CN115043821A - 作为alk抑制剂的氨基嘧啶 - Google Patents
作为alk抑制剂的氨基嘧啶 Download PDFInfo
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- CN115043821A CN115043821A CN202210533398.XA CN202210533398A CN115043821A CN 115043821 A CN115043821 A CN 115043821A CN 202210533398 A CN202210533398 A CN 202210533398A CN 115043821 A CN115043821 A CN 115043821A
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- compound
- pharmaceutically acceptable
- cancer
- acceptable salt
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Abstract
Description
本申请是申请日为2017年8月28日、发明名称为“作为ALK抑制剂的氨基嘧啶”的中国专利申请201780057518.0的分案申请。
技术领域
本公开提供了间变性淋巴瘤激酶抑制剂和治疗其中抑制间变性淋巴瘤激酶提供益处的病状和疾病的治疗方法。
背景技术
间变性淋巴瘤激酶(ALK)是受体酪氨酸激酶的胰岛素受体超家族的成员,已涉及造血和非造血肿瘤的发生。已经报道了在神经母细胞瘤和胶质母细胞瘤中全长ALK受体蛋白的异常表达;并且ALK融合蛋白出现在间变性大细胞淋巴瘤中。ALK融合蛋白的研究也为ALK阳性恶性肿瘤患者提出了新治疗处理的可能性。Pulford等人《细胞和分子生命科学(Cell.Mol.Life.Sci.)》61:2939-2953(2004)。
小分子ALK抑制剂具有治疗其中ALK起作用的疾病和病状的治疗潜力,所述疾病和病状包括癌症。Roskoski,《药理学研究(Pharmacological Research)》68:68–94(2013)。ALK抑制剂公开于U.S.8,039,479和WO 2015/130014中。
持续需要新的用于治疗和/或预防癌症和其它响应ALK抑制的疾病的药剂,例如小分子。
发明内容
一方面,本公开提供由以下式I-VI中的任一个表示的化合物,及其医药学上可接受的盐和溶剂化物,统称为“本公开化合物”。本公开化合物是ALK抑制剂,因此可用于治疗或预防其中ALK抑制提供益处的疾病或病状。
另一方面,本公开提供了通过向需要其的个体(例如人)施用治疗有效量的本公开化合物来治疗或预防病状或疾病的方法。所关注的疾病或病状是可通过抑制ALK来治疗或预防的,例如癌症、慢性自体免疫性病症、炎性病状、增殖性病症、败血症或病毒感染。还提供了在受试者中预防不需要的增殖细胞增殖(例如癌症中)的方法,所述方法包括向有风险发生以不需要的增殖细胞为特征的病状的受试者施用治疗有效量的本公开化合物。在一些实施例中,本公开化合物可通过诱导那些细胞的细胞凋亡来减少不需要的细胞的增殖。
另一方面,本公开提供了一种抑制个体ALK的方法,包括向个体施用有效量的至少一种本公开化合物。
另一方面,本公开提供了一种药物组合物,其包含本公开化合物和赋形剂和/或医药学上可接受的载剂。
另一方面,本公开提供了一种包含本公开化合物和赋形剂和/或医药学上可接受的载剂的组合物,其用于治疗或预防其中抑制ALK提供益处的疾病或病状,例如癌症。
另一方面,本公开提供了一种组合物,其包含:(a)本公开化合物;(b)第二治疗活性剂;以及(c)任选的赋形剂和/或医药学上可接受的载剂。
另一方面,本公开提供了一种本公开化合物,其用于治疗或预防所关注的疾病或病状,例如癌症。
另一方面,本公开提供了本公开化合物在制备用于治疗所关注的疾病或病状如癌症的药物中的用途。
另一方面,本公开提供了一种试剂盒,其包含本公开化合物,和任选的包装组合物,所述组合物包含可用于治疗所关注的疾病或病状的第二治疗剂,以及包装说明书,所述包装说明书含有用于治疗疾病或病状如癌症的说明。
另一方面,本公开提供了制备本公开化合物的方法。
本公开的其它实施例和优点将部分地在下面的说明中阐述,并且将从说明中得出,或者可以通过本公开的实践来学习。将借助于所附权利要求中特别指出的元件和组合,实现和获得本公开的实施例和优点。
应理解,前面的概述和以下详细描述都仅是示例性和说明性的,而并非是对要求保护的本发明的限制。
附图说明
图1是显示化合物编号5和6抑制小鼠KARPAS 299异体移植模型的肿瘤生长的线形图。
具体实施方式
本公开化合物是ALK抑制剂。
在一个实施例中,本公开化合物是由式I表示的化合物:
或其医药学上可接受的盐或溶剂化物,其中:
R1a和R1b独立地选自由氢、C1-6烷基和C3-8环烷基组成的组;
R2a和R2b独立地选自由氢、C1-6烷基和C3-8环烷基组成的组;
R3选自由氢、C1-6烷基、C3-6环烷基和C4-8杂环组成的组,
R4选自由C1-4烷基和C3-6环烷基组成的组;
R5为卤素;
R6选自由C1-4烷基和C3-6环烷基组成的组;以及
R7选自由氢、C1-4烷基和C3-6环烷基组成的组,
条件是当R1a、R1b、R2a和R2b各自是氢时,则R3选自由C3-6环烷基和C4-8杂环组成的组。
在另一个实施例中,本公开化合物是由式II表示的化合物:
或其医药学上可接受的盐或溶剂化物,其中:
R1a和R1b独立地选自由氢、C1-4烷基和C3-6环烷基组成的组;
R2a和R2b独立地选自由氢、C1-4烷基和C3-6环烷基组成的组;以及
R3选自由氢、C1-4烷基、C3-6环烷基和C4-8杂环组成的组,
条件是当R1a、R1b、R2a和R2b各自是氢时,则R3选自由C3-6环烷基和C4-8杂环组成的组。
在另一个实施例中,本公开化合物是由式I或II表示的化合物,条件是当R1a、R1b、R2a和R2b各自是氢时,则R3为C4-8杂环。
在另一个实施例中,本公开化合物是由式I或II表示的化合物,或其医药学上可接受的盐或溶剂化物,其中R1b和R2b各自是氢。
在另一个实施例中,本公开化合物是由式I或II表示的化合物,或其医药学上可接受的盐或溶剂化物,其中R1a、R1b、R2a和R2b各自是氢。
在另一个实施例中,本公开化合物是由式I或II表示的化合物,或其医药学上可接受的盐或溶剂化物,其中R1b和R2b各自是氢;R1a和R2a各自是C1-4烷基。在另一个实施例中,R1a和R2a各自是甲基。在另一个实施例中,R1a和R2a具有顺式立体化学关系。在另一个实施例中,R1a和R2a具有反式立体化学关系。
在另一个实施例中,本公开化合物是由式I或II表示的化合物,或其医药学上可接受的盐或溶剂化物,其中R1b和R2b各自是氢;R1a和R2a各自是C3-6环烷基。在另一个实施例中,R1a和R2a各自是环丙基。在另一个实施例中,R1a和R2a具有顺式立体化学关系。在另一个实施例中,R1a和R2a具有反式立体化学关系。
在另一个实施例中,本公开化合物是由式I或II表示的化合物,或其医药学上可接受的盐或溶剂化物,其中R1a、R1b、R2a和R2b各自是C1-3烷基。在另一个实施例中,R1a、R1b、R2a和R2b各自是甲基。
在另一个实施例中,本公开化合物是由式III表示的化合物:
或其医药学上可接受的盐或溶剂化物,其中所述化合物具有约90%或更高的对映体过量;R1a和R2a各自独立地为C1-4烷基或C3-6环烷基;R3如式II所定义。在另一个实施例中,化合物具有约91%或更高,约92%或更高,约93%或更高,约94%或更高,约95%或更高,约96%或更高,约97%或更高,约98%或更高,或约99%或更高的对映体过量。
在另一个实施例中,本公开化合物是由式IV表示的化合物:
或其医药学上可接受的盐或溶剂化物,其中所述化合物具有约90%或更高的对映体过量;R1a和R2a各自独立地为C1-4烷基或C3-6环烷基;R3如式II所定义。在另一个实施例中,化合物具有约91%或更高,约92%或更高,约93%或更高,约94%或更高,约95%或更高,约96%或更高,约97%或更高,约98%或更高,或约99%或更高的对映体过量。
在另一个实施例中,本公开化合物是由式V表示的化合物:
或其医药学上可接受的盐或溶剂化物,其中所述化合物具有约90%或更高的对映体过量;R1a和R2a各自独立地为C1-4烷基或C3-6环烷基;R3如式II所定义。在另一个实施例中,化合物具有约91%或更高,约92%或更高,约93%或更高,约94%或更高,约95%或更高,约96%或更高,约97%或更高,约98%或更高,或约99%或更高的对映体过量。
在另一个实施例中,本公开化合物是由式VI表示的化合物:
或其医药学上可接受的盐或溶剂化物,其中所述化合物具有约90%或更高的对映体过量;R1a和R2a各自独立地为C1-4烷基或C3-6环烷基;R3如式II所定义。在另一个实施例中,化合物具有约91%或更高,约92%或更高,约93%或更高,约94%或更高,约95%或更高,约96%或更高,约97%或更高,约98%或更高,或约99%或更高的对映体过量。
在另一个实施例中,本公开化合物是由式III-VI中任一个表示的化合物,或其医药学上可接受的盐或溶剂化物,其中R1a和R2a各自是C1-3烷基。在另一个实施例中,R1a和R2a各自是甲基。
在另一个实施例中,本公开化合物是由式III-VI中任一个表示的化合物,或其医药学上可接受的盐或溶剂化物,其中R1a和R2a各自是C3-6环烷基。在另一个实施例中,R1a和R2a各自是环丙基。
在另一个实施例中,本公开化合物是由式I-VI中任一个表示的化合物,或其医药学上可接受的盐或溶剂化物,其中R3为氢。
在另一个实施例中,本公开化合物是由式I-VI中任一个表示的化合物,或其医药学上可接受的盐或溶剂化物,其中R3为C1-3烷基。在另一个实施例中,R3为甲基。
在另一个实施例中,本公开化合物是由式I-VI中任一个表示的化合物,或其医药学上可接受的盐或溶剂化物,其中R3为C3-6杂环。在另一个实施例中,R3为C3-6杂环,其选自由以下组成的组:
在另一个实施例中,本公开化合物是表1的化合物,及其医药学上可接受的盐和溶剂化物。表1的化合物是外消旋体。
表1
在另一个实施例中,本公开化合物是表2的化合物,及其医药学上可接受的盐和溶剂化物。表2的化合物是对映体富集的。
表2
在另一个实施例中,本公开化合物是5-氯-N2-(2-异丙氧基-5-甲基-4-(1-(四氢-2H-吡喃-4-基)-1,2,3,6-四氢吡啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺,或其医药学上可接受的盐或水合物。
本公开化合物抑制ALK并且可用于治疗或预防多种疾病和病状。特别地,本公开化合物可用于治疗或预防其中抑制ALK提供益处的疾病或病状的方法,所述疾病或病状例如癌症和增殖性疾病。本公开的治疗方法包括向需要其的个体施用治疗有效量的本公开化合物。除了本公开化合物之外,本方法还包括向个体施用第二治疗剂。第二治疗剂选自已知可用于治疗折磨需要其的个体的疾病或病状的药物,例如已知可用于治疗特定癌症的化学治疗剂和/或辐射。
本公开的某些化合物可以作为立体异构体存在,即仅原子的空间排列有所不同的异构体,包括光学异构体和构象的异构体(或构象异构体)和互变异构体。本公开包括所有立体异构体,作为纯的单独立体异构体制剂和各自的富集制剂,和这种立体异构体的外消旋混合物以及可以根据本领域技术人员熟知的方法分离的单独的非对映异构体和对映异构体。
如本文所用,术语“立体异构体”是单个分子的所有异构体的通用术语,所述异构体仅在其空间原子的取向上不同。它包括具有多于一个手性中心的化合物的对映异构体和异构体,所述异构体彼此不成镜像(非对映异构体)。
术语“手性中心”或“不对称碳原子”是指与四个不同基团连接的碳原子。
术语“对映异构体”和“对映异构体的”是指不能叠加在其镜像上并因此具有光学活性的分子,其中对映异构体使平面偏振光在一个方向上旋转并且其镜像化合物使平面偏振光在相反方向上旋转。
术语“外消旋”或“外消旋体”是指等份的对映异构体的混合物,并且该混合物是无光学活性的。
术语“绝对构型”是指手性分子实体(或基团)的原子的空间排列和其立体化学描述,例如R或S。
本说明书中使用的立体化学术语和惯例旨在与《纯化学与应用化学(Pure&Appl.Chem)》68:2193(1996)中描述的那些一致,除非另有说明。
术语“对映体过量”或“ee”是指一种对映异构体与另一种对映异构体相比存在多少的量度。对于R和S对映异构体的混合物,对映体过量百分比定义为|R-S|*100,其中R和S是混合物中对映异构体各自的摩尔或重量分数,使得R+S=1。通过了解手性物质的旋光度,对映体过量百分比定义为([α]obs/[α]max)*100,其中[α]obs是对映异构体混合物的旋光度,[α]max是纯对映异构体的旋光度。可以使用各种分析技术确定对映体过量,包括NMR光谱、手性柱色谱或光学偏振测定。本公开的某些化合物可具有约70%或更高,例如约80%或更高,约90%或更高,约91%或更高,约92%或更高,约93%或更高,约94%或更高,约95%或更高,约96%或更高,约97%或更高,约98%或更高,或约99%或更高的ee。
术语“对映体纯的”或“对映体纯”是指其所有分子(在检测限内)具有相同的手性矢向的手性物质的样品。
术语“对映体富集的”或“对映体富集”是指对映体比率大于50:50的手性物质样品。对映体富集的化合物可以是对映体纯的。
