CN103003283A - 激酶抑制剂的结晶形式 - Google Patents
激酶抑制剂的结晶形式 Download PDFInfo
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- CN103003283A CN103003283A CN2011800375187A CN201180037518A CN103003283A CN 103003283 A CN103003283 A CN 103003283A CN 2011800375187 A CN2011800375187 A CN 2011800375187A CN 201180037518 A CN201180037518 A CN 201180037518A CN 103003283 A CN103003283 A CN 103003283A
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- pyridin
- thieno
- fluorophenyl
- pyrazoles
- hydroxyethyl
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Abstract
N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的盐和其结晶形式是可用于治疗疾病例如癌症的药物组合物的合适的药物组分。
Description
相关申请的交叉引用
本申请要求2010年6月09日申请的美国临时申请No. 61/353,170的优先权,其全部内容以引证的方式包括在本文中。
发明领域
本发明涉及结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的盐,制备结晶形式的方法,其药物制剂,和治疗癌症的方法。
发明背景
有丝分裂是一种过程,通过这种过程,复制的染色体组的完整副本通过微管纺缍体装置分离成两个子细胞。极光-激酶,其是染色体组稳定性所需要的关键有丝分裂调节剂,发现其在人肿瘤中被过度表达。因此,在治疗领域仍需要抑制极光-激酶的化合物、包含该抑制剂的组合物和治疗其间极光-激酶未被调节或过度表达的疾病的方法。
蛋白的可逆磷酸化是介导真核细胞信号的主要生物化学机理之一。这种反应由蛋白激酶催化,该蛋白激酶将ATP的g-磷酸基转移至靶向蛋白的羟基上。在人染色体组存在518种这样的酶,其中~90种选择性催化酪氨酸羟基的磷酸化。胞液酪氨酸激酶存在于细胞内,然而受体酪氨酸激酶(RTKs)同时具有胞外和胞内域两者,且起跨膜细胞表面受体的作用。因此,RTKs介导细胞对环境信号的反应,便于广范围的细胞代谢过程(cellular process),包括增殖、迁移和存活。
RTK信号途径通常被高度调节,但已经表明,它们的过度活化可促进癌细胞的生长、存活和转移。失调的RTK信号通过基因过度表达或突变发生,且与各种人癌症的进展有相互关系。
VEGF受体(VEGFR)家族由三个RTK组成∶KDR(含有激酶嵌入域的受体;VEGFR2),FLT1(Fms类酪氨酸激酶;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))的生物功能,其是具有变化的亲合性的、结合VEGF受体的同源二聚体糖蛋白家族。
KDR是VEGF-A的促有丝分裂、生成血管和提高渗透性效果的主要介质,下文称为VEGF。许多不同的细胞类型能够产生VEGF,但其生物活性主要通过KDR的内皮细胞选择性表达限定于血管系统。非意外地,VEGF/KDR轴是血管生成的主要介质,其是由先前存在的血管形成新血管的手段。
FLT1与VEGF、VEGF-B和胎盘生长因子结合。除了内皮细胞之外,FLT1还在平滑肌细胞、单核白细胞和造血干细胞的表面上表达。FLT1信号的活化导致起源于骨髓的内皮祖细胞的活动,这些细胞补充到肿瘤中,它们在此促进新血管形成。
FLT4介导该VEGF-C和VEGF-D的信号,其介导肿瘤-相关的淋巴管形成(淋巴管生成)。淋巴管是在转移病变期间癌细胞从实质固态瘤扩散的途径之一。
PDGF受体(PDGFR)家族由五个RTK组成,其是PDGFR-a和-b、CSF1R、KIT和FLT3。
CSF-1R由逆转录病毒癌基因v-fms的细胞同系物编码,且是巨噬细胞演变的主要调节剂。巨噬细胞是肿瘤基质(stroma)常见的组分,已经表明其可以以有益于肿瘤生长和转移病变的方式改变胞外基质。
KIT由肠管中的造血祖细胞、柱状细胞、性细胞和起搏细胞表达(Cajal的间质细胞)。其通过两种常规机理促进肿瘤进程,即通过其配体干细胞生长因子(SCF)的自分泌刺激作用和通过导致配体非依赖性激酶活性的突变。
FLT3通常在造血干细胞上表达,在其中,其与FLT3配体(FL)的相互作用刺激干细胞存活、增殖和分化。除了在各种白血病细胞中被过度表达之外,FLT3通常还在血液学恶性肿瘤中突变,大约三分之一患有急性骨髓性白血病(AML)的患者隐藏有活化突变。
因此,确认有效的小分子化合物是合乎需要的,这种化合物通过调节酪氨酸激酶活性来特异性抑制信号转导和细胞增殖,从而调整和调节异常或不适当的细胞增殖、分化或代谢。尤其是,确认特异性抑制酪氨酸激酶功能的方法和化合物可能是有益的,这种酪氨酸激酶功能对能够导致浮肿、腹水、渗出、溢泌和大分子的溢出和基质沉积以及相关病症的生成血管过程或形成脉管渗透性过高是必不可少的。
已经鉴定的抑制蛋白激酶例如极光-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。这些化合物和生产它们的方法公开在美国专利申请No.12/632183(在下文称作“'183 申请”)中,本文以引证的方式包括其全部内容。
现在已经发现N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的盐可以转变为结晶形式,其可以有利地作为癌症治疗的活性药物组分使用。为了此目的,这些结晶形式可转变为药物制剂。
结晶形式是分子的彼此相对位置是按照三维点阵结构组织起来的形式。多晶型物是由在固态时分子的不同排列产生的同样化合物的不同结晶形式。多晶型物彼此的物理性能不同,而不是它们的化学组成不同。
在合适的药物剂型的研发中对多晶型现象特别感兴趣。某些多晶形式可以显示出优良的稳定性和耐藏性,导致提高药物产品的贮存期限。此外,某些多晶形式更容易以高纯度大批量制备。
决定性地,活性药物组分的多晶型物可以具有不同的水溶性和溶解速率,由于同样化合物的在多晶型物之间在生物利用率方面的潜在区别,其可以具有治疗学后果。
本发明提供了结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的盐,具有下列一或多种特性的有益性能∶能够被配制成药物剂型,在药物剂型中充足的贮存期限,和/或具有以药物剂型有效地给予的能力。
本发明概述
在一个实施方案中,本发明提供了固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸盐。
在一个实施方案中,本发明提供了固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸盐。
在一个实施方案中,本发明提供了固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲HCl盐。
在一个实施方案中,本发明提供了固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐。
在一个实施方案中,本发明提供了固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲酒石酸氢盐。
在一个实施方案中,本发明提供了固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸氢盐。
在一个实施方案中,本发明提供了固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲抗坏血酸盐。
在一个实施方案中,本发明提供了固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲马来酸盐。
在一个实施方案中,本发明提供了固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲硫酸盐。
在一个实施方案中,本发明提供了固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲磷酸盐。
在进一步的实施方案中,本发明提供了本文表征的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸盐的晶体多晶型物,以I型表示。在进一步的实施方案,本发明提供I型的水合物形式,包括四水合物形式。
在进一步的实施方案中,本发明提供了本文表征的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸盐的晶体多晶型物,以II型表示。在进一步的实施方案中,本发明提供II型的水合物形式,包括四水合物形式。
在进一步的实施方案中,本发明提供了本文表征的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲HCl的晶体多晶型物,以III型表示。在进一步实施方案中,本发明提供了无水形式的III型。
在进一步的实施方案中,本发明提供了本文表征的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐的晶体多晶型物,以IV型表示。在进一步实施方案中,本发明提供了无水形式的IV型。
在进一步的实施方案中,本发明提供了本文表征的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲酒石酸氢盐的晶体多晶型物,以V型表示。在进一步实施方案中,本发明提供了无水形式的V型。
在进一步的实施方案中,本发明提供了本文表征的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸氢盐的晶体多晶型物,以VI型表示。在进一步实施方案中,本发明提供了无水形式的VI型。
在进一步的实施方案中,本发明提供了本文表征的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲抗坏血酸盐的晶体多晶型物,以VII型表示。在进一步实施方案中,本发明提供了无水形式的VII型。
在进一步的实施方案中,本发明提供了本文表征的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸盐的晶体多晶型物,以VIII型表示。在进一步的实施方案中,本发明提供了水合物形式的VIII型。
在进一步的实施方案中,本发明提供了本文表征的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲硫酸盐的晶体多晶型物,以IX型表示。在进一步的实施方案中,本发明提供了水合物形式的IX型。
在进一步的实施方案中,本发明提供了本文表征的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲磷酸盐的晶体多晶型物,以X型表示。在进一步的实施方案中,本发明提供了水合物形式的X型。
进一步提供了包括I型,II型,III型,IV型,V型,VI型,VII型,VIII型,IX型或X型和一或多种可药用赋形剂的药物组合物。
进一步提供了制备固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸盐的方法,其中结晶形式是I型,包括∶
a)提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸氢盐固体,水,和四氢呋喃的混合物;和b)得到存在于混合物中的I型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸盐。
进一步提供了制备固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸盐的方法,其中结晶形式是II型,包括∶
a)提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸氢盐固体,水,和四氢呋喃的混合物;和b)得到存在于混合物中的II型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸盐。
进一步提供了制备固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲HCl盐的方法,其中结晶形式是III型,包括∶a)提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-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,水,醇和盐酸的混合物;和 b)得到存在于混合物中的III型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲HCl盐。
进一步提供了制备固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐的方法,其中结晶形式是权利要求34-38任一项的IV型,包括∶a)提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-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,二甲基甲酰胺,甲磺酸和乙腈的混合物;b)得到存在于混合物中的IV型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐。
进一步提供了制备固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸氢盐的方法,其中结晶形式是V型,包括∶a)提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-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,四氢呋喃,水和L-酒石酸的混合物;b)得到存在于混合物中的V型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸氢盐。
进一步提供了制备固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸氢盐的方法,其中结晶形式是VI型,包括∶a)提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-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,四氢呋喃,水和丙二酸的混合物;b)得到存在于混合物中的VI型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸氢盐。
