RU2248206C1 - Medicinal preparation for treatment of chronic cardiac insufficiency - Google Patents

Abstract

FIELD: organic chemistry, medicine, cardiology, pharmacy.

SUBSTANCE: invention relates to a medicinal preparation used in treatment of chronic cardiac insufficiency. The preparation represents 3-methyl-5-[2-(3-tert.-butylamino-2-oxypropoxy)- phenoxymethyl]-1,2,4-oxadoazole hydrochloride. The preparation provides expanding assortment of medicinal agents used in treatment of chronic cardiac insufficiency.

EFFECT: valuable medicinal properties of drug.

5 tbl

Description

The invention relates to medicine and relates to the use of 3-methyl-5- / 2- (3-tert-butylamino-2-hydroxypropoxy) phenoxymethyl / 1,2,4-oxadiazole hydrochloride of the formula I as a medicament for chronic heart failure.

Compound I was previously known as a biologically active compound with β- and α-adrenergic blocking properties (1), as well as a drug that has antihypertensive, antiarrhythmic, coronary expansion, anti-ischemic and anti-glaucomatous effects (2). A drug based on compound I is used in medical practice under the name proxodolol (3).

The closest pharmacological analogue of the claimed compounds in the presence of β- and α-adrenergic blocking action is labetalol, which has been used as an antihypertensive agent (4), but not for congestive heart failure (5), as well as carvedilol, used as an antihypertensive, antianginal agent and a drug for treating congestive heart failure (6). It should be noted, however, that there is no convincing evidence of the ability of carvedilol (in monotherapy) to improve the survival of patients with chronic heart failure due to coronary heart disease (7).

In addition, carvedilol is rarely used in our country, primarily because of the high cost.

The purpose of the invention is a new tool that is effective in congestive heart failure.

This goal is achieved by using the well-known compound of 3-methyl-5- / 2- (3-tert-butylamino-2-hydroxypropoxy) phenoxymethyl / 1,2,4-oxadiazole hydrochloride as a medicine used in congestive heart failure.

A study of the pharmacological activity of compound I (proxodolol) was carried out in comparison with its pharmacological analogue, carvedilol.

In rats with an ischemic model of chronic heart failure, in response to occlusion of the left descending coronary artery, intraperitoneal administration of proxodolol at a dose of 2 mg / kg 2 times a day, starting from the first day after coronary occlusion and for 28 days, led to a decrease in the frequency of deaths ( Table 1), the volume and area of myocardial nephrosis-postinfarction scar (Table 2), as well as the mass indices (myocardial hypertrophy) of the right and left ventricles (Table 3). Similar results were obtained in the study of carvedilol. However, no significant differences were found in the effect of proxodolol and carvedilol in terms of their effect on the above parameters.

Table 1
The effect of proxodol and caverdilol on mortality in rats with an ischemic model of chronic heart failure Groups The number of operated animals The number of dead animals False-operated animals (without coronary occlusion) thirteen 0 Control (with coronary occlusion) 24 4 Proxodolol 19 1 Carvedilol 14 0

table 2
The effect of proxodopol and carvedilol on the size of myocardial necrosis in rats with an ischemic model of chronic heart failure Groups The volume of postinfarction scar ratio in% of the area of necrotic segments and cut The area of the postinfarction scar (ratio in% of the lengths of the outer surfaces of the postinfarction scars and the circumference of the sections) Control (n = 14) 35.0 ± 3.6 42.6 ± 4.9 Proxodolol (n = 13) 16.3 ± 1.5 * 19.6 ± 2.1 * Carvedilol (n = 10) 16.6 ± 3.7 * 23.1 ± 4.5 * * P <0.001 compared to control

Table 3
The effect of proxodolol and caverdilol on myocardial hypertrophy in rats with an ischemic model of chronic heart failure Groups Mass index of the left ventricle (ratio in% of the mass of the ventricle and the body of the animal) Mass index of the right ventricle (ratio in% of the mass of the ventricle and the body of the animal) False-operated animals (n = 11) 2.082 ± 0.068 0.6 ± 0.734 Control (n = 11) 2,424 ± 0,056 ¹ 0.926 ± 0.085 ¹ Proxodolol (n = 13) 2.204 ± 0.07 * 0.715 ± 0.082 * Carvedilol (n = 10) 2.281 ± 0.096 * 0.655 ± 0.059 * ¹ P <0.001 compared to falsely operated animals
* P <0.001 compared to control

Data on the effectiveness of proxodolol in an experimental model of heart failure were the basis for its clinical study in patients with chronic heart failure.

A clinical randomized, blind, placebo-controlled study of proxodolol (in the form of 10 mg tablets) was performed on 90 patients with functional class II-III chronic heart failure and a left ventricular ejection fraction of less than 40%. Patients were distributed within 1 week after admission two observation groups based on randomization. Patients of the first group received proxodolol; patients of the second group received placebo. The average daily dose of the drug was 49.8 ± 18.8 mg. Patients received concomitant therapy, with the exception of beta-blockers and calcium ion antagonists, which were canceled in at least 1 week. before the inclusion of patients in the study. The observation duration was 12 weeks.

