RU2068261C1 - Antiarrythmic agent - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: 9-diethylaminoethyl-2-tert. -butylimidazo-[1,2-a] -benzimidazole dihydrochloride of the formula

Description

 The present invention relates to medicines, namely, to antiarrhythmic.

 The search for new effective antiarrhythmic drugs has recently acquired significant significance. This is due to an increase in the number of patients suffering from arrhythmias, and an increase in diseases that provoke the appearance of arrhythmias: coronary heart disease, myocardial infarction, atherosclerosis, hypertension and hypotensive conditions, rheumatism, etc. Arrhythmias are the leading cause of death in a number of cardiovascular diseases. (E.I. Chazov, Cardiology, 1975, N 1, p. 5-10). The expediency of the search for antiarrhythmic drugs is also due to the limited number of specific drugs used to treat arrhythmias (E.I. Chazov, Therapist. Archive, 1975, 5, p. 33 [2] A.V. Sumarokov, A.A. Mikhailov. Heart arrhythmias. , M. 1976, p.163 [3] V. S. Nesterov. Clinic of diseases of the heart and blood vessels. Kiev, 1971, p.230 [4]).

Currently, a large number of different medicinal substances are used in the pharmacotherapy of arrhythmias, which according to the classification of BNSingh and EMV Williams (Cardiovasc. Res. 1972, N 6, p. 109-119 [5]) are divided into 4 groups (or classes) depending on their membranotropic properties:
Group I inhibitors of rapidly incoming transmembrane ion current;
Group II beta-blockers;
Group III extending the action potential of a cardiomyocyte;
Group IV calcium antagonists.

 Of the I group of drugs, quinidine, procainamide, ethmosine, trimecaine, and lidocaine were widely used in the USSR. All of them, except lidocaine, are produced in our country. The pharmacological effect of novocainamide and quinidine is caused by a decrease in myocardial excitability and conductivity, as well as a suppression of the formation of ectopic foci of automatism. Therefore, these drugs are used for the prevention and treatment of paroxysmal tachycardia, atrial fibrillation and extrasystoles (/ 4 /; MD Mashkovsky. Medicines, M. Medicine, 1972, part 1, p. 333/6 /; / 3 /; EI Chazov. Essays on emergency cardiology. M. 1973, p.136 / 7 /). But their wide clinical use is hampered due to side effects: a decrease in myocardial contractile function, a drop in blood pressure up to a collapse reaction, dyspeptic disorders, general weakness, agitation, insomnia, allergic reactions, and lupus syndrome. Individual hypersensitivity to procainamide is sometimes detected, leading to ventricular fibrillation and suppression of cardiac activity (see literary sources cited above).

 The drug ethmosin, recently introduced into clinical practice, has antiarrhythmic activity in nature, similar to the action of quinidine and is also used for extrasystoles, bouts of atrial, atrial and paroxysmal tachycardia (N.V. Kaverina, Z.N. Senova, Yu.V. Vikhlyaev , OV Ulyanova, Pharmacol. And Toxicol. 1970, No. 6, p. 6393/8 /; Z. N. Senova. New Medicines, 1976, No. 2, p. 21/9 /). Etmozin is the best in action from existing antiarrhythmic drugs.

 The 2nd group includes beta-blockers such as anaprilin (inderal, obzidan, propranolol), oxyprenalol, alprenalol, pindolol. In the USSR, only anaprilin is produced. (V.I. Metelitsa. Handbook of a cardiologist in clinical pharmacology, M. Medicine, 1980/10 /, p. 83).

 The 3rd group of antiarrhythmic drugs include amiodarone (cordaron, trangorex) and bretilium tosylate (ornide). The latter is produced in the USSR, however, due to the presence of a number of side effects, it is rarely used as an antiarrhythmic substance (/ 10 /, p. 83).

 Substances belonging to the 4th group of verapamil (isoptin, finoptin), D-600, diltiazem are not produced in the USSR. (/ 10 /, p. 83).

