CN103298809A - 1,2,4-三唑并[4,3-a]吡啶衍生物及其作为MGLUR2受体的正变构调节剂的用途 - Google Patents
1,2,4-三唑并[4,3-a]吡啶衍生物及其作为MGLUR2受体的正变构调节剂的用途 Download PDFInfo
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- CN103298809A CN103298809A CN2011800536367A CN201180053636A CN103298809A CN 103298809 A CN103298809 A CN 103298809A CN 2011800536367 A CN2011800536367 A CN 2011800536367A CN 201180053636 A CN201180053636 A CN 201180053636A CN 103298809 A CN103298809 A CN 103298809A
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- methyl
- phenyl
- pyridine
- disorder
- trifluoromethyl
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Abstract
本发明涉及新的式(I)的三唑并[4,3-a]吡啶衍生物
Description
发明领域
本发明涉及新的三唑并[4,3-a]吡啶衍生物,其是代谢型谷氨酸受体亚型2 (“mGluR2”)的正变构调节剂,并且可用于治疗或预防与谷氨酸功能障碍有关的神经和精神障碍和其中涉及代谢型受体mGluR2亚型的疾病。本发明还涉及包含这类化合物的药物组合物、制备这类化合物和组合物的方法以及这类化合物用于预防或治疗其中涉及mGluR2的神经与精神障碍和疾病的用途。
发明背景
谷氨酸是哺乳动物中枢神经系统中的主要氨基酸神经递质。谷氨酸在例如以下多种生理机能中起重要作用:学习和记忆及感官知觉、突触可塑性的发生、运动控制、呼吸和心血管功能的调节。此外,谷氨酸处于其中存在谷氨酸能神经传递失衡的几种不同的神经和精神疾病的中心。
谷氨酸通过激活离子型谷氨酸受体通道(iGluR)和负责快速兴奋性转递的NMDA、AMPA和红藻氨酸受体来介导突触神经传递。
另外,谷氨酸激活具有促使突触效能微调的更多调节作用的代谢型谷氨酸受体(mGluR)。
谷氨酸通过与受体的大的胞外氨基端结构域(本文称为正构结合部位(orthosteric
binding site))结合而激活mGluR。这种结合诱导受体的构象变化,这导致G蛋白和胞内信号转导途径的活化。
MGluR2亚型通过激活Gαi蛋白而与腺苷酸环化酶负偶联,其活化导致突触中谷氨酸释放受抑制。在中枢神经系统(CNS)中,mGluR2受体主要在整个皮质、丘脑区、副嗅球、海马、杏仁核、尾状壳核和伏隔核(nucleus
accumbens)中极丰富。
临床试验显示,激活mGluR2对治疗焦虑障碍有效。另外,表明在各种动物模型中激活mGluR2是有效的,因此代表了用于治疗以下疾病的有潜力的新的治疗方法:精神分裂症、癫痫、药瘾/药物依赖、帕金森病(Parkinson’s
disease)、疼痛、睡眠障碍和亨廷顿病(Huntington’s disease)。
迄今为止,大多数可获得的靶向mGluR的药理工具是激活该家族若干成员的正构配体(orthosteric
ligand),因为它们是谷氨酸的结构类似物。
用于开发作用于mGluR的选择性化合物的一种新手段是鉴定通过变构机制起作用的化合物,其通过与不同于高度保守的正构结合部位的部位结合而调节受体。
mGluR的正变构调节剂最近作为新的药理学实体而出现,提供了这种有吸引力的备选方法。已描述了作为mGluR2正变构调节剂的各种化合物。2009年5月22日公布的WO 2009/062676
(Ortho-McNeil-Janssen Pharmaceuticals,Inc.和Addex Pharma S.A.)公开了咪唑并[1,2-a]吡啶衍生物作为mGluR2正变构调节剂。2010年11月18日公布的WO2010/130424、WO2010/130423和WO2010/130422公开了1,2,4-三唑并[4,3-a]吡啶衍生物作为mGluR2正变构调节剂。
已表明,这类化合物自身并不激活受体。相反地,它们使受体能够对谷氨酸的浓度产生最大反应,谷氨酸的浓度本身诱导最小反应。突变分析明确证实了mGluR2正变构调节剂的结合不发生在正构部位,但却发生在位于受体七跨膜区内的变构部位。
动物数据表明mGluR2的正变构调节剂在焦虑和精神病模型中具有类似于用正构激动剂获得的作用。已表明mGluR2的变构调节剂在恐惧增强惊吓和焦虑的应激诱导性体温过高模型中有活性。此外,这类化合物显示在逆转氯胺酮或苯丙胺诱导的快速移动行为(hyperlocomotion)中和在逆转精神分裂症声音惊吓效应模型的苯丙胺诱导性前脉冲抑制的破坏中有活性。
最新动物研究还揭示了代谢型谷氨酸受体亚型2的选择性正变构调节剂联苯-印满酮(BINA)阻滞精神病的致幻觉药物模型,这就支持靶向mGluR2受体用于治疗精神分裂症的谷氨酸能功能障碍的策略。
正变构调节剂使得能够增强谷氨酸反应,但还表明它们增加对正构mGluR2激动剂(例如LY379268或DCG-IV)的反应。这些数据为治疗上述涉及mGluR2的神经和精神疾病的又一种新的治疗方法提供了证据,所述方法可使用mGluR2的正变构调节剂与mGluR2的正构激动剂的组合。
发明详述
本发明涉及具有有利的性质平衡的有效的mGluR2 PAM化合物。具体来讲,本发明的化合物作为mGluR2 PAM化合物显示高效能。
因此,本发明涉及具有代谢型谷氨酸受体2调节剂活性的化合物,所述化合物具有式(I)
及其立体化学异构形式,
其中
R1选自C1-6烷基、(C3-8环烷基)C1-3烷基、(C1-3烷基氧基)C1-3烷基和被1、2或3个氟取代基取代的C1-3烷基;
R2选自Cl、CF3、-CN和环丙基;
R3选自氢、甲基和CF3;
R4选自氢和甲基;
或者R3和R4与它们结合的碳一起形成环丙基环或羰基;
L选自(L-a)、(L-b)、(L-c)、(L-d)、(L-e)、(L-f)、(L-g)和(L-h):
其中
R5a、R5b、R5c和R5d各自独立选苯基;被1或2个各自独立选自C1-3烷基氧基和卤代基的取代基取代的苯基;吡啶基;被1或2个各自独立选自C1-3烷基、C1-3烷基氧基和卤代基的取代基取代的吡啶基;嘧啶基;和被1或2个各自独立选自C1-3烷基、C1-3烷基氧基和卤代基的取代基取代的嘧啶基;
R6e选自氢和C1-3烷基;
R5f、R5g和R5h各自独立选自苯基和被1或2个氟取代基取代的苯基;
R6a、R6b和R6c各自独立选自氢;氟代基;C1-3烷基;被1、2或3个氟取代基取代的C1-3烷基;C1-3烷基氧基;被1、2或3个氟取代基取代的C1-3烷基氧基;和C3-6环烷基;
R6h是C1-3烷基;
R7a、R8a、R7b、R8b、R7c、R8c、R7d和R8d各自独立选自氢、卤代基和甲基;或者R7a和R8a、R7b和R8b、R7c和R8c、R7d和R8d各自与它们连接的碳一起形成环丙基或羰基;
R9b选自氢、C1-3烷基和C3-6环烷基;
其中
卤代基各自选自氟代基、氯代基、溴代基和碘代基;
及其药学上可接受的盐和溶剂合物。
本发明还涉及包含治疗有效量的式(I)化合物和药学上可接受的载体或赋形剂的药物组合物。
另外,本发明涉及用作药物的式(I)化合物并涉及用作用于治疗或预防其中涉及mGluR2的神经和精神障碍的药物的式(I)化合物。
本发明还涉及式(I)化合物或本发明药物组合物在制备用于治疗或预防其中涉及mGluR2的神经和精神障碍的药物中的用途。
另外,本发明涉及式(I)化合物与其它药剂的组合用于制备用于治疗或预防其中涉及mGluR2的神经和精神障碍的药物中的用途。
此外,本发明涉及用于制备本发明的药物组合物的方法,其特征在于将药学上可接受的载体与治疗有效量的式(I)化合物密切混合。
本发明还涉及包含作为用于同时、单独或序贯用于治疗或预防神经或精神障碍和疾病的组合制剂的式(I)化合物和其它药剂的产品。
发明详述
本发明涉及上文定义的式(I)化合物、其立体化学异构形式及其药学上可接受的盐和溶剂合物。式(I)化合物具有mGluR2调节活性,并可用于治疗或预防神经和精神障碍。
在一个实施方案中,本发明涉及如前限定的式(I)化合物,其中R1是(C3-8环烷基)C1-3烷基。
在另一个实施方案中,R1是(环丙基)甲基。
在又一个实施方案中,R2是CF3。
在另一个实施方案中,R3和R4是氢。
在又一个实施方案中,L是(L-a),其中R5a是苯基;R6a选自氢和甲基;R7a和R8a是氢。
在又一个实施方案中,L是(L-b),其中R5b是被1或2个氟取代基任选取代的苯基;R6b选自氢和甲基;R7b和R8b是氢;R9b选自氢和甲基。
在又一个实施方案中,L是(L-b),其中R5b是被氟取代基任选取代的苯基;R6b选自氢和甲基;R7b和R8b是氢;R9b选自氢和甲基。
在又一个实施方案中,L是(L-b),其中R5b是被氟取代基任选取代的苯基;R6b选自氢和甲基;R7b、R8b和R9b是氢。
在又一个实施方案中,L是(L-c),其中R5c是被1或2个氟取代基任选取代的苯基;R6c选自氢和甲基;R7c和R8c是氢。
在又一个实施方案中,L是(L-c),其中R5c是苯基;R6c选自氢和甲基;R7c和R8c是氢。
在又一个实施方案中,L是(L-c),其中R5c是苯基;R6c是甲基;R7c和R8c是氢。
在又一个实施方案中,L是(L-c),其中R5c是被1或2个氟取代基取代的苯基;R6c、R7c和R8c是氢。
在又一个实施方案中,L是(L-g),其中R5g选自苯基,被1或2个氟取代基任选取代。
在又一个实施方案中,L是(L-h),其中R5h是苯基且R6h是甲基。
在又一个实施方案中,L是(L-f),其中R5f选自苯基,被1或2个氟取代基任选取代。
上文所示的引人关注的实施方案的所有可能组合都视为包括在本发明范围内。
具体化合物可选自
3-(环丙基甲基)-7-[(3-苯基-1-哌啶基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶,
3-(环丙基甲基)-7-[[(2R)-2-苯基-4-吗啉基]甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶,
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R),
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R)盐酸盐,
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R)盐酸盐水合物,
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S),
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S)盐酸盐,
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S)盐酸盐水合物,
3-(环丙基甲基)-7-[[(2S)-2-苯基-4-吗啉基]甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶,
3-(环丙基甲基)-7-[(3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶,
3-(环丙基甲基)-7-[(3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R),
3-(环丙基甲基)-7-[(3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S),
3-(环丙基甲基)-7-[[3-(2-氟苯基)-1-哌嗪基]甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R),
3-(环丙基甲基)-7-[[3-(2-氟苯基)-1-哌嗪基]甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S),
3-(环丙基甲基)-7-[(4-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶,
3-(环丙基甲基)-7-[(4-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R),
3-(环丙基甲基)-7-[(4-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S),
3-(环丙基甲基)-7-[(2-甲基-2-苯基-4-吗啉基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R),
3-(环丙基甲基)-7-[(2-甲基-2-苯基-4-吗啉基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R)盐酸盐,
3-(环丙基甲基)-7-[(2-甲基-2-苯基-4-吗啉基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R)盐酸盐水合物,
3-(环丙基甲基)-7-[(2-甲基-2-苯基-4-吗啉基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S),
3-(环丙基甲基)-7-[(2-甲基-2-苯基-4-吗啉基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S)盐酸盐,
3-(环丙基甲基)-7-[(2-甲基-2-苯基-4-吗啉基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S)盐酸盐水合物,
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌啶基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶,
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌啶基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶盐酸盐,
3-甲基-7-[(3-甲基-3-苯基-1-哌啶基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S),
3-甲基-7-[(3-甲基-3-苯基-1-哌啶基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R),
2-[[3-(环丙基甲基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-基]甲基]-5-(2,4-二氟苯基)-2,5-二氮杂双环[4.1.0]庚烷(顺式),
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-吡咯烷基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R),
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-吡咯烷基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S),
3-(环丙基甲基)-7-{[(2*R)-2-(2,4-二氟苯基)吗啉-4-基]甲基}-8-(三氟甲基)[1,2,4]三唑并[4,3-a]吡啶,
3-(环丙基甲基)-7-{[(2*S)-2-(2,4-二氟苯基)吗啉-4-基]甲基}-8-(三氟甲基)[1,2,4]三唑并[4,3-a]吡啶,
3-(环丙基甲基)-7-{[3-(2,4-二氟苯基)哌嗪-1-基]甲基}-8-(三氟甲基)[1,2,4]三唑并[4,3-a]吡啶,
3-(环丙基甲基)-7-{[(3*R)-3-(2,4-二氟苯基)哌嗪-1-基]甲基}-8-(三氟甲基)[1,2,4]三唑并[4,3-a]吡啶和
3-(环丙基甲基)-7-{[(3*S)-3-(2,4-二氟苯基)哌嗪-1-基]甲基}-8-(三氟甲基)[1,2,4]三唑并[4,3-a]吡啶。
其立体异构形式、药学上可接受的盐和溶剂合物包括在该列表范围内。
按照化学文摘服务处(Chemical Abstracts Service,CAS)同意的命名原则,应用Advanced Chemical Development,Inc.,软件(ACD/Name
product 10.01版;Build 15494,2006年12月1日),或者按照国际理论和应用化学联合会(International Union of Pure and Applied
Chemistry,IUPAC)同意的命名原则,应用Advanced
Chemical Development,Inc.,软件(ACD/Name product 10.01.0.14105版,2006年10月),生成本发明化合物的命名。在互变异构形式的情况下,生成该结构已描述的互变异构形式的命名。然而应当清楚,其它未描述的互变异构形式也包括在本发明的范围内。
定义
本文单独或作为另一基团的部分使用的表示法“C1-3烷基”或“C1-6烷基”,定义除非另作说明否则具有1-3个或1-6个碳原子的饱和直链或支链烃基,例如甲基、乙基、1-丙基、1-甲基乙基、丁基、1-甲基-丙基、2-甲基-1-丙基、1,1-二甲基乙基、3-甲基-1-丁基、1-戊基、1-己基等。
本文单独或作为另一基团的部分使用的表示法“C3-6环烷基”和“C3-8环烷基”,定义具有3-6或3-8个碳原子的饱和环状烃基,例如环丙基、环丁基、环戊基、环己基、环庚基和环辛基。
本文单独或作为另一基团的部分使用的表示法“卤素”或“卤代”,指氟代基、氯代基、溴代基或碘代基,优选氟代基或氯代基。
除非另有规定,本文单独或作为另一基团的部分使用的表示法“被1、2或3个氟取代基取代的C1-3烷基”,定义被1、2或3个氟原子取代的上文定义的烷基,例如氟甲基、二氟甲基、三氟甲基、2,2,2-三氟乙基、1,1-二氟乙基、3,3,3-三氟丙基。这些基团的具体实例为三氟甲基、2,2,2-三氟乙基和1,1-二氟乙基。
每当术语“取代的”用于本发明时,意指除非另有说明或从上下文中显而易见,否则表明在使用“取代的”的表述中所标明的原子或者基团上的一个或多个氢、优选1-3个氢、更优选1-2个氢、更优选1个氢被来自指定基团的选定基团置换,条件是不超过常价,且该取代导致化学上稳定的化合物,即足够稳固以经历从反应混合物中分离至有用纯度并配制成治疗剂之后仍存在的化合物。
应了解,一些式(I)化合物及其药学上可接受的加成盐及其溶剂合物可含有一个或多个手性中心并以立体异构形式存在。
上文和下文中的术语“式(I)化合物”欲包括其立体异构体。上文或下文中的术语“立体异构体”或“立体化学异构形式”可互换使用。
本发明包括作为纯立体异构体或作为两种或更多种立体异构体的混合物的式(I)化合物的所有立体异构体。对映体是彼此为不能重叠的镜像的立体异构体。对映体对的1:1混合物是外消旋体或者外消旋混合物。非对映体(或非对映异构体)是不是对映体的立体异构体,即它们并不作为镜像相关联。如果化合物含有双键,则取代基可呈E构型或Z构型。如果化合物含有至少二取代的非芳族环状基团,则取代基可呈顺式或反式构型。因此,本发明包括对映体、非对映体、外消旋体、E异构体、Z异构体、顺式异构体、反式异构体及其混合物。
按照Cahn-Ingold-Prelog体系规定绝对构型。不对称原子上的构型规定为R或S。可根据拆分化合物旋转平面偏振光的方向,将其绝对构型尚未知的拆分化合物用(+)或(-)标明。
当鉴定出具体的立体异构体时,这就意味着所述立体异构体基本不含其它异构体,即伴随小于50%、优选小于20%、更优选小于10%、甚至更优选小于5%、尤其是小于2%和最优选小于1%的其它异构体。因此,当式(I)化合物规定为例如(R)时,这就意味着化合物基本不含(S)异构体;当式(I)化合物规定为例如E时,这就意味着化合物基本不含Z异构体;当式(I)化合物规定为例如顺式时,这就意味着化合物基本不含反式异构体。
对于治疗用途,式(I)化合物的盐是其中抗衡离子是药学上可接受的那些盐。然而,非药学上可接受的酸和碱的盐也可用于例如药学上可接受的化合物的制备或纯化。所有的盐,不论是否是药学上可接受的,都包括在本发明的范围内。
上文或下文所述的药学上可接受的酸和碱加成盐欲包括式(I)化合物能够形成的有治疗活性的无毒酸和碱加成盐形式。药学上可接受的酸加成盐可通过将碱形式用这类合适的酸处理而方便地获得。合适的酸包括例如无机酸例如氢卤酸(例如盐酸或氢溴酸)、硫酸、硝酸、磷酸等;或有机酸例如乙酸、丙酸、羟基乙酸、乳酸、丙酮酸、草酸(即乙二酸)、丙二酸、琥珀酸(即丁二酸)、马来酸、富马酸、苹果酸、酒石酸、柠檬酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、环拉酸、水杨酸、对氨基水杨酸、双羟萘酸等。相反地,所述盐形式可通过用合适的碱处理转化成游离碱形式。
含有酸式质子的式(I)化合物还可通过用合适的有机碱和无机碱处理转化成其无毒的金属或胺加成盐形式。合适的碱盐形式包括例如铵盐、碱金属盐和碱土金属盐,例如锂盐、钠盐、钾盐、镁盐、钙盐等;与有机碱的盐,例如伯、仲和叔脂族和芳族胺,例如甲胺、乙胺、丙胺、异丙胺、4种丁胺异构体、二甲胺、二乙胺、二乙醇胺、二丙胺、二异丙胺、二正丁胺、吡咯烷、哌啶、吗啉、三甲胺、三乙胺、三丙胺、奎宁环、吡啶、喹啉和异喹啉;苄星(benzathine)、N-甲基-D-葡糖胺、海巴明(hydrabamine)盐;以及与氨基酸例如精氨酸、赖氨酸等的盐。相反地,盐形式可通过用酸处理转化成游离酸形式。
术语溶剂合物包括式(I)化合物能够形成的溶剂加成形式及其盐。这类溶剂加成形式的实例为例如水合物、醇化物等。
一些式(I)化合物还可以其互变异构形式存在。这类形式虽然在上式中未明确指明,但也欲包括在本发明的范围内。
在本申请架构中,元素,特别在有关式(I)化合物提及时,包括天然存在的或合成产生的、具有天然丰度或呈同位素富集形式的该元素的所有同位素和同位素混合物。放射性同位素标记的式(I)化合物可包含选自以下的放射性同位素:3H、11C、18F、122I、123I、125I、131I、75Br、76Br、77Br和82Br。优选放射性同位素选自3H、11C和18F。
制备
本发明的化合物一般可通过一连串的步骤制备,其每一步均为技术人员所知。具体地讲,化合物可按照以下合成方法制备。
式(I)化合物可以对映体的外消旋混合物的形式合成,所述混合物可按照本领域已知拆分方法彼此分离。式(I)的外消旋化合物可通过与合适的手性酸反应而转化成相应的非对映体的盐形式。所述非对映体的盐形式随后通过例如选择性结晶或分级结晶,并用碱从中释放出对映体而分离。分离式(I)化合物的对映体形式的备选方法包括使用手性固定相的液相层析法。所述纯的立体化学异构形式还可衍生自合适起始原料相应的纯的立体化学异构形式,条件是反应立体有择地发生。
A.
