Hydrolysis of N-(α-hydroxybenzyl)benzamide and other N-(α-hydroxyalkyl) amide derivatives: implications for the design of N-acyloxyalkyl-type prodrugs

Abstract

N-Acyloxyalkylation has become a commonly used approach to obtain prodrug forms of various NH-acidic drug substances. The regeneration of the parent drug occurs via a two-step reaction, enzymatic cleavage of the ester grouping followed by spontaneous decomposition of the N-hydroxyalkyl intermediate. The usefulness of this approach depends on the rate of decomposition of the latter intermediate and for several compounds such as amides their N-hydroxymethyl derivatives are too stable to make the approach useful. In this work the kinetics of decomposition of various N-α-hydroxyalkyl compounds derived from benzamide, thiobenzamide and various aldehydes (benzaldehyde, acetaldehyde and chloral) in aqueous solution at 37° C was determined and compared with that for the corresponding N-hydroxymethyl compounds derived from formaldehyde. All compounds showed apparent specific base catalysis and for N-(α-hydroxybenzyl)benzamide, specific acid catalysis was also observed. The derivatives were much more unstable at physiological conditions of pH and temperature than the N-hydroxymethyl derivatives; thus, whereas the half-life of decomposition of N-(hydroxymethyl)benzamide is 183 h at pH 7.4 and 37 ° C the half-life for N-(α-hydroxybenzyl)benzamide is only 6.5 min under the same conditions. The latter compound appears to be the first reported N-alkylol amide derived from an aromatic aldehyde and its synthesis is described. It is concluded that N-acyloxyalkylation may be a useful means of obtaining prodrug forms of also weakly NH-acidic compounds if the (acyloxy)alkyl α-halide normally used for the N-acyloxyalkylation is prepared from other aldehydes than formaldehyde e.g. benzaldehyde.