FI60868C - FREQUENCY REQUIREMENT FOR PHARMACEUTICAL ACTIVATION OF ACTIVE 7-ACYLES - Google Patents

Description

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C (45) Patent granted on 13 04 1932 Patent aeddelat V y '(51) Kv.lk.3 / lnt.CI.3 C 07 D 501/36 FINLAND —FINLAND (21) Patent application - Patentanaöknlng 7 ^ 30 ^ (22) Hakemlapllvi - Ansöknlngtdag 26.10.76 (23) Alkupllvt - Glltl (hetadag 26.10.76 (41) Become Public - Bllvlt offentllj 01.05-77

Patent and Registration Holders .... ......,,. .....

_ ,,. (44) Date of issue and date of publication. -

Patent- oeh registerstyrelsen 'An «ök» n utltgd och utl.skrlften publkersd 31.12.8l (32) (33) (31) Privilege requested — Bejlrd prlorltet 30.10.75 11.03.76, i2.O7.76 USA (US) 627161 *, 665837, 70i * ll * 2 (71) Smithkline Corporation, 1500 Spring Garden Street, Philadelphia, Pennsylvania 19101, USA (72) David Alan Berges, Wayne, Pennsylvania, USA (7! *) Berggren The present invention relates to a process for the preparation of novel 7-acylated cephalosporins which have an antibacterial activity against the intestinal tract.

According to the invention there is thus provided a process for the preparation of the above compounds of formula "1 -'-Y 0 COOH XN- h

(CH2) 2 -NHSO3H

wherein R1 is one of the following acyl groups:

OO O

""> 1 -CH-C-, Y-CH2-C- and CF3-S-CH2-C-

OH

2 60868

wherein Y is thienyl or tetrazolyl, or a non-toxic pharmaceutically acceptable salt thereof, and the process of the invention is characterized in that the compound of formula H H

Rli J

* - »Ϊ O | CH2OCCH3

COOH

wherein is as defined above, or a salt thereof is reacted with a formula

N -N

HS -? 11

N -N

(ch2) 2-nhso3h or a salt thereof, followed by removal of the protecting group or groups, if necessary, and acidification or other conversion of the resulting product, if necessary, to the free acid and optionally to a non-toxic pharmaceutically acceptable salt.

It is clear that the 4-carboxylic acid group of the compounds of the formula I can be easily esterified by methods known per se.

These esters include, for example, simple alkyl and aryl esters, as well as esters which are predominantly cleaved to the parent acids in the base, such as indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglyloxymethyl and thienylglycyl oxymethyl.

Cephalosporin derivatives comprising 7-acyl substituents are previously known. Although the substitution of various S-heterocyclic thiomethyl groups (-Cl 2 SHet) at the 3-position of the cephem nucleus is also known, apparently no compounds containing the 3- (sulfaminoalkyl-substituted tetrazolyl) thiomethyl moiety present herein are known.

60868

Thus, compounds of formula I are prepared by acylation of 7-amino-cephalosphoric acid with a suitable protected acylating agent and then replacement of the 3-acetoxy group with the desired sulfaminoalkyltetrazolithiol or equivalent salt and finally removal of the protecting group or groups, if present. The carboxylic acid group of the acylating agent is activated by any commonly used method, such as conversion to a mixed anhydride, acid chloride, acid imidazole or activated ester. In addition, a reagent such as dicyclohexylcarbodiimide may be used, provided that the carboxyl group of the cephem core is protected with an easily removable protecting group such as benzhydryl, t-butyl, trichloroethyl, benzyl, benzyloxymethyl, p-methoxybenzyl or p-nitro-benzyl.

The protecting groups can be removed according to known methods, such as with trifluoroacetic acid when using t-butyl or t-butoxycarbonyl as protecting groups. The resulting salt is converted to an amphoteric ion product or free acid by an ion exchange resin such as polystyrene amine ion exchange resin (Amberlite IR-45) or otherwise by basifying an aqueous salt solution.

The acylating agents used as starting materials are either known or prepared by known methods.

