RU2469720C1 - Agent possessing antiarrhythmic and hepatoprotective properties - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to the use of 9-(2-diethylaminomethyl)-2-(3,4-dioxyphenyl)imidazo[1,2-a]benzimidazole dihydrobromide of formula

I: as an agent possessing antiarrhythmic and hepatoprotective properties. The invention also refers to the use of 9-(2-diethylaminomethyl)-2-(3,4-dioxyphenyl)imidazo[1,2-a]benzimidazole dihydrobromide for preparing pharmaceutical compositions.

EFFECT: higher antiarrhythmic and hepatoprotective activity.

2 cl, 11 tbl, 4 ex

Description

The invention relates to pharmacology, in particular to biologically active substances having cardioprotective and hepatoprotective types of activity for protecting the myocardium from various damaging factors in cardiovascular pathologies and protecting liver tissue from damage by various toxic substances.

Cardiovascular disease is the leading cause of death and disability in the population. A special place in the structure of cardiovascular pathologies is occupied by sudden death (Chazov E.I., Ruda M.Ya. Development of the main directions in the treatment of patients with myocardial infarction over the past 25 years. Cardiology, 1989, v.29, No. 11, p.11 -15), which is most often based on cardiac arrhythmias. Therefore, the search and creation of new effective agents with cardioprotective activity is an urgent task of pharmacology.

The formation of oxygen free radicals has been shown to have a damaging effect on the myocardial cell, especially with myocardial ischemia and reperfusion (Loeper J., Coy J., Bodu O. et al. Lipid peroxidation and protective enzymes during the course of myocardial infarction. Agents and actions , 1987, v. 22, p. 340-342). The most common complication of coronary heart disease is arrhythmias (Mazur N.A. Sudden death of patients with coronary heart disease. M: Medicine, 1986, 192 S.). The literature contains data on the experimental and clinical use of antioxidant drugs for heart rhythm disturbances (Kudrin AN, Smolensky BC, Kogan A.Kh. et al. Antioxidants in the treatment of experimental myocardial ischemia and coronary heart disease. Cardiology, 1988, vol. 28, No. 7, pp. 115-121). The antiarrhythmic properties of dibunol are described (Frolkis V.V., Frolkis R.A., Dubur G.Ya. et al. Antioxidants as antiarrhythmic drugs. Physiological Journal, 1986, No. 1, pp. 24-32) for arrhythmias caused by calcium chloride and adrenaline intoxication, myocardial ischemia and reperfusion, the cardioprotective effects of which are manifested in anti-ischemic myocardial protection.

However, the use of dibunol can be accompanied by paradoxical effects when its antioxidant effect is transformed into the opposite - prooxidant, with the suppression of the enzymatic antioxidant system of mitochondria, an increase in the formation of oxygen radicals, and a decrease in the functioning of the electron transfer chain in microsomes (Kahl, R. Synthetic antioxidants: Biochemical actions and interference with radiation, toxic compounds, chemical mutagens and chemical cancerogens // Toxicology. - 1984. - Vol. 33. - P.185-228.). In this connection, it is necessary to search for new drugs with a similar effect.

It is known that the severity and outcomes of various exo- and endogenous intoxications largely depend on the functional state of the liver. As a rule, functional liver failure is accompanied by metabolic disturbances, among which a change in lipid metabolism and the structural organization of hepatocyte membranes is of particular importance (Ivanov Yu.V., Matyushin IA, Mishnev OD, etc. The effect of mexidol in toxic damage liver.Vestnik of new medical technologies: periodic theoretical and scientific-practical journal. - 2003, No. 3. - P.68-70). Despite the variety of etiological factors at the subcellular level, the mechanisms of destruction of the same type are revealed, among which the processes of free radical oxidation (SRO) with the participation of reactive oxygen species (ROS) and active oxygen metabolites (AKM) play a special role. The disposal of ROS and AKM is carried out by the enzymatic and non-enzymatic antioxidant systems of the body, an important place in which is given to the glutathione reductase / glutathione peroxidase antioxidant system (Levenkova M.V., Popova T.N., Semenikhina A.V. Some regulatory properties of glucose-6-phosphate dehydrogenase from the liver rats are normal and experimental toxic hepatitis. Bulletin of the Voronezh State University. Series: Chemistry. Biology. Pharmacy. - 2004, No. 1. - P.134-138).

