Salts of 2-[2-(diethylamino)ethylthio] -5,6-dimethylbenzimidazole with anti-ischemic, hypoxic and anti-arrhythmic activity and 2-[2-(diethylamino)ethylthio] - 5,6-dimethylbenzimidazole as an intermediate product for the synthesis of salts of 2-[2-(diethylamino)ethylthio] -5,6 - dimethylbenzimidazole

 

(57) Abstract:

Usage: salt is used as a drug that has anti-ischemic, anti-toxic and anti-arrhythmic activity; 2-[2 - (diethylamino) ethylthio] -5,6-dimethylbenzimidazole - as an intermediate product for the synthesis dihydrochloride and succinate. The inventive product of General formula (I) , where I X = 2 HCl ; II X = 0,5(CH2COOH)2the product of General formula (II) Reagent I: 5,6 - dimethyl - 2 mercaptobenzimidazole. Reagent II: 2 - (diethylamino) ethylchloride in the environment introductory ethanol or dimethylformamide in the presence of a base. Reagent III: ethereal solution of hydrogen chloride or an alcoholic solution of succinic acid. 2 C. p. F.-ly, 3 ill., 9 table.

The invention relates to new chemical compounds of benzimidazole series, namely salts of 2-[2-(diethylamino)ethylthio]-5,6-dimethylbenzimidazole General formula

where I X = 2HCl;

II X = 0,5 (CH2COOH)2that have anti-ischemic, hypoxic and anti-arrhythmic activity and can find application in medicine for the treatment of ischemic heart disease, as well as to the intermediate product to obtain them.

The proposed compounds, their properties and the biological is II).

The literature describes a number of S-alkyl(dialkyl)aminoalkyl derivatives of 2-mercaptobenzimidazole with cardiotropic [1], antihistaminic [2-4] , antiallergic [2, 3], analgesic [4-6], anti-inflammatory [4, 7, 8], as well as antidepressant [7, 8], antimicrobial [9, 10] and radioprotective activity [11].

The proposed compounds exhibit anti-ischemic activity characteristic of a bradycardia selective drugs, and, in addition, antihypoxic and antiarrhythmic activity of broad-spectrum. In accordance with this as a prototype for anti-ischemic action selected verapamil, antihypoxic - piracetam, antiarrhythmic - quinidine, procainamide, lidocaine, propranolol, verapamil.

The aim of the invention is the creation of new connections in a series of derivatives of 2-mercaptobenzimidazole with anti-ischemic activity in combination with antihypoxic and antiarrhythmic activity.

The claimed compounds are synthesized according to standard techniques by alkylation of 5,6-dimethyl-2-mercaptobenzimidazole by 2-(diethylamino)ethylchloride in aqueous ethanol or dimethylcarbamate in Pris is thio]-5,6-dimethylbenzimidazole in ethanol ether solution of hydrogen chloride or alcoholic solution of succinic acid.

The invention is illustrated in the following examples.

P R I m e R 1. The dihydrochloride of 2-[2-(diethylamino)ethylthio]-5,6-dimethylbenzamide-ash (I).

To a solution of 1.4 g (0.035 mol) of sodium hydroxide in 2 ml of water and 20 ml of alcohol was added 2.67 g (0.015 mol) of 2-mercapto-5,6-dimethylbenzimidazole and 2.75 g (to 0.016 mol) of the hydrochloride of 2-(diethylamino)ethylchloride and boiled for 5 hours After cooling, the reaction mixture is diluted with water and extracted with chloroform. The extract was washed with 10% sodium hydroxide solution and water, dried with calcium chloride and evaporated. Obtain 3.7 g (84%) of the monohydrate of 2-[2-(diethylamino)ethylthio] -5,6-dimethylbenzamide-ash; so pl. 82-83about(From aq. SP.).

Found, %:60,76; N 8,20; N 14,22; S 10,97.

WITH15H23N3S.H2O.

Calculated, %:C 60,98; N 8,53; N, 14.22; S 10,85.

UV-spectrum (ethanol),maxnm (lg): 293 (4,32); 301 (4,38).

