FI69468C - PROCEDURE FOR THE FRAMSTATION OF A PHARMACOLOGICAL VARIABLE OXIMDERIVAT AV 3-THIADIAZOLYL-THIOMETHYL-7-AMINO-THIAZOLYLACETAMIDO-CEPHALOSPORANSYRA - Google Patents

Description

[B] (11) NOTICE OF PUBLICATION 694 6 8 • ϊΗΡνϊΗΡ LJ utläggningsskrift C (45) Patent granted ψ £ 7 & \ Patent me 10 cl it 10 CC 1036 (51) Kv.ik.4 / lnt.ci.4 C 07 D 501 / 36 FINLAND —FINLAND (21) Patent application - Patentansöknlng 78044 ** (22) Application date— Ansökningsdag 10.02.78 (FI) (23) Starting date - Giltighetsdag 10.02.78 (41) Published public - Blivit offentlig 1 9.08.78

National Board of Patents and Registration / 44) Date of display and publication - 31.10.85

Patent- och registerstyrelsen '' Ansökan utlagd och utl.skriften publicerad (32) (33) (31) Pyydetty etuoikeus — Begärd priorltet 1 8.02.77

France-France (FR) 7704745 (71) Roussel-Uclaf, 35, Boulevard des Invalides, 75007 Paris,

French-French (FR) (72) Renä Heymes, Romainville, Andr6 Lutz, Strasbourg, French-French (FR) (74) Oy Jalo Ant-Wuorinen Ab (54) Method for the development of new, pharmacologically valuable 3-thiadiazolyl 1 i- thio-methyl-7-amino-thiazolylacetamido-cephalosporanic acid for the preparation of oxime derivatives

This invention relates to a process for the preparation of novel 3-thiadiazolyl-thiomethyl-7-amino-thiazolyl-acetamido-cephalosporanic acid oxime derivatives of the general formula NH

a:

S K

w? Ύ "S- / R3 ^ AvA-A - c ° 2a \ s / wherein R2 represents an alkyl group having 1 to 4 carbon atoms, represents an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, A represents a hydrogen atom or an alkali metal, and OR2 is in the syn position.

2 69468

As the group R2, a methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl or tert-butyl group can be mentioned.

Of the meanings of group A, mention should be made in particular of sodium, potassium and lithium.

Meanings of the group R1 include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, sec- butyloxy and tert-butyloxy radicals.

In particular, the invention relates to a process for the preparation of compounds of formula I in which R 2 represents a methyl radical, R 1 represents a methyl or methoxy radical and A represents a hydrogen atom or a sodium atom.

Among the compounds of the general formula I, mention should be made in particular of the compounds mentioned in the Examples below and, in particular, of the following compounds: 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) -3 - ((3-methyl -1,2,4-thiadiazol-5-yl) -thiomethyl) -cef-3-em-4-carboxylic acid, the syn-isomer and its salts with alkali metals; 7- [2- (2-amino-4-thiazolyl) -2-methoxyimino-acetamido) -3 - ((3-methoxy-1,2,4-thiadiazol-5-yl) thiomethyl) - cef-3-em-4-carboxylic acid, the syn-isomer and its salts with alkali metals.

A process for the preparation of compounds of formula I as defined above comprises treating a compound of formula II as

co2a * S

wherein R 1 represents the same as above and A 'represents a hydrogen atom or a group easily removed by acid hydrolysis, with an acid of formula III 3 69468 NH R' SA.

S N

CO 2 H 111

Nn or2 or a functional derivative of this acid, in which in formula III R '^ represents a group which can be easily removed by acid hydrolysis and R2 represents the same as above, for the preparation of a compound of formula 1' NH R * A.