One of the common factors of liver damage remains intoxication with various substances. The liver is the main organ of xenobiotic metabolism and is susceptible to their toxic effects. Oxidative metabolism of substances is catalyzed by the cytochrome P450-dependent monooxygenase system and other enzymes (Pentyuk A.A., Moroz L.V., Palamarchuk O.V. Lesions of the liver by xenobiotics. Current problems of toxicology. - 2001, No. 2. - P.8- 16; Lyakhovich, VV, Vavilin VA, Zenkov NK, Menshikova EB Activated oxygen metabolites in monooxygenase reactions. Bulletin SB RAMS. - 2005, No. 4 (118). - P.7 -12). The syndrome of endogenous intoxication of the body, caused by the breakdown of hepatic parenchyma cells and the accumulation of toxic products in the pericellular space, leads to disruption of cellular metabolism and weakening of the regulatory and adaptive functions of organs and systems that cleanse the body's internal environment - the liver and lymphatic system. Hepatotoxins cause cell death by both necrosis and apoptosis. These processes are triggered, possibly by both ROS and AKM, initiating receptor-independent mechanisms, which leads to the activation of regulatory proteins that stop the mitotic activity of the cell, cause defragmentation of DNA (endonucleases), degradation of vital proteins (cascade of proteolytic enzymes, caspases), disrupt connection with the extracellular matrix (Al-Shabanah OA, El-Hadiyah TM, Mansour M.A. Effects of volatile oil constituents of Nigella Sativa against carbon tetrachloride-induced hepatotoxicity in mice: Evidence of antioxidant effects of ip administration of thymoquinone // Abstracts of the IXth International Congress of Toxicology. 8-12 July 2001, Brisbane, Australi a. Toxicology. - 2001. - V.164 (1-3). - P.1-266).

ROS and AKM can appear as a product of the catalytic cycle of cytochrome P450, nitric oxide synthase, NADPH reductase, diaphorase, and other enzymes either due to the participation of xenobiotic semiquinones in single electron transfer reactions with oxygen, or due to the activation of macrophages by xenobiotics (Pentuk A.A., Moroz L.V., Palamarchuk O.V. Lesions of the liver by xenobiotics.Modern problems of toxicology. - 2001. - No. 2. - P.8-16). The mechanism of the damaging effect of carbon tetrachloride is associated with the formation of a free trichloromethyl radical, which initiates lipid peroxidation processes in the membranes of hepatocytes, which leads to the accumulation of lipid peroxides and may be the direct mechanism of cell cytolysis (Tkachishin BC Professional toxic hepatitis. Gastroenterology, No. 14, 2003, 2003, ), p. 4-7; Levenkova M.V., Popova T.N., Semenikhina A.V. Some regulatory properties of glucose-6-phosphate dehydrogenase from rat liver are normal and experimental toxin hepatitis. Bulletin of the Voronezh State University. Series: Chemistry. Biology. Pharmacy, 2004, No. 1, p.134-138). This suggests that pharmacological substances that inhibit the processes of SRO should have hepatoprotective properties (Ivanov Yu.V., Matyushin IA, Mishnev OD and others. The effect of mexidol in toxic liver damage // Bulletin of new medical technologies : periodic theoretical and scientific-practical journal. - 2003. - No. 3. - S.68-70).

