RU2449994C1 - 6-(4-benzylpiperazino)-1,3-dimethyluracyl dihydrochloride showing biological activity - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound - 6-(4-benzylpiperazino)-1,3-dimethyluracyl dihydrochloride of formula I

showing antispasmodic and bronchial spasmolytic activity.

EFFECT: invention extends the range of antispasmodic and bronchial spasmolytic low-toxic agents.

3 cl, 3 tbl

Description

The invention relates to medicine, namely to pharmacology, and can be used to obtain new antispasmodic and bronchodilator drugs.

As a prototype and comparison drug, the reference bronchodilator aminophylline (ethylenediamine salt of 1,3-dimethylxanthine) was taken, the bronchodilator and antispasmodic activity of which is described in numerous scientific works (Mashkovsky MD Medicines. // M., New Wave LLC, 2004 - v. 1, pp. 40-404).

The objective of the invention is to expand the arsenal of biologically active substances, including those with antispasmodic and bronchodilator activity.

EFFECT: obtaining a biologically active substance with antispasmodic and bronchodilator activity.

The inventive 6- (4-benzylpiperazino) -1,3-dimethyluracil dihydrochloride of the formula (I):

showing antispasmodic and bronchodilator activity.

The inventive compound is synthesized as follows.

By the interaction of 1,3-dimethyl-6-chlororacil with piperazine hexahydrate, 1,3-dimethyl-6-piperazinouracil is obtained, which is converted by alkylation with benzyl chloride in an alkaline alcohol solution to 6- (4-benzylpiperazino) -1,3-dimethyluracil. A water-soluble dihydrochloride compound is prepared by precipitation of 6- (4-benzylpiperazino) -1,3-dimethyluracil in acetone with a solution of hydrochloric acid.

Example 1. Synthesis of the claimed compound.

1,3-Dimethyl-6-chlororacil 3.48 g (20 mmol) was dissolved in 50 ml of ethanol, 11.65 g (60 mmol) of piperazine hexahydrate was added and boiled for 5 hours. The precipitate formed is filtered off, the filtrate is distilled off in vacuum to ¼ volume, 150 ml of water are added and extraction is carried out three times (15 ml each) with chloroform. The chloroform extracts are combined, the solvent is distilled off. The precipitate was washed with diethyl ether. Obtain 3.56 g (79%) of 1,3-dimethyl-6-piperazinouracil, purified by crystallization from iso-butanol.

¹³ C NMR spectrum (CDCl ₃ ), δ, ppm:

27.39 and 32.35 (1.3-NCH ₃ )

44.96 and 53.13 (2N (CH ₂ ) ₂ )

¹ H NMR Spectrum (CDCl ₃ ), δ, ppm:

3.28 (3H, 3-NCH ₃ )

3.37 (3H, 1-NCH ₃ )

5.21 (1H, 5-CH)

2.85-3.01 (8H, N piperazine)

Elemental analysis

Found,%: С 53.5 Н 7.0 N 24.7 - С ₁₀ Н ₁₆ N ₄ O ₂

Calculated,%: C 53.6 N 7.2 N 24.9

To a solution of 2.24 g (10 mmol) of 1,3-dimethyl-6-piperazinouracil in 40 ml of ethanol, 0.84 g (15 mmol) of potassium hydroxide in 10 ml of ethanol and 1.9 g (15 mmol) of benzyl chloride are added and boil for 1 hour. The hot reaction mixture is filtered, the solvent is distilled off to ¼ volume, the precipitate formed is filtered off, washed with water, and dried. 1.93 g (62%) of 6- (4-benzylpiperazino) -1,3-dimethyluracil are obtained, purified by crystallization from ethanol-water (2: 1).

¹ H NMR Spectrum ((CD ₃ ) ₂ CO), δ, ppm:

3.07 (3H, 3-NCH ₃ )

3.35 (3H, 1-NCH ₃ )

5.00 (1H, 5-CH)

2.39-2.70 (4H, N (CH ₂ ) ₂ )

2.80-3.00 (4H, N (CH ₂ ) ₂ )

3.49 (2H, NCH ₂ )

7.15 (br.s 5H, arom.)