本公开化合物的盐、水合物和溶剂化物也可用于本文公开的方法中。本公开包括本公开化合物的盐的制备和用途。如本文所用,药学“医药学上可接受的盐”是指本公开化合物的盐或两性离子形式。本公开化合物的盐可以在化合物的最终分离和纯化过程中制备,或者通过使化合物与具有合适阳离子的酸反应而单独制备。本公开化合物的医药学上可接受的盐可以是与医药学上可接受的酸形成的酸加成盐。可用于形成医药学上可接受的盐的酸的示例包括无机酸,如硝酸、硼酸、盐酸、氢溴酸、硫酸和磷酸,和有机酸,如草酸、马来酸、琥珀酸和柠檬酸。本公开化合物的盐的非限制性示例包括但不限于盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、2-羟基乙磺酸盐、磷酸盐、磷酸氢盐、乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、甲酸盐、琥珀酸盐、富马酸盐、马来酸盐、抗坏血酸盐、羟乙基磺酸盐、水杨酸盐、甲磺酸盐、均三甲苯磺酸盐、萘磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、三氯乙酸盐、三氟乙酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐、十一酸盐、乳酸盐、柠檬酸盐、酒石酸盐、葡糖酸盐、甲磺酸盐、乙二磺酸盐、苯磺酸盐和对甲苯磺酸盐。此外,可用甲基、乙基、丙基和丁基的氯化物、溴化物和碘化物;硫酸二甲酯、硫酸二乙酯、硫酸二丁酯和硫酸二戊酯;癸基、月桂基、肉豆蔻基和甾基的氯化物、溴化物和碘化物;以及苄基溴和苯乙基溴将存在于本公开化合物中的可用氨基季铵化。鉴于前述内容,本文出现的本公开的任何参考化合物意在包括本公开化合物的化合物以及其医药学上可接受的盐、水合物或溶剂化物。
本公开包括本公开化合物的溶剂化物的制备和用途。溶剂化物通常不会显著改变化合物的生理活性或毒性,因此可以起到药理学等价物的作用。如本文所用,术语“溶剂化物”是本公开化合物与溶剂分子的组合、物理缔合和/或溶剂化,例如,二溶剂化物、单溶剂化物或半溶剂化物,其中溶剂分子与本公开化合物的比例分别为约2:1、约1:1或约1:2。这种物理缔合涉及不同程度的离子键和共价键,包括氢键。在某些情况下,可以分离溶剂化物,例如当一种或多种溶剂分子结合到结晶固体的晶格中时。因此,“溶剂化物”包括溶液相和可分离的溶剂化物二者。本公开化合物可以溶剂化形式与医药学上可接受的溶剂(例如水、甲醇和乙醇)一起存在,并且本公开意在包括本公开化合物的溶剂化和非溶剂化形式二者。
一种溶剂化物类型是水合物。“水合物”涉及溶剂化物的特定亚组,其中溶剂分子是水。溶剂化物通常可以起到药理学等价物的作用。溶剂化物的制备在本领域中是已知的。参见例如M.Caira等人,《药物科学杂志(J.Pharmaceut.Sci.)》93(3):601-611(2004),其描述了氟康唑与乙酸乙酯的溶剂化物和与水的溶剂化物的制备。van Tonder等人,《美国药学科学家协会医药科技(AAPS Pharm Sci.Tech.)》5(1):Article 12(2004)和A.L.Bingham等人,《化学通讯(Chem.Commun.)》603-604(2001)描述了溶剂化物、半溶剂化物、水合物等的类似制备。制备溶剂化物的典型的非限制性方法包括在高于20℃至约25℃的温度下将本公开化合物溶解在所需的溶剂(有机物、水或其混合物)中,然后以足以形成晶体的速率冷却溶液,并通过已知方法(例如过滤)分离晶体。诸如红外光谱的分析技术可用于确认溶剂化物晶体中溶剂的存在。
本公开提供了作为ALK抑制剂的本公开化合物,其用于治疗其中抑制具有有益效果的多种疾病和病状。本公开化合物对ALK的结合亲和力(IC50)通常小于100μM,例如小于约50μM,小于约25μM,和小于约5μM,小于约1μM,小于约0.5μM,小于约0.1μM,小于约0.05μM,小于约0.01μM,小于约0.005μM,或小于约0.001μM。在一个实施例中,本公开涉及治疗患有其中抑制ALK提供益处的疾病或病状的个体的方法,包括向需要其的个体施用治疗有效量的本公开化合物。
由于本公开化合物是ALK抑制剂,因此可以通过使用这些化合物来治疗由ALK介导的许多疾病和病状。因此,本公开总体上涉及治疗动物(例如人类患者)中响应ALK或其同种型或突变体的抑制的病状或病症的方法,所述动物患有所述病状或病症或存在这种风险,所述方法包括向所述动物施用有效量的一种或多种本公开化合物。
本公开还涉及在需要其的动物中抑制ALK或其同种型或突变体的方法,所述方法包括向所述动物施用有效量的至少一种本公开化合物。
本公开方法可以通过施用作为纯化合物或作为药物组合物的本公开化合物来实现。可以在所关注的疾病或病状发作期间或之后进行本公开化合物的药物组合物或纯化合物的施用。通常,药物组合物是无菌的,并且不含在施用时会引起不良反应的有毒性、致癌性或诱变性化合物。
还提供了试剂盒,其包含单独或一起包装的本公开化合物和任选的第二治疗剂,所述第二治疗剂可用于治疗其中抑制ALK或其同种型或突变体提供益处的疾病和病状,以及说明如何使用这些活性剂的说明书。
在一个实施例中,本公开化合物与可用于治疗其中抑制ALK蛋白提供益处的疾病或病状的第二治疗剂联合施用。第二治疗剂不同于本公开化合物。本公开化合物和第二治疗剂可以同时或顺序施用以达到所需效果。此外,本公开化合物和第二治疗剂可以单一组合物或两个单独的组合物施用。
第二治疗剂以提供其所需治疗效果的量施用。每种第二治疗剂的有效剂量范围是本领域已知的,并且在这样确定的范围内将第二治疗剂施用于需要其的个体。
本公开化合物和第二治疗剂可以作为单一单位剂量一起施用或作为多单位剂量单独施用,其中本公开化合物在第二治疗剂之前施用,或反之亦然。可以施用一种或多种剂量的本公开化合物和/或一种或多种剂量的第二治疗剂。因此,本公开化合物可以与一种或多种第二治疗剂联合使用,所述第二治疗剂例如但不限于抗癌剂。
可通过本公开方法治疗的疾病和病状包括但不限于癌症和其它增殖性病症、炎性疾病、败血症、自体免疫性病症和病毒感染。在一个实施例中,可通过本公开方法治疗的疾病和病状是癌症、慢性自体免疫性病症、炎性病状或增殖性病症。在一个实施例中,用本公开化合物或包含本公开化合物的药物组合物治疗人类患者,其中以足以抑制患者中ALK的量施用所述化合物。
在一个实施例中,本公开化合物待治疗或预防的疾病是癌症。在另一个实施例中,本公开提供了在需要其的受试者中治疗或预防癌症的方法,包括向所述受试者施用治疗有效量的本公开化合物。虽然不限于具体机制,但在一些实施例中,本公开化合物可通过抑制ALK来治疗或预防癌症。可治疗的癌症的示例包括但不限于表3的任何一种或多种癌症。
表3
在另一个实施例中,癌症是白血病,例如选自急性单核细胞白血病、急性髓性白血病、慢性髓性白血病、慢性淋巴细胞白血病和混合谱系白血病(MLL)的白血病。在另一个实施例中,癌症是NUT-中线癌。在另一个实施例中,癌症是多发性骨髓瘤。在另一个实施例中,癌症是肺癌,例如小细胞肺癌(SCLC)。在另一个实施例中,癌症是神经母细胞瘤。在另一个实施例中,癌症是伯基特淋巴瘤。在另一个实施例中,癌症是***。在另一个实施例中,癌症是食道癌。在另一个实施例中,癌症是卵巢癌。在另一个实施例中,癌症是结直肠癌。在另一个实施例中,癌症是***癌。在另一个实施例中,癌症是乳腺癌。
在另一个实施例中,癌症是间变性大细胞淋巴瘤、非小细胞肺癌、弥漫性大B细胞淋巴瘤、炎性肌纤维母细胞瘤、神经母细胞瘤、间变性甲状腺癌和横纹肌肉瘤。
在另一个实施例中,癌症是乳腺癌、结直肠癌、食道鳞状细胞癌和肾细胞癌。
在另一个实施例中,本公开提供了治疗良性增殖性病症的方法,例如但不限于良性软组织肿瘤、骨肿瘤、脑和脊柱肿瘤、眼睑和眼眶肿瘤、肉芽肿、脂肪瘤、脑膜瘤、多发性内分泌肿瘤、鼻息肉、垂体肿瘤、催乳素瘤、假性脑瘤、脂溢性角化病、胃息肉、甲状腺结节、胰腺囊性肿瘤、血管瘤、声带小结、息肉和囊肿、Castleman病、慢性藏毛病、皮肤纤维瘤、毛发囊肿、化脓性肉芽肿和青少年息肉综合征。
本公开化合物还可以通过向哺乳动物,特别是需要这种治疗的人施用有效量的本化合物来治疗感染性和非感染性炎性事件和自体免疫性和其它炎性疾病。使用本文描述的化合物和方法治疗的自体免疫性和炎性疾病、病症和综合征的示例包括***性疾病、尿道炎、皮肤晒伤、鼻窦炎、肺炎、脑炎、脑膜炎、心肌炎、肾炎、骨髓炎、肌炎、肝炎、胃炎、肠炎、皮炎、牙龈炎、阑尾炎、胰腺炎、胆囊炎、低丙种球蛋白血症、牛皮癣、过敏、克罗恩病、肠易激综合征、溃疡性结肠炎、斯耶格伦氏病、组织移植排斥、移植器官超急性排斥、哮喘、过敏性鼻炎、慢性阻塞性肺病(COPD)、自体免疫性多腺体疾病(也称为自体免疫性多腺体综合征)、自体免疫性秃发、恶性贫血、肾小球肾炎、皮肌炎、多发性硬化、硬皮病、血管炎、自体免疫性溶血和血小板减少状态、Goodpasture综合征、动脉粥样硬化、艾迪生病、帕金森病、阿尔兹海默病、I型糖尿病、感染性休克、***性红斑狼疮(SLE)、类风湿性关节炎、银屑病关节炎、幼年型关节炎、骨关节炎、慢性特发性血小板减少性紫癜、华氏巨球蛋白血症、重症肌无力、桥本氏甲状腺炎、特应性皮炎、退行性关节病、白癜风、自体免疫性垂体机能减退、格林-巴利综合征、***、硬皮病、蕈样真菌病、急性炎性反应(如急性呼吸窘迫综合征和缺血/再灌注损伤)和格雷夫斯病。
在另一个实施例中,本公开提供了通过向哺乳动物(特别是需要这种治疗的人)施用有效量的本公开化合物治疗全身性炎性反应综合征(例如LPS诱导的内毒素休克和/或细菌诱导的败血症)的方法。
在另一个实施例中,本公开提供了治疗病毒感染和疾病的方法。使用本文描述的化合物和方法治疗的病毒感染和疾病的示例包括基于附加体的DNA病毒,包括但不限于人***瘤病毒、疱疹病毒、EB病毒、人免疫缺陷病毒、乙型肝炎病毒和丙型肝炎病毒。
在另一个实施例中,本公开提供了通过向需要这种治疗的受试者施用治疗有效量的本公开化合物来提供的在上述疾病(特别是癌症、炎性疾病和/或病毒性疾病)中体内调节蛋白质甲基化、基因表达、细胞增殖、细胞分化和/或细胞凋亡的治疗方法。
在另一个实施例中,本公开提供了通过使细胞与本公开化合物接触来调节内源或异源启动子活性的方法。
在本公开的方法中,向需要其的人施用治疗有效量的本公开化合物(通常根据药学实践配制)。是否指示这种治疗取决于个体情况,并且需要进行医学评估(诊断),其中考虑到存在的体征、症状和/或功能障碍,发生特定体征、症状和/或功能障碍的风险,以及其它因素。
本公开化合物可以通过任何合适的途径施用,例如通过口服、颊、吸入、舌下、直肠、***、脑池内或经由腰椎穿刺的鞘内、经尿道、经鼻、经皮,即透皮或肠胃外(包括静脉内、肌内、皮下、冠状动脉内、皮内、***内、腹膜内、关节内、鞘内、眼球后、肺内注射和/或特定部位的手术植入)施用。肠胃外施用可以使用针和注射器或使用高压技术完成。
药物组合物包括其中以有效量施用本公开化合物以实现其预期目的的那些。确切的制剂、施用途径和剂量由个体医师根据诊断的病状或疾病确定。剂量和间隔可以单独调节,以提供足以维持治疗效果的本公开化合物的水平。
本公开化合物的毒性和治疗功效可通过细胞培养物或实验动物的标准药学程序确定,例如,用于测定化合物的最大耐受剂量(MTD),其定义为不引起动物毒性的最高剂量。最大耐受剂量和治疗效果(例如抑制肿瘤生长)之间的剂量比是治疗指数。剂量可在此范围内变化,这取决于使用的剂型和施用途径。治疗有效量的确定完全在本领域技术人员的能力范围内,尤其是根据本文提供的详细公开。
用于治疗所需的本公开化合物的治疗有效量随正在治疗的病状的性质,所需活动的时间长度,以及患者的年龄和状况而变化,并最终由巡诊医生确定。可以单独调整剂量和间隔以提供足以维持所需治疗效果的ALK抑制剂的血浆水平。所需剂量可方便地以单剂量施用,或作为以适当间隔施用的多剂量施用,例如每天一个、两个、三个、四个或更多个分剂量。通常期望或需要多剂量。例如,本公开化合物可以以下列频率施用:以四天间隔,每天一剂,分四次给药(q4d x 4);以三天间隔,每天一剂,分四次给药(q3d x 4);以五天间隔,每天一剂(qd x 5);每周一剂,持续三周(qwk3);一天五次,休息两天,再一天五次(5/2/5);或者,任何确定适合该情况的剂量方案。
用于本公开的方法的本公开化合物可以以每剂约0.005至约500毫克,每剂约0.05至约250毫克,或每剂约0.5至约100毫克的量施用。例如,本公开化合物可以以每剂约0.005、0.05、0.5、5、10、20、30、40、50、100、150、200、250、300、350、400、450或500毫克的量施用,包括0.005至500毫克的所有剂量。
含有本公开化合物的组合物或含有其的组合物的剂量可以为约1ng/kg至约200mg/kg,约1μg/kg至约100mg/kg,或约1mg/kg至约50mg/kg。组合物的剂量可以是任何剂量,包括但不限于约1μg/kg。组合物的剂量可以是任何剂量,包括但不限于约1μg/kg、约10μg/kg、约25μg/kg、约50μg/kg、约75μg/kg、约100μg/kg、约125μg/kg、约150μg/kg、约175μg/kg、约200μg/kg、约225μg/kg、约250μg/kg、约275μg/kg、约300μg/kg、约325μg/kg、约350μg/kg、约375μg/kg、约400μg/kg、约425μg/kg、约450μg/kg、约475μg/kg、约500μg/kg、约525μg/kg、约550μg/kg、约575μg/kg、约600μg/kg、约625μg/kg、约650μg/kg、约675μg/kg、约700μg/kg、约725μg/kg、约750μg/kg、约775μg/kg、约800μg/kg、约825μg/kg、约850μg/kg、约875μg/kg、约900μg/kg、约925μg/kg、约950μg/kg、约975μg/kg、约1mg/kg、约5mg/kg、约10mg/kg、约15mg/kg、约20mg/kg、约25mg/kg、约30mg/kg、约35mg/kg、约40mg/kg、约45mg/kg、约50mg/kg、约60mg/kg、约70mg/kg、约80mg/kg、约90mg/kg、约100mg/kg、约125mg/kg、约150mg/kg、约175mg/kg、约200mg/kg或更多。上述剂量是平均情况的示例,但可以存在其中应为更高或更低剂量的个别情况,并且这些都在本公开的范围内。在实践中,医生确定最适合于个体患者的实际给药方案,其可以随着特定患者的年龄、体重和反应而变化。
如上所述,本公开化合物可与第二治疗活性剂组合施用。在一些实施例中,第二治疗剂是表观遗传药物。如本文所用,术语“表观遗传药物”是指靶向表观遗传调节剂的治疗剂。表观遗传调节剂的示例包括组蛋白赖氨酸甲基转移酶、组蛋白精氨酸甲基转移酶、组蛋白去甲基化酶、组蛋白去乙酰化酶、组蛋白乙酰化酶和DNA甲基转移酶。组蛋白去乙酰化酶抑制剂包括但不限于伏立诺他。
