Kondo H, Sakamoto F, Inoue Y, Tsukamoto G
Pharmaceuticals Research Center, Kanebo, Ltd., Osaka, Japan.
J Med Chem. 1989 Mar;32(3):679-82. doi: 10.1021/jm00123a031.
As a prodrug approach to norfloxacin (NFLX, 2), we have prepared several N-masked NFLXs (1a-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 (1a-f) with m-chloroperbenzoic acid (MCPBA) and their subsequent cleavage to 2 in chloroform at room temperature or at 50 degrees 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 alpha carbon of the nitrogen atom. In in vivo experiments, N-masked NFLXs having acidic hydrogens on the alpha carbon to the nitrogen atom also liberated NFLX (2) after oral administration.
作为诺氟沙星（NFLX，2）的前药方法，我们制备了几种N-掩蔽的NFLX（1a-f），并利用以下实验研究了N-掩蔽的NFLX的C-N键的裂解机制：（1）用间氯过苯甲酸（MCPBA）氧化N-掩蔽的NFLX（1a-f），随后在室温或50℃下于氯仿中将其裂解为2；（2）在小鼠口服给药后从N-掩蔽的NFLX中释放出NFLX。发现当在氮原子的α碳上存在阴离子稳定基团（例如，CN、COR、COOR）时，N-掩蔽的NFLX的化学氧化脱烷基反应会进行。在体内实验中，在氮原子的α碳上具有酸性氢的N-掩蔽的NFLX在口服给药后也会释放出NFLX（2）。
