CN102105147B - 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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- CN102105147B CN102105147B CN2009801286427A CN200980128642A CN102105147B CN 102105147 B CN102105147 B CN 102105147B CN 2009801286427 A CN2009801286427 A CN 2009801286427A CN 200980128642 A CN200980128642 A CN 200980128642A CN 102105147 B CN102105147 B CN 102105147B
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Abstract
本发明提供一种治疗组合,其包含(a)如说明书中所述的式(A)的化合物1和(b)一种或多种选自铂衍生物、抗代谢药、拓扑异构酶I抑制剂和抗微管剂的抗肿瘤药,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。
Description
技术领域
本发明一般涉及癌症治疗领域,更具体地,提供一种具有协同或加合抗肿瘤效果的抗肿瘤组合物,包含aurora激酶抑制剂和铂衍生物和/或抗代谢药和/或拓扑异构酶I抑制剂和/或抗微管剂。
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组分所能达到的效果,即大于仅用一种组合组分的单一治疗的效果。
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
在第一个方面,本发明提供一种治疗组合,其包含(a)式(A)的化合物1:
和(b)一种或多种选自铂衍生物、抗代谢药、拓扑异构酶I抑制剂和抗微管剂的抗肿瘤药,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。
本发明还提供用于同时、分开或依次使用上述组合的组合制剂。
本发明还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或延缓增殖性疾病的进程的方法,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,本发明提供治疗组合,其包含(a)式(A)的化合物1:
和(b)一种或多种选自铂衍生物、抗代谢药、拓扑异构酶I抑制剂和抗微管剂的抗肿瘤药,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。
在另一个实施方案中,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受试者同时、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,包含该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受试者同时、依次或分开地施用如上定义的式(A)的化合物1和一种或多种选自铂衍生物、抗代谢药、拓扑异构酶I抑制剂和抗微管剂的抗肿瘤药。
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)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1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。
根据本发明一个更优选的实施方案,铂衍生物是顺铂或奥沙利铂。
抗代谢药包括但不限于,5-氟尿嘧啶(5-FU)、卡培他滨、吉西他滨、阿糖胞苷(Ara-C)、培美曲塞、甲氨蝶呤和依达曲沙。卡培他滨可以例如以如的商标的市售形式施用。吉西他滨可以例如以如的商标的市售形式施用。培美曲塞可以例如以如的商标的市售形式施用。
根据本发明一个更优选的实施方案,抗代谢药是吉西他滨、5-FU或Ara-C。
拓扑异构酶I抑制剂包括但不限于,托泊替康、伊立替康、SN-38和9-硝基喜树碱。伊立替康可以例如以如的商标的市售形式施用。托泊替康可以例如以如的商标的市售形式施用。SN-38是伊立替康的活性代谢产物,通过伊立替康的体内水解获得。
根据本发明一个更优选的实施方案,拓扑异构酶I抑制剂是伊立替康或SN 38。
根据本发明一个更优选的实施方案,抗微管剂是多西他赛和紫杉醇。
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,该组合制剂包含上述定义的式(A)的化合物1和一种或多种选自铂衍生物、抗代谢药、拓扑异构酶I抑制剂和抗微管剂的抗肿瘤药。
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与铂衍生物、抗代谢药、拓扑异构酶I抑制剂或抗微管剂的组合,抑制肿瘤的生长,优选使肿瘤完全消退。
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对的(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,一般使用的治疗过程是在以体表面积计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在以体表面积计约150mg/m2/日-约350mg/m2/日的范围,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计190或250mg/m2/日的剂量,在三周周期的第1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,对于施用铂衍生物,优选卡铂,一般使用的治疗过程取决于全身暴露(表示为AUC值)、患者的肾功能和施用方案。一般采用目标为在1-4周的治疗计划中AUC为2-6的方案。更优选地,使用目标为在4周的治疗计划中AUC为4-6的方案。对于施用奥沙利铂,一般使用的治疗过程是每2-3周10mg/m2/日-100mg/m2/日。更优选地,一般使用的治疗过程是在第1天为约30mg/m2/日-85mg/m2/日,每2周1次。
对于施用抗代谢药,优选吉西他滨,一般使用的治疗过程是每周施用200mg/m2/日-2000mg/m2/日。更优选地,一般使用的治疗过程是在21天周期的第1天和第8天,或者在28天周期的第1天、第8天和第15天时施用约800mg/m2/日-1250mg/m2/日。
对于施用拓扑异构酶I抑制剂,优选托泊替康,一般使用的治疗过程是每日0.1mg/m2-2mg/m2,连续2-10天。更优选地,一般使用的治疗过程是在21天周期中每日约0.5mg/m2-1.5mg/m2,连续3-5天。
对于施用伊立替康,一般使用的治疗过程是在6周周期的第1、8、15和22天,每日50mg/m2-350mg/m2。更优选地,一般使用的治疗过程是在6周周期的第1、8、15和22天,每日约125mg/m2-180mg/m2。
