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 (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.
Kondo
H
H
Pharmaceuticals Research Center, Kanebo, Ltd., Osaka, Japan.
Sakamoto
F
F
Inoue
Y
Y
Tsukamoto
G
G
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D003640:Dealkylation; D051379:Mice; D009643:Norfloxacin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism; D013329:Structure-Activity Relationship
D011355:Prodrugs; D009643:Norfloxacin