NO865176L - PROCEDURE FOR THE PREPARATION OF NEW CEPHALOSPORIN DERIVATIVES. - Google Patents

Description

The present invention relates to new 7(3-["2-(2-aminothiazol-4-yl)-(Z)-2-alkoxyimino-acetamido]-3-[(2-mercapto-1,3,4-thiadiazol- 5-yl)thiomethyl]-cef-3-em-4-carboxylic acids of formula

V-s-å—way— as—f-a^ma-søy-t-i-s-k—^a-ksept:a-b±e—s"a±t:er—og—es-fee-r-e—ée-^a-v-.—|

Several experiments are known from the literature, in which 3,7-disubstituted cephalosporin derivatives, containing optionally substituted 5-membered heterocyclic rings in both of these positions, were prepared. There are several patents (see later) which describe the preparation of derivatives of 7-ACA containing substituted thiazole and thiadiazole rings in the 3- and 7-position. It is also known for

search for the preparation of 7 (3 — [ 2-( 2-aminothiazol-4-yl)-( Z )-2-alkoxyimino-acetamido]-3-[(1,2,3-thiadiazol-5-yl)thiometh- yl ] -cef-3-em-4-carboxylic acids and testing these regarding antibacterial activity (J. Antibiot., vol. XXXVI, no. 2,

179-180, 1983). ,

According to fbel-giskj patent document V8-2-3—8-6-H, a 2-amino-thiazole ring can be introduced in the 7-position of 7-ACA via an acetyl-amino group. Some of the compounds produced according to this patent, namely 7-[2-(2-aminothiazol-4-yl)acetamido]-3-[(1,3,4-thiadiazol-2-yl)thiomethyl]-cef-3-em-4-carboxyl-

acid, 7-[2-(2-aminothiazol-4-yl)acetamido]-3-[(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl]-cef-3-em-4 -carboxylic acid and 7-[2-(2-aminothiazol-4-yl)acetamido]-3-[(5-mercapto-1,3,4-thiadiazol-2-yl)-thiomethyl]-cef-3-em- 4-carboxylic acid, exhibits a significant antibacterial effect similar to that of Cefazolin {7-(1-(1H)-tetrazolyl-acetamido)-3-[2-(5-methyl-1,3,4-thiadiazolyl)thiomethyl]-cef -3-em-4-carboxylic acid; The Merck Index, 10th edition, 1901}. An excellent effect could be observed against Proteus vulgaris and S^pliylococcus aureus.

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iBelcxisk^ patent document \8;8-9-9d-3i describes 7(3-[ 2-( 2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-[(substituted 1.2.3- thiadiazol-5 -yl)thiomethyl]-cef-3-em-4-carboxylic acid derivatives containing a C^_g-alkyl group as the substituent in the 4-position of the thiadiazole moiety. If this alkyl group is a methyl group, the corresponding compound is very active against gram-negative bacteria in a broad spectrum, while it exhibits little activity against Gram-positive bacteria.

European patent publication 0 113 243 describes 7(3-[2-(2-aminothiazol-4-yl)-2-methoxyimino-acetamido]-3-[(2-amino-1.3.4-thiadiazol-5-yl)- thiomethyl]-cef-3-em-4-carboxylic acid and its pivaloyloxymethyl ester as pharmacologically active compounds These compounds show better activity against E. coli, S. aureus, P. vulgaris, P. aeruginiosa and S. marce-scens than Cefotaxime {7-[2-(2-amino-4-thiazolyl)-2-methoxy-iminoacetamido]-cephalosporanic acid; The Merck Index, 10th edition, 19.07}.

It has now been found that the new 7(3-[ 2-(2-Aminothiazol-4-yl)-(Z)-2-Alkoxyimino-acetamido]-3-[(2-mercapto-1,3,4-thia -diazol-5-yl)thiomethyl]-cef-3-em-4-carboxylic acids of formula (I) wherein R denotes a C-1-4 alkyl group and their pharmaceutically acceptable salts and esters exhibit excellent antibacterial activity compared to the known and tested analogues.^ rjy>^ Jj^ s^ ±i S ^

One aspect of the invention thus relates to compounds of the ) formula

wherein R denotes a C 1-4 alkyl group and their pharmaceutically acceptable salts and esters.

