CN101171241A - 抗细胞凋亡的bcl-2家族成员的色烯-4-酮抑制剂及其应用 - Google Patents
抗细胞凋亡的bcl-2家族成员的色烯-4-酮抑制剂及其应用 Download PDFInfo
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- CN101171241A CN101171241A CNA2006800148318A CN200680014831A CN101171241A CN 101171241 A CN101171241 A CN 101171241A CN A2006800148318 A CNA2006800148318 A CN A2006800148318A CN 200680014831 A CN200680014831 A CN 200680014831A CN 101171241 A CN101171241 A CN 101171241A
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Abstract
本发明涉及用作抗细胞凋亡的Bcl-2家族成员蛋白(例如,Bcl-2和Bcl-xL)的抑制剂的小分子。本发明还涉及这些化合物用于诱导细胞凋亡细胞死亡和使细胞对凋亡细胞死亡的诱导敏感的应用。
Description
发明背景
发明领域
本发明为药物化学领域。具体而言,本发明涉及用作抗细胞凋亡的Bcl-2家族成员蛋白(例如,Bcl-2和Bcl-xL)的抑制剂的小分子。本发明还涉及这些化合物用于诱导凋亡细胞死亡和使细胞对凋亡细胞死亡的诱导敏感的应用。
相关技术
侵害性的癌细胞表型为导致胞内信号传导途径失调的各种遗传和外遗传改变的结果(Ponder,Nature 411:336(2001))。然而,所有癌细胞的共同特性是其衰竭以执行细胞凋亡程序,而因正常细胞凋亡机制中的缺陷导致缺乏适当的细胞凋亡程序是癌症的标志(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细胞凋亡起作用。于是因正常细胞凋亡机制中的缺陷而导致癌细胞不能执行细胞凋亡程序通常与对化疗、放射或免疫疗法诱导的细胞凋亡产生的抗性增加有关。因细胞凋亡缺陷而导致的不同来源的人癌对目前的治疗方案产生原发性或获得性抗性是目前癌症疗法中的主要问题(Lowe等,Carcinogenesis 21:485(2000);Nicholson,Nature 407:810(2000))。因此,目前和未来为改善癌症患者存活和生活质量而针对设计和研发新的分子靶-特异性抗癌疗法的努力必须包括特异性靶向癌细胞对细胞凋亡产生抗性的策略。在这方面,靶向在直接抑制癌细胞中细胞凋亡中起重要作用的关键负调节物代表了用于新的抗癌药物设计的非常有希望的治疗策略。
已经鉴定了两类细胞凋亡的重要负调节物。第一类细胞凋亡负调节物为细胞凋亡蛋白抑制剂(IAPs)(Deveraux等,Genes Dev.13:239(1999);Salvesen等,Nat.Rev.Mol.Cell.Biol.3:401(2002))。IAP蛋白有效抑制各种细胞凋亡刺激物,包括化疗剂、放射和免疫疗法在癌细胞中诱导的细胞凋亡。
第二类细胞凋亡的重要负调节物为Bcl-2家族蛋白(Adams等,Science 281:1322(1998);Reed,Adv.Pharmacol.41:501(1997);Reed等,J.Cell.Biochem.60:23(1996))。Bcl-2为该家族中的基本成员并且首先作为癌基因产物分离。Bcl-2家族目前包括:抗-细胞凋亡分子,诸如Bcl-2、Bcl-xL和Mcl-1,以及促细胞凋亡分子,诸如Bax、Bak、Bid和Bad。Bcl-2、Bcl-xL和Mcl-1在许多类型的人癌(例如乳腺、前列腺、结肠直肠、肺)中得到超表达,包括因导致Bcl-2超表达的染色体易位(t14,18)引起的非何杰金淋巴瘤。这提示许多癌细胞类型依赖于Bcl-2家族蛋白水平升高以幸免于其它细胞紊乱,其同时定义这些细胞为癌症或前-癌症细胞并且使它们尝试完成细胞凋亡途径。此外,已经将Bcl-2家族蛋白表达增加视为是对以不同途径在肿瘤细胞中诱导细胞死亡的癌症治疗药物和放射产生抗性的基础。
认为Bcl-2和Bcl-xL在肿瘤细胞迁移和侵入和由此的转移中起作用。Amberger等,Cancer Res.58:149(1998);Wick等,FEBS Lett,440:419(1998);Mohanam等,Cancer Res.53:4143(1993);Pedersen等,Cancer Res.,53:5158(1993)。Bcl-2家族蛋白看起来为肿瘤细胞提供在新的和非允许环境(例如转移部位)中存活的机制,并且有助于临床转移癌扩散的器官特异性模式。Rubio,LabInvest.81:725(2001);Fernáder等,Cell Death Differ.7:350(2000)。还认为抗细胞凋亡蛋白,诸如Bcl-2和/或Bcl-xL例如通过调节细胞表面整联蛋白调节细胞-细胞相互作用。Reed,Nature387:773(1997);Frisch等,Curr.Opin.Cell Biol.9:701(1997);Del Bufalo等,FASEB J.11:947(1997)。
已经广泛综述了用于靶向癌症中的Bcl-2、Bcl-xL和Mcl-1以恢复癌细胞的敏感性并且克服癌细胞对细胞凋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反义疗法处于治疗实体瘤和非实体瘤的几个III期临床试验阶段。
棉酚为天然存在的来源于粗棉籽油(草棉属)的双重双酚化合物。棉酚作为男性避孕剂的人体试验已经证实了长期给予这些化合物的安全性(Wu,Drugs 38:333(1989))。近来已经证实棉酚具有抗增殖作用(Flack等,J.Clin.Endocrinol.Metab.76:1019(1993);Bushunow等,J.Neuro-Oncol.43:79,(1999);Van Poznak等,Breast CancerRes.Treat.66:239(2001))。近来已经证实(-)-棉酚及其衍生物为Bcl-2、Bcl-xL和Mcl-1的有效抑制剂并且具有强抗-癌活性(美国专利申请US2003/0008924;2004/0214902)。
发明简述
通常公认的是癌细胞或其支持细胞不能发生细胞凋亡响应遗传损伤或接触细胞凋亡诱导物(诸如抗癌药和放射)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)中的细胞凋亡实际上是市售的所有有效癌症治疗药或放疗或当今实践的普遍作用机制。细胞不能发生细胞凋亡的一个原因在于抗-细胞凋亡Bcl-2家族蛋白表达增加和蓄积。
本发明预期,患有癌症的动物接触抑制抗-细胞凋亡Bcl-2家族成员功能的治疗有效量的药物(例如,小分子)可以彻底杀灭癌细胞或支持细胞(其持续存活依赖于抗-细胞调亡Bcl-2家族成员的过度活性的那些细胞)和/或使得这类作为群体的细胞对诱导细胞死亡活性的癌症治疗药物或放疗更为敏感。本发明预期,当在依赖于抗-细胞凋亡Bcl-2家族成员功能的癌细胞中诱导细胞凋亡作为单一疗法给予时,或当以与诱导细胞死亡的其它癌症治疗药物或放疗时间相关给予以使更大比例的癌细胞或支持细胞比仅用癌症治疗药或单独的放疗治疗的动物中相应比例的细胞易于执行细胞凋亡程序时,抗-细胞凋亡Bcl-2家族成员的抑制剂将满足对治疗多种癌症类型尚未满足的需求。
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一系列抗癌药或放射疗法与单独使用上述化合物或抗癌药/放射治疗相比可以在这类动物中产生更大的肿瘤反应和临床有益性。作为另一种方式,因为所述的化合物可降低表达抗-细胞凋亡Bcl-2家族成员的所有细胞的细胞凋亡阈值,所以成功执行细胞凋亡程序响应诱导细胞凋亡的抗癌药/放射的活性的细胞比例增加。可替代地,本发明的化合物能够以较低且由此以低毒性和更为可耐受的剂量的抗癌药和/或放射给药,从而产生与单独抗癌药和/或放射的常规剂量相同的肿瘤反应/临床有益性。由于已知所有经批准的抗癌药和放疗的剂量,所以本发明关注它们与本发明化合物的各种组合。此外,由于本发明的化合物至少部分通过抑制抗-细胞凋亡Bcl-2家族成员起作用,所以将癌细胞和支持细胞接触治疗有效量的所述化合物可以是时间上关联的以与细胞执行细胞凋亡程序响应抗癌药或放疗的尝试相符。因此,在某些实施方案中,与某些时间关联有关给予本发明的组合物可以提供特别有效的治疗实践。
本发明涉及的化合物可以用于抑制抗-细胞凋亡Bcl-2家族成员的活性并增加细胞对细胞凋亡诱导的敏感性。在一个特别的实施方案中,该化合物具有通式I:
或其药学上可接受的盐或前药,其中:
R1是H、OH、F、Cl、Br、I,或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基或杂环;
R2,R3,R4,R5和R6独立地是H、F、Cl、Br、I、OH,或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基、杂环、CO2R′、C(O)NR′R″、SO2NR′R″、SR′、OR′、NR″C(O)R′、NR′SO2R″、或NR′R″;R′和R″独立地是H或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基或杂环,或者R′和R′′与和它们连接的N一起形成杂环或杂芳环。
在一个实施方案中,通式I的化合物具有通式II:
或其药学上可接受的盐或前药,其中:
Ar是任选取代的芳基或杂芳基。
在另一个实施方案中,通式I的化合物具有通式III:
或其药学上可接受的盐或前药,其中:
Ar1和Ar2独立地是任选取代的芳基或杂芳基;
X是O、NR′、SO2、S、C(O)N(R′)、SO2NR′、R′NCO、R′NSO2、N(R′)R″、N(R′)-R″-N(R_)、R′、OR′、OR′O或C(O)N(R′)R″;和R′,R″和R_独立地是H或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基或杂环,
或R′,R″和R_中的两个形成杂环或杂芳环。
在另一个实施方案中,通式I的化合物具有通式IV:
或其药学上可接受的盐或前药。
在另一个实施方案中,通式I的化合物具有通式V:
或其药学上可接受的盐或前药。
在另一个实施方案中,通式I的化合物具有通式VI:
或其药学上可接受的盐或前药;其中
L是任选取代的芳基、二-芳基、杂芳基、杂环、烷基、环烷基、烯基、环烯基、炔基、醚、酯、胺、酰胺、磺酰基、氨磺酰基或硫醚;R1和R1′独立地是H,OH,F,Cl,Br,I,或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基或杂环;和
R2,R2′,R3,R3′,R4,R4′,R6和R6′独立地是H,F,Cl,Br,I,OH,或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基、杂环,CO2R′,C(O)NR′R″,SO2NR′R″,SR′,OR′,NR″C(O)R′,NR′SO2R″或NR′R″。
