CN102105148B - 包含aurora激酶抑制剂和抗肿瘤药的治疗组合 - Google Patents
包含aurora激酶抑制剂和抗肿瘤药的治疗组合 Download PDFInfo
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- CN102105148B CN102105148B CN2009801286342A CN200980128634A CN102105148B CN 102105148 B CN102105148 B CN 102105148B CN 2009801286342 A CN2009801286342 A CN 2009801286342A CN 200980128634 A CN200980128634 A CN 200980128634A CN 102105148 B CN102105148 B CN 102105148B
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Abstract
本发明提供用于治疗肿瘤的治疗组合,包含式(A)的化合物1和一种或多种抗肿瘤药,所述抗肿瘤药选自抑制生长因子或生长因子受体的抗体、蛋白酶体抑制剂或其衍生物或前药、和激酶抑制剂或其衍生物或前药。
Description
技术领域
本发明一般涉及癌症治疗领域,更具体地,提供一种具有协同抗增殖效果的抗肿瘤组合物,包含aurora激酶抑制剂与抑制生长因子的抗体和/或蛋白酶体抑制剂和/或激酶抑制剂。
背景技术
蛋白激酶(PK)的功能障碍是很多疾病的标志。大部分癌基因和原癌基因都与PK的人癌编码有关。PK的活性增强也涉及很多非恶性疾病,例如良性前列腺增生、家族性腺瘤病、息肉病、神经纤维瘤病、银屑病、与动脉粥样硬化有关的血管平滑细胞增殖、肺纤维化、关节炎、肾小球肾炎及手术后狭窄和再狭窄。
PK也与炎性疾病以及病毒和寄生虫的繁殖有关。PK也在神经变性疾病的发病机制和发生中发挥主要作用。
对于PK功能障碍或失调的一般参考,参见,例如Current Opinionin Chemical Biology,1999,3,459-465。
本领域已知的与癌细胞生长有关的几种激酶是Aurora激酶,特别是Aurora-2。
人们发现,Aurora-2在很多不同的肿瘤类型中过度表达。在很多癌症包括乳腺癌[Cancer Res.1999,59(9),2041-4]和结肠癌中,其基因位图常在20q 13(一个染色体区)处扩增。
20q13扩增与瘤-阴性的乳腺癌患者中预后不良有关,Aurora-2表达增加表明预后不良并会减少膀胱癌患者的存活时间[J.Natl.Cancer Inst.,2002,94(17),1320-9]。对于Aurora-2在癌症的中心体功能异常中的作用的一般参考,也可参见Molecular CancerTherapeutics,2003,2,589-595。
本领域已知数种杂环化合物是蛋白激酶抑制剂,其中,在国际专利申请WO01/12189、WO12188、WO02/48114和WO02/70515中已经披露了3-甲酰氨基-吡唑和3-脲基-吡唑及其衍生物是蛋白激酶抑制剂。
在WO 00/69846、WO 02/12242、WO 03/028720和WO 03/97610中也已经披露了包含吡唑部分且具有激酶抑制活性的稠合双环化合物。
已经披露,特殊的四氢吡咯并[3,4-c]吡唑衍生物是Aurora激酶的有效的ATP-竞争性抑制剂(Fancelli,D.等人:Journal ofMedicinal Chemistry.2005,vol.48,no.8,p.3080-3084.PCT/WO2005005427)。
