CN106458929A - N‑(氰基甲基)‑4‑(2‑(4‑吗啉代苯基氨基)嘧啶‑4‑基)苯甲酰胺盐酸盐 - Google Patents
N‑(氰基甲基)‑4‑(2‑(4‑吗啉代苯基氨基)嘧啶‑4‑基)苯甲酰胺盐酸盐 Download PDFInfo
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- CN106458929A CN106458929A CN201580031169.6A CN201580031169A CN106458929A CN 106458929 A CN106458929 A CN 106458929A CN 201580031169 A CN201580031169 A CN 201580031169A CN 106458929 A CN106458929 A CN 106458929A
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- pyrimidine
- cyano methyl
- disease
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Abstract
本发明涉及适用于制备药物制剂的N‑(氰基甲基)‑4‑(2‑(4‑吗啉代苯基氨基)嘧啶‑4‑基)苯甲酰胺的稳定的新型盐形式及其治疗用途。
Description
技术领域
本申请涉及适用于制备药物制剂的N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺的稳定的新型盐形式及其治疗用途。
背景技术
抑制Janus激酶(JAK)已经在治疗过度增殖性疾病中进行了评价。已开发了几种JAK抑制剂:鲁索替尼、托法替尼、巴瑞替尼、来他替尼、帕克替尼、fedratinib、XL019、SB1518和AZD1480(Sonbol,Ther.Adv.Hematol.4:15–35,2013)。化合物N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)是JAK激酶抑制剂。
在临床研究中,CYT-0387有效地治疗过度增殖性疾病,诸如真性红细胞增多症(PV)、自发性血小板增多(ET)和原发性骨髓纤维化(PMF)。此外,患有骨髓纤维化的患者接受CYT-0387,显示贫血和/或脾反应的改善(参见美国专利号8,486,941和专利公开号2014-0073643,各自以其整体通过引用并入本文中)。
期望具有适用于制备包含CYT-0387的药物制剂的不同的化合物形式及其治疗用途。
发明内容
本发明涉及新型CYT-0387形式。
一方面,本发明涉及CYT-0387一盐酸盐无水形式I:
其具有如下X射线粉末衍射(XRPD)图谱,该图谱具有在约13.5°、20.9°、26.1°、26.6°和28.3°2-θ±0.2°2-θ的峰。
另一方面,本发明涉及CYT-0387二盐酸盐一水合物形式II:
其具有如下X射线粉末衍射(XRPD)图谱,该图谱具有在约7.7°、19.3°、24.0°、25.7°和29.6°2-θ±0.2°2-θ的峰。
另一方面,本发明涉及CYT-0387一盐酸盐无水形式III(形式III):
其具有如下X射线粉末衍射(XRPD)图谱,该图谱具有在约12.7°、14.6°、17.8°、19.7°、和23.3°2-θ±0.2°2-θ的峰。
本发明还提供组合物(包括药物组合物)、包含所述化合物的试剂盒、以及使用和制备所述药物组合物的方法。本发明提供的药物组合物可用于治疗由JAK介导的疾病、障碍或病症。在某些实施方案中,由JAK介导的疾病、障碍或病症是骨髓增殖性的和癌症。
在一个实施方案中,本申请涉及包含CYT-0387形式III的剂型,具体作为片剂的剂型,更具体包含相当于30-250mg的CYT-0387游离碱的量的CYT-0387形式III的剂型。在一个实施方案中,剂型包含相当于100-200mg的CYT-0387游离碱的量的CYT-0387形式II。
在其他实施方案中,本申请涉及包含相当于200mg的CYT-0387游离碱的量的CYT-0387形式III的剂型或药物组合物,其提供的药代动力学曲线基本上类似于包含相当于300mg的CYT-0387游离碱的量的CYT-0387二盐酸盐无水形式I的剂型或药物组合物。
在一些实施方案中,本申请涉及作为片剂的包含CYT-0387二盐酸盐一水合物形式II的剂型,其中该剂型包含CYT-0387二盐酸盐一水合物形式II的量相当于约100mg至约300mg的CYT-0387游离碱。在某些实施方案中,本申请涉及作为片剂的包含CYT-0387二盐酸盐一水合物形式II的剂型,其中该剂型包含CYT-0387二盐酸盐一水合物形式II的量相当于约100mg、约150mg、约200mg、约250mg或约300mg的CYT-0387游离碱。在某些实施方案中,本申请涉及作为片剂的包含CYT-0387二盐酸盐一水合物形式II的剂型,其中该剂型包含CYT-0387二盐酸盐一水合物形式II的量相当于约100mg的CYT-0387游离碱。在某些实施方案中,本申请涉及作为片剂的包含CYT-0387二盐酸盐一水合物形式II的剂型,其中该剂型包含CYT-0387二盐酸盐一水合物形式II的量相当于约200mg的CYT-0387游离碱。在某些实施方案中,本申请涉及作为片剂的包含CYT-0387二盐酸盐一水合物形式II的剂型,其中该剂型包含CYT-0387二盐酸盐一水合物形式II的量相当于约250mg的CYT-0387游离碱。在某些实施方案中,本申请涉及作为片剂的包含CYT-0387二盐酸盐一水合物形式II的剂型,其中该剂型包含CYT-0387二盐酸盐一水合物形式II的量相当于约300mg的CYT-0387游离碱。在另外的实施方案中,本申请涉及包含CYT-0387二盐酸盐一水合物形式II的量相当于200mg的CYT-0387游离碱的一些剂型或药物组合物,其提供与包含CYT-0387二盐酸盐一水合物形式II的量相当于300mg的CYT-0387游离碱的一种剂型或药物组合物基本上类似的药代动力学曲线。
还提供包含式(I)化合物或其药学上可接受的盐、异构体或混合物的试剂盒。该试剂盒可进一步包含标签和/或说明书,用于在有此需要的人类中治疗疾病、障碍或病症中使用所述化合物。
还提供包括容器和式(I)化合物或其药学上可接受的盐、异构体或混合物的制品。在一个实施方案中,所述容器可以是小瓶、罐、安瓿、预装注射器或静脉注射袋(intravenous bag)。
附图说明
图1:N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)二盐酸盐无水形式I的XRPD。
图2:N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)二盐酸盐无水形式I的DSC。
图3:N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)二盐酸盐无水形式I的TGA。
图4:N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)二盐酸盐无水形式I的DVS。
图6:N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物形式II的XRPD图谱。
图7:N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺一盐酸盐无水形式I的XRPD图谱。
图8:N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺一盐酸盐无水形式III的XRPD图谱。
图9:N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物形式II的DSC。
图10:N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺一盐酸盐无水形式I的DSC。
图11:N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺一盐酸盐无水形式III的DSC。
图12:N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物形式II的TGA。
图13:N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺一盐酸盐无水形式I的TGA。
图14:N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺一盐酸盐无水形式III的TGA。
图15:N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物形式II的DVS。
具体实施方式
以下描述阐述了示例性组合物和方法、参数等。然而,应认识到这些描述不旨在用于限制本申请的范围,而是作为示例性实施方案的描述而提供。
JAK抑制剂CYT-0387,即N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺,公开于美国专利号8,486,941中,具有以下结构:
CYT-0387的二盐酸盐无水形式披露于PCT申请WO 2012/071612中。CYT-0387二盐酸盐无水形式具有以下结构:
图1、2、3和4中分别示出了CYT-0387二盐酸盐无水形式I(形式IV)的XRPD、差示扫描量热(DSC)、热重分析(TGA)、动态蒸气吸附(DVS)。
本申请提供CYT-387的其它新型形式:一盐酸盐无水形式I(形式I)、二盐酸盐一水合物形式II(形式II)和一盐酸盐无水形式III(形式III)。
如本文所使用,术语“形式I”或“CYT-0387形式I”用于表示CYT-0387一盐酸盐无水形式I;术语“形式II”或“CYT-0387形式II”用于表示CYT-0387二盐酸盐水合物、CYT-0387二盐酸盐一水合物或者CYT-0387二盐酸盐一水合物形式II;术语“形式III”或“CYT-0387形式III”用于表示CYT-0387一盐酸盐无水形式III;术语“形式IV”或“CYT-0387形式IV”用于表示CYT-0387二盐酸盐无水形式I。
在一个实施方案中,形式I或CYT-0387形式I的特征在于图7所示的XRPD、图10所示的DSC、或者图13所示的TGA。在一个实施方案中,形式I或CYT-0387形式I的XRPD图谱具有在约13.5°、20.9°、26.1°、26.6°和28.3°2-θ±0.2°2-θ的峰。
在一些实施方案中,形式II或CYT-0387形式II的特征在于图6所示的XRPD、图9所示的DSC、图12所示的TGA、或者图15所示的DVS。在一个实施方案中,形式II或CYT-0387形式II的XRPD图谱具有在约7.7°、19.3°、24.0°、25.7°和29.6°2-θ±0.2°2-θ的峰。
在一些其它实施方案中,形式III或CYT-0387形式III的特征在于图8所示的XRPD、图11所示的DSC、或者图14所示的TGA。在一个实施方案中,形式IV或CYT-0387形式IV的XRPD图谱具有在约12.7°、14.6°、17.8°、19.7°和23.3°2-θ±0.2°2-θ的峰。
在某些实施方案中,形式IV或CYT-0387形式IV的特征在于图8所示的XRPD、图11所示的DSC、或者图14所示的TGA。在一个实施方案中,形式IV或CYT-0387形式IV的XRPD图谱具有在约5.5°、10.1°、14.9°、25.1°和26.6°2-θ±0.2°2-θ的峰。
本申请的结果发现CYT-0387二盐酸盐一水合物(形式II)具有在某些条件下比CYT-387的其它盐或形式增强的稳定性。本申请中所述的结果还发现CYT-387形式II的这种性质使得其更适合于开发或采用各种合成或工艺。在一个实施方案中,CYT-387形式II适合用于片剂形式的药物组合物。此外,本文中所述的研究表明片剂制剂显示类似于胶囊制剂的生物利用度性质。在某些实施方案中,包含相当于200mg的CYT-0387游离碱的量的CYT-0387二盐酸盐一水合物形式II的片剂提供类似于包含相当于300mg的CYT-0387游离碱的量的CYT-0387二盐酸盐无水形式I的胶囊的生物利用度。
本申请的结果表明CYT-0387二盐酸盐无水形式I是吸湿性的,并且当暴露于湿气时是物理不稳定的。此外,以下所述的结果表明CYT-0387二盐酸盐一水合物形式II是二盐酸盐在适合制造和/或存贮的条件下的热力学稳定形式。此外,本申请描述了使用没食子酸丙酯(自由基清除氧化剂)有效地抑制或阻止CYT-0387二盐酸盐一水合物形式II在水溶液和片剂制剂中的氧化降解。另外,结果表明CYT-0387二盐酸盐一水合物形式II显示比CYT-0387二盐酸盐无水形式I和CYT-0387游离碱提高的生物利用度。
在另一些实施方案中,本发明还提供无定形的N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)二盐酸盐一水合物。在其他实施方案中,本发明还提供无定形的无水N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)一盐酸盐和无定形的无水N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)一盐酸盐。在其他实施方案中,本发明还提供无定形的N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)二盐酸盐和无定形的N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)一盐酸盐。
在具体的一些实施方案中,N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)二盐酸盐一水合物形式II为晶型。
在其他实施方案中,N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)一盐酸盐无水形式I为晶型。
在某些实施方案中,N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)一盐酸盐无水形式III为晶型。
在一个实施方案中,晶型的特征在于通过X射线粉末衍射图谱(XRPD)确定的晶面间距(interlattice plane interval)。XRPD的衍射图通常通过峰强度对峰位置(即以度计的衍射角2θ(two-theta))作图表示。强度常常借助以下缩写在括号中给出:非常强=vst;强=st;中等=m;弱=w;非常弱=vw。给定的XRPD的特征峰可根据峰位置及其相对强度进行选择,以方便地区分这种晶体结构与其它晶体结构。
本领域技术人员认识到对于同一化合物的给定晶型的XRPD峰位置和/或强度的测量会在误差幅度(margin of error)内变化。度数2θ允许适当的误差幅度。通常,误差幅度用“±”表示。例如约“8.7±0.3”的2θ表示约8.7+0.3即约9.0至约8.7-0.3即约8.4的范围。依据样品制备技术、应用于仪器的校正技术、人操作差异等,本领域技术人员认识到XRPD的适当的误差幅度可以是±0.5;±0.4;±0.3;±0.2;±0.1;±0.05;或更小。在本发明的某些实施方案中,XRPD的误差幅度为±0.2。
用于XRPD分析的方法和设备的另外详情描述于实施例部分。
CYT-0387二盐酸盐无水形式I、CYT-0387,二盐酸盐一水合物形式II、CYT-0387一盐酸盐无水形式I和CYT-0387一盐酸盐无水形式III的XRPD可见于下表1。
表1:多种CYT-0387形式的XRPD峰
如本文中所用,以下词语、短语及符号通常意欲具有如在下文中阐述的含义,但使用其的上下文另外指示的情况除外。
本文中,提及“约”一个值或参数包括(且描述)针对该值或参数本身的实施方案。例如,提及“约X”的描述包括“X”的描述。在某些实施方案中,术语“约”包括指示量±10%。在其他实施方案中,术语“约”包括指示量±5%。在某些其他实施例中,术语“约”包括指示量±1%。此外,除非上下文另外明确规定,否则单数形式“一(a/an)”及“该(the)”包括多个提及物。因此,例如提及“该化合物”包括多个这种化合物且提及“该分析”包括提及一或多个分析及其本领域技术人员已知的等效物。
“药学上可接受的”或“生理学上可接受的”指的是化合物、盐、组合物、剂型以及其它物质适用于制备适用于兽医学或人类医药用途的医药组合物。
