NO743582L - - Google Patents

Description

^Procedure for the preparation of 7-(a-substituted

acetamido)- 3~ cephem- 4- carboxylic acid derivatives' >

The present invention relates to a process for the production of previously unknown 7-(α-substituted acetemido)-3-cef©m-4-carboxylic acid derivatives, derivatives thereof at the carboxyl group and salts thereof, particularly pharmaceutically tolerable salts, which compounds exhibit antibacterial activity.

The heretofore unknown 7-(α-substituted acetamido)-3-cephem-4-carboxylic acid derivatives can be represented by the general formula I

where R1 denotes hydrogen, hydroxy-lower alkylthio or a heterocyclic thio group, which may be substituted with lower alkyl or alkanoyloxy-lower alkyl, R denotes lower alkyl, lower

alkylthio-lower alkyl, acyl-lower alkyl, acyiamino-lower alkyl lower alkenyl, ar-lower alkenyl or lower alkynyl,. R denotes hydrogen, lower alkyl or aryl, and X denotes sulphur,

sulfinyl or sulfonyl, with the proviso that R 2 is not a lower alkyl group, when R 1 is hydrogen*

The term "lower" here, when used in the context of groups derived from alkane, alkene or alkyne, such as alkyl, alkenyl or alkynyl, means groups with 1-6 carbon atoms, unless otherwise indicated*

Examples of suitable hydroxy-lower alkylthio groups can be groups with 1-6 carbon atoms such as 2-hydroxyethylthio, 2-hydroxypropylthio, 3-hydroxypropylthio, 2-hydroxybutylthio, 3-hydroxybutylthio, 2-hydroxypentylthio, 3-hydroxypentylthio, 2-hydroxyhexylthio, 3 -hydroxyhexylthio and 5-hydroxyhexylthio, preferably groups with 1-4 carbon atoms, more preferably groups with 2-3 carbon atoms.

The heterocyclic thio group can be an unsaturated ionocyclic heterocyclic thio group, which contains at least one heteroatom selected from oxygen, sulfur and nitrogen. As examples of suitable heterocyclic thio groups groups with a heterocyclic group such as an unsaturated 5-membered heteromonocyclic group containing one svbvol atom and 1-3 nitrogen atoms can be given, e.g. thiazolyl, thiadiazolyl 1,2,4-thiadia9Soly, 1,3,4-thiadia20lyl and 1,2,5-thiadiazoyl) an unsaturated 5-membered heteromonocyclic group containing one oxygen atom and 1-3 nitrogen atoms, e.g. oxazolyl, oxadiazolyl (e.g.

.1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and 1,2,5-oxadiazolyl), and an unsaturated 5-membered heteromonocyclic group containing 2-4

nitrogen atoms, e.g.* triazolyl (e.g. 4H-1,2,4-triazolyl and 2H-1,2,3-triazolyl) and tetrazolyl (e.g. 1H-tetrazolyl and 2H-tetrazolyl), and these heterocyclic groups may optionally be substituted

with lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, cyclopentyl, pentyl, oxycyclohexyl and hexyl), preferably groups with 1-4 carbon atoms, or alkanoyloxy lower alkyl (e.g. . formyloxymethyl, acetoxymethyl, acetoxyethyl,

acetoxypropyl, propionyloxymethyl, butyryloxymethyl, isobutyryloxymethyl, i80butyryloxyethyl, isobutyryloxypropyl, hexanoyloxymethyl, pivaloyloxymethyl, lauroyloxymethyl, lauroyloxyethyl, lauroyloxypropyl, palmitoyloxymethyl, palmitoyloxyethyl and stearoyloxymethyl), preferably lower alkanoyloxy-lower alkyl and higher alkanoyloxy-lower alkyl with 2- 24 carbon atoms, more preferably groups with 5-17 carbon atoms.

As examples of suitable lower alkyl groups groups with 1-6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl; tert.butyl, pentyl and hexyl, preferably groups with 1-4 carbon atoms.

Examples of suitable lower alkylthio-lower alkyl groups can be given groups with 2-12 carbon atoms, i.e. groups, where the

above stated higher alkyl group is substituted with lower alkylthio such as methylthio, ethylthio, propylthio, isopropylthio, butylthio,

tert.butylthio, pentylthio and hexylthio, preferably groups with 2-6 carbon atoms, more preferably groups with 2-3 carbon atoms*

Examples of suitable acyl-lower alkyl groups include lower alkanoyl-lower alkyl groups with 2-12 carbon atoms, 1 in which the above-mentioned lower alkyl group is substituted by lower alkanoyl (e.g. formyl, acetyl, propionyl and butyry1),

aroyl-lower alkyl of 7-14 carbon atoms such as benzoyl-lower alkyl, where the above-mentioned lower alkyl group is substituted with aroyl (e.g. benzoyl, toluoyl and xyloyl), or heterocyclic-carbonyl-lower alkyl of 6-12 carbon atoms, where the above-mentioned lower alkyl group is substituted with heterocyclic carbonyl (e.g. nicotinoyl, furoyl and thenoyl).

Examples of suitable acylamino-lower alkyl groups include lower alkanoylamino-lower alkyl groups with 2-12 carbon atoms,

where the above-mentioned lower alkyl group is substituted with lower alkanoylamino (e.g. formamido, acetamido, pro^ionamido and butyramido), aroylamino-lower alkyl of 7-14 carbon atoms such as

benzamido-lower alkyl, where the above-mentioned lower alkyl group is substituted with aroylamino (e.g. benzamldo and toluamldo), or heterocyclic-carbonylamino-lower alkyl with 6-12 carbon atoms, where the above-mentioned lower alkyl group is substituted with

heterocyclic-carbonylamino (e.g. nicotihamido, furamido and thiophenecarboxamido)•

Examples of suitable lower alkenyl groups include groups with 2-6 carbon atoms such as vinyl, 1-propenyl, allyl, isopropenyl, 2-butenyl, 3-pentenyl, 1-cyclohexenyl and 1,3-cyclohexadienyl, preferably groups with 2- 4 carbon atoms, more preferably groups with 2-3 carbon atoms.

As examples of suitable ar-lower alkenyl groups, groups with 8-9 carbon atoms such as styryl and cinnamyl can be given. As examples of lower alkynyl groups, groups with 2-4 carbon atoms can be given, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and 3-butynyl.

As examples of suitable aryl groups groups with 6-10 carbon atoms such as phenyl, tolyl, xylyl, mesityl, cumenyl and naphthyl can be given, preferably groups with 6-8 carbon atoms. Suitable derivatives at the carboxy group include esters, amides and acid anhydrides, preferably esters (e.g. methyl esters, trichloroethyl esters, pivaloyloxymethyl esters, 1-cyclopropyl ethyl esters, acetoxymethyl esters, methoxymethyl esters, acetonyl esters and

phenyl acyl esters). Examples of suitable pharmaceutically acceptable salts include inorganic salts such as alkali metal salts

(e.g. sodium salts and potassium salts) and alkaline earth metal salts

(e.g. calcium salts and magnesium salts) and salts with an organic base such as trimethylamine, triethylamine and dicyclohexyamine. All or some of the lier mentioned connections with dan general

formula I can be prepared using various methods and some typical methods are set out below*

A typical method for the preparation of the compounds of the general formula I referred to herein is indicated by the following reaction cores where R 1 , R 2 , R 3 and X each have the meaning indicated above.

The reaction in question is carried out by reacting a 3-substituted 7-amino-3-cephem-4-carboxylic acid of general formula II or a derivative thereof at the carboxyl group or a salt thereof with an α-substituted acetic acid with the general formula III

or a reactive derivative thereof at the carboxyl group or et

salt thereof.

With regard to suitable derivatives of the carboxyl group in compounds of the general formula II, reference is made to the examples given in connection with compounds of the general formula I. - ■ Suitable reactive derivatives of the carboxyl group in compounds of the general formula III include e.g. . acid halides, acid anhydrides, activated amides, activated esters, preferably acid chlorides, acid azides, mixed acid anhydrides with an acid such as a dialkylphosphoric acid, phenylphosphoric acid, diphenyl-

phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphoric acid, sulfuric acid, thiosulphuric acid, sulfuric acid, alkyl

carbonic acid, aliphatic carboxylic acid (e.g. pivolic acid, pentanoic acid,

isopantanoic acid, 2-ethylbutyric acid and trichloroacetic acid), aromatic carboxylic acid (e.g. benzoic acid), a symmetrical acid anhydride, an acid amide medimidazole, 4-substituted imidazole, dimethylpyrazole,

triazole or tetrazole, or an ester (e.g. cyanomethyl ester,

methoxymethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dlnltrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester„ methanesulfonylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester and 8-quinolylthioester or an ester with N ,N-dimethylhydroxylamine, l-hydroxy-2-(lH)-pyridone, N-hydroxysuecinimide or N-hydroxyphthalimide). formula lii, to be used in practice..

