CN112823153A - 喹唑啉化合物及其盐酸盐的结晶形式 - Google Patents
喹唑啉化合物及其盐酸盐的结晶形式 Download PDFInfo
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- CN112823153A CN112823153A CN201980060170.XA CN201980060170A CN112823153A CN 112823153 A CN112823153 A CN 112823153A CN 201980060170 A CN201980060170 A CN 201980060170A CN 112823153 A CN112823153 A CN 112823153A
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Abstract
本专利文件涉及一种喹唑啉化合物及其盐酸盐的结晶形式。更特别是,本专利文件涉及一种1‑(4‑(4‑(3,4‑二氯‑2‑氟苯氨基)‑7‑甲氧基喹唑啉‑6‑基氧基)哌啶‑1‑基)丙‑2‑烯‑1‑酮及其盐酸盐的结晶形式的制备方法。
Description
相关申请的交叉引用
本申请要求于2018年9月14日提交的美国临时申请号为62/731,500的专利的优先权,其全部公开内容通过引用纳入本申请。
技术领域
本专利文献涉及一种喹唑啉化合物及其盐酸盐形式的结晶形式。更特别地,这些结晶形式来自1-(4-(4-(3,4-二氯-2-氟苯氨基)-7-甲氧基喹唑啉-6-基氧基)哌啶-1-基)丙-2-烯-1-酮,以及一种包含其的药物组合物。
背景技术
在韩国专利号为1,013,319的专利和美国专利号为8,003,658的专利中公开了具有通式为1-(4-(4-(3,4-二氯-2-氟苯氨基)-7-甲氧基喹唑啉-6-基氧基)哌啶-1-基)丙-2-烯-1-酮的以下化学式(1)的化合物,并且这些专利公开了上述化合物具有抗增殖活性(如抗癌活性),并能够选择性地且有效地治疗由酪氨酸激酶突变诱导的耐药性:
[化学式(1)]
然而,在上述引用的专利中制备的化学式(1)的化合物通常以非晶固体或不完全晶体的形式制备,该非晶固体或不完全晶体不太适合大规模药物加工,并且没有关于制备特定结晶形式的描述。
通过以上引用的专利制备的化学式(1)的化合物存在在水中的溶解度非常低的缺点。此外,由于通过引用的专利制备的化学式(I)的化合物无法以均一晶体的形式获得,满足药物所要求的物理化学的稳定性标准可能会令人苦恼。
因此,需要制备结晶形式的化学式(1)的化合物的盐,该结晶形式改善了在水中的溶解度,同时仍能够充分满足药物制剂的严格要求和规格。
在本背景技术部分公开的上述信息仅用于增强对本发明的背景技术的理解,因此,这绝不意味着旨在承认本发明包含的信息构成本领域普通技术人员已知的现有技术。
发明内容
本专利文献的一个目的是提供上述化学式(1)的喹唑啉化合物的结晶形式以及其结晶盐酸盐形式,和包含其的药物组合物。
特别地,化学式(1)的喹唑啉化合物的优选的结晶形式为
1)化学式(1)的喹唑啉化合物的结晶水合物形式,和
2)化学式(1)的喹唑啉化合物的无水结晶形式。
此外,优选的化学式(1)的喹唑啉化合物的结晶盐酸盐形式为
1)化学式(1)的喹唑啉化合物的结晶盐酸盐水合物形式,
2)化学式(1)的喹唑啉化合物的无水结晶盐酸盐形式。
结晶形式的更优选的实例如下:
当用Cu-Kα光源照射时,化学式(1)的化合物的结晶二水合物(2H2O)形式具有包含在衍射角(2θ±0.2°)为9.4°、13.0°和18.5°处的峰的X-射线粉末衍射(XRPD)图;
当用Cu-Kα光源照射时,化学式(1)的化合物的无水结晶形式I具有包含在衍射角(2θ±0.2°)为6.0°、18.3°和22.7°处的峰的XRPD图;
当用Cu-Kα光源照射时,化学式(1)的化合物的无水结晶形式II具有包含在衍射角(2θ±0.2°)为4.9°、5.9°和11.8°处的峰的X-射线粉末衍射图;
当用Cu-Kα光源照射时,化学式(1)的化合物的结晶单盐酸盐一水合物(1HCl·1H2O)形式具有包含在衍射角(2θ±0.2°)为8.9°、13.4°、21.1°和23.5°处的峰的X-射线粉末衍射图;和
当用Cu-Kα光源照射时,化学式(1)的化合物的无水结晶单盐酸盐(1HCl)形式具有包括在衍射角(2θ±0.2°)为9.5°、23.0°、23.2°和23.5°处的峰的X-射线粉末衍射图;以及化学式(1)的化合物的结晶二水合物(2H2O)形式具有包含165.4ppm、156.2ppm和147.7ppm的化学位移(ppm±0.5ppm)的13C CP/MAS TOSS(交叉极化/魔角旋转边带的总抑制)固态核磁共振(ssNMR)光谱;
化学式(1)的化合物的无水结晶形式I具有包含156.7ppm、146.9ppm、127.3ppm和54.3ppm的化学位移(ppm±0.5ppm)的13C CP/MAS TOSS固态核磁共振光谱;
化学式(1)的化合物的无水结晶形式II具有包含165.2ppm、156.7ppm、153.1ppm和129.2ppm的化学位移(ppm±0.5ppm)的13C CP/MAS TOSS ssNMR光谱;
化学式(1)的化合物的结晶单盐酸盐一水合物(1HCl·1H2O)形式具有包含164.5ppm、157.8ppm和145.8ppm的化学位移(ppm±0.5ppm)的13C CP/MAS TOSS固态核磁共振光谱;和
化学式(1)的化合物的无水结晶单盐酸盐(1HCl)形式具有包含163.0ppm、158.7ppm和146.9ppm的化学位移(ppm±0.5ppm)的13C CP/MAS TOSS固态核磁共振光谱。
化学式(1)的化合物或其盐酸盐的结晶形式为“基本上纯的”,其中表述“基本上纯的”表示至少95%,优选99%。
也就是说,95%–99%的纯度表示化学式(1)的化合物或其盐酸盐的特定结晶形式是95%–99%或更高,且其他结晶形式(化学式(1)的化合物的非晶或结晶形式,除了特定结晶形式之外)为5%–1%或更低。
此外,本专利文献提供了化学式(1)的所述喹唑啉化合物的非晶单盐酸盐形式。
根据本发明的另一个目的,本专利文献提供了一种药物组合物,包含化学式(1)的化合物的结晶形式或其盐酸盐的结晶形式,以及至少一种药学上可接受的载体或稀释剂。
药物组合物具有抗增殖活性(如抗癌活性),可用于选择性地且有效地治疗由酪氨酸激酶突变诱导的耐药性。
根据本专利文献的化学式(1)的化合物的结晶形式及其盐酸盐结晶形式在各种物理和化学性能(如在水中的溶解度、吸湿性和化学稳定性)方面是优异的,并且因此可以容易地用于生产含有其作为活性成分的药物组合物。
还提供了一种在受试者中治疗肿瘤的方法,包括向对需要其的受试者给药化学式(1)的化合物的新型结晶形式、其药物组合物或其与一种或多种其他药剂的组合物。
本专利文献的另一个方面提供了制备本发明所述的结晶形式的方法。
附图说明
现在将参照在附图中举例说明的某些示例性实施方案,详细地描述结晶形式的上述和其他特征,这些附图在下文中仅通过说明的方式给出,因此不限制本发明,并且其中:
图1A、图1B、图1C、图1D和图1E示出了根据实施例的化学式(1)的化合物及其结晶盐酸盐形式的X-射线粉末衍射(XRPD)光谱:图1A示出了实施例1中制备的结晶形式的XRPD;图1B示出了实施例2中制备的结晶形式的XRPD;图1C示出了实施例3中制备的结晶形式的XRPD;图1D示出了实施例4中制备的结晶形式的XRPD;图1E示出了实施例5中制备的结晶形式的XRPD。
图1F和图1G示出了根据对比例的化学式(1)的化合物及其非晶盐酸盐形式的XRPD光谱;图1F示出了实施例6中制备的非晶形式的XRPD;图1G示出了参考例中制备的化学式(1)的化合物的XRPD。
图2A、图2B、图2C、图2D和图2E示出了根据实施例的化学式(1)的化合物及其结晶盐酸盐形式的固态核磁共振(ssNMR)光谱;图2A示出了实施例1中制备的结晶形式的ssNMR;图2B示出了实施例2中制备的结晶形式的ssNMR;图2C示出了实施例3中制备的结晶形式的ssNMR;图2D示出了实施例4中制备的结晶形式的ssNMR;图2E示出了实施例5中制备的结晶形式的ssNMR。
图2F和图2G示出了根据比较例的化学式(1)的化合物及其非晶盐酸盐形式的ssNMR光谱;图2F示出了实施例6中制备的非晶形式的DVS;图2G示出了参考例中制备的化学式(1)的化合物的ssNMR。
图3A、图3B、图3C、图3D和图3E示出了根据实施例的化学式(1)的化合物及其结晶盐酸盐形式的差示扫描量热(DSC)图;图3A示出了实施例1中制备的结晶形式的DSC;图3B示出了实施例2中制备的结晶形式的DSC;图3C示出了实施例3中制备的结晶形式的DSC;图3D示出了实施例4中制备的结晶形式的DSC;图3E示出了实施例5中制备的结晶形式的DSC。
图4A、图4B、图4C、图4D和图4E示出了根据实施例的化学式(1)的化合物及其结晶盐酸盐形式的动态蒸气吸附(DVS)图;图4A示出了实施例1中制备的结晶形式的DVS;图4B示出了实施例2中制备的结晶形式的DVS;图4C示出了实施例3中制备的结晶形式的DVS;图4D示出了实施例4中制备的结晶形式的DVS;图4E示出了实施例5中制备的结晶形式的DVS。
图4F和图4G示出了根据比较例的化学式(1)的化合物及其非晶盐酸盐形式的DVS图;图4F示出了实施例6中制备的非晶形式的ssNMR;和图4G示出了参考例中制备的化学式(1)的化合物的DVS。
具体实施方式
参照本发明优选的实施方案,详细描述了本发明。然而,本领域技术人员将理解,在不脱离本发明的原理和精神的情况下,可以对这些实施方案做出改变,其范围由所附权利要求及其等同物限定。
定义
在本说明书中未具体限定的术语具有本领域技术人员根据技术和上下文理解到的含义。然而,除非另外说明,否则贯穿本说明书的以下术语具有以下所指出的含义:
