Acyloxymethyl as a drug protecting group. Part 6: N-Acyloxymethyl- and N-[(aminocarbonyloxy)methyl]sulfonamides as prodrugs of agents containing a secondary sulfonamide group Original Research Article

Tertiary N-acyloxymethyl- and N-[(aminocarbonyloxy)methyl]sulfonamides were synthesised and evaluated as novel classes of potential prodrugs of agents containing a secondary sulfonamide group. The chemical and plasma hydrolyses of the title compounds were studied by HPLC. Tertiary N-acyloxymethylsulfonamides are slowly and quantitatively hydrolysed to the parent sulfonamide in pH 7.4 phosphate buffer, with half-lives ranging from 20 h, for 7d, to 30 days, for 7g. Quantitative formation of the parent sulfonamide also occurs in human plasma, the half-lives being within 0.2–2.0 min for some substrates. The rapid rate of hydrolysis can be ascribed to plasma cholinesterase, as indicated by the complete inhibition observed at [eserine]=0.10 mM. These results suggest that tertiary N-acyloxymethylsulfonamides are potentially useful prodrugs for agents containing a secondary sulfonamide group, especially with pKa<8, combining a high stability in aqueous media with a high rate of plasma activation. In contrast, N-[(aminocarbonyloxy)methyl]sulfonamides –j do not liberate the parent sulfonamide either in aqueous buffers or in human plasma and thus appear to be unsuitable for development as sulfonamide prodrugs.