Prodrugs as drug delivery systems. 65. Hydrolysis of α-hydroxy-and α-acyloxy- N-benzoylglycine derivatives and implications for the design of prodrugs of NH-acidic compounds

Abstract

N-Hydroxymethylation and N-acyloxymethylation of weakly NH-acidic compounds such as carboxamides, carbamates and ureas are not useful approaches to obtain prodrug forms of such agents because of the too high stability of the N-hydroxymethyl derivatives at physiological pH and temperature. In an attempt to explore more unstable N-hydroxyalkyl derivatives various N-hydroxyalkyl compounds derived from benzamide and glyoxylic acid derivatives were prepared and their hydrolysis kinetics studied in aqueous solution in the pH range 1–12 and in human plasma solutions. All compounds degraded with the quantitative formation of benzamide and the glyoxylic acid component (the acid itself or esters and amides thereof) and they showed both specific base and acid catalysis as well as spontaneous decomposition. The derivatives were much more unstable at pH 7.4 and 37° C than the corresponding N-hydroxymethyl derivative. Thus, whereas the half-life of decomposition of N-fhydroxymethyl)benzamide is 160 h under these conditions the half-lives for the glyoxylic acid derivatives are only 22 min–6.7 h, the most reactive compounds being those derived from glyoxylic acid esters and amides. These results suggest that N-hydroxyalkylation of amides and similar weakly NH-acidic agents using glyoxylic acid or esters or amides thereof as the aldehyde component may be a potentially useful prodrug approach. The hydrolysis kinetics of N-(α-acyloxyalkyl)benzamide derivatives, prepared by acylation of the benzamide-glyoxylate derivatives, was also studied. Surprisingly, these derivatives were extremely unstable in neutral aqueous solution, rendering such compounds unsuitable as prodrug forms.