进一步提供了制备固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲抗坏血酸盐的方法,其中结晶形式是VII型,包括∶a)提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-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,四氢呋喃,水和抗环血酸的混合物;b)得到存在于混合物中的VII型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲抗坏血酸盐。
进一步提供了制备固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲马来酸盐的方法,其中结晶形式是VIII型,包括∶a)提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-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,二甲基甲酰胺,和马来酸的混合物;b)得到存在于混合物中的VIII型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲马来酸盐。
进一步提供了制备固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲硫酸盐的方法,其中结晶形式是IX型,包括∶a)提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-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,丙醇,和硫酸的混合物;b)得到存在于混合物中的IX型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲硫酸盐。
进一步提供了制备固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲磷酸盐的方法,其中结晶形式是X型,包括∶a)提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-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,丙醇,和磷酸的混合物;b)得到存在于混合物中的X型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲磷酸盐。
在进一步的实施方案中,本发明提供了在哺乳动物中治疗癌症的方法,包括给予具有该疾病的患者治疗有效量的固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的盐,其中结晶形式是I,II,III,IV,V,VI,VII,VIII,IX,或X型,或(b)药物组合物,包括以固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的盐,其中结晶形式是I,II,III,IV,V,VI,VII,VIII,IX,或X型,一或多种可药用赋形剂。这样的癌症的实例包括骨髓增生异常综合征,急性骨髓性白血病,结肠直肠癌,非小细胞肺癌,和卵巢癌。
本发明的另外的实施方案,包括上面提供的更特别的方面,将在后面的详细说明中得到,或使这些实施方案更明显。
附图的简要说明
图1是I型N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸二氢盐的晶体多晶型物的PXRD扫描图。
图2是II型N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸氢盐的晶体多晶型物的PXRD扫描图。
图3是III型N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲HCl盐的晶体多晶型物的PXRD扫描图。
图4是IV型N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐的晶体多晶型物的PXRD扫描图。
图5是V型N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸氢盐的晶体多晶型物的PXRD扫描图。
图6是VI型N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸氢盐的晶体多晶型物的PXRD扫描图。
图7是VII型N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲抗坏血酸盐的晶体多晶型物的PXRD扫描图。
图8是VIII型N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲马来酸盐的晶体多晶型物的PXRD扫描图。
图9是IX型N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲硫酸盐的晶体多晶型物的PXRD扫描图。
图10是X型N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲磷酸盐的晶体多晶型物的PXRD扫描图。
详细说明
本发明包括结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的盐。N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲游离碱的制备如上面引用的美国专利申请No. 12/632183的实施例1所举例说明,其全部公开以引证的方式包括在本文中。为方便起见本文使用术语“游离碱”,用来指N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的母体化合物,以区别于其任何盐。
本领域技术人员将也会理解术语“一水合物”,当提及N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲时,是指每分子的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲存在一个水分子。本领域技术人员将也会理解术语“四水合物”,当提及N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲时,是指每分子的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲存在四个水分子。
在一个实施方案中,本发明包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸盐。
在本发明一个实施方案中包括以固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸盐的结晶形式,其中结晶形式是I型,特征至少在于在下列位置的任何一个或多个处的粉末X射线衍射峰∶6.14,10.70,19.54,21.22,23.14,24.00°2θ,± 0.2°2θ,本文定义为I型。或者,本发明包括型I型,特征至少在于在每个所述位置处的粉末X射线衍射峰。在又一个实施方案中本发明包括型I型,特征至少在于在每个所述位置处的粉末X射线衍射峰∶6.14,9.36,10.70,11.68,12.28,13.30,16.32,16.54,16.97,18.47,19.54,21.22,21.50,23.14,23.46,23.68,24.00° 2θ,± 0.2° 2θ。
在一个实施方案中,本发明包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸盐。
在本发明一个实施方案中包括以固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸盐的结晶形式,其中结晶形式是II型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶6.21,8.88,10.28,10.64,19.18,20.58,21.16,21.38,21.75,22.50,22.86,23.86,24.50,24.92° 2θ,± 0.2° 2θ,本文定义为II型。或者,本发明包括型II型,特征至少在于在每个所述位置处的粉末X射线衍射峰。在又一个实施方案中,本发明包括II型,特征至少在于在每个所述位置处的粉末X射线衍射峰∶6.21,8.88,10.28,10.64,11.96,12.44,12.76,15.93,18.48,19.18,20.58,21.16,21.38,21.75,22.50,22.86,23.86,24.50,24.92° 2θ,± 0.2° 2θ。
在一个实施方案中,本发明包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲HCl盐。
在本发明一个实施方案中,包括以固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲HCl盐的结晶形式,其中结晶形式是III型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.80,6.36,8.00,9.71,10.22,13.63,16.66,18.69,19.49,19.77,21.59,22.35,22.76° 2θ,± 0.2° 2θ,本文定义为IV型。或者,本发明包括IV型,特征至少在于在每个所述位置处的粉末X射线衍射峰。在又一个实施方案中,本发明包括IV型,特征至少在于在每个所述位置处的粉末X射线衍射峰∶5.37,7.40,10.69,11.92,14.31,16.04,18.02,18.39,18.78,20.42,21.20° 2θ,± 0.2° 2θ。
在一个实施方案中,本发明包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐。
在本发明一个实施方案中,包括以固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐的结晶形式,其中结晶形式是IV型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.37,7.40,10.69,18.39,18.78,20.42,21.20° 2θ,± 0.2° 2θ,本文定义为IV型。或者,本发明包括IV型,特征至少在于在每个所述位置处的粉末X射线衍射峰。在又一个实施方案中,本发明包括IV型,特征至少在于在每个所述位置处的粉末X射线衍射峰∶5.37,7.40,10.69,11.92,14.31,16.04,18.02,18.39,18.78,20.42,21.20° 2θ,± 0.2° 2θ。
在一个实施方案中,本发明包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸氢盐。
在本发明一个实施方案中,包括以固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸氢盐的结晶形式,其中结晶形式是V型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶3.04,3.80,7.62,16.12,23.58° 2θ,± 0.2° 2θ,本文定义为V型。或者,本发明包括V型,特征至少在于在每个所述位置处的粉末X射线衍射峰。在又一个实施方案中,本发明包括V型,特征至少在于在每个所述位置处的粉末X射线衍射峰∶2.70,3.04,3.80,5.64,6.58,7.62,16.12,16.55,18.68,19.10,19.83,21.81,23.00,23.58° 2θ,± 0.2° 2θ。
在一个实施方案中,本发明包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸氢盐。
在本发明一个实施方案中,包括以固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸氢盐的结晶形式,其中结晶形式是VI型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶6.10,8.72,15.76° 2θ,± 0.2° 2θ,本文定义为VI型。或者,本发明包括VI型,特征至少在于在每个所述位置处的粉末X射线衍射峰。在又一个实施方案中,本发明包括VI型,特征至少在于在每个所述位置处的粉末X射线衍射峰∶6.10,8.72,10.67,11.25,13.08,15.27,15.76,17.46,18.27,18.77,19.42° 2θ,± 0.2° 2θ。
在一个实施方案中,本发明包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲抗坏血酸盐。
在本发明一个实施方案中,包括以固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲抗坏血酸盐的结晶形式,其中结晶形式是VII型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.20,16.01,17.44,18.83° 2θ,± 0.2° 2θ,本文定义为VII型。或者,本发明包括VII型,特征至少在于在每个所述位置处的粉末X射线衍射峰。在又一个实施方案中,本发明包括VII型,特征至少在于在每个所述位置处的粉末X射线衍射峰∶4.62,5.20,6.99,9.09,9.66,10.40,13.96,16.01,17.44,18.83,20.93,22.52,22.80,24.13° 2θ,± 0.2° 2θ。
在一个实施方案中,本发明包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲马来酸盐。
在本发明一个实施方案中,包括以固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲马来酸盐的结晶形式,其中结晶形式是VIII型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.00,15.23,19.79,23.63° 2θ,± 0.2° 2θ,本文定义为VIII型。或者,本发明包括VIII型,特征至少在于在每个所述位置处的粉末X射线衍射峰。在又一个实施方案中,本发明包括VIII型,特征至少在于在每个所述位置处的粉末X射线衍射峰∶5.00,8.10,9.30,10.00,11.11,12.22,13.67,15.23,16.85,18.37,19.79,23.63° 2θ,± 0.2° 2θ。
在一个实施方案中,本发明包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲硫酸盐。
