- H- H- H- H-H-H- H- H- H- H- H - H- ú 6ú 8ú The products of Examples 33-40 are obtained in the syn- or anti-configuration following the configuration of the 3-acetoxymethyl starting material which is indicated in column I above. Similarly, when m is equal to one, the compounds are obtained in the form of α-sulfoxide or 3-

  sulfoxide according to the orientation of the 3-acetoxy sulfoxide

  starting methyl. In addition, when R 1 and R 2 are not identical, the products are obtained in the form D-, L- or D, L according to the optical activity of the indicated starting material.

in column I above.

EXAMPLE 41

  Sodium salt of [6R- [6a, 73 (Z)]] - 7 - [[(2-amino-4-)

  thiazolyl) [(1H-imidazol-2-yl-methoxy) imino] acetyl] amino] -3-

  [[(5-methyl-1,3,4-thiadiazolyl) thio] methyl] -8-oxo-5-thia-1-

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 0.002 moles of the sodium salt obtained in Example 1 are dissolved in 100 ml of a phosphate buffer.

  at a pH of 6.4. Then 0.0024 mole of 5-methyl-

  1,3,4-thiadiazolyl-2-thiol. The solution is heated at 60 for 6 hours. After cooling, the pH is adjusted to 7.0 and the solution is subjected to ion exchange resin chromatography "Amberlite XAD2". We make

  the fraction containing the desired product a freeze-dried product

  to obtain the sodium salt of [6R [6a, 7f (Z)] -

  7 - [[(2-amino-4-thiazolyl) [(1H-imidazol-2-yl-methoxy) imino] -

  acetyl] amino] -3 - [[(5-methyl-1,3,4-thiadiazolyl) thio] -

  methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2

carboxylic acid.

EXAMPLES 42 to 47

  Following the procedure of Example 41 but using the cephalosporanic acid sodium salt indicated in column I below and the thiol indicated in column II below, the product indicated in

column III below.

Collar. I

CH2-O-C-CH3

  R5 Col. II HS-het erocycle Col. 1Ii SA. 2-s-heterocycle R3 N H H2N'i R6 R5

a xnap H- úHO-

  Z (HD) Nz (aH) NoN eNOOD HD IIE ú eNEOS HD L1L IH oaHEîo q oiDz

a. H- H- H-

an o: az He- he- I-

an oetaz u

an EID-

xnop úID-

ozaz úHZ) -

_ 9I

  uw. year 4. 0 i. The products of Examples 42 to 47 are obtained in the syn- or anti-doping configuration. Examples of the products of Examples 42 to 47 are obtained in the syn- or anti-doping configuration. following the configuration of the 3-acetoxymethyl starting material shown in column I above. Similarly, when m is equal to one, the compounds are obtained in the form of α-sulfoxide or

  i-sulfoxide according to the orientation of the 3-acetoxy sulfoxide

  starting methyl. Moreover, when R1 and R2 are not

  identical products are obtained in the form D-, L-

  or D, L depending on the optical activity of the starting material

  indicated in column I above.

EXAMPLE 48

  Sodium salt of 5S [5S, 63,7a (Z)] - 3- [5S] oxide

  [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl [(1H-imidazol-2-

  yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo

  [4.2.0] oct-2-ene-2-carboxylic acid (β-sulphoxide, syn-isomer). The product of the Example can also be prepared.

2 by the following procedure.

  Dissolve in 35 ml of methylene chloride and

  Cools to 0 ° C. 1.69 g of [6R- [6a, 7 (Z)]] - 3- acid.

  [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-imidazol

  2-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo

  [4.2.0] oct-2-ene-2-carboxylic acid obtained as in Example 1 (e). 17 ml of trifluoroacetic acid are added with stirring. 0.459 g of m-chloroperbenzoic acid is added and stirring is continued for 2.5 hours. The solvent is removed in vacuo and about 400 ml of ether are added. The precipitate is filtered off and washed with ether to give 1.5 g of 5-oxide trifluoroacetate.

  [5S [5a, 61,7a (Z)]] - 3 - [(acetyloxy) methyl] -7 - [[(2-amino-4-

  thiazolyl [(1H-imidazol-2-yl-methoxy) imino] acetyl] amino] -8

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid having

a melting point of 160 to 165 C.

  This acid can be converted into its sodium salt

  by the procedure of Example 1 (f).

EXAMPLES 49 to 57

  By following the procedure of Example 48, the sulphides indicated in column I below can be oxidized.

  to the p-sulfoxides shown in column II below.

Collar. I

-NOT --'

H N- H2R4

  COOH n-R2 -N y-R 3 R5 Col. II H -y HR ll HH2R4 COOH R5 a one H1- H H- Hozz

H- ú HiD-

  Hl- a u% r n Co% 0 Nr úHD rSI 14I- lH- H- úel.- HD- EHD- úHi N s úIID-9- ú IS H- Id H- il- Zu Il- Ri- lu 0o aidu1ox4

HIN - O-

9IIN-D-O-

o '

ZHN- -O-

  H 9S aldwoaxS% ran o -r H- run H- a úHD- EHD- úH1D- 9H H- H- Il- úH úHoD- úHD- H- z U úH1D- IlI- il- 1 m il- A u The products of Examples 49 to 57 are obtained in the syn- or anti-configuration of the starting sulfide configuration shown in column I above. Moreover, when R1 and R2 are not identical, the products are obtained in the form of the D-, L- or D, L isomer depending on the optical activity of the indicated starting material.

in column I above.

  The acids obtained in Examples 1 to 57 can also be converted to various esterified forms (i.e. compounds in which R is

O O

  -CH2-O-C-C (CH3) 31 <,, etc.), according to modes

known operating procedures.

EXAMPLE 58

  Disodium salt of [6R- [6a, 713 (Z)]] - 3 - [(acetyloxy) -

  methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-tetrazol-5-ylmethoxy)]

  imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-

  2-Cyanomethoxy-1H-isoindole-1,3 (2H) -dione-2-carboxylic acid (i.e., syn-isomer) (i.e.) A solution in 400 ml dimethylformamide, 50 g of N-hydroxyphthalimide (0.31 mole), 25.4 g of chloroacetonitrile (0.34 mole) and 37.2 g (0.37 mole) of triethylamine. This solution is added to two liters of water. The precipitated compound is then filtered off, washed with water and

  to give 65.8 g of 2-cyanomethoxy-1H-isoindole-

  1,3 (2H) dione having a melting point of 150 to 152 C.

  b) 2- (1H-Tetrazol-5-ylmethoxy) -1H-isoindole-1,3 (2H) dione

  56.8 g of 2-cyanomethoxy-1H-isoindole are dissolved.

  1.3 (2H) dione (0.28 mol) in 500 ml of dry tetrahydrofuran.

  55.5 g of sodium azide (0.85 mol) are added to the stirred mixture. A solution of 40.1 g of aluminum chloride in 250 ml of dry tetrahydrofuran is added with cooling. The solution is kept at the reflux temperature for 32 hours. After cooling to 0 ° C., approximately 250 ml of 2N hydrochloric acid are added dropwise, followed by a quantity of water sufficient to form a clear solution. The organic layer is separated, then the aqueous sodium chloride layer is saturated and extracted twice with 200 ml portions of tetrahydrofuran. The combined organic layers are dried with sodium sulfate and concentrated to dryness. The oily residue is treated with alcohol and the tetrazole is filtered off.

  precipitated to obtain 2- (1H-tetrazol-5-yl-methoxy) -1H-

  isoindole-1,3 (2H) dione having a melting point of 227 to

228 C.

  c) 5 - [(Aminoxy) methyl] -1H-tetrazole hydrochloride

  70.8 g of 2- (1H) were refluxed with stirring.

  tetrazol-5-yl-methoxy) -1H-isoindole-1,3 (2H) dione (0.29 moles) in 700 ml of 20% aqueous hydrochloric acid. We cool

  the solution and filter. The filtrate is concentrated to dryness.

  150 ml of water are added and filtered. Evaporation from

  solvent gives 43 g of 5 - [(aminoxy) methyl] hydrochloride -

  1H-crude tetrazole, having a melting point of 1630C (alcohol

ether).

  (d) 2-amino-α - [(1H-tetrazol-5-ylmethoxy) imino] -4-

  thiazole acetic acid (syn-isomer) 1.0 g of hydrochloride are stirred for 24 hours at 50 [deg.] C.

  5 - [(aminoxy) methyl] -1H-tetrazole and 1.3 g of 2-

  formylamino-4-thiazole glyoxylic. The solution is then cooled to room temperature and the precipitated compound is filtered off to give 1.9 g of 2-amino-α - [(1H-tetrazol-5-ylmethoxy) imino] -4 thiazole acetic acid ( isomer syn-) having a melting point of 192 to

193 C (H20).

  e) Diphenylmethyl ester of [6R- [6a, 7 (Z)]] - 3- acid

  [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-tetrazol)

  1-methyl-methoxy) iminolacetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (syn-isomer)

  4 g of 2-amino-α - [(1H-tetrazol-5-yl)

  methoxy) imino] 4-thiazole acetic acid in 50 ml of dimethyl

  dry formamide, with 6.1 ml of monosilyltrifluoroacetamide at C for 15 minutes with stirring. To the cooled solution,

  7.5 g of 3-diphenylmethyl acid ester are added.