如本发明中使用的术语“约”表示给定数值或范围的5%内、优选在1%与2%之间。例如,表述“约10%”指9.5%–10.5%,优选9.8%–10.2%。作为另一个实例,表述“约100℃”指95℃–105℃,优选98℃–102℃。
如本发明中使用的术语“化学纯度”指的是特定的化学实体的重量%,包括特定的多晶型物形式。例如,当化学式(1)的化合物的结晶二水合物(2H2O)的特征在于具有大于95%的化学纯度时,这意味着,大于95重量%的物质为化学式(1)的化合物的结晶二水合物(2H2O),小于5重量%的任何其他化合物(包括其他非晶形式和/或多晶型物)。类似地,当化学式(1)的化合物的特定的单盐酸盐一水合物结晶形式(1HCl·1H2O)的特征在于具有大于95%的化学纯度时,这种特定的结晶形式在相同的组合物中的化学式(1)的化合物的所有形式(包括例如,结晶或非晶形式、盐形式或非盐形式、水合物或无水形式)中占大于95重量%。在本上下文中,术语“衍生的”指的是在不改变该化合物的化学结构的情况下,形成化学式(1)的化合物的期望的结晶形式(例如,无水形式、水合物形式、或药学上可接受的盐)。如本发明中使用的术语“波齐替尼(poziotinib)”指的是化学式(1)的化合物的任何结晶形式。
本专利文献报道的X-射线粉末衍射(XRPD)光谱的衍射角(2θ)的峰值优选为本领域中通常可观察到的,±0.5%、更优选为±0.2%的实验误差。
而且,本专利文献报道的固态核磁共振光谱中的化学位移将优选解释为±0.5ppm内,更优选为±0.2%内。
化学式(1)的喹唑啉化合物的结晶形式及其结晶盐酸盐形式
本专利文献提供了以下式(1)的化合物,1-(4-(4-(3,4-二氯-2-氟苯基氨基)-7-甲氧基喹唑啉-6-基氧基)哌啶-1-基)丙-2-烯-1-酮及其结晶盐酸盐形式:
[化学式(1)]
上述化学式(1)的化合物可以根据韩国专利号为1,013,319的专利和美国专利号为8,003,658的专利中描述的一般过程制备。所有这些专利文献的全部内容通过引用纳入本申请。
上述文献中描述的化学式(1)的化合物是一种难溶的化合物,该化合物是非晶的,并且在水中的溶解度小于1.0μg/mL。
通常,已知将游离基转变成盐形式有助于溶解水不溶性药物物质。然而,这些盐必须具有药理学上所需的各种物理化学性质,例如制备特定的结晶形式的再现性、高结晶性、结晶形式的稳定性、化学稳定性和非吸湿性等。
为了选择化学式(1)的化合物的合适的盐形式,根据不同的条件和过程,使用不同的酸和溶剂制备化学式(1)的化合物的不同盐,并且评估它们的物理化学性质。在如此制备的盐中,化学式(1)的化合物的盐酸盐的不同形式的结晶形式在药理学上所需的不同物理化学性质(如制备特定的结晶形式的再现性、高结晶性、结晶形式的稳定性、化学稳定性和非吸湿性等)方面是最优异的。
化学式(1)的喹唑啉化合物的结晶形式及其结晶盐酸盐形式
化学式(1)的化合物的盐可以结晶形式、非晶形式或其混合物制备,但优选盐为结晶形式。化学式(1)的化合物的结晶盐酸盐形式是优选的,因为其具有优异的稳定性和易于配制的物理化学性质。
根据本发明,化学式(1)的化合物可以为各种晶型的形式,例如,其结晶二水合物(2H2O)形式和非晶形式。
根据本发明,化学式(1)的化合物还可以为各种结晶盐酸盐形式,例如,结晶单盐酸盐一水合物(1HCl·1H2O)形式及其无水结晶单盐酸盐(1HCl)形式。
在结晶盐酸盐中,作为稍后描述的测试例1的测试结果,无水结晶单盐酸盐形式在水中的溶解度是最优异的,且作为测试例2的测试结果,其在非吸湿性和稳定性方面可能是有利的,因此在药物组合物中作为有用的活性成分可能是所希望的。
在下文中,将更详细地描述根据本专利文献的每种结晶形式。
作为一个实例,本专利文献提供了化学式(1)的化合物的结晶二水合物(2H2O)形式。
当用Cu-Kα光源照射时,化学式(1)的化合物的结晶二水合物(2H2O)形式具有包含在衍射角(2θ±0.2°)为9.4°、11.4°、13.0°、16.1°、18.5°、19.3°、24.9°以及26.3°处的峰的XRPD光谱。这些峰可以是相对强度为约10%–20%或更大的峰。
上述结晶形式可以在13C CP/MASTOSS固态核磁共振(交叉极化/魔角自旋边带固态核磁共振的总抑制,ssNMR)光谱中具有147.7ppm、156.2ppm和165.4ppm的化学位移(ppm±0.5ppm)。
上述结晶形式可具有约7.5%的水分含量(6.83%的理论水分含量)、约117–122℃的冷凝温度和约190–195℃的熔点。
如通过DSC(10℃/min)测量的,当从约79℃的起点运行时,上述结晶形式可以在约111℃下具有最低点的吸热峰。
如通过DVS测量的,上述结晶形式在0%–90%的相对湿度范围内测得具有约2%–5%的吸湿度。
作为另一个实例,本专利文献提供了化学式(1)的化合物的无水结晶形式I。
当用Cu-Kα光源照射时,化学式(1)的化合物的无水结晶形式I具有包含在衍射角(2θ±0.2°)为6.0°、10.6°、10.9°、12.1°、16.0°、17.5°、18.3°、19.2°、20.3°、22.7°、23.7°和26.3°处的峰的XRPD光谱。这些峰可以是相对强度为约10%–20%或更大的峰。
上述结晶形式在13C CP/MAS TOSS固态核磁共振(ssNMR)光谱中可具有54.3ppm、127.3ppm、146.9ppm和156.7ppm的化学位移(ppm±0.5ppm)。
上述结晶形式可具有约0.1%的水分含量和约190℃–195℃的熔点。
如通过DSC(10℃/min)测量的,当从约186℃的起点运行时,上述结晶形式可以在约191℃下具有最低点的吸热峰。
如通过DVS测量的,上述结晶形式在10%–50%的相对湿度范围内测得具有约0.5%的吸湿度,以及在50%–90%的相对湿度范围内测得具有约3%的吸湿度。
作为另一个实例,本专利文献提供了化学式(1)的化合物的无水结晶形式II。
当用Cu-Kα光源照射时,化学式(1)的化合物的无水结晶形式II可以具有包含在衍射角(2θ±0.2°)为4.9°、5.9°、11.8°、18.8°和19.9°处的峰的XRPD光谱。这些峰可以是相对强度为约10%–20%或更大的峰。
上述结晶形式在13C CP/MASTOSS固态核磁共振(ssNMR)谱中可以具有129.2ppm、153.1ppm、156.7ppm和165.2ppm的化学位移(ppm±0.5ppm)。
上述结晶形式可具有约0.3%的水分含量和约183℃–185℃的熔点。
如通过DVS测量的,上述结晶形式在0%–90%的相对湿度范围内测得具有非常低的吸湿度。
如通过DSC(10℃/min)测量的,当从约181℃的起点运行时,上述结晶形式可以在约185℃下具有最低点的吸热峰。
如通过DVS测量的,上述结晶形式在0%–90%的相对湿度范围内测得具有非常低的吸湿度。
作为另一个实例,本专利文献提供了化学式(1)的化合物的结晶单盐酸盐一水合物(1HCl·1H2O)形式。
当用Cu-Kα光源照射时,化学式(1)的化合物的结晶单盐酸盐一水合物(1HCl·1H2O)形式可以具有包含在衍射角(2θ±0.2°)为8.9°、13.4°、14.1°、16.0°、19.8°、21.1°、21.7°、23.5°、25.7°及32.7°处的峰的XRPD光谱。这些峰可以是相对强度为约10%–20%或更大的峰。
上述结晶形式在13C CP/MASTOSS固态核磁共振(ssNMR)谱中可以具有145.8ppm、157.8ppm和164.5ppm的化学位移(ppm±0.5ppm)。
如通过DSC(10℃/min)测量的,当从约127℃的起点运行时,上述结晶形式可以在约151℃下具有最低点的吸热峰和在约178℃的吸热峰。
上述结晶形式可以有约3.2%的水分含量(3.30%的理论水分含量)和约187℃–193℃的熔点。
如通过DVS测量的,上述结晶形式在10%–90%的相对湿度范围内测得具有非常低的吸湿度。
作为另一个实例,本专利文献提供了化学式(1)的化合物的无水结晶单盐酸盐(1HCl)形式。
当用Cu-Kα光源照射时,化学式(1)的化合物的无水结晶单盐酸盐(1HCl)形式可以具有包含在衍射角(2θ±0.2°)为9.5°,12.3°、13.0°、13.5°、14.2°、21.4°、23.0°、23.2°、23.5°,27.2°和27.5°处的峰的XRPD光谱。这些峰可以是相对强度为约10%–20%或更大的峰。
上述结晶形式在13C CP/MASTOSS固态核磁共振(ssNMR)谱中可以具有146.9ppm、158.7ppm和163.0ppm的化学位移(ppm±0.5ppm)。
如通过DSC(10℃/min)测量的,当从约20℃的起点运行时,上述结晶形式可以在约230℃下具有最低点的吸热峰。
上述结晶形式可以有约0.1%的水分含量和约238℃–243℃的熔点。
如通过DVS测量的,上述结晶形式在10%–90%的相对湿度范围内测得具有非常低的吸湿度。
根据本专利文献提供了一种制备化学式(1)的化合物的结晶形式(水合物或无水)的一般方法。该方法包括:
(a)提供化学式(1)的化合物在溶剂体系(质子的、非质子的或混合的)中的溶液;
(b)冷却该溶液以形成化学式(1)的化合物的结晶形式(水合物或无水);和
(c)分离化学式(1)的化合物的结晶形式(水合物或无水)。
还提供了一种用于制备化学式(1)的化合物的结晶盐酸盐形式(水合物或无水)的方法。该方法包括:
(a)提供化学式(1)的化合物在溶剂体系(质子的、非质子的或混合的)中的溶液;
(b)向该溶液中添加盐酸;
(c)冷却该溶液以形成化学式(1)的化合物的结晶盐酸盐形式(水合物或无水);和
(d)分离化学式(1)的化合物的结晶盐酸盐形式(水合物或无水)。
溶剂体系的非限制性实例如下:丙酮;乙腈;丙酮/水;乙腈/水;乙醇;乙醇/水、DMSO;DMSO/水;DMF;DMF/水。
该方法是高度可再现的,且所得的结晶产物具有良好的可滤性。
根据本专利文献的化学式(1)的化合物的结晶形式(水合物或无水)及其结晶盐酸盐形式(水合物或无水)不需要特定的储存条件,且可以长时间稳定地维持。能够满足药物所需的物理化学性质(包括优异的水溶性),它们可容易地用于制造含有其作为活性成分的药物组合物。
