CN107915728A - Iap抑制剂 - Google Patents
Iap抑制剂 Download PDFInfo
- Publication number
- CN107915728A CN107915728A CN201711212712.XA CN201711212712A CN107915728A CN 107915728 A CN107915728 A CN 107915728A CN 201711212712 A CN201711212712 A CN 201711212712A CN 107915728 A CN107915728 A CN 107915728A
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- Prior art keywords
- compound
- acid
- iap
- cell
- cancer
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Abstract
本申请涉及具有通式(I)的IAP抑制剂,其可用作治疗恶性肿瘤的治疗剂:,其中R1、R2、R3、R4、R5和R6如本文所述。
Description
本申请是2013年1月3日提交的发明名称为“IAP抑制剂”的中国专利申请201380012308.1的分案申请。
本发明涉及可用于哺乳动物的治疗和/或预防的有机化合物,并且特别涉及可用于治疗癌症的IAP蛋白抑制剂。
细胞凋亡或程序性细胞死亡是在基因和生物化学方面受调节的机制,其在无脊椎动物及脊椎动物的发育和体内平衡方面发挥重要作用。已将导致过早细胞死亡的细胞凋亡异常与多种发育障碍关联起来。导致细胞死亡缺乏的细胞凋亡缺陷已与癌症和慢性病毒感染关联起来(Thompson等,(1995)Science 267,1456-1462)。
细胞凋亡的关键效应器分子之一是胱天蛋白酶(含半胱氨酸的天冬氨酸特异性蛋白酶)。胱天蛋白酶是强蛋白酶,在天冬氨酸残基之后裂解,且一旦激活,从细胞内部消化关键的细胞蛋白。因为胱天蛋白酶是此类强蛋白酶,对该家族的蛋白的紧密控制对于防止过早细胞死亡是必要的。通常,胱天蛋白酶被合成为大部分失活的酶原,其需要蛋白水解处理以变得有活性。这种蛋白水解处理仅是胱天蛋白酶被调节的方式之一。另一机制是通过结合并抑制胱天蛋白酶的蛋白家族。
抑制胱天蛋白酶的分子家族是细胞凋亡抑制因子(IAP)(Deveraux等,J ClinImmunol(1999),19:388-398)。IAP最初在杆状病毒中由于其替代P35蛋白、即抗细胞凋亡基因的功能性能力而被发现(Crook等,(1993)J Virology 67,2168-2174)。已描述IAP在果蝇至人类范围内的生物体中。不管其来源如何,在结构上,IAP包含一至三个杆状病毒IAP重复(BIR)域,并且它们中的大部分还具有羧基端RING指基序。BIR域自身为约70个残基的锌结合域,包括4个α-螺旋和3个β链,具有配位锌离子的半胱氨酸和组氨酸残基(Hinds等,(1999)Nat.Struct.Biol.6,648-651)。BIR域被认为通过抑制胱天蛋白酶并由此抑制细胞凋亡而导致抗细胞凋亡作用。例如,人X-染色体连接的IAP(XIAP)抑制胱天蛋白酶3、胱天蛋白酶7和Apaf-1-细胞色素C介导的胱天蛋白酶9的激活(Deveraux等,(1998)EMBO J.17,2215-2223)。胱天蛋白酶3和7被XIAP的BIR2域抑制,而XIAP的BIR3域负责抑制胱天蛋白酶9的活性。XIAP在大部分成人和胎儿组织中普遍表达(Liston等,Nature,1996,379(6563):349),并且在NCI 60细胞系组(cell line panel)的许多肿瘤细胞系中过表达(Fong等,Genomics,2000,70:113;Tamm等,Clin.Cancer Res.2000,6(5):1796)。已证明XIAP在肿瘤细胞中的过表达给予对多种促细胞凋亡刺激的保护并促进对化学治疗的抗性(LaCasse等,Oncogene,1998,17(25):3247)。与此相符的是,对于患有急性髓性白血病的患者,已证明了XIAP蛋白水平与存活之间的强相关性(Tamm等,同上)。已表明由反义寡核苷酸下调XIAP表达使肿瘤细胞在体外和体内对由广泛的促细胞凋亡试剂诱导的死亡敏感(Sasaki等,Cancer Res.,2000,60(20):5659;Lin等,Biochem J.,2001,353:299;Hu等,Clin.CancerRes.,2003,9(7):2826)。还已证明Smac/DIABLO衍生的肽使多种不同的肿瘤细胞系对由多种促细胞凋亡药物诱导的细胞凋亡敏感(Arnt等,J.Biol.Chem.,2002,277(46):44236;Fulda等,Nature Med.,2002,8(8):808;Guo等,Blood,2002,99(9):3419;Vucic等,J.Biol.Chem.,2002,277(14):12275;Yang等,Cancer Res.,2003,63(4):831)。
黑素瘤IAP(ML-IAP)是在大部分正常成人组织中检测不到但在黑素瘤中强烈上调的IAP(Vucic等人,(2000)Current Bio 10:1359-1366)。蛋白结构的确定表明ML-IAP BIR和RING指域与在人XIAP、C-IAP1和C-IAP2中存在的相应域的显著同源性。ML-IAP的BIR域可能具有与XIAP、C-IAP1和C-IAP2的BIR2和BIR3的大部分相似性,并且可能负责抑制细胞凋亡,如删除分析所测定的。此外,Vucic等证明了ML-IAP可抑制化学治疗剂诱导的细胞凋亡。在过表达ML-IAP的黑素瘤的细胞培养系统中测试了诸如阿霉素和4-叔丁基苯酚(4-TBP)的药剂,当与正常黑素细胞对照相比时,化学治疗剂在杀灭细胞方面的效力明显更低。ML-IAP产生抗细胞凋亡活性的机制是部分通过抑制胱天蛋白酶3和9。ML-IAP不有效抑制胱天蛋白酶1、2、6或8。
因为细胞凋亡是具有多种相互作用的因子的严格受控途径,所以IAP自身调节的发现是不寻常的。在果蝇中,Reaper(rpr)、Head Involution Defective(hid)和GRIM蛋白与果蝇家族的IAP物理地相互作用并抑制其的抗细胞凋亡活性。在哺乳动物中,蛋白SMAC/DIABLO起到阻断IAP的作用并使细胞凋亡进行。已表明,在正常细胞凋亡期间,SMAC被加工成活性形式,并且其从线粒体释放入细胞质,在那里其与IAP物理地结合并抑制IAP与胱天蛋白酶结合。这种IAP抑制使胱天蛋白酶保持活性,由此进行细胞凋亡。有趣的是,IAP抑制剂之间的序列同源性表明,在经加工的活性蛋白的N-端中存在四种氨基酸基序。这种四肽可以结合到BIR域的疏水性口袋中,并且扰乱BIR域与胱天蛋白酶的结合(Chai等,(2000)Nature 406:855-862,Liu等,(2000)Nature 408:1004-1008,Wu等,(2000)Nature 4081008-1012)。
发明概述
在本发明的一方面,提供新的IAP蛋白抑制剂或其药学可接受的盐,所述化合物具有通式(I)
其中
R1为C3-7环烷基,
Ph为苯基,
R2、R3、R4、R5和R6在每次出现时各自独立地为H或C1-6烷基。
