The mixture of isomers 2-monoethanolamine-5(6)-nitro-1-(titanyl-3) benzimidazole


The invention relates to new compounds of the mixture of isomers of 2-monoethanolamine-5(6)-nitro-1-(titanyl-3)benzimidazole of the formula I. the Isomers are present in a molar ratio of 1:3 and show anti-inflammatory activity. The invention can be used for new anti-inflammatory drugs. 1 C.p. f-crystals, 4 PL.

The invention relates to medicine, namely to pharmacology, and can be used for new anti-inflammatory drugs.

The technical result - expanding Arsenal of biologically active substances, including possessing anti-inflammatory activity.

The inventive mixture of the isomers 2-monoethanolamine-5(6)-nitro-1-(titanyl-3)benzimidazole in a molar ratio of 1:3 of the General formulaexhibiting anti-inflammatory activity.

As the comparison drug taken reference synthetic nonsteroidal anti-inflammatory drug diclofenac sodium (2-[(2,6-dichlorophenyl)amino] benzooxazol acid sodium salt), anti-inflammatory activity which is described in numerous original and review papers (Schwartz(review). Chem. farm.-journal, 1980, T. 14, vol. 9, S. 22-41; Saratikov A. S., prima, Etc., the Modern concept antiflogistic actions of nonsteroidal anti-inflammatory drugs (review). - Pharmacol. and toxicol., 1982, T. 45, vol. 2, S. 133-138; Schwartz, J., Subai P. D. Ratio antiexudative, analgesic and antipyretic components in action nonsteroidal anti-inflammatory drugs. - Pharmacol. and toxicol., 1982, T. 45, vol. 1, S. 46-49).

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 that boiling in the environment of acetone with monoethanolamine make a 2-monoethanolamine-5(6)-nitro-1-(titanyl-3)benzimidazole.

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%) of a mixture of isomers 5(6)-nitro-1-(titanyl-3)-2-chlorobenzimidazole purify by crystallization from a mixture of ethanol-water (1:1).

sup>1H (CDC13),, M. D.: a 3.6-3.7 m (2N, S(CN)2) 4,12-to 4.23 m (2N, S(CN)2) 5.9 to 6.1 m (1H, NCH) of 7.7-8.7 m (3H, H-arene.) Elemental analysis.

Found, %: C 44,15, N, 3,3, N 13,85, S 12,04 - C10H8N3ClO2S
Calculated, %: C 44,52, N 2,96, N 15,58, S 11,80
An NMR spectrum135(6)-nitro-1-(titanyl-3)-2-chlorobenzimidazole (l3),, memorial plaques:
5-nitro-1-(titanyl-3)-2-chlorobenzimidazole: 32,57 (11With12); 51,73 (10); 110,40 (7); 116,40 (4); 119,30 (6); 132,83 (8); 141,30 (2); 144, 0mm (With9); 144,20 (5).

6-Nitro-1-(titanyl-3)-2-chlorobenzimidazole: 32,77 (11With12): 51,81 (10); 107,10 (7); 119,0 (5); 120,2 (4); 137,65 (9); 141,30 (2); 143,90 (8); 146,10 (6).

The quantitative composition of both isomers is determined by comparing the integral intensities of the signals of the respective carbon atoms of 6-nitro-1-(titanyl-3)-2-chlorobenzimidazole and 5-nitro-1-(titanyl-3)-2-chlorobenzimidazole in a molar ratio of 3:1.

To a solution of 2.70 g (10 mmol) 5(6)-nitro-1-(titanyl-3)-2-chlorobenzimidazole in 50 ml of acetone add a 3.06 g (50 mmol) of monoethanolamine and boil for 4 hours. The solution is filtered hot, the filtrate is evaporated to 1/4 of the initial objectmenu 2 monoethanolamine-5(6)-nitro-1-(titanyl-3)benzimidazole, purify by crystallization from dioxane.

Elemental analysis.

