Hosokami T, Kuretani M, Higashi K, Asano M, Ohya K, Takasugi N, Mafune E, Miki T
Exploratory Research Laboratories III, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
Chem Pharm Bull (Tokyo). 1992 Oct;40(10):2712-9. doi: 10.1248/cpb.40.2712.
A series of acyl derivatives of 2-(3,4-dimethoxyphenyl)ethylamine (4) were synthesized and evaluated for their effectiveness to prevent water-immersion stress-induced gastric ulceration when given intraperitoneally to rats. Among them N-[2-(3,4-dimethoxyphenyl)ethyl]-2-phenylaminoacetamide hydrochloride (15) had significant antiulcer activity. Further modification of the four parts of 15 revealed that only the introduction of a carbamoyl group into 2- or 3-position of the phenylamino part gave compounds (49-51, 54 and 55) which retained antiulcer activity comparable to the lead compound. However, the compounds (49-51 and 54) did not exert a prophylactic effect when administered orally except for the 3-substituted bezamide derivative 55. Alkyl substitution on the nitrogen of benzamide gave 3-[[[2-(3,4-dimethoxyphenyl)ethyl]carbamoyl]methyl] amino-N-methylbenzamide (66, DQ-2511) and the related compounds (67, 70, 74 and 77) which all had potent antiulcer activities at oral doses of 50-400 mg/kg.
合成了一系列2-(3,4-二甲氧基苯基)乙胺(4)的酰基衍生物，并对其腹腔注射给予大鼠时预防水浸应激诱导的胃溃疡的有效性进行了评估。其中N-[2-(3,4-二甲氧基苯基)乙基]-2-苯基氨基乙酰胺盐酸盐(15)具有显著的抗溃疡活性。对15的四个部分进行进一步修饰发现，只有在苯基氨基部分的2-或3-位引入氨基甲酰基才能得到具有与先导化合物相当的抗溃疡活性的化合物(49-51、54和55)。然而，除了3-取代的苯甲酰胺衍生物55外，化合物(49-51和54)口服给药时没有预防作用。苯甲酰胺氮上的烷基取代得到3-[[[2-(3,4-二甲氧基苯基)乙基]氨基甲酰基]甲基]氨基-N-甲基苯甲酰胺(66, DQ-2511)和相关化合物(67、70、74和77)，它们在50-400 mg/kg的口服剂量下均具有强大的抗溃疡活性。