根据本专利文献的化学式(1)的化合物的结晶形式(水合物或无水)具有高化学纯度。在一些实施方案中,化学纯度大于约75%、大于约80%、大于约85%、大于约90%、大于约95%或大于约99%。
药物组合物
如韩国专利号为1,013,319的专利和美国专利号为8,003,658的专利中公开的(其全部内容纳入本申请),已证实化学式(1)的化合物具有抗增殖活性(如抗癌活性),并且具有选择性地且有效地抑制由酪氨酸激酶或其突变诱导的癌细胞的生长和耐药性的活性。
在这方面,化学式(1)的化合物的结晶形式及其盐酸盐可用于制备用于治疗或预防由酪氨酸激酶或其突变引起的各种实体癌(如癌症或肿瘤,特别是肺癌、乳腺癌等)的药物组合物。
化学式(1)的化合物的结晶形式及其盐酸盐的剂量可以根据待治疗的受试者、疾病或病症的严重程度、给药速率以及开处方的医师的判断而变化,但它们通常可作为活性成分以1–2000mg/kg体重(基于化学式(1)的化合物的游离碱计)的量给药至70kg的个体,优选5–1000mg,基于化学式(1)的化合物,通常通过口服或非肠道途径按照每天一至四次按时或不按时给药。在某些情况下,小于上述范围的剂量可能更合适,在不会引起有害的副作用的情况下,也可以使用大于上述范围的剂量,并且在更高剂量的情况下,每天以分开的剂量多次给药。
可以根据常规的方法配制根据本专利文献的药物组合物,并且可以制备成各种口服剂型(例如片剂、丸剂、散剂、胶囊、糖浆、乳液或微乳液等),或以非肠道剂型(例如肌肉内、静脉内或皮下)给药。
当根据本专利文献的药物组合物以口服制剂的形式制备时,载体的实例包括纤维素、硅酸钙、玉米淀粉、乳糖、蔗糖、葡萄糖、磷酸钙、硬脂酸、硬脂酸镁、硬脂酸钙、明胶、滑石粉、表面活性剂、悬浮剂、乳化剂和稀释剂等。当根据本专利文献的药物组合物以注射剂的形式制备时,载体的实例包括水、生理盐水、葡萄糖水溶液、假糖(pseudosugar)水溶液、醇、二醇、醚(例如聚乙二醇400)、油、脂肪酸、脂肪酸酯、甘油酯、表面活性剂、悬浮剂和乳化剂等。
在一些实施方案中,药物组合物还包含非金属盐润滑剂,所述非金属盐润滑剂选自山嵛酸甘油酯、硬脂酸棕榈酸甘油酯、单硬脂酸甘油酯、三肉豆蔻酸甘油酯、甘油三硬脂酸酯、蔗糖脂肪酸酯、棕榈酸、棕榈酰醇、硬脂酸、硬脂醇、富马酸、聚乙二醇4000、聚乙二醇6000、聚四氟乙烯、淀粉、滑石粉、氢化蓖麻油、矿物油、氢化植物油、二氧化硅及其任意组合物。
在一些实施方案中,该药物组合物还包含金属盐润滑剂。非限制性实例包括硬脂酸镁、硅酸镁、硬脂酸和硬脂酸钙。
本发明的一个相关方面包括一种用于治疗癌症的试剂盒,所述试剂盒包含本发明所述的结晶形式或其药物组合物。试剂盒或药物组合物可以含有额外的细胞毒剂或分子靶向剂。根据受试者的具体病症,本发明所述的结晶形式或其药物组合物以及额外的细胞毒剂可以顺序地或同时地给药。
细胞毒剂指的是对细胞有细胞毒性作用的试剂。细胞毒性作用指的是靶细胞(即肿瘤细胞)的消耗、消除和/或杀死。细胞毒剂可以为选自抗代谢物、有丝分裂抑制剂、烷化剂、铂基抗肿瘤药物、mTOR抑制剂、VEGF抑制剂、芳香酶抑制剂和CDK4/6抑制剂中的至少一种。试剂盒或药剂组合物可以包含至少两种细胞毒剂。例如,组合物可以包含选自抗代谢物、有丝分裂抑制剂、烷化剂、铂基抗肿瘤药物、mTOR抑制剂、VEGF抑制剂、芳香酶抑制剂、CDK4/6抑制剂和其全部中的至少2种、至少3种或至少4种。
抗代谢物可以是一种通过抑制嘌呤或嘧啶(其为核苷酸的基础)的形成来抑制细胞中的DNA合成的药物。抗代谢物可以选自卡培他滨(Capecitabine)、5-氟尿嘧啶、吉西他滨(Gemcitabine)、培美曲塞(Pemetrexed)、甲氨蝶呤(Methotrexate)、6-巯嘌呤、克拉屈滨(Cladribine)、阿糖孢苷(Cytarabine)、多西氟啶(Doxifludine)、氟尿苷、氟达拉滨(Fludarabine)、羟基尿素(Hydroxycarbamide)、达卡巴嗪(decarbazine)、羟基脲(hydroxyurea)和天冬酰胺酶。
有丝分裂抑制剂可以为微管去稳定剂、微管稳定剂或其组合物。有丝分裂抑制剂可以为紫杉烷(taxane)、长春花生物碱(vincaalkaloid)、埃坡霉素(epothilone)或其组合物。
有丝分裂抑制剂可以选自BT-062、HMN-214、甲磺酸艾日布林(eribulinmesylate)、长春地辛(vindesine)、EC-1069,EC-1456、EC-531、vintafolide、2-甲氧雌二醇、GTx-230、曲妥珠单抗(trastuzumab emtansine)、crolibulin、D1302A-美登木素生物基共轭物IMGN-529(D1302A-maytansinoid conjugates IMGN-529)、莫星-洛沃妥珠单抗(lorvotuzumab mertansine)、SAR-3419、SAR-566658、IMP-03138、拓扑替康(topotecan)/长春新碱(vincristine)组合物、BPH-8、CA4P单氨丁三醇盐(fosbretabulintromethamine)、雌莫司汀磷酸钠、长春新碱(vincristine)、长春氟宁(vinflunine)、长春瑞滨(vinorelbine)、RX-21101、卡巴他塞(cabazitaxel)、STA-9584、长春花碱(vinblastine)、埃坡霉素A、帕土匹龙(patupilone)、伊沙匹隆(ixabepilone)、埃坡霉素D、紫杉醇、多西他赛(docetaxel)、DJ-927、圆皮海绵内酯(discodermolide)、五加素(eleutherobin)及其药学上可接受的盐或其组合物。
如本发明使用的,“烷化剂”是一种将一个或多个烷基(CnHm,其中n和m是整数)添加到核酸中的物质。在本发明中,烷化剂选自氮芥、亚硝基脲、烷基磺酸盐、三嗪、乙烯亚胺及其组合物。氮芥的非限制性实例包括二氯甲基二乙胺、苯丁酸氮芥、环磷酰胺、苯达莫司汀(bendamustine)、异环磷酰胺、美法仑(melphalan)、美法仑氟芬酰胺(melphalanflufenamide)及其药学上可接受的盐。亚硝基脲的非限制性实例包括链脲霉素(streptozocin)、卡莫司汀(carmustine)、环己亚硝脲及其药学上可接受的盐。烷基磺酸盐的非限制性实例包括白消安(busulfan)及其药学上可接受的盐。三嗪的非限制性实例包括达卡巴嗪、替莫唑胺(temozolomide)及其药学上可接受的盐。乙烯亚胺的非限制性实例包括噻替派(thiotepa)、六甲蜜胺(altretamine)及其药学上可接受的盐。其他烷化剂包括ProLindac、Ac-225BC-8、ALF-2111、曲磷胺、MDX-1203、硫脲基丁腈,二溴甘露醇、二溴卫矛醇、尼莫司汀(nimustine)、葡磷酰胺、HuMax-TAC和PBD ADC的组合物、BP-C1、苏消安(tresulfan)、硝呋莫司(nifurtimox)、英丙舒凡甲苯磺酸酯(improsulfan tosilate)、雷诺氮芥(ranimustine)、ND-01、HH-1、22P1G细胞和异环磷酰胺的组合物、磷酸雌二醇氮芥(estramustine phosphate)、泼尼氮芥(prednimustine)、鲁贝替定(lurbinectedin)、他比特啶(trabectedin)、六甲密胺(altreatamine)、SGN-CD33A、福莫司汀(fotemustine)、奈达铂(nedaplatin)、庚铂(heptaplatin)、阿帕齐醌(apaziquone)、SG-2000、TLK-58747、兰瑞肽(laromustine)、甲基苄肼以及其药学上可接受的盐。
铂基抗肿瘤药物可以为例如,顺铂(Cisplatin)、卡铂(carboplatin)、双环铂(Dicycloplatin)、依铂(Eptaplatin)、洛铂(Lobaplatin)、米铂(Miriplatin)、奈达铂、奥沙利铂(Oxaliplatin)、吡铂(Picoplatin)或赛特铂(Satraplatin)。
如本发明使用的术语“mTOR抑制剂(mTOR抑制剂)”是一种用于抑制常规抗癌剂或免疫抑制剂的mTOR信号通路的材料。mTOR抑制剂可以是雷帕霉素(rapamycin)、替西罗莫司(temsirolimus)、依维莫司(everolimus)、地磷莫司(ridaforolimus)、MLN4924、XL388、GDC-0349、AZD2014、AZD8055、GSK105965、MLN0128地磷莫司等。
如本发明使用的“VEGF抑制剂”是减少VEGF-VEGFR通路信号的任何物质。仅举几个实例,VEGF抑制剂可以为小分子、肽、多肽、蛋白质,包括更具体的抗体、包括抗VEGF抗体、抗VEGFR抗体、胞内抗体、巨型抗体(maxibody)、微型抗体(minibody)、双抗体、Fc融合蛋白(如肽体、受体、可溶性VEGF受体蛋白和片段)、以及多种其他的抗体。许多VEGF抑制剂通过与VEGF或VEGF受体结合而起作用。其他VEGF抑制剂通过与VEGF或VEGF受体或VEGF信号通路的其他组分的要素结合而更间接地起作用。还有其他VEGF抑制剂通过改变调节VEGF通路信号的调节转译后的修饰而起作用。根据本发明的VEGF抑制剂还可以通过更间接的机制而起作用。不管涉及什么机制,如本发明使用的,在给定情况下,VEGF抑制剂降低VEGF信号通路的有效活性,超过其在不存在抑制剂的相同情况下的情况。
