CN103038239A - 激酶抑制剂的晶体形式 - Google Patents
激酶抑制剂的晶体形式 Download PDFInfo
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- CN103038239A CN103038239A CN2011800393912A CN201180039391A CN103038239A CN 103038239 A CN103038239 A CN 103038239A CN 2011800393912 A CN2011800393912 A CN 2011800393912A CN 201180039391 A CN201180039391 A CN 201180039391A CN 103038239 A CN103038239 A CN 103038239A
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- pyridin
- thieno
- fluorophenyl
- phenyl
- hydroxyethyl
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Abstract
N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸盐及其晶体形式是在疾病例如癌症的治疗中有用的药物组合物的合适的药物成分。
Description
相关申请的交叉引用
本申请要求于2010年6月9日提交的序列号为61/353038的美国临时申请的优先权,其被以引用的方式整体并入。
发明领域
本发明涉及N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸盐的晶体形式,用于制备其晶体形式、药物制剂的方法,和治疗癌症的方法。
发明背景
有丝分裂是微管纺锤体使重复染色体组分离成两个子细胞的完全复制的过程。已经发现极光激酶—基因组稳定性所需的关键有丝分裂调节剂—在人类肿瘤中过度表达。因此,在治疗领域中存在对抑制极光激酶的化合物、包含抑制剂的组合物和治疗在其过程中极光激酶失调或过度表达的疾病的方法的需要。
蛋白质的可逆磷酸化是介导真核细胞信号传导的主要生物化学机制之一。这个反应通过将ATP的g-磷酸基转移给靶蛋白质上的羟基的蛋白激酶催化。518种此类酶存在于人基因组中,其中~90种选择性催化酪氨酸羟基的磷酸化。胞质酪氨酸激酶位于细胞内,而受体酪氨酸激酶(RTKs)具有细胞外和细胞内结构域且充当跨膜细胞表面受体。像这样,RTKs介导针对环境信号的细胞应答,且促进广泛范围的细胞过程,包括增殖、迁移和存活。
RTK信号传导途径通常是高度调节的,然而,它们的超活化已显示促进癌细胞的生长、存活和转移。失调的RTK信号传导通过基因超表达或突变发生,并且已与多种人癌症的进展关联。
VEGF受体(VEGFR)家族由3种RTKs组成:KDR(含激酶插入结构域的受体;VEGFR2)、FLT1(Fms样酪氨酸激酶;VEGFR1)和FLT4(VEGFR3)。这些受体介导血管内皮生长因子(VEGF-A、-B、-C、-D、-E和胎盘生长因子(PlGF))的生物学功能,该因子为以不同亲和力结合VEGF受体的同二聚糖蛋白家族。
KDR是VEGF-A,下文称为VEGF的促有丝分裂、血管生成和通透性增强效应的主要介质。许多不同细胞类型能够产生VEGF,然而,它的生物学活性通过KDR的内皮细胞选择性表达占优势地限制于脉管系统。并不令人惊讶地,VEGF/KDR轴是血管生成的主要介质,所述血管生成是新血管通过其由预先存在的脉管形成的方式。
FLT1结合VEGF、VEGF-B和胎盘生长因子。FLT1在平滑肌细胞、单核细胞和造血干细胞加上内皮细胞的表面上表达。FLT1信号传导的活化导致骨髓源性的内皮祖细胞的动员,其召募至它们在其中促成新血管形成的肿瘤。
FLT4介导VEGF-C和VEGF-D的信号传导,这介导肿瘤相关的淋巴管形成(淋巴管生成)。淋巴管是在转移过程中癌细胞通过其从实体瘤散布的途径之一。
CSF-1R由逆转录病毒癌基因v-fms的细胞同系物编码,并且是巨噬细胞发育的主要调节物。巨噬细胞是肿瘤间质的常见组分,并且已显示其以对于肿瘤生长和转移有利的方式修饰细胞外基质。
KIT由造血祖细胞、肥大细胞、生殖细胞和由肠中的起搏细胞(Cajal的间质细胞)表达。它通过2种一般机制促成肿瘤进展,即通过其配体干细胞因子(SCF)的自分泌刺激和通过导致配体依赖性激酶活性的突变。
[0012] FLT3通常在造血干细胞上表达,在其中它与FLT3配体(FL)的相互作用刺激干细胞存活、增殖和分化。除在多种白血病细胞中超表达外,FLT3在血液恶性肿瘤中频繁突变,其中约三分之一具有急性髓样白血病(AML)的患者具有活化突变。
通过调整酪氨酸激酶的活性以调节和调整异常或不适当的细胞增殖、分化或代谢的特异性抑制信号转导和细胞增殖的有效小化合物的鉴定因此是希望的。特别地,特异性抑制酪氨酸激酶的功能的方法和化合物的鉴定将是有利的,所述酪氨酸激酶对于血管生成过程或血管高渗透性形成(导致水肿、腹水、渗出、渗出物和大分子外渗和基质沉积以及相关病症)是必需的。
已经鉴定了抑制蛋白激酶如极光激酶和激酶的VEGFR和PDGFR家族的化合物,包括N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲。这些化合物和制备它们的方法公开于美国专利申请号12/632183(下文的“’183申请”)中,该申请被以引用的方式整体并入本文中。
目前已经发现N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸盐能够转化为晶体形式,其能够有利地用作癌症治疗中的活性药物成分。为了这个目的,将这些晶体形式转化为药物制剂。
晶体形式是其中分子相对于彼此的位置根据三维晶格结构来排列的形式。多晶形物是由固态分子的不同排布产生的同一化合物的不同晶体形式。多晶形物在其物理性质而非其化学组成上彼此不同。
多晶形物在开发合适的药物剂型中尤其受关注。某些多晶形物形式可以展示出优越的稳定性和可保存性,导致药物产品提高的贮存期限。另外,某些多晶形物形式更易于以高纯度的大量的方式制造。
重要的是,活性药物成分的多晶形物能够具有不同的水溶解度和溶解速率,其由于在同一化合物的多晶形物之间的生物利用度的潜在差异而可以具有治治疗有效果。
本发明提供了N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸盐的晶体形式,其在一个或多个以下特性中具有有益性质:配制成药物剂型的能力、药物剂型的足够的贮存期限、和/或有效地以药物剂型给药的能力。
发明概述
在一种实施方案中,本发明提供了固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐。
在一种实施方案中,本发明提供了固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐。
在其它实施方案中,本发明提供了在本文中表征的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐的晶态多晶形物,并将其称为柠檬酸二氢盐形式I。
在其它实施方案中,本发明提供了柠檬酸二氢盐形式I的水合形式,包括一水合物形式。
在其它实施方案中,本发明提供了在本文中表征的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐的晶态多晶形物,并将其称为柠檬酸氢盐形式II。
在其它实施方案中,本发明提供了柠檬酸氢盐形式II的水合形式,包括一水合物形式。
还提供了包含N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐形式I和一种或多种药学上可接受的赋形剂的药物组合物。
还提供了包含N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐形式II和一种或多种药学上可接受的赋形剂的药物组合物。
还提供了用于制备N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐形式I的方法,所述方法包括提供包含N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲、水、丙酮和柠檬酸的混合物,并使N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐形式I存在于该混合物中。
