CN106458999B - 组合 - Google Patents
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- CN106458999B CN106458999B CN201580027758.7A CN201580027758A CN106458999B CN 106458999 B CN106458999 B CN 106458999B CN 201580027758 A CN201580027758 A CN 201580027758A CN 106458999 B CN106458999 B CN 106458999B
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Abstract
本发明涉及选自N‑(3,5‑二甲氧基苯基)‑N'‑(1‑甲基乙基)‑N‑[3‑(1‑甲基‑1H‑吡唑‑4‑基)喹喔啉‑6‑基]乙烷‑1,2‑二胺或其药学上可接受的盐或其溶剂合物,和N‑(2‑氟‑3,5‑二甲氧基苯基)‑N‑(1H‑咪唑‑2‑基甲基)‑3‑(1‑甲基‑1H‑吡唑‑4‑基)吡啶并[2,3‑b]吡嗪‑6‑胺或其药学上可接受的盐或其溶剂合物的第一化合物;和作为cMet抑制剂的第二化合物的组合。该组合用于治疗增殖性病症,特别是用于治疗癌症。FGFR抑制剂(N‑(3,5‑二甲氧基苯基)‑N'‑(1‑甲基乙基)‑N‑[3‑(1‑甲基‑1H‑吡唑‑4‑基)喹喔啉‑6‑基]乙烷‑1,2‑二胺或其药学上可接受的盐或其溶剂合物,和N‑(2‑氟‑3,5‑二甲氧基苯基)‑N‑(1H‑咪唑‑2‑基甲基)‑3‑(1‑甲基‑1H‑吡唑‑4‑基)吡啶并[2,3‑b]吡嗪‑6‑胺或其药学上可接受的盐或其溶剂合物)和cMet抑制剂可以同时,分开或顺序给予。本发明还涉及包含药学上可接受的载体和根据本发明的组合的药物组合物。
Description
发明领域
本发明涉及选自N-(3,5-二甲氧基苯基)-N'-(1-甲基乙基)-N-[3-(1-甲基-1H-吡唑-4-基)喹喔啉-6-基]乙烷-1,2-二胺或其药学上可接受的盐或其溶剂合物,和N-(2-氟-3,5-二甲氧基苯基)-N-(1H-咪唑-2-基甲基)-3-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-b]吡嗪-6-胺或其药学上可接受的盐或其溶剂合物的第一化合物;和作为cMet抑制剂的第二化合物的组合。
该组合用于治疗增殖性病症,特别是用于治疗癌症。
FGFR抑制剂(N-(3,5-二甲氧基苯基)-N'-(1-甲基乙基)-N-[3-(1-甲基-1H-吡唑-4-基)喹喔啉-6-基]乙烷-1,2-二胺或其药学上可接受的盐或其溶剂合物,和N-(2-氟-3,5-二甲氧基苯基)-N-(1H-咪唑-2-基甲基)-3-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-b]吡嗪-6-胺或其药学上可接受的盐或其溶剂合物)和cMet抑制剂可以同时、分开或顺序给予。
本发明还涉及包含药学上可接受的载体和根据本发明的组合的药物组合物。
发明概述
本发明涉及选自N-(3,5-二甲氧基苯基)-N'-(1-甲基乙基)-N-[3-(1-甲基-1H-吡唑-4-基)喹喔啉-6-基]乙烷-1,2-二胺(化合物A)或其药学上可接受的盐或其溶剂合物,和N-(2-氟-3,5-二甲氧基苯基)-N-(1H-咪唑-2-基甲基)-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-b]吡嗪-6-胺(化合物B)或其药学上可接受的盐或其溶剂合物的第一化合物;和作为cMet抑制剂的第二化合物的组合。
发明背景
N-(3,5-二甲氧基苯基)-N'-(1-甲基乙基)-N-[3-(1-甲基-1H-吡唑-4-基)喹喔啉-6-基]乙烷-1,2-二胺(化合物A)由下式表示
化合物A
N-(2-氟-3,5-二甲氧基苯基)-N-(1H-咪唑-2-基甲基)-3-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-b]吡嗪-6-胺(化合物B)由下式表示
化合物B
化合物N-(3,5-二甲氧基苯基)-N'-(1-甲基乙基)-N-[3-(1-甲基-1H-吡唑-4-基)喹喔啉-6-基]乙烷-1,2-二胺(化合物A)或其药学上可接受的盐或其溶剂合物,和N-(2-氟-3,5-二甲氧基苯基)-N-(1H-咪唑-2-基甲基)-3-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-b]吡嗪-6-胺(化合物B)或其药学上可接受的盐或其溶剂合物,以及它们的化学合成描述于WO2011/135376和WO2013/061080,其通过引用并入本文。它们被描述为某些蛋白酪氨酸激酶,特别是FGFR的活性的抑制剂或调节剂,因此所述化合物可用于治疗或预防,特别是治疗由这些酪氨酸激酶特别是FGFR介导的疾病状态或病况。所述化合物可用于治疗或预防,特别是治疗癌症。
在WO2011/135376中,本发明化合物A也作为盐酸盐示例。在WO2013/061080中,本发明化合物B还以硫酸盐,盐酸盐,磷酸盐,乳酸盐,富马酸盐示例。
FGFR
蛋白质酪氨酸激酶(PTK)受体的成纤维细胞生长因子(FGF)家族调节多种多样的生理功能,包括有丝***发生、伤口愈合、细胞分化和血管生成和发育。正常和恶性细胞两者的生长以及增殖都受FGF局部浓度变化的影响,FGF是胞外信号转导分子,起自分泌以及旁分泌因子作用。自分泌FGF信号转导在类固醇激素依赖性癌症向激素非依赖性状态的发展中可能特别重要。FGF及其受体在几种组织和细胞系以高水平表达,过量表达被认为促成恶性表型。此外,多个癌基因是编码生长因子受体的基因的同源物,并且在人胰腺癌中存在FGF依赖性信号转导异常活化的可能性(Knights等, Pharmacology and Therapeutics2010 125:1 (105-117);Korc M.等, Current Cancer Drug Targets 2009 9:5 (639-651))。
两种原型成员是酸性成纤维细胞生长因子(aFGF或FGF1)和碱性成纤维细胞生长因子(bFGF或FGF2),迄今已经鉴定出至少二十种截然不同的FGF家族成员。经由编号为1-4的四种类型的高亲和力跨膜蛋白酪氨酸-激酶成纤维细胞生长因子受体(FGFR) (FGFR1-FGFR4)传导对FGF的细胞反应。
破坏FGFR1途径可能影响肿瘤细胞增殖,因为除使内皮细胞增殖以外,这种激酶在许多肿瘤类型中被激活。肿瘤相关血管***中FGFR1的过量表达和活化表明了这些分子在肿瘤血管生成中的作用。
最近的研究表明,在典型性小叶癌(CLC)中FGFR1表达与致瘤性之间的关系。CLC导致全部乳腺癌的10-15%,一般缺乏p53和Her2表达同时保持***受体的表达。在约50%的CLC病例中证实了8p12-p11.2的基因扩增,并且表明这与FGFR1表达增加有关。用针对FGFR1的siRNA或该受体的小分子抑制剂的初步研究表明具有这种扩增的细胞系对这种信号转导途径的抑制特别敏感。横纹肌肉瘤(RMS)是可能因在骨骼肌生成期间异常增殖和分化所引起的最常见的小儿软组织肉瘤。FGFR1在原发性横纹肌肉瘤肿瘤中过量表达,并且与5' CpG岛的甲基化不足和AKT1、NOG和BMP4基因表达异常相关。FGFR1还与肺鳞状细胞癌、结肠直肠癌、成胶质细胞瘤、星形细胞瘤、***癌、小细胞肺癌、黑素瘤、头颈癌、甲状腺癌、子宫癌有关。
成纤维细胞生长因子受体2对酸性和/或碱性成纤维细胞生长因子以及角质形成细胞生长因子配体具有高亲和力。成纤维细胞生长因子受体2还在成骨细胞生长和分化期间传导FGF的有力成骨作用。导致复杂功能变化的成纤维细胞生长因子受体2中的突变表明诱导颅缝的异常骨化(颅缝早闭),意味着FGFR信号转导在膜内骨形成中起主要作用。例如,在以过早颅缝骨化为特征的Apert (AP)综合征中,大多数病例与造成成纤维细胞生长因子受体2中的功能获得的点突变相关。此外,综合征型颅缝早闭患者中的突变筛查表明,许多复发性FGFR2突变是重型斐弗综合征(Pfeiffer syndrome)的原因。FGFR2的特定突变包括FGFR2中的W290C、D321A、Y340C、C342R、C342S、C342W、N549H、K641R。
人骨骼发育中的几种严重异常情况,包括Apert综合征、Crouzon综合征、Jackson-Weiss综合征、Beare-Stevenson皮肤旋纹综合征和斐弗综合征,与成纤维细胞生长因子受体2中的突变发生有关。斐弗综合征(PS)的大多数病例(即使不是全部)还由成纤维细胞生长因子受体2基因的新生突变引起,最近表明,成纤维细胞生长因子受体2中的突变打破控制配体特异性的基本原则之一。也就是说,成纤维细胞生长因子受体的两种突变体剪接形式FGFR2c和FGFR2b已获得与非典型FGF配体结合并被非典型FGF配体激活的能力。配体特异性的这种损失导致信号转导异常,并表明这些疾病综合征的严重表型由成纤维细胞生长因子受体2的异位配体依赖性活化造成。
FGFR3受体酪氨酸激酶的遗传畸变(例如染色体易位或点突变)导致异位表达或失调的、有组成型活性的FGFR3受体。这种异常与多发性骨髓瘤的亚类和在膀胱癌、肝细胞癌、口腔鳞状细胞癌和***中有关。因此,FGFR3抑制剂可用于治疗多发性骨髓瘤、膀胱癌和***。FGFR3还在膀胱癌、特别是浸润性膀胱癌中过量表达。FGFR3常常被尿路上皮癌(UC)中的突变激活。升高的表达与突变相关(85%的突变肿瘤表现出高水平表达),但42%的无可检出突变的肿瘤也显示过量表达,包括许多肌肉浸润性肿瘤。FGFR3还与子宫内膜癌和甲状腺癌有关。
FGFR4的过量表达与***癌和甲状腺癌两者的预后差有关。此外,种系多态性(Gly388Arg)与肺癌、乳腺癌、结肠癌、肝癌(HCC)和***癌的发病率提高有关。此外,还发现FGFR4的截短形式(包括激酶结构域)存在于40%的垂体瘤中,但不存在于正常组织中。在肝、结肠和肺肿瘤中观察到FGFR4过量表达。FGFR4涉及结肠直肠癌和肝癌,其中其配体FGF19的表达常常升高。FGFR4也与星形细胞瘤、横纹肌肉瘤有关。
纤维化状况是由纤维组织的异常或过度沉积造成的严重医学问题。这出现在许多疾病中,包括肝硬化、肾小球肾炎、肺纤维化、***性纤维化、类风湿性关节炎以及伤口愈合的自然过程。尚未充分了解病理性纤维化的机制,但是认为由参与成纤维细胞的增殖和细胞外基质蛋白(包括胶原和纤连蛋白)的沉积的各种细胞因子(包括肿瘤坏死因子(TNF)、成纤维细胞生长因子(FGF)、血小板衍生生长因子(PDGF)和转化生长因子β(TGFβ))的作用造成。这导致组织结构与功能和后续病理学的改变。
许多临床前研究已证实在肺纤维化临床前模型中成纤维细胞生长因子上调。据报道TGFβ1和PDGF参与纤维发生过程,其它已发表的著作表明,FGF升高和随之而来的成纤维细胞增殖的增加可能响应升高的TGFβ1。已报道的抗纤维化药吡非尼酮的临床效果表明在特发性肺纤维化(IPF)等病况中靶向纤维化机制的潜在治疗益处。特发性肺纤维化(亦称为隐源性致纤维化肺泡炎)是涉及肺瘢痕形成的进行性病况。肺的肺泡逐渐被纤维化组织替代,其变得更厚,引起组织将氧传送到血流中的能力不可逆地丧失。该病况的症状包括呼吸急促、慢性干咳、疲劳、胸痛和食欲减退以致体重快速减轻。该病况极严重,5年死亡率约50%。
因此,抑制FGFR的化合物可特别通过抑制血管生成,而用于提供在肿瘤中防止生长或引发细胞凋亡的手段。因此预期该化合物将证实可用于治疗或预防增殖性病症,例如癌症。特别是具有受体酪氨酸激酶(RTK)的激活突变体或受体酪氨酸激酶上调的肿瘤可能对该抑制剂特别敏感。具有本文论述的特定RTK(受体酪氨酸激酶)的任何同种型的激活突变体的患者还会发现用RTK抑制剂治疗特别有益。
