Amine prodrugs which utilize hydroxy amide lactonization. I. A potential redox-sensitive amide prodrug

Several amides of 3-(3',6'-dioxo-2',4'-dimethylcyclohexa-1',4'-diene)-3,3- dimethylpropionic acid (2) have been synthesized and tested as model redox-sensitive pro-prodrugs of amines. The reduction of these model pro-prodrugs generated hydroxy amide intermediates 4a-4h, the lactonization of which resulted in amine release. The rates of lactonization of 4a-4h were investigated at pH 7.4 and 37 degrees C. The half-lives for appearance of the product lactone 1a from these intermediates were found to range from 1.4 to 3.4 min. With such rapid lactonization rates, it is believed that reduction will be the rate-limiting step in the two-step conversion of the pro-prodrug to the amine.