Synthesis of C-ribosyl 1,2,4-triazolo[3,4-f][1,2,4]triazines as inhibitorsof adenosine and AMP deaminases

Modified C-nucleosides and nucleotides with an enhanced tendency to undergo covalent hydration are of interest as potential inhibitors of adenosine de aminase (ADA) and AMP deaminase, respectively. In a search for such compoun ds we have synthesized 6-dimethylamino-3-(beta-D-ribofuranosyl)-1,2,4-triaz olo[3,4-f][1,2,4]triazine 4 in four steps (42% overall yield) from the read ily available allonic acid 6 and the hydrazine 7. The hydrazide 16 derived from 6 and 7 (78%) is converted directly into the cyclised chloro compound 19 (62%) with phosphorus trichloride oxide, followed by dechlorination (96% ) and deprotection (90%). Riboside 4 undergoes partial hydration in water t o the covalent hydrate 22, and is a modest inhibitor of mammalian ADA (IC50 180 mu M).