对于施用抗微管剂,优选多西他赛,一般使用的治疗过程是每3周约50mg/m2/日-100mg/m2/日、或者每周20mg/m2/日-100mg/m2/日。优选地,施用是在3周周期的第1天和第8天进行3小时输注。
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)一种或多种选自铂衍生物、抗代谢药、拓扑异构酶I抑制剂和抗微管剂的抗肿瘤药,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或任意水合物的形式存在。
在本发明的包装中,配对组分(a)和(b)存在于单个容器装置中或分别存在于不同的容器装置中。
本发明的另一个实施方案是一种商业包装,其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卵巢癌(A2780)和/或人结肠癌(HCT-116)细胞株,并在37℃和潮湿的5%CO2的大气下培养。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。试验下列治疗方案中的一个或全部:同时施用(两种药物施用于细胞72小时)和依次施用(施用另一种药物24小时后施用化合物1)。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Assay Explorer(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 Regul1984;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:与顺铂的组合的体外细胞毒性活性
表1所示的结果表明,对于人卵巢癌A2780和人结肠癌HCT-116细胞株,组合施用化合物1与顺铂产生了协同抗肿瘤效果。
实施例3:与奥沙利铂的组合的体外细胞毒性活性
表2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与奥沙利铂产生了协同抗肿瘤效果。
实施例4:与5-FU的组合的体外细胞毒性活性
表3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5-FU产生了协同抗肿瘤效果。
实施例5:与SN38的组合的体外细胞毒性活性
表4所示的结果表明,对于人卵巢癌A2780细胞株,组合施用化合物1与拓扑异构酶I抑制剂SN 38产生了协同抗肿瘤效果。
实施例6:与AraC的组合的体外细胞毒性活性
表5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AraC产生了协同抗肿瘤效果。
实施例7:与吉西他滨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。在裸鼠中皮下接种BX-PC3人胰腺癌肿瘤片段。选择该肿瘤模型是因为人们先前已经证明,它对于吉西他滨是敏感的,同时也是因为吉西他滨是胰腺癌的标准治疗药。当肿瘤可触知时,在接种肿瘤后第9天开始用吉西他滨治疗。在临治疗前制备化合物。
连续9天(第9,10,11,12,13,14,15,16和17天),以10ml/kg的体积,15mg/kg的剂量,每日2次(BI D),通过腹腔途径施用式(A)的化合物1。每4天3次(在第9、13、17天),以10ml/kg的体积,80mg/kg的剂量静脉施用吉西他滨。当组合施用这两种化合物时,在第9、13、17天施用吉西他滨,在施用吉西他滨后的3天里施用化合物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。用抑制肿瘤生长的百分比(TGI%)来评价抗肿瘤治疗的效果。基于体重减轻来评价毒性。结果在表6中报告。化合物1与抗代谢药吉西他滨的组合施用产生了加合/协同效果。
*在第9-17天腹膜内治疗2次
**在第9、13、17天静脉内治疗
***在第9、13、17天吉西他滨治疗;在第10,11,12,14,15,16,18,19,20天化合物1治疗
实施例8:与顺铂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。A2780人卵巢癌细胞是从American Type Culture Collection(Rockville,MD)购得的,并在37℃、5%CO2下保持在体外,作为在补充有10%FBS的RPMI培养基中的连续培养物。为进行体内实验,在裸鼠中皮下接种8×106个A2780细胞。选择该肿瘤模型是因为它对于铂衍生物是敏感的,同时也是基于该药物在治疗卵巢癌中的应用。
当肿瘤可触知时(第13天)开始治疗。在临治疗前制备这两种化合物。
从第13天至第17天,以10ml/kg的体积,15mg/kg的剂量,每日2次(BID),通过腹腔途径施用式(A)的化合物1。在第5天以10ml/kg的体积、8mg/kg的剂量,通过静脉内途径施用顺铂。当组合施用这两种化合物时,在第1至5天施用化合物1,在第17天施用顺铂。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。在接种肿瘤后第37天,即开始治疗后的第24天处死动物,将肿瘤称重。用治疗组相对于对照组的抑制肿瘤生长的百分比来评价抗肿瘤治疗的效果。基于体重减轻来评价毒性。结果在表7中报告。
*在第13,14,15,16,17天ip治疗2次。
**在第17天通过静脉内途径治疗。
***第17天:顺铂治疗,第13-17天:化合物1治疗。
式(A)的化合物1与烷化剂顺铂的组合治疗产生了明显的协同效果。并且在任何治疗组中均未观察到毒性。
实施例9:与伊立替康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。A2780人卵巢癌细胞是从American Type Culture Collection(Rockville,MD)购得的,并在37℃、5%CO2下保持在体外,作为补充有10%FBS的RPMI培养基中的连续培养物。为进行体内实验,在裸鼠中皮下接种8×106个A2780细胞。选择该肿瘤模型是因为它对于铂衍生物是敏感的,同时也是基于该药物在治疗卵巢癌中的应用
当肿瘤可触知时(第13天)开始治疗。在临治疗前制备这两种化合物。
从第13天至第17天,以10ml/kg的体积,30mg/kg的剂量,每日2次(BID),通过腹腔途径施用式(A)的化合物1。在第1天以10ml/kg的体积、60mg/kg的剂量,通过静脉内途径施用伊立替康。当组合施用这两种化合物时,在第1至5天施用化合物1,在第1天施用伊立替康。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。在接种肿瘤后第37天,即开始治疗后的第24天处死动物,将肿瘤称重。用治疗组相对于对照组的抑制肿瘤生长的百分比来评价抗肿瘤治疗的效果。基于体重减轻来评价毒性。结果在表8中报告。
*在第13,14,15,16,17天ip治疗2次。