PMR-spectrum (deuterochloroform), , M. D.: 1,19 (6N, t, 2 N-C-CH3); 2,34 (6N, s, 2 CH3-Ar); 2,72 (4H, q, 2 N--CH3); to 2.99 (2H, m, S-CH2); the 3.11 (2H, m, N-CH2); from 7.24 (2H, s, Harene.).

The solution 4,43 g (0.015 mol) of monohydrate base in 10 ml of absolute alcohol and 50 ml of absolute ether is treated with ethereal solution of hydrogen chloride. Fallen UP>about(From a mix of see-EA).

Found, %: C 51,48; N 7,30; Cl 20,47; N 12,08; S 9,18.

WITH15H23N3S.2HCl.

Calculated, %: 51,42; N 7,19; CL 20,24; 12,00 N; S 9,15.

UV-spectrum (ethanol),maxnm (lg): 292 (4,30); 299 (4,30).

PMR-spectrum (deuterium oxide), , M. D.: 1,33 (6N, t, 2 N-C-CH3); 2.40 a (6N, s, 2 CH3-Ar) to 3.35 (4H, q, 2 N--CH3); of 3.57 (2H, m, S-CH2); 3,74 (2H, m, N-CH2); the 7.43 (2H, s, Harene.).

P R I m m e R 2. Succinate 2-[2-(diethylamino)ethylthio]-5,6-dimethylbenzimidazole (II).

To a solution of 1.78 g (0.01 mol) 2-mercapto-5,6-dimethylbenzimidazole and of 2.06 g (0.012 mol) of the hydrochloride of 2-(diethylamino)ethylchloride in 25 ml of dimethylformamide is added to 4.14 g (0.03 mol) of potash and stirred for 1 h at 80-90aboutC. After cooling, the reaction mixture is diluted with 250 ml of water. Separated oily product crystallized upon standing. The precipitate is filtered off, washed with water and dried in air. Obtain 2.24 g (76%) of the monohydrate of 2-[2-(diethylamino)ethylthio]-5,6-dimethylbenzimidazole; so pl. 82-83about(From aq. SP.).

The substance does not depression so plasma sample obtained above and is identical to him in the UV and IR spectrum.

To a solution 4,43 g (0.015 mol) of the monohydrate of the base in 30 ml of absolute alcohol portiamo the beginning of sedimentation, then add 50 ml of absolute ether. The precipitate is filtered off, washed with water and dried in air. Get to 4.33 g (87%) of compound (II); so pl. 180-181about(From the abs. SP.).

Found, %: C 60,94; N. Of 7.68; N 12,17; S 9,46.

WITH15H23N3S.0.5 C4H6O4.

Calculated, %: C 60,68; N 7,79; N 12,49; S At 9.53.

UV-spectrum (ethanol),maxnm (lg): 293 (4,44); 301 (4,44).

PMR-spectrum (deuterium oxide + 2 drops triperoxonane acid), M. D.: 1,45 (N, t, 4 N-C-CH3); 2,47 (N, s, 4 CH3Ar); 2,73 (4H, s, PRAS2CH2CO); 3,43 (8H, kV, 4 N--CH3); to 3.64 (8H, s, SCH2CH2N); 742 (4H, c, Harene.).

Pharmacological study of the claimed compounds was carried out on various models of ischemia, hypoxia and arrhythmia, in comparison with reference drugs.

1. Anti-ischemic activity.

For the evaluation of anti-ischemic properties of the claimed compounds were investigated for their influence on hemodynamics and activity of the intact heart cats. We also used two models of myocardial ischemia: a model of acute failure of coronary circulation and the model 20-minute occlusion and subsequent 30-min reperfusion of the coronary artery in cats. It was found that with the e 30 min after injection. However, other hemodynamic parameters and cardiac activity (mean arterial pressure, heart rate, average acceleration of blood flow in the aorta) was almost unchanged (see table. 1 and 2 of the act biological testing). Comparison drug verapamil also cause significant bradycardia. However, under his influence more significantly reduced systemic arterial pressure and decrease the average acceleration of blood flow in the aorta, which indicates the inhibition of the contractile function of cardiac muscle (see tab. 3).