令人惊奇地,已经发现,当与某些抗肿瘤药组合施用时,可以增强上述四氢吡咯并[3,4-c]吡唑衍生物的抗肿瘤效果,即,特别是能延缓增殖性疾病进程或治疗增殖性疾病、特别是治疗对其他已知为抗肿瘤药的化学治疗药耐受的肿瘤。特别地,这种组合的抗肿瘤效果大于单独使用任一组合成员所能达到的效果,即大于仅用一种组合成员的单一治疗的效果。
因此,本发明提供四氢吡咯并[3,4-c]吡唑衍生物与已知药物的新组合,该组合特别适合于治疗增殖性疾病,尤其是癌症。更具体地,本发明的组合作为抗肿瘤药在治疗中是特别有用的,没有毒性和副作用,而毒性和副作用正是与当前使用的抗肿瘤药有关的缺点。
发明内容
本发明提供一种治疗组合,其包含(a)式(A)的化合物1:
和(b)一种或多种抗肿瘤药,所述抗肿瘤药选自抑制生长因子或生长因子受体的抗体、蛋白酶体抑制剂或其衍生物或前药、和激酶抑制剂或其衍生物或前药,其中在各情况下活性成分以游离形式或以其药学可接受的盐或任意水合物的形式存在。
本发明也提供用于同时、分开或依次使用上述组合的组合制剂。
本发明也提供一种包含上述组合的药物组合物,所述组合还与药学可接受的载体、稀释剂或赋形剂混合。
本发明还提供一种治疗增殖性疾病的方法,包括给有此需要的患者施用治疗有效量的上述组合。
具体实施方式
在第一个实施方案中,本发明提供一种治疗组合,其包含(a)式(A)的化合物1:
和(b)一种或多种抗肿瘤药,所述抗肿瘤药选自抑制生长因子或生长因子受体的抗体、蛋白酶体抑制剂或其衍生物或前药、和激酶抑制剂或其衍生物或前药,其中在各情况下活性成分以游离形式或以其药学可接受的盐或任意水合物的形式存在。
在另一个方面,本发明的组合是用于同时、分开或依次使用的组合制剂。
另一个实施方案涉及在治疗增殖性疾病或延缓增殖性疾病的进程的方法中的本发明的组合,其中该方法包括给有此需要的患者同时、依次或分开地施用该治疗组合。
在再一个实施方案中,本发明提供一种药物组合物,包含本发明的治疗组合与药学可接受的载体、稀释剂或赋形剂混合。
再一个实施方案涉及如上定义的式(A)的化合物1在制备治疗增殖性疾病的药物中的应用,其中所述治疗包括给有此需要的患者同时、依次或分开地施用如上定义的式(A)的化合物1和一种或多种抗肿瘤药,所述抗肿瘤药选自抑制生长因子或生长因子受体的抗体、蛋白酶体抑制剂或其衍生物或前药、和激酶抑制剂或其衍生物或前药。
式(A)的化合物1具有化学名称N-{5-[(2R)-2-甲氧基-2-苯乙酰基]-1,4,5,6-四氢吡咯并[3,4-c]吡唑-3-基}-4-(4-甲基哌嗪-1-基)苯甲酰胺。它可以如WO2005/005427(通过参考引入本文)中所述来制备,具有蛋白激酶抑制活性,因此可以作为抗肿瘤药用于治疗。
式(A)的化合物的药学可接受的盐包括与无机或有机酸的酸加成盐,这些酸是例如,硝酸、盐酸、氢溴酸、硫酸、高氯酸、磷酸、乙酸、三氟乙酸、丙酸、羟乙酸、乳酸、草酸、丙二酸、苹果酸、马来酸、甲磺酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲烷磺酸、羟乙磺酸和水杨酸等。
根据本发明一个优选的实施方案,抑制生长因子或生长因子受体的抗体选自贝伐单抗(血管内皮生长因子的抗体)、西妥昔单抗、帕尼单抗、马妥珠单抗、尼妥珠单抗(表皮生长因子受体的抗体)、曲妥珠单抗和帕妥珠单抗(ErbB2的抗体)。
蛋白酶体抑制剂是阻断蛋白酶体作用的药物,蛋白酶体是破坏蛋白质的细胞复合物。根据本发明一个优选的实施方案,蛋白酶体抑制剂优选是硼替佐米。硼替佐米由Millennium Pharmaceuticals以销售,是在人体中试验的第一种治疗性蛋白酶体抑制剂。在美国它被批准用于治疗复发性多发性骨髓瘤和外套细胞淋巴瘤。
根据本发明一个更优选的实施方案,激酶抑制剂是黄酮吡多或达沙替尼。
在本发明中,该组合的各活性成分是以有效产生协同的抗肿瘤效果的量提供的。
本发明也提供一种在有此需要的哺乳动物包括人中减轻由采用抗肿瘤药的抗肿瘤治疗导致的副作用的方法,该方法包括以有效产生协同抗肿瘤效果的量给所述哺乳动物施用组合制剂,所述组合制剂包含上述定义的式(A)的化合物和一种或多种抗肿瘤药,所述抗肿瘤药选自抑制生长因子或生长因子受体的抗体、蛋白酶体抑制剂或其衍生物或前药、和激酶抑制剂或其衍生物或前药。
