Synthesis of ω-(7-aryl-8-oxo-7,8-dihydro[1,2,4]-triazolo-[4,3-a]pyrazin-3-yl)alkylcarboxylic acids and their amides as perspective pharmaceutical agents

Abstract

[1,3,[8][9][10] have been found. One can assume that these compounds, being isosteric analogues of inosine, have a broad potential of the pharmacological activity; therefore, development of synthetic methods and the study of pharmacological properties of these compounds are up-to-date directions of pharmaceutical chemistry. Derivatives of [1,2,4]triazolo [4,3-a]pyrazin-8(7H)-one containing N-alkyl, alkylthio, alkylsulfinyl or alkylsulfonyl substituents in position 3show antagonism towards receptors P 2 X 7 , and it is essential for treating pain or inflammatory diseases [7]. As their structural analogues 3-alkyl[1,2,4]triazolo[4,3-a]pyrazin-8(7H)-ones can reveal a broad spectrum of pharmacological effects. Our previous studies of probable types of the biological activity of 7-aryl/benzyl-3-alkyl [1,2,4]triazolo[4,3-a]pyrazin-8(7H)-ones using the PASS (Prediction of Activity Spectra for Substances) computer program [6] showed a high potential of the cytotoxic, membrane-stabilizing, cerebroprotective, cardioprotective activity of the compounds [8].To enlarge the synthetically accessible 3,7-disubstituted [1,2,4]triazolo[4,3-a]pyrazin-8(7H)-one as promising pharmaceutical agents the study of ω- (7-substituted-8-oxo-7,8-dihydro[1,2,4]triazolo [4,3-a]pyrazin-3-yl) alkylcarboxylic acids and their amides is of a certain interest. Previous studies of this group of BAS in silico in addition to the above potential types of activity indicated that all the structures had a high obvious probability of pharmacological effects associated with regulation of the lipid metabolism and the ability of these compounds to have an impact on the level of lipoproteins, metabolism of purines and suseptibility of tissues to glucose [5].The aim of this study was to develop the methods of synthesis and research of ω- (7-aryl-8-oxo-7,8-dihydro [1,2,4]triazolo [4,3-a]pyrazin-3-yl)alkylcarboxylic acids containing 2 or 3 carbon atoms and their amide derivatives in the acid residue. Results and DiscussionEarlier we announced about the methods for the synthesis of N 7 -substituted [1,2,4]triazolo[4,3-a]pyrazines using monoamides, monoesters, oxalic acids as initial compounds. Via the stages of pyrazin-2,3-diones, 3-chloropyrazin-2-ones and 3-hydrazinopyrazin-2-ones formation and further cyclization, using derivatives of carbonic acids, 3-alkyl/aryl-N 7 -substituted[1,2,4]triazolo[4,3-a]pyrazin-8(7H)-ones were synthesized [2,4].For the synthesis of ω- (7-aryl-8-oxo-7,8-dihydro[1,2,4] triazolo[4,3-a]pyrazin-3-yl)alkylcarboxylic acids 3{1-14} containing 2 or 3 carbon atoms in the acid residue the cyclization of the corresponding N 1 -aryl-3-hydrazino-