RU2027709C1 - 2-[2-(diethylamino) -ethylthio]-5,6- dimethylbenzimidazole salts showing antiischemic, antihypoxic and antiarrhythmic activity and 2-[2-(diethylamino) -ethylthio]-5,6- dimethylbenzimidazole as an intermediate product for synthesis of 2-[2-(diethylamino) -ethylthio] -5,6-dimethylbenzimidazole salts - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product is used as a preparation showing antiischemic, antihypoxic and antiarrhythmic activity and 2-[2-(diethylamino) -ethylthio] -5,6- dimethylbenzimidazole as an intermediate product for synthesis of its dihydrochloride and succinate. Product of the general formula

where I X - 2HCl; II X - 0,5(CH₂COOH)₂, product of the general formula

Description

где I X = 2HCl;
II X = 0,5 (CH₂COOH)₂, которые обладают противоишемической, антигипоксической и антиаритмической активностью и могут найти применение в медицине для лечения ишемической болезни сердца, а также к промежуточному продукту для их получения.The invention relates to new chemical compounds of the benzimidazole series, namely, salts of 2- [2- (diethylamino) ethylthio] -5,6-dimethylbenzimidazole of the general formula

where IX = 2HCl;
II X = 0.5 (CH ₂ COOH) ₂ , which have anti-ischemic, antihypoxic and antiarrhythmic activity and can be used in medicine for the treatment of coronary heart disease, as well as an intermediate product for their preparation.

 The proposed compounds, their properties and biological activity are not described in the literature. They are registered as original in SC BAS under N 10147491 (I) and N 10304991 (II).

 The literature describes the preparation of a number of S-alkyl (dialkyl) aminoalkyl derivatives of 2-mercaptobenzimidazoles having cardiotropic [1], antihistamine [2-4], anti-allergic [2, 3], analgesic [4-6], anti-inflammatory [4, 7, 8], antipyretic and antidepressant [7, 8], antimicrobial [9, 10] and radioprotective activity [11].

 The proposed compounds exhibit anti-ischemic activity inherent to selective bradycardic drugs, and, in addition, antihypoxic and antiarrhythmic activity of a wide spectrum of action. In accordance with this, verapamil was selected as a prototype for anti-ischemic action, piracetam for anti-hypoxic action, quinidine, novocainamide, lidocaine, propranolol, verapamil for anti-ischemic action.

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

 The inventive compounds are synthesized according to standard methods by alkylation of 5,6-dimethyl-2-mercaptobenzimidazole with 2- (diethylamino) ethyl chloride in aqueous ethanol or dimethyl dormamide in the presence of a base (sodium hydroxide or potash), followed by treatment of the resulting 2- [2- (diethylamino ) ethylthio] -5,6-dimethylbenzimidazole in a solution of ethanol with an ethereal solution of hydrogen chloride or an alcoholic solution of succinic acid.

 The invention is illustrated by the following examples.

 Example 1. 2- [2- (Diethylamino) ethylthio] -5,6-dimethylbenzimidazole dihydrochloride (I).

2.67 g (0.015 mol) of 2-mercapto-5,6-dimethylbenzimidazole and 2.75 g (0.016 mol) of 2- hydrochloride are added to a solution of 1.4 g (0.035 mol) of sodium hydroxide in 2 ml of water and 20 ml of alcohol. (diethylamino) ethyl chloride and boil 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. 3.7 g (84%) of 2- [2- (diethylamino) ethylthio] -5,6-dimethylbenzimidezole monohydrate are obtained; t. pl. 82-83 ^{° C} (from aq. Sp.).

 Found,%: C 60.76; H, 8.20; N, 14.22; S 10.97.

C ₁₅ H ₂₃ N ₃ ^S. H ₂ O.

 Calculated,%: C 60.98; H 8.53; N, 14.22; S 10.85.

UV spectrum (alcohol), λ _max , nm (log ε): 293 (4.32); 301 (4.38).

-CH₃); 2,99 (2H, м, S-CH₂); 3,11 (2H, м, N-CH₂); 7,24 (2Н, с, Н_аром.).PMR spectrum (deuterochloroform), δ, ppm: 1.19 (6H, t, 2 NC-CH ₃ ); 2.34 (6H, s, 2 CH ₃ -Ar); 2.72 (4H, q, 2 N-

-CH ₃ ); 2.99 (2H, m, S-CH ₂ ); 3.11 (2H, m, N-CH ₂ ); 7.24 (2H, s, H _arom .).

