CN106999490A - 晶体形式的谷氨酰胺酶抑制剂 - Google Patents
晶体形式的谷氨酰胺酶抑制剂 Download PDFInfo
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Abstract
本发明涉及具有式(I)结构的化合物的结晶盐,它们的制备方法,及包含结晶盐的相关的药物组合物。本发明还涉及治疗或预防癌症或免疫疾病或神经疾病的方法,其包括给予本发明的结晶盐。
Description
相关申请
本申请要求2014年8月7日提交的美国临时专利申请系列号62/034,547的优先权益,其内容通过引用结合到本文中。
背景
谷氨酰胺通过代谢和非-代谢机制支持癌细胞的细胞生存、生长和增殖。在活性增殖细胞中,谷氨酰胺的代谢是细胞的构建块和能量的主要来源。当谷氨酰胺从癌细胞生长于其中的培养基中撤消时,细胞经常停止生长或死亡。在癌细胞中,由细胞摄取的大量谷氨酰胺通过酶谷氨酰胺酶的作用转化为谷氨酸。因此,谷氨酰胺经由谷氨酰胺酶向谷氨酸的转化是谷氨酰胺代谢的控制点。
自从Warburg观察到腹水肿瘤细胞在氧的存在下显示出高的葡萄糖消耗和乳酸分泌速率以来,研究人员一直在探索癌细胞如何利用代谢途径以便能够继续活性增殖。数个报道已经证实谷氨酰胺代谢如何支持细胞复制必需的大分子合成。
因此,已有理论认为谷氨酰胺酶为治疗以活性增殖细胞为特征的疾病,例如癌症的潜在性治疗靶标。具有良好药用性质的合适谷氨酰胺酶抑制剂的缺乏使得难以开发出用于临床用途的谷氨酰胺酶抑制剂。因此,创建特异性的并能够配制为体内使用的谷氨酰胺酶抑制剂可导致一种新的类型的治疗剂。特别地,用于制备和配制谷氨酰胺酶抑制剂的改进的组合物和方法是需要的。
发明简述
本发明的一个方面涉及具有式(I)结构的结晶化合物或化合物的结晶盐,
(I)。
本发明的另一方面涉及制备式(I)的结晶化合物和结晶盐的方法。
在某些实施方案中,本发明提供适合用于人患者的药物制剂,其包含式(I)化合物的结晶化合物或结晶盐,和一种或多种药学上可接受的赋形剂。在某些实施方案中,药物制剂可用于治疗或预防如本文描述的病症或疾病。在某些实施方案中,药物制剂具有适合静脉用于人患者的足够低的热源活性。
本发明还提供治疗或预防如本文描述的癌症、免疫疾病或神经疾病的方法,其包括给予本发明的结晶化合物或结晶盐。
附图详述
图1是CB-839 HCl,晶型I的X-射线衍射(XRD)图谱。
图2是CB-839 HCl,晶型II的XRD图谱。
图3是CB-839 TsOH的XRD图谱。
图4是CB-839 MsOH的XRD图谱。
图5是CB-839 HBr的XRD图谱。
图6是CB-839,游离碱,晶型B的XRD图谱。
图7是CB-839,游离碱,晶型A的XRD图谱。
发明详述
在某些实施方案中,本发明提供具有式(I)结构的结晶化合物,或具有式(I)结构的化合物的结晶盐,
(I)。
在某些实施方案中,本发明提供包含式(I)化合物的结晶化合物或结晶盐和一种或多种药学上可接受的赋形剂的药物制剂。在某些实施方案中,药物制剂可用于治疗或预防如本文描述的病症或疾病。在某些实施方案中,药物制剂具有适合静脉用于人患者的足够低的热源活性。
在某些实施方案中,本发明涉及治疗或预防癌症或免疫疾病或神经疾病的方法,其包括给予式(I)化合物的结晶化合物或结晶盐。
在某些实施方案中,本发明涉及用于制备具有式(I)结构的化合物的结晶盐的方法,其包括a) 提供在第一有机溶剂中的式(I)化合物的游离碱浆液;b) 使游离碱浆液与包含酸和任选的第二有机溶剂的试剂溶液在足以形成包含式(I)化合物的盐的混合物的条件下接触;和c) 从包含式(I)化合物的盐的混合物结晶式(I)化合物的盐。
本文描述的任何结晶化合物或其结晶盐可用于制备治疗本文公开的任何疾病或病症的药物。
在某些实施方案中,结晶盐是盐酸盐、甲苯磺酸盐、硝酸盐、甲磺酸盐,或氢溴酸盐。在特定实施方案中,结晶盐是盐酸盐。
在某些实施方案中,本发明的盐可装配成一个以上的晶体形成。在示例性实施方案中,具有式(I)结构的化合物的结晶盐酸盐作为如下文详细描述的“晶型I”和“晶型II”存在。
在某些实施方案中,结晶盐的多晶型物通过粉末X-射线衍射(XRD)来表征。θ代表以度测量的衍射角。在某些实施方案中,用于XRD的衍射计测量作为2倍衍射角θ的衍射角。因此,在某些实施方案中,本文描述的衍射图谱指针对角2θ测量的X-射线强度。
在某些实施方案中,结晶HCl盐的晶型I具有2θ值16.70;17.26;21.09;和22.69。在进一步的实施方案中,晶型I具有2θ值16.70;17.26;18.18;21.09;22.69;23.46;25.22;25.49;和26.72。在更进一步的实施方案中,晶型I具有2θ值9.53;11.63;16.70;17.26;18.18;19.10;19.80;21.09;22.16;22.69;23.46;24.63;25.22;25.49;25.91;26.72;28.45;29.38;31.39;31.82;和34.91。在更进一步的实施方案中,晶型I具有2θ值8.62;9.53;11.63;15.89;16.70;17.26;18.18;19.10;19.80;21.09;22.16;22.69;23.46;24.63;25.22;25.49;25.91;26.72;28.45;29.38;31.39;31.82;32.76;33.61;33.74;34.27;34.91;35.53;39.36;和39.73。
在某些实施方案中,式(I)化合物的结晶HCl盐的晶型I具有基本上如图1所示的XRD图谱。
在某些实施方案中,结晶HCl的晶型II具有2θ值8.34;18.83;和21.10。在进一步的实施方案中,晶型II具有2θ值6.26;8.34;15.82;18.83;21.10;23.42;24.10;24.45;25.25;和25.74。在更进一步的实施方案中,晶型II具有2θ值6.26;8.34;11.02;12.58;14.80;15.61;15.82;17.58;18.20;18.83;19.81;20.00;21.10;22.58;23.42;24.10;24.45;25.25;25.74;26.36;27.83;28.70;29.84;30.46;31.81;和32.38。在更进一步的实施方案中,晶型II具有2θ值3.10;6.26;8.34;9.04;9.96;11.02;12.58;13.47;14.80;15.61;15.82;16.15;17.58;18.20;18.83;19.81;20.00;21.10;22.02;22.58;23.42;24.10;24.45;25.25;25.74;26.36;27.22;27.83;28.70;29.84;30.46;31.81;32.38;33.23;35.68;36.57;37.40;39.36;和41.79。
在某些实施方案中,式(I)化合物的结晶HCl盐的晶型II具有基本上如图2所示的XRD图谱。
在某些实施方案中,式(I)化合物的盐是二盐酸盐。在某些这样的实施方案中,所述盐是非晶形的。
在某些实施方案中,本发明的游离碱可装配成一个以上的晶体形成。在示例性实施方案中,具有式(I)结构的化合物的结晶游离碱作为如下文详细描述的“晶型A”、“晶型B”或者其混合物存在。
在某些实施方案中,本发明涉及式(I)的游离碱结晶化合物。在某些实施方案中,结晶游离碱的晶型B具有2θ值18.39;19.10;21.37;24.65。在进一步的实施方案中,结晶游离碱的晶型B具有2θ值7.92;18.39;19.10;20.12;21.37;24.10;24.65;25.14。在更进一步的实施方案中,结晶游离碱的晶型B具有2θ值7.32;7.92;11.98;15.54;15.87;18.06;18.39;19.10;20.06;20.12;21.37;22.41;22.74;24.10;24.65;25.14;25.78;27.32。在进一步的实施方案中,结晶游离碱的晶型B具有2θ值3.64;7.32;7.92;8.53;9.30;9.38;11.02;11.98;14.70;15.54;15.87;16.50;16.59;18.06;18.39;19.10;20.06;20.12;20.61;21.37;21.89;22.41;22.74;23.72;24.10;24.65;25.14;25.78;26.49;27.32;27.55;28.26;29.88;31.20;31.80;31.52;32.80;34.30;35.20;36.41;38.53;40.08;40.94;和43.86。在其它实施方案中,结晶游离碱的晶型B具有基本上如图6所示的XRD图谱。
在某些实施方案中,结晶游离碱的晶型A具有2θ值7.57;18.50;18.69。在某些实施方案中,结晶游离碱的晶型A具有2θ值7.57;9.67;11.00;12.93;15.20;18.50;18.69;23.33;24.87。在某些实施方案中,结晶游离碱的晶型A具有2θ值5.47;7.57;9.67;11.00;12.93;14.14;15.20;17.74;18.50;18.69;19.40;20.54;21.13;23.33;24.37;24.87;25.52。在进一步的实施方案中,结晶游离碱的晶型A具有2θ值5.47;6.01;7.57;9.20;9.67;10.15;11.00;12.93;14.14;15.20;15.81;16.56;17.74;18.50;18.69;19.40;19.94;20.54;20.59;21.13;22.00;22.60;23.33;23.98;24.37;24.87;25.52;26.27;26.62;27.79;29.59;30.64;33.30;35.01;37.93;38.72。在其它实施方案中,结晶游离碱的晶型A具有基本上如图7所示的XRD图谱。
在某些实施方案中,式(I)的结晶化合物不是溶剂化的(例如,晶格不包含溶剂的分子)。在某些备选的实施方案中,式(I)的结晶化合物是溶剂化的。
在某些实施方案中,本发明的结晶盐化合物可以是式(I)化合物的前药的盐,例如,其中母体化合物中的C(O)-NH部分被衍生为用可被水解或者另外裂解以恢复C(O)-NH部分的基团替代酰胺的氢原子。在某些这样的实施方案中,前药在体内被代谢为活性母体化合物。
在某些实施方案中,本发明涉及一种药物组合物,其包含式(I)化合物的结晶化合物或结晶盐和一种或多种药学上可接受的赋形剂。在某些实施方案中,药物组合物选自片剂、胶囊,和混悬剂。
如本文所用的术语“基本纯的”,指大于90%纯的结晶多晶型物,意指含有少于10%的任何其它化合物,包括相应的非晶型化合物或可供选择的结晶盐的多晶型物。优选地,结晶多晶型物是大于95%纯,或甚至大于98%纯的。
术语“前药”意欲涵盖在生理条件下转化为本发明的治疗活性剂(例如,式I的化合物)的化合物。一种制备前药的普通方法是包括在生理条件下被水解以显示所需分子的一或多个选择的部分。在其它实施方案中,前药通过宿主动物的酶活性被转化。
制备结晶盐的方法
在某些实施方案中,本发明涉及用于制备具有式(I)结构的化合物的结晶盐的方法,其包括a) 提供在第一有机溶剂中的式(I)化合物的游离碱混合物;b) 使游离碱混合物与包含酸和任选的第二有机溶剂的试剂溶液在足以形成包含式(I)化合物的盐的混合物的条件下接触;和c) 从包含式(I)化合物的盐的混合物结晶式(I)化合物的盐。
在某些实施方案中,在步骤b)中形成的包含式(I)化合物的盐的混合物是溶液。在某些实施方案中,在步骤b)中形成的混合物是浆液或悬浮液。
在某些实施方案中,包含式(I)化合物的盐的混合物是溶液,和从混合物结晶所述盐的步骤包括使所述溶液过度饱和,导致式(I)化合物的盐从溶液沉淀出来。
在某些实施方案中,使包含式(I)化合物的盐的混合物过度饱和包括缓慢加入反溶剂,例如庚烷、己烷、乙醇,或另一种与所述有机溶剂混溶的极性或非-极性液体,使溶液冷却(有或没有种晶溶液),减少溶液的体积,或其任何组合。在某些实施方案中,使包含式(I)化合物的盐的混合物过度饱和包括加入反溶剂,冷却溶液至室温或室温以下的温度,和减少溶液的体积,例如,通过从溶液蒸发溶剂。在某些实施方案中,使溶液冷却可以是被动的(例如,使溶液静置在环境温度下)或主动的(例如,在冰浴或冷冻装置中冷却溶液)。
在某些实施方案中,制备方法还包括分离所述盐晶体,例如通过过滤晶体,通过从晶体中倾析流体,或通过任何其它合适的分离技术。在进一步的实施方案中,制备方法还包括洗涤晶体。
在某些实施方案中,制备方法还包括诱导结晶。该方法还可包括例如在减压下干燥晶体的步骤。在某些实施方案中,诱导沉淀或结晶包括二次成核,其中成核在种子晶体或与环境的相互作用(结晶器壁、搅拌叶轮、超声处理等)的存在下发生。
