CN109956931B - 四氢吡咯类化合物、其制备方法、药物组合物及用途 - Google Patents
四氢吡咯类化合物、其制备方法、药物组合物及用途 Download PDFInfo
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- CN109956931B CN109956931B CN201811600639.8A CN201811600639A CN109956931B CN 109956931 B CN109956931 B CN 109956931B CN 201811600639 A CN201811600639 A CN 201811600639A CN 109956931 B CN109956931 B CN 109956931B
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Classifications
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Abstract
本发明公开了一种四氢吡咯类化合物、其制备方法、药物组合物及用途。本发明的四氢吡咯类化合物如通式(I)所示。本发明的四氢吡咯类化合物对精神分裂症阳性症状具有较佳抑制作用,其作用强度与阳性药物奥氮平相当,或略强。另外,本发明的化合物对D2受体和DAT受体具有双重抑制作用,可以有效治疗精神分裂症并改善阴性症状和认知功能,同时减少椎体副作用和催乳素的分泌。
Description
技术领域
本发明涉及一种四氢吡咯类化合物、其制备方法、药物组合物及用途。
背景技术
精神分裂症(Schizophrenic disorder)是一种极为严重的精神疾病,其表现为与现实缺乏联系,存在幻觉、妄想和异常思维,社会功能明显损害。精神分裂症是一种世界性的公共卫生问题,其全球的总患病率大约在0.8-1%。
精神分裂症的发病高峰年龄在男性为18-25岁,女性则在26-45岁。但在儿童或青少年以及晚年发病的患者并不少见。不同的患者其症状的严重程度和临床表现形式各不相同。精神分裂症可归纳为阳性症状、阴性症状和识别记忆障碍三种。
阳性症状(Positive symptoms),表现为幻觉和妄想,躁动,偏执狂,思维障碍和行为异常;阴性症状(Negative Symptoms)表现为情感迟钝、寡言少语、兴趣缺乏,快感缺失以及孤僻不合群;识别记忆障碍(Cognitive Deficits),表现为注意力不能集中,记忆力严重衰退,无能力按计划行为。
一个精神分裂症患者可以存在以上一组或所有的症状,这些症状常常比较严重,明显影响患者的工作、人际交往,甚至是个人生活。治疗精神分裂症的总目的是减轻症状,避免复发,恢复功能缺陷,尽可能地增进康复。
目前对精神分裂症的发病机制有多种假说,其中大脑多巴胺能神经系统功能亢奋假说是精神分裂症传统的假说,认为发病原因可能与大脑中多巴胺功能失调有关。多巴胺(DA)是一种儿茶酚胺神经递质,其生物活性通过G蛋白偶联受体(GPCR)介导。在人体中已经发现了5种多巴胺受体亚型D1-D5。多巴胺转运体(dopamine transporter,DAT)是位于多巴胺神经元突触前膜的糖蛋白,重摄取突触间隙中的多巴胺进入前膜,是终止多巴胺生理效应的主要方式。
多巴胺在脑内有几条通路,其中中脑-边缘通路(Mesolimbic Pathway)和中脑-皮质通路(Nigtostriatal Pathway)与精神,情绪,情感等行为有关。第三条是结节-漏斗通路(Hypophyseal-Infundibular),主管垂体前叶的内分泌功能。第四条是黑质-纹状体通路(Nigro-Striatal),属于锥体外系,使运动协调。
当对中脑-边缘通路中的多巴胺受体抑制时可产生抗精神分裂症阳性症状作用;对黑质-纹状体通路的多巴胺受体抑制时则产生锥体外系副作用;对大脑皮质系统内多巴胺受体阻断会产生阴性症状;阻断结节-漏斗通路内多巴胺通路会导致内分泌方面改变。
第一代抗精神分裂症药物又叫典型抗精神病药物,该类药物主要包括选择性多巴胺D2受体抑制剂,但常常伴随较严重的锥体外系副作用。第二代抗精神分裂症药物又叫非典型抗精神病药物,这类药物以五羟色胺5-HT2A/5-HT2C受体阻断剂和多巴胺D2受体抑制剂为主,对精神分裂症阳性症状的治疗作用与第一代抗精神分裂症药物相近,但具有明显较小的锥体外系副作用。
目前临床使用的第一代和第二代精神分裂症治疗药物对精神分裂症阳性症状有比较好的治疗作用,可以减轻或消除妄想、幻觉和思维障碍等症状。在急性症状消除以后,维持使用抗精神病药物可以减少复发的可能。但是,几乎所有的临床药物对精神分裂症阴性症状、认知缺陷和记忆障碍均无显著治疗作用,这导致了患者生活质量的降低。
Kulagowski等人(J.Med.Chem.1996,39,1941-1942)报道了带有4-苯基和4-羟基取代的哌啶类化合物L741626作为多巴胺D2受体拮抗剂的活性,但未见其DAT抑制活性的报道。Sikazwe等人(Bioorg.Med.Chem.17(2009)1716-1723)报道了具有3-苯基和3-羟基取代的四氢吡咯类化合物4,显示了中等强度的D4受体拮抗作用,而对D2受体基本没有拮抗作用。化合物L741626和化合物4的结构如下:
目前未见其它具有类似结构化合物作为D2受体和DAT受体双重拮抗剂或抑制剂的报道。
发明内容
本发明提供了一种四氢吡咯类化合物、其制备方法、药物组合物及用途。本发明的四氢吡咯类化合物对精神分裂症阳性症状具有较佳抑制作用,其作用强度与阳性药物奥氮平相当,或略强。另外,本发明的化合物对D2受体和DAT受体具有双重抑制作用,可以有效治疗精神分裂症并改善阴性症状和认知功能,同时减少椎体副作用和催乳素的分泌。
本发明提供了一种通式(I)所示的四氢吡咯类化合物,其对映异构体、非对映异构体、同位素化合物、药学上可接受的前药、药用酯或药学上可接受的盐:
其中:
A1为C-R1或N;
A2为C-R1a或N;
A3为C-R1b或N;
A4为C-R1c或N;
A5为C-R1d或N;
A1、A2、A3、A4和A5中最多不超过3个氮原子;
R1、R1a、R1b、R1c和R1d分别独立地为氢原子、卤素、氰基、硝基、取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基、取代或未取代的C3-C8的环烷基、取代或未取代的C6-C14的芳基、取代或未取代的C2-C10的杂芳基、
或者,相邻的两个R1、R1a;或R1a、R1b;或R1b、R1c;或R1c、R1d和与其相连的原子一起形成取代或未取代的C3-C8的环烷基、取代或未取代的C2-C8的杂环基、取代或未取代的C6-C14的芳基、或、取代或未取代的C2-C10的杂芳基;所述的C2-C8的杂环基中的杂原子选自N、O和S,杂原子数为1-3,当杂原子数为2或3时,杂原子相同或不同;所述的C2-C8的杂环基为饱和C2-C8的杂环基或不饱和C2-C8的杂环基,环原子选自C、N、O和S中的两种、三种或四种,当环原子为C或S时,C或S可与氧形成
R2和R3分别独立地为氢原子、羟基、氨基、取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基、取代或未取代的C3-C8的环烷基、取代或未取代的C6-C14的芳基、取代或未取代的C2-C10的杂芳基、
R2a和R2b分别独立地为氢原子、取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基、取代或未取代的C3-C8的环烷基、取代或未取代的C6-C14的芳基、取代或未取代的C2-C10的杂芳基、羟基或
R2c为取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基、取代或未取代的C3-C8的环烷基、取代或未取代的C6-C14的芳基、或,取代或未取代的C2-C10的杂芳基;
R2d和R2e分别独立地为氢原子、取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基、取代或未取代的C3-C8的环烷基、取代或未取代的C6-C14的芳基、或,取代或未取代的C2-C10的杂芳基;
R4和R5分别独立地为氢原子、取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基、取代或未取代的C3-C8的环烷基、取代或未取代的C6-C14的芳基、取代或未取代的C2-C10的杂芳基、
R4a为氢原子、取代或未取代的C1-C4的烷基、取代或未取代的C2-C4的烯基、取代或未取代的C2-C4的炔基、取代或未取代的C1-C4的烷氧基、取代或未取代的C3-C8的环烷基、取代或未取代的C6-C14的芳基、取代或未取代的C2-C10的杂芳基或
R4b、R4c、R4d和R4e分别独立地为氢原子、取代或未取代的C1-C4的烷基、取代或未取代的C3-C8的环烷基、取代或未取代的C6-C14的芳基、或,取代或未取代的C2-C10的杂芳基;
R6为氢原子、取代或未取代的C1-C4的烷基、取代或未取代的C3-C8的环烷基、取代或未取代的C6-C14的芳基、取代或未取代的C2-C10的杂芳基、R6a、R6b、R7和R8分别独立地为氢原子、氨基、羟基、取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基、取代或未取代的C3-C8的环烷基、取代或未取代的C6-C14的芳基、或,取代或未取代的C2-C10的杂芳基;
R6c和R6d分别独立地为氢原子、氨基、取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基、取代或未取代的C3-C8的环烷基、取代或未取代的C6-C14的芳基、或,取代或未取代的C2-C10的杂芳基;
R9和R10分别独立地为取代或未取代的C1-C4的烷基、取代或未取代的C3-C8的环烷基、取代或未取代的C6-C14的芳基、或,取代或未取代的C2-C10的杂芳基;
B1为氢原子、氰基、卤素、巯基、羧基、氨基、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基;
B2、B3、B4、B5、B6和B7分别独立地为氢原子、羟基、取代或未取代的C1-C4的烷氧基、氰基、卤素、巯基、羧基、氨基、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基;
R11a为氢原子、取代或未取代的C1-C4的烷基、取代或未取代的C3-C8的环烷基、取代或未取代的C6-C14的芳基、或,取代或未取代的C2-C10的杂芳基;
Z为取代或未取代的C2-C10的杂芳基;
所述的取代的C1-C4的烷基(R1、R2、R3、R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R4b、R4c、R4d、R4e、R6、R6a、R6b、R7、R8、R6c、R6d、R9、R10、B1、B2、B3、R11或R11a)、所述的取代的C1-C4的烷氧基(R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R6a、R6b、R7、R8、R6c、R6d、B2或B3)、所述的取代的C3-C8的环烷基(R1、R2、R3、R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R4b、R4c、R4d、R4e、R6、R6a、R6b、R7、R8、R6c、R6d、R9、R10、B1、B2、B3、R11或R11a)、所述的C6-C14的芳基(R1、R2、R3、R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R4b、R4c、R4d、R4e、R6、R6a、R6b、R7、R8、R6c、R6d、R9、R10、R11或R11a)、所述的C2-C10的杂芳基(R1、R2、R3、R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R4b、R4c、R4d、R4e、R6、R6a、R6b、R7、R8、R6c、R6d、R9、R10、R11、R11a或Z)、所述的取代的C2-C4的烯基(R4a)、所述的取代的C2-C4的炔基(R4a)和所述的取代的C2-C8的杂环基中的取代基各自独立地为下列基团中的一个或多个:C1-C4的烷基、被卤素和/或羟基取代的C1-C4的烷基、卤素、羟基、氨基、氰基、硝基、巯基或羧基;当所述的取代基为多个时,所述的取代基相同或不同;
所述的C2-C10的杂芳基中的杂原子选自O、N和S,杂原子数为1-3个,杂原子相同或不同;
用*标注的碳是指S构型手性碳、R构型手性碳或非手性碳。
在本发明一优选实施方案中,当取代基为C1-C4的烷基时,所述的C1-C4的烷基优选甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
在本发明一优选实施方案中,当取代基为被卤素和/或羟基取代的C1-C4的烷基时,所述的被卤素和/或羟基取代的C1-C4的烷基优选C1-C4的烷基中的一个或多个氢被卤素和/或羟基所取代。所述的被卤素和/或羟基取代的C1-C4的烷基优选
在本发明一优选实施方案中,当取代基为卤素时,所述的卤素优选F、Cl、Br或I。
在本发明一优选实施方案中,所述的取代的C1-C4的烷基(R1、R1a、R1b、R1c、R1d、R2、R3、R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R4b、R4c、R4d、R4e、R6、R6a、R6b、R7、R8、R6c、R6d、R9、R10、B1、B2、B3、R11和R11a中)、所述的取代的C1-C4的烷氧基(R2、R3、R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R6a、R6b、R7、R8、R6c、R6d、B2和B3中)、所述的取代的C3-C8的环烷基(R1、R1a、R1b、R1c、R1d、R2、R3、R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R4b、R4c、R4d、R4e、R6、R6a、R6b、R7、R8、R6c、R6d、R9、R10、B1、B2、B3、R11和R11a中)、所述的C6-C14的芳基(R1、R1a、R1b、R1c、R1d、R2、R3、R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R4b、R4c、R4d、R4e、R6、R6a、R6b、R7、R8、R6c、R6d、R9、R10、R11、R11a和Z中)、所述的C2-C10的杂芳基(R1、R1a、R1b、R1c、R1d、R2、R3、R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R4b、R4c、R4d、R4e、R6、R6a、R6b、R7、R8、R6c、R6d、R9、R10、R11、R11a和Z中)、所述的取代的C2-C4的烯基(R4a)、所述的取代的C2-C4的炔基(R4a)和所述的取代的C2-C8的杂环基中的取代基各自独立地为下列基团中的一个或多个:卤素、羟基、氨基、氰基或巯基。
在本发明一优选实施方案中,所述的取代的C1-C4的烷基(R1、R2、R3、R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R4b、R4c、R4d、R4e、R6、R6a、R6b、R7、R8、R6c、R6d、R9、R10、B1、B2、B3、R11和R11a中)、所述的取代的C1-C4的烷氧基(R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R6a、R6b、R7、R8、R6c、R6d、B2和B3中)、所述的取代的C3-C8的环烷基(R1、R2、R3、R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R4b、R4c、R4d、R4e、R6、R6a、R6b、R7、R8、R6c、R6d、R9、R10、B1、B2、B3、R11和R11a中)、所述的C6-C14的芳基(R1、R2、R3、R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R4b、R4c、R4d、R4e、R6、R6a、R6b、R7、R8、R6c、R6d、R9、R10、R11和R11a中)、所述的C2-C10的杂芳基(R1、R2、R3、R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R4b、R4c、R4d、R4e、R6、R6a、R6b、R7、R8、R6c、R6d、R9、R10、R11、R11a和Z中)、所述的取代的C2-C4的烯基(R4a)、所述的取代的C2-C4的炔基(R4a)和所述的取代的C2-C8的杂环基中的取代基各自独立地为下列基团中的一个或多个:C1-C4的烷基、C3-C8的环烷基、卤素、羟基、氨基、氰基或巯基。
R1、R1a、R1b、R1c、R1d、B1、B2、B3、B4、B5、B6和B7中,所述的卤素优选F、Cl、Br或I。
R1、R1a、R1b、R1c、R1d、R2、R3、R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R4b、R4c、R4d、R4e、R6、R6a、R6b、R7、R8、R6c、R6d、R9、R10、B1、B2、B3、R11和R11a中,所述的取代或未取代的C1-C4的烷基中的C1-C4的烷基优选甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基;所述的取代的C1-C4的烷基中的取代基优选下列基团中的一个或多个:卤素、羟基或C3-C8的环烷基;所述的取代的C1-C4的烷基优选
R2、R3、R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R6a、R6b、R7、R8、R6c、R6d、B2和B3中,所述的取代或未取代的C1-C4的烷氧基中的C1-C4的烷氧基优选甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基或叔丁氧基。
R1、R1a、R1b、R1c、R1d、R2、R3、R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R4b、R4c、R4d、R4e、R6、R6a、R6b、R7、R8、R6c、R6d、R9、R10、B1、B2、B3、R11和R11a中,所述的取代或未取代的C3-C8的环烷基中的C3-C8的环烷基优选环丙基、环丁基、环戊基、环己基、环庚基或环辛基。R1、R1a、R1b、R1c、R1d、R2、R3、R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R4b、R4c、R4d、R4e、R6、R6a、R6b、R7、R8、R6c、R6d、R9、R10、R11和R11a中,所述的取代或未取代的C6-C14的芳基中的C6-C14的芳基优选苯基、萘基、蒽基或菲基。
R1、R1a、R1b、R1c、R1d、R2、R3、R2a、R2b、R2c、R2d、R2e、R4、R5、R4a、R4b、R4c、R4d、R4e、R6、R6a、R6b、R7、R8、R6c、R6d、R9、R10、R11、R11a和Z中,所述的取代或未取代的C2-C10的杂芳基中的C2-C10的杂芳基优选C2-C8的杂芳基,所述的C2-C8的杂芳基优选杂原子选自O,N和S,杂原子数为1-2个,例如吡啶基(例如 呋喃基(例如)、噻吩基(例如)、噻唑基(例如 异噻唑基噁唑基(例如 异噁唑基(例如吡咯基(例如咪唑基(例如吡唑基(例如吲哚基(例如 4-氮杂吲哚基(例如5-氮杂吲哚基(例如6-氮杂吲哚基(例如7-氮杂吲哚基(例如喹啉基、异喹啉基、喹唑啉基、喹喔啉基、噌啉基、1,5-萘啶基、1,6-萘啶基、1,7-萘啶基、1,8-萘啶基、嘌呤基、吲唑基、苯并咪唑基、苯并噻吩基(例如苯并呋喃基(例如苯并三氮唑基、苯并吡唑基(例如苯并噁唑基、苯并异噁唑基(例如苯并噻唑基或苯并异噻唑基;所述的取代的C2-C10的杂芳基中的取代基优选下列基团中的一个或多个:卤素或C1-C4的烷基;所述的取代的C2-C10的杂芳基优选
当相邻的两个R1、R1a;或R1a、R1b;或R1b、R1c;或R1c、R1d和与其相连的原子一起形成取代或未取代的C3-C8的环烷基、取代或未取代的C6-C14的芳基、或、取代或未取代的C2-C10的杂芳基时,所述的C3-C8的环烷基、所述的C6-C14的芳基、或、所述的C2-C10的杂芳基的定义均同前所述。
在本发明一优选实施方案中,当相邻的两个R1、R1a;或R1a、R1b;或R1b、R1c;或R1c、R1d和与其相连的原子一起形成取代或未取代的C2-C8的杂环基,且还原子为C或S时,C可与氧形成或者S可与氧形成
在本发明一优选实施方案中,当相邻的两个R1、R1a;或R1a、R1b;或R1b、R1c;或R1c、R1d和与其相连的原子一起形成取代或未取代的C2-C8的杂环基时,所述的C2-C8的杂环基优选C2-C6的杂环基。所述的C2-C6优选杂原子选自N、O和S,杂原子数为2-4个,优选2-3个。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,A1、A2、A3、A4和A5中,最多不超过1个或2个为氮原子。
在本发明另一优选实施方案中,
A1为C-R1;A2为C-R1a;A3为C-R1b或N;A4为C-R1c或N;和A5C-R1d或N;
或者,A1为CH;A2为CH;A3为C-R1b或N;A4为C-R1c或N;和A5C-R1d或N;
或者A1为C-R1;A2为C-R1a;A3为C-R1b;A4为C-R1c和A5为C-R1d;
或者A1为C-R1;A2为CH;A3为CH;A4为C-R1c和A5为CH;
或者A1为CH;A2为C-R1a;A3为CH;A4为C-R1c和A5为CH;
或者A1为CH;A2为CH;A3为C-R1b;A4为C-R1c和A5为CH;
或者A1为CH;A2为CH;A3为CH;A4为C-R1c和A5C-R1d;或R1c、R1d和与其相连的C一起形成取代或未取代的C2-C8的杂环基;
或者A1为CH;A2为CH;A3为CH;A4为C-R1c和A5为CH。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,R1、R1a、R1b、R1c和R1d分别独立地为氢原子、卤素、氰基、硝基、取代或未取代的C1-C4的烷基、 或者,相邻的两个R1、R1a;或R1a、R1b;或R1b、R1c;或R1c、R1d和与其相连的原子一起形成取代或未取代的C3-C8的环烷基、取代或未取代的C2-C8的杂环基、取代或未取代的C6-C14的芳基、或、取代或未取代的C2-C10的杂芳基;优选地,R1、R1a、R1b、R1c和R1d分别独立地为氢原子、卤素、氰基、硝基、取代或未取代的C1-C4的烷基、 或者,相邻的两个R1、R1a;或R1a、R1b;或R1b、R1c;或R1c、R1d和与其相连的原子一起形成取代或未取代的C3-C8的环烷基、取代或未取代的C2-C8的杂环基、取代或未取代的C6-C14的芳基、或、取代或未取代的C2-C10的杂芳基;进一步优选地,R1、R1a、R1b、R1c和R1d分别独立地为氢原子、卤素、取代或未取代的C1-C4的烷基、或相邻的两个R1、R1a;或R1a、R1b;R1c、R1d和与其相连的原子一起形成C2-C8的杂环基。在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,R2和R3分别独立地为氢原子、羟基、氨基、取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基,取代或未取代的C3-C8的环烷基、优选地R2和R3分别独立地为氢原子、羟基、氨基、取代或未取代的C1-C4的烷基、C1-C4的烷氧基、取代或未取代的C3-C8的环烷基、更优选地R2和R3一个为氢,另一个为取代或未取代的C1-C4的烷基、或者R2和R3同时为取代或未取代的C1-C4的烷基;R2和R3一个为氢,另一个为取代或未取代的C1-C4的烷基、 或者R2和R3同时为C1-C4的烷基。在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,R2a和R2b分别独立地为氢原子、取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基、取代或未取代的C3-C8的环烷基取代或
