CN1780627B - 用于治疗涉及细胞增殖、骨髓瘤细胞迁移或凋亡或者血管增殖疾病的联用药物 - Google Patents
用于治疗涉及细胞增殖、骨髓瘤细胞迁移或凋亡或者血管增殖疾病的联用药物 Download PDFInfo
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Abstract
本发明是关于治疗涉及细胞增殖、骨髓瘤细胞的迁移或凋亡或者血管生成的疾病的联用药物。本发明还涉及治疗这些疾病的方法,其包括联合给予有效量的特定活性化合物,和/或以增效及协同作用的比例的放射治疗联合治疗,及这些特定化合物和/或放射治疗在制备相应联用药物制剂中的联用用途。
Description
发明领域
本发明是关于一种治疗涉及细胞增殖、骨髓瘤细胞的迁移或凋亡或者血管生成的疾病的方法,该方法包括向需要这种治疗和/或这种联合治疗(co-treatment)的人联合给予(co-administration)有效量的:
(i)选择性的蛋白质酪氨酸激酶受体拮抗剂;和
(ii)至少一种其它化学治疗剂或天然存在的、半合成或合成治疗剂;和/或
(iii)放射线治疗或放射免疫治疗。
本发明还涉及适合的药物组合物(pharmaceutical composition),其包括有效量的:
(i)选择性的蛋白质酪氨酸激酶受体拮抗剂;和
(ii)至少一种其它化学治疗剂或天然存在的、半合成或合成治疗剂;以及任选与放射治疗或放射免疫治疗联合作为联合制剂用于联合治疗,该联合制剂可同时、分开或连续用于治疗涉及细胞增殖、骨髓瘤细胞的迁移或凋亡或者血管生成的疾病,特别是用于抑制肿瘤生长、存活及转移。
本发明还涉及联合使用有效量的:
(i)选择性的蛋白质酪氨酸激酶受体拮抗剂;和
(ii)至少一种其它化学治疗剂或天然存在的、半合成或合成治疗剂;用于制备联用药物制剂(pharmaceutical combined preparation),其可同时、分开或连续使用以治疗涉及细胞增殖、骨髓瘤细胞的迁移或凋亡或者血管生成的疾病,特别用于抑制肿瘤生长、存活及转移,其任选与放射治疗或放射免疫治疗联合。
本发明还涉及使用有效量的选择性蛋白质酪氨酸激酶受体拮抗剂在制备药物组合物中的用途,该药物组合物适于同时、分开或连续地与放射治疗或放射免疫治疗联合治疗涉及细胞增殖、骨髓瘤细胞的迁移或凋亡或者血管生成的疾病,特别用于抑制肿瘤生长、存活及转移。
现有技术
在过去十年中,已经描述了蛋白质酪氨酸激酶受体家族中一些类型和亚型的生物活性,例如表皮生长因子受体EGFR及其亚型ErbB-2及ErbB-4(Brignola等人,Journal of Biological Chemistry,Vol.277,No.2,pp.1576-1585,2002),或血管内皮生长因子受体VEGFR 1-3与其配体VEGF及其目前已知的四种亚型(Jung等人,European Journal of Cancer,Vol.38,pp 1133-1140,2002)。在之前类似的研究报告中显示,某些这些受体的过度表达与肿瘤的多种形式有关联。例如研究提出如下证据,表皮生长因子EGF在肿瘤中为生长因子,并且血管内皮生长因子VEGF为最常见的肿瘤血管生成介质之一,是实体肿瘤生长及转移所必须的。因此这些受体的抑制剂已经并且仍然被用于肿瘤治疗(参见例如Cerrington等人的文献,In Advancesin Cancer Research,Academic Press 2000,pp.1-38)。
最近的研究还建议将几种受体拮抗剂结合,或进一步与化学治疗剂或放射线结合。例如在WO 02/070008中指出将特定针对VEGF受体的拮抗剂与特定针对EGF受体的拮抗剂结合,任选与放射线或化学治疗剂结合,用于抑制肿瘤生长。作为适合的特定拮抗剂的例子,在WO 02/070008中公开了VEGF受体的单克隆抗体及EGF受体的单克隆抗体。
因此,目前在临床发展中许多蛋白质酪氨酸激酶受体拮抗剂被用于治疗癌症(参见例如Expert Opinion Review ofLaid&Cherrington in Expert Opin.Invest.Drugs,Vol.12,NO.1,pp.51-64,2003)。然而,因为缺乏优于标准疗法的效果或因为发现了无法接受的副作用,到目前为止尚无法证明单独使用这些物质或与其它癌症疗法联合时在治疗肿瘤疾病方面的功效。
例如,最近公开一种血管生成抑制剂,其已于临床试验并与化学治疗相结合,它是由Pharmacia所开发的代号名称为SU5416的用于治疗癌症的抑制剂,但是其伴随干扰副作用(disturbing side effect),即增加血栓(KenGarber及Ann Arbor,Nature Biotechnology,Vol.20,pp.1067-1068,Nov.2002)。
对于治疗肿瘤性质(oncological nature)疾病,已建议了许多种化学治疗剂,其可用于单一疗法(以一种药剂治疗)或用于联合治疗(以多于一种的药剂同时、分开或连续治疗)和/或可与放射治疗或放射免疫治疗联合应用。在这方面,化学治疗剂是指一种天然存在、半合成或合成化合物,其可单独地或通过进一步活化,例如在放射免疫治疗中与放射线一起抑制或杀死生长中的细胞,并且其可用于或已被证明可用于治疗通常称为癌症的肿瘤性质疾病。在文献中,这些药剂一般是根据其作用机制来分类。例如美国化学学会(American Chemical Society),1995年,W.O.Foye所编辑的“癌症化学治疗剂(Cancer Chemotherapeutic Agents)”中所作的分类可作为本项的参照。
因此,在本发明的范围中,对于下列各类化学治疗剂特别感兴趣,但并不限制于此:
·合成的小分子VEGF受体拮抗剂
·小分子生长因子(GF)受体拮抗剂
·EGF受体和/或VEGF受体和/或整联蛋白受体或任何其它蛋白质酪氨酸激酶受体的抑制剂,该抑制剂不属于合成的小分子
·EGF受体和/或VEGF受体和/或整联蛋白受体或任何其它蛋白质酪氨酸激酶受体的抑制剂,其为融合蛋白
·与核酸相互作用并且被分类为烷化剂的化合物或铂化合物
·与核酸相互作用并且被分类为蒽环类抗生素(anthracycline)、DNA插入剂(intercalator)或DNA交联剂的化合物
·抗代谢物
·天然存在、半合成或合成的博来霉素(bleomycin)类抗生素(BLM-族抗生素)
·DNA转录酶抑制剂,特别是拓扑异构酶I或拓扑异构酶II的抑制剂
·染色质(chromatin)修饰剂
·有丝分裂抑制剂、抗有丝分裂剂或细胞周期抑制剂
·蛋白酶体(proteasome)抑制剂
·酶
·荷尔蒙、荷尔蒙拮抗剂或荷尔蒙抑制剂、或类固醇生物合成抑制剂
·类固醇
·细胞因子、缺氧选择性细胞毒素、细胞因子抑制剂、淋巴因子、细胞因子或经口和非肠胃耐受诱导系统(tolerance induction strategies)的抗体
·载剂(supportive agents)
·化学放射敏化剂及保护剂
·光化学活化的药物
·合成的聚核苷酸或寡核苷酸
·其它化学治疗剂或天然存在的、半合成或合成治疗剂,例如细胞毒性抗生素、癌细胞表面分子的靶向抗体、金属蛋白酶抑制剂、癌基因(oncogene)抑制剂、基因转录或RNA翻译或蛋白质表达的抑制剂、或稀土元素络合物(complex)
对于到目前为止未分类为化学治疗剂的其它种类化合物,将其用于联合治疗也很感兴趣,该其它种类化合物为天然存在的、半合成或合成治疗剂,例如非甾体抗炎药,具体是环氧化酶(COX)抑制剂,更具体的为COX-2抑制剂。
尽管已提出联合几种治疗剂或治疗法的观念,尽管各种联合的治疗法正在被研究并用于临床试验,但仍需要一种新颖并且有效的治疗剂用于治疗细胞增殖、骨髓瘤细胞的迁移或凋亡或者血管生成的疾病,并且仍需开发其它可增进功效并降低副作用的联合。
这些疾病也可为肿瘤性质的疾病,其包括所有形式的恶性肿瘤或癌症,或非肿瘤性质的疾病例如糖尿病视网膜病变、类风湿关节炎或牛皮癣。
发明内容
目前已发现向需要此种治疗的人联合给予和/或向需要此种治疗的人联合治疗有效量的
(i)选择性的蛋白质酪氨酸激酶受体拮抗剂;和
(ii)至少一种其它化学治疗剂或天然存在的、半合成或合成治疗剂;和/或
(iii)放射治疗或放射免疫治疗,与仅单独给予任何这些物质和/或单独用放射治疗或放射免疫进行治疗的情况相比较,对于需要此种治疗的人,在高效的治疗涉及细胞增殖、骨髓瘤细胞的迁移或凋亡或者血管生成的疾病上能够提供了意想不到的优点。
另外发现,若选择性蛋白质酪氨酸激酶受体拮抗剂为选自VEGFR1至3,PDGFR α和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂时,该联合给药或联合治疗特别有效。
另外发现,若选择性蛋白质酪氨酸激酶受体拮抗剂为选自VEGFR1至3,PDGFRα和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂时,并且进一步为src酪氨酸激酶家族成员的拮抗剂,特别是src、lck、lyn和fyn时,和/或为下述复合物中至少一种的拮抗剂,所述复合物是由细胞周期调节蛋白依赖性激酶与其特异性的细胞周期调节蛋白(cyclin)或与病毒细胞周期调节蛋白所形成的时,例如CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7、CDK8及CDK9与其特异性的细胞周期调节蛋白A、B1、B2、C、D1、D2、D3、E、F、G1、G2、H、I及K所形成的时,和/或为另一种旁分泌(paracrine)IL-6分泌作用的抑制剂时,该联合给药或联合治疗特别有效。
另外发现,可用根据本发明联合来治疗的疾病为涉及细胞增殖、骨髓瘤细胞的迁移或凋亡或者血管生成的疾病,可以为肿瘤性质,例如所有种类的恶性肿瘤或癌症,或非肿瘤性质,例如糖尿病视网膜病变、类风湿关节炎或牛皮癣。
另外发现,根据本发明的联合治疗对于抑制肿瘤生长、存活及转移特别有效。
另外发现,根据本发明的联合治疗对于选择性活性物质、选择性剂量及选择性剂型特别有效。
因此,本发明提供了一种治疗涉及细胞增殖、骨髓瘤细胞的迁移或凋亡或者血管生成的疾病的方法,该方法包括同时、分开或连续将有效量的:
(i)下述抑制剂或其多晶型物、代谢物或可药用盐,该抑制剂选自VEGFR1至3,PDGFRα和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂,并进一步为src酪氨酸激酶家族成员的拮抗剂;和
(ii)至少一种其它的化学治疗剂或天然存在的、半合成或合成治疗剂;向需要此种治疗的人以联合制剂的形式联合给药,任选与放射治疗或放射免疫治疗联合治疗。
本发明还提供一种治疗涉及细胞增殖、骨髓瘤细胞的迁移或凋亡或者血管生成的疾病的方法,该方法包括与有效量的选自VEGFR1至3,PDGFRα和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂同时、分开或连续地进行联合治疗,所述拮抗剂还为src酪氨酸激酶家族成员的拮抗剂;或与其多晶型物、代谢物或可药用盐同时、分开或连续地进行联合治疗;以及与放射线治疗或放射免疫治疗同时、分开或连续地进行联合治疗。
用于根据本发明方法中的蛋白质酪氨酸激酶受体拮抗剂,优选为选自VEGFR1至3,PDGFR α和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂,并且进一步为src酪氨酸激酶家族成员的拮抗剂,特别是src、lck、lyn或fyn的拮抗剂。
在另一优选的实施方案中,蛋白质酪氨酸激酶受体拮抗剂还可以是下述复合物中至少一种的拮抗剂,所述复合物由细胞周期调节蛋白依赖性激酶与其特异性的细胞周期调节蛋白或与病毒细胞周期调节蛋白所形成的,例如CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7、CDK8及CDK9与其特异性的细胞周期调节蛋白A、B1、B2、C、D1、D2、D3、E、F、G1、G2、H、I及K所形成的,或是旁分泌IL-6分泌作用的抑制剂。
在一种优选的实施方案中,蛋白质酪氨酸激酶受体拮抗剂选自特异的化合物。
用于本发明方法中的化学治疗剂或天然存在的、半合成或合成治疗剂可为任何可获得的化学治疗剂或天然存在的、半合成或合成治疗剂,具体是一般用于治疗癌症的化学治疗剂。优选的化学治疗剂是选自下组:合成的小分子VEGF受体拮抗剂;小分子生长因子(GF)受体拮抗剂;EGF受体和/或VEGF受体和/或整联蛋白受体或任何其它蛋白质酪氨酸激酶受体的抑制剂,该抑制剂不属于合成小分子;EGF受体和/或VEGF受体和/或整联蛋白受体或任何其它蛋白质酪氨酸激酶受体抑制剂,该抑制剂为融合蛋白;与核酸相互作用并被分类为烷化剂的化合物或铂化合物;与核酸相互作用并被分类为蒽环类抗生素、DNA插入剂(包括DNA小沟(minor-groove)结合化合物)或DNA交联剂的化合物;抗代谢物;天然存在、半合成或合成博来霉素类抗生素(BLM-族的抗生素);DNA转录酶抑制剂,特别是拓扑异构酶I或拓扑异构酶II抑制剂;染色质修饰剂;有丝分裂抑制剂;抗有丝分裂剂;细胞周期抑制剂;蛋白酶体抑制剂;酶;荷尔蒙、荷尔蒙拮抗剂或荷尔蒙抑制剂、或类固醇生物合成抑制剂;类固醇;细胞因子、缺氧选择性细胞毒素、细胞因子抑制剂、淋巴因子、细胞因子或经口及非肠胃耐受诱导系统的抗体;载剂;化学放射敏化剂及保护剂;光化学活化药物;合成聚核苷酸或寡核苷酸,其可任选被修饰或共轭;非甾体抗炎药;细胞毒性抗生素;癌细胞表面分子的靶向抗体;金属蛋白酶抑制剂;金属;癌基因抑制剂;基因转录或RNA翻译或蛋白质表达的抑制剂;稀土元素络合物或光化学治疗剂。
在一种优选的实施方案中,在化学治疗剂或天然存在的、半合成或合成治疗剂中,优选特异性的化合物。
在一种实施方案中,以根据本发明方法治疗的疾病优选为肿瘤性疾病。在一种优选的实施方案中,该疾病选自实体肿瘤,例如泌尿生殖器癌症(例如前列腺癌、肾细胞癌、膀胱癌)、妇科癌症(例如卵巢癌、子宫颈癌、子宫内膜癌)、肺癌、肠胃道癌症(例如结肠直肠癌、胰脏癌、胃癌、食道癌、肝细胞癌、胆管细胞癌)、头及颈癌、恶性间皮瘤、乳腺癌、恶性黑色素瘤或骨头及软组织肉瘤、和血液肿瘤,例如多发性骨髓瘤、急性骨髓性白血病、慢性骨髓性白血病、骨髓增生异常综合症及急性淋巴细胞性白血病。在一种优选的实施方案中,该疾病为荷尔蒙敏感性或荷尔蒙抗性的前列腺癌、卵巢癌、或小细胞肺癌。