The sulfaminoalkyltetrazolithiols of formula II are prepared by administering the corresponding 1-aminoalkyl-5- (2,4-dinitrophenylthio) -tetrazole compounds prepared from 2,4-dinitrofluorobenzene and 1-acetamidoalkyltetrazole-5-thiol followed by acetamidation. acid hydrolysis of the moiety, reacting with the sulfur trioxide-trimethylamine complex and then cleaving the 2,4-dinitrophenyl protecting group. 1-Acetamidoalkyl tetratrol-5-thiols are prepared by reacting an acetamidoalkyl dithiocarbonate such as methyl 2-acetamethyldithiocarbamate with an azide such as sodium azide. Acetamidoalkyl idithiocathamates are prepared by treating N-aminoalkylacetamide such as N- (2-aminoethyl) acetamide with carbon disulfide and an alkyl halide such as methyl iodide in the presence of a base such as triethylamine.

4,60868

Due to the asynchronous α-carbon atom, the 7-acetamido group of formula I

II

When R 1 - is 2 H -CH-C-, optical isomers will be present.

OH

Racemic or separated products are obtained depending on whether racemic or separated side chain acid is used as the acylating agent. Separated side chain acids are readily obtained from racemic compounds by resolution by known methods involving partitioning of a salt formed with an optically active acid or base. All isomers, both separated isomers and mixtures thereof, are within the scope of the invention.

The compounds of formula I have antibacterial activity against both gram-positive and gram-negative organisms. The lowest inhibitory concentrations (MIC values) range from 0.2 to 200 μg / ml in an in vitro assay. The experimental results obtained with typical compounds are shown in Table 1 below. The in vivo control values (ED 1 values) obtained in mice are shown in Table 2. The names of the compounds corresponding to the numbers are given in Table 3.

Table 1 MIC values (μg / ml) in vitro __Compound number_

Bacteria 1,234 S. aureus HH 127 3.1, 3.1 1.6 3.1 1.6 S. aureus SK 23390 0.8, 0.8 0.4 3.1 1.6 S. villaluz SK 70390 50, 200 25> 200> 200

Strep, faecalis HH 34358 100, 50 12.5 50 100 E. coli SK 12140 0.8, 0.8 3.1 0.8 0.8 E. coli HH 33779 3.1, 1.6 12.5 0 .8 1.6

Kleb. pneumo. SK 4200 1.6 * 0.8 3.1 0.8 0.8

Kleb. pneumo. SK 1200 0.4.0.2 0.8 0.4 0.2

Salmonella ATCC 12176 0.2, 1.6 12.5 0.4 0.4

Shigella HH 117 0.4, 0.2 - 0.4 0.8

Pseudo, aerug. HH 63> 200,> 200> 200> 200> 200

Serratia marc. ATTCC 13880 100, 100> 200 200 100

Proteus morgani 179 1.6 3.1> 200 200> 200

Entero. aerog. ATCC 12048 50, 6.3 25 3.1 6.3

Entero. cloacae HH 31254 1.6 1.6 6.3 0.8 1.6 5 60868

Table 2 EDgQ values (mg / kg) in vivo E. coli SK 12140 Kleb.pneumo.SK 4200

Compound number s. c. pp. s. c. o.

1 0.46 50 0.46 2 1.02> 50 3 1.56 - 4 1.82 50

Table 3

Compound Number - Compound Name - 17-D-Almond Amido-3- [N- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid 2 7- (2-thienylacetamido) -3- [1- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl-3-cephem-4-carboxylic acid 3 7- (1-tetrazolylacetamido) -3- [1- (2-sulfaminoethyl) tetrazol-5-ylthioethyl] -3 -Cephem-4-carboxylic acid 4 7-Trifluoromethylthioacetamido-3- [N- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid.

The compound of the formula I is compared below with the compounds known from DE-A-2 415 402; 7- (2-thienylacetamido) -3- (5-methanesulfonylaminomethyl-1,3,4-thiadiazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid (hereinafter referred to as Compound No. 5), 7- (2- thienylacetamido) -3- [1- (2-methanesulfonylaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid (Compound No. 6), and 7-mandelamido-3- (5-methanesulfonylaminomethyl-1,3 , 4, -thiadiazol-2-ylthiomethyl) -3-cephem-4-carboxylic acid (Compound No. 7) and cefamandole known from U.S. Patent 3,641,021. The former compound is the closest compound to the prior art.