在另一个实施例中,化学治疗剂或其它抗增殖剂可与本公开化合物组合以治疗增殖性疾病和癌症。可以与本公开化合物组合使用的疗法和抗癌剂的示例包括手术、放射疗法(例如,γ射线、中子束放射疗法、电子束放射疗法、质子疗法、近距离放射疗法和全身放射性同位素)、内分泌疗法、生物反应调节剂(例如,干扰素、白细胞介素、肿瘤坏死因子(TNF)、高温和冷冻疗法、减轻任何副作用的药剂(例如止吐药)和任何其它批准的化学治疗药物。
抗增殖化合物的示例包括但不限于芳香酶抑制剂;抗***;抗雄激素;***释放激素激动剂;拓扑异构酶I抑制剂;拓扑异构酶II抑制剂;微管活性剂;烷化剂;类维生素A、类胡萝卜素或生育酚;环氧合酶抑制剂;MMP抑制剂;mTOR抑制剂;抗代谢物;铂化合物;甲硫氨酸氨肽酶抑制剂;二膦酸盐;抗增殖抗体;乙酰肝素酶抑制剂;Ras致癌异构体的抑制剂;端粒酶抑制剂;蛋白酶体抑制剂;用于治疗血液***恶性肿瘤的化合物;Flt-3抑制剂;Hsp90抑制剂;纺锤体驱动蛋白抑制剂;MEK抑制剂;抗肿瘤抗生素;亚硝基脲;靶向/降低蛋白质或脂质激酶活性的化合物,靶向/降低蛋白质或脂质磷酸酶活性的化合物,或任何其它抗血管生成化合物。
非限制性示例性芳香酶抑制剂包括但不限于类固醇,例如阿他美坦、依西美坦和福美司坦,以及非类固醇,例如氨鲁米特、罗谷米特(roglethimide)、吡鲁米特、曲洛司坦、睾内酯、酮康唑、伏氯唑、法倔唑、阿那曲唑和来曲唑。
非限制性抗***包括但不限于他莫昔芬、氟维司群、雷洛昔芬和盐酸雷洛昔芬。抗雄激素包括但不限于比卡鲁胺。***释放激素激动剂包括但不限于阿巴瑞克、戈舍瑞林和醋酸戈舍瑞林。
示例性拓扑异构酶I抑制剂包括但不限于拓扑替康、吉马替康、伊立替康、喜树碱及其类似物9-硝基喜树碱和大分子喜树碱缀合物PNU-166148。拓扑异构酶II抑制剂包括但不限于蒽环类,例如多柔比星、柔红霉素、表柔比星、伊达比星和奈莫柔比星;蒽醌类,例如米托蒽醌和洛索蒽醌;和鬼臼毒素,例如依托泊苷和替尼泊苷。
微管活性剂包括微管稳定化、微管去稳定化合物和微管蛋白聚合抑制剂,包括但不限于紫杉烷类,例如紫杉醇和多西紫杉醇;长春花生物碱类,例如长春碱、硫酸长春碱、长春新碱和硫酸长春新碱和长春瑞滨;圆皮海绵内酯;秋水仙素和埃博霉素及其衍生物。
示例性非限制性烷化剂包括环磷酰胺、异环磷酰胺、美法仑和亚硝基脲,例如卡莫司汀和洛莫司汀。
示例性非限制性环氧合酶抑制剂包括Cox-2抑制剂,5-烷基取代的2-芳基氨基苯基乙酸和衍生物,例如塞来昔布、罗非考昔、依托考昔、伐地考昔,或5-烷基-2-芳基氨基苯基乙酸,例如罗美昔布。
示例性非限制性基质金属蛋白酶抑制剂(“MMP抑制剂”)包括胶原肽类和非肽类抑制剂、四环素衍生物、巴马司他、马马司他、普马司他、美他司他(metastat)、BMS-279251、BAY 12-9566、TAA211、MMI270B和AAJ996。
示例性非限制性mTOR抑制剂包括抑制哺乳动物雷帕霉素靶标(mTOR)并具有抗增殖活性的化合物,例如西罗莫司、依维莫司、CCI-779和ABT578。
示例性非限制性抗代谢物包括5-氟尿嘧啶(5-FU),卡培他滨,吉西他滨,DNA去甲基化化合物如5-氮杂胞苷和地西他滨、甲氨蝶呤和依达曲沙,和叶酸拮抗剂如培美曲塞。
示例性的非限制性铂化合物包括卡铂、顺铂(cis-platin)、顺铂(cisplatinum)和奥沙利铂。
示例性的非限制性甲硫氨酸氨肽酶抑制剂包括bengamide或其衍生物和PPI-2458。
示例性的非限制性二膦酸盐包括依替膦酸、氯膦酸、替鲁膦酸、帕米膦酸、阿仑膦酸、伊班膦酸、利塞膦酸和唑来膦酸。
示例性的非限制性抗增殖抗体包括曲妥珠单抗、曲妥珠单抗-DM1、西妥昔单抗、贝伐单抗、利妥昔单抗、PR064553和2C4。术语“抗体”包括完整的单克隆抗体、多克隆抗体、由至少两种完整抗体形成的多特异性抗体和抗体片段,只要它们表现出所需的生物学活性即可。
示例性的非限制性乙酰肝素酶抑制剂包括靶向、降低或抑制硫酸肝素降解的化合物,例如PI-88和OGT2115。
如本文所用,术语“Ras致癌异构体的抑制剂”,例如H-Ras、K-Ras或N-Ras,是指靶向、降低或抑制Ras的致癌活性的化合物,例如法尼基转移酶抑制剂,例如L-744832、DK8G557、替吡法尼和洛那法尼。
示例性非限制性端粒酶抑制剂包括靶向、降低或抑制端粒酶活性的化合物,例如抑制端粒酶受体的化合物,例如端粒抑素。
示例性非限制性蛋白酶体抑制剂包括靶向、降低或抑制蛋白酶体活性的化合物,包括但不限于硼替佐米。
如本文所用,短语“用于治疗血液恶性肿瘤的化合物”包括FMS样酪氨酸激酶抑制剂,它是靶向、降低或抑制FMS样酪氨酸激酶受体(Flt-3R)活性的化合物;干扰素,I-β-D-***呋喃糖基胞嘧啶(ara-c)和白消安;和ALK抑制剂,它们是靶向、降低或抑制间变性淋巴瘤激酶的化合物。
示例性的非限制性Flt-3抑制剂包括PKC412、米哚妥林、星形孢菌素衍生物、SU11248和MLN518。
示例性的非限制性HSP90抑制剂包括靶向、降低或抑制HSP90的固有ATP酶活性的化合物;或通过泛素蛋白酶体途径降解、靶向、降低或抑制HSP90客户蛋白的化合物。靶向、降低或抑制HSP90的固有ATP酶活性的化合物尤其是抑制HSP90的ATP酶活性的化合物、蛋白质或抗体,例如17-烯丙基氨基,17-去甲氧基格尔德霉素(17AAG),格尔德霉素衍生物;其它格尔德霉素相关化合物;根赤壳菌素和HDAC抑制剂。
如本文所用,短语“靶向/降低蛋白质或脂质激酶活性;或蛋白质或脂质磷酸酶活性的化合物;或任何其它抗血管生成化合物”包括蛋白质酪氨酸激酶和/或丝氨酸和/或苏氨酸激酶抑制剂或脂质激酶抑制剂,例如a)靶向、降低或抑制血小板衍生生长因子受体(PDGFR)活性的化合物,例如靶向、降低或抑制PDGFR活性的化合物,例如N-苯基-2-嘧啶-胺衍生物,如伊马替尼、SUlOl、SU6668和GFB111;b)靶向、降低或抑制成纤维细胞生长因子受体(FGFR)活性的化合物;c)靶向、降低或抑制***受体I(IGF-IR)活性的化合物,例如靶向、降低或抑制IGF-IR活性的化合物;d)靶向、降低或抑制Trk受体酪氨酸激酶家族活性的化合物或肝配蛋白B4抑制剂;e)靶向、降低或抑制Axl受体酪氨酸激酶家族活性的化合物;f)靶向、降低或抑制Ret受体酪氨酸激酶活性的化合物;g)靶向、降低或抑制Kit/SCFR受体酪氨酸激酶活性的化合物,例如伊马替尼;h)靶向、降低或抑制c-Kit受体酪氨酸激酶活性的化合物,例如伊马替尼;i)靶向、降低或抑制c-Abl家族成员、其基因融合产物(例如Bcr-Abl激酶)和突变体的活性的化合物,例如N-苯基-2-嘧啶-胺衍生物,如伊马替尼或尼罗替尼;PD180970;AG957;NSC 680410;PD173955;或达沙替尼;j)靶向、降低或抑制蛋白激酶C(PKC)成员和丝氨酸/苏氨酸激酶的Raf家族成员,MEK、SRC、JAK、FAK、PDK1、PKB/Akt和Ras/MAPK家族成员的成员,和/或细胞周期蛋白依赖性激酶家族(CDK)的成员的活性的化合物,例如美国专利第5,093,330号中公开的星形孢菌素衍生物,如米哚妥林;其它化合物的示例包括UCN-01、沙芬戈、BAY 43-9006、苔藓抑素1、哌立福辛;伊莫福新;RO 318220和RO320432;GO 6976;Isis 3521;LY333531/LY379196;异喹啉化合物;法尼基转移酶抑制剂;PD184352或QAN697,或AT7519;k)靶向、降低或抑制蛋白质酪氨酸激酶活性的化合物,例如甲磺酸伊马替尼或酪氨酸磷酸化抑制剂(tyrphostin),例如Tyrphostin A23/RG-50810;AG99;Tyrphostin AG 213;Tyrphostin AG 1748;Tyrphostin AG490;Tyrphostin B44;Tyrphostin B44(+)对映体;Tyrphostin AG 555;AG 494;Tyrphostin AG 556、AG957和adaphostin(4-{[(2,5-二羟基苯基)甲基]氨基}-苯甲酸金刚烷基酯;NSC 680410,adaphostin);1)靶向、降低或抑制受体酪氨酸激酶的表皮生长因子家族(作为同源或异源二聚体的EGFR、ErbB2、ErbB3、ErbB4)及其突变体活性的化合物,例如CP 358774、ZD 1839、ZM 105180;曲妥珠单抗、西妥昔单抗、吉非替尼、厄洛替尼、OSI-774、Cl-1033、EKB-569、GW-2016、抗体El.l、E2.4、E2.5、E6.2、E6.4、E2.11、E6.3和E7.6.3和7H-吡咯并-[2,3-d]嘧啶衍生物;以及m)靶向、降低或抑制c-Met受体活性的化合物。
靶向、降低或抑制蛋白质或脂质磷酸酶活性的示例性化合物包括磷酸酶1、磷酸酶2A或CDC25的抑制剂,例如冈田酸或其衍生物。
其它抗血管生成化合物包括具有与蛋白质或脂质激酶抑制无关的其它活性机制的化合物,例如沙利度胺和TNP-470。
另外的非限制性示例性化学治疗化合物(其中一种或多种可与本发明的ALK抑制剂组合使用)包括:柔红霉素、阿霉素、Ara-C、VP-16、替尼泊苷、米托蒽醌、伊达比星、卡铂、PKC412、6-巯基嘌呤(6-MP)、磷酸氟达拉滨、奥曲肽、SOM230、FTY720、6-硫鸟嘌呤、克拉屈滨、6-巯基嘌呤、喷司他丁、羟基脲、2-羟基-1H-异吲哚-1,3-二酮衍生物、1-(4-氯苯胺基)-4-(4-吡啶基甲基)酞嗪或其医药学上可接受的盐、1-(4-氯苯胺基)-4-(4-吡啶基甲基)酞嗪琥珀酸盐、血管抑制素、内皮抑素、邻氨基苯甲酸酰胺、ZD4190、ZD6474、SU5416、SU6668、贝伐单抗、rhuMAb、rhuFab、macugon;FLT-4抑制剂、FLT-3抑制剂、VEGFR-2IgGI抗体、RPI4610、贝伐单抗、卟吩姆钠、阿奈可他、曲安奈德、氢化可的松、11-a-表氢化皮质醇、脱氧皮醇、17a-羟基孕酮、皮质酮、去氧皮质酮、睾酮、雌酮、***、氟轻松、植物生物碱、激素化合物和/或拮抗剂、生物反应调节剂如淋巴因子或干扰素、反义寡核苷酸或寡核苷酸衍生物、shRNA和siRNA。
第二治疗剂的其它示例(其中一种或多种也可与本发明的ALK抑制剂组合使用)包括但不限于:阿尔茨海默病的治疗,例如多奈哌齐和利凡斯的明;帕金森病的治疗,例如L-DOPA/卡比多巴、恩他卡朋、罗匹尼罗、普拉克索、溴隐亭、培高利特、苯海索和金刚烷胺;用于治疗多发性硬化(MS)的药剂,例如β干扰素(例如和)、醋酸格拉替雷和米托蒽醌;哮喘的治疗,例如沙丁胺醇和孟鲁司特;用于治疗精神***症的药剂,例如再普乐、维思通、思瑞康和氟哌啶醇;抗炎剂,例如皮质类固醇、TNF阻滞剂、IL-1RA、硫唑嘌呤、环磷酰胺和柳氮磺胺吡啶;免疫调节剂,包括免疫抑制剂,例如环孢菌素、他克莫司、雷帕霉素、霉酚酸酯、干扰素、皮质类固醇、环磷酰胺、硫唑嘌呤和柳氮磺胺吡啶;神经营养因子,例如乙酰胆碱酯酶抑制剂、MAO抑制剂、干扰素、抗惊厥药、离子通道阻滞剂、利鲁唑或抗帕金森药;用于治疗心血管疾病的药剂,例如β-受体阻滞剂、ACE抑制剂、利尿剂、硝酸盐、钙通道阻滞剂或他汀类;用于治疗肝脏疾病的药剂,例如皮质类固醇、消胆胺、干扰素和抗病毒剂;用于治疗血液病症的药剂,例如皮质类固醇、抗白血病药或生长因子;或用于治疗免疫缺陷症的药剂,例如丙种球蛋白。
如本领域所述制备和施用上述第二治疗活性剂,其中一种或多种可与本公开化合物组合使用。
本公开化合物通常与药物载剂混合施用,所述药物载剂是根据预期的施用途径和标准药学实践来选择的。使用一种或多种生理学上可接受的载剂以常规方式配制根据本公开使用的药物组合物,所述载剂包含有助于加工本公开化合物的赋形剂和/或助剂。
这些药物组合物可以通过例如常规的混合、溶解、制粒、制糖衣、乳化、包封、包埋或冻干方法制备。适当的制剂取决于所选择的施用途径。当口服施用治疗有效量的本公开化合物时,该组合物通常为片剂、胶囊、粉末、溶液或酏剂的形式。当以片剂形式施用时,组合物另外可含有固体载剂,例如明胶或佐剂。片剂、胶囊和粉末含有约0.01%至约95%,优选约1%至约50%的本公开化合物。当以液体形式施用时,可以加入液体载剂,例如水、石油或动物或植物来源的油。液体形式的组合物可进一步含有生理盐水溶液、右旋糖或其它糖溶液或二醇。当以液体形式施用时,该组合物,以重量计,含有约0.1%至约90%,优选约1%至约50%的本公开化合物。
当通过静脉内、皮肤或皮下注射施用治疗有效量的本公开化合物时,该组合物是无热原的肠胃外可接受的水溶液形式。在适当考虑pH、等渗性、稳定性等的情况下制备这种肠胃外可接受的溶液在本领域的技术范围内。用于静脉内、皮肤或皮下注射的优选组合物通常含有等渗媒介物。
本发明化合物可以容易地与本领域熟知的医药学上可接受的载剂组合。在一个实施例中,提供了药物组合物,其包含本公开化合物或其医药学上可接受的盐或水合物和医药学上可接受的载剂。标准药物载剂描述于《雷氏药学大全(Remington's PharmaceuticalSciences)》,Mack Publishing公司,宾夕法尼亚州,伊斯顿,第19版,1995中。这种载剂使得活性剂能够配制成片剂、丸剂、糖衣丸、胶囊、液体、凝胶、糖浆、浆液、混悬剂等,用于待治疗患者的口服。口服的药物制剂可以通过将本公开化合物加入固体赋形剂中,任选地研磨所得混合物,并在需要时加入合适的助剂后加工颗粒混合物,以获得片剂或糖衣丸核心来获得。合适的赋形剂包括例如填充剂和纤维素制剂。如果需要,可以加入崩解剂。
本公开化合物可以配制用于通过注射,例如通过团注或连续输注进行肠胃外施用。用于注射的制剂可以以单位剂量形式存在于,例如添加有防腐剂的安瓿或多剂量容器中。该组合物可以采取诸如油性或水性媒介物中的混悬剂、溶液或乳剂的形式,并且可以含有配制剂,例如悬浮剂、稳定剂和/或分散剂。
用于肠胃外施用的药物组合物包括水溶形式的活性剂的水溶液。另外,本公开化合物的混悬剂可以制备成适当的油性注射混悬剂。合适的亲脂性溶剂或媒介物包括脂肪油或合成脂肪酸酯。水性注射混悬剂可含有增加混悬剂粘度的物质。任选地,混悬剂还可含有合适的稳定剂或增加化合物溶解度并允许制备高浓度溶液的试剂。或者,本组合物可以是粉末形式,用于在使用前用合适的媒介物(例如无菌无热原水)构建。