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,R2a为氢原子、或,取代或未取代的C1-C4的烷基,优选R2a为C1-C4的烷基。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,R2c为取代或未取代的C1-C4的烷基、取代或未取代的C3-C8的环烷基、或,取代或未取代的C2-C10的杂芳基;优选地,R2c为取代或未取代的C1-C4的烷基、C3-C8的环烷基或C2-C10的杂芳基。
在本发明一优选实施方案中,R2c中,所述的取代的C1-C4的烷基中的取代基优选选自下列基团中的一个或多个:卤素和C3-C8的环烷基。在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,R2d和R2e独立地为氢原子、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,R4和R5分别独立地为氢原子、取代或未取代的C1-C4的烷基、取代或未取代的C3-C8的环烷基、 (例如氨基);优选地,R4为氢原子或R5为氢原子。在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,R4a为氢原子、取代或未取代的C1-C4的烷基、取代或未取代的C3-C8的环烷基或优选为氢原子、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基,在进一步优选为氢原子或C1-C4的烷基。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,R4b、R4c、R4d和R4e分别独立地为氢原子、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,R6为氢原子、取代或未取代的C3-C8的环烷基、优选在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,R6a和R6b分别独立地为氢原子、氨基、羟基、取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基、或,取代或未取代的C3-C8的环烷基,更优选分别独立地为氢原子、氨基、羟基、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基,进一步优选分别独立地为氢原子、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基;更进一步优选独立地为氢原子或C1-C4的烷基。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,R6c和R6d分别独立地为氢原子、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基,优选R6c和R6d为H。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,R7和R8分别独立地为氢原子、氨基、羟基、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基,优选分别独立地为氢原子、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基,更优选独立地为氢原子或C1-C4的烷基。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,R9和R10分别独立地为取代或未取代的C1-C4的烷基、取代或未取代的C3-C8的环烷基,或,取代或未取代的C2-C10的杂芳基。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,R9为取代或未取代的C1-C4的烷基。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,R10为C1-C4的烷基。
R1、R1a、R1b、R1c和R1d中,所述的取代的C1-C4的烷基中的取代基选自下列基团中的一个或多个:羟基和卤素;
R2和R3一个为氢,另一个为取代或未取代的C1-C4的烷基、或者R2和R3同时为C1-C4的烷基;R2a为C1-C4的烷基;R2c为取代或未取代的C1-C4的烷基、C3-C8的环烷基或C2-C10的杂芳基,R2c中,所述的取代的C1-C4的烷基中的取代基选自下列基团中的一个或多个:卤素和C3-C8的环烷基;
R5为氢原子;
R7和R8分别独立地为氢原子或C1-C4的烷基;
R9为取代或未取代的C1-C4的烷基;和
R10为C1-C4的烷基。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,B1为氢原子、氰基、卤素、巯基、氨基、或,取代或未取代的C1-C4的烷基,优选为氢原子、氰基、卤素、或,取代或未取代的C1-C4的烷基;优选B1为氢原子。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,B2、B3、B4、B5、B6和B7分别独立地为氢原子、羟基、C1-C4的烷氧基、氰基、卤素、巯基、羧基、氨基、或,取代或未取代的C1-C4的烷基;优选地B2、B3、B4、B5、B6和B7为氢原子。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,B1、B2、B3、B4、B5、B6和B7均为H。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,L为直键。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,R11a为氢原子、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,Z为至少含有一个氮原子的取代或未取代的C2-C10的杂芳基,优选至少含一个氮原子的取代或未取代的C6-C8的杂芳基;更优选杂原子选自N、O和S,杂原子数为1或2个的取代或未取代的C6-C8的杂芳基;所述的C6-C8的杂芳基优选为双环并环杂芳基,更优选杂芳环并芳环杂芳基。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,Z中,所述的取代的C2-C10的杂芳基中的取代基选自下列基团中的一个或多个:卤素或C1-C4的烷基。
A1为C-R1;A2为C-R1a;A3为C-R1b或N;A4为C-R1c或N;和A5C-R1d或N;
R1、R1a、R1b、R1c和R1d分别独立地为氢原子、卤素、氰基、硝基、取代或未取代的C1-C4的烷基、或者,相邻的两个R1、R1a;或R1a、R1b;或R1b、R1c;或R1c、R1d和与其相连的原子一起形成取代或未取代的C3-C8的环烷基、取代或未取代的C2-C8的杂环基、取代或未取代的C6-C14的芳基、或、取代或未取代的C2-C10的杂芳基;
R2和R3分别独立地为氢原子、羟基、氨基、取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基,取代或未取代的C3-C8的环烷基、R2a和R2b分别独立地为氢原子、取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基、取代或未取代的C3-C8的环烷基取代或
R2a为氢原子、或,取代或未取代的C1-C4的烷基;
R2c为取代或未取代的C1-C4的烷基、取代或未取代的C3-C8的环烷基、或,取代或未取代的C2-C10的杂芳基;
R2d和R2e独立地为氢原子、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基;
R4b、R4c、R4d和R4e分别独立地为氢原子、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基;
R6a和R6b分别独立地为氢原子、氨基、羟基、取代或未取代的C1-C4的烷基、取代或未取代的C1-C4的烷氧基、或,取代或未取代的C3-C8的环烷基;
R6c和R6d分别独立地为氢原子、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基;
R7和R8分别独立地为氢原子、氨基、羟基、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基;
R9和R10分别独立地为取代或未取代的C1-C4的烷基、取代或未取代的C3-C8的环烷基,或,取代或未取代的C2-C10的杂芳基;
B1为氢原子、氰基、卤素、巯基、氨基、或,取代或未取代的C1-C4的烷基;
B2、B3、B4、B5、B6和B7分别独立地为氢原子、羟基、C1-C4的烷氧基、氰基、卤素、巯基、羧基、氨基、或,取代或未取代的C1-C4的烷基;
R11a为氢原子、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基;
和Z为至少含有一个氮原子的取代或未取代的C2-C10的杂芳基。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,
A1为CH;A2为CH;A3为C-R1b或N;A4为C-R1c或N;和A5C-R1d或N;
或者A1为C-R1a;A2为C-R1a;A3为C-R1b;A4为C-R1c和A5为C-R1d;
R1a、R1b;或R1b、R1c;或R1c、R1d和与其相连的原子一起形成取代或未取代的C3-C8的环烷基、取代或未取代的C2-C8的杂环基、取代或未取代的C6-C14的芳基、或、取代或未取代的C2-C10的杂芳基;优选地,R1、R1a、R1b、R1c和R1d分别独立地为氢原子、卤素、氰基、硝基、取代或未取代的C1-C4的烷基、C1-C4的烷氧基、 或者,相邻的两个R1、R1a;或R1a、R1b;或R1b、R1c;或R1c、R1d和与其相连的原子一起形成取代或未取代的C3-C8的环烷基、取代或未取代的C2-C8的杂环基、取代或未取代的C6-C14的芳基、或、取代或未取代的C2-C10的杂芳基;
R2a为氢原子、或,取代或未取代的C1-C4的烷基;
R2c为取代或未取代的C1-C4的烷基、取代或未取代的C3-C8的环烷基、或,取代或未取代的C2-C10的杂芳基;
R5为氢原子;
R6a和R6b分别独立地为氢原子、氨基、羟基、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基;
R6c和R6d分别独立地为氢原子、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基;
R7和R8分别独立地为氢原子、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基;
R9和R10分别独立地为取代或未取代的C1-C4的烷基、取代或未取代的C3-C8的环烷基,或,取代或未取代的C2-C10的杂芳基;
B1、B2、B3、B4、B5、B6和B7为氢原子;
和Z为至少含有一个氮原子的取代或未取代的C2-C10的杂芳基;所述的取代的C2-C10的杂芳基中的取代基选自下列基团中的一个或多个:卤素或C1-C4的烷基。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,
A1为C-R1;A2为CH;A3为CH;A4为C-R1c和A5为CH;
或者A1为CH;A2为C-R1a;A3为CH;A4为C-R1c和A5为CH;
或者A1为CH;A2为CH;A3为C-R1b;A4为C-R1c和A5为CH;
或者A1为CH;A2为CH;A3为CH;A4为C-R1c和A5C-R1d;或R1c、R1d和与其相连的C一起形成取代或未取代的C2-C8的杂环基;
或者A1为CH;A2为CH;A3为CH;A4为C-R1c和A5为CH;
R2a为氢原子、或,取代或未取代的C1-C4的烷基;
R2c为取代或未取代的C1-C4的烷基、取代或未取代的C3-C8的环烷基、或,取代或未取代的C2-C10的杂芳基;
R4和R5为氢原子;
R6a和R6b分别独立地为氢原子、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基;
R6c和R6d分别独立地为氢原子、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基;
R7和R8分别独立地为氢原子、取代或未取代的C1-C4的烷基、或,取代或未取代的C3-C8的环烷基;
R9和R10分别独立地为取代或未取代的C1-C4的烷基、取代或未取代的C3-C8的环烷基,或,取代或未取代的C2-C10的杂芳基;
B1为氢原子;
B2、B3、B4、B5、B6和B7为氢原子;
L为直键;
和Z为至少含有一个氮原子的取代或未取代的C2-C10的杂芳基;所述的取代的C2-C10的杂芳基中的取代基选自下列基团中的一个或多个:卤素或C1-C4的烷基。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,
A1为C-R1;A2为CH;A3为CH;A4为C-R1c和A5为CH;
或者A1为CH;A2为C-R1a;A3为CH;A4为C-R1c和A5为CH;
或者A1为CH;A2为CH;A3为C-R1b;A4为C-R1c和A5为CH;
或者A1为CH;A2为CH;A3为CH;A4为C-R1c和A5C-R1d;或R1c、R1d和与其相连的C一起形成取代或未取代的C2-C8的杂环基;
或者A1为CH;A2为CH;A3为CH;A4为C-R1c和A5为CH;
R1、R1a、R1b、R1c和R1d中,所述的取代的C1-C4的烷基中的取代基选自下列基团中的一个或多个:羟基和卤素;
R2和R3一个为氢,另一个为取代或未取代的C1-C4的烷基、或者R2和R3同时为C1-C4的烷基;R2a为C1-C4的烷基;R2c为取代或未取代的C1-C4的烷基、C3-C8的环烷基或C2-C10的杂芳基,R2c中,所述的取代的C1-C4的烷基中的取代基选自下列基团中的一个或多个:卤素和C3-C8的环烷基;
R5为氢原子;
R7和R8分别独立地为氢原子或C1-C4的烷基;
R9为取代或未取代的C1-C4的烷基;
R10为C1-C4的烷基;
B1、B2、B3、B4、B5、B6和B7为氢原子;
L为直键;
和Z为至少含有一个氮原子的取代或未取代的C2-C10的杂芳基;所述的取代的C2-C10的杂芳基中的取代基选自下列基团中的一个或多个:卤素或C1-C4的烷基。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,
A1为CH;A2为C-R1a;A3为CH;A4为CH和A5为CH;
B1、B2、B3、B4、B5、B6和B7为氢原子;
L为直键;
和Z为至少含有一个氮原子的C2-C10的杂芳基;所述的取代的C2-C10的杂芳基中的取代基选自下列基团中的一个或多个:卤素或C1-C4的烷基。
在本发明一优选实施方案中,通式(I)所示的四氢吡咯类化合物中,
A1为C-R1;A2为C-R1a;A3为C-R1b;A4为C-R1c和A5为C-R1d;
R1、R1a、R1b、R1c和R1d分别独立地为氢原子、卤素或或者相邻的两个R1、R1a;或R1a、R1b;或R1b、R1c;或R1c、R1d和与其相连的原子一起形成取代或未取代的C2-C8的杂环基;
B1、B2、B3、B4、B5、B6和B7为氢原子;
L为直键;
和Z为至少含有一个氮原子的C2-C10的杂芳基;所述的取代的C2-C10的杂芳基中的取代基选自下列基团中的一个或多个:卤素或C1-C4的烷基。
本发明一些优选的实施方案中,所述通式(I)所示的四氢吡咯类化合物、其对映异构体、非对映异构体、同位素化合物、药学上可接受的前药、药用酯或药学上可接受的盐为下列任一化合物:
其中,*标注的碳表示为S构型手性碳、R构型手性碳或非手性碳。
本发明还提供了一种下列化合物的S构型或R构型:
其通过将上述化合物进行手性HPLC拆分得到。其中,所述的手性HPLC拆分的方法可为本领域此类化合物手性HPLC拆分常规的方法和条件。本发明优选下列方法和条件:
方法(i)分析HPLC;条件优选如下:分析柱为CHIRALCE OJ-H(OJH0CE-VD046)(0.46cm I.D.×25cm L)(Chiralpak AD-3R(4.6mm×150mm)或CHIRALPAK AD-RH(4.6mm×150mm)或Chiradex(5μm,4.0×250mm)或Ultron ES-OVM 4.6×250mm),流动相为MeOH/DEA(或MeOH/甲酸铵或MeOH/乙酸铵或MeOH/氨水)=100/0.1(V/V)(等度洗脱);流速为1.0ml/min;进样量为10.0uL;检测波长为UV 254nm(或UV 214nm);柱温为35℃(可根据实际需要,选择30℃-40℃范围的柱温);其中保留时间6.17分钟得到第一构型化合物,保留时间为8.74分钟得到第二构型化合物(其中第一构型化合物的旋光度[α]D 20=+34(c 0.5,CH3OH),第二构型化合物的旋光度[α]D 20=-32(c 0.5,CH3OH));
方法(ii)制备HPLC;条件优选如下:制备柱为CHIRALCE OJ(5.0cm I.D.×25cmL),流动相为MeOH/DEA(或MeOH/甲酸铵或MeOH/乙酸铵或MeOH/氨水)=100/0.1(V/V);流速为60.0mL/min;检测波长为UV 214nm(或UV 254nm);柱温为35℃(可根据实际需要,选择30℃-40℃范围的柱温)。
本发明中,所述的通式(I)所示的四氢吡咯类化合物的S构型或R构型均可参照上述HPLC拆分方法获得。
本发明还提供了一种所述的通式(I)所示的四氢吡咯类化合物的S构型或R构型的拆分方法,其包括下列步骤:将所述的通式(I)所示的四氢吡咯类化合物采用分析HPLC拆分或者采用制备HPLC拆分即可。
所述的分析HPLC的方法和所述的所述的制备HPLC的方法中,所述的流动相优选醇类溶剂和有机胺的混合溶液。所述的醇类溶剂优选甲醇,所述的有机胺优选二乙醇胺、甲酸铵、乙酸铵和氨水中的一种或多种。所述的混合溶液中,醇类溶剂和有机胺的体积比优选1000:1。所述的分析HPLC的方法优选等度洗脱。
所述的分析HPLC的方法中,除流动相外,其他色谱条件均可为本领域分析HPLC的方法中常规的条件,本发明优选如下:
HPLC色谱仪优选Shimadzu LC-20AD色谱仪、CP-HPLC-05色谱仪、Agilent 1200/1260色谱仪或Waters E2695色谱仪。分析柱优选CHIRALCE OJ-H(OJH0CE-VD046)(0.46cmI.D.×25cm L)、Chiralpak AD-3R(4.6mm×150mm),CHIRALPAK AD-RH(4.6mm×150mm),Chiradex(4.0×250mm)或Ultron ES-OVM 4.6×250mm。流速优选0.5-1.5ml/min,更优选1.0ml/min。进样量优选为5-20uL,更优选10.0uL。检测波长为UV 254nm。柱温优选30-40℃,更优选35℃。
所述的制备HPLC的方法中,除流动相外,其他色谱条件均可为本领域制备HPLC的方法常规的条件,本发明优选如下:
制备柱优选CHIRALCE OJ(5.0cm I.D.×25cm L)、HIRALPAK AD-RH(20mm×150mm),或Ultron ES-OVM(20×250mm)。流速优选为50.0mL/min-100.0mL/min,更优选60.0mL/min。检测波长为UV 214nm或UV 214nm。柱温优选为30-40℃,更优选35℃。
制备HPLC的色谱仪优选Agilent 1200/1260Infinity II制备型液相色谱仪、Shimadzu Prominence LC-20AP色谱仪或Waters 2545色谱仪。进样量不作具体限定,通常根据实际选择的制备柱进行选择。
本发明还提供了一种所述的通式(I)所示的四氢吡咯类化合物的制备方法。
其中B1-B7、A1-A5、Z和*的定义均同前所述。
路线1:
其中A1-A5和Z的定义均同前所述;取代的醛基M-1通过Wittig反应得到M-2,再与取代的苄胺发生σ-1,3加成构建五元环M-3,脱去苄基得到M-4后再与相应的芳基甲醛发生还原胺化得到产物。
路线2:
其中A1-A5和Z的定义均同前所述;取代的溴代物T1和T2进行Suzuki反应得到T3,氢化得到T4,脱去Boc再和相应的芳基甲醛发生还原胺化得到产物。
通式(I)所示的四氢吡咯类化合物中,当Z为含有至少一个N的氮原子的取代或未取代的C2-C10的杂芳基时,其采用下列方法二制备,方法二包括下列步骤:将化合物I-Ma进行如下所述的脱氨基保护基的反应,制得所述的通式(I)所示的四氢吡咯类化合物;
其中,L、Z、K、B1-B7、A1-A5、Z和*的定义均同前所述;化合物I-Ma中,G是指氨基保护基,其中G与Z中的氮原子相连。
例如通式(I)所示的四氢吡咯类化合物中,可采用下述合成路线制备:
其中R2a如前文中所定义,X为氯、溴、碘,Y为氨基保护基。
卤素取代的苯基四氢吡咯P-1通过硝化反应得到间位硝化产物P-2,再与·N保护的吲哚甲醛P-3发生还原胺化反应得到P-4,氢化还原硝基同时脱去卤素得到P-5,与相应的酰氯P-6反应得到相应酰胺P-7后再脱去保护基得到产物。
本发明还提供了一种药物组合物,其包含所述的通式(I)所示的四氢吡咯类化合物,其对映异构体、非对映异构体、同位素化合物、药学上可接受的前药、药用酯或药学上可接受的盐,和药学上可接受的辅料。
本发明还提供了一种药物组合物,其包含所述的通式(I)所示的四氢吡咯类化合物,其对映异构体、非对映异构体、同位素化合物、药学上可接受的前药、药用酯或药学上可接受的盐,以及其他治疗药物。所述的其他治疗药物包括但不限于用于治疗或预防与多巴胺受体、多巴胺转运体功能异常相关的病变和中枢神经系统疾病的药物。与多巴胺受体、多巴胺转运体功能异常相关的病变和中枢神经系统疾病包括但不限于精神分裂症,与精神分裂症相关的阳性、阴性、认知障碍,分裂情感性障碍,双相性精神病,躁狂症,抑郁症,焦虑症,痴呆,记忆缺陷和涉及偏执狂和/或妄想的其他精神病。
本发明的药物组合物可制成任何广泛的剂型,例如片剂、胶囊剂、水性混悬剂、油性混悬剂、可分散的粉剂、颗粒剂、锭剂、乳剂、糖浆剂、乳膏剂、软膏剂、栓剂或注射剂。
本发明的药物组合物可以通过任何合适的方式给药,包括口服、局部(包括含服和舌下)、直肠、阴道、透皮、胃肠外、皮下、腹膜内、肺内、皮内、鞘内、硬膜外、鼻内、以及如果需要用于局部治疗、病灶内给药。胃肠外输注包括肌内、静脉内、动脉内、腹膜内和皮下给药。
本发明还提供了一种所述的通式(I)所示的四氢吡咯类化合物,其对映异构体、非对映异构体、同位素化合物、药学上可接受的前药、药用酯或药学上可接受的盐在制备D2受体和DAT受体抑制剂中的应用。
本发明还提供了一种所述的通式(I)所示的四氢吡咯类化合物,其对映异构体、非对映异构体、同位素化合物、药学上可接受的前药、药用酯或药学上可接受的盐在制备用于治疗或预防精神分裂症或其相关疾病的药物中的应用。所述的精神分裂症的相关疾病优选与精神分裂症相关的阳性、阴性、认知障碍;分裂情感性障碍、双相性精神病、躁狂症、抑郁症、焦虑症、痴呆、记忆缺陷和涉及偏执狂和/或妄想的其他精神病.