还提供了用于制备N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐形式II的方法,所述方法包括提供包含N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲、水、四氢呋喃和柠檬酸的混合物,并使N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐形式II存在于该混合物中。
在其它实施方案中,本发明提供了用于治疗哺乳动物中癌症的方法,所述方法包括对患有所述疾病的受试者给药治疗有效量的固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸盐,其中所述晶体形式为形式I或II或(b)包含固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸盐和一种或多种药学上可接受的赋形剂的药物组合物,其中所述晶体形式为形式I或II。这样的癌症的实例包括骨髓增生异常综合征、急性髓样白血病、结肠直肠癌、非小细胞肺癌和卵巢癌。
还提供了用于治疗哺乳动物中癌症的方法,所述方法包括将固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐溶于药学上可接受的溶剂或溶剂混合物中,并对患有所述疾病的受试者给药治疗有效量的所得溶液,其中所述晶体形式为形式I。
还提供了用于治疗哺乳动物中癌症的方法,所述方法包括将固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐溶于药学上可接受的溶剂或溶剂混合物中,并对患有所述疾病的受试者给药治疗有效量的所得溶液,其中所述晶体形式为形式I。
还提供了用于治疗哺乳动物中癌症的方法,所述方法包括将固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐分散于药学上可接受的聚合物载体中,并对患有所述疾病的受试者给药治疗有效量的所得固体分散体,其中所述晶体形式为形式II。
还提供了用于治疗哺乳动物中癌症的方法,所述方法包括将固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐溶于药学上可接受的溶剂或溶剂混合物中,并对患有所述疾病的受试者给药治疗有效量的所得溶液,其中所述晶体形式为形式II。
包括上文提供的那些更具体的方面的本发明另外的实施方案将在下文的详细描述中找到或将从其变得清楚。
附图的简要说明
图1是晶态多晶形物形式I N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐的PXRD扫描。
图2是晶态多晶形物形式II N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐的PXRD扫描。
具体描述
本发明包括N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸盐的晶体形式。按照上文引用的美国专利申请号12/632183的实施例1中的描述示例性地制备N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的游离碱,该申请的整个公开内容被以引用的方式并入本文中。在本文中出于方便起见所使用的术语“游离碱”是指与N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的任何盐相区别的其母体化合物。
本领域那些技术人员也将理解,当提及N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲时,术语“一水合物”是指每个N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲分子具有一个水分子。
在一种实施方案中,本发明包括固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐。
在一种实施方案中,本发明包括N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐的晶体形式,其特征至少在于在任何一个或多个以下位置的粉末X射线衍射峰:11.80、14.59、15.95、21.38、26.12°2θ, ± 0.2°2θ,在本文中被定义为形式I。
本发明的另一方面包括N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐形式I的晶体形式,其特征至少在于在每个以下位置的粉末X射线衍射峰:11.80、14.59、15.95、21.38、26.12°2θ, ± 0.2°2θ。
本发明的另一方面包括N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐形式I的晶体形式,其特征至少在于在每个以下位置的粉末X射线衍射峰:7.56、7.96、11.80、12.42、13.44、14.59、15.66、15.95、16.69、21.38、22.40、22.82、23.98、24.50、24.99、26.12°2θ, ± 0.2°2θ。
在另一种实施方案中,本发明包括一水合物形式的形式I。
在另一种实施方案中,本发明提供了用于制备固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐的方法,其中所述晶体形式为形式I。所述方法包括a) 提供包含(i) N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲、水、丙酮和柠檬酸的混合物;b)使N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐晶体形式I存在于该混合物中。该方法还可以包括分离固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐,其中所述晶体形式为形式I。
本发明还包括包含N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐形式I和一种或多种药学上可接受的赋形剂的药物组合物。
在一种实施方案中,本发明包括固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐。
在另一种实施方案中,本发明包括固态晶体形式的化合物N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐,其中所述晶体形式为形式II,其特征至少在于在任何一个或多个以下位置的粉末X射线衍射峰:8.65、15.18、24.47、28.02°2θ, ± 0.2°2θ。
本发明的另一方面包括N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐形式II的晶体形式,其特征至少在于在每个以下位置的粉末X射线衍射峰:8.65、15.18、24.47、28.02°2θ, ± 0.2°2θ。
本发明的另一方面包括N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐形式II的晶体形式,其特征至少在于在每个以下位置的粉末X射线衍射峰:5.71、6.30、7.27、8.65、9.80、13.06、14.31、15.18、15.92、16.68、17.71、20.17、21.98、23.30、24.47、26.11、28.02°2θ, ± 0.2°2θ。
在另一种实施方案中,本发明提供了用于制备固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐的方法,其中所述晶体形式为形式II。所述方法包括a) 提供包含(i) N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲、水、四氢呋喃和柠檬酸的混合物;和b)使N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐晶体形式I存在于该混合物中。该方法还可以包括分离固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐,其中所述晶体形式为形式II。