式I包括所有立体异构体。
在本发明的另一方面,提供包含式I的化合物及载体、稀释剂或赋形剂的组合物。
在本发明的另一方面,提供在细胞中诱导细胞凋亡的方法,其包括向所述细胞引入式I的化合物。
在本发明的另一方面,提供使细胞对细胞凋亡信号敏感的方法,其包括向所述细胞引入式I的化合物。
在本发明的另一方面,提供抑制IAP蛋白与胱天蛋白酶蛋白结合的方法,其包括使所述IAP蛋白与式I的化合物接触。
在本发明的另一方面,提供治疗哺乳动物中与IAP蛋白过表达相关的疾病或病症的方法,其包括向所述哺乳动物给药有效量的式I的化合物。
在本发明的另一方面,提供用于治疗癌症的方法。
附图简述
图1示出在利用Calu-6肺腺癌细胞的异种移植模型中,单独的Ia以及其与Apomab联合的效力,连同单独的现有技术化合物III以及其与Apomab联合的效力数据。Ia是口服给药。III是经静脉内给药。选择剂量以产生药物的最大耐受剂量。
图2示出在利用Colo205结肠直肠腺癌细胞的异种移植模型中,单独的Ia以及其与Apomab联合的效力,连同单独的现有技术化合物III以及其与Apomab联合的效力数据。Ia是口服给药。III是经静脉内给药。选择剂量以产生药物的最大耐受剂量。
本文使用的短语“一个(a)”或“一个(an)”实体是指一个或多个所述实体;例如,化合物是指一个或多个化合物或者至少一个化合物。因此,在本文可互换使用术语“一个(a)”(或“一个(an)”)、“一个或多个”和“至少一个”。
如本说明书所用,无论在过渡短语中或在权利要求的主体中,术语“包扩”与“包含”应理解为具有开放式含义。即,该术语应理解为与短语“具有至少”或“包括至少”同义。当用于方法的语境中时,术语“包括”表示该方法至少包括所列举的步骤,但可以包括额外的步骤。当用于化合物或组合物的语境中时,术语“包含”意指该化合物或组合物至少包含所列举的特征或组分,但还可包含额外的特征或组分。
术语“独立地”在本文用于表示变量适用于任何一种情况,而无需考虑在相同化合物中存在或不存在具有相同或不同定义的变量。因此,在其中R”出现两次并被定义为“独立地为碳或氮”的化合物中,两个R”皆可为碳,两个R”皆可为氮,或者一个R”可为碳而另一个为氮。
本文所用的术语“任选存在的”或“任选地”意指随后所述的事件或情况可能、但不一定发生,且该描述包括发生该事件或情况的情形以及不发生该事件或情况的情形。例如,“任选取代的”意指任选取代的部分可以包括氢或取代基。
术语“约”在本文用于意指近似、接近、粗略或大约。当术语“约”与数值范围连用时,其通过扩大所列数值的上边界和下边界而改变该范围。通常,术语“约”在本文用于使数值以所述值上下变化20%的形式改变。
如本文所用,变量的数值范围的列举旨在说明可通过等于该范围内的任何值的变量实施本发明。因此,对于本身是离散的变量而言,该变量可等于该数值范围的任何整数值,包括该范围的端点。类似地,对于本身是连续的变量而言,该变量可等于该数值范围的任何实数值,包括该范围的端点。例如,被描述为具有0至2之间的值的变量,对于本身是离散的变量而言,可为0、1或2,而对于本身是连续的变量而言,可为0.0、0.1、0.01、0.001或任何其他实数值。
式I的化合物呈现互变异构现象。互变异构化合物可以两种或更多种可相互转化的种类而存在。质子移变互变异构体是由两个原子之间共价键合的氢原子的迁移所产生。互变异构体通常以平衡形式存在,且分离单个互变异构体的尝试通常产生混合物,其化学和物理性质与化合物的混合物一致。平衡位置取决于分子内的化学特征。例如,在许多脂族醛和酮(诸如乙醛)中,酮形式占主导;而在酚类中,烯醇形式占主导。常见质子移变互变异构体包括酮/烯醇酰胺/亚胺酸及脒 互变异构体。后两者在杂芳基和杂环中尤其常见。本发明涵盖本文所述化合物的所有互变异构形式。
除非另有规定,“烷基”意指具有至多6个碳原子的支链或无支链的饱和脂族烃基,当作为另一术语(例如“烷基氨基”)的一部分时亦如此。优选的烷基的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、2-甲基戊基、2,2-二甲基丁基等。术语“低级烷基”、“C1-C4烷基”及“1至4个碳原子的烷基”为同义的,且可互换地用于表示甲基、乙基、1-丙基、异丙基、环丙基、1-丁基、仲丁基或叔丁基。
环烷基可为3至7个碳原子的单-、二-或三-环脂族环。优选的基团包括环丙基、环丁基、环戊基和环己基,且更优选为环丙基和环己基,且最优选为环己基。
“氨基保护基”是指当在化合物的其他官能团上进行反应时常用于封闭或保护氨基的基团的衍生物。此类保护基的实例包括氨基甲酸酯、酰胺、烷基和芳基、亚胺,以及可被移除以再生成所需氨基的许多N-杂原子衍生物。优选的氨基保护基是Boc、Fmoc和Cbz。这些基团的其他实例可见于T.W.Greene和P.G.M.Wuts,“Protective Groups in OrganicSynthesis”,第2版,John Wiley&Sons,Inc.,New York,NY,1991,第7章;E.Haslam,“Protective Groups in Organic Chemistry”,J.G.W.McOmie,Ed.,Plenum Press,NewYork,NY,1973,第5章,以及T.W.Greene,“Protective Groups in Organic Synthesis”,John Wiley and Sons,New York,NY,1981。术语“受保护的氨基”是指被上述氨基保护基之一取代的氨基。可在合成过程中使用这些基团。
“羧基保护基”是指在化合物的其他官能团上进行反应时常用于封闭或保护羧酸基团的羧酸基团的酯衍生物之一。此类羧酸保护基的实例包括4-硝基苄基、4-甲氧基苄基、3,4-二甲氧基苄基、2,4-二甲氧基苄基、2,4,6-三甲氧基苄基、2,4,6-三甲基苄基、五甲基苄基、3,4-亚甲二氧基苄基、二苯甲基、4,4’-二甲氧基二苯甲基、2,2’,4,4’-四甲氧基二苯甲基、烷基(诸如叔丁基或叔戊基)、三苯甲基、4-甲氧基三苯甲基、4,4’-二甲氧基三苯甲基、4,4’,4”-三甲氧基三苯甲基、2-苯基丙-2-基、三甲基甲硅烷基、叔丁基二甲基甲硅烷基、苯甲酰甲基、2,2,2-三氯乙基、β-(三甲基甲硅烷基)乙基、β-(二(正丁基)甲基甲硅烷基)乙基、对甲苯磺酰基乙基、4-硝基苄基磺酰基乙基、烯丙基、肉桂基、1-(三甲基甲硅烷基甲基)丙-1-烯-3-基及类似基团。所采用的羧基保护基的种类并不严格,只要衍生的羧酸对分子其他位置上的后续反应的条件是稳定的,且可在适当时机移除而不会破坏该分子的剩余部分。特别地,重要的是,不使羧基受保护的分子经受强亲核碱(例如氢氧化锂或NaOH)或者采用高度活化的金属氢化物(例如LiAlH4)的还原性条件。当移除氨基保护基和羟基保护基时也要避免此类剧烈的移除条件。优选的羧酸保护基为烷基(例如甲基、乙基、叔丁基)、烯丙基、苄基和对硝基苄基。也可采用头孢菌素、青霉素和肽技术中使用的类似羧基保护基来保护羧基取代基。这些基团的其他实例可见于T.W.Greene和P.G.M.Wuts,“ProtectiveGroups in Organic Synthesis”,第2版,John Wiley&Sons,Inc.,New York,N.Y.,1991,第5章;E.Haslam,“Protective Groups in Organic Chemistry”,J.G.W.McOmie,Ed.,PlenumPress,New York,N.Y.,1973,第5章,以及T.W.Greene,“Protective Groups in OrganicSynthesis”,John Wiley and Sons,New York,NY,1981,第5章。术语“受保护的羧基”是指被上述羧基保护基之一取代的羧基。可在合成过程中使用这些基团。