VEGF抑制剂的非限制性实例包括:(a)4TBPPAPC或者在US2003/0125339或美国专利号为6,995,162的专利中所述的密切相关的化合物,这些专利的全部内容通过引用纳入本申请,特别是公开了4TBPPAPC和密切相关的VEGF抑制剂部分;(b)AMG 706或者在US2003/0125339或US2003/0225106或美国专利号为6,995,162的专利或美国专利号为6,878,714的专利中所述的密切相关的取代的烷基胺衍生物,这些专利各自的全部内容通过引用纳入本申请,特别是公开了AMG 706和这些密切相关的VEGF抑制剂部分;(c)AvastinTM或结合至VEGF的密切相关的非天然存在的人源化单克隆抗体为VEGF抑制剂,并且在序列上与AvastinTM至少90%相同;(d)或者在WO00/42012、WO00/41698、US2005/0038080A1、US2003/0125359A1、US2002/0165394A1、US2001/003447A1、US2001/0016659A1和US2002/013774A1中所述的密切相关的取代的Ω-羧芳基二苯基尿素或其衍生物,这些专利的全部内容通过引用纳入本申请,特别是公开了这些VEGF抑制剂的部分;(e)PTK/ZK或结合至且抑制多种受体酪氨酸激酶活性的密切相关的苯胺酞嗪(anilinophthalazine)或其衍生物,包括结合至蛋白激酶结构域,以及VEGFR1和VEGFR2的抑制;(f)或为VEGF抑制剂的(5-[5-氟-2-氧代-1,2-二氢吲哚-(3Z)-亚基甲基]-2,4-二甲基-1H-吡咯-3-羧酸[2-二乙氨乙基]酰胺)的密切相关的衍生物;和(g)如US2006/0241115中所述的VEGF抑制剂,包括其中的化学式IV的那些。
VEGF抑制剂的其他实例如下:(a)如在US2003/0125339或美国专利号为No.6,995,162的专利中所述的4TBPPAPC,这些专利的全部内容通过引用纳入本申请,特别是公开了4TBPPAPC的部分;(b)如在US2003/0125339或美国专利号为6,995,162的专利或美国专利号为6,878,714的专利中所述的AMG 706,这些专利的全部内容通过引用纳入本申请,特别是公开了AMG 706的部分;(c)AvastinTM;(d)如在WO00/42012、WO00/41698、US2005/0038080A1、US2003/0125359A1、US2002/0165394A1、US2001/003447A1、US2001/0016659A1和US2002/013774A1中所述的这些专利的全部内容通过引用纳入本申请,特别是公开了的部分;(e)PTK/ZK;(f)和(g)如在US2006/0241115中所述的化学式IV的VEGF抑制剂。
在一些实施方案中,VEGF抑制剂为哌加他尼(pegaptanib)。在一个实施方案中,VEGF抑制剂为贝伐单抗(bevacizumab)。在一个实施方案中,VEGF抑制剂为兰尼单抗(ranibizumab)。在一个实施方案中,所述VEGF抑制剂为拉帕替尼(lapatinib)。在一个实施方案中,所述VEGF抑制剂为索拉非尼(sorafenib)。在一个实施方案中,VEGF抑制剂为舒尼替尼(sunitinib)。在一个实施方案中,VEGF抑制剂为阿西替尼(axitinib)。在一个实施方案中,VEGF抑制剂为帕唑帕尼(pazopanib)。在一个实施方案中,VEGF抑制剂为阿柏西普(aflibercept)。
“芳香化酶抑制剂”指的是抑制芳香化酶的非甾族和甾族化合物,从而阻止雄激素转化为雌激素,优选那些在体外抑制芳香化酶活性且IC50值小于10–5M的化合物及其药学上可接受的盐。在本发明所述方法中所使用的示例性芳香化酶抑制剂包括但不限于阿那曲唑(anastrozole)、来曲唑(letrozole)、依西美坦(exemestane)、伏罗唑(vorozole)、福美司坦(formestane)、法倔唑(fadrozole)、氨鲁米特(aminoglutethimide)、睾内酯、4-羟基雄甾烯二酮、l,4,6-雄甾三烯-3,17-二酮和4-雄甾烯-3,6,17-三酮。
如本发明所用的术语“周期素依赖性蛋白激酶4/6抑制剂”和“CDK4/6抑制剂”指的是一种选择性靶向、降低或抑制CDK4和/或CDK6的至少一种活性的化合物。CDK4/6抑制剂的非限制性实例包括阿贝克利布(Abemaciclib)(LY2835219)、帕博西尼(palbocicllb)(PD0332991),LEE-011(瑞博西尼(ribociclib))、LY2835219(阿贝克利布)、G1T28-1、SHR6390、或P276-00、或者帕博西尼、LEE-011、G1T28-1、SHR6390或P276-00的任何一种的衍生物。在某些实施方案中,CDK4/6抑制剂可能源自吡啶并嘧啶、吡咯并嘧啶或吲哚并咔唑化合物。
如本发明所用的“分子靶向剂”是一种当给药受试者时会干扰单分子或分子组的功能物质,优选为那些涉及肿瘤生长和发展的功能物质。本专利文献的分子靶向剂的非限制性实例包括单向信号转导抑制剂、基因表达和其他细胞功能的调节剂、免疫系统调节剂、抗体-药物偶联物(ADC)及其组合物。
分子靶向剂可选自表皮生长因子受体家族抑制剂(EGFRi)、哺乳动物雷帕霉素靶蛋白(mTor)抑制剂、免疫检查点抑制剂、间变性淋巴瘤激酶(ALK)抑制剂、B细胞淋巴瘤-2(BCL-2)抑制剂、B-Raf抑制剂、周期素依赖性蛋白激酶抑制剂(CDKi)、ERK抑制剂、组蛋白脱乙酰酶抑制剂(HDACi)、热休克蛋白90抑制剂(HSP90i)、Janus激酶抑制剂、丝裂原激活蛋白激酶(MAPK)抑制剂、MEK抑制剂、聚ADP核糖聚合酶(PARP)抑制剂、磷酸肌醇3-激酶抑制剂(PI3Ki)、Ras抑制剂及其组合物。
分子靶向剂可以选自ado-曲妥珠单抗、阿仑单抗(alemtuzumab)、西妥昔单抗(cetuximab)、易普利姆玛(ipilimumab)、奥法木单抗(ofatumumab)、帕尼单抗(panitumumab)、帕妥珠单抗(pertuzumab)、利妥昔单抗(rituximab)、托西莫单抗(tositumomab)、131I-托西莫单抗、曲妥珠单抗、本妥昔单抗(brentuximab vedotin)、地尼白介素(denileukin diftitox)、替伊莫单抗(ibritumomab tiuxetan)、阿昔替尼(axitinib)、硼替佐米(bortezomib)、博舒替尼(bosutinib)、卡博替尼(cabozantinib)、克里唑蒂尼(crizotinib)、卡非佐米(carfilzomib)、达沙替尼(dasatinib)、埃罗替尼(erlotinib)、吉非替尼(gefitinib)、甲磺酸伊马替尼(imatinib mesylate)、拉帕替尼、尼洛替尼(nilotinib)、帕唑帕尼、帕纳替尼(ponatinib)、瑞格拉非尼(regorafenib)、鲁索替尼(ruxolitinib)、索拉非尼、舒尼替尼、托法替尼(tofacitinib)、凡德他尼(vandetanib)、维莫非尼(vemurafenib)、阿利维A酸(alitretinoin)、蓓萨罗丁(bexarotene)、依维莫司、罗米地辛(romidepsin)、替西罗莫司、维甲酸(tretinoin)、伏立诺他(vorinostat)及其药学上可接受的盐或其组合物。分子靶向剂可包括抗体或抗体部分。
EGFRi可选自埃罗替尼、吉非替尼、拉帕替尼、卡奈替尼(canetinib)、培利替尼(pelitinib)、来那替尼(neratinib)、(R,E)-N-(7-氯-1-(1-(4-(二甲基氨基)丁-2-烯酰)氮杂-3-基)-1H-苯并[d]咪唑-2-基)-2-甲基异烟酰胺、曲妥珠单抗、Margetuximab、帕尼单抗、马妥珠单抗(matuzumab)、耐昔妥珠单抗(Necitumumab)、帕妥珠单抗、尼妥珠单抗(nimotuzumab)、zalutumumab、耐昔妥珠单抗、西妥昔单抗、埃克替尼(icotinib)、阿法替尼(afatinib)及其药学上可接受的盐。分子靶向剂可以为抗EGFR家族抗体或包括抗EGFR家族抗体的复合物。抗EGFR家族抗体可以是抗HER1抗体、抗HER2抗体或抗HER4抗体。
治疗癌症的方法
本发明的另一方面提供了一种在受试者中治疗肿瘤的方法,包括向需要其的受试者给药本发明所述的新型结晶形式、其药物组合物(与一种或多种药剂结合的组合物)或包含该新型结晶形式的试剂盒。
根据本专利文献可以治疗的肿瘤的非限制性实例包括含非小细胞肺癌的肺癌、乳腺癌、胃癌、结肠癌、胰腺癌、前列腺癌、骨髓瘤、头颈癌、卵巢癌、食道癌或转移性细胞癌。在一些实施方案中,与HER1、HER2和HER4或其突变体的至少一个基因的过表达或扩增有关的肿瘤可以是组织的异常生长,如果该组织形成了肿块,其通常称为具有HER1、HER2、HER4及其突变体中的至少一种的过表达,或HER1、HER2和HER4或其突变体的至少一个基因编码的扩增的肿瘤。突变体可以为有外显子19缺失、T790M取代、L828R取代或其组合物的HER1。如本发明所用的“过表达”指示蛋白质以比正常细胞更高的水平表达。可以使用免疫组织化学、荧光原位杂交(FISH)或发色原位杂交(CISH)来测量表达水平。
如本发明所用的术语“野生型”在本领域内理解为指在天然群体中发生而没有遗传修饰的多肽或多核苷酸序列。如本领域所理解的,“突变体”包括分别与野生型多肽或多核苷酸中发现的相应氨基酸或核酸相比,对氨基酸或核酸有至少一种修饰的多肽或多核苷酸序列。术语突变体中包括单核苷酸多态性(SNP),其中与最普遍发现的(野生型)链核酸相比,单链核酸的序列中存在单碱基对差别。
包括野生型、或者HER1、HER2或HER4突变体、或者具有HER1、HER2或HER4基因的扩增、或者具有HER1、HER2或HER4蛋白过表达的癌症的肿瘤可以通过已知方法鉴定。
例如,野生型或突变体HER1、HER2和HER4肿瘤细胞可以分别通过DNA扩增和测序技术、DNA和RNA检测技术(包括但不限于Northern和Southern印迹杂交),和/或各种生物芯片和阵列技术或原位杂交来识别。野生型和突变体多肽可以通过多种技术(包括但不限于免疫诊断技术,如ELISA、Western印迹杂交或免疫细胞化学)检测。
