DE2330296A1 - CEPHALOSPORINE COMPOUNDS, THEIR SALTS, THE PROCESS FOR THEIR MANUFACTURING AND THE MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS - Google Patents

Description

SMITH KLINE & FRENCH LABORATORIES
Philadelphia, Pennsylvania, V.St.A.

"Cephalosporin compounds, their salts, processes for their Manufacture and medicinal products containing these compounds "

Priority:

June 14, 1972, V.St.A., No. 262 903

September 15, 1972, V.St.A., No. 289 499 May 11, 1973, V.St.A., No. 359 566

The invention relates to new cephalosporin compounds in general Formula I.

HIGH

(D

COOH

and their salts, in which A is a hydrogen atom, an acetoxy, Methoxy or methyl mercapto group or a monocyclic group Is heterocyclomercapto radical.

The term "heterocyclo" means a monocyclic hetero cyclic radical with one or more carbon atoms and one or more nitrogen, sulfur or oxygen atoms, by one or more alkyl or alkoxy radicals

309881/1215

with 1 to 4 carbon atoms, especially the methyl group, can be substituted. Preferred heterocyclic radicals are 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, • 1,3,4-oxadiazolyl or tetrazolyl radical, the one with a methyl group can be substituted. Particularly preferred examples of heterocyclic radicals are 1,2,3-triazol-5-yl, 2-methyl-1,3,4-thiadiazol-5-yl and i-methyltetrazol-5-yl groups, The salts are preferably derived from basic alkali metal compounds or ammonia. .

The invention also relates to a process for the preparation of the cephalosporin compounds of the general formula

I, which is characterized in that (a) a 7-aminocephalosporanic acid of the general formula II

(II) COOH

in which A has the above meaning, with the p-hydroxy methylphenylglycine of the formula III

(III)

whose amino group is optionally protected, or its reactive derivative is acylated and optionally a splits off existing protective group and, if necessary

309881/1215

(b) - when A is an acetoxy group - that obtained from (a)

7- (α-Amino-p-hydroxymethylphenylacetamido) -3 ~ acetoxymethyl-3-cephem - ^ - carboxylic acid of formula IV

HIGH ₂ - / \ _ CHCONH

₂ - /

NH ₂ ο-

, / ^S N

H Λ— CHpOCOCH,

ι (IV)

COOH

reacts with a heterocyclomercaptan, the heterocyclic Remainder has the above meaning, and optionally the compound of the obtained according to (a) or (b) general formula I converted into their salt by reaction with a base or an acid.

The invention also relates to those used in accordance with the method Compounds p-hydroxymethylphenylglycine and p-hydroxymethyln-tert-butoxycarbonyl-phenylglycine.

The cephalosporin compounds of the invention are according to embodiment (a) by acylation of a 7-aminocephalosporanic acid of the general formula II with p-hydroxymethylphenylglycine of the formula III produced. The p-hydroxymethylphenylglycine used is obtained by reducing an aldehyde group of terephthalaldehyde with lithium tri- (tert-butoxy ^ aluminum hydride, Condensation of the remaining aldehyde group of the

hold p-hydroxymethylbenzaldehyde with ammonium carbonate and Sodium cyanide and hydrolysis of the hydantoin obtained with barium hydroxide.

309881/1215

The acylation according to (a) is preferably protected with one on the (x-amino group of the p-hydroxymethylphenylglycine radical Compound carried out which has a customary protective group that can easily be split off again, such as the tert-butoxycarbonyl, Benzyloxycarbonyl or trichloroethoxycarbonyl group or a

other protective group commonly used in peptide syntheses. The carboxyl group of p-hydroxymethylphenylglycine is used for acylation preferably into an acid chloride or a mixed anhydride with, for example, a lower alkyl chloroformate convicted. The carboxyl group can, however, also be converted into the 2,4-dinitrophenyl or N-hydroxysuccinimidyl ester made more responsive. If an ester of the corresponding cephalosporin, e.g. the benzhydryl, tert-butyl, Trichloroethyl or benzyl ester is used, the protected p-hydroxymethylphenylglycine can also be used directly for acylation of the 7-position amino group using a carbodiimide such as dicyclohexylcarbodiimide can be used. The protected p-Hydroxyphenylglycine can also "for condensation with the corresponding cephalosporin just as well beforehand by reaction with a carbonyldiimidazole or an equivalent compound be brought into a more reactive form.

