CN116057049A - 甲酰胺衍生物和含其作为活性成分的用于预防或治疗精神疾病的药物组合物 - Google Patents
甲酰胺衍生物和含其作为活性成分的用于预防或治疗精神疾病的药物组合物 Download PDFInfo
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- CN116057049A CN116057049A CN202180058701.9A CN202180058701A CN116057049A CN 116057049 A CN116057049 A CN 116057049A CN 202180058701 A CN202180058701 A CN 202180058701A CN 116057049 A CN116057049 A CN 116057049A
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- carboxamide
- indole
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Classifications
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- C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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- C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
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Abstract
本发明公开了甲酰胺衍生物和包含其作为活性成分的用于预防或治疗精神疾病的药物组合物。该衍生物作为血清素、去甲肾上腺素和多巴胺的三重再摄取抑制剂非常有效,因此可有效用于治疗精神疾病。
Description
技术领域
本发明涉及甲酰胺衍生物和含有其作为活性成分的用于预防或治疗精神疾病的药物组合物。
背景技术
精神疾病是指以导致认知、情感、情绪或情感异常的可识别症状为特征的脑部病理异常。代表性精神疾病包括注意力缺陷多动障碍(ADHD)、恐慌症、双相情感障碍、抑郁症、精神分裂症、进食障碍、分离性障碍、创伤后应激障碍等,并且这些病症以功能障碍、严重程度和症状持续时间等各不相同为特征。导致精神疾病的因素包括:1)神经递质过多或不足影响脑神经功能而引起的脑分泌障碍,2)脑损伤和脑功能退化,3)激素分泌异常,4)应激等。
构成大脑的众多神经元通过与不同神经元进行通讯来调节神经功能,并且这些神经元有两种主要的传递方式。一种方式是电传递,这是神经元内传递的方式,并且另一种方式是化学传递,这是神经元之间神经元外传递的方式。化学传递发生在突触(一个神经元的轴突末端与下一个神经元的树突的连接处),它是在突触前过程中分泌神经递质(即化学物质)并将其转移到另一个突触的方式。作为突触后过程,根据神经递质的数量,当超过阈值时,通过突触接收神经递质的神经元被激活和兴奋。如此被激活的神经元在树突中产生电信号并将信号传递至轴突,轴突通过突触分泌神经递质,如此重复整个过程。已知神经元分泌的神经递质调节与神经元的突触反应并最终控制神经回路是调节人行为的最重要因素。
当神经元分泌神经递质时,与神经元形成突触的突触后神经元中的特定受体与神经递质结合而被激活,突触后神经元和突触激活可以根据受体的信号传导进行调节。假定人行为是通过神经递质对神经元和突触激活的调节来调节的,并且已报道神经递质基因(当神经递质是肽时)、产生神经递质的酶或神经递质受体基因的突变与行为控制障碍相关。此外,已知调节神经递质的量或通过受体传递信号的药物可以调节人行为。
如上所述调节行为的神经递质包括单价胺(例如,儿茶酚胺和血清素)、乙酰胆碱、兴奋性或抑制性氨基酸,以及各种神经肽及其受体主要分类为离子型受体、G蛋白偶联受体和酪氨酸激酶受体。
在大脑中的各种神经递质中,多巴胺是基于儿茶酚胺的神经递质,根据突触后多巴胺受体的类型,它可能是兴奋信号或抑制信号。多巴胺与我们体内的行为、注意力、学习、动机、奖赏系统、强化效应等有关。当多巴胺活性降低时,出现抑郁症状(例如,嗜睡、动力下降、精力下降等)。此外,多巴胺兴奋额叶神经元并影响精神活动,例如短期记忆、计划和策略。尤其是多巴胺提供的奖赏在早期大脑神经通路的构建中起着非常重要的作用,因为奖赏使人重复行为并学习感受这种奖赏带来的快感。
去甲肾上腺素是在自主神经系统中发现的基于儿茶酚胺的神经递质,被称为多巴胺的次级神经递质,其通过多巴胺的释放作用而分泌。去甲肾上腺素与唤醒有关,这使身体紧张、注意并警惕周围环境,并参与恐惧或应激反应。特别是,去甲肾上腺素与情绪密切相关,并被认为是情绪障碍(例如,抑郁症和双相情感障碍)的病因。即有假说认为抑郁症是去甲肾上腺素或多巴胺的功能降低的状态,并且躁狂症是去甲肾上腺素的功能过度加速的状态。
血清素是通常以抑制方式起作用的神经递质,其与许多基本的人生理现象(例如,睡眠、食欲、疼痛、体温调节、心血管反应、性欲、焦虑、抑郁等)有关。临床上,血清素被认为与多种神经精神障碍(例如,抑郁症、精神分裂症、强迫症、焦虑症、进食障碍、睡眠障碍、性障碍、冲动控制障碍、发育障碍、退行性脑病、应激障碍、运动障碍等)的病因有关,尤其是与抑郁症的关系非常重要。
神经递质被包含在神经元的突触小泡中,并且当刺激传递至神经元时,钙离子通道在神经元之间的突触之前打开,导致钙流入神经元以使突触小泡移动到神经元的细胞膜。囊泡迁移到细胞膜并通过轴突末端的胞吐作用释放到突触中。释放的神经递质与受体相互作用,兴奋或抑制已接受神经递质的神经元,作用于受体后剩余的神经递质在突触前神经元的轴突末端被重新摄取,被突触后膜中存在的酶降解,或向外扩散并被神经胶质细胞清除。
再摄取过程通过神经递质转运蛋白发生。根据神经递质的类型,存在特定神经递质转运蛋白,它们存在于突触膜中,负责将突触间隙中存在的神经递质再摄取到突触前神经元中。通过该过程调节神经递质的浓度最终影响突触后神经元中存在的各种受体的激活强度和持续时间。
如上所述,神经递质的再摄取是指神经递质被释放神经递质的突触前神经元的膜中的特定神经递质转运体再摄取到突触前神经元中而失活的过程。神经递质再摄取的增加导致神经递质缺乏和失衡,导致与神经递质再摄取相关的疾病。这些与再摄取相关的疾病的治疗通过阻断这些物质的再摄取来增加突触中神经递质的浓度来改善症状。
神经递质再摄取抑制剂包括选择性血清素再摄取抑制剂、血清素-去甲肾上腺素再摄取抑制剂、选择性去甲肾上腺素再摄取抑制剂、多巴胺-去甲肾上腺素再摄取抑制剂、血清素受体拮抗剂-血清素再摄取抑制剂等,这些抑制剂用于治疗抑郁症、情绪障碍、多动症、慢性神经性疼痛、强迫症、恐慌症、焦虑症、更年期症状等。
正在不断开发用于治疗精神疾病的药物,其中,作为与神经递质再摄取抑制剂相关的相关技术,韩国专利公开号10-2009-0089439公开了色原-2-酮衍生物、其作为单胺类神经递质再摄取抑制剂的用途和用于治疗精神疾病的用途,以及韩国专利公开号10-2009-0117736涉及用于选择性血清素再摄取抑制的组合物及其制备方法,公开了含有积雪草苷和羟基积雪草苷的组合物。
然而,目前用于脑神经领域的精神疾病的治疗方法仅作用于被认为是相关病因机制的多种神经递质中的一种神经系统,或者对神经递质的选择性不足,因此在治疗效果和患者依从性方面存在诸多问题,并导致严重的不良影响(例如,生长迟缓、睡眠障碍和依赖性);因此,需要开发能够灵活调节对神经递质具有不同选择性的多个靶标的药物。
在这方面,调节多个靶标的药物开发正在进行中,其中韩国专利公开号10-2013-0026292,其涉及一种新型氮杂环丁烷衍生物和含有其的抗抑郁组合物,公开了含有能够同时抑制多巴胺、血清素和去甲肾上腺素再摄取的氮杂环丁烷衍生物的抗抑郁组合物;韩国专利公开号2002-0079730公开了芳基和杂芳基取代的四氢异喹啉用于阻断去甲肾上腺素、多巴胺和血清素再摄取的用途;和韩国专利公开号10-2010019982,其涉及作为单胺再摄取抑制剂的苯基取代的环烷基胺,公开了苯基取代的环烷基胺,其抑制内源性单胺(例如多巴胺、血清素和去甲肾上腺素)从突触间隙再摄取并调节一种或更多种单胺转运蛋白。
本发明人已尝试开发基于同时调节多巴胺、去甲肾上腺素和血清素神经系统的物质,能够通过确保其神经元功能控制的差异选择性来灵活调节多个靶标的药物,并证实甲酰胺衍生物对血清素、去甲肾上腺素和多巴胺的三重再摄取的抑制作用优异,因此可用于治疗精神疾病,从而完成本发明。
发明技术问题的公开
本发明的一个目的在于提供甲酰胺衍生物。
本发明的另一目的在于提供用于预防或治疗精神疾病的药物组合物,其含有甲酰胺衍生物作为活性成分。
本发明的还一目的在于提供用于预防或治疗精神疾病的血清素、去甲肾上腺素和多巴胺的三重再摄取抑制剂,其含有甲酰胺衍生物作为活性成分。
本发明的还一目的在于提供用于预防或改善精神疾病的保健功能食品组合物,其含有甲酰胺衍生物作为活性成分。
技术方案
为了实现这些目的,
本发明的一方面提供了下式1所示的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐。
[式1]
在式1中,R1、R2、R3和L1与说明书中定义的相同。
本发明的另一方面提供了用于预防或治疗精神疾病的药物组合物,其含有上述式1所示的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分
本发明的还一方面提供了用于预防或治疗精神疾病的血清素、去甲肾上腺素和多巴胺的三重再摄取抑制剂,其含有上式1所示的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。
本发明的还一方面提供了用于预防或改善精神疾病的保健功能食品组合物,其含有上述式1所示的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。
本发明的还一方面提供了用于预防或治疗精神疾病的方法,该方法包括向有需要的受试者施用含有上述式1所示的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分的药物组合物或保健功能食品组合物。
本发明的还一方面提供了含有上述式1所示的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分的药物组合物或保健功能食品组合物的在预防或治疗精神疾病中的用途。
有益效果
根据本发明的式1所示的化合物在血清素、去甲肾上腺素和多巴胺的三重再摄取抑制作用方面表面优异,因此可用于治疗精神疾病。
附图说明
图1示出了显示施用对应于溶媒和用于使用作为一种开场实验的Ethovision系统观察和分析小鼠的过度活动的各组的药物的小鼠的行为模式的测量结果图,其中图a测量运动距离,并且图b测量运动持续时间。
图2示出了显示施用对应于溶媒和用于评价通过腹腔注射施用戊巴比妥钠是否引起睡眠障碍的各组的药物的小鼠进行睡眠诱导后的入睡时间(图a)和睡眠持续时间(图b)的测量结果图。
具体实施方式
以下,对本发明进行详细说明。
同时,可以以各种形式修改本发明的实施方案,并且本发明的范围不限于以下描述的实施方案。另外,提供本发明的实施方案以向本领域的技术人员更完整地解释本发明。此外,在整个说明书中,“包括”某组分意指可以进一步包括其他组分而不是排除其他组分,除非另有说明。
