Prodrugs as drug delivery systems IV: N-Mannich bases as potential novel prodrugs for amides, ureides, amines, and other NH-acidic compounds.

The hydrolysis kinetics of a series of N-Mannich bases of carboxamides, thioamides, and other NH-acidic compounds were studied to assess their suitability as prodrugs for various drugs. The pH-rate profiles for the compounds were determined at 37 degrees and were accounted for by assuming the spontaneous decomposition of both free and protonated Mannich bases. The reaction rate for the free base increased sharply with increasing steric effects of the amine component of the N-Mannich bases and also with increasing acidity of the amide component. N-Mannich bases may be potentially useful prodrugs for NH-acidic compounds such as various amides, and ureides and for amines.