Following the acylation, the protective group is split off again with an acid, preferably trifluoroacetic acid. That The salt obtained is obtained in aqueous solution by treatment with an anion exchange resin in the base form, e.g., polystyrene-amine ion exchange resin (Amberlite IR-45), or another base converted into the betaine.

309881/1215

According to process variant (b) v / ground the cephalosporin compounds of the invention in a similar manner only by acylating 7-aminocephalosporanic acid (7-ACS) with p-hydroxymethylphenylglycine and then prepared by replacing the acetoxy group with a heterocyclomercapto group in a manner known per se. To prepare the compounds of the general formula I in which A is a methoxy or methyl mercapto group, the acetoxy group of the acylated 7-aminocephalosporanic acid is used in a manner known per se against the methoxy or methyl mercapto group exchanged.

Those which can be used as starting compounds according to the invention 7-Aminocephalosporanic acids of general formula II are either known or can be prepared in a manner known per se. The replacement of the acetoxy group in 7-aminocephalosporanic acid against a heterocyclomercapto group is also known.

The presence of both an amino group and a carboxyl group in the cephalosporin compounds of the general formula I makes it possible, in a manner known per se, to use salts with acids and To prepare salts with bases as well as the betaines of these compounds. The salts can be in a manner known per se in the transfer corresponding betaines. All of the above salts are within the scope of the invention.

Due to the asymmetric α-carbon atom in the 7-acetamido radical there are two optical antipodes. The 'D shape is the preferred shape; but the L-form and racemic form are also

309881/1215

if subject of this invention. Ground the pure antipodes by splitting the racemisehen mixtures into known ones V / one received. For this purpose, either the intermediate product can be split up before the acylation or the end product can be split up.

The CephaLosporin compounds of the general formula I are valuable antibiotics. The minimum inhibitory concentration (MIC) is in the range of about 3 to 200 µg / ml, but against many microorganisms in the range of 3 to 50 µg / ml. The determined values of the minimum inhibitory concentration are summarized in Table II. Some EDj- _Q values are also shown in Table III.

Table I. The "designation of the investigated compounds

Link; No. A

47216 H 37316 OCOCH ₃

■ XU

62516

43026 - _n

76026

CH ₃

309881/1215

link
No. S. aureus S. aurews 47216 6.3 25th 37316 12.5 6.3 ω
ο
ta 62516 25th 12.5. 1881 43026 3.1
12.5 6.3
3.1 κ> 76026 50 50

Table II 7th E. coll E. cell - 7 - Klebs. pneumo . MIC {μκ / τΆ \} 25th 50 25th Strep, faecalts 12.5 25th Klebs. pneutno. 25th 200
25th 50
25th 25th 25th
12.5 200 12.5
12.5 12.5
12.5 3.1 6 _; 3 200 25th 50 25th
12.5 25th 100
200 2 * ³ > 200 25th

Table II - continued

MIC

link

No. Pseudomonas sp. Salmonella ShiRella Entero. aero.a; . Serratia marc. Staph. Villaluz

47216 > 200 to 37316 > 200 O CO Λ200 OO 62516 OO χ »» > 200 __ * 43026 > 200

25th 5 12th 7th 25th 5 12, 1 3. 3 «;

76026

> 200

25th

25th
6 _; 3

25th
12 ₇ 5

6.3

* 3

25th

200 50

25 25

50

> 200 > 200

> 200

^ 200 > 2C0

> 200

200 100

100 200

200

CD CJ)

E. subcutaneous Table le III Klebs. pneurao. OS 5 33 ED ₅₀ (mg / kg) subcutaneous by 2 link 8.7 coli > 50 50 12.5 No. 17; 25th ,by OS 20th ) 50 14, 47216 11; 11.2 29 12.5; 17th 18; 6, 37316 8th > 50 14.5; 7.2 , 8.3; ; < 62516 39; 46 9.5; 7th 16.7 43026 7.4 ; 21 76026 25th

The cephalosporin compounds of the present invention become injectable in the same manner as other cephalosporin antibiotics or orally administrable drugs in the form of solutions, suspensions, tablets or capsules. To the preventive or acute treatment of bacterial infections, the cephalosporin compounds of the invention are injected or administered orally. The amount of dose depends on the type and severity of the infection and on the age, weight and General condition of the patient.

