CN1960728A - 构象受限的smac模拟物及其应用 - Google Patents
构象受限的smac模拟物及其应用 Download PDFInfo
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- CN1960728A CN1960728A CNA200580008403XA CN200580008403A CN1960728A CN 1960728 A CN1960728 A CN 1960728A CN A200580008403X A CNA200580008403X A CN A200580008403XA CN 200580008403 A CN200580008403 A CN 200580008403A CN 1960728 A CN1960728 A CN 1960728A
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- smac
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Abstract
本发明涉及Smac的构象受限的模拟物,其作为调亡蛋白抑制剂的抑制剂起作用。本发明还涉及这些模拟物在诱导编程性细胞死亡和使细胞对凋亡诱导物敏感中的应用。
Description
发明背景
发明领域
本发明涉及药物化学领域。特别地,本发明涉及作为编程性细胞死亡蛋白抑制剂的抑制剂而起作用的Smac构象受限性模拟物。本发明还涉及这些模拟物在使细胞对编程性细胞死亡的诱导敏感的应用。
相关领域
侵害性的癌细胞表型是导致胞内信号传导途径失调的多种遗传和渐成式改变的结果(Ponder,Nature 411:336(2001))。然而,对所有癌细胞而言具有普遍性的是它们不能完成编程性细胞死亡程序,而因正常编程性细胞死亡机制的缺陷导致的缺乏适当的编程性细胞死亡为癌症的标志(Lowe等,Carcinogenesis 21:485(2000))。目前癌症疗法中的大部分,包括化疗剂、放射和免疫疗法均通过间接诱导癌细胞中的编程性细胞死亡起作用。因此,癌细胞因正常编程性细胞死亡机制中的缺陷而缺乏完成编程性细胞死亡程序的能力通常与对化疗、放射或免疫疗法诱导的编程性细胞死亡的耐受性相关。不同来源的人体癌症因编程性细胞死亡缺陷而对目前治疗方案具有的原发性或获得性抗性为目前癌症疗法中的主要问题(Lowe等Carcinogeraesis21:485(2000);Nicholson,Nature 407:810(2000))。因此,目前和未来对为改善癌症患者存活期和生活质量而设计并且研发新分子靶-特异性抗癌疗法的努力必须包括特异性地靶向于对编程性细胞死亡有耐受性的癌细胞的策略。在这方面,靶向于在直接抑制癌细胞中的编程性细胞死亡方面起重要作用的关键负调节物代表了用于新抗癌药设计的非常富有前途的治疗策略。
已经鉴定了两类编程性细胞死亡的重要负调节物。第一类调节物为Bcl-2族蛋白,以两种有效的抗编程性细胞死亡分子Bcl-2和Bcl-XL蛋白为典型(Adams等,Science 281:1322(1998);Reed,Adv.Pharmacol.41:501(1997);Reed等,J.Cell.Biochem.60:23(1996))。已经广泛综述了在癌症中靶向于Bcl-2和Bcl-XL以恢复癌细胞敏感性并且克服癌细胞对编程性细胞死亡的抗性的治疗策略(Adams等,Science 281:1322(1998);Reed,Adv.Pharmacol.41:501(1997);Reed等,J.Cell.Biochem.60:23(1996))。目前,Bcl-2反义疗法正处于治疗实体瘤和非实体瘤的几种III期临床试验中。几个实验室致力于设计Bcl-2和Bcl-XL的小分子抑制剂。
编程性细胞死亡的第二类重要负调节物为编程性细胞死亡蛋白抑制剂(IAPs)(Deveraux等,Genes Dev.13:239(1999);Salvesen等,Nat.Rev.Mol.Cell.Biol.3:401(2002))。IAP蛋白有效抑制相当多种编程性细胞死亡刺激,包括化疗剂、放射和免疫疗法在癌细胞中诱导的编程性细胞死亡。
X-连锁的IAP(XIAP)为所有IAP成员中在抑制编程性细胞死亡方面最有效的抑制剂(Holcik等,编程性细胞死亡6:253(2001);LaCasse等,Oncogene 17:3247(1998);Takahashi等,J.Bio Chem273:7787(1998);Deveraux等,Nature 388:300(1997);Sun等,Nature 401:818(1999);Deveraux等,EMBO J.18:5242(1999);Asselin等,Cancer Res.61:1862(2001))。XIAP在死亡受体-介导的和线粒体-介导的两种途径中的编程性细胞死亡负调节中起关键作用。XIAP作为有效的内源性编程性细胞死亡抑制剂通过直接结合和有效抑制半胱天冬酶家族酶中的三个成员半胱天冬酶-3、-7和-9起作用(Takahashi等,J.Biol.Chem.273:7787(1998);Deveraux等,Nature 388:300(1997);Sun等,Nature 401:818(1999);Deveraux等EMBO J.18:5242(1999);Asselin等,Cancer Res.61:1862(2001);Riedl等Cell 104:791(2001);Chai等,Cell 104:769(2001);Huang等,Cell 104:781(2001))。XIAP含有三个杆状病毒编程性细胞死亡抑制剂重复(BIR)结构域和C-末端RING指状结构。第三个BIR结构域(BIR3)选择性靶向半胱天冬酶-9,即线粒体途径中的起始物半胱天冬酶,而BIR1与BIR2之间的连接区抑制半胱天冬酶-3和半胱天冬酶-7二者(Salvesen等,Nat.Rev.Mol.Cell.Biol.3:401(2002))。尽管与XIAP的结合可以防止所有三种半胱天冬酶活化,但是显然与半胱天冬酶-9的相互作用对其抑制编程性细胞死亡而言最为关键(Ekert等,J.Cell Biol.152;483(2001);Srinivasula等,Nature 410:112(2001))。因为XIAP在下游效应期、即多个信号传导途径的汇集点阻断编程性细胞死亡,所以靶向XIAP的策略可以证实对于克服癌细胞对编程性细胞死亡的抗性是尤其有效的(Fulda等,Nature Med.8:808(2002);Arnt等,J.Biol.Chem,277:44236(2002))。
尽管XIAP在每种类型癌症中的确切作用远未得到完全了解,但是有证据确切地表明XIAP在许多类型的癌症中广泛得到过表达,并且可能在癌细胞对多种目前的治疗剂的抗性中起重要作用(Holcik等,Apoptosis 6:253(2001);LaCasse等,Oncogene 17:3247(1998))。
已发现XIAP蛋白在大部分NCI 60人癌细胞系中表达(Tamm等,Clin.Cancer Res.6:1796(2000))。对在78位预先未治疗的患者的肿瘤样品的分析表明,那些具有低水平XIAP的患者显然具有更长的存活期(Tamm等,Clin.Cancer Res.6:1796(2000))。已发现XIAP在人恶性胶质瘤中表达(Wagenknecht等,Cell Death Differ.6:370(1999);Fulda等,Nature Med.8:808(2002))。发现XIAP在人前列腺癌细胞中表达,并且阻断与Apo2配体/肿瘤坏死因子-相关的编程性细胞死亡,这种编程性细胞死亡在有线粒体活化存在下诱导配体介导的前列腺癌细胞编程性细胞死亡(McEleny等,Prostate 51:133(2002);Ng等,Mol.Cancer Ther:1:1051(2002))。XIAP在患者的非小细胞肺癌(NSCLC)中超表达,已发现与NSCLC发病机制有关(Hofmann等,J.Cancer Res.Clin.Ostcol.128:554(2002))。XIAP的表达和使用顺铂治疗时XIAP减量调节的缺乏与人卵巢癌的顺铂抗性有关(Li等Endocrinology 142:370(2001);Cheng等,DrugResist.Update 5:131(2002))。这些数据共同提示XIAP可能在几种人癌对目前治疗剂的抗性中起重要作用。
近来,将Smac/DIABLO(第二种线粒体衍生的半胱天冬酶激活物)鉴定为响应于编程性细胞死亡刺激物而从线粒体释放入胞质溶胶的蛋白质(Budiliardjo等,Annu.Rev.Cell Dev.Biol.15:269(1999);Du等,Cell 102:33(2000))。使用在成熟为成熟多肽过程中通过蛋白水解除去的N-末端线粒体引导肽合成Smac。已证实Smac直接与XIAP和其它IAPs发生相互作用,破坏其与半胱天冬酶的结合,并促进半胱天冬酶活化。Smac为有效的XIAP内源性抑制剂。
近来已经确定了XIAP的BIR3结构域与Smac蛋白和肽相复合的高分辨率实验性三维(3D)结构(Sun等,J.Biol.Chem.275:36152(2000);Wu等,Nature 408:1008(2000))(附图1)。Smac的N-末端四肽(Ala-Val-Pro-Ile或AVPI(SEQ ID NO:1))通过几种氢键相互作用和范德瓦耳斯相互作用识别XIAP的BIR3结构域上的表面沟。还证实BIR3与半胱天冬酶-9之间的相互作用涉及半胱天冬酶-9小亚单位的氨基末端上的四个残基(Ala-Thr-Pro-Phe或ATPF(SEQ ID NO:2))到BIR3结构域上的同一表面沟。近来几种研究已经令人信服地证实Smac通过与半胱天冬酶-9竞争BIR3结构域表面上的相同结合沟而促进半胱天冬酶-9的催化活性(Eket等,J.CellBiol.152:483(2001);Srinivasula等,Nature 410:112(2001))。
不同于大部分蛋白-蛋白相互作用,Smac-XIAP相互作用仅由Smac蛋白上的四个氨基酸残基和XIAP的BIR3结构域上的明确确定的表面沟介导。Smac肽AVPI(SEQ ID NO:1)与XIAP结合的Kd值(Kd=0.4μM)基本上与成熟Smac蛋白相同(Kd=0.42μM)。这种明确确定的相互作用位点对模拟Smac与XIAP之间结合的非肽药物类小分子的设计而言是理想的。
近来证实,由与载体肽结合以促进胞内递送的Smac N-末端前四个氨基酸残基组成的细胞可渗透性Smac肽(AVPI(SEQ ID NO:1))可以在体外使不同肿瘤细胞和在体内使恶性胶质瘤细胞对死亡受体连接或细胞毒性药物诱导的编程性细胞死亡敏感(Fulda等,Nature Med.8:808(2002))。重要的是,这种Smac肽强烈促进Apo2L/TRAIL在颅内恶性胶质瘤的体内异种移植物模型中的抗肿瘤活性。完全根除已建立的肿瘤和小鼠的存活仅在使用Smac肽类和Apo2L/TRAIL的联合疗法时得以实现。具有重要意义的是Smac肽对正常脑组织没有可检测到的毒性。
第二种近期的独立研究还证实,由与不同载体肽结合的Smac N-末端前4-8个氨基酸残基组成的肽促进了编程性细胞死亡的诱导和不同化疗药,包括紫杉醇、依托泊苷、SN-38和多柔比星在MCF-7和其它人乳腺癌细胞系中的长期抗增殖作用(Arnt等,J.Biol.Chem.277:44236(2002))。该研究令人信服地证实了XIAP和cIAP-1为这些肽类在细胞中的主要分子靶。
第三种研究证实与聚精氨酸结合的前7个N-末端残基的Smac肽在非小细胞肺癌H460细胞中可恢复凋亡体活性并且逆转编程性细胞死亡抗性(Yang等Cancer Res.63:831(2003))。已证实XIAP与H460细胞中凋亡体活性的缺乏和半胱天冬酶活性的抑制有关。当与化疗联用时,细胞可渗透的Smac肽使小鼠体内肿瘤生长退化,而对小鼠几乎没有毒性。这些近期独立的研究共同强烈提示,有效的稳定的细胞可渗透Smac肽模拟物可能对人乳腺癌和其它类型的癌症具有显著的治疗潜能。
基于肽的抑制剂为阐明IAPs的抗编程性细胞死亡功能和IAPs在癌细胞对化疗剂的响应方面的作用的有用工具。但基于肽的抑制剂作为可能有用的治疗剂一般存在内在局限性。这些限制包括其细胞渗透性差和体内稳定性差。实际上,在这三种公布的使用基于Smac的肽抑制剂的研究中,所述的肽类必须与载体肽类融合以使其具有相对的细胞渗透性。
为了克服基于肽的抑制剂的内在局限性,本发明包括基于Smac肽和Smac与XIAP BIR3结构域复合的高分辨率实验性三维结构设计非肽模拟物。
发明概述
已普遍接受的是,癌细胞或其支持细胞不能响应于遗传损害或对编程性细胞死亡诱导物(诸如抗癌药和放射)的暴露而经历编程性细胞死亡是癌症发作和发展的主要因素。认为诱导癌细胞或其支持细胞(例如肿瘤脉管系统中的新血管细胞)中的编程性细胞死亡是实际上市场上或当今实际应用的所有有效癌症治疗药或放射疗法的普遍作用机制。细胞不能进行编程性细胞死亡的一个原因在于IAPs的表达和蓄积增加。
本发明认为,患有癌症的动物接触治疗有效量的抑制IAPs功能的药物(例如小分子)将完全杀伤癌细胞或支持细胞(其持续存活依赖于IAPs的过度活性的那些细胞)和/或使得这类细胞作为群体对癌症治疗药或放疗的细胞死亡诱导活性敏感。本发明认为,IAPs的抑制剂满足了对治疗多种癌症类型的尚未得到满足的需求,无论是作为单一疗法进行施用以在依赖于IAP功能的癌细胞中诱导编程性细胞死亡,还是以时间关系与诱导细胞死亡的其它癌症治疗药或放疗组合施用,以使得与仅单独使用癌症治疗药或放疗治疗的动物中相应比例的细胞相比,更大比例的癌细胞或支持细胞对进行编程性细胞死亡程序敏感。
在本发明的某些实施方案中,使用治疗有效量的本发明化合物和抗癌药或放射疗程对动物进行组合治疗在这类动物中产生了与单独使用所述化合物或抗癌药/放射治疗相比更大的肿瘤反应和临床有益性。另一方面,因为所述的化合物可以降低表达IAPs的所有细胞的编程性细胞死亡阈值,所以响应于抗癌药/放射的凋亡诱导活性而成功进行编程性细胞死亡程序的细胞比例增加。或者,使用本发明的化合物可以使得施用较低、因此为低毒性和更具耐受性的剂量的抗癌药和/或放射,同时产生与单独常规剂量的抗癌药/放射相同的肿瘤反应/临床有益性。因为所有经批准的抗癌药和放疗的剂量都是已知的,所以本发明关注它们与本发明化合物的各种组合。此外,因为本发明的化合物至少部分通过抑制IAPs起作用,所以使癌细胞和支持细胞接触治疗有效量的这些化合物可以在时间上使细胞响应于抗癌药或放疗而执行编程性细胞死亡程序的尝试一致进行。因此,在某些实施方案中,给予本发明的组合物与某些临时的相关方案尤其提供了有效的治疗实践。
本发明涉及可用于抑制IAP蛋白活性并且增加细胞对编程性细胞死亡诱导物的敏感性的Smac模拟物。在一个具体的实施方案中,所述的Smac模拟物为通式I的化合物:
或其药物上可接受的盐或前体药物,其中:
R1为C1-2烷基或C1-2卤代烷基;
R2为支链或非支链的烷基或环烷基或者取代或未被取代的芳基、烷基芳基、杂芳基或烷基杂芳基;
