新型环磷酸腺苷磷酸二酯酶III抑制剂：咪唑并[4,5 - b]吡啶 - 2(3H) - 酮和噻唑并[4,5 - b]吡啶 - 2(3H) - 酮及其类似物。

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.

作者信息

Singh B, Bacon E R, Robinson S, Fritz R K, Lesher G Y, Kumar V, Dority J A, Reuman M, Kuo G H, Eissenstat M A

机构信息

Sterling Winthrop Pharmaceuticals Research Division, Collegeville, Pennsylvania 19426.

出版信息

J Med Chem. 1994 Jan 21;37(2):248-54. doi: 10.1021/jm00028a007.

DOI:10.1021/jm00028a007

PMID:8295212

Abstract

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.

摘要

米力农转化为1,3 - 二氢 - 5 - 甲基 - 6 - (4 - 吡啶基)-2H - 咪唑并[4,5 - b]吡啶 - 2 - 酮(13a)、5 - 甲基 - 6 - (4 - 吡啶基)噻唑并[4,5 - b]吡啶 - 2(3H) - 酮(51)和7 - 甲基 - 6 - (4 - 吡啶基)-1,8 - 萘啶 - 2(1H) - 酮(22)后，得到了非常有效的环磷酸腺苷磷酸二酯酶III抑制剂，其体外活性在纳摩尔范围内。1,3 - 二氢 - 2H - 咪唑并[4,5 - b]吡啶 - 2 - 酮13是由2 - 氨基吡啶 - 3 - 羧酸(7,10)通过库尔提斯重排反应制备的。1,8 - 萘啶 - 2(1H) - 酮22和相应的3,4 - 二氢衍生物28分别由5 - 溴 - 2 - 甲基[3,4'-联吡啶]-6 - 胺(21)和5 - 溴 - 2 - 甲基[3,4 - 联吡啶]-6(1H) - 酮(24)通过赫克反应制备。噻唑并[4,5 - b]吡啶 - 2(3H) - 酮35是由6 - 溴[3,4'-联吡啶]-6 - 胺30和32通过一个四步反应序列制备的。用溴乙酸乙酯和溴二氟乙酸乙酯处理6 - 氨基 - 2 - 甲基[3,4'-联吡啶]-5 - 硫醇(59)，分别得到吡啶并噻嗪酮60和61。