“药学上可接受的盐”或“生理学上可接受的盐”指的是保留基础化合物的生物有效性和特性且在生物学上或在其它方面并非不合需要的医药化合物的盐。存在酸加成盐和碱加成盐。药学上可接受的酸加成盐可以由无机酸和有机酸制备。适用于与基础化合物反应形成药学上可接受的盐(分别为酸加成盐或碱加成盐)的酸和碱为所属领域技术人员已知。类似地,从基础化合物(披露时)制备药学上可接受的盐的方法为所属领域的技术人员所已知且披露于例如Berge等人Journal of Pharmaceutical Science,1977年1月第66卷第1期和其它来源中。如果本文中所述的化合物以酸加成盐形式获得,那么可通过使酸式盐溶液碱化获得游离碱。相反,如果产物为游离碱,那么可根据由碱化合物制备酸加成盐的常规程序,通过将所述游离碱溶解于适合有机溶剂中且用酸处理所述溶液,产生加成盐,具体来说药学上可接受的加成盐。“治疗”或“治”是用于得到有益的或者希望的结果(包括临床结果)的方法。有益的或者希望的临床结果可包括以下中的一个或者多个:a)抑制疾病或者病症(例如,减少疾病或者病症所导致的一个或者多个症状和/或减轻疾病或者病症的程度);b)减慢或者阻止与疾病或者病症相关联的一个或者多个临床症状的发展(例如,稳定疾病或者病症,防止或者延缓疾病或者病症的恶化或者进展和/或防止或者延缓疾病或者病症的传播(例如,转移));和/或c)减轻疾病,即,导致临床症状消退(例如,改善疾病状态,提供疾病或者病症的部分或者全部缓解,增强其它药疗法的效果,延缓疾病进展,提高生命质量和/或延长存活)。
本申请所述的化合物其中1到n个连接到碳原子的氢原子可置换为氘原子或D,其中n为分子中氢原子的数目。已知氘原子为氢原子的非放射性同位素。此类化合物可增加抗代谢性,且因此当向哺乳动物给予时,可适用于增加本文中所述的化合物或其药学上可接受的盐、异构体、前药或溶剂合物的半衰期。参看例如Foster,“Deuterium IsotopeEffects in Studies of Drug Metabolism”,Trends Pharmacol.Sci.,5(12):524-527(1984)。此类化合物通过所属领域中熟知的手段,例如通过采用一或多个氢原子已经氘置换的起始物质来合成。在一些实施方案中,本申请所述化合物是CYT-0387二盐酸盐一水合物形式II、CYT-0387一盐酸盐无水形式I、CYT-0387一盐酸盐无水形式III、CYT-0387二盐酸盐无水形式IV、化合物3、化合物4、化合物8、化合物10、化合物12和化合物13。
“预防”或“防止”是指疾病或病症的任何处理,其使得疾病或病症的临床症状不发展。在一些实施方案中,化合物可给药于处于疾病或病症风险或具有疾病或病症家族史的受试者(包括人)。
术语“受试者”或“患者”指的是动物,如哺乳动物(包括人),其已经或者将要为治疗、观察或实验的对象。本申请所述方法可用于人类治疗和/或兽医应用。在一些实施方案中,所述受试者为哺乳动物。在一个实施方案中,受试者为人类。“有此需要的人类”指的是可已经患有或者被怀疑患有会从某治疗(例如用根据本申请的化合物治疗)受益的疾病或病症的人类。术语“有此需要的受试者”或“有此需要的患者”指的是受试者或患者,其可已经诊断患有或者被怀疑患有会从本申请所述治疗受益的疾病、障碍或病症。在某些实施方案中,所述受试者或患者可为以下人类,其(i)未接受任何治疗(即,初治的),(ii)已经接受先前的治疗且不反应或者未显示改善的,或者(iii)对先前的治疗复发或耐性的(即,难治的)。例如,患者可已经接受基于铂的化疗或含有吉西他滨的治疗。另外的实例包括可能对基于铂的化疗或含有吉西他滨的治疗复发或难治的患者。
术语“治疗有效量”的本申请的化合物或其药学上可接受的盐、异构体、前药或溶剂合物是指当给予受试者时足以实现治疗的量,以提供治疗益处,如改善症状或减缓疾病进展。所述治疗有效量可取决于受试者和治疗的疾病或者病症、受试者的体重和年龄、疾病或者病症的严重性和给药方式而改变,其可由本领域普通技术人员容易地确定。在一个实施方案中,本申请所述的化合物的“治疗有效量”是100mg、150mg、200mg、250mg或300mg。
术语“抑制”指示生物活性或过程的基线活性的降低。
药物组合物和给药
本文提供的化合物通常以药物组合物形式给药。因此,本文还提供药物组合物,其包含一种或多种文中所述的任一式的化合物或其药学上可接受的盐、异构体、前药或溶剂合物,以及一种或多种药学上可接受的选自载体、佐剂和赋形剂的媒介物。合适的药学上可接受的媒介物可包括,例如,惰性固体稀释剂和填料,稀释剂,包括无菌水溶液和多种有机溶剂,渗透增强剂,增溶剂和佐剂。此类组合物以药学领域公知的方式制备。参见,例如,Remington’s Pharmaceutical Sciences,Mace Publishing Co.,Philadelphia,Pa.17thEd.(1985);和Modern Pharmaceutics,Marcel Dekker,Inc.3rd Ed.(G.S.Banker&C.T.Rhodes,Eds.)。本申请所用的“溶剂合物”通过溶剂和化合物的相互作用形成。还提供了本文所述的任何化学式化合物的盐的溶剂合物。还提供了所述任何化学式化合物的水合物。此外,“前药”在药物领域定义为药物无生物活性的衍生物,其在给药至人体后根据一些化学或酶途径转化为有生物活性的母体药物。
药物组合物可以单一剂量或多剂量形式给药。药物组合物可通过各种方法给药,包括例如经直肠、经颊、鼻内以及经皮途径。在某些实施方案中,药物组合物可藉由动脉内注射、静脉内、腹膜内、非经肠、肌肉内、皮下、经口、局部或以吸入剂形式给药。在一些实施方案中,该药物组合物口服给药。
一种给药模式是肠胃外,例如通过注射给药。可并入本文所述的药物组合物用于通过注射给药的形式包括例如水性或油性悬浮液或乳液,其含芝麻油、玉米油、棉籽油或花生油以及酏剂、甘露糖醇、右旋糖或无菌水溶液以及类似医药媒介物。
经口给药可为用于给药本文所述的化合物的另一途径。举例来说,可通过胶囊或包覆肠溶包衣的片剂给药。在制造包括至少一种具有本文所述的任何化学式的化合物或其药学上可接受的盐、前药或溶剂合物的药物组合物中,通常通过赋形剂稀释活性成分和/或将其密封于可呈胶囊、药囊、纸张或其它容器形式的载剂内。当赋形剂用作稀释剂时,其可以呈固体、半固体或液体材料形式,其充当活性成分的媒介物、载体或介质。因此,组合物可以呈以下形式:片剂、丸剂、散剂、口含剂、药囊、扁胶剂、酏剂、悬浮液、乳液、溶液、糖浆、气雾剂(呈固体形式或于液体介质中)、含有例如高达10重量%的活性化合物的软膏、软和硬明胶胶囊、无菌可注射溶液以及无菌封装粉末。
关于制备例如片剂的固体组合物,主要活性成分可与医药赋形剂混合,以形成含有具有上述任何化学式的化合物或其药学上可接受的盐、前药或溶剂合物的均匀混合物的固体预配制组合物。当提到这些预配制组合物为均匀组合物时,活性成分可均匀分散在整个组合物中,以便组合物可以容易地再分成同等有效的单位剂型,例如片剂、丸剂和胶囊。
本文所述的化合物的片剂或丸剂可以经涂布或以其它方式混配以提供剂型,其具有作用时间长或保护免受胃的酸性条件的作用的优势。举例来说,片剂或丸剂可以包括内部剂量和外部剂量组分,外部剂量组分呈内部剂量组分上的包膜形式。两个组分可以由用以在胃中抵抗崩解并且允许内部组分完好传递到十二指肠中或延迟释放的肠溶性层间隔开。多种材料可以用于此类肠溶性层或涂层,此类材料包括多种聚合酸和聚合酸与此类材料(如虫胶、鲸蜡醇以及乙酸纤维素)的混合物。
本文所述的化学式的化合物针对任何具体受试者的具体剂量将视多种因素而定,所述因素包括在经历疗法的受试者中所采用的具体化合物的活性、年龄、体重、总体健康状况、性别、饮食、给药时间、给药途径以及排泄率、药物组合以及具体疾病的严重程度。举例来说,剂量可表示为每公斤受试者体重各化学式的化合物的毫克数(mg/kg)。约0.01到200mg/kg的剂量可能适当。在一些实施方案中,约0.01到150mg/kg可能适当。在其它实施方案中,0.05到100mg/kg的剂量可能适当。当在体型广泛不同的受试者之间调整剂量时,例如当在儿童与成人中使用药物时或当将例如狗的非人类受试者中的有效剂量转换成适用于人类受试者的剂量时所发生,根据受试者的体重标准化尤其适用。
本申请的化合物或其组合物可使用上文所述的任何适合模式每天给药一次、两次、三次或四次。此外,根据本文所述的任何化学式的化合物的给药或用其治疗可持续多天;举例来说,针对一个治疗周期,治疗通常将持续至少7天、14天或28天。治疗周期为熟知的,且常常与介于周期之间的约1到28天、通常约7天或约14天的休息期交替。在其它实施方案中,治疗周期也可以是连续的。
在一些实施方案中,采用药学上可接受的载体将本申请公开的形式或组合物配制用于口服给药。配制用于口服给药的药物组合物可呈片剂,丸剂,胶囊,药囊,糖衣丸,口含剂,液体,凝胶,糖浆,浆液,酏剂,悬浮液或散剂的形式。
药学上可接受的载体
术语“载体”是指与化合物一起给药的稀释剂或填料、崩解剂、沉淀抑制剂、表面活性剂、助流剂、粘合剂、润滑剂、抗氧化剂和其他赋形剂和载剂。载体通常在本发明中描述,也在E.W.Martin的“Remington's Pharmaceutical Sciences”中进行描述。载体的实例包括但不限于,单硬脂酸铝、硬脂酸铝、羧甲基纤维素、羧甲基纤维素钠、交聚维酮、异硬脂酸甘油酯、单硬脂酸甘油酯、羟乙基纤维素、羟乙基纤维素、羟甲基纤维素、羟二十八醇羟基硬脂酸酯(hydroxyoctacosanyl hydroxystearate)、羟丙基纤维素、羟丙基纤维素、羟丙基甲基纤维素、乳糖、乳糖单水合物、硬脂酸镁、甘露醇、微晶纤维素、泊洛沙姆124、泊洛沙姆181、泊洛沙姆182、泊洛沙姆188、泊洛沙姆237、泊洛沙姆407、聚维酮、二氧化硅、胶体二氧化硅、硅酮、硅酮胶粘剂4102和硅酮乳剂。但是,应理解,本公开所提供的药物组合物中所选择的载体和所述载体在该组合物中的量可根据配制方法(例如,干法造粒配制、固态分散体配制)而变化。
术语“稀释剂”或“填料”通常是指在递送前用于稀释感兴趣的化合物的物质。稀释剂也可用于稳定化合物。稀释剂的实例可包括淀粉、糖、二糖、蔗糖、乳糖、多糖、纤维素、纤维素醚、羟丙基纤维素、糖醇、木糖醇、山梨醇、麦芽糖醇、微晶纤维素、碳酸钙或碳酸钠、乳糖、乳糖单水合物、磷酸二钙、纤维素、可压缩糖、磷酸氢钙脱水合物、甘露醇、微晶纤维素和磷酸钙。
术语“崩解剂”通常是指一旦加至固体制剂,可在给药后促进该制剂破碎或分裂,并使得活性成分尽可能有效地释放,从而得以快速溶出的物质。崩解剂的实例可包括玉米淀粉、淀粉羟乙酸钠、交联羧甲纤维素钠、交聚维酮、微晶纤维素、改性的玉米淀粉、羧甲基淀粉钠、聚维酮、预胶化淀粉和海藻酸。
术语“沉淀抑制剂”通常是指防止或抑制活性剂析出的物质。沉淀抑制剂的一个实例包括羟丙基甲基纤维素。
术语“表面活性剂”通常是指降低两种液体之间或者液体和固体之间的表面张力的化合物。表面活性剂的实例包括泊洛沙姆和十二烷基硫酸钠。
术语“助流剂”通常是指用在片剂和胶囊制剂中提高压片过程中的流动性并产生抗结块效果的物质。助流剂的实例可包括胶体二氧化硅、滑石、烟雾硅胶、淀粉、淀粉衍生物和膨润土。
术语“粘合剂”通常是指任何药学上可接受的膜,其可用于将载体的活性成分和惰性成分粘合到一起以维持内聚和离散部分。粘合剂的实例可包括羟丙基纤维素、羟丙基甲基纤维素、聚维酮、共聚维酮、乙基纤维素、明胶和聚乙二醇。
术语“润滑剂”通常是指被添加至粉末掺合物以预防在压片或包囊处理过程中该压实的粉块粘到设备上的物质。润滑剂可帮助从模具排出片剂,并提高粉末流动。润滑剂的实例可包括硬脂酸镁、硬脂酸、二氧化硅、脂肪、硬脂酸钙、聚乙二醇、硬脂酰富马酸钠或滑石;和增溶剂,例如脂肪酸,包括月桂酸、油酸和C8/C10脂肪酸。
术语“抗氧化剂”通常是指抑制其它物质的氧化的物质。在本发明的某些实施方案中,向药物组合物添加抗氧化剂。抗氧化剂的实例可包括乙二胺四乙酸、乙二胺四乙酸二钠盐、亚硫酸钠、焦亚硫酸钠(sodium metabisulfite)、亚硫酸氢钠、丁羟甲苯(BHT)、丁羟茴香醚(BHA)、抗坏血酸、抗坏血酸棕榈酸酯、硫代甘油、巯基乙酸、生育酚(维生素E)、D-α生育酚基聚乙二醇1000琥珀酸酯(维生素E TPGS)和没食子酸丙酯。在某些实施方案中,所述抗氧化剂是没食子酸丙酯。在一个实施方案中,药物组合物包含CYT-0387二盐酸盐一水合物形式II和选自丁羟茴香醚(BHA)、抗坏血酸和没食子酸丙酯的抗氧化剂。在某些实施方案中,药物组合物包含CYT-0387二盐酸盐一水合物形式II和抗氧化剂,其中所述抗氧化剂是没食子酸丙酯。
所述抗氧化剂或抗氧化试剂可以按足以阻止、抑制和/或降低活性成分(诸如CYT-0387形式II)的降解的量存在。例如,所述抗氧化剂可以按约0.001%、约0.002%、约0.005%、约0.01%、约0.02%、约0.05%、约0.1%、约0.2%、约0.5%或约1%的量存在。在一个实施方案中,药物组合物包含约0.001%、约0.01%、约0.1%、约0.2%、约0.5%或约1%的量的没食子酸丙酯。在一些实施方案中,药物组合物包含CYT-0387二盐酸盐一水合物形式II和约0.2%的没食子酸丙酯。
在某些方面,提供一种药物组合物,其包含至少一种活性试剂(包括例如CYT-0387二盐酸盐一水合物形式II)以及(a)-(e)中的一种或多种:a)至少一种稀释剂;b)至少一种崩解剂;c)至少一种助流剂;d)至少一种润滑剂;和e)至少一种抗氧化剂。
在一些实施方案中,所述药物组合物包含至少一种或至少两种稀释剂。在某些实施方案中,所述药物组合物包含一种或两种稀释剂。在某些实施方案中,所述稀释剂选自:甘露醇、微晶纤维素、乳糖、葡萄糖、蔗糖、ludiflash、F-melt、advantose、GalenIQ,或其任意混合物。在一种实施方案中,所述稀释剂是甘露醇、微晶纤维素、或者其混合物。
在一些实施方案中,药物组合物包含至少一种崩解剂。在某些实施方案中,药物组合物包含一种崩解剂。在一具体实施方案中,崩解剂是淀粉羟乙酸钠。在一个实施方案中,崩解剂是交联羧甲纤维素钠。在其他实施方案中,崩解剂是交聚维酮。
在一些实施方案中,药物组合物包含至少一种助流剂。在某些实施方案中,药物组合物包含一种助流剂。在一个实施方案中,所述助流剂是是胶体二氧化硅。
在一些实施方案中,药物组合物包含至少一种润滑剂。在某些实施方案中,药物组合物包含一种润滑剂。在一个实施方案中,所述润滑剂是硬脂酸镁。
在具体的一些实施方案中,药物组合物包含CYT-0387二盐酸盐一水合物形式II、至少一种稀释剂、至少一种崩解剂、至少一种助流剂、至少一种润滑剂和至少一种抗氧化剂。在其他实施方案中,所述至少一种稀释剂是微晶纤维素,所述至少一种崩解剂是淀粉羟乙酸钠,所述至少一种助流剂是胶体二氧化硅,所述至少一种润滑剂是硬脂酸镁,至少一种抗氧化剂是没食子酸丙酯。在进一步的另一些实施方案中,所述至少一种稀释剂是乳糖,所述至少一种崩解剂是淀粉羟乙酸钠,所述至少一种助流剂是胶体二氧化硅,所述至少一种润滑剂是硬脂酸镁,至少一种抗氧化剂是没食子酸丙酯。
在一些其它实施方案中,药物组合物包含CYT-0387二盐酸盐一水合物形式II、至少两种稀释剂、至少一种崩解剂、至少一种助流剂、至少一种润滑剂和至少一种抗氧化剂。在又一些其它实施方案中,所述至少两种稀释剂是微晶纤维素和乳糖,所述至少一种崩解剂是淀粉羟乙酸钠,所述至少一种助流剂是胶体二氧化硅,所述至少一种润滑剂是硬脂酸镁,至少一种抗氧化剂是没食子酸丙酯。
在某些实施方案中,药物组合物包含CYT-0387,其中至少约80%是CYT-0387二盐酸盐一水合物形式II。在其他实施方案中,药物组合物包含CYT-0387,其中至少约85%是CYT-0387二盐酸盐一水合物形式II。在又进一步的一些实施方案中,药物组合物包含CYT-0387,其中至少约90%是CYT-0387二盐酸盐一水合物形式II。在进一步的另一些实施方案中,药物组合物包含CYT-0387,其中至少约95%是CYT-0387二盐酸盐一水合物形式II。在具体的一些实施方案中,药物组合物包含CYT-0387,其中至少约97%是CYT-0387二盐酸盐一水合物形式II。在一些其它实施方案中,药物组合物包含CYT-0387,其中至少约98%是CYT-0387二盐酸盐一水合物形式II。在又一些其它实施方案中,药物组合物包含CYT-0387,其中至少约99%是CYT-0387二盐酸盐一水合物形式II。在又一些其它实施方案中,药物组合物包含CYT-0387,其中至少约99.5%是CYT-0387二盐酸盐一水合物形式II。在具体的一些实施方案中,药物组合物包含CYT-0387,其中至少约99.9%是CYT-0387二盐酸盐一水合物形式II。
应理解,所述药物组合物包含本文详述的药学上可接受的载体,如同药学上可接受的载体各自和每一种组合具体和单独地列出。
单位剂型
