SU839544A1 - Agent possessing antiggreation activity - Google Patents

Description

(54) MEANS OWNED ANTIAGREGATION ACTIVITY

This invention relates to chemical and pharmaceutical industry, specifically to agents having antiaggregatory activity.

Known acetylsalicylic acid).

A disadvantage of acetylsalicylic acid is its lack of solubility in water, which is why it cannot be introduced into the blood in sufficient concentrations, and. therefore, it takes a long time to achieve the effect inherent in this substance.

Also known drugs decatrana23.

However, they are often contraindicated in patients, and their antiaggregation effect is negligible.

1,4-Naphthoquinone derivatives are known as electron-acceptor substances t3. The purpose of the invention is to expand the range of agents having anti-aggregation activity.

The goal is achieved by using as an anti-aggregation agent derivatives of 1,4-naphthoquinone of the general formula

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1,4-Naphthoquinone derivatives listed above are biologically active substances with high anti-aggregation activity in in vitro and in vivo experiments and low toxicity. These substances, by their activity, are superior to the antiaggregant effect of reopolyglukine and are well soluble in water, which is very important in their practical use. The antiaggregatory activity of substances has been studied in in vitro experiments with platelet-rich human plasma. The compounds under study are introduced into a plasma cuvette at a dose of 0.2 ml of an aqueous solution containing 10 mg of substance in 1 ml before adding an aggregation-stimulating agent (the effect of preventing platelet aggregation) or in the second minute after the start of aggregation (for detecting disaggregating properties) . In experiments in v i vo, studies were carried out on a model of increased platelet aggregation in dogs, which is caused by massive blood loss (4% of body weight). The dynamics of platelet aggregation are recorded before crushing, after blood loss, 15 and 60 minutes after intravenous administration of the drug at a dose of 20 mg / kg dissolved in 5 ml of 0.9% sodium chloride solution. Controls are similar tests with the introduction of the same volume of 0.9% sodium chloride thief solution. Example 1. In in vitro experiments, all test compounds (1-4) added to platelet-rich plasma 2 minutes after the start of aggregation, stimulated by ADP, almost halved the intensity of aggregate formation. This also appears when comparing the indicators for the period between the 2nd and Bth, as well as the 2nd and 10th minutes of the reaction. Reopoliklyukin under the same conditions does not reduce platelet aggregation activity. Table 1 shows the results of blood pressure platelet aggregation. Example 2. With the introduction of drugs before the start of the aggregation process, both ADP and adrenaline practically lose the ability to stimulate the aggregation of normal platelets. Rheopoliglyukin, added prior to the introduction of aggregation-stimulating agents into the plasma, only slightly reduces the intensity of ADP-aggregation and does not alter the adrenaline-aggregation of platelets at all. Table 2 presents the result of platelet aggregation. Example 3. When investigating the effect of compound 1 in experiments on dogs with increased platelet aggregation induced by massive blood loss, it was found that this drug significantly inhibits the in vivo aggregation of platelets in vivo after 15 min of nocj e-intravenous (p.0.03) . This determines the preservation of platelet levels in animals after massive experimental blood loss. Table 3 presents the number of platelets and the aggregation index in dogs after blood loss and administration of NaCl solutions and L. compound. Example 4 The unequal effect of the studied compounds on the blood coagulation process was established in experiments in vitru. Compounds 3 and 4 reduce the hemocoagulation potential, but 4 accelerates the formation of fibrin coarse, although elastically. The latter is reduced. Compound 3 does not affect the first two phases of hemostasis, but due to the slowing down of the fibrin polymerization process, it reduces the maximum elasticity of the clot and the overall coagulation index. Compound 2 accelerates the process of thromboplastin formation, while compound 1 has virtually no effect on blood coagulation. In tab. 4 presents the data of thromboelastography (TEG) of citrated blood of healthy people with the addition of the studied compounds (5: 1). The reopolyglukine used as a control leads to a drastic (slowing down of the I and II hemostasis phases, a decrease in the elasticity of the fibrin clot and a general coagulation index. Therefore, the RPG has a pronounced hypocoagulative effect, slowing down the thromboplastin formation and the formation of the fibrin clot. Similar, the results were obtained in the study effects of compound 1 on thromboelastogram indicators in in vivo experiments in dogs with massive blood loss (Table 5). As can be seen from the tables, compounds 1–4 have significant Platelet disaggregation effect in various models in vitro and in vivo, far exceeding the effectiveness of reapoliglucin. This effectiveness is combined with a simultaneous lack of effect on blood clotting. The use of the proposed agent will expand the range of agents with anti-aggregation activity.

Table 1 M 209.31 151.20 106.49 0.9% solution ± t 31.37 33.27 37.59 Compound 1 (20 mg in M 362.56 145.23 230.01 5 MP fiziol92, 93 52.44 122.85 g)

Table 3 57.74 7.9 12.7 16.3 12.3 7.29 1.58 4.56 4.77 2.6 82.85 6.32 11.7 5.6 6.3 15.50 1,532.11 1.85 2.39

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Claims (3)

and 3.24 4.08 44.6 26.2 3.72 N solution, 4 t 0.41 0.59 4.81 2.41 1.10 NaCl M 3.12 2.34 62.0 38.8 2,22 Compounds 0,66 7,76 7,52 3,71 0,52 Niya 1 it m Claims of the invention The use of 1,4-Naphthoquinone of the general formula where. tg ce, CH2COONoi ,, tg, N-oH cHjCooH CO-CHj i-COONCx T2, CHj, TJ. , gth tee, yl, 1 ,, - n // v3 P, Ce, -R ,, NH-CH, CH2. (four) Table 5 (i) 3, „(b) 3.32 49.0. 30.0 2.22 4.02 46.6 29.4 0.94 7.01 5.26 0.24 0.71 5.21 4.31 2.40 62.4 42.0 3.22 4, 8 53,0 32,0 0,69 6,21 5,76 0,78 2,17 5,06 6,3 as an agent with anti-aggregation activity. Sources of information taken into account in the examination 1.I.V. Kuibyshev. The functional properties of platelets are normal and in pathological conditions. Obninsk, 1975, 44. 2.L.P. Sviridkina. The effect of reopolyglukine on hemocoagulation in hemodynamia. Problems of Hematology, 10, 1978, 46-52. 3. Ya. Ya. Y. Ryderis, I. Ya. Liepin, Ya.F. Freimanis Synthesis of 1,4-naphthoquinone. Lime Academy of Sciences of the Latvian SSR, eh. Chem., № 4, 1977, p. 460-464. ep.chem .. №4. . p. 4fin-4fi4