Kumazawa T, Harakawa H, Obase H, Oiji Y, Tanaka H, Shuto K, Ishii A, Oka T, Nakamizo N
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Japan.
J Med Chem. 1988 Apr;31(4):779-85. doi: 10.1021/jm00399a016.
A series of substituted 5,11-dihydro[1]benzoxepino[3,4-b]pyridines was synthesized and evaluated for antiulcer activity in water immersion/restrained stress ulcer assay in rats. Structure-activity relationships are described. Most of the tested compounds exhibited low affinity to the muscarinic acetylcholine receptor. The molecular features for the best activities are the 2-(diethylamino)ethylenediamine group at the 5-position of the oxepin ring and an oxepin skeleton rather than a thiepin or a pyran skeleton. Methyl and chlorine substitution on the benzene ring reduced the activity. Compound 11, 5-[[2-(diethylamino)ethyl]amino]-5,11-dihydro[1]benzoxepino [3,4-b]pyridine trihydrochloride was selected for further evaluation. Synthesis and antiulcer activity of optically active 11 is described. There were no statistically significant differences between (+)-, (-)-, and (+/-)-11. Compound 11 showed weak antisecretory activity in pylorus-ligated rats. It is now under clinical evaluation as KW 5805.
合成了一系列取代的5,11-二氢[1]苯并氧杂环庚并[3,4-b]吡啶，并在大鼠水浸/束缚应激性溃疡试验中评估其抗溃疡活性。描述了构效关系。大多数受试化合物对毒蕈碱型乙酰胆碱受体的亲和力较低。具有最佳活性的分子特征是在氧杂环庚烷环的5位上有2-(二乙氨基)乙二胺基团以及氧杂环庚烷骨架而非硫杂环庚烷或吡喃骨架。苯环上的甲基和氯取代降低了活性。选择化合物11，即5-[[2-(二乙氨基)乙基]氨基]-5,11-二氢[1]苯并氧杂环庚并[3,4-b]吡啶三盐酸盐进行进一步评估。描述了光学活性的11的合成及抗溃疡活性。(+)-、(-)-和(+/-)-11之间没有统计学上显著的差异。化合物11在幽门结扎的大鼠中显示出较弱的抗分泌活性。它目前作为KW 5805正在进行临床评估。