 Analyzing the effect of all of the above antiarrhythmic drugs, we can note their common property is a relatively high selective mechanism of antiarrhythmic influence and, accordingly, a narrow spectrum of antiarrhythmic effect. Therefore, in clinical practice, various combinations of antiarrhythmic drugs are often used to enhance the pharmacotherapeutic effect. (L. Tomov, Il. Tomov. Heart rhythm disturbances. Medicine and physical education, Sofia, 1976, p.329 / 11 /; / 9 /, p.83).

 The closest in nature of action and the best in effect is the drug ethmosin. (/ 8 /, / 9 /).

However, it remains insufficiently effective in terms of action (the minimum concentration acting on the refractory period of the rat atrium, 5.1 × 10 ^-5 M / l and on the refractory period of the rat’s heart, is 1.1 × 10 ^-5 M / kg) and does not have a wide spectrum of action (in Ethmosin has the properties of only one (I) group of antiarrhythmics on the ionic conductivity of myocardiocytes). [Etmozin, like many other antiarrhythmic drugs, is characterized by an insufficiently wide spectrum of antiarrhythmic action, because belongs to the I group of membrane-stabilizing antiarrhythmics]
The aim of the invention is to increase efficiency and expand the spectrum of action.

(рег. N 074273).The goal is achieved by using, as an antiarrhythmic agent, the previously synthesized dihydrochloride of 9-diethylaminoethyl-2-tert-butylimidazo [1,2-a] benzimidazole (the proposed name of the drug is rhythmidazole) of the formula:

(reg. N 074273).

The proposed antiarrhythmic substance in comparison with the prototype (ethmosine) is characterized by greater strength and breadth of action. Pharmacological studies showed that rhythmidazole, when comparing its effect with the action of drugs with membrane-stabilizing effects (ethmosine, quinidine, aymalin), turned out to be the leader in this group of antiarrhythmics in terms of strength (the minimum concentration of rhythmidazole acting on the refractory period of the rat atrium 4.3 • 10 ^-5 M / l and for the refractory period of the heart of the rat 1 • 10 ^-5 M / kg, which is lower than the corresponding concentrations for ethmosin). In addition, rhythmidazole combines the properties of antiarrhythmics of groups I, III and IV in terms of its effect on the ionic conductivity of the myocardiocyte, due to which it has a wide spectrum of antiarrhythmic action and is highly active for rhythm disturbances of various genesis.

The proposed compound is known as a biologically active substance with antihypertensive activity (A. M. Simonov, G. V. Kovalev, V. A. Anisimova, S. M. Hoffman, I. N. Tyurenkov, J. K. Fomin. Auth. certificate N 566588, MKI ² A 61 K 31/475 (1977) / 12 /; G.V. Kovalev, V.A. Anisimova, A.M.Simonov et al. Chemical Pharmaceutical Journal, 1979, No. 8 , p. 57, / 13 /). It has been established that in antiarrhythmic doses (1–3 mg / kg) it does not affect blood pressure and myocardial contractility, practically does not change antireventular and intraventricular conductivity (see test report).

 A method of obtaining the proposed compounds based on 2-amino-1-diethylaminoethylbenzimidazole is described in / 12, 13 /. However, the synthesis of the starting amine, as well as the conditions for some of the further steps, are technologically complex and inconvenient for implementation in industrial production.

Ниже приведены методики синтеза предлагаемого соединения по этой схеме:
Стадия 1. Получение 2-аминобензимидазола. К перемешиваемой суспензии 500 г (2,615 моль) метил-N-(2-бензимидазолил)карбамата (БМК-2) в 3000 мл воды прибавляют 585 г 42% раствора едкого натра. Смесь доводят до кипения и кипятят 2 часа 30 мин. Затем добавляют 50 г активированного угля (марки ОУ "А" техн. ) и продолжают кипячение еще 30 мин. Активированный уголь отфильтровывают из горячего раствора на нагретой воронке Бюхнера, на фильтре промывают 400 мл горячей воды (4•100 мл); фильтрат обрабатывают 200 мл конц. НCl, осторожно прибавляя последнюю небольшими порциями (наблюдается сильное пенообразование из-за выделения СO₂) до рН 8-9, охлаждают до комнатной температуры. Выпавший осадок отфильтровывают и промывают на фильтре ≈750 мл ледяной воды (5•150 мл), при этом последние порции промывной воды должны быть бесцветными. Осадок высушивают в сушильном шкафу при 100-120^oC. Выход 226-268 г (65-77% в зависимости от качества партии технического БМК-2), т.пл. 229 230^oС. Полученный 2-аминобензимидазол не требует дополнительной очистки.The authors proposed the following scheme for the synthesis of rhythmidazole based on methyl N- (2-benzimidazolyl) carbamate (BMK-2), the production of which has recently been mastered in the Soviet Union at the Fergana plant of the Azot production association

