CN110294750A - 作为alk抑制剂的5,6-二氢-11h-吲哚并[2,3-b]喹啉-11-酮化合物 - Google Patents
作为alk抑制剂的5,6-二氢-11h-吲哚并[2,3-b]喹啉-11-酮化合物 Download PDFInfo
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- CN110294750A CN110294750A CN201810234363.XA CN201810234363A CN110294750A CN 110294750 A CN110294750 A CN 110294750A CN 201810234363 A CN201810234363 A CN 201810234363A CN 110294750 A CN110294750 A CN 110294750A
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Abstract
本发明提供了式I的化合物:及其药学上可接受的盐和溶剂合物,其中R1a、R1b、R2a、R2b、R3、R4、R5、R6、R7、R8、E、Z和
Description
发明背景
发明领域
本发明提供了间变性淋巴瘤激酶抑制剂以及治疗病症或疾病的方法,其中对间变性淋巴瘤激酶的抑制提供了益处。
背景
间变性淋巴瘤激酶(ALK)作为受体酪氨酸激酶的胰岛素受体大家族一员,已显示参与造血和非造血肿瘤中的肿瘤生成。已报道在神经母细胞瘤和成胶质细胞瘤中全长ALK受体蛋白质异常表达;在间变性大细胞淋巴瘤中存在ALK融合蛋白。ALK融合蛋白的研究也提高了患有ALK-阳性恶性肿瘤的患者的新的治疗方式的可能性。Pulford等,Cell.Mol.Life.Sci.61:2939-2953(2004)。
小分子ALK抑制剂对于治疗其中ALK发挥作用的疾病和病症(包括癌症)具有治疗潜力。Roskoski,Pharmacological Research 68:68-94(2013)。ALK抑制剂参见美国专利8,039,479和WO 2015/130014。
一直以来需要新的药剂(例如小分子)来治疗和/或预防响应ALK抑制的癌症以及其他疾病。
发明概述
在一个方面,本发明提供了式I-V中任一种代表的化合物及其药学上可接受的盐和溶剂合物,统称为“本发明的化合物”。本发明的化合物是ALK抑制剂,因而可用于治疗或预防其中对ALK的抑制提供益处的疾病或病症。
在另一方面,本发明提供了治疗或预防疾病或病症的方法,包括给予需要的对象(例如人)治疗有效量的本发明的化合物。可通过抑制ALK来治疗或预防的感兴趣的疾病或病症是,例如,癌症、慢性自身免疫疾病、炎性病症、增殖性疾病、脓毒血症或病毒感染。还提供了阻止对象中不需要的增殖性细胞增殖(例如癌症中)的方法,包括向处于发生以不需要的增殖性细胞为特征的病症的风险下的对象给予治疗有效量的本发明的化合物。在一些实施方式中,本发明的化合物可以通过诱导细胞凋亡降低不希望的细胞的增殖。
在另一方面,本发明提供了抑制对象ALK的方法,包括给予所述对象有效量的至少一种本发明的化合物。
在另一方面,本发明提供了一种包含本发明的化合物以及赋形剂和/或药学上可接受的运载体的药物组合物。
在另一方面,本发明提供了一种包含本发明的化合物以及赋形剂和/或药学上可接受的运载体的组合物,用于治疗或预防其中对ALK的抑制提供益处的疾病或病症,例如癌症。
在另一方面,本发明提供了一种组合物,包含:(a)本发明的化合物;(b)第二治疗活性剂;和(c)任选的赋形剂和/或药学上可接受的运载体。
在另一方面,本发明提供了一种本发明的化合物,用于治疗或预防感兴趣的疾病或病症,例如癌症。
在另一方面,本发明提供了一种本发明的化合物在制备用于治疗感兴趣疾病或病症(例如癌症)的药物中的应用。
在另一方面,本发明提供了一种药盒,包含本发明的化合物,任选地包含可用于治疗感兴趣疾病或病症的第二治疗剂的包装组合物,以及含有用于治疗疾病或病症(例如癌症)的说明的包装插入页。
在另一方面,本发明提供了制备本发明的化合物的方法。
本发明的其它实施方式和优点将在以下描述中指出,并将来自该描述,或者可通过本发明的实践进行了解。借助所附权利要求中特别指出的要素和组合,将会认识和实现本发明的实施方式和优点。
应理解,上文的内容和下文的详细描述都只是示例和说明性的,不构成对要求保护的本发明的限制。
发明详述
本发明的化合物是ALK抑制剂。在一个实施方式中,本发明的化合物是具有式I的化合物:
及其药学上可接受的盐和溶剂合物,
式中:
R1a和R1b独立地选自:氢、C1-6烷基和C3-6环烷基;或者
R1a和R1b与它们连接的碳原子一起形成3-6元任选取代的环烷基;或者
R1a和R1b与它们连接的碳原子一起形成4-6元杂环基;
R2a和R2b独立地选自:氢、C1-6烷基和C3-6环烷基;或者
R2a和R2b与它们连接的碳原子一起形成3-6元环烷基;或者
R2a和R2b与它们连接的碳原子一起形成4-6元杂环基;或者
Z选自:-N-和-C(H)-;
R3选自:氢、C1-6烷基、C3-6环烷基和任选取代的4-8元杂环基;
R4选自:氢、C1-6烷基、C1-4烷氧基和4-8元杂烷基;
R5选自:氢、氟和氯;
R6选自:氢、C1-6烷基、C3-6环烷基、4-8元杂环基;
R7选自:氢、-CF3、-NO2和-CN;
R8选自:氢,氟和氯;
E是碳原子且是双键;或者
E是-C(H)-且是单键;或者
E是氮原子且是单键。
在另一实施方式中,本发明的化合物是具有式I的化合物及其药学上可接受的盐和溶剂合物,式中,R5和R8中至少一个选自:氟和氯。
在另一实施方式中,本发明的化合物是式II的化合物:
及其药学上可接受的盐和溶剂合物,式中,R1a、R1b、R2a、R2b、R3、R4、E、Z和如式I中所定义。
在另一实施方式中,本发明的化合物是具有式III的化合物:
及其药学上可接受的盐和溶剂合物,式中,R1a、R1b、R2a、R2b、R3和R4如式I中所定义。
在另一实施方式中,本发明的化合物是具有式IV的化合物代表的化合物:
及其药学上可接受的盐和溶剂合物,式中,R1a、R1b、R2a、R2b、R3和R4如式I中所定义。
在另一实施方式中,本发明的化合物是具有式I-IV中任一项的化合物及其药学上可接受的盐和溶剂合物,式中,R4选自:-OMe和-OiPr。
在另一实施方式中,本发明的化合物是式V的化合物:
及其药学上可接受的盐和溶剂合物,式中,R1a、R1b、R2a、R2b、R3和R4如式I中所定义。
在另一实施方式中,本发明的化合物是具有式I或V的化合物及其药学上可接受的盐和溶剂合物,式中,R4选自:C1-4烷氧基和4-8元杂烷基。
在另一实施方式中,本发明的化合物是具有式I或V的化合物及其药学上可接受的盐和溶剂合物,式中,R4是-OCH2CH2OCH3。
在另一实施方式中,本发明的化合物是具有式I-V中任一项的化合物及其药学上可接受的盐和溶剂合物,式中,R1a和R1b独立地选自:氢和甲基。
在另一实施方式中,本发明的化合物是具有式I-V中任一项的化合物及其药学上可接受的盐和溶剂合物,式中,R2a和R2b独立地选自:氢和甲基。
在另一实施方式中,本发明的化合物是具有式I-V中任一项的化合物及其药学上可接受的盐和溶剂合物,式中,R1a和R2a是甲基且R1b和R2b是氢。
在另一实施方式中,本发明的化合物是具有式I-V中任一项的化合物及其药学上可接受的盐和溶剂合物,式中,R1a,R1b,R2a和R2b是氢。
在另一实施方式中,本发明的化合物是具有式I-V中任一项的化合物及其药学上可接受的盐和溶剂合物,式中,R1a,R1b,R2a和R2b是甲基。
在另一实施方式中,本发明的化合物是具有式I-V中任一项的化合物及其药学上可接受的盐和溶剂合物,式中,R3选自:C1-4烷基和任选取代的4-8元杂环基。
在另一实施方式中,本发明的化合物是具有式I-V中任一项的化合物及其药学上可接受的盐和溶剂合物,式中,R3是C1-4烷基。
在另一实施方式中,本发明的化合物是具有式I-V中任一项的化合物及其药学上可接受的盐和溶剂合物,式中,R3是4-8元杂环基。在另一实施方式中,R3选自:
在另一实施方式中,本发明的化合物是表1的化合物及其药学上可接受的盐和溶剂合物。
表1
本发明的化合物抑制ALK,可用于治疗或预防各种疾病和病症。具体说,本发明的化合物可用于治疗或预防其中通过抑制ALK提供益处的疾病或病症(例如癌症和增殖性疾病)的方法中。本发明的治疗方法包括给予需要的对象治疗有效量的本发明的化合物。本发明的方法还包括除了本发明的化合物之外给予需要的对象第二治疗剂。所述第二治疗剂选自:已知可用于治疗影响有此需要的对象的疾病或病症,例如已知可用于治疗特定癌症的化疗药物和/或辐射。