The invention thus also relates to medicaments which contain a cephalosporin compound of the general formula I or its salt and conventional carriers and / or diluents and / or auxiliaries.

The examples illustrate the invention.

309881/1215

- ίο -

B ₁ eis ρ ie 1 1

7β- (DL-α-amino-p-hydroxymethylphenylacetamido) -desacetoxvcephalosporanic acid

A solution of 50.0 g (0.373 mol) of terephthalaldehyde in 200 ml of anhydrous tetrahydrofuran is added dropwise in an ice bath under a nitrogen atmosphere with a solution of 104.0 g (0.410 mol) of lithium tri- (tert-butoxy) - aluminum hydride added in 500 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred for a further 1/2 hour in the ice bath and then poured into 2 liters of ice-cold 2N hydrochloric acid. The aqueous solution obtained is extracted four times with 800 ml of diethyl ether each time. The combined diethyl ether extracts are washed with 500 ml of ice-cold 5 percent sodium bicarbonate solution and then with 500 ml of saturated sodium chloride solution. After drying, the diethyl ether is evaporated off under reduced pressure. 46 g of crude p-hydroxymethylbenzaldehyde are obtained. The crude product is chromatographed on 1 kg of aluminum oxide using diethyl ether. The eluted fractions are concentrated. On cooling, 17.6 g (35 % of theory ) of p-hydroxymethylbenzaldehyde with a melting point of 44.5 ° to 46 ° C. crystallize out.

A mixture of 10.0 g (0.0735 mol) of p-hydroxymethylbenzaldehyde and 17.1 g (0.15 mol) of ammonium carbonate in 110 ml of 60 percent strength A solution of 4.0 g (0.081 mol) of sodium cyanide in 10 ml of water is added dropwise with stirring at 50 ° C. to ethanol. The mixture is heated to 55 to 60 ° C. for 3 hours and then to 85 ° C. for 1 hour, while stirring. After cooling in the solution is adjusted to pH 6 with concentrated hydrochloric acid in an ice bath. After 15 to 18 hours of cooling

309881/1215

a substance precipitates which is filtered off, washed with cold water and dried. Yield 11.0 g (72 % of theory ) of 5- (p-hydroxymethylphenyl) hydantoin with a melting point of 189 ° to 196 ° C. (decomposition), which is processed further without further purification.

A mixture of 10.9 g (0.053 mol) 5- (p-hydroxymethylphenyl) hydantoin and 25.5 g (0.081 mol) barium hydroxide (8.H ₂ O) in 125 ml water is refluxed for 18 hours and stirred . After cooling on the ice bath, the reaction mixture is diluted with 125 ml v / water. The aqueous solution is acidified to pH 1 with concentrated sulfuric acid. The precipitated barium sulfate is filtered off and the filtrate is adjusted to a pH of 6 with lead carbonate. After the lead sulfate has been filtered off, the filtrate is saturated with hydrogen sulfide and the lead sulfide is filtered off. The aqueous solution is then evaporated to a volume of 100 ml by azeotropic distillation with ethanol under reduced pressure. On cooling, 5.2 g (54 % of theory ) of p-hydroxymethylphenylglycine with a melting point of 228 to 229 ° C. (decomp.) Precipitate. "After recrystallization from an ethanol / water mixture, the compound melts at 230-231 ^G C (dec.).

A solution of 8.0 g (0.044 moles) of p-hydroxymethylphenylglycine and 8.8 g (0.087 mol) of triethylamine in 160 ml of water is treated with a solution of 6.95 g (0.049 mol) of tert-butoxycarbonylazide added in 120 ml of tetrahydrofuran. After 15 to 18 hours Stirring at room temperature, the reaction mixture is extracted twice with 200 ml of diethyl ether each time. The aqueous phase is with Diethyl ether and placed on an ice bath with 3 η hydrochloric acid

308881/1215 "^

acidified to a pH of 3 to 3.5. The aqueous acidic solution is extracted three times with 200 ml of diethyl ether each time. The combined diethyl ether extracts are washed with saturated sodium chloride solution, dried and evaporated under reduced pressure. The oil obtained is digested with a chloroform / hexane mixture and the solid substance which precipitates out is filtered off. Yield 7.74 g (63 % of theory) of N-tert-butoxycarbonyl-p-hydroxymethylphenylglycine of melting point.

up to 141.5 ° C (dec.).