本文使用的术语“协同抗肿瘤效果”是指通过给哺乳动物(包括人)施用有效量的如上定义的式(A)的化合物1与一种或多种抗肿瘤药的组合,以抑制肿瘤的生长,优选使肿瘤完全消退。所述抗肿瘤药选自抑制生长因子或生长因子受体的抗体、蛋白酶体抑制剂或其衍生物或前药、和激酶抑制剂或其衍生物或前药。
本文使用的术语“组合制剂”在一定意义上特别定义为“试剂盒的一部分”,如上定义的组合组分(a)和(b)可以独立地给药,或者使用不同量的组合组分(a)和(b)的不同固定组合,即,同时或在不同时间点给药。然后可以例如同时或时间交错地施用试剂盒的各部分的组分,也就是说,在不同时间点、以相同或不同的时间间隔来施用试剂盒的各部分的任意组分。最优选地,选择时间间隔,使得组合使用各部分对所治疗疾病的治疗效果大于仅使用组合组分(a)和(b)的任一种所得到的治疗效果。在该组合制剂中,所施用的组合组分(a)与组合组分(b)的总量的比例可以不同,例如为了满足所要治疗的患者亚群的需要或单个患者的需要,不同的需要可取决于患者的具体疾病、年龄、性别、体重等。优选地,具有至少一种有益效果,例如共同增强作为组合组分(a)和(b)的效果,特别是协同效果,例如,大于加合效果,其他的有益效果,副作用较小,毒性较小,或者在组合组分(a)和(b)的一种或两种的非有效剂量下得到组合治疗的效果,特别优选是组合组分(a)和(b)的强的协同作用。
本文使用的术语“施用”是指胃肠外和/或口服施用。“胃肠外”是指静脉内、皮下或肌内施用。
在本发明的方法中,对于施用式(A)的化合物1,一般使用的治疗过程是按体表面积的100mg/m2/日-1500mg/m2/日的范围,最多连续21天。更优选地,所使用的治疗过程是按体表面积的约150mg/m2/日-约350mg/m2/日,最多连续21天。
在一个特别优选的方案中,式(A)的化合物以体表面积的190或250mg/m2/日的剂量,在三周周期的第1天和第8天输注3小时。例如,在2008年5月8日公开的WO2008/052931(通过参考引入本文)中公开了其他可能的治疗方案。
式(A)的化合物1可以以各种剂型施用,例如口服施用时,以片剂、胶囊、糖或薄膜包衣片、液体溶液或混悬液的形式;直肠施用时,以栓剂的形式;胃肠外施用时,例如以肌内,或通过静脉和/或鞘内和/或脊椎内注射或输注的形式。
在本发明的方法中,对于施用蛋白酶体抑制剂,优选硼替佐米,一般使用的治疗过程是每3周约50mg/m2-100mg/m2或每周30mg/m2以上。
对于施用抑制生长因子的抗体,优选贝伐单抗,一般使用的治疗过程是0.1mg/kg-100mg/kg。更优选使用的治疗过程是在3周周期的第1天1mg/kg-20mg/kg。
对于施用激酶抑制剂,优选黄酮吡多,一般使用的治疗过程可以是0.1mg/kg-100mg/kg。更优选使用的治疗过程是1mg/kg-20mg/kg。
本发明的抗肿瘤治疗特别适合于治疗任何形式的癌症,包括但不限于:癌,例如膀胱癌、乳腺癌、结肠癌、肾癌、肝癌、肺癌(包括小细胞肺癌)、食道癌、胆囊癌、卵巢癌、胰腺癌、胃癌、宫颈癌、甲状腺癌和皮肤癌(包括鳞状细胞癌);淋巴系的造血性肿瘤,包括白血病、急性淋巴细胞性白血病、急性成淋巴细胞性白血病、B细胞淋巴瘤、T细胞淋巴瘤、何杰金淋巴瘤、非何杰金淋巴瘤、外套细胞淋巴瘤、毛细胞淋巴瘤和Burkett淋巴瘤;骨髓系的造血性肿瘤,包括急性和慢性髓性白血病、骨髓增生异常综合征和早幼粒细胞白血病;多发性骨髓瘤;间质细胞来源的肿瘤,包括纤维肉瘤和横纹肌肉瘤;中枢和外周神经系统的肿瘤,包括星细胞瘤、成神经细胞瘤、神经胶质瘤和神经鞘瘤;其他肿瘤,包括黑素瘤、精原细胞瘤、畸胎瘤、骨肉瘤、着色性干皮病、角质黄瘤(keratoxanthoma)、甲状腺囊癌和卡波西肉瘤。