待治疗的癌症可能与EGFR和/或HER2外显子20突变(例如外显子20插入突变)有关。例如,本专利文献的化合物的新型结晶形式或其与一种或多种药剂的组合物可以用于治疗患有EGFR外显子20突变的NSCLC患者。
在一些方面中,用本专利文献的化合物的新型晶体形式或其与一种或多种药剂的组合物来治疗的癌症为口腔癌、口咽癌、鼻咽癌、呼吸道癌、泌尿生殖癌、胃肠道癌、中枢或周围神经系统组织癌、内分泌或神经内分泌癌或造血系统癌、神经胶质瘤、肉瘤、恶性上皮肿瘤(carcinoma)、淋巴瘤、黑色素瘤、纤维瘤、脑膜瘤、脑癌、口咽癌、鼻咽癌、肾癌、胆管癌、嗜铬细胞瘤、胰岛细胞癌、Li-Fraumeni肿瘤、甲状腺癌、甲状旁腺癌、垂体瘤、肾上腺肿瘤、骨肉瘤肿瘤、I型和II型多发性神经内分泌肿瘤、乳腺癌、肺癌、头颈癌、前列腺癌、食道癌、气管癌、肝癌、膀胱癌、胃癌、胰腺癌、卵巢癌、子宫癌、宫颈癌、睾丸癌、结肠癌、直肠癌或皮肤癌。在特定方面,癌症是非小细胞肺癌。
本发明所用的术语“治疗”及其衍生词指的是治疗疗法。针对特定疾病,治疗指的是:(1)改善或预防该疾病的一种或多种生理表现的症状,(2)干扰(a)导致或负责该疾病的生物级联中的一个或多个点,或(b)该疾病的一个或多个生理表现,(3)减轻与该疾病或其治疗有关的一种或多种症状、效应或副作用,或(4)减缓该疾病的发展或者该疾病的一种或多种生理表现。因此也考虑了预防性治疗。技术人员将理解,“预防”不是绝对术语。在医学中,“预防”应理解为指的是预防性给药药物,以从实质上降低病症或其生理表现的可能性或严重性,或者延迟此类疾病的发作或其生理表现。预防性治疗是适当的,例如,当认为受试者有患癌症的高风险时,如当受试者具有很强的癌症家族病史或当受试者暴露于致癌物时。
给药治疗有效量的化学式(1)的化合物的新型结晶形式或其与其他药剂的组合物优于许多其他传统疗法,包括:i)比最具活性的单一药剂更强的抗癌作用,ii)协同的或高度协同抗癌活性,iii)提供增强抗癌活性并减少副作用的给药方案,iv)减少毒性作用,v)增加治疗窗,vi)提高一种或两种组分化合物的生物利用度,或vii)增加单个组分化合物的细胞凋亡。
在一些实施方案中,本专利文献的化学式(1)的化合物的新型结晶形式的试剂盒或组合物可以包含波齐替尼和抗EGFR家族抗体。抗EGFR家族抗体可以为曲妥珠单抗、西妥昔单抗、Margetuximab、马妥珠单抗、帕尼单抗、耐昔妥珠单抗或帕妥珠单抗。组合物的一个实例可以为波齐替尼和曲妥珠单抗;或波齐替尼和西妥昔单抗。波齐替尼可以为盐酸盐。组合物可以进一步包含细胞毒剂。细胞毒剂可以为有丝分裂抑制剂。有丝分裂抑制剂可以为紫杉烷、长春花生物碱、埃博霉素或其组合物。长春花生物碱可以选自长春花碱、长春新碱、长春地辛和长春瑞滨的至少一种药物。组合物的一个实例可以包含波齐替尼;和曲妥珠单抗和长春瑞滨。长春瑞滨可以为注射剂的形式。紫杉烷可以为紫杉醇或多西他赛。组合物的实例可以包含波齐替尼;和西妥昔单抗和紫杉醇。紫杉醇可以为注射的形式。
本专利文献的化学式(1)的化合物的新型结晶形式可以以0.1mg–50mg的量给药。曲妥珠单抗可以以0.5mg–10mg/kg体重的量给药。西妥昔单抗可以以100mg/m2至500mg/m2身体表面积的量给药。
长春瑞滨可以以0.5mg/m2至50mg/m2身体表面积的量给药。而且,紫杉醇可以以100mg/m2至300mg/m2身体表面积的量给药。
曲妥珠单抗(其中以商标名称HerceptinTM出售)是一种用于治疗乳腺癌的单克隆抗体。特别地,它是用于HER2受体阳性的乳腺癌。曲妥珠单抗是通过缓慢注射到静脉以及皮下注射给药。
西妥昔单抗是一种用于治疗转移性结肠直肠癌、转移性非小细胞肺癌和头颈癌的表皮生长因子受体(EGFR)抑制剂。西妥昔单抗是一种通过静脉内输注给药的嵌合(小鼠/人)单克隆抗体,其在美国和加拿大境内通过Bristol-Myers Squibb药物公司,在美国和加拿大境外通过MerckKGaA药物公司,以商标名Erbitux分销。在日本,MerckKGaA、Bristol-Myers Squibb和Eli Lilly共同分销。
紫杉醇(PTX)(其中以商标名Taxol出售)是一种用于治疗多种类型的癌症的化学疗法药物。这包括卵巢癌、乳腺癌、肺癌、卡波西肉瘤(Kaposi sarcoma)、宫颈癌和胰腺癌。其通过注射到静脉中给药。
在一个实施方案中,试剂盒/组合物可以包含本专利文献的化学式(1)的化合物的新型结晶形式和有丝分裂抑制剂。有丝分裂抑制剂可以选自BT-062、HMN-214、甲磺酸艾日布林、长春地辛、EC-1069、EC-1456、EC-531、vintafolide、2-甲氧雌二醇、GTx-230、曲妥珠单抗、crolibulin、D1302A-美登木素生物基共轭物、IMGN-529、莫星-洛沃妥珠单抗、SAR-3419、SAR-566658、IMP-03138、拓扑替康/长春新碱组合物、BPH-8、CA4P单氨丁三醇盐、雌莫司汀磷酸钠、长春新碱、长春氟宁、长春瑞滨、RX-21101、卡巴他赛、STA-9584、长春花碱、埃博霉素A、帕土匹龙、伊沙匹隆、埃博霉素D、紫杉醇、多西他赛、DJ-927、圆皮海绵内酯、五加素以及其药学上可接受的盐或其组合物。组合物的一个实例可以包含波齐替尼和紫杉烷、长春花生物碱或其组合物。长春花生物碱可以为选自长春花碱、长春新碱、长春地辛和长春瑞滨的至少一种药物。紫杉烷可以为紫杉醇或多西他赛。组合物的一个实例可以包含波齐替尼和紫杉醇(pacliataxel);或波齐替尼和长春瑞滨。肿瘤可以为乳腺癌,其中Her2是过表达的。
波齐替尼可以以0.1mg–50mg的量给药。而且,长春瑞滨可以以0.5mg/m2至50mg/m2身体表面积的量给药。同样,紫杉醇可以以100mg/m2至300mg/m2身体表面积的量给药。
长春瑞滨(NVB)(其中以商标名Navelbine出售)是一种用于治疗多种类型的癌症的化学疗法药物。这包括乳腺癌和非小细胞肺癌。其通过静脉注射或口服给药。长春瑞滨属于长春花生物碱家族药物。它被认为是通过扰乱微管的正常功能从而阻止细胞分裂而起作用。
在一个实施方案中,组合物可包含本专利文献的化学式(1)的化合物的新型结晶形式和mTOR抑制剂。mTOR抑制剂可以选自唑他莫司(zotarolimus)、umirolimus、替西罗莫司、西罗莫司、西罗莫司NanoCrvstal、西罗莫司TransDerm、西罗莫司-PNP、依维莫司、biolimusA9、地磷莫司(ridaforolimus)、雷帕霉素、TCD-10023、DE-109、MS-R001、MS-R002、MS-R003、Perceiva、XL-765、奎纳克林、PKI-587、PF-04691502、GDC-0980、dactolisib、CC-223、PWT-33597、P-7170、LY-3023414、INK-128、GDC-0084、DS-7423、DS-3078、CC-115、CBLC-137、AZD-2014、X-480、X-414、EC-0371、VS-5584、PQR-401、PQR-316、PQR-311、PQR-309、PF-06465603、NV-128、nPT-MTOR、BC-210、WAY-600、WYE-354、WYE-687、LOR-220、HMPL-518、GNE-317、EC-0565、CC-214、ABTL-0812以及其药学上可接受的盐或其组合物。组合物的一个实例可包含波齐替尼和雷帕霉素。雷帕霉素可以是注射剂的形式。雷帕霉素(Rapamycin)(也称为西罗莫司(sirolimus)),是由细菌吸水链霉菌(Streptomyces hygroscopicus)产生的化合物。
本专利文献的化学式(1)的化合物的新型结晶形式可以以0.1mg至50mg的量给药。雷帕霉素也可以以0.5mg/m2至10mg/m2身体表面积的量给药。
在一个实施方案中,试剂盒/组合物可以包含本专利文献的化学式(1)的化合物的新型结晶形式和抗代谢物。抗代谢物可以选自卡培他滨、5-氟尿嘧啶、吉西他滨、培美曲塞、甲氨蝶呤、6-巯嘌呤、克拉屈滨、阿糖孢苷、多西氟啶、氟尿苷、氟达拉滨、羟基尿素、达卡巴嗪、羟基脲和天冬酰胺酶。组合物的一个实例可以包含波齐替尼和5-氟尿嘧啶。5-氟尿嘧啶可以是注射剂的形式。
本专利文献的化学式(1)化合物的新型结晶形式可以以0.1mg至50mg的量给药,5-氟尿嘧啶可以以100mg/m2至3000mg/m2身体表面积的量给药。
氟尿嘧啶(5-FU)(尤其以商标名Adrucil出售)是一种用于治疗癌症的药物。通过注射到静脉中,其用于结肠癌、食道癌、胃癌、胰腺癌、乳腺癌和宫颈癌。[2]作为一种霜剂,其被用于治疗基底细胞癌。氟尿嘧啶属于抗代谢物和嘧啶类似物药物家族。其如何起作用是不完全清楚的,但是被认为涉及阻断胸苷酸合成酶的作用并且因此停止DNA的产生。
在一个实施方案中,试剂盒/组合物可以包含本专利文献的化学式(1)的化合物的新型结晶形式和铂基抗肿瘤药物。铂基抗肿瘤药物可以选自顺铂、卡铂、双环铂、依铂、洛铂、米铂、奈达铂、奥沙利铂、吡铂和赛特铂。组合物的一个实例可以包含波齐替尼和顺铂。顺铂可以是注射的形式。
波齐替尼可以以0.1mg至50mg的量给药。顺铂可以以1mg/m2至100mg/m2身体表面积的量给药。
顺铂是一种用于治疗多种癌症的化学疗法药物。这包括睾丸癌、卵巢癌、宫颈癌、乳腺癌、膀胱癌、头颈癌、食道癌、肺癌、间皮瘤、脑部肿瘤和成神经细胞瘤。其通过注射到静脉中来使用。顺铂属于铂基抗肿瘤药物家族。其部分的通过结合并抑制DNA复制而起作用。
试剂盒中的药物制剂或药剂可以以每单位剂量包含预定量的活性成分的单位剂型存在。如本领域技术人员公知的,每剂量活性成分的量将取决于所治疗的疾病、给药路径以及患者的年龄、体重和病症。优选的单位剂量制剂是那些含有每日剂量或次剂量或其适当部分的活性成分的制剂。此外,这种药物制剂可以通过药学领域中公知的任何方法来制备