本发明还包括包含N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐形式II和一种或多种药学上可接受的赋形剂的药物组合物。
N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸盐的晶体形式,例如形式I或II,可以用作用于制备适合于对需要其的受试者以任何途径给药(包括口服)的药物组合物的API。其它给药途径包括但不限于胃肠外、舌下、含服、鼻内、肺部、局部、透皮、皮内、眼、耳、直肠、阴道、胃内、颅内、滑膜内和关节内的途径。
当期望以溶液形式(例如用于口服或胃肠外给药的液体制剂)提供N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸盐例如形式I或II时,N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸盐当然将不以晶体形式存在于这样的制剂中;确实,通常不期望晶体存在于这样的制剂中。然而,尽管如此,本发明的晶体N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐或柠檬酸氢盐在用于制备这样的制剂的方法中可以是重要的(作为API)。
甚至当期望的制剂为含有无定形形式(例如固体分散体制剂)的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐或柠檬酸氢盐的一种制剂时,晶体N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐或柠檬酸氢盐在用于制备这样的制剂的方法中仍然可以是有用的(作为API)。
作为API,N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐或柠檬酸氢盐的晶体形式如形式I或II相对于无定形形式具有优越性。例如,API至大部分监管机构所要求的高纯度的纯化是更有效率的,并因此当API为晶体而非无定形形式时花费更少。对于晶体,API固体的物理和化学稳定性以及因此的贮存期限也通常好于无定形形式。相对于倾向于呈油性或粘性的无定形形式,处理的容易度得到了改善。在晶体材料的情况下(具有很好地确定的干燥或去溶剂化温度),与无定形材料的情况(对于有机溶剂具有更大的亲和力并且没有很好地确定的干燥温度)相比,干燥更直接并且更容易控制。使用晶体API的下游加工实现改进的方法控制。这些优点是示例性的而非限定性的。
当根据适当的方案将所述组合物给药于需要其的受试者时,N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲以能够是治疗有效的量存在于本发明的药物组合物中。通常,取决于所讨论的化合物,单位剂量(单次的给药量)为约10-约1000 mg,其可以以适当的频率例如每日两次至每周一次给药。当给药频率为每日一次(q.d.)时,单位剂量和每日剂量相同。示例性地,单位剂量通常为约25-约1,000 mg,更通常为约50-约500 mg,例如为约50、约100、约150、约200、约250、约300、约350、约400、约450或约500 mg。
赋形剂包括但不限于,例如,包封材料和添加剂,如吸收促进剂、抗氧化剂、粘合剂、缓冲剂、载体、包衣剂、着色剂、稀释剂、崩解剂、乳化剂、增充剂、填充剂、调味剂、助流剂、保湿剂、润滑剂、芳香剂、防腐剂、推进剂、释放剂、灭菌剂、甜味剂、增溶剂、润湿剂、其混合物等。
用于制备包含待以固体剂型口服给药的晶体N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐形式I或柠檬酸氢盐形式II的制剂或采用其制备的制剂的赋形剂包括例如琼脂、海藻酸、氢氧化铝、苄醇、苯甲酸苄酯、1,3-丁二醇、卡波姆、蓖麻油、纤维素、乙酸纤维素、可可脂、共聚维酮、玉米淀粉、玉米油、棉籽油、交联聚维酮、甘油二脂、乙醇、乙基纤维素、月桂酸乙酯、油酸乙酯、脂肪酸酯、明胶、胚油、葡萄糖、甘油、花生油、羟基丙基甲基纤维素、异丙醇、等渗盐水、乳糖、氢氧化镁、硬脂酸镁、麦芽、甘露醇、甘油单酯、橄榄油、聚维酮、花生油、磷酸钾盐、马铃薯淀粉、聚维酮、丙二醇、林格氏溶液、红花油、芝麻油、二氧化硅、羧甲基纤维素钠、磷酸钠盐、月桂基硫酸钠、山梨醇钠、硬脂酰富马酸钠、大豆油、硬脂酸、硬脂酰富马酸盐或酯(stearyl fumarate)、蔗糖、表面活性剂、滑石、西黄蓍胶、四氢糠醇、甘油三酯、维生素E及其衍生物、水、其混合物等。
用于制备包含待以液体剂型经眼或口服给药的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐形式I或柠檬酸氢盐形式II的组合物或采用其制备的组合物的赋形剂包括,例如,1,3-丁二醇、蓖麻油、玉米油、棉籽油、乙醇、去水山梨糖醇的脂肪酸酯、胚油、花生油、甘油、异丙醇、橄榄油、聚乙二醇、丙二醇、芝麻油、水、其混合物等。
用于制备包含待以渗透形式给药的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐形式I或柠檬酸氢盐形式II的组合物或采用其制备的组合物的赋形剂包括,例如,氯氟烃、乙醇、水、其混合物等。
用于制备包含待以胃肠外给药的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐形式I或柠檬酸氢盐形式II的组合物或采用其制备的组合物的赋形剂包括,例如,1,3-丁二醇、蓖麻油、玉米油、棉籽油、右旋糖、胚油、花生油、脂质体、油酸、橄榄油、花生油、林格氏溶液、红花油、芝麻油、大豆油、U.S.P. 或等渗氯化钠溶液、水、其混合物等。
用于制备包含待以直肠或阴道给药的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐形式I或柠檬酸氢盐形式II的组合物或采用其制备的组合物的赋形剂包括但不限于可可脂、聚乙二醇、蜡、其混合物等。
所述组合物通常以提供药物的治疗有效的每日剂量的量给药。本文中的术语“每日剂量”是指每天给药的药量,无论给药的频率如何。例如,如果受试者每日接受两次150 mg的单位剂量,那么每日剂量为300 mg。术语“每日剂量”的使用将理解为并非暗示每日必须给药一次特定剂量。然而,在特定的实施方案中,给药频率是每日一次(q.d.),并且每日剂量和单位剂量在这种实施方案中是同样的情况。
构成治疗有效剂量的情况取决于特定化合物、受试者(包括受试者的种和体重)、待治疗的疾病(例如,癌症的特定类型)、该疾病的阶段和/或严重性、个体受试者对该化合物的耐受性、该化合物是在单一疗法中给药还是与一种或多种其它药物(例如用于治疗癌症的其它化学治疗)联合给药,以及其它因素。因此,每日剂量可以在宽范围内变化,例如从约10至约1000 mg。更大或更小的每日剂量在特定情况下可以是合适的。将理解本文中的“治疗有效”剂量在本文中的表述并非必须要求药物是有治疗有效的(如果仅给药单次这样的剂量);通常治疗效果取决于根据方案(包括给药的合适的频率和持续时间)重复给药的组合物。非常优选地是,尽管所选择的每日剂量足以在治疗癌症方面提供益处,但不应该足以引发不利的副作用至不可接受的或不可忍受的程度。合适的治疗有效剂量可以基于本文的公开内容和本文引用的技术、通过普通技能的医师考虑如上所提及的那些因素来选择而无需经过过度实验。医师可以例如采用相对低的每日剂量开始癌症患者的治疗过程,并在数天或数周的时间内逐步提高剂量,以降低不利的副作用的风险。
示例性地,N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的合适剂量通常为约10-约1,000 mg/天,更通常为约50-约500 mg/天或约200-约400 mg/天,例如约50、约100、约150、约200、约250、约300、约350、约400、约450或约500 mg/天,以3-10天、或约4-8天、或约7天的平均剂量间隔给药。
包含本发明的晶体N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲柠檬酸二氢盐形式I或柠檬酸氢盐形式II(或制备用作API)的组合物适合用于单一疗法或组合疗法(例如与其它化学疗法一起或与电离辐射一起)。
