CN112041319B - 三唑、咪唑和吡咯稠合的哌嗪衍生物及其作为mGlu5受体的调节剂的应用 - Google Patents
三唑、咪唑和吡咯稠合的哌嗪衍生物及其作为mGlu5受体的调节剂的应用 Download PDFInfo
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- CN112041319B CN112041319B CN201980021802.1A CN201980021802A CN112041319B CN 112041319 B CN112041319 B CN 112041319B CN 201980021802 A CN201980021802 A CN 201980021802A CN 112041319 B CN112041319 B CN 112041319B
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Abstract
公开了三唑、咪唑和吡咯稠合的哌嗪衍生物及其作为mGlu5受体活性的别构调节剂的应用、包括这样的化合物的药物组合物、及用其治疗的方法。本发明的化合物可以用于治疗和/或预防与谷氨酸功能障碍相关的神经紊乱和精神紊乱(如精神分裂症或认知减退、痴呆或认知损害)、或者可以直接地或间接地与谷氨酸功能障碍有关的其他病害(即,通过mGluR5的正向别构调节(PAM)或负向别构调节(NAM)可治疗的紊乱)。
Description
发明领域
本发明涉及三唑、咪唑和吡咯稠合的哌嗪衍生物及其作为mGlu5受体活性的别构调节剂的应用、包括这样的化合物的药物组合物、及用其治疗的方法。本发明的化合物可以用于治疗和/或预防与谷氨酸功能障碍相关的神经紊乱和精神紊乱(如精神分裂症或认知减退、痴呆或认知损害)、或者可以直接地或间接地与谷氨酸功能障碍有关的其他病害(即,通过mGluR5的正向别构调节(PAM)或通过负向别构调节(NAM)可治疗的紊乱)。
谷氨酸是哺乳动物中枢神经系统中的主要兴奋性氨基酸,通过离子型谷氨酸受体和代谢型谷氨酸受体两者发挥其作用。由谷氨酸介导的神经传递已经被证明在许多生理过程(如突触可塑性、涉及学习和记忆两者以及感官知觉的长时程增强)中是关键的(Riedelet al.,Behav.Brain Res.(2003),Vol.140,pp.1-47,Rose et al.J.Neurosci.,November8,2006·26(45):11582-11587)。此外,已经证明谷氨酸神经传递的失衡在各种神经疾病和精神疾病的病理生理学中起关键作用。
谷氨酸的兴奋性神经传递通过至少两种不同类别的受体介导:离子型谷氨酸受体,如N-甲基-D-天冬氨酸受体(NMDA)、α-氨基-3-羟基-5-甲基-4-异噁唑丙酸受体(AMPA)或红藻氨酸受体;以及代谢型谷氨酸受体(mGluR)和代谢型谷氨酸受体。离子型受体是配体门控性离子通道,并且被认为负责调控两个神经元之间的快速神经元传递。代谢型谷氨酸受体是G蛋白偶联受体(GPCR),G蛋白偶联受体(GPCR)显现为不仅介导突触传递,而且调控神经递质释放的程度以及突触后受体激活。代谢型谷氨酸受体(mGluR)属于g蛋白偶联受体(GPCR)的家族C(也称为家族3)。代谢型谷氨酸受体的特征在于经由半胱氨酸富集区与大双叶细胞外氨基端域(谷氨酸配体结合在其中)连接的七跨膜(7TM)α-螺旋域。mGluR家族包括8种已知的mGluR受体类型(命名为mGluR1至mGluR8)。受体类型中的几种被表达为特定的剪接变体(例如,mGluR5a和mGluR5b或mGluR8a、mGluR8b和mGluR8c)。基于氨基酸同源性及其调控的细胞内信号级联放大(Schoepp et al.,Neuropharma,(1999),Vol.38,pp.1431-1476)和药理学特性,该超家族被进一步分成三组(组I、组II和组III)。组I受体(mGluR1和mGluR5)与Gαq偶联(一种造成磷脂酶C的刺激以及细胞内钙和肌醇磷酸水平的增加的过程)。组II受体(mGluR2和mGluR3)和组iii受体(mGluR4、mGluR6、mGluR7和mGluR8)与Gαi偶联,导致环磷酸腺苷(cAMP)水平的降低。虽然组I受体主要位于突触后,并且通常增强突触后信号传导,但组II受体和组III受体位于突触前,并且通常对神经递质释放具有抑制作用。
已经在各种神经紊乱和精神紊乱中证明了谷氨酸能神经传递中的调节异常(例如,通过改变的谷氨酸释放或突触后受体激活)。NMDA受体的机能减退不仅在阿尔茨海默病的患者中被证明,而且愈发被认为是精神分裂症的推定原因(Farber et al.,Prog.BrainRes.,(1998),Vol.116,pp.421-437;Coyle et al.,Cell.and Mol.Neurobiol.,(2006),Vol.26,pp.365-384)。这得到了临床研究的支持,临床研究表明NMDA受体的拮抗剂诱导与精神分裂症患者患有的症状难以区别的症状(Javitt et al.,Am J.Psychiatry,(1991),Vol.148,pp.1301-1308;Meltzer HY,Biol.Psychiatry,(1999),Vol.46(10),pp.1321-1327)。因此,可以使NMDA受体信号传导强化或正常化的方法具有治疗神经紊乱和精神紊乱的潜力。
已经证明由GRM5基因编码的mGluR5在中枢神经系统(CNS)中(主要在皮质、海马体、伏隔核和尾状核壳中)表达。已知这些脑区参与记忆形成和认知功能以及情绪反应。mGluR5已经被证明在突触后、邻近于突触后致密物质定位(Lujan et al.,Eur.J.Neurosci.(1996),Vol.8,pp.1488-1500)。也已经证明了mGluR5与NMDA受体之间的功能性相互作用,其中mGluR5的激活强化NMDA受体的激活状态(Mannaioni et al.,NeuroSci.,(2001),Vol.21,pp.5925-5924;Rosenbrock et al.,Eur.J.Pharma.,(2010),Vol.639,pp.40-46)。此外,已经在临床前体内模型中证明mGluR5的激活挽救认知损害以及由NMDA受体拮抗剂诱导的精神病性障碍(Chan et al.,Psychopharma.(2008),Vol.198,pp.141-148)。因此,mGluR5的激活以及由此的NMDA受体信号传导的强化或正常化是治疗精神紊乱和神经紊乱的潜在机制。
mGluR5的大部分激动剂结合正构谷氨酸结合位点。由于mGluR家族成员之间的谷氨酸结合位点是高度保守的,因此开发具有可接受的CNS渗透的选择性mGluR5激动剂并且证明体内活性一直具有挑战性。
实现mGluR家族成员之间的选择性的可替代的方法是开发在家族成员之间非高度保守的与别构位点结合的化合物。这些别构结合化合物不会干扰天然谷氨酸结合和信号传导,但调节受体激活状态。在不存在正构配体的情况下具有激动活性或反向激动活性的别构配体分别被称为别构激动剂或别构拮抗剂。在不存在正构配体的情况下没有作用的别构配体被称为调节剂(负向或正向)。
最近已经鉴别mGluR5的正向别构调节剂(O’Brien et al.,Mol.Pharma.(2003),Vol.64,pp.731-740;Lindsley et al.,J.Med.Chem.(2004),Vol.47,pp.5825-5828),其中已经确定这些化合物在存在结合型谷氨酸的情况下强化mGluR5活性。在不存在结合型谷氨酸的情况下,mGluR5正向调节剂未展现出任何固有活性。
因此,与以永久、非天然的方式激活受体的激动剂截然相反,这些化合物强化mGluR5的天然信号传导。因此,mGluR5正向别构调节剂代表一种强化mGluR5信号传导的方法,这转而使得在神经紊乱和精神紊乱中检测到的NMDA受体机能减退强化并且正常化。mGluR5负向别构调节剂对于阻抑mGluR5信号传导是有用的,这转而使得在一些神经紊乱、精神紊乱和更普遍CNS紊乱中检测到的NMDA受体机能亢进减小并且正常化。不希望受特定理论的束缚,包含mgluR5的代谢型谷氨酸受体已经涉及广泛的生物学功能,表明mGluR5受体在哺乳动物的多种疾病过程中的潜在作用。代谢型谷氨酸受体的配体可以用于治疗或预防与谷氨酸功能障碍相关的急性和/或慢性的神经紊乱和/或精神紊乱(如精神病、精神分裂症、年龄相关性认知减退等)。此外,不希望受到理论的束缚,越来越多的证据表明mGlu受体在突触传递的持久变化中起重要作用,并且在FMR1敲除小鼠中对突触可塑性的研究已经确定了脆性X染色体表型与mGluR信号传导之间的联系。这两种类型的别构调节剂也可以与一些罕见疾病(例如,不受任何限制,脆性X染色体综合征、雷特综合征、费伦-麦克德米德综合征(Phelan-McDermid syndrome)或结节性硬化)有关。
对在正构位点处结合的小分子mGluR激动剂的鉴别已经大大增加了对这些受体所起的作用及其与疾病的相应关系的认识。由于这些激动剂中的大多数被设计为谷氨酸的类似物,因此其通常缺乏靶向mGluR的药物的期望的特性(如口服生物利用度和/或向中枢神经系统(CNS)的分布)。此外,由于谷氨酸结合位点的高度保守性,因此大部分正构激动剂在各种mGluR中缺乏选择性。
别构结合位点在形态上不同于内源性配体(正构)结合位点。两个位点的内源性配体和别构调节剂对受体的同时占据可以造成不同的结果。强化内源性配体的作用(正协同性)的别构配体被定义为“正向别构调节剂”(PAM),而减小或阻滞内源性配体的作用(负协同性)的别构配体被定义为负向别构调节剂(NAM)(Christopoulos A,Advances in Gprotein-coupled receptor allostery:from function to structure,MolPharmacol.2014;86(5):463-78)。
因此,PAM和NAM两者都是用于调节适当的生理受体响应的有吸引力的机制。
遗憾的是,缺乏针对mGluR5受体的选择性正向别构调节剂。此外,常规的mGluR5受体调节剂通常缺乏令人满意的水溶性,并且展现出不良的口服生物利用度。因此,仍然需要克服这些缺陷并且有效地提供针对mGluR5受体的选择性正向别构调节剂和负向别构调节剂的方法和组合物。
发明概述
本发明提供具有通式I的化合物:
(I)
或者具有通式I的化合物化合物的对映异构体、非对映异构体、N-氧化物、或药学上可接受的盐,其中:
R1是可选地被取代的单环、双环或三环C6-C14芳基基团、可选地被取代的含有选自N、O和S的从1个至5个杂原子的单环、双环或三环C1-C13杂环基团、可选地被取代的C3-C6环烷基基团、或可选地被取代的C3-C6环烯基基团、或可选地被取代的C1-C20直链或支链的烷基基团;并且
A是三键、可选地被卤素基团取代的双键、或表示含有选自N、S、O的从1个至4个杂原子的五原子或六原子杂环基团、或表示烷基链(C1-4)、或被选自N、S、O的1个至3个杂原子取代的烷基链;
R2、R3各自独立地为不存在的、氢、烷基基团、或氟原子,或者R2和R3彼此连接以形成含有选自N、S、O的1个至3个杂原子的稠合的杂环;
n是0与2之间的整数;
R4是羰基、或硫代羰基、或磺酰基基团、或键、或是不存在的;
B是氧或硫或氮或键或是不存在的,其中氮可选地被C1-5烷基或烷氧基(如甲氧基)取代;
R5是可选地被取代的单环、双环或三环C6-C14芳基基团、可选地被取代的含有选自N、O和S的从1个至5个杂原子的单环、双环或三环C1-C13杂环基团、可选地被取代的C3-C6环烷基基团、或可选地被取代的C3-C6环烯基基团、或可选地被取代的直链或支链的C1-C20烷基基团。
上述可选的取代基独立地选自卤族元素原子和C1-C6烷基、C1-C6烷氧基、羟基、巯基、硝基、氰基、氧代、卤素(C1-C6)烷基、卤素(C1-C6)烷氧基、C1-C6烷基硫代、C1-C6烷基磺酰基、C1-C6烷基羰基、氨磺酰基、C1-C6烷基氨磺酰基、二(C1-C6)烷基氨磺酰基、(C1-C6)烷氧基羰基和(C1-C6)烷基羰基(C1-C6)烷基基团,以及选自式-NR*R*、-C(=O)-NR*R*、-A、-O-A、-C(=O)-A、-(CH2)q-A、-NR**-A、-C(=O)-NR**-A、-NR**C(=O)-A和-O-C(=O)-A的组,其中每个R*独立地表示氢原子或C1-C6烷基、C1-C6烷氧基、C1-C6烷基羰基、苯基或苄基基团,R**表示氢原子或C1-C6烷基基团,q是从1至6的整数,并且A表示苯基基团或含有选自N、O和S的从1个至3个杂原子的C1-C8杂环基团;C1-C6环烷基基团;每个基团A可选地被独立地选自卤素、羟基、氰基、硝基和C1-C6烷基的从1个至3个基团取代,优选地,其中可选的取代基选自由卤族元素原子和C1-C6烷基基团组成的组。
在优选的实施方案中,A是可选地被卤素基团取代的三键或双键。R1优选地是可选地被取代的C3-C6环烷基基团、或可选地被取代的C3-C6环烯基基团、或含有选自N、O、和S的至少一个杂原子的C3-C5杂环基团,优选地,其中杂原子是N。X和Y优选地各自独立地是N或C。最优选地,n=1。
在优选的实施方案中,R4是羰基基团或是不存在的;B是O、可选地被C1-5烷基或烷氧基(如甲氧基)取代的N、键、或是不存在的;并且R5如上文所定义。
在一些实施方案中,如果B是O,则R5是含有选自N、O、和S的从1个至5个杂原子的C1-C13杂环基团、或可选地被取代的直链或支链的C1-C20烷基基团。如果B是不存在的,则R5优选地是可选地被取代的单环、双环或三环C6-C14芳基基团、可选地被取代的含有选自N、O、和S的从1个至5个杂原子的单环、双环或三环C1-C13杂环基团、可选地被取代的C3-C6环烷基基团、或可选地被取代的C3-C6环烯基基团。如果B是可选地被C1-5烷基或烷氧基(如甲氧基)取代的N,则R5优选地是可选地被取代的直链或支链的C1-C20烷基基团。
在一些实施方案中,仅存在位于环氮原子的侧面的一个可能的n(=1),从而得到式IA:
IA
其中A、B、以及R1、R4和R5具有与上文式I相关的赋予它们的含义。
在一些实施方案中,仅存在位于环氮原子的侧面的一个可能的n(=1),从而得到式IB:
IB
其中A、B、以及R1、R4和R5具有与上文式I相关的赋予它们的含义。
在一些实施方案中,仅存在邻近于环氮原子的一个可能的n(=1),从而得到式IC:
IC
其中A、B、以及R1、R4和R5具有与上文式I相关的赋予它们的含义。
优选的根据本发明的化合物是这样的化合物:其中R1和R5是可选地被取代的单环、双环或三环C6-C14芳基基团、可选地被取代的含有选自N、O、和S的从1个至5个杂原子的单环、双环或三环C1-C13杂环基团,A是三键或氧基亚甲基或亚甲基氧基基团,R4表示CO基团,n是1,X和Y是氮,R2和R3是不存在的,并且B是不存在的(键)。
在本发明的实施方案中,R1、R5优选地独立地选自可选地被取代的单环、双环或三环C6-C14芳基基团、或可选地被取代的含有选自N、O、S的从1个至5个杂原子的单环、双环或三环C1-C13杂环基团,A是三键或氧基亚甲基或亚甲基氧基基团,X和Y是氮,R2和R3是不存在的,并且B是选自N、O、S的杂原子。
在本发明的另外的实施方案中,R1、R5优选地独立地选自可选地被取代的单环、双环或三环C6-C14芳基基团、或可选地被取代的单环、双环或三环C1-C13杂环基团、或可选地被取代的含有选自N、O、和S的从1个至5个杂原子的烷基或环烷基或环烯基基团,X是碳,并且Y是氮,R3是不存在的,并且R2是氢或甲基基团,A是三键或氧基亚甲基或亚甲基氧基基团,并且B是不存在的(键)。
在本发明的另外的实施方案中,R1、R5优选地独立地选自可选地被取代的单环芳基基团、或可选地被取代的含有选自N、O、S的从1个至5个杂原子的单环杂环基团、或可选地被取代的烷基或环烷基或环烯基基团,X是碳,并且Y是氮,R3是不存在的,并且R2是氢或甲基基团,A是三键、氧基亚甲基或亚甲基氧基基团,其中R4是CO基团,并且B是选自N、O、S的杂原子。
在本发明的另外的实施方案中,R1、R5优选地独立地选自可选地被取代的单环芳基基团、或可选地被取代的含有选自N、O、和S的从1个至5个杂原子的单环杂环基团、或可选地被取代的烷基或环烷基或环烯基基团,X是氮,并且Y是碳,R2是不存在的,并且R3是氢或甲基基团,A是三键、氧基亚甲基或亚甲基氧基基团,其中R4是CO基团,并且B是不存在的(键)。
在本发明的另外的实施方案中,R1、R5优选地独立地选自可选地被取代的单环芳基基团、或可选地被取代的含有选自N、O、S的从1个至5个杂原子的单环杂环基团、或可选地被取代的烷基或环烷基或环烯基基团,X是氮,并且Y是碳,R2是不存在的,并且R3是氢或甲基基团,A是三键、氧基亚甲基或亚甲基氧基基团,其中R4是CO基团,并且B是选自N、O、S的杂原子。