本文所述的FGFR激酶抑制剂具有不同的选择性特征,其提供了在其疾病由FGFR失调驱动的患者亚组中使用这些靶向剂的新机会。本文所述的FGFR激酶抑制剂对另外的激酶,特别是VEGFR,更特别是VEGFR2和PDGFR,特别是PDGFR-β表现出降低的抑制作用,并且提供了具有不同的副作用或毒性特征的机会,因此允许更有效地治疗这些适应症。VEGFR2和PDGFR-β的抑制剂分别与毒性例如高血压或水肿相关。在VEGFR2抑制剂的情况下,这种高血压效应通常是剂量限制性的,在某些患者群体中可能是禁忌的,并且需要临床管理。
血管内皮生长因子受体(VEGFR)
血管内皮生长因子(VEGF),一种多肽,在体外对内皮细胞是促有丝***的,并且在体内刺激血管生成反应。VEGF也与不适当的血管生成有关。VEGFR是蛋白酪氨酸激酶(PTK)。PTK催化参与细胞功能的蛋白质中的特定酪氨酸残基的磷酸化,由此调节细胞生长、存活和分化。
已鉴定出VEGF的三种PTK受体:VEGFR-1 (Flt-1);VEGFR-2 (Flk-1或KDR)和VEGFR-3 (Flt-4)。这些受体参与血管生成并且参与信号转导。特别引人关注是VEGFR-2,其是主要在内皮细胞中表达的跨膜受体PTK。通过VEGF激活VEGFR-2是引发肿瘤血管生成的信号转导途径中的关键步骤。VEGF表达对于肿瘤细胞可能是组成型的,并且还可在响应某些刺激时上调。一种这样的刺激是缺氧,其中VEGF表达在肿瘤和相关宿主组织中均上调。VEGF配体通过与其细胞外VEGF结合部位结合而激活VEGFR-2。这导致VEGFR的受体二聚体形成和VEGFR-2的细胞内激酶结构域处的酪氨酸残基的自磷酸化。激酶结构域起将磷酸从ATP转移至酪氨酸残基的作用,由此为VEGFR-2下游的信号转导蛋白提供结合部位,最终导致引发血管生成。
PDGFR
恶性肿瘤是细胞增殖不受控制的结果。生长促进因子与生长抑制因子之间的微妙平衡控制着细胞生长。在正常组织中,这些因子的产生和活性导致分化的细胞以保持器官的正常完整性和功能的受控和受调节的方式生长。恶性细胞逃避这种控制;自然平衡受干扰(通过各种机制)并失调,发生异常细胞生长。肿瘤发展中重要的生长因子是血小板衍生生长因子(PDGF),其包含通过细胞表面酪氨酸激酶受体(PDGFR)传送信号并刺激包括生长、增殖和分化在内的各种细胞功能的肽生长因子家族。
cMet
肝细胞生长因子(HGF)(也称为扩散因子)受体c-Met(Met)是调节细胞增殖、形态发生和运动性的受体酪氨酸激酶。c-Met基因翻译成170kD蛋白,其被加工成由140kDβ跨膜亚基和50kD糖基化细胞外α亚基组成的细胞表面受体。
c-Met中的突变,c-Met和/或HGF/SF(扩散因子)的过表达,c-Met和HGF/SF通过相同细胞的表达,以及过表达和/或异常c-Met信号传导存在于多种人类实体瘤中,认为其参与血管生成,肿瘤发展,侵袭和转移。例如,具有不受控制的c-Met激活的细胞系是高度侵袭性的和转移性的。表达c-Met受体的正常细胞和转化细胞之间的显著差异是肿瘤细胞中酪氨酸激酶结构域的磷酸化通常不依赖于配体的存在。
已经在许多人类疾病(包括肿瘤和癌症)中鉴定了C-Met突变/改变,例如遗传性和散发性人***状肾癌,乳腺癌,任选伴有肝转移的结肠直肠癌,胃癌,神经胶质瘤,卵巢癌,肝细胞癌,头颈鳞状细胞癌,睾丸癌,基底细胞癌,肝癌,肉瘤,恶性胸膜间皮瘤,黑色素瘤,多发性骨髓瘤,骨肉瘤,胰腺癌,***癌,滑膜肉瘤,甲状腺癌,非小细胞肺癌(NSCLC)和小细胞肺癌,膀胱移行细胞癌,睾丸癌,基底细胞癌,肝癌和白血病,淋巴瘤和骨髓瘤,例如急性淋巴细胞性白血病(ALL),急性髓性白血病(AML),急性早幼粒细胞性白血病(APL),慢性淋巴细胞性白血病(CLL),慢性髓性白血病(CML),慢性中性粒细胞性白血病(CNL),急性未分化性白血病(AUL),间变性大细胞淋巴瘤(ALCL),前淋巴细胞白血病(PML),青少年骨髓单核细胞白血病(JMML),成人T细胞ALL,具有三谱系骨髓发育不良的AML(AML/TMDS),混合性白血病(MLL),骨髓增生异常综合征(MDS),骨髓增生性病症(MPD),多发性骨髓瘤(MM),骨髓肉瘤,非霍奇金淋巴瘤和霍奇金病(也称为霍奇金淋巴瘤)。
c-Met的过表达也被认为是某些疾病的预后的潜在有用的预测因子,所述疾病例如乳腺癌,非小细胞肺癌,胰腺内分泌肿瘤,***癌,食管腺癌,结肠直肠癌,唾液腺癌,弥漫性大B细胞淋巴瘤和子宫内膜癌。
由于异常HGF/SF-Met信号传导在各种人类癌症的发病机理中的作用,c-Met受体酪氨酸激酶的抑制剂在治疗癌症中具有广泛的应用,在所述癌症中Met活性有助于侵袭性/转移性表型,包括其中c-Met不被过表达或以其它方式改变的那些癌症。c-Met的抑制剂也抑制血管生成,因此被认为可用于治疗与新血管形成相关的疾病,例如类风湿性关节炎和视网膜病变。
通过引用并入本文的WO2007/075567和WO2008/155378描述了cMet抑制剂,例如6-{二氟[6-(1-甲基-1H-吡唑-4-基)[1,2,4]***并[4,3-b]哒嗪-3-基]甲基}喹啉或其药学上可接受的盐或其溶剂合物,和6-[二氟(6-吡啶-4-基[1,2,4]***并[4,3-b]哒嗪-3-基)甲基]喹啉或其药学上可接受的盐或其溶剂合物,以及它们的化学合成物及其多晶型物。它们被描述为蛋白酪氨酸激酶调节剂,特别是c-Met的抑制剂,以及这些化合物用于降低或抑制细胞或受试者中c-Met的激酶活性和调节细胞或受试者中c-Met表达的用途,以及所述化合物用于在受试者中预防或治疗细胞增殖性病症和/或与c-Met相关的病症特别是癌症的用途。
6-{二氟[6-(1-甲基-1H-吡唑-4-基)[1,2,4]***并[4,3-b]哒嗪-3-基]甲基}喹啉(化合物C)由以下结构表示
化合物C
6-[二氟(6-吡啶-4-基[1,2,4]***并[4,3-b]哒嗪-3-基)甲基]喹啉(化合物D)由下式表示
化合物D
在WO2008/155378中,还例示了化合物C的晶体形式和水合物,特别是I型,II型,III型和本发明化合物C的水合物形式。
在WO2008/155378中,本发明化合物C也作为HBr盐,作为HCl盐,作为甲磺酸盐(mesylate),作为乙磺酸盐(esylate)和作为对甲苯磺酸盐(tosylate)示例。
化合物C或其药学上可接受的盐或其溶剂合物和化合物D或其药学上可接受的盐或其溶剂合物是选择性cMet抑制剂。
WO2013/151913涉及酪氨酸激酶抑制剂组合及其用途。
附图简述
图1:来源于不用(-)或用(+)Met抑制剂,300nM化合物C处理30分钟的亲本和抗性NCI-H1581细胞的蛋白质裂解物的蛋白质印迹。
图2:Incucyte图(随时间的%汇合),代表用单一试剂(化合物A [1μM]或化合物D[1μM])或化合物A [1μM]和化合物D [1μM]的组合处理的NCI-H1581细胞的增殖,并且DMSO作为溶媒对照。
图3. 单一试剂化合物A,以及化合物A和化合物D的组合在抗性NCI-H1581异种移植物中的功效。
图4. Incucyte图(随时间的%汇合),代表用化合物A [0.1μM]或化合物A [0.1μM]和化合物D [1μM]的组合处理的NCI-H1581细胞和NCI-H1581Met(+)细胞的增殖,并且DMSO作为溶媒对照。
发明详述
本发明涉及选自N-(3,5-二甲氧基苯基)-N'-(1-甲基乙基)-N-[3-(1-甲基-1H-吡唑-4-基)喹喔啉-6-基]乙烷-1,2-二胺(化合物A)或其药学上可接受的盐或其溶剂合物,和N-(2-氟-3,5-二甲氧基苯基)-N-(1H-咪唑-2-基甲基)-3-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-b]吡嗪-6-胺(化合物B)或其药学上可接受的盐或其溶剂合物的第一化合物;和作为cMet抑制剂(特别是如本文所述的cMet抑制剂)的第二化合物的组合。
在一个实施方案中,本发明涉及N-(3,5-二甲氧基苯基)-N'-(1-甲基乙基)-N-[3-(1-甲基-1H-吡唑-4-基)喹喔啉-6-基]乙烷-1,2-二胺(化合物A)或其药学上可接受的盐或其溶剂合物,和cMet抑制剂,特别是如本文所述的cMet抑制剂的组合。
在一个实施方案中,本发明涉及N-(3,5-二甲氧基苯基)-N'-(1-甲基乙基)-N-[3-(1-甲基-1H-吡唑-4-基)喹喔啉-6-基]乙烷-1,2-二胺(化合物A)或其药学上可接受的盐或其溶剂合物,和6-{二氟[6-(1-甲基-1H-吡唑-4-基)[1,2,4]***并[4,3-b]哒嗪-3-基]甲基}喹啉或其药学上可接受的盐或其溶剂合物的组合。
在一个实施方案中,本发明涉及N-(3,5-二甲氧基苯基)-N'-(1-甲基乙基)-N-[3-(1-甲基-1H-吡唑-4-基)喹喔啉-6-基]乙烷-1,2-二胺(化合物A)或其药学上可接受的盐或其溶剂合物,和6-[二氟(6-吡啶-4-基[1,2,4]***并[4,3-b]哒嗪-3-基)甲基]喹啉或其药学上可接受的盐或其溶剂合物的组合。
在一个实施方案中,本发明涉及N-(2-氟-3,5-二甲氧基苯基)-N-(1H-咪唑-2-基甲基)-3-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-b]吡嗪-6-胺(化合物B)或其药学上可接受的盐或其溶剂合物,和cMet抑制剂特别是如本文所述的cMet抑制剂的组合。
在一个实施方案中,本发明涉及N-(2-氟-3,5-二甲氧基苯基)-N-(1H-咪唑-2-基甲基)-3-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-b]吡嗪-6-胺(化合物B)或其药学上可接受的盐或其溶剂合物,和6-{二氟[6-(1-甲基-1H-吡唑-4-基)[1,2,4]***并[4,3-b]哒嗪-3-基]甲基}喹啉或其药学上可接受的盐或其溶剂合物的组合。
在一个实施方案中,本发明涉及N-(2-氟-3,5-二甲氧基苯基)-N-(1H-咪唑-2-基甲基)-3-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-b]吡嗪-6-胺(化合物B)或其药学上可接受的盐或其溶剂合物,和6-[二氟(6-吡啶-4-基[1,2,4]***并[4,3-b]哒嗪-3-基)甲基]喹啉或其药学上可接受的盐或其溶剂合物的组合。
在一个实施方案中,本发明的组合的FGFR抑制剂(化合物A或其药学上可接受的盐或其溶剂合物,或化合物B或其药学上可接受的盐或其溶剂合物)和cMet抑制剂,特别是本文所述的cMet抑制剂,更特别是化合物C或其药学上可接受的盐或其溶剂合物,或化合物D或其药学上可接受的盐或其溶剂合物同时(例如在单独或单一组合物中)给予,大约在同一时间以任一顺序依次给予。在这种情况下,两种化合物将以足以确保实现有利或协同效应的量和方式给予。
在一个实施方案中,本发明的组合的FGFR抑制剂(化合物A或其药学上可接受的盐或其溶剂合物,或化合物B或其药学上可接受的盐或其溶剂合物)和cMet抑制剂,特别是本文所述的cMet抑制剂,更特别是化合物C或其药学上可接受的盐或其溶剂合物,或化合物D或其药学上可接受的盐或其溶剂合物,按照分开的给药方案以任一顺序依次给药。在这种情况下,两种化合物将以足以确保获得有利的或协同效应的时间段和量和方式给予。
应当理解,所述组合的每个组分的优选给药方法和顺序以及各自的剂量和方案将取决于所给予的具体化疗剂,其给药途径,所治疗的具体肿瘤和所治疗的特定宿主。
最佳给药方法和顺序以及剂量和方案可以由本领域技术人员使用常规方法并考虑到本文所述的信息容易地确定。
在本发明的组合中,FGFR抑制剂和cMet抑制剂可以配制成分开的药物剂型,其可以彼此独立地出售,但具有它们组合使用的指示或说明书。所述指示或说明书可以是患者传单等的形式,或者以任何通信的形式,例如以书面或口头形式。
在本发明的组合中,FGFR抑制剂和cMet抑制剂可以通过相同的给药途径或通过不同的给药途径给予。
在一个实施方案中,本发明组合的FGFR抑制剂和cMet抑制剂通过相同的给药途径,特别是通过口服途径给予。
