FI56843C - FRAMSTARABILATION OF ANTIBACTERIA 7- (ALPHA-AMINO-β-HYDROXYPHENYLACETAMIDO) -3-HETEROCYCLIC THIOMETHYLPHALOSPORINER - Google Patents

Description

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Patent- and Register-Laws Antdkm utiagd och utLskrKton pubUcerad 21 12.79 (32) (33) (31) Requested «uolkuu * —Begird prloriut # q6.72 I5.O9.72 USA (US) 262903, 289 ^ 99 Proven-Styrkt (71) ) Smith Kline & French Laboratories, 1500 Spring Garden Street, Philadelphia, Pennsylvania 19101, USA (72) George Lawrence Dunn, Wayne, Pennsylvania, John Russel Eugene Hoover,

Glenside, Pennsylvania, USA (US) (7 * 0 Berggren Oy Ab (54) Method for the preparation of bactericidal 7- (c * -amino-p-hydroxyphenylacetamido) -3-heterocyclic thiomethylcephalosporins - Förfarande för framställning av antibacteriella 7 - (# -amino-p-hydroxyphenylacetamido) -3-heterocyclic thiomethylcephalosporin

The present invention relates to a process for the preparation of bactericidal 7- (α-amino-p-hydroxyphenylacetamido) -3-heterocyclic thiomethylcephalosporins of the formula

HO— / / —CHCO0H -— 1-S '> N

\ = / NH2 0 = 1 — _ ch ^ s.r

m * I

C00H

wherein R is 1,2,3, -triazol-4-yl, 4-methyl-1,2,3-triazol-5-yl or 1-methyl-1,2,3-triazol-5-yl.

Finnish patent publication 50427 discloses a process for the preparation of antibacterial 3,7-disubstituted cephalosporan compounds. However, these known compounds do not contain a 1,2,3-triazol-5-ylthiomethyl group in the 3-position. The structure of the acyl groups of these prior art compounds also differs quite substantially from the structure of the acyl groups in the compound of formula I.

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Finnish patent publication 51201 discloses a process for the preparation of 3-mercaptothiazole or mercaptotetrazole cephalosporins. However, it does not specifically and specifically show the acyl groups of the above formula I, and this previously known compound does not have 1,2,3-triazole substituents of the above formula.

Finnish patent application 355/71 further discloses a process for the preparation of 7 '(α-amino-p-hydroxyphenylacetamido) -3- (5-methyl-1,2,4-triazol-3-ylthiomethyl) -3-cephem-4-carboxylic acid, however, which differs with respect to the triazole derivative from the compounds prepared by the method of the present invention, and which further provides a significantly lower ED 2 value in mouse protection experiments, as will be explained in more detail from the description below.

EDj-q means the total dose (in milligrams / kg) required to protect half of the mice.

DE-A-2202271 *, published in July 1972, discloses a process for the preparation of the antibacterial 7- (α-aminophenylacetamido) -3- (1,2,3-triazol-4-ylthiomethyl) -3-cephem-4-carboxylic acid.

The invention relates to a process for the preparation of compounds of formula I (1) by reacting an acetoxymethylcephalosporin compound of formula

R1NHT-r \ 0 = l — ch2ococh5

C00H

wherein R "* · is HO-γ-CHCO, wherein the NH2 group is suitably protected, if necessary, or is H, to react with a heterocyclic thiol compound of formula

HS-R III

wherein R is as defined above, and (2) when R 1 is H, acylation of the compound obtained with a p-hydroxyphenylacetic acid compound of the formula

HO— \ V — CHCOOH IV

\ = / NH2 or an acylated or activated derivative thereof, wherein the NH2 group is suitably protected, if necessary, and (3) subsequently removing any protecting group.

Preferred compounds prepared according to the invention include e.g. the following: 7- (p-hydroxy-α-aminophenylacetamido) -3 ”(1,2,3-triazol-yl-thiomethyl) -3-cephem-1 H -carboxylic acid 7- (p-hydroxy-α-aminophenylacetamido) ) -3- (N-methyl-1,2,3-triazol-5-ylthiomethyl) -3-cephem-ylcarboxylic acid.