"In the transaction referred to here, the connection with

the general formula II is previously reacted with a silyl compound (e.g. chlorotrimethylsilane or bistrimethylsilylacetamide) to produce an allyl derivative of the compound of the general formula II at the araino and carboxyl group, which is reacted with a compound of the general formula III to produce the desired compound with the general formula I, and the present invention also includes this method. Derivatives at the carboxyl group in compounds with the general formula II map during the reaction are converted to the free form, and the present invention also includes such reactions.

• (The reaction is usually carried out in a solvent such as acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene

chloride, tetrahydrofuran, ethyl acetate, dimethylformamide, pyridine or any other organic solvent, which does not adversely affect the turnover. Among these solvents, hydrophilic solvents can be used 1 mixture with water.

When the α-substituted acetic acids of the general formula III are used in the reaction in question here in the form of free acids or salts thereof, the reaction is preferably carried out in the presence of a co-sensing agent, such as N,N,-dicyclohexylcarbodiimide,

N-cyclohexyl-N*-morpholinoethylcarbodiimide, N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiiraid, N,N'-diethylcarbodiimide, N/N<V>r diisopropylcarbodilmld, N-ethyl-N'-(3 -dimethylaminopropyl)carbodiimide, N,N'-carbonyldi(2-methylimidazole), pentamethyleneketene-N-cyclohexyl-imine, diphenylketene-H-oxyclohexylimine, alkoxyacetylene, 1-alkoxy-1-chloroethylene,:trialkylphosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphorus oxychloride, phosphorus trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, 2-ethyl-7-hydroxybenzisoxa3olium salt, 2-ethyl-5-(m-sulfophenyDisoxazolium hydroxide intramolecular salt or

(chloromethylene)dimethylammonium chloride. Salts of compounds of the general formula II may be salts at the carboxyl group such as an alkali metal salt. (e.g. sodium or callum salt), an alkaline earth metal salt (e.g. calcium or magnesium salt) or a salt with

one organic base such as trimethylamine or dicyclohexylamine and 8alter at the amino group such as a salt with one acid (e.g. hydrochloric acid, sulfuric acid, acetic acid, tartaric acid, maleic acid, benzenesulfonic acid or

toluenesulfonic acid), and salts of compounds of the general formula III can be an alkali metal salt (e.g. sodium or potassium salt), an alkaline earth metal salt (e.g. calcium or

magnesium salt) or a salt with an organic base such as trimethylamine or dicyclohexylamine.

The reaction is also preferably carried out in the presence of a base such as an alkali metal hydrogen carbonate, trialkylamine, N,N-dialkylbenzylamine or pyridine. When the base or condensing agent is liquid, it can also constitute the solvent. The reaction temperature is not limited, and the reaction is usually carried out under cooling or at room temperature. The reaction product can be isolated in a manner known per se.

The compound with the general formula II used as starting compound and the desired compound with the general formula I are both relatively unstable compounds, which easily split during the reaction, and it is therefore desirable to carry out the reaction and isolation of the product under mild conditions.

Another typical method for the preparation of some of the compounds with the general formula I referred to here appears from the following reaction scheme

2 3 1 where R , R and X each have the above meaning, R' denotes hydroxy-lower alkylthio or a heterocyclic thio group,

which may be substituted with lower alkyl or alkanoyloxy-lower alkyl, and Y denotes azido or lower alkanoyloxy.

The specified reaction is carried out by reacting a compound of the general formula IV or a derivative thereof at the carboxyl group or a salt thereof with a thio compound of the general formula V or an alkali metal salt thereof.

As examples of suitable lower alkanoyloxy groups groups with 1-6 carbon atoms such as formyloxy, acetoxy, propionyloxy, butyryloxy and pentanoyloxy can be given, preferably groups with 1-4 carbon atoms, more preferably groups with 2-3 carbon atoms.

With regard to suitable hydroxy-lower alkylthio groups, heterocyclic thio groups and derivatives of compounds of the general formula IV at the carboxyl group, reference is made to the examples given in connection with compounds of the general formula I, and with regard to salts of compounds of the general formula formula IV, reference is made to the examples given in connection with compounds of the general formula III.

Examples of suitable alkali metal salts include sodium salts and potassium salts.

Derivatives of the carboxyl group in compounds with the general formula IV can be converted to the free group during the reaction

form, and the present invention also relates to such sales.

The reaction referred to herein can be carried out in the presence of a solvent such as water, acetone, chloroform, nitrobenzene, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethyl sulfoxide or any other organic solvent which does not have an adverse influence on turnover, preferably

.in a strongly polar solvent• Among the solvents, hydrophilic solvents can be used in mixture with water. The reaction is preferably carried out in an approximately neutral medium. When the compound of the general formula IV or the thio compound

with the general formula V is used in free form, the reaction is preferably carried out in the presence of a base such as an alkali metal hydroxide, alkali metal carbonate, alkali metal hydrogencarbonate or trialkylamine. The reaction temperature is not limited, and the turnover is carried out

usually at room temperature or by heating. The reaction product can be isolated from the reaction mixture in a manner known per se. The compound with the general formula IV used as starting material and the desired compound with the general formula I" are both relatively unstable compounds, which are easily split during the reaction, and it is therefore desirable to carry out the reaction and isolation of the product under mild conditions.

A further alternative method of manufacture

of some of the compounds with the general formula I referred to here can be seen from the following reaction core

4

where R . denotes lower© alkyl, A denotes lower© alkylene,

5' •

2 denotes thiadiazoldiyl, and R denotes alkanoyl.

The said reaction is carried out by reacting a compound of the general formula VI or a reactive derivative thereof at the carboxyl group or a salt thereof with a carboxylic acid of the general formula VI or a reactive derivative thereof at the carboxyl group or a salt thereof.

With regard to examples of suitable lower alkyl groups, derivatives of compounds of the general formula VI at the carboxyl group and: reactive derivatives of compounds of the general formula VII at the carboxyl group, reference is made to the above, and with regard to salts of compounds of the general formula VI and VII reference is made to the examples given in connection with compounds of the general formula III.

Examples of suitable lower alkylene groups can be groups with 1-4 carbon atoms such as methylene, ethylene, propylene, isopropylene and butylene, preferably groups with 1-2 carbon atoms. Examples of suitable alkanoyl groups can be groups with 1-18 carbon atoms such as formyl, acetyl, propionyi, butyryl, isobutyryl valeryl, hexanoyl, pivaloyl, lauroyl., palmitoyl and stearoyl) preferably lower alkanoyl groups and higher alkanoyl groups with 1-18 carbon atoms, more preferred groups of 4-16

carbon atoms.

In the reaction described here, the compound with the general formula VI can be reacted in advance with a silyl compound (e.g. chlorotrimethylsilane or bistrimethylsilylacetamide) to produce silyl derivatives of compounds with the general formula VI at the carboxyl group, which are reacted with a compound with

the general formula VII for the preparation of the desired compound with the general formula I", and the present invention also includes such reactions. Derivatives of the carboxyl group in compounds with the general formula VI can be converted to free form during the reaction, and the present invention also includes such reactions .

The reaction is preferably carried out at room temperature or

by heating, and almost the same solvent and condensation agent and the same base can be used in the reaction, if desired, as is used in the above-described reaction of compounds of the general formula II with compounds of the general formula III.

When the compounds with the general formula I, I' and I" produced in this way are in the form of free acids, these compounds can be converted into pharmaceutically acceptable salts thereof using methods known per se. The compounds described here with the general formula I Exhibits high antibacterial activity and inhibits the growth of a large number of microorganisms, including gram-positive and gram-negative bacteria The cephalosporin compounds described here can

therapeutic !administration is used in the form of pharmaceuticals

preparations containing the compounds in admixture with pharmaceutically acceptable carriers such as organic or inorganic solid or liquid excipients, which are suitable for oral, parenteral or

external administration. The pharmaceutical preparations can be in solid form such as capsules, tablets, dragees, ointments or suppositories or in liquid form such as solutions, suspensions or emulsions. In the preparations indicated above, excipients, stabilizers, wetting agents, emulsifiers, buffer substances and other commonly used additives may be present if desired.

The dosage of the compounds depends on the patient's age and condition, but a consistent single dose of approx. 100 mg, 250 mg and 500 mg of the compounds described here have been shown to be effective in the treatment of diseases caused by bacterial infection. Amounts between 10 mg and about 1000 mg or more can generally be administered.

The method according to the invention is explained in more detail by the following examples

Example 1

a) 2.76 g of methylthioacetic acid and a few drops of dimethylformamide are added to 3 g of thionyl chloride and the mixture is stirred at

room temperature. Excess thionyl chloride is distilled off under reduced pressure, and the residue is dissolved in 30 ml of dry acetone.

6.60g. 7-amino-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3~cephem-4-carboxylic acid and 6.0 g of sodium bicarbonate are dissolved in a

mixture of 90 ml water and 70 ml acetone. The previously prepared solution is added dropwise to the solution at a temperature between -5 and 0°C, and the mixture is stirred at room temperature for 2 hours.

