Synthesis and evaluation of 2-amino-6-fluoro-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine mono- and diesters as potential prodrugs of penciclovir

Abstract

2-Amino-6-fluoro-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (7), and its mono- and diesters 8–15 were prepared and evaluated for their potential as prodrugs of penciclovir. Treatment of 2-amino-6-chloro-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (5) with trimethylamine in THF followed by a reaction of the resulting trimethylammonium chloride salt 6 with KF in DMF afforded 2-amino-6-fluoro-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (7) in 80% yield. Esterification of 7 with an appropriate acid anhydride [Ac2O, (EtCO)2O, (n-PrCO)2O, or (i-PrCO)2O] in DMF in the presence of a catalytic amount of DMAP produced the mono-esters 8–11 in 42–45% yields and diesters 12–15 in 87–99% yields. Of the prodrugs tested in rats, the mono-isobutyrate 11 was the most efficiently absorbed and metabolized to 7, showing the mean maximum total concentration of penciclovir (5.5μg/mL) and 7 (10.8μg/mL) in the blood was much higher than the mean maximum concentration of penciclovir (11.5μg/mL) from famciclovir. However, the mean concentrations of penciclovir from 11 were lower than those from famciclovir because of the limited conversion of a major metabolite 7 to penciclovir by adenosine deaminase.