在另一实施例中,以根据本发明方法治疗的疾病优选为选自糖尿病视网膜病变、类风湿关节炎或牛皮癣的非肿瘤性疾病。
因此,根据本发明方法的有利的功效主要是基于联合治疗的添加及协同效应,或由于例如给予较低剂量的相关治疗剂而增进患者对治疗的耐受性。
上述意想不到的好处也可能因为,当通过肿瘤介导的蛋白质酪氨酸激酶受体的构成性活性存活信号被选择性的蛋白质酪氨酸激酶受体拮抗剂抑制时,化学治疗剂诱导了更有效的细胞凋亡。
在使用蛋白质酪氨酸激酶受体拮抗剂或其它与血管生成有关的介质拮抗剂时,例如血管内皮生长因子(VEGF)、血管渗透因子、基本的成纤维细胞生长因子(bFGF)、白细胞介素-6(IL-6)或白细胞介素-8(IL-8)、表皮生长因子(EGF)或血小板衍生生长因子(PDGF),根据本发明的方法及组合物的优点之一在于对与肿瘤有关的血管系统进行靶向治疗,以切断癌细胞的能量供应,而不是对肿瘤本身的或与肿瘤一起的治疗。
另一项优点为,可在患者中诱导或重建对化学治疗剂的敏感性,所述患者应用在治疗中丧失敏感性的化学治疗剂和VEGFR拮抗剂进行联合治疗。这特别适用于在罹患难治的多发性骨髓瘤以及用类固醇作为化学治疗剂进行治疗的患者的情况。用类固醇和VEGFR拮抗剂进行的联合治疗可使罹患难治的多发性骨髓瘤的患者恢复对类固醇的敏感性。
根据本发明,增效联合制剂是指包括一定量的选择性蛋白质酪氨酸激酶受体拮抗剂,或该活性物质的多晶型物、代谢物或可药用盐;和一定量的化学治疗剂或天然存在的、半合成或合成治疗剂;和/或放射治疗或放射免疫治疗,其中单独的各个治疗剂的量并不足以达到给予该治疗剂的联合所达到的效果,并且其中该量治疗剂的联合效果比由各个治疗剂该量下所能达到的总治疗效果更好。
从另一方面来看,本发明还涉及用于治疗涉及细胞增殖、骨髓瘤细胞的迁移或凋亡或者血管生成的疾病的联用药物(pharmaceuticalcombination),其包括选择性的特定蛋白质酪氨酸激酶受体拮抗剂,和其它化学治疗剂或天然存在的、半合成或合成治疗剂,和/或放射治疗或放射免疫治疗,作为用于同时、分开或连续使用以治疗这些疾病的联合制剂,可任选与一或多种可药用稀释剂和/或载体并用。
从另一方面来看,本发明还涉及用于治疗涉及细胞增殖、骨髓瘤细胞的迁移或凋亡或者血管生成的疾病的联用药物制剂试剂盒(pharmaceuticalcombination preparation kit),其包括治疗有效量的选择性蛋白质酪氨酸激酶受体拮抗剂或其多晶型物、代谢物或可药用盐,和治疗有效量的其它化学治疗剂或天然存在的、半合成或合成治疗剂,其特征在于该蛋白质酪氨酸激酶受体拮抗剂包括于第一隔室而另一化学治疗剂或天然存在的、半合成或合成治疗剂包括于第二隔室,因此可同时、分开或连续向需要该联合治疗的患者给药,该联合制剂试剂盒可任选进一步适合与放射治疗或放射免疫治疗的联合治疗。
根据本发明的一种实施方案,在联用药物制剂试剂盒的每个隔室中,将每种活性物质配制用于经口给药。
从另一方面来看,本发明因此还提供了选择性蛋白质酪氨酸激酶受体拮抗剂与其它化学治疗剂或天然存在的、半合成或合成治疗剂的联合,和/或适合与放射治疗或放射免疫治疗联合治疗的用途,其是用于制备治疗前文所述的疾病或症状的联用药物制剂。
在本发明的定义中,治疗剂的有效量和/或以放射治疗或放射免疫疗法的治疗处理,是指药剂的量和/或以放射治疗或放射免疫治疗法的处理,当以联合使用时可达到有效的治疗效果。
发明详述
疾病
如前文所述,可用根据本发明联合来治疗的疾病为所有涉及细胞增殖、骨髓瘤细胞的迁移或凋亡或者血管生成的疾病,其可为肿瘤性质,例如所有种类的恶性肿瘤或癌症,或非肿瘤性质,例如糖尿病视网膜病变、类风湿关节炎或牛皮癣。在癌症中,选择的特定目标症状为实体肿瘤,例如泌尿生殖器癌症(例如前列腺癌、肾细胞癌、膀胱癌)、妇科癌症(例如卵巢癌、子宫颈癌、子宫内膜癌)、肺癌、肠胃道癌症(例如结肠直肠癌、胰脏癌、胃癌、食道癌、肝细胞癌、胆管细胞癌)、头及颈癌、恶性间皮瘤、乳腺癌、恶性黑色素瘤或骨头及软组织肉瘤、及血液肿瘤,例如多发性骨髓瘤、急性骨髓性白血病、慢性骨髓性白血病、骨髓增生异常综合症及急性淋巴细胞性白血病。
根据本发明的联合治疗对于抑制肿瘤生长、存活及转移特别有效。
特别感兴趣的联合治疗为荷尔蒙敏感性或荷尔蒙抗性的前列腺癌、卵巢癌、非小细胞肺癌、小细胞肺癌或多发性骨髓瘤的治疗。
选择性蛋白质酪氨酸激酶受体拮抗剂
如前文所述,可用于本发明文中的选择性蛋白质酪氨酸激酶受体拮抗剂包括所有可通过蛋白质酪氨酸激酶受体的配体来抑制蛋白质酪氨酸激酶受体刺激或活化的物质。对于属于生长因子受体家族的蛋白质酪氨酸激酶受体而言,该刺激或活化的抑制作用抑制了表达该受体的细胞的生长。
一些与肿瘤生成有关的生长因子受体的例子为表皮生长因子受体(EGFR)、血管内皮生长因子受体(VEGFRs)、血小板衍生生长因子受体(PDGFR)、胰岛素样生长因子受体(IGFR)、神经生长因子受体(NGFR)及纤维细胞生长因子受体(FGFR)。
抑制蛋白质酪氨酸激酶受体刺激或活化是指受体的活化任何程度的减少,其并不需要完全防止或停止受体的活化。
而且,正如本发明的所定义的,抑制受体刺激或活化是指因拮抗剂与受体或其配体相互作用所产生的抑制。相互作用是指拮抗剂及受体间有效的物理或化学作用,因而抑制了蛋白质酪氨酸激酶的活性。本领域技术人员应了解,化学作用的例子已为本领域所熟知,其中该化学作用包括联合或结合,所述例子包括在拮抗剂与受体或其配体间的共价键结、离子键结、氢键结等。
增加的蛋白质酪氨酸激酶刺激或活化可由高水平的配体、受体基因扩增、增加受体转录或导致不规则受体信号传导的突变而引起。编码受体基因的扩增使结合至受体的配体增加,其能进一步刺激细胞增殖。在不发生基因扩增时,蛋白质酪氨酸激酶受体也可过度表达,这或许是由于突变增加了其转录、mRNA翻译或蛋白质的稳定性。EGFR型蛋白质酪氨酸激酶受体的突变体已在神经胶质瘤(gliomas)、非小细胞肺癌、卵巢癌及前列腺癌中识别出,其具有构成性活性的蛋白质酪氨酸激酶,显示其在这些癌症中为高水平的EGFR活性而不是EGFR过度表达(参见例如Pedersen等人,Ann.Oncol.,Vol.12(6),pp.745-60,2001)。
在根据本发明的一种实施方案中,选择性蛋白质酪氨酸激酶受体拮抗剂抑制了蛋白质酪氨酸激酶受体与其配体的结合。
配体与受体外部的胞外区域结合刺激了受体二聚作用、受体自磷酸化作用、受体内部细胞质内蛋白质酪氨酸激酶区域的活化,以及引发了在DNA合成调节中的多信号传导途径、细胞分裂、血管新生或者血管生成。通过本发明拮抗剂的存在所产生的抑制将因此降低这种刺激作用。
在根据本发明的另一实施方案中,选择性蛋白质酪氨酸激酶受体拮抗剂直接与受体结合。该拮抗剂可从外部结合至受体的胞外部分,这可能或不能抑制配体的结合,或者可以从内部结合至蛋白质酪氨酸激酶区域。该拮抗剂的例子包括但不限于,生物分子例如该受体的特异性抗体(及其功能相当的同等物),以及可直接作用在受体细胞质区域的合成的激酶抑制剂(例如名称为“小分子酪氨酸激酶激抑制剂”)。小分子酪氨酸激酶激抑制剂的非详尽列表请参见Laid&Cherrington,Expert Opinion Invest.Drugs,Vol.12,No.1,2003文献,其内容在此引入本文作为参考。
其它蛋白质酪氨酸激酶受体拮抗剂可容易的通过熟知的方法来测定。本发明所用的选择性受体拮抗剂抑制了受体的蛋白质酪氨酸激酶活性,所述受体通常与磷酸化有关。因此,磷酸化分析例如可有效的用于测定本发明文中所用的拮抗剂。此外,也可利用检测受体表达的方法。这些方法包括检测蛋白质表达的免疫组织化学、检测基因扩增的萤光原位杂交、竞争性放射配体结合分析、固定基质印迹技术(例如RNA印迹及DNA印迹)、逆转录酶聚合酶连锁反应及ELISA。
根据本发明,选择性蛋白质酪氨酸激酶受体拮抗剂优选为下述抑制剂或其多晶型物、代谢物或可药用盐,该抑制剂选自VEGFR1至3,PDGFRα和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂,并且为另一种src酪氨酸激酶家族成员特别是src、lck、lyn和fyn的拮抗剂。选择性蛋白质酪氨酸激酶受体拮抗剂,
还可以是下述复合物中至少一种的拮抗剂,所述复合物由细胞周期调节蛋白依赖性激酶与其特异性的细胞周期调节蛋白或与病毒细胞周期调节蛋白所形成的,例如CDK1、CDK2、CDK3、CDK4、CDK5、CDK6、CDK7、CDK8及CDK9与其特异性的细胞周期调节蛋白A、B1、B2、C、D1、D2、D3、E、F、G1、G2、H、I及K所形成的,和/或另一种旁分泌IL-6分泌作用的抑制剂。
在根据本发明的另一实施方案中,活性物质的联合是希望用于治疗涉及血管生成的肿瘤疾病。
肿瘤的血管生成在人类的恶性肿瘤发展上扮演一个重要的角色。抑制该过程在癌症的治疗上被认为是最佳的治疗点。血管内皮生长因子受体2(VEGFR-2)的信号传导被认为在肿瘤血管生成中内皮细胞的增殖、存活及迁移上扮演一个重要角色。
在这一项目中,已经研究得到有效及可经口的低分子量VEGFR-2拮抗剂,其可有效的作为治疗涉及细胞增殖、骨髓瘤细胞的迁移或凋亡或者血管生成的疾病的新型化合物,特别是作为一种新颖的癌症治疗剂。这些拮抗剂因此也是受体活性的抑制剂。有些拮抗剂也可为其它生长因子受体例如VEGFR3、PDGFRα和β、FGFR1、2和3、EGFR、HER2、IGF1R、HGFR或c-Kit的拮抗剂,有些也可为src酪氨酸激酶家族成员src、lck、lyn或fyn的拮抗剂。
这些化合物公开于WO 02/36564、WO 99/52869、WO 00/18734、WO00/73297、WO 01/27080、WO 01/27081及WO 01/32651。关于任何与揭示这些相关的特定化合物各方面有关的引用文献在此引入本文作为参考。
下列化合物特别具代表性且为VEGFR-2及lck的联合抑制剂,其在本发明定义中可作为蛋白质酪氨酸激酶受体拮抗剂。
(A)(Z)-3-(1-(4-(N-(2-二甲基氨基-乙基)-N-甲基磺酰基-氨基)-苯基氨基)-1-苯基-亚甲基)-2-吲哚满酮(indolinone);
(B)(Z)-3-(1-(4-(N-(3-二甲基氨基-丙基)-N-丙酰基-氨基)-苯基氨基)-1-苯基-亚甲基)-2-吲哚满酮;
(C)(Z)-3-(1-(4-(二甲基氨基-甲基)-苯基氨基)-1-苯基-亚甲基)-5-(丁基氨基甲酰基)-2-吲哚满酮;
(D)(Z)-3-(1-(4-(二甲基氨基-甲基)-苯基氨基)-1-苯基-亚甲基)-5-(环己基甲基-氨基甲酰基)-2-吲哚满酮;
(E)(Z)-3-(1-(4-(N-甲基磺酰基-N-(2-二甲基氨基-乙基)-氨基)-苯基氨基)-1-苯基-亚甲基)-5-(环己基甲基-氨基甲酰基)-2-吲哚满酮;
(F)(Z)-3-(1-(4-(丁基氨基甲基)-苯基氨基)-1-苯基-亚甲基)-5-(环己基甲基-氨基甲酰基)-2-吲哚满酮;
(G)(Z)-3-(1-(4-(吡咯烷-1-基-甲基)-苯基氨基)-1-苯基-亚甲基)-5-(环己基甲基-氨基甲酰基)-2-吲哚满酮;
(H)(Z)-3-(1-(4-(二乙基氨基甲基)-苯基氨基)-1-苯基-亚甲基)-5-(环己基甲基-氨基甲酰基)-2-吲哚满酮;
(I)(Z)-3-(1-(4-(二乙基氨基甲基)-苯基氨基)-1-苯基-亚甲基)-5-(N-(3-氯苄基)-氨基甲酰基)-2-吲哚满酮;
(J)(Z)-3-(1-(4-(二乙醇胺基甲基)-苯基氨基)-1-苯基-亚甲基)-5-(丁基氨基甲酰基)-2-吲哚满酮;
(K)(Z)-3-(1-(4-(二甲基氨基甲基)-苯基氨基)-1-苯基-亚甲基)-5-(N-(3-氯苄基)-氨基甲酰基)-2-吲哚满酮;
(L)(Z)-3-(1-(4-(N-乙酰基-N-(2-二甲基氨基-乙基)-氨基)-苯基氨基)-1-苯基-亚甲基)-5-(N-(3-氯苄基)-氨基甲酰基)-2-吲哚满酮;
(M)(Z)-3-(1-(4-(丁基氨基甲基)-苯基氨基)-1-苯基-亚甲基)-5-(N-(3-氯苄基)-氨基甲酰基)-2-吲哚满酮;
(N)(Z)-3-(1-(4-(二甲基氨基甲基)-苯基氨基)-1-苯基-亚甲基)-6-甲氧羰基-2-吲哚满酮;
(O)(Z)-3-(1-(4-(N-(3-二甲基氨基-丙基)-N-乙酰基-氨基)-苯基氨基)-1-苯基-亚甲基)-6-甲氧羰基-2-吲哚满酮;
(P)(Z)-3-(1-(4-(乙基氨基甲基)-苯基氨基)-1-苯基-亚甲基)-6-甲氧羰基-2-吲哚满酮;
(Q)(Z)-3-(1-(4-(1-甲基-咪唑-2-基)-苯基氨基)-1-苯基-亚甲基)-6-甲氧羰基-2-吲哚满酮;
(R)(Z)-3-(1-(4-(N-(二甲基氨基甲基羰基)-N-甲基-氨基)-苯基氨基)-1-苯基-亚甲基)-6-甲氧羰基-2-吲哚满酮;
(S)(Z)-3-(1-(4-(甲基氨基甲基)-苯胺基)-1-苯基-亚甲基)-6-甲氧羰基-2-吲哚满酮;
(T)(Z)-3-(1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯基氨基)-1-苯基-亚甲基)-6-甲氧羰基-2-吲哚满酮;以及
(U)4-(4-溴-2-氟苯胺基)-6-甲氧基-7-(1-甲基哌啶-4-基甲氧基)-喹唑啉及其多晶型物、代谢物或可药用盐。
化合物(A)至(B)公开于WO 00/18734中,化合物(C)至(M)公开于WO00/73297中,化合物(N)至(T)公开于WO 01/27081中,化合物(U)公开于WO01/32651中。
特别具代表性的为下述抑制剂及其多晶型物、代谢物或可药用盐,该抑制剂为有效及可经口的低分子量VEGFR1至3、PDGFRα和β、FGFR1、2和3、EGFR、HER2、IGF1R、HGFR或c-Kit的拮抗剂,其进一步为src酪氨酸激酶家族成员特别是src、lck、lyn和fyn的拮抗剂,进一步为由细胞周期调节蛋白依赖性激酶与其特异性的细胞周期调节蛋白或与病毒细胞周期调节蛋白所形成的复合物的拮抗剂,以及进一步为旁分泌IL-6分泌作用的抑制剂,例如公开于WO 01/27081中作为例子的473号化合物。上表中(T)这一化合物为3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮。
与上述其它示例性化合物相比较,该化合物为特别优选的化合物,因为其是高效的抑制剂并且具有优选的毒理学性质。