As shown by experiments on a model of acute failure of coronary circulation have shot cats, compounds I and II (1.0 mg/kg bolus + 50 µg/kg/min during the intravenous experience) significantly reduce the average ST segment elevation in multiple leads epicardial electrogram during the 5-minute occlusion of the coronary artery. This is reflected in Fig. 1 and 2. On the y - axis the average rise in segment SI mV; the abscissa shows the time of occlusion and reperfusion of the coronary artery, min. Curve 1 - control occlusion; curve 2 - occlusion immediately after the introduction of the connection; curve 3 - 20 minutes and the comparator Drug verapamil on this model operates in a similar manner.

In the control series of experiments in animals during occlusion and reperfusion frequently encountered arrhythmia various severity. Compound I under these conditions reduces the incidence of arrhythmias, the time of occurrence of arrhythmia shifted by a period of reperfusion (see tab. 4).

Thus, compounds I and II have a pronounced anti-ischemic action which, apparently, is associated with reduced need of the heart for oxygen during emergent bradycardia. The advantage over the comparison drug verapamil is that the claimed compounds causing bradycardia does not inhibit the contractile function of the heart and not have a practical impact on other hemodynamic parameters.

Recently in the clinic coronary heart disease has greatly increased the interest in the new class antianginal funds - a bradycardia selective agents type alinidine and valiamala. From lechitel is even reduce the need of the heart for oxygen, without significant impact on other hemodynamic parameters. In this respect they differ from other drugs classes used for treatment of myocardial infarction-blockers, which inhibit the contractile function of the heart muscle and reduce cardiac output, and calcium antagonists, reduces systemic blood pressure and decreasing the contractility of the myocardium.

On the basis of obtained results it can be assumed that the proposed compounds belong to this class antianginal funds type valiamala (similar to verapamil) and can find application in medicine for the treatment of ischemic heart disease.

2. Antihypoxic activity.

To assess antihypoxic effect of the claimed compounds, in comparison with piracetam, conducted experiments on different hypoxic conditions: acute hypobaric hypoxia (AGBG), hypoxia in the containment, acute Himicheskaya hypoxia (Ageg), acute histologically hypoxia (AGTG), apoxia in mice.

The effect of compound I on portability AGBG was studied in the pressure chamber when the "rise" over 1 min to a height of 11000 feet was Estimated life expectancy (TJ) animal who's rats-males, pre-divided according to their sensitivity to AGBG to highly resistant (WU) and discostick (WELL). The proposed connection I and the comparator drug was administered intraperitoneally in saline solution for 30 minutes before experienced climb to 11000 m experimental Data (see tab. 5) show that in terms AGBG the inventive compound in a dose of 40 mg/kg increases the life expectancy of WELL and WU animals, respectively, 1.5 and 1.7 times. Piracetam has a similar antihypoxic effect on the animals WELL and does not affect the resistance to AGBG WU animals. Therefore, in conditions of simulated hypoxia connection I has a wider range than piracetam.

The effect of compound I on the lifespan of animals in terms of containment was studied in outbred mice, which were put in glass jars with a volume of 200 ml; cans tightly closed. Register the lifetime of the mice before the onset of their death from lack of oxygen. The data obtained (see tab. 6) indicate that compound I, as well as piracetam, does not significantly impact on the duration of life of the animals on this model of hypoxia.

It was also studied the influence soedinen the males of sodium nitrite at a dose of 300 mg/kg Compound I was administered intraperitoneally 30 min before the injection of sodium nitrite. Control served as saline solution, administered 30 min prior to hypoxia. Estimated lifespan of mice from the moment of introduction of the sodium nitrate to the death of the animal. The results of this series of experiments show that the claimed compound I in a dose of 40 mg/kg, as well as piracetam, not having antihypoxic action, and at a dose of 80 mg/kg is superior in efficacy of the drug in comparison to 1.4 times (see tab. 7).

In terms OGTG connection I, like piracetam, none of the investigated doses does not show antihypoxic properties (see tab. 8).