It is known that along with the traditional hepatoprotectors carlsil (silymarin) (Pradhan SC, Girish C. Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical medicine // Indian J. Med. Res. - 2006. - Vol. 124 (5) .-- P.491-504) and essentiale (Kunts E., Gunderman K.-J., Schneider E. "Essential" lipids in hepatology (experimental and clinical experience) // Therapeutic archive. - 1994. - T.66, No. 2. - P.66-72), tocopherol is used as a hepatoprotector (Falasca K, Ucciferri C, Mancino P, Vitacolonna E, De Tullio D, Pizzigallo E, Conti P, Vecchiet J. Treatment with silybin-vitamin E-phospholipid complex in patients with hepatitis C infection // J. Med. Virol. - 2008. - Vol.80 (11). - P.1900-1906).

However, its activity remains not high enough.

The technical result of the invention is to increase cardiac and hepatoprotective activity.

The technical result is achieved by a composition containing, as an active principle, 9- (2-diethylaminoethyl) -2- (3,4-dioxiphenyl) imidazo [1,2-a] benzimidazole dihydrobromide of the formula I:

taken in effective amount.

The technical result is also achieved by the use of 9- (2-diethylaminoethyl) -2- (3,4-dioxiphenyl) imidazo [1,2-a] benzimidazole dihydrobromide of the formula I as an agent exhibiting cardio and hepatoprotective activity.

Dihydrobromide 9- (2-diethylaminoethyl) -2- (3,4-dioxiphenyl) imidazo [1,2-a] benzimidazole of formula I is known as a biologically active compound exhibiting antioxidant properties (Kosolapov V.A., Spasov A.A. ., Anisimova V.A. Study of the antiradical activity of new compounds by chemiluminescence, Biomedical Chemistry, 2005, vol. 51, No. 3, p. 287-294; Anisimova V.A., Spasov A.A., Kosolapov V.A. et al. Synthesis and biological activity of 9-dialkylaminoethyl-2-hydroxy (dioxi) -phenyl-imidazo [1,2-a] benzimidazoles. Chemical-Pharmaceutical Journal, 2006, v.40, No. 10, p.3- 10). Compound I exhibits a cerebroprotective effect in radiation injuries (Vereshchagin V.K., Spasov A.A., Anisimova V.A., Senchukov I.D. Derivative of imidazo [1,2-a] benzimidazole - a drug with cerebroprotective effect in radiation lesions Pat. RF №2238938 (2004)). Compound I also revealed anti-ischemic, hemorheological and antiradical properties (Anisimova V.A., Kosolapov V.A., Minkin V.I. et al. 2- (3,4-Dihydroxyphenyl) -9-diethylaminoethylimidazo dihydrobromide [1,2 -a] benzimidazole and a pharmaceutical composition based on it, RF Patent No. 2391979 (2010)).

Among the salts of 9- (2-diethylaminoethyl) -2- (3,4-dioxiphenyl) imidazo [1,2-a] benzimidazole, compounds having cardioprotective and hepatoprotective properties are not known.

Methods for producing 2- (3,4-dihydroxyphenyl) -9-diethylaminoethylimidazo [1,2-a] benzimidazole I dihydrobromide are described in the above article and patents and involve the condensation of 1-diethylaminoethyl-2-aminobenzimidazole with 3,4-dimethoxyphenacyl bromide or 3,4-dioxiphenacyl chloride, followed by cyclization of the condensations of 1-diethylaminoethyl-3- (3,4-dimethoxy (3,4-dihydroxy) phenacyl) -2-aminobenzimidazolium halides in 48% hydrobromic acid (i.e. boiling . 127 ° C), resulting in the formation of the desired product I.

The following are examples of studies of the cardioprotective and hepatoprotective properties of this compound.

The experiments were performed on 242 white non-inbred rats weighing 180-400 g and 30 cats of both sexes weighing 2.5-3.7 kg. The animals were kept on a standard diet in vivarium conditions (temperature 22-24 ° C, relative humidity 40-50%) on a standard diet in compliance with all the rules and the International Recommendations of the European Convention for the Protection of Vertebrate Animals used in experimental studies (1997). At the time of the experiments, the animals were healthy, no changes in behavior, appetite, sleep and wakefulness were found.