Elemental analysis

Found,%: C 65.2 H 7.4 N 18.0 - C ₁₇ H ₂₂ N ₄ O ₂

Calculated,%: C 64.9 H 7.1 N 17.8

3.14 g (10 mmol) of 6- (4-benzylpiperazino) -1,3-dimethyluracil are dissolved in 50 ml of acetone, a 5% solution of hydrochloric acid in ethanol is added to a pH of 1-2, cooled. The precipitate formed is filtered off, washed with acetone, and dried. 3.24 g (84%) of 6- (4-benzylpiperazino) -1,3-dimethyluracil dihydrochloride are obtained, and purified by crystallization from a mixture of ethanol.

Elemental analysis

Found,%: С 52.4 Н 6.2 N 14.7 - C ₁₇ H ₂₂ N ₄ O ₂ 2НСl

Calculated,%: C 52.7 N 6.3 N 14.5

The inventive compound is a white crystalline powder, soluble in water.

Example 2. Acute toxicity of the claimed compound.

Acute toxicity was determined by intraperitoneal administration to intact mice according to the method of Litchfield J. and Wilcoxon F. modified by Roth (Belenky M. L. Elements of a quantitative assessment of the pharmacological effect. - L .: Medghiz, 1963).

Animal survival was observed for 14 days. The results are shown in table 1.

As can be seen from table 1, the claimed compound with intraperitoneal administration is low toxic (Sidorov K.K. Toxicology of new industrial chemicals. // Issue 13, L., Medicine, 1973. - S. 47-51).

Example 3. Bronchospasmolytic activity.

The bronchospasmolytic activity of the claimed compound was studied on the preparation of smooth muscle of open tracheal rings of guinea pig (Blattner R., Klassen X., Denert X. et al. Experiments on isolated preparations of smooth muscles. // transl. From English, M., Mir, 1983 . - p.206). The load on the tracheal rings was 2 g, the exposure time of the studied compounds was 4 minutes. Comparison drug aminophylline.

As a result of the studies, it was found that the claimed compound is not inferior in activity to aminophylline with carbacholine spasm (10 ^-3 M) (table 2). A distinctive property of the claimed compound was the absence of a relaxing effect in doses of up to 3 · 10 ^-4 M for spasms of the smooth muscles of the guinea pig trachea caused by barium chloride (10 ^-3 M), which suggests the absence of a direct myotropic component of the action in the presence of a pronounced cholinolytic (Komissarov I .V. Elements of the theory of receptors in molecular pharmacology. // M., Mir, 1969. - p. 215).

Example 4. Bronchodilator activity.

The bronchodilator activity of the claimed compounds was studied on anesthetized (Nembutal 30 mg / kg, intraperitoneally) cats weighing 2.3-2.4 kg. Tonus of the bronchi was recorded using the method of Concett and Roslsra in the modification of T.M. Turpaeva (Turpaev T.M. // Fiziol. Zh. USSR. - 1953. - T. 39, No. 6. - S. 732-734).

Experimental bronchospasm was caused by proserin (0.25 mg / kg) and carbacholine (5 μg / kg). The inventive compound and used for comparison aminophylline was administered at a dose of 8 mg / kg (ED ₅₀ ) in the form of aqueous solutions.

The effect of the claimed compounds on the tone of the bronchi is presented in table 3.

The presented chemical compound has a bronchodilator activity 1.5 times greater than aminophylline and is not inferior to it in antispasmodic activity with carbacholine spasm, is a low-toxic compound.

Table 1 Acute toxicity of the claimed compounds in mice Compound Route of administration LD ₅₀ mg / kg I W / b 175.0 (158.6 ÷ 193.0)

table 2 The effect of the claimed compounds on spasm of smooth muscles of the isolated trachea of the guinea pig caused by carbacholine Compound EU ₅₀ I 2.7 · 10 ^-4 (2.2 ÷ 3.5) M Eufillin 3.4 · 10 ^-4 (3.5 ÷ 4.6) M

Table 3 The effect of the claimed compounds on bronchospasm of cats caused by carbacholine and proserin Compound Dose mg / kg Decrease in bronchospasm in% I 8.0 60.0 ± 2.8 Eufillin 8.0 40.11 ± 4.2

Claims (3)

1. 6- (4-Benzylpiperazino) -1,3-dimethyluracil dihydrochloride of the formula:

2. The substance according to claim 1, having antispasmodic activity. 3. The substance according to claim 1, having bronchodilator activity.