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Aspirin prodrugs: synthesis and hydrolysis of 2-acetoxybenzoate esters of various N-(hydroxyalkyl) amides

1988; Elsevier BV; Volume: 44; Issue: 1-3 Linguagem: Inglês

10.1016/0378-5173(88)90111-1

1873-3476

Henning Bundgaard, Niels Mørk Nielsen, Anders Buur,

Synthetic Organic Chemistry Methods

Three new esters of aspirin were synthesized and evaluated in vitro as potential prodrug forms of aspirin with the aim of depressing the gastrotoxicity of the drug by temporarily masking the carboxylic acid function. The esters, derived from N-(hydroxymethyl)acetamide, N-(hydroxymethyl)benzamide and ga-hydroxy-N-benzoylglycine benzyl ester, were all found to undergo a facile hydrolysis in aqueous solution of pH 0–8 with a quantitative regeneration of aspirin. The compounds were very easily cleaved at pH 7.4 but were more stable at lower pH values. Due to the great lability at pH 7.4 the compounds were also found to be cleaved quantitatively or predominantly to aspirin in the presence of human plasma rather than to the corresponding salicylate esters and hence salicylic acid.