6 60868

An in vitro experiment was performed to determine the MIC values of the compounds in 16 microorganisms. The results are shown in Table 4.

Table 4 MIC (μg / ml) in vitro MICRO-COMPOUND no ORGANISM 1_5__6_7_Cefamandole

Staph. aureus HH 127 6.3 0.2 0.8 1.6 1.6, 0.8

Staph. aureus 671 3.1 0.2 0.8 6.3 1.6, 0.8

Staph.aureus 674 1.6 i0.1 0.8 0.2 0.8, 0.2

Strep.faec.

HH 34358> 100 6.3 50 25 50, 50 E.coli SK&F 12140 0.4 3.1 0.8 1.6 0.8, 0.8 E.coli 804> 100> 100> 100> 100> 100 ,> 100

Kleb. pneumo.

SK&F 4200 0.2 0.8 0.4 0.8 0.4, 0.4

Kleb.pneumo.

SK&F 1200 i 0.1 0.8 0.2 0.8 0.2, 0.2

Kleb.pneumo.

982 50 100 12.5> 100 6.3, 12.5

Pseudo.aerug.

HH6 3 _> 100 _> 100 _, 100

Pseudo.aerug.

647> 100> 100> 100> 100> 100,> 100

Serratia marc.

ATCC 13880_ 100 * 100> 100_100_25, 50

Proteus morgani £ 79_ 12.5> 100_ * 100_ £ J> _6.3, 0.4

Proteus mirabilis £ 44_ * 0.1_12.5_ £ j_6_6 ^ 3_0.4, 0.4

Entero.aerog.

ATCC 13048_ 3.1 12.5_6 ^ 3_12.5_3.1, 1.6_

Entero. cloacae 921__6.3 _12.5_6, 3_ £ ^ 3_1.6, 1.6 7 60868

It can be seen from Table 4 that compound 1 of formula I (7-almond amido-3 - [= 1- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid) and compounds no. and 7 are approximately as active microorganisms tested other than Proteus mirabilik from its knife, against which, the compound of formula I is significantly more active than compounds Nos. 5,6 and 7 and Proteus irorgan, against which it is considerably more active than compounds 5 and 6

An in vivo standard assay described in "Cephalosporins and Penicillins, Chemistry and Biology" by E.H. Flynn, Academic Press, N.Y. (1972) 502. In the experiment, a test compound is administered at a two- to five-fold dilution to groups of ten mice subcutaneously in water or orally in a suitable vehicle 1 and 5 hours after intraperitoneal injection of lethal doses of E. coli and Klebsiella pneumoniae. Mice are observed for three days. The total dose of test compound required to protect mice over three days is the ED 2 Q value, so the effective compound has a low ED 2 Q value. The amount of bacteria that kills 50% of the test mice is denoted LD, -0. The results are shown in Table 5.

Table 5 EDcq (mg / kg) in vivo (subcutaneous)

Compound No. E. coli SK 12140 (LD ^) Kleb.pneumo.SK 4200 (LD ^) 1 0.46 (570) 0.46 (250) δ 25.0 (207) 50.0 (308) 6 1, 02 (150) 2.1 (50) 7 14.0 (757) 46.0 (100)

Cefazoline 4.4 (570) 6.25 (250)

It can be seen from Table 5 that the compound of formula I is significantly more active against E. coli than compounds No. 5 and 7 and slightly more active than compound No. 6. The compound of formula I has significantly higher activity against K. pneumoniae than compounds No. 5, 6 and 7.

An experiment was also performed to determine the serum concentration of compounds and the half-life of this concentration, the method of which is described in "Antimicrobial Agents and Chemotherapy", 8 60868 Vol. 6, No. 2 (1974) 150. Serum concentrations are determined at specified intervals (15,30,60,120 and 240 minutes) after administration of 20 mg / kg of test compound to mice. Blood tests are taken by cutting off the heads of mice and blood samples are stored at 4 ° C until coagulated; and serum samples obtained after centrifugation are stored at -20 ° C. Serum concentrations are determined by disc-plate analysis using Bacillus subtilis as an indicator organism. For each test compound, standard curves of dose-response results are made using normal serum as the solvent for the standard experiment. Using a standardized computer linear regression program, the concentration half-life after subcutaneous administration is calculated. The results are shown in Table 6.