某些本发明的化合物可以是立体异构体,即仅仅在原子的空间排布上存在差异的异构体,包括光学异构体和构象异构体和互变异构体。本发明包括所有的立体异构体,作为纯的单独的立体异构体制剂以及富含各自异构体的制剂,这些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已知的方法拆分的单独的非对映异构体和对映异构体。
本文所用术语“立体异构体”是仅在原子的空间排布上具有差异的单个分子的全部异构体的统称。其包括对映异构体以及具有超过一个相互间不是镜像图像的手性中心的化合物的异构体(非对映异构体)。
术语“手性中心”或“不对称碳原子”指连有四个不同基团的碳原子。
术语“对映异构体”和“对映异构”指无法与其镜像叠加从而具有光学活性的分子,其中对映异构体以某一方向旋转偏振光平面,而其镜像化合物以相反方向旋转偏振光平面。
术语“外消旋”或“外消旋物”指具有等量对映异构体的混合物且该混合物不具光学活性
术语“绝对构型”指手性分子实体(或基团)的原子的空间排布及其立体化学描述,例如R或S。
除非另有说明,说明书中使用的立体化学术语和惯例与Pure&Appl.Chem68:2193(1996)中描述的相一致。
术语“对映异构体过量”或“ee”表示衡量一种对映异构体相对于另一种对映异构体的多少。对于R和S对映异构体的混合物,对映异构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,R+S=1。已知手性物质的光学旋转,对映异构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光学旋转,[α]max是纯的对映异构体的光学旋转。采用各种分析技术可以确定对映异构体过量,包括NMR光谱,手性柱色谱或光学偏振测量。
术语“对映异构纯”或“对映异构体纯”指其所有分子具有相同手性含义(在检测限内)的手性物质的样品。
术语“富含对映异构”或“富含对映异构体”指对映异构体比率大于50:50的手性物质的样品。富含对映异构体的化合物可以是对映异构体纯的。
本发明包括同位素标记(即放射标记)的任意本发明的化合物,其中一个或多个原子被不同的原子质量或质量数取代。可掺入本发明的化合物的同位素的示例包括:氢、碳、氮、硫、氧、氟和氯的同位素,例如2H(或氘(D))、3H、11C、13C、14C、15N、18O、17O、35S、18F和36Cl,如2H、3H和13C。在一个实施方式中,本发明的化合物中一部分的原子被取代,即本发明的化合物富含具有不同原子质量或质量数的原子。在一个实施方式中,至少约1%的原子被具有不同原子质量或质量数的原子取代。在另一实施方式中,至少约5%,至少约10%,至少约15%,至少约20%,至少约25%,至少约30%,至少约35%,至少约40%,至少约45%,至少约50%,至少约55%,至少约60%,至少约65%,至少约70%,至少约75%,至少约80%,至少约85%,至少约90%,至少约95%,或至少约100%的原子被具有不同原子质量或质量数的原子取代。例如,式I-V中任一项的化合物中R3是甲基,甲基上的一个、两个或三个氢原子被氘取代,分别得到-CH2D,-CHD2或-CD3。同位素标记的本发明的化合物可以通过本领域已知的方法制备。
本发明的化合物的盐、水合物和溶剂合物也可用于本文所述的方法。本发明涉及本发明的化合物的盐的制备和应用。本发明中,“药学上可接受的盐”指本发明的化合物的盐或两性离子形式。本发明的化合物的盐可在这些化合物的最终分离和纯化期间制备,或通过使化合物与具有合适阳离子的酸反应来单独制备。本发明的化合物的药学上可接受的盐可以是与药学上可接受的酸形成的酸加成盐。可用于形成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)。本发明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、樟脑烷磺酸盐、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、均三甲基苯磺酸盐、亚萘基磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、双羟萘酸盐(pamoate)、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、十一烷酸盐、乳酸盐、柠檬酸盐、酒石酸盐、葡萄糖酸盐、甲磺酸盐、乙二磺酸盐、苯磺酸盐和对甲苯磺酸盐。此外,本发明的化合物存在的可用氨基基团可以被以下基团季铵化:氯代、溴代和碘代的甲基、乙基、丙基和丁基;硫酸盐化二甲基、二乙基、二丙基、二丁基和二戊基;氯代、溴代和碘代的癸基、月桂基、肉豆蔻基和甾醇基(steryl);以及溴代的苄基和苯乙基。鉴于前文,在本文中提及本发明的化合物时都包括本发明的化合物及其药学上可接受的盐、水合物或溶剂合物。
本发明涉及本发明的化合物的溶剂合物的制备和应用。溶剂合物通常不会显著改变化合物的生理学活性或毒性,因此可用作药理学等价物。本文中的术语“溶剂合物”是本发明的化合物与溶剂分子的组合、物理缔合和/或溶剂化,例如二溶剂合物、单溶剂合物或半溶剂合物,其中,溶剂分子与本发明的化合物的比率分别约为2:1、1:1或1:2。这种物理缔合涉及不同程度的离子和共价键,包括氢键。在某些情况下,例如当一个或多个溶剂分子掺入结晶固体的晶格中时,可以分离出溶剂合物。因此,“溶剂合物”包括溶液相和可分离的溶剂化物。本发明的化合物可以是与药学上可接受的溶剂形成的溶剂合物的形式,所述药学上可接受的溶剂例如是水、甲醇和乙醇,本发明旨在包括本发明的化合物的溶剂合物和非溶剂合物形式。
一种类型的溶剂合物是水合物。“水合物”指溶剂分子是水的溶剂合物的具体亚群。溶剂合物通常可以用作药理学等价物。溶剂合物的制备是本领域已知的。参见例如,M.Caira等,J.Pharmaceut.Sci.,93(3):601-611(2004),其描述了氟康唑与乙酸乙酯和水的溶剂合物的制备。溶剂合物、半溶剂合物、水合物等的类似制备参见van Tonder等,AAPSPharm.Sci.Tech.,5(1):Article 12(2004)和A.L.Bingham等,Chem.Commun.603-604(2001)。制备溶剂合物的常规非限制性方法包括将本发明的化合物在大于20℃至约25℃的温度下溶解在期望的溶剂(有机溶剂、水、或其混合物),然后以足以形成结晶的速率冷却溶液,以及通过已知的方法(例如过滤)分离结晶。分析技术(例如红外光谱)可用于验证溶剂合物的结晶中溶剂的存在。
本发明提供了作为ALK抑制剂的本发明的化合物用于治疗其中对ALK的抑制具有有益效果的各种疾病和病症。通常,本发明的化合物与ALK的结合亲和力(IC50)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。在一个实施方式中,本发明涉及治疗患有其中对ALK的抑制提供益处的疾病或病症的对象的方法,包括向有此需要的对象给予治疗有效量的本发明的化合物。
由于本发明的化合物是ALK抑制剂,采用这些化合物可以治疗许多ALK介导的疾病和病症。因此,本发明通常涉及一种在患有疾病或病症,或者存在患有所述疾病或病症风险的动物(例如人类患者)中,治疗对ALK或其亚型或突变体的抑制有响应的的疾病或病症的方法,所述方法包括给予所述动物有效量的一种或多种本发明的化合物。
本发明进一步涉及一种在需要的动物中抑制ALK或其亚型或突变体的方法,所述方法包括给予所述动物有效量的至少一种本发明的化合物。
本发明的方法可通过给予纯化合物或药物组合物形式的本发明的化合物来实现。可在感兴趣的疾病或病症期间或开始后进行本发明的化合物的药物组合物或纯化合物的给药。通常,该药物组合物是无菌的,且不含有给药时会导致不良反应的毒性、致癌或诱变化合物。
还提供了药盒,其包含本发明的化合物和任选的用于治疗其中对ALK的抑制提供益处的疾病和病症的第二治疗剂,其单独包装或包装在一起,还包含具有使用这些活性剂的说明的插入页。
在一个实施方式中,本发明的化合物与用于治疗其中ALK蛋白的抑制提供益处的疾病或病症的第二治疗剂共同给予。该第二治疗剂不同于本发明的化合物。本发明的化合物和第二治疗剂可同时或依次给予以实现所需效果。此外,本发明的化合物和第二治疗剂可从单个组合物或两个单独的组合物中给予。
第二治疗剂的给药量提供了其所需的治疗效果。各种第二治疗剂的有效剂量范围是本领域已知的,并在这类已建立的范围内将第二治疗剂给予有此需要的对象。
本发明的化合物和第二治疗剂可作为单一单位剂量共同给予或作为多单位剂量单独给予,其中,本发明的化合物在第二治疗剂之前给药,反之亦然。可给予一次或多次剂量的本发明的化合物和/或一次或多次剂量的第二治疗剂。因此,本发明的化合物可与一种或多种第二治疗剂联用,例如但不限于抗癌剂。