本发明还涉及包含根据本发明的组合,特别是连同说明书的药物产品或商业包装,以同时,分开或顺序地用于治疗FGFR酪氨酸激酶活性介导的疾病,特别是癌症。
在一个实施方案中,在本发明的组合中,同时给予FGFR抑制剂和cMet抑制剂。
在一个实施方案中,在本发明的组合中,FGFR抑制剂和cMet抑制剂分开给予,特别是以选择的时间间隔给予,使得组合使用的效果大于仅给予FGFR抑制剂或cMet抑制剂时获得的效果。
在包含化合物A或其药学上可接受的盐或其溶剂合物作为FGFR抑制剂的本发明的组合的情况下,可能有利的是,比cMet抑制剂较少频繁地给予所述化合物,因为化合物A显示抗溶酶体性质和延长的靶关闭。
本发明的组合的FGFR抑制剂和cMet抑制剂也可以共同配制在单一制剂中。
在一个实施方案中,本发明涉及药物组合物,其包含药学上可接受的载体和作为第一活性成分的选自N-(3,5-二甲氧基苯基)-N'-(1-甲基乙基)-N-[3-(1-甲基-1H-吡唑-4-基)喹喔啉-6-基]乙烷-1,2-二胺或其药学上可接受的盐或其溶剂合物,和N-(2-氟-3,5-二甲氧基苯基)-N-(1H-咪唑-2-基甲基)-3-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-b]吡嗪-6-胺或其药学上可接受的盐或其溶剂合物的化合物;和作为第二活性成分的cMet抑制剂,特别是如本文所述的cMet抑制剂,更特别地选自6-{二氟[6-(1-甲基-1H-吡唑-4-基)[1,2,4]***并[4,3-b]哒嗪-3-基]甲基}喹啉或其药学上可接受的盐或其溶剂合物和6-[二氟(6-吡啶-4-基[1,2,4]***并[4,3-b]哒嗪-3-基)甲基]喹啉或其药学上可接受的盐或其溶剂合物的化合物。
在一个实施方案中,本发明涉及药物组合物,其包含药学上可接受的载体和作为第一活性成分的N-(3,5-二甲氧基苯基)-N'-(1-甲基乙基)-N-[3-(1-甲基-1H-吡唑-4-基)喹喔啉-6-基]乙烷-1,2-二胺或其药学上可接受的盐或其溶剂合物,以及作为第二活性成分的cMet抑制剂,特别是本文所述的cMet抑制剂。
在一个实施方案中,本发明涉及药物组合物,其包含药学上可接受的载体和作为第一活性成分的N-(3,5-二甲氧基苯基)-N'-(1-甲基乙基)-N-[3-(1-甲基-1H-吡唑-4-基)喹喔啉-6-基]乙烷-1,2-二胺或其药学上可接受的盐或其溶剂合物,以及作为第二活性成分的6-{二氟[6-(1-甲基-1H-吡唑-4-基)[1,2,4]***并[4,3-b]哒嗪-3-基]甲基}喹啉或其药学上可接受的盐或其溶剂合物。
在一个实施方案中,本发明涉及药物组合物,其包含药学上可接受的载体和作为第一活性成分的N-(3,5-二甲氧基苯基)-N'-(1-甲基乙基)-N-[3-(1-甲基-1H-吡唑-4-基)喹喔啉-6-基]乙烷-1,2-二胺或其药学上可接受的盐或其溶剂合物,以及作为第二活性成分的6-[二氟(6-吡啶-4-[1,2,4]***并[4,3-b]-哒嗪-3-基)甲基]喹啉或其药学上可接受的盐或其溶剂合物。
在一个实施方案中,本发明涉及药物组合物,其包含药学上可接受的载体和作为第一活性成分的N-(2-氟-3,5-二甲氧基苯基)-N-(1H-咪唑-2-基甲基)-3-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-b]吡嗪-6-胺或其药学上可接受的盐或其溶剂合物;和作为第二活性成分的cMet抑制剂,特别是如本文所述的cMet抑制剂。
在一个实施方案中,本发明涉及药物组合物,其包含药学上可接受的载体和作为第一活性成分的N-(2-氟-3,5-二甲氧基苯基)-N-(1H-咪唑-2-基甲基)-3-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-b]吡嗪-6-胺或其药学上可接受的盐或其溶剂合物;和作为第二活性成分的6-{二氟[6-(1-甲基-1H-吡唑-4-基)[1,2,4]***并[4,3-b]哒嗪-3-基]甲基}喹啉或其药学上可接受的盐或其溶剂合物。
在一个实施方案中,本发明涉及药物组合物,其包含药学上可接受的载体和作为第一活性成分的N-(2-氟-3,5-二甲氧基苯基)-N-(1H-咪唑-2-基甲基)-3-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-b]吡嗪-6-胺或其药学上可接受的盐或其溶剂合物;和作为第二活性成分的6-[二氟(6-吡啶-4-基[1,2,4]***并[4,3-b]哒嗪-3-基)甲基]喹啉或其药学上可接受的盐或溶剂合物。
在一个实施方案中,本发明的组合或药物组合物经口服给予。
在一个实施方案中,本发明的组合或药物组合物包含作为单一活性成分的FGFR抑制剂和cMet抑制剂,包括本发明的任何实施方案中所述的那些。
在本发明中,在一个实施方案中,本发明的组合或者药物组合物的cMet抑制剂还可以选自:
(E)-2-(1-(3-((7-氟喹啉-6-基)甲基)咪唑并[1,2-b]哒嗪-6-基)亚乙基)肼甲酰胺(WO2011/018454的实施例1);2-氟-N-甲基-4-[(7-喹啉-6-基-甲基)-咪唑并[1,2-b]三嗪-2-基]苯甲酰胺(WO 2008/064157的实施例7);克唑替尼(crizotinib);卡博替尼(cabozantinib);替加替尼(tivatinib);foretinib;MGCD-265; AMG-208; AMG-337; MK-8033; E-7050; EMD-1204831; EMD-1214063;阿莫替尼(amuvatinib);BMS-817378; DP-3590; ASP-08001; HM-5016504; PF-4217903; SGX523;抗体或相关分子,例如ficlatuzumab,onartuzumab,rilotuzumab,Tak-701,LA-480;或其药学上可接受的盐或其溶剂合物。
在一个实施方案中,本发明的组合或本发明的药物组合物包含至少一种其它治疗剂,特别是至少一种另外的抗癌剂或佐剂,特别是用作药物,更具体地用于治疗癌症或相关疾病。可以包含在本发明的组合或药物组合物中的抗癌剂或佐剂(该疗法中的载剂(supporting agents))的实例包括但不限于:
- 铂配位化合物,例如任选与氨磷汀、卡铂或奥沙利铂组合的顺铂;
- 紫杉烷类化合物,例如紫杉醇、紫杉醇蛋白质结合粒子(Abraxane™)或多西他赛;
- 拓扑异构酶I抑制剂,例如喜树碱化合物,例如伊立替康、SN-38、托泊替康、盐酸托泊替康;
- 拓扑异构酶II抑制剂,例如抗肿瘤表鬼臼毒素或鬼臼毒素衍生物,例如依托泊苷、磷酸依托泊苷或替尼泊苷;
- 抗肿瘤长春花生物碱,例如长春碱、长春新碱或长春瑞滨;
- 抗肿瘤核苷衍生物,例如5-氟尿嘧啶、亚叶酸、吉西他滨、盐酸吉西他滨、卡培他滨、克拉屈滨、氟达拉滨、奈拉滨;
- 烷基化剂,例如氮芥或亚硝基脲,例如环磷酰胺、苯丁酸氮芥、卡莫司汀、塞替派、马法兰(美法仑)、洛莫司汀、六甲蜜胺、白消安、达卡巴嗪、雌莫司汀、任选与美司钠组合的异环磷酰胺、哌泊溴烷、丙卡巴肼、链佐星、替莫唑胺(telozolomide)、尿嘧啶;
- 抗肿瘤蒽环类衍生物,例如柔红霉素、任选与右雷佐生组合的多柔比星、doxil、伊达比星、米托蒽醌、表柔比星、盐酸表柔比星、戊柔比星;
- tetracarcin衍生物,例如tetrocarcin A;
- 糖皮质激素,例如***;
- 抗体,例如曲妥珠单抗(HER2抗体)、利妥昔单抗(CD20抗体)、吉妥珠单抗、吉妥珠单抗奥佐米星、西妥昔单抗、培妥珠单抗、贝伐单抗、阿仑珠单抗、依库珠单抗、替伊莫单抗、诺莫单抗、帕尼单抗、托西莫单抗、CNTO 328;
- ***受体拮抗剂或选择性***受体调节剂或***合成抑制剂,例如他莫昔芬、氟维司群、托瑞米芬、屈洛昔芬、faslodex、雷洛昔芬或来曲唑;
- 芳香酶抑制剂,例如依西美坦、阿那曲唑、来曲唑、睾内酯和伏氯唑;
- 分化剂,例如类视黄醇、维生素D或视黄酸和视黄酸代谢阻滞剂(RAMBA),例如异维甲酸(accutane);
- DNA甲基转移酶抑制剂,例如氮胞苷或地西他滨;
- 抗叶酸剂,例如培美曲塞二钠(premetrexed disodium);
- 抗生素,例如放线菌素D (antinomycin D)、博来霉素、丝裂霉素C、更生霉素、洋红霉素、道诺霉素、左旋咪唑、普卡霉素、光神霉素;
- 抗代谢药,例如氯法拉滨、氨基喋呤、阿糖胞苷或甲氨蝶呤、阿扎胞苷、阿糖胞苷(cytarabine)、氟尿苷、喷司他丁、硫鸟嘌呤;
- 凋亡诱导剂和抗血管生成剂,例如Bcl-2抑制剂,例如YC 137、BH 312、ABT 737、棉酚、HA 14-1、TW 37或癸酸;
- 微管蛋白结合剂,例如康普瑞汀、秋水仙素或诺考达唑;
- 激酶抑制剂(例如EGFR (上皮生长因子受体)抑制剂、MTKI (多靶激酶抑制剂)、mTOR抑制剂),例如黄酮吡多(flavoperidol)、甲磺酸伊马替尼、埃罗替尼、吉非替尼、达沙替尼、拉帕替尼、二甲苯磺酸拉帕替尼、索拉非尼、舒尼替尼、马来酸舒尼替尼、坦罗莫司;
- 法尼基转移酶抑制剂,例如替匹法尼;
- 组蛋白脱乙酰酶(HDAC)抑制剂,例如丁酸钠、辛二酰苯胺异羟肟酸(SAHA)、缩肽(FR 901228)、NVP-LAQ824、R306465、JNJ-26481585、曲古抑菌素A、伏林司他;
- 泛素-蛋白酶体途径抑制剂,例如PS-341、MLN.41或硼替佐米;
- Yondelis;
- 端粒酶抑制剂,例如Telomestatin;
- 基质金属蛋白酶抑制剂,例如巴马司他、马立马司他、普啉司他(prinostat)或美他司他(metastat);
- 重组白介素,例如阿地白介素、地尼白介素-毒素连接物(denileukindiftitox)、干扰素α 2a、干扰素α 2b、聚乙二醇干扰素α 2b;
- MAPK抑制剂;
- 类视黄醇,例如阿利维A酸、贝沙罗汀、维A酸(tretinoin);
- 三氧化二砷;
- 天冬酰胺酶;
- 类固醇,例如丙酸屈他雄酮、醋酸甲地孕酮、诺龙(癸酸诺龙、苯丙酸诺龙)、***;
- 促性腺素释放激素激动剂或拮抗剂,例如阿巴瑞克、醋酸戈舍瑞林、醋酸组氨瑞林、醋酸亮丙瑞林;
- 沙利度胺、来那度胺;
- 巯基嘌呤、米托坦、帕米膦酸盐、培加酶、培门冬酶、拉布立酶;
- BH3模拟物,例如ABT-737;
- MEK抑制剂,例如PD98059、AZD6244、CI-1040;
- 集落刺激因子类似物,例如非格司亭、培非司亭、沙格司亭;***或其类似物(例如达贝泊汀α);白介素11;奥普瑞白介素;唑来膦酸盐、唑来膦酸;芬太尼;二膦酸盐;帕利夫明;
- 甾体细胞色素P450 17 α-羟化酶-17,20-裂解酶抑制剂(CYP17),例如阿比特龙、醋酸阿比特龙。
本发明的组合或药物组合物还在敏化肿瘤细胞以进行放射疗法和化学疗法中具有治疗应用。
因此本发明的组合或药物组合物可用作“放射致敏剂”和/或“化学致敏剂”,或可以与另一种“放射致敏剂”化合物和/或“化学致敏剂”化合物联合给予。
本文所用术语“放射致敏剂”或“放射致敏剂”化合物定义为当以治疗有效量给予动物时提高细胞对电离辐射的敏感性和/或促进电离辐射可治疗的疾病的治疗的本发明的组合或药物制剂,或分子,优选低分子量分子。
本文所用术语“化学致敏剂”或“化学致敏剂”化合物定义为当以治疗有效量给予动物时提高细胞对化学疗法的敏感性和/或促进化学疗法可治疗的疾病的治疗的本发明的组合或药物组合物,或分子,优选低分子量分子。
在文献中已提出放射致敏剂的作用方式的几种机制,包括:低氧细胞放射致敏剂(例如2-硝基咪唑化合物和苯并三嗪二氧化物化合物)模拟氧或者在缺氧条件下表现得像生物还原剂;非低氧细胞放射致敏剂(例如卤化嘧啶)可以是DNA碱基的类似物并优先掺入癌细胞的DNA中,并由此促进放射诱导的DNA分子断裂和/或阻碍正常DNA修复机制;已提出了放射致敏剂在疾病治疗中的各种其它可能的作用机制的假设。
