RU2404974C2 - 1-(β-PHENYLETHYL)-4-AMINO-1,2,4-TRIAZOLIUM BROMIDE (MT) - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: there is described a new compound - 1-(β-phenylethyl)-4-amino-1,2,4-triazolium bromide exhibiting cardioprotective, anti-ischemic, antihypertensive, antioxidant, protein synthetic and energotropic action.

EFFECT: improved clinical effectiveness.

1 cl, 5 ex, 4 tbl

Description

The invention relates to medicine and pharmacy, in particular, to the creation of a new biologically active compound, which is an active basis for the creation of drugs with a wide range of pharmacological effects.

One of the urgent tasks of medicine and pharmacy is the development of means for the prevention and treatment of diseases of the cardiovascular system. Coronary heart disease, and especially myocardial infarction, are the leading cause of mortality in Ukraine and the countries of the European Union and North America [Kovalenko VN, 2004].

Intensive care in the acute and acute period of myocardial infarction seems to be the most difficult and important cardiology problem. The acute period of myocardial infarction, which lasts 2-3 hours, is the most difficult and short-term; the second - an acute period - lasts from 2 to 14 days. Therefore, the faster and more effective the pharmacological effect of drugs used in the first and second periods of a heart attack will be manifested, the more effective its treatment will be.

In the acute period of myocardial infarction, β-blockers are used, one of which is the “hybrid” - (α + β) blocker of the latest generation - carvedilol [Mashkovsky M. D. Medicines. - M.: New Wave, 2008.- P.275]. Carvedilol has a beneficial effect on intracardiac and regional hemodiamics, normalizes the oxygen regime of the myocardium in conditions of ischemia, and has an antioxidant effect. Carvedilol is taken by us as an analogue in pharmacological action.

The disadvantage of carvedilol is the absence or insignificant cardioprotective effect in the acute and acute periods of myocardial infarction, as well as a mild energetic effect [Rylova AK, Rozanov AV Therapy with β-blockers in special patient groups (review of the analysis results in the subgroups of the CIBIS 11, COMET, COPER-NICUS.MERIT HF studies) // Heart. - 2003. - No. 4. - S.190-196]. A significant drawback of carvedilol, limiting its use, is the occurrence of a number of adverse reactions from various organs and systems. Nervous system: loss of consciousness, depression, sleep disturbance, paresthesia are possible. Cardiovascular system: bradycardia, orthostatic hypotension, atrioventricular block II-III art., Rarely - peripheral circulatory disturbance, progression of heart failure (with increasing doses), edema of the lower extremities, angina pectoris, marked decrease in blood pressure, exacerbation of the syndrome of “intermittent” lameness and Raynaud's syndrome. Digestive tract: dry mouth, nausea, diarrhea or constipation, vomiting, abdominal pain, loss of appetite, increased activity of “liver” transaminases. Metabolism: weight gain and hypercholesterolemia; in patients with pre-existing diabetes mellitus - hyperglycemia or hypoglycemia, decompensation of carbohydrate metabolism. Allergic reactions: skin allergic reactions, exacerbation of psoriasis. From the respiratory system: shortness of breath and bronchospasm (in predisposed patients). Other: visual impairment, decreased lacrimation, flu-like syndrome, sneezing, myalgia, arthralgia, pain in the extremities, “intermittent” claudication, rarely - urination impairment, impaired renal function [Instructions for use of carvedilol]. [Mashkovsky M.D. Medicines - M .: New wave, 2008. - P.275].

The biologically active compound “1- (β-Phenylethyl) -4- (p-dimethylaminobenzylideneamino) -1,2,4-triazolium bromide possessing antioxidant, anti-ischemic, β-adrenoblocking, uterotonic and intraocular pressure-reducing action” (working name “ Trianol ") [Patent of Ukraine No. 28494, IPC7 C07D 249/08, АКК 31/41. 05/12/97 / 01/15/2002 // Promislova Vlasnist. - 2001. - No. 1. C.3.43]. Preclinical studies have shown that trianol, administered in doses of 1-5 mg / kg to animals with experimental myocardial infarction, reduces the area of myocardial necrosis, improves ECG, normalizes energy metabolism, and activates the antioxidant system of cardiomyocytes on the 3rd day of the experiment. With the introduction of trianol at a dose of 10-30 mg / kg to animals with spontaneous hypertension, blood pressure decreases.