本发明涉及通式I表示的化合物,其是抗-细胞凋亡Bcl-2家族成员的抑制剂。本发明涉及本发明化合物诱导细胞中细胞凋亡的应用。本发明还涉及本发明化合物用于使细胞对细胞调亡的诱导敏感的应用。本发明的化合物可用于治疗、改善或预防应答诱导凋亡细胞死亡的障碍,例如特征在于细胞凋亡失调的障碍,包括过度增殖性疾病,诸如癌症。在某些实施方案中,所述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抗性(例如为化学抗性、放射抗性、激素抗性等)的癌症。在其它实施方案中,所述化合物可以用于治疗特征在于抗-细胞凋亡Bcl-2家族成员过度表达的过度增殖性疾病。
本发明提供药物组合物,其包含在细胞中诱导细胞凋亡或使细胞对细胞凋亡的诱导敏感的治疗有效量的通式I的化合物。
本发明还提供包含通式I的化合物和将该化合物给予动物的说明的试剂盒。该试剂盒可任选地包含其他治疗剂,例如抗癌剂、细胞凋亡调节剂。
本发明还提供制备通式I的化合物的方法。
图/附图简述
附图1显示的是棉酚和Bcl-xL之间的相互作用
发明详述
本发明涉及式I代表的化合物,其作为抗-细胞凋亡Bcl-2家族成员的抑制剂起作用。通过抑制抗-细胞凋亡Bcl-2家族成员,这些化合物使细胞对细胞凋亡的诱导敏感,在某些情况下,它们本身诱导细胞凋亡。因此,本发明涉及抑制使细胞对细胞凋亡诱导剂敏感的方法和在细胞中诱导细胞凋亡的方法,包括使细胞与单独的通式I的化合物或其和细胞凋亡诱导剂的组合相接触。本发明还涉及治疗、改善或预防动物中应答诱导细胞凋亡的障碍的方法,包括给予动物通式I的化合物和细胞凋亡诱导剂。这类障碍包括特征在于细胞凋亡失调的那些和特征在于抗-细胞凋亡Bcl-2家族成员过度表达的那些。
此处所用术语“抗-细胞凋亡Bcl-2家族成员”是指具有抗细胞凋亡活性的Bcl-2家族蛋白的任何已知成员,包括但不限于Bcl-2、Bcl-xL、Mcl-1、A1/BFL-1、BOO-DI VA、Bcl-w、Bcl-6、Bcl-8和Bcl-y。
本文所用的术语″抗-细胞凋亡Bcl-2家族成员的过度表达″指的是与表达基础水平的编码抗-细胞凋亡Bcl-2家族成员蛋白的mRNAs或具有基础水平的抗-细胞凋亡Bcl-2家族成员蛋白的相似的相应非病理细胞相比,编码抗-细胞凋亡Bcl-2家族成员蛋白的mRNAs水平升高(例如水平异常)和/或细胞中抗-细胞凋亡Bcl-2家族成员蛋白水平升高。用于检测细胞中编码抗-细胞凋亡Bcl-2家族成员的mRNAs水平或抗-细胞凋亡Bcl-2家族成员水平的方法包括但不限于使用抗-细胞凋亡Bcl-2家族成员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。与细胞中抗-细胞凋亡Bcl-2家族成员蛋白的绝对水平同样重要的是确定它们过度表达抗-细胞凋亡Bcl-2家族成员蛋白,这类细胞中,抗-细胞凋亡Bcl-2家族成员相对于其它促-细胞凋亡信号传导分子(例如促-细胞凋亡Bcl-2家族蛋白)的相对水平同样也是如此。当这两种分子达到平衡,使得并非是抗-细胞凋亡Bcl-2家族成员蛋白的水平时,促-细胞凋亡信号传导分子可足以使细胞执行细胞凋亡程序并且死亡,所述细胞依赖于抗-细胞凋亡Bcl-2家族成员才能存活。在这类细胞中,接触抑制有效量的抗-细胞凋亡Bcl-2家族成员蛋白抑制剂将足以使得细胞执行细胞凋亡程序并且死亡。因此,术语″抗-细胞凋亡Bcl-2家族成员蛋白的过度表达″还指因促-细胞凋亡信号和抗-细胞凋亡信号的相对水平而导致细胞经历细胞凋亡来应答抑制有效量的抑制抗-细胞凋亡Bcl-2家族成员蛋白功能的化合物。
本文所用的术语″抗癌剂″和″抗癌药物″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。
处所用术语“前药”是指母“药物”分子的药理学非活性衍生物,其需要在靶生理学系统内生物转化(例如,自发的或酶促的)而释放,或将前药(例如,酶促地、机械地、电磁地)转化成活性药物。前药被设计用于克服与稳定性、毒性、缺少特异性、或生物可利用率有限有关的问题。举例性的前药包括本身活性的药物分子和化学掩蔽基团(例如,可逆地抑制药物活性的基团)。一些优选的前药是具有可在代谢条件下裂解的基团的化合物的变体或衍生物。当它们在生理学条件下经历溶剂分解或经历酶降解或其它生物化学转化(例如,磷酸化、氢化、脱氢化、糖基化)时,举例性的前药变成体内或体外药学活性的。前药常常提供溶解性、组织相容性或在哺乳动物生物体中延迟释放的益处(见例如Bundgard,Design of Prodrugs,pp.7-9,21-24,Elsevier,Amsterdam(1985);和Silverman,The Organic Chemistry of DrugDesign and Drug Action,pp.352-401,Academic Press,San Diego,CA(1992))。常见的前药包括酸衍生物如通过母体酸与适宜的醇(例如,低级醇)反应制备的酯,和通过母体酸化合物与胺反应制备的酰胺,或与碱性基团反应形成酰化的碱性衍生物(例如,低级烷基酰胺)。
此处所用术语“药学上可接受的盐”是指本发明化合物的任意盐(例如,通过与酸或碱反应获得),其在靶动物(例如,哺乳动物)中是生理学耐受的。本发明化合物的盐可得自无机或有机酸和碱。酸的例子包括但不限于,盐酸、氢溴酸、硫酸、硝酸、高氯酸、富马酸、马来酸、磷酸、羟基乙酸、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。尽管本身不是药学可接受的其他酸例如草酸可以在盐的制备中使用,所述的盐在获得本发明的化合物和它们药学可接受的酸加成盐中可作为中间体。
碱的例子包括但不限于,碱金属(例如,钠)的氢氧化物,碱土金属(例如,镁)的氢氧化物、氨、和通式NW4 +的化合物等,其中W是C1-4烷基,等等。
盐的例子包括但不限于:乙酸盐、己二酸盐、海藻酸盐、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、氟代庚酸盐(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(mesylate)、甲磺酸盐(methanesulfonate)、2-萘磺酸盐、烟酸盐、草酸盐、扑酸盐、果胶酸盐、过硫酸盐、苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、琥珀酸盐、酒石酸盐、硫氰酸盐、甲苯磺酸盐、十一烷酸盐等等。盐的其他例子包括本发明的化合物的阴离子与适当的阳离子例如Na+、NH4 +和NW4 +(其中W是C1-4烷基)等等。在治疗使用时,本发明的化合物的盐预期是药学可接受的。但是,也可以使用非药学可接受的酸和碱的盐,例如,在药学可接受的化合物的制备或纯化中。
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得以改善,或预防疾病发展,或使得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产生如下效果的治疗剂用量:减缓肿瘤生长速率、减小肿瘤块、减少转移病灶的数量、增加肿瘤发展的时间,或将存活时间增加至少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%。
本文所用的术语″敏感″和″致敏″指的是通过给予第一种活性剂(例如通式1的化合物)使得动物或动物体内的细胞对第二种活性剂的生物作用(例如促进或阻止细胞功能的方面,包括但不限于细胞生长、增殖、侵入、血管发生或细胞凋亡)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作用测定为在给予第二种活性剂并给予或不给第一种活性剂时观察到的指定生物作用(例如促进或阻止细胞功能的方面,包括但不限于细胞生长、增殖、侵入、血管发生或细胞凋亡)的差异。致敏细胞的反应相对于没有第一种活性剂存在下的反应可以增加至少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″细胞凋亡失调″指的是细胞通过细胞凋亡发生细胞死亡的能力上的任何异常(例如遗传缺陷)。细胞凋亡失调与各种病症有关或由其诱导,包括例如自身免疫病(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伦综合症)、慢性炎症疾病(例如牛皮癣、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、乳头状瘤或HIV)和其它疾病,诸如骨关节炎和动脉粥样硬化。应注意当失调由病毒感染诱导或与之相关时,病毒感染在失调发生或观察到失调时可能检测到,也可能无法检测到。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″指的是动物体内增殖细胞的局部群体不受通常正常生长限制的任意病症。过度增殖性疾病包括肿瘤、赘生物、淋巴瘤等。如果赘生物不发生侵入或转移,那么认为赘生物为良性的,而如果它出现上述情况之一,那么认为赘生物是恶性的。″转移性″细胞指的是细胞可以侵入和破坏附近的身体结构。超常增生为细胞增殖的一种形式,包括组织或器官中细胞数量的增加,而结构或功能没有显著改变。组织变形为细胞生长受控的一种形式,其中一种类型的完全分化的细胞取代了另一种类型的分化的细胞。
活化的淋巴样细胞的病理性生长通常导致自身免疫病或慢性炎症病症。本文所用的术语″自身免疫病″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、慢性疲劳综合征、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、牛皮癣、风湿热、风湿性关节炎、硬皮病、斯耶格伦综合征、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″瘤形成疾病″指的是良性(非-癌性)或恶性(癌性)的细胞的任何异常生长。
本文所用的术语″抗瘤形成剂″指的是阻止靶向的(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)″、″预防(preventing)″和″预防(prevention)″指的是减少动物体内病理细胞(例如过度增殖性或赘生性细胞)的出现。预防可以是完全的,例如在受试者体内病理细胞总体上不存在。预防还可以是部分的,使得受试者体内出现的病理细胞少于在不使用本发明时出现的病理细胞。
本文使用的术语“细胞凋亡调节剂”是指调节(例如,抑制、减少、增加、促进)细胞凋亡的试剂。细胞凋亡调节剂的例子包括包含死亡结构域的蛋白质,例如但不限于Fas/CD95、TRAMP、TNF RI、DR1、DR2、DR3、DR4、DR5、DR6、FADD和RIP。细胞凋亡调节剂的其他例子包括但不限于,TNFα、Fas配体、Fas/CD95的抗体和其他TNF家族受体、TRAIL、TRAIL-R1或TRAIL-R2的抗体、Bcl-2、p53、BAX、BAD、Akt、CAD、PI3激酶、PP1和半胱天冬酶蛋白。调节剂广义地包括TNF家族受体和TNF家族配体的激动剂和拮抗剂。细胞凋亡调节剂可以是可溶性或膜结合的(例如配体或受体)。优选的细胞凋亡调节剂是细胞凋亡的诱导剂,例如TNF或TNF-相关配体,特别是TRAMP配体、Fas/CD95配体、TNFR-1配体或TRAIL。
已经证明了双重双酚(biphenolic)化合物棉酚(化合物1)是Bcl-2和Bcl-xL的有效抑制剂,并具有强烈的抗癌活性(Flack等,J.Clin.Endocrinol.Metab.76:1019(1993);Bushunow等,J.Neuro-Oncol.43:79,(1999);Van Poznak等,Breast Cancer Res.Treat.66:239(2001);U.S.专利申请2003/0008924;2004/0214902)。基于棉酚/Bcl-xL之间相互作用的NMR研究,然后基于计算结构的模型,设计出了一系列的用化合物2例举的异黄酮类似物,并进行合成,其显示具有抗癌活性。基于这些研究,已经鉴定出了一类抑制抗-细胞凋亡Bcl-2家族成员的化合物。