如上所述,本发明的组合的效果显著增强,同时毒性并没有相应增强。换句话说,本发明的组合治疗增强了本发明组合的组分(a)和/或组分(b)的抗肿瘤效果,因此得到了最有效和毒性较小的肿瘤治疗方法。
本发明的药物组合物可用于抗癌治疗。
本发明还提供一种商业包装,在适当的容器装置中包含(a)如上述定义的式(A)的化合物和(b)一种或多种抗肿瘤药,所述抗肿瘤药选自抑制生长因子或生长因子受体的抗体、蛋白酶体抑制剂或其衍生物或前药、和激酶抑制剂或其衍生物或前药,其中在各情况下活性成分以游离形式或以其药学可接受的盐或任意水合物的形式存在,以及用于同时、分开或依次使用的说明书。
在本发明的包装中,各组分(a)和(b)存在于单个容器装置中或在不同的容器装置中。
本发明的另一个实施方案是一种商业包装,包含如上所述的药物组合物或产品。
由于aurora激酶蛋白在调节细胞有丝分裂和增殖中的关键作用,本发明的组合也可以用于治疗各种细胞增殖性疾病,例如,良性前列腺增生、家族性腺瘤病、息肉病、神经纤维瘤病、银屑病、与动脉粥样硬化有关的血管平滑细胞增殖、肺纤维化、关节炎、肾小球肾炎及手术后狭窄和再狭窄。
本发明的组合作为细胞凋亡的调节剂,也可以用于治疗癌症、病毒感染、在感染HIV的个体中防止AIDS发生、自身免疫性疾病和神经变性疾病。
例如,通过下列的体外和体内试验显示了本发明的组合的活性,它们是用于解释,而非限制本发明。
实施例1:体外细胞毒性活性试验的材料和方法
接种指数级生长的人结肠癌(HCT-116)细胞株,并在37℃和潮湿的5%CO2气氛下培养。向实验培养基中加入药物,并在黑暗中在37℃下培养72小时。在接种24小时后向该培养基中加入数个剂量的上述定义的式(A)的化合物1和抗肿瘤药。试验依次施用方案(施用另一种药物24小时后施用化合物1)。在临用前制备药物溶液。在治疗结束时,通过细胞内三磷腺苷监测系统(CellTiterGlo-Promega),使用Envision(PerkinElmer)作为读数器来测定细胞增殖。用AssayExplorer(MDL)程序比较治疗组和对照组的数据来评价抑制活性。用S型插值曲线来计算抑制50%细胞生长的剂量。基于用于互不排斥药物的Chou-Talalay方程(Adv Enzyme Regul 1984;22:27-55),使用用于多种药物效果分析的计算机程序来计算组合指数(C.I.),其中C.I.<1表示大于加合效果(C.I.>3表示强的拮抗作用;1.3<C.I.<3,表示拮抗作用;0.8<C.I.<1.3,表示加合作用;0.3<C.I.<0.8,表示协同作用;C.I.<0.3,表示强的协同作用)。
实施例2:与黄酮吡多的组合的体外细胞毒性活性
表1所示的结果表明,对于人结肠癌HCT-116细胞株,组合施用化合物1与黄酮吡多产生了协同抗肿瘤效果。
表1
实施例3:与单克隆抗体贝伐单抗的组合的体内抗肿瘤效力
将来自Harlan(意大利)的Balb,Nu/Nu雄性小鼠保持于带有过滤纸覆盖物的笼中,将食物和睡具消毒,并将水酸化。在裸鼠中皮下注射2.5x106个DU145前列腺癌细胞(来自American Type CultureCollection)。选择该肿瘤模型是因为先前已经证明,贝伐单抗在体内模型中抑制血管生成和生长(参见参考文献:The Prostate 36:1-10,1998)。当用肿瘤称重工具称重所有组都为0.15g即肿瘤可触知时,在注射肿瘤细胞9天后开始治疗。根据化合物已知的稳定性,贝伐单抗仅在临治疗前制备,化合物1是每天制备的。