1. Cardioprotective activity

It was studied on models of myocardial resistance to peroxides, calcium chloride and adrenaline arrhythmias, as well as ventricular fibrillation during coronary artery occlusion followed by myocardial reperfusion. The reference drug was the antioxidant dibunol.

Example 1. The study of myocardial resistance to peroxides

The studies were performed on 30 non-inbred white rats of both sexes weighing 185-220 g, contained in a standard diet (intact animals), or animals with systemic peroxidation syndrome contained in a semi-natural antioxidant diet developed by Voskresensky and Witt (Voskresensky O.N., Witt VV Changes in the arterial wall of rabbits with prolonged feeding of their native oxidized fat (on the issue of a cholesterol-free model of atherosclerosis). Pathology Archive, 1971, v. 33, No. 6, p. 51-55). The effect on myocardial resistance was determined according to the Didenko method (Didenko V.V. Arrhythmias caused by induction of lipid peroxidation in an isolated atrium. M., 1985, 15 pp.) Compound I (20.5 mg / kg) and the comparison drug dibunol (22 mg / kg) was administered intraperitoneally (ip) for 1 r / day for three days in isoeffective antioxidant doses equal to 100 × IEC ₅₀ calculated according to the antioxidant activity of substances in vitro on the model of ascorbate-dependent lipid peroxidation (LPO). The animals were decapitated under ether anesthesia, isolated atria were isolated, which were placed in a thermostatic bath with a volume of 33 ml, t 34 ° C with an oxygenated Krebs-Genseleit pH 7.4 solution. Atrial contractions were recorded in isotonic mode with a diastolic load of 1 g using a tensometric technique (Kovalev G.V., Spasov A.A., Simonov AM et al. Prospects and results of the search for physiologically active substances that affect the cardiovascular system, among derivatives imidazo-benzimidazoles Materials of the 3rd All-Russian symposium on the purposeful search for new physiological active substances. Riga, 1979, p.40) on the N-327-1 recorder. After 40-50 minutes, a LPO inducer of hydrogen peroxide was added to the incubation medium at concentrations from 0.1 mM to 1 M. Peroxide concentrations were determined, which caused the stopping of contractions of the isolated atria.

When studying the resistance of myocardium to the action of peroxide in animals with systemic peroxidation syndrome, it was found (Table 1) that compound I, when administered three times, significantly exceeded dibunol in the case of stopping atrial contractions when using high oxidant concentrations.

Table 1 The effect of compound I on the resistance of isolated atria of animals with systemic peroxidation syndrome to hydrogen peroxide-induced arrhythmias (M ± m) n The concentration of hydrogen peroxide ¹ , mmol The control 5 25.40 ± 2.58 Compound I 5 374.33 ± 21.89 * Dibunol 5 187.17 ± 5.36 * ¹ - the concentration of hydrogen peroxide (mmol), causing a stop of contractions of the isolated atria * - differences are statistically significant in relation to the control (p≤0,05) n is the number of animals

Example 2. Arrhythmias caused by intoxication with calcium chloride

The experiments were performed on 42 white non-inbred male rats weighing 180-230 g, anesthetized with sodium thiopental (40 mg / kg iv). Compound I (20.5 mg / kg) was administered iv for 5 minutes, and the comparison drug dibunol (22 mg / kg) was administered iv in 5% Tween-80 for 60 minutes in isoeffective antioxidant doses prior to injection calcium chloride in rats on a standard diet (intact) and animals with systemic peroxidation syndrome on an antioxidant-free diet. Calcium chloride was introduced intravenously by biological titration in doses of a logarithmic scale (Kudrin A.N., Aslanyants Zh.K. Dependence of the arrhythmogenic effect of calcium chloride on its dose in white mice and rabbits // Blood circulation. - 1974. - T.7, No. 3. - P.8-14; Muravyova TI Dependence of cardiac dysfunction on the magnitude of calcium chloride doses (model for reproducing differentiated cardiac arrhythmias) Abstract, All-Russian Congress of Pharmacists, Voronezh, 1981, p.531-532) namely 20, 25, 30, 40, 50, 63, 80, 100, 125, 158, 200, 250, 320, 398 and 501 mg / kg at a rate of 3 seconds regardless of the volume of the solution before the formation of ventricular fibrillation of the heart and the death of animals. The effectiveness of the substances was determined by increasing the resistance of the animal myocardium to a dose of calcium chloride, causing death in 100% of the animals.