本发明的抗-细胞凋亡Bcl-2家族成员的抑制剂是具有通式I的化合物:
或其药学上可接受的盐或前药,其中:
R1是H、OH、F、Cl、Br、I,或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基或杂环;
R2,R3,R4,R5和R6独立地是H、F、Cl、Br、I、OH,或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基、杂环,CO2R′、C(O)NR′R″、SO2NR′R″、SR′、OR′,、NR″C(O)R′、NR′SO2R″或NR′R″;R′和R″独立地是H或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基或杂环,或R′和R″与和它们连接的N一起形成杂环或杂芳环。
在一个实施方案中,通式I的化合物具有通式II:
或其药学上可接受的盐或前药,其中:
Ar是任选取代的芳基或杂芳基。
在另一个实施方案中,通式I的化合物具有通式III:
或其药学上可接受的盐或前药,其中:
Ar1和Ar2独立地是任选取代的芳基或杂芳基;
X是O、NR′、SO2、S、C(O)N(R′)、SO2NR′、R′NCO、R′NSO2、N(R′)R″、N(R′)-R″-N(R_)、R′、OR′、OR′O或C(O)N(R′)R″;和R′,R″和R_独立地是H或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基或杂环,
或R′,R″和R_中的两个形成杂环或杂芳环。
在另一个实施方案中,通式I的化合物具有通式IV:
或其药学上可接受的盐或前药。
在另一个实施方案中,通式I的化合物具有通式V:
或其药学上可接受的盐或前药。
在另一个实施方案中,通式I的化合物具有通式VI:
或其药学上可接受的盐或前药;其中
L是任选取代的芳基、二-芳基、杂芳基、杂环,烷基、环烷基、烯基、环烯基、炔基、醚、酯、胺、酰胺、磺酰基、氨磺酰基或硫醚;R1和R1′独立地是H、OH、F、Cl、Br、I,或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基或杂环;和
R2,R2′,R3,R3′,R4,R4′,R6和R6′独立地是H、F、Cl、Br、I、OH,或任选取代的烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基、杂环、CO2R′、C(O)NR′R″、SO2NR′R″、SR′、OR′、NR″C(O)R′、NR′SO2R″或NR′R″。
有用的烷基包括直链或支链C1-18烷基,特别是甲基、乙基、丙基、异丙基、叔丁基、仲丁基、3-戊基、金刚烷基、降冰片烷基和3-己基。
有用的烯基包括直链或支链C2-18烷基,特别是乙烯基、丙烯基、异丙烯基、丁烯基、异丁烯基和己烯基。
有用的炔基是C2-18炔基,特别是乙炔基、丙炔基、丁炔基和2-丁炔基。
有用的环烷基是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。
有用的环烯基是C3-8环烷基。典型的环烯基包括环丙烯基、环丁烯基、环戊烯基、环己烯基和环庚烯基。
有用的芳基包括C6-14芳基,特别是苯基、萘基、菲基、蒽基、茚基、薁基、联苯基、联苯撑基(biphenylenyl)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、苯并呋喃基、异苯并呋喃基、色烯基、chromenonyl、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、萘啶基、喹唑啉基、噌啉基、蝶啶基、卡唑基、β-卡啉基、菲啶基、吖啶基、萘嵌间二氮杂苯基、菲咯啉基、酚嗪基、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-氨基异香豆素、吡啶并[1,2-a]嘧啶-4-酮、1,2-苯并异_唑基-3-基、苯并咪唑基、2-羟吲哚基和2-氧代苯并咪唑基。当杂芳基在环中包含氮原子时,该氮原子可以是N-氧化物的形式,例如吡啶基N-氧化物、吡嗪基N-氧化物、嘧啶基N-氧化物等。
有用的杂环基包括四氢呋喃基、四氢吡喃基、四氢喹啉基、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、异色满基、色满基、吡咯烷基、吡唑啉基、tetronoyl、tetramoyl或四氢异喹啉基。
任选的取代基包括一个或多个烷基;卤素;卤代烷基;环烷基;羟基;任选被一个或多个低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、羟基、酰基、氨基磺酰基、芳基磺酰基、芳基、芳氧基、酰氧基、酰氨基或杂芳基取代的芳基;任选被一个或多个低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、羟基、酰基、氨基磺酰基、芳基磺酰基、芳基、芳氧基、酰氧基、酰氨基或杂芳基取代的芳氧基;任选被一个或多个低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、羟基、酰基、氨基磺酰基、芳基磺酰基、芳基、芳氧基、酰氧基、酰氨基或杂芳基取代的酰氨基;芳烷基;任选被一个或多个低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、羟基、酰基、氨基磺酰基、芳基磺酰基、芳基、芳氧基、酰氧基、酰氨基或杂芳基取代的杂芳基;任选被一个或多个低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、羟基、酰基、氨基磺酰基、芳基磺酰基、芳基、芳氧基、酰氧基、酰氨基或杂芳基取代的杂芳氧基;任选被一个或多个低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、羟基、酰基、氨基磺酰基、芳基磺酰基、芳基、芳氧基、酰氧基、酰氨基或杂芳基取代的烷氧基;烷硫基;芳硫基;酰氨基;氨基;酰氧基;任选被一个或多个低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、羟基、酰基、氨基磺酰基、芳基磺酰基、芳基、芳氧基、酰氧基、酰氨基或杂芳基取代的芳基酰氧基;任选被一个或多个低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、羟基、酰基、氨基磺酰基、芳基磺酰基、芳基、芳氧基、酰氧基、酰氨基或杂芳基取代的二苯基氧膦基氧基;任选被一个或多个低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、羟基、酰基、氨基磺酰基、芳基磺酰基、芳基、芳氧基、酰氧基、酰氨基、杂芳基、氨基酸取代的磺酰基、或氨基酸衍生物取代的磺酰基取代的杂环基;任选被一个或多个低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、羟基、酰基、氨基磺酰基、芳基磺酰基、芳基、芳氧基、酰氧基、酰氨基或杂芳基取代的杂环烷氧基;任选被一个或多个低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、羟基、酰基、氨基磺酰基、芳基磺酰基、芳基、芳氧基、酰氧基、酰氨基或杂芳基取代的部分不饱和杂环烷基;或任选被一个或多个低级烷基、低级烷氧基、亚甲二氧基、卤素、卤代烷基、羟基、酰基、氨基磺酰基、芳基磺酰基、芳基、芳氧基、酰氧基、酰氨基或杂芳基取代的部分不饱和杂环烷氧基。此外,一个以上的任选取代基可以互相连接,例如酰氨基、杂环和芳基连接在一起等等。
特别的任选取代基包括但不限于异丙基、羟基、甲基、乙氧基、乙基、异丁基、2-甲基-5,6,7-甲氧基-8-异丁基-色烯-4-酮-3-基、4-(2-甲基-5,6,7-羟基-8-异丁基-色烯-4-酮-3-基)苯基、N-苯甲酰氨基、2-甲基-5,6,7-羟基-8-异丁基-色烯-4-酮-3-基、羧甲基、N-(3-异丙基苯基)酰氨基、羧基、N-(2-异丙基苯基)酰氨基、N-苯基酰氨基、N-(1(S)-羧甲基异戊基)酰氨基、N-(1-苄基哌啶-4-基)酰氨基、N-[1(S)-羧甲基-2-吲哚-2-基]-乙基]酰氨基、N-(1-羧甲基苄基)酰氨基、N-[(2-吲哚-3-基)-乙基]酰氨基、N-(二苯基)酰氨基、N-(1(S)-羧甲基-2-苯基乙基)酰氨基、苯基、N-(金刚烷-1-基)酰氨基、氯、N-(萘-2-基)酰氨基、N-[(1(S),2-二羧甲基)乙基]酰氨基、[4-(3-甲氧基苯基)哌嗪-1-基]羰基、N-(2,2-二苯基乙基)酰氨基、[(4-苄基)[1,4]二氮杂_-1-基]羰基、N-[1-苄基-2-(4-甲基-哌嗪-1-基-2-氧代)乙基]酰氨基、N-[(1-苄基-2-氧代-2-(4-[5-(2-氧代-六氢-噻吩并[3,4-d]咪唑-6-基)-戊酰基]-哌嗪-1-基}-乙基)酰氨基、N-[(1(S)-羧甲基-2-苯基)乙基]酰氨基、(4-苯基哌嗪-1-基)羰基和(4-苄基哌啶-1-基)羰基。
本发明的某些化合物可以以立体异构体包括旋光异构体的形式存在。本发明包括所有立体异构体和这类立体异构体的外消旋混合物以及各自的对映异构体,其可按照本领域技术人员熟知的方法分离。
结合下面的合成方案,本发明的化合物和方法将更容易理解,其中所述合成方案说明的是可以制备本发明的化合物的方法。原料可以是来自商业来源,或通过本领域技术人员已知的成熟的文献方法来制备。本领域技术人员显而易见地,上述定义的化合物可以通过替换下面所示合成的适当反应试剂和试剂来合成。
可以如合成化合物2的方案I中所例举的那样来进行具有通式I的化合物的合成。
方案1.
反应试剂和条件:(a)BF3-Et2O,异丁酰氯,1,2-二氯乙烷,回流;(b)Et3SiH,CF3CO2H;(c)BF3-Et2O,乙酰氯,1,2-二氯乙烷,回流;(d)AcONa,(AcO)2O;(e)Na2CO3,H2O,1,4-二_烷;(f)I2,CF3CO2Ag;(g)BF3-Me2S,(AcO)2O,二氯甲烷;(h)MDF,MeI,K2CO3;(i)THF,MeMgBr;(j)甲苯,PTSA,回流;(k)t-BuLi,B(OMe)3,THF;(1)H2,Pd-C;(m)Pd(dpf)2Cl2-CH2Cl2,Na2CO3,DMF,H2O,EtOH;(n)CH2Cl2,BBr3,0℃~1R.T.
如方案2所示,可以通过用不同硼酸处理化合物9并用相同的方法来获得其它化合物。
方案2.
反应试剂和条件:(m)Pd(dpf)2Cl2-CH2Cl2,Na2CO3,DMF,H2O,EtOH;(n)CH2Cl2,BBr3,0℃~1R.T.
方案3显示的是色烯-4-酮成环的改进的环化方法和化合物20的合成。简言之,通过室温下在吡啶中的酰基化将α-乙酰苯酚6转化成丙酸酯16。0℃下在无水DMF中用氢化钠处理化合物16得到1,3-二酮中间体。小心加入乙酸使反应停止,用乙酸乙酯和水后处理。粗制的中间体可以用于酸催化的分子内环化而无需进一步纯化。化合物色烯-4-酮17可以由乙酰苯酚6以总收率86%得到。通过与上述类似的方法,可以通过碘化作用和钯催化的Suzuki偶联将色烯-4-酮17转化成对称化合物19。多羟基色烯-4-酮20是通过用回流的乙酸和氢溴酸处理六甲基醚19获得的。
方案3.