包含晶体N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲柠檬酸二氢盐形式I或柠檬酸氢盐形式II(或制备用作API)的组合物可以在组合疗法中与一种或多种包括但不限于以下物质的治疗剂一起给药:烷化剂、血管发生抑制剂、抗体、抗代谢药、抗有丝分裂物质、抗增殖剂、抗病毒剂、极光激酶抑制剂、其它凋亡启动子(例如Bcl-xL、Bcl-w和Bfl-1抑制剂)、死亡受体途径的激活物、Bcr-Abl激酶抑制剂、BiTE(双特异性T细胞衔接子)抗体、抗体-药物缀合物、生物学应答调节剂、细胞周期蛋白依赖性激酶(CDK)抑制剂、细胞周期抑制剂、环氧化酶-2(COX-2)抑制剂、双重可变结构域结合蛋白(DVDs)、人类表皮生长因子受体2(ErbB2或HER/2neu)受体抑制剂、生长因子抑制剂、热休克蛋白(HSP)-90抑制剂、组蛋白脱乙酰基酶(HDAC)抑制剂、激素疗法、免疫学试剂、凋亡蛋白质抑制剂(IAPs)、嵌入抗生素、激酶抑制剂、驱动蛋白抑制剂、JAK2抑制剂、雷帕霉素的哺乳动物靶标(mTOR)抑制剂、微小RNAs、丝裂原激活的细胞外信号调节的激酶(MEK)抑制剂、多价结合蛋白、非甾体抗炎药(NSAIDs)、聚-ADP(腺苷二磷酸)-核糖聚合酶(PARP)抑制剂、铂化疗药物、polo样激酶(Plk)抑制剂、磷酸肌醇-3激酶(PI3K)抑制剂、蛋白酶体抑制剂、嘌呤类似物、嘧啶类似物、受体酪氨酸激酶抑制剂、类视黄醇、deltoids、植物生物碱、小抑制性核糖核酸(small inhibitory ribonucleic acids)(siRNAs)、拓扑异构酶抑制剂、泛素连接酶抑制剂等。
BiTE抗体是通过同时结合2个细胞指导T细胞攻击癌细胞的双特异性抗体。T细胞随后攻击靶癌细胞。BiTE抗体的实例包括但不限于阿德木单抗(Micromet MT201)、兰妥莫单抗(Micromet MT103)等。不受理论所限,T细胞引起靶癌细胞凋亡的机理之一是溶细胞的颗粒组分的胞吐作用,该颗粒组分包括穿孔素和粒酶B。在这方面,Bcl-2已经显示出减弱穿孔素和粒酶B对细胞凋亡的诱导。这些数据暗示,当靶向癌细胞时,Bcl-2的抑制能够提高T细胞引起的细胞毒效应(Sutton et al. (1997) J. Immunol. 158:5783–5790)。
SiRNAs是具有内源RNA碱基或化学修饰的核苷酸的分子。修饰不取消细胞活性,而是赋予增加的稳定性和/或增加的细胞效力。化学修饰的实例包括硫代磷酸酯基团、2'-脱氧核苷酸、含2'-OCH3-核糖核苷酸、2'-F-核糖核苷酸、2'-甲氧基乙基核糖核苷酸、其组合等。siRNA可以具有不同长度(例如10-200 bps)和结构(例如发夹、单/双链、凸起、切口/缺口、错配),且在细胞中加工,以提供主动基因沉默。双链siRNA(dsRNA)可以具有在每条链上相同数目的核苷酸(平端)或不对称末端(突出端)。1-2个核苷酸的突出端可以存在于有义和/或反义链上,以及存在于给定链的5'-末端和/或3'-末端上。例如,靶向Mcl-1的siRNAs已经显示出在各种肿瘤细胞系中提高ABT-263或ABT-737的活性(Tse et al. (2008) Cancer Res. 68:3421–3428和其中的参考文献)。
多价结合蛋白是包含2个或更多抗原结合位点的结合蛋白。多价结合蛋白被改造为具有3个或更多抗原结合位点,并且一般不是天然存在的抗体。术语“多特异性结合蛋白”意指能够结合2个或更多相关或无关靶的结合蛋白。双重可变结构域(DVD)结合蛋白是四价或多价结合蛋白结合蛋白,包含2个或更多抗原结合位点。此类DVDs可以是单特异性的(即能够结合一种抗原)或多特异性的(即能够结合2种或更多抗原)。包含2条重链DVD多肽和2条轻链DVD多肽的DVD结合蛋白被称为DVD Ig’s。DVD Ig的每一半包含重链DVD多肽、轻链DVD多肽和2个抗原结合位点。每个结合位点包含重链可变结构域和轻链可变结构域,具有总共6个CDRs涉及抗原结合/抗原结合位点。
烷化剂包括六甲蜜胺、AMD-473、AP-5280、apaziquone、苯达莫司汀、brostallicin、白消安、卡波醌、卡莫司汀(BCNU)、苯丁酸氮芥、CloretazineTM(拉莫司汀、VNP 40101M)、环磷酰胺、氨烯咪胺、雌氮芥、福莫司汀、葡磷酰胺、异环磷酰胺、KW-2170、罗莫司汀(CCNU)、马磷酰胺、美法仑、二溴甘露醇、二溴卫矛醇、尼莫司汀、氮芥N-氧化物、雷莫司汀、替莫唑胺、噻替派、曲奥舒凡、曲磷胺等。
血管发生抑制剂包括表皮生长因子受体(EGFR)抑制剂、内皮特异性受体酪氨酸激酶(Tie-2)抑制剂、胰岛素生长因子-2-受体(IGFR-2)抑制剂、基质金属蛋白酶-2(MMP-2)抑制剂、基质金属蛋白酶-9(MMP-9)抑制剂、血小板衍生生长因子受体(PDGFR)抑制剂、凝血酶敏感蛋白类似物、血管内皮生长因子受体酪氨酸激酶(VEGFR)抑制剂等。
抗代谢药包括Alimta?(培美曲塞二钠,LY231514,MTA)、5-阿扎胞苷、Xeloda?(卡培他滨)、卡莫氟、Leustat?(克拉屈滨)、氟法拉滨、阿糖胞苷、阿糖胞苷十八烷基磷酸盐(cytarabine ocfosfate)、阿糖胞苷、地西他滨、去铁胺、去氧氟尿苷、依氟鸟氨酸、EICAR(5-乙炔基-1-β-D-呋喃核糖基咪唑-4-甲酰胺)、依诺他滨、乙烯基胞苷(ethenylcytidine)、氟达拉滨、单独或与甲酰四氢叶酸组合的5-氟尿嘧啶(5-FU)、Gemzar?(吉西他滨)、羟基脲、Alkeran?(美法仑)、巯嘌呤、6-巯嘌呤核苷、氨甲蝶呤、霉酚酸、奈拉滨、诺拉曲塞、十八烷基磷酸盐、pelitrexol、喷司他丁、雷替曲塞、病毒唑、S-1、triapine、三甲曲沙、TS-1、噻唑羧胺核苷、替加氟、阿糖腺苷、UFT等。
抗病毒剂包括利托那韦、羟氯喹等。
极光激酶抑制剂包括ABT-348、AZD-1152、MLN-8054、VX-680、极光A特异性激酶抑制剂、极光B特异性激酶抑制剂、泛极光激酶抑制剂等。
除了ABT-263或本文中式I的化合物之外,Bcl-2家族蛋白抑制剂还包括AT-101((-)棉子酚)、GenasenseTM Bcl-2-靶向反义寡核苷酸(G3139或oblimersen)、IPI-194、IPI-565、N-(4-(4-((4'-氯(1,1'-联苯)-2-基)甲基)哌嗪-1-基)苯甲酰基)-4-(((1R)-3-(二甲基氨基)-1-((苯基硫基)甲基)丙基)氨基)-3-硝基苯磺酰胺)(ABT-737)、GX-070(obatoclax)等。
Bcr-Abl激酶抑制剂包括达沙替尼(BMS-354825)、GleevecTM (伊马替尼)等。
CDK抑制剂包括AZD-5438、BMI-1040、BMS-387032、CVT-2584、黄酮吡醇、GPC-286199、MCS-5A、PD0332991、PHA-690509、seliciclib(CYC-202或R-roscovitine)、ZK-304709等。
COX-2抑制剂包括ABT-963、ArcoxiaTM (依托考昔)、BextraTM (伐地昔布)、BMS347070、CelebrexTM (塞来昔布)、COX-189(鲁米昔布)、CT-3、DeramaxxTM (地拉考昔)、JTE-522、4-甲基-2-(3,4-二甲基苯基)-1-(4-氨磺酰基苯基-1H-吡咯)、MK-663(依托考昔)、NS-398、帕瑞考昔、RS-57067、SC-58125、SD-8381、SVT-2016、S-2474、T-614、VioxxTM (罗非昔布)等。
EGFR抑制剂包括ABX-EGF、抗EGFR免疫脂质体、EGF-疫苗、EMD-7200、ErbituxTM (西妥昔单抗)、HR3、IgA抗体、IressaTM (吉非替尼)、TarcevaTM (厄洛替尼或OSI-774)、TP-38、EGFR融合蛋白、TykerbTM (拉帕替尼)等。
ErbB2受体抑制剂包括CP-724-714、CI-1033(卡纽替尼)、HerceptinTM (曲妥珠单抗)、TykerbTM (拉帕替尼)、OmnitargTM (2C4、帕妥珠单抗)、TAK-165、GW-572016(ionafarnib)、GW-282974、EKB-569、PI-166、dHER2(HER2疫苗)、APC-8024(HER2疫苗)、抗HER/2neu双特异性抗体、B7.her2IgG3、AS HER2三功能双特异性抗体、mAB AR-209、mAB 2B-1等。
