pH-rate profiles were calculated for the hydrolysis of the glycine (II), P-aspartic acid (III), and a-aspartic acid (IV) esters of pacetamidopbenol (I) at 25" and = 1.0 M. The hydrolysis of esters I1 and 111 occurred predominantly uia intermolecular reactions involving water, hydroxide ion, and the various ionic forms of the substrates. The hydrolysis of ester IV occurred predominantly uia intramolecular reactions. The catalytic effects of formate, acetate, and phosphate ions as well as of tromethamine on the degradation on ester I1 were similar to their effects on the hydrolysis of ethyl dichloroacetate. The efficient catalysis of the hydrolysis of ester I1 in bicarbonate buffers was consistent with a mechanism that involved carbon dioxide and the formation and decomposition of a carbamate intermediate.
Keyphrases 0 Prodrugs-of p-acetamidophenol, amino acid esters 0 p-Acetamidophenol-amino acid esters as prodrugs, synthesis and analysis Phenols-amino acid esters as prodrugs, synthesis and analysis 0 Amino acid esters-as prodrugs of p-acetamidophenol, synthesis and analysis Amino acid esters of p-acetamidophenol (I) were proposed (1) as potentially useful prodrugs. Appropriate selection of the amino acid can yield derivatives having greater or less water solubility than p-acetamidophenol and a range of chemical stabilities with respect to transformation to the parent drug. When the amino acid is a normal dietary constituent, the transformation of the prodrug to I within the body will not yield a toxic byproduct.
Similar arguments can be used to support the investigation of amino acid esters of other phenolic drugs as prodrugs. This paper describes the synthesis and stability against degradation of the glycine (II), P-aspartic (III), and a-aspartic acid (IV) esters of I.
Results
Characterization of Reactants-The elemental analysis and NMR spectrum of the glycine (11) derivative of p-acetamidophenol (I) were completely consistent with the conclusion that it was the hydrobromide salt of 11. The I esters of L-aspartic acid had elemental analyses and NMR spectra consistent with the conclusion that they were the hydrochloride salts of the isomers 111 and IV. Only one isomer could be obtained pure.
This isomer was concluded to be ester I11 rather than ester IV because its pKa value (2.04) was closer to that of ðyl aspartate (2.00) (2) than it was to that of a-ethyl aspartate (3.04) (2). Its pKa value also was very close to the first pKa values of aspartic acid (1.88) (3) and histidine (1.78) (3), two molecules in which the carboxyl group adjacent to an ammonium group is the first to ionize. The greater reactivity of IV made it difficult to isolate and characterize.