本发明的重要方面在于通式I的化合物诱导细胞凋亡,同时也能增强对诱导细胞凋亡的信号应答而诱导细胞凋亡。因此,预计这些化合物使细胞、包括对这种诱导剂耐受的细胞对细胞凋亡的诱导剂敏感。本发明的抗-细胞凋亡Bcl-2家族成员抑制剂可通过细胞凋亡诱导治疗、改善或预防的任意障碍中诱导细胞凋亡。因此,本发明为特征为过度表达抗-细胞凋亡Bcl-2家族成员蛋白的靶动物提供了组合物和方法。在其中一些实施方案中,细胞(例如,癌细胞)显示出比非-病理学样品(例如,非-癌细胞)更高表达水平的抗-细胞凋亡Bcl-2家族成员蛋白。在其它实施方案中,所述细胞操作上表现出更高表达水平的抗-细胞凋亡Bcl-2家族成员蛋白,这是由于执行细胞凋亡程序并在响应抑制有效量的通式I的化合物时死亡,所述响应发生至少部分是由于在这类细胞中,它们的存活取决于抗-细胞凋亡Bcl-2家族成员蛋白的功能。
在另一个实施方案中,本发明涉及与一种或多种细胞凋亡调节剂有关的调节与细胞凋亡有关的状态。细胞凋亡调节剂的例子包括但不限于Fas/CD95、TRAMP、TNF RI、DR1、DR2、DR3、DR4、DR5、DR6、FADD、RIP、TNFα、Fas配体、TRAIL、TRAIL-R1或TRAIL-R2的抗体、Bcl-2、p53、BAX、BAD、Akt、CAD、PI3激酶、PP1和半胱天冬酶蛋白。也包括其他与细胞凋亡的初始、决定和降解期有关的其他试剂。细胞凋亡调节剂的例子包括其活性、存在或浓度改变可以在患者中调节细胞凋亡的试剂。优选的细胞凋亡调节剂是细胞凋亡的诱导剂,例如TNF或TNF-相关配体,特别是TRAMP配体、Fas/CD95配体、TNFR-1配体或TRAIL。
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)患病的细胞、组织、器官或病理情况和/或疾病状态。在这方面,使用本发明的方法和组合物易于治疗或预防各种疾病和病理情况。这些疾病和病症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、蕈样霉菌病、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、特发性血小板增多症、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成神经细胞瘤等;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剂产生耐药性。
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由病毒、细菌、真菌、支原体、阮病毒导致的感染。
本发明的某些实施方案提供了给予有效量的通式I的化合物和至少一种附加的治疗剂(包括但不限于化疗性抗肿瘤药、细胞凋亡调节剂、抗微生物剂、抗病毒药、抗真菌药和抗炎药)和/或治疗技术(例如外科手术和/或放疗)的方法。
预期许多合适的抗癌剂可以用于本发明方法。实际上,本发明预期但不限于许多抗癌剂的给药,诸如:诱导细胞凋亡的活性剂;多核苷酸(例如反义物、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家族成员、诸如Bax结合的活性剂(例如寡聚物或复合物);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(例如与抗癌剂、毒素、防卫素缀合的抗体)、毒素;放射性核素;生物学反应修饰剂(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;血管发生抑制剂;蛋白体抑制剂;NF-KB调节剂;抗-CDK化合物;HDAC抑制剂等。适合于与所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所公知。
在优选的实施方案中,抗癌剂包括诱导或刺激细胞凋亡的活性剂。诱导细胞凋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、血小板衍生的生长因子受体(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);抗炎药(例如保泰松、DECADRON、DELTASONE、地塞米松、地塞米松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、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、硼替佐米、吉非替尼、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;十字孢碱等。
在其它实施方案中,本发明的组合物和方法提供了式I化合物和至少一种抗过度增殖药或抗肿瘤药;例如选自烷化剂、抗代谢物和天然产物(例如草药和其它植物和/或动物来源的化合物)。
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(例如双氯乙基甲胺、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);环己亚硝脲(CCNU);司莫司汀(甲基-CCNU);和链佐星(链唑霉素));和5)三氮烯类(例如达卡巴嗪(DTIC;二甲基-三氮烯-咪唑羧酰胺)。
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)、氟尿嘧啶脱氧核苷(去氧氟尿苷;FudR)和阿糖胞苷(cytosine arabinoside);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′-脱氧考福霉素))。
在其它实施方案中,适用于本发明组合物和方法的化疗药包括但不限于:1)长春花生物碱(例如长春碱、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;柔红霉素)、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)生物学反应修饰剂(例如干扰素-α);6)铂配位配合物(例如顺铂(Cis-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)丙卡巴肼衍生物(例如丙卡巴肼(N-丙卡巴肼));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(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(例如己烯雌酚和乙炔雌二醇);14)抗雌激素药(例如他莫昔芬);15)雄激素(例如丙酸睾丸酮和氟甲睾酮);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)。
发现常用于癌症疗法环境中的任意溶瘤细胞药可以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保存有批准应用于美国的溶瘤细胞药的处方集。U.S.F.D.A.的国际对应机构保存有类似的处方集。表1中提供了批准在美国使用的典型的抗肿瘤药。本领域技术人员可以理解有关全部美国批准的化疗药所需的″产品标签″描述了典型的活性剂的批准的适应症、给药信息、毒性数据等。
表1
阿地白介素(脱-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(IgGlκ抗CD52抗体) | Campath | Millennium和ILEXPartners,LP,Cambridge,MA |
阿利维A酸(9-顺式-视黄酸) | Panretin | LigandPharmaceuticals,Inc.,San Diego CA |
别嘌呤醇(1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮一钠盐) | Zyloprim | GlaxoSmithKline.Research TrianglePark.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]-,二氢磷酸盐(酯)) | Ethyol | 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 | AstraZenecaPharmaceuticals,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[BCG],次代株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(轮丝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 SquibbCo.,NY,NY |
卡培他滨(5′-脱氧-5-氟-N-[(戊氧基)羰基]-胞苷) | Xeloda | Roche |
卡铂(铂,二氨络物(diammine)[1,1-环丁烷二羧酸(2-)-0,0′]-,(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-Myers Squibb |
卡莫司汀与Polifeprosan 20植入物 | GliadelWafer | 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,2--CdA | R.W.JohnsonPharmaceuticalResearch Institute,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(oxazaphosphorine)2-氧化物一水合物) | Cytoxan,Neosar | Bristol-Myers Squibb |
阿糖胞苷(1-b-D-阿拉伯呋喃糖基胞嘧啶,C9H13N3O5) | Cytosar-U | Pharmacia & UpjohnCompany |
阿糖胞苷脂质体 | DepoCyt | Skye Pharmaceuticals,Inc.,San Diego,CA |
达卡巴嗪(5-(3,3-二甲基-1-三氮烯并(triazeno))-咪唑-4-甲酰胺(DTIC) | DTIC-Dome | Bayer AG,Leverkusen,Germany |
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.,ThousandOaks,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-六吡喃糖基)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) | DanuoXome | NexstarPharmaceuticals,Inc.,Boulder,CO |
柔红霉素HCl,柔红霉素((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-六吡喃糖苷盐酸盐) | Cerubidine | Wyeth Ayerst,Madison,NJ |
地尼白介素-毒素连接物(diftitox)(重组肽) | Ontak | Seragen,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 & UpjohnCompany |
多西他赛((2R,3S)-N-羧基-3-苯基异丝氨酸,N-叔丁酯,13-酯与5b-20-环氧-12a,4,7b,10b,13a-六羟基紫杉(tax)-11-烯-9-酮4-乙酸酯2-苯甲酸酯,三水合物) | Taxotere | AventisPharmaceuticals,Inc.,Bridgewater,NJ |
多柔比星HCl((8S,10S)-10-[(3-氨基-2,3,6-三脱氧-a-L-来苏-六吡喃糖基)氧基]-8-乙醇酰-7,8,9,10-四氢-6,8,11-三羟基-甲氧基-5,12-萘二酮盐酸盐) | AdriamycinRubex | Pharmacia & UpjohnCompany |
多柔比星 | AdriamycinPFS静脉内注射液 | Pharmacia & UpjohnCompany |
多柔比星脂质体 | Doxil | SequusPharmaceuticals,Inc.,Menlo park,CA |
丙酸屈他雄酮(17b-羟基-2a-甲基-5a-雄烷-3-酮丙酸酯) | Dromostanolone | Eli Lilly & Company,Indianapolis,IN |
丙酸屈他雄酮 | Masterone注射液 | Syntex,Corp.,PaloAlto,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-六吡喃糖基)氧基]-7,8,9,10-四氢-6,8,11-三羟基-8-(羟基乙酰基)-1-甲氧基-5,12-萘二酮盐酸盐)) | Ellence | Pharmacia & UpjohnCompany |
α红细胞生成素(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-(二氢磷酸盐),二钠盐,一水合物,或雌二醇3-[双(2-氯乙基)氨基甲酸酯]17-(二氢磷酸盐),二钠盐,一水合物) | Emcyt | Pharmacia & UpjohnCompany |
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-吡喃葡糖苷]) | Vepesid | Bristol-Myers Squibb |
依西美坦(6-亚甲基雄(androsta)-1,4-二烯-3,17-二酮) | Aromasin | Pharmacia & UpjohnCompany |
非格司亭(r-metHuG-CSF) | Neupogen | Amgen,Inc. |
氟尿嘧啶脱氧核苷(动脉内)(2′-脱氧-5-氟脲嘧啶) | FUDR | Roche |
氟达拉滨(抗病毒药阿糖腺苷,9-b-D-阿拉伯呋喃糖基腺嘌呤(ara-A)的氟化核苷酸类似物) | Fludara | Berlex 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,Guayama,Puerto Rico |
吉西他滨(2′-脱氧-2′,2′-二氟胞苷一盐酸 | Gemzar | Eli Lilly |
盐(b-异构体)) | ||
吉姆单抗奥佐米星(抗-CD33 hP67.6) | Mylotarg | Wyeth Ayerst |
醋酸戈舍瑞林([D-Ser(But)6,Azgly10]LHRH的乙酸盐;焦-Glu-His-Trp-Ser-Tyr-D-Ser(But)-Leu-Arg-Pro-Azgly-NH2乙酸酯[C59H84N18O14·(C2H4O2)x) | ZoladexImplant | AstraZenecaPharmaceuticals |
羟基脲 | Hydrea | Bristol-Myers Squibb |
替伊莫单抗(由单克隆抗体Ibritumomab与连接物-螯合物tiuxetan[N-[2-双(羧甲基)氨基]-3-(对异硫氰酸根合苯基)-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键形成的免疫缀合物) | 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-六吡喃糖基)氧基]-7,8,9,10-四氢-6,9,11-三羟基盐酸盐,(7S-)顺式)) | Idamycin | Pharmacia & UpjohnCompany |
异环磷酰胺(3-(2-氯乙基)-2-[(2-氯乙基)氨基]四氢-2H-1,3,2-氧杂氮杂磷杂环己烯2-氧化物 | IFEX | Bristol-Myers Squibb |
甲磺酸Imatinib(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) | Intron A(冻干的重组干扰素β-1b) | Schering AG,Berlin,Germany |
伊立替康HCl((4S)-4,11-二乙基-4-羟基-9-[(4-哌啶子基哌啶子基)羰基氧基]-1H-吡喃并[3′,4′∶6,7]吲嗪并[1,2-b]喹啉-3,14(4H,12H)二酮盐酸盐三水合物) | Camptosar | Pharmacia & UpjohnCompany |
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.,Seattle,WA |
左旋咪唑HCl((-)-(S)-2,3,5,6-四氢-6- | Ergamisol | Janssen Research测定 |
苯基咪唑并[2,1-b]噻唑一盐酸盐C11H12N2S·HCl) | 值ation,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-氟乙基)-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) | Methot rexate | 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 |
苯丙酸诺龙 | Durabolin-50 | Organon,Inc.,WestOrange,NJ |
若莫单抗 | Verluma | Boehringer IngelheimPharma KG,Germany |
奥普瑞白介素(IL-11) | Neumega | Genetics Institute,Inc.,Alexandria,VA |
奥沙利铂(顺式-[(1R,2R)-1,2-环己烷二胺-N,N′][草酸(2-)-0,0′]铂) | Eloxatin | Sanofi Synthelabo,Inc.,NY,NY |
紫杉醇(包含(2R,3S)-N-苯甲酰基-3-苯基异丝氨酸的5β,20-环氧-1,2a,4,7β,10β,13a-六羟基紫杉-11-烯-9-酮4,10-二乙酸2-苯甲酸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(牛甲氧聚乙二醇琥珀酰胺腺苷脱氨酶(PegademaseBovine)) | Enzon Pharmaceuticals,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共轭物) | Neulasta | Amgen,Inc |
喷司他丁 | Nipent | Parke-DavisPharmaceuticals,Co.,Rockville,MD |
哌泊溴烷 | Vercyte | Abbott Laboratories,Abbott Park,IL |
普卡霉素,光辉霉素(褶皱链霉菌产生的抗生素) | Mithracin | Pfizer,Inc.,NY,NY |
卟吩姆钠 | Photofrin | QLT PhototherapeuticsInc.,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 TauPharmaceuticals,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(重组肽) | Elitek | Sanofi-Synthelabo,Inc., |
美罗华(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-吡喃葡萄糖和220mg无水柠檬酸) | Zanosar | Pharmacia & UpjohnCompany |
滑石粉 | Sclerosol | Bryan,Corp.,Woburn, |
(Mg3Si4O10(OH)2) | 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-[4,6-0-(R)-2-噻吩甲叉-(β)-D-吡喃葡萄苷]) | Vumon | Bristol-Myers Squibb |
睾内脂(13-羟基-3-氧代-13,17-开环雄-1,4-二烯-17-酸[dgr]-内酯) | Teslac | 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″-硫次膦基(phosphinothioylidyne)三-,或三(1-氮丙啶基)膦硫化物) | Thioplex | Immunex Corporation |
托泊替康HCl((S)-10-[(二甲氨基)甲基]-4-乙基-4,9-二羟基-1H-吡唑并[3′,4′∶6,7]吲嗪并[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.,Eatontown,NJ |
托西莫单抗,I131托西莫单抗(重组鼠免疫治疗单克隆IgG2aλ抗-CD20抗体(I131为放射性免疫治疗抗体)) | Bexxar | Corixa Corp.,Seattle,WA |
曲妥单抗(Trastuzumab)(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 | UracilMustard胶囊 | Roberts Labs |
戊柔比星,N-三氟乙酰基阿霉素-14-戊酸 | Valstar | Anthra→Medeva |
盐((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-[[42,3,6-三脱氧-3-[(三氟乙酰基)-氨基-α-L-来苏-六吡喃糖基]氧基]-2-萘基]-2-氧代乙基戊酸盐) | ||
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′-正长春碱(norvincaleukoblastine)[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 |
抗癌剂进一步包括那些已经鉴定具有抗癌活性但目前尚未被美国食品和药品管理局或其它类似机构批准的化合物,或正在进行新用途评价的化合物,实例包括但不限于3-AP、12-O-四癸酰基佛波醇-13-乙酸酯、17AAG、852A、ABI-007、ABR-217620、ABT-751、ADI-PEG20、AE-941、AG-013736、AGRO100、阿拉诺新、AMG706、抗体G250、抗癌肽类、AP23573、apaziquone、APC8015、阿替莫德、ATN-161、atrasenten、阿扎胞苷、BB-10901、BCX-1777、贝伐单抗、BG00001、比卡鲁胺、BMS247550、硼替佐米、苔藓抑制素-1、布舍瑞林、钙三醇、CCI-779、CDB-2914、头孢克肟、西妥昔单抗、CG0070、西仑吉肽、氯法拉滨(clofarabine)、考布他汀A4磷酸酯、CP-675,206、CP-724,714、CpG7909、姜黄、地西他滨、DENSPM、度骨化醇、E7070、E7389、ecteinascidin743、乙丙昔罗(efaproxiral)、依氟鸟氨酸、EKB-569、enzastaurin、埃罗替尼(erlotinib)、依昔舒林、芬维A胺、flovopiridol,氟达拉滨、氟他胺、福莫司汀、FR901228、G17DT、galiximab、吉非替尼(吉非替尼),染料木黄酮、葡磷酰胺、GTI-2040、组氨瑞林、HKI-272、高三尖杉酯碱、HSPPC-96、hu14,18-白介素-2融合蛋白、HuMax-CD4、伊洛前列素、咪喹莫特、英夫利昔单抗、白介素-12、IPI-504、伊罗夫文、ixabepilone、拉帕替尼、来那度胺、lestaurtinib、醋酸亮丙瑞林、LMB-9免疫毒素、lonafarnib、luniliximab、马磷酰胺、MB07133、MDX-010、MLN2704、单克隆抗体3F8、单克隆抗体J591、莫特沙芬,MS-275、MVA-MUC1-IL2、尼鲁米特、硝基喜树碱、诺拉曲塞二盐酸化物、他莫昔芬、NS-9、06-苄基鸟嘌呤、利奥默森钠、ONYX-015、oregovomab、OSI-774、panitumumab、卡铂、PD-0325901、培美曲塞、PHY906、匹格列酮、吡非尼酮、pixantrone、PS-341、PSC833、PXD101、吡唑啉吖啶、R115777、RAD001、豹蛙酶、蝴蝶霉素类似物、rhu血管他汀蛋白、rhuMab2C4、罗格列酮、卢比替康、S-1、S-8184、沙铂、SB-15992、SGN-0010、SGN-40、sorafenib、SR31747A、ST1571、SU011248、辛二酰苯胺异羟肟酸、苏拉明、talabostat、他仑帕奈、tariquidar、temsirolimus、TGFa-PE38免疫毒素、沙利度胺、胸腺法新、tipifarnib、替拉扎明、TLK286、trabectedin、三甲曲沙、葡糖醛酸酯、TroVax,UCN-1、丙戊酸、长春氟宁、VNP40101M、volociximab、vorinostat、VX-680、ZD1839、ZD6474、齐留通、和zosuquidar三盐酸化物.
