DE2447194A1 - 7- (ALPHA-SUBSTITUTED ACETAMIDO) -3CEPHEM-4-CARBONIC ACID DERIVATIVES, THE PROCESS FOR THEIR MANUFACTURING AND THEIR USE IN PHARMACEUTICAL PREPARATIONS - Google Patents

Description

T 49 615

Applicant: FUJISAWA PHARMACEUTICAL CO., LTD.

• No. 3, 4-chome Doshomachi, Higashi-ku, Osaka ,. Japan

7- (α-substituted-acetamido) -3-cephem-4-carboxylic acid derivatives, Process for their production and their use in pharmaceutical preparations

The invention relates to new 7 - (<x-substituted-acetamido) -3-cephera-4-carboxylic acid derivatives, their derivatives on the carboxy group and pharmaceutical compatible salts thereof exhibiting antibacterial activity and processes for their preparation and their use in pharmaceutical preparations.

The new 7- (α-substituted-acetamido) -3-cephem-4-carboxylic acid derivatives which are an object of the invention can be represented by the general formula

(I) R ₀ -X-CH-CONH '^S>
* ■ t

00H

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where mean:

R, hydrogen, hydroxy (lower) alkylthio or heterocyclic thio, which can be substituted by lower alkyl or alkanoyl oxy (lower) alkyl, R ₂ lower alkyl, lower alkylthio (lower) 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 sulfur, sulfinyl or sulfonyl, with the proviso that when R is hydrogen, R _{2 is} not lower alkyl.

The here in connection with the radicals alkane, alkene or alkyne, such as alkyl, alkenyl or alkynyl, Unless otherwise specified, the term "low" used stands for a group from 1 to 6 carbon atoms.

A suitable example of hydroxy (lower) alkylthio is one with 1 to 6 carbon atoms, such as 2-hydroxyethylthio, 2-hydroxypropylthio, 3-hydroxypropylthio, 2-hydroxybutylthio, 3-hydroxybutylthio, 2-hydroxypentylthio, 3-hydroxypentylthio , 2 -Hydroxyhexylthio, 3-hydroxyhexylthio, 5-. Hydroxyhexylthio or the like, and preferred is one having 1 to 4 carbon atoms, particularly one having 2 to 3 carbon atoms.

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The heterocyclic thio group can be an unsaturated, monocyclic, heterocyclic thio group containing at least one heteroatom from the group consisting of oxygen, sulfur, nitrogen or the like. A suitable example of a heterocyclic thio group is one with a heterocyclic group such as an unsaturated, 5-membered heteromonocyclic group, which contains a sulfur atom and 1 to 3 nitrogen atoms, for example thiazolyl, thiadiazolyl (e.g. 1,2,4-thiadiazolyl, 1,3, A-thiadiazolyl or 1,2,5-thiadiazolyl) and the like, an unsaturated 5-membered heteromonocyclic group containing a Contains oxygen atom and 1 to 3 nitrogen atoms, for example oxazolyl, oxadiazolyl (e.g. 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl or 1,2,5-oxadiazo-IyI) and the like, an unsaturated, 5-membered heteromonocyclic group containing 2 to 4 nitrogen atoms, for example triazolyl (e.g. 4H-1,2,4-triazolyl or 2H-1,2,3-triazolyl), tetrazolyl (e.g. IH-tetrazolyl or 2H-tetrazolyl) and the like, and these heterocyclic groups may optionally be used. by lower alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, cyclopentyl, pentyl, Cyclohexyl or hexyl), preferably one with 1 to 4 carbon atoms, or alkanoyloxy (lower) alkyl (e.g. Fonnylqxymethyl, Acetoxymethy1, Acetoxyäthyl, Acetoxypropyl, Propionyloxymethyl, Butyryloxy-

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methyl, isobutyryloxymethyl, isobutyryloxyethyl, Isobutyryloxypropyl, hexanoyloxymethyl, pivaloyloxymethyl, Lauroyloxymethyl, lauroyloxyethyl, lauroyloxypropyl, Palmitoyloxymethyl, Palmitoyloxyäthyl or Stearoyloxymethyl), preferably by lower Alkanoyloxy (lower) alkyl and higher alkanoyloxy (lower) alkyl substituted with 2 to 24 carbon atoms and in particular with 5 to 17 carbon atoms be.

A suitable example of lower alkyl is one with 1 to 6 carbon atoms, such as methyl, ethyl, Propyl, isopropyl, butyl, isobutyl, t-buty, pentyl, hexyl or the like and preferably one with 1 to 4 carbon atoms.

A suitable example of lower alkylthio (lower) alkyl is one with 2 to 12 carbon atoms and this also includes a group in which the above-mentioned Lower alkyl by lower alkylthio, such as methylthio, ethylthio, propylthio, isopropylthio, Butylthio, t-butylthio, pentylthio, hexylthio or the like, and preferably one those with 2 to 6 carbon atoms, in particular those with 2 to 3 carbon atoms.

A suitable example of acyl (lower) alkyl is lower alkanoyl (lower) alkyl with 2 to 12 carbons

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Substance atoms in which the above-mentioned lower alkyl is replaced by lower alkanoyl (e.g. formyl, acetyl, propionyl or butyryl), aroyl (lower) alkyl having 7 to 14 carbon atoms, such as benzoyl (lower) alkyl, in which the above-mentioned lower alkyl is substituted by aroyl (e.g. benzoyl, toluoyl or xyloyl) is, heterocyclic carbonyl (lower) alkyl of 6 to 12 carbon atoms in which the above Lower alkyl is substituted by heterocyclic carbonyl (e.g. nicotinoyl, furoyl or thienoyl) or similar.

A suitable example of acylamino (lower) alkyl is lower alkanoylamino (lower) alkyl of 2 to carbon atoms in which the above-mentioned lower alkyl substituted by lower alkanoylamino (e.g. formamido, acetamido, propionamido or butyramido) is, aroylamino (lower) alkyl of 7 to 14 carbon atoms, such as benzamido (lower) alkyl, in which the lower alkyl mentioned above is substituted by aroylamino (e.g. benzamido or toluamido), heterocyclic Carbonylamino (lower) alkyl of 6 to carbon atoms in which the above-mentioned lower alkyl is replaced by heterocyclic carbonylamino (e.g. Nicotinamido, furamido or thiophenecarboxamido) is substituted or the like.

A suitable example of lower alkenyl is one with 2 to 6 carbon atoms, such as vinyl,

60 9-81 6/1 280 '- 6 -

1-propenyl, allyl, isopropenyl, 2-butenyl, 3-pentenyl, 1-cyclohexenyl, 1,3-cyclohexadienyl or the like, and preferably one with 2 to 4 carbon atoms, in particular one with 2 to 3 carbon atoms.

A suitable example of ar (lower) alkenyl is one with 8 to 9 carbon atoms, such as styryl, Cinnamyl or the like.

A suitable example of lower alkynyl is one with 2 to 4 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl or similar.

A suitable example of aryl is one with 6 to 10 carbon atoms, such as phenyl, ToIyI, XyIyI, Mesityl, cumenyl, naphthyl or the like, and preferably one with 6 to 8 carbon atoms.

Suitable derivatives on the carboxy group include the esters, amides, acid anhydrides and the like, preferably the esters ( e.g. the methyl, trichloroethyl, pivaloyloxymethyl, 1-cyclopropylethyl, acetoxymethyl , methoxymethyl, acetonyl or phenacyl esters )

A suitable example of pharmaceutically acceptable salts is an inorganic salt such as

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an alkali metal salt (e.g. sodium or potassium salt), an alkaline earth metal salt (e.g. the calcium or magnesium salt) or a salt with an organic Base, such as trimethylamine, triethylamine, dicyclohexylamine or similar.

All or some of the compounds of the formula (I) forming the subject of the invention can according to Various processes can be prepared and some typical processes are detailed below explained.

A typical process for the preparation of the compounds of the formula (I) according to the invention can be carried out by the following reaction scheme can be shown:

+ R-X-CH-COOH

COOH

(II) (IH)

R ₀ -X-CH-CONH
* ι

^R 3

(D

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wherein R ,, R ₂ , R_ and X have the meanings given above.

The inventive method is carried out by Implementation of 7-amino-3-substituted-3-cephem-4-carboxylic acids of the formula (II) or their derivatives the carboxy group or salts thereof with α-substituted acetic acids of the formula (III) or their reactive ones Derivatives on the carboxy group or salts thereof.

With regard to suitable derivatives of the compound of the formula (II) on the carboxy group, refer to those for the compound of the formula (I) given examples.