在某些实施方案中,在第一有机溶剂中的式(I)化合物的游离碱混合物是浆液。在某些实施方案中,式(I)化合物在第一有机溶剂中的游离碱混合物是溶液。
在某些实施方案中,第一有机溶剂和第二有机溶剂,如果存在,包含乙腈、N,N-二甲基乙酰胺(DMA)、二甲基甲酰胺(DMF)、二甲亚砜(DMSO)、乙醇、乙酸乙酯、庚烷、己烷、乙酸异丙酯、甲醇、甲乙酮、N-甲基-2-吡咯烷酮(NMP)、四氢呋喃、甲苯、2-丙醇、1-丁醇、水,或其任何组合。在某些优选的实施方案中,有机溶剂是乙醇、甲苯、四氢呋喃,或乙腈。在一个示例性实施方案中,第一有机溶剂和第二有机溶剂各自独立地包含乙醇或乙腈。在另一个示例性实施方案中,第一有机溶剂和第二有机溶剂各自独立地包含二甲亚砜或乙醇。在另一个示例性实施方案中,第一有机溶剂和第二有机溶剂各自独立地包含N-甲基-2-吡咯烷酮或乙醇。
在某些实施方案中,第一有机溶剂和第二有机溶剂,如果存在,是相同的。在备选的实施方案中,第一有机溶剂和第二有机溶剂,如果存在,是不同的。
在某些实施方案中,洗涤晶体包括用选自反溶剂、乙腈、乙醇、庚烷、己烷、甲醇、四氢呋喃、甲苯、水,或其组合的液体洗涤。如本文所用的,“反溶剂”意指盐晶体是不溶、微溶,或部分可溶于其中的溶剂。实际上,将反溶剂加入到盐晶体溶于其中的溶液中降低盐晶体在溶液中的溶解性,从而刺激所述盐的沉淀。在某些实施方案中,晶体用反溶剂和有机溶剂的组合洗涤。在某些实施方案中,反溶剂是水,而在其它实施方案中,它是链烷烃溶剂,例如己烷或戊烷,或芳烃溶剂,例如苯、甲苯,或二甲苯。在某些实施方案中,反溶剂是乙醇。
在某些实施方案中,洗涤晶体包括用上文描述的溶剂或一种或多种溶剂的混合物洗涤式(I)的结晶化合物。在某些实施方案中,溶剂或溶剂的混合物在洗涤之前被冷却。
在某些实施方案中,所述酸是盐酸、对-甲苯磺酸、甲磺酸、硝酸,或氢溴酸。在该方法的某些实施方案中,在其中游离碱浆液和试剂溶液彼此接触的反应容器中,试剂溶液的酸以在游离碱浆液中的式(I)化合物的摩尔量的从约1.0至约1.5倍的摩尔量的存在。
酶抑制剂的应用
谷氨酰胺作为氮、碳和能量的载体起着重要的作用。其用于肝脲合成、用于肾脏氨产生、用于糖异生,和作为许多细胞的呼吸燃料。谷氨酰胺转化为谷氨酸通过线粒体酶,谷氨酰胺酶(“GLS”)启动。有两种主要形式的酶,K-型和L-型,它们通过其对谷氨酰胺的Km值和对谷氨酸的反应来区别,其中Km值或米氏常数(Michaelis constant),是达到最大速率一半所需的底物浓度。L-型,也称为“肝-型”或GLS2,具有对谷氨酰胺的高Km并且为谷氨酸抗性的。K-型,也称为“肾-型”或GLS1,具有对谷氨酰胺的低Km并且受谷氨酸的抑制。GLS1的可选剪接形式,称为谷氨酰胺酶C或“GAC”,最近已被鉴定并具有GLS1特有的类似活性。在某些实施方案中,所述化合物可选择性地抑制GLS1、GLS2和GAC。在优选的实施方案中,所述化合物选择性地抑制GLS1和GAC。
除了用作蛋白合成的基本结构块,还已经显示氨基酸对生长和分裂细胞至关重要的许多过程有贡献,并且这对于癌细胞尤其如此。几乎所有的癌症定义包括涉及失调的增殖。对癌症中的谷氨酰胺代谢的大量研究表明许多肿瘤是谷氨酰胺的饥渴消费者。
在某些实施方案中,本发明是使用如本文描述的式(I)化合物的结晶化合物或结晶盐治疗或预防癌症或免疫疾病或神经疾病的方法。
如本文所用的,“预防”疾病或病症的治疗剂指在统计样本中,相对于未治疗的对照样本在治疗的样本中减少疾病或病症的发生或频率,或相对于未治疗的对照样本延迟疾病或病症的一种或多种症状的发作或减轻其严重性的化合物。因此,癌症的预防包括,例如,相对于未治疗的对照群体减少在接受预防性治疗的患者群体中的可检测的癌症生长数目,和/或相对于未治疗的对照群体延迟治疗的群体出现可检测的癌症生长,例如,达统计学和/或临床显著量。感染的预防包括,例如,相对于未治疗的对照群体减少治疗的群体中感染的诊断数目,和/或相对于未治疗的对照群体延迟治疗的群体中感染的症状的发作。疼痛的预防包括,例如,相对于未治疗的对照群体,在治疗的群体中减轻由受试者经历的疼痛感觉的强度,或可供选择地延迟由受试者经历的疼痛感觉。
术语“治疗”包括预防性治疗和/或治疗性治疗。术语“预防性或治疗性”治疗为本领域公认的并包括给予宿主一种或多种本组合物。如果在不需要的病症(例如,宿主动物的疾病或其它不需要的状态)的临床表现之前给药,那么治疗是预防性的(即,它保护宿主免于出现不需要的病症),而如果在不需要的病症表现之后给药,则治疗是治疗性的(即,它意欲减轻、缓解或稳定已存在的不需要的病症或其副作用)。
在某些实施方案中,癌症可以是以下癌症的一种或其变体:急性成淋巴细胞白血病(ALL)、急性髓性白血病(AML)、肾上腺皮质癌、肛门癌、阑尾癌、非典型畸胎样瘤/横纹肌样瘤、基底细胞癌、胆管癌、膀胱癌、骨癌、脑瘤、星形细胞瘤、脑和脊髓瘤、脑干神经胶质瘤、中枢神经系统非典型畸胎样瘤/横纹肌样瘤、中枢神经系统胚胎瘤、乳腺癌、支气管肿瘤、伯基特氏淋巴瘤、类癌肿瘤、未知的原发性癌、中枢神经系统癌、宫颈癌、儿童期癌症、脊索癌、慢性淋巴细胞白血病(CLL)、慢性髓性白血病(CML)、慢性骨髓增生性疾病、结肠癌、结肠直肠癌、颅咽管瘤、皮肤T-细胞淋巴瘤、导管原位癌(DCIS)、胚胎瘤、子宫内膜癌、成室管膜细胞瘤、室管膜瘤、食道癌、鼻腔神经胶质瘤、尤因氏肉瘤、颅外生殖细胞瘤、性腺外生殖细胞瘤、肝外胆管癌、眼癌、骨的纤维组织细胞瘤、胆囊癌、胃癌、胃肠道类癌肿瘤、胃肠道间质瘤(GIST)、生殖细胞瘤、颅外生殖细胞瘤、性腺外生殖细胞瘤、卵巢生殖细胞瘤、妊娠滋养层肿瘤、神经胶质瘤、毛细胞白血病、头颈癌、心脏癌、肝细胞癌、组织细胞增多症、郎格罕氏细胞癌、霍奇金氏淋巴瘤、下咽癌、眼内黑色素瘤、胰岛细胞瘤、卡波济氏肉瘤、肾癌、朗格罕氏细胞组织细胞增多症、喉癌、白血病、嘴唇和口腔癌、肝癌、小叶原位癌(LCIS)、肺癌、淋巴瘤、AIDS-相关淋巴瘤、巨球蛋白血症、男性乳腺癌、成神经管细胞瘤、髓质上皮瘤、黑色素瘤、默克尔细胞癌、恶性间皮瘤、隐匿性原发性转移鳞状颈癌、涉及NUT基因的中线道癌、口腔癌、多发性内分泌瘤综合征、多发性骨髓瘤/浆细胞瘤、蕈样真菌病、骨髓增生异常综合征、骨髓增生异常/骨髓增殖性肿瘤、慢性髓性白血病(CML)、急性髓性白血病(AML)、骨髓瘤、多发性骨髓瘤、慢性骨髓增殖性病症、鼻腔癌、副鼻窦癌、鼻咽癌、神经母细胞瘤、非-霍奇金氏淋巴瘤、非-小细胞肺癌、口癌、口腔癌、唇癌、口咽癌、骨肉瘤、卵巢癌、胰腺癌、乳头状瘤病、副神经节瘤、副鼻窦癌、鼻腔癌、甲状旁腺癌、阴茎癌、咽癌、嗜铬细胞瘤、中间分化松果体实质瘤、松果体母细胞瘤、垂体瘤、浆细胞瘤、胸膜肺母细胞瘤、乳腺癌、原发性中枢神经系统(CNS)淋巴瘤、前列腺癌、直肠癌、肾细胞癌、肾盂癌、输尿管癌、移行细胞癌、成视网膜细胞瘤、横纹肌肉瘤、唾腺癌、肉瘤、塞泽里综合征(Sézary Syndrome)、皮肤癌、小细胞肺癌、小肠癌、软组织肉瘤、鳞状细胞癌、隐匿性原发性转移鳞状颈癌、胃癌、幕上原始神经外胚层瘤、T-细胞淋巴瘤、睾丸癌、喉癌、胸腺瘤、胸腺癌、甲状腺癌、肾盂和输尿管移行细胞癌、不明原因的原发性妊娠滋养层肿瘤、不寻常的儿童癌症、尿道癌、子宫癌、子宫肉瘤、瓦尔登斯特伦巨球蛋白血症和维尔姆斯肿瘤(Wilms Tumor)。
在某些情况下,致瘤突变促进谷氨酰胺代谢。表达致瘤K-Ras的细胞显示出谷氨酰胺利用的增加。在某些实施方案中,癌细胞具有突变的K-Ras基因。在某些实施方案中,癌症与膀胱、骨髓、乳腺、结肠、肾、肝、肺、卵巢、胰腺、前列腺、皮肤或甲状腺的组织有关。已知c-Myc基因在许多癌症中有改变。增加的Myc蛋白表达与增加的谷氨酰胺酶的表达相关,导致谷氨酰胺代谢的上调。在某些实施方案中,癌细胞具有致瘤c-Myc基因或升高的Myc蛋白表达。在某些实施方案中,癌症与膀胱、骨、肠、乳腺、中枢神经系统(例如,脑)、结肠、胃系统(例如胃和肠)、肝、肺、卵巢、前列腺、肌肉和皮肤的组织相关。
肾细胞癌(RCC)的最常见类型,透明细胞型(ccRCC)与希伯尔-林德奥二氏病(vonHippel-Lindau) (VHL)基因突变密切相关。由于自葡萄糖制备脂肪酸的能力丧失,已显示VHL-缺陷细胞系具有对谷氨酰胺的增加的需要(Metallo等,Nature 2013)。这种对谷氨酰胺的依赖性使得细胞易受谷氨酰胺酶抑制剂的影响(Gameiro等, Cell Metab. 2013)。本发明的某些实施方案涉及本文描述的化合物治疗VHL-缺陷癌症的用途。在某些实施方案中,所述癌症是RCC。在某些实施方案中,所述癌症是ccRCC。
谷氨酰胺酶抑制在某些具有TCA循环酶包括延胡索酸水合酶(FH)、琥珀酸脱氢酶(SDH),或异柠檬酸脱氢酶(IDH)的突变或缺失的罕见癌症中可以是有效的。谷氨酸在这些突变或缺失发生的上游进入TCA循环。发表的研究显示谷氨酰胺代谢在延胡索酸和琥珀酸的合成中是重要的。除了FH和SDH外,有证据显示谷氨酰胺有助于2-羟基戊二酸的产生,其为肿瘤形成的另一个驱动因素,它在带有酶异柠檬酸脱氢酶突变的肿瘤患者中积聚。因此,谷氨酰胺酶的抑制剂可通过限制上游起始原料的可利用性阻断这些突变或缺失的作用。FH中的罕见的突变导致遗传性平滑肌瘤病和肾细胞癌(HLRCC)的发生,其中患者可出现皮肤、子宫或肾的肿瘤。一些胃肠道间质瘤(GIST),因缺乏SDH的表达而发生,并且常常是遗传性的。其它缺乏SDH功能的突变发现于带有罕见的头颈癌(称为副神经节瘤),和罕见的肾上腺或肾上腺外(extra-adrenal)癌(称为嗜铬细胞瘤),和罕见的亚群透明细胞RCC的患者中。一些患有神经胶质瘤、脑癌形式、软骨肉瘤、罕见的骨癌、胆管癌、罕见的胆管瘤、AML、高危险脊髓发育不良/骨髓增生性疾病、血液疾病类型的患者具有IDH1或IDH2驱动因子突变。在本发明的某些实施方案中,本文描述的化合物可被用来治疗经鉴定具有FH、SDH或IDH (1和2)突变的疾病。在某些实施方案中,所述疾病是遗传性平滑肌瘤病或肾细胞癌(HLRCC)。在某些实施方案中,所述疾病是GIST、副神经节瘤、嗜铬细胞瘤,或透明细胞RCC。在某些实施方案中,疾病是神经胶质瘤、软骨肉瘤、胆管癌、AML,或脊髓发育不良/骨髓增生性疾病。
虽然许多癌细胞的存活依赖于外源性谷氨酰胺,但谷氨酰胺在肿瘤细胞亚型中的依赖程度可使得细胞群更容易受谷氨酰胺的减少的影响。作为一个例子,乳腺癌的基因表达分析已鉴定5个内在亚型(腔(luminal) A、腔B、基底的(basal)、HER2+和正常-样)。虽然谷氨酰胺剥夺对细胞生长和生存力具有影响,基底样细胞似乎对外源性谷氨酰胺的减少更加敏感。这支持了谷氨酰胺是基底样乳腺癌细胞系中的非常重要的能量来源的概念,并提示谷氨酰胺酶的抑制作用在治疗包含基底样细胞的乳腺癌中将是有益的。三阴乳腺癌(TNBC)的特征在于缺乏雌激素受体、孕酮受体和人上皮生长因子受体2表达。这种癌症在化学疗法后具有较高的复发率,和与其它乳腺癌亚型相比较差的预后。有趣的是,在TNBC细胞和基底样乳腺癌细胞之间的代谢概况中似乎有着明显的相似性(未公布的数据)。因此,本发明的某些实施方案涉及本文所述的化合物用于治疗TNBC和基底-型乳腺癌的用途。
恶病质,即肌肉质量的大量丧失,常常与癌症患者的差的功能状态和高的死亡率有关。这种过程背后的理论是肿瘤需要比由膳食正常供应的更多的谷氨酰胺,所以肌肉,谷氨酰胺的主要来源,开始分解以向肿瘤供应足够的营养素。因此,抑制谷氨酰胺酶可以减少对分解肌肉的需要。在某些实施方案中,本发明涉及本化合物预防、抑制或减轻恶病质的用途。
最常见的神经递质是谷氨酸,其衍生自谷氨酰胺经由谷氨酰胺酶的酶促转化。已显示高水平的谷氨酸是神经毒性的。在对神经元细胞的创伤损害后,出现神经递质释放的升高,特别是谷氨酸。因此,谷氨酰胺酶的抑制作用已被假设为缺血性损害,例如中风后的治疗的一种手段(Newcomb, PCT WO 99/09825)。亨廷顿氏病(Huntington’s disease)是一种进行性、致命性神经性病症。在亨廷顿氏病的遗传小鼠模型中,观察到该病的早期表现与失调的谷氨酸释放相关。在HIV-相关痴呆中,HIV感染的巨噬细胞表现出谷氨酰胺酶活性上调和谷氨酸释放增加,导致神经元损伤。类似地,在另一种神经性疾病中,在雷特综合征(Rett Syndrome)中的激活的小胶质细胞释放谷氨酸,引起神经元损害。过量的谷氨酸释放已与谷氨酰胺酶的上调相关。在经繁殖而减少谷氨酰胺酶水平的小鼠中,对精神病刺激性药物,例如安非他明的敏感性被极大地降低,因此提示谷氨酰胺酶抑制作用在治疗精神分裂症中可为有益的。双相型障碍是一种破坏性疾病,其以狂躁和抑郁的反复发作为标志。这种疾病用情绪稳定剂例如锂和丙戊酸盐治疗;然而,这些药物的长期使用似乎增加谷氨酸受体的丰度,其可导致药物的有效性随时间的推移而降低。因此,可供选择的治疗可以是通过抑制谷氨酰胺酶而减少谷氨酸的量。这可以与或可以不与情绪稳定剂联合使用。美金刚,一种N-甲基-D-天冬氨酸受体(NMDAR)的部分拮抗剂,是经批准治疗阿尔茨海默氏病的治疗剂。当前,正在进行将美金刚视为治疗血管性痴呆和帕金森氏病的手段的研究。因为已显示美金刚也部分地阻断NMDA谷氨酸受体,有理由推测通过抑制谷氨酰胺酶来降低谷氨酸水平也可治疗阿尔茨海默氏病、血管性痴呆和帕金森氏病。阿尔茨海默氏病、双相型障碍、HIV-相关痴呆、亨廷顿氏病、缺血性损害、帕金森氏病、精神分裂症、中风、创伤性损害和血管性痴呆仅仅是几种与增加的谷氨酸水平相关的神经性疾病。因此,用本文描述的化合物抑制谷氨酰胺酶可减轻或预防神经性疾病。因此,在某些实施方案中,所述化合物可以用于治疗或预防神经性疾病。