可提供本发明的方法治疗的疾病和病症包括但不限于:癌症和其他增殖性疾病、炎性疾病、脓毒血症、自身免疫疾病和病毒感染。在一个实施方式中,可通过本发明的方法治疗的疾病和病症是癌症、慢性自身免疫疾病、炎性病症或增殖性疾病。在一个实施方式中,采用本发明的化合物,或包含本发明的化合物的药物组合物治疗人患者,其中,所述化合物以足以在患者中抑制ALK的量给予。
在一个实施方式中,待使用本发明的化合物治疗或预防的疾病是癌症。在另一实施方式中,本发明提供了一种在需要的对象中治疗或预防癌症的方法,包括给予所述对象治疗有效量的本发明的化合物。虽然不受具体机制的限制,在一些实施方式中,本发明的化合物能通过抑制ALK治疗或预防癌症。可治疗的癌症的例子包括但不限于表2所示的癌症中的任一种或多种。
表2
在另一实施方式中,癌症是白血病,例如选自急性单核细胞白血病,急性粒细胞白血病、慢性粒细胞白血病、慢性淋巴细胞白血病和混合系白血病(MLL)的白血病。在另一实施方式中,癌症是NUT-中线癌。在另一实施方式中,癌症是多发性骨髓瘤。在另一实施方式中,癌症是肺癌,例如小细胞肺癌(SCLC)。在另一实施方式中,癌症是神经母细胞瘤。在另一实施方式中,癌症是伯基特淋巴瘤。在另一实施方式中,癌症是宫颈癌。在另一实施方式中,癌症是食道癌。在另一实施方式中,癌症是卵巢癌。在另一实施方式中,癌症是结直肠癌。在另一实施方式中,癌症是前列腺癌。在另一实施方式中,癌症是乳腺癌。
在另一实施方式中,癌症是间变性大细胞淋巴瘤,非小细胞肺癌,弥散性大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。
在另一实施方式中,癌症是乳腺癌,结直肠癌,食道鳞状细胞癌和肾细胞癌。
在另一个实施方式中,本发明提供了治疗良性增殖性疾病的方法,所述良性增殖性疾病是例如但不限于:良性软组织肿瘤、骨瘤、脑和脊髓瘤、眼睑和眼眶瘤、肉芽肿瘤、脂肪瘤、脑膜瘤、多发性内分泌瘤、鼻息肉、垂体瘤、泌乳素瘤、假性脑瘤、脂漏性角化症、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、卡斯曼病、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。
本发明的化合物和方法还通过向需要这类治疗的哺乳动物(特别是人)给予有效量的本发明的化合物来治疗感染性和非感染性炎性事件和自身免疫和其他炎性疾病。使用本发明的化合物和方法治疗的自身免疫和炎性疾病、病症和综合征的示例包括:盆腔炎、尿道炎、皮肤晒斑、窦炎、肺炎、脑炎、脑膜瘤、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、丙种球蛋白缺乏血症、牛皮癣、过敏、克罗恩氏病、肠道易激综合症、溃疡性结肠炎、干燥综合征、组织移植排斥、移植器官的超急性排斥、哮喘、过敏性鼻炎、慢性阻塞性肺病(COPD)、自身免疫性多腺病(也称作自身免疫性多腺综合征)、自身免疫性落髪、恶性贫血、肾小球性肾炎、皮肌炎、多发性硬化、硬皮病、血管炎、自身免疫溶血和血小板减少状态、古德帕斯彻氏综合征、动脉粥样硬化、爱迪生氏病、帕金森病、阿尔茨海默病、I型糖尿病、败血性休克、系统性红斑狼疮(SLE)、类风湿性关节炎、牛皮癣性关节炎、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、特异性皮炎、退行性关节病、白癜风、自身免疫垂体机能减退、格林-巴利综合征、白塞氏病、硬化病(scleracierma)、蕈样真菌病、急性炎性应答(如急性呼吸窘迫综合征和缺血/再灌注损伤),和格雷夫斯氏病。
在另一实施方式中,本发明提供了治疗系统性炎性应答综合征(如LPS诱导的内毒素性休克和/或细菌诱导的脓毒血症)的方法,具体方法为向需要这类治疗的哺乳动物(特别是人)给予有效量的本发明的化合物。
在另一实施方式中,本发明提供了一种用于治疗病毒感染和疾病的方法。使用本发明所述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:人乳头瘤病毒、疱疹病毒、爱波斯坦-巴尔病毒、人免疫缺陷病毒、乙型肝炎病毒和丙型肝炎病毒。
在另一实施方式中,提供了在上文所述疾病(特别是癌症、炎性疾病和/或病毒疾病)中调控体内蛋白质甲基化、基因表达、细胞增殖、细胞分化和/或凋亡的方法,具体方法为向需要这类治疗的对象给予治疗有效量的一种或多种本发明的化合物。
在另一实施方式中,本发明提供了一种通过使细胞与本发明的化合物接触调节内源或异源启动子活性的方法。
在本发明的方法中,将治疗有效量的本发明的化合物(根据药学实践配制)给予有此需要的人。是否指示这类治疗取决于个体病例并需要进行医疗评估(诊断),其考虑存在的迹象、症状和/或功能紊乱、发生特定迹象、症状和/或功能紊乱的风险,以及其他因素。
本发明的化合物可通过任何合适途径给予,例如通过口服、经颊、吸入、舌下、直肠、阴道、脑池内或鞘内(通过腰椎穿刺)、经尿道、经鼻、经皮(即透皮)或胃肠道外(包括静脉内、肌内、皮下、冠状动脉内、皮内、乳房内、腹膜内、关节腔内、鞘内、眼球后、肺内注射和/或外科植入特定位点)给药。可使用针或注射器或使用高压技术来实现胃肠道外给药。
药物组合物包括其中本发明的化合物以有效量给予以实现其预定目的的那些。可以由单个医师根据诊断的疾病或病症选择确切的制剂、给药途径和剂量。可单独调节剂量和间隔以提供足以维持疗效的本发明的化合物的水平。
可在细胞培养物或实验动物中通过药学方法测定本发明的化合物的毒性和疗效,例如,用于确定某种化合物的最大耐受剂量(MTD),其定义为在动物中不导致毒性的最高剂量。最大耐受剂量和治疗效果(例如抑制肿瘤生长)之间的剂量比例是治疗指数。该剂量可根据所用的剂型和所用的给药途径在此范围内变化。治疗有效量的测定在本领域技术范围内,尤其是在本发明的详细公开内容的教导下。
治疗所需的本发明的化合物的治疗有效量根据待治疗病症的性质、活性所需时间的长度和患者的年龄和状态而变化,并最终由参与的医师确定。可单独调节剂量和间隔以提供足以维持所需疗效的ALK抑制剂的血浆水平。所需剂量可容易地在单个剂量中给予,或以适当间隔作为多重剂量给予,例如每天1、2、3、4或更多次子剂量。通常需要多次剂量。例如,可以以下频率给予本发明的化合物:以四天间隔每天一次剂量递送四次剂量(q4d x4);以三天间隔每天一次剂量递送四次剂量(q3d x 4);以五天间隔每天递送一次剂量(qdx 5);每周一次剂量持续三周(qwk3);五次每日剂量,间隔两天,再给予五次每日剂量(5/2/5);或根据实际情况确定的任何剂量方案。
本发明的方法中使用的本发明的化合物的给药剂量可以是约0.005至约500毫克/剂量,约0.05至约250毫克/剂量,或约0.5至约100毫克/剂量。例如,本发明的化合物的给药剂量可以是约0.005、0.05、0.5、5、10、20、30、40、50、100、150、200、250、300、350、400、450或500毫克/剂量,包括0.005至500毫克之间的所有剂量。
含有本发明的化合物的组合物或含有同一物质的组合物的剂量可以是约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意剂量,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或更高。上述剂量是平均情况的示例,但也存在应使用较高或较低剂量的单独情况,这类剂量也在本发明的范围内。实践中,医师确定最适用于个体对象(即患者)的试剂剂量方案,其可随具体患者的年龄、体重和应答变化。
如上文所述,本发明的化合物可与第二治疗活性剂联用。在一些实施方式中,该第二治疗剂是表观遗传药物。本文中,术语“表观遗传药物”指靶向表观遗传调控因子的治疗剂。表观遗传调控因子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。
在另一个实施方式中,化疗剂或其他抗增殖剂可与本发明的化合物联用以治疗增殖性疾病和癌症。可与本发明的化合物联用的治疗和抗癌剂的示例包括手术、放疗(例如γ-辐射、中子束辐射、电子束辐射、质子治疗、近程治疗和系统性放射性同位素)、内分泌治疗、生物应答改性剂(例如干扰素、白介素、肿瘤坏死因子(TNF))、高热和冷冻疗法、减弱任何不良作用的试剂(如止吐药)和任何其他批准的化疗药物。
抗增殖化合物的示例包括但不限于:芳香酶抑制剂;抗雌激素;抗雄激素;促性激素释放素激动剂;拓扑异构酶I抑制剂;拓扑异构酶II抑制剂;微管激活剂;烷化剂;类视黄醇、类胡萝卜素或生育酚;环加氧酶抑制剂;MMP抑制剂;mTOR抑制剂;抗代谢剂;铂化合物;甲硫氨酸氨基肽酶抑制剂;双磷酸盐;抗增殖性抗体;类肝素酶抑制剂;Ras癌基因同种型抑制剂;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,或任何其他抗血管原性化合物。
