CN103298810A - 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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- CN103298810A CN103298810A CN2011800536460A CN201180053646A CN103298810A CN 103298810 A CN103298810 A CN 103298810A CN 2011800536460 A CN2011800536460 A CN 2011800536460A CN 201180053646 A CN201180053646 A CN 201180053646A CN 103298810 A CN103298810 A CN 103298810A
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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WO2009/062676(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。
发明内容
本发明涉及具有有利的性质均衡的有效的mGluR2PAM化合物。具体地讲,本发明的化合物在口服给药后显示适当的功效和/或代谢平衡和脑存留(brain occupancy)。
因此,本发明涉及式(I)化合物或其立体化学异构形式或其药学上可接受的盐或溶剂化物
其中
R1选自C1-6烷基;(C3-8环烷基)C1-3烷基;(C1-3烷氧基)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与它们所结合的碳一起形成环丙基环;
L选自(L-a)、(L-b)、(L-c)、(L-d)、(L-e)、(L-f)、(L-g)和(L-h):
其中
ma、mb和mc各自独立选自0和1;
me和mg各自独立选自1和2;
na、nb、nc、nd、ne、nf、hg和nh各自独立选自0、1和2;
R5a、R5b、R5c、R5d、R5e、R5f、R5g和R5h各自独立选自卤素;C1-3烷基;被1、2或3个氟取代基取代的C1-3烷基;C1-3烷氧基和被1、2或3个氟取代基取代的C1-3烷氧基。
R6a选自氢;卤素;C1-3烷基;被1、2或3个氟取代基取代的C1-3烷基;C1-3烷氧基和被1、2或3个氟取代基取代的C1-3烷氧基;
R6c选自氢;卤素;C1-3烷基;被1、2或3个氟取代基取代的C1-3烷基;C1-3烷氧基;被1、2或3个氟取代基取代的C1-3烷氧基和环丙基;
R7a、R8a、R7b和R8b各自独立选自氢、氟和甲基;或者R7a和R8a及R7b和R8b与它们所连接的碳一起形成环丙基或羰基;
其中
每个卤素选自氟、氯、溴和碘;
前提条件是(L-c)不通过对于氧原子是α位的碳原子与三唑并吡啶核结合。
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化物。式(I)化合物具有mGluR2调节剂活性,并可用于治疗或预防神经和精神障碍。
在一个实施方案中,本发明涉及如前定义的式(I)化合物,其中R1选自(环丙基)甲基、乙基和(乙氧基)甲基。
在另一个实施方案中,R1为(C3-8环烷基)C1-3烷基。
在另一个实施方案中,R1为(环丙基)甲基。
在另一个实施方案中,R2为CF3或Cl。
在另一个实施方案中,R3和R4均为氢。
在另一个实施方案中,L为
其中R5a为氟,na选自0、1和2。
在另一个实施方案中,L为
其中R5b为氟,nb选自0、1和2。
在另一个实施方案中,L选自(L-c1)、(L-c2)、(L-c3)和(L-c4)
其中各个R6c独立选自氢和甲基。
在另一个实施方案中,L为(L-d),其中nd为0。
在另一个实施方案中,L选自(L-e1)、(L-e2)和(L-f1)
其中me选自1和2。
在另一个实施方案中,L为(L-g1)
其中mg选自1和2。
在另一个实施方案中,L为(L-d1)
在另一个实施方案中,L为(L-h1)
在另一个实施方案中,L选自(L-a1)、(L-b1)、(L-c1)、(L-c2)、(L-c3)、(L-c4)、(L-e1)、(L-e2)、(L-f1)、(L-g1)和(L-d),其中nd为0。
上文指出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的范围内。
具体化合物可选自:
3-(环丙基甲基)-N-[反式-4-(2,4-二氟苯基)环己基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
3-(环丙基甲基)-N-[1-(2,4-二氟苯基)-4-哌啶基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
3-(环丙基甲基)-N-(反式-4-苯基环己基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
3-乙基-N-(反式-4-苯基环己基)-8-(三氟甲基)-1,2,4-三唑并-[4,3-a]吡啶-7-甲胺,
3-(环丙基甲基)-N-[顺式-4-(2,4-二氟苯基)环己基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
3-(环丙基甲基)-N-(2,3-二氢-1H-茚-2-基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
3-(环丙基甲基)-N-(顺式-4-苯基环己基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
3-乙基-N-(顺式-4-苯基环己基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
N-[顺式-4-(2,4-二氟苯基)环己基]-3-乙基-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
3-(乙氧基甲基)-N-(顺式-4-苯基环己基)-8-(三氟甲基)-1,2,4-三唑并-[4,3-a]吡啶-7-甲胺,
3-(乙氧基甲基)-N-(反式-4-苯基环己基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
8-氯-3-(环丙基甲基)-N-(顺式-4-苯基环己基)-1,2,4-三唑并-[4,3-a]吡啶-7-甲胺,
8-氯-3-(环丙基甲基)-N-(反式-4-苯基环己基)-1,2,4-三唑并-[4,3-a]吡啶-7-甲胺,
反式-N-{[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}-2-苯基环丙胺,
N-{[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}-3,4-二氢-2H-苯并吡喃-4-胺,
(4*R)-N-{[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}-3,4-二氢-2H-苯并吡喃-4-胺,
(4*S)-N-{[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}-3,4-二氢-2H-苯并吡喃-4-胺,
(2S,4S)-N-{[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}-2-苯基四氢-2H-吡喃-4-胺,
(2R,4R)-N-{[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}-2-苯基四氢-2H-吡喃-4-胺,和
顺式-N-{[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}-4-苯基四氢呋喃-3-胺。
其立体异构形式、药学上可接受的盐和溶剂化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/Nameproduct10.01版;Build15494,2006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 AppliedChemistry,IUPAC)同意的命名原则,应用Advanced ChemicalDevelopment,Inc.,软件(ACD/Name product10.01.0.14105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“C3-8环烷基”,定义具有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”,是指氟、氯、溴或碘,其中优选氟或氯。
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”,除非另有说明否则定义被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。
本文所用表述“(L-c)不通过对于氧原子是α位的碳原子与三唑并吡啶核结合”意指(L-c)不通过与氧原子邻接的碳原子即环中的醚键与三唑并吡啶核结合,因此如果mc为0且(L-c)因此表示四氢呋喃环,或mc为1且(L-c)因此表示四氢吡喃环,则可获得下列可能的结构:
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化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。
术语溶剂化物包括式(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色谱法。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,例如卤素、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,在典型加热或微波辐射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,卤素为氯、溴或碘。
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
可通过使式(XIV)的中间体经历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(10)中予以说明,其中所有变量如上文所述定义。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),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10
实验方法10a
式(X)的中间体化合物可通过使式(XV)的中间体在本领域技术人员已知的二羟基化和氧化解离条件下反应来制备,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(10a)中予以说明,其中所有变量如上文所述定义。
反应流程10a
实验方法11
