CN101636401A - 四氢喹啉衍生物及其用于治疗癌症的应用 - Google Patents
四氢喹啉衍生物及其用于治疗癌症的应用 Download PDFInfo
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- CN101636401A CN101636401A CN200880008933A CN200880008933A CN101636401A CN 101636401 A CN101636401 A CN 101636401A CN 200880008933 A CN200880008933 A CN 200880008933A CN 200880008933 A CN200880008933 A CN 200880008933A CN 101636401 A CN101636401 A CN 101636401A
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Classifications
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- C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
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- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
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Landscapes
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Abstract
其中E、R3、R4、R5、X、Y、W、Q1、Q2、Z、s和m具有权利要求1所示含义的式(I)的化合物特别是可用于治疗肿瘤。
Description
发明背景
本发明的目的是发现具有有价值的性质,特别是可用于制备药物的那些性质的新化合物。
本发明涉及式I的化合物以及其用于治疗和预防其中有丝分裂动力蛋白,特别是有丝分裂动力蛋白Eg5的抑制、调节和/或调控起一定作用的疾病的应用,此外,本发明还涉及包含这些化合物的药物组合物。
详细地讲,本发明涉及优选地抑制、调节和/或调控一种或多种有丝分裂动力蛋白的式I的化合物、包含这些化合物的组合物以及其用于治疗诸如血管生成、癌症、肿瘤形成、生长和扩散、动脉硬化、眼部疾病、脉络膜新血管形成和糖尿病性视网膜病、炎性疾病、关节炎、神经变性、再狭窄、伤口愈合或移植排斥之类的疾病和并发症的应用。本发明的化合物特别是适于治疗或预防癌症疾病。
在有丝分裂期间,各种驱动蛋白调节纺锤体装置的形成和动力学,该装置负责染色体的正确和协调的排列以及分离。已经观察到有丝分裂动力蛋白-Eg5的特定抑制导致了纺锤丝的断裂。其结果是染色体在子细胞上不再正确分配。这导致了有丝分裂停止并且因此可造成细胞死亡。例如已经描述了在得自乳房、肺和结肠肿瘤的组织中,动力蛋白Eg5上调。由于Eg5呈现出有丝分裂特异性的功能,因此受Eg5抑制影响的主要是正在迅速分裂的细胞和未完全分化的细胞。此外,Eg5仅调节有丝分裂微管(纺锤体装置)的移动,并不调节细胞骨架的移动。这对于本发明化合物的副反应特征是极其重要的,本发明化合物不会发生例如在紫杉醇(Taxol)的情况中观察到的神经病变或仅在微弱的程度上发生该类神经病变。因此,本发明化合物对Eg5的抑制是一种用于治疗恶性肿瘤的相关治疗概念。
一般而言,所有的实体瘤和非实体瘤都可以用式I的化合物来进行治疗,例如,单核细胞白血病、脑癌、泌尿生殖器癌、淋巴系统癌、胃癌、喉癌和肺癌,包括肺腺癌和小细胞肺癌。进一步的实例包括前列腺癌、胰腺癌和乳癌。
已经令人吃惊地发现,本发明的化合物特异性地抑制有丝分裂动力蛋白,特别是Eg5。本发明的化合物优选地表现出有利的生物学活性,例如可以在本文所述的试验中容易地检测该类活性。在该试验中,本发明的化合物优选表现出和引起抑制作用,其通常通过位于适宜范围内的IC50值而得到证明,其IC50值优选位于微摩尔范围内并且更优选位于毫微摩尔范围内。
如本文所讨论的那样,本发明化合物的作用与许多疾病相关。因此,本发明化合物可用于预防和/或治疗可以通过抑制一种或多种有丝分裂动力蛋白,特别是Eg5来对其产生影响的疾病。
因此,本发明涉及在所述疾病的治疗和/或预防中作为药物和/或药物活性成分的本发明化合物以及本发明的化合物用于制备治疗和/或预防所述疾病的药物的应用,并且本发明还涉及一种治疗所述疾病的方法,其包括给需要该类给药的患者施用一种或多种本发明的化合物。
可以在异种移植物肿瘤模型中证实本发明的化合物具有有利作用。
所述主体或患者可属于任何哺乳动物种属,例如灵长目动物,特别是人;啮齿类动物,包括小鼠、大鼠和仓鼠;兔子;马、牛、狗、猫等。动物模型对实验研究是很有用的,它们为人类疾病的治疗提供了一种模型。
可以用体外试验来测定某些细胞对本发明化合物处理的敏感性。通常,将细胞培养物与各种浓度的本发明化合物混合一段时间,该段时间足以确保所述活性成分诱导细胞死亡或抑制其迁移,通常为大约1小时至1周。对于体外实验而言,可以使用得自活组织检查样品的培养细胞。然后,对处理后仍然有活力的细胞进行计数。其剂量根据所用具体化合物、具体疾病和患者状态等而进行变化。治疗剂量通常足以大大降低靶组织中不希望的细胞群体,同时维持患者的活力。该治疗通常持续至细胞负荷发生极大降低,例如使细胞负荷降低至少约50%,并且可持续至在体内基本检测不到不希望的细胞。
发明概述
式I的化合物以及其可药用的衍生物、溶剂化物、互变异构体、盐和立体异构体,包括其所有比例的混合物
其中
E表示
X表示O、NR或S,
R1、R2彼此独立地表示H、A、Hal、SA、(CH2)pCN、SCN、(CF2)pCF3、SF5、OA、O(CF2)pCF3、S(CF2)pCF3、NR2、NRCOR、NRSO2R、NR(CH2)pNR2、CONR(CH2)pNR2、SO2NR(CH2)pNR2、CONR2、SO2NR2、COOR,
R3表示H、A,
A表示具有1至10个C原子的直链或支链烷基或具有3至7个C原子的环烷基,
R4表示芳基或杂芳基,其各自未被取代或被下列基团单或多取代:可被Hal、NO2、CN、A、OR、OCOR、NR2、CF3、OCF3、OCH(CF3)2
取代的芳基或杂芳基,或Hal、NO2、CN、OR、A、-(CY2)n-OR、-OCOR、-(CY2)n-CO2R、-(CY2)n-CN或-(CY2)n-NR2,
Y表示H、A、Hal、OR,
R表示H、A、(CH2)pO(CH2)pR3、(CH2)pNA(CH2)pR3,
W表示CH2、C=O、C=S或单键,
Q1表示NR、O、S或单键,
Z表示-SO2-、-SO-、CO、CS、或单键,
Q2表示NR、S、O或单键,
Hal表示F、Br或Cl
n表示1、2、3或4,
m表示0、1或2,
p表示0、1、2、3、4、5、6、7或8,并且
s表示0、1或2。
本申请优选地涉及式I1的化合物:
其中E、R3、R4、R5、Y、W、Q1、Q2、Z、X、m和s具有上面所示的含义。
本发明还涉及这些化合物的旋光体、对映体、外消旋体、非对映异构体和水合物以及溶剂化物。术语该化合物的溶剂化物是指惰性溶剂分子被加合到式I化合物上形成的加合物,其是由二者相互作用的吸引力形成的。溶剂化物有例如单-或二水合物或醇化物。
术语可药用的衍生物是指例如本发明化合物的盐,并且还指所谓的前体药物化合物的盐。
术语前体药物衍生物是指被例如烷基或酰基、糖或寡肽修饰并且在生物体内迅速裂解形成有效的本发明化合物的式I化合物。
这些化合物还包括本发明化合物的生物可降解的聚合物衍生物,例如如Int.J.Pharm.115,61-67(1995)中所述。