  [(Acetyloxy) methyl] -7-amino-8-oxo-5-thia-l-azabicyclo [4.2.0] -

  oct-2-ene-2-carboxylic acid in 100 ml of dry acetonitrile. The solution is cooled to 15 ° C. and 4.4 g of dicyclohexylcarbodiimide are slowly and dropwise added to 100 ml of acetonitrile, and the temperature is maintained for 12 hours. The urea formed is filtered off and the solvent is distilled off in vacuo. The residue is treated with 500 ml of a saturated aqueous solution of sodium chloride and extracted three times with 1 ml portions of ethyl acetate. The organic layers are extracted ten times with 30 ml portions of saturated aqueous sodium bicarbonate solution. The extracts are combined with sodium bicarbonate and 300 ml of ethyl acetate are added.

  and the mixture is acidified with 2N phosphoric acid.

  The aqueous layer is extracted once more with 100 ml of ethyl acetate. The organic extracts are dried with sodium sulfate and the solvent is removed in vacuo. The residue is dissolved in 50 ml of acetone and poured into a 2: 1 mixture of ethyl ether and petroleum ether with stirring. The precipitated diphenylmethyl ester is filtered off to give 5 g of diphenylmethyl acid ester.

  [6R- [6a, 7 (Z)]] - 3 - [(acetyloxy) methyl] -7 - [[(2-amino-4-

  thiazolyl) [(1H-tetrazol-5-yl-methoxy) imino] acetyl] amino] -8

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid,

  having a melting point of 138 to 143 C (decomposition).

  f) Trifluoroacetate of [6R- [6a, 75 (Z)]] - 3- [Acetyl-

  oxy) methyl] -7 - [[(2-amino-4-thiazolyl)] - (1H-tetrazol-5-yl)

  methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] -

  oct-2-ene-2-carboxylic acid (syn-isomer) 5 g of the diphenylmethyl ester of Example 1 (e) are suspended in 14 ml of anisole. The stirred solution is cooled to 0 ° C. At this temperature, 28 g of trifluoroacetic acid are added dropwise and the temperature is maintained at 0 ° C. for 30 minutes; 100 ml of methanol are added and the mixture is poured into one liter of ethyl ether, with vigorous stirring. The compound is filtered off and dried in vacuo to give 3.5 g of

  [6R- [6a, 7p (Z)]] - 3 - [(acetyloxy)] trifluoroacetate

  methyl--7 - [[(2-amino-4-thiazolyl) [(lH-tetrazol-5-yl-methoxy)

  imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-

  ene-2-carboxylic acid having a melting point of 130 to 135 ° C (decomposition).

  (g) Disodium salt of [6R- [6a, 75 (Z)]] - 3 - [(acetyloxy) -

  methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-tetrazol-5-yl-methoxy) -

  iminolacetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (syn-isomer) 5 g of the product of Example 1 (f) are dissolved in ml of a 1: 1 mixture of methanol and acetonitrile. 20 ml of a solution of 1N sodium ethylhexanoate in butyl alcohol are added and the mixture is poured into 500 ml of diethyl ether. The precipitated crude disodium salt is filtered off. The compound is about 60% pure and gives

  3.6 g of disodium salt of [6R- [6a, 75 (Z)]] - 3 - [(acetyl)

  oxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-tetrazol-5-yl

  methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] -

  oct-2-ene-2-carboxylic acid having a melting point greater than 300 C. A further purification is carried out by high performance liquid chromatography using a column solvent ('%' LiChrosorb RP 18 '' (10 pm ) "Hibor III" with a buffer consisting of a 52:48 mixture of CH30H and 2-

HPO4 0.01M.

EXAMPLE 59

  Disodium salt of [6R- [6a, 75 (E)]] - 3 - [(acetyloxy) -

  methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-tetrazol-5-yl-methoxy) -

  imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-

  ene-2-carboxylic (anti isomer)

  a) Ethyl ester of 2- (formylamino) -a - [(1H-)

  tetrazol-5-yl-methoxy) imino] -4-thiazole acetic acid (isomer). Stirred in anhydrous pyridine overnight.

  at 60 ° C, 3 g of 2-formylamino-4-ethyl-ethyl ester

  thiazoleglyoxylic acid and 2 g of 5- [(aminoxy) hydrochloride

  methyl 1H-tetrazole of Example 58 (c). The insoluble precipitate is filtered off and the filtrate is concentrated to dryness. The residue is chromatographed on silica gel with ethyl acetate as eluent. We

  2.9 g of 2- (formylamino) -acrylic acid ethyl ester are obtained.

  [(1H-tetrazol-5-ylmethoxy) imino] -4-thiazole acetic acid having

  a melting point of 88 to 96 ° C (CH 3 OH / H 2 O).

  (b) 2-amino-α - [(1H-tetrazol-5-ylmethoxy) imino] -4-

  thiazole acetic acid (isomer) 0.5 g of the product of Example 59 (a) are stirred for 40 hours in 6.6 ml of concentrated hydrochloric acid and 3.3 ml of water at 30 ° C. The compound crystallizes

  cooling to give 0.25 g of 2-amino-α - [(1H-

  tetrazol-5-yl-methoxy) imino] -4-thiazole acetic acid (isomer

  anti-) having a melting point of 174 C.

  (c) Diphenylmethyl ester of [6R- [6a, 7 (E)] - 3- acid

  [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-tetrazol

  1-methyl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (isomer)

  When treating 2-amino-α - [(1H-tetrazol-5-

  1-methoxy) imino] -4-thiazole acetic acid (isomer)

  the diphenylmethyl ester of 3 - [[acetyloxy) methyl] -

  7-amino-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2

  carboxylic acid according to the procedure given in the Example

  (E), the diphenylmethyl ester of the [6R-

  [6a, 71 (E)]] [(acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) - -

  [(1H-tetrazol-5-ylmethoxy) imino] acetyl] amino] -8-oxo-5-thia-

* 1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (isomer)

  having a melting point of 118 to 120 ° C (decomposition).

  (d) Disodium salt of [6R- [6a, 71 (E)] - 3 - [(acetyloxy) -

  methyl] -7 - [[(2-amino-4-thiazolyl) (1H-tetrazol-5-ylmethoxy) -

  imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-

  The treatment of the diphenylmethyl ester of Example 59 (c) with trifluoroacetic acid according to the procedure of Example 58 (f) results in the formation of the corresponding cephalosporanic acid, but under the

  anti-form (melting point 142 to 150 C) (decomposition).

  When this acid is treated with sodium ethyl hexanoate according to Example 58 (g), the disodium salt of

  [6R- [6a, 71 (E)] - 3 - [(acetyloxy) methyl] -7 - [[(2-amino)] -

  4-thiazolyl) [(lH-tetrazol-5-yl-methoxy) imino] acetyl] amino] -

  8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

  (anti isomer) having a melting point greater than 280 ° C.

EXAMPLE 60

  Disodium salt of [6R- [6a, 7 (Z)]] - 7 - [[2-amino-4-

  thiazolyl) [(1H-tetrazol-5-yl-methoxy) imino] acetyl] amino] -3-

  [[(1-methyl-lH-tetrazol-5-yl) thio] methyl] -8-oxo-5-thia-1-

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (i.e., syn-isomer)

  a) Ethyl ester of 2- (tritylamino) -a - [(1-

  benzoyl-1H-tetrazol-5-yl-methoxy) imino] -4-thiazole acetic acid (syn-isomer). 1.2 g is stirred together in room temperature in dimethylformamide (20 ml) overnight.

  2- (tritylamino) -α (oximino) acid ethyl ester

  thiazole acetic acid, 0.6 g of 1-benzoyl-5-chloromethyl-1H-

  Tetrazole and 0.5 g of potassium carbonate. 20 ml of acetone are added and the insoluble potassium chloride is filtered off. The mother liquor is concentrated to dryness and chromatographed in a silica gel column using a 3: 2: 1 mixture of ethyl acetate, chloroform and ether as eluent, to obtain

  1.4 g of 2- (tritylamino) -α- [(1-ethyl) ethyl ester

  benzoyl-1H-tetrazol-5-yl-methoxy) imino] -4-thiazole acetic acid

  (syn-isomer) having a melting point of 132 to 134 ° C.

  b) 2- (Amino) -α - [(1H-tetrazol-5-ylmethoxy) imino] -4-

  Thiazole acetic acid (syn-isomer) 1.4 g of the product of Example 60 (a) was stirred in 1 ml of 5% hydrochloric acid at room temperature overnight. The precipitate is separated by filtration and

  it is washed with ether to obtain 0.5 g of 2- (amino) -acetic acid.

  [(1H-tetrazol-5-ylmethoxy) imino] -4-thiazole acetic acid

(syn-isomer).