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(11)中予以说明,其中所有变量如上文所述定义,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,并且一般在介于约室温与约200℃的温度下进行该方法。
反应流程11
实验方法12
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(12)中,所有变量如式(I)所定义,卤素为氯、溴或碘。
反应流程12
实验方法13
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(13)中,所有变量如式(I)所定义。
反应流程13
实验方法14
可按照反应流程(14),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(14)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(14)中,R2如式(I)中的定义,卤素为氯、溴或碘。
反应流程14
实验方法15
可按照反应流程(15),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(15)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(15)中,R2如式(I)中所定义,卤素为氯、溴或碘。
反应流程15
实验方法16
可按照反应流程(16),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(16)中,卤素为氯、溴或碘。
反应流程16
实验方法17
可按照反应流程(17)和下列参考文献:a)Tetrahedron2001,57(19),4059-4090或b)Tetrahedron2001,57(21),4489-4505,在合适的碱(例如二异丙基氨基锂或丁基锂)存在下,通过使式(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(17)中,卤素可为氯、溴或碘,E表示环丙基。如有需要,可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17
实验方法18
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,通过在碱(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。
反应流呈18
实验方法19
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(19)中予以说明,其中所有变量如上文所述定义。可例如在合适的溶剂(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(19)中予以说明,其中所有变量如上文所述定义。
反应流程19
实验方法20
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(20)中,所有变量如式(I)所定义,卤素为氯、溴或碘。
反应流程20
实验方法21
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(21)中,所有变量如式(I)所定义,卤素为氯、溴或碘。
反应流程21
实验方法22
可按照反应流程(22),通过使式(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(22)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(22)中,R2如式(I)中所定义,卤素为氯、溴或碘。
反应流程22
实验方法23
可按照应用本领域已知方法的反应流程(23),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(23)中,所有变量如式(I)所定义。
反应流程23
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CAS1082662-38-1、CAS1228117-53-0、CAS109926-35-4、CAS1035093-81-2、CAS2338-18-3、CAS5769-08-4、CAS5769-09-5、CAS911826-56-7、CAS946413-75-8、CAS173601-49-5、CAS946125-04-8、CAS548465-08-3的化合物或其前体例如CAS183255-68-7、CAS907997-17-5、CAS741260-53-7、CAS1150633-65-0和CAS741260-59-3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。在一个典型的方法中,除非另作说明,否则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1N 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化物。
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化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化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化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化物或本发明的药物组合物,其用于治疗、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所述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化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所述神经和精神障碍的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(migraineheadachee))、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 malstatus 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化物。
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化物。
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化物。
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化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化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化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0.5nM-200μM、更通常5nM-50μM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0.01mg/kg-约50mg/kg体重、优选约0.01mg/kg-约25mg/kg体重、更优选约0.01mg/kg-约10mg/kg体重、更优选约0.01mg/kg-约2.5mg/kg体重、甚至更优选约0.05mg/kg-约1mg/kg体重、更优选约0.1-约0.5mg/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、改善式(I)化合物或其它药物可对其具有效用的疾病或病况或降低所述疾病或病况的风险,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、其溶剂化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、其溶剂化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’sPharmaceutical 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0.1mg与约1000mg之间的活性化合物。优选的单位剂量介于1mg-约500mg之间。更优选的单位剂量介于1mg-约300mg之间。甚至更优选的单位剂量介于1mg-约100mg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70kg成人的总剂量为每次给药0.001-约15mg/kg受试者体重的范围。优选剂量为每次给药0.01-约1.5mg/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1mg-约100mg片剂或1mg-约300mg,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、改善式(I)化合物或其它药物可对其具有效用的疾病或病况或降低所述疾病或病况的风险。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、改善式(I)化合物或其它药物可对其具有效用的疾病或病况或降低所述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化物,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;“DMSO”意指二甲亚砜;“EtOAc”意指乙酸乙酯;“DCM”或“CH2Cl2”意指二氯甲烷;“DCE”意指二氯乙烷;“DME”意指1,2-二甲氧基乙烷;“DIPEA”意指N,N-二异丙基乙胺;“HPLC”意指高效液相色谱法;“l”或“L”意指升;“LCMS”意指液相色谱法/质谱法;“LRMS”意指低分辨率质谱分析法/质谱;“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;“MS”意指质谱法;“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;“NH4CI”意指氯化铵;“Pd/C”意指披钯活性碳;“Pd(PPh3)4”意指四(三苯基膦)-钯(0);“PPh3”意指三苯基膦;“eq”意指当量;“RP”意指反相;“r.t.”意指室温;“Rt”意指保留时间;“mp”意指熔点;“min”意指分钟;“h”意指小时;“s”意指秒钟;“quant.”意指定量;“sat.”意指饱和,“TOF”意指飞行时间。
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。
薄层色谱法(TLC)使用试剂级溶剂在硅胶60F254板(Merck)上进行。开柱色谱法采用标准技术在粒径筛目=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ArmenInstrument的SPOT或LAFLASH系统中的不规则硅胶,粒径15-40μm(正相一次性快速柱)中进行自动快速柱色谱法。
中间体1(I-1)