It was found that compound I and dibunol increase myocardial resistance to calcium chloride arrhythmia by 37.5 and 18.5% (Table 2) in intact animals and by 56.1% and 53.9% in animals with systemic peroxidation syndrome, respectively .

table 2 The effect of compound I on rat ventricular fibrillation caused by calcium chloride intoxication (M ± m) Group of animals Dose, mg / kg Dose (mg / kg) of CaCl ₂ causing ventricular fibrillation I II The control - 334.33 ± 22.97
n = 6 292.00 ± 14.14
n = 7 Compound I 20.5 459.80 ± 20.81 *
n = 7 374.33 ± 21.89 *
n = 8 Dibunol 22.0 396.25 ± 9.68
n = 8 187.17 ± 5.36 *
n = 6 I - animals kept on a standard diet II - animals kept on a semi-natural antioxidant-free diet * - differences are statistically significant in relation to the control (p≤0,05) n is the number of experiments

Example 3. Arrhythmias caused by intoxication with adrenaline

The experiments were carried out on 30 white non-inbred rats of both sexes weighing 180-230 g, anesthetized with urethane (1 mg / kg iv). Compound I (20.5 mg / kg) was administered iv for 5 min, and the comparison drug dibunol (22 mg / kg) was administered iv in 5% Tween-80 solution 60 min before rat adrenaline injection on standard diet (intact) and animals with systemic peroxidation syndrome on an antioxidant-free diet. Adrenaline was administered iv in the method of biological titration in doses of a logarithmic scale [Kudrin, Aslanyants, 1974; Muravyova, 1981], namely 20, 25, 30, 40, 50, 63, 80, 100, 125, 158, 200, 250, 320, 398 and 501 mg / kg at a rate of 3 seconds regardless of the volume of the solution at intervals of 20 min The effectiveness of the substances was determined by increasing the resistance of the animal myocardium to a dose of adrenaline, causing death in 100% of the animals.

On the model of adrenaline intoxication, it was found that compound I and dibunol increased myocardial resistance to adrenaline intoxication by 1.6 and 1.3 times, respectively (Table 3).

Table 3 The effect of compound I on arrhythmias caused by adrenaline intoxication (M ± m) Group of animals Dose, mg / kg n Dose (mg / kg) of adrenaline causing death of rats The control - 10 210.00 ± 6.61 Compound I 20.5 10 337.20 ± 18.61 * Dibunol 22.0 10 282.00 ± 16.38 * * - differences are statistically significant in relation to the control (p≤0,05) n is the number of experiments

Example 4. Ventricular fibrillation

Ventricular fibrillation was caused by 15 min ligation of the descending branch of the left coronary artery (Penkoske PA, Sobel BE, Corr PB Disparate electrophysiological alterations accompanying disrhythmia due to coronary occlusion and reperfusion in the cat // Circulation. - 1978. - V. 58. - P. 58. 1023-1035) with subsequent restoration of blood flow. The experiments were performed on 30 cats of both sexes weighing 2.5-3.7 kg, anesthetized with sodium ethaminol (40 mg / kg iv). Compound I (20.5 mg / kg) was administered iv for 10 minutes, and the comparison drug dibunol (22 mg / kg) was administered iv in 5% Tween-80 solution 60 minutes before coronary artery occlusion.

It was found that in the control group, ventricular fibrillation occurred in the first 2-7 minutes after reperfusion of the ischemic zone in 70% of cases. Compound I and dibunol in 100% prevented the formation of fibrillation after occlusion of the coronary artery with subsequent reperfusion (table 4).