本发明中所述的通式(I)所示的四氢吡咯类化合物的药学上可接受的盐优选为其的盐酸盐、氢溴酸盐、硫酸盐、磷酸盐、硝酸盐、甲酸盐、乙酸盐、羟基乙酸盐、葡糖酸盐、乳酸盐、丙酮酸盐、草酸盐、丙二酸盐、天冬氨酸盐、抗坏血酸盐、谷氨酸盐、肉桂酸盐、苯甲酸盐、苯乙酸盐、扁桃酸盐、三氟乙酸盐、甲磺酸盐、三氟甲磺酸盐、乙磺酸盐、对苯甲磺酸盐、酒石酸盐、马来酸盐、富马酸盐、琥珀酸盐、苹果酸盐、枸橼酸盐、柠檬酸盐或水杨酸盐。
本发明中所述的通式(I)所示的四氢吡咯类化合物的药学上可接受的盐还可以为通式(I)化合物与有机或无机碱形成的加合盐。所述有机或无机碱包括但不限于钠、钾、钙、镁、铁、锌、铜、铝、氨、异丙胺、三甲胺、三乙胺、二乙胺、三丙胺、二异丙基胺、二异丙基乙胺、乙醇胺、2-二乙基氨基乙醇、二环己基胺、赖氨酸、精氨酸、鸟氨酸、组氨酸、咖啡因、普鲁卡因、海巴明、胆碱、甜菜碱、葡糖胺、甲基葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-甲基哌嗪、N-乙基哌嗪、羟乙基哌嗪、四氢吡咯或吗啉。
本发明中通式(I)所示的四氢吡咯类化合物的对映异构体包括顺式和反式异构体、(-)-和(+)-对映体,(R)-和(S)-对映体。
本发明中通式(I)所示的四氢吡咯类化合物的同位素化合物是指通式(I)化合物中的化学元素被一种或多种同位素替代的化合物。例如,具有本发明的结构,用“氘”或“氚”代替氢,或用18F同位素代替氟,或者用11C、13C、14C同位素代替碳,用18O同位素代替氧的化合物处于本发明的范围内。这样的化合物可用作例如生物学测定中的分析工具或探针,或者可以用作疾病的体内诊断成像示踪剂,或者作为药效学、药动学或受体研究的示踪剂。
本发明的化合物可以在官能团处衍生化以提供能够在体内转化回母体化合物的衍生物。能够在体内产生本发明的母体化合物且代谢不稳定的衍生物也在本发明的范围内,包括药学可接受的前药和药用酯。
术语“药学可接受形式的前药”是指向接受者给药时,能够直接或间接提供本发明的化合物或其活性的代谢物或残余物的任何无毒的盐、酯、酯的盐或其他衍生物。
术语“药用酯”是指将本发明的化合物中的羧基转化为酯或将羟基转化为与其他无机或有机酸形成的酯的衍生物,无机或有机酸包括但不限于:硝酸、硫酸、磷酸、甲酸、乙酸、三氟乙酸、甲磺酸、三氟甲磺酸、对甲苯磺酸、酒石酸、马来酸、富马酸、琥珀酸、苹果酸、枸橼酸或柠檬酸。
术语“赋形剂”包括但不限于由国家食品和药品监督管理局批准作为可用于人类或家畜的任何辅剂、载体、赋形剂、助流剂、甜味剂、分散剂、稀释剂、防腐剂、助悬剂、稳定剂、染料/着色剂、增味剂、表面活性剂、润湿剂、等渗剂、溶剂或乳化剂。
本发明中,术语环烷基优选选C3-C8环烷基。环烷基的实例包括但不限于:环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
本发明中,术语杂环基是指杂原子选自O、N和S,杂原子数为1、2、3或4个的C2-C8的非芳香环。杂环基的实例包括但不限于:四氢吡喃基、氮杂环丁烷基、1,4-二噁烷基、哌嗪基、哌啶基、吡咯烷基、吗啉基、硫代吗啉基、二氢呋喃基、二氢咪唑基、二氢吲哚基、二氢异噁唑基、二氢异噻唑基、二氢噁二唑基、二氢噁唑基、二氢吡嗪基、二氢吡唑基、二氢吡啶基、二氢嘧啶基、二氢吡咯基、二氢喹啉基、二氢四唑基、二氢噻二唑基、二氢噻唑基、二氢噻吩基、二氢三唑基、二氢氮杂环丁烷基、亚甲基二氧基苯甲酰基、四氢呋喃基、四氢噻吩基、
本发明中,术语芳基优选C6-C14芳基,更优选C6-C10芳基。芳基的实例包括但不限于苯基、萘基、四氢萘基、2,3-二氢化茚基、联苯基、菲基、蒽基和苊基(acenaphthyl)。
本发明中,术语杂芳基优选杂原子选自O、N和S,杂原子个数为1、2、3或4个的C2-C10的杂芳基,进一步优选杂原子选自O、N和S,杂原子个数为1、2、3或4个的C2-C8的杂芳基。杂芳基的实例包括但不限于吡啶基(例如呋喃基(例如噻吩基(例如噻唑基(例如异噻唑基噁唑基(例如异噁唑基(例如吡咯基(例如咪唑基(例如吡唑基(例如吲哚基(例如 4-氮杂吲哚基(例如5-氮杂吲哚基(例如6-氮杂吲哚基(例如7-氮杂吲哚基(例如喹啉基、异喹啉基、喹唑啉基、喹喔啉基、噌啉基、1,5-萘啶基、1,6-萘啶基、1,7-萘啶基、1,8-萘啶基、嘌呤基、吲唑基、苯并咪唑基、苯并噻吩基(例如苯并呋喃基(例如苯并三氮唑基、苯并吡唑基(例如苯并噁唑基、苯并异噁唑基(例如苯并噻唑基或苯并异噻唑基。
本发明中,术语卤素优选氟、氯、溴或碘。
本发明中,术语烷基优选甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
本发明中,术语烷氧基表示通过氧桥连接的具有所述碳原子数目的环状或者非环状烷基。由此,烷氧基包含以上烷基和环烷基的定义。本发明中烷氧基优选C1-C4烷氧基,更优选甲氧基、乙氧基、正丙氧基、异丙氧基或叔丁氧基。在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明中,室温是指10-30℃。过夜是指8-15小时。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:
本发明的四氢吡咯类化合物对精神分裂症阳性症状具有较佳抑制作用,其作用强度与阳性药物奥氮平相当,或略强。另外,本发明的化合物对D2受体和DAT受体具有双重抑制作用,可以有效治疗精神分裂症并改善阴性症状和认知功能,同时减少椎体副作用和催乳素的分泌。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
下述实施例中,室温是指10-30℃。未限定具体操作温度的,均是指在室温(例如10-30℃)条件下进行。过夜是指8-15小时。化合物纯度利用高效液相色谱(HPLC)进行检测纯度。Min是指分钟。
实施例1
1-(吲哚-3-甲基)-3-(3-羟苯基)吡咯烷(MDC-161502-002)
步骤一
1-苄基-3-(3-甲氧基苯基)吡咯烷的合成
将3-甲氧基乙烯苯(10g,74.5mmol,10.34mL,1eq)溶解于二氯甲烷(250mL)中,加入三氟乙酸(0.85g,7.45mmol,552uL,0.1eq),0℃下滴加N-(甲氧基甲基)-N-(三甲基硅基甲基)苄胺(35.4g,149mmol,2eq),30分钟内滴加完。反应升至室温搅拌48小时,反应液用二氯甲烷(250mL)稀释后加水(300mL)洗3遍,有机相用无水硫酸钠干燥,过滤,浓缩,残余物用硅胶层析(洗脱剂为石油醚:乙酸乙酯=10:1~1:1)纯化得淡黄色固体(13g,收率65%)。1HNMR(400MHz,CDCl3):δ7.35-7.08(m,6H),6.80-6.75(m,2H),6.70-6.60(m,1H),3.72(s,3H),3.59(s,2H),3.32-3.20(m,1H),2.93(t,J=8.4Hz,1H),2.80-2.70(m,1H),2.65-2.55(m,1H),2.43(t,J=8.4Hz,1H),2.30-2.20(m,1H),1.85-1.75(m,1H).
步骤二
3-(3-甲氧基苯基)吡咯烷的合成
将1-苄基-3-(3-甲氧基苯基)吡咯烷(13.0g,48.6mmol,1eq)溶解于甲醇(150mL)中,加入Pd(OH)2(20%,3.41g,4.86mmol,0.1eq),氮气置换三次,氢气环境下(50Psi)室温搅拌4小时。过滤,滤液蒸干得灰白色固体(7.0g,收率81%),粗品直接用于下一步。
步骤三
1-(吲哚-3-甲基)-3-(3-甲氧基苯基)吡咯烷(MDC-161502-001)的合成
将3-(3-甲氧基苯基)吡咯烷(4.91g,33.8mmol,1eq)和3-吲哚甲醛溶于四氢呋喃(120mL)中,加入NaBH(OAc)3(14.35g,67.7mmol,2eq),室温下搅拌5小时。冰浴下加入氯化铵饱和水溶液(50mL)淬灭,用乙酸乙酯(200mL)萃取3次,有机相用氯化钠饱和溶液洗涤,无水硫酸钠干燥,过滤,浓缩,残余物用硅胶柱层析(洗脱剂为二氯甲烷:甲醇=100:1~20:1)纯化得淡黄色固体(5.5g,收率51%,纯度96%)。1H NMR(400MHz,CDCl3):δ9.05(s,1H),7.70-7.65(m,1H),7.52(s,1H),7.50-7.45(m,1H),7.25-7.20(m,3H),6.85-6.25(m,3H),4.22(s,2H),3.78(s,3H),3.57-3.42(m,2H),3.30-3.12(m,2H),3.30-2.90(m,1H),2.45-2.35(m,1H),2.15-2.00(m,1H);13C NMR(200MHz,CDCl3):δ160.12,136.17,130.11,128.15,127.18,122.68,120.74,119.36,117.48,113.18,112.95,112.48,58.33,58.30,55.47,49.39,42.82;高分辨质谱HRMS(ESI):C20H23N2O+[M+H]+计算值:307.1810,实测值:307.1802;HPLC纯度:96.4%。
步骤四
1-(吲哚-3-甲基)-3-(3-羟苯基)吡咯烷(MDC-161502-002)的合成
将化合物1-(吲哚-3-甲基)-3-(3-甲氧基苯基)吡咯烷(700mg,2.28mmol)装入反应瓶中,氩气置换三次,加入无水二氯甲烷(20mL),冷却至-20℃。随后缓慢加入三溴化硼的二氯甲烷溶液(三溴化硼含量17%,3.23mL,5.70mmol),保温搅拌30分钟。然后将反应液升温至室温并搅拌反应过夜。反应完成后将反应体系降温至-20℃,缓慢滴加甲醇(3mL)淬灭反应,有机相随后用饱和碳酸氢钠水溶液(10mL)洗涤三次后,将水相和有机相全部浓缩后后加甲醇溶解,抽滤除去无机盐后用硅胶柱(二氯甲烷:甲醇=19:1)纯化,得到目标物化合物(480mg,收率72%)。1H NMR(800MHz,CDCl3):δ8.37(s,1H),7.68(d,J=7.9Hz,1H),7.34(d,J=8.1Hz,1H),7.18(dd,J=10.9,3.8Hz,2H),7.11(ddd,J=28.3,11.7,4.3Hz,2H),6.70(d,J=7.6Hz,1H),6.66-6.62(m,1H),6.61(s,1H),4.02-3.96(m,2H),3.31-3.25(m,1H),3.19-3.14(m,1H),2.99(dd,J=16.9,7.5Hz,1H),2.93(dt,J=14.7,7.4Hz,1H),2.70(t,J=9.2Hz,1H),2.30-2.23(m,1H),1.90-1.84(m,1H);HRMS(ESI)C19H21N2O[M+H]+计算值293.1654,实测值:293.1653;HPLC纯度:97.5%。
上述得到的消旋体可以利用以下方法进行手性HPLC拆分
分析方法:
峰1(MDC-161502-010):RT=6.17min,[α]D 20=+34(c 0.5,CH3OH);峰2(MDC-161502-011):RT=8.74min,[α]D 20=-32(c 0.5,CH3OH)。
制备条件:
参照实施例1所述方法,利用不同取代的苯乙烯为原料可以制备如表1所列举的化合物。
表1
具有酚羟基取代的化合物可以与烷基酸酐反应制备可作为酯,例如表2:
表2
实施例2
1-(吲哚-3-甲基)-3-(3-乙酰氨基苯基)吡咯烷(MDC-161502-003)
步骤一
3-(2-氯-5-硝基苯基)吡咯烷的合成
将3-(2-氯苯基)吡咯烷盐酸盐(900mg,4.12mmol)溶解于浓硫酸(15mL)中,-15℃下滴加发烟硝酸(1.0mL),保持低温下搅拌1小时。冰浴下将反应液滴入冰水(150mL)中,用1N NaOH溶液调节pH至8-9,用乙酸乙酯(200mL)萃取3遍,有机相用氯化钠饱和溶液洗涤,无水硫酸钠干燥,过滤,浓缩得黄色油状液体(900mg,粗收率96%),粗品直接用于下一步。1HNMR(800MHz,CDCl3)δ8.26(s,1H),8.05(d,J=8.7Hz,1H),7.56(d,J=8.7Hz,1H),3.83(p,J=8.2Hz,1H),3.61-3.58(m,1H),3.40-3.33(m,1H),3.28-3.22(m,1H),3.04(dd,J=11.0,8.1Hz,1H),2.43-2.38(m,1H),2.03-1.95(m,1H).13C NMR(200MHz,CDCl3)δ146.89,142.44,141.06,130.56,122.59,122.45,52.33,46.58,41.37,32.44;HRMS(ESI)C10H12ClN2O2 +[M+H]+计算值:227.0582,实测值:227.0583。
步骤二
1-(1-叔丁氧羰基吲哚-3-甲基)-3-(2-氯-5-硝基苯基)吡咯烷的合成
将3-(2-氯-5-硝基苯基)吡咯烷(900mg,3.97mmol),1-叔丁氧羰基3-吲哚甲醛(1.2g,4.8mmol)溶于无水四氢呋喃(30mL)中,室温下加入乙酸(240mg,4mmol)和NaBH(OAc)3(2.5g,12mmol),室温搅拌3小时。减压浓缩,残余物用乙酸乙酯(50mL)溶解,碳酸氢钠饱和溶液(30mL)洗涤1次,有机相用无水硫酸钠干燥,过滤,浓缩,残余物用硅胶柱(石油醚:乙酸乙酯=3:1)纯化,得到黄色油状液体(1.4g,收率77%)。HRMS(ESI)C24H27ClN3O4 +[M+H]+计算值:456.1685,实测值:456.1674。
步骤三
1-(1-叔丁氧羰基吲哚-3-甲基)-3-(3-氨基苯基)吡咯烷的合成
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(2-氯-5-硝基苯基)吡咯烷(1.4g,3.07mmol)溶解于甲醇(40mL)中,加入钯碳(1.4g,10%),氢气环境下(20Psi)室温搅拌2小时。过滤,滤液浓缩得到棕色油状液体(1.1g,粗收率92%),粗品直接用于下一部反应。1HNMR(800MHz,Methanol-d4)δ8.18(d,J=8.3Hz,1H),7.97(s,1H),7.81(d,J=7.8Hz,1H),7.43-7.38(m,1H),7.35(t,J=7.5Hz,1H),7.07(t,J=7.8Hz,1H),6.65(s,1H),6.62(dd,J=7.8,2.0Hz,2H),4.56(ABq,2H),3.73(dd,J=11.2,8.1Hz,1H),3.60-3.45(m,3H),3.28(t,J=10.8Hz,1H),2.47-2.41(m,1H),2.20-2.14(m,1H),1.70(s,9H).HRMS(ESI)C24H30N3O2 +[M+H]+计算值:392.2333,实测值:392.2334。
步骤四
1-(1-叔丁氧羰基吲哚-3-甲基)-3-(3-乙酰氨基苯基)吡咯烷的合成
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(3-氨基苯基)吡咯烷(100mg,0.25mmol),三乙胺(80mg,0.78mmol),DMAP(5mg,0.04mmol),溶解于二氯甲烷(5mL)中,滴加乙酰氯(30mg,0.38mmol),室温搅拌16小时。减压浓缩,残余物硅胶柱层析(二氯甲烷/甲醇=10:1)纯化得无色油状液体(90mg,收率80%)。HRMS(ESI)C26H32N3O3 +[M+H]+计算值:434.2438,实测值:434.2424。
步骤五
1-(吲哚-3-甲基)-3-(3-乙酰氨基苯基)吡咯烷(MDC-161502-003)的合成
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(3-乙酰氨基苯基)吡咯烷(90mg,0.2mmol)溶解于二氯甲烷(5mL)中,滴加三氟乙酸(2.0mL),室温下搅拌4小时。减压浓缩,残余物用制备HPLC纯化得白色固体(35mg,收率50%)。1H NMR(500MHz,Methanol-d4)δ7.77(d,J=8.0Hz,1H),7.68(s,1H),7.57(s,1H),7.45(d,J=8.1Hz,1H),7.32-7.25(m,2H),7.22(t,J=8.1Hz,1H),7.17(t,J=7.5Hz,1H),7.04(d,J=6.7Hz,1H),4.67(ABq,J=22.4Hz,6.4Hz,2H),3.83(dd,J=11.5,8.0Hz,1H),3.68–3.60(m,1H),3.59-3.51(m,1H),3.42-3.34(m,1H),3.21(q,J=7.3Hz,1H),2.54-2.45(m,1H),2.19(t,J=7.6Hz,1H),2.12(s,3H);HRMS(ESI)C21H24N3O+[M+H]+计算值:334.1914,实测值:334.1925;HPLC纯度:97.7%(RT=13.82min,λ=254nm)。