“羟基保护基”是指当在化合物的其他官能团上进行反应时常用于封闭或保护羟基的羟基的衍生物。此类保护基的实例包括四氢吡喃基氧基、苯甲酰基、乙酰氧基、氨基甲酰氧基、苄基和甲硅烷基醚(例如TBS、TBDPS)。这些基团的其他实例可见于T.W.Greene和P.G.M.Wuts,“Protective Groups in Organic Synthesis”,第2版,John Wiley&Sons,Inc.,New York,NY,1991,第2-3章;E.Haslam,“Protective Groups in OrganicChemistry”,J.G.W.McOmie,Ed.,Plenum Press,New York,NY,1973,第5章,以及T.W.Greene,“Protective Groups in Organic Synthesis”,John Wiley and Sons,NewYork,NY,1981。术语“受保护的羟基”是指被上述羟基保护基之一取代的羟基。可在合成过程中使用这些基团。
“抑制剂”意指减少或防止IAP蛋白与胱天蛋白酶蛋白结合,或者减少或防止IAP蛋白(例如,c-IAP1、c-IAP2、X-IAP或ML-IAP)抑制细胞凋亡的化合物。或者,“抑制剂”意指防止X-IAP与胱天蛋白酶的结合相互作用或防止ML-IAP与SMAC的结合相互作用的化合物。
“药学可接受的盐”包括酸加成盐和碱加成盐。“药学可接受的酸加成盐”是指与无机酸和有机酸形成的盐,所述盐保留游离碱的生物学效力和性质且不是生物学上或其他方面不期望的,所述无机酸是例如盐酸、氢溴酸、硫酸、硝酸、碳酸、磷酸等,并且有机酸可以选自脂族、环脂族、芳族、芳脂族、杂环、羧酸及磺酸类的有机酸,例如甲酸、乙酸、丙酸、乙醇酸、葡糖酸、乳酸、丙酮酸、草酸、苹果酸、马来酸、丙二酸、琥珀酸、富马酸、酒石酸、柠檬酸、天冬氨酸、抗坏血酸、谷氨酸、邻氨基苯甲酸、苯甲酸、肉桂酸、扁桃酸、双羟萘酸、苯乙酸、甲磺酸、乙磺酸、对甲苯磺酸、水杨酸等。“药学可接受的碱加成盐”包括由无机碱所衍生的盐,例如钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。特别优选的是铵盐、钾盐、钠盐、钙盐和镁盐。衍生自药学可接受的有机无毒碱的盐包括以下的盐:伯胺、仲胺和叔胺、包括天然存在的取代的胺在内的取代的胺、环胺和碱性离子交换树脂,例如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二乙氨基乙醇、氨基丁三醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、海巴胺、胆碱、甜菜碱、乙二胺、葡糖胺、甲基葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。特别优选的有机无毒碱是异丙胺、二乙胺、乙醇胺、氨基丁三醇、二环己胺、胆碱和咖啡因。式I还旨在涵盖所述化合物的水合物和溶剂化物。
本发明提供具有通式I的新化合物,
在一具体实施方案中,R1为环己基。在另一具体实施方案中,R1为环戊基。在一特定实施方案中,R1被取向以使它包含的氨基酸或氨基酸类似物呈L-构型。
R2和R3独立地为H或C1-6烷基。在一实施方案中,R2和R3皆为H。在另一实施方案中,R2为甲基,且R3为H。
R4为H或C1-6烷基。在一具体实施方案中,R4为H或甲基。在另一实施方案中,R4为甲基。在另一实施方案中,R4被取向以使它包含的氨基酸或氨基酸类似物呈L-构型。
R5和R6各自独立为H或C1-6烷基。在一实施方案中,R5和R6为H或甲基。在一实施方案中,R5为H,且R6为甲基。在另一实施方案中,R5为甲基,且R6为H。在另一实施方案中,R5和R6皆为甲基。在另一实施方案中,R5和R6皆为H。
在本发明的另一方面,式I的化合物是(S)-1-[(S)-2-环己基-2-((S)-2-甲基氨基丙酰基氨基)乙酰基]吡咯烷-2-羧酸(2-噁唑-2-基-4-苯基噻唑-5-基)酰胺(Ia)。
本发明的化合物包含一个或多个不对称碳原子。因此,所述化合物可以立体异构体形式存在,包括非对映异构体、对映异构体或其混合物。所述化合物的合成可采用外消旋物、非对映异构体或对映异构体作为起始材料或作为中间体。可通过色谱或结晶法分离非对映异构化合物。类似地,可利用相同技术或本领域已知的其他技术分离对映异构混合物。各不对称碳原子可呈R或S构型,且这两种构型皆在本发明的范围内。优选地,本发明的化合物具有以下式Ib的立体化学构型,其中R1、R2、R3、R4、R5及R6如本文所述。
第20060014700号美国公开中已披露式II的化合物,其中A为包含1至4个杂原子的任选取代的5-元杂环。在该公开中所披露的一些化合物中,A为N-(4-苯基噻唑-5-基)。
现已发现,根据本发明的其中A为2-(噁唑-2-基)-4-苯基噻唑-5-基的化合物出乎意料地增加效力和口服生物利用度。此外,例如与化合物III(第20060014700号美国公开中披露的化合物)相比,本发明的化合物通常具有较低副作用,包括改善的肺毒性。图1和图2示出在异种移植肿瘤模型中,经静脉内给药的化合物III与口服给药的本发明化合物Ia相比活性相当。
合成
本发明的化合物是利用标准有机合成技术由可商购的起始材料和试剂而制备的。WO 98/46576和USP 7,244,851披露了一般技术,其以援引方式加入本文用于本文披露的制备方法。应认识到,如有机合成中的标准那样,在制备本发明的化合物中采用的合成步骤会取决于化合物中存在的特定取代基,并且可能需要各种保护和脱保护。在一般合成路线中,可利用典型的肽化学技术,通过典型的酰胺偶联步骤,使氨基酸残基类似物偶联,来制备本发明的化合物。在路线1中,利用肽合成方案,使胺受保护的氨基酸残基类似物偶联,随后脱保护,从而产生最终化合物。
路线1
应认识到,氨基酸类似物可以任何次序偶联,且可以利用本领域常规的固相载体制备。
当本发明的化合物包含不为H的R2或R3取代基时,其可通过用所需的胺取代包含离去基的合适的酸中间体来制备。例如,根据路线2,用胺R2-NH2或R2-NH-R3取代Br-CH(R4)-C(O)-OH。
路线2
或者,可以进行引入R2或R3取代基的取代反应,作为化合物的制备中的最后步骤,如路线3所示。
路线3
在一特定实施方案中,2-溴丙酸与溶于DMF的合适的胺反应,并鼓泡,直至取代完成,从而形成N-取代的丙氨酸残基。
作为用于制备本发明化合物的中间体的胺取代的环A化合物是可商购的,或由可商购试剂采用标准有机化学技术制得。可通过使α-氨基苯乙腈盐酸盐与噁唑-2-甲醛在硫和TEA的存在下缩合来制备2-(噁唑-2-基)-4-苯基噻唑-5-胺(路线4)。
实用性