本公开化合物还可以配制成直肠组合物,例如栓剂或保留灌肠剂,其例如含有常规栓剂基质。除了先前描述的制剂之外,本公开化合物还可以配制成Depot制剂。这种长效制剂可以通过植入(例如,皮下或肌内)或通过肌内注射施用。因此,例如,本公开化合物可以用合适的聚合或疏水材料(例如,作为可接受油中的乳剂)或离子交换树脂配制。
特别地,本公开化合物可以以含有赋形剂(例如淀粉或乳糖)的片剂的形式或者以胶囊或胚珠的形式(单独或与赋形剂混合),或以含有调味剂或着色剂的酏剂或混悬剂形式口服、颊或舌下施用。这种液体制剂可以用医药学上可接受的添加剂如悬浮剂制备。本公开化合物还可以肠胃外注射,例如静脉内、肌内、皮下或冠状动脉内注射。对于肠胃外施用,本公开化合物通常以无菌水溶液的形式使用,其可含有其它物质,例如盐或单糖,如甘露醇或葡萄糖,以使溶液与血液等渗。
在另一个实施例中,本公开提供了以便于其用于实施本公开方法的方式包装的试剂盒,所述试剂盒包含本公开化合物(或包含本公开化合物的组合物)。在一个实施例中,所述试剂盒包括包装在容器(例如密封的瓶子或容器)中的本公开化合物(或包含本公开化合物的组合物),其中标签贴在容器上或包括在试剂盒中,用来描述使用化合物或组合物来实施本公开方法。在一个实施例中,化合物或组合物以单位剂型包装。试剂盒还可包括适于根据预期施用途径施用组合物的装置。
术语“其中抑制ALK提供益处的疾病或病状”涉及其中ALK对于例如该疾病或病状的发作、进展、表达是重要或必需的疾病或病状,或已知用ALK抑制剂治疗的疾病或病状。这种病状的示例包括但不限于癌症、慢性自体免疫性疾病、炎性疾病、增殖性疾病、败血症和病毒感染。本领域普通技术人员能够例如通过可方便地用于评估特定化合物的活性的测定容易地确定化合物是否治疗由ALK抑制剂介导的任何特定细胞类型的疾病或病状。术语“间变性淋巴瘤激酶”或“ALK”包括ALK的同种型和突变体。
术语“第二治疗剂”是指不同于本公开化合物并且已知治疗所关注的疾病或病状的治疗剂。例如,当癌症是所关注的疾病或病状时,第二治疗剂可以例如是已知的化学治疗药物,如紫杉酚或辐射。
术语“疾病”或“病状”表示通常被认为是病理状态或功能的干扰和/或异常,并且其可以表现为特定体征、症状和/或功能障碍。如下所证明的,本公开化合物是ALK的抑制剂,并且可用于治疗或预防抑制ALK提供益处的疾病和病状。
如本文所用,术语“治疗(treat、treating或treatment)”等是指消除、减轻或改善疾病或病状,和/或与其相关的症状。尽管不排除,但治疗疾病或病状不需要完全消除与其相关的疾病、病状或症状。术语“治疗”和同义词考虑将治疗有效量的本公开化合物施用于需要这种治疗的受试者。可以对症治疗例如以抑制症状。它可以在短时段内实现,在中期内定向,或者可以是长期治疗,例如在维持疗法的背景下。
如本文所用,术语“预防(prevent、preventing和prevention)”是指预防疾病或病状和/或其伴随症状发作或阻止受试者患病的方法。如本文所用,“预防(prevent、preventing和prevention)”还包括延迟疾病和/或其伴随症状发作并降低受试者患病的风险。术语“预防(prevent、preventing和prevention)”可以包括“预防性治疗”,其是指降低受试者重新发展疾病或病状或先前控制的疾病或病状复发的可能性,所述受试者还未重新发展疾病或病状或疾病或病状复发,但有重新发展疾病或病状或疾病或病状复发的风险或易于重新发展疾病或病状或疾病或病状复发。
如本文所用,术语“治疗有效量”或“有效剂量”是指当通过本公开方法施用时,足以向需要其的个体有效递送活性成分以用于治疗所关注的病状或疾病的活性成分的量。在癌症或其它增殖病症的情况下,治疗有效量的药剂可以减少(即,在某种程度上延迟并且优选地阻止)不需要的细胞增殖;减少癌细胞的数量;减少肿瘤尺寸;抑制(即,在某种程度上延迟并优选阻止)癌细胞浸润到外周器官中;抑制(即,在一定程度上延迟并优选阻止)肿瘤转移;在一定程度上抑制肿瘤生长;和/或在一定程度上缓解与癌症相关的一种或多种症状。在施用的化合物或组合物阻止生长和/或杀死现有癌细胞的程度上,它可以是细胞抑制性的和/或细胞毒性的。
术语“容器”是指因此适合于储存、运输、调剂和/或处理药物产品的任何容器和封盖。
术语“说明书”是指伴随药物产品的信息,其提供如何施用产品的描述,以及允许医师、药剂师和患者就产品的使用做出明智决定所需的安全性和功效数据。包装说明书通常被认为是药物产品的“标签”。
“同时施用(concurrent administration)”、“组合施用”、“同时施用(simultaneous administration)”和类似短语是指将两种或更多种药剂同时施用于所治疗的受试者。“同时地”是指每种药剂在不同时间点以任何顺序同时或相继施用。然而,如果不同时施用,则意味着它们按顺序施用于个体并且时间足够接近以提供所需的治疗效果并且可以共同起作用。例如,本公开化合物可以与第二治疗剂同时或在不同的时间点以任何顺序相继施用。本公开化合物和第二治疗剂可以以任何适当的形式并通过任何合适的途径分开施用。当本公开化合物和第二治疗剂不同时施用时,应理解它们可以以任何顺序施用于需要其的受试者。例如,本公开化合物可以在施用第二治疗剂治疗方式(例如,放射疗法)之前(例如,5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周或12周之前)、同时或之后(例如,5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周或12周之后),施用于需要其的个体。在各种实施例中,本公开化合物和第二治疗剂的施用间隔1分钟,间隔10分钟,间隔30分钟,间隔小于1小时,间隔1小时,间隔1小时至2小时,间隔2小时至3小时,间隔3小时至4小时,间隔4小时至5小时,间隔5小时至6小时,间隔6小时至7小时,间隔7小时至8小时,间隔8小时至9小时,间隔9小时至10小时,间隔10小时至11小时,间隔11小时至12小时,间隔不超过24小时或间隔不超过48小时。在一个实施例中,组合疗法的组分以约1分钟至约24小时间隔施用。
除非另有说明,否则在描述本公开的上下文中(尤其是在权利要求的上下文中)使用术语“一种”、“一个”、“所述”和类似的指示物将被解释为涵盖单数和复数。除非本文另有说明,否则本文中对数值范围的引用仅旨在用作个别提及落入该范围内的每个单独值的简写方法,并且每个单独值并入本说明书中,如同其在本文中个别引用一样。除非另有声明,否则本文提供的任何和所有示例或示例性语言(例如,“诸如”)的使用旨在更好地说明本公开,而不是对本公开范围的限制。说明书中的任何语言都不应被解释为表明任何未声明的要素对于本公开的实践是必不可少的。
在本公开中,术语“烷基”本身或作为另一基团的一部分使用是指未取代的直链或支链脂族烃,其含有1至12个碳原子,即C1-12烷基,或指定碳原子数,例如,C1烷基如甲基,C2烷基如乙基,C3烷基如丙基或异丙基,C1-3烷基如甲基、乙基、丙基或异丙基等等。在一个实施例中,烷基是C1-4烷基。非限制性示例性C1-12烷基包括甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基、异丁基、3-戊基、己基、庚基、辛基、壬基和癸基。示例性的C1-4烷基是甲基、乙基、丙基、异丙基、丁基、仲丁基、叔丁基和异丁基。
在本公开中,术语“环烷基”本身或作为另一基团的一部分使用是指饱和的和部分不饱和的(含有一个或两个双键)环状脂族烃,其含有一个或两个具有3-12个碳原子的环(即,C3-12环烷基)或指定的碳数的环。在一个实施例中,环烷基具有两个环。在一个实施例中,环烷基具有一个环。在另一个实施例中,环烷基选自C3-8环烷基。在另一个实施例中,环烷基选自C3-6环烷基。非限制性示例性环烷基包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基、降冰片基、十氢化萘、金刚烷基、环己烯基、环戊烯基和环己烯基。
在本公开中,术语“杂环(heterocycle或heterocyclo)”本身或作为另一基团的一部分使用是指饱和的和部分不饱和的(例如,含有一个或两个双键)环状基团,其含有具有3至14个环成员的一个、两个或三个环(即,3-至14-元杂环),其中一个环的至少一个碳原子被杂原子替换。每个杂原子独立地选自由以下组成的组:氧,硫(包括亚砜和砜),和/或氮原子,其可以被氧化或季铵化。术语“杂环”是指包括环中-CH2-被-C(=O)-替换的基团,例如,环状脲基如2-咪唑烷酮,和环酰胺基团如β-内酰胺、γ-内酰胺、δ-内酰胺、ε-内酰胺和哌嗪-2-酮。在一个实施例中,杂环基是含有一个环和一个或两个氧和/或氮原子的3-至8-元环状基团。在一个实施例中,杂环基是含有一个环和一个或两个氧和/或氮原子的4-、5-或6-元环状基团。在一个实施例中,杂环基是含有一个环和一个氧或氮原子的4-或6-元环状基团。杂环可以任选地通过任何可用的碳或氮原子与分子的其余部分连接。非限制性示例性杂环基包括二噁烷基、四氢吡喃基、2-氧代吡咯烷-3-基、哌嗪-2-酮、哌嗪-2,6-二酮、2-咪唑烷酮、哌啶基、吗啉基、哌嗪基、吡咯烷基和二氢吲哚基。
实例
实例1
5-氯-N2-(2-异丙氧基-5-甲基-4-(2,2,6,6-四甲基-1,2,3,6-四氢吡啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺的合成(化合物编号2)
步骤A:4-(5-氟-2-甲基-4-硝基苯基)-2,2,6,6-四甲基-1,2,3,6-四氢吡啶的合成。
将2,2,6,6-四甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-1,2,3,6-四氢吡啶(1.0g,3.77mmol),Pd(dppf)Cl2(110mg,0.15mmol)和K2CO3(1.56g,11.31mmol)加入1-溴-5-氟-2-甲基-4-硝基苯(883mg,3.77mmol)的DME-H2O(22mL,10:1混合物)溶液中。在氮气下将混合物在80℃下搅拌12小时。将反应冷却至室温,并用乙酸乙酯萃取产物。减压除去溶剂,并通过硅胶色谱用乙酸乙酯/甲醇(9/1,v/v)纯化残余物以得到标题化合物(0.99g,90%产率)。1H NMR(400MHz,CDCl3)δppm 7.88(d,J=7.6Hz,1H),6.97(d,J=11.6Hz,1H),5.63(s,1H),2.34(s,3H),2.09–2.02(m,3H),1.28(s,6H),1.26(s,6H)。
步骤B:4-(5-异丙氧基-2-甲基-4-硝基苯基)-2,2,6,6-四甲基-1,2,3,6-四氢吡啶的合成。
向4-(5-硝基-2-乙烯基苯基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯(0.99g,3.4mmol)的2-丙醇(20mL)溶液中加入Cs2CO3(3.32g,10.2mmol)。将混合物在60℃搅拌过夜,冷却至室温后,减压蒸发大部分2-丙醇。加入水,并用乙酸乙酯萃取溶液。将有机层合并,经无水Na2SO4干燥,浓缩,并通过硅胶色谱用乙酸乙酯/甲醇(9/1,v/v)纯化粗产物以得到标题化合物(0.9g,79%),其是淡黄色的油状物。1H NMR(400MHz,CDCl3)δ7.62(s,1H),6.72(s,1H),5.57(t,J=1.7Hz,1H),4.63-4.60(m,1H),2.26(s,3H),2.10-2.20(m,3H),1.38(d,J=6.0Hz,6H),1.28(s,6H),1.25(s,6H)。
步骤C:2-异丙氧基-5-甲基-4-(2,2,6,6-四甲基-1,2,3,6-四氢吡啶-4-基)苯胺的合成。
向4-(5-异丙氧基-2-甲基-4-硝基苯基)-2,2,6,6-四甲基-1,2,3,6-四氢吡啶(320mg,0.96mmol)的乙醇(20mL)溶液中加入几滴10%HCl,然后加入铁粉(322mg,5.76mmol)。将混合物在60℃下搅拌3小时。将反应冷却至室温,并滤出铁粉。减压除去乙醇,并获得标题化合物,其是无色油状物(250mg,86%产率)。1H NMR(400MHz,CDCl3)δ6.54(s,1H),6.51(s,1H),5.47(s,1H),4.49-4.45(m,1H),3.68(s,2H),2.17(s,3H),2.05(s,2H),1.34(d,J=6.0Hz,6H),1.25(s,6H),1.23(s,6H)。
步骤D:5-氯-N2-(2-异丙氧基-5-甲基-4-(2,2,6,6-四甲基-1,2,3,6-四氢吡啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺的合成。
2-异丙氧基-5-甲基-4-(2,2,6,6-四甲基-1,2,3,6-四氢吡啶-4-基)苯胺(250mg,0.828mmol)、2,5-二氯-N-(2-(异丙基磺酰基)苯基)嘧啶-4-胺(286mg,0.828mmol)、Xantphos(48mg,0.083mmol)、Pd(OAc)2(9.3mg,0.042mmol)和Cs2CO3(810mg,2.48mmol)溶于无水THF(10mL)中。将N2鼓泡通过反应混合物5分钟,然后将反应容器密封并在微波辐射下加热至150℃达30分钟。过滤混合物,并减压浓缩滤液。浓缩后,通过制备型HPLC(梯度为10%至60%乙腈/水)纯化粗产物以得到标题化合物(130mg,26%产率)。1H NMR(400MHz,CD3OD)δ8.37(dd,J=8.3,1.1Hz,1H),8.24(s,1H),7.99(dd,J=8.0,1.6Hz,1H),7.80-7.62(m,2H),7.52-7.38(m,1H),6.76(s,1H),5.62(t,J=1.7Hz,1H),4.70-4.58(m,1H),3.44–3.33(m,1H),2.50(d,J=1.7Hz,2H),2.14(s,3H),1.63(s,6H),1.59(s,6H),1.34(d,J=6.0Hz,6H),1.27(d,J=6.8Hz,6H)。