制备液相纯化条件:Shim-pack GIST C18柱(250×20mm,粒径5μM);水(含0.05%三氟乙酸)/甲醇(含0.05%三氟乙酸)梯度洗脱;流速10.0mL/min。
实施例3
1-(吲哚-3-甲基)-3-(3-甲磺酰胺基苯基)吡咯烷(MDC-161502-005)
步骤一
1-(1-叔丁氧羰基吲哚-3-甲基)-3-(3-甲磺酰胺基苯基)吡咯烷的合成
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(3-氨基苯基)吡咯烷(100mg,0.25mmol),吡啶(65mg,0.78mmol),DMAP(5mg,0.04mmol),溶解于二氯甲烷(5mL)中,加入甲磺酰氯(30mg,0.26mmol),室温搅拌16小时。减压浓缩,残余物硅胶柱层析(二氯甲烷/甲醇=10:1)纯化得无色油状液体(70mg,收率60%)。HRMS(ESI)C25H32N3O4S+[M+H]+计算值:470.2108,实测值:470.2111。
步骤二
1-(吲哚-3-甲基)-3-(3-甲磺酰胺基苯基)吡咯烷(MDC-161502-005)的合成
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(3-甲磺酰胺基苯基)吡咯烷(70mg,0.15mmol)溶解于二氯甲烷(5mL)中,滴加三氟乙酸(2.0mL),室温下搅拌4小时。减压浓缩,残余物用制备高效液相纯化得白色固体(25mg,收率45%)。1H NMR(800MHz,Methanol-d4)δ7.78(d,J=8.0Hz,1H),7.58(s,1H),7.47(d,J=8.2Hz,1H),7.35(t,J=7.9Hz,1H),7.28-7.22(m,2H),7.19(t,J=8.0Hz,1H),7.15(d,J=8.0Hz,1H),7.12(d,J=7.7Hz,1H),4.67(ABq,J=22.4Hz,13.6Hz,2H),3.84(dd,J=11.6,8.1Hz,1H),3.66-3.61(m,2H),3.59-3.54(m,1H),3.37(t,J=11.1Hz,1H),2.96(s,3H),2.54-2.48(m,1H),2.23-2.16(m,1H);HRMS(ESI)C20H24N3O2S+[M+H]+计算值:370.1584,实测值:370.1590;HPLC纯度:95.7%(RT=13.42min,λ=280nm)。
制备液相纯化条件:Shim-pack GIST C18柱(250×20mm,粒径5μM);水(含0.05%三氟乙酸)/甲醇(含0.05%三氟乙酸)梯度洗脱;流速10.0mL/min。
实施例4
1-(吲哚-3-甲基)-3-(3-三氟乙磺酰胺基苯基)吡咯烷(MDC-161502-006)
步骤一
1-(1-叔丁氧羰基吲哚-3-甲基)-3-(3-三氟乙磺酰胺基苯基)吡咯烷的合成
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(3-氨基苯基)吡咯烷(90mg,0.23mmol),吡啶(65mg,0.78mmol),DMAP(5mg,0.04mmol),溶解于二氯甲烷(5mL)中,加入三氟乙磺酰氯(45mg,0.25mmol),室温搅拌16小时。减压浓缩,残余物用硅胶柱(二氯甲烷/甲醇=10:1)纯化得无色油状液体(70mg,收率57%)。HRMS(ESI)C26H31F3N3O4S+[M+H]+计算值:538.1982,实测值:538.1969。
步骤二
1-(吲哚-3-甲基)-3-(3-三氟乙磺酰胺基苯基)吡咯烷(MDC-161502-006)的合成
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(3-三氟乙磺酰胺基苯基)吡咯烷(70mg,0.13mmol)溶解于二氯甲烷(5mL)中,滴加三氟乙酸(2.0mL),室温下搅拌4小时。减压浓缩,残余物用制备高效液相纯化得白色固体(35mg,收率62%)。1H NMR(500MHz,DMSO-d6)δ10.86(s,1H),7.61(d,J=7.8Hz,1H),7.31(d,J=8.1Hz,1H),7.21(s,1H),7.04(t,J=7.5Hz,1H),6.96(t,J=7.4Hz,1H),6.87(t,J=7.7Hz,1H),6.70(s,1H),6.67(d,J=8.6Hz,1H),6.46(d,J=7.4Hz,1H),4.10(s,1H),3.73(s,2H),3.46(q,J=10.8Hz,2H),3.12-3.03(m,1H),2.91(t,J=8.4Hz,1H),2.71(q,J=8.1Hz,1H),2.57(q,J=8.5Hz,1H),2.36(t,J=8.3Hz,1H),2.18-2.08(m,1H),1.75-1.65(m,1H);HRMS(ESI)C21H23F3N3O2S+[M+H]+计算值:438.1458,实测值:438.1454;HPLC纯度:98.6%(RT=15.34min,λ=254nm)。
制备液相纯化条件:Shim-pack GIST C18柱(250×20mm,粒径5μM);水(含0.05%三氟乙酸)/甲醇(含0.05%三氟乙酸)梯度洗脱;流速10.0mL/min。
实施例5
1-(吲哚-3-甲基)-3-[3-(2-噻吩磺酰胺基)苯基]吡咯烷(MDC-161502-008)
步骤一
1-(1-叔丁氧羰基吲哚-3-甲基)-3-[3-(2-噻吩磺酰胺基)苯基]吡咯烷的合成
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(3-氨基苯基)吡咯烷(90mg,0.23mmol),吡啶(5mL),DMAP(5mg,0.04mmol),溶解于二氯甲烷(5mL)中,加入2-噻吩磺酰氯(70mg,0.38mmol),室温搅拌3小时。减压浓缩,残余物硅胶柱层析(二氯甲烷/甲醇=10:1)纯化得无色油状液体(90mg,收率67%)。HRMS(ESI)C28H32N3O4S2 +[M+H]+计算值:538.1829,实测值:538.1834。
步骤二
1-(吲哚-3-甲基)-3-[3-(2-噻吩磺酰胺基)苯基]吡咯烷(MDC-161502-008)的合成
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-[3-(2-噻吩磺酰胺基)苯基]吡咯烷(90mg,0.17mmol)溶解于二氯甲烷(5mL)中,滴加三氟乙酸(2.0mL),室温下搅拌4小时。减压浓缩,残余物用制备高效液相纯化得白色固体(45mg,收率60%)。1H NMR(800MHz,Methanol-d4)δ7.66(d,J=7.9Hz,1H),7.52(d,J=5.0Hz,1H),7.40-7.35(m,2H),7.25(s,1H),7.11(t,J=8.1Hz,1H),7.09(t,J=7.8Hz,1H),7.05(t,J=8.0Hz,1H),6.95(s,1H),6.94-6.91(m,2H),6.87(d,J=7.6Hz,1H),3.92(s,2H),3.26(t,J=8.4Hz,1H),3.13(t,J=9.8Hz,1H),2.99-2.95(m,1H),2.80-2.75(m,1H),2.47(t,J=9.4Hz,1H),2.28-2.21(m,1H),1.83-1.77(m,1H);HRMS(ESI)C23H24N3O2S2 +[M+H]+计算值:438.1304,实测值:438.1309;HPLC纯度:95.3%(RT=15.55min,λ=254nm)。
制备液相纯化条件:Shim-pack GIST C18柱(250×20mm,粒径5μM);水(含0.05%三氟乙酸)/甲醇(含0.05%三氟乙酸)梯度洗脱;流速10.0mL/min。
实施例6
1-(吲哚-3-甲基)-3-(3-乙磺酰胺基苯基)吡咯烷(MDC-161502-009)
步骤一
1-(1-叔丁氧羰基吲哚-3-甲基)-3-(3-乙磺酰胺基苯基)吡咯烷的合成
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(3-氨基苯基)吡咯烷(100mg,0.25mmol),吡啶(65mg,0.78mmol),DMAP(5mg,0.04mmol),溶解于二氯甲烷(5mL)中,加入乙磺酰氯(50mg,0.38mmol),室温搅拌16小时。减压浓缩,残余物用硅胶柱(二氯甲烷/甲醇=10:1)纯化得无色油状液体(70mg,收率58%)。HRMS(ESI)C26H34N3O4S+[M+H]+计算值:484.2265,实测值:484.2263。
步骤二
1-(吲哚-3-甲基)-3-(3-乙磺酰胺基苯基)吡咯烷(MDC-161502-009)的合成
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(3-乙磺酰胺基苯基)吡咯烷(70mg,0.14mmol)溶解于二氯甲烷(5mL)中,滴加三氟乙酸(2mL),室温下搅拌4小时。减压浓缩,残余物用制备高效液相纯化得白色固体(40mg,收率74%)。1H NMR(800MHz,Methanol-d4)δ7.66(d,J=7.9,1H),7.35(d,J=8.1,1H),7.24(s,1H),7.21(t,J=7.8Hz,1H),7.12(s,1H),7.10(t,J=8.1Hz,1H),7.07(dd,J=8.1,2.2Hz,1H),7.03(t,J=8.0Hz,1H),7.01(d,J=7.8Hz,1H),3.93(ABq,J=16.8,12.8Hz,2H),3.37-3.33(m,1H),3.18(dd,J=9.8,8.1Hz,1H),3.03(q,J=7.4Hz,2H),2.98-2.94(m,1H),2.82(td,J=9.2,6.3Hz,1H),2.58(t,J=8.8Hz,1H),2.36-2.26(m,1H),1.91-1.84(m,1H),1.26(t,J=7.4Hz,3H);HRMS(ESI)C21H26N3O2S+[M+H]+计算值:384.1740,实测值:384.1730;HPLC纯度:95.7%(RT=14.06min,λ=280nm)。
制备液相纯化条件:Shim-pack GIST C18柱(250×20mm,粒径5μM);水(含0.05%三氟乙酸)/甲醇(含0.05%三氟乙酸)梯度洗脱;流速10.0mL/min。
参照实施例2至实施例6的方法还可以制备如下表3所列举的化合物:
表3
实施例7
1-(吲哚-3-甲基)-3-(3-羟基-4-氯苯基)吡咯烷(MDC-161502-013)的合成
步骤一
1-叔丁氧羰基-3-(3-羟基-4-氯苯基)-2,5-二氢吡咯的合成
将2-氯-5-溴苯酚(253mg,1.22mmol,1.2eq),1-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯(300mg,1.02mmol,1eq),K2CO3(564mg,4.08mmol,4eq)和Pd(dppf)Cl2(75mg,0.103mmol,0.1eq)混合于DMF(6mL)中,氮气保护下100℃搅拌过夜,反应结束后加入乙酸乙酯(400mL),依次用水(50mL×2),饱和氯化钠溶液(50mL×3)洗涤,有机相用无水硫酸钠干燥,浓缩,粗品用柱层析(石油醚/乙酸乙酯=10/1)纯化,得到浅黄色固体(230mg,收率76%)。LCMS(ESI)[M-56+H]+:240.0.
步骤二
1-叔丁氧羰基-3-(3-羟基-4-氯苯基)-吡咯烷的合成
将1-叔丁氧羰基-3-(3-羟基-4-氯苯基)-2,5-二氢吡咯(200mg,0.676mmol,1eq)溶于乙酸乙酯(50mL)中,加入Pd/C(40mg,10%),在H2(20Psi)条件下室温搅拌过夜,过滤除去Pd/C,滤液减压除去溶剂,柱层析(石油醚/乙酸乙酯=10/1-5/1)纯化,得到淡黄色固体(130mg,收率65%)。LCMS(ESI)[M-56+H]+:242.0.
步骤三
3-(3-羟基-4-氯苯基)-吡咯烷的合成
将1-叔丁氧羰基-3-(3-羟基-4-氯苯基)-吡咯烷(130mg,0.437mmol,1eq)溶于二氯甲烷(3mL)和三氟乙酸(3mL)中,室温下搅拌2小时,随后减压除去溶剂得到粗品,直接用于下一步反应。LCMS(ESI)[M+H]+:198.0.
步骤四
1-(吲哚-3-甲基)-3-(3-羟基-4-氯苯基)吡咯烷(MDC-161502-013)的合成
将上一步粗品和3-吲哚甲醛(76mg,0.524mmol,1.2eq)溶于干燥四氢呋喃(5mL),加入乙酸(0.2mL),室温下搅拌2h,然后加入三乙酰氧基硼氢化钠(400mg,1.89mmol,4eq),室温下继续搅拌3小时,反应液浓缩后用制备TLC(二氯甲烷/甲醇=8/1)纯化,再用柱层析(二氯甲烷/甲醇=20/1)纯化得到近白色固体(80mg,收率56.0%)。LCMS(ESI)[M+H]+:327.0.HNMR(400MHz,DMSO-d6)δ:11.44(bs,1H),10.17(bs,1H),7.82(d,J=6.4Hz,1H),7.65(s,1H),7.45(d,J=8.0Hz,1H),7.29(d,J=8.0Hz,1H),7.07-7.21(m,2H),6.89(s,1H),6.79(d,J=6.8Hz,1H),4.55(s,2H),3.50-3.75(m,2H),3.05-3.21(m,1H),2.27-2.42(m,1H),1.85-2.13(m,1H).
实施例8
1-(吲哚-3-甲基)-3-(2-氯-3-羟基苯基)吡咯烷(MDC-161502-014)的合成
步骤一
1-叔丁氧羰基-3-(2-氯-3-羟基苯基)-2,5-二氢吡咯的合成
将2-氯-3-溴苯酚(338mg,1.63mmol,1.2eq),1-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯(400mg,1.36mmol,1eq),K2CO3(770mg,5.57mmol,4eq)和Pd(dppf)Cl2(100mg,0.137mmol,0.1eq)混合于DMF(10mL)中,氮气保护下100℃搅拌过夜,反应结束后加入乙酸乙酯(400mL),依次用水(50mL×2),饱和氯化钠溶液(50mL×3)洗涤,有机相用无水硫酸钠干燥,浓缩,粗品用柱层析(石油醚/乙酸乙酯=10/1)纯化,得到浅黄色固体(350mg,收率87%)。LCMS(ESI)[M-56+H]+:240.0.
步骤二
1-叔丁氧羰基-3-(2-氯-3-羟基苯基)-吡咯烷的合成
将1-叔丁氧羰基-3-(2-氯-3-羟基苯基)-2,5-二氢吡咯(220mg,0.744mmol,1eq)溶于乙酸乙酯(10mL)中,加入Pd/C(50mg,10%),在H2(20Psi)条件下室温搅拌过夜,过滤除去Pd/C,滤液减压除去溶剂,柱层析(石油醚/乙酸乙酯=10/1-5/1)纯化,得到淡黄色固体(180mg,收率81%)。LCMS(ESI)[M-56+H]+:242.0.
步骤三
3-(2-氯-3-羟基苯基)-吡咯烷的合成
将1-叔丁氧羰基-3-(2-氯-3-羟基苯基)-吡咯烷(90mg,0.302mmol,1eq)溶于二氯甲烷(3mL)和三氟乙酸(3mL)中,室温下搅拌2小时,随后减压除去溶剂得到粗品,直接用于下一步反应。LCMS(ESI)[M+H]+:198.0.
步骤四
1-(吲哚-3-甲基)-3-(2-氯-3-羟基苯基)吡咯烷(MDC-161502-014)的合成
将上一步粗品和3-吲哚甲醛(50mg,0.344mmol,1.2eq)溶于干燥四氢呋喃(5mL),加入乙酸(0.1mL),室温下搅拌2h,然后加入三乙酰氧基硼氢化钠(300mg,1.42mmol),室温下继续搅拌3小时,反应液浓缩后用制备TLC(二氯甲烷/甲醇=8/1)纯化,再用柱层析(二氯甲烷/甲醇=20/1)纯化得到近白色固体(45mg,收率46%)。LCMS(ESI)[M+H]+:327.0.HNMR(400MHz,DMSO-d6)δ:11.43(bs,1H),10.23(s,1H),7.83(d,J=7.6Hz,1H),7.64(s,1H),7.44(d,J=8.0Hz,1H),7.07-7.19(m,3H),6.95(d,J=7.2Hz,1H),6.91(d,J=8.0Hz,1H),4.57(s,1H),3.79-4.06(m,1H),3.61-3.76(m,1H),3.38-3.57(m,1H),3.15-3.27(m,1H),2.30-2.42(m,1H),1.94-2.12(m,1h).