将本发明的新型晶体形式或组合物掺入方便的剂型,如胶囊、片剂或血管注射剂。使用固体或液体药物载体。固体载体包括淀粉、乳糖、二水合硫酸钙、白土、蔗糖、滑石粉、明胶、琼脂、果胶、阿拉伯树胶、硬脂酸镁和硬脂酸。液体载体包括糖浆、花生油、橄榄油、盐水和水。类似地,载体可以包括一种长时间释放材料,如单硬脂酸甘油酯或二硬脂酸甘油酯,单独或与蜡一起。固体载体的量变化很大,但适合地,可以为每剂量单位约25mg至约1g。当使用液体载体时,制剂将适合地呈糖浆、酏剂、乳剂、软胶囊、无菌可注射液体(如安瓿)、或水性或非水性液体悬浮液的形式。
例如,对以片剂或胶囊的形式的口服给药,活性药物组分可以与口服的、无毒的药学上可接受的惰性载体(如乙醇、甘油、水等)组合。通过将化合物粉碎成合适的细粒度并与类似的粉碎的药物载体(如可食用碳水化合物(如淀粉或甘露醇))混合来制备粉末。还可以含有调味剂、防腐剂、分散剂和着色剂。
应理解的是,除了上述成分之外,考虑到制剂的类型的问题,制剂可以包含本领域中其他常规的药剂,例如那些适合于口服给药的制剂可以包含调味剂。
在下文中,本专利文献将通过参考具体实施例描述。然而,以下实施方案仅用于说明本发明,并且本专利文献的范围不限于此。
分析仪器和测量方法
1.X-射线粉末衍射(XRPD)
将样品在D8 Advance(Bruker ASX,德国)分析仪上从3°2θ至40°2θ测试X-射线粉末衍射(XRPD)光谱。当样品的量<100mg时,将约5–10mg的样品轻轻地挤压到载玻片上,安装到样品支座上。当样品的量>100mg时,将约100mg的样品轻轻地挤压到塑料样品支座上,使得样品表面光滑并且刚好在该样品支座的水平上方。
进行如下测量:
阳极材料(Kα):Cu Kα(1.54056A)
扫描范围:3–40度
发生器设置:100mA,40.0kV
扫描速度:1秒/步
发散狭缝尺寸(发散狭缝):0.3度
防散射狭缝:0.3度
温度:20℃
步长:0.022θ度
旋转:使用
测角仪半径:435mm
2.差示扫描量热法(DSC)
在STA-1000(Scinco,韩国)分析仪上,在30℃–350℃下进行差示扫描量热(DSC)分析。将5mg至10mg的样品在铝DSC盘中进行称重,并且用穿孔的铝盖非不透气地密封,然后以10℃/min的扫描速率,通过将样品从30℃加热至350℃,产生热流反应(DSC)进行监测。
3.动态蒸气吸附(DVS)
在25℃和0%–90%的相对湿度下,在DVS advantage(表面测量系统,英国)分析仪上进行动态蒸汽吸附(DVS)分析。
将10mg样品置于钢丝网蒸汽吸附平衡盘中,并通过表面测量系统连接到DVS-advantage动态蒸汽吸附平衡上。将该样品应用于10%–90%的相对湿度(RH)(以10%增量)的渐变曲线上,同时在每个步骤中维持该样品直到达到稳定的重量(99.5%步骤完成)。在吸附循环完成之后,使用相同的步骤干燥样品,在此期间,相对湿度一直返回到低于0%的相对湿度。记录吸附/解吸循环(重复3次)期间的重量变化以确定样品的吸湿度。
4.固态核磁共振(ssNMR)
为了使用核磁共振光谱仪比较固态中结晶多晶型物,在将100mg样品置于4mm样品管中后,在室温下,使用Bruker Avance II 500MHz固体NMR系统(Bruker,德国)分析仪进行固态核磁共振(ssNMR)分析。13C NMR光谱(13C CP/MAS TOSS ssNMR)的分析条件如下。
频率:125.76MHz
谱宽:20kHz
魔角下样品旋转速度:5kHz
脉冲序列:有去耦合的CP(交叉极化)SPINAL64
(80kHz的去耦合功率)
重复延迟:5秒
接触时间:2ms
扫描次数:4096
外标:金刚烷
5.高效液相色谱(HPLC)
在AGilent 1100/1200系列HPLC系统(Agilent,美国)分析仪上进行高效液相色谱(HPLC),用于纯度和含量分析(包括稳定性测试等)。HPLC的分析条件如下。
纯度和含量分析条件:化学式(1)的噻吩并嘧啶化合物
柱:Hydrosphere C18(YMC),5μm(150mm×4.6mm)
柱温:30℃
检测器:紫外线吸收计
检测波长:254nm
流速:1.0mL/min
分析时间:35分钟
洗脱液:NaC1O4-NaH2PO4-磷酸盐缓冲溶液(pH 2.5±0.1)/CH3CN=40/60(v/v%)
6.离子色谱法(IC)
离子色谱(IC)分析是在Thermo Fisher Scientific ICS-2500系列IC系统(Thermo Fisher Scientific,美国)分析仪上进行的,用于分析盐酸盐中的盐酸含量分析。IC的分析条件如下。
含量分析的条件:化学式(1)的噻吩并嘧啶化合物
柱:IonPacAS19(Dionex),(250mm×4mm),防护装置(50mm×4mm)
柱温:30℃
检测器:电导率检测器(CD)
抑制器:ASRS 4mm,电流40mA
流速:1.0mL/min
分析时间:30分钟
洗脱液:10mM氢氧化钾溶液
7.水分测量
使用795KFT Titrino(Metrohm,瑞士)Karl-Fischer水分分析仪进行水分测量。
8.熔点测量
使用IA9200(Electrothermal,英国)熔点设备进行熔点测量。
参考例:化学式(1)的化合物的制备
将100g根据本说明书中引用的韩国专利登记号为1,013,319的专利和美国专利号为8,003,658的专利的方法或类似的方法制备的化学式(1)的化合物溶解于300mL二氯甲烷和300mL甲醇的混合溶液中,在40℃下搅拌30分钟,并使用滤纸过滤不溶性固体。在减压下蒸馏出93g(产率93%)的目标化合物。
水分含量:2.1%
特征分析
在图1G、图2G和图4G中分别示出了参考例中制备的化学式(1)的化合物的XRPD、ssNMR、DSC和DVS的分析结果。
在参考例中制备的化学式(1)的化合物在XRPD光谱中没有示出任何特定的衍射值,该XRPD光谱示出了非晶物质的典型谱图。
此外,参考例的化合物在ssNMR的光谱中示出了宽峰,该宽峰是非晶结构的典型峰图。
此外,如通过DSC(10℃/min)测得的,参考例的化合物没有表现出任何特定的吸热放热曲线。
此外,如通过DVS测得的,参考例的化合物在10%-90%的相对湿度范围内,表现出连续吸收1%-3%的水分的趋势。
此外,如通过Karl-Fischer水分分析仪测量的,非晶形式的水分含量为2.1%,并且没有观察到特征熔点。
实施例:化学式(I)的化合物及其盐酸盐的结晶多晶型物的制备
实施例1.化学式(1)的化合物的结晶二水合物(2H2O)形式的制备
向10.0g参考例的化学式(1)的化合物中添加80mL丙酮和20mL水,随后通过在回流下加热,将化学式(1)的化合物完全溶解,然后冷却至20℃-25℃,并搅拌4小时。将得到的固体过滤,并用20mL的丙酮∶水为4∶1的混合溶剂洗涤。将过滤的固体在50℃下干燥,得到10g(收率:93%)的目标化合物。
水分含量:7.5%(二水合物的理论值:6.83%)
特征分析
在图1A、图2A、图3A和图4A中分别示出了实施例1中制备的结晶形式的XRPD、ssNMR、DSC和DVS的分析结果。
在下表1中总结了结晶形式在XRPD光谱中的相对强度(I/Io)为15%或更多的峰。在I/Io≥30%或更多的峰的情况下,在衍射角(2θ±0.2°)为9.4°、11.4°、13.0°、16.1°、18.5°、19.3°、24.9°和26.3°处出现峰。
表1:
2θ(±0.2) | d | I/I<sub>o</sub>(%) | 2θ(±0.2) | d | I/I<sub>o</sub>(%) |
9.4 | 9.4 | 100 | 20.8 | 4.3 | 28.9 |
11.4 | 7.7 | 40.1 | 21.4 | 4.1 | 23.4 |
12.3 | 7.2 | 25.4 | 22.0 | 4.0 | 15.2 |
13.0 | 6.8 | 70.6 | 23.6 | 3.8 | 23.9 |
15.6 | 5.7 | 21.8 | 24.4 | 3.6 | 18.8 |
16.1 | 5.5 | 35.5 | 24.9 | 3.6 | 40.6 |
17.2 | 5.1 | 18.8 | 26.3 | 3.4 | 36.5 |
18.5 | 4.8 | 66.0 | 27.5 | 3.2 | 27.4 |
19.3 | 4.6 | 43.1 | 28.5 | 3.1 | 33.5 |
2θ:衍射角,d:晶面间的距离,
I/Io(%):相对强度(I:每个峰的强度;Io:最大峰的强度)。
在下表2中总结了结晶形式在13C CP/MAS TOSS ssNMR光谱中的化学位移(ppm±0.5ppm)的峰。
表2:
化学位移(ppm±0.5ppm)。
如通过DSC(10℃/min)测得的,当从约79℃的起始点运行时,上述结晶形式在约100.7℃处示出最低点的吸热峰,且当从约186.5℃的起始点运行时,上述结晶形式在约190.8℃处示出最低点的吸热峰。如通过DSC测得的,在约100.7℃处的吸热峰表示化学式(1)化合物的结晶形式I的结晶水合物形式的脱水点,在约190.8℃处的吸热峰表示熔点。
在Karl-Fischer水分分析仪中,结晶形式表现出约7.5%的水分含量(理论水分含量为6.83%),并示出约117-122℃的冷凝温度和约190-195℃的熔点。
如通过DVS测得的,在10%-90%的相对湿度范围内,结晶形式的吸湿度为约2%-5%。
实施例2.化学式(1)的化合物的无水结晶形式I的制备
向5.0g通过实施例1的方法得到的化学式(1)的化合物中添加50mL的丙酮,然后在20-25℃下搅拌6小时。将得到的固体过滤,并用7.5mL的丙酮洗涤。将过滤的固体在50℃下干燥,得到3.7g(产率:80%)的目标化合物。
水分含量:0.1%
特征分析
在图1B、图2B、图3B和图4B中分别示出了实施例2中制备的结晶形式的XRPD、ssNMR、DSC和DVS的分析结果。
下表3中总结了结晶形式在XRPD光谱中的相对强度(I/Io)为15%或更多的峰。在I/Io≥30%或更多的峰的情况下,在衍射角(2θ±0.2°)为6.0°、10.6°、10.9°、12.1°、16.0°、17.5°、18.3°、19.2°、20.3°、22.7°、23.7°和26.3°处出现峰。