Suitable reactive derivatives of the compound of formula (III) on the carboxy group include e.g., an acid halide, an acid anhydride, an activated amide, an activated ester, preferably an acid chloride, an acid azide, a mixed acid anhydride with an acid such as dialkyl phosphoric acid, Phenyl phosphoric acid, diphenyl phosphoric acid, Dibenzy! Phosphoric acid, halogenated phosphoric acid, Dialkylphosphorous acid, sulphurous acid, thiosulphuric acid, sulfuric acid, alky! Carbonic acid, an aliphatic carboxylic acid (e.g. pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid or Trichloroacetic acid), an aromatic carboxylic acid

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(e.g. benzoic acid) or a symmetrical acid anhydride, an acid amide with imidazoI, 4-substituted Imidazole, dimethylpyrazole, triazole or tetrazole or an ester (e.g. a cyanomethyl, methoxymethyl, vinyl, propargyl, p-nitrophenyl, 2,4-. Dinitrophenyl-, Trichlorpheriyl-, Pentachlorphenyl-, Methanesulfonylphenyl-j Phenylazophenyl-, Phenylthio-, p-nitrophenylthio-, p-cresylthio-, carboxymethylthio-, Pyranyl, pyridyl, piperidyl, 8-quinolyl thioester or an ester with N, N-dimethylhydroxylamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide or N-hydroxyphthalimide) or the like. A suitable reactive derivative can be selected from these compounds, if desired, depending on the kinds of those practically used α-substituted acetic acids of the formula (III).

According to the invention, the compound of the formula (II) previously reacted with a silyl compound (e.g. chlorotrimethylsilane or bistrimethylsilylacetamide) are formed with the formation of a silyl derivative of the compound of formula (II) on the amino and carboxy groups, which is reacted with the compound of the formula (III) to form the compounds according to the invention Compound of formula (I) and this variant also fall within the scope of the present invention. The derivatives of the compound of the formula (II) on the carboxy group can in the course of the reaction in

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their free form and this also falls within the scope of the present invention.

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 that does not contain any exerts a detrimental effect on the implementation. Among these solvents can be the hydrophilic Solvents can be used in admixture with water.

If the α-substituted acetic acids of the formula (III) are used in the form of the free acid or in the form of a salt thereof in the process according to the invention, the reaction is preferably carried out in the presence of a condensing ^{agent such as N, N 1} -dicyclohexylcarbodiimide, N -Cyclohexyl-N'-morpholinoethylcarbodiimide, N-cyclohexyl-N ¹ - ^ - diethylaminocyclo · hexyl) carbodiimide, N ^ -diethylcarbodiimide, Ν, Ν'-diisopropylcarbodiimide, N-ethyl-N '- (3-dimethylaminopropyl) , N ^l -Carbonyldi- (2-methylimidazole), pentamethylene ketene-N-cyclohexylimine, diphenylketene-N-cyclohexylimine, alkoxyacetylene, 1-alkoxy-I-chloroethylene, trialkyl phosphite, ethyl polyphosphate, isopropyl polyphosphate, phosphor oxychloride, phosphorus chloride

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trichloride, thionyl chloride, oxalyl chloride, triphenylphosphine, of the Z-ethyl-T-hydroxybenzisoxazolium salt, the intramolecular 2-ethyl-5- (rasulfophenyl) isoxazolium hydroxide salt, (Chloromethylene) dimethylammonium chloride or the like. In the case of the salts of the compound of the formula (II) it can be salts on the carboxy group, such as alkali metal salts (e.g. sodium or potassium salts), Alkaline earth metal salts (e.g. Calciura or magnesium salts), salts with an organic Base, such as trimethylamine, dicyclohexylamine or the like, and salts on the amino group, such as a salt with an acid (such as hydrochloric acid, Sulfuric acid, acetic acid, tartaric acid, maleic acid, benzenesulfonic acid or toluenesulfonic acid) and the salts of the compound of formula (III) can be alkali metal salts (e.g. sodium or Potassium salts), alkaline earth metal salts (e.g. calcium or magnesium salts), to salts with an organic Base, such as trimethylamine, dicyclohexylamine or like that, act.

The reaction can also preferably be carried out in the presence of a base, such as, for example, an alkali metal bicarbonate, trialkylamine, Ν, Ν-dialkylbenzylamine, pyridine or the like. When the base or the condensing agent is liquid, it can also be used as a solvent. The reaction

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temperature is in no way limited and the reaction is usually carried out under cooling or at Carried out at room temperature. The reaction product can be isolated by customary methods

Since the starting compound of the formula (II) and the compound of the present invention of the formula (I) both are comparatively unstable compounds and are easily decomposed in the course of the reaction it is convenient to carry out the reaction and the process for isolating the product under mild conditions perform.

Another typical process for making some of the compounds of the formula of the present invention (I) can be represented by the following reaction scheme:

R ₂ -X-CH-CONH

(IV)

COOH

R [- H (V)

R ₂ -X-CH-CONH

(I ¹ )

COOH

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" ¹³ "

wherein R ", R_ and X have the meanings given above have, R! Hydroxy (lower) alkylthio or heterocyclic Thio, which can be substituted by lower alkyl or alkanoyloxy (lower) alkyl, and Y Mean azido or lower alkanoyloxy.

The process according to the invention is carried out by reacting a compound of the formula (EV) or their derivatives on the carboxy group or salts thereof with a thiol compound of the formula (V) or alkali metal salts thereof.

A suitable example of lower alkanoyloxy is one having 1 to 6 carbon atoms, e.g. Formyloxy, acetoxy, propionyloxy, butyryloxy, pentanoyloxy or the like, and preferably one with 1 to 4 carbon atoms, especially one with 2 to 3 carbon atoms.

Regarding suitable examples of hydroxy (lower) alkylthio, heterocyclic thio or the derivatives of the compounds of the formula (IV) on the carboxy group, reference is also made to those examples which are given for the compound of formula (I), and with respect to the salts of the compound of Formula (IV), reference is made to those examples which are given for the compound of the formula (III) are.

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A suitable example of alkali metal salts is the sodium, potassium salt or the like.

The derivatives of the compound of the formula (IV) on the carboxy group can in the course of the reaction in their free form and this also falls within the scope of the present invention.

The process according to the invention can be carried out in a solvent, e.g. in water, acetone, chloroform, Nitrobenzene, dimethylformamide, methanol, ethanol, ether, tetrahydrofuran, dimethyl sulfoxide or any other organic solvent that does not adversely affect the reaction exercises, preferably in a strongly polar solvent. Among these solvents, the hydrophilic solvents can be used in admixture with water. The implementation is preferably carried out in an approximately neutral medium. When the compound of the formula (IV) or the thiol compound of the formula (V) is used in its free form, the reaction is carried out preferably in the presence of a base, such as an alkali metal hydroxide, an alkali metal carbonate, of an alkali metal bicarbonate, of trialkylamine and the like, performed. The reaction temperature is not subject to any restriction and the implementation is usually used at room temperature or below

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warming carried out. The reaction product can be isolated from the reaction mixture by customary processes will.

Since the starting compound of the formula (IV) and the compound of the formula (I ¹ ) according to the invention are both comparatively unstable compounds and are easily decomposed in the course of the reaction, it is advisable to carry out the reaction and the isolation of the product under mild conditions.

Another alternative method of making some of the compounds of the formula of the present invention (I) can be represented by the following reaction scheme will:

R ₄ -S-CH ₂ CONH

R ₄ -S-CH ₂ CONH

CH ₂ -SZA-OH + R ₅ -OH

(VII)

CH ₂ -SZAOR ₅

wherein R _{4 is} lower alkyl, A is lower alkylene, Z is thiadiazole _{diyl and R 5 is} alkanoyl.

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· "Io -

The process according to the invention is carried out by reacting a compound of the formula (VI) or their derivatives on the carboxy group or salts thereof with a carboxylic acid of the formula (VII) or their reactive derivatives on the carboxy group or salts thereof.

Regarding suitable examples of lower alkyl, the derivatives of the compound of formula (VI) on the Carboxy group and the reactive derivatives of the compound of formula (VII) on the carboxy group reference is made in each case to the above information and with regard to the salts of the compounds of the formula (VI) and of the formula (VII), reference is made to the examples given above for the compound of the formula (III).

A suitable example of lower alkylene is one with ltis 4 carbon atoms, such as methylene, Ethylene, propylene, isopropylene, butylene or the like, and preferably one having 1 to 2 carbon atoms.

A suitable example of alkanoyl is one with 1 to 18 carbon atoms, such as formyl, acetyl, propionyl, butyl, isobutyryl, valeryl, hexanoyl, pivaloyl, lauroyl, palmitoyl, stearoyl or the like, and preferably lower alkanoyl and higher alkanoyl with 1 to 18 carbon atoms, in particular

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with 4 to 16 carbon atoms.

In the process of the present invention, the compound of the formula (VI) can previously be treated with a silyl compound (e.g. chlorotrimethylsilane or bistrimethylsilylacetaraid) are reacted to form Silyl derivatives of the compound of the formula (VI) on the carboxy group, which then with the compound of the formula (VII) is reacted to form the compound of the formula (I ") according to the invention and these Variants also fall within the scope of the present invention. The derivatives of the compound of Formula (VI) on the carboxy group can be converted into their free form in the course of the reaction and this also falls within the scope of the present invention.

The reaction is preferably carried out at room temperature or with heating and for the reaction can, if desired, almost the same solvent, the same condensing agent and the same base as in the above-mentioned reaction of the compound of formula (II) with the Compound of formula (III) can be used.

If the compounds according to the invention of the formulas (I), (I ¹ ) and (I ^M ) prepared in this way are free acids, these compounds can

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fertilizers are converted into their pharmaceutically acceptable salts according to conventional methods.

