Preliminary evaluation of mesoionic 6-substituted 1-methylimidazo[2,1-b][1,3]thiazine-5,7-diones as potential novel prodrugs of methimazole.

A series of five 6-alkyl- and 6-aryl-mesoionic 1-methylimidazo[2,1-b][1,3]thiazine-5,7-diones was synthesized and found to produce 1-methyl-3H-imidazole-2-thione (methimazole) upon alkaline hydrolysis or treatment with amine or thiol reagents. The alkaline hydrolysis followed a second-order rate expression, being dependent on both substrate and hydroxide-ion concentrations. The rate constants for the five derivatives fell within 6-15 x 10(-2) liter/mole min at 40 degrees. These compounds were stable in aqueous acidic solutions and in human serum or rat liver homogenate under conditions producing rapid hydrolysis of the methimazole prodrug 1-carbethoxy-2-methylimidazole-2-thione (carbimazole).