T淋巴细胞的激活诱导细胞生长、增殖和细胞因子产生,从而使细胞具有能量和生物合成需求。谷氨酰胺用作核苷酸合成的胺基团供体,而谷氨酸,谷氨酰胺代谢中的第一个成分,在氨基酸和谷胱甘肽合成中起直接的作用,以及能够进入用于能量产生的三羧酸循环(Krebs cycle)。有丝分裂原-诱导的T细胞增殖和细胞因子产生需要高水平的谷氨酰胺代谢,因此抑制谷氨酰胺酶可用作免疫调节的手段。在多发性硬化,即一种炎性自身免疫性疾病中,激活的小胶质细胞显示出上调的谷氨酰胺酶和释放增加的细胞外谷氨酸水平。谷氨酰胺水平经脓毒症、损伤、烧伤、手术和耐力训练而降低。这些情形将个体置于免疫抑制的危险中。事实上,一般来说,谷氨酰胺酶基因表达和酶活性两者在T细胞活动期间均增加。骨髓移植后给予谷氨酰胺的患者导致较低水平的感染和减少的移植物抗宿主疾病。T细胞增殖和激活涉及许多免疫性疾病,例如炎性肠病、克罗恩氏病、脓毒症、牛皮癣、关节炎(包括类风湿性关节炎)、多发性硬化、移植物抗宿主疾病、感染、狼疮和糖尿病。在本发明的某些实施方案中,本文所述的化合物可用于治疗或预防免疫性疾病。
肝性脑病(HE)表示肝病或门体分流术的患者中的一系列短暂性和可逆性神经和精神病功能障碍。HE不是一种单一的临床实体并可反映可逆性代谢性脑病、脑萎缩、脑水肿,或这些因素的组合;然而,目前的假设是大部分来自肠的氨的积聚在病理生理学方面起关键作用。谷氨酰胺在小肠、肾和肌肉合成中的脱氨作用都有利于氨的产生。由肝细胞清除或门体分流术造成的受损肝清除引起氨的积聚增加。氨毒性经由谷氨酰胺合成酶而影响脑中的星形胶质细胞,所述谷氨酰胺合成酶使氨代谢以产生增加的谷氨酰胺。谷氨酰胺继而将水吸收进星形胶质细胞,导致线粒体肿胀和氧化性功能障碍。所产生的脑水肿被认为引起在HE中观察到的神经功能障碍。在本发明的某些实施方案中,本文所述的化合物可用来治疗或预防HE。
已显示出背根神经节中的初级感觉神经元在炎症后升高其谷氨酰胺酶活性。认为作为结果的增加的谷氨酸产生促使中枢和外周二者敏感化,确定为疼痛。本发明的一个方面为本文的化合物用于治疗或减轻疼痛的用途。在某些实施方案中,疼痛可以是神经性疼痛、化学疗法-诱导的疼痛或炎性疼痛。
高血糖水平、高胰岛素水平,和胰岛素抵抗是发展糖尿病的危险因素。类似地,高血压是发生心血管疾病的危险因素。在最近得自大规模的人群组(cohort)研究的报告中,这四种危险因素与血流中的谷氨酰胺-对-谷氨酸的比率呈负相关性。此外,血浆谷氨酰胺-对-谷氨酸的比率与糖尿病在12年中的最终发病率呈负相关性。采用动物模型的实验与这些结果一致。喂给富含谷氨酰胺饮食的小鼠在空腹6小时后的葡萄糖耐受试验中表现出较低的血糖水平,和将谷氨酰胺腹膜内注射进入小鼠快速地降低其血压。因此,似乎合理的是谷氨酰胺酶抑制剂,其引起谷氨酰胺水平增加并降低谷氨酸水平,将降低糖尿病和心血管性疾病的发病率。特别是,肝和小肠是患糖尿病动物的谷氨酰胺利用的主要场所,而谷氨酰胺酶活性在链脲霉素(streptozotocin)-诱导的糖尿病大鼠的这些器官中高于正常(Watford等, Biochem J, 1984;Mithieux等, Am J Physiol Endrocrinol Metab,2004)。在本发明的某些实施方案中,本文所述的化合物可用于治疗糖尿病。在本发明的其它实施方案中,本化合物可用于降低高血压。
在某些实施方案中,治疗或预防癌症、免疫性疾病和神经性疾病的方法可包括联合化疗剂给予如本文描述的式(I)化合物的结晶化合物或盐。可以与本发明的化合物联合给予的化疗剂包括:氨鲁米特、安吖啶、阿那曲唑、天冬酰胺酶、卡介苗(BacillusCalmette-Guérin vaccine) (bcg)、比卡鲁胺、博来霉素、布舍瑞林、白消安、喜树碱(campothecin)、卡倍他滨、卡铂、卡莫司汀、苯丁酸氮芥、氯喹、顺铂、克拉屈滨、氯膦酸(clodronate)、秋水仙碱、环磷酰胺、环丙孕酮、阿糖胞苷、达卡巴嗪、放线菌素D、柔红霉素、脱甲绿胶酶素、二氯乙酸酯、己二烯雌酚、己烯雌酚、多西他赛、多柔比星、表阿霉素、雌二醇、雌莫司汀、依托泊苷、依维莫司、依西美坦、非格司亭、氟达拉滨、氟氢可的松、氟尿嘧啶、氟甲睾酮、氟他胺、吉西他滨、染料木素、戈舍瑞林、羟基脲、伊达比星、异环磷酰胺、伊马替尼、干扰素、伊立替康、来曲唑、亚叶酸、亮丙瑞林、左旋咪唑、洛莫司汀、氯尼达明、氮芥、甲羟孕酮、甲地孕酮、美法仑、巯基嘌呤、美司钠、二甲双胍、甲氨蝶呤、丝裂霉素、米托坦、米托蒽醌、尼鲁米特、诺考达唑、奥曲肽、奥沙利铂、紫杉醇、帕米膦酸盐、喷司他丁、哌立福辛、普卡霉素、卟吩姆(porfimer)、丙卡巴肼、雷替曲塞、利妥昔单抗、索拉非尼、链佐星、舒尼替尼、苏拉明、他莫昔芬、替莫唑胺、坦罗莫司、替尼泊苷、睾酮、硫鸟嘌呤、塞替派、二氯二茂钛(titanocene dichloride)、托泊替康、曲妥珠单抗、维A酸、长春碱、长春新碱、长春地辛,或长春瑞滨。
已开发用于治疗癌症的许多组合疗法。在某些实施方案中,本发明的化合物可以与组合疗法联合给予。本发明的化合物可以联合给予的组合疗法的实例包括在表1中。
表1:用于治疗癌症的示例性组合疗法
在某些实施方案中,本发明的化合物可与免疫调节剂联合给予。本发明的化合物可以在组合疗法中与之联合给予的免疫调节剂的实例包括粒细胞集落刺激因子(G-CSF)、干扰素、咪喹莫特、IL-2、IL-7、IL-12、各种趋化因子、合成的胞嘧啶磷酸-鸟苷(CpG)寡脱氧核苷酸、葡聚糖,和合成小分子例如阿普斯特(apremilast)、CC-122、CC-11006、CC-10015、来那度胺、泊马度胺(pomalidomide),和沙利度胺。在某些实施方案中,免疫调节剂是沙利度胺类似物,例如在WO 1999/46258、WO 2008/033567、WO 2010/093434、WO 2010/093605、WO2011/100380,和WO 2012/097116中公开的那些。
在某些实施方案中,本发明的化合物可与选自酶抑制剂(例如激酶抑制剂)、有丝分裂抑制剂、DNA-改性剂,和胞苷类似物的抗癌剂联合给予。本发明的化合物可以在组合疗法中与之联合给予的抗癌剂的实例包括微管装配抑制剂、AKT抑制剂、mTOR抑制剂、MEK抑制剂、RTK抑制剂、ATM抑制剂、ATR抑制剂、PI3K抑制剂、EGFR抑制剂、B-Raf抑制剂、C-kit抑制剂、DNA交联剂、DNA嵌入剂,和胞苷类似物。在某些实施方案中,抗癌剂是长春新碱、卡铂、顺铂、吉西他滨、MK2206、依维莫司、曲美替尼(trametinib)、舒尼替尼、索拉非尼、BEZ235、紫杉醇、多西他赛、厄洛替尼、司美替尼(selumetinib)、西罗莫司、曲美替尼(trametinib)、坦罗莫司、帕唑帕尼(pazopanib),或GSK1120212。
癌细胞的增殖需要脂质合成。正常地,用于脂质合成的乙酰基辅酶A由丙酮酸的线粒体库形成,丙酮酸衍生自糖酵解。然而在低氧条件下,例如通常在肿瘤环境中发现的那些低氧条件下,在线粒体内丙酮酸向乙酰基辅酶A的转化被下调。最近的研究揭示,在这样的低氧条件下,细胞取而代之地主要转变成使用这样的途径,所述途径涉及α-酮戊二酸的还原性羧化作用以生产用于脂质合成的乙酰基辅酶A。在这个途径中的第一个步骤涉及经由谷氨酰胺酶将谷氨酰胺转化为谷氨酸。随后,谷氨酸被转化为α-酮戊二酸,而生成的α-酮戊二酸在由异柠檬酸脱氢酶介导的还原性羧化步骤中被转化为异柠檬酸。转换到这种还原性羧化作用途径也发生在某些肾癌细胞系中,所述肾癌细胞系含有或者受损的线粒体或者减弱的信号,供诱导负责将糖酵解丙酮酸转化为乙酰基辅酶A的酶。一种类似的转换发生在暴露于线粒体呼吸链抑制剂例如二甲双胍、鱼藤酮和抗霉素的细胞中。因此,在本发明的某些实施方案中,发明人提议使用线粒体呼吸链抑制剂和谷氨酰胺酶抑制剂的组合以同时地增加癌细胞对用于脂质合成的谷氨酰胺酶-依赖性途径的依赖性,同时恰好抑制这些途径。
对肿瘤细胞中糖酵解的依赖性增加很可能是由于低氧的肿瘤环境削弱了线粒体呼吸。此外,葡萄糖的耗尽诱导用MYC致癌基因转化的细胞的细胞凋亡。这些结果提示抑制糖酵解将具有预防癌细胞增殖的治疗价值。目前存在许多文献记载的糖酵解抑制剂。然而,如Zhao等(2012)所指出的,“可获得的糖酵解抑制剂通常不是很有效的,且需要高剂量,而高剂量可引起高水平的系统毒性”。因为癌细胞典型地以比正常细胞更高的水平利用葡萄糖和谷氨酰胺二者,那些代谢物的每一种的弱化的利用将可能具有协同作用。因此,在本发明的某些实施方案中,发明人提议使用糖酵解途径抑制剂和谷氨酰胺酶抑制剂的组合。这样的糖酵解抑制剂包括2-脱氧葡萄糖、氯尼达明、3-溴代丙酮酸、伊马替尼(imatinib)、羟基硫胺素、雷帕霉素,及其药理学等价物。糖酵解可通过耗尽NAD+,经由通过聚(ADP-核糖)聚合酶激活的途径的DNA烷基化剂而诱导的DNA损害被间接地抑制。因此,在本发明的某些实施方案中,发明人提议使用DNA烷基化剂和谷氨酰胺酶抑制剂的组合。癌细胞利用磷酸戊糖途径连同糖酵解途径一起,以产生衍生自葡萄糖的代谢中间体。因此,在本发明的另一个实施方案中,发明人提议使用磷酸戊糖抑制剂例如6-氨基烟酰胺连同谷氨酰胺酶抑制剂的组合。
在某些实施方案中,本发明的结晶化合物或盐可以与癌症治疗的非化学方法联合给予。在某些实施方案中,本发明的化合物可以与放射疗法联合给予。在某些实施方案中,本发明的化合物可以与手术、与热消融疗法、与聚焦超声疗法、与冷冻疗法,或与这些疗法的任何组合联合给予。
在某些实施方案中,不同的本发明的化合物可以与一种或多种本发明的其它化合物联合给予。而且,这样的组合可以与其它治疗剂,例如其它适合用于治疗癌症、免疫性疾病或神经性疾病的药物,例如上文指定的药物联合给予。
在某些实施方案中,本发明提供一种药剂盒,其包含:a) 一种或多种单一剂型的本发明的结晶化合物或盐;b) 一种或多种如上提及的单一剂型的化疗剂;和 c) 给予本发明的结晶化合物或盐和化疗剂的使用说明书。
本发明提供一种药剂盒,其包含:
a) 含有本发明的结晶化合物或盐的药物制剂(例如,一种或多种单一剂型);和
b) 给予药物制剂,例如用于治疗或预防上文讨论的任何病症的使用说明书。
在某些实施方案中,药剂盒还包括用于联合给予包含本发明的结晶化合物或盐的药物制剂与如上提及的化学治疗剂的使用说明书。在某些实施方案中,药剂盒还包括第二种药物制剂(例如,作为一种或多种单一剂型),其包含如上提及的化学治疗剂。
药物组合物
在某些实施方案中,本发明涉及包含式(I)化合物的结晶化合物或盐和一种或多种药学上可接受的赋形剂的药物组合物。
示例性的药学上可接受的赋形剂在此提出,并包括例如粘合剂、崩解剂、润滑剂、矫味剂、增溶剂、助悬剂、乳化剂、包衣剂、环糊精,和/或缓冲剂。虽然剂量将根据患者的症状、年龄和体重,要治疗或预防的疾病性质和严重性,给药途径和药物的形式而变化,一般来说,对于成人患者推荐从0.01至3000 mg化合物的每日剂量,并且这可以单一剂量或以分剂量给予。可与载体材料混合以产生单一剂型的活性成分的量将通常是产生治疗效果的化合物的量。
就给定的患者中的治疗效果而言,将产生最有效的结果的给药的准确次数和/或组合物的量将取决于特定化合物的活性、药代动力学,和生物利用度,患者的生理状况(包括年龄、性别、疾病类型和阶段,一般身体状况,对给定剂量的响应,和药物类型),给药途径等。然而,上述指导方针可被用作微调治疗的基础,例如,确定给药的最佳次数和/或量,这将不需要超过由监测患者和调整剂量和/或时间选择组成的常规实验。
在某些实施方案中,组合物被给予的个体是哺乳动物例如人,或非-人哺乳动物。当给予动物,例如人时,所述组合物或化合物优选地作为包含,例如,本发明的化合物和药学上可接受的载体的药物组合物给予。药学上可接受的载体是本领域熟知的并包括,例如,含水溶液例如水或生理缓冲盐水或其它溶剂或溶媒例如二醇、甘油、油例如橄榄油,或可注射的有机酯。在一个优选的实施方案中,当这样的药物组合物给予人,特别是用于侵入途径给药(即,避开通过上皮屏障运输或扩散的途径,例如注射或植入)时,含水溶液是无热原的,或基本上无热原的。可选择赋形剂,例如,以实现药物的延迟释放或选择性地靶向一或多个细胞、组织或器官。药物组合物可呈剂量单位形式例如片剂、胶囊(包括粉末胶囊和明胶胶囊)、颗粒剂、用于重构的冻干制剂、粉末剂、溶液剂、糖浆剂、栓剂、注射剂等。组合物也可存在于透皮递送系统,例如皮肤贴剂中。组合物也可存在于适合局部给药的溶液剂,例如通过眼粘膜给予的滴眼剂中。