在例如Tetrahedron Lett.1988,29,5855-5858,Tetrahedron Lett.2003,44,217-219,J.Org.Chem.1997,62,4880-4882,J.Org.Chem.1999,64,6462-6467,Chem.Lett.1995,423-424,J.Org.Chem.2000,65,5009-5013,Chem.Lett.2083,32,222-223,US2003149069A1中描述了一些相似化合物,但是并没有提及癌症的治疗和/或不包含本发明的必要技术特征。
措辞“有效量”表示在组织、系统、动物或人体内引起例如研究者或医师所寻求或希望的生物学或医学响应的药物或药学活性成分的量。
此外,措辞“治疗有效量”表示(与没有接受该量的相应个体相比)在人或其它哺乳动物体内产生至少一种如下作用的量:改善治疗、痊愈、预防或消除疾病、综合征、情况、并发症、病症或副作用或者减缓疾病、并发症或病症的进程。
术语“治疗有效量”还包括可有效增加或加强正常生理学功能的量。
本发明还涉及式I化合物的混合物例如两种非对映异构体的混合物,例如比例为1∶1、1∶2、1∶3、1∶4、1∶5、1∶10、1∶100或1∶1000的混合物的应用。
这些混合物特别优选地是立体异构化合物的混合物。
本发明还涉及一种制备本专利所要保护的式I化合物及其可药用的衍生物、盐、溶剂化物和立体异构体的方法,其特征在于使选自下组的式II的化合物:
其中R1、R2和R具有上面所示的含义,
与其中R4具有上面所示含义的式III的化合物
和其中X和s具有上面所示含义的式IV的化合物进行反应,
优选在存在质子酸或路易斯酸例如三氟乙酸、六氟异丙醇、氯化铋(III)、三氟甲磺酸镱(III)、三氟甲磺酸钪(III)或硝酸铈(IV)铵的情况下进行反应,
并且对于R3而言,任选地用常规方法引入除H外的基团和/或任选地将式I的碱或酸转化成其一种盐。
优选用色谱法或通过结晶对用上述方法获得的式I化合物的任何非对映异构体和对映异构体混合物进行拆分。
如果需要的话,将用上述方法获得的式I的碱或酸转化成其盐。
除非明确指明,否则在上下文中,基团Hal、R、R1、R2、R3、R4、R5、W、Q1、Q2、Z、m、n、s和p具有式I所示的含义。如果某个基团在一种化合物中出现一次以上,则其彼此独立地采取所示含义。
烷基优选地是无分支(直链)或支链的,并具有1、2、3、4、5、6、7、8、9或10个C原子。烷基优选表示甲基,还优选表示乙基、丙基、异丙基、丁基、异丁基、仲-丁基或叔-丁基,此外还表示戊基、1-、2-或3-甲基丁基、1,1-、1,2-或2,2-二甲基丙基、1-乙基丙基、己基、1-、2-、3-或4-甲基戊基、1,1-、1,2-、1,3-、2,2-、2,3-或3,3-二甲基-丁基、1-或2-乙基丁基、1-乙基-1-甲基丙基、1-乙基-2-甲基丙基、1,1,2-或1,2,2-三甲基丙基,进一步优选表示例如三氟甲基。
烷基特别优选表示具有1、2、3、4、5或6个C的烷基,优选表示甲基、乙基、丙基、异丙基、丁基、异丁基、仲-丁基、叔-丁基、戊基、己基、三氟甲基、五氟乙基或1,1,1-三氟-乙基。烷基还表示环烷基。
环烷基优选地表示环丙基、环丁基、环戊基、环己基或环庚基,但特别是环戊基。
X优选地是O或NR,特别是O。
R1优选地表示烷基、CF3、OCF3、SCN、COOR、CH2CN、OH、S烷基、O烷基、Hal、SCF3。R1特别是表示叔丁基、CF3、Br、Cl、CF3或COOR。
R2优选地是H或Br,特别是H。
R3优选地是H或甲基、乙基、正丙基或正丁基,特别是H。
R4优选地是芳基,其可以被F、Cl、OR或芳基所取代。R4特别是表示苯基、羟基苯基或烷基苯基。
R优选地是H或A或(CH2)pNA(CH2)p、R3
W优选地是CH2或单键,特别是CH2。
Q1优选地是NR、单键或O,特别是NR。Q1特别优选地表示NH。
Z优选地表示SO2、CO、CS或单键。
Q2优选地是NR、O或单键。
R5优选地是H、(CY2)pNR2或(CY2)pOR,特别是(CY2)pNR或H。
Y优选地表示H、A或F,特别是H。
n优选地表示0、1、2或3。
m优选地表示0或1,特别是0。
p优选地表示0或2。
s优选地表示0或1。
芳基优选地表示苯基、萘基或联苯基,其各自未被取代或者被Hal、A、OH、OA、NH2、NO2、CN、COOH、COOA、CONH2、NHCOA、NHCONH2、NHSO2A、CHO、COA、SO2NH2、SO2A、-CH2-COOH或-OCH2-COOH单-、二-或三取代。
芳基优选地表示苯基、邻-、间-或对-甲苯基、邻-、间-或对-乙基苯基、邻-、间-或对-丙基苯基、邻-、间-或对-异丙基苯基、邻-、间-或对-叔-丁基-苯基、邻-、间-或对-羟基苯基、邻-、间-或对-甲氧基苯基、邻-、间-或对-硝基苯基、邻-、间-或对-氨基苯基、邻-、间-或对-(N-甲基氨基)苯基、邻-、间-或对-(N-甲基氨基羰基)苯基、邻-、间-或对-乙酰氨基苯基、邻-、间-或对-甲氧基苯基、邻-、间-或对-乙氧基苯基、邻-、间-或对-乙氧基羰基-苯基、邻-、间-或对-(N,N-二甲基氨基)苯基、邻-、间-或对-(N,N-二甲基-氨基羰基)苯基、邻-、间-或对-(N-乙基氨基)苯基、邻-、间-或对-(N,N-二乙基氨基)苯基、邻-、间-或对-氟苯基、邻-、间-或对-溴苯基、邻-、间-或对-氯苯基、邻-、间-或对-(甲基磺酰氨基)苯基、邻-、间-或对-(甲基磺酰基)苯基,还优选表示2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氟苯基、2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二氯苯基、2,3-、2,4-、2,5-、2,6-、3,4-或3,5-二溴苯基、2,4-或2,5-二硝基苯基、2,5-或3,4-二甲氧基苯基、3-硝基-4-氯苯基、3-氨基-4-氯-、2-氨基-3-氯-、2-氨基-4-氯-、2-氨基-5-氯-或2-氨基-6-氯苯基、2-硝基-4-N,N-二甲基氨基-或3-硝基-4-N,N-二甲基氨基苯基、2,3-二氨基苯基、2,3,4-、2,3,5-、2,3,6-、2,4,6-或3,4,5-三氯苯基、2,4,6-三甲氧基苯基、2-羟基-3,5-二氯苯基、对-碘苯基、3,6-二氯-4-氨基苯基、4-氟-3-氯苯基、2-氟-4-溴苯基、2,5-二氟-4-溴苯基、3-溴-6-甲氧基苯基、3-氯-6-甲氧基苯基、3-氯-4-乙酰氨基苯基、3-氟-4-甲氧基苯基、3-氨基-6-甲基-苯基、3-氯-4-乙酰氨基苯基或2,5-二甲基-4-氯苯基。
杂芳基优选表示具有一个或多个N、O和/或S原子的单-或二环芳族杂环,其未被取代或者被Hal、A、NO2、NHA、NA2、OA、COOA或CN单-、二-或三取代。
杂芳基特别优选表示具有一个N、S或O原子的单环饱和或芳族杂环,其可未被取代或者被Hal、A、NHA、NA2、NO2、COOA或苄基单-、二-或三取代。