The following are the synthesis methods of the proposed compounds according to this scheme:
Stage 1. Obtaining 2-aminobenzimidazole. To a stirred suspension of 500 g (2.615 mol) of methyl N- (2-benzimidazolyl) carbamate (BMK-2) in 3000 ml of water was added 585 g of a 42% sodium hydroxide solution. The mixture is brought to a boil and boiled for 2 hours 30 minutes. Then add 50 g of activated carbon (grade OU "A" tech.) And continue boiling for another 30 minutes. Activated carbon is filtered from a hot solution on a heated Buchner funnel, washed with 400 ml of hot water (4 • 100 ml) on the filter; the filtrate is treated with 200 ml of conc. HCl, carefully adding the latter in small portions (strong foaming is observed due to the release of CO ₂ ) to a pH of 8–9, is cooled to room temperature. The precipitate formed is filtered off and washed on a filter with ≈750 ml of ice water (5 • 150 ml), while the last portions of the wash water should be colorless. The precipitate is dried in an oven at 100-120 ^o C. The yield of 226-268 g (65-77% depending on the quality of the batch of technical BMK-2), so pl. 229 230 ^o C. The obtained 2-aminobenzimidazole does not require additional purification.

Stage 2. Synthesis of 2-amino-1-diethylaminoethylbenzimidazole. To a suspension of 20 g (0.15 mol) of 2-aminobenzimidazole in 200-250 ml of acetone, placed in a three-necked flask, 3-5 times excess of 42% alkali is added with vigorous stirring. The mixture is warmed up to 35-40 ^o C and abundant precipitation of Na-salt. After stirring for 10 minutes, 27.5 g (0.16 mol) of diethylaminoethyl chloride hydrochloride was added to the flask. The mixture is boiled for 1 hour in a water bath. Then the acetone solution is drained from the semi-crystalline precipitate collected at the bottom, the precipitate is additionally treated with acetone (≈50 ml). Both portions of acetone solutions are mixed and the acetone is distilled off. 20-30 ml of xylene are added to the residue, the mixture is thoroughly stirred, and after 30 minutes the snow-white coarse-grained precipitate is filtered off from the cooled mixture, washed on the filter with a small amount of xylene, then with water. The amine is dried in air or in an oven at 80-90 ^o C. The yield is 76.5-79.8% (26.6-27.8 g), so pl. 133-134 ^o C. The resulting amine is introduced into further transformations without further purification.

 Stage 3. Obtaining brompinacoline.

In a 0.25 L three-necked flask equipped with a mechanical stirrer, a refrigerator and a dropping funnel, 24.4 ml (20 g, 20 mmol) of pinacoline (mp. 106 ^° C), 10 ml of glacial acetic acid and 40 ml of water are placed . The mixture is heated in a water bath to 70-80 ^o C (bath temperature) and with vigorous stirring, 10.3 ml (32 g, 20 mmol) of bromine are added dropwise at such a rate that it is uniformly provided and does not accumulate in the reaction mixture. Upon completion of the addition, the mixture is cooled, 20 ml of water are added, partially neutralized with dry or with sodium carbonate solution. The colorless tear oil is separated, washed with a solution of soda, water. 26.5-27 ml of crude product are obtained (98.5-100% of theory). The oil is dried with anhydrous sodium sulfate or calcium chloride, and then distilled under reduced pressure. T.kip. 77-78 ^o C / 15 mm Hg Yield 22-23 ml. For the quaternization reaction, unreacted brompinacoline can also be used.