药学上可接受的载体可含有生理学上可接受的试剂,其起着例如稳定、增加化合物例如本发明的化合物的溶解性,或增加其吸收的作用。这样的生理学上可接受的试剂包括,例如,碳水化合物,例如葡萄糖、蔗糖或右旋糖酐、抗氧化剂,例如抗坏血酸或谷胱甘肽,螯合剂,低分子量蛋白或其它稳定剂或赋形剂。药学上可接受的载体,包括生理学上可接受的试剂的选择取决于例如,组合物的给药途径。制剂或药物组合物可以是自乳化药物递送系统或自微乳化药物递送系统。药物组合物(制剂)也可以是脂质体或其它聚合物基质,其中可包含例如本发明的化合物。例如包括磷脂或其它脂质的脂质体是无毒性的、生理学上可接受的和可代谢的载体,其制备和给药都是相对简单的。
本文使用短语"药学上可接受的"是指在合理的医学判断范围内,适合用于与人和动物的组织接触,而无过度的毒性、刺激性、过敏反应,或其它问题或并发症,与合理的利益/风险比相称的那些化合物、材料、组合物和/或剂型。
如本文所用的短语"药学上可接受的载体"意指药学上可接受的材料、组分或溶媒,例如液体或固体填充剂、稀释剂、赋形剂、溶剂或包封材料。每种载体在与制剂的其它成分适配和对患者无害的意义上,必须是"可接受的"。可用作药学上可接受的载体的材料的一些例子包括:(1) 糖,例如乳糖、葡萄糖和蔗糖;(2) 淀粉,例如玉米淀粉和马铃薯淀粉;(3) 纤维素,及其衍生物,例如羧基甲基纤维素钠、乙基纤维素和醋酸纤维素;(4) 粉末化黄蓍胶;(5) 麦芽;(6) 明胶;(7) 滑石粉;(8) 赋形剂,例如可可酯和栓剂蜡;(9) 油,例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油和豆油;(10) 二醇,例如丙二醇;(11) 多元醇,例如甘油、山梨醇、甘露醇和聚乙二醇;(12) 酯,例如油酸乙酯和月桂酸乙酯;(13)琼脂;(14) 缓冲剂,例如氢氧化镁和氢氧化铝;(15) 藻酸;(16) 无热原水;(17) 等渗盐水;(18) 林格氏溶液;(19) 乙醇;(20) 磷酸盐缓冲溶液;和 (21) 其它用于药物制剂中的无毒适配物质。在某些实施方案中,本发明的药物组合物是无热原的,即,当给予患者时,并不引起显著的温度升高。
术语“药学上可接受的盐”指所述化合物的相对无毒的、无机和有机酸加成盐。这些盐可在化合物的最终分离和纯化期间原位制备,或通过使其游离碱形式的纯化的化合物分别与合适的有机或无机酸反应,并分离如此形成的所述盐。代表性的盐包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、磷酸盐、硝酸盐、乙酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、苯甲酸盐、乳酸盐、磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、延胡索酸盐、琥珀酸盐、酒石酸盐、萘酸盐(naphthylate)、甲磺酸盐、葡庚糖酸盐、乳糖醛酸盐、月桂基磺酸盐,和氨基酸盐等。结晶盐的制备在以下实施例中详细说明(见,例如,Berge等(1977) “药用盐”, J. Pharm. Sci. 66: 1-19)。
在其它情况下,可用于本发明的方法的化合物可含有一或多个酸性官能团,因此,能够与药学上可接受的碱形成药学上可接受的盐。术语“药学上可接受的盐”在这些例子中指化合物的相对无毒的无机和有机碱加成盐。这些盐可同样地在化合物的最终分离和纯化期间原位制备,或通过使其游离酸形式的纯化的化合物分别与合适的碱,例如药学上可接受的金属阳离子的氢氧化物、碳酸盐,或碳酸氢盐,与氨,或与药学上可接受的有机伯胺、仲胺或叔胺反应。代表性的碱金属或碱土金属盐包括锂、钠、钾、钙、镁,和铝盐等。对形成碱加成盐有用的代表性有机胺包括乙胺、二乙胺、乙二胺、乙醇胺、二乙醇胺、哌嗪等(见,例如,Berge等,同上)。
可通过多种给药途径中的任何一种给予患者药物组合物(制剂),所述给药途径包括,例如,口服(例如,作为在水性或非-水性溶液或悬浮液中的浸液、片剂、胶囊(包括粉末胶囊和明胶胶囊)、大丸剂(boluses)、粉末剂、颗粒剂、应用于舌头的糊剂);通过口腔粘膜吸收(如,舌下);肛门、直肠或阴道(例如,作为阴道栓、霜剂或泡沫剂);胃肠外(包括肌内、静脉内、皮下或鞘内,作为例如,无菌溶液或悬浮液);鼻内;腹膜内;皮下;透皮(例如作为应用于皮肤的贴剂);和局部(例如,作为应用于皮肤的霜剂、软膏剂或喷雾剂,或作为滴眼剂)。所述化合物也可为吸入而配制。在某些实施方案中,化合物可简单地溶于或悬浮于无菌水中。合适的给药途径和适合于所述给药途径的组合物的细节可例如参见美国专利号6,110,973、5,763,493、5,731,000、5,541,231、5,427,798、5,358,970和4,172,896,以及其中引用的专利。
制剂可以便利地以单位剂型存在并可以通过制药领域中熟知的任何方法制备。可与载体材料混合以产生单一剂型的活性成分的量将取决于要治疗的宿主、特定的给药方式而变化。可与载体材料混合以产生单一剂型的活性成分的量将通常是产生治疗效果的化合物的量。一般来说,按照百分比计,该量范围为从约1 %至约99 %活性成分,优选从约5 %至约70 %,最优选从约10 %至约30 %。
制备这些制剂或组合物的方法包括使活性化合物,例如本发明的化合物,与载体和任选的一种或多种辅助成分混合的步骤。一般来说,通过使本发明的化合物与液体载体,或细分散的固体载体,或二者均匀和充分地混合,然后如果必要的话,使产物成形来制备制剂。
适合于口腔给药的本发明的制剂可以胶囊(包括粉末胶囊和明胶胶囊)、扁囊剂、丸剂、片剂、糖锭剂(使用香料基质(flavored basis),通常是蔗糖和阿拉伯胶或黄蓍胶)、冻干制剂、粉剂、颗粒剂、或作为在水性或非水性液体中的溶液剂或悬浮剂,或作为水包油或油包水液体乳剂,或作为酏剂或糖浆剂,或作为软锭剂(使用惰性基质,例如明胶和甘油,或蔗糖和阿拉伯胶)和/或作为漱口剂等,各自含有预定量的本发明化合物作为活性成分。组合物或化合物也可作为大丸剂、药糖剂或糊剂给药。
为制备口腔给药的固体剂型(胶囊(包括粉末胶囊和明胶胶囊)、片剂、丸剂、糖衣丸、粉末剂、颗粒剂等),将活性成分与一种或多种药学上可接受的载体混合,例如柠檬酸钠或磷酸二钙、和/或任何以下的载体:(1)填充剂或增量剂,例如淀粉、乳糖、蔗糖、葡萄糖、甘露醇和/或硅酸;(2) 粘合剂,例如,羧甲基纤维素、藻酸盐、明胶、聚乙烯吡咯烷酮、蔗糖和/或阿拉伯胶;(3) 湿润剂,例如甘油;(4) 崩解剂,例如琼脂-琼脂、碳酸钙、马铃薯或木薯淀粉、藻酸、某些硅酸盐,和碳酸钠;(5) 溶液阻滞剂,例如石蜡;(6) 吸收促进剂,例如季胺化合物;(7) 润湿剂,例如,鲸蜡醇和单硬脂酸甘油酯;(8) 吸收剂,例如高岭土和膨润土;(9)润滑剂,例如滑石粉、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,及其混合物;(10) 络合剂(complexing agents),例如,改性和未改性的环糊精;和 (11) 着色剂。在胶囊(包括粉末胶囊和明胶胶囊)、片剂和丸剂的情况下,药物组合物也可包含缓冲剂。也可使用类似类型的固体组合物,使用这样的赋形剂如乳糖(lactose)或乳糖(milk sugars),以及高分子量聚乙二醇等作为在软和硬-填充明胶胶囊中的填充剂。
片剂可以通过压制或模制,任选地用一种或多种辅助成分制得。压制片剂可以使用粘合剂(例如,明胶或羟丙基甲基纤维素)、润滑剂、惰性稀释剂、防腐剂、崩解剂(例如,羟基乙酸淀粉钠或交联羧甲基纤维素钠)、表面活性剂或分散剂制备。模制片剂可以通过在合适的机器中将经惰性液体稀释剂湿润的粉末化化合物的混合物模压成形而制得。
药物组合物的片剂和其它固体剂型,例如糖锭剂、胶囊(包括粉末胶囊和明胶胶囊)、丸剂和颗粒剂,可任选划痕或用包衣和壳制备,例如肠溶包衣和制药领域熟知的其它包衣。它们也可使用例如各种比例的羟丙基甲基纤维素(以提供所需的释放曲线)、其它聚合物基质、脂质体和/或微球体来配制,以提供缓慢释放或控制释放其中的活性成分。它们可以例如,通过细菌截留滤器而过滤,或通过包括可溶于无菌水的无菌固体组合物形式的灭菌剂,或通过在临用前包括某些其它无菌可注射的介质来灭菌。这些组合物也可任选地含有遮光剂并且可以具有仅释放活性成分的组分,或优先地在胃肠道的某些部分,任选地,以延迟方式释放。可以使用的包埋组合物的实例包括聚合物质和蜡。活性成分也可以微囊形式存在,如果合适的话,与一种或多种上述赋形剂一起。
可用于口腔给药的液体剂型包括药学上可接受的乳剂、用于重构的冻干制剂、微乳剂、溶液剂、混悬剂、糖浆剂和酏剂。除了活性成分,液体剂型还可含有本领域常用的惰性稀释剂,例如,水或其它溶剂、环糊精及其衍生物、增溶剂和乳化剂,例如乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苄醇、苯甲酸苄酯、丙二醇、1,3-丁二醇、油(特别是棉籽油、花生油、玉米油、胚芽油、橄榄油、蓖麻油和芝麻油)、甘油、四氢呋喃醇、聚乙二醇和脱水山梨醇脂肪酸酯,及其混合物。
除了惰性稀释剂,本发明的口服组合物还可包括辅助剂例如湿润剂、润滑剂、乳化剂和助悬剂例如月桂基硫酸钠和硬脂酸镁,或甜味剂、矫味剂、着色剂、香料、防腐剂,或抗氧化剂。
除了活性化合物,混悬剂还可含有助悬剂,例如,乙氧基化异硬脂醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、偏氢氧化铝(aluminum metahydroxide)、膨润土、琼脂-琼脂和黄蓍胶,及其混合物。
用于直肠、阴道或尿道给药的药物组合物的制剂可以作为栓剂呈现,其可以通过使一种或多种活性化合物与一种或多种合适的非刺激性赋形剂或载体混合来制备,所述赋形剂或载体包括,例如,可可酯、聚乙二醇、栓剂蜡或水杨酸酯(salicylate),且其于室温下为固体,但在体温下为液体,因而将在直肠或阴道腔中融化并释放活性化合物。
给予口腔的药物组合物的制剂可以作为漱口剂,或口腔喷雾剂,或口腔软膏剂呈现。
作为选择或另外地,组合物可被配制为用于经由导管、支架、线(wire),或其它管腔内装置递送。经由这样的装置递送可以特别用于递送至膀胱、尿道、输尿管、直肠或小肠。
适合于阴道给药的制剂也包括阴道栓、棉塞、霜剂、凝胶剂、糊剂、泡沫剂或喷雾剂制剂,所述制剂含有本领域已知合适的此类载体。
用于局部或透皮给药的剂型包括粉末剂、喷雾剂、软膏剂、糊剂、霜剂、洗剂、凝胶剂、溶液剂、贴剂和吸入剂。活性化合物可以在无菌条件下与药学上可接受的载体,和与可能需要的任何防腐剂、缓冲剂,或抛射剂混合。
除了活性化合物,软膏剂、糊剂、霜剂和凝胶剂还可含有赋形剂,例如动物和植物脂肪、油、蜡、石蜡、淀粉、黄蓍胶、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅酸、滑石粉和氧化锌,或其混合物。
除了活性化合物,粉末剂和喷雾剂还可含有赋形剂例如乳糖、滑石粉、硅酸、氢氧化铝、硅酸钙和聚酰胺粉末,或这些物质的混合物。喷雾剂可另外地含有惯用的抛射剂,例如氯氟烃和挥发性的未取代烃,例如丁烷和丙烷。
本文描述的化合物可供选择地经气溶胶给予。这通过制备含水气溶胶、脂质体制剂,或含有组合物的固体颗粒实现。可使用一种非水性(例如,碳氟化合物抛射剂)混悬剂。声波喷雾器是优选的,因为它们最大限度地减少药物对剪切力的暴露,后者可导致化合物的降解。
普通地,含水气溶胶通过将药物的水性溶液或混悬液与常规的药学上可接受的载体和稳定剂一起配制来制备。载体和稳定剂随着特定组合物的需求而变化,但通常包括非离子型表面活性剂(吐温类,、普流罗尼克、脱水山梨醇酯、卵磷脂、乳浮)、药学上可接受的共溶剂例如聚乙二醇、无害蛋白像血清白蛋白、油酸、氨基酸例如甘氨酸、缓冲剂、盐、糖,或糖醇。气溶胶一般由等渗溶液制备。
透皮贴剂具有提供控制递送本发明的化合物至身体的附加优点。这样的剂型可通过将活性化合物溶解于或分散于适当介质中而制得。也可使用吸收促进剂以增加化合物穿过皮肤的流量。这样的流通速率可通过或者提供速率控制膜,或者将化合物分散于聚合物基质或凝胶中进行控制。
也考虑了在本发明的范围内的眼科制剂,眼膏剂、粉末剂、溶液等。示例性眼科制剂描述于美国公布号2005/0080056、2005/0059744、005/0031697和2005/004074和美国专利号6,583,124中,其内容通过引用结合到本文中。如果需要,液体眼科制剂具有类似于泪液、房水或玻璃体液的性质或与这样的液体相容。优选的给药途径是局部给药(例如,局部给药,例如滴眼剂,或经由植入物给药)。