不考虑进一步取代,未被取代的杂芳基表示例如2-或3-呋喃基、2-或3-噻吩基、1-、2-或3-吡咯基、1-、2-、4-或5-咪唑基、1-、3-、4-或5-吡唑基、2-、4-或5-噁唑基、3-、4-或5-异噁唑基、2-、4-或5-噻唑基、3-、4-或5-异噻唑基、2-、3-或4-吡啶基、2-、4-、5-或6-嘧啶基,还优选表示1,2,3-三唑-1-、-4-或-5-基、1,2,4-三唑-1-、-3-或5-基、1-或5-四唑基、1,2,3-噁二唑-4-或-5-基、1,2,4-噁二唑-3-或-5-基、1,3,4-噻二唑-2-或-5-基、1,2,4-噻二唑-3-或-5-基、1,2,3-噻二唑-4-或-5-基、3-或4-哒嗪基、吡嗪基、1-、2-、3-、4-、5-、6-或7-吲哚基、4-或5-异吲哚基、1-、2-、4-或5-苯并咪唑基、1-、3-、4-、5-、6-或7-苯并吡唑基、2-、4-、5-、6-或7-苯并噁唑基、3-、4-、5-、6-或7-苯并异噁唑基、2-、4-、5-、6-或7-苯并噻唑基、2-、4-、5-、6-或7-苯并异噻唑基、4-、5-、6-或7-苯并-2,1,3-噁二唑基、2-、3-、4-、5-、6-、7-或8-喹啉基、1-、3-、4-、5-、6-、7-或8-异喹啉基、3-、4-、5-、6-、7-或8-噌啉基、2-、4-、5-、6-、7-或8-喹唑啉基、5-或6-喹喔啉基、2-、3-、5-、6-、7-或8-2H-苯并-1,4-噁嗪基,进一步更优选表示1,3-苯并间二氧杂环戊烯-5-基、1,4-苯并二噁烷-6-基、2,1,3-苯并噻二唑-4-或5-基或2,1,3-苯并噁二唑-5-基。
Hal优选表示F、Cl或Br,特别是F或Cl。
在本发明中,所有出现一次以上的基团可以是相同的或不同的,即为各自独立的。
式I化合物可以具有一个或多个手性中心并且因此可以以各种立体异构形式存在。式I包含所有这些形式。
特别优选的式I化合物是子式IA至IF的那些化合物:
其中
Y、W、Q1、Q2、Z、R、R1、R2、R4、R5和n具有上面所示的含义。
此外,式I化合物以及用于制备它们的起始材料可以采用如文献中所述的本身已知的方法(例如在标准专著中所述的方法,如Houben-Weyl,Methoden der organischen Chemie[有机化学方法],Georg-Thieme-Verlag,Stuttgart),在已知并且适于所述反应的反应条件下进行制备。起始材料优选根据WO 2005/063735来进行制备。也可以采用此处并未更详细说明的本身已知的变通方法进行制备。
如果需要的话,起始材料也可以原位形成,从而可以不将其从反应混合物中分离出来,而是立即将其进一步转化成式I的化合物。
式III化合物与式II化合物的反应通常是在惰性溶剂中进行的。根据所用条件,其反应时间为数分钟至14天,反应温度为约0°至180°,通常为0°至100°,特别优选地为0℃至70℃。
适宜的惰性溶剂有例如烃类,如己烷、石油醚、苯、甲苯或二甲苯;氯代烃类,如三氯乙烯、1,2-二氯乙烷、四氯化碳、氯仿或二氯甲烷,或所述溶剂的混合物。
如果需要的话,可以通过用常规方法进行溶剂分解或氢解来释放出式I化合物中进行了官能团修饰的氨基和/或羟基。其例如可以用NaOH或KOH在水、水/THF或水/二恶烷中在0至100°下来进行。
可以用本领域技术人员已知的和有机化学标准著作中所著的方法来将酯还原成醛或醇或将腈还原成醛或胺。
所述本发明的化合物可以以它们最终的非盐形式应用。另一方面,本发明也包括可药用盐形式的这些化合物的应用,所述盐可以通过本领域已知的方法衍生自多种有机和无机酸和碱。大部分式I化合物的可药用盐形式可以通过常规方法制备。如果式I化合物包含羧基基团,它的适当的盐之一可以通过将该化合物与适当的碱反应得到相应的碱加成盐来形成。所述的碱为例如碱金属氢氧化物,包括氢氧化钾、氢氧化钠和氢氧化锂;碱土金属氢氧化物,如氢氧化钡和氢氧化钙;碱金属醇盐,例如乙醇钾和丙醇钠;以及各种有机碱,如哌啶、二乙醇胺和N-甲基葡糖胺。也包括式I化合物的铝盐。在某些式I化合物的情况中,可以通过将这些化合物用可药用的有机和无机酸处理来形成酸加成盐,例如氢卤酸,如盐酸、氢溴酸或氢碘酸;其它无机酸和它们相应的盐,如硫酸盐、硝酸盐或磷酸盐等;以及烷基-和单芳基磺酸盐,如乙磺酸盐、甲苯磺酸盐和苯磺酸盐;以及其它有机酸和它们相应的盐,如乙酸盐、三氟乙酸盐、酒石酸盐、马来酸盐、琥珀酸盐、柠檬酸盐、苯甲酸盐、水杨酸盐、抗坏血酸盐等。因此,式I化合物的可药用酸加成盐包括下列:乙酸盐、己二酸盐、藻酸盐、精氨酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、亚硫酸氢盐、溴化物、丁酸盐、樟脑酸盐、樟脑磺酸盐、辛酸盐、氯化物、氯苯甲酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、磷酸二氢盐、二硝基苯甲酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、半乳糖酸盐(得自半乳糖二酸)、半乳糖醛酸盐、葡庚糖酸盐、葡糖酸盐、谷氨酸盐、甘油磷酸盐、半琥珀酸盐、半硫酸盐、庚酸盐、己酸盐、马尿酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟基乙磺酸盐、碘化物、羟乙基磺酸盐、异丁酸盐、乳酸盐、乳糖酸盐、苹果酸盐、马来酸盐、丙二酸盐、扁桃酸盐、偏磷酸盐、甲磺酸盐、甲基苯甲酸盐、磷酸一氢盐、2-萘磺酸盐、烟酸盐、硝酸盐、草酸盐、油酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、苯基乙酸盐、3-苯基丙酸盐、磷酸盐、膦酸盐、邻苯二甲酸盐,但本发明并不限于此。
另外,本发明的化合物的碱盐包括铝、铵、钙、铜、铁(III)、铁(II)、锂、镁、锰(III)、锰(II)、钾、钠和锌盐,但本发明并不限于此。对于上文所述的盐,优选为铵盐;碱金属钠和钾的盐,以及碱土金属钙和镁的盐。衍生自可药用的有机无毒碱的式I化合物的盐包括伯胺、仲胺和叔胺的盐,取代的胺的盐,也包括天然存在的取代的胺、环胺和碱性的离子交换树脂的盐,例如精氨酸、甜菜碱、咖啡因、氯普鲁卡因、胆碱、N,N′-二苄基乙二胺(苄星)、二环己基胺、二乙醇胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡糖胺、氨基葡糖、组氨酸、哈胺(hydrabamine)、异丙基胺、利多卡因、赖氨酸、葡甲胺、N-甲基-D-葡糖胺、吗啉、哌嗪、哌啶、聚胺树脂、普鲁卡因、嘌呤类、可可碱、三乙醇胺、三乙胺、三甲胺、三丙胺和三(羟甲基)甲胺(氨基丁三醇)的盐,但本发明并不限于此。
可以用如下物质将包含碱性含氮基团的本发明化合物季铵化:(C1-C4)烷基卤化物,例如甲基、乙基、异丙基和叔丁基氯化物、溴化物和碘化物;二(C1-C4)烷基硫酸酯,例如二甲基、二乙基和二戊基硫酸酯;(C10-C18)烷基卤化物,例如癸基、十二烷基、月桂基、肉豆蔻基和十八烷基氯化物、溴化物和碘化物;以及芳基(C1-C4)烷基卤化物,例如苄基氯化物和苯乙基溴化物。水溶性和油溶性的本发明的化合物均可使用此类盐制备。
优选的上文所述的药用盐包括乙酸盐、三氟乙酸盐、苯磺酸盐、柠檬酸盐、富马酸盐、葡糖酸盐、半琥珀酸盐、马尿酸盐、盐酸盐、氢溴酸盐、羟乙基磺酸盐、扁桃酸盐、葡甲胺、硝酸盐、油酸盐、膦酸盐、新戊酸盐、磷酸钠、硬脂酸盐、硫酸盐、磺基水杨酸盐、酒石酸盐、硫代苹果酸盐、甲苯磺酸盐和氨基丁三醇,但本发明并不限于此。
碱性式I化合物的酸加成盐可以以常规方式,通过将游离碱形式与足量的所需酸接触成盐来进行制备。游离碱可以以常规方式,通过将该盐形式与碱接触并将游离碱分离而再生。游离碱形式在某些方面不同于它们相应的盐形式,如某些物理性质(例如在极性溶剂中的溶解度);然而,就本发明的目的而言,盐与它们各自的游离碱形式是相当的。
如前文所述,式I化合物的可药用的碱加成盐可以由金属或胺形成,例如碱金属和碱土金属或有机胺。优选的金属为钠、钾、镁和钙。优选的有机胺为N,N’-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基-D-葡糖胺和普鲁卡因。
本发明的酸性化合物的碱加成盐可以以常规方式,通过将游离酸形式与足量的所需碱接触成盐来进行制备。游离酸可以以常规方式,通过将该盐形式与酸接触并将游离酸分离而再生。游离酸形式在某些方面不同于它们相应的盐形式,如某些物理性质(例如在极性溶剂中的溶解度);然而,就本发明的目的而言,盐与它们各自的游离酸形式是相当的。
如果本发明的化合物包含一个以上能形成此类可药用盐的基团,那么本发明也包括多盐。典型的多盐形式包括例如二酒石酸盐、二乙酸盐、二富马酸盐、二葡甲胺、二磷酸盐、二钠盐和三盐酸盐,但本发明并不限于此。