Stage 4. Obtaining dihydrochloride of 2-tert-butyl-9-diethylaminoethylimidazo / 1,2-a / benzimidazole. To a warm, stirred solution of 27.8 g (0.12 mol) of 2-amino-1-diethylaminoethylbenzimidazole in 250-300 ml of acetone, 17.8 ml (23.4 g; 0.13 mol) of technical brompinacoline are added. The mixture is thoroughly mixed for 1-2 hours, and then left to stand at room temperature for 3-4 hours (preferably until the next day). Precipitated snow-white heavy precipitate of 2-amino-1-diethylaminoethyl-3-pivaloylmethylbenzimidazolium bromide is filtered off, washed with acetone, ether. Yield 47.2 g (95.5%). Mp 197 ^o C (decomp. From alcohol with ether).

 41 g (0.1 mol) of the resulting bromide are boiled in 250-300 ml of water until the reaction is complete, which is monitored by TLC. At the end, its solution is cooled, made alkaline with stirring with a solution of ammonia, soda or alkali to pH 9 (control universal indicator paper). The extracted oil is carefully extracted with benzene or chloroform. The extract is subjected to distillation at atmospheric pressure, using a water bath for heating, while the final compound is simultaneously dried, since the water available in the extract is removed as an azeotrope with a stripping solvent. 9-Diethylaminoethyl-2-tert-butylimidazo / 1,2-a / benzimidazole remains after distillation of the solvent from the extract in the form of a slightly yellowish clear oil. The output is almost quantitative.

The resulting oil is dissolved in 250-300 ml of acetone and 18-19 ml of conc. Are added to the solution with vigorous stirring. HCl (pH of the reaction solution 1-2). The precipitated dihydrochloride is filtered off, washed with acetone and dried in an oven at 100 ^° C. The salt yield is 36.8 g (95.8% based on the starting quaternary benzimidazolium salt).

Dihydrochloride 9-diethylaminoethyl-2-tert-butylimidazo / 1,2-a / benzimidazole (rhythmidazole) is a white or white with a light cream tint hygroscopic crystalline powder with a decomposition temperature not lower than 232 ^o C, readily soluble in water; The pH of a 2.5% solution is 2.8-3.5.

 For rhythmidazole, regulatory and technological requirements have been developed, methods of analysis for the substance necessary to identify the qualitative and quantitative characteristics of the drug, as well as its dosage forms (ampoules and tablets), have been proposed.

 A pharmacological study of rhythmidazole was carried out in in vitro and in vivo experiments in acute and chronic experiments.

 In in vitro studies, to identify changes in the refractory period of the heart muscle, the method of Ya.I. Zaydler (1967) was used, based on a change in a given frequency threshold. As a test, a preparation of an isolated rat atrium was selected, which was irritated for 15 seconds with a frequency of 3 hertz and a voltage twice the threshold (ESL-2 electrical stimulator). For a refractory period, such a concentration of a substance was taken that led to a violation of the assimilation of the imposed rhythm. The results of the studies are presented in table 1.

From the above data, it can be seen that according to the effect on the refractory period of rat atria (in M / L), rhythmidazole is 86 times higher than novocainamide, 8.1 times quinidine, and 18.6% ethmosine
The effect of rhythmidazole was studied in experiments in vivo on the refractory period of the heart muscle. To this end, its effect on the ECG of anesthetized (Nembutal 40 mg / kg, intraperitoneally) rats was investigated. The test substances were administered intravenously at a constant rate. As a unit of activity of changes in the refractory period, a dose of a substance was taken that extended the Q-T interval by 33%. The experimental results are presented in table 2.

The results of the experiments showed that the new substance is more active than ethmosine by 30.7% quinidine by 4.35 times and procainamide by 19.2 times. In this case, the therapeutic index (the ratio of the acute toxicity of LD ₅₀ in M / kg to the dose of the substance in M / kg, which lengthens the refractory period) of rhythmidazole (see Table 2) is higher than that of ethmosine and quinidine.