The compounds of formula (I) are active primarily against gram-negative bacteria. Furthermore, it has been found that one of the compounds according to the invention, namely 7(3-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyimino-acetamido]-3-[(2-mer capto-1 ,3,4-thiadiazol-5-yl)thiomethyl]-cef-3-em-4-carboxylic acid |og—de£-s~-f-a*wa^søy^i^^ has an antibacterial effect that surpasses the effect of the other compounds produced according to the invention. These compounds are relatively active against a wide range of gram-negative bacteria, and they exhibit, in contrast to the analogous cephalosporins, an excellent effect against Pseudomonas Spp. Indicated 7(3-[ 2-( 2-aminothiazol- 4-yl)-( Z )-2-methoxyimino-acetamido]-3-[(2-mercapto-1,3,4-thiadiazol-5-yl)thiomethyl]-cef-3-em-4-carboxylic acid was subjected to chemotherapeutic tests in the form of its sodium salt This derivative is indicated under the code number "SZMFO 110" in the tests described below.

The MIC values expressed in mcg/ml of SZMFO 110 after

24 hours appears from table 1.

The subsequent table 2 clearly shows that SZMFO 110 is much more active against Pseudomonas aeruginosa than several well-known and widely used third-generation cephalosporin derivatives.

1) 1-//(6R,7R)-7-(2-(2-amino-4-thiazolyl)glyoxyl-amido/2-carboxy-8-oxo-5-thia-1-azabicyclo/4,2, 0/(oeth-2-en-3-yl/methyl/pyridinium hydroxide inner salt 7^-(z)-/0-(1-car-boxy-1-methylethyl)oxime/; The Merck Index, 10th Edition, 1913. 2) (6R,7R)-7-(2-(2-amino-4-thiazolyl)glyoxylamido/-8-oxo-5-thia-1-azabicyclo/4,2,0/oct-2-ene -2-carboxylic acid 7^-(Z)-(O-methyloxime); The Merck Index, 10th edition, 1915. 3) (6R,7R)-7-/2-(2-amino-4-thiazolyl)glyoxylamido/- 3-//(1-methyl-1H-tetrazol-5- yl)-thio/methyl/-8-oxo-5-thia-1-azabicyclo/4,2,0/oct-2-en-2-carboxylic acid 7^-(Z)-(O-methyl-oxime); The Merck Index, 10th edition, 1902. The efficacy of SZMFO 110 was tested in vivo against Salmonella typhi murium and Proteus vulgaris using female CFLP mice as test animals in groups comprising five animals weighing 79-125 g per group. The test compounds were administered subcutaneously. As a control compound, a known cephalosporin derivative was used, i.e. Cefoperazone {7-[D-(-)-α-(4-ethyl-2,3-dioxo-1-piperazinecarboxamido)-α-(4-hydroxyphenyl)-acetamido] -3-[[ (1-methyl-1H-tetraylol-5-yl)thio]methyl]-cef-3-em-4-carboxylic acid; The Merck Index, 10th edition, 1905}. The results of this test are listed in Table 3.

With regard to the data given in Table 3, the following explanation can be given.

During the tests in question, the animals were artificially infected in a way that causes death without treatment. This was achieved by injecting directly the microorganisms used for infection into the abdomen of the mice. In light of this treatment, the animals died within 24 hours. When using SZMFO 110 in a dose as low as 1 mg/kg body weight, practically all of the test animals remained alive. Higher doses are similarly effective. It is very characteristic that one dose of SZMFO 110 kept the animals alive, in sharp contrast to Cefoperazone, which was able to finally keep the test animals alive only at much higher doses or when it was used several times. The data in Table 3 clearly show this: the number of mice kept alive on the 3rd day is different for SZMFO 110 and Cefoperazone. While a fully complete therapeutic effect can be achieved with SZMFO 110 at a dose of 1 mg/kg body weight, the same effect can only be achieved at a dose of 25 mg/kg body weight in the case of Cefoperazone.