如上文所述,可知本文中的术语“可药用盐”是指包含一种盐形式的式I化合物的活性成分,特别是如果这种盐形式使活性成分的药代动力学性质与之前使用的活性成分的游离形式或活性成分的任何其它盐形式相比有所改善时。活性成分的可药用盐形式还可以为该活性成分首次提供之前没有的所需药代动力学性质,并且甚至可以对该活性成分的药效学在其体内治疗效果方面产生积极的作用。
另外,本发明涉及包含至少一种式I化合物和/或其可药用的衍生物、溶剂化物和立体异构体(包括其所有比例的混合物)以及任选的赋形剂和/或辅剂的药物。
药物制剂可以以剂量单位的形式给药,每个剂量单位包含预定量的活性成分。该剂量单位可以包含例如0.5mg-1g、优选1mg-700mg、特别优选5mg-100mg的本发明化合物,具体剂量取决于所治疗的疾病、给药方法和患者的年龄、体重和状况,或者药物制剂可以以剂量单位的形式给药,该剂量单位每剂量单位包含预定量的活性成分。优选的剂量单位制剂为包含上文所述日剂量或分份剂量或其相应比例的活性成分的那些制剂。另外,此类药物制剂可以应用药学领域所熟知的方法来制备。
药物制剂可以通过任何所需的适当方法给药,例如通过口服(包括口腔或舌下)、直肠、鼻、局部(包括口腔、舌下或经皮)、阴道或非胃肠(包括皮下、肌内、静脉内或真皮内)方法给药。此类制剂可以应用药学领域已知的所有方法通过例如将活性成分与赋形剂或辅剂混合来制备。
适用于口服给药的药物制剂可以以分开的独立单位形式给药,如胶囊剂或片剂;散剂或颗粒剂;在水或非水液体中的溶液剂或混悬剂;可食用的泡沫剂或泡沫食物;或者水包油液体乳剂或油包水液体乳剂。
因此,例如,在以片剂或胶囊剂形式口服给药的情况中,可以将活性成分与口服、无毒并且可药用的惰性赋形剂如乙醇、甘油、水等混合。散剂可以通过将化合物粉碎成适当的细粉末并将其与以类似方法粉碎的药物赋形剂混合来制备,所述赋形剂是例如可食用的碳水化合物,如淀粉或甘露醇。也可以应用矫味剂、防腐剂、分散剂和染料等。
胶囊剂可以通过制备如上所述的粉末混合物并且将其填入成形的明胶壳中来制备。可以在填充操作前向该粉末混合物中加入助流剂和润滑剂如高分散硅酸、滑石粉、硬脂酸镁、硬脂酸钙或固体形式的聚乙二醇。同样可以加入崩解剂或增溶剂例如琼脂、碳酸钙或碳酸钠,以便在服用胶囊剂后提高药物的利用度。
另外,如果需要或必须,也可以向混合物中掺入适当的粘合剂、润滑剂和崩解剂以及染料。适当的粘合剂包括淀粉、明胶、天然糖(如葡萄糖或β-乳糖、用玉米制备的甜味剂)、天然的和合成的橡胶(如阿拉伯胶、黄蓍胶或海藻酸钠)、羧甲基纤维素、聚乙二醇、蜡等。这些剂型中所用的润滑剂包括油酸钠、硬脂酸钠、硬脂酸镁、苯甲酸钠、乙酸钠、氯化钠等。崩解剂包括但不限于淀粉、甲基纤维素、琼脂、膨润土、黄原胶等。片剂通过例如制备粉末混合物、制粒或干法压制混合物、加入润滑剂和崩解剂并压制全部混合物以得到片剂来配制。粉末混合物可以通过如上文所述将以适当方式粉碎的化合物与稀释剂或基质混合,并任选地与粘合剂(例如羧甲基纤维素、海藻酸盐、明胶或聚乙烯吡咯烷酮)、溶解阻滞剂(如石蜡)、吸收促进剂(如季盐)和/或吸附剂(如膨润土、高岭土或磷酸二钙)混合来制备。粉末混合物可以通过用粘合剂(如糖浆、淀粉糊、阿拉伯胶浆或纤维素或聚合物材料的溶液)将其润湿并且挤压过筛来制粒。作为制粒的替代方案,粉末混合物可以通过压片机操作,压制成形状不一的团块,该团块粉碎后形成颗粒。颗粒可以通过加入硬脂酸、硬脂酸盐、滑石粉或矿物油来润滑,以避免其粘附于片剂冲模。然后压制已润滑的混合物以得到片剂。本发明的化合物也可以与自由流动的惰性赋形剂混合,然后不经制粒或干法压制步骤直接压制得到片剂。可以存在由紫胶密封层、糖或聚合物材料层和蜡抛光层组成的透明或不透明的保护层。可以向这些包衣剂中加入染料以便区分不同的剂量单位。
口服的液体例如溶液剂、糖浆剂和酏剂可以以剂量单位形式制备,以使给定的量中包含预定量的化合物。糖浆剂可以通过将化合物溶于含有合适矫味剂的水溶液中来制备,而酏剂可以应用无毒醇介质制备。混悬剂可以通过将化合物分散于无毒介质中来制备。也可以加入增溶剂和乳化剂(如乙氧基化的异十八烷醇和聚氧乙烯山梨醇醚)、防腐剂、矫味添加剂(如薄荷油或天然的甜味剂或糖精)或者其它的人工甜味剂等。
如果需要,可以将口服给药的剂量单位制剂包封到微囊中。该制剂也可以以延长或延缓释放的方式制备,例如通过包衣或将微粒材料包埋于聚合物、蜡等中。
式I化合物及其盐、溶剂化物以及有生理学功能的衍生物也可以以脂质体传递系统的形式,例如小单室脂质体、大单室脂质体和多复层脂质体形式给药。脂质体可以由各种磷脂例如胆固醇、硬脂胺或磷脂酰胆碱形成。
式I化合物及其盐、溶剂化物和有生理学功能的衍生物也可以用与该化合物分子偶联的单克隆抗体作为单一载体来传递。该化合物也可以与作为靶向药物载体的可溶性聚合物偶联。此类聚合物可包括聚乙烯吡咯烷酮、吡喃共聚物、聚羟丙基甲基丙烯酰氨基苯酚、聚羟乙基天冬氨酰氨基苯酚或聚氧乙烯聚赖氨酸,其可以被棕榈酰基取代。另外,该化合物还可以与一类适合获得药物控释的可生物降解的聚合物偶联,该聚合物是例如聚乳酸、聚-ε-己内酯、聚羟基丁酸、聚原酸酯、聚缩醛、聚二羟基吡喃、聚氰基丙烯酸酯和水凝胶的交联或两亲的嵌段共聚物。
适于经皮给药的药物制剂可以以用于长时间紧密接触受体表皮的独立硬膏剂的形式给药。因此,例如活性成分可以从硬膏剂通过如Pharmaceutical Research,3(6),318(1986)中所述的离子电渗疗法传递。
适于局部给药的药用化合物可以配制为软膏剂、乳膏剂、混悬剂、洗剂、散剂、溶液剂、糊剂、凝胶剂、喷雾剂、气雾剂或油剂。
对于眼或其它外部组织例如口腔和皮肤的治疗而言,制剂优选以局部软膏剂或乳膏剂的形式来应用。在制剂为软膏剂的情况下,活性成分可以与石蜡或易与水混溶的膏基共同应用。或者,活性成分可以用水包油型乳膏基或油包水型乳膏基配制成乳膏剂。
适于局部应用于眼部的药物制剂包括滴眼剂,其中活性成分溶于或混悬于合适载体中,特别是水性溶剂中。
适于局部应用于口腔的药物制剂包括锭剂、软锭剂和漱口剂。
适于直肠给药的药物制剂可以以栓剂或灌肠剂的形式给药。
其中的载体物质为固体的适于鼻腔给药的药物制剂包括具有例如20-500微米范围内的粒径的粗粉剂,其以鼻吸的方式给药,即通过鼻道从接近鼻腔的装有粉末的容器内快速吸入。用液体作为载体物质的适于以鼻喷雾剂或滴鼻剂的形式给药的制剂包括活性成分的水或油溶液。
适于吸入给药的药物制剂包括细颗粒的粉末或喷雾,其可以通过多种类型的具有气雾剂、喷雾器或吹入器的加压分散器来产生。
适于阴道给药的药物制剂可以以阴道栓剂、阴道塞、乳膏剂、凝胶剂、糊剂、泡沫剂或喷雾制剂给药。
适于胃肠外给药的药物制剂包括含有抗氧化剂、缓冲剂、抑菌剂和溶质的水性和非水无菌注射液,通过所述溶质使该制剂与被治疗的患者的血液等张;以及水性和非水无菌混悬液,其可以包含助悬介质和增稠剂。这些制剂可以在单剂量或多剂量容器,例如密封的安瓿和小瓶中被给药,并存贮于冷冻干燥(冻干)状态下,从而仅需在临用之前加入无菌液体载体,例如注射用水。依照处方制备的注射溶液和混悬液可以由无菌粉末、颗粒和片剂制备。
不言而喻,除了上文所特别指出的组分外,对于特定类型的制剂而言,制剂中也可以包含本领域常用的其它物质;因此,例如适于口服给药的制剂可以包含矫味剂。
式I化合物的治疗有效量取决于多种因素,包括例如动物的年龄和体重、需要治疗的具体病症及其严重性、制剂的性质以及给药方法,并且最终由主治医生或兽医确定。然而,本发明的化合物用于治疗肿瘤生长(例如结肠或乳腺癌)的有效量通常为每日0.1-100mg/kg受体(哺乳动物)体重,特别是每日1-10mg/kg体重。因此,对于体重为70kg的成年哺乳动物而言,每日的实际量通常为70-700mg,其中该剂量可以以单剂量形式每日给药,或者通常以一系列部分剂量形式(如每天给药2、3、4、5或6次)每日给药,以使总的日剂量不变。其盐或溶剂化物或有生理学功能的衍生物的有效量可以确定为本发明化合物本身的有效量的分数。可以推断适于治疗上述其它病症的类似剂量。