2,3-二氯-4-碘-吡啶(I-1)
在氮气氛下,向于-78℃冷却的正丁基锂(27.6ml,69mmol,2.5M的己烷溶液)的无水Et2O(150ml)溶液中滴加2,2,6,6-四甲基-哌啶(11.64ml,69mmol)。在-78℃下搅拌所得反应混合物10分钟,然后滴加2,3-二氯吡啶(10g,67.57mmol)的无水THF(75ml)溶液。在-78℃下搅拌混合物30分钟。然后加入碘(25.38g,100mmol)的无水THF(75ml)溶液。使混合物加热至室温过夜,用Na2S2O3(饱和水溶液)猝灭后,用EtOAc萃取两次。合并的有机萃取物用NaHCO3(饱和水溶液)洗涤、干燥(Na2SO4)后真空浓缩。粗制残余物用庚烷沉淀,滤出后干燥,得到中间体化合物I-1(8.21g,44%),为灰白色乳膏状固体。
中间体2(I-2)
(3-氯-4-碘-吡啶-2-基)肼(I-2)
向化合物I-1(8g,29.21mmol)的1,4-二噁烷(450ml)溶液中加入肼一水合物(14.169ml,175.255mmol)。将反应混合物在密封管中于70℃加热16小时。冷却后,加入NH4OH(32%水溶液),将所得混合物真空浓缩。将如此获得的白色固体残余物溶于EtOH。将由此获得的悬浮液加热,然后滤出,使滤过溶液冷却至室温。将所形成的沉淀滤出,然后滤液经真空浓缩,得到中间体化合物I-2(2.67g,52%),为白色固体。
中间体3(I-3)
N-(3-氯-4-碘-吡啶-2-基)-2-环丙基乙酰肼(I-3)
向于0℃冷却的I-2(0.73g,2.709mmol)的无水DCM(8ml)溶液中加入Et3N(0.562ml,4.064mmol)和环丙基-乙酰氯(0.385g,3.251mmol)。在室温下搅拌所得反应混合物16小时,然后加入NaHCO3(饱和水溶液)。所得溶液用DCM萃取。有机层经分离、干燥(MgSO4)后真空浓缩,得到中间体化合物I-3(0.94g,99%)。
中间体4(I-4)
8-氯-3-环丙基甲基-7-碘[1,2,4]三唑并[4,3-a]吡啶(I-4)
将I-3(0.74g,2.389mmol)在160℃下加热40分钟。冷却后,由此获得的褐色树胶状物用DIPE研磨,得到中间体化合物I-4(0.74g,93%)。
中间体5(I-5)
7-乙烯基-3-环丙基甲基-8-氯[1,2,4]三唑并[4,3-a]吡啶(I-5)
在氮气氛下向I-4(12g,35.976mmol)、含乙烯基硼酸频哪醇酯(6.713ml,39.573mmol)的NaHCO3(饱和水溶液,90ml)的1,4-二噁烷(360ml)溶液中加入Pd(PPh3)4(2.079,1.8mmol)。将所得混合物在密封管中于100℃加热16小时。冷却后,所得反应混合物用NaHCO3(饱和水溶液)稀释后,用DCM萃取。有机层经分离、干燥(Na2SO4)后真空浓缩。残余物用柱色谱法纯化(二氧化硅;含EtOAc的DCM0/100-80/20)。收集所需流分后真空浓缩。由此获得的残余物用DIPE研磨,得到中间体I-5(6.09g,72%),为黄色固体。
中间体6(I-6)
8-氯-3-(环丙基甲基)[1,2,4]三唑并[4,3-a]吡啶-7-甲醛(I-6)
向在室温下搅拌的I-5(6.09g,25.059mmol)的1,4-二噁烷(320ml)溶液中加入四氧化锇(2.5%的叔丁醇溶液,13.483ml,1.042mmol)。然后滴加高碘酸钠(16.721g,78.177mmol)的水(80ml)溶液。在室温下搅拌所得混合物2小时,然后,用水稀释,用EtOAc萃取。有机层经分离,干燥(Na2SO4)后真空浓缩。固体残余物用Et2O研磨,过滤后真空干燥,得到中间体I-6(5.48g,89%),为乳膏状固体。
中间体7(I-7)
2,4-二氯-3-碘-吡啶(I-7)
在氮气氛下,向于-78℃冷却的2,4-二氯吡啶(5.2g,35.14mmol)和DIPEA(3.91g,38.65mmol)的无水THF(40mL)溶液中滴加正丁基锂(24.16mL,38.65mmol,1.6M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(9.81g,38.651mmol)的无水THF(20mL)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。粗产物用柱色谱法纯化(硅胶;含DCM的庚烷0/100-20/80)。收集所需流分后真空浓缩,得到中间体化合物I-7(7.8g,81%)。
中间体8(I-8)
2,4-二氯-3-三氟甲基-吡啶(I-2)
向化合物I-7(2g,7.30mmol)与DMF(50mL)的混合物中加入氟磺酰基-二氟-乙酸甲酯[C.A.S.680-15-9](1.86ml,14.60mmol)和碘化铜(I)(2.79g,14.60mmol)。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。粗产物用柱色谱法纯化(硅胶,DCM)。收集所需流分后真空浓缩,得到中间体化合物I-8(1.5g,95%)。
中间体9(I-9)
4-苄氧基-2-氯-3-三氟甲基-吡啶(I-9)
向于0℃冷却的NaH(0.49g,12.73mmol,60%矿物油)的DMF(50mL)悬浮液中加入苯甲醇(1.26mL,12.2mmol)。将所得混合物搅拌2分钟。然后;加入中间体化合物I-8(2.5g,11.57mmol)。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Et2O萃取。有机层经分离,干燥(Na2SO4)后真空浓缩。粗产物用柱色谱法纯化(硅胶;含DCM的庚烷0/100-100/0)。收集所需流分后真空浓缩,得到中间体化合物I-9(1.1g,33%)。
中间体10(I-10)
4-(苄氧基)-2-肼基-3-(三氟甲基)吡啶(I-10)
向化合物I-9(1.09g,3.79mmol)的1,4-二噁烷(9mL)悬浮液中加入肼一水合物(3.67mL,75.78mmol)。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-10(0.89g,83%),为白色固体。
中间体11(I-11)
N′-[4-(苄氧基)-3-(三氟甲基)吡啶-2-基]-2-环丙基乙酰肼(I-11)
向I-10(0.89g,3.14mmol)的无水DCM(3mL)溶液中加入Et3NH(0.65mL,4.71mmol)和环丙基-乙酰氯[C.A.S.543222-65-5](0.37g,3.14mmol)。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-11(1.1g,96%)。
中间体12(I-12)
丙酸N′-(4-苄氧基-3-三氟甲基-吡啶-2-基)-酰肼(I-12)
中间体I-12按照中间体I-11所述相同方法合成。自I-10(3.2g,11.3mmol)开始并将环丙基氯置换成丙酰氯。在室温下搅拌反应混合物18小时,得到中间体I-12(2.3g,59.7%),为白色固体。
中间体13(I-13)
乙氧基-乙酸N′-(4-苄氧基-3-甲基-吡啶-2-基)-酰肼(I-13)
中间体I-13按照中间体I-11所述相同方法合成。自I-10(4g,14.12mmol)开始并将环丙基氯置换成乙氧基-乙酰氯,得到中间体I-13(5g,96%)。化合物无需纯化便用于下一步。
中间体14(I-14)
7-氯-3-环丙基甲基-8-三氟甲基[1,2,4]三唑并[4,3-a]吡啶(I-14)
将I-11(1.14g,1.87mmol)和三氯氧化磷(V)(0.35g,3.74mmol)的CH3CN(10mL)溶液在微波辐射下于150℃加热10分钟。冷却后,所得反应混合物用DCM稀释,用NaHCO3(饱和水溶液)洗涤,干燥(Na2SO4)后真空浓缩。粗产物用柱色谱法纯化(硅胶;NH3在MeOH中的7M溶液/DCM0/100-20/80)。收集所需流分后真空浓缩,得到中间体化合物I-14(0.261g,51%),为白色固体。
中间体15(I-15)
7-氯-3-乙氧基甲基-8-三氟甲基-[1,2,4]三唑并[4,3-a]吡啶(I-15)
中间体I-15按照中间体1-14所述类似方法合成。自I-13(12.4g,30.3mmol)和DIPEA(6.35ml,36.45mmol)开始,得到中间体I-15(2.5g,29.8%),为浅褐色固体。
中间体16(I-16)
7-氯-3-乙基-8-三氟甲基-[1,2,4]三唑并[4,3-a]吡啶(I-16)
中间体I-16按照中间体I-14所述类似方法合成。自I-12[2.3g(纯度80%),5.4mmol]和DIPEA(0.707ml,4.039mmol)开始,得到中间体I-16(1.12g,83%),为褐色固体。
中间体17(I-17)
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-17)
将I-14(1.65g,5.986mmol)、乙烯基硼酸频哪醇酯(1.218ml,7.183mmol)、Pd(PPh3)4(0.346,0.3mmol)和NaHCO3(饱和水溶液,12.5ml)在1,4-二噁烷(64.5ml)中的悬浮液在微波辐射于150℃加热13分钟。冷却后,所得反应混合物用EtOAc/水稀释后,经硅藻土过滤。滤液用水和NaCl(饱和水溶液)洗涤,用EtOAc萃取。有机层经分离,干燥(Na2SO4)后真空浓缩。残余物再次用柱色谱法纯化(二氧化硅;EtOAc/DCM,0/100-40/60)。收集所需流分后真空浓缩,得到中间体I-17(1.34g,83.7%)。
中间体18(I-18)
3-乙基-8-三氟甲基-7-乙烯基-[1,2,4]三唑并[4,3-a]吡啶(I-18)
中间体I-18按照中间体I-17所述相同方法合成。自I-16(2.8g,15.22mmol)开始,合成中间体I-18(4g,94%),为乳膏状固体。
中间体19(I-19)
3-乙氧基甲基-8-三氟甲基-7-乙烯基-[1,2,4]三唑并[4,3-a]吡啶(I-19)
中间体I-19按照中间体I-17所述相同方法合成。自I-15(4g,14.3mmol)开始,得到中间体I-19(定量收率),为浅褐色固体。
中间体20(I-20)
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-20)
将含I-17(6.24g,21.014mmol)、高碘酸钠(13.484g,63.041mmol)、四氧化锇(2.5%的叔丁醇溶液,10.873ml,0.841mmol)的水(55ml)和1,4-二噁烷(221ml)的溶液在室温下搅拌2小时。所得反应混合物用EtOAc/水稀释后,经硅藻土过滤。滤液用EtOAc萃取。有机层经分离,干燥(Na2SO4)后真空浓缩。固体残余物用Et2O洗涤,过滤后真空干燥,得到中间体I-20(3.84g,67.9%)。
中间体21(I-21)
3-乙基-8-三氟甲基-[1,2,4]三唑并[4,3-a]吡啶-7-甲醛(I-21)
中间体I-21按照中间体I-20所述相同方法合成。自I-18(4g,16.5mmol)开始,得到中间体I-21(1.88g,46.6%),为乳膏状固体。
中间体22(I-22)
3-乙氧基甲基-8-三氟甲基-[1,2,4]三唑并[4,3-a]吡啶-7-甲醛(I-22)
中间体I-22按照中间体I-20所述相同方法合成。自I-19(3.88g,14.3mmol)开始,得到中间体I-22(2.2g,56.7%),为浅褐色固体。