本文所用短语"胃肠外给药"和"非肠道给药"意指非经肠的给药和局部给药的方式,通常通过注射,并包括,但不限于静脉内、肌内、动脉内、鞘内、囊内、眼眶内、心内、皮内、腹膜内、经气管、皮下、角质层下、关节内、囊下、蛛网膜下、脊椎内和胸骨内注射和输注。适合于胃肠外给药的药物组合物包含与一种或多种药学上可接受的无菌等渗水性或非水性溶液、分散液、悬浮液或乳液,或无菌粉末组合的一种或多种活性化合物,所述粉末可以在临用前重构成无菌可注射的溶液或分散液,其可含有抗氧化剂、缓冲剂、抑菌剂、使制剂与计划的接受者的血液等渗的溶质,或助悬剂或增稠剂。
如本文所用的短语“系统给药”、“全身给药”、“外周给药”和“周围给药”意指给予不直接进入中枢神经系统的配体、药物,或其它材料,以使它进入患者的系统,因而经受代谢和其它类似的过程,例如,皮下给予。
可以用于本发明的药物组合物中的合适的水性和非水性载体的实例包括水、乙醇、多元醇(例如甘油、丙二醇、聚乙二醇等),及其合适的混合物,植物油,例如橄榄油,和可注射的有机酯,例如油酸乙酯。例如,通过使用包衣材料,例如卵磷脂,通过在分散液的情况下维持需要的粒度,和通过使用表面活性剂,可维持适当的流动性。
这些组合物也可含有辅助剂例如防腐剂、润湿剂、乳化剂和分散剂。预防微生物的作用可以通过包含各种抗菌剂和抗真菌剂,例如,对羟基苯甲酸酯,氯丁醇、苯酚、山梨酸等来确保。在组合物中包含等渗剂,例如糖、氯化钠等也可是需要的。此外,可注射的药物形式的延长吸收可通过包含延长吸收的试剂例如单硬脂酸铝和明胶来实现。
在某些情况下,为延长药物的作用,期望减慢来自皮下或肌内注射的药物的吸收。这可通过使用具有水溶性差的结晶或无定形材料的液体混悬剂实现。药物的吸收速率则取决于其溶解速率,这继而可取决于结晶粒度和晶型。作为选择,胃肠外给予药物形式的延迟吸收可通过使药物溶解于或悬浮于油性溶媒中实现。
可注射的贮库形式通过在生物可降解的聚合物例如聚乙交酯-聚丙交酯中形成本化合物的微囊化基质而制得。根据药物与聚合物的比例,和所用的特定聚合物的性质,可控制药物释放的速率。其它生物可降解的聚合物的实例包括聚(原酸酯)和聚(酐)。可注射的贮库制剂也通过使药物嵌入与身体组织相容的脂质体或微乳液中制备。
药物的制剂可经口服、胃肠外、局部,或直肠给予。当然,它们通过适合于各自的给药途径的形式给予。例如,它们以片剂或胶囊形式,通过注射、吸入、眼用洗剂、软膏剂、栓剂、输注给予;通过洗剂或软膏剂局部给予;和通过栓剂经直肠给予。优选口服给药。
为用于本发明的方法,活性化合物可原样给予或作为含有,例如,与药学上可接受的载体组合的0.1-99.5% (更优选0.5-90%)的活性成分的药物组合物给予。
也可由可再填充的或生物可降解的装置提供导入的方法。近年来为控制递送药物,包括蛋白质的生物药物,已开发了各种缓慢释放聚合物装置并在体内进行了测试。各种生物相容性聚合物(包括水凝胶),包括生物可降解的和非-降解的聚合物二者,可用于形成在特定的靶位点持续释放化合物的植入物。
这些化合物可给予人和其它动物,以供经任何合适的给药途径的疗法,所述给药途径包括经口、鼻,如通过例如喷雾、直肠、阴道内、非肠道、脑池内,以及局部,如通过粉末剂、软膏剂或滴剂,包括颊下和舌下。
不管选择的给药途径,化合物(其可以合适的水合形式使用),和/或本发明的药物组合物,通过本领域技术人员熟知的常规方法配制为药学上可接受的剂型。
药物组合物中活性成分的实际剂量水平可以变化,以获得有效达到对特定患者的所需治疗反应的一定量的活性成分、组合物,和给药方式,而对患者没有毒性。
选择的剂量水平将取决于多种因素,包括具体化合物的活性或所用化合物,或其酯、盐或酰胺的组合、给药途径、给药次数、所用具体化合物的排泄速率、治疗持续时间、与具体化合物组合使用的其它药物、化合物和/或物质、所治疗患者的年龄、性别、体重、状况、一般健康和先前病史等医学领域熟知的因素。一般来说,本发明的组合物可以供胃肠外给予的含有约0.1-10% w/v的本文公开化合物(在其它物质中)的水性溶液提供。典型的剂量范围是从约0.01至约50 mg/kg体重每天,以1个单一剂量或2-4个分剂量给予。每个分剂量可含有相同的或不同的本发明的化合物。
具有本领域普通技能的医师或兽医可容易地确定和开具治疗有效量的所需药物组合物。例如,医师或兽医可以低于达到所需治疗效果所需要的水平的药物组合物或化合物的剂量开始并逐渐增加剂量直至达到所需效果。涉及本治疗方法的化合物的“治疗有效量”,指化合物在制剂中的量,其当作为所需剂量方案的部分给予(哺乳动物,优选人)时,根据为治疗疾病或病症或为化妆目的的临床可接受的标准(例如,以合理的利益/风险比应用于任何医学治疗),可减轻症状,改善病情,或延缓疾病状态的发作。一般认为化合物的有效量将根据患者的体重、性别,年龄及病史而变化。影响有效量的其它因素可包括,但不限于患者病症的严重性、所治疗的疾病、化合物的稳定性,以及如果需要,与本发明化合物一起给予的另一种类型的治疗剂。较大的总剂量可通过多次给予药物而递送。确定功效和剂量的方法是本领域技术人员已知的(Isselbacher等(1996) 哈里森内科学原理(Harrison’sPrinciples of Internal Medicine) 第13版, 1814-1882,通过引用结合到本文中)。
一般来说,用于本发明的组合物和方法的活性化合物的合适日剂量将是有效产生治疗效果的最低剂量的化合物的量。这样的有效剂量通常将取决于上述因素。
如果需要,活性化合物的有效日剂量可作为1、2、3、4、5、6或更多个亚剂量给予,其在整天以合适间隔,任选地以单位剂型分开给予。在本发明的某些实施方案中,活性化合物可以每日给予2或3次。在优选的实施方案中,活性化合物将每日给予1次。
接受这种治疗的患者是有需要的任何动物,包括灵长类动物,特别是人,和其它哺乳动物例如马、牛、猪和羊;以及一般家禽和宠物。
在某些实施方案中,本发明的化合物可以单独使用或与另一种类型的治疗剂联合使用。如本文所用的,短语“联合给药”指二种或更多种不同的治疗化合物的任何给药形式,以便在先前给予的治疗化合物在体内仍然有效时给予第二化合物(例如,两种化合物在患者中同时有效,这可包括两种化合物的协同作用)。例如,不同的治疗化合物可以同一制剂或者以分开的制剂,同时地或者顺序地给予。在某些实施方案中,不同的治疗化合物可彼此在1小时、12小时、24小时、36小时、48小时、72小时或1周内给予。因此,接受这样治疗的个体可得益于不同的治疗化合物的联合作用。
本发明包括本发明化合物的药学上可接受的盐在本发明的组合物和方法中的用途。在某些实施方案中,本发明考虑的盐包括,但不限于烷基、二烷基、三烷基或四烷基铵盐。在某些实施方案中,本发明考虑的盐包括,但不限于L-精氨酸、苯乙苄胺(benenthamine)、苄星、甜菜碱、氢氧化钙、胆碱、地阿诺、二乙醇胺、二乙胺、2-(二乙基氨基)乙醇、乙醇胺、乙二胺、N-甲基葡糖胺、海巴明(hydrabamine)、1H-咪唑、锂、L-赖氨酸、镁、4-(2-羟基乙基)吗啉、哌嗪、钾、1-(2-羟基乙基)吡咯烷、钠、三乙醇胺、氨丁三醇和锌盐。在某些实施方案中,本发明考虑的盐包括,但不限于Na、Ca、K、Mg、Zn或其它金属盐。
药学上可接受的酸加成盐也可作为各种溶剂合物,例如与水、甲醇、乙醇、二甲基甲酰胺等的溶剂合物存在。也可制备这样的溶剂合物的混合物。这样的溶剂合物的来源可来自结晶的溶剂,制剂或结晶的溶剂固有的,或对于所述溶剂为外来的。
润湿剂、乳化剂和润滑剂,例如十二烷基硫酸钠和硬脂酸镁,以及着色剂、释放剂、包衣剂、甜味剂、矫味剂和芳香剂、防腐剂和抗氧化剂也可存在于组合物中。
药学上可接受的抗氧化剂的实例包括:(1)水-溶性抗氧化剂,例如抗坏血酸、半胱氨酸盐酸盐、硫酸氢钠、偏亚硫酸氢钠、亚硫酸钠等;(2) 油-溶性抗氧化剂,例如抗坏血酸棕榈酸酯、丁羟茴醚(BHA)、丁羟甲苯(BHT)、卵磷脂、没食子酸丙酯、α-生育酚等;和(3) 金属-螯合剂,例如柠檬酸、乙二胺四乙酸(EDTA)、山梨醇、酒石酸、磷酸等。
现在一般描述本发明,通过参考以下实施例将更容易理解本发明,包括所述实施例仅仅是为了说明本发明的某些方面和实施方案的目的,并不打算限制本发明。
实施例
材料和方法
X-射线衍射
用PANalytical X'Pert PRO MPD衍射计,使用Cu辐射的入射光束(使用Optix的长的、细焦点源产生),收集大多数X-射线粉末衍射图谱。椭圆分级多层镜(elliptically gradedmultilayer mirror)被用来聚焦通过样品并到达检测器上的Cu KαX-射线。在分析前,分析硅样品(NIST SRM 640d)以验证Si 111峰的观察位置与NIST-认证的位置一致。样本的样品被夹在3-μm-厚薄膜之间并以传输几何分析。光束截止、短的防散射延伸,和防散射刀口被用来最大限度地减少空气产生的背景。对于入射光束和衍射光束的索勒狭缝(Sollerslits)被用来最大限度地减少来自轴向散度的扩大。使用定位于240 mm的扫描位敏探测器(X'Celerator),从样品和数据收集器软件 v. 2.2b收集衍射图谱。
一个XRPD图谱用PANalytical X'Pert PRO MPD衍射计,使用采用一个长的、细焦点源和镍过滤器产生的Cu Kα辐射的入射光束收集。衍射计使用对称的Bragg-Brentano几何配置。在分析之前,分析硅样品(NIST SRM 640d)以验证Si 111峰的观察位置与NIST-认证的位置一致。样本的样品被制备为一种中心在硅零背景底物上的薄的环形层。防散射狭缝(SS)被用来最大限度地减少空气产生的背景。对于入射光束和衍射光束的索勒狭缝被用来最大限度地减少来自轴向散度的扩大。使用定位于240 mm的扫描位敏探测器(X'Celerator),从样品和数据收集器软件 v. 2.2b收集衍射图谱。
差示扫描量热法
DSC使用TA Instruments Q2000差示扫描量热仪进行。使用NIST-可追踪的铟金属进行温度校准。将样本放置在一个用盖覆盖的DSC铝盘中,并准确记录重量。将配置为样本盘的经称重的铝盘放置在单元格的参考侧。所用的盘为Tzero卷边盘(Tzero crimped pans),在热谱图上的注释域中缩写为“T0C”。将样本以10℃/min,从-30℃加热至250℃ (在热谱图上的方法领域中缩写为“(-30)-250-10”)。
热重分析
TG分析使用TA Instruments 2050热重分析仪进行。温度校准使用镍和Alumel™进行。将样本放置在一个铂盘中并插入TG炉中。在氮气吹洗下加热炉。将样本以10℃/min,从25℃加热至300℃ (在热谱图上的方法领域中缩写为“00-300-10”)。
实施例1:化合物CB-839的合成方案
注释:化合物670备选地被称为CB-839
向3升反应容器中装入2-(3-(三氟甲氧基)苯基)乙酸(93.34 g, 0.43 mol, 1.0equiv)、6-氯哒嗪-3-胺(55.51 g, 0.43 mol, 1.0 equiv.)、乙酸乙酯(1.42 L, 15 vol.相对于酸)、N,N-二异丙基乙胺(60.92 g, 0.47 mol, 1.1 equiv.),然后配备搅拌棒和温度探针。将反应容器的内容物置于氩气氛(g)下并搅拌15分钟,此时混合物是混浊的,在反应容器底部有固体。经由压力均衡加料漏斗,在40分钟的过程中,伴有20.3℃增加至28.1℃的温度下,向搅拌的混合物中加入丙基膦酸酐(T3P;300 mL在乙酸乙酯中的50%溶液, 0.47mmol, 1.1 equiv.)。在加入的过程中,混合物的颜色变红/橙色且浑浊消除。通过TLC (6:4己烷/乙酸乙酯)监测反应,通常运行时间为4-6小时。当认为反应完成时,加入水(1.5 L)并将混合物搅拌另外15分钟。将该混合物转移至分液漏斗并分层。有机层用水(1.5 L)洗涤,分离各层且有机层用10%氯化钠溶液(500 mL)洗涤。分离各层,将有机层转移至圆底烧瓶中并在减压下除去挥发物,得到灰白色、黄色固体。向烧瓶中加入己烷(500 mL)并剧烈搅拌内容物15分钟,然后过滤。用己烷(500 mL)再次洗涤固体并风干至恒定重量,提供N-(6-氯哒嗪-3-基)-2-(3-(三氟甲氧基)苯基)乙酰胺(112824):得量121.1 g, (85%)。1H NMR (300MHz, DMSO-d6) δ 11.63 (s, 1H), 8.38(d, J=9.4 Hz, 1H), 7.88(d, J=9.4 Hz, 1H),7.52 – 7.27(m, 4H), 3.90(s, 2H)。