300 ml of water is added to the reaction mixture, and the mixture is washed

with 200 ml of ethyl acetate. The aqueous phase is separated, set

at a pH value of 2 with 1N hydrochloric acid and then extracted with 300 ml of ethyl acetate. The aqueous phase is extracted twice with 100 ml of ethyl acetate. The ethyl acetate extracts are combined, washed three times with water and then dried over magnesium sulfate. The solvent is distilled off from the solution. A small amount of ethyl acetate is added to the residue, and the mixture is allowed to stand, whereby 2.5 g of 7-methylthio-acetamido-rj-(1,3,4-thiadiazol-2~yl)thiomethyl-3-cephem-4- carboxylic acid 1 form of a brown powder. The powder is dissolved in an aqueous sodium bicarbonate solution. The solution is treated with activated charcoal, acidified with IN hydrochloric acid and then extracted with ethyl acetate.

The extract is dried, and the solvent is distilled off below

reduced pressure from the solution, whereby 1.2 g of the dan rena are obtained

compound with melting point 128-131°C (decomposition) in the form of a yellow powder. . b) 1 g of methylthioacetic acid and three drops of dlmethylformamide are added to 6 ml of thionyl chloride, and the mixture is stirred at 40°C for 2 hours. Excess thionyl chloride is distilled off from the mixture,

and 70 ml of acetone are added to the residue.

6.8 g of 7-amino-3-(1~methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid are dissolved in a mixture of 75 ml of aqueous solution and 5.9 g of sodium bicarbonate bg 50 ml of acetone, to the solution is added dropwise while cooling the previously prepared © acetone reading, and the mixture is stirred for 2 hours.'- The reaction mixture is concentrated under reduced pressure. To the residue, ice water is added, and the mixture is washed with ethyl acetate. The aqueous solution is acidified

with 10% hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, treated with activated carbon, dried and then concentrated under reduced pressure. Ethyl acetate is added to the residue, and the precipitated crystals are collected by filtration and washed with ether, thereby obtaining 4.8 g of 7-methylthioacetamido-3-(1-methyl-1H-tetrazol-5-yl)-thiomethyl-3-cephem-4 -carboxylic acid with melting point 81-84°C. c) 3.44 g of 7-amino~3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-,4-carboxylic acid are dissolved in a mixture of 12 g of triethylamine, . 15 ml of acetone and 15 ml of water, and the solution is cooled to 0°C 1.59 g of methylthioacetic acid is added to 80 ml of tetrahydrofuran, which has been refluxed and distilled over lithium aluminum hydride, and the mixture is stirred while cooling (from -20 to -18°C ) with dry ice and acetone. 1.6 g of triethylamine and 2.0 g of isobutyl chloroformate are added to the solution. The mixture is stirred vigorously, and the previously prepared solution is added to the mixture at once at 0°C. The mixture is stirred for one hour, and the solvent. is distilled from the mixture under reduced pressure at a temperature below 40°C. 30 ml of water is added to the residue, and the mixture is adjusted to a pH value of 8 and washed with ethyl acetate. 150 ml of ethyl acetate is added to the aqueous phase, and the solution is adjusted to a pH value of 2 with 2N hydrochloric acid. The precipitate is filtered off, and the ethyl acetate phase is separated. The resulting aqueous phase is extracted twice with 50 ml of ethyl acetate, and the extracts are added to the previously prepared ethyl acetate phase. , the ethyl acetate solution<y>ash3twice with water and twice with an aqueous saturated sodium chloride solution and then dried over magnesium sulfate. The solution is concentrated under reduced pressure, whereby 1.9 g of yellowish brown 7-methylthio-acetamido-3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4- carboxylic acid with melting point 167-168°C (decomposition). d) A mixture of 3.45 g of 7~amino-3-(3-methyl-1,2,4-thiadiazol-5-yl)t±omethyl-3-ce£am-4«carboxylic acid? 1.20. g of t-acetylamine, 11.5 ml of acetone and 17.5 ml of water are added at 0°C to a mixture of 2.12 g of methylthioacetic acid, 2.74 g of isobutyl chloroformate, 2.03 g of triethylamine and 80 ral of tetrahydrofuran. The mixture is treated in an analogous manner as described in example 1c, whereby 3.5 g of 7-methylthioacetamido-3-(3-methyl-1,2,4-thladiazol-5-yl)thiomatyl-3-aQfem-4-carboxylic acid is obtained with melting point 179-180°C (decomposition) in the form of a yellow powder. e) 7.6 g of 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid and 3.0 g of mesylacetic acid are used as starting compounds. The reaction and post-treatment are carried out in an analogous manner to that described in example 1a, whereby 1.1 g of 7-mesyl-acetamido-3-(5-methyl-1,3?4-tladia2:ol-2~yl)thiomethyl-3- c<3fem-4-carboxylic acid with melting point 155-161°C. f) 3.3 g of allylthioacetic acid is added to 6 ml of thionyl chloride containing 3 drops of dimethylformamide. The mixture is allowed to stand until bubbling ceases, and then the mixture is heated at 50°C for 30 minutes <> Excess thionyl chloride is distilled off from the reaction mixture, and the residue is dissolved in 70 ml of dry acetone. 75 ml. aqueous solution of 7.6 g of 7-amino-3-'(57methyl-1,3,4--' thiadiazol-2-yl)thiomethyl-3=-CQphos~4-carboxylic acid and 5.9 g of sodium hydrogen carbonate is added to 50 ml of acetone. The previously prepared solution is added dropwise to the solution while cooling, and the mixture is stirred for 12 hours. The reaction mixture is concentrated, ice water is added to the residue, and the mixture is washed with ethyl acetate. The aqueous solution is acidified with 105 lg hydrochloric acid and extracted. with: ethyl acetate. The extract is washed against water and dried, and the solvent is distilled off under reduced pressure, thereby obtaining 5.6 g of 7-allyltioaeatamido~3-(5-msty 1-1,3,4-thiadiazol-2-yl)tlomety 1- 3-cef©m-4-carboxylGyr<a with cmalto point 156-158°c (decomposition).

g) A mixture of 2.58 g of 7-amino-3-(3-methyl-1-1,2,4-thiadia501-5-yl)-7-thiomethyl-3'c@f©m^4-carboxylic acid, 1.0 g triethylamine, 15 ml

acetone and 15 ml of water and a mixture of 1.65 g of allylthioacetic acid, 1.70 g of isobutyl chloroformate, 1.4 g of triethylamine and 60 ml of tetrahydrofuran are allowed to react with each other and are post-treated in an analogous manner as described in ekeempol le. The precipitated crystals are recrystallized from a mixture of ethyl acetate/otor and acetonitrile,

whereby 1.6 g of colorless 7-allylthioacetamido-3-(3-methyl-1,2,4-thiadlazol-5-yl)thiomethyl-3-eefem-4-carbofecylic acid with melting point

■ii4~ii5°c« •/•/>.•

h) A mixture of 2.58 g of 7-amino-3-(3-methyl-1^,4-thiadiazol-5.-yl)thiomethyl-3-cephem-4-chlorocarboxylic acid, 1.0 g of triethylamine, 15 ml of water and 15 ml of acetone and a..mixture of 1.65 g of 2~propynylthio~

acetic acid, 1.70 g of isobutyl chloroformate, 1.4 g of triethylamine and 60 ml of tetrahydrofuran are allowed to react with each other and are processed in an analogous manner as described in example 1c, whereby 7-(2~propynyl)-thioacetamido-3-(3-methyl) is obtained -1,2,4-thiadiazole-5-yi)thiomstyl-3-cephem-4-

carboxylic acid.* The product produced is recrystallized from a mixture of ethyl acetate and ether, thereby obtaining 1*75 g of the pure

compound with melting point 127-129°C in the form of light brown granular crystals.

i) 1.48 g of allyl thiol is added to a solution of 1.04 g of sodium methoxide in 30 ml of dry methanol, 2.15 g of a-bromophenylacetic acid is added to the solution while stirring in a nitrogen atmosphere, and the mixture is stirred for 3 hours at room temperature. A large part of the methanol is removed under reduced pressure, and the residue is dissolved in 1 water and washed with ethyl acetate. The aqueous phase is acidified with 2K hydrochloric acid and extracted three times with 100 ml ethyl acetate» The extract is washed with water and dried over magnesium sulfate» The ethyl acetate is distilled off under reduced pressure, whereby a viscous

oil, and the oil is allowed to stand, thereby obtaining 1.8 g of 2-allyl thio-2-phenylacetic acid with a melting point of 58-65°C in the form of crystals» A mixture of 3.44 g of 7-amino-3-(5- methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3~cephem-4-carboxylic acid, 1.1 g of triethylamine, 10 ml of water and 10 ml of acetone and a mixture of 2.0 g of the previously prepared 2 -allyl-thio-2-phenylacetic acid, 1.3 g of isobutyl chloroformate, 1.1 g of triethylamine and 50 ml of tetrahydrofuran are allowed to react with each other and post-processed in an analogous manner as described in example 1c, whereby 2.0 g of 7-(2-allylthio) is obtained -2-phenylacetamido)-3-(5-methyl-1,3,4-thladiazol-2-yl)thiomethyl~3-cephem-4-carboxylic acid with melting point 8?-94°C