本发明的化合物抑制IAP蛋白与胱天蛋白酶的结合,特别是X-IAP与胱天蛋白酶3和7的结合相互作用。所述化合物也抑制ML-IAP与Smac蛋白的结合。因此,本发明的化合物可用于在细胞中诱导细胞凋亡,或使细胞、特别是癌细胞对细胞凋亡信号敏感。本发明的化合物可用于在过表达IAP蛋白(例如,c-IAP1、c-IAP2、X-IAP或ML-IAP)的细胞中诱导细胞凋亡。或者,本发明的化合物可用于在这样的细胞中诱导细胞凋亡,在所述细胞中粒线体细胞凋亡途径被破坏以至于Smac由ML-IAP蛋白的释放例如通过Bcl-2的上调或Bax/Bak的下调被抑制。更广泛地,所述化合物可用于治疗癌症。
其尤其可用于治疗未能经历细胞凋亡的所有癌症类型。此类癌症类型的实例包括神经母细胞瘤、肠癌诸如直肠癌、结肠癌、家族性腺瘤性息肉癌及遗传性非息肉性结肠直肠癌、食道癌、唇癌、喉癌、下咽癌、舌癌、唾液腺癌、胃癌、腺癌、甲状腺髓样癌、乳头状甲状腺癌、肾癌、肾实质癌、卵巢癌、子宫颈癌、子宫体癌、子宫内膜癌、绒毛膜癌、胰腺癌、前列腺癌、睪丸癌、乳腺癌、泌尿系统癌、黑素瘤、脑瘤诸如胶质母细胞瘤、星形细胞瘤、脑膜瘤、髓母细胞瘤及周围神经外胚层瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、伯基特淋巴瘤、急性淋巴性白血病(ALL)、慢性淋巴性白血病(CLL)、急性髓性白血病(AML)、慢性髓性白血病(CML)、成人T-细胞白血病淋巴瘤、肝细胞癌、胆囊癌、支气管癌、小细胞肺癌、非小细胞肺癌、多发性骨髓瘤、基底细胞瘤、畸胎瘤、视网膜母细胞瘤、脉络膜黑素瘤、精原细胞瘤、横纹肌肉瘤、颅咽瘤(craniopharyngeoma)、骨肉瘤、软骨肉瘤、肌肉瘤、脂肪肉瘤、纤维肉瘤、尤因肉瘤及浆细胞瘤。可用于治疗实体瘤。还可用于治疗乳腺癌、胰腺癌或恶性黑素瘤。
本发明化合物可用于使细胞对细胞凋亡信号敏感。因此,所述化合物可在辐射治疗或者细胞增殖抑制性化疗或抗肿瘤化疗之前、同时或之后给药。合适的细胞增殖抑制性化疗化合物包括但不限于:(i)抗代谢物,诸如阿糖胞苷、氟达拉滨、5-氟-2’-脱氧尿苷、吉西他滨、羟基脲或甲氨喋呤;ii)DNA断裂剂,诸如博来霉素;(iii)DNA交联剂,诸如苯丁酸氮芥、顺铂、环磷酰胺或氮芥;(iv)嵌入剂(intercalating agent),诸如阿霉素(多柔比星)或米托蒽醌;(v)蛋白合成抑制剂,诸如L-天冬酰胺酶、环己酰亚胺、嘌呤霉素或白喉毒素;(vi)拓扑异构酶I毒素,诸如喜树碱或托泊替康;(vii)拓扑异构酶II毒素,诸如依托泊苷(VP-16)或替尼泊苷;(viii)微管靶向剂(microtubule-directed agent),诸如秋水仙酰胺、秋水仙碱、紫杉醇、长春碱或长春新碱;(ix)激酶抑制剂,诸如夫拉平度、星形孢菌素、STI571(CPG 57148B)或UCN-01(7-羟基星形孢菌素);(x)各种试验药剂,诸如Thioplatin、PS-341、苯丁酸盐、ET-18-OCH3,或法呢基转移酶抑制剂(L-739749、L-744832);多元酚,诸如槲皮素、白藜芦醇、四羟反式芪(piceatannol)、表没食子儿茶素没食子酸酯(epigallocatechin gallate)、茶黄素、黄烷醇、原花青素、桦木酸及其衍生物;(xi)激素,诸如糖皮质激素或芬维A胺;(xii)激素拮抗剂,诸如他莫昔芬、非那雄胺或LHRH拮抗剂。在一优选实施方案中,本发明的化合物与一种选自下列的细胞增殖抑制性化合物联合给药:顺铂、多柔比星、紫杉醇、多西他赛及丝裂霉素C。最优选的是地,所述细胞增殖抑制性化合物为多柔比星。可使用与5-FU、吉西他滨、卡培他滨、长春瑞滨、贝伐单抗或紫杉烷的组合。
另一类可用于本发明的活性化合物为可通过与死亡受体结合而对细胞凋亡敏感或诱导细胞凋亡的化合物(“死亡受体激动剂”)。此类死亡受体激动剂包括死亡受体配体,诸如肿瘤坏死因子α(TNF-α)、肿瘤坏死因子β(TNF-β,淋巴毒素-α)、LT-β(淋巴毒素-β)、TRAIL(Apo2L,DR4配体)、CD95(Fas,APO-1)配体、TRAMP(DR3,Apo-3)配体、DR6配体以及所述配体中任一个的片段和衍生物。优选的是,所述死亡受体配体为TNF-α。更优选的是,所述死亡受体配体为Apo2L/TRAIL。此外,死亡受体激动剂包括死亡受体的激动抗体,诸如抗-CD95抗体、抗-TRAIL-R1(DR4)抗体、抗-TRAIL-R2(DR5)抗体、抗-TRAIL-R3抗体、抗-TRAIL-R4抗体、抗-DR6抗体、抗-TNF-R1抗体及抗-TRAMP(DR3)抗体,以及所述抗体中任一个的片段和衍生物。
出于使细胞对细胞凋亡敏感的目的,也可将本发明的化合物与辐射治疗联合使用。短语“辐射治疗”是指在肿瘤的治疗中使用电磁辐射或微粒辐射。辐射治疗基于以下原理:递送至靶标区域的高剂量辐射会导致肿瘤和正常组织两者中繁殖细胞的死亡。辐射剂量方案通常依据辐射吸收剂量(rad)、时间和分级(fractionation)来限定,且必须由肿瘤科医师慎重限定。患者接受的辐射量将取决于各种因素,但两个最重要的因素为肿瘤相对于身体的其他关键结构或器官的位置,以及肿瘤扩散的程度。辐射治疗剂的实例提供于辐射治疗(但不限于辐射治疗)中,并且所述实例是本领域已知的(Hellman,Principles ofRadiation Therapy,Cancer,in Principles I and Practice of Oncology,24875(Devita等,第4版,第1卷,1993)。辐射治疗的最新进展包括三维适形体外射线束辐射治疗、强度调节辐射治疗(IMRT)、立体定向辐射外科治疗和短距离辐射治疗(组织间辐射治疗),后者将辐射源直接放入肿瘤中作为植入的“种子”。这些较新的治疗方式将更大剂量的辐射递送至肿瘤,当与标准体外射线束辐射治疗相比时,这导致有效性增加。
对于辐射治疗应用,使用发射β射线的放射性核素的电离辐射被认为是最有用的,原因在于电离粒子(电子)的线性能量转移(LET)适度,且其范围适中(在组织中通常为数毫米)。γ射线在较低水平的剂量下递送远得多的距离。α粒子代表另一极端,其递送非常高的LET剂量,但具有极有限的范围,因此必须与待治疗的组织的细胞紧密接触。另外,α放射体通常为重金属,这限制潜在的化学过程,并且存在放射性核素从待治疗区域泄漏的不适当危害。根据待治疗的肿瘤,所有类型的放射体皆在本发明的范围内。
此外,本发明涵盖多种类型的非电离辐射,例如紫外(UV)辐射、高能可见光、微波辐射(高温治疗)、红外(IR)辐射和激光。在本发明的一特定实施方案中,应用UV辐射。
更通常地,本发明的化合物可用于联合治疗。“联合治疗”包括以进一步与其他生物活性成份(例如、但不限于第二且不同的抗肿瘤药剂)和非药物治疗(例如、但不限于手术或辐射治疗)组合的方式给药本发明的化合物。例如,本发明的化合物可与其他药学活性化合物、优选能提高本发明化合物的效力的化合物联合使用。本发明的化合物可与其他药物治疗同时给药(以单一制剂或分开的制剂的形式)或依次给药。通常,联合治疗预期在单一周期或疗程期间给药两种或更多种药物。