Another aspect of the invention relates to a method for producing the compounds of formula

wherein R represents a C 1-4 alkyl group and their pharmaceutically acceptable salts and esters. This method is characterized by a) a carboxy-protected derivative of the compound of formula is acylated with a compound of formula in which T is an amino protecting group and R is as previously defined, or a reactive derivative, after which the protecting groups are removed, or b) a carboxy-protected derivative of the compound of formula is reacted with a compound of formula

after which the protecting group is removed, or j

c) the T-amino protecting group, and if present, the carboxy protecting group of a compound of

formula

in which R and T are as defined above, is removed, and if desired, the thus obtained compound of formula (I) is converted into a pharmaceutically acceptable salt or ester.

Methods a), b) and c), and furthermore the preparation of the protected derivatives of the intermediates used in these methods, the removal of the protective groups and finally the conversion of the products into pharmaceutically acceptable salts and esters, are well known methods. The respective patent literature is very extensive, and as examples only reference is made to US patent publication 4 421 912, European patent publication 0 148 004 and German publication publication 28 04 040.

Procedure a) can preferably be carried out as follows.

To prepare the starting material, 7-ACA of formula is reacted

with 2,5-dimercapto-1,3,4-thiadiazole of formula in acetonitrile. The thus obtained 7-amino-3-[(2-mercapto-1,3,4-thiadiazol-5-yl)thiomethyl]-cef-3-em-4-carboxylic acid of formula (IV) is converted into the corresponding silyl ether by treatment with bis(trimethylsilyl)urea. The protected acid of formula (IV) obtained in this way is reacted with a previously prepared 2-(2-tritylamino-thiazol-4-yl)-(Z)-2-alkoxyiminoacetyl chloride of formula in which R is as defined above, under cooling. The trityl group of the thus obtained 7(3-[ 2-( 2-tritylaminothiazol-4-yl)-(Z)-2-alkoxyimino-acetamido]-3-[(2-mercapto-1,3,4-thiadiazole -5-yl)-thiomethyl]-cef-3-em-4-carboxylic acid of formula

is removed by treatment with formic acid, and the product of formula (I) is recovered in a manner known per se.

The carboxylic acids of formula (I) can be converted into salts, e.g. alkali metal or alkaline earth metal salts, or esters, e.g. acetoxymethyl or pivaloyloxymethyl esters, according to methods well known in the art, e.g. by the methods described in European patent publication 0 113 243.

The antibiotically active compounds produced according to the invention can be formulated for administration in any suitable way for use in human or veterinary medicine, according to techniques and procedures per se kjjwJt in the field with reference to other antibiotics, and the invention therefore includes within its scope a pharmacist -ical preparation comprising an antibiotic active compound produced according to the invention, such as e.g. a pharmaceutically acceptable compound of formula (I) or a salt, or an in vivo hydrolysable ester thereof, together with a pharmaceutically acceptable carrier or excipient.

The preparations may be formulated for administration by any suitable route, such as oral or parenteral

administration, or by topical administration. The preparations can be in the form of tablets, capsules, powders,

granules, pills, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

Tablets and capsules for oral administration can be

in unit dosage form and may contain conventional excipients such as binders, e.g. syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl pyrrolidone; fillers, e.g. lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tableting/lubricants, e.g. magnesium stearate, talc, polyethylene/glycol or silica; break-up agents such as, for example, J potato starch; or acceptable humectants such as sodium lauryl sulfate. The tablets can be coated according to well-known methods in the pharmaceutical industry. Oral liquid preparations can be in the form of e.g. aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable carrier before use. Such/liquid preparations may contain conventional additives such as suspending agents, e.g. sorbitol, methylcellulose, glucose syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose,

aluminum stearate gel or hydrogenated edible fat; emulsifiers, e.g. lecithin, sorbitan monooleate, or acacia; non-aqueous carriers such as vats/ include edible oils, e.g. almond oil, oil esters such as glycerol, 'propylene glycol or ethyl alcohol; in preservatives such as e.g. methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavoring or coloring agents.

Suppositories will contain conventional suppository bases, e.g. cocoa butter and other/glyceride.