Table 4 Antiarrhythmic activity of substances during reperfusion of a cat's ischemic heart Group of animals Dose mg / kg n The frequency of fibrillation,% The death of rats,% The duration of fibrillation, min The control - 10 70.0 50,0 7.8 ± 1.41 Compound I 20.5 10 0 * 0 * - Dibunol 22.0 10 0 * 0 * - * - differences are statistically (F) significant in relation to control (p≤0,05) n is the number of experiments

2. Hepatoprotective properties

The connection of bromosulfalein with protein, the transportation of this complex and the secretion into bile resemble the biotransformation of low molecular weight substances (bilirubin, etc.). Therefore, the deterioration of clearance of bromosulfalein (BSF) from the blood is one of the earliest and most sensitive signs of impaired absorption of the liver (Khazanov A.I. Functional diagnosis of liver diseases. M: Medicine, 1988, 304 p.).

When screening for hepatoprotective activity, all studied substances improved the absorption and excretory function of the liver during CCl ₄ intoxication (Table 5). The lowest DER was found for compound I. The results obtained indicate that it exceeds tocopherol acetate, carlsil and essentiale in terms of the effect on the detoxifying function of the liver in 6.2; 9.3 and 12.9 times, respectively.

Table 5 The minimum effective doses of compounds I, tocopherol acetate, essentiale and carzil, which have a hepatoprotective effect in acute toxicity with carbon tetrachloride No. Learning Compounds MED (mg / kg) * one Compound I 0.45 2 Tocopherol acetate 2.80 3 Karsil 4.22 four Essentiale 5.81

When studying the hepatoprotective properties of compound I with a three-day prophylactic administration at a dose of 2.25 mg / kg on an acute tetrachloromethane hepatitis model, it was found that in the control group, carbon tetrachloride at a dose of 0.75 ml / kg led to disruption of the process of liver cell uptake of bromosulfalein (table. 6). Moreover, its content in serum was 18.4 times higher than in the control (p <0.05), which undoubtedly indicates significant damage to the liver parenchyma. Compound I did not affect the clearance of bromosulfalein by the cells of the intact liver, but statistically significantly normalized it in case of CCl ₄ poisoning, almost completely preventing liver damage with carbon tetrachloride.

Table 6 The effect of compound I on the performance of bromosulfalein test in acute tetrachloromethane hepatitis (M ± m) No. Groups of animals n Bromosulfalein content (extinction value) one The control 6 0.035 ± 0.004 2 Compound I (2.25 mg / kg) 6 0.040 ± 0.004 3 CCl ₄ (0.75 mg / kg) 6 0.592 ± 0.058 * four CCl ₄ + Compound I (2.25 mg / kg) 6 0.045 ± 0.002 ** * - values are statistically significant in relation to the control (p <0.05) ** - values are statistically significant to the action of CCl ₄ (p <0.05) n is the number of animals

Hexenal test reflects the metabolic function of hepatocyte microsomes. This indicator, along with the BSF load, is the most important indicator of hepatosuppressive syndrome (Pentyuk A.A., Moroz L.V., Palamarchuk O.V. Liver lesions by xenobiotics. Current problems of toxicology, 2001, No. 2, pp. 8-16).

When performing a test with hexenal under the influence of carbon tetrachloride, as in the previous sample, significant deviations from the norm were found. So, the duration of sleep caused by hexenal in animals with acute hepatitis increased by 2.8 times (p <0.05) compared with the control (Table 7).

Compound I did not affect the duration of sleep in intact rats and significantly reduced it in rats with hepatitis, reliably shortening the duration of sleep by 1.9 times.

