RU2373929C1 - Haemostasis system corrector manifesting inhibitory action on adhesive aggregative function of thrombocytes to prevent pathological thrombosis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to pharmacology and concerns applications of dihydrochloride hydrazide 2-[1-(thietanyl-3)benzimidazolyl-2-thio]acetic acid as a haemostasis system corrector - inhibitor of adhesive aggregative function of thrombocytes to prevent pathological thrombosis.

EFFECT: invention provides high effective inhibition of thrombosis.

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Description

The present invention relates to medicine, namely to pharmacology, and can be used to obtain substances that have an inhibitory effect on the adhesive-aggregation function of platelets.

Known pentoxifylline (trental) as a means of suppressing platelet aggregation (State Register of Medicines. - M. - 2004. - T. 2. - S. 1141-1142). Clinical studies indicate the ability of pentoxifylline to have a pronounced positive effect on hemodynamics due to vasodilation and increased collateral circulation and the state of microcirculation, mainly due to an increase in erythrocyte deformability (Reilly DT, Quinton DN, Barrie WW. A controlled trial of pentoxifylline (Trental 400) in intermittent claudication: clinical, haemostatic and rheological effects. NZ Med J .. 1987; 100: 445-447. Dettori AG, Pini M, Moratti A, Paolicelli M, Basevi P, Quintavalla R, Manotti C, Di Lecce C Acenocoumarol and pentoxifylline in intermittent claudication: a controlled clinical study: the APIC study group.Angiology. 1989; 40 (pt 1): 237-248.), what about It restricts the use of it as effective and selectively inhibiting platelet aggregation agents.

The prototype of the invention is acetylsalicylic acid, which reduces aggregation, platelet adhesion and thrombosis and is widely used as a prophylactic antithrombotic agent (State Register of Medicines. - M. - 2004. - v. 2. - p.142-145).

The objective of the invention is to expand the arsenal of tools for the prevention of pathological thrombosis.

EFFECT: obtaining a biologically active substance possessing prophylactic agents and preventing thrombosis, exhibiting thrombolytic activity.

The essence of the invention: the use of dihydrochloride hydrazide 2- [1- (thietanyl-3) benzimidazolyl-2-thio] acetic acid (compound 1) as a corrector of the hemostatic system exhibiting an inhibitory effect on the platelet adhesion-aggregation function (synthesis of compound 1 is described: .A. Khaliullin, E.K. Alekhin, E.E. Klen, L.A. Ryabchinskaya, V.A. Kataev, A.Sh. Bogdanova. “Synthesis and immunotropic activity of derivatives of (benzimidazolyl-2-thio) acetic acids containing thietane cycle ”// HFZh T.35 No. 1 2001, p.12-15).

The study of anti-aggregation activity and disaggregation effect was carried out in vitro according to the Brn method in the modification of O'Brien (Brn GVR ... "Aggregation of blood platelets by adenosine diphosphate and its reversal". // Nature - 1962 - Vol.194 4832 - p.924-929 ) on the Thromlite-1006A aggregometer on human donated blood. The method is based on recording changes in the optical density of platelet-rich plasma before and after the introduction of a certain amount of platelet aggregation inducer. Adenosine diphosphate (ADP) at a concentration of 20 μM was used as an aggregation inducer.

Acetylsalicylic acid (ASA) was used as a reference drug, due to its widespread use as a prophylactic antithrombotic agent (the leading place in the “frequency of prescription” in the world), availability and cost-effectiveness, sufficient effectiveness, proven by numerous fundamental and clinical (AITIA, CCS, AICLA, ESPS, ACCS, SPAF, DTT, etc.) research (Mashkovsky MD Medicines // M: Medicine, 2000. - T.1, p.122. Antiplatelet therapy of acetylsalicylic acid (Transl. From English) / Under the editorship of Ore M.Ya. // M .: Chemical properties, 1999. - Ores M.Ya. - 345 p.). Clinical studies indicate the ability of pentoxifylline to exert a pronounced positive effect on hemodynamics due to vasodilation and increased collateral circulation and the state of microcirculation, mainly due to increased deformability of red blood cells (Reilly DT, Quinton DN, Barrie WW. A controlled trial of pentoxifylline (Trental 400) in intermittent claudication: clinical, haemostatic and rheological effects. NZ Med J .. 1987; 100: 445-447. Dettori AG, Pint M, Moratti A, Paolicelli M, Basevi P, Quintavalla R, Manotti C, Di Lecce C Acenocoumarol and pentoxifylline in intermittent claudication: a controlled clinical study: the APIC study group.Angiology. 1989; 40 (pt 1): 237-248.), which granichivaet its use as effective and selectively inhibiting platelet aggregation agents. According to published data, ASA in vitro and in vivo exhibits an exclusively antiplatelet effect, the ability to cause disaggregation of platelet aggregates is insignificant, and data on ASA inefficiency in a certain category of patients (EI Kinoshenko. Aspirin for coronary heart disease: why, when, how much? // Bulletin of new medical technologies - 1999 - T.VI, No. 3-4. Barkagan ZS Pros and cons of the prophylactic and therapeutic use of aspirin for coronary heart disease.In the book: Progress and problems in the treatment of heart and vascular diseases. Materials of the jubilee conference of St. Petersburg University // St. Petersburg; 1997. 7-8. Barkagan ZS The basics of controlled antithrombotic therapy in the elderly and senile // Clinical Gerontology T.9 No. 5 2003) indicates the need for new corrections hemostatic systems.

Example 1. The effect of compound 1 on ADP-induced platelet aggregation. The degree of decrease in ADP-induced aggregation was assessed after a preliminary 5-minute incubation of the substance in platelet-rich plasma. The study of the dependence of the effect on concentration (table 1).

According to the results of the study, it was found that the introduction of 10 ^-3 M of the substance into the cuvette of the aggregometer 5 minutes before the inducer leads to the suppression of platelet aggregation by an average of 53.147% relative to the control. The resulting aggregates quickly disintegrate: after 2 minutes after the introduction of ADP - 19.0%, and after 5 minutes - already 57.4% of the originally existing aggregates. 50% of platelet aggregates disintegrate within 3.5 minutes after reaching maximum aggregation. When studying the dependence of the effect on concentration, it was found that the EC ₅₀ corresponds to 10 ^-4 M / L.

Example 2. The effect of compound 1 on platelet disaggregation

The disaggregation effect was calculated in% of decayed platelet aggregates after administration of compound 1 5 minutes after ADP (table 2).

The introduction of compound 1 at a height of ADP-induced aggregation for 5 min leads to a disaggregation of an average of 15.2% of the initially existing platelet aggregates, which exceeds the ASA values.

Table 1 The effect of compound 1 on ADP-induced platelet aggregation Group Conc., M / L Suppression of ADP-induced platelet aggregation,% of control Compound 1 10 ^-3 53.147 ± 7.76 * 10 ^-4 50.0 ± 3.18 * 10 ^-5 49.0 ± 4.72 * ASK 10 ^-3 56.0 ± 1.95 * Note: * - the difference from the control is significant (p <0.05);

table 2 The effect of compound 1 on platelet disaggregation Group Conc., M / L % decay of platelet aggregates to control Compound 1 10 ^-3 15.2 ± 3.6 * ASK 10 ^-3 - Note: * - the difference from the control is significant (p <0.05);

Claims (1)

The use of dihydrochloride of hydrazide 2- [1- (thietanyl-3) benzimidazolyl-2-thio] acetic acid of the formula

as a corrector of the hemostasis system - an inhibitor of the platelet adhesion-aggregation function for the prevention of pathological thrombosis.