实例2
5-氯-N2-(2-异丙氧基-5-甲基-4-(1,2,2,6,6-五甲基-1,2,3,6-四氢吡啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺的合成(化合物编号1)
步骤A:4-(5-异丙氧基-2-甲基-4-硝基苯基)-1,2,2,6,6-五甲基-1,2,3,6-四氢吡啶的合成。
将37%甲醛(365mg,4.5mmol),乙酸(135mg,2.25mmol)和三乙酰氧基硼氢化钠(477mg,2.25mmol)加入到4-(5-异丙氧基-2-甲基-4-硝基苯基)-2,2,6,6-四甲基-1,2,3,6-四氢吡啶(500mg,1.5mmol)的DCM(20mL)溶液中,并将混合物在室温下搅拌12小时。加入水以淬灭反应,并用DCM萃取混合物。除去溶剂,并通过硅胶色谱用乙酸乙酯/甲醇(9/1,v/v)纯化残余物以得到标题化合物(460mg,88%产率),其是浅黄色油状物。1H NMR(400MHz,CDCl3)δppm 7.62(s,1H),6.76(s,1H),5.42(s,1H),4.65-4.56(m,1H),2.38(s,3H),2.28(s,3H),2.22(s,2H),1.37(d,J=6.1Hz,6H),1.24(s,6H),1.20(s,6H)。
步骤B:2-异丙氧基-5-甲基-4-(1,2,2,6,6-五甲基-1,2,3,6-四氢吡啶-4-基)苯胺的合成。
向4-(5-异丙氧基-2-甲基-4-硝基苯基)-1,2,2,6,6-五甲基-1,2,3,6-四氢吡啶(460mg,1.33mmol)的乙醇(20mL)溶液中加入几滴10%HCl,然后加入铁粉(448mg,8.0mmol)。将混合物在60℃下搅拌3小时。将反应冷却至室温,并滤出铁粉。减压除去乙醇,并获得标题化合物,其是无色油状物(410mg,98%产率)。MS m/z=317[M+H]。1H NMR(400MHz,CDCl3)δ6.53(s,2H),5.32(s,1H),4.40-4.40(m,1H),3.67(s,2H),2.35(s,3H),2.19(s,3H),2.20-2.17(m,2H),1.33(d,J=6.1Hz,6H),1.20(s,6H),1.17(s,6H)。
步骤C:5-氯-N2-(2-异丙氧基-5-甲基-4-(1,2,2,6,6-五甲基-1,2,3,6-四氢吡啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺的合成。
2-异丙氧基-5-甲基-4-(1,2,2,6,6-五甲基-1,2,3,6-四氢吡啶-4-基)苯胺(154mg,0.488mmol)、2,5-二氯-N-(2-(异丙基磺酰基)苯基)嘧啶-4-胺(168mg,0.488mmol)、Xantphos(28mg,0.0488mmol)、Pd(OAc)2(5.5mg,0.0244mmol)和Cs2CO3(477mg,1.464mmol)溶解在无水THF(10mL)中。将N2鼓泡通过反应混合物5分钟,然后将反应容器密封并在微波辐射下加热至150℃达30分钟。过滤混合物,并减压浓缩滤液。浓缩后,通过制备型HPLC(梯度为10%至60%乙腈/水)纯化粗产物以得到标题化合物(110mg,36%产率)。1HNMR(400MHz,CD3OD)δ8.36(d,J=8.3Hz,1H),8.25(s,1H),8.00(dd,J=7.9,1.6Hz,1H),7.80-7.62(m,2H),7.55-7.40(m,1H),6.78(s,1H),5.62(d,J=2.5Hz,1H),4.72-4.55(m,1H),3.42–3.33(m,1H),2.98(s,3H),2.95–2.82(m,1H),2.44(d,J=18.1Hz,1H),2.15(s,3H),1.65(s,3H),1.61(s,3H),1.59(s,3H),1.56(s,3H),1.34(dd,J=6.0,1.8Hz,6H),1.27(d,J=6.8Hz,6H)。
实例3
5-氯-N2-(2-异丙氧基-5-甲基-4-(1-(四氢-2H-吡喃-4-基)-1,2,3,6-四氢吡啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺的合成
(化合物编号5)
步骤A:4-(5-氟-2-甲基-4-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成。
将4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(620mg,2mmol)、Pd(dppf)Cl2(58mg,0.08mmol)和K2CO3(828mg,6mmol)加入到1-溴-5-氟-2-甲基-4-硝基苯(470mg,2mmol)的DME-H2O(22mL,10:1混合物)溶液中。在氮气下将混合物在80℃下搅拌12小时。将反应冷却至室温,并用乙酸乙酯萃取产物。减压除去溶剂,并通过硅胶色谱用己烷/乙酸乙酯(9/1,v/v)纯化残余物以得到标题化合物(640mg,95%产率),其是浅黄色油状物。1H NMR(400MHz,CDCl3)δppm 7.89(d,J=7.5Hz,1H),7.02(d,J=11.5Hz,1H),5.68(s,1H),4.10-4.07(m,2H),3.65(t,J=5.6Hz,2H),2.39–2.32(m,2H),2.33(s,3H),1.52(s,9H)。
步骤B:4-(5-异丙氧基-2-甲基-4-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成。
向4-(5-氟-2-甲基-4-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(640mg,1.9mmol)的2-丙醇(20mL)溶液中加入Cs2CO3(1.862g,5.7mmol)。将混合物在60℃搅拌过夜,冷却至室温后,减压蒸发大部分2-丙醇。加入水,并用乙酸乙酯萃取溶液。合并有机层,经无水Na2SO4干燥,浓缩,并通过硅胶色谱用己烷/乙酸乙酯(8/2,v/v)纯化粗产物以得到标题化合物(650mg,91%),其是黄色油状物。1H NMR(400MHz,CDCl3)δ7.63(s,1H),6.79(s,1H),5.62(s,1H),4.65-4.62(m,1H),4.4.10-4.07(m,2H),3.64(t,J=5.6Hz,2H),2.36-2.34(m,2H),2.25(s,3H),1.52(s,9H),1.39(d,J=6.1Hz,6H)。
步骤C:4-(5-异丙氧基-2-甲基-4-硝基苯基)-1-(四氢-2H-吡喃-4-基)-1,2,3,6-四氢吡啶的合成。
向4-(5-异丙氧基-2-甲基-4-硝基苯基)-5,6-二氢吡啶-1(2H)-羧酸叔丁酯(217mg,0.576mmol)的二氯甲烷(5mL)溶液中加入三氟乙酸(1mL)并将反应混合物在室温下搅拌6小时。真空除去二氯甲烷和三氟乙酸,并加入100mL二氯甲烷,用饱和NaHCO3溶液洗涤。将水层用二氯甲烷萃取另外两次(各100mL)。将有机层合并,用盐水洗涤,经Na2SO4干燥并蒸发。将残余物溶于二氯甲烷(10mL)中,然后加入四氢-4H-吡喃-4-酮(173mg,1.728mmol)、三乙酰氧基硼氢化钠(244mg,1.152mmol)和乙酸(69mg,1.152mmol)。将反应在室温下搅拌过夜。通过加入水(80mL)将反应淬灭,并用二氯甲烷(3×100mL)萃取。将有机层合并,用盐水洗涤,经Na2SO4干燥,浓缩并通过硅胶柱色谱用乙酸乙酯/甲醇(9/1,v/v)纯化以得到标题化合物(170mg,82%,两步),其是黄色油状物。1H NMR(400MHz,CDCl3)δ7.63(s,1H),6.83(s,1H),5.62-5.59(m,1H),4.58-4.56(m,1H),4.11–4.01(m,2H),3.43-3.28(m,4H),2.78(t,J=5.6Hz,2H),2.60-2.56(m,1H),2.40-2.36(m,2H),2.23(s,3H),1.86-1.82(m,2H),1.69-1.65(m,2H),1.35(d,J=6.1Hz,6H)。
步骤D:2-异丙氧基-5-甲基-4-(1-(四氢-2H-吡喃-4-基)-1,2,3,6-四氢吡啶-4-基)苯胺的合成。
向4-(5-异丙氧基-2-甲基-4-硝基苯基)-1-(四氢-2H-吡喃-4-基)-1,2,3,6-四氢吡啶(2.4g,6.66mmol)的乙醇(30mL)溶液中加入4mL的10%HCl,然后加入铁粉(2.23g,40mmol)。将混合物在60℃下搅拌3小时。将反应冷却至室温,并滤出铁粉。减压除去乙醇,并获得标题化合物,其是淡黄色油状物(2.0g,91%产率)。MS m/z=331[M+H]。
步骤E:5-氯-N2-(2-异丙氧基-5-甲基-4-(1-(四氢-2H-吡喃-4-基)-1,2,3,6-四氢吡啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺的合成。
2-异丙氧基-5-甲基-4-(1-(四氢-2H-吡喃-4-基)-1,2,3,6-四氢吡啶-4-基)苯胺(330mg,1mmol)、2,5-二氯-N-(2-(异丙基磺酰基)苯基)嘧啶-4-胺(345mg,1mmol)、Xantphos(58mg,0.1mmol)、Pd(OAc)2(11mg,0.05mmol),和Cs2CO3(975mg,3mmol)溶解在无水THF(20mL)中。将N2鼓泡通过反应混合物5分钟,然后将反应容器密封并在微波辐射下加热至150℃达30分钟。过滤混合物,并减压浓缩滤液。浓缩后,通过制备型HPLC(梯度为10%至60%乙腈/水)纯化粗产物以得到标题化合物(125mg,20%产率)。1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.46(d,J=8.3Hz,1H),8.27(s,1H),8.06(s,1H),7.85(dd,J=8.3,1.5Hz,1H),7.66(t,J=8.3Hz,1H),7.59(s,1H),7.37(t,J=7.6Hz,1H),6.73(s,1H),5.57–5.50(m,1H),4.58-4.54(m,1H),3.96–3.87(m,2H),3.47-3.43(m,1H),3.31(t,J=11.1Hz,2H),3.17(d,J=3.1Hz,2H),2.70(t,J=5.5Hz,2H),2.29(t,J=4.5Hz,2H),2.07(s,3H),1.78-1.74(m,2H),1.49-1.45(m,2H),1.23(d,J=6.0Hz,6H),1.16(d,J=6.8Hz,6H)。
实例4
5-氯-N2-(2-异丙氧基-5-甲基-4-(1-(氧杂环丁烷-3-基)-1,2,3,6-四氢吡啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺的合成
(化合物编号6)
步骤A:4-(4-氨基-5-异丙氧基-2-甲基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成
向4-(5-异丙氧基-2-甲基-4-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(217mg,0.576mmol)的乙醇(20mL)溶液中加入几滴10%HCl,然后加入铁粉(194mg,3.457mmol)。将混合物在60℃下搅拌3小时。将反应冷却至室温,并滤出铁粉。减压除去乙醇,并获得标题化合物,其是淡黄色油状物。该产物无需进一步纯化即可直接使用。
步骤B:5-氯-N2-(2-异丙氧基-5-甲基-4-(1-(氧杂环丁烷-3-基)-1,2,3,6-四氢吡啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺的合成
将4-(4-氨基-5-异丙氧基-2-甲基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(120mg,0.348mmol)、2,5-二氯-N-(2-(异丙基磺酰基)苯基)嘧啶-4-胺(120mg,0.348mmol)、Xantphos(28mg,0.048mmol)、Pd(OAc)2(5.5mg,0.024mmol)和Cs2CO3(400mg,1.23mmol)溶于无水THF(8mL)中。将N2鼓泡通过反应混合物5分钟,然后将反应容器密封并在微波辐射下加热至150℃达30分钟。过滤混合物,并减压浓缩滤液。将残余物溶于二氯甲烷(5mL)中。加入三氟乙酸(1mL)并将反应在室温下搅拌6小时。真空除去二氯甲烷和三氟乙酸,并加入40mL二氯甲烷,用饱和NaHCO3溶液洗涤。将水层用二氯甲烷萃取另外两次(各40mL)。将有机层合并,用盐水洗涤,经Na2SO4干燥并蒸发。将残余物溶于二氯甲烷(10mL)中,然后加入氧杂环丁烷-3-酮(75mg,1.04mmol)、三乙酰氧基硼氢化钠(118mg,0.56mmol)和乙酸(34mg,0.56mmol)。将反应在室温下搅拌过夜。通过加入水(80mL)将反应淬灭,并用二氯甲烷(3×40mL)萃取。将有机层合并,用盐水洗涤,经Na2SO4干燥。浓缩后,通过制备型HPLC(梯度为10%至60%乙腈/水)纯化粗产物,以得到标题化合物(40mg,19%产率)。1H NMR(400MHz,CD3OD)δppm 8.38(d,J=8.0Hz,1H),8.23(s,1H),8.00-7.98(m,1H),7.78–7.69(m,2H),7.48-7.44(m,1H),6.82(s,1H),5.69–5.62(m,1H),5.02–4.90(m,4H),4.70–4.55(m,2H),4.00-3.80(m,2H),3.65-3.40(m,2H),3.42–3.35(m,1H),2.74(s,2H),2.14(s,3H),1.34(d,J=6.1Hz,6H),1.27(d,J=6.8Hz,6H)。
实例5
