Watanabe Y, Usui H, Kobayashi S, Yoshiwara H, Shibano T, Tanaka T, Morishima Y, Yasuoka M, Kanao M
Research Institute, Daiichi Pharmaceutical Co., Ltd., Tokyo, Japan.
J Med Chem. 1992 Jan;35(1):189-94. doi: 10.1021/jm00079a026.
A series of bicyclic 1,2,4-triazol-3(2H)-one and 1,3,5-triazine-2,4(3H)-dione derivatives with a 4-[bis(4-fluoro-phenyl)methylene]piperidine or 4-(4-fluorobenzoyl)piperidine group has been prepared and tested for 5-HT2 and alpha 1 receptor antagonist activity. Among the compounds prepared, 2-[2-[4-[bis(4-fluorophenyl)methylene]-piperidin-1-yl]ethyl]- 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyridin-3(2H)-one (7b) had the most potent 5-HT2 antagonist activity, which was greater than ritanserin (2), while 7b did not show alpha 1 antagonist activity in vivo. The central 5-HT2 receptor antagonism was approximately 1/30 that of 2 when tested for the ability to block head twitches induced by 5-hydroxytryptophan. Compound 21b, 3-[2-[4-(4-fluorobenzoyl)piperidin-1-yl]ethyl]-6,7,8,9-tetrahydro- 2H- pyrido[1,2-a]-1,3,5-triazine-2,4(3H)-dione also displayed potent 5-HT2 antagonist activity. The compound had moderate alpha 1 receptor antagonism, and the potency inhibiting head twitches was about one-third that of ketanserin (1). These results indicate that 5,6,7,8-tetrahydro-1,2,4-triazolo[4,3-a]pyrimidin-3(2H)-one and 6,7,8,9-tetrahydro-2H-pyrido-[1,2-a]-1,3,5-triazine-2,4(3H)-dione ring systems are useful components of 5-HT2 antagonists.
已制备了一系列带有4-[双(4-氟苯基)亚甲基]哌啶或4-(4-氟苯甲酰基)哌啶基团的双环1,2,4-三唑-3(2H)-酮和1,3,5-三嗪-2,4(3H)-二酮衍生物，并对其5-HT2和α1受体拮抗剂活性进行了测试。在所制备的化合物中，2-[2-[4-[双(4-氟苯基)亚甲基]哌啶-1-基]乙基]-5,6,7,8-四氢-1,2,4-三唑并[4,3-a]吡啶-3(2H)-酮(7b)具有最强的5-HT2拮抗剂活性，其活性大于利坦色林(2)，而7b在体内未表现出α1拮抗剂活性。当测试其阻断5-羟色氨酸诱导的头部抽搐的能力时，其对中枢5-HT2受体的拮抗作用约为2的1/30。化合物21b，3-[2-[4-(4-氟苯甲酰基)哌啶-1-基]乙基]-6,7,8,9-四氢-2H-吡啶并[1,2-a]-1,3,5-三嗪-2,4(3H)-二酮也表现出强效的5-HT2拮抗剂活性。该化合物具有中等强度的α1受体拮抗作用，抑制头部抽搐的效力约为酮色林(1)的三分之一。这些结果表明，5,6,7,8-四氢-1,2,4-三唑并[4,3-a]嘧啶-3(2H)-酮和6,7,8,9-四氢-2H-吡啶并[1,2-a]-1,3,5-三嗪-2,4(3H)-二酮环系是5-HT2拮抗剂的有用组成部分。