组蛋白脱乙酰基酶抑制剂包括缩肽、LAQ-824、MS-275、trapoxin、辛二酰苯胺异羟肟酸(SAHA)、TSA、丙戊酸等。
HSP-90抑制剂包括17AAG、CNF-101、CNF-1010、CNF-2024、17-DMAG、格尔德霉素、IPI-504、KOS-953、MycograbTM (针对HSP-90的人类重组抗体)、nab-17AAG、NCS-683664、PU24FCl、PU-3、根赤壳菌素、SNX-2112、STA-9090、VER49009等。
凋亡蛋白质的抑制剂包括HGS-1029、GDC-0145、GDC-0152、LCL-161、LBW-242等。
抗体-药物缀合物包括抗CD22-MC-MMAF、抗CD22-MC-MMAE、抗CD22-MCC-DM1、CR-011-vcMMAE、PSMA-ADC、MEDI-547、SGN-19A、SGN-35、SGN-75等。
死亡受体途径的激活物包括TRAIL和靶向TRAIL或死亡受体(例如DR4和DR5)的抗体或其它试剂,例如apomab、西他土珠(conatumumab)、ETR2-ST01、GDC0145(来沙木单抗)、HGS-1029、LBY-135、PRO-1762、曲妥珠单抗等。
驱动蛋白抑制剂包括Eg5抑制剂例如AZD-4877和ARRY-520;CENPE抑制剂例如GSK-923295A等。
JAK-2抑制剂包括CEP-701(来他替尼)、XL019、INCB-018424等。
MEK抑制剂包括ARRY-142886、ARRY-438162、PD-325901、PD-98059等。
mTOR抑制剂包括AP-23573、CCI-779、依维莫司、RAD-001、雷帕霉素、替西罗莫司、ATP-竞争性TORC1/TORC2抑制剂(包括PI-103、PP242、PP30和Torin 1)等。
非甾体抗炎药包括AmigesicTM (双水杨酸酯)、DolobidTM (二氟尼柳)、MotrinTM (布洛芬)、OrudisTM (酮洛芬)、RelafenTM (萘丁美酮)、FeldeneTM (吡罗昔康)、布洛芬乳膏、AleveTM 和NaprosynTM (萘普生)、VoltarenTM (双氯芬酸)、IndocinTM (吲哚美辛)、ClinorilTM (舒林酸)、TolectinTM (托美丁)、LodineTM (依托度酸)、ToradolTM (酮咯酸)、DayproTM (奥沙普秦)等。
PDGFR抑制剂包括CP-673451、CP-868596等。
铂化疗药物包括顺铂、EloxatinTM (奥沙利铂)、依铂、洛铂、奈达铂、ParaplatinTM (卡铂)、吡铂、沙铂等。
Polo样激酶抑制剂包括BI-2536等。
磷酸肌醇-3激酶抑制剂包括渥曼青霉素、LY-294002、XL-147、CAL-120、ONC-21、AEZS-127、ETP-45658、PX-866、GDC-0941、BGT226、BEZ235、XL765等。
凝血酶敏感蛋白类似物包括ABT-510、ABT-567、ABT-898、TSP-1等。
VEGFR抑制剂包括AvastinTM (贝伐珠单抗)、ABT-869、AEE-788、AngiozymeTM (抑制血管发生的核酶(Ribozyme Pharmaceuticals(Boulder,CO)和Chiron(Emeryville,CA))、阿西替尼(AG-13736)、AZD-2171、CP-547632、IM-862、MacugenTM (哌加他尼)、NexavarTM (索拉非尼、BAY43-9006)、帕唑帕尼(GW-786034)、瓦他拉尼(PTK-787或ZK-222584)、SutentTM (舒尼替尼或SU-11248)、VEGF阱、ZactimaTM (凡德他尼或ZD-6474)等。
抗生素包括嵌入抗生素如阿柔比星、放线菌素D、氨柔比星、脂质体蒽环霉素(annamycin)、AdriamycinTM (多柔比星)、BlenoxaneTM (博来霉素)、柔红霉素、CaelyxTM 和MyocetTM (多柔比星脂质体)、依沙芦星、epirbucin、glarubicin、伊达比星、丝裂霉素C、奈莫柔比星、新制癌菌素、培洛霉素、吡柔比星、蝴蝶霉素、苯马聚合物、链佐星、ValstarTM (戊柔比星)、净司他丁等。
拓扑异构酶抑制剂包括阿柔比星、9-氨基喜树碱、氨萘非特、安吖啶、becatecarin、贝洛替康、BN-80915、CamptosarTM (盐酸伊立替康)、喜树碱、CardioxaneTM (右雷佐生)、二氟替康、艾特咔林、EllenceTM 和PharmorubicinTM (表柔比星)、依托泊苷、依沙替康、10-羟基喜树碱、吉马替康、勒托替康、米托蒽醌、鲁比替康、pirarbucin、pixantrone、卢比替康、索布佐生、SN-38、他氟前列素、托泊替康等。
抗体包括AvastinTM (贝伐珠单抗)、CD40特异性抗体、chTNT-1/B、地诺单抗、ErbituxTM (西妥昔单抗)、Humax-CD4TM (扎木单抗)、IGF1R特异性抗体、林妥珠单抗、PanorexTM (依决洛单抗)、RencarexTM (WX G250)、RituxanTM (利妥昔单抗)、ticilimumab、曲妥珠单抗、I和II型CD20抗体等。
激素疗法包括ArimidexTM (阿那曲唑)、AromasinTM (依西美坦)、阿佐昔芬、CasodexTM (比卡鲁胺)、CetrotideTM (西曲瑞克)、地加瑞克、地洛瑞林、DesopanTM (曲洛司坦)、地塞米松、DrogenilTM (氟他胺)、EvistaTM (雷洛昔芬)、AfemaTM (法倔唑)、FarestonTM (托瑞米芬)、FaslodexTM (氟维司群)、FemaraTM (来曲唑)、福美坦、糖皮质激素、HectorolTM (度骨化醇)、RenagelTM (碳酸司维拉姆)、拉索昔芬、乙酸亮丙瑞林、MegaceTM (甲地孕酮)、MifeprexTM (米非司酮)、NilandronTM (尼鲁米特)、他莫昔芬(包括NolvadexTM (柠檬酸他莫昔芬))、PlenaxisTM (阿巴瑞克)、泼尼松、PropeciaTM (非那雄胺)、rilostane、SuprefactTM (布舍瑞林)、促黄体激素释放激素(LHRH)(包括TrelstarTM (曲普瑞林))、组氨瑞林(包括VantasTM (组氨瑞林植入剂))、ModrastaneTM (曲洛司坦)、ZoladexTM (戈舍瑞林)等。
Deltoids和类视黄醇包括西奥骨化醇(EB1089或CB1093)、来沙骨化醇(KH1060)、芬维A胺、PanretinTM (阿利维A酸)、维甲酸(包括AtragenTM (维甲酸脂质体))、TargretinTM (贝沙罗汀)、LGD-1550等。
PARP抑制剂包括ABT-888、奥拉帕尼、KU-59436、AZD-2281、AG-014699、BSI-201、BGP-15、INO-1001、ONO-2231等。
植物生物碱包括长春新碱、长春碱、长春地辛、长春瑞滨等。
蛋白酶体抑制剂包括VelcadeTM (硼替佐米)、MG132、NPI-0052、PR-171等。
免疫学试剂的实例包括干扰素及其它免疫增强剂。干扰素包括干扰素α、干扰素α-2a、干扰素α-2b、干扰素β、干扰素γ-1a、ActimmuneTM (干扰素γ-1b)或干扰素γ-n1,其组合等。其它试剂包括Alfaferone (IFN-α)、BAM-002(氧化谷胱甘肽)、BeromunTM (他索那敏)、BexxarTM (托西莫单抗)、CampathTM (阿仑珠单抗)、CTLA4(细胞毒性淋巴细胞抗原4)、达卡巴嗪、地尼白介素、依帕珠单抗、GranocyteTM (来格司亭)、香菇多糖、白细胞α干扰素、咪喹莫特、MDX-010(抗CTLA-4)、黑色素疫苗、米妥莫单抗、莫拉司亭、MylotargTM (吉妥珠单抗奥唑米星)、NeupogenTM (非格司亭)、OncoVAC-CL、OvarexTM (奥戈伏单抗)、帕尼单抗(Y-muHMFG1)、ProvengeTM (sipuleucel-T)、沙格司亭、西佐喃、替西白介素、TheracysTM (BCG或卡介苗)、乌苯美司、VirulizinTM (免疫治疗,Lorus Pharmaceuticals)、Z-100(Maruyama的特异性物质或SSM)、WF-10(tetrachlorodecaoxide或TCDO)、ProleukinTM (阿地白介素)、ZadaxinTM (胸腺法新)、ZenapaxTM (达可珠单抗)、ZevalinTM (90Y-替伊莫单抗)等。