在本发明的另外的实施方案中,A优选地是烷氧基基团。
在本发明的另外的实施方案中,A优选地是杂环或双键。
在本发明的另外的实施方案中,R2和R3优选地是氢原子。
在本发明的另外的实施方案中,R2和R3优选地是可选地被取代的C1-C4烷基基团。
例如,当R4是CO基团,并且R1表示可选地被取代的含有选自氮、氧和硫的从1个至3个杂原子的单环或双环C1-C9杂环基团时,R5优选地是(但不限于)2-呋喃基、3-甲基苯基、3-氯苯基、5-甲基-2-呋喃基、3-呋喃基、2,5-二甲基-3-呋喃基、4-吗啉基、哌啶基、吡咯烷基基团。
例如,当R4是CO基团,B是氧,并且R1表示可选地被取代的含有选自氮、氧和硫的从1个至3个杂原子的单环或双环C1-C9杂环基团时,n为1,并且R5优选地是(但不限于)可选地被取代的烷基基团,烷基基团选自甲基、乙基、异丙基、丙基、叔丁基、丁基、异丁基,化合物优先地是负向别构调节剂。
例如,当R4是CO基团,B是氮或N-烷基(选自甲基、乙基、异丙基、丙基、叔丁基、丁基、异丁基)或甲氧基,并且R1表示可选地被取代的含有选自氮、氧和硫的从1个至3个杂原子的单环或双环C1-C9杂环基团时,n是1,并且R5优选地是(但不限于)可选地被取代的烷基基团(选自甲基、乙基、异丙基、丙基、叔丁基、丁基、异丁基),可选地被取代的化合物优先地是负向别构调节剂。
非限制性实例是3-[2-(3-氯苯基)乙炔基]-N,N-二乙基-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-羧酰胺。在该化合物中,R1是3-氯苯基,B是乙基化的氮,并且R5是乙基基团,R2和R3是不存在的,R4是羰基,n是1,并且A是三键。
例如,当R4是CO基团,B是不存在的,并且R1表示可选地被取代的单环、双环或三环C6-C14芳基基团时,n是1,并且R5优选地是(但不限于)可选地被取代的单环芳基基团、或可选地被取代的含有选自N、O、和S的从1个至5个杂原子的单环杂环基团,化合物优先地是正向别构调节剂。
非限制性实例是(3-氯苯基)-[3-[2-(3-氯苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-基]甲酮。在该化合物中,R1和R5是3-氯苯基,R2和R3以及B是不存在的,R4是羰基,n是1,并且A是三键。实施例8中进一步描述了该化合物。
例如,当X是氮,并且Y是碳,R4是CO基团,B是不存在的,并且R1表示可选地被取代的单环、双环或三环C6-C14芳基基团时,R5优选地是(但不限于)可选地被取代的单环芳基基团、或可选地被取代的含有选自N、O、和S的从1个至5个杂原子的单环杂环基团,化合物优先地是正向别构调节剂。
非限制性实例是(3-氯苯基)-[3-[2-(3-氯苯基)乙炔基]-6,8-二氢-5H-咪唑并[1,2-a]吡嗪-7-基]甲酮。在该化合物中,R1和R5是3-氯苯基,A是三键,B是不存在的,R2是不存在的,并且R3是氢,R4是羰基,并且n是1。
在本发明的实施方案中,提供根据通式I的化合物或对映异构体、非对映异构体、N-氧化物或药学上可接受的盐,选自下文表1中化合物:
在本发明的另外的实施方案中,优选地提供药物组合物,药物组合物包括式I的化合物:
或式I的化合物的对映异构体、非对映异构体、N-氧化物或药学上可接受的盐、以及药学上可接受的载体,其中n、R1至R6、A和B具有上文归于其的含义;并且在更具体的实施方案中,优选地提供用于治疗和/或预防与谷氨酸功能障碍相关的神经紊乱、精神病性紊乱、疼痛或精神紊乱的式IA的化合物:
或式IA的化合物的对映异构体、非对映异构体、N-氧化物或药学上可接受的盐。
在本发明的实施方案中,根据式I或式IA的化合物用于治疗和/或预防与谷氨酸功能障碍相关的神经紊乱、精神病性紊乱、或精神紊乱,包含(但不限于):对于mGlu5正向别构调节剂:雷特综合征、费伦-麦克德米德综合征、精神病、精神分裂症、孤独症认知紊乱、结节性硬化、认知紊乱、阿尔茨海默型痴呆),以及对于mGlu5负向别构调节剂:成瘾、重度抑郁症、焦虑、癫痫、脆性X染色体综合征、胃食管反流病(GERD)、物质滥用和依赖、帕金森病和L-多巴诱导的运动障碍、尿失禁、肠易激综合征(IBS)和疼痛。
优选地,与谷氨酸功能障碍相关的神经紊乱、精神病性紊乱或精神紊乱是精神分裂症、分裂情感性精神障碍、物质诱导的精神病性紊乱、年龄相关性学习和记忆损害或损失、脑卒中后痴呆、集中力缺损(deficits in concentration)、轻度认知损害、阿尔茨海默病认知功能障碍、精神分裂症的认知功能障碍、认知减退、痴呆或认知损害。
更优选地,紊乱是脆性X染色体综合征、雷特综合征、费伦-麦克德米德综合征、或结节性硬化。
发明的详细说明
使用的术语和定义
除非另有说明,否则以下定义适用于整个说明书和权利要求书。无论术语是单独使用还是与其他术语结合使用,这些定义均适用。例如,“烷基”的定义不仅适用于烷基基团本身,还适用于烷氧基基团、烷基氨基基团、烷基硫代基团或烷基羰基基团等的烷基部分。此外,针对化学基团描述的全部范围(例如,“从1个至13个碳原子”或“C1-C6烷基”)包含其中碳原子的范围和具体数量的全部组合和子组合。
“烷基”意为在链中具有从1个至20个碳原子的直链或支链的脂肪族烃基。优选的烷基基团在链中具有从1个至12个碳原子。更优选的烷基基团在链中具有从1个至6个碳原子。“低级烷基”意为在链(可以为直链的或支链的)中具有约1个至约6个碳原子的烷基基团。适合的烷基基团的实例包含甲基、乙基、正丙基、异丙基、仲丁基、正丁基和叔丁基。
“烯基”意为具有至少一个碳碳双键并且在链中具有从2个至15个碳原子的直链或支链的脂肪族烃基。优选的烯基基团在链中具有从2个至12个碳原子。更优选的烯基基团在链中具有从2个至6个碳原子。“低级烯基”意为在链(可以为直链的或支链的)中具有2个至约6个碳原子的烯基基团。适合的烯基基团的实例包含乙烯基、丙烯基、异丙烯基、正丁烯基、1-己烯基和3-甲基丁-2-烯基。
“炔基”意为具有至少一个碳碳三键并且在链中具有从2个至15个碳原子的直链或支链的脂肪族烃基。优选的炔基基团在链中具有从2个至12个碳原子。更优选的炔基基团在链中具有从2个至6个碳原子。“低级炔基”意为在链(可以为直链的或支链的)中具有2个至约6个碳原子的炔基基团。适合的炔基基团的实例包含乙炔基、丙炔基和2-丁炔基。
“单环杂环、双环杂环或三环杂环”意为具有从2个至14个环碳原子且含有从1个至5个单独地或组合地选自N、O和S的环原子的芳族的或非芳族的饱和的单环环系、双环环系或三环环系。双环杂环基团和三环杂环基团在2个或4个点处稠合或者在1个点处经由键或杂原子连接物(O、S、NH、或N(C1-C6烷基))连接。通过用一个或更多个取代基(可以相同或不同)代替环上的可用氢原子,“单环杂环、双环杂环或三环杂环”可以在环上可选地被取代。杂环的氮原子或硫原子可以可选地被氧化成相应的N-氧化物、S-氧化物或S-二氧化物。适合的杂环的实例包含呋喃基、咪唑基、异噁唑基、噁二唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、三唑基、四唑基、噻吩基、咔唑基、苯并咪唑基、苯并噻吩基、苯并呋喃基、吲哚基、喹啉基、苯并三唑基、苯并噻唑基、苯并噁唑基、苯并咪唑基、异喹啉基、异吲哚基、吖啶基和苯并异噁唑基、吖丙啶基、哌啶基、吡咯烷基、哌嗪基、四氢吡喃基、四氢呋喃基、四氢苯硫基、吗啉基和硫代吗啉基。
具有芳族特性的杂环可以被称为杂芳基或杂芳族化合物。适合的杂芳族化合物的实例包含呋喃基、咪唑基、异噁唑基、噁二唑基、噁唑基、吡咯基、吡啶基、嘧啶基、哒嗪基、噻唑基、三唑基、四唑基、噻吩基、咔唑基、苯并咪唑基、苯并噻吩基、苯并呋喃基、吲哚基、喹啉基、苯并三唑基、苯并噻唑基、苯并噁唑基、苯并咪唑基、异喹啉基、异吲哚基、吖啶基、苯并异噁唑基、四氢喹啉基、四氢异喹啉基、3-苯基吡啶、3-环己基吡啶、3-(吡啶-3-基)吗啉、3-苯基异噁唑和2-(哌啶-1-基)嘧啶。
“单环芳基、双环芳基或三环芳基”意为包括6个至14个碳原子的芳族的单环环系、双环环系或三环环系。双环芳基基团和三环芳基基团在2个或4个点处稠合或者在1个点处经由键或杂原子连接物(O、S、NH或N(C1-C6烷基))连接(例如,联苯基、1-苯基萘基)。芳基基团可以在环上可选地被一个或更多个取代基(可以相同或不同,优选地1个至6个取代基)取代。适合的芳基基团的实例包含苯基和萘基。
“环烷基”意为具有从3个至14个碳原子(优选地从3个至6个碳原子)的单环碳环系或双环碳环系。通过用一个或更多个取代基(可以相同或不同)代替环上的可用氢原子,环烷基可以在环上可选地被取代。适合的单环环烷基的实例包含环丙基、环戊基、环己基和环庚基。适合的多环环烷基的实例包含1-十氢萘基、降冰片基和金刚烷基。
“环烯基”具有与环烷基相对应的含义,除了在环内具有一个或两个双键(例如,环己烯基、环己二烯)。
“胺”是氨的衍生物,其中一个或更多个氢原子已经被取代基(如烷基基团或芳基基团)代替。这些可以分别被称为烷基胺和芳基胺;两种类型的取代基都与一个氮原子连接的胺可以被称为烷基芳基胺。
胺可以被进一步地划分成四个子类。当氨中的三个氢原子中的一个被烷基基团或芳族基团代替(分别为N-烷基氨基或N-芳基氨基)时,产生伯胺。适合的伯烷基胺的实例包含甲胺或乙醇胺,或者作为芳族胺的实例的苯胺(aniline)(苯胺(phenylamine))。仲胺具有两个有机取代基(独立地烷基基团或芳基基团),两个有机取代基与一个氢一起与氮原子结合(或者如果一个取代基键是双键,则无氢)。适合的仲胺的实例包含二甲胺和甲基乙醇胺,而芳族胺的实例是二苯胺。根据取代基的性质,这样的化合物也可以被称为“N,N-二烷基氨基”、“N,N-二芳基氨基”或“N,N-烷基芳基氨基”基团。如本文中定义的,被烷氧基基团取代的仲胺将被称为例如“N-烷基-N-烷氧基氨基”化合物。在叔胺中,全部三个氢原子被有机取代基代替,如三甲胺。最后的子类是环胺,环胺是仲胺或叔胺。适合的环胺的实例包含3-元环氮杂环丙烷和六元环哌啶。N-甲基哌啶和N-苯基哌啶是环叔胺的适合的实例。
“酰胺”是具有与羰基基团连接的氮原子而具有结构R-CO-NR’R”的化合物,其中基团R’和R”独立地选自如本文中定义的烷基基团或芳族基团。例如,当R’是氢并且R”是3-吡啶基基团时,所得到的酰胺具有3-吡啶基氨基取代基。可替代地,当R’是氢并且R”是环戊基基团时,所得到的酰胺具有环戊基氨基取代基。
“卤族元素(halogen)”、“卤化物(halide)”或“卤素(halo)”意为氟、氯、溴或碘。优选的卤素是氟、氯或溴,并且最优选的是氟和氯。
术语“酰基”(无论单独使用或在术语(如“酰氨基”)内使用)表示由从有机酸中移除羟基之后的剩余部分提供的基团。术语“酰氨基”指被酰基基团取代的氨基基团。“酰氨基”基团的实例为CH3C(=O)-NH-,其中胺可以进一步被烷基基团、芳基基团或芳烷基基团取代。
可以在子式或基团中使用星号来表示与如本文中定义的母体或核心分子连接的键。
如本文所使用的,术语“治疗”等包含消除或减轻mGluR5介导的疾病或紊乱的症状和/或标志物,或者使mGluR5介导的疾病或紊乱的症状和/或标志物免于恶化(稳定化)并且更一般地带来期望的生理作用或药理作用。如本文所使用的,术语“预防”等包含抑制或延迟这样的疾病或紊乱的症状表现、或者降低(或视情况而增加)或消除其标志物的异常值。
立体化学
除非特别指明,否则在整个说明书和权利要求书中,给定的化学式或名称应当包含互变异构体和全部立体异构体、光学异构体和几何异构体(例如,对映异构体、非对映异构体、+/-异构体、R/S异构体、E/Z异构体等)外消旋混合物及其外消旋体。这包含单独对映异构体的不同比例的混合物、非对映异构体的混合物、或这样的异构体和对映异构体存在的任何前述形式的混合物、以及其盐(包含药学上可接受的盐)和溶剂合物(如水合物、游离化合物的溶剂合物或化合物的盐的溶剂合物)。
本发明化合物的衍生物
本发明还包含式I的化合物的盐、溶剂合物、水合物、N-氧化物、前体药物和活性代谢物。
短语“药学上可接受的”在本文中用于指在合理的医学判断范围内适用于与人类和动物的组织接触,而没有过度毒性、刺激、变态反应、或者其他问题或并发症,与合理的利益/风险比相称的那些化合物、材料、组合物、和/或剂型。
如本文所使用的,“药学上可接受的盐”指所公开的化合物的衍生物,其中母体化合物通过制备其酸式盐或碱式盐被修饰。药学上可接受的盐的实例包含(但不限于)碱性残基的无机盐或有机酸盐(如胺);酸性残基的碱金属盐或有机盐(如羧酸);等等。例如,这样的盐包含来自下列的盐:氨、L-精氨酸、甜菜碱、苯乙苄胺、苄星青霉素、氢氧化钙、胆碱、二甲基乙醇胺、二乙醇胺(2,2’-亚氨基双(乙醇))、二乙胺、2-(二乙基氨基)-乙醇、2-氨基乙醇、乙二胺、N-乙基-葡糖胺、哈胺、1H-咪唑、赖氨酸、氢氧化镁、4-(2-羟乙基)-吗啉、哌嗪、氢氧化钾、1-(2-羟乙基)-吡咯烷、氢氧化钠、三乙醇胺(2,2’,2”-次氮基三(乙醇))、氨丁三醇、氢氧化锌、乙酸、2,2-二氯乙酸、己二酸、海藻酸、抗坏血酸、L-天冬氨酸、苯磺酸、苯甲酸、2,5-二羟基苯甲酸、4-乙酰氨基-苯甲酸、(+)-樟脑酸、(+)-樟脑-10-磺酸、碳酸、肉桂酸、柠檬酸、环己氨磺酸、癸酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基-乙磺酸、乙二胺四乙酸、甲酸、富马酸、粘酸、龙胆酸、D-葡庚糖酸、D-葡萄糖酸、D-葡萄糖醛酸、谷氨酸、戊二酸、2-氧代-戊二酸、甘油磷酸、甘氨酸、乙醇酸、己酸、马尿酸、氢溴酸、盐酸、异丁酸、DL-乳酸、乳糖酸、月桂酸、赖氨酸、马来酸、(-)-L-苹果酸、丙二酸、DL-扁桃酸、甲磺酸、粘酸、萘-1,5-二磺酸、萘-2-磺酸、1-羟基-2-萘甲酸、烟酸、硝酸、辛酸、油酸、乳清酸、草酸、棕榈酸、扑酸(双羟萘酸)、磷酸、丙酸、(-)-L-焦谷氨酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、鞣酸、(+)-L-酒石酸、硫氰酸、p-甲苯磺酸和十一碳烯酸。可以用来自金属(如铝、钙、锂、镁、钾、钠、锌等)的阳离子形成另外的药学上可接受的盐(参见Pharmaceutical salts,Berge,S.M.et al.,J.Pharm.Sci.,(1977),Vol.66,pp.1-19)。
可以通过常规的化学方法由含有碱性部分或酸性部分的母体化合物来合成本发明的药学上可接受的盐。通常,可以通过使这些化合物的游离酸形式或碱形式与足够量的适当的碱或酸在水中或有机稀释剂(如乙醚、乙酸乙酯、乙醇、异丙醇、或乙腈、或其混合物)中反应来制备这样的盐。
除了上述那些盐以外,例如对于纯化或分离本发明的化合物有用的其他酸的盐(例如,三氟乙酸盐)也构成本发明的一部分。
通常,可以酌情通过使用期望的酸或碱容易地制备式I的化合物的药学上可接受的盐。可以从溶液中沉淀盐,并且通过过滤收集,或者可以通过溶剂的蒸发回收。例如,可以向式I的化合物的水性悬浮液中添加酸的水性溶液(如盐酸),并且所得到的混合物被蒸干(冻干)以获得为固体的酸加成盐。可替代地,式I的化合物可以溶解在适合的溶剂(例如,醇,如异丙醇)中,并且可以在相同溶剂或另外的适合的溶剂中添加酸。然后,可以直接地或者通过添加较小极性的溶剂(如二异丙醚或己烷)来使所得到的酸加成盐沉淀,并且通过过滤分离。
可以以常规方式通过游离碱形式与足够量的期望的酸接触产生盐来制备式I化合物的酸加成盐。可以以常规方式通过使盐形式与碱接触并且分离游离碱来再生游离碱形式。游离碱形式在某些物理性质(如在极性溶剂中的溶解度)方面稍微区别于其各自的盐形式,但除此之外,对于本发明的目的,盐等同于其各自游离碱。
还包含总盐和偏盐两者,即,每摩尔式I的酸具有1、2或3(优选2)当量碱的盐,或者每摩尔式I的碱具有1、2或3当量(优选1当量)酸的盐。
用金属或胺类(如碱金属和碱土金属或有机胺)形成药学上可接受的碱加成盐。用作阳离子的金属的实例为钠、钾、镁、钙等。适合的胺类的实例为N,N’-二苯基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、二环己基胺、乙二胺、N-甲葡糖胺和普鲁卡因。
以常规方式通过使游离酸形式与足够量的期望的碱接触产生盐来制备所述酸性化合物的碱加成盐。可以通过使盐形式与酸接触并且分离游离酸来再生游离酸形式。
本发明的化合物可以具有碱性中心和酸性中心两者,并且因此可以是两性离子或内盐的形式。