Table 6

Compound Animal T1 / 2 (min) Maximum concentration (μg / ml)% bound 1 mouse 81.1 62.3 15 min 47 rabbit 90.5 65.5 30 min 88 marmosets 59.5 75.4 15 min 57 5 mice 18, 5 13.5 15 min 57 6 mice 16.6 24.8 15 min 25 7 mice 18 10 15 min 23

It can be seen from the table that compound 1 of formula I achieves a significantly higher maximum serum concentration than the reference compounds and also has a much longer half-life compared to these.

The compound of formula (I) may be administered as a pharmaceutical preparation parenterally, such as by subcutaneous, intramuscular or intravenous injection. Injection of suitably prepared sterile solutions or suspensions containing an effective non-toxic amount of the novel cephalosporin compound is the most convenient route of administration.

The compounds of formula I are formulated and administered to patients in the same manner as preparations made from other cephalosporins. The dosage regimen comprises administering a compound of formula I in an amount that is active but non-toxic, with a dosage unit of between 100-1000 mg and a total daily dose of between 400 mg and 6 g. The exact dosages will depend on the age and weight of the patient and the nature of the infection being treated, and the skilled artisan can determine the dosage based on the values reported herein by comparing them with available data on the administration of known cephalosporins.

9 60868

The following examples further illustrate the invention.

Example 1 7-D-Mandelamido-3- [N- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid

To a solution of 20.4 g (0.20 mol) of N- (2-aminoethyl) acetamide in 200 ml of 95% ethanol were added 27.9 ml (0.20 mol) of triethylamine and 12.0 ml of (0.20 moles) of carbon disulphide. Due to the exothermic reaction, the boiling mixture was refluxed, after which the mixture was cooled to ambient temperature over 1 1/2 hours. Methyl iodide (28.4 g, 0.20 mol) was added, again causing an exothermic reaction. After 1 3/4 hours, the reaction mixture was evaporated to dryness and the solid residue was dissolved in 200 ml of water. The aqueous solution was extracted twice with 250 ml portions of ethyl acetate. The extracts were combined, shaken with sodium thiosulfate, dried (MgSO 4) and evaporated to dryness to give methyl 2-acetamidoethyldithiocarbamate.

To a solution of 38.4 g (0.198 mol) of methyl 2-acetamidoethyldithiocarbamate in 100 ml of 95% ethanol was added a solution of 13.5 g (0.208 mol) of sodium azide in 100 ml of water. The reaction mixture was heated at reflux for 24 hours, after which it was cooled and evaporated under reduced pressure to about half volume. The solution was cooled to 15 ° C and 50 ml of 6 N sulfuric acid was added. The acidic solution was filtered, and the filtrate was evaporated to a volume of about 100 ml and cooled to 5 ° C to crystallize 1- (2-acetamidoethyl) tetrazole-5-thiol, which product was collected by filtration, m.p. 139-139.5 ° C. Additional product was obtained by continuous extraction of the filtrate with ethyl acetate.

A solution of 9.3 g (0.050 mol) of 2,4-dinitrofluorobenzene in 50 ml of acetone was added to a solution of 9.35 g (0.050 mol) of 1- (2-acetamidoethyl) tetrazole-5-thiol and 6 , 85 ml (0.050 mol) of triethylamine in 100 ml of acetone, and the reaction mixture was stirred for 1 hour. The solid was collected by filtration, and recrystallization from acetonitrile afforded 1- (2-acetamidoethyl) -5- (2,4-dinitrophenylthio) tetrazole, m.p. 197-198 ° C.

A mixture of 6.5 g (0.02 mol) of 1- (2-acetamidoethyl) -5- (2,4-dinitrophenylthio) tetrazole, 100 ml of 12N hydrochloric acid and 100 ml of 95% ethanol was heated to reflux. For 1/2 hour. The mixture was evaporated to dryness to give a gummy residue which crystallized on addition of ethanol to give 1- (2-aminoethyl) -3- (2,4-dinitrophenylthio) tetrazole hydrochloride, m.p. 217-219 ° C (dec).

