Synthesis and Hypoglycemic Activity of the Derivatives of 4-(1,3-Thiazolidine-5-Ylidene)Pyrazole-3-Carbonic Acid and its Esters

Abstract

A preparatively convenient method for synthesizing a series of new (pyrazole-4-yl)methylenethiazolidine structures fictionalized by the carboxylate or carboxylic group in the 3rd position of the pyrazole cycle and by the oxo- thio- or imine groups in the 3rd and 5th positions of the thiazolidine ring is discussed. The method is based on the condensation of 4-formylpyrazole-3-carbonic acids and their ethyl esters with a series of substituted thiazolidines: 1,3-thiazolidine-2,4-dione, 4-thioxo-1,3-thiazolidine-2-one, 2-thioxo-1,3-thiazolidine-4-one, and 2-imino-1,3-thiazolidine-4-one. As seen from the biochemical investigations results, a clear hypoglycemic activity has been registered for the compounds mentioned in this work. Five of ten products have ensured a prolonged effect embracing the entire duration of the experiment. 1-Methyl-4[(4-oxo-2-thioxo-1,3-thiazolidine-5-iliden)methyl]-1H-pyrazole-3-carbonic acid caused the deepest decrease in the glucose content (by 2.0 mmole/L or 30.4 %), while in the case of the reference medicine pioglitazone, it was only by 1.35 mmole/L (23.9 %). Some dependence between the compound structure and its pharmaceutical activity was also found. The most prolonged and steady hypoglycemic activity was registered for (pyrazole-4-il)methylethiazolidines with methyl group as a substitute in the 1st position and carboxylic group – in the 3rd position. The additional introduction of the methyl and carboxylate groups into the pyrazole scaffold results in a prolonged and more in-depth hypoglycemic effect leading to the 1.4 times lesser drop in glucose concentration as compared to that after administration of the reference medicine.