The bactericidal compounds prepared according to the invention have unexpectedly advantageous properties compared to similar compounds. For example, the compound 7- (α-amino-p-hydroxyphenylacetamido) -3- (1,2,3-triazol-1'-ylthiomethyl) -3-cephem-4-carboxylic acid (Compound 60771) is the preferred 7- (α-amino -phenylacetamido) -3- (1,2,3-triazol-11-ylthiomethyl-3-cephem-1-carboxylic acid (Compound 60222) because of its higher maximal serum concentrations in mice and, in particular, longer serum half-lives. the effect observed after both oral and subcutaneous administration in mice was significantly improved, as evidenced by the lower ED 2 Q values, which are shown in Tables A and B.

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Table A

Serum concentration in mice

Dosage - Maximum concentration Half-life

Compound Dose Route (pg / ml) (min.) 60771 20 mg / kg p.o. 52 62 60222 20 mg / kg p.o. 13 48 60771 20 mg / kg s.c. 54 71 60222 20 mg / kg s.c. 35 34

Table B

Mouse protection experiments

Compound Test organism Method of administration ^ 50 (mg / kg) 60771 E. coli 12140 S.c. <0.8, 0.8 60222 E. coli 12140 s.c. <3, 3.6 60771 E. coli 12140 p.o. <0.8, 1.2 60222 E. coli 12140 p.o. <12.5, 4,60771 K. pneumoniae 4200 s.c. 0.6, 0.6 60222 K. pneumoniae 4200 s.c. 4.8, 60771 K. pneumoniae 4200 p.o. 0.4, 0.5 60222 K. pneumoniae 4200 p.o. 12.5

Compound 60771 is also preferred for 7- (α-amino-p-hydroxyphenylacetamido) -3 '(5-methyl-1,2,4-triazol-3-ylthiomethyl) -3-cephem-4-carboxylic acid (Compound 61529) compared because it provides a significantly lower ED 2 g value in mouse protection experiments. The values obtained are shown in Table C.

Table C

Mouse protection experiments

Compound Test organism Method of administration ED 2 q (mg / kg) 60771 E. coli 12140 s.c. · <0.8, 0.8 61529 E. coli 12140 s.c. 10.7, 60771 E. coli 12140 p.o. <0.8, 1.2 61529 E. coli 12140 p.o. 7.5 60771 K. pneumoniae 4200 s.c. 0.6, 0.6 61529 K. pneumoniae 4200 s.c. 8.6 6077I K. pneumoniae 4200 p.o. 0.4, 0.5 61529 K. pneumoniae 4200 p.o. 16

In addition, 7- (α-amino-p-hydroxyphenylacetamido) -3- (4-methyl-5,56843] -1,2,3-triazol-5-ylthiomethyl) -3'-cephem-4-carboxylic acid (61775) is preferred. - (a “aminophenylacetamido) -3” (4-methyl-1,2,3-triazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid (61348) due to its lower ED 2 value in mouse protection experiments. The values are shown in Table D below.

Table D

Mouse protection experiments

Compound Test organism Method of administration ED50 (mg / k8) 61775 E. coli 12140 m.p. 1.8 61348 E. coli 12140 s.c. 42, 18.2 61775 E. coli 12140 p.o. 3.6 3 61348 E. coli 12140 p.o. 50, 19 61775 K. pneumoniae 4200 s.c. 2.8 61348 K. pneumoniae 4200 s.c. 20 61775 K. pneumoniae 4200 p.o. 5.2 61348 K. pneumoniae 4200 p.o. 146 7- (α-Amino-p-hydroxyphenylacetamido) -3 '(1-methyl-1,2,3-triazol-5-ylthiomethyl) -3'-cephem-4-carboxylic acid (60876) is also preferred. (Craminophenylacetamido) -3- (1'-methyl-1,2,3-triazol-5-ylthiomethyl) -3'-cephem-4-carboxylic acid (60637) due to its lower ED50 value and higher maximum -the drum concentration and half-life as shown in the following Tables E and F.

