Studies on Prodrugs. 10. Possible Mechanism of N-Dealkylation of N-Masked Norfloxacins Having Several Active Methylene Groups

As a prodrug approach to norfloxacin (NFLX, 2), we have prepared several N-masked NFLXs (la-f) and studied the cleavage mechanism of the C-N bond of N-masked NFLXs utilizing the following experiments: (1) the oxidation of N-masked NFLXs (la-f) with m-chloroperbenzoic acid (MCPBA) and their subsequent cleavage to 2 in chloroform at room temperature or at 50 °C; (2) the liberation of NFLX from N-masked NFLXs after oral administration in mice. It was found that the chemical oxidative dealkylation of N-masked NFLXs proceeded when anion-stabilizing groups (e.g., CN, COR, COOR) are present on the a carbon of the nitrogen atom. In in vivo experiments, N-masked NFLXs having acidic hydrogens on the a carbon to the nitrogen atom also liberated NFLX (2) after oral administration.