在一些实施方案中,本申请所述的药物组合物是以单位剂型配制的。术语“单位剂型”是指适合作为单一剂量用于受试者(例如,人受试者和其他哺乳动物)的物理分散单元,各单元含有计算产生所需治疗效果的预定量的活性物质,以及合适的药物载体。
在一种进一步的实施方案中,本发明涉及包含CYT-0387二盐酸盐一水合物形式II的单位剂型。在一些实施方案中,单位剂型包含CYT-0387二盐酸盐一水合物形式II的量相当于约10mg至约1000mg、约10mg至约800mg、约10mg至约700mg、约10mg至约500mg、约10mg至约400mg、约10mg至约300mg、约10mg至约250mg、约10mg至约200mg、约10mg至约150mg、约10mg至约100mg、约10mg至约50mg、约50mg至约1000mg、约50mg至约800mg、约50mg至约700mg、约50mg至约500mg、约50mg至约400mg、约50mg至约300mg、约50mg至约250mg、约50mg至约200mg、约50mg至约150mg、约50mg至约100mg、约100mg至约1000mg、约100mg至约800mg、约100mg至约700mg、约100mg至约500mg、约100mg至约400mg、约100mg至约300mg、约100mg至约250mg、约100mg至约200mg、约150mg至约300mg、约150mg至约250mg、约150mg至约200mg、约200mg至约300mg、约200mg至约250mg、或者约200mg至约300mg的CYT-0387游离碱。
在另外的实施方案中,所述剂型包含CYT-0387二盐酸盐一水合物形式II的量相当于约100mg的CYT-0387游离碱、约150mg CYT-0387游离碱、200mg的CYT-0387游离碱、约250mg CYT-0387游离碱、300mg的CYT-0387游离碱、约400mg CYT-0387游离碱、或者约500mg的CYT-0387游离碱。在某些实施方案中,单位剂型包含CYT-0387二盐酸盐一水合物形式II的量相当于约50mg的CYT-0387游离碱。在一些其它实施方案中,单位剂型包含CYT-0387二盐酸盐一水合物形式II的量相当于约100mg的CYT-0387游离碱。在又一些其它实施方案中,单位剂型包含CYT-0387二盐酸盐一水合物形式II的量相当于约150mg的CYT-0387游离碱。在又一些其它实施方案中,所述剂型包含CYT-0387二盐酸盐一水合物形式II的量相当于约200mg的CYT-0387游离碱。在具体的一些实施方案中,所述剂型包含CYT-0387二盐酸盐一水合物形式II的量相当于约250mg的CYT-0387游离碱。在其他实施方案中,所述剂型包含CYT-0387二盐酸盐一水合物形式II的量相当于约300mg的CYT-0387游离碱。在进一步的另一些实施方案中,所述剂型包含CYT-0387二盐酸盐一水合物形式II的量相当于约400mg的CYT-0387游离碱。在又进一步的一些实施方案中,所述剂型包含CYT-0387二盐酸盐一水合物形式II的量相当于约500mg的CYT-0387游离碱。在一些其它实施方案中,药物组合物为片剂,其剂型包含CYT-0387二盐酸盐一水合物形式II的量相当于约300mg的CYT-0387游离碱。
在其他实施方案中,本发明涉及包含CYT-0387二盐酸盐一水合物形式II的剂型,所述CYT-0387二盐酸盐一水合物形式II的量相当于200mg的N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺游离碱,其提供与包含CYT-0387二盐酸盐无水形式I(量相当于300mg的N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺游离碱)的剂型基本类似的药代动力学曲线。
在本发明的某些实施方案中,单位剂型包含至少一种药学上可接受的载体。在一些其它实施方案中,单位剂型包含CYT-0387二盐酸盐一水合物形式II、至少两种稀释剂、至少一种崩解剂、至少一种助流剂、至少一种润滑剂和至少一种抗氧化剂。在又进一步的一些实施方案中,单位剂型包含约36%至44%的CYT-0387二盐酸盐一水合物形式II;约44%至58%的稀释剂;约4%至8%的崩解剂,约0.25%至0.75%的助流剂,约1.2%至1.8%的润滑剂,和约0.1%至0.5%抗氧化剂。在又一些其它实施方案中,所述至少两种稀释剂是微晶纤维素和乳糖,所述至少一种崩解剂是淀粉羟乙酸钠,所述至少一种助流剂是胶体二氧化硅,所述至少一种润滑剂是硬脂酸镁,至少一种抗氧化剂是没食子酸丙酯。在又进一步的一些实施方案中,单位剂型包含约36%至44%的CYT-0387二盐酸盐一水合物形式II;约30%至38%的微晶纤维素;约14%至20%的乳糖,约4%至8%的淀粉羟乙酸钠,约0.25%至0.75%的胶体二氧化硅,约1.2%至1.8%的硬脂酸镁和约0.1%至0.5%的没食子酸丙酯。
药物组合物的制备
本申请所述的药物组合物可使用任何常规方法制备,例如但不限于混合、溶解、造粒、糖衣化、研磨(levigating)、乳化、包封、包埋、熔体纺丝、喷雾干燥或冻干法。
技术人员会认识到通过常规配制制备片剂的方法和技术。制备用于压制成片剂的粉末的示例性方法和技术包括干法造粒或湿法造粒。干法造粒通常是指不使用液体溶液的制粒工艺,而湿法造粒通常是指将液体溶液添加到粉末进行制粒的工艺。
试剂盒
本申请还提供试剂盒,其包括适当的包装和本申请的化学式的化合物或其药学上可接受的盐、异构体、前药或溶剂合物。在一个实施方案中,试剂盒还包括使用说明书。一方面,试剂盒包括本文所述化学式的化合物或其药学上可接受的盐、异构体、前药或溶剂合物,以及使用所述化合物治疗适应症(包括本文所述的疾病或病症)的标签和/或说明书。
本申请还提供在适当的容器中的包括本文所述任意化学式的化合物或其药学上可接受的盐、异构体、前药或溶剂合物的制品。所述容器可以是小瓶、罐、安瓿、预装注射器或静脉注射袋。
治疗方法
本发明的CYT-0387形式可以用于治疗激酶相关性疾病,包括JAK激酶相关性疾病,例如免疫性疾病和炎性疾病(包括器官移植);过度增殖性疾病(包括癌症和骨髓增殖性疾病);病毒性疾病;代谢性疾病;以及血管疾病。
除了灵长类例如人类之外,利用本发明的化合物、组合物和方法可以治疗各种其它哺乳动物。例如,可以治疗哺乳动物,包括但不局限于牛、绵羊、山羊、马、狗、猫、豚鼠、大鼠或其它牛族动物、绵羊类动物(ovine)、马科动物、犬科动物、猫科动物、啮齿动物或鼠科动物。但是,也可以在其它物种例如鸟类(如鸡)中实施本发明。
术语“给药”应理解为意指向需要治疗的受试者提供本发明的化合物。
术语“治疗”是指达到期望的药理学和/或生理学效果。该效果可以是就完全或部分防止疾病而言预防性的和/或可以是就疾病和/或归因于疾病的不良作用的部分或完全治愈而言治疗性的。治疗可以涵盖哺乳动物中疾病的任何治疗,包括:阻止疾病在可能易患疾病但尚未诊断为患有疾病的受试者中发生;抑制疾病,即遏制其发展;或缓解疾病,即引起疾病消退。治疗剂可以在疾病发作之前,期间或之后给药。特别感兴趣的是对正在进行的疾病的治疗,其中治疗稳定或减少患者的不良临床症状。预期的无进展生存时间可以按几个月至几年计,这取决于预后因素,包括复发的数量、疾病的阶段和其他因素。延长存活包括但不限于至少1个月、约至少2个月、约至少3个月、约至少4个月、约至少6个月、约至少1年、约至少2年、约至少3年或更长。总生存期也可以按几个月至几年计。患者的症状可能保持静止或可能减少。
术语“有效量”是指可以有效地引起所期望的生物或医学反应的量,包括当给予受试者用于治疗疾病时足以实现这种疾病治疗的化合物的量。有效量将根据化合物、疾病及其严重性和待治疗的受试者的年龄,体重等而变化。有效量可以包括一定范围的量。
术语“激酶相关性疾病”是指直接或间接地由激酶活性异常,特别是JAK活性异常造成的或者加重的一种或多种障碍,和/或通过抑制一种或多种的这些激酶而减轻的一种或多种障碍。
在优选的实施方案中,所述激酶相关性疾病状态涉及一种或多种JAK激酶——JAK1、JAK2、JAK3或TYK2。在特别优选的实施方案中,所述疾病涉及JAK2激酶。这样的疾病包括但不局限于列于下表中的那些疾病。
在各种病况中JAK/STAT途径的活化
术语“免疫性疾病和炎性疾病”是指免疫性疾病、炎性疾病或自身免疫性疾病,包括但不局限于类风湿性关节炎、多关节炎、类风湿性脊柱炎、骨关节炎、痛风、哮喘、支气管炎、变应性鼻炎、慢性阻塞性肺病、囊性纤维化病、炎性肠病、肠易激综合征、粘液性结肠炎、溃疡性结肠炎、溃破性结肠炎(diabrotic colitis)、克罗恩病、自身免疫性甲状腺病、胃炎、食管炎、肝炎、胰腺炎、肾炎、银屑病、湿疹、寻常痤疮、皮炎、荨麻疹、多发性硬化症、阿尔茨海默病、运动神经元病(Lou Gehrig病)、佩吉特疾病、败血症、结膜炎、鼻卡他(neranlcatarrh)、慢性关节风湿病、全身炎症反应综合征(SIRS)、多发性肌炎、皮肌炎(DM)、结节性多动脉炎(Polaritis nodoa)(PN)、混合型结缔组织病(MCTD)、干燥综合征、克鲁宗综合征、软骨发育不全、系统性红斑狼疮、硬皮病、血管炎、致死性发育不全、胰岛素抗性、I型糖尿病以及糖尿病导致的并发症和代谢综合征。
术语“过度增殖性疾病”包括癌症和骨髓增殖性疾病状态例如细胞增殖性疾病状态,包括但不局限于:心脏:肉瘤(血管肉瘤、纤维肉瘤、横纹肌肉瘤、脂肪肉瘤)、粘液瘤、横纹肌瘤、纤维瘤、脂肪瘤和畸胎瘤;肺:支气管原癌(鳞状细胞癌、未分化的小细胞癌、未分化的大细胞癌、腺癌)、肺泡(细支气管)癌、支气管腺瘤、肉瘤、淋巴瘤、软骨性过误瘤(chondromatous hanlartoma)、中皮瘤(inesothelioma);胃肠道:食道(鳞状细胞癌、腺癌、平滑肌肉瘤、淋巴瘤)、胃(癌、淋巴瘤、平滑肌肉瘤)、胰(导管腺癌、胰岛素瘤、高血糖素瘤、胃泌素瘤、类癌瘤、舒血管肠肽瘤)、小肠(腺癌、淋巴瘤、类癌瘤、卡波西肉瘤、平滑肌瘤、血管瘤、脂肪瘤、神经纤维瘤、纤维瘤)、大肠(腺癌、管状腺瘤、绒毛状腺瘤、错构瘤、平滑肌瘤);泌尿生殖道:肾(腺癌、维尔姆斯肿瘤[肾母细胞瘤]、淋巴瘤、白血病)、膀胱和尿道(鳞状细胞癌、移行细胞癌、腺癌)、前列腺(腺癌、肉瘤)、睾丸(精原细胞瘤、畸胎瘤、胚胎性癌、畸胎癌、绒毛膜癌、肉瘤、间质细胞癌、纤维瘤、纤维腺瘤、腺瘤样瘤、脂肪瘤);肝:肝细胞性肝癌(肝细胞癌)、胆管上皮癌、肝母细胞瘤、血管肉瘤、肝细胞性腺瘤、血管瘤;骨:成骨性肉瘤(骨肉瘤)、纤维肉瘤、恶性纤维组织细胞瘤、软骨肉瘤、尤因肉瘤、恶性淋巴瘤(网状细胞肉瘤)、多发性骨髓瘤、恶性巨细胞肿瘤、脊索癌、骨软骨瘤(骨软骨外生骨疣)、良性软骨瘤、软骨母细胞瘤、软骨粘液样纤维瘤(chondromyxofibroma)、骨样骨瘤和巨细胞瘤;神经系统:颅骨(骨瘤、血管瘤、肉芽肿、黄色瘤、畸形性骨炎)、脑膜(脑膜瘤、脑膜肉瘤、神经胶质瘤)、脑(星形细胞瘤、髓母细胞瘤、神经胶质瘤、室管膜瘤、生殖细胞瘤[松果体瘤]、胶质母细胞瘤、少突神经胶质瘤、神经鞘瘤、视网膜母细胞瘤、先天性肿瘤)、脊髓神经纤维瘤、脑膜瘤、神经胶质瘤、肉瘤);妇科:子宫(子宫内膜癌)、子宫颈(宫颈癌、肿瘤前宫颈发育不良(pre-tumor cervical dysplasia))、卵巢(卵巢癌[浆液囊腺癌、粘液性囊腺癌、未分类的癌]、颗粒-泡膜细胞瘤(granulosa-thecal cell tumors)、Sertoli-Leydig细胞瘤、无性细胞瘤、恶性畸胎瘤)、外阴(鳞状细胞癌、上皮内癌、腺癌、纤维肉瘤、黑色素瘤)、阴道(透明细胞癌、鳞状细胞癌、葡萄状肉瘤[胚胎性横纹肌肉瘤])、输卵管(癌);血液学:血液(髓样白血病[急性和慢性]、急性成淋巴细胞性白血病、慢性淋巴细胞白血病、多发性骨髓瘤、骨髓增生异常综合征)、霍奇金病、非霍奇金淋巴瘤[恶性淋巴瘤;皮肤:恶性黑色素瘤、基底细胞癌、鳞状细胞癌、卡波西肉瘤、发育异常痣、脂肪瘤、血管瘤、皮肤纤维瘤、瘢痕瘤、银屑病;肾上腺:神经母细胞瘤;和骨髓增殖性疾病例如真性红细胞增多症(PV)、原发性骨髓纤维化、血小板增多症、自发性血小板增多(ET)、原因不明性髓样化生(AMM)(也被称为特发性骨髓纤维化症(IMF))、慢性髓性白血病(CML)、系统性肥大细胞增多症(SM)、慢性嗜中性粒细胞白血病(CNL)、骨髓增生异常综合征(MDS)和系统性肥大细胞病(SMCD)。在某些实施方案中,所述骨髓纤维化疾病选自真性红细胞增多症(PV)、原发性骨髓纤维化、血小板增多症和自发性血小板增多(ET)。在一个实施方案中,本申请的药物组合物可适用于治疗骨髓增殖性疾病,其中所述骨髓纤维化疾病选自真性红细胞增多症(PV)、原发性骨髓纤维化、血小板增多症和自发性血小板增多(ET)。在一些实施方案中,本申请的药物组合物可适用于治疗原发性骨髓纤维化。
术语“血管疾病”是指包括但不局限于心血管疾病、高血压、肥大、高胆固醇血症、高脂血症、血栓病、卒中、雷诺现象、POEMS综合征、心绞痛、缺血、偏头痛、外周动脉病、心力衰竭、再狭窄、动脉粥样硬化、左心室肥大症、心肌梗塞、心脏缺血性疾病、肾脏缺血性疾病、肝脏缺血性疾病和脑缺血性疾病、和肺动脉高压的疾病。
对于JAK2选择性抑制剂,优选的疾病包括免疫性疾病和炎性疾病例如自身免疫性疾病如特应性皮炎、哮喘、类风湿性关节炎、克罗恩病、银屑病、克鲁宗综合征、软骨发育不全、系统性红斑狼疮、硬皮病、混合型结缔组织病、血管炎、致死性发育不全和糖尿病;过度增殖性疾病例如癌症如前列腺癌、结肠癌、乳腺癌、肝癌例如肝细胞性肝癌、肺癌、头颈癌例如神经胶质瘤、皮肤癌例如转移性黑色素瘤、白血病、淋巴瘤、多发性骨髓瘤,和骨髓增殖性疾病例如真性红细胞增多症(PV)、骨髓纤维化、血小板增多症、自发性血小板增多(ET)、原因不明性髓样化生(AMM)(也被称为特发性骨髓纤维化(IMF))和慢性髓性白血病(CML);和血管疾病例如高血压、肥大、卒中、雷诺现象、POEMS综合征、心绞痛、缺血、偏头痛、外周动脉病、心力衰竭、再狭窄、动脉粥样硬化和肺动脉高压。
在其他实施方案中,所述疾病是实体瘤。作为实例,所述实体瘤包括但不限于胰腺癌、膀胱癌、结肠直肠癌、乳腺癌、前列腺癌、肾脏癌(renal cancer)、肝细胞癌、肺癌、卵巢癌、子宫颈癌、直肠癌、肝癌、肾癌(kidney cancer)、胃癌(stomach cancer)、皮肤癌、胃部癌(gastric cancer)、食管癌、头颈癌、黑素瘤、神经内分泌癌、CNS癌症(例如神经母细胞瘤)、脑肿瘤(例如神经胶质瘤、间变性少突胶质细胞瘤、成人成胶质细胞瘤、以及成人间变性星形细胞瘤)、骨癌或软组织肉瘤。在一些实施方案中,所述实体瘤是非小细胞肺癌、小细胞肺癌、结肠癌、CNS癌、黑素瘤、卵巢癌、肾脏癌、胰腺癌、前列腺癌或乳腺癌。在一些具体实施方案中,所述实体瘤是非小细胞肺癌、结肠癌、胰腺癌或乳腺癌。在进一步的实施方案中,所述实体瘤是非小细胞肺癌。在一个实施方案中,所述实体瘤是转移性非小细胞肺癌(NSCLC)。在一些实施方案中,所述实体瘤是表皮生长因子受体(EGFR)突变的EGFR酪氨酸激酶抑制剂(TKI)原初转移性非小细胞肺癌(NSCLC)。举例来说,EGFR突变可以是EGFRexon 19缺失或外显子21(L858R)取代突变。在某些实施方案中,实体瘤是转移性柯斯顿大鼠肉瘤病毒癌基因同源物(KRAS)突变的非小细胞肺癌(NSCLC)。在又进一步的一些实施方案中,实体瘤是结肠癌。在另外的实施方案中,实体瘤是胰腺癌。在另一些实施方案中,实体瘤是转移性胰腺导管腺癌。在甚至进一步的实施方案中,实体瘤是乳腺癌。
在本发明的一些其它方法中,CYT387或其形式(包括CYT-0387二盐酸盐一水合物形式II)用于保持或提高在经受贫血或血红蛋白下降的受试者中的血红蛋白水平。贫血受试者具有比相同年龄和性别的健康受试者的正常水平更低的内源性血红蛋白水平。可接受的或“正常”的水平目前在医疗实践中已完全确定。对于成年人类男性,当血红蛋白水平低于约13.0g/dL时,贫血是明显的;对于非怀孕的成年人类女性,当血红蛋白低于约12.0g/dL时,不足是明显的。利用完全确立的技术来进行血红蛋白水平的测定。当血红蛋白水平小于约8.0g/dL时,严重贫血的状态是明显的。
在使用中,向贫血受试者给药有效保持或提高所述受试者中血红蛋白水平的量的CYT387。由此,所述药物的给药在所治疗的受试者中具有抑制血红蛋白水平进一步降低的最小效力。更期望地,所述药物的给药在所述受试者中具有增加血红蛋白水平的效力。