The compounds of the formula (I) according to the invention have a high antibacterial activity and inhibit the growth of a number of microorganisms including Gram-positive and Gram-negative bacteria. When administered therapeutically, the cephalosporin compounds according to the invention are in the form of pharmaceutical preparations used which these compounds in admixture with pharmaceutically acceptable carriers, such as a organic or inorganic solid, or a Contain liquid excipient and are suitable for oral, parenteral or external administration. the pharmaceutical preparations can be in solid form, e.g. in the form of capsules, tablets, coated tablets, ointments or suppositories, or in liquid form, e.g. in the form of solutions, suspensions or emulsions. If desired, the preparations given above can also contain auxiliary substances, stabilizers, wetting or emulsifying agents, buffers and others contain commonly used additives.

Although the dosage of the compounds of the invention varies and depends on the age and the State of health of the patient, a mean single dose of about 100 mg, 250 mg and

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500 mg of the compounds according to the invention as effective for the treatment of infections caused by bacteria proven diseases. In general, amounts can be between about 10 and about 1000 mg or higher amounts can be administered.

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

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example 1

(A) 2.76 g of methylthioacetic acid and a few drops of dimethylformamide were added to 3 g of thionyl chloride, and the mixture was stirred at room temperature. The excess thionyl chloride was distilled off under reduced pressure, and the residue was dissolved in 30 ml of dried acetone. In addition, 6.60 g of 7-amino-3- (1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-3-carboxylic acid and 6.0 g of sodium bicarbonate in a solvent mixture of 90 ml of water and 70 ml Dissolved acetone. The solution obtained above was added dropwise to the solution at -5 to 0 C and the mixture was stirred for 2 hours at room temperature. To the reaction mixture was added 300 ml of water and the mixture was washed in 200 ml of ethyl acetate. The aqueous layer was separated, adjusted to pH 2 with 1 η hydrochloric acid, and then extracted with 300 ml of ethyl acetate. The aqueous layer was extracted again twice with 100 ml of ethyl acetate. The ethyl acetate extracts were combined, washed three times with water and then dried over magnesium sulfate. The solvent was distilled off from the solution. To the residue a small amount of ethyl acetate was added and the mixture was allowed to stand to give 2.5 g of 7-Methylthioacetamido-3- (l, 3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid in Form of a brown powder. The powder was dissolved in an aqueous sodium bicarbonate solution. The solution was treated with activated charcoal, and 1 η hydrochloric acid was added.

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acidified and then extracted with ethyl acetate. The extract was dried and the solvent was reduced under reduced pressure Pressure distilled from the solution to give 1.2 g of the pure desired compound in Yellow powder form, mp 128-131 ° C (decomp.).

(B) 2.6 g of methylthioacetic acid and 3 drops of dimethylformamide were added to 6 ml of thionyl chloride and the mixture was stirred at 40 ° C. for 2 hours. The excess thionyl chloride was removed the mixture was distilled off, and 70 ml of acetone were added to the residue. In addition, 6.8 g 7-Amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid in a mixed solvent of 75 ml of an aqueous solution of 5.9 g Dissolved sodium bicarbonate and 50 ml of acetone. The acetone solution obtained above was added to the solution Cooling was added dropwise and the mixture was stirred for 2 hours. The reaction mixture was reduced under Pressure restricted. Ice water was added to the residue, and the mixture was washed with ethyl acetate washed. The aqueous solution was acidified with 10% hydrochloric acid and with Ethyl acetate extracted. The extract was washed with water, treated with activated carbon powder, dried and then concentrated under reduced pressure. Ethyl acetate was added to the residue and the precipitated Crystals were through. Filter collected and washed with ether, giving 4.8 g of 7-methylthioacetamido-3- (1-methyl-IH-tetrazol-5-y1) thiomethyl-.

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S-cephem - ^ - carboxylic acid, F, 81 to 84 ° C.

(C) 3.44 g of 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid were in a solvent mixture of 12 g of triethylamine, 15 ml Acetone and 15 ml of water were dissolved and the solution was cooled to 0.degree. In addition, 1.59 g of methylthioacetic acid was added to 80 ml of tetrahydrofuran, which was refluxed, boiled and distilled over lithium aluminum hydride, and the mixture was stirred while cooling with dry ice and acetone (-20 to -18 ° C). 1.6 g of triethylamine and 2.0 g of isobutyl chloroformate were added to the solution. The mixture was stirred vigorously and the solution obtained above was added ^{all at once at 0 ° C. to the mixture.} The mixture was stirred for 1 hour and the solvent was distilled off from the mixture under reduced pressure at a temperature below 40 ° C. To the residue was added 30 ml of water, and the mixture was adjusted to pH 8 and then washed with ethyl acetate. To the aqueous layer was added 150 ml of ethyl acetate and the solution was adjusted to pH 2 with 2η hydrochloric acid. The precipitate was filtered off and the ethyl acetate layer was separated. The remaining aqueous layer was extracted twice with 150 ml of ethyl acetate, and the extracts were added to the ethyl acetate layer obtained above. The ethyl acetate solution was washed twice with water and twice with an aqueous saturated sodium chloride

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solution washed and then dried over magnesium sulfate. The solution was concentrated under reduced pressure and 1.9 g of yellowish brown 7-methyl-thioacetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethy were obtained l-S-cephem-A ^ carboxylic acid, m.p. 167 to 168 ° C (dec.).

(D) A mixture of 3.45 g of 7-amino-3- (3-methyl-1,2,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, 1.20 g of triethylamine, 17 , 5 ml of acetone and 17.5 ml of water were 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 ml of tetrahydrofuran. The mixture was treated in the same manner as in Example 1 (C) to obtain 3.5 g of 7-methylthioacetamido-3- (3-methy 1-1,2,4-thisdiazol-5-yl) thiomethyl 1-3 -cephem-4-carboxylic acid, m.p. 179 to 180 ⁰ C (decomp.), 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 were used as starting materials. The reaction and post-treatment were carried out in the same manner as in Example 1 (A), using 1.1 g of 7-mesylacetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl- 3-cephem-4-carboxylic acid, m.p. 155 to 161 ° C, obtained.

(F) 3.3 g of allyl thioacetic acid was added to 6 ml of thionyl chloride containing 3 drops of dimethylformamide. The mixture was left to stand until the

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Senformation was complete, and then heated to 50 ° C for 30 minutes. The excess thionyl chloride was distilled off from the reaction mixture and the residue was dissolved in 70 ml of dried acetone. In addition, an aqueous solution (75 ml) of 7.6 g of 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid and 5.9 g sodium bicarbonate was added to 50 ml acetone. To the solution, the solution obtained above was added dropwise with cooling, and the mixture was stirred for 2 hours. The reaction mixture was concentrated, and ice water was added to the residue and washed with ethyl acetate. The aqueous solution was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with water and dried, and the solvent was distilled off under reduced pressure, whereby 5.6 g of 7-allylthioacetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem -4-carboxylic acid, m.p. 156 to 158 ° C (dec.) .

(G) A mixture of 2.58 g of 7-amino-3- (3-methyll, 2,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, 1.0 g of triethylamine, 15 ml of acetone and 15 ml of water and a mixture of 1.65 g Allylthioessig- acid, 1.70 g of isobutyl chloroformate, triethyl- amine, 1.4 g and 60 ml of tetrahydrofuran were reacted in the same manner as in example 1 (C)

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and treated. The precipitated crystals were made from a mixture of ethyl acetate, ether and Recrystallized acetonitrile and 1.6 g of colorless 7-Aylthioacetamido-3- (3-methyl-1,2,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid were obtained, 114 to 115 ° C.

(H) A mixture of 2.58 g of 7-amino-3- (3-methyl-1,2,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, 1.0 g of triethylamine, 15 ml of water and 15 ml of acetone and a mixture of 1.65 g of 2-propynylthioacetic acid, 1.70 g of isobutyl chloroformate, 1.4 g of triethylamine and 60 ml of tetrahydrofuran were added to the in the same way as in Example 1 (C) reacted with one another and post-treated to form 7- (2-propynyl) thioacetamido-3- (3-methyl-1,2,4-thiadiazol-5-yl) thiomethyl-3-cephem- 4-carboxylic acid. The substance thus obtained was recrystallized from a mixture of ethyl acetate and ether to obtain 1> 75 g of yellow-brown granular crystals of the pure desired compound, m.p. 127 to 129 ° C,

(I) 1.48 g of allyl thiol was added to a solution of 1.04 g of sodium methylate in 30 ml of dry methanol, and to the solution was added 2.15 g of α-bromophenylacetic acid with stirring in a nitrogen atmosphere, and the mixture was stirred for 3 hours Room temperature stirred. A large part of the methanol was removed under reduced pressure and

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the residue was dissolved in water and washed with ethyl acetate. The aqueous layer was acidified with 2η hydrochloric acid and extracted three times with 100 ml of ethyl acetate. The extract was washed with water and dried over magnesium sulfate. The ethyl acetate was distilled off under reduced pressure to give a viscous oil, and the oil was allowed to stand to give 1.8 g of 2-allylthio-2-phenylacetic acid, mp 58 to 65 ° C, in the form of crystals. A mixture of 3.44 g of 7-amino-3- (5-raethy1-1,3,4-thiadiazol-2-y1) thiomethy1-3-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 2-allylthio-2-phenylacetic acid obtained above, 1.3 g of isobutyl chloroformate, 1.1 g of triethylamine and 50 ml of tetrahydrofuran were mixed together in the same manner as in Example 1 (C) reacted and aftertreated with the formation of 2.0 g of white, granular crystals from the 7- (2-allylthio-2-phenylacetamido) -3- (5-methyl-1,3,4-thiadiazol-2-y1) thiomethyl-3 -cephem-4-carboxylic acid, m.p. 89 to 94 ° C (dec.).

