Synthesis and evaluation of amino acid esters of 6-deoxypenciclovir as potential prodrugs of penciclovir

The amino acid ester derivatives of 6-deoxypenciclovir, 11-20, were synthesized as potential prodrugs of penciclovir, and were evaluated for their oral penciclovir bioavailability in mice and rats. Esterification of 6-deoxypenciclovir with N-carbobenzyloxyglycine, -l-alanine, -l-valine, -l-leucine, or -l-isoleucine (3.75equiv.) using conventional coupling method (DCC/DMAP) afforded the mono-O-ester derivatives 1-5 in 47-55% yields as a mixture of two diastereomers along with the di-O-ester derivatives 6-10 in 20-29% yields. Reductive cleavage of carbobenzyloxy (Cbz) group (10% Pd/C, 1 atmosphere of H₂, room temperature in methanol) followed by subsequent treatment of the resulting free amine with methanolic HCl solution provided the mono-O-ester derivatives 11-15 as di-HCl salt in 51-98% yields and the di-O-ester derivatives 16-20 as tri-HCl salt in 65-98% yields. Of the prodrugs tested in mice and rats, 6-deoxypenciclovir O-l-valinate (13), O-l-isoleucinate (15), and O,O-di-glycinate (16) showed significantly higher urinary recovery of penciclovir compared with that of penciclovir, but those are somewhat lower than that of famciclovir. Copyright (C) 1999 Elsevier Science Ltd.