本发明的一方面提供式1所示的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐。
[式1]
在式1中,
R1是未取代的或取代的C3-6环烷基,未取代的或取代的C6-10芳基,含有选自由N、S和O组成的组的一个或更多个杂原子的未取代的或取代的5至14个原子的杂芳基,取代的直链或支链C1-8烷基,或取代的C4-6环烯基以与取代的碳原子一起形成C6-10芳基,
取代的环烷基被直链或支链C1-8烷基取代,取代的芳基被选自由直链或支链C1-10烷氧基和卤素组成的组的一个或更多个取代基取代,或被取代以与取代的碳原子一起形成含有一个或更多个O的C3-6杂环烯基,取代的杂芳基被选自由以下组成的组的一个或更多个取代基取代:未取代的或被一个或更多个卤素取代的直链或支链C1-8烷基,未取代的或被C6-10芳基、C1-10羧基、C1-10氨基羰基、苄氧基、羟基、腈基和卤素取代的直链或支链C1-10烷氧基,或被取代以与取代的碳原子一起形成含有一个或更多个O的C3-6杂环烯基,并且取代的烷基被选自由以下组成的组的一个或更多个取代基取代:含有选自由N、S和O组成的组的杂原子的被4至8个原子的苄基取代的杂环烷基,以及氧代;
L1是单键、未取代的或取代的直链或支链C1-8亚烷基或取代的C4-6亚环烯基,
取代的亚烷基被选自由氧代和直链或支链C1-5烷基组成的组的一个或更多个取代基取代,或取代的亚烷基被取代以与取代的碳一起形成C3-6环烷基,并且取代的亚环烯基被取代以与取代的碳原子一起形成C6-10芳基;
R2是含有选自由N、S和O组成的组的一个或更多个杂原子的未取代的或取代的4至8个原子的杂环烷基,含有选自由N、S和O组成的组的一个或更多个杂原子的未取代的或取代的5至14个原子的杂芳基,被一个或更多个卤素取代的C6-10芳基,未取代的或取代的C3-6环烷基,或NR2aR2b,
取代的杂环烷基、取代的杂芳基和取代的环烷基各自独立地被选自由以下组成的组的一个或更多个取代基取代:含有选自由N、S和O组成的组的一个或更多个杂原子的未取代的或被卤素取代的5至14个原子的杂芳基,取代的直链或支链C1-10烷基和取代的C6-10芳基,其中取代的烷基被选自由以下组成的组的一个或更多个取代基取代:含有选自由N、S和O组成的组的一个或更多个杂原子的4至8个原子的杂环烷基,羟基和未取代的或被一个或更多个卤素取代的C6-10芳基,并且取代的芳基被选自由被一个或更多个卤素取代的直链或支链C1-8烷基和卤素组成的组的一个或更多个取代基取代,
在这种情况下,R2a和R2b各自独立地是氢、未取代的或取代的直链或支链C1-5烷基,其中取代的烷基被选自由氧代和C6-10芳基组成的组的一个或更多个取代基取代;以及
R3是氢或直链或支链C1-5烷基;
或如果L1是单键,则R2和R3能与键合的氮原子形成未取代的或取代的4至8个原子的杂环烷基,其包含选自由N、S和O组成的组的一个或更多个杂原子,并且取代的杂环烷基被取代有C6-10芳基的直链或支链C1-10烷基取代。
在式1中,
R1是未取代的或取代的C3-5环烷基,未取代的或取代的C6-10芳基,含有选自由N、S和O组成的组的一个或更多个杂原子的未取代的或取代的5至10个原子的杂芳基,取代的直链或支链C1-3烷基,或取代的C5-6环烯基以与取代的碳原子一起形成C6-8芳基,
取代的环烷基被直链或支链C1-3烷基取代,取代的芳基被选自由直链或支链C1-5烷氧基和卤素组成的组的一个或更多个取代基取代,或被取代以与取代的碳原子一起形成含有一个或更多个O的C4-6杂环烯基,取代的杂芳基被选自由以下组成的组的一个或更多个取代基取代:未取代的或被一个或更多个卤素取代的直链或支链C1-3烷基,未取代的或被C6-8芳基、C1-5羧基、C1-5氨基羰基、苄氧基、羟基、腈和卤素取代的直链或支链C1-5烷氧基,或被取代以与取代的碳原子一起形成含有一个或更多个O的C4-6杂环烯基,并且取代的烷基被选自由以下组成的组的一个或更多个取代基取代:含有选自由N、S和O组成的组的一个或更多个杂原子的被4至6个原子的苄基取代的杂环烷基,以及氧代;
L1是单键、未取代的或取代的直链或支链C1-3亚烷基或取代的C4-6亚环烯基,
取代的亚烷基被选自由氧代和直链或支链C1-3烷基组成的组的一个或更多个取代基取代,或取代的亚烷基被取代以与取代的碳一起形成C3-5环烷基,并且取代的亚环烯基被取代以与取代的碳原子一起形成C6-8芳基;
R2是含有选自由N、S和O组成的组的一个或更多个杂原子的未取代的或取代的4至6个原子的杂环烷基,含有选自由N、S和O组成的组的一个或更多个杂原子的未取代的或取代的5至10个原子的杂芳基,被一个或更多个卤素取代的C6-8芳基,未取代的或取代的C3-6环烷基,或NR2aR2b,
取代的杂环烷基、取代的杂芳基和取代的环烷基各自独立地被选自由以下组成的组的一个或更多个取代基取代:含有选自由N、S和O组成的组的一个或更多个杂原子的未取代的或被卤素取代的5至10个原子的杂芳基,取代的直链或支链C1-5烷基和取代的C6-8芳基,其中取代的烷基被选自由以下组成的组的一个或更多个取代基取代:含有选自由N、S和O组成的组的一个或更多个杂原子的4至6个原子的杂环烷基,羟基和未取代的或被一个或更多个卤素取代的C6-8芳基,并且取代的芳基被选自由被一个或更多个卤素取代的直链或支链C1-3烷基和卤素组成的组的一个或更多个取代基取代,
在这种情况下,R2a和R2b各自独立地是氢、未取代的或取代的直链或支链C1-3烷基,其中取代的烷基被选自由氧代和C6-10芳基组成的组的一个或更多个取代基取代;以及
R3是氢或直链或支链C1-3烷基;
或如果L1是单键,则R2和R3能与键合的氮原子形成未取代的或取代的4至6个原子的杂环烷基,其包含选自由N、S和O组成的组的一个或更多个杂原子,并且取代的杂环烷基被取代有C6-8芳基的直链或支链C1-5烷基取代。
在式1中,
R1是未取代的或取代的环丙基、未取代的或取代的苯基、未取代的或取代的萘基、含有选自由N、S和O组成的组的一个或更多个杂原子的未取代的或取代的5至9个原子的杂芳基,取代的直链或支链C1-3烷基,或取代的环戊烯基以与取代的碳原子一起形成苯基,
取代的环丙基被甲基取代,取代的苯基和取代的萘基各自独立地被选自由直链或支链C1-4烷氧基、氯和溴组成的组的一个或更多个取代基取代,或取代的苯基被取代以与取代的碳原子一起形成含有一个或更多个O的杂环戊烯基,取代的杂芳基被选自由以下组成的组的一个或更多个取代基取代:未取代的或被一个或更多个卤素取代的甲基,未取代的或被苯基、C1-3羧基、C1-3氨基羰基、苄氧基、羟基、腈和卤素取代的直链或支链C1-4烷氧基,或被取代以与取代的碳原子一起形成含有一个或更多个O的C5-6杂环烯基,并且取代的烷基被选自由被苄基取代的哌啶基和氧代组成的组的一个或更多个取代基取代;
L1是单键、未取代的或取代的亚乙基或取代的C4-6亚环己烯基,
取代的亚乙基被选自由氧代和甲基组成的组的一个或更多个取代基取代,或取代的亚乙基被取代以与取代的碳原子一起形成环丙基,并且取代的亚环己烯基被取代以与取代的碳原子一起形成苯基;
R2是取代的哌啶基、取代的哌嗪基、未取代的或取代的吡唑、吲哚、被一个或更多个氯原子取代的苯基、被苄基取代的环己基或NR2aR2b,
取代的哌啶基、取代的哌嗪基和取代的吡唑各自独立地被选自由吲哚、被氟取代的吡啶、取代的甲基和取代的苯基组成的组的一个或更多个取代基取代,其中取代的甲基被选自由四氢吡喃、羟基和未取代的或被一个或更多个卤素取代的苯基组成的组的一个或更多个取代基取代,并且取代的苯基被选自由被一个或更多个氟原子取代的甲基和氯组成的组的一个或更多个取代基取代,
在这种情况下,R2a和R2b各自独立地是氢、未取代的或取代的甲基,其中取代的甲基被选自由氧代基和萘基组成的组的一个或更多个取代基取代;以及
R3是氢;
或如果L1是单键,则R2和R3能与键合的氮原子一起形成哌啶基,并且取代的哌啶基被取代的苯基取代。
在式1中,
R1是
R2是
R3是氢;或
根据本发明的式1所示的化合物的实例可以包括以下组的化合物:
<1>6-溴-N-(2-(4-(3,4-二氯苄基)哌嗪-1-基)乙基)-2-萘甲酰胺;
<2>6-溴-N-(2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙基)-2-萘甲酰胺;
<3>6-溴-N-(2-(4-(3,4-二氯苯基)哌嗪-1-基)乙基)-2-萘甲酰胺;
<4>6-溴-N-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-2-萘甲酰胺;
<5>N-(2-(4-苄基哌嗪-1-基)乙基)-6-溴-2-萘甲酰胺;
<6>6-溴-N-(2-(4-(3,4-二氟苄基)哌啶-1-基)乙基)-2-萘甲酰胺;
<7>6-溴-N-(2-(4-(3,4-二氟苄基)哌嗪-1-基)乙基)-2-萘甲酰胺;
<8>6-溴-N-(2-(3-(5-氟吡啶-2-基)-1H-吡唑-1-基)乙基)-2-萘甲酰胺;
<9>6-溴-N-(2-(4-(3,4-二氯苄基)哌啶-1-基)乙基)-2-萘甲酰胺;
<10>3,5-二氯-N-(2-(4-(3,4-二氯苄基)哌啶-1-基)乙基)苯甲酰胺;
<11>3,4-二氯-N-(2-(4-(3,4-二氯苄基)哌嗪-1-基)乙基)苯甲酰胺;
<12>3,4-二氯-N-(2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙基)苯甲酰胺;
<13>3,4-二氯-N-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)苯甲酰胺;
<14>3,4-二氯-N-(2-(4-(3,4-二氯苯基)哌嗪-1-基)乙基)苯甲酰胺;
<15>N-(2-(4-苄基哌嗪-1-基)乙基)-3,4-二氯苯甲酰胺;
<16>3,4-二氯-N-(2-(4-(3,4-二氟苄基)哌嗪-1-基)乙基)苯甲酰胺;
<17>3,4-二氯-N-(2-(4-(3,4-二氯苄基)哌啶-1-基)乙基)苯甲酰胺;
<18>N-(2-(4-苄基哌啶-1-基)乙基)-3,4-二氯苯甲酰胺;
<19>N-(2-(4-(3,4-二氯苄基)哌啶-1-基)乙基)-1H-吲哚-2-甲酰胺;
<20>N-(2-(4-苄基哌啶-1-基)乙基)-3-甲基-1H-吲哚-2-甲酰胺;
<21>N-(2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙基)-1H-吲哚-2-甲酰胺;
<22>N-(2-(4-(3,4-二氯苄基)哌嗪-1-基)乙基)-1H-吲哚-2-甲酰胺;
<23>N-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-1H-吲哚-2-甲酰胺;
<24>N-(2-(4-(3,4-二氯苯基)哌嗪-1-基)乙基)-1H-吲哚-2-甲酰胺;
<25>N-(2-(4-苄基哌嗪-1-基)乙基)-1H-吲哚-2-甲酰胺;
<26>(4-苄基哌啶-1-基)(1H-吲哚-2-基)甲酮;
<27>N-(2-(4-(3,4-二氟苄基)哌啶-1-基)乙基)-1H-吲哚-2-甲酰胺;
<28>N-(2-(4-(3,4-二氯苯基)哌啶-1-基)乙基)-1H-吲哚-2-甲酰胺;
<29>N-(2-(4-((四氢-2H-吡喃-4-基)甲基)哌嗪-1-基)乙基)-1H-吲哚-2-甲酰胺;<30>N-(2-(4-苄基哌啶-1-基)乙基)-5-溴-1H-吲哚-2-甲酰胺;
