RU2504546C1 - Cyclohexyl ammonium salt of 2-[3-methyl-7-(1,1-dioxotiethanyl-3)-1-ethyl xanthenyl-8-tio]acetic acid, which shows antithromboembolic action - Google Patents

Abstract

FIELD: biotechnologies.

SUBSTANCE: invention refers to cyclohexyl ammonium salt of 2-[3-methyl-7-(1,1-dioxotiethanyl-3)-1-ethyl xanthenyl-8-tio]acetic acid of the following formula:

.

EFFECT: obtaining a new compound that shows antithromboembolic action and can be used in medicine.

2 cl, 2 tbl, 3 ex

Description

The invention relates to medicine, namely to pharmaceutical chemistry and pharmacology, and can be used to create new drugs for the prevention of thromboembolic conditions.

The prototype and reference drug is pentoxifylline (3,7-dimethyl-1- (5-oxohexyl) xanthine), which has been used for a long time and successfully in practical medicine and has proven effectiveness as a means of preventing and treating thromboembolic diseases and complications (Hsu, CY Pentoxifylline in acute nonhemorrhagic stroke. A randomized, placebo-controlled double-blind trial / CYHsu, JWNorris, ELHogan, P.Bladin, HBDinsdale, FMYatsu, MPEarnest, P.Scheinberg, LRCaplan, HRKarp // Stroke . - 1988. - Vol.19. - No. 6. - P.716-722. De Sanctis, MT Treatment of retinal vein thrombosis with pentoxifylline: a controlled, randomized trial / MT De Sanctis, MRCesarone, G. Belcaro, L .Incandela ea // Angiology. - 2002. - No. 53. - P.72- 73).

The objective of the invention is to expand the arsenal of biologically active substances exhibiting antithromboembolic action.

EFFECT: obtaining a substance exhibiting an antithromboembolic effect.

The inventive cyclohexylammonium salt of 2- [3-methyl-7- (1,1-dioxothietanyl-3) -1-ethylxanthinyl-8-thio] acetic acid (Ia) of the formula

exhibiting antithromboembolic effect.

The inventive compound was synthesized as follows.

Compound Ia is synthesized from 8-bromo-3-methyl-7- (1,1-dioxothietanyl-3) -1-ethylxanthine (Thietanyl protection in the synthesis of 1-alkyl-8-bromo-3-methyl-3,7-dihydro 1H-purine-2,6-dione / F.A. Khaliullin, Yu.V. Shabalina, PM Sharafutdinov // ZhORKh. - 2010. - T. 46, No. 5. - S.698-701) in 2 stages. When boiling 8-bromo-3-methyl-7- (1,1-dioxothietanyl-3) -1-ethylxanthine with a 2-fold molar excess of thioglycolic acid in an aqueous medium in the presence of potassium hydroxide, 2- [3-methyl-7- (1,1-dioxothietanyl-3) -1-ethylxanthinyl-8-thio] acetic acid, the interaction of which with cyclohexylamine in acetone leads to the cyclohexylammonium salt [3-methyl-7- (1,1-dioxothietanyl-3) -1 ethyl ethylanthinyl-8-thio] acetic acid.

Example 1. The synthesis of compound Ia.

To a solution of 0.84 g (15 mmol) of potassium hydroxide in 50 ml of water, 0.92 g (10 mmol) of thioglycolic acid and 1.89 g (5 mmol) of 8-bromo-3-methyl-7- (1.1) are added. -dioxothiethanyl-3) -1-ethylxanthine, boiled for 1 hour. It is cooled, neutralized with a 3.7% hydrochloric acid solution to pH 2. The precipitate formed is filtered off, washed with water, and dried. 1.52 g (78%) of 2- [3-methyl-7- (1,1-dioxothietanyl-3) -1-ethylxanthinyl-8-thio] acetic acid are obtained. _Mp 201-203 ° C (from water).

Elemental analysis.

Found,%: C 40.2 H 4.2 N 14.4 - C ₁₃ H ₁₆ N ₄ O ₆ S ₂

Calculated,%: C 40.4 H 4.1 N 14.6

IR spectrum (tablets with KBr), ν, cm ^-1 : 1133.6; 1312.0 (SO ₂ val.), 1650.6; 1658.5; 1666.3; 1,671.6; 1,693.6; 1699.1 (C = C shaft., C = N shaft., C = O shaft.), 2380-3030 (acc. O-H shaft.).

¹ H NMR spectrum (CDCl ₃ ), δ, ppm: 1.26 (3H, t, J 7.0 Hz, CH ₃ ), 3.55 (3H, s, 3-CH ₃ ), 4, 06-4.18 (4H, m, SCH ₂ and 1-CH ₂ ), 4.35-4.44 (2H, m, S (CH) ₂ ), 5.17-5.28 (2H, m, S (CH) ₂ ), 5.53-5.66 (1H, m, 7-CH).

To a solution of 1.94 g (5 mmol) of 2- [3-methyl-7- (1,1-dioxothietanyl-3) -1-ethylxanthinyl-8-thio] acetic acid in 80 ml of acetone was added 0.64 g (6 5 mmol) cyclohexylamine. The precipitate formed is filtered off, washed with acetone, and dried. 2.18 g (89%) of compound Ia are obtained. _Mp 223-225 ° C (from dioxane).

