SYNTHESIS AND BIOLOGICAL-ACTIVITY OF BETA-D-RIBOFURANOSYL)IMIDAZO[4,5-D]PYRIDAZIN-7-ONE

The Lewis acid catalyzed ribosylation of -4(5)-(5-methyl-1,2,4-oxadiaz ol-3-yl)-1H-imidazole (2) with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-r ibose gave only zoyl-beta-D-ribofuranosyl)imidazole-5-carbonitrile (3) . Treatment of 3 with methanolic ammonia gave )-1-(beta-D-ribofuranosy l)imidazole-5-carbonitrile (4). Treatment of 4 with hydrogen peroxide in ammonia gave l)-1-(beta-D-ribofuranosyl)imidazole-5-carboxamide (5) . When 5 was treated with sodium hydride in dimethyl-sulfoxide a rearr angement (mononuclear heterocyclic rearrangement, m.h.r.) occurred to give a modest 17% yield of 4-acetamido-1-(beta-D ribofuranosyl)imidazo [4,5-d]pyridazin-7-one (6). Treatment of 6 with aqueous ammonia gave 4 -amino-1-(beta-D-ribofuranosyl)imidazo [4,5-d]pyridazin-7-one(1). The synthesis of compound 1 using the m.h.r. for the preparation of a sing le regioisomer of the imidazo[4,5-d]pyridazin-7-one ring system, has d emonstrated the potential of this methodology. Neither compound 5 nor 6 affected the growth or replication of human foreskin fibroblasts (HF F cells) or human cytomegalovirus (HCMV). In contrast, compound 1 inhi bited the replication of HCMV (IC50=29 mu M) but produced visual cytot oxicity in uninfected HFF cells (IC50=70 mu M). Compound 1 also inhibi ted the proliferation of L1210 murine leukemic cells (IC50=25 mu M), w hereas the precursors 4 and 6 did not.