实施例9
1-(吲哚-3-甲基)-3-(3-环丙基磺酰胺基苯基)吡咯烷(MDC-161502-015)
步骤一
3-硝基乙烯苯的合成
将甲基三苯基碘化膦(64.2g,158.8mmol,1.2eq)溶于1,4-二氧六环(500ml)中,氮气保护下加入碳酸钾(27.4g,198.5mmol,1.5eq),室温搅拌1小时。将3-硝基苯甲醛(20g,132.3mmol,1.0eq)加入反应体系。氮气保护下110℃搅拌16小时。减压去除溶剂,加入乙酸乙酯(200ml),水洗(80ml×3),有机相用无水硫酸钠干燥,过滤,浓缩,残余物用柱层析(正己烷)纯化得到黄色油状液体(17.8g,收率90%)。HNMR(400MHz,CDCl3)δ8.22(t,1H),8.08(dt,J=8.0Hz,1H),7.70(d,J=7.6Hz,1H),7.48(t,J=8.0Hz,1H),6.76(dd,J1=17.2Hz,J2=10.8Hz,1H),5.88(d,J=17.6Hz,1H),5.43(d,J=10.8Hz,1H).
步骤二
1-苄基-3-(3-硝基苯基)吡咯烷的合成
将3-硝基乙烯苯(13.2g,88.4mmol,1eq)溶解于二氯甲烷(90mL)中,加入三氟乙酸(1.0g,8.84mmol,0.1eq),0℃下滴加N-(甲氧基甲基)-N-(三甲基硅基甲基)苄胺(45.7g,192.5mmol,2.1eq),30分钟内滴加完。反应升至室温搅拌16小时,减压去除溶剂,残余物用二氯甲烷(250mL)稀释后加水(100mL)洗3遍,有机相用无水硫酸钠干燥,过滤,浓缩,残余物用硅胶层析(二氯甲烷:甲醇=100:1)纯化得淡黄色油状液体(21.5g,收率86%)。LCMS(ESI)[M+H]+:283.1.
步骤三
1-苄基-3-(3-氨基苯基)吡咯烷的合成
将1-苄基-3-(3-硝基苯基)吡咯烷(19.82g,70.2mmol,1eq)溶解于水(50mL)和乙醇(300mL)中,加入还原铁粉(31.35g,561.6mmol,8eq),NH4Cl(30.04g,561.6mmol,8eq),70℃搅拌16小时。过滤,滤液减压浓缩,残余物加入乙酸乙酯(300mL)溶解,用饱和碳酸氢钠溶液(100mL)和饱和食盐水(100mL)各洗涤一遍,有机相用无水硫酸钠干燥后浓缩,残余物用硅胶层析(二氯甲烷:甲醇=30:1,10:1)纯化得淡黄色油状液体(13.8g,收率78%)。LCMS(ESI)[M+H]+:253.0.
步骤四
1-苄基-3-(3-氨基苯基)吡咯烷的合成
将1-苄基-3-(3-氨基苯基)吡咯烷(190mg,0.79mmol,1eq),DMAP(10mg,0.08mmol,0.1eq),吡啶(1mL)混合于二氯甲烷中(3mL),搅拌下加入环丙基磺酰氯(127mg,0.90mmol,1.1eq),室温反应16小时,反应结束后,减压除去溶剂,加入乙酸乙酯(100mL),依次用水(20mL×2),饱和氯化钠溶液(20mL)洗涤,有机相用硫酸钠干燥,浓缩后用柱层析(二氯甲烷/甲醇=50/1)纯化得到无色油状液体(190mg,产率71%)。
步骤五
3-(3-氨基苯基)吡咯烷的合成
1-苄基-3-(3-环丙基磺酰胺基苯基)吡咯烷(140mg,0.39mmol,1eq),甲酸铵(247mg,3.9mmol,10eq),Pd/C(20mg,10%)混合于甲醇(3mL)和氨/甲醇溶液(3mL,2mol/L)中,70℃条件下搅拌16小时,过滤,滤液减压除去溶剂,残余物经过柱层析(二氯甲烷/甲醇=20/1,10/1)纯化得到白色固体(50mg,产率48%)。
步骤六
1-(吲哚-3-甲基)-3-(3-环丙基磺酰胺基苯基)吡咯烷(MDC-161502-015)的合成
3-(3-环丙基磺酰胺基苯基)吡咯烷(50mg,0.19mmol,1eq)和3-吲哚甲醛(30mg,0.21mmol,1.1eq)溶于干燥四氢呋喃(3mL)中,加入乙酸(0.1mL),室温下搅拌2h,加入三乙酰氧基硼氢化钠(162mg,0.77mmol,4eq),室温下继续搅拌2小时,反应液浓缩后用柱层析(二氯甲烷/甲醇=20/1)纯化得到白色固体(25mg,收率34%)。1H NMR(400MHz,Methanol-d4)δ7.76(d,J=8.0Hz,1H),7.56(s,1H),7.45(d,J=8.0Hz,1H),7.32-7.29(m,1H),7.29–7.24(m,4H),7.09(d,J=8.0Hz,1H),4.61(s,2H),3.79(dd,J=12,8.0Hz,1H),3.60–3.51(m,3H),2.53-2.49(m,2H),2.48-2.16(m,1H),1.41-1.36(m,1H),1.02-0.94(m,2H),0.93-0.89(m,2H);LCMS(ESI)[M+H]+:396.2.
实施例10
1-(吲哚-3-甲基)-3-(3-环丁基甲基磺酰胺基苯基)吡咯烷(MDC-161502-017)
步骤一
1-苄基-3-(3-环丁基甲基磺酰胺基苯基)吡咯烷的合成
将1-苄基-3-(3-氨基苯基)吡咯烷(200mg,0.793mmol,1eq),DMAP(10mg,0.0820mmol,0.1eq),吡啶(1mL)混合于二氯甲烷(3mL)中,搅拌下加入环丁基甲磺酰氯(150mg,0.890mmol,1.1eq),室温反应过夜,反应结束后,减压除去溶剂,加入乙酸乙酯(100mL),依次用水(20mL×2),饱和氯化钠溶液(20mL)洗涤,有机相用硫酸钠干燥,浓缩后用柱层析(二氯甲烷/甲醇=50/1)纯化得到淡黄色固体(160mg,产率53%)。LCMS(ESI)[M+H]+:385.0.
步骤二
3-(3-环丁基甲基磺酰胺基苯基)吡咯烷的合成
1-苄基-3-(3-环丁基甲基磺酰胺基苯基)吡咯烷(62mg,0.161mmol,1eq),甲酸铵(82mg,1.30mmol,8eq),Pd/C(10mg,10%)混合于甲醇(5mL)中,70℃条件下搅拌3小时,过滤,滤液减压除去溶剂,残余物经过柱层析(二氯甲烷/甲醇=20/1,10/1)纯化得到白色固体(40mg,产率85%)。LCMS(ESI)[M+H]+:295.0.
步骤三
1-(吲哚-3-甲基)-3-(3-环丁基甲基磺酰胺基苯基)吡咯烷(MDC-161502-017)的合成
3-(3-环丁基甲基磺酰胺基苯基)吡咯烷(40mg,0.136mmol,1eq)和3-吲哚甲醛(25mg,0.172mmol,1.2eq)溶于干燥四氢呋喃(5mL)中,加入乙酸(0.1mL),室温下搅拌2h,加入三乙酰氧基硼氢化钠(120mg,0.566mmol,4eq),室温下继续搅拌2小时,反应液浓缩后用柱层析(二氯甲烷/甲醇=20/1)纯化得到白色固体(28mg,收率49%)。LCMS(ESI)[M+H]+:424.0;HNMR(400MHz,DMSO-d6)δ:11.43(bs,1H),9.75(s,1H),7.82(d,J=5.6Hz,1H),7.64(s,1H),7.44(d,J=8.0Hz,1H),7.30(t,J=8.0Hz,1H),7.17(t,J=8.0Hz,1H),7.05-7.10(m,4H),4.58(s,2H),3.37-3.81(m,3H),3.07-3.25(m,3H),2.61-2.72(m,1H),2.31-2.43(m,1H),1.94-2.11(m,3h),1.67-1.87(m,4H).
实施例11
1-(3-吲哚基甲基)-3-(3-二乙氧基磷酰氧基苯基)吡咯烷(MDC-161502-030)
将3-(3-羟苯基)吡咯烷(1.65g,10.1mmol)和1-叔丁氧羰基3-吲哚甲醛(2.75g,11.2mmol)溶于干燥的四氢呋喃(40mL)中,加入醋酸(2mL),室温下搅拌2小时,随后加入三醋酸硼氢化钠(8.60g,40.6mmol),继续室温条件下搅拌16小时。加入乙酸乙酯(450mL)稀释反应体系,体系依次用饱和碳酸氢钠溶液(100mL×3),饱和食盐水(100mL2)洗涤,有机相用无水硫酸钠干燥。过滤除去干燥剂,减压浓缩除去溶剂,随后柱层析纯化(二氯甲烷/甲醇=8/1),得到浅黄色固体(3.5g,收率76%)。LCMS:m/z=393[M+H]+。
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(3-羟苯基)吡咯烷(400mg,1.02mmol)溶于干燥的乙腈(20mL),冷却到零下10℃,依次加入二异丙基乙基胺(264mg,2.04mmol),N,N-二甲基吡啶(13mg,0.106mmol),四氯化碳(786mg,5.11mmol),和二乙基亚磷酸酯(212mg,1.54mmol),随后室温条件下搅拌16小时。加入乙酸乙酯(300mL)稀释体系,依次用水(80mL×2),饱和食盐水(80mL×2),无水硫酸钠干燥,过滤除去干燥剂,减压除去溶剂,用快速硅胶柱纯化(石油醚/乙酸乙酯/乙醇=12/3/1-4/3/1),得到淡黄色固体(360mg,收率67%)。LCMS:m/z=529[M+H]+。
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(3-二乙氧基磷酰氧基苯基)吡咯烷(300mg,0.568mmol)溶于干燥的二氯甲烷(10mL),加入三氟乙酸(8mL),室温条件下搅拌3小时,减压除去溶剂,加入三乙胺碱化体系,再次减压除去溶剂,用制备液相纯化(乙腈-水-乙酸),得到淡黄色粘性固体(180mg,收率74%)。LCMS:m/z=429[M+H]+;1H NMR(500MHz,DMSO-d6)δ11.18(s,1H),7.73(d,J=8.0Hz,1H),7.44(s,1H),7.40(d,J=8.5Hz,1H),7.33(t,J=8.0Hz,1H),7.16(d,J=8.5Hz,1H),7.15(s,1H),7.12(td,J1=8.0Hz,J2=0.5Hz,1H),7.03-7.08(m,2H),4.09-4.23(m,6H),3.73(m,1H),3.14(m,1H),3.03(m,1H),2.88(m,1H),2.33(m,1H),1.87(m,1H),1.25(m,3H),1.13(m,1H).
实施例12(MDC-161502-031)
步骤一
将1-叔丁氧碳基-3-吡咯烷酮(15g,80.98mmol,1.0eq)装入1L三颈反应瓶中,用氮气置换三次,加入无水四氢呋喃(200mL),并降温至-78℃。随后缓慢加入双三甲基硅基胺基锂(121ml,1M)的四氢呋喃溶液,保温搅拌1h。然后将N-苯基双(三氟甲磺酰亚胺)(43.4g,121.5mmol,1.5eq)溶于(80ml)四氢呋喃溶液,并缓慢加入到反应体系中,然后将反应液升至室温,搅拌反应过夜。反应液加入饱和碳酸氢钠溶液(100ml),用乙酸乙酯(80ml)萃取3次,合并有机相然后用饱和食盐水(80ml)洗涤3次,无水硫酸钠干燥,过滤,浓缩,得到黄色的粗品60g。LCMS:m/z=318[M+H]+.
步骤二
将3-(三氟甲基磺酰氧基)-2H-吡咯-1(5H)-羧酸叔丁酯粗产品(6g),频哪醇硼酸脂(2.45g,9.64mmol,1.2eq),乙酸钾(1.32g,16.1mmol,2eq)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(131mg,0.16mmol.0.02eq)溶于1,4-二氧六环(60ml)中。用氮气置换三次,升温至95℃,保温搅拌5h。反应液加入水(80ml),用乙酸乙酯(80ml)萃取3遍,合并有机相,然后每次用饱和食盐水(80ml)洗涤三次,无水硫酸钠干燥,过滤,浓缩,得到黑色的粗品。LCMS:m/z=296[M+H]+.
步骤三
将1-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯(1220mg,5.08mmol,1.0eq),5-溴-2-氟苯酚(970mg,5.08mmol,1.0eq),碳酸钾(2.11g,15.24mmol,3eq)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(82mg,0.1mmol.0.02eq)溶于N,N-二甲基甲酰胺(20ml)中,用氮气置换三次,升温至90℃,反应搅拌过夜。反应液加入水(50ml),用乙酸乙酯(30ml)萃取3遍,合并有机相,然后每次用饱和食盐水(30ml)洗涤三次,无水硫酸钠干燥,过滤,浓缩后用硅胶柱(二氯甲烷:甲醇=19:1)纯化,得到白色的目标物化合物(500mg,1.79mmol,35%)。LCMS:m/z=280[M+H]+.
步骤四
将1-叔丁氧羰基-3-(4-氟-3-羟苯基)-2,5-二氢-1H-吡咯烷(500mg,1.79mmol)溶解于甲醇(30ml)中,加入钯碳(200mg),氢气环境下(15Psi)室温搅拌16小时。过滤,滤液浓缩得到白色固体(450mg,1.60mmol,89.3%yield)。粗品直接用于下一步。LCMS:m/z=282[M+H]+.
步骤五
将1-叔丁氧羰基-3-(4-氟-3-羟苯基)吡咯烷(450mg,1.6mmol)溶解于二氯甲烷(5ml)中,滴加三氟乙酸(5ml),室温下搅拌2小时。减压浓缩得白色固体(280mg,1.54mmol,yield:96.6%)。LCMS:m/z=182[M+H]+.
步骤六
将3-(4-氟-3-羟苯基)吡咯烷(170mg,0.939mmol),1-叔丁氧羰基-3-吲哚甲醛(230mg,0.94mmol,1.0eq)溶于无水四氢呋喃(10ml)中,室温下加入乙酸(60mg,1mmol)和NaBH(OAc)3(795mg,3.75mmol),室温搅拌3小时。减压浓缩,残余物用乙酸乙酯(50ml)溶解,碳酸氢钠(30ml)饱和溶液洗涤,有机相用无水硫酸钠干燥,过滤,浓缩,残余物用硅胶柱(二氯甲烷/甲醇=10:1)纯化,得到白色固体(150mg,0.37mmol,yield:38.9%)。LCMS:m/z=411[M+H]+.
步骤七
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(4-氟-3-羟苯基)吡咯烷(150mg,0.37mmol)溶解于二氯甲烷(5ml)中,滴加三氟乙酸(5ml),室温下搅拌2小时。减压浓缩,残余物用prep-HPLC纯化得白色固体(70mg,0.23mmol,yield:62%)。1H NMR(500MHz,DMSO-d6)δ11.18(s,1H),9.81(brs,1H),7.72(d,J=7.5Hz,1H),7.44(s,1H),7.40(d,J=8.0Hz,1H),7.13-7.10(m,1H),7.06-7.02(m,2H),6.88(dd,J1=2.0Hz,J2=8.5Hz,1H),6.71-6.68(m,1H),4.19(s,2H),3.34-3.32(m,1H),3.11-3.05(m,3H),2.82-2.80(m,1H),2.28-2.25(m,1H),1.85-1.79(m,1H).LCMS:m/z=311[M+H]+;Prep-HPLC method:Shim-pack GIST C18column(250×50mm,particle size 5μM);0.1%CH3COOH in H2O/0.1%CH3COOH in ACN gradienteluting system;flow rate=40.0mL/min.
实施例13(MDC-161502-032)
步骤一
将1-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯(584mg,2.43mmol,1.0eq),3-二氟甲基溴苯(500mg,2.43mmol,1.0eq),碳酸钾(1g,7.25mmol,3eq)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(40mg,0.05mmol.0.02eq)溶于N,N-二甲基甲酰胺(20ml)中,用氮气置换三次,升温至90℃,反应搅拌过夜。反应液加入水(50ml),用乙酸乙酯(30ml)萃取3遍,合并有机相,然后每次用饱和食盐水(30ml)洗涤三次,无水硫酸钠干燥,过滤,浓缩后用硅胶柱(二氯甲烷:甲醇=19:1)纯化,得到目标物化合物(500mg,1.69mmol,69.5%)。LCMS:m/z=296[M+H]+;
步骤二
将1-叔丁氧羰基-3-(3-二氟甲基苯基)-2,5-二氢-1H-吡咯烷(400mg,1.35mmol)溶解于甲醇(30ml)中,加入钯碳(200mg),氢气环境下(15Psi)室温搅拌16小时。过滤,滤液浓缩得到白色固体(370mg,1.24mmol,91.8%yield),粗品直接用于下一步反应。LCMS:m/z=298[M+H]+;
步骤三
将1-叔丁氧羰基-3-(3-二氟甲基苯基)吡咯烷(370mg,1.25mmol)溶解于二氯甲烷(5ml)中,滴加三氟乙酸(5ml),室温下搅拌2小时。减压浓缩得棕色油状物(245mg,1.24mmol,yield:99.2%)。LCMS:m/z=198[M+H]+;
步骤四
将3-(3-二氟甲基苯基)吡咯烷(245mg,1.24mmol),1-叔丁氧羰基3-吲哚甲醛(304mg,1.24mmol,1.0eq)溶于无水四氢呋喃(10ml)中,室温下加入乙酸(72mg,1.2mmol)和NaBH(OAc)3(1.04g,4.96mmol),室温搅拌3小时。减压浓缩,残余物用乙酸乙酯(50ml)溶解,碳酸氢钠饱和溶液(30ml)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩,残余物用硅胶柱(二氯甲烷/甲醇=10:1)纯化,得到白色固体(280mg,0.66mmol,yield:53.2%)。LCMS:m/z=427[M+H]+.
步骤五
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(3-二氟甲基苯基)吡咯烷(280mg,0.66mmol)溶解于二氯甲烷(5ml)中,滴加三氟乙酸(5ml),室温下搅拌2小时。减压浓缩,残余物用prep-HPLC纯化得白色固体(150mg,0.46mmol,yield:70%)。1H NMR(500MHz,DMSO-d6)δ11.38(s,1H),10.09(brs,1H),7.79(d,J=7.5Hz,1H),7.57-7.43(m,5H),7.15(d,J=7.5Hz,1H),7.12-7.08(m,1H),6.95(d,J=55.5Hz,1H),4.50(s,2H),3.54-3.53(m,3H),3.32-3.31(m,2H),2.41-2.36(m,1H),2.01-2.00(m,1H).LCMS:m/z=327[M+H]+;Prep-HPLCmethod:Shim-pack GIST C18column(250×50mm,particle size 5μM);0.1%CH3COOH inH2O/0.1%CH3COOH in ACN gradient eluting system;flow rate=40.0mL/min.
实施例14(MDC-161502-033)
将3-溴苯酚(13.6g,78.6mmol),1-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯(16.8g,57.1mmol),1,1'-双二苯基膦二茂铁二氯化钯(2.1g,2.87mmol)和碳酸钾(23.7g,172mmol)混合于N,N-二甲基甲酰胺(100mL)中,氮气置换除氧,随后加热到95℃反应16小时。反应体系用乙酸乙酯(300mL)稀释,依次用水(300mL×2),饱和食盐水(200mL×5)洗涤,之后用无水硫酸钠干燥。过滤除去干燥剂,减压浓缩除去溶剂,柱层析纯化(石油醚/乙酸乙酯=3/1,2/1,乙酸乙酯),得到淡黄色固体(3.1g,收率21%)。LCMS:m/z=262[M+H]+.