<31>N-(2-(4-苄基哌啶-1-基)乙基)-5-氯-1H-吲哚-2-甲酰胺;
<32>N-(2-(4-苄基哌啶-1-基)乙基)-5,6-二氟-1H-吲哚-2-甲酰胺;
<33>N-(2-(4-苄基哌啶-1-基)乙基)-5-甲氧基-1H-吲哚-2-甲酰胺;
<34>N-(1-(4-苄基哌啶-1-基)-2-甲基丙-2-基)-1H-吲哚-2-甲酰胺;
<35>N-(2-(4-苄基哌啶-1-基)乙基)-5,6-二甲氧基-1H-吲哚-2-甲酰胺;
<36>N-(2-(4-(羟基(苯基)甲基)哌啶-1-基)乙基)-1H-吲哚-2-甲酰胺;
<37>N-(2-(4-(1H-吲哚-3-基)哌啶-1-基)乙基)-1H-吲哚-2-甲酰胺;
<38>N-(2-(3-苄基哌啶-1-基)乙基)-1H-吲哚-2-甲酰胺;
<39>N-(2-(4-苄基哌啶-1-基)乙基)-4,6-二氯-1H-吲哚-2-甲酰胺;
<40>N-(2-(4-苄基哌啶-1-基)乙基)-5-(三氟甲基)-1H-吲哚-2-甲酰胺;
<41>N-(2-(4-苄基哌啶-1-基)乙基)-5-氰基-1H-吲哚-2-甲酰胺;
<42>N-(2-(4-苄基哌啶-1-基)乙基)-6-丁氧基-1H-吲哚-2-甲酰胺;
<43>N-(1-(4-苄基哌啶-1-基)丙-2-基)-1H-吲哚-2-甲酰胺;
<44>N-(4-苄基环己基)-1H-吲哚-2-甲酰胺;
<45>N-(2-(2-萘氨基)乙基)-1H-吲哚-2-甲酰胺;
<46>5-(苄氧基)-N-(2-(4-苄基哌啶-1-基)乙基)-1H-吲哚-2-甲酰胺;
<47>N-(2-(4-苄基哌啶-1-基)乙基)-5,6-二氯-1H-吲哚-2-甲酰胺;
<48>N-(2-(4-(3,4-二氯苄基)哌啶-1-基)乙基)-5,6-二甲氧基-1H-吲哚-2-甲酰胺;
<49>N-(2-(4-苄基哌啶-1-基)乙基)-5-氟-1H-吲哚-2-甲酰胺;
<50>N-(2-(4-苄基哌啶-1-基)-2-氧代乙基)-1H-吲哚-2-甲酰胺;
<51>N-(2-(4-(3,4-二氯苄基)哌啶-1-基)乙基)-5-氟-1H-吲哚-2-甲酰胺;
<52>N-(2-(3-(5-氟吡啶-2-基)-1H-吡唑-1-基)乙基)-1H-吲哚-2-甲酰胺;
<53>N-(1-((4-苄基哌啶-1-基)甲基)环丙基)-1H-吲哚-2-甲酰胺;
<54>N-(2-((萘-2-基甲基)氨基)乙基)-1H-吲哚-2-甲酰胺;
<55>N-(2-(4-苄基哌啶-1-基)乙基)苯并[d]噻唑-2-甲酰胺;
<56>N-(2-(4-苄基哌啶-1-基)乙基)-1H-吡咯[2,3-b]吡啶-2-甲酰胺;
<57>N-(2-(4-苄基哌啶-1-基)乙基)二氢吲哚-2-甲酰胺;
<58>(R)-N-(2-(4-苄基哌啶-1-基)乙基)二氢吲哚-2-甲酰胺;
<59>N-(2-(4-苄基哌啶-1-基)乙基)-5-甲氧基-1H-苯并[d]咪唑-2-甲酰胺;
<60>N-(2-(4-苄基哌啶-1-基)乙基)-5-氟苯并[d]噻唑-2-甲酰胺;
<61>N-(2-(4-苄基哌啶-1-基)乙基)-1H-苯并[d]咪唑-2-甲酰胺;
<62>N-((1R,4S)-4-(3,4-二氯苯基)-1,2,3,4-四氢萘-1-基)-1H-吲哚-2-甲酰胺;
<63>N-(2-(4-苄基哌啶-1-基)乙基)-5,6-二羟基-1H-吲哚-2-甲酰胺;
<64>N-(2-(4-苄基哌啶-1-基)乙基)-5-羟基-1H-苯并[d]咪唑-2-甲酰胺;
<65>N-(2-(4-(3,4-二氯苄基)哌啶-1-基)乙基)-5,6-二羟基-1H-吲哚-2-甲酰胺;
<66>N-(2-(4-苄基哌啶-1-基)乙基)-5-羟基-1H-吲哚-2-甲酰胺;
<67>N-(2-(4-苄基哌啶-1-基)乙基)-5-丁氧基-1H-吲哚-2-甲酰胺;
<68>N-(2-(甲基(萘-2-基甲基)氨基)乙基)-1H-吲哚-2-甲酰胺;
<69>N-(2-(4-苄基哌啶-1-基)乙基)环丙烷甲酰胺;
<70>N-(2-(4-苄基哌啶-1-基)乙基)-1-甲基环丙烷甲酰胺;
<71>N-(2-(4-苄基哌啶-1-基)乙基)吡啶酰胺;
<72>N-(2-(4-(1H-吲哚-3-基)哌啶-1-基)乙基)-4-丁氧基苯甲酰胺;
<73>N-(2-(4-苄基哌啶-1-基)乙基)-1H-吲哚-3-甲酰胺;
<74>N-(2-(4-苄基哌啶-1-基)乙基)-1-甲基-1H-吲哚-2-甲酰胺;
<75>N-(2-(4-苄基哌啶-1-基)乙基)-1H-吡咯-2-甲酰胺;
<76>3-(4-苄基哌啶-1-基)-N-(1H-吲哚-2-基)丙酰胺;
<77>4-(4-苄基哌啶-1-基)-N-(1H-吲哚-2-基)-4-氧代丁酰胺;
<78>N-(2-(4-苄基哌啶-1-基)乙基)苯并[d][1,3]二氧杂环己醇-5-甲酰胺;
<79>N-(2-(4-苄基哌啶-1-基)乙基)-2,3-二氢-6H-[1,4]二氧并[2,3-f]吲哚-7-甲酰胺;
<80>N-(2-(4-苄基哌啶-1-基)乙基)-5H-[1,3]二氧代[4,5-f]吲哚-6-甲酰胺;
<81>2-((2-(4-苄基哌啶-1-基)乙基)氨基甲酰基)-1H-吲哚-5-羧酸;和
<82>N2-(2-(4-苄基哌啶-1-基)乙基)-1H-吲哚-2,5-二甲酰胺。
本发明的式1所示的化合物可以以药学上可接受的盐的形式使用,并且由药学上可接受的游离酸形成的酸加成盐可用作该盐。酸加成盐由以下获得:无机酸(例如,盐酸、硝酸、磷酸、硫酸、氢溴酸、氢碘酸、亚硝酸、亚磷酸等);无毒有机酸(例如,脂肪族单羧酸和二羧酸、苯基取代的链烷酸盐、羟基链烷酸盐和链烷二酸盐、芳香酸、脂肪族和芳香族磺酸等;有机酸(例如,三氟乙酸、乙酸盐、苯甲酸、柠檬酸、乳酸、马来酸、葡萄糖酸、甲磺酸、4-甲苯磺酸、酒石酸、富马酸等)。这些类型的药学上无毒盐包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸氯化物、溴化物、碘化物、氟化物、乙酸盐、丙酸盐、癸酸盐(decanoate)、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、癸酸盐(caprate)、庚酸、丙炔酸、草酸、丙二酸、琥珀酸、辛二酸、癸二酸、富马酸、马来酸、1,4-二酸丁炔酸、1,6-二酸己酸、苯甲酸、氯苯甲酸、苯甲酸甲酯、二硝基苯甲酸、羟基苯甲酸、甲氧基苯甲酸、邻苯二甲酸、对苯二甲酸、苯磺酸盐、甲苯磺酸盐、氯苯磺酸盐、二甲苯磺酸盐、乙酸苯酯、丙酸苯酯、丁酸苯酯、柠檬酸盐、乳酸盐、β-羟基丁酸盐、乙醇酸盐、马来酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、1-萘磺酸盐、2-萘磺酸盐、扁桃酸盐等。
根据本发明的酸加成盐可以通过常规方法制备,例如可以通过将式1的衍生物溶解于有机溶剂(例如,甲醇、乙醇、丙酮、二氯甲烷、乙腈等)中,并加入有机酸或无机酸以过滤和干燥所得沉淀进行制备;或者可以通过在减压下蒸馏溶剂和过量的酸、干燥并在有机溶剂中结晶进行制备。
此外,药学上可接受的金属盐可以使用碱进行制备。例如,通过将化合物溶解于过量的碱金属氢氧化物或碱土金属氢氧化物溶液中,过滤未溶解的化合物盐,并蒸发和干燥滤液得到碱金属盐或碱土金属盐。在这种情况下,制备钠盐、钾盐或钙盐作为金属盐在药学上是合适的。此外,通过将碱金属盐或碱土金属盐与合适的负盐(例如,硝酸银)反应得到相应的盐。
此外,本发明不仅包括式1所示的化合物及其药学上可接受的盐,还包括可由其制备的溶剂化物、旋光异构体、水合物等。
术语“水合物”是指本发明的化合物或其盐,该化合物含有化学计量的或非化学计量的量的通过非共价分子间力结合的水。本发明的式1所示的化合物的水合物可以含有化学计量的或非化学计量的量的通过非共价分子间力结合的水。水合物可以含有1当量或更多,优选1-5当量的水。可以通过从水或含水溶剂结晶本发明的式1所示的化合物、其异构体或其药学上可接受的盐来制备此类水合物。
术语“溶剂化物”是指本发明的化合物或其盐,其含有化学计量的或非化学计量的量的通过非共价分子间力结合的溶剂。优选的溶剂本身包括挥发性的、无毒的和/或适合施用于人的溶剂。
术语“异构体”是指具有相同化学式或分子式但结构或空间不同的本发明的化合物或其盐。这些异构体包括结构异构体(例如,互变异构体等)、具有不对称碳中心的R或S异构体、立体异构体(例如,几何异构体(反式、顺式)和光学异构体(对映体))。所有这些异构体及其混合物也包括在本发明的范围内。
根据本发明的式1所示的化合物可以如以下反应1所示进行制备,可以根据制备方法进行制备,该制备方法包括通过使式2所示的化合物与式3所示的化合物反应来制备式1所示的化合物。
[反应1]
在式1中,
R1、R2、R3和L1与本公开中定义的相同。
反应1的制备方法为以下方法:使式2所示的化合物的羧基与式3所示的化合物的胺反应形成羧酰胺键并制备式1所示的化合物。制备方法可以采用本领域熟知的反应条件,并且可以根据本发明的实施例进行制备,但这仅是示例性的并不限于此。
本发明的另一方面提供了用于预防或治疗精神疾病的药物组合物,其含有式1所示的化合物、其旋光异构体或其药学上可接受的盐作为活性成分。
该化合物可以抑制血清素、去甲肾上腺素和多巴胺的再摄取。
精神疾病可以是选自由以下组成的组的至少一种:神经性贪食症、情绪障碍、抑郁症、非典型抑郁症、疼痛继发性抑郁症、重度抑郁症、心境恶劣障碍、双相情感障碍、I型双相情感障碍、II型双相情感障碍、循环性精神障碍、一般躯体疾病引起的情绪障碍、物质诱发的情绪障碍、假性痴呆、Ganger综合征、强迫症、恐慌症、恐慌症不伴广场恐惧症、恐慌症伴广场恐惧症、无恐慌症病史的广场恐惧症、恐慌症发作、记忆缺陷、记忆丧失、注意力缺陷多动障碍、肥胖、焦虑、广泛性焦虑症、进食障碍、帕金森病、帕金森症状、痴呆、衰老性痴呆、老年痴呆、阿尔茨海默病、唐氏综合症、获得性免疫缺陷综合征痴呆综合症、衰老记忆障碍、特定恐惧症、社交恐惧症、社交焦虑症、创伤后应激障碍、急性应激障碍、慢性应激障碍、药物成瘾、药物滥用、药物滥用倾向、可卡因滥用、尼古丁滥用、烟草滥用、酒精成瘾、酒精中毒、病理性盗窃癖、因戒断醉人物质引起的戒断综合征、疼痛、慢性疼痛、炎性疼痛、神经性疼痛、糖尿病性神经性疼痛、偏头痛、紧张型头痛、慢性紧张型头痛、抑郁相关性疼痛、背痛、癌症疼痛、肠易激痛、肠易激综合征、术后疼痛、乳房切除术后疼痛综合征(PMPS)、中风后疼痛、药物引起的神经病变、糖尿病性神经病变、交感神经系统持续性疼痛、三叉神经痛、牙痛、面部肌肉疼痛、幻肢痛、厌食、经前期综合征、经前期烦躁障碍、黄体晚期综合征、创伤后综合征、慢性疲劳综合征、持续性植物状态、尿失禁、压力性尿失禁、急迫性尿失禁、夜间尿失禁、性功能障碍、早泄、勃起困难、勃起功能障碍、不宁腿综合征、周期性肢体运动障碍、进食障碍、神经性厌食症、睡眠障碍、广泛性发育障碍、自闭症、亚斯伯格症、Rett障碍、儿童瓦解性障碍、学习障碍、运动能力障碍、缄默症、拔毛癖、发作性睡病、中风后抑郁症、中风引起的脑损伤、中风-诱发的神经损伤、Tourette综合征、耳鸣、抽动障碍、身体变形障碍、对立违抗性障碍和中风后障碍。
根据本发明的式1所示的化合物具有优异的血清素、去甲肾上腺素和多巴胺的再摄取抑制作用,因此可用于治疗精神疾病(参见实验实施例1和表15)。
在本发明的实验实施方案中,证实用比较实施例1的化合物处理未抑制MK801诱导的小鼠过度活动,但用实施例35或66的化合物处理对其有显著抑制(参见实验实施例2和图1)。