会得益于用CYT387的治疗的贫血受试者包括已经受或正在经受化疗或放疗的受试者,例如癌症患者。已知许多种化疗剂具有降低功能性红细胞的水平的后果。此外,作为CYT387治疗候选者的受试者是罹患包括血癌在内的、导致红细胞计数降低或与红细胞计数降低有关的血液病症的受试者。在实施方案中,要治疗的受试者是具有与诸如骨髓增生异常综合征的血液病症相关或由其导致的贫血的受试者。骨髓增生异常综合征(MDS)是用于描述特征为导致血液细胞减少和骨髓细胞过多的无效血细胞生成的一组疾病的术语。由于转化为急性髓细胞性白血病(AML)的风险增加,MDS惯常被认为与“白血病前期”是同义的。向AML的进展和细胞减少的临床结果是MDS的发病率和死亡率的主要原因。DMS的虚弱症状包括疲劳、苍白、感染和出血。贫血、嗜中性粒细胞减少症和血小板减少也为MDS的常见临床表现。在其他实施方案中,要治疗的受试者是具有与其他血液病症有关或由其导致的贫血的受试者,所述其他血液病症例如为与其他恶性血液病相关的贫血、再生障碍性贫血、影响红细胞的慢性疾病的贫血等。慢性疾病的贫血与诸如以下的疾病有关:包括淋巴瘤和霍奇金氏病在内的某些癌症;诸如类风湿性关节炎、系统性红斑狼疮、炎性肠病和风湿性多肌痛的自身免疫疾病;诸如尿路感染、HIV和骨髓炎的长期感染;心衰;以及慢性肾病。此外,患有由与增加的破坏、缩短的红细胞存活和脾隔离症相关的病症造成的贫血的患者也可得益于CYT387治疗。由此,可以治疗罹患这些病症的患者以改善他们的血红蛋白下降或不足的状态。
在某些实施方案中,要治疗的受试者是经受地中海贫血的贫血受试者。在其他实施方案中,要治疗的受试者是除经受地中海贫血的受试者之外的受试者。
在实施方案中,向诊断患有诸如骨髓增殖性肿瘤的骨髓增殖性疾病的受试者给药本发明的CYT387形式(诸如CYT-0387二盐酸盐一水合物形式II),由此改善疾病的进展,并在一些实施方案中特别用于治疗与所述疾病相关的血红蛋白不足或下降。在其他实施方案中,向除诊断患有骨髓增殖性疾病的贫血受试者之外的贫血受试者给药本发明的CYT387形式(诸如CYT-0387二盐酸盐一水合物形式II)。这类可治疗的受试者具有与骨髓增殖性疾病不相关的贫血。在一些实施方案中,本申请的CYT-0387形式诸如CYT-0387二盐酸盐一水合物形式II给药于诊断患有癌症的贫血受试者。
“骨髓增殖性疾病”和“骨髓增殖性肿瘤(MPN)”,最特别地,真性红细胞增多症(PV)、原发性血小板增多症(ET)和原发性骨髓纤维化(PMF)是多能造血干细胞的一组不同但互相关联的同源细胞病症(clonal disorders),所述病症共同具有一系列的生物学、病理学和临床特征,包括:骨髓来源的一种或多种细胞的相对过度产生、非生长因子依赖性的体外克隆形成、骨髓细胞过多、髓外造血、脾肿大和肝肿大,以及血栓形成素质和/或出血素质。已经成立了骨髓增殖性肿瘤研究和治疗国际工作小组(IWG-MRT)以描述和定义这些病症(参见,例如Vannucchi等人,CA Cancer J.Clin.,2009,59:171-191),并且那些疾病定义要用于本说明书的目的。在本领域中,利用上述IWG-MRT标准可鉴别具有MPN并且特别是PMF的受试者,最特别地是人类患者。处于特定形式的MPN的“风险”的受试者是具有该疾病的早期形式的受试者,并且可以例如包括具有其遗传标记(例如JAK2V617F等位基因,其与以下相关:PV(>95%)、ET(60%)以及PMF(60%))的受试者。如果受试者已经表现出更早期形式的症状,则也认为他们处于MFN的形式的“风险”。因此,具有MFN的受试者处于PV后和ET后(二者均在MPN之后形成)的风险。
当根据本发明,MPN患者以及特别是PMF患者是基于下列标准中的一个或多个而被选择用于CYT387治疗的患者时,则他们对CYT387治疗的反应是特别强烈的:
(i)使用选自下列的药物的既往治疗:沙利度胺、来那度胺、泊马度胺以及除CYT387之外的JAK2抑制剂;
(ii)选自下列之一或二者的临床标准:(1)脾尺寸更小和(2)更低的循环胚细胞百分比;
(iv)选自下列之一或多种的生化标记物标准:(1)选自EGF、TNF-α、G-CSF、IFN-α、MIP-1β、HGF、MIG和VEGF的至少一种蛋白的水平增加;(2)嗜酸细胞活化趋化因子的水平降低;以及(3)选自EPO、铁调素和BMP-2的至少一种蛋白的水平变化;
由现有患者选择产生的CYT387治疗的改善的结果表现为在贫血反应和/或在脾反应方面的强烈改善。“贫血反应”是指患者血红蛋白水平的增加或输血依赖性患者变成非输血依赖性。期望地,实现持续最少8周的为2.0g/dL的血红蛋白的最小增加,这是国际工作小组(IWG)一致标准所规定的改善水平。然而,更小但仍是医疗显著性的血红蛋白增加也被认为在术语“贫血反应”的范围之内。
“脾反应”是指患者脾尺寸的减小,这是通过在体检期间触诊以前可触及的脾或通过诊断显像来评估的。IWG一致标准规定,在基线(治疗前)时为至少10cm的脾的可触及的脾肿大(脾增大)降低最小50%,或者在基线时在多于5cm处可触及的脾变得不可触及。然而,更小的降低也被认为在术语“脾反应”的范围之内。
在一个实施方案中,所选患者为已经接受既往药物治疗的患者。更具体地,选择用于CYT387治疗的患者包括已经使用沙利度胺(CAS号50-35-1)或使用其衍生物、特别是来那度胺(CAS号191732-72-6)治疗或正在进行该治疗的患者。这些药物均用于治疗多发性骨髓瘤,并且还似乎在罹患骨髓增殖性病症的患者中表现出一些益处。为了接受由随后的CYT387治疗产生的其他益处,患者会接受使用沙利度胺、来那度胺、泊马度胺或类似药剂的治疗,或者会用这些药物之一在相对于CYT387治疗启动并足以表现出这些药物的效力的时间范围内治疗。当随后用CYT387治疗时,相对于未接受该药物治疗的患者,满足这些标准的患者经受显著的贫血反应。在一个优选实施方案中,CYT387患者是接受使用来那度胺的既往治疗的患者。
选择用于CYT387治疗的患者还包括已经使用除CYT387之外的JAK抑制剂治疗或正在进行该治疗的患者。还特别发现,以前用称为INCB018424的JAK抑制剂或称为TG101348的JAK抑制剂治疗的患者与未经受这样的既往治疗的患者相比,具有更显著的对CYT387治疗的脾反应。在一个优选实施方案中,选择用于CYT387治疗的患者是除接受用除CYT387之外的JAK抑制剂的治疗之外,还是输血依赖性患者的患者。以15mg po BID或20mg po BID的起始剂量,并且以5mg BID至25mg BID的剂量递增,给药INCB018424。每天一次给药TG101348,并且最大耐受剂量(MTD)确定为680mg/天。除CYT387之外的JAK抑制剂包括所有以及任何其他JAK抑制剂,并且特别包括与CYT387在JAK亲和力、选择性或结合位点方面不同的其他JAk抑制剂。可以用US 7593820(其全部公开内容通过援引加入本文)中描述的JAK2晶体结构和建模方法以及活性测定来测定这些性质。为了接受由随后的CYT387治疗产生的其他益处,患者会接受使用其他JAK2抑制剂的治疗或会用这类药物在相对于CYT387治疗启动并足以在所述患者中表现出该JAK2抑制剂的效力的时间范围内治疗。
选择用于CYT387治疗的患者还包括具有可检测蛋白标记物水平变化的患者。更具体地,其中包括某些细胞因子和趋化因子在内的某些蛋白标记物的水平提高的患者,当用CYT387治疗时,在他们对CYT387治疗的贫血反应和/或脾反应方面能经受显著的益处。在实施方案中,下列蛋白标记物中的一种或多种的水平的提高表示患者是CYT387治疗的优选候选者:
(1)EGF或表皮生长因子,其成熟形式包括Swiss-Prot名称为P01133的序列的残基971-1023;
(2)TNF-α或肿瘤坏死因子α,其成熟且可溶形式包括Swiss-Prot名称为P01375的序列的残基77-233;
(3)G-CSF或粒细胞集落刺激因子,其成熟形式包括Swiss-Prot名称为P09919的序列的残基30-207;
(4)IFN-α或干扰素α,其包括亚型家族,其成熟形式是本领域公知的;
(5)MIP-1β或巨噬细胞炎性蛋白1-β(目前还已知为C-C模体趋化因子4或CCL4),其成熟形式包括Swiss-Prot名称为P13236的序列的残基24-92或26-92;
(6)HGF或肝细胞生长因子,其成熟形式基于Swiss-Prot名称为P14210的序列并包括具有残基32-494的α链和具有残基495-728的β链;
(7)MIG或通过γ干扰素诱导的单核因子(目前还已知为CXCL9),其在趋化细胞因子家族内,其成熟形式包括Swiss-Prot名称为Q07325的序列的残基23-125;
(8)VEGF或血管内皮生长因子A,其成熟形式包括Swiss-Prot名称为P15692的序列的残基27-232。
提供用于CYT387治疗的患者,当他们最初基于上述标记物中任一种或多种的水平提高而被选择时,经受显著的脾反应。提高的水平是大于正常受试者的水平的水平。
提供用于CYT387治疗的患者,当他们最初基于蛋白嗜酸细胞活化趋化因子水平的抑制而被选择时,还可经受显著的贫血反应。该蛋白还已知为嗜酸细胞活化趋化蛋白并包括Swiss-Prot名称为P51671的序列的残基24-97,该蛋白通过与CC3相互作用而用于促进应答变应原的嗜酸性粒细胞聚集(变应性炎性反应的显著特征)。
可用于选择进行CYT387治疗的患者的其他标记物包括EPO、铁调素和BMP-2的水平变化。可用于选择进行CYT387治疗的患者的标记物的另一实例包括BMP-6的水平。
其他标记物可用于监控CYT-0387治疗或给药方案。举例来说,所述标记物可包括但不限于化合物3、化合物4、化合物8、化合物10、化合物12和化合物13。这些标记物的水平可通过常用的方法诸如本申请实施例中所述的那些方法检测。
当在给定患者中测定的给定标记物的水平与正常受试者中的相应水平的差异达到统计学显著的程度时,则认为给定标记物的“水平”发生变化,即提高或降低。所具有的标记物水平的变化达到足以期望地获得至少0.05或更高显著性(即,更好)的p值的程度的患者被选作CYT387治疗的候选者。在实施方案中,p值至少为0.03、0.02或0.01,并且在优选实施方案中,p值至少为0.009、0.007、0.005、0.003、0.001或更好。
可利用已经完全确立的用于检测上述标记物的分析来测定给定标记物的水平。在实施方案中,这是通过从患者候选者中提取生物样品(例如全血样品或者其部分如血浆或血清的样品)来实现的。然后,若需要,对所述样品进行处理以富集目标标记物,并且例如利用所述标记物的可检测配体,例如与所述标记物特异性结合的标记抗体,来测定富集或纯的样品。然后,可以半定量或定量地测定在所述样品中存在的标记物的量以获得值,然后将所述值与参考值(为所述标记物在健康受试者中的正常水平)进行比较。如上所述,足以达到至少0.05的p值的标记物水平的差异指示显著的标记物水平变化,并且具有提高水平的该标记物(或在嗜酸细胞活化趋化因子的情况下,为降低的水平)的患者为CYT387治疗的候选者。
还适于作为CYT387治疗的候选者的是满足某些临床标准的那些患者,包括具有相对小尺寸的脾的那些患者以及具有提高水平的循环或外周胚细胞的那些患者。这些患者在他们的脾反应方面对CYT387治疗的反应特别好。在一个实施方案中,所选患者是还未进展成输血依赖性的患者。由触诊来评价脾增大。脾尺寸和体积还可以通过诊断显像(例如超声、CT或MRI)来测定。正常的脾尺寸为头尾向长度约11.0cm。
还适于作为CYT387治疗候选者的是具有更低的循环胚细胞百分比的那些患者。胚细胞是未成熟的前体细胞,其通常在骨髓中发现而不在外周血中发现。它们通常产生成熟血细胞。通过外周血涂片的细胞形态分析以及多参数流式细胞仪和免疫组织化学来测定所述更低的循环胚细胞百分比。使用>/=1%的胚细胞作为预后因子。
根据本申请的化合物可以与一种或多种治疗剂组合使用。所述治疗剂可以是化合物、抗体、多肽或多核苷酸的形式。治疗剂包括但不限于化学治疗剂、免疫治疗剂、放射治疗剂,抗肿瘤剂,抗癌剂,抗增殖剂,抗纤维化剂、抗血管形成剂、治疗用抗体,或其任意组合。
在一个实施方案中,本申请提供本文所述的制剂和另外的治疗剂,作为组合制剂(preparation)用于在治疗例如治疗由JAK介导的疾病、障碍或病症的方法中同时、分开或先后使用。所述治疗剂可为抑制或调节以下激酶活性的那些:布鲁顿酪氨酸激酶、脾酪氨酸激酶、凋亡信号调节激酶、Janus激酶、赖氨酰氧化酶、赖氨酰氧化酶-样蛋白、基质金属肽酶、含溴结构域蛋白、腺苷A2B受体、异柠檬酸脱氢酶、丝氨酸/苏氨酸激酶TPL2、盘状结构域受体(discoidin domain receptor)、丝氨酸/苏氨酸-蛋白激酶、IKK、MEK、EGFR、组蛋白脱乙酰基酶、蛋白激酶C,或其任意组合。在某些实施方案中,所述治疗剂可选自PI3K(包括PI3Kγ,PI3Kδ,PI3Kβ,PI3Kα,和/或泛-PI3K)抑制剂、JAK(Janus激酶,包括JAK1,JAK2,和/或JAK3)抑制剂、SYK(脾酪氨酸激酶)抑制剂、BTK(布鲁顿酪氨酸激酶)抑制剂、A2B(腺苷A2B受体)抑制剂、ACK(活化的CDC激酶,包括ACK1)抑制剂、ASK(凋亡信号调节激酶,包括ASK1)抑制剂,Auroa激酶、BRD(含溴结构域蛋白,包括BRD4)抑制剂、Bcl(B-细胞CLL/淋巴瘤,包括Bcl-1和/或Bcl-2)抑制剂、CAK(CDK-活化激酶)抑制剂、CaMK(钙调蛋白-依赖性蛋白激酶)抑制剂、CDK(细胞周期蛋白依赖性激酶,包括CDK1、2、3、4和/或6)抑制剂、CK(酪蛋白激酶,包括CK1和/或CK2)抑制剂、DDR(盘状结构域受体,包括DDR1和/或DDR2)抑制剂、EGFR抑制剂、FXR(法尼醇x受体)抑制剂、FAK(粘着斑激酶)抑制剂、GSK(糖原合酶激酶)抑制剂、HDAC(组蛋白脱乙酰基酶)抑制剂、IDO(吲哚胺2,3-二氧化酶)抑制剂、IDH(异柠檬酸脱氢酶,包括IDH1)抑制剂、IKK(l-Kappa-B激酶)抑制剂、KDM5(赖氨酸脱甲基酶)抑制剂、LCK(淋巴细胞-特异性蛋白酪氨酸激酶)抑制剂、LOX(赖氨酰氧化酶)抑制剂、LOXL(赖氨酰氧化酶样蛋白,包括LOXL1,LOXL2,LOXL3,LOXL4,和/或LOXL5)抑制剂、MTH(mut T同系物)抑制剂、MEK(促分裂原-活化的蛋白激酶激酶)抑制剂、基质金属蛋白酶(MMP,包括MMP2和/或MMP9)抑制剂、促分裂原-活化的蛋白激酶(MAPK)抑制剂、PD-1(程序性细胞死亡蛋白1)抑制剂、PD-L1(程序性死亡-配体1)抑制剂、PDGF(血小板-衍生的生长因子)抑制剂、磷酸化酶激酶(PK)抑制剂、PLK(polo样激酶,包括PLK1、2、3)抑制剂、蛋白激酶(PK,包括蛋白激酶A、B、C)抑制剂、STK(丝氨酸/苏氨酸激酶)抑制剂、STAT(信号转导和转录)抑制剂、丝氨酸/苏氨酸-蛋白激酶抑制剂、TBK(tank-结合激酶)抑制剂、TLR(toll样受体调节剂,包括TLR-1,TLR-2,TLR-3,TLR-4,TLR-5,TLR-6,TLR-7,TLR-8,TLR-9,TLR-10,TLR-11,TLR-12,和/或TLR-13)抑制剂、TK(酪氨酸激酶)抑制剂、TPL2(丝氨酸/苏氨酸激酶)抑制剂、NEK9抑制剂、Abl抑制剂、p38激酶抑制剂、PYK抑制剂、PYK抑制剂、c-Kit抑制剂、NPM-ALK抑制剂、Flt-3抑制剂、c-Met抑制剂、KDR抑制剂、TIE-2抑制剂、VEGFR抑制剂、SRC抑制剂、HCK抑制剂、LYN抑制剂、FYN抑制剂、YES抑制剂、化学治疗剂、免疫治疗剂、放射治疗剂、抗肿瘤剂、抗癌剂、抗增殖剂、抗纤维化剂、抗血管形成剂、治疗用抗体,或其任意组合。在一些实施方案中,所述PI3K-δ抑制剂为(S)-2-(1-((9H-嘌呤-6-基)氨基)丙基)-5-氟-3-苯基喹唑啉-4(3H)-酮(通过ChemDraw命名)(也可称为5-氟-3-苯基-2-[(1S)-1-(9H-嘌呤-6-基氨基)丙基]喹唑啉-4(3H)-酮)且可通过美国专利号7,932,260所述的方法合成。在某实施方案中,该SyK抑制剂为6-(1H-吲唑-6-基)-N-(4-吗啉代苯基)咪唑并[1,2-a]吡嗪-8-胺(通过ChemDraw命名)(也可称为6-(1H-吲唑-6-基)-N-[4-(吗啉-4-基)苯基]咪唑并[1,2-a]吡嗪-8-胺)且可通过美国专利号8,450,321所述的方法合成。在其它实施方案中,BTK抑制剂为按照ChemDraw命名的(S)-6-氨基-9-(1-(丁-2-炔酰基)吡咯烷-3-基)-7-(4-苯氧基苯基)-7H-嘌呤-8(9H)-酮(也可为6-氨基-9-[(3R)-1-(2-丁炔酰基)-3-吡咯烷基]-7-(4-苯氧基苯基)-7,9-二氢-8H-嘌呤-8-酮),且可通过美国专利8,557,803的方法合成。在某些实施方案中,MEK抑制剂是曲美替尼(trametinib)。在一些实施方案中,EGFR抑制剂是厄洛替尼(erlotinib)。在一个实施方案中,本申请的制剂可以与PI3K抑制剂、MEK抑制剂、TBK抑制剂、EGFR抑制剂或其组合一起使用。在另外的实施方案中,本申请的制剂可以与曲美替尼组合使用。在其它的实施方案中,本申请的制剂可以与厄洛替尼组合使用。