中间体23(I-23)
7-羟基甲基-3-环丙基甲基-8-三氟甲基[1,2,4]三唑并[4,3-a]吡啶(I-23)
向在0℃下搅拌的I-20(1.73g,6.426mmol)的MeOH(58ml)溶液中分批加入硼氢化钠(0.243,6.426mmol)。在室温下搅拌所得混合物1小时。将所得混合物真空浓缩。残余物用水和NaCl(饱和水溶液)处理后,用EtOAc萃取。有机层经分离后真空浓缩。残余物用柱色谱法纯化(二氧化硅;含MeOH/NH3的DCM0/100-5/95)。收集所需流分后真空浓缩,得到中间体I-23(1.015g,58%),为褐色糖浆状物。
中间体24(I-24)
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-24)
向在0℃下搅拌的I-23(1.341g,9.678mmol)和Et3N(0.778ml,5.612mmol)的DCM(42ml)溶液中滴加甲磺酰氯(0.749ml,9.678mmol),在室温下搅拌2小时。所得混合物用NaHCO3(饱和水溶液)处理后,用DCM萃取。有机层经分离后真空浓缩,得到中间体I-24(2.6g,87%)。
中间体25(I-25)
三氟-甲磺酸1,4-二氧杂-螺[4.5]癸-7-烯-8-基酯(I-25)
在-78℃和氮气氛下,将正丁基锂(2.5M的THF溶液,8.64mL,21.6mmol)滴加到DIPEA(3.12mL,22.26mmol)的12ml THF溶液中。搅拌混合物15分钟,然后,滴加1,4-环己二酮单乙烯乙缩醛(3g,19.208mmol)的15ml THF溶液。在-78℃下搅拌混合物1小时。然后,加入N-苯基-三氟甲烷磺酰亚胺(6.924g,19.381mmol)的15ml THF溶液,将混合物保持在冰水浴上,然后使之加温至室温并搅拌16小时。将混合物真空蒸发,粗产物用短开柱纯化(二氧化硅;含EtOAc的庚烷0/100-15/85),收集所需流分后真空浓缩,得到中间体I-25(6.13g,纯度89%),为浅褐色油状物,其无需任何进一步纯化便用于下一反应步骤。
中间体26(I-26)
8-(2,4-二氟-苯基)-1,4-二氧杂-螺[4.5]癸-7-烯(I-26)
将中间体I-25(6.11g,纯度89%,18.86mmol)、2,4-二氟苯基-硼酸(4.55g,28.86mmol)、LiCl(3.26g,1.41mmol)、Na2CO3(8.1g,76.46mmol)在DME(70.2mL)和H2O(38mL)中的混合物用氮气流脱氧。然后,加入四(三苯基膦)钯(0)(1.63g,1.41mmol),在氮气氛下,将混合物在回流下搅拌5小时。冷却后,混合物用EtOAc/H2O稀释,经硅藻土过滤。滤液用饱和NaHCO3洗涤后,用EtOAc萃取。有机层经分离,干燥(Na2SO4),过滤后,真空蒸发溶剂。粗产物用2次快速柱色谱法纯化(二氧化硅;EtOAc/庚烷0/100-5/95,然后二氧化硅;CH2Cl2100%)。收集所需流分后真空浓缩,得到中间体I-26(1.56g,32.7%),为油状物。
中间体27(I-27)
4-(2,4-二氟-苯基)-环己酮(I-27)
将中间体I-26(1.5g,5.89mmol)在HCl(5M的H2O溶液,26mL)和THF(26mL)的溶液在回流下搅拌4小时。混合物用冰水浴冷却,用Na2CO3碱化后,用EtOAc萃取。有机层经分离,干燥(Na2SO4),过滤后,真空蒸发溶剂。粗产物用快速柱色谱法纯化(二氧化硅;EtOAc/庚烷0/100-15/85)。收集所需流分后真空浓缩,得到中间体I-27,为在静置时固化的无色油状物。
中间体28(I-28)
顺式-二苯甲基-[4-(2,4-二氟-苯基)-环己基]-胺(I-28)
将中间体I-27(1.05g,4.99mmol)、二苯甲基胺(0.94mL,5.49mmol)在DME(30mL)中的混合物在室温下搅拌16小时。然后,加入三乙酰氧基硼氢化钠(1.58g,7.49mmol),在室温下搅拌混合物4天。将混合物在0℃下用饱和Na2CO3处理后,用EtOAc萃取。有机层经分离,干燥(Na2SO4),过滤后,真空蒸发溶剂。粗产物用快速柱色谱法纯化(二氧化硅;EtOAc/庚烷10/90)。收集所需流分后真空浓缩,得到中间体I-28(1.32g,70%),为在静置时固化的无色油状物。
中间体29(I-29)
顺式-4-(2,4-二氟-苯基)-环己胺(I-29)
将中间体I-28和披钯活性碳10%(1.18g,3.47mmol)在HCO2H/MeOH4.4%(60mL)中的混合物在室温下搅拌过夜。冷却的粗制反应物经硅藻土过滤,催化剂用MeOH和MeOH/NH3洗涤。将滤液蒸发至干,残余物用开柱色谱法纯化(二氧化硅;含MeOH/NH3的CH2Cl20/100和15/85)。收集所需流分后真空浓缩,得到中间体I-29(0.67g,91.3%),为白色固体。
中间体30(I-30)
顺式-4-(2,4-二氟-苯基)-环己醇(I-30)
在氮气氛下,向在-78℃下冷却的中间体I-27(1.36g,6.46mmol)的THF(17mL)溶液中滴加(7.18mL,7.18mmol),在-78℃下搅拌所得反应混合物2小时,并在室温下搅拌过夜。然后在-78℃下加入更多的(1.3ml),在-78℃下搅拌混合物2小时,并在室温下再搅拌2小时。冷却的粗制反应物逐滴用水、接着用NaOH(1M的H2O溶液,13.12ml)和含水H2O2(13.12ml)猝灭。混合物用饱和Na2CO3(197ml)稀释后,用Et2O(3×70ml)萃取。有机层经分离,干燥(Na2SO4),过滤后真空蒸发。残余物用快速色谱法纯化(二氧化硅;EtOAc/庚烷0∶100-20∶80),得到I-30(0.72g,70%)。
中间体31(I-31)
顺式-甲磺酸4-(2,4-二氟-苯基)-环己酯(I-31)
向用冰水浴冷却的中间体I-30(0.97g,4.57mmol)和Et3NH(1.26ml,9.14mmol)的DCM(20mL)溶液中滴加甲磺酰氯(0.531mL,6.85mmol),将所得反应混合物搅拌2小时。粗制反应物用水和盐水洗涤,用CH2Cl2萃取,干燥(Na2SO4),过滤后真空蒸发,得到中间体I-31(1.52g,87%纯度)。残余物无需任何进一步的纯化便用于下一反应步骤。
中间体32(I-32)
反式-1-(4-叠氮基-环己基)-2,4-二氟-苯(I-32)
将中间体I-31(0.892g,纯度87%,2.67mmol)、叠氮化钠(0.265g,4mmol)在DMSO(9mL)中的混合物在微波辐射下于120℃加热10分钟。混合物用水洗涤,用EtOAc萃取,有机层经分离,干燥(Na2SO4)后真空蒸发。残余物用快速色谱法纯化(二氧化硅;EtOAc/庚烷0∶100-4∶96),收集所需流分后蒸发,得到中间体I-32(收率76.8%)。
中间体33(I-33)
反式-4-(2,4-二氟-苯基)-环己胺(I-33)
使中间体I-32(0.685g,2.88mmol)和Pd/C在EtOH(20mL)中的悬浮液在室温下氢化(大气压)过夜。粗制混合物经硅藻土过滤,将滤液真空蒸发,得到中间体I-33(0.52g,85%),其原样用于下一反应步骤。中间体34(I-34)
7-(氯甲基)-3-(环丙基甲基)-8-(三氟甲基)[1,2,4]三唑并[4,3-a]-吡啶(I-34)
在0℃下向在密封管中的I-23(0.376g,1.39mmol)的CH2Cl2(4mL)溶液中分批加入吡啶(0.336mL,4.16mmol),接着分批加入对甲苯磺酰基氯(0.529g,0.77mmol),在室温下搅拌混合物24小时
混合物用HCl(2N)处理后,用CH2Cl2萃取。有机层经分离,干燥(Na2SO4),过滤后真空蒸发。粗产物用快速柱色谱法纯化(二氧化硅;含MeOH/NH3的CH2Cl20/100和4/96)。收集所需流分后真空浓缩,得到中间体I-34(114.3mg,28%),为浅黄色固体。
中间体35(I-35)
3-(环丙基甲基)-7-(碘甲基)-8-(三氟甲基)[1,2,4]三唑并[4,3-a]-吡啶(I-35)
方法A
将I-34(0.114g,0.40mmol)、NaI(0.237g,1.58mmol)和丙酮(8.4mL)的混合物在密封管中在回流下搅拌1小时。将混合物浓缩,用水稀释,用CH2Cl2萃取。有机层经分离,干燥(Na2SO4),过滤后,将溶剂蒸发至干。残余物无需进一步纯化便用于下一步。
方法B
将I-24(16.485mg,0.05mmol)、NaI(28.29mg,0.19mmol)和丙酮(1mL)的混合物在密封管中在回流下搅拌1小时。将混合物浓缩,用水稀释,用CH2Cl2萃取。有机层经分离,干燥(Na2SO4),过滤后,将溶剂蒸发至干。残余物无需进一步纯化便用于下一步。
中间体36(I-36)
(4E)-2,3-二氢-4H-苯并吡喃-4-酮肟(I-36)
将乙酸钠(503.852mg,6.14mmol)加入4-苯并二氢吡喃酮([CAS491-37-2],700mg,4.73mmol)和盐酸羟胺([CAS5470-11-1],426.808mg,6.14mmol)在EtOH(31mL)中的搅拌溶液中。在80℃下搅拌混合物16小时。使混合物冷却至室温,用EtOAc稀释,并用水洗涤。有机层经分离,干燥(Na2SO4),过滤后真空浓缩,得到I-36(727.7mg,93%),为白色固体,其无需进一步纯化便用于下一步。
中间体37(I-37)
3,4-二氢-2H-苯并吡喃-4-胺(I-37)
使I-36(727.7mg,4.46mmol)的NH3(7N的MeOH溶液,85mL,595mmol)溶液在H-cube反应器中氢化(1.5mL/分钟,70mm,兰尼镍柱体(Raney Ni Cartridge),全H2模式,80℃,1个循环)。将产物真空蒸发,得到I-37,为绿色油状物,其无需进一步纯化便使用。
中间体38(I-38)
顺式-2-苯基四氢-2H-吡喃-4-醇(I-38)
在5℃下,将硫酸(1.05mL,19.70mmol)滴加到3-丁烯-1-醇(1.79mL,20.80mmol)和苯甲醛(无水,1.076mL,10.59mmol)的搅拌悬浮液中,在室温下搅拌混合物16小时。将冰水加入混合物中;混合物然后用1N NaOH碱化后,用EtOAc萃取。有机层经分离,干燥(Na2SO4)后真空蒸发,得到粗产物,将其用快速色谱法纯化(二氧化硅;MeOH/DCM0/100-5/95)。收集所需流分后真空蒸发溶剂,得到I-38(600mg,16%),为褐色油状物。
中间体39(I-39)
顺式-2-苯基四氢-2H-吡喃-4-基甲磺酸酯(I-39)
在0℃下,将DIPEA(1.95mL,11.32mmol)和甲磺酰氯(350mg,3.06mmol)加入I-38(540mg,2.58mmol)在DCM(10mL)中的搅拌悬浮液中,在室温下搅拌混合物2小时。混合物用水和盐水稀释后,用DCM萃取。有机层经分离,干燥(Na2SO4),过滤后,真空蒸发溶剂,得到I-39,为褐色油状物。
中间体40(I-40)
反式-4-叠氮基-2-苯基四氢-2H-吡喃(I-40)
将叠氮化钠(8g,121.18mmol)加入I-39(10g,31.21mmol)在DMF(128.5mL)的搅拌悬浮液中,在100℃下搅拌混合物4小时。混合物然后用水和盐水稀释后,用DCM萃取。有机层经分离,干燥(Na2SO4),过滤后,真空蒸发溶剂,得到粗产物,将其用色谱法纯化(二氧化硅;DCM100%)。收集所需流分后真空蒸发溶剂,得到I-40(6.6g),为黄色泡沫。
