SYNTHESIS OF FUNCTIONAL DERIVATIVES OF 3-AMINO-2-R-7-(R'-PHENYL)-3H-THIENO[2,3-d]PYRIMIDINE-4-ONES AND STUDY OF THEIR ANTI-DIABETIC ACTIVITY

Abstract

SYNTHESIS OF FUNCTIONAL DERIVATIVES OF 3-AMINO-2-R-7-(R'-PHENYL)-3H-THIENO[2,3-d]PYRIMIDINE-4-ONES AND STUDY OF THEIR ANTI-DIABETIC ACTIVITY

Ovsjanykova Yu.O., Sytnik K.M., Shemchuk L.A., Zagayko A.L., Fylymonenko V.P.

National University of Pharmacy, Kharkiv

Introduction. Synthesis of 3-amino-2-R-7-(R'-phenyl)-3H-thieno[3,2-d] pyrimidine-4-ones was accomplished using interaction between 3-amino-4-(R-phenyl)-tiofen-2-carboxylic acids hydrazides with aliphatic carboxylic acids. The proposed reaction was proved itself as an efficient and convenient method for thienopyrimidine system constructing using available reagents under mild conditions, due to the fact that the obtained compounds contain primary amino group in the 3-d position. The main aim of this work was to study the reactivity of 3-amino-2-R-7-phenyl-3H-thieno[3,2-d]pyrimidine-4-one, to study possible chemical modification of the amino group in the 3-d position and to make an initial pharmacological screening of the obtained compounds.

Investigation methods. The melting points were determined by capillary method. NMR spectra of synthesized compounds were recorded on the Varian Mercury VX-200, the operating frequency – 200MHz, solvent – DMSO-D6, internal standard – TMS. Elemental analysis was performed using analyzer Carbo Erba CHNS-O EA 1108.

Diabetes was modeled by prolonged injection of low doses of dexamethasone. The experiment was performed on male Wistar rats, with 160-200 g weight. The blood serum was the studied object. Statistical data analysis was performed using the program STATISTICA (StatSoft Inc., USA, version 6.0). The significance of the intergroup differences was evaluated by nonparametric Mann-Whitney criterion.

Results and discussion. The amides were obtained by treating the amines with corresponding chlorine anhydrides in dioxane medium. The interaction of the initial amine with methanesulfonyl chloride in dimethylformamide medium led to the formation of methansulfonamide. The interaction of amines with isocyanates or isothiocyanates led to corresponding ureas or thioureas formation. Heating the amine with 2,5-dimethoxytetrahydrofurane in glacial acetic acid medium for 2 hours leads to N-pyryl-derivative formation, that is proved by the appearance of characteristic pyryl methyn protons signals instead the amino group signal – triplet (β position) at 6.24 ppm and doublet (α position) at 7.08 ppm.

According to recent literature data obtained thienopyrimidine compounds show the potential antidiabetic activity. Therefore we decided to study this type of activity. The examined synthetic compound, 3-amino-2-ethyl-7-(2-methoxy-phenyl)-3Н-thieno[2,3-d]pyrimidin-4-one, showed protective properties against diabetes. The high level of the studied activity can be attributed to the presence of methoxy group in the ortho position of the phenyl moiety and possible disturbance of the molecule planarity.

Conclusions.

1. Derivatives of 3-amino-2-R-7-(R'-phenyl)-3H-thieno[2,3-d] pyrimidine-4-one were synthesized by chemical modification of the amino group in the 3-d  position of the heterocycle. Conclusions concerning the amino group reactivity were formulated.

2. The structure of the synthesized compounds was proved using Н¹NMR spectroscopy, elemental analysis, and counter synthesis in some cases.

3. Antidiabetic activity research (diabetes was caused by prolonged injection of low doses of dexamethasone) showed that the synthetic compound 3-amino-2-ethyl-7-(2-methoxy-phenyl)-3Н-thieno[2,3-d]pyrimidin-4-one reduced all studied indicators: level of blood glucose, insulin, lipids. Identified antidiabetic properties can be used to develop new medicines in order to correct the insulin resistance.

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