化疗剂可由其作用机理分类为例如下组:抗代谢/抗癌剂,例如嘧啶类似物(氟尿苷、卡培他滨、和阿糖胞苷);和嘌呤类似物、叶酸拮抗剂和相关抑制剂;抗增殖/抗有丝分裂剂,包含天然产物例如长春花生物碱(长春碱、长春新碱、和微管蛋白抑制剂例如紫杉烷(紫杉醇、多西紫杉醇)、长春碱、诺考达唑、埃坡霉素(epothilone)和诺维本(navelbine)、表鬼臼毒素(epidipodophyllotoxins)(依托泊苷、替尼泊苷);DNA破坏剂(放线菌素、安吖啶、白消安、卡铂、苯丁酸氮芥、顺铂、环磷酰胺(cyclophosphamide)、环磷酰胺(Cytoxan)、放线菌素D、柔红霉素、多柔比星、表柔比星、异环磷酰胺、美法仑、氮芥(merchlorehtamine)、丝裂霉素、米托蒽醌、亚硝基脲、丙卡巴肼、紫杉酚、泰索帝、替尼泊苷、依托泊苷、三亚乙基硫代磷酰胺;抗生素例如更生霉素(放线菌素D)、柔红霉素、多柔比星(阿霉素)、伊达比星、蒽环类抗生素、米托蒽醌、博来霉素、普卡霉素(光神霉素)和丝裂霉素;酶(L-天门冬酰胺酶,全身性代谢L-天冬酰胺和消灭没有能力合成其自身天冬酰胺的细胞);抗血小板剂;抗增殖/抗有丝分裂烷化剂,例如氮芥环磷酰胺及类似物,美法仑、苯丁酸氮芥),和(六甲蜜胺和塞替哌)、烷基亚硝基脲(BCNU)及类似物,链佐星)、三氮烯-达卡巴嗪(DTIC);抗增殖/抗有丝分裂抗代谢剂,例如叶酸类似物(氨甲喋呤);铂配位复合物(顺铂、奥沙利铂(oxiloplatinim)、卡铂)、丙卡巴肼、羟基脲、米托坦、氨鲁米特;激素、激素类似物(雌激素、他莫昔芬、戈舍瑞林(goserelin)、比卡鲁胺(bicalutamide),尼鲁米特(nilutamide))和芳香酶抑制剂(来曲唑、阿那曲唑);抗凝剂(肝素、合成肝素盐和其他凝血酶抑制剂);纤维蛋白溶解剂(例如组织纤溶酶原激活剂,链激酶和尿激酶)、阿司匹林、双嘧达莫、噻氯匹定、氯吡格雷;抗转移剂;抑分泌剂(布雷菲德菌素(breveldin));免疫抑制剂、他克莫司、西罗莫司、硫唑嘌呤、霉酚酸酯;化合物(TNP-470、染料木黄酮)和生长因子抑制剂(血管内皮生长因子抑制剂、成纤维细胞生长因子抑制剂);血管紧张素受体阻滞剂,一氧化氮供体;反义寡核苷酸;抗体(曲妥珠单抗、利妥昔单抗);细胞周期抑制剂和分化诱导剂(维甲酸);抑制剂,拓扑异构酶抑制剂(多柔比星(阿霉素)、柔红霉素、更生霉素、替尼泊苷、表柔比星、依托泊苷、伊达比星、伊立替康和米托蒽醌、拓扑替康、伊立替康、喜树碱),皮质激素(可的松、地塞米松、氢化可的松、甲基泼尼松龙、泼尼松和泼尼松龙);生长因子信号转导激酶抑制剂;功能障碍诱导剂,毒素例如霍乱毒素、蓖麻毒素、假单胞菌外毒素、百日咳杆菌腺苷酸环化酶毒素,或白喉毒素,和胱天蛋白酶激活剂;和染色质。
本文所用的术语“化疗剂”或“化疗药”(或“化疗”,在用化疗剂的治疗的情况中)指包含用于治疗癌症的任何非蛋白质的(即非肽的)化学化合物。化疗剂的实例包含烷化剂,例如塞替哌和环磷酰胺(CYTOXAN);烷基磺酸酯诸如白消安、英丙舒凡和哌泊舒凡;氮丙啶如benzodopa、卡波醌、meturedopa和uredopa;乙撑亚胺(ethylenimine)和甲基氨基吖啶(methylamelamine),包括六甲蜜胺、三亚胺嗪(triethylenemelamine)、三亚乙基磷酰胺(triethylenephosphoramide)、三亚乙基硫化磷酰胺(triethylenethiophosphoramide)和三羟甲蜜胺(trimethylomelamine);番荔枝内酯(acetogenin)(尤其是布拉它辛(bullatacin)和布拉它辛酮(bullatacinone));喜树碱(包括合成性类似物托泊替康(topotecan));苔藓抑素(bryostatin);callystatin;CC-1065(包括其阿多来新(adozelesin)、卡折来新(carzelesin)和比折来新(bizelesin)合成性类似物);cryptophycins(特别是cryptophycin 1和cryptophycin 8);多拉司他汀(dolastatin);duocarmycin(包括合成性类似物KW-2189和CB1-TM1);艾榴塞洛素(eleutherobin);pancratistatin;sarcodictyin;spongistatin;氮芥如苯丁酸氮芥、萘氮芥、氯磷酰胺(chlorophosphamide)、雌莫司汀、异环磷酰胺、双氯乙基甲胺(mechlorethamine)、盐酸氧氮芥(mechlorethamine oxide hydrochloride)、美法仑、新氮芥(novembichin)、苯芥胆甾醇(phenesterine)、泼尼莫司汀(prednimustine)、曲磷胺(trofosfamide)、尿嘧啶氮芥(uracil mustard);硝基脲如卡莫司汀、氯脲菌素(chlorozotocin)、福莫司汀、洛莫司汀、尼莫斯汀和雷莫司汀;抗生素如烯二炔(enediyne)抗生素(例如刺孢霉素(calicheamicin),尤其是刺孢霉素γ1I、刺孢霉素phiI1(AngewChem.Intl.Ed.Engl.199433:183-186);蒽环类抗生素(dynemicin),包括dynemicin A;二膦酸盐(bisphosphonate)如氯膦酸盐(clodronate);埃斯培拉霉素(esperamicin);以及新抑癌蛋白生色团(neocarzinostatin chromophore)和相关色蛋白烯二炔抗生素生色团(enediyne antibiotic chromophore)、aclacinomysin、放线菌素(actinomycin)、authramycin、偶氮丝氨酸(azaserine)、博来霉素、放线菌素C(cactinomycin)、carabicin、去甲柔红霉素(carminomycin)、嗜癌素(carzinophilin)、色霉素(chromomycin)、放线菌素D(dactinomycin)、柔红霉素(daunorubicin)、地拖比星(detorubicin)、6-重氮基-5-氧代-L-正亮氨酸(6-diazo-5-oxo-L-norleucine)、多柔比星(包括吗啉代-多柔比星、氰基吗啉代-多柔比星、2-吡咯啉子基-多柔比星和去氧多柔比星)、表柔比星(epirubicin)、依索比星、伊达比星、麻西罗霉素(marcellomycin)、丝裂霉素如丝裂霉素C、麦考酚酸(mycophenolic acid)、诺拉霉素(nogalamycin)、橄榄霉素(olivomycins)、培洛霉素(peplomycin)、泊非霉素(porfiromycin)、嘌罗霉素(puromycin)、三铁阿霉素(quelamycin)、罗多比星(rodorubicin)、链黑霉素(streptonigrin)、链佐星(streptozocin)、杀结核菌素(tubercidin)、乌苯美司(ubenimex)、净司他丁(zinostatin)、佐柔比星;抗代谢物如甲氨喋呤和5-氟尿嘧啶(5-FU);叶酸类似物如二甲叶酸、甲氨喋呤、喋罗呤(pteropterin)、三甲曲沙(trimetrexate);嘌呤类似物如氟达拉滨(fludarabine)、6-巯嘌呤、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(thioguanine);嘧啶类似物如安西他滨(ancitabine)、阿扎胞苷(azacytidine)、6-氮鸟苷(6-azauridine)、卡莫氟(carmofur)、阿糖胞苷(cytarabine)、二脱氧尿苷(dideoxyuridine)、去氧氟尿苷(doxifluridine)、伊诺他滨(enocitabine)、氟尿苷(floxuridine);雄激素如卡普睾酮(calusterone)、丙酸甲雄烷酮(dromostanolone propionate)、环硫雄醇(epitiostanol)、美雄烷(mepitiostane)、睾内酯(testolactone);抗肾上腺素(anti-adrenal)如氨鲁米特(aminoglutethimide)、米托坦(mitotane)、曲洛司坦(trilostane);叶酸补充剂(folicacid replenisher)如亚叶酸(frolinic acid);醋葡醛内酯(aceglatone);醛磷酰胺糖苷(aldophosphamide glycoside);氨基乙酰丙酸(aminolevulinic acid);恩尿嘧啶(eniluracil);安吖啶(amsacrine);bestrabucil;比生群(bisantrene);伊达曲杀(edatraxate);地磷酰胺(defofamine);秋水仙胺(demecolcine);地吖醌(diaziquone);elfornithine;依利醋铵(elliptinium acetate);埃坡霉素(epothilone);依托格鲁(etoglucid);硝酸镓(gallium nitrate);羟基脲(hydroxyurea);香菇多糖(lentinan);甲酰四氢叶酸;氯尼达明(lonidainine);美登醇(maytansinoid)如美登素(maytansine)和安丝菌素(ansamitocin);米托胍腙(mitoguazone);米托蒽醌(mitoxantrone);mopidanmol;根瘤菌剂(nitraerine);喷司他丁(pentostatin);蛋氨氮芥(phenamet);吡柔比星(pirarubicin);洛索蒽醌(losoxantrone);氟嘧啶;亚叶酸;鬼臼酸(podophyllinicacid);2-乙基肼;丙卡巴肼(procarbazine);PSK(r);雷佐生(razoxane);根霉素(rhizoxin);西佐喃(sizofiran);锗螺胺(spirogermanium);细交链孢菌酮酸(tenuazonicacid);三亚胺醌(triaziquone);2,2',2"-三氯三乙胺;单端孢菌毒素(trichothecene)(尤其是T-2毒素、verracurin A、杆孢菌素A和anguidine);乌拉坦;长春地辛;达卡巴嗪(dacarbazine);甘露莫司汀(mannomustine);二溴甘露醇(mitobronitol);二溴卫矛醇(mitolactol);哌泊溴烷(pipobroman);gacytosine;阿糖胞苷(arabinoside)(“Ara-C”);环磷酰胺;塞替派;紫衫烷,例如例如紫杉醇(TAXOL(r))和多西他赛(TAXOTERE(r));苯丁酸氮芥;吉西他滨(Gemzar(r));6-硫鸟嘌呤;巯基嘌呤;氨甲喋呤;铂类似物,例如顺铂和卡铂;长春碱;铂;依托泊苷(VP-16);异环磷酰胺;米托蒽醌;长春新碱(vancristine);长春瑞滨(Navelbine(r));诺消灵(novantrone);替尼泊苷(teniposide);伊达曲杀(edatrexate);柔红霉素;氨基喋呤;希罗达(xeoloda);伊班膦酸盐(ibandronate);CPT-11;拓扑异构酶抑制剂RFS 2000;二氟甲基鸟氨酸(difluoromethylornithine,DMFO);类视黄醇(retinoid)如视黄酸(retinoic acid);卡培他滨(capecitabine);FOLFIRI(氟尿嘧啶,甲酰四氢叶酸和伊立替康),和上述任何物质的药学可接受盐、酸或衍生物。在本申请中使用或包括一种或多种化学治疗剂。例如,吉西他滨(gemcitabine)、白蛋白结合型紫杉醇(nab-paclitaxel)、吉西他滨/白蛋白结合型紫杉醇、卡培他滨、奥沙利铂、以及卡培他滨/奥沙利铂可以与本申请的制剂一起使用。
“化疗剂”定义还包括用于调节或抑制激素对肿瘤作用的抗激素剂,例如抗雌激素剂和选择性雌激素受体调节剂(SERM),包括,例如他莫昔芬(包括NolvadexTM)、雷洛昔芬、屈洛昔芬、4-羟基他莫昔芬、曲沃昔芬、雷洛昔芬(keoxifene)、LY117018、奥那司酮和托瑞米芬(Fareston(r));芳香酶抑制剂,其调节肾上腺中调节雌激素的生成,例如4(5)-咪唑类、氨鲁米特(aminoglutethimide)、乙酸甲地孕酮(Megace(r))、依西美坦、福美坦、法倔唑、伏氯唑(Rivisor(r))、来曲唑(Femara(r))和阿那曲唑(Arimidex(r));和抗雄激素药,例如氟他胺、尼鲁米特、比卡鲁胺、亮丙瑞林和戈舍瑞林;和上述任何一个的药学上可接受盐、酸或衍生物。
抗血管新生药的示例包括但不限于,视黄酸和其衍生物、2-甲氧基雌二醇、血管他丁(r),内皮他丁(r)、舒拉明、角鲨胺、金属蛋白酶-1的组织抑制剂、金属蛋白酶-2的组织抑制剂、纤溶酶原激活物抑制剂-1、纤溶酶原激活物抑制剂-2、软骨衍生的抑制剂、紫杉醇(蛋白结合型紫杉醇)、血小板因子4、硫酸鱼精蛋白(鲱精蛋白)、硫酸化壳多糖衍生物(从雪花蟹壳中制备)、硫酸化多糖肽多糖复合物(sp-pg)、星形孢菌素、基质代谢调节物,包含例如脯氨酸类似物((1-氮杂环丁烷-2-羧酸(LACA)、顺羟基脯氨酸、d,I-3,4-脱氢脯氨酸、硫杂脯氨酸(thiaproline)、α-联吡啶、β-氨基丙腈富马酸、4-丙基-5-(4-吡啶)-2(3h)-噁唑酮;氨甲喋呤、米托蒽醌、肝素、干扰素、2-巨球蛋白血清、chimp-3、糜蛋白酶抑制素、β-环糊精十四硫酸酯、eponemycin;烟曲霉素、硫代苹果酸金钠、d-青霉胺(CDPT)、β-1-抗胶原酶-血清、α-2-抗纤溶酶、比生群、氯苯扎利二钠、n-2-羧基苯基-4-氯邻氨苯甲酸二钠或"CCA"、沙利度胺;血管抑制性类固醇、羧基氨基咪唑(cargboxynaminolmidazole);金属蛋白酶抑制剂如BB94。其他抗血管生成剂包含抗体,优选针对下述血管生长因子的单克隆抗体:β-FGF、α-FGF、FGF-5、VEGF同工型、VEGF-C、HGF/SF和Ang-1/Ang-2。参见Ferrara N.和Alitalo,K."Clinical application of angiogenic growth factors and their inhibitors"(1999)Nature Medicine5:1359-1364。
抗纤维化剂包括,但不限于,化合物如β-氨基丙腈(BAPN),以及以下公开的化合物:Palfreyman等人在1990年10月23日公开的名称为"Inhibitors of lysyl oxidase"的美国专利4,965,288公开的化合物,其涉及赖氨酰氧化酶抑制剂及其在治疗与胶原异常沉积相关的疾病和病症的用途;Kagan等人在1991年3月5日公开的名称为"Anit-fibroticagents and methods for inhibiting the activity of lysyl oxidase in situ usingadjacently positioned diamine analogue substrate"的美国专利4,997,854中的化合物,其涉及抑制LOX以治疗多种病理纤维化状态的化合物,其在此引入作为参考。其它示例性抑制剂描述于Palfreyman等人在1990年7月24日公开的名称为"Inhibitors of lysyloxidase"的美国专利4,943,593中的化合物,其涉及化合物如2-异丁基-3-氟-、氯-或溴-烯丙基胺;以及例如,美国专利5,021,456;美国专利5,5059,714;美国专利5,120,764;美国专利5,182,297;美国专利5,252,608中的化合物(涉及2-(1-萘基氧基甲基)-3-氟烯丙基胺);和美国专利申请号2004/0248871,其在此引入作为参考。示例性抗纤维化剂还包括与赖氨酰氧化酶的活性位点的羰基反应的伯胺,且更具体为那些在与羰基结合后产生经共振稳定的产物的伯胺,如以下伯胺:乙二胺、肼、苯基肼、以及它们的衍生物,氨基脲,和脲衍生物,氨基腈,如β-氨基丙腈(BAPN),或2-硝基乙基胺,不饱和或饱和卤代胺,如2-溴-乙基胺、2-氯乙基胺、2-三氟乙基胺、3-溴丙基胺、对-卤代苄基胺,硒代高半胱氨酸内酯。此外,该抗纤维化剂为铜螯合剂,渗透或不渗透细胞。示例性化合物包括间接抑制剂,如阻断醛衍生物(源自通过赖氨酰氧化酶对赖氨酰和羟赖氨酰残基的氧化脱氨)的化合物,如硫醇胺,特别是D-青霉胺,或其类似物如2-氨基-5-疏基-5-甲基己酸,D-2-氨基-3-甲基-3-((2-乙酰氨基乙基)二硫基)丁酸,对-2-氨基-3-甲基-3-((2-氨基乙基)二硫基)丁酸,4-((对-1-二甲基-2-氨基-2-羧基乙基)二硫基)丁烷硫化钠(sodium-4-((p-1-dimethyl-2-amino-2-carboxyethyl)dithio)butane sulphurate),2-乙酰氨基乙基-2-乙酰氨基乙烷硫醇磺酸盐(sulphanate),4-疏基丁烷亚磺酸钠三水合物。