中间体41(I-41)、41a(I-41a)和41b(I-41b)
反式-2-苯基四氢-2H-吡喃-4-胺(I-41)、(2*R,4*R)-2-苯基四氢-2H-吡喃-4-胺(I-41a)、(2*S,4*S)-2-苯基四氢-2H-吡喃-4-胺(I-41b)
在室温和标准压力下,将I-40(6.6g,32.31mmol)的EtOH(200.87mL)溶液用作为催化剂的Pd(145.459mg,1.37mmol)氢化过夜。粗制反应物经硅藻土过滤,将滤液蒸发至干。残余物用快速色谱法纯化(二氧化硅;MeOH/DCM0/100-10/90)。收集所需流分后真空蒸发溶剂,得到I-41(1.3g,23%),为黄色油状物。
I-41然后用手性SFC在CHIRALPAK AD-H5μtm250×20mm上纯化(流动相:0.3%异丙胺,80%CO2,20%MeOH),得到I-41a(563mg,10%)和I-41b(610mg,11%),为乳膏状固体。
中间体42(I-42)
反式-4-苯基四氢呋喃-3-醇
在氮气、0℃下,将3,4-环氧基四氢呋喃(3.9g,45.30mmol)的无水THF(9mL)溶液滴加到苯基溴化镁(15.1mL,45,30mmol)、CuI(604.13mg,3.17mmol)和无水THF(5mL)的搅拌悬浮液中,在室温下搅拌混合物3小时。混合物用NH4Cl饱和水溶液稀释后,用EtOAc萃取。有机层经分离,干燥(Na2SO4),过滤后真空蒸发。
按照上述方法,使3,4-环氧基-四氢呋喃(1.0g,11.62mmol)、苯基溴化镁(3.872mL,11.62mmol)、CuI(155.67mg,0.813mmol)和无水THF(3.6mL的总体积)反应,得到第二批。
将获自上两批的残余物混合,通过快速色谱法纯化(二氧化硅;DCM/MeOH0/100-10/90)。收集所需流分后真空蒸发,得到I-42(5.5g,74%),为黄色油状物。
中间体43(I-43)
(4S)-4-苯基二氢呋喃-3(2H)-酮(I-43)
使I-42(2.02g,12.30mmol)的DCM溶液在室温下以5mL/分钟通过氧化铬(VI)柱体(50g二氧化硅载琼斯试剂0.6mmol/克,2.609g,24.60mmol)。使反应溶液蒸发,得到I-43(1.36g,68%),为褐色油状物。
中间体44(I-44)
顺式-N-苄基-4-苯基四氢呋喃-3-胺(I-44)
将苄胺(0.859g,8.02mmol)滴加到I-43(1g,6.17mmol)在无水DCM(25mL)中的搅拌悬浮液中,在室温下搅拌混合物40分钟。在此之后,加入乙酸(352.97μL,6.17mmol)和三乙酰氧基硼氢化钠(1.96g,9.25mmol),在室温下搅拌混合物18小时。混合物用水稀释,用DCM萃取。有机层经分离,干燥(Na2SO4),过滤后真空蒸发,得到I-44(500mg,32%),为褐色油状物。
中间体45(I-45)
顺式-N-苄基-4-苯基四氢呋喃-3-胺(I-45)
将I-44(500mg,1.97mmol)的EtOH(40mL)溶液在H-Cube反应器中氢化(1.5mL/分钟(70mm)Pd(OH)2/C柱体,1.97mmol,全H2,80℃,1个循环)。将溶剂真空蒸发,得到残余物,将其用快速色谱法纯化(二氧化硅;NH3在MeOH中的7M溶液/DCM0/100-10/90)。收集所需流分后真空蒸发溶剂,得到I-45(212.4mg,66%),为黄色油状物。
最终产物
实施例1(E-1)
3-(环丙基甲基)-N-[反式-4-(2,4-二氟苯基)环己基]-8-(三氟-甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺(E-1)
将中间体I-20(0.11g,0.409mmol)加入中间体I-33(0.103g,0.49mmol)的DCE(2.4mL)溶液中,将混合物在室温下搅拌2小时。然后,加入AcOH(0.041mL)和三乙酰氧基硼氢化钠(0.095g,0.44mmol),将混合物在室温下搅拌18小时。然后加入更多的三乙酰氧基硼氢化钠(1.1当量,0.095g),再搅拌混合物2小时。在此之后,再次加入更多的三乙酰氧基硼氢化钠(0.55当量,0.047g),再连续搅拌2个小时。混合物然后用饱和NaHCO3处理,用CH2Cl2萃取。有机层经分离,干燥(Na2SO4),过滤后,真空蒸发溶剂。粗产物用快速柱色谱法纯化两次(二氧化硅;含MeOH/NH3的CH2Cl20/100-4/96)。收集所需流分后真空浓缩。最后,产物用DIPE研磨,过滤后干燥,得到产物E-1(0.085g,45%),为白色固体化合物。M.P.110.1℃(Mettler FP81HT/FP90)。
实施例2(E-2)
3-(环丙基甲基)-N-[1-(2,4-二氟苯基)-4-哌啶基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺(E-2)
将中间体I-20(0.11g,0.41mmol)加入1-(2,4-二氟-苯基)哌啶-4-胺[(C.A.S.1016777-81-3),0.133g,0.49mmol]的DCE(2.4mL)溶液中,将混合物在室温下搅拌2小时。然后,加入AcOH(0.041mL)和三乙酰氧基硼氢化钠(0.095g,0.45mmol),将混合物在室温下搅拌18小时。此后,加入更多的三乙酰氧基硼氢化钠(0.8当量,0.069g),将混合物在室温下再搅拌2小时。混合物用饱和NaHCO3处理后,用CH2Cl2萃取。有机层经分离,干燥(Na2SO4),过滤后,真空蒸发溶剂。粗产物用柱色谱法纯化两次(二氧化硅;含EtOAc的CH2Cl20/100-100/0;然后MeOH/CH2Cl20/100-5/95)。收集所需流分后真空浓缩。最后,产物用DIPE研磨,过滤后干燥,得到E-2(0.079g,41.3%),为白色固体化合物。M.P.118.2℃(Mettler FP81HT/FP90)。
实施例3(E-3)
3-(环丙基甲基)-N-(反式-4-苯基环己基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺(E-3)
将中间体I-24(0.25g,0.64mmol)的CH3CN(4ml)溶液加入在密封管中的反式-4-苯基环己胺[(C.A.S.5769-10-8),0.14g,0.8mmol]和DIPEA(0.166mL,0.961mmol)在CH3CN(4ml)中的搅拌溶液中。在85℃下搅拌混合物6小时,然后真空蒸发溶剂。粗产物用柱色谱法纯化两次(二氧化硅;含MeOH/NH3的CH2Cl20/100-5/95;然后含EtOAc的CH2Cl20/100-100/0)。收集所需流分后真空浓缩,得到所需化合物,纯度仅63%。因此混合物再次用RP HLC纯化(C18XBridgeTM(30×1005μm),流动相(梯度自80%0.1%NH4CO3H/NH4OH pH9的水溶液,20%CH3CN至0%0.1%NH4CO3H/NH4OH pH9的水溶液,100%CH3CN)),得到E-3(0.034g,12.2%),为白色固体。
实施例4(E-4)
3-乙基-N-(反式-4-苯基环己基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]-吡啶-7-甲胺(E-4)
将三乙酰氧基硼氢化钠(0.104g,0.49mmol)加入I-21(0.1g,0.33mmol,纯度80%)和反式-4-苯基环己胺[(C.A.S.5769-10-8)、0.069g,0.39mmol]在DCE(3.5mL)中的搅拌溶液中。将混合物在微波辐射下于120℃加热20分钟。然后用饱和NaHCO3处理后,用CH2Cl2萃取。有机层经分离,干燥(Na2SO4),过滤后,真空蒸发溶剂。然后将粗制混合物悬浮于MeOH(3.5mL)中,加入硼氢化钠(0.013g,0.39mmol)。在室温下搅拌混合物5小时。有机层经分离,干燥(Na2SO4),过滤后,真空蒸发溶剂。粗产物用快速柱色谱法纯化(二氧化硅;NH3在MeOH中的7N溶液/DCM0/100-10/90),收集所需流分后真空浓缩,得到所需产物,纯度89%。化合物进一步用RP HPLC纯化(C18XBridgeTM(19×1005um))。流动相(梯度自80%0.1%NH4CO3H/NH4OH pH9的水溶液,20%CH3CN至0%0.1%NH4CO3H/NH4OH pH9的水溶液,100%CH3CN),得到E-4(0.028g,21%),为白色固体。M.P.>300℃(MettlerFP81HT/FP90)。
实施例5(E-5)
3-(环丙基甲基)-N-[顺式-4-(2,4-二氟苯基)环己基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺(E-6)
实施例E-5按照E-1所述相同方法合成。自I-20(0.11g,0.41mmol)开始并将中间体I-33置换成中间体I-29,得到了最终产物E-5(0.088g,46.3%),为白色固体化合物。
M.P.123.1℃(Mettler FP81HT/FP90)。
实施例6(E-6)
3-(环丙基甲基)-N-(2,3-二氢-1H-茚-2-基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺(E-6)
实施例E-6按照E-1所述相同方法合成。自I-20(0.11g,0.41mmol)开始并将中间体I-33置换成2-氨基茚满[(C.A.S.2975-41-9),0.058mL,0.44mmol],得到最终产物E-6(0.065g,45.4%),为灰白色固体化合物。M.P.>300℃(Mettler FP81HT/FP90)。
实施例7(E-7)
3-(环丙基甲基)-N-(顺式-4-苯基环己基)-8-(三氟甲基)-1,2,4-三唑并-[4,3-a]吡啶-7-甲胺(E-6)
实施例E-7按照E-1所述相同方法合成。自I-20(0.11g,0.41mmol)和顺式-4-苯基环己胺[(C.A.S.5992-23-4),0.050mg,0.4mmo1]开始,得到最终产物E-7(0.050g,35.2%),为白色固体化合物。M.P.212.8℃(Mettler FP81HT/FP90)。
实施例8(E-8)
3-乙基-N-(顺式-4-苯基环己基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺(E-8)
实施例E-8按照E-4所述相同方法合成。自I-21(0.1g,0.33mmol,纯度80%)和顺式-4-苯基环己胺(C.A.S.5992-23-4)开始,得到最终产物E-8(0.012g,9.2%),为黄色油状物。
实施例9(E-9)
N-[顺式-4-(2,4-二氟苯基)环己基]-3-乙基-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺(E-9)
实施例E-9按照E-4所述相同方法合成。自I-21(0.1g,0.41mmol)和I-29开始,得到最终产物E-9(0.003g),为透明油状物。
实施例10(E-10)
3-(乙氧基甲基)-N-(顺式-4-苯基环己基)-8-(三氟甲基)-1,2,4-三唑并-[4,3-a]吡啶-7-甲胺(E-10)
实施例E-10按照E-1所述相同方法合成,自I-22(0.15g,0.55mmol)和顺式-4-苯基环己胺(C.A.S.5992-23-4)开始。在加入三乙酰氧基硼氢化钠后,将反应物在微波辐射下于120℃加热20分钟,而不是对最终产物E-1合成所报道的室温。得到所需化合物E-10(0.037g,15.5%),为乳膏状固体。M.P.137.3℃(Mettler FP81HT/FP90)。