7.560 grams (0.0269 moles) of DL-N-tert-butoxycarbonyl-p-hydroxymethylphenylglyein and 10.199 g (0.0269 mol) of quinine are dissolved in 110 ml of boiling ethanol. After cooling the solution to room temperature a salt crystallizes out in the course of 15 to 18 hours. The salt is filtered off and recrystallized three times. 17.76 g of the salt (m.p. 198 to 201 ° C decomp., / Α / jp = -149.8 °, 1-form, methanol) give after three recrystallization 4.6 g of the pure optical antipode (melting point 205 to 206 ° decomp., / Oc / jj = -163.4 °, 1-form, methanol). By further recrystallization the rotation value can no longer be increased.

The (-) - quinine salt of (-J-N-tert-butoxycarbonyl-p-hydroxymethylphenylglycine is suspended in 75 ml of water and 175 ml of diethyl ether on an ice bath. The suspension is 3 η Hydrochloric acid added up to a pH value of 2.5. The aqueous phase is separated off and twice with 100 ml of diethyl ether each time extracted. The combined diethyl ether phases are washed with 100 ml of saturated sodium chloride solution and dried

309881/1215

and evaporated under reduced pressure. The residue is digested with a chloroform / hexane mixture. Yield 1.68 g (98 % of theory ) of D (-) - N-tert-butoxycarbonyl-p-hydroxymethylphenylglycine, melting point 111 to 113.5 ° C decomp., Fa '/ ψ = -136.5 ° , 1-form, methanol.

A solution of 3.0 g (0.011 mol) of dl-N-tert-butoxycarbonyl-phydroxymethylphenylglycine and 1.25 g (0.011 mol) of N-hydroxysuccinimide in a mixture of 10 ml of anhydrous tetrahydrofuran and 50 ml of anhydrous acetonitrile is 2.238 g (0.011 mol) N, N ¹ -bicyclohexylcarbodiimide added. The mixture is stirred at room temperature for 15 to 18 hours, and then the precipitated dicyclohexyl urea is filtered off. The filtrate is evaporated under reduced pressure. The solid residue obtained is digested with diethyl ether. After filtering off, 3.4 g (yield 83 % of theory ) of N-tert-butoxycarbonyl-p-hydroxymethylphenylglycine-N-hydroxysuccinimide ester with a melting point of 141 ° to 148 ° C. (decomposition) are obtained.

Becomes D (r) -N-tert-butoxycarbonyl-p-hydroxymethylphenylglycine used, the corresponding optically active ester is obtained (melting point 86 to 90 ° C. decomp., / a / jp = -47.6 °, 1-form, methanol ).

line solution of 0.452 g (1.61 mol) of N-tert-butoxycarbonyl-phydroxymethylphenylglycine and 0.434 g (1.61 mol) of 7-aminodeacetoxycephalosporanic acid tert-butyl ester in a mixture of 5 ml of tetrahydrofuran and 5 ml of acetonitrile is at 0 ⁰ C mixed with 0.363 g (1.76 mol) of N, N ^f -dicyclohexylcarbodiimide. Then

309881/1215

. - 14 -

the reaction mixture is stirred for 15 to 18 hours at room temperature. 10 ml of methylene chloride are added to the reaction mixture, and the precipitated N, N ^f -dicyelohexylurea is filtered off and washed with methylene chloride. The filtrate is washed with ice-cold 1 percent phosphoric acid, ice-cold 1 percent sodium bicarbonate solution and saturated sodium chloride solution. The dried filtrates are chromatographed on silica gel and with a methylene chloride / ethyl acetate mixture. The eluted fractions are combined and evaporated to dryness. The residue is digested with diethyl ether. After filtering 0.638 to 126 g is obtained (yield 75% d. Th.) 7ß- (DL-oc-N-tert-butoxycarbonylamino-p-hydroxymethylphenylace tamido) -desacetoxycephalosporansäure tert-butyl ester, mp. 130 ⁰ C to (Decomposition).

