RU2475243C1 - Agent possessing antihypertensive activity - Google Patents

Abstract

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutics and medicine and concerns an agent representing 2-benzoyl-1-hydroxy-4,5-dimethylimidazole of formula

1 possessing antihypertensive activity, lower toxicity, and being as active as reference preparations with antihypertensive activity.

EFFECT: preparing the agent exhibiting antihypertensive activity and lower toxicity.

1 tbl, 1 ex

Description

The invention relates to medicine, specifically to an antihypertensive drug, which is used 2-benzoyl-1-hydroxy-4,5-dimethylimidazole of the formula (1):

To date, in all industrialized countries, including Russia, mortality from cardiovascular diseases continues to occupy a leading position among diseases in people of working age. Arterial hypertension is the most common risk factor for this group of diseases. It is predicted that the number of hypertensive patients by 2020 will increase worldwide to 1.5 billion people [American College of Cardiology Scientific Sessions; Orlando, Florida: 6-9 March 2005, p.1425-1436]. In Russia today, about 40 million people have been found to have high blood pressure (23-30% of the population, depending on the regions).

Currently, significant progress has been made in the development of antihypertensive drugs belonging to various classes of chemical compounds. An example would be nifedipine, which is a Ca ²⁺ channel blocker. The advantage of this effective antihypertensive agent in clinical cardiological practice is its metabolic neutrality. It does not affect lipid metabolism, carbohydrate metabolism and insulin sensitivity, does not change the electrolyte balance [Martsevich S.Yu. // Cardiology. 1999. No. 9. p. 91-96]. However, the side effects of this compound are well-known, associated with the activation of the renin-angiotensin-aldosterone and sympathetic-adrenal systems (tachycardia, peripheral edema, increased angina attacks) [Furberg CD, Psaty BM, Meyer JV Nifedipine. Dose-related increase in mortality in patients with coronary heart disease. Ciculation 1995; 92: 1326-1331].

At the same time, to improve the therapy and prophylaxis of various kinds of cardiovascular diseases, it is necessary to create new drugs that are effectively active in much lower doses and have less toxicity than known pharmaceutical preparations.

The objective of the invention is to expand the arsenal of antihypertensive drugs with low toxicity.

The problem is solved by using as an antihypertensive agent 2-benzoyl-1-hydroxy-4,5-dimethylimidazole of the formula (1):

The method for producing 2-benzoyl-1-hydroxy-4,5-dimethylimidazole (1) is described in the article [S.A. Amitina, A.Ya. Tikhonov, I.A. Grigoryev, Yu.V. Gatilov, B.A. Selivanov, Chemistry heterocycle. compounds, 2009, p.868].

Imidazoles are an important class of heterocyclic compounds with a wide range of biological activity and practical significance [G.S.Shaimardanova, R.A. Kamburg, R.P. Evstigneeva, N.V. Sergeeva, Chemical Pharm. Journal, 1992, 26, No. 3, 31]. However, in the literature, data on the biological activity of 1-hydroxyimidazole derivatives are limited [G.V. Nikitina, M.S. Pevzner, Chemistry heterocycle. compounds 1993, 147; L. M. Junker, J. Clardy, Antimicrob. Agents Chemother., 2007, 51, 3582].

For the claimed drug was determined acute toxicity and antihypertensive effect.

Acute toxicity was determined on outbred white mice weighing 18-22 g with oral administration in doses from 200 mg / kg to 3000 mg / kg. The toxicity parameters were calculated by the method of Kerber [Belenky M.L. Elements of a quantitative assessment of the pharmacological effect. - L .: State publishing house of medical literature, 1963]. The LD ₅₀ for the compound was greater than 1500 mg / kg. According to the toxicity parameters of the claimed tool can be attributed to the 3rd class of moderately toxic compounds.

The antihypertensive effect of the claimed agent 2-benzoyl-1-hydroxy-4,5-dimethylimidazole (1) was determined by intravenous administration of the agent in the femoral vein during pressure monitoring by introducing a sensor into the carotid artery of Wistar rats weighing 180-220 g. The results are shown in the table.

It was found that intravenous administration of the test compound in the dose range from 5 to 0.05 mg / kg reduces the pressure by 11-20% of the initial value in rats with normal blood pressure. A decrease in pressure is observed 5 minutes after injection of the test substance into the femoral vein. In addition, the claimed tool has an advantage over the reference drug clonidine in terms of toxicity and therapeutic index, while the tool does not affect the heart rate (table).

Thus, the inventive tool combines low toxicity and antihypertensive activity, comparable with the reference drug clonidine, is promising as a low toxicity agent that positively affects blood pressure.

The invention is illustrated by the following example.

Example. Study of the antihypertensive properties of 1-hydroxy-2-benzoyl-4,5-dimethylimidazole.

The experiments were carried out on anesthetized (thiopental sodium at a dose of 30 mg / kg ip) adult male rats weighing 190-220 g. The experiments were carried out at the same time from 9 ⁰⁰ to 12 ⁰⁰ . To perform research, animals were divided into groups of 10 animals each.

Blood pressure was measured in an acute experiment by introducing a cannula into the carotid artery. The indicators were recorded using a Coulbourn instruments instrument (USA). Data processing was carried out using the program “Statistica 6.0” by averaging the main indicators of systolic blood pressure. The average statistical error was used as a deviation from the average value, Student t-test was taken as a reliability criterion. The data obtained are presented in the table.

Table Antihypertensive effect of 2-benzoyl-1-hydroxy-4,5-dimethylimidazole (1) Compound LD ₅₀ , mg / kg Dose mg / kg Native pressure (mmHg) Pressure 5 minutes after administration of the agent (mmHg) % reduction TI (one) > 1500 5,0 179.0 ± 10.0 144.2 ± 9.3 20.0 ± 2.0 300 2,5 158.0 ± 7.1 140.2 ± 8.3 12.0 ± 1.2 600 0.5 180.3 ± 13.6 149.0 ± 15.3 17.4 ± 2.0 3000 0.05 150.8 ± 10.6 130.6 ± 15.1 13.4 ± 1.6 Clonidine * 465 10 13-25 46.5 * - [Medvedev B.A. The new antihypertensive drug clonidine. - Chem. Farm. Zhurn. 1980, No. 1, pp. 115-118]

The table shows that the inventive tool reduces pressure in the dose range from 5 to 0.05 mg / kg by 11-20% of the initial value in rats with normal blood pressure. A decrease in pressure is observed 5 minutes after intravenous administration of the test substance. The inventive compound has an advantage over the reference drug clonidine in terms of toxicity and therapeutic index.

Thus, the claimed tool 2-benzoyl-1-hydroxy-4,5-dimethylimidazole (1) has a pronounced antihypertensive effect.

Advantages over the reference preparation (clonidine):

- low toxicity;

- smooth pressure reduction;

- a larger therapeutic index;

- A simple technological way to obtain the claimed funds in two stages from available commercial products.

Claims (1)

The tool is a 2-benzoyl-1-hydroxy-4,5-dimethylimidazole of the formula 1

possessing antihypertensive activity.