Synthesis and evaluation of 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl)purines as potential prodrugs of penciclovir.
A series of 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl)purines (4-10) and 2-amino-9-(2-(2-oxo-1,3-dioxan-5-yl)ethyl)purine (1) were synthesized as potential prodrugs of penciclovir and evaluated for their oral penciclovir bioavailability in mice and rats. Treatment of 2-(2-benzyloxyethyl)propane-1,3-diol (11) with 1,1'-carbonyldiimidazole in THF followed by hydrogenolytic removal of the benzyl group of the resulting cyclic carbonate 12 gave 5-(2-hydroxyethyl)-1,3-dioxan-2-one (13). Mesylation 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 2-amino-6-chloro-9-(2-(2-oxo-1,3-dioxan-5-yl)ethyl)purine (16) after purification by flash column chromatography on silica gel using EtOAc/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 SiO2 as a Lewis acid afforded the corresponding alkyl monocarbonate derivatives 3-10 in fair to good yields. Of the prodrugs tested in mice, the isopropyl monocarbonate 6 achieved the highest mean urinary recovery of penciclovir (53%), followed in order by the propyl monocarbonate 5 (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 mean urinary recovery of penciclovir similar to that from famciclovir (40%). The alkyl monocarbonates 4-10 were found to be quite stable in the aqueous buffer solutions, and among them, 6 was the most stable with the half-lives (t1/2) 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/mL, 20 degrees C).
Life Science Research Center, SK Chemicals, 600 Jungja-Dong, Changan-Ku, Suwon-Si, Kyungki-Do 440-745, Korea.
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Kim
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Lee
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Kim
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Chang
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JS
Kim
G J
GJ
Im
W S
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Choi
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Jung
T S
TS
Kim
Y Y
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Hwang
D S
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Min
K A
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Um
Y B
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Cho
K H
KH
Kim
D000212:Acyclovir / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D002461:Cell Line, Transformed; D002522:Chlorocebus aethiops; D004355:Drug Stability; D006147:Guanine; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
C114188:2-amino-9-(3-hydroxymethyl-4-isopropoxycarbonyloxybut-1-yl)pyrine; D000998:Antiviral Agents; D011355:Prodrugs; D011687:Purines; C053539:penciclovir; D006147:Guanine; D000212:Acyclovir