X为CONH、CH2O、CH2NH、CH2S或(CH2)1-3;
Y1为(CH2)1-5其中一个或多个碳可以被一个或多个选自氧、硫和氮的杂原子取代,并且CH2基团上的一个或多个氢可以被支链或非支链的烷基或环烷基或者取代或未被取代的芳基、烷基芳基、杂芳基或烷基杂芳基取代;
Y2为(CH2)1-5,其中一个或多个碳可以被一个或多个选自氧、硫和氮的杂原子取代,并且CH2基团上的一个或多个氢可以被支链或非支链的烷基或环烷基或者取代或未被取代的芳基、烷基芳基、杂芳基或烷基杂芳基取代;且
Z为CONH、CH2O、NHCO、(CH2)1-4、(CH2)1-3CONH(CH2)0-3、(CH2)1-3S(CH2)0-3、(CH2)1-3NH(CH2)0-3、(CH2)1-3NHCO(CH2)0-3、(CH2)1-3NHSO2(CH2)0-3、(CH2)1-3NHC(O)NH(CH2)0-3、(CH2)1-3NHC(S)NH(CH2)0-3或(CH2)1-3NR′(CH2)1-3,其中R′为支链或非支链的烷基或环烷基或者取代或未被取代的芳基、烷基芳基、杂芳基或烷基杂芳基。
本发明涉及通式I表示的化合物,它们为IAP蛋白的抑制剂。本发明还涉及本发明的化合物诱导细胞中的编程性细胞死亡的用途。本发明还涉及本发明的化合物在使细胞对编程性细胞死亡诱导物敏感中的应用。这些化合物可用于治疗、改善或预防对凋亡性细胞死亡的诱导有反应性的疾病,例如特征在于编程性细胞死亡失调的疾病,包括过度增殖性疾病,诸如癌症。在某些实施方案中,这些化合物可以用于治疗、改善或预防特征在于对癌症疗法产生耐受性的癌症(例如那些为化学抗性、放射抗性、激素抗性等的癌症)。在其它实施方案中,这些化合物可以用于治疗特征在于IAPs过表达的过度增殖性疾病。
本发明提供了包含通式I化合物的药物组合物,其中所述通式I化合物的存在量为诱导细胞中的编程性细胞死亡或使细胞对编程性细胞死亡诱导物敏感的治疗有效量。
本发明进一步提供了包含通式I化合物和用于对动物给予所述化合物的说明书的试剂盒。这些试剂盒可以可选地含有其它治疗剂,例如抗癌药。
本发明还提供了制备通式I化合物的方法。
附图简述
图1表示Smac肽与XIAP BIR3的模型化复合物。
图2表示基于FP的试验的饱和结合曲线。
图3表示在基于FP的试验中肽类的结合。
图4表示表2中的化合物1与XIAP BIR3的模型化复合物。
图5表示表2中的化合物19与XIAP BIR3的模型化复合物。
图6表示表2中的化合物21与XIAP BIR3的模型化复合物。
图7表示在基于FP的试验中Smac模拟物的结合。
图8表示表4中的化合物34与XIAP BIR3的模型化复合物。
图9表示不同细胞系中XIAP、cIAP-1/2、存活蛋白和Smac的蛋白质印迹分析。
图10A和10B表示PC-3细胞中对顺铂(CDDP)和Smac模拟物产生响应而诱导的编程性细胞死亡。
图11表示PC-3细胞中对CDDP和Smac肽模拟物产生响应而诱导编程性细胞死亡。
图12表示PC-3细胞中对CDDP和Smac模拟物产生响应而诱导的编程性细胞死亡。
图13表示PC-3细胞中对TAXOTERE和Smac模拟物产生响应而诱导编程性细胞死亡。
图14表示MDA-231细胞中对CDDP和Smac模拟物产生响应而诱导编程性细胞死亡。
图15表示超表达XIAP的Jurkat细胞中对依托泊苷和Smac模拟物产生响应而诱导编程性细胞死亡。
图16表示超表达XIAP-Bir3的Jurkat细胞中对依托泊苷和Smac模拟物产生响应而诱导的编程性细胞死亡。
图17表示对放射和Smac模拟物产生响应的集落生长抑制。
图18A-18C表示响应于Smac模拟物的乳腺癌细胞生长抑制。
发明详述
本发明涉及通式I表示的构象受限的化合物,它们为Smac的模拟物并且作为IAPs抑制剂起作用。通过抑制IAPs,这些化合物使细胞对编程性细胞死亡诱导物敏感,并且在某些情况中,其自身诱导编程性细胞死亡。因此,本发明涉及使细胞对编程性细胞死亡诱导物敏感的方法和诱导细胞中的编程性细胞死亡的方法,包括使所述的细胞接触单独的通式I化合物或通式I化合物与编程性细胞死亡诱导物的组合。本发明进一步涉及治疗、改善或预防动物中对诱导编程性细胞死亡有反应性的疾病的方法,包括对所述的动物给予通式I的化合物和编程性细胞死亡诱导物。这类疾病包括那些特征在于编程性细胞死亡失调的疾病和那些特征在于IAPs超表达的疾病。
本文所用的术语″IAP蛋白″指的是编程性细胞死亡蛋白家族抑制剂中的任意已知的成员,包括,但不限于XIAP、cIAP-1、cIAP-2和ML-IAP。
本文所用的术语″IAP超表达″指的是细胞中与表达编码IAP蛋白的mRNAs基础水平或具有IAP蛋白基础水平的相应非病态细胞相比,编码IAP蛋白的mRNAs水平升高(例如异常水平)和/或IAP蛋白的水平升高。用于检测细胞中编码IAP蛋白的mRNAs水平或IAP蛋白水平的方法包括,但不限于使用IAP蛋白抗体的蛋白质印迹、免疫组织化学法和核酸扩增或直接RNA检测法。与细胞中IAP蛋白的绝对水平同样重要的是测定它们超表达IAP蛋白,故还有这类细胞中IAP蛋白与其他促编程性细胞死亡信号传导分子(例如促编程性细胞死亡Bcl-2族蛋白)相比的相对水平。当这两种分子的平衡处于若不是由于IAP蛋白水平、促编程性细胞死亡信号传导分子将足以使细胞进行编程性细胞死亡程序并且死亡这种状态时,所述的细胞将依赖于IAP蛋白才能存活。在这类细胞中,接触抑制有效量的IAP蛋白抑制剂将足以使细胞进行编程性细胞死亡程序并且死亡。因此,术语″IAP蛋白的超表达″还指因促编程性细胞死亡信号和抗-编程性细胞死亡信号的相对水平而导致细胞响应抑制IAP蛋白功能的抑制有效量的化合物发生编程性细胞死亡。
本文所用的术语″抗癌剂(anticancer agent)″和″抗癌药(anticancer drug)″指的是用于治疗过度增殖性疾病,诸如癌症(例如哺乳动物中)的任意治疗剂(例如化疗化合物和/或分子治疗化合物)、放疗或外科手术。
本文所用的术语″前体药物″指的是需要在靶生理系统中发生生物转化(例如自发或酶促)以将前体药物释放或转化(例如通过酶、机械、电磁方式)成活性药物的母体″药物″分子的药物上无活性的衍生物。设计前体药物是为了克服与稳定性、毒性、缺乏特异性或生物利用度有限相关的问题。典型的前体药物包括活性药物分子自身和化学掩蔽基团(例如可逆地抑制所述药物活性的基团)。某些优选的前体药物为带有在代谢条件下可裂解的基团的化合物的变化形式或衍生物。典型的前体药物在它们在生理条件进行进行溶剂解或进行酶降解或其它生物转化(例如磷酸化、氢化、脱氢、糖基化)时在体内或体外变成具有药学活性。前体药物通常提供在哺乳动物体内溶解度、组织相容性或延缓释放的优点(例如,参见Bundgard,Design of Prodrugs,pp.7-9,21-24,Elsevier,Amsterdam(1985);和Silverman,The OrganicChemistry of Drug Design and Drug Action,pp.352-401,AcademicPress,San Diego,CA(1992))。常用的前体药物包括酸性衍生物,诸如通过使母体酸与合适的醇(例如低级链烷醇)反应制备的酯类,通过使母体酸与胺反应制备的酰胺类,或反应生成酰化碱性衍生物的碱性基团(例如低级烷基酰胺)。
本文所用的术语″药物上可接受的盐″指的是在靶动物(例如哺乳动物)体内为生理上耐受的本发明化合物的任意盐(例如通过与酸或碱反应获得)。本发明化合物的盐可以来源于无机酸和碱或者有机酸和碱。酸的实例包括,但不限于盐酸、氢溴酸、硫酸、硝酸、高氯酸、富马酸、马来酸、磷酸、乙醇酸、乳酸、水杨酸、琥珀酸、对甲苯磺酸、酒石酸、乙酸、柠檬酸、甲磺酸、乙磺酸、甲酸、苯甲酸、丙二酸、磺酸、萘-2-磺酸、苯磺酸等。其它自身并非药物上可接受的酸,诸如草酸,可以用于制备用作获得本发明化合物及其药物上可接受的酸加成盐的中间体。
碱的实例包括,但不限于碱金属(例如钠)氢氧化物、碱土金属(例如镁)氢氧化物、氨和通式NW4 +的化合物,其中W为C1-4烷基,等。
盐的实例包括,但不限于:乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、氟庚酸盐(flucoheptanoate)、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、氯化物、溴化物、碘化物、2-羟基乙磺酸盐、乳酸盐、马来酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、草酸盐、棕榈酸盐、果胶酸盐、过硫酸盐、苯基丙酸盐、苦味酸盐、新戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐、十一酸盐等。盐的其它实例包括与合适的阳离子诸如Na+、NH4 +和NW4 +(其中W为C1-4烷基)化合的本发明化合物的阴离子等。为了治疗应用,关注药物上可接受的本发明化合物的盐。然而,例如,非药物上可接受的酸和碱的盐也可以应用于制备或纯化药物上可接受的化合物。
本文所用的术语″治疗有效量″指的是足以使得疾病的一种或多种症状改善或者预防疾病进展或者导致疾病退化的治疗剂用量。例如,就治疗癌症而言,治疗有效量优选指的是减小肿瘤生长率、减小肿瘤块、减少转移瘤的数量、增加肿瘤进展的时间或增加存活时间至少5%,优选至少10%,至少15%,至少20%,至少25%,至少30%,至少35%,至少40%,至少45%,至少50%,至少55%,至少60%,至少65%,至少70%,至少75%,至少80%,至少85%,至少90%,至少95%或至少100%的治疗剂用量。
本文所用的术语″致敏(sensitize)″和″敏感(sensitizing)″指的是通过给予第一种治疗剂(例如通式I的化合物)使动物或动物体内的细胞对第二种活性剂的生物作用(例如促进或阻滞细胞功能的方面,包括,但不限于细胞生长、增殖、侵害、血管发生或编程性细胞死亡)更为敏感或更具反应性。可以将第一种活性剂对靶细胞的致敏效应以在与和不与第一种活性剂一起给予第二种活性剂时观察到的指定生物作用(例如促进或阻滞细胞功能的方面,包括,但不限于细胞生长、增殖、侵害、血管发生或编程性细胞死亡)的差异来度量。致敏细胞的反应可以比在没有第一种活性剂存在下的反应增加至少10%,至少20%,至少30%,至少40%,至少50%,至少60%,至少70%,至少80%,至少90%,至少100%,至少150%,至少200%,至少350%,至少300%,至少350%,至少400%,至少450%或至少500%。
本文所用的术语″编程性细胞死亡失调″指的是细胞通过编程性细胞死亡发生细胞死亡(例如遗传倾向性)的能力上的任何异常。编程性细胞死亡失调与各种状况相关或由它们诱导,包括:例如自身免疫性疾病(例如系统性红斑狼疮、类风湿性关节炎、移植物抗宿主病、重症肌无力或斯耶格仑综合症)、慢性炎症疾病(例如银屑病、哮喘或克罗恩病)、过度增殖性疾病(例如肿瘤、B细胞淋巴瘤或T细胞淋巴瘤)、病毒感染(例如疱疹、乳头瘤或HIV)和其它疾病,诸如骨关节炎和动脉粥样硬化。应注意当这种失调由病毒感染诱导或与之相关时,在发生或观察到失调时可能检测到病毒感染,也可能未检测到病毒感染。即病毒-诱导的失调甚至可能在病毒感染症状消失后发生。
本文所用的术语″过度增殖性疾病″指的是动物体内的增殖细胞的局限化群体不受通常的正常生长限制的控制。过度增殖性疾病的实例包括肿瘤、赘生物、淋巴瘤等。如果赘生物未发生侵害或转移,那么认为赘生物为良性的;如果这两种情况中发生一种,那么认为是恶性的。″转移″细胞指的是细胞可以侵入和破坏附近的身体结构。增生是细胞增殖的一种形式,包括组织或器官中的细胞数量增加,而结构或功能没有显著改变。组织变形是受控细胞生长的一种形式,其中一种类型的完全分化细胞取代了另一种类型的分化细胞。
活化淋巴样细胞的病理性生长通常导致自身免疫性疾病或慢性炎症疾病。本文所用的术语″自身免疫性疾病″指的是生物体产生识别生物体自身分子、细胞或组织的抗体或免疫细胞的任何疾病。自身免疫性疾病的非限制性实例包括自身免疫性溶血性贫血、自身免疫性肝炎、贝格尔病或IgA肾病、口炎性腹泻、慢性疲乏综合征、克罗恩病、皮肌炎、纤维肌痛、移植物抗宿主病、格雷夫斯病、桥本甲状腺炎、特发性血小板减少性紫癜、扁平苔癣、多发性硬化、重症肌无力、银屑病、风湿热、风湿性关节炎、硬皮病、斯耶格伦综合症、系统性红斑狼疮、1型糖尿病、溃疡性结肠炎、白癜风等。
本文所用的术语″肿瘤性疾病″指的是为良性(非癌性)或恶性(癌性)的任何异常细胞生长。
本文所用的术语″抗肿瘤药″指的是阻止被靶向的(例如恶性)赘生物增殖、生长或扩散的任意化合物。
本文所用的术语″预防(prevent)″指的是动物体内病态细胞(例如过度增殖性或赘生性细胞)的出现减少。预防可以为完全性的,例如受试者体内的病态细胞总体上不存在。预防还可以为部分的,使得受试者体内出现的病态细胞少于未使用本发明出现的病态细胞。
本发明的IAPs抑制剂为具有一般通式I的化合物:
或其药物上可接受的盐或前体药物,其中:
R1为C1-2烷基或C1-2卤代烷基;
R2为支链或非支链的烷基或环烷基或取代或未被取代的芳基、烷基芳基、杂芳基或烷基杂芳基;
X为CONH、CH2O、CH2NH、CH2S或(CH2)1-3;
Y1为(CH2)1-5,其中一个或多个碳可以被一个或多个选自氧、硫和氮的杂原子取代,并且CH2基团上的一个或多个氢可以被支链或非支链的烷基或环烷基或取代或未被取代的芳基、烷基芳基、杂芳基或烷基杂芳基取代;
Y2为(CH2)1-5,其中一个或多个碳可以被一个或多个选自氧、硫和氮的杂原子取代,并且CH2基团上的一个或多个氢可以被支链或非支链的烷基或环烷基或取代或未被取代的芳基、烷基芳基、杂芳基或烷基杂芳基取代;且
Z为CONH、CH2O、NHCO、(CH2)1-4、(CH2)1-3CONH(CH2)0-3、(CH2)1-3S(CH2)0-3、(CH2)1-3NH(CH2)0-3、(CH2)1-3NHCO(CH2)0-3、(CH2)1-3NHSO2(CH2)0-3、(CH2)1-3NHC(O)NH(CH2)0-3、(CH2)1-3NHC(S)NH(CH2)0-3或(CH2)1-3NR′(CH2)0-3,其中R′为支链或非支链的烷基或环烷基或取代或未被取代的芳基、烷基芳基、杂芳基或烷基杂芳基。
有用的烷基包括直链或支链C1-10烷基,尤其是甲基、乙基、丙基、异丙基、叔丁基、仲丁基、3-戊基、金刚烷基、降冰片基和3-己基。
有用的芳基包括C6-14芳基,尤其是苯基、萘基、菲基、蒽基、茚基、薁基、联苯基、联亚苯基和芴基。
有用的杂芳基包括噻吩基、苯并[b]噻吩基、萘并[2,3-b]噻吩基、噻蒽基、呋喃基、吡喃基、异苯并呋喃基、色烯基、呫吨基、吩呫吨基(phenoxanthenyl)、2H-吡咯基、吡咯基、咪唑基、吡唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、中氮茚基、异吲哚基、3H-吲哚基、吲哚基、吲唑基、嘌呤基、4H-喹嗪基、异喹啉基、喹啉基、酞嗪基(phthalzinyl)、萘啶基、喹喔啉基(quinozalinyl)、噌啉基、蝶啶基、咔唑基、β-咔啉基、菲啶基、吖啶基、咱啶基、菲咯啉基、吩嗪基、异噻唑基、吩噻嗪基、异唑基、呋咱基、吩嗪基、1,4-二氢喹喔啉-2,3-二酮、7-氨基香豆素、吡啶并[1,2-a]嘧啶-4-酮、1,2-苯并异唑-3-基、苯并咪唑基、2-羟吲哚基和2-氧代苯并咪唑基。如果杂芳基在环上含有氮原子,那么这类氮原子可以为N-氧化物形式,例如吡啶基N-氧化物、吡嗪基N-氧化物、嘧啶基N-氧化物等。