实施例11(E-11)
3-(乙氧基甲基)-N-(反式-4-苯基环己基)-8-(三氟甲基)-1,2,4-三唑并-[4,3-a]吡啶-7-甲胺(E-10)
实施例E-11按照E-1所述相同方法合成,自I-22(0.15g,0.55mmol)和反式-4-苯基环己胺(C.A.S.5769-10-8)开始。在加入三乙酰氧基硼氢化钠后,将反应物在微波辐射下于120℃加热20分钟,而不是最终产物E-1合成所报道的室温。得到所需化合物E-11(0.042g,20.1%),为白色固体。M.P.144.2℃(Mettler FP81HT/FP90)。
实施例12(E-12)
8-氯-3-(环丙基甲基)-N-(顺式-4-苯基环己基)-1,2,4-三唑并-[4,3-a]吡啶-7-甲胺(E-12)
实施例E-12按照E-1所述相同方法合成,自I-6(0.1g,0.42mmol)和顺式-4-苯基环己胺(C.A.S.5992-23-4)开始。得到最终产物E-12(0.045g,26.8%),为白色固体。M.P.267.9℃(Mettler FP62)。
实施例13(E-13)
8-氯-3-(环丙基甲基)-N-(反式-4-苯基环己基)-1,2,4-三唑并-[4,3-a]吡啶-7-甲胺(E-13)
实施例E-13按照E-1所述相同方法合成,自I-6(0.1g,0.42mmol)和反式-4-苯基环己胺(C.A.S.5769-10-8)开始。得到最终产物E-13(0.108g,64.4%),为乳膏状固体。
M.P.171.1℃(Mettler FP62)。
实施例27(E-27)
反式-N-{[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}-2-苯基环丙胺(E-27)
将I-35(113mg,0.30mmol)的CH3CN(2ml)溶液加入在密封管中的反式-2-苯基环丙胺盐酸盐([CAS1986-47-6],60.359mg,0.36mmol)和DIPEA(0.155mL,0.89mmol)在CH3CN(1mL)中的搅拌溶液中。在90℃下搅拌混合物18小时。混合物用饱和NaHCO3处理后,用EtOAc萃取。有机层经分离,干燥(Na2SO4),过滤后真空蒸发。粗产物用快速柱色谱法纯化(二氧化硅;EtOAc/CH2Cl20/100-20/80)。收集所需流分后真空浓缩。产物用乙醚/二异丙醚研磨,得到粗产物E-27,将其用RP HPLC纯化(C18XBridge30×1005μm)。流动相(梯度自80%0.1%NH4CO3H/NH4OH pH9的水溶液,20%MeOH至0%0.1%NH4CO3H/NH4OH pH9的水溶液,100%MeOH),得到34.37mg粗产物,将其用快速柱色谱法纯化(二氧化硅;NH3在MeOH中的7N溶液/DCM0/100-10/90)。收集所需流分后真空浓缩,得到最终产物E-27(24mg,21%),为无色油状物。
实施例25(E-25)、28a(E-28a)和28b(E-28b)
N-{[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}-3,4-二氢-2H-苯并吡喃-4-胺(E-25)、(4*R)-N-{[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}-3,4-二氢-2H-苯并吡喃-4-胺(E-28a)和(4*S)-N-{[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}-3,4-二-氢-2H-苯并吡喃-4-胺(E-28b)
其中*R和*S各自表示其中绝对立体化学结构未确定但化合物本身作为单一立体异构体分离且是对映体纯的立体化学构型。
将三乙酰氧基硼氢化钠([CAS56553-60-7],295.21mg,1.39mmol)加入I-20(150mg,0.56mmol)和I-37(137.916mg,0.67mmol)在DCE(5.5mL)中的搅拌溶液中。在微波辐射下于120℃搅拌混合物20分钟。残余物用DCM稀释,用NaHCO3饱和溶液洗涤。有机层经分离,干燥(Na2SO4),过滤后真空浓缩。将残余物溶于CH3OH(4.1mL),然后加入硼氢化钠(47.081mg,1.9mmol)。在室温下搅拌混合物2小时。将溶剂真空蒸发,粗产物用快速色谱法纯化(二氧化硅,EtOAc/DCM0/100-100/0)。收集所需流分后真空浓缩。产物用快速柱色谱法纯化(二氧化硅;MeOH中NH3的7N溶液/DCM0/100-10/90)。收集所需流分后,真空浓缩,得到最终化合物E-25(88mg,37%),为乳膏状固体。
E-25用手性SFC进一步纯化(CHIRALPAK AD-H5μm250×20mm;流动相:0.3%异丙胺,60%CO2,40%EtOH/iPrOH50/50v/v的混合物),得到最终化合物E-28a(28mg,13%)和最终化合物E-28b(24mg,11%)。
实施例29(E-29)
(2S,4S)-N-{[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}-2-苯基四氢-2H-吡喃-4-胺(E-29)
将I-24(0.15g,0.429mmol)的CH3CN(3mL)溶液加入在密封管中的I-41b(0.101g,0.47mmol)、DIPEA(221.99μL,1.29mmol)和NaI(0.00644g,0.043mmol)在CH3CN(2mL)中的搅拌溶液中。在90℃下搅拌混合物18小时。溶剂经蒸发后,残余物用快速色谱法纯化(二氧化硅;MeOH中NH3的7M溶液/DCM0/100-10/90)。收集所需流分后真空蒸发溶剂。所需产物用DIPE研磨,得到E-26(58.8mg,32%),为乳膏状固体。
实施例30(E-30)
(2R,4R)-N-{[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}-2-苯基四氢-2H-吡喃-4-胺
实施例E-30按照E-29所述相同方法合成,自I-24(0.15g,0.43mmol)和I-41a(0.101g,0.47mmol)开始。得到最终产物E-30(50mg,27%),为乳膏状固体
实施例31(E-31)
顺式-N-{[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}-4-苯基四氢呋喃-3-胺(E-31)
在氮气下,将I-24(0.25g,0.72mmol)的CH3CN(3mL)溶液加入密封管中的I-45(0.143g,0.79mmol)、DIPEA(370.0μL,2.15mmol)和NaI(0.011g,0.072mmol)在CH3CN(2mL)中的搅拌溶液中。在90℃下搅拌混合物18小时。溶剂经蒸发后,残余物用快速色谱法纯化两次(二氧化硅;MeOH/DCM0/100-5/95和MeOH中NH3的7M溶液/DCM0/100-10/90)。收集所需流分后真空蒸发溶剂,得到褐色油状物,将其用RP HPLC纯化(C18XBridge19×1005um;流动相:梯度自80%0.1%NH4CO3H/NH4OH pH9的H2O溶液,20%CH3CN至0%0.1%NH4CO3H/NH4OH pH9H2O的溶液,100%CH3CN),得到最终产物E-31(55.33mg,18%),为黄色油状物。
下表1列出其它的式(I)化合物。
表1:式(I)的实施例化合物。
可通过上述实施例(实施例编号)的类似方法制备其它的化合物15-16、18-25及其立体异构体,特别是对映体(如果适用于实验部分列举的那些化合物)。一些化合物的立体化学构型在其绝对立体化学结构未确定时被标为*R或*S,尽管该化合物本身已作为单一立体异构体分离,并且是对映体纯的。
C.分析部分
熔点
值为峰值,并且以通常与该分析方法有关的实验不确定性获得。对于多种化合物,在Mettler FP62或Mettler FP81HT-FP90仪器上于开口毛细管中测定熔点。熔点以10℃/分钟的温度梯度测量。最高温度为300℃。从数字显示屏读取熔点。
LCMS
对于本发明化合物的LCMS表征,采用下列方法。
通用方法A(用于Waters MS仪器)(TOF,ZQ,SQD)
HPLC测量采用HP1100(Agilent Technologies)系统进行,该系统包括具有脱气装置的泵(四元或二元)、自动进样器、柱式加热炉、二极管阵列检测器(DAD)和下面各个方法规定的柱。来自柱的液流被分流至MS质谱仪。MS检测器配备了电喷雾电离源或ESCI双重电离源(电喷雾与大气压化学电离组合)。氮气用作喷雾器气体。将源温保持在140℃。数据采集用MassLynx-Openlynx软件进行。
通用方法B(用于Waters MS仪器(Acquity-SQD))
UPLC(超高效液相色谱法)测量采用Acquity UPLC(Waters)系统进行,该系统包括取样器管理器(sampler organizer)、具有脱气装置的二元泵、4柱加热炉、二极管阵列检测器(DAD)和下面各个方法规定的柱。采用无需分流至MS检测器的柱流液。MS检测器配备了ESCI双重电离源(电喷雾与大气压化学电离组合)。氮气用作喷雾器气体。将源温保持在140℃。数据采集用MassLynx-Openlynx软件进行。
方法1
除通用方法A以外:反相HPLC在得自Agilent的Eclipse Plus-C18柱(3.5μm,2.1×30mm)上以1.0ml/分钟的流速,在60℃下无需分流至MS检测器的情况下进行。所用梯度条件为:95%A(0.5g/l乙酸铵溶液+5%乙腈),5%B(乙腈/甲醇的混合物,1/1),保持0.2分钟,在3.0分钟内至100%B,保持直到3.15分钟,在3.30分钟时平衡至初始条件直到5.0分钟。注射体积2μl。采用0.08秒钟的通道间延迟,通过在0.1秒钟内从100扫描至1000,来获得低分辨率质谱(单四极,SQD检测器)。毛细管针电压为3kV。锥孔电压对于正电离模式为20V和50V,对于负电离模式为30V。
方法2
除通用方法B以外:反相UPLC在得自Waters的BEH-C18柱(1.7μm,2.1×50mm)是以流速为1.0ml/分钟在50℃下无需分流至MS检测器的情况下进行。所用梯度条件为:95%A(0.5g/l乙酸铵溶液+5%乙腈),5%B(乙腈),在3.8分钟内至40%A,60%B,在4.6分钟内至5%A,95%B,保持直到5.0分钟。注射体积2.0μl。采用0.08秒钟的通道间延迟,通过在0.1秒钟内从100扫描至1000,来获得低分辨率质谱(单四极,SQD检测器)。毛细管针电压为3kV。锥孔电压对于正电离模式为25V,对于负电离模式为30V。
方法3
与方法2相同的梯度;所使用的柱:得自Agilent的RRHD EclipsePlus-C18(1.8μm,2.1×50mm)。
通用方法C(用于Acquity-UPLC QUATTRO)
LC测量采用UPLC(超高效液相色谱法)Acquity(Waters)系统进行,该系统包括具有脱气装置的二元泵、自动进样器、二极管阵列检测器(DAD)和下面各个方法规定的柱,将柱保持40℃的温度。柱的液流被引入MS检测器。MS检测器配备了电喷雾电离源。采用0.1秒钟的内扫描延迟,通过在0.2秒钟内自100扫描至1000,来获得质谱。毛细管针电压为3kV,将Quattro(得自Waters的三重四极质谱仪)中的源温保持在130℃。氮气用作喷雾器气体。数据采集用MassLynx-Openlynx软件进行(Waters)。