5-氯-N2-(4-((顺式)-2,6-二甲基-1,2,3,6-四氢吡啶-4-基)-2-异丙氧基-5-甲基苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺的合成
(化合物编号9)
步骤A:顺式-1-(4-甲氧基苄基)-2,6-二甲基哌啶-4-酮的合成。
向丙酮二羧酸(4g,27.4mmol)的水(20mL)溶液中加入40%乙醛(6g,54.8mmol)。然后在10分钟内分小份加入4-甲氧基苯基甲胺(3.75g,27.4mmol)。将得到的黄色溶液在室温下搅拌3天。用二氯甲烷(3×60mL)萃取反应混合物。将合并的萃取液用盐水洗涤并用无水Na2SO4干燥。将溶液过滤并蒸发以得到棕色残余物。通过硅胶色谱用二氯甲烷/乙酸乙酯(9/1,v/v)分离异构的哌啶酮。获得所需标题化合物(4.0g,59%),其是淡黄色油状物。1H NMR(400MHz,CDCl3)δ7.30(d,J=8.5Hz,2H),6.87(d,J=8.5Hz,2H),3.86(d,J=13.7Hz,1H),3.81(s,3H),3.55(d,J=13.7Hz,1H),3.28-3.24(m,2H),2.49-2.45(m,2H),2.20-2.16(m,2H),1.09(d,J=6.6Hz,6H)。
步骤B:顺式-2,6-二甲基哌啶-4-酮的合成。
将顺式-1-(4-甲氧基苄基)-2,6-二甲基哌啶-4-酮(4.0g,16.2mmol)溶解在乙醇(20mL)中,并加入催化剂(0.4g,10%Pd-C)。将混合物在氢气氛下搅拌12小时。过滤除去催化剂,并减压蒸发滤液,以得到标题化合物(1.8g,88%产率)。1H NMR(400MHz,CDCl3)δ3.58–3.50(m,2H),2.50-2.48(m,2H),2.20-2.11(m,2H),1.17(d,J=6.6Hz,6H)。
步骤C:顺式-2,6-二甲基-4-氧代哌啶-1-羧酸叔丁酯
将二碳酸二叔丁酯(3.14g,14.4mmol)和N,N-二异丙基乙胺(3.1g,24mmol)加入到顺式-1-(4-甲氧基苄基)-2,6-二甲基哌啶-4-酮(1.54g,12mmol)的二氯甲烷(30mL)溶液中,并将混合物在室温下搅拌12小时。减压除去溶剂,并通过硅胶色谱用己烷/乙酸乙酯(8/2,v/v)纯化残余物以得到标题化合物(2.0g,73%产率),其是白色固体。1H NMR(400MHz,CDCl3)δ4.41-4.39(m,2H),2.85(dd,J=17.8,6.5Hz,2H),2.37(dd,J=17.8,1.9Hz,2H),1.50(s,9H),1.25(d,J=6.8Hz,6H)。
步骤D:顺式-2,6-二甲基-4-(((三氟甲基)磺酰基)氧基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成。
在-78℃下向顺式-2,6-二甲基-4-氧代哌啶-1-羧酸叔丁酯(500mg,2.2mmol)的THF(20mL)溶液中缓慢加入2.0M LDA(1.1mL,2.2mmol)。20分钟后,将1,1,1-三氟-N-苯基-N-(三氟甲基磺酰基)甲磺酰胺(786mg,2.2mmol)的溶液缓慢加入混合物中。将反应混合物在0℃下搅拌3小时。减压蒸发溶剂,并通过柱色谱用己烷/乙酸乙酯(20/1,v/v)纯化残余物以获得标题化合物(600mg,76%产率)。1H NMR(400MHz,CDCl3)δ5.78-5.70(m,1H),4.45-4.30(m,2H),2.85-2.78(m,1H),2.25-2.15(m,1H),1.48(s,9H),1.37(d,J=6.3Hz,3H),1.24(d,J=6.5Hz,3H)。
步骤E:顺式-2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成。
将顺式-2,6-二甲基-4-(((三氟甲基)磺酰基)氧基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(600mg,1.67mmol)、双(频哪醇合)二硼(467mg,1.84mmol)、乙酸钾(490mg,5.01mmol)、1,10-双(二苯基膦基)二茂铁(47mg,0.084mmol)和[1,10-双(二苯基膦基)二茂铁]二氯化钯(II)络合物的二氯甲烷(61mg,0.084mmol)混悬剂在80℃下在1,4-二噁烷(10mL)中搅拌12小时。用乙酸乙酯萃取反应混合物,将有机层用盐水洗涤,经无水Na2SO4干燥,并过滤。减压蒸发溶剂,并通过柱色谱用己烷/乙酸乙酯(9/1,v/v)纯化残余物以获得标题化合物(500mg,89%产率)。1H NMR(400MHz,CDCl3)δ6.61-6.57(m,1H),4.21-4.17(m,2H),2.44–2.33(m,1H),2.22–2.13(m,1H),1.48(s,9H),1.30-1.20(m,15H),1.05(d,J=6.4Hz,3H)。
步骤F:顺式-4-(5-氟-2-甲基-4-硝基苯基)-2,6-二甲基-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成
将顺式-2,6-二甲基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(500mg,1.48mmol)、Pd(dppf)Cl2(43mg,0.06mmol)和K2CO3(613mg,4.44mmol)加入到1-溴-5-氟-2-甲基-4-硝基苯(417mg,1.78mmol)的DME-H2O(22mL,10:1混合物)溶液中。在氮气下将混合物在80℃下搅拌12小时。将反应冷却至室温,并用乙酸乙酯萃取产物。减压除去溶剂,并通过硅胶色谱用己烷/乙酸乙酯(9/1,v/v)纯化残余物以得到标题化合物(420mg,78%产率)。1H NMR(400MHz,CDCl3)δ7.89(d,J=7.5Hz,1H),7.00(d,J=11.5Hz,1H),5.87-5.84(m,1H),4.44–4.32(m,2H),2.94–2.84(m,1H),2.35(s,3H),2.11–2.02(m,1H),1.51(s,9H),1.38(d,J=6.4Hz,3H),1.21(d,J=6.4Hz,3H)。
步骤G:顺式-4-(5-异丙氧基-2-甲基-4-硝基苯基)-2,6-二甲基-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成。
向顺式-4-(5-氟-2-甲基-4-硝基苯基)-2,6-二甲基-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(420mg,1.15mmol)的2-丙醇(20mL)溶液中加入Cs2CO3(1.128g,3.46mmol)。将混合物在60℃搅拌过夜,冷却至室温后,减压蒸发大部分2-丙醇。加入水,并用乙酸乙酯萃取溶液。将有机层合并,经Na2SO4干燥,浓缩,并通过硅胶色谱用己烷/乙酸乙酯(9/1,v/v)纯化粗产物以得到标题化合物(450mg,97%),其是微黄色油状物。1H NMR(400MHz,CDCl3)δ7.63(s,1H),6.77(s,1H),5.82-5.79(m,1H),4.63-4.60(m,1H),4.38-4.34(m,2H),2.92-2.87(m,1H),2.27(s,3H),2.11–2.00(m,1H),1.51(s,9H),1.39-1.36(m,9H),1.21(d,J=6.3Hz,3H)。
步骤H:顺式-4-(4-氨基-5-异丙氧基-2-甲基苯基)-2,6-二甲基-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成。
向顺式-4-(5-异丙氧基-2-甲基-4-硝基苯基)-2,6-二甲基-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(230mg,0.569mmol)的乙醇(20mL)溶液中加入几滴10%HCl,然后加入铁粉(191mg,3.42mmol)。将混合物在60℃下搅拌3小时。将反应冷却至室温,并滤出铁粉。减压除去乙醇,并获得标题化合物,其是淡黄色油状物。该产物无需进一步纯化即可直接使用。
步骤I:5-氯-N2-(4-(顺式-2,6-二甲基-1,2,3,6-四氢吡啶-4-基)-2-异丙氧基-5-甲基苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺的合成。
将顺式-4-(4-氨基-5-异丙氧基-2-甲基苯基)-2,6-二甲基-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(213mg,0.57mmol)、2,5-二氯-N-(2-(异丙基磺酰基)苯基)嘧啶-4-胺(197mg,0.57mmol)、Xantphos(33mg,0.057mmol)、Pd(OAc)2(6mg,0.029mmol)和Cs2CO3(555mg,1.71mmol)溶解在无水THF(20mL)中。将N2鼓泡通过反应混合物5分钟,然后将反应容器密封并在微波辐射下加热至150℃达30分钟。过滤混合物,并减压浓缩滤液。将残余物溶于二氯甲烷(5mL)中。加入三氟乙酸(1mL)并将反应在室温下搅拌6小时。真空除去二氯甲烷和三氟乙酸。通过制备型HPLC(梯度为10%至60%乙腈/水)纯化残余物以得到标题化合物(110mg,33%产率)。1H NMR(400MHz,CD3OD)δ8.35(d,J=8.3Hz,1H),8.24(s,1H),7.99(d,J=7.7Hz,1H),7.74(t,J=7.7Hz,1H),7.64(s,1H),7.49(t,J=7.7Hz,1H),6.80(s,1H),5.65–5.59(m,1H),4.65-4.61(m,1H),4.21-4.17(m,1H),3.82-3.78(m,1H),3.41-3.37(m,1H),2.70–2.60(m,1H),2.40-2.36(m,1H),2.12(s,3H),1.54(d,J=6.9Hz,3H),1.49(d,J=6.5Hz,3H),1.33(d,J=6.0Hz,6H),1.26(d,J=6.8Hz,6H)。
实例6
5-氯-N2-(2-异丙氧基-5-甲基-4-((顺式)-1,2,6-三甲基-1,2,3,6-四氢吡啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺的合成(化合物编号10)
步骤A:顺式-4-(5-异丙氧基-2-甲基-4-硝基苯基)-1,2,6-三甲基-1,2,3,6-四氢吡啶的合成。
向顺式-4-(5-异丙氧基-2-甲基-4-硝基苯基)-2,6-二甲基-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(230mg,0.57mmol)的二氯甲烷(5mL)溶液中加入三氟乙酸(1mL),并将反应混合物在室温下搅拌6小时。真空除去二氯甲烷和三氟乙酸,并加入100mL二氯甲烷,用饱和NaHCO3溶液洗涤。将水层用二氯甲烷萃取另外两次(各100mL)。将有机层合并,用盐水洗涤,经Na2SO4干燥并蒸发。将残余物溶于二氯甲烷(10mL)中,然后加入37%甲醛(138mg,1.71mmol)、三乙酰氧基硼氢化钠(181mg,0.855mmol)和乙酸(51mg,0.855mmol)。将反应在室温下搅拌过夜。通过加入水(80mL)将反应淬灭,并用二氯甲烷(3×100mL)萃取。将有机层合并,用盐水洗涤,经Na2SO4干燥,浓缩并通过硅胶柱色谱用乙酸乙酯/甲醇(9/1,v/v)纯化以得到标题化合物(190mg,91%,两步),其是黄色油状物。1H NMR(400MHz,CDCl3)δ7.61(s,1H),6.79(s,1H),5.50-5.46(m,1H),4.60-4.56(m,1H),3.27–3.09(m,2H),2.55-2.51(m,1H),2.43(s,3H),2.25(s,3H),2.01-1.97(m,1H),1.36(dd,J=6.0,2.2Hz,6H),1.21(d,J=6.7Hz,3H),1.12(d,J=6.5Hz,3H)。
步骤B:2-异丙氧基-5-甲基-4-(顺式-1,2,6-三甲基-1,2,3,6-四氢吡啶-4-基)苯胺的合成。
向顺式-4-(5-异丙氧基-2-甲基-4-硝基苯基)-1,2,6-三甲基-1,2,3,6-四氢吡啶(181mg,0.57mmol)的乙醇(20mL)溶液中加入几滴10%HCl,然后加入铁粉(191mg,3.42mmol)。将混合物在60℃下搅拌3小时。将反应冷却至室温,并滤出铁粉。减压除去乙醇,并获得标题化合物,其是黄色油状物。该产物无需进一步纯化即可直接使用。
步骤C:5-氯-N2-(2-异丙氧基-5-甲基-4-(顺式-1,2,6-三甲基-1,2,3,6-四氢吡啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺的合成。
将2-异丙氧基-5-甲基-4-(顺式-1,2,6-三甲基-1,2,3,6-四氢吡啶-4-基)苯胺(164mg,0.57mmol)、2,5-二氯-N-(2-(异丙基磺酰基)苯基)嘧啶-4-胺(197mg,0.57mmol)、Xantphos(33mg,0.057mmol)、Pd(OAc)2(6mg,0.029mmol)和Cs2CO3(555mg,1.71mmol)溶于无水THF(20mL)中。将N2鼓泡通过反应混合物5分钟,然后将反应容器密封并在微波辐射下加热至150℃达30分钟。过滤混合物,并减压浓缩滤液。通过制备型HPLC(梯度为10%至60%乙腈/水)纯化残余物以得到标题化合物(50mg,15%产率)。1H NMR(400MHz,CD3OD)δ8.35(d,J=8.2Hz,1H),8.24(s,1H),7.81-7.89(m,1H),7.76-7.71(m,1H),7.65(s,1H),7.51-7.47(m,1H),6.84(s,1H),5.59-5.57(m,1H),4.68-4.64(m,1H),4.08-3.95(m,2H),3.42–3.36(m,1H),2.97(s,3H),2.81–2.71(m,1H),2.46-2.44(m,1H),2.13(s,3H),1.60(d,J=6.8Hz,3H),1.50(d,J=5.5Hz,3H),1.33(d,J=6.0Hz,6H),1.27(d,J=6.8Hz,6H)。