(cleavage) in the form of white granular crystals.,

j) 7~amino->3-(4-methyl-4E-1,2^-triazol-S-yl)thiomethyl-S-cephem-^-carboxylic acid and methylthioacetic acid are used as starting compounds, and the reaction and often treatment are carried out on

, analogous way as described in example la, whereby 7-methylthio-acetamidb-3-(4-methyl-4H-1,2,4-triazol-3-yl)thiomethyl-3-cephem-4-carboxylic acid is obtained with a melting point of 154 -159°C (decomposition). k) 3.4 g of 7-amino-3-(5-methyl-1,3,4-thiadiazol~2-yl)thiomethyl-3-cephem-4-carboxylic acid are dissolved while cooling at 0-5°C in a mixture of 35 ml of acetone/water (1:1) and 3.0 g of triethylamino pet are added dropwise over the course of 20 minutes while stirring at the same temperature to the solution, a solution of 2.0 g of isopropyl thioacetyl chloride in 10 ml of dry acetone. During the addition, the pH value of the solution is adjusted to 7-8 with triethylamine. The mixture is stirred for 30 minutes at the same temperature, and then the reaction temperature is increased to room temperature. After distillation of some of the acetone at 40°C under reduced pressure, the mixture is washed with 50 ml of ethyl acetate. 80 ml of ethyl acetate are added to the aqueous phase, and the mixture is adjusted little by little to a pH value of 1.8 with

1N hydrochloric acid." The precipitated unreacted 7-amino-3-(5-methyl-1,3^4-thiadiazbl-2-yl)thiomethyl-3-cephem-4-carboxylic acid is filtered off, and the ethyl acetate phase is separated. The aqueous phase is extracted further with 70 ml of ethyl acetate, cg the ethyl acetate fractions are collected. The extract is washed three times with 30 ml of saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is removed under reduced pressure, thereby obtaining 2.8 g of 7-isopropyltriocetaraido-3-(5-raethyi-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid with a melting point of 156- rl57°C in the form of colorless crystals.

1) A solution of 3.25 g of tert.butylthioacetyl chloride in 10 ml of acetone is placed during 5 minutes while stirring and cooling at

—5~0°C to eh solution of 5.16 g of 7-amino-3-(5-arethyl-1,3,4-thiadiazol-2-yl)thiomethyl~3-cephem-4-carboxylic acid in a mixture of 20 ml of acetone, 30 ml of water and 4.1 g of triethylamine. The mixture is stirred for 30 minutes at the same temperature and for a further 30 minutes at room temperature. The reaction mixture is washed twice with 30 ml of benzene, and 150 ml of ethyl acetate is added to the aqueous phase.

The mixture is adjusted to a pH value of 2 with 10% hydrochloric acid, and it

.precipitated unreacted 7-araino~3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (0.75 g) from raf Utres. The ethyl acetate phase is separated, and the aqueous phase is extracted twice with 50 ml of ethyl acetate. The ethyl acetate fractions are collected, washed three times with 30 ral of water and twice with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is removed, thereby obtaining 4.6 g of 7-tert.butylthioacetamido-3-(5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid with melting point 154-155° C (cleavage). %. m) A solution of .2.1 g of 2-methylthio-2-methylacetyl chloride in 10 ml of dry acetone is placed during approx. 5 minutes with stirring and cooling at -5 - 0°C to a solution of 3.4 g of 7-amino-3*-(5-methyl-*1,3,4-thiadiazol-2-yl)ticiaethyl-3- cephem-4-carboxylic acid 1 a mixture of 35 ml of acetone/water (Isl) and 4.0 g of triethylamine» The mixture is stirred for 10 minutes at the same temperature and 20 minutes at room temperature. Some of the acetone is distilled off at 35°C under reduced pressure, and the residue is washed with 50 ml of ethyl acetate. 50 ml of ethyl acetate are added to the aqueous phase, and the mixture is adjusted to a pH value of 2.2 with 1K hydrochloric acid. After filtering off the precipitated unreacted 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl 1-3-cephem-4-carboxylic acid (0.35 g), the ethyl acetate phase is separated. The aqueous phase is extracted with 50 ml of ethyl acetate, and the two ethyl acetate phases are separated. Wash the solution four times with 20 ml of water

and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is removed under reduced pressure, whereby 2.7 g of 7-(2-methylthio-2-methylacetamido)-3-(5-methyl-1,3,4-

thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid. The crystals are recrystallized from a mixture of ethanol and water (5 ti), thereby obtaining 1.95 g of the desired compound with a melting point of 171-172°C.

n) The following compounds are prepared in an analogous manner as described in examples la-1m using the corresponding starting compounds. 1) 7-Raethylthioacetamido-3-(5-isobutyryloxymethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (oil) and its sodium salt (melting point 200.5 - 202°C ( cleavage)). 2) 7-methylthioacetamido-3-(5-palmitoyloxymethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (powder) and its sodium salt (melting point 145-150°C (decomposition) ).

o) 3.96 g of allylthioacetic acid are dissolved in a mixture of 3.4 g, triethylamine and 15 ml of methylene chloride. 4.22 g of benzoyl chloride are added dropwise at a temperature between -15 and -20°C to the solution, and the mixture is stirred at the same temperature for 20 minutes.

4.28 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid and 2.42 g of triethylamine are dissolved in a mixture of 22.5 ml of acetone and 22.5 ml of water. Tii the solution is placed at -10°C the previously prepared solution

solution, and the mixture is stirred at the same temperature for 10 minutes. The reaction mixture is washed with 200 ml of benzene, the

aqueous phase is adjusted to a pH value of 5-6 with 1N hydrochloric acid, and the precipitate is filtered off. The filtrate is adjusted to a pH value of 4 and washed three times with 150 ml of ether. The aqueous phase is adjusted

at a pH value of 1 with 1N hydrochloric acid and extracted three times with ethyl acetate. The extract is washed with water and dried over magnesium sulfate, and the ethyl acetate is distilled off from the solution, whereby

1.7 g of 7-allythioacetamido-3-methyl-3-cephei^4-carboxylic acid with melting point 118-119°C is obtained in the form of a colorless powder.

p) 5.04 g of benzoylmethylthioacetic acid is added to 6 ml of thionyl chloride containing three drops of dimethylformamide, and the mixture is allowed to stand at room temperature until bubbling ceases, and is then heated to 50°C for 30 minutes. Excess thionyl chloride is distilled off from the counterion mixture, and the residue is dissolved in 170 ml of dry acetone.

4.3 g of 7-amino-3-methyl-3-eefem-4-carboxylic acid and 75 ml of aqueous

solution of 5.9 g of sodium carbonate is added to 50 ml of acetone. The previously prepared solution is added dropwise to the mixture while cooling, and the mixture is stirred for 2 hours. The reaction mixture is concentrated, ice water is added to the residue, and the mixture is washed with ethyl acetate. The aqueous solution is acidified with 10% hydrochloric acid and then extracted with ethyl acetate. The extract is washed against water and dried, and the solvent is distilled off under reduced pressure, thereby obtaining 0.9g of 7-benzylmethylthioacetamido-3-methyl-3-CQfem-4-carboxylic acid with a melting point of 120-124°c. q) To a solution of 10.2 g of potassium hydroxide in water, 7.6 g of mercaptocddicoyre and then 8.0 g of chloromethyl methyl sulphide are added dropwise while stirring at 5°C in a nitrogen atmosphere.

The mixture is stirred for 22 hours at room temperature. The reaction mixture is washed with ether, acidified with concentrated hydrochloric acid and extracted. with chloroform. The extract is washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off, thereby obtaining 4.4 g of methylthiomethylthioacetic acid 1 ta a<y>,

a colorless oil©[XR spectrum» 2680, 2570, 1710, 1420, 1295, 1200

and 1130 cm"1, spectrum (CDCl 3 , 6) 2.17 (3H, s), 3.40 (2H> o), 3.80 (2H, s), 10.37 (1H, s)]. 2 .14 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid is dissolved at 0°K in 40 ml of an aqueous solution containing 1.11 g of triethylamine.

1.67 g of the previously extracted methylthiomethylthioacetic acid. is dissolved in 60 ml of dry tetrahydrofuran, and the solution is cooled to a temperature between -17 and -15°C. 1.11 g of triethylamine and 1.5 g of isobutyl chloroformate are added to the solution. The previously extracted solution is added dropwise to the mixture at 0-5°C, and the mixture is stirred. at room temperature for one hour. Tetrahydrofuranot av=^ is distilled under reduced pressure, and ethyl acetate is added to the residue. The mixture is acidified by the dropwise addition of concentrated hydrochloric acid with stirring* The ethyl acetate phase is separated and dried over magnesium sulphate, and the solvent is distilled off. The oily residue was washed with diisopropyl ether, with ethyl acetate and with ether, which gave 6.65 g of 7-methylthiomethylthiacetamide-3-mQtyl-3-ephen-4-carboxylic acid with a melting point of 140 °C (splitting) in the form of a

block yellow powder. r) A mixture of 1.01 g mercaptoacetic acid, 1.5 g bengamido-methanol and 100 mg p-toluenesulfonic acid is refluxed for 12 hours in an oil bath at 120°C. The reaction mixture is dissolved in ethyl acetate and dried. The solvent is removed under reduced pressure, whereby

whereby 1.6 g of benzamidomethylthioacetic acid is obtained in the form of an oil

[IR spectrum (film) 3450, 2650, 2550, 1730, 1640, 1580, 1535, 1490, 1375, 1275, 1245, 1150, 1045, 720, 695 cm"1, NMR spectrum (CDC13, 6), 3 .40 (2H, s), 4.66 (2H, d, J « 6 Hz), 7.25-7.56 (2H, m), 7.67 - 7.93 (3H, m), 11, 9 (1H, s)]. 4.3 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid is dissolved in a mixture of 2.02 g of triethylamine, 20 ml of acetone and 20 ml of water, and the mixture is cooled to 0°C.