**在第13天通过静脉内途径治疗。
***第13天:伊立替康治疗,第13-17天:化合物1治疗。
式(A)的化合物1与拓扑异构酶I抑制剂伊立替康的组合治疗产生了明显的协同效果。并且在任何治疗组中均未观察到毒性。
实施例10:与多西他赛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2.5×106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,多西他赛抑制体内模型生长(参见文献:Cancer Res.2004Oct 15,(64):7426-31),同时也是基于该药物在治疗前列腺癌中的应用(参见文献:Approvalsummary:docetaxel in combination with prednisone for thetreatment of androgen-independent hormone-refractory pros tatecancer,Clin.Cancer Re s.2004Dec 15;10(24):8147-51)。
当肿瘤可触知时,在注射肿瘤细胞10天后开始治疗。根据化合物已知的稳定性,多西他赛是在临治疗前制备的,式(A)的化合物1是每天制备的。
以10ml/kg的体积,30mg/kg的剂量,每日2次(BID),通过腹腔途径施用化合物1,共9天(第10至18天)。在细胞注射后的第10、14、18天,以10ml/kg的体积、7.5mg/kg的剂量,通过静脉内途径施用多西他赛。当组合施用这两种化合物时,在多西他赛治疗的间隔期,即在第11,12,13,15,16,17,19,20和21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(参见文献:Anticancer drugs7:437-60,1996)。延迟(T-C值)定义为治疗组(T)和对照组(C)的肿瘤达到预定大小(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。式(A)的化合物1与多西他赛的组合施用产生了明显的协同效果:化合物1与多西他赛组合施用时观察到的T-C(11.5天)好于预期的单一治疗获得的T-C的简单加合(9天)。并且在任何治疗组中均未观察到毒性。结果报告于表9。
*在第10-18天腹膜内治疗2次。
**在第10,14,18天通过静脉内途径治疗
***第10,14,18天:多西他赛治疗,第11,12,13,15,16,17,19,20和21天:化合物1治疗
Claims (7)
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。
6.根据权利要求5的应用,其中所述哺乳动物是人。
7.一种商业包装品,用于抗肿瘤治疗,其在适当的容器装置中包含(a)式(A)的化合物1和(b)一种或多种抗肿瘤药、以及用于同时、分开或依次使用的说明书,所述抗肿瘤药选自顺铂、奥沙利铂、5-氟尿嘧啶、吉西他滨、阿糖胞苷、SN-38、伊立替康和多西他赛,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,
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US8323208P | 2008-07-24 | 2008-07-24 | |
US61/083,232 | 2008-07-24 | ||
PCT/EP2009/058413 WO2010009967A1 (en) | 2008-07-24 | 2009-07-03 | Therapeutic combination comprising an aurora kinase inhibitor and an antineoplastic agent |
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CN102105147B true CN102105147B (zh) | 2013-07-03 |
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US (1) | US20110117212A1 (zh) |
EP (1) | EP2344156B1 (zh) |
JP (1) | JP5518062B2 (zh) |
CN (1) | CN102105147B (zh) |
AR (1) | AR072871A1 (zh) |
ES (1) | ES2703739T3 (zh) |
HK (1) | HK1154344A1 (zh) |
TW (1) | TW201008944A (zh) |
WO (1) | WO2010009967A1 (zh) |
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US7141568B2 (en) * | 2003-07-09 | 2006-11-28 | Pfizer Italia S.R.L. | Pyrrolo[3,4-c]pyrazole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them |
US20090142337A1 (en) * | 2006-05-08 | 2009-06-04 | Astex Therapeutics Limited | Pharmaceutical Combinations of Diazole Derivatives for Cancer Treatment |
WO2007136615A2 (en) * | 2006-05-16 | 2007-11-29 | Merck & Co., Inc. | Combination cancer therapy |
EP2117539B1 (en) * | 2006-11-03 | 2010-09-01 | Nerviano Medical Sciences S.r.l. | A method of administering an antitumor compound |
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WO2010009967A1 (en) | 2010-01-28 |
AR072871A1 (es) | 2010-09-29 |
US20110117212A1 (en) | 2011-05-19 |
JP2011528680A (ja) | 2011-11-24 |
ES2703739T3 (es) | 2019-03-12 |
CN102105147A (zh) | 2011-06-22 |
EP2344156A1 (en) | 2011-07-20 |
JP5518062B2 (ja) | 2014-06-11 |
EP2344156B1 (en) | 2018-10-17 |
HK1154344A1 (en) | 2012-04-20 |
TW201008944A (en) | 2010-03-01 |
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