(J) As the starting materials, 7-amino-3- (4-methyl-4H-1,2,4-triazol-3-yl) thiomethyl-3-cephem-4-carboxylic acid and methylthioacetic acid were used, and the reaction and post-treatment were carried out similar Heise as in Example 1 (A) carried out, using the 7-methylthioacetamido-3- (4-methyl-4H-l, 2,4-triazol-3-yl) thiomethyl-3-cephem-4-carboxylic acid, F. 154 to 159 ° C (dec.).

509815/1280 - 27 -

(K) 3.4 g of 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid were taken under Cool to 0 to 5 ° C dissolved in a mixture of 35 ml acetone / water (1/1) and 3.0 g triethylamine. A solution of 2.0 g of isopropylthioacetyl chloride in 10 ml was added to the solution at the same temperature over a period of 20 minutes with stirring dry acetone added dropwise. During the encore the pH of the solution was adjusted to 7 to 8 with triethylamine. The mixture was 30 minutes stirred for a long time at the same temperature and then the reaction temperature became room temperature elevated. After distilling off part of the acetone at 40 ° C. under reduced pressure, the Mixture washed with 50 ml of ethyl acetate. To the aqueous layer, 80 ml of ethyl acetate was added and the mixture was gradually adjusted to pH 1.8 with 1η hydrochloric acid. The precipitated, unreacted 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid was filtered off and the ethyl acetate layer was separated. The aqueous layer was added with 70 ml Ethyl acetate was further extracted and the ethyl acetate layers were combined. The extract was washed three times with a saturated aqueous solution of sodium chloride (30 ml) and dried over magnesium sulfate. The solvent was removed under reduced pressure, leaving 2.8 g of 7-isopropylthioacetamido-3- (5-methy1-1,3,4-thiadiazol-2-yl) thio-

509815/1280. ₂ 8 -

methyl-3-cephem-4-carboxylic acid, mp 156 to 157 ° C, precipitated in the form of colorless crystals.

(L) A solution of 3.25 g t-Butylthioacetylchlorid in 10 ml of acetone was added with stirring and under cooling to -5 to 0 ⁰ C over a period of more than 5 minutes to a solution of 5.16 g of 7-amino 3- (5-methyl-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 was added. The mixture was stirred for 30 minutes at the same temperature and further 30 minutes at room temperature. The reaction mixture was washed twice with 30 ml of benzene, and 150 ml of ethyl acetate was added to the aqueous solution. The mixture was adjusted to pH 2 with 10% hydrochloric acid and the precipitated unreacted 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (0.75 g) was filtered off. The ethyl acetate layer was separated and the aqueous layer was further extracted twice with 50 ml of ethyl acetate. The ethyl acetate layers were combined, washed three times with 30 ml of water and twice with a saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was removed and 4.6 g of 7-t-butylthioacetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, mp 154 bis, were obtained 155 ° C (dec.).

509815/1280. ₂ 9 -

(M) A solution of 2.1 g of 2-methylthio-2-methylacetyl chloride in 10 ml of dry acetone was stirred and cooled to -5 to 0 C over a Time of about 5 minutes to a solution of 3.4 g of 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid in a mixture of 35 ml of acetone / water (1/1) and 4.0 g of triethylamine admitted. The mixture was kept at the same temperature for 10 minutes and for 20 minutes stirred at room temperature. Part of the acetone was distilled off at 35 ° C. under reduced pressure and the residue was washed with 50 ml of ethyl acetate. 50 ml of ethyl acetate was added to the aqueous Layer was added and the mixture was adjusted to pH 2.2 with 1 η hydrochloric acid. To filtering off the precipitated unreacted 7-amino-3- (5-methy1-1,3,4-thiadiazo1-2-yl) thiomethy1-3-cephem-4-carboxylic acid (0.35 g) the ethyl acetate layer was separated. The aqueous layer was further extracted with 50 ml of ethyl acetate and both ethyl acetate layers were united with each other. The solution was four times with 20 ml of water and with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was removed under reduced pressure 'and' 2.7 g of 7- (2-methylthio-2-methylacetamido) -3- (5-methyl-1,3,4-thiadiazo1-2-yl) were obtained thiomethy 1-3-cephem-4-carboxylic acid in the form of crystals. The crystals

509815/1280

- 30 -

were recrystallized from a mixture of ethanol and water (5: 1) and 1.95 g of the desired compound were obtained, mp 171 ° to 172 ° C.

(N) In a similar manner to Examples 1 (A) to 1 (M) were given below using the appropriate starting materials Get connections:

(1) 7-Methylthioacetamido-3- (5-isobutyryloxymethyl-1,3,4-thiadiazol-2-y1) thiomethyl-S-cephem-A-carboxylic acid (oil) and its sodium salt [F. 200.5 to 2O2 ° C (decomp.)]

(2) 7-Methylthioacetamido-3- (5-palmitoyloxymethyl-1,3,4-thiadiazo1-2-y1) thiomethyl-3-cephem-4-carboxylic acid (powder) and its sodium salt [F. 145 to 150 ° C (decomp.)]

(0) 3.96 g of allylthioacetic acid were dissolved in a solvent mixture of 3.4 g of triethylamine and 15 ml of methylene chloride. 4.22 g of benzoyl chloride were added dropwise to the solution at -15 to -20 ° C. and the mixture was stirred at the same temperature for 20 minutes. In addition, 4.28 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid and 2.42 g of triethylamine were dissolved in a solvent mixture of 22.5 ml of acetone and 22.5 ml of water. To the lo-

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509815/1280

solution, the solution obtained above was added at -10 C and the mixture was 10 minutes stirred at the same temperature. The reaction mixture was washed with 200 ml of benzene and the aqueous layer was treated with 1 η hydrochloric acid adjusted to pH 5 to 6 and then the precipitate was filtered off. The filtrate was adjusted to pH 4 set and washed three times with 150 ml of ether. The aqueous layer was adjusted to pH 1 with 1 η hydrochloric acid and extracted three times with ethyl acetate. The extract was washed with water and dried over magnesium sulfate and that Ethyl acetate was distilled off from the solution, 1.7 g of 7-allylthioacetamido-3-methyl-3-cephem-4-carboxylic acid, mp 118 to 119 ° < loose powder were obtained.

4-carboxylic acid, m.p. 118 to 119 C, in the form of a color

(P) 5.04 g of benzoylmethylthioacetic acid was added to 6 ml of thionyl chloride containing 3 drops of dimethylformamide was added and the mixture was allowed to stand at room temperature until bubbles formed stopped, then it was warmed to 50 ° C for 30 minutes. The excess thionyl chloride was removed the reaction mixture was distilled off and the residue was dissolved in 70 ml of dried acetone. Besides 4.3 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid and 75 ml of an aqueous solution of 5.9 g of sodium carbonate were added to 50 ml of acetone. To the mix

509815/1280

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244719A

the solution obtained above was added dropwise with cooling, and the mixture was stirred for 2 hours. The reaction mixture was concentrated, and ice water was added to the residue, and ethyl acetate was added extracted. The aqueous solution was acidified with 10% hydrochloric acid and then extracted with ethyl acetate .. The extract was washed with water and dried and the solvent was distilled off under reduced pressure, 0.9 g of y-benzoylmethylthioacetamido-S-methyl-3-cephem-4-carboxylic acid, Mp 120 to 124 ° C.

(Q) 7.6 g of mercaptoacetic acid and then 8.0 g of chloromethylmethyl sulfide were added dropwise with stirring at 5 ° C. in a nitrogen atmosphere to a solution of 10.2 g of potassium hydroxide in water. The mixture was stirred at room temperature for 22 hours. The reaction mixture was washed with ether, acidified with concentrated hydrochloric acid, and extracted with chloroform. The extract was washed with a saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off and 4.4 g of methylthiomethylthioacetic acid were obtained [IR spectrum: 2680, 2570, 1710, 1420, 1295, 1200, 1130 cm " ¹ , NMR spectrum: (CDCl ₃ , &) 2.17 (3H, s), 3.40 (2H, s), 3.80 (2H, s), 10.37 (1H, s)], in the form of a colorless oil.

- 33 -

509815 / 128Ö

2.14 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid were added at 0 ⁰ C in 40 of a 1.11 g of triethylamine aqueous solution containing ml. In addition, 1.67 g of the methylthiomethylthioacetic acid obtained above were dissolved in 60 ml of dried tetrahydrofuran and the solution was cooled to -17 to -15.degree. 1.11 g of triethylamine and 1.5 g of isobutyl chloroformate were added to the solution. To the mixture, the solution obtained above was added dropwise at 0 to 5 ° C., and the mixture was stirred at room temperature for 1 hour. The tetrahydrofuran was distilled off under reduced pressure, and ethyl acetate was added to the residue. The mixture was acidified by adding dropwise concentrated hydrochloric acid with stirring. The ethyl acetate layer was separated and dried over magnesium sulfate, and the solvent was distilled off.