特别优选的为该化合物的单乙磺酸盐,称为3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的单乙磺酸盐,其揭示于未公开的德国专利申请DE 102 33 500.1、未公开的PCT/03/07822及未公开的美国专利申请10/623,971中。
根据未公开的德国专利申请DE 102 33 500.1、未公开的PCT/03/07822及未公开的美国专利申请10/623,971中所揭示的,3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的单乙磺酸盐具有下列结构:
化合物MES(T)
(化合物(T)的单乙磺酸盐)
该化合物可通过选择适合的制备条件来选择性制得,优选的是以其结晶半水合物的形式。
该化合物的特征为熔点T=305±5℃(使用DSC=差示扫描热计,METTLER-TOLEDO DSC82装置来测量,加热速率:10K/min)。
可使用下述的步骤来制备3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的单乙磺酸盐。
用于制备该3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的单乙磺酸盐的起始物质可为3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的游离碱,其可根据现有技术中已知的方法例如01/27081中所述的来制得。
因此,第一步骤根据WO 01/27081中所描述的,如下制备3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮。
将10.5g(30.0mmol)1-乙酰基-3-(1-乙氧基-1-苯基亚甲基)-6-甲氧羰基-2-吲哚满酮(如WO 01/27081中所述制备)及8.60g(33.0mmol)的N-[(4-甲基-哌嗪-1-基)-甲基羰基]-N-甲基-对-苯二胺(如WO 01/27081中所述制备)溶于80ml二甲基甲酰胺中,并于80℃下混合1小时。待冷却后,加入6.50ml的哌啶,然后于室温下混合2小时。加入水,吸去所产生的沉淀上的水,将沉淀以少量的水再次清洗。将残余物悬浮于200ml甲醇中,吸去液体并将剩余的残余物以冷水及乙醚清洗。将所得到的产物于110℃下真空干燥。
回收产物:12.4g(理论值的77%)
红外线光谱学:1610,1655,1711cm-1
Tsmp=253℃
分子式:C31H33N5O4
电喷雾质谱仪:m/z=540[M+H]+
元素分析:
计算值:C68.99H6.16N12.98
实测值:C68.32H6.29N12.85
第二步骤,根据DE 10233500.1中所揭示的,如下制备3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的单乙磺酸盐。
将605g(1.12mol)的3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮悬浮于9升的甲醇中,并加热至50℃。加入183.7g(1.121mol)的70%的乙磺酸盐水溶液。将得到的溶液冷却至40℃并与4.5升的叔丁基甲基醚混合。数分钟后有结晶产生。将整个溶液于室温下混合16小时,以达到完全沉淀。待冷却至10℃时,将液体抽出,并以2升的叔丁基甲基醚清洗沉淀并于40℃下真空干燥。
回收产物:638g(理论值的87.6%)
Tsmp=305±5℃(DSC 10K/min)
纯度(以HPLC测量):99.4%
水含量:1.0bis2.0%(KF)
3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的单乙磺酸盐非常易于溶于生理上可接受增溶剂中。
此外,化合物MES(T)在小鼠中为可经口生物利用的化合物。
3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的单乙磺酸盐抑制人VEGFR-2激酶(huVEGFR-2)的IC50为21nM,鼠VEGFR-2激酶(muVEGFR-2)的IC50为13nM,及VEGFR刺激的内皮细胞的增殖作用(HUVEC:IC50=9nM,HSMEC:IC50=12nM)。
而且,血管生成信号传导中两个重要的分裂激酶区域家族中的成员,FGFR-1及PDGFRα,也可被该化合物抑制,IC50分别为69nM及59nM。
如下表I所示,当对许多不同的激酶进行试验时,化合物MES(T)具高度选择性。
表I
另外值得注意的是该特异性拮抗剂对受体VEGFR-2具有长持续性的抑制作用。在分子及细胞水平上,将化合物MES(T)短暂的暴露于细胞(例如内皮细胞)便足以抑制受体激酶本身及下游信号传导分子(例如MAP激酶,MAPK)的活化及细胞增殖作用,至少达32小时。
下列的实验结果证实了此种长持续性抑制效果。为了测定由MES(T)在受体上所引发的抑制作用的持续性,进行了冲刷(washout)实验。将HUVEC及NIH 3T3KDR细胞暴露于MES(T)一段限定的时间,将MES(T)冲掉,并在一段不同的时间段后分析细胞增殖作用(HUVEC)或VEGFR-2活化/磷酸化作用。如图1所示,在暴露于50nM MES(T)1小时后,VEGFR-2的自磷酸化作用被阻断了至少32小时。在无MES(T)8小时、24小时及32小时后,细胞再度以VEGF刺激并分析受体活化现象。即使在32小时后,仍没有观测到受体活性。由此强烈的显示出即使在MES(T)血浆浓度非常低时,MES(T)对受体激酶仍具有持续性的效用。
下列在活体异种移植实验结果证实了化合物MES(T)在肿瘤细胞上的作用。为了测定此作用,以化合物MES(T)经口治疗带有皮下FaDu肿瘤(FaDu肿瘤是由人的鳞状肿瘤细胞所构成)的裸鼠。如图2所示,当以100mg/kg的剂量每周二次治疗小鼠时,肿瘤生长降低的T/C(肿瘤/控制)值为31%。若增加至200mg/kg每周二次的经口剂量,预计其抗肿瘤效果会更好。
这说明该拮抗剂特别适合与其它化学治疗剂或天然存在的、半合成或合成治疗剂,和/或放射线治疗或放射免疫治疗进行连续的联合给药和/或联合治疗。该拮抗剂的治疗方案可以为,例如一天给药/一天不给药、一天给药/二天不给药、一星期给药/一星期不给药或甚至二星期给药/二星期不给药的交替治疗。
因此,3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的单乙磺酸盐显然是一种有效并可口服的VEGFR-2激酶抑制剂及抗肿瘤剂。
有关于本发明的各个方面,适合的选择性蛋白质酪氨酸激酶受体拮抗剂也可以是选择性蛋白质酪氨酸激酶受体拮抗剂在活体中的活性代谢物。例如,在活体中蛋白质酪氨酸激酶受体拮抗剂的活性代谢物3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮可为未酯化的化合物3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-羰基-2-吲哚满酮。
在本发明定义中,所有上述作为例子的化合物,特别是化合物(T)及其单乙磺酸盐MES(T),也可用作单一疗法以治疗上述疾病,即所有涉及细胞增殖、骨髓瘤细胞的迁移或凋亡或者血管生成的疾病,其可为肿瘤性质,例如所有类型的恶性肿瘤或癌症,或非肿瘤性质例如糖尿病视网膜病变、类风湿关节炎或牛皮癣。在癌症中,作为单一疗法的选择性特定目标疾病为实体肿瘤,例如泌尿生殖器癌症(例如前列腺癌、肾细胞癌、膀胱癌)、妇科癌症(例如卵巢癌、子宫颈癌、子宫内膜癌)、肺癌、肠胃道癌症(例如结肠直肠癌、胰脏癌、胃癌、食道癌、肝细胞癌、胆管细胞癌)、头及颈癌、恶性间皮瘤、乳腺癌、恶性黑色素瘤或骨头及软组织肉瘤、及血液肿瘤,例如多发性骨髓瘤、急性骨髓性白血病、慢性骨髓性白血病、骨髓增生异常综合症及急性淋巴细胞性白血病。其中特别感兴趣的为治疗荷尔蒙敏感性或荷尔蒙抗性的前列腺癌、卵巢癌、非小细胞肺癌、小细胞肺癌、或多发性骨髓瘤。上述作为例子的化合物对于抑制肿瘤生长、存活及转移特别有效。
其它化学治疗剂或天然存在的、半合成或合成治疗剂
该化合物优选选自但不限于下列种类的化合物及化合物的例子,而该列项不应视为一种限制。
合成的小分子VEGF受体拮抗剂
特别感兴趣的合成小分子VEGF受体拮抗剂为2型VEGF受体的拮抗剂,其也为基本的成纤维细胞生长因子(bFGF)及血小板衍生生长因子(PDGF)的拮抗剂。代表性的化合物,例如吲哚满酮衍生物,如公开于WO 02/36564、WO 99/52869、WO 00/18734、WO 00/73297、WO 01/27080、WO 01/27081及WO 01/32651中的那些。其它代表性的小分子VEGF受体拮抗剂为如描述于WO 01/60814、WO 99/48868及WO 98/35958中的化合物,及特别是vatalanib(PTK-787/ZK222584)、SU-5416、SU-6668、SU-11248、SU-14813、AZD-6474、AZD-2171、CP-547632、CEP-7055、AG-013736、IM-842(L-谷氨酰及L-色胺酸的二酞)或GW786034。
小分子生长因子(GF)受体拮抗剂
特别感兴趣的小分子生长因子(GF)受体拮抗剂为蛋白质酪氨酸激酶(PTK)受体的拮抗剂,特别是表皮生长因子(EGF)拮抗剂及表皮生长因子(EGF)和2型人表皮生长因子(2型的HE)受体的双重拮抗剂,或促分裂原活化蛋白激酶(MAPK)的拮抗剂。EGFR及HER-2双重拮抗剂的代表性化合物为,例如描述于WO 00/78735及WO 02/50043的喹唑啉衍生物、gefitinib、erlotinib、CI-1033及GW-2016。EGFR单一拮抗剂的代表性化合物为iressa(ZD-1839)、塔赛瓦(tarceva)(OSI-774)、PKI-166、EKB-569、HKI-272及赫赛汀(herceptin)。促分裂原活化蛋白激酶(MAPK)拮抗剂的代表性化合物为BAY-43-9006(一种Raf蛋白质激酶家族的抑制剂)及BAY-57-9006(一种Kdr酪氨酸激酶抑制剂)。
在此类中优选的化合物为其公开于WO 02/50043实施例1(10)中作为示例性化合物的喹唑啉衍生物,即4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-((S)-四氢呋喃-3-基氧基)-喹唑啉,或其互变异构体、立体异构体及盐类,特别是带有无机或有机酸或碱的其生理上可接受的盐类。更优选的为该化合物的二马来酸盐,其可容易的以下列步骤来制得。将6.0kg(12.35mol)的4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-((S)-四氢呋喃-3-基氧基)-喹唑啉于84升的乙醇中加热至70℃。加入2.94kg(25.31mol)马来酸在36升乙醇中的溶液。在开始结晶时,将反应混合物冷却至20℃并搅拌2小时。将反应混合物冷却至0℃并搅拌3小时。将沉淀抽吸过滤。将滤饼以19升的乙醇清洗并于40℃下真空干燥。
在此类中另一优选的化合物为4-[(3-氯-4-氟苯基)氨基]-6-{[4-(4-[(高吗啉(homomorpholin)-4-基)-1-氧代-2-丁烯-1-基]氨基}-7-[(S)-(四氢呋喃-3-基)氧基]-喹唑啉或其盐类。该化合物的化学结构为
使用下列制备条件以三个步骤可得到该化合物。
·起始化合物I:4-[(3-氯-4-氟-苯基)氨基]-6-[(二乙氧基-磷酸基)-乙酰基氨基]-7-[(S)-(四氢呋喃-3-基)氧基]-喹唑啉的制备
将60.07g的二乙氧磷酸基醋酸置于750ml的N,N-二甲基甲酰胺中,并于环境温度下与48.67g的N,N′-羰基二咪唑混合。待气体停止产生后,加入90.00g的4-[(3-氯-4-氟-苯基)氨基]-6-氨基-[(S)-(四氢呋喃-3-基)氧基]-喹唑啉,并于环境温度下搅拌反应混合物4-5小时,直到反应完成。然后将反应混合物以水浴缓慢加热,并分两次加入750ml的水。将该浓稠的悬浮液搅拌过夜,第二天早晨另外加入350ml的水。将悬浮液以冰浴冷却,搅拌一小时并抽吸过滤。将滤饼以240ml的N,N-二甲基甲酰胺/水(1∶2)及240ml二异丙醚再次清洗,并以循环式空气干燥机于40℃下干燥。
产率:117.30g(理论值的88%)
Rf值:0.37(硅胶,二氯甲烷/甲醇=9∶1)
质谱(ESI+):m/z=553,555[M+H]+
·起始化合物II:高吗啉-4-基-乙醛-盐酸的制备
于80℃下搅拌(2.5小时)4-(2,2-二甲氧基-乙基)-高吗啉与半浓盐酸进行制备。将得到的溶液直接如下述进一步反应。
·最终化合物:4-[(3-氯-4-氟-苯基)氨基]-6-{[4-(高吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-7-[(S)-(四氢呋喃-3-基)氧基]-喹唑啉的制备
于环境温度下将3.9g 4-[(3-氯-4-氟苯基)氨基]-6-[2-(二乙氧基-磷酸基)-乙酰基氨基]-7-[(S)-四氢呋喃-3-基])氧基)-喹唑啉(起始化合物I)在20ml四氢呋喃中的溶液加到300mg氯化锂在20ml水的溶液中。然后加入2.35g的氢氧化钾薄片,并以冰/丙酮冷却浴将反应混合物冷却至-3℃。然后于0℃下将上步骤所得的高吗啉-4-基-乙醛-盐酸(起始化合物II)溶液,于五分钟内逐滴的加入。加完后,于0℃下另外搅拌反应混合物10分钟,并于环境温度下另搅拌1小时。然后加入100ml的乙酸乙酯并将水相分离出。将有机相以饱和的氯化钠溶液清洗,以硫酸镁干燥并蒸发。通过色谱法用硅胶柱使用乙酸乙酯/甲醇/浓甲醇氨为洗脱液纯化粗产物。将获得的产物与少许二异丙醚搅拌、抽吸过滤并干燥。
产率:2.40g(理论值的68%)
Rf值:0.09(硅胶,二氯甲烷/乙酸乙酯/甲醇/浓氨水溶液=90∶10∶1)
质谱:(ESI+):m/z=542,544[M+H]+
不属于合成小分子的EGF受体和/或VEGF受体和/或整联蛋白受体或任何其它蛋白质酪氨酸激酶受体的抑制剂
