Synthesis of C-ribosyl imidazo[2,1-f][1,2,4]triazines as inhibitors of adenosine and AMP deaminases

The 3-beta-D-ribofuranoside 6 of the new imidazo[2,1-f][1,2,4]triazine 27 i s isomeric and isoelectronic with the nucleoside deaminoformycin 1 which is a good inhibitor of adenosine deaminase (ADA) while its 5'-monophosphate 2 is a good inhibitor of adenosine 5'-monophosphate deaminase (AMPDA). The 6 -methylsulfanyl derivative 7 of 6 is synthesized by condensation of the mon ocyclic 1,2,4-triazine 9 with bromo aldehyde 10, which is accompanied by cy clization to give the protected C-nucleoside 21; the 8-methylsulfanyl group of 21 is removed by replacement by hydrazine and oxidation. The 1,2,4-tria zine 9 cyclizes similarly with chloroacetaldehyde or its dimethyl acetal to give 6,8-bis(methylsulfanyl)imidazo[2,1-f][1,2,4]triazine 17, which is con verted into the parent heterocycle 27 by two routes, and into mono- and di- substituted derivatives (19, 20, 24, 25, 28-30) of the new ring system. Rib oside 7 is an inhibitor of mammalian ADA (IC50 40 mu M).