7 ml of trifluoroacetic acid, which contain 8 drops of anisole, are treated with 0.628 g (1.2 mmol) of 7β- (DL-aN-tert-butoxycarbonylamino-p-hydroxymethylphenylacetamido) -desacetoxycephalosporanic acid-tert-butyl ester at 0 ° C. The solution is then stirred at 0 ° C. for 1 hour. The trifluoroacetic acid is then distilled off from the reaction mixture under reduced pressure and the residue is digested four times with diethyl ether. 0.51 g (yield 90 % of theory ) of the salt of 7β- (DL-α-amino-phydroxymethylphenylacetamido) -desacetoxycephalosporanic acid with trifluoroacetic acid are obtained; Mp. 141-170 ⁰ C (dec.).

To convert it into betaine form, the salt is dissolved in water and after being treated with a polystyrene-amine ion

309881/1215

exchange resin, such as Amberlite IR-45, for about 1 hour at room temperature touched. After the ion exchange resin has been filtered off, the aqueous solution is freeze-dried Title compound.

The salt can be converted into betaine with trifluoroacetic acid but can also be dissolved in water and only with methyl isobutyl ketone and then added tributylamine. The betaine precipitates in the process; it is filtered off, washed and dried.

Example 2

7ß- (DL-a-Amino-p-hydroxyl methylphenylacetamido) '- cephalosporan-

t acid

A device of 0.60 g (2.14 mmol) of N-tert-butoxycarbonyl-hydroxymethylphenylglycine, 0.705 g (2.14 mmol) of 7-aminocephalosporanic acid tert-butyl ester and 0.485 g (2.35 mmol) of N, N ^f -Dicyclohexylcarbodiimid is implemented according to Example 1. After chromatographing twice on silica gel and digesting the residue with hexane, 0.238 g (yield 19 % of theory ) of 7β- (DL-aN-tert-butoxycarbonylamino-p-hydroxymethylphenylacetamido) cephalosporanic acid tert-butyl ester of melting point is obtained. 111 to 115 ° C (dec.).

Analogously to Example 1, 0.222 g (0.376 mmol) of 7β- (DL-a-N-tert-butoxycarbonyl-amino-p-hydroxymethylphenylacetamido) -cephalosporanic acid-tert-butyl ester into an ice-cold mixture of trifluoroacetic acid and anisole entered. 0.159 g is obtained

309881/1215

-. 16 -

(Yield 77 % of theory ) of the salt of 7β- (DL-α-amino-p-hydroxymethylphenylacetamido) -cephalosporanic acid with trifluoroacetic acid; Mp. 136 to 15O ⁰ C (dec.).

The salt with trifluoroacetic acid is converted into the title compound as in Example 1.

Example 3

3- (i, 2,3-Triazol-5-ylmercaDtomethvl) -7ß- (DL-y-amino-p-hydroxymethylOhenylacetamido) -3-cephem-A-carboxylic acid 0.60 g (1.92 mmol) 3- (i, 2,3-Triazol-5-ylmercaptomethyl) -7-amino-3-cephem-4-carboxylic acid dissolved with stirring in 12 ml of anhydrous pyridine, the 0.39 g (3.84 mol) of triethylamine contains. 0.73 g (1.92 mmoles) of N-tert-butoxycarbonyl-p-hydroxymethylphenylglycine-N-hydroxysuccinimide ester are added to the solution. The reaction mixture is then stirred for 4 hours at room temperature and then poured into 200 ml of diethyl ether. The solid substance which precipitates out is filtered off and dissolved in 100 ml of water. The aqueous solution is covered with a layer of ethyl acetate and the pH is adjusted to 2 with 3 η hydrochloric acid on an ice bath. Undissolved substances are filtered off, the ethyl acetate phase is separated off and the aqueous phase is extracted twice more with ethyl acetate. The combined ethyl acetate extracts are washed with saturated sodium chloride solution, dried and evaporated under reduced pressure. The residue is digested with diethyl ether. 0.651 g (yield 59 % of theory ) of 3- (1,2,3-triazol-5-ylmercaptomethyl) -7β- (DL-aN-tert-butoxycarbonylamino-p-hydro-

309881/1215

xymethylphenylacetamido) -3-cephem-4-carboxylic acid of m.p. 197 to 220 ° C (dec.).

Used as a pure optical antipode D (-) - hydroxymethy! Phenylglycine derivative if used, a product of melting point 173 ° to 198 ° C. (decomp.) is obtained.