最终化合物的制备
实验方法
1
可按照本领域已知方法,通过在卤化剂(例如三氯氧化磷(V) (POCl3)或三氯乙腈-三苯基膦混合物)存在下,在合适的溶剂(例如DCE或CH3CN)中,在微波辐射下,在介于140-200℃的温度下搅拌允许完成反应的适当的一段时间(例如50分钟),使式(II)的中间体化合物环化,来制备最终的式(I)化合物。
或者,可通过在介于140-200℃的温度下,将式(II)的中间体化合物加热允许完成反应的适当的一段时间(例如1小时),来制备式(I)的最终化合物。在反应流程(1)中,所有变量如式(I)所定义。
反应流程
1
实验方法
2
可通过与描述于J. Org. Chem., 1966, 31, 251或J. Heterocycl. Chem., 1970,
7, 1019的合成法类似的本领域已知方法,通过按照反应流程(2),在合适的式(IV)原酸酯存在时,在合适的条件下使式(III)的中间体化合物环化,来制备式(I)的最终化合物,其中R1为如式(I)化合物定义的合适取代基,例如甲基。反应可在合适的溶剂(例如二甲苯)中进行。通常,可将混合物在介于100-200℃的温度下搅拌1-48小时。在反应流程(2)中,所有变量如式(I)所定义。
或者,可通过与描述于Tetrahedron Lett., 2007,48,2237-2240的合成法类似的本领域已知方法,通过使式(III)的中间体化合物与式(V)的羧酸或酸等同物(例如式(VI)的酰基卤)反应,得到式(I)的最终化合物,来制备式(I)的最终化合物。可使用卤化剂(例如三氯乙腈-三苯基膦混合物),在合适的溶剂(例如二氯乙烷)存在下,在介于100-200℃的温度下搅拌1-48小时或在微波辐射下搅拌20分钟,来进行该反应。在反应流程(2)中,所有变量如式(I)所定义。
反应流程
2
实验方法
3
可按照本领域已知方法,通过在合适的条件下,在合适的氧化剂(例如氯化铜(II))存在下,在合适的溶剂(例如DMF)中,在介于室温与200℃的温度下搅拌1-48小时,使式(VII)的中间体化合物环化,来制备式(I)的最终化合物。在反应流程(3)中,所有变量如式(I)所定义。
反应流程
3
实验方法
4
或者,可在本领域技术人员已知的烷基化条件下,通过使式(VIII)的中间体与式(IX)的中间体反应,来制备式(I)的最终化合物。这描述于反应流程(4)中,其中所有变量如上文中所定义,X为适于烷基化反应的基团,例如卤代基、甲基磺酸基或对甲苯磺酸基。例如,可在合适温度(例如120℃)下,在合适的碱(例如二异丙基乙胺)存在下,在合适的反应溶剂(例如DMF)中持续允许完成反应的合适的一段时间,来进行该反应。
反应流程
4
实验方法
5
其中介于L与三唑并嘧啶核之间的碳被R3或R4单取代从而表示为(I-a)的式(I)的最终化合物,可通过在本领域技术人员已知的还原胺化条件下使式(X)的中间体与式(IX)的中间体反应来制备。这描述于反应流程(5)中,其中所有变量如式(I)所定义。可例如在三乙酰氧基硼氢化钠存在下,在合适的反应惰性溶剂(例如1,2-二氯乙烷)中,在合适的温度下,例如介于室温与150℃的温度下,典型加热或微波辐射,持续允许完成反应的适当的一段时间,来进行该反应。
反应流程
5
B. 中间体的制备
实验方法
6
可按照本领域技术人员已知的条件,在合适的偶联试剂存在下通过酰胺键形成反应,通过使式(III)的中间体与式(V)的羧酸反应,来制备式(II)的中间体化合物。这在反应流程(6)中予以说明,其中所有变量如式(I)所定义。
或者,可通过本领域已知方法,通过使式(III)的中间体与式(V)的羧酸反应,来制备式(II)的中间体化合物。可使用卤化剂(例如三氯乙腈-三苯基膦混合物),在合适的溶剂(例如二氯乙烷)存在下,在介于100-200℃的温度下搅拌1-48小时或在微波辐射下搅拌20分钟来进行该反应。在反应流程(6)中,所有变量如式(I)所定义。
或者,可通过本领域已知方法,通过使式(III)的中间体与式(VI)的酰基卤反应,来制备式(II)的中间体化合物。可在碱(例如TEA)存在下,使用惰性溶剂(例如DCM),在例如室温下持续允许完成反应的一段适当时间,来进行该反应。在反应流程(6)中,所有变量如式(I)所定义。
反应流程
6
实验方法
7
可按照反应流程(7),通过使式(XI)的中间体化合物与肼反应,来制备式(III)的中间体化合物,反应流程(7)为一种在合适的反应惰性溶剂(例如乙醇或THF)中,在热条件下例如在微波辐射下于例如160℃加热反应混合物20分钟或在90℃下典型加热16小时而进行的反应。在反应流程(7)中,所有变量如式(I)所定义,卤代基为氯代基、溴代基或碘代基。
反应流程
7
实验方法
8
可按照本领域技术人员已知的条件,通过亚胺键形成反应,使式(III)的中间体与式(XII)的醛反应,来制备式(VII)的中间体化合物。可使用质子溶剂(例如EtOH),在例如介于室温与150℃的温度下持续允许完成反应的适当的一段时间,来进行该反应。在反应流程(8)中,所有变量如式(I)所定义。
反应流程
8
实验方法
9
其中介于L与三唑并嘧啶核之间的碳被R3或R4单取代从而表示为(XI-a)的式(XI)的中间体化合物,可在本领域技术人员已知的还原胺化条件下,通过使式(XIII)的中间体与式(IX)的中间体反应来制备。这在反应流程(9)中予以说明,其中所有变量如式(I)所定义。例如,可在三乙酰氧基硼氢化物存在下,在合适的反应惰性溶剂(例如DCE)中,在合适的温度下(通常在室温下)持续允许完成反应的适当的一段时间,来进行该反应。
反应流程
9
实验方法
10
可按照本领域技术人员已知的条件,在合适的偶联试剂存在下,通过经由酰胺键形成反应,使式(XIII-a)的中间体与式(IX)的胺反应,来制备其中CR3R4形成羰基从而表示为(XI-b)的式(XI)的中间体化合物。
反应流程
10
可按实验方法7、6和1中相继定义的步骤直到最终化合物。
实验方法
11
可通过使式(XIV)的中间体经受本领域技术人员已知的条件,来制备式(XIII)的中间体化合物。这在反应流程(11)中予以说明,其中所有变量如上述定义。例如,可通过首先将芳基卤转化为其中金属可为锂、镁、硼或锌的芳基金属衍生物,接着通过与合适的羰基化合物反应,来进行该反应。实现这些转化的方法为本领域技术人员所熟知,包括在合适的反应惰性溶剂(例如THF、乙醚或甲苯,优选THF)中,在介于-78℃与40℃的温度下,用格氏试剂(Grignard reagent) (例如异丙基氯化镁)或强碱(例如BuLi)进行金属-卤素交换,接着在介于-78℃与100℃的温度下,与羰基化合物(例如DMF)反应。
反应流程
11
实验方法
12
式(X)的中间体化合物可在本领域技术人员已知的二羟基化和氧化解离条件下,使式(XV)的中间体反应来制备,并且可例如用过硫酸氢钾制剂、四氧化锇来实现。该方法可任选在溶剂(例如1,4-二噁烷、水)中且一般在介于约-100℃与约100℃的温度下进行。该方法的概要可参见“Comprehensive Organic Transformations”,VCH Publishers,(1989),R.C.Larock,第595-596页。这在反应流程(12)中予以说明,其中所有变量如上述定义。
反应流程
12
实验方法
13
可在本领域技术人员已知条件下,通过式(XVI)中间体与式(XVII)化合物的偶联反应,例如Stille或Suzuki反应,来制备式(XV)的中间体化合物。这在反应流程(13)中予以说明,其中所有变量如上述定义,其中M为三烷基锡、硼酸或硼酸酯和钯催化剂。可在碱存在时,任选在溶剂(例如1,4-二噁烷、水)中,并且一般在约室温和约200℃的温度下进行该方法。
反应流程
13
实验方法
14
可按照本领域已知方法,通过在卤化剂(例如三氯氧化磷(V) (POCl3))存在下,在合适的溶剂(例如二氯乙烷)中,在微波辐射下搅拌允许完成反应的适当的一段时间,例如在介于140-200℃的温度下搅拌5分钟,使式(XVIII)的中间体化合物环化,来制备式(XVI)的中间体化合物。在反应流程(14)中,所有变量如式(I)所定义,卤代基为氯代基、溴代基或碘代基。
反应流程
14
实验方法
15
可通过本领域已知方法,通过使式(XIX)的肼中间体与式(VI)的酰基卤反应,来制备式(XVIII)的中间体化合物。可使用惰性溶剂(例如DCM),在碱(例如三乙胺)存在下,例如在室温下持续允许完成反应的适当的一段时间(例如20分钟),来进行该反应。在反应流程(15)中,所有变量如式(I)所定义。
反应流程
15
实验方法
16
可按照反应流程(16),通过使式(XX)的中间体化合物与肼反应,来制备式(XIX)的中间体化合物,反应流程(16)为一种在合适的反应惰性溶剂(例如乙醇、THF或1,4-二噁烷)中,在热条件下,例如在微波辐射下于160℃加热反应混合物30分钟或在70℃的经典加热下加热反应混合物16小时而进行的反应。在反应流程(16)中,R2如式(I)中所定义,卤代基为氯代基、溴代基或碘代基。
反应流程
16
实验方法
17
可按照反应流程(17),通过使式(XXI)的中间体化合物与苯甲醇反应,来制备式(XX)的中间体化合物,反应流程(17)为一种在合适的反应惰性溶剂(例如N,N-二甲基甲酰胺)中,在合适的碱(例如氢化钠)存在下,在室温下持续允许完成反应的适当的一段时间(例如1小时)而进行的反应。在反应流程(17)中,R2如式(I)中所定义,卤代基为氯代基、溴代基或碘代基。
反应流程
17
实验方法
18
可按照反应流程(18),使其中R2为碘因此称为(XXI-b)的式(XXI)的中间体与合适的三氟甲基化剂(例如氟磺酰基(二氟)乙酸甲酯)反应,来制备其中R2为三氟甲基因此称为(XXI-a)的式(XXI)的中间体化合物。在合适的反应惰性溶剂(例如N,N-二甲基甲酰胺)中,在合适的偶联剂(例如碘化铜(I))存在下,在热条件下例如在微波辐射下于例如160℃加热反应混合物45分钟,来进行该反应。在反应流程(18)中,卤代基为氯代基、溴代基或碘代基。
反应流程
18
实验方法
19
可按照反应流程(19)和下列参考文献:a) Tetrahedron 2001,57(19),4059-4090或b) Tetrahedron 2001,57(21),4489-4505,通过在合适的碱(例如二异丙基氨基锂或丁基锂)存在下,使式(XXII)的中间体与取代或未取代的烷基或烯基卤化物(XXIII)反应,通过邻位金属化策略,来制备其中R2为环丙基因此称为(XXI-c)的式(XXI)的中间体化合物。在合适的反应惰性溶剂(例如THF)中,在低温(例如-78℃)下持续允许完成反应的一段时间(例如2-5小时),来进行该反应。在反应流程(19)中,卤代基可为氯代基、溴代基或碘代基,E表示环丙基。如有需要,按照本领域已知的产生所需的最终R2基团的方法,对中间体(XXI-c)进行进一步的简单官能团互变步骤。
反应流程
19
实验方法
20
可在本领域技术人员已知的合适条件下,由将存在于式(XXIV)的中间体化合物的羟基转化成合适的离去基团(例如卤素或甲磺酸基),来制备式(VIII)的中间体化合物。例如,可在碱(例如三乙胺、吡啶)或卤化试剂(例如P(O)Br3)存在下,在合适的反应惰性溶剂(例如DCM或DMF或两者的混合物)中,在合适的温度下,通常在室温下持续允许完成反应的适当的一段时间,使式(XXIV)的中间体化合物与甲基磺酰氯反应,来进行该反应。
反应流程
20
实验方法
21
可在本领域技术人员已知条件下,通过使式(X)的中间体反应,来制备其中OH与三唑并嘧啶核之间的碳被R3或R4单取代从而表示为(XXIV-a)的式(XXIV)的中间体化合物。这在反应流程(21)中予以说明,其中所有变量如上述定义。例如,可在合适的溶剂(例如甲醇)中,通过使式(XVII)的中间体与还原试剂(例如硼氢化钠)反应,来进行该反应。可在合适的温度(通常为室温)下持续允许完成反应的适当的一段时间,来进行该反应。这在反应流程(21)中予以说明,其中所有变量如上述定义。
反应流程
21
实验方法
22
或者,可按照本领域已知方法,通过在加热下持续允许完成反应的适当的一段时间,例如在介于140-200℃的温度下1小时,使式(XXV)的中间体化合物环化,来制备式(XVI)的中间体化合物。在反应流程(22)中,所有变量如式(I)所定义,卤代基为氯代基、溴代基或碘代基。
反应流程
22
实验方法
23
可通过本领域已知方法,通过使式(XXVI)的中间体化合物与式(VI)的酰基卤反应,来制备式(XXV)的中间体化合物。可使用惰性溶剂(例如DCM),在碱(例如三乙胺)存在时,例如在室温下持续允许完成反应的适当的一段时间(例如20分钟),来进行该反应。在反应流程(23)中,所有变量如式(I)所定义,卤代基为氯代基、溴代基或碘代基。
反应流程
23
实验方法
24
可按照反应流程(24),使式(XXVII)的中间体化合物与肼反应,来制备式(XXVI)的中间体化合物,反应流程(24)为一种在合适的反应惰性溶剂(例如乙醇、THF或1,4-二噁烷)中,在热条件下例如在微波辐射下于160℃加热反应混合物30分钟或在70℃的经典加热下加热反应混合物16小时所进行的反应。在反应流程(24)中,R2如式(I)中所定义,卤代基为氯代基、溴代基或碘代基。
反应流程
24
实验方法25
可按照应用本领域已知方法的反应流程(25),通过对式(XXVIII)的中间体化合物中的氮原子脱保护,来制备式(IX)的中间体化合物,其中PG表示氮原子的合适保护基,例如叔丁氧基羰基、乙氧基羰基、苄氧基羰基、苄基和甲基。例如,如果PG表示苄基,则可在合适的反应惰性溶剂(例如醇,即甲醇和1,4-环己二烯)中,在合适的催化剂(例如披钯木炭)存在下,在适度高温(例如100℃)下,在密封容器中进行脱保护反应。或者,如果PG表示烷基氧基羰基,则可在合适的反应惰性溶剂(例如1,4-二噁烷)中,在适度高温(例如回流温度)下,通过与合适的酸(例如盐酸)反应,来进行脱保护反应。在反应流程(25)中,所有变量如式(I)所定义。
反应流程
25
式(IV)、式(V)、式(VI)、式(IX)、式(XII)、式(XVII)或式(XXVIII)的起始原料是市售可获得的或可按照本领域技术人员普遍已知的常规反应方法制备的化合物。例如,式(IX)化合物,例如具有CAS编号CAS 90821-77-5、CAS 90821-76-4、CAS
67644-21-7、CAS 66505-14-4、CAS 66504-36-7和CAS
66504-04-9、CAS 56606-73-6的化合物是本领域已知的。
为了获得化合物的HCl盐形式,可采用本领域技术人员已知的几种方法,除非另有说明。在一个典型的方法中,可将例如游离碱溶于DIPE或Et2O,随后可滴加2-丙醇中的6N HCl溶液或Et2O中的1 N HCl溶液。通常搅拌混合物10分钟,之后可滤出产物。通常将HCl盐真空干燥。本文提供的盐化学计量值通过元素分析在实验上获得,当使用不同的分析方法时可不同。
本领域技术人员应了解,在上述方法中,中间体化合物的官能团可能需要用保护基封闭。在中间体化合物的官能团被保护基封闭的情况下,它们可在反应步骤后脱保护。
药理学
本发明提供的化合物是代谢型谷氨酸受体的正变构调节剂(PAM),特别地它们是mGluR2的正变构调节剂。本发明的化合物似乎不与谷氨酸识别部位、正构配体部位结合,但却与受体的七跨膜区内的变构部位结合。在谷氨酸或mGluR2的激动剂存在下,本发明的化合物提高mGluR2反应。预期本发明提供的化合物通过其提高这类受体对谷氨酸或mGluR2激动剂的反应从而增强受体的反应的能力而在mGluR2上具有其作用。
本文所用术语“治疗”欲指其中可存在疾病进程的减慢、中断、阻止或终止,但不一定表明完全消除所有症状的全部过程。