将1-叔丁氧羰基-3-(3-羟苯基)-2,5-二氢-1H-吡咯烷(400mg,1.53mmol)溶于甲醇(40mL)中,加入钯碳(80mg),氢气(1atm)条件下室温搅拌3小时。过滤除去钯碳,滤液减压浓缩得到浅黄色固体(402mg,收率>99%)。LCMS:m/z=208[M-56+H]+.
将1-叔丁氧羰基-3-(3-羟苯基)吡咯烷(380mg,1.44mmol)溶于干燥的二氯甲烷(15mL),加入三氟乙酸(10mL),室温下搅拌3小时,随后减压浓缩除去二氯甲烷和过量的三氟乙酸,得到浅褐色粘稠油状物。LCMS:m/z=164[M+H]+.
将3-(3-羟苯基)吡咯烷粗品(375mg,1.44mmol)和3-醛基吲唑(220mg,1.51mmol)溶于干燥的四氢呋喃(20mL)中,加入醋酸(0.3mL),室温下搅拌4小时,随后加入三醋酸硼氢化钠(1.50g,7.08mmol),继续室温条件下搅拌16小时。加入乙酸乙酯(300mL)稀释反应体系,体系用饱和碳酸氢钠溶液洗涤(50mL×3),有机相用无水硫酸钠干燥。过滤除去干燥剂,减压浓缩除去溶剂,随后依次用制备硅胶板(二氯甲烷/甲醇=9/1)和制备液相纯化(乙腈-水-乙酸),得到白色固体(80mg,收率19%)。LCMS:m/z=294[M+H]+;1H NMR(500MHz,DMSO-d6)δ12.82(bs,1H),9.23(s,1H),7.87(d,J=8.0Hz,1H),7.48(d,J=8.5Hz,1H),7.33(ddd,J1=8.0Hz,J2=7.0Hz,J3=1.0Hz,1H),7.10(t,J=7.5Hz,1H),7.04(t,J=8.0Hz,1H),6.65-6.68(m,2H),6.55(ddd,J1=8.0Hz,J2=2.0Hz,J3=1.0Hz,1H),4.03(s,2H),3.22(m,1H),2.98(m,1H),2.72-2.81(m,2H),2.54(m,1H),2.21(m,1H),1.74(m,1H).
实施例15(MDC-161502-034)
将3-(3-羟苯基)吡咯烷粗品(210mg,0.759mmol)和1H-吡咯并[2,3-B]吡啶-3-甲醛(115mg,0.787mmol)溶于干燥的四氢呋喃(10mL)中,加入醋酸(0.2mL),室温下搅拌4小时,随后加入三醋酸硼氢化钠(805mg,3.80mmol),继续室温条件下搅拌16小时。加入乙酸乙酯(300mL)稀释反应体系,体系用饱和碳酸氢钠溶液洗涤(50mL×3),有机相用无水硫酸钠干燥。过滤除去干燥剂,减压浓缩除去溶剂,随后依次用制备硅胶板(二氯甲烷/甲醇=8/1)和制备液相纯化(乙腈-水-乙酸),得到白色固体(60mg,收率27%)。LCMS:m/z=294[M+H]+;1H NMR(500MHz,DMSO-d6)δ11.61(s,1H),9.29(s,1H),8.22(dd,J1=4.5Hz,J2=1.5Hz,1H),8.11(d,J=7.0Hz,1H),7.50(s,1H),7.08(dd,J1=8.0Hz,J2=4.5Hz,1H),7.06(t,J=8.0Hz,1H),6.69(d,J=3.5Hz,1H),6.68(d,J=1.5Hz,1H),6.59(dd,J1=7.0Hz,J2=1.5Hz,1H),4.04(s,2H),3.14(m,1H),2.92(m,2H),2.70(m,1H),2.25(m,1H),1.81(m,1H).
实施例16(MDC-161502-035)
步骤一
将1-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯(584mg,2.43mmol,1.0eq),2-羟基-5-溴吡啶(500mg,2.43mmol,1.0eq),碳酸钾(1g,7.25mmol,3.0eq)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(40mg,0.05mmol.0.02eq)溶于的N,N-二甲基甲酰胺(20ml)中,用氮气置换三次,升温至90℃,反应搅拌过夜。反应液加入水(50ml),用乙酸乙酯(30ml)萃取3遍,合并有机相,然后用饱和食盐水(30ml)洗涤三次,无水硫酸钠干燥,过滤,浓缩后用硅胶柱(二氯甲烷:甲醇=19:1)纯化,得到目标物化合物(350mg,1.34mmol,54.9%)。LCMS:m/z=262[M+H]+.
步骤二
将1-叔丁氧羰基-3-(6-羟基-3-吡啶基)-2,5-二氢-1H-吡咯烷(370mg,1.34mmol)溶解于甲醇(30ml)中,加入钯碳(180mg),氢气环境下(15Psi)室温搅拌16小时。过滤,滤液浓缩得到白色固体(350mg,1.33mmol,98.8%yield),粗品直接用于下一步反应。LCMS:m/z=264[M+H]+.
步骤三
将1-叔丁氧羰基-3-(6-羟基-3-吡啶基)吡咯烷(350mg,1.33mmol)溶解于二氯甲烷(5ml)中,滴加三氟乙酸(5ml),室温下搅拌2小时。减压浓缩得棕色油状物(210mg,1.28mmol,yield:96.2%)。LCMS:m/z=164[M+H]+.
步骤四
将3-(6-羟基-3-吡啶基)吡咯烷(210mg,1.28mmol),1-叔丁氧羰基3-吲哚甲醛(313mg,1.28mmol,1.0eq)溶于无水四氢呋喃(10ml)中,室温下加入乙酸(90mg,1.5mmol)和NaBH(OAc)3(1.08g,5.12mmol),室温搅拌3小时。减压浓缩,残余物用乙酸乙酯(50ml)溶解,碳酸氢钠饱和溶液(30ml)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩,残余物用硅胶柱(二氯甲烷/甲醇=10:1)纯化,得到白色固体(120mg,0.31mmol,yield:24.2%)。LCMS:m/z=394[M+H]+.
步骤五
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(6-羟基-3-吡啶基)吡咯烷(120mg,0.31mmol)溶解于二氯甲烷(5ml)中,滴加三氟乙酸(5ml),室温下搅拌1小时。减压浓缩,残余物用prep-HPLC纯化得白色固体(60mg,0.204mmol,yield:84.6%)。1H NMR(500MHz,DMSO-d6)δ11.49-11.48(m,1H),10.13-10.08(m,2H),8.07-7.04(m,2H),7.84-7.80(m,1H),7.65-7.63(m,1H),7.45(d,J=8.0Hz,1H),7.26-7.06(m,2H),4.62(s,2H),3.79-3.54(m,3H),3.42-3.37(m,1H),3.31-3.28(m,2H),2.47-2.35(m,1H),2.17-1.95(m,1H).LCMS:m/z=294[M+H]+;Prep-HPLC method:Shim-pack GIST C18column(250×50mm,particle size5μM);0.1%CH3COOH in H2O/0.1%CH3COOH in ACN gradient eluting system;flow rate=40.0mL/min.
实施例17(MDC-161502-036)
步骤一
将1-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯(610mg,2.54mmol,1.0eq),6-溴吲唑(500mg,2.54mmol,1.0eq),碳酸钾(1.05g,7.61mmol,3.0eq)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(40mg,0.05mmol.0.02eq)溶于N,N-二甲基甲酰胺(20ml)中,用氮气置换3次,升温至90℃,反应搅拌过夜。反应液加入水(50ml),用乙酸乙酯(30ml)萃取3遍,合并有机相,然后用饱和食盐水(30ml)洗涤3次,无水硫酸钠干燥,过滤,浓缩后用硅胶柱(二氯甲烷:甲醇=19:1)纯化,得到目标物化合物(320mg,1.12mmol,44%)。LCMS:m/z=286[M+H]+;
步骤二
将1-叔丁氧羰基-3-(6-吲唑基)-2,5-二氢-1H-吡咯烷(320mg,1.12mmol)溶解于甲醇(30ml)中,加入钯碳(160mg),氢气环境下,15Psi)室温搅拌16小时。过滤,滤液浓缩得到白色固体(260mg,0.91mmol,80.9%yield),粗品直接用于下一步反应。LCMS:m/z=288[M+H]+;
步骤三
将1-叔丁氧羰基-3-(6-吲唑基)吡咯烷(260mg,0.91mmol)溶解于二氯甲烷(5ml)中,滴加三氟乙酸(5ml),室温下搅拌2小时。减压浓缩得棕色油状物(160mg,0.85mmol,yield:93.5%)。LCMS:m/z=188[M+H]+;
步骤四
将3-(6-吲唑基)吡咯烷(160mg,0.85mmol),1-叔丁氧羰基3-吲哚甲醛(209mg,0.85mmol,1.0eq)溶于无水四氢呋喃(10ml)中,室温下加入乙酸(60mg,1.0mmol)和NaBH(OAc)3(724mg,3.42mmol),室温搅拌3小时。减压浓缩,残余物用乙酸乙酯(50ml)溶解,碳酸氢钠饱和溶液(30ml)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩,残余物用硅胶柱(二氯甲烷/甲醇=9:1)纯化,得到白色固体(200mg,0.48mmol,yield:56.4%)。LCMS:m/z=417[M+H]+;
步骤五
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(6-吲唑基)吡咯烷(200mg,0.47mmol)溶解于二氯甲烷(5ml)中,滴加三氟乙酸(5ml),室温下搅拌0.5小时。减压浓缩,残余物用prep-HPLC纯化得白色固体(120mg,0.378mmol,yield:80.5%)。1H NMR(500MHz,DMSO-d6)δ13.05(s,1H),11.45(s,1H),8.03(s,1H),7.82(d,J 1=7.5Hz,1H),7.73(d,J 1=8.5Hz,1H),7.63(s,1H),7.45-7.44(m,2H),7.18-7.09(m,3H),4.62(s,2H),3.78-3.55(m,4H),3.34-3.33(m,1H),2.50-2.48(m,1H),2.18-2.03(m,1H).LCMS:m/z=317[M+H]+;Prep-HPLC method:Shim-pack GIST C18column(250×50mm,particle size 5μM);0.1%CH3COOH in H2O/0.1%CH3COOH in ACN gradient eluting system;flow rate=40.0mL/min.
实施例18(MDC-161502-037)
步骤一
将1-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯(610mg,2.54mmol,
1.0eq),5-溴-1H-苯并咪唑(500mg,2.54mmol,1.0eq),碳酸钾(1.05g,7.61mmol,3eq)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(40mg,0.05mmol.0.02eq)溶于N,N-二甲基甲酰胺(20ml)中,用氮气置换三次,升温至90℃,反应搅拌过夜。反应液加入水(50ml),用乙酸乙酯(30ml)萃取3遍,合并有机相,然后用饱和食盐水(30ml)洗涤3次,无水硫酸钠干燥,过滤,浓缩后用硅胶柱(二氯甲烷:甲醇=19:1)纯化,得到目标物化合物(100mg,0.35mmol,13.8%)。LCMS:m/z=286[M+H]+;
步骤二
将1-叔丁氧羰基-3-(6-苯并咪唑基)-2,5-2氢-1H-吡咯烷(320mg,1.12mmol)溶解于甲醇(30ml)中,加入钯碳(160mg),氢气环境下,15Psi)室温搅拌16小时。过滤,滤液浓缩得到白色固体(260mg,0.91mmol,80.9%yield),粗品直接用于下一步反应。LCMS:m/z=288[M+H]+;
步骤三
将1-叔丁氧羰基-3-(6-苯并咪唑基)吡咯烷(260mg,0.91mmol)溶解于二氯甲烷(5ml)中,滴加三氟乙酸(5ml),室温下搅拌2小时。减压浓缩得棕色油状物(160mg,0.85mmol,yield:93.5%)。LCMS:m/z=188[M+H]+;
步骤四
将3-(6-苯并咪唑基)吡咯烷(160mg,0.85mmol),1-叔丁氧羰基-3-吲哚甲醛(209mg,0.85mmol,1.0eq)溶于无水四氢呋喃(10ml)中,室温下加入乙酸(60mg,1.0mmol)和NaBH(OAc)3(724mg,3.42mmol),室温搅拌3小时。减压浓缩,残余物用乙酸乙酯(50ml)溶解,碳酸氢钠饱和溶液(30ml)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩,残余物用硅胶柱(二氯甲烷/甲醇=10:1)纯化,得到白色固体(200mg,0.48mmol,yield:56.4%)。LCMS:m/z=417[M+H]+;
步骤五
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(6-苯并咪唑基)吡咯烷(200mg,0.47mmol)溶解于二氯甲烷(5ml)中,滴加三氟乙酸(5ml),室温下搅拌1小时。减压浓缩,残余物用prep-HPLC纯化得白色固体(120mg,0.378mmol,yield:80.5%)。1H NMR(500MHz,DMSO-d6)δ12.28(s,1H),10.91(brs,1H),8.13(s,1H),7.67(d,J=7.5Hz,1H),7.49-7.48(m,2H),7.34(d,J=8.0Hz,1H),7.26(d,J=2.0Hz,1H),7.12(d,J=8.0Hz,1H),7.08-7.05(m,1H),7.01-6.98(m,1H),3.84(s,2H),3.42-3.37(m,1H),3.00(t,J=8.0Hz,1H),2.78-2.76(m,2H),2.57-2.54(m,1H),2.32-2.25(m,1H),1.85-1.79(m,1H).LCMS:m/z=317[M+H]+;Prep-HPLCmethod:Shim-pack GIST C18column(250×50mm,particle size 5μM);0.1%CH3COOH inH2O/0.1%CH3COOH in ACN gradient eluting system;flow rate=40.0mL/min.
实施例19(MDC-161502-038)
将4-溴-1H-吲唑(421g,2.14mmol),1-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯(630mg,2.13mmol),1,1'-双二苯基膦二茂铁二氯化钯(157mg,0.215mmol)和碳酸钾(890mg,6.44mmol)混合于N,N-二甲基甲酰胺(20mL)中,氮气置换除氧,随后加热到110℃反应7小时。反应体系用乙酸乙酯(500mL)稀释,依次用水(200mL),饱和食盐水(100mL×5)洗涤,之后用无水硫酸钠干燥。过滤除去干燥剂,减压浓缩除去溶剂,快速柱层析纯化(石油醚/乙酸乙酯/乙醇=40/3/1-16/3/1-3/3/1),得到淡黄色固体(450mg,收率33%)。LCMS:m/z=286[M+H]+;
将1-(1-叔丁氧羰基)-3-(4-吲唑基)-2,5-二氢-1H-吡咯烷(300mg,1.05mmol)溶于甲醇(30mL)中,加入钯碳(60mg),氢气(1atm)条件下室温搅拌16小时。过滤除去钯碳,滤液减压浓缩除去溶剂,得到浅黄色固体(301mg,收率97%)。LCMS:m/z=288[M+H]+;
将1-(1-叔丁氧羰基)-3-(4-吲唑基)吡咯烷(301mg,1.05mmol)溶于干燥的二氯甲烷(10mL),加入三氟乙酸(10mL),室温条件下搅拌1小时,减压除去溶剂,将残余物溶于干燥的四氢呋喃(15mL)中,加入1-叔丁氧羰基3-吲哚甲醛(260mg,1.06mmol),醋酸(0.2mL),室温下搅拌2小时,随后加入三醋酸硼氢化钠(1.12mg,5.28mmol),继续室温条件下搅拌2小时。加入乙酸乙酯(300mL)稀释反应体系,体系依次用饱和碳酸氢钠溶液(100mL),饱和食盐水(100mL×2)洗涤,有机相用无水硫酸钠干燥。过滤除去干燥剂,减压浓缩除去溶剂,随后硅胶制备板纯化(二氯甲烷/甲醇=12/1),得到浅黄色固体(180mg,收率41%)。LCMS:m/z=417[M+H]+。
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(4-吲唑基)吡咯烷
(150mg,0.360mmol)溶于干燥的二氯甲烷(8mL)中,加入三氟乙酸(8mL),室温下搅拌1小时,减压除去溶剂,将残留物溶于二氯甲烷,加入氨的甲醇溶液碱化体系,再次减压除去溶剂,随后用制备液相纯化(乙腈-水-乙酸),得到白色固体(30mg,收率26%)。LCMS:m/z=317[M+H]+;1H NMR(500MHz,DMSO-d6)δ13.06(s,1H),11.09(s,1H),8.22(s,1H),7.73(d,J=7.5Hz,1H),7.40(s,1H),7.39(s,1H),7.37(s,1H),7.25(t,J=7.5Hz,1H),7.11(t,J=7.5Hz,1H),7.04(t,J=7.5Hz,1H),7.00(d,J=7.0Hz,1H),4.13(s,2H),3.80(m,1H0,3.14(m,1H),2.39(m,1H),2.03(m,1H).
实施例20(MDC-161502-039)
将4-溴-1H-苯并咪唑(1.20g,6.09mmol),1-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯(1.77g,6.00mmol),1,1'-双二苯基膦二茂铁二氯化钯(230mg,0.314mmol)和碳酸钾(2.49g,18.0mmol)混合于N,N-二甲基甲酰胺(30mL)中,氮气置换除氧,随后加热到100℃反应16小时。反应体系用乙酸乙酯(300mL)稀释,有机相依次用水(100mL),饱和食盐水(100mL×5)洗涤,之后用无水硫酸钠干燥。过滤除去干燥剂,减压浓缩除去溶剂,快速柱层析纯化(石油醚/乙酸乙酯/乙醇=40/3/1-3/3/1),得到淡黄色固体(450mg,收率26%)。LCMS:m/z=286[M+H]+;
将1-(1-叔丁氧羰基)-3-(4-苯并咪唑基)-2,5-2氢-1H-吡咯烷(450mg,1.58mmol)溶于甲醇(30mL)中,加入钯碳(90mg),氢气(1atm)条件下室温搅拌48小时。过滤除去钯碳,滤液减压浓缩除去溶剂,快速硅胶柱纯化(二氯甲烷/甲醇=20/1),得到浅褐色固体(210mg,收率44%)。LCMS:m/z=288[M+H]+;
将1-(1-叔丁氧羰基)-3-(4-苯并咪唑基)吡咯烷(210mg,0.731mmol)溶于干燥的二氯甲烷(10mL),加入三氟乙酸(8mL),室温条件下搅拌2小时,减压除去溶剂,将残余物溶于干燥的四氢呋喃(10mL)中,加入1-叔丁氧羰基3-吲哚甲醛(180mg,0.734mmol),醋酸(0.2mL),室温下搅拌3小时,随后加入三醋酸硼氢化钠(620mg,2.93mmol),继续室温条件下搅拌3小时。加入乙酸乙酯(300mL)稀释反应体系,体系依次用饱和碳酸氢钠溶液(100mL×2),饱和食盐水(100mL×2)洗涤,有机相用无水硫酸钠干燥。过滤除去干燥剂,减压浓缩除去溶剂,随后硅胶制备板纯化(二氯甲烷/甲醇=20/1),得到浅黄色固体(47mg,收率15%)。LCMS:m/z=417[M+H]+。
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(4-苯并咪唑基)吡咯烷(35mg,0.0840mmol)溶于干燥的二氯甲烷(10mL)中,加入三氟乙酸(8mL),室温下搅拌2小时,减压除去溶剂,将残留物溶于二氯甲烷,加入氨的甲醇溶液碱化体系,再次减压除去溶剂,随后用制备液相纯化(乙腈-水-乙酸),得到白色固体(14mg,收率54%)。LCMS:m/z=317[M+H]+;1H NMR(500MHz,DMSO-d6)δ11.06(s,1H),8.03(s,1H),7.77(d,J=7.5Hz,1H),7.37-7.42(m,3H),7.05-7.14(m,4H),4.16(d,J=13.0Hz,1H),4.04(d,J=13.0Hz,1H),3.81(m,1H),3.20(m,1H),2.96(m,1h),2.88(m,1H),2.39(m,1H),1.95(m,2H).