S N

V = ^ 9 ^ 0 * 2 N __ / "3 cf ch2-s / Λ I · CO2A 'and the compound of formula 1' is treated with an acidic hydrolysis agent to give a compound of formula I" nh2

S ^ N

corresponding to a compound of formula I in which A represents a hydrogen atom and R 2 and R 2 have the same meaning as above, and optionally 4 69468 is converted to a compound of formula I ". a compound according to known methods to a compound of formula I wherein A represents an alkali metal.

According to a preferred embodiment, the compound of formula II is treated with a functional derivative of an acid of formula III, such as an acid anhydride or chloride, which anhydride may be formed in situ by exposing the acid to an acid or chlorohexylcarbodiimide. Other halides or anhydrides formed in situ using another alkyl chloroformate, dialkyl carbodiimide or other dicycloalkyl carbodiimide may also be used. Other acid derivatives can also be used, such as an acid azide, an activated amide of an acid or an activated ester of an acid formed, for example, with hydroxysuccinimide, peranitrophenol or 2,4-dinitrophenol. When the reaction is carried out using a compound of formula II and a halide of an acid of general formula III or an anhydride formed with iso-butyl chloroformate, it is preferred to work in the presence of a basic substance.

As the basic substance, for example, an alkali metal carbonate or a tertiary organic base such as N-methylmorpholine, pyridine or a trialkylamine such as triethylamine can be used.

The reaction is carried out in a solvent or mixture of solvents such as methylene chloride, chloroform, tetrahydrofuran, acetone or dioxane.

In the conversion reaction of compounds of formula 1 'to compounds of formula I ", the substituent R' is replaced by a hydrogen atom and when A 'is other than a hydrogen atom, A' is replaced by a hydrogen atom.

In this case, the compound of formula 1 'is treated with an acid hydrolysis agent when R' ^ represents a group easily removed by acid hydrolysis and when A 'represents a hydrogen atom or a group easily removed by acid hydrolysis.

As the acid hydrolysis agent to which the compounds of formula 1 'are exposed, formic acid, trifluoroacetic acid or acetic acid can be mentioned. These acids are used as anhydrous or aqueous solutions. A zinc-acetic acid system can also be used.

Preferably, an acidic hydrolysis agent such as anhydrous trifluoroacetic acid or aqueous formic acid or acetic acid is used to remove tert-butoxycarbonyl or trityl radicals or to remove benzhydryl, tert-butyl or para-toxobenzyl groups.

Preferably, a zinc-acetic acid system is used to remove the trichlorethyl group R 1 and A '.

The compounds of the formulas 1 'and I "may be formed into salts as required. For example, salt formation may be effected by allowing these acids to act on a mineral base such as sodium or potassium hydroxide, sodium bicarbonate or sodium acetate.

This salt formation is preferably carried out in a solvent or mixture of solvents such as water, ethyl ether, methanol, ethanol or acetone. The salts can be obtained in amorphous or crystalline form.

The compounds of the general formula I have very good antibiotic activity, both against gram - (+) bacteria such as staphylococci, streptococci and in particular penicillin-resistant staphylococci and against gram - (-) bacteria such as coloformic bacteria, Klebsiella and Salmonella. against.

Pharmacological examination of the compounds according to the invention:

In vitro activity:

Dilution method in liquid medium.

The same amount of sterile nutrient medium is added to the series of tubes. An increasing amount of test compound is added to each tube and then each tube is inoculated with the bacterial strain. Incubate for 24 or 48 hours in a 37 ° C oven, after which growth inhibition is determined by X-ray to determine the lowest inhibitory concentrations (CMI) expressed in μg / cm.

The following results are obtained; The reference substance X is Glaxo's "Cefuroxime" (3-carbamoyloxymethyl) -7 - ((Z) -2-fur-2-yl) -methoxyiminoacetamido) -ef-3-em-4 sodium salt of carbonyl acid).

Compound A is the compound of Example 2 and Compound B is the compound of Example 4.