因此,本发明涉及用作药物的通式(I)化合物、其立体异构形式及其药学上可接受的酸或碱加成盐和溶剂合物。
本发明还涉及通式(I)化合物、其立体异构形式及其药学上可接受的酸或碱加成盐和溶剂合物或本发明的药物组合物用于制备药物的用途。
本发明还涉及通式(I)化合物、其立体异构形式及其药学上可接受的酸或碱加成盐和溶剂合物或本发明的药物组合物,其用于治疗或预防、特别用于治疗哺乳动物(包括人)的病况,所述病况的治疗或预防受mGluR2的变构调节剂、特别是其正变构调节剂的神经调节作用影响或促进。
本发明还涉及通式(I)化合物、其立体异构形式及其药学上可接受的酸或碱加成盐和溶剂合物或本发明的药物组合物用于制备用于治疗或预防、特别用于治疗哺乳动物(包括人)的病况的药物中的用途,所述病况的治疗或预防受mGluR2的变构调节剂、特别是其正变构调节剂的神经调节作用影响或促进。
本发明还涉及通式(I)化合物、其立体异构形式及其药学上可接受的酸或碱加成盐和溶剂合物或本发明的药物组合物,其用于治疗、预防、改善、控制或降低哺乳动物(包括人)的与谷氨酸功能障碍有关的各种神经和精神障碍的风险,所述神经和精神障碍的治疗或预防受mGluR2的正变构调节剂的神经调节作用影响或促进。
此外,本发明涉及通式(I)化合物、其立体异构形式及其药学上可接受的酸或碱加成盐和溶剂合物或本发明的药物组合物用于制备用于治疗、预防、改善、控制哺乳动物(包括人)的与谷氨酸功能障碍有关的各种神经和精神障碍或降低其风险的药物中的用途,所述神经和精神障碍的治疗或预防受mGluR2的正变构调节剂的神经调节作用影响或促进。
具体地讲,与谷氨酸功能障碍有关的神经和精神障碍包括一种或多种下列病况或疾病:急性神经和精神障碍例如心脏旁路手术和移植后的脑缺陷(cerebral
deficit)、中风、脑缺血、脊髓创伤、头部创伤、围产期缺氧、心脏停搏、低血糖性神经元损伤、痴呆(包括AIDS诱发性痴呆)、阿尔茨海默病(Alzheimer’s
disease)、亨廷顿舞蹈病(Huntington’s Chorea)、肌萎缩性侧索硬化、眼损伤、视网膜病、认知障碍、特发性和药物诱发性帕金森病、肌肉痉挛和肌痉挛状态相关病症包括震颤、癫痫、惊厥、偏头痛(包括偏头痛性头痛(migraine headachee))、尿失禁、物质依赖/滥用、物质戒断(包括例如阿片制剂、尼古丁、烟制品、酒精、苯并二氮杂䓬类、可卡因、镇静药、安眠药等物质)、精神病、精神分裂症、焦虑(包括泛化性焦虑症、惊恐障碍和强迫性神经失调)、心境障碍(包括抑郁症、严重的抑郁性障碍、难治性抑郁症、躁狂症、双相性精神障碍例如双相躁狂症)、创伤后应激障碍、三叉神经痛、听力损失、耳鸣、眼黄斑变性、呕吐、脑水肿、疼痛(包括急性和慢性状态、重度痛、顽固性疼痛、神经性疼痛和创伤后疼痛)、迟发性运动障碍、睡眠障碍(包括发作性睡病)、注意力缺陷/多动症和品行障碍。
具体地讲,所述病况或疾病是选自以下的中枢神经系统障碍:焦虑障碍、精神障碍、人格障碍、物质相关障碍、进食障碍、心境障碍、偏头痛、癫痫或惊厥性疾患、儿童期障碍(childhood
disorder)、认知障碍、神经变性、神经毒性和缺血。
优选中枢神经系统障碍为选自以下的焦虑障碍:广场恐怖、泛化性焦虑症(GAD)、混合性焦虑和抑郁、强迫性神经失调(OCD)、惊恐障碍、创伤后应激障碍(PTSD)、社交恐怖症和其它恐怖症。
优选中枢神经系统障碍为选自以下的精神障碍:精神分裂症、妄想性障碍、情感分裂性精神障碍、精神分裂症样精神障碍和物质诱发性精神障碍。
优选中枢神经系统障碍为选自以下的人格障碍:强迫型人格障碍和精神分裂样分裂型障碍(schizoid,schizotypal disorder)。
优选中枢神经系统障碍为选自以下的物质滥用或物质相关障碍:酒精滥用、酒精依赖、酒精戒断、酒精戒断性谵妄、酒精诱发性精神障碍、苯丙胺依赖、苯丙胺戒断、可卡因依赖、可卡因戒断、尼古丁依赖、尼古丁戒断、阿片样物质依赖和阿片样物质戒断。
优选中枢神经系统障碍为选自以下的进食障碍:神经性厌食症和神经性贪食症。
优选中枢神经系统障碍为选自以下的心境障碍:双相性精神障碍(I和II)、循环情感性障碍、抑郁症、情绪恶劣性障碍、严重的抑郁性障碍、难治性抑郁症、双相抑郁症和物质诱发性心境障碍。
优选中枢神经系统障碍为偏头痛。
优选中枢神经系统障碍为选自以下的癫痫或惊厥性疾患:全身性非惊厥性癫痫、全身性惊厥性癫痫、癫痫小发作持续状态(petit
mal status epilepticus)、癫痫大发作持续状态、有或无认知减退的部分性癫痫、婴儿痉挛、部分性癫痫持续状态(epilepsy
partialis continua)和其它癫痫形式。
优选中枢神经系统障碍为注意力缺陷/多动症。
优选中枢神经障碍选自精神分裂症、痴呆的行为和精神症状、严重的抑郁性障碍、难治性抑郁症、双相抑郁症、焦虑、抑郁症、泛化性焦虑症、创伤后应激障碍、双相躁狂症、癫痫、注意力缺陷/多动症、物质滥用及混合性焦虑和抑郁。
优选中枢神经系统障碍为选自以下的认知障碍:谵妄、物质诱发性持续性谵妄、痴呆、HIV病所致痴呆、亨廷顿舞蹈病所致痴呆、帕金森病所致痴呆、阿尔茨海默病型痴呆、痴呆的行为和精神症状、物质诱发性持续性痴呆和轻度认知减退。
上述提及的病症中,精神病、精神分裂症、痴呆的行为和精神症状、严重的抑郁性障碍、难治性抑郁症、双相抑郁症、焦虑、抑郁症、泛化性焦虑症、创伤后应激障碍、双相躁狂症、物质滥用及混合性焦虑和抑郁的治疗特别重要。
上述提及的病症中,焦虑、精神分裂症、偏头痛、抑郁症和癫痫的治疗特别重要。
目前,美国精神病学会(American Psychiatric Association)的Diagnostic & Statistical Manual of Mental Disorders
(DSM-IV)第4版提供用于鉴定本文所述病症的诊断工具。本领域技术人员应认识到,存在本文所述神经和精神障碍的替代命名法、疾病分类学和分类系统,且这些随医学和科学发展而演变。
因此,本发明还涉及用于治疗上述任一种疾病的通式(I)化合物、其立体异构形式及其药学上可接受的酸或碱加成盐和溶剂合物。
本发明还涉及用于治疗上述任一种疾病的通式(I)化合物、其立体异构形式及其药学上可接受的酸或碱加成盐和溶剂合物。
本发明还涉及用于治疗或预防、特别是治疗上述任一种疾病的通式(I)化合物、其立体异构形式及其药学上可接受的酸或碱加成盐和溶剂合物。
本发明还涉及通式(I)化合物、其立体异构形式及其药学上可接受的酸或碱加成盐和溶剂合物用于制备用于治疗或预防上述任一种疾病状况的药物中的用途。
本发明还涉及通式(I)化合物、其立体异构形式及其药学上可接受的酸或碱加成盐和溶剂合物用于制备用于治疗上述任一种疾病状况的药物中的用途。
可将本发明的化合物给予哺乳动物优选人,用于治疗或预防上述任一种疾病。
鉴于式(I)化合物的用途,提供治疗患有上述任一种疾病的温血动物(包括人)的方法和预防温血动物(包括人)的上述任一种疾病的方法。所述方法包括将治疗有效量的式(I)化合物、其立体异构形式及其药学上可接受的加成盐或溶剂合物给予即全身或局部给予、优选口服给予温血动物(包括人)。
因此,本发明还涉及预防和/或治疗上述任一种疾病的方法,所述方法包括将治疗有效量的本发明的化合物给予有需要的患者。
本领域的技术人员应认识到,治疗有效量的本发明的PAM是足以调节mGluR2的活性的量且该量尤其随疾病的类型、治疗制剂中化合物的浓度和患者的状况而变化。总的来讲,待作为用于治疗其中调节mGluR2是有益的疾病(例如本文所述病症)的治疗剂给予的PAM的量,可由主治医师根据每个病例来确定。
总的来讲,合适的剂量是导致在治疗部位PAM浓度的范围为0.5
nM-200 μM、更通常5
nM-50 μM的剂量。为了获得这些治疗浓度,将给予可能需要治疗的患者约0.01
mg/kg-约50 mg/kg体重、优选约0.01
mg/kg-约25 mg/kg体重、更优选约0.01
mg/kg-约10 mg/kg体重、更优选约0.01
mg/kg-约2.5 mg/kg体重、甚至更优选约0.05
mg/kg-约1 mg/kg体重、更优选约0.1-约0.5 mg/kg体重的每日有效治疗量。获得治疗作用所需要的本发明化合物(本文亦称为活性成分)的量,当然将以每个病例为基础而变化,随具体化合物、给药途径、接受者的年龄和状况及正被治疗的具体病症或疾病而变化。治疗方法还可包括按每天摄取1-4次的方案给予活性成分。在这些治疗方法中,优选在给予前,配制本发明的化合物。如下文所述,合适的药物制剂使用众所周知的和容易获得的成分,通过已知方法制备。
由于mGluR2的这类正变构调节剂(包括式(I)化合物)提高mGluR2对谷氨酸的反应,因此本发明方法利用内源谷氨酸是有利的。
由于mGluR2的正变构调节剂(包括式(I)化合物)提高mGluR2对激动剂的反应,因此要了解,本发明延伸至通过给予有效量的与mGluR2激动剂组合的mGluR2的正变构调节剂(包括式(I)化合物)治疗与谷氨酸功能障碍有关的神经和精神障碍。mGluR2激动剂的实例包括例如LY-379268、DCG-IV、LY-354740、LY-404039、LY-544344、LY-2140023、LY-181837、LY-389795、LY-446433、LY-450477、他谷美特、MGS0028、MGS0039、(-)-2-氧杂-4-氨基二环[3.1.0]己烷-4,6-二甲酸酯、(+)-4-氨基-2-磺酰基二环[3.1.0]己烷-4,6-二甲酸、(+)-2-氨基-4-氟二环-[3.1.0]己烷-2,6-二甲酸、1S,2R,5S,6S-2-氨基-6-氟-4-氧代二环-[3.1.0]己烷-2,6-二甲酸、1S,2R,4S,5S,6S-2-氨基-6-氟-4-羟基-二环[3.1.0]己烷-2,6-二甲酸、1S,2R,3R,5S,6S-2-氨基-3-氟-二环[3.1.0]己烷-2,6-二甲酸、1S,2R,3S,5S,6S-2-氨基-6-氟-3-羟基二环[3.1.0]己烷-2,6-二甲酸、(+)-4-氨基-2-磺酰基-二环[3.1.0]己烷-4,6-二甲酸、(+)-2-氨基-4-氟二环[3.1.0]己烷-2,6-二甲酸、1S,2R,5S,6S-2-氨基-6-氟-4-氧代二环[3.1.0]己烷-2,6-二甲酸、1S,2R,4S,5S,6S-2-氨基-6-氟-4-羟基二环-[3.1.0]己烷-2,6-二甲酸、1S,2R,3R,5S,6S-2-氨基-3-氟二环-[3.1.0]己烷-2,6-二甲酸、或1S,2R,3S,5S,6S-2-氨基-6-氟-3-羟基-二环[3.1.0]己烷-2,6-二甲酸。更优选的mGluR2激动剂包括LY-379268、DCG-IV、LY-354740、LY-404039、LY-544344或LY-2140023。
本发明的化合物可与一种或多种其它药物组合用于治疗、预防、控制、改善或降低式(I)化合物或其它药物可对其具有效用的疾病或病况的风险,其中药物组合在一起比单独的任一种药物更安全或更有效。
药物组合物
本发明还提供用于预防或治疗其中调节mGluR2受体是有益的疾病(例如本文所述病症)的组合物。虽然可能单独给予活性成分,但优选将其作为药物组合物来提供。因此,本发明还涉及包含药学上可接受的载体或稀释剂和作为活性成分的治疗有效量的本发明化合物、特别是式(I)化合物、其药学上可接受的盐、其溶剂合物或其立体化学异构形式的药物组合物。从与组合物的其它成分是相容的且对其接受者无害的意义上来讲,载体或稀释剂必须是“可接受的”。
可将本发明的化合物、特别是式(I)化合物、其药学上可接受的盐、其溶剂合物和立体化学异构形式或其任何亚类或组合配制成用于给药目的的各种药物形式。作为合适的组合物,可引用常常用于全身给予药物的所有组合物。
本发明的药物组合物可通过药学领域众所周知的任何方法制备,例如采用例如描述于以下文献的方法:Gennaro等,Remington’s Pharmaceutical
Sciences (第18版,Mack
Publishing Company,1990,尤其参见第8部分:Pharmaceutical
preparations and their Manufacture)。为了制备本发明的药物组合物,将治疗有效量的作为活性成分的特定化合物(任选呈盐形式)与药学上可接受的载体或稀释剂混合成均匀混合物,所述载体或稀释剂可根据给药所需的制剂形式而呈各种形式。这些药物组合物适宜呈单位剂型,所述单位剂型尤其适于口服、局部、直肠或经皮给予、通过胃肠外注射或通过吸入给予。例如,在制备呈口服剂型的组合物时,可采用任何常用的药用介质,其在口服液体制剂(例如混悬剂、糖浆剂、酏剂、乳剂和溶液剂)的情况下例如为水、二醇、油、醇等;或在散剂、丸剂、胶囊剂和片剂的情况下为固体载体,例如淀粉、糖、高岭土、稀释剂、润滑剂、粘合剂、崩解剂等。由于易于给药,优选口服给药,且片剂和胶囊剂代表了最有利的口服单位剂型,在此情况下,显然采用固体药用载体。对于胃肠外组合物,载体常常可包括至少大部分的无菌水,但可包括有助于溶解性的其它成分,例如表面活性剂。例如,可以制备其中载体包含盐水溶液、葡萄糖溶液或盐水与葡萄糖溶液的混合物的注射用溶液剂。还可制备注射用混悬剂,在此情况下,可采用合适的液体载体、助悬剂等。还包括预定在临用前不久转化成液体形式制剂的固体形式制剂。在适于经皮给予的组合物中,载体任选包含任选与少量的任何性质的合适添加剂混合的渗透促进剂和/或合适的润湿剂,所述添加剂不会对皮肤造成显著有害作用。所述添加剂可有利于给予皮肤和/或可有助于制备所需组合物。这些组合物可以不同方式给予,例如作为透皮贴剂、作为点施制剂(spot-on)、作为软膏剂。
尤其有利的是以单位剂型配制前述药物组合物以易于给药和剂量均匀性。本文所用单位剂型是指适于作为单位剂量的物理离散单位,每个单位含有经计算产生所需治疗作用的预定量的活性成分以及所需药用载体。这类单位剂型的实例为片剂(包括划痕片剂或包衣片剂)、胶囊剂、丸剂、袋装散剂(powder packet)、糯米纸囊剂、栓剂、注射用溶液剂或混悬剂等、一茶匙量制剂(teaspoonful)、一大汤匙量制剂(tablespoonful)及其分隔的多剂量制剂(segregated
multiple)。
因为本发明的化合物是可口服给予的化合物,用于口服给药的包含辅助化合物的药物组合物尤其有利。
为了提高药物组合物中式(I)化合物的溶解性和/或稳定性,可能有利的是使用α-环糊精、β-环糊精或γ-环糊精或其衍生物,特别是羟基烷基取代的环糊精,例如2-羟基丙基-β-环糊精或磺基丁基-β-环糊精。此外助溶剂(例如醇)可提高药物组合物中本发明化合物的溶解性和/或稳定性。
给药的确切剂量和频率取决于本领域技术人员所熟知的所用的具体式(I)化合物、待治疗的具体病况、待治疗病况的严重程度、具体患者的年龄、体重、性别、病症程度和整体身体状况以及个体可服用的其它药物。此外,显然可降低或提高所述有效的日用量,这取决于受治疗受试者的反应和/或取决于处方开予本发明化合物的医师的评价。
根据给药方式,药物组合物可包含0.05-99%重量、优选0.1-70%重量、更优选0.1-50%重量的活性成分和1-99.95%重量、优选30-99.9%重量、更优选50-99.9%重量的药学上可接受的载体,所有百分比均以组合物的总重量计。
可与载体材料组合以产生单一剂型的式(I)化合物的量将随待治疗的疾病、哺乳动物物种和具体的给药方式而变化。然而,一般来说,用于本发明化合物的合适单位剂量可优选含有例如介于0.1