实施例21(MDC-161502-040)
将5-溴-1H-苯并三氮唑(423g,2.14mmol),1-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯(630mg,2.13mmol),1,1'-双二苯基膦二茂铁二氯化钯(157mg,0.215mmol)和碳酸钾(890mg,6.44mmol)混合于N,N-二甲基甲酰胺(20mL)中,氮气置换除氧,随后加热到96℃反应16小时。反应体系用乙酸乙酯(400mL)稀释,依次用水(100mL),饱和食盐水(100mL5)洗涤,之后用无水硫酸钠干燥。过滤除去干燥剂,减压浓缩除去溶剂,快速柱层析纯化(石油醚/乙酸乙酯/乙醇=16/3/1-3/3/1),得到淡黄色固体(100mg,收率11%)。LCMS:m/z=287[M+H]+;
将1-(1-叔丁氧羰基)-3-(5-苯并三氮唑基)-2,5-2氢-1H-吡咯烷(96mg,0.335mmol)溶于甲醇(20mL)中,加入钯碳(20mg),氢气(1atm)条件下室温搅拌16小时。过滤除去钯碳,滤液减压浓缩除去溶剂,得到浅黄色固体(96mg,收率97%)。LCMS:m/z=289[M+H]+;
将1-(1-叔丁氧羰基)-3-(5-苯并三氮唑基)吡咯烷(96.0mg,0.335mmol)溶于干燥的二氯甲烷(6mL),加入三氟乙酸(6mL),室温条件下搅拌1小时,减压除去溶剂,将残余物溶于干燥的四氢呋喃(10mL)中,加入1-叔丁氧羰基3-吲哚甲醛(85mg,0.347mmol),醋酸(0.1mL),室温下搅拌2小时,随后加入三醋酸硼氢化钠(360mg,1.70mmol),继续室温条件下搅拌2小时。加入乙酸乙酯(150mL)稀释反应体系,体系依次用饱和碳酸氢钠溶液(60mL),饱和食盐水(50mL×2)洗涤,有机相用无水硫酸钠干燥。过滤除去干燥剂,减压浓缩除去溶剂,随后硅胶制备板纯化(二氯甲烷/甲醇=12/1),得到浅黄色固体(65mg,收率46%)。LCMS:m/z=418[M+H]+。
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-(5-苯并三氮唑基)吡咯烷(60mg,0.144mmol)溶于干燥的二氯甲烷(5mL)中,加入三氟乙酸(5mL),室温下搅拌1小时,减压除去溶剂,将残留物溶于二氯甲烷,加入氨的甲醇溶液碱化体系,再次减压除去溶剂,随后用制备液相纯化(乙腈-水-乙酸),得到白色固体(18mg,收率39%)。LCMS:m/z=318[M+H]+;1HNMR(500MHz,DMSO-d6)δ10.93(s,1H),7.82(d,J=8.5Hz,1H),7.71(s,1H),7.68(d,J=8.0Hz,1H),7.40(dd,J1=9.0Hz,J2=1.0Hz,1H),7.35(d,J=8.0Hz,1H),7.28(d,J=2.0Hz,1H),7.07(td,J1=7.5Hz,J2=1.0Hz,1H),7.00(td,J1=7.5Hz,J2=1.0Hz,1H),3.88(s,2H),3.50(m,1H),3.01(m,1H),2.86(m,1H),2.75(m,1H),2.63(m,1H),2.32(m,1H0,1.84(m,1H).
实施例22(MDC-161502-041)
步骤一
将1-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯(452mg,2mmol,1.2eq),2,3-二羰基-4-溴吲哚(491mg,1.67mmol,1.0eq),碳酸钾(690mg,5mmol,3eq)和[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(25mg,0.03mmol.0.02eq)溶于的N,N-二甲基甲酰胺(15ml)中,用氮气置换三次,升温至90℃,反应搅拌过夜。反应液加入水(50ml),用乙酸乙酯(30ml)萃取3遍,合并有机相,然后每次用饱和食盐水(30ml)洗涤3次,无水硫酸钠干燥,过滤,浓缩后用硅胶柱(二氯甲烷:甲醇=19:1)纯化,得到目标物化合物(150mg,0.477mmol,28.6%)。LCMS:m/z=315[M+H]+;
步骤二
将1-叔丁氧羰基-3-[4-(2,3-二羰基吲哚基)]-2,5二氢-1H-吡咯烷(150mg,0.477mmol)溶解于甲醇(30ml)中,加入钯碳(80mg),氢气环境下(15Psi)室温搅拌16小时。过滤,滤液浓缩得到黄色固体(90mg,0.284mmol,59.7%yield),粗品直接用于下一步反应。LCMS:m/z=263[M-56]+;
步骤三
将1-叔丁氧羰基-3-[4-(2-羰基-3-羟基吲哚基)]吡咯烷(90mg,0.284mmol)溶解于二氯甲烷(5ml)中,滴加三氟乙酸(5ml),室温下搅拌2小时。减压浓缩得棕色油状物(50mg,0.23mmol,yield:80.7%)。LCMS:m/z=219[M+H]+;
步骤四
将3-[4-(2-羰基-3-羟基吲哚基)]吡咯烷(50mg,0.23mmol),1-叔丁氧羰基-3-吲哚甲醛(56mg,0.23mmol,1.0eq)溶于无水四氢呋喃(10ml)中,室温下加入乙酸(20mg,0.3mmol)和NaBH(OAc)3(194mg,0.92mmol),室温搅拌3小时。减压浓缩,残余物用乙酸乙酯(50ml)溶解,碳酸氢钠饱和溶液(30ml)洗涤,有机相用无水硫酸钠干燥,过滤,浓缩,残余物用硅胶柱(二氯甲烷/甲醇=10:1)纯化,得到黄色固体(50mg,0.11mmol,yield:48.6%)。LCMS:m/z=448[M+H]+;
步骤五
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-[4-(2-羰基-3-羟基吲哚基)]吡咯烷(50mg,0.11mmol)溶解于二氯甲烷(8ml)中,加入戴斯马丁试剂(73mg,0.167mmol,1.5eq),室温下搅拌2小时。反应完成之后加入饱和碳酸氢钠溶液(20ml),然后用乙酸乙酯(20ml)溶解,有机相用无水硫酸钠干燥,过滤,浓缩,残余物用TLC板(二氯甲烷/甲醇=9:1)纯化得到黄色固体(30mg,0.07mmol,yield:61.2%)。LCMS:m/z=446[M+H]+;
步骤六
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-[4-(2,3-二羰基吲哚基)]吡咯烷(30mg,0.07mmol)溶解于二氯甲烷(2ml)中,滴加三氟乙酸(2ml),室温下搅拌0.5小时。减压浓缩,残余物用prep-HPLC纯化得黄色固体(20mg,0.06mmol,yield:82.5%)。1H NMR(500MHz,DMSO-d6)δ10.98(brs,1H),10.87(s,1H),7.64(d,J=8.0Hz,1H),7.46(t,J=8.0Hz,1H),7.33(d,J=8.0Hz,1H),7.22(d,J=2.0Hz,1H),7.10-7.04(m,2H),6.99-6.96(m,1H),6.69-6.67(m,1H),4.12-4.08(m,1H),3.80-3.78(m,2H),2.80-2.76(m,2H),2.66-2.60(m,1H),2.54-2.52(m,1H),2.25-2.17(m,1H),1.74-1.68(m,1H).LCMS:m/z=346[M+H]+;Prep-HPLCmethod:Shim-pack GIST C18column(250×50mm,particle size 5μM);0.1%CH3COOH inH2O/0.1%CH3COOH in ACN gradient eluting system;flow rate=40.0mL/min.
实施例23(MDC-161502-042)
将6-溴靛红(540mg,2.39mmol),1-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯(700mg,2.37mmol),1,1'-双二苯基膦二茂铁二氯化钯(180mg,0.246mmol)和碳酸钾(1.53g,7.21mmol)混合于N,N-二甲基甲酰胺(20mL)中,氮气置换除氧,随后加热到93℃反应2小时。反应体系用乙酸乙酯(500mL)稀释,依次用水(200mL),饱和食盐水(100mL×5)洗涤,之后用无水硫酸钠干燥。过滤除去干燥剂,减压浓缩除去溶剂,快速柱层析纯化(石油醚/乙酸乙酯=4/1-1/1),得到淡黄色固体(106mg,收率14%)。LCMS:m/z=315[M+H]+;
将1-叔丁氧羰基-3-[6-(2,3-二羰基吲哚基)]-2,5二氢-1H-吡咯烷(106mg,0.337mmol)溶于甲醇(20mL)中,加入钯碳(21mg),氢气(1atm)条件下室温搅拌16小时。过滤除去钯碳,滤液减压浓缩除去溶剂,得到浅黄色固体(100mg,收率93%)。LCMS:m/z=319[M+H]+;
将1-叔丁氧羰基-3-[6-(2-羰基-3-羟基吲哚基)]吡咯烷(301mg,1.05mmol)溶于干燥的二氯甲烷(10mL),加入三氟乙酸(8mL),室温条件下搅拌1小时,减压除去溶剂,将残余物溶于干燥的四氢呋喃(15mL)中,加入1-叔丁氧羰基-3-吲哚甲醛(80mg,0.326mmol),醋酸(0.1mL),室温下搅拌2小时,随后加入三醋酸硼氢化钠(333mg,1.57mmol),继续室温条件下搅拌2小时。加入乙酸乙酯(300mL)稀释反应体系,体系依次用饱和碳酸氢钠溶液(50mL),饱和食盐水(50mL×2)洗涤,有机相用无水硫酸钠干燥。过滤除去干燥剂,减压浓缩除去溶剂,将残留物溶于干燥二氯甲烷中,敞口条件下室温搅拌16小时,减压除去溶剂,随后硅胶制备板纯化(二氯甲烷/甲醇=12/1),得到浅黄色固体(50mg,收率36%)。LCMS:m/z=446[M+H]+。
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-[6-(2-羰基-3-羟基吲哚基)]吡咯烷(50mg,0.112mmol)溶于干燥的二氯甲烷(5mL)中,加入三氟乙酸(3mL),室温下搅拌2小时,减压除去溶剂,将残留物溶于二氯甲烷,加入三乙胺碱化体系,再次减压除去溶剂,随后用制备液相纯化(乙腈-水-乙酸),得到浅黄色固体(6mg,收率15%)。LCMS:m/z=346[M+H]+;1H NMR(500MHz,DMSO-d6)δ10.99(bs,1H),10.89(s,1H),7.64(d,J=7.5Hz,1H),7.39(d,J=8.0Hz,1H),7.33(d,J=8.0Hz,1H),7.24(d,J=2.5Hz,1H),7.06(td,J1=7.5Hz,J2=1.0Hz,1H),7.00(td,J1=7.5Hz,J2=1.0Hz,1H),6.98(dd,J1=7.5Hz,J2=1.5Hz,1H),6.85(s,1H),3.78(m,2H),3.34(m,1H),2.76-2.84(m,2H),2.59(m,1h),2.53(m,1H),2.26(m,1H),1.72(m,1H).
实施例24(MDC-161502-043)
将5-溴-1,3-二氢苯并咪唑-2-酮(1.30g,6.10mmol),1-叔丁氧羰基-2,5-二氢-1H-吡咯-3-硼酸频哪醇酯(1.77g,6.00mmol),1,1'-双二苯基膦二茂铁二氯化钯(230mg,0.314mmol)和碳酸钾(2.49g,18.0mmol)混合于N,N-二甲基甲酰胺(30mL)中,氮气置换除氧,随后加热到100℃反应16小时。反应体系用乙酸乙酯(300mL)稀释,有机相依次用水(100mL×2),饱和食盐水(100mL×5)洗涤,之后用无水硫酸钠干燥。过滤除去干燥剂,减压浓缩除去溶剂,柱层析纯化(石油醚/乙酸乙酯/乙醇=12/3/1,3/3/1),得到淡黄色固体(300mg,收率17%)。LCMS:m/z=302[M+H]+.
将1-叔丁氧羰基-3-[5-(1,3-二氢苯并咪唑-2-酮基)]-2,5二氢-1H-吡咯烷(300mg,0.996mmol)溶于甲醇(30mL)中,加入钯碳(60mg),氢气(1atm)条件下室温搅拌16小时。过滤除去钯碳,滤液减压浓缩得到浅黄色固体(300mg,收率>99%)。LCMS:m/z=304[M+H]+.
将1-叔丁氧羰基-3-[5-(1,3-二氢苯并咪唑-2-酮基)]吡咯烷(120mg,0.396mmol)溶于干燥的二氯甲烷(10mL),加入三氟乙酸(8mL),室温条件下搅拌2小时,减压除去溶剂,将残余物溶于干燥的四氢呋喃(10mL)中,加入1-叔丁氧羰基-3-吲哚甲醛(100mg,0.408mmol),醋酸(0.2mL),室温下搅拌3小时,随后加入三醋酸硼氢化钠(420mg,1.98mmol),继续室温条件下搅拌16小时。加入乙酸乙酯(300mL)稀释反应体系,体系依次用饱和碳酸氢钠溶液(50mL×3),水(100mL)和饱和食盐水(100mL×2)洗涤,有机相用无水硫酸钠干燥。过滤除去干燥剂,减压浓缩除去溶剂,随后硅胶制备板纯化(二氯甲烷/甲醇=20/1),得到浅黄色固体(60mg,收率35%)。LCMS:m/z=433[M+H]+。
将1-(1-叔丁氧羰基吲哚-3-甲基)-3-[5-(1,3-二氢苯并咪唑-2-酮基)]吡咯烷(60mg,0.139mmol)溶于干燥的二氯甲烷(5mL)中,加入三氟乙酸(5mL),室温下搅拌2小时,减压除去溶剂,将残留物溶于二氯甲烷,加入三乙胺碱化体系,再次减压除去溶剂,随后用制备液相纯化(乙腈-水-乙酸),得到白色固体(20mg,收率43%)。LCMS:m/z=333[M+H]+;1HNMR(500MHz,DMSO-d6)δ10.93(s,1H),10.49(s,1H),10.46(s,1H),7.66(d,J=8.0Hz,1H),7.35(d,J=8.0Hz,1H),7.27(d,J=2.0Hz,1H),7.08(td,J1=7.5Hz,J2=1.0Hz,1H),7.00(td,J1=7.5Hz,J2=1.0Hz,1H),6.85(s,1H),6.82(dd,J1=8.0Hz,J2=1.0Hz,1H),6.79(d,J=8.0Hz,1H),3.86(s,2H),3.28(m,1H),2.96(m,1H),2.76(m,2H),2.23(m,1H),1.74(m,1H).
生物活性测试
I、D2受体亲和力试验:所述化合物对D2受体的亲和力采用放射性配体竞争的试验进行测定,克隆D2受体在HEK293细胞系进行表达。
II、D2受体功能试验:所述化合物拮抗D2受体的能力利用钙流检测实验(FLIPR)来测定。
III、DAT受体功能试验:所述化合物抑制DAT的能力用神经递质转运体吸收实验检测。
I、D2受体亲和力试验
1、实验材料
1.1、试剂及化合物
3H-7-OH-DPAT(PerkinElmer)
Tris base(Sigma,Cat:T1503-1KG),配置成1M溶液,pH调至7.4
PEI(Sigma-P3143)
Microscint 20cocktail闪烁液(PerkinElmer-6013329)
7-OH-DPAT(Sigma)
氟哌利多(Droperidol,Sigma)
1.2、仪器与耗材
Unifilter-96GF/C微孔孔板(Perkin Elmer-6005174)
96孔聚丙烯板(Agilent-5042-1385)
TopSeal-A密封膜(Perkin Elmer-6005250)
MicroBeta2微孔板检测仪平台(PerkinElmer)
细胞计数仪(Perkin Elmer)
2、实验步骤
2.1、缓冲液配制:
实验缓冲液:50mM Tris-HCl,pH 7.4,5mM MgCl2
洗板缓冲液:50mM Tris-HCl pH 7.4,储存在4℃备用。
2.2、化合物配制:
化合物和阳性对照7-OH-DPAT用DMSO进行梯度稀释,起始浓度分别为2mM,10个浓度4倍连续稀释。转移1μL至96孔板指定位置。
阳性对照孔加入1μL氟哌利多(终浓度10μM)。阴性对照孔加入1μL DMSO。
2.3、细胞膜配制:
受体细胞膜用对应的实验缓冲液稀释到10μg/孔,每孔100μL细胞膜。
2.4、同位素配制:
3H-7-OH-DPAT用对应的实验缓冲液稀释到2nM,终浓度为1nM。
2.5、实验步骤
在各加入100μL的细胞膜和同位素后,D2受体的反应板在室温孵育1小时。GF/C过滤板用0.3%的PEI溶液浸泡半小时以上。待反应结束之后,将细胞膜用细胞计数仪收集到GF/C过滤板上,用冷的洗板缓冲液洗4次后再50℃烘箱中烘干1小时。把干燥好的GF/C过滤板底部封膜,每孔加入50μL闪烁液,并密封。用MicroBeta读数,数据用GraphPad Prism 5.0进行分析。
3、项目数据的计算公式:
%抑制率=100×[1-(样品孔读值–阴性对照孔读值)/(阳性对照孔读值-阴性对照孔读值)]
Ki=IC50/(1+同位素浓度/Kd)
II、D2受体功能性试验
1、实验材料
1.1、细胞株及培养基
细胞株:HEK293
DMEM培养基(Invitrogen)
胎牛血清(FBS,Invitrogen)
L-Glutamine(Invitrogen)G418(Invitrogen)
杀稻瘟菌素(Invitrogen)
1.2、试剂
Fluo-4Direct试剂盒(Invitrogen)
1.3、仪器
384孔多聚赖氨酸包被细胞板(Greiner)
384孔化合物板(Greiner)
FLIPR仪器(Molecular Device)
POD810仪器(Labcyte)
细胞计数仪(Beckman,Vi-cell XR)
微量试剂加液器(Thermo)
1.4、参照化合物
Amisulpride(Sigma)
2、实验方法
2.1、试剂准备
配制250mM Probenecid溶液:按照试剂盒操作说明,在77mg probenecid中加入1mL FLIPR缓冲盐溶液,现用现配。
配制2X(8μM)Fluo-4Direct TM加样缓冲液:提前融化实验用量管数Fluo-4DirectTM,每管加入10ml FLIPR缓冲盐溶液,加入0.2mL 250mM Probenecid溶液,避光振荡涡旋>5分钟,现用现配。
2.2、准备细胞
a)从液氮罐中取1管细胞并快速的在37℃水浴中溶解。
b)将细胞悬液加到提前加入预热的20ml培养基的离心管中。
c)在室温下1000转离心5分钟。
d)缓慢的倒掉上清,避免影响到沉降的细胞。
e)用10-30ml培养基重悬细胞,用移液器轻柔的吹打细胞。
f)用细胞计数仪计算细胞的活力及数目
g)用培养基将细胞稀释至1×105cells/ml,20μL/孔种入384孔多聚赖氨酸包被细胞板。
h)5%CO2,37℃培养箱孵育16-20小时。
2.3、FLIPR试验
a)化合物剂量曲线板:待测化合物的起始浓度是2mM用Bravo在100%DMSO中4倍梯度稀释为10个点,然后Echo转移900nL到化合物板中。
b)加30μL FLIPR缓冲盐溶液至相应的化合物板,备用。
c)将前一天准备好的细胞板从培养箱中取出,每孔加入20μL 2X Fluo-4DirectTM缓冲液,5%CO2,37℃培养箱孵育50分钟,室温放置10分钟。
d)取出化合物板,放好枪头,在FLIPR中运行。
e)运行FLIPR仪器软件,按照设定程序,添加10μL实验用缓冲盐溶液到细胞板中,读取荧光信号。再添加10μL既定浓度的激动剂参考化合物到细胞板中,读取荧光信号。读数后,通过软件中“Max-Min”,“Read 90to Maximum allowed”方法导出数据,计算相应细胞系的EC80,准备6X EC80浓度的参考化合物。
f)运行FLIPR仪器软件,按照设定程序,添加10μL既定浓度的检测化合物及参考化合物到细胞板中,读取荧光信号。再添加10μL 6X EC80浓度的参考化合物激动剂到细胞板中,读取荧光信号。
g)数据分析
项目数据的计算公式:
抑制剂%活力=100-(每孔信号值-抑制剂高剂量对照组平均值)/(DMSO对照组平均值-抑制剂高剂量对照组平均值)*100%.
