Synthesis and Antithrombotic Activity Determination of (2-Methyl-4-[4-methyl-2-(4-trifluoromethylphenyl)-thiazole-5-ylmethylsulfanyl]phenoxy)acetic Acid Derivatives

Abstract

The article proposes an approach for obtaining the derivatives of hetarylmethylthioaryloxyalcane PPARS/fi agonists containing sulfoxide and sulfone fragments in the linker, the parent compound for the synthesis being GSK-516 - (2-methyl-4-[4-methyl-2-(4-trifiuoromethylph.enyl)-th.iazole-5-ylmethylsulfanyl]phenoxy)acetic acid obtained as a result of sequential S- and O-alkylation of mercaptocresol by thiazolyl methyl chloride and ethyl bromacetate at key stages. Derivatives of GSK-516, as well as sulfoxide and sulfone were synthesized for the first time by oxidating acyclic sulfur with meta-chloroperbenzoic acid. The structures of the synthesized compounds were confirmed by HPLC-MS, elemental analysis and JH, 13C NMR. The spectral characteristics of target compounds were compared by NMR. When passing from sulfide to sulfoxide and further to sulfone, it was found that the shift of the methylene group connecting the thiazole ring with the sulfur atom is moved to the weaker field. The antithrombotic activity of the obtained compounds was investigated by measuring platelet aggregation in platelet-rich plasma by the Bourne turbidimetric method. It was stated that sulfonic derivative GSK-516 has the highest antithrombotic activity.

Keywords

• ppar agonists
• antithrombotic activity
• aryloxyacetic acid
• peroxisome proliferation receptors
• thiazoles
• gsk-516
• ppar6/fi