Elemental analysis.

Found,%: C 46.8 H 6.0 N 14.4 - C ₁₉ H ₂₉ N ₅ O ₆ S ₂

Calculated,%: C 46.7 N 6.2 N 14.6

IR spectrum (tablets with KBr), ν, cm ^-1 : 1135.5; 1320.1 (SO ₂ shaft.), 1661.5; 1698.6 (CC shaft., C = N shaft., CO shaft.), 2400-3150 (N ⁺ H ₃ shaft.).

¹ H NMR spectrum (DMSO-d ₆ ), δ, ppm: 1.09-1.31 (9H, m, CH ₃ and (CH ₂ ) ₃ ), 1.51-1.91 (4H, m, 2CH ₂ ), 2.82-2.93 (1H, m, NCH), 3.42 (3H, s, 3-CH ₃ ), 3.79 (2H, s, SCH ₂ ), 3.94 (2H, q, J 6.9 Hz, 1-CH ₂ ), 4.50-4.61 (2H, m, S (CH) ₂ ), 5.00-5.11 (2H, m, S ( CH) ₂ ), 5.52-5.65 (1H, m, 7-CH). The inventive compound is a white crystalline substance, soluble in water, when heated in ethanol and dimethyl sulfoxide.

Acute toxicity

Determination of acute toxicity was carried out according to the method of Deichman and Le Blanc (Sanotsky I.V. Methods for the determination of toxicity and hazard of chemicals. - M .: Medicine, 1989. - 150 p.). For this purpose, the test compounds were administered intraperitoneally to the rats in increasing doses in increments of 100 mg / kg. Observation of laboratory animals was carried out for 2 weeks after injection. For LD ₅₀ , the lowest dose was taken, which caused a fatal outcome.

Example 2. Acute toxicity

When studying the LD _{50 of the} claimed compound, it was found that its toxicity is significantly less (2.4 times) than the toxicity of the comparison drug: according to the classification of K.K. Sidorov when administered intraperitoneally, it belongs to hazard class IV (low toxicity) (table 1).

Antithromboembolic effect of compound Ia.

The antithromboembolic effect of compound Ia was determined on a model of pulmonary embolism according to the method of DiMinno G. and Silver MJ (DiMinno, GS Mouse antithrombotic assay: a simple method for the evaluation of antithrombotic agents in vivo. Potentiation of antithrombotic activity by ethyl alcohol / GSDiMinno // J Pharmacol. Exp. Ther. - 1983. - V. 225. - P.57-60). A mixture of collagen and adrenaline solutions (0.5 mg / kg and 0.06 mg / kg, respectively) was injected into the tail vein of mice. The number of surviving animals compared to the control group was noted as a criterion for the effectiveness of the studied compounds. The test compounds in equimolar doses were administered intraperitoneally 1 hour before thromboembolism modeling: 70 mg / kg of compound Ia and 40 mg / kg of pentoxifylline. The control group of mice was injected with saline in similar volumes. Statistical data processing was performed using the χ ² test.

Example 3. Antithromboembolic effect of compound Ia.

When studying collagen-adrenaline thrombosis, compound Ia and pentoxifylline reduced the death of animals to varying degrees.

With the introduction of a solution containing 0.5 mg of collagen and 0.06 mg of adrenaline per kilogram of body weight into the tail vein of the animals of the control group, the death of animals was observed within the first hour after the introduction of thrombosis inducers. In the first hour after injection, death was 60% of the mice; in the first 3 days, mortality was 100%.

Pentoxifylline reduced the death of mice when modeling pulmonary embolism compared to control. The survival rate was 58.3%. The main death occurred on the first day after the introduction of thrombosis inducers. In the experimental group, in animals treated with compound Ia, death is significantly less in comparison with the control and the comparison drug. The survival rate was 75.1%, the main deaths occurred on the first day of the experiment (table 2).

The survival of animals in the group treated with compound Ia was significantly higher than that in the control group and 1.3 times in the group in animals treated with pentoxifylline.

Thus, the claimed compound Ia has a pronounced antithromboembolic effect in excess of the action of pentoxifylline, and favorably differs in lower toxicity.

Table 1 The toxicity parameters of the comparison drug and the claimed compounds Compound LD ₅₀ , mg / kg Pentoxifylline 250 Compound Ia > 600

table 2 Survival rates for modeling pulmonary embolism, n = 12 Compound The control Pentoxifylline Compound Ia P ₂ Survival rate,% 0,0 58.3 * 75.1 * <0.05 Note: * - level of statistical significance of differences in the characteristics of the control and experimental groups (P ₁ <0.01); P ₂ - level of statistical significance of differences in the signs of groups receiving pentoxifylline and the claimed compound Ia

Claims (2)

1. The cyclohexylammonium salt of 2- [3-methyl-7- (1,1-dioxothietanyl-3) -1-ethylxanthinyl-8-thio] acetic acid of the formula

2. The compound according to claim 1, exhibiting antithromboembolic action.