在本发明一个实施方案中,包括以固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲硫酸盐的结晶形式,其中结晶形式是IX型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶3.85,7.67,11.23,16.87° 2θ,± 0.2° 2θ,本文定义为IX型。或者,本发明包括IX型,特征至少在于在每个所述位置处的粉末X射线衍射峰。在又一个实施方案中,本发明包括IX型,特征至少在于在每个所述位置处的粉末X射线衍射峰∶3.85,5.62,6.70,6.91,7.67,11.23,11.53,12.99,16.87,17.42° 2θ,± 0.2° 2θ。
在一个实施方案中,本发明包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲磷酸盐。
在本发明一个实施方案中,包括以固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲磷酸盐的结晶形式,其中结晶形式是X型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.85,6.57,6.91,20.85° 2θ,± 0.2° 2θ,本文定义为X型。或者,本发明包括X型,特征至少在于在每个所述位置处的粉末X射线衍射峰。在又一个实施方案中,本发明包括X型,特征至少在于在每个所述位置处的粉末X射线衍射峰∶5.85,6.57,6.91,13.83,17.65,18.74,19.12,20.85° 2θ,± 0.2° 2θ。
结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的盐,例如 I,II,III,IV,V,VI,VII,VIII,IX,或X型,可以有效用作API用于制备适合于以任何给药途径,包括口服给予需要其的患者的药物组合物。其它给药途径包括但不限于肠胃外,舌下,口腔,鼻内,肺,局部,透皮,皮内,眼睛,耳部,直肠,阴道,胃内,颅内,滑膜内和关节内的途径。
在希望提供在溶液中的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的盐的情况下,例如I,II,III,IV,V,VI,VII,VIII,IX,或X型,例如在用于口服或肠胃外给药的液体制剂的情况下,当然在这样的制剂中不会存在结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲柠檬酸盐;实际上,在这样的制剂中晶体的存在通常是不希望有的。然而,尽管如此,本发明的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的结晶性盐在制备这样的制剂的方法中作为API是重要的。
甚至在所希望的制剂是含有非晶态的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的盐,例如在固态分散体制剂的情况下,还可以在制备这样的制剂的方法中使用N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的结晶性盐作为API。
作为API,结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的盐,例如I,II,III,IV,V,VI,VII,VIII,IX,或X型,比非晶态具有优点。例如,与非晶态相反,在API是晶体的情况下,将API纯化至大多数管理机关所要求的高纯度是更有效的,且因此成本减少。由于物理和化学稳定性,API固体的贮存期限典型地晶体好于非晶态。操作的方便性比非晶态有改善,非晶态倾向于油状或粘稠。在结晶物质的情况下,干燥更直接且更容易控制,其比非晶形物质具有明确的干燥或去溶剂化温度,非晶形物质对于有机溶剂具有更大的亲合性且没有明确的干燥温度。使用晶体API的后续加工容许提高的工艺控制。这些优点是例证性的而非限制性的。
当将组合物按照合适的方案给予需要的患者时,N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲以治疗有效的数量存在于本发明的药物组合物中。典型地,可以合适的频率例如每日两次至每周一次给予的单位剂量(单次给予的数量)是大约10至大约1,000 mg,取决于所讨论的化合物。在给予频率是每日一次(q.d.)的情况下,单位剂量和日剂量是相同的。举例说明,单位剂量典型地是大约25至大约1,000
mg,更典型地是大约50至大约500
mg,例如大约50,大约100,大约150,大约200,大约250,大约300,大约350,大约400,大约450或大约500 mg。
赋形剂包括但不局限于,例如,密封材料和添加剂例如吸收促进剂,抗氧化剂,粘合剂,缓冲剂,载体,涂布剂,着色剂,稀释剂,崩解剂,乳化剂,膨胀剂,填料,调味剂,助流剂,保湿剂,润滑剂,香料,防腐剂,发射剂,防粘剂,杀菌剂,甜味剂,增溶剂,润湿剂,其混合物等等。
制备以固体剂型方式口服给药的包括N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的晶体盐I,II,III,IV,V,VI,VII,VIII,IX,或X型的制剂或由其制成的制剂的赋形剂包括,例如,琼脂,海藻酸,氢氧化铝,苯甲醇,苯甲酸苄酯,1,3-丁二醇,卡波姆,蓖麻油,纤维素,醋酸纤维素,可可脂,共聚维酮,玉米淀粉,玉米油,棉子油,交聚维酮,甘油二酯,乙醇,乙基纤维素,月桂酸乙酯,油酸乙酯,脂肪酸酯,明胶,胚芽油,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,甘露糖醇,甘油一酯,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,山梨糖醇钠,硬脂基富马酸钠,大豆油,硬脂酸,硬脂基延胡索酸酯,蔗糖,表面活化剂,滑石粉,黄芪胶,四氢糠醇,甘油三酯,维生素E和它们的衍生物,水,其混合物等等。
制备以液体剂型眼科或口服给药的、包括N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的晶体盐I,II,III,IV,V,VI,VII,VIII,IX,或X型的组合物或由其制成的组合物的赋形剂包括,例如,1,3-丁二醇,蓖麻油,玉米油,棉子油,乙醇,脱水山梨糖醇的脂肪酸酯,胚芽油,花生油,甘油,异丙醇,橄榄油,聚乙二醇,丙二醇,芝麻油,水,其混合物等等。
制备渗透给药的包括N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的晶体盐I,II,III,IV,V,VI,VII,VIII,IX,或X型的组合物或由其制成的组合物的赋形剂包括,例如,氯氟烃,乙醇,水,其混合物等等。
制备胃肠外给药的包括N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的晶体盐I,II,III,IV,V,VI,VII,VIII,IX,或X型的组合物或由其制成的组合物的赋形剂包括,例如,1,3-丁二醇,蓖麻油,玉米油,棉子油,葡萄糖,胚芽油,花生油,脂质体,油酸,橄榄油,花生油,林格溶液,红花油,芝麻油,大豆油,U.S.P.或等渗氯化钠溶液,水,其混合物等等。
制备直肠或阴道给药的包括N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的晶体盐I,II,III,IV,V,VI,VII,VIII,IX,或X型的组合物或由其制成的组合物的赋形剂包括,但不局限于,可可脂,聚乙二醇,蜡,其混合物等等。
通常以提供治疗有效的药物日剂量的数量给予组合物。本文的术语“日剂量”是指每天给予的药物的量,不考虑给予频率。例如,如果患者每日两次接受150
mg的单位剂量,日剂量是300 mg。使用术语“日剂量”将被理解为并不意味着规定的剂量一定是每日一次给予。然而,在特别的实施方案中,给药频率是每日一次(q.d.),则日剂量与单位剂量在此实施方案中是相同的。
构成治疗有效剂量的因素取决于具体的化合物、患者(包括患者的种类和体重)、要治疗的疾病(例如癌症的具体类型)、疾病的阶段和/或严重程度、个体患者对化合物的耐受性、化合物是单疗法给予还是与一或多种其它药物例如治疗癌症的其它化疗药物组合给予、及其它因素。因此日剂量可以在宽的范围之内变化,例如从大约10至大约1,000 mg。在特定的状况下,更大或较小的每日剂量可能是合适的。很清楚,本文中讲述的“治疗有效”剂量在本文中未必是要求该药物是在给予单一的这样剂量时是治疗有效的;典型地,治疗效果取决于按照与合适的频率和给予时间有关的方案所要重复给予的组合物。在选择的日剂量足以提供在治疗癌症方面的益处时,特别优选该剂量不应该足以引起不利的副作用至无法接受的或无法忍受的程度。合适的治疗有效剂量可基于本文的公开内容和本文引用的技术,由常规技术人员医生在考虑了例如上述的那些因素的情况下无需过度实验就可选择。医生可以例如对一个癌症患者开始给予一个相对低日剂量的治疗过程,和在几天或几周的期间内逐步向上调高剂量,以减少不利的副作用的危险。
举例说明,N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的合适剂量通常是大约10至大约1,000 mg/天,更典型地大约50至大约500 mg/天或大约200至大约400 mg/天,例如大约50,大约100,大约150,大约200,大约250,大约300,大约350,大约400,大约450或大约500 mg/天,给药的平均间隔为3至10天,或大约4至8天,或大约7天。
包括本发明的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的晶体盐I,II,III,IV,V,VI,VII,VIII,IX,或X型(或用作API制备的)的组合物适合于在单疗法或在例如与其它化疗药物或与电离辐射的联合治疗中使用。
包括本发明的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的晶体盐I,II,III,IV,V,VI,VII,VIII,IX,或X型(或用作API制备的)的组合物可以在与一或多种治疗试剂的联合治疗中给予,治疗试剂包括,但不局限于,烷基化剂,血管生成抑制剂,抗体,代谢拮抗剂,抗有丝分裂剂,抗增殖剂,抗病毒剂,极光激酶抑制剂,其它细胞程序死亡启动子(例如,Bcl-xL,Bcl-w和Bfl-1抑制剂),死亡受体途径的活化剂,Bcr-Abl激酶抑制剂,BiTE(双-特异T细胞接合器)抗体,抗体-药物共轭物,生物反应调节物,依赖细胞周期蛋白的激酶(CDK)抑制剂,细胞周期抑制剂,环加氧酶-2(COX-2)抑制剂,双重变量域结合蛋白(DVDs),人表皮生长因子受体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,激素治疗,免疫,细胞程序死亡蛋白抑制剂(IAPs),插入抗生素,激酶抑制剂,驱动蛋白抑制剂,JAK2抑制剂,哺乳动物靶向的雷帕霉素(mTOR)抑制剂,microRNAs,丝裂原-活化的胞外信号调节激酶(MEK)抑制剂,多价结合蛋白,非甾体抗炎药物(NSAIDs),聚-ADP(腺苷二磷酸)-核糖聚合酶(PARP)抑制剂,铂化疗药物,Polo类激酶(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,德尔托伊德α-β黄酮(deltoids),植物生物碱,小抑制核醣核酸(siRNAs),拓扑异构酶抑制剂,泛素连接酶抑制剂,等等。
BiTE是双特异的抗体,其通过同时与两个细胞结合指引T细胞去攻击癌细胞。然后T细胞攻击靶向癌细胞。BiTE抗体的实例包括,但不局限于,阿德木单抗(Micromet
MT201),blinatumomab(Micromet MT103)等等。不受理论的限制,T细胞引起靶向癌细胞细胞程序死亡的机理之一是通过溶细胞的颗粒剂组分的胞吐作用,其包括穿孔素和粒酶B。在这方面,已经表明Bcl-2可衰减穿孔素和粒酶B两者的细胞程序死亡诱导作用。这些数据说明了Bcl-2的抑制可以提高当靶向癌细胞时由T细胞引起的细胞毒素效果(Sutton等人,(1997)J.Immunol.
158∶5783-5790)。
SiRNAs是具有内源RNA碱基或化学上修饰的核苷酸的分子。该修饰不会消除细胞活性,而是赋予增加的稳定性和/或增加细胞的效能。化学修饰的实例包括硫代磷酯基团,2'-脱氧核苷酸,含有2'-OCH3-的核苷酸,2'-F-核苷酸,2'-甲氧基乙基核苷酸,其组合等等。siRNA可以具有变化的长度(例如,10-200 bps)和结构(例如,发夹形物,单/双链,突起,凹隙/缺口染色体,错位),且在细胞中加工以提供活性基因沉默。双-链siRNA(dsRNA)在每个链(钝端)或非对称端(突出端)上具有相同的核苷酸数目。1-2核苷酸的突出端可以在正义和/或反义链上存在,以及在所给链的5'-和/或3'-端上存在。例如,已经表明siRNAs靶向的Mcl-1可提高ABT-263或ABT-737在各种肿瘤细胞品系中的活性(Tse等人,(2008) Cancer
Res. 68∶3421-3428 和其中包含的参考文献)。
多价结合蛋白是包括两个或多个抗原结合位点的结合蛋白。可将多价结合蛋白工程化为具有三个或多个抗原结合位点,其通常不是天然存在的抗体。术语“多特异性结合蛋白”是指能够结合两个或多个相关或无关靶向的结合蛋白。双重变量域(DVD)结合蛋白是包括两个或多个抗原结合位点的四价或多价的结合蛋白。这样的DVDs可以是单特异性的(即,能够结合一个抗原)或多特异性的(即,能够结合两个或多个抗原)。包括两个重链DVD多肽和两个轻-链DVD多肽的DVD结合蛋白被称为DVD Ig’s。每半个DVD Ig包括一个重链DVD多肽和一个轻-链DVD多肽和两个抗原结合位点。每个结合位点包括一个重链可变域和一个轻-链可变域,每个抗原结合位点具有涉及抗原结合的总共6
CDRs。
烷基化剂包括六甲蜜胺,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,达卡巴嗪,雌莫司汀,福莫司汀,葡膦酰胺,异环磷酰胺,KW-2170,环己亚硝脲(CCNU),马磷酰胺(mafosfamide),苯丙氨酸氮芥,二溴甘露醇,二溴卫矛醇,嘧啶亚硝脲,氮芥N氧化物,雷莫司汀(Ranimustine),替莫唑胺,硫替派,曲奥舒凡(treosμlfan),氯乙环磷酰胺等等。
血管生成抑制剂包括表皮生长因子受体(EGFR)抑制剂,内皮-特异的受体酪氨酸激酶(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,血小板衍生的生长因子受体(PDGFR)抑制剂,凝血栓蛋白类似物,血管内皮生长因子受体酪氨酸激酶(VEGFR)抑制剂等等。
代谢拮抗剂包括AlimtaTM(培美曲唑(Pemetrexed)二钠,LY231514,MTA),5-阿扎胞苷,XelodaTM