EGF受体和/或VEGF受体和/或整联蛋白受体或任何其它蛋白质酪氨酸激酶受体的抑制剂,该抑制剂不属于合成小分子,特别感兴趣的为EGF受体和/或VEGF受体和/或整联蛋白(integrin)受体或任何其它蛋白质酪氨酸激酶受体的单克隆抗体。代表性的化合物,例如有阿曲生坦(atrasentan)(整联蛋白拮抗剂)、美罗华(rituximab)、西妥昔单抗(cetuximab)、AvastinTM(贝伐单抗(bevacizumab))、ICM-1C11、erbitux(C-225)、DC-101、EMD-72000(人化的EGF受体特异性单克隆抗体)、vitaxin(α、β3整联蛋白的抗体)及imatinib(c-kit抑制剂)。在这方面,对于可特异性识别相关受体上其抗原表位的单克隆抗体特别感兴趣。可成功的用于体外及动物模型的这些抗体,作为单一药物疗法时对患者没有令人满意的效果。当在临床试验中使用其它的抗血管生成或EGF受体拮抗剂而不是抗体时,得到相似的结果。若一些特定位点被阻断,肿瘤似乎可使用其它细胞表面分子来补偿所述的原有阻断。因此,肿瘤在各种抗血管生成或抗增殖治疗期间并没有真正的缩小。基于这些理由,针对这种问题建议在这种情况下采用联合治疗,例如使用单克隆抗体与特异的细胞毒性剂或化学治疗剂或与放射治疗或放射免疫治疗并用。事实上,临床试验已显示这些联合治疗比同等的单一给药更为有效。
EGF受体和/或VEGF受体和/或整联蛋白受体或任何其它蛋白质酪氨
酸激酶受体的抑制剂,其为融合蛋白
本类的代表性化合物为,例如Regeneropn and Aventis医药公司所开发名称为VEGFtrap的化合物。
与核酸相互作用,并且分类为烷化剂的化合物或铂化合物
对于与核酸相互作用并且分类为烷化剂的化合物或铂化合物在治疗肿瘤性质疾病中的用途已有描述。该类化合物的代表性种类和例子为美法仑(melphalan)、环磷酸胺(cyclophosphamide)、沙膦酸(oxazaphosphorine)、顺铂(cisplatin)、卡铂(carboplatin)、奥沙利铂(oxaliplatin)、沙铂(satraplatin)、四铂(tetraplatin)、异丙铂(iproplatin)、丝裂霉素(mitomycin)、链佐星(streptozocin)、卡莫司汀(carmustine)(BCNU)、洛莫司汀(lomustine)(CCNU)、白消安(busulfan)、异环磷酰胺(ifosfamide)、链佐星(streptozocin)、塞替派(thiotepa)、苯丁酸氮芥(chlorambucil)、氮芥(nitrogen mustards)(例如双氯乙基甲胺(mechlorethamine))、乙撑亚胺(ethyleneimine)化合物及烷基磺酸盐。
与核酸相互作用并且被分类为蒽环类、DNA插入剂或DNA交联剂的
化合物
与核酸相互作用并且被分类为蒽环类、DNA插入剂(包括DNA小沟结合化合物)或DNA交联剂的化合物也可有效地用于治疗肿瘤性疾病。该化合物代表性的种类及例子为柔红霉素(daunorubicin)、多柔比星(doxorubicin)(阿霉素adriamycin)、脂质体阿霉素(liposomal doxorubicin)(盐酸多柔比星脂质体doxil)、表柔比星(epirubicin)、伊达比星(idarubicin)、米托蒽醌(mitoxantrone)、安吖啶(amsacrine)、更生霉素(dactinomycin)、偏端霉素(distamycin)及衍生物、纺锤菌素(netropsin)、pibenzimol、丝裂霉素(mitomycin)、CC-1065(链霉菌(Streptomyces zelensis)发酵产物)、duocarmycin、光辉霉素(mithramycin)、色霉素(chromomycin)、橄榄霉素(olivomycin)、phtalanilide(普罗帕脒(propamidine)、二脒草替(stilbamidine))、氨茴霉素(anthramycin)、氮丙啶(aziridine)或亚硝脲及其衍生物。
抗代谢物
感兴趣的抗代谢物的代表性种类有嘧啶及嘌呤类似物或拮抗剂,例如氟嘧啶及硫嘌呤,或核苷二磷酸还原酶的抑制剂。其代表性的化合物为,例如阿糖胞苷(cytarabine)、5-氟尿嘧啶(5-FU)、乌拉莫司汀(uracil mustard)、氟达拉滨(fludarabine)、吉西他滨(gemcitabine)、卡培他滨(capecitabine)、巯嘌呤(mercaptopurine)、克拉屈滨(cladribine)、硫鸟嘌呤(thioguanine)、甲氨蝶呤(methotrexate)、喷司他丁(pentostatin)、羟脲(hydroxyurea)或叶酸。
天然存在、半合成或合成博来霉素类抗生素(BLM-族的抗生素)
感兴趣的代表性种类及化合物为腐草霉素(phleomycin)、博来霉素、博来霉素衍生物及盐类、CHPP、BZPP、MTPP、BAPP、liblomycin。这些药剂被认为是通过染色体DNA的降解或RNA的降解(特别是选择性的tRNA股分裂(strand scission))来调节其治疗效果。
DNA转录酶抑制剂,特别是拓扑异构酶I或拓扑异构酶II的抑制剂。
感兴趣的化合物的代表性种类及例子为吖啶(acridine)及吖啶衍生物、利福霉素(rifamycin)、放线菌素(actinomycin)、甲烯土霉素(adramycin)、喜树碱(camptothecin)(伊立替康(irinotecan)或camptosar、托泊替康(topotecan)、安吖啶(amsacrine)及类似物,及三环甲酰胺(tricyclic carboxamides)。
染色质修饰剂
感兴趣的化合物代表性种类及例子为组蛋白脱乙酰基酶抑制剂例如SAHA(suberoyl anilide hydroxamic acid)、MD-275、曲古抑菌素A(trichostatinA)、CBHA(M-羧基肉桂酸双羟酰胺(M-carboxycinnamic acidbishydroxamide))、LAQ824或丙戊酸(valproic acid)。
有丝分裂抑制剂、抗有丝分裂剂或细胞周期抑制剂
感兴趣的化合物代表性种类及例子为来源于植物的抗癌剂,例如紫杉烷类(taxane)(紫杉醇(paclitaxel)或泰素(taxol)、多西紫杉醇(docetaxel)或泰索帝(taxotere))、长春生物碱类(诺维本(navelbine)、长春碱(vinblastin)、长春新碱(vincristin)、长春地辛(vindestine)或长春瑞滨(vinorelbine))、托酚酮(tropolone)生物碱(秋水仙素及衍生物)、大环内酯(macrolide)(美登素(maytansine)、柄型菌素(ansamitocin)、根霉素(rhizoxin)),抗有丝分裂性肽(拟茎点霉毒素(phomopsin)、多拉司他汀(dolastatin))、鬼臼乙叉甙(epipodophyllotoxin)或鬼臼毒素(podophyllotoxin)衍生物(依托泊苷(etoposide)、替尼泊苷(teniposide))、斯的甘辛(steganacin)及抗有分裂氨基甲酸酯衍生物(考布他汀(combretastatin)、苯丙氨乙茶碱(amphetinile))或丙卡巴肼(procarbazine)。这些化合物为cdk抑制剂、微管蛋白(tubulin)结合剂或波罗样激酶(polo-like kinase)抑制剂。
蛋白酶体抑制剂
属于该类的代表性化合物有例如VelcadeTM(bortezomib或PS-341)。
酶
感兴趣的化合物代表性种类及例子为例如天门冬酰胺酶(asparaginase)、聚乙二醇化天门冬酰胺酶(pegylated asparaginase)(培门冬酶(pegaspargase))及胸腺嘧啶-磷酸酶抑制剂。
荷尔蒙、荷尔蒙拮抗剂或荷尔蒙抑制剂、或类固醇生物合成抑制剂
感兴趣的荷尔蒙代表性种类及例子为,例如孕酮(gestagen)及雌激素,例如雌莫司汀(estramustine)或T-66、或甲地孕酮(megestrol)。感兴趣的荷尔蒙拮抗剂代表性种类和例子为,例如抗雄激素如氟他米特(flutamide)、康士得(casodex)、尼鲁米特(anandron)及醋酸环丙孕酮(cyproterone acetate),芳香酶抑制剂例如amonogluthetimide、阿那曲唑(anastrozole)、福美坦(formestan)和来曲唑(letrozole)、GNrH类似物如亮丙瑞林(leuprorelin)、布舍瑞林(buserelin)、戈舍瑞林(goserelin)及曲普瑞林(triptorelin),抗雌激素剂如他莫昔芬(tamoxifen)以及特别是其柠檬酸盐、屈洛昔芬(droloxifene)、曲沃昔芬(trioxifene)、雷洛昔芬(raloxifene)、秦哚昔芬(zindoxifene)、17β-雌二醇衍生物(ICI 164,384及ICI 182,780)、氨鲁米特(aminoglutethimide)、福美坦(formestane)、法倔唑(fadrozole)、非那雄胺(finasteride)、或酮康唑(ketoconazole)或LH-RH拮抗剂亮丙瑞林。类固醇荷尔蒙抑制剂特别适合作为乳腺癌及前列腺癌的治疗。
类固醇
感兴趣的代表化合物,例如泼尼松(prednisone)、泼尼松龙(prednisolone)、甲基泼尼松龙(methylprednisolone)、地塞米松(dexamethasone)、布地奈德(budenoside)、氟可龙(fluocortolone)及曲安西龙(triamcinolone)。类固醇可用于治疗某些癌症的理由及以类固醇治疗癌症所得到的效果取决于所治疗的癌症的类型。以实体肿瘤的治疗而言,类固醇首先是用于控制症状。以转移性脑瘤而言,类固醇是属于降低水肿的标准治疗。其也可用于控制肿瘤病变周围的发炎现象。在治疗淋巴细胞株的血液恶性肿瘤(所有,非何杰金士淋巴瘤、骨髓瘤),因其细胞溶解效应,类固醇可单独或与传统化学治疗剂联合用于抗肿瘤治疗。天然存在的类固醇四氢皮质醇、合成的环状糊精衍生物β-环状糊精十四硫酸盐(tetradecasulfate)及四环素衍生物米诺环素(minocycline),因为其的抗血管生成活性,已建议与细胞毒性标准抗癌治疗例如铂、美法仑(melphalan)、环磷酰胺、阿霉素、博来霉素或放射线基本治疗联合用于联合治疗(Teicher等人,Cancerresearch,vol.52,pp.6702-6704,1992)。已经测试类固醇地塞米松用于多发性骨髓瘤的初级治疗(Dimopoulos等人,Blood,Vol.80(4),pp.887-890,1992)。而且,在最近使用地塞米松与沙利度胺(thalidomide)联合治疗的评估研究中,已揭示一种已知其活性为TNF-α合成抑制剂及细胞因子拮抗剂的物质。这些研究关注于先前无法治疗的多发性骨髓瘤(Weber等人,Journal ofClinical Oncology,Vol.21,No.1,pp.16-19,2003)、新诊断出的骨髓瘤(Rajkumar等人,Journal of Clinical Oncology,Vol.20,No.21,pp.4319-4323,2002)及高强度化疗后的多发性骨髓瘤(Ann.Oncol.,Vol.13,No.7,pp.1116-1119,2002)。
在本发明的所有方面,适合作为联合治疗的类固醇包括但不限于泼尼松、泼尼松龙、甲基泼尼松龙、地塞米松、布地奈德、氟可龙及曲安西龙。优选的类固醇为地塞米松。
细胞因子、缺氧选择性细胞毒素、细胞因子抑制剂、淋巴因子、抗细
胞因子抗体或经口及非肠胃耐受诱导剂
感兴趣的化合物代表性种类及例子为,例如干扰素(特别是干扰素β)、白介素(特别是IL-10及12)、抗TNF-α抗体(依那西普(etanercept))、免疫调节药剂(或IMiDs,特别是TNF-α生成抑制剂,例如沙利度胺(thalidomide)及其R-及S-对映异构体及衍生物,或revimid(CC-5013)、白细胞三烯(leukotrien)拮抗剂、丝裂霉素C、aziridoquinone(BMY-42355,AZQ,EO-9)、2-硝基咪唑(米索硝唑(misonidazole)、NLP-1、NLA-1)、硝基吖啶(nitroacridine)、硝基喹啉、硝基吡唑吖啶、“双官能”硝基芳香化合物RSU-1069、RB-6145、经硝基芳香化合物灭活的芥末(CB-1954)、氮芥的N-氧化物例如氧氮芥(nitromin)、氮芥的金属络合物、抗-CD3或抗-CD25抗体、已获得耐受性的基因改性的肠内细菌。
载剂
感兴趣的化合物代表种类为,例如二膦酸盐及其衍生物,例如米诺膦酸(minodronic acid)(YM-529、Ono-5920、YH-529)、唑来膦酸(zoledronic acid)单水合物、伊班膦酸钠水合物(ibandronate sodium hydrate)、氯屈磷酸二钠(clodronate disodium)。在临床发展中这些化合物最近已被证明可治疗从乳腺癌/肺癌转移的骨癌以及多发性骨髓瘤(Drugs of the Future 2002,27(10),pp.935-941)。
化学放射敏化剂及保护剂
感兴趣的化合物代表种类为,例如硝基咪唑(甲硝唑(metronidazole)、米索硝唑(misonidazole)、苄硝唑(benznidazole)、硝唑吗啉(nimorazole))及其它硝基芳基化合物,例如RSU-1069、硝酰基及N-氧化物,如SR-4233、卤化嘧啶类似物(溴去氧尿嘧啶核苷(bromodeoxyuridine)、碘去氧尿嘧啶核苷(iododeoxyuridine))或硫代磷酸盐(如WR-2721)作为放射线保护剂。
光化学活化药物
感兴趣的代表化合物及种类为,例如卟菲尔钠(porfimer)、光敏素(photofrin)、苯并卟啉(benzoporphyrin)衍生物、脱镁叶绿酯(pheophorbide)衍生物、部花青(merocyanin540,MC-540)、及tin etioporpurin。
合成的聚或寡核苷酸
对于经改性或共轭的合成的聚或寡核苷酸也很感兴趣。代表的聚核苷酸或寡核苷酸种类为,例如反模板RNA及DNA(合成或经化学改性的寡核苷酸,其本身不具有活性但能与功能性模板引物竞争酶上的特异性结合位点,因而阻断其功能)、反义RNA及DNA(特定序列的蛋白质合成抑制剂,其可与给出的m-RNA的互补碱基序列杂交,例如oblimersen),特别是针对癌基因、生长因子基因或肿瘤抑制基因、抗基因的聚或寡核苷酸(能形成三链DNA结构的寡核苷酸,其可选择性抑制靶基因的转录)及核酶(ribozyme)。