mg与约1000 mg之间的活性化合物。优选的单位剂量介于1 mg-约500 mg之间。更优选的单位剂量介于1 mg-约300 mg之间。甚至更优选的单位剂量介于1 mg-约100 mg之间。这种单位剂量可一天给予不止一次,例如一天2、3、4、5或6次,但优选每天1或2次,使得70 kg成人的总剂量为每次给药0.001-约15 mg/kg受试者体重的范围。优选剂量为每次给药0.01-约1.5 mg/kg受试者体重,并且这种治疗可延长数周或数月,在某些情况下甚至数年。然而应了解,任何具体患者的特定剂量水平将取决于各种因素,包括本领域技术人员十分了解的所用具体化合物的活性;待治疗个体的年龄、体重、一般健康状况、性别和饮食;给药时间和途径;排泄率;之前曾给予的其它药物;和接受治疗的特定疾病的严重程度。
典型剂量可为一天一次或每天多次服用的一片1 mg-约100
mg片剂或1 mg-约300
mg,或者一天一次服用并且含有适当较高的活性成分含量的一粒定时释放胶囊剂或片剂。定时释放作用可通过溶于不同pH值的胶囊材料、通过经渗透压慢慢释放的胶囊或通过任何其它已知的控释方法而获得。
对本领域技术人员显而易见的是,在某些情况下,可能必需使用这些范围以外的剂量。此外,要注意,临床医师或治疗医师应知道结合各个患者反应,如何以及何时开始、中断、调整或终止治疗。
已经注意到,本发明还涉及包含本发明的化合物和一种或多种其它药物的药物组合物,其用作药物或用于治疗、预防、控制、改善或降低式(I)化合物或其它药物可对其具有效用的疾病或病况的风险。还考虑了这类组合物用于制备药物的用途以及这类组合物用于制备用于治疗、预防、控制、改善或降低式(I)化合物或其它药物可对其具有效用的疾病或病况的风险的药物中的用途。本发明还涉及本发明的化合物和mGluR2正构激动剂的组合。本发明还涉及用作药物的这类组合。本发明还涉及包含作为组合制剂用于同时、单独或序贯用于治疗或预防哺乳动物(包括人)的(a)本发明的化合物或其药学上可接受的盐或其溶剂合物,和(b) mGluR2正构激动剂的产品的病况,所述病况的治疗或预防受mGluR2变构调节剂、特别是mGluR2正变构调节剂的神经调节作用影响或促进。这类组合或产品的不同药物可与药学上可接受的载体或稀释剂一起混合在单一制剂中,或者它们可各自与药学上可接受的载体或稀释剂一起存在于分开的制剂中。
以下实施例旨在说明但不限制本发明的范围。
化学法
在以下的实施例中举例说明了用于制备本发明化合物的若干方法。除非另有说明,否则所有起始原料均获自供应商且无需进一步纯化便使用。
在下文中,“CI”意指化学电离;“DAD”意指二极管阵列检测器;“THF”意指四氢呋喃;“DIPE”意指二异丙醚;“DMF”意指N,N-二甲基甲酰胺;“EtOAc”意指乙酸乙酯;“DCM”或“CH2Cl2”意指二氯甲烷;“DCE”意指二氯乙烷;“DIPEA”意指N,N-二异丙基乙胺;“l”或“L”意指升;“LRMS”意指低分辨率质谱分析法/质谱;“HPLC”意指高效液相层析法;“HRMS”意指高分辨率质谱/质谱分析法;“NH4Ac”意指乙酸铵;“NH4OH”意指氢氧化铵;“NaHCO3”意指碳酸氢钠;“Et2O”意指乙醚;“MgSO4”意指硫酸镁;“EtOH”意指乙醇;“ES”意指电喷雾;“Na2SO4”意指硫酸钠;“CH3CN”意指乙腈;“NaH”意指氢化钠;“MeOH”意指甲醇;“NH3”意指氨;“Na2S2O3”意指硫代硫酸钠;“AcOH”意指乙酸;“Et3N”或“TEA”意指三乙胺;“NH4Cl”意指氯化铵;“K2CO3”意指碳酸钾;“iPrOH”指异丙醇;“Pd(PPh3)4”意指四(三苯基膦)钯(0);“eq”意指当量;“RP”意指反相;“室温”意指室温;“mp”意指熔点;“min”意指分钟;“h”意指小时;“s”意指秒钟;“TOF”指飞行时间;“sat.”意指饱和;“SFC”指超临界液相层析。
在下文,“CI”指化学电离;“DAD”指二极管阵列检测器;“THF”指四氢呋喃;“DIPE”指二异丙醚;“DMF”指N,N-二甲基甲酰胺;“EtOAc”指乙酸乙酯;“DCM”或“CH2Cl2”指二氯甲烷;“DCE”指二氯乙烷;“DIPEA”指N,N-二异丙基乙胺;“l”或“L”指升;“LRMS”指低分辨率质谱测定/质谱;“HPLC”指高效液相层析;“HRMS”指高分辨率质谱/质谱测定;“NH4Ac”指乙酸铵;“NH4OH”指氢氧化铵;“NaHCO3”指碳酸氢钠;“Et2O”指乙醚;“MgSO4”指硫酸镁;“EtOH”指乙醇;“ES”指电喷射;“Na2SO4”指硫酸钠;“CH3CN”指乙腈;“NaH”指氢化钠;“MeOH”指甲醇;“NH3”指氨;“Na2S2O3”指硫代硫酸钠;“AcOH”指乙酸;“Et3N”或“TEA”指三乙胺;“NH4Cl”指氯化铵;“K2CO3”指碳酸钾;“iPrOH”指异丙醇;“Pd(PPh3)4”指四(三苯基膦)钯(0);“eq”指当量;“RP”指反相;“r.t.”指室温;“mp”指熔点;“min”指分钟;“h”指小时;“s”指秒;“TOF”指飞行时间;“sat.”指饱和的;“SFC”指超临界液相层析。
微波辅助反应在单模反应器InitiatorTM Sixty EXP微波反应器(Biotage AB)或多模反应器MicroSYNTH
Labstation (Milestone,Inc.)中进行。
薄层层析法(TLC)使用试剂级溶剂在硅胶60 F254板(Merck)上进行。开柱层析法采用标准技术在粒径60 Å,筛目= 230-400的硅胶(Merck)上进行。使用得自Merck的即连接即用型柱体,在得自Armen Instrument的SPOT或LAFLASH系统中的不规则硅胶,粒径15-40 µm (正相一次性快速柱)中进行自动快速柱层析法。
中间体
1 (I-1)
2,4-二氯-3-碘-吡啶(I-1)
在氮气氛下,向于-78℃冷却的2,4-二氯吡啶(5.2 g,35.14 mmol)和二异丙胺(3.91 g,38.65 mmol)的无水THF (40 mL)溶液中滴加正丁基锂(24.16
mL,38.65 mmol,1.6 M的己烷溶液)。在-78℃下搅拌所得反应混合物45分钟。然后滴加碘(9.81 g,38.651 mmol)的无水THF
(20 mL)溶液。在-78℃下搅拌混合物1小时,使之加温至室温,用EtOAc稀释后,用NH4Cl
(饱和水溶液)和Na2S2O3
(饱和水溶液)猝灭。有机层经分离,用NaHCO3
(饱和水溶液)洗涤,干燥(Na2SO4)后真空浓缩。粗产物用柱层析法纯化(硅胶;DCM/庚烷0/100-20/80)。收集所需流分后真空浓缩,得到中间体化合物I-1 (7.8
g,81%)。
中间体
2 (I-2)
2,4-二氯-3-三氟甲基-吡啶(I-2)
向化合物I-1 (2g,7.30 mmol)与DMF
(50 mL)的混合物中加入氟磺酰基-二氟-乙酸甲酯[C.A.S. 680-15-9] (1.86 ml,14.60
mmol)和碘化铜(I) (2.79 g,14.60 mmol)。将反应混合物在密封管中于100℃加热5小时。冷却后,将溶剂真空蒸发。粗产物用柱层析法纯化(硅胶,DCM)。收集所需流分后真空浓缩,得到中间体化合物I-2 (1.5
g,95%)。
中间体
3 (I-3)
4-苄氧基-2-氯-3-三氟甲基-吡啶(I-3)
向于0℃冷却的NaH
(0.49 g,12.73 mmol,60%矿物油)在DMF (50 mL)的悬浮液中加入苯甲醇(1.26 mL,12.2
mmol)。将所得混合物搅拌2分钟。然后,加入中间体化合物I-2 (2.5
g,11.57 mmol)。使所得反应混合物逐步加热至室温并搅拌1小时。反应混合物用水猝灭后,用乙醚萃取。有机层经分离,干燥(Na2SO4)后真空浓缩。粗产物用柱层析法纯化(硅胶;DCM/庚烷0/100-100/0)。收集所需流分后真空浓缩,得到中间体化合物I-3 (1.1
g,33%)。
中间体
4 (I-4)
4-(苄氧基)-2-肼基-3-(三氟甲基)吡啶(I-4)
向化合物I-3 (1.09 g,3.79 mmol)在1,4-二噁烷(9 mL)的悬浮液中加入肼一水合物(3.67 mL,75.78 mmol)。将反应混合物在微波辐射下于160℃加热30分钟。冷却后,将所得溶液真空浓缩。将由此获得的残余物溶于DCM,用NaHCO3 (饱和水溶液)洗涤。有机层经分离,干燥(Na2SO4)后真空浓缩,得到中间体化合物I-4 (0.89 g,83%),为白色固体。
中间体
5 (I-5)
N'-[4-(苄氧基)-3-(三氟甲基)吡啶-2-基]-2-环丙基乙酰肼(I-5)
向I-4 (0.89 g,3.14 mmol)的无水DCM
(3 mL)溶液中加入三乙胺(0.65 mL,4.71
mmol)和环丙基-乙酰氯[C.A.S.
543222-65-5] (0.37 g,3.14 mmol)。在0℃下搅拌所得反应混合物20分钟。然后将所得混合物真空浓缩,得到中间体化合物I-5 (1.1 g,96%)。
中间体
6 (I-6)
乙酸N'-(4-苄氧基-3-三氟甲基-吡啶-2-基)-酰肼(I-6)
按照关于中间体I-5描述的相同方法合成中间体I-6。从I-4 (2 g, 7.06 mmol)开始并用乙酰氯代替环丙基氯。获得呈浅黄色固体的中间体I-6 (1.8 g, 78%)。
中间体
7 (I-7)
7-氯代-3-环丙基甲基-8-三氟甲基[1,2,4]三唑并[4,3-a]吡啶(I-6)
将I-5 (1.14 g, 1.87
mmol)和氯氧化磷(V) (0.35 g, 3.74 mmol)在CH3CN (10 mL)中在微波照射下150℃加热10分钟。冷却后,将所得反应混合物用DCM稀释,用NaHCO3 (饱和水溶液)洗涤,干燥(Na2SO4)和真空浓缩。通过柱层析(硅胶; 7M NH3在MeOH中的溶液/DCM 0/100至20/80)纯化粗产物。将所需流分收集和真空浓缩以得到中间体化合物I-7
(0.261 g, 51%),为白色固体。
中间体
8 (I-8)
7-氯-3-甲基-8-三氟甲基-[1,2,4]三唑并[4,3-a]吡啶(I-8)
按照关于中间体I-7描述的相同方法合成中间体I-8。从I-6 (1.8 g, 5.5 mmol)开始,获得呈浅褐色固体的中间体I-8 (0.75 g, 57.3%)。
中间体
9 (I-9)
7-乙烯基-3-环丙基甲基-8-三氟甲基[1,2,4]三唑并[4,3-a]吡啶(I-9)
将I-7 (1.65 g, 5.986
mmol)、硼酸频哪醇乙烯酯(1.218 ml, 7.183 mmol)、Pd(PPh3)4 (0.346, 0.3 mmol)和NaHCO3 (饱和水溶液,
12.5 ml)在1,4-二氧六环(64.5
ml)中的悬浮液在微波照射下150℃加热13分钟。冷却后,将所得反应混合物用EtOAc/水稀释,用硅藻土垫过滤。将滤液用水和NaCl
(饱和水溶液)洗涤,用EtOAc萃取。将有机层分离,干燥(Na2SO4)和真空浓缩。通过柱层析(二氧化硅; EtOAc在DCM中0/100至40/60)再纯化残留物。将所需流分收集和真空浓缩以得到中间体I-9
(1.34 g, 83.7%)。
中间体
10 (I-10)
3-甲基-8-三氟甲基-7-乙烯基-[1,2,4]三唑并[4,3-a]吡啶(I-10)
按照关于中间体I-9描述的相同方法合成中间体I-10。从I-8 (0.74 g, 3.14 mmol)开始,合成中间体I-10。中间体I-10作为粗化合物用于下一步。
中间体
11 (I-11)
7-甲醛-3-环丙基甲基-8-三氟甲基[1,2,4]三唑并[4,3-a]吡啶(I-11)
将I-8 (6.24 g, 21.014
mmol)、高碘酸钠(13.484 g, 63.041 mmol)、四氧化锇(2.5%在叔丁醇中, 10.873 ml,
0.841 mmol)在水(55 ml)和1,4-二氧六环(221 ml)中的溶液在室温搅拌2小时。将所得反应混合物用EtOAc/水稀释,用硅藻土垫过滤。用EtOAc萃取滤液。将有机层分离,干燥(Na2SO4)和真空浓缩。将固体残留物用Et2O洗涤,过滤和真空干燥以得到中间体I-11
(3.84 g, 67.9%)。
中间体
12 (I-12)
3-甲基-8-三氟甲基-[1,2,4]三唑并[4,3-a]吡啶-7-甲醛(I-12)
按照关于中间体I-11描述的相同方法合成中间体I-12。从I-10 (1 g, 4.4 mmol)开始,获得呈黄色固体的中间体I-12 (0.18 g, 17.8%)。
中间体
13 (I-13)
7-羟甲基-3-环丙基甲基-8-三氟甲基[1,2,4]三唑并[4,3-a]吡啶(I-13)
向I-11 (1.73 g, 6.426
mmol)在MeOH (58 ml)中在0℃搅拌的溶液内,分批加入硼氢化钠(0.243,
6.426 mmol)。将所得混合物在室温搅拌1小时。真空浓缩所得混合物。将残留物用水和NaCl
(饱和水溶液)处理,用EtOAc萃取。将有机层分离和真空浓缩。通过柱层析(二氧化硅;
MeOH/NH3在DCM中0/100至5/95)纯化残留物。将所需流分收集和真空浓缩以得到中间体I-13 (1.015 g, 58%),为褐色浆状。
中间体
14 (I-14)
7-(甲基磺酰基氧基)甲基-3-环丙基甲基-8-三氟甲基[1,2,4]三唑并[4,3-a]吡啶(I-14)
向I-13 (1.341 g, 9.678
mmol)和Et3N (0.778 ml, 5.612 mmol)在DCM (42 ml)中在0℃搅拌的溶液内,滴加甲磺酰氯(0.749 ml, 9.678 mmol)并在室温搅拌2小时。将所得混合物用NaHCO3 (饱和水溶液)处理,用DCM萃取。将有机层分离和真空浓缩以得到中间体I-14 (2.6
g, 87%)。
中间体
15 (I-15a
和
I-15b)
(*S)-3-甲基-3-苯基-哌啶(I-15a)和(*R)-3-甲基-3-苯基-哌啶(I-15b)
在CHIRALPAK® ICTM (5µm 250×20mm)上通过手性超临界液相层析纯化(±)-3-甲基-3-苯基哌啶[(C.A.S. 19735-13-8), 1.29 g, 7.36 mmol]。流动相(0.3%异丙胺, 80% CO2,
20% EtOH),得到I-15a (0.514 g,
39.4%)和I-15b (0.518, 40.1%)。
中间体
15
4-(2,4-二氟-苯基)-3-氧代-哌嗪-1-甲酸叔丁酯
将3-氧代-1-哌嗪甲酸1,1-二甲基乙酯(3 g, 14.982
mmol; C.A.S. 76003-29-7)、2,4-二氟-碘苯(3.269 g, 13.62
mmol; C.A.S. 2265-93-2)、乙二胺(0.12 g, 1.362
mmol; C.A.S. 110-70-3)、碘化铜(I) (0.13 g,
0.681 mmol)和K3PO4 (0.13 g,
0.681 mmol)在1,4-二氧六环(10
ml)中的悬浮液在密封管中100℃加热2天。冷却后,将所得反应混合物用NaHCO3 (饱和水溶液)稀释和用EtOAc萃取。用NH4OH
(饱和水溶液)洗涤滤液。将有机层分离,干燥(Na2SO4)和真空浓缩。通过柱层析(二氧化硅; MeOH在DCM中0/100至2/98)纯化残留物。将所需流分收集和真空浓缩以得到中间体15 (2.2
g, 51.8%)。
中间体
16
4-(2,4-二氟-苯基)-3,4-二氢-2H-吡嗪-1-甲酸叔丁酯
在氮气氛下向15 (1.8 g, 5.763
mmol)在CH2Cl2 (36 ml)中在-78℃搅拌的溶液内,滴加二异丁基氢化铝(8.645
ml, 8.645 mmol;1.0 M在己烷中的溶液)。将所得混合物在-78℃搅拌3小时,然后让其加温至室温并搅拌18小时。使混合物冷却至0℃,用(2R,3R)-酒石酸钾钠四水合物(Rochelle盐)猝灭,搅拌10分钟,用硅藻土垫过滤。用CH2Cl2萃取滤液。将有机层分离,干燥(Na2SO4)和真空浓缩以得到中间体15 (1.65 g, 67.6%)。