0.570 g (0.99 mmol) 3- (1,2,3-triazol-5-ylmercaptomethyl) -7β- (DL-oc-N-tert-butoxycarbonylamino-p-hydroxymethylphenylacetamido) -3-cephem-4-carboxylic acid are added to 10 ml of trifluoroacetic acid containing 2 ml of anisole on the ice bath. The solution is then stirred at 0 ° for 1/2 hour. After the trifluoroacetic acid has been distilled off under reduced pressure, the residue obtained is digested four times with diethyl ether. 0.44 g (yield 75 % of theory ) of the salt of 3- (1,2,3-triazol-5-ylmercaptomethyl) -7β- (DL-a-amino-p-hydroxymethylphenylacetamido) -3- is obtained cephem-4-carboxylic acid with trifluoroacetic acid; Mp 155-162 ° C (dec.).

If the pure diastereoisomer is used, a

Product from m.p. 164 to 170 ° C (dec.); / aj ?? = -13.1 ° (l-form, methanol).

The salts are converted into their betaines as in Example 1.

309881/1215

Example 4 3- (2-MethYl-1,3,4-thiadiazol-5-Ylfflercaptomethyl) -7β- (DL-a amino-p-hydroxymethylphenylacetamido) -5-cephem-4-carboxylic acid A mixture of 0.695 g (2 mmol ) 3- (2-Methyl-1,3,4-thiadiazol-5-ylmercaptomethyl) -7-araino-3 ~ cephem-4-carboxylic acid, 0.760 g (2 mmol) DL-N-tert-butoxycarbonyl-p- hydroxymethylphenylglycine-N-hydroxysuccinimide ester and 0.41 g (4 mmol) of triethylamine are reacted according to Example 3. After the ethyl acetate has been distilled off, the residue is digested with hexane. 0.709 g are obtained (yield 59 % of theory ). 3- (2-Methyl-1,3,4-thiadiazol-5-ylmercaptomethyl) -7β- (DL-aN-tert -butoxycarbonylamino-p-hydroxymethylphenylacetamido) -3-cephem-4-carboxylic acid of m.p. 129 to 138 ° C (dec.).

0.659 g (1.1 mmol) 3- (2-methyl-1,3,4-thiadiazol-5-ylmercaptomethyl) -7ß- (DL-a-N-tert-butoxycarbonylamino-p-hydroxymethyl-

phenylacetamido) -3-cephem-4-carboxylic acid are converted according to Example 3 into 0.574 g (yield 85 % of theory ) of the salt with trifluoroacetic acid, melting point 142 ° to 154 ° C. (decomposition).

The salt is converted into the betaine as in Example 1.

Example 5

3- (1 -Methyltetrazol-S-ylmercaptomethyl) -7ß- (DL-a-N-tert -butoxycarbonvlamino-p-hydroxymethylphenvlacetamido) -3-cephem-4-

carboxylic acid

A mixture of 1.22 g (3.7 mmol) 3- (1-methyltetrazol-5-ylmercaptomethyl) -7-amino-3-cephem-4-carboxylic acid, 1.40 g (3.7 mmol) DL-N-tert. -Butoxycarbonyl-p-hydroxymethylphenylglycine-N-hydro-

309881/1215

- 19 -

Xysuccinimide ester and 0.75 g (7.4 mmol) of triethylamine are reacted according to Example 3. After digestion with hexane, 1.3 g (yield 59 % of theory ) of 3- (i-methyltetrazol-5-ylmereaptomethyl) -7β- (DL-aN-tert-butoxycarbonylamino-hydroxymethylpheny / acetamido) -3 are obtained -cephem-4-carboxylic acid of m.p. 138 to 148 ° C (Ze.rs.).

3- (1-Methyltetrazol-5-ylmercaptomethyl) -7ß- (DL-aN-tert. Butoxycarbonylamino-p-hydroxymethylphenylacetamido) -3-cephem-4-carboxylic acid is obtained according to Example 3 in 0.946 g (yield 71 % of theory . ) of the salt with trifluoroacetic acid, melting point 158 to 165 ° C (dec.), transferred.

The salt is converted into the betaine as in Example 1.

Example 6

If the following 7-aminocephalosporin compounds are made according to Example 1 to. 5 acylated, the corresponding 7- (a-amino-p-hydroxymethylphenylacetaraido) -cephalosporin compounds are obtained.