非甾体抗炎药物
在本发明定义中,非甾体抗炎药物(NSSAID)也代表一种可用于联合治疗的感兴趣的化合物种类。特别感兴趣的为环氧化酶(COX)抑制剂为,例如非选择性COX抑制剂乙酰水杨酸、美沙拉秦(mesalazin)、布洛芬(ibuprofen)、萘普生(naproxen)、氟比洛芬(flurbiprofen)、菲诺洛芬(fenoprofen)、芬布芬(fenbufen)、酮洛芬(ketoprofen)、吲哚洛芬(indoprofen)、吡洛芬(pirprofen)、卡洛芬(carprofen)、奥沙普秦(oxaprozine)、普拉洛芬(pranoprofen)、咪洛芬(miroprofen)、硫噁洛芬(tioxaprofen)、舒洛芬(suprofen)、阿明洛芬(alminoprofen)、噻洛芬酸(tiaprofenic acid)、氟洛芬(fluprofen)、吲哚美辛(indomethacin)、舒林酸(sulindac)、托美丁(tolmetin)、佐美酸(zomepirac)、萘丁美酮(nabumetone)、双氯芬酸(diclofenac)、芬氯酸(fenclofenac)、阿氯芬酸(alclofenac)、溴芬酸(bromfenac)、异丁芬酸(ibufenac)、醋氯芬酸(aceclofenac)、阿西美辛(acemetacin)、芬替酸(fentiazac)、环氯茚酸(clidanac)、依托度酸(etodolac)、oxpinac、甲芬那酸(mefenamic acid)、甲氯芬那酸(meclofenamicacid)、氟芬那酸(flufenamic acid)、尼氟灭酸(nifluminic acid)、托芬那酸(tolfenamic acid)、二氟尼柳(diflunisal)、氟苯柳(flufenisal)、吡罗昔康(piroxicam)、替诺昔康(tenoxicam)、氯诺昔康(lornoxicam)及尼美舒利(nimesulide)或其可药用盐,或选择性的COX抑制剂美洛昔康(meloxicam)、塞来考昔(celecoxib)或罗非考昔(rofecoxib)。特别优选的为选择性的COX-2抑制剂美洛昔康。
其它化学治疗剂或天然存在的、半合成或合成治疗剂
在本发明定义中,其它可作为联合治疗的感兴趣的化合物种类及例子为,例如细胞毒性抗生素、癌细胞表面分子的靶向抗体(特别是HLA-DR抗体,例如apolizumab及1D09C3)、金属蛋白酶抑制剂(TIMP-1、TIMP-2)、锌、癌基因抑制剂(特别是c-myc、Ras、v-raf或c-src抑制剂,如P53及Rb)、基因转录抑制剂(特别是,例如描述于WO 03/097855中,转录因子复合物ESX/DRIP130/Sur-2的抑制剂,其可控制Her-2的表达)或者RNA翻译或蛋白质表达的抑制剂(特别是Her-2表达抑制剂,如热激蛋白HSP90调节剂格尔德霉素(geldanamycin)及其衍生物17-烯丙基氨基格尔德霉素或17-AAG)、稀土元素络合物例如描述于德国专利Nr.101 38 538实施例中的镧系杂环络合物、光化学治疗剂(PUVA,补骨脂内酯(psoralen)(P)与长波紫外线放射线(UVA)的联合)、IM-842、四硫钼酸盐(tetrathiomolybdate)、角鲨胺(squalamine)、combrestatin A4、TNP-470、马立马司他(marimastat)、新伐司他(neovastat)、比卡鲁胺(bicalutamide)、阿巴瑞克(abarelix)、oregovomab、米妥莫单抗(mitumomab)、TLK-286、阿仑单抗(alemtuzumab)、ibritumomab、替莫唑胺(temozolomide)、地尼白介素(denileukin diftitox)、阿地白介素(aldesleukin)、达卡巴嗪(dacarbazine)、氟脲嘧啶脱氧核苷(floxuridine)、普卡霉素(plicamycin)、米托坦(mitotane)、哌泊溴烷(pipobroman)、tamloxifen、睾内酯(testolactone)。
根据本发明优选实施方案,另一化学治疗剂或天然存在的、半合成或合成治疗剂是选自合成小分子VEGF受体拮抗剂;小分子生长因子受体拮抗剂;EGF受体和/或VEGF受体和/或整联蛋白受体或任何其它蛋白质酪氨酸激酶受体的抑制剂,该抑制剂没有被分类为合成小分子;EGF受体和/或VEGF受体和/或整联蛋白受体或任何其它蛋白质酪氨酸激酶受体的抑制剂,该抑制剂为融合蛋白;与核酸相互作用并被分类为烷化剂的化合物或铂化合物;与核酸相互作用并被分类为蒽环类抗生素、DNA插入剂或DNA交联剂的化合物,该DNA插入剂或DNA交联剂包括DNA小沟结合化合物;抗代谢物;天然存在、半合成或合成博来霉素类抗生素;DNA转录酶抑制剂,特别是拓扑异构酶I或拓扑异构酶II抑制剂;染色质修饰剂;有丝分裂抑制剂;抗有丝分裂剂或细胞周期抑制剂;蛋白酶体抑制剂;酶、荷尔蒙、荷尔蒙拮抗剂;荷尔蒙抑制剂;类固醇生物合成抑制剂;类固醇;细胞因子;缺氧选择性细胞毒素;细胞因子抑制剂;淋巴因子;抗细胞因子抗体;经口及非肠胃耐受诱导剂;载剂;化学放射敏化剂及保护剂;光化学活化药物;合成的聚核苷酸或寡核苷酸,可任选被改性或共轭;非甾体抗炎药;细胞毒性抗生素;癌细胞表面分子的靶向抗体,特别是HLA-DR抗体,例如金属蛋白酶抑制剂、金属、癌基因抑制剂、基因转录或RNA翻译或蛋白质表达的抑制剂、稀土元素络合物或光化学治疗剂。
根据本发明另一优选的实施方案,其它化学治疗剂或天然存在的、半合成或合成治疗剂是选自小分子VEGF受体拮抗剂,例如vatalanib(PTK-787/ZK222584),SU-5416,SU-6668,SU-11248,SU-14813,AZD-6474,AZD-2171,CP-547632,CEP-7055,AG-013736,IM-842或GW-786034,EGFR/HER2双重拮抗剂,例如gefitinib,erlotinib,CI-1033或GW-2016,EGFR拮抗剂,例如iressa(ZD-1839),tarceva(OSI-774),PKI-166,EKB-569,HKI-272及赫赛汀(herceptin),促分裂原活化蛋白激酶的拮抗剂例如BAY-43-9006或BAY-57-9006,喹唑啉衍生物,例如4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-((S)-(四氢呋喃-3-基氧基)-喹唑啉或4-[(3-氯-4-氟-苯基)氨基]-6-{[4-(高吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-7-[(S)-四氢呋喃-3-基)氧基]-喹唑啉,或其可药用盐,不分类为合成小分子的蛋白质激酶受体拮抗剂,例如阿曲生坦(atrasentan),美罗华(rituximab),西妥昔单抗(cetuximab),AvastinTM(贝伐单抗(bevacizumab)),IMC-1C11,erbitux(C-225),DC-101,EMD-72000,vitaxin及imatinib,是融合蛋白的蛋白质酪氨酸激酶抑制剂,例如VEGFtrap,烷化剂或铂化合物,例如美法仑(melphalan),环磷酸胺(cyclophosphamide),oxazaphosphorine,顺铂(cisplatin),卡铂(carboplatin),奥沙利铂(oxaliplatin),沙铂(satraplatin),四铂(tetraplatin),异丙铂(iproplatin),丝裂霉素(mitomycin),链佐星(streptozocin),卡莫司汀(carmustine)(BCNU),洛莫司汀(lomustine)(CCNU),白消安(busulfan),异环磷酰胺(ifosfamide),链佐星(streptozocin),塞替派(thiotepa),苯丁酸氮芥(chlorambucil),氮芥(nitrogen mustard)例如双氯乙基甲胺(mechlorethamine),乙撑亚胺(ethyleneimine)化合物,烷基磺酸盐,柔红霉素(daunorubicin),多柔比星(doxorubicin(阿霉素(adriamycin))),脂质体阿霉素(liposomal doxorubicin)(盐酸多柔比星脂质体doxil),表柔比星(epirubicin),伊达比星(idarubicin),米托蒽醌(mitoxantrone),安吖啶(amsacrine),更生霉素(dactinomycin),偏端霉素(distamycin)或其衍生物,纺锤菌素(netropsin),pibenzimol,丝裂霉素(mitomycin),CC-1065,duocarmycin,光辉霉素(mithramycin),色霉素(chromomycin),橄榄霉素(olivomycin),phtalanilide例如普罗帕脒(propamidine)或二脒草替(stilbamidine),氨茴霉素(anthramycin),氮丙啶(aziridine)或亚硝脲或其衍生物,嘧啶及嘌呤类似物或拮抗剂或者核苷二磷酸还原酶抑制剂,例如阿糖胞苷(cytarabine),5-氟尿嘧啶(5-FU),乌拉莫司汀(uracil mustard),氟达拉滨(fludarabine),吉西他滨(gemcitabine),卡培他滨(capecitabine),巯嘌呤(mercaptopurine),克拉屈滨(cladribine),硫鸟嘌呤(thioguanine),甲氨蝶呤(methotrexate),喷司他丁(pentostatin),羟脲(hydroxyurea)或叶酸,腐草霉素(phleomycin),博来霉素,其衍生物或其盐类,CHPP,BZPP,MTPP,BAPP,liblomycin,吖啶(acridine)或其衍生物,利福霉素(rifamycin),放线菌素(actinomycin),甲烯土霉素(adramycin),喜树碱(camptothecin)例如伊立替康(irinotecan(camptosar))或托泊替康(topotecan),安吖啶(amsacrine)或其类似物,三环甲酰胺(tricycliccarboxamide),组蛋白脱乙酰基酶抑制剂例如SAHA,MD-275,曲古抑菌素A(trichostatin A),CBHA,LAQ824或丙戊酸(valproic acid),来源于植物的抗癌剂,例如紫杉醇(paclitaxel)(泰素(taxol)),多西紫杉醇(docetaxel)或泰索帝(taxotere)),长春生物碱类例如诺维本(navelbine),长春碱(vinblastin),长春新碱(vincristin),长春地辛(vindesine)或长春瑞滨(vinorelbine),托酚酮(tropolone)生物碱,例如秋水仙素或其衍生物,大环内酯(macrolide)例如美登素(maytansine),柄型菌素(ansamitocin),根霉素(rhizoxin),抗有丝分裂性肽例如拟茎点霉毒素(phomopsin)或多拉司他汀(dolastatin),鬼臼乙叉甙(epipodophyllotoxin)或鬼臼毒素衍生物例如依托泊苷(etoposide),替尼泊苷(teniposide),斯的甘辛(steganacin),抗有丝分裂氨基甲酸酯衍生物,例如考布他汀(combretastatin)或苯丙氨乙茶碱(amphetinile),丙卡巴肼(procarbazine),蛋白酶体抑制剂例如VelcadeTM(bortezomib或PS-341),酶例如天门冬酰胺酶(asparaginase),聚乙二醇化天门冬酰胺酶(培门冬酶(pegaspargase))及胸腺嘧啶-磷酸酶抑制剂,孕酮(gestagen)及雌激素,例如雌莫司汀(estramustine)(T-66)或甲地孕酮(megestrol),抗雄激素例如氟他米特(flutamide),康士得(casodex),尼鲁米特(anandron)或醋酸环丙孕酮(cyproterone acetate),芳香酶抑制剂例如aminogluthetimide,阿那曲唑(anastrozole),福美坦(formestan)或来曲唑(letrozole),GNrH类似物如亮丙瑞林(leuprorelin),布舍瑞林(buserelin),戈舍瑞林(goserelin)及曲普瑞林(triptorelin),抗雌激素剂如他莫昔芬(tamoxifen)或其柠檬酸盐,屈洛昔芬(droloxifene),曲沃昔芬(trioxifene),雷洛昔芬(raloxifene)或秦哚昔芬(zindoxifene),17β-雌二醇衍生物例如ICI 164,384及ICI182,780,氨鲁米特(aminoglutethimide),福美坦(formestane),法倔唑(fadrozole),非那雄胺(finasteride),酮康唑(ketoconazole),LH-RH拮抗剂例如亮丙瑞林,类固醇例如泼尼松(prednisone),泼尼松龙(prednisolone),甲基泼尼松龙(methylprednisolone),地塞米松(dexamethasone),布地奈德(budenoside),氟可龙(fluocortolone)及曲安西龙(triamcinolone),干扰素例如干扰素β,白介素例如IL-10及IL-12,抗TNF-α抗体例如依那西普(etanercept),免疫调节药剂例如沙利度胺(thalidomide),其R-及S-对映异构体及其衍生物,或revimid(CC-5013),白细胞三烯(leukotrien)拮抗剂,丝裂霉素C,aziridoquinone例如BMY-42355,AZQ或EO-9,2-硝基咪唑例如米索硝唑(misonidazole),NLP-1,NLA-1,硝基吖啶(nitroacridine),硝基喹唑,硝基吡唑吖啶,“双官能”硝基芳香化合物例如RSU-1069或RB-6145,CB-1954,氮芥的N-氧化物例如氧氮芥(nitromin),氮芥的金属络合物,抗-CD3或抗-CD25抗体,具耐受性诱发剂,二膦酸盐及其衍生物,例如米诺膦酸(minodronic acid)或其衍生物(YM-529、Ono-5920、YH-529),唑来膦酸(zoledronic