表3:
2θ(±0.2) | d | I/I<sub>o</sub>(%) | 2θ(±0.2) | d | I/I<sub>o</sub>(%) |
6.0 | 14.6 | 75.6 | 20.3 | 4.4 | 58.1 |
10.6 | 8.3 | 47.1 | 20.8 | 4.3 | 18.6 |
10.9 | 8.1 | 48.8 | 22.1 | 4.0 | 26.7 |
12.1 | 7.3 | 62.2 | 22.7 | 3.9 | 100 |
13.0 | 6.8 | 25.0 | 23.7 | 3.8 | 55.2 |
16.0 | 5.5 | 57.6 | 24.2 | 3.7 | 15.1 |
17.5 | 5.1 | 32.0 | 26.3 | 3.4 | 62.2 |
18.3 | 4.9 | 85.5 | 28.1 | 3.2 | 18.0 |
18.7 | 4.7 | 23.3 | 32.1 | 2.8 | 17.4 |
19.2 | 4.6 | 36.0 |
2θ:衍射角,d:晶面间距离,
I/Io(%):相对强度(I:每个峰的强度;Io:最大峰的强度)。
在下表4中总结了结晶形式在13C CP/MAS TOSS ssNMR光谱中的化学位移(ppm±0.5ppm)的峰。
表4:
化学位移(ppm+0.5ppm)。
如通过DSC(10℃/min)测得的,当从约185.8℃的起始点运行时,上述结晶形式在约190.8℃处表现出最低点的吸热峰,且在约190.8℃处的吸热峰表示熔点。
如通过Karl-Fischer水分分析仪测得的,结晶形式表现出约0.1%的水分含量,并在约190-195℃处示出熔点。
如通过DVS测得的,在10%-50%的相对湿度范围内,结晶形式的吸湿度为约0.3%-0.5%的水平,这是非常低的,且在50-90%的范围内,测量吸湿度为约3%的水平。
实施例3.化学式(1)的化合物的无水结晶形式II的制备
向2.0g实施例2的化学式(1)的化合物中添加20mL的乙腈,然后在70-80℃下加热,并搅拌2小时,然后在20-25℃下搅拌12小时。将得到的固体过滤,并用5mL的乙腈洗涤。将过滤的固体在50℃下干燥,得到1.7g(收率:85%)的目标化合物。
水分含量:0.3%。
特征分析
在图1C、图2C、图3C和图4C中分别示出了实施例3中制备的结晶形式的XRPD、ssNMR、DSC和DVS的分析结果。
在下表5中总结了结晶形式在XRPD光谱中的相对强度(I/Io)为15%或更高的峰。在I/Io≥30%或更多的峰的情况下,在衍射角(2θ±0.2°)为4.9°、5.9°、11.8°、18.8°和19.9°处出现峰。
表5:
2θ(±0.2) | d | I/I<sub>o</sub>(%) | 2θ(±0.2) | d | I/I<sub>o</sub>(%) |
4.9 | 18.2 | 50.3 | 19.5 | 4.6 | 25.7 |
5.9 | 15.1 | 35.6 | 19.9 | 4.5 | 32.6 |
11.8 | 7.5 | 100 | 22.0 | 4.0 | 17.3 |
13.9 | 6.4 | 24.5 | 25.2 | 3.5 | 26.1 |
14.7 | 6.0 | 24.3 | 25.5 | 3.5 | 23.3 |
16.1 | 5.5 | 24.3 | 27.0 | 3.3 | 18.5 |
18.8 | 4.7 | 38.6 |
2θ:衍射角,d:晶面间距离,
I/Io(%):相对强度(I:每个峰的强度;Io:最大峰的强度)。
在下表6中总结了结晶形式在13C CP/MAS TOSS ssNMR光谱中的化学位移(ppm±0.5ppm)的峰。
表6:
化学位移(ppm±0.5ppm)。
如通过DSC(10℃/min)测得的,当从约181.3℃的起始点运行时,上述结晶形式在约184.8℃下表现出最低点的吸热峰,且在约184.8℃处的吸热峰表示熔点。
如通过Karl-Fischer水分分析仪测得的,结晶形式表现出约0.3%的水分含量,并示出约183-185℃的熔点。
如通过DVS测得的,在10%-90%的相对湿度范围内,结晶形式的吸湿度为约0.7%的水平,这是非常低的。该结晶形式在长期储存条件(例如25℃和60%的相对湿度)、加速条件(例如40℃和75%的相对湿度)和苛刻条件(例如60℃)下是足够稳定的。
实施例4.化学式(1)的化合物的结晶单盐酸盐一水合物(1HCl·1H2O)形式的制备向10g通过参考例或实施例1至3的方法制备的化合物中添加100mL乙醇∶水为(9∶1)的混合溶剂。添加4.9mL的35%浓盐酸,并在室温下搅拌6小时。将得到的固体过滤,并用30mL的乙醇洗涤。将过滤的固体在50℃下干燥,得到9.1g(收率:82%)的目标化合物。
水分含量:3.2%(一水合物的理论值:3.3%)
离子色谱法:6.5%(单盐酸盐的理论值:6.92%)
特征分析
在图1D、图2D、图3D和图4D中分别示出了实施例4中制备的结晶形式的XRPD、ssNMR、DSC和DVS的分析结果。
在下表7中总结了该结晶形式在XRPD光谱中的相对强度(I/Io)为15%或更高的峰。在I/Io≥30%或更高的峰的情况下,在衍射角(2θ±0.2°)为8.9°、13.4°、14.1°、16.0°、19.8°、21.1°、21.7°、23.5°、25.7°和32.7°处出现峰。
表7:
2θ(±0.2) | d | I/I<sub>o</sub>(%) | 2θ(±0.2) | d | I/I<sub>o</sub>(%) |
8.9 | 10.0 | 61.5 | 21.7 | 4.1 | 42.0 |
10.5 | 8.4 | 18.3 | 22.0 | 4.0 | 18.3 |
12.3 | 7.4 | 28.4 | 22.4 | 4.0 | 15.4 |
12.6 | 7.0 | 17.8 | 23.5 | 3.8 | 100 |
13.4 | 6.6 | 94.7 | 24.2 | 3.7 | 21.3 |
14.1 | 6.3 | 35.5 | 25.7 | 3.5 | 52.1 |
16.0 | 5.5 | 36.1 | 27.5 | 3.2 | 20.7 |
16.4 | 5.4 | 17.8 | 28.0 | 3.2 | 17.2 |
17.3 | 5.1 | 21.3 | 28.7 | 3.1 | 20.1 |
18.1 | 4.9 | 27.2 | 29.9 | 3.0 | 25.4 |
19.3 | 4.6 | 18.3 | 30.6 | 2.9 | 21.9 |
19.8 | 4.5 | 32.0 | 32.3 | 2.7 | 20.1 |
21.1 | 4.2 | 92.3 | 32.7 | 2.7 | 30.2 |
2θ:衍射角,d:晶面间距离,
I/Io(%):相对强度(I:每个峰的强度;Io:最大峰的强度)。
在下表8中总结了该结晶形式在13C CP/MAS TOSS固态核磁共振(ssNMR)光谱中的化学位移(ppm±0.5ppm)的峰。
表8:
化学位移(ppm±0.5ppm)。
如通过DSC(10℃/min)测得的,当从约126.7℃的起始点运行时,上述结晶形式在约151.0℃处表现出最低点的吸热峰,以及在约177.7℃处的吸热峰。如通过DSC测得的,在约151.0℃处的吸热峰表示结晶单盐酸盐一水合物形式的脱水点,在约177.7℃处的吸热峰表示熔点。
如通过Karl-Fischer水分分析仪测得的,该结晶形式表现出约3.2%的水分含量,并示出了约187-193℃的熔点。
如通过DVS测得的,在10%-90%的相对湿度范围内,该结晶形式的吸湿度为约0.4%的水平,这是非常低的。可以预期,该结晶形式在长期储存条件(例如25℃的温度和60%的相对湿度)和加速条件(例如40℃的温度和75%的相对湿度)下会吸收水分,以保持一水合物的结晶形式。
实施例5.化学式(1)的化合物的无水结晶单盐酸盐(1HCl)形式的制备
向20g通过与实施例2类似的方法制备的无水化合物1中添加60mL的DMSO。添加5.1mL的35%浓盐酸,并将混合物在室温下搅拌6小时。将得到固体过滤出来,并用40mL的DMSO洗涤。然后将过滤的固体在50℃下干燥,得到18.3g(产率:85%)的目标化合物。
水分含量:0.1%
离子色谱法:6.6%(单盐酸盐的理论值:6.92%)
另外,向20g通过与实施例2类似的方法制备的无水化合物1中,添加60mL的DMF。添加5.1mL的35%浓盐酸,并在室温下搅拌6小时。将得到固体过滤出来,并用40mL的DMF洗涤。将过滤的固体在50℃下干燥,得到16.6g(收率:77%)的目标化合物。
特征分析
在图1E、图2E、图3E和图4E中分别示出了实施例5中制备的结晶形式的XRPD、ssNMR、DSC和DVS的分析结果。
在下表9中总结了该结晶形式在XRPD光谱中的相对强度(I/Io)为15%或更高的峰。在I/Io≥30%或更高的峰的情况下,在衍射角(2θ±0.2°)为9.5°、12.3°、13.0°、13.5°、14.2°、21.4°、23.0°、23.2°、23.5°、27.2°和27.5°处出现峰。
表9:
2θ(±0.2) | d | I/I<sub>o</sub>(%) | 2θ(±0.2) | d | I/I<sub>o</sub>(%) |
9.5 | 9.3 | 100 | 23.0 | 3.9 | 59.3 |
10.7 | 8.3 | 17.5 | 23.2 | 3.8 | 57.5 |
12.3 | 7.2 | 34.4 | 23.5 | 3.8 | 52.1 |
13.0 | 6.8 | 39.2 | 24.7 | 3.6 | 17.8 |
13.5 | 6.5 | 32.7 | 25.2 | 3.5 | 20.9 |
14.2 | 6.2 | 33.6 | 27.2 | 3.3 | 36.9 |
16.1 | 5.5 | 20.2 | 27.5 | 3.2 | 40.7 |