可选的取代基包括一个或多个烷基;卤素;卤代烷基;环烷基;可选地被一个或多个低级烷基、卤素、卤代烷基或杂芳基取代的芳基;可选地被一个或多个低级烷基、卤代烷基或杂芳基取代的芳氧基;可选地被一个或多个低级烷基、卤代烷基和芳基取代的芳烷基、杂芳基;可选地被一个或多个低级烷基、卤代烷基和芳基取代的杂芳氧基;烷氧基;烷硫基;芳硫基;氨基;酰氧基;可选地被一个或多个低级烷基、卤代烷基和芳基取代的芳基酰氧基;可选地被一个或多个低级烷基、卤素或卤代烷基取代的二苯基氧膦基氧基;可选地被一个或多个低级烷基、卤代烷基和芳基取代的杂环;可选地被一个或多个低级烷基、卤代烷基和芳基取代的杂环烷氧基;可选地被一个或多个低级烷基、卤代烷基和芳基取代的部分不饱和的杂环烷基;或可选地被一个或多个低级烷基、卤代烷基和芳基取代的部分不饱和的杂环烷氧基。
有用的环烷基为C3-8环烷基。典型的环烷基包括环丙基、环丁基、环戊基、环己基和环庚基。
有用的饱和或部分饱和的碳环基为如上述定义的环烷基以及环烯基,诸如环戊烯基、环庚烯基和环辛烯基。
有用的卤素或卤素基团包括氟、氯、溴和碘。
有用的芳基烷基包括被任意上述C6-14芳基取代的任意上述C1-10烷基。有用的值包括苄基、苯乙基和萘基甲基。
有用的卤代烷基包括被一个或多个氟、氯、溴或碘原子取代的C1-10烷基,例如氟甲基、二氟甲基、三氟甲基、五氟乙基、1,1-二氟乙基、氯甲基、氯氟甲基和三氯甲基。
有用的烷氧基包括被上述C1-10烷基之一取代的氧。
有用的烷硫基包括被上述C1-10烷基之一取代的硫。还包括这类烷硫基的亚砜类和砜类。
有用的酰氨基包括羰基酰氨基和与氨基氮连接的任何C1-6酰基(烷酰基),例如乙酰氨基、丙酰氨基、丁酰氨基、戊酰氨基、己酰氨基和芳基-取代的C2-6取代的酰基。
有用的酰氧基为与氧(--O--)基团连接的任意C1-6酰基(烷酰基),例如甲酰氧基、乙酰氧基、丙酰氧基、丁酰氧基、戊酰氧基、己酰氧基等。
有用的芳基酰氧基包括在上述任意酰氧基上被取代的任意上述芳基,例如2,6-二氯苯甲酰氧基、2,6-二氟苯甲酰氧基和2,6-二-(三氟甲基)-苯甲酰氧基。
有用的氨基包括-NH2、--NHR11和--NR11R12,其中R11和R12为如上述定义的C1-10烷基或环烷基。
有用的饱和或部分饱和的杂环基包括四氢呋喃基、吡喃基、哌啶基、哌嗪基、吡咯烷基、咪唑烷基、咪唑啉基、二氢吲哚基、异二氢吲哚基、奎宁环基、吗啉基、异苯并二氢吡喃基、苯并二氢吡喃基、吡唑烷基、吡唑啉基、特窗酰基(tetronoyl)和tetramoyl。
本发明的某些化合物可以作为立体异构体存在,包括旋光异构体。本发明包括所有的立体异构体和这类立体异构体的外消旋混合物以及可以按照本领域技术人员众所周知的方法分离的各对映体。
在一个实施方案中,本发明的化合物具有通式II的立体化学,其中变量如上述定义。
在本发明的某些实施方案中,通式I的化合物包括:
可以使用本领域技术人员公知的方法制备本发明的化合物。特别地,可以如实施例中的典型方案中所解释的制备具有通式I的化合物。
本发明的一个重要方面在于通式I的化合物可诱导编程性细胞死亡并且还强化诱导编程性细胞死亡作为对编程性细胞死亡诱导信号的反应。因此,关注这些化合物使细胞对编程性细胞死亡诱导物敏感,包括对这类诱导物产生抗性的细胞。本发明的IAP抑制剂可以用于诱导可以通过诱导编程性细胞死亡进行治疗、改善或预防的任何疾病中的编程性细胞死亡。因此,本发明提供了靶向于特征为超表达IAP蛋白的动物的组合物和方法。在某些实施方案中,所述的细胞(例如癌细胞)与非病理性样品(例如非癌细胞)相比IAP蛋白的表达水平升高。在其它实施方案中,所述的细胞通过响应于抑制有效量的通式I化合物进行编程性细胞死亡程序和死亡而可操作地表现出IAP蛋白的表达水平升高,所述的反应至少部分因这类细胞中其存活对IAP蛋白功能的依赖性而发生。
在某些实施方案中,本发明的组合物和方法用于治疗动物(例如哺乳动物受试者,包括,但不限于人和兽类动物)中患病细胞、组织、器官或病理情况和/或疾病状态。在这方面,各种疾病和病理情况易于使用本发明的方法和组合物进行治疗或预防。这些疾病和情况的非限制性典型实例包括,但不限于乳腺癌、前列腺癌、淋巴瘤、皮肤癌、胰腺癌、结肠癌、黑素瘤、恶性黑素瘤、卵巢癌、脑癌、原发性脑癌、头-颈癌、神经胶质瘤、成胶质细胞瘤、肝癌、膀胱癌、非-小细胞肺癌、头或颈癌、乳腺癌、卵巢癌、肺癌、小细胞肺癌、维尔姆斯肿瘤、宫颈癌、睾丸癌、膀胱癌、胰腺癌、胃癌、结肠癌、前列腺癌、泌尿生殖器癌、甲状腺癌、食道癌、骨髓瘤、多发性骨髓瘤、肾上腺癌、肾细胞癌、子宫内膜癌、肾上腺皮质癌、恶性胰腺胰岛素瘤、恶性类癌瘤、绒毛膜癌、蕈样真菌病、恶性血钙过多、宫颈超常增生、白血病、急性淋巴细胞性白血病、慢性淋巴细胞性白血病、急性骨髓性白血病、慢性髓细胞性白血病、慢性粒细胞性白血病、急性粒细胞性白血病、毛细胞性白血病、成神经细胞瘤、横纹肌肉瘤、卡波西肉瘤、真性红细胞增多、原发性血小板增多、何杰金病、非何杰金淋巴瘤、软组织肉瘤、骨肉瘤、原发性巨球蛋白血症和视网膜母细胞瘤等;T和B细胞介导的自身免疫病;炎性疾病;感染;过度增殖性疾病;AIDS;变性疾病、血管疾病等。在某些实施方案中,所治疗的癌细胞为转移性的。在其它实施方案中,所治疗的癌细胞对抗癌药有抗性。
在某些实施方案中,适合于用本发明组合物和方法治疗的感染包括,但不限于因病毒、细菌、真菌、支原体、肮病毒等导致的感染。
本发明的某些实施方案提供了给予有效量的通式I化合物和至少一种额外的治疗剂(包括,但不限于化疗抗肿瘤药、抗菌药、抗病毒药和抗炎药)和/或治疗技术(例如外科手术和/或放疗)的方法。
预计许多合适的抗癌药可用于本发明方法。实际上,本发明关注,但不限于大量抗癌药的给药,诸如:诱导编程性细胞死亡的活性剂;多核苷酸(例如反义,核酶,siRNA);多肽类(例如酶和抗体);生物模拟物(例如棉酚或BH3模拟物);与Bcl-2族蛋白,诸如Bax结合(例如寡聚化或复合)的活性剂;生物碱类;烷化剂;抗肿瘤抗生素;抗代谢物;激素;铂化合物;单克隆或多克隆抗体(例如与抗癌药、毒素、防御素缀合的抗体)、毒素;放射性核素;生物反应调节剂(例如干扰素(例如IFN-α)和白细胞介素(例如IL-2));过继免疫治疗剂;造血生长因子;诱导肿瘤细胞分化的活性剂(例如全反式视黄酸);基因疗法试剂(例如反义疗法试剂和核苷酸);肿瘤疫苗;血管生成抑制剂;蛋白体抑制剂;NF-κB调节剂;抗-CDK化合物;HDAC抑制剂等。适合于与披露的化合物共同给药的化疗化合物和抗癌疗法的大量其它实例为本领域技术人员公知的。
在优选的实施方案中,抗癌药包括诱导或刺激编程性细胞死亡的活性剂。诱导编程性细胞死亡的活性剂包括,但不限于放射(例如X-射线、γ射线、UV);激酶抑制剂(例如表皮生长因子受体(EGFR)激酶抑制剂、血管生长因子受体(VGFR)激酶抑制剂、成纤维细胞生长因子受体(FGFR)激酶抑制剂、血小板衍生生长因子受体(PDGFR)激酶抑制剂和Bcr-Abl激酶抑制剂(诸如GLEEVEC));反义分子;抗体(例如HERCEPTIN、RITUXAN、ZEVALIN和AVASTIN);抗雌激素药(例如雷洛昔芬和他莫昔芬);抗雄激素药(例如氟他胺、比卡鲁胺、非那雄胺、氨鲁米特、酮康唑和皮质类固醇);环加氧酶2(COX-2)抑制剂(例如塞来考昔、美洛昔康、NS-398和非类固醇抗炎药(NSAIDs));消炎药(例如保泰松、DECADRON、DELTASONE、地塞米松、dexamethasone intensol、DEXONE、HEXADROL、羟氯喹、METICORTEN、ORADEXON、ORASONE、羟布宗、PEDIAPRED、保泰松、PLAQUENIL、泼尼松龙、泼尼松、PRELONE和TANDEARIL);和癌症化疗药(例如伊立替康(CAMPTOSAR)、CPT-11、氟达拉滨(FLUDARA)、达卡巴嗪(DTIC)、地塞米松、米托蒽醌、MYLOTARG、VP-16、顺铂、卡铂、奥沙利铂、5-FU、多柔比星、吉西他滨、bortezomib、gefitinib、贝伐单抗、TAXOTERE或TAXOL);细胞信号传导分子;神经酰胺类和细胞因子;星孢素等。
在其它实施方案中,本发明的组合物和方法提供了通式I的化合物和至少一种选自烷化剂、抗代谢物和天然产物(例如草药和其它植物和/或动物衍生的化合物)的抗-过度增殖药或抗肿瘤药。
适用于本发明组合物和方法的烷化剂包括,但不限于:1)氮芥类(例如氮芥、环磷酰胺、异环磷酰胺、美法仑(L-沙可来新);和苯丁酸氮芥);2)氮丙啶类和甲基蜜胺类(例如六甲蜜胺和塞替派);3)磺酸烷基酯类(例如白消安);4)亚硝基脲类(例如卡莫司汀(BCNU);洛莫司汀(CCNU);司莫司汀(赛氮芥);和链佐星(链唑霉素));和5)三氮烯类(例如达卡巴嗪(DTIC;二甲基三嗪并咪唑甲酰胺)。
在某些实施方案中,适用于本发明组合物和方法的抗代谢物包括,但不限于:1)叶酸类似物(例如甲氨蝶呤(氨甲蝶呤));2)嘧啶类似物(例如氟尿嘧啶(5-氟尿嘧啶;5-FU)、氟尿苷(氟脱氧尿苷;FudR)和阿糖胞苷(阿糖胞苷));和3)嘌呤类似物(例如巯嘌呤(6-巯嘌呤;6-MP)、硫鸟嘌呤(6-硫鸟嘌呤;TG)和喷司他丁(2′-脱氧柯福霉素))。
在其它实施方案中,适用于本发明组合物和方法的化疗剂包括,但不限于:1)长春花生物碱(例如长春碱(VLB)、长春新碱);2)表鬼臼毒素(例如依托泊苷和替尼泊苷);3)抗生素(例如更生霉素(放线菌素D)、柔红霉素(道诺霉素;柔毛霉素)、多柔比星、博来霉素、普卡霉素(光辉霉素)和丝裂霉素(丝裂霉素C));4)酶(例如L-天冬酰胺酶);5)生物响应调节剂(例如干扰素-α);6)铂配位复合物(例如顺铂(顺式-DDP)和卡铂);7)蒽二酮类(例如米托蒽醌);8)取代的脲类(例如羟基脲);9)甲基肼衍生物(例如丙卡巴肼(N-甲基肼;MIH));10)肾上腺皮质抑制剂(例如米托坦(o,p′-DDD)和氨鲁米特);11)肾上腺皮质类固醇类(例如泼尼松);12)黄体酮(例如己酸羟孕酮、醋酸甲羟孕酮和醋酸甲地孕酮);13)雌激素(例如己烯雌酚和炔雌醇);14)抗雌激素药(例如他莫昔芬);15)雄激素(例如丙酸睾酮和氟甲睾酮);16)抗雄激素药(例如氟他胺);和17)促性腺激素释放激素类似物(例如亮丙瑞林)。
常用于癌症疗法的任何溶瘤剂可应用于本发明的组合物和方法中。例如,美国食品与药品监督管理局维持了批准用于美国的溶瘤剂配方集。U.S.F.D.A.的国际合作机构维持了相似的配方集。表1中提供了批准用于美国的典型抗肿瘤药的实例。本领域技术人员可以理解,对所有美国批准的化疗药所需的″产品标签″描述了所列举的活性剂被批准的适应征、给药信息、毒性数据等。
表1
阿地白介素(去-丙氨酰基-1,丝氨酸-125人白细胞介素-2) | Proleukin | Chiron Corp.,Emeryville,CA |
阿仑单抗(IgG1κ抗CD52抗体) | Campath | Millennium和ILEXPartners,LP,Cambridge,MA |
阿利维A酸(9-顺式-维A酸) | Panretin | LigandPharmaceuticals,Inc.,San Diego CA |
别嘌醇(1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮一钠盐) | Zyloprim | GlaxoSmithKline,ResearchTriangle Park,NC |
六甲蜜胺(N,N,N’,N’,N”,N”,-六甲基-1,3,5-三嗪-2,4,6-三胺) | Hexalen | US Bioscience,WestConshohocken,PA |
氨磷汀(乙硫醇,2-[3-氨基丙基)氨基)-,二氢磷酸(酯)) | Bthyol | US Bioscience |
阿那曲唑(1,3-苯二乙腈,a,a,a’a’-四甲基-5-(1H-1,2,4-三唑-1-基甲基)) | Arimidex | AstraZencaPharmaceuticals,LP,Wilmington,DE |
三氧化二砷 | Trisenox | Cell Therapeutic,Inc.,Seattle,WA |
天冬酰胺酶(L-天冬酰胺酰胺水解酶,EC-2型) | Elspar | Merck & Co.,Inc.,Whitehouse Station.NJ |
活BCG(牛分枝杆菌减毒株的冻干制品(卡介苗(Bacilluscalmette-Gukin))[BCG],次代菌株Montreal) | TICE BCG | Organon Teknika,Corp.,Durham,NC |
贝沙罗汀胶囊(4-[1-(5,6,7,8-四氢-3,5,5,8,8-五甲基-2-萘基)乙烯基]苯甲酸) | Targretin | Ligand Pharmaceuticals |
贝沙罗汀凝胶 | Targretin | Ligand Pharmaceuticals |
博来霉素(轮枝链霉菌产生的细胞毒性糖肽抗生素;博来霉素A2和博来霉素B2) | Blenoxane | Bristol-Myers Squibb Co.,NY,NY |
卡培他滨(5’-脱氧-5-氟-N-[(戊氧基)羰基]-胞苷) | Xeloda | Roche |
卡铂(铂,二胺[1,1-环丁烷二羧酸(2-)-O,O’]-,(SP-4-2)) | Paraplatin | Bristol-Myers Squibb |
卡莫司汀(1,3-双(2-氯乙基)-1-亚硝基脲) | BCNU,BiCNU | Bristol-MyersSquibb |
卡莫司汀与聚苯丙生20植入物 | Gliadel Wafer | GuilfordPharmaceuticals,Inc.,Baltimore,MD |
塞来考昔(为4-[5-(4-甲基苯基)-3-(三氟甲基)-1H-吡唑-1-基]苯磺酰胺) | Celebrex | SearlePharmaceuticals,England |
苯丁酸氮芥(4-[双(2氯乙基)氨基]苯丁酸) | Leukeran | GlaxoSmithKline |
顺铂(PtCl2H6N2) | Platinol | Bristol-Myers Squibb |
克拉屈滨(2-氯-2’-脱氧-b-D-腺苷) | Leustatin,2CdA | R.W.JohnsonParmaceutical ResearchInstitute,Raritan,NJ |
环磷酰胺(2-[双(2-氯乙基)氨基]四氢-2H-13,2-氧杂氮杂磷杂环己烯2-氧化物一水合物 | Cytoxan,Neosar | Bristol-Myers Squibb |