6 69468

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7 69468

The above properties make the novel compounds pharmaceutically acceptable for use as medicaments against bacterial diseases, in particular staphylococcal infections such as staphylococcal septicemia, facial or cutaneous staphylococcal diseases, pyodermitic or suppurative wounds, anthrax (anthrax), anthrax , against rosacea, simple acute or post-influenza staphylococcal diseases, catarrhal pneumonia, pulmonary congestion.

These compounds can also be used as medicaments against inflammations caused by colibacilli and the like, such as Proteus, Salmonella and Klebsiella infections, and diseases caused by other gram (-) bacteria.

In particular, the compounds of the formula I in which R2 represents a methyl group, R1 represents a methyl group or a methoxy group and A represents a hydrogen atom, and their pharmaceutically acceptable salts are selected as medicaments.

From the latter, the compounds described in the examples are selected in particular, and in particular 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) -3 - [(3-methyl-1,2,4-thiadiazole-5 -yl) -thiomethyl) -cef-3-em-4-carboxylic acid, and its pharmaceutically acceptable alkali metal salts, and 7- (2- (2-amino-4-thiazolyl) -2-methoxyimino- Acetamido] -3 - ((3-methoxy-1,2,4-thiadiazol-5-yl) -thiomethyl) -ceph-3em-4-carboxylic acid syn-isomer and its pharmaceutically acceptable alkali salts.

The novel oximes of the formula I can also be used for the preparation of pharmaceutical compositions containing at least one of said oximes as active ingredient.

These compositions are administered buccally, rectally, parenterally, intramuscularly or topically by topical application to the skin or mucous membranes.

They may be solid or liquid, in pharmaceutical forms commonly used in human medicine, such as simple or granulated tablets, coated tablets, granules, suppositories, injectables, pomades, ointments, gels; they are prepared according to conventional methods. The active ingredient or ingredients may be incorporated with carriers commonly used in pharmaceutical compositions, such as talc, acacia, lactose, amidone, magnesium stearate, cocoa butter, aqueous or non-aqueous carriers, animal or vegetable fats, various paraffin derivatives, glycine derivatives, -, dispersing or emulsifying agents, preservatives.

The dose to be administered depends on the disease to be treated, the individual to be treated, the mode of administration and the compound used. It may be, for example, 0.250 to 4 g per day, orally for human administration of a compound of Example 2 or 4, or 0.500 to 1 g three times a day intramuscularly.

Compounds of formula II may be prepared by an exchange reaction to give a compound of formula _ / R 3 X "/ 1

HS

acts on 7-amino-cephalosporanic acid according to previously known methods.

9 69468

Compounds of formula V may be prepared by reacting a compound of formula sodium sulfhydrate or thiourea in the presence of potassium.

/ X

a

Examples for the preparation of compounds of formulas V and II are given in the experimental section below.

Compounds of formula III may be prepared according to the method described in Belgian patent 850 662, which comprises reacting a thiourea with a compound of formula B

ClCH- - C - C - CO-alc

"" B

O N / w 01 * 2 wherein R 2 is as defined above and ale is an alkyl radical having 1 to 4 carbon atoms, whereby treatment with a base gives a compound of formula NH-

X

S N

1 = R 11 R 2 which is treated by acid hydrolysis or hydrogenolysis with a functional derivative of a readily removable group to give a compound of formula 10 69468 NH-R '.

A.

s N

\ __ / ^ V10 ^ c

II

OF

Wherein R 1, R 7a and R 2c are as defined above, which compound is treated with a base and then an acid to give the desired compounds of formula III. An example of such a preparation is explained in the experimental section below.

Compounds of formula B are prepared by reacting diazomethane or similar alkyl halides or sulfates with γ-chloro-α-oximinoacetyl ethyl acetate as described in J. of Midicinal Chemistry 1973, 1-6 (9), 978.

Compounds of formula III having the syn configuration are obtained by allowing a thiourea to act on a compound of formula B in an aqueous solvent which, working at ambient temperature using mainly a stoichiometric amount of thiourea and limiting the reaction time to a few hours, or combining all the above conditions.

