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-naphthyridin-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-carboxylic acids (7, 10) via Curtius 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 bromoacetate and ethyl bromodifluoroacetate gave pyridothiazinones 60 and 61, respectively.
Singh
B
B
Sterling Winthrop Pharmaceuticals Research Division, Collegeville, Pennsylvania 19426.
Bacon
E R
ER
Robinson
S
S
Fritz
R K
RK
Lesher
G Y
GY
Kumar
V
V
Dority
J A
JA
Reuman
M
M
Kuo
G H
GH
Eissenstat
M A
MA
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000818:Animals; D004285:Dogs; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D020105:Milrinone; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D011728:Pyridones / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
D007093:Imidazoles; D011725:Pyridines; D011728:Pyridones; D013844:Thiazoles; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D020105:Milrinone