III、DAT转运体试验
1、实验材料
1.1、试剂及耗材
神经递质转运蛋白重摄取测定试剂盒(Molecular devices)
HEPES,Invitrogen(Cat#15630130)
HBSS,Invitrogen(Cat#14025126)
BSA,Sigma(Cat#7030)
1.2、检测缓冲液
HBSS1X、HEPES20mM。
1.3、含BSA的检测缓冲液
HBSS1X、HEPES20mM、BSA0.1%。
1.4、染料溶液
Lyophilized fluorescent dye 1vial、Assay buffer10mL。
1.5、参照化合物
BTCP–hydrochloride(Sigma)
1.6、仪器设备
384孔多聚赖氨酸包被细胞板(Greiner)
Vi-cell XR细胞活力分析仪(Beckman Coulter)
培养箱(Thermo)
Flexstation多功能酶标仪(Molecular devices)
2、实验步骤
2.1、准备细胞
a)提前37℃水浴预热培养基,预热时间大于30分钟,备用。
b)取出预热好的培养基,用75%酒精消毒,放入生物安全柜。
c)从培养箱中取出培养细胞,利用真空泵吸去培养基,加入1X DPBS,孵育片刻,利用真空泵吸去,加入适量0.05%trypsin-EDTA进行细胞消化,用10%FBS培养基终止消化,吹散细胞。
d)用移液管将吹散细胞吸入50mL离心管中,800转/分钟,离心5分钟,用培养基重悬,吹散,计数。
e)用培养基将细胞稀释至1x 106cells/mL,20μL/孔种入384孔多聚赖氨酸包被细胞板。
2.2、DAT转运体试验
a)用含0.1%BSA的检测缓冲液将参照化合物以1:3的比例稀释为10个浓度梯度,其中最高浓度为2μM。待测化合物用含0.1%BSA的检测缓冲液稀释为20uM。
b)利用离心机(750rpm,15s)将细胞培养板中培养液甩干,并将第1步中化合物溶液转移至细胞培养板(25uL/孔)。
HC(High control):25μL含0.2%DMSO的0.1%BSA检测缓冲液。
LC(Low control):25μL含2μM的阳性拮抗剂溶液。
c)以300rpm离心15秒后,37℃培养30分钟。化合物孵育完成后加入染料溶液(25μL/孔),并以37℃孵育30分钟。孵育完成后在Flexstation中读数。
参数见表4:
表4
Temperature setting | 37℃ |
Excitatio wavelength(nM) | 440 |
Emissio wavelength(nM) | 520 |
Emission cut-off(nM) | 515 |
PMT sensitivity | medium |
Reads/well | 3 |
d)数据分析
项目数据的计算公式:
抑制剂%活力=100-(每孔信号值-LC孔的平均值)/(H孔平均值-LC孔的平均值)*100%.
本发明的化合物是D2受体和DAT的双重调节剂,如下表5中所示。实施例在以上测定中进行测试并发现具有约10nM至1μM的Ki(D2)和100nM至1μM的Ki(DAT)。
表5
IV、所述化合物对于小鼠“类精神分裂症”活动的治疗活性检测
1.利用对苯环己哌啶(PCP)诱导的小鼠高自发活动(Locomotor activity,LMA)的影响进行检测。
受试化合物MDC为乳白色粉末,阴凉处保存(临用前以1%DMSO新鲜配制)。奥氮平(Olanzapine),购自Adamas,为淡黄色粉末(临用前以1%DMSO新鲜配制)。苯环己哌啶(PCP),购自Sigma Aldrich,灰白色粉末(临用前以生理盐水配制)。1%DMSO,由纯DMSO(纯度>99.5,购自Sigma-Aldrich),经生理盐水稀释而成。
ICR小鼠,体重22±2g,雄性,8只/笼饲养,12/12小时光/暗周期调节,温度23±1℃,湿度50~60%,自由进食进水。
受试化合物和奥氮平采用DMSO配制,受试化合物剂量为5mg,10mg,20mg。奥氮平剂量为5mg/kg。给药体积为0.1ml/10g体重;PCP用生理盐水配制,剂量为5mg/kg。
受试化合物MDC、奥氮平给药方式为灌胃,PCP为皮下注射。
小鼠在适应性饲养一周后,按体重随机分为6组,阴性对照组,模型组,阳性对照组,受试药小剂量组、中剂量组及大剂量组。每组动物8-10只。
第一组:阴性对照组:生理盐水(s.c.)+1%DMSO(10.0ml/kg,p.o.);
第二组:模型组:PCP(5.0mg/kg,s.c.)+1%DMSO(10.0ml/kg,p.o.);
第三组:阳性对照组:PCP(5.0mg/kg,s.c.)+奥氮平(5mg/kg,p.o.);
第四组:MDC小剂量组:PCP(5.0mg/kg,s.c.)+MDC(5mg/kg,p.o.);
第五组:MDC中剂量组:PCP(5.0mg/kg,s.c.)+MDC(10mg/kg,p.o.);
第六组:MDC大剂量组:PCP(5.0mg/kg,s.c.)+MDC(20mg/kg,p.o.)。
小鼠皮下注射PCP(5.0mg/kg,s.c.)或生理盐水,半小时后经口灌胃DMSO、小、中、大剂量的MDC或奥氮平。
动物经口给药后,立即置于自发活动箱内,由上海吉量动物视频分析系统进行记录,记录时间为1小时。
实验结束后,由上海吉量动物视频分析系统的轨迹分析软件对动物在1小时内的活动情况进行分析,得出活动总路程。
试验结果
表6
**P<0.01(ANNOVA followed by Dunnett’s t test,与阴性对照组相应时间段数值相比);
##P<0.01(ANNOVA followed by Dunnett’s t test,与模型组相应时间段数值相比);
#P<0.05(ANNOVA followed by Dunnett’s t test,与模型组相应时间段数值相比);
皮下注射PCP(5.0mg/kg,s.c.)显著增加了小鼠自发活动(P<0.01)。化合物MDC-161502-002,MDC-161502-006,及MDC-161502-008(5,10,20mg/kg,p.o.)均不同程度抑制了PCP诱导的小鼠高自发活动(P<0.05-0.01),此作用与阳性药奥氮平对PCP诱导的小鼠的高自发活动相当,其中MDC-161502-002对PCP诱导的高自发活动的抑制作用较奥氮平具有较显著优势。
结论:化合物MDC口服给药有效抑制PCP诱导的小鼠高自发活动,显示,该类化合物可能对精神分裂症阳性症状具有较佳抑制作用。其作用强度与阳性药物奥氮平相当,或略强。
V、代表性实施例对Amphetamine诱导的小鼠高自发活动(Locomotor activity,LMA)的作用
受试化合物MDC,为乳白色粉末,阴凉处保存(临用前以1%DMSO配制)。奥氮平(Olanzapine),购自Adamas,为黄色粉末(临用前以1%DMSO配制)。Amphetamine,由Sigma-Aldrich购入,为白色粉末(临用前以生理盐水配制)。1%DMSO,由纯DMSO(纯度>99.5,购自Sigma公司)经生理盐水稀释而成。
ICR小鼠,体重22±2g,雄性,8只/笼饲养,12/12小时光/暗周期调节,温度23±1℃,湿度50~60%,自由进食进水。
受试化合物和奥氮平采用DMSO新鲜配置,受试化合物MDC剂量为5mg,10mg,20mg,灌胃给药。奥氮平剂量为5mg/kg,灌胃给药。给药体积为0.1ml/10g体重;Amphetamine采用生理盐水新鲜配制,剂量为1.0mg/kg,皮下给药。
小鼠在适应性饲养一周后,按体重随机分为6组,即阴性对照组,模型组,阳性对照组,及受试药小剂量组、中剂量组及大剂量组。每组动物8-10只。
第一组:阴性对照组:生理盐水(s.c.)+1%DMSO(10.0ml/kg,p.o.);
第二组:模型组:Amphetamine(1.0mg/kg,s.c.)+1%DMSO(10.0ml/kg,p.o.);
第三组:阳性对照组:Amphetamine(1.0mg/kg,s.c.)+奥氮平(5mg/kg,p.o.);
第四组:MDC小剂量组:Amphetamine(1.0mg/kg,s.c.)+MDC(5mg/kg,p.o.);
第五组:MDC中剂量组:Amphetamine(1.0mg/kg,s.c.)+MDC(10mg/kg,p.o.);
第六组:MDC大剂量组:Amphetamine(1.0mg/kg,s.c.)+MDC(20mg/kg,p.o.)。
小鼠皮下注射Amphetamine(1.0mg/kg,s.c.),或生理盐水,半小时后灌胃DMSO、以及小、中、大剂量的MDC或阳性药物奥氮平。
动物给药后,立即置于自发活动箱内,由上海吉量动物视频分析系统进行记录,记录时间为1小时。
实验结束后,由上海吉量动物视频分析系统的轨迹分析软件对动物在1小时内的活动情况进行分析,得出活动总路程。
试验结果见表7。
表7
**P<0.01(ANNOVA followed by Dunnett’s t test,与阴性对照组相应时间段数值相比)
##P<0.01(ANNOVA followed by Dunnett’s t test,与模型组相应时间段数值相比)
#P<0.05(ANNOVA followed by Dunnett’s t test,与模型组相应时间段数值相比)
Amphetamine(1.0mg/kg,s.c.)显著增加了小鼠自发活动(P<0.01)。化合物MDC-161502-002,MDC-161502-006和MDC-161502-008(5,10,20mg/kg,p.o.)显著抑制了Amphetamine(1.0mg/kg,s.c.)诱导的小鼠高自发活动(P<0.05-0.01),此抑制作用与奥氮平(5.0mg/kg,p.o.)相当,其中MDC-161502-002对Amphetamine诱导的高自发活动的抑制作用较奥氮平更优。
试验结果显示,本发明化合物口服给药有效抑制Amphetamine诱导的小鼠高自发活动,表明,该类化合物可能对精神分裂症阳性症状具有较佳抑制作用。其作用强度与阳性药物奥氮平相当,或略强。
Claims (15)
1.一种通式(I)所示的四氢吡咯类化合物,其对映异构体、非对映异构体或药学上可接受的盐:
其中:
A1为C-R1或N;
A2为C-R1a或N;
A3为C-R1b或N;
A4为C-R1c或N;
A5为C-R1d或N;
A1、A2、A3、A4和A5中最多不超过3个氮原子;
R1、R1a、R1b、R1c和R1d分别独立地为氢原子、卤素、C1-C4的烷基、 或者,相邻的两个R1、R1a;或R1a、R1b;或R1b、R1c;或R1c、R1d和与其相连的原子一起形成C2-C8的杂环基、或、C2-C10的杂芳基;所述的C2-C8的杂环基为 所述的C2-C10的杂芳基为呋喃基、噻吩基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡咯基、咪唑基或吡唑基;
R2c为取代或未取代的C1-C4的烷基、或,C2-C10的杂芳基;所述的C2-C10的杂芳基为呋喃基、噻吩基、噻唑基、异噻唑基、噁唑基、异噁唑基、吡咯基、咪唑基或吡唑基;
R4和R5分别独立地为氢原子或C1-C4的烷基;
B1为氢原子或C1-C4的烷基;
B2、B3、B4、B5、B6和B7分别独立地为氢原子或C1-C4的烷基;
L为直键;
Z为取代或未取代的C2-C10的杂芳基;所述的C2-C10的杂芳基为:吲哚基、4-氮杂吲哚基、5-氮杂吲哚基、6-氮杂吲哚基、7-氮杂吲哚基或苯并吡唑基;
用*标注的碳是指S构型手性碳、R构型手性碳或非手性碳;
2.如权利要求1所述的通式(I)所示的四氢吡咯类化合物,其对映异构体、非对映异构体或药学上可接受的盐,其特征在于,
当所述的取代的C1-C4的烷基的取代基为卤素时,所述的卤素为F、Cl、Br或I。
3.如权利要求1或2所述的通式(I)所示的四氢吡咯类化合物,其对映异构体、非对映异构体或药学上可接受的盐,其特征在于,
R1、R1a、R1b、R1c和R1d中,所述的卤素为F、Cl、Br或I;
和/或,R1、R1a、R1b、R1c、R1d、R2、R3、R2c、R4和R5中,所述的取代或未取代的C1-C4的烷基中的C1-C4的烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基。
5.如权利要求1或2所述的通式(I)所示的四氢吡咯类化合物,其对映异构体、非对映异构体或药学上可接受的盐,其特征在于,
A1、A2、A3、A4和A5中,最多不超过1个或2个为氮原子;
或者,A1为C-R1;A2为C-R1a;A3为C-R1b或N;A4为C-R1c或N;和A5为C-R1d或N;
或者,A1为CH;A2为CH;A3为C-R1b或N;A4为C-R1c或N;和A5为C-R1d或N;
或者A1为C-R1;A2为C-R1a;A3为C-R1b;A4为C-R1c和A5为C-R1d;
或者A1为C-R1;A2为CH;A3为CH;A4为C-R1c和A5为CH;
或者A1为CH;A2为C-R1a;A3为CH;A4为C-R1c和A5为CH;
或者A1为CH;A2为CH;A3为C-R1b;A4为C-R1c和A5为CH;
或者A1为CH;A2为CH;A3为CH;A4为C-R1c和A5为CH。
7.如权利要求1或2所述的通式(I)所示的四氢吡咯类化合物,其对映异构体、非对映异构体或药学上可接受的盐,其特征在于,
A1为C-R1;A2为CH;A3为CH;A4为C-R1c和A5为CH;
或者A1为CH;A2为C-R1a;A3为CH;A4为C-R1c和A5为CH;
或者A1为CH;A2为CH;A3为C-R1b;A4为C-R1c和A5为CH;
或者A1为CH;A2为CH;A3为CH;A4为C-R1c和A5为CH;
R4为氢原子或C1-C4的烷基;
R5为氢原子;
B1为氢原子;
B2、B3、B4、B5、B6和B7为氢原子;
L为直键;
和Z为取代或未取代的C2-C10的杂芳基;所述的C2-C10的杂芳基为:吲哚基、4-氮杂吲哚基、5-氮杂吲哚基、6-氮杂吲哚基、7-氮杂吲哚基或苯并吡唑基。
9.一种如权利要求1-8中任一项所述的通式(I)所示的四氢吡咯类化合物的制备方法:
其中B1-B7、A1-A5、Z和*的定义均同权利要求1-8任一项所述;
当Z为含有至少一个N的氮原子的取代或未取代的C2-C10的杂芳基时,其采用下列方法二制备,方法二包括下列步骤:将化合物I-Ma进行如下所述的脱氨基保护基的反应,制得所述的通式(I)所示的四氢吡咯类化合物;
其中,L、Z、K、B1-B7、A1-A5、Z和*的定义均同权利要求1-8任一项所述;化合物I-Ma中,G为氨基保护基,其中G与Z中的氮原子相连。
10.一种药物组合物,其包含如权利要求1-8中任一项所述的通式(I)所示的四氢吡咯类化合物,其对映异构体、非对映异构体或药学上可接受的盐,和药学上可接受的辅料。
11.一种药物组合物,其包含如权利要求1-8中任一项所述的通式(I)所示的四氢吡咯类化合物,其对映异构体、非对映异构体或药学上可接受的盐,以及其他治疗药物;所述的其他治疗药物为治疗或预防与多巴胺受体、多巴胺转运体功能异常相关的病变和中枢神经系统疾病的药物。
12.如权利要求11所述的药物组合物,当其他治疗药物为治疗或预防与多巴胺受体、多巴胺转运体功能异常相关的病变和中枢神经系统疾病的药物时,所述的与多巴胺受体、多巴胺转运体功能异常相关的病变和中枢神经系统疾病为精神分裂症、与精神分裂症相关的阳性、阴性、认知障碍,分裂情感性障碍、双相性精神病、躁狂症、抑郁症、焦虑症、痴呆、记忆缺陷和涉及偏执狂和/或妄想的精神病中的一种或多种。
13.一种如权利要求1-8中任一项所述的通式(I)所示的四氢吡咯类化合物,其对映异构体、非对映异构体或药学上可接受的盐在制备D2受体和DAT受体抑制剂中的应用。
14.一种如权利要求1-8中任一项所述的通式(I)所示的四氢吡咯类化合物,其对映异构体、非对映异构体或药学上可接受的盐在制备用于治疗或预防精神分裂症或与其相关疾病的药物中的应用。
15.如权利要求14所述应用,所述的与精神分裂症的相关疾病为精神分裂症相关的阳性、阴性、认知障碍、分裂情感性障碍、双相性精神病、躁狂症、抑郁症、焦虑症、痴呆、记忆缺陷和涉及偏执狂和/或妄想的精神病中的一种或多种。
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