CN103402519A - 肿瘤治疗剂 - Google Patents

肿瘤治疗剂 Download PDF

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CN103402519A
CN103402519A CN201280010898XA CN201280010898A CN103402519A CN 103402519 A CN103402519 A CN 103402519A CN 201280010898X A CN201280010898X A CN 201280010898XA CN 201280010898 A CN201280010898 A CN 201280010898A CN 103402519 A CN103402519 A CN 103402519A
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CN103402519B (zh
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成田悠介
松井顺二
船桥泰博
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Eisai R&D Management Co Ltd
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Abstract

本发明涉及肿瘤治疗剂，其包括联合使用的式(I)表示的化合物或其药学上可接受的盐和式(II)表示的化合物，该肿瘤治疗剂与各化合物单独使用的情况相比表现出优异的抗肿瘤效果。式中，R1是C1-6烷基或C3-8环烷基，R2是氢原子或C1-6烷氧基，R3是氢原子或卤素原子。
Figure DPA0000176913290000011

Description

肿瘤治疗剂
技术领域
本发明涉及包括联合使用的具有激酶抑制效果的化合物和具有BRAF抑制效果的化合物的肿瘤治疗剂。具体地，本发明涉及包括联合使用的具有多-酪氨酸激酶抑制作用(multi-tyrosine kinase inhibition)的化合物和N-(3-{[5-(4-氯苯基)-1H-吡咯并[2，3-b]吡啶-3-基]羰基}-2,4-二氟苯基)丙烷-1-磺酰胺(PLX4032)的肿瘤治疗剂。
背景技术
Figure BPA0000176913320000011
[式中，R1是C1-6烷基或C3-8环烷基，R2是氢原子或C1-6烷氧基，R3是氢原子或卤素原子。]
式(I)表示的化合物具有抗血管形成的作用(专利文献1)，对报告与肿瘤恶化有关的酪氨酸激酶(非专利文献1至5)具有抑制效果(专利文献2至5)，等等；并且该化合物已知是用于不同肿瘤的治疗剂，这些肿瘤是例如甲状腺癌症、肺癌、黑色素瘤、子宫内膜癌、胃癌、膀胱癌、肾癌、神经胶质瘤、肝癌、以及卵巢癌等。
另一方面，N-(3-{[5-(4-氯苯基)-1H-吡咯并[2，3-b]吡啶-3-基]羰基}-2,4二氟苯基)丙烷-1-磺酰胺是式(II)表示的化合物，已知它为一种强力的BRAF激酶活性抑制剂(专利文献6)。这个化合物被称为PLX4032，目前开发作为肿瘤(例如黑色素瘤)治疗剂。
总体而言，肿瘤治疗剂在单独使用时经常不能对所有的患者都有效。因此，到目前为止正尝试着通过联合使用多种抗肿瘤剂来提高治愈率(专利文献7至9)。
专利文献
专利文件1：美国专利申请公开号2004-053908
专利文件2：美国专利申请公开号2004-253205
专利文件3：美国专利申请公开号2010-105031
专利文件4：美国专利申请公开号2009-209580
专利文件5：美国专利申请公开号2009-264464
专利文献6：WO 2007/002325
专利文献7：WO 2009/140549
专利文件8：美国专利申请公开号2004-259834
专利文献9：美国专利号6217866
非专利文献