因此,在本发明的一方面,本发明的化合物可与一种或多种分开的药剂联合给药,所述药剂调节涉及多种疾病状态的蛋白激酶或其下游标靶。此类激酶的实例可包括但不限于:丝氨酸/苏氨酸特异性激酶、受体酪氨酸特异性激酶和非受体酪氨酸特异性激酶。丝氨酸/苏氨酸激酶包括有丝分裂原活化蛋白激酶(MAPK)、减数分裂特异性激酶(MEK)、RAF和极光激酶(aurora kinase)。受体激酶家族的实例包括:表皮生长因子受体(EGFR)(例如HER2/neu、HER3、HER4、ErbB、ErbB2、ErbB3、ErbB4、Xmrk、DER、Let23);成纤维细胞生长因子(FGF)受体(例如FGF-R1、GFF-R2/BEK/CEK3、FGF-R3/CEK2、FGF-R4/TKF、KGF-R);肝细胞生长/分散因子受体(HGFR)(例如,MET、RON、SEA、SEX);胰岛素受体(例如IGFI-R、PI3K、AKT、mTor);Eph(例如CEK5、CEK8、EBK、ECK、EEK、EHK-1、EHK-2、ELK、EPH、ERK、HEK、MDK2、MDK5、SEK);Axl(例如Mer/Nyk、Rse);RET;以及血小板衍生生长因子受体(PDGFR)(例如PDGFα-R、PDGβ-R、CSF1-R/FMS、SCF-R/C-KIT、VEGF-R/FLT、NEK/FLK1、FLT3/FLK2/STK-1)。非受体酪氨酸激酶家族包括但不限于:BCR-ABL(例如p43abl、ARG);BTK(例如ITK/EMT、TEC);CSK、FAK、FPS、JAK、SRC、BMX、FER、CDK和SYK。
在本发明的另一方面,本发明的化合物可与一种或多种分开的药剂联合给药,所述药剂调节非激酶生物标靶或过程。此类标靶包括组蛋白脱乙酰基酶(HDAC)、DNA甲基转移酶(DNMT)、热休克蛋白(例如HSP90)、刺猬因子抑制剂(hedgehog inhibitor)和蛋白体。
在一优选实施方案中,本发明的化合物可与抑制一种或多种生物标靶的抗肿瘤癌药剂(例如小分子、单克隆抗体、反义RNA和融合蛋白)联合,诸如艾维奇(Erivedge)、伏立诺他(Zolinza)、特罗凯(Tarceva)、易瑞沙(Iressa)、拉帕替尼(Tykerb)、伊马替尼(Gleevec)、舒尼替尼(Sutent)、达沙替尼(Sprycel)、索拉非尼(Nexavar)、CNF2024、RG108、BMS387032、阿非他克(Affinitak)、贝伐单抗(Avastin)、赫赛汀(Herceptin)、爱必妥(Erbitux)、AG24322、PD325901、ZD6474、PD184322、Obatodax、ABT737以及AEE788。还包括针对特异性激酶和/或受体的单克隆抗体,例如本文所提及的那些及其他。此类联合可提高疗效,使其超过所述药剂中任一个单独所达到的疗效,并且可预防或延迟耐药性突变体(resistant mutational variant)的出现。
在某些优选实施方案中,本发明的化合物与化疗剂联合给药。化疗剂涵盖肿瘤领域中的众多治疗处理。这些药剂在疾病的不同阶段给药,以使肿瘤缩小、破坏术后遗留的残余癌细胞、诱导缓解、维持缓解和/或减轻与癌症或其治疗相关的症状。此类药剂的实例(上文也论述了其中一些)包括但不限于:烷化剂,诸如芥子气衍生物(氮芥、环磷酰胺、苯丁酸氮芥、美法仑、异环磷酰胺)、乙烯亚胺(噻替哌、六甲蜜胺)、烷基磺酸盐(白消安)、肼和三嗪(六甲蜜胺、丙卡巴肼、达卡巴嗪和替莫唑胺)、亚硝基脲(卡莫司汀、洛莫司汀和链佐星)、异环磷酰胺及金属盐(卡铂、顺铂和奥沙利铂);植物生物碱,诸如鬼臼毒素(依托泊苷和替尼泊苷)、紫杉烷(紫杉醇和多西他赛)、长春花生物碱(长春新碱、长春碱、长春地辛和长春瑞滨)及喜树碱类似物(伊立替康和托泊替康);抗肿瘤抗生素,诸如色霉素(放线菌素D和普卡霉素)、蒽环类药物(多柔比星、柔红霉素、表柔比星、米托蒽醌、戊柔比星和伊达比星),以及各种抗生素,诸如丝裂霉素、放线菌素和博来霉素;抗代谢物,诸如叶酸拮抗剂(甲氨喋呤、培美曲塞、雷替曲塞、氨基蝶呤)、嘧啶拮抗剂(5-氟尿嘧啶、氟尿苷、阿糖胞苷、卡培他滨和吉西他滨),嘌呤拮抗剂(6-巯基嘌呤和6-硫鸟嘌呤)以及腺苷脱氨酶抑制剂(克拉屈滨、氟达拉滨、巯基嘌呤、氯法拉滨、硫鸟嘌呤、奈拉滨和喷司他丁);拓扑异构酶抑制剂,诸如拓扑异构酶I抑制剂(伊立替康、托泊替康)和拓扑异构酶II抑制剂(安吖啶、依托泊苷、磷酸依托泊苷、替尼泊苷);单克隆抗体(阿仑珠单抗、吉妥单抗(Gemtuzumabozogamicin)、利妥昔单抗、曲妥珠单抗、替伊莫单抗(IbritumomabTioxetan)、西妥昔单抗、帕尼单抗(Panitumumab)、托西莫单抗、贝伐单抗);以及各种抗肿瘤药剂,诸如核糖核苷酸还原酶抑制剂(羟基脲);肾上腺皮质类固醇抑制剂(米托坦);酶(天冬酰胺酶和培门冬酶);抗微管药剂(雌氮芥);以及类视色素(贝沙罗汀、异维甲酸、维甲酸(ATRA),等等。
本发明还包括包含本发明化合物和治疗惰性载体、稀释剂或赋形剂的药物组合物或药物,以及利用本发明化合物制备此类组合物和药物的方法。通常,通过在环境温度下、在合适的pH下和在所需的纯度下与生理可接受的载体(即在所用的剂量和浓度下对接受者无毒的载体)混合,将本发明的方法中使用的式I化合物配制成盖伦给药形式。制剂的pH主要取决于特定用途和化合物浓度,但在任何情况下优选范围为约3至约8。适当的实施方案是在pH为5的乙酸盐缓冲液中的制剂。
用于本文的抑制性化合物优选是无菌的。所述化合物通常以固体组合物形式储存,然而冻干制剂或水溶液是可接受的。
本发明的组合物以符合良好医学实践的方式进行配制、定剂量(dosed)和给药。在该情形中供考虑的因素包括所治疗的特定病症、所治疗的特定哺乳动物、个体患者的临床状况、病症的原因、递送药剂的位置、给药方法、给药方案以及医学从业者已知的其他因素。待给药的化合物的“有效量”会受此类因素的控制,且是治疗靶标疾病(例如抑制IAP与胱天蛋白酶的相互作用、诱导细胞凋亡或使恶性肿瘤细胞对细胞凋亡信号敏感)所必需的最小量。这样的量优选低于对正常细胞或整体的哺乳动物有毒性的量。
通常,本发明的化合物可每天给药一次或多次。它们也可以在无治疗间隔的情况下以连续的每天方案来给药。它们还可以在有治疗间隔的情况下如此给药。这些选择在与其他药剂或方式一起使用时也是可行的。肠胃外给药的本发明化合物每次给药的初始药学有效量为约0.01-100mg/kg患者体重/天,优选为约0.1-20mg/kg患者体重/天,其中所用化合物的典型初始范围为0.3-15mg/kg/天。口服单位剂型(诸如片剂和胶囊)优选包含约25至约1000mg的本发明化合物。口服给药是优选的。可采用癌症治疗常用的开/关(On/Off)给药方案,例如,每天口服给药持续1、2、3、4周等,然后是1、2周等的治疗间隔,然后每天口服给药持续1、2、3、4周等,等等。在优选的选择中,以约25至约3000mg/天,更优选以约300至约1500mg化合物/天,每天给药本发明的化合物。
可通过任何合适的方式给药本发明的化合物,包括口服、局部、经皮、肠胃外、皮下、腹膜内、肺内和鼻内给药,以及病灶内给药(如果局部治疗需要的话)。肠胃外输注包括肌肉内、静脉内、动脉内、腹膜内或皮下给药。合适的口服剂型的实例为片剂,其包含约25mg、50mg、100mg、250mg或500mg的本发明化合物,以及约90-30mg无水乳糖、约5-40mg交联羧甲基纤维素纳、约5-30mg聚乙烯吡咯烷酮(PVP)K30和约1-10mg硬脂酸镁。先将粉状成份混合在一起,然后与PVP溶液混合。可将所得组合物干燥、粒化、与硬脂酸镁混合,并利用常规设备压成片剂形式。气溶胶制剂可以通过以下制备:将本发明的化合物(例如5-400mg)溶解于合适的缓冲溶液(例如磷酸盐缓冲液)中,若需要,添加张力调节剂(tonicifier),例如,诸如氯化钠的盐。该溶液通常经过滤(例如使用0.2微米过滤器)以移除杂质和污染物。