Found, %: C 49,2, N. 4,7, N 19,2, S 10,7 - C12H14N4O3S
Calculated, %: 49,0, N 4,8, N, 19,0, S 10,9
An NMR spectrum1N (DMFA-d7),, memorial plaques:
3,55-3,65 m (4H, (CH2)2)
the 3.7-3.85 m (2N, S(CH)2)
a 4.2-4.35 m (2N, S(CN)2)
5,15-5,25 m (NH and OH)
the 7.8-8.6 m (3H, H-arene.)
An NMR spectrum132-monoethanolamine-5(6)-nitro-1-(titanyl-3)-benzimidazole (DMFA-d7),, memorial plaques:
2 monoethanolamine-5-nitro-1 -(titanyl-3)-benzimidazole:
33,05 (11With12); 50,90 (10); 52,80 (C13); of 60.50 (C14); 112,60 (C7); 115,80 (C4); 119,30 (C6); 135,20 (C8); 138,20 (C5); 141,80 (C9); 147,50 (C2).

2 monoethanolamine-6-nitro-1-(titanyl-3)-benzimidazole:
33,10 (11With12); 50,90 (10); 52,80 (C13); of 60.50 (C14); 108,50 (C7); 119,10 (C5); 120,20 (C4); 134,20 (8); 139,90 (C9); 144,20 (6); 147,50 (C2).

When comparing the integral intensities of the signals of the respective carbon atoms of 2-monoethanolamine-6-nitro-1-(titanyl-3)-2-chlorobenzimidazole and 2 monoethanolamine-5-nitro-1-(titanyl-3)-2-chlorobenzimidazole confirmed the molar ratio of the isomers of 3:1.

Declare the e, hot dioxane.

Example 2. Acute toxicity of the claimed compounds
Acute toxicity was determined after intragastric and intraperitoneal administration weinbrenner mysam the males, according to the method of J. Litchfield and F. Wilcoxon modification Rota (Belenky, M. L. elements of a quantitative evaluation of the pharmacological effect. - L.: Medgiz, 1963). Survival of animals 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 Settings 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. - HP - Medicine. - 1973. - S. 47-51).

Example 3. Anti-inflammatory activity
Anti-inflammatory activity was studied on models carragenine inflammation of the paws of mice and rats.

Mice received inside the studied compound at a dose of from 1/10 LD50. Next in animals caused inflammation of the paws subplanetary the introduction of 0.1 ml of 1% suspension carragenin. One day after injection animals Sabha joint and weighed. About anti-inflammatory activity was assessed by the difference of weight "inflamed" and "healthy" paws.

Comparison of anti-inflammatory action of these compounds was carried out with such effect of diclofenac sodium at a dose of ED50(10 mg/kg).

The results of the experiment are presented in table 2.

As can be seen from table 2, the compound has a statistically significant reduction in inflammation compared with the standard drug diclofenac sodium (P<0,001).

Pre-determined initial volume feet, then the animals received the compound at a dose of from 1/10 LD50inside. Drug comparison also served diclofenac sodium at a dose of ED50(10 mg/kg). Then subplantar were injected 0.1 ml of 1% solution carragenin. Next was determined by the amount of feet through 1, 3, 6, 12, 24, 48 and 72 hours.

The results of the study are presented in table 3.

As can be seen from table 3, starting with 12 hours of the experiment there was a statistically significant inhibition of inflammation compared with control (P<0,02). At the 48th hour surveillance in animals treated with 2-mono is e and in the group of animals take diclofenac sodium, swelling was significant.

In the third series of experiments studied the effect on exudative and proliferative phases of inflammation by Selye model implantation of sterile cotton swabs (m= 50 mg) in subcutaneous tissue of rats (I. P. Giroud et al., 1973). Then the animals for 7 days were treated orally with a suspension of the studied compounds at a dose of from 1/10 LD50, group of animals received diclofenac sodium at a dose of ED50(10 mg/kg).

About the impact of drugs on the exudative phase of inflammation judged by weight of exudate, which was determined by different weights between "wet" and "dried" tampons.

On the influence of compounds on the proliferative phase of inflammation was assessed by the difference of weight "dried" cotton swabs and the initial weight of the tampon (50 mg). The results of the experiments are presented in table 4.

As can be seen from table 4, the connection is statistically significantly reduces the weight of exudate (P<0,002), and significantly more diclofenac sodium inhibits the proliferative phase of inflammation (P<0,001).
Formula izobretaia formula

2. The mixture of isomers under item 1, which has anti-inflammatory activity.


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