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 × 10⁻² liter/mole min at 40°. 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‐3‐methylimidazole‐2‐thione (carbimazole).