Prodrug forms for the sulfonamide group. I. Evaluation of N-acyl derivatives, N-sulfonylamidines, N-sulfonylsulfilimines and sulfonylureas as possible prodrug derivatives

Several derivatives of model sulfonamides were prepared and evaluated as potential prodrug forms for the sulfonamide group occurring in several drugs such as diuretics and carbonic anhydrase inhibitors. The derivatives studied included N-acyl and N-alkoxycarbonyl derivatives, N-sulfonylamidines, sulfonylureas, an N-sulfonyl sulfilimine and an N- sulfonyl sulfoximine. The stability characteristics of the derivatives was examined in aqueous solution at various pH values as well as in the presence of human plasma and rat liver homogenate. The results obtained showed that N-sulfonylamidines and sulfonylureas are too stable to be considered as potentially useful prodrug forms. N-Acyl and N-alkoxycarbonyl derivatives of primary sulfonamides also proved very resistant to undergo chemical or enzymatic hydrolysis whereas N-acyl derivatives of secondary sulfonamides are easily hydrolyze enzymatically. Since N-alkylated sulfonamides are known to undergo dealkylation in vivo a promising prodrug approach for a primary sulfonamide involving both N-alkylation and N-acylation was suggested. N-Sulfonyl sulfilimes may also represent a potentially useful prodrug type for the sulfonamide group as assessed on the basis of the hydrolytic and enzymatic lability observed for N-p-toluenesulfonyl dimethylsulfilimine.