6.75 g of the previously extracted benzamidomethylthioacetic acid is added to 100 ml of tetrahydrofuran, which has been refluxed and distilled over lithium aluminum hydride, and the mixture is stirred while cooling (between -20 and -18°C) with dry ice and acetone. For the mixture

add 3.04 g of triethylamine and 4.1 g of isobutyl chloroformate. The mixture is stirred vigorously, and the previously prepared solution is added

once at 0°C to the mixture. The mixture is stirred for Sn hour, and then the solvent is distilled off under reduced pressure at a temperature below 40°C. 30 ml of water is added to the residue, and the mixture is adjusted to a pH value of 8 and washed with ethyl acetate* 150 ml of ethyl acetate is added to the aqueous solution, and the aqueous phase is adjusted to a pH value of 2 with 2N hydrochloric acid. The precipitate from raf is filtered off,<p>and the ethyl acetate phase is separated. The remaining aqueous phase is extracted twice with 50 ml of ethyl acetate, and the extracts are added to the previously prepared ethyl acetate phase.

The solution is washed twice with water and with a saturated aq

sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure, whereby 4.4 g of 7-benzamidomethyl-thioacetamido-3-methyl-3-cephem-4-carboxylic acid with melting point 95-97°C are obtained. s) 2.14 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid is dissolved

in a mixture of 1.2 g of triethylamine, 15 ml of water and 15 ml of acetone, and the solution is cooled to -10°C. Dissolve 1.95 g of 2-propynylthioacetic acid in 70 ml of dry tetrahydrofuran* Add 1.8 g of triethylamine and 2.05 g of isobutyl chloroformate to the solution at -20°C, and stir the mixture* Add the mixture all at once while stirring at -10° C the former

manufactured solution. The mixture is stirred at room temperature for 1 30 minutes and then concentrated under reduced pressure. 150 ml of ethyl acetate are added to the residue, the mixture is acidified with dilute hydrochloric acid, and then the ethyl acetate phase is separated. The extract is washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate,

and then the solvent is distilled off, whereby 1.0 g of 7-(2-^propynyl)thioacetamido-3-methyl-3-cephem-4-carboxylic acid with melting point

133°C (decomposition).

t) 2.14 g of 7-amino-3-methyl^3-cephem-4-carboxylic acid is dissolved in a mixture of 1.1 g of triethylamine, 10 ml of water and 10 ml of acetone. The solution is added once at 0°C to a solution of 3.1 g of 2-allylti©-2-phenylacetic acid, 2.0 g of isobutyl chloroformate, 1.6 g of triethylamine and 60 ml of tetrahydrofuran, and the mixture is stirred at

room temperature 1 2 hours, The precipitate from raf is filtered off, and the filtrate is concentrated under reduced pressure at 40°C. 20 ml of water is added to the residue, and 150 ml of ethyl acetate is added to the aqueous solution. The mixture is adjusted to a pH value of 2 with 2N hydrochloric acid. The aqueous phase is separated and extracted twice with 50 ml of ethyl acetate. The ethyl acetate extract is added to the previously extracted ethyl acetate solution, washed with water and twice with saturated aqueous sodium chloride solution in the order indicated and dried

then over magnesium sulfate. The ethyl acetate: is distilled off under reduced pressure from the solution, and the residue is treated with a mixture of ethyl acetate and ether, whereby 1.2 g of 7-(2-allylthio-2-phenylacetamide©)-3-methyl-3-cephem-4-carboxylic acid is obtained with melting point 68-73°C.

u) Dissolve 1.7 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid in a mixture of 1.0 g of triethylamine, 15 ml of water and 15 ml of acetone.

1.9 g of glacial styrylthioacetic acid are dissolved in 60 ml of dry tetrahydrofuran. 1.3 g of triethylamine and 1.4 g of isobutyl chloroformate are added to the solution under vigorous stirring at -20°c, and the mixture

stir for three minutes. The mixture is added at once at ^10°C

with vigorous stirring the previously prepared solution, and the mixture is stirred at room temperature for one hour. The reaction mixture is concentrated under reduced pressure at 40°c, and the residue is washed with ethyl acetate. Ethyl acetate is added to the residue, and the mixture is adjusted at 5°C to a pH value of 2 with 100% hydrochloric acid. The ethyl acetate phase is separated, and the remaining aqueous phase is extracted with ethyl acetate. The extract is placed in the previously extracted ethyl acetate phase, washed with water and dried over magnesium sulfate. The solvent is distilled off under reduced pressure from the solution. The yellow oily residue is treated with diisopropyl ether and ethyl acetate, thereby obtaining 1.0 g of 7-^(cis-st<y>r<y>l-thioacet<a>mido)•=■<3>-m©t<y >1-3-cephem-4-carboxylic acid with melting point 142-146°C (decomposition).

v) Since the following compounds are prepared in an analogous manner as described in example la lm or lolu using de

corresponding output connections. 1) 7-Mathyltideacetamido-3-(2-hydroxyethyl)thiomethyl-3-cephem-4-carboxylic acid with melting point 134-138°C. 2) 7-allylthioacetamido-3-(2-hydroxyethyl)thiomethyl-3"cephem-4-carboxylic acid 1 form of a hygroscopic powder [IR spectrum (nujol) 3350, 1780, 1720, 1665, 1525 cm"1].

w) At 0°C, 6.5 mg

sodium tungstate pg 6 ml hydrogen peroxide* The resulting mixture is stirred at 3°C until the starting compounds disappear.

Water is added to the reaction mixture, and the methylene chloride is distilled off. The residue is strongly acidified and extracted after adding sodium chloride four times with ethyl acetate. The extract is dried over magnesium sulfate, and the solvent is distilled off. The residue is recrystallized from methylene chloride, thereby obtaining 7 g of 2f-methanesulfin<y>l-2-phen<y>acetic acid with a melting point of 123-126°C. Dan prepared 2-mesansulfinyl-2-phenylacetic acid (198 mg) and 100 mg

triethylamine is dissolved in 5 ml of methylene chloride. The solution is set drop by drop over 10 minutes to a temperature between -65

and -60°C cooled solution of 136 mg of isobutyl chloroformate in 5 ml of methylene chloride* The resulting mixture is stirred for 30 minutes, after which a solution of 344 mg of 7-aminoO-3- is added dropwise at a temperature between -65 and -60°C (5-methyl-1,3,4-thiadiazol-2-yl)-thiomethyl-3-cefear-4-carboxylic acid and to this 2 molar equivalents of bistrimethylisilylacetaraide in 5 ml of methylene chloride* The resulting mixture is stirred for 2 hours. 10 ml of aqueous sodium bicarbonate solution is added to the reaction mixture, and the water phase is separated using a separatory funnel, then extracted little by little with ethyl acetate and kept neutral with 10% hydrochloric acid. The extract is dried over magnesium sulfate, and the solvent is distilled off. Ether is added to the residue for pulverization; The powder obtained in this way is collected by filtration and dried, thereby obtaining 110 mg of 7-(2-methanesulfinyl~2-phenylacetamido)-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3 -cephem-4-carboxylic acid with melting point 110-130°C [IR spectrum (nujol) 3300, 1785, 1715, 1680 cm"<1>, NMR spectrum (DjO + NaHCOj, 6) 2.51

(s, 3H), 2.72 (s, 3H), 3.75, 3.42 (AB-q, 2H, J> 17Hz), 4.00

(d, 1H, J « 13 Hz), 4.50 (d, 1H, J » 13 Hz), 5.10 (d, 1H, J 4.5 Hz), 5.68 (d, 1H, J » 4.5 Hz)].

x) Using the method described in examples la - lm, lo - lu or lw, 7-methaneulfinyl-acetamido-3-' (5-methyl-1, 3,4-thiadiazol-2-yl) thiomethyl-3- cefera-4-carboxyl with melting point 117-119°C (decomposition) using 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid and ethanesulfinylacetic acid as starting compound.

Example 2

a) 3.18 g of methylthioacetic acid are dissolved in 3.4 g of triethylamine, until the mixture is set at a temperature between -10 and -15°C 4.22 g

benzoyl chloride, and then the mixture is stirred at the same temperature for 20 minutes.