用于与本发明化合物给药的优选常用抗癌剂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、硼替佐米、吉非替尼和贝伐单抗。可以制备这些活性剂并且将其单独、在联用的治疗组合物中、在药盒中使用或与其他免疫治疗剂联用等。
为了更为详细的描述抗癌剂和其它治疗剂,本领域技术人员参考了大量指导性手册,包括但不限于Physician′s Desk Reference和Goodman和Gilman的″Pharmaceutical Basis of Therapeutics″第10版,Eds.Hardman等,2002。
本发明提供了用于给予通式I的化合物与放疗的方法。本发明并不受放射的类型、用量或用于给动物递送治疗剂量的递送和给药系统的限制。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。
放射源可以在动物体外或体内。外部放射治疗是最常用的并且涉及使用例如线性加速器将高能辐射束通过皮肤定向于肿瘤部位。尽管射线束可以局限于肿瘤部位,但是它几乎不可能避免正常健康组织的暴露。然而,外部放射通常可以被患者很好耐受。内部射疗法包括将射线发射源,诸如珠、金属线、丸粒、胶囊、颗粒等植入体内的肿瘤部位或接近肿瘤部位,包括使用特异性靶向癌细胞的递送系统(例如使用附着在与癌细胞结合配体上的颗粒)。可以在治疗后将这类植入物取出,或将其以非活性状态保留在体内。内部放射疗法的类型包括但不限于近距离放射疗法、间质照射、腔内照射、放射免疫疗法等。
动物可以任选地接受放射致敏剂(例如双唑泰栓、米索硝唑、动脉内Budr、静脉内碘去氧尿苷(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-亲和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、含氟硝基吡咯衍生物、苯甲酰胺、烟酰胺、吖啶-嵌入剂、5-硫代四唑衍生物、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、亚硝脲、巯嘌呤、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(过高热)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(WR2721)、IL-1、IL-6等)。放射致敏剂促进肿瘤细胞的杀伤。辐射防护剂保护健康组织免受放射有害作用。
可以对患者给予任意类型的放射,只要该放射剂量是患者可耐受的并没有不可接受的不良副作用。放疗的合适类型包括:例如电离(电磁)放疗(例如X-射线或γ线)或粒子束放疗(例如高线能量放射)。将电离放射定义为包括具有产生电离,即得电子或失电子的足够能量的粒子或光子的放射(例如,如US5,770,581中所述,将该文献的全部内容引入本文作为参考)。放射的作用至少可以部分受到临床医师控制。针对最大靶细胞暴露并且降低毒性优选分次给予放射剂量。
对动物给予的总放射剂量优选约为.01戈瑞(Gy)到约100Gy。更优选在治疗过程中给予约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天的过程中给予完全放射剂量,但是理想的情况是将总剂量分次在几天内给予。理想的情况是,在至少约3天,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)过程中给予放疗。因此,每日放射剂量约为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靶向的细胞破坏。如果延长期限,优选非每天给予放射,由此使动物休息并且实现疗法的效果。例如,理想的是在每周的治疗中,连续5天给予放射并且在2天不给予,由此使每周有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/周或全部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。可以在治疗期中任意时间开始放疗。优选在第1周或第2周中开始放射,并且在剩余的治疗期间给予放射。例如,在包括6周的治疗期的第1-6周或2-6周中给予放射,例如用于治疗实体瘤。可替代地,在包括5周的治疗期的第1-5周或2-5周中给予放射。不过,本发明并不限于这些可仿效的放疗给药方案。
其他抗微生物治疗剂也可以用作本发明中的其他治疗剂。可以使用能够杀伤、抑制微生物,或使微生物减毒的任何活性剂以及预期具有这类活性的任意活性剂。抗微生物剂包括但不限于天然和合成抗生素、抗体、抑制蛋白(例如防卫素)、反义核酸、膜破裂剂等,可以将它们单独使用或联用。实际上,可以使用任意类型的抗生素,包括但不限于抗菌药、抗病毒药、抗真菌药等。
在本发明的某些实施方案中,可以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其他的治疗剂或抗癌剂:以不同的周期;以不同的持续时间;以不同的浓度;通过不同的给药途径等。在某些实施方案中,在治疗剂或抗癌剂之前,例如在给予治疗剂或抗癌剂之前例如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,在治疗剂或抗癌剂之后,例如在给予抗癌剂之后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,同时但以不同的时间表给予该化合物和治疗剂或抗癌剂,例如,每日给予该化合物,而每周1次、每两周1次、每三周1次或每四周1次给予治疗剂或抗癌剂。在其它实施方案中,每周1次给予该化合物,而每天1次、每周1次、每两周1次、每三周1次或每四周1次给予治疗剂或抗癌剂。
本发明范围内的组合物包括所有的组合物,其中本发明的组合物以有效实现其指定目的的用量被包含。尽管个体需要不同,但是每种成分的有效量的最佳范围的确定属于本领域技术人员能力的范围。一般来说,对于响应诱导细胞凋亡的疾病,可以每天口服给予哺乳动物、例如人0.0025到50mg/kg接受治疗的哺乳动物体重的组合物或等量的其药学上可接受的盐。优选口服给予约0.01到约10mg/kg以便治疗、改善或预防这类疾病。就肌内注射而言,剂量一般约为口服剂量的一半。例如,合适的肌内剂量约为0.0025到约25mg/kg,并且最优选约0.01到约5mg/kg。
单位口服剂量可以包括约0.01-约1000mg、优选约0.1-约100mg化合物。可以以各自包含约0.1-约100mg、便利的是0.25-50mg化合物或其溶剂化物的1片或多片片剂或1粒或多粒胶囊每天1次或多次给予单位剂量。
在局部用制剂中,化合物的存在浓度约为0.01-100mg/g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。
除作为原料药给予该化合物外,还可以将本发明的化合物作为包含合适的药学上可接受的载体的药物制剂的组成部分给予,所述的载体包括有利于将化合物加工成可以在药物上使用的制剂的赋形剂和助剂。优选制剂、特别是那些可以通过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、口腔清洗剂和漱口剂、凝胶、液体混悬液、润发剂、发胶、香波且还有可以通过直肠给药的制剂,诸如栓剂以及适合于通过注射、局部或口服给药的适宜的溶液包含约0.01-99%、优选约0.25-75%的活性化合物,还包含赋形剂。
可以将本发明的药物组合物给予可能体验本发明化合物有益作用的任意动物。在这类动物中排在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)。
可以通过实现其指定目的的任意方式给予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、颊、鞘内、颅内、鼻内或局部途径进行给药。可替代地或同时,可以通过口服途径进行给药。给药剂量取决于接受者的年龄、健康和体重、同时治疗的类型(如果有的话)、治疗频率和所需作用的性质。
可以按照本身已知的方式,例如通过常规的混合、制粒、制锭、溶解或冻干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应用的药物制剂:将活性化合物与固体赋形剂混合,任选地研磨所得混合物,并且如果需要或必要,在加入合适的助剂后加工颗粒混合物得到片芯或锭芯。
特别地,合适的赋形剂为:填充剂,诸如糖类,例如乳糖或蔗糖;甘露糖醇或山梨糖醇;纤维素制品;和/或磷酸钙,例如磷酸三钙或磷酸氢钙;以及粘合剂,诸如淀粉糊(例如使用玉米淀粉、小麦淀粉、稻米淀粉、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,且还有羧甲基淀粉、交联聚乙烯吡咯烷酮、琼脂或藻酸或其盐,诸如藻酸钠。助剂首先为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,可以给锭芯包耐胃液的合适的包衣层。为了这一目的,可以使用浓糖溶液,它可以任选地包含阿拉伯树胶、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层,使用合适的纤维素制品、诸如邻苯二甲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,为了鉴定或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和由明胶和增塑剂、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包含颗粒形式的活性化合物,所述的颗粒中可以混合有:填充剂、诸如乳糖;粘合剂、诸如淀粉;和/或润滑剂、诸如滑石粉或硬脂酸镁;和任选的稳定剂。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。合适的栓剂基质为:例如天然或合成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的组合组成的直肠用明胶胶囊。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的水溶液,例如水溶性盐和碱性溶液。此外,可以给予作为合适的油注射混悬液的活性化合物的混悬液。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。含水注射混悬液可以包含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。该混悬液中还可以任选地包含稳定剂。
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、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于其中可溶的载体。如果需要,还可以包括乳化剂、稳定剂、湿润剂和抗氧化剂以及赋予颜色或香味的试剂。另外,还可以在这些局部用制剂中使用透皮渗透增强剂。这类增强剂的实例可以在美国专利US3,989,816和US4,444,762中找到。
优选由矿物油、自乳化蜂蜡和水的混合物配制霜剂,在该混合物中混合有溶于少量油、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冷却来配制软膏剂。这类软膏剂的典型实例为包括按重量计约30%杏仁油和约70%白软石蜡的软膏剂。
可以通过将活性成分溶于合适的高分子量醇、诸如丙二醇或聚乙二醇中便利地制备洗剂。
下列实施例用于解释本发明的方法和组合物,但不限于它们。临床疗法中通常遇到并且对本领域技术人员而言显而易见的条件和参数种类的其它合适的变型和修改属于本发明的精神和范围。
实施例1
1-(6-羟基-2,3,4-三甲氧基-苯基)-2-甲基-丙-1-酮
向3,4,5-三甲氧基苯酚(9.21g,50mmol)的150mL 2,2-二氯乙烷溶液中加入三氟化硼二乙基醚合物(28.5mL,220mmol)和异丁酰氯(5.9mL,55mmol)。将所得到的混合物回流12小时,真空除去溶剂。在冰浴下向所得到的残留物中加入80mL 3M HCl,在室温下搅拌该混合物1小时,然后用乙酸乙酯萃取,在Na2SO4上干燥,通过硅胶柱色谱(己烷∶乙酸乙酯=6∶1)纯化并得到产物。收率:80%。
1H NMR(CDCl3,300MHz),δ13.45(s,1H);6.26(s,1H);4.01(s,3H);3.94(s,3H);3.87(s,3H);3.80~3.70(m,1H);1.21(d,J=6.76Hz,6H);13C NMR(CDCl3,75MHz),δ162.00;159.64;154.88;134.63;107.35;96.20;61.54;60.94;56.01;39.03;19.46.