For parenteral administration, liquid unit dosage forms are prepared using the compound and a sterile carrier, with water being preferred. Depending on the carrier and the concentration used, the compound can either be suspended/dissolved in the carrier. When preparing solutions, the compound can be dissolved in water for injection and filter sterilized before filling in a suitable ampoule which is then sealed. Preferably, agents such as local anesthetics, preservatives and buffers can be dissolved in the carrier. To increase stability, the preparation can be frozen after filling the ampoule, and the water can be removed under vacuum. The dry lyophilized powder is then sealed in the ampoule, and an accompanying ampoule of water for injection may be provided to reconstitute the liquid prior to use. Parenteral suspensions are prepared in essentially the same manner, except that the compound is suspended in the carrier rather than dissolved therein, and the sterilization cannot be accomplished by filtration. The compound may be sterilized by exposure to ethylene oxide prior to suspension in the sterile vehicle. Preferably, a surfactant or a wetting agent is included in the preparation to facilitate even distribution of the compound.

The preparation can contain from 0.1 to 99.5% by weight, preferably from 10 to 60% by weight, of the active ingredient, depending on the method of administration. Where the preparations comprise dosage units, each unit will preferably contain from 50 to 500 mg of active ingredient. The dose used for adult patients will preferably vary from 100 mg to 12 g per day for an average adult patient (70 kg), e.g. 1500 mg per day, depending on the method of administration and frequency. Such doses correspond to approx. 1.5 to 170 mg/kg per day^ Appropriately, the dose is from 1 to 6 g per day.

The daily dose is conveniently provided by administering the compound multiple times during a 24 hour period. Typically, 250 mg is administered four times a day. day, although the administration dose and frequency that will be most suitable for a particular patient will in practice vary with age, weight and the patient's response, and there will thus be cases where the doctor will choose a larger or smaller dose and a

different frequency of administration. Such dosage regimens are within the scope of the invention.

No toxicological effects are indicated when a pharmaceutically acceptable compound of formula (I), or a salt or ester thereof, is administered within the dosage range indicated above.

The invention also includes a method for treating bacterial infections in humans and animals, comprising administering a therapeutically effective amount of a pharmaceutically acceptable antibiotic compound of formula (I) or a salt or ester thereof.

The following examples illustrate the invention.

Example 1

Preparation of 7ft-[ 2-( 2-aminothiazol-4-yl)-( Z )- 2- methoxy-imino-acetamido]-3-[( 2- mercaptol-1, 3, 4- thiadiazol-5- yl) thio-methyl]-cef-3-em-4-carboxylic acid

(a) Activation of 2-(2-tritylamino-thiazol-4-yl)-(Z)-2-methoxyiminoacetic acid with Vilsmeyer's reagent

At a temperature between +5 and 0°C, 1.8 ml (19.7 mmol) of phosphorus oxychloride was added to 1.5 ml (19.7 mmol) of dry dimethylformamide with constant stirring. The mixture thus obtained was kept at 40°C for 30 min., was then cooled to 20°C, whereupon 60 ml of ethyl acetate was added. At a temperature between -s-5 and 0°C, 7.32 g (16.47 mmol) of 2-(2-tritylamino-thiazol-4-yl)-(Z)-2-methoxyiminoacetic acid was added in small portions to the mixture with constant stirring. After the addition, the reaction mixture was stirred at the same temperature for 30 min.

(b) Silylation of 7(3-amino-3-[(2-mercapto-1,3,4-thia-diazol-5-yl)thiomethyl]-cef-3-em-4-carboxylic acid

5.1 g (14 mmol) 7β-amino-3-[(2-mercapto-1,3,4-thiadia-zol-5-yl)thiomethyl]-cef-3-em-4-carboxylic acid and 19.8 g (150 mmol) of monosilylacetamide was suspended in 180 ml of ethyl acetate. The suspension was boiled in a nitrogen atmosphere with constant stirring for 30 min.

