SU535301A1 - 1,2-dialkylbenzimidazole derivatives exhibiting hypotensive action - Google Patents

Description

SKZ-CH.EHGY: 3. The preparation of 1- (3-diethylamino-2-hydroxypropnl) -2-alklbenzimidazoles is carried out by heating the displacement of 1-diethyl-5 (C, H5) CHg-CH-CH. SNG - CH-SI g (gNa) g I I he 01 but-2,3-epoxypropane with 2-alkyl benzimidazoles

Jv 1

  CH2-CHOH-ClL2N ((i ,, H5) 2

1- (3-diethylamino-2-hydroxypropyl) -2-tsropilbenzimidazol (abazole).

Example 1. 2-Propylbenzimidazole. A mixture of 54 g (0.5 mol) of o-phenylenediamine and 66 g (0.75 mol) of butyric acid is heated at low boiling for 4 h. The reaction mixture is neutralized with caustic soda, the precipitated precipitate is filtered and recrystallized from alcohol. Get a white crystalline powder with a yellowish tinge, so pl. 156-157 ° C.

Example 2. 1-Diethylamino-2,3-epoxypropane. Equimolecular amounts of epichlorohydrin and diethylamine in the presence of water are re-mastered for 3 hours at a temperature of 32-34 ° C. The mixture is then stirred for about 1 hour with an equimolar amount of a 35% aqueous solution of sodium hydroxide. After the usual treatment, the reaction product is distilled under vacuum. Colorless liquid. T. Kip. 65 ° С (20 mm of mercury).

Example 3. 1- (3-diethylamino-2-hydroxypropyl) -2-procylbenzimidazole. 1 mol of 2-propylbenzimidazole is heated with 1.1 mol of 1-diethylamino-2,3-epoxypropane in the presence of catalytic amounts of water. The process is carried out at a temperature of 50-60 ° C until the reaction mass thickens. Solid cooling mass is recrystallized from 50% ethanol. Get white crystalline powder, poorly soluble in water. The aqueous solution is alkaline. It is well soluble in acids. T. pl. 79 ° C.

Found,%: C 59.97; H 5.47; N 14.61.

Calculated,%: C 60.20; H 5.88; N 14.52.

The given structure of the substance is confirmed by counter synthesis.

To test the synthesized substances for biological activity, primary solutions are prepared at a 10% concentration by dissolving the wax in an equivalent amount of 1N. hydrochloric acid, RP initial solution 7.2. Working solutions are prepared by diluting the primary solutions to the desired concentration.

The tests of the proposed substances on mice, rabbits, dogs show that they have a hypotensive and antispasmodic action with low toxicity. The optimal combination of various manifestations of biological activity has 1- (3-diethylamino-2-hydroxypropyl) -2-niroylbenzimidazole (abazole), for which the results of the research are given below.

46 mice were used to determine the toxicity of abazole. It is established that DL 50 is equal to 460 mg / kg, DL 100 is 500 mg / kg. Upon intravenous administration of abazole to dogs in a complex experiment (with simultaneous recording of arterial pressure, respiration, electrocardiogram and encephalogram), the dose of the substance 50 mg / kg was found to cause a 60% decrease in blood pressure (P 0.001, which is gradually restored within 1 hour ).

With the fractional administration of abazole at a dose of 10 mg / kg (every 3 min) in experiments on dogs, it was found that when 10 mg / kg was introduced into the vein, the blood pressure decreased by 10 mm Hg. Art., with the introduction of 30 mg / kg - 25 mm Hg. Art. The frequency and amplitude of respiratory excursions vary little. After a dose of 30 mg / kg, respiratory rate is slowed by 11%. On the electrocardiogram, there is a slight increase in the amplitude of the T wave, a slight shortening of the P-2 interval, and an increase in the rhythm of heartbeats (from 110 to 120 in 1 minute). On the electroencephalogram after a dose of 10 mg / kg, there are no significant shifts in the frequency rhythm, after a dose of 40 mg / kg, the wave process is slowed down, the frequency of the frequency betarithm decreases.

Five experiments carried out to determine the effect of abazole on the vessels of the isolated ears of rabbits show that abazole at a concentration of 1: 1000 has vasodilating properties; The number of flowing drops of Ringer's solution increases by 47%. At a concentration of 1: 5000, it has a less constant effect, on average, the transmission rate of the solution increases by 14% (Table 1).

In the study of the convulsive activity of Abazol, convulsions were recorded with the intravenous administration of 232 mg / kg of the drug.

Table 1

Effect of Abazole on the vessels of an isolated rabbit ear

Biological action of abazole, dibazole and papaveria

In order to study the advantages of the drug in comparison with the known antihypertensive drugs, 5 experiments were conducted on dogs and 5 on mice with the administration of dibazol and 5 experiments on dogs with the administration of papaverine. Studies have shown that Dibazol has a more pronounced cramping effect than the proposed drug. This effect of dibazol occurred after intravenous administration to mice 120 mg / kg, abazole - 232 mg / kg (Table 2).

table 2

Similar results were obtained in dogs. Convulsions developed from lower doses of dibazol (30–40 mg / kg) than abazole (60–80 mg / kg).

Abazole also compares favorably with the classic antispasmodic papaverine. A fatal dose is when administered intravenously to dogs 40–120 mg / kg, and papaverine 20–30 mg / kg under similar experimental conditions. With intravenous administration of 20 mg / kg of papaverine, the respiratory rate is reduced by 77%, abazole by 11%. The lethal dose of papaverine causes a primary cessation of breathing in the still-preserved function of the circulatory system.

Thus, the positive effect of the proposed substances is expressed in the reduction of toxicity, the reduction of convulsive effects, the weakening of the inhibitory effect on respiration, while simultaneously increasing the profile effect on arterial pressure.

Claims (1)

Invention Formula 1. Derivatives of 1,2-dialkylbenzimidazole of General formula 4.f, JLR 2 I R. where RI is 3-diethylamino-2-hydroxypropyl, R2 is hydrogen or alkyl, exhibiting a hypotensive effect. 2. 1- (3-Diethylamino-2-hydroxypropyl) -2-propplbenzimidazole. SOURCE: information taken in attention during examination: 1. S. V. Anichkov. Povo medicine, 1949, 12.1 (prototype).