Table E

Mouse protection experiments

Compound Test organism Method of administration ED 2 q (mg / kg) 60876 E. coli 12140 m.p. 5.2 60637 E. coli 12140 s-c- 21.5 60876 E. coli 12140 p.o. 6.2 60637 E. coli 12140 p.o. > 50 60876 K. pneumoniae 4200 s.c. 3.5 60637 K. pneumoniae 4200 s.c. 40 60876 K. pneumoniae 4200 p.o. 6 60637 K. pneumoniae 4200 p.o. > 200 6 56843

Table F

Serum concentration in mice

Dosage - Maximum Concentration Half-life Compound Dose Route (jug / ml) Time (min.) 60876 20 mg / kg p.o. 1 48 48637 20 mg / kg p.o. 1.8 x 60876 20 mg / kg s.c. 44 48 60637 20 mg / kg s.c. 21 12 xToo low to matter.

In general, the compounds of the invention are superior in that they can be used in lower protective doses and / or provide higher and longer lasting serum concentrations.

Compounds of formula I may be prepared by acylation of a 7-amino group on the desired 7-amino-3-heterocyclic thiomethylcephalosporin ring with p-hydroxyphenylglycine. For acylation, it is desirable to protect the amino group of the glycine moiety with an easily removable protecting group such as t-butoxycarbonyl, benzyloxycarbonyl, trichloroethoxycarbonyl, or the like, as is commonly used in peptide syntheses. For acylation, the carboxyl group of the acylating agent can be activated by conversion to an acid chloride or mixed anhydride using, for example, a lower alkyl chloroformate. The carbonyl group can also be activated by conversion to 2,4-dinitrophenyl or N-hydroxysuccinimidoyl ester. When using an ester containing a cephalosporin ring, e.g. benzhydryl, t-butyl, trichloroethyl or benzyl ester, the protected phenylglycine can be coupled directly to the 7-amino group using a carbodiimide such as dicyclohexylcarbodiimide. Alternatively, the protected phenylglycine can be activated for condensation with the desired cephalosporin ring by first reacting it with carbonyldiimidazole or an equivalent compound.

Compounds of formula I may also be prepared by reacting a compound which differs from compounds of formula I in that the 3-substituent is acetoxymethyl and not R-thiomethyl with a mercaptoheterocyclic compound. The reaction is preferably carried out at a pH close to neutral. Water or water-acetone is preferably used as the solvent. The reaction can be carried out at a temperature ranging from about room temperature to the boiling point of the solvent, with the reaction time varying depending on the temperature used, the solvent and the reactants. The reaction product is isolated by careful acidification of the reaction mixture and extraction as a suitable organic solvent. The α-amino group of the phenylglycine starting material must be protected with an easily removable group such as t-butoxycarbonyl, carbobenzyloxy or trichloroethoxycarbonyl. The substitution reaction at the 3-position is then carried out, followed by deprotection in a conventional manner.

“The starting materials used in the 3-substitution reaction of 7-acylated cephalosporic acid are described in the literature or can be prepared by known methods. The starting materials used in the 7-acylation of the 3-heterocyclic thiomethyl ring are prepared by replacing the 3-acetoxy group of the alkali metal salt of 7-aminocephalosporanic acid (7-ACA) with an alkali metal salt of the heterocyclic thiol, e.g. in hot aqueous acetone.

It can be stated that due to the asymmetric a-hi. too much in the 7-acetamido group, optical isomers exist. The D-isomer is the most preferred isomer. However, the L-isomer and the racemic mixture are also within the scope of the invention.

These compounds are formulated into injectable or orally ingestible mixtures in the same manner as other cephalosporin antibiotics. They are administered by injection or orally to prevent bacterial infections and to treat them in doses that vary depending on the nature and severity of the disease and the patient's age, weight and condition. The compounds are generally administered either orally or parenterally.

Due to the presence of both an amine group and a carboxylic acid group in the cephalosporin compounds of formula I, it is possible to prepare pharmaceutically acceptable acid and base salt and non-amphoteric forms of non-toxic acids and bases as well as compounds by conventional methods. After preparation, the salts can be easily converted into amphoteric compounds by known methods. Salts of compounds containing only an acidic function are also prepared using pharmaceutically acceptable non-toxic bases. It is to be understood that all of these salts are within the scope of the invention.

The following examples illustrate the methods of the invention.

