Synthetic study of the highly potent and selective anti-platelet activating factor thiazolidin-4-one agents and related compounds

Abstract

Stereoselective cyclo-condensation of α-sulfanylcarboxylic acids (or esters)6 with N-methylarylimines 7 afforded the title compounds, 2-arylthiazolidin-4-ones, some of which exhibit highly potent anti-PAF activity. The reaction without added catalyst gave predominantly cis products, however, when titanium(IV) isopropoxide was added as catalyst trans products were predominantly formed. Allylation of 3-methyl-2-(3-pyridyl)thiazolidin-4-one 22 with allyl bromide using lithium amides gave the trans-5-allyl-2-(3-pyridyl)thiazolidin-4-one 23 with good selectivity. To study the stereostructure–activity relationship, the four optically active isomers of 3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one 4 and 5-(4-chlorophenyl)-3-methyl-2-(3-pyridyl)thiazoIidin-4-one 5 were synthesized. The absolute configurations of compounds 4 and 5 were determined by X-ray analyses and 1H NMR measurements. Epimerization of the 5-position of compounds 4 and 5 was found to be effected by bases with high regioselectivity (>99%), which was checked by a cross-over experiment using several optically active compounds.