To a solution of 3.5 g (0.01 mol) of 1- (2-aminoethyl) -5- (2,4-dinitrophenylthio) tetrazole hydrochloride in 30 ml of dry dimethylformamide was added 1.4 g (0.01 mol) of moles) of sulfur trioxide trimethylamine complex followed by 1.4 ml (0.01 moles) of triethylamine. The mixture was stirred for 1/2 hour, after which it was filtered. The filtrate was evaporated in vacuo, acetone was added to the residue, the precipitate was removed by filtration and the filtrate was evaporated to dryness. Methanol was added to the residue, and the solid formed on trituration was removed by filtration. The pH of the methanol filtrate was adjusted to 11.3 by the addition of 5% methanolic sodium methoxide solution, the mixture was stirred for 1 1/4 hours, then filtered and diluted with 300 ml of ether. The solid formed was removed by filtration, the filtrate was evaporated to dryness and the resulting residue was triturated with 95% ethanol to crystallize it. The solid product was collected by filtration and dissolved in methanol. The methanol solution was evaporated to a volume of 10 ml, diluted with 11,608 6,875 ml of 95% ethanol and re-evaporated to a volume of 5 ml with the product 1- (2-sulfaminoethyl) tetrazole-5-thiol disodium salt, m.p. 122-127 ° C.

C3H5N503S2 · 2 Na · 1.5 H2O

Calculated: 12.16% C, 2.72% H, 23.64% N

Found: 12.25% C, 2.98% H, 23.77% N

An aqueous solution of the 1- (2-sulfaminoethyl) tetrazole-5-thiol disodium salt is passed through an "Amberlite 1R-120H" ion exchange resin column to give, after lyophilization, 1- (2-sulfaminoethyl) tetrazole-5-thiol.

To a mixture of 2.71 g (0.006 moles) of the sodium salt of 7-D-mandelamidocephalosporanic acid and 1.18 g (0.004 moles) of 1- (2-sulfaminoethyl) tetrazole-5-thiol disodium salt in 30 ml of water, 10% aqueous sodium hydroxide solution was added followed by 5% aqueous sodium hydrogen carbonate solution until the pH reached 7.3. The reaction mixture was heated at 70 ° C for 2 2/3 hours, then cooled, covered with ethyl acetate, acidified to pH 2.5 with 3N hydrochloric acid and extracted twice with ethyl acetate. The aqueous phase was neutralized to pH 7.0 by the addition of 10% aqueous sodium hydroxide solution followed by 5% aqueous sodium hydrogencarbonate solution and chromatographed on "XAD-7" resin using water and ethanol as eluents. After removal of methanol in vacuo, the chromatography fractions were treated with lyophile to give 7-D-mandelamido-3- [T- (2-sulfaminoethyl) -tetrazol-5-ylthiomethyl] -3'-cephem-4-carboxylic acid disodium salt.

C19H19N7 ° 8S3 · 2 Na · 3 H2O

Calculated: 34.08% C, 3.76% H, 14.64% N

Found: 34.56% C, 3.25% H, 13.96% N

An aqueous solution of 7-D-mandelamido-3- [1- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid disodium salt is passed through an "Amber-lite IR-120H" ion exchange resin column to give the title compound.

60868

Example 2 7- (2-Thienylacetamido) -3- [N- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid

A mixture of 1.89 g (0.064 mol) of 1- (2-sulfaminoethyl) tetrazole-5-thiol disodium salt and 2.67 g (0.064 mol) of 7- (2-thienylacetamido) cephalosporanic acid sodium salt in 40 ml of water, heated at 69 ° C for 5 1/2 hours maintaining the pH at 7.4 by the addition of dilute aqueous sodium hydrogen carbonate solution. After cooling, the mixture was extracted with ethyl acetate. The aqueous phase was neutralized, evaporated to dryness and the residue passed through an "XAD-4" column eluting with water and methanol. The methanol was removed by evaporation and the aqueous residue was lyophilized to give a solid. The solid was suspended in methanol, the insoluble matter was removed by filtration and the filtrate was evaporated to dryness to give 7- (2-thienylacetamido) -3- [N- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid. disodium salt.