5.45 g of 7-aminocephalosporanic acid are dissolved in a mixture of 2.42 g of triethylamine, 10 ml of acetone and 10 ml of water, and the mixture is cooled to a temperature between -5 and -10°C. Add to the mixture

dropwise at a temperature between -5 and -10°C the previously extracted

solution/ as the mixture is kept at a pH value of 7.5-8 by the addition of triethylamine. The reaction mixture is washed with benzene. The aqueous solution is adjusted to a pH value of 4, and the precipitate from raf is removed. The filtrate is washed three times with ether, adjusted to a pH value of 1 and then extracted three times with ethyl acetate. The extract is washed with water and dried over magnesium sulphate, and the ethyl acetate is distilled off under reduced pressure. The white powdery residue is washed with a mixture of ethyl acetate and ether, thereby obtaining 3.4 g of 7-methylthioacetamidocephalosporanic acid with a melting point of 164°C (decomposition). The recovered 7-methyl-thioacetamido-cephalosporanic acid (720 mg) and 340 mg of sodium bicarbonate are dissolved in 30 ml of phosphate buffer with a pH value of 5.2. 330 mg of 4-methyl-4H-1,2,4-triazole-3-thiol are added to the solution, and the mixture is stirred for 4.5 hours at 60-35°C. The reaction mixture is cooled, adjusted to a pH value of 1-2 with 10% hydrochloric acid, washed against ethyl acetate and freeze-dried. 70 ml of acetone is added to the residue, and undissolved material is filtered off. The acetone is distilled off from the filtrate, and the residue is washed with a small amount of acetone and then with a small amount of water, whereby 260 mg of 7-methylthioacetamido~3-(4-methyl-4H-1,2,4-triazole) are obtained (iii) Thiomethyl-3-cephem-4-carboxyyl ester with melting point 154-1596C (decomposition). '

IR spectrum» v^l®3" ■ 1765, 1700 (shoulder) and 1(550 cm"1.

NMR spectrum 6 (b26+ WaHCO3) in ppm 2.17 (3H,, s) 0 3.33 (2H, s),

3.38 (1H, d, J o 17 Hs), 3.70 (3H, s),, 3.77 (1H, d,

J a 13 Hz), 3.86 (lH, d, J 17 Hz), 4.30 (1H, d,

J ■» 13 Hz), 5.08 (1H, d, J w 4.5 Hz), 8.58 (lH, d,

J » 4.5 He), 8.50 (1H, p).

b) 15 g of potassium 3-(1-hydroxyacetyl) ditlocarbaate is added little by little over 10 minutes at 0-5°C to a mixture of

20 ml of sulfuric acid and 100 ml of ethyl acetate, and the mixture is stirred in one

hour at the same temperature. The reaction mixture is poured into one liter of ethyl acetate, and the mixture is washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate* The solvent is distilled off under reduced pressure, whereby 3.7 g of 5-hydroxymethyl-1,3,4-thiadiazole-2- thiol with melting point 120-125°C.

To a solution of 5.0 g of the previously extracted 5-hydroxy=methyl-1,3,4-thiadiazole-2-thiol in 50 ml of pyridine is added dropwise with stirring at 0-5°C for 30 minutes 7.9 g of isobutyryl chloride . The solution is stirred for 1 30 minutes at the same temperature and i

2 hours at room temperature. Add 100 ml to the reaction mixture

water, and the mixture is concentrated under reduced pressure at 50°C on

a water bath. Add to the oily residue. 100 ml cold water,

and until the mixture is carefully stirred at room temperature

9.3 g of sodium bicarbonate. After stirring for 2.5 hours at room temperature, the reaction mixture is washed with ether, acidified with 10% hydrochloric acid and extracted with ether. The extract is washed with water and dried, and the solvent is distilled off, whereby 7.7 g of an oily residue are obtained. The residue is chromatographed on 100 g of silica gel using a mixture of benzene and chloroform (7.3) as a developing solvent, whereby 4.0 g of 5-isobutyryloxymethyl-1,3,4-thiadiazole-2-thiol are obtained in the form of a pure oil [NMR spectrum (CCl^, 6) 1.23 (6H, d, J 7 Hz), 2.54 (1H, q, J - 7 Hz), 5.1 (2H, s)l. A solution of 2.50 g of the previously extracted 5-isobutyryloxy-methyl-1,3,4-thiadiazole-2-thiol in 5 ml of acetone is added to one solution of 3.66 g of 7-methylthioacetamldocephalosporanic acid (prepared according to example 2a) and 1.68 g of sodium bicarbonate in 75 ml of phosphate buffer with a pH value of 6.4, and the mixture is stirred for 7 hours at 65°C. The reaction mixture is cooled and washed with ethyl acetate. The watery one

phase is adjusted to a pH value of 2 with dilute hydrochloric acid and extracted with ethyl acetate. The extract is washed with water, dried and concentrated, thereby obtaining 4.0 g of 7-methylthio-acetamido-3-(5-isobutyryloxymethyl-1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid in form of an oil. The oil is chromatographed on silica gel using a mixture of ethyl acetate, chloroform and acetic acid

(20:20:1) as developing solvent, and the eluate is separated into 1 fractions of 50 ml. The 6th to 10th fraction Collected and. be concentrated. After dissolving the residue in 18 ml of methanol, add 16 ml of sodium α-ethyl hexanoate solution while cooling; the solution/, which is allowed to stand until crystals precipitate. The crystals are collected by filtration, washed with cold methanol and ether and dried, thereby obtaining 1.81 g of sodium 7-methylthioacetamido-3-(5-isobutyryloxy-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-3 -ca£em~4-carboxylate with melting point 200.5-202°C (decomposition). c) The following compounds are prepared in an analogous manner as described in examples 2a - 2b using corresponding starting compounds. 1) N-methylthioacetamido-S-(1,3,4-thiadiaEol-2-yl)thiomethyl-3-ephem-4-carboxylic acid with melting point 128-131°C (decomposition). 2) 7-methylthioacetamido-3-(1-methyl-1H-tetrasol-5-yl)thio-methyl-3-cephem-4-carboxylic acid with melting point 81-84°C. 3) 7-methylthioacetamido-3-(5-methyl-1,3,4"thiadia2ol-2-yl)-thiomethyl-3^cephem-4-carboxylic acid with melting point 167-168 C (decomposition). 4) 7-methylthioacetamido-3 -(3-methyl-1,2,4-thiadiaol-5-yl)-thiomethyl-3-oepheHt-4-carboxylic acid with melting point 179~180°C (decomposition). 5) 7-Mesylacetamido-3-(5- methyl-1,3,4-thiadlazol-2-yl)thiomethyl-3-ee£©m-4-carboxylic acid with melting point 155-161° C. 6) 7-allylthioacetamido-3-(5-methyl-1,3 ,4~thiadiazole-2-yi)-thiomethyl-3-cephem-4-carboxylic acid with melting point 156-158°C (spl.) 7) ^-allylthioacetamido-S-O-methyl-1^^-tladiaEol-S-ylJ- thiomethyl-S-cephem-carboxylic acid with melting point 114-115°C. 8) 7-(2-propynylthioacetamido)-3-(3-[methyl-1,2,4-thiadiaol-5-yl)thiomethyl-3- cephem-4-carboxylic acid with melting point 127^129°C0 9) 7-(2-©ilylthio-2-phenylacetamido)-3-(5-methyl-1,3j4-tla-diazol-2-yl) thiom©thyl- 3-cephem-4'-carboxylic acid with melting point 89-94°C (decomposition). 10) 7-isopropylthioacetamido-3-(5-methyl-1,3,4-thiadlasol-2=yl)i-tlomethyl-3- cephem'r4-carboxylic acid with melting point 156-157°C 11) 7-ter t.butylthioacetamido-3-(5-methyl-1,3,4-thiadiaol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid with melting point 154-155°C (decomposition). 12) 7-(2-methylthio-2-methylacetamido)->3-(5-methyl-1,3,4-thiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid with melting point 171-172°C . 13) 7-methylthioaaetamidb-3-(5-palmitoyloxymethyl-1,3,4- thiadiazol-2ryi)thiomethyl-3-cephem-4-carboxylic acid (powder) and its sodium salt, melting point 145-150°c (decomposition).. d) 6.88 g 7-(2-meth<y>ltioaeetamido)cephalos<p >oranic acid (prepared according to example 2a) is dissolved in 20 ml of an aqueous solution containing 1.68 g of sodium bicarbonate. In the solution, 120 ml of phosphate buffer with a pH* value of 6.86 and 4.68 g of 2~raercaptoethanol are stirred, and the mixture is stirred for 4 hours at 6b°G, while it is kept at a pH value of 6.5 -6.8. After cooling, the reaction mixture is adjusted to a pH value of 8-9 and washed with ethyl acetate. The aqueous solution is adjusted to a pH value of 2 and extracted with ethyl acetate. The extract is washed with water and then with a saturated aqueous poricium chloride solution and dried. The solvent is distilled off under reduced pressure, whereby 0.2 g of 7-(2-ethylthioacetamido)- 3-(2-Hydroxyethyl)thiomethyl-3-cephem-4-carboxylic acid with melting point 134-138°C.