  (c) Disodium salt of [6R- [6a, [7i (Z)] - 7 - [[(2-amino)]

  4-thiazolyl) [1H-tetrazol-5-ylmethoxy) imino] acetyl] amino] -3-

  [[(1-methyl-lH-tetrazol-5-yl) thio] methyl] -8-oxo-5-thia-1-

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (syn-isomer) When the carboxylic acid of Example 60 (b) is reacted as described in Example 58 (e)

  using the diphenylmethyl ester of 7-amino-3-

  [[(L-methyl) -LH-tetrazol-5-yl) thio] methyl] -8-oxo-5-thia-1-

I- i.- - -

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid instead of ester

  3 - [(acetyloxy) methoxy] -7-amino acid diphenylmethyl

  8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, after which the protective ester portion is cut as described in Example 58 (f) and the the disodium salt is then formed as described in Example 58 (g), the

  Disodium salt of [6R- [6a, 7B (Z)]] - 7-f [(2-amino-4-)

  thiazolyl) - [(1H-tetrazol-5-ylmethoxy) imino] acetyl] amino -3-

  [[(1-methyl-lH-tetrazol-5-yl) thio] methyl--8-oxo-5-thia-1-

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, having a

  melt from 240 to 245 C (decomposition).

EXAMPLE 61

  Disodium salt of [6R- [6u, 7 (E)]] - 7 - [[(2-amino-4-)

  thiazolyl) [(1H-tetrazol-5-yl-methoxy) imino] acetyl] amino] -3-

  [[(1-methyl-lH-tetrazol-5-yl) thio] methyl] -8-oxo-5-thia-1-

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (i.e., anti isomer). The corresponding anti isomer is obtained by treating

  2-amino-α - [(1H-tetrazol-5-ylmethoxy) imino] -4-

  acetic thiazole (anti isomer) of Example 59 (b), as

described in Example 60 (c).

EXAMPLE 62

  Disodium salt of [6R- [6a, 7f (Z)]] - 3 - [(acetyloxy) -

  methyl] -7 - [[(2-amino-4-thiazolyl) [(lH-tetrazol-5-yl

  dimethylmethoxy) imino] acetyl] amino] -8-oxo-5-thia-1-

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (i.e., syn-isomer)

  When treating 5- [1- (aminoxy) -1-hydrochloride

  methylethyl] -1H-tetrazole (which is obtained by replacing

  in Example 58 (a) chloroacetonitrile by bromine

  isobutyronitrile and then the compound formed is treated as in Examples 58 (b) and 58 (c)) as described in Examples 58 (d), 58 (e), 58 (f) and 58 (g) , we get the salt

  disodium of [6R- [6a, 7g (Z)]] - 3 - [(acetyloxy) methyl] -7-

  [[(2-amino-4-thiazolyl)] (1H-tetrazol-5-yl-dimethylmethoxy) -

  imino] acetyl] amino] -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-

ene-2-carboxylic acid.

EXAMPLE 63

  Sodium salt of [6R- [6a, 7 (Z)] - 1-3 - [(acetyloxy) -

  methyl] -7 - [[(2-amino-4-thiazolyl) [(l-methyl-lH-tetrazol-5-

  yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-l-azabicyclo

  [4.2.0-L-2-ene-2-carboxylic acid (syn-isomer) a) 2- (1-methyl-1H-tetrazol-5-yl-methoxy) -1H-isoindole-1,3 (2H) -dione

  5 g of the 2 - (] H- are stirred at room temperature.

  tetrazol-5-yl-methoxy) -1H-isoindole-1,3 (2H) dione of Example 58 (b) at room temperature in 50 ml of dimethylformamide with 5 g of methyl iodide in the presence of 5 g of potassium carbonate for 24 hours. The insoluble inorganic precipitates are filtered off, the mother liquor is concentrated to dryness and crystallized.

  the residue with alcohol to obtain 4.8 g of 2- (1-

  methyl-lH-tetrazol-5-yl-methoxy) -LH-isoindole-1,3 (2H) dione

  having a melting point of 128 to 130 C.

  b) 5 - [(Aminoxy) methyl] -1-methyl-1H-tetrazole hydrochloride Using the procedure of Example 58 (c)

  in which 2- (1H-tetrazol-5-yl-methoxy) -1H-

  iso-indole-1,3 (2H) dione by 2- (1-methyl-1H-tetrazol-5-

  1-methoxy) -1H-iso-indole-1, 3 (2H) dione, the

  5 - [(aminoxy) methyl] -1-methyl-1H-tetrazole hydrochloride.

  (c) Sodium salt of [6R- [6a, 7p (Z)]] - 3 - [(acetyloxy) -

  methyl] -7 - [[2-amino-4-thiazolyl) [(1-methyl-lH-tetrazol-5-

  yl-methoxy) iminolacétyl] amino] -8-oxo-5-thia-l-azabicyclo

  [4.2.0Ooct-2-ene-2-carboxylic acid (syn-isomer)

  When treating 5 - [(aminoxy) hydrochloride -

  methyl-1-methyl-1H-tetrazole of Example 63 (b) by 2formylamino-4-thiazoleglyoxylic acid as described in Example 58 (d), the corresponding syn-isomer of

  2-amino-α - [(1-methyl-1H-tetrazol-5-yl-methoxy) -

  imino] -4-thiazole acetic acid which is treated as described in Example 58 (e), 58 (f), 58 (g). By this way, we obtain the

  sodium salt of [6R- [6a, 7p (Z)]] - 3 - [(acetyloxy) -

  methyl] -7 - [[2-amino-4-thiazolyl) [(1-methyl-1H-tetrazol) -5-yl)

  methoxy) imino] acetyl] -amino-8-oxo-5-thia-1-azabicyclo [4.2.0] -

  oct-2-ene-2-carboxylic acid (syn-isomer).

EXAMPLE 64

  Disodium salt of [5S- [5a, 61,7a (Z)] 5-oxide 5-oxide

  [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) - [(lH-tetrazol

  (N-methylmethoxy) imino] acetyl] amino] -8-oxo-5-thi-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (g-sulfoxide, syn-isomer) is suspended in 20 ml of dry methylene chloride and cooled to 0 10 mmol of the acid

  [6R- [6a, 7 (Z)]] - 3 - [(acetyloxy) methyl] -7 - [[(2-amino-4-

  thiazolyl) [(1H-tetrazol-5-yl-methoxy) imino] acetyl] amino] -8

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

  Example 58 (f). To 0, 10 ml of trifluoric acid is added.

  acetic acid and stirring is continued until dissolution is complete. 10 mmol of m-chloroperbenzoic acid are then added and the solution is stirred at 0 for 3 hours. The solvent is removed in vacuo and the residue is stirred with ethyl acetate and filtered. The precipitate is then dissolved in a 1: 1 mixture of methanol and

  of acetone and an equivalent amount of ethyl-

  sodium hexanoate in butyl alcohol (1N solution), and the solution is stirred. After 10 minutes, the mixture is poured into 200 ml of diethyl ether and the precipitated compound is filtered off to obtain the salt.

  disodium 5-oxide [5S- [5a, 6p, 7a (Z)]] - 3-

  [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-tetrazol)

  1-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0-O] oct-2-ene-2-carboxylic acid (p-sulfoxide, syn-isomer)

  having a melting point of 250 to 256 C.

EXAMPLE 65

  Disodium salt of 5S- [5a, 6p, 7a (Z)]] - 5-oxide acid

  [(Acetyloxy) methyl-7 - [[(2-amino-4-thiazolyl) (1H-tetrazol-5-

  yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-l-azabicyclo

  [4.2.0] oct-2-ene-2-carboxylic acid (} 3-sulfoxide, syn-isomer)

  a) Diphenylmethyl ester of [5S- [5a] 5-oxide,

  6r, 7a] -3 - [(acyloxy) methyl] -7-amino-8-oxo-5-thia-1-aza;

  bicyclo [4.2.01oct-2-ene-2-carboxylic acid (i.e. 5-

  sulfoxide) and diphenylmethyl ester of 5-oxide of the acid

  [5R- [5a, 6a, 7d] -3 - [(acétyl1oxy) methyl] -7-amino-8-oxo-5-thia-

  1-azabicyclo [4-2-O] oct-2-ene-2-carboxylic acid (i.e.

  sulfoxide) A suspension of 50 g of 7-aminocephalosporanic acid (7-ACA) in a liter of water is magnetically stirred.

  at the same time as one adds drop by drop of

  octylamine, which has the effect of maintaining the pH between 7 and 8. After one hour, the undissolved solid is filtered on "CELITE" and the filtrate is treated with a solution prepared by adjusting to pH 8.0, using 6N hydrochloric acid, a mixture of 10 ml of tert-octylamine and 20 ml of water. The resulting solution is then treated with 10 ml of salicylaldehyde. After two minutes, a solid is formed,

  and after five minutes another 10 ml of salicylate is added.

  aldehyde. The suspension is stirred for a further 10 minutes, cooled to 0 for 4.5 hours and filtered. The filter cake is stirred twice with 300 ml of cold water and filtered. The cake, still wet, is dried under vacuum over a large amount of phosphoric anhydride to obtain 66 g of 7-salicylaldiminococephalosporanic acid tert-octylamine salt in the form of a

solid beige color.

  A suspension of 25.25 g (0.05 mole) of the above tert-octylamine salt (pulverized with a mortar and pestle) is treated in 250 ml of dry acetonitrile,

  9.5 g (0.05 mole) of para-toluenesulfonic acid monohydrate.