许多癌症治疗方案目前采用与X-射线放射联合的放射致敏剂。X-射线激活的放射致敏剂的实例包括但不限于:甲硝唑、米索硝唑、去甲基米索硝唑、哌莫硝唑、依他硝唑、尼莫唑、丝裂霉素C、RSU 1069、SR 4233、ΕO9、RB 6145、烟酰胺、5-溴脱氧尿苷(BUdR)、5-碘脱氧尿苷(IUdR)、溴脱氧胞苷、氟脱氧尿苷(FudR)、羟基脲、顺铂和所述放射致敏剂的治疗有效的类似物和衍生物。
癌症的光动力疗法(PDT)利用可见光作为该敏化剂的放射活化剂。光动力放射致敏剂的实例包括但不限于血卟啉衍生物、光敏素、苯并卟啉衍生物、锡初卟啉、pheoborbide-a、细菌叶绿素-a、萘酞菁、酞菁、酞菁锌和所述光动力放射致敏剂的治疗有效的类似物和衍生物。
放射致敏剂可以与治疗有效量的一种或多种其它化合物联合给予,所述其它化合物包括但不限于:促进放射致敏剂掺入靶细胞中的化合物;控制治疗剂、营养物和/或氧流向靶细胞的化合物;在有或没有其它放射的情况下作用于肿瘤的化疗剂;或用于治疗癌症或其它疾病的其它治疗有效化合物。
化学致敏剂可以与治疗有效量的一种或多种其它化合物联合给予,所述其它化合物包括但不限于:促进化学致敏剂掺入靶细胞中的化合物;控制治疗剂、营养物和/或氧流向靶细胞的化合物;作用于肿瘤的化疗剂或用于治疗癌症或其它疾病的其它治疗有效化合物。发现钙拮抗剂(例如维拉帕米)可以与抗肿瘤药联用,以在耐受公认化疗剂的肿瘤细胞中建立化学敏感性并增强这类化合物在药物敏感的恶性肿瘤中的功效。
本发明还涉及本发明的组合在制备用于治疗FGFR介导的病症,特别是癌症的药物中的用途。
本发明还涉及本发明的药物组合物在制备用于治疗FGFR介导的病症,特别是癌症的药物中的用途。
本发明还涉及本发明的组合在制备用于预防肿瘤或癌症对所述组合的FGFR抑制剂的抗性或用于延迟肿瘤或癌症对所述组合的FGFR抑制剂的抗性的药物中的用途。
本发明还涉及本发明的药物组合物在制备用于预防肿瘤或癌症对所述药物组合物的FGFR抑制剂的抗性或延迟肿瘤或癌症对所述药物组合物的FGFR抑制剂的抗性的药物中的用途。
本发明还涉及本发明的组合用于制备药物的用途,所述药物用于预防肿瘤或癌症对所述组合的FGFR抑制剂的抗性的出现或用于延迟肿瘤或癌症对组合的FGFR抑制剂的抗性的出现。
本发明还涉及本发明的药物组合物用于制备药物的用途,所述药物用于预防肿瘤或癌症对药物组合物的FGFR抑制剂的抗性的出现或用于延迟肿瘤或癌症对药物组合物的FGFR抑制剂的抗性的出现。
本发明还涉及本发明的组合在制备用于预防或治疗,特别是用于***或癌症的药物中的用途,其中Met信号传导通路激活是肿瘤或癌症对FGFR抑制剂的抗性机制。
本发明还涉及本发明的药物组合物在制备用于预防或治疗,特别是用于***或癌症的药物中的用途,其中Met信号传导通路激活是肿瘤或癌症对FGFR抑制剂的抗性机制。
本发明还涉及cMet抑制剂,特别是如本文所述的cMet抑制剂,更特别是化合物C或其药学上可接受的盐或其溶剂合物和化合物D或其药学上可接受的盐或其溶剂合物防止肿瘤或癌症对FGFR抑制剂,特别是本文所述的FGFR抑制剂的抗性,延迟该抗性,预防抗性出现或延迟抗性出现的用途。
本发明还涉及本发明的组合在制备用于预防或治疗特别是用于治疗由FGFR激酶介导的并具有高Met表达的肿瘤或癌症的药物中的用途。
本发明还涉及本发明的药物组合物在制备用于预防或治疗,特别是用于治疗由FGFR激酶介导的并具有高Met表达的肿瘤或癌症的药物中的用途。
本发明组合或药物组合物的化合物的盐形式通常是药学上可接受的盐,Berge等,1977, “Pharmaceutically Acceptable Salts”, J. Pharm. Sci., 第66卷, 第1-19页论述了药学上可接受的盐的实例。但是,也可将非药学上可接受的盐制成中间体形式,然后可将其转化为药学上可接受的盐。可用于例如纯化或分离本发明化合物的这样的非药学上可接受的盐也构成本发明的部分。
可通过常规化学方法例如通过描述于Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (编辑), Camille G. Wermuth (编辑),ISBN: 3-90639-026-8, Hardcover, 第388页, August 2002的方法,自含有碱性或酸性部分的母体化合物合成本发明的盐。一般可通过在水或在有机溶剂中,或在两者的混合物中,使这些化合物的游离酸或碱形式与合适的碱或酸反应来制备所述盐;一般使用非水介质例如***、乙酸乙酯、乙醇、异丙醇或乙腈。本发明的化合物可作为一盐或二盐存在,这取决于自其中形成盐的酸的pKa。
可与各种各样的酸(无酸机和有机酸两者)形成酸加成盐。酸加成盐的实例包括与选自以下的酸形成的盐:乙酸、2,2-二氯乙酸、己二酸、藻酸、抗坏血酸(例如L-抗坏血酸)、L-天冬氨酸、苯磺酸、苯甲酸、4-乙酰胺基苯甲酸、丁酸、(+)樟脑酸、樟脑磺酸、(+)-(1S)-樟脑-10-磺酸、癸酸、己酸、辛酸、肉桂酸、柠檬酸、环拉酸、十二烷基硫酸、乙烷-1,2-二磺酸、乙磺酸、2-羟基乙烷磺酸、甲酸、富马酸、半乳糖二酸、龙胆酸、葡庚糖酸、D-葡糖酸、葡糖醛酸(例如D-葡糖醛酸)、谷氨酸(例如L-谷氨酸)、α-氧代戊二酸、乙醇酸、马尿酸、氢溴酸、盐酸、氢碘酸、羟乙磺酸、乳酸(例如(+)-L-乳酸和(±)-DL-乳酸)、乳糖酸、马来酸、苹果酸、(-)-L-苹果酸、丙二酸、(±)-DL-扁桃酸、甲磺酸、萘磺酸(例如萘-2-磺酸)、萘-1,5-二磺酸、1-羟基-2-萘甲酸、烟酸、硝酸、油酸、乳清酸、草酸、棕榈酸、双羟萘酸、磷酸、丙酸、L-焦谷氨酸、丙酮酸、水杨酸、4-氨基-水杨酸、癸二酸、硬脂酸、琥珀酸、硫酸、鞣酸、(+)-L-酒石酸、硫氰酸、甲苯磺酸(例如对甲苯磺酸)、十一碳烯酸和戊酸,以及酰化氨基酸和阳离子交换树脂。
一组具体的盐包括自乙酸、盐酸、氢碘酸、磷酸、硝酸、硫酸、柠檬酸、乳酸、琥珀酸、马来酸、苹果酸、羟乙磺酸、富马酸、苯磺酸、甲苯磺酸、甲磺酸(mesylate)、乙磺酸、萘磺酸、戊酸、乙酸、丙酸、丁酸、丙二酸、葡糖醛酸和乳糖酸形成的盐。另一组酸加成盐包括自乙酸、己二酸、抗坏血酸、天冬氨酸、柠檬酸、DL-乳酸、富马酸、葡萄糖酸、葡糖醛酸、马尿酸、盐酸、谷氨酸、DL-苹果酸、甲磺酸、癸二酸、硬脂酸、琥珀酸和酒石酸形成的盐。
如果化合物是阴离子或具有可为阴离子的官能团,那么可与合适的阳离子形成盐。合适的无机阳离子的实例包括但不限于碱金属离子(例如Na+和K+)、碱土金属阳离子(例如Ca2+和Mg2+)和其它阳离子(例如A13+)。合适的有机阳离子的实例包括但不限于铵离子(即NH4 +)和取代的铵离子(例如NH3R+、NH2R2 +、NHR3 +、NR4 +)。
某些合适的取代铵离子的实例是衍生自以下的铵离子:乙胺、二乙胺、二环己基胺、三乙胺、丁胺、乙二胺、乙醇胺、二乙醇胺、哌嗪、苄胺、苯基苄胺、胆碱、葡甲胺和氨丁三醇以及氨基酸(例如赖氨酸和精氨酸)。常用的季铵离子的实例是N(CH3)4 +。
在一个实施方案中,本发明的组合或药物组合物的FGFR抑制剂或cMet抑制剂的药学上可接受的盐是酸加成盐。
在一个实施方案中,本发明的组合或药物组合物包含如上文发明背景部分中所述的化合物A,化合物B或化合物C的盐。
在一个实施方案中,本发明的组合或药物组合物包含游离碱形式的FGFR抑制剂。
在一个实施方案中,本发明的组合或药物组合物包含游离碱形式的cMet抑制剂。
在一个实施方案中,本发明的组合或药物组合物包含游离碱形式的FGFR抑制剂和cMet抑制剂。
本发明的组合或药物组合物的化合物可与例如水(即水合物)或普通有机溶剂形成溶剂合物。本文所用术语“溶剂合物”意指本发明的化合物与一个或多个溶剂分子的物理缔合。这种物理缔合包括不同程度的离子和共价键合,包括氢键合。在某些情况下,例如当一个或多个溶剂分子掺入结晶固体的晶格时,溶剂合物将能够分离。术语“溶剂合物”欲包括溶液相和可分离的溶剂合物两者。合适的溶剂合物的非限制性实例包括本发明的化合物与水、异丙醇、乙醇、甲醇、DMSO、乙酸乙酯、乙酸或乙醇胺等的组合。当本发明的化合物在溶液中时,可发挥其生物作用。本发明的组合或药物组合物的化合物的药学上可接受的盐的溶剂合物也包括在术语“溶剂合物”中。
溶剂合物在制药化学中众所周知。它们对物质制备(例如有关其纯化)、物质保存(例如其稳定性)的方法和物质处理的容易性将会很重要,并常常构成化学合成的分离或纯化阶段的部分。本领域技术人员可通过标准和长期采用的技术确定通过用于制备指定化合物的分离条件或纯化条件是否形成水合物或其它溶剂合物。这种技术的实例包括热解重量分析法(TGA)、示差扫描量热法(DSC)、X射线晶体学检测(例如单晶X射线晶体学检测或X射线粉末衍射法)和固态NMR (SS-NMR,亦称为魔角自旋NMR或MAS-NMR)。这样的技术同NMR、IR、HPLC和MS一样是技术化学家的标准分析工具包的部分。或者技术人员可采用结晶条件,包括具体溶剂合物所需的溶剂的量,特意形成溶剂合物。之后可采用上述标准方法以确定是否形成了溶剂合物。本文所述化合物还包括化合物的任何络合物(例如与化合物(例如环糊精)的包合络合物或包合物,或与金属的络合物)。
此外,本发明的组合或药物组合物的化合物可具有一种或多种多晶型物(结晶)或非晶体形式,同样欲包括在本发明的范围内。
在一个实施方案中,本发明的组合或药物组合物包含如上文在发明部分背景中所述的化合物C的多晶型物或溶剂合物。
本文所用的术语“调节”在用于激酶活性时旨在定义蛋白激酶生物活性水平的变化。因此,调节包括引起相关蛋白激酶活性的提高或降低的生理变化。在后一情况下,该调节可以被描述为“抑制”。调节可直接或间接发生,可在任何生理水平上由任何机制介导,生理水平包括例如基因表达水平(包括例如转录、翻译和/或翻译后修饰)、编码直接或间接作用于激酶活性水平的调节元件的基因的表达水平。因此,调节可意味着激酶的升高/抑制表达或过量表达或表达不足,包括基因扩增(即多个基因拷贝)和/或由转录作用造成的表达增加或降低,以及由一种或多种突变造成的一种或多种蛋白激酶的活性过高(或不足)和活化(失活)(包括活化(失活))。术语“调节的”、“调节性”和“调节”也照此解释。
例如与本文所述激酶联用(并且适用于例如各种生理过程、疾病、状况、病况、疗法、治疗或干预)的本文所用术语“介导(的)”,是指有限制的操控使得该术语适用的各种过程、疾病、状况、病况、治疗或干预是其中所述激酶发挥生物学作用的那些。在该术语适用于疾病、状况或病况的情况下,激酶所起的生物学作用可以是直接或间接的,并且对于疾病、状况或病况(或其病因或进程)的症状表现可能是必需和/或足够的。因此,激酶活性(特别是异常水平的激酶活性,例如激酶过量表达)不必是该疾病、状况或病况的近因:相反,预期激酶介导的疾病、状况或病况包括具有多因素病因并且其中所述激酶仅是部分参与的复杂进程的那些疾病、状况或病况。在该术语适用于治疗、预防或干预的情况下,激酶所起的作用可以是直接或间接的,并且对于治疗、预防的实施或干预的结果应是必需和/或足够的。因此,由激酶介导的疾病、状况或病况包括对任何具体的癌症药物或治疗产生抗性。
因此,例如,本发明的组合或药物组合物可用于减少或降低癌症发病率。
所述组合和药物组合物的FGFR抑制剂具有针对FGFR1,FGFR2,FGFR3和/或FGFR4,特别是针对FGFR1,FGFR2,FGFR3和FGFR4的活性。
由于其调节或抑制FGFR的活性,本发明的组合或药物组合物可特别通过抑制血管生成,而用于提供在肿瘤中防止生长或引发细胞凋亡的手段。因此预期本发明的组合或药物组合物将证实可用于治疗或预防增殖性病症,例如癌症。此外,本发明的组合或药物组合物可用于治疗其中存在增殖、凋亡或分化的病症的疾病。