acid)单水合物,伊班膦酸钠水合物(ibandronate sodium hydrate),氯屈磷酸二钠(clodronatedisodium),硝基咪唑例如甲硝唑(metronidazole),米索硝唑(misonidazole),苄硝唑(benznidazole)或硝唑吗啉(nimorazole),硝基芳基化合物,例如RSU-1069,硝酰基及N-氧化物,如SR-4233,卤化嘧啶类似物例如溴去氧尿嘧啶核苷(bromodeoxyuridine),碘去氧尿嘧啶核苷(iododeoxyuridine),硫代磷酸盐例如WR-2721,光化学活化药物例如卟菲尔钠(porfimer),光敏素(photofrin),苯并卟啉(benzoporphyrin)衍生物,脱镁叶绿酯(pheophorbide)衍生物,部花青(merocyanin 540,MC-540),tin etioporpurin,反模板或反义RNA及DNA例如oblimersen,非甾体抗炎药物例如乙酰水杨酸,美沙拉秦(mesalazin),布洛芬(ibuprofen),萘普生(naproxen),氟比洛芬(flurbiprofen),菲诺洛芬(fenoprofen),芬布芬(fenbufen),酮洛芬(ketoprofen),吲哚洛芬(indoprofen),吡洛芬(pirprofen),卡洛芬(carprofen),奥沙普秦(oxaprozin),普拉洛芬(pranoprofen),咪洛芬(miroprofen),硫噁洛芬(tioxaprofen),舒洛芬(suprofen),阿明洛芬(alminoprofen),噻洛芬酸(tiaprofenic acid),氟洛芬(fluprofen),吲哚美辛(indomethacin),舒林酸(sulindac),托美丁(tolmetin),佐美酸(zomepirac),萘丁美酮(nabumetone),双氯芬酸(diclofenac),芬氯酸(fenclofenac),阿氯芬酸(alclofenac),溴芬酸(bromfenac),异丁芬酸(ibufenac),醋氯芬酸(aceclofenac),阿西美辛(acemetacin),芬替酸(fentiazac),环氯茚酸(clidanac),依托度酸(etodolac),oxpinac,甲芬那酸(mefenamic acid),甲氯芬那酸(meclofenamic acid),氟芬那酸(flufenamic acid),nifluminic acid,托芬那酸(tolfenamic acid),二氟尼柳(diflunisal),氟苯柳(flufenisal),吡罗昔康(piroxicam),替诺昔康(tenoxicam),氯诺昔康(lomoxicam)及尼美舒利(nimesulide),美洛昔康(meloxicam),塞来考昔(celecoxib)或罗非考昔(rofecoxib)或非甾体抗炎药物的可药用盐,细胞毒性抗生素,癌细胞表面分子的靶向抗体例如apolizumab及1D09C3,金属蛋白酶抑制剂例如TIMP-1,TIMP-2,锌,癌基因抑制剂例如P53及R6,稀土元素络合物例如镧系杂环络合物,光化学治疗剂如PUVA,转录因子复合物ESX/DRIP130/Sur-2的抑制剂,HER-2表达抑制剂例如热激蛋白HSP90调节剂格尔德霉素(geldanamycin)及其衍生物17-烯丙基氨基格尔德霉素或17-AAG,或选自IM-842,四硫钼酸盐(tetrathiomolybdate),角鲨胺(squalamine),combrestatinA4,TNP-470,马立马司他(marimastat),新伐司他(neovastat),比卡鲁胺(bicalutamide),阿巴瑞克(abarelix),oregovomab,米妥莫单抗(mitumomab),TLK-286,阿仑单抗(alemtuzumab),ibritumomab,替莫唑胺(temozolomide),地尼白介素(denileukin diftitox),阿地白介素(aldesleukin),达卡巴嗪(dacarbaxine),氟脲嘧啶脱氧核苷(floxuridine),普卡霉素(plicamycin),米托坦(mitotane),哌泊溴烷(pipobroman),普卡霉素(plicamycin),tamloxifen或睾内酯(testolactone)的治疗剂。
根据本发明另一优选的实施方案,另一化学治疗剂或天然存在的、半合成或合成治疗剂是选自来源于植物的抗癌药,例如紫杉醇(paclitaxel)(秦素(taxol)),多西紫杉醇(docetaxel)或泰索帝(taxotere)),长春生物碱类,例如诺维本(navelbine),长春碱(vinblastin),长春新碱(vincristin),长春地辛(vindesine)或长春瑞滨(vinorelbine),烷化剂或铂化合物,例如美法仑(melphalan),环磷酸胺(cyclophosphamide),oxazaphosphorine,顺铂(cisplatin),卡铂(carboplatin),奥沙利铂(oxaliplatin),沙铂(satraplatin),四铂(tetraplatin),异丙铂(iproplatin),丝裂霉素(mitomycin),链佐星(streptozocin),卡莫司汀(carmustine)(BCNU),洛莫司汀(lomustine)(CCNU),白消安(busulfan),异环磷酰胺(ifosfamide),链佐星(streptozocin),塞替派(thiotepa),苯丁酸氮芥(chlorambucil),氮芥(nitrogen mustard)例如双氯乙基甲胺(mechlorethamine),免疫调节药剂例如沙利度胺(thalidomide),其R-及S-对映异构体及其衍生物,或revimid(CC-5013),乙撑亚胺(ethyleneimine)化合物,烷基磺酸盐,柔红霉素(daunorubicin),多柔比星(doxorubicin)(阿霉素adriamycin),脂质体阿霉素(liposomal doxorubicin)(盐酸多柔比星脂质体doxil),表柔比星(epirubicin),伊达比星(idarubicin),米托蒽醌(mitoxantrone),安吖啶(amsacrine),更生霉素(dactinomycin),偏端霉素(distamycin)或其衍生物,纺锤菌素(netropsin),pibenzimol,丝裂霉素(mitomycin),CC-1065,duocarmycin,光辉霉素(mithramycin),色霉素(chromomycin),橄榄霉素(olivomycin),phtalanilide,例如普罗帕脒(propamidine),二脒草替(stilbamidine),氨茴霉素(anthramycin),氮丙啶(aziridine)或亚硝脲或其衍生物,嘧啶及嘌呤类似物或核苷二磷酸还原酶拮抗剂或抑制剂,例如阿糖胞苷(cytarabine),5-氟尿嘧啶(5-FU),乌拉莫司汀(uracil mustard),氟达拉滨(fludarabine),吉西他滨(gemcitabine),卡培他滨(capecitabine),巯嘌呤(mercaptopurine),克拉屈滨(cladribine),硫鸟嘌呤(thioguanine),甲氨喋呤(methotrexate),喷司他丁(pentostatin),羟脲(hydroxyurea)或叶酸,吖啶(acridine)或其衍生物,利福霉素(rifamycin),放线菌素(actinomycin),甲烯土霉素(adramycin),喜树碱(camptothecin)例如伊立替康(irinotecan(camptosar))或托泊替康(topotecan),安吖啶(amsacrine)或其类似物,三环甲酰胺(tricyclic carboxamide),组蛋白脱乙酰基酶抑制剂例如SAHA,MD-275,曲古抑菌素A(trichostatin A),CBHA,LAQ824或丙戊酸(valproic acid),蛋白酶体抑制剂例如VelcadeTM(bortezomib或PS-341),小分子VEGF受体拮抗剂,例如vatalanib(PTK-787/ZK222584),SU-5416,SU-6668,SU-11248,SU-14813,AZD-6474,AZD-2171,CP-547632,CEP-7055,AG-013736,IM-842或GW-786034,促分裂原活化蛋白激酶拮抗剂例如BAY-43-9006或BAY-57-9006,EGFR/HER2双重拮抗剂,例如gefitinib,erlotinib,CI-1033或GW-2016,EGFR拮抗剂,例如iressa(ZD-1839),tarceva(OSI-774),PKI-166,EKB-569,HKI-272及赫赛汀(herceptin),喹唑啉衍生物,例如4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-((S)-四氢呋喃-3-基氧基)-喹唑啉或4-[(3-氯-4-氟-苯基)氨基]-6-{[4-(高吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-7-[(S)-四氢呋喃-3-基)氧基]-喹唑啉,或其可药用盐,转录因子复合物ESX/DRIP130/Sur-2的抑制剂,HER-2表达抑制剂例如热激蛋白HSP90调节剂格尔德霉素(geldanamycin)及其衍生物17-烯丙基氨基格尔德霉素或17-AAG,不分类为合成小分子的蛋白质激酶受体拮抗剂,例如阿曲生坦(atrasentan),美罗华(rituximab),西妥昔单抗(cetuximab),AvastinTM(贝伐单抗(bevacizumab)),IMC-1C11,erbitux(C-225),DC-101,EMD-72000,vitaxin及imatinib,或癌细胞表面分子的靶向抗体例如apolizumab及1D09C3。
在根据本发明的另一优选实施方案中,其它的化学治疗剂或天然存在、半合成或合成治疗剂选自公开于WO 02/50043实施例1(10)中作为示例性化合物的上述喹唑啉衍生物,即4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-((S)-四氢呋喃-3-基氧基)-喹唑啉,或其互变异构体、立体异构体及盐类,特别是带有无机或有机酸或碱的其生理上可接受的盐类。
在根据本发明的另一优选实施方案中,其它的化学治疗剂或天然存在、半合成或合成治疗剂选自化合物4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-((S)-四氢呋喃-3-基氧基)-喹唑啉或其互变异构体或立体异构体的二马来酸盐。
在根据本发明的另一优选实施方案中,其它的化学治疗剂或天然存在、半合成或合成治疗剂选自4-[(3-氯-4-氟苯基)氨基]-6-{[4-(高吗啉-4-基)-1-氧代-2-丁烯-1-基]氨基}-7-[(S)-(四氢呋喃-3-基)氧基]-喹唑啉,或其具有无机或有机酸或碱的其生理上可接受的盐类。
放射治疗、放射免疫治疗或预靶向的放射免疫治疗
放射治疗、放射免疫治疗或预靶向的放射免疫治疗被用于治疗癌症性质的疾病。“放射治疗”或射线治疗是指以电离辐射治疗癌症及其它疾病。电离辐射储存能量,在需要治疗的区域(靶向组织),通过破坏其基因物质来毁坏或摧毁细胞,使这些细胞无法继续生长。放射治疗可用于治疗局部性的实体肿瘤,例如皮肤癌、舌癌、喉癌、脑癌、乳腺癌、肺癌或子宫颈癌。其也可用于治疗血癌或淋巴癌,也即分别为血液形成细胞及淋巴系统的癌症。通常用于放射线治疗的一种类型包括光子,例如X-光。依照其所具有能量的多少,该光线可用于摧毁身体表面或深层的癌细胞。X-光的能量越高,X-光所能进入的靶向组织就越深。直线加速器及电子加速器是为产生具有巨大能量的X-光的机器。这些机器使用时是将放射线(如X-光)集中在癌细胞的位置,称为体外放射线治疗。γ射线为另一种用于放射治疗的光子形式。γ射线是某些元素(如镭、铀及钴60)在其分解或衰变时释出放射线而自然产生的。另一种将放射线递送至癌细胞的技术是将放射性植入物直接置于肿瘤或身体内腔中。该方法称为体内放射治疗。近距离放射疗法(brachytherapy),组织内照射治疗(interstitial irradiation)及腔内照射治疗(intracavitary irradiation)为体内放射治疗的类型。在此项治疗中,放射线剂量是集中在一小区域中,患者需要住院几天。体内放射治疗常用于舌癌、子宫癌及子宫颈癌。另一种技术为手术放射治疗,其是在手术中将大剂量的体外放射线针对肿瘤及周围组织照射。另一种为粒子放射线治疗。此种类型治疗与光子放射治疗不同,其是涉及使用快速迁移的亚原子粒子(subatomic particle)以治疗局部性癌症。一些粒子(中子、介子(pion)及重离子)储存了比X-光或γ射线更多能量,其沿着其路径穿过组织,因而对其撞击到的细胞造成更大的破坏。这类的放射线通常是指高线性能量传递(高LET)放射线。放射敏化剂使肿瘤更易被破坏,而放射保护剂则保护正常组织免于放射线伤害。高热疗法(hyperthermia),使用热,也可用于敏化组织对放射线的敏感性。另一种选择涉及使用放射性标记抗体以针对癌症位点递送放射线剂量(放射免疫治疗)。在本领域中有许多可用的方法,可将放射性同位素连接至抗体上。例如,也可以使用抗体的放射碘化处理法,如WO93/05804中所揭示的方法。另一种选择是在抗体及放射性同位素间使用一种连结分子,例如MAG-3(US 5,082,930、EP 0 247 866)、MAG-2 GABA(US5,681,927、EP 0 284 071)及N2S2(phenthioate,US 4,897,255、US 5,242,679、EP 0 188 256)。另一种选择为预靶向的放射免疫治疗,其可通过将长循环抗体与快速清除的放射核种分开使放射线毒性最小化(Drugs of the future2003,28(2),pp.167-173)。详细的放射治疗方案为专家所熟知(CancerRadiotherapy:Methods and Protocols(Methods in Molecular Medicine),HuddartRA Ed.,Human Press 2002)。依照疾病的性质及患者的体质,专家了解如何决定适当的剂量及给药进度。具体是,因而专家了解如何评价剂量限定毒性(DLT)及如何决定最大耐受剂量(MTD)。