方法4
除通用方法C以外:反相UPLC在Waters Acquity BEH(桥接乙基硅氧烷/二氧化硅混杂)苯基-己基柱(1.7μm,2.1×100mm)上以流速为0.343ml/分钟进行。采用两种流动相(流动相A:95%7mM乙酸铵/5%乙腈;流动相B:100%乙腈)运行以下梯度条件:在2.18分钟内自84.2%A和15.8%B(保持0.49分钟)至10.5%A和89.5%B,保持1.94分钟,在0.73分钟内回到初始条件,保持0.73分钟。使用2ml的注射体积。对于正电离模式和负电离模式锥孔电压为20V。
SFCMS
对于本发明化合物的SFCMS表征,采用下列方法:
通用方法
采用得自Berger仪器的分析系统进行SFC测量,该系统包括用于递送二氧化碳(CO2)和改性剂的FCM-1200二元泵流体控制模块、CTC Analytics自动液体取样器、用于将柱从室温加热至80℃的TCM-20000热控制模块。使用了配备耐受高达400巴的高压贯流分析池的Agilent1100UV光电二极管阵列检测器。液流从柱分流至MS质谱仪。MS检测器配备了大气压电离源。用于Waters ZQ质谱分光光度计的下列电离参数为:电晕:9μa,源温:140℃,锥:30V,探针温度450℃,提取器3V,脱溶剂气体(desolvatation gas)400L/小时,锥孔气体70L/小时。氮气用作喷雾器气体。数据采集用Waters-Micromass MassLynx-Openlynx数据系统进行。
方法
除通用方法以外:SFC中的手性分离在CHIRALPAK AD DAICEL柱(10μm,4.6×250mm)上于35℃以流速为3.0ml/分钟进行。流动相为等度模式的60%CO2,20%EtOH+20%iPrOH(含有0.3%iPrNH2,在EtOH/iPrOH1∶1中)。
旋光度
用带钠灯的Perkin-Elmer341偏光计测量旋光度,并如下报告:[α]λt℃(cg/100ml,溶剂)。
对映体纯的化合物的旋光值见表2a。
分析测量的结果见表2a和表2b。
表2a:一些化合物的物理化学数据,以分钟计的保留时间(Rt),[M+H]+峰(质子化分子),LCMS方法和mp(单位为℃的熔点)。(nd=未测定)。
表2b:分析SFC数据-Rt意指保留时间(单位为分钟),[M+H]+意指化合物的质子化质量,方法是指用于对映体纯化合物的SFC/MS分析的方法。
化合物编号 | Rt | [M+H]+ | UV面积% | 异构体洗脱 |
次序 | ||||
28a | 2.27 | 403 | 100 | A |
28b | 3.49 | 403 | 100 | B |
核磁共振(NMR)
对于多种化合物,在带有标准脉冲序列,分别在400MHz和500MHz操作的Bruker DPX-400或Bruker AV-500质谱仪中记录1H NMR光谱。化学位移(δ)以自用作内标的四甲基硅烷(TMS)向低磁场位移的百万分之几(ppm)低磁场报告。
化合物编号1
1H NMR(400MHz,CDCl3)δppm0.28-0.41(m,2H),0.56-0.70(m,2H),1.14-1.23(m,1H),1.24-1.36(m,2H),1.58(br.s.,1H),1.51(qd,J=12.9,2.8Hz,2H),1.84-1.96(m,2H),2.04-2.16(m,2H),2.57(tt,J=11.1,3.8Hz,1H),2.81(tt,J=12.2,3.3Hz,1H),3.11(d,J=6.7Hz,2H),4.07(br.d,J=1.8Hz,2H),6.71-6.84(m,2H),7.14(td,J=8.4,6.5Hz,1H),7.34(d,J=7.4Hz,1H),8.07(d,J=7.4Hz,1H)。
化合物编号2
1H NMR(500MHz,CDCl3)δppm0.29-0.40(m,2H),0.58-0.68(m,2H),1.14-1.23(m,1H),1.54-1.69(m,3H),1.98-2.06(m,2H),2.62-2.74(m,3H),3.11(d,J=6.6Hz,2H),3.34(m,J=12.7Hz,2H),4.08(br.d,J=1.4Hz,2H),6.74-6.84(m,2H),6.87-6.94(m,1H),7.36(d,J=7.2Hz,1H),8.07(d,J=7.2Hz,1H)。
化合物编号3
1H NMR(500MHz,CDCl3)δppm0.29-0.40(m,2H),0.57-0.68(m,2H),1.14-1.23(m,1H),1.23-1.34(m,2H),1.52(qd,J=13.0,3.0Hz,2H),1.58(br.s.,1H),1.90-2.01(m,2H),2.04-2.16(m,2H),2.52(tt,J=12.2,3.4Hz,1H),2.58(tt,J=11.1,3.9Hz,1H),3.11(d,J=6.6Hz,2H),4.08(br.d,J=1.4Hz,2H),7.15-7.23(m,3H),7.27-7.31(m,2H),7.33(d,J=7.2Hz,1H),8.07(d,J=7.2Hz,1H)。
化合物编号4
1H NMR(400MHz,CDCl3)δppm1.21-1.36(m,2H),1.46-1.55(m,2H),1.49(t,J=7.5Hz,3H),1.58(br.s.,1H),1.91-2.00(m,2H),2.05-2.14(m,2H),2.45-2.65(m,2H),3.13(q,J=7.6Hz,2H),4.08(br.d,J=1.8Hz,2H),7.16-7.22(m,3H),7.27-7.32(m,2H),7.34(d,J=7.2Hz,1H),7.96(d,J=7.2Hz,1H)。
化合物编号5
1H NMR(400MHz,CDCl3)δppm0.28-0.41(m,2H),0.56-0.70(m,2H),1.13-1.24(m,1H),1.54-1.67(m,3H),1.67-1.75(m,2H),1.75-1.84(m,2H),1.84-1.94(m,2H),2.85(tt,J=11.4,3.0Hz,1H),2.97-3.03(m,1H),3.11(d,J=6.7Hz,2H),4.01(br.d,J=1.8Hz,2H),6.72-6.85(m,2H),7.19(td,J=8.5,6.6Hz,1H),7.32(d,J=7.2Hz,1H),8.08(d,J=7.2Hz,1H)。
化合物编号6
1H NMR(500MHz,CDCl3)δppm0.28-0.39(m,2H),0.55-0.68(m,2H),1.13-1.22(m,1H),1.62(br.s.,1H),2.81(dd,J=15.6,5.8Hz,2H),3.10(d,J=6.6Hz,2H),3.21(dd,J=15.6,6.9Hz,2H),3.68(quin,J=6.4Hz,1H),4.08(br.d,J=1.4Hz,2H),7.12-7.24(m,4H),7.31(d,J=7.2Hz,1H),8.05(d,J=7.2Hz,1H)。
化合物编号7
1H NMR(500MHz,CDCl3)δppm0.29-0.40(m,2H),0.57-0.69(m,2H),1.14-1.23(m,1H),1.34(br.s.,1H),1.64-1.75(m,4H),1.77-1.91(m,4H),2.58(s,1H),2.92-3.02(m,1H),3.11(d,J=6.6Hz,2H),4.01(br.d,J=1.4Hz,2H),7.17-7.22(m,1H),7.22-7.26(m,2H),7.28-7.33(m,2H),7.34(d,J=7.2Hz,1H),8.07(d,J=7.2Hz,1H)。
化合物编号8
1H NMR(400MHz,CDCl3)δppm1.50(t,J=7.6Hz,3H),1.56(br.s.,1H),1.62-1.75(m,4H),1.76-1.90(m,4H),2.52-2.65(m,1H),2.93-3.00(m,1H),3.13(q,J=7.6Hz,2H),4.01(br.d,J=1.8Hz,2H),7.17-7.26(m,3H),7.28-7.33(m,2H),7.35(d,J=7.2Hz,1H),7.97(d,J=7.2Hz,1H)。
化合物编号9
1H NMR(500MHz,CDCl3)δppm1.50(t,J=7.7Hz,3H),1.56(br.s.,1H),1.60-1.67(m,2H),1.67-1.74(m,2H),1.76-1.91(m,4H),2.85(tt,J=11.6,3.3Hz,1H),2.97-3.02(m,1H),3.12(q,J=7.5Hz,2H),4.01(br.d,J=1.4Hz,2H),6.73-6.79(m,1H),6.79-6.84(m,1H),7.19(td,J=8.5,6.6Hz,1H),7.32(d,J=7.2Hz,1H),7.97(d,J=7.2Hz,1H)。
化合物编号10
1H NMR(400MHz,CDCl3)δppm1.21(t,J=6.9Hz,3H),1.57(br.s.,1H),1.63-1.75(m,4H),1.77-1.91(m,4H),2.54-2.64(m,1H),2.95-3.01(m,1H),3.56(q,J=7.0Hz,2H),4.03(br.d,J=1.8Hz,2H),5.08(s,2H),7.17-7.22(m,1H),7.22-7.26(m,2H),7.28-7.34(m,2H),7.39(d,J=7.2Hz,1H),8.36(d,J=7.2Hz,1H)。
化合物编号11
1H NMR(400MHz,CDCl3)δppm1.21(t,J=7.1Hz,3H),1.23-1.35(m,2H),1.57(br.s,1H),1.52(qd,J=12.7,3.2Hz,2H),1.91-2.00(m,2H),2.06-2.15(m,2H),2.52(tt,J=12.3,3.4Hz,1H),2.59(tt,J=11.1,3.7Hz,1H),3.55(q,J=6.9Hz,2H),4.09(br.d,J=1.8Hz,2H),5.08(s,2H),7.16-7.23(m,3H),7.27-7.32(m,2H),7.38(d,J=7.2Hz,1H),8.35(d,J=7.2Hz,1H)。
化合物编号12
1H NMR(500MHz,CDCl3)δppm0.29-0.39(m,2H),0.56-0.68(m,2H),1.15-1.24(m,1H),1.57(br.s.,1H),1.63-1.73(m,4H),1.80-1.92(m,4H),2.53-2.64(m,1H),2.91-2.98(m,1H),3.09(d,J=6.6Hz,2H),4.00(s,2H),7.14(d,J=7.2Hz,1H),7.17-7.22(m,1H),7.22-7.28(m,2H),7.28-7.34(m,2H),7.90(d,J=7.2Hz,1H)。
化合物编号13
1H NMR(400MHz,CDCl3)δppm0.27-0.41(m,2H),0.56-0.69(m,2H),1.15-1.23(m,1H),1.23-1.36(m,2H),1.43-1.64(m,3H),1.89-1.99(m,2H),2.07-2.16(m,2H),2.46-2.60(m,2H),3.09(d,J=6.7Hz,2H),4.06(s,2H),7.11(d,J=7.2Hz,1H),7.15-7.22(m,3H),7.26-7.32(m,2H),7.89(d,J=6.9Hz,1H)。