本发明还涉及包含至少一种式I化合物和/或其可药用的衍生物、溶剂化物和立体异构体(包括其所有比例的混合物)以及至少一种其他药物活性成分的药物。
本发明也涉及药盒,该药盒由单独包装的
(a)有效量的式I化合物和/或其可药用的衍生物、溶剂化物和立体异构体(包括其所有比例的混合物),以及
(b)有效量的其他药物活性成分所组成。
所述药盒包括适当的容器,如盒、单独的瓶、袋或安瓿。该药盒可以包含例如单独的安瓿,各安瓿分别包含有效量的式I化合物和/或其可药用的衍生物、溶剂化物和立体异构体(包括其所有比例的混合物),以及有效量的溶解或冻干形式的其他药物活性成分。
优选将表1的药物与式I化合物联合用药,但并不排除其它药物。也可以将式I化合物与表1中药物的组合与式V的化合物联用。
优选地将式I的化合物与已知的抗癌剂联合。
这些已知的抗炎剂包括下面的物质:雌激素受体调节剂、雄激素受体调节剂、类维生素A受体调节剂、细胞毒性剂、抗增殖剂、异戊二烯基-蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白酶抑制剂、逆转录酶抑制剂和其它血管生成抑制剂。本发明的化合物特别适于与放疗同时使用。专家们已经描述了与放疗联合时对VEGF的协同抑制作用(见WO00/61186)。
“雌激素受体调节剂”指的是无论其机理如何,可以干扰或抑制雌激素与受体结合的化合物。雌激素受体调节剂的实例非限制性地包括他莫昔芬、雷洛昔芬、艾多昔芬、LY353381、LY117081、托瑞米芬、氟维司群、4-[7-(2,2-二甲基-1-氧代丙氧基-4-甲基-2-[4-[2-(1-哌啶基)乙氧基]苯基]-2H-1-苯并吡喃-3-基]-苯基-2,2-二甲基丙酸酯、4,4’-二羟基二苯甲酮-2,4-二硝基苯基-腙和SH646。
“雄激素受体调节剂”指的是无论其机理如何,可以干扰或抑制雄激素与受体结合的化合物。雄激素受体调节剂的实例包括非那雄胺和其它5α-还原酶抑制剂、尼鲁米特、氟他胺、比卡鲁胺、利阿唑和醋酸阿比特龙。
“类维生素A受体调节剂”指的是无论其机理如何,可以干扰或抑制类维生素A与受体结合的化合物。该类类维生素A受体调节剂的实例包括贝沙罗汀、维甲酸、13-顺式-视黄酸、9-顺式-视黄酸、α-二氟甲基鸟氨酸、ILX23-7553、反式-N-(4’-羟基苯基)视黄酰胺和N-4-羧基苯基视黄酰胺。
“细胞毒性剂”指的是主要通过直接作用于细胞功能或抑制或干扰细胞有丝分裂而造成细胞死亡的化合物,包括烷化剂、肿瘤坏死因子、嵌入剂、微管抑制剂和拓扑异构酶抑制剂。
细胞毒性剂的实例非限制性地包括替拉扎明、Sertenef、恶病质素、异环磷酰胺、他索纳明、氯尼达明、卡铂、六甲密胺、泊尼莫司汀、二溴卫矛醇、雷莫司汀、福莫司汀、奈达铂、奥沙利铂、替莫唑胺、庚铂、雌莫司汀、英丙舒凡甲苯磺酸盐、曲磷胺、尼莫司汀、二溴螺氯铵、嘌嘧替派、洛铂、沙铂、甲基丝裂霉素、顺铂、伊罗夫文、右异环磷酰胺、顺式-胺化二氯(2-甲基-吡啶)铂、苄基鸟嘌呤、葡磷酰胺、GPX100、(反式,反式,反式)-二-mu-(己烷-1,6-二胺)-mu-[二胺-铂(II)]二[二胺(氯)铂(II)]四氯化物、二氮杂环丙烯基精胺、三氧化二砷、1-(11-十二烷基氨基-10-羟基十一烷基)-3,7-二甲基黄嘌呤、佐柔比星、伊达比星、柔红霉素、比生群、米托蒽醌、吡柔比星、吡萘非特、戊柔比星、氨柔比星、抗瘤酮(antineoplaston)、3’-脱氨基-3’-吗啉代-13-脱氧代-10-羟基洋红霉素、Annamycin、加柔比星、依利奈法德、MEN10755、和4-脱甲氧基-3-脱氨基-3-环乙亚胺基-4-甲基磺酰基-柔红霉素(见WO 00/50032)。
微管抑制剂的实例包括紫杉醇、硫酸长春地辛、3’,4’-二脱氢-4’-脱氧-8’-去长春花碱、多西紫杉醇、根霉素、多拉司他汀、米伏布林羟乙基磺酸盐、Auristatin、西马多丁、RPR109881、BMS184476、长春氟宁、自念珠藻环肽、2,3,4,5,6-五氟-N-(3-氟-4-甲氧基苯基)苯磺酰胺、脱水长春碱(anhydrovinblastine)、N,N-二甲基-L-缬氨酰基-L-缬氨酰基-N-甲基-L-缬氨酰基-L-脯氨酰基-L-脯氨酸-叔-丁酰胺、TDX258和BMS188797。
拓扑异构酶抑制剂的一些实例有托泊替康、Hycaptamine、伊立替康、卢比替康、6-乙氧基丙酰基-3’,4’-O-外-亚苄基-教酒菌素、9-甲氧基-N,N-二甲基-5-硝基吡唑并[3,4,5-kl]吖啶-2-(6H)丙胺、1-氨基-9-乙基-5-氟-2,3-二氢-9-羟基-4-甲基-1H,12H-苯并[de]吡喃并[3’,4’:b,7]-吲嗪并[1,2b]喹啉-10,13(9H,15H)二酮、勒托替康、7-[2-(N-异丙基氨基)乙基]-(20S)喜树碱、BNP1350、BNPI1100、BN80915、BN80942、磷酸依托泊苷、替尼泊苷、索布佐生、2’-二甲基氨基-2’-脱氧-依托泊苷、GL331、N-[2-(二甲基氨基)乙基]-9-羟基-5,6-二甲基-6H-吡啶并[4,3-b]咔唑-1-甲酰胺、Asulacrine、(5a,5aB,8aa,9b)-9-[2-[N-[2-(二甲基氨基)乙基]-N-甲基氨基]乙基]-5-[4-羟基-3,5-二甲氧基苯基]-5,5a,6,8,8a,9-六氢呋喃并(3’,4’:6,7)萘并(2,3-d)-1,3-间二氧杂环戊烯-6-酮、2,3-(亚甲二氧基)-5-甲基-7-羟基-8-甲氧基苯并[c]-啡啶鎓、6,9-二[(2-氨基乙基)氨基]苯并[g]异喹啉-5,10-二酮、5-(3-氨基丙基氨基)-7,10-二羟基-2-(2-羟基乙基氨基甲基)-6H-吡唑并[4,5,1-de]吖啶-6-酮、N-[1-[2(二乙基氨基)乙基氨基]-7-甲氧基-9-氧代-9H-噻吨-4-基甲基]甲酰胺、N-(2-(二甲基氨基)乙基)吖啶-4-甲酰胺、6-[[2-(二甲基氨基)乙基]氨基]-3-羟基-7H-茚并[2,1-c]喹啉-7-酮和地美司钠。
“抗增殖剂”包括反义RNA和DNA寡核苷酸如G3139、ODN698、RVASKRAS、GEM231、和INX3001,以及抗代谢物如依诺他滨、卡莫氟、替加氟、喷司他丁、去氧氟尿苷、曲美沙特、氟达拉滨、卡培他滨、加洛他滨、阿糖胞苷十八烷基磷酸钠、Fosteabine钠水合物、雷替曲塞、Paltitrexid、乙嘧替氟、噻唑呋林(tiazofurin)、地西他滨、诺拉曲塞、培美曲塞、Nelzarabine、2’-脱氧-2’-亚甲基胞苷、2’-氟亚甲基-2’-脱氧胞苷、N-[5-(2,3-二氢-苯并呋喃基)磺酰基]-N’-(3,4-二氯苯基)脲、N6-[4-脱氧-4-[N2-[2(E),4(E)-十四碳二烯酰基]甘氨酰基氨基]-L-甘油-B-L-甘露-吡喃庚糖基]腺嘌呤、Aplidine、Ecteinascidin、曲沙他滨、4-[2-氨基-4-氧代-4,6,7,8-四氢-3H-嘧啶并[5,4-b][1,4]噻嗪-6-基-(S)-乙基]-2,5-噻吩酰基-L-谷氨酸、氨基蝶呤、5-氟尿嘧啶、阿拉诺新、11-乙酰基-8-(氨基甲酰氧基甲基)-4-甲酰基-6-甲氧基-14-氧杂-1,11-二氮杂四环(7.4.1.0.0)-十四碳-2,4,6-三烯-9-基醋酸酯、苦马豆碱、洛美曲索、右雷佐生、蛋氨酸酶、2’-氰基-2’-脱氧-N4-棕榈酰基-1-B-D-呋喃阿糖基胞嘧啶和3-氨基吡啶-2-醛缩氨基硫脲。“抗增殖剂”还包括除“血管生成抑制剂”下列出的那些物质外的生长因子的单克隆抗体,如曲妥单抗和肿瘤抑制基因,如p53,其可以通过重组的病毒介导的基因转移来进行传递(例如见US专利6,069,134)。
特别优选用本发明的化合物来治疗和预防肿瘤疾病。
