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 1,3-dihydro-5-methyl-6-(4-pyridinyl)- 2H-imidazo[4,5-b]pyridin-2-one (13a), 5-methyl-6-(4-pyridinyl)thiazolo [4,5-b]pyridin-2(3H)-one (51), and 7-methyl-6-(4-pyridinyl)-1,8-naphthy- ridin-2(1H)-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 (13) were prepared from 2-aminopyridine-3-carbo- xylic acids (7, 10) via Curtis rearrangement. 1,8-Naphthyridin-2(1H)-one (22) and the corresponding 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)-one (24), respectively, via Heck reaction. Thiazolo[4,5-b]pyridin-2(3H)-ones (35) were prepared from 6-bromo[3,4'- bipyridin]-6-amines (30) and (32) via a four-step sequence. Treatment of 6-amino-2-methyl[3,4'-bipyridine]-5-thiol (59) with ethyl bromoace- tate and ethyl bromodifluoroacetate gave pyridothiazinones (60) and (61), respectively