联合给药和/或联合治疗的疗法
选择性蛋白质酪氨酸激酶受体拮抗剂及其它化学治疗剂或天然存在的、半合成或合成治疗剂的联合给药,和/或与放射线治疗或放射免疫治疗的联合治疗,是指包括在时间上连续或同时给药和/或治疗。对于连续给药和/或治疗而言,选择性蛋白质酪氨酸激酶受体拮抗剂可在其它化学治疗剂或天然存在的、半合成或合成治疗剂给予前或给予后给药,和/或在放射线治疗或放射免疫治疗前或治疗后给药。
该活性物质可以经口、舌下含服(bucally)、非肠胃、通过吸入喷雾、直肠或局部给药,优选经口给药。非肠胃给药包括皮下、静脉、肌内及胸腔内注射及推注技术。
该活性物质可以各种不同剂型经口给药,也即可与各种可药用惰性载剂一起配制成片剂、胶囊、锭剂(lozenge)、糖锭剂(troch)、硬糖剂、粉剂、喷剂、水性悬浮剂、酏剂、糖浆等形式。该载剂包括固体稀释剂或填充剂、无菌水性溶媒及各种无毒的有机溶剂。而且,这些经口药物制剂可适当的以用于该目的的常用试剂加入甜味和/或调味。一般而言,本发明化合物经口剂型的浓度范围以总组合物的重量计为约0.5%至约90%,该量足以提供所需要的单位剂量。其它本发明化合物的适合的剂型包括控释制剂及本领域普通技术人员所熟知的装置。
为用于经口给药的目的,含有各种赋形剂如柠檬酸钠、碳酸钙、磷酸钙的片剂可与各种崩解剂如淀粉及优选的马铃薯淀粉或木薯淀粉、海藻酸及某些复合硅酸盐,及与结着剂如聚乙烯吡咯酮、蔗糖、明胶及阿拉伯胶一起应用。此外,润滑剂如硬脂酸镁、月桂基硫酸钠及滑石或相同形态的组合物也可在软或硬填充明胶胶囊中作为填充剂使用;也可包括乳糖(lactose)或乳糖(milk sugar)及高分子量聚乙二醇。当希望以水性悬浮剂或酏剂用于经口给药时,其中基本的活性成分可与各种甜味剂或调味剂、着色剂或色素混合,并且如果需要可与乳化剂和/或水、乙醇、丙二醇、甘油及各种其组合进行混合。
为用于经口给药的目的,特别适于根据本发明的选择性蛋白质酪氨酸激酶受体拮抗剂的药物制剂为软明胶胶囊。适于将药物制剂装入胶囊的软明胶胶囊及其制备方法被描述于例如英国专利第395546号、美国专利第2,720,463号、美国专利第2,870,062号、美国专利第4,829,057号及下列出版物中:ANON(Verpack-Rundsch.,Vol.21,NO.1,Jan 1970,pp.136-138)、Lachman等人(The Theory and Practice of Industrial Pharmacy,第13章,Lea&Febiger出版,1970年)、Ebert(Soft Gelatine Capsules:A Unique Dosage Form,reprint from Pharmaceutical Technology,Oct.1977)及R.F.Jimerson(SoftGelatine Capsule Update,Drug Development and Industrial Pharmacy Vol.12(8&9),pp.1133-1144,1986)。
为用于非肠胃给药的目的,可使用化合物在芝麻油或花生油或水性丙二醇中的溶液以及其相对应的可药用盐的无菌水溶液。如果需要,可适当缓冲这些水溶液,并且液体稀释剂应以足量的食盐或葡萄糖给予等张渗透。这些特别的水溶液特别适合用于静脉、肌内及皮下注射的目的。在这一方面,所用的无菌水性溶媒可以按照本领域普通技术人员所熟知的标准技术来制得。例如蒸馏水是为最常使用的液体稀释剂并将最终的制备物通过适合的细菌过滤器,例如烧结玻璃过滤器或硅藻土或无釉的陶瓷过滤器。这种类型中优选的过滤器为Berkefeld、Chamberland及Asbestos Disk-MetalSeitz filter,其中该溶液是用抽吸泵抽到一无菌容器中。整个可注射溶液制备中必须进行步骤是要确定所得到最终产物是否为无菌状态。
为用于透皮给药的目的,一种或多种具体化合物的剂型可包括,例如溶液、乳液、软膏、乳霜、凝胶、栓剂、速度限制的持续释放制剂及其装置。这些剂型包括一种或多种具体化合物,以及可包括乙醇、水、促渗剂及惰性载剂,例如产生胶体的物质、矿物油、乳化剂、苯甲醇等。
根据一种实施方案,选择性蛋白质酪氨酸激酶受体拮抗剂,或其多晶型物或可药用盐,按照下述进行给药,每日给药剂量在24小时的给药区间中的至少12小时能够使活性物质的血浆水平在10-500ng/ml之间。
根据另一种实施方案,选择性蛋白质酪氨酸激酶受体拮抗剂,或其多晶型物或可药用盐,按照每日给药剂量在2mg-20mg/体重之间进行给药。
其它化学治疗剂或天然存在的、半合成或合成治疗剂可以按照本领域普通技术人员所熟知的适当剂型、剂量及装置进行给药。根据一种实施方案,若该化学治疗剂或天然存在的、半合成或合成治疗剂为类固醇时,该类固醇的每日给药剂量为5至500mg。
如上所述,详细的放射治疗方案为专家所熟知。依照疾病的性质及患者的体质,专家了解如何决定适当的剂量及应用方案。具体地,专家了解如何评价剂量限定毒性(DLT)以及如何决定最大耐受剂量(MTD)。
体内及体外联合研究显示可有效抑制肿瘤细胞增殖和/或引发肿瘤细胞的凋亡
在下列联合实施例中,是以代表性的细胞株进行体外实验,或以带有特定肿瘤的裸鼠进行体内实验,其证实了选择性蛋白质酪氨酸激酶受体拮抗剂与另一化学治疗剂和/或与放射治疗的联合是有效,抑制了内皮或肿瘤细胞的增殖,和/或引发肿瘤细胞的凋亡。这些实施例因此证明了本发明。
图式简单说明
图1
在变化暴露于化合物MES(T)后,在NIH3T3 KDR细胞上对于VEGFR-2磷酸化作用的抑制。上板显示以磷酸化酪氨酸残基(α-PY)的特异性抗体为探针的蛋白质印迹。下板显示使用VEGFR-2(α-KDR)特异性抗体的蛋白质印迹。
图2
具有皮下FaDu肿瘤的裸鼠中,对于肿瘤体积的评价,未治疗(虚线),以50mg/kg化合物MES(T)的剂量每周二次进行经口治疗(黑线),或以100mg/kg化合物MES(T)的剂量每周二次进行经口治疗(灰线)。
图3
评估带有皮下卵巢癌SKOV-3肿瘤的裸鼠的肿瘤体积,未治疗(破折线),每天二次以15mg/kg EGFR/HER2抑制剂经口治疗(三角形),每天以50mg/kg C12(T)治疗(正方形),以15mg/kg EGFR/HER2抑制剂及50mg/kgC12(T)联合治疗(菱形)。
联合实施例
1.选自VEGFR1至3,PDGFR α和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂联合,其进一步为src酪氨酸激酶家族成员的拮抗剂,或其多晶型物、代谢物或可药用盐,用于治疗难治的或复发的多发性骨髓瘤。
在3-Z[1-(4-(N-(4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮(化合物MES(T))的单乙磺酸盐的体外研究中显示,这个特定化合物具有意想不到的性质,使其特别适于治疗根据本发明的疾病,具体是当与类固醇联合时,更具体是与地塞米松联合时。
在这些意想不到的性质中,下述与靶向适应症特别关联:VEGFR1至3、FGFR1及3、PDGFRα的酪氨酸激酶抑制;src酪氨酸激酶家族成员分抑制以及骨髓瘤细胞增殖的有效抑制;由VEGF及bFGF引发的新-血管生成的抑制;旁泌素IL-6分泌作用的抑制;对于细胞传导介导的IL-6分泌作用的抑制;自体分泌VEGF及bFGF效应的抑制;用t(4;14)在细胞株上直接诱导的细胞凋亡。
该特定化合物似乎还特别适合治疗多发性骨髓瘤。下列新进的发现为选择该特定化合物用于这一适应症提供了一系列证据:在小鼠多发性骨髓瘤模型中(Yaccoby等人,Blood 1998,Vol.92(8)pp.2908-2913)以及在多发性骨髓瘤患者的病情恶化中(Vacca等人,Blood 1999,Vol.93(9),pp.3064-3073;Kumar等Blood 2002,Blood First Edition Paper,Pre-published Online October17,2002,DOI 10.1182/Blood-2002-08-2441)新血管生成与骨髓渗透相平行;已显示VEGF是有效的血管生成刺激物(Toi等人,Lancet Oncol.2001,Vol.2,pp.667-673);VEGF在多发性骨髓瘤细胞中表达并分泌(Dankbar等人,Blood 2000,Vol.95(8),pp.2630-2636;Bellamy等,Cancer Res.1999,Vol.59(3),pp.728-33);VEGF诱导IL-6从骨髓间质细胞中分泌,其依次增进VEGF从同源血浆细胞(clonal plasma cell)的表达(Dankbar等人,Blood 2000,Vol.95(8),pp.2630-2636);在活体中IL-6被认为是一种多发性骨髓瘤细胞的主要的生长因子(Klein等人,Blood 1995,Vol.85(4),pp.863-872);IL-6抑制了地塞米松诱导的多发性骨髓瘤细胞死亡(Hardin等人,Blood 1994,Vol.84(9),pp.3063-3070);VEGF引发多发性骨髓瘤细胞的增殖及触发迁移(trigger migration)(Podar等人,Blood 2001,Vol.98(2),pp.428-435);VEGF促进了破骨的骨再吸收(osteoclastic bone resorption),其以多发性骨髓瘤为主要特性(Nakagawa等人,FEBS Lett.2000,Vol.473(2),pp.161-164;Niida等人,J.Exp.Med.1999,Vol.190(2),pp.293-298);FGFR3引发增殖作用,抑制细胞凋亡并与骨髓瘤细胞的发展有关(Chesi等人,Blood 2001,Vol.97(3),pp.729-736;Plowright等人,Blood 2000,Vol.95(3),pp.992-998);在骨髓瘤患者的子集(subset)中FGFR3被不正常地及组成性地活化(Chesi等人,Blood 2001,Vol.97(3),pp.729-736;Chesi等人,Nat.Genet.1997,Vol.16(3),pp.260-264);Src家族激酶与在骨髓瘤中引发的增殖反应有关(Ishikawa等人,Blood 2002,Vol.99(6),pp.2172-2178)。
下列体外实验的结果证实化合物MES(T)的特性使其特别适合治疗多发性骨髓瘤。
在第一实验中,化合物MES(T)对骨髓基质细胞(BMSC细胞)IL-6分泌作用的抑制作用是在不同的MES(T)浓度下(0、10、50、125、250及500nM),在自然状态下(其本身(native))及在以bFGF(+bFGF)或以VEGF(+VEGF)生长因子刺激细胞的状态下研究的。为了进行比较,也研究了抑制抗-bFGF(+抗-bFGF)、抗-VEGF(+抗-VEGF)以及抑制-bFGF与抗-VEGF(+抗-bFGF+抗-VEGF)联合的抑制作用。实验结果如下表II所示。
表II
该项实验结果显示化合物MES(T)的浓度≥250nM时,抑制了基本(本身)及骨髓基质细胞(BMSC细胞)的bFGF/VEGF所诱导的IL-6分泌作用,且该抑制作用比抗体的抑制作用更有效。因为先前已显示bFGF及VEGF生长因子(由骨髓瘤细胞所释放)可刺激BMSC细胞及微血管内皮细胞产生及分泌IL-6,其本身刺激骨髓瘤细胞产生bFGF及VEGF生长因子,根据本发明的化合物对IL-6分泌的抑制作用,显示出其可有效的治疗多发性骨髓瘤。
在另一项实验中,在不同的MES(T)浓度(0、50、125、250及500nM),研究了化合物MES(T)在骨髓瘤细胞(U-266骨髓瘤细胞株)与骨髓基质细胞(BMSC细胞)的转移盘(transwell)及接触共培养中对分泌IL-6的抑制作用。为了进行比较,也研究了BMSC单培养(本身)的抑制作用及作为对照的U266单培养的分泌水平。实验结果如下表III所示。
表III
该项实验结果显示化合物MES(T)能降低在转移盘及接触共培养中由骨髓瘤细胞刺激BMSC培养的IL-6分泌量的基础(本身)值。因此,可断定通过大幅减少NFkB依赖的IL-6产生,化合物MES(T)妨碍了以骨髓微观环境为目标的骨髓-基质的相互作用。其进一步显示了本发明化合物对治疗多发性骨髓瘤的效用。
在另一实验中,可能显示化合物MES(T)提供了在t(14;16)MM1.s骨髓瘤细胞(带有易位t(14;16)的MM1.s骨髓瘤细胞)的前凋亡(pro-apoptotic)效应,化合物MES(T)增加了由地塞米松引发的细胞凋亡。
因为这些特性,可断定化合物MES(T)特别适合与类固醇,具体是地塞米松,联合治疗难治的或复发的多发性骨髓瘤。
2.选自VEGFR1至3,PDGFR α和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂或其多晶型物、代谢物或可药用盐,该拮抗剂还为src酪氨酸激酶家族成员的拮抗剂;该拮抗剂以及表皮生长因子(EGF)受体与2型人表皮生长因子(2型HE)受体的双重拮抗剂的联合,用于治疗前列腺癌、非小细胞肺癌或结肠直肠癌。
下列实验是为了研究在减缓肿瘤生长方面,与相同剂量的单一疗法相比较时,欠佳的剂量下下述拮抗剂的联合治疗效果,该拮抗剂包括两种拮抗剂,第一种为选自VEGFR1至3,PDGFRα和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂,其进一步为src酪氨酸激酶家族成员的拮抗剂,即(Z)-3-(1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯基氨基)-1-苯基-亚甲基)-6-甲氧羰基-2-吲哚满酮的二氯化物盐类(是指C12(T)化合物),其为上述示例性化合物(T)的二氯化物盐类,以及第二种为表皮生长因子(EGF)受体及2型人表皮生长因子(2型HE)受体的双重拮抗剂,即化合物4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-((S)-四氢呋喃-3-基氧基)-喹唑啉(化合物是指EGFR/HER2inh.,并描述于WO 02/50043作为实施例1(10)的示例性化合物)。