非专利文件1：莱萨特(Lasota)等人，″Mutations in Exons9and13of KITGene Are Rare Events in Gastrointestinal Stromal Tumors″(“在胃肠道间质瘤中KIT基因的外显子9和13上的突变是稀少事件”)，American Journal of Pathology(《美国病理学杂志》)，vol.157，p.1091-1095，2000。
非专利文献2：波代尔(Berdel)等人，″Recombinant Human Stem CellFactor Stimulates Growth of a Human Glioblastoma Cell Line Expressing c-kitProtooncogenl″(“重组人干细胞因子刺激表达c-kit原癌基因1的人恶性胶质瘤细胞系生长”)，Cancer Research(《癌症研究》)，vol.52，p.3498-3502，1992。
非专利文献3：伦纳特森(Lennartsson)等人，″The stem cellfactorreceptor/c-Kit as a drug target in cancer″(“在癌症中作为药物标靶的干细胞因子受体/c-Kit”)，Current Cancer Drug Targets(《癌症药靶研究最新进展》)，vol.6，p.65-75，2006。
非专利文献4：特纳(Turner)等人，″Fibroblast growthfactor signaling：from development to cancer″(“成纤维细胞生长因子信号：从发展到癌症”)，Nature Reviews Cancer(《自然评论癌症》)，vol.10，p.116-129，2010。
非专利文献5：威尔斯(Wells)等人，″Targeting the RET Pathway inThyroid Cancer″(“在甲状腺癌症中靶向RET路径”)，Clinical Cancer Research(《临床癌症研究》)，vol.15，p.7119-7123，2009。
发明内容
技术问题
然而，目前已经报告的通过联合使用多种肿瘤治疗剂获得的治疗效果是不够的，并且期望研发一种新的肿瘤治疗剂的联合用药疗法。
问题的解决方案
鉴于此类情况，本发明人等经深入研究发现了通过联合使用式(I)和具有BRAF激酶活性抑制作用的化合物、给予肿瘤患者，出人意料地获得了所期待以上的优异的抗肿瘤效果，从而完成了本发明。
即，本发明提供了以下[1]至[8]。
[1]肿瘤治疗剂，其包括联合使用的式(I)表示的化合物或其药学上可接受的盐、以及式(II)表示的化合物。
Figure BPA0000176913320000041
[其中，R1是C1-6烷基或C3-8环烷基，
R2是氢原子或C1-6烷氧基，
R3是氢原子或卤素原子。]
Figure BPA0000176913320000042
[2]肿瘤治疗剂，同时或分别给予上述式(I)表示的化合物或其药学上可接受的盐、以及上述式(II)表示的化合物。
[3]肿瘤治疗剂，包括上述式(I)表示的化合物或其药学上可接受的盐，以及上述式(II)表示的化合物。
[4]一种上述式(II)表示的化合物，用于通过与上述式(I)表示的化合物或其药学上可接受的盐联合使用来治疗肿瘤。
[5]一种上述式(I)表示的化合物或其药学上可接受的盐，用于通过与上述式(II)表示的化合物联合使用来治疗肿瘤。
[6]一种治疗肿瘤的方法，联合使用上述式(I)表示的化合物或其药学上可接受的盐及上述式(II)表示的化合物。
[7]一种药物组合物，包括上述式(I)表示的化合物或其药学上可接受的盐、上述式(II)表示的化合物以及赋形剂。
[8]一种试剂盒，包括：
含有上述式(I)表示的化合物或其药学上可接受的盐以及赋形剂的药物组合物、以及
含有上述式(II)表示的化合物以及赋形剂的药物组合物。
上述式(I)表示的化合物优选是选自下组中的一种以上的化合物，该组由以下各项组成：
4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺；
Figure BPA0000176913320000051
4-[3-氯-4-(甲基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺；
