CS259693B1 - Beta-lactam antibiotics with/z/-2-alkoxyimino-2-(2-/4-amino benzenesulphonamido/-4-thiazolyl)-acetyl group - Google Patents

Abstract

The present invention relates to beta-lactam antibiotics se / Z / -2-alkoxyimino-2- / 2- / 4- aminobenzenesulfonamido [4-thiazolyl] acetyl, a new group of active -1actaut antibiotics. These new substances are accessible by the reaction of N, O-bistrylmethylsilyl derivatives 6-aminopenicillanic acid and 7-aminodesacoxycephalosporanic acid s hydrochloride (Z) -2-alkoxyamino-2-zS- / 4- -aminobenzenesulfonaniido [4-thiazolyl7] ethyl chlorides in the presence of a base.

Description

The invention relates to beta-lactam antibiotics with a (Z) -2-alkoxyimino-2- (2- (4-aminobenzenesulfonamido) -4-thiazolyl) acetyl group. in the branch chain of formula I

λ / 1 /, where Z .CH,

CH * or

COOH

CH ^ and R znač are C až-C alkyl alkyl. As is known, cephalosporins with a (Z) -2-alkoxyimino-2- (2-amino-4-thiazolyl) acetylate in the branched chain at position 7 of the cephem nucleus are superior antibiotics with superior activity against Gram positive and Gram negative microorganisms including pseudomonads / British Pat . At the same time, these antibiotics are also effective against most beta-lactamase producing bacteria, enzymes that prevent the bacteria from acting against beta-lactam antibiotics.

By combining the structure of these antibiotics with the 4-aminobenzenesulfonamido group, a new group of beta-lactam antibiotics of the formula I effective against both Gram-positive and Gram-negative microorganisms / minimal growth inhibitory concentrations of bacterial strains Streptococcus pyogenes, Staphylococcus aureus, Escherichia coli and Proteus up to 8 mg / l, growth inhibitory strains of Pseudomonas aeruginosa occur at concentrations of about 32 mg / l.

The novel beta-lactam antibiotics of the formula I can be advantageously prepared, for example, by acylation of the 6-aminopenicillanic acid and 7-aminodesacetoxycephalosporanic acid Z, Ο-bistrimethylsilyl derivative with 7-aminodesacetoxycephalosporanic acid hydrochloride / Z / -2-alkoxyimino-2- / 2- (4-aminobenzenesulfonamido) -4- The thiazolyl ^acetyl chlorides of formula II

wherein R is 1 to 2 carbon atoms. Suitably chlorinated hydrocarbons having 1 to 2 carbon atoms and 1 to 4 chlorine atoms, preferably methylene chloride, are used as reaction medium. As a rule, an organic base such as triethylamine, pyridine or diraethylaniline is added to a solution of the 6-aminopenicillanic or 7-aminodesacetoxycephalosporanic acid Ν, b-bistrimethylsilyl derivative in said solvent, at a temperature of -60 to 45 ° C, preferably at a temperature -50 to 0 ° C, (Z) -2-alkoxyimino-2- [4- (4-aminobenzenesulfonamido) -4-thiazolyl] acetyl chloride hydrochloride is added. The product can be isolated preferably by mixing with an alkaline solution having a pH of 7-9, for example saturated aqueous sodium bicarbonate solution, extraction with a water-immiscible solvent and acidification to pH 2-4, for example dilute hydrochloric acid 1: 1 with water.

The following examples illustrate the preparation process in more detail. It goes without saying that, in addition to the above methods, other alternatives to the desired compounds of formula (I), which are common to the person skilled in the art, are not possible and are therefore not explicitly mentioned here.

Example 1

6- (2-Z) - ( ^z -Aminobenzenesulfonamido) -4-thiazolyl (Z) -2-methoxyiminoacetamido / penicillanic acid

To a suspension of 2 g (0.009 mol) of 6-aminopenicillanic acid in 15 ml of methylene chloride is added a drop of concentrated acid

3 sulfuric acid and 1.6 g (0.01 mol) hexamethyldisilazane. The mixture was heated to reflux for 8 h with a chloro-calcium cap. After filtering off the undissolved turbidity and cooling to -25 ° C, 1.1 g (0.009 mol) of dimethylaniline and 2.5 g of 2- (2- (4-aminobenzenesulfonamido) -4-thiazolyl7- (Z) -) hydrochloride are added with stirring. Of 2-methoxyiminoacetyl chloride and the reaction mixture was stirred for 1 h without cooling. The solution obtained is added with stirring to 100 ml of saturated sodium bicarbonate solution and after stirring for 0.5 h, the solution is shaken with 50 ml of methylene chloride, filtered with activated carbon and acidified with dilute hydrochloric acid (1: 1) to pH 3. and washed with water and diethyl ether. 1.8 g of the title acid of melting point 195 DEG-210 DEG C. (decomposition) is obtained. The structure was confirmed by NMR and IC spectra.

Example 2

6- (2- / 2- / 4-Aminobenzenesulfonamido) -4-thiazolyl7- (Z) -2-ethoxyiminoacetamido / penicillanic acid

Following the procedure described in Example 1, using an equivalent amount of 2- [5- (4-aminobenzenesulfonamido) -4-thiazolyl] -7- (Z) -2-ethoxyiminoacetyl chloride hydrochloride, the title compound was obtained as a yellowish product in 32% yield. 195 ° C decomposes. Its structure was confirmed by NWR and IC spectra.

Example 3

7- (2- / 2- (4-Arainobenzenesulfonamido) -4-thiazolyl) ^{, z} / 2-methoxyiminoacetamido desacetoxycephalosporanic acid

To a suspension of 2 g (0.009 mol) of 7-arainodesacetoxycephalosporanic acid in 20 ml of methylene chloride was added 1.6 g (0.01 mol) of hexaraethyldisilazane and a drop of conc. sulfuric acid. The mixture was heated to reflux with a chloro-calcium cap for 6 h. After cooling to -30 ° C, 1.1 g (0.009 mol) of dimethylaniline and 3.3 g (0.008 mol) of hydrochloride 2 were added with stirring. - [2- (4-Aminobenzenesulfonamido) -4-thiazol-3-yl] -2-methoxyimino-acetyl chloride and stirred for 40 min without cooling. Addition of the reaction mixture to a solution of 4 g of sodium bicarbonate in 70 ml of water, separation of the aqueous layer, washing with methylene chloride and filtration with activated charcoal gives a colorless solution from which upon acidification with dilute hydrochloric acid (1: 1) to pH 2.2 desired product »After washing the aspirated product with water and drying at room temperature, 2.8 g (44%) of the title acid are obtained which decomposes when heated above 210 ° C.

Its structure was proved by NMR and IC spectra.

Example 4

7- [2- (5-) 4-Aminobenzenesulfonamido] -4-thiazolyl7- (Z) -2-ethoxyiminoacetamido) desacetoxycephalosporanic acid

Following the procedure of Example 3, using an equivalent amount of the corresponding ethoxy derivative in 32% yield, the title compound was obtained as a yellowish product which was decomposed when heated above 180 ° C. The structure of the compound was demonstrated by NMR and IC spectra.

Claims (1)

OBJECT OF THE INVENTION The beta-lactam antibiotics are (Z) -2-alkoxyimino-2- (2- / 4-amino). benzenesulfonamido / -4-thiazolyl7-acetyl in the branched chain of formula I NH, COOH 1, OH, and where or OH, and R is C 1 -C 2 alkyl.