Philip Dudfield

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

The 3-β-D-ribofuranoside 6 of the new imidazo[2,1-f][1,2,4]triazine 27 is 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 monocyclic 1,2,4-triazine 9 with bromo aldehyde 10, which is accompanied by cyclization 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-triazine 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 converted 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. Riboside 7 is an inhibitor of mammalian ADA (IC50 40 µM).

Synthesis of C-ribosyl 1,2,4-triazolo[3,4-f][1,2,4]triazines as inhibitors of 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 deaminase (ADA) and AMP deaminase, respectively. In a search for such compounds we have synthesized 6-dimethylamino-3-(β-D-ribofuranosyl)-1,2,4-triazolo[3,4-f][1,2,4]triazine 4 in four steps (42% overall yield) from the readily 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 to the covalent hydrate 22, and is a modest inhibitor of mammalian ADA (IC50 180 µM).