(卡培他滨),卡莫氟,LeustatTM(克拉屈滨),氯法拉滨,阿糖胞苷,阿糖胞苷十八烷基磷酸钠,胞嘧啶阿拉伯糖苷,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-羧酰胺),依诺他滨,乙烯基胞苷,氟达拉滨,5-氟尿嘧啶(5-FU)单独或与亚叶酸组合,GemzarTM(吉西他滨),羟基脲,AlkeranTM(苯丙氨酸氮芥),巯基嘌呤,6-巯基嘌呤核糖核苷,氨甲喋呤,霉酚酸,奈拉滨,诺拉曲特(nolatrexed),十八烷基磷酸钠,吡利曲索,喷司他丁,雷替曲塞(raltitrexed),利巴韦林,S-1,triapine,三甲曲沙,TS-1,噻唑呋啉,替加氟,阿糖腺苷,UFT等等。
抗病毒剂包括利托那韦,羟氯奎等等。
极光激酶抑制剂包括ABT-348,AZD-1152,MLN-8054,VX-680,极光A-特异的激酶抑制剂,极光B-特异的激酶抑制剂,泛极光激酶抑制剂等等。
不同于ABT-263或本文的式I化合物的 Bcl-2家族蛋白抑制剂包括AT-101((-)棉子酚),GenasenseTM
Bcl-2-靶向反义寡核苷酸(G3139或奥利默森(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)等等。
Bcr-Abl激酶抑制剂包括达沙替尼(BMS-354825),GleevecTM(伊马替尼)等等。
CDK抑制剂包括AZD-5438,BMI-1040,BMS-387032,CVT-2584,夫拉平度(flavopyridol),GPC-286199,MCS-5A,PD0332991,PHA-690509,seliciclib(CYC-202
或R-roscovitine),ZK-304709 等等。
COX-2
抑制剂包括ABT-963,ArcoxiaTM(默沙东),BextraTM(伐地考昔),BMS-347070,CelebrexTM(西乐葆),COX-189(罗美昔布(lumiracoxib)),CT-3,DeramaxxTM(德拉昔布(deracoxib)),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(默沙东),NS-398,帕瑞考营,RS-57067,SC-58125,SD-8381,SVT-2016,S-2474,T-614,VioxxTM(罗非考昔)等等。
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(埃洛替尼或OSI-774),TP-38,EGFR融合蛋白,TykerbTM(拉帕替尼(lapatinib))等等。
ErbB2
受体抑制剂包括CP-724714,CI-1033(卡拉替尼(Canertinib)),HerceptinTM(曲妥珠单抗),TykerbTM(拉帕替尼(lapatinib)),OmnitargTM(2C4,帕妥珠单抗(petuzumab)),TAK-165,GW-572016(ionafamib),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 HER2三官能双特异性抗体,mAB AR-209,mAB 2B-1 等等。
组蛋白脱乙酰基酶抑制剂包括缩酚酸肽,LAQ-824,MS-275,trapoxin,辛二酰苯胺异羟肟酸(SAHA),TSA,丙戊酸等等。
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(对HSP-90的人重组体抗体),nab-17AAG,NCS-683664,PU24FCl,PU-3,根赤壳菌素,SNX-2112,STA-9090,VER-49009 等等。
细胞程序死亡蛋白抑制剂包括HGS-1029,GDC-0145,GDC-0152,LCL-161,LBW-242 等等。
抗体-药物共轭物包括抗CD22-MC-MMAF,抗CD22-MC-MMAE,抗CD22-MCC-DM1,CR-011-vcMMAE,PSMA-ADC,MEDI-547,SGN-19A,SGN-35,SGN-75 等等。
死亡受体途径的活化剂包括TRAIL和抗体或其它靶向TRAIL或死亡受体(例如,DR4和DR5)的试剂例如apomab,Conatumumab,ETR2-ST01,GDC0145(来沙木单抗(lexatumumab)),HGS-1029,LBY-135,PRO-1762,曲妥珠单抗等等。
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,等等。
JAK2 抑制剂包括CEP-701(lesaurtinib),XL019,INCB-018424 等等。
MEK 抑制剂包括ARRY-142886,ARRY-438162,PD-325901,PD-98059 等等。
mTOR 抑制剂包括AP-23573,CCI-779,依维莫司,RAD-001,雷帕霉素,西罗莫司(temsirolimus),ATP-竞争性的TORC1/TORC2抑制剂,包括PI-103,PP242,PP30 和Torin1,等等。
非甾体抗炎症的药物包括AmigesicTM(双水杨酯),DolobidTM(二氟尼柳),MotrinTM(布洛芬),OrudisTM(酮洛芬),RelafenTM(萘丁美酮),FeldeneTM(吡罗昔康),布洛芬乳膏剂,AleveTM和NaprosynTM(萘普生),VoltarenTM(双氯芬酸),IndocinTM(消炎痛),ClinorilTM(舒林酸),TolectinTM(甲苯酰吡酸),LodineTM(依托度酸),ToradolTM(酮咯酸),DayproTM(奥沙普秦)等等。
PDGFR抑制剂包括 CP-673451,CP-868596
等等。
铂化疗药物包括顺铂,EloxatinTM(奥沙利铂),依他铂,乐铂,奈达铂,ParaplatinTM(卡铂),picoplatin,沙铂等等。
Polo类激酶抑制剂包括BI-2536等等。
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 等等。
凝血栓蛋白类似物包括ABT-510,ABT-567,ABT-898,TSP-1 等等。
VEGFR抑制剂包括AvastinTM(贝伐单抗),ABT-869,AEE-788,AngiozymeTM(抑制血管生成的核糖酶(核糖酶药物(Boμlder,CO)和希龙(Emeryville,CA)),阿西替尼(axitinib)(AG-13736),AZD-2171,CP-547632,IM-862,MacugenTM(哌加他尼(pegaptanib)),NexavarTM(索拉非尼(sorafenib),BAY43-9006),帕唑帕尼(pazopanib)(GW-786034),瓦他拉尼(vatalanib)(PTK-787或ZK-222584),SutentTM(舒尼替尼(Sunitinib)或SU-11248),VEGF捕获剂,ZactimaTM(凡德他尼(vandetanib)或ZD-6474)等等。
抗生素包括插入抗生素例如阿柔比星,放线菌素D,氨柔比星,蒽环霉素(annamycin),AdriamycinTM(多柔比星),BlenoxaneTM(博来霉素),柔红霉素,CaelyxTM和MyocetTM(脂质体多柔比星),依沙芦星,表柔比星,glarubicin,伊达比星,丝裂霉素C,奈莫柔比星,新制癌菌素(neocarzinostatin),硫酸培洛霉素,吡柔比星,蝴蝶霉素(rebeccamycin),净司他丁(stimalamer),链脲霉素,ValstarTM(戊柔比星(valrubicin)),新制癌菌素(zinostatin)等等。
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(belotecan),BN-80915,CamptosarTM(依立替康盐酸盐),喜树碱,CardioxaneTM(右雷佐生),二氟替康(diflomotecan),伊朵堤卡林(edotecarin),EllenceTM和PharmorubicinTM(表柔比星),依托泊苷,依沙替康(exatecan),10-羟基喜树碱,吉马替康,勒托替康,米托蒽醌,卢比替康(orathecin),吡柔比星(pirarbucin),匹杉琼(pixantrone),鲁比替康,索布佐生,SN-38,tafluposide,托泊替康等等。
抗体包括AvastinTM(贝伐单抗),CD40-特异的抗体,chTNT-1/B,denosumab,ErbituxTM(西妥昔单抗),Humax-CD4TM(zanolimumab),IGF1R-特异的抗体,林妥珠单抗,PanorexTM(依决洛单抗),RencarexTM(WX
G250),RituxanTM(美罗华),ticilimumab,曲妥珠单抗,CD20抗体I和II型等等。
激素治疗包括ArimidexTM(阿那曲唑),AromasinTM(依西美坦),阿佐昔芬,CasodexTM(比卡鲁胺),CetrotideTM(西曲瑞克),地盖瑞利(degarelix),地洛瑞林,DesopanTM(曲洛司坦),地塞米松,DrogenilTM(氟他胺),EvistaTM(雷诺昔酚),AfemaTM(法屈唑),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(doxercalciferol)),RenagelTM(司维拉姆(sevelamer)碳酸酯),拉索昔芬,亮丙瑞林乙酸酯,MegaceTM(甲地孕酮),MifeprexTM(美服培酮),NilandronTM(尼鲁米特),它莫西芬包括NolvadexTM(枸橼酸它莫西芬),PlenaxisTM(阿倍瑞克(Abarelix)),脱氢可的松,PropeciaTM(非那雄胺),rilostane,SuprefactTM(布舍瑞林),促黄体素释放激素(LHRH)包括TrelstarTM(曲普瑞林),组氨瑞林(histrelin)包括VantasTM(组氨瑞林(histrelin)植入物),ModrastaneTM(曲洛司坦),ZoladexTM(戈舍瑞林)等等。
德尔托伊德α-β黄酮(Deltoids)和类视黄醇包括西奥骨化醇(seocalcitol)(EB1089或
CB1093),来沙骨化醇(lexacalcitol)(KH1060),芬维A胺(fenretinide),PanretinTM(alitretinoin),维甲酸包括AtragenTM(脂质体维甲酸),TargretinTM(贝沙罗汀(bexarotene)),LGD-1550等等。
PARP抑制剂包括 ABT-888,olaparib,KU-59436,AZD-2281,AG-014699,BSI-201,BGP-15,INO-1001,ONO-2231 等等。
植物生物碱包括长春花新碱,长春碱,去乙酰长春酰胺,长春瑞宾等等。
蛋白酶体抑制剂包括VelcadeTM(硼替佐米(Bortezomib)),MG132,NPI-0052,PR-171 等等。
免疫试剂的例子包括干扰素及其它免疫-提高试剂。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),干扰素γ-n1,其组合等等。其它试剂包括Alfaferone(IFN-α,BAM-002(氧化型谷胱甘肽),BeromunTM(他索纳明(tasonermin)),BexxarTM(托西莫单抗(tositumomab)),CampathTM(阿仑单抗(alemtuzumab)),CTLA4(细胞毒素淋巴细胞抗原4),达卡巴嗪,地尼白介素(denileukin),依帕珠单抗,GranocyteTM(来格司亭),蘑菇多糖,白细胞α干扰素,咪喹莫特,MDX-010(抗CTLA-4),黑素瘤疫苗,米妥莫单抗(mitumomab),莫拉司亭,MylotargTM(吉妥珠单抗奥唑米星(gemtuzumab
ozogamicin)),NeupogenTM(非格司亭),OncoVAC-CL,OvarexTM(oregovomab),pemtumomab(Y-muHMFG1),ProvengeTM(sipuleucel-T),sargaramostim,西佐喃,替西白介素(teceleukin),TheracysTM(BCG或卡介苗),乌苯美司,VirμlizinTM(免疫治疗剂,Lorus Pharmaceuticals),Z-100(Maruyama或SSM的特异物质),WF-10(四氯十氧化物(tetrachlorodecaoxide)或TCDO),ProleukinTM(阿地白介素),ZadaxinTM(胸腺法新(thymalfasin)),ZenapaxTM(达(克)珠单抗),ZevalinTM(90Y-替伊莫单抗(ibritumomab tiuxetan))等等。
生物反应调节物是改进生物机体的防卫机理或生物学反应,例如组织细胞的存活,生长或分化以它们至具有抗肿瘤活性的试剂,和包括云芝多糖K(krestin),蘑菇多糖,西佐喃,溶链菌制剂(picibanil),PF-3512676(CpG-8954),乌苯美司等等。
嘧啶类似物包括阿糖胞苷(胞嘧啶阿拉伯糖苷,ara C或阿拉伯糖苷C),去氧氟尿苷,FludaraTM(氟达拉滨),5-FU(5-氟尿嘧啶),氮尿苷,GemzarTM(吉西他滨),TomudexTM(雷替曲塞(raltitrexed)),三乙酰尿苷,TroxatylTM(曲沙他滨(troxacitabine))等等。
嘌呤类似物包括LanvisTM(硫鸟嘌呤),PurinetholTM(巯基嘌呤)等等。
抗有丝分裂剂包括巴他布林(batabμlin),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(ixabepilone)(BMS-247550),太平洋紫杉醇,TaxotereTM(多西他赛),拉洛他赛(larotaxel)(PNU-100940,RPR-109881或XRP-9881),伊沙匹隆(patupilone),长春氟宁,ZK-EPO(合成的埃坡霉素)等等。
泛素连接酶抑制剂包括MDM2抑制剂例如nutlins,NEDD8抑制剂例如MLN4924,等等。
包括N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的晶体盐I,II,III,IV,V,VI,VII,VIII,IX,或X型(或用作API制备的)的组合物可以用作放射致敏剂以提高放疗效果。放疗的例子包括,但不局限于,外束放疗(XBRT),远距离治疗,近距疗法,密封源放疗,未密封源放疗等等。
另外或者替代地,包括N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的晶体盐I,II,III,IV,V,VI,VII,VIII,IX,或X型(或用作API制备的)的组合物可以在与选自下列的一或多种抗肿瘤或化学治疗剂的联合治疗中给予;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),一种合成的RNA),AptosynTM(依昔舒林(exisμlind)),ArediaTM(帕米膦酸),arglabin,左天冬酰胺酶,阿他美坦(1-甲基-3,17-二酮-雄烷-1,4-二烯),AvageTM(维生素A酸(tazarotene)),AVE-8062(康普瑞汀衍生物),BEC2(米妥莫单抗(mitumomab)),恶液质素或cachexin(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(二盐酸组按),CervarixTM(AS04助剂-吸附的人乳头状瘤病毒(HPV)疫苗),CHOP(CytoxanTM(环磷酰胺)+
