3-methyl-8-piperazine-7-(thiethanyl-3)-1-ethylxanthine hydrochloride, exhibiting antiaggregant and disaggregation activity

FIELD: chemistry.

SUBSTANCE: invention relates to 3-methyl-8-piperazino-7-(thiethanyl-3)-1-ethylxanthine hydrochloride of formula .

EFFECT: novel compound which can be used in medicine as an antiaggregation and disaggregation agent is obtained and described.

3 cl, 2 tbl, 1 ex

 

The invention relates to medicine, namely to pharmaceutical chemistry and pharmacology, and can be used to create new drugs with antiaggregatory and disaggregating activity.

Prototype and product comparison is pentoxifylline (3,7-dimethyl-1-(5-oxohexyl)xanthine), which is used in the clinic as a corrector of rheological disorders, causing a decrease in blood viscosity and disaggregation of platelets (State register of medicines. / The official publication.- M.: Medicine, 2004. - Vol.2. - S. 1791).

The objective of the invention is to expand the Arsenal of biologically active substances exhibiting antiaggregatory and disaggregating activity.

The technical result - obtaining substances exhibiting antiaggregatory and disaggregating activity.

The inventive 3-methyl-8-piperazine derivatives-7-(titanyl-3)-1-metilksantina hydrochloride (Ia) of the formula

showing antiaggregatory and disaggregating activity.

The proposed connection is synthesized as follows.

Compound Ia was synthesized from 8-bromo-3-methyl-7-(titanyl-3)-1-metilksantina (alkylation Reaction of 8-bromo-3-methyl-7-(titanyl-3)xanthine N-1 position. / Uwhealth, Paholyothin // Honey. journal of Bashkortostan. - 2006. - V.4, No. 1. - S-211) in the 2 study is. When boiling 8-bromo-3-methyl-7-(titanyl-3)-1-metilksantina with 3-fold molar excess of the piperazine of uranyl in ethanol is produced 3-methyl-8-piperazine derivatives-7-(titanyl-3)-1-Edilkamin, whose interaction in the environment of dioxane with 5% solution of hydrogen chloride in ethanol leads to 3-methyl-8-piperazine derivatives-7-(titanyl-3)-1-metilksantina hydrochloride.

Example 1. The synthesis of compounds Ia

A solution of 1.38 g (4 mmol) of 8-bromo-3-methyl-7-(titanyl-3)-1-metilksantina and of 2.33 g (12 mmol) of piperazine of uranyl in 50 ml of ethanol is boiled for 5 hours. Cool, filter. The filtrate is evaporated in vacuo, to the residue was added water, the precipitate filtered off, washed with water, dried. Get 1,11 g (79%) of 3-methyl-8-piperazine derivatives-7-(titanyl-3)-1-metilksantina. Tpl.210-213°C (from ethanol).

Elemental analysis.

Found, %: 51.5 N 6,4 N 23,8 - C15H22N6O2S

Calculated, %: C 51,4 H 6,3 N 24,0

An NMR spectrum1H (CDC13), δ, ppm: of 1.27 (3H, t, J 7.0 Hz, CH3), 3,02-3,10 (4H, m, N(CH2)2), 3,11-3,19 (4H, m, N(CH2)2), 3,21-3,30 (2H, m, S(CH)2), 3,52 (3H, s, 3-NCH3), 4,14 (2H, q, J 7.0 Hz, 1-NCH2), 4,32-4,43 (2H, m, S(CH)2), 5,43-5,59 (1H, m, NCH).

To a solution of 0.53 g (1.5 mmol) of 3-methyl-8-piperazine derivatives-7-(titanyl-3)-1-metilksantina in 15 ml of dioxane is added a 5% solution of hydrogen chloride in ethanol to pH 1-2. Cool, the precipitation is filtered off, washed with dioxane and dried. P is to obtain 0.55 g (95%) of compound Ia. Tpl.247°C decomp. (from ethanol).

Elemental analysis.

Found, %: From 46.4 N 6,2 N a 21.5 - C15H23ClN6O2S

Calculated, %: 46.6 N 6,0 N 21,7

IR Spectrum (tablets with KBr), ν, cm-1: 1659,4; 1672,0; 1706,7 (C=NVal.C=OVal.), 2430-2500, 2570-2720 (N+H2 shaft.).

