TY - JOUR
T1 - Synthesis and evaluation of 2-amino-9-(1,3-dihydroxy-2-propoxymethyl)- 6-fluoropurine mono- and diesters as potential prodrugs of ganciclovir
AU - Kim, Dae Kee
AU - Chang, Kieyoung
AU - Im, Guang Jin
AU - Kim, Hun Taek
AU - Lee, Namkyu
AU - Kim, Key H.
PY - 1999
Y1 - 1999
N2 - 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 ganciclovir bioavailability 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 trimethylammonium chloride 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, (nPrCO)2O, or (i- PrCO)2O) (6 equiv for 6a-d or 1 equiv for 6e-h) in DMF in the presence of a catalytic amount of DMAP produced the diesters 6a-d in 92-98% yields and the monoesters 6e-h in 37-44% yields. Of the prodrugs tested in rats, the monoisobutyrate 6h achieved the highest 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%), and the monoacetate 6e (29%). The prodrugs 6e-h were found to be quite stable at pH 6.0 (t( 1/2 ) = >29 days), 7.4 (t( 1/2 ) = >7 days), and 8.0 (t( 1/2 ) = >2 days) but had relatively short half-lives at pH 1.2 (t( 1/2 ) = 60- 83 min).
AB - 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 ganciclovir bioavailability 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 trimethylammonium chloride 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, (nPrCO)2O, or (i- PrCO)2O) (6 equiv for 6a-d or 1 equiv for 6e-h) in DMF in the presence of a catalytic amount of DMAP produced the diesters 6a-d in 92-98% yields and the monoesters 6e-h in 37-44% yields. Of the prodrugs tested in rats, the monoisobutyrate 6h achieved the highest 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%), and the monoacetate 6e (29%). The prodrugs 6e-h were found to be quite stable at pH 6.0 (t( 1/2 ) = >29 days), 7.4 (t( 1/2 ) = >7 days), and 8.0 (t( 1/2 ) = >2 days) but had relatively short half-lives at pH 1.2 (t( 1/2 ) = 60- 83 min).
UR - http://www.scopus.com/inward/record.url?scp=0032960410&partnerID=8YFLogxK
U2 - 10.1021/jm980321+
DO - 10.1021/jm980321+
M3 - Article
C2 - 9925738
AN - SCOPUS:0032960410
SN - 0022-2623
VL - 42
SP - 324
EP - 328
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 2
ER -