所述肿瘤优选选自鳞状上皮、膀胱、胃、肾、头和颈、食管、宫颈、甲状腺、小肠、肝、脑、前列腺、泌尿生殖道、淋巴系统、胃、喉和/或肺的肿瘤。
该肿瘤还优选选自肺腺癌、小细胞肺癌、胰腺癌、成角质细胞瘤、结肠癌和乳癌。
还优选用其来治疗血液和免疫系统的肿瘤,优选用其来治疗选自急性骨髓性白血病、慢性骨髓性白血病、急性淋巴性白血病和/或慢性淋巴性白血病的肿瘤。
本发明还包括治疗患有肿瘤如癌的患者的方法,该方法包括给予
a)一种或多种式I的化合物:
b)和一种或多种式V的化合物或其酸加成盐,特别是盐酸盐:
其中Y′和Z′彼此独立地表示O或N,R9和R10彼此独立地表示H、OH、卤素、OC1-10-烷基、OCF3、NO2或NH2,s′表示2至6的整数(包括2和6),R8和R11彼此独立地优选地位于间-或对-位并选自:
其中将第一种和第二种化合物以足以抑制肿瘤生长的量同时给药或在14天之内各自给药。
将式I化合物与式V的化合物和其它喷他脒(pentamedine)类似物联合在瘤形成的抑制中产生了协同作用。例如在WO 02058684中提及了包含式V化合物的组合。
目前仍未能清楚解释喷他脒或其衍生物的作用机理:因为其导致了DNA、RNA和蛋白合成降低,因此喷他脒或其衍生物看起来具有多效作用。最近描述了喷他脒是PRL1、-2和3磷酸酶(Pathak等人,2002)以及酪氨酸磷酸酶的有效抑制剂,在人类恶性肿瘤中伴有这些酶的过表达。另一方面,已经描述了喷他脒是一种与DNA小沟结合的药物(Puck-owska等人,2004)并且能通过破坏基因表达和/或DNA合成来发挥其作用。
另一些适宜的喷他脒类似物包括芪脒(G-1)和羟基芪脒(G-2)以及其吲哚类似物(例如G-3):
各脒单元可彼此独立地被上面R8和R11所定义的单元之一代替。如在苯并咪唑和喷他脒的情况中,芪脒的盐、羟基芪脒以及其吲哚衍生物也适用于本发明的方法。优选的盐包括例如二盐酸盐和甲磺酸盐。
另一些类似物是那些落在US专利5,428,051、5,521,189、5,602,172、5,643,935、5,723,495、5,843,980、6,172,104和6,326,395或US专利申请公开US 2002/0019437A1(其各自被全部引入作为参考)之一所提供的结构式的范围内的那些物质。用作例证的类似物包括1,5-二(4′-(N-羟基脒基)苯氧基)戊烷、1,3-二(4′-(N-羟基脒基)苯氧基)丙烷、1,3-二(2′-甲氧基-4′-(N-羟基脒基)苯氧基)丙烷、1,4-二(4’-(N-羟基脒基)苯氧基)丁烷、1,5-二(4’-(N-羟基脒基)苯氧基)戊烷、1,4-二(4’-(4-羟基脒基)苯氧基)丁烷、1,3-二(4′-(4-羟基脒基)苯氧基)丙烷、1,3-二(2′-甲氧基-4’-(N-羟基脒基)苯氧基)丙烷、2,5-二[4-脒基苯基]呋喃、2,5-二[4-脒基苯基]呋喃双酰胺肟、2,5-二[4-脒基苯基]呋喃、2,5-二[4-脒基苯基]呋喃二-O-甲基-酰胺肟、2,5-二[4-脒基苯基]呋喃二-O-乙酰胺肟、2,8-二脒基二苯并噻吩、2,8-二(N-异丙基脒基)咔唑、2,8-二-(N-羟基脒基)咔唑、2,8-二(2-咪唑啉基)二苯并噻吩、2,8-二(2-咪唑啉基)-5,5-二氧代二苯并噻吩、3,7-二脒基二苯并噻吩、3,7-二(N-异丙基脒基)二苯并噻吩、3,7-二(N-羟基-脒基)二苯并噻吩、3,7-二氨基二苯并噻吩、3,7-二溴-二苯并噻吩、3,7-二氰基二苯并噻吩、2,8-二脒基二苯并-呋喃、2,8-二-(2-咪唑啉基)二苯并呋喃、2,8-二-(N-异丙基脒基)-二苯并呋喃、2,8-二-(N-羟基脒基)二苯并呋喃、3,7-二-(2-咪唑啉基)二苯并呋喃、3,7-二(异丙基脒基)二苯并呋喃、3,7-二-(A-羟基脒基)二苯并呋喃、2,8-二氰基二苯并呋喃、4,4′-二溴-2,2′-二硝基-联苯、2-甲氧基-2′-硝基-4,4′-二溴联苯、2-甲氧基-2′-氨基-4,4′-二溴联苯、3,7-二溴二苯并呋喃、3,7-二氰基二苯并呋喃、2,5-二(5-脒基-2-苯并咪唑基)吡咯、2,5-二[5-(2-咪唑啉基)-2-苯并-咪唑基]吡咯、2,6-二[5-(2-咪唑啉基)-2-苯并咪唑基]吡啶、1-甲基-2,5-二(5-脒基-2-苯并咪唑基)吡咯、1-甲基-2,5-二[5-(2-咪唑基)-2-苯并咪唑基]吡咯、1-甲基-2,5-二[5-(1,4,5,6-四氢-2-嘧啶基)-2-苯并咪唑基]吡咯、2,6-二(5-脒基-2-苯并咪唑基)-吡啶、2,6-二[5-(1,4,5,6-四氢-2-嘧啶基)-2-苯并咪唑基]吡啶、2,5-二(5-脒基-2-苯并咪唑基)呋喃、2,5-二[5-(2-咪唑啉基)-2-苯并咪唑基]呋喃、2,5-二(5-N-异丙基脒基-2-苯并咪唑基)呋喃、2,5-二(4-脒基苯基)呋喃、2,5-二(4-脒基苯基)-3,4-二甲基呋喃、2,5-二-对-[2-(3,4,5,6-四氢嘧啶基)苯基呋喃、2,5-二[4-(2-咪唑啉基)-苯基]呋喃、2,5-[二{4-(2-四氢嘧啶基))苯基]-对-(甲苯氧基)呋喃、2,5-[二(4-(2-咪唑啉基))苯基]-3-对-(甲苯氧基)呋喃、2,5-二{4-[5-(N-2-氨基乙酰氨基)苯并咪唑-2-基]苯基}呋喃、2,5-二[4-(3a,4,5,6,7,7a-六氢-1H-苯并咪唑-2-基)苯基]呋喃、2,5-二[4-(4,5,6,7-四氢-1H-1,3-二氮杂-2-基)苯基]呋喃、2,5-二(4-N,N-二甲基羧基酰肼基-苯基)呋喃、2,5-二{4-[2-(N-2-羟基乙基)咪唑啉基]苯基呋喃、2,5-二[4-(N-异丙基脒基)苯基)呋喃、2,5-二{4-[3-(二甲基氨基丙基)-脒基]苯基}呋喃、2,5-二{4-[N-(3-氨基丙基)脒基]苯基}呋喃、2,5-二[2-(咪唑啉基)苯基]-3,4-二(甲氧基甲基)呋喃、2,5-二[4-N-(二甲基氨基乙基)脒基]苯基呋喃、2,5-二(4-[(N-2-羟基乙基)-脒基]苯基)呋喃、2,5-二[4-N-(环丙基脒基)苯基]呋喃、2,5-二[4-(N,N-二乙基氨基丙基)脒基]苯基呋喃、2,5-二{4-[2-(N-乙基咪唑啉基)]苯基}呋喃、2,5-二{4-[2-(N-(3-戊基脒基)]}苯基呋喃、2,5-二[4-(2-咪唑啉基)苯基]-3-甲氧基呋喃、2,5-二[4-(N-异丙基脒基)苯基]-3-甲基呋喃、二[5-脒基-2-苯并咪唑基]甲烷、二[5-(2-咪唑基)-2-苯并咪唑基]甲烷、1,2-二[5-脒基-2-苯并咪唑基]乙烷、1,2-二[5-(2-咪唑基)-2-苯并咪唑基]乙烷、1,3-二[5-脒基-2-苯并咪唑基]丙烷、1,3-二[5-(2-咪唑基)-2-苯并咪唑基]丙烷、1,4-二[5-脒基-2-苯并咪唑基]丙烷、1,4-二[5-(2-咪唑基)-2-苯并咪唑基]丁烷、1,8-二[5-脒基-2-苯并咪唑基]辛烷、反式-1,2-二[5-脒基-2-苯并咪唑基]乙烯、1,4-二[5-(2-咪唑基)-2-苯并咪唑基]-1-丁烯、1,4-二[5-(2-咪唑基)-2-苯并咪唑基]-2-丁烯、1,4-二[5-(2-咪唑基)-2-苯并咪唑基]-1-甲基丁烷、1,4-二[5-(2-咪唑基)-2-苯并咪唑基]-2-乙基丁烷、1,4-二[5-(2-咪唑基)-2-苯并咪唑基]-1-甲基-1-丁烯、1,4-二[5-(2-咪唑基)-2-苯并咪唑基]-2,3-二乙基-2-丁烯、1,4-二[5-(2-咪唑基)-2-苯并咪唑基]-1,3-丁二烯、1,4-二[5-(2-咪唑基)-2-苯并咪唑基]-2-甲基-1,3-丁二烯、二[5-(2-嘧啶基)-2-苯并咪唑基]甲烷、1,2-二[5-(2-嘧啶基)-2-苯并咪唑基]乙烷、1,3-二[5-脒基-2-苯并咪唑基]丙烷、1,3-二[5-(2-嘧啶基)-2-苯并-咪唑基]丙烷、1,4-二[5-(2-嘧啶基)-2-苯并咪唑基]丁烷、1,4-二-[5-(2-嘧啶基)-2-苯并咪唑基)