  After 10 minutes, a solution of 9.7 g (0.05 mol) of diphenyldiazomethane in 50 ml of acetonitrile is added over 15 minutes. After one hour, the suspension is filtered, the solid is washed with acetonitrile, and the combined filtrate and washings are concentrated under vacuum. The resulting oil is chromatographed in a column of 300 g of silica gel which is eluted with methylene chloride. Fractions 2 and 3 (500 ml) contain 7.5 g of the desired diphenylmethyl ester plus a little higher Rf impurity (controlled by TLC on silica gel with development using a mixture of 3: 1 of chloroform and ethyl acetate); Fractions 4 to 11

  contain 12.3 g of diphenylmethyl acid ester 7-

  pure salicylaldiminocéphalosporanique; NMR (CDCl3) δ 1.97 (s, 3H, CH3CO); 3.23 and 3.60 (AB q, J = 19 Hz, 2H, C-2); 4.67 and 5.01 (AB q, J = 14 Hz, 2H, C-3 '); 4.99 (d, J = Hz, 1H, C-6); 5.20 (broadened d, J = 5 Hz, 1H, C-7); 6.62 -

  7.60 (m, about 15H); 9.07 (broad s, 1H, -CH = N-).

  A solution of 12.3 g (0.023 mol) of the diphenylmethyl ester obtained above in ml of methylene chloride is cooled to 0 and added in 15 minutes.

  a solution of 4.6 g (0.023 mole) of m-chloroper-

  benzoic acid at 85% in 70 ml of methylene chloride. After one hour, the suspension is washed with a mixture of 100 ml of 5% sodium bicarbonate and 50 ml of a 6% sodium sulphite solution. The organic layer is dried and concentrated in vacuo. The resulting oil crystallized from 70 ml of ethyl acetate to give 8.7 g of a mixture of α- and 5-sulfoxides. We also obtain

  a second harvest of 1.5 g of a mixture of a- and 5-

  sulfoxides. The major isomer (a) has a methyl acetate (2.02 ppm) and a C-2 quartet (3.57 and 4.10 ppm) lower field than those of the minor isomer (<) (1). , 97, 3.26 and

3.94 ppm, respectively).

  A suspension of 10 g (0.018 mol) of

  above mixture of α- and β-diphenyl ester sulfoxides

  7-salicylaldiminococephalosporanic acid methyl ester in ml of ethyl acetate, by 3.42 g (0.018 mole) of para-toluenesulphonic acid monohydrate. After 3.5 hours, 300 ml of ether are added and the rubbery solid is triturated, filtered and washed twice with ether. The remaining wet solid is dissolved in 200 ml of ethyl acetate and the solution is washed with 100 ml of 5% sodium bicarbonate solution, dried and evaporated to obtain 8.0 g of residue. . Column chromatography in a column of 300 g of silica gel eluted with a 3: 1 mixture of chloroform and ethyl acetate gives

  (fractions of 500 ml): fraction 3, 1.0 g of diphenyl ester

  recovered 7-salicylaldiminocéphalosporanic acid methyl; fractions 6 to 16, 4.5 g of diphenylmethyl ester

  5R- [5a, 6a, 73i]] - 3 - [(acetyloxy) methyl] 5-oxide oxide

  amino-8-oxo-5-thia-1-azabicyclo [4.2.0-oct-2-ene-2-carboxylic acid (i.e., isomer α-sulfoxide): NMR (CDCl3) δ 2.00 (CH3COO-); 3.43 and 4.06 ppm (AB q, C-2); Fractions 22 to 30 (the eluent for ethyl acetate is changed after fraction 16): 1.5 g of 5-oxide-diphenylmethyl ester

  [5S- [5a, 61,7a]] - 3 - [(acetyloxy) methyl] -7-amino-8-oxo-5-thia-

  1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (i.e. isomer 3sulfoxide): NMR (CDCl3) δ 2.10 (CH3COO-); 2.97

and 3.54 ppm (AB q, C-2).

  b) Diphenylmethyl ester of [5S- [5a] 5-oxide,

  6F, 7a (Z)]] - 3 - [(acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl)] -

  (1H-tetrazol-5-yl-methoxy) imino] acetyl] amino-8-oxo-5-thia-1-

  azabicyclo [4.2.01] oct-2-ene-2-carboxylic acid 2-amino-α - [(1 H -tetrazol-5-ylmethoxy) imino] -4 thiazole acid is dissolved in 50 ml of dimethylsulfoxide.

  acetic acid of Example 58 (d), the diphenylmethyl ester of

  sulfoxide of part (a), and N-hydroxybenzotriazole.

  After addition of 25 ml of acetonitrile, the

  solution at 0 with stirring. Dicyclohexyl-

  carbodiimide and stirring is continued at 0 for 15 hours. At the end of this time, the insoluble urea is filtered off. The mother liquor is poured on ice and the resulting precipitate is filtered off and washed with water. The crude product is suspended in 20 ml of a cold aqueous solution of sodium bicarbonate and extracted three times with methyl ethyl ketone. The aqueous phase is filtered and acidified with phosphoric acid

  cold, and extracted three more times with methyl-

  ethyl ketone. The organic layers are combined, dried, and the solvent is distilled off. The residue is dissolved in a few milliliters of methanol and poured into diethyl ether to give the acidic diphenylmethyl ester as a precipitate.

  [5S- [5a, 6f3,7a (Z)]] - 3 - [(acetyloxy) methyl] -7 - [[(2-amino-4-

  thiazolyl) (lH-tetrazol-5-yl-methoxy) imino] acetyl] amino] -8

  oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

  (c) Disodium salt of 5S - [5a, 66,7a (Z)] 5-oxide acid -

  3 - [(acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) (lH-tetrazol

  Methyl-methoxy) iminolacetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (F-sulfoxide, syn-isomer) The diphenylmethyl ester obtained is in part (b) suspended in 3 ml of anisole at 0, and

  slowly add 6 ml of trifluorinated acid

  acetic, shaking. After the addition is complete, the mixture is stirred for a further hour at 00. The solution is then poured into 200 ml of diethyl ether, with stirring, to give the acid in the form of a precipitate.

  [5S- [5a, 6,7u (Z)]] - 3 - [(acetyloxy) methyl] -7 - [[(2-amino-4-

  thiazolyl) (1H-tetrazol-5-ylmethoxy) imino] acetylamino] -8-

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

  This acid is dissolved in 20 ml of methanol and an equivalent amount of 1N sodium ethylhexanoate in butanol is added at 0 with stirring. After 30 minutes, 200 ml of ether are added, which precipitates the salt.

  disodium salt of 5S- [5a, 6,7a (Z)]] - 5-oxide

  [(Acetyloxy) methyl-7 - [[(2-amino-4-thiazolyl)] 1H-tetrazol

  -yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid, m.p. 250-256 C (decomposition).

EXAMPLE 66

  Disodium salt of [5R- [5a, 6a, 7'P (Z)]] - 5-oxide acid

  [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-tetrazol)

  1-methyl-methoxy) imino] acetylaminol-8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (α-sulfoxide, syn-isomer)

  a) Diphenylmethyl ester of [5R- [5a] 5-oxide,

  6a, 7 (Z)], 3 - [(acetyloxy) methyl-7 - [[(2-amino-4-thiazolyl)] -

  (1H-tetrazol-5-yl-methoxy) iminolacétyl] amino] -8-oxo-5-thia-

  1-azabicyclo [4.2.01oct-2-ene-2-carboxylic acid

  2-Amino-α - [(1H-tetrazol) acid is reacted with

  5-yl-methoxy) iminol-4-thiazole acetic acid and the diphenylmethyl ester of asulfoxide of Example 65 (a)

  presence of N-hydroxybenzotriazole and dicyclohexylcarbonyl

  diimide, according to the procedure of Example 65 (b), to obtain the diphenyl dimethyl ester of 5-oxide of the acid

  [5R- [5a, 6a, 7 (Z) -]] 3 - [(acetyloxy) methyl--7 - [[(2-amino-4-

  thiazolyl) [(1H-tetrazol-5-ylmethoxy) imino] acetyl] amino] -8-

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

  (b) Disodium salt of [5R- [5a, 6a, 7p (Z)] - 3- [5R] -3-oxide

  [(Acetyloxy) methyl--7 - [[(2-amino-4-thiazolyl) [- (l (-tétrazol-

  1-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (α-sulfoxide, syn-isomer) Diphenylmethyl ester is treated of part (a) with anisole and trifluoroacetic acid at 0, according to the procedure of Example 65 (c) to obtain

  5R- [5a, 6a, 7 (Z)]] - 3 - [(acetyloxy)] - 5-oxide

  methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-tetrazol-5-yl-methoxy) -

  imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-

ene-2-carboxylic acid.

  This acid is treated with sodium ethyl hexanoate to give the disodium salt of the 5-oxide of the acid.