实施例2
2-异丁基-3,4,5-三甲氧基-苯酚
在室温下将1-(6-羟基-2,3,4-三甲氧基-苯基)-2-甲基-丙-1-酮(5.1g,20mmol)溶解于30mL三氟乙酸和3mL三乙基硅烷中。将所得到的溶液搅拌过夜,真空除去溶剂。通过硅胶柱色谱(己烷∶乙酸乙酯=4∶1)纯化残留物并得到产物。收率:>95%。
1H NMR(CDCl3,300MHz),δ6.27(s,1H);3.90(s,3H);3.85(s,3H);3.82(s,3H);2.43(d,J=7.35Hz,2H);1.91~1.80(m,1H);0.89(d,J=6.63Hz,6H)。
实施例3
1-(2-羟基-3-异丁基-4,5,6-三甲氧基-苯基)-乙酮
向实施例2的化合物(4.86g,20mmol)的80mL 2,2-二氯乙烷溶液中加入三氟化硼二乙基醚合物(14.3mL,110mmol)和乙酰氯(1.75mL,22mmol)。将所得到的混合物回流12小时,真空除去溶剂。在冰浴下向所得到的残留物中加入50mL 3M HCl,在室温下搅拌该混合物1小时,然后用乙酸乙酯萃取,经Na2SO4干燥,通过硅胶柱色谱(己烷∶乙酸乙酯=8∶1)纯化并得到产物。收率:65%。
1H NMR(CDCl3,300MHz),δ13.28(s,1H);3.99(s,3H);3.96(s,3H);3.87(s,3H);2.69(s,3H);2.49(d,J=7.27Hz,2H);1.97~1.88(m,1H);0.92(d,J=6.65Hz,6H);13C NMR(CDCl3,75MHz),δ204.05;158.99;153.84;138.04;118.47;110.46;61.00;60.82;60.64;32.25;31.99;28.20;22.62.
实施例4
3-乙酰基-8-异丁基-5,6,7-三甲氧基-2-甲基-色烯-4-酮
向实施例3的化合物(5.65g,20mmol)的60mL乙酸酐溶液中加入乙酸钠(4.1g,50mmol)。将所得到的混合物回流12小时,真空除去溶剂。向所得到的残留物中加入100mL水,用乙酸乙酯萃取,经Na2SO4干燥,通过硅胶柱色谱(己烷∶乙酸乙酯=8∶1)纯化并得到化合物。
1H NMR(CDCl3,300MHz),δ3.92(s,3H);3.91(s,3H);3.82(s,3H);2.50(s,3H);2.34(d,J=7.20Hz,2H);2.23(s,3H);1.86~1.75(m,1H);0.89(d,J=6.64Hz,6H);13C NMR(CDCl3,75MHz),δ200.25;171.08;169.37;166.34;154.25;149.77;143.71;141.08;124.32;124.23;61.66;60.84;60.61;33.49;31.63;28.82;22.64;20.74.
实施例5
8-异丁基-5,6,7-三甲氧基-2-甲基-色烯-4-酮
向实施例4的化合物(3.50g,10.1mmol)的30mL 1,4-二_烷溶液中加入30mL水和碳酸钠(2.12g,20mmol)。将所得到的混合物回流1.5小时,用乙酸乙酯萃取,经Na2SO4干燥,通过硅胶柱色谱(己烷∶乙酸乙酯=1∶1)纯化并得到化合物。收率:60%.
1H NMR(CDCl3,300MHz),δ6.03(s,1H);4.05(s,3H);3.95(s,3H);3.93(s,3H);2.68(d,J=7.20Hz,2H);2.32(s,3H);1.97~1.88(m,1H);0.95(d,J=6.66Hz,6H)。
实施例6
3-碘-8-异丁基-5,6,7-三甲氧基-2-甲基-色烯-4-酮
在0℃下,向实施例5的化合物(4.58g,15.0mmol)的80mL二氯甲烷溶液中,加入碘(5.08g,20mmol)和三氟乙酸银(4.42g,20mmol)。所得到的混合物搅拌过夜。过滤除去固体,真空除去溶剂。通过硅胶柱色谱(己烷∶乙酸乙酯=8∶1)纯化并得到化合物。收率96%.
1H NMR(CDCl3,300MHz),δ4.07(s,3H);3.96(s,3H);3.88(s,3H);2.73(s,3H);2.68(d,J=7.20Hz,2H);1.99~1.89(m,1H);0.94(d,J=6.66Hz,6H);13C NMR(CDCl3,75MHz),δ172.44;164.11;156.39;151.25;150.71;144.11;118.96;111.42;89.78;62.14;61.27;61.22;32.55;28.96;25.22;22.65.
实施例7
6-溴-1-乙酰基-2-甲氧基-萘
在氩气和-78℃下通过注射器向剧烈搅拌的10mmol Me2S:BF3复合物的10mL CH2Cl2溶液中加入10mmol乙酸酐的2mL CH2Cl2溶液。混合物搅拌10分钟,然后加入5mmol 6-溴-2-甲氧基-萘的3mL CH2Cl2溶液,在-78℃下将所得到的溶液再搅拌15分钟。加热该溶液至室温并搅拌24小时,然后倾倒至饱和NaHCO3的混合物中,用CH2Cl2萃取并经Na2SO4干燥。真空除去溶剂,将残留物溶解于5mL DMF中,向所得到的溶液中加入10mmol Na2CO3和2mL MeI。将所得到的混合物搅拌过夜。过滤除去固体,真空除去溶剂。通过硅胶柱色谱(己烷∶乙酸乙酯=4∶1)纯化并得到化合物。收率:85%。
1H NMR(CDCl3,300MHz),δ7.97(s,1H);7.82(d,J=8.27Hz,1H);7.68(d,J=7.80Hz,1H);7.55(d,J=8.59Hz,1H);7.32(d,J=9.00Hz,1H);4.00(s,3H);2.66(s,3H)。
实施例8
6-溴-1-异丙烯基-2-甲氧基-萘
在-78℃下向实施例7的化合物(2.78g,10mmol)的50mL THF溶液中加入11mL MeMgCl(1.0M,11mmol)。搅拌混合物2小时,用10mL饱和NH4Cl使反应停止,用乙酸乙酯萃取并经Na2SO4干燥。真空除去溶剂,将残留物溶解于25mL甲苯中。向该溶液中加入100mgPTSA中,并回流2.0小时。真空除去溶剂,通过硅胶柱色谱(己烷∶乙酸乙酯=7∶1)纯化并得到化合物。收率:60%.
1H NMR(CDCl3,300MHz),δ7.95(d,J=1.99Hz,1H);7.86(d,J=9.06Hz,1H);7.72(d,J=9.02Hz,1H);7.50(dd,J=2.06,9.05Hz,1H);7.32(d,J=9.08Hz,1H);5.55(s,1H);4.96(s,1H);3.97(s,3H);2.13(s,3H)。
实施例9
1-异丙烯基-2-甲氧基-萘基-6-硼酸
根据标准方法,然后氢化来合成硼酸。
异黄酮类似物的一般合成途径
向干燥烧瓶中加入实施例6的化合物(1.0mmol)、芳香硼酸(1.1mmol)、Na2CO3(1.2mmol)和[1,1′-双(二苯基膦)二茂铁]二氯钯(II)复合物和二氯甲烷(1∶1)(30mg)。通过注射器加入5mL DMF、2mLEtOH和2mL H2O。在氩气和60℃下搅拌所得到的混合物4-8小时。过滤除去固体,真空除去溶剂。通过硅胶柱色谱(己烷∶乙酸乙酯=2∶1~4∶1)纯化并得到偶联产物(70%~90%)。
在-78℃下,将偶联产物(1.0mmol)溶解于25mL CH2Cl2和3.3mLBBr3(1.0M在CH2Cl2中)中。在3小时内将混合物加热到室温。加入MeOH(1.0mL)使反应停止,真空除去溶剂。通过硅胶柱色谱除去残留物或从丙酮-H2O中结晶,得到异黄酮(60%~75%)。
实施例10
5,6,7-三羟基-3-(6-羟基-5-异丙基-萘-2-基)-8-异丁基-2-甲基-色烯-4-酮
1H NMR(CDCl3,300MHz),δ12.85(s,1H);8.21(d,J=8.91Hz,1H);7.69(s,1H);7.59(d,J=8.66Hz,1H);7.41(d,J=8.84Hz,1H);6.99(d,J=8.62Hz,1H);6.16(s,1H);5.47(s,1H);5.04(s,1H);3.99~3.83(m,1H);2.73(d,J=7.29Hz,2H);2.38(s,3H);2.09~2.00(m,1H);1.55(d,J=7.03Hz,6H);0.99(d,J=6.64Hz,6H);13C NMR(CDCl3,75MHz),δ181.86;164.35;148.93;148.86;143.81;132.46;130.45;128.20;127.86;126.84;126.45;125.37;120.83;119.03;106.34;104.37;34.66; 31.39;28.66;22.61;21.09;19.59;HRMS(EI,[M+H]+)计算值:449.1964。测定值:449.1973;元素分析:C27H28O6-0.2H2O的计算值:C,71.73;H,6.33。测定值:C,71.70;H,6.32.
实施例11
5,6,7-三羟基-3-(6-羟基-5-甲基-萘-2-基)-8-异丁基-2-甲基-色烯-4-酮
1H NMR(DMSO-d6,300MHz),δ12.88(s,1H);9.83(s,1H);9.58(s,1H);9.10(s,1H);7.90(d,J=8.76Hz,1H);7.72(s,1H);7.63(d,J=8.94Hz,1H);7.39(d,J=8.67Hz,1H);7.19(d,J=8.94Hz,1H);2.62(d,J=7.11Hz,2H);2.45(s,3H);2.31(s,3H);1.99~1.90(m,1H);0.92(d,J=6.59Hz,6H);13C NMR(DMSO-d6,75MHz),δ181.91;164.90;153.44;152.79;148.89;146.04;133.92;130.96;129.54;129.14;128.65;127.77;126.93;123.46;120.71;119.13;115.51;106.48;104.00;32.17;31.65;18.99;23.41;20.29;HRMS(EI,[M+H]+)计算值:421.1651。测定值:421.1644;元素分析:C25H24O6的计算值:C,71.41;H,5.75。测定值:C,71.14;H,6.03.