非限制性示例性芳香酶抑制剂包括但不限于:类固醇(如阿他美坦、依西美坦和福司曲星),以及非类固醇(如氨鲁米特(aminoglutethimide)、罗利米特(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)。
非限制性抗雌激素包括但不限于: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。促性激素释放素激动剂包括但不限于阿巴瑞克、戈舍瑞林和乙酸戈舍瑞林。
例举的拓扑异构酶I抑制剂包括但不限于:拓扑替康、吉马替康、伊立替康、喜树碱和其类似物、9-硝基喜树碱、和大分子喜树碱共轭物PNU-166148。拓扑异构酶II抑制剂包括但不限于:蒽环类抗生素(如阿霉素、柔红霉素、表柔比星、伊达比星和奈莫柔比星);蒽醌(如米托蒽醌和洛索蒽醌);以及鬼臼乙叉戒类(podophillotoxines)(如依托泊甙和替尼泊苷)。
微管活性剂包括微管稳定、微管去稳定化合物和微管聚合抑制剂,包括但不限于:紫杉烷(如紫杉醇和多西他赛);长春花生物碱(如长春花碱、硫酸长春花碱、长春新碱和硫酸长春新碱,以及长春瑞滨);淅皮海绵内酯;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,如卡莫司汀和洛莫司汀。
示例性非限制性环加氧酶抑制剂包括Cox-2抑制剂、5-烷基取代的2-芳基氨基苯乙酸及其衍生物,如塞来考昔、罗非考昔、依托考昔、伐地考昔或5-烷基-2-芳基氨基苯乙酸,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”)包括胶原拟肽和非拟肽抑制剂、四环素衍生物、巴马司他、马立马司他、普啉司他、梅塔司他、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的雷帕霉素(mTOR)靶标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)、氨甲蝶呤和依达曲沙以及叶酸拮抗剂(如培美曲塞)。
示例性非限制性铂化合物包括卡铂、顺-铂(cis-platin)、顺铂(cisplatinum)和奥沙利铂。
示例性非限制性甲硫氨酸氨基肽酶抑制剂包括苯甲酰胺或其衍生物和PPI-2458。
示例性非限制性双磷酸盐包括埃区膦酸(etridonic acid)、氯屈膦酸、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。
示例性非限制性抗增殖性抗体包括曲妥珠单抗、曲妥珠单抗-DMl、西妥昔单抗、贝伐单抗、利妥昔单抗、PR064553和2C4。术语“抗体”旨在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,前提是其具有所需生物活性。
示例性非限制性类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。
本文中,术语“Ras癌基因异构体的抑制剂”(如H-Ras、K-Ras或N-Ras)指靶向、降低或抑制Ras的癌基因活性的化合物,例如法尼基转移酶抑制剂,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,如端粒酶抑素(telomestatin)。
示例性非限制性蛋白酶体抑制剂包括靶向、降低或抑制端粒酶活性的化合物,包括但不限于硼替佐米。
本文中,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,其是靶向、降低或抑制FMS样酪氨酸激酶受体(Flt-3R)的化合物;干扰素、Ι-β-D-阿拉伯呋喃胞嘧啶(ara-c)和二硫酸酐(bisulfan);以及ALK抑制剂,其是靶向、降低或抑制间变性淋巴瘤激酶的化合物。
示例性非限制性Flt-3抑制剂包括PKC412、米哚妥林、十字孢碱衍生物、SU11248和MLN518。
示例性非限制性HSP90抑制剂包括靶向、降低或抑制HSP90的内源性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(clientprotein)的化合物。靶向、降低或抑制HSP90的内源性ATP酶活性的化合物具体而言是抑制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-去甲氧格尔德霉素(17AAG),一种格尔德霉素衍生物;其他格尔德霉素相关化合物;根赤壳菌素和HDAC抑制剂。
本文中,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;或任何其他抗血管原性化合物”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的生长因子受体(PDGFR)的活性的化合物,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)的活性的化合物;c)靶向、降低或抑制胰岛素样生长因子受体I(IGF-IR)的活性的化合物,如靶向、降低或抑制IGF-IR的活性的化合物;d)靶向、降低或抑制Trk受体酪氨酸激酶家族的活性的化合物,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的活性的化合物;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,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,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(如Bcr-Abl激酶)和突变体的活性的化合物,如N-苯基-2-嘧啶-胺衍生物,如伊马替尼或尼洛替尼;PD180970;AG957;NSC680410;PD173955;或达沙替尼;j)靶向、降低或抑制丝氨酸/苏氨酸激酶的蛋白质激酶C(PKC)和Raf家族成员,MEK、SRC、JAK、FAK、PDK1、PKB/Akt和Ras/MAPK家族成员,和/或细胞周期素依赖性激酶家族(CDK)成员的活性的化合物,如通过引用纳入本文的美国专利号5,093,330公开的星形孢菌素衍生物,如米哚妥林;其他化合物的示例包括:UCN-01、沙芬戈、BAY 43-9006、苔藓抑素1、哌立福辛;伊莫福新;RO 318220和RO 320432;GO 6976;lsis3521;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的活性的化合物,如甲磺酸伊马替尼或酪氨酸磷酸化抑制剂,如酪氨酸磷酸化抑制剂A23/RG-50810;AG 99;酪氨酸磷酸化抑制剂AG213;酪氨酸磷酸化抑制剂AG 1748;酪氨酸磷酸化抑制剂AG 490;酪氨酸磷酸化抑制剂B44;酪氨酸磷酸化抑制剂B44(+)对映异构体;酪氨酸磷酸化抑制剂AG 555;AG 494;酪氨酸磷酸化抑制剂AG 556、AG957和阿达斯廷(adaphostin)(4-{[(2,5-二羟基苯基)甲基]氨基}-苯甲酸金刚烷基酯;NSC 680410,阿达斯廷);1)靶向、降低或抑制受体酪氨酸激酶的表皮生长因子家族(同源二聚体和异源二聚体形式的EGFR、ErbB2、ErbB3、ErbB4)及其突变体的活性的化合物,例如CP 358774、ZD 1839、ZM 105180;曲妥珠单抗、西妥昔单抗、吉非替尼、埃罗替尼、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,以及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的示例性化合物包括磷酸酶1、磷酸酶2A或CDC25的抑制剂,如冈田酸或其衍生物。
其他的抗血管原性化合物包括具有与蛋白质或脂质激酶抑制无关的其他活性机制的化合物,例如沙利度胺和TNP-470。