生物学应答调节剂是这样的试剂,其修饰活生物的防御机制或生物学应答,例如组织细胞的存活、生长或分化,以引导它们具有抗瘤活性,并且包括云芝多糖、香菇多糖、西佐喃、溶链菌制剂、PF-3512676(CpG-8954)、乌苯美司等。
嘧啶类似物包括阿糖胞苷(阿糖胞苷、ara C或阿糖胞苷C)、去氧氟尿苷、FludaraTM (氟达拉滨)、5-FU(5-氟尿嘧啶)、氟尿苷、GemzarTM (吉西他滨)、TomudexTM (雷替曲塞)、三乙酰尿苷、TroxatylTM (曲沙他滨)等。
嘌呤类似物包括LanvisTM (硫鸟嘌呤)、PurinetholTM (巯嘌呤)等。
抗有丝分裂剂包括巴他布林、埃坡霉素D(KOS-862)、N-(2-((4-羟基苯基)氨基)吡啶-3-基)-4-甲氧基苯磺酰胺、伊沙匹隆(BMS-247550)、紫杉醇、TaxotereTM (多西他赛)、larotaxel (PNU-100940、RPR-109881或XRP-9881)、帕土匹龙、长春氟宁、ZK-EPO(合成埃坡霉素)等。
泛素连接酶抑制剂包括MDM2抑制剂例如nutlins、NEDD8抑制剂例如MLN4924等。
包含晶体N-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲柠檬酸二氢盐形式I或柠檬酸氢盐形式II(或制备用作API)的组合物还可以用作增强放射疗法功效的放射增敏剂。放射疗法的实例包括但不限于外线束放射疗法(XBRT)、远距离放射疗法、近距离放射疗法、封闭源放射疗法、非封闭源放射疗法等。
另外地或可选择地,包含晶体N-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲柠檬酸二氢盐形式I或柠檬酸氢盐形式II(或制备用作API)的组合物可以在组合疗法中与一种或多种选自如下物质的抗肿瘤剂或化学治疗剂一起给药:AbraxaneTM (ABI-007)、ABT-100(法尼基转移酶抑制剂)、AdvexinTM (Ad5CMV-p53疫苗或contusugene ladenovec)、AltocorTM 或MevacorTM (洛伐他汀)、AmpligenTM (聚(I)-聚(C12U),合成RNA)、AptosynTM (依昔舒林)、ArediaTM (帕米膦酸)、arglabin、L-天冬酰胺酶、阿他美坦(1-甲基-3,17-二酮-雄甾-1,4-二烯)、AvageTM (他扎罗汀)、AVE-8062(考布他汀衍生物)、BEC2(米妥莫单抗)、恶液质素或恶病质素(肿瘤坏死因子)、CanvaxinTM (黑素瘤疫苗)、CeaVacTM (癌症疫苗)、CeleukTM (西莫白介素)、组胺(包括CepleneTM (组胺二盐酸盐))、CervarixTM (AS04佐剂-吸附的人乳头状瘤病毒(HPV)疫苗)、CHOPTM (CytoxanTM (环磷酰胺)+AdriamycinTM (多柔比星)+OncovinTM (长春新碱)+泼尼松)、考布他汀A4P、CypatTM(环丙孕酮)、DAB(389)EGF(经由His-Ala接头与人表皮生长因子融合的白喉毒素的催化和易位结构域)、达卡巴嗪、更生霉素、DimericineTM (T4N5脂质体洗剂)、5,6-二甲基呫吨酮-4-乙酸(DMXAA)、discodermolide、DX-8951f(依沙替康甲磺酸盐)、恩尿嘧啶(乙炔基尿嘧啶)、角鲨胺(包括EvizonTM (乳酸角鲨胺))、enzastaurin、EPO-906(埃坡霉素B)、GardasilTM (四价人乳头状瘤病毒(6、11、16、18型)重组疫苗)、GastrimmuneTM 、GenasenseTM (奥利默森)、GMK(神经节苷脂缀合物疫苗)、GVAXTM (前列腺癌疫苗)、卤夫酮、histerelin、羟基脲、伊班膦酸、IGN-101、IL-13-PE38、IL-13-PE38QQR(cintredekin besudotox)、IL-13-假单胞菌外毒素、干扰素-α、干扰素-γ、JunovanTM或MepactTM(米伐木肽)、lonafarnib、5,10-亚甲基四氢叶酸、米替福新(十六烷基胆碱磷酸)、NeovastatTM (AE-941)、NeutrexinTM (葡醛酸三甲曲沙)、NipentTM (喷司他丁)、OnconaseTM (豹蛙酶,为核糖核酸酶)、OncophageTM (vitespen,为黑素瘤疫苗治疗)、OncoVAXTM (IL-2疫苗)、OrathecinTM (卢比替康)、OsidemTM (基于抗体的细胞药物)、OvarexTM MAb(鼠单克隆抗体)、紫杉醇白蛋白稳定化的纳米粒、紫杉醇、PandimexTM(来自人参的糖苷配基皂苷,其包含20(S)-原人参二醇(aPPD)和20(S)-原人参三醇(aPPT))、帕木单抗、PanvacTM -VF(研究的癌症疫苗)、培门冬酶、聚乙二醇干扰素α (PEG 干扰素 A)、脱氢雌马酚、丙卡巴肼、瑞马司他、RemovabTM (卡妥索单抗)、RevlimidTM (来那度胺)、RSR13(乙丙昔罗)、SomatulineTM LA(兰瑞肽)、SoriataneTM (阿维A)、星状孢子素(链霉菌属星状孢子)、talabostat(PT100)、TargretinTM (贝沙罗汀)、TaxoprexinTM (二十二碳六烯酸(DHA)+紫杉醇)、TelcytaTM (canfosfamide、TLK-286)、TemodarTM (替莫唑胺)、替米利芬、粉防己碱、沙利度胺、TheratopeTM (STn-KLH疫苗)、ThymitaqTM (诺拉曲塞二盐酸盐)、TNFeradeTM(腺病毒载体:含有肿瘤坏死因子-α的基因的DNA载体)、TracleerTM 或ZavescaTM (波生坦)、TransMID-107RTM (KSB-311、白喉毒素)、维甲酸(维生素A酸)、TrisenoxTM (三氧化二砷)、UkrainTM (来自白屈菜植物的生物碱的衍生物)、VirulizinTM 、VitaxinTM (抗αvβ3抗体)、XcytrinTM (莫特沙芬钆)、XinlayTM(阿曲生坦)、XyotaxTM(聚谷氨酸紫杉醇)、YondelisTM (曲贝替定)、ZD-6126 (N-乙酰基秋水仙醇-O-磷酸(N-acetylcolchinol-O-phosphate))、ZinecardTM (右雷佐生)、唑来膦酸、佐柔比星等。
在一种实施方案中,将包含晶体N-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲柠檬酸二氢盐形式I或柠檬酸氢盐形式II(或制备用作API)的组合物以治疗有效量给药于需要其的受试者以治疗癌症。
实例包括但不限于哺乳动物中的听神经瘤,急性白血病,急性淋巴细胞白血病,急性髓细胞白血病(单核细胞、成髓细胞、腺癌、血管肉瘤、星形细胞瘤、骨髓单核细胞和前髓细胞),急性t细胞白血病,基底细胞癌,胆管癌,膀胱癌,脑癌,乳腺癌,支气管癌,宫颈癌,软骨肉瘤,脊索瘤,绒毛膜癌,慢性白血病,慢性淋巴细胞白血病,慢性髓细胞(粒细胞)白血病,慢性骨髓性白血病,结肠癌,结肠直肠癌,颅咽管瘤,囊腺癌,弥漫性大B细胞淋巴瘤,增殖异常变化(发育不良和化生),胚胎性癌,子宫内膜癌,内皮肉瘤,室管膜瘤,上皮癌,红白血病,食管癌,雌激素受体阳性乳腺癌,原发性血小板增多症,尤因瘤,纤维肉瘤,滤泡型淋巴瘤,生殖细胞睾丸癌,神经胶质瘤,重链病,成血管细胞瘤,肝癌,肝细胞癌,激素不敏感性前列腺癌,平滑肌肉瘤,脂肪肉瘤,肺癌,淋巴管内皮肉瘤(lymphagioendotheliosarcoma),淋巴管肉瘤,成淋巴细胞白血病,淋巴瘤(霍奇金氏和非霍奇金氏),膀胱、乳腺、结肠、肺、卵巢、胰腺、前列腺、皮肤和子宫的恶性肿瘤和过度增殖性病症,T细胞或B细胞起源的淋巴样恶性肿瘤,白血病,淋巴瘤,髓质癌,成髓细胞瘤,黑素瘤,脑膜瘤,间皮瘤,多发性骨髓瘤,髓性白血病,骨髓瘤,粘液肉瘤,成神经细胞瘤,非小细胞肺癌,少突神经胶质瘤,口腔癌,成骨性肉瘤,卵巢癌,胰腺癌,乳头状腺癌,乳头状癌,松果体瘤,真性红细胞增多症,前列腺癌,直肠癌,肾细胞癌,成视网膜细胞瘤,横纹肌肉瘤,肉瘤,皮脂腺癌,精原细胞瘤,皮肤癌,小细胞肺癌,实体瘤(癌和肉瘤),小细胞肺癌,胃癌,鳞状细胞癌,滑膜瘤,汗腺癌,甲状腺癌,Waldenstr?m氏巨球蛋白血症,睾丸瘤,子宫癌和肾母细胞瘤。
