CS273704B1 - Derivatives of trimethoprine - Google Patents

Abstract

The invention concerns substances of general formula I, where R represents the group of 3,4,5-trimethoxybenzyl and 4-chlorobenzyl group, X represents the nitro group and cyano group. The substances are prepared by reaction of nitroguanidine or dicyandiamide with corresponding 3-anilino-2-substituted acrylonitrile of general formula II, where R represents the group as in formula I, by the action of sodium methylate with excess of ethanol. The substances can be used as anthelmintics.<IMAGE>

Description

The invention relates to trimethoprim derivatives of the general formula g.

(i) in which:

R is 3,4,5-trimethoxybenzyl or 4-chlorobenzyl,

X is nitro or cyano.

These novel substances, which have not been described yet, were tested for anthelmintic activity. The tests were performed on a model helminth of Hymenolepis nana and were compared to a standard substance with the piperazine salt of niclosamide.

Quantitative screening was performed at doses of 50 mg, 100 mg, 200 mg and 400 mg / kg body weight. The substances described show good efficacy and have indisputable advantages over the standard substance. The standard piperazine salt of niclosamide (4-nitro-2-chloroanilide 5-chlorosalicylic acid) is difficult to prepare, demanding on equipment, because it works with aggressive chemicals. It therefore worsens the living and working environment in production. On the other hand, the new substances are relatively easy to access, the equipment is neither demanding in terms of technology nor the maintenance of the working environment, and is generally more economically advantageous.

In addition, the introduction of the nitramine and cyanamine groups at the 2-position of the pyrimidine ring makes it possible to prepare a number of derivatives which cannot be prepared in any other way.

Therefore, these compounds are of significant importance as intermediates for the synthesis of a variety of heterocyclic compounds.

The compounds of the invention are prepared by reacting nitroguanidine and / or dicyandiamide with the corresponding 3-anilino-2-substituted acrylonitrile of formula

NH-CH = C-R

AND

CN (II), in which R stands for the same in formula (I), by treatment with sodium methylate in excess ethanol. The necessary substituted acrylonitriles were prepared by known reactions from morpholine and the corresponding aubstituted benzaldehyde. In the next step, the morpholine group was displaced by the anilino group also known by reaction with aniline hydrochloride in methanol.

The compounds of the invention are prepared by first preparing sodium methylate by dissolving sodium in excess methanol. After the methanol has been evaporated, ethanol, nitroguanidine, optionally dicyandiamide and the corresponding substituted acrylonitrile are added. The mixture was boiled under reflux for 24 hours. The progress of the reaction was monitored by chromatography. After cooling, the precipitate is filtered off with suction, washed with ethanol and dried at 50 DEG C. to constant weight. The substances and e are crystallized from ethanol or dimethylformamide or mixtures thereof, as appropriate.

CS 273704 Bl

The following examples illustrate, but do not limit, the substance of the present invention.

Example 1

Sodium methylate (2.7 g; 0.05 mol), nitroguanidine (5.15 g; 0.049 mol) and 3-anilio-2- (3,4,5-trimsthoxybenzyl) acrylonitrile (9 g) were added to a solution of 50 ml of ethanol. 5 g (0.029 mol). Boiling at reflux for 24 hours. After cooling to 20 ° C, the product is filtered off with suction and washed with ethanol (30 ml). It is read by dissolution in water (300 ml) with the addition of sodium hydroxide solution, filtration with activated carbon and acidification with acetic acid to pH 5 (15 ml). The product is filtered off with suction, washed with water and dried at 60 ° C.

6.5 g (66.8%) are obtained. Elemental analysis of which corresponds to 4-amino-2-nitramino-5- (3,4,5-trimethoxybenzyl) pyrimidine, m.p. 241-245 ° C.

Analogously to Example 1, 4-amino-2-nitramino-5- (4-chlorobenzyl) pyrimidine (82.9%) was prepared from the corresponding acrylonitrile, m.p. 236-239 ° C.

Example 2

Sodium methylate (2.7 g; 0.05 mol), dicyandiamide (8 g; 0.095 mol) and 3-anilino-2- (3,4,5-trimethoxybenzyl) acrylonitrile (9.5 g) were added to a solution of 50 ml of ethanol. gj 0.029 mol). Boiling at reflux for 27 hours. The precipitated product is filtered off with suction and washed with cold ethanol. The product was purified by dissolution in water at 50 ° C (100 ml) with the addition of sodium hydroxide solution and, after filtration with activated carbon, precipitated with acetic acid to pH 5. The precipitate was filtered off with suction and washed with water. Dry at 60 ° C.

7.5 g (82.0%) of 4-amino-2-cyanamino-5- (3,4,5-trimethoxybenzyl) pyrimidine are obtained, which, after crystallization from dimethylformamide, has a melting point of 295-298 ° C.

In the same manner as in Example 2, 4-amino-2-acid-amino-5- (4-chlorobenzopyrimidine (95.28%)) was obtained, which crystallized from dimethylformamide / ethanol (3: 2; 200 ml); 286 ° C.

Claims (1)

SUBJECT OF THE INVENTION Trimethoprim derivatives of the general formula in which: R is 3,4,5-trimethoxybenzyl or 4-chlorobenzyl; X is nitro or cyano.