The following examples illustrate the invention.

Example 1; 7- (2- (2-trityyliamino4-thiazolyl) -2-methoxyimino-acetamido) -3 - ((3-methoxy-1,2,4-thiadiazol-5-yl) thiomethyl) ceph-3- em-4-carboxylic acid, syn-isomer To 3.36 g of the sodium salt of 2- (2-tritylamino-4-thiazolyl) -2-methoxyimino-3-acetic acid, the syn-isomer, is added 60 cm of methylene chloride and 10 cm of 2N hydrochloric acid. Decant, wash with water, dry and evaporate to dryness. The free acid is obtained.

The residue obtained above is dissolved in 30 cm of methylene chloride and 950 mg of dicyclohexylcarbodiimide are added. Stir for one hour and suction filtered (750 mg dicyclohexylurea). The filtrate is cooled to -10 ° C and a solution of 1.3 g of 7-amino-3 - ((3-methoxy-1,2,4-thiadiazol-5-yl)) is added in one portion. -thiomethyl) -cef-3-em-4-carboxylic acid (Rf = 0.35 for silica gel thin layer chromatography; eluent 2M NaCl in water with 10% acetic acid) 3 3 in 13 cm of chloroform and 1.3 cm of triethylamine. The mixture is allowed to warm to room temperature, washed with 2N hydrochloric acid and then with water, dried, filtered, evaporated to dryness to give 4.8 g of crude product. This product is purified by chromatography on 500 g of silica gel, eluting with a mixture of acetone and water (90-10). 1.6 g of purified product are isolated, Rf = 0.45. The product is purified by a second chromatography on 160 g of silica gel. Finally, 1.1 g of pure product are obtained.

The sodium salt of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid, the syn-isomer used as starting material in Example 1, is described in Belgian Patent 850,662. It is prepared as follows:

Step A: γ-Chloro-α-methoxyiminoacetyl-ethyl acetate.

22.5 g of γ-chloro-α-oximonoacetyl-ethyl acetate are mixed with 100 cm of methylene chloride.

Cool in an ice bath and gradually add while stirring.

O

275 cm of freshly prepared diazomethane solution (21.6 g / l). Allow to stand for 5 minutes, after which the excess diazomethane is discarded with a small amount of aluminum. Concentrate, then purify by eluting through silica gel with methylene chloride. 11.93 g of recovered product are obtained.

Step B: 2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetyl-ethyl acetate.

Mix 1 g of γ-chloro-α-methoxyiminoacetyl ethyl acetate, 3 cm3 of absolute ethanol and 0.52 g of crushed thiourea. Stir at room temperature for about two hours. Dilute with 3 to 60 cm of ether to crystallize the hydrochloride, stir, filter under suction, wash with ether, dry to give 685 mg of hydrochloride. This is dissolved in 4 cm of water at 50 ° C, potassium acetate is added until the pH is 6, whereupon the liberated amine crystallizes. Cool, suction filter, wash with water, dry to give 270 mg of the desired product, m.p. 161 ° C.

The product has a syn configuration.

NMR: (CDCl 3/60 MHz) ppm: δ (NOCH 2) t 6.7 (thiazole ring proton).

69468

Step C: 2- (2-Tritylamino-4-thiazolyl) -2-methoxyimino-ethyl acetate, syn-isomer 4.6 g of the compound prepared in the previous step are dissolved at 92 ° C in 92 cm 3 of methylene chloride. Cool to -10 ° C, add 2.9 cm 3 of triethylamine, cool again to -35 ° C, add 6.1 g of trityl chloride over 15 minutes, allow to warm to room temperature, for a total of 2.5 hours. Wash with water, then 0.5 N hydrochloric acid and sodium acetate in water. Dry, concentrate, dissolve in ether, reconcentrate, dissolve in methanol, add water and ether, allow to crystallize, suck off, wash with ether to give 6.15 g of the desired product, m.p. 120 ° C.