通常,可以通过酌情使用期望的酸或碱来容易地制备式I的化合物的药学上可接受的盐。可以从溶液中沉淀盐,并且通过过滤收集,或者可以通过溶剂的蒸发回收。例如,可以向式I的化合物的水性悬浮液中添加酸的水性溶液(如盐酸),并且所得到的混合物被蒸干(冻干)以获得为固体的酸加成盐。可替代地,式I的化合物可以溶解在适合的溶剂(例如,醇,如异丙醇)中,并且可以在相同溶剂或另外的适合的溶剂中添加酸。然后,可以直接地或者通过添加较小极性的溶剂(如二异丙醚或己烷)来使所得到的酸加成盐沉淀,并且通过过滤分离。
有机化学领域的技术人员将理解,许多有机化合物可以与溶剂(有机化合物在其中反应、或者有机化合物从其中沉淀或结晶)形成复合物。这些复合物被称为“溶剂合物”。例如,与水的复合物被称为“水合物”。本发明的化合物的溶剂合物在本发明的范围内。式I的化合物的盐可以形成溶剂合物(例如,水合物),并且本发明还包含全部这样的溶剂合物。词语“溶剂合物”的含义对于本领域技术人员来说公知为通过溶剂与溶质的相互作用(即,溶剂化作用)形成的化合物。用于制备溶剂合物的技术在本领域中确立已久(例如,参见Brittain.Polymorphism in Pharmaceutical solids.Marcel Decker,New York,1999)。
本发明还包含式I的化合物的N-氧化物。术语“N-氧化物”意为,对于含有另外的未被取代sp2 N原子的杂环化合物,N原子可以承载共价结合的O原子,即-N→O。这样的经N-氧化物取代的杂环化合物的实例包含吡啶基N-氧化物、嘧啶基N-氧化物、吡嗪基N-氧化物和吡唑基N-氧化物。
本发明还包含式I的化合物的前体药物,即当向哺乳动物受试者施用时,在体内释放根据式I的活性母体药物的化合物。前体药物是药理学活性化合物,或者更典型地通过代谢转换转化成药理学活性药剂的非活性化合物。通过修饰存在于式I的化合物中的功能性基团来制备式I的化合物的前体药物,以这样的方式,可以在体内切割修饰以释放母体化合物。在体内,前体药物在生理条件下容易经历化学变化(例如,通过天然存在的一种或多种酶而起作用),造成药理学活性药剂的释出。前体药物包含式I的化合物,其中式I的化合物的羟基基团、氨基基团或羧基基团与可以在体内被切割以分别再生游离的羟基基团、氨基基团或羧基基团的任何基团结合。前体药物的实例包含式I的化合物的酯类(例如,乙酸酯、甲酸酯和苯甲酸酯衍生物)、或者在处于生理pH或通过酶作用时被转化成活性母体药物的任何其他衍生物。本领域中已经描述了用于适合的前体药物衍生物的选择和制备的常规程序(参见,例如,Bundgaard.Design of Prodrugs.Elsevier,1985)。
前体药物可以以与其转变成的活性成分相同的方式以及类似的有效量被施用,或者前体药物可以以储库形式被递送,例如,经皮贴剂或适合于容许(通过提供酶或其他适当的试剂)前体药物随时间向活性成分的缓慢转化和活性成分向患者的递送的其他储库。
本发明还包含代谢物。本文公开的化合物的“代谢物”是当化合物被代谢时形成的该化合物的衍生物。术语“活性代谢物”指当化合物被代谢时形成的该化合物的生物学活性衍生物。术语“代谢”指活体中改变特定物质的过程的总和。简言之,存在于身体中的全部化合物在身体内被酶操控,以便获得能量和/或以便将它们从身体中去除。特定酶对化合物产生特定的结构改变。例如,细胞色素P450催化各种氧化反应和还原反应,而尿苷二磷酸葡糖醛酸基转移酶催化经激活的葡糖醛酸分子向芳族醇、脂肪醇、羧酸、胺类和游离巯基基团的转变。可以从The Pharmacological Basis of Therapeutics,9th Edition,McGraw-Hill(1996),pages 11-17获得关于代谢的另外的信息。
通过向宿主施用化合物并且分析来自宿主的组织样品,或者通过体外孵育化合物与肝细胞并且分析所得到的化合物,可以鉴别本文公开的化合物的代谢物。两种方法是本领域中公知的。
术语“载体”指与活性化合物一起施用的稀释剂、赋形剂和/或运载体(vehicle)。本发明的药物组合物可以含有超过一种载体的组合。这样的药物载体可以是无菌液体,如水、盐溶液、葡萄糖水溶液、甘油水溶液和油类(包含石油来源、动物来源、植物来源或合成来源的那些油类,如花生油、大豆油、矿物油、芝麻油等)。水或水溶液盐水溶液和葡萄糖水溶液和甘油水溶液优选地用作载体,特别是用于可注射溶液。E.W.Martin的第18版的“Remington’s Pharmaceutical Sciences”中描述了适合的药物载体。
“药学上可接受的赋形剂”意为通常安全、无毒且无论是生物学上还是其他方面均符合期望的在制备药物组合物中有用的赋形剂,并且包含适用于兽用用途以及人用药物用途的赋形剂。本申请中使用的“药学上可接受的赋形剂”包含一种和超过一种这样的赋形剂。
为了用于人用药物或兽用药物而以任何方便的方式施用,本发明的化合物可以被制成制剂,并且因此本发明在其范围内包含适合用于人用药物或兽用药物的包括本发明的化合物的药物组合物。借助于一种或更多种适合的载体,这样的组合物可以以常规方式被提供以便使用。用于治疗用途的可接受的载体是药物领域中公知的,并且被描述于例如Remington’s Pharmaceutical Sciences,Mack Publishing Co.(A.R.Gennaroedit.1985)中。可以针对预期的施用途径和标准药学实践来选择药物载体的选择。除了载体之外,药物组合物还可以包括任何适合的一种或多种粘结剂、一种或多种润滑剂、一种或多种悬浮剂、一种或多种涂覆剂、和/或一种或多种增溶剂。
包括式I、IA、IB或IC的化合物的药物组合物
虽然化合物I可以作为原料药被施用是可能的,但优选在药物制剂中提供活性成分,例如,其中药剂在具有针对预期施用途径和标准药学实践选择的药学上可接受的载体的掺合物中。
因此,本发明还提供药物组合物,药物组合物包括与药学上可接受的载体掺合的式I的化合物、或式I的化合物的溶剂合物、水合物、异构体(例如,对映异构体、非对映异构体等)、N-氧化物或药学上可接受的盐。术语“载体”指与活性化合物一起施用的稀释剂、赋形剂和/或运载体。
式I的化合物可以与其他疗法和/或活性药剂组合使用。因此,在另外的方面,本发明提供药物组合物,药物组合物包括式I的化合物或式I的化合物的溶剂合物、水合物、异构体(例如,对映异构体、非对映异构体等)、N-氧化物或药学上可接受的盐、第二活性药剂、以及药学上可接受的载体。
除了载体之外,药物组合物还可以包括任何适合的粘结剂、润滑剂、悬浮剂、涂覆剂、和/或增溶剂。
也可以在药物组合物中提供防腐剂、稳定剂、染料和矫味剂。也可以使用抗氧化剂和悬浮剂。
可以将本发明的化合物降低至精细颗粒形式(例如,使用已知的研磨程序(如湿磨)研磨),以获得适于片剂形成和适于其他制剂类型的颗粒尺寸。可以通过本领域中已知的工艺来制备本发明的化合物的精细粉碎的(纳米颗粒)制剂,例如参见通过引用并入本文的WO02/00196。
施用途径和单位剂型
施用途径包含口服(例如,作为片剂、胶囊剂,或作为可摄取的溶液剂)、局部、粘膜(例如,作为鼻用喷雾或用于吸入的气雾剂)、鼻、肠胃外(例如,通过可注射形式)、胃肠、脊柱内、腹膜内、肌内、静脉内、子宫内、眼内、皮内、颅内、囊内、气管内、阴道内、脑室内、大脑内、皮下、眼(包含玻璃体内或前房内)、经皮、直肠、颊、硬脑膜外和舌下。本发明的组合物可以被特别地配制用于那些施用途径的任何一种。在优选的实施方案中,本发明的药物组合物被配制成适合于口服递送的形式。
根据不同的递送系统,可以存在不同的组合物/制剂要求。将理解的是,并非全部化合物都需要通过相同的途径来施用。同样地,如果组合物包括超过一种活性组分,则可以通过不同的途径施用那些组分。例如,本发明的药物组合物可以被配制成使用微型泵、或通过粘膜途径(例如,作为鼻用喷雾或用于吸入的气雾剂或可摄取的溶液剂)、或肠胃外地(其中组合物被配制成用于通过例如静脉内途径、肌内途径或皮下途径递送的可注射形式)。可替代地,制剂可以被设计为通过多种途径递送。
在待通过胃肠粘膜以粘膜方式递送药剂的情况下,药剂应当能够在运输通过胃肠道期间保持稳定;例如,药剂应当耐受蛋白水解降解,在酸性pH下稳定并且耐受胆汁的去污作用(detergent effect)。例如,可以用肠溶衣层包覆式I的化合物。肠溶衣层材料可以分散或溶解在水中或适合的有机溶剂中。下列中的一种或更多种(单独地或组合地)可以用作肠溶衣层聚合物:例如,甲基丙烯酸共聚物、邻苯二甲酸乙酸纤维素、乙酸丁酸纤维素、羟丙基甲基纤维素苯二甲酸酯、乙酸羟丙甲基纤维素琥珀酸酯、聚乙酸乙烯邻苯二甲酸酯、偏苯三酸乙酸纤维素、羧甲基乙基纤维素、虫胶或其他适合的一种或多种肠溶衣层聚合物的溶液或分散体。出于环保理由,水性包衣工艺可以是优选的。在这样的水性工艺中,甲基丙烯酸共聚物是最优选的。
在适当时,可以以下列方式施用药物组合物:通过吸入;以栓剂或阴道栓剂的形式;以洗剂、溶液剂、乳膏剂、软膏剂或撒布剂(dusting powder)的形式局部地;通过使用皮肤贴剂;以含有赋形剂(如淀粉或乳糖)的片剂的形式、或以单独的或与赋形剂掺合的胶囊剂或胚珠(ovule)的形式口服地;或者以含有矫味剂或着色剂的酏剂、溶液剂或混悬剂的形式;或者药物组合物可以被肠胃外地(例如,静脉地、肌内地或皮下地)注射。对于颊施用或舌下施用,可以以片剂或锭剂的形式施用组合物,可以以常规方式配制片剂或锭剂。
当待肠胃外施用本发明的组合物时,这样的施用包含下列中一种或更多种:静脉内、动脉内、腹腔内、鞘内、心室内、尿道内、胸骨内、颅内、肌内或皮下施用药剂;和/或通过使用输注技术。
可以肠胃外施用(例如,通过输注或注射)本发明的药物组合物。适合于注射或输注的药物组合物可以是含有活性成分的无菌水性溶液、分散体或无菌粉剂的形式,如果必要,活性成分被调整用于制备这样的适合于输注或注射的无菌溶液或分散体。该制剂可以可选地被包封到脂质体中。在全部情况下,最终制剂在生产条件和储存条件下必须是无菌的、液态的和稳定的。为了改进储存稳定性,这样的制剂也可以含有防腐剂以防止微生物的生长。可以通过添加各种抗细菌剂和抗真菌剂(例如,尼泊金、氯丁醇、乙酸钠、乳酸钠、柠檬酸钠或抗坏血酸)来实现微生物作用的防止。在很多情况下,推荐等渗物质(例如,糖类、缓冲剂和氯化钠),以确保与体液(特别是血液)的渗透压类似的渗透压。可以通过引入吸收延迟剂(如单硬脂酸铝或明胶)来实现这样的可注射混合物的延长的吸收。
可以在液态载体或中间产物(如甘油、液态聚乙二醇、三醋汀油、及其混合物)中制备分散体。液态载体或中间产物可以是溶剂或液态分散介质,溶剂或液态分散介质含有例如水、乙醇、多元醇(例如,甘油、丙二醇等)、植物油、无毒甘油酯、及其适合的混合物。通过脂质体的生成、在分散体的情况下适合的颗粒尺寸的施用、或通过表面活性剂的添加,可以维持适合的流动性。
对于肠胃外施用,最好以无菌水性溶液的形式使用化合物,无菌水性溶液可以含有其他物质(例如,足够的盐或葡萄糖)以使溶液与血液等渗。如果必要,水性溶液应当是经适当缓冲的(优选地达到从3至9的pH)。通过本领域技术人员公知的标准制药技术容易地完成无菌条件下适合的肠胃外制剂的制备。
通过将式I的化合物与适当的溶剂和前述载体中的一种或更多种混合,然后无菌过滤,可以制备无菌可注射溶液。在适合用于制备无菌可注射溶液的无菌粉剂的情况下,优选的制备方法包含真空干燥和冻干,这提供了用于无菌溶液的随后制备的醛固酮受体拮抗剂与期望的赋形剂的粉状混合物。
根据本发明的化合物可以被配制成在通过注射(例如,通过静脉内团注(bolusinjection)或输注或者经由肌内途径、皮下途径或鞘内途径)的人用药物或兽用药物中使用,并且可以以单位剂型存在于安瓿或其他单位剂量容器中、或者多剂量容器中(如果必要,伴随以额外的防腐剂)。用于注射的组合物可以是油性运载体或水性运载体中的混悬剂、溶液剂或乳剂的形式,并且可以含有配制剂(formulatory agent)(如悬浮剂、稳定剂、增溶剂和/或分散剂)。可替代地,活性成分可以是用于在使用之前用适合的运载体(例如,无菌无热原的水)重构的无菌粉剂的形式。
可以以片剂、胶囊剂、胚珠、酏剂、溶液剂或混悬剂(可以含有矫味剂或着色剂)的形式施用(例如,口服地或局部地)本发明的化合物,以用于快速释放应用、延迟释放应用、调节释放应用、持续释放应用、脉冲释放应用或受控释放应用。
本发明的化合物也可以针对人用用途或兽用用途以适合于口服施用或颊施用的形式存在,例如以溶液剂、凝胶剂、糖浆剂、漱口剂或混悬剂、或者在使用之前用水或其他适合的运载体构建的干燥粉剂的形式(可选地伴随有矫味剂和着色剂)。也可以使用固体组合物(如片剂、胶囊剂、锭剂、软锭剂、丸剂、大丸剂(bolus)、粉剂、糊剂、颗粒剂、弹丸剂(bullet)或预混合制剂)。可以根据本领域中公知的方法制备用于口服使用的固体组合物和液体组合物。这样的组合物也可以含有一种或更多种固体形式或液体形式的药学上可接受的载体和赋形剂。
片剂可以含有赋形剂(如微晶纤维素、乳糖、柠檬酸钠、碳酸钙、磷酸氢钙和甘氨酸)、崩解剂(如淀粉(优选地玉米淀粉、马铃薯淀粉或木薯淀粉)、羟基乙酸淀粉钠、交联羧甲基纤维素钠和某些络合硅酸盐)、以及造粒粘结剂(granulation binder)(如聚乙烯吡咯烷酮、羟丙基甲基纤维素(HPMC)、羟丙基纤维素(HPC)、蔗糖、明胶和阿拉伯胶)。
此外,可以包含润滑剂(如硬脂酸镁、硬脂酸、甘油二十二烷酸酯和滑石)。
可以以快速释放或受控释放的片剂、微粒剂、微型片剂、胶囊剂、囊袋剂和口服溶液剂或混悬剂、或者用于其制备的粉剂的形式口服地施用组合物。除了作为活性物质的本发明的新型固态形式的泮托拉唑之外,口服制剂还可以可选地包含各种标准药物载体和赋形剂(如粘结剂、填充剂、缓冲剂、润滑剂、助流剂、染料、崩解剂、气味剂、甜味剂、表面活性剂、脱模剂、抗粘着剂和包衣)。一些赋形剂可以在组合物中具有多重作用,例如,充当粘结剂和崩解剂两者。
用于口服组合物的药学上可接受的崩解剂的实例包含淀粉、预糊化淀粉、羧基乙酸淀粉钠、羧甲基纤维素钠、交联羧甲基纤维素钠、微晶纤维素、藻酸盐、树脂、表面活性剂、泡腾组合物、水性硅酸铝和交联聚乙烯吡咯烷酮。
用于口服组合物的药学上可接受的粘结剂的实例包含阿拉伯胶;纤维素衍生物,如甲基纤维素、羧甲基纤维素、羟丙基甲基纤维素、羟丙基纤维素或羟乙基纤维素;明胶、葡萄糖、右旋糖、木糖醇、聚甲基丙烯酸酯、聚乙烯吡咯烷酮、山梨糖醇、淀粉、预糊化淀粉、黄芪胶、苍耳烷树脂(xanthane resin)、藻酸盐、硅酸镁铝、聚乙二醇或膨润土。
用于口服组合物的药学上可接受的填充剂的实例包含乳糖、无水乳糖、乳糖一水合物、蔗糖、右旋糖、甘露糖醇、山梨糖醇、淀粉、纤维素(特别是微晶纤维素)、二氢磷酸钙或无水磷酸钙、碳酸钙和硫酸钙。
在本发明的组合物中有用的药学上可接受的润滑剂的实例包含硬脂酸镁、滑石、聚乙二醇、环氧乙烷的聚合物、十二烷基硫酸钠、十二烷基硫酸镁、油酸钠、十八烷基富马酸钠和胶体二氧化硅。
适合于口服组合物的药学上可接受的气味剂的实例包含合成香料和天然芳香油,如油、花、果实(例如,香蕉、苹果、酸樱桃、桃)的提取物及其组合,以及类似的香料。其使用取决于许多因素,最重要的因素是将要服用该药物组合物的人群的感官可接受度。
适合于口服组合物的药学上可接受的染料的实例包含合成染料和天然染料,如二氧化钛、β-胡萝卜素和葡萄柚皮的提取物。
对于口服组合物有用的药学上可接受的包衣的实例包含羟丙基甲基纤维素、羟丙基纤维素和丙烯酸酯-甲基丙烯酸酯共聚物,该包衣通常用于便利吞咽、修改释放性质、改进外观、和/或掩蔽组合物的味道。
用于口服组合物的药学上可接受的甜味剂的实例包含阿斯巴甜、糖精、糖精钠、甜蜜素、木糖醇、甘露糖醇、山梨糖醇、乳糖和蔗糖。
药学上可接受的缓冲剂的实例包含柠檬酸、柠檬酸钠、碳酸氢钠、磷酸氢二钠、氧化镁、碳酸钙和氢氧化镁。
药学上可接受的表面活性剂的实例包含十二烷基硫酸钠和聚山梨醇酯。
在明胶胶囊中,相似类型的固体组合物也可以用作填充剂。在这一点上,优选的赋形剂包含乳糖(lactose)、淀粉、纤维素、乳糖(milk sugar)或高分子量聚乙二醇。对于水性混悬剂和/或酏剂,药剂可以与各种甜味剂或矫味剂、着色物质或染料,与乳化和/或悬浮剂,以及与稀释剂(如水、乙醇、丙二醇和甘油),及其组合组合。
例如,本发明的化合物也可以被配制成用于人用药物或兽用药物的栓剂(例如,含有常规的栓剂基质),或者被配制成阴道栓剂(例如,含有常规的阴道栓剂基质)。
根据本发明的化合物可以被配制成以软膏剂、乳膏剂、凝胶剂、水凝胶、洗剂、溶液剂、洗发剂、粉剂(包含喷雾粉或撒布剂)、阴道栓剂、填塞物、喷雾剂、浸渍剂(dip)、气雾剂、滴剂(例如,眼滴剂、耳滴剂或鼻滴剂)或浇淋剂(pour-on)的形式在人用药物和兽用药物中使用以用于局部施用。