在本发明的实验实施方案中,证实用比较实施例1的化合物处理增加小鼠的入睡时间,减少睡眠持续时间,并且显示睡眠障碍,但用实施例35或66的化合物处理未改变入睡时间和睡眠持续时间,并且未显示睡眠障碍(参见实验实施例3和图2)。
在根据本发明的药物组合物中,上式1所示的化合物或其药学上可接受的盐在临床施用过程中可以以多种口服和肠胃外剂型施用,更优选地,肠胃外剂型。当配制时,使用稀释剂或赋形剂(例如常用的填充剂、增量剂、粘合剂、润湿剂、崩解剂和表面活性剂)制备药物组合物。用于口服施用的固体制剂包括片剂、丸剂、散剂、颗粒剂、胶囊剂等,并且通过将由至少一种赋形剂(例如,淀粉、碳酸钙、蔗糖或乳糖、明胶等)与一种或更多种化合物混合制备此类固体制剂。除了简单的赋形剂之外,还使用润滑剂(例如硬脂酸镁和滑石粉)。用于口服施用的液体剂型包括混悬剂、内服溶液剂、乳剂、糖浆剂等,并且除了水和液体石蜡(它们是常用的简单稀释剂)之外,还可以包括各种赋形剂,例如润湿剂、甜味剂、香料和防腐剂。用于肠胃外施用的制剂包括灭菌水溶液、非水溶液、混悬剂和乳剂。作为非水溶剂和混悬溶剂,可以使用丙二醇、聚乙二醇、植物油(例如,橄榄油)、可注射酯(例如,油酸乙酯)等。
式1所示的化合物或其药学上可接受的盐在临床施用过程中可以以多种口服和肠胃外剂型施用。当配制时,使用稀释剂或赋形剂(例如常用的填充剂、增量剂、粘合剂、润湿剂、崩解剂和表面活性剂)制备药物组合物。用于口服施用的固体制剂包括片剂、丸剂、散剂、颗粒剂、胶囊剂等,并且通过将由至少一种赋形剂(例如,淀粉、碳酸钙、蔗糖或乳糖、明胶等)与一种或更多种化合物混合制备此类固体制剂。除了简单的赋形剂之外,还使用润滑剂(例如硬脂酸镁和滑石粉)。用于口服施用的液体剂型包括混悬剂、内服溶液剂、乳剂、糖浆剂等,并且除了水和液体石蜡(它们是常用的简单稀释剂)之外,还可以包括各种赋形剂,例如润湿剂、甜味剂、香料和防腐剂。用于肠胃外施用的制剂包括灭菌水溶液、非水溶液、混悬剂和乳剂。作为非水溶剂和混悬溶剂,可以使用丙二醇、聚乙二醇、植物油(例如,橄榄油)、可注射酯(例如,油酸乙酯)等。
含有式1所示的化合物或其药学上可接受的盐作为活性成分的药物组合物可以肠胃外施用,并且肠胃外施用通过皮下注射、静脉内注射、肌内注射或胸腔内注射进行。
在这种情况下,为了配制成用于肠胃外施用的剂型,可以将上式1所示的化合物或其药学上可接受的盐与稳定剂或缓冲剂一起在水中混合以制备溶液剂或混悬剂,其可以以安瓿瓶或小瓶中的单位剂型进行制备。该组合物可以经灭菌和/或含有防腐剂、稳定剂、润湿剂或乳化促进剂、盐和/或用于控制渗透压的缓冲剂,以及其他治疗上有用的物质,并且可以根据常规方法(例如混合、制粒或包衣法)进行配制。
用于口服施用的剂型包括,例如,片剂、丸剂、硬/软胶囊剂、液体剂、混悬剂、乳化剂、糖浆剂、颗粒剂、酏剂、锭剂等,并且除了活性成分之外,这些剂型还含有稀释剂(例如,乳糖、右旋糖、蔗糖、甘露糖醇、山梨糖醇、纤维素和/或甘氨酸),润滑剂(例如,二氧化硅、滑石粉、硬脂酸及其镁盐或钙盐和/或聚乙二醇)。片剂可以含有粘合剂(例如,硅酸镁铝、淀粉糊、明胶、甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷);任选地含有崩解剂(例如,淀粉、琼脂、海藻酸或其钠盐)或泡腾混合物,和/或吸收剂、着色剂、调味剂和甜味剂。
含有式1所示的化合物、其旋光异构体或其药学上可接受的盐作为活性成分的用于预防或治疗精神疾病的药物组合物在使用中可以作为单独的治疗剂施用或与其他治疗剂联合使用。
本发明的还一方面提供了用于预防或治疗精神疾病的血清素、去甲肾上腺素和多巴胺的三重再摄取抑制剂,其含有上式1所示的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐,作为活性成分。
本发明的又一方面提供了用于预防或改善精神疾病的保健功能食品组合物,其含有上述式1所示的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐,作为活性成分。
此外,本发明的另一方面提供了用于预防或治疗精神疾病的方法,该方法包括向有需要的受试者施用含有上述式1所示的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分的药物组合物或保健功能食品组合物。
本发明的又另一方面提供了含有上述式1所示的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分的药物组合物或保健功能食品组合物的在预防或治疗精神疾病中的用途。
实施本发明的方式
以下通过实施例和实验实施例对本发明进行详细说明。
然而,以下实施例和实验实施例仅用于说明本发明,而本发明的内容不限于实施例和实验实施例。
<制备实施例1>2-(4-苄基哌啶-1-基)乙-1-胺的制备
步骤1:将4-苄基哌啶(1eq)和K2CO3(1.5eq)溶解于DMF中,然后搅拌约5分钟后,然后加入(2-溴乙基)氨基甲酸叔丁酯(1.2eq)。将反应混合物在60℃下搅拌12小时。反应完成后,减压去除溶剂。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到2-(4-苄基哌啶-1-基)乙基)氨基甲酸叔丁酯。
步骤2:将步骤1的2-(4-苄基哌啶-1-基)乙基)氨基甲酸叔丁酯(1eq)溶解于过量的在1,4-二噁烷中的4M HCl,并且将反应物是在室温下搅拌1-2小时。反应完成后,将所得物用二氯甲烷萃取,有机层依次用NaHCO3饱和水溶液和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到制备实施例1的化合物。
通过与制备实施例1相同的方法,除了在步骤1中使用表1中列出的R代替4-苄基哌啶之外,得到制备实施例2至14的化合物。
[表1]
<制备实施例15>N-(2-氨基乙基)-2-萘甲酰胺的制备
步骤1:将2-萘甲酸(1eq)、(2-氨基乙基)氨基甲酸叔丁酯(1eq)、EDC(2.5eq)、HOBT(1.5eq)和DIPEA(3eq)溶解于DCM中,并将反应物在室温下搅拌12小时。反应完成后,将所得物用二氯甲烷萃取,有机层依次用NaHCO3饱和水溶液和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到(2-(2-萘氨基)乙基)氨基甲酸叔丁酯。
步骤2:将步骤1中得到的(2-(2-萘胺基)乙基)氨基甲酸叔丁酯(1eq)和在1,4-二噁烷中的4M HCl(3.25eq)溶解于EA中,并将反应物在室温下搅拌12小时。反应完成后,减压去除溶剂。产物不经另外的纯化得到制备实施例15的化合物。
<制备实施例16>1-(4-苄基哌啶-1-基)-2-甲基丙-2-胺的制备
步骤1:将4-苄基哌啶(1eq)和2-硝基丙烷(1eq)溶解于ACN中,并将反应物冷却至0℃。然后,向其中加入甲醛(3eq)和0.5M NaOH(0.1eq),并将反应混合物在50℃下搅拌2小时。向其中加入甲醛(3eq)和0.5M NaOH(0.1eq),并将反应物在50℃下搅拌12小时。反应完成后,减压去除溶剂,并通过MPLC分离和纯化反应混合物,得到4-苄基-1-(2-甲基-2-硝基丙基)哌啶。
步骤2:将步骤1中得到的4-苄基-1-(2-甲基-2-硝基丙基)哌啶溶解于MeOH中,并将反应混合物在雷尼镍柱和50psi条件下使用H-CUBE氢化反应器搅拌12小时。反应完成后,减压去除溶剂。产物不经另外的纯化得到制备实施例16的化合物。
<制备实施例17>1-(4-苄基哌啶-1-基)丙-2-胺的制备
步骤1:将(叔丁氧基羰基)丙氨酸(1eq)、4-苄基哌啶(1eq)、HATU(2.5eq)和DIPEA(3eq)溶解于DMF中,并将反应物在室温下搅拌12小时。反应完成后,减压去除溶剂。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到(1-(4-苄基哌啶-1-基)-1-氧代丙烷)氨基甲酸叔丁酯。
步骤2:将步骤1中得到的(1-(4-苄基哌啶-1-基)-1-氧代丙烷)氨基甲酸叔丁酯(1eq)溶解于乙醚中,并将反应物冷却至0℃。然后,向其中缓慢加入LiAlH4(2eq),并将反应物在氮气球气流下在室温下搅拌4小时。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到(1-(4-苄基哌啶-1-基)丙-2-基)氨基甲酸叔丁酯。
步骤3:将步骤2中得到的(1-(4-苄基哌啶-1-基)丙-2-基)氨基甲酸叔丁酯(1eq)溶解于过量的6M HCl中,然后在室温下搅拌12小时。反应完成后,减压去除溶剂。产物不经另外的纯化得到制备实施例17的化合物。
<实施例1>6-溴-N-(2-(4-(3,4-二氯苄基)哌嗪-1-基)乙基)-2-萘甲酰胺的制备
将6-溴-2-萘甲酸(1eq)、2-(4-(3,4-二氯苄基)哌啶-1-基)乙-1-胺(1.2eq)、DIPEA(3eq)和HATU(2.5eq)或PyBOB(1.1eq)溶解于DMF中,并将反应物在室温下搅拌12小时。反应完成后,减压去除溶剂。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到实施例1的化合物。
通过与实施例1相同的方法,除了使用表2中列出的R代替2-(4-(3,4-二氯苄基)哌啶-1-基)乙-1-胺之外,得到实施例2至7的化合物。
[表2]
<实施例8>6-溴-N-(2-(3-(5-氟吡啶-2-基)-1H-吡唑-1-基)乙基)-2-萘甲酰胺的制备
步骤1:将6-溴-2-萘甲酸(1eq)、2-氯乙烷-1-胺盐酸盐(1.2eq)、HATU(2.5eq)和DIPEA(3eq)溶解于DMF中,并将反应物在室温下搅拌12小时。反应完成后,减压去除溶剂。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到6-溴-N-(2-氯乙基)-2-萘甲酰胺。
步骤2:将5-氟-2-(1H-吡唑-3-基)吡啶(1-1.5eq)溶解于DMF或DMSO中,并在0℃下向其中加入NaH(60%油分散液;1.2eq)或CS2CO3(1.5eq)。在室温下搅拌5分钟后,加入步骤1中制备的6-溴-N-(2-氯乙基)-2-萘甲酰胺(1eq),并将反应物在室温下搅拌12小时。反应完成后,减压去除溶剂。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到实施例8的化合物。
通过与实施例8相同的方法,除了使用表3中列出的R代替步骤1中得到的5-氟-2-(1H-吡唑-3-基)吡啶之外,得到实施例9的化合物。
[表3]
<实施例10>3,5-二氯-N-(2-(4-(3,4-二氯苄基)哌啶-1-基)乙基)苯甲酰胺的制备
将3,4-二氯苯甲酸(1eq)、2-(4-(3,4-二氯苄基)哌啶-1-基)乙-1-胺(1.2eq)、HATU(2.5eq)和DIPEA(3eq)溶解于DMF中,并将反应物在室温下搅拌12小时。反应完成后,减压去除溶剂。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到实施例10的化合物。
通过与实施例10相同的方法,除了使用3,5-二氯苯甲酸代替3,4-二氯苯甲酸以及使用表4中列出的R代替2-(4-(3,4-二氯苄基)哌啶-1-基)乙-1-胺之外,得到实施例11至16的化合物。