(c) Acylation

The solution obtained in step (b) was cooled to -5-20°C, and under a nitrogen atmosphere the solution obtained in step (a) was added with constant stirring thereto over 15-20 min. After the addition, the reaction mixture was allowed to heat up to 10°C and was stirred at this temperature for 2 hours. After completion of the reaction, the reaction mixture was slowly added to a mixture of 210 ml of saturated potassium chloride solution and 420 ml of ethyl acetate, cooled to -20°C. The insoluble precipitate was removed on a perlite pad, the phases were separated, and the aqueous phase was extracted twice with 100 ml of ethyl acetate each time. The combined organic phases were extracted twice with 100 ml saturated potassium chloride solution each time, dried over magnesium sulfate and evaporated to dryness under reduced pressure. The residue was triturated with ether, filtered, washed with ether and finally dried first with air and then over phosphorus pentoxide in vacuum.

Yield: 8 g.

(d) 7(3-[ 2-( 2-aminothiazol-4-yl)-( Z )-2-methoxyimino-acetamido ]-3-[(2-mercapto-1,3,4-thiadiazol-5-yl )thiomethyl]-cef-3-em-4-carboxylic acid

0.6 g 7(3-[2-(2-tritylamino-thiazol-4-yl)-(Z)-2-methoxyimino-acetylamino]-3-[(2-mercapto-1,3,4- thiadiazol-5-yl)-thiomethyl]-cef-3-em-4-carboxylic acid was dissolved in 10 ml of 85% formic acid. The solution was stirred at room temperature for 2 hours. After adding 5 ml of water, the precipitated triphenylcarbinol was filtered from and washed with a small amount of water The filtrate was evaporated to dryness at 40-45°C, the residue was triturated with ether, filtered off and washed with ether and

finally dried first with air and then over phosphorus pentoxide in vacuum.

Yield: 0.4 g.

<1>H NMR (ppm) DMSO-d6: 3.67 (ABq, 2H, H-2), 3.95 (s, 3H, OCH3), 4.23 (ABq, 2H, H-10), 5 .2 (d, 1H, H-6), 5.8 (q, 1H, H-7), 6.9 (s, 1H, s, H).

Example 2

Preparation of 73-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxy-imino-acetamido]-3-[(2-mercaptol-1,3,4-thiadiazol-5-yl) thio-methyl]-cef-3-em-4-carboxylic acid

(a) 7-amino-3-[(2-mercapto-1,3,4-thiadiazol-5-yl)-thiomethyl]-cef-3-em-4-carboxylic acid

20 g (7.34 mmol) of 7-ACA and 12 g (7.98 mmol) of 2,5-di-mercapto-1,3,4-thiadiazole were suspended in 150 ml of dry acetonitrile. The suspension was cooled to -h5°C with constant stirring. At this temperature, 30 ml of chlorosulphonic acid was added, so that the internal temperature was not exceeded

-f5°C. After the addition was complete, the reaction mixture was allowed to heat up to 10°C and was stirred at this temperature for 40 min. After completion of the reaction, the reaction mixture was added dropwise to 500 ml of water at 0°C with constant cooling and stirring, so that the internal temperature did not exceed 0°C. After the addition was finished, the pH of the thus obtained solution was adjusted to 3.8 using first 10 N, then 5 N sodium hydroxide solution at 0°C while cooling and under

stirring. The precipitated material settled to the bottom at 0°C i

2 hours and was then recovered by filtration. It was

washed successively with water at pH 3.8, methanol and acetone, and finally dried over phosphorus pentoxide in vacuum.

(b) 7(3- [ 2 - ( 2-tritylamino-thiazol-4-yl)-( Z )-methoxy-imino-acetamido]-3-[(2-mercapto-1,3,4-thiadiazol-5 -yl)thiomethyl]-cef-3-em-4-carboxylic acid

(i) Preparation of acid chloride from 2-(2-tritylamino-thiazol-4-yl)-(Z)-methoxyiminoacetic acid

1.32 g (3 mmol) of 2-(2-tritylamino-thiazol-4-yl)-(Z)-2-methoxyiminoacetic acid and 0.42 ml (3 mmol) of triethylamine were dissolved in 24 ml of dry dichloromethane. The solution was cooled

to a temperature between -s-5 and -M0°C, and at this temperature a solution of 0.66 g (3 mmol) phosphorus pentachloride in 10 ml of dry dichloromethane was added dropwise with constant stirring. After the addition, the reaction mixture was stirred at a temperature between +5 and -^10°C for 10 min. The dichloromethane was evaporated. The residue was thoroughly triturated with dry benzene, whereupon the benzene was evaporated. The residue was thoroughly triturated with dry petroleum ether, decanted, and the remainder of the petroleum ether removed by evaporation. The solid material thus obtained was dissolved in acetonitrile. This solution was used for acylation.