Trianol is taken as the closest structural analogue of the claimed biologically active substance.

However, trianol does not have a rapid and pronounced cardioprotective effect in the acute and acute periods of myocardial infarction, which greatly complicates its use in intensive care of cardiovascular diseases.

The basis of the invention is the task of creating an effective biologically active substance that surpasses known analogues in spectrum and degree of activity and ensures the production of pharmacologically active drugs for the treatment of myocardial infarction in the initial - acute and acute - periods of its development.

The solution to this problem provides a biologically active substance - 1 - (β-phenylethyl) -4-amino-1,2,4-triazolium bromide of the formula

possessing cardioprotective, anti-ischemic, antihypertensive, antioxidant, protein-synthetic and energetic action.

The working name of the drug is MT.

The claimed biologically active substance differs from the nearest structural analogue in that the claimed substance is 1 - (β-phenylethyl) -4-amino-1,2,4-triazolium bromide in chemical structure, and the closest structural analogue is characterized in that the amino group at position 4 is blocked by the residue of p-dimethylaminobenzaldehyde.

The pharmacological effect of the use of the invention.

Administration of MT in doses of 1-5 mg / kg, and especially in an optimally effective dose of 2 mg / kg, which is 1/86 of LD ₅₀ , in the acute period of myocardial infarction leads to a decrease in the degree of damage to cardiomyocytes, starting from 15 minutes of experimental development pathology, as well as to reduce the death of cardiomyocytes, inhibition of free radical processes, activation of adaptive protein synthesis, lowering blood pressure, improving myocardial energy metabolism, improving electrocardiography. The use of MT in the acute period of myocardial infarction in terms of therapeutic effect exceeds the effectiveness of the basic therapy - an analogue in the pharmacological action of carvedilol and a structural analogue of trianol. Administration of MT in doses of 10-50 mg / kg, and especially in an optimally effective dose of 30 mg / kg, which is 1/6 of LD ₅₀ , in animals with spontaneous hypertension leads to a decrease in blood pressure 30 minutes after injection of the drug. By the strength of the antihypertensive effect, the MT preparation is superior to the effectiveness of the basic therapy - an analogue in the pharmacological action of carvedilol and a structural analogue of trianol.

The invention and its advantages over known analogues are illustrated by the following examples of preclinical animal studies and the results of these studies are presented in tables.

To illustrate the implementation of this invention, we give examples of the preparation of the claimed substance and its pharmacological activity.

Example 1. Synthesis of 1 - (β-phenylethyl) -4-amino-1,2,4-triazolium bromide

The synthesis is carried out in a four-necked flask with a capacity of 0.5 l, equipped with a stirrer, thermometer, reflux condenser and dividing funnel with a capacity of 0.25 l.

42.04 g (0.5 mol) of 4-amino-1,2,4-triazole and 120 ml of isopropanol are charged into the flask and heated to 70 ° C. until 4-amino-1,2,4-triazole is completely dissolved. To the resulting solution was added dropwise a solution consisting of 93.45 g (0.505 mol) of β-bromoethylbenzene in 100 ml of isopropanol. Then the reaction mass is heated to boiling (83-85 ° C) and boiled for 8 hours. After which the reaction mass is cooled with periodic stirring, first in air to room temperature, and then in an ice bath to 5-6 ° C. The precipitated crystalline precipitate is filtered off, carefully squeezed out and washed on the filter twice with 10 ml of chilled isopropanol or acetone.

The yield of the target product is 123.8 g (98% of theory).

White crystalline powder with a slightly yellowish or greenish tint is soluble in water, soluble in methanol, 95% ethanol, DMF, insoluble in ether, acetone. Melting point 102-107 ° C (melts within 2 ° C).

Found,%: C 44.48; H 4.90; Br 29.65; N, 20.81.

Gross formula: C ₁₂ H ₁₃ BrN ₄ .

Calculated,%: C 44.63; H 4.87; Br 29.69; N, 20.81.

IR Spectrum: 3389; 3280 cm ^-1 (symmetric and asymmetric stretching vibrations of NH ₂ 3025 cm ^-1 (ν CH of the aromatic nucleus); 1631 cm ^-1 (ν C = H bond of the heterocyclic nucleus).