17.5 | 5.1 | 20.0 | 28.9 | 3.1 | 15.4 |
18.9 | 4.7 | 26.0 | 29.1 | 3.1 | 16.4 |
20.0 | 4.4 | 15.2 | 30.1 | 3.0 | 20.3 |
20.3 | 4.4 | 16.4 | 30.4 | 2.9 | 17.8 |
21.4 | 4.1 | 42.2 | 34.8 | 2.6 | 16.5 |
22.2 | 4.0 | 15.3 |
2θ:衍射角,d:晶面间距离,
I/Io(%):相对强度(I:每个峰的强度;Io:最大峰的强度)。
在下表10中总结了该结晶形式在13C CP/MAS TOSS固态核磁共振(ssNMR)光谱中的化学位移(ppm±0.5ppm)的峰。
表10:
化学位移(ppm±0.5ppm)。
如通过DSC(10℃/min)测得的,当从约200.7℃的起始点运行时,上述结晶形式在约230.1℃处表现出最低点的吸热峰。在约230.1℃处的吸热峰表示熔点。
如通过Karl-Fischer水分分析仪测得的,该结晶形式表现出约0.1%的水分含量,并示出了约238-243℃的熔点。
如通过DVS测得的,在10%-90%的相对湿度范围内,该结晶形式的吸湿度为约0.35%的水平,这是非常低的。该结晶形式在长期储存条件(例如25℃的温度和60%的相对湿度)和加速条件(例如40℃的温度和75%的相对湿度)下不会吸收水分,以保持无水结晶形式。
实施例6.化学式(1)的化合物的单盐酸盐(1HCl)非晶形式的制备
将5g实施例5中得到的化学式1化合物的无水结晶形式溶解于150mL甲醇中。将溶液通过过滤器过滤,去除异物,并将滤液在减压下浓缩,得到固体形式的4.9g(收率:98%)的目标化合物。
水分含量:1.2%
特征分析
在图1F、图2F和图4F中分别示出了实施例6中制备的非晶形式的XRPD、DVS和ssNMR的分析结果。
非晶式在XRPD光谱中没有示出任何衍射值。
另外,如通过DVS测得的,在10–90%的相对湿度范围内,非晶形式表现出非常高的吸湿度。通过这种方式,可以预期,在长期存储条件(25℃温度和60%的相对湿度)和加速条件(40℃温度和75%的相对湿度)下吸收水分会导致不稳定。实际上,在25℃,60%的相对湿度条件下和40℃,75%相对湿度条件下,确认吸湿率为7–9%。
另外,如Karl-Fischer水分分析仪测得的,该非晶形式的水分含量为1.2%,且未观察到特征熔点。
试验例1:盐酸盐的非晶形式和结晶多晶型物的溶解度的比较试验
为了比较盐酸盐非晶形式和盐酸盐结晶多晶型物的溶解度,在以下条件下,根据非离子水和酸度(pH),使用实施例4至6中制备的化学式(1)的化合物的盐酸盐的多晶型物和非晶形式来制备样品。此后,根据化学式(1)的化合物的含量的测定条件,通过高效液相色谱法(HPLC)对各溶液进行分析,以化学式(1)的化合物为基准,测定溶解量(LOD:0.1μg/mL)。在下表11中示出了根据测量值计算的结果。
特别地,将5mg的每种多晶型物添加到5mL的水中,并使用Voltamixer在20–25℃下混合。此后,将通过使用GH Polypro薄膜Acrodisc,PALL(孔径0.2μm)过滤而得到的滤液与用于高效液相色谱法(HPLC)的稀释溶剂以1/100的比例进行稀释,得到样品。
表11:
如上述表11所示,化学式(1)的化合物的盐酸盐的溶解度明显高于化学式(1)的化合物的溶解度(小于1.0μg/mL),且结晶多晶型物中的盐酸盐形式的无水结晶形式在水中的溶解度最高。
因此,就药物组合物而言,当考虑洗脱等时,预期化学式(1)的化合物的无水结晶盐酸盐形式是最有利的。
试验例2:盐酸盐的非晶形式和结晶多晶型物的稳定性比较试验
为了比较盐酸盐非晶形式和盐酸盐结晶多晶型物的稳定性,将实施例4至6中制备的化学式(1)的化合物的盐酸盐的多晶型物和非晶形式的每个样品,在长期条件(例如25±2℃的温度和60±5%的相对湿度)和加速条件(例如40℃的温度和75%的相对湿度)下,放置4周。根据化学式(1)的化合物的纯度测量条件,通过高效液相色谱法(HPLC)分析每个样品。在下表12中示出了纯度测量值(%)。
表12:
如表12所示,与化学式(1)的化合物的非晶盐酸盐形式相比,化学式(1)的化合物的结晶盐酸盐形式是稳定的,特别是化学式(1)的化合物的盐酸盐的无水结晶形式示出了最好的结果。
因此,通过比较试验1和2,就药物组合物而言,当考虑到各种物理化学性质(如溶解度、纯度、稳定性、吸湿度、熔点等)时,预期化学式(1)的化合物的无水结晶盐酸盐形式是最具优势的。
Claims (24)
1.化学式(1)的化合物的结晶形式:
[化学式(1)]
其中所述结晶形式的化学纯度大于约80%,以及
其中所述结晶形式选自
(a)化学式(1)的化合物的二水合物结晶形式,当用Cu-Kα光源照射时,所述结晶形式具有包含在衍射角2θ值为9.4°±0.2°、13.0°±0.2°和18.5°±0.2°处的峰的X-射线粉末衍射图;
(b)化学式(1)的化合物的无水形式I,当用Cu-Kα光源照射时,其具有包含在衍射角2θ值为6.0°±0.2°、18.3°±0.2°和22.7°±0.2°处的峰的XRPD图;
(c)化学式(1)的化合物的无水形式II,当用Cu-Kα光源照射时,其具有包含在衍射角2θ值为4.9°±0.2°、5.9°±0.2°和11.8°±0.2°处的峰的XRPD图;
(d)化学式(1)的化合物的单盐酸盐一水合物(1HCl·1H2O)结晶形式,当用Cu-Kα光源照射时,其有包含在衍射角2θ值为8.9°±0.2°、13.4°±0.2°、21.1°±0.2°和23.5°±0.2°处的峰的XRPD图;和
(e)化学式(1)的化合物的无水单盐酸盐的结晶形式,当用Cu-Kα光源照射时,其具有包含在衍射角2θ值为9.5°±0.2°、23.0°±0.2°、23.2°±0.2°和23.5°±0.2°处的峰的XRPD图。
2.根据权利要求1所述的化学式(1)的化合物的结晶形式,其中所述结晶形式的化学纯度大于95%。
3.根据权利要求1所述的结晶形式,其中所述结晶形式如(a)中所述。
4.根据权利要求1所述的结晶形式,其中所述结晶形式如(b)中所述。
5.根据权利要求1所述的结晶形式,其中所述结晶形式如(c)中所述。
6.根据权利要求1所述的结晶形式,其中所述结晶形式如(d)中所述。
7.根据权利要求1所述的结晶形式,其中所述结晶形式如(e)中所述。
8.根据权利要求1所述的结晶形式,其中所述结晶形式如(a)中所述,其中所述结晶形式具有包含以下化学位移的峰的13C固态核磁共振光谱(ssNMR):147.7±0.5、156.2±0.5和165.4±0.5ppm。
9.根据权利要求1所述的结晶形式,其中所述结晶形式如(b)中所述,其中所述结晶形式具有包含以下化学位移的峰的13C ssNMR光谱:54.3±0.5、127.3±0.5、146.9±0.5和156.7±0.5ppm。
10.根据权利要求1所述的结晶形式,其中所述结晶形式如(c)中所述,其中所述结晶形式具有包含以下化学位移的峰的13C ssNMR光谱:129.2±0.5、153.1±0.5、156.7±0.5和165.2±0.5ppm。
11.根据权利要求1所述的结晶形式,其中所述结晶形式如(d)中所述,其中所述结晶形式具有包含以下化学位移的峰的13C ssNMR光谱:145.8±0.5、157.8±0.5和164.5±0.5ppm。
12.根据权利要求1所述的结晶形式,其中所述结晶形式如(e)中所述,其中所述结晶形式具有包含以下化学位移的峰的13C ssNMR光谱:146.9±0.5、158.7±0.5和163.0±0.5ppm。
13.一种药物组合物,包含权利要求1至12中任一项所述的结晶形式,和至少一种药学上可接受的载体或稀释剂。
14.根据权利要求13所述的药物组合物,其中所述药物组合物用于治疗由酪氨酸激酶或其突变体诱导的癌症。
15.根据权利要求14所述的药物组合物,其中所述癌症为实体癌症。
16.根据权利要求13所述的药物组合物,其中所述结晶形式的化学纯度大于约95%。
17.根据权利要求13所述的药物组合物,还包含非金属盐润滑剂,所述非金属盐润滑剂选自山嵛酸甘油酯、硬脂酸棕榈酸甘油酯、单硬脂酸甘油酯、三肉豆蔻酸甘油酯、甘油三硬脂酸酯、蔗糖脂肪酸酯、棕榈酸、棕榈酰醇、硬脂酸、硬脂醇、富马酸、聚乙二醇4000、聚乙二醇6000、聚四氟乙烯、淀粉、滑石粉、氢化蓖麻油、矿物油、氢化植物油、二氧化硅及其任意组合物。
18.根据权利要求13所述的药物组合物,还包含金属盐润滑剂。
19.一种制备权利要求3所述的二水合物(2H2O)结晶形式的方法,包括:
(a)将化学式1的化合物添加至丙酮和水的混合物中,其中所述丙酮和水为这样的比例,即使得不能使所述化合物在室温下完全地溶解在所述混合物中;
(b)将所述混合物加热至所述化合物完全溶解的温度;和
(c)将所述混合物冷却,并去除所述丙酮和水,以得到所述化合物的二水合物(2H2O)。
20.一种制备权利要求4所述的无水形式I的方法,包括
(a)将权利要求3所述的化合物的二水合物(2H2O)与丙酮混合;和
(b)分离所述化合物的无水形式I。
21.一种制备权利要求5所述的无水形式II的方法,包括
(a)将权利要求4所述的化合物的无水形式I与乙腈混合;
(b)加热至约80℃以上;和
(c)冷却并分离所述化合物的无水形式II。
22.一种制备权利要求6所述的单盐酸盐一水合物(1HCl·1H2O)的方法,包括
(a)将化学式1的化合物与乙醇、水和盐酸水溶液混合;和
(b)分离所述化合物的单盐酸盐一水合物(1HCl·1H2O)。
23.一种制备权利要求7所述的无水单盐酸盐结晶形式的方法,包括
(a)将化学式1的无水化合物与非质子极性溶剂和浓度为约30%或更多的盐酸混合;和
(b)分离所述化合物的无水单盐酸盐。
24.根据权利要求23所述的方法,其中所述非质子极性溶剂为DMSO或DMF。
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