对于向皮肤的局部施加,本发明的药剂可以被配制成适合的软膏剂,该软膏剂含有悬浮或溶解在例如具有下列中的一种或更多种的混合物中的活性化合物:矿物油、液体凡士林、白凡士林、丙二醇、聚氧乙烯聚氧丙烯化合物、乳化蜡、山梨醇酐单硬脂酸酯、聚乙二醇、液体石蜡、聚山梨醇酯60、十六醇酯蜡、鲸蜡硬脂醇、2-辛基十二烷醇、苯甲醇和水。这样的组合物也可以含有其他药学上可接受的赋形剂,如聚合物、油类、液体载体、表面活性剂、缓冲剂、防腐剂、稳定剂、抗氧化剂、保湿剂、软化剂、着色剂和气味剂。
适合用于这样的局部用组合物的药学上可接受的聚合物的实例包含丙烯酸聚合物;纤维素衍生物,如羧甲基纤维素钠、甲基纤维素或羟丙基纤维素;天然聚合物,如藻酸盐、黄芪胶、果胶、黄原胶和壳聚糖(cytosan)。
如此有用的适合的药学上可接受的油类的实例包含矿物油、硅酮油、脂肪酸、醇类和二醇类。
适合的药学上可接受的液体载体的实例包含水、醇类或二醇类(如乙醇、异丙醇、丙二醇、己二醇、甘油和聚乙二醇)、或其混合物,假多晶型物被溶解或分散在其中,可选地伴随有无毒阴离子型表面活性剂、阳离子型表面活性剂或非离子型表面活性剂、以及无机缓冲剂或有机缓冲剂的添加。
药学上可接受的防腐剂的实例包含苯甲酸钠、抗坏血酸、对羟基苯甲酸的酯类、以及各种抗细菌剂和抗真菌剂,如溶剂,例如乙醇、丙二醇、苯甲醇、氯丁醇、季铵盐、以及对羟基苯甲酸酯类(如对羟基苯甲酸甲酯、对羟基苯甲酸乙酯和对羟基苯甲酸丙酯)。
药学上可接受的稳定剂和抗氧化剂的实例包含乙二胺四乙酸(EDTA)、硫脲、生育酚和丁基羟基茴香醚。
药学上可接受的保湿剂的实例包含甘油、山梨糖醇、尿素和聚乙二醇。
药学上可接受的软化剂的实例包含矿物油、肉豆蔻酸异丙酯和棕榈酸异丙酯。
化合物也可以皮肤施用或经皮施用(例如,通过使用皮肤贴剂)。
对于眼部应用,化合物可以被配制成等渗的、经pH调节的、无菌的盐水中经微粒化的混悬液,或者优选地被配制成等渗的、经pH调节的、无菌的盐水中的溶液,可选地与防腐剂(如氯化苄基烷醇盐(benzylalkonium chloride))组合。
如所指明的,本发明的化合物可以被鼻内施用或通过吸入施用,并且在使用适合的喷射剂(例如,二氯二氟甲烷、三氯氟甲烷、二氯四氟乙烷、氢氟烷烃(如1,1,1,2-四氟乙烷(HFA 134AT)或1,1,1,2,3,3,3-七氟丙烷(HFA 227EA))、二氧化碳、或其他适合的气体)的情况下从加压的容器、泵、喷雾器或雾化器以干粉吸入剂或气雾喷雾剂制剂的形式被方便地递送。在加压气雾剂的情况下,可以通过提供阀来递送经计量的量而确定剂量单位。加压的容器、泵、喷雾器或雾化器可以含有活性化合物的溶液或混悬液,例如,使用乙醇和喷射剂的混合物作为溶剂,溶剂可以附加地含有润滑剂(例如,山梨醇酐三油酸酯)。
用于在吸入器或吹入器中使用的胶囊和灌流器(cartridge)(例如,由明胶制成)可以被配制成含有化合物和适合的粉末基质(如乳糖或淀粉)的粉末混合物。
对于通过吸入的局部施用,根据本发明的化合物可以经由雾化器被递送用于在人用药物或兽用药物中使用。
本发明的药物组合物可以含有每体积从0.01%至99%重量的活性材料。对于局部施用,例如,组合物将通常含有0.01-10%(更优选地0.01-1%)的活性材料。
也可以以脂质体递送系统(如小单室囊泡(vesicle)、大单室囊泡和多室囊泡)的形式施用活性药剂。可以由各种磷脂(如胆固醇、硬脂胺或磷脂酰胆碱)形成脂质体。
可以按照上文给出的指导方针、根据由常规测试限定的剂量和施用方案来施用本发明的药物组合物或单位剂量形式,以便获得最佳活性,同时最小化对于特定患者的毒性或副作用。然而,按照本文给出的指导方针,治疗方案的这样的微调是常规的。
本发明的活性药剂的剂量可以根据各种因素(如潜在的疾病状况、个体的病况、体重、性别和年龄、以及施用方式)变化。可以通过本领域技术人员已知的经验方法(例如,通过建立剂量和施用频率的模型(matrix),并且将模型中的一组实验单元或每个点处的受试者进行比较)来容易地确定对于治疗紊乱的有效量。待施用至患者的准确量将根据紊乱的状态和严重程度以及患者的身体状况而变化。任何症状或参数的可测量的改善可以被本领域技术人员测量或者由患者向医师报告。
待施用的药剂的量可以在约0.01mg/kg/天与约25mg/kg/天之间(优选地在约0.1mg/kg/天与约10mg/kg/天之间、最优选地在0.2mg/kg/天与约5mg/kg/天之间)变动。将理解的是,本发明的药物制剂不需要必须含有全部量的有效治疗紊乱的药剂,因为通过这样的药物制剂的多个剂量的施用也可以达到这样的有效量。通常,“有效量”指以与临床相关的方式施用以改善、抑制或减轻受试者的疾病或紊乱或病况、或者疾病或紊乱的症状的药物组合物的量。受试者中任何与临床相关的改善都被认为足以实现治疗。优选地,足以治疗的量是防止感染的发生或一种或更多种症状的量,或者是相对于未用本发明的组合物治疗的对照受试者,降低受试者患有或发展出感染的一种或更多种症状的严重程度或持续时间的量。
在本发明的优选的实施方案中,根据式I的化合物被配制成优选地含有10mg至200mg本发明的化合物的胶囊剂或片剂,并且优选地以10mg至300mg(优选地20mg至150mg、最优选地约50mg)的总日剂量被施用至患者。
基于总药物组合物的100%重量,用于肠胃外施用的药物组合物含有从约0.01重量%至约100重量%的本发明的活性药剂。
通常,与剂型的100%总重量相比,经皮剂型含有从约0.01重量%至约100重量%的活性药剂。
药物组合物或单位剂型可以以单日剂量施用,或总日剂量可以以分剂量施用。此外,用于治疗紊乱的另外的化合物的共同施用或顺序施用可以是期望的。为此,组合的活性成分被配制成简单的剂量单位。
对于化合物为单独剂量制剂的组合治疗,可以同时施用化合物,或者可以以交错的间隔施用每种化合物。例如,可以在早晨施用本发明的化合物,而可以在晚上施用抗毒蕈碱化合物,反之亦然。还可以以特定的间隔施用附加的化合物。施用顺序将取决于各种因素,所述因素包含患者的年龄、体重、性别和身体状况;待治疗的紊乱的严重程度和病因、施用途径、患者的肾功能和肝功能、患者的治疗史、以及患者的响应能力。可以微调施用顺序的决定,并且按照本文给出的指导方针,这样的微调是常规的。
合成
可以通过下文概述的一般方法制备式I的化合物、以及式I的化合物的对映异构体、非对映异构体、N-氧化物和药学上可接受的盐,所述方法构成本发明的另外的方面。
通过采用下列方案中示出的(除了文献中已知的其他标准操作以外)、在实验部分中被例示、或者对本领域技术人员而言清楚的反应,可以制备本发明的化合物。本文中未描述的起始材料是可商业获得的,或者可以通过采用文献中描述的反应被制备,或者对于本领域技术人员而言清楚。下列实施例被提供以便可以更充分地理解本发明,仅是说明性的,而不应当被解释为限制性。
本领域技术人员将理解的是,使用在根据式I的化合物的制备中所使用的经保护的中间产物的衍生物是期望的。可以通过本领域已知的方法执行官能团的保护和脱保护(参见,例如,Green and Wuts Protective Groups in Organic Synthesis.John Wileyand Sons,New York,1999)。
缩写PG描述“保护基团”,“保护基团”在进行某些操作之前被引入到反应性基团中,并且随后被去除。用于保护反应性基团的PG的实例包含:用于氨基基团的乙酰基-、三氟乙酰基-、苯甲酰基-、乙氧基羰基-、N-叔丁氧基羰基-(BOC)、N-苄氧基羰基-(Cbz)、苄基-、甲氧基苄基-、2,4-二甲氧基苄基,附加地以及用于氨基-烷基氨基基团或亚氨基基团的邻苯二甲酰基-基团;用于酰胺基团的N-甲氧基甲基-(MOM)、N-苄氧基甲基-(BOM)、N-(三甲基甲硅烷基)乙氧基甲基-(SEM)、N-叔丁基-二甲基甲硅烷氧基甲基-、N-叔丁基-二甲基甲硅烷基-(TBDMS)、N-三异丙基甲硅烷基(TIPS)、N-苄基-、N-4-甲氧基苄基(PMB)、N-三苯甲基-(Tr)、N-叔丁氧基羰基-(BOC)、N-苄氧基羰基-(Cbz)或N-三甲基甲硅烷基乙基磺酰基-(SES);用于羟基基团的甲氧基-、苄氧基-、三甲基甲硅烷基-(TMS)、乙酰基-、苯甲酰基-、叔丁基-、三苯甲基-、苄基-、或四氢吡喃基(THP)基团;或者用于羧基基团的三甲基甲硅烷基-(TMS)、甲基-乙基-、叔丁基-、苄基-、或四氢吡喃基(THP)基团。
通常根据下列方案制备本发明的化合物,其中基团R、A、B和n如本文先前所定义:
方案1。
在一些实施方案中,可以进一步修饰最终产物(例如,通过取代基的操作)。这些操作可以包含(但不限于)本领域技术人员公知的还原反应、氧化反应、烷化反应、酰化反应和水解反应。在一些实施方案中,可以改变进行上述反应方案的顺序,以便便利反应或者避免不需要的反应产物。提供下列实施例,以便可以更全面地理解本发明。这些实施例仅是说明性的,而不应当以任何方式解释成限制本发明。
如方案1所示,通过使用本领域技术人员公知的合并方法,可商业获得的起始材料1可以容易地转化成N-经保护的3-溴-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪(2)。转而使用Sonogashira偶联方法或Sonogashira-Heck偶联方法将2与适当的经单取代的炔基衍生物反应,以获得化合物3。在下一步骤中,然后用已知的方法将N-经保护的化合物3脱保护以产生化合物4,化合物4与R5-B-R4-LG中间产物直接反应以获得化合物IA、IB或IC。LG表示离去基团,如(但不限于)卤族元素、甲磺酸酯、甲苯磺酸酯、烷基磺酸酯、三氟甲磺酸酯、或其他。可以使用标准方法(如布赫瓦尔德反应,酰化反应,与烷基/芳基异氰酸酯、烷基/芳基氯甲酸酯、氯甲酰胺、活性碳酸酯或脲的反应,还原胺化,烷化、或者对于形成根据式IA、IB或IC的化合物的目的有用并且对于本领域技术人员公知的任何类型的N-衍生化反应)来进行该最后的衍生化过程。也可以通过预先形成适合的中间产物(例如,中间产物4的氯磺酰基或氯羰基1-咪唑基羰基N-衍生物)来进行该最后的反应。
可替代地,也可以根据方案1通过与以上所述类似的化合物1的直接衍生化来制备本发明的化合物以产生化合物5,化合物5转而可以通过与针对化合物3所描述的相同的炔基化方法转化成化合物IA、IB或IC。
一般性说明中目前未描述的其他化合物的合成在接下来本发明的实验部分中被充分记载。
在本领域公知的标准条件下,根据式I的化合物的游离碱、其非对映异构体或对映异构体可以转化成相应的药学上可接受的盐。例如,游离碱溶解在适合的有机溶剂(如甲醇)中,用例如一当量的马来酸或草酸、一当量或二当量的盐酸或甲基磺酸处理,并且然后在真空下浓缩以提供相应的药学上可接受的盐。然后,可以通过重结晶从适合的有机溶剂或有机溶剂混合物(如甲醇/二乙醚)中纯化剩余物。
可以通过本领域技术人员已知的简单的氧化程序来合成根据式I的化合物的N-氧化物。
通式Ⅰ的化合物的制备
除非另有说明,否则可以原位制备和/或分离下文所描述的实施例的化合物的一种或更多种互变异构形式。应当认为下文所描述的实施例的化合物的全部互变异构形式都已公开。
通过下列实施例来说明本发明,其中可以采用下列缩写:
AcOH 乙酸
MeCN 乙腈
Aq. 水性
BOC 叔丁氧基羰基
conc. 经浓缩的
DCM 二氯甲烷
DCE 1,2-二氯乙烷
DIPEA N,N-二异丙基乙胺
DMF N,N-二甲基甲酰胺
DMSO 二甲亚砜
EI 电子电离作用
ESI 电喷雾电离
EtOAc 乙酸乙酯
EtOH 乙醇
HCl 盐酸
HCOOH 甲酸
MeOH 甲醇
MS 质谱分析
MW 分子量
NaOH 氢氧化钠
NH4OH 氢氧化铵(水中30%氨)
PE 石油醚
Rf 保留值(来自薄层色谱)
RT或r.t. 室温
Rt 保留时间(来自HPLC)
THF 四氢呋喃
TEA 三乙胺
TFA 三氟乙酸
UPLC 超高效液相色谱
UPLC-MS 超高效液相色谱联用质谱
下列实施例说明了上文所描述的通式I的化合物中的一些。这些实施例仅是说明性的,而不旨在限制本发明的范围。试剂和起始材料对于本领域技术人员而言容易获得。
实施例1
3-[2-(3-氯苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-羧酸叔
丁酯
将3-溴-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-羧酸叔丁酯(1.65mmol,500mg)、1-氯-3-乙炔基-苯(3.3mmol,450.5mg,0.406mL)、四钯(0.083mmol,95.3mg)和乙酸钠(3.3mmol,448.9mg)在无水DMF(10mL)中的混合物在120℃在微波Biotage Robot8烘箱中搅拌10分钟,冷却至室温,倒入水中,并且用EtOAc提取。用盐水洗涤合并的有机层,并且在Na2SO4上干燥。在真空中去除溶剂,并且经由用石油醚/EtOAc梯度从30%至100%的EtOAc中洗脱的自动快速色谱(Biotage Isolera,SNAP25柱)纯化粗剩余物。
将标题产物(280mg,47%产率)分离为浅黄色固体。
可替代的制备:
向微波瓶中3-溴-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-羧酸叔丁酯(3g,9.90mmol)在无水DMF(15mL)中的溶液添加1-氯-3-乙炔基苯(1.622g,11.88mmol,1.2当量,1.462mL),然后添加双(三苯基膦)二氯化钯(II)(0.278g,0.396mmol,0.04当量)、碘化亚铜(0.057g,0.297mmol,0.03当量)和TEA(1.302g,12.87mmol,1.30当量,1.80mL)。用氮气冲洗微波瓶,密封,并且在Biotage Initiator设备中在微波辐射下在110℃加热11分钟。然后,添加0.02当量的钯催化剂和0.02当量的碘化亚铜,并且将溶液在微波辐射下加热另外的6分钟。在室温冷却之后,添加水和EtOAc,分离两相,用水和盐水洗涤有机层,在Na2SO4上干燥,过滤并且蒸发。通过BiotageOne快速色谱设备(柱型:SNAP50)、使用从3:7至0:1的石油醚:EtAcO的梯度来纯化粗剩余物,从而产生1.4g黄色粉末(如通过LC-MS所检测的,除了希望的产物以外还含有三苯基氧化膦)。因此,通过相同的设备在反相柱色谱(SNAP60)上使用从2:8至1:1的梯度NH4HCO3缓冲液:MeCN来再次纯化样品,从而在蒸发收集的级分之后回收1.175g的标题化合物。
UPLC-MS[M+H]+=359.58,361.61,362.63
1H NMR(400MHz,DMSO-d6)δppm 1.45(s,9H),3.82(t,2H),4.14(t,2H),4.74(s,2H),7.49-7.56(m,1H),7.61(ddd,1H),7.66(dt,1H),7.81(t,1H)
实施例2
{3-[(3-氯苯基)乙炔基]-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基}(4-甲
基呋喃-2-基)甲酮
3-[2-(3-氯苯基)乙炔基]-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪(化合物
2a)
向实施例1的最终化合物(1.170g,3.26mmol)在CHCl3(50mL)中的经冰浴冷却的溶液中添加三氟乙酸(7.436g,5.02mL,65.22mmol),并且将所得的混合物在回流下搅拌30分钟。在室温冷却之后,在减压下去除氯仿和过量的TFA。添加碳酸钾饱和水溶液和DCM;分离两相,并且用DCM提取水层。用盐水洗涤合并的有机相,在Na2SO4上干燥,过滤,并且在真空中蒸干,以产生840mg为浅棕色粉末的标题化合物,标题化合物用于下一步骤,而无需任何进一步的纯化。
{3-[(3-氯苯基)乙炔基]-5,6-二氢[1,2,4]三唑并[4,3-a]吡嗪-7(8H)-基}(4-甲
基呋喃-2-基)甲酮
将4-甲基呋喃-2-羰基氯(45mg,0.311mmol)、3-[2-(3-氯苯基)乙炔基]-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪(60mg,0.232mmol)和DIPEA(59.95mg,0.464mmol,2当量,0.081mL)在无乙醇氯仿(3mL)中的溶液搅拌3小时。用水洗涤反应混合物。再次用盐水洗涤有机层,在Na2SO4上干燥,并且蒸发溶剂以产生粗产物,经由自动快速色谱联用质量检测(Biotage)纯化粗产物两次(首先用SNAP10柱以从10:0至9:1的梯度EtOAc:MeOH洗脱,其次用SNAP12 RP柱以从8:2至7:3的梯度H2O/ACN洗脱),以产生17mg标题化合物(产率:20%)。
UPLC-MS[M+H]+=367.20