实例7
5-氯-N2-(4-((顺式)-2,6-二环丙基-1,2,3,6-四氢吡啶-4-基)-2-异丙氧基-5-甲基苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺的合成
(化合物编号15)
步骤A:顺式-2,6-二环丙基-1-(4-甲氧基苄基)哌啶-4-酮的合成。
向丙酮二羧酸(3.0g,20.5mmol)的水(20mL)溶液中加入环丙烷甲醛(2.876g,41mmol)。然后在10分钟内分小份加入4-甲氧基苯基甲胺(2.8g,20.5mmol)。将得到的黄色溶液在室温下搅拌3天。用二氯甲烷(3×60mL)萃取反应混合物。将合并的萃取液用盐水洗涤并用无水Na2SO4干燥。将溶液过滤并蒸发以得到棕色残余物。通过硅胶色谱用己烷/乙酸乙酯(7/1,v/v)分离同分异构的哌啶酮。获得所需标题化合物(34.0g,54%),其是淡黄色油状物。1H NMR(400MHz,CDCl3)δ7.35(d,J=8.6Hz,2H),6.88(d,J=8.6Hz,2H),4.34(d,J=13.9Hz,1H),3.95(d,J=13.9Hz,1H),3.83(s,3H),2.64–2.38(m,6H),0.81-0.77(m,2H),0.71–0.38(m,4H),0.35-0.30(m,2H),0.10-0.03(m,2H)。
步骤B:顺式-2,6-二环丙基哌啶-4-酮的合成。
将顺式-2,6-二环丙基-1-(4-甲氧基苄基)哌啶-4-酮(3.0g,11mmol)溶解在乙醇(20mL)中,并加入催化剂(0.3g,10%Pd-C)。将混合物在氢气氛下搅拌12小时。过滤除去催化剂,并减压蒸发滤液以得到标题化合物(1.52g,91%产率)。该产物无需进一步纯化即可直接用于下一步。
步骤C:顺式-2,6-二环丙基-4-氧代哌啶-1-羧酸叔丁酯的合成。
将二碳酸二叔丁酯(1.73g,7.95mmol)和N,N-二异丙基乙胺(1.71g,13.24mmol)加入到顺式-2,6-二环丙基哌啶-4-酮(1.0g,6.62mmol)的二氯甲烷(20mL)溶液中,并将混合物在室温下搅拌12小时。减压除去溶剂,并通过硅胶色谱用己烷/乙酸乙酯(9/1,v/v)纯化残余物以得到标题化合物(0.85g,51%产率),其是无色油状物。1H NMR(400MHz,CDCl3)δ3.83-3.81(m,2H),2.90(dd,J=17.4,6.0Hz,2H),2.54(dd,J=17.4,2.7Hz,2H),1.52(s,9H),0.91-0.88(m,2H),0.75-0.72(m,2H),0.62–0.43(m,4H),0.18-0.15(m,2H)。
步骤D:顺式-2,6-二环丙基-4-(((三氟甲基)磺酰基)氧基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成。
在-78℃下向顺式-2,6-二环丙基-4-氧代哌啶-1-羧酸叔丁酯(1.7g,6.77mmol)的THF(20mL)溶液中缓慢加入2.0M于THF中的LDA(3.39mL,6.78mmol)。20分钟后,将1,1,1-三氟-N-苯基-N-(三氟甲基磺酰基)甲磺酰胺(2.417g,6.77mmol)的溶液缓慢加入混合物中。在0℃下搅拌反应混合物3小时。减压蒸发溶剂,并通过柱色谱用己烷/乙酸乙酯(20/1,v/v)纯化残余物以获得标题化合物(1.6g,58%产率)。1H NMR(400MHz,CDCl3)δ5.77(d,J=4.7Hz,1H),4.20-4.18(m,1H),2.82-2.84(m,1H),2.73–2.61(m,1H),2.57–2.49(m,1H),1.55-1.53(m,1H),1.49(s,9H),1.09-1.06(m,1H),0.62-0.42(m,6H),0.35–0.25(m,1H),0.22–0.11(m,1H)。
步骤E:顺式-2,6-二环丙基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁基酯的合成。
在80℃下将顺式-2,6-二环丙基-4-(((三氟甲基)磺酰基)氧基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1.6g,4.13mmol)、双(频哪醇合)二硼(1.255mg,4.96mmol)、乙酸钾(1.214mg,12.39mmol)、1,10-双(二苯基膦基)二茂铁(114mg,0.21mmol)和[1,10-双(二苯基膦基)二茂铁]二氯化钯(II)络合物的二氯甲烷(154mg,0.21mmol)混悬剂在1,4-二噁烷(20mL)中搅拌12小时。用乙酸乙酯萃取反应混合物,并用盐水洗涤有机层,经无水Na2SO4干燥并过滤。减压蒸发溶剂,并通过柱色谱用己烷/乙酸乙酯(9/1,v/v)纯化残余物以获得标题化合物(1.6g,99%产率)。1H NMR(400MHz,CDCl3)δ6.49(d,J=4.7Hz,1H),4.07-4.05(m,1H),2.80-2.78(m,1H),2.50–2.38(m,1H),2.30-2.28(m,1H),1.48(s,9H),1.39-1.25(m,1H),1.28(s,12H),1.08-1.00(m,1H),0.55–0.37(m,6H),0.30-0.20(m,1H),0.14-0.05(m,1H)。
步骤F:顺式-2,6-二环丙基-4-(5-氟-2-甲基-4-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成。
将顺式-2,6-二环丙基-4-(4,4,5,5-四甲基-1,3,2-二氧硼杂环戊烷-2-基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(1.35g,3.74mmol)、Pd(dppf)Cl2(109mg,0.15mmol)和K2CO3(1.55g,11.22mmol)加入到1-溴-5-氟-2-甲基-4-硝基苯(1.05g,4.49mmol)的DME-H2O(22mL,10:1混合物)溶液中。在氮气下将混合物在80℃下搅拌12小时。将反应冷却至室温,并用乙酸乙酯萃取产物。减压除去溶剂,通过硅胶色谱用己烷/乙酸乙酯(9/1,v/v)纯化残余物以得到标题化合物(1.20g,77%产率)。1H NMR(400MHz,CDCl3)δ7.90(d,J=7.5Hz,1H),7.04(d,J=11.5Hz,1H),5.80-5.65(m,1H),4.30-4.26(m,1H),3.30-3.20(m,1H),2.65–2.55(m,1H),2.49(dd,J=16.2,5.8Hz,1H),2.37(s,3H),1.53(s,9H),1.40-1.30(m,1H),0.95–0.83(m,1H),0.68–0.49(m,6H),0.35-0.14(m,2H)。
步骤G:顺式-2,6-二环丙基-4-(5-异丙氧基-2-甲基-4-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成。
向顺式-2,6-二环丙基-4-(5-氟-2-甲基-4-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(670mg,1.61mmol)的2-丙醇(20mL)溶液中加入Cs2CO3(1.574g,4.83mmol)。将混合物在60℃搅拌过夜,冷却至室温后,减压蒸发大部分2-丙醇。加入水,并用乙酸乙酯萃取溶液。将有机层合并,经Na2SO4干燥,浓缩,并通过硅胶色谱用己烷/乙酸乙酯(9/1,v/v)纯化粗产物以得到标题化合物(700mg,95%),其是黄色油状物。1H NMR(400MHz,CDCl3)δ7.65(s,1H),6.82(s,1H),5.70-5.66(m,1H),4.66-4.56(m,1H),4.33-4.30(m,1H),3.28-3.20(m,1H),2.67–2.56(m,1H),2.47(dd,J=16.0,5.1Hz,1H),2.28(s,3H),1.53(s,9H),1.42-1.24(m,2H),1.40(d,J=6.0Hz,6H),0.70-0.44(m,6H),0.34–0.25(m,1H),0.20-0.10(m,1H)。
步骤H:顺式-4-(4-氨基-5-异丙氧基-2-甲基苯基)-2,6-二环丙基-3,6-二氢吡啶-1(2H)-羧酸叔丁酯的合成。
向顺式-2,6-二环丙基-4-(5-异丙氧基-2-甲基-4-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(380mg,0.833mmol)的乙醇(20mL)溶液中加入几滴10%HCl,然后加入铁粉(280mg,5.0mmol)。将混合物在60℃下搅拌3小时。将反应冷却至室温,并滤出铁粉。减压除去乙醇,并获得标题化合物,其是淡黄色油状物。该产物无需进一步纯化即可直接使用。
步骤I:5-氯-N2-(4-((顺式)-2,6-二环丙基-1,2,3,6-四氢吡啶-4-基)-2-异丙氧基-5-甲基苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺的合成。
将顺式-4-(4-氨基-5-异丙氧基-2-甲基苯基)-2,6-二环丙基-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(350mg,0.822mmol),2,5-二氯-N-(2-(异丙基磺酰基)苯基)嘧啶-4-胺(283mg,0.822mmol)、Xantphos(48mg,0.0822mmol),Pd(OAc)2(9mg,0.0411mmol),和Cs2CO3(801mg,2.466mmol)溶解在无水THF(20mL)中。将N2鼓泡通过反应混合物5分钟,然后将反应容器密封并在微波辐射下加热至150℃达30分钟。过滤混合物,并减压浓缩滤液。将残余物溶于二氯甲烷(5mL)中。加入三氟乙酸(1mL)并将反应在室温下搅拌6小时。真空除去二氯甲烷和三氟乙酸。通过制备型HPLC(梯度为10%至60%乙腈/水)纯化残余物以得到标题化合物(150mg,29%产率)。1H NMR(400MHz,CD3OD)δ8.36(d,J=8.3Hz,1H),8.24(s,1H),7.99(d,J=8.0,1H),7.79–7.68(m,1H),7.67(s,1H),7.48(t,J=7.7Hz,1H),6.83(s,1H),5.62(s,1H),4.70–4.58(m,1H),3.44–3.35(m,2H),2.90-2.79(m,1H),2.72–2.52(m,2H),2.14(s,3H),1.33(d,J=6.1Hz,6H),1.27(d,J=6.9,6H),1.20-1.03(m,2H),0.84–0.71(m,6H),0.54–0.44(m,2H)。
实例8
5-氯-N2-(4-((顺式)-2,6-二环丙基-1-甲基-1,2,3,6-四氢吡啶-4-基)-2-异丙氧基-5-甲基苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺的合成
(化合物编号16)
步骤A:顺式-2,6-二环丙基-4-(5-异丙氧基-2-甲基-4-硝基苯基)-1-甲基-1,2,3,6-四氢吡啶的合成。
向顺式-2,6-二环丙基-4-(5-异丙氧基-2-甲基-4-硝基苯基)-3,6-二氢吡啶-1(2H)-羧酸叔丁酯(390mg,0.855mmol)的二氯甲烷(5mL)溶液中加入三氟乙酸(1mL),并将反应混合物在室温下搅拌6小时。真空除去二氯甲烷和三氟乙酸,并加入100mL二氯甲烷,用饱和NaHCO3溶液洗涤。将水层用二氯甲烷萃取另外两次(各100mL)。将有机层合并,用盐水洗涤,经Na2SO4干燥并蒸发。将残余物溶于二氯甲烷(10mL)中,然后加入37%甲醛(208mg,2.56mmol)、三乙酰氧基硼氢化钠(290mg,1.368mmol)和乙酸(82mg,1.368mmol)。将反应在室温下搅拌过夜。通过加入水(80mL)将反应淬灭,并用二氯甲烷(3×100mL)萃取。将有机层合并,用盐水洗涤,经Na2SO4干燥,浓缩并通过硅胶柱色谱用乙酸乙酯/甲醇(9/1,v/v)纯化以得到标题化合物(275mg,87%,两步),其是黄色油状物。MS m/z=371(M+H)。
步骤B:4-(顺式-2,6-二环丙基-1-甲基-1,2,3,6-四氢吡啶-4-基)-2-异丙氧基-5-甲基苯胺的合成。
向顺式-2,6-二环丙基-4-(5-异丙氧基-2-甲基-4-硝基苯基)-1-甲基-1,2,3,6-四氢吡啶(370mg,1.0mmol)的乙醇(20mL)溶液中加入几滴10%HCl,然后加入铁粉(336mg,6.0mmol)。将混合物在60℃下搅拌3小时。将反应冷却至室温,并滤出铁粉。减压除去乙醇,并获得标题化合物,其是淡黄色油状物。该产物无需进一步纯化即可直接使用。
步骤C:5-氯-N2-(4-(顺式-2,6-二环丙基-1-甲基-1,2,3,6-四氢吡啶-4-基)-2-异丙氧基-5-甲基苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺的合成。
将4-(顺式-2,6-二环丙基-1-甲基-1,2,3,6-四氢吡啶-4-基)-2-异丙氧基-5-甲基苯胺(270mg,0.794mmol)、2,5-二氯-N-(2-(异丙基磺酰基)苯基)嘧啶-4-胺(274mg,0.794mmol)、Xantphos(46mg,0.0794mmol)、Pd(OAc)2(9mg,0.040mmol)和Cs2CO3(801mg,2.465mmol)溶于无水THF(20mL)中。将N2鼓泡通过反应混合物5分钟,然后将反应容器密封并在微波辐射下加热至150℃达30分钟。过滤混合物,并减压浓缩滤液。通过制备型HPLC(梯度为10%至60%乙腈/水)纯化残余物以得到标题化合物(110mg,21%产率)。MS m/z=650(M+H)。