  [5R- [5a, 6a, 7f (Z)]] - 3 - [(acetyloxy) methyl] -7-r [(2-amino-4-

  thiazolyl) (1H-tetrazol-5-ylmethoxy) imino] acetyl] amino-8-

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

EXAMPLE 67

  Disodium salt of 5S-a, 65,7a (Z)] 5-oxide acid [- (2-

  amino-4-thiazolyl) (1H-tetrazol-5-yl-methoxy) imino] acetyl] -

  amino] -3 - [[(1-methyl-lH-tetrazol-5-yl) thio] methyl] -8-oxo-5-

  thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (.sulfoxide, syn-isomer) a) Diphenylmethyl ester of 5S- [5a, 65,

  7a] 1-7-amino-3 - [[(1-methyl-lH-tetrazol-5-yl) thio] methyl] -8

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (i.e., psulfoxide) and diphenylmethyl ester of 5-r-[5a, 6a] 7 '] -7-amino-3 - [[(1-methyl)

  1H-tetrazol-5-yl) thio] methyl] -8-oxo-5-thia-1-azabicyclo

  [4.2.0] oct-2-ene-2-carboxylic acid (i.e., α-sulfoxide) Following the procedure of Example 65 (a)

  but replacing 7-ACA with 7-amino-3 - [[(1-

  methyl-lH-tetrazol-5-yl) thio] methyl] -8-oxo-5-thia-1-aza-

  bicyclo [4.2.0] oct-2-ene-2-carboxylic acid, a mixture of the desired sulphoxides is obtained, which is then separated by chromatography to obtain the α-sulphoxide and the i-sulphoxide.

separately.

  b) Diphenylmethyl ester of [5S- [5a] 5-oxide, 65, -

  7a (Z)]] - 7 - [[(2-amino-4-thiazolyl) - (1H-tetrazol-5-yl-methoxy) -

  imino] acetyl] amino] -3 - [[(1-methyl-lH-tetrazol-5-yl) thio] -

  methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2

  carboxylic acid It is dissolved in 100 ml of dimethylsulfoxide and 50 ml

  of acetonitrile 1 g of 2-amino-α - [(1H-tetrazol-5-yl)

  methoxy) imino] -4-thiazole acetic acid from Example 58 (d),

  1.82 g of diphenylmethyl ester of 5-oxide acid [5S-

  [5a, 6k, 7a] 1-7-amino-3 - [[(1-methyl-lH-tetrazol-5-yl) thio] -

  methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2

  carboxylic acid (i.e., sulfoxide) of part (a), and 0.52 g of N-hydroxybenzotriazole. The solution was cooled to 0 ° and 1.04 g of dicyclohexylcarbodiimide in 20 ml of acetonitrile was added dropwise with stirring. The temperature is kept at 0 for 12 hours. At the end of this time, the insoluble urea is filtered off. The mother liquor is poured into 500 ml of ice water and the precipitated product is filtered off, washed with water and dried to give the 5-oxide diphenylmethyl ester.

  [5S- [5a, 6,7a (Z)]] - 7 - [[(2-amino-4-thiazolyl)] - [1H-

  tetrazol-5-yl-methoxy) imino] acetyl] amino] -3 - [[(1-methyl-lh-

  tetrazol-5-yl) thio] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] -

oct-2-ene-2-carboxylic acid.

  (c) Disodium salt of [5S- [5a, 65,7a (Z)] 5-oxide -

  7 - [[(2-amino-4-thiazolyl) (1H-tetrazol-5-ylmethoxy) imino] -

  acetyl] amino] -3 - [[(1-methyl-lH-tetrazol-5-yl) thio] methyl] -8

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (f-

  sulfoxide, isomer syn-) The diphenylmethyl ester obtained in part (b) is suspended in 0 in 3 ml of anisole. All in

  stirring vigorously, 6 ml of trifluorinated

  acetic acid and stirring is continued for another hour.

  The resulting solution is poured into 500 ml of diethyl ether and the crystalline product is separated by

  filtration to obtain the 5-oxide of 5S- [5a, 6p, -

  7a (Z)] - 7 - [[(2-amino-4-thiazolyl) (1H-tetrazol-5-yl-methoxy)]

  imino] acetyl] amino-3 - [[(1-methyl-lH-tetrazol-5-yl) thio] -

  methyl] -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2

  carboxylic acid. This acid is converted to its disodium salt by suspending the acid in 10 ml of methanol and adding 6.3 ml of a 1N solution of sodium ethylhexanoate in butanol. The mixture is stirred for 30 minutes and then diluted with 200 ml of ether to crystallize the mixture.

  disodium salt of 5S- [5a, 63,7a (Z) [- 7-]

  [[(2-amino-4-thiazolyl) (1H-tetrazol-5-yl-methoxy) iminolacétyl] -

  amino] -3 - [[(1-methyl-lH-tetrazol-5-yl) thio] methyl] -8-oxo-5-

  thia-l-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

EXAMPLE 68

  Disodium salt of [5R- [5a, 6a, 75 (Z)] -5-oxide-5-oxide

* [[(2-amino-4-thiazolyl) [(1H-tetrazol-5-ylmethoxy) imino] -

  acetyl] amino] -3 - [[(1-methyl-lH-tetrazol-5-yl) thio] methyl] -8

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (a-

sulfoxide, syn-isomer

  a) Diphenylmethyl ester of [5R- [5a, 6a] 5-oxide

  7 (Z)]] - 7 - [[(2-amino-4-thiazolyl) [(1H-tetrazol-5-ylmethoxy)] -

  imino] acetyl] amino] -3 - [[(1-methyl-lH-tetrazol-5-yl) thio] -

  methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2

  Carboxylic acid Following the procedure of Example 67 (b)

  but replacing the 5-sulfoxide with the diphenyl ester

  [5R- [5a, 6a, 7]] -7-amino-3-methyl-5-oxide

  methyl] H-tetrazol-5-yl) thio] methyl] -8-oxo-5-thia-1-aza-

  bicyclo [4.2.0] oct-2-ene-2-carboxylic acid of Example 67 (a), the diphenylmethyl ester of 5-oxide of the acid is obtained

  [5R- [5a, 6a, 7g (Z)]] - 7 - [[(2-amino-4-thiazolyl)] (1H-tetrazole)

  1-methyl-methoxy) imino] acetyl] amino] -3 - [[(1-methyl-1H-tetrazol-yl) thio] methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0-oct-2] -En-2-carboxylic acid.

  (b) Disodium salt of [5R- [5a, 6a, 75 (Z)] 5-oxide 5-oxide

  [[(2-amino-4-thiazolyl) [(1H-tetrazol-5-yl-methoxy) imino] -

  acetyl] amino] -3 - [[(1-methyl-lH-tetrazol-5-yl) thio] methyl--8-

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (a-

  sulfoxide, isomer syn-) The diphenylmethyl ester obtained in

  part (a) with anisole and trifluorinated acid

  acetic acid at 0, according to the procedure of Example 10 (c),

  to obtain the 5-oxide of [5R- [5a, 6a, 71 (Z)]] - 7-

  [[(2-amino-4-thiazolyl) [(1H-tetrazol-5-yl-methoxy) imino] -

  acetyl] amino] -3 - [[(1-methyl-lH-tetrazol-5-yl) thio] methyl] -8

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. This acid is converted into its disodium salt by treating it with sodium ethylhexanoate to obtain the

  disodium salt of [5R- [5a, 6a, 7p (Z)] 5-oxide 5-oxide

  [[(2-amino-4-thiazolyl) [(l1H-tetrazol-5-yl-methoxy) imino] -

  acetyl] amino] -3 - [[(1-methyl-lH-tetrazol-5-yl) thio] methyl] -8

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

EXAMPLE 69

  Disodium salt of 5,5-dioxide acid [6R- [6a, 7p (Z)]] - 3-

  [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-tetrazol

  1-methyl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (syn-isomer)

  a) Diphenylmethyl ester of 5,5-dioxide of [6R-

  [6a, 73]] - 3 - [(acetyloxy) methyl] -7-amino-8-oxo-5-thia-1-

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid The diphenylmethyl 5-oxide ester is added

  of [5R- [5a, 6a, 7g]] - 3 - [(acetyloxy) methyl] -7-amino-8-

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid of Example 65 (a) to methylene chloride and cooled to

  0. An equimolar amount of m-chloroper-

  benzole in methylene chloride. After completion of the reaction, the slurry is treated with 5% sodium bicarbonate and 5% sodium sulfite. The organic layer is dried and concentrated in vacuo. Thin layer chromatography preparation of the residue gives the diphenylmethyl ester of the acid 5,5-dioxide

  [6R- [6a, 73]] - 3 - [(acetyloxy) methyl] -7-amino-8-oxo-5-thia-1-

  azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

  (b) Diphenylmethyl ester of 5,5-dioxide [6R-

  [6ac, 7 (Z)]] - 3 - [(acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) -

  [(1H-tetrazol-5-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-

  1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

  The 2-amino-α - [(1H-tetrazol-5-yl)

  methoxy) imino] -4-thiazole acetic acid of Example 1 (d) and

  Diphenylmethyl ester of 5,5-dioxide of acid [6R- [6a, -

  7g] | -3 - [[(acetyloxy) methyl] -7-amino-8-oxo-5-thia-l-azabicyclo

  [4.2.0] oct-2-ene-2-carboxylic acid of part (a) in the presence of N-hydroxybenzotriazole and dicyclohexylcarbodiimide,

24678S4

  according to the procedure of Example 65 (b), to obtain

  the diphenylmethyl ester of 5,5-dioxide of the acid [6R-

  [6a, 7P3 (Z)]] - 3 - [(acetyloxy) methyl] -7 - [[(2-amino-4-

  thiazolyl) [(1H-tetrazol-5-yl-methoxy) imino] acetyl] amino] -8

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.