It was also investigated antihypoxic action of the compounds I and II on the model of apoxie caused by compression of the trachea in mice. On the protective effect of substances judged by the duration of preservation of the bioelectric activity of the heart. Experiments showed that control the duration of the bioelectric activity of the heart in conditions of simulated hypoxia was 453 43,8 C. the Compounds I and II in a dose of 80 mg/kg (intraperitoneally) increased this figure to 980,4103,2 with and 775,889,9 s, respectively. The claimed compounds increased the number of animals living in conditions of apoxie more than 1 compounds I and II are distinct antihypoxic protective effect on different models of hypoxia. Compound I shows antihypoxic activity in acute hypobaric and acute himicheskoi hypoxia and exceeds piracetam on spectrum use in hypoxia of different etiology; AGBG shows antihypoxic effect, regardless of individual resistance of the animal to it, unlike piracetam, increasing life expectancy only discostick animals and, in addition, is effective in smaller doses than piracetam used in the clinic at a dose of 400 mg/kg and above.

All this allows us to consider the connection I more promising antihypoxic drug compared with piracetam used in the clinic.

3. Antiarrhythmic activity.

Pharmacological study of the claimed compounds I spent on experimental models of arrhythmias: chloralkali - in awake rats, adrenaline - in awake rabbits and arabanoo in anesthetized Guinea pigs.

The results of the experiment showed that the model adrenaline arrhythmia connection I has a pronounced antiarrhythmic effect. The effect was more significant than antiaritmikov class I - quinidine, procainamide hydrochloride and lidocaine, and almost no witeska tests).

A significant antiarrhythmic effect of compound I showed on the model chloralkali arrhythmia: it's at a dose of 1.75 mg/kg prevented the death of rats from lethal fibrillatio ventricles. This model comparison I several times was more procainamide hydrochloride or lidocaine, but was slightly less than the propranolol and verapamil (see tab. 9).

It is important to note that arabanoo models of arrhythmias in Guinea pigs connection I 2-3 times increased the survival time of the animals (see table. 9).

As the experiments showed, the claimed compound I has a relatively low toxicity (LD5048 mg/kg when administered intravenously to rats), and, most importantly, it has high anti-arrhythmic index, i.e., a greater breadth of therapeutic action. By this measure, the compound I is superior also widely known antiaritmiki as quinidine, procainamide, lidocaine, verapamil and propranolol.

Thus, on the basis of obtained data we can conclude that the claimed compound I is an antiarrhythmic agent that combines the properties of antiaritmikov I, II and IV classes. In comparison with the known means of complications, taken as Comparators, soedineniya I is the unlike most antiaritmikov, as shown by experiments on models of ischemia, does not cause inhibition of contractility.

These data suggest that the proposed connection I may be promising for the creation of new antiarrythmia with a wide spectrum of action.

SALTS OF 2-[2-(DIETHYLAMINO)ETHYLTHIO] -5,6-DIMETHYLBENZIMIDAZOLE WITH ANTI-ISCHEMIC, HYPOXIC AND ANTI-ARRHYTHMIC ACTIVITY AND 2-[2-(DIETHYLAMINO)ETHYLTHIO] -5,6-DIMETHYLBENZIMIDAZOLE AS AN INTERMEDIATE PRODUCT FOR THE SYNTHESIS OF SALTS OF 2-[2-(DIETHYLAMINO)ETHYLTHIO]-5,6-DIMETHYLBENZIMIDAZOLE.

1. Salts of 2-[2-(diethylamino)ethylthio]-5,6-dimethylbenzimidazole General formula

< / BR>
where I X - 2HCl;

II X - 0,5 (CH2COOH)2,

with anti-ischemic, hypoxic and anti-arrhythmic activity.

2. 2-[2-(Diethylamino)ethylthio]-5,6-dimethylbenzimidazole

< / BR>
as an intermediate product for the synthesis of salts of 2-[2-(diethylamino)ethylthio]-5,6-dimethylbenzimidazole.

 

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1 ex

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EFFECT: valuable properties of compounds.

5 cl, 3 sch, 5 tbl, 6 ex

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