[表4]
<实施例17>3,4-二氯-N-(2-(4-(3,4-二氯苄基)哌啶-1-基)乙基)苯甲酰胺的制备
步骤1:将3,4-二氯苯甲酸(1eq)、2-氯乙-1-胺盐酸盐(1.2eq)、HATU(2.5eq)和DIPEA(3eq)溶解于DMF中,并将反应物在室温下搅拌12小时。反应完成后,减压去除溶剂。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到3,4-二氯-N-(2-氯乙基)苯甲酰胺。
步骤2:将4-(3,4-二氯苄基)哌啶(1-1.5eq)和TEA(4eq)溶解于DMF中,向其中加入步骤1中制备的3,4-二氯-N-(2-氯乙基)苯甲酰胺(1eq),并将反应物在60℃下搅拌12小时。反应完成后,减压去除溶剂。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到实施例17的化合物。
通过与实施例17相同的方法,除了使用表5中列出的R代替4-(3,4-二氯苄基)哌啶外,得到实施例18的化合物。
[表5]
<实施例19>N-2-(4-(3,4-二氯苄基)哌啶-1-基)乙基)-1H-吲哚-2-甲酰胺的制备
将羧酸衍生物(1eq)、胺衍生物(1.1eq)、HATU(2.5eq)和DIPEA(1.5eq)溶解于DMF中,并将反应物在室温下搅拌12小时。反应完成后,减压去除溶剂。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到实施例19的化合物。
通过与实施例19相同的方法,除了使用表6中列出的Ra代替1H-吲哚-2-羧酸以及使用表6中列出的Rb代替2-(4-(3,4-二氯苄基)哌啶-1-基)乙胺之外,得到实施例20至51的化合物。
[表6]
<实施例52>N-(2-(3-(5-氟吡啶-2-基)-1H-吡唑-1-基)乙基)-1H-吲哚-2-甲酰胺的制备
步骤1:将1H-吲哚-2-羧酸(1eq)、2-氯乙烷-1-胺盐酸盐(1.2eq)、HATU(2.5eq)和DIPEA(3eq)溶解于DMF中,并将反应物在室温下搅拌12小时。反应完成后,用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到1H-吲哚-2-甲酰胺衍生物。
步骤2:将5-氟-2-(1H-吡唑-3-基)吡啶(1-1.5eq)和Cs2CO3(1.5eq);或5-氟-2-(1H-吡唑-3-基)吡啶(1-1.5eq)和TEA(4eq)溶解于DMSO中,向其中加入步骤1中制备的1H-吲哚-2-甲酰胺衍生物(1eq),并将反应物在60℃下搅拌12小时。反应完成后,减压去除溶剂。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到实施例52的化合物。
通过与实施例52相同的方法,除了在步骤1中使用1-(溴甲基)环丙-1-胺氢溴酸盐代替2-氯乙-1-胺盐酸盐,不使用CS2CO3,而是使用TEA,以及在步骤2中使用表7中列出的R代替5-(氟-2-(1H-吡唑-3-基)吡啶,得到实施例53的化合物
[表7]
通过与实施例52相同的方法,除了在步骤2中使用表8中列出的R代替5-(氟-2-(1H-吡唑-3-基)吡啶之外,得到实施例54的化合物。
[表8]
<实施例55>N-(2-(4-苄基哌啶-1-基)乙基)苯并[d]噻唑-2-甲酰胺的制备
将羧酸衍生物(1eq)、胺衍生物(1.1eq)、PyBOP(1.1eq)和DIPEA(3eq)溶解于DMF中,并将反应物在室温下搅拌12小时。反应完成后,将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到实施例55的化合物。
通过与实施例52相同的方法,除了使用表9中列出的R代替苯并[d]噻唑-2-羧酸之外,得到实施例56至60的化合物。
[表9]
<实施例61>N-(2-(4-苄基哌啶-1-基)乙基)-1H-苯并[d]咪唑-2-甲酰胺的制备
将胺衍生物(1.2eq)溶解于DCM中,并在0℃下向其中加入在甲苯中的2M三甲基铝(1.25eq)。在室温下搅拌5分钟后,向其中缓慢加入溶解于DCM中的1H-苯并[d]咪唑-2-羧酸乙酯(1eq),并将反应物在40℃下搅拌12小时。反应完成后,减压去除溶剂。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到实施例61的化合物。
通过与实施例61相同的方法,除了使用1H-苯并[d]咪唑-2-甲酸乙酯代替1H-苯并[d]咪唑-2-羧酸乙酯以及使用表10中列出的R代替2-(4-苄基哌啶-1-基)乙胺之外,得到实施例62的化合物。
[表10]
<实施例63>N-(2-(4-苄基哌啶-1-基)乙基)-5,6-二羟基-1H-吲哚甲酰胺的制备
将实施例35的(N-(2-(4-苄基哌啶-1-基)乙基)-5,6-二甲氧基-1H-吲哚-2-甲酰胺)溶解于DCM中,并在氮气球气流下于0℃下缓慢加入1M BBr3(2eq)。将反应物在室温下搅拌12小时。反应完成后,减压去除溶剂。将所得物用甲醇萃取,并减压去除有机层中的溶剂。然后,通过MPLC分离和纯化反应混合物,得到实施例63的化合物。
通过与实施例63相同的方法,除了使用表11中列出的R代替实施例35的(N-(2-(4-苄基哌啶-1-基)乙基)-5,6-二甲氧基-1H-吲哚-2-甲酰胺),得到实施例64和65的化合物。
[表11]
<实施例66>N-(2-(4-苄基哌啶-1-基)乙基)-5-羟基-1H-吲哚-2-甲酰胺的制备
将实施例33的(N-(2-(4-苄基哌啶-1-基)乙基)-5-甲氧基-1-H-吲哚-2-甲酰胺)溶解于MeOH中,并向其中加入钯碳(10%wt)。将反应物在室温下在氢气球气流下搅拌3小时。反应完成后,使用硅藻土过滤反应混合物,并减压去除有机层的溶剂。然后,通过MPLC分离和纯化反应混合物,得到实施例66的化合物。
<实施例67>N-(2-(4-苄基哌啶-1-基)乙基)-5-丁氧基-1H-吲哚-2-甲酰胺的制备
将实施例66得到的N-(2-(4-苄基哌啶-1-基)乙基-5-羟基-1H-吲哚-2-甲酰胺(1eq)、1-溴丁烷(1.2eq)和k2CO3(1.5eq)溶解于丙酮中,并将反应物回流搅拌3小时。反应完成后,减压去除溶剂。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到实施例67的化合物。
<实施例68>N-(2-(甲基(萘-2-基甲基)氨基)乙基)-1H-吲哚-2-甲酰胺的制备
将实施例54得到的N-(2-((萘-2-基-甲基)氨基)乙基)-1H-吲哚-2-甲酰胺(1eq)、甲醛溶液(1.5eq)和NaBH(Oac)3(5eq)溶解于DCE中,并将反应物在室温下搅拌12小时。反应完成后,将所得物用1M NaOH和二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到实施例68的化合物。
<实施例69>N-(2-(4-苄基哌啶-1-基)乙基)环丙甲酰胺的制备
将环丙甲酸(1eq)、2-(4-苄基哌啶-1-基)乙-1-胺(1.1eq)、PyBOB(1.1eq)和DIPEA(3eq)溶解于DMF中,并将反应物在室温下搅拌12小时。反应完成后,减压去除溶剂。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到实施例69的化合物。
通过与实施例69相同的方法,除了使用表13中列出的Ra代替环丙烷甲酸以及使用表13中列出的Rb代替2-(4-苄基哌啶-1-基)乙-1-胺之外,得到实施例70至74的化合物。
[表12]
<实施例75>N-(2-(4-苄基哌啶-1-基)乙基)-1H-吡咯-2-甲酰胺的制备
将2-(4-苄基哌啶-1-基)乙胺(1.2eq)溶解于DCM中,并在0℃下向其中加入在甲苯中的2M三甲基铝(1.25eq)。在室温下搅拌5分钟后,向其中缓慢加入溶解于DCM中的1H-吡咯-2-羧酸甲酯(1eq),并将反应物在40℃下搅拌12小时。反应完成后,减压去除溶剂。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到实施例75的化合物。
<实施例76>3-(4-苄基哌啶-1-基)-N-(1H-吲哚-2-基)丙酰胺的制备
步骤1:将4-苄基哌啶(0.301ml,1.712mmol)和丙烯酸甲酯(0.186ml,2.054mmol)溶解于DCM中,并将反应物在室温下搅拌12小时。反应完成后,减压去除溶剂得3-(4-苄基哌啶-1-基)丙酸甲酯,并将所得物溶解于5%NaOH水溶液(0.5ml)中,然后在40℃下搅拌30分钟。反应完成后,将反应混合物冷却至室温并使用盐酸酸化。将由此得到的固体过滤并干燥,得到3-(4-苄基哌啶-1-基)丙酸。
步骤2:将步骤1中得到的1H-吲哚-2-胺盐酸盐(1eq)、3-(4-苄基哌啶-1-基)丙酸(1.1eq)、HATU(2.5eq)和DIPEA(3eq)溶解于DMF中,并将反应物在室温下搅拌12小时。反应完成后,减压去除溶剂。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过制备型HPLC分离和纯化反应混合物,得到实施例76的化合物。
<实施例77>4-(4-苄基哌啶-1-基)-N-(1H-吲哚-2-基)-4-氧代丁酰胺的制备
步骤1:将1H-吲哚-2-胺盐酸盐(1eq)、二氢呋喃-2,5-二酮(1.2eq)和DIPEA(3eq)溶解于EtOH中,并将反应物在90℃下搅拌3-4个小时。反应完成后,将所得物用1M HCl稀释并用二氯甲烷-甲醇(20%)萃取,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到羧酸衍生物。
步骤2:将步骤1中得到的羧酸衍生物(1eq)、哌啶衍生物(1.1eq)、HATU(2.5eq)和DIPEA(3eq)溶解于DMF中,并将反应物在室温下搅拌12小时。反应完成后,减压去除溶剂。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经无水Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到实施例77的化合物。
<实施例78>N-(2-(4-苄基哌啶-1-基)乙基)苯并[d][1,3]二氧杂环己醇-5-甲酰胺的制备
通过与实施例19相同的方法,除了使用苯并[d][1,3]二氧杂环己醇-5-羧酸代替1H-吲哚-2-羧酸以及使用2-(4-苄基哌啶-1-基)乙-1-胺代替2-(4-(3,4-二氯苄基)哌啶-1-基)乙胺之外,得到实施例78的化合物。
<实施例79>N-(2-(4-苄基哌啶-1-基)乙基)-2,3-二氢-6H-[1,4]二氧并[2,3-f]吲哚-7-甲酰胺的制备
通过与实施例19相同的方法,除了使用2,3-二氢-6H-[1,4]二氧并[2,3-f]吲哚-7-羧酸代替1H-吲哚-2-羧酸以及使用2-(4-苄基哌啶-1-基)乙胺代替2-(4-(3,4-二氯苄基)哌啶-1-基)乙胺之外,得到实施例79的化合物。
<实施例80>N-(2-(4-苄基哌啶-1-基)乙基)-2,3-二氢-6H-[1,4]二氧并[2,3-f]吲哚-7-甲酰胺的制备
通过与实施例19相同的方法,除了使用5H-[1,3]二氧代[4,5-f]吲哚-6-羧酸代替1H-吲哚-2-羧酸以及使用2-(4-苄基哌啶-1-基)乙-1-胺代替2-(4-(3,4-二氯苄基)哌啶-1-基)乙胺之外,得到实施例80的化合物。