  (c) Disodium salt of 5,5-dioxide of [6R- [6a, 7 (Z) 11]] -

  3 - [(acetyloxy) methyl-7 - [[(2-amino-4-thiazolyl) [(1H-tetrazol

  [Methyl] methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (syn-isomer). The diphenylmethyl ester obtained in the part (b) with anisole and trifluoroacetic acid at 00, according to the procedure of Example 65 (c), for

  obtain 5,5-dioxide of [6R- [6a, 7 (Z)]] - 3 - [(Acetyl)

  oxy) methyl] -7 - [[(2-amino-4-thiazolyl) (1H-tetrazol-5-yl)

  methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] -

  oct-2-ene-2-carboxylic acid. This acid is converted into its disodium salt by treating it with sodium ethylhexanoate to obtain the

  disodium salt of 5,5-dioxide acid [6R- [6a, 70 (Z)] J-3-

  [(acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-tetrazol-5-

  yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo

[4.2.0] oct-2-ene-2-carboxylic acid.

EXAMPLES 70 to 95

  Following the procedure of Examples 58 to 63 and 65 to 69 but using the ester indicated in column I below and the acid indicated in column II below,

  the ester indicated in column III below is obtained.

  Removal of the ester protecting group gives as

  produces the acid indicated in column IV below.

Collar. I R16 (V m

H2N -

COOR 21

  Collar. II Hzenk s i-COOH Col. III _fi> R16 (<)

H2N N - \ H2X

  2% 0 2I oCOOR21 R -A Col. IV R16 (m

N C C N

2S N O CH2X

o OOH

R (C) -R

  RN N = - N a 0: [3Z a o: gz a oWaz a o-gz a xnap Ln w> a Oeaz a 0oaz a xnap u H- H- H- H- H- H- H- H- H -% s 0 1 a wi H- H- H- SHZD_ H- H-

ú HID-

H100o-

  H-E HD_H- H- HE_H- H- úHD- H- H- Eú H- H- H- H- H-

úEHDO-

H- H_ 9 T

(<) HD-

z ((<- HD-

z (eD HO-

(H> ED-

(SHO-

(<HD-

EHDO - EHD-

E (EHD) D-

E (<-HD-

I Zd H He

 HZE- -O-

o

EHD-D-O-

EHID-D-0-

IHD-D-O-

úEID -_- O-

úHDO-D-O-

  X * X Do Atu N 8L LL 9L SL PL EL úL IL OL a; ld ua x an otaz an az an olaz an olaz a xnap a xnap o; gz a o.az u ui

an H-HOOD-

H- H- H- H- H- H- H- H- Sl1 H H- H-

EúH D-

H- úHD- H- H- H- H- ú% H- H-

ú HDO-

  H- H- H- H- H- H- úHD- H- H- H- H- H-

z (HO) -

z (v HD-

(+ HD-

((HD-

Z (has H-

z IDZ -HD úHDS- I -V

úHDY, S T S-

S-úHD-Si SlS N-N

EHN-D-O-

e4

ZHN-D-O-

0f

UEIN-D-O-

HMN-D-O-

  X x te N Co% O <'a ú8 S8 ú8 Z8 6L olduld.ax

H-z (11D-

an o.az H-

an oasis H

an oasis H-

úHa-

SH zD ..

H- Z (<Ha-

H- Z () -H-

Hú OSZHD

s-

- N- N

  úHD úHD N N-N -N-N an ozOZ an o.az ST- _ _ Id

H-11OOD-

H- úHD; O-

H- Z (<Ha-

ITE

7 EU

qr Co r- NiNS úHD I N-N úHD I

N ---- N

X eTdTuaxz

H_ z (HO-

z (HD-

9r- E X

-CH-)) 2

-CH2--

N - N - S 1 9i

LH2COOH

N-N h

N-N-CH- 6) 2

(-S H2) 2N CH3) 2

(& 2) 2N (CH 3) 2

  R16 -H -H -H R13 -H -H -H R14 -H -H -H R m n -H zero -H a -H zero

Example

  The acids obtained in Examples 70 to 95 can be converted into their sodium or potassium salts in accordance with

known procedures.

  The products of Examples 70 to 95 are obtained as the syn- or anti-isomer according to the configuration of the acid indicated in column II above. Moreover, when R13 and R14 are not identical, the products are obtained in the form D-, L- or D, L depending on the activity.

  optical acid indicated in column II above.

EXAMPLE 96

  [6R- [6a, 7 (Z) i]] - 3 - [[4- (aminocarbonyl) pyridino] methyl acid] -

  7 - [[(2-amino-4-thiazolyl) [1H-tetrazol-5-ylmethoxy) imino] -

  acetyl] amino] -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-ene-2

  carboxylic acid (syn-isomer) A mixture of 0.005 mole of the disodium salt obtained in Example 58, 0.075 mole of 4-pyridinecarboxamide, 12 g of sodium thiocyanate and 7.5 ml of sodium hydroxide was heated at 50 for 24 hours. 'water. The resulting solution was passed through a chromatography column packed with "Amberlite XAD-2". This column is washed with water and the title compound is eluted with an 8: 2 mixture of water and methanol. The methanol is evaporated from the eluate and the aqueous solution is lyophilized. The amorphous residue is triturated with ether and filtered under suction to obtain

  [6R- [6:, 7- (Z) 11-3 - [[4- (aminocarbonyl) pyridino] acid -

  methyl] -7 - [[(2-amino-4-thiazolyl) [(lH-tetrazol-5-yl-methoxy) -

  imino] acetyl] amino] -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-

ene-2-carboxylic acid.

EXAMPLES 97-104

  Following the procedure of Example 96 but using the cephalosporanic acid sodium salt which is indicated in column I below and the pyridine derivative which is indicated in column II below,

  obtain the product indicated in column III below.

  Collar. I - R16 COONa Col. II X Col. III R16 H2N '(o) m 1m> as 04 go

-0 - CH3

o () ZHND-oIDZEHD-H-H-H-POT

(aH-oHpz H- H-H-

HND-E0

  () ZHN-oazH-HD-EHD-H-o (1) 1H-NH-H-H-H-O-O-OH ## STR2 ## The products of Examples 97 to 104 are obtained in the syn-configuration. or anti-following the configuration of the 3-acetoxymethyl starting material which is indicated in column I. As well, when m is equal to one, the compounds are obtained in the form of asulfoxide or Q-

  sulfoxide according to the orientation of the 3-acetoxy sulfoxide

  starting methyl. Moreover, when R13 and R14 are not identical, the products are obtained in the D-, L- or D-isomer form, depending on the optical activity of the starting material.

  indicated in column I above.

EXAMPLE 105

  Disodium salt of [6R- [6a, 7f (Z)]] - 7 - [[(2-amino-4-)

  thiazolyl) [(l1H-tetrazol-5-yl-methoxy) iminolacétyl] amino] -3-

  [[(5-methyl-1,3,4-thiadiazolyl) thio] methyl] -8-oxo-5-thia-1-

  azabicyclo [4.2.0.] oct-2-ene-2-carboxylic acid The 0.002 mole of the disodium salt obtained in Example 58 is dissolved in 100 ml of a buffer of

  phosphate at a pH of 6.4. Then 0.0024 mole of 5-

  methyl-1,3,4-thiadiazolyl-2-thiol. The solution is heated at 600 for six hours. After cooling, the pH is adjusted to 7.0 and the solution is subjected to ion exchange resin chromatography "Amberlite XAD-2". The fraction containing the product is freeze-dried

  to obtain the disodium salt of [6R- [6a, 7P-]

  (Z) I]] - 7 - [[(2-amino-4-thiazolyl) [(1H-tetrazol-5-yl-methoxy) -

  imino] acetyl] amino] -3 - [[(5-methyl-1,3,4-thiadiazolyl) thio] -

  methyl] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2

carboxylic acid.

EXAMPLES 106 to 111

  Following the procedure of Example 105 but using the cephalosporanic acid sodium salt indicated in column I below and the thiol shown in column II below, the product indicated in

column III below.

  Collar. I and R16 Y Vm R1j (C) n-R14 R1 -N1 N N -N Col. II HS-heterocycle Col. III

R16 (O)

  C-C- He l l fCC | NI N H d-N. CH2-S-heterocycle 2 I COONa R1 (C) n-R14 R1NNN Co wr z (EHD) NZ (zHD) eNOODZHD If 7aH-H-H-H-O1 and OS HD NN I l> tN o : ## STR2 ##

oioo'a:, aqtiii Sr iua H a '-

  The products of Examples 106 to 111 are obtained in the syn- or anti-configuration according to the configuration of the acetoxymethyl starting material which is indicated in column I above. Similarly, when m is equal to one, the compounds are obtained in the form of asulfoxide or

  sulphoxide following the orientation of the sulphoxide of 3-

  acetoxymethyl starting. Moreover, when R13 and R14 are not identical, the products are obtained in the form of the D-, L- or D, L isomer depending on the optical activity of the product.

  starting point in column I above.

EXAMPLE 112

  Disodium salt of 5S- [5a, 6,7a (Z)]] - 5-oxide acid

  r (acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl)] - (1H-tetrazol

  1-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid (ç-sulfoxide syn-isomer). the product of the Example

8 by the following procedure.