免疫治疗剂包括且不限于适用于治疗患者的治疗性抗体;诸如阿巴伏单抗(abagovomab)、阿达木单抗(adecatumumab)、阿托珠单抗(afutuzumab)、阿仑单抗(alemtuzumab)、阿妥莫单抗(altumomab)、阿玛西单抗(amatuximab)、anatumomab、阿西莫单抗(arcitumomab)、巴维昔单抗(bavituximab)、贝妥莫单抗(bectumomab)、贝伐单抗(bevacizumab)、比伐珠单抗(bivatuzumab)、布林莫单抗(blinatumomab)、贝伦妥单抗(brentuximab)、坎妥珠单抗(cantuzumab)、卡妥索单抗(catumaxomab)、西妥昔单抗(cetuximab)、西他土珠(citatuzumab)、西妥木单抗(cixutumumab)、昔瓦土单抗(clivatuzumab)、康纳木单抗(conatumumab)、达土木单抗(daratumumab)、德珠单抗(drozitumab)、杜里土单抗(duligotumab)、杜西吉土单抗(dusigitumab)、地莫单抗(detumomab)、达西珠单抗(dacetuzumab)、达洛图单抗(dalotuzumab)、依美昔单抗(ecromeximab)、埃罗妥珠单抗(elotuzumab)、恩斯土昔单抗(ensituximab)、鄂托默单抗(ertumaxomab)、埃达珠单抗(etaracizumab)、法里土珠单抗(farietuzumab)、费拉妥珠单抗(ficlatuzumab)、非吉单抗(figitumumab)、法兰土单抗(flanvotumab)、浮土西单抗(futuximab)、加尼图单抗(ganitumab)、吉妥珠单抗(gemtuzumab)、吉瑞昔单抗(girentuximab)、格雷巴土木单抗(glembatumumab)、替伊莫单抗(ibritumomab)、伊戈伏单抗(igovomab)、伊姆加土珠单抗(imgatuzumab)、因达西单抗(indatuximab)、伊诺妥珠单抗(inotuzumab)、英妥木单抗(intetumumab)、伊匹单抗(ipilimumab)、伊妥木单抗(iratumumab)、拉贝珠单抗(labetuzumab)、来沙木单抗(lexatumumab)、林妥珠单抗(lintuzumab)、洛瓦土珠单抗(lorvotuzumab)、鲁卡木单抗(lucatumumab)、马帕木单抗(mapatumumab)、马妥珠单抗(matuzumab)、米拉珠单抗(milatuzumab)、明瑞莫单抗(minretumomab)、米妥莫单抗(mitumomab)、莫昔土莫单抗(moxetumomab)、纳纳土单抗(narnatumab)、那莫单抗(naptumomab)、耐昔妥珠单抗(necitumumab)、尼妥珠单抗(nimotuzumab)、诺伐木单抗(nofetumomabn)、奥卡拉珠单抗(ocaratuzumab)、奥伐木单抗(ofatumumab)、奥拉单抗(olaratumab)、奥那组单抗(onartuzumab)、奥普珠单抗(oportuzumab)、奥戈伏单抗(oregovomab)、帕尼单抗(panitumumab)、帕萨珠单抗(parsatuzumab)、帕特里土单抗(patritumab)、潘妥莫单抗(pemtumomab)、帕妥珠单抗(pertuzumab)、平妥单抗(pintumomab)、普托木单抗(pritumumab)、拉克莫单抗(racotumomab)、拉德瑞单抗(radretumab)、里乐木单抗(rilotumumab)、利妥昔单抗(rituximab)、罗妥木单抗(robatumumab)、沙妥莫单抗(satumomab)、西罗珠单抗(sibrotuzumab)、思图昔单抗(siltuximab)、辛图珠单抗(simtuzumab)、索利托单抗(solitomab)、他卡珠单抗(tacatuzumab)、他普莫单抗(taplitumomab)、泰纳莫单抗(tenatumomab)、泰普洛单抗(teprotumumab)、替加珠单抗(tigatuzumab)、托西莫单抗(tositumomab)、曲妥珠单抗(trastuzumab)、土库珠单抗(tucotuzumab)、尤必昔单抗(ublituximab)、维托珠单抗(veltuzumab)、沃尔希珠单抗(vorsetuzumab)、伏妥莫单抗(votumumab)、扎鲁姆单抗(zalutumumab)、欧比托珠单抗(obinutuzumab)、CC49及3F8。所例示的治疗性抗体可进一步用放射性同位素粒子标记或与其组合,该放射性同位素粒子诸如铟In 111、钇Y 90、碘1-131。
本申请还提供治疗正经历一种或多种标准治疗,如化学治疗、放射治疗、免疫治疗、外科手术、或其组合的受试者的方法。因此,一种或多种治疗剂或抑制剂可在给予化学治疗、放射治疗、免疫治疗、外科手术或其组合之前、之中或之后给予。
化疗治疗的其他实例(包括标准或实验的化疗)在下文中描述。此外,一些淋巴瘤的治疗见于Cheson,B.D.,Leonard,J.P.,“Monoclonal Antibody Therapy for B-CellNon-Hodgkin’s Lymphoma”The New England Journal of Medicine 2008,359(6),p.613-626;和Wierda,W.G.,“Current and Investigational Therapies for Patients withCLL”Hematology 2006第285-294页。在美国,淋巴瘤的发病模式在Morton,L.M.等人“Lymphoma Incidence Patterns by WHO Subtype in the United States,1992-2001”Blood 2006,107(1),第265-276页进行分析。
免疫治疗剂的实例包括,但不限于,利妥昔单抗(如Rituxan)、阿仑单抗(如Campath、MabCampath)、抗CD19抗体、抗CD20抗体、抗MN-14抗体、抗TRAIL、抗TRAIL DR4和DR5抗体、抗CD74抗体、阿泊珠单抗、贝伐单抗、CHIR-12.12、依帕珠单抗(hLL2-抗CD22人源化抗体)、加利昔单抗、ha20、替伊莫单抗、鲁昔单抗、米拉珠单抗、奥伐木单抗、PRO131921、SGN-40、WT-1类似物肽疫苗、WT1 126-134肽疫苗、托西莫单抗、自体人肿瘤-衍生的HSPPC-96和维托珠单抗。其它免疫治疗剂包括使用基于个体患者肿瘤的基因构成(geneticmakeup)的癌症疫苗,如淋巴瘤疫苗实例为GTOP-99
化学治疗剂的实例包括阿地白介素、alvocidib、抗癌肽AS2-1、抗癌肽A10、抗胸腺细胞球蛋白、氨磷汀三水合物、氨基喜树碱、三氧化二砷、βalethine、Bcl-2家族蛋白抑制剂ABT-263、ABT-199、BMS-345541、硼替佐米苔藓抑素1、白消安、卡铂、campath-1H、CC-5103、卡莫司汀、乙酸卡泊芬净、氯法拉滨、顺铂、克拉屈滨(Leustarin)、苯丁酸氮芥(Leukeran)、姜黄素、环孢菌素、环磷酰胺(Cyloxan、Endoxan、Endoxana、Cyclostin)、阿糖胞苷、地尼白介素、地塞米松、DT PACE、多西紫杉醇、多拉司他汀10、多柔比星(Adriblastine)、盐酸多柔比星、enzastaurin、阿法依伯汀、依托泊苷、依维莫司(RAD001)、芬维A胺、非格司亭、美法仑、美司钠、夫拉平度、氟达拉滨(Fludara)、格尔德霉素(17-AAG)、异环磷酰胺、盐酸伊立替康、伊沙匹隆、来那度胺(CC-5013)、淋巴因子-活化的杀伤细胞、美法仑、甲氨蝶呤、盐酸米托蒽醌、莫特沙芬钆、霉酚酸酯、奈拉滨、奥利默森(Genasense)Obatoclax(GX15-070)、奥利默森、乙酸奥曲肽、ω-3脂肪酸、奥沙利铂、紫杉醇、PD0332991、PEG化脂质体盐酸多柔比星、培非司亭、喷司他丁(Nipent)、哌立福辛、泼尼松龙、泼尼松、R-roscovitine(Selicilib、CYC202)、重组干扰素α、重组白介素-12、重组白介素-11、重组flt3配体、重组人血小板生成素、利妥昔单抗、沙格司亭、柠檬酸西地那非、辛伐他汀、西罗莫司、苯乙烯基砜、他克莫司、坦螺旋霉素、坦西莫司(CCl-779)、沙利度胺、治疗性同种异体淋巴细胞、塞替派、替吡法尼、(硼替佐米或PS-341)、长春新碱(Oncovin)、硫酸长春新碱、长春瑞滨二酒石酸盐、伏立诺他(SAHA)、伏立诺他、和FR(氟达拉滨、利妥昔单抗)、CHOP(环磷酰胺、多柔比星、长春新碱、泼尼松)、CVP(环磷酰胺、长春新碱和泼尼松)、FCM(氟达拉滨、环磷酰胺、米托蒽醌)、FCR(氟达拉滨、环磷酰胺、利妥昔单抗)、hyperCVAD(超分割环磷酰胺(hyperfractionated cyclophosphamide)、长春新碱、多柔比星、地塞米松、甲氨蝶呤、阿糖胞苷)、ICE(异环磷酰胺、卡铂和依托泊苷)、MCP(米托蒽醌、苯丁酸氮芥和泼尼松龙)、R-CHOP(利妥昔单抗加CHOP)、R-CVP(利妥昔单抗加CVP)、R-FCM(利妥昔单抗加FCM)、R-ICE(利妥昔单抗-ICE)和R-MCP(R-MCP)。例如奥沙利铂可以与本申请的制剂组合使用。
所述治疗可补充有任何上述用干细胞移植或处理的治疗或与其组合。一种改良的方法的实例为放射免疫治疗,其中单克隆抗体与放射性同位素粒子,如铟In 111、钇Y90、碘I-131组合。组合治疗的实例包括,但不限于,碘-131托西莫单抗钇-90替伊莫单抗与CHOP。
其它治疗过程包括外周血干细胞移植、自体造血干细胞移植、自体骨髓移植、抗体疗法、生物疗法、酶抑制剂疗法、全身照射、输注干细胞、干细胞支持的骨髓去除(干细胞支持的骨髓根除)、体外处理的外周血干细胞移植、脐带血移植、免疫酶技术、药理学研究、低-LET钴-60γ射线治疗、博来霉素、常规手术、放射疗法和非骨髓根除的同种异基因造血干细胞移植。
本申请提供在治疗骨髓增殖性疾病和癌症中单独或者与一种或多种治疗剂组合使用的制剂。本申请还提供治疗疾病的方法,包括向有此需要的患者给药本文所述制剂(包括片剂形式的CYT-0387二盐酸盐一水合物形式II),其中所述疾病选自真性红细胞增多症(PV)、骨髓纤维化、血小板增多症、自发性血小板增多(ET)、胰腺癌、转移性胰腺导管腺癌(metastatic pancreatic ductal adenocarcinoma)、乳腺癌、结肠癌、非小细胞肺癌(NSCLC)和转移性NSCLC(包括EGFR突变的EGFR TKI原初转移性NSCLC和转移性KRAS突变的NSCLC)。此外,本申请还提供治疗疾病的方法,包括向有此需要的患者给药本文所述制剂(包括片剂形式的CYT-0387二盐酸盐一水合物形式II)以及任选地给药一种或多种治疗剂,其中所述一种或多种治疗剂选自曲美替尼、厄洛替尼、吉西他滨、白蛋白结合型紫杉醇、奥沙利铂、卡培他滨、或者其组合。
应当理解,以下实施例说明了本申请的某些方面。还应当理解,实施例中所示的值和参数可以在合理的变化范围内进行修改,并且可以在本申请的范围内进行各种修改。
实施例1 制备方法
N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)可如美国专利号8,486,941和PCT申请WO 2012/071612中所述合成。
由CYT-0387二盐酸盐无水形式I制备CYT-0387二盐酸盐一水合物形式II
向N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)二盐酸盐无水形式I在甲醇中的悬浮液中加入摩尔过量的盐酸水溶液。分离出所得的固体,用甲醇和盐酸水溶液洗涤,得到CYT-0387二盐酸盐一水合物形式II。
由CYT-0387游离碱制备CYT-0387二盐酸盐一水合物形式II
向N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)游离碱在甲醇中的悬浮液中加入摩尔过量的浓盐酸。所得的悬浮液任选地用N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)二盐酸盐一水合物形式II种晶,并加入水。任选种晶的N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)二盐酸盐一水合物形式II可如上所制备。分离出所得的固体,用甲醇和盐酸水溶液洗涤,得到CYT-0387二盐酸盐一水合物形式II。
由CYT-0387游离碱制备CYT-0387一盐酸盐无水形式I
向N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)游离碱在甲醇中的悬浮液中加入1.0摩尔当量的浓盐酸。分离出所得的固体,用甲醇洗涤,得到CYT-0387一盐酸盐无水形式I。
由CYT-0387一盐酸盐无水形式I制备CYT-0387一盐酸盐无水形式III
将CYT-0387一盐酸盐无水形式I的悬浮液在水/THF(30%水;v/v)中搅拌。分离出所得的固体,用水/THF混合物洗涤,得到CYT-0387一盐酸盐无水形式III。
由CYT-0387二盐酸盐一水合物形式II制备CYT-0387一盐酸盐无水形式III
将CYT-0387二盐酸盐一水合物形式II的悬浮液在甲醇/水(30%水;v/v)中搅拌。分离出所得的固体,用甲醇/水混合物洗涤,得到CYT-0387一盐酸盐无水形式III。
上面的形式通过各种分析技术表征,包括使用下述工序的X射线粉末衍射图谱(XPPD)、差示扫描量热(DSC)、热重分析(TGA)和动态蒸气吸附(DVS)。
X射线粉末衍射:XRPD分析在衍射仪(PANanalytical XPERT-PRO,PANanalyticalB.V.,Almelo,Netherlands)上进行,采用铜辐射(Cu Kα, )。分析用样品通过在装备零背景盘的铝支托的中心放置粉末样品来制备。发生器在45kV的电压和40mA的安培数工作。所用的狭缝是Soller0.02rad.,防散射1.0°,以及发射。样品转速为2秒。从2至40°2θ进行扫描,历时15min,步长为0.0167°2θ。数据分析通过X’Pert Highscore version 2.2c(PANalytical B.V.,Almelo,Netherlands)和X’Pert data viewer version 1.2d(PANalytical B.V.,Almelo,Netherlands)进行。
图6表示N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物形式II的XRPD图谱。
图7表示N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺一盐酸盐无水形式I的XRPD图谱。
图8表示N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺一盐酸盐无水形式III的XRPD图谱。
不同CYT-0387形式的XRPD峰可见于上表1中。
差示扫描量热:N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物形式II的热性质使用差示扫描量热(DSC)仪器(TA Q1000,TAInstruments,New Castle,DE,USA)进行评价。每次实验将约5至10mg固体样品置于借助针孔通风的标准铝盘中,以10℃/min的速率在50mL/min氮气清扫下加热。数据分析使用Universal Analysis 2000 Version 4.7A(TA Instruments,New Castle,DE,USA)进行。熔化热分析通过吸热熔融峰的S函数积分(sigmoidal integration)进行。
图9表示N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物形式II的DSC。
图10表示N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺一盐酸盐无水形式I的DSC。
图11表示N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺一盐酸盐无水形式III的DSC。