阿糖胞苷(1-b-D-阿糖呋喃糖胞噻啶,C9H13N3O5) | Cystosar-U | Pharmaceuticals,Inc.,San Diego,CA |
阿糖胞苷脂质体 | DepoCyt | Bayer AG,Leverkusen,Germany |
达卡巴嗪(5-(3,3-二甲基-1-三氮烯基)-咪唑-4-甲酰胺(DTIC) | DTIC-Dome | Merck |
更生霉素,放线菌素D(微小链霉菌产生的放线菌素,C62H86N12O16) | Cosmegen | Merck |
Darbepoetin alfa(重组肽) | Aranesp | Amgen,Inc.,TousandOaks,CA |
柔红霉素脂质体((8S-顺式)-8-乙酰基-10-[(3-氨基-2,3,6-三脱氧-á-L-来苏-吡喃己糖基(hexopyranosyl))氧基]-7,8,9,10-四氢-6,8,11-三羟基-1-甲氧基-5,12-萘二酮盐酸盐 | DauoXome | Nexstar Pharmaceuticals,Inc.,Boulder,CO |
盐酸柔红霉素,道诺霉素((1S,3S)-3-乙酰基-1,2,3,4,6,11-六氢-3,5,12-三羟基-10-甲氧基-6,11-二氧代-1-萘基3-氨基-2,3,6-三脱氧-(α)-L-来苏-吡喃己糖苷(hexopyranoside)盐酸盐) | Cerubidine | Wyeth Ayerst,Madison,NJ |
地尼白介素-毒素连接物(重组肽) | Ontak | Sergen,Inc.,Hopkinton,MA |
右雷佐生((S)-4,4’-(1-甲基-1,2-乙二基)双-2,6-哌嗪二酮 | Zinecard | Pharmacia & UpjohmCompany |
多西他赛((2R,3S)-N-羧基-3-苯基异丝氨酸,N-叔丁基酯,13-酯与5b-20-环氧-12a,4,7b,10b,13a-六羟基tax-11-烯-9-酮4-乙酸酯2-苯甲酸酯三水合物) | Taxotere | Aventis PharmaceuticalsInc.,Bridgewater,NJ |
盐酸多柔比星(8S,10S)-10-[(3-氨基-2,3,6-三脱氧-a-L-来苏-吡喃己糖基(hexopyranosyl))氧基]-8-乙醇酰基-7,8,9,10-四氢-6,8,11-三羟基-1-甲氧基-5,12-萘二酮盐酸盐 | Adriamycin,Rubex | Pharmacia & UpjohmCompany |
多柔比星 | Adrimycin PFS静脉内注射剂 | Pharmacia & UpjohmCompany |
多柔比星脂质体 | Doxil | Sequus Pharmaceuticlas,Inc.,Menlo park,CA |
丙酸甲雄烷酮(17b-羟基-2a-甲基-5a-雄烷-3-酮丙酸酯) | Dromostanolone | Eli Lilly & Company,Indianapolis,IN |
丙酸甲雄烷酮 | Masterone注射剂 | Syntex,Corp.,Palo Alt,CA |
Elliott’s B溶液 | Elliott’s B溶液 | Orphan Medical,Inc. |
表柔比星((8S-顺式)-10-[(3-氨基-2,3,6-三脱氧-a-L-阿拉伯糖-吡喃己糖基(hexopyranosyl))氧基-7,8,9,10-四氢-6,8,11-三羟基-8-(羟 | Eilence | Pharmacia & UpjohmCompany |
基乙酰基)-1-氧基-5,12-萘二酮盐酸盐 | ||
阿法依伯汀(重组肽) | Epogen | Amgen.Inc. |
雌莫司汀(雌-1,3,5(10)-三烯-3,17-二醇(17(β))-,3-[双(2-氯乙基)氨基甲酸酯]17-(二氢磷酸),二钠盐,一水合物,或雌二醇3-[双(2-氯乙基)氨基甲酸酯]17-(二氢磷酸),二钠盐,一水合物) | Emcyt | Pharmacia & UpjohmCompany |
磷酸依托泊苷(4’-去甲基表鬼臼毒素9-[4,6-O-(R)-亚乙基-(β)-D-吡喃葡萄糖苷],4’-(二氢磷酸盐) | Etopophos | Bristol-Myers Squibb |
依托泊苷,VP-16(4’-去甲基表鬼臼毒素9-[4,6-O-(R)-亚乙基-(β)-D-吡喃葡萄糖苷]) | Vepesid | Bristol-Myers Squibb |
依西美坦(6-亚甲基雄-1,4-二烯-3,17-二酮) | Aromasin | Pharmacia & UpjohmCompany |
非格司亭(r-metHuG-CSF) | Neupogen | Amgen,Inc. |
氟尿苷(动脉内)(2’-脱氧-5-氟尿苷) | FUDR | Roche |
氟达拉滨(抗病毒药阿糖腺苷的氟化核苷酸类似物,9-b-阿糖呋喃糖腺嘌呤)(ara-A) | Fludara | Beriex Laboratories,Inc.,Cedar Knolls,NJ |
氟尿嘧啶,5-FU(5-氟-2,4(1H,3H)-嘧啶二酮) | Adrucil | ICN Pharmaceuticals,Inc.,Humacao,PuertoRico |
氟维司群(7-α-[9-(4,4,5,5,5-五氟戊基亚磺酰基)壬基]雌-1,3,5-(10)-三烯-3,17-β-二醇) | Faslodex | IPR Pharmaceuticals,Guyama,Peurto Rico |
吉西他滨(2’-脱氧-2’,2’-二氟胞苷一盐酸盐(b-异构体)) | Cemzar | Eli lilly |
吉姆单抗奥佐米星(抗-CD33 hP67.6) | Mylotag | Wyeth Ayerst |
醋酸戈舍瑞林[D-Ser(But)5,Azgly10]LHRH的乙酸盐;pyro-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2乙酸盐[C59H84N18O14·(C2H4O2)x | Zoladex植入物 | AstraZenecaPhrmaceuticals |
羟基脲 | Hydrea | Bristol-MyersSquibb |
替伊莫单抗(因单克隆抗体Ibritumomab与连接剂-螯合剂tiuxetan[N-[2-双(羧甲基)氨基]-3-(对-异硫氰酸苯基)-丙基]-[N-[2-双(羧甲基)氨基]-2-(甲基)-乙基]甘氨酸之间的硫脲共价价形成的免疫缀合物) | Zevalin | Biogen IDEC,Inc.,Cambridge MA |
伊达比星(5,12-萘二酮,9-乙酰基-7-[(3-氨基-2,3,6-三脱氧-(α)-L-来苏-吡喃己糖基(hexopyranosyl))氧基]-7,8,9,10-四氢-6,9,11-三羟基盐酸盐,(7S-顺式)) | Idamycin | Pharmacia & UpjohmCompany |
异环磷酰胺(3-(2-氯乙基)-2-[(2-氯乙基)氨基]四氢-2H-1,3,2-oxazaphosphorine 2-氧化物 | IFEX | Bristol-Myers Squibb |
甲磺酸伊马替尼(4-[(4-甲基-1-哌嗪基)甲基]-N-[4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]-苯基]苯甲酰胺甲磺酸盐) | Gleevec | Novartis AG,Basel,Switzerland |
干扰素α-2a(重组肽) | Roferon-A | Hoffmann-La Roche,Inc.,Nutley,NJ |
干扰素α-2b(重组肽) | Intro A(冻干的重组干扰素β-1b) | Schering AG,Berlin,Germany |
盐酸伊立替康((4S)-4,11-二乙基-4-羟基-9-[(4-哌啶并哌啶子基)羰基氧基]-1H-吡喃并[3’,4’;6,7]中氮茚并[1,2-b]喹啉-3,14(4H,12H)二酮盐酸盐三水合物 | Camptosar | Pharmacia & UpjohmCompany |
来曲唑(4,4’-(1H-1,2,4-三唑-1-基亚甲基)二苄腈 | Femara | Novartis |
亚叶酸(L-谷氨酸,N[4[2氨基-5-甲酰基-1,4,5,6,7,8六氢4氧代6-喋啶基]甲基]氨基)苯甲酰基],钙盐(1∶1)) | Wellcovorin.Leucovorin | Immunex,Corp.,Seatlle,WA |
盐酸左旋咪唑(-)-(S)-2,3,5,6-四氢-6-苯基咪唑并[2,1-b]-噻唑一盐酸盐C11H12N2S·HCl | Ergamisol | Janssen ResearchFoundation,Titusville,NJ |
洛莫司汀(1-(2-氯-乙基)-3-环己基-1-亚硝基脲) | CeeNU | Bristol-Myers Squibb |
Meclorethamine,氮芥(2-氯-N-(2-氯乙基)-N-甲基乙胺盐酸盐) | Mustargen | Merck |
醋酸甲地孕酮17α(乙酰氧基)-6-甲基孕-4,6-二烯-3,20-二酮 | Megace | Bristol-Myers Squibb |
美法仑,L-PAM(4-[双(2-氯乙基)氨基]-L-苯丙氨酸) | Alkeran | GlaxoSmithKline |
巯嘌呤,6-MP(1,7-二氢-6H-嘌呤-6-硫酮一水合物) | Purinethol | GlaxoSmithKline |
美司钠(2-巯基乙烷磺酸钠) | Mesnex | Asta Medica |
甲氨蝶呤(N-[4-[[(2,4-二氨基-6-喋啶基)甲基]甲氨基]苯甲酰基]-L-谷氨酸) | Methotrexate | Lederle Laboratories |
甲氧沙林(9-甲氧基-7H-呋喃并[3,2-g][1]-苯并吡喃-7-酮) | Uvadex | Therakos,Inc.,WayExton,Pa |
丝裂霉素C | Mutamycin | Bristol-Myers Squibb |
丝裂霉素C | Mitozytrex | SuperGen,Inc.,Dublin,CA |
米托坦(1,1-二氯-2-(邻-氯苯基)-2-(对-氯苯基)乙烷) | Lysodren | Bristol-Myers Squibb |
米托蒽醌(1,4-二羟基-5,8-双[[2-[(2-羟乙基)氨基]乙基]氨基]-9,10-蒽二酮二盐酸盐) | Novantrone | Immunex,Corporation |
苯丙酸南诺龙 | Durabolin-50 | Organon,Inc.,WestOrange,NJ |
诺非单抗 | Verluma | Boheringer IngelheimPharma KG Germany |
奥普瑞白介素(IL-11) | Neumega | Genetics Institute,Inc.,Alexadria,VA |
奥沙利铂(顺式-[(1R,2R)-1,2-环己烷二胺-N,N’][草酸(2-)-O,O’]铂) | Eloxatin | Sanofi Synthelabo,Inc.,NY,NY |
紫杉醇与(2R,3S)-N-苯甲酰基-3-苯基异丝氨酸形成的(5β,20-环氧-1,2a,4,7β,10β,13a-六羟基tax-11-烯-9-酮4,10-二乙酸酯2-苯甲酸酯13-酯) | TAXOL | Bristol-Myers Squibb |
氨羟二磷酸二钠(膦酸(3-氨基-1-羟基亚丙基)双-,二钠盐,五水合物,(APD)) | Aredia | Novartis |
培加酶((一甲氧基聚乙二醇琥珀酰亚胺基)11-17-腺苷脱氨酶 | Adagen(PegademaseBovine) | Enzon Phrmaceuticals,Inc.,Bridgewater,NJ |
培门冬酶((一甲氧基聚乙二醇琥珀酰亚胺基)L-天冬酰胺酶) | Oncaspar | Enzon |
Pegfilgrastim(重组甲硫氨酰基人G-CSF(非格司亭)和一甲氧基聚乙二醇的共价缀合物) | Neulasta | Amgen,Inc |
喷司他丁 | Nipent | Parke-DavisPharmaceutical Co.,Rockville,MD |
哌泊溴烷 | Vercyte | Abbott Laboratories,Abbott Park,JL |
普卡霉素,光辉霉素(褶链霉菌产生的抗生素) | Mithracin | Pfizer,Inc.,NY,NY |
卟吩姆钠 | Photofrin | QLT Phototherapeutics,Inc.,Vancouver,Canada |
丙卡巴肼(N-异丙基-μ-(2-甲基肼基)-对-甲苯酰胺一盐酸盐) | Matulane | Sigma TauPharmaceuticlas,Inc.,Gaithersburg,MD |
米帕林(6-氯-9-(1-甲基-4-二乙基-胺)丁氨基-2-甲氧基吖啶 | Atabrine | Abbott Labs |
拉布立酶 | Elitek | Sanofi-Synthelabo,Inc., |
(重组肽) | ||
利妥昔单抗(重组抗-CD20抗体) | Rituxan | Genentech,Inc.,SouthSan Francisco,CA |
沙格司亭(重组肽) | Prokine | Immunex Corp |
链佐星(链佐星2-脱氧-2-[[(甲基亚硝基氨基)羰基]氨基]-a(和b)-D-吡喃葡糖和220mg无水柠檬酸) | Zanosar | Pharmacia & UpjohmCompany |
滑石粉(Mg3Si4O10(OH)2) | Sclerosol | Bryan,Corp.,Woburn,MA |
他莫昔芬((Z)2-[4-(1,2-二苯基-1-丁烯基)苯氧基]-N,N-二甲基乙胺2-羟基-1,2,3-丙烷三羧酸酯(1∶1)) | Nolvadex | AstraZenecaPharmaceuticals |
替莫唑胺(3,4-二氢-3-甲基-4-氧代咪唑并[5,1-d]-as-四嗪-8-甲酰胺 | Temodar | Schering |
替尼泊苷,VM-26(4’-去甲基表鬼臼毒素9-[4,6-O-(R)-2-噻吩甲叉-(β)-D-吡喃葡萄糖苷 | Vumon | Bristol-Myers Squibb |
睾内酯(13-羟基-3-氧代-13,17-secoandrosta-1,4-二烯-17-酸[dgr]-内酯) | Tesalac | Bristol-Myers Squibb |
硫鸟嘌呤,6-TG(2-氨基-1,7-二氢-6H-嘌呤-6-硫酮) | Thioguanine | GlaxoSmithKline |
塞替派(氮丙啶,1,1’1”-膦基硫酰基次基三-,或三(1-氮丙啶基)硫膦) | Thioplex | Immunex Corporation |