Step D: Sodium salt of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid, syn-isomer 3 7.01 g of the ester obtained in Step C are dissolved in 35 cm of dioxane. Heat to 110 ° C in an oil bath and add 9 cm 2N sodium hydroxide within 5 minutes 3 and boil under reflux for 30 minutes with stirring. The sodium salt crystallizes. Cool, suction filter, wash with dioxane and then ether to give 5.767 g of salt as a first crop. The mother liquor is concentrated to give a second crop of 1.017 g, i.e. a total of 6.784 g of sodium salt.

7-Amino-3 - ((3-methoxy-1,2,4-thiadiazol-5-yl) -thiomethyl) -ceph-3-em-4-carboxylic acid is prepared as follows:

Step A: 3-Methoxy-5-mercapto-1,2,4-thiadiazole Cool a suspension of 6.16 g of powdered sodium sulphate in 300 cm -1 of ethanol to 0 ° C and gradually add 15 g of 3-methoxy -5-chloro-l, 2,4-thiadiazole. Stir for 3 hours at 0 ° C and then keep on ice overnight. Filter, wash with methylene chloride to give 13.6 g of a crystalline mixture. Chromatograph on silica gel using chloroform-methanol (95-5) as eluent. 3 g of the expected product are obtained (Rf = 0.35). These 3 g are dissolved in 150 3 cm of hot methylene chloride. Filter and concentrate until crystallization. Let be on ice overnight. Suction filter, wash with methylene chloride, dry to give a total of 2.6 g of the desired product, m.p. 146 ° C.

Step B: 7-Amino-3 - ((3-methoxy-1,2,4-thiadiazol-5-yl) -thiomethyl) -cef-3-em-4-carboxylic acid

Under a nitrogen atmosphere, 2.72 g of 7-amino-cephalosporanic acid, 27 cm of distilled water, 840 mg of sodium bicarbonate and 1.48 g of 3-methoxy-5-mercapto-1,2,4-thiadiazole are stirred.

ii 13 69468 Stir for 5 hours at 60 ° C, add a further 0.74 g of 3-methoxy-5-mercapto-1,2,4-thiadiazole, stir for 2 hours at 60 ° C, acidify to pH 4 acetic acid, filtered off with suction, washed with water and then with acetone, dried to give 2.2 g of crude product.

The product is purified by dissolving in sodium bicarbonate solution, treated with charcoal and filtered. The filtrate is acidified with acetic acid, filtered off with suction, washed with water and acetone, dried to give 1.3 g of the desired product.

Example 2: 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) 3 - ((3-methoxy-1,2,4-thiadiazol-5-yl) - thiomethyl) -cef-3-em-4-carboxylic acid, syn-isomer

Heat to 55 ° C 5.5 cm3 of 50% formic acid. 1.1 g of the crude product prepared according to Example 1 are added and heated for 25 minutes at 55-60 ° C. Suction filtered to give a triphenylcarbolinol precipitate, 390 mg.

The filtrate is evaporated to dryness, triturated in ethanol, filtered off with suction, washed with ethanol, dried to give 470 mg. This product is re-triturated in water, filtered off with suction and dried. 330 mg of the desired product are obtained.

Microanalysis: c17H17N7 ° gS4 calculated C% 37.56 H% 3.15 obtained 37.4 3.2 UItraviolet spectrum (ethanol-0.1N in hydrochloric acid) inflation = 240 nm = 310 ε = 17000 max: 270 nm E1 = ^ 23 e = 23000 inflation = 280 nm = 403

Example 3; 7- (2- (2-tritylamino-4-thiazolyl) -2-methoxyimino-acetamido) -3 - ((3-methyl-l, 2,4-thiadiazol-5-yl) thiomethyl) -kef- 3-Em-4-carboxylic acid, syn isomer To 2.7 g of the sodium salt of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid, the syn isomer, is added 60 cm3 of methylene 3 chloride and 6 cm 2N hydrochloric acid. Decant, wash with water, dry and evaporate to dryness.