  1 g of the acid [6R- [5a, 7 (Z)]] - 3

  [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(l1H-tetrazol-5-

  yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo

  [4.2.0] oct-2-ene-2-carboxylic acid of Example 58 in 10 ml

  of trifluoroacetic acid at 0, 0.39 g of

  chloroperbenzoic acid, and the solution is stirred at 0 for 1.5 hours. 500 ml of diethyl ether are then added

  and the precipitated product is filtered to obtain the [5S-

  [5a, 6f, 7a (Z)]] - 3 - [(acetyloxy) methyl] -7 - [[(2-amino-4-

  thiazolyl) [(1H-tetrazol-5-yl-methoxy) imino] acetyl] amino] -8

  oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. This acid can be converted to its disodium salt by treating it with sodium ethylhexanoate as indicated

in Example 65.

EXAMPLES 113 to 121

  Following the procedure of Example 112,

  can oxidize the sulphides indicated in column I above.

  below in the p-sulfoxides shown in Column II below.

  below. Collar. I N__s H2 tI 1l 7 N CH2X

H2M S N00

R1 () -R14 OOH

N-- N

Collar. II

HR16, X

R1a (C) n-PR4

R1N YN

1i1- Example RP16 R13 R14 R15 X

113 --H -H -H -O- -CH

N N 114 -H -H-1-HCi 3 S 1i

-H -H -H -H -0ES - N.

CH3 -

116 0OCH 3 -CH 3 -CH3 -H * -OC-C

117 -Hi -H -H -H -O-CH3

118 -H -C2H5 -H -H -

## EQU1 ## ## STR1 ##

HD-ú H- HT-

zHN-H-O-H-t-IS-611

X \ HNTU - '- O61

Td P 'ú1

x olduiox <-

  The products of Examples 113 to 121 are obtained in the syn- or anti-configuration configuration.

  starting sulphide indicated in column I above.

  In addition, when R13 and R14 are not identical, the products are obtained in the form of the D-, L- or D, L isomer depending on the optical activity of the indicated starting material.

in column I above.

EXAMPLE 122

  Disodium salt of 5,5-dioxide of [6R- [6a, 7g (Z)]] - 7-

  [[(2-amino-4-thiazolyl) [(1H-tetrazol-5-yl-methoxy) imino] -

  acetyl] amino] -3 - [[(1-methyl-lH-tetrazol-5-yl) thio] methyl] -

  8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid

  The [5R- [5a, 6a, 7n (Z)] - 7 - [[(2-

  amino-4-thiazolyl) [(1H-tetrazol-5-yl-methoxy) imino] acetyl] -

  amino] -3 - [[(1-methyl-lH-tetrazol-5-yl) thio] methyl] -8-oxo-5-

  thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid of Example 68 in trifluoroacetic acid and the solution is reacted with mchloroperbenzoic acid, according to

  procedure of Example 112 to obtain the 5.5

  [6R- [6a, 7 (Z)]] - 7 - [[(2-amino-4-thiazolyl)] - acid dioxide

  [(1H-tetrazol-5-yl-methoxy) imino] acetyl] amino] -3 - [[(1-

  methyl-lH-tetrazol-5-yl) thio] methyl] -8-oxo-5-thia-1-aza-

  bicyclo [4.2.0] oct-2-ene-2-carboxylic acid. This acid can be converted to its disodium salt by treating it with sodium ethylhexanoate as

  indicated in the previous examples.

EXAMPLES 123 to 129

  Following the procedure of Example 122,

  can oxidize the sulphoxides indicated in column I above.

  below in the sulphones indicated in column II below.

below. Collar. I 16

N {: - C:

H N-) I'1% S4 \ H 'CH2X

H2NNS O 6 COOH

R1 (at) n-R14 N, N, Col. II

1 R16 0 / to

YN AJ CC V rNWCH 'HNS) h H N CH2X

H2N 2O .....

  and preferably an HH-H-H-6H is a HH-H-6H an HH-HHHH HH a ZHN-DO-H-LI CoOunN-H-H-HDO- 9ZI an OSliii - El- úED-1Z I -N XflO CIH-H- H - úHD-9E xnop EI D> _0_H- H- - -ZI a úHO-DO- H- HH- H- úZI u 5 \ bTuSl úItd 911: 1 oldumox The products of Examples 123 to 129 are obtained in the syn- or anti-configuration configuration

  of the starting d-sulfoxide shown in column I above.

  above. In addition, when R13 and R14 are not identical, the products are obtained in the form of the D-, L- or D, L isomer depending on the optical activity of the starting material.

  indicated in column I above.

  The acids obtained in Examples 58 to 129 can also be converted to various esterified forms (i.e. compounds in which R is

O O

  -CH 2-0-C-C (CH 3) V etc.), according to modes

known operating procedures.

Q

Claims (19)