盐酸托泊替康((S)-10-[(二甲氨基)甲基]-4-乙基-4,9-二羟基-1H-吡喃并[3’,4’:6,7]中氮茚并[1,2-b]喹啉-3,14-(4H,12H)-二酮一盐酸盐) | Hycamtin | GlaxoSmithKline |
托瑞米芬(2-(对-[(Z)-4-氯-1,2-二苯基-1-丁烯基]-苯氧基)-N,N-二甲基乙胺柠檬酸盐(1∶1) | Fareston | Roberts PharmaceuticalCorp.,Batontown,NJ |
托西莫单抗,I 131托西莫单抗(重组鼠免疫治疗性单克隆IgC2aλ抗-CD20抗体(I 131为放射性免疫治疗抗体) | Bexxar | Corixa Corp.,Seattle,WA |
曲妥单抗(重组单克隆IgG1κ抗-HER2抗体) | Herceptin | Genentech,Inc |
维A酸,ATRA(全反式视黄酸) | Vesanoid | Roche |
乌拉莫司汀 | Urancil Mustard胶囊 | Roberts Labs |
戊柔比星,N-三氟乙酰基阿霉素-14-戊酸酯((2S)-顺式)-2-[1,2,3,4,6,11-六氢-2,5,12-三羟基-7甲氧基-6,11-二氧代-[[4 2,3,6,-三脱氧-3-[(三氟乙酰基)-氨基-α-L-来苏-吡喃己糖基(hexopyranosyl)]氧基]-2-萘基]-2-氧代乙基戊酸酯] | Valstar | Anthra→Medeva |
长春碱,长春新碱(C46H56N4O10·H2SO4) | Velban | Eli Lilly |
长春新碱(C46H56N4O10·H2SO4) | Oncovin | Eli Lilly |
长春瑞滨(3’,4’-双脱氢-4’-脱氧-C”-去甲长春碱R-(R*,R*)-2,3-二羟基丁二酸(1∶2)(盐))) | Navelbine | GlaxoSmithKline |
唑来膦酸盐,唑来膦酸((1-羟基-2-咪唑-1-基-膦酰基乙基)膦酸一水合物 | Zometa | Novartis |
用于与本发明化合物一起给药的优选常用抗癌药包括,但不限于阿霉素、5-氟尿嘧啶、依托泊苷、喜树碱、放线菌素D、丝裂霉素C、顺铂、多西他赛、吉西他滨、卡铂、奥沙利铂、bortezomib、gefitinib和贝伐单抗。可以制备这些活性剂,并且可以单独地、在联用的治疗组合物中、试剂盒中或与免疫治疗剂组合等使用。
就抗癌药和其它治疗剂的更详细描述而言,本领域技术人员可以参考任何数量的说明性手册,包括,但不限于Physician′s DeskReference以及Goodman和Gilman的″Pharmaceutical Basis ofTherapeutics″第9版Eds.Hardman等,1996。
本发明提供了给予通式I的化合物与放疗的方法。本发明并不限于用于将治疗剂量的放射递送给动物的类型、用量或递送和给药系统。例如,动物可以接受光子放疗、粒子束放疗、其它类型的放疗及其组合。在某些实施方案中,使用线性加速器将放射递送给动物。在其它实施方案中,使用γ刀递送放射。
放射源可以在动物的内部或外部。例如,外部放射治疗最为常用并且包括使用例如线性加速器使高能辐射束通过皮肤定向于肿瘤部位。尽管辐射束局限于肿瘤,但是几乎不可能避免接触正常健康组织。然而外辐射通常为患者充分耐受。内照射疗法包括在体内肿瘤部位处或接近肿瘤部位处植入辐射发射源,诸如珠、金属线、丸粒、胶囊、颗粒等,包括使用特异性靶向癌细胞的递送系统(例如使用与癌细胞结合配体结合的颗粒)。这类植入物可以在治疗后除去或在体内保持失活状态。内照射疗法的类型包括,但不限于近距离放射疗法、间质内照射、腔内照射、放射免疫疗法等。
动物可以可选地接受放射致敏剂(例如甲硝唑、米索硝唑、动脉内溴甙、静脉内碘苷(IudR)、硝基咪唑、5-取代的-4-硝基咪唑类、2H-异吲哚二酮类、[[(2-溴乙基)-氨基]甲基]-硝基-1H-咪唑-1-乙醇、硝基苯胺衍生物、DNA-亲合性低氧选择性细胞毒素、卤化DNA配体、1,2,4苯并三嗪氧化物、2-硝基咪唑衍生物、含氟的硝基吡咯衍生物、苯甲酰胺、烟酰胺、吖啶-嵌入剂、5-硫代四唑(thiotretrazole)衍生物、3-硝基-1,2,4-三唑、4,5-二硝基咪唑衍生物、羟基化texaphrins、顺铂、丝裂霉素、tiripazamine、亚硝基脲、巯基嘌呤、氨甲蝶呤、氟尿嘧啶、博来霉素、长春新碱、卡铂、表柔比星、多柔比星、环磷酰胺、长春地辛、依托泊苷、紫杉醇、热(过热)等)、辐射防护剂(例如巯乙胺、氨基烷基二氢硫代磷酸酯、氨磷汀(WR 2721)、IL-1、IL-6等)。放射致敏剂促进杀伤肿瘤细胞。辐射防护剂防止健康组织受到放射的有害作用。
可以对患者给予任意类型的放射,只要患者耐受放射剂量而没有不可接受的负面副作用即可。合适类型的放疗包括:例如电离(电磁)放疗(例如X-射线或X射线)或粒子束放疗(例如高线性能量放射)。将电离放射定义为包括具有产生电离,即得到或失去电子的足够能量的粒子或光子的放射(例如,如US 5,770,581中所述,将该文献的全部内容引入本文作为参考)。放射的作用至少部分可以受到临床医师控制。为最大限度地接触靶细胞并且降低毒性,优选将放射剂量分次给予。
对动物给予的总放射剂量优选约为.01戈瑞(Gy)-约100Gy。更优选在治疗期过程中给予约10Gy-约65Gy(例如约15Gy,20Gy,25Gy,30Gy,35Gy,40Gy,45Gy,50Gy,55Gy或60Gy)。尽管在某些实施方案中,可以在1天过程中给予完整剂量的放射,但是理想的是将总剂量分次并且在几天内给予。理想的是在至少约3天过程中给予放疗,例如至少5、7、10、14、17、21、25、28、32、35、38、42、46、52或56天(约1-8周)。因此,每日放射剂量包括约1-5Gy(例如约1Gy,1.5Gy,1.8Gy,2Gy,2.5Gy,2.8Gy,3Gy,3.2Gy,3.5Gy,3.8Gy,4Gy,4.2Gy或4.5Gy),优选1-2Gy(例如1.5-2Gy)。每日放射剂量应足以诱导破坏被靶向的细胞。如果延长超过一定期限,那么并不优选每天给予放射,从而使动物休息并且实现该疗法的作用。例如,对每周治疗而言,理想的是连续5天给予放射,并且有2天不给予,由此每周有2天休息。然而,可以1天/周,2天/周,3天/周,4天/周,5天/周,6天/周或所有7天/周给予放射,这取决于动物的反应性和任何可能的副作用。可以在治疗期中的任意时间时启动放疗。优选在第1周或第2周启动放射并且在该治疗期的剩余期限内给予。例如,在包括6周治疗例如实体瘤的治疗期间,在第1-6周或第2-6周内给予放射。或者,在包括5周治疗期的第1-5周或第2-5周内给予放射。不过,本发明并不限于这些典型的放疗给药方案。
抗菌治疗剂也可以用作本发明中的治疗剂。可以使用可以杀伤、抑制或者减弱微生物功能的任意活性剂以及预计具有这类活性的任意活性剂。抗菌剂包括,但不限于天然和合成的抗生素、抗体、抑制蛋白(例如防御素)、反义核酸、膜破裂剂等,可以单独使用或以组合方式使用。实际上,可以使用任意类型的抗生素,包括,但不限于抗细菌剂、抗病毒剂、抗真菌剂等。
在本发明的某些实施方案中,在下列条件中的一种或多种下对动物给予通式I的化合物和一种或多种治疗剂或抗癌药:以不同的周期性;以不同的期限;以不同的浓度;通过不同的给药途径等。在某些实施方案中,在治疗剂或抗癌药之前给予所述的化合物,例如在给予治疗剂或抗癌药之前0.5、1、2、3、4、5、10、12或18小时,1、2、3、4、5或6天,1、2、3或4周。在某些实施方案中,在给予治疗剂或抗癌药之后给予所述的化合物,例如在给予抗癌药之后0.5、1、2、3、4、5、10、12或18小时,1、2、3、4、5或6天,1、2、3或4周给予该化合物。在某些实施方案中,同时给予所述的化合物和治疗剂或抗癌药,但使用不同的日程表,例如每日给予所述的化合物,而每周1次、每2周1次、每3周1次或每4周1次给予所述的治疗剂或抗癌药。在其它实施方案中,每周1次给予所述的化合物,而每日、每周1次、每2周1次、每3周1次或每4周1次给予所述的治疗剂或抗癌药。
本发明范围内的组合物包括以有效实现其指定目的的量包含本发明化合物的所有组合物。尽管个体需要可变,但是确定每种成分的有效量的最佳范围属于本领域技术人员的范围。一般来说,对哺乳动物,例如人而言,口服给予0.0025-50mg/kg/天为对诱导编程性细胞死亡有反应性的疾病而治疗的哺乳动物体重的剂量的化合物或等量的其药物上可接受的盐。优选口服给予约0.01-约10mg/kg以治疗、改善或预防这类疾病。就肌内注射而言,剂量一般为口服剂量的约一半。例如,合适的肌内剂量为约0.0025-约25mg/kg,最优选约0.01-约5mg/kg。
单位口服剂量可以包括约0.01-约50mg,优选约0.1-约10mg的化合物。每天可以将单位剂量作为一片或多片片剂或者一粒或多粒胶囊给予一次或多次,所述的片剂或胶囊各自含有约0.1-约10,便利的是约0.25-50mg化合物或其溶剂化物。
在局部用制剂中,化合物的存在浓度约为0.01-100mg/克载体。在优选的实施方案中,化合物的存在浓度约为0.07-1.0mg/ml,更优选约0.1-0.5mg/ml,最优选约0.4mg/ml。
除将化合物作为原料化学品给药外,还可以将本发明的化合物作为药物制剂的组成部分给予,所述的药物制剂含有合适的药物上可接受的载体,包括有利于将所述化合物加工成可以在药学上使用的制剂的赋形剂和助剂。优选所述的制剂含有约0.01-99%,优选约0.25-75%的活性化合物与赋形剂,特别是那些可以口服或局部给药并且可以用于优选给药类型的制剂,诸如片剂、锭剂、缓释锭剂和胶囊、口腔清洗剂和口腔洗剂、凝胶、液体混悬液、洗发剂、发胶、洗发香波;还有可以通过直肠给药的制剂,诸如栓剂;以及通过注射、局部或口服给药的合适的溶液。
可以将本发明的药物组合物对可以经历本发明化合物有益作用的任意动物给药。在这类动物中位于最前列的是哺乳动物,例如人,不过,本发明并不限于此。其它动物包括兽类动物(牛、绵羊、猪、马、狗、猫等)。
可以通过实现指定目的的任意方式给予所述的化合物及其药物组合物。例如,可以通过非肠道、皮下、静脉内、肌内、腹膜内、透皮、口含、鞘内、颅内、鼻内或局部途径给药。或者可以通过口服途径给药,或同时进行口服给药。给药剂量取决于接受者的年龄、健康情况和体重、并行治疗的种类(如果有的话)、治疗频率和所需效果的性质。
可按照自身公知的方式,例如通过常规的混合、制粒、制锭、溶解或冻干方法制备本发明的药物制剂。因此,可以通过下列步骤获得口服使用的药物制剂:将活性化合物与固体赋形剂合并,可选地研磨所得混合物并且如果需要或必要,在添加合适的助剂后加工颗粒混合物,从而得到片芯或锭芯。
特别地,合适的赋形剂为:填充剂,诸如糖类,例如乳糖或蔗糖、甘露糖醇或山梨醇;纤维素制品和/或磷酸钙,例如磷酸三钙或磷酸氢钙;和粘合剂,诸如淀粉糊,例如使用玉米淀粉、小麦淀粉、稻淀粉、马铃薯淀粉、明胶、西黄蓍胶、甲基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠和/或聚乙烯吡咯烷酮。如果需要,可以加入崩解剂,诸如上述淀粉和羧甲基淀粉、交联聚乙烯吡咯烷酮、琼脂或藻酸或其盐,诸如藻胶钠。助剂尤其是流动调节剂和润滑剂,例如二氧化硅、滑石粉、硬脂酸或其盐,诸如硬脂酸镁或硬脂酸钙,和/或聚乙二醇。如果需要,可以给锭芯包上耐胃液的合适的包衣材料。为了这一目的,可以使用浓糖溶液,它可以可选地含有阿拉伯胶、滑石粉、聚乙烯吡咯烷酮、聚乙二醇和/或二氧化钛、漆溶液和合适的有机溶剂或溶剂混合物。为了生产耐胃液的包衣材料,使用合适的纤维素制品,诸如邻苯二酸乙酰纤维素或邻苯二甲酸羟丙基甲基纤维素的溶液。例如,为了鉴别或为了表征活性化合物剂量的组合,可以向片剂或锭剂包衣层中加入染料或色素。
可以口服使用的其它药物制剂包括由明胶制成的推入-配合式胶囊以及由明胶和增塑剂诸如甘油或山梨醇制成的密封软胶囊。推入-配合式胶囊可以含有颗粒形式的活性化合物,所述的颗粒中可以混合有诸如乳糖这类填充剂、诸如淀粉这类粘合剂和/或诸如滑石粉或硬脂酸镁这类润滑剂以及可选地稳定剂。在软胶囊中,优选将活性化合物溶于或悬浮于合适的液体中,诸如脂肪油或液体石蜡。此外,可以加入稳定剂。
可以通过直肠使用的可能的药物制剂包括:例如由一种或多种活性化合物与栓剂基质的组合组成的栓剂。合适的栓剂基质例如为天然或合成的甘油三酯类或链烷烃类。此外,还能够使用由活性化合物与基质组合组成的直肠用胶囊。可能的基质材料包括:例如液体甘油三酯类、聚乙二醇类或链烷烃类。
用于非肠道给药的合适的制剂包括水溶性形式的活性化合物,例如水溶性盐和碱性溶液的水溶液。此外,可以将活性化合物的混悬液以合适的油性注射混悬液形式给药。合适的亲脂性溶剂或媒介物包括:脂肪油,例如芝麻油;或合成的脂肪酸酯类,例如油酸乙酯或甘油三酯类或聚乙二醇-400。含水的注射混悬液可以含有增加该混悬液粘度的物质,包括:例如羧甲基纤维素钠、山梨醇和/或葡聚糖。该混悬液中还可以可选地含有稳定剂。
优选通过选择合适的载体将本发明的局部用组合物配制成油剂、霜剂、洗剂、软膏剂等。合适的载体包括植物油或矿物油、白凡士林(白软石蜡)、支链脂肪或油、动物脂肪和高分子量醇(大于C12)。优选的载体为那些活性组分在其中可溶的载体。还可以包括乳化剂、稳定剂、湿润剂和抗氧化剂,并且如果需要,还可以包括赋予颜色或香味的试剂。另外,透皮促进剂可以用于这些局部用制剂中。这类促进剂的实例可以在美国专利US 3,989,816和US 4,444,762中找到。
优选由矿物油、自乳化蜂蜡和水的混合物配制霜剂,在该混合物中混合了混合溶于少量油诸如杏仁油的活性组分。这类霜剂的典型实例为一种包括约40份水、约20份蜂蜡、约40份矿物油和约1份杏仁油的霜剂。
可以通过将活性组分在植物油诸如杏仁油中的溶液与温热的软石蜡混合并且使该混合物冷却而配制软膏剂。这类软膏剂的典型实例为一种包括按重量计约30%杏仁油和约70%白软石蜡的软膏剂。
可以通过将活性组分溶于合适的高分子量醇诸如丙二醇或聚乙二醇而便利地制备洗剂。
下列实施例用于解释本发明的方法和组合物,而非起限定作用。在临床疗法中通常遇到并且对本领域技术人员显而易见的对条件和参数的其它合适的修改和改变属于本发明的实质和范围内。
实施例1
荧光偏振试验的研发
研发了使用荧光偏振的定量体外结合试验。Smac与XIAP的结合由Smac的N-末端上的几个氨基酸残基介导(附图1)。合成了两种不同的荧光探针:天然的9-mer Smac肽(AVPIAQKSEK(SEQ ID NO:3))和突变的5-mer Smac肽(AbuRPFK,其中Abu=2-氨基丁酸(SEQ ID NO:4))。用6-羧基荧光素琥珀酰亚胺酯(FAM)作为荧光标记标记每种探针(分别为AVPIAQKSEK-FAM,称作S9F;和AbuRPFK-FAM,称作SM5F)。将未标记的9-mer和5-mer Smac肽类(S9和SM5)用作阳性对照。具有His标记的人XIAP-BIR3蛋白(残基241-356)是稳定、可溶的,将其用于本结合试验。