Figure BPA0000176913320000052
4-[3-氯-4-(乙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺；
N6-甲氧基-4-(3-氯-4-{[(环丙基氨基)羰基)氨基]苯氧基}-7-甲氧基-6-喹啉甲酰胺；
以及N6-甲氧基-4-(3-氯-4-{[(乙基氨基)羰基]氨基}苯氧基)-7-甲氧基-6-喹啉甲酰胺。
Figure BPA0000176913320000062
更优选4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺
Figure BPA0000176913320000063
(在下文，有时表示为化合物A)。
发明的有利效果
本发明提供了包括联合使用的具有多-酪氨酸激酶抑制作用的化合物和具有BRAF激酶活性抑制效果的化合物的肿瘤治疗剂。此种肿瘤治疗剂与这些化合物单独使用的情况相比表现出优异的抗肿瘤效果，并且表现出针对多种癌症类型的抗肿瘤效果。
附图简要说明
图1是表示在移植了人黑色素瘤细胞系(A375)的动物模型中化合物A和PLX4032联合给药的效果的图。
图2是表示在开始给予后第23天时的各组的相对肿瘤体积的图。
具体实施方式
本发明的式(I)表示的化合物或其药学上可接受的盐可以通过专利文献1中描述的方法来生产。此外，本发明的式(II)表示的化合物(在下文，简单地被称为PLX4032)可以通过专利文献6中描述的方法来生产。
并且，已知具有BRAF抑制效果的化合物可以代替PLX4032用于本发明的肿瘤治疗剂。作为上述化合物可以举出：
4-{4-[({[4-氯-3-(三氟甲基)苯基]氨基}羰基)氨基]苯氧基}-N-甲基吡啶-2-甲酰胺4-甲基苯磺酸盐(索拉非尼)
1-甲基-5-({2-[4-(三氟甲基)-1H-咪唑-2-基]吡啶-4-基}氧基)-N-[4-(三氟甲基)苯基]-1H-苯并咪唑-2-胺(RAF-265)
5-(2-{4-[2-(二甲氨基)乙氧基]苯基}-4-吡啶-4-基-1H-咪唑-5-基)茚满-1-酮肟(SB-590885)
Figure BPA0000176913320000081
1-N-(4-氯苯基)-6-甲基-5-N-[3-(9H-嘌呤-6-基)吡啶-2-基]异喹啉-1，5-二胺(在下文，缩写为氨基异喹啉)
Figure BPA0000176913320000082
以及[3-(3-羟基-5-甲基苯基)-4-(2-{[(2S)-2-羟基丙基]氨基}嘧啶-4-基)-1H-吡唑-1-基]乙腈(PF-0419789)，等。
Figure BPA0000176913320000083
索拉非尼、RAF-265、SB-590885、氨基异喹啉、以及PF-0419789可以分别通过WO 2000/041698、美国专利申请公开号2007-0049622、WO2002/024680、WO 2008/153947、以及WO 2007/105058中描述的方法来生产。
所谓药学上可接受的盐，例如可以举出与无机酸的盐、与有机酸的盐、与无机碱的盐、与有机碱的盐以及与酸性或碱性氨基酸的盐等。
作为与无机酸的盐的优选实例，例如可以举出与盐酸、氢溴酸、硫酸、硝酸、磷酸等形成的盐。作为与有机酸的盐的优选实例，例如可以举出与乙酸、琥珀酸、富马酸、马来酸、酒石酸、柠檬酸、乳酸、硬脂酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸等形成的盐。
作为与无机碱的盐的优选实例，例如可以举出钠盐、钾盐等碱金属盐，钙盐、镁盐等碱土金属盐，铝盐，铵盐等。作为与有机碱的盐的优选实例，例如可以举出与二乙胺、二乙醇胺、葡甲胺(Meglumine)、N,N-二苄基乙二胺等形成的盐。
作为与酸性氨基酸的盐的优选实例，例如可以举出与天冬氨酸、谷氨酸等形成的盐。作为与碱性氨基酸的盐的优选实例，例如可以举出与精氨酸、赖氨酸、鸟氨酸等形成的盐。
尤其优选的药学上可接受的盐是与有机酸的盐。
本发明的肿瘤治疗剂能够以片剂、颗粒剂、精细颗粒剂、粉剂、胶囊剂等固形制剂的形式、或以液体制剂、凝胶剂、糖浆剂等的形式口服给予。
