| Abstract
| - A series of 2-amino-9-(1,3-dihydroxy-2-propoxymethyl)-6-fluoropurine mono- and diesters, 6a−h, were synthesized as potential prodrugs of ganciclovir and evaluated for their oral ganciclovirbioavailability in rats. Treatment of 2-amino-6-chloro-9-(1,3-dihydroxy-2-propoxymethyl)purine(4) with Me3N in DMF/THF (1/4) followed by the reaction of the resulting trimethylammoniumchloride salt 5 with KF in DMF gave 2-amino-9-(1,3-dihydroxy-2-propoxymethyl)-6-fluoropurine(2) in 83% yield. Esterification of 2 with an appropriate acid anhydride (Ac2O, (EtCO)2O, (n-PrCO)2O, or (i-PrCO)2O) (6 equiv for 6a−d or 1 equiv for 6e−h) in DMF in the presence of acatalytic amount of DMAP produced the diesters 6a−d in 92−98% yields and the monoesters6e−h in 37−44% yields. Of the prodrugs tested in rats, the monoisobutyrate 6h achieved thehighest ganciclovir bioavailability (45%) that is 15-fold higher than that from ganciclovir (3%),followed in order by the diisobutyrate 6d (42%), the diacetate 6a (41%), the monobutyrate 6g(41%), the monopropionate 6f (39%), the dipropionate 6b (35%), the dibutyrate 6c (35%), andthe monoacetate 6e (29%). The prodrugs 6e−h were found to be quite stable at pH 6.0 (t1/2 =>29 days), 7.4 (t1/2 = >7 days), and 8.0 (t1/2 = >2 days) but had relatively short half-lives atpH 1.2 (t1/2 = 60−83 min).
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