首先使用恒定浓度的肽(5nM)并且使用逐步增加浓度的蛋白(0-40μM)明显高于预计的Kd滴定来测定荧光标记的S9F和SM5F与XIAP-BIR3的解离常数值,。附图2表示对用于饱和实验的单位点结合模型的非线性最小二乘法拟合。测得S9F具有的Kd值为0.24μM,最大结合范围在236mP±1.21mP。SM5F探针具有的Kd值为0.018μM(17.92nM),并具有较大的动态范围,最大结合为276mP±0.75mP。本试验在24小时期间内保持稳定,Kd值和结合范围保持不变,并且4%DMSO没有影响。
因为SM5F具有比天然Smac肽S9F更高的结合亲合力(约10倍以上)和更大的动态范围,选择这种标记的肽用于竞争性结合试验。所用的试验条件为5nM SM5F和0.030μM XIAP-BIR3蛋白,这基于的是下述考虑:0.030μM XIAP高于SM5F的Kd约2倍;并且5nM SM5F具有足够的荧光强度,可以克服在某些抑制剂具有一定水平的荧光情况中的荧光背景。在这些条件下,将示踪物饱和约60%,使得本试验敏感。mP范围(结合肽的mP-游离肽的mP)为88±2.43mP,这是精确检测mP变化的较大偏振信号窗。用于本试验质量的统计参数的Z′因子为0.88,这证实了基于SM5F探针的荧光偏振试验足以用于高通量筛选。
在竞争性实验中使用相应未标记的突变Smac 5-mer(SM5)和天然Smac 9-mer(S9)肽类验证本试验的特异性(附图3)。在两种情况中,数据显示未标记的肽类能够消除标记示踪物的结合。测得S9的IC50值为1.49±0.21μM(Ki=0.54±0.15μM),SM5的IC50值为0.22±0.01μM(Ki=0.075±0.005μM)。所得到的IC50值高于蛋白质/肽对的Kd值,因为为了使信-噪比最大化,竞争性FP结合试验中的蛋白质浓度要高于所测定的Kd。然而,这两种未标记的肽的IC50值之比与其相应的被标记肽的IC50值之比密切相关。未标记的SM5与S9肽的IC50值之比为6.7倍,而标记的SM5F与S9F的Kd值之比为7.2倍。由于这一原因,所以就设计的Smac模拟物而言,其IC50值与相同条件下天然Smac肽(S9)和突变Smac肽(SM5)的IC50值报导以及标记的SM5F和S9F的Kd值一起报导,以便正确比较它们的结合亲合力。另外,研发了用于计算基于FP的结合试验中抑制剂的结合亲合力(Ki)的新数学方程式,从而克服了高IC50值的问题。通过直接结合实验测定获得的被标记肽(S9F和SM5F)的Kd值与由竞争试验获得并且使用新方程式计算的未标记肽的Ki值类似。
为了进一步评价试验条件,测试对XIAP BIR3具有不同结合亲合力的两种额外公布的Smac四肽(附图3)(Kipp等,Biochemistry 41:7344(2002))。天然Smac肽AVPI(SEQ ID NO:1)具有的IC50值为1.58±0.22μM(Ki=0.58±0.15μM),基本上与天然Smac 9-mer S9相同。经测定,据报导具有远弱于AVPI(SEQ ID NO:1)肽的亲合力的另一种肽AVPR(SEQ ID NO:5)在这些试验条件下具有的IC50值为79.31±8.8μM(Ki=29.09±1.88μM)。在这些结合实验中获得的对XIAP蛋白的肽亲合力的顺序与公布的结果极其相关(AbuRPFK(SEQ IDNO:4)>AVPI(SEQ ID NO:1)=AVPIAQSEK(SEQ ID NO:3)>AVPR(SEQ ID NO:5))。这些结果提示基于FP的结合试验适合于精确和定量地测定具有极为不同的结合亲合力的Smac肽的结合亲合力。
实施例2
基于实验性3D结构的Smac与XIZP BIR3之间相互作用的分析
与Smac蛋白和肽复合的XIAP BIR3结构域的高分辨率实验性3D结构(附图1)为设计有效的Smac模拟物提供了稳固的结构基础。1位上丙氨酸(A1′)的氨基与Q319和E314侧链和D309骨架羰基形成四个氢键。丙氨酸上的甲基结合小的、但明确界定的疏水袋。我们的分析证实这种疏水袋可以容纳稍大于甲基的疏水性基团。丙氨酸的骨架羰基与W323的侧链形成氢键,但该氢键基于其几何参数考虑并非最佳。
Smac中缬氨酸(V2′)的氨基和羰基分别与T308的骨架羰基和氨基形成两个最佳的氢键。其侧链异丙基看起来不与XIAP BIR3上的残基密切接触,并且与XIAP BIR3上的W323相距约4-5。
3位上的脯氨酸残基(P3′)在控制Smac肽构象方面起重要作用,并且密切靠近XIAP BIR3中的W323的疏水侧链。其骨架羰基朝向溶剂中,并且与该蛋白不具有特异性相互作用。
4位上的异亮氨酸残基(I4′)的疏水侧链结合XIAP BIR3中明确界定的疏水袋。I4′的氨基与G306的骨架羰基形成氢键,该羰基与所述蛋白不具有特异性相互作用。
显然,在近来测定的半胱天冬酶-9和XIAP BIR3的高分辨率X-射线结构中观察到了类似的相互作用,其中半胱天冬酶-9中的四个残基ATPF(SEQ ID NO:2)介导与XIAP BIR3的相互作用。这些原子明确的高分辨率实验性结构为设计Smac模拟物提供了具体的结构基础。
实施例3
构象受限的非肽Smac模拟物的设计
Smac AVPI肽的设计和修饰产生了有效的简单Smac肽-模拟物。然而,这些Smac模拟物带有2-3个天然氨基酸和1-2个天然肽键。为了进一步减少这些简单Smac模拟物中的肽特征,基于3D复合结构和获自简单Smac肽-模拟物的数据设计并且合成了构象受限的非肽Smac模拟物。
Smac与XIAP BIR3复合的实验性3D结构和我们的其中异亮氨酸被苄胺取代的Smac AVPI(SEQ ID NO:1)模型化结构(化合物1)(附图1和4)显示了Smac AVPI肽(SEQ ID NO:1)和化合物1上的缬氨酸和脯氨酸环侧链指向结合沟的溶剂侧。因此,能够通过形成额外的环系来环化这两个残基,而不会与蛋白质产生立体化学冲突。化合物1(表2)用作检验这一设计策略的模板分子。随新形成的环上碳原子数量的不同,可以构建不同大小的环系。在最初的设计中,设计了三种大小的环系,即[5,5]、[6,5]和[7,5]双环环系,因为它们易于合成。
表2
需要指出的是,这种环化策略能够将两种天然氨基酸(缬氨酸和脯氨酸)转化成非氨基酸的双环内酰胺环系,并且所得Smac模拟物成为非-肽化合物。
就每一环系而言,因在桥连碳原子上生成手性中心而存在两种立体异构体。因此,针对每种环系对每种立体异构体模型化。发现对于具有[5,5]双环系的化合物17和18(表2)而言,相当于与XIAP BIR3的AVPI(SEQ ID NO:1)结合构象和化合物1中的肽骨架和脯氨酸环的那些原子存在明显的构象偏差。因此,化合物17和18不能象针对Smac AVPI肽(SEQ ID NO:1)和化合物1中观察到的那样形成最佳的氢键和有利的疏水相互作用。因此,预计具有[5,5]双环内酰胺环系的17和18与XIAP可能仅具有微弱的结合。并未继续进行这些化合物的合成。
具有[6,5]双环系的化合物19(表2)在X-射线结构方面十分接近地模拟Smac AVPI肽(SEQ ID NO:1)/XIAP BIR3的相互作用,并且在模型化结构中的氢键和疏水相互作用方面十分接近地模拟化合物1/XIAP BIR3。与Smac AVPI肽(SEQ ID NO:1)/XIAP BIR3的X-射线复合物结构相比,化合物19的模型化复合物结构如附图5中所示。正如可以观察到的,在化合物19与XIAP BIR3之间形成了在X-射线结构中对Smac AVPI(SEQ ID NO:1)发现的所有重要的氢键。化合物19的苯环插入疏水袋,密切模拟化合物1上的I4′疏水侧链和苯环。发现Smac AVPI肽(SEQ ID NO:1)上的脯氨酸环紧密接触W323的侧链(附图1)。然而,化合物19上的5-元环向外弯曲并且与AVPI Smac肽(SEQ ID NO:1)和化合物1上的脯氨酸环相比存在适度偏差(附图5)。总之,基于我们的模型化结果,预计化合物19可能具有合理的与XIAP BIR3的结合亲合力。相反,发现立体异构体化合物20(表2)不能有效地与XIAP BIR3发生相互作用。尽管化合物20上密切维持了相当于Smac AVPI肽(SEQ ID NO:1)上的骨架原子和脯氨酸环的原子的构象,但是新形成的6-元环与XIAP上的W323残基之间存在严重的范德瓦耳斯力冲突(应答)。因此,预计化合物20可能与XIAP仅具有极弱的亲合力。
就具有[7,5]双环系的化合物21而言(表2),发现化合物21在氢键和疏水相互作用方面甚至更密切地模拟AVPI(SEQ ID NO:1)和化合物1(附图6)。实际上,看起来新形成的7-元环具有与XIAP上W323残基额外有利的疏水接触(附图6)。相反,发现另一种立体异构体化合物22(表2)不能维持模型化结构中与XIAP BIR3的氢键和疏水相互作用。
实施例4
含有[6,5]和[7,5]双环系的Smac模拟物的合成
一般方法:以300MHz的质子频率获得NMR光谱。使用Me4Si(0.00ppm)、CHCl3(7.26ppm)或CD2HOD(3.31ppm)作为内标报导1H化学位移。使用CDCl3(77.00ppm)或CD3OD(49.00ppm)作为内标报导13C化学位移。在室温下测定旋光度。
一般操作步骤A(用于水解甲酯类):
在室温下向底物在1,4-二烷中的充分搅拌的溶液中加入2NLiOH溶液(2eq)。在所有原料消耗完后,加入1N HCl,直到PH=5。使用二氯甲烷萃取产物,并且用盐水洗涤合并的有机层,用Na2SO4干燥。浓缩后,对残余物进行硅胶色谱而得到产物。
一般操作步骤B(用于制备酰胺):
在室温下向两种底物EDCI(1.2eq)和HOBt(1.2eq)的充分搅拌的混合物中加入二异丙基乙胺。将该混合物搅拌过夜并且浓缩。对残余物进行硅胶色谱而得到产物。
一般操作步骤C(用于Boc的脱保护):
向底物的充分搅拌的溶液中加入在1,4-二烷中的4.0M HCl溶液(4eq)。搅拌过夜后,在真空中浓缩该溶液。将残余物冻干而得到产物。
按照一般操作步骤A水解一般通式III的化合物而得到酸。按照一般操作步骤B使这些酸与胺类缩合而得到一般通式IV的酰胺。按照一般操作步骤C除去Boc保护基,随后按照一般操作步骤B与相应的(L)-N-Boc-氨基酸缩合而得到一系列酰胺。除去这些酰胺上的Boc保护基而得到一般通式V的化合物。
1H NMR(300MHz,CD3OD,TMS)δ7.41-7.24(m,5H),4.48-4.32(m,4H),3.80-3.68(m,2H),2.23-1.79(m,10H),1.05(t,J =7.46Hz,3H);13CNMR(75MHz,CD3OD)δ174.01,169.91,169.70,139.88,129.50,128.51,128.10,61.02,55.67,51.45,44.01,32.56,30.37,29.57,28.49,25.67,9.53.
1H NMR(300MHz,CD3OD,TMS)δ7.45(m,1H),6.36(m,1H),6.30(m,1H),4.51-4.36(m,4H),3.97(m,1H),3.67(m,1H),2.50-1.70(m,8H),1.30(d,J=8.5Hz,3H);13C NMR(75MHz,CD3OD)δ173.93,170.81,169.79,152.86,143.32,111.36,108.06,61.01,59.89,53.03,50.36,37.34,32.78,30.47,28.28,26.95,17.54.
1H NMR(300MHz,CD3OD,TMS)δ7.42-7.22(m,5H),4.56-4.24(m,4H),3.92(m,1H),3.68(m,1H),2.45-1.55(m,8H),1.50(d,J=8.2Hz,3H);13C NMR(75MHz,CD3OD)δ174.23,170.80,169.69,142.33,135.32,131.05,128.37,128.18,126.45,61.08,59.97,50.37,43.49,32.83,30.44,28.35,26.91,17.58.
1H NMR(300MHz,CD3OD,TMS)δ7.47(d,J=8.5Hz,2H),7.23(d,J=8.5Hz,2H),4.65-4.19(m,4H),3.92(m,1H),3.75(m,1H),2.52-1.65(m,8H),1.52(d,J=8.2Hz,3H);13C NMR(75 MHz,CD3OD)δ174.29,170.75,169.76,139.25,132.53,130.28,121.74,61.11,60.06,50.37,43.42,32.87,29.42,28.44,26.86,17.54.
1H NMR(300MHz,CD3OD,TMS)δ7.51-7.22(m,5H),4.52-4.31(m,4H),3.95(m,1H),3.65(m,1H),2.40-1.72(m,8H),1.56(d,J=8.0Hz,3H);13C NMR(75 MHz,CD3OD)δ174.19,170.80,169.81,142.59,131.33,131.21,127.20,123.38,61.09,60.01,50.37,43.43,32.81,30.40,28.36,26.90,17.61.
1H NMR(300MHz,CD3OD,TMS)δ7.62(m,1H),7.51(m,1H),7.35(m,1H),7.21(m,1H),4.52-4.38(m,4H),3.92(m,1H),3.75(m,1H),2.45-1.68(m,8H),1.55(d,J =8.0Hz,3H);13C NMR(75MHz,CD3OD)δ174.31,170.76,169.81,138.42,133.70,130.11,129.95,128.80,123.90,61.08,60.02,50.37,44.58,32.86,30.45,28.40,26.90,17.57.
1H NMR(300MHz,CD3OD,TMS)δ7.45-7.26(m,10H),6.13(s,1H),4.55(m,2H),3.91(m,1H),3.68(m,1H0,2.31-1.65(m,8H),1.53(d,J=6.5Hz,3H);13C NMR(75MHz,CD3OD)δ173.25,170.74,169.74,143.03,142.70,129.65,129.41,128.71,128.57,128.49,128.19,68.11,60.90,59.78,58.43,50.41,32.84,30.41,28.18,26.94,17.55.
1H NMR(300MHz,CD3OD,TMS)δ7.36-7.23(m,5H),4.47-4.38(m,4H), 3.84(m,1H),3.76(m,1H),2.20-1.65(m,10H),1.52(m,2H),0.99(t,J=7.3Hz,3H);13C NMR(75MHz,CD3OD)δ174.07,170.09,169.66,139.81,129.70,128.68,128.35,61.09,59.94,54.56,53.39,44.06,34.75,32.85,30.49,28.36,26.92,19.22,14.04.