实施例12
5,6,7-三羟基-3-(6-羟基-萘-2-基)-8-异丁基-2-甲基-色烯-4-酮
1H NMR(DMSO-d6,300MHz),δ12.86(s,1H);9.85(s,1H);9.35(s,1H);9.12(s,1H);7.79~7.71(m,2H);7.51(d,J=8.60Hz,1H);7.33(dd,J=1.46,8.18Hz,1H);7.16~7.12(m,1H);7.01~6.95(m,1H);2.61(d,J=8.37Hz,2H);2.31(s,3H);1.99~1.90(m,1H);0.91(d,J=6.62Hz,6H);13CNMR(DMSO-d6,75MHz),δ181.93;164.93;156.61;152.81;148.91;146.06;134.83;130.40;129.78;129.16;128.41;127.40;126.58;120.80;119.74;109.48;106.51;104.02;32.18;29.02;23.43;20.30;HRMS(EI,[M+H]+)计算值:407.1495。测定值:407.1497;元素分析:C24H22O6的计算值:C,70.92;H,5.46。测定值:C,70.96;H,5.61。
实施例13
5,6,7-三羟基-8-异丁基-2-甲基-3-萘-2-基-色烯-4-酮
1H NMR(CDCl3,300MHz),δ12.83(s,1H);8.17~7.80(m,3H);7.56~7.42(m,2H);6.19(s,1H);5.58(s,1H);2.73(d,J=7.18Hz,2H);2.38(s,3H);2.09~2.00(m,1H);0.99(d,J=6.63Hz,6H);13C NMR(CDCl3,75MHz),δ181.69;164.31;148.95;148.90;143.83;133.32;132.89;129.63;128.14;128.08;128.01;127.72;126.88;126.33;126.17;120.95;106.36;104.34;31.39;28.65;22.56;19.57;HRMS(EI,[M+H]+)计算值:391.1545。测定值:391.1537;元素分析:C23H20O5的计算值:C,73.39;H,5.36。测定值:C,73.53;H,5.64.
实施例14
3-(6-羟基-萘-2-基)-8-异丁基-5,6,7-三甲氧基-2-甲基-色烯-4-酮
1H NMR(CDCl3,300MHz),δ7.55(s,1H);7.42~7.34(m,2H);7.23(d,J=9.21Hz,1H);7.03(br,1H):6.88(d,J=7.11Hz,1H):6.80(s,1H);4.05(s,3H);4.01(s,3H);3.97(s,3H);2.75(d,J=7.22Hz,2H);2.30(s,3H);2.05~1.96(m,1H);1.00(d,J=6.62Hz,6H);13C NMR(CDCl3,75MHz),δ177.70;162.23;156.38;154.19;151.82;151.26;143.93;133.81;129.22;128.94;128.41;128.17;127.36;126.53;123.83;119.29;118.32;114.57;109.46;62.13;61.32;61.29;32.49;29.03;22.74;19.24;HRMS(EI,[M+H]+)计算值:449.1964。测定值:449.1965;元素分析:C27H28O6的计算值:C,72.30;H,6.29。测定值:C,72.12;H,6.11.
实施例15
3-(6-乙氧基-萘-2-基)-8-异丁基-5,6,7-三甲氧基-2-甲基-色烯-4-酮
1H NMR(CDCl3,300MHz),δ7.78(d,J=8.48Hz,1H);7.74(d,J=9.78Hz,1H);7.70(s,1H);7.39(dd,J=1.67,8.40Hz,1H);7.17(s,1H);7.15(dd,J=2.20,7.00Hz,1H);4.19(q,J=6.68Hz,2H);4.03(s,3H);3.95(s,3H);3.94(s,3H);2.74(dd,J=7.20Hz,2H);2.32(s,3H);2.05~1.96(m,1H);1.51(t,J=6.97Hz,3H);0.99(d,J=6.65Hz,6H);13C NMR(CDCl3,75MHz),δ176.43;161.17;157.11;156.03;151.66;151.23;143.75;134.01;129.46;129.42;128.97;128.77;128.38;126.59;123.40;119.19;118.96;114.64;106.36;63.43;62.06;61.29;61.23;32.47;29.03;22.74;19.17;14.80;HRMS(EI,[M+H]+)计算值:477.2277。测定值:477.2273;元素分析:C29H32O6的计算值:C,73.09;H,6.77。测定值:C,73.26;H,7.13.
实施例16
5,6,7-三羟基-8-异丁基-2-甲基-3-苯基-色烯-4-酮
1H NMR(CDCl3,300MHz),δ12.83(s,1H);7.51~7.28(m,5H);6.15;(s,1H);5.49(s,1H);2.71(d,J=7.23Hz,2H);2.34(s,3H);2.05~2.01(m,1H);0.98(d,J=6.66Hz,6H);13C NMR(CDCl3,75MHz),δ181.58;164.07;148.87;143.81;132.07;130.41;128.54;128.00;126.83;120.98;110.59;106.30;104.32;31.37;28.63;22.55;19.49;HRMS(EI,[M+H]+)计算值:341.1389。测定值:341.1384;元素分析:C20H20O5的计算值:C,70.57;H,5.92。测定值:C,70.37;H,6.16.
实施例17
5,6,7-三羟基-8-异丁基-2-甲基-色烯-4-酮
1H NMR(DMSO-d6,300MHz),δ12.77(s,1H);9.78(s,1H);9.07(s,1H);6.13(s,1H);2.55(d,J=7.20Hz,2H);2.38(s,3H);1.93~1.84(m,1H);0.86(d,J=6.65Hz,6H);13C NMR(DMSO-d6,75MHz),δ183.39;168.10;152.67;149.43;145.90;129.14;107.95;106.76;104.06;32.17;28.93;23.35;20.93;HRMS(EI,[M+H]+)计算值:265.1076。测定值:265.1077;元素分析:C14H16O5的计算值:C,63.63;H,6.10。测定值:C,63.43;H,6.23.
实施例18
3-苯并[b]噻吩-2-基-5,6,7-三羟基-8-异丁基-2-甲基-色烯-4-酮
1H NMR(CDCl3,300MHz),δ12.63(s,1H);7.90~7.8 1(m,2H);7.42~7.37(m,2H);7.30(s,1H); 6.18(s,1H);5.48(s,1H);2.71(d,J=7.24Hz,2H);2.53(s,3H);2.08~1.08(m,1H);0.99(d,J=6.62Hz,6H);13C NMR(CDCl3,75MHz),δ180.97;165.83;148.92;148.60;143.76;140.94;139.46;133.11;127.14;125.84;124.49;124.25;123.69;122.11;114.66;106.56;31.37;28.63;22.54;20.03.
实施例19
3-(5-乙基-6-羟基-萘-2-基)-5,6,7-三羟基-8-异丁基-2-甲基-色烯-4-酮
1H NMR(CDCl3,300MHz),δ12.84(s,1H);8.03(d,J=8.73Hz,1H);7.70(d,J=1.68Hz,1H);7.62(d,J=8.97Hz,1H);7.43(dd,J=1.77;8.73Hz,1H);7.08(d,J=8.97Hz,1H);6.14(s,1H);5.40(s,1H);5.02(s,1H);3.09(q,J=7.35Hz,2H);2.73(d,J=7.27Hz,2H);2.38(s,3H);2.08~2.00(m,1H);1.32(t,J=7.54Hz,3H);0.99(d,J=6.65Hz,6H)。
实施例20
5,6,7-三羟基-8-异丁基-2-甲基-3-喹啉-3-基-色烯-4-酮
1H NMR(DMSO-d6,300MHz),δ12.46(br 1H);10.03(br,1H);9.70(s,1H);9.18(s,1H);8.30(d,J=9.33Hz,1H);8.27(d,J=9.56Hz,1H);8.11(dd,J=7.03;7.25 Hz,1H);7.93(dd,J=7.19,7.95,1H);6.53(br,1H);2.64(d,J=7.06Hz,2H);2.46(s,3H);2.00~1.91(m,1H);0.92(d,J=6.62Hz,6H)。13C NMR(DMSO-d6,75MHz),δ180.87;166.64;153.34;149.61;148.86;145.90;140.45;134.37;130.05;129.91;129.78;128.99;127.26;124.05;115.96;107.06;103.59;32.15;29.00;23.37;20.43.
实施例21
8-双环[2.2.1]庚-2-基甲基-5,6,7-三羟基-2-甲基-3-(4-苯氧基-苯基)-色烯-4-酮(反式/顺式=3∶1~2∶1)
1H NMR(CDCl3,300MHz),δ12.81(s,1H);7.41~7.36(m,2H);7.27~7.26(m,1H);7.19~7.04(m,6H);6.15(br,1H);5.49(br,1H);2.92~2.66(m,2H);2.44~2.20(m,5H);2.06~0.98(m,8H);0.9 3~0.8 5(m,2H);13C NMR(CDCl3,75 MHz),δ181.64;164.14;157.27;156.67;148.49;131.86;129.81;126.81;126.56;123.65;120.39;119.45;118.45;106.91;104.33;40.50;40.28;39.94;37.28;36.11;35.07;31.59;30.57;24.90;22.66;22.58;19.54.
实施例22
8-联苯基-4-基-5,6,7-三羟基-2-甲基-3-(4-苯氧基-苯基)-色烯-4-酮
1H NMR(CDCl3,300MHz),δ7.73~7.67(m,4H);7.61(d,J=8.15Hz,2H);7.48(t,J=7.41Hz,2H);7.41~7.36(m,3H);7.26(d,J=8.67Hz,1H);7.18~7.07(m,6H);2.23(s,3H);13C NMR(CDCl3,75MHz),δ181.45;164.23;157.22;156.67;147.74;145.46;140.75;140.05;131.85;131.33;130.54;129.80;128.80;127.33;127.04;126.80;126.58;123.63;120.37;119.40;118.44;107.48;104.16;19.49.
实施例23
5,6,7-三羟基-2-甲基-3,8-双-(4-苯氧基-苯基)-色烯-4-酮
1H NMR(DMSO-d6,300MHz),δ13.08(s,1H);7.63~7.08(m,18H);6.28(br 1H);4.82(br,1H);2.24(s,3H)。
实施例24
5,6,7-三羟基-8-(6-羟基-萘-2-基)-2-甲基-3-(4-苯氧基-苯基)-色烯-4-酮
1H NMR(DMSO-d6,300MHz),δ7.88(s,1H);7.73(d,J=8.89Hz,1H);7.65(d,J=8.90Hz,1H);7.53(d,J=8.53Hz,1H);7.45~7.40(m,3H);7.31(d,J=8.53Hz,2H);7.22~7.17(m,2H);7.11~7.02(m,4H);2.09(s,3H)。
实施例25
5,6,7-三羟基-2-甲基-3-(4-苯氧基-苯基)-8-苯基-色烯-4-酮
1H NMR(CDCl3,300MHz),δ13.08(s,1H);7.59~7.35(m,7H);7.28~6.93(m,7H);6.16(s,1H);5.59(s,1H);2.22(s,3H);13C NMR(CDCl3,75MHz),δ182.02;165.07;157.78;157.04;148.12;145.79;132.21;131.25;131.09;130.23;128.83;128.29;127.76;126.70;124.10;121.06;119.88;118.87;108.11;105.02;19.89.
实施例26
5,6,7-三羟基-2-甲基-3-(4-苯氧基-苯基)-色烯-4-酮
1H NMR(DMSO-d6,300MHz),δ12.80(s,1H);8.75(br,1H);7.43(t,J=7.63Hz,2H);7.32~7.29(m,2H);7.17(t;J=7.22Hz,1H);7.09~6.96(m,4H);6.46(s,1H);2.28(s,3H);13C NMR(DMSO-d6,75MHz),δ181.24;164.96;157.21;157.11;154.25;150.44;148.02;133.23;131.00;129.85;127.92;124.59;120.23;119.80;118.85;104.35;94.16;20.13.
实施例27
8-溴-5,6,7-三羟基-2-甲基-3-(4-苯氧基-苯基)-色烯-4-酮
1H NMR(CDCl3,300MHz),δ12.91(s,1H);7.42~7.09(m,9H);6.55(s,1H);5.73(s,1H);2.34(s,3H)。
实施例28
3-(6-羟基-5-异丁基-萘-2-基)-8-异丁基-5,6,7-三甲氧基-2-甲基-色烯-4-酮
1H NMR(CDCl3,300MHz),δ 7.9 2(d,J=8.76Hz,1H);7.65(d,J=1.58Hz,1H);7.52(d,J=8.70Hz,1H);7.29(dd,J=1.74,8.78Hz,1H);7.02(d,J=8.76Hz,1H);5.29(s,1H);4.07(s,3H);3.96(s,3H);3.93(s,3H);2.90(d,J=7.24Hz,2H);2.74(d,J=7.22Hz,2H);2.32(s,3H);2.13~1.96(m,2H);1.03(d,J=6.67Hz,6H);1.00(d,J=6.68Hz,6H)。
实施例29
1H NMR(DMSO-d6,300MHz),δ7.37(s,4H);3.96(s,6H);3.90(s,6H);3.87(s,6H);2.72(d,J=7.16Hz,4H);2.33(s,6H);2.06~1.95(m,2H);0.99(d,J=6.64Hz,12H)。
实施例30
1H NMR(DMSO-d6,300MHz),δ12.85(s,2H);9.86(s,2H);9.13(s,2H);7.80(d,J=8.28Hz,4H);7.46(d,J=8.21Hz,4H);2.62(d,J=6.98Hz,4H);2.35(s,6H);1.99~1.90(m,2H);0.91(d,J=6.63Hz,12H);13C NMR(DMSO-d6,75MHz),δ181.73;164.96;152.93;148.92;146.09;140.01;132.59;132.36;129.26;127.39;120.35;106.60;104.01;32.24;31.73;23.49;20.41.