从第9至17天,共9天,以10ml/kg的体积、15mg/kg的剂量,每日2次(BID),通过腹腔途径施用化合物1。在肿瘤细胞注射后的第9,13,17天以10ml/kg的体积,20mg/kg的剂量腹膜内施用贝伐单抗。当组合施用时,在第9,10,11,12,13,14,15,16,17,18和19天施用化合物1,在第9,13,17天施用化合物1后立即施用贝伐单抗。每3天测定肿瘤生长和体重。通过测径器评价肿瘤生长。记录两个直径,根据下式计算肿瘤重量:长度(mm)×宽度2/2。用延迟肿瘤指数式生长的发生来评价抗肿瘤治疗的效果(参见参考文献:Anticancer drugs 7:437-60,1996)。延迟(T-C值)定义为治疗组(T)和对照组(C)达到预定大小(1g)所需的时间差(单位:天)。基于体重减轻来评价毒性。结果报告于下表2。化合物1与贝伐单抗的组合施用产生了明显的加合/协同效果:化合物1与贝伐单抗组合时观察到的T-C好于预期的单一治疗获得的T-C的简单加合。在任何治疗组中均未观察到毒性。
表2
*在第9,10,11,12,13,14,15,16,17,18和19天腹膜内治疗2次。
**在第9,13,17天腹膜内治疗。
***第9,13,17天,贝伐单抗治疗;第9,10,11,12,13,14,15,16,17,18和19天,化合物1治疗
实施例4:与硼替佐米的组合的体内抗肿瘤效力
将来自Harlan(意大利)的SCID雄性小鼠保持于带有过滤纸覆盖物的笼中,将食物和睡具消毒,并将水酸化。在SCID小鼠中皮下注射5x106个HL-60人急性髓性白血病细胞(来自American Type CultureCollection)。选择该模型是因为先前已经证明,化合物1抑制在体内的该模型生长,同时也是基于该模型作为血液病学恶性肿瘤的代表的应用。
当肿瘤可触知时,在注射肿瘤细胞12天后开始治疗。根据化合物已知的稳定性,硼替佐米是在临治疗前制备的,化合物1是每天制备的。
以10ml/kg的体积,15mg/kg的剂量,每日2次(BID),通过腹腔途径施用化合物1,共12天(第12-23天)。在肿瘤细胞注射后的第12,16,20和24天,以10ml/kg的体积,0.5mg/kg的剂量通过静脉内途径施用硼替佐米;另外,在肿瘤细胞注射后的第12,16,20和24天,以以10ml/kg的体积、1mg/kg的剂量通过静脉内途径施用硼替佐米。当组合施用时,在硼替佐米治疗的间隔期,即第13,14,15,17,18,19,21,22,23,25,26和27天施用化合物1。每3天测定肿瘤生长和体重。通过测径器评价肿瘤生长。记录两个直径,根据下式计算肿瘤重量:长度(mm)×宽度2/2。用延迟肿瘤指数式生长的发生来评价抗肿瘤治疗的效果(参见参考文献:Anticancer drugs7:437-60,1996)。延迟(T-C值)定义为治疗组(T)和对照组(C)达到预定大小(1g)所需的时间差(单位:天)。基于体重减轻来评价毒性。结果报告于下表3。化合物1与0.5mg/kg的硼替佐米的组合施用产生了明显的加合/协同效果:化合物1与0.5mg/kg的硼替佐米组合时观察到的T-C好于预期的单一治疗获得的T-C的简单加合。在任何治疗组中均未观察到毒性。化合物1与1mg/kg的硼替佐米的组合施用产生了强协同效果:化合物1与1mg/kg的硼替佐米组合时观察到的T-C(35.7)明显好于预期的单一治疗获得的T-C的简单加合(17.3)。在治疗组中观察到一些毒性的迹象。
表3
*在第12,13,14,15,16,17,18,19,20,21,22,23天腹膜内治疗2次。
**在第12,16,20,24天通过静脉途径治疗。
***在第12,16,20,24天硼替佐米治疗,在第13,14,15,17,18,19,21,22,23,25,26和27天化合物1治疗。
Claims (5)
2.根据权利要求1的组合制剂,其是用于同时、分开或依次使用的组合制剂。
5.一种商业包装品,在适当的容器装置中包含(a)式(A)的化合物1和(b)蛋白酶体抑制剂、以及用于同时、分开或依次使用的说明书,其中在各情况下活性成分以游离形式或以其药学可接受的盐的形式存在,其中所述蛋白酶体抑制剂是硼替佐米,
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