Synthesis and hypoglycemic activity of derivatives of 4-((1,3-thiazolydine-5-yliden)methy)pyrazole-3-carbonic acid and its esters

An effective preparative method of synthesis of a series of new (pyrazole-4-il)methylenethiazolidine structures has been elaborated. The structures are functionalized in the 3rd position by the carboxylate or carboxyle group and in the 3rd and 5th positions of the thiazolidine cycle – by the oxo-, thio- or iminogroups. The method involves condensation of 4-formylpyrazole-3-carbonic acids and their ethyl esters with a series of the 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. A group of 112 white adult nonlinear rats of both genders was used to investigate the hypoglycemic activity of the synthesized compounds. Pioglitazonum (5-{4-[2-(5-ethylpyridine-2-il)etoxy]benzyl}thiazolidine-2,4-dione, M=246) was used as a reference medicine in the standard dosage of 0.0214 mmole/kg. All compounds were administered intragastrically on an empty stomach using a non-traumatic catheter as a 3 % starch suspension while same dosage of the neutral suspension (without any acting medicine) was administered to the animals of the control group. Possible hypoglycemic activity of the compounds was evaluated by the changes in glucose concentration in blood measured before and 2, 4, 6, 8 and 10 hours after the single administration of a compound. An express glucometer “One Touch Select Simple” was employed for the above tests. Then all the data were processed by MS Excel. As seen from the results of the biochemical investigations, 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-thiooxo-1,3-thiazolidine-5-iliden)methyl]-1H-pyrazole-3-carbonic acid caused the deepest decrease in the glucose content (2.0 units or 30.4 %) while in case of the reference medicine it was only 1.35 units (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. Additional introduction of the methyl and carboxylate groups into pyrazolic scaffold results in a prolonged and deeper hypoglycemic effect leading to the 1.4 times lesser drop in glucose concentration as compared to that after administration of the reference medicine.