3 The oily residue is dissolved in 30 cm of methylene chloride, and 690 mg of dicyclohexylcarbodiimide are added. After stirring for one hour at room temperature, the dicyclohexyl-69468 14-urea precipitate formed, 570 mg, is filtered off with suction.

Cool to -10 ° C and add in one portion 1 g of 7-amino-3 - ((3-methyl-1,2,4-thiadiazol-5-yl) -thiomethyl) -cef-3-em-4-carb -carboxylic acid (Rf = 0.35 for silica gel thin layer chromatography, 3 eluent 2M NaCl in water with 10% acetic acid) in 10 cm 3 of methylene chloride and 1 cm of triethylamine. Allow to warm to room temperature in 1.5 hours. Wash with 1N hydrochloric acid and then water, dry, filter and evaporate to dryness. The residue is redissolved in 10 cm of dioxane and 1 cm of water, 3 and 2 cm of sodium bicarbonate are added to this solution as a saturated solution. Allow to stand for 30 minutes, stirring, at which point some of the sodium salt of the starting acid precipitates. Suction filtered and dried to give 580 mg. The filtrate is evaporated to dryness, redissolved in 20 cm of methylene chloride, washed with water, 1N hydrochloric acid, dried, filtered and evaporated to dryness. 1.95 g of the expected product are obtained. This product is triturated with ether, filtered off with suction, dried to give 1.7 g of purified product. The product is chromatographed on 450 g of silica gel using a 10% aqueous solution of acetone (Rf = 0.45) as eluent. 1.2 g of the desired product 3 are obtained, which is dissolved in 4 cm of ethyl acetate. The product precipitates when the same volume of ether is added. Finally, 940 mg of pure product are obtained.

The 7-amino-3 - ((3-methyl-1,2,4-thiadiazol-5-yl) -thiomethyl) -cef-3-em-4-carboxylic acid used as a starting material in Example 3 is prepared as follows:

2.72 g of 7-amino-cephalosporanic acid, 27 cm of distilled water and 0.84 g of sodium bicarbonate are stirred under a nitrogen atmosphere. Partial dissolution occurs, 1.45 g of 3-methyl-5-mercapto-1,2,4-thiadiazole are added. Stir for 4.5 hours at 60-70 ° C. Acidify with acetic acid to pH 4. Suction filter, wash with water, acetone and then ether. Dry to give 2.4 g of the desired product.

Example 4: 7- (2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetamido) -3 - ((3-methyl-1,2,4-thiadiazol-5-yl) - thiomethyl) -cef-3-em-4-carboxylic acid, syn-isomer 4 cm-50% aqueous formic acid is heated to 55 ° C to 69468. 940 mg of the product obtained in Example 3 are added. After stirring for 20 minutes at 55 ° C, the triphenylcarbinol is filtered off with suction, washed with water to give 340 mg, m.p. 158 ° C.

The filtrate is evaporated to dryness and the product precipitates and is dissolved in ethanol. Suction filter, wash with ethanol and then ether, dry to give 415 mg of the desired product. Ultraviolet spectrum in ethanol-1,1N-hydrochloric acid.

Inflection = 234 nm Emax = 325 = 17000 max = 269-270 nm e] = 525 = 27500 inflexion = 280 nm e! = 488

Example 5: 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) -3 - ((3-methoxy-1,2,4-thiadiazol-5-yl) - thiomethyl) -cef-3-em-4-carboxylic acid syn-isomer sodium salt.

To 300 mg of the compound prepared according to Example 3 is added 3.7 ml of 0.1N soda and the resulting solution is kept at ambient temperature for about 10 minutes, evaporated in vacuo at a temperature not exceeding 30 ° C and the desired sodium salt is isolated. It decomposes at 250-260 ° C.