中间体
17
5-(2,4-二氟-苯基)-2,5-二氮杂-双环[4.1.0]庚烷-2-甲酸叔丁酯
在氮气氛下向17 (1.5 g, 5.062
mmol)在Et2O (15 ml)中在室温搅拌的溶液内,滴加在Et2O (15 ml)中的二乙基锌(21.261 ml, 21.261 mmol),搅拌10分钟。然后加入亚甲基碘(1.509 ml, 18.73 mmol)并在室温搅拌18小时。将所得混合物冷却至0℃,用NH4Cl
(饱和水溶液)猝灭,用硅藻土垫过滤。用Et2O和NH4Cl (饱和水溶液)萃取滤液。将有机层分离,干燥(Na2SO4)和真空浓缩。通过柱层析(二氧化硅; 庚烷在DCM中50/50至35/65)纯化残留物。将所需流分收集和真空浓缩以得到中间体17
(0.389 g, 24.7%)。
中间体
18
2-(2,4-二氟-苯基)-2,5-二氮杂-双环[4.1.0]庚烷盐酸盐
向中间体17 (0.389 g, 1.253
mmol)在Et2O (10 ml)中在室温搅拌的溶液内加入HCl (6 ml; 4M在1,4-二氧六环中)。将所得混合物在室温搅拌7小时。然后真空蒸发混合物。将粗固体残留物用E2O洗涤以得到呈浅褐色固体的中间体化合物18 (0.3 g, 97 %)。
中间体
19
2-(2,4-二氟苯基)环氧乙烷
将硼氢化钠(0.367 g, 10.85 mmol)加至2-溴-2′,4′-二氟苯乙酮([CAS 102429-07-2], 5.1 g, 21.7 mmol)在MeOH (152 mL)中在10℃搅拌的溶液内。将混合物在室温搅拌1小时。然后加入K2CO3
(4.499 g, 32.55 mmol),将混合物在室温搅拌1小时。用硅藻土过滤混合物,真空浓缩滤液。将残留物用水处理,用CH2Cl2/THF萃取。将有机层分离,干燥(Na2SO4),过滤和真空蒸发溶剂以得到呈黄色油状物的I-19 (2.24 g, 66%)。
中间体
20
1-(2,4-二氟苯基)-2-[(2-羟乙基)氨基]乙醇
将I-19 (2.15 g, 13.77
mmol)和乙醇胺(5.33 mL)的溶液在室温搅拌过夜。将混合物用水/盐水稀释,用CH2Cl2萃取。将有机层分离,干燥(Na2SO4),过滤和真空蒸发。通过快速柱层析(二氧化硅; 7 M
NH3/MeOH溶液在EtOAc中0/100至10/90)纯化残留物。将所需流分收集和真空浓缩以得到呈无色油状物的I-20 (1.68 g, 48%)。
中间体
21
[2-(2,4-二氟苯基)-2-羟乙基](2-羟乙基)氨基甲酸叔丁酯
在室温将Et3N (1.608 mL, 11.60 mmol)滴加至I-20 (1.68 g, 7.73 mmol)和二碳酸二叔丁酯(1.853 g, 8.49 mmol)在CH2Cl2中的搅拌的溶液内。将混合物在室温搅拌16小时。然后,将混合物用水/盐水处理,用CH2Cl2萃取。将有机层分离,干燥(Na2SO4),过滤和真空蒸发溶剂。通过快速柱层析(二氧化硅; 7M
NH3/MeOH溶液在CH2Cl2中0/100至4/96)纯化残留物。将所需流分收集和真空浓缩以得到呈无色油状物的I-21。
中间体
22
2-(2,4-二氟苯基)吗啉-4-甲酸叔丁酯
在0℃和在氮气下将偶氮二甲酸二异丙酯(1.023
mL, 2.36 mmol)滴加至I-21 (1.498 g, 4.72
mmol)和PPh3 (1.362 g, 5.19 mmol)在THF (60 mL)中的搅拌的溶液内。将混合物在微波照射下100℃搅拌15分钟。然后,在0℃和在氮气下连续加入更多PPh3 (1.362 g, 5.19 mmol)和偶氮二甲酸二异丙酯(1.023 mL, 2.36 mmol),将混合物在微波照射下在100℃再搅拌18分钟。将混合物用5% NaOH和盐水处理,用EtOAc萃取。将有机层分离,干燥(Na2SO4),过滤和真空蒸发溶剂。将残留物用二异丙醚处理,Ph3PO沉淀。过滤混合物,真空蒸发滤液。通过快速层析(二氧化硅; CH2Cl2)纯化粗产物以得到呈无色油状物的I-22 (0.882 g, 62%)。
中间体
23
、
23a
和
23b
2-(2,4-二氟苯基)吗啉(I-23)、(2*R)-2-(2,4-二氟苯基)吗啉(I-23a)和(2*S)-2-(2,4-二氟苯基)吗啉(I-23b)
将三氟乙酸(2.8 mL)加至I-22
(0.882 g, 2.95 mmol)在CH2Cl2
(19 mL)中的溶液内,将混合物在室温搅拌2小时。将混合物蒸发至干。将残留物冷却至0℃,用1 N NaOH碱化,用CH2Cl2萃取。将有机层分离,干燥(Na2SO4),过滤和真空蒸发溶剂。使产物溶于Et2O中,用6 M HCl在2-丙醇中转化为盐酸盐。将盐过滤,然后用NaOH水溶液处理,用CH2Cl2萃取。将有机层分离,干燥(Na2SO4),过滤和真空蒸发溶剂以得到I-23 (0.421 g, 72%),为无色油状物,静置后沉淀。通过手性SFC在CHIRALPAK IC 5 µm 250×20
mm; 流动相: 0.3%异丙胺, 90%
CO2, 10% MeOH上纯化I-23,得到I-23a (136 mg, 23%)和I-23b (138 mg, 23%),为白色固体。
中间体
24
(2,4-二氟苯基)乙酸甲酯
在室温将硫酸(3.35 mL)加至2,4-二氟苯基乙酸([CAS 81228-09-3], 3.5 g, 20.33 mmol)在MeOH (70 mL)中的搅拌的溶液内。将混合物回流搅拌18小时。真空除去甲醇。将残留物用EtOAc稀释,用H2O、饱和NaHCO3水溶液和盐水连续洗涤。将有机层分离,干燥(Na2SO4),过滤,真空蒸发溶剂以得到呈浅黄色油状物的I-24 (3.34 g, 88%)。
中间体
25
溴代(2,4-二氟苯基)乙酸甲酯
在室温将N-溴代琥珀酰亚胺(3.826
g, 21.50 mmol)和2,2′-偶氮双(2-甲基丙腈) (AIBN) (14.709
mg, 0.090 mmol)加至I-24
(3.335 g, 17.91 mmol)在四氯化碳(15.6 mL)中的搅拌的溶液内。将混合物回流搅拌16小时。将混合物用CH2Cl2稀释,用H2O和盐水连续洗涤。将有机层分离,干燥(Na2SO4),过滤和真空蒸发溶剂。通过快速柱层析(二氧化硅; CH2Cl2在庚烷中0/100至100/0)纯化残留物。将所需流分收集,真空蒸发溶剂以得到呈黄色油状物的I-25 (4.116 g, 87%)。
中间体
26
3-(2,4-二氟苯基)哌嗪-2-酮
在氮气下将乙二胺(2.075 mL, 31.04 mmol)加至I-25 (4.114 g, 15.52 mmol)在MeOH (42 mL)中的搅拌的溶液内。将混合物在室温搅拌15分钟。然后,一次性加入甲醇钠(0.922 g, 17.07 mmol),将混合物回流搅拌3.5小时。真空蒸发溶剂。将残留物用H2O/盐水稀释,用CH2Cl2萃取。将水相的pH用2N HCl调节至pH 7.5,用更多CH2Cl2萃取。将合并的有机层分离,干燥(Na2SO4),过滤和真空蒸发溶剂。将粗产物与二异丙醚/Et2O研磨以得到呈浅黄色固体的I-26 (2.228 g, 68%)。
中间体
27
2-(2,4-二氟苯基)哌嗪
在室温在氮气下将硼烷四氢呋喃络合物溶液(1 M在THF中, 41.98 mL,
41.78 mmol)加至I-26 (2.227 g, 10.50
mmol)在THF (272.06 mL, 3342.84 mmol)中的搅拌的溶液内。将混合物在80℃搅拌16小时。然后,加入MeOH (2.13 mL, 52.47 mmol)和HCl
(1M在H2O中, 52.47 mL, 52.47 mmol)。将混合物在室温搅拌1小时。然后,将混合物用50% NaOH碱化并搅拌30分钟。用EtOAc萃取混合物。将有机层分离,干燥(Na2SO4),过滤和真空蒸发溶剂。将粗产物与CH2Cl2研磨以得到白色固体(保留滤液),将其用2-丙醇洗涤,将其过滤和干燥以得到白色固体。真空蒸发滤液,通过快速柱层析(二氧化硅; 7 M NH3/甲醇溶液在DCM中0/100至20/80)纯化残留物。将所需流分收集和真空浓缩。将期望的产物与2-丙醇研磨以得到白色固体。然后,将固体混合(0.8456
g),用酒石酸钾钠四水合物(1.2当量,
1.44 g)在EtOH中在85℃处理18小时。用硅藻土过滤混合物,真空蒸发滤液。将残留物用H2O处理,用CH2Cl2萃取。将有机层分离,干燥(Na2SO4),过滤和真空蒸发以得到呈白色固体的I-27 (0.757 g, 36%))。
终化合物
实施例
1 (E-1)
3-(环丙基甲基)-7-[(3-苯基-1-哌啶基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(E-1)
将中间体I-14 (0.123 g, 0.315
mmol)在乙腈(1 ml)中的溶液加至3-苯基哌啶(0.063 g, 0.394 mmol)、二异丙基乙胺(0.081
mL, 0.473 mmol)和NaI (0.004 g,
0.03 mmol)在乙腈(1 ml)中在密封管中的搅拌的溶液内。将混合物在85℃搅拌4小时,然后真空蒸发溶剂,通过快速柱层析(二氧化硅; MeOH在CH2Cl2中0/100至4/96)纯化粗产物。将所需流分收集和真空浓缩以得到期望的化合物,87%纯。然后将衍生物通过RP
HPLC (C18 XBridgeTM 19×100 5
um)纯化。流动相(梯度从80%
0.1% NH4CO3H/NH4OH pH 9在水中的溶液, 20% CH3CN至0%
0.1% NH4CO3H/NH4OH pH 9在水中的溶液, 100% CH3CN),得到呈白色固体的E-1
(0.011 g, 9%)。
实施例
2 (E-2)
3-(环丙基甲基)-7-[[(2R)-2-苯基-4-吗啉基]甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(E-2)
将三乙酰氧基硼氢化钠(0.118 g, 0.0557 mmol)加至I-11 (0.1 g, 0.371 mmol)和(R)-2-苯基吗啉[(C.A.S.
1225376-02-2), 0.072 g, 0.446 mmol]在1,2-二氯乙烷(2.5 mL)中的搅拌的溶液内。将混合物在微波照射下120℃搅拌20分钟,然后将其用饱和NaHCO3处理和用CH2Cl2萃取。将有机层分离,干燥(Na2SO4),过滤和真空蒸发溶剂。通过快速柱层析(二氧化硅;
MeOH在CH2Cl2中0/100至4/96)纯化粗产物。将所需流分收集和真空浓缩。将产物与二异丙醚研磨,将其过滤和干燥以得到呈白色固体的E-2
(0.07 g, 45.5 %)。
实施例
3 (E-3a
和
E-3b)
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R)盐酸盐水合物(.2HCl .2.5H2O) (E-3a)和3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S)盐酸盐水合物(.2.4HCl .2.7H2O)
(E-3b)
将三乙酰氧基硼氢化钠(0.413 g, 1.95 mmol)加至2-甲基-2-苯基-哌嗪[(C.A.S.
13157-36-3), 0.275 g, 1.56 mmol]和中间体I-11
(0.35 g, 1.3 mmol)在1,2-二氯乙烷(14 mL)中的搅拌的溶液内。将混合物在微波照射下120℃搅拌20分钟,然后将其用饱和NaHCO3处理并用CH2Cl2萃取。将有机层分离,干燥(Na2SO4),过滤和真空蒸发溶剂。通过柱层析(二氧化硅; 7M氨/MeOH溶液在乙酸乙酯中0/100至3/97)纯化粗产物,将所需流分收集和真空浓缩以得到E-3a和E-3b的外消旋混合物。然后将外消旋混合物通过手性SFC在CHIRALPAK® ICTM (5µm 250×20mm)上纯化,流动相(0.3%异丙胺, 60% CO2, 40% EtOH/iPrOH 50/50 v/v的混合物),得到E-3a
(0.135 g, 24.1%)和E-3b
(0.148 g, 26.5%),为纯对映体。使化合物E-3a
(0.135 g, 0.314 mmol)溶于1,4-二氧六环(7.5 mL)和MeOH (0.5 mL)中,然后加入4M HCl在二氧六环中的溶液(0.253 mL, 1.01
mmol)。将混合物蒸发,然后用乙醚处理。将所得固体过滤,用更多乙醚洗涤,然后干燥以最终得到作为盐酸盐的E-3a
(0.145 g, 81.7%)。按照关于E-3a描述的相同程序将化合物E-3b (0.148 g, 0.345 mmol)也转化为其盐酸盐,得到呈淡粉红色固体的E-3b (0.17 g, 90%)。
实施例
4 (E-4)
3-(环丙基甲基)-7-[[(2S)-2-苯基-4-吗啉基]甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(E-4)
从中间体I-11 (0.117 g, 0.44
mmol)和(S)-2-苯基吗啉(C.A.S.
74572-15-9)开始按照关于E-2描述的相同方法合成实施例E-4。获得呈霜状固体的实施例E-4 (0.033 g, 18%)。
实施例
E-5 (E-5a
和
E-5b)
3-(环丙基甲基)-7-[(3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R) (E-5a)和3-(环丙基甲基)-7-[(3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S) (E-5b)
从中间体I-11 (0.350 g, 1.3
mmol)开始并用2-苯基-哌嗪(C.A.S. 5271-26-1)代替2-甲基-2-苯基-哌嗪按照关于E-3描述的相同方法合成实施例E-5。将两种对映体(本文称为E-5的外消旋混合物)通过手性SFC分离以得到E-5a (0.107 g, 19.9%)和E-5b (0.105 g, 19.5%),两者都作为游离碱,呈霜状固体。
实施例
E-6 (E-6a
和
E-6b)
3-(环丙基甲基)-7-[[3-(2-氟苯基)-1-哌嗪基]甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R) (E-6a)和3-(环丙基甲基)-7-[[3-(2-氟苯基)-1-哌嗪基]甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S) (E-6b)
从中间体I-11 (0.4 g, 1.5
mmol)开始并用2-(2-氟苯基)哌嗪(C.A.S. 137684-18-5)代替2-甲基-2-苯基-哌嗪按照关于E-3描述的相同方法合成实施例E-6。将两种对映体通过手性SFC分离以得到E-6a (0.072
g, 11.2%)和E-6b (0.045 g,
7.11%),两者都作为游离碱,呈霜状固体。
实施例
E-7 (E-7a
和
E-7b)
3-(环丙基甲基)-7-[(4-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R) (E-7a)和3-(环丙基甲基)-7-[(4-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S) (E-7b)
从中间体I-11 (0.35 g, 1.3
mmol)开始并用1-甲基-2-苯基-哌嗪(C.A.S.