此外，本发明的肿瘤治疗剂也能以注射剂、栓剂、软膏剂、糊剂等的形式非口服给予。
式(I)表示的化合物或其药学上可接受的盐的剂量可以根据症状的程度、患者的年龄、性别、体重、敏感性差异、给药方法、给药时间、给药间隔、药物制剂的类型等进行适当地选择。通常，在对成人口服给药的情况下(60kg体重)，每天1mg～600mg，优选5mg～400mg，更优选5mg～200mg。可以每天分成1～3次给予。
PLX4032的剂量与上述情况相同可以进行适当地选择。通常，在对成人口服给药的情况下(60kg体重)，每天1mg～2000mg，优选100mg～1500mg，更优选240mg～1200mg。可以每天分成1～3次给予。
在制备口服用固形制剂的情况下，可以将赋形剂以及根据需要将粘合剂、崩解剂、润滑剂、着色剂、矫味矫臭剂等添加到主药(即，式(I)表示的化合物或其药学上可接受的盐以及PLX4032)中，随后根据常规方法制备成片剂、颗粒剂、精细颗粒剂、散剂、胶囊剂等。
作为赋形剂，例如可以举出乳糖、玉米淀粉、绵白糖、葡萄糖、山梨糖醇、结晶纤维素、二氧化硅等。作为粘合剂，例如可以举出聚乙烯醇、乙基纤维素、甲基纤维素、阿拉伯胶、羟丙基纤维素、羟丙基甲基纤维素等。作为润滑剂，例如可以举出硬脂酸镁、滑石、硅石等。作为着色剂，例如可以举出氧化钛、三氧化二铁、黄色三氧化二铁、胭脂虫红、洋红、核黄素等。作为矫味矫臭剂，例如可以举出可可粉、抗坏血酸、酒石酸、薄荷油、冰片、肉桂粉等。这些片剂和颗粒可以根据需要进行包衣。
在制备注射剂的情况下，可以根据需要向主药中添加pH调节剂、缓冲剂、悬浮剂、增溶剂、稳定剂、等渗剂、防腐剂等，通过常规方法制备成静脉内、皮下、肌内注射剂或静脉内滴注剂。此时根据需要可以通过常规的方法制备成冻干产品。
作为悬浮剂，例如可以举出甲基纤维素、聚山梨酯80、羟乙基纤维素、阿拉伯胶、西黄蓍胶粉、羧基甲基纤维素钠、聚氧乙烯脱水山梨醇单月桂酸酯等。
作为增溶剂，例如可以举出聚氧乙烯氢化蓖麻油、聚山梨酯80、烟酰胺、聚氧乙烯脱水山梨醇单月桂酸酯、聚乙二醇、甘油脂肪酸酯等。
作为稳定剂，例如可以举出亚硫酸钠、焦亚硫酸钠等。作为防腐剂，例如可以举出对羟基苯甲酸甲基酯、对羟基苯甲酸乙基酯、山梨酸、苯酚、甲酚、氯甲酚等。
本发明的肿瘤治疗剂可以将式(I)表示的化合物或其药学上可接受的盐、和PLX4032分别制成制剂，将两者同时或者分别给予。此外，也可以将两个制剂置于一个包装体中，制成所谓的试剂盒制剂。此外，这两种化合物也可以包含在一个制剂中。
本发明的肿瘤治疗剂治疗的肿瘤类型没有特别限制，例如可以举出纤维瘤，脂瘤，粘液瘤，软骨瘤，骨瘤，血管瘤，血管内皮瘤，淋巴瘤，骨髓瘤，髓样肉瘤，网状内皮细胞瘤，网状细胞肉瘤，黑色素瘤，肌瘤，神经瘤，神经胶质瘤，神经细胞瘤，肉瘤，骨肉瘤，肌瘤，纤维肉瘤，乳头瘤，腺瘤，囊瘤，脑肿瘤，宫颈癌，舌癌，鼻咽癌，喉癌，甲状腺癌，食道癌，肺癌，乳腺癌，胰腺癌，胃癌，十二指肠·空肠·回肠等的小肠癌，结肠·盲肠·直肠等的大肠癌，膀胱癌，肾癌，肝癌，胆囊癌，前列腺癌，子宫癌，子宫宫颈癌，卵巢癌等癌症，以及它们的混合瘤、转移瘤等。
实施例
在下文中举出实施例，更详细地说明本发明。
实施例1针对人黑色素瘤细胞系(A375)联合使用化合物A和PLX4032的肿瘤增殖抑制效果
各组使用五只裸鼠(CAnN.Cg-Foxnlnu/CrlCrlj，雌性，日本查尔斯河实验室公司(Charles River Laboratories Japan，Inc.))，对给予化合物A、PLX4032或给予两化合物的抗肿瘤效果进行评估。将人源性黑色素瘤细胞系A375(ATCC)以5×106个细胞/ml的浓度悬浮于PBS(和光纯药工业株式会社)中，充分混合。将所得混合物以每只0.1mL的量移植到每只小鼠身体的右侧胁腹皮下部。移植十四天后，通过一个数显卡尺(DIGIMATICTM CALIPER，Mitsutoyo公司)测量肿瘤的长径和短径。将小鼠进行分组使各组的肿瘤体积的平均值几乎相等。并且，根据下式计算肿瘤体积。
肿瘤体积(mm3)＝长径(mm)×短径(mm)×短径(mm)/2