在更具体的实施方案中,将包括晶体N-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲柠檬酸二氢盐形式I或柠檬酸氢盐形式II(或制备用作API)的组合物以治疗有效量给药于需要其的受试者以治疗骨髓增生异常综合征、急性髓样白血病、结肠直肠癌、非小细胞肺癌和卵巢癌。
在本发明的其它实施方案中,提供了用于治疗哺乳动物中癌症的方法,所述方法包括将N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐形式I或柠檬酸氢盐形式II溶于药学上可接受的溶剂或溶剂混合物中,并对患有所述疾病的受试者给药治疗有效量的所得溶液。
在本发明的其它实施方案中,提供了用于治疗哺乳动物中癌症的方法,所述方法包括将N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐形式I或柠檬酸氢盐形式II分散于药学上可接受的聚合物载体中,并向患有所述疾病的受试者给药治疗有效量的所得固体分散体。
实施例
以下实施例仅是示例性的,并非以任何方式限定这篇公开。
使用装有弯曲的位置灵敏探测器(curved position sensitive detector)和平行光束光学器件的G3000衍射仪(Inel Corp., Artenay, France)采集PXRD数据。该衍射仪采用铜阳极管(1.5 kW细焦点)在40 kV和30 mA下工作。入射光束锗单色仪提供了单色辐射。使用衰减的直接光束、以一度的间隔校准衍射仪。使用Silicon Powder Line Position参照标准(NIST 640c)检查校准。该仪器使用Symphonix软件(Inel Corp., Artenay, France)进行计算机控制并使用Jade软件(6.5版, Materials Data, Inc., Livermore, CA)分析数据。将样品装载于铝制试样架上并用载玻片弄平。
实施例1
N
-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐形式I的制备
将N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲游离碱固体(399.87 mg )加入20 mL丙酮 : 水混合物(75:25 v:v)中,并在搅拌下在70℃加热30分钟。样品保持为悬浮液。在70℃,伴随着连续搅拌,加入柠檬酸(1.2 mL, 1 M)水溶液。在约1小时结束的,样品几乎完全溶解。使样品缓慢冷却至环境温度过夜。通过0.22微米PTFE注射器式滤器过滤悬浮液。通过施加真空将滤液蒸发冷却。有无定形材料沉淀,形成乳状悬浮液,数分钟后其转化为“树胶状的”材料(粘性物料)。将样品声处理约30分钟,之后发生结晶。通过真空过滤收集晶态固体。
实施例2
N
-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐形式I的制备
将N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲游离碱固体(398.06 mg)加入20 mL丙酮 : 水混合物(75:25 v:v)中,并在搅拌下在70℃加热30分钟。样品保持为悬浮液。在70℃下,伴随着连续搅拌,加入柠檬酸(1.2 mL, 1 M)的水溶液。在加入该柠檬酸溶液之后,观察到略微更多的固体溶解。在加入柠檬酸后的12分钟内,形成悬浮液。在70℃搅拌该悬浮液约1小时。通过真空过滤分离固体。
表1. PXRD峰列表:N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐形式I
峰位置(°2θ) |
7.560 |
7.959 |
11.797 |
12.421 |
13.435 |
14.587 |
15.657 |
15.953 |
16.686 |
21.381 |
22.396 |
22.815 |
23.983 |
24.504 |
24.993 |
26.122 |
实施例3
N
-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐形式II的制备
在70℃,将N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲游离碱固体(102.65 mg)溶于5 mL的THF/水混合物(80/20 v/v)中。将柠檬酸(21.94 mg)加入该溶液中,然后缓慢加入庚烷(7.5 mL)。注意到在庚烷层中形成的少量沉淀物的出现。随着其进入THF/水层中,沉淀物溶解。将该溶液冷却至环境温度。数天后,在环境温度形成晶态固体。通过真空过滤收集固体。
表2. PXRD峰列表:N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐形式II
峰位置(°2θ) |
5.71 |
6.30 |
7.27 |
8.65 |
9.80 |
13.06 |
14.31 |
15.18 |
15.92 |
16.68 |
17.71 |
20.17 |
21.98 |
23.30 |
24.47 |
26.11 |
28.08 |
Claims (26)
1.固态晶体形式的化合物N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐。
2.固态晶体形式的化合物N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐,其中所述晶体形式为形式I,其特征至少在于在任何一个或多个以下位置的粉末X射线衍射峰:11.80、14.59、15.95、21.38、26.12°2θ, ± 0.2°2θ。
3.权利要求2的化合物,其中所述晶体形式为形式I,其特征至少在于在每个所述位置的粉末X射线衍射峰。
4.权利要求2的化合物,其中所述晶体形式为形式I,其特征至少在于在每个所述位置的粉末X射线衍射峰:7.56、7.96、11.80、12.42、13.44、14.59、15.66、15.95、16.69、21.38、22.40、22.82、23.98、24.50、24.99、26.12°2θ, ± 0.2°2θ。
5.权利要求1-4任一项的化合物,其中所述晶体形式为一水合物。
6.包含权利要求1-5任一项的化合物和一种或多种药学上可接受的赋形剂的药物组合物。
7.用于制备固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐的方法,其中所述晶体形式为权利要求1-5任一项的形式I,所述方法包括:
a) 提供包含(i) N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲、水、丙酮和柠檬酸的混合物;
b) 使N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐晶体形式I存在于该混合物中。
8.权利要求7的方法,所述方法还包括分离固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐,其中所述晶体形式为形式I。
9.用于治疗哺乳动物中癌症的方法,所述方法包括对患有所述疾病的受试者给药治疗有效量的(a)固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐,其中所述晶体形式为形式I,其特征至少在于在任何一个或多个以下位置的粉末X射线衍射峰:11.80、14.59、15.95、21.38、26.12°2θ, ± 0.2°2θ,或(b)包含固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐和一种或多种药学上可接受的赋形剂的药物组合物,其中所述晶体形式为形式I,其特征至少在于在任何一个或多个以下位置的粉末X射线衍射峰:11.80、14.59、15.95、21.38、26.12°2θ, ± 0.2°2θ。
10.权利要求9的方法,其中通过口服、胃肠外、舌下、含服、鼻内、肺部、局部、透皮、皮内、眼、耳、直肠、阴道、胃内、颅内、滑膜内或关节内的途径给药晶体N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐形式I或药物组合物。