5271-28-3)代替2-甲基-2-苯基-哌嗪按照关于E-3描述的相同方法合成实施例E-7。将两种对映体(本文称为E-7的外消旋混合物)通过手性SFC分离以得到E-7a
(0.154 g, 27.5%)和E-7b
(0.155 g, 27.7%),两者都作为游离碱,呈白色固体。
实施例
E-8 (E-8a
和
E-8b)
3-(环丙基甲基)-7-[(2-甲基-2-苯基-4-吗啉基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R)盐酸盐水合物(.1.1HCl .1.1H2O) (E-8a)和3-(环丙基甲基)-7-[(2-甲基-2-苯基-4-吗啉基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S)盐酸盐水合物(.1.3HCl .1.6H2O)
(E-8b)
从中间体I-11 (0.35 g, 1.3
mmol)和2-甲基-2-苯基吗啉(C.A.S. 109461-41-8)开始按照关于E-2描述的相同方法合成实施例E-8。通过手性SFC分离从反应物(下文称为E-8的混合物)产生的两种对映体。然后如先前在实施例E-3描述将它们转化为其盐酸盐,得到E-8a (0.050 g)和E-8b (0.033 g),两者都呈白色固体。
实施例
9 (E-9)
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌啶基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(E-9)
从中间体I-11 (0.085 g, 0.316
mmol)开始并用3-甲基-3-苯基哌啶(C.A.S. 19735-13-8)代替(R)-2-苯基吗啉按照关于E-2描述的相同方法合成实施例E-9。获得呈白色固体的实施例E-9 (0.057 g, 42%)。
实施例
10 (E-10)
3-甲基-7-[(3-甲基-3-苯基-1-哌啶基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S) (E-10)
从中间体I-12 (0.090 g, 0.393
mmol)开始并用中间体I-15a代替(R)-2-苯基吗啉按照关于E-2描述的相同方法合成实施例E-10。获得呈白色固体的实施例E-10 (0.070 g, 45%)。
实施例
11 (E-11)
3-甲基-7-[(3-甲基-3-苯基-1-哌啶基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R) (E-11)
从中间体I-12 (0.090 g, 0.393
mmol)开始并用中间体I-15b代替(R)-2-苯基吗啉按照关于E-2描述的相同方法合成实施例E-11。获得呈白色固体的实施例E-11 (0.030 g, 19.6%)。
实施例
12
2-[[3-(环丙基甲基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-基]甲基]-5-(2,4-二氟苯基)-2,5-二氮杂双环[4.1.0]庚烷(顺式) (E-12)
向I-18 (0.290 mg,
1.176 mmol)在二氯乙烷(6 ml)中在室温搅拌的悬浮液内加入二异丙基乙胺(0.304
ml, 1.763 mmol)、中间体I-11
(0.380 g, 1.411 mmol)和三乙酰氧基硼氢化钠(0.747 mg, 3.527
mmol)。将混合物在室温搅拌16小时。然后将混合物用NaHCO3
(饱和水溶液)处理和用DCM萃取。将有机层分离,干燥(Na2SO4)和真空浓缩。通过柱层析(二氧化硅; EtOAc在DCM中20/80)纯化残留物。将所需流分收集和真空浓缩以得到残留物,然后将其通过RP HPLC (C18 XBridgeTM
19×100 5 um)纯化。流动相(梯度从80% 0.1% NH4CO3H/NH4OH
pH 9水中的溶液, 20% CH3CN至0% 0.1% NH4CO3H/NH4OH pH
9在水中的溶液, 100% CH3CN),得到残留物,将其与Et2O研磨以得到呈白色固体的E-12
(0.155 g, 28.45%)。
实施例
17 (E-17)
3-(环丙基甲基)-7-{[(2*R)-2-(2,4-二氟苯基)吗啉-4-基]甲基}-8-(三氟甲基)[1,2,4]三唑并[4,3-a]吡啶(E-17)
将I-14 (60 mg, 0.149
mmol)在CH3CN (1.5 mL)中的溶液,然后将DIPEA (38.63 µL, 0.224 mmol)加至I-23a (32.74 mg, 0.164 mmol)和NaI (2.24 mg, 0.0149 mmol)在CH3CN
(1 mL)中在密封管中的搅拌的混合物内。将混合物在90℃搅拌4.5小时。真空蒸发混合物。通过快速柱层析(二氧化硅; MeOH在CH2Cl2中0/100至5/95)纯化残留物。将所需流分收集和真空浓缩。将产物与二异丙醚研磨以得到呈白色固体的E-17
(35.2 mg, 52%)。
实施例
18 (E-18)
3-(环丙基甲基)-7-{[(2*S)-2-(2,4-二氟苯基)吗啉-4-基]甲基}-8-(三氟甲基)[1,2,4]三唑并[4,3-a]吡啶(E-18)
从中间体I-14 (60 mg, 0.149
mmol)和中间体I-23b (32.74 mg,
0.164 mmol)开始按照关于E-17描述的相同方法合成实施例E-18。获得呈白色固体的实施例E-18 (35.7 mg, 53%)。
实施例
19 (E-19)
、
19a
(E-19a)
和
19b (E-19b)
3-(环丙基甲基)-7-{[3-(2,4-二氟苯基)哌嗪-1-基]甲基}-8-(三氟甲基)[1,2,4]三唑并[4,3-a]吡啶(E-19)、3-(环丙基甲基)-7-{[(3*R)-3-(2,4-二氟苯基)哌嗪-1-基]甲基}-8-(三氟甲基)[1,2,4]三唑并[4,3-a]吡啶(E-19a)和3-(环丙基甲基)-7-{[(3*S)-3-(2,4-二氟苯基)哌嗪-1-基]甲基}-8-(三氟甲基)[1,2,4]三唑并[4,3-a]吡啶(E-19b)
将I-14 (0.45 g, 1.12
mmol)在CH3CN (12 mL)中的溶液,然后将DIPEA (0.29 mL, 1.68 mmol)加至I-27
(0.244 g, 1.23 mmol)和NaI (16.8 mg,
0.11 mmol)在CH3CN (2 mL)中在密封管中的搅拌的混合物内。将混合物在90℃搅拌3.5小时。真空蒸发混合物。通过快速柱层析(二氧化硅;
MeOH在CH2Cl2中0/100至6/94)纯化残留物。将所需流分收集和真空浓缩。将产物与二异丙醚/Et2O研磨以得到粉红色固体,将其通过快速柱层析(二氧化硅;
EtOAc)再纯化。将所需流分收集和真空浓缩。用二异丙醚研磨产物以得到呈白色固体的E-19
(162.3 mg, 32%)。然后将E-19通过手性SFC在CHIRALPAK AD-H 5
µm 250×20 mm; 流动相:
0.3%异丙胺, 70% CO2, 30% iPrOH上纯化,得到E-19a (59 mg, 12%)和E-19b (61 mg, 12%),在用二异丙醚研磨后呈白色固体。
下文表1列出另外的式(I)化合物。
表
1
:式
(I)
的实例化合物
除非另外指出,否则无论何时指出RS,都表示所有可能的立体异构形式的混合物,特别是外消旋混合物。当分离混合物时已将一些化合物的立体化学构型指定为R或S;对于一些化合物,当未确定绝对立体化学时已将立体化学构型指定为*R或*S,虽然已将化合物本身分离为单种立体异构体并且是对映体纯的。通过与上述实施例(实施例编号)类似的方式可制备除在实验部分举例说明以外的另外的化合物15和16及其对映体。还将化合物9分离为盐酸盐(.HCl)。
C.
分析部分
熔点
数值是峰值,其获得具有与这种分析方法通常关联的实验不确定性。对于多种化合物,在Mettler
FP62或在Mettler FP81HT-FP90装置上在开放毛细管中确定熔点。用10℃/min温度梯度测量熔点。最高温度是300℃。从数字显示器读取熔点。
旋光度
:
在具有钠灯的Perkin-Elmer 341旋光计上测量旋光度,报告如下:[α]º (λ, c g/100ml, 溶剂, T℃)。
[α]λ T =
(100α)/(l×c):其中l是长度dm,c是样品在温度T (℃)和波长λ (nm)的浓度g/100 ml。如果所用光的波长是589 nm (钠D线),则可改用符号D。应当总是给出旋转的符号(+或-)。当使用该方程式时,在旋转后的括号中总是提供浓度和溶剂。将旋转用度报告,不给出浓度的单位(假定为g/100 ml)。
LCMS
关于本发明化合物的LCMS鉴定,使用下列方法。
Waters
MS
仪器
(TOF, ZQ, SQD)
的通用程序
A
HPLC测量用HP 1100 (Agilent Technologies)系统进行,该系统包含具有除气器的泵(四元或双元)、自动采样器、柱加热器、二极管阵列检测器(DAD)和在下列各方法中指定的柱。流体从柱分散至MS分光计。MS检测器配置电喷射电离源或ESCI双重电离源(电喷射组合大气压化学电离)。用氮气作为雾化气体。源温度维持在140℃。用MassLynx-Openlynx软件进行数据采集。
方法
1
除了通用程序A以外:反相HPLC在来自Agilent的Eclipse Plus-C18柱(3.5 μm, 2.1×30 mm)上进行,流速1.0 ml/min,在60℃。使用的梯度条件是:95 % A (0.5 g/l乙酸铵溶液+5 %乙腈), 5 % B (乙腈), 保持0.2分钟, 在3.0分钟内达到100 % B,保持直至3.15分钟,在3.3分钟平衡至初始条件直至5.0分钟。注射体积2 μl。MS:用0.1秒停留时间通过用0.5秒从100扫描至750只在正电离模式获取高分辨率质谱(Time of Flight,
TOF检测器)。正电离模式的毛细管针电压是2.5
kV,锥孔电压是20 V。Leucine-Enkephaline是用于锁定质量(lock mass)校正的标准物。
方法
2
除了通用程序A以外:反相HPLC在来自Agilent的Eclipse Plus-C18柱(3.5 μm, 2.1×30 mm)上进行,流速1.0 ml/min,在60℃,不分散至MS检测器。使用的梯度条件是:95 % A (0.5 g/l乙酸铵溶液+5 %乙腈),5 % B (乙腈/甲醇混合物, 1/1),在5.0分钟达到100 % B,保持直至5.15分钟,在5.30分钟平衡至初始条件直至7.0分钟。注射体积2 μl。用0.08秒的通道间延迟通过用0.1秒从100扫描至1000获取低分辨率质谱(单四极杆, SQD检测器)。毛细管针电压是3 kV。锥孔电压在正电离模式是20 V,在负电离模式是30 V。
方法
3:
除了通用程序A以外:反相HPLC在来自Agilent的Eclipse Plus-C18柱(3.5 μm, 2.1×30 mm)上进行,流速1.0 ml/min,在60℃。使用的梯度条件是:95 % A (0.5 g/l乙酸铵溶液+ 5 %乙腈),5 % B (乙腈),在5.0分钟达到100 % B,保持直至5.15分钟,在5.3分钟平衡至初始条件直至7.0分钟。注射体积2 μl。MS:用0.1秒停留时间通过用0.5秒从100扫描至750只在正电离模式获取高分辨率质谱(Time of Flight, TOF检测器)。正电离模式的毛细管针电压是2.5 kV,锥孔电压是20 V。Leucine-Enkephaline是用于锁定质量校正的标准物。
Waters
MS
仪器
(Acquity-SQD)
的通用程序
B
UPLC (超高效液相层析)测量用Acquity
UPLC (Waters)系统进行,该系统包括采样器组织器、具有除气器的二元泵、四柱加热器、二极管阵列检测器(DAD)和在下文各方法中指定的柱。柱流不分散至MS检测器而使用。MS检测器配置ESCI双重电离源(电喷射组合大气压化学电离)。氮气用作雾化气体。源温度维持在140℃。用MassLynx-Openlynx软件进行数据采集。
方法
1
除了通用程序B以外:反相UPLC在来自Waters的BEH-C18柱(1.7 μm, 2.1×50 mm)上进行,流速1.0 ml/min,在50℃,不分散至MS检测器。使用的梯度条件是:95 % A (0.5 g/l乙酸铵溶液+ 5 %乙腈),5 % B (乙腈),在3.8分钟达到40 % A,60 % B,在4.6分钟达到5 % A,95 % B,保持直至5.0分钟。注射体积2.0 μl。用0.08秒的通道间延迟通过在0.1秒从100扫描至1000获取低分辨率质谱(单四极杆, SQD检测器)。毛细管针电压是3 kV。锥孔电压在正电离模式是25 V,在负电离模式是30 V。
方法 2 :与方法B1相同的梯度;使用的柱:来自Agilent的RRHD
Eclipse Plus-C18 (1.8 μm, 2.1×50 mm)。
通用程序
C
LC测量用Acquity UPLC (Waters)系统进行,该系统包括二元泵、样品组织器、柱加热器(设定在55℃)、二极管阵列检测器(DAD)和下文各方法指定的柱。流体从柱分散至MS分光计。MS检测器配置电喷射电离源。用0.02秒的停留时间在0.18秒内从100扫描至1000获取质谱。毛细管针电压是3.5 kV,源温度维持在140℃。氮气用作雾化气体。用Waters-Micromass MassLynx-Openlynx数据系统进行数据采集。
方法
C1
反相UPLC (超高效液相层析)在桥接乙基硅氧烷/二氧化硅杂合体(BEH) C18柱(1.7 μm, 2.1×50 mm; Waters Acquity)上进行,流速0.8
ml/min。两种流动相(25 mM乙酸铵在H2O中/乙腈95/5; 流动相B:乙腈)用于产生在1.3分钟内从95 % A和5 % B至5 % A和95 % B并保持0.3分钟的梯度条件。使用0.5 μl注射体积。
锥孔电压在正电离模式是30 V,在负电离模式是30 V。
通用程序
D
HPLC测量用Alliance HT 2795 (Waters)系统进行,该系统包括具有除气器的四元泵、自动采样器、二极管阵列检测器(DAD)和下文各方法指定的柱,将柱保持在30℃温度。流体从柱分散至MS分光计。MS检测器配置电喷射电离源。在LCT (来自Waters的Time of Flight
ZsprayTM质谱仪)上毛细管针电压是3 kV,源温度维持在100℃。氮气用作雾化气体。用Waters-Micromass MassLynx-Openlynx数据系统进行数据采集。
方法
1
除了通用程序D以外:反相HPLC在Supelco Ascentis Express C18柱(2.7 µm, 3.0×50 mm)上进行,流速0.7 ml/min。两种流动相(流动相A: 100 % 7 mM乙酸铵; 流动相B: 100 %乙腈)用于产生下述梯度条件:用2.5分钟从80 % A和20 % B (保持0.5分钟)达到5% A和95 % B,保持4.5分钟,用1.5分钟恢复至初始条件并保持1分钟。使用5 ml注射体积。正和负电离模式的锥孔电压都是20 V。用0.3秒扫描间延迟在0.4秒内从100扫描至1000获取质谱。
通用程序
E
LC测量用UPLC (超高效液相层析)
Acquity (Waters)系统进行,该系统包括具有除气器的二元泵、自动采样器、二极管阵列检测器(DAD)和下文各方法指定的柱,将柱保持在40℃温度。流体从柱到达MS检测器。MS检测器配置电喷射电离源。在Quattro (来自Waters的三重四极杆质谱仪)上毛细管针电压是3 kV,源温度维持在130℃。氮气用作雾化气体。用Waters-Micromass MassLynx-Openlynx数据系统进行数据采集。
方法
1
除了通用程序E以外:反相UPLC在Waters Acquity BEH (桥接的乙基硅氧烷/二氧化硅杂合体)苯基-己基柱(1.7 µm, 2.1×100 mm)上进行,流速0.343 ml/min。两种流动相(流动相A: 95 % 7 mM乙酸铵/5 %乙腈; 流动相B: 100 %乙腈)用于产生下述梯度条件:用2.18分钟从84.2 % A和15.8 % B (保持0.49分钟)达到10.5 % A和89.5 % B,保持1.94分钟,用0.73分钟恢复至初始条件,保持0.73分钟。使用2 ml注射体积。正和负电离模式的锥孔电压都是20V。用0.1秒的扫描间延迟在0.2秒内从100扫描至1000获取质谱。
SFCMS
方法
关于本发明化合物的SFCMS鉴定,使用下列方法。
通用程序
F
SFC测量用来自Berger instrument的Analytical系统进行,该系统包括用于递送二氧化碳(CO2)和调节剂的FCM-1200二元泵流体控制模块、CTC Analytics自动化液体采样器、用于将柱从室温加热至80℃的TCM-20000热控制模块。使用配备经受至多400 bar的高压流动室(flow
cell)的Agilent 1100 UV光电二极管阵列检测器。流体从柱分散至MS分光计。MS检测器配置大气压电离源。Waters ZQ质谱分光光度计的电离参数如下:放电针电流(corona):9µa,源温度:140℃,锥孔电压:30 V,探针温度450℃,提取锥孔电压(Extractor) 3 V,脱溶液气体400L/小时,锥孔气体70 L/小时。氮气用作雾化气体。用Waters-Micromass
MassLynx-Openlynx数据系统进行数据采集。
方法
1
除了通用程序F以外:在SFC中手性分离在CHIRALPAK IC DAICEL柱(5
µm, 4.6×250 mm)上进行,流速3.0 ml/min。流动相是恒溶剂模式的CO2
40%异丙醇60%和异丙胺0.3%
(在异丙醇中)。
方法
2
除了通用程序F以外:在SFC中手性分离在CHIRALPAK IC DAICEL柱(5
µm, 4.6×250 mm)上进行,流速3.0 ml/min。流动相是恒溶剂模式的CO2
60%乙醇20%异丙醇20%和异丙胺0.3% (在乙醇和在异丙醇中)。
方法
3
除了通用程序F以外:在SFC中手性分离在CHIRALPAK AD DAICEL柱(10
µm, 4.6×250 mm)上进行,流速3.0 ml/min。流动相是恒溶剂模式的CO2
70%乙醇30%和异丙胺0.3%
(在乙醇中)。
方法
4
除了通用程序F以外:在SFC中手性分离在CHIRALPAK AD DAICEL柱(10
µm, 4.6×250 mm)上进行,流速3.0 ml/min。流动相是恒溶剂模式的CO2
85%甲醇7.5%异丙醇7.5%和异丙胺0.3% (在甲醇和在异丙醇中)。
方法
5
除了通用程序F以外:在SFC中手性分离在CHIRALPAK AD DAICEL柱(5
µm, 4.6×250 mm)上在35℃进行,流速3.0 ml/min。流动相是恒溶剂模式的70% CO2、30%
iPrOH (含有0.3 % iPrNH2)。
通用程序
G SFC-MS
来自Berger Instruments (Newark, DE, USA)的Analytical SFC系统包括用于递送二氧化碳(CO2)和调节剂的二元泵控制模块(FCM-1200)、用于柱加热将温度控制在1-150℃范围的热控制模块(TCM2100)和用于6个不同柱的柱选择阀门(Valco, VICI, Houston, TX, USA)。光电二极管阵列检测器(Agilent 1100, Waldbronn, Germany)配备高压流动室(至多400 bar)和配置CTC LC Mini PAL自动采样器(Leap
Technologies, Carrboro, NC , USA)。将具有正交Z-电喷射界面的的ZQ质谱仪(Waters,
Milford, MA, USA)与SFC-系统偶联。用由SFC ProNTo软件和Masslynx软件组成的整合平台进行仪器控制、数据采集和处理。
分析测量的结果显示于表2a和2b。
表 2a:一些化合物的物理化学数据,分钟保留时间(Rt),[M+H]+峰(质子化的分子),LCMS方法和mp (℃熔点)。(nd =未测定)。
熔点在Mettler FP 62 (a)、Mettler
FP 81HT/FP90 (b)装置上或通过DSC (25℃至300℃/10℃min/40µ)(c)测定。
表 2b:分析SFC数据-Rt指保留时间(分钟),[M+H]+指化合物的质子化质量,方法指用于对映体纯化合物的SFC/MS分析方法。
核磁共振
(NMR)
对于多种化合物,在具有标准脉冲序列的Bruker DPX-400或在Bruker AV-500分光计上记录1H NMR谱,分别以400 MHz和500 MHz操作。将化学位移(δ)报告为从作为内标物的四甲基甲硅烷(TMS)向低磁场位移的百万分之几(ppm)。
化合物编号
1
1H NMR (500 MHz, CDCl3) δ ppm 0.29 - 0.40 (m, 2 H), 0.58 - 0.69 (m, 2 H), 1.14 -
1.24 (m, 1 H), 1.50 (qd, J=12.5, 4.2 Hz, 1 H), 1.69 - 1.77 (m, 1 H), 1.78 -
1.86 (m, 1 H), 1.91 - 2.02 (m, 1 H), 2.18 (td, J=11.5, 2.7 Hz, 1 H), 2.24 (t,
J=11.0 Hz, 1 H), 2.77 - 2.87 (m, 2 H), 2.88 - 2.95 (m, 1 H), 3.09 (d, J=6.6 Hz,
2 H), 3.68 - 3.84 (m, 2 H), 7.16 - 7.24 (m, 3 H), 7.27 - 7.33 (m, 2 H), 7.46
(d, J=7.2 Hz, 1 H), 8.05 (d, J=7.2 Hz, 1 H).