<实施例81>2-((2-(4-苄基哌啶-1-基)乙基)氨基甲酰基)-1H-吲哚-5-羧酸的制备
步骤1:将5-(甲氧基羰基)-1H-吲哚-2-羧酸(1eq)、2-(4-苄基哌啶-1-基)乙胺(1.1eq)、HATU(2.5eq)和DIPEA(1.5eq)溶解于DMF中,并将反应物在室温下搅拌12小时。反应完成后,减压去除溶剂。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到2-((2-(4-苄基哌啶-1-基)乙基)氨基甲酰基)-1H-吲哚-5-羧酸甲酯。
步骤2:将步骤1中得到的2-((2-(4-苄基哌啶-1-基)乙基)氨基甲酰基)-1H-吲哚-5-羧酸甲酯(1eq)溶解于甲醇中,并向其中滴加4M氢氧化钾水溶液(150eq,过量),然后在50℃下反应12小时。反应完成后,所得物用1M盐酸水溶液中和,用二氯甲烷萃取并经Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到标题化合物2-((2-(4-苄基哌啶-1-基)乙基)氨基甲酰基)-1H-吲哚-5-羧酸。
<实施例82>N2-(2-(4-苄基哌啶-1-基)-1H-吲哚-2,5-二甲酰胺的制备
将实施例81的2-((2-(4-苄基哌啶-1-基)乙基)氨基甲酰基)-1H-吲哚-5-羧酸(1eq)溶解于DMF中,并在0℃下向其中滴加HBTU(2.5eq)、氯化铵(7eq)和三乙胺(6eq)。将反应物在室温下搅拌12小时。
反应完成后,将所得物用乙酸乙酯萃取,有机层依次用饱和NaHCO3水溶液和盐水洗涤并经Na2SO4干燥,并减压去除溶剂。然后,通过MPLC和制备型TLC分离和纯化反应混合物,得到标题化合物N2-(2-(4-苄基哌啶-1-基)乙基)-1H-吲哚-2,5-二甲酰胺。
实施例1至实施例82的化合物名称、NMR分析结果和NMR分析结果汇总于表13和14中。
[表13]
[表14]
<比较实施例1>N-(2-(4-苄基哌啶-1-基)乙基)-1H-吲哚-2-甲酰胺的制备
步骤1:将1H-吲哚-2-羧酸(1eq)、2-氯乙烷-1-胺盐酸盐(1.5eq)、HATU(2.5eq)和DIPEA(3eq)溶解于DMF中,并将反应物在室温下搅拌12小时。反应完成后,减压去除溶剂。将所得物用二氯甲烷萃取,有机层依次用H2O和盐水洗涤并经Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到N-(2-氯乙基)-1H-吲哚-2-甲酰胺。
步骤2:将N-(2-氯乙基)-1H-吲哚-2-甲酰胺(1eq)溶解于DMF中,并向其中加入TEA(4eq)和4-苄基哌啶(2eq),然后在60℃下搅拌12小时。反应完成后,减压去除溶剂。将所得物用乙酸乙酯萃取,有机层依次用H2O和盐水洗涤并经Na2SO4干燥,并减压去除溶剂。然后,通过MPLC分离和纯化反应混合物,得到比较实施例1的化合物。
<实验实施例1>三重再摄取抑制作用的评价
为评价根据本发明的实施例和比较实施例的化合物对多巴胺、去甲肾上腺素和血清素的再摄取抑制作用,进行以下实验,并且结果如表15所示。
为了评价对多巴胺的再摄取抑制作用,使用HEK-293细胞系转染多巴胺转运蛋白cDNA,然后于次日接种到24孔板中。去除培养基后,加入在摄取缓冲液中稀释至1μM的实施例或比较实施例的各化合物至200μl/孔的浓度,并在37℃下培养15分钟。加入100μl含20-30nM[3H]-DA的摄取缓冲液,并在37℃下培养5分钟。迅速去除反应液,并用1ml冰冷的摄取缓冲液洗涤3次。将所得物溶解于1%SDS(0.5ml)中后,测量放射性同位素标记的多巴胺与转运蛋白的结合程度。
对于去甲肾上腺素(NE)和血清素(5-HT),放射性同位素标记的去甲肾上腺素或血清素与转运蛋白的结合程度以与上述相同的方式进行测量,除了使用转染有NE或5-HT转运蛋白cDNA的细胞[3H]-NE或[3H]-5-HT作为底物之外。
此外,在评价对多巴胺、去甲肾上腺素和血清素的再摄取抑制作用时,进行同样的方法,但不对实施例或比较实施例的各化合物进行处理作为对照,测量放射性同位素标记的多巴胺、去甲肾上腺素和血清素与转运蛋白的结合程度,并通过将其作为标准(100%),以相对比率(比率%)评价三重再摄取抑制作用。即,在对照组中,多巴胺、去甲肾上腺素和血清素与转运蛋白的结合未被抑制,但是当实施例的各化合物被处理并因此结合被抑制时,比率%值降低。
同时,比较比率%值,并且在实施例6、9、10、19、20、22、24、28、30、31、32、33、35、41、42、48、49、51、55、56、59、61、63、64、65、66、74和76的化合物的情况下对多巴胺、去甲肾上腺素和血清素具有优异的再摄取抑制作用,使用总共6个浓度(1nM、5nM、10nM、50nM、100nM和1μM)计算比率%为50%的浓度,并以IC50表示。另外,在比较实施例1的化合物的情况下,通过与实施例化合物相同的方法得出IC50。
[表15]
在上表16中,SERT表示血清素转运蛋白,NET表示去甲肾上腺素转运蛋白,以及DAT表示多巴胺转运蛋白。
如上表15所示,
可见本发明的实施例和比较实施例的化合物可以抑制血清素、去甲肾上腺素和多巴胺的再摄取,并且实施例28、35、41、42、48、51、59、63、66和76的IC50值低于比较实施例1。
因此,根据本发明的式1所示的化合物具有优异的血清素、去甲肾上腺素和多巴胺的三重再摄取抑制作用,因此可用于治疗精神疾病。
<实验实施例2>过度活动抑制作用的评价
为评价根据本发明的实施例35和实施例66的化合物或比较实施例1的化合物的过度活动抑制作用,进行如下实验,并且结果如图1所示。开场实验是用于寻找运动功能、镇静、兴奋、回避程度和毒性的过度和下降的实验方法。
使用作为一种开场实验的EthoVision系统(Noldus IT b.v.,Netherlands)对动物的过度活动和行为分析进行观察。实验使用的动物为4周龄雄性ICR小鼠。为诱导过度活动,使用腹腔施用0.15mg/kg的MK801(药物名称:地佐环平)的动物模型,并且在施用MK801之前30分钟,腹腔施用5mg/kg的实施例35、实施例66或比较实施例1的化合物。施用作为溶解药物的溶剂的10%DMSO和10%Tween-80的雄性ICR小鼠被视为溶媒,并且施用MK801而未用实施例化合物或比较化合物处理的雄性ICR小鼠被视为阳性对照。之后,在使用黑色亚克力制作的测试盒(40×40×30cm)的中央放置被测小鼠并使其适应15分钟,观察、记录和分析行为模式15分钟。通过测量运动距离和运动持续时间进行比较分析。
与溶媒组相比,用MK801处理的所有组的小鼠运动距离(cm)增加约两倍,并且与仅用MK801处理的阳性对照和用比较实施例1的化合物处理的组相比,用实施例35的化合物处理的组和用实施例66的化合物处理的组的运动减少。具体地,对于溶媒的运动距离为约7000cm,对于仅用MK801处理的阳性对照为约14000cm,对于用比较实施例1的化合物处理的组为约13400cm,对于用实施例35的化合物处理的组为约10000cm,以及用实施例66的化合物处理的组的约8800cm。
与溶媒组相比,用MK801处理的所有组中均显示出小鼠的高运动持续时间(秒),并且与仅用MK801处理的阳性组和用比较实施例1的化合物处理的组相比,在用实施例35的化合物处理的组和用实施例66的化合物处理的组中显示出较低运动持续时间。特别地,溶媒显示出约880秒(s),仅用MK801处理的阳性对照显示出约1070秒,用比较实施例1的化合物处理的组显示出约1100秒,用实施例35的化合物处理的组显示出约950秒,并且用实施例66的化合物处理的组显示出约880秒(参见图1)。
结果表明,用比较实施例1的化合物处理未抑制MK801诱导的小鼠过度活动,但用实施例35或实施例66的化合物处理对其有显著抑制。由此可知,与比较实施例1的化合物相比,实施例35或66的化合物具有优异的血清素、去甲肾上腺素和多巴胺的三重再摄取抑制作用,并且可以抑制小鼠的过度活动。
因此,根据本发明的式1所示的化合物具有优异的血清素、去甲肾上腺素和多巴胺的三重再摄取抑制作用,因此可用于治疗精神疾病。
<实验实施例3>关于是否引起睡眠障碍的评价
为了评价根据本发明的实施例35、实施例66或比较实施例1的化合物的副作用是否引起睡眠障碍,进行如下实验,并且结果如图2所示。戊巴比妥钠是诱导睡眠的药物,通过观察使用该药物诱导睡眠的动物的行为,可以判断是否引起睡眠障碍。另外,咖啡因是公知的导致睡眠障碍的药物,并且地西泮是公知的具有睡眠保持作用的安眠药。
作为实验动物,准备3周龄的雄性ICR小鼠,每组8只。准备仅服用水的溶媒组,以下组:每天腹腔施用10mg/kg的咖啡因一次持续5天、2mg/kg的地西泮、10mg/kg的比较实施例1,以及10mg/kg的实施例35和10mg/kg的实施例66。5天后,向各组小鼠腹腔注射42mg/kg的戊巴比妥钠以诱导睡眠。
用戊巴比妥钠处理后,如果小鼠翻身露出腹部,则视为睡眠;并且如果小鼠改变姿势并露出背部,则视为完全苏醒。确认入睡时间和睡眠持续时间。
用地西泮处理的组的小鼠入睡时间最低,用咖啡因处理的组最高,用比较实施例1处理的组高于溶媒组,并且用实施例35或实施例66处理的组与溶媒组类似。具体地,溶媒组为约225秒,用咖啡因处理的组为约400秒,用地西泮处理的组为约170秒,用比较实施例1处理的组为约300秒,用实施例35处理的组为约220秒,并且用实施例66处理的组为约230秒。
用地西泮处理的组的小鼠睡眠持续时间最高,用咖啡因处理的组最低,用比较实施例1处理的组低于溶媒组,并且用实施例35或实施例66处理的组与溶媒组类似。具体地,溶媒组为约2100秒,用咖啡因处理的组为约790秒,用地西泮处理的组为约2900秒,用比较实施例1处理的组为约1100秒,用实施例35处理的组为约1950秒,并且用实施例66处理的组为约2090秒。
结果显示,如果用比较实施例1的化合物处理,小鼠的入睡时间增加并且睡眠持续时间减少,表现出睡眠障碍,但如果用实施例35或66的化合物处理,则对入睡时间和睡眠持续时间的诱导没有变化,未显示睡眠障碍。由此可知,作为副作用,比较实施例1的化合物诱导睡眠障碍,而实施例35或66的化合物不诱导睡眠障碍。
因此,根据本发明的式1所示的化合物具有优异的血清素、去甲肾上腺素和多巴胺的三重再摄取抑制作用,因此可用于治疗精神疾病。
工业实用性
根据本发明的式1所示的化合物具有优异的血清素、去甲肾上腺素和多巴胺的三重再摄取抑制作用,因此可用于治疗精神疾病。
Claims (10)
1.一种下式1所示的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐:
[式1]
在式1中,
R1是未取代的或取代的C3-6环烷基,未取代的或取代的C6-10芳基,含有选自由N、S和O组成的组的一个或更多个杂原子的未取代的或取代的5至14个原子的杂芳基,取代的直链或支链C1-8烷基,或取代的C4-6环烯基以与取代的碳原子一起形成C6-10芳基,