1H NMR(400MHz,DMSO-d6)δppm 8.75(brd,1H),7.82(t,1H),7.58-7.71(m,4H),7.49-7.56(m,1H),7.07(s,1H),5.06(brs,2H),4.10-4.34(m,4H),2.05(d,3H),1.21-1.37(m,14H)
根据以上文公开的相同方法,通过用适当的酰基/芳酰基氯酰化/芳酰化来由化合物2a制备下列化合物。
实施例3
[3-[2-(3-氯苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-基]-
(4,5-二甲基-2-呋喃基)甲酮
得自化合物2a和4,5-二甲基-2-呋喃甲酰氯。
UPLC-MS[M+H]+=381.25
1H NMR(400MHz,CDCl3)δppm 7.57-7.62(m,1H),7.42-7.53(m,2H),7.32-7.40(m,1H),7.00(s,1H),5.32(s,2H),4.14-4.30(m,4H),2.32(s,3H),2.01(s,3H)
实施例4
[3-[2-(3-氯苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-基]-
[3-(三氟甲基)苯基]甲酮
得自化合物2a和3-三氟甲基苯甲酰氯。
UPLC-MS[M+H]+=431.21
1H NMR(400MHz,CDCl3)δppm 7.74-7.86(m,2H),7.60-7.72(m,2H),7.57(t,1H),7.48(dt,1H),7.41-7.46(m,1H),5.01(d,2H),4.00-4.33(m,4H)
实施例5
[3-[2-(3-氯苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-基]-
(间甲苯基)甲酮
得自化合物2a和3-甲基苯甲酰氯。
UPLC-MS[M+H]+=377.11
1H NMR(400MHz,DMSO-d6)δppm 7.81(t,1H),7.66(dt,1H),7.61(ddd,1H),7.49-7.56(m,1H),7.26-7.42(m,4H),4.92(s,2H),4.22(t,2H),3.69-4.06(m,2H),2.37(s,3H)
实施例6
[3-[2-(3-氯苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-基]-苯
基-甲酮
得自化合物2a和苯甲酰氯。
UPLC-MS[M+H]+=363.15
1H NMR(400MHz,DMSO-d6)δppm 7.81(t,1H),7.66(dt,1H),7.59-7.64(m,1H),7.44-7.58(m,6H),4.93(s,2H),4.23(t,2H),3.58-4.13(m,2H)
实施例7
[3-[2-(3-氯苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-基]-
(2-呋喃基)甲酮
得自化合物2a和2-呋喃甲酰氯。
UPLC-MS[M+H]+=353.35,355.38,356.36
1H NMR(400MHz,DMSO-d6)δppm 4.18(d,2H),4.23-4.33(m,2H),5.09(br.s.,2H),6.70(dd,1.8Hz,1H),7.20(d,1H),7.54(t,1H),7.61(dd,1H),7.67(dt,1H),7.82(t,1H),7.93(d,1H)
实施例8
(3-氯苯基)-[3-[2-(3-氯苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡
嗪-7-基]甲酮
得自化合物2a和3-氯苯甲酰氯。
UPLC-MS[M+H]+=397.09,399.07,400.06
1H NMR(400MHz,DMSO-d6)δppm 7.81(t,1H),7.45-7.70(m,8H),4.94(s,2H),4.21(t,2H),3.58-4.11(m,2H)
根据上文针对实施例2的化合物公开的相同方法,通过与适当的氯甲酰胺或氯甲酸酯或异氰酸酯或活性碳酸酯或其他酰化试剂反应,由化合物2a制备下列化合物。
实施例9
[3-[2-(3-氯苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-基]-吗
啉代甲酮
得自化合物2a和4-吗啉羰酰氯。获得为白色固体。
UPLC-MS[M+H]+=372.57,374.52,375.54
1H NMR(400MHz,DMSO-d6)δppm 3.21-3.28(m,4H),3.56-3.63(m,4H),3.66(t,2H),4.18(t,2H),4.57(s,2H),7.53(t,1H),7.61(ddd,1.0Hz,1H),7.66(dt,1H),7.81(t,1H)
实施例10
[3-[(Z)-1-氯-2-(3-氯苯基)乙烯基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡 嗪-7-基]-吗啉代-甲酮得自化合物2a和4-吗啉羰酰氯。获得为实施例9的化合物的副产物。
UPLC-MS[M+H]+=408.40,410.43,411.37
1H NMR(400MHz,DMSO-d6)δppm 3.26(t,4H),3.57-3.68(m,6H),4.18(t,2H),4.58(s,2H),7.33(s,1H),7.51-7.58(m,2H),7.79-7.85(m,1H),7.92-7.96(m,1H)
实施例11
[3-[2-(3-氯苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-基]-
(1-哌啶基)甲酮
得自化合物2a和4-哌啶羰酰氯。获得为白色固体。
UPLC-MS[M+H]+=370.61,372.57,373.58
1H NMR(400MHz,DMSO-d6)δppm 1.44-1.62(m,6H),3.19-3.27(m,4H),3.61(t,2H),4.17(t,2H),4.52(s,2H),7.53(t,1H),7.61(ddd,1H),7.66(dt,1H),7.81(t,1H)
实施例12
[3-[2-(3-氯苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-基]-吡
咯烷-1-基-甲酮
得自化合物2a和1-吡咯烷羰酰氯。获得为白色固体。
UPLC-MS[M+H]+=356.54,358.57,359.58
1H NMR(400MHz,DMSO-d6)δppm 1.73-1.85(m,4H),3.32-3.40(m,4H),3.68(t,2H),4.16(t,2H),4.56(s,2H),7.53(t,1H),7.61(ddd,1H),7.66(dt,1H),7.81(t,1H)
实施例13
3-[2-(3-氯苯基)乙炔基]-N-(2,2-二甲基丙基)-6,8-二氢-5H-[1,2,4]三唑并
[4,3-a]吡嗪-7-羧酰胺
得自化合物2a和1-异氰酰基-2,2-二甲基-丙烷。获得为白色固体。
UPLC-MS[M+H]+=372.15,374.13,375.13
1H NMR(400MHz,DMSO-d6)δppm 7.79-7.86(m,1H),7.66(dt,1H),7.58-7.63(m,1H),7.48-7.56(m,1H),6.78(t,1H),4.79(s,2H),4.11(t,2H),3.85(t,2H)2.93(d,2H),0.83(s,9H)
实施例14
3-[2-(3-氯苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-羧酸2,
2-二甲基丙酯
得自化合物2a和2,2-二甲基氯甲酸丙酯。获得为白色固体。
UPLC-MS[M+H]+=373.14,375.13
1H NMR(400MHz,DMSO-d6)δppm 7.81(t,1H),7.66(dt,1H),7.58-7.63(m,1H),7.50-7.57(m,1H),4.81(s,2H),4.18(t,2H),3.90(t,2H)3.79(s,2H),0.95(s,9H)
实施例15
3-[2-(3-氯苯基)乙炔基]-N,N-二乙基-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡
嗪-7-羧酰胺
得自化合物2a和二乙基氨基羰酰氯。获得为白色固体。
UPLC-MS[M+H]+=358.57,360.60,361.61
1H NMR(400MHz,DMSO-d6)δppm 1.09(t,6H),3.22(q,4H),3.60(t,2H),4.16(t,2H),4.48(s,2H),7.53(t,1H),7.61(ddd,1H),7.66(dt,1H),7.81(t,1H)
实施例16
3-[2-(3-氯苯基)乙炔基]-N,N-二甲基-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡
嗪-7-羧酰胺
得自化合物2a和二甲基氨基羰酰氯。获得为白色固体。
UPLC-MS[M+H]+=330.57,332.53,333.55
1H NMR(400MHz,DMSO-d6)δppm 2.84(s,6H),3.62(t,2H,)4.17(t,,2H),4.51(s,2H),7.53(t,1H),7.61(ddd,1H),7.66(dt,1H),7.81(t,1H)
实施例17
3-[2-(3-氯苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-羧酸甲
酯
得自化合物2a和氯甲酸甲酯,以获得为淡黄色固体的实施例17的化合物。
UPLC-MS[M+H]+=317.3,319.3,320.4
1H NMR(400MHz,DMSO-d6)δppm 3.69(s,3H)3.87(t,2H),4.16(t,,2H),4.79(s,2H),7.53(t,1H),7.61(ddd,1H),7.66(dt,1H),7.81(t,1H)
实施例18
[3-[2-(3-氯苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-基]-
(2,2-二甲基吗啉-4-基)甲酮
得自化合物2a和2,2-二甲基吗啉-4-羰酰氯。
实施例19
四氢吡喃-4-基3-[2-(3-氯苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]
吡嗪-7-羧酸酯
得自化合物2a和(2,5-二氧代吡咯烷-1-基)四氢吡喃-4-基碳酸酯(US2016/0250276)。获得为白色固体。
UPLC-MS[M+H]+=387.28,389.26,390.25
1H NMR(400MHz,DMSO-d6)δppm 7.81(t,1H),7.59-7.70(m,2H),7.50-7.57(m,1H),4.76-4.89(m,3H),4.17(t,2H),3.89(t,2H),3.76-3.84(m,2H),3.49(ddd,2H),1.82-1.95(m,2H),1.60(dtd,2H)。
实施例20
3-[2-(3-氯苯基)乙炔基]-N-(2-异丙氧基-1,1-二甲基-乙基)-6,8-二氢-5H-[1,
2,4]三唑并[4,3-a]吡嗪-7-羧酰胺
得自化合物2a和(2,5-二氧代吡咯烷-1-基)N-(2-异丙氧基-1,1-二甲基-乙基)氨基甲酸酯的白色固体依次如下制备:
在室温向双-(2,5-二氧代吡咯烷-1-基)碳酸酯(0.99mmol,253.8mg)在干MeCN(5mL)中的经搅拌的溶液添加1-异丙氧基-2-甲基-丙烷-2-胺(0.76mmol,100mg),并且将所得到的混合物在相同条件下搅拌2小时。LC/MS显示完全转化,因此在减压下浓缩混合物,并且用水性NaHCO3稀释剩余物,并且用EtOAc提取。用盐水洗涤合并的提取物,并且在Na2SO4上干燥。溶剂的蒸发提供200mg为白色固体的(2,5-二氧代吡咯烷-1-基)N-(2-异丙氧基-1,1-二甲基-乙基)氨基甲酸酯,(2,5-二氧代吡咯烷-1-基)N-(2-异丙氧基-1,1-二甲基-乙基)氨基甲酸酯被使用而无需进一步纯化。
实施例20分析数据:
UPLC-MS[M+H]+=416.18,418.16,419.15
1H NMR(400MHz,DMSO-d6)δppm 7.79-7.83(m,1H),7.59-7.68(m,2H),7.53(dd,1H),6.14(s,1H),4.72(s,2H),4.10(t,2H),3.81(t,2H),3.47(spt,1H),3.42(s,2H),1.23(s,6H),1.03(d,6H)
实施例21
3-[2-(3-氯苯基)乙炔基]-N-(2-吡啶基)-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]
吡嗪-7-羧酰胺
得自化合物2a和(2,5-二氧代吡咯烷-1-基)N-(2-吡啶基)氨基甲酸酯(US20070049618第110页)。获得为白色固体。
UPLC-MS[M+H]+=379.27,381.25,382.24
1H NMR(400MHz,DMSO-d6)δppm 9.63(s,1H),8.28(dt,1H),7.82(t,1H),7.77-7.81(m,1H),7.69-7.76(m,1H),7.67(dt,1H),7.58-7.64(m,1H),7.50-7.57(m,1H),7.02(ddd,1H),4.92(s,2H),4.16-4.25(m,2H),4.01(t,2H)
实施例22
3-[2-(3-氯苯基)乙炔基]-N-(2-甲氧基乙基)-N-甲基-6,8-二氢-5H-[1,2,4]三
唑并[4,3-a]吡嗪-7-羧酰胺
得自化合物2a和N-(2-甲氧基乙基)-N,3-二甲基咪唑-3-鎓-1-羧酰胺碘化物(购买的)。获得为浅棕色固体。
UPLC-MS[M+H]+=374.0,376.06,377.12
1H NMR(400MHz,DMSO-d6)δppm 2.90(s,3H),3.25(s,3H),3.36(t,2H),3.49(t,2H),3.62(t,2H),4.16(t,2H),4.50(s,2H),7.53(t,1H),7.61(ddd,1H),7.66(dt,1H),7.81(t,1H)
实施例23
3-[2-(3-氯苯基)乙炔基]-N-乙基-N-甲基-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]
吡嗪-7-羧酰胺
得自化合物2a和1-[乙基(甲基)氨基甲酰基]-3-甲基-1H-咪唑-3-鎓碘化物。获得为淡黄色固体。
UPLC-MS[M+H]+=344.11,346.12,347.22
1H NMR(400MHz,DMSO-d6)δppm 1.09(t,3H),2.84(s,3H),3.21(q,2H),3.61(dd,2H),4.17(dd,2H),4.49(s,2H),7.53(dd,1H),7.61(ddd,1H),7.66(ddd,1H),7.81(dd,1H)
实施例24
3-[2-(3-氯苯基)乙炔基]-N-甲氧基-N-甲基-6,8-二氢-5H-[1,2,4]三唑并[4,3-
a]吡嗪-7-羧酰胺
得自化合物2a和N-甲氧基-N-甲基氨基甲酰氯。产物被回收为淡黄色固体。
UPLC-MS[M+H]+=346.38,348.41,349.42
1H NMR(400MHz,DMSO-d6)δppm 2.94(s,3H),3.63(s,3H),3.85(t,2H),4.18(t,2H),4.76(s,2H),7.53(t,1H),7.61(ddd,1H),7.67(dt,1H),7.82(t,1H)
实施例25
3-[2-(3-氯苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-羧酸乙
酯
得自化合物2a和氯甲酸乙酯。产物被回收为淡黄色固体。
UPLC-MS[M+H]+=331.4,333.4,334.4
1H NMR(400MHz,DMSO-d6)δppm 1.24(t,3H),3.87(t,2H),4.12(t,2H),4.16(dd,2H),4.79(s,2H),7.53(t,1H),7.59-7.64(m,1H),7.66(dt,1H),7.81(t,1H)
实施例26
(3-氯苯基)-[3-[2-(6-甲基-2-吡啶基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并
[4,3-a]吡嗪-7-基]甲酮
3-溴-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-基)-(3-氯苯基)甲酮(化合物