可通过本发明的组合或药物组合物治疗(或抑制)的癌症的实例包括但不限于癌,例如膀胱癌、乳腺癌、结肠癌(例如结肠直肠癌,如结肠腺癌和结肠腺瘤)、肾癌、尿路上皮癌、子宫癌、表皮癌、肝癌、肺癌(例如腺癌、小细胞肺癌和非小细胞肺癌、肺鳞状细胞癌)、食管癌、头颈癌、胆囊癌、卵巢癌、胰腺癌(例如外分泌性胰腺癌)、胃癌、胃肠癌(也称作胃癌)(例如胃肠间质瘤)、***、子宫内膜癌、甲状腺癌、***癌或皮肤癌(例如鳞状细胞癌或隆凸性皮肤纤维肉瘤);垂体癌、淋巴系造血***肿瘤例如白血病、急性淋巴细胞白血病、慢性淋巴细胞白血病、B细胞淋巴瘤(例如弥漫性大B细胞淋巴瘤)、T细胞淋巴瘤、霍奇金淋巴瘤(Hodgkin’s lymphoma)、非霍奇金淋巴瘤、毛细胞淋巴瘤或伯基特淋巴瘤(Burkitt'slymphoma);骨髓系造血***肿瘤,例如白血病、急性和慢性髓细胞白血病、慢性髓单核细胞白血病(CMML)、骨髓增生性疾病、骨髓增生性综合征、骨髓增生异常综合征或前髓细胞白血病;多发性骨髓瘤;甲状腺滤泡癌;肝细胞癌、间充质来源的肿瘤(例如尤因肉瘤(Ewing’ssarcoma)),例如纤维肉瘤或横纹肌肉瘤;中枢或***神经***肿瘤,例如星形细胞瘤、成神经细胞瘤、神经胶质瘤(如多形性成胶质细胞瘤)或神经鞘瘤;黑素瘤;***瘤;畸胎癌;骨肉瘤;着色性干皮病;角化棘皮瘤(keratoctanthoma);甲状腺滤泡癌;或卡波西肉瘤(Kaposi's sarcoma)。特别是肺鳞状细胞癌、乳腺癌、结肠直肠癌、成胶质细胞瘤、星形细胞瘤、***癌、小细胞肺癌、黑素瘤、头颈癌、甲状腺癌、子宫癌、胃癌、肝细胞癌、***、多发性骨髓瘤、膀胱癌、子宫内膜癌、尿路上皮癌、结肠癌、横纹肌肉瘤、垂体腺癌。
可治疗(或抑制)的癌症的实例包括但不限于膀胱癌、尿路上皮癌、转移性尿路上皮癌、手术不能切除的尿路上皮癌、乳腺癌、成胶质细胞瘤、肺癌、非小细胞肺癌、鳞状细胞肺癌、肺的腺癌、肺腺癌、小细胞肺癌、卵巢癌、子宫内膜癌、***、软组织肉瘤、头颈鳞状细胞癌、胃癌、食管癌、食管鳞状细胞癌、食管的腺癌、胆管癌、肝细胞癌。
某些癌症对特定药物的治疗具有抗性。这可能由肿瘤类型所致或可能由于用化合物治疗而产生。就此而言,提及多发性骨髓瘤时包括硼替佐米敏感性多发性骨髓瘤或难治性多发性骨髓瘤。同样,提及慢性髓细胞性白血病包括伊马替尼(imitanib)敏感性慢性髓细胞性白血病和难治性慢性髓细胞性白血病。慢性髓细胞性白血病也被称作慢性髓细胞白血病、慢性粒细胞性白血病或CML。同样地,急性髓细胞性白血病也被称作急性成髓细胞性白血病、急性粒细胞性白血病、急性非淋巴细胞白血病或AML。
本发明的组合或药物组合物还可用于治疗细胞增殖异常的造血***疾病(无论是恶变前还是稳定的),例如骨髓增生性疾病。骨髓增生性疾病("MPD")是其中生成过多细胞的一类骨髓疾病。它们涉及并可能发展成骨髓增生异常综合征。骨髓增生性疾病包括真性红细胞增多、特发性血小板增多症和原发性骨髓纤维化。另一造血***病症是嗜酸性粒细胞增多综合症。T细胞淋巴增生性疾病包括衍生自天然杀伤细胞的那些疾病。
此外,本发明的组合或药物组合物可用于治疗胃肠(也称作胃)癌,例如胃肠间质瘤。胃肠癌是指包括食管、胃、肝、胆管***、胰腺、肠和***在内的胃肠道的恶性病况。
因此,在一个实施方案中,在用于治疗包括异常细胞生长的疾病或病况的本发明的组合、药物组合物、用途或方法中,包括异常细胞生长的疾病或病况是癌症。
癌症的特定亚类包括多发性骨髓瘤、膀胱癌、***、***癌和甲状腺癌、肺癌、乳腺癌和结肠癌。
癌症的其它亚类包括多发性骨髓瘤、膀胱癌、肝细胞癌、口腔鳞状细胞癌和***。
癌症的其它亚类包括膀胱癌、肺癌、乳腺癌、胃癌、肝细胞癌、结肠癌、血液恶性肿瘤、卵巢癌、成胶质细胞瘤。
癌症的其它亚类包括膀胱癌、肺癌、乳腺癌、胃癌和肝细胞癌。
具有FGFR如FGFR1抑制活性的本发明的组合或药物组合物特别可用于治疗或预防乳腺癌,特别是典型性小叶癌(CLC)。
由于本发明的组合或药物组合物具有FGFR4活性,因此它们也可用于治疗***癌或垂体癌,或它们可用于治疗乳腺癌、肺癌、***癌、肝癌(HCC)或肺癌。
特别是包含FGFR抑制剂的本发明的组合或药物组合物可用于治疗多发性骨髓瘤、骨髓增生性病症、子宫内膜癌、***癌、膀胱癌、肺癌、卵巢癌、乳腺癌、胃癌、结肠直肠癌和口腔鳞状细胞癌。
癌症的其它亚类是多发性骨髓瘤、子宫内膜癌、膀胱癌、***、***癌、肺癌、乳腺癌、结肠直肠癌和甲状腺癌。
特别是本发明的组合或药物组合物可用于治疗多发性骨髓瘤(特别是具有t(4;14)易位或过量表达FGFR3的多发性骨髓瘤)、***癌(激素难治性***癌)、子宫内膜癌(特别是具有FGFR2激活突变的子宫内膜肿瘤)和乳腺癌(特别是小叶乳腺癌)。
特别是本发明的组合或药物组合物可用于治疗小叶癌,例如CLC (典型性小叶癌)。
由于本发明的组合或药物组合物具有针对FGFR3的活性,因此它们可用于治疗多发性骨髓瘤和膀胱癌。
特别是,所述化合物具有针对具有FGFR3-TACC3易位的肿瘤的活性,特别是具有FGFR3-TACC3易位的膀胱或脑肿瘤。
特别是本发明的组合或药物组合物可用于治疗t (4;14)易位阳性的多发性骨髓瘤。
在一个实施方案中,本发明的组合或药物组合物可用于治疗肉瘤。在一个实施方案中,本发明的组合或药物组合物可用于治疗肺癌,例如鳞状细胞癌。
由于本发明的组合或药物组合物具有针对FGFR2的活性,因此它们可用于治疗子宫内膜癌、卵巢癌、胃癌、肝细胞癌、子宫癌、***和结肠直肠癌。FGFR2在上皮性卵巢癌中也过量表达,因此本发明的组合或药物组合物尤其可用于治疗卵巢癌,例如上皮性卵巢癌。
在一个实施方案中,本发明的组合或药物组合物可用于治疗肺癌特别是NSCLC(非小细胞肺癌)、鳞状细胞癌、肝癌、肾癌、乳腺癌、结肠癌、结肠直肠癌、***癌。
本发明的组合或药物组合物还可用于治疗用VEGFR2抑制剂或VEGFR2抗体(例如Avastin)预先治疗的肿瘤。
特别是本发明的组合或药物组合物可用于治疗VEGFR2-耐受肿瘤。VEGFR2抑制剂和抗体用于治疗甲状腺癌和肾细胞癌,因此本发明的组合或药物组合物可用于治疗VEGFR2-耐受的甲状腺癌和肾细胞癌。
癌症可以是对选自FGFR1、FGFR2、FGFR3、FGFR4的任一种或多种、例如选自FGFR1、FGFR2或FGFR3的一种或多种FGFR的抑制敏感的癌症。
可以借助如下文提供的细胞生长测定法或借助如在标题为“诊断方法”的章节中提供的方法确定特定癌症是否是对FGFR信号转导抑制敏感的癌症。
本发明的化合物,特别是具有FGFR抑制活性的那些化合物特别可用于治疗或预防与存在升高水平的FGFR相关或以存在升高水平的FGFR为特征的类型的癌症,例如在本文中在本申请前言部分中提到的癌症。
本发明的组合或药物组合物可用于治疗成年人群。本发明的组合或药物组合物可用于治疗儿童人群。
本发明的组合或药物组合物可用于治疗由增殖病症造成的其它病况例如II型或非胰岛素依赖型糖尿病、自身免疫病、头部创伤、中风、癫痫、神经变性疾病例如阿尔茨海默氏症(Alzheimer’s)、运动神经元病、进行性核上性麻痹、皮层基底节变性和皮克病(Pick’sdisease)例如自身免疫病和神经变性疾病。
本发明的组合或药物组合物可能是有用的疾病状态和病况的一个亚组由以下组成:炎性疾病、心血管疾病和伤口愈合。
还已知FGFR在细胞凋亡、血管生成、增殖、分化和转录中发挥作用,因此本发明的化合物、组合、药物组合物还可用于治疗下列非癌症疾病:慢性炎性疾病,例如***性红斑狼疮、自身免疫介导的肾小球肾炎、类风湿性关节炎、银屑病、炎性肠病、自身免疫性糖尿病、湿疹过敏反应、哮喘、COPD、鼻炎和上呼吸道疾病;心血管疾病,例如心脏肥大、再狭窄、动脉粥样硬化;神经变性病症,例如阿尔茨海默病、AIDS相关性痴呆、帕金森病(Parkinson’s disease)、肌萎缩性侧索硬化症、色素性视网膜炎、脊髓性肌萎缩和小脑变性;肾小球肾炎;骨髓增生异常综合征、缺血性损伤相关的心肌梗死、中风和再灌注损伤、心律失常、动脉粥样硬化、毒性诱发肝病或酒精相关肝病、血液病例如慢性贫血和再生障碍性贫血;肌肉骨骼***的退行性疾病,例如骨质疏松症和关节炎、阿司匹林敏感的鼻窦炎、囊性纤维化、多发性硬化、肾病和癌症疼痛。
此外,FGFR2的突变与人骨骼发育中的几种严重异常相关,因此本发明的化合物可用于治疗人骨骼发育异常,包括颅缝异常骨化(颅缝早闭)、Apert (AP)综合征、Crouzon综合征、Jackson-Weiss综合征、Beare-Stevenson皮肤旋纹综合征和斐弗综合征。
具有FGFR例如FGFR2或FGFR3抑制活性的本发明的组合或药物组合物特别可用于治疗或预防骨骼疾病。具体的骨骼疾病是软骨发育不全或致死性侏儒症(也被称作致死性发育异常)。
具有FGFR例如FGFR1、FGFR2或FGFR3抑制活性的本发明的组合或药物组合物特别可用于治疗或预防其中以进行性纤维化为症状的病理。可用本发明的化合物治疗的纤维化病况包括表现出纤维组织的异常或过度沉积的疾病,例如在肝硬化、肾小球肾炎、肺纤维化、***性纤维化、类风湿性关节炎以及伤口愈合的自然过程中。本发明的化合物、组合、药物组合物还特别可用于治疗肺纤维化,特别是在特发性肺纤维化中。
FGFR在肿瘤相关血管***中过量表达和活化还表明本发明的组合或药物组合物在预防和干扰肿瘤血管生成的引发中的作用。本发明的组合或药物组合物特别可用于治疗癌症、转移、白血病例如CLL、眼病例如年龄相关性黄斑变性,特别是湿性年龄相关性黄斑变性、缺血性增殖性视网膜病变例如早产儿视网膜病(ROP)和糖尿病性视网膜病、类风湿性关节炎和血管瘤。
在一个实施方案中,提供用于疗法、用作药物的本文定义的组合或药物组合物。在另一个实施方案中,提供用于预防或治疗,特别是用于治疗由FGFR激酶介导的疾病状态或病况的本文定义的组合或药物组合物。
因此,例如,本发明的组合或药物组合物可用于减少或降低癌症发病率。因此,在另一个实施方案中,提供用于预防或治疗,特别是用于治疗癌症的本文定义的组合或药物组合物。在一个实施方案中,本文定义的组合或药物组合物用于预防或治疗FGFR依赖性癌症。在一个实施方案中,本文定义的组合或药物组合物用于预防或治疗由FGFR激酶介导的癌症。
因此,本发明尤其提供:
-用于预防或治疗由FGFR激酶介导的疾病状态或病况的方法,所述方法包括给予有需要的受试者本文定义的组合或药物组合物。
-用于预防或治疗本文所述疾病状态或病况的方法,所述方法包括给予有需要的受试者本文定义的组合或药物组合物。
-用于预防或治疗癌症的方法,所述方法包括给予有需要的受试者本文定义的组合或药物组合物。
-用于减少或降低由FGFR激酶介导的疾病状态或病况的发病率的方法,所述方法包括给予有需要的受试者本文定义的组合或药物组合物。
-抑制FGFR激酶的方法,所述方法包括使激酶与本文定义的抑制激酶的组合或药物组合物接触。
-通过使用本文定义的组合或药物组合物抑制FGFR激酶的活性来调节细胞过程(例如细胞***)的方法。
-通过抑制FGFR激酶的活性用作细胞过程(例如细胞***)的调节剂的本文定义的组合或药物组合物。
-用于预防或治疗癌症、特别是治疗癌症的本文定义的组合或药物组合物。
-用作FGFR调节剂(例如抑制剂)的本文定义的组合或药物组合物。
-本文定义的组合或药物组合物用于制备用于预防或治疗由FGFR激酶介导的疾病状态或病况的药物的用途。
-本文定义的组合或药物组合物用于制备用于预防或治疗本文所述疾病状态或病况的药物的用途。
-本文定义的组合或药物组合物用于制备用于预防或治疗、特别用于治疗癌症的药物的用途。
-本文定义的组合或药物组合物用于制备用于调节(例如抑制) FGFR的活性的药物的用途。
-本文定义的组合或药物组合物在制备通过抑制FGFR激酶的活性调节细胞过程(例如细胞***)的药物中的用途。
-本文定义的组合或药物组合物用于制备用于预防或治疗以FGFR激酶(例如FGFR1或FGFR2或FGFR3或FGFR4)上调为特征的疾病或病况的药物的用途。
-本文定义的组合或药物组合物用于制备用于预防或治疗癌症的药物的用途,所述癌症是以FGFR激酶(例如FGFR1或FGFR2或FGFR3或FGFR4)上调为特征的癌症。
-本文定义的组合或药物组合物用于制备用于预防或治疗患者的癌症的药物的用途,所述患者选自具有FGFR3激酶遗传畸变的亚群。