所述取代的环烷基被直链或支链C1-8烷基取代,所述取代的芳基被选自由直链或支链C1-10烷氧基和卤素组成的组的一个或更多个取代基取代,或被取代以与取代的碳原子一起形成含有一个或更多个O的C3-6杂环烯基,所述取代的杂芳基被选自由以下组成的组的一个或更多个取代基取代:未取代的或被一个或更多个卤素取代的直链或支链C1-8烷基,未取代的或被C6-10芳基、C1-10羧基、C1-10氨基羰基、苄氧基、羟基、腈基和卤素取代的直链或支链C1-10烷氧基,或被取代以与取代的碳原子一起形成含有一个或更多个O的C3-6杂环烯基,并且所述取代的烷基被选自由以下组成的组的一个或更多个取代基取代:含有选自由N、S和O组成的组的杂原子的被4至8个原子的苄基取代的杂环烷基,以及氧代;
L1是单键、未取代的或取代的直链或支链C1-8亚烷基或取代的C4-6亚环烯基,
所述取代的亚烷基被选自由氧代和直链或支链C1-5烷基组成的组的一个或更多个取代基取代,或所述取代的亚烷基被取代以与取代的碳一起形成C3-6环烷基,并且所述取代的亚环烯基被取代以与取代的碳原子一起形成C6-10芳基;
R2是含有选自由N、S和O组成的组的一个或更多个杂原子的未取代的或取代的4至8个原子的杂环烷基,含有选自由N、S和O组成的组的一个或更多个杂原子的未取代的或取代的5至14个原子的杂芳基,被一个或更多个卤素取代的C6-10芳基,未取代的或取代的C3-6环烷基,或NR2aR2b,
所述取代的杂环烷基、取代的杂芳基和取代的环烷基各自独立地被选自由以下组成的组的一个或更多个取代基取代:含有选自由N、S和O组成的组的一个或更多个杂原子的未取代的或被卤素取代的5至14个原子的杂芳基,取代的直链或支链C1-10烷基和取代的C6-10芳基,其中取代的烷基被选自由以下组成的组的一个或更多个取代基取代:含有选自由N、S和O组成的组的一个或更多个杂原子的4至8个原子的杂环烷基,羟基和未取代的或被一个或更多个卤素取代的C6-10芳基,并且所述取代的芳基被选自由被一个或更多个卤素取代的直链或支链C1-8烷基和卤素组成的组的一个或更多个取代基取代,
在这种情况下,R2a和R2b各自独立地是氢、未取代的或取代的直链或支链C1-5烷基,其中取代的烷基被选自由氧代和C6-10芳基组成的组的一个或更多个取代基取代;以及
R3是氢或直链或支链C1-5烷基;
或如果L1是单键,则R2和R3能与键合的氮原子形成未取代的或取代的4至8个原子的杂环烷基,其包含选自由N、S和O组成的组的一个或更多个杂原子,并且取代的杂环烷基被取代有C6-10芳基的直链或支链C1-10烷基取代。
2.根据权利要求1所述的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中
R1是未取代的或取代的C3-5环烷基,未取代的或取代的C6-10芳基,含有选自由N、S和O组成的组的一个或更多个杂原子的未取代的或取代的5至10个原子的杂芳基,取代的直链或支链C1-3烷基,或取代的C5-6环烯基以与取代的碳原子一起形成C6-8芳基,
所述取代的环烷基被直链或支链C1-3烷基取代,所述取代的芳基被选自由直链或支链C1-5烷氧基和卤素组成的组的一个或更多个取代基取代,或被取代以与取代的碳原子一起形成含有一个或更多个O的C4-6杂环烯基,所述取代的杂芳基被选自由以下组成的组的一个或更多个取代基取代:未取代的或被一个或更多个卤素取代的直链或支链C1-3烷基,未取代的或被C6-8芳基、C1-5羧基、C1-5氨基羰基、苄氧基、羟基、腈和卤素取代的直链或支链C1-5烷氧基,或被取代以与取代的碳原子一起形成含有一个或更多个O的C4-6杂环烯基,并且所述取代的烷基被选自由以下组成的组的一个或更多个取代基取代:含有选自由N、S和O组成的组的一个或更多个杂原子的被4至6个原子的苄基取代的杂环烷基,以及氧代;
L1是单键、未取代的或取代的直链或支链C1-3亚烷基或取代的C4-6亚环烯基,
所述取代的亚烷基被选自由氧代和直链或支链C1-3烷基组成的组的一个或更多个取代基取代,或所述取代的亚烷基被取代以与取代的碳一起形成C3-5环烷基,并且所述取代的亚环烯基被取代以与取代的碳原子一起形成C6-8芳基;
R2是含有选自由N、S和O组成的组的一个或更多个杂原子的未取代的或取代的4至6个原子的杂环烷基,含有选自由N、S和O组成的组的一个或更多个杂原子的未取代的或取代的5至10个原子的杂芳基,被一个或更多个卤素取代的C6-8芳基,未取代的或取代的C3-6环烷基,或NR2aR2b,
所述取代的杂环烷基、取代的杂芳基和取代的环烷基各自独立地被选自由以下组成的组的一个或更多个取代基取代:含有选自由N、S和O组成的组的一个或更多个杂原子的未取代的或被卤素取代的5至10个原子的杂芳基,取代的直链或支链C1-5烷基和取代的C6-8芳基,其中取代的烷基被选自由以下组成的组的一个或更多个取代基取代:含有选自由N、S和O组成的组的一个或更多个杂原子的4至6个原子的杂环烷基,羟基和未取代的或被一个或更多个卤素取代的C6-8芳基,并且所述取代的芳基被选自由被一个或更多个卤素取代的直链或支链C1-3烷基和卤素组成的组的一个或更多个取代基取代,
在这种情况下,R2a和R2b各自独立地是氢、未取代的或取代的直链或支链C1-3烷基,其中取代的烷基被选自由氧代和C6-10芳基组成的组的一个或更多个取代基取代;以及
R3是氢或直链或支链C1-3烷基;
或如果L1是单键,则R2和R3能与键合的氮原子形成未取代的或取代的4至6个原子的杂环烷基,其包含选自由N、S和O组成的组的一个或更多个杂原子,并且取代的杂环烷基被取代有C6-8芳基的直链或支链C1-5烷基取代。
3.根据权利要求1所述的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中
R1是未取代的或取代的环丙基、未取代的或取代的苯基、未取代的或取代的萘基、含有选自由N、S和O组成的组的一个或更多个杂原子的未取代的或取代的5至9个原子的杂芳基,取代的直链或支链C1-3烷基,或取代的环戊烯基以与取代的碳原子一起形成苯基,
所述取代的环丙基被甲基取代,所述取代的苯基和所述取代的萘基各自独立地被选自由直链或支链C1-4烷氧基、氯和溴组成的组的一个或更多个取代基取代,或所述取代的苯基被取代以与取代的碳原子一起形成含有一个或更多个O的杂环戊烯基,所述取代的杂芳基被选自由以下组成的组的一个或更多个取代基取代:未取代的或被一个或更多个卤素取代的甲基,未取代的或被苯基、C1-3羧基、C1-3氨基羰基、苄氧基、羟基、腈和卤素取代的直链或支链C1-4烷氧基,或被取代以与取代的碳原子一起形成含有一个或更多个O的C5-6杂环烯基,并且所述取代的烷基被选自由被苄基取代的哌啶基和氧代组成的组的一个或更多个取代基取代;
L1是单键、未取代的或取代的亚乙基或取代的C4-6亚环己烯基,
所述取代的亚乙基被选自由氧代和甲基组成的组的一个或更多个取代基取代,或所述取代的亚乙基被取代以与取代的碳原子一起形成环丙基,并且所述取代的亚环己烯基被取代以与取代的碳原子一起形成苯基;
R2是取代的哌啶基、取代的哌嗪基、未取代的或取代的吡唑、吲哚、被一个或更多个氯原子取代的苯基、被苄基取代的环己基或NR2aR2b,
所述取代的哌啶基、取代的哌嗪基和取代的吡唑各自独立地被选自由吲哚、被氟取代的吡啶、取代的甲基和取代的苯基组成的组的一个或更多个取代基取代,其中所述取代的甲基被选自由四氢吡喃、羟基和未取代的或被一个或更多个卤素取代的苯基组成的组的一个或更多个取代基取代,并且所述取代的苯基被选自由被一个或更多个氟原子取代的甲基和氯组成的组的一个或更多个取代基取代,
在这种情况下,R2a和R2b各自独立地是氢、未取代的或取代的甲基,其中所述取代的甲基被选自由氧代基和萘基组成的组的一个或更多个取代基取代;以及
R3是氢;
或如果L1是单键,则R2和R3能与键合的氮原子一起形成哌啶基,并且所述取代的哌啶基被取代的苯基取代。
5.根据权利要求1所述的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐,其中式1所示的化合物是选自由以下化合物组成的组中的任一种:
<1>6-溴-N-(2-(4-(3,4-二氯苄基)哌嗪-1-基)乙基)-2-萘甲酰胺;
<2>6-溴-N-(2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙基)-2-萘甲酰胺;
<3>6-溴-N-(2-(4-(3,4-二氯苯基)哌嗪-1-基)乙基)-2-萘甲酰胺;
<4>6-溴-N-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-2-萘甲酰胺;
<5>N-(2-(4-苄基哌嗪-1-基)乙基)-6-溴-2-萘甲酰胺;
<6>6-溴-N-(2-(4-(3,4-二氟苄基)哌啶-1-基)乙基)-2-萘甲酰胺;
<7>6-溴-N-(2-(4-(3,4-二氟苄基)哌嗪-1-基)乙基)-2-萘甲酰胺;
<8>6-溴-N-(2-(3-(5-氟吡啶-2-基)-1H-吡唑-1-基)乙基)-2-萘甲酰胺;
<9>6-溴-N-(2-(4-(3,4-二氯苄基)哌啶-1-基)乙基)-2-萘甲酰胺;
<10>3,5-二氯-N-(2-(4-(3,4-二氯苄基)哌啶-1-基)乙基)苯甲酰胺;
<11>3,4-二氯-N-(2-(4-(3,4-二氯苄基)哌嗪-1-基)乙基)苯甲酰胺;
<12>3,4-二氯-N-(2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙基)苯甲酰胺;
<13>3,4-二氯-N-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)苯甲酰胺;
<14>3,4-二氯-N-(2-(4-(3,4-二氯苯基)哌嗪-1-基)乙基)苯甲酰胺;
<15>N-(2-(4-苄基哌嗪-1-基)乙基)-3,4-二氯苯甲酰胺;
<16>3,4-二氯-N-(2-(4-(3,4-二氟苄基)哌嗪-1-基)乙基)苯甲酰胺;
<17>3,4-二氯-N-(2-(4-(3,4-二氯苄基)哌啶-1-基)乙基)苯甲酰胺;
<18>N-(2-(4-苄基哌啶-1-基)乙基)-3,4-二氯苯甲酰胺;
<19>N-(2-(4-(3,4-二氯苄基)哌啶-1-基)乙基)-1H-吲哚-2-甲酰胺;
<20>N-(2-(4-苄基哌啶-1-基)乙基)-3-甲基-1H-吲哚-2-甲酰胺;
<21>N-(2-(4-(3-(三氟甲基)苯基)哌嗪-1-基)乙基)-1H-吲哚-2-甲酰胺;
<22>N-(2-(4-(3,4-二氯苄基)哌嗪-1-基)乙基)-1H-吲哚-2-甲酰胺;
<23>N-(2-(4-(2,3-二氯苯基)哌嗪-1-基)乙基)-1H-吲哚-2-甲酰胺;
<24>N-(2-(4-(3,4-二氯苯基)哌嗪-1-基)乙基)-1H-吲哚-2-甲酰胺;
<25>N-(2-(4-苄基哌嗪-1-基)乙基)-1H-吲哚-2-甲酰胺;
<26>(4-苄基哌啶-1-基)(1H-吲哚-2-基)甲酮;
<27>N-(2-(4-(3,4-二氟苄基)哌啶-1-基)乙基)-1H-吲哚-2-甲酰胺;
<28>N-(2-(4-(3,4-二氯苯基)哌啶-1-基)乙基)-1H-吲哚-2-甲酰胺;
<29>N-(2-(4-((四氢-2H-吡喃-4-基)甲基)哌嗪-1-基)乙基)-1H-吲哚-2-甲酰胺;
<30>N-(2-(4-苄基哌啶-1-基)乙基)-5-溴-1H-吲哚-2-甲酰胺;
<31>N-(2-(4-苄基哌啶-1-基)乙基)-5-氯-1H-吲哚-2-甲酰胺;
<32>N-(2-(4-苄基哌啶-1-基)乙基)-5,6-二氟-1H-吲哚-2-甲酰胺;
<33>N-(2-(4-苄基哌啶-1-基)乙基)-5-甲氧基-1H-吲哚-2-甲酰胺;
