Cyclization-Activated Prodrugs. Basic Carbamates of 4-Hydroxyanisole

Article abstract of DOI:10.1021/jm00163a016

A series of basic carbamates of 4-hydroxyanisole was prepared and evaluated as progenitors of this melanocytotoxic phenol.All of the carbamates were relatively stable at low pH but released 4-hydroxyanisole cleanly at pH 7.4 at rates that were structure dependent.A detailed study of the N-methyl-N-<2-(methylamino)ethyl>carbamate showed that generation of the parent phenol followed first-order kinetics with t_1/2 = 36.3 min at pH 7.4, 37 deg C, and was accompanied by formation of N,N'-dimethylimidazolidinone.These basic carbamates are examples of cyclization-activated prodrugs in which generation of the active drug is not linked to enzymatic cleavage but rather depends solely upon a predictable, intramolecular cyclization-elimination reaction.