此外,一种或多种非限制性示例性化疗化合物可与本发明的ALK抑制剂联用,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-lH-异吲哚-l,3-二酮衍生物、l-(4-氯苯胺基)-4-(4-吡啶甲基)酞嗪或其药学上可接受的盐、1-(4-氯苯胺基)-4-(4-吡啶甲基)酞嗪琥珀酸酯/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、马库刚(macugon);FLT-4抑制剂、FLT-3抑制剂、VEGFR-2IgGI抗体、RPI 4610、贝伐单抗、卟吩姆钠、阿奈可他、去炎松、氢化可的松、11-a-泛氢皮质醇(epihydrocotisol)、皮质龙(cortex olone)、17a-羟孕酮、皮质酮、去氧皮质酮、睾酮、雌酮、地塞米松、氟轻松、植物生物碱、激素化合物和/或拮抗剂、生物应答改性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(其一种或多种也可与本发明的ALK抑制剂联用)的其他示例包括但不限于:针对阿尔茨海默病的治疗物,如多奈哌齐和利凡斯的明;针对帕金森病的治疗物,如L-DOPA/卡比多巴、恩他卡朋、罗比罗(ropinrole)、普拉克索、溴麦角环肽、培高利特、三己芬迪和金刚烷胺;用于治疗多发性硬化(MS)的试剂,如β干扰素(如和)、醋酸格拉替雷和米托蒽醌;针对哮喘的治疗物,如沙丁胺醇和孟鲁司特;针对精神分裂症的治疗物,如再普乐、维思通、思瑞康和氟哌啶醇;抗炎剂,如皮质类固醇、TNF阻断剂、IL-1RA、硫唑嘌呤、环磷酰胺和柳氮磺吡啶;免疫调节剂,包括免疫抑制剂,如环孢菌素、他克莫司、雷帕霉素、麦考酚酸吗乙酯、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,如乙酰胆碱酯酶抑制剂、MAO抑制剂、干扰素、抗惊厥剂、离子通道阻断剂、利鲁唑或抗帕金森剂;用于治疗心血管疾病的试剂,如β-阻断剂、ACE抑制剂、利尿剂、硝酸盐、钙通道阻断剂或他汀;用于治疗肝疾病的试剂,如皮质类固醇、考来替泊、干扰素和抗病毒剂;用于治疗血液疾病的试剂,例如皮质类固醇、抗白血病剂或生长因子;或者用于治疗免疫缺陷疾病的试剂,如γ球蛋白。
可如本领域所述制备和给予上述第二治疗剂(其一种或多种可与本发明的结构式(I)的化合物联用)。
本发明的化合物填充与药物运载体混合给药,所述药物运载体根据预定给药途径和标准药物实践选择。可使用一种或多种生理上可接受的运载体以常规方式配制用于本发明的药物组合物,所述运载体包括促进本发明的化合物的加工的赋形剂和助剂。
这些药物组合物可通过例如常规的混合、溶解、造粒、制造糖衣丸、乳化、封装、包封或冻干工艺进行制造。适当的制剂依赖于所选的给药途径。当仅给予治疗有效量的本发明的化合物时,该组合物的形式通常是片剂、胶囊、溶液、粉末或酏剂。以片剂形式给予时,该组合物还可含有固体运载体,如明胶或佐剂。片剂、胶囊剂和粉末剂含有约0.01%至约95%,且优选约1%至约50%的本发明的化合物。以液体形式给予时,可添加液体运载体,如水、石油或动物或植物来源的油。液体形式的组合物还可含有生理盐水溶液、右旋糖或其他糖溶液或甘油。以液体形式给予时,该组合物可含有含有约0.1重量%至约90重量%,且优选约1重量%至约50重量%的本发明的化合物。
在通过静脉内、经皮或皮下注射给予治疗有效量的本发明的化合物时,该组合物可以是不含热原、胃肠道外可接受的水溶液形式。这类胃肠道外可接受的溶液(具有适当的pH、等张性、稳定性等)的配制是本领域常规技术。用于静脉内、经皮或皮下注射的优选组合物通常含有等张载剂。
本发明的化合物可容易地与本领域熟知的药学上可接受的运载体合并。在一个实施方式中提供一种药物组合物,其包含本发明的化合物或其药学上可接受的盐或水合物,以及药学上可接受的载体。标准药物运载体可参见雷明顿药物科学(Remington'sPharmaceutical Sciences),Mack Publishing Co.,Easton,PA,第19版,1995。此类载体使活性剂能配制为片剂、丸剂、糖衣丸、胶囊、液体、凝胶剂、糖浆、浆液、混悬剂等,以供待治疗的患者口服摄取。可通过以下方法获得口服用途的药物制剂:将本发明的化合物加入固体赋形剂,任选地研磨所得混合物,并在加入合适的辅助剂(如果需要)后加工该颗粒混合物,以获得片剂或糖衣丸芯体。合适的赋形剂包括例如填充剂和纤维素制剂。需要时,可添加崩解剂。
本发明的化合物可以配制用于通过注射的胃肠外给药,例如,通过推注注射或连续输注。用于注射的制剂可以单位剂型存在,例如装在安瓿或多剂量容器中,其添加有防腐剂。该组合物可以是诸如油性或水性载剂中的悬浮液、溶液或乳剂的形式,可含有配方试剂,如助悬剂、稳定剂和/或分散剂。
用于胃肠外给药的药物组合物包括水溶性形式的活性剂水溶液。此外,本发明的化合物的悬浮液可配置为合适的油性注射悬浮剂。合适的亲脂溶剂或载剂包括脂肪油或合成的脂肪酸酯。水性注射悬浮剂可含有提高悬浮剂粘度的物质。所述悬液还可选包含合适的稳定剂或增加化合物溶解度以制备高浓缩溶液的试剂。或者,本发明的组合物可以是使用前用合适的运载体如无菌无热原的水进行重建的粉末形式。
本发明的化合物还可配置为直肠组合物,例如,如含有常规栓剂基料的栓剂或滞留灌肠剂。除前述制剂外,本发明的化合物还可配制成长效制剂。这种长效制剂可通过植入(例如皮下或肌肉内植入)或肌肉内注射给药。因此,例如,本发明的化合物可与合适的聚合物材料或疏水材料(例如,溶于可接受油的乳剂)或离子交换树脂一同配制。
具体而言,本发明的化合物可以含有赋形剂(如淀粉或乳糖)的片剂形式口服、经颊或舌下给予,或在胶囊或胚珠中给予,单独或与赋形剂混合,或以含有调味剂或着色剂的酏剂或悬浮剂形式给予。可使用药学上可接受的添加剂(如悬浮剂)来制备这类液体制品。本发明的化合物还可通过胃肠道外注射,例如静脉内、肌内、皮下或冠状动脉内。对于胃肠外给药,本发明的化合物通常是无菌水溶液形式,可包含其他物质(例如盐和单糖,如甘露醇或葡萄糖)以使溶液与血液等渗。
在另一实施方式中,本发明提供了药盒,包含以有利于其应用于实践本发明的方法的方式包装的本发明的化合物(或者含有本发明的化合物的组合物)。在一个实施方式中,药盒包括包装在容器(例如密封瓶或器皿)中的本发明的化合物(或者含有本发明的化合物的组合物),容器上粘贴标签或者药盒内包括标签,标签描述了化合物或组合物的应用以实践本发明的方法。在一个实施方式中,化合物或组合物以单位剂型形式包装。该药盒还可包含适用于以预定给药途径给予该组合物的装置。
短语“对ALK的抑制提供益处的疾病或病症”涉及其中ALK是重要的或必要的疾病或病症,例如对于疾病或病症的发生、进程、表达,或者已知可以通过ALK抑制剂进行治疗的疾病或病症。这类病症的示例包括但不限于:癌症、慢性自身免疫疾病、炎性病症、增殖性疾病、脓毒血症或病毒感染。本领域普通技术人员可以容易地确定某种化合物是否针对任何特定细胞类型治疗ALK抑制剂介导的疾病或病症,例如通过可常规使用来评估特定化合物活性的试验。术语“间变性淋巴瘤激酶”或“ALK”包括ALK的亚型和突变体。
术语“第二治疗剂”指不同于本发明的化合物的治疗剂,且其已知能够治疗感兴趣的疾病或病症。例如,当感兴趣的疾病或病症是癌症时,该治疗剂可以是例如已知的化疗药物(如紫杉醇)或辐射。
术语“疾病”或“病症”指通常被认为是病理状态或功能的扰乱和/或异常,并且可以特定迹象、症状和/或功能失调的形式来表现。如下所述,本发明的化合物是ALK的抑制剂,可用于治疗或预防其中对ALK的抑制提供益处的疾病和病症。
本文中,术语“治疗”、“处理”等表示消除、降低或缓解疾病或病症和/或其相关症状。虽然不是排除性的,但治疗疾病或病症不需要完全消除该疾病或病症或其相关症状。术语“治疗”和同义词涵盖向需要这类治疗的对象给予治疗有效量的本发明的化合物。该治疗可以是症状取向的,例如以抑制症状。其可在短时间段内有效,在中期内导向,或可以是长期治疗,例如在维持疗法中。
在本文中,术语“预防”是指预防疾病或病症的发生和/或其伴随的症状或者阻止对象患上疾病的方法。在本文中,“预防”也包括延迟疾病和/或其伴随的症状的发生以及降低对象患上疾病的风险。本文中,术语“预防”可包括“预防性处理”,指降低对象中疾病或病症再发展的可能性或先前已得到控制的疾病或病症的复发,所述对象中不存在疾病或病症的再发展或复发,但其处于风险中或可能再发展或复发。
本文中,术语“治疗有效量”或“有效剂量”指活性成分的含量,其通过本发明的方法给予时足以向有此需要的个体有效递送用于治疗感兴趣的疾病或病症的活性成分。在癌症或其他增殖性疾病的情况中,治疗有效量的试剂可降低(即在一定程度上延缓并优选停止)不需要的细胞增殖;减少癌细胞数目;降低肿瘤尺寸;抑制(即在一定程度上延缓并优选停止)癌细胞浸润至周边器官;抑制(即在一定程度上延缓并优选停止)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一种或多种癌症相关的症状。根据所给予化合物或组合物阻止生长和/或杀伤现有癌细胞的程度,其可以是细胞生长抑制性的和/或细胞毒性的。
术语“容器”指适用于储存、运输、分散和/或处理药物产品的任何接受器和封闭件。