<34>N-(1-(4-苄基哌啶-1-基)-2-甲基丙-2-基)-1H-吲哚-2-甲酰胺;
<35>N-(2-(4-苄基哌啶-1-基)乙基)-5,6-二甲氧基-1H-吲哚-2-甲酰胺;
<36>N-(2-(4-(羟基(苯基)甲基)哌啶-1-基)乙基)-1H-吲哚-2-甲酰胺;
<37>N-(2-(4-(1H-吲哚-3-基)哌啶-1-基)乙基)-1H-吲哚-2-甲酰胺;
<38>N-(2-(3-苄基哌啶-1-基)乙基)-1H-吲哚-2-甲酰胺;
<39>N-(2-(4-苄基哌啶-1-基)乙基)-4,6-二氯-1H-吲哚-2-甲酰胺;
<40>N-(2-(4-苄基哌啶-1-基)乙基)-5-(三氟甲基)-1H-吲哚-2-甲酰胺;
<41>N-(2-(4-苄基哌啶-1-基)乙基)-5-氰基-1H-吲哚-2-甲酰胺;
<42>N-(2-(4-苄基哌啶-1-基)乙基)-6-丁氧基-1H-吲哚-2-甲酰胺;
<43>N-(1-(4-苄基哌啶-1-基)丙-2-基)-1H-吲哚-2-甲酰胺;
<44>N-(4-苄基环己基)-1H-吲哚-2-甲酰胺;
<45>N-(2-(2-萘氨基)乙基)-1H-吲哚-2-甲酰胺;
<46>5-(苄氧基)-N-(2-(4-苄基哌啶-1-基)乙基)-1H-吲哚-2-甲酰胺;
<47>N-(2-(4-苄基哌啶-1-基)乙基)-5,6-二氯-1H-吲哚-2-甲酰胺;
<48>N-(2-(4-(3,4-二氯苄基)哌啶-1-基)乙基)-5,6-二甲氧基-1H-吲哚-2-甲酰胺;
<49>N-(2-(4-苄基哌啶-1-基)乙基)-5-氟-1H-吲哚-2-甲酰胺;
<50>N-(2-(4-苄基哌啶-1-基)-2-氧代乙基)-1H-吲哚-2-甲酰胺;
<51>N-(2-(4-(3,4-二氯苄基)哌啶-1-基)乙基)-5-氟-1H-吲哚-2-甲酰胺;
<52>N-(2-(3-(5-氟吡啶-2-基)-1H-吡唑-1-基)乙基)-1H-吲哚-2-甲酰胺;
<53>N-(1-((4-苄基哌啶-1-基)甲基)环丙基)-1H-吲哚-2-甲酰胺;
<54>N-(2-((萘-2-基甲基)氨基)乙基)-1H-吲哚-2-甲酰胺;
<55>N-(2-(4-苄基哌啶-1-基)乙基)苯并[d]噻唑-2-甲酰胺;
<56>N-(2-(4-苄基哌啶-1-基)乙基)-1H-吡咯[2,3-b]吡啶-2-甲酰胺;
<57>N-(2-(4-苄基哌啶-1-基)乙基)二氢吲哚-2-甲酰胺;
<58>(R)-N-(2-(4-苄基哌啶-1-基)乙基)二氢吲哚-2-甲酰胺;
<59>N-(2-(4-苄基哌啶-1-基)乙基)-5-甲氧基-1H-苯并[d]咪唑-2-甲酰胺;
<60>N-(2-(4-苄基哌啶-1-基)乙基)-5-氟苯并[d]噻唑-2-甲酰胺;
<61>N-(2-(4-苄基哌啶-1-基)乙基)-1H-苯并[d]咪唑-2-甲酰胺;
<62>N-((1R,4S)-4-(3,4-二氯苯基)-1,2,3,4-四氢萘-1-基)-1H-吲哚-2-甲酰胺;
<63>N-(2-(4-苄基哌啶-1-基)乙基)-5,6-二羟基-1H-吲哚-2-甲酰胺;
<64>N-(2-(4-苄基哌啶-1-基)乙基)-5-羟基-1H-苯并[d]咪唑-2-甲酰胺;
<65>N-(2-(4-(3,4-二氯苄基)哌啶-1-基)乙基)-5,6-二羟基-1H-吲哚-2-甲酰胺;
<66>N-(2-(4-苄基哌啶-1-基)乙基)-5-羟基-1H-吲哚-2-甲酰胺;
<67>N-(2-(4-苄基哌啶-1-基)乙基)-5-丁氧基-1H-吲哚-2-甲酰胺;
<68>N-(2-(甲基(萘-2-基甲基)氨基)乙基)-1H-吲哚-2-甲酰胺;
<69>N-(2-(4-苄基哌啶-1-基)乙基)环丙烷甲酰胺;
<70>N-(2-(4-苄基哌啶-1-基)乙基)-1-甲基环丙烷甲酰胺;
<71>N-(2-(4-苄基哌啶-1-基)乙基)吡啶酰胺;
<72>N-(2-(4-(1H-吲哚-3-基)哌啶-1-基)乙基)-4-丁氧基苯甲酰胺;
<73>N-(2-(4-苄基哌啶-1-基)乙基)-1H-吲哚-3-甲酰胺;
<74>N-(2-(4-苄基哌啶-1-基)乙基)-1-甲基-1H-吲哚-2-甲酰胺;
<75>N-(2-(4-苄基哌啶-1-基)乙基)-1H-吡咯-2-甲酰胺;
<76>3-(4-苄基哌啶-1-基)-N-(1H-吲哚-2-基)丙酰胺;
<77>4-(4-苄基哌啶-1-基)-N-(1H-吲哚-2-基)-4-氧代丁酰胺;
<78>N-(2-(4-苄基哌啶-1-基)乙基)苯并[d][1,3]二氧杂环己醇-5-甲酰胺;
<79>N-(2-(4-苄基哌啶-1-基)乙基)-2,3-二氢-6H-[1,4]二氧并[2,3-f]吲哚-7-甲酰胺;
<80>N-(2-(4-苄基哌啶-1-基)乙基)-5H-[1,3]二氧代[4,5-f]吲哚-6-甲酰胺;
<81>2-((2-(4-苄基哌啶-1-基)乙基)氨基甲酰基)-1H-吲哚-5-羧酸;和
<82>N2-(2-(4-苄基哌啶-1-基)乙基)-1H-吲哚-2,5-二甲酰胺。
6.一种用于预防或治疗精神疾病的药物组合物,其包含权利要求1的式1所示的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。
7.根据权利要求6所述的药物组合物,其中所述化合物抑制血清素、去甲肾上腺素和多巴胺的再摄取。
8.根据权利要求6所述的药物组合物,其中精神障碍是选自由以下组成的组的一种或多种:神经性贪食症、情绪障碍、抑郁症、非典型抑郁症、疼痛继发性抑郁症、重度抑郁症、心境恶劣障碍、双相情感障碍、I型双相情感障碍、II型双相情感障碍、循环性精神障碍、一般躯体疾病引起的情绪障碍、物质诱发的情绪障碍、假性痴呆、Ganger综合征、强迫症、恐慌症、恐慌症不伴广场恐惧症、恐慌症伴广场恐惧症、无恐慌症病史的广场恐惧症、恐慌症发作、记忆缺陷、记忆丧失、注意力缺陷多动障碍、肥胖、焦虑、广泛性焦虑症、进食障碍、帕金森病、帕金森症状、痴呆、衰老性痴呆、老年痴呆、阿尔茨海默病、唐氏综合症、获得性免疫缺陷综合征痴呆、衰老记忆障碍、特定恐惧症、社交恐惧症、社交焦虑症、创伤后应激障碍、急性应激障碍、慢性应激障碍、药物成瘾、药物滥用、药物滥用倾向、可卡因滥用、尼古丁滥用、烟草滥用、酒精成瘾、酒精中毒、病理性盗窃癖、因戒断醉人物质引起的戒断综合征、疼痛、慢性疼痛、炎性疼痛、神经性疼痛、糖尿病性神经性疼痛、偏头痛、紧张型头痛、慢性紧张型头痛、抑郁相关性疼痛、背痛、癌症疼痛、肠易激痛、肠易激综合征、术后疼痛、乳房切除术后疼痛综合征(PMPS)、中风后疼痛、药物引起的神经病变、糖尿病性神经病变、交感神经系统持续性疼痛、三叉神经痛、牙痛、面部肌肉疼痛、幻肢痛、厌食、经前期综合征、经前期烦躁障碍、黄体晚期综合征、创伤后综合征、慢性疲劳综合征、持续性植物状态、尿失禁、压力性尿失禁、急迫性尿失禁、夜间尿失禁、性功能障碍、早泄、勃起困难、勃起功能障碍、不宁腿综合征、周期性肢体运动障碍、进食障碍、神经性厌食症、睡眠障碍、广泛性发育障碍、自闭症、亚斯伯格症、Rett障碍、儿童瓦解性障碍、学习障碍、运动能力障碍、缄默症、拔毛癖、发作性睡病、中风后抑郁症、中风引起的脑损伤、中风-诱发的神经损伤、Tourette综合征、耳鸣、抽动障碍、身体变形障碍、对立违抗性障碍和中风后障碍。
9.一种用于预防或治疗精神疾病的血清素、去甲肾上腺素和多巴胺的三重再摄取抑制剂,其包含权利要求1的式1所示的化合物、其异构体、其溶剂化物、其水合物或药学上可接受的盐作为活性成分。
10.一种用于预防或改善精神疾病的保健功能食品组合物,其包含权利要求1的式1所示的化合物、其异构体、其溶剂化物、其水合物或其药学上可接受的盐作为活性成分。
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Application Number | Priority Date | Filing Date | Title |
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KR20200065504 | 2020-05-29 | ||
KR10-2020-0065504 | 2020-05-29 | ||
KR10-2021-0041817 | 2021-03-31 | ||
KR1020210041817A KR102445298B1 (ko) | 2020-05-29 | 2021-03-31 | 카복사미드 유도체 및 이를 유효성분으로 함유하는 정신질환의 예방 또는 치료용 약학적 조성물 |
PCT/KR2021/004209 WO2021241876A1 (ko) | 2020-05-29 | 2021-04-05 | 카복사미드 유도체 및 이를 유효성분으로 함유하는 정신질환의 예방 또는 치료용 약학적 조성물 |
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US (1) | US20240018119A1 (zh) |
EP (1) | EP4159725A4 (zh) |
JP (1) | JP2023528546A (zh) |
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KR101784964B1 (ko) * | 2016-05-04 | 2017-10-12 | 전남대학교산학협력단 | 신규한 카복사마이드 유도체 염 및 그 용도 |
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GB0021670D0 (en) * | 2000-09-04 | 2000-10-18 | Astrazeneca Ab | Chemical compounds |
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BRPI0806793B8 (pt) | 2007-02-12 | 2021-05-25 | Indus Biotech Private Ltd | composição para a inibição seletiva da absorção de serotonina e processo da mesma |
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- 2021-04-05 CN CN202180058701.9A patent/CN116057049A/zh active Pending
- 2021-04-05 EP EP21812765.2A patent/EP4159725A4/en active Pending
- 2021-04-05 US US17/928,044 patent/US20240018119A1/en active Pending
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WO2021241876A1 (ko) | 2021-12-02 |
EP4159725A4 (en) | 2023-12-20 |
JP2023528546A (ja) | 2023-07-04 |
US20240018119A1 (en) | 2024-01-18 |
EP4159725A1 (en) | 2023-04-05 |
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