It was established that treatment with proxodolol led to an improvement in the clinical condition of patients, which was expressed in a decrease in the functional class of chronic heart failure, an increase in the distance traveled by patients, and an improvement in the quality of life (decrease in the average score of the Minnesota Quality of Life Questionnaire) (Table 4). In addition, under the influence of proxodolol, a significant increase in the ejection fraction of the left ventricle was noted, as well as a decrease in systemic blood pressure and a tendency to a decrease in heart rate (Table 4). In the group of patients receiving placebo, the above parameters did not change significantly, with the exception of a decrease in diastolic blood pressure at the end of the study (Table 5).

Over the entire period of observation in both groups, no changes were detected when monitoring the biochemical parameters of blood, the general analysis of urine and blood. Among the side effects of proxodolol, bradycardia (5 patients), arterial hypotension (2 patients), the occurrence of severe weakness (4 patients) and severe headache (1 patient) were noted.

Table 4
The effect of proxodolol on the main parameters in patients with chronic heart failure Parameter Baseline (n = 45) 4 weeks after starting treatment (n = 43) 12 weeks after starting treatment (n = 43) Function class 2.38 ± 0.5 2.05 ± 0.4 6 minute walk test, m 315.2 ± 61.4 343.3 ± 69.4 358 ± 73 * End-diastolic volume of the left ventricle, ml 197.4 ± 45.3 192 ± 50.9 End-systolic volume of the left ventricle, ml 132.3 ± 62.2 121.6 ± 58.6 Left ventricular ejection fraction,% 32.8 ± 4.3 37.12 ± 5.4 * Quality of life, points 41.3 ± 18.9 35.93 ± 21 * 32.9 ± 21.8 * Heart rate, beats / min 77.5 ± 12.7 72.3 ± 13.6 70.2 ± 12.8 Systemic blood pressure (mmHg): systolic diastolic 131.5 ± 13.5
83.2 ± 8.0 123.5 ± 14.6 *
76.5 ± 10.2 * 122.4 ± 17.1 *
75.4 ± 9 * * P <0.05 compared to baseline

Table 5
The effect of placebo on the main parameters in patients with chronic heart failure Parameter Baseline (n = 45) 4 weeks after the start of treatment (n = 42) 12 weeks after the start of treatment (n = 40) Function class 2.26 ± 0.4 2.22 ± 0.36 6 minute walk test, m 323.8 ± 48.6 326.1 ± 63.7 322.6 ± 57 End-diastolic volume of the left ventricle, ml 201.7 ± 89.8 192.6 ± 73.6 End-systolic volume of the left ventricle, ml 139.4 ± 81 127.5 ± 75.9 Left ventricular ejection fraction,% 33.1 ± 7.9 34.9 ± 7.4 Quality of life, points 32.2 ± 17.6 37.2 ± 27.6 27.8 ± 21.7 Heart rate, beats / min 75.8 ± 12.5 74.7 ± 10.9 72.1 ± 11.2 Systemic blood pressure (mmHg): systolic diastolic 133.6 ± 16.7
83.5 ± 10.6 131.6 ± 12.0
82.5 ± 8.1 132.1 ± 9.2
79.3 ± 6.3 * * P <0.05 compared with baseline

Thus, the claimed drug in patients with mild to moderate chronic heart failure causes a decrease in the functional class of heart failure, an increase in the ejection fraction of the left ventricle and load tolerance, as well as an improvement in the quality of life with good tolerance. For the first time, a drug with these properties was identified in a series of derivatives of 5-phenoxymethyloxadiazole.

The creation of the proposed drug allows you to expand the arsenal of effective and safe domestic drugs for the treatment of chronic heart failure.

Literature

1. RF patent N 1132505, class C 07 D 271/06, A 61 K 31/41, published 1994

2. RF patent N 1827067, class A 61 K 31/41, published 1994

3. Mashkovsky M.D. Medicines Moscow, "New Wave", 2000, vol. 1, p. 262.

4. Levy G.P., Richards D.A. - Labetalol-Pharmacology of Antihypertensive Drugs., 325-347, Raven Press, New York, 1980.

5. Drug information for the Health Care Professional, 605, Micromedex, 20-th edition, 2000.

6. Encyclopedia of drugs, 2002, 9th edition, p. 405.

7. Preobrazhensky D.V. B.A. Sidorenko - Successes and failures in the development of new approaches to the medical treatment of chronic heart failure. Cardiology, 2001, N 5, p. 65-73.

Claims (1)

A drug for the treatment of chronic heart failure, which is 3-methyl-5- / 2- (3-tert-butylamino-2-hydroxy-propoxy) phenoxymethyl / -1,2,4-oxadiazole hydrochloride of the formula