Example 2. Cardioprotective and anti-ischemic activity of the drug MT

The cardioprotective and anti-ischemic activity of MTs was studied using a model of sequential occlusion of the left descending and left envelope of the coronary artery in Wistar rats weighing 220-240 g, obtained from the nursery of the Institute of Pharmacology and Toxicology of the Academy of Medical Sciences of Ukraine. Coronary artery occlusion was performed under thiopental anesthesia (40 mg / kg) by applying silk ligature [2,8]. MT, trianol was administered at a dose of 2 mg / kg intraperitoneally 15 minutes before ligation. Venous blood was collected from experimental animals after 15 minutes, 60 minutes and 120 minutes. In the blood serum, the activity of the cardiospecific isoenzyme MV-KFK was determined (determined by the Warburg optical test after chromatographic separation) [7, 8].

With coronary occlusion, acute ischemia occurs, cardiomyocytes die and the cardiospecific isoenzyme of creatine phosphokinase MV-KFK is released into the blood serum, as evidenced by an increase in its activity by 17%, 52%, 75%, 102%, respectively, 15, 30, 60, 120 min after overlapping ligatures.

Table 1 The effect of MT and comparison drugs on the activity of the marker enzyme MV-CPK (mmol / l / h) in the acute period of myocardial ischemia caused by coronary artery occlusion in rats Observation groups and number of animals Occlusion time 15 minutes 30 minutes 60 min 120 min Intact
n = 5 0.04 ± 0.001 0.04 ± 0.002 0.04 ± 0.001 0.04 ± 0.002 Occlusion (control)
n = 5 0.047 ± 0.001
(+ 17%) 0.061 ± 0.003
(+ 52%) 0.070 ± 0.002
(+ 75%) 0.081 ± 0.002
(+ 102%) MT
n = 5 0.04 ± 0.001 * #
(-fifteen%) 0.042 ± 0.002 * #
(-32%) 0.052 ± 0.002 *
(-26%) 0.058 ± 0.002 *
(-28%) Trianol
n = 5 0.046 ± 0.001
(-2%) 0.051 ± 0.002 *
(-17%) 0.058 ± 0.003 *
(-eighteen%) 0.064 ± 0.002 *
(-twenty%) Note: * - significance of differences (p <0.05) in relation to the control group, # - significance of differences (p <0.05) in relation to the trianol group

As can be seen from the data presented in table 1, the claimed drug MT shows a pronounced cardioprotective effect in occlusion of the descending coronary artery. So, for 15, 30, 60 and 120 min after coronary occlusion, the MT preparation reduced MV-KFK hyperenzymemia by 15%, 32%, 26% and 28%, and trianol - by 2%, 17%, 18% and 20%, respectively.

The advantage of the use of the MT drug was that it had the appearance of a reliable cardioprotective effect was observed already from 15 minutes after occlusion, with the most pronounced effect for 30 minutes of occlusion.

A reliable cardioprotective effect of trianol showed from 30 minutes after occlusion, which was 15% less effective than a similar effect from the use of the drug MT during this period of time. The cardioprotective effect of trianol was inferior in strength to the effect of the MT preparation at 60 and 120 min of observation by 8%.

Thus, the MT preparation has a reliable cardioprotective effect in the acute period of myocardial ischemia, significantly superior to the action of trianol not only in strength of the main effect, but also in the time of its manifestation, which is a clear advantage of the claimed drug.

Example 3

Cardioprotective, antioxidant and protein-synthetic activity of the drug MT

The cardioprotective, antioxidant, and protein-synthesizing activity of the MT preparation was studied in a model of acute myocardial infarction in Wistar rats weighing 200-230 g, which was induced by the administration of isadrin and pituitrin. Small focal myocardial infarction was modeled by the administration of pituitrin (1U / kg) subcutaneously, and then isadrin (200 mg / kg) intramuscularly for 3 days [2, 3, 8]. The inventive preparation MT, trianol and carvedilol was administered at a dose of 2 mg / kg intraperitoneally for 3 days, in parallel with the formation of myocardial infarction. These types of activity were judged by reducing the product of oxidative protein modification (OMB) - carboxyphenylhydrazide (CPH) (determined spectrophotometrically by reaction with 2,4-dinitrophenylhydrazine) [10]; the RNA content in the cytoplasm of cardiomyocytes and the density of the nuclei of cardiomyocytes per unit area (after staining myocardial sections with halocyanine-chromium alum according to Einarson) [9] and morphometric analysis using an Axioskop microscope. Simulation of myocardial infarction led to the accumulation in the heart tissue of a marker product of oxidative protein modification - CPG by 213%, which reflects the activation of free radical processes; a decrease in the density of cardiomyocyte nuclei by 4%, which indicates cell death and a decrease in their RNA content by 23%, indicating a violation of protein synthesis processes.

