Kakigami T, Usui T, Tsukamoto K, Kataoka T
General Research Park, Sanwa Kagaku Kenkyusho Co., Ltd, Gifu, Japan.
Chem Pharm Bull (Tokyo). 1998 Jan;46(1):42-52. doi: 10.1248/cpb.46.42.
The title compounds (6-9) were prepared and evaluated for serotonin 5-HT4 agonistic activity in in vitro tests. Introducing a propyl or allyl group at the 3-position of benzamide caused only a slight enhancement of agonistic activity. Construction of the benzo[b]furan skeleton and 2,3-dihydrobenzo[b]furan skeleton caused a significant enhancement of the activity. 4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2-methylbenzo[b]furan-7-carboxamide (7b) hemifumarate was as potent as cisapride. 4-Amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2,3-dihydro-2-methylbenzo[b]furan-7-carboxamide (8a) hemifumarate, 4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2,3-dihydro-2-ethylbenzo[b]furan-7-carboxamide (8c) hemifumarate, and 4-amino-N-[2-(1-azabicyclo[3.3.0]octan-5-yl)ethyl]-5-chloro- 2,3-dimethylbenzo[b]furan-7-carboxamide (8d) hemifumarate were more potent than cisapride. Furthermore, 8a hemifumarate was free from dopamine D1, D2, serotonin 5-HT1, 5-HT2 and muscarine M1, M2 receptor binding activity in the in in vitro tests. On the other hand, construction of the indole skeleton caused a remarkable decrease in activity.
制备了标题化合物（6 - 9），并在体外试验中评估了它们对5 - 羟色胺5 - HT4的激动活性。在苯甲酰胺的3 - 位引入丙基或烯丙基仅使激动活性略有增强。苯并[b]呋喃骨架和2,3 - 二氢苯并[b]呋喃骨架的构建导致活性显著增强。4 - 氨基 - N - [2 - (1 - 氮杂双环[3.3.0]辛 - 5 - 基)乙基] - 5 - 氯 - 2 - 甲基苯并[b]呋喃 - 7 - 甲酰胺（7b）半富马酸盐与西沙必利效力相当。4 - 氨基 - N - [2 - (1 - 氮杂双环[3.3.0]辛 - 5 - 基)乙基] - 5 - 氯 - 2,3 - 二氢 - 2 - 甲基苯并[b]呋喃 - 7 - 甲酰胺（8a）半富马酸盐、4 - 氨基 - N - [2 - (1 - 氮杂双环[3.3.0]辛 - 5 - 基)乙基] - 5 - 氯 - 2,3 - 二氢 - 2 - 乙基苯并[b]呋喃 - 7 - 甲酰胺（8c）半富马酸盐和4 - 氨基 - N - [2 - (1 - 氮杂双环[3.3.0]辛 - 5 - 基)乙基] - 5 - 氯 - 2,3 - 二甲基苯并[b]呋喃 - 7 - 甲酰胺（8d）半富马酸盐比西沙必利更有效。此外，在体外试验中，8a半富马酸盐没有多巴胺D1、D2、5 - 羟色胺5 - HT1、5 - HT2以及毒蕈碱M1、M2受体结合活性。另一方面，吲哚骨架的构建导致活性显著降低。
