N. M. Nielsen, H. Bundgaard
Mar 1, 1986
Citations
0
Influential Citations
13
Citations
Journal
International Journal of Pharmaceutics
Abstract
Abstract Several 2-hydroxymethylbenzamides derived from various primary and secondary amines were prepared and evaluated as potential prodrug models for the amino group occurring in several drugs. The hydroxy-amides were found to undergo a quantitative cyclization in aqueous solution to phthalide and the parent amine. The lactonization was specific acid- and base-catalyzed as well as subject to buffer catalysis. The structural factor being predominantly responsible for the different reactivities of the hydroxy-amides was found to be the steric properties of the amines, the amine basicity being only of minor importance. The cyclization proceeded only slowly at pH 7.4 and 37°C and in order to be a useful prodrug principle it may be necessary to accelerate the reaction rate, e.g. by introducing sterically or catalytically accelerating substituents in the hydroxy-amide moiety. Acylation of the hydroxymethyl group was shown to block the lactonization and hence to stabilize the hydroxy-amides. However, in the presence of human plasma the ester grouping was readily hydrolyzed yielding the parent 2-hydroxymethylbenzamide. Such cascade latentiation may thus be a particularly useful prodrug principle affording at the same time adequate in vitro stability and in vivo lability.