table 2 The effect of MT on the death rates of cardiomyocytes, the activity of protein synthesis and the intensity of free-radical processes in acute myocardial infarction Surveillance Groups and Quantity Indicators CFG, cu / g protein RNA, E on The density of nuclei per 1 mm ^{2 of} the myocardium Intact (n = 5) 12.33 ± 1.78 0.098 ± 0.001 8116 ± 221 Heart attack (control) (n = 5) 38.6 ± 2.22
(+ 213%) 0.076 ± 0.001
(-23%) 7832 ± 285
(-four%) MT (n = 5) 17.2 ± 1.00 * + ^#
(-55.4%) 0.117 ± 0.001 * + ^#
(+ 54%) 9511 ± 166 * + ^#
(+ 21.5%) Trianol (n = 5) 21.4 ± 1.11 * +
(-45.4%) 0.115 ± 0.001 *
+ (+ 51%) 9326 ± 296 * +
+ (+ 19%) Carvedilol (n = 5) 27.3 ± 1.33 *
(-29.0%) 0.098 ± 0.001 *
(+ 28%) 8706 ± 151 *
(+ 11%) Note: * - significance of differences (<0.05) in relation to the control group, # - significance of differences (p <0.05) in relation to the trianol group, + - significance of differences (p <0.05) in relation to the group carvedilol

As can be seen from the data presented in table 2, the introduction of the MT preparation had a pronounced antioxidant effect, as evidenced by a statistically significant decrease in CPH accumulation in the myocardium by 55.4% after modeling myocardial infarction, compared with comparison groups. The introduction of trianol had a less pronounced effect (reduction of CFG by 45.4%), and the administration of carvedilol reduced this indicator by 29.0%. The MT preparation had a protein-synthetic effect, as evidenced by an increase in RNA in the cytoplasm of cardiomyocytes by 54%, the introduction of comparison drugs - trianol and carvedilol - had a significantly worse effect (RNA increase by 51% and 28%, respectively). The introduction of the drug MT led to a decrease in the death of cardiomyocytes, as evidenced by an increase in the density of nuclei of cardiomyocytes by 21.5%. Comparison preparations trianol and carvedilol had a less pronounced effect (an increase in the sought-for indicator was observed by 19% and 11%, respectively).

Thus, the MT preparation has a more pronounced antioxidant, cardioprotective and protein-synthetic effect than in trianol and carvedilol in the conditions of an acute period of myocardial infarction, which is a clear advantage of the use of the claimed drug.

Example 4. Cardioprotective, anti-ischemic and energetic activity of MT

The cardioprotective, anti-ischemic, and energotropic activity of the MT preparation was studied on the model of acute myocardial infarction in Wistar rats weighing 220-230 g, which was caused by the administration of isadrine and pituitrin. Small focal myocardial infarction was modeled by the administration of pituitrin (1 U / kg) subcutaneously, and then isadrin (200 mg / kg) intramuscularly for 3 days [2, 3, 8]. The inventive preparation (MT), trianol and carvedilol was administered at a dose of 2 mg / kg intraperitoneally for 3 days in parallel with the formation of myocardial infarction. These types of activity were judged by a decrease in the serum activity of the cardiospecific isoenzyme of MV-CPK creatine phosphokinase (determined by the Warburg optical test after chromatographic separation [8], by a decrease in the total degree of ST segment shift relative to the isoline (Σ _Δ ST) (determined by electrocardiography) [2 , 8], as well as to increase the level of ATP in the myocardium (determined spectrophotometrically) [4].

