Synthesis of 4-substituted imidazo[4,5-d][1,2,3]triazine (2-azapurine)nucleosides

Several methods for functionalization of the 4-position of imidazo[4,5-d][1 ,2,3]triazin-4-one were investigated. These investigations were successful and led to the preparation of 4-amino, 4-triazol-1-yl, 4-methoxy, 4-methylt hio, 4-methylamino, 4-thio, 4-nitrobenzyl, and 4-unsubstituted 9-(beta-D-ri bofuranosyl)-imidazo-[4,5-d][1,2,3]triazine (2-azapurine ribosides). The 4- unsubstituted compound (19) was slightly active against HCMV in plaque and yield reduction experiments and was not cytotoxic at 100 mu M. The methylam ino (15), hydrazino (16), and p-nitrobenzylthio (20) were inactive against HCMV but slightly cytotoxic. The thiomethyl-substituted analog (21) was the most active with activity comparable to ganciclovir but with greater cytot oxicity. We conclude that even though none of the tested compounds had anti viral activity superior to ganciclovir, the new synthetic methods will prov ide a route to more interesting compounds.