向5升反应容器中装入4-氰基丁基溴化锌(2 L, 0.5 M在THF中, 1000 mmol, 3.0equiv,相对于112824),接着加入二氯(1,3-双(二苯基膦基)丙烷)镍(27.10 g, 0.05 mol,0.15 equiv.)、2-甲基四氢呋喃(400 mL, 3.6 vol. 相对于112824),然后配备搅拌棒和温度探针。将反应容器的内容物置于氩气氛下并经由压力均衡加料漏斗,在45分钟的过程中,伴有24.8℃增加至32.9℃的温度下,加入112824的2-甲基四氢呋喃溶液(110.56 g, 0.33mol, 1.0 equiv., 900 mL)。(在T=15分钟时插入25分钟中止,加入400 mL以允许混合物从32.6℃冷却至28.8℃)。通过TLC (1:1己烷/乙酸乙酯)监测反应,通常运行时间为4-6小时。当认为反应完成时,加入0.5 M HCl (1.5 L)并搅拌1小时,此时可见断相,低相变得透明并呈蓝色。将混合物转移至分液漏斗并分层。有机层用含水的、饱和乙二胺四乙酸溶液(1 L)洗涤2x、水(1 L)洗涤1x、10%氯化钠溶液(500 mL)洗涤1x,分离有机层,转移至3L圆底烧瓶中并在减压下除去挥发物,得到稠厚的深红色油。用乙酸乙酯(300 mL)稀释油状物并在减压下除去挥发物(重复两次添加)。然后使油与己烷(300 mL)混合并在减压下除去挥发物,得到赭石色蜡样固体。然后将该固体与己烷(500 mL)一起搅拌、过滤并风干至恒定重量,提供N-(6-(4-氰基丁基)哒嗪-3-基)-2-(3-(三氟甲氧基)苯基)乙酰胺(112825):得量105.7g(84%)。1H NMR (300 MHz, DMSO-d6) δ 11.41 (s, 1H), 8.28(d, J=9.2 Hz, 1H), 7.65(d, J=9.2 Hz, 1H), 7.52 – 7.27(m, 4H), 3.89(s, 2H), 2.92(t, J=7.5 Hz, 2H),2.56(t, J=7.0 Hz, 2H), 1.80 (m, 2H), 1.61 (m, 2H)。
使112825 (92.3 g, 0.24 mol, 1.0 equiv)溶于在3000 mL的3颈圆底烧瓶中的三氟甲苯(923 mL, 10.0 vol,相对于112825)中。向反应溶液中加入氨基硫脲(26.7 g,0.29 mol, 1.2 equiv.)。将三氟乙酸(369 mL, 4 vol.)边搅拌边缓慢加入到反应容器中。在具有顶部开放的回流冷凝器的65℃浴中加热反应浆液。5小时后,反应通常完成(通过LC/MS确定)。将反应溶液转移至4000 mL锥形烧瓶中并于0℃浴中冷却。用2.5N氢氧化钠(aq)(1800 mL, ~20 vol.)将pH调节至pH~8。当pH变成中性时出现沉淀。在复查pH之前,搅拌浆液30分钟。如果必要,用更多的2.5N氢氧化钠(aq)或1M HCl再次调节pH至pH = 6.5-8.5的范围内。通过Büchner漏斗过滤沉淀物并用乙酸乙酯(2 x 185 mL, 2 vol)淋洗两次。在高真空下干燥过滤材料至恒定重量,提供N-(6-(4-(5-氨基-1,3,4-噻二唑-2-基)丁基)哒嗪-3-基)-2-(3-(三氟甲氧基)苯基)乙酰胺(110826);得量94.2 g (87%)。1H NMR (300 MHz,DMSO-d6) δ 11.33 (s, 1H), 8.21(d, J=9.2 Hz, 1H), 7.58(d, J=9.2 Hz, 1H), 7.51-7.26(m, 4H), 6.99(s, 2H), 3.88(s, 2H), 2.87(m, 4H), 1.71 (m, 4H)。
向在250 mL的3颈圆底烧瓶中的110826 (5.5 g, 12.3 mmol, 1.0 equiv.)的N, N-二甲基乙酰胺(44 mL, 8.0 vol. 相对于110826)溶液中加入2-吡啶基乙酸(2.56 g,14.8 mmol, 1.2 equiv.)。将丙基膦酸酐(在乙酸乙酯中的11.0 g 50%溶液,17.3 mmol,1.41 equiv.)加入25 mL加料漏斗中并以5mL/min的速率滴加入反应溶液中。在加入期间,内部温度从20.1℃增加至26.1℃。4小时后,反应通常完成(通过LC/MS确定)。然后使反应溶液于0℃浴中冷却,用甲乙酮(50 mL)稀释。向搅拌的反应溶液中加入H2O (50 mL)。用2.5N氢氧化钠(aq) (28 mL)将pH调节至pH~6。黄色沉淀经抽吸过滤收集并用异丙醇和水(1:1,50 mL)淋洗。然后将风干的固体转移至100 mL圆底烧瓶中并在异丙醇和水(9:1, 50 mL)中制浆。将浆液加热至65.1℃的内部温度8小时,然后经16小时冷却至室温。经抽吸过滤收集灰白色沉淀物并用1 x 异丙醇(10mL)淋洗。在高真空下干燥滞留物至恒定重量,提供2-(吡啶-2-基)-N-(5-(4-(6-(2-(3-(三氟甲氧基)苯基)乙酰氨基)哒嗪-3-基)丁基)-1,3,4-噻二唑-2-基)乙酰胺(CB-839);得量5.27 g (76%)。1H NMR (300 MHz, DMSO-d6) δ 12.67(s, 1H), 11.32 (s, 1H), 8.53-8.49 (m, 1H), 8.22-8.19 (d, J = 9.12 Hz, 1H),7.78-7.76 (t, 1H), 7.58-7.26 (m, 7H), 4.01 (s, 2H), 3.87 (s, 2H), 3.01 (bs,2H), 2.90 (bs, 2H), 1.73 (bs, 4H)。
CB-839结晶游离碱,晶型B的XRD图谱示于图6中。CB-839游离碱,晶型B具有2θ值3.64;7.32;7.92;8.53;9.30;9.38;11.02;11.98;14.70;15.54;15.87;16.50;16.59;18.06;18.39;19.10;20.06;20.12;20.61;21.37;21.89;22.41;22.74;23.72;24.10;24.65;25.14;25.78;26.49;27.32;27.55;28.26;29.88;31.20;31.80;31.52;32.80;34.30;35.20;36.41;38.53;40.08;40.94;和43.86。
CB-839结晶游离碱,晶型A如下制备:
使CB-839游离碱,晶型B (2.02 g, 3.53 mmol)悬浮于配备有磁力搅拌棒、半球形加热罩和内部温度探针的150 mL 3颈圆底烧瓶中的异丙醇:甲苯:水(36.8 mL: 24.6 mL: 3.2mL, 32体积)的混合物中。经90分钟将淡黄色浆液加热至70℃的内部温度。移去加热罩以使黄色溶液冷却至室温。将反应浆液搅拌18小时,然后通过抽吸过滤收集。于70℃烘箱中真空干燥滤饼至恒定重量,提供结晶2-(吡啶-2-基)-N-(5-(4-(6-(2-(3-(三氟甲氧基)苯基)乙酰氨基)哒嗪-3-基)丁基)-1,3,4-噻二唑-2-基)乙酰胺(CB-839),游离碱,晶型A;得量1.60g (79%)。1H NMR (300 MHz, DMSO-d6) δ 12.65 (s, 1H), 11.29 (s, 1H), 8.50-8.48(m, 1H), 8.20-8.17 (d, J = 9.11 Hz, 1H), 7.77-7.75 (t, 1H), 7.57-7.54 (m,1H), 7.47-7.40 (m, 1H), 7.40-7.35 (m, 3H), 7.26-7.24 (m, 2H), 4.00 (s, 2H),3.85 (s, 2H), 3.01 (bs, 2H), 2.89 (bs, 2H), 1.73 (bs, 4H)。
CB-839结晶游离碱,晶型A的XRD图谱示于图7。CB-839游离碱,晶型A具有2θ值5.47;6.01;7.57;9.20;9.67;10.15;11.00;12.93;14.14;15.20;15.81;16.56;17.74;18.50;18.69;19.40;19.94;20.54;20.59;21.13;22.00;22.60;23.33;23.98;24.37;24.87;25.52;26.27;26.62;27.79;29.59;30.64;33.30;35.01;37.93;和38.72。
DSC数据显示结晶,无水CB-839,晶型A于约189℃熔化。
实施例2:化合物CB-839的盐的制备
2-(吡啶-2-基)-N-(5-(4-(6-(2-(3-(三氟甲氧基)苯基)乙酰氨基)哒嗪-3-基)丁基)-1,3,4-噻二唑-2-基)乙酰胺盐酸盐,晶型I (CB-839 HCl,晶型I)。在配备有内部温度探针、50 mL加料漏斗和磁力搅拌器的250 mL 3-颈圆底烧瓶中,将化合物670,或CB-839游离碱(4.57g, 8.00 mmol)在无水乙醇(69mL)中制浆。设置半球形织物罩以加热浆液至70℃的内部温度并于此所需的温度下保持90分钟。在一个关闭的50 mL圆底烧瓶中,将无水乙醇(23mL)与乙酰氯(0.682mL, 9.59 mmol)一起搅拌5分钟,然后加入加料漏斗中。以15 mL/min的速率加入乙醇化HCl。反应物的内部温度在加入期间下降至60.3℃。将浆液加入到溶液中并澄清5分钟,此时可见沉淀物。生成的浆液在5分钟内用湿冰浴冷却至15℃。移开浴并将浆液于室温下搅拌4小时。通过抽吸过滤收集灰白色固体,并将滞留物于75℃真空烘箱中干燥过夜,提供2-(吡啶-2-基)-N-(5-(4-(6-(2-(3-(三氟甲氧基)苯基)乙酰氨基)哒嗪-3-基)丁基)-1,3,4-噻二唑-2-基)乙酰胺盐酸盐晶型I (CB-839 HCl, 3.98g)。1H NMR (300MHz, DMSO-d6) δ 12.80 (s, 1H), 11.37 (s, 1H), 8.73 (d, J=5.31 Hz, 1H), 8.23(m, 2H), 7.75 (d, J=7.93 Hz, 1H), 7.68 (t, J=6.32 Hz, 1H), 7.62 (d, J=9.19Hz, 1H), 7.47 (t, J=8.09 Hz, 1H), 7.36 (m, 2H), 7.24 (d, J=7.90 Hz, 1H), 4.25(s, 2H), 3.86 (s, 2H), 3.03 (s, 2H), 2.89 (s, 2H), 1.73(s, 4H)。
XRD图谱示于图1。CB-839 HCl,晶型I具有2θ值8.62;9.53;11.63;15.89;16.70;17.26;18.18;19.10;19.80;21.09;22.16;22.69;23.46;24.63;25.22;25.49;25.91;26.72;28.45;29.38;31.39;31.82;32.76;33.61;33.74;34.27;34.91;35.53;39.36;和39.73。
2-(吡啶-2-基)-N-(5-(4-(6-(2-(3-(三氟甲氧基)苯基)乙酰氨基)哒嗪-3-基)丁基)-1,3,4-噻二唑-2-基)乙酰胺盐酸盐晶型II (CB-839 HCl,晶型II)。在配备有内部温度探针、1000 mL加料漏斗和机械搅拌器的5000 mL 3-颈圆底烧瓶中,将化合物670,或CB-839游离碱(129.5 g, 227 mmol)在无水乙醇(2590 mL)中制浆。设置半球形织物罩以加热浆液至60℃的内部温度并于此所需的温度下保持60分钟。在一个关闭的1000 mL圆底烧瓶中,将无水乙醇(648 mL)与乙酰氯(23.1 g, 295 mmol)一起搅拌10分钟,然后加入加料漏斗中。以34 mL/min的速率加入乙醇化HCl。加料漏斗用无水乙醇(130 mL)淋洗。使生成的浆液经15小时冷却至19℃。通过抽吸过滤收集灰白色固体,并将滞留物于75℃真空烘箱中干燥过夜,提供2-(吡啶-2-基)-N-(5-(4-(6-(2-(3-(三氟甲氧基)苯基)乙酰氨基)哒嗪-3-基)丁基)-1,3,4-噻二唑-2-基)乙酰胺盐酸盐晶型II (CB-839 HCl, 117.2 g)。1H NMR (300MHz, DMSO-d6) δ 12.76 (s, 1H), 11.32 (s, 1H), 8.67 (d, J=4.56 Hz, 1H), 8.21(d, J=9.16 Hz, 1H), 8.12 (t, J=7.33 Hz, 1H), 7.67 (d, J=7.78 Hz, 1H), 7.59(d, J=9.19 Hz, 2H), 7.44 (t, J=7.84 Hz, 1H), 7.35 (m, 2H), 7.24 (d, J=7.90Hz, 1H), 4.18 (s, 2H), 3.85 (s, 2H), 3.00 (s, 2H), 2.89 (s, 2H), 1.73(s, 4H)。