11.权利要求9的方法,其中所述癌症为骨髓增生异常综合征、急性髓样白血病、结肠直肠癌、非小细胞肺癌和卵巢癌。
12.用于治疗哺乳动物中癌症的方法,所述方法包括将固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐溶于药学上可接受的溶剂或溶剂混合物中,并对患有所述疾病的受试者给药治疗有效量的所得溶液,其中所述晶体形式为形式I,其特征至少在于在任何一个或多个以下位置的粉末X射线衍射峰:11.80、14.59、15.95、21.38、26.12°2θ, ± 0.2°2θ。
13.用于治疗哺乳动物中癌症的方法,所述方法包括将固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐分散于药学上可接受的聚合物载体中,并对患有所述疾病的受试者给药治疗有效量的所得固体分散体,其中所述晶体形式为形式I,其特征至少在于在任何一个或多个以下位置的粉末X射线衍射峰:11.80、14.59、15.95、21.38、26.12°2θ, ± 0.2°2θ。
14.固态晶体形式的化合物N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐。
15.固态晶体形式的化合物N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐,其中所述晶体形式为形式II,其特征至少在于在任何一个或多个以下位置的粉末X射线衍射峰:8.65、15.18、24.47、28.02°2θ, ± 0.2°2θ。
16.权利要求15的化合物,其中所述晶体形式为形式II,其特征至少在于在每个所述位置的粉末X射线衍射峰。
17.权利要求15的化合物,其中所述晶体形式为形式II,其特征至少在于在每个所述位置的粉末X射线衍射峰:5.71、6.30、7.27、8.65、9.80、13.06、14.31、15.18、15.92、16.68、17.71、20.17、21.98、23.30、24.47、26.11、28.02°2θ, ± 0.2°2θ。
18.权利要求14-17任一项的化合物,其中所述晶体形式为水合物。
19.包含权利要求14-18任一项的化合物和一种或多种药学上可接受的赋形剂的药物组合物。
20.用于制备固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸二氢盐的方法,其中所述晶体形式为权利要求14-18任一项的形式I,所述方法包括:
a) 提供包含(i) N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲、水、四氢呋喃和柠檬酸的混合物;
b) 使N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐晶体形式II存在于该混合物中。
21.权利要求20的方法,所述方法还包括分离固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐,其中所述晶体形式为形式II。
22.用于治疗哺乳动物中癌症的方法,所述方法包括对患有所述疾病的受试者给药治疗有效量的(a)固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐,其中所述晶体形式为形式II,其特征至少在于在任何一个或多个以下位置的粉末X射线衍射峰:8.65、15.18、24.47、28.02°2θ,± 0.2°2θ,或(b)包含固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐和一种或多种药学上可接受的赋形剂的药物组合物,其中所述晶体形式为形式II,其特征至少在于在任何一个或多个以下位置的粉末X射线衍射峰:8.65、15.18、24.47、28.02°2θ,± 0.2°2θ。
23.权利要求22的方法,其中通过口服、胃肠外、舌下、含服、鼻内、肺部、局部、透皮、皮内、眼、耳、直肠、阴道、胃内、颅内、滑膜内或关节内的途径给药晶体N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐形式II或药物组合物。
24.权利要求22的方法,其中所述癌症为骨髓增生异常综合征、急性髓样白血病、结肠直肠癌、非小细胞肺癌和卵巢癌。
25.用于治疗哺乳动物中癌症的方法,所述方法包括将固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐溶于药学上可接受的溶剂或溶剂混合物中,并对患有所述疾病的受试者给药治疗有效量的所得溶液,其中所述晶体形式为形式II,其特征至少在于在任何一个或多个以下位置的粉末X射线衍射峰:8.65、15.18、24.47、28.02°2θ,± 0.2°2θ。
26.用于治疗哺乳动物中癌症的方法,所述方法包括将固态晶体形式的N-(4-{4-氨基-7-[1-(2-羟基乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的柠檬酸氢盐分散于药学上可接受的聚合物载体中,并对患有所述疾病的受试者给药治疗有效量的所得固体分散体,其中所述晶体形式为形式II,其特征至少在于在任何一个或多个以下位置的粉末X射线衍射峰:8.65、15.18、24.47、28.02°2θ,± 0.2°2θ。
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WO2005010009A1 (en) * | 2003-07-24 | 2005-02-03 | Abbott Laboratories | Thienopyridine and furopyridine kinase inhibitors |
CN101336244A (zh) * | 2005-12-08 | 2008-12-31 | 艾博特公司 | 用作蛋白激酶抑制剂的9元杂二环化合物 |
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Also Published As
Publication number | Publication date |
---|---|
JP2013528221A (ja) | 2013-07-08 |
TW201202235A (en) | 2012-01-16 |
TWI482770B (zh) | 2015-05-01 |
US20140296284A1 (en) | 2014-10-02 |
ZA201209648B (en) | 2013-08-28 |
SG186250A1 (en) | 2013-01-30 |
BR112012031485A2 (pt) | 2016-11-01 |
CA2802029A1 (en) | 2011-12-15 |
AR083152A1 (es) | 2013-02-06 |
RU2012157469A (ru) | 2014-07-20 |
EP2580220A1 (en) | 2013-04-17 |
HK1179255A1 (zh) | 2013-09-27 |
US8633217B2 (en) | 2014-01-21 |
SG2014014278A (en) | 2014-06-27 |
US20120202844A1 (en) | 2012-08-09 |
NZ604649A (en) | 2014-11-28 |
WO2011156464A8 (en) | 2012-10-11 |
AU2011264902A1 (en) | 2013-01-10 |
ES2536503T3 (es) | 2015-05-26 |
AU2011264902B2 (en) | 2015-01-29 |
WO2011156464A1 (en) | 2011-12-15 |
JP5727598B2 (ja) | 2015-06-03 |
EP2580220B1 (en) | 2015-02-11 |
US8940759B2 (en) | 2015-01-27 |
MX2012014348A (es) | 2013-04-24 |
KR20130112856A (ko) | 2013-10-14 |
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