将化合物A以1mg/mL的浓度溶解于净化水中。并且，将PLX4032以200mg/mL的浓度溶解于DMSO中。此外，将该溶解液用1％的甲基纤维素水溶液稀释20倍来制备10mg/mL的PLX4032悬浮液。
设立对照组、化合物A组、PLX4032组、以及化合物A和PLX4032联合用药组(在下文，记作联合用药组)。向化合物A组或PLX4032组的小鼠分别口服给予化合物A的水溶液或PLX4032悬浮液10mL/kg，每天一次。向联合用药组的小鼠口服给予两药液，各10mL/kg，每天一次。给予时间是23天。并且，没有对对照组小鼠进行给予。
在给予开始日测量肿瘤体积并且在给予开始后的第2、5、7、9、12、14、16、19、21、以及23天测量肿瘤体积。计算各测量日的肿瘤体积相对于给予开始日的肿瘤体积的比率，将其作为相对肿瘤体积(在下文，记作RTV)。此外，计算各组小鼠的RTV的平均值。其经日的变化示于表1和图1中，第23天的各组的值示于图2中。
[表1]
第2天 第5天 第7天 第9天 第12天
对照组 1.80 3.47 5.29 6.52 8.77
化合物A组 1.77 2.62 3.40 3.85 5.12
PLX4032组 0.98 0.94 1.00 1.13 1.46
联合用药组 0.90 0.84 0.77 0.75 0.78
第14天 第16天 第19天 第21天 第23天
对照组 10.66 11.95 15.49 17.29 19.31
化合物A组 5.40 6.30 7.89 9.16 10.17
PLX4032组 1.38 1.52 1.63 1.80 1.93
联合用药组 0.69 0.63 0.55 0.56 0.48

Claims (5)

1.肿瘤治疗剂，其包括联合使用的式(I)表示的化合物或其药学上可接受的盐及式(II)表示的化合物，
Figure FPA0000176913310000011
式中，R1是C1-6烷基或C3-8环烷基，
R2是氢原子或C1-6烷氧基，
R3是氢原子或卤素原子，
2.肿瘤治疗剂，其同时或分别给予式(I)表示的化合物或其药学上可接受的盐及式(II)表示的化合物，
式中，R1是C1-6烷基或C3-8环烷基，
R2是氢原子或C1-6烷氧基，
R3是氢原子或卤素原子，
Figure FPA0000176913310000021
3.肿瘤治疗剂，其包括式(I)表示的化合物或其药学上可接受的盐及式(II)表示的化合物，
Figure FPA0000176913310000022
式中，R1是C1-6烷基或C3-8环烷基，
R2是氢原子或C1-6烷氧基，
R3是氢原子或卤素原子，
Figure FPA0000176913310000023
4.根据权利要求1至3中任一项所述的肿瘤治疗剂，其中，式(I)表示的化合物是选自下组中的一种以上的化合物，该组由以下各项组成：
4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺；
Figure FPA0000176913310000031
4-[3-氯-4-(甲基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺；
Figure FPA0000176913310000032
4-[3-氯-4-(乙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺；
Figure FPA0000176913310000033
N6-甲氧基-4-(3-氯-4-{[(环丙基氨基)羰基)氨基]苯氧基}-7-甲氧基-6-喹啉甲酰胺；
Figure FPA0000176913310000034
以及
N6-甲氧基-4-(3-氯-4-{[(乙基氨基)羰基]氨基}苯氧基)-7-甲氧基-6-喹啉甲酰胺
Figure FPA0000176913310000041
5.根据权利要求1至4中任一项所述的肿瘤治疗剂，其中，式(I)表示的化合物是4-[3-氯-4-(环丙基氨基羰基)氨基苯氧基]-7-甲氧基-6-喹啉甲酰胺，
Figure FPA0000176913310000042
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