ENHANCEMENT OF THE BASE FOR 3 , 7-DISUBSTITUTED [ 1 , 2 , 4 ] TRIAZOLO [ 4 , 3-a ] PYRAZIN-8 ( 7 H )-ONE DERIVATIVES AS PROMISING PHARMACEUTICAL AGENTS

A suitable and effective scheme for the synthesis of 3,7-disubstituted [1,2,4]triazolo[4,3-a]pyrazin-8(7H)-ones has been suggested and tested. It can provide a wide chemical diversity of the final products containing practically any substituent in position 3. The scheme previously developed starts from esters of oxalamic acid following with the cyclization of intermediate 3-hydrazinopyrazin-2-ones with carbonyl-containing compounds (orthoesters or alkylcarbonic acid anhydrides). To introduce aryl or heteryl substituents in position 3 of the heterocyclic system we propose to use the reaction of 3-hydrazinopyrazin-2-ones with the corresponding carbonic acids preliminary activated by carbonyldiimidazole (CDI). The further cyclization is carried out by reflux for 24 hours in anhydrous DMFA. The structure of the compounds obtained has been proven by elemental analysis and 1H NMR spectroscopy data. Formation of [1,2,4]triazolo[4,3-a]pyrazin-8(7H)-one condensed system is in good correlation with spectral data, and is confirmed by the presence of signals of H-5 and H-6 protons of the pyrazinone fragment as doublets at d 7.15-7.28 ppm and d 7.50-7.59 ppm, respectively. The compounds synthesized are of particular interest as potential pharmacological objects with the cytotoxic, membrane-stabilizing, cerebroprotective, cardioprotective activity.

A suitable and effective scheme for the synthesis of 3,7-disubstituted [1,2,4]triazolo [4,3-a]pyrazin-8(7H)-ones has been suggested and tested.It can provide a wide chemical diversity of the final products containing practically any substituent in position 3.The scheme previously developed starts from esters of oxalamic acid following with the cyclization of intermediate 3-hydrazinopyrazin-2-ones with carbonyl-containing compounds (orthoesters or alkylcarbonic acid anhydrides).To introduce aryl or heteryl substituents in position 3 of the heterocyclic system we propose to use the reaction of 3-hydrazinopyrazin-2-ones with the corresponding carbonic acids preliminary activated by carbonyldiimidazole (CDI).The further cyclization is carried out by reflux for 24 hours in anhydrous DMFA.The structure of the compounds obtained has been proven by elemental analysis and 1 H NMR spectroscopy data.Formation of [1,2,4]triazolo [4,3-a]pyrazin-8(7H)-one condensed system is in good correlation with spectral data, and is confirmed by the presence of signals of H-5 and H-6 protons of the pyrazinone fragment as doublets at d 7.15-7.28ppm and d 7.50-7.59ppm, respectively.The compounds synthesized are of particular interest as potential pharmacological objects with the cytotoxic, membrane-stabilizing, cerebroprotective, cardioprotective activity.

ISSN 2308-8303
Modern research in the therapy of oncological diseases testify an essential role of glutamic acid derivatives in cancer pathogenesis.Substances competitively inhibiting glutamate in the interaction with АМРА-and NMDA-receptors will be most likely very useful in oncopathology treatment [1,2].Therefore, a promising area of pharmaceutical science is further study of [1,2,4]triazolo [4,3-a]pyrazines, which exhibit the pharmacological effects mentioned above, as well as creation of medicines on their basis.
With the help of the computer programme PASS (Prediction of Activity Spectra for Substances) [3], which enable to estimate the pharmacological effect, the mechanism of action and specific toxicity of a substance, we carried out the investigation of the base of N 7 -aryl- [1,2,4]triazolo [4,3-a]pyrazines derivatives with alkyl substituents in position 3 previously synthesized [4].Computational results indicate a high potential of cytotoxic, membrane-stabilizing, cerebroprotective, cardioprotective activity of the compounds obtained.
Variation of substituents in molecules with the same heterocyclic structure can affect the ligand-receptor interaction; it can be relevant in therapy of not only oncopathologies, but many diseases associated with the protein-receptor competitive antagonism.
On the basis of analysis of the chemical potential of [1,2,4]triazolo [4,3-a]pyrazine structure, which is bioisosteric analogue of nucleic acids, the most promising randomization points of this basic structure have been determined and the synthetic transformation schemes that are suitable for focused combinatorial libraries construction have been developed.
The scheme of [1,2,4]triazolo [4,3-a]pyrazines synthesis that is used in organic synthesis the most frequently starts from 2,3-dichloropyrazine and consists in cyclization of 2-chloro-3-hydrazinopyrazine obtained under the action of acid halides of carbonic acid with hydrolysis of intermediate 8-chloro [1,2,4] triazolo [4,3-a]pyrazine and subsequent N-alkylation [5].The principal lack of this method is a limited set of substituents in position 7 of the cyclization product.In our previous work approaches to N 7 -substituted [1,2,4]triazolo [4,3-a]pyrazines with alkyl and aryl substituents in position 7 were discussed.The aim of the present paper is the use of a wide range of carbonyl reagents for modification of position 3 in the target [1,2,4]triazolo [4,3-a]pyrazines by various substituents.
The aim of our next work was enhancement of the series of N 7 -substituted [1,2,4]triazolo [4,3-a]pyrazin-8(7H)-ones previously synthesized by means of aryl or heteryl substituents introduction in position 3 of the cycle.
For this purpose the scheme of interaction of N 1aryl/benzyl-3-hydrazinopyrazin-2-ones 4{1-4} with the corresponding carbonic acids 1{1-4} has been suggested.However, low electrophility of the carboxylic group hinders the effective course of the reaction.Hence, for the carboxylic group activation we suggest to use carbonyldiimidazole (CDI) 2 in anhydrous DMFA in the molar ratio of 1:1 (Scheme).Thus, imidazolide of the corresponding acid 3{1-4} is formed; it is very suitable reagent for the synthesis of intermediate hydrazides, which with further heating form the target products that precipitate.Possible impurities (starting acid or its imidazolide) are more soluble than the final product and stay in solution when precipitating.
The use of acid chlorides is less appropriate for the target products synthesis because of the presence of the thionyl chloride excess, and it can lead to formation of by-products impurities.
It should be mentioned that attempts to conduct the synthesis of compounds 5 by interaction of 3-chloropyrazin-2-ones and the corresponding acid hydrazides have failed since starting chlorides are easily hydrolyzed by traces of water in solvents or even by air moisture.