-1-丁烯、1,4-二[5-(2-嘧啶基)-2-苯并-咪唑基-2-丁烯、1,4-二[5-(2-嘧啶基)-2-苯并咪唑基]-1-甲基-丁烷、1,4-二[5-(2-嘧啶基)-2-苯并咪唑基]-2-乙基丁烷、1,4-二[5-(2-嘧啶基)-2-苯并咪唑基]-1-甲基-1-丁烯、1,4-二[5-(2-嘧啶基)-2-苯并咪唑基]-2,3-二乙基-2-丁烯、1,4-二[5-(2-嘧啶基)-2-苯并咪唑基]-1,3-丁二烯和1,4-二[5-(2-嘧啶基)-2-苯并咪唑基]-2-甲基-1,3-丁二烯、2,4-二(4-脒基苯基)嘧啶、2,4-二(4-咪唑啉-2-基)-嘧啶、2,4-二[(四氢嘧啶基-2-基)苯基]嘧啶、2-(4-[N-异-丙基脒基]苯基)-4-(2-甲氧基-4-[N-异-丙基脒基]苯基)嘧啶、4-(N-环戊基脒基)-1,2-亚苯基二胺、2,5-二[2-(5-脒基)苯并咪唑基]呋喃、2,5-二[2-(5-(2-咪唑啉代))苯并咪唑基]呋喃、2,5-二[2-(5-N-异丙基脒基)苯并咪唑基]呋喃、2,5-二[2-(5-N-环戊基-脒基)苯并咪唑基]呋喃、2,5-二[2-(5-脒基)苯并咪唑基]吡咯、2,5-二[2-{5-(2-咪唑啉代)}苯并咪唑基]吡咯、2,5-二[2-(5-N-异丙基-脒基)苯并咪唑基]吡咯、2,5-二[2-(5-N-环戊基脒基)苯并咪唑基]吡咯、1-甲基-2,5-二[2-(5-脒基)苯并咪唑基]吡咯、2,5-二[2-(5-(2-咪唑啉代)苯并咪唑基]-1-甲基吡咯、2,5-二[2-(5-N-环戊基脒基)苯并咪唑基]-1-甲基吡咯、2,5-二[2-(5-N-异丙基-脒基)苯并咪唑基]噻吩、2,6-二[2-(5-(2-咪唑啉代))苯并咪唑基]吡啶、2,6-二[2-(5-脒基)苯并咪唑基]吡啶、4,4′-二[2-(5-N-异丙基脒基)苯并咪唑基]-1,2-二苯基乙烷、4,4′-二[2-(5-N-环戊基脒基)苯并咪唑基]-2,5-二苯基呋喃、2,5-二[2-(5-脒基)苯并咪唑基]苯并[b]呋喃、2,5-二[2-(5-N-环戊基脒基)苯并咪唑基]-苯并[b]呋喃、2,7-二[2-(5-N-异丙基脒基)苯并咪唑基]氟、2,5-二[4-(3-(N-吗啉代丙基)氨基甲酰基)苯基]呋喃、2,5-二[4-(2-N,N-二甲基氨基乙基氨基甲酰基)苯基]呋喃、2,5-二[4-(3-N,N-二甲基氨基-丙基氨基甲酰基)苯基]呋喃、2,5-二[4-(3-N-甲基-3-N-苯基氨基-丙基氨基甲酰基)苯基]呋喃、2,5-二[4-(3-N,N8,N11-三甲基氨基丙基-氨基甲酰基)苯基]呋喃、2,5-二[3-脒基苯基]呋喃、2,5-二[3-(N-异-丙基脒基)脒基苯基]呋喃、2,5-二[3-[(N-(2-二甲基氨基乙基)-脒基)苯基呋喃、2,5-二[4-(N-2,2,2-三氯乙氧基羰基)脒基-苯基]呋喃、2,5-二[4-(N-硫代乙基羰基)脒基苯基]呋喃、2,5-二[4-(N-苄氧基羰基)脒基苯基]呋喃、2,5-二[4-(N-苯氧基羰基)-脒基苯基]呋喃、2,5-二[4-(N-(4-氟)苯氧基羰基)脒基-苯基]呋喃、2,5-二[4-(N-(4-甲氧基)苯氧基羰基)脒基苯基]-呋喃、2,5-二[4-(1-乙酰氧基乙氧基羰基)脒基苯基]呋喃和2,5-二[4-(N-(3-氟)苯氧基羰基)脒基苯基]呋喃。在US专利5,428,051、5,521,189、5,602,172、5,643,935、5,723,495、5,843,980、6,172,104和6,326,395或US专利申请公开US 200210019437A1中描述了制备上面化合物之一的方法。
喷他脒代谢物同样适用于本发明的抗增殖组合中。喷他脒在体内被迅速代谢成至少七种初级代谢物。这些代谢物中的一些具有一种或多种同喷他脒一样的作用。当与苯并咪唑或其类似物联合时,喷他脒代谢物具有抗增殖作用。
七种喷他脒类似物如下所示。
本发明式I化合物和式V化合物或其类似物以及其代谢物的组合适用于治疗肿瘤。组合疗法可以单独进行或者与另一种治疗(例如手术、辐射、化疗、生物疗法)联用。此外,形成肿瘤风险更高的人(例如某些有遗传倾向或之前有肿瘤的人)可进行预防治疗以抑制或延迟肿瘤形成。
本发明还涉及驱动蛋白ATPase Eg5/KSP与式V化合物、喷他脒、其类似物以及其代谢物的组合。
可独立控制该组合中各化合物的给药剂量和频率。例如,一种化合物可以每天口服给药三次,而第二种化合物可每天肌内给药一次。这些化合物可一起配制,从而使得将两种化合物一起给药。
本发明的抗增殖组合也可以以药物包装的组分的形式被提供。所述两种药物可被一起配制或者可以独立配制并单独使用各自的剂量。
本发明另一方面包括一种通过与抗增殖剂联合给予式(I)和(V)的化合物来对患有肿瘤如癌的患者进行治疗的方法。适宜的抗增殖剂包括表1中提供的那些化合物。
上下文中所有的温度都是以℃为单位给出的。在下面的实施例中,“常规后处理”是指:如果需要的话,加入水,如果需要的话,根据终产物的组成将pH调至2至10,用乙酸乙酯或二氯甲烷对该混合物进行萃取,进行相分离,将有机相用硫酸钠干燥并对其进行蒸发,然后用硅胶色谱和/或通过结晶对产物进行纯化。硅胶上的Rf值;洗脱剂:乙酸乙酯/甲醇9∶1。
质谱(MS):EI(电子撞击电离)M+
FAB(快原子轰击)(M+H)+
ESI(电喷射电离)(M+H)+
APCI-MS(大气压化学电离-质谱)(M+H)+
实施例1
1-甲基-5-苯基-1,4,5,5a,6,7,8,9a-八氢-9-氧杂-1,4-二氮杂-环戊二烯并[a]萘-2-甲酸甲酯2的合成
a.将胺1的TFA/HCl盐在乙腈中的溶液(向胺1(320mg,1.68mmol)中加入乙腈(2ml),将其冷却至0℃并在搅拌的情况下缓慢向其中加入TFA(0.13ml,1.68mmol))迅速加入到冷却至0℃的苯甲醛(178mg,1.68mmol)和3,4-二氢-2H-吡喃(141mg,1.68mmol)在乙腈(1ml)中的溶液中,将混合物在该温度下再搅拌18小时。向粗品中加入叔-丁基甲基醚(5ml),使所需产物沉淀出来。将其滤出,用叔-丁基甲基醚洗涤并对其进行干燥,得到无色固体(232mg,0.71mmol,42%),证实其是化合物2的顺/反式混合物。
实施例2
(4aS,10R,10aS)-10-苯基-6-三氟甲基-2,3,4a,9,10,10a-六氢-1H-4-氧杂-5,9-二氮杂菲3的合成
b.将5-氨基-2-三氟甲基吡啶的TFA/HCl盐在乙腈中的溶液(向5-氨基-2-三氟甲基吡啶(120mg,0.74mmol)中加入乙腈(1ml),冷却至0℃并在搅拌的情况下缓慢向其中加入TFA(60μl,0.74mmol))迅速加入到冷却至0℃的苯甲醛(80μl,0.79mmol)和3,4-二氢-2H-吡喃(70μl,0.77mmol)在乙腈(1ml)中的溶液中,并将该混合物在80℃下在耐压瓶中再搅拌18小时。将粗品真空蒸发至干,用柱色谱对其进行纯化(乙酸乙酯/环己烷)得到无色固体(80mg,0.24mmol,32%),证实其是化合物3的反式异构体。
实施例3
2-乙基-5-苯基-2,4,5,5a,6,7,8,9a-八氢-9-氧杂-2,4-二氮杂-环戊二烯并[a]萘6的合成
c.在0℃下,将发烟HNO3(0.5ml)加入到位于2ml冰乙酸中的1-乙基吡咯(1.00g,10.5mmol)中,向其中滴加乙酸酐(10ml)并将该混合物在RT下搅拌15小时。将该溶液倾倒到冰上并用乙酸乙酯进行萃取。将有机相用水洗涤,干燥并将其真空蒸发至干。将剩余的深色油状物(0.8g,主要是化合物4)不经进一步纯化直接进行反应。
d.向粗品化合物4(0.4g,约2.85mmol)中加入30ml MeOH,向其中加入Pd/C(5%,H2O湿度为54%,200mg)并将该混合物在氢气气氛下搅拌15小时。将反应混合物过滤并将其蒸发至干。将剩余的深色油状物(0.33g,主要是化合物5)不经进一步纯化直接进行反应。