Table 3 The effect of the MT preparation and comparison drugs on ischemia indicators, bioenergetics of the heart muscle in experimental myocardial infarction Observation groups and number of animals Indicators MV-KFK, mmol / l / h (∑ _Δ ST) (μV) ATP, μm / g Intact group
n = 5 0.05 ± 0.005 0 3.38 ± 0.253 Heart attack (control)
n = 5 0.22 ± 0.02
(+ 340%) 225 ± 21 2,30 ± 0,14
(-32%) MT
n = 5 0.068 ± 0.01 * + ^#
(-70%) 23 ± 13 * + ^# 3.10 ± 0.14 * + ^#
(+ 34.7%) Trianol
n = 5 0.092 ± 0.02 *
+ (- 58%) 34 ± 21 * + 2.98 ± 0.14 *
+ (+ 29.5%) Carvedilol
n = 5 0.12 ± 0.02 *
(-46%) 64 ± 21 * 2.68 ± 0.11 *
(+ 16.5%) Note: * - significance of differences (p <0.05) in relation to the control group, # - significance of differences (p <0.05) in relation to the trianol group, + - significance of differences (p <0.05) in relation to carvedilol group

Modeling of myocardial infarction led to the development of energy deficiency, as evidenced by a decrease in the level of ATP in the myocardium by 32%; the appearance of ischemic changes in heart tissues, which was expressed in an increase in the total degree of ST segment shift relative to the isoline (∑ _Δ ST) on the electrocardiogram by 225 ± 21 μV and a violation of the integrity of the membranes of cardiomyocytes, as evidenced by an increase in the serum activity of the cardiospecific creatine phosphokinase isoenzyme -MB- CPK by 340%, compared with the intact group. As can be seen from the data presented in table 3, the MT preparation has a pronounced energotropic effect and, against the background of modeling a heart attack, increased the level of ATP in the myocardium by 34% (administration of drugs comparing trianol and carvedilol led to an increase in ATP by 29.5% and 16.5% respectively). The administration of MT to animals in the acute period of myocardial infarction had a statistically significantly more pronounced cardioprotective effect compared to the comparison drugs, which was judged by a 70% decrease in MV-KFK (the comparison drug trianol reduced MV-KFK activity by 58%, and the administration of carvedilol by 46%). The administration of the MT preparation to animals with myocardial infarction in the acute period had a pronounced anti-ischemic effect, as evidenced by a decrease in the total degree of ST segment displacement relative to the isoline (∑ _Δ ST) to 23 ± 13 μV (the introduction of trianol reduced this myocardial ischemia to 34 ± 21 μV and the administration of carvedilol is up to 64 ± 21 μV (p <0.05)).

Example 5

Antihypertensive activity of the drug MT

Studies of the antihypertensive effect of the MT preparation were carried out on rats of the NICAH line with spontaneous arterial hypertension weighing 260 ± 5 g. The MT preparation, trianol and carvedilol were administered intraperitoneally in the same dose of 30 mg / kg. Blood pressure was measured 30 minutes, 1, 3 and 6 hours after administration of drugs on the caudal artery using a plethysmograph.

Table 4 The effect of the MT preparation and comparison drugs on blood pressure (BP) indices in spontaneously hypertensive rats, mmHg Observation groups and number of animals The level of PD in terms of observation HELL
source HELL
after 30 min HELL
after 1 h HELL
after 3 hours HELL
after 6 hours Hypertension Rats
(control) n = 5 163 ± 2 167 ± 7 165 ± 5 166 ± 3.1 164 ± 2.5 Rats with hypertension + MT
(n = 8) 159 ± 1.4 133 ± 2.4 * ^{# +}
(-16.4%) 139 ± 1.8 *
(- 12.6%) 139 ± 1.2 *
(-12.6%) 156 ± 1.4 Rats with hypertension + trianol
(n = 8) 155 ± 2.5 142 ± 3
(-8.4%) 140 ± 3.8 *
(-9.6%) 142 ± 1.2 *
(-8.4%). 156 ± 1.4 Rats with hypertension + carvedilol
(n = 8) 169 ± 3.9 163 ± 3.0
(-3.6%) 155 ± 4.0 *
(-8.3%) 148 ± 4.7 *
(-12.5%) 169 ± 4.3 Note: * - significance of differences (p <0.05) in relation to the control group, # - significance of differences (p <0.05) in relation to the trianol group, + - significance of differences (p <0.05) in relation to carvedilol group

In spontaneously hypertensive rats (control), the blood pressure practically did not change throughout the experiment.

