Pro-drugs as drug delivery systems XIX. Bioreversiblf derivatization of aromatic amines by formation of N-Mannich bases with succinimide

The kinetics of decomposition of various N-Mannich bases derived from succinimide or 5,5-dimethylhydantoin and a series of primary aromatic amines in aqueous solution at 37°C was studied to assess their suitability as pro-drugs for such amino compounds. The pH-rate profile for each compound showed a sigmoid shape and could be accounted for by assuming spontaneous decomposition of unprotonated Mannich base. The reaction rate increased markedly with increasing amine basicity. For the succinimide Mannich bases the half-lives of decomposition at pH 7.4 and 37°C were found to range from 0.9 min for the p-toluidine derivative to 4 h for derivatives of procaine and benzocaine. The results suggested the potential utility of such N-Mannich bases as pro-drug candidates for drugs containing a primary aromatic amino group, e.g. with the aim of protecting such drugs against metabolic inactivation by N-acetylation.