1H NMR(300MHz,D2O)δ7.34-7.21(m,10H),5.96(s,1H),4.51-4.44(m,2H),3.96-3.84(m,2H),2.20-1.52(m,12H),0.93(t,J=7.6Hz,3H);13C NMR(75MHz,D2O)δ173.49,172.53,169.23,141.28,141.12,129.30,129.19,128.15,127.66,127.49,62.41,59.93,58.01,54.60,54.07,33.14,32.82,29.66,28.16,27.33,24.75,8.76.
1H NMR(300MHz,CD3OD,TMS)δ7.38-72.3(m,5H),4.61(m,1H),4.36(m,1H),4.02(m,1H),3.85-3.65(m,2H),3.21-3.12(m,2H),2.38-1.72(m,8H),1.55(t,J=6.9Hz,3H);13C NMR(75MHz,CD3OD)δ173.60,173.41,171.08,170.23,138.66,130.37,129.53,127.79,61.39,60.57,55.73,52.68,50.35,38.17,32.38,29.91,29.12,27.01,17.57.
[0151]1H NMR(300MHz,CD3OD,TMS)δ7.37-7.21(m 3H),4.53-4.34(m,4H),3.93(m,1H), 3.67(m,1H),2.42-1.65(m,8H),1.54(d,J=7.0Hz,3H);13C NMR(75MHz,CD3OD)δ174.01,170.69,169.82,139.78,129.52,128.33,128.14,61.08,60.12,50.47,44.01,32.82,30.54,28.32,26.92,17.55.
[0152]1H NMR(300MHz,D2O)δ7.32-7.20(m,10H),5.94(s,1H),4.48-4.41(m,2H),4.02-3.88(m,2H),2.16-1.50(m,10H),1.44(d,J=7.2Hz,3H);13C NMR(75MHz,D2O)δ173.48,172.62,170.13,141.29,141.11,129.30,129.20,128.15,128.11,127.66,127.49,62.45,59.89,57.99,54.01,49.32,33.16,32.83,29.43,28.15,27.31,16.89.
[0153]1H NMR(300MHz,CD3OD,TMS)δ7.35-7.18(m,5H),4.56-4.32(m,4H),3.85-3.62(m,2H),2.42-1.70(m,9H),1.18(d,J=7.2Hz,6H);13CNMR(75MHz,CD3OD)δ174.07,169.62,169.27,139.83,129.50,128.35,128.11,61.09,59.90,44.06,32.84,31.55,30.49,28.33,26.96,18.98,18.05.
1H NMR(300MHz,CD3OD,TMS)δ7.42-7.18(m,10H),6.13(s,1H),4.59-4.52(m,2H),3.87-3.67(m,2H),2.21-1.71(m,10H),1.07(t,J=7.5Hz,3H);13C NMR(75MHz,CD3OD)δ173.31,169.90,169.64,143.04,142.74,129.76,129.41,128.70,128.59,128.53,128.18,60.88,59.79,58.46,55.71,32.85,30.36,28.19,26.90,25.97,9.62.
1H NMR(300MHz,CD3OD,TMS)δ7.34-7.09(m,10H),4.51-4.43(m,2H),3.90-3.55(m,3H),3.27-2.98(m,2H),2.52-1.43(m,10H),1.10(t,J=7.5Hz,3H);13C NMR(75MHz,CD3OD)δ173.04,169.90,168.78,143.05,139.35,130.33,129.38,129.25,128.25,127.93,127.63,61.01,59.76,56.94,55.71,43.45,32.59,30.18,28.23,26.97,25.97,9.62.
1H NMR(300MHz,CD3OD,TMS)δ7.37-7.19(m,5H),4.52-4.45(m,2H),4.13(m,1H),3.80-3.54(m,2H),2.56-1.69(m,8H),1.60-1.45m,6H);13C NMR(75MHz,CD3OD)δ173.11,170.73,169.68,144.89,129.45,128.41,127.21,61.04,59.93,53.06,50.31,32.89,30.78,28.37,26.94,22.60,17.59.
1H NMR(300MHz,CD3OD,TMS)δ7.39-7.20(m,5H),4.52-4.30(m,4H),3.88-3.62(m,2H),2.45-1.76(m,10H),1.04(t,J=7.5Hz,3H);13CNMR(75MHz,CD3OD)δ174.07,169.88,169.65,139.79,129.48,128.32,128.08,61.08,59.93,55.68,44.02,32.81,30.46,29.14,28.36,26.89,9.58.
1H NMR(300MHz,CD3OD,TMS)δ7.57(m,1H),7.38(m,1H,7.12-6.95(m,3H),4.52(m,1H),4.31(m,1H),4.05(m,1H),3.80-3.65(m,2H),3.55(m,1H),3.20-2.82(m,2H),2.43-1.82(m,8H),1.52(d,J=7.0Hz,3H);13C NMR(75MHz,CD3OD)δ172.96,171.30,169.53,138.11,128.74,123.71,122.36,119.67,119.33,112.79,112.29,62.19,61.20,59.93,53.07,41.60,32.66,30.28,29.22,26.03,17.57.
1H NMR(300MHz,CD3OD,TMS)δ7.26-7.05(m,4H),4.55-4.20(m,4H),4.05(m,1H),3.59(m,1H),2.52-1.68(m,11H),1.60(d,J=7.1Hz,3H);13C NMR(75MHz,CD3OD)δ172.96,171.29,169.79,139.55,139.17,129.43,129.18,128.80,125.72,62.24,61.34,53.41,53.03,44.51,30.45,29.45,29.19,21.42,17.56.
1H NMR(300MHz,CD3OD,TMS)δ7.45-7.22(m,5H),4.55-4.36(m,2H),3.95(m,1H),3.68(m,2H), 2.30-1.68(m,8H),1.53(d,J=7.2Hz,3H),1.48(d,J=7.0Hz,3H);13C NMR(75MHz,CD3OD)δ172.90,170.75,169.71,145.30,132.41,129.58,128.10,126.91,68.13,60.93,59.79,50.40,32.73,30.31,29.11,28.20,26.77,22.53,17.52.
[0161]1H NMR(300MHz,CD3OD,TMS)δ7.64-7.57(m,2H),7.38-7.29(m,2H),7.10(m,1H),4.60-4.52(m,2H),3.94(m,1H),3.79(m,1H),2.42-1.70(m,8H),1.54(d,J=7.2Hz,3H);13C NMR(75MHz,CD3OD)δ172.24,170.82,169.86,139.72,129.80,125.29,121.10,68.12,61.68,59.79,50.38,32.89,30.47,28.18,27.06,17.52.
[0162]1H NMR(300MHz,CD3OD,TMS)δ7.40-7.19(m,5H),4.54-4.29(m,4H),3.92(m,1H),3.80(m,1H),2.52-1.78(m,8H),1.55(d,J=7.5Hz,3H);13C NMR(75MHz,CD3OD)δ174.44,170.99,169.62,139.90,129.49,128.34,128.11,62.06,61.41,51.73,50.29,43.84,33.86,29.79,28.84,28.45,17.30.
[0163]1H NMR(300MHz,CD3OD,TMS)δ4.53(m,1H),4.36(m,1H),4.08(m,1H),3.68(m,1H),3.32-3.14(m,2H),2.52-1.65(m,8H),1.56(d,J=7.2Hz,3H),1.52-1.30(m,5H),0.92(t,J=7.4Hz,6H);13C NMR(75MHz,CD3OD)δ172.93,171.38,169.72,62.28,61.28,53.41,53.03,43.37,42.21,30.79,30.43,29.42,29.20,24.66,17.56,11.19.
1H NMR(300MHz,D2O)δ7.32-7.16(m,5H),4.36-4.28(m,4H),3.94(m,1H),3.60(m,1H),2.43-1.52(m,8H),1.43(d,J=7.0Hz,3H).
1H NMR(300MHz,D2O)δ7.45-7.18(m,5H),4.47-4.38(m,2H),4.30(brs,2H),4.01-3.92(m,2H),2.32-1.51(m,10H),1.48(d,J=7.1Hz,3H);13C NMR(75MHz,D2O)δ174.26,172.74,170.16,138.35,129.12,127.76,127.45,62.70,60.00,54.05,49.32,43.28,33.20,32.83,29.44,28.20,27.34,16.91.
实施例5
含有[8,5]双环系的Smac模拟物的合成
按照Harris等在Org.Lett.1847(2003)中所述制备通式VI的化合物。使用10%Pd-C催化的氢化还原VI上的双键而得到通式VII的化合物。水解VI上的乙酯,随后与胺类缩合而得到通式VIII的酰胺。除去VIII上的Boc保护基,随后与相应的氨基酸缩合而得到一系列酰胺。除去这些酰胺上的Boc保护基而得到所需的通式IX的化合物。可以按照与VII相同的操作步骤合成通式XI的化合物。
实施例6
Smac模拟物与[6,5]双环系的结合亲合力
如实施例4中所述合成具有[6,5]双环系的化合物19。为了验证模型化预测,还合成了化合物20。在基于FP的结合试验中测试这两种化合物,结合数据提供在表3中。发现化合物19具有低于10μM的Ki值,而化合物20在高达200μM时也未表现出任何结合。结合数据与模型化结果一致。显然,化合物19在功效上约低于化合物1和SmacAVPI肽(SEQ ID NO:1)15-倍,这可以归因于与化合物1和Smac AVPI肽(SEQ ID NO:1)上的脯氨酸环相比,在化合物19上的5-元环与XIAP上的W323之间的相互作用更为低效。
使用简单Smac模拟物的研究提示用乙基取代A1′上的甲基可以改善化合物19的结合。由此合成了化合物31(表3),其中用乙基取代化合物19上的甲基。使用简单Smac模拟物的数据还提示用二苯基甲基取代化合物19上的苄基可以进一步改善结合亲合力。由此合成了化合物32(表3)。在基于FP的试验中测试了这些化合物,其结合数据提供在表3中。正如可以观察到的,化合物31具有的Ki值为1.41μM,功效比化合物19高3倍(附图7)。化合物32具有的Ki值为0.35μM,功效比化合物31高4倍,比化合物19高12倍(附图7)。需要指出的是,化合物32与天然AVPI Smac肽(SEQ ID NO:1)和简单的模拟物化合物1同样有效。
表3
实施例7
Smac模拟物与[7,5]双环系的结合亲合力
模型化结果提示具有[7,5]双环系的化合物21与XIAP BIR3的结合优于具有[6,5]双环系的化合物19。由此合成了化合物21。基于化合物19和20的结合数据,仅立体异构体19具有活性,因此未合成化合物22。
使用实施例4中详述的方法合成化合物21。经测定化合物21具有的Ki值为0.15μM,因此在效力上比具有[6,5]双环系的化合物19高30倍(表4)。化合物21实际上在功效上比简单的Smac模拟物化合物1和天然Smac AVPI肽(SEQ ID NO:1)高2倍,代表了一种富有前途的引导化合物,并且证实了模型化预测和设计的策略。
表4
受到化合物21的良好结合亲合力的鼓舞,使用与对化合物21所述类似的方法设计并且合成了化合物33和34(表4)。化合物33具有的Ki值为0.06μM(60nM),而化合物34具有的Ki值为0.02μM(20nM)(附图7)。因此,化合物34代表了一种非常有效的非肽类构象受限性Smac模拟物,其结合亲合力比天然Smac AVPI肽(SEQ ID NO:1)高29-倍。
已经设计、合成并且在基于FP的结合试验中测试了几种其它的非肽类构象受限性Smac模拟物。结果如表5中所示。
表5
实施例8
通过NMR法最终证实化合物34与XIAP的结合
为了最终证实化合物34(表4,与表5中的SH-102相同)结合其中Smac发生结合的XIAP BIR3内结合沟,使用核磁共振(NMR)法进行分析。在含有15N氯化铵的M9培养基中由BL21(DE3)细胞表达与His-tag融合的人XIAP BIR3结构域(残基241-356),以便用15N均匀地标记蛋白,纯化之。在30℃下使用样品记录15N异核单量子相干性光谱法(HSQC)NMR光谱,所述的样品中含有在50mM Tris(pH 7.2)、50μM ZnCl2、1mM DTT中的100μM 15N蛋白质,并且含有或不含100μM化合物34。将含有和不含化合物34时人XIAP的BIR3结构域的两个15N HSQC光谱重叠,显示出化合物34与该蛋白质结合并且在XIAP BIR3中的几个残基上产生了诱导的化学位移(附图8)。此外,在使用化合物34的光谱中出现了一些新的峰(附图8),提示XIAP BIR3上的柔性环在接触化合物34时形成结构,正如在XIAP BIR3与Smac的复合物结构上观察到的(Sun等J.Biol.Chem.275:33777(2000))。
为了鉴定XIAP BIR3上的哪些残基受到化合物34的影响,制备13C和15N双标记的XIAP BIR3,并且进行3D NMR三重共振实验以使骨架原子共振分配。将HNCA、HNCACB、HN(CO)CBCA、HNCO、TOCSY-HSQC、C(CO)NH和公布的结果(Sun等,J.Biol.Chem.275:33777(2000))用于接近完成骨架分配,其中两个柔性环(残基276-280和308-314)除外。基于XIAP BIR3接近完成的骨架分配,发现残基G306、W323、K297、L292和K299受到化合物34的影响(附图8)。此外,在NMR分析中还发现这些残基受到Smac AVPI肽(SEQ ID NO:1)的影响。基于Smac/XIAP BIR3的实验性复合物结构(附图1),受到化合物34和SmacAVPI肽(SEQ ID NO:1)影响的XIAP BIR3上的这些残基直接与Smac肽接触。使用相同的方法测定到化合物32使得与化合物34和SmacAVPI肽(SEQ ID NO:1)所引起的XIAP BIR3上的相同残基组产生诱导的化学位移,表明这些Smac模拟物与化合物34和Smac AVPI肽(SEQID NO:1)一样结合相同的结合沟。NMR实验结果最终共同证实化合物32和34以及其它Smac模拟物结合XIAP BIR3上Smac与之结合的结合沟。这些实验还证实Smac肽和设计的模拟物不会使该蛋白质解折叠。
实施例9
癌细胞和正常细胞中IAP家族蛋白的表达
为了研究所设计的Smac模拟物的活性和特异性,在几种人癌细胞系和正常细胞中对XIAP、cIAP-1/2、存活蛋白和Smac蛋白进行蛋白质印迹分析(附图9)。
