Kato S, Morie T, Hino K, Kon T, Naruto S, Yoshida N, Karasawa T, Matsumoto J
Research Laboratories, Dainippon Pharmaceutical Company, Ltd., Osaka, Japan.
J Med Chem. 1990 May;33(5):1406-13. doi: 10.1021/jm00167a020.
With the purpose of obtaining more potent and selective gastric prokinetic than metoclopramide (1), a new series of N-[(2-morpholinyl)alkyl]benzamides (17-52) were synthesized and their gastric prokinetic activity was evaluated by determining effects on the gastric emptying of phenol red semisolid meal and of resin pellets solid meal in rats and mice. The morpholinyl moiety was newly designed after consideration of the side-chain structure of cisapride (2) and produced the desired activity when coupled with the 4-amino-5-chloro-2-methoxybenzoyl group of both metoclopramide and cisapride. Modification of the substituents of the benzoyl group markedly influenced the activity. In particular, 4-amino-N-[(4-benzyl-2-morpholinyl)methyl]-5-chloro-2-methoxybenzamide (17) and the 4-(dimethylamino) and 2-ethoxy analogues (25 and 29) of 17 showed potent and selective gastric prokinetic activity along with a weak dopamine D2 receptor antagonistic activity.
为了获得比甲氧氯普胺（1）更有效且更具选择性的胃促动力药物，合成了一系列新的N-[(2-吗啉基)烷基]苯甲酰胺（17-52），并通过测定对大鼠和小鼠胃内酚红半固体餐和树脂小球固体餐排空的影响来评估它们的胃促动力活性。在考虑西沙必利（2）的侧链结构后新设计了吗啉基部分，当它与甲氧氯普胺和西沙必利的4-氨基-5-氯-2-甲氧基苯甲酰基偶联时产生了预期的活性。苯甲酰基取代基的修饰显著影响活性。特别是，4-氨基-N-[(4-苄基-2-吗啉基)甲基]-5-氯-2-甲氧基苯甲酰胺（17）以及17的4-(二甲氨基)和2-乙氧基类似物（25和29）显示出强效且选择性的胃促动力活性以及较弱的多巴胺D2受体拮抗活性。