化合物编号
2
1H NMR (500 MHz, CDCl3) δ ppm 0.30 - 0.41 (m, 2 H), 0.58 - 0.70 (m, 2 H), 1.15 -
1.24 (m, 1 H), 2.31 (t, J=10.8 Hz, 1 H), 2.47 (td, J=11.4, 3.2 Hz, 1 H), 2.69
(br. d, J=11.3 Hz, 1 H), 2.85 (br. d, J=11.6 Hz, 1 H), 3.11 (d, J=6.9 Hz, 2 H),
3.72 - 3.83 (m, 2 H), 3.84 (td, J=11.4, 2.6 Hz, 1 H), 4.01 - 4.10 (m, 1 H),
4.56 (dd, J=10.3, 2.5 Hz, 1 H), 7.27 - 7.37 (m, 5 H), 7.43 (d, J=7.2 Hz, 1 H),
8.08 (d, J=7.2 Hz, 1 H).
化合物编号
4
1H NMR (500 MHz, CDCl3) δ ppm 0.31 - 0.41 (m, 2 H), 0.58 - 0.70 (m, 2 H), 1.15 -
1.25 (m, 1 H), 2.31 (t, J=10.8 Hz, 1 H), 2.47 (td, J=11.4, 3.2 Hz, 1 H), 2.69
(br. d, J=11.0 Hz, 1 H), 2.85 (br. d, J=11.6 Hz, 1 H), 3.11 (d, J=6.6 Hz, 2 H),
3.71 - 3.83 (m, 2 H), 3.84 (td, J=11.4, 2.3 Hz, 1 H), 4.01 - 4.10 (m, 1 H),
4.56 (dd, J=10.4, 2.3 Hz, 1 H), 7.27 - 7.38 (m, 5 H), 7.43 (d, J=7.2 Hz, 1 H),
8.08 (d, J=7.2 Hz, 1 H).
化合物编号
3a (
游离碱
)
1H NMR (500 MHz, DMSO-d6) δ ppm 0.24 - 0.34 (m, 2 H), 0.47 - 0.56 (m, 2 H), 1.20
(br. s., 3 H), 1.15 - 1.27 (m, 1 H), 2.18 - 2.33 (m, 2 H), 2.33 - 2.43 (m, 2
H), 2.53 - 2.61 (m, 1 H), 2.68 - 2.79 (m, 1 H), 3.04 (br. s., 1 H), 3.01 - 3.12
(m, 2 H), 3.58 - 3.67 (m, 1 H), 3.67 - 3.76 (m, 1 H), 7.10 (d, J=7.3 Hz, 1 H),
7.16 - 7.20 (m, 1 H), 7.29 (t, J=7.7 Hz, 2 H), 7.46 (d, J=7.3 Hz, 2 H), 8.64
(d, J=7.3 Hz, 1 H).
化合物编号
3b (
游离碱
)
1H NMR (500 MHz, DMSO-d6) δ ppm 0.23 - 0.37 (m, 2 H), 0.45 - 0.58 (m, 2 H), 1.20 (br.
s., 3 H), 1.11 - 1.29 (m, 1 H), 2.16 - 2.33 (m, 2 H), 2.33 - 2.43 (m, 2 H),
2.53 - 2.62 (m, 1 H), 2.66 - 2.82 (m, 1 H), 3.04 (br. s., 1 H), 3.02 - 3.14 (m,
2 H), 3.63 (d, J=14.5 Hz, 1 H), 3.72 (d, J=14.5 Hz, 1 H), 7.10 (d, J=6.9 Hz, 1
H), 7.14 - 7.24 (m, 1 H), 7.29 (t, J=7.6 Hz, 2 H), 7.46 (d, J=7.6 Hz, 2 H),
8.64 (d, J=7.3 Hz, 1 H).
化合物编号
5b
1H NMR (500 MHz, DMSO-d6) δ ppm 0.24 - 0.34 (m, 2 H), 0.46 - 0.58 (m, 2 H), 1.16 -
1.25 (m, 1 H), 2.00 (t, J=10.2 Hz, 1 H), 2.16 (td, J=10.9, 2.5 Hz, 1 H), 2.61
(br. s., 1 H), 2.70 (br. d, J=10.4 Hz, 1 H), 2.75 (br. d, J=10.7 Hz, 1 H), 2.82
(td, J=11.3, 2.5 Hz, 1 H), 2.95 (br. d, J=11.7 Hz, 1 H), 3.06 (d, J=6.9 Hz, 2
H), 3.65 - 3.77 (m, 3 H), 7.19 - 7.25 (m, 1 H), 7.25 - 7.33 (m, 3 H), 7.33 -
7.39 (m, 2 H), 8.66 (d, J=7.3 Hz, 1 H).
化合物编号
5a
1H NMR (500 MHz, DMSO-d6) δ ppm 0.23 - 0.35 (m, 2 H), 0.45 - 0.58 (m, 2 H), 1.15 -
1.27 (m, 1 H), 2.00 (t, J=10.4 Hz, 1 H), 2.16 (td, J=10.4, 2.5 Hz, 1 H), 2.65
(br. s., 1 H), 2.70 (br. d, J=10.7 Hz, 1 H), 2.75 (br. d, J=10.4 Hz, 1 H), 2.83
(td, J=11.7, 2.5 Hz, 1 H), 2.95 (br. d, J=11.7 Hz, 1 H), 3.06 (d, J=6.9 Hz, 2
H), 3.65 - 3.78 (m, 3 H), 7.18 - 7.25 (m, 1 H), 7.25 - 7.32 (m, 3 H), 7.33 -
7.39 (m, 2 H), 8.66 (d, J=7.3 Hz, 1 H).
化合物编号
6b
1H NMR (500 MHz, DMSO-d6) δ ppm 0.24 - 0.34 (m, 2 H), 0.46 - 0.57 (m, 2 H), 1.15 -
1.29 (m, 2 H), 2.01 (t, J=10.4 Hz, 1 H), 2.12 - 2.24 (m, 1 H), 2.71 (br. d,
J=10.4 Hz, 1 H), 2.79 (br. d, J=10.4 Hz, 1 H), 2.81 - 2.89 (m, 1 H), 2.97 (br.
d, J=11.7 Hz, 1 H), 3.07 (d, J=6.9 Hz, 2 H), 3.65 - 3.78 (m, 2 H), 4.07 (br. d,
J=8.8 Hz, 1 H), 7.05 - 7.15 (m, 1 H), 7.15 - 7.20 (m, 1 H), 7.24 - 7.30 (m, 1
H), 7.31 (d, J=6.9 Hz, 1 H), 7.54 - 7.61 (m, 1 H), 8.67 (d, J=7.3 Hz, 1 H).
化合物编号
6a
1H NMR (500 MHz, DMSO-d6) δ ppm 0.24 - 0.34 (m, 2 H), 0.46 - 0.57 (m, 2 H), 1.15 -
1.26 (m, 1 H), 2.01 (t, J=10.4 Hz, 1 H), 2.12 - 2.23 (m, 1 H), 2.71 (br. d,
J=10.7 Hz, 1 H), 2.79 (br. d, J=10.1 Hz, 1 H), 2.81 - 2.89 (m, 1 H), 2.97 (br.
d, J=11.7 Hz, 1 H), 3.07 (d, J=6.9 Hz, 2 H), 3.65 - 3.78 (m, 2 H), 4.07 (br. d,
J=8.5 Hz, 1 H), 7.07 - 7.15 (m, 1 H), 7.15 - 7.20 (m, 1 H), 7.24 - 7.30 (m, 1
H), 7.31 (d, J=7.3 Hz, 1 H), 7.54 - 7.61 (m, 1 H), 8.67 (d, J=7.3 Hz, 1 H).
化合物编号
7a
1H NMR (500 MHz, DMSO-d6) δ ppm 0.24 - 0.33 (m, 2 H), 0.48 - 0.55 (m, 2 H), 1.16 -
1.25 (m, 1 H), 1.92 (s, 3 H), 2.13 (t, J=10.7 Hz, 1 H), 2.24 - 2.31 (m, 1 H),
2.31 - 2.39 (m, 1 H), 2.62 - 2.68 (m, 1 H), 2.73 - 2.80 (m, 1 H), 2.88 (br. d,
J=11.0 Hz, 1 H), 3.02 (dd, J=10.2, 3.0 Hz, 1 H), 3.06 (d, J=6.9 Hz, 2 H), 3.71
(br. s, 2 H), 7.22 - 7.36 (m, 6 H), 8.65 (d, J=7.3 Hz, 1 H).
化合物编号
7b
1H NMR (500 MHz, DMSO-d6) δ ppm 0.23 - 0.34 (m, 2 H), 0.47 - 0.55 (m, 2 H), 1.16 -
1.25 (m, 1 H), 1.92 (s, 3 H), 2.13 (t, J=10.7 Hz, 1 H), 2.24 - 2.31 (m, 1 H),
2.31 - 2.39 (m, 1 H), 2.61 - 2.68 (m, 1 H), 2.74 - 2.80 (m, 1 H), 2.88 (br. d,
J=11.0 Hz, 1 H), 3.02 (dd, J=10.2, 3.0 Hz, 1 H), 3.06 (d, J=6.9 Hz, 2 H), 3.67
- 3.76 (m, 2 H), 7.20 - 7.36 (m, 6 H), 8.65 (d, J=7.3 Hz, 1 H).
化合物编号
8a (
游离碱
)
1H NMR (500 MHz, DMSO-d6) δ ppm 0.24 - 0.35 (m, 2 H), 0.46 - 0.57 (m, 2 H), 1.15 -
1.25 (m, 1 H), 1.34 (s, 3 H), 2.34 - 2.48 (m, 3 H), 3.06 (br. s, 1 H), 3.02 -
3.12 (m, 2 H), 3.45 - 3.54 (m, 1 H), 3.62 - 3.71 (m, 2 H), 3.74 - 3.80 (m, 1
H), 7.14 (d, J=7.3 Hz, 1 H), 7.21 - 7.27 (m, 1 H), 7.31 - 7.40 (m, 4 H), 8.67
(d, J=7.3 Hz, 1 H).
化合物编号
8b (
游离碱
)
1H NMR (500 MHz, DMSO-d6) δ ppm 0.24 - 0.35 (m, 2 H), 0.47 - 0.56 (m, 2 H), 1.15 -
1.25 (m, 1 H), 1.34 (s, 3 H), 2.34 - 2.48 (m, 3 H), 3.06 (br. s, 1 H), 3.02 -
3.12 (m, 2 H), 3.45 - 3.54 (m, 1 H), 3.61 - 3.72 (m, 2 H), 3.73 - 3.80 (m, 1
H), 7.14 (d, J=7.3 Hz, 1 H), 7.22 - 7.27 (m, 1 H), 7.31 - 7.40 (m, 4 H), 8.67
(d, J=7.3 Hz, 1 H).
化合物编号
9
1H NMR (400 MHz, CDCl3) δ ppm 0.29 - 0.41 (m, 2 H), 0.57 - 0.70 (m, 2 H), 1.14 -
1.22 (m, 1 H), 1.22 - 1.27 (m, 1 H), 1.30 (br. s, 3 H), 1.53 - 1.62 (m, 1 H),
1.67 - 1.82 (m, 1 H), 1.88 - 2.06 (m, 1 H), 2.32 - 2.45 (m, 1 H), 2.51 (br. d,
J=10.9 Hz, 2 H), 2.78 (br. d, J=9.7 Hz, 1 H), 3.03 - 3.16 (m, 2 H), 3.67 - 3.80
(m, 2 H), 7.16 - 7.24 (m, 1 H), 7.27 - 7.40 (m, 5 H), 8.00 (d, J=7.4 Hz, 1 H).
化合物编号
10
1H NMR (500 MHz, CDCl3) δ ppm 1.30 (s, 3 H), 1.61 - 1.80 (m, 3 H), 1.87 - 2.05 (m,
1 H), 2.31 - 2.43 (m, 1 H), 2.51 (br. d, J=11.0 Hz, 2 H), 2.77 (s, 3 H), 2.67 -
2.86 (m, 1 H), 3.68 - 3.80 (m, 2 H), 7.15 - 7.23 (m, 1 H), 7.28 - 7.41 (m, 5
H), 7.87 (d, J=7.2 Hz, 1 H).
化合物编号
11
1H NMR (500 MHz, CDCl3) δ ppm 1.30 (s, 3 H), 1.61 - 1.80 (m, 3 H), 1.87 - 2.05 (m,
1 H), 2.31 - 2.43 (m, 1 H), 2.51 (br. d, J=11.0 Hz, 2 H), 2.77 (s, 3 H), 2.67 -
2.86 (m, 1 H), 3.68 - 3.80 (m, 2 H), 7.15 - 7.23 (m, 1 H), 7.28 - 7.41 (m, 5
H), 7.87 (d, J=7.2 Hz, 1 H).
化合物编号
12
1H NMR (400 MHz, CDCl3) δ ppm 0.29 - 0.42 (m, 2 H), 0.58 - 0.68 (m, 3 H), 0.68 -
0.75 (m, 1 H), 1.13 - 1.24 (m, 1 H), 2.44 - 2.57 (m, 2 H), 2.69 - 2.85 (m, 2
H), 3.11 (d, J=6.7 Hz, 2 H), 3.27 (dt, J=12.5, 3.5 Hz, 1 H), 3.31 - 3.43 (m, 1
H), 3.92 (dd, J=15.0, 1.4 Hz, 1 H), 4.04 (dd, J=15.0, 1.4 Hz, 1 H), 6.71 - 6.87
(m, 2 H), 6.94 (td, J=9.4, 5.7 Hz, 1 H), 7.41 (d, J=7.4 Hz, 1 H), 8.07 (d,
J=7.2 Hz, 1 H).
化合物编号
13
1H NMR (500 MHz, CDCl3) δ ppm 0.30 - 0.40 (m, 2 H), 0.58 - 0.70 (m, 2 H), 1.15 -
1.24 (m, 1 H), 1.47 (s, 3 H), 2.03 (ddd, J=12.9, 7.9, 5.5 Hz, 1 H), 2.28 (ddd,
J=12.6, 9.0, 6.4 Hz, 1 H), 2.73 (td, J=9.0, 5.3 Hz, 1 H), 2.81 (d, J=8.7 Hz, 1
H), 2.91 (d, J=8.7 Hz, 1 H), 2.96 (td, J=8.5, 6.4 Hz, 1 H), 3.10 (d, J=6.9 Hz,
2 H), 3.87 - 4.01 (m, 2 H), 7.18 - 7.23 (m, 1 H), 7.28 - 7.36 (m, 4 H), 7.42
(d, J=7.2 Hz, 1 H), 8.04 (d, J=7.2 Hz, 1 H).
化合物编号
14
1H NMR (500 MHz, CDCl3) δ ppm 0.32 - 0.38 (m, 2 H), 0.60 - 0.67 (m, 2 H), 1.15 -
1.24 (m, 1 H), 1.47 (s, 3 H), 2.03 (ddd, J=12.9, 7.8, 5.3 Hz, 1 H), 2.28 (ddd,
J=12.7, 9.0, 6.4 Hz, 1 H), 2.73 (td, J=9.1, 5.5 Hz, 1 H), 2.81 (d, J=9.0 Hz, 1
H), 2.91 (d, J=9.0 Hz, 1 H), 2.93 - 3.00 (m, 1 H), 3.10 (d, J=6.6 Hz, 2 H),
3.87 - 4.01 (m, 2 H), 7.18 - 7.23 (m, 1 H), 7.28 - 7.36 (m, 4 H), 7.42 (d, J=7.2
Hz, 1 H), 8.04 (d, J=7.2 Hz, 1 H).
化合物编号
18
1H NMR (500 MHz, CDCl3) δ ppm 0.30 - 0.42 (m, 2 H), 0.59 - 0.70 (m, 2 H), 1.15 -
1.25 (m, 1 H), 2.22 (t, J=10.7 Hz, 1 H), 2.46 (td, J=11.4, 3.2 Hz, 1 H), 2.69
(br. d, J=11.3 Hz, 1 H), 2.87 (br. d, J=11.3 Hz, 1 H), 3.11 (d, J=6.6 Hz, 2 H),
3.71 - 3.84 (m, 2 H), 3.81 - 3.91 (m, 1 H), 4.05 (dd, J=11.4, 1.9 Hz, 1 H),
4.85 (dd, J=10.0, 1.6 Hz, 1 H), 6.71 - 6.81 (m, 1 H), 6.84 - 6.93 (m, 1 H),
7.45 (d, J=7.2 Hz, 1 H), 7.46 - 7.52 (m, 1 H), 8.09 (d, J=7.2 Hz, 1 H).
化合物编号
19
1H NMR (500 MHz, CDCl3) δ ppm 0.30 - 0.41 (m, 2 H), 0.59 - 0.70 (m, 2 H), 1.15 -
1.24 (m, 1 H), 1.64 (br. s., 1 H), 2.19 (t, J=10.4 Hz, 1 H), 2.36 (td, J=11.0,
3.2 Hz, 1 H), 2.76 (dd, J=11.0, 1.7 Hz, 1 H), 2.83 (br. d, J=10.7 Hz, 1 H),
3.02 - 3.16 (m, 2 H), 3.10 (d, J=6.6 Hz, 2 H), 3.71 - 3.84 (m, 2 H), 4.20 (dd,
J=10.1, 2.6 Hz, 1 H), 6.72 - 6.80 (m, 1 H), 6.86 (td, J=8.3, 1.9 Hz, 1 H), 7.46
(d, J=7.2 Hz, 1 H), 7.48 - 7.55 (m, 1 H), 8.07 (d, J=7.2 Hz, 1 H)。
D.
