CS254541B1 - Sulfonamides based on trimethoprim - Google Patents

Abstract

The solution relates to substances of general formula I, nh2 in which R denotes a benzyl group; 3,4- -dimethoxybenzyl; 3,4,5-trimethoxybenzyl or 4-dimethylaminobenzyl. The new substances are prepared by reacting sulfaguanidine with 3-anilino-2-substituted acrylonitrile of general formula II Q-NH—CH=C—R I CN (II) in which R denotes a group as in formula I, by the action of sodium ethylate in excess ethanol. The new substances are used as chemotherapeutic agents against infectious diseases in human and veterinary medicine.

Description

The invention relates to trimethoprim-based sulfonamides of the general formula I (I)

R nh ₂ in which R represents a benzyl; 3,4-dimethoxybenzyl; 3,4,5-trimethoxybenzyl or 4-dimethylaminobenzyl group.

These new, previously undescribed substances were tested for antibacterial activity against streptococcal, pneumococcal, genococcal, meningococcal and enterococcal infections. They can therefore serve as chemotherapeutic agents in human and veterinary medicine. Since they contain both a sulfonamide and trimethoprim group in the molecule, they could replace the currently used mixed preparations such as the Czechoslovak Duon, the Polish Biseptol, the West German Bactrin, which are a mixture of trimethoprim and sulfamethoxazole.

The compounds of the invention were prepared by reacting sulfaguanidine with the corresponding 3-anilino-2-substituted acrylonitrile of general formula II

NH—CH=C-R (II)

CN in which R represents the same as oo in formula I, by the action of sodium ethylate in excess ethanol. The sulfaguanidine used was freed from crystal water before the reaction by drying at 105 °C to constant weight. The required substituted acrylonitriles were prepared by known reactions from morpholine, acrylonitrile and the corresponding substituted benzaldehyde. The morpholine group was displaced in the next reaction step by an anilino group also by the generally known reaction with aniline hydrochloride in methanol.

The substances according to the invention were prepared by first dissolving sodium in excess ethanol, adding sulfaguanidine and after 10 minutes of stirring, adding the starting substituted acrylonitrile, after which the reaction mixture was boiled for 10 hours. The course of the reaction was monitored by chromatography. After cooling, the precipitated substance was filtered off with suction, washed with ethanol and distilled water and then the unreacted sulfaguanidine was removed by boiling in water. The crude products were purified by dissolving in dimethylformamide and precipitating with water.

The substances according to the invention have been tested for anti-infective activity and it has been found that the relatively low activity is probably due to the very low solubility of the substances. Therefore, the use of more effective solvents and the preparation of more soluble forms of the substances are being tested.

The following examples of embodiments of the substance according to the invention are merely illustrative, but not limiting.

Example 1

To a solution of 92 ml of ethanol, 2.41 g (0.105 mol) of sodium was gradually added. To the resulting solution of sodium ethylate, 12.55 g (0.058 mol) of sulfaguanidine were added at 50 °C and, after 10 minutes of stirring, 19 g (0.058 mol) of 3-anilino-2-(3,4,5-trimethoxybenzyl)acrylonitrile were added. The reaction mixture was refluxed with stirring for 10 hours. After this time, the reaction mixture was cooled to room temperature. The precipitate was filtered off with suction and washed with ethanol and distilled water. Then the crude substance was boiled in 200 ml of water, adjusting the pH to 4.5 with dilute acetic acid (1:1). After cooling, the precipitate was filtered off again, washed with water and dried at 60 °C. The dry substance is dissolved in 200 ml of dimethylformamide, filtered with the addition of activated carbon and precipitated with 250 ml of water. The separated purified substance is filtered off with suction and dried at 60 °C.

Yield: 18 g of substance, mp 268 to 271 °C, lysis corresponds to the molecular formula ^C 20 ^H 23 ^N 5 ^S (mh -(3,4,5-trimethoxybenzyl)pyrimidine.

Example 2 chromatographically pure, the elemental analysis of which is 4-amino-2-sulfanilamido-5-yl-1-yl-2

Example Substituted acrylonitrile (0.058 mol) Profit Melting point (°C) Summary formula Mol. mass 2 16.27 g 3-anilino-2- 17.8 g 4-amino-2- 277 ^C 19 ^H 22 ^N 6°2 ^S 398.49 -(4-dimethylamino- -sulfanilamido-5- until benzyl)-acrylonitrile -(4-dimethylaminobenzyl)pyrimidine 278 3 17.24 g 3-anilino-2- 18.2 g 4-amino-2- 269 ^C 19 ^H 21 ^N 5°4 ^S 415.31 -(3,4-dimethoxybenzyl)- -sulfanilamido-5- until -acrylonitrile -(3,4-dimethoxybenzyl)-pyrimidine 270 4 19 g 3-anilino-2- 18.1 g 4-amino-2- 267 c ₁₇ h ₁₇ n ₅ o ₂ s 355.42 -benzylacrylonitrile -sulfanilamido-5- until -benzyl-pyrimidine 274

SUBJECT OF THE INVENTION

Claims (1)

OBJECT OF THE INVENTION Sulfonamides based on trimethoprim of the general formula I H ₂ N (I) wherein R represents a benzyl group; 3,4 dimethoxybenzyl; 3,4,5-trimethylbenzyl or 4-dimethylaminobenzyl.