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Example 1 7- (α-Amino-p-hydroxyphenylacetamido) -3- (1,2,3-triazol-4-yl-thiomethyl) -3-cephem-4-carboxylic acid

To a stirred solution of 10.75 g (0.0375 moles) of N-t-butoxycarbonyl-p-hydroxyphenylglycine in 150 ml of dry tetrahydrofuran was added 5.2 ml (0.0375 moles) of triethylamine. The mixture was cooled to -10 ° and 4.92 ml (0.0375 moles) of isobutyl chloroformate was then added dropwise over 10 min. within. The reaction mixture was stirred at -10 ° for 70 min, and then a cold solution of 7-ACA (10.1 g, 0.0375 moles) in 140 mL of 50 μl of aqueous tetrahydrofuran and 6.75 g (0 .0487 moles) of triethylamine for 15 min. within. The reaction mixture was stirred at a temperature between -5 and 0 ° for 1 hour and at room temperature for a2 hours. The organic solvent was evaporated off and 150 ml of water were added to the aqueous residue. The residue was extracted with ethyl acetate and the aqueous phase was separated, covered with fresh ethyl acetate, acidified to pH 2.8 and filtered. The phases were separated and the acidic solution was extracted again with ethyl acetate. The extracts of the acidified aqueous solution were combined, dried and evaporated to give the N-butoxycarbonyl derivative of 7- (α-amino-p-hydroxyphenylacetamido) -cephalosporanic acid.

A mixture of 3.0 g (0.00493 moles) of the above product in phosphate buffer pH 6.4 (30 ml) was treated with 1.0 85 g (0.01233 moles) of NaHCO 3 followed by 0.748 g : 11a (0.0074 mol) of 4-mercapto-1,2,3 'triazole. The solution was heated to 70 ° and stirred at 70 ± 3 ° for 2.75 hours. The solution was cooled, filtered and acidified to pH 2.5 to give a residue. The solvent was decanted off and the residue was washed with water. The product was dissolved in ethyl acetate, washed with water, dried and evaporated to an N-protected product which was reprecipitated from acetone-chloroform.

The protected product was stirred at 0-5 ° with trifluoroacetic acid anisole solution (9: 1) for 70 min. The solvents were evaporated off and the residue was poured into 350 ml of ether with rapid stirring. The solid was collected, dissolved in water and mixed with a basic ion exchange resin ("Amberlite IR-45" polystyrene amine anionic resin) until the pH remained constant. The resin was filtered off and the aqueous solution was lyophilized to give the product.

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Analysis for C 18 H 18 N 6 O 5 S 2 * 2H 2 O requires C, 43.37; H 4.45; N 16.86 Found: C 43.67; H 4.14; N 16.62

In the same manner as described above, the 7- (α-amino-p-hydroxyphenylacetamido) cephalosporanic acid t-butoxycarbonyl derivative was reacted with 7- (α-amino-p-hydroxyphenylacetamido) -3- (1-methyl-1,2, 3 (triazol-5-ylthiomethyl) -3 "cephem-4-carboxylic acid. Calculated for C 9 H 19 N 2 O 2 • C 21.52; H 4.76; N 16.40 Found: C 44.71; H 4.42, N 15.74

Example 2 7- (Da-amino-p-hydroxyphenylacetamido) -3- (4-methyl-1,2,3-triazol-5-ylthiomethyl) -3-cephem-4-carboxylic acid 5-benzamido-4-methyl-1 , 2,3-thiadiazole (6.60 g, 0.03 mol, prepared as described in Berichte 99, 1629, (1966)) was combined with 60 ml of 2N NaOH and the solution was heated under reflux overnight. About 25 hours After heating for a long time, the reaction mixture was cooled with ice and 120 ml of 2N HCl was added with stirring, the mixture was cooled over the weekend, and the precipitated solid (benzoic acid) was then filtered off with continuous cooling, washed with a small amount of water and adjusted to pH 3. With 10% NaOH, the aqueous solution was extracted four times with ethyl acetate, the extracts were dried and filtered, then sodium 2-ethylhexanoate was added until no more precipitation occurred.5-mercapto-4-methyl-1,2,3 -triazoline sodium the salt was filtered off and then dried in vacuo.