药理学实施例
[35S]GTPγS结合测定法
本发明提供的化合物是mGluR2的正变构调节剂。这些化合物似乎通过与变构部位而不是与谷氨酸结合部位结合来提高谷氨酸反应。当式(I)化合物存在时,mGluR2对谷氨酸浓度的反应增加。预期式(I)化合物通过其提高受体功能的能力而实质上在mGluR2上发挥其作用。采用下述[35S]GTPγS结合测定方法(其适于鉴定这类化合物、更特别地适于鉴定式(I)化合物)对mGluR2测试的正变构调节剂的作用见表3。
[35S]GTP
γ
S
结合测定法
[35S]GTPγS结合测定法是一种用于研究G蛋白偶联受体(GPCR)功能,籍此测量GTP的不可水解形式[35S]GTPγS (用γ放射性35S标记的鸟苷5’-三磷酸)的掺入的基于功能膜的测定法。G蛋白α亚基催化鸟苷5’-二磷酸(GDP)被鸟苷三磷酸(GTP)交换,且在GPCR被激动剂[35S]GTPγS激活时,变成掺入其中,且无法切割以继续交换循环(Harper
(1998) Current Protocols in Pharmacology 2.6.1-10, John Wiley & Sons, Inc.)。放射性[35S]GTPγS掺入的量直接衡量G蛋白的活性,因此可确定激动剂的活性。已表明mGluR2受体优先与Gαi蛋白偶联(一种用于该方法的优先偶联),因此其广泛用于研究重组细胞系和组织两者中mGluR2受体的受体活化。在此我们描述了将使用得自用人mGluR2受体转染的细胞的膜和改编自Schaffhauser等人((2003)
Molecular Pharmacology 4:798-810)的[35S]GTPγS结合测定法,用于检测本发明化合物的正变构调节(PAM)性质。
膜制备
将CHO细胞培养至汇合前,用5 mM丁酸盐刺激24小时。然后通过在PBS中刮下来收集细胞,将细胞悬液离心(台式离心机中在4000
RPM下10分钟)。弃去上清液,通过用涡旋混合和用移液管上下抽吸,将沉淀轻轻重新悬浮于50 mM Tris-HCl
(pH 7.4)中。使悬液以16,000 RPM离心(Sorvall
RC-5C+转子SS-34) 10分钟,弃去上清液。使用ultra-turrax匀浆器将沉淀在5 mM Tris-HCl (pH 7.4)中匀浆,再次离心(18,000
RPM,20分钟,4℃)。将最终的沉淀再次悬浮于50 mM Tris-HCl
(pH 7.4)中,用前按适当的等分量保存于-80℃。通过使用牛血清白蛋白作为标准品的Bradford方法(Bio-Rad,USA)测定蛋白质浓度。
[35S]GTPγS结合测定法
如下进行试验化合物的mGluR2正变构调节活性的测量。将试验化合物和谷氨酸稀释于含有10 mM
HEPES酸、10 mM HEPES盐(pH 7.4)、100 mM NaCl、3 mM MgCl2和10 μM GDP的测定缓冲液中。将含有人mGlu2受体的膜在冰上融化,并稀释于补充14 μg/ml皂苷的测定缓冲液中。将膜与单独或与预先确定(约EC20)浓度的谷氨酸(PAM测定法)一起的化合物在30℃下预温育30分钟。在加入[35S]GTPγS
(f.c. 0.1 nM)后,轻轻振摇测定混合物,并进一步温育以供[35S]GTPγS在激活时掺入(30分钟,30℃)。最终的测定混合物在10 mM HEPES酸、10 mM
HEPES盐(pH 7.4)、100
mM NaCl、3 mM MgCl2、10 μM GDP和10 μg/ml皂苷中含有7 μg的膜蛋白。总反应体积为200 μl。使用96孔filtermate通用收获器,经快速通过Unifilter-96 GF/B板(Perkin
Elmer,Massachusetts,USA)过滤来终止反应。过滤器用冰冷的10 mM NaH2PO4/10
mM Na2HPO4 (pH 7.4)洗涤6次。然后将过滤器风干,将40 µl液体闪烁混合物(Microscint-O)加入各孔中。在得自Perkin Elmer的微量培养板闪烁和发光计数器(Microplate
Scintillation and Luminescence Counter)中统计膜结合的放射性。
数据分析
采用Lexis软件界面(于J&J开发),生成本发明的代表性化合物的浓度反应曲线(在确定正变构调节(PAM)的EC20的mGluR2激动剂谷氨酸存在下获得)。数据计算为对照谷氨酸反应的%,所述对照谷氨酸反应定义为在只加入谷氨酸时产生的最大反应。采用非线性回归分析,对描绘这些百分比对比试验化合物的log浓度的曲线的S型浓度反应曲线进行了分析。然后将产生半最大作用的浓度计算为EC50。
如果EC50以M表示,则以下pEC50值计算为-log
EC50。Emax定义为相对最大作用(即相对于对照谷氨酸反应的最大%作用)。
下表3显示获自式(I)化合物的药理学数据。
表 3. 本发明化合物的药理学数据
n.c.指pEC50不可计算
n.t.指未测试
当浓度-反应曲线不达到平台(plateau)水平时不计算pEC50值。
所有化合物均在预定EC20浓度的mGluR2激动剂谷氨酸存在下测定,以确定正变构调节。pEC50值自至少8种浓度的浓度反应实验计算。如果进行更多实验,则报告平均pEC50值,误差偏差为<0.5。
E.
预示性组合物实施例
贯穿这些实施例使用的“活性成分”涉及式(I)的最终化合物、其药学上可接受的盐、其溶剂合物和立体化学异构形式。
用于本发明制剂的配方的典型实施例如下:
1.
片剂
活性成分 5-50 mg
磷酸二钙 20 mg
乳糖 30 mg
滑石粉 10 mg
硬脂酸镁 5 mg
土豆淀粉 加至200 mg
在该实施例中,活性成分可替换为等量的任一种本发明化合物,特别是等量的任一种例示性化合物。
2.
混悬剂
制备用于口服给药的水性混悬剂,使得每1毫升均含有1-5 mg的活性化合物之一、50 mg羧甲基纤维素纳、1 mg苯甲酸纳、500 mg山梨糖醇和加至1 ml的水。
3.
注射剂
通过将1.5%重量的本发明的活性成分在含10%体积丙二醇的水中搅拌,来制备胃肠外组合物。
4.
软膏剂
活性成分 5-1000 mg
硬脂醇 3 g
羊毛脂 5 g
白凡士林(White petroleum) 15 g
水 加至100 g
在该实施例中,活性成分可替换为等量的任一种本发明化合物,特别是等量的任一种例示性化合物。
合理的变化不得视为偏离本发明的范围。显而易见的是,本领域技术人员可以许多方式改变如此描述的发明。
Claims (15)
1. 一种式(I)化合物
或其立体化学异构形式,
其中
R1选自C1-6烷基、(C3-8环烷基)C1-3烷基、(C1-3烷基氧基)C1-3烷基和被1、2或3个氟取代基取代的C1-3烷基;
R2选自Cl、CF3、-CN和环丙基;
R3选自氢、甲基和CF3;
R4选自氢和甲基;
或者R3和R4与它们结合的碳一起形成环丙基环或羰基;
L选自(L-a)、(L-b)、(L-c)、(L-d)、(L-e)、(L-f)、(L-g)和(L-h):
其中
R5a、R5b、R5c和R5d各自独立选苯基;被1或2个各自独立选自C1-3烷基氧基和卤代基的取代基取代的苯基;吡啶基;被1或2个各自独立选自C1-3烷基、C1-3烷基氧基和卤代基的取代基取代的吡啶基;嘧啶基;和被1或2个各自独立选自C1-3烷基、C1-3烷基氧基和卤代基的取代基取代的嘧啶基;
R6e选自氢和C1-3烷基;
R5f、R5g和R5h各自独立选自苯基和被1或2个氟取代基取代的苯基;
R6a、R6b和R6c各自独立选自氢;氟代基;C1-3烷基;被1、2或3个氟取代基取代的C1-3烷基;C1-3烷基氧基;被1、2或3个氟取代基取代的C1-3烷基氧基;和C3-6环烷基;
R6h是C1-3烷基;
R7a、R8a、R7b、R8b、R7c、R8c、R7d和R8d各自独立选自氢、卤代基和甲基;或者R7a和R8a、R7b和R8b、R7c和R8c、R7d和R8d各自与它们连接的碳一起形成环丙基或羰基;
R9b选自氢、C1-3烷基和C3-6环烷基;
其中
卤代基各自选自氟代基、氯代基、溴代基和碘代基;
或其药学上可接受的盐或溶剂合物。
2. 权利要求1的化合物,或其立体异构形式,其中R1是(C3-8环烷基)C1-3烷基。
3. 权利要求1或2的化合物,其中R2是CF3。
4. 权利要求1至3中任一项的化合物,其中R3和R4是氢。
5. 权利要求1至4中任一项的化合物,其中L选自
(L-a),其中R5a是苯基;R6a选自氢和甲基;R7a和R8a是氢;
(L-b),其中R5b是被1或2个氟取代基任选取代的苯基;R6b选自氢和甲基;R7b和R8b是氢;R9b选自氢和甲基;
(L-c),其中R5c是被1或2个氟取代基任选取代的苯基;R6c选自氢和甲基;R7c和R8c是氢;
(L-g),其中R5g选自被1或2个氟取代基任选取代的苯基;
(L-h),其中R5h是苯基且R6h是甲基;和
L是(L-f),其中R5f选自被1或2个氟取代基任选取代的苯基。
6. 权利要求1至5中任一项的化合物,其中L选自
(L-a),其中R5a是苯基;R6a选自氢和甲基;R7a和R8a是氢;
(L-b),其中R5b是被氟取代基任选取代的苯基;R6b选自氢和甲基;R7b和R8b是氢;R9b选自氢和甲基;
(L-c),其中R5c是苯基;R6c选自氢和甲基;R7c和R8c是氢;
(L-g),其中R5g选自被1或2个氟取代基任选取代的苯基;
(L-h),其中R5h是苯基且R6h是甲基;
L是(L-f),其中R5f选自被1或2个氟取代基任选取代的苯基。
7. 权利要求1的化合物或其立体异构形式、药学上可接受的盐或溶剂合物,其选自
3-(环丙基甲基)-7-[(3-苯基-1-哌啶基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶,
3-(环丙基甲基)-7-[[(2R)-2-苯基-4-吗啉基]甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶,
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R),
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R)盐酸盐,
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R)盐酸盐水合物,
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S),
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S)盐酸盐,
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S)盐酸盐水合物,
3-(环丙基甲基)-7-[[(2S)-2-苯基-4-吗啉基]甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶,
3-(环丙基甲基)-7-[(3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶,
3-(环丙基甲基)-7-[(3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R),
3-(环丙基甲基)-7-[(3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S),
3-(环丙基甲基)-7-[[3-(2-氟苯基)-1-哌嗪基]甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R),
3-(环丙基甲基)-7-[[3-(2-氟苯基)-1-哌嗪基]甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S),
3-(环丙基甲基)-7-[(4-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶,
3-(环丙基甲基)-7-[(4-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R),
3-(环丙基甲基)-7-[(4-甲基-3-苯基-1-哌嗪基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S),
3-(环丙基甲基)-7-[(2-甲基-2-苯基-4-吗啉基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R),
3-(环丙基甲基)-7-[(2-甲基-2-苯基-4-吗啉基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R)盐酸盐,
3-(环丙基甲基)-7-[(2-甲基-2-苯基-4-吗啉基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R)盐酸盐水合物,
3-(环丙基甲基)-7-[(2-甲基-2-苯基-4-吗啉基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S),
3-(环丙基甲基)-7-[(2-甲基-2-苯基-4-吗啉基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S)盐酸盐,
3-(环丙基甲基)-7-[(2-甲基-2-苯基-4-吗啉基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S)盐酸盐水合物,
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌啶基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶,
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-哌啶基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶盐酸盐,
3-甲基-7-[(3-甲基-3-苯基-1-哌啶基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S),
3-甲基-7-[(3-甲基-3-苯基-1-哌啶基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R),
2-[[3-(环丙基甲基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-基]甲基]-5-(2,4-二氟苯基)-2,5-二氮杂双环[4.1.0]庚烷(顺式),
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-吡咯烷基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*R),
3-(环丙基甲基)-7-[(3-甲基-3-苯基-1-吡咯烷基)甲基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶(*S),
3-(环丙基甲基)-7-{[(2*R)-2-(2,4-二氟苯基)吗啉-4-基]甲基}-8-(三氟甲基)[1,2,4]三唑并[4,3-a]吡啶,
3-(环丙基甲基)-7-{[(2*S)-2-(2,4-二氟苯基)吗啉-4-基]甲基}-8-(三氟甲基)[1,2,4]三唑并[4,3-a]吡啶,
3-(环丙基甲基)-7-{[3-(2,4-二氟苯基)哌嗪-1-基]甲基}-8-(三氟甲基)[1,2,4]三唑并[4,3-a]吡啶,
3-(环丙基甲基)-7-{[(3*R)-3-(2,4-二氟苯基)哌嗪-1-基]甲基}-8-(三氟甲基)[1,2,4]三唑并[4,3-a]吡啶和
3-(环丙基甲基)-7-{[(3*S)-3-(2,4-二氟苯基)哌嗪-1-基]甲基}-8-(三氟甲基)[1,2,4]三唑并[4,3-a]吡啶。
8. 一种药物组合物,其包含治疗有效量的权利要求1-7中任一项的化合物和药学上可接受的载体或赋形剂。
9. 用作药物的权利要求1-7中任一项的化合物。
10. 用于治疗或预防选自以下的中枢神经系统障碍的权利要求1-7中任一项的化合物或权利要求8的药物组合物:焦虑障碍、精神障碍、人格障碍、物质相关障碍、进食障碍、心境障碍、偏头痛、癫痫或惊厥性疾患、儿童期障碍、认知障碍、神经变性、神经毒性和缺血。
11. 权利要求10的化合物,其中
所述精神障碍选自精神分裂症、妄想性障碍、情感分裂性精神障碍、精神分裂症样精神障碍和物质诱发性精神障碍;
所述焦虑障碍选自广场恐怖、泛化性焦虑症(GAD)、混合性焦虑和抑郁、强迫性神经失调(OCD)、惊恐障碍、创伤后应激障碍(PTSD)、社交恐怖症和其它恐怖症;
所述人格障碍选自强迫型人格障碍和精神分裂样、分裂型障碍;
所述物质滥用或物质相关障碍选自酒精滥用、酒精依赖、酒精戒断、酒精戒断性谵妄、酒精诱发性精神障碍、苯丙胺依赖、苯丙胺戒断、可卡因依赖、可卡因戒断、尼古丁依赖、尼古丁戒断、阿片样物质依赖和阿片样物质戒断;
所述进食障碍选自神经性厌食症和神经性贪食症;
所述心境障碍选自双相性精神障碍(I和II)、循环情感性障碍、抑郁症、情绪恶劣性障碍、严重的抑郁性障碍、难治性抑郁症、双相抑郁症和物质诱发性心境障碍;
所述癫痫或惊厥性疾患选自全身性非惊厥性癫痫、全身性惊厥性癫痫、癫痫小发作持续状态、癫痫大发作持续状态、有或无认知减退的部分性癫痫、婴儿痉挛、部分性癫痫持续状态和其它癫痫形式;
所述认知障碍选自谵妄、物质诱发性持续性谵妄、痴呆、HIV病所致痴呆、亨廷顿舞蹈病所致痴呆、帕金森病所致痴呆、阿尔茨海默病型痴呆、痴呆的行为和精神症状、物质诱发性持续性痴呆和轻度认知减退。
12. 用于治疗或预防选自以下的中枢神经系统障碍的权利要求10的化合物或权利要求8的药物组合物:精神分裂症、痴呆的行为和精神症状、严重的抑郁性障碍、难治性抑郁症、双相抑郁症、焦虑、抑郁症、泛化性焦虑症、创伤后应激障碍、双相躁狂症、癫痫、注意力缺陷/多动症、物质滥用及混合性焦虑和抑郁。
13. 用于治疗或预防权利要求10-12中任一项引述的障碍的与mGluR2的正构激动剂组合的权利要求1-7中任一项的化合物。
14. 一种用于制备权利要求8中限定的药物组合物的方法,其特征在于将药学上可接受的载体与治疗有效量的权利要求1-7中任一项限定的化合物密切混合。
15. 一种产品,其包含
(a) 权利要求1-7中任一项限定的化合物;和
(b) mGluR2正构激动剂,
作为用于同时、单独或序贯用于治疗或预防选自以下的中枢神经系统障碍的组合制剂:焦虑障碍、精神障碍、人格障碍、物质相关障碍、进食障碍、心境障碍、偏头痛、癫痫或惊厥性疾患、儿童期障碍、认知障碍、神经变性、神经毒性和缺血。
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CN111116582A (zh) * | 2019-12-18 | 2020-05-08 | 大连大学 | 一种mGluR2拮抗剂 |
CN111116582B (zh) * | 2019-12-18 | 2022-07-29 | 大连大学 | 一种mGluR2拮抗剂 |
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CN103298809B (zh) | 2016-08-31 |
JP5852666B2 (ja) | 2016-02-03 |
AU2011328203A1 (en) | 2013-05-02 |
ES2552879T3 (es) | 2015-12-02 |
US20140155393A1 (en) | 2014-06-05 |
EP2661435B1 (en) | 2015-08-19 |
CA2815002A1 (en) | 2012-05-18 |
JP2013541579A (ja) | 2013-11-14 |
US8993591B2 (en) | 2015-03-31 |
AU2011328203B2 (en) | 2015-03-19 |
CA2815002C (en) | 2019-10-22 |
WO2012062759A1 (en) | 2012-05-18 |
EP2661435A1 (en) | 2013-11-13 |
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