The following models of experimental heart rhythm disturbance were used in in vivo experiments:
ventricular fibrillation during calcium chloride intoxication of anesthetized (sodium thiopental 40 mg / kg) rats according to Malinov et al. (1956)
mixed type arrhythmia caused by aconitine (intravenous administration of aconitine nitrate in 40 μg / kg of anesthetized (Nembutal 40 mg / kg) rats),
ventricular arrhythmia with intoxication of guinea pigs with ubaine (intravenous administration of ubaine at a dose of 0.18 mg / kg to anesthetized (urethane 1 g / kg) animal),
atrial arrhythmia, caused by the application of a 0.05% solution of acotinin nitrate to the zone of the sinus node of a cat’s heart,
early postischemic fibrillation of cats ventricles,
late ischemic ventricular rhythm disturbances obtained by two-stage ligation of the left coronary artery according to the Harris method (Harris, 1950).

 The antiarrhythmic activity of rhythmidazole was compared with membrane-stabilizing antiarrhythmic substances such as novocainamide, quinidine, ethmosine, aymalin, lidocaine, β-adrenergic blocking anaprilin and calcium antagonist isoptin. Rhythm disturbances were judged by an ECG recorded in the 2nd standard lead. Rhythmidazole was administered intravenously 2-3 minutes before the arrhythmogenic substance. As a criterion of antiarrhythmic activity during calcium chloride intoxication, the minimum dose of the substance was used, which completely prevents ventricular fibrillation; in case of aconitin and oubain arrhythmias of the ventricular type, the dose in 50% of all cases prevents rhythm disturbances (calculated graphically according to Miller and Teitner); with aconitine atrial rhythm disturbances, a dose of a substance that stabilizes the work of the atria for 3 minutes. For convenience, comparing the antiarrhythmic activity of rhythmidazole with drugs used in practice, their specific effect is given in arbitrary units relative to the effect of quinidine. The results showed that in case of calcium chloride ventricular fibrillation, the studied antiarrhythmic drugs and rhythmidazole can be arranged according to their strength in the following order: rhythmidazole> isoptin aymalin> quinidine> procainamide> ethmosin, in the ratio 6.4: 3.2: 3.2: 1.0 : 0.1: 0; with ubainic arrhythmias - rhythmidazole> aymalin> quinidine> ethmosin in a ratio of 1.8: 1.4: 1.0: 0.7; with aconitine heart rhythm disturbances in rats, rhythmidazole> ethmosin> quinidine> lidocaine in a ratio of 1.7: 1.4: 1.0: 0.4; with aconitine atrial fibrillation in cats, rhythmidazole> ethmosin> quinidine in a ratio of 4.1: 2.2: 1.0.

 Early postischemic ventricular fibrillation was induced in cats under nembutal anesthesia (40 mg / kg, ip) and with mechanical ventilation. The heart in the middle third was exposed and ligated to the descending branch of the left coronary artery. Recovery after a 20-minute occlusion of blood flow led to ventricular fibrillation in 70% of the animals and death of some (40%) of the animals, spontaneous restoration of the rhythm in animals occurred after 6.8 ± 1.2 minutes. Rhythmidazole at a dose of 5 mg / kg, like isoptin at a dose of 1 mg / kg, was prevented by ventricular fibrillation when administered before reperfusion in 100% of cases.