更通常地,可按照WO 98/46576和USP 7,244,851所提供的公开内容使用本发明的化合物,其公开内容通过援引加入本文作为如何使用所述化合物的通用指导。
实施例
通过参考以下实施例来更全面地理解本发明。然而,它们不应被解释为限制本发明的范围。本文所用的缩写如下:
ACN:乙腈;
Chg:环己基甘氨酸;
DCM:二氯甲烷;
DIPEA:二异丙基乙胺;
DMAP:4-二甲基氨基吡啶;
DME:1,2-二甲氧基乙烷;
DMF:二甲基甲酰胺;
DMSO:二甲亚砜;
EDC:1-乙基-3-(3-二甲基氨基丙基)碳二亚胺;
EEDQ:2-乙氧基-1-乙氧基羰基-1,2-二氢喹啉;
LCMS:液相色谱质谱;
HATU:O-(7-氮杂苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐;
HOBt:N-羟基苯并三唑;
HBTU:2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲六氟磷酸盐;
HPLC:高效液相色谱;
NBS:N-溴琥珀酰亚胺;
TASF:三(二甲基氨基)二氟三甲基硅酸锍;
TEA:三乙胺;
TFA:三氟乙酸盐;
THF:四氢呋喃;
参考例1
1-[2-环己基-2-(2-甲基氨基丙酰基氨基)乙酰基]吡咯烷-2-羧酸(2-苯基-2H-吡唑-3-基)酰胺
将Boc-MeAla-Chg-Pro-OH(47.0mg,0.107mmol)和吡啶(26μL,0.32mmol)在无水二氯甲烷(300μL)中的溶液冷却至0℃,并滴加草酰氯在二氯甲烷中的溶液(54μL,2.0M,0.11mmol),历时10分钟。将混合物在0℃搅拌15分钟,然后在环境温度下搅拌45分钟,并且添加5-氨基-1-苯基吡唑(15.9mg,0.100mmol;TCI America目录号A0174)和吡啶(15.5μL,0.191mmol)在二氯甲烷(0.5mL)中的溶液。将所得混合物在环境温度下搅拌16小时,用二氯甲烷稀释至20mL,并用0.2N氢氧化钠水溶液(20mL)洗涤。将有机相干燥(MgSO4)并减压浓缩。通过柱色谱(硅胶,含60%乙酸乙酯的己烷,接着100%乙酸乙酯)纯化粗制产物,得到黄色油:m/z581(M+H+)。用含5%三氟乙酸的二氯甲烷(2mL)处理该油,并在18小时后真空移除溶剂。所得油(29.3mg,基于2步的收率57%)通过反相HPLC进一步纯化,得到产物(TFA盐,9.6mg,15%收率):m/z 481(M+H+),503(M+Na+)。
参考例2
酰基氟偶联步骤
将Boc-MeAla-Chg-Pro-OH(2.3mmol)和吡啶(6.9umol)于无水DCM(23ml)中的溶液冷却至0℃,并滴加氰尿酰氟(cyanuric fluoride)(2.3mmol),历时30秒。将混合物在0℃搅拌15分钟,在室温下搅拌5小时,然后用水终止反应。将混合物用DCM(总计100ml)萃取三次,并将合并的有机相用盐水洗涤并干燥(Na2SO4)。过滤和真空浓缩,得到透明无色油形式的肽酰基氟,其在不进一步纯化的情况下直接使用。
向固体胺(14,0.50mmol)添加粗制酰基氟(0.50mmol)和吡啶(1.5mmol)于DCM(2.5ml)中的溶液,并将所得混合物在室温或50℃下搅拌(密封容器)。将混合物倾入NaHCO3水溶液,然后用二氯甲烷(总计100ml)萃取三次。将合并的有机相用盐水洗涤,干燥(Na2SO4)、过滤并真空浓缩。粗制的肽酰胺在不进一步纯化的情况下直接使用。
参考例3
1-[2-环己基-2-(2-甲基氨基丙酰基氨基)乙酰基]吡咯烷-2-羧酸(4-苯基-[1,2,3]噻二唑-5-基)酰胺
步骤1:向Boc-L-Pro-OH(2eq)、HOBt(1.9eq)、EDC-HCl(1.9eq)和DIPEA(5eq)于DMF(10-15vol)中的溶液添加4-苯基-1,2,3-噻二唑-5-胺(16)。将起初温和放热的反应加热至75℃,并过夜搅拌,冷却至室温,并真空部分除去DMF。将溶液用EtOAc(10-15vol)稀释,然后用1M HCl(2×)、NaHCO3(1×)和盐水(1×)洗涤(1:1水相/有机相)。将有机层真空浓缩,并将所得的固体在回流的MeCN(易于搅拌所需的最小体积)中成浆30分钟,然后冷却至室温。抽吸过滤以约77%的收率得到灰白色结晶固体形式的经Boc保护的缀合产物。将经Boc保护的产物悬浮于4M HCl/二氧六环(4-5eq酸)和MeCN(相当于二氧六环溶液的1体积当量)的溶液中,并在室温下搅拌,直至LCMS指示完全脱保护(约1小时)。将反应混合物真空浓缩,并使所得固体于回流的MeCN(易于搅拌所需的最小体积)中剧烈成浆,冷却至室温,并通过抽吸过滤来收集固体,并用冷MeCN进行清洗,直至从滤饼除去残余颜色,这以几乎定量收率得到灰白色固体形式的(S)-N-(4-苯基-1,2,3-噻二唑-5-基)吡咯烷-2-甲酰胺盐酸盐(17)。
步骤2:向17和DIPEA(5eq)于DMF(10-15vol)中的溶液添加Boc-L-Chg(1.5eq)、HOBt(1.4eq)和EDC-HCl(1.4eq)。将反应搅拌约2小时,然后用EtOAc(15vol)稀释,并用1MHCl(2×)、NaHCO3(1×)和盐水(1×)洗涤(1:1水相/有机相)。将有机萃取物干燥(Na2SO4)、过滤并真空浓缩。将所得固体在EtOH/己烷(20:80)(易于搅拌所需的最小体积)中成浆,并过滤,从而以约80%收率得到絮状白色固体形式的经Boc保护的缀合产物。将经Boc保护的产物溶解于4M HCl/二氧六环(4-5eq酸)和MeCN(相当于二氧六环溶液的0.25体积当量)的溶液中,并在室温下搅拌约1小时。将反应用甲苯(2×)(与脱保护溶液体积相同)浓缩至干,以几乎定量收率得到白色结晶固体形式的(S)-1-((S)-2-氨基-2-环己基乙酰基)-N-(4-苯基-1,2,3-噻二唑-5-基)吡咯烷-2-甲酰胺盐酸盐(18)。
步骤3:向18和DIPEA(5eq)于DMF(10-15vol)中的溶液添加Boc-L-N-甲基Ala(1.5eq)、HOBt(1.4eq)和EDC-HCl(1.4eq)。将反应搅拌1小时,用EtOAc(15vol)稀释,并用1MHCl(2×)、NaHCO3(1×)和盐水(1×)洗涤(1:1水相/有机相)。有机萃取物经干燥(Na2SO4)、过滤,并真空浓缩,以约85%收率得到米黄色的泡沫状固体形式的经Boc保护的缀合产物。将经Boc保护的产物溶解于4M HCl/二氧六环(4-5eq酸)和MeCN(相当于二氧六环溶液的0.25体积当量)的溶液中,并在室温下搅拌约1小时。反应用甲苯(2×)(与脱保护溶液体积相同)浓缩至干,并使所得固体在MTBE/EtOAc(70:30)(易于搅拌所需的最小体积)溶液中成浆,过滤并收集,得到灰白色自由流动固体形式的粗制(S)-1-((S)-2-环己基-2-((S)-2-(甲基氨基)丙酰胺基)乙酰基)-N-(4-苯基-1,2,3-噻二唑-5-基)吡咯烷-2-甲酰胺(d)。将粗制盐酸盐悬浮于MeOH(最少4vol)中,并通过在65℃搅拌而溶解。分两部分添加温乙酸异丙酯(6-8vol),将温度保持在约60℃,然后在搅拌下使该溶液冷却。迅速发生结晶,在室温下搅拌悬浮液数小时,然后在0℃下搅拌一小时,然后通过抽吸过滤来收集固体。将粗制产物用MeOH/iPrOAc(1:4,2vol)洗涤并干燥,以约80%收率得到白色/灰白色结晶固体形式的19。