-本文定义的组合或药物组合物用于制备用于预防或治疗患者的癌症的药物的用途,所述患者被诊断为构成具有FGFR3激酶遗传畸变,特别是具有FGFR3-TACC3易位,更特别是具有FGFR3-TACC3易位的膀胱癌的亚群的一部分。
-用于预防或治疗以FGFR激酶(例如FGFR1或FGFR2或FGFR3或FGFR4)上调为特征的疾病或病况的方法,所述方法包括给予本文定义的组合或药物组合物。
-用于减少或降低以FGFR激酶(例如FGFR1或FGFR2或FGFR3或FGFR4)上调为特征的疾病或病况的发病率的方法,所述方法包括给予本文定义的组合或药物组合物。
-用于预防或治疗患有或疑似患有癌症的患者的癌症(或减少或降低其发病率)的方法;所述方法包括(i)对患者进行诊断试验以确定患者是否具有FGFR3基因遗传畸变,特别是具有FGFR3-TACC3易位,更特别是具有FGFR3-TACC3易位的膀胱癌;和(ii)当患者确实具有所述变体时,随之给予患者具有FGFR3激酶抑制活性的本文定义的组合或药物组合物。
-用于预防或治疗以FGFR激酶(例如FGFR1或FGFR2或FGFR3或FGFR4)上调为特征的疾病状态或病况(或减少或降低其发病率)的方法;所述方法包括(i)对患者进行诊断试验以检测FGFR激酶(例如FGFR1或FGFR2或FGFR3或FGFR4)上调特有的标志物和(ii)当诊断试验表明FGFR激酶上调时,随之给予患者具有FGFR激酶抑制活性的本文定义的组合或药物组合物。
在一个实施方案中,由FGFR激酶介导的疾病是肿瘤学相关疾病(例如癌症)。在一个实施方案中,由FGFR激酶介导的疾病是非肿瘤学相关疾病(例如癌症以外的本文中公开的任何疾病)。在一个实施方案中,由FGFR激酶介导的疾病是本文所述的病况。在一个实施方案中,由FGFR激酶介导的疾病是本文所述的骨骼病况。人骨骼发育中的特定异常包括颅缝的异常骨化(颅缝早闭)、Apert (AP)综合征、Crouzon综合征、Jackson-Weiss综合征、Beare-Stevenson皮肤旋纹综合征、斐弗综合征、软骨发育不全和致死性侏儒症(也称作致死性发育异常)。
突变激酶
在用激酶抑制剂治疗的患者群中可能出现耐药激酶突变。这些部分发生在与治疗中所用的特定抑制剂结合或相互作用的蛋白质区域。所述突变降低或提高抑制剂结合并抑制所述激酶的能力。这会发生在与抑制剂相互作用或对支持所述抑制剂与靶结合是重要的任何氨基酸残基处。与靶激酶结合而无需与突变氨基酸残基相互作用的抑制剂很可能不受该突变影响并且仍将是该酶的有效抑制剂。
胃癌患者样品的研究表明在FGFR2中存在两种突变——在外显子IIIa中的Serl67Pro和在外显子IIIc中的剪接位点突变940-2A-G。这些突变与引起颅缝早闭综合征的种系激活突变相同并在13%所研究的原发性胃癌组织中观察到。此外,在5%的受试患者样品中观察到FGFR3的激活突变,并且FGFR的过量表达与该患者组中的预后差有关。
此外,存在在FGFR中观察到的染色体易位或点突变,其造成功能获得性的、过量表达的或有组成型活性的生物状态。
本发明的化合物、组合或药物组合物因此特别适用于表达突变分子靶(例如FGFR)的癌症。可以采用本领域技术人员已知和本文所述的技术(例如RTPCR和FISH)对具有所述突变的肿瘤进行诊断。
已经表明,FGFR的ATP结合位点处的保守苏氨酸残基的突变会导致抑制剂耐受性。氨基酸缬氨酸561在FGFR1中已突变成甲硫氨酸,这相当于之前报道的存在于Abl (T315)和EGFR (T766)中的突变,已表明该突变赋予对选择性抑制剂的耐受性。FGFR1 V561M的测定数据表明,与野生型相比,这种突变赋予对酪氨酸激酶抑制剂的耐受性。
诊断方法
给予本文所述的组合或药物组合物之前,可对患者进行筛查,以确定患者所患或可能患上的疾病或病况是否是对用具有针对FGFR的活性的化合物治疗敏感的疾病或病况。
例如,可以分析取自患者的生物样品以确定该患者所患或可能患上的病况或疾病(例如癌症)是否是以遗传异常或蛋白质表达异常为特征的病况或疾病,其中所述异常导致FGFR的水平或活性上调或导致正常FGFR活性的通路敏化,或导致这些生长因子信号转导途径(例如生长因子配体水平或生长因子配体活性)上调或导致在FGFR活化下游的生化途径上调。
导致FGFR信号活化或敏化的这种异常的实例包括凋亡途径的丧失或抑制、受体或配体的上调、或受体或配体的突变型变体(例如PTK变体)的存在。具有FGFR1、FGFR2或FGFR3或FGFR4的突变体或FGFR1的上调特别是过量表达,或FGFR2或FGFR3的功能获得性突变体的肿瘤可能对FGFR抑制剂特别敏感。
例如,在许多病况中已鉴定出造成FGFR2的功能获得的点突变。特别是在10%的子宫内膜肿瘤中已鉴定出FGFR2的激活突变。
此外,已鉴定出导致异位表达或失调、有组成型活性的FGFR3受体的FGFR3受体酪氨酸激酶的遗传畸变(例如染色体易位或点突变),并且它们与多发性骨髓瘤、膀胱癌和***的子类相关联。在伊马替尼治疗的患者中已鉴定出PDGF受体的特定突变T674I。此外,在约50%的小叶乳腺癌(CLC)病例中证实8p12-p11.2的基因扩增,这表明与FGFR1的表达增加有关。使用针对FGFR1的siRNA或该受体的小分子抑制剂的初步研究表明,存在这种扩增的细胞系对这种信号转导途径的抑制特别敏感。
或者,针对FGFR的负调节剂或抑制剂的丧失,可以对取自患者的生物样品进行分析。在本文中,术语“丧失”包括编码调节剂或抑制剂的基因的缺失、基因的截短(例如通过突变)、基因转录产物的截短、或转录产物的失活(例如通过点突变)或通过其它基因产物的隔绝。
术语上调包括表达升高或过量表达,包括基因扩增(即多个基因拷贝)和通过转录作用使表达增加以及活性过高和活化,包括通过突变的活化。因此,可以对患者进行诊断试验以检测FGFR上调特有的标志物。术语诊断包括筛查。标志物包括遗传标志物,包括例如测定DNA组成以鉴定FGFR的突变。术语标志物还包括FGFR上调特有的标志物,包括酶活性、酶水平、酶状态(例如磷酸化与否)和前述蛋白质的mRNA水平。
诊断试验和筛查通常用生物样品进行,生物样品选自肿瘤活检样品、血样(脱落肿瘤细胞的分离和富集)、粪便活检样品、痰、染色体分析、胸膜液、腹膜液、口腔涂片、活检样品或尿液。
蛋白质的突变和上调的鉴定和分析方法为本领域技术人员所知。筛查方法可包括但不限于标准方法,例如反转录酶聚合酶链反应(RT-PCR)或原位杂交例如荧光原位杂交(FISH)。
鉴定出携带FGFR突变的个体可指患者特别适于用FGFR抑制剂治疗。在治疗之前,可优先筛查肿瘤中FGFR变体的存在情况。筛查方法通常可包括直接测序、寡核苷酸微阵列分析或突变型特异性抗体。另外,可采用本领域技术人员已知和本文所述技术(例如RT-PCR和FISH)对具有所述突变的肿瘤进行诊断。
此外,可通过采用PCR对例如肿瘤活检样品的直接测序和通过如上所述对PCR产物直接测序的方法,鉴定例如FGFR的突变形式。技术人员应了解,用于检测上述蛋白质的过量表达、活化或突变的所有这种公知技术都可适用于本发明。
在通过RT-PCR的筛查中,通过产生mRNA的cDNA拷贝,接着通过PCR扩增cDNA来评价肿瘤中的mRNA水平。PCR扩增方法、引物选择和扩增条件为本领域技术人员所知。通过例如Ausubel, F.M.等编辑(2004) Current Protocols in MolecularBiology, John Wiley &Sons Inc.;或Innis, M.A.等编辑(1990) PCR Protocols: a guide to methods andapplications, Academic Press, San Diego中描述的标准方法进行核酸操作和PCR。在Sambrook等(2001),第3版, Molecular Cloning: A Laboratory Manual, Cold SpringHarbor Laboratory Press中也描述了涉及核酸技术的反应和操作。或者,可以使用市售RT-PCR试剂盒(例如Roche Molecular Biochemicals)或如美国专利4,666,828、4,683,202、4,801,531、5,192,659、5,272,057、5,882,864和6,218,529中提供且通过引用结合到本文中的方法。用于评价mRNA表达的原位杂交技术的实例是荧光原位杂交(FISH) (参见Angerer (1987) Meth. Enzymol., 152: 649)。
通常,原位杂交包括下列主要步骤:(I)固定待分析的组织;(2)样品预杂交处理以提高靶核酸的可及性,并降低非特异性结合;(3)核酸的混合物与生物结构或组织中的核酸杂交;(4)杂交后洗涤以除去在杂交中没有结合的核酸片段,和(5)检测杂交的核酸片段。用于这种应用中的探针通常用例如放射性同位素或荧光报道分子标记。优选的探针足够长,例如约50、100或200个核苷酸至约1000个或更多个的核苷酸,以便能够在严格条件下与靶核酸特异性杂交。用于进行FISH的标准方法描述于Ausubel, F.M.等编辑(2004) CurrentProtocols in Molecular Biology, John Wiley & Sons Inc和John M. S. Bartlett的Fluorescence In Situ Hybridization: Technical Overview, 载于MolecularDiagnosis of Cancer, Methods and Protocols, 第2版; ISBN: 1-59259-760-2; 2004年3月,第077-088页;系列丛刊: Methods in Molecular Medicine。
(DePrimo等人(2003),BMC Cancer, 3:3)描述了基因表达谱分析的方法。简单来讲,方案如下:使用引发第一链cDNA合成的(dT)24寡聚体,由总RNA合成双链cDNA,接着用随机六聚体引物合成第二链cDNA。双链cDNA用作模板,使用生物素化核糖核苷酸体外转录cRNA。根据Affymetrix (Santa Clara, CA, USA)所述方案,使cRNA化学断裂,然后在人基因组阵列(Human Genome Arrays)上杂交过夜。
或者,可以通过肿瘤样品的免疫组织化学、用微量滴定板的固相免疫测定法、蛋白印迹法、二维SDS-聚丙烯酰胺凝胶电泳、ELISA、流式细胞术和本领域已知的用于检测特定蛋白的其它方法,测定由mRNA表达的蛋白质产物。检测方法可包括使用位点特异性抗体。技术人员应了解,用于检测FGFR上调或检测FGFR变体或突变体的所有这类公知技术都可适用于本发明。
可以采用标准酶测定法,例如本文所述的那些测定法,测量蛋白质例如FGFR的异常水平。也可以在组织样品中,例如在肿瘤组织中检测活化或过量表达。通过用例如来自Chemicon International的测定法测量酪氨酸激酶活性。从样品裂解液中使目标酪氨酸激酶免疫沉淀并测量其活性。
用于测量FGFR(包括其同种型)的过量表达或活化的备选方法包括测量微血管密度。这可以例如使用Orre和Rogers (Int J Cancer (1999), 84(2) 101-8)描述的方法测量。
因此,所有这些技术也可用于鉴定特别适于用本发明的组合或药物组合物治疗的肿瘤。
本发明的组合或药物组合物特别可用于治疗具有突变FGFR的患者。在62%的口腔鳞状细胞癌中观察到FGFR3中的G697C突变,该突变引起激酶活性的组成型活化。在膀胱癌病例中也已鉴定出FGFR3的激活突变。这些突变为具有不同程度的发病率(prevelence)的6种突变:R248C、S249C、G372C、S373C、Y375C、K652Q。此外发现FGFR4中的Gly388Arg多态性与提高的***癌、结肠癌、肺癌、肝癌(HCC)和乳腺癌发病率和侵袭性有关。
因此,在又一方面,本发明包括本发明的组合或药物组合物用于制备用于治疗或预防患者中的疾病状态或病况的药物的用途,所述患者已经筛查并确定为患有对用具有针对FGFR活性的化合物治疗敏感的疾病或病况或有患所述疾病或病况的风险。