A solution of 4.43 g (0.015 mol) of base monohydrate in 10 ml of absolute alcohol and 50 ml of absolute ether is treated with an ethereal solution of hydrogen chloride. The precipitate formed is filtered off, washed with absolute ether and dried over potassium hydroxide. Obtain 5.0 g (95%) of compound I, so pl. 183-184 ^about With (from a mixture see-EA).

 Found,%: C 51.48; H, 7.30; Cl 20.47; N, 12.08; S 9.18.

C ₁₅ H ₂₃ N ₃ ^S. 2HCl.

 Calculated,%: C 51.42; H, 7.19; Cl 20.24; N, 12.00; S 9.15.

UV spectrum (alcohol), λ _max , nm (log ε): 292 (4.30); 299 (4.30).

-CH₃); 3,57 (2Н, м, S-CH₂); 3,74 (2H, м, N-CH₂); 7,43 (2Н, с, Н_аром.).1 H-NMR spectrum (deutero guide), δ, ppm: 1.33 (6H, t, 2 NC-CH ₃ ); 2.40 (6H, s, 2CH ₃ -Ar), 3.35 (4H, q, 2 N-

-CH ₃ ); 3.57 (2H, m, S-CH ₂ ); 3.74 (2H, m, N-CH ₂ ); 7.43 (2H, s, H _arom .).

 PRI me R 2. Succinate of 2- [2- (diethylamino) ethylthio] -5,6-dimethylbenzimidazole (II).

To a solution of 1.78 g (0.01 mol) of 2-mercapto-5,6-dimethylbenzimidazole and 2.06 g (0.012 mol) of 2- (diethylamino) ethyl chloride hydrochloride in 25 ml of dimethylformamide was added 4.14 g (0.03 mol) potash and stirred for 1 h at 80-90 ^about C. After cooling, the reaction mixture was diluted with 250 ml of water. The released oily product crystallizes upon standing. The precipitate is filtered off, washed with water and dried in air. 2.24 g (76%) of 2- [2- (diethylamino) ethylthio] -5,6-dimethylbenzimidazole monohydrate are obtained; t. pl. 82-83 ^{° C} (from aq. Sp.).

 The substance does not give depression t. Pl. with the sample obtained above and is identical to it in the UV and IR spectrum.

To a solution of 4.43 g (0.015 mol) of base monohydrate in 30 ml of absolute alcohol, a solution of 1.33 g (0.023 mol) of succinic acid in 50 ml of absolute alcohol is added in portions and left for several minutes before precipitation begins, then 50 ml of absolute ether. The precipitate is filtered off, washed with water and dried in air. Obtain 4.33 g (87%) of compound II; t. pl. 180-181 ^о С (from abs. Sp.).

 Found,%: C 60.94; H 7.68; N, 12.17; S 9.46.

C ₁₅ H ₂₃ N ₃ ^S. 0.5 C ₄ H ₆ O ₄ .

 Calculated,%: C 60.68; H 7.79; N, 12.49; S 9.53.

UV spectrum (alcohol), λ _max , nm (log ε): 293 (4.44); 301 (4.44).

-CH₃); 3,64 (8Н, с, SCH₂CH₂N); 742 (4H, c, H_аром.).PMR spectrum (deutero guide + 2 drops of trifluoroacetic acid), δ, ppm: 1.45 (12H, t, 4 NC-CH ₃ ); 2.47 (12H, s, 4 CH ₃ Ar); 2.73 (4H, s, OCCH ₂ CH ₂ CO); 3.43 (8H, q, 4 N-

-CH ₃ ); 3.64 (8H, s, SCH ₂ CH ₂ N); 742 (4H, s, H _arom .).

 A 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.

 To assess the anti-ischemic properties of the claimed compounds, their effect on the hemodynamics and activity of the intact heart of cats was investigated. Two models of myocardial ischemia were also used: a model of acute coronary circulatory failure and a 20-minute occlusion model followed by a 30-minute coronary artery reperfusion in cats. It was found that compounds I and II at a dose of 1 mg / kg, administered intravenously, cause severe bradycardia, continuing for 30 minutes after administration. However, other indicators of hemodynamics and cardiac activity (mean arterial pressure, heart rate, average acceleration of blood flow in the aorta) remained virtually unchanged (see Tables 1 and 2 of the biological test report). Verapamil comparison drug also causes noticeable bradycardia. However, under its influence, systemic blood pressure decreases more significantly and the average acceleration of blood flow in the aorta decreases, which indicates inhibition of the contractile function of the heart muscle (see table. 3).