Analysis:% Na found% Na theor.

4 4.7

Example 6: 7 - ((2-Amino-thiazolyl) -2-methoxyimino-acetamido) -3 - ((3-methyl-1,2,4-thiadiazol-5-yl) -thiomethyl) -ef-3 -em-4-carboxylic acid syn-isomer sodium salt To 50 mg of the product obtained according to Example 4 is added 0.9 ml of 0.1N soda, the solution obtained is kept at ambient temperature for about 10 minutes, evaporated in vacuo at a temperature not exceeding 30 ° C, and isolating the desired sodium salt. It decomposes at about 250 ° C.

Analysis:% Na found% Na theor.

4.17 4.18

Claims (5)

16 69468 A process for the preparation of novel pharmacologically valuable oxime derivatives of 3-thiadiazolyl-thiomethyl-7-amino-thiazolylacetamido-cephalosporanic acid having the general formula NH XSN - N \ 'c ° 2A \ s / wherein R2 represents an alkyl group having 1 to 4 carbon atoms R3 represents an alkyl group having 1 to 4 carbon atoms or an alkoxy group having 1 to 4 carbon atoms, A represents a hydrogen atom or an alkali metal, and OR2 is in the syn position, characterized in that a compound of formula II is treated with HN ΥτΛ rC CO2A 's in which R3 is as defined above and A 'is a hydrogen atom or a group easily removed by acid hydrolysis, with an acid of formula III 69468 NH R' ASN \ _ ^ CO? H III N \ ^ OR2 or a functional derivative of this acid, wherein III R 1 represents a group easily removed by acid hydrolysis and R 2 represents the same as above, for the preparation of a compound of formula 1 'is NH R' A. SN "·«! Υγ "ί„ _γ *> <r n'y # j ^ 'ch2-s- ^ \ i * co2a · and the compound of formula 1' is treated with an acid hydrolysis agent to prepare a compound of formula I "is nh2 S ^ N ay 18 69468 corresponding to a compound of formula I wherein A represents a hydrogen atom and R 2 and R 3 have the same meaning as above, after which the compound of formula I "is optionally converted according to known methods to a compound of formula I in which A represents an alkali metal. Process according to Claim 1, characterized in that 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) -3 - ((3-methyl-1,2, Syn-isomer of 4-thia-diazol-5-yl) -thiomethyl) -cef-3-em-4-carboxylic acid. Process according to Claim 1, characterized in that 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido) -3 - ((3-methoxy-1,2, 4-Thia-diazol-5-yl) -thiomethyl) -cef-3-em-4-carboxylic acid syn isomer. A process for the preparation of a pharmacologically active oxime derivative of 3-thiadiazolyl-thiomethyl-7-amino-thiazolylacetamido-cephalosporans with the formula NH X S H w S * \ _ / S Nv ° r2 jlZIT. "X j — ζ 1 co2a \ g / i vilken R2 is a alkyl group having 1-4 cholatomers, R3 is a alkyl group having 1-4 cholatomers or an alkoxy group having 1-4 cholaters, A is a substituent or a hydrogen atom of 19 69468 alkali metal and Groups OR2 in the syndication / kernetecking of the group, to which is used in the preparation of form II "'Vf'X, -c *. or * II C02A 's i vilken betecknar decamma som ovan oca A * betecknar en väteatom eller en grupp, sa lätt kan elimineras genom sur hydrolys, med en syrra med formula III NH R * 6A. ε n \ __ ^ CO? H III 0R2 or a functional group of which is present in the group, the color of which is a group III R'betecknar in a group, which can be eliminated from the genome by hydrolysis and R2 is a decanted form of formeln 1 'NH R' A. SN dr nY ^ -ch2-s- / n 1 'CO22'