Administration to the rats with spontaneous hypertension of the MT preparation at a dose of 30 mg / kg led to a significant decrease in blood pressure by 16.4% within 30 minutes after administration. Moreover, during this observation period, the MT preparation was significantly superior in strength of antihypertensive effect to trianol and carvedilol. Over the next 3 hours, the MT preparation provided a stable reliable decrease in blood pressure by 12.6%, which exceeded the antihypertensive effect of trianol and carvedilol in strength. 6 hours after the administration of MT, a decrease in its antihypertensive effect was observed. Trianol slightly decreased blood pressure after 30 minutes. A significant decrease of this parameter by 9.7% was observed only 1 hour after the injection of the drug. The antihypertensive effect of trianol persisted for the next 3 hours after administration (a decrease in blood pressure by 8.4%), but was significantly weaker than a similar effect after the use of the drug MT. Carvedilol slightly decreased blood pressure 30 minutes after administration. A significant antihypertensive effect was recorded 1 hour after the injection of the drug (decrease in blood pressure by 8.3%). The maximum antihypertensive effect of carvedilol, comparable with the effect of the MT drug, was observed 3 hours after drug administration (blood pressure reduction by 12%). 6 hours after the administration of carvedilol, its antihypertensive effect disappears.

Thus, the claimed MT preparation has a significantly more pronounced antihypertensive effect than that of trianol and carvedilol, the maximum manifestation of which occurs faster than in comparison preparations 30-120 minutes after administration of HICAG to rats and lasts up to 6 hours of observation.

Summarizing the results of the use of the MT preparation, an analogue in the pharmacological action of carvedilol and trianol, the closest structural analogue, the following conclusion can be drawn.

Under conditions of sequential occlusion of the left descending and left envelope of the coronary artery in Wistar rats, the MT preparation at a dose of 2 mg / kg has a reliable cardioprotective effect in the conditions of the acute period of myocardial ischemia, preventing the death of cardiomyocytes and reducing the level of MV-KFK hyperenzyme by 15%, 32% , 26% and 28%, with the most pronounced effect for 30 min of occlusion, significantly exceeding the action of trianol not only in the strength of the main effect, but also in the time of its manifestation.

Under the conditions of modeling the pituitrin-isadrine model of myocardial infarction, the MT preparation at a dose of 2 mg / kg significantly reduced the level of marker product of oxidative protein modification, CPH, in the heart tissue, thereby exerting an antioxidant effect one and a half times higher than that of trianol and two times higher than carvedilol; had a pronounced anti-ischemic effect, manifested in a decrease in the total degree of ST segment shift relative to the isoline (∑ _Δ ST) to 23 ± 13 μV (the introduction of trianol reduced this indicator of myocardial ischemia to 34 ± 21 μV, and carvedilol to 64 ± 21 μV); showed a pronounced energetic effect, increasing the level of ATP in the myocardium by 34% (administration of drugs comparing trianol and carvedilol led to an increase in ATP by 29.5% and 16.5%, respectively); increased the RNA content in the cytoplasm of cardiomyocytes by 54%, exerting a protein-synthetic effect, which is significantly higher than after the use of trianol and carvedilol (RNA increase by 51% and 28%, respectively); showed the maximum cardioprotective effect compared to analogues, preventing the death of cardiomyocytes, and reduced the level of MV-CPK by 70% (trianol reduced the activity of MV-CPK by 58%, and carvedilol by 46%).

The inventive MT preparation at a dose of 30 mg / kg has a significantly more pronounced antihypertensive effect than that of trianol and carvedilol, the maximum manifestation of which occurs faster than in comparison preparations 30-120 minutes after administration of HISAG spontaneously hypertensive rats.

The data on the pharmacological effects of the drug MT, trianol and carvedilol are evidence of the clear advantage of using the claimed drug.

Another advantage of MT is its lower toxicity compared to trianol. So, the LD ₅₀ of MT is 172 mg / kg when administered intraperitoneally to rats, and the LD _{50 of} trianol is 112 mg / kg.

As can be seen from the above results of preclinical studies of the effectiveness of the claimed biologically active substance, 1 - (β-phenylethyl) -4-amino-1,2,4 triazolium bromide (MT preparation) in the treatment of myocardial infarction in acute and acute periods and arterial hypertension in terms of effectiveness use significantly exceeds in all respects the efficiency of using for the same purpose known means and the closest structural analogue.

This determines the advisability of patent protection of the claimed substance and the development of specific dosage forms based on it for the treatment of myocardial infarction, in particular, in its initial periods, as well as for its prevention.

Information sources

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Claims (1)

1- (β-Phenylethyl) -4-amino-1,2,4-triazolium bromide of the formula

possessing cardioprotective, anti-ischemic, antihypertensive, antioxidant, protein-synthetic and energetic action.