26a)
向在0℃冷却的3-溴-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪盐酸盐(4.18mmol,1g)在CH2Cl2(30mL)中的溶液添加TEA(12.53mmol,1.268g,1.61mL),然后添加3-氯苯甲酰氯(6.26mmol,0.80mL,1.096g),并且将混合物在室温搅拌3h。然后,添加水,分离两相,用水和盐水洗涤有机层,在Na2SO4上干燥,过滤,并且蒸发。通过Biotage Isolera One(柱型SNAP50)、使用从EtOAc 100%至EtOAc:MeOH 8:2的梯度纯化粗剩余物,收集1.320g的标题化合物(黄色油状物)。
(3-氯苯基)-[3-[2-(6-甲基-2-吡啶基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并
[4,3-a]吡嗪-7-基]甲酮
向微波瓶中化合物26a(150mg,0.44mmol)在DMF(1mL)中的溶液添加2-乙炔基-6-甲基-吡啶(0.88mmol,102.9mg),随后添加三水合乙酸钠(0.88mmol,119.5mg)和四(三苯基膦)钯(0.022mmol,25.38mg),并且将混合物在Biotage Initiator微波烘箱中在微波辐射下在120℃加热15min。然后,添加水,分离两相,用水和盐水洗涤有机层,在Na2SO4上干燥,过滤,并且蒸发。通过Biotage Isolera Four(与Dalton MS检测器联用)(柱型SNAP25)(收集全部模式)、使用从EtAcO 100%至EtAcO:MeOH 8:2的梯度纯化粗剩余物。收集20mg的标题化合物(棕色油状物)以及杂质。然后,使用从NH4HCO3缓冲液:MeCN 85:15至NH4HCO3缓冲液:MeCN 1:1的梯度在反相柱色谱(柱型SNAP12)上重新纯化样品。收集9mg希望的化合物(白色粉末)。
UPLC-MS[M+H]+=378.28,380.17,381.34
1H NMR(400MHz,DMSO-d6)δppm 7.62-7.71(m,1H),7.45-7.55(m,3H),7.43(t,1H),7.31-7.39(m,1H),7.23(d,1H),5.02(br.s.,2H),4.23-4.37(m,2H),3.94-4.21(m,2H),2.62(s,3H)
使用上文针对实施例26报告的方法,并且用适当的炔烃代替2-乙炔基-6-甲基-吡啶,制备下列化合物:
实施例27
3-[2-[7-(3-氯苯甲酰基)-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-3-基]乙炔
基]苄腈
得自化合物26a和3-乙炔基苄腈。获得为白色固体。
UPLC-MS[M+H]+=388.18,390.25,391.06
1H NMR(400MHz,DMSO-d6)δppm 7.88(t,1H),7.83(dt,1H),7.75(dt,1H),7.55-7.63(m,1H),7.48-7.55(m,2H),7.45(t,1H),7.35-7.40(m,1H),5.04(s,2H),3.96-4.31(m,4H)
实施例28
(3-氯苯基)-[3-[2-(4-氯-2-吡啶基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,
3-a]吡嗪-7-基]甲酮
使用双(三苯基膦)二氯化钯(II)(而非四(三苯基膦)钯)得自化合物26a和4-氯-2-乙炔基吡啶。产物被回收为深色粉末。
UPLC-MS[M+H]+=398.21,400.19,401.10
1H NMR(400MHz,CDCl3)δppm 8.58(d,1H),7.66(d,1H),7.32-7.57(m,6H),5.04(s,2H),4.22-4.36(m,2H),4.12(s,1H)
实施例29
(3-氯苯基)-[3-[2-(3-氟苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡
嗪-7-基]甲酮
得自化合物26a和1-乙炔基-3-氟苯。获得为白色固体。
实施例30
(3-氯苯基)-[3-(2-环己基乙炔基)-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-
7-基]甲酮
得自化合物26a和环己乙炔。回收为浅黄色固体。
UPLC-MS[M+H]+=369.18,371.25
1H NMR(400MHz,DMSO-d6)δppm 7.43-7.63(m,4H),4.58-5.09(m,2H),3.96-4.14(m,2H),3.59-3.95(m,2H),2.75-2.87(m,1H)1.26-1.93(m,10H)
实施例31
(3-氯苯基)-[3-(2-苯基乙炔基)-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-
基]甲酮
得自化合物26a和苯乙炔。回收为黄色油状物。
UPLC-MS[M+H]+=363.15,365.13
1H NMR(400MHz,CDCl3)δppm 7.32-7.64(m,9H),5.02(d,2H),4.03-4.26(m,4H)
实施例32
3-[2-(间甲苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-羧酸叔
丁酯
使用上文针对实施例1报告的方法,并且用3-甲苯乙炔代替1-氯-3-乙炔基苯,制备标题化合物,并且获得为白色固体。
UPLC-MS[M+H]+=339.64
1H NMR(400MHz,DMSO-d6)δppm 1.45(s,9H),2.36(s,3H),3.82(t,2H),4.11(t,2H),4.73(s,2H),7.31-7.42(m,2H),7.47(d,1H),7.51(s,1H)
实施例33
[3-[2-(间甲苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-基]-
(1-哌啶基)甲酮盐酸盐
3-[2-(间甲苯基)乙炔基]-5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪(化合物
33a)
将实施例32的化合物(187mg,0.553mmol)在异丙醇中4.4M HCl(5.03mL,22.1mmol)中的溶液在室温搅拌2h。然后,在真空中蒸干,从而产生170mg为白色固体的标题化合物,标题化合物用于下一步骤而无需进一步纯化。
[3-[2-(间甲苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-基]-
(1-哌啶基)甲酮
在搅拌下向化合物33a(50mg,0.21mmol)的悬浮液添加TEA(87.5μL,0.63mmol),然后添加1-哌啶羰酰氯。将溶液在搅拌下保持16h。然后,通过自动快速色谱(BiotageIsolera)、使用从EtOAc 100%至EtOAc:MeOH 8:2的梯度纯化由溶剂蒸发获得的粗品,从而产生32mg的粘性固体。
UPLC-MS[M+H]+=359.59
1H NMR(400MHz,DMSO-d6)δppm 1.39-1.61(m,6H),2.35(s,3H),3.06-3.26(m,4H),3.60(t,2H),4.14(t,2H),4.50(s,2H),7.34(d,1H),7.38(t,1H),7.47(d,1H),7.49-7.52(m,1H)
按照针对实施例33的化合物制定的合成方法,并且用适当的酰化试剂代替1-哌啶羰酰氯,制备下列化合物:
实施例34
2-呋喃基-[3-[2-(间甲苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡
嗪-7-基]甲酮
得自化合物33a和2-呋喃甲酰氯。回收为白色固体。
UPLC-MS[M+H]+=333.46
1H NMR(400MHz,DMSO-d6)δppm 2.35(s,3H),4.16(br.s.,2H),4.23(d,2H),5.07(br.s.,2H),6.69(dd,1H),7.19(dd,1H),7.32-7.36(m,1H),7.39(t,1H),7.47(d,1H),7.51(s,1H),7.92(dd,1H)
实施例35
N,N-二乙基-3-[2-(间甲苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡
嗪-7-羧酰胺
得自化合物33a和二乙基氨基羰酰氯。回收为白色固体。
UPLC-MS[M+H]+=338.55
1H NMR(400MHz,DMSO-d6)δppm 1.08(t,6H),2.35(s,3H),3.21(q,4H),3.58(t,2H),4.13(t,2H),4.45(s,2H),7.34(d,1H),7.38(t,1H),7.47(d,1H),7.50(s,1H)
实施例36
N,N-二甲基-3-[2-(间甲苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡
嗪-7-羧酰胺
得自化合物33a和二甲基氨基羰酰氯。产物被回收为粘性固体。
UPLC-MS[M+H]+=310.49
1H NMR(400MHz,DMSO-d6)δppm 2.36(s,3H),2.84(s,6H),3.62(t,2H),4.15(t,2H),4.50(s,2H),7.35(d,1H),7.39(t,1H),7.48(d,1H),7.52(s,1H)
实施例37
N-甲氧基-N-甲基-3-[2-(间甲苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-
a]吡嗪-7-羧酰胺
得自化合物33a和N-甲氧基-N-甲基氨基甲酰氯。产物被回收为粘性固体。
UPLC-MS[M+H]+=326.51
1H NMR(400MHz,DMSO-d6)δppm 2.36(s,3H),2.94(s,3H),3.62(s,3H),3.85(t,2H),4.15(t,2H),4.75(s,2H),7.35(d,1H),7.39(t,1H),7.48(d,1H),7.51(s,1H)
实施例38
N-异丙基-N-甲基-3-[2-(间甲苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-
a]吡嗪-7-羧酰胺
得自化合物33a和N-异丙基-N,3-二甲基-咪唑-3-鎓-1-羧酰胺碘化物。产物被回收为浅黄色固体。
UPLC-MS[M+H]+=338.43
1H NMR(400MHz,CDCl3)δppm 1.19(d,6H),2.38(s,3H),2.79(s,3H),3.68(t,2H),4.04-4.17(m,1H),4.20(t,2H),4.65(s,2H),7.19-7.33(m,2H),7.35-7.43(m,2H)
实施例39
N-(2-甲氧基乙基)-N-甲基-3-[2-(间甲苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三
唑并[4,3-a]吡嗪-7-羧酰胺
得自化合物33a和N-(2-甲氧基乙基)-N,3-二甲基咪唑-3-鎓-1-羧酰胺碘化物(购买的)。产物被回收为黄色油状物。
UPLC-MS[M+H]+=354.26
1H NMR(400MHz,DMSO-d6)δppm 2.36(s,3H),2.90(s,3H),3.25(s,3H),3.34-3.39(m,2H),3.46-3.52(m,2H),3.62(s,2H),4.14(t,2H),4.49(s,2H),7.32-7.36(m,1H),7.39(t,1H),7.47(d,1H),7.51(s,1H)
实施例40
N-乙基-N-甲基-3-[2-(间甲苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]
吡嗪-7-羧酰胺
得自化合物33a和1-[乙基(甲基)氨基甲酰基]-3-甲基-1H-咪唑-3-鎓碘化物。产物(负向别构调节剂)被回收为淡黄色固体。
UPLC-MS[M+H]+=324.28
1H NMR(400MHz,DMSO-d6)δppm 1.09(t,3H),2.36(s,3H),2.84(s,3H),3.21(q,2H),3.61(t,2H),4.14(t,2H),4.48(s,2H)7.31-7.37(m,1H),7.39(t,1H),7.47(d,1H),7.51(s,1H)
实施例41
1-哌啶基3-[2-(间甲苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-
7-羧酸酯
在室温向化合物33a(140mg,0.588mmol)在DCM(15mL)和DIPEA(206μl,1.18mmol)中的溶液逐滴添加三光气(69.8mg,0.235mmol)在5mL DCM中的溶液。在5min之后,添加1-羟基哌啶(89.2mg,0.882mmol)和DIPEA(103μl,0.59mmol)的溶液。在室温搅拌过夜之后,用DCM稀释反应混合物,分离有机层,在硫酸钠上干燥,并且蒸干。通过自动快速色谱(BiotageIsolera,FLASH 12+柱)、使用从PE:EtOAc 2:8至EtOAc 100%的梯度的纯化提供了13mg白色粘性固体,在SNAP 12RP柱上以从NH4HCO3缓冲液:ACN 6:4至NH4HCO3缓冲液:ACN 1:1的梯度重新纯化白色粘性固体。获得为粘性固体的6mg标题化合物。
UPLC-MS[M+H]+=366.79
1H NMR(400MHz,CDCl3)δppm 1.28(s,1H),1.65(br.s.,1H),1.74-1.88(m,4H),2.39(s,3H),2.70(br.s.,2H),3.46(br.s.,2H),3.97(t,2H),4.14(t,2H),4.91(s,2H),7.20-7.36(m,2H),7.36-7.46(m,2H)
实施例42
吗啉代-[3-[2-(间甲苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-
7-基]甲酮
得自化合物33a和1-吗啉代羰酰氯,其中产物被回收为白色固体。
UPLC-MS[M+H]+=352.48
1H NMR(400MHz,DMSO-d6)δppm 2.35(s,3H),3.25(t,4H),3.59(t,4H),3.65(t,2H),4.15(t,2H),4.55(s,2H),7.34(d,1H),7.38(t,1H),7.46(d,1H),7.49-7.52(m,1H)
实施例43
(3-氯苯基)-[3-[2-(间甲苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡
嗪-7-基]甲酮
得自化合物33a和苯甲酰氯,其中产物被回收为米黄色固体。
UPLC-MS[M+H]+=377.43
1H NMR(400MHz,DMSO-d6)δppm 2.36(s,3H),3.68-4.00(m,2H),4.19(t,2H),4.61-5.33(m,2H),7.33-7.42(m,2H),7.45-7.57(m,4H),7.57-7.64(m,2H)
实施例44
[3-[2-(间甲苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-基]-吡
咯烷-1-基-甲酮
得自化合物33a和1-吡咯烷羰酰氯,其中产物被回收为粘性固体。
UPLC-MS[M+H]+=336.52
1H NMR(400MHz,DMSO-d6)δppm 1.74-1.81(m,4H),2.34(s,4H),3.21-3.46(m,2H),3.66(t,3H),4.12(t,2H),4.52(s,2H),7.33(d,1H),7.37(t,1H),7.46(d,1H),7.49(s,1H)
实施例45
3-[2-(间甲苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-羧酸乙
酯
得自化合物33a和氯甲酸乙酯,其中产物被回收为白色固体。
UPLC-MS[M+H]+=311.58
1H NMR(400MHz,DMSO-d6)δppm 1.24(t,3H),2.36(s,3H),3.86(t,2H),4.06-4.20(m,4H),4.78(s,2H),7.35(d,1H),7.39(t,1H),7.47(d,1H),7.51(s,1H)
实施例46