XR spectrum v''JJjJj1 " 3310'1775'1635 °9 1S30. about"1.

e) Dissolve .7.73 g of 7-(2-allylthioacetamido)cephalosporanic acid

in 20 ral of aqueous solution containing 1.68 g of sodium bicarbonate. To the solution are added 6.2 g of 2-mercaptoethanol, 120 ml of phosphate buffer with a pH value of 6.8 and an aqueous solution of sodium bicarbonate, and the mixture is stirred for 2 hours at 60°C, while maintaining a pH value of 6.4-6.5. The reaction mixture is adjusted to a pH value of 7.5 with sodium bicarbonate and washed with ethyl acetate. Ethyl acetate is added to the aqueous phase and the mixture is adjusted to a pH value of 4-5 with hydrochloric acid. The ethyl acetate phase is separated, washed with water and then dried with a saturated aqueous sodium chloride solution. The solvent is distilled off, whereby 4.2 g of 7-(2-allylthioacetamido)-3-(2-hydroxyethyl)-thiomethyl-3-cephem-4-carboxylic acid are obtained in the form of a hygroscopic powder.

IR spectrum VJ^®1« 3350, 1780, 1720, 1665, 1525 cm"1.

f) Mixed aldehyde of 2-methanesulfinyl-2-phenylacetic acid, which is prepared from 2-methanesulfinyl-2-phenylacetic acid (prepared under

application of the method described in example lw),1 methyene chloride at a temperature of 78°C in nsrvsr of isobutyl chloroformate is added at once to 7-aminocephalosporachic acid, which is dissolved in methyene chloride and cooled to -78°C in the presence of trimethylslylacetamide. The resulting 7-(2-methanesulfinyl-2-phenylacetamido)cephalosporanic acid

is treated with 5-methyl-1,3,4-thiadiazole-2-thiol in an analogous manner as described in examples 2a and 2b, whereby 7-(2-methanesul£inyl~2~phenylacetamido)-3-(S^motyl **!,3,4-thiadiazole-=2~yi) thiomethyl-3-eefem-4- . carboxylic acid with melting point 110-130°C. Eia-epektrum (nujol) 3300,;

1785, 1715 and 1680 cm""1, NMR spectrum (D 2 O + WaHCO 3 , 6) 2.51 (s, 3H),

2, 12 (s, 3H), 3.75, 3,"42 (AB-g, 2H, J°17 Hs)>4.00 (d, lH, 3 13 Hs), 4.50 (d, 1H , J°13 Ra), 5.10 (d, 1H, J = 4.5 Hs) , 5.68 (d, 1H, J « 4.5 Hs)j.

g) Mixed anhydride of methanesulfinylacetic acid, which is prepared from methanesulfinylacetic acid in methylene chloride at -78°C in cold weather

of isobutyl chloroformate, is added 6 times to 7-aminocephalosporanic acid, which is dissolved in 1 methylene chloride and cooled to ~78°C in the presence of trimethylsilylacetamide» The resulting 7-methanesulfinylactamido-cophalosporanic acid® is treated with 5-methyl-1,3,4 -thiadiazole-2-thol in an analogous way as described in examples 2a and 2b, whereby 7-methane-sulfinylacetamido-3-(5-methyl-1,3,4-thiadia3ol=2'=yl)thiomethyl-3- c©fem-■-4rcarboxylic acid with melting point 117~119°C (decomposition),,

Example 3

a) A solution of 9.25 g of palmitoyl chloride in 25 ml of hard methylene chloride is added dropwise under ice-cooling to a solution

of 5 g of 7-methylthioacetamido-3-(5-hydroxymethyl-1,3,4-thiadiazol-2-yl)-thiomethyl-3-cephem-4-carboxylic acid in 50 ml of dry pyridine. The solution is stirred for 3.5 hours at the same temperature and 12 hours at room temperature. The reaction mixture is poured into a mixture of 300 ml of ice water and 400 ral of ethyl acetate and adjusted to a pH of 1-2 with

hydrochloric acid, and the ethyl acetate phase is separated. The aqueous phase is extracted with ethyl acetate, and the two ethyl acetate phases are combined. The solution is washed with 5% hydrochloric acid and water and dried over magnesium sulfate. The solvent is removed and the residue is dissolved in chloroform. The solution is chromatographed on 100 g silica gel below

use of chloroform as a pre-potassium eluent and eluted with a mixture of methanol and chloroform (le5), thereby obtaining 5.7 g of 7-methylthioacetamide Q-3-<(5-palmitoyloxyroethyl-1,3,4-thiadia!Sol-2-yl) = thiom©tyl-3i-cephem-4-carbox<y>ls<y>r© in the form of ot.powder.' The powder. is dissolved in 60 ml of dry acetone, and 14 ml of sodium α-ethyl hexanoate solution is added to the solution. After standing overnight in a cold place, the precipitated crystals are collected by filtration and washed

with acetone, thereby obtaining 3.58 g of sodium 7-methyl-thioacetamido-3-(5-palmitoyloxymethyl-1,3,4-thiadiazol-2°yl)thiomethyl-3-cephem-3-carboxylic acid with melting point 14S ~150°C (decomposition).. b) The following compounds are prepared in an analogous manner as described in example 3a using the corresponding output compounds Iser. 1) 7-methylthioacetamido~3~(5-isobutyryloxymethyl-1,3,4-thia-diazol-2-yl)thioraethyl-3-cepheny-4-carboxylic acid (oil) and its sodium salt, melting point 200»5-202° C (cleavage).

Claims (1)