  A compound of the formula: wherein R is a hydrogen or alkali metal atom R7   or a radical -HO-CO-lower alkyl, Si (CH 3) 3, para-   methoxybenzyl, diphenylmethyl, benzyl, trichloroethyl, O or lower alkyl; R 1 is R 2 is R 3 is hydrogen, hydrogen or hydrogen or methyl; a methyl radical; a methyl radical; R4 is a hydrogen atom or the formula -OCONH2, XR -S; L1 a group of O il I or -O-C-lower alkyl; R5 is a R6 atom is a benzyl or acetyl atom; R7 is a hydrogen atom or hydrogen or a methyl radical; a methyl radical, hydrogen or a lower alkyl radical; R8 is a hydrogen atom or a group -CONH2;   R9 is a hydrogen atom, a lower alkyl radical or a group of formula - (CH2) p-C-OR11, II - (CH2) p -S-OR11 or - (CH2) p-N (lower alkyl) 2; R0 is a hydrogen atom or a lower alkyl radical; R11 is a hydrogen, sodium or potassium atom; n is 1, 2, 3 or 4; m is 0, 1 or 2; pest equal to 1, 2, 3 or 4; or compound of formula: R16 (O) m C-C-N H 16 H 2 A d X <2 éI CH 2X N H H2X H2I COOR12   N-N-N including its imino tautomeric form, wherein the -C- moiety is in the syn- or anti- configuration; I N O   R12 is a hydrogen, sodium or potassium atom or   a benzyl, para-methoxybenzyl, 2,2,2-trichloro-   ethyl, diphenylmethyl, tert-butyl, -CH 2 -O-lower alkyl O-I -CH-OC-lower alkyl, or R 13 and R 14 are independently selected from the group consisting of   the hydrogen atom and the methyl, ethyl, iso-,   propyl, n-propyl and carboxyl; R15 is a hydrogen atom, a methyl radical or a sodium or potassium atom; R16 is in the configuration a and is a hydrogen atom or a methoxy radical; m is 0, 1 or 2; n is zero or is an integer from 1 to 4; R17 is a hydrogen atom or a lower alkyl radical; X is a hydrogen atom or a group of formula -Q-C-alkyl hydrogen atom or a group of formula -O-C-alkyl or lower, -OCNH 2, -S 2 O NH N N18   N NJ or _sN to R19 R18 is a hydrogen atom or a lower alkyl radical; R 18 is a hydrogen atom, a lower alkyl radical or R 19 is a hydrogen atom, a lower alkyl radical or a group of formula - (CH 2) p - COOR 20, (CH 2) p - SO 3 R 20, or - (CH 2) pN- (lower alkyl) 2; R20 is a hydrogen, sodium or potassium atom; and p is an integer of 1 to 4. 2. A compound according to claim 1 having the formula: wherein: R is a hydrogen or alkali metal atom or a R   group of formula -CHO-CO-lower alkyl or -   R1 is a hydrogen atom or a methyl radical; R2 is a hydrogen atom or a methyl radical; R3 is a hydrogen atom or a methyl radical; R4 is a hydrogen atom or a group of formula OCONH2, -, SL i 2 OO, S, R, N O 9   I or -O-C-lower alkyl; R5 is a hydrogen atom or a methyl radical; R6 is a hydrogen atom or a methyl, benzyl or acetyl radical; R7 is a hydrogen atom or a lower alkyl radical; R8 is a hydrogen atom or a group of formula -CONH2; R9 is a hydrogen atom, an alkyl radical O   lower or a group of formula - (CH2) p-C-OR11, II - (CH2) p -S-OR11 or - (CH2) p-N- (lower alkyl) 2; O R1 is a hydrogen atom or a lower alkyl radical; R11 is a hydrogen, sodium or potassium atom; n is 1, 2, 3 or 4; m is 0, 1 or 2; p is 1, 2, 3 or 4.   The compound of claim 2 wherein: the C moiety is in the syn- configuration; N Xz1O n is one or two; m is zero or one, provided that when m is one, the sulfoxide is in configuration 3; R is a hydrogen, sodium or potassium atom or a group of formula or -CH 2 O-CO-lower alkyl; R1, R2, R3 and R5 are independently selected from hydrogen and methyl; O 0   R4 is a group of formula -O-C-CH3, -O-C-NH2, R8, H1 H3 or -SAX; R6 is a hydrogen atom or a methyl, benzyl or acetyl radical; R8 is a hydrogen atom or a -C-NH2 group; R9 is a hydrogen atom, a methyl radical or 0 O   A group of formula - (CH 2) p-C-OR 11, - (CH 2) p -S-OR 11 or (CH 2) pN (CH 3) 2; R11 is a hydrogen, sodium or potassium atom; and p is 1 or 2.   The compound of claim 3 wherein O I R4 is -O-C-CH3.   5. Compound according to claim 4, which is salt   Sodium 5-oxide [5S- [5a, 65,7a (Z)]] - 3-oxide   (Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-imidazol-2-   yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo   [4.2.0] oct-2-ene-2-carboxylic acid. 6. Compound according to claim 4, which is the   sodium salt of [6R- [6a, 75 (Z)]] - 3 - [(acetyloxy) -   methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-imidazol-2-yl-methoxy) -   imino] acetyl] amino] -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2-   ene-2-carboxylic acid. The compound of claim 3 wherein R4 is -SQNJN, and R9 is hydrogen or R9 methyl radical.   8. A compound according to claim 7 which is salt   Sodium [6R- [6o, 75 (Z)]] - 7 - [[(2-amino-4- 246? 854   thiazolyl) [(1H-imidazol-2-yl-methoxy) imino] acétyllamino] -3-   [[(1-methyl-lH-tetrazol-5-yl) thio] methyl] -8-oxo-5-thia-1-   azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.   9. Pharmaceutical composition with anti-   bacterial, characterized in that it comprises a pharmaceutically acceptable carrier and one or more compounds with antibacterial action, of formula: HgN <t HNJL U 2 's.   Where R is a hydrogen or alkali metal atom R or a group of formula -CHO-CO-lower alkyl or R1 is a hydrogen atom or R2 is a hydrogen atom or R3 is a hydrogen atom or an R4 is a hydrogen atom or a Mi-t '1 Mf, methyl radical; methyl radical; methyl radical; a group of formula -OCONH2, -S-k 3LR10, -S- -N ', R or -O-C-lower alkyl; R5 is a hydrogen atom or a methyl radical; R6 is a hydrogen atom or a methyl, benzyl or acetyl radical; R7 is a hydrogen atom or a lower alkyl radical; R8 is a hydrogen atom or -CONH2; R is a hydrogen atom, an alkyl radical O   Lower or a group of formula - (CH 2) p-C-OR 11, OO - (CH 2) p -SOR 11 or - (CH 2) p-N- (lower alkyl) 2; R10 is a hydrogen atom or a lower alkyl radical; Ri is a hydrogen, sodium or potassium atom; n is 1, 2, 3 or 4; m is 0, 1 or 2; and p is 1, 2, 3 or 4.   10. Compound according to claim 1, having the formula: R16 (O) (m --N he I N H CHX H2 COOR12 Ri (C) n-R14 R   N-N including its imino tautomeric form, wherein: -C- is in the syn- or anti- configuration; R12 is a hydrogen, sodium or potassium atom or a benzyl, paramethoxybenzyl, 2,2,2-trichloroethyl, diphenylmethyl, tert-butyl, -CH2O-lower alkyl, -CH-OC-lower alkyl group; where and R are R13 14   R17 independently selected from the group consisting of the atom   of hydrogen and the methyl, ethyl, isopropyl,   propyl and carboxyl; R15 is a hydrogen atom, a methyl radical or a sodium or potassium atom; R16 is in the configuration a and is a hydrogen atom or a methoxy radical; m is zero, one or two; n is zero or is an integer from 1 to 4; R17 is a hydrogen atom or a lower alkyl radical; X is o I!   a hydrogen atom or a group of formula -O-C- O Lower alkyl, -O-CNH2, -O * N N N-N,   Is a hydrogen atom or a lower alkyl radical; R19 is a hydrogen atom, a lower alkyl radical or a group of formula - (CH2) p- COOR20, - (CH2) p-SO3R20 or (CH2) pN- (lower alkyl) 2; R20 is a hydrogen, sodium or potassium atom; and p is a number integer from 1 to 4.   The compound of claim 10 wherein R 12 is hydrogen, sodium or potassium; R12 R16 is a hydrogen atom; R13 and R14 are both 16 1314   hydrogen atoms; m is zero or one, provided that when m is one, the sulfoxide is in the H configuration; X is a hydrogen atom or a group where it is CNH1 of the formula -O-C-CH3, -O-C-NH2, N --- N 3 ON2   or R19 is a hydrogen atom, a methyl radical or a group of formula -CH2-COOR 20 '-CH2 S3R20 or - (CH2) 2N (CH3) 2; and R20 is a hydrogen, sodium or potassium atom, and wherein   the group -C- is in the syn- configuration.   12. wherein X is 13. formula: Compound according to claim 11, wherein a hydrogen atom.   Compound according to claim 11, having for H (O) m (-) Oo II   wherein Z is a hydrogen atom or -CNH 2.   14. Compound according to claim 11, wherein X is -O-C-NH2.   15. The compound according to claim 11, wherein NN X is -S CH and R19 is a R19 -Z atom, of which 1 is hydrogen, a methyl radical or a group of formulas -CH2-COOR20, -CH2-SO3R20 or - (CH2) 2N (CH3) 2; and R20 is   a hydrogen, sodium or potassium atom.   The compound of claim 15, wherein X is -S N CH3. 17. The compound of claim 16, wherein m is zero.   18. A compound according to claim 17, which is the   disodium salt of [6R- [6a, 7P (Z)]] - 7 - [[(2-amino-4-)   thiazolyl) [(1H-tetrazol-5-ylmethoxy) imino] acetyl] amino] -3-   [[(L-methyl-IH-tetrazol-5-yl) thio] methyl] -8-oxo-5-thia-1-   azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. The compound of claim 16, wherein m is equal to one.   The compound of claim 19 which is   disodium salt of 5S- [5a, 6j, 7a (Z)] 5-oxide   (2-amino-4-thiazolyl) [(1H-tetrazol-5-yl-methoxy) imino] -   acetyl] amino] -3 - [[(1-methyl-lH-tetrazol-5-yl) thio] methyl] -8   oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. 21. The compound of claim 11, wherein o X is -O-C-CH3.   22. The compound of claim 21 wherein m is zero.   23. A compound according to claim 22, which is the   disodium salt of [6R- [6a, 7p (Z)]] - 3 - [(acetyloxy) -   methyl] -7 - [[(2-amino-4-thiazolyl) (lH-tetrazol-5-yl-methoxy) -   imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-   ene-2-carboxylic acid. 24. The compound of claim 22 which is   disodium salt of [6R- [6a, 71 (Z)]] - 3 - [(acetyloxy) -   methyl] -7 - [[(2-amino-4-thiazolyl) - [(1-methyl-lH-tetrazol) -   1-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid. The compound of claim 21, wherein m is equal to one.   26. A compound according to claim 25, which is the   disodium salt of 5S- [5a, 6P, 7a (Z)]] - 5-oxide acid   [(Acetyloxy) methyl] -7 - [[(2-amino-4-thiazolyl) (lH-tetrazol   1-yl-methoxy) imino] acetyl] amino] -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid.   27. Pharmaceutical composition with anti-   bacterial, characterized in that it comprises a pharmaceutically acceptable carrier and one or more compounds with antibacterial action, of formula: CH2X COOR12   including its imino tautomeric form, wherein: C- is in the syn- or anti- configuration; I N O o R12 is a hydrogen, sodium or potassium atom or a 0 he   group of formula -CH2-O-lower alkyl, -CH-O-C-   R17 lower alkyl or; R13 and R14 are independently selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, n-propyl and carboxyl; Ri15 is a hydrogen atom, a methyl radical or a sodium or potassium atom; R16 is in the configuration a and is a hydrogen atom or a methoxy radical; m is zero, one or two; R17 is a hydrogen atom or a lower alkyl radical; X is a hydrogen atom or a group of the formula -OC-lower alkyl, formula -OC-lower alkyl, -O-C-NH 2, IKNH 2 -S a, -R 1 or R 18 is a hydrogen atom or a lower alkyl radical; R19 is a hydrogen atom, a lower alkyl radical or a group of formula - (CH2) p -COOR20, - (CH2) p -SO3R20 or - (CH2) p-N- (lower alkyl) 2; R20 is a hydrogen, sodium or potassium atom; n is equal to zero or is a   integer from 1 to 4; and p is an integer of 1 to 4.   28. The composition of claim 27, wherein R12 is a hydrogen, sodium or potassium atom; R13 and R14 are both hydrogen atoms; R15 is a hydrogen atom, a methyl radical or a sodium or potassium atom; R16 is a hydrogen atom; m is zero or one, provided that when m is one, the sulfoxide is in the configuration ç; X is a hydrogen atom or a group of formula -O-C-CH 3, 0 N-N   -O-C-NH 2, NH 2 -S-CH 3, or -S R 19 R 19 is a hydrogen atom, a methyl radical or a group of formula -CH 2 COOR 20, -CH 2 SO 3 R 20 or (CH 2) 2 N (CH 3) 2; R20 is a hydrogen, sodium or potassium atom; and n is equal to zero or is a number integer from 1 to 4.   29. A compound according to claim 10, which is the   disodium salt of [6R- [6a, 7 (E) [[-3 - [(acetyloxy) -   methyl] -7 - [[(2-amino-4-thiazolyl) [(1H-tetrazol-5-yl-methoxy) -   iminolacétyl] amino] -8-oxo-5-thia-l-azabicyclo [4.2.0] oct-2- ene-2-carboxylic acid.