7-Amino-3- (5-methyl-1,2,4-triazol-3-ylmercaptomethyl) -3-cephem-4-carboxylic acid,

7-Amino-3- {1-methyl-1,2,3-triazol-5-ylmercaptomethyl5-3-cephem-4-carboxylic acid,

7-Amino-3- (4-methyl-1,2,3-triazol-5-ylmercaptomethyl) -3-cephem-4-carboxylic acid,
7-amino-3- (tetrazol-5-ylmercaptomethyl) -3-cephem-4-carboxylic acid,

309881/1215

7-Amino-3- (2-methyl-1,3 »4-oxydiazol-5-ylmercaptomethyl) - 3-

cephem-4-carboxylic acid,

7-Amino-3-O, 2,4-triazol-3-ylme (3 ° captomethyl) -3-eephem-4-carbon-

acid, 7-amino-3-methylmercapto-3-cephem-4-carboxylic acid and 7-Araino-3-methoxymethyl-3-cephem-4-carboxylic acid.

Example 7

A drug for parenteral administration can be prepared by dissolving of 500 mg of the sodium salt of 7- (ct-amino-p-hydroxymethylphenylacetamido) -3- (1,2,3-triazol-5-ylmercaptomethyl) -3-eephem-4-carboxylic acid can be prepared in 2 ml of sterile water or physiological saline solution. Any cephalosporin compound of the invention, in particular that of Examples 1, 2, 4 and 5 »can be applied in a similar manner to a medicament processed v / earth.

B e i s ρ i-e 1 8

A capsule for oral administration can be prepared by mixing together 500 mg of one of the cephalosporin compounds of the invention, in particular that from Examples 1 to 5, with 250 mg of lactose and 75 mg of magnesium stearate.

309881/1215

Claims (1)

- 21 claims 1. Cephalosporin compounds of the general formula I ^ - CH ₂ A COOH and their salts, in which A is a hydrogen atom, an acetoxy, Methoxy or methyl mercapto group or a monocyclic group Is heterocyclomercapto radical. - 2. Cephalosporin compounds according to claim 1 of the general formula I, characterized in that the heterocyclic radical in the Heterocyclomercaptoest a 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3,4-thiadiazolyl, 1,3,4-oxadiazolyl or Tetrazolyl means which is replaced by one or more alkyl or alkoxy groups with 1 to "4 carbon atoms per alkyl or Alkoxy radical, in particular the methyl group, can be substituted. 3. 7- (α-Amino-p-hydroxymethylphenylacetamido) -3- (5-methyl-1,3,4-thiadiazol-2-ylmercaptomethyl) -3-cephem-4-carboxylic acid. 4. 7- (ά-amino-p-hydroxymethylphenylacetamido) -3- (1,2,3-triazol-5-ylmercaptomethyl) -3-cephem-4-carboxylic acid. 309881/1215 5. 7- (α-Amino-p-hydroxymethylpheny / acetamido) -3- (1 -methyl-1 »2,3,4-tetrazol-5-ylmercaptomethyl) -3-cephem-4-carboxylic acid. 6. 7- (α-Amino-p-hydroxymethylphenylacetamido) -3-deacetoxycephalosporanic acid. 7. 7- (α-Amino-p-hydroxymethylphenylacetamido) -cephalosporanic acid. qJ Process for the preparation of the cephalosporin compounds according to Claim 1 of the general formula I, characterized in that
(a) a 7-aminocephalosporanic acid of the general formula II -S. (H) COOH in which A has the above meaning with p-hydroxymethylphenylglycine of formula III HIGH ₂ - (/ vy_ CHcooH (m) whose amino group is optionally protected, or its reactive derivative is acylated and optionally splitting off an existing protecting group and optionally (b) - if A is an acetoxy group - the one obtained from (a) 7- (a-Amino-p-hydroxymethylphenylacetamido) -3-acetoxyme- ethyl-3-cephem-4-carboxylic acid of the formula IV 309881/1215 ^ CH ₂ OCOCH ₃ (IV) OOH reacts with a heterocyclomercaptan, the hetero-. cyclic radical has the above meaning, and optionally the compound of the obtained according to (a) or (b) general formula I converted into their salt by reaction with a base or an acid. 9. Medicaments containing a cephalosporin compound according to claim 1 or its salt and customary carriers and / or Diluents and / or auxiliaries. 10. p-Hydroxymethylphenylglycine. 11. p-Hydroxymethyl-N-tert-butoxycarbonylphenylglycine. 309881/1216