3-[2-(间甲苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-羧酸甲
酯
得自化合物33a和氯甲酸甲酯,其中产物被回收为白色固体。
UPLC-MS[M+H]+=297.61
1H NMR(400MHz,DMSO-d6)δppm 2.36(s,3H),3.69(s,3H),3.86(t,2H),4.13(t,2H),4.78(s,2H),7.35(d,1H),7.39(t,1H),7.47(d,1H),7.51(s,1H)
实施例47
3-[2-(3-氰基-5-氟-苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-
7-羧酸叔丁酯
使用上文针对实施例1报告的方法,并且用3-氰基-5-氟苯乙炔代替1-氯-3-乙炔基苯来制备。
UPLC-MS[M+H]+=368.35
1H NMR(400MHz,CDCl3)δppm 1.53(s,9H),3.89-4.00(m,2H),4.09-4.16(m,2H),4.90(s,2H),7.45(ddd,1H),7.51-7.56(m,1H),7.66-7.69(m,1H)
实施例48
3-[2-(4-氯-2-吡啶基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-羧
酸叔丁酯
使用上文针对实施例1报告的方法,并且用4-氯-2-乙炔基吡啶代替1-氯-3-乙炔基苯来制备。产物被回收为米黄色固体。
UPLC-MS[M+H]+=360.38
1H NMR(400MHz,CDCl3)δppm 1.53(s,9H)3.92(t,2H),4.17(t,2H),4.90(s,2H),7.39(dd,1H),7.61-7.69(m,1H),8.57(d,1H)
实施例49
3-[2-(1-羟基环己基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-羧
酸叔丁酯
使用上文针对实施例1报告的方法,并且用1-乙炔环己醇代替1-氯-3-乙炔基苯来制备。产物被回收为淡黄色固体。
UPLC-MS[M+H]+=347.62
1H NMR(400MHz,DMSO-d6)δppm 1.26(dd,1H),1.39-1.62(m,5H),1.44(s,9H),1.63-1.74(m,2H),1.85-1.95(m,2H),3.80(t,2H),3.98(t,2H),4.68(br.s.,2H),5.72(s,1H)
实施例50
3-(2-苯基乙炔基)-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-羧酸叔丁酯
使用上文针对实施例1报告的方法,并且用苯乙炔代替1-氯-3-乙炔基苯来制备。
UPLC-MS[M+H]+=325.43
实施例51
3-[2-(6-甲基-2-吡啶基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-
羧酸叔丁酯
使用上文针对实施例1报告的方法,并且用6-甲基-2-吡啶基乙炔代替1-氯-3-乙炔基苯来制备。
UPLC-MS[M+H]+=340.58
通过用三氟乙酸或者使用EtOAc或i-PrOH中的HCl使上文描述的实施例47-48和50-51的化合物的叔丁氧基羰基酸裂解,并且随后用氯甲酸乙酯或氯甲酸甲酯或N,N-二乙基氨基甲酰氯酰化或者按照标准程序用2-氯-6-甲基吡啶芳基化,来制备下列化合物。
实施例52
3-[2-(3-氰基-5-氟-苯基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-
7-羧酸乙酯
可以由3-氟-5-[2-(5,6,7,8-四氢-[1,2,4]三唑并[4,3-a]吡嗪-3-基)乙炔基]苄腈和氯甲酸乙酯制备该化合物。
UPLC-MS[M+H]+=340.45
实施例53
3-[2-(4-氯-2-吡啶基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-羧
酸乙酯
得自3-[(4-氯吡啶-2-基)乙炔基]-5,6,7,8-四氢[1,2,4]三唑并[4,3-a]吡嗪和氯甲酸乙酯。产物被回收为淡黄色固体。
UPLC-MS[M+H]+=332.33,320.07,321.08
1H NMR(400MHz,CDCl3)δppm 1.33(t,3H),3.97(t,2H),4.19(t,2H),4.25(q,2H),4.95(s,2H),7.39(dd,1H),7.66(d,1H),8.57(d,1H)
实施例54
3-[2-(4-氯-2-吡啶基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-羧
酸甲酯
得自3-[(4-氯吡啶-2-基)乙炔基]-5,6,7,8-四氢[1,2,4]三唑并[4,3-a]吡嗪和氯甲酸甲酯。产物被回收为米黄色固体。
UPLC-MS[M+H]+=318.05,334.35,335.36
1H NMR(400MHz,CDCl3)δppm 3.83(s,3H),3.98(d,2H),4.16-4.23(m,2H),4.95(s,2H),7.39(dd,1H),7.66(d,1H),8.58(d,1H)
实施例55
3-[2-(6-甲基-2-吡啶基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-
羧酸甲酯
得自3-[(6-甲基吡啶-2-基)乙炔基]-5,6,7,8-四氢[1,2,4]三唑并[4,3-a]吡嗪和氯甲酸甲酯。产物被回收为浅棕色固体。
UPLC-MS[M+H]+=298.38
1H NMR(400MHz,DMSO-d6)δppm 2.52(s,3H),3.69(s,3H),3.87(t,2H),4.15(t,2H),4.79(s,2H),7.39(d,1H),7.60(d,1H),7.78-7.85(m,1H)
实施例56
3-[2-(6-甲基-2-吡啶基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,3-a]吡嗪-7-
羧酸乙酯
得自3-[(6-甲基吡啶-2-基)乙炔基]-5,6,7,8-四氢[1,2,4]三唑并[4,3-a]吡嗪和氯甲酸乙酯。产物被回收为浅棕色固体。
UPLC-MS[M+H]+=312.38
1H NMR(400MHz,DMSO-d6)δppm 1.24(t,3H),2.52(s,3H),3.87(t,2H),4.08-4.19(m,4H),4.79(s,2H),7.39(d,1H),7.60(d,1H),7.82(t,1H)
实施例57
N,N-二乙基-3-[2-(6-甲基-2-吡啶基)乙炔基]-6,8-二氢-5H-[1,2,4]三唑并[4,
3-a]吡嗪-7-羧酰胺
得自3-[(6-甲基吡啶-2-基)乙炔基]-5,6,7,8-四氢[1,2,4]三唑并[4,3-a]吡嗪和二乙基氨基羰酰氯。产物被回收为淡黄色固体。
UPLC-MS[M+H]+=339.42
1H NMR(400MHz,DMSO-d6)δppm 1.09(t,6H),2.52(s,3H),3.22(q,4H),3.60(t,2H),4.16(t,2H),4.48(s,2H),7.39(d,1H),7.60(d,1H),7.82(t,1H)
实施例58
7-(6-甲基-3-硝基-2-吡啶基)-3-(2-苯基乙炔基)-6,8-二氢-5H-[1,2,4]三唑并
[4,3-a]吡嗪
通过使3-(苯基乙炔基)-5,6,7,8-四氢[1,2,4]三唑并[4,3-a]吡嗪与2-氯-6-甲基-3-硝基吡啶反应来获得。
UPLC-MS[M+H]+=361.18
1H NMR(400MHz,CDCl3)δppm 2.56(s,3H),3.92(t,2H),4.36(t,2H),4.88(s,2H),6.85(d,1H),7.39-7.50(m,3H),7.60-7.65(m,2H),8.24(d,1H)
实施例59
3-[(3-氰基苯基)乙炔基]-5,6-二氢咪唑并[1,5-a]吡嗪-7(8H)-羧酸叔丁酯
向微波瓶中3-溴-6,8-二氢-5H-咪唑并[1,5-a]吡嗪-7-羧酸叔丁酯(0.662mmol,200mg)在干DMF(1mL)中的溶液添加3-乙炔基苄腈(0.993mmol,126.23mg),然后添加三水合乙酸钠(1.324mmol,180.14mg)和四(三苯基膦)钯(0.033mmol,38.24mg),将小瓶密封,用氮气冲洗,并且将混合物在微波辐射下在120℃加热15min。然后,添加水,分离两相,用水和盐水洗涤有机层,在Na2SO4上干燥,过滤,并且蒸发。通过Biotage Isolera One(柱型SNAP25)、使用从石油醚:EtOAc 1:1至石油醚:EtOAc 2:8的梯度来纯化粗剩余物。收集105mg的标题化合物(深色油状物)。
HPLC-MS[M+H]+=349.4
实施例60
3-({7-[(2,5-二甲基呋喃-3-基)羰基]-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-3-基}
乙炔基)苄腈
3-[2-(5,6,7,8-四氢咪唑并[1,5-a]吡嗪-3-基)乙炔基]苄腈(化合物60a)
向实施例59131953_I52907的化合物在CHCl3(5mL)中的经冰浴冷却的溶液添加三氟乙酸(6.028mmol,687.3mg,0.464mL),并且将所得到的混合物在60℃搅拌30min。在室温冷却之后,在减压下去除氯仿和过量的TFA。添加碳酸氢钠饱和溶液和DCM,分离两相,并且用DCM提取水层。用盐水洗涤合并的有机相,在Na2SO4上干燥,过滤,并且蒸发。收集50mg的标题化合物(浅棕色油状物),并且用于下一步骤而无需进一步纯化。
HPLC-MS[M+H]+=249.3
3-({7-[(2,5-二甲基呋喃-3-基)羰基]-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-3-基}
乙炔基)苄腈
向化合物60a在无乙醇氯仿(5mL)中的经冰浴冷却的溶液添加TEA(0.031g,0.302mmol,3.00当量,0.0422mL),然后添加2,5-二甲基呋喃-3-羰酰氯(0.121mmol,0.016mL,0.019g),并且将混合物在室温搅拌1h。用水淬灭反应,分离两相,用盐水洗涤有机层,在Na2SO4上干燥,过滤,并且蒸发。通过Biotage Isolera One(柱型SNAP10)、使用石油醚:EtOAc 6:4至EtOAc 100%的梯度纯化粗剩余物。收集31mg的标题化合物(浅黄色粉末)。
UPLC-MS[M+H]+=371.4
1H NMR(400MHz,CDCl3)δppm 7.83(t,1H),7.78(dt,1H),7.64-7.71(m,1H),7.47-7.56(m,1H),6.98(s,1H),5.98(s,1H),4.88(s,2H),4.17-4.26(m,2H),4.03-4.13(m,2H),2.40(s,3H),2.30(t,3H)
实施例61
3-{[7-(3-氯苯甲酰基)-5,6,7,8-四氢咪唑并[1,5-a]吡嗪-3-基]乙炔基}苄腈
按照上文针对实施例60的化合物报告的方法由化合物60a和苯甲酰氯制备。浅黄色粉末。
UPLC-MS[M+H]+=387.8
1H NMR(400MHz,CDCl3)δppm 7.82-7.88(m,1H),7.76-7.81(m,1H),7.65-7.71(m,1H),7.47-7.57(m,3H),7.41-7.46(m,1H),7.33-7.39(m,1H),6.98(br d,1H),4.63-5.09(m,2H),3.72-4.38(m,4H)
实施例62
3-[(3-氯苯基)乙炔基]-5,6-二氢咪唑并[1,5-a]吡嗪-7(8H)-羧酸叔丁酯
按照上文针对实施例59的化合物报告的方法用3-氯苯基乙炔代替3-乙炔基苄腈制备。产物被回收为深色油状物。
UPLC-MS[M+H]+=358.02,359.99,361.08
1H NMR(400MHz,CHLOROFORM-d)δppm 1.53(s,9H),3.88(t,2H),4.14(t,2H),4.70(s,2H),6.97(s,1H),7.32(t,1H),7.36-7.40(m,1H),7.45(dt,1H),7.55(t,1H)
在实施例62的化合物的BOC脱保护(参见化合物60a的合成方法)之后,所得到的中间产物3-[2-(3-氯苯基)乙炔基]-5,6,7,8-四氢咪唑并[1,5-a]吡嗪与针对实施例60化合物报告的指定试剂反应,并且产生下列化合物:
实施例63
{3-[(3-氯苯基)乙炔基]-5,6-二氢咪唑并[1,5-a]吡嗪-7(8H)-基}(2,5-二甲基
呋喃-3-基)甲酮
得自3-[2-(3-氯苯基)乙炔基]-5,6,7,8-四氢咪唑并[1,5-a]吡嗪和2,5-二甲基呋喃-3-羰酰氯。产物被回收为浅黄色粉末。
实施例64
(3-氯苯基){3-[(3-氯苯基)乙炔基]-5,6-二氢咪唑并[1,5-a]吡嗪-7(8H)-基}甲
酮
得自3-[2-(3-氯苯基)乙炔基]-5,6,7,8-四氢咪唑并[1,5-a]吡嗪和3-氯苯甲酰氯。获得为浅黄色粉末。
实施例65
3-[(3-氯苯基)乙炔基]-5,6-二氢咪唑并[1,5-a]吡嗪-7(8H)-羧酸乙酯
得自3-[2-(3-氯苯基)乙炔基]-5,6,7,8-四氢咪唑并[1,5-a]吡嗪和氯甲酸乙酯。
实施例66
3-[(3-氰基苯基)乙炔基]-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-羧酸叔丁酯
按照上文针对实施例59的化合物报告的方法用3-溴-6,8-二氢-5H-咪唑并[1,2-a]吡嗪-7-羧酸叔丁酯代替3-溴-6,8-二氢-5H-咪唑并[1,5-a]吡嗪-7-羧酸叔丁酯来制备。
在实施例66的化合物的BOC脱保护(参见化合物60a的合成方法)之后,如针对实施例60的化合物所报告的,所得到的中间产物3-[2-(5,6,7,8-四氢咪唑并[1,2-a]吡嗪-3-基)乙炔基]苄腈与指定试剂反应,并且产生下列化合物:
实施例67
3-{[7-(3-氯苯甲酰基)-5,6,7,8-四氢咪唑并[1,2-a]吡嗪-3-基]乙炔基}苄腈
得自3-[2-(5,6,7,8-四氢咪唑并[1,2-a]吡嗪-3-基)乙炔基]苄腈和3-氯苯甲酰氯。
实施例68
3-({7-[(4,5-二甲基呋喃-2-基)羰基]-5,6,7,8-四氢咪唑并[1,2-a]吡嗪-3-基}
乙炔基)苄腈
得自3-[2-(5,6,7,8-四氢咪唑并[1,2-a]吡嗪-3-基)乙炔基]苄腈和4,5-二甲基呋喃-2-羰酰氯。
实施例69
3-({7-[(2,5-二甲基呋喃-3-基)羰基]-5,6,7,8-四氢咪唑并[1,2-a]吡嗪-3-基}
乙炔基)苄腈
得自3-[2-(5,6,7,8-四氢咪唑并[1,2-a]吡嗪-3-基)乙炔基]苄腈和2,5-二甲基呋喃-3-羰酰氯。
实施例70
3-[(3-氯苯基)乙炔基]-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-羧酸叔丁酯
按照上文针对实施例59的化合物报告的方法、用3-溴-6,8-二氢-5H-咪唑并[1,2-a]吡嗪-7-羧酸叔丁酯代替3-溴-6,8-二氢-5H-咪唑并[1,5-a]吡嗪-7-羧酸叔丁酯并且使用3-氯苯基乙炔(而非3-乙炔基苄腈)来制备。
在实施例70的化合物的BOC脱保护(参见化合物60a的合成方法)之后,如针对实施例60的化合物所报告的,所得到的中间产物3-[2-(3-氯苯基)乙炔基]-5,6,7,8-四氢咪唑并[1,2-a]吡嗪与指定的试剂反应,并且产生下列化合物:
实施例71
3-({3-[(3-氯苯基)乙炔基]-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基}羰基)苄腈
得自3-[2-(3-氯苯基)乙炔基]-5,6,7,8-四氢咪唑并[1,2-a]吡嗪和3-氰基苯甲酰氯。
实施例72
{3-[(3-氯苯基)乙炔基]-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基}(2,5-二甲基
呋喃-3-基)甲酮
得自3-[2-(3-氯苯基)乙炔基]-5,6,7,8-四氢咪唑并[1,2-a]吡嗪和2,5-二甲基呋喃-3-羰酰氯。
实施例73
(3-氯苯基){3-[(3-氯苯基)乙炔基]-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-基}甲
酮
