Synthesis and evaluation of 2-Amino-9-(3-acyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines and 2-Amino-9-(3-alkoxycarbonyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines as potential prodrugs of penciclovir

A series of 2-amino-9-(3-acyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines Chart 1 ;  Scheme 2 Chart 1.  Figure options Download full-size image Download high-quality image (148 K) Download as PowerPoint slide Scheme 2.  (a) (i) Trimethyl orthoacetate or triethyl orthopropionate (1.2 equiv), p-TsOH·H2O (0.1 equiv), DMF, rt, 2 h; (ii) H2O, 1 h; (b) methyl, ethyl, n-propyl, or isopropyl 4-nitrophenyl carbonate (1.2 equiv), DMAP (0.1 equiv), pyridine, 80°C, 20 h; (c) methyl, ethyl, n-propyl, or isopropyl 4-nitrophenyl carbonate (2.1 equiv), DMAP (0.1 equiv), pryidine, 80°C, 24 h. Figure options Download full-size image Download high-quality image (67 K) Download as PowerPoint slide and 2-amino-9-(3-alkoxycarbonyloxymethyl-4-alkoxycarbonyloxybut-1-yl)purines Chart 1 ;  Scheme 2 were synthesized as potential prodrugs of penciclovir. Treatment of 6-deoxypenciclovir with trimethyl orthoacetate or triethyl orthopropionate (1.2 equiv) in DMF in the presence of p-TsOH·H2O (0.1 equiv) followed by quenching with excess H2O gave the corresponding mono-O-acetyl or mono-O-propionyl compound, Scheme 2 ;  Scheme 4 Scheme 4.  (a) Lipase (PPL, PFL or CAL), sodium phosphate buffer (pH 7.0), rt; (b) lipase (PPL, PFL or CAL), vinyl acetate, acetone or toluene, rt. Figure options Download full-size image Download high-quality image (79 K) Download as PowerPoint slide or 18, in excellent yields of 95 and 92%, respectively. Reactions of Scheme 2 ;  Scheme 4 or 18 with an appropriate alkyl (Me, Et, n-Pr, and i-Pr) 4-nitrophenyl carbonate (1.2 equiv) in pyridine in the presence of a catalytic amount of DMAP (0.1 equiv) at 80°C afforded the monoacyl, monocarbonate derivatives of 6-deoxypenciclovir, Chart 1 ;  Scheme 2, in 86–94% yields. Similar reactions of 6-deoxypenciclovir with 2.1 equiv of alkyl 4-nitrophenyl carbonate produced the dicarbonate derivatives Chart 1 ;  Scheme 2 in 81–83% yields. Of the prodrugs tested in rats, 2-amino-9-(3-acetoxymethyl-4-isopropoxycarbonyloxybut-1-yl)purine Chart 1 ;  Scheme 2 achieved the highest mean urinary recovery of penciclovir (36%), followed in order by compounds Chart 1 ;  Scheme 2 (35%), Chart 1 ;  Scheme 2 (35%), Chart 1 ;  Scheme 2 (34%), Chart 1 ;  Scheme 2 (34%), Chart 1 ;  Scheme 2 (32%), Chart 1 ;  Scheme 2 (32%), and famciclovir (31%). The mean urinary recovery of penciclovir and concentrations of penciclovir in the blood from Chart 1 ;  Scheme 2 in mice were also slightly higher than those from famciclovir. The in vivo antiviral efficacy of Chart 1 ;  Scheme 2 in HSV-1-infected normal BALB/c mice was higher than those of famciclovir and valaciclovir in terms of mortality (100, 80, and 40%) and mean survival time (>21, 13±5.0 (SEM), and 13±1.6 days). Compound Chart 1 ;  Scheme 2 demonstrated an effective anti-hepadnaviral response with intrahepatic viral load being reduced by 90%, the viral supercoiled DNA levels reduced by 70% and Pre-S expression inhibited by 30% against duck hepatitis B virus (DHBV) in vivo, and did not cause any significant hepatotoxicity after 4 weeks of treatment.