所筛查的患者的特定突变包括FGFR3中的G697C、R248C、S249C、G372C、S373C、Y375C、K652Q突变和FGFR4中的Gly388Arg多态性。
另一方面,本发明包括用于预防或治疗选自具有FGFR基因变体(例如FGFR3中的G697C突变和FGFR4中的Gly388Arg多态性)的亚群的患者的癌症的本发明化合物、组合或药物组合物。
鉴于其有用的药理性质,FGFR抑制剂和cMet抑制剂可配制成用于给药目的的各种药物形式。
在一个实施方案中,药物组合物(例如制剂)包含至少一种FGFR抑制剂,或至少一种cMet抑制剂,或至少一种FGFR抑制剂和本发明的一种cMet抑制剂,以及一种或多种药学上可接受的载体、辅料、赋形剂、稀释剂、填充剂、缓冲剂、稳定剂、防腐剂、润滑剂或本领域技术人员熟知的其它材料和任选其它治疗或预防剂。
为了制备本发明的药物组合物,将有效量的本发明的化合物作为活性成分与药学上可接受的载体以充分混合组合,所述载体可根据给药所需制剂的形式呈各种形式。药物组合物可以是适于口服、肠胃外、局部、鼻内、眼、耳、直肠、***内或透皮给药的任何形式。这些药物组合物适宜为优选适于口服、直肠、经皮给药或通过肠胃外注射给药的单位剂型。例如,在口服剂型的组合物的制备中,可以使用任何常见的药用介质,例如在口服液体制剂例如混悬剂、糖浆剂、酏剂和溶液剂的情况下,使用水、二醇、油、醇等;或在散剂、丸剂、胶囊剂和片剂的情况下,使用固体载体例如淀粉、糖、高岭土、润滑剂、粘合剂、崩解剂等。
由于它们易给药,片剂和胶囊剂代表最有利的口服单位剂型,在这种情况下显然使用固体药用载体。对于肠胃外组合物,载体通常至少在很大程度上包含无菌水,尽管也可以包含例如有助于溶解的其它成分。例如可以制备可注射溶液剂,其中载体包含盐水溶液、葡萄糖溶液或盐水和葡萄糖溶液的混合物。也可以制备可注射混悬剂,在这种情况下可以使用适当的液体载体、悬浮剂等。在适于经皮给药的组合物中,载体任选包含渗透增强剂和/或合适的润湿剂,任选与较小比例的任何性质的合适添加剂组合,所述添加剂不会对皮肤造成显著的有害作用。所述添加剂可利于向皮肤给药和/或可有助于制备所需组合物。这些组合物可以以各种方式给药,例如作为透皮贴剂、作为点施制剂(spot-on)、作为软膏剂。为了易于给药和剂量均匀性,以单位剂型配制上述药物组合物尤其有利。本文中的说明书和权利要求书中所用的单位剂型是指适于作为单一剂量的物理分立单位,各单位含有预定量的经计算以产生所需疗效的活性成分以及所需药用载体。这类单位剂型的实例为片剂(包括划痕片或包衣片)、胶囊剂、丸剂、袋装散剂(powder packet)、糯米纸囊剂(wafer)、可注射溶液剂或混悬剂、茶匙量制剂(teaspoonfuls)、汤匙量制剂(tablespoonfuls)等及其分隔的多剂量制剂(segregated multiples)。
为了易于给药和剂量均匀性,以单位剂型配制上述药物组合物尤其有利。本文中的说明书和权利要求书中所用的单位剂型是指适于作为单一剂量的物理分立单位,各单位含有预定量的经计算以产生所需疗效的活性成分以及所需药用载体。这类单位剂型的实例为片剂(包括划痕片或包衣片)、胶囊剂、丸剂、袋装散剂、糯米纸囊剂、可注射溶液剂或混悬剂、茶匙量制剂、汤匙量制剂等及其分隔的多剂量制剂。
本发明的组合或药物组合物以足以发挥其抗肿瘤活性的量给予。
本领域技术人员可容易确定本文所述FGFR抑制剂和cMet抑制剂的有效量。一般预期治疗有效量为0.005 mg/kg-100 mg/kg体重,特别是0.005 mg/kg-10 mg/kg体重。在一天中以适当间隔以1、2、3、4或更多个分剂量给予所需剂量可为合适的。所述分剂量可以配制成单位剂型,例如每单位剂型含有0.5-500 mg,特别是1 mg-500 mg,更特别10 mg-500 mg的活性成分。
根据给药方式,药物组合物优选包含0.05-99%重量、更优选0.1-70%重量、甚至更优选0.1-50%重量的本文所述的FGFR抑制剂、cMet抑制剂、或FGFR抑制剂和cMet抑制剂的组合,以及1-99.95%重量,更优选30-99.9%重量,甚至更优选50-99.9%重量的药学上可接受的载体,所有百分比以组合物的总重量计。
为了治疗上述病况,本发明的组合或药物组合物可以有利地在癌症疗法中与一种或多种其它药剂、更特别与其它抗癌药或辅助剂联用,如上文所指出的。
因此,本发明还涉及包含一种或多种其它药剂和本发明的组合以及药用载体的药物组合物。
本发明还涉及本发明的组合在制备用于抑制肿瘤细胞生长的药物组合物中的用途。
本发明还涉及含有本发明的FGFR抑制剂作为第一活性成分和作为第二活性成分的cMet抑制剂,特别是如本文所定义的cMet抑制剂,更特别是化合物C或其药学上可接受的盐或其溶剂合物,或化合物D或其药学上可接受的盐或其溶剂合物,以及作为其它活性成分的一种或多种抗癌药的产品,其作为组合制剂用于在患有癌症的患者的治疗中同时、分开或序贯使用。
一种或多种其它药剂和本发明的组合可以同时(例如在分开的组合物或单一组合物中)或以任一顺序序贯给予。在后一情况下,在一段时间内以足以确保实现有利或协同效应的时段和量及方式给予三种或更多种化合物。要认识到,优选的给药方法和顺序及组合的各组分的各自剂量和方案取决于要给予的特定的其它药剂和本发明的组合的化合物、其给药途径、受治疗的特定肿瘤和受治疗的特定宿主。本领域技术人员采用常规方法和根据本文提供的信息,可容易地确定最佳给药方法和顺序及剂量和方案。
本领域技术人员可以确定当作为组合给予时本发明的组合的化合物与一种或多种其它抗癌药的重量比。如本领域技术人员所熟知的一样,所述比率和确切剂量和给药频率取决于所用的本发明的组合的特定化合物和其它抗癌药、待治疗的特定病况、待治疗的病况的严重程度、特定患者的年龄、体重、性别、饮食、给药时间和一般身体状况、给药方式以及个体可能正使用的其它药物。此外,显而易见的是,可以根据治疗对象的反应和/或根据开据本发明的组合处方的医师的评估来降低或提高有效每日量。FGFR抑制剂、cMet抑制剂与另一抗癌药的各对的具体重量比范围可以为1/10-10/1,更特别1/5-5/1,甚至更特别1/3-3/1。
铂配位化合物有利地以每疗程1-500 mg/平方米(mg/m2)体表面积,例如50-400mg/m2的剂量给予,特别对顺铂而言为约75 mg/m2的剂量,对卡铂而言为约300mg/m2。
紫杉烷类化合物有利地以每疗程50-400 mg/平方米(mg/m2)体表面积,例如75-250 mg/m2的剂量给予,特别对紫杉醇而言为约175-250 mg/m2剂量,对多西他赛而言为约75-150 mg/m2。
喜树碱化合物有利地以每疗程0.1-400 mg/平方米(mg/m2)体表面积,例如1-300mg/m2的剂量给予,特别对伊立替康而言为约100-350 mg/m2剂量,对托泊替康而言为约1-2mg/m2。
抗肿瘤的鬼臼毒素衍生物有利地以每疗程30-300 mg/平方米(mg/m2)体表面积,例如50-250mg/m2的剂量给予,特别对依托泊苷而言为约35-100 mg/m2剂量,对替尼泊苷而言为约50-250 mg/m2。
抗肿瘤长春花生物碱有利地以每疗程2-30 mg/平方米(mg/m2)体表面积的剂量给予,特别对长春花碱而言为约3-12 mg/m2的剂量,对长春新碱而言为约1-2 mg/m2的剂量,对长春瑞滨而言为约10-30 mg/m2的剂量。
抗肿瘤的核苷衍生物有利地以每疗程200-2500 mg/平方米(mg/m2)体表面积,例如700-1500 mg/m2的剂量给予,特别对5-FU而言为200-500mg/m2的剂量,对吉西他滨而言为约800-1200 mg/m2的剂量,对卡培他滨而言为约1000-2500 mg/m2。
烷基化剂(例如氮芥或亚硝基脲)有利地以每疗程100-500 mg/平方米(mg/m2)体表面积,例如120-200 mg/m2的剂量给予,特别对环磷酰胺而言为约100-500 mg/m2的剂量,对苯丁酸氮芥而言为约0.1-0.2 mg/kg的剂量,对卡莫司汀而言为约150-200mg/m2的剂量,对洛莫司汀而言为约100-150 mg/m2的剂量。
抗肿瘤蒽环类衍生物有利地以每疗程10-75 mg/平方米(mg/m2)体表面积,例如15-60 mg/m2的剂量给予,特别对多柔比星而言为约40-75 mg/m2的剂量,对柔红霉素而言为约25-45mg/m2的剂量,对伊达比星而言为约10-15 mg/m2的剂量。
抗***药有利地根据特定药剂和待治疗的病况以每日约1-100 mg的剂量给予。他莫昔芬有利地以5-50 mg,优选10-20 mg的剂量每天两次口服给予,继续该治疗足够的时间以实现和保持疗效。托瑞米芬有利地以约60mg的剂量每天一次口服给予,继续该治疗足够的时间以实现和保持疗效。阿那曲唑有利地以约1mg的剂量每天一次口服给予。屈洛昔芬有利地以约20-100mg的剂量每天一次口服给予。雷洛昔芬有利地以约60mg的剂量每天一次口服给予。依西美坦有利地以约25mg的剂量每天一次口服给予。
抗体有利地以约1-5 mg/平方米(mg/m2)体表面积的剂量给予,或如有不同,则按本领域已知给予。曲妥珠单抗有利地以每疗程1-5 mg/平方米(mg/m2)体表面积,特别是2-4mg/m2的剂量给予。
这些剂量可以每疗程例如一次、两次或更多次给予,其可以例如每7、14、21或28天重复。
本发明组合或药物组合物的化合物可具有有价值的诊断性质,因为它们可用于检测或鉴定在标记化合物与其它分子、肽、蛋白质、酶或受体之间的复合物的形成。
该检测或鉴定方法可以使用用标记试剂如放射性同位素、酶、荧光物质、发光物质等标记的化合物。放射性同位素的实例包括125I、131I、3H和14C。通常通过与合适的底物缀合进而催化可检出反应使得酶可被检出。其实例包括例如β-半乳糖苷酶、β-葡糖苷酶、碱性磷酸酶、过氧化物酶和苹果酸脱氢酶,优选辣根过氧化物酶。发光物质包括例如鲁米诺、鲁米诺衍生物、萤光素、水母发光蛋白和萤光素酶。
生物样品可定义为体组织或体液。体液的实例是脑脊液、血液、血浆、血清、尿液、痰、唾液等。
实验部分
在评价作为FGFR抑制剂的上述化合物A和B时,当在基于细胞的增殖测定(alamarblue测定,参见下文)中测试化合物时,发现甚至最敏感的癌细胞系(IC50 <10nM ),具有对化合物不敏感的细胞亚群。这例如通过在约10%的DMSO对照的增殖曲线中的平稳期所观察到(在用于DMSO的测定中观察到的值被视为100%,并且用化合物的剂量处理观察到的值以100%DMSO的%计算)。例如,当在增殖测定中用N-(3,5-二甲氧基苯基)-N'-(1-甲基乙基)-N-[3-(1-甲基-1H-吡唑-4-基)喹喔啉-6-基]乙烷-1,2-二胺处理NCI-H1581细胞(具有FGFR1扩增的大细胞肺癌细胞系)时,该曲线在约10%的DMSO对照下显示平稳,表明存在约10%的细胞对该化合物处理不敏感。
分离不敏感细胞并进行概况分析,目的是确定作为其存活和/或增殖的驱动因子的活性信号传导途径。因此,将NCI-H1581细胞接种在10cm胶原I包被的平板上,并置于37℃,5%CO2的培养箱中。在延长的时间内,对于具有或不具有DMSO对照的亲本细胞,将细胞在生长培养基(参见下文)中培养,或对于抗性细胞在补充有高剂量的化合物A (培养基中化合物A的终浓度为1μM,将化合物A作为在DMSO中从储备溶液稀释的样品加入)的生长培养基中培养。在化合物不敏感细胞的生长时间期间,每周两次更换补充有化合物A [1μM]的培养基。在具有或不具有DMSO对照的亲本细胞的情况下,当细胞达到接近100%的汇合时,它们用胰蛋白酶消化并重新铺板在平板上。在化合物处理的平板中观察到抗性克隆的生长。在初始处理约3周后,通过胰蛋白酶消化从平板中取出细胞,并在新平板上传代以进一步扩增。抗性细胞,与亲本细胞相同,每周传代两次,但是抗性细胞的培养基总是补充有化合物A[1μM]。(试验1)