The oily residue was with diisopropyl ether, with Ethyl acetate and then washed with ether and 0.65 g of 7-methylthiomethylthioacetamido-3-methyl-3-cephem-4-carboic acid was obtained, M.p. 140 ° C (dec.), In the form of a pale yellow powder.

(R) A mixture of 1.01 g of mercaptoacetic acid, 1.5 g of benzamidomethanol and 100 mg of p-toluenesulfonic acid was refluxed on an oil bath at 120 ° C. for 2 hours. The reaction mixture

509815/1280

- 34 -

was dissolved in ethyl acetate and dried. The solvent was removed under reduced pressure and 1.6 g of benzamidomethylthioacetic acid were 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 (CDCl ₃ , S), 3.40 (2H, s), 4.66 (2H, d, J» 6Hz), 7.25 to 7.56 ( 2H, m), 7.67 to 7.93 (3H, m), ll, 9 (1H, s)]. 4.3 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid were in a The mixture of 2.02 g of triethylamine, 20 ml of acetone and 20 ml of water was dissolved and the mixture was cooled to 0 C. In addition, 6.75 g of the benzamidomethylthioacetic acid obtained above were added to 100 ml of tetrahydrofuran, which was refluxed and distilled over lithium aluminum hydride , and the mixture was stirred while cooling (-20 to -18 ° C.) with dry ice and acetone. 3.04 g of triethylamine and 4.1 g of isobutyl chloroformate were added to the mixture. The mixture was stirred vigorously and the solution obtained above was added to the mixture at 0 C at once given. The mixture was stirred for 1 hour and then the solvent was distilled off under reduced pressure at a temperature below 40 ° C. To the residue was added 30 ml of water, and the mixture was adjusted to pH 8 and then washed with ethyl acetate. 150 ml of ethyl acetate were added to the aqueous solution and the

- 35 -609615- / 1280

aqueous solution was treated with 2 η hydrochloric acid adjusted to pH 2. The precipitate was filtered off and the ethyl acetate layer was separated. The remaining aqueous layer was extracted twice with 50 ml of ethyl acetate and the Extracts were added to the ethyl acetate layer obtained above. The solution was used twice Water and washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate and then concentrated under reduced pressure to give 4.4 g of 7-benzamidomethylthioacetamido-3-methyl-3-cephem-4-carboxylic acid, M.p. 95 to 97 ° C.

(S) 2.14 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid were in a mixture of 1.2 g of triethylamine, 15 ml of water and 15 ml of acetone were dissolved and the solution was cooled to -10.degree. In addition, 1.95 g 2-propynylthioacetic acid in 7 ml of dried tetrahydrofuran solved. 1.8 g of triethylamine and 2.05 g of isobutyl chloroformate were added to the solution at -20.degree was added and the mixture was stirred. The above solution was added to the mixture at one time -10 C was added with stirring. The mixture was stirred for 30 minutes at room temperature and then under concentrated under reduced pressure. 150 ml of ethyl acetate were added to the residue and it was diluted with Hydrochloric acid acidified and then

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509815/1280

the ethyl acetate layer was separated. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate and then the solvent was distilled off, whereby 1.0 g of 7- (2-propynyl) thioacetamido-3-methyl-3-cephem-4-carboxylic acid, mp 133 C (dec.), was obtained.

(T) 2.14 g of acid were dissolved in a mixture of 1.1 g of triethylamine, 10 ml of water and 10 ml of acetone. The solution became that of 3.1 g all at once at 0 C 2-Allylthio-2-phenylacetic acid, 2.0 g of isobutyl chloroformate, 1.6 g of triethylamine and 60 ml of tetrahydrofuran were added and the mixture was added was stirred at room temperature for 2 hours. The precipitate was filtered off and the filtrate was concentrated under reduced pressure at 40.degree. To the residue, 20 ml of water were added and 150 ml of ethyl acetate were added to the aqueous solution. The mixture was adjusted to pH 2 with 2η hydrochloric acid. The aqueous layer was separated and extracted twice with 50 ml of ethyl acetate. The ethyl acetate extract became the above ethyl acetate solution obtained, washed twice with water and with a saturated aqueous sodium chloride solution and then washed over Dried magnesium sulfate. The ethyl acetate was distilled off from the solution under reduced pressure

509815/1280 -37-

and the residue was treated with a mixture of ethyl acetate and ether to give 1.2 g of 7- (2-allylthio-2-phenylacetamido) -3-methyl-3-cephem-4-carboxylic acid, F. 68 to 73 C,

(U) 1.7 g of 7-amino-3-methyl-3-cephem-4-carboxylic acid were dissolved in a mixture of 1.0 triethylamine, 15 ml of water and 15 ml of acetone. Besides 1.9 g of cis-styrylthioacetic acid in 60 ml dissolved dried tetrahydrofuran. 1.3 g of triethylamine and 1.4 g of isobutyl chloroformate were added to the solution at -20 C with vigorous stirring and the mixture was stirred for 3 minutes. The solution obtained above was added all at once to the mixture at -10 ° C. with vigorous stirring and the mixture was stirred at room temperature for 1 hour. The reaction mixture was reduced under The pressure was concentrated at 40 ° C. and the residue was washed with ethyl acetate. Ethyl acetate was added to the residue was added and the mixture was adjusted to pH 2 with 10% hydrochloric acid at 5 ° C. The ethyl acetate layer was separated and the remaining aqueous layer was washed with ethyl acetate extracted. The extract was added to the ethyl acetate layer obtained above, washed with water and then dried over magnesium sulfate. The solvent was removed from the under reduced pressure Solution distilled off. The yellow oily residue was treated with diisopropyl ether and ethyl acetate

509815/1280 -38-

delt and 1.0 g of 7- (cis-styrylthioacetamido) -3-methyl-3-cephem-4-carboxylic acid was obtained, M.p. 142 to 146 ° C (dec.).

(V) Using a similar procedure to Examples 1 (A) to 1 (M) or 1 (0) to 1 (U) using the appropriate starting materials, the following compounds were obtained:

(1) 7-Methylthioacetamdio-3- (2-hydroxyethyl) -thiomethyl-3-cephem-4-carboxylic acid, F. 134 to 138 ° C,

(2) 7-Allylthioacetamido-3- (2-hydroxyethyl) -thiomethyl-3-cephem-4-carboxylic acid, hygroscopic powder [IR spectrum (Nujol) 335Ö, 1780, 1720, 1665, 1525 cm " ¹ ]

(W) 6.5 mg of sodium tungstate and 6 ml of hydrogen peroxide were added at 0 ° C. to a solution of 10 g of 2-methylthio-2-phenylacetic acid in 100 ml of methylene chloride and 5 ml of acetic acid. The mixture obtained was stirred at 3 ° C. until the starting compounds had disappeared. Water was added to the reaction mixture and methylene chloride was distilled off. The residue was strongly acidified and, after the addition of sodium chloride, it was extracted four times with ethyl acetate. The extract was dried over magnesium sulfate

509815/1280 " ³⁹ "

and the solvent was distilled off. The residue was recrystallized from methylene chloride and 7 g of 2-methanesulfinyl-2-phenylacetic acid, mp 123.degree. To 126.degree. C., were obtained.

198 mg of the 2-methanesulfinyl-2-phenylacetic acid thus obtained and 100 mg of triethylamine were in 5 ml Dissolved methylene chloride. This solution became a -65 over a period of 10 minutes to -60 C cooled solution of 136 mg isobutyl chloroformate in 5 ml methylene chloride was added dropwise. The resulting mixture was stirred for 30 minutes, after which it became a solution of 344 mg 7-Amino-3- (5-methy1-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid and its two molar

Equivalents of bistrimethylsilylacetamide in 5 ml of methylene chloride were slowly added dropwise at -65 to -60.degree. The obtained mixture was 2 hours long stirred. To the reaction mixture, 10 ml of an aqueous sodium bicarbonate solution was added and the water layer was separated by means of a separatory funnel and then gradually with it Ethyl acetate extracted, keeping it neutral with 10% hydrochloric acid. Of the The extract was dried over magnesium sulfate and the solvent was distilled off. Ether was added to the residue for pulverization. the powders obtained in this way were

- 40 -

.509815 / 1280

collected and dried, and 110 mg of 7- (2-methanesulfinyl-2-phenylacetamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, F. 110 to 130 ⁰ C [IR spectrum (Nujol) 3300, 1785, 1715, 1680 cm " ¹ , NMR spectrum (D ₂ O + NaHCO ₃ , £) 2.51 (s, 3H), 2.72 ( s, 3H), 3.75, 3.42 (AB-q, 2H, JI Hz), 4.00 (d, IH, J-13 Hz), 4.50 (d, IH, J-13 Hz) , 5.10 (d, IH, J-4.5 Hz), 5.68 (d, IH, J-4.5 Hz)].

(X) Following a similar procedure to Examples 1 (A) to 1 (M), 1 (0) to 1 (U) or 1 (W) was made using 7-amino-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem- 4-carboxylic acid and methanesulfinyl acetic acid as Starting materials 7-Methanesulfinylacetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, mp 117-119 ° C (dec.).