实例9
体外活性
H3122和Kappas-299细胞购自美国模式培养物集存库(美国,维吉尼亚州,马纳萨斯),并在从初始原种开始后2个月内使用。按推荐培养所有细胞系。对于细胞生长抑制测定,用不同浓度的测试化合物处理细胞,从原种稀释到含有0.2%DMSO作为最终浓度的培养基。使用WST-8细胞增殖测定试剂盒(Dojindo Molecular Technologies)根据制造商的说明测定细胞活力。一式三份进行三次独立实验。使用Prism软件分析数据以确定相对于DMSO对照的50%细胞生长抑制(IC50)值。
表4
实例10
野生型和突变体ALK的抑制
表达为N-末端GST-融合蛋白的野生型人ALK蛋白的胞浆区(氨基酸1058-1620)购自Carna Biosciences公司(日本)。突变的ALK蛋白在SF9昆虫细胞中表达,纯化后切割N末端标签。使用来自Perkin Elmer Life Sciences(沃尔瑟姆,马萨诸塞州)的TR-FRET测定试剂盒评估所有酶的激酶活性。将2.5μL化合物溶液和5μL蛋白质溶液加入至黑色低体积384孔微量滴定板中,将其在室温下温和振荡孵育30分钟,然后加入2.5μL荧光标记的肽底物(ULightTM-IRS-1(Tyr983)肽)和ATP混合物溶液。激酶反应在50mM HEPES(pH 7.5)中进行,其中刚好在测定之前加入1mM EGTA,1mM MgCl2和2mM DTT,0.01%Tween-20。ATP、底物和DMSO的最终浓度分别为100μM、20nM和0.5%。相应地调节不同ALK蛋白的浓度以实现野生型和所有突变的ALK蛋白的相当的酶活性。对于野生型、F1174L、L1196M、S1206Y、G1269A和G1202R,最终ALK浓度分别为1nM、1nM、1nM、128nM、2nM和4nM。使反应在黑暗中在室温下温和振荡进行90分钟,然后加入来自制造商的于检测缓冲液中的10μL的20mM EDTA和2nM Eu-W1024抗磷酸化酪氨酸抗体(PT66)混合物溶液以终止反应并检测肽底物的磷酸化。将最终混合物在黑暗中孵育1小时,然后在Tecan Infinite M-1000多模式读板仪(Tecan,达勒姆,北卡罗来纳州)上读取板,其中激发波长为320nm。在620和665nm处测量发射强度,其中665和620nm之间的强度比对应于肽底物磷酸化。抑制剂的IC50值通过在S形剂量-反应曲线(可变斜率)中用非线性回归拟合665/620nm的比与抑制剂浓度获得。参见表5和6
表5
表6
G1202R | 化合物编号5 | 克唑替尼 | 艾乐替尼 | 色瑞替尼 | 劳拉替尼 | CJ-2360 |
IC<sub>50</sub>(nM) | 9.2 | 46.2 | 34.7 | 11.5±5.0 | 2.1±0.4 | 119 |
实例11
激酶活性
使用来自LeadHunter Discovery Services(目前为DiscoverX Corporation(菲蒙市,CA 94538,美国))的KINOMEscanTM筛选平台筛选化合物编号5对一组人激酶的活性。参见表7。
表7
实例12
药代动力学
在SD大鼠和比格犬中对化合物编号5进行常规药代动力学研究。参见表8和9。
实例13
体内功效
药物制备
将化合物编号5和6溶解在98%PEG200:2%TPGS(Sigma)的溶液中。LDK378(色瑞替尼)是已知的ALK抑制剂。
细胞培养
在37℃,95%空气,5%二氧化碳下,将人淋巴瘤细胞KARPAS 299维持在补充有10%胎牛血清,100单位/ml青霉素和100单位/ml链霉素(GIBCOTM,英杰公司(InvitrogenCorp.))的RPMI 1640培养基中,并每周传代两次。
异种移植肿瘤细胞注射
将用于异种移植的肿瘤细胞在PBS中洗涤两次,并重悬于1:1PBS和Matrigel(BDBiosciences,英杰公司)的冰冷混合物中,最终Matrigel蛋白浓度为5mg/ml。将细胞以5×106个细胞/0.1ml皮下(s.c.)注射到每只小鼠的胁腹区域。将所有肿瘤接种到SCID小鼠(品种:236C.B-17SCID,Charles River)中。
异种移植肿瘤生长和体重监测
使用卡尺在两个维度上测量小鼠中生长的肿瘤的大小。肿瘤体积(mm3)=(AxB2)/2,其中A和B分别是肿瘤长度和宽度(以mm计)。在治疗期间,每周测量三次肿瘤体积和体重。停止治疗后,每周至少测量一次肿瘤体积和体重。
毒性评估和终点
肿瘤不允许超过动物总体重的10%。如果动物有两个或更多个肿瘤,则不允许所有肿瘤的总重量超过动物总体重的10%。在实验期结束时或当肿瘤大小接近总体重的10%时,对动物实施安乐死。对表现出严重发病率或体重减轻超过体重20%的动物实施安乐死。
确定体内抗肿瘤功效
在治疗开始之前,允许肿瘤体积生长至平均150mm3(70-270mm3),此时对肿瘤的血管供应应该已经很好地建立了。将具有可接受大小范围内的肿瘤的小鼠随机分成7只小鼠的治疗组。口服给予药物,每天一次达3周。对照组仅接受媒介物。参见图1。
表8
表9
应理解,前述实施例和示例不旨在在任何方面限制本公开的范围,并且本文提出的权利要求旨在涵盖所有实施例和示例,无论是否在本文中明确呈现。
本文引用的所有专利和出版物均通过引用整体全部并入。
Claims (50)
3.根据权利要求1或2所述的化合物,或其医药学上可接受的盐或溶剂化物,其中R1b和R2b各自是氢。
4.根据权利要求3所述的化合物,或其医药学上可接受的盐或溶剂化物,其中R1a和R2a各自是氢。
5.根据权利要求3所述的化合物,或其医药学上可接受的盐或溶剂化物,其中R1a和R2a各自是C1-4烷基。
6.根据权利要求5所述的化合物,或其医药学上可接受的盐或溶剂化物,其中R1a和R2a各自是甲基。
7.根据权利要求3所述的化合物,或其医药学上可接受的盐或溶剂化物,其中R1a和R2a各自是C3-6环烷基。
8.根据权利要求3所述的化合物,或其医药学上可接受的盐或溶剂化物,其中R1a和R2a各自是环丙基。
9.根据权利要求5至8中任一项所述的化合物,或其医药学上可接受的盐或溶剂化物,其中R1a和R2a具有顺式立体化学关系。
10.根据权利要求5至8中任一项所述的化合物,或其医药学上可接受的盐或溶剂化物,其中R1a和R2a具有反式立体化学关系。
11.根据权利要求1或2所述的化合物,或其医药学上可接受的盐或溶剂化物,其中R1a、R1b、R2a和R2b各自是C1-3烷基。
12.根据权利要求1或2所述的化合物,或其医药学上可接受的盐或溶剂化物,其中R1a、R1b、R2a和R2b各自是甲基。
17.根据权利要求13至16中任一项所述的化合物,或其医药学上可接受的盐或溶剂化物,其中R1a和R2a各自是C1-3烷基。
18.根据权利要求16所述的化合物,或其医药学上可接受的盐或溶剂化物,其中R1a和R2a各自是甲基。
19.根据权利要求13至16中任一项所述的化合物,或其医药学上可接受的盐或溶剂化物,其中R1a和R2a各自是C3-6环烷基。
20.根据权利要求19所述的化合物,或其医药学上可接受的盐或溶剂化物,其中R1a和R2a各自是环丙基。
21.根据权利要求1至20中任一项所述的化合物,或其医药学上可接受的盐或溶剂化物,其中R3为氢。
22.根据权利要求1至20中任一项所述的化合物,或其医药学上可接受的盐或溶剂化物,其中R3为C1-3烷基。
23.根据权利要求22所述的化合物,或其医药学上可接受的盐或溶剂化物,其中R3为甲基。
24.根据权利要求1至20中任一项所述的化合物,或其医药学上可接受的盐或溶剂化物,其中R3为C3-6杂环。
26.根据权利要求1所述的化合物,或其医药学上可接受的盐或水合物,其选自表1中的化合物中的任一种或多种。
27.根据权利要求26所述的化合物,或其医药学上可接受的盐或水合物,其是5-氯-N2-(2-异丙氧基-5-甲基-4-(1-(四氢-2H-吡喃-4-基)-1,2,3,6-四氢吡啶-4-基)苯基)-N4-(2-(异丙基磺酰基)苯基)嘧啶-2,4-二胺。
28.一种药物组合物,其包含根据权利要求1至27中任一项所述的化合物或其医药学上可接受的盐或水合物,以及医药学上可接受的载剂。
29.一种治疗患者的方法,所述方法包含向所述患者投予治疗有效量的根据权利要求1至27中任一项所述的化合物或其医药学上可接受的盐、水合物或溶剂化物,其中所述患者患有癌症、慢性自体免疫性病症、炎性病状或增生性病症。
30.根据权利要求29所述的方法,其中所述患者患有癌症。
31.根据权利要求30所述的方法,其中所述癌症选自表3中的癌症中的任一种或多种。
32.根据权利要求30所述的方法,其中所述癌症选自由以下组成的组:间变性大细胞淋巴瘤、非小细胞肺癌、弥漫性大B细胞淋巴瘤、炎性肌纤维母细胞瘤、神经母细胞瘤、间变性甲状腺癌、横纹肌肉瘤、乳腺癌、结直肠癌、食道鳞状细胞癌和肾细胞癌。
33.根据权利要求29至32中任一项所述的方法,其还包含投予治疗有效量的适用于治疗所述疾病或病状的第二治疗剂。
34.根据权利要求28所述的药物组合物,其用于治疗癌症、慢性自体免疫性病症、炎性病状或增生性病症。
35.根据权利要求34所述的药物组合物,其用于治疗癌症。
36.根据权利要求35所述的药物组合物,其中所述癌症选自表3中的癌症中的任一种或多种。
37.根据权利要求35所述的药物组合物,其中所述癌症选自由以下组成的组:间变性大细胞淋巴瘤、非小细胞肺癌、弥漫性大B细胞淋巴瘤、炎性肌纤维母细胞瘤、神经母细胞瘤、间变性甲状腺癌、横纹肌肉瘤、乳腺癌、结直肠癌、食道鳞状细胞癌和肾细胞癌。
38.根据权利要求1至27中任一项所述的化合物或其医药学上可接受的盐、水合物或溶剂化物,其用于治疗癌症、慢性自体免疫性病症、炎性病状或增生性病症。
39.根据权利要求38所述的化合物,其用于治疗癌症。
40.根据权利要求39所述的化合物,其中所述癌症选自表3中的癌症中的任一种或多种。
41.根据权利要求39所述的化合物,其中所述癌症选自由以下组成的组:间变性大细胞淋巴瘤、非小细胞肺癌、弥漫性大B细胞淋巴瘤、炎性肌纤维母细胞瘤、神经母细胞瘤、间变性甲状腺癌、横纹肌肉瘤、乳腺癌、结直肠癌、食道鳞状细胞癌和肾细胞癌。
42.根据权利要求1至27中任一项所述的化合物或其医药学上可接受的盐、水合物或溶剂化物的用途,其用于制备用以治疗癌症、慢性自体免疫性病症、炎性病状或增生性病症的药物。
43.根据权利要求42所述的用途,其用于治疗癌症。
44.根据权利要求43所述的用途,其中所述癌症选自表3中的癌症中的任一种或多种。
45.根据权利要求43所述的用途,其中所述癌症选自由以下组成的组:间变性大细胞淋巴瘤、非小细胞肺癌、弥漫性大B细胞淋巴瘤、炎性肌纤维母细胞瘤、神经母细胞瘤、间变性甲状腺癌、横纹肌肉瘤、乳腺癌、结直肠癌、食道鳞状细胞癌和肾细胞癌。
46.一种试剂盒,其包含根据权利要求1至27中任一项所述的化合物或其医药学上可接受的盐、水合物或溶剂化物,以及用于向患者投予所述化合物或其医药学上可接受的盐、水合物或溶剂化物的说明,所述患者患有癌症、慢性自体免疫性病症、炎性病状或增生性病症。
47.根据权利要求46所述的试剂盒,其中所述患者患有癌症。
48.根据权利要求47所述的试剂盒,其中所述癌症选自表3中的癌症中的任一种或多种。
49.根据权利要求47所述的试剂盒,其中所述癌症选自由以下组成的组:间变性大细胞淋巴瘤、非小细胞肺癌、弥漫性大B细胞淋巴瘤、炎性肌纤维母细胞瘤、神经母细胞瘤、间变性甲状腺癌、横纹肌肉瘤、乳腺癌、结直肠癌、食道鳞状细胞癌和肾细胞癌。
50.根据权利要求46至49中任一项所述的试剂盒,其还包含一种或多种其它治疗剂。
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BR112019003897A2 (pt) | 2019-05-21 |
CN109715620B (zh) | 2022-05-06 |
US20190175595A1 (en) | 2019-06-13 |
JP2019528307A (ja) | 2019-10-10 |
SG11201901251SA (en) | 2019-03-28 |
JP7094566B2 (ja) | 2022-07-04 |
AU2017319135B2 (en) | 2021-03-18 |
IL264638B (en) | 2021-08-31 |
KR102530871B1 (ko) | 2023-05-09 |
CN109715620A (zh) | 2019-05-03 |
WO2018044767A3 (en) | 2018-04-12 |
US11110090B2 (en) | 2021-09-07 |
EP3504203A2 (en) | 2019-07-03 |
US20200330464A1 (en) | 2020-10-22 |
EP3504203B1 (en) | 2022-09-28 |
JP2022120151A (ja) | 2022-08-17 |
WO2018044767A2 (en) | 2018-03-08 |
MX2019002393A (es) | 2019-07-08 |
MX2022000376A (es) | 2022-02-10 |
KR20190039760A (ko) | 2019-04-15 |
AU2021203098B2 (en) | 2023-05-25 |
EP4001273A2 (en) | 2022-05-25 |
AU2017319135A1 (en) | 2019-04-04 |
EP4001273A3 (en) | 2022-08-24 |
CA3033223A1 (en) | 2018-03-08 |
AU2021203098A1 (en) | 2021-06-10 |
NZ751713A (en) | 2022-07-01 |
US10709705B2 (en) | 2020-07-14 |
SG10201914030UA (en) | 2020-03-30 |
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