参考例4
5-氨基-2-(噁唑-2-基)-4-苯基噻唑
用TEA(1.88mL,13.5mmol)处理α-氨基苯乙腈盐酸盐(1.52g,8.99mmol)、硫粉(289mg,9.01mmol)和噁唑-2-甲醛(873mg,8.99mmol)于EtOH(18mL)中的悬浮液,并在50℃下搅拌混合物60分钟。在室温下用羟胺水溶液(1.00ml,50%wt,15mmol)处理冷却的混合物过夜,过滤并真空浓缩。将残余物在EtOAc与NaHCO3水溶液之间分配,并将所分离的有机相用盐水洗涤,干燥(Na2SO4)、过滤,并真空浓缩,得到深棕色油。将粗制油预先吸附在SiO2上,并通过自动快速色谱(用在己烷中的5-70%乙酸乙酯梯度洗脱)纯化,得到5-氨基-2-(噁唑-2-基)-4-苯基噻唑(20,159mg,7.3%)。
实施例1
(S)-1-[(S)-2-环己基-2-((S)-2-甲基氨基丙酰基氨基)乙酰基]吡咯烷-2-羧酸(2-噁唑-2-基-4-苯基噻唑-5-基)酰胺(Ia)。
步骤1:向在冰浴中冷却的Boc-L-脯氨酸(4.5g,0.02mmol)和吡啶(8.45mL,0.104mmol)于DCM(20mL)中的溶液逐滴添加氰尿酰氟(5.35mL,0.0627mmol)。在添加之后,反应变成乳状。将溶液在0℃下搅拌10分钟,然后升温至室温,并搅拌4小时。用水终止反应,并用DCM萃取三次。将合并的有机萃取物用盐水洗涤,干燥,并真空浓缩,得到2-(氟羰基)吡咯烷-1-羧酸叔丁酯。将粗制酰基氟立即用于接下来的偶联反应。
将新鲜制备的酰基氟(4.55g,0.02mmol)溶解于MeCN(20mL)中,并用20(1.7g,0.007mmol)和吡啶(2.82mL,0.035mmol)处理。将反应加热至50°过夜。将反应混合物用饱和NaHCO3终止反应并用EtOAc萃取三次。将合并的有机层用盐水洗涤,干燥并浓缩。通过SiO2色谱(用EtOAc/己烷梯度(50至80%EtOAc)洗脱)纯化粗产物,得到(S)-2-(2-(噁唑-2-基)-4-苯基噻唑-5-基氨基甲酰基)吡咯烷-1-羧酸叔丁酯(21)。
按照参考例3的步骤2和3的过程进行Boc保护基的移除,并依次与BocHN-Chg-OH和H(Me)N-Ala-OH偶联。还通过SiO2色谱(用EtOAc/己烷梯度(50至80%EtOAc)洗脱)来完成Chg偶联产物的纯化。通过ISCO(50-80%EtOAc/己烷)纯化粗制的经Boc保护的三肽产物。在除去Boc基团之后,通过制备型HPLC纯化最终产物,得到纯Ia:(M+H)+=ms565.3。
实施例2
可以使用相应地类似于实施例1的过程中的起始材料,与实施例1的化合物类似地制备本发明的其他化合物,例如,
1.(S)-1-[(S)-2-环丙基-2-((S)-2-甲基氨基丙酰基氨基)乙酰基]吡咯烷-2-羧酸(2-噁唑-2-基-4-苯基噻唑-5-基)酰胺;
2.(S)-1-[(S)-2-环戊基-2-((S)-2-甲基氨基丙酰基氨基)乙酰基]吡咯烷-2-羧酸(2-噁唑-2-基-4-苯基噻唑-5-基)酰胺;
3.(S)-1-[(S)-2-环庚基-2-((S)-2-甲基氨基丙酰基氨基)乙酰基]吡咯烷-2-羧酸(2-噁唑-2-基-4-苯基噻唑-5-基)酰胺;
4.(S)-1-[(S)-2-环己基-2-((S)-2-乙基氨基丙酰基氨基)乙酰基]吡咯烷-2-羧酸(2-噁唑-2-基-4-苯基噻唑-5-基)酰胺;
5.(S)-1-[(S)-2-环己基-2-((S)-2-甲基氨基丙酰基氨基)乙酰基]吡咯烷-2-羧酸(2-噁唑-2-基-4-苯基噻唑-5-基)-N-甲基酰胺;以及
6.(S)-1-[(S)-2-环己基-2-((S)-2-甲基氨基丙酰基氨基)-2-甲基乙酰基]吡咯烷-2-羧酸(2-噁唑-2-基-4-苯基噻唑-5-基)酰胺。
实施例3
IAP抑制测定
在下列实验中采用称为MLXBIR3SG的嵌合型BIR域,其中110个残基中有11个与XIAP-BIR3中所发现的相对应,而剩余部份与ML-IAP-BIR相对应。与这些天然BIR域中任一个相比,嵌合蛋白MLXBIR3SG表现出显著更好地结合并抑制胱天蛋白酶-9,但与Smac系肽和成熟Smac结合的亲和力与天然ML-IAP-BIR类似。当转染进MCF7细胞时,嵌合型BIR域MLXBIR3SG对胱天蛋白酶-9抑制的改善已与多柔比星诱导的细胞凋亡抑制增加关联起来。
MLXBIR3SG序列:
MGSSHHHHHHSSGLVPRGSHMLETEEEEEEGAGATLSRGPAFPGMGSEELRLASFYDWPLTAEVPPELLAAAGFFHTGHQDKVRCFFCYGGLQSWKRGDDPWTEHAKWFPGCQFLLRSKGQEYINNIHLTHSL(SEQ ID NO.:1)
TR-FRET肽结合测定
根据Kolb等人(Journal of Biomolecular Screening,1996,1(4):203)的方法,于Wallac Victor 2Multilabeled Counter Reader(Perkin Elmer Life and AnalyticalSciences,Inc.)上进行时间解析荧光共振能量转移竞争实验。在试剂缓冲液(50mM Tris[pH 7.2],120mM NaCl,0.1%牛球蛋白,5mM DTT和0.05%辛基葡糖苷)中制备含有300nMhis-标记的MLXBIR3SG;200nM生物素化的SMAC肽(AVPI);5μg/mL抗-his别藻蓝素(XL665)(CISBio International);以及200ng/mL链霉亲和素-铕(Perkin Elmer)的试剂混合剂(cocktail)。(或者,可使用浓度分别为6.5nM和25nM的铕标记的抗-His(Perkin Elmer)和链霉亲和素-别藻蓝素(Perkin Elmer)制得这种混合剂)。将试剂混合剂在室温孵育30分钟。在孵育后,将混合剂添加至在384-孔黑色FIA板(Greiner Bio-One,Inc.)中的拮抗剂化合物的1:3连续稀释液(起始浓度为50μM)。在室温下孵育90分钟后,以滤波器读取铕(340nm)激发的荧光以及铕(615nm)和别藻蓝素(665nm)的发射波长的荧光。拮抗剂数据计算为别藻蓝素在665nm处发射信号与铕在615nm处发射信号之比(为易于数据操作,这些比乘以10000的系数)。将所得值作为拮抗剂浓度的函数作图,并利用Kaleidograph软件(Synergy Software,Reading,PA)拟合为4-参数方程。由IC50值确定拮抗剂效力的指示。发现本发明化合物具有IAP抑制活性,这在本测定中证实。
荧光偏振肽结合测定