术语“插入物”指药物产品附带的信息,其描述了如何给予该产品,以及所需安全性和效力数据以允许医师、药师和患者做出涉及产品使用的知情决定。包装插入物通常称作药物产品的“标签”。
“共同给予”、“组合给予”、“同时给予”和类似短语指将两种或更多种试剂共同给予正在治疗的患者。“共同”表示各试剂同时给予或在不同时间点处以任意顺序依次给予。然而,如果不是同时给予,其表示各试剂依次给予患者且在时间上足够接近以提供所需的治疗效果并能够一齐作用。例如,本发明的化合物可同时给予或在不同时间点处以任意顺序依次给予作为第二治疗剂。本发明的化合物和第二治疗剂可单独给予,以任何适当形式并通过任何合适途径。当本发明的化合物和第二治疗剂不是共同给予时,应理解其可以任意顺序给予有此需要的对象。例如,可在向有此需要的个体给予第二治疗剂疗法(如放疗)之前(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周前)、同时或之后(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周后)给予本发明的化合物。在多个实施方式中,本发明的化合物和第二治疗剂的给药之间相隔1分钟、相隔10分钟、相隔30分钟、相隔小于1小时、相隔1小时、相隔1-2小时、相隔2-3小时、相隔3-4小时、相隔4-5小时、相隔5-6小时、相隔6-7小时、相隔7-8小时、相隔8-9小时、相隔9-10小时、相隔10-11小时、相隔11-12小时、相隔不超过24小时,或相隔不超过48小时。在一个实施方式中,组合疗法的各组分的给药之间相隔约1分钟至约24小时。
描述本发明的内容时使用的术语“一个”、“一种”和“该”等类似表达(尤其在权利要求书的内容中)应解释为涵盖单数和复数,除非另有说明。本文中对数值范围的引用仅仅是一种速记方法,单独表示落在该范围内的各个独立的值,除非本文中另有说明,且各个独立的值包括在说明书范围内,如同它们被单独引用。本文涉及的任何和所有实施例,或者示例性的语言(例如,“例如”)的使用是为了更好地阐述本发明,而不是对本发明范围的限制,除非权利要求中另有说明。说明书中的所有语言都不应解释为指示对本发明实践所必需的非权利要求的要素。
在本文中,术语"约"包括列举的数字±10%。因此,“约10”表示9-11。
在本发明中,术语“卤素”本身或作为其他基团的一部分表示-Cl,-F,-Br或-I。
在本发明中,术语“硝基”本身或作为其他基团的一部分表示-NO2。
在本发明中,术语"氰基"本身或作为其他基团的一部分表示-CN。
在本发明中,术语"羟基"本身或作为其他基团的一部分表示-OH。
在本发明中,术语"烷基"本身或作为其他基团的一部分表示含有1-12个碳原子的未取代的直链或支链脂肪族烃,即C1-12烷基,或指定的碳原子数,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。在一个实施方式中,烷基是C1-6烷基。在另一实施方式中,烷基是C1-4烷基。在另一实施方式中,烷基部分或完全氘化,即烷基的一个或多个氢原子被氘原子取代。非限制性的示例性C1-12烷基包括:甲基(包括-CH2D、-CHD2和-CD3)、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。
在本发明中,术语"环烷基"本身或作为其他基团的一部分表示具有3-12个碳原子的含有1个或两个环的饱和或部分不饱和(包含一个或两个双键)的环状脂肪族烃,即C3-12环烷基,或者指定的碳原子数。在一个实施方式中,环烷基具有两个环。在一个实施方式中,环烷基具有一个环。在另一实施方式中,环烷基选自C3-8环烷基。在另一实施方式中,环烷基选自C3-6环烷基。非限制性的示例性环烷基包括:环丙基、环丁基、环戊基、环己基、环庚基、环辛基、降冰片基、萘烷、金刚烷基、环己烯基、环戊烯基和环己烯基。
在本发明中,术语"任选取代的环烷基"本身或作为其他基团的一部分表示上文所述的环烷基未取代或者被1-4个独立地选自下组的取代基取代:卤素、氰基、羟基、烷基和烷氧基。非限制性的示例性任选取代的环烷基包括:
在本发明中,术语"杂环基"本身或作为其他基团的一部分表示含有一个、两个或三个具有3-14个环原子的环的例如含有一个或两个双键的饱和和部分饱和的环状基团,即3-14元杂环基,其中所述环中的一个的至少一个碳原子被杂原子取代。各个杂原子独立地选自下组:氧,硫(包括亚砜和砜),和/或氮原子,它们可以氧化或季铵化。术语"杂环基"旨在包括环-CH2-被-C(=O)-取代的基团,例如环脲基,如2-咪唑啉酮(和环状酰胺基团如β-内酰胺,γ-内酰胺,δ-内酰胺,ε-内酰胺和哌嗪-2-酮。在一个实施方式中,杂环基是含有一个环以及一个或两个氧和/或氮原子的3-8元环状基团。在一个实施方式中,杂环基是含有一个环以及一个或两个氧和/或氮原子的4-,5-或6元环状基团。在另一实施方式中,杂环基是含有一个环以及一个氧或氮原子的4-或6元环状基团。在另一实施方式中,杂环基是含有两个环以及一个或两个氮原子的7-或10元环状基团。杂环基可以通过任何可利用的碳或氮原子任选地连接至分子的其他部分。非限制性的示例性杂环基包括: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-咪唑啉酮、哌啶基、吗啉基、哌嗪基、吡咯烷基和二氢吲哚基。
在本发明中,术语"任选取代的杂环基"本身或作为其他基团的一部分表示上文所述的杂环基未取代或者被1-4个独立地选自下组的取代基取代:卤素、氰基、羟基、烷基和烷氧基。取代可以发生在任意可利用的碳或氮原子上,或者两者上。非限制性的示例性任选取代的杂环基包括:
在本发明中,术语"烷氧基"本身或作为其他基团的一部分表示连接末端氧原子的烷基或环烷基。在一个实施方式中,烷氧基是C1-4烷氧基。在另一实施方式中,烷氧基是连接末端氧原子的C1-4烷基,如甲氧基、乙氧基和叔丁氧基。
在本发明中,术语"4-8元杂烷基"本身或者作为其他基团的一部分表示其中至少两个-CH2-基团独立地被-O-、-N(H)-或-S-基团取代的C4-8烷基。-O-、-N(H)-或-S-基团可位于任意位置,只要各个-O-、-N(H)-或-S-基团被至少两个-CH2-基团隔开。在一个实施方式中,两个-CH2-基团被两个-O-基团取代。在另一实施方式中,一个-CH2-基团被-O-基团取代,一个-CH2-基团被-N(H)-基团取代。非限制性的示例性杂烷基包括-OCH2CH2OCH3,-OCH2CH2CH2OCH3和-OCH2CH2OCH2CH2OCH3。
本发明的化合物的一般合成
根据以下一般合成方案制备本发明的化合物。在方案1,6-氰基-1H-吲哚-3-羧酸甲酯(中间体1.1)与中间体1.2反应,得到中间体1.3。中间体1.3环化得到中间体1.4。中间体1.4与式VI的化合物反应,式中R1a,R2a,R2a,R2b,R3和R4参照式I的定义,得到式V的化合物。
一般方案1
在一般方案2中,式V的化合物(式中R3是氢)用(C1-5烷基)-CHO还原胺化,得到式V的化合物(式中R3是C1-6烷基)。
一般方案2
实施例
实施例1
合成1-氟-2-异丙氧基-5-异丙基-3-(4-吗啉代哌啶-1-基)-11-氧代-6,11-二氢-5H-吲哚并[2,3-b]喹啉-8-腈(化合物1)
方案1
步骤1:制备2-氟-1-异丙氧基-4-硝基苯。
将1,2-二氟-4-硝基苯(15.9g,0.1mol)加入氢氧化钠(14.8g,0.37mol)和异丙醇(7.7ml,0.1mol)的DMSO(50mL)溶液中,反应混合物在0℃搅拌3小时。将混合物倒入冰中,pH调节至3~4。收集沉淀,用水清洗,然后干燥,得到黄色固体的2-氟-1-异丙基-4-硝基苯(16.83g)。1H NMR(400MHz,CDCl3)δ8.10-7.95(m,2H),7.04(dd,J=8.0,9.0Hz,1H),4.80-4.70(m,1H),1.45(d,J=6.1Hz,6H)。
步骤2:制备1-溴-3-氟-2-异丙氧基-5-硝基苯。
将浓硫酸(3滴)加入2-氟-1-异丙基-4-硝基苯(1g,5.03mmol)和N-溴琥珀酰亚胺(984mg,5.53mmol)的乙酸(10mL)溶液中,该混合物加热至回流保持7小时。反应用水(100mL)淬灭,用乙酸乙酯萃取(100mL,3次)。将合并的有机层在硫酸镁上干燥,过滤并浓缩。残留物通过硅胶色谱纯化,用乙酸乙酯/己烷(1/5,v/v)洗脱,得到黄色油状的1-溴-3-氟-2-异丙氧基-5-硝基苯(1.0g)。1HNMR(400MHz,CDCl3)δ8.31(dd,J=2.7,1H),7.99(dd,J=2.7,10.8Hz,1H),4.90-4.75(m,1H),1.43(d,J=6.2Hz,6H)。
步骤3:制备4-(1-(3-氟-2-异丙氧基-5-硝基苯基)哌啶-4-基)吗啉。