结果显示人前列腺癌PC-3细胞具有高水平的XIAP和cIAP-1/2以及低水平的存活蛋白;人乳腺癌MDA-MB-231细胞具有高水平的cIAP-1、中等水平的XIAP和低水平的cIAP-2和存活蛋白;人前列腺癌DU-145细胞具有高水平的XIAP和中等水平的cIAP-1/2和存活蛋白。
正常人成纤维细胞WI-38细胞具有低水平的XIAP、cIAP-1/2和存活蛋白;正常前列腺上皮细胞(PrEC)具有可检测到的、但远低于PC-3和DU-145细胞中的水平的XIAP,中等水平的cIAP-1以及极低水平的cIAP-2和存活蛋白;正常人乳腺上皮细胞系MCF-10A和MCF-12A具有可检测到的、但远低于DU-145和PC-3中的水平的XIAP,具有可检测到的、但远低于PC-3和MDA-231中的水平的cIAP-1,以及极低水平的cIAP-2和存活蛋白。
Jurkat细胞具有低水平的XIAP和cIAP-2以及中等水平的cIAP-1和存活蛋白。正如预计的,用XIAP蛋白转染的Jurkat细胞具有极高水平的XIAP,而其它IAP蛋白与亲代细胞系相比未发生改变。Smac蛋白水平看起来与在此处检验的癌细胞和正常细胞系中的结果相同。
实施例10
Smac模拟物促进前列腺癌PC-3细胞中顺铂-诱导的编程性细胞死
亡
采用与载体肽融合的短Smac肽类进行的在先研究令人信服地证实了细胞可渗透的Smac肽类能够增加由各种化疗剂在神经胶质瘤、黑素瘤、乳腺癌和非小细胞肺癌细胞中诱导的癌细胞编程性细胞死亡(Fulda等,Nature Med.8:808(2002);Arnt等,J.Biol.Chem.277:44236(2002);Yang等,Cancer Re s.63:831(2003))。在这些研究中有几个特征常见。这些细胞可渗透的Smac肽类自身在诱导癌细胞中的编程性细胞死亡方面几乎没有作用。必须使用相当高浓度的所述肽(50-100μM)以便显著强化化疗药在编程性细胞死亡诱导方面的活性。
本发明的基本论题在于有效的非肽Smac模拟物比细胞可渗透的Smac肽类更有效地增加化疗药诱导的癌细胞的编程性细胞死亡。上述实施例中披露了十分有效的非肽的Smac模拟物化合物33和34,它们具有的结合亲合力比Smac AVPI肽(SEQ ID NO:1)高至少10-倍。一种丙氨酸的侧链被乙基取代并且异亮氨酸被二苯基甲基取代的肽-模拟物SH-97用于测试这一基本论题。需要指出的是,SH-97仍然带有两个天然氨基酸(缬氨酸和脯氨酸)和一个天然肽键。就对照化合物而言,预先公布的细胞可渗透的Smac肽(Smac8-C)(Arnt等,J.Biol.Chem.277:44236(2002))用作阳性对照,不含载体肽的Smac肽(AVPIAQKS)(SEQ ID NO:6)用作阴性对照(Smac-8),且无活性化合物(SH-93,表5)作为另一种阴性对照。本实验使用表达高水平XIAP和cIAP-1/2蛋白的PC-3细胞和作为化疗药的顺铂(CDDP)。CDDP为DNA损伤剂,可以有效地诱导PC-3细胞中的编程性细胞死亡,它还是前列腺癌的临床用化疗药。
用单独或组合形式的CDDP、Smac肽类和模拟物将PC-3细胞处理42小时,通过膜联蛋白V-FITC染色分析编程性细胞死亡。与上述使用细胞可渗透的Smac肽类的研究一致,达50μM的SH-97与未处理的癌细胞相比并没有显著地诱导更多的编程性细胞死亡,而与对照组细胞相比,25μM CDDP诱导12-15%的癌细胞进行编程性细胞死亡(附图10A)。25μM CDDP与10μM或25μMSH-97的组合分别诱导编程性细胞死亡超过对照组细胞29.3%±1.9%和35.8%±0.4%(附图10A)。与公布的结果一致的是,细胞可渗透的Smac肽增加化疗药在各种具有高水平IAP蛋白的癌细胞中导致的编程性细胞死亡,25μM CDDP与100μM Smac8-C组合诱导的编程性细胞死亡比对照细胞增加34%,而Smac8-C自身没有显著性作用(附图10B)。
使用SH-102(表5)进行类似的实验。用单独或组合形式的SH-102和CDDP将PC-3细胞在6-孔平板中处理42小时。收集细胞并且用膜联蛋白V-FITC和碘化丙锭染色。通过流式细胞术分析各细胞的膜联蛋白V-FITC和碘化丙锭的荧光。与未处理的癌细胞相比,达100μM的SH-102不会诱导显著更多的编程性细胞死亡,而与对照组细胞相比,25μM和50μMCDDP分别诱导约15%和25%的癌细胞进行编程性细胞死亡(附图11)。与对照组细胞相比,25μM CDDP与10μMSH-102的组合诱导了32%的编程性细胞死亡(附图11)。如上所述,25μM CDDP与100μM Smac8-C的组合诱导的编程性细胞死亡增加至超过对照组细胞约34%,而Smac8-C自身没有显著作用(附图12)。
使用另一种化疗药TAXOTERE(多西他赛)进行相同的实验。用单独或组合形式的SH-102和TAXOTERE将PC-3细胞在6-孔平板中处理42小时。收集细胞并且用膜联蛋白V-FITC和碘化丙锭染色。通过流式细胞术分析各细胞的膜联蛋白V-FITC和碘化丙锭的荧光。与未处理的癌细胞相比,达100μM的SH-102不会诱导显著更多的编程性细胞死亡,而与对照组细胞相比,10μM和20μM TAXOTERE分别诱导约5%和8%的癌细胞进行编程性细胞死亡(附图13)。10μM泰索帝与10μM SH-102的组合诱导超过对照组约18%的编程性细胞死亡,(附图13)。
使用乳腺癌细胞系MDA-231进行类似的实验。用单独或组合形式的SH-102和CDDP将MDA-231细胞在6-孔平板中处理42小时。收集细胞并且用膜联蛋白V-FITC和碘化丙锭染色。通过流式细胞术分析各细胞的膜联蛋白V-FITC和碘化丙锭的荧光。与对照组细胞相比,25μM和50μM CDDP分别诱导约25%和42%的癌细胞进行编程性细胞死亡(附图14)。25和50μM CDDP与25μM SH-93的组合与对照组细胞相比没有显著作用。25和50μM CDDP与10μM SH-102的组合分别诱导约35%和75%的编程性细胞死亡,超过了对照组细胞(附图14)。10μMSH-102使细胞对CDDP敏感的能力与100μM pSmac8-C同样巨大(附图14)。
结果共同表明有效的Smac模拟物可有效地强化CDDP和TAXOTERE在诱导PC-3细胞和MDA-231细胞中的编程性细胞死亡方面的活性。另外,本发明的Smac模拟物看起来比上述研究中使用的与载体肽融合的Smac肽(Smac8-C)更为有效,而不带有载体肽的Smac肽或无活性的Smac模拟物(SH-93)不能强化CDDP在PC-3细胞或MDA-231细胞中诱导编程性细胞死亡的活性。
实施例11
SH-102克服了XIAP的防护作用
为了研究Smac模拟物对具有升高水平的XIAP(正如许多癌症所显示的那样)的细胞所具有的作用,用表达人XIAP的载体或对照载体稳定转染Jurkat T细胞。如蛋白质印迹分析的,用对照载体(Jurkat-Vec)转染的Jurkat细胞具有极低水平的XIAP蛋白,而用编码人XIAP的载体稳定转染的Jurkat细胞(Jurkat-XIAP)具有极高水平的XIAP蛋白。
用单独或组合形式的癌症化疗药依托泊苷和SH-102将两种稳定转染的细胞系处理15小时。收集细胞并且在冰上的70%乙醇中固定。离心后,在50μg/ml碘化丙锭和0.1μg/ml RNA酶A中染色细胞并且通过流式细胞术分析。对每份样品至少扫描5000个细胞。分析数据以便使用CellQuest软件(Becton Dickinson)计算亚G1细胞(编程性细胞死亡细胞)的百分比。Jurkat-XIAP细胞比Jurkat-Vec细胞(约50%的编程性细胞死亡细胞)更耐受10μM依托泊苷(约10%的编程性细胞死亡细胞)(附图15)。10μM SH-102与依托泊苷的组合诱导约15%的编程性细胞死亡,表明用Smac模拟物可以克服XIAP对药物诱导的编程性细胞死亡的防护作用(附图15)。10μM SH-102至少与50μMSmac8-C同样有效(附图15)。
建立了表达其中Bir1和Bir2结构域被缺失的人XIAP的另一种稳定转染的Jurkat细胞系(Jurkat-Bir3)。缺失型XIAP蛋白的表达防止了细胞发生依托泊苷诱导的编程性细胞死亡。尽管20μM依托泊苷在Jurkat-Bir3细胞中诱导约18%的编程性细胞死亡,但是依托泊苷与10或20μM SH-102的组合分别导致约25和30%的编程性细胞死亡(附图16),表明SH-102可以克服XIAP-Bir3对药物诱导的编程性细胞死亡的防护作用,并且还显示Bir3结构域与SH-102的细胞活性有关。
实施例12
在产克隆试验中SH-97使PC-3细胞对X-射线辐射敏感
已经证实XIAP和其它IAP蛋白在癌细胞中的超表达抑制由化疗药和放射诱导的编程性细胞死亡(Holcik等,Oncogene 19:4174(2000))。因此,预计用有效和细胞可渗透的Smac模拟物诸如SH-97处理PC-3细胞,可以通过直接克服IAP蛋白对癌细胞的保护作用而使PC-3细胞对X-射线辐射敏感。
为了检验这种预测,在6-孔平板中单独用SH-97和X-射线辐射或将二者组合应用,使用标准产克隆试验处理PC-3细胞。再次将细胞可渗透的Smac肽(Smac8-C)用作阳性对照。在培养10天后,用结晶紫给平板染色,并且使用ColCount集落计数器对含有超过50个细胞的集落进行计数。使用线性二次方曲线拟合绘制细胞存活曲线(附图17)。与编程性细胞死亡实验一致,SH-97或Smac8-C自身没有显著作用。用10和25μM SH-97或用100uM Smac8-C处理PC-3细胞显著增加了放射活性。正如可以观察到的,在6Gy放射剂量下,10和25μM SH-97导致集落形成比单独放射减少10-倍。在8Gy放射下,10和25μM SH-97使得集落形成比单独放射减少40-和50-倍。与获自上述SH-97与CDDP组合实验的结果一致,在6和8Gy放射剂量下,10μM SH-97看起来也比100μM细胞可渗透的Smac肽Smac8-C更为有效。因此,有关SH-97在编程性细胞死亡和集落形成实验中的初步结果提供了支持如下基本论题的证据:有效的细胞可渗透的肽模拟物或非肽的肽模拟物可比细胞可渗透的Smac肽类更为有效地克服具有高水平XIAP和其它IAP蛋白的癌细胞对化疗药和放射的编程性细胞死亡抗性。
实施例13
SH-102在人癌细胞中对细胞生长的抑制
为了检验Smac模拟物自身抑制人癌细胞中细胞生长的效果,对三种不同的乳腺癌细胞系给予SH-102。将MDA-435、MDA-468和T47D细胞与增加浓度的SH-102、Smac8或Smac8-C一起接种在96-孔平板上。然后将细胞在37℃、5%CO2下保温5天,随后使用WST-8检测细胞存活率。将未处理的细胞视作100%生长。SH-102抑制每种细胞系的细胞生长,IC50在约30-70μM的范围(附图18A-18C)。相反,细胞可渗透的Smac肽(Smac8-C)在所有这些细胞系中抑制细胞生长的功效均低于SH-102(附图18A-18C)。来源于Smac蛋白质序列、但不含载体肽的天然Smac肽(Smac8)在所有三种细胞中基本上无效(附图18A-18C)。这些数据表明Smac模拟物能够抑制人癌细胞中的细胞生长。
上面已经完整地描述了本发明,本领域技术人员将能够理解,可以在广泛和等同条件、配制和其它参数的范围内实施它们,而不会影响本发明的范围或其任何实施方案。将本文引述的所有专利、专利申请和公开文献的全部内容完整地引入本文作为参考。
Claims (40)
1.具有通式I的化合物:
或其药物上可接受的盐或前体药物,其中:
R1为C1-2烷基或C1-2卤代烷基;
R2为支链或非支链的烷基或环烷基或取代或未被取代的芳基、烷基芳基、杂芳基或烷基杂芳基;
X为CONH、CH2O、CH2NH、CH2S或(CH2)1-3;
Y1为(CH2)1-5,其中一个或多个碳可以被一个或多个选自氧、硫和氮的杂原子取代,并且CH2基团上的一个或多个氢可以被支链或非支链的烷基或环烷基或取代或未被取代的芳基、烷基芳基、杂芳基或烷基杂芳基取代;
Y2为(CH2)1-5,其中一个或多个碳可以被一个或多个选自氧、硫和氮的杂原子取代,并且CH2基团上的一个或多个氢可以被支链或非支链的烷基或环烷基或取代或未被取代的芳基、烷基芳基、杂芳基或烷基杂芳基取代;且
Z为CONH、CH2O、NHCO、(CH2)1-4、(CH2)1-3CONH(CH2)0-3、(CH2)1-3S(CH2)0-3、(CH2)1-3NH(CH2)0-3、(CH2)1-3NHCO(CH2)0-3、(CH2)1-3NHSO2(CH2)0-3、(CH2)1-3NHC(O)NH(CH2)0-3、(CH2)1-3NHC(S)NH(CH2)0-3、(CH2)1-3NR′(CH2)0-3,其中R′为支链或非支链的烷基或环烷基或取代或未被取代的芳基、烷基芳基、杂芳基或烷基杂芳基。
2.权利要求1所述的化合物,其中X为CONH。
3.权利要求1所述的化合物,其中Z为CONH。
4.权利要求1所述的化合物,其中X和Z为CONH。
6.药物组合物,其中包含权利要求1的化合物和药物上可接受的载体。
7.权利要求6所述的药物组合物,其中X为CONH。
8.权利要求6所述的药物组合物,其中Z为CONH。
9.权利要求6所述的药物组合物,其中X和Z为CONH。
11.诱导细胞中的编程性细胞死亡的方法,包括使所述的细胞接触权利要求1的化合物。
12.权利要求11所述的方法,其中X为CONH。
13.权利要求11所述的方法,其中Z为CONH。
14.权利要求11所述的方法,其中X和Z为CONH。
16.使细胞对编程性细胞死亡诱导物敏感的方法,包括使所述的细胞接触权利要求1的化合物。
17.权利要求16所述的方法,进一步包括使所述的细胞接触编程性细胞死亡诱导物。
18.权利要求17所述的方法,其中所述的编程性细胞死亡诱导物为化疗剂。
19.权利要求17所述的方法,其中所述的编程性细胞死亡诱导物为放射。
20.权利要求16所述的方法,其中X为CONH。
21.权利要求16所述的方法,其中Z为CONH。
22.权利要求16所述的方法,其中X和Z为CONH。
24.治疗、改善或预防对动物中编程性细胞死亡的诱导有反应性的疾病的方法,包括对所述的动物给予治疗有效量的权利要求1的化合物和编程性细胞死亡诱导物。
25.权利要求24所述的方法,其中所述的编程性细胞死亡诱导物为化疗剂。
26.权利要求24所述的方法,其中所述的编程性细胞死亡诱导物为放射。
27.权利要求24所述的方法,其中所述对编程性细胞死亡的诱导有反应性的疾病为过度增殖性疾病。
28.权利要求27所述的方法,其中所述的过度增殖性疾病为癌症。
29.权利要求24所述的方法,其中在所述的编程性细胞死亡诱导物之前给予权利要求1所述的化合物。
30.权利要求24所述的方法,其中在所述的编程性细胞死亡诱导物之后给予权利要求1所述的化合物。
31.权利要求24所述的方法,其中将权利要求1所述的化合物与所述的编程性细胞死亡诱导物同时给予。
32.权利要求24所述的方法,其中X为CONH。
33.权利要求24所述的方法,其中Z为CONH。
34.权利要求24所述的方法,其中X和Z为CONH。
36.包含权利要求1的化合物和对动物给予所述化合物的说明书的试剂盒。
37.权利要求36所述的试剂盒,其中进一步包含编程性细胞死亡诱导物。
38.权利要求37所述的试剂盒,其中所述的编程性细胞死亡诱导物为化疗剂。
39.权利要求36所述的试剂盒,其中所述的说明书为对患有过度增殖性疾病的动物给予所述化合物的说明书。
40.权利要求39所述的试剂盒,其中所述的过度增殖性疾病为癌症。
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Cited By (2)
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CN110028508A (zh) * | 2019-05-16 | 2019-07-19 | 南京华威医药科技集团有限公司 | 一种抗肿瘤的重氮双环类细胞凋亡蛋白抑制剂 |
CN110028508B (zh) * | 2019-05-16 | 2021-05-28 | 南京华威医药科技集团有限公司 | 一种抗肿瘤的重氮双环类细胞凋亡蛋白抑制剂 |
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WO2005069894A3 (en) | 2005-10-06 |
US7932382B2 (en) | 2011-04-26 |
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