AdriamycinTM(多柔比星)+ OncovinTM(长春花新碱)+脱氢可的松),康普瑞汀A4P,CypatTM(环丙孕酮),DAB(389)EGF(借助于His-Ala连接基与人表皮生长因子稠合的白喉毒素的催化和迁移域),达卡巴嗪,放线菌素,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(乙炔尿嘧啶(ethynyluracil)),角鲨胺(squalamine)包括EvizonTM(角鲨胺乳酸酯),enzastaurin,EPO-906(埃坡霉素B),GardasilTM(四价人乳头状瘤病毒(类型6,11,16,18)重组体疫苗),GastrimmuneTM,GenasenseTM(奥利默森(oblimersen)),GMK(神经节糖苷共轭物疫苗),GVAXTM(前列腺癌症疫苗),卤夫酮(halofuginone),组氨瑞林(histerelin),羟基脲,依班膦酸,IGN-101,IL-13-PE38,IL-13-PE38QQR(cintredekin
besudotox),IL-13-假单胞菌属外毒素,干扰素-α,干扰素-γ,JunovanTM和 MepactTM(米伐木肽(mifamurtide)),洛那法尼(lonafarnib),5,10-methylenetetrahydrofolate,米特福辛(十六烷基磷酸胆碱),NeovastatTM(AE-941),NeutrexinTM(三甲曲沙葡糖醛酸盐),NipentTM(喷司他丁),OnconaseTM(豹蛙酶(RANPIRNASE),一种核糖核酸酶酶),OncophageTM(维特斯朋(vitespen),黑素瘤疫苗治疗),OncoVAXTM(IL-2疫苗),OrathecinTM(鲁比替康),OsidemTM(基于抗体的细胞药物),OvarexTM MAb(鼠单克隆抗体),太平洋紫杉醇白蛋白-稳定化纳米颗粒,太平洋紫杉醇,PandimexTM(糖苷配基皂草苷从人参包括20(S)-原人参萜二醇(aPPD)和20(S)-原人参萜三醇(aPPT)),帕尼单抗(panitumumab),PanvacTM-VF(调查研究的癌症疫苗),培加帕酶,聚乙二醇化干扰素α(PEG干扰素A),苯妥帝尔(phenoxodiol),普鲁苄肼,瑞马司他(rebimastat),RemovabTM(Catumaxomab),RevlimidTM(来那度胺(lenalidomide)),RSR13(乙丙昔罗(efaproxiral)),SomatulineTM LA(兰瑞肽),SoriataneTM(阿维A),星孢菌素(链霉菌属星状孢子),talabostat(PT100),TargretinTM(贝沙罗汀(bexarotene)),TaxoprexinTM(二十二碳六烯酸(DHA)+太平洋紫杉醇),TelcytaTM(Canfosfamide,TLK-286),TemodarTM(替莫唑胺),替米利芬(tesmilifene),汉防己碱,反应停,TheratopeTM(STn-KLH疫苗),ThymitaqTM(诺拉曲特(nolatrexed)二盐酸盐),TNFeradeTM(腺病毒载体∶含有针对肿瘤坏死因子-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(retin-A),TrisenoxTM(三氧化二砷),UkrainTM(来源于白屈菜植物的生物碱衍生物),VirulizinTM,VitaxinTM(抗αvβ3抗体),XcytrinTM(莫特沙芬(motexafin)钆),XinlayTM(阿曲生坦(atrasentan)),XyotaxTM(聚谷氨酸紫杉醇(paclitaxel
poliglumex)),YondelisTM(曲贝替定(trabectedin)),ZD-6126(N-乙酰基秋水仙醇-O-磷酸酯),ZinecardTM(右雷佐生),唑来膦酸,佐柔比星等等。
在一个实施方案中,包括N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的晶体盐I,II,III,IV,V,VI,VII,VIII,IX,或X型(或用作API制备的)的组合物以治疗有效量向需要其治疗癌症的患者给药。
实例包括,但不局限于,听神经瘤,急性白血病,急性淋巴细胞性白血病,急性髓细胞性白血病(单核细胞,成髓细胞,腺癌,血管肉瘤,星形细胞瘤,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,子宫颈癌,软骨肉瘤,脊索瘤,绒膜癌,慢性白血病,慢性淋巴细胞性白血病,慢性髓细胞的(粒细胞)白血病,慢性粒细胞白血病,结肠癌,结肠直肠癌,颅咽管瘤,囊腺癌,扩散的大B细胞淋巴瘤,增殖异常性变化(发育异常和组织变形),胚胎性癌,子宫内膜癌,内皮肉瘤,室管膜瘤,上皮癌,红白血病,食道癌,雌激素-受体阳性乳腺癌,特发性血小板增多症,尤因氏瘤,纤维肉瘤,滤泡性淋巴瘤,生殖细胞睾丸癌症,胶质瘤,重链病,成血管细胞瘤,肝癌,肝细胞癌症,激素不敏感的前列腺癌症,平滑肌肉瘤,脂肉瘤,肺癌,淋巴管内皮肉瘤,淋巴管肉瘤,淋巴细胞性白血病,淋巴瘤(霍奇金和非霍奇金),膀胱、乳房、结肠、肺、卵巢、胰腺、前列腺、皮肤和子宫的恶性肿瘤和高增殖性病症,T细胞或B细胞起源的淋巴恶性肿瘤,白血病,淋巴瘤,髓样癌,成髓细胞瘤,黑素瘤,脑膜瘤,间皮瘤,多发性骨髓瘤,粒细胞性白血病,骨髓瘤,粘液肉瘤,神经母细胞瘤,非小细胞肺癌,寡枝神经胶质细胞瘤,口腔癌,骨源性肉瘤,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,实质固态瘤(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,Waldenström’s巨球蛋白血症,睾丸肿瘤,哺乳动物的子宫癌和Wilms’肿瘤。
在更具体的实施方案中,包括本发明的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的晶体盐I,II,III,IV,V,VI,VII,VIII,IX,或X型(或用作API制备的)的组合物以治疗有效量向需要其治疗的患者给药以治疗 骨髓增生异常综合征,急性骨髓性白血病,结肠直肠癌症,非小细胞肺癌,和卵巢癌症。
在本发明更进一步的实施方案中,提供了在哺乳动物中治疗癌症的方法,包括在可药用溶剂或溶剂的混合物中溶解N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的I,II,III,IV,V,VI,VII,VIII,IX,或X型晶体盐,将得到的溶液以治疗有效量对患有该疾病的患者给药。
在本发明更进一步的实施方案中,提供了在哺乳动物中治疗癌症的方法,包括在可药用聚合物载体中分散N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲的I,II,III,IV,V,VI,VII,VIII,IX,或X型晶体盐,将得到的固态分散体以治疗有效量对患有该疾病的患者给药。
实施例
下列实施例是仅仅例证性的,和不会以任何方式限制这一公开内容。
PXRD数据使用配备有曲线位置灵敏探测器和平行束光学装置的G3000衍射仪(Inel
Corp.,Artenay,法国)收集。衍射仪用铜阳极管(1.5 kW细焦点)在40 kV和30 mA下操作。入射束锗单色仪提供单色辐射。使用衰减的直射光束以一度间隔校正衍射仪。使用硅粉线位置参考标准(NIST 640c)检测校准。该仪器使用Symphonix软件(Inel
Corp.,Artenay,法国)电脑控制,并将数据使用Jade软件(version6.5,Materials Data,Inc.,Livermore,CA)分析。将样品装填在铝样品座上并与玻璃载物片水平。
实施例1
N-(4-{4- 氨基 -7-[1-(2- 羟乙基 )-1H- 吡唑 -4- 基 ] 噻吩并 [3,2-c] 吡啶 -3- 基 } 苯基 )-N'-(3- 氟苯基 ) 脲丙二酸盐 I 型的制备
将N-(4-{4-氨基-7-[1-(2-羟乙基)-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(100 mg)悬浮在THF/水混合物(80/20 v/v,500 μL)中。在环境条件下平衡三天之后通过离心过滤收集固体。
表⒈PXRD峰列表∶N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸盐I型
峰位置(° 2θ) |
6.136 |
9.363 |
10.696 |
11.684 |
12.280 |
13.297 |
16.321 |
16.543 |
16.966 |
18.474 |
19.538 |
21.217 |
21.498 |
22.177 |
23.137 |
23.456 |
23.684 |
24.001 |
实施例2
N-(4-{4- 氨基 -7-[1-(2- 羟乙基 )-1H- 吡唑 -4- 基 ] 噻吩并 [3,2-c] 吡啶 -3- 基 } 苯基 )-N'-(3- 氟苯基 ) 脲二氢 L- 酒石酸盐 II 型的制备
将N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸氢盐固体(30 mg)溶于THF/水混合物(80/20 v/v,500 μl)中。在环境条件下平衡六周之后观察到单晶。
表2.PXRD峰列表∶N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸盐II型
峰位置(° 2θ) |
6.205 |
8.879 |
10.277 |
10.644 |
11.958 |
12.436 |
12.763 |
15.933 |
18.479 |
19.181 |
20.581 |
21.155 |
21.382 |
21.745 |
22.504 |
22.861 |
23.855 |
24.500 |
24.916 |
实施例
3
N-(4-{4- 氨基 -7-[1-(2- 羟乙基 )-1H- 吡唑 -4- 基 ] 噻吩并 [3,2-c] 吡啶 -3- 基 } 苯基 )-N'-(3- 氟苯基 ) 脲 HCl 盐 III 型的制备
在40℃磁力搅拌下将N-(4-{4-氨基-7-[1-(2-羟乙基)-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(27 mg)悬浮在2-丙醇(750 μl)中。将盐酸(60 μl,1 N)用2-丙醇(250 μl)稀释。然后在40℃磁力搅拌下向A-968660游离碱悬浮液中慢慢地加入盐酸溶液。在完全加入HCl溶液之后不久观察到结晶。通过离心过滤收集固体。
实施例
4
N-(4-{4- 氨基 -7-[1-(2- 羟乙基 )-1H- 吡唑 -4- 基 ] 噻吩并 [3,2-c] 吡啶 -3- 基 } 苯基 )-N'-(3- 氟苯基 ) 脲 HCl 盐 III 型的制备
在40℃磁力搅拌下将N-(4-{4-氨基-7-[1-(2-羟乙基)-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(126 mg)悬浮在2-丙醇(2.0 mL)中。将盐酸(284 μl,1 N)用2-丙醇(216 μl)稀释。然后在40℃磁力搅拌下向A-968660游离碱悬浮液中慢慢地加入盐酸溶液。在完全加入HCl溶液之后不久观察到结晶。通过离心过滤收集固体。
实施例
5
N-(4-{4- 氨基 -7-[1-(2- 羟乙基 )-1H- 吡唑 -4- 基 ] 噻吩并 [3,2-c] 吡啶 -3- 基 } 苯基 )-N'-(3- 氟苯基 ) 脲 HCl 盐 III 型的制备
在40℃磁力搅拌下将N-(4-{4-氨基-7-[1-(2-羟乙基)-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(89 mg)悬浮在乙醇(2.5 mL)中。将盐酸(380 μl,1 N)用水(620 μl)稀释。然后在40℃磁力搅拌下向A-968660游离碱悬浮液中慢慢地加入盐酸溶液。在完全加入HCl溶液之后不久观察到结晶。通过离心过滤收集固体。
表3.PXRD峰列表∶N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲HCl盐III型
峰位置(° 2θ) |
5.804 |
6.358 |
7.995 |
9.714 |
10.222 |
13.630 |
16.664 |
18.691 |
19.493 |
19.766 |
21.590 |
22.345 |
22.755 |
实施例
6
N-(4-{4- 氨基 -7-[1-(2- 羟乙基 )-1H- 吡唑 -4- 基 ] 噻吩并 [3,2-c] 吡啶 -3- 基 } 苯基 )-N'-(3- 氟苯基 ) 脲甲磺酸盐 IV 型的制备
在40℃磁力搅拌下将N-(4-{4-氨基-7-[1-(2-羟乙基)-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(26 mg)悬浮在二甲基甲酰胺(125 μl)中。然后在40℃磁力搅拌下向A-968660游离碱悬浮液中慢慢地加入甲磺酸(59 μl,1 M)。 加入甲磺酸之后获得澄清溶液。然后在40℃磁力搅拌下将乙腈(150 μl)加入到澄清溶液中。在完全加入酸性溶液之后不久观察到非晶型淀析。将无定形悬浮液加热至80℃,获得澄清溶液,而后自然冷却至环境温度。冷却时观察到结晶。通过离心过滤收集固体。
实施例
7
N-(4-{4- 氨基 -7-[1-(2- 羟乙基 )-1H- 吡唑 -4- 基 ] 噻吩并 [3,2-c] 吡啶 -3- 基 } 苯基 )-N'-(3- 氟苯基 ) 脲甲磺酸盐 IV 型的制备
在40℃磁力搅拌下将N-(4-{4-氨基-7-[1-(2-羟乙基)-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(26 mg)悬浮在乙酸乙酯(100μl)中。然后在40℃磁力搅拌下向A-968660游离碱悬浮液中慢慢地加入甲磺酸(6.6 μl,4 M)。当加入酸性溶液时沉淀出非晶形物质。加入另外的乙酸乙酯(250 μl),并将悬浮液在40℃下搅拌30分钟。通过离心过滤收集固体。
实施例
8
N-(4-{4- 氨基 -7-[1-(2- 羟乙基 )-1H- 吡唑 -4- 基 ] 噻吩并 [3,2-c] 吡啶 -3- 基 } 苯基 )-N'-(3- 氟苯基 ) 脲甲磺酸盐 IV 型的制备
在45℃磁力搅拌下将N-(4-{4-氨基-7-[1-(2-羟乙基)-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(71 mg)悬浮在乙酸乙酯(1.0 mL)中。然后在40℃磁力搅拌下向A-968660游离碱悬浮液中慢慢地加入甲磺酸(36 μl,4 M)。当加入酸性溶液时沉淀出非晶形物质。将悬浮液在40℃搅拌过夜。通过离心过滤收集固体。