Table 7 The effect of compound I (4.5 mg / kg) on the duration of hexenal sleep in acute tetrachloromethane hepatitis (M ± m) No. Groups of animals n Hexenal sleep, min. one The control 10 17.7 ± 1.98 2 Compound I (4.5 mg / kg) 10 16.8 ± 4.69 3 CCl ₄ (2.0 ml / kg) 10 155.7 ± 14.23 * four CCl ₄ + Compound I (4.5 mg / kg) 10 81.2 ± 9.42 * + * - data are statistically significant (p <0.05) in relation to the control + - data are statistically significant (p <0.05) in relation to the action of CCl ₄ n is the number of animals

An increase in blood activity of AlAT, AsAT, LDH, hepatocyte-specific enzymes, is considered as a manifestation of the cytolytic syndrome, while hyperfermentemia of alkaline phosphatase is characteristic of cholestatic syndrome (Khazanov, 1988).

When studying the activity of liver-specific enzymes in blood serum, acute toxic hepatitis was caused by the introduction of a 50% oil solution of carbon tetrachloride in a dose of 2.5 ml / kg. The entrainment of the seed dose of CCl ₄ in comparison with the previous series is due to the fact that only in this case hyperfermentemia was detected. After 24 hours, the animals were killed and investigated the activity of enzymes. CCl ₄ when administered once at a dose of 2.5 ml / kg causes an increase in the activity of AlAT and AsAT in the blood serum by 5.2 and 5.1 times (p <0.05), respectively, compared with the control (table 8). In addition, under its action, the activity of LDH (Table 9) and ShchD (Table 10) increased statistically significantly 6.7 times, respectively. That is, 24 hours after seeding with carbon tetrachloride in animals, pronounced hyperenzymemia AlAT, AsAT and LDH was observed - the most important sign of hepatocytolysis, as well as alkaline phosphatase - a sign of cholestasis.

Table 8 The effect of compound I (2.25 mg / kg) on the activity of alanine aminotransferase (AlAT) and aspartate aminotransferase (AcAT) in blood serum in acute tetrachloromethane hepatitis (M ± m) No. Groups of animals n AlAT activity, µmol / ml / h Activity AsAT, mol / ml / hour one The control 9 1.14 ± 0.19 1.67 ± 0.20 2 Compound I (2.25 mg / kg) eleven 1.27 ± 0.26 1.60 ± 0.20 3 CCl ₄ (2.5 ml / kg) 6 6.0 ± 0.20 * 8.58 ± 1.04 * four CCl ₄ + Compound I (2.25 mg / kg) 6 4.52 ± 0.22 + 5.59 ± 0.69 * + * - data are statistically significant (p <0.05) in relation to the control + - data are statistically significant (p <0.05) in relation to the action of CCl ₄ n is the number of animals

Table 9 The effect of compound I (2.25 mg / kg) on the activity of lactate dehydrogenase (LDH) in rat blood serum in acute tetrachloromethane hepatitis (M ± m) No. Groups of animals n LDH activity, U / L one The control 9 74.76 ± 8.15 2 Compound I (2.25 mg / kg) eleven 89.69 ± 1.55 3 CCl ₄ (2.0 ml / kg) 6 501.23 ± 19.18 * four CCl + Compound I (2.25 mg / kg) 6 351.69 ± 47.64 * + * - data are statistically significant (p≤0,05) in relation to the control + - data are statistically significant (p≤0,05) in relation to the action of CCl ₄ n is the number of animals

Table 10 The effect of compound I (2.25 mg / kg) on the content of alkaline phosphatase (ALP) in blood serum in acute tetrachloromethane hepatitis (M ± m) No. Groups of animals n The activity of alkaline phosphatase, units / l one The control 6 66.1 ± 2.40 2 Compound I (4.5 mg / kg) 6 71.3 ± 3.30 3 CCl ₄ (1.0 ml / kg) 6 224.6 ± 2.60 * four CCl ₄ + Compound I (4.5 mg / kg) 6 140.3 ± 1.70 * + * - data are statistically significant (p <0.05) in relation to the control + - data are statistically significant (p <0.05) in relation to the action of CCl ₄ n is the number of animals

Compound I did not affect the activity of these enzymes in the blood serum of control animals and reduced hyperfermentemia in acute hepatitis. In animals exposed to CCl ₄ , under the influence of I, the activity of AlAt, AsAT (Table 8), LDH (Table 9), and ALP (Table 10) decreased by 25, 35, 30, and 38% (p <0.05 ) respectively.