1* Process for the preparation of 7-(α-substituted acetamido)-3-oepheme-4-carboxylic acid derivatives with the general © formula I where R1 denotes hydrogen/hydroxy-lower alkylthio or a heterocyclic thio group, which may be substituted with lower alkyl or alkanoyloxy-lower alkyl, R denotes lower alkyl, lower alkylthio-lower alkyl, acyl-lower alkyl, acylamino-lower alkyl, .'' 3 lower alkenyl, ar-lower alkenyl or lower alkynyl, R denotes hydrogen, lower alkyl or aryl , and X denotes sulfur» sulfinyl or sulfonyl, with the proviso that R 2 is not a lower alkyl group, when R 1 is hydrogen, or derivatives thereof at carboxyl the group or salts thereof, characterized in that a) a 3-substituted 7-amino-3-cephem-4-carboxylic acid with the general formula II where R has the meaning given above, or a derivative thereof at the carboxyl group or a salt thereof, is reacted with a «-substituted acetic acid of the general formula 211 where R , R and X each have the meaning stated above, or a reactive derivative thereof at the carboxyl group or a salt thereof, or b) for the preparation of compounds with the general formula I" 2 3 X where R R and X each have the meaning stated above, and R' denotes hydroxy-lower alkylthio or one heterocyclic thio group, which can be substituted with lower alkyl or alkanoyloxy-lower alkyl, © Iler derivatives thereof at the carboxyl group or salts thereof, a compound mad the general formula ZV 2-3 • where R , R and X hyer have the meaning indicated above, and Y denotes asido.or lower.alkanoyloxy, or; a derivative thereof at the carboxyl group but a salt thereof, reacting with a thio compound. with the general formula V where R* has the above meaning, or an alkali metal salt thereof, or c) for the preparation of compounds of the general formula X." where R 4 denotes lower alkyl, R 5 denotes alkanoyl, Z denotes thiadiazoldiyl, and A denotes lower alkylene, or derivatives thereof at the carboxyl group or salts thereof, one compound of the general formula VI 4 where R, Z and A each have the above meaning, or a derivative thereof at the carboxyl group or a salt thereof is reacted with a carboxylic acid of the general formula VII ■'5 where R has the above meaning, or a derivative thereof at the carboxyl group or a salt thereof, and a resulting compound is optionally converted into a salt thereof. 2. Method according to claim 1, characterized in that compounds are produced, where R 1 is hydrogen, R 2 is lower alkylthio-lower alkyl, acyl-lower alkyl, acylamino-lower alkyl, lower alkenyl, ar-lower alkenyl or lower alkynyl, R is hydrogen or aryl, and X is sulfur, and salts thereof, especially pharmaceutically acceptable salts thereof; 3. Method according to claim 2, characterized in that compounds are produced, 3 where R is hydrogen. 4. Method © according to claim 3, characterized in that compounds are produced, where R 2 ■© is methylthioraety1, benaoyl-lower alkyl, benzamido-lower© alkyl, allyl, styryl or propynyl. 5. Procedure according to claim 4, v. c a r, a c t e r 1 s e r t by producing the compound, 2 where R is methylthiomethyl. . 6. Method according to claim 4, kar akt© r i s e r t' by producing the compound, where, R<2> ': is, :benzoylmethyl. 7o Method according to claim 4, character 1 s © r t in that the compound is prepared, where R is ben2amidomethyl. So Method according to claim 4, characterized in that the compound is prepared, where R2 is aylyl* 1 - {Jo'- Method according to claim 4, characterized in that the compound is prepared, 2 where.R.© r els-styryl. 10o Method according to claim 4, c a r a c ' t e r i s' e r t vod that the compound is produced, where R 2 ©r 2~propynyl* . lio Method according to claim 2, characterized in that compounds are produced, where R 2 is lower alkenyl, and R<3> is ary. 12o Method according to claim 11, kar act © ri s © r t in that the compound is prepared, where R ©rally1, and R is phenyl. 13o Method according to claim 1t characterized in that compounds are formed: 1" 9 where R ©r hydroxy-lower © r© alkylthio, R ©r lower alkyl ©Iler lower alkenyl, •R •© r hydrogen, and X is sulfur, or pharmaceutically acceptable salts thereof* .14" Method according to claim 13, characterized in that compounds are produced, 1 2 •. • s ■■- ■ • where R ,©r hydroxyethyltlo, and n is methyl or al"lyl" -\ l5o Method © according to claim 14, characterized in that the compound is produced, where R ©r 2-hydroxyethylthio and R ©f methyl» / 16c .Procedure according to claim 14, ; c a r .a c' t e r i s e r t vod that the compound is produced, in 2 where R.© r 2~ hydroxy©tyltio, and R is allyl 17. Method © according to claim 1, characterized by the fact that compounds are produced, where R1© is a heterocyclic thiogy group, room can be substituted with lower alkyl© Iler alkanoyloxy-lower© alkyl, R is lower alkyl, lower alkylthio-layer alkyl, acyl©lower alkyl, acylamino-lower©alkyl. lower alkenyl, ar-lower alkenyl or lower alkynyl, R is hydrogen, lower alkyl or aryl, and X is sulphur, sulfinyl or sulfonyl. or pharmaceutically acceptable salts thereof. 18. Method according to claim 17, characterized in that compounds are produced, where X is sulphur, and R is hydrogen. 19. Process according to claim 18, characterized in that compounds are prepared, where R1 is an unsaturated 5-membered heteromonocyclic thio group consisting of 1 sulfur atom and 1-3 nitrogen atoms, which may be substituted with lower alkyl or alkanoyloxy-lower alkyl or an unsaturated 5-membered heteromonocyclic thio group consisting of 2-4 nitrogen atoms substituted with lower alkyl, and R is lower alkyl, lower alkenyl or lower alkynyl. 20. Method according to claim 19, characterized in that compounds are produced, 1 where R is an unsaturated 5-membered heteromonocyclic thio group consisting of 1 sulfur atom and 2 nitrogen atoms, which may be substituted with lower alkyl or alkanoyloxy-lower alkyl, an unsaturated 5-membered heteromonocyclic thio group consisting of 3-nitrogen atoms substituted with lower alkyl or an unsaturated 5-membered heteromonocyclic thio group consisting of 4-nitrogen atoms substituted with lower alkyl. 21. Method according to claim 20, characterized by the fact that compounds are produced, where R1 is thiadiazolylthio, which can be substituted with methyl, ispbutyryloxymethyl or paimitoyloxymethyl, triazolylthio substituted with methyl or tetraazolylthio substituted with methyl, and R 2© is methyl, isopropyl, t@rt.butyl, allyl or 2-propynyl. 22. Method © according to claim 21, character! cert by preparing the compound, where R is 1,3,4-thiadia2ol-2-ylthio, and R is methyl. v-.'- ;23. Procedure©: According to claim 21, characterized by the fact that the compound is produced, • •1 2 ■• where R is 5-methyl-1,3,4-thiadlazol-2-ylthio, and R is methyl. 24o Procedure according to claim 21, . characterized in that the compound is prepared, 1 2 where R is 3~ methyl-1,2,4-thiadlazo~ 5-ylthio, and R© r methyl. 25«* Method according to claim 21, characterized in that the compound is prepared, where R is 5-methyl-1,3,4-thiadiazol-2-yl io, and R is allyl* 20, Method according to claim 21, characterized in that the compound is prepared, where R is 3-methyl~l,2,4-thiadiaol«-5-ylthio, and R is allyl„ 2:7» ■ Process according to 'claim 21, ka-r, ak. t© r i s-e r t v©d that the compound is produced, where. R is 3-m©.tyl-1,2,4-thia&ia2ol»5=ylthio> and R is -2-propynyl„.. 20o Process© According to claim 21, characterized in that the compound is prepared,' 2 where R or 4-methyl-4H-1,2,4-triaaol-3-ylthio,- and R*' is methyl. -29..Procedure According to claim 21, k' a t a k t e. r i' s,e -r' t in that the compound is prepared, where R i is 1-methyl-1H-tetsrazol-5-ylthio, and R 2 is methyl. 30. Method according to claim 21, character! black vod that dat is prepared the compound, where R is 5-methyl-1,3,' 5-thiadiGSol-2-ylthio, and R 2 is isopropyl. 31o Procedure According to claim 21, characterized in that the compound is produced, 1 2 where R© r 5-methyl'-1,3,4-thiadiaol~2-ylthio, and R sr tert,butyl„ 32. Method according to claim 21, k a r>a c t © f l-s e r t v© d that the compound is produced, 1 2 where R is S-isobutyryloxymatyl-lt,3,4-thiadiazol-2-ylthio, and R is methyl, or its sodium salt. 33. Procedure according to claim 21, characterized in that the compound is represented, 1 2 where R© is 5-palmitoyloxyHtetyl-1,3,4~thiadiazol-2~ylthio, and R is methyl, ©Ilar the sodium salt thereof.' ' - 34o Method © according to claim 17, characterized by the preparation of compounds, where R1 is an unsaturated 5-membered heteroiconocyclic thio group consisting of 1 sulfur atom and 1-3 nitrogen atoms substituted with lower alkyl, R 2" is lower alkyl, X is sulfur and R 3 is lower alkyl0 35o Method © according to claim 34, k-a. r.'ak t-e r -i s e r t in that compounds are prepared, where R1 is, an unsaturated 5-membered heteromonocyclic thiogroup consisting of 1 sulfur atom and 2 nitrogen atoms substituted with lower alkyl. 36-o ' Method according to claim 35, characterized in that compounds are produced, 1 2 where R is thiadiazolylthio substituted with methyl, R is methyl, and 3 -.R is methyl.- 37.. Method according to claim 36, characterized in that the compound is prepared, where R1 is 5-methyl-1,3,4-thladiazol-2-yltlo. 38. Method according to claim 17, characterized in that a compound is prepared, where R* is an unsaturated 5-membered heteromonocyclic thio group consisting of 1 sulfur atom and 1-3 nitrogen atoms substituted with lower alkyl, R 2 is lower alkenyl, X is sulphur, and R 3 is aryl. 39. Method according to claim 38, character! by preparing compounds, where R* is an unsaturated 5-membered heteromonocyclic thio group consisting of 1 sulfur atom and 2-nitrogen atoms substituted with lower alkyl.. 40. Method according to claim 39, characterized in that compounds are produced, 1 2 where R is tladiazolylthio substituted with methyl, R is allyl, and 3 R is phenyl. 41. Method according to claim 40, characterized in that the compound is prepared, where R* is 5-methyl-1,3,4-thiadiazol-2-ylthio. 42. Method according to claim 17, characterized in that compounds are prepared, where R^* is an unsaturated 5-membered heteromonocyclic thio group consisting of 1 sulfur atom and 1-3 nitrogen atoms substituted with 2 3 lower alkyl, R is lower alkyl, X is sulfinyl , and R is hydrogen or aryl. 43. Process according to claim 42, characterized in that compounds are prepared, where R* is an unsaturated 5-membered heteromonocyclic thiogroup consisting of 1 sulfur atom and 2 nitrogen atoms substituted with lower alkyl. 44. Method according to claim 43, characteristics in particular that compounds are produced, in 2 where R is tladiazolylthio substituted with methyl, R is methyl, and R** is hydrogen or phenyl. '45. Procedure according to claim 44. characterized in that the compound is produced, where R 1 is 5-methyl-1,3,4=thiadiazol~ 2~ ylthio, and R 3 is hydrogen. 4S. Procedure according to © claim 44, c a r a c t e r i s © x t in that the compound is produced, where R 1© r. 5-methyl° 1,3,4-thladiazol~ 2~ yitio, and'R ^' is phenyl. .47 <.> Procedure according to claim 17, characterized • by the fact that compounds are produced, where R1 is an unsaturated 5=-bonded heteroionocyclic thiogroup consisting of 1 sulfur atom and 1-3 nitrogen atoms substituted with lower alkyl, R 2 is lower alkyl, 2 is sulfonyl and R<3> is hydrogen. '. 43. Method according to claim 42, k a r.: -characterized by the preparation of compounds, where R or ©a unsaturated 5-membered hG terosaoonooykiic thio group consisting of 1 sulfur atom and. ^«nitrogen atoms substituted with © d lower alkyl. • 49.■. Method according to claim 43, character.-i o' ert in that compounds are prepared, where R 1© is tladiazolylthio substituted sa©d methyl, and R 2© is methyl. ,50.. Procedure according to claim 44, k a r a kt© r i-a ert '.vod that the compound is prepared, where R 1 is 5-methyl-1,3,4~thiadiao~2-ylthio. ■