To a stirred suspension of 6.78 g (0.013 mol) of 7- (α-t-butoxycarbonylamino-p-hydroxyphenylacetamido) -cephalosporanic acid and 3.82 g (0.02 mol) of 5-mercapto-4-methyl- The sodium salt of 1,2,3-triazole in 100 ml of phosphate buffer pH 6.4 was added 1.09 g (0.013 mol) of NaHCO 3. The mixture was heated at 70 ° for 4 1/2 hours while being adjusted by the addition of TLC. It was allowed to cool and the resulting gum was mixed with water and any insolubles were filtered off. The solution was covered with ethyl acetate and allowed to refrigerate overnight.

The layers were then separated and the aqueous layer was acidified to pH 3.0 with 3N HCl. It was then extracted several times with ethyl acetate and the extracts were dried and evaporated. The resulting Kumai material was triturated with ether to give 2.69 g of a solid. Small amounts thereof were then reprecipitated twice from methanol ether and the desired product was then precipitated from petroleum ether. The resulting solid (1.75 g) was chromatographed on 100 g of silica gel using chloroform-methanol-formic acid (90: 10: 3). 0.80 g of the t-butoxycarbonyl derivative of the title compound was obtained from the column.

0.80 g (0.00139 moles) of the above derivative was placed in a small round-bottomed flask with a drying tube and immersed in an ice bath. About 10 ml of cold trifluoroacetic acid was then added and the mixture was stirred in the cold for about 15 min. and then evaporated for 15 min. within. The residue was poured into about 100 ml of ether and the resulting solid was collected and dissolved in about 25 ml of water. It was then mixed with "IR 45-Amberlite" resin, a basic ion exchange polystyrene resin (washed three times) until the pH of the solution was about 5.5 · The resin was separated by filtration and the solution was lyophilized overnight to give the title product. .

Analysis for C 19 H 20 N 6 O 5 S 2 · 2 3/4 H 2 O Calculated: C, 43.38; H 4.89; N 15.97 Found: C 43.75; H 4.80; N 15.27.

Example 3

The compounds described in Examples 1 and 2 can also be prepared by reacting the desired 7-amino-3-heterocyclic thiomethyl-3-cephem-4-carboxylic acid with a mixed anhydride formed from N-t-butoxycarbonyl-p-hydroxyphenylglycine and isobutyl chloroformate or isobutyl chloroformate. The N-protecting group is removed with trifluoroacetic acid or glacial acetic acid HCl.

Example 4 7- (α-Amino-p-hydroxyphenylacetamido) -3- (1,2,3-triazol-4-ylthiomethyl) -3-cephem-4-carboxylic acid.

A mixture of 7-aminocephalosporanic acid (23.4 g, 0.06 mol) and 4-mercapto-1,2,3-triazole (13.0 g, 0.13 mol) in 170 ml of water and 170 ml of Acetone was treated with a sufficient amount of solid sodium bicarbonate to give a solution of pH 7.0, which was then refluxed for 4.25 hours while maintaining the pH at 7.0-7.5 by the addition of solid sodium bicarbonate. After cooling to room temperature, 11,56843 acetone was evaporated in vacuo and the resulting aqueous solution was cooled with ice and treated with dilute hydrochloric acid to pH 3.4. The resulting precipitate was collected, washed with water and then acetone, and dried to give 18.8 g (70%) of 7-amino-3- (1,2,3-triazol-4-ylthiomethyl) -3-cephem-4-carboxylic acid.