Example 2

(A) 3.18 g of methylthioacetic acid was dissolved in 3.4 g of triethylamine and 4.22 g of benzoyl chloride were added added to the solution at -10 to -15 C and then the mixture became 20 at the same temperature Stirred for minutes. In addition, 5.45 g of 7-aminocephalosporanic acid in a mixture of 2.42 g Dissolved triethylamine, 10 ml of acetone and 10 ml of water

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509815/1280

and the mixture was cooled to -5 to -10 ° C. The solution obtained above was added to the mixture -5 to -10 C was added dropwise, while the mixture was kept at pH 7.5 to 8 by adding triethylamine became. The reaction mixture was washed with benzene. The aqueous solution was adjusted to pH 4 and the precipitate was filtered off. The filtrate was washed three times with ether to pH 1 and then extracted three times with ethyl acetate. The extract was washed with water and dried over magnesium sulfate, and the ethyl acetate was distilled off under reduced pressure. The white powdery residue was washed with a mixture of ethyl acetate and ether and 3.4 g of 7-methylthioacetamidocephalosporanic acid were obtained, 164 ° C (dec.). 720 mg of the 7-methylthioacetamidocephalosporanic acid thus obtained and 340 mg Sodium bicarbonate was dissolved in a phosphate buffer (pH 5.2, 30 ml). 330 mg were added to the solution 4-Methyl-4H-1,2,4-triazol-3-thiol was added and the mixture was stirred at 60 to 65 ° C. for 4.5 hours. The reaction mixture was cooled, adjusted to pH 1 to 2 with 10% hydrochloric acid, washed with ethyl acetate and then lyophilized. To the residue was added 70 ml of acetone was added and the insoluble matter was filtered off. Acetone was distilled off from the filtrate and the residue became with a small amount

509815/1280 -42-

Acetone and then washed with a small amount of water to give 260 mg of 7-methylthioacetamido-3- (4-methyl-4H-1,2,4-triazol-3-yl) thiomethyl-3-cephem-4-carboxylic acid, F. . 154-159 ⁰ C (dec.) · IR spectrum

γ; Nujol cm " ¹ ι 1765, 1700 (shoulder) *** 1650

NMR spectrum S (D ₂ O ₊ NaHCO ₃ ) ppm: 2.17 (3H, s),

3.3T3 (2H, s), 3.38 (IH, d, J-17 Hz), 3.70 (3H, s), 3.77 (IH, d, J-13 Hz), 3.86 (lH, d, J-17 Hz), 4.30 (IH, d, J-13 Hz), 5.08 (lH, d, J-4.5 Hz), 5.58 (lH, d, J-4.5 Hz), 8.50 (IH, s)

(B) 15 grams of potassium 3- (1-hydroxyacetyl) dithiocarbazate were slowly added over a period of 10 minutes at 0 to 5 C to a mixture of 20 ml of sulfuric acid and 100 ml of ethyl acetate and the Mixture was stirred for 1 hour at the same temperature · The reaction mixture became 1 1 Poured ethyl acetate, and the mixture was washed with an aqueous saturated sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and man received 3.7 g of S-hydroxymethyl-l ^^ - thiadiazol ^ -thiol, mp 120 to 125 ° C. With stirring at 0 to 5 ⁰ C over a period of 30 minutes, 7.9 g of isobutyryl

509815/1280

chloride was added dropwise to a solution of 5.0 g of the 5-Hydroxymethy1-1,3,4-thiadiazo1-2-thiol obtained above in 50 ml of pyridine. The solution was stirred for 30 minutes at the same temperature and for 2 hours at room temperature. To the reaction mixture was added 100 ml of water, and the mixture was concentrated on a water bath of 50 ° C. under reduced pressure. To the oily residue, 100 ml of cold water was added and, with stirring, 9.3 g of sodium bicarbonate was carefully added to the mixture at room temperature. After stirring at room temperature for 2.5 hours, the reaction mixture was washed with ether, acidified with 10% hydrochloric acid, and extracted with ether. The extract was washed with water, dried, and the solvent was distilled off, whereby 7.7 g of an oily residue was obtained. The residue was chromatographed on 100 g of silica gel using a mixture of benzene and chloroform (7s3) as a developing solvent, to give 4.0 of a pure oil from 5-isobutyryloxymethyl-1,3,4-thiadiazole-2-thiol [NMR spectrum (CCl ₄ , S), 1.23 (H, d, J-7 Hz), 2.54 (IH, q, J-7 Hz), 5.1 (2H, s)].

A solution of 2.50 g of the 5-isobutyryloxymethyl-1,3,4-thiadiazole-2-thiol obtained above in 5 ml Acetone was added to a solution of 3.60 g of the

509815/1280

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244719A

game 2 (A) obtained 7-methylthioacetamidocephalosporanic acid and 1.68 g of sodium bicarbonate in 76 ml of a pH 6.4 phosphate buffer are added and the mixture was stirred at 65 ° C. for 7 hours. The reaction mixture was cooled and washed with ethyl acetate washed. The aqueous layer was adjusted to pH 2 with dilute hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried and concentrated to give of 4.0 g of an oil of 7-methylthioacetamido-3- (5-isobutyryloxymethyl-1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid. The oil was made using a mixture of ethyl acetate and chloroform and acetic acid (20: 20: 1) as a developing solvent chromatographed on silica gel and the eluate was separated into 50 ml fractions. the sixth to tenth fractions were collected and concentrated. After dissolving the residue in 8 ml Methanol was added to the solution with cooling, 16 ml of a sodium α-ethylhexanoate solution and left to precipitate the crystals. The crystals were collected by filtration with washed cold methanol and ether and dried to give 1.81 g of sodium 7-methylthioacetamido-3- (5-isobutyryloxymethyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylate, F. 200.5 to 2O2 ° C (dec.).

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50981 5/1 280

(C) Following a similar procedure to Examples 2 (A) and 2 (B) were using the following compounds are produced from the corresponding starting materials:

(1) 7-methylthioacetamido-3- (1,3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid, M.p. 128 to 131 ° C (decomp.),

(2) 7-methylthioacetamido-3- (l-methyl-1H-tetrazol-S-yiythiomethyl-S-cephem ^ -carboxylic acid, F. 81 to 84 C,

(3) 7-Methy1thioacetamido-3- (5-methy1-1,3,4-thiadiazole " 2-yl) thiomethyl-3-cephem-4-carboxylic acid, mp 167 to 168 ° C (decomp.),

(4) 7-methylthioacetamido-3- (3-methyl-1,2,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, F. up to 180 ° C (decomp.),

(5) 7-Mesylacetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, F. 155 to

(6) 7-Allylthioacetamido-3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, F. 156 to 158 ° C (dec.),

(7) 7-Allylthioacetamido-3- (3-methyl-1,2,4-thiadiazol-5-yl) thiomethyi-3-cephem-4-carboxylic acid _f F. 114-115 ° C,

(8) 7- (2-Propynylthioacetamido) -3- (3-methyl-1,2,4-thiad iazo1-5-y1) thiomethy1-3-cephem-4-carboxylic acid, F. 127 to 129 ° C,

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(9) 7- (2-Allylthio-2-phenylacetamido) -3- (5-methyl-1,3,4-thiadiazol-2-y 1) thiorae thy IS-cephem-A-carboxylic acid, m.p. 89-94 ° C (dec.),

(10) 7-1sopropylthioac.etamido-3- (5-methy1-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, mp 156-157 ⁰ C,

(11) 7-t-Butylthioacetamido-3- (5-methy1-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, F. 154 to 155 ° C (dec.),

(12) 7- (2-M ^ thio-2-methylacetamido) -3- (5-methyl-1,3,4-thiadiazo 1-2-y 1) thiomethyl-3-cephem-4-carboxylic acid, F. 171 to 172 ° C,

(13) 7-Methylthioacetamido-3- (5-palmitoyloxy-methyl-1,3,4-thiadiazo 1-2-y 1) thiomethyl-3-cephem-4-carboxylic acid (powder) and its sodium salt, F. 145 up to 150 ° C, (Decomposition).

(D) 6.88 g of the 7- (2-methylthioacetamido) cephalosporanic acid obtained in Example 2 (A) were dissolved in 20 ml of an aqueous solution of 1.68 g of sodium bicarbonate. 120 ml of a pH 6.86 phosphate buffer and 4.68 g of 2-mercaptoethanol were added to the solution with stirring and the mixture was ^{stirred for 4 hours at 60 °} C. while it was kept at pH 6.5 to 6.8 . After cooling, the reaction mixture was adjusted to pH 8 to 9 and washed with ethyl acetate. The aqueous solution was adjusted to pH 2 and extracted with ethyl acetate. Of the

509815/1280

The extract was washed with water and then with an aqueous saturated sodium chloride solution and dried. The solvent was reduced under Distilled off under pressure and 0.2 g of 7- (2-methylthioacetamido) -3- (2-hydroxyäthy1) thiomethyl-3-cephem-4-carboxylic acid, melting point 134 ° to 138 ° C., was obtained. IR spectrum

V ¹ ^ ⁰¹ ^ ¹ * 3310, 1775, 1655, 1530 max.