热重分析:N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物形式II的热重分析(TGA)在TGA仪器(TA Q500,TA Instruments,New Castle,DE,USA)上进行。每次实验将约5至10mg固体样品置于开放的铝盘中,以10℃/min的速率在60mL/min氮气清扫下加热。数据分析使用Universal Analysis 2000Version 4.7A(TAInstruments,New Castle,DE,USA)进行。
图12表示N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物形式II的TGA。
图13表示N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺一盐酸盐无水形式I的TGA。
图14表示N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺一盐酸盐无水形式III的TGA。
动态蒸气吸附:N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物形式II的吸湿性使用动态蒸气吸附(DVS)仪器(TGA Q5000TAInstruments,New Castle,DE)在室温进行评价。研究水吸附和解吸,其作为在室温0至90%范围的相对湿度(RH)的函数。室中的湿度从初始水平50%RH升至60%RH并保持直到固体和气氛达到平衡。持续平衡测试,直到10小时后通过或失效。在这一点上,相对湿度升高10%以上,重复该工序直到达到90%RH并平衡。在此期间,对水吸附进行监控。对于解吸,相对湿度以类似的方式降低来测量一个完整的吸附/解吸循环。所有的实验在dm/dt的模式(随时间的质量变化)操作来确定平衡端点。使用约4毫克的固体CYT-0387。数据分析使用Universal Analysis 2000Version 4.7A(TA Instruments,New Castle,DE,USA)进行。
图15表示N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物形式II的DVS。
N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺(CYT-0387)二盐酸盐一水合物形式II和N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺CYT-0387)一盐酸盐无水形式I的单晶X射线晶体学数据总结在下表2中。晶体的进一步表征数据总结于下表3中。
表2:单晶X射线晶体学数据
表3:晶体数据和结构优化
100(2)K表示100±2°K
使用奥林巴斯偏振显微镜(BX-51,Olympus,Center Valley,PA,USA)获得本发明的各种形式的显微镜图像。将样品分散在矿物油中并使用530nm波片在交叉偏振光下检查(结果未显示)。
实施例2
包含相当于100mg、150mg和200mg CYT-0387游离碱的量的CYT-0387二盐酸盐一水合物形式II的片剂可以根据本文所述的方法制备。制备包含相当于100mg、150mg、200mg、250mg和300mgCYT-0387游离碱的量的CYT-0387二盐酸盐一水合物形式II的片剂。下表4总结了这种片剂的配方。
表4:片剂制剂
*0.75%颗粒内,0.75%颗粒外硬脂酸镁
表4的片剂制剂包含没食子酸丙酯,其降低CYT-0387形式II的氧化降解的程度或水平并导致CYT-0387形式II的稳定性提高。这是从调查不同抗氧化剂在抑制或预防CYT-0387二盐酸盐一水合物形式II的降解中的潜在影响的研究中确定的。在最初的研究中,检查了三种不同作用机制的五种抗氧化剂:自由基清除剂抗氧化剂(没食子酸丙酯、丁羟茴香醚(BHA)和丁羟甲苯(BHT))、牺牲还原剂(抗坏血酸)、以及氧清除剂(焦亚硫酸钠)。
在不存在(用作对照)和存在0.1%(w/v)抗氧化剂的情况下于60℃孵育含有在70%(v/v)50mM乙酸盐缓冲液(pH 4.0)和30%(v/v)甲醇中的20μg/mL的CYT-0387二盐酸盐一水合物形式II的水溶液达7天。在第0、5和7天,使用具有Zorbax SB-C8柱(Phenomenex,Torrance,CA)的反相HPLC分析溶液。如表7所示,相对于相同水平的BHT和焦亚硫酸钠,0.1%(w/v)水平的没食子酸丙酯、BHA或抗坏血酸的存在抑制或防止CYT-0387形式II的降解。小于1%的CYT-0387形式II在没食子酸丙酯或BHA的存在下被降解。尽管由于干扰不能针对0.1%抗坏血酸测定总降解产物,但未观察到主要的氧化降解产物(数据未显示)。
在另外的研究中,在相同条件下检查较低浓度的0.01%和0.001%(w/v)的没食子酸丙酯、BHA和抗坏血酸对CYT-0387的稳定性的影响。这些研究的结果总结在表7中。结果表明,在0.01%(w/v)抗氧化剂水平,在没食子酸丙酯或抗坏血酸的存在下在60℃观察到CYT-0387形式II的稳定性提高达7天。此外,在0.001%(w/v)抗氧化剂水平,相对于BHA和抗坏血酸,没食子酸丙酯的存在降低或抑制CYT-0387的降解(表7)。这些结果表明,在测试的抗氧化剂中,没食子酸丙酯在抑制或预防CYT-0387二盐酸盐一水合物形式II的降解中是最有效的。
表7:抗氧化剂在pH 4缓冲水溶液中在60℃对CYT-0387形式II降解的影响
a包括制剂中存在的杂质
bN/A:不可得
接下来,在25℃/60%RH(相对湿度)或40℃/75%RH,在0%、0.2%、0.5%或1.0%没食子酸丙酯的存在下检查包含CYT-0387形式II的100mg片剂制剂的稳定性达6个月。在第0、1、3和6个月测定降解曲线。在40℃/75%RH下长达6个月的研究结果总结在表8中。结果表明,在40℃/75%RH,与CYT-0387形式II片剂制剂(100mg,含有0%、0.5%或1.0%没食子酸丙酯)相比,CYT-0387形式II片剂制剂(100mg,含有0.2%没食子酸丙酯)表现出稳定性提高。在25℃/60%RH的研究结果显示CYT-0387形式II的降解也通过0.2%、0.5%和1.0%的没食子酸丙酯得到降低(数据未显示)。观察到的趋势在25℃/60%RH与在40℃/75%RH观察到的降解曲线类似,即与0%、0.5%和1%没食子酸丙酯相比,在0.2%没食子酸丙酯观察到片剂制剂中CYT-0387形式II的稳定性提高(数据未显示)。总之,这些结果表明,在这些研究中检查的抗氧化剂和百分比中,0.2%的没食子酸丙酯提供了CYT-0387二盐酸盐一水合物形式II的最佳水平的稳定性。
表8:100mg片剂制剂中没食子酸丙酯水平对CYT-0387形式II降解的影响
实施例3
在健康受试者中,在1期、单剂量研究中评价包含CYT-0387二盐酸盐一水合物形式II(剂量相当于100、150、200和300mg游离碱)的片剂和包含CYT-0387二盐酸盐无水形式I(剂量相当于300mg游离碱)的胶囊。
在给药后0.5小时至36小时进行密集的PK和PD取样。在整个研究中监测安全性。使用混合效应模型的方差参数分析(ANOVA)用于拟合PK参数(AUC和Cmax)的自然对数转化。对于CYT-0387二盐酸盐一水合物形式II片剂在100、150、200和300mg的几何平均与CYT-0387二盐酸盐无水形式I胶囊在300mg的比值构建90%置信区间,针对AUC和Cmax使用70%至143%的等效界限(equivalence bound)。药代动力学数据示于表5中。
表5:CYT-0387二盐酸盐一水合物形式II片剂和CYT-0387二盐酸盐无水形式I胶囊制剂的药代动力学数据
实施例4
CYT-0387是目前正在研究的治疗骨髓纤维化的Janus激酶1和2(JAK1/JAK2)的选择性小分子抑制剂。该研究评估了放射性标记的CYT-0387在人中的质量平衡/回收、代谢曲线、药代动力学和安全性。
6位健康的个体(受试者)接受单一口服剂量的包含~100μCi的[14C]-CYT-0387的200mg CYT-0387。收集血样直到21天或直到2个连续样品中的血浆放射性低于检测限或尿和粪便取样停止。收集尿/粪便样品至21天或直到在粪便和尿中回收≥90%的给药剂量并且在2个连续取样间隔中的放射性≤1%给药剂量。使用LC-MS/MS测量CYT-0387和代谢物的血浆浓度,并通过液体闪烁计数评估总放射性。在选择的尿、粪便和血浆样品中进行代谢曲线分析。在整个研究中进行安全性评估。
结果:CYT-0387耐受性良好。没有报告3级或4级AE、SAE或导致研究终止的AE。最常见的AE是头晕、头痛和恶心。在给药后2.5小时观察到药物衍生的放射性在血浆中的最大浓度。平均血液-血浆浓度比在给药后整个24小时内在0.7至0.9的范围内,表明放射性与血细胞低关联。放射性的总回收率为96.7%(粪便:69.3%;尿:27.5%)。循环的放射性主要由代谢物M21(64.2%)、CYT-0387(17.3%)和代谢物(M8:5.8%;代谢物M19:5.2%;M5:2.7%;M28:2.5%;和M20:2.3%)组成。在粪便中排泄的主要组分是M14(剂量的21.4%),以及CYT-0387(剂量的12.6%)和其它代谢物(M21:剂量的12.7%;共洗脱的M19/M33:剂量的7.1%)。在粪便中剩余的识别出的10种代谢物各自占小于剂量的5%。在尿中,代谢物M21是主要物种(剂量的11.5%),观察到低水平的次要代谢物。
在健康受试者中口服给药后,[14C]-CYT-0387,作为代谢物和未改变的母体药物的组合,主要在粪便中被除去。
实施例5
CYT-0387是目前正在研究的治疗骨髓纤维化的Janus激酶1和2(JAK1/JAK2)的选择性小分子抑制剂。在骨髓纤维化患者中的1/2期研究中,基于有利的益处:风险曲线,选择每天一次300mg CYT-0387胶囊作为3期剂量。速释片剂制剂(CYT-0387片剂)被开发用于进一步的临床评价。在本研究中评价CYT-0387片剂相对于胶囊的相对生物利用度,以鉴定CYT-0387片剂的3期剂量。
在健康受试者中评价单剂量后的CYT-0387片剂(100至300mg)与胶囊(300mg)药代动力学(PK)。还评估了在进食和禁食条件下在超治疗剂量(400和800mg)和酸还原剂(即奥美拉唑)下的CYT-0387片剂PK。在给药后36小时内进行密集的PK取样。在整个研究中监测安全性。使用混合效应模型的方差参数分析(ANOVA)用于拟合PK参数(AUC和Cmax)的自然对数转化。对于CYT-0387片剂PK在100、150、200和300mg的几何平均与CYT-0387胶囊在300mg的比值构建90%置信区间,针对AUC和Cmax使用70%至143%的等效界限。使用类似的方法来评估食物和奥美拉唑的效果。
200mg的CYT-0387片剂提供相当于300mg的CYT-0387胶囊的血浆暴露(表6)。CYT-0387血浆暴露以低于剂量比例地从100增加到800mg。轻脂肪膳食和高脂肪膳食的摄取适度地增加CYT-0387片剂的Cmax(对于轻脂肪膳食和高脂肪膳食分别增加38%和28%)和AUCinf(对于轻脂肪膳食和高脂肪膳食分别增加16%和28%)。奥美拉唑使CYT-0387片剂的暴露减少了36%的Cmax和33%的AUCinf。这些差异不被认为是临床相关的。
200mg的CYT-0387片剂提供与300mg的CYT-0387胶囊相当的暴露。CYT-0387片剂血浆暴露以低于剂量比例的方式增加。在CYT-0387片剂PK上没有观察到食物或酸还原剂的临床相关作用。
表6:在单剂量CYT-0387给药之后CYT-0387的3期片剂与胶囊的相对生物利用度
%CV=%变异系数;CI=置信区间;数据四舍五入(如适用)并且显示三位有效数字
实施例6
本实施例描述了M14(化合物3)、M8(化合物4)、M20(化合物12)、M21(化合物13)、化合物8和化合物10的制备。
向烧瓶中装入4-(2-氯嘧啶-4-基)苯甲酸(3.0g,12.8mmol)、4-吗啉代苯胺(2.7g,14.0mmol,1.1当量)和NMP(30mL)。所得溶液在120℃进行搅拌。完成后,冷却反应液并加入30mL的NaHCO3水溶液。所得的浆料进行过滤,用水淋洗,在45℃真空干燥,提供具有以下结构的4-(2-((4-(3-氧代吗啉代)苯基)氨基)嘧啶-4-基)苯甲酸(化合物3):
1H NMR(400MHz,DMSO-d6):δ=13.21(s,1H),9.85(s,1H),8.62(d,J=5.2Hz,1H),8.28(d,J=8.2Hz,2H),8.10(d,J=8.2Hz,2H),7.85(d,J=8.4Hz,2H),7.49(d,J=5.2Hz,1H),7.33(d,J=9.0Hz,2H),4.19(s,2H),3.98(m,2H),3.71(m,2H)
向烧瓶中装入化合物3(1.0g,2.43mmol)、TBTU(1.0g,3.15mmol,1.3当量)、甘氨酰胺盐酸盐(0.32g,1.2当量)、DMSO(9mL)和i-Pr2NEt(0.65g,2.92mmol,1.2当量)。反应完成后,加入水(7.7mL),所得的浆料进行过滤,用DMSO/水(2:1)和水淋洗。分离出的固体在10mL的MeOH中再次浆化,过滤,用MeOH洗涤,在45℃在真空烘箱中干燥,提供具有以下结构的N-(2-氨基-2-氧代乙基)-4-(2-((4-(3-氧代吗啉代)苯基)氨基)嘧啶-4-基)苯甲酰胺(化合物4):
1H NMR(400MHz,DMSO-d6):δ=9.83(s,1H),8.81(t,J=6.0Hz,1H),8.60(d,J=2.9Hz,1H),8.27(d,J=8.5Hz,2H),8.05(d,J=8.4Hz,2H),7.85(d,J=6.9Hz,2H),7.51(d,J=4.8Hz,1H),7.41(bs,1H),7.32(d,J=8.9Hz,2H),7.06(bs,1H),4.19(s,2H),3.98(m,2H),3.85(d,J=5.8Hz,2H),3.72(m,2H);HRMS(ESI+):C23H23N6O4[M+H]+计算值447.18,实测447.19。
{4-[(氰基甲基)氨基甲酰基]苯基}硼酸(4.2g,20.6mmol)、2,4-二氯嘧啶(4.3g,28.8mmol)、碳酸钾(2.8kg,20.6mmol)和与二氯甲烷复合(1:1)的[1,1'-双(二苯基膦基)二茂铁]二氯钯(II)(84mg,0.10mmol)在乙腈(21mL)和水(11mL)中的混悬液用氮气喷射30分钟。混合物加热至75℃直至反应完成。混合物冷却至60℃,分层。加入N-乙酰基半胱氨酸水溶液(6mL),然后添加水(15mL)。混合物冷却至20℃。固体进行过滤,用H2O/CH3CN(3:1)洗涤,在50℃干燥,提供具有以下结构的4-(2-氯嘧啶-4-基)-N-(氰基甲基)苯甲酰胺:
1H NMR(300MHz,DMSO-d6):δ4.36(d,J=5.5Hz,2H),8.05(m,J=8.5Hz,2H),8.24(d,J=5.3Hz,1H),8.32(m,J=8.5Hz,2H),8.89(d,J=5.2Hz,1H),9.39(t,J=5.5Hz,1H).HRMS(ESI+):C13H10ClN4O[M+1]计算值273.15,实测273.25。
向烧瓶中装入4-(2-氯嘧啶-4-基)-N-(氰基甲基)苯甲酰胺(6.7g,24.6mmol)、2-((4-氨基苯基)氨基)乙醇(7.5g,49.3mmol,2.0当量)、i-Pr2NEt(4.8g,36.9mmol,1.5当量)和DMSO(20mL)。所得溶液在100℃进行搅拌。反应完成后,溶液冷却至20℃,然后将其加至135mL的水上。所得的浆料进行过滤,用70mL水淋洗。固体在i-PrOH(70mL)中再次浆化。所得的浆料进行过滤,用i-PrOH淋洗。固体真空干燥,溶解在30mL的THF中,加热至50℃。缓慢添加水(85mL),浆料冷却至20℃。所得固体经过滤分离,用THF/水(1:3)和水淋洗,在40℃干燥,提供具有以下结构的N-(氰基甲基)-4-(2-((4-((2-羟基乙基)氨基)苯基)氨基)嘧啶-4-基)苯甲酰胺(化合物8):
1H NMR(DMSO-d6):9.33(t,J=5.5Hz,1H),9.24(s,1H),8.48(d,J=5.1Hz,1H),8.24(d,J=8.4Hz,2H),8.01(d,J=8.5Hz,2H),7.46(d,J=8.8Hz,2H),7.33(d,J=5.2Hz,1H),6.58(d,J=8.9Hz,2H),5.20(t,J=5.8Hz,1H),4.66(t,J=5.4Hz,1H),4.35(d,J=5.4Hz,2H),3.57(q,J=5.8Hz,2H),3.08(q,J=5.8Hz,2H);HRMS(ESI+):C21H21N6O2[M+1]计算值389.17,实测389.27。