 As experiments on the model of acute coronary circulatory failure in anesthetized cats showed, compounds I and II (1.0 mg / kg bolus + 50 μg / kg / min during the intravenous experiment) significantly reduce the average ST segment elevation on multiple leads of the epicardial electrogram during time of 5-minute occlusion of the coronary artery. This is reflected in FIG. 1 and 2. On the ordinate axis - the average rise of the SI mV segment; along the abscissa - the time of occlusion and reperfusion of the coronary artery, min. Curve 1 - control occlusion; curve 2 - occlusion immediately after the start of administration of the compound; curve 3 - after 20 minutes. The verapamil comparison drug on this model acts in a similar way.

 In conditions of longer coronary artery occlusion (20 min) followed by reperfusion (30 min), compound I (1.0 mg / kg bolus immediately after occlusion + 50 μg / kg / min for 30 min, intravenously) significantly prevents a decrease pumping and contractile function of the heart caused by ischemic damage, as shown in FIG. 3. I - systolic discharge; II - cardiac output; III - the average acceleration of blood flow in the aorta.

 In the control series of experiments in animals during occlusion and reperfusion, arrhythmias of various severity often occurred. Compound I under these conditions reduces the number of cases of occurrence of rhythm disturbances, while the time of occurrence of arrhythmia is shifted to the period of reperfusion (see table. 4).

 Thus, compounds I and II have a pronounced anti-ischemic effect, which, apparently, is associated with a decrease in the oxygen demand of the heart during bradycardia. The advantage over verapamil comparison drug is that the claimed compounds, causing bradycardia, do not inhibit the contractile function of the heart and do not practically affect other hemodynamic parameters.

 Recently, in the clinic of coronary heart disease, interest in a new class of antianginal drugs, selective bradycardic agents such as alinidine and falipamil, has significantly increased. A distinctive feature of this group of substances is their ability to improve the function of the ischemic myocardium by reducing the oxygen demand of the heart, without significantly affecting other hemodynamic parameters. In this respect, they differ from drugs of other classes used to treat myocardial infarction β-blockers, which inhibit the contractile function of the heart muscle and reduce cardiac output, and calcium antagonists, which reduce systemic blood pressure and reduce myocardial contractility.

 Based on the results obtained, it can be assumed that the proposed compounds belong to this class of antianginal drugs such as falipamil (an analogue of verapamil) and may find application in medicine for the treatment of coronary heart disease.

 2. Antihypoxic activity.

 In order to evaluate the antihypoxic effect of the claimed compounds, in comparison with piracetam, experiments were carried out on various models of hypoxic conditions: acute hypobaric hypoxia (OGBH), hypoxia in a hermetic volume, acute hemic hypoxia (OGE), acute histotoxic hypoxia (OGTG), and apoxia in mice.

 The effect of compound I on the tolerance of OGBH was studied in a pressure chamber during “rise” for 1 min to a height of 11000 m. The life expectancy (Tg) of the animal at the “height” was estimated from the moment it was reached until the 2nd agonal inhalation. The experiments were carried out on white outbred male rats, previously divided by their sensitivity to OGBH into highly stable (WL) and low resistant (WL). The proposed compound I and the reference drug were administered intraperitoneally in physiological saline 30 minutes before the experimental climb of 11,000 m. The experimental data (see table. 5) show that, under conditions of OGBG, the claimed compound at a dose of 40 mg / kg increases the lifespan of OH and VU animals, respectively, 1.5 and 1.7 times. Piracetam has a similar antihypoxic effect only on the OH of animals and does not affect the resistance to OGBH of the OH of animals. Therefore, under the conditions of simulated hypoxia, compound I has a wider range of action than piracetam.

 The effect of compound I on the life span of animals under pressure conditions was studied on white outbred mice, which were planted in 200 ml glass jars; banks tightly closed. The life time of mice was recorded before they died from a lack of oxygen. The data obtained (see table. 6) indicate that compound I, like piracetam, does not significantly affect the lifespan of animals in this hypoxia model.