(E) 7.73 g of 7- (2-allylthioacetamido) cephalosporanic acid was dissolved in 20 ml of an aqueous solution of 1.68 g of sodium bicarbonate. 6.2 g of 2-mercaptoethanol, 120 ml of a pH 6.8 phosphate buffer and an aqueous sodium bicarbonate solution were added to the solution, and the mixture was ^{stirred at 60 °} C. for 2 hours, while its pH was 6.4 to 6.5 was held. The reaction mixture was adjusted to pH 7.5 with sodium bicarbonate and washed with ethyl acetate. Ethyl acetate was added to the aqueous layer and the mixture was adjusted to pH 4-5 with hydrochloric acid. The ethyl acetate layer was separated and washed with water and then with a saturated aqueous solution of sodium chloride. The solvent was distilled off and 4.2 g of a hygroscopic powder of 7- (2-allylthioacetamido) -3- (2-hydroxyethyl) thiomethyl-3-cephem-4-carboxylic acid were obtained.

- 48 -B09815 / 1280

IR spectrum

-1

χ.
Max

cm " ¹ : 3350, 1780, 1720, 1665, 1525

(F) That from 2-methanesulfinyl-2-phenylacetic acid obtained by following the procedure of Example 1 (W) in methylene chloride at -78 C in the presence of isobutyl chloroformate obtained mixed anhydride of 2-Methanesulfinyl-2-phenylacetic acid was added all at once to 7-aminocephalosporanic acid, which was dissolved in methylene chloride, cooled to -78 ° C., in the presence of trimethylsilylacetamide. The obtained 7- (2-methanesulfinyl-2-phenylacetamido) cephalosporanic acid was treated with 5-methyl-1,3,4-thiadiazole-2-thiol in a manner similar to Examples 2 (A) and 2 (B) to give of 7- (2-methane • sulfynyl-2-pheny! .acetamido) -3- (5-methyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid, F. . 110 to 130 ° C, [IR spectrum (Nujol) 3300, 1785, 1715, 1680 cm " ¹ , NMR spectrum (D ₂ O + NaHCO ₃₁ &) 2.51 (β, 3H), 272 (s, 3H ), 3.75, 3.42 (AB-q, 2H, J-17 Hz), 4.00 (d, IH, J-14 Hz), 4.50 (d, IH, J-13 Hz), 5.10 (d, IH, J-4.5 Hz), 5.68 (d, IH, J-4.5 Hz)]

(G) The mixed anhydride of methanesulfinyl acetic acid prepared from methanesulfinyl acetic acid in methylene chloride at -78 ° C in the presence of isobutyl chloroformate was converted all at once to 7-aminocephalosporan

SÖ981571280. - 49 -

acid, dissolved in methylene chloride and cooled to -78 C, added in the presence of trimethylsilylacetamide. The 7-methanesulfinylacetamidocephalosporanic acid obtained was treated with 5-methy1-1,3,4-thiadiazole-2-thiol in a manner similar to Examples 2 (A) and 2 (B) treated to form 7-methane-sulfinylacetamido-3- (5-methy1-1-3,4-thiadiazol-2-yl) -thiomethyl-3-cephem-4-carboxylic acid, M.p. 117 to 119 ° C (dec.).

Example 3

(A) A solution of 9.25 g of falmitoyl chloride in 25 ml of dry methylene chloride was added to a solution of 5 g of 7-methylthioacetamido-3- (5-hydroxymethyl-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid while cooling with ice added dropwise in 50 ml of dry pyridine. The solution was for 3.5 hours at the same temperature and stirred for 2 hours at room temperature. The reaction mixture was poured into a Poured mixture of 300 ml of ice water and 400 ml of ethyl acetate, with 10 Ziger hydrochloric acid to pH Set 1 to 2 and the ethyl acetate layer was separated. The aqueous layer was washed with ethyl acetate extracted and both ethyl acetate layers were combined. The solution was with 5% Hydrochloric acid and water and washed over Dried magnesium sulfate. The solvent was

809815/1260. " ⁵⁰ "

removed and the residue was dissolved in chloroform. The solution was applied to 100 g of silica gel using chloroform as a developing solvent chromatographed and then with a methanol A. Chloroform (1/5) mixture eluted with isan 5.7 g of a powder of 7-methylthioacetamido-3 "(5-palmitoyloxymethy1-1,3,4-thiadiazo1-2-y1) thiomethyl-3-cephem-4-carboxylic acid received. The powder was dissolved in 60 ml of dry acetone and added to the solution 14 ml of a sodium a-ethylhexanoate solution were added. After standing overnight in the The precipitated crystals were collected by filtration and washed with acetone while cold 3.58 g of sodium "7" methylthioacetamido-3- (5-palmitoyloxymethy1-1,3,4-thiadiazol-2-yl) thiomethy1-3-> cephem-4-carboxylate, M.p. 145 to 150 ° C (dec.).

(B) Following a similar procedure to Example 3 (A) using the corresponding Starting materials the following connections are made:

7 "Methylthioacetamido-3- (5-isobutyry loxymethy 1-1,3,4-thiadiazol-2-yl) thiomethyl-3-cephem-4-carboxylic acid (oil) and its sodium salt ( mp 200.5-2O2 ° C (Dec.)].

- 51 -

S0981S / 1280

Claims (1)

