NOVEL CAMP PDE-III INHIBITORS - IMIDAZO[4,5-B]PYRIDIN-2(3H)-ONES AND THIAZOLO[4,5-B]PYRIDIN-2(3H)-ONES AND THEIR ANALOGS

The transformation of milrinone to hyl-6-(4-pyridinyl)-2H-imidazo[4,5- b]pyridin-2-one (13a), yl-6-(4-pyridinyl)thiazolo[4,5-b]pyridin-2(3H)- one (51), and -methyl-6-(4-pyridinyl)-1,8-naphthyridin-2(vl)-one (22) resulted in very potent cAMP PDE III inhibitors with in vitro activity in the nanomolar range. 1,3-Dihydro-2H-imidazo[4,5-b]pyridin-2-ones 1 3 were prepared from 2-aminopyridine-3-carboxylic acids (7, 10) via Cu rtius rearrangement. 1,8-Naphthyridin-2(1H)-one 22 and the correspondi ng 3,4-dihydro derivative 28 were prepared from 5-bromo-2-methyl[3,4'- bipyridin]-6-amine (21) and 5-bromo-2-methyl[3,4-bipyridin]-6(1H)-on ( 24), respectively, via Heck reaction. Thiazolo[4,5-b] pyridin-2(3H)-on es 35 were prepared from 6-bromo[3,4'-bipyridin]-8-amines 30 and 32 vi a a four-step sequence. Treatment of 6-amino-2-methyl[3,4'-bipyridine] -5-thiol (59) with ethyl bromoacetate and ethyl bromodifluoroacetate g ave pyridothiazinones 60 and 61, respectiveiy.