Thus, CCl _4, when administered once at a dose of 2.5 ml / kg, caused the development of cytolysis phenomena in the liver, the manifestation of which is hyperenzyme. Compound I, when prophylactically administered for three days, does not affect the structure of hepatocytes, but significantly reduces their damage by carbon tetrachloride.

Less pronounced CCl ₄ affected the metabolic functions of the liver. This, in principle, is consistent with the idea that indicators such as total protein and glucose in the blood change only with massive lesions of the hepatic parenchyma and then, usually, after a long time (Khazanov, 1988).

The protein content (Table 11) a day after seeding of animals decreased by 19.2% (p> 0.05), and the performance of the zinc-sulfate sample increased by 27.7% (p> 0.05). Although these changes were trendy, they obviously indicate that the amount of albumin synthesized in the liver decreases in serum and the content of γ-globulins increases (Tugarinova V.N., Miklashevsky V.E. Modeling, methods of study and experimental therapy of pathological processes. - M., 1967. - S.262-265), and this indicates the development of a mesenchymal-inflammatory syndrome in the liver. In addition, in these animals, blood glucose decreased by 21.6% (p> 0.05), which is considered a sign of hepatosuppressive syndrome.

Table 11 The effect of compound I (4.5 mg / kg) on the performance of the zinc sulfate test, the protein and glucose levels in blood serum in acute tetrachloromethane hepatitis (M ± m) No. Groups of animals n Zn ₂ SO ₄ test, Unit turbidity Protein, gr% Glucose, mg% one The control 6 2.88 ± 0.32 8.61 ± 0.64 18.52 ± 1.13 2 Compound I (4.5 mg / kg) 7 2.68 ± 0.12 8.61 ± 0.34 18.95 ± 2.34 3 CCl ₄ (2.0 ml / kg) 6 3.68 ± 0.36 6.96 ± 0.54 14.52 ± 1.56 four CCl ₄ + Compound I (4.5 mg / kg) 10 3.01 ± 0.21 7.36 ± 0.13 16.39 ± 1.91 n is the number of animals

Compound I did not affect these parameters in control animals and stabilized them in rats with toxic hepatitis (Table 11).

Conclusion

1. Compound I has a pronounced cardioprotective activity in models of myocardial resistance to peroxides, calcium chloride and adrenaline arrhythmias, ventricular fibrillation during postischemic myocardial reperfusion, not inferior to or superior to the comparison drug dibunol.

2. Compound I significantly improves the absorption and excretory function of the liver and improves its detoxification abilities in acute toxic hepatitis. Compound I, when administered prophylactically in acute toxic hepatitis, exhibits pronounced hepatoprotective properties. Under its influence, the development of signs of cytolytic, hepatosuppressive and mesenchymal-inflammatory, cholestatic syndrome is significantly inhibited, and detoxification functions of the liver are improved. Compound I is superior to tocopherol acetate in terms of its effect on the detoxification function of the liver in 6.2.

Thus, the proposed tool can be used in the manufacture of pharmaceutical compositions having antiarrhythmic and hepatoprotective properties.

Claims (2)

1. The use of 9- (2-diethylaminoethyl) -2- (3,4-dioxiphenyl) -imidazo [1,2-a] benzimidazole dihydrobromide of the formula I:

as an agent with antiarrhythmic and hepatoprotective properties. 2. The use of 9- (2-diethylaminoethyl) -2- (3,4-dioxiphenyl) imidazo [1,2-a] benzimidazole dihydrobromide according to claim 1 for the manufacture of pharmaceutical compositions having antiarrhythmic and hepatoprotective properties.