The ventricular form of late ischemic arrhythmia was obtained by high ligation of the descending branch of the left coronary artery in dogs, which was performed under aseptic conditions under anesthesia in 2 stages with a 30-minute interval. Such ligation led after 18-24 hours to the development of cardiac arrhythmias (tachycardia, multiple ventricular extrasystole). The experiments showed (Table 3) that rhythmidazole, administered intravenously at doses of 1-10 mg / kg, eliminates ventricular disturbances by 82-100% within 6-45 minutes. At the same time, a normal sinus rhythm appeared. Tachycardia, as a rule, decreased by 16-35%
The effect of rhythmidazole on the action potential and ionic currents of the heart fiber was carried out on isolated trabeculae of the frog’s atrium (diameter 150 μR, length 5–6 mm) at a temperature of 18–20 ^° C. Rhythmidazole was studied in the concentration range 10 ^–6 –10 ^–4 . Using the method of fixing the potential on a double sucrose bridge setup, it was shown that rhythmidazole with a concentration of 1 • 10 ^-6 M and higher inhibited a slow calcium incoming current and then the outgoing potassium current (in the potential range from 0 to 40 mV from the base of the action potential) and, only starting from a substance concentration of 7 • 10 ^-6 , the fast incoming (sodium) current of the frog's atrial trabeculae was clearly blocked. Rhythmidazole was superior to calcium antagonist diltiazem in its effect on calcium current, superior to novocainamide and quinidine in its inhibition of fast (sodium) current, and quinidine in its effect on outgoing (potassium) current. Such a complex effect of rhythmidazole on transmembrane ionic currents of cardiomyocytes determines its more pronounced effect on the refractory period (lengthening the refractory period, the main mechanism of the antiarrhythmic effect of drugs) than the effects of ethmosin, quinidine, and novokainamide.

 In order to study the effect of rhythmidazole on coronary circulation and heart function in acute experiments on cats anesthetized with Nembutal, the volumetric rate of blood outflow from the coronary sinus was recorded. The experiments showed that rhythmidazole at a dose of 3 mg / kg increased the rate of blood outflow by 15-46% (compared with the initial level) lasting from 10 to 30 minutes. At the time of administration of rhythmidazole, a short-term decrease in blood pressure is observed, depending on the dose and rate of administration of the new substance. Large doses of rhythmidazole (more than 10 mg / kg), superior to antiarrhythmic, cause a decrease in blood pressure (by 20 mmHg).

 Phase blood flow in the ascending aorta was recorded in acute experiments on anesthetized cats with the electromagnetic method, followed by calculation of hemodynamic parameters and heart activity.

 Ritmidazole, when administered intravenously at doses of 1-5 mg / kg, did not alter systolic ejection and blood pressure and slightly reduced the minute volume of blood, due to its negative chronotropic effect. The proposed drug increased the time of diastolic relaxation (at a dose of 1 3 mg / kg by 25 33%), without changing the time of systolic ejection. He did not change the maximum acceleration rate of myocardial contractility, and when it was introduced at doses of 3 and 5 mg / kg, a tendency to increase this indicator of cardiodynamics was noted.

 In the study of the effect of rhythmidazole on the mechanisms of central regulation of blood circulation, it was found that rhythmidazole inhibits the central sympathetic structures. Given that emotional stress activates sympathetic reactions to the heart and, as a result, fibrillation occurs (N.V. Kaverina et al. 1981), this property of rhythmidazole is positive and can expand the indications for its use.

 In experiments on anesthetized cats and on isolated organs (segments of an isolated rectum), it was found that rhythmidazole does not have b-adrenergic blocking, anticholinergic and anticholinesterase effects.

The effect on the smooth muscles of the intestines was studied in experiments on isolated sections of the intestines of rats. It was found that rhythmidazole at a concentration of 5.8 • 10 ^-6 M / L removes half the intestinal spasm caused by the introduction of barium chloride (2 • 10 ^-4 g / L).

 The effect of rhythmidazole on neuropsychotropic status was studied in mice using a special set of tests: on the behavior of animals and their reactions to stimuli, body temperature, motor orientational activity, fear and aggression reactions, and the effects of apomorphine and phenamine. The experiments showed the presence of moderate psychostimulating properties in rhythmidazole in doses exceeding antiarrhythmic.

 With the introduction of rhythmidazole at a dose of 2-5 mg / kg (rat, dog) intravenously and 40-200 mg / kg (rat) inside, no significant changes in the general condition of animals were noted. The antiarrhythmic effect of the substance develops directly with intravenous administration and after 30 minutes with enteral administration.

 The acute toxicity of rhythmidazole was determined in mice and rats. The substance was administered intravenously (at a constant rate), intraperitoneally, enteral and subcutaneous. The experiments were carried out at room temperature. Observations of animals were carried out for 24 hours. It was found that the death of 50% of mice occurs with the introduction of rhythmidazole at a dose of 158 mg / kg intraperitoneally, 431.5 mg / kg enteral and 248 mg / kg subcutaneously. The death of 50% of rats with the introduction of rhythmidazole at a dose of 63 mg / kg intravenously and 2.8 g / kg enteral. An effective antiarrhythmic dose for rats when administered intravenously is 1.5-3 mg / kg.

