N-Alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) prodrugs of carboxylic acid containing drugs

Synthesis and hydrolysis in aqueous buffers of novel N-alkyl-N-alkyloxycarbonylaminomethyl (NANAOCAM) and N-aryl-N-alkyloxycarbonylaminomethyl (NArNAOCAM) derivatives of carboxylic acid containing drugs were carried out. The hydrolysis follows a SN1 type mechanism and is dependent on the nucleofugacity of the leaving group. Topical delivery of the NANAOCAM derivative of naproxen from IPM across hairless mice skin was examined in in vitro diffusion cell experiments. The prodrug was 4.5-fold less lipid soluble, 2.4-fold less water soluble and 3.6-fold less permeable than the parent drug.

Graphical abstractN-Alkyl-N-alkyloxycarbonylaminomethyl and N-aryl-N-alkyloxycarbonylaminomethyl derivatives of carboxylic acids hydrolyse to the parent carboxylic acid both chemically and thereby serving as useful prodrugs of carboxylic acid containing drugs.Figure optionsDownload full-size imageDownload as PowerPoint slide