 The effect of compound I on the longevity of animals under OGeH conditions was also studied, which was modeled by the administration of 300 mg / kg of sodium nitrite subcutaneously to outbred male mice. Compound I was administered intraperitoneally 30 minutes before sodium nitrite injection. The control was physiological saline, administered 30 minutes before hypoxia. Estimated life expectancy of mice from the time of introduction of sodium nitrate to the death of the animal. The results of this series of experiments show that the claimed compound I at a dose of 40 mg / kg, like piracetam, does not have an antihypoxic effect, and at a dose of 80 mg / kg it is 1.4 times more effective than the comparison drug (see table. 7).

 Under OGTG conditions, compound I, like piracetam, does not exhibit antihypoxic properties in any of the doses studied (see Table 8).

 The antihypoxic effect of compounds I and II on a model of apoxia caused by tracheal compression in mice was also investigated. The protective effect of the substances was judged by the duration of the bioelectric activity of the heart. The experiments showed that in the control, the duration of the bioelectric activity of the heart under the conditions of simulated hypoxia was 453 ± 43.8 s. Compounds I and II at a dose of 80 mg / kg (intraperitoneally) increased this indicator to 980.4 ± 103.2 s and 775.8 ± 89.9 s, respectively. The inventive compounds increased the number of animals living under conditions of apoxia for more than 10 minutes

 Thus, the results of the studies indicate the presence of the claimed compounds I and II of a distinct antihypoxic protective effect on different models of hypoxia. Compound I exhibits antihypoxic activity in conditions of acute hypobaric and acute hemic hypoxia and is superior to piracetam in the spectrum of application under conditions of hypoxia of various etiologies; under conditions of OGBG, it exhibits antihypoxic action regardless of the individual resistance of the animal to it, in contrast to piracetam, which increases the life expectancy of only low-resistance animals and, moreover, is effective in lower doses than piracetam, used in the clinic at a dose of 400 mg / kg and above.

 All this allows us to consider compound I as a more promising antihypoxant, compared to the piracetam used in the clinic.

 3. Antiarrhythmic activity.

 A pharmacological study of the claimed compound I was carried out on experimental models of arrhythmias: calcium chloride in waking rats, adrenaline in waking rabbits and ouabain in anesthetized guinea pigs.

 The experimental results showed that in the model of adrenaline arrhythmia, compound I exerts a pronounced antiarrhythmic effect. The effect was more significant than that of class I antiarrhythmics - quinidine, novocainamide and lidocaine, and almost did not concede to class II and IV standard antiarrhythmics - propranolol and verapamil, respectively (see table 9 of the biological test report).

 Compound I showed a significant antiarrhythmic effect in the model of calcium chloride arrhythmia: it at a dose of 1.75 mg / kg prevented the death of rats from lethal ventricular fibrillation. In this model, comparison I was several times more active than procainamide or lidocaine, but somewhat inferior to propranolol and verapamil (see table 9).

 It is important to note that in the ouabain model of arrhythmia in guinea pigs, compound I increased the survival time of animals by a factor of 2–3 (see Table 9).

As experiments showed, the claimed compound I has a fairly low toxicity (LD ₅₀ 48 mg / kg when administered intravenously to rats), and, most importantly, it has a high antiarrhythmic index, i.e. large breadth of therapeutic action. In this indicator, compound I also surpasses well-known antiarrhythmics such as quinidine, procainamide, lidocaine, verapamil and propranolol.

 Thus, on the basis of the data obtained, we can conclude that the claimed compound I is an antiarrhythmic agent that combines the properties of antiarrhythmics I, II and IV classes. Compared with the known antiarrhythmic drugs taken as reference drugs, compound I has a wide spectrum and greater breadth of therapeutic effect. An advantage of the claimed compound I is also that, unlike most antiarrhythmics, as shown by experiments on models of ischemia, it does not cause inhibition of myocardial contractility.

 The data presented suggest that the proposed compound I may be promising for the creation of a new antiarrhythmic with a wide spectrum of action.

Claims (3)

 Salts of 2- [2- (DIETHYLAMINO) Ethylthio] -5,6-DIMETHYLBENZIMIDAZYLOISEZYLOISYTIMESIS - [2- (DIETHYLAMINO) ETHYLTHIO] -5,6-DIMETHYLBENZIMIDAZOLE. 1. Salts of 2- [2- (diethylamino) ethylthio] -5,6-dimethylbenzimidazole of the general formula

where IX is 2HCl;
II X - 0.5 (CH ₂ COOH) ₂ ,
possessing anti-ischemic, antihypoxic and antiarrhythmic activity. 2.2- [2- (Diethylamino) ethylthio] -5,6-dimethylbenzimidazole

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

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