e.与实施例1类似地使5的TFA盐(330mg,3.00mmol)与苯甲醛(0.32g,3.01mmol)和3,4-二氢-2H-吡喃(0.27ml,2.99mmol)在乙腈(5ml)中进行反应。将粗品蒸发至干并用柱色谱对其进行纯化(乙酸乙酯/环己烷),得到无色固体(26mg,0.09mmol,3%),证实其是化合物6的顺/反混合物。
实施例4
2-异丁基-5-苯基-2,4,5,5a,6,7,8,9a-八氢-9-氧杂-1,2,4-三-氮杂环戊二烯并[a]萘9的合成
4-硝基吡唑按照J.Med.Chem.2005,48,5780-5793中的描述进行合成。
f.将4-硝基吡唑(610mg,5.40mmol)溶解于90ml MeOH中,向其中加入1-碘-2-甲基丙烷(3.8ml,32.9mmol)和KOH小丸(0.91g,16.2mmol)并将该混合物在回流下加热3小时。向反应溶液中加入水,然后反复用DCM对其进行萃取,将所合并的有机相干燥,过滤并将其真空蒸发至干。将剩余的深色油状物(0.67g,主要是化合物7)不经进一步纯化直接进行反应。
d.向粗品化合物7(0.3g,约1.77mmol)中加入10ml MeOH,向其中加入Pd/C(5%,H2O湿度为54%,300mg)并将该混合物在氢气气氛下搅拌15小时。将该反应混合物过滤并将其蒸发至干。将剩余的深色油状物用柱色谱进行纯化(乙酸乙酯/MeOH)得到深色油状的化合物8(190mg,77%)。
e.与实施例1相似地,使8的TFA盐(170mg,1.22mmol)与苯甲醛(0.13g,1.29mmol)和3,4-二氢-2H-吡喃(0.11ml,1.229mmol)在乙腈(2ml)中反应。将粗品蒸发至干并用柱色谱对其进行纯化(乙酸乙酯/环己烷),得到无色固体(42mg,0.13mmol,11%),证实其是化合物9的顺/反混合物。
用相应前体类似地获得下面的本发明化合物:
下面的实施例涉及药物:
实施例C:注射小瓶
用2N盐酸将100g式I的活性成分和5g磷酸氢二钠在3L双蒸水中的溶液调至pH6.5,无菌过滤,将其转移到注射小瓶中,在无菌条件下冷冻干燥并在无菌条件下对其进行密封。每个注射小瓶包含5mg活性成分。
实施例D:栓剂
将20g式I的活性成分与100g大豆卵磷脂和1400g可可豆脂的混合物熔化,倾倒到模具中并使其冷却。每个栓剂包含20mg活性成分。
实施例E:溶液剂
制备1g式I的活性成分、9.38g NaH2PO4·2H2O、28.48g Na2HPO4·12H2O和0.1g苯扎氯铵在940ml双蒸水中的溶液。将其pH调至6.8,将该溶液制备至1L并将其辐射灭菌。该溶液可以以滴眼液的形式使用。
实施例F:软膏剂
在无菌条件下将500mg式I的活性成分与99.5g凡士林混合。
实施例G:片剂
将1kg式I的活性成分、4kg乳糖、1.2kg土豆淀粉、0.2kg滑石粉和0.1kg硬脂酸镁的混合物按照常规方法压制获得片剂,使每片包含10mg活性成分。
实施例H:糖锭剂
按照类似于实施例E的方法压制片剂并随后按照常规方法用蔗糖、土豆淀粉、滑石粉、西黄蓍胶和染色剂的包衣剂进行包衣。
实施例I:胶囊剂
将2kg式I的活性成分按照常规方法装入硬明胶胶囊中,使每粒胶囊包含20mg活性成分。
实施例J:安瓿剂
将1kg式I的活性成分在60L双蒸水中的溶液进行无菌过滤,转移至安瓿中,在无菌条件下冷冻干燥并在无菌条件下密封。每个安瓿包含10mg活性成分。
Claims (24)
1.式I的化合物以及其可药用的衍生物、溶剂化物、互变异构体、盐和立体异构体,包括其所有比例的混合物
其中
E表示
X 表示O、NR或S,
R1、R2彼此独立地表示H、A、Hal、SA、(CH2)pCN、SCN、(CF2)pCF3、SF5、OA、O(CF2)pCF3、S(CF2)pCF3、NR2、NRCOR、NRSO2R、NR(CH2)pNR2、CONR(CH2)pNR2、SO2NR(CH2)pNR2、CONR2、SO2NR2、COOR,
R3表示H、A,
A 表示具有1至10个C原子的直链或支链烷基或具有3至7个C原子的环烷基,
R4表示芳基或杂芳基,其各自未被取代或被下列基团单或多取代:可被Hal、NO2、CN、A、OR、OCOR、NR2、CF3、OCF3、OCH(CF3)2取代的芳基或杂芳基,或Hal、NO2、CN、OR、A、-(CY2)n-OR、-OCOR、-(CY2)n-CO2R、-(CY2)n-CN或-(CY2)n-NR2,
Y 表示H、A、Hal、OR,
R 表示H、A、(CH2)pO(CH2)pR3、(CH2)pNA(CH2)pR3,
W 表示CH2、C=O、C=S或单键,
Q1表示NR、O、S或单键,
Q2表示NR、S、O或单键,
R5表示H、(CY2)pNR2、(CY2)pOR、(CY2)pSR、(CY2)pQ1COQ1R、(CY2)pCOOR,并且,如果Q2表示单键,则R5还表示Hal,
Hal表示F、Br或Cl
n 表示1、2、3或4,
m 表示0、1或2,
p 表示0、1、2、3、4、5、6、7或8,并且
s 表示0、1或2。
2.权利要求1的化合物,其中R1表示烷基、CF3、OCF3、SCN、COOR、CH2CN、OH、S烷基、O烷基、Hal或SCF3。
3.权利要求1或2的化合物,其中R2表示H或Br。
4.权利要求1-3中一项或多项的化合物,其中R3表示H、甲基、乙基、正丙基或正丁基。
5.权利要求1-4中一项或多项的化合物,其中R4表示可被F、Cl、OR或芳基取代的芳基。
6.权利要求1-5中一项或多项的化合物,其中W表示CH2或单键。
7.权利要求1-6中一项或多项的化合物,其中Z表示-SO2-、-SO-、-CO-、-CS或单键。
8.权利要求1-7中一项或多项的化合物,其中Q1和Q2彼此独立地表示单键、NR或O。
9.权利要求1-8中一项或多项的化合物,其中R5表示H、(CY2)pNR2或(CY2)pOR。
10.权利要求1-9中一项或多项的化合物,其中R表示H、A或(CH2)pNA(CH2)pR3。
13.包含至少一种如权利要求1至11所述的式I化合物和/或其可药用的衍生物、盐、溶剂化物、互变异构体和立体异构体,包括其所有比例的混合物,并任选地包含赋形剂和/或辅料的药物。
15.权利要求14的应用,其中所用式V的化合物是喷他脒或其盐。
16.权利要求1至11的化合物以及其可药用的衍生物、盐、溶剂化物、互变异构体和立体异构体,包括其所有比例的混合物,或权利要求14的混合物用于制备治疗可以通过抑制、调节和/或调控有丝分裂动力蛋白Eg5来进行影响的疾病的药物的应用。
17.权利要求1至11的化合物或权利要求14的混合物用于制备治疗和预防癌症疾病的药物的应用。
18.权利要求17的应用,其中所述的癌症疾病伴有选自鳞状上皮、膀胱、胃、肾、头和颈、食管、宫颈、甲状腺、小肠、肝、脑、前列腺、泌尿生殖道、淋巴系统、胃、喉和/或肺肿瘤的肿瘤。
19.权利要求18的应用,其中所述肿瘤来源自单核细胞白血病、肺腺癌、小细胞肺癌、胰腺癌、成角质细胞瘤和乳癌以及结肠癌。
20.权利要求19的应用,其中所治疗的癌症疾病是血液和免疫系统的肿瘤。
21.权利要求20的应用,其中所述肿瘤源自急性骨髓性白血病、慢性骨髓性白血病、急性淋巴性白血病和/或慢性淋巴性白血病。
23.权利要求22的应用,其中所用式V的化合物是喷他脒或其盐。
24.权利要求1至11所述的式I化合物和/或其可药用的盐和溶剂化物用于制备治疗肿瘤的药物的应用,其中将治疗有效量的式I的化合物与放疗和选自1)雌激素受体调节剂、2)雄激素受体调节剂、3)类维生素A受体调节剂、4)细胞毒性剂、5)抗增殖剂、6)异戊二烯基-蛋白转移酶抑制剂、7)HMG-CoA还原酶抑制剂、8)HIV蛋白酶抑制剂、9)逆转录酶抑制剂和10)其它血管生成抑制剂的化合物联合给药。
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