Synthesis of 4-Substituted Imidazo[4,5-d][1,2,3]triazine (2-Azapurine)nucleosides |
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| Authors: | Steven Krawczyk Michael T. Migawa John C. Drach Leroy B. Townsend |
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| Affiliation: | 1. Department of Chemistry, College of Literature, Science and the Arts, Department of Medicinal Chemistry, College of Pharmacy, and Department of Biologic and Material Sciences, School of Dentistry , University of Michigan , Ann Arbor, Michigan, 48109-1065;2. Gilead Sciences , 333 Lakeside Drive, Foster City, California, 94404;3. ISIS Pharmaceuticals, Inc. , 2292 Faraday Avenue, Carlsbad, CA, 92008 |
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| Abstract: | Abstract 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-methylthio, 4-methylamino, 4-thio, 4-nitrobenzyl, and 4-unsubstituted 9-(β-D-ribofuranosyl)-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 μM. The methylamino (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 cytotoxicity. We conclude that even though none of the tested compounds had antiviral activity superior to ganciclovir, the new synthetic methods will provide a route to more interesting compounds. |
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