生长培养基
RPMI-1640(Gibco,31870-025)500ml; 10%FCS(Hyclone,SV30160.03)57ml; 1mM丙酮酸钠(Gibco,11360)5.7ml; 2mM L-谷氨酰胺(Gibco,25030)5.7ml; 50μg/ ml庆大霉素(Gibco,15750)5.7ml。
使用微阵列技术,对抗性细胞中与亲代细胞相比差异表达的基因进行概况分析。进行了两个微阵列实验。在第一个实验中,对亲本细胞和抗性细胞进行概况分析以定义两个群体之间不同的基因和途径,并理解驱动对化合物A的抗性的途径。在第二个微阵列实验中,对化合物A处理后基因表达随时间的变化进行概况分析。为此目的,NCI-H1581细胞用DSMO或1μM化合物A处理或在1天,1周和2周的时间过程中未处理。
在两种微阵列分析中,Met癌基因被鉴定为在抗性细胞中以时间依赖性方式上调。
该实验也用化合物B进行,并且同样对于化合物B,Met癌基因被鉴定为在抗性细胞中以时间依赖性方式上调。
Met基因被上调的观察结果促进了以下实验:检查Met受体在蛋白质水平上是否被上调并且被激活,以及Met驱动的信号传导途径是否起到抗性的驱动作用。因此,亲本和抗性细胞在磷酸RTK(受体酪氨酸激酶)阵列上进行概况分析,并还对Met总蛋白表达和磷酸化进行概况分析。还在Alamar blue增殖测定中测试了细胞对选择的Met抑制剂(化合物C和D)的敏感性。发现Met蛋白表达上调,Met蛋白仅在抗性细胞中磷酸化,而不在亲本细胞中磷酸化,表明Met信号传导途径在抗性细胞中被激活。除了该观察结果,用有效的和选择性的Met抑制剂化合物C处理抗性细胞显著下调Met磷酸化。亲本NCI-H1581细胞具有非常低的可检测水平的Met蛋白,并且没有Met蛋白磷酸化的信号(参见图1)。此外,在用Met抑制剂化合物C和D处理的亲本和抗性细胞的alamar blue增殖测定中,Met抑制剂强烈抑制抗性NCI-H1581细胞的增殖,但不抑制亲本NCI-H1581细胞的增殖(参见下表,示出了重复实验的结果)。
根据这些数据可以得出结论,对测试的FGFR抑制剂具有抗性的NCI-H1581细胞具有激活的Met受体,并且依赖于Met信号传导途径进行其增殖和存活。
Met信号传导活化作为对NCI-H1581中测试的FGFR抑制剂的抗性的驱动因子的发现支持FGFR和Met抑制剂的组合治疗,以克服在NCI-H1581细胞中对FGFR抑制剂的抗性的出现。进行实验,其中从开始组合两种试剂(FGFR抑制剂:1μM化合物A和Met抑制剂:1μM化合物D)。还用单一试剂(1μM化合物A或1μM化合物D)或DMSO处理细胞。使用Incucyt机器追踪细胞的增殖,测量细胞随时间的汇合。在以与上述试验1类似的方式进行的该实验中,观察到Met抑制剂化合物D处理以及DMSO处理不影响NCI-H1581细胞的增殖。用FGFR抑制剂(1μM化合物A)处理细胞最初阻断增殖,但是在约三周后,观察到化合物不敏感细胞出现增长,其与上文指出的发现相符,即在用化合物A连续抑制FGFR途径约三周后,NCI-H1581细胞中的不敏感抗性亚群的细胞获得生长的能力。重要的是,FGFR抑制剂(化合物A 1 μM)和Met抑制剂(化合物D 1 μM)的联合治疗完全防止了抗性的出现。参见图2。
体内研究
无胸腺裸鼠用抗性NCI-H1581细胞接种(10e6细胞/200μl,含基质胶,比例为1:1,到小鼠的腹股沟区域中)。
将所有小鼠(84)分成组(4)并从细胞注射的当天处理。
每天一次口服(po),正常体积(250μl/ 25g)处理小鼠,持续37天(QDx37)。在第0、5、12、15、20、23、27、30、33、37天进行肿瘤体积的测量。
在第37天,处死所有动物。
下表说明了研究设计:
该体内研究的结果显示在图3中。
所有测试剂在整个研究中耐受良好。然而,在组合组中观察到增加的体重减轻。
在该研究中,观察到用化合物A的处理对肿瘤生长没有影响,因为先前已经使这些细胞对该处理有抗性。有趣的是,两种组合治疗显示影响肿瘤的生长。此外,当两种药剂同时给药时观察到最强的抗增殖作用。该模型对于两种靶向药剂的组合敏感且对单独的化合物A处理不敏感的事实表明两种途径在这些肿瘤的生长中起重要作用。
ALAMAR BLUE测定
将细胞以优化的细胞密度接种在具有透明平底的黑色96孔板中的180μl培养基中。向外部孔中装入180μl培养基。将细胞在37℃和5%CO2下孵育24小时。
第二天,在具有圆底的96孔板(Corning#3365)中制备化合物稀释液。在96孔板(Corning#3585)中在培养基中制备化合物的50x稀释液(4μl化合物原液在196μl培养基中)。将化合物/培养基平板置于振荡器上10分钟,然后将20μl化合物/培养基加入细胞中(10倍稀释)。将细胞在37℃和5%CO2下孵育4天,直到alamarBlue®读数。
AlamarBlue®制剂:
材料:
刃天青片剂(100片)(PROLABO)
亚铁***(Sigma)
铁***(Sigma)
KH2PO4 (Sigma)
K2HPO4 (Sigma)
磷酸钾缓冲液(PPB)1升
20 mM KH2PO42.72 g
80 mM K2HPO413.86 g
pH 7,4 (用几滴KOH 5M)
用MilliQ填充至500ml
将溶液调至pH 7.4,并调至1升的最终体积。
PPB-A试剂
1刃天青片剂/ ml PPB(1片剂+800μl PPB)
PPB-B试剂,30mM铁***在PPB中
0.987g铁***+ 100ml PPB
在0.22μm过滤器上过滤灭菌,在4℃保存
PPB-C试剂,30mM亚铁***在PPB中
1.266g亚铁***+ 100ml PPB
在0.22μm过滤器上过滤灭菌,在4℃保存
即用型Alamar blue混合物
1ml备选的PPB-A + 1ml PPB-B + 1ml PPB-C
加入57ml PPB
在0.22μm过滤器上过滤灭菌,在4℃保存
与化合物孵育4天后:向每个孔中加入40μl alamarBlue®即用型混合物。在37℃和5%CO2下孵育平板。孵育4或6小时后测量板(取决于细胞系)。摇动板并在ex.:544nm和em.:590nm测量RFU。
alamarBlue®测定结合了基于代谢活性检测的荧光/比色生长指示剂。具体地,***包括氧化还原(REDOX)指示剂,其响应于由细胞生长产生的生长培养基的化学还原而发荧光并改变颜色。
通过FGFR和MET抑制剂的组合抑制H1581MET(+)细胞的生长。
将亲本的,未分选的H1581细胞和分选的H1581Met(+)细胞(具有高Met表达的H1581细胞亚群)以75000个细胞/孔接种在24孔板中。一天后,用化合物A(0.1mM)或化合物A(0.1mM)和化合物D(1mM)的组合或作为溶媒的DMSO处理细胞,通过使用Incucyte活细胞成像,测量细胞在四天时间内的汇合,评估细胞增殖。每两小时获取图像。细胞增殖表示为汇合百分比的平均值±SD(n = 2)。
H1581细胞生长通过用化合物A或化合物A和化合物D的组合处理而受到同等抑制,表明H1581细胞生长的抑制由FGFR抑制剂驱动。H1581MET(+)显示对化合物A的较小的敏感性,并且它们的增殖被化合物A和化合物D的组合强烈抑制,表明在该细胞群中,MET激酶在生长和增殖中起重要作用。这些发现表明H1581MET(+)亚群介导H1581细胞中对FGFR抑制剂的内在抗性。
Claims (24)
1.选自N-(3,5-二甲氧基苯基)-N'-(1-甲基乙基)-N-[3-(1-甲基-1H-吡唑-4-基)喹喔啉-6-基]乙烷-1,2-二胺或其药学上可接受的盐,和N-(2-氟-3,5-二甲氧基苯基)-N-(1H-咪唑-2-基甲基)-3-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-b]吡嗪-6-胺或其药学上可接受的盐的第一化合物和作为cMet抑制剂的第二化合物的组合,其中cMet抑制剂选自6-{二氟[6-(1-甲基-1H-吡唑-4-基)[1,2,4]***并[4,3-b]哒嗪-3-基]甲基}喹啉或其药学上可接受的盐和6-[二氟(6-吡啶-4-基[1,2,4]***并[4,3-b]哒嗪-3-基)甲基]喹啉或其药学上可接受的盐。
2.权利要求1的组合,其中第一化合物是N-(3,5-二甲氧基苯基)-N'-(1-甲基乙基)-N-[3-(1-甲基-1H-吡唑-4-基)喹喔啉-6-基]乙烷-1,2-二胺或其药学上可接受的盐。
3.权利要求2的组合,其中第一化合物是N-(3,5-二甲氧基苯基)-N'-(1-甲基乙基)-N-[3-(1-甲基-1H-吡唑-4-基)喹喔啉-6-基]乙烷-1,2-二胺碱。
4.权利要求1的组合,其中第一化合物是N-(2-氟-3,5-二甲氧基苯基)-N-(1H-咪唑-2-基甲基)-3-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-b]吡嗪-6-胺或其药学上可接受的盐。
5.权利要求4的组合,其中第一化合物是N-(2-氟-3,5-二甲氧基苯基)-N-(1H-咪唑-2-基甲基)-3-(1-甲基-1H-吡唑-4-基)吡啶并[2,3-b]吡嗪-6-胺碱。
6.权利要求1的组合,其中cMet抑制剂是6-{二氟[6-(1-甲基-1H-吡唑-4-基)[1,2,4]***并[4,3-b]哒嗪-3-基]甲基}喹啉或其药学上可接受的盐。
7.权利要求6的组合,其中cMet抑制剂是6-{二氟[6-(1-甲基-1H-吡唑-4-基)[1,2,4]***并[4,3-b]哒嗪-3-基]甲基}喹啉碱。
8.权利要求1的组合,其中cMet抑制剂是6-[二氟(6-吡啶-4-基[1,2,4]***并[4,3-b]哒嗪-3-基)甲基]喹啉或其药学上可接受的盐。
9.权利要求8的组合,其中cMet抑制剂是6-[二氟(6-吡啶-4-基[1,2,4]***并[4,3-b]哒嗪-3-基)甲基]喹啉碱。
10.一种药物组合物,其包含药学上可接受的载体和前述权利要求中任一项的组合。
11.权利要求1至9中任一项的组合或权利要求10的药物组合物,其用作药物。
12.权利要求1至9中任一项的组合或权利要求10的药物组合物在制备用于预防或治疗癌症的药物中的用途。
13.权利要求12的组合或药物组合物在制备用于治疗癌症的药物中的用途。
14.权利要求1至9中任一项的组合或权利要求10的药物组合物,用于预防或治疗癌症。
15.权利要求14的组合或药物组合物,用于治疗癌症。
16.权利要求12的用途或根据权利要求14的组合或药物组合物,用于治疗肺癌、膀胱癌、乳腺癌、胃癌或肝细胞癌。
17.根据权利要求15的组合或药物组合物,其中所述癌症是膀胱癌。
18.根据权利要求15的组合或药物组合物,其中
(i) 所述癌症是具有FGFR3染色体易位的膀胱癌;或
(ii) 所述癌症是具有FGFR3点突变的膀胱癌。
19.根据权利要求15的组合或药物组合物,其中
(i) 所述癌症是具有FGFR1、FGFR2、FGFR3或FGFR4的突变体的肿瘤;或
(ii) 所述癌症是具有FGFR2或FGFR3的功能获得性突变体的肿瘤;或
(iii) 所述癌症是具有FGFR1的过量表达的肿瘤。
20.根据权利要求14的组合或药物组合物,其中所述癌症是膀胱癌、尿路上皮癌、乳腺癌、成胶质细胞瘤、肺癌、卵巢癌、子宫内膜癌、***、软组织肉瘤、头颈鳞状细胞癌、胃癌、食管癌、胆管癌、肝细胞癌。
21.根据权利要求20的组合或药物组合物,其中所述癌症是转移性尿路上皮癌、手术不能切除的尿路上皮癌、非小细胞肺癌、鳞状细胞肺癌、小细胞肺癌。
22.根据权利要求20的组合或药物组合物,其中所述癌症是尿路上皮癌。
23.根据权利要求22的组合或药物组合物,其中所述癌症是转移性尿路上皮癌、手术不能切除的尿路上皮癌。
24.一种药物产品,其包含权利要求1至9中任一项的组合作为癌症治疗中同时、分别或顺序使用的组合制剂。
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