通过另外的方法制备化合物,但其由3-[2-(3-氯苯基)乙炔基]-5,6,7,8-四氢咪唑并[1,2-a]吡嗪和3-氯苯甲酰氯的制备被预期为优选的。
实施例74
3-[(3-氯苯基)乙炔基]-N-甲氧基-N-甲基-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-
羧酰胺
通过另外的方法制备化合物,但其由3-[2-(3-氯苯基)乙炔基]-5,6,7,8-四氢咪唑并[1,2-a]吡嗪和N-甲氧基-N-甲基氨基甲酰氯的制备被预期为优选的。
实施例75
3-[(3-氯苯基)乙炔基]-N,N-二甲基-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-羧酰
胺
通过另外的方法制备化合物,但其由3-[2-(3-氯苯基)乙炔基]-5,6,7,8-四氢咪唑并[1,2-a]吡嗪和N,N-二甲基氨基甲酰基氯的制备被预期为优选的。
实施例76
3-[(3-氯苯基)乙炔基]-N,N-二乙基-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-羧酰
胺
通过另外的方法制备化合物,但其由3-[2-(3-氯苯基)乙炔基]-5,6,7,8-四氢咪唑并[1,2-a]吡嗪和N,N-二乙基氨基甲酰氯的制备被预期为优选的。
实施例77
3-[(3-氯苯基)乙炔基]-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-羧酸乙酯
通过另外的方法制备化合物,但其由3-[2-(3-氯苯基)乙炔基]-5,6,7,8-四氢咪唑并[1,2-a]吡嗪和氯甲酸乙酯的制备被预期为优选的。
实施例78
3-[(3-甲基苯基)乙炔基]-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-羧酸叔丁酯
按照上文针对实施例59的化合物报告的方法、用3-溴-6,8-二氢-5H-咪唑并[1,2-a]吡嗪-7-羧酸叔丁酯代替3-溴-6,8-二氢-5H-咪唑并[1,5-a]吡嗪-7-羧酸叔丁酯并且使用3-甲基苯乙炔(而非3-乙炔基苄腈)来制备。
在实施例78的化合物的BOC脱保护(参见化合物60a的合成方法),如针对实施例60的化合物所报告的,所得到的中间产物3-[2-(间甲苯基)乙炔基]-5,6,7,8-四氢咪唑并[1,2-a]吡嗪与指定的试剂反应,并且产生下列化合物:
实施例79
N-甲氧基-N-甲基-3-[(3-甲基苯基)乙炔基]-5,6-二氢咪唑并[1,2-a]吡嗪-7
(8H)-羧酰胺
通过另外的方法制备化合物,但其由3-[2-(间甲苯基)乙炔基]-5,6,7,8-四氢咪唑并[1,2-a]吡嗪和N-甲氧基-N-甲基氨基甲酰氯的制备被预期为优选的。
实施例80
N,N-二甲基-3-[(3-甲基苯基)乙炔基]-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-羧
酰胺
通过另外的方法制备化合物,但其由3-[2-(间甲苯基)乙炔基]-5,6,7,8-四氢咪唑并[1,2-a]吡嗪和N,N-二甲基氨基甲酰氯的制备被预期为优选的。
实施例81
3-[(3-甲基苯基)乙炔基]-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-羧酸乙酯
通过另外的方法制备化合物,但其由3-[2-(间甲苯基)乙炔基]-5,6,7,8-四氢咪唑并[1,2-a]吡嗪和氯甲酸乙酯的制备被预期为优选的。
实施例82
N,N-二乙基-3-[(3-甲基苯基)乙炔基]-5,6-二氢咪唑并[1,2-a]吡嗪-7(8H)-羧
酰胺
通过另外的方法制备化合物,但其由3-[2-(间甲苯基)乙炔基]-5,6,7,8-四氢咪唑并[1,2-a]吡嗪和N,N-二乙基氨基甲酰氯的制备被预期为优选的。
实施例83
生物学测定
使用经四环素调控的表达系统(T-RExTM系统,Invitrogen,Life Technologies)、使用编码人mGlu5受体的诱导型表达运载体生成稳定转染的细胞系。将包含终止密码子的人mGluR5开放阅读框(ORF)克隆到携带TetO2的pcDNA4/TO/myc-HisTM A运载体中。插入位点是mGluR5受体的HindIII-PstI。然后,使用FuGENE方案(Roche)将获得的构建体转染到T-REx CHOTM细胞系中;在选择杀稻瘟菌素(10μg/ml)的情况下,CHO T-RExTM细胞系稳定地表达Tet阻抑物(来自pcDNA6/TR质粒)。用博莱霉素(zeocin)(1mg/ml)选择,并且在5%CO2的气氛中在37℃维持在补充有经透析的FBS、博莱霉素、杀稻瘟菌素的ULTRA CHO培养基(LONZA)中,获得稳定的克隆物。在结合实验之前用1μg/ml四环素对h-mGluR5受体的表达进行脱阻抑达18h,而在钙荧光实验之前分别用3ng/ml四环素和10ng/ml四环素对h-mGluR5受体的表达进行脱阻抑达18h。
实施例84
天然mGluR5和mGluR5受体亚型的放射性配体结合测定
根据Anderson的方法(Anderson et al.,J Pharmacol.Exp.Ther.,(2002),Vol.303(3),pp.1044-51)(具有一些修改)来评价跨膜谷氨酸代谢型mGluR5受体亚型的亲和力。通过将CHO T-REx h-mGluR5细胞(50μg/孔)重新悬浮在20mM HEPES、2mM MgCl2、2mMCaCl2(pH 7.4)中来获得克隆的mGluR5,然后在不存在竞争药物的情况下或者存在竞争药物的情况下将克隆的mGluR5与4nM[3H]MPEP在1ml最终体积中在25℃孵育60min。在存在10μMMPEP的情况下测定非特异性结合。通过冷Tris缓冲液(pH 7.4)的添加和通过经0.2%聚乙烯亚胺预处理的Filtermat 1204-401(Perkin Elmer)过滤器的快速过滤来停止孵育。然后,用冷缓冲液洗涤过滤器,并且通过液体闪烁光谱法(Betaplate 1204 BS-Wallac)对保留在过滤器上的放射性进行计数。本发明的化合物对mGlu5受体的亲和力(Ki)为0.1nM与1000nM之间。例如,实施例8的化合物具有33.75nM的Ki,并且实施例40的化合物具有32nM的Ki。
实施例85
用钙荧光测量测定在mGlu5受体上的功能活性
将细胞以80000个细胞/孔的密度接种至黑色壁、透明底部、96孔板中的补充有10%经透析的FBS的RPMI(无酚红、无L-谷氨酰胺;Gibco LifeTechnologies,CA)中。在与四环素孵育18h之后,在37℃使细胞加载汉克斯平衡盐溶液(HBSS,Gibco LifeTechnologies,CA)(具有20μM Hepes(Sigma)和2.5mM丙磺舒(Sigma))中的2mM Ca2+-敏感性荧光染料Fluo-4/AM(分子探针)达1h。用HBSS洗涤细胞3次,以去除细胞外染料。通过使用荧光酶标仪Flexstation III(Molecular Devices)以1.5s的采样间隔测量荧光信号达60s。
使用使君子氨酸(quisqualate)(用作激动剂)的EC80来测定拮抗剂效力,并且使用激动剂(使君子氨酸或谷氨酸)的EC20来测定mGlu5激活的增强。在施加激动剂之前10分钟施加化合物。对于结合研究和钙测定研究,根据化合物的溶解度将其溶解在DMSO或软化水中。全部报告的剂量均为相应盐或碱的剂量。本发明的化合物显示出正向别构调节活性或负向别构调节活性。例如,实施例8的化合物显示出正向别构活性(EC50:294.5nM)。例如,实施例40的化合物具有负向别构调节活性(IC50=60.9nM)。
统计分析
使用Prism 4.0软件(Graphpad,San Diego,CA)通过非线性回归分析确定被测化合物对天然和克隆的mGluR1和mGluR5亚型的抑制曲线。程序估算了IC50值和伪希尔斜率(pseudo-Hill slope coefficient)。根据方程Ki=IC50/(1+[L]/Kd)计算抑制常数Ki的值,其中[L]是放射性配体的浓度,并且Kd是放射性配体-受体复合物的平衡解离常数(Chenget al.,Biochem.Pharmacol.(1973),Vol.22,pp.3099-3108)。
Claims (4)
1.一种化合物或其药学上可接受的盐,所述化合物选自由下列组成的组:
2.根据权利要求1所述的化合物在制造用于治疗或预防与谷氨酸功能障碍相关的神经紊乱和精神紊乱的药物中的应用。
3.根据权利要求2所述的应用,其中所述与谷氨酸功能障碍相关的神经紊乱和精神紊乱是精神分裂症或认知减退、痴呆或认知损害。
4.根据权利要求2所述的应用,其中治疗的所述紊乱选自由雷特综合征、费伦-麦克德米德综合征、精神病、精神分裂症、孤独症认知紊乱、结节性硬化、认知紊乱、阿尔茨海默型痴呆组成的组,或者其中所述化合物是mGlu5负向别构调节剂,并且所述紊乱选自由成瘾、重度抑郁症、焦虑、癫痫、脆性X染色体综合征、胃食管反流病、物质滥用和依赖、帕金森病和L-多巴诱导的运动障碍、尿失禁、肠易激综合征和疼痛组成的组。
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Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2085398A1 (en) * | 2008-02-01 | 2009-08-05 | Merz Pharma GmbH & Co. KGaA | Pyrazolopyrimidines, a process for their preparation and their use as medicine |
EP2090576A1 (en) * | 2008-02-01 | 2009-08-19 | Merz Pharma GmbH & Co.KGaA | 6-halo-pyrazolo[1,5-a]pyridines, a process for their preparation and their use as metabotropic glutamate receptor (mGluR) modulators |
WO2011121137A1 (en) * | 2010-04-02 | 2011-10-06 | Euroscreen S.A. | Novel nk-3 receptor selective antagonist compounds, pharmaceutical composition and methods for use in nk-3 receptors mediated disorders |
WO2012172093A1 (en) * | 2011-06-17 | 2012-12-20 | Merz Pharma Gmbh & Co. Kgaa | Dihydroindolizine derivate as metabotropic glutamate receptor modulators |
CN106573936A (zh) * | 2014-08-01 | 2017-04-19 | 詹森药业有限公司 | 6,7‑二氢吡唑并[1,5‑a]吡嗪‑4(5H)‑酮化合物和其作为MGLUR2受体的负性别构调节物的用途 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2413330A1 (en) | 2000-06-28 | 2002-01-03 | Smithkline Beecham P.L.C. | Wet milling process |
TW200538108A (en) * | 2004-02-19 | 2005-12-01 | Astrazeneca Ab | Fused heterocyclic compounds and their use as metabotropic glutamate receptor antagonists |
TW200801005A (en) | 2005-08-15 | 2008-01-01 | Astrazeneca Ab | Acetylenic piperazines as metabotropic glutamate receptor antagonists |
CA2822094C (en) | 2005-08-31 | 2015-10-27 | Celgene Corporation | Isoindole-imide compounds and compositions comprising and methods of using the same |
AU2009279936A1 (en) | 2008-08-05 | 2010-02-11 | Banyu Pharmaceutical Co., Ltd. | Therapeutic compounds |
US8501946B2 (en) | 2009-04-29 | 2013-08-06 | Glaxo Group Limited | 5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine derivatives as P2X7 modulators |
CN102372716A (zh) | 2010-08-09 | 2012-03-14 | 江苏恒瑞医药股份有限公司 | 酞嗪酮类衍生物、其制备方法及其在医药上的应用 |
US9539298B2 (en) | 2010-11-29 | 2017-01-10 | Osaka City University | Lissencephaly therapeutic agent |
CN106146391A (zh) | 2015-04-15 | 2016-11-23 | 中国科学院上海药物研究所 | 5-芳香炔基取代的苯甲酰胺类化合物及其制备方法、药物组合物和用途 |
CA3088288A1 (en) * | 2018-01-26 | 2019-08-01 | Recordati Industria Chimica E Farmaceutica S.P.A | Triazole, imidazole and pyrrole condensed piperazine derivatives and their use as modulators of mglu5 receptors |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2085398A1 (en) * | 2008-02-01 | 2009-08-05 | Merz Pharma GmbH & Co. KGaA | Pyrazolopyrimidines, a process for their preparation and their use as medicine |
EP2090576A1 (en) * | 2008-02-01 | 2009-08-19 | Merz Pharma GmbH & Co.KGaA | 6-halo-pyrazolo[1,5-a]pyridines, a process for their preparation and their use as metabotropic glutamate receptor (mGluR) modulators |
WO2011121137A1 (en) * | 2010-04-02 | 2011-10-06 | Euroscreen S.A. | Novel nk-3 receptor selective antagonist compounds, pharmaceutical composition and methods for use in nk-3 receptors mediated disorders |
WO2012172093A1 (en) * | 2011-06-17 | 2012-12-20 | Merz Pharma Gmbh & Co. Kgaa | Dihydroindolizine derivate as metabotropic glutamate receptor modulators |
CN106573936A (zh) * | 2014-08-01 | 2017-04-19 | 詹森药业有限公司 | 6,7‑二氢吡唑并[1,5‑a]吡嗪‑4(5H)‑酮化合物和其作为MGLUR2受体的负性别构调节物的用途 |
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