 Chronic toxicity of rhythmidazole was studied for 6 months. The experiments were conducted on 125 white rats weighing 160 g and 6 dogs weighing 6-10 kg. The rhythmidazole solution was administered orally daily (once) at a dose of 40 mg / kg for 1.3 and 6 months. The control groups of animals were injected with distilled water in an equal volume. In one group of animals (rats), rhythmidazole was administered enteral at a dose (200 mg / kg), five times higher than the initial one for studying the harmlessness of the compound in high concentrations. The toxicity of rhythmidazole was evaluated by its effect on the general condition and weight gain of animals, according to the results of cytological and biochemical studies of peripheral blood and pathomorphological studies of internal organs. In addition, embryotoxic and teratogenic effects of rhythmidazole were studied in experiments on 35 white Wistar rats (23 experimental and 12 control). The latter was administered orally at a dose of 300 mg / kg once at various stages of pregnancy (1-17 days).

 The experiments showed that rhythmidazole for all periods of observation does not significantly affect the weight of animals, does not change the cytological picture of blood, the level of protein and non-protein components of the blood and urine composition in relation to the control group of animals. Rhythmidazole does not have a locally irritating effect. The drug with a single enteral administration to rats at various doses during pregnancy at a dose of 300 mg / kg does not have teratogenic and embryotoxic effects. Using indicator strains of S. typhimurium under conditions of metabolic activation by rat liver homogenate, it was found that rhythmidazole does not have mutagenic activity.

 Studies of the pharmacokinetics of rhythmidazole were carried out on white male rats weighing 250-300 g. Rhythmidazole was administered orally, intraperitoneally and intravenously. The substance content in tissues and biological fluids was determined by extraction-spectrophotometric method. An analysis of the data showed that with enteral administration, rhythmidazole penetrates well through the intestinal wall. The highest concentration of the test substance is observed in the liver (by 30 minutes), followed by a decrease and redistribution in the tissues of the brain and heart (by 60 minutes) and kidneys (by 2 3 hours). Rhythmidazole is excreted 90% through the kidneys.

 Thus, rhythmidazole is a leader in strength in the group of antiarrhythmics with membrane-stabilizing effects.

 Based on the results of studying antiarrhythmic activity and the mechanism of action of rhythmidazole, it was found that the new substance increases the absolute refractory period of the myocardium, suppresses the automatism of both the sinus node and ectopic foci of pulse generation in the atria and ventricles more efficiently than ethmosin. These effects can probably be explained by the membrane-stabilizing effect of rhythmidazole.

 In addition, rhythmidazole blocks the transmembrane ionic current of calcium, therefore, it is effective in strophanthin, calcium chloride arrhythmias and in post-reperfusion fibrillations.

 According to the mechanism of action, rhythmidazole belongs to groups I, III, and IV of antiarrhythmic drugs, but, unlike the known antiarrhythmic drugs of the above groups (each separately), it has high activity for rhythm disturbances of various genesis.

 The drug rhythmidazole in antiarrhythmic doses does not affect blood pressure and myocardial contractility, practically does not change atrioventricular and intraventricular conduction. It is effective both for intravenous and enteral administration. The proposed drug has a slight coronary expansion, antispasmodic and central sympatholytic effect. A study of the chronic toxicity of rhythmidazole with a six-month enteral administration to rats and dogs indicates its safety.

 Based on the results of experimental studies, it can be concluded that a new antiarrhythmic drug is advisable to use to stabilize the rhythm of the heart during supraventricular and ventricular tachycardia, flutter and atrial fibrillation, atrial and ventricular extrasystoles, especially due to myocardial infarction, rhythm disturbances in coronary heart disease and intoxication .

Claims (1)

The use of 9-diethylamino-ethyl-2-tert-butylimidazo (1,2-a) benzimidazole dihydrochloride of the formula

as an antiarrhythmic agent.

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