SYNTHESIS AND ANTIVIRAL ACTIVITY OF 9-ALKOXYPURINES .1. 9-(3-HYDROXYPROPOXY)PURINES AND 9-[3-HYDROXY-2-(HYDROXYMETHYL)PROPOXY]PURINES

Reaction of hydroxyl-protected derivatives of hydroxyalkoxyamines (3a,b,c) with either 4,6-dichloro-2,5-diform-amidopyrimidine (5) or 4,6-dichloro-5-formamidopyrimidine (31) and subsequent cyclization of the resultant 6-(alkoxyamino)pyrimidines (6,17, 32, 35) by heating with diethoxymethyl acetate afforded 9-alkoxy-6-chloropurines (7, 18, 33, 36), which were converted subsequently to 9-(3-hydroxypropoxy)- and 9-[3-hydroxy-2-(hydroxymethyl)propoxy] derivatives of guanine, 2-amino-6-chloropurine, 2-amino-6-alkoxypurines, 2-aminopurine, 2,6-diaminopurine, adenine, hypoxanthine, and 6-methoxypurine (8,12,13,19-21,23-26, 34, 37-39). Carboxylic acid esters (9-11, 14-16, 27-29) and a cyclic phosphate derivative (22) of the 9-(hydroxyalkoxy)guanines (8, 21) and 2-amino-9-(hydroxyalkoxy)purines (13, 26) were also prepared. The guanine derivatives (8, 21) showed potent and selective activity against herpes simplex virus types 1 and 2 and varicella zoster virus in cell cultures and 8 is more active than acyclovir. Although without significant antiviral activity in cell cultures, the 2-aminopurines (13,14-16, 26-29) and 2-amino-6-alkoxypurines (12,23-25) are well absorbed after oral administration to mice and are converted efficiently to the antiviral guanine derivatives (8, 21) in vivo. © 1990, American Chemical Society. All rights reserved.