Synthesis and the hypoglycemic activity of pyrazolidene-3-carboxylic acids and their derivatives exo-functionalized with the hydrazinilidene-1,3-thiazolidine fragment

M. K. Bratenko, M. M. Barus, O. M. Denysenko, R. V. Rodik, M. V. Vovk, O. K. Yarosh

Abstract


It has been shown that 4- formylpyrazole-3-carboxylic acids and their ethyl esters interact selectively with thiosemicarbazide and its N4-aryl-derivatives in boiling acetic acid with formation of the corresponding 4-pyrazolylthiosemicarbazones with the yields of 76-91%. It has been found that heating of 4-pyrazolylthiosemicarbazones with diethyl acetylenedicarboxylate in boiling ethanol for 3 hours leads to formation of 1,3-thiazolidine-containing polyfunctional pyrazole derivatives with yields of 73-95%. Formation of compounds of this type indicates that the process occurs according to the scheme of the primary attack of a highly electrophilic triple bond of acetylenedicarboxylate by the nucleophilic atom of sulfur of the thiosemicarbazone fragment with subsequent intramolecular condensation, which leads to formation of the 4-oxo-1,3-thiazolidine-5-ilidene cycle. The structure of the 1,3-thiazolidinilidenehydrazonepyrazoles synthesized has been proven by a complex of spectral methods; the most informative of them are 13C NMR spectra with signals of carbon atoms of the thiazolidine cycle: C4 (159-161 ppm), C2 (162-165 ppm), C5 (163-165 ppm), as well as of the exo-cyclic ethoxycarbonylethylidene fragment: HC= (114-118 ppm); and of C(O) O (165 ppm). It has been determined that the compounds synthesized cause the hypoglycemic dose-dependent effect in mice, which is much more potent than the same effect of the reference medicine – pioglitazone.

Keywords


4-formylpyrazole-3-carboxylic acids; thiosemicarbazones; diethylacetylenedicarboxylate; 1,3-thiazolidine-4-ones; cyclocondensation; hypoglycemic activity

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DOI: https://doi.org/10.24959/ophcj.15.837

Abbreviated key title: Ž. org. farm. hìm.

ISSN 2518-1548 (Online), ISSN 2308-8303 (Print)