C17H17N7O7S4 * 2 Na '1 CH4O

Calculated: 33.90% C, 3.31% H, 15.37% N

Found: 34.04% C, 3.57% H, 14.74% N

7- (2-Thienylacetamido) -3- [N- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid disodium salt is converted to the title compound as described in Example 1.

Example 3 7- (1-Tetrazolylacetamido) -3- [N- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid_____

A mixture of 3.5 g (8.5 mmol) of 7- (1-tetrazolylacetamido) -cephalosporanic acid as triumium salt and 2.96 g (10 mmol) of 1- (2-sulfaminoethyl) tetrazole-5- thiol disodium salt in 50 ml of water was stirred at 65 ° C for 6 1/2 hours while maintaining the pH of the reaction mixture at 7.0 by the addition of 5% aqueous sodium hydrogen carbonate solution. The mixture was cooled to ambient temperature, acidified to pH 1.5 with 3N hydrochloric acid, filtered and extracted three times with ethyl acetate. The pH of the aqueous phase was adjusted to 7.0 by the addition of sodium hydrogen carbonate, the solution was chromatographed on an "XAD-2" column, and the product was freeze-dried to give 7- (1-tetrazolylacetamido) -3- [T- (2-sulfaminoethyl) tetrazole-5- yylitiometyyli7-3-cephem-4-carboxylic acid disodium salt.

60868 C14H15N11 ° 7S3 * 2 Na '2 H2 °

Calculated: 26.80% C, 3.37% H, 24.55% N

Found: 27.11% C, 3.40% H, 24.18% N.

7- (1-Tetrazolylacetamido) -3- [N- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid disodium salt is converted to the title compound in the same manner as in Example 1.

Example 4 7-Trifluoromethylthioacetamido-3- [N- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid

A solution of 3.05 g (0.01 mol) of 1- (2-sulfaminoethyl) tetrazole-5-thiol disodium salt and 4.36 g (0.01 mol) of 7-trifluoromethylthioacetamidocephalosporanic acid sodium salt in 50 ml of water , was heated at 70 ° C for 5 1/2 hours maintaining the pH at 7.5 with 5% sodium bicarbonate solution. The reaction mixture was diluted with 50 ml of water and extracted twice with ethyl acetate. The aqueous phase was acidified to pH 2 and extracted three times with ethyl acetate. The pH of the aqueous layer was adjusted to 7.4 by the addition of 5% aqueous sodium hydrogencarbonate solution, and the solution was passed through an "XAD-4" resin column eluting first with water and then with methanol. ether and petroleum ether, after which it was lyophilized, the lyophilized substance was dissolved in methanol, the solution was evaporated to dryness and the residue was triturated with ether to give 7-trifluoromethylthioacetamido-3- [1- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3- cephem-4-carboxylic acid disodium salt.

C14H14F3N7 ° 7S4 * 2 Wa * 2 H2 °

Calculated: 25.49% C, 2.75% H, 14.86% N Found: 25.85% C, 2.78% H, 14.13% H.

7-Trifluoromethylthioacetamido-3- [N- (2-sulfaminoethyl) tetrazol-5-ylthiomethyl] -3-cephem-4-carboxylic acid disodium salt is converted to the title compound by the same procedure as in Example 1.

Claims (2)

60868 Claim A process for the preparation of fasmasically active 7-acylated cephalosporins of the formula f £ / S i - * —— \ R -N I | "X_en J / -N 1 o '- / CH 2 S -7 COOH X, N-N (CH") - -NHSO H 22 3 wherein R is one of the following acyl groups: 0 0 0 n <„ O-CH-C-, y-ch2-c- and cf3-s-ch2-c-OH where Y is thienyl or tetrazolyl, or a non-toxic pharmaceutically acceptable salt thereof, characterized in that the compound of formula HH - s R1-N i ..... ”/ \ f // CH ^ OCCH _ q / I zi dOOH where R is the same as above, or a salt thereof is reacted with the formula N - N HS - // II N- -N (CH2 ) 2 -NHSO 3 H or a salt thereof, followed by removal of the protecting group or groups, if necessary, and acidification or other conversion of the resulting product to the free acid, if necessary, and optionally to a non-toxic pharmaceutically acceptable salt.