N2下将4-(哌啶-4-基)吗啉(2.43g,14.38mmol),BINAP(448mg,0.72mmol),乙酸钯(65mg,0.29mmol)和碳酸铯(4.69g,14.38mmol)加入1-溴-3-氟-2-异丙氧基-5-硝基苯(2g,7.19mmol)的甲苯(30mL)溶液中,混合物在100℃加热过夜。反应用水淬灭,将混合物用乙酸乙酯萃取(100mL,3次)。将合并的有机层干燥在硫酸镁上干燥,过滤并浓缩。残留物通过硅胶色谱纯化,用乙酸乙酯/己烷(1/2,v/v)洗脱,得到油状的4-(1-(3-氟-2-异丙氧基-5-硝基苯基)哌啶-4-基)吗啉(2.08g)。1H NMR(400MHz,CDCl3)δ7.70-7.58(m,2H),4.85-4.71(m,1H),3.79-3.66(m,6H),2.75-2.59(m,6H),2.33-2.28(m,1H),2.10-2.02(m,2H),1.70-1.65(m,2H),1.33(d,J=6.2Hz,6H)。
步骤4:制备3-氟-4-异丙氧基-5-(4-吗啉代哌啶-1-基)苯胺。
将10%钯-碳(500mg)加入4-(1-(3-氟-2-异丙氧基-5-硝基苯基)哌啶-4-基)吗啉(2.08g,5.66mmol)的甲醇(80mL)溶液中,混合物氢化过夜。将钯碳过滤,浓缩滤出液,得到黄色固体的3-氟-4-异丙氧基-5-(4-吗啉代哌啶-1-基)苯胺(1.60g),无需纯化即可用于下一步骤。1H NMR(400MHz,CDCl3)δ6.10(dd,J=2.7,11.5Hz,1H),6.01(dd,J=1.5,2.7Hz,1H),4.46-4.40(m,1H),3.78-3.61(m,6H),3.52(d,J=11.5Hz,2H),2.65-2.49(m,4H),2.26-2.18(m,1H),2.01-1.89(m,2H),1.72-1.58(m,2H),1.26(d,J=6.1Hz,6H)。
步骤5:制备3-氟-4-异丙氧基-N-异丙基-5-(4-吗啉代哌啶-1-基)苯胺。
将三乙酸基硼氢化钠(2.01g,9.48mmol)加入3-氟-4-异丙氧基-5-(4-吗啉代哌啶-1-基)苯胺(1.60g,4.74mmol)和丙酮(0.55g,9.48mmol)的1,2-二氯乙烷(80mL)溶液中,室温搅拌该混合物2小时。真空去除溶剂,残留物通过硅胶色谱纯化,用乙酸乙酯/己烷(1/2,v/v)洗脱,得到油状的3-氟-4-异丙氧基-N-异丙基-5-(4-吗啉代哌啶-1-基)苯胺(1.44g)。MS:m/z=380[M+H]。
步骤6:制备6-氰基-2-((3-氟-4-异丙氧基-5-(4-吗啉代哌啶-1-基)苯基)(异丙基)氨基)-1H-吲哚-3-羧酸甲酯。
将N-氯琥珀酰亚胺(482mg,3.6mmol)加入6-氰基-吲哚-3-羧酸甲酯(654mg,3.27mmol)和1,4-二氮杂双环[2.2.2]辛烷(221mg,1.98mmol)的二氯甲烷(20mL)溶液中,混合物在0℃搅拌2小时。然后,加入3-氟-4-异丙氧基-N-异丙基-5-(4-吗啉代哌啶-1-基)苯胺(1.24g,3.27mmol)和三氯乙酸(150mg,0.9mmol)的二氯甲烷(8mL)溶液,在室温下搅拌该混合物过夜。反应用碳酸氢钠溶液淬灭,用乙酸乙酯萃取。将合并的有机层浓缩,残留物通过硅胶色谱纯化,用甲醇/乙酸乙酯(1/20,v/v)洗脱,得到棕色固体的6-氰基-2-((3-氟-4-异丙氧基-5-(4-吗啉代哌啶-1-基)苯基)(异丙基)氨基)-1H-吲哚-3-羧酸甲酯(700mg)。1HNMR(400MHz,DMSO-d6)δ12.20(s,1H),8.03(d,J=8.4Hz,1H),7.80(s,1H),7.50(d,J=8.4Hz,1H),6.24(d,J=12.8Hz,1H),6.08(s,1H),4.45-4.30(m,2H),3.65-3.40(m,11H),2.23-2.00(m,5H),1.90-1.84(m,2H),1.55-1.35(m,2H),1.25-1.16(m,12H)。
步骤7:制备甲基1-氟-2-异丙氧基-5-异丙基-3-(4-吗啉代哌啶-1-基)-11-氧代-6,11-二氢-5H-吲哚并[2,3-b]喹啉-8-腈。
将6-氰基-2-((3-氟-4-异丙氧基-5-(4-吗啉代哌啶-1-基)苯基)(异丙基)氨基)-1H-吲哚-3-羧酸甲酯(700mg,1.21mmol)和二苯醚(15mL)加入25mL圆底烧瓶,将该混合物加热至回流2小时。反应冷却,收集沉淀,用甲基叔丁基醚洗涤,干燥后得到黄色固体的粗产物。将该粗产物通过硅胶色谱纯化,用甲醇/二氯甲烷(1/20,v/v)洗脱,得到黄色固体的1-氟-2-异丙氧基-5-异丙基-3-(4-吗啉代哌啶-1-基)-11-氧代-6,11-二氢-5H-吲哚并[2,3-b]喹啉-8-腈(107mg)。1H NMR(400MHz,DMSO-d6)δ12.13(s,1H),8.28(d,J=8.1Hz,1H),7.87(d,J=1.3Hz,1H),7.59(dd,J=1.3,8.1,Hz,1H),6.94(s,1H),5.27-5.25(m,1H),4.51-4.48(m,1H),3.83-2.75(m,8H),2.33-2.31(m,3H),2.01-1.95(m,2H),1.73(d,J=7.0Hz,6H),1.60-1.49(m,4H),1.26(d,J=6.1Hz,6H)。
实施例2
根据实施例1对化合物1的描述或者根据上述一般合成过程制备表3的化合物。
表3
实施例3
酶抑制实验
表达N-末端GST融合蛋白的野生型人ALK蛋白的胞质结构域(氨基酸1058-1620)购自CB有限公司(Carna Biosciences,Inc(日本))。将化合物溶液(2.5μL)和5μL蛋白质溶液加入黑色低容量384孔微量滴定板中,室温下轻微摇晃的条件下孵育30分钟,然后加入2.5μL荧光标记的肽底物和ATP混合物溶液。在含有1mM EGTA、1mM MgCl2和2mM DTT的50mMHEPES(pH 7.5)中进行激酶反应,加入0.01%吐温-20后立即进行分析。ATP、底物和DMSO的最终浓度分别为100μM、20nM和0.5%。对于野生型,ALK最终浓度为1nM,1nM,1nM,128nM,2nM和4nM。反应在室温下轻微摇晃的情况下在黑暗中进行90分钟,然后加入在购自生产商的检测缓冲液中的10μL 20mM EDTA和2nM Eu-W1024抗磷酸酪氨酸抗体(PT66)混合物溶液以终止反应并检测肽底物的磷酸化。最终的混合物在黑暗中孵育1小时,然后在Tecan InfiniteM-1000多模式酶标仪(Tecan,Durham NC)上读取板,激发波长320nm。在620和665nm测量发射强度,665和620nm之间的强度比率对应于肽底物磷酸化。在S形剂量-响应曲线(可变斜率)中以非线性回归将665/620nm比率相对于抑制剂浓度拟合,获得抑制剂的IC50值。结果如表4所示。
表4
应理解上面描述的实施方式和实施例并不意在限定本发明范围的任何方面,并且本文所述的权利要求旨在包含所有实施方式和实施例,不论本文是否明确讲述。
本文引用的所有专利和公开均通过引用全文纳入本文。
Claims (38)
1.一种具有式I的化合物或其药学上可接受的盐或溶剂合物:
式中:
R1a和R1b独立地选自:氢、C1-6烷基或C3-6环烷基;或者
R1a和R1b与它们连接的碳原子一起形成3-6元任选取代的环烷基;或者
R1a和R1b与它们连接的碳原子一起形成4-6元杂环基;
R2a和R2b独立地选自:氢,C1-6烷基和C3-6环烷基;或者
R2a和R2b与它们连接的碳原子一起形成3-6元环烷基;或者
R2a和R2b与它们连接的碳原子一起形成4-6元杂环基;或者
Z选自:-N-和-C(H)-;
R3选自:氢、C1-6烷基、C3-6环烷基和任选取代的4-8元杂环基;
R4选自:氢、C1-6烷基、C1-4烷氧基和4-8元杂烷基;
R5选自:氢、氟和氯;
R6选自:氢、C1-6烷基、C3-6环烷基、4-8元杂环基;
R7选自:氢、-CF3、-NO2和-CN;
R8选自:氢、氟和氯;
E是碳原子且双键;或者
E是-C(H)-且是单键;或者
E是氮原子且是单键。
2.如权利要求1所述的化合物,具有式II:
或其药学上可接受的盐或溶剂合物。
3.如权利要求2所述的化合物,具有式III:
或其药学上可接受的盐或溶剂合物。
4.如权利要求2所述的化合物,具有式IV:
或其药学上可接受的盐或溶剂合物。
5.如权利要求1-4中任一项所述的化合物,或其药学上可接受的盐或溶剂合物,式中R4选自:-OMe和-OiPr。
6.如权利要求1所述的化合物,具有式V:
或其药学上可接受的盐或溶剂合物。
7.如权利要求1或6所述的化合物,或其药学上可接受的盐,式中R4选自:C1-4烷氧基和4-8元杂烷基。