(ii) Silylation of 7(3-amino-3-[(2-mercapto-1,3,4-thiadiazol-5-yl)thiomethyl]-cef-3-em-4-carboxylic acid

0.72 g (2 mmol) 7β-amino-3-[(2-mercapto-1,3,4-thia-diazol-5-yl)thiomethyl]-cef-3-em-4-carboxylic acid and 1, 2 g (6.0 mmol) of bis(trimethylsilyl)urea was suspended in 30 ml of dry acetonitrile. The suspension was heated to the boiling point under stirring and nitrogen atmosphere and was then boiled for 40 min.

(iii) Acylation

The solution obtained in step (ii) was cooled to -h10°C. At this temperature, the solution of the acid chloride obtained in step (i) was added dropwise to this solution under a nitrogen atmosphere. After the addition, the reaction mixture was allowed to warm to room temperature and was stirred at this temperature for 2 hours. After completion of the reaction, the acetonitrile was removed by evaporation. The residue was taken up with a mixture of water and ethyl acetate at 0°C, the insoluble components were removed by filtration, and the phases were separated. The aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated, and the residue was triturated with ether, filtered and dried over phosphorus pentoxide in vacuo.

Yield: 0.60 g.

<1>H NMR (ppm) DMSO-d6: 3.60 (ABq, 2H, H-2), 3.80 (s, 3H, OCH3), 4.17 (ABq, 2H, H-10), 5 .10 (d, 1H, H-6), 5.7 (q, 1H, H-7), 6.7 (s, 1H, 2, H), 7.12-7.47 (m, 15H, H-Ar), 8.92 (s, 1H, Ar-NH), 9.57 (d, 1H, C-7NH).

(c) 7(3- [ 2-( 2-aminothiazol-4-yl)-( Z )-2-methoxyimino-acetamido]-3- [ (2-mercapto-1,3,4-thiadiazol-5-yl )thiomethyl]-cef-3-em-4-carboxylic acid

The procedure was as described in step (d) in example 1. The same product was obtained in the same amount, with an identical NMR spectrum.

Claims (2)

1. method for the production of YTp-[2-(2-aminothiazol-4-yl)-(Z)-2-alkoxyimino-acetamido]-3-[(2-mercapto-1,3,4-thiadiazol-5-yl )thiomethyl]-cef-3-em-4-carboxylic acids of formula in which R denotes a^An C1 _/j -alkyl group, fieldT—et—f-a-rma-—— -søy t i s-k—-aJisept a he 1 f . s.aJLt_je.l,lex—e.s±>ex—de-r-a v-/ characterized by a) a carboxy-protected derivative of a compound of formula is acylated with a compound of formula in which T is an amino-protecting group and R is as defined above, or a reactive derivative thereof, after which the protecting groups are removed^ b) a carboxy-protected derivative of a compound of formula is reacted with a compound of formula after which the protecting group is removed; or c) the T-amino protecting group, and if present, the carboxy protecting group of a compound of formula j in which R and T are as defined above, is removed and, if desired, that a thus obtained compound of formula (I) is converted into a pharmaceutically acceptable salt or ester. 2. Process according to claim 1 for the preparation of 7(3-[2-(2-aminothiazol-4-yl)-(Z)-2-methoxyimino-acetamido]-3-[(2-mercapto-1,3,4 -thiadiazol-5-yl)thiomethyl]-cef-3-em-4-carboxylic acid, te41ex--^fe-Æ-a^ma-s^syTj^k— -e s-te-r-.de r a characterized in that corresponding starting materials are used.