XRD图谱示于图2。CB-839 HCl,晶型II具有2θ值3.10;6.26;8.34;9.04;9.96;11.02;12.58;13.47;14.80;15.61;15.82;16.15;17.58;18.20;18.83;19.81;20.00;21.10;22.02;22.58;23.42;24.10;24.45;25.25;25.74;26.36;27.22;27.83;28.70;29.84;30.46;31.81;32.38;33.23;35.68;36.57;37.40;39.36;和41.79。
2-(吡啶-2-基)-N-(5-(4-(6-(2-(3-(三氟甲氧基)苯基)乙酰氨基)哒嗪-3-基)丁基)-1,3,4-噻二唑-2-基)乙酰胺盐酸盐晶型I (CB-839 HCl,晶型I)。
在配备有内部温度探针和磁力搅拌器的250 mL 3-颈圆底烧瓶中,将CB-839 HCl晶型II (2.35g , 3.89 mmol)在无水乙醇(71 mL)中制浆。设置半球形织物罩以加热浆液至65℃的内部温度并于此所需的温度下保持60分钟。用2% CB-839 HCl晶型I晶体(47 mg)种晶浆液并于该温度保持7.5小时。然后经18小时使浆液冷却至室温,通过抽吸过滤收集灰白色固体并将滞留物于50℃真空烘箱中干燥,提供2-(吡啶-2-基)-N-(5-(4-(6-(2-(3-(三氟甲氧基)苯基)乙酰氨基)哒嗪-3-基)丁基)-1,3,4-噻二唑-2-基)乙酰胺盐酸盐晶型I(CB-839 HCl, 2.13 g)。
2-(吡啶-2-基)-N-(5-(4-(6-(2-(3-(三氟甲氧基)苯基)乙酰氨基)哒嗪-3-基)丁基)-1,3,4-噻二唑-2-基)乙酰胺二盐酸盐(CB-839 2xHCl)。在配备有内部温度探针、25 mL加料漏斗和机械搅拌棒的100 mL 3-颈圆底烧瓶中,将化合物670,或CB-839游离碱(1.05g, 1.84 mmol)在无水乙醇(21 mL)中制浆。设置半球形织物罩以加热浆液至65℃的内部温度并于此所需的温度下保持60分钟。在一个关闭的25 mL圆底烧瓶中,将无水乙醇(5.3 mL)与乙酰氯(640 µL, 9.19 mmol)一起搅拌5分钟,然后加入加料漏斗中。经2分钟加入乙醇化HCl,使反应混合物溶于黄色溶液,此时移去加热罩。于38℃的内部温度经20分钟后观察到沉淀。将反应物经18小时进一步冷却至19℃。通过抽吸过滤收集浅黄色固体,并将滞留物于60℃真空烘箱中干燥过夜,提供2-(吡啶-2-基)-N-(5-(4-(6-(2-(3-(三氟甲氧基)苯基)乙酰氨基)哒嗪-3-基)丁基)-1,3,4-噻二唑-2-基)乙酰胺二盐酸盐(CB-839 2xHCl, 754mg)。1H NMR (300 MHz, DMSO-d6) δ 13.05 (s, 1H), 11.55 (s, 1H), 8.87 (d, J=4.74Hz, 1H), 8.47 (m, 1H), 8.38 (d, J=9.22 Hz, 1H), 7.96 (d, J=7.99 Hz, 1H), 7.90(t, J=6.72 Hz, 2H), 7.78 (d, J=9.22 Hz, 1H), 7.49 (t, J=8.09 Hz, 1H), 7.39(m, 2H), 7.28 (d, J=8.50 Hz, 1H), 4.42 (s, 2H), 3.90 (s, 2H), 2.89 (m, 4H),1.77 (s, 4H)。
CB-839 2xHCl盐是非晶形的。
2-(吡啶-2-基)-N-(5-(4-(6-(2-(3-(三氟甲氧基)苯基)乙酰氨基)哒嗪-3-基)丁基)-1,3,4-噻二唑-2-基)乙酰胺4-甲基苯磺酸盐(CB-839 TsOH)。
在配备有内部温度探针、50 mL加料漏斗和磁力搅拌器的500 mL 3-颈圆底烧瓶中,将化合物670,或CB-839游离碱(8.20 g, 14.3 mmol)在无水乙醇(205 mL)中制浆。设置半球形织物罩以加热浆液至65℃的内部温度并于此所需的温度下保持120分钟。在一个关闭的50 mL圆底烧瓶中,将无水乙醇(41 mL)与对-甲苯磺酸(3.27 g, 17.2 mmol)一起搅拌10分钟,然后加入加料漏斗中。以14 mL/min的速率加入乙醇化对-甲苯磺酸。浆液短暂地转变成溶液,经4小时使之冷却至19℃。通过抽吸过滤收集白色固体,并将滞留物于60℃真空烘箱中干燥过夜,提供2-(吡啶-2-基)-N-(5-(4-(6-(2-(3-(三氟甲氧基)苯基)乙酰氨基)哒嗪-3-基)丁基)-1,3,4-噻二唑-2-基)乙酰胺4-甲基苯磺酸盐(CB-839 TsOH, 4.44g)。1HNMR (300 MHz, DMSO-d6) δ 12.77 (s, 1H), 11.32 (s, 1H), 8.70 (t, J=4.65 Hz,1H), 8.22 (d, J=9.16 Hz, 1H), 8.15 (t, J=7.40 Hz, 1H), 7.65 (d, J=18.70 Hz,1H), 7.61 (m, 2H), 7.45 (m, 3H), 7.36 (m, 2H), 7.25 (d, J=8.38 Hz, 1H), 7.10(d, J=7.87 Hz, 2H), 4.18 (s, 2H), 3.85 (s, 2H), 3.02 (s, 2H), 2.89 (s, 2H),2.28 (s, 3H), 1.74 (s, 4H)。
CB-839 TsOH的XRD图谱示于图3。CB-839 TsOH具有2θ值5.66;6.84;7.97;11.34;11.55;12.04;13.78;14.42;15.44;15.99;16.58;17.09;18.10;18.66;19.69;20.23;21.11;22.03;22.16;22.50;22.84;23.48;24.05;25.59;25.89;27.80;29.35;30.46;31.10;33.82;35.65;36.67;38.93;39.99;42.65;和43.68。
2-(吡啶-2-基)-N-(5-(4-(6-(2-(3-(三氟甲氧基)苯基)乙酰氨基)哒嗪-3-基)丁基)-1,3,4-噻二唑-2-基)乙酰胺硝酸盐(CB-839 HNO3)。在配备有内部温度探针和机械搅拌棒的25 mL 3-颈圆底烧瓶中,将化合物570,或CB-839游离碱(498 mg, 0.87 mmol)在四氢呋喃(2 mL)和乙腈(3.5 mL)中制浆。设置半球形织物罩以加热浆液至60℃的内部温度并于此所需的温度下保持60分钟。在一小瓶中,将乙腈(200 µL)与硝酸(100 µL, 1.13 mmol)一起搅拌5分钟,然后加入浆液中。使生成的溶液经6小时冷却至19℃。通过抽吸过滤收集褐色固体,并将滞留物于60℃真空烘箱中干燥过夜,提供2-(吡啶-2-基)-N-(5-(4-(6-(2-(3-(三氟甲氧基)苯基)乙酰氨基)哒嗪-3-基)丁基)-1,3,4-噻二唑-2-基)乙酰胺硝酸盐(CB-839 HNO3, 150 mg)。1H NMR (300 MHz, DMSO-d6) δ 12.85 (s, 1H), 11.36 (s, 1H),8.76 (d, J=5.16 Hz, 1H), 8.27 (m, 2H), 7.78 (d, J=7.93 Hz, 1H), 7.71 (m, 1H),7.63 (d, J=9.37 Hz, 1H), 7.49 (t, J=7.917 Hz, 1H), 7.39 (m, 2H), 7.28 (d, J=8.17 Hz, 1H), 4.24 (s, 2H), 3.88 (s, 2H), 3.04 (s, 2H), 2.92 (s, 2H), 1.76(s, 4H)。
2-(吡啶-2-基)-N-(5-(4-(6-(2-(3-(三氟甲氧基)苯基)乙酰氨基)哒嗪-3-基)丁基)-1,3,4-噻二唑-2-基)乙酰胺甲磺酸盐(CB-839 MSA)。在配备有内部温度探针和机械搅拌棒的50 mL 3-颈圆底烧瓶中,将化合物670,或CB-839游离碱(1.55 g, 2.71 mmol)在无水乙醇(23 mL)中制浆。设置半球形织物罩以加热浆液至65℃的内部温度并于此所需的温度下保持30分钟。然后将甲烷磺酸(2.71 mmol, 180 µL)加入到反应浆液中。浆液短暂地转变成溶液,经5小时使之冷却至19℃。通过抽吸过滤收集灰白色固体,并将滞留物在60℃真空烘箱中干燥过夜,提供2-(吡啶-2-基)-N-(5-(4-(6-(2-(3-(三氟甲氧基)苯基)乙酰氨基)哒嗪-3-基)丁基)-1,3,4-噻二唑-2-基)乙酰胺甲磺酸盐(CB-839 MSA, 960 mg)。1HNMR (300 MHz, DMSO-d6) δ 12.87 (s, 1H), 11.38 (s, 1H), 8.79 (t, J=5.40 Hz,1H), 8.29 (m, 2H), 7.82 (d, J=7.68 Hz, 1H), 7.76 (m, 1H), 7.64 (d, J=9.10 Hz,1H), 7.49 (t, J=8.08 Hz, 1H), 7.38 (m, 2H), 7.28 (d, J=8.47 Hz, 1H), 4.27 (s,2H), 3.88 (s, 2H), 3.05 (s, 2H), 2.92 (s, 2H), 2.35 (s, 3H), 1.76 (s, 4H)。
CB-839 MSA的XRD图谱示于图4中。CB-839 MSA具有2θ值5.86;7.00;8.00;9.37;10.04;11.13;11.76;13.20;14.82;14.42;15.30;15.98;16.50;17.26;17.98;18.88;19.55;19.96;20.25;21.08;21.53;22.07;22.17;22.50;23.09;23.12;23.80;24.05;24.66;25.22;25.73;26.02;26.66;27.13;27.58;29.16;29.53;30.35;31.07;31.87;32.98;33.87;34.34;36.76;37.48;39.35;40.05;40.10;和41.77。
2-(吡啶-2-基)-N-(5-(4-(6-(2-(3-(三氟甲氧基)苯基)乙酰氨基)哒嗪-3-基)丁基)-1,3,4-噻二唑-2-基)乙酰胺氢溴酸盐(CB-839 HBr)。
在配备有内部温度探针和磁力搅拌器的50 mL 3-颈圆底烧瓶中,将化合物670,或CB-839游离碱(1.07 g, 1.87 mmol)在无水乙醇(27mL)中制浆。设置半球形织物罩以加热浆液至65℃的内部温度并于此所需的温度下保持60分钟。在一个20 mL的闪烁瓶(scintillation vial)中,将无水乙醇(5 mL)与乙酰溴(0.166 mL, 2.25 mmol)一起搅拌5分钟,然后经2分钟加入到反应浆液中。浆液变稀且颜色稍稍变深。使浆液冷却至室温并搅拌6.5小时。通过抽吸过滤收集灰白色固体,并将滞留物在50℃真空烘箱中干燥过夜,提供2-(吡啶-2-基)-N-(5-(4-(6-(2-(3-(三氟甲氧基)苯基)乙酰氨基)哒嗪-3-基)丁基)-1,3,4-噻二唑-2-基)乙酰胺氢溴酸盐晶型I (CB-839 HBr, 1.02g)。1H NMR (300 MHz, DMSO-d6) δ 12.80 (s, 1H), 11.33 (s, 1H), 8.73 (d, J = 4.47 Hz, 1H), 8.21 (d, J =8.76 Hz, 2H), 7.75 (d, J = 7.86 Hz, 1H), 7.68 (m, 1H), 7.60 (d, J = 8.89 Hz,1H), 7.45 (t, J = 7.42 Hz, 1H), 7.35 (m, 2H), 7.24 (d, J = 7.87 Hz, 1H), 4.21(s, 2H), 3.84(s, 2H), 3.00 (s, 2H), 2.88 (s, 2H), 1.72 (s, 4H)。
XRD图谱示于图5。CB-839 HBr具有2θ值5.08;6.58;10.20;10.83;12.52;12.89;15.19;15.98;16.32;17.28;18.60;19.36;19.96;20.54;21.13;21.76;22.34;22.92;24.44;25.77;25.84;26.43;26.49;和30.27。
实施例3:化合物测定
在体外生物化学测定和细胞增殖测定二者中测定化合物670。实验方案和测定的结果见于美国专利号8,604,016中,或者见于美国专利申请公布号2014/0050699 A1中。
通过引用结合
本文提及的所有的出版物和专利通过引用以其全文结合到本文中,如同各个出版物和专利特别地和单独地指明通过引用结合到本文中一样。在有冲突的情况下,以本申请,包括本文的任何定义为准。
等同物