A mixture of N- (t-butoxycarbonyl) -p-hydroxyphenyl) glycine (4.5 g, 0.0169 mol) and dry triethylamine (2.33 ml, 0.0169 mol) in 67 ml of dry tetrahydrofuran was cooled. To -5 ° C and isobutyl chloroformate (2.21 mL, 0.0169 mol) was added dropwise over 10 min. stirring quickly. 40 min. after stirring at -5 ° C, 7-amino-3- (1,2,3-triazol-4-ylthiomethyl) -3-cephem-4-carboxylic acid (5.28 g, 0.0169 mol) was added to the reaction mixture, and triethylamine (3SO 3 ml, 0.029 mol) in 60 ml of a 50% aqueous solution of tetrahydrofuran dropwise over 15 minutes, after stirring for 1 hour at -5 ° C and then after 2.25 hours at room temperature, the tetrahydrofuran was evaporated in vacuo and the resulting aqueous solution was diluted with 100 The aqueous fraction was covered with ethyl acetate (150 mL), cooled in an ice bath and the pH was adjusted to 3.0 with dilute hydrochloric acid. The latter ethyl acetate extracts were combined, dried over magnesium sulphate and evaporated in vacuo to give 3.0 g of a glassy solid which was chromatographed on silica gel. (90 g) using a solvent system of 90 parts by volume of chloroform and 10 parts of methanol and 3 parts of formic acid. The fractions which were best combined by thin layer chromatography were evaporated and re-chromatographed as above to give 90 ml (1%) of 7- (ant-butoxycarbonylamino-p-hydroxyphenylacetamido) -3- (1,2,3 triazol-4-ylthiomethyl) -3-cephem-4-carboxylic acid.

To an ice-cooled mixture of trifluoroacetic acid (60 ml) and anisole (6 ml) was added 7- (α-t-butoxycarbonylamino-p-hydroxyphenylacetamido) -3- (1,2,3-triazol-4-ylthiomethyl) -3-cephem-4 carboxylic acid (5.6 g, 0.010 mol). 20 min. after stirring at 0 ° C, the solution was concentrated in vacuo to about 30 mL and poured into 1.0 L of vigorously stirred ether. The resulting precipitate was washed with ether, then ethyl acetate and finally pentane, and then dissolved in 500 ml of water. The aqueous solution was mixed with 12 5G843 with a sufficient amount of Amberlite IR.45®. (weakly basic ion exchange resin) to raise the pH from 2.4 to 5.4. Lyophilization of the aqueous solution gave 3.6 g (72%) of 7- (α-amino-p-hydroxy-phenylacetamido) -3- (1,2,3'-triazol-4-ylthiomethyl) -3-cephem-4-carboxylic acid dihydrate.

Infrared: 5.64 and 5.91 microns; 1 H nmr (trifluoroacetic acid, tetramethylsilane) δ 3.77 (S, broad, 2H), δ 3.80 and 4.64 (doublet pair, J-v. 13Hz, 2H), δ 5.30 (d, J ' v- 5Hz, 1H), δ 5.53 (d, broad, J -x. 6Hz, 1H), δ 5.80 (dd, J ^ 6 Hz, 1H), δ 7.18 and 7.57 (doublet -R, J (9Hz, 4h), δ 7.75-7.97 (m, ^ 4H), δ 8.53 (S, 1H).

Analysis for C 18 H 18 N 6 O 5 S 2 * 2H 2 O Calculated: C, 43.37; H 4.45; N 16.86 Found: C 43.67; H 4.14; N 16.62

Claims (1)

A process for the preparation of bactericidal 7- (α-amino-p-hydroxyphenylacetamido) -3-heterocyclic thiomethylcephalosporins of the formula H 0 x Vhconh-I-r 'Ί NH 2 O = -CH 2 S -R C00H wherein R is 1 , 2,3-triazol-4-yl, 4-methyl-1,2,3-triazol-5-yl or 1-methyl-1,2,3-triazol-5-yl, characterized in that (1 ) an acetoxymethylcephalosporin compound of the formula R1NH - | - O = I — CH2OCOCH3 Ό00Η wherein R1 is HO- ^ y —CHCO, wherein the NH2- group is suitably x = / nh2 protected, if necessary, or is H, is reacted with a with a heterocyclic thiol compound represented by the formula HS-R, wherein R is as defined above, and (2) when R · * - is H, the compound obtained is acylated with a p-hydroxyphenylacetic acid compound represented by the formula ho-v ^ \ <: ηοοοη ^ === / NH 2 or an acylating or activated derivative thereof, wherein the NH 2 group is suitably protected, if necessary, and (3) any protecting group is removed. For the preparation of antibacterial 7- (ot-amino-p-hydroxy-phenylacetamido) -3-heterocyclic thiomethylcephalosporin with the formula _ / ~ H0 “V 7-CHCONH-1-Γ NH2 0 = Ln v ^ Lch2s-r COOH