向烧瓶中装入4-(2-氯嘧啶-4-基)-N-(氰基甲基)苯甲酰胺(4.0g,14.7mmol)、苯二胺(3.2g,29.3mmol,2.0当量)、i-Pr2NEt(2.9g,22.1mmol,1.5当量)和DMSO(12mL)。所得溶液在60℃搅拌。反应完成后,混合物冷却至20℃然后将其加至50mL水上。所得的浆料进行过滤,先后用水和i-PrOH淋洗。固体在i-PrOH(50mL)中再次浆化,过滤,用i-PrOH淋洗,在40℃干燥,提供具有以下结构的4-(2-((4-氨基苯基)氨基)嘧啶-4-基)-N-(氰基甲基)苯甲酰胺(化合物10):
1H NMR(400MHz,DMSO-d6):δ=9.33(t,J=5.6Hz,1H),9.21(s,1H),8.47(d,J=5.2Hz,1H),8.24(d,J=8.5Hz,2H),8.01(d,J=8.2Hz,2H),7.39(d,J=8.4Hz,2H),7.33(d,J=5.1Hz,1H),6.56(d,J=8.4Hz,2H),4.78(bs,2H),4.36(d,J=6.4Hz,2H);HRMS(ESI+):C19H17N6O[M+H]计算值345.15,实测345.28。
向烧瓶中装入4-(2-氯嘧啶-4-基)-N-(氰基甲基)苯甲酰胺(4.0g,14.7mmol)、4’-氨基乙酰苯胺(2.6g,17.6mmol,1.2当量)、i-Pr2NEt(2.9g,22.1mmol,1.5当量)和DMSO(12mL)。所得溶液在120℃进行搅拌。反应完成后,混合物冷却至20℃,缓慢加入甲醇(30mL)。所得的浆料进行过滤,用MeOH淋洗。固体在40mL的MeOH中再次浆化,过滤,用甲醇淋洗,在40℃干燥,提供具有以下结构的4-(2-((4-乙酰氨基苯基)氨基)嘧啶-4-基)-N-(氰基甲基)苯甲酰胺(化合物12):
1H NMR(DMSO-d6):9.82(s,1H),9.64(s,1H),9.33(t,J=5.5Hz,1H),8.57(d,J=5.1Hz,1H),8.28(d,J=8.1Hz,2H),(8.04,J=8.5Hz,2H),7.72(d,J=8.9Hz,2H),7.52(d,J=8.9Hz,2H),7.45(d,J=5.0Hz,1H),4.36(d,J=5.3Hz,2H),2.03(s,3H);HRMS(ESI+):C21H19N6O2[M+1]计算值387.16,实测387.28。
将4-(2-氯嘧啶-4-基)-N-(氰基甲基)苯甲酰胺(2.0g,7.2mmol)、4-(4-氨基苯基)吗啉-3-酮(1.4g,7.2mmol)和二氯化锌(98mg,0.72mmol)在N-甲基吡咯烷酮(10mL)中的混合物用氮气喷射10分钟,然后加热至90℃直至反应视为完成。混合物冷却至50℃,然后将水(15mL)缓慢加入反应混合物中。所得的浆料冷却至20℃,固体进行过滤,用水淋洗,干燥。将固体溶解在15mL的DMSO中,加热至50℃。向混合物中加入甲醇(25mL)然后冷却至20℃。所得的固体进行过滤,用甲醇淋洗,在60℃真空干燥,提供具有以下结构的N-(氰基甲基)-4-(2-{[4-(3-氧代吗啉-4-基)苯基]氨基}嘧啶-4-基)苯甲酰胺(化合物13):
1H NMR(300MHz,DMSO-d6):δ9.83(s,1H),9.34(t,J=5.5Hz,1H),8.62(d,J=5.2Hz,1H),8.30(m,J=8.6Hz,2H),8.04(m,J=8.6Hz,2H),7.85(m,J=8.9Hz,2H),7.51(d,J=5.2Hz,1H),7.33(m,J=8.9Hz,2H),4.36(d,J=5.4Hz,2H),4.20(s,2H),3.98(dd,J=5.9,4.19Hz,2H),3.62-3.79(m,2H).HRMS(ESI+):C23H21N6O3[M+1]计算值429.17,实测429.0。
实施例7
本研究表征CYT-0387对HepG2细胞(肝细胞癌细胞系)中铁调素(hepcidin)生产的影响。通过促进组成型活性(constitutively active)II型BMP受体激酶(BMPR激酶)与I型BMPR激酶的结合,骨形态发生蛋白(Bone morphogenic protein,BMP)显示参与肝细胞中铁调素的转录诱导(Andriopoulos,et al.Nat Genet,2009.41(4):p482-7;Zhao,et al.,JClin Invest,2013.123(6):p2337-43)。这导致I型BMPR激酶的磷酸化和活化以及随后的效应蛋白SMAD蛋白(SMAD1/5/8)的下游活化,随后与SMAD4相关的核转位(Wrana,Cold SpringHarb Perspect Biol,2013.5:a011197)。
HepG2细胞在1%FBS存在下用CYT-0387(范围为0μM至10μM)预孵育2小时,然后用10ng/mL的BMP6刺激6小时。从细胞中分离总RNA,并通过qRT-PCR分析铁调素的水平。使用GUSB(β-葡萄糖醛酸苷酶)作为内参对照(house keeping control)以使通过qRT-PCR测量的水平标准化。计算铁调素倍数变化诱导(fold-change induction)的百分比(100%等于媒介物处理的细胞中的铁调素诱导),并总结于表9中。结果显示CYT-0387导致BMP6介导的铁调素诱导的剂量依赖性抑制。
HepG2细胞在1%FBS存在下用增加浓度的CYT-0387(0.02至10μM CYT387)预孵育2小时,然后用10ng/mL的BMP6刺激30分钟。从裂解的细胞中提取蛋白质,并使用对磷酸-SMAD1(Ser463/465)、磷酸-SMAD5(Ser463/465)和磷酸-SMAD8(Ser465/467)和β-肌动蛋白特异性的抗体进行免疫印迹分析。使用密度计量学软件(Image Studio)定量原始的磷酸-SMAD1/5/8水平,并标准化为β-肌动蛋白水平。计算磷酸-SMAD1/5/8水平的百分比(100%等于用10ng/mL的BMP6刺激的媒介物处理的细胞中的磷酸-SMAD1/5/8水平),并总结于表9中。结果显示,CYT-0387导致BMP6介导的磷酸-SMAD1/5/8水平的剂量依赖性抑制。
表9:在CYT-0387存在下用BMP6刺激的HepG2细胞中铁调素倍数变化诱导和磷酸-SMAD1/5/8水平的标准化百分比
a平均诱导(n=2)。
bSD:标准偏差。
c平均诱导(n=6)。
此外,进行生物化学结合测定(DiscoveRx)和体外酶抑制测定(LanthaScreen,Life Technologies)以确定CYT-0387对I型BMPR激酶(ALK2、ALK3和ALK6)的结合亲和力和抑制活性。使用转化生长因子β受体1(TGFBR1、ALK5)作为对照,以确定对I型BMPR激酶的选择性。结果总结在表10中,结果表明:与ALK3相比,CYT-0387对ALK2和ALK6具有更高的亲和力和抑制活性。
表10:CYT-0387对BMPR-激酶的生化Kd和IC50值
aAVG:平均值(n=3)。
bSD:标准偏差。
实施例8
进行研究以调查CYT-0387制剂对治疗转移性非小细胞肺癌(NSCLC)或转移性胰腺导管腺癌(PDA)的作用。在一项研究中,转移性柯斯顿大鼠肉瘤病毒癌基因同源(KRAS)突变的NSCLC患者(其基于铂的化疗已经失败)仅接受CYT-0387制剂、仅接受曲美替尼、或接受CYT-0387和曲美替尼的组合至少一个28天治疗周期。CYT-0387制剂(其可包含片剂形式的CYT-0387二盐酸盐一水合物形式II)可以按00mg、150mg、200mg、250mg或300mg的剂量每天口服一次或两次给药;曲美替尼(其化学名称可以为N-(3-{3-环丙基-5-[(2-氟-4-碘苯基)氨基]-6,8-二甲基-2,4,7-三氧代-3,4,6,7-四氢吡啶并[4,3-d]嘧啶-1(2H)-基}苯基)乙酰胺)可以按0.5mg、1mg或2mg的剂量每天口服一次给药。该研究招募患有KRAS突变的转移性或复发性非小细胞肺癌的患者,其已经接受了基于铂的化疗的先前治疗或多达两线的先前化疗,具有如RECIST v1.1的可测量的疾病和0或1的东方合作肿瘤组(EasternCooperative Oncology Group,ECOG)的性能状态。
在另一项研究中,表皮生长因子受体(EGFR)突变的EGFR酪氨酸激酶抑制剂(TKI)原初转移性NSCLC的患者接受单独的厄洛替尼或CYT-0387和厄洛替尼的组合至少一个28天治疗周期。CYT-0387制剂(其可以包含片剂形式的CYT-0387二盐酸盐一水合物形式II)可以按100mg、150mg、200mg、250mg或300mg的剂量每日口服给药一次或两次;和厄洛替尼(其化学名称可以是N-(3-乙炔基苯基)-6,7-双(2-甲氧基乙氧基)-4-喹唑啉胺)可以按25mg、100mg或150mg的剂量每天一次口服给药。本研究招募具有EGFR外显子19缺失或外显子21(L858R)置换突变的转移性NSCLC患者,其没有接受先前治疗或基于铂的化疗,具有0、1或2的东部合作肿瘤组(ECOG)性能状态。
在另外的研究中,复发性或难治性转移性胰腺腺癌患者接受卡培他滨和CYT-0387(具有片剂形式的CYT-0387二盐酸盐一水合物形式II)的组合或者奥沙利铂、卡培他滨和CYT-0387的组合至少一个21天的治疗周期。CYT-0387制剂(其可以包含片剂形式的CYT-0387二盐酸盐一水合物形式II)可以按100mg、150mg、200mg、250mg或300mg的剂量每日口服给药一次或两次。卡培他滨(其化学名称可以是[1-(3,4-二羟基-5-甲基四氢呋喃-2-基)-5-氟-2-氧代-1H-嘧啶-4-基]氨基甲酸戊酯)可口服给药每日两次持续14天,然后7天不给药,直到治疗结束;奥沙利铂(其化学名称可以是[(1R,2R)-环己烷-1,2-二胺](乙二酸-O,O')铂(II))可在每个所述21天治疗周期的第1天经120分钟静脉内给药。患者具有复发性或难治性转移性胰腺癌,并且已经接受了含有吉西他滨的方案的在先治疗,具有根据RECISTv1.1可测量的疾病和0或1的东部合作肿瘤组(ECOG)性能状态。
研究监测若干因素,包括但不限于在各治疗点的安全性、毒性、耐受性、实体肿瘤响应评价标准(RECIST)v1.1评估的完全响应(CR)或部分响应(PR)或稳定疾病(SD)、总生存期(即从治疗到任何原因导致死亡的时间间隔)、无进展生存期(即从研究的首次剂量日期到基于RECIST标准v1.1的死亡或明确的疾病进展的首次记录的间隔)、和/或总体响应率(即实现完全响应或部分响应的患者的比例)。
包括本申请中引用的所有专利、专利申请和出版物在内的每个参考文献通过引用其整体并入本文,如同它们中的每一个被单独地并入。此外,应当理解,在本发明的上述教导中,本领域技术人员可以对本发明进行某些改变或修改,并且这些等同物仍然在由本申请的所附权利要求限定的本发明的范围内。包括本申请中引用的所有专利、专利申请和出版物在内的每个参考文献通过引用其整体并入本文,如同它们中的每一个被单独地并入。此外,应当理解,在本发明的上述教导中,本领域技术人员可以对本发明进行某些改变或修改,并且这些等同物仍然在由本申请的所附权利要求限定的本发明的范围内。
Claims (23)
1.化合物,其选自:
N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物形式II;
N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺一盐酸盐无水形式I;和
N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺一盐酸盐无水形式III。
2.权利要求1的化合物,其为晶型。
3.权利要求1-2的晶型,其中所述晶型是
N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物形式II。
4.权利要求3的晶型,其中晶体在T=100°K的晶胞参数如下:
α=83.297(2)°,β=87.649(2)°,γ=67.445(2)°,和三斜P-1空间群。
5.权利要求3的晶型,其特征在于x射线粉末衍射(XRPD)图谱基本上如图6所示。
6.权利要求3的晶型,其特征在于x射线粉末衍射(XRPD)图谱具有在约7.7°、19.3°、24.0°、25.7°和29.6°2-θ±0.2°2-θ的峰。
7.权利要求3的晶型,其特征在于差示扫描量热(DSC)图谱基本上如图9所示。
8.权利要求3的晶型,其特征在于动态蒸气吸附(DVS)图谱基本上如图15所示。
9.权利要求2的晶型,其中所述晶型是结晶的N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺一盐酸盐无水形式I。
10.权利要求9的晶型,其特征在于x射线粉末衍射(XRPD)图谱基本上如图7所示。
11.权利要求9的晶型,其特征在于X射线粉末衍射(“XRPD”)图谱具有在约13.5°、20.9°、26.1°、26.6°和28.3°2-θ±0.2°2-θ的峰。
12.权利要求9的晶型,其特征在于差示扫描量热(DSC)图谱基本上如图10所示。
13.权利要求2的晶型,其中所述晶型是结晶的N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺一盐酸盐无水形式III。
14.权利要求13的晶型,其特征在于x射线粉末衍射(XRPD)图谱基本上如图8所示。
15.权利要求13的晶型,其特征在于X射线粉末衍射(“PXRD”)图谱具有在约12.7°、14.6°、17.8°、19.7°和23.3°2-θ±0.2°2-θ的峰。
16.权利要求13的晶型,其特征在于差示扫描量热(DSC)图谱基本上如图11所示。
17.药物组合物,其包含权利要求1-16中任一项的化合物。
18.权利要求17的药物组合物,其中权利要求1的化合物是N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物形式II。
19.权利要求17或18的药物组合物,其中N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物形式II按相当于50mg、100mg、150mg或200mg的N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺游离碱的量存在。
20.权利要求17-19中任一项的药物组合物,其呈片剂的形式。
21.权利要求17-20中任一项的药物组合物,其中在单一口服给药之后,所述组合物提供:
260至405ng/mL的N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺范围内的Cmax,
2,057至3,214ng·hr/mL的N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺范围内的AUCinf,或者
260至405ng/mL的N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺范围内的Cmax和2,057至3,214ng·hr/mL的N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺范围内的AUCinf二者。
22.权利要求21的药物组合物,其中在单一口服给药之后,所述组合物提供药代动力学曲线,其基本上类似于包含N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐无水形式I的剂型的药代动力学曲线,所述N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐无水形式I的量相当于300mg的N-(氰基甲基)-4-(2-(4-吗啉代苯基氨基)嘧啶-4-基)苯甲酰胺游离碱。
23.一种用于治疗Janus激酶(JAK)相关性疾病的方法,其包括向有需要的受试者给予有效量的权利要求18的药物组合物,其中所述疾病为选自的骨髓增殖性疾病权利要求31的方法,其中所述骨髓增殖性疾病选自:真性红细胞增多症(PV)、骨髓纤维化、血小板增多症、自发性血小板增多(ET)、特发性骨髓纤维化症、慢性髓性白血病、系统性肥大细胞增多症(SM)、慢性嗜中性粒细胞白血病(CNL)、骨髓增生异常综合征(MDS)和系统性肥大细胞病(SMCD)。
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