8.如权利要求7所述的化合物,或其药学上可接受的盐,式中R4是-OCH2CH2OCH3。
9.如权利要求1-8中任一项所述的化合物,或其药学上可接受的盐或溶剂合物,式中R1a和R1b独立地选自:氢和甲基。
10.如权利要求1-9中任一项所述的化合物,或其药学上可接受的盐或溶剂合物,式中R2a和R2b独立地选自:氢和甲基。
11.如权利要求1-10中任一项所述的化合物,或其药学上可接受的盐或溶剂合物,式中R1a和R2a是甲基,R1b和R2b是氢。
12.如权利要求1-10中任一项所述的化合物,或其药学上可接受的盐或溶剂合物,式中R1a、R1b、R2a和R2b是氢。
13.如权利要求1-10中任一项所述的化合物,或其药学上可接受的盐或溶剂合物,式中R1a、R1b、R2a和R2b是甲基。
14.如权利要求1-13中任一项所述的化合物,或其药学上可接受的盐或溶剂合物,式中R3选自:C1-4烷基和任选取代的4-8元杂环基。
15.如权利要求1所述的化合物,或其药学上可接受的盐或溶剂合物,选自下组:
1-氟-2-异丙氧基-5-异丙基-3-(4-吗啉代哌啶-1-基)-11-氧代-6,11-二氢-5H-吲哚并[2,3-b]喹啉-8-腈;
1-氟-2-异丙氧基-5-异丙基-11-氧代-3-(4-(四氢-2H-吡喃-4-基)哌嗪-1-基)-6,11-二氢-5H-吲哚并[2,3-b]喹啉-8-腈;
1-氟-2-异丙氧基-5-异丙基-11-氧代-3-(顺式-3,4,5-三甲基哌嗪-1-基)-6,11-二氢-5H-吲哚并[2,3-b]喹啉-8-腈;
1-氟-2-异丙氧基-5-异丙基-3-(4-异丙基哌嗪-1-基)-11-氧代-6,11-二氢-5H-吲哚并[2,3-b]喹啉-8-腈;
1-氟-2-异丙氧基-5-异丙基-3-(4-(氧杂环丁-3-基)哌嗪-1-基)-11-氧代-6,11-二氢-5H-吲哚并[2,3-b]喹啉-8-腈;
1-氟-5-异丙基-2-甲氧基-3-(4-(氧杂环丁-3-基)哌嗪-1-基)-11-氧代-6,11-二氢-5H-吲哚并[2,3-b]喹啉-8-腈;
1-氟-5-异丙基-2-甲氧基-11-氧代-3-(4-(四氢-2H-吡喃-4-基)哌嗪-1-基)-6,11-二氢-5H-吲哚并[2,3-b]喹啉-8-腈;
1-氟-5-异丙基-2-甲氧基-11-氧代-3-(顺式-3,4,5-三甲基哌嗪-1-基)-6,11-二氢-5H-吲哚并[2,3-b]喹啉-8-腈;
4-氟-5-异丙基-2-(2-甲氧基乙氧基)-11-氧代-3-(4-(四氢-2H-吡喃-4-基)哌嗪-1-基)-6,11-二氢-5H-吲哚并[2,3-b]喹啉-8-腈;
4-氟-5-异丙基-2-(2-甲氧基乙氧基)-11-氧代-3-(顺式-3,4,5-三甲基哌嗪-1-基)-6,11-二氢-5H-吲哚并[2,3-b]喹啉-8-腈;和
4-氟-2-异丙氧基-5-异丙基-11-氧代-3-(顺式-3,4,5-三甲基哌嗪-1-基)-6,11-二氢-5H-吲哚并[2,3-b]喹啉-8-腈。
16.一种药物组合物,其包含如权利要求1-15中任一项所述的化合物或其药学上可接受的盐或水合物以及药学上可接受的运载体。
17.一种治疗患者的方法,所述方法包括给予所述患者治疗有效量的如权利要求1-15中任一项所述的化合物或其药学上可接受的盐或溶剂合物,其中,所述患者患有癌症、慢性自身免疫疾病、炎性病症或增殖性疾病。
18.如权利要求17所述的方法,其中,所述患者患有癌症。
19.如权利要求18所述的方法,其中,所述癌症选自:表2所示癌症的任一种或多种。
20.如权利要求19所述的方法,其中,所述癌症选自:间变性大细胞淋巴瘤、非小细胞肺癌、弥散性大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。
21.如权利要求17-20中任一项所述的方法,还包括给予治疗有效量的在治疗所述疾病或病症中有用的第二治疗剂。
22.如权利要求18所述的药物组合物,用于治疗癌症、慢性自身免疫疾病、炎性病症或增殖性疾病。
23.如权利要求22所述的药物组合物,用于治疗癌症。
24.如权利要求23所述的药物组合物,其中,所述癌症选自表2所示癌症的任一种或多种。
25.如权利要求23所述的药物组合物,其中,所述癌症选自:间变性大细胞淋巴瘤、非小细胞肺癌、弥散性大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。
26.如权利要求1-15中任一项所述的化合物,或其药学上可接受的盐或溶剂合物,用于治疗癌症、慢性自身免疫疾病、炎性病症或增殖性疾病。
27.如权利要求26所述的化合物,用于治疗癌症。
28.如权利要求27所述的化合物,其中,所述癌症选自表2所示癌症的任一种或多种。
29.如权利要求27所述的化合物,其中,所述癌症选自:间变性大细胞淋巴瘤、非小细胞肺癌、弥散性大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。
30.如权利要求1-15中任一项所述的化合物或其药学上可接受的盐或溶剂合物在制备用于治疗癌症、慢性自身免疫疾病、炎性病症或增殖性疾病的药物中的应用。
31.如权利要求30所述的应用,用于治疗癌症。
32.如权利要求31所述的应用,其中,所述癌症选自表2所示癌症的任一种或多种。
33.如权利要求31所述的应用,其中,所述癌症选自:间变性大细胞淋巴瘤、非小细胞肺癌、弥散性大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。
34.一种药盒,其包含如权利要求1-15中任一项所述的化合物或其药学上可接受的盐或溶剂合物以及用于将所述化合物或其药学上可接受的盐或溶剂合物给予患有癌症、慢性自身免疫疾病、炎性病症或增殖性疾病的患者的说明书。
35.如权利要求34所述的药盒,其中,所述患者患有癌症。
36.如权利要求35所述的药盒,其中,所述癌症选自表2所示癌症的任一种或多种。
37.如权利要求35所述的药盒,其中,所述癌症选自:间变性大细胞淋巴瘤、非小细胞肺癌、弥散性大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.如权利要求34-37中任一项所述的药盒,还包括一种或多种额外的治疗剂。
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US16/980,462 US20210087188A1 (en) | 2018-03-21 | 2019-03-21 | 5,6-dihydro-1 1h-indolo{2,3-b}quinolin- 11-one compounds as alk inhibitors |
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CN104987324A (zh) * | 2015-06-04 | 2015-10-21 | 湖北生物医药产业技术研究院有限公司 | 作为alk抑制剂的嘧啶衍生物 |
CN106146387A (zh) * | 2015-03-30 | 2016-11-23 | 湖北生物医药产业技术研究院有限公司 | Alk抑制剂的制备方法 |
CN106459033A (zh) * | 2014-02-27 | 2017-02-22 | 江苏亚盛医药开发有限公司 | 作为间变性淋巴瘤酶(alk)抑制剂的吲哚并喹诺酮类化合物 |
CN110191886A (zh) * | 2016-11-18 | 2019-08-30 | 密执安大学评议会 | 5,6-二氢-11h-吲哚并[2,3-b]喹啉-11-酮作为alk抑制剂 |
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CN106459033A (zh) * | 2014-02-27 | 2017-02-22 | 江苏亚盛医药开发有限公司 | 作为间变性淋巴瘤酶(alk)抑制剂的吲哚并喹诺酮类化合物 |
CN106146387A (zh) * | 2015-03-30 | 2016-11-23 | 湖北生物医药产业技术研究院有限公司 | Alk抑制剂的制备方法 |
CN104987324A (zh) * | 2015-06-04 | 2015-10-21 | 湖北生物医药产业技术研究院有限公司 | 作为alk抑制剂的嘧啶衍生物 |
CN110191886A (zh) * | 2016-11-18 | 2019-08-30 | 密执安大学评议会 | 5,6-二氢-11h-吲哚并[2,3-b]喹啉-11-酮作为alk抑制剂 |
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