D.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。
[
35
S]GTPγS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)功能的基于功能膜的测定法,其中测量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。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 Pharmacology2.6.1-10,JohnWiley&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 Pharmacology4:798-810)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5mM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4000RPM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50mM Tris-HCl(pH7.4)中。使悬液以16,000RPM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5mM Tris-HCl(pH7.4)中匀浆,再次离心(18,000RPM,20分钟,4℃)。将最终的沉淀再次悬浮于50mMTris-HCl(pH7.4)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10mM HEPES酸、10mM HEPES盐(pH7.4)、100mM NaCl、3mM MgCl2和10μM 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14μg/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.0.1nM)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10mM HEPES酸、10mM HEPES盐(pH7.4)、100mM NaCl、3mM MgCl2、10μM GDP和10μg/ml皂苷中含有7μg的膜蛋白。总反应体积为200μl。使用96孔filtermate通用收获器,经快速通过Unifilter-96GF/B板(PerkinElmer,Massachusetts,USA)过滤来终止反应。过滤器用冰冷的10mMNaH2PO4/10mM Na2HPO4(pH7.4)洗涤6次。然后将过滤器风干,将40μl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 andLuminescence 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1og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.意指无法计算pEC50
在浓度反应曲线不能达到坪值水平的情况下,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、其溶剂化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
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1-5mg的活性化合物之一、50mg羧甲基纤维素纳、1mg苯甲酸纳、500mg山梨糖醇和加至1ml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
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或其药学上可接受的盐或溶剂化物
其中
R1选自C1-6烷基;(C3-8环烷基)C1-3烷基;(C1-3烷氧基)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与它们所结合的碳一起形成环丙基环;
L选自(L-a)、(L-b)、(L-c)、(L-d)、(L-e)、(L-f)、(L-g)和(L-h):
其中
ma、mb和mc各自独立选自0和1;
me和mg各自独立选自1和2;
na、nb、nc、nd、ne、nf、hg和nh各自独立选自0、1和2;
R5a、R5b、R5c、R5d、R5e、R5f、R5g和R5h各自独立选自卤素;C1-3烷基;被1、2或3个氟取代基取代的C1-3烷基;C1-3烷氧基和被1、2或3个氟取代基取代的C1-3烷氧基;
R6a选自氢;卤素;C1-3烷基;被1、2或3个氟取代基取代的C1-3烷基;C1-3烷氧基和被1、2或3个氟取代基取代的C1-3烷氧基;
R6c选自氢;卤素;C1-3烷基;被1、2或3个氟取代基取代的C1-3烷基;C1-3烷氧基;被1、2或3个氟取代基取代的C1-3烷氧基和环丙基;
R7a、R8a、R7b和R8b各自独立选自氢、氟和甲基;或者R7a和R8a以及R7b和R8b与它们所连接的碳一起形成环丙基或羰基;
其中
每个卤素选自氟、氯、溴和碘;
前提条件是(L-c)不通过对于氧原子是α位的碳原子与三唑并吡啶核结合。
2. 权利要求1的化合物或其立体异构形式,其中
R1选自(环丙基)甲基、乙基和(乙氧基)甲基。
3. 权利要求1或2的化合物,其中R1为(环丙基)甲基。
4. 权利要求1-3中任一项的化合物,其中R2为CF3或Cl。
5. 权利要求1-4中任一项的化合物,其中R3和R4均为氢。
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化物,其选自
3-(环丙基甲基)-N-[反式-4-(2,4-二氟苯基)环己基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
3-(环丙基甲基)-N-[1-(2,4-二氟苯基)-4-哌啶基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
3-(环丙基甲基)-N-(反式-4-苯基环己基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
3-乙基-N-(反式-4-苯基环己基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
3-(环丙基甲基)-N-[顺式-4-(2,4-二氟苯基)环己基]-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
3-(环丙基甲基)-N-(2,3-二氢-1H-茚-2-基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
3-(环丙基甲基)-N-(顺式-4-苯基环己基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
3-乙基-N-(顺式-4-苯基环己基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
N-[顺式-4-(2,4-二氟苯基)环己基]-3-乙基-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
3-(乙氧基甲基)-N-(顺式-4-苯基环己基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
3-(乙氧基甲基)-N-(反式-4-苯基环己基)-8-(三氟甲基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
8-氯-3-(环丙基甲基)-N-(顺式-4-苯基环己基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
8-氯-3-(环丙基甲基)-N-(反式-4-苯基环己基)-1,2,4-三唑并[4,3-a]吡啶-7-甲胺,
反式-N-{[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}-2-苯基环丙胺,
N-{[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}-3,4-二氢-2H-苯并吡喃-4-胺,
(4*R)-N-{[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}-3,4-二氢-2H-苯并吡喃-4-胺,
(4*S)-N-{[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}-3,4-二氢-2H-苯并吡喃-4-胺,
(2S,4S)-N-{[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}-2-苯基四氢-2H-吡喃-4-胺,
(2R,4R)-N-{[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}-2-苯基四氢-2H-吡喃-4-胺,和
顺式-N-{[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}-4-苯基四氢呋喃-3-胺。
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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CN114008053A (zh) * | 2019-07-03 | 2022-02-01 | H.隆德贝克有限公司 | Nmda受体调节剂的前药 |
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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PL2649069T3 (pl) | 2016-01-29 |
CA2814996C (en) | 2019-10-01 |
US9271967B2 (en) | 2016-03-01 |
EP2649069A1 (en) | 2013-10-16 |
US20130338185A1 (en) | 2013-12-19 |
AU2011328194B2 (en) | 2015-04-16 |
JP2013541577A (ja) | 2013-11-14 |
JP5852664B2 (ja) | 2016-02-03 |
AU2011328194A1 (en) | 2013-05-02 |
EP2649069B1 (en) | 2015-08-26 |
CA2814996A1 (en) | 2012-05-18 |
WO2012062750A1 (en) | 2012-05-18 |
PT2649069E (pt) | 2015-11-20 |
CN103298810B (zh) | 2016-03-16 |
ES2552455T3 (es) | 2015-11-30 |
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