为了这一目的,将SKOV-3细胞(人卵巢肿瘤)皮下注射到裸鼠(NMRInu/nu)上。将带有构建的肿瘤的小鼠任意分配到控制组及治疗组(N=10)。控制组的小鼠只接受载体溶液(0.5%Natrosol),第二组每天以15mg/kgEGFR/HER2抑制剂经口治疗,第三组每天接受一次50mg/kg C12(T),第四组的小鼠以15mg/kg EGFR/HER2抑制剂及50mg/kg C12(T)联合治疗。实验结果如图3所示。
最初每天经口治疗进行31天。将在这一时间点控制组中肿瘤大于2000mm3小鼠处死。此时,计算的治疗组肿瘤与控制组肿瘤(T/C)的比例,在以15mg/kg EGFR/HER2抑制剂治疗的组为35%,在以50mg/kg C12(T)治疗的组为32%,在联合治疗的组为13%。此项结果清楚的证明了VEGFR-2与EGFR/HER-2抑制剂联合在活体中的抗肿瘤效果。持续治疗至64天显示,与事实上其肿瘤长到与控制组的肿瘤大小相当的单一治疗组相比较,联合治疗组的肿瘤生长极度缓慢。
从此项实验结果可以总结得出,着眼于与肿瘤生长有关及重要的不同反应机制的化合物的联合,具有协力的抗肿瘤功效,所述化合物例如抑制肿瘤血管生成的VEGFR-2抑制剂C12(T),以及通过第1类受体酪氨酸激酶抑制增殖信号传导的联合的EGFR/HER-2抑制剂EGFR/HER2抑制剂。因此,所有肿瘤血管生成抑制剂(例如描述于WO 02/36564、WO 99/52869、WO00/18734、WO 00/73297、WO 01/27080、WO 01/27081及WO 01/32651中的吲哚满酮衍生物,描述于WO 01/60814、WO 99/48868及WO 98/35958的小分子VEGF受体拮抗剂,具体是化合物vatalanib(PTK-787/ZK222584)、SU-5416、SU-6668、SU-11248、SU-14813、AZD-6474、AZD-2171、CP-547632、CEP-7055、AG-013736、IM-842或GW 786034,VEGF受体的单克隆抗体,具体是AvastinTM(贝伐单抗(bevacizumab))或IMC-1C11)与EGFR抑制剂(例如iressa(ZD-1839)、tarceva(OSI-774)、PKI-166、EKB-569、HKI-272及赫赛汀(herceptin))或联合的EGFR/HER-2抑制剂(例如描述于WO 00/78735及WO 02/50043的喹唑啉衍生物、gefitinib、erlotinib、CI-1033及GW-2016)的所有联合,预计对抗肿瘤治疗将具有相同或相似效果。
3.选自VEGFR1至3,PDGFRα和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂或其多晶型物、代谢物或可药用盐(例如化合物MES(T)),与放射线治疗的联合用于治疗乳腺癌或卵巢癌,其中所述拮抗剂还为src酪氨酸激酶家族成员的拮抗剂。
4.选自VEGFR1至3,PDGFRα和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂或其多晶型物、代谢物或可药用盐(例如化合物MES(T)),其中该拮抗剂还为src酪氨酸激酶家族成员的拮抗剂,与另一种VEGFR2、PDGFR或bFGFR拮抗剂(例如vatalanib(PTK-787、ZD-6474或单克隆抗体AvastinTM)或EGFR拮抗剂(例如tarceva(OSI-774))的联合,用于治疗结肠直肠癌、实体肿瘤、乳腺癌、非小细胞肺癌、小细胞肺癌或多发性骨髓瘤。
5.选自VEGFR1至3,PDGFR α和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂或其多晶型物、代谢物或可药用盐(例如化合物MES(T)),其中该拮抗剂还为src酪氨酸激酶家族成员的拮抗剂,与抗代谢物(例如吉西他滨)及铂化合物(例如顺铂),或植物来源的抗癌药物(例如紫杉醇)及铂化合物(例如卡铂)的联合,用于治疗非小细胞肺癌或卵巢癌。
6.选自VEGFR1至3,PDGFR α和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂或其多晶型物、代谢物或可药用盐(例如化合物MES(T)),其中该拮抗剂还为src酪氨酸激酶家族成员的拮抗剂,与荷尔蒙拮抗剂(例如亮丙瑞林及氟他米特)的联合,用于转移的荷尔蒙敏感性前列腺癌的持续和/或间歇性治疗。
7.选自VEGFR1至3,PDGFR α和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂或其多晶型物、代谢物或可药用盐(例如化合物MES(T)),其中该拮抗剂还为src酪氨酸激酶家族成员的拮抗剂,与鬼臼毒素衍生物(例如依托泊苷)及铂化合物(例如卡铂或顺铂)的联合,用于治疗小细胞肺癌。
8.选自VEGFR1至3,PDGFR α和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂或其多晶型物、代谢物或可药用盐(例如化合物MES(T)),其中该拮抗剂还为src酪氨酸激酶家族成员的拮抗剂,与植物来源的抗癌药物(例如派克紫杉醇或秦素)的联合,用于治疗卵巢癌、小细胞肺癌或前列腺癌。
9.选自VEGFR1至3,PDGFR α和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂或其多晶型物、代谢物或可药用盐(例如化合物MES(T)),其中该拮抗剂还为src酪氨酸激酶家族成员的拮抗剂,与植物来源的抗癌药物(例如泰索帝)的联合,用于治疗前列腺癌。
10.选自VEGFR1至3,PDGFR α和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂或其多晶型物、代谢物或可药用盐(例如化合物MES(T)),其中该拮抗剂还为src酪氨酸激酶家族成员的拮抗剂,与铂化合物(例如卡铂)及植物来源的抗癌药物(例如派克紫杉醇)的联合,用于治疗卵巢癌,具体是用于削体外科(debulkingsurgery)后。
11.选自VEGFR1至3,PDGFRα和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂,其另为一种src酪氨酸激酶家族成员的拮抗剂,或其多晶型物、代谢物或可药用盐(例如化合物MES(T)),与一拓扑异构酶I抑制剂(例如托泊替康(topotecan))及一蒽环类(anthracycline)(例如多柔比星(doxorubicin))的联合,用于治疗卵巢癌。
12.选自VEGFR1至3,PDGFR α和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂或其多晶型物、代谢物或可药用盐(例如化合物MES(T)),其中该拮抗剂还为src酪氨酸激酶家族成员的拮抗剂,与拓扑异构酶I抑制剂(例如拓扑替康)的联合,用于治疗小细胞肺癌或卵巢癌。
13.选自VEGFR1至3,PDGFRα和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂或其多晶型物、代谢物或可药用盐(例如化合物MES(T)),其中该拮抗剂还为src酪氨酸激酶家族成员的拮抗剂,与植物来源的抗癌药物(例如派克紫杉醇)及类固醇荷尔蒙(例如雌莫司汀)的联合,用于治疗荷尔蒙抗性前列腺癌。
14.选自VEGFR1至3,PDGFR α和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂或其多晶型物、代谢物或可药用盐(例如化合物MES(T)),其中该拮抗剂还为src酪氨酸激酶家族成员的拮抗剂,与长春生物碱(例如长春瑞宾)的联合,用于治疗肺癌。
15.选自VEGFR1至3,PDGFRα和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂或其多晶型物、代谢物或可药用盐(例如化合物MES(T)),其中该拮抗剂为src酪氨酸激酶家族成员的拮抗剂,与铂化合物(例如卡铂或顺铂,优选为卡铂)的联合,用于治疗卵巢癌或非小细胞肺癌。
16.选自VEGFR1至3,PDGFRα和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂或其多晶型物、代谢物或可药用盐(例如化合物MES(T)),其中该拮抗剂为src酪氨酸激酶家族成员的拮抗剂,与COX-2抑制剂(例如塞来考昔、罗非考昔或美洛昔康)的联合,用于治疗结肠或直肠癌。
17.选自VEGFR1至3,PDGFRα和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂或其多晶型物、代谢物或可药用盐(例如化合物MES(T)),其中该拮抗剂还为src酪氨酸激酶家族成员的拮抗剂,与5-α还原酶抑制剂(例如非那雄胺)的联合,用于治疗前列腺癌。
18.选自VEGFR1至3,PDGFRα和β,FGFR1、2和3,EGFR,HER2,IGF1R,HGFR或c-Kit受体中至少一种的拮抗剂或其多晶型物、代谢物或可药用盐(例如化合物MES(T)),其中该拮抗剂为src酪氨酸激酶家族成员的拮抗剂,与光化学治疗剂(PUVA,补骨脂内酯(P)与长波紫外线放射线(UVA)的联合))的联合,用于治疗牛皮癣。
实质上,对于肿瘤疾病的治疗,根据本发明的联合治疗的基本原理为,将特异性及作用机制的分子与更广泛起作用的治疗观念相结合,对于癌症患者具有以下方面的治疗上的好处:
·通过联合治疗,目标细胞通过可能逃避的化学作用机制而存活的机会将更少;
·与单一疗法的剂量相比,因为联合治疗的附加及协同作用,所需药物的各个剂量可以被减少;
·联合治疗中各个药剂的时间安排降低了肿瘤细胞产生抗药性的可能性,使某些药物更容易传递至肿瘤(降低肿瘤内压)中,并可以为肿瘤细胞另辟死亡路径。
因此,通过以不同细胞结构及隔室为目标,希望根据本发明的联合治疗在存活率或肿瘤恶化的时间上,为广大的患者提供与相应的单一疗法同样的临床上适当的利益。因此,以例如化合物MES(T)进行特定抗血管生成治疗,肿瘤似乎无法从常用化学治疗的损伤中复原。并且,通过阻断VEGF在血管渗透性的作用,在肿瘤中似乎会产生间质压力下降,使得细胞毒性药物更易渗入。以特异的抗血管生成剂例如化合物MES(T)进行的维持治疗,在标准细胞减少后,似乎也能导致对于由细胞毒性治疗得到的效果的巩固。该现象已由临床前证据证实,抗血管生成化合物与细胞毒性治疗产生了协同的抗肿瘤活性。
对于治疗非肿瘤疾病,用于本发明联合治疗的原理也为,将特异性及作用机制的分子与更广泛起作用的治疗观念相结合,对于癌症患者具有治疗上的好处。该联合治疗的预期效果是,与单一疗法所用的剂量相比避免目标细胞可能的逃避作用机制(因为联合治疗的附加或协同作用),降低所需药物的各个剂量,并降低目标细胞对药物产生抗药性的可能性。
Claims (9)
1.联用药物,其包括有效量的:
(i)(Z)-3-(1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯基氨基)-1-苯基-亚甲基)-6-甲氧羰基-2-吲哚满酮或可药用盐;和
(ii)EGFR/HER2双重拮抗剂4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-((S)-四氢呋喃-3-基氧基)-喹唑啉或者其可药用盐或者互变体;
并任选适于与放射治疗或放射免疫治疗联合治疗,以联合制剂的形式同时、分开或连续用于治疗泌尿生殖器癌。
2.根据权利要求1的联用药物,其中(i)是(Z)-3-(1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯基氨基)-1-苯基-亚甲基)-6-甲氧羰基-2-吲哚满酮的单乙磺酸盐。
3.根据权利要求1的联用药物,其中(ii)选自EGFR/HER2双重拮抗剂4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-((S)-四氢呋喃-3-基氧基)-喹唑啉的二马来酸盐或者互变体。
4.一种用于治疗泌尿生殖器癌的联用药物制剂试剂盒,其包括治疗有效量的
(i)(Z)-3-(1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯基氨基)-1-苯基-亚甲基)-6-甲氧羰基-2-吲哚满酮或可药用盐;和
(ii)EGFR/HER2双重拮抗剂4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-((S)-四氢呋喃-3-基氧基)-喹唑啉或者其可药用盐或者互变体;
并任选适于与放射治疗或放射免疫治疗联合治疗,
其特征为(i)包含在第一隔室中,以及(ii)包含在第二隔室中,因而同时、分开或连续给药于需要此种治疗的患者。
5.根据权利要求4的联用药物制剂试剂盒,其中(i)为3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的单乙磺酸盐。
6.根据权利要求4或5的联用药物制剂试剂盒,其中(i)的制剂用于经口给药。
7.根据权利要求1至6任一项的联用药物或联用药物制剂试剂盒的用途,是用于制备药物,任选适于与放射治疗或放射免疫治疗联合治疗,以治疗人或非人哺乳动物中的泌尿生殖器癌。
8.有效量的(i)(Z)-3-(1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯基氨基)-1-苯基-亚甲基)-6-甲氧羰基-2-吲哚满酮或其可药用盐;和(ii)EGFR/HER2双重拮抗剂4-[(3-氯-4-氟苯基)氨基]-6-{[4-(N,N-二甲基氨基)-1-氧代-2-丁烯-1-基]氨基}-7-((S)-四氢呋喃-3-基氧基)-喹唑啉或者其可药用盐或者互变体,
在制备联用药物制剂中的用途,该制剂任选适于与放射治疗或放射免疫治疗联合治疗,用于同时、分开或连续地治疗人或非人的哺乳动物中的泌尿生殖器癌。
9.根据权利要求8的用途,其中(i)选自3-Z-[1-(4-(N-((4-甲基-哌嗪-1-基)-甲基羰基)-N-甲基-氨基)-苯胺基)-1-苯基-亚甲基]-6-甲氧羰基-2-吲哚满酮的单乙磺酸盐。
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