SYNTHESIS AND EVALUATION OF -HYDROXYMETHYL-4-ALKOXYCARBONYLOXYBUT-1-YL)PURINES AS POTENTIAL PRODRUGS OF PENCICLOVIR

A series of -hydroxymethyl-4-alkoxycarbonyloxybut-1-yl)purines (4-10) and 2-amino-9-(2-(2-oxo-1,3-dioxan-5-yl)ethyl)purine (1) were synthesi zed as potential prodrugs of penciclovir and evaluated for their oral penciclovir bioavailability in mice and rats. Treatment of 2-(2-benzyl oxyethyl)propane-1,3-diol (11) with 1,1'-carbonyldiimidazole in THF fo llowed by hydrogenolytic removal of the benzyl group of the resulting cyclic carbonate 12 gave 5-(2-hydroxyethyl)-1,3-dioxan-2-one 13). Mesy lation of the alcohol 13 and then a coupling reaction of the resulting mesylate 14 with 2-amino-6-chloropurine using anhydrous Cs2CO3 in DMF afforded -6-chloro-9-(2-(2-oxo-1,3-dioxan-5-yl)ethyl)purine (16) afte r purification by flash column chromatography on silica gel using EtOA c/MeCN/Et3N as eluent. Hydrogenation of the 6-chloro cyclic carbonate 16 followed by a ring-opening reaction of the 6-deoxy cyclic carbonate 1 in a mixture of an appropriate alcohol and CHCl3 using activated Si O2 as a Lewis acid afforded the corresponding alkyl monocarbonate deri vatives 3-10 in fair to good yields. Of the prodrugs tested in mice, t he isopropyl monocarbonate 6 achieved the highest mean urinary recover y of penciclovir (53%), followed in order by the propyl monocarbonate 6 (51%), the isopentyl monocarbonate 10 (51%), the ethyl monocarbonate 4 (50%), and famciclovir (48%). In rats, the methyl monocarbonate 3, 4, 6, the n-butyl monocarbonate 7, and 10 (39-41%) showed levels of me an urinary recovery of penciclovir similar to that from famciclovir (4 0%). The alkyl monocarbonates 4-10 were found to be quite stable in th e aqueous buffer solutions, and among them, 6 was the most stable with the half-lives (t(1/2)) of 88, >200, 61, and 26 days at pH 1.2, 6.0, 7.4, and 8.0, respectively. In addition, 6 was highly soluble in H2O ( 138.8 mg/ mt, 20 degrees C).