表4.PXRD峰列表∶N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐IV型
峰位置(° 2θ) |
5.37 |
7.399 |
10.687 |
11.921 |
14.311 |
16.043 |
18.017 |
18.385 |
18.784 |
20.416 |
21.195 |
实施例
9
∶
N-(4-{4- 氨基 -7-[1-(2- 羟乙基 )-1H- 吡唑 -4- 基 ] 噻吩并 [3,2-c] 吡啶 -3- 基 } 苯基 )-N'-(3- 氟苯基 ) 脲酒石酸氢盐 V 型的制备
L-酒石酸饱和溶液是在25℃下通过将酒石酸溶解在85/15
v/v THF/水的混合物中制备的。将此溶液(2 mL)加热2至65℃。然后加入大约200 mg的N-(4-{4-氨基-7-[1-(2-羟乙基)-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,其容易溶解。在30分钟之内从此澄清溶液中结晶出N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸氢盐。然后用饱和L-酒石酸溶液(在25℃)稀释浆液,而后冷却至环境温度。继续搅拌浆液过夜,并将该固体借助于过滤分离。将过滤的固体用85/15
v/v THF/水混合物洗涤,以除去过量的L-酒石酸,而后在烘箱中在45℃下干燥。
表5.PXRD峰列表∶N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐V型
峰位置(° 2θ) |
2.696 |
3.038 |
3.796 |
5.641 |
6.579 |
7.615 |
16.124 |
16.553 |
18.678 |
19.095 |
19.826 |
21.807 |
22.998 |
23.576 |
实施例
10
N-(4-{4- 氨基 -7-[1-(2- 羟乙基 )-1H- 吡唑 -4- 基 ] 噻吩并 [3,2-c] 吡啶 -3- 基 } 苯基 )-N'-(3- 氟苯基 ) 脲丙二酸氢盐 VI 型的制备
丙二酸饱和溶液是在25℃下通过将丙二酸溶解在85/15
v/v THF/水的混合物中制备的。将此溶液(2 mL)加热至65℃。然后加入大约250 mg的N-(4-{4-氨基-7-[1-(2-羟乙基)-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。在10分钟之内形成澄清溶液。冷却溶液至环境温度,并继续搅拌过夜。在过夜保持期间结晶出固体。借助于过滤分离固体,而后用85/15
v/v THF/水混合物洗涤,以除去过量的丙二酸,而后在烘箱中在45℃下干燥。
表6.PXRD峰列表∶N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸氢盐VI型
峰位置(° 2θ) |
6.096 |
8.716 |
10.674 |
11.250 |
13.084 |
15.273 |
15.755 |
17.461 |
18.269 |
18.770 |
19.416 |
实施例
11
N-(4-{4- 氨基 -7-[1-(2- 羟乙基 )-1H- 吡唑 -4- 基 ] 噻吩并 [3,2-c] 吡啶 -3- 基 } 苯基 )-N'-(3- 氟苯基 ) 脲抗坏血酸盐 VII 型的制备
抗环血酸饱和溶液是在25℃下通过将抗环血酸溶解在85/15
v/v THF/水的混合物中制备的。将此溶液(2 mL)加热至65℃。加入大约250 mg的N-(4-{4-氨基-7-[1-(2-羟乙基)-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。在10分钟之内形成澄清溶液。将该溶液冷却至环境温度。在冷却过程期间在45℃下固体开始结晶。将悬浮液搅拌过夜,然后借助于过滤分离出固体。用85/15 v/v THF/水混合物洗涤,以除去过量的抗环血酸,而后在烘箱中在45℃下干燥。
表7.PXRD峰列表∶N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲抗坏血酸盐VIII型
峰位置(° 2θ) |
4.651 |
5.203 |
6.986 |
9.086 |
9.660 |
10.402 |
13.964 |
16.011 |
17.435 |
18.833 |
20.930 |
22.521 |
22.797 |
24.128 |
实施例
12
N-(4-{4- 氨基 -7-[1-(2- 羟乙基 )-1H- 吡唑 -4- 基 ] 噻吩并 [3,2-c] 吡啶 -3- 基 } 苯基 )-N'-(3- 氟苯基 ) 脲马来酸盐 VIII 型的制备
在40℃磁力搅拌下将N-(4-{4-氨基-7-[1-(2-羟乙基)-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(27 mg)悬浮在二甲基甲酰胺(125 μl)中。然后在50℃磁力搅拌下向A-968660游离碱悬浮液中慢慢地加入马来酸溶液(120μl,0.5M)。在完全加入酸性溶液之后时观察到结晶。通过离心过滤收集固体。
表8.PXRD峰列表∶N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲马来酸盐VIII型
峰位置(° 2θ) |
4.998 |
8.103 |
9.302 |
9.996 |
11.113 |
12.223 |
13.668 |
15.233 |
16.851 |
18.372 |
19.790 |
23.634 |
实施例
13
N-(4-{4- 氨基 -7-[1-(2- 羟乙基 )-1H- 吡唑 -4- 基 ] 噻吩并 [3,2-c] 吡啶 -3- 基 } 苯基 )-N'-(3- 氟苯基 ) 脲硫酸盐 IX 型的制备
将N-(4-{4-氨基-7-[1-(2-羟乙基)-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(15 mg)悬浮在2-丙醇(150 μl)中。将硫酸溶液(98%,4 μl)加入到悬浮液中。将该悬浮液在环境温度下搅拌10天。通过离心过滤收集固体。
表9.PXRD峰列表∶N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲硫酸盐IX型的制备
峰位置(° 2θ) |
3.848 |
5.619 |
6.704 |
6.906 |
7.673 |
11.230 |
11.533 |
12.986 |
16.868 |
17.418 |
实施例
14
N-(4-{4- 氨基 -7-[1-(2- 羟乙基 )-1H- 吡唑 -4- 基 ] 噻吩并 [3,2-c] 吡啶 -3- 基 } 苯基 )-N'-(3- 氟苯基 ) 脲磷酸盐 X 型的制备
将N-(4-{4-氨基-7-[1-(2-羟乙基)-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(18 mg)悬浮在2-丙醇(150 μl)中。将磷酸溶液(85%,5 μl)加入到悬浮液中。将该悬浮液在环境温度下搅拌10天。通过离心过滤收集固体。
表10.PXRD峰列表∶NN-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲磷酸盐X型
峰位置(° 2θ) |
5.854 |
6.567 |
6.911 |
13.838 |
17.646 |
18.736 |
19.121 |
20.850 |
Claims (112)
1. 固体结晶形式的化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸盐。
2. 化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸盐,其中结晶形式是I型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶6.14,10.70,19.54,21.22,23.14,24.00° 2θ,± 0.2° 2θ。
3. 权利要求2的化合物,其中结晶形式是I型,特征至少在于在每个所述位置具有粉末X射线衍射峰。
4. 权利要求2的化合物,其中结晶形式是I型,特征至少在于在每个所述位置具有粉末X射线衍射峰∶6.14,9.36,10.70,11.68,12.28,13.30,16.32,16.54,16.97,18.47,19.54,21.22,21.50,23.14,23.46,23.68,24.00° 2θ,± 0.2° 2θ。
5. 权利要求1-4的任一项的化合物,其中结晶形式是四水合物。
6. 药物组合物,包含权利要求1-5的任一项的化合物和一或多种可药用赋形剂。
7. 制备权利要求1-5任一项的固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸盐的方法,其中结晶形式是II型,包括∶
a) 提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸氢盐固体,水,和四氢呋喃的混合物;
b) 得到存在于混合物中的I型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸盐。
8. 权利要求7的方法,进一步包括分离固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸盐,其中结晶形式是I型。
9. 在哺乳动物中治疗癌症的方法,包括给予具有该疾病的患者治疗有效量的(a)固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸盐,其中结晶形式是I型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶6.14,10.70,19.54,21.22,23.14,24.00° 2θ,± 0.2° 2θ或(b)药物组合物,包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸盐,其中结晶形式是I型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶6.14,10.70,19.54,21.22,23.14,24.00° 2θ,± 0.2° 2θ 和一或多种可药用赋形剂。
10. 权利要求9的方法,其中晶体N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸盐I型或药物组合物是通过下列途径给药的∶口服,肠胃外,舌下,口腔,鼻内的,肺部,局部,透皮,皮内,眼睛,耳部,直肠,阴道,胃内,颅内,滑膜内,或关节内的途径。
11. 权利要求9的方法,其中癌症是骨髓增生异常综合征,急性骨髓性白血病,结肠直肠癌,非小细胞肺癌,和卵巢癌。
12. 固体结晶形式的化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸盐。
13. 固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸盐化合物,其中结晶形式是II型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶6.21,8.88,10.28,10.64,19.18,20.58,21.16,21.38,21.75,22.50,22.86,23.86,24.50,24.92° 2θ,± 0.2° 2θ。
14. 权利要求13的化合物,其中结晶形式是II型,特征至少在于在每个所述位置具有粉末X射线衍射峰。
15. 权利要求13的化合物,其中结晶形式是II型,特征至少在于在每个所述位置具有粉末X射线衍射峰∶6.21,8.88,10.28,10.64,11.96,12.44,12.76,15.93,18.48,19.18,20.58,21.16,21.38,21.75,22.50,22.86,23.86,24.50,24.92° 2θ,± 0.2° 2θ。
16. 权利要求12-15的任一项的化合物,其中结晶形式是四水合物。
17. 药物组合物,包含权利要求12-16的任一项的化合物和一或多种可药用赋形剂。
18. 制备权利要求12-16任一项的固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸盐的方法,其中结晶形式是II型,包括∶
a) 提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸氢盐固体,水,和四氢呋喃的混合物;和
b) 得到存在于混合物中的II型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸盐。
19. 权利要求20的方法,进一步包括分离固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸盐,其中结晶形式是II型。
20. 在哺乳动物中治疗癌症的方法,包括给予具有该疾病的患者治疗有效量的(a)固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸盐,其中结晶形式是II型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶6.21,8.88,10.28,10.64,19.18,20.58,21.16,21.38,21.75,22.50,22.86,23.86,24.50,24.92° 2θ,± 0.2° 2θ
或(b)包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸盐和一或多种可药用赋形剂的药物组合物,其中结晶形式是II型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶86.21,8.88,10.28,10.64,19.18,20.58,21.16,21.38,21.75,22.50,22.86,23.86,24.50,24.92° 2θ,± 0.2° 2θ。
21. 权利要求22的方法,其中晶体N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸盐II型或药物组合物是通过下列途径给药的∶口服,肠胃外,舌下,口腔,鼻内的,肺部,局部,透皮,皮内,眼睛,耳部,直肠,阴道,胃内,颅内,滑膜内,或关节内的途径。
22. 权利要求22的方法,其中癌症是骨髓增生异常综合征,急性骨髓性白血病,结肠直肠癌,非小细胞肺癌,和卵巢癌。
23. 固体结晶形式的化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲HCl盐。
24. 固体结晶形式的化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲HCl盐,其中结晶形式是III型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.80,8.00,9.71,13.63,16.66,18.69,19.49,22.35° 2θ,± 0.2° 2θ。
25. 权利要求24的化合物,其中结晶形式是III型,特征至少在于在每个所述位置具有粉末X射线衍射峰。
26. 权利要求24的化合物,其中结晶形式是III型,特征至少在于在每个所述位置具有粉末X射线衍射峰∶5.80,6.36,8.00,9.71,10.22,13.63,16.66,18.69,19.49,19.77,21.59,22.35,22.76° 2θ,± 0.2° 2θ。
27. 权利要求23-26的任一项的化合物,其中结晶形式是无水合的。
28. 药物组合物,包含权利要求23-27的任一项的化合物和一或多种可药用赋形剂。
29. 制备权利要求23-27任一项的固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲HCl盐的方法,其中结晶形式是III型,包括∶
a) 提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-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,水,醇和盐酸的混合物;
b) 得到存在于混合物中的III型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲HCl盐。
30. 权利要求29的方法,进一步包括分离固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲HCl盐,其中结晶形式是III型。
31. 在哺乳动物中治疗癌症的方法,包括给予具有该疾病的患者治疗有效量的(a)固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲HCl盐,其中结晶形式是III型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.80,8.00,9.71,13.63,16.66,18.69,19.49,22.35° 2θ,± 0.2° 2θ
或(b)包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲HCl盐和一或多种可药用赋形剂的药物组合物,其中结晶形式是III型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.80,8.00,9.71,13.63,16.66,18.69,19.49,22.35° 2θ,± 0.2° 2θ。
32. 权利要求31的方法,其中晶体N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲HCl盐III型或药物组合物是通过下列途径给药的∶口服,肠胃外,舌下,口腔,鼻内的,肺部,局部,透皮,皮内,眼睛,耳部,直肠,阴道,胃内,颅内,滑膜内,或关节内的途径。
33. 权利要求31的方法,其中癌症是骨髓增生异常综合征,急性骨髓性白血病,结肠直肠癌,非小细胞肺癌,和卵巢癌。
34. 固体结晶形式的化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐。
35. 固体结晶形式的化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐,其中结晶形式是IV型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.37,7.40,10.69,18.39,18.78,20.42,21.20° 2θ,± 0.2° 2θ。
36. 权利要求35的化合物,其中结晶形式IV型,特征至少在于在每个所述位置具有粉末X射线衍射峰。
37. 权利要求35的化合物,其中结晶形式IV型,特征至少在于在每个所述位置具有粉末X射线衍射峰∶5.37,7.40,10.69,11.92,14.31,16.04,18.02,18.39,18.78,20.42,21.20° 2θ,± 0.2° 2θ。
38. 权利要求34-37的任一项的化合物,其中结晶形式是无水合的。
39. 药物组合物,包含权利要求34-38的任一项的化合物和一或多种可药用赋形剂。
40. 制备权利要求34-38任一项的固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐的方法,其中结晶形式是IV型,包括∶
a) 提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-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,二甲基甲酰胺,甲磺酸和乙腈的混合物;
b) 得到存在于混合物中的IV型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐。
41. 权利要求40的方法,进一步包括分离固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐,其中结晶形式是IV型。
42. 制备权利要求34-38任一项的固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐的方法,其中结晶形式是IV型,包括∶
a) 提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-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,甲磺酸,和乙酸乙酯的混合物;
b) 得到存在于混合物中的IV型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐。
43. 权利要求42的方法,进一步包括分离固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐,其中结晶形式是IV型。
44. 在哺乳动物中治疗癌症的方法,包括给予具有该疾病的患者治疗有效量的(a)固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐,其中结晶形式是IV型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.37,7.40,10.69,18.39,18.78,20.42,21.20° 2θ,± 0.2° 2θ 或(b)包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲HCl盐和一或多种可药用赋形剂的药物组合物,其中结晶形式是II型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.37,7.40,10.69,18.39,18.78,20.42,21.20° 2θ,± 0.2° 2θ。
45. 权利要求44的方法,其中晶体N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲甲磺酸盐IV型或药物组合物是通过下列途径给药的∶口服,肠胃外,舌下,口腔,鼻内的,肺部,局部,透皮,皮内,眼睛,耳部,直肠,阴道,胃内,颅内,滑膜内,或关节内的途径。
46. 权利要求44的方法,其中癌症是骨髓增生异常综合征,急性骨髓性白血病,结肠直肠癌,非小细胞肺癌,和卵巢癌。
47. 固体结晶形式的化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸氢盐。
48. 固体结晶形式的化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸氢盐,其中结晶形式是V型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶3.04,3.80,7.62,16.12,23.58° 2θ,± 0.2° 2θ。
49. 权利要求48的化合物,其中结晶形式是V型,特征至少在于在每个所述位置处的粉末X射线衍射峰。
50. 权利要求48的化合物,其中结晶形式是V型,特征至少在于在每个所述位置处的粉末X射线衍射峰∶2.70,3.04,3.80,5.64,6.58,7.62,16.12,16.55,18.68,19.10,19.83,21.81,23.00,23.58° 2θ,± 0.2° 2θ。
51. 权利要求47-50的任一项的化合物,其中结晶形式是无水合的。
52. 药物组合物,包含权利要求47-51的任一项的化合物和一或多种可药用赋形剂。
53. 制备权利要求47-50任一项的固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸氢盐的方法,其中结晶形式是V型,包括∶
a) 提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-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,四氢呋喃,水和L-酒石酸的混合物;
b) 得到存在于混合物中的V型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸氢盐。
54. 权利要求53的方法,进一步包括分离固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸氢盐,其中结晶形式是V型。
55. 在哺乳动物中治疗癌症的方法,包括给予具有该疾病的患者治疗有效量的(a)固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸氢盐,其中结晶形式是V型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶3.04,3.80,7.62,16.12,23.58° 2θ,± 0.2° 2θ
或(b)包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸氢盐和一或多种可药用赋形剂的药物组合物,其中结晶形式是V型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶3.04,3.80,7.62,16.12,23.58° 2θ,± 0.2° 2θ。
56. 权利要求55的方法,其中晶体N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲L-酒石酸氢盐V型或药物组合物是通过下列途径给药的∶口服,肠胃外,舌下,口腔,鼻内的,肺部,局部,透皮,皮内,眼睛,耳部,直肠,阴道,胃内,颅内,滑膜内,或关节内的途径。
57. 权利要求55的方法,其中癌症是骨髓增生异常综合征,急性骨髓性白血病,结肠直肠癌,非小细胞肺癌,和卵巢癌。
58. 固体结晶形式的化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸氢盐。
59. 固体结晶形式的化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸氢盐,其中结晶形式是VI型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶6.10,8.72,15.76° 2θ,± 0.2° 2θ。
60. 权利要求59的化合物,其中结晶形式是VI型,特征至少在于在每个所述位置处的粉末X射线衍射峰。
61. 权利要求59的化合物,其中结晶形式是VI型,特征至少在于在每个所述位置处的粉末X射线衍射峰∶6.10,8.72,10.67,11.25,13.08,15.27,15.76,17.46,18.27,18.77,19.42° 2θ,± 0.2° 2θ。
62. 权利要求58-61的任一项的化合物,其中结晶形式是无水合的。
63. 药物组合物,包含权利要求58-62的任一项的化合物和一或多种可药用赋形剂。
64. 制备权利要求58-62任一项的固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸氢盐的方法,其中结晶形式是VI型,包括∶
a) 提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-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,四氢呋喃,水和丙二酸的混合物;
b) 得到存在于混合物中的VI型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸氢盐。
65. 权利要求64的方法,进一步包括分离固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸氢盐,其中结晶形式是VI型。
66. 在哺乳动物中治疗癌症的方法,包括给予具有该疾病的患者治疗有效量的(a)固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸氢盐,其中结晶形式是VI型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶6.10,8.72,15.76° 2θ,± 0.2° 2θ 或(b)包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸氢盐和一或多种可药用赋形剂的药物组合物,其中结晶形式是VI型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶6.10,8.72,15.76° 2θ,± 0.2° 2θ。
67. 权利要求66的方法,其中晶体N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲丙二酸氢盐VI型或药物组合物是通过下列途径给药的∶口服,肠胃外,舌下,口腔,鼻内的,肺部,局部,透皮,皮内,眼睛,耳部,直肠,阴道,胃内,颅内,滑膜内,或关节内的途径。
68. 权利要求66的方法,其中癌症是骨髓增生异常综合征,急性骨髓性白血病,结肠直肠癌,非小细胞肺癌,和卵巢癌。
69. 固体结晶形式的化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲抗坏血酸盐。
70. 固体结晶形式的化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲抗坏血酸盐,其中结晶形式是VII型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.20,16.01,17.44,18.83° 2θ,± 0.2° 2θ。
71. 权利要求70的化合物,其中结晶形式是VII型,特征至少在于在每个所述位置处的粉末X射线衍射峰。