The proposed connection is a white crystalline substance, soluble in water, dimethylformamide, when heated in ethanol, chloroform.

Antiaggregatory and disaggregating activity.

Antiaggregatory and disaggregating activity proposed compounds were studied in vitro by the method of Born (Born G.V.R. Aggregation of blood platelets by adenosine diphosphate and its reversal. / G.V.R.Born // Nature. - 1962. - Vol.194, No. 4832. - P.924-929) aggregometry "Thromlite-1006A using donated human blood. The method is based on registration of the change of optical density platelet-rich plasma before and after the introduction of the inducer of platelet aggregation. As inducer of aggregation used adenosine diphosphate (ADP) at a concentration of 20 μg/ml as the reference product used "Trental", produced by Aventis Pharma Ltd., Mumbai, India, in equimolar concentrations.

Antiaggregatory activity of compound Ia.

The effect of compound Ia on ADP-induced platelet aggregation was assessed by the degree of reduction of aggregation in the prior 5-minute Incubus and substances in platelet-rich plasma (table 1). The results of the study found that the introduction of 10-3mol/l of the claimed compounds in the cell of aggregometry 5 minutes before ADP leads to a complete suppression of platelet aggregation relative to the control. Pentoxifylline in this concentration inhibits platelet aggregation by 13.9%. When studying the dependence of the effect on the concentration determined that the effective concentration (EC50) compounds Ia, causing inhibition of platelet aggregation by 50%, equal to 5·10-4mol/L. Effective concentration (EC50) pentoxifylline equal to 2·10-3mol/L. Introduction to 2.5·10-4mol/l proposed connection in the cell of aggregometry inhibited platelet aggregation in an average of 24.3%. In this concentration pentoxifylline is inactive.

Disaggregating the potency of the compound Ia.

Disaggregating activity was calculated in percent of the collapsed platelet aggregates after entering the claimed connection after 5 minutes of ADP (table 2). The introduction of compound Ia in a concentration of 10-3mol/l at a height of ADP-induced aggregation within 5 minutes leads to disaggregation average of 52.9% of the originally existing units of platelets, which is higher than the comparison drug (pentoxifylline in this concentration causes a breakdown in the middle 37,4% platelet aggregates). BB is Denia compound Ia in a concentration of 5·10 -4mol/l at a height of ADP-induced aggregation leads to decay on average 37.4% of units of platelets. Pentoxifylline in this concentration is inactive.

Accordingly, the chemical compound (Ia) is very antiaggregatory and disaggregating activity than pentoxifylline.

3-METHYL-8-piperazine derivatives-7-(TITANYL-3)-1-METILKSANTINA HYDROCHLORIDE, SHOWING ANTIAGGREGATORY AND DISAGGREGATING ACTIVITY

Table 1
The effect of the claimed compounds and drug comparisons on ADP-induced platelet aggregation
ConnectionConcentration, mol/lInhibition of ADP-induced platelet aggregation, % of control
Ia10-3100±0,0*
5·10-450,2±2,1*
2,5·10-424,3±1,8*
pentoxifylline2·10-351,9±1,3*
10-3 13,9±2,6*
5·10-4-
Note: * - the difference from the control was significantly (p<0,05).

Table 2
The effect of the claimed compounds and drug comparisons on the disaggregation of platelets
ConnectionConcentration, mol/l% broken platelet aggregates
Ia10-352,9±3,2*
5·10-437,4±2,1
pentoxifylline10-337,4±2,7*
5·10-4-
Note: * - the difference from the control was significantly (p<0,05).

1. 3-Methyl-8-piperazine derivatives-7-(titanyl-3)-1-metilksantina hydrochloride formula

2. The compound according to claim 1, exhibiting antiaggregatory activity.

3. The compound according to claim 1, times the total disaggregating activity.



 

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16 cl, 64 ex, 1 tbl

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2 tbl, 3 ex

Rgd-like peptides // 2396271

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SUBSTANCE: invention discloses novel synthetic RGD-like peptides capable of dose-dependant inhibition of thrombocyte aggregation.

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2 tbl, 1 ex

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