Claims 1 · 7- (α-substituted-acetamido) -S-cephem-A-carboxylic acid derivatives, characterized by the general formula (I) R ₂ -X-CH-CONH-J | "^ ι COOH where mean: R _{1 is} hydrogen, hydroxy (lower) alkylthio or
heterocyclic thio replaced by lower alkyl
or alkanoyloxy (lower) alkyl can be substituted, R ₂ lower alkyl, lower alkylthio (lower) alkyl, acyl (lower) alkyl, acylamino (lower) alkyl,
Lower alkeny1, Ar (lower) alkenyl or lower alkynyl, R, hydrogen, lower alkyl or aryl and
X sulfur, sulfinyl or sulfonyl,
with the proviso that when R. is hydrogen, then R _{2 is} not lower alkyl , as well as their derivatives on the carboxy group and their pharmaceutically acceptable salts. 609815/1280 - 52 - 2. Compounds according to claim 1, characterized in that in the general formula (I) R, hydrogen, R ₂ lower alkylthio (lower) alkyl, acyl (lower) alkyl, acylamino (lower) alkyl, lower alkenyl, Ar (lower) alkenyl or lower alkynyl, R, hydrogen or aryl and X is sulfur, and the pharmaceutically acceptable salts thereof. 3. Compounds according to claim 2, characterized in that R- is hydrogen. 4. Compounds according to claim 3, characterized in that that R_ methylthiomethyl, benzoyl (lower) alkyl, Benzamido (lower) alkyl, allyl, styryl or propynyl. 5. A compound according to claim 4, characterized in that R «denotes methylthiomethyl. 6. A compound according to claim 4, characterized in that R _{9 is} benzoylmethyl. 7. Compound according to Claim 4, characterized in that R _{2 is} benzamidomethyl. 8. A compound according to claim 4, characterized in that R _{2 is} allyl. - 53 S0981S / 1280 9. A compound according to claim 4, characterized in that R _{2 is} cis-styryl. 10. A compound according to claim 4, characterized in that R _{2 is} 2-propynyl. 11. Compounds according to claim 2, characterized in that R _{2 is} lower alkenyl and R ^ is aryl. 12. A compound according to claim 11, characterized in that R _{2 is} allyl and R _{3 is} phenyl. 13. Compounds according to claim 1, characterized in that R, hydroxy (lower) alkylthio, R _{2 is} lower alkyl or lower alkenyl, R, hydrogen and X is sulfur, and the pharmaceutically acceptable salts thereof. 14. Compounds according to claim 13, characterized in that R, hydroxyethylthio and R _{2 are} methyl or allyl. 15. A compound according to claim 14, characterized in that R, 2-hydroxyethylthio and R _{2 are} methyl. 16. A compound according to claim 14, characterized in that R _{1 is} 2-hydroxyethylthio and R _{2 is} allyl. - 54 5G981S / 1280 .17. Compounds according to claim 1, characterized in that R, heterocyclic thio, which can be substituted by lower alkyl or alkanoyloxy (lower) alkyl, R "lower alkyl, lower alkylthio (lower) alkyl, acyl (lower) alkyl, acylamino (lower) alkyl, Lower alkenyl, ar (lower) alkenyl or lower alkynyl, R _{3 is} hydrogen, lower alkyl or aryl and X is sulfur, sulfinyl or sulfonyl, and the pharmaceutically acceptable salts thereof. 18 · Compounds according to claim 17, characterized in that X is sulfur and R ~ is hydrogen. 19. Compounds according to claim 18, characterized in that R _{1 is} an unsaturated, 5-membered heteromonocyclic thio group containing a sulfur atom and Containing 1 to 3 nitrogen atoms and substituted by lower alkyl or alkanoyloxy (lower) alkyl may be, or an unsaturated, 5-membered heteromonocyclic thio group, the 2 to A contains nitrogen atoms and through lower alkyl may be substituted, and R "is lower alkyl, lower alkenyl or lower alkynyl. 20 · Compounds according to claim 19, characterized in that R, an unsaturated, 5-membered heteromonocyclic Thio group, which is a sulfur atom and. Contains 2 nitrogen atoms and through lower alkyl 609815/1280 - 55 - or alkanoyloxy (lower) alkyl may be substituted, an unsaturated, 5-membered heteromonocyclic thio group which contains 3 nitrogen atoms and can be substituted by lower alkyl, or an unsaturated, 5-membered heteromonocyclic thio group which contains 4 nitrogen atoms and can be substituted by lower alkyl can. 21. Compounds according to claim 20, characterized in that R ₁ thiadiazolylthio, which can be substituted by methyl, isobutyryloxymethyl or palmitoyloxymethyl, triazolylthio substituted by methyl or tetrazolylthio substituted by methyl and R «methyl, isopropyl, t-butyl, allyl or 2- Mean propynyl. 22. A compound according to claim 21, characterized in that R, l, 3,4-thiadiazol-2-ylthio and R "are methyl. Compound according to Claim 21, characterized in that R _{1 is} 5-methyl-1,3,4-thiadiazol-2-ylthio and R "is methyl. 24. A compound according to claim 21, characterized in that R _{1 is} 3-methyl-l, 2,4-thiadiazol-5-ylthio and R _{2 is} methyl - 56 - 509815/1280 25. A compound according to claim 21, characterized in that R _{1 is} 5-methyl-l, 3,4-thiadiazol-2-ylthio and R _{2 is} allyl. 26. A compound according to claim 21, characterized in that R _{1 is} 3-methyl-l, 2,4-thiadiazol-5-ylthio and R _{2 is} allyl. 27. A compound according to claim 21, characterized in that R _{1 is} 3-methyl-l, 2,4-thiadiazol-5-ylthio and R «is 2-propynyl. 28. A compound according to claim 21, characterized in that R _{1 is} 4-methyl-4H-l, 2,4-triazol-3-ylthio and R _{2 is} methyl. 29. A compound according to claim 21, characterized in that R _{1 is} l-methyl-1H-tetrazol-5-ylthio and R _{2 is} methyl. 30. A compound according to claim 21, characterized in that R 5-methyl-l, 3,4-thiadiazol-2-ylthio and R _{2 is} isopropyl. 31. A compound according to claim 21, characterized in that R _{1 is} 5-methyl-l, 3,4-thiadiazol-2-ylthio and R _{2 is} t-butyl. - 57 509815/1280 32. A compound according to claim 21, characterized in that R-S-isobutyryloxymethyl-ljSjA-thiadiazol-2-ylthio and R- are methyl, and their sodium salt 33. A compound according to claim 21, characterized in that R, S-palmitoyloxymethyl-ljS ^ -thiadiazol-2-ylthio and R ~ represent methyl, and their sodium salt. 34. Compounds according to claim 17, characterized in that R, an unsaturated, 5-membered heteromonocyclic thio group which contains a sulfur atom and 1 to 3 nitrogen atoms which are substituted by lower alkyl, R _{2 is} lower alkyl, X is sulfur and R_ is lower alkyl. 35. Compounds according to claim 34, characterized in that that R, denotes an unsaturated, 5-membered heteromonocyclic thio group which is a sulfur atom and contains two nitrogen atoms and is substituted by lower alkyl. 36. Compounds according to claim 35, characterized in that that R- thiadiazolylthio substituted by methyl, R «denotes methyl and R-methyl. 37. A compound according to claim 36, characterized in that R, 5-methyl-l, 3,4-thiadiazpl-2-ylthio means. 509Ö15 / 1280 - 58 - 38. Compounds according to claim 17, characterized in that R is an unsaturated, 5-membered heteromonocyclic. Thio group which contains one sulfur atom and 1 to 3 nitrogen atoms and is substituted by lower alkyl, R _{9 is} lower alkenyl, X is sulfur and R is aryl. 39. Compounds according to claim 38, characterized in that that R 1 denotes an unsaturated, 5-membered heteromonocyclic thio group which has a sulfur atom and contains 2 nitrogen atoms and is substituted by lower alkyl. 40. Compounds according to claim 39, characterized in that R _{1 is} methyl-substituted thiadiazolylthio, R 2 is allyl and R «is phenyl. 41. Connection according to claim 40, characterized in that that R, 5-methyl-l, 3,4-thiadiazol-2-ylthio means. 42. Compounds according to claim 17, characterized in that R, an unsaturated, 5-membered heteromonocyclic thio group which contains a sulfur atom and 1 to 3 nitrogen atoms and is substituted by lower alkyl, R _{2 is} lower alkyl, X is sulfinyl and R _{3 is} hydrogen or aryl . - 59 80981 S / 1 280 43. Compounds according to claim 42, characterized in that R is an unsaturated, 5-membered means heteromonocyclic thio group containing one sulfur atom and two nitrogen atoms and is substituted by lower alkyl. 44. Compounds according to claim 43, characterized in that that R, thiadiazolylthio substituted by methyl, R «methyl and R. hydrogen or phenyl. 45. A compound according to claim 44, characterized in that R _{1 is} 5-methyl-l, 3,4-thiadiazol-2-ylthio and R_ is hydrogen. 46. A compound according to claim 44, characterized in that R, 5-methyl-l, 3,4-thiadiazol-2-ylthio and R_ denote phenyl. 47. Compounds according to claim 17, characterized in that R, an unsaturated, 5-membered heteromonocyclic thio group which contains a sulfur atom and 1 to 3 nitrogen atoms and is substituted by lower alkyl, R _{2 is} lower alkyl, X is sulfonyl and R. is hydrogen. 48. Compounds according to claim 42, characterized in that R _{1 is} an unsaturated, 5-membered hetero- 509815/1280 -60- monocyclic thio group means having a sulfur atom and contains 2 nitrogen atoms and is substituted by lower alkyl. 49. Compounds according to claim 43, characterized in that R _{1 is} methyl substituted thiadiazolylthio and R 2 is methyl. 50. A compound according to claim 44, characterized in that R, 5-methyl-l, 3,4-thiadiazol-2-ylthio means. 51 Process for the preparation of 7- (cc-substituted en Acetamido) -3-cephem-4-carboxylic acid derivatives of the general formula (I) R ₂ -XC HCONH where mean: R, hydrogen, hydroxy (lower) alkylthio or heterocyclic thio, which can be substituted by lower alkyl or alkanoyloxy (lower) alkyl, 509.815 / 1280 - 61 - R ₂ lower alkyl, lower alkylthio (lower) 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 sulfur, sulfinyl or sulfonyl, with the proviso that when R _{1 is hydrogen, R 2 is} not lower alkyl, or its derivatives on the carboxy group or their pharmaceutically acceptable salts, characterized that a 7-amino-3-substituted · te-3-cephem-4-carboxylic acid of the general formula wherein R, has the meanings given above, or their derivatives on the carboxy group or their salts with an α-substituted acetic acid the general formula (III) R ₀ -X-CH-COOH
* t ^R 3 wherein R ₂ , R- and X have the meanings given above, or their reactive derivatives 509815/1280 I. vaten on the carboxy group or its salts implements and, if desired, the resulting Compound converted in the usual manner into their pharmaceutically acceptable salts. 52. Method of making a Compound of the general formula (I ¹ ) R ₂ -X-GH-CONH COOH where mean: R ₂ lower alkyl, lower alkylthio (lower) alkyl, acyl (lower) alkyl, acylamino (lower) alkyl, lower alkenyl, ar (lower) alkenyl or lower alkynyl, R, hydrogen, lower alkyl or aryl, X sulfur, sulfinyl or sulfonyl and R, ¹ hydroxy (lower) alkylthio or heterocyclic thio, which can be substituted by lower alkyl or alkanoyl oxy (lower) alkyl, or derivatives on the carboxy group or their pharmaceutically acceptable salts, characterized in that a compound of the general formula - 63 509815/1280 (IV) R ₂ -X-CHCONH in which R ₁ R. and X have the meanings given above and Y denotes azido or lower alkanoyloxy, or their derivatives on the carboxy group or salts thereof with a thiol compound of the general formula (V) R '- H wherein R 'has the meanings given above, or converts alkali metal salts thereof and is desired If the compound obtained is converted into its pharmaceutically acceptable manner in the usual manner Salts transferred. 53. Method of making a Compound of the general formula (I ") R ₄ -S-CH ₂ CONH _n -f ^ V COOH - 64 - 509815/1280 where mean: R, lower alkyl, Rc alkanoyl, Z thiadiazole diyl and A lower alkylene, or their derivatives on the carboxy group or pharmaceutically acceptable salts thereof, there characterized in that one is a compound of the general formula (VI) R ₄ -S-CH ₂ -CONHq-f '^ Ljj ^ J-CH ₂ -SZA-OH COOH Ljjj ^ J-CH ₂ in which R 1, Z and A have the meanings given above, or their derivatives on the carboxy group or salts thereof with a carboxylic acid of the general formula (VII) R ₅ -OH wherein R _{5 has} the meanings given above, or converts its reactive derivatives on the carboxy group or salts thereof and, if desired, the compound obtained on 5098 15/128 0 borrowed way converted into their pharmaceutically acceptable salts. 54. Pharmaceutical preparation, characterized in that it contains at least one compound according to at least any one of claims 1 to 50 together with a pharmaceutically acceptable, substantially Contains non-toxic carrier or excipient. 509815/1280