5(6)-nitro-1-(1,1-dissociator-3)-2-chlorobenzimidazole displaying biological activity


The invention relates to organic chemistry and medicine, in particular to a new connection - 5(6)-nitro-1-(1,1-dissociator-3)-2-chlorobenzimidazole formula I, manifesting antispasmodic and bronchodilator activity. The invention expands the Arsenal antispasmodic and bronchodilator funds with low toxicity. 2 C.p. f-crystals, 4 PL.

The present invention relates to medicine, namely to pharmacology, and can be used to produce new skin and bronchodilators.

The technical result - expanding Arsenal of biologically active substances, including having spasmolytic and bronchodilator activity.

The essence of the invention: 5(6)-nitro-1-(1,1-dissociator-3)-2-chlorobenzimidazole (1) formulashowing antispasmodic and bronchodilator activity.

As comparative drugs taken reference bronholitin aminophylline (ethylendiamine salt of 1,3-dimethylxanthine), cholinolytic platifillin (3-ethylidene-6-hydroxy-5,6-dimethylpyridine-1,8-dioxocyclohexa[2,3,4-gh] pyrrolizine-2,7-dione hydrotartrate), myotropic spasmolysant papaverine (1-[(3,4-DemeTech described in numerous scientific papers (Gusel C. A., Sicilian A. D., Smirnov, D. P. //Pediatrics. - 1990. - 7. - S. 52-54. Saudi F. S. //Pharmacol. and toxicol. - 1985.- 5.-S. 105-108. Slutsky, M. E. Aminophylline. - M.: Medgiz, 1960. Chuchalin A. G., Kamenova C. A., Kukes Century, etc. //Ter. Arch. - 1989. - 8. - S. 30-37. Hazura centuries, Saratikov A. S. Pharmacological agents in experimental medicine and biology, Tomsk, 1977, S. 39).

The inventive compound is synthesized as follows.

Interaction 5(6)-nitro-2-chlorobenzimidazole with epimyocardium in an alkaline environment get 5(6)-nitro-1-(titanyl-3)-2-chlorobenzimidazole, which by oxidation with potassium permanganate solution in the environment of glacial acetic acid turn 5(6)-nitro-1-(1,1-dissociator-3)-2-chlorobenzimidazole.

Example 1. The synthesis of the claimed compounds 5(6)-Nitro-2-chlorobenzimidazole 9.88 g (50 mmol) dissolved in 22 ml of 10% sodium hydroxide solution. To the solution at a temperature of 30-35oWith added 6.0 g (55 mmol) of aetiocholanolone and stirred for 1 hour. The crystalline precipitate is filtered off, washed with diethyl ether, water, dried at 60oC. Get to 2.29 g (85%) 5(6)-nitro-1-(titanyl-3)-2-chlorobenzimidazole purify by crystallization from a mixture of ethanol-water (1:1).

The IR spectrummaxcm-1: 750 and 845 (C-NO2), 1350 and 1522 (NO2), 1470 (C=N) WITH THE 1H, NCH) of 7.7-8.7 m (3H, H-arene.) Elemental analysis
Found, %: C 44,15 N 3,30 N 13,85 S 12,04 - C10H8N3ClO2S
Calculated, %: C 44,52 N 2,96 N 15,58 S 11,80
To a solution of 5.4 g (20 mmol) 5(6)-nitro-1-(titanyl-3)-2-chlorobenzimidazole in 300 ml of glacial acetic acid are added dropwise within 30 minutes 9,48 g of potassium permanganate (60 mmol) in 150 ml of water. The mixture is stirred at a temperature of 30o2 h, add 500 g of ice and stirred for 1 h, then a solution discolor with saturated solution of sodium thiosulfate. The formed precipitate is filtered off, washed with water and dried. Obtain 4.7 g (78%) of compound (I). Purify by crystallization from n-butanol.

The IR spectrummaxcm-1: 753 and 845 (C-NO2), 1165 and 1298 (SO2), 1350 and 1527(NO2),1480(C=N).

Elemental analysis
Found, %: 39.9 N 2.6 N S 13,7 10,5 - C10H8N3O4SCl
Calculated, %: C 39,80 N 2,65 N 13,93 S 10,61
The inventive compound is a yellow crystalline powder, soluble in dimethylsulfoxide, dimethylformamide.

Example 2. Acute toxicity of the claimed compounds.

Acute toxicity was determined after intragastric and intraperitoneal administration weinbrenner mice-males according to the method of J. Litchfield and F. Wilcoxon modification Rota (Bolotnyh observed for 14 days. The results are shown in table 1.

As can be seen from table 1, the claimed connection with the introduction into the stomach belongs to the 3rd class of hazard - moderate hazard (N. F. Izmerov, I. C. Sanotski, K. K. Sidorov. Options toxicometric industrial poisons single exposure (reference). //M Medicine, 1977). Substance intraperitoneal injection is low toxic (Sidorov, K. K. Toxicology of new industrial chemical substances. //Vol.13, L. Medicine, 1973. - S. 47-51).

Example 3. Antispasmodic activity
Spasmolytic activity of the claimed compounds was studied on the preparation of smooth muscle of the isolated intestine of the rat [the Biogenesis of natural compounds. /Under. ed L. M. Hindman. - M., 1965.- C. - 581-588]. The experiments were carried out in thermostated at 37oWith aerated by air bath volume of 50 ml with a solution of ringer-Locke. The reduction of smooth muscles caused by adding karbaholina (1:100000) or barium chloride (1:5000) and registered under isotonic conditions, the duration of exposure of spasmogens and connection was 2 minutes

As a result of researches it is established that the claimed compound has no effect on the initial tone of smooth muscles of the intestine of the rat, but causes pronounced snijanafleur connection re-introduction karbaholina does not cause spasms of the intestine, indicating the presence of an anticholinergic action.

The claimed compound has a myotropic antispasmodic effect, as evidenced by the decrease spasm caused by barium chloride (table 3).

Example 4. Bronchodilatory activity
Bronchodilatory activity of the synthesized compounds was studied in anesthetized (Nembutal, 40 mg/kg, intraperitoneally) and correzioni (myorelaxing 1 mg/kg) cats weight of 2.3 and 3.4 kg of the bronchial Tone was detected by methods Concetta and Rosler modification So M Turpaeva (Turpaev So M //Fiziol. Journe. Of the USSR. - 1953. , 39, 6. - S. - 732-734).

Experimental bronchospasm caused by proserin (0.25 mg/kg) and karbaholina (5 µg/kg). The claimed compound was administered at a dose of from 1/10 LD50in suspension (tween-60) of isotonic sodium chloride and used for comparison of aminophylline dose of 8 mg/kg (ED50) in aqueous solution (Yu Century Strokin, F. S. of Sarudi, A. A., Kremser, N. M.Nazipov etc. //Synthesis, transformation and biological properties of 7,8-disubstituted xantina/ //Chem. Pharm. log. - 5. - S. 566-569).

The influence of the proposed connection on the tone of bronchi are presented in table 4.

Presents the chemical compound has a mechanism of spasma,3 times less toxic.


1. 5 (6)-Nitro-1-(1,1-dissociator-3)-2-chlorobenzimidazole formulas

2. Substance under item 1, have antispasmodic activity.

3. Substance under item 1, with bronchodilator activity.


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