虽然已经讨论了本发明的特定实施方案,上述说明书仅仅举例说明而不是限制性的。本发明的许多变化在本领域技术人员审阅本说明书和所附权利要求书后,将变得显而易见。本发明的全部范围应通过参考权利要求书,连同它们的等同物的全部范围,以及说明书,连同此类变化来确定。
Claims (49)
1.一种具有式(I)结构的化合物的结晶盐,
(I)。
2.权利要求1的结晶盐,其中所述盐是盐酸盐、甲苯磺酸盐、硝酸盐、甲磺酸盐,或氢溴酸盐。
3.权利要求2的结晶盐,其中所述盐是盐酸盐。
4.权利要求3的结晶盐,其具有以下的2θ值:16.70;17.26;21.09;22.69。
5.权利要求4的结晶盐,其具有以下的2θ值:16.70;17.26;18.18;21.09;22.69;23.46;25.22;25.49;26.72。
6.权利要求5的结晶盐,其具有以下的2θ值:9.53;11.63;16.70;17.26;18.18;19.10;19.80;21.09;22.16;22.69;23.46;24.63;25.22;25.49;25.91;26.72;28.45;29.38;31.39;31.82;34.91。
7.权利要求6的结晶盐,其具有以下的2θ值:8.62;9.53;11.63;15.89;16.70;17.26;18.18;19.10;19.80;21.09;22.16;22.69;23.46;24.63;25.22;25.49;25.91;26.72;28.45;29.38;31.39;31.82;32.76;33.61;33.74;34.27;34.91;35.53;39.36;39.73。
8.权利要求7的结晶盐,其具有基本上如图1所示的XRD图谱。
9.权利要求3的结晶盐,其具有以下的2θ值:8.34;18.83;21.10。
10.权利要求9的结晶盐,其具有以下的2θ值:6.26;8.34;15.82;18.83;21.10;23.42;24.10;24.45;25.25;25.74。
11.权利要求10的结晶盐,其具有以下的2θ值:6.26;8.34;11.02;12.58;14.80;15.61;15.82;17.58;18.20;18.83;19.81;20.00;21.10;22.58;23.42;24.10;24.45;25.25;25.74;26.36;27.83;28.70;29.84;30.46;31.81;32.38。
12.权利要求11的结晶盐,其具有以下的2θ值:3.10;6.26;8.34;9.04;9.96;11.02;12.58;13.47;14.80;15.61;15.82;16.15;17.58;18.20;18.83;19.81;20.00;21.10;22.02;22.58;23.42;24.10;24.45;25.25;25.74;26.36;27.22;27.83;28.70;29.84;30.46;31.81;32.38;33.23;35.68;36.57;37.40;39.36;41.79。
13.权利要求12的结晶盐,其具有基本上如图2所示的XRD图谱。
14.一种具有式(I)结构的化合物的盐,
(I);
其中所述盐是二盐酸盐。
15.一种药物组合物,其包含权利要求1-14的任一项的盐和一种或多种药学上可接受的赋形剂。
16.一种治疗或预防癌症或免疫疾病或神经疾病的方法,其包括给予权利要求1-14的任一项的盐或权利要求15的药物组合物。
17.权利要求16的方法,其中所述癌症包括急性成淋巴细胞白血病(ALL)、急性髓性白血病(AML)、肾上腺皮质癌、肛门癌、阑尾癌、非典型畸胎样瘤/横纹肌样瘤、基底细胞癌、胆管癌、膀胱癌、骨癌、脑瘤、星形细胞瘤、脑和脊髓瘤、脑干神经胶质瘤、中枢神经系统非典型畸胎样瘤/横纹肌样瘤、中枢神经系统胚胎瘤、乳腺癌、支气管肿瘤、伯基特氏淋巴瘤、类癌肿瘤、未知的原发性癌、中枢神经系统癌、宫颈癌、儿童期癌症、脊索癌、慢性淋巴细胞白血病(CLL)、慢性髓性白血病(CML)、慢性骨髓增生性疾病、结肠癌、结肠直肠癌、颅咽管瘤、皮肤T-细胞淋巴瘤、导管原位癌(DCIS)、胚胎瘤、子宫内膜癌、成室管膜细胞瘤、室管膜瘤、食道癌、鼻腔神经胶质瘤、尤因氏肉瘤、颅外生殖细胞瘤、性腺外生殖细胞瘤、肝外胆管癌、眼癌、骨的纤维组织细胞瘤、胆囊癌、胃癌、胃肠道类癌肿瘤、胃肠道间质瘤(GIST)、生殖细胞瘤、颅外生殖细胞瘤、性腺外生殖细胞瘤、卵巢生殖细胞瘤、妊娠滋养层肿瘤、神经胶质瘤、毛细胞白血病、头颈癌、心脏癌、肝细胞癌、组织细胞增多症、郎格罕氏细胞癌、霍奇金氏淋巴瘤、下咽癌、眼内黑色素瘤、胰岛细胞瘤、卡波济氏肉瘤、肾癌、朗格罕氏细胞组织细胞增多症、喉癌、白血病、嘴唇和口腔癌、肝癌、小叶原位癌(LCIS)、肺癌、淋巴瘤、AIDS-相关淋巴瘤、巨球蛋白血症、男性乳腺癌、成神经管细胞瘤、髓质上皮瘤、黑色素瘤、默克尔细胞癌、恶性间皮瘤、隐匿性原发性转移鳞状颈癌、涉及NUT基因的中线道癌、口腔癌、多发性内分泌瘤综合征、多发性骨髓瘤/浆细胞瘤、蕈样真菌病、骨髓增生异常综合征、骨髓增生异常/骨髓增殖性肿瘤、慢性髓性白血病(CML)、急性髓性白血病(AML)、骨髓瘤、多发性骨髓瘤、慢性骨髓增殖性病症、鼻腔癌、副鼻窦癌、鼻咽癌、神经母细胞瘤、非-霍奇金氏淋巴瘤、非-小细胞肺癌、口癌、口腔癌、唇癌、口咽癌、骨肉瘤、卵巢癌、胰腺癌、乳头状瘤病、副神经节瘤、副鼻窦癌、鼻腔癌、甲状旁腺癌、阴茎癌、咽癌、嗜铬细胞瘤、中间分化松果体实质瘤、松果体母细胞瘤、垂体瘤、浆细胞瘤、胸膜肺母细胞瘤、乳腺癌、原发性中枢神经系统(CNS)淋巴瘤、前列腺癌、直肠癌、肾细胞癌、肾盂癌、输尿管癌、移行细胞癌、成视网膜细胞瘤、横纹肌肉瘤、唾腺癌、肉瘤、塞泽里综合征、皮肤癌、小细胞肺癌、小肠癌、软组织肉瘤、鳞状细胞癌、隐匿性原发性转移鳞状颈癌、胃癌、幕上原始神经外胚层瘤、T-细胞淋巴瘤、睾丸癌、喉癌、胸腺瘤、胸腺癌、甲状腺癌、肾盂和输尿管移行细胞癌、不明原因的原发性妊娠滋养层肿瘤、不寻常的儿童癌症、尿道癌、子宫癌、子宫肉瘤、瓦尔登斯特伦巨球蛋白血症,或维尔姆斯肿瘤。
18.权利要求16或权利要求17的方法,其中该方法还包括共同给予一种或多种化疗剂。
19.权利要求18的方法,其中一种或多种化疗剂包括氨鲁米特、安吖啶、阿那曲唑、天冬酰胺酶、卡介苗(bcg)、比卡鲁胺、博来霉素、硼替佐米、布舍瑞林、白消安、喜树碱、卡倍他滨、卡铂、卡非佐米、卡莫司汀、苯丁酸氮芥、氯喹、顺铂、克拉屈滨、氯膦酸、秋水仙碱、环磷酰胺、环丙孕酮、阿糖胞苷、达卡巴嗪、放线菌素D、柔红霉素、脱甲绿胶酶素、地塞米松、二氯乙酸酯、己二烯雌酚、己烯雌酚、多西他赛、多柔比星、表阿霉素、雌二醇、雌莫司汀、依托泊苷、依维莫司、依西美坦、非格司亭、氟达拉滨、氟氢可的松、氟尿嘧啶、氟甲睾酮、氟他胺、吉西他滨、染料木素、戈舍瑞林、羟基脲、伊达比星、异环磷酰胺、伊马替尼、干扰素、伊立替康、来曲唑、亚叶酸、亮丙瑞林、左旋咪唑、洛莫司汀、氯尼达明、氮芥、甲羟孕酮、甲地孕酮、美法仑、巯基嘌呤、美司钠、二甲双胍、甲氨蝶呤、丝裂霉素、米托坦、米托蒽醌、尼鲁米特、诺考达唑、奥曲肽、奥沙利铂、紫杉醇、帕米膦酸盐、喷司他丁、哌立福辛、普卡霉素、卟吩姆、丙卡巴肼、雷替曲塞、利妥昔单抗、索拉非尼、链佐星、舒尼替尼、苏拉明、他莫昔芬、替莫唑胺、坦罗莫司、替尼泊苷、睾酮、硫鸟嘌呤、塞替派、二氯二茂钛、托泊替康、曲妥珠单抗、维A酸、长春碱、长春新碱、长春地辛、长春瑞滨、MK2206、曲美替尼、BEZ235、厄洛替尼、司美替尼、西罗莫司、曲美替尼、帕唑帕尼,或GSK1120212。
20.权利要求16-19的任一项的方法,其中该方法还包括给予一种或多种非-化学癌症治疗方法。
21.权利要求20的方法,其中一种或多种非-化学方法包括放射疗法。
22.权利要求20的方法,其中一种或多种非-化学方法包括手术、热消融疗法、聚焦超声疗法、冷冻疗法,或前述的任何组合。
23.权利要求16-22的任一项的方法,其中该方法还包括共同给予一种或多种免疫调节剂。
24.权利要求23的方法,其中免疫调节剂是粒细胞集落刺激因子(G-CSF)、干扰素、咪喹莫特、IL-2、IL-7、IL-12、趋化因子、合成的胞嘧啶磷酸-鸟苷(CpG)寡脱氧核苷酸、葡聚糖、阿普斯特、CC-122、CC-11006、CC-10015、来那度胺、泊马度胺,和沙利度胺,或沙利度胺类似物。
25.一种制备具有式(I)结构的化合物的结晶盐的方法:
(I);
其包括:
a) 提供在第一有机溶剂中的式(I)化合物的游离碱混合物;
b) 使游离碱混合物与试剂溶液在足以形成包含式(I)化合物的盐的混合物的条件下接触,其中试剂溶液包含酸和任选的第二有机溶剂;和
c) 使式(I)化合物的盐从包含式(I)化合物的盐的混合物中结晶。
26.权利要求25的方法,其中结晶盐是盐酸盐、甲苯磺酸盐、硝酸盐、甲磺酸盐,或氢溴酸盐。
27.权利要求25的方法,其中第一有机溶剂和第二有机溶剂,如果存在,是相同的。
28.权利要求25的方法,其中第一有机溶剂和第二有机溶剂,如果存在,是不同的。
29.权利要求25-28的任一项的方法,其中第一有机溶剂和第二有机溶剂各自独立地包含乙醇和/或乙腈。
30.权利要求25-29的任一项的方法,其中所述酸是盐酸、对-甲苯磺酸、甲磺酸、硝酸,或氢溴酸。
31.权利要求25-30的任一项的方法,其中步骤b)的酸以在游离碱混合物中的式(I)化合物的摩尔量的从约1.0至约1.5倍的摩尔量存在于试剂溶液中。
32.权利要求25-31的任一项的方法,其中包含式(I)化合物的盐的混合物是溶液,和从所述混合物结晶式(I)化合物的盐的步骤包括使所述溶液过度饱和,导致式(I)化合物的盐从溶液沉淀出来。
33.权利要求32的方法,其中使所述溶液过度饱和的步骤包括缓慢加入反溶剂,使溶液冷却,减少溶液的体积,或其任何组合。
34.权利要求32的方法,其中使所述溶液过度饱和的步骤包括冷却溶液至室温或更低的温度。
35.权利要求25-34的任一项的方法,其还包括分离结晶盐。
36.权利要求35的方法,其中分离结晶盐包括从混合物过滤结晶盐。
37.权利要求35或权利要求36的方法,其还包括在减压下干燥结晶盐。
38.权利要求25-37的任一项的方法,其中结晶盐是权利要求1-19的任一项的结晶盐。
39.一种具有式(I)结构的结晶化合物,
(I)。
40.权利要求39的结晶化合物,其具有以下的2θ值:18.39;19.10;21.37;24.65。
41.权利要求40的结晶化合物,其具有以下的2θ值:7.92;18.39;19.10;20.12;21.37;24.10;24.65;25.14。
42.权利要求41的结晶化合物,其具有以下的2θ值:7.32;7.92;11.98;15.54;15.87;18.06;18.39;19.10;20.06;20.12;21.37;22.41;22.74;24.10;24.65;25.14;25.78;27.32。
43.权利要求42的结晶化合物,其具有以下的2θ值:3.64;7.32;7.92;8.53;9.30;9.38;11.02;11.98;14.70;15.54;15.87;16.50;16.59;18.06;18.39;19.10;20.06;20.12;20.61;21.37;21.89;22.41;22.74;23.72;24.10;24.65;25.14;25.78;26.49;27.32;27.55;28.26;29.88;31.20;31.80;31.52;32.80;34.30;35.20;36.41;38.53;40.08;40.94;和43.86。
44.权利要求43的结晶化合物,其具有基本上如图6所示的XRD图谱。
45.权利要求39的结晶化合物,其具有以下的2θ值:7.57;18.50;18.69。
46.权利要求45的结晶化合物,其具有以下的2θ值:7.57;9.67;11.00;12.93;15.20;18.50;18.69;23.33;24.87。
47.权利要求46的结晶化合物,其具有以下的2θ值:5.47;7.57;9.67;11.00;12.93;14.14;15.20;17.74;18.50;18.69;19.40;20.54;21.13;23.33;24.37;24.87;25.52。
48.权利要求47的结晶化合物,其具有以下的2θ值:5.47;6.01;7.57;9.20;9.67;10.15;11.00;12.93;14.14;15.20;15.81;16.56;17.74;18.50;18.69;19.40;19.94;20.54;20.59;21.13;22.00;22.60;23.33;23.98;24.37;24.87;25.52;26.27;26.62;27.79;29.59;30.64;33.30;35.01;37.93;38.72。
49.权利要求48的结晶化合物,其具有基本上如图7所示的XRD图谱。
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