根据Keating,S.M.,Marsters,J,Beresini,M.,Ladner,C.,Zioncheck,K.,Clark,K.,Arellano,F.和Bodary.,S.(2000)在Proceedings of SPIE:In Vitro DiagnosticInstrumentation(Cohn,G.E.,Ed.)pp 128-137,Bellingham,WA.中的方法,于Analyst HT96-384(Molecular Devices Corp.)上进行偏振实验。荧光偏振亲和力测量的样品通过如下制备:以MLXBIR3SG在偏振缓冲液(50mM Tris[pH 7.2],120mM NaCl,1%牛球蛋白,5mMDTT和0.05%辛基葡糖苷)中的最终浓度为5μM开始,将1:2连续稀释液添加至5-羧基荧光素缀合的AVPdi-Phe-NH2(AVP-diPhe-FAM)(最终浓度5nM)。
在室温下孵育10分钟的时间后,在96-孔黑色HE96板(Molecular Devices Corp.)中,以荧光素荧光团(λex=485nm;λem=530nm)的标准截止滤波器读取反应。将荧光值绘作为蛋白浓度的函数作图,并利用Kaleidograph软件(Synergy software,Reading,PA)将该数据拟合成4-参数方程来得到IC50。通过将30nM的MLXBIR3SG添加至含5nM AVP-diPhe-FAM探针以及拮抗剂化合物在偏光缓冲液中的1:3连续稀释液(以300μM浓度开始)的孔中,来进行竞争实验。在10分钟孵育后读取样品。将荧光偏振值作为拮抗剂浓度的函数作图,并利用Kaleidograph软件(Synergy software,Reading,PA)将该数据拟合成4-参数方程来得到IC50值。由IC50值确定拮抗剂的抑制常数(Ki)。发现本发明化合物具有IAP抑制活性,这在本测定中证实。例如,化合物Ia的Ki值为0.014(ML-IAP-BIR)。
实施例4
肿瘤异种移植研究(图1和图2)
所有涉及动物的操作皆按照Genentech Institutional Animal Care and UseCommittee的指导方针进行。癌细胞获得自美国典型培养物保藏中心(Manassas,VA),诸如人类乳腺MDA-MB-231癌细胞、结肠直肠Colo205癌细胞、或NSCLC癌细胞、Calu6癌细胞。将细胞悬浮于HBSS(Colo205),或将细胞悬浮液与基质胶(Matrigel)(BD Biosciences;MDA-MB-231,Calu6)进行1:1混合。然后,将细胞(MDA-MB-231为1.5×107;Colo205、Calu6为5.0×107)皮下植入6-8周龄的雌性裸小鼠(Charles River Laboratories,Hollister,CA)的右侧腹。利用通过游标卡尺测量的平均直径,利用公式v=0.5×a×b2计算肿瘤体积,其中a和b分别为最大和最小垂直肿瘤直径。将具有适当平均肿瘤体积的十只小鼠随机分配至六个小组中的一个。在治疗开始时(第0天),所有六个小组的平均肿瘤体积±平均值标准差(SEM)为168±3mm3。在研究的每一天观察小鼠,每周测量肿瘤体积和体重两次。利用公式%TGI=100×(1-肿瘤体积剂量/肿瘤体积载剂)计算肿瘤生长抑制。
在该利用人类乳腺MDA-MB-231·X1细胞的测定中,本发明的化合物Ia具有3.4mg/kg的MED值(iv Qwk)。这比现有技术化合物III在相同条件下的相同测定中所需的量(MED=18.6mg/kg)低五倍。Ia的AUC比相似效力的III低四倍。
若需要,在上述描述或下列权利要求中公开的、以其特定形式或者依据执行所公开功能的装置或用于达到所公开结果的方法或过程表示的特征,可分开地或以此类特征的任意组合的形式用于实现不同形式的本发明。
出于清楚和理解的目的,已通过例示和实例的方式详细描述了前述发明。对本领域技术人员显而易见的是,可在随附的权利要求的范围内实施改变和修改。因此,应理解上述描述是例示性而非限制性的。因此,本发明的范围不应参考以上描述来决定,而应参考下列随附的权利要求以及此类权利要求有权要求的等同的全部范围来决定。
本文所引用的专利、公布的申请和科学文献构建了本领域技术人员的知识,并以其整体通过援引加入本文,其程度如同各自具体且单独地被指出通过援引方式加入本文。本文所引用的任何参考文献与本说明书的具体教导之间的任何冲突应以后者为准。同样,词语或短语的本领域所理解的定义与本说明书中明确教导的所述词语或短语的定义之间的任何冲突应以后者为准。
Claims (8)
1.式I的化合物或其药学可接受的盐,
其中
Ph是苯基;
R1是C3-7环烷基;
R2、R3、R4、R5和R6在每次出现时各自独立地为H或C1-6烷基。
2.如权利要求1所述的化合物或其药学可接受的盐,所述化合物为(S)-1-[(S)-2-环己基-2-((S)-2-甲基氨基丙酰基氨基)乙酰基]吡咯烷-2-羧酸(2-噁唑-2-基-4-苯基噻唑-5-基)酰胺(Ia)。
3.如权利要求1所述的化合物,其中R2–R6各自独立地为H或甲基。
4.如权利要求1所述的化合物,其中R1为环己基。
5.如权利要求3所述的化合物,其中R1为环己基。
6.如权利要求3所述的化合物,其中R2和R3之一为H且另一个为甲基;或R4为甲基;或R5和R6各自为H。
7.药物组合物,其包含权利要求1所述的化合物和至少一种药学可接受的载体、稀释剂或赋形剂。
8.药物组合物,其包含权利要求2所述的化合物和至少一种药学可接受的载体、稀释剂或赋形剂。
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WO2016079527A1 (en) | 2014-11-19 | 2016-05-26 | Tetralogic Birinapant Uk Ltd | Combination therapy |
WO2016097773A1 (en) | 2014-12-19 | 2016-06-23 | Children's Cancer Institute | Therapeutic iap antagonists for treating proliferative disorders |
CN109705191B (zh) * | 2017-10-25 | 2022-04-29 | 广东东阳光药业有限公司 | Iap抑制剂及其在药物中的应用 |
WO2019091492A1 (zh) | 2017-11-13 | 2019-05-16 | 南京明德新药研发股份有限公司 | 用作iap抑制剂的smac模拟物及其用途 |
EP3831811A4 (en) | 2018-07-31 | 2022-04-20 | Fimecs, Inc. | HETEROCYCLIC COMPOUND |
WO2021020585A1 (ja) | 2019-07-31 | 2021-02-04 | ファイメクス株式会社 | 複素環化合物 |
WO2021110011A1 (en) * | 2019-12-02 | 2021-06-10 | Ascentage Pharma (Suzhou) Co., Ltd. | Combination of iap inhibitors and parp or mek inhibitors or other chemotherapeutic agents |
KR20220130190A (ko) | 2020-01-20 | 2022-09-26 | 아스트라제네카 아베 | 암 치료를 위한 표피성장인자 수용체 티로신 키나제 억제제 |
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