72. 权利要求70的化合物,其中结晶形式是VII型,特征至少在于在每个所述位置处的粉末X射线衍射峰∶4.62,5.20,6.99,9.09,9.66,10.40,13.96,16.01,17.44,18.83,20.93,22.52,22.80,24.13° 2θ,± 0.2° 2θ。
73. 权利要求69-72的任一项的化合物,其中结晶形式是水合物。
74. 药物组合物,包含权利要求69-73的任一项的化合物和一或多种可药用赋形剂。
75. 制备权利要求69-73任一项的固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲抗坏血酸盐的方法,其中结晶形式是VII型,包括∶
a) 提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-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,四氢呋喃,水和抗环血酸的混合物;
b) 得到存在于混合物中的VII型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲抗坏血酸盐。
76. 权利要求75的方法,进一步包括分离固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲抗坏血酸盐,其中结晶形式是VII型。
77. 在哺乳动物中治疗癌症的方法,包括给予具有该疾病的患者治疗有效量的(a)固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲抗坏血酸盐,其中结晶形式是VII型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.20,16.01,17.44,18.83° 2θ,± 0.2° 2θ 或(b)包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲抗坏血酸盐和一或多种可药用赋形剂的药物组合物,其中结晶形式是VII型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.20,16.01,17.44,18.83° 2θ,± 0.2° 2θ 。
78. 权利要求77的方法,其中晶体N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲抗坏血酸盐VII型或药物组合物是通过下列途径给药的∶口服,肠胃外,舌下,口腔,鼻内的,肺部,局部,透皮,皮内,眼睛,耳部,直肠,阴道,胃内,颅内,滑膜内,或关节内的途径。
79. 权利要求77的方法,其中癌症是骨髓增生异常综合征,急性骨髓性白血病,结肠直肠癌,非小细胞肺癌,和卵巢癌。
80. 固体结晶形式的化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲马来酸盐。
81. 固体结晶形式的化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲马来酸盐,其中结晶形式是VIII型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.00,15.23,19.79,23.63° 2θ,± 0.2° 2θ。
82. 权利要求81的化合物,其中结晶形式是VIII型,特征至少在于在每个所述位置处的粉末X射线衍射峰。
83. 权利要求81的化合物,其中结晶形式是VIII型,特征至少在于在每个所述位置处的粉末X射线衍射峰∶5.00,8.10,9.30,10.00,11.11,12.22,13.67,15.23,16.85,18.37,19.79,23.63° 2θ,± 0.2° 2θ。
84. 权利要求80-83的任一项的化合物,其中结晶形式是水合物。
85. 药物组合物,包含权利要求80-84的任一项的化合物和一或多种可药用赋形剂。
86. 制备权利要求80-84任一项的固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲马来酸盐的方法,其中结晶形式是VIII型,包括∶
a) 提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-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,二甲基甲酰胺,和马来酸的混合物;
b) 得到存在于混合物中的VIII型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲马来酸盐。
87. 权利要求86的方法,进一步包括分离固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲马来酸盐,其中结晶形式是VIII型。
88. 在哺乳动物中治疗癌症的方法,包括给予具有该疾病的患者治疗有效量的(a)固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲马来酸盐,其中结晶形式是VIII型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.00,15.23,19.79,23.63° 2θ,± 0.2° 2θ 或(b)包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲马来酸盐和一或多种可药用赋形剂的药物组合物,其中结晶形式是VIII型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.00,15.23,19.79,23.63° 2θ,± 0.2° 2θ。
89. 权利要求88的方法,其中晶体N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲马来酸盐VIII型或药物组合物是通过下列途径给药的∶口服,肠胃外,舌下,口腔,鼻内的,肺部,局部,透皮,皮内,眼睛,耳部,直肠,阴道,胃内,颅内,滑膜内,或关节内的途径。
90. 权利要求88的方法,其中癌症是骨髓增生异常综合征,急性骨髓性白血病,结肠直肠癌,非小细胞肺癌,和卵巢癌。
91. 固体结晶形式的化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲硫酸盐。
92. 固体结晶形式的化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲硫酸盐,其中结晶形式是IX型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶3.85,7.67,11.23,16.87° 2θ,± 0.2° 2θ。
93. 权利要求92的化合物,其中结晶形式是IX型,特征至少在于在每个所述位置处的粉末X射线衍射峰。
94. 权利要求92的化合物,其中结晶形式是IX型,特征至少在于在每个所述位置处的粉末X射线衍射峰∶3.85,5.62,6.70,6.91,7.67,11.23,11.53,12.99,16.87,17.42° 2θ,± 0.2° 2θ。
95. 权利要求91-94的任一项的化合物,其中结晶形式是水合物。
96. 药物组合物,包含权利要求91-95的任一项的化合物和一或多种可药用赋形剂。
97. 制备权利要求91-94任一项的固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲硫酸盐的方法,其中结晶形式是IX型,包括∶
a) 提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-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,丙醇,和硫酸的混合物;
b) 得到存在于混合物中的IX型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲硫酸盐。
98. 权利要求97的方法,进一步包括分离固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲硫酸盐,其中结晶形式是IX型。
99. 在哺乳动物中治疗癌症的方法,包括给予具有该疾病的患者治疗有效量的(a)固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲硫酸盐,其中结晶形式是IX型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶3.85,7.67,11.23,16.87° 2θ,± 0.2° 2θ 或(b)包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲硫酸盐和一或多种可药用赋形剂的药物组合物,其中结晶形式是IX型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶3.85,7.67,11.23,16.87° 2θ,± 0.2° 2θ。
100. 权利要求99的方法,其中晶体N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲硫酸盐IX型或药物组合物是通过下列途径给药的∶口服,肠胃外,舌下,口腔,鼻内的,肺部,局部,透皮,皮内,眼睛,耳部,直肠,阴道,胃内,颅内,滑膜内,或关节内的途径。
101. 权利要求99的方法,其中癌症是骨髓增生异常综合征,急性骨髓性白血病,结肠直肠癌,非小细胞肺癌,和卵巢癌。
102. 固体结晶形式的化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲磷酸盐。
103. 固体结晶形式的化合物N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲磷酸盐,其中结晶形式是X型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.85,6.57,6.91,20.85° 2θ,± 0.2° 2θ。
104. 权利要求103的化合物,其中结晶形式是X型,特征至少在于在每个所述位置处的粉末X射线衍射峰。
105. 权利要求103的化合物,其中结晶形式是X型,特征至少在于在每个所述位置处的粉末X射线衍射峰∶5.85,6.57,6.91,13.83,17.65,18.74,19.12,20.85° 2θ,± 0.2° 2θ。
106. 权利要求102-105的任一项的化合物,其中结晶形式是水合物。
107. 药物组合物,包含权利要求102-106的任一项的化合物和一或多种可药用赋形剂。
108. 制备权利要求102-105任一项的固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲磷酸盐的方法,其中结晶形式是IX型,包括∶
a) 提供包括(i)N-(4-{4-氨基-7-[1-(2-羟乙基)-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,丙醇,和磷酸的混合物;
b) 得到存在于混合物中的X型结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲磷酸盐。
109. 权利要求108的方法,进一步包括分离固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲磷酸盐,其中结晶形式是X型。
110. 在哺乳动物中治疗癌症的方法,包括给予具有该疾病的患者治疗有效量的(a)固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲磷酸盐,其中结晶形式是X型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.85,6.57,6.91,20.85° 2θ,± 0.2° 2θ 或(b)包括固体结晶形式的N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲磷酸盐和一或多种可药用赋形剂的药物组合物,其中结晶形式是X型,特征至少在于在下列的任何一个或多个位置处的粉末X射线衍射峰∶5.85,6.57,6.91,20.85° 2θ,± 0.2° 2θ 。
111. 权利要求110的方法,其中晶体N-(4-{4-氨基-7-[1-(2-羟乙基)-1H-吡唑-4-基]噻吩并[3,2-c]吡啶-3-基}苯基)-N'-(3-氟苯基)脲磷酸盐X型或药物组合物是通过下列途径给药的∶口服,肠胃外,舌下,口腔,鼻内的,肺部,局部,透皮,皮内,眼睛,耳部,直肠,阴道,胃内,颅内,滑膜内,或关节内的途径。
112. 权利要求110的方法,其中癌症是骨髓增生异常综合征,急性骨髓性白血病,结肠直肠癌,非小细胞肺癌,和卵巢癌。
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CN111848611A (zh) * | 2015-12-08 | 2020-10-30 | 浙江亚太药业股份有限公司 | 一种吡啶衍生物的q晶型及其制备方法、用途 |
CN109476700A (zh) * | 2016-03-11 | 2019-03-15 | 隐形生物治疗公司 | 结晶盐形式 |
US11555053B2 (en) | 2016-03-11 | 2023-01-17 | Stealth Biotherapeutics Inc. | Crystalline salt forms |
US11773136B2 (en) | 2017-04-05 | 2023-10-03 | Stealth Biotherapeutics Inc. | Crystalline salt forms of Boc-D-Arg-DMT-Lys-(Boc)-Phe-NH2 |
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US20120203002A1 (en) | 2012-08-09 |
EP2580221A1 (en) | 2013-04-17 |
HK1182383A1 (zh) | 2013-11-29 |
US8633317B2 (en) | 2014-01-21 |
MX2012014386A (es) | 2013-05-01 |
WO2011156473A1 (en) | 2011-12-15 |
JP2013528222A (ja) | 2013-07-08 |
EP2580221B1 (en) | 2015-10-21 |
JP5727599B2 (ja) | 2015-06-03 |
ES2559212T3 (es) | 2016-02-11 |
CA2802042A1 (en) | 2011-12-15 |
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