实施例31
N-苄基-3-(5,6,7-三羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酰胺
1H NMR(DMSO-d6,300MHz),δ12.74(s,1H);9.82(s,1H);9.11(s,1H);9.06(t,J=6.00Hz,1H);7.94~7.91(m,1H);7.86(s,1H);7.57~7.47(m,2H);7.33~7.22(m,4H);4.49(d,J=5.88Hz,2H);2.60(d,J=7.15Hz,2H);2.28(s,3H);1.98~1.89(m,1H);0.90(d,J=6.64Hz,6H);13C NMR(DMSO-d6,75MHz),δ181.51;166.76;164.8 5;152.88;148.87;145.97;140.56;135.12;134.40;133.43;130.42;129.22;129.18;128.22;127.66;127.57;120.27;106.58;103.89;43.64;32.13;31.63;23.39;20.23.
实施例32
1H NMR(DMSO-d6,300MHz),δ12.85(s,2H);9.85(s,2H);9.13(s,2H);7.40(s,4H);2.61(d,J=7.03Hz,4H);2.33(s,6H);1.99~1.88(s,2H);0.91(d,J=6.63Hz,12H);13C NMR(DMSO-d6,75MHz),δ181.69;164.97;152.90;148.89;146.07;132.56;131.39;129.23;120.47;106.57;104.00;32.21;29.03;23.47;20.36.
实施例33
4-(8-异丁基-5,6,7-三甲氧基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酸甲基酯
1H NMR(CDCl3,300MHz),δ8.11(dd,J=1.81,6.45Hz,2H);7.40(d,J=6.43Hz,2H);4.02(s,3H);3.95(s,3H);3.90(s,3H);3.88(s,3H);2.72(d,J=7.20Hz,2H);2.28(s,3H);2.00~1.91(m,1H);0.89(d,J=6.98Hz,6H)。
实施例34
4-(8-异丁基-5,6,7-三甲氧基-2-甲基-4-氧代-4H-色烯-3-基)-N-(3-异丙基-苯基)-苯甲酰胺
1H NMR(CDCl3,300MHz),δ8.29(s,1H);7.89(d,J=8.06Hz,2H);7.58~7.54(m,2H);7.36~7.26(m,3H);7.02(d,J=7.27Hz,1H);4.03(s,3H);3.94(s,3H):3.88(s,3H);2.96~2.84(m,1H);2.73(d,J=7.10Hz,2H);2.27(s,3H):2.00~1.94(m,1H);1.23(d,J=7.00Hz,6H);0.91(d,J=6.39Hz,6H)。
实施例35
4-(5,6,7-三羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酸
1H NMR(DMSO-d6,300MHz),δ13.03(br,1H);12.66(s,1H);10.19(s,1H);9.15(Br,1H);7.99(d,J=8.19Hz,2H);7.48(d,J=8.18Hz,2H);2.60(d,J=7.20Hz,2H);2.22(s,3H);2.00~1.91(m,1H);0.90(d,J=6.66Hz,6H);13C NMR(DMSO-d6,75MHz),δ181.20;168.02;164.91;152.86;148.74;145.91;137.94;131.87;130.77;129.86;129.19;106.54;103.78;32.06;28.90;23.32;20.16.
实施例36
3-(8-异丁基-5,6,7-三甲氧基-2-甲基-4-氧代-4H-色烯-3-基)-N-(2-异丙基-苯基)-苯甲酰胺
1H NMR(CDCl3,300MHz),δ7.90~7.75(m,3H);7.62~7.50(m,2H);7.38~7.35(m,1H);7.26~7.22(m,4H);4.03(s,3H);3.95(s,3H);3.89(s,3H);3.19~3.10(m,1H);2.73(d,J=7.10Hz,2H);2.38(s,3H);2.01~1.94(m,1H);1.29(d,J=6.84Hz,6H);0.99(d,J=6.64Hz,6H)。
实施例37
4-(6,7-双-乙氧基甲氧基-5-羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-N-苯基-苯甲酰胺
1H NMR(CDCl3,300MHz),δ12.80(s,1H);7.95(d,J=8.34Hz,2H);7.94(s,1H);7.69(d,J=8.54Hz,2H);7.44~7.35(m,4H);7.19(t,J=7.49Hz,1H);5.36 (s,2H);5.25(s,2H);3.94~3.91(m,4H);2.73(d,J=7.18Hz,2H);2.34(s,3H);2.07~1.95(m,1H);1.29(t,J=7.08Hz,3H);1.24(t,J=7.06Hz 3H);0.97(d,J=6.63Hz,6H)。
实施例38
4-(6,7-双-乙氧基甲氧基-5-羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酸
1H NMR(丙酮-d6,300MHz),δ13.07(s,1H);8.14(d,J=8.49Hz,2H);7.56(d,J=8.41Hz,2H);5.37(s,2H);5.22(s,2H);3.90~3.82(m,4H);2.78(d,J=7.21Hz,2H);2.42(s,3H);2.01~1.95(m,1H);1.28~1.12(m,6H);0.98(d,J=6.66Hz,6H)。
实施例39
(S)4-甲基-2-[4-(5,6,7-三羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酰基氨基]-戊酸甲基酯
1H NMR(DMSO-d6,300MHz),δ12.75(s,1H);9.88(s,1H);9.14(s,1H);8.80(d,J=7.68Hz,1H);7.95(d,J=8.28Hz,2H);7.46(d,J=8.28Hz,2H);4.55~4.5 2(m,1H);3.66(s,3H);2.60(d,J=7.12Hz,2H);2.28(s,3H);1.99~1.55(m,4H);0.90(d,J=6.64Hz,6H);0.84(d,J=6.76Hz,6H);13CNMR(DMSO-d6,75MHz),δ181.10;173.79;167.00;164.65;152.63;148.55;145.72;136.33;133.51;131.34;128.96;127.93;119.80;106.31;103.59;52.58;51.60;31.86;28.69;25.15;23.55;23.11;21.80;19.93.
实施例40
N-(1-苄基-哌啶-4-基)-4-(5,6,7-三羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酰胺:盐酸盐
1H NMR(DMSO-d6,300MHz),δ12.72(s,1H);10.85(s,1H);9.88(s,1H);9.30(s,1H);8.66(s,1H);7.93(br,2H);7.64(br,2H);7.46(m,5H);4.26(s,2H);3.90(m,1H);3.45(m,2H);3.07(m,2H);2.58(m,2H);2.26(s,3H);2.08~1.90(m,5 H);0.90(d,J=6.65Hz,6H);13C NMR(DMSO-d6,75MHz),δ181.30;166.58;164.81;152.79;148.72;145.96;136.25;134.25;132.37;131.44;130.77;130.32;129.64;129.17;128.03;120.00;106.51;103.80;59.79;51.50;45.77;32.06;29.26;28.88;23.32;20.15.
实施例41
(S)3-(1H-吲哚-2-基)-2-[4-(5,6,7-三羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酰基氨基]-丙酸甲基酯
1H NMR(DMSO-d6,300MHz),δ12.74(s,1H);10.93(s,1H);9.87(s,1H);9.14(br,1H);8.89(d,J=7.61Hz,1H);7.89(d,J=8.28Hz,2H);7.54(d,J=7.74Hz,1H);7.43(d,J=8.27Hz,2H);7.34(d,J=7.87Hz,1H);7.24(d,J=2.00Hz,1H);7.10~6.94(m,2H);4.76~4.68(m,1H);3.66(s,3H);3.34~3.21(m,2H);2.60(d,J=7.20Hz,2H);2.22(s,3H);1.98~1.91(m,1H);0.90(d,J=6.63Hz,6H);13C NMR(DMSO-d6,75MHz),δ181.09;173.23;166.88;164.66;152.64;148.55;145.73;136.78;136.32;133.49;131.33;128.96;127.86;127.72;124.34;121.67;119.78;119.12;118.67;112.16;110.64;106.32;103.60;54.50;52.63;31.87;28.70;27.29;22.74;19.95.
实施例42
(S)苯基-[4-(5,6,7-三羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酰基氨基]-乙酸甲基酯
1H NMR(DMSO-d6,300MHz),δ12.75(s,1H);9.88(s,1H);9.28(d,J=7.14Hz,1H);9.14(s,1H);7.99(d,J=8.28Hz,2H);7.52~7.35(m,7H);5.71(d,J=7.08Hz,1H);3.68(s,3H);2.60(d,J=7.07Hz,2H);2.28(s,3H);1.98~1.89(m,1H);0.90(d,J=6.63Hz,6H);13C NMR(DMSO-d6,75MHz),δ181.08;171.74;166.96;164.64;152.61;148.53;145.72;136.85;136.42;133.30;129.21;128.94;128.87;128.18;119.78;106.30;103.59;57.57;52.96;31.84;28.68;23.10;22.73;19.92.
实施例43
N-[2-(1H-吲哚-3-基)-乙基]-4-(5,6,7-三羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酰胺
1H NMR(DMSO-d6,300MHz),δ12.76(s,1H);10.83(s,1H);9.87(s,1H);9.13(br,1H);8.69(t,J=5.50Hz,1H);7.91(d,J=8.25Hz,2H);7.60(d,J=7.50Hz,1H);7.43(d,J=8.25Hz,2H);7.35(d,J=8.01Hz,1H);7.20(s,1H);7.13~6.97(m,2H);3.59~3.50(m,2H);2.98(t,J=7.50Hz,2H);2.60(d,J=7.20Hz,2H);2.29(s,3H);1.96~1.91(m,1H);0.90(d,J=6.60Hz,6H)。
实施例44
N-二苯甲基-4-(5,6,7-三羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酰胺
1H NMR(DMSO-d6,300MHz),δ12.75(s,1H);9.87(s,1H);9.36(d,J=8.80Hz,1H);9.12(s,1H);8.00(d,J=8.38Hz,2H);7.46~7.26(m,12H);6.45(d,J=8.64Hz,1H);2.60(d,J=7.48Hz,2H);2.28(s,3H);1.98~1.91(m,1H);0.84(d,J=6.46Hz,6H);13C NMR(DMSO-d6,75MHz),δ181.33;166.60;164.84;152.82;148.75;145.93;143.18;136.34;131.46;129.22;128.50;128.29;127.87;120.04;106.50;103.80;57.22;35.05;28.89;23.32;20.14.
实施例45
3-(5,6,7-三羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酸
1H NMR(DMSO-d6,300MHz),δ12.69(br,1H);9.75(br,1H);7.95(s,1H);7.89(m,1H);7.57~7.49,2H);2.60(d,J=6.70Hz,2H);2.28(s,3H);1.96~1.91(m,1H);0.90(d,J=6.35Hz,6H)。
实施例46
N-苄基-4-(5,6,7-三羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酰胺
1H NMR(DMSO-d6,300MHz),δ12.75(s,1H);9.87(s,1H);9.14(s,1H);9.12(s,1H);7.96(d,J=8.25Hz,2H);7.42(d,J=8.24Hz,2H);7.41~7.24M,5H);4.51(d,J=5.84Hz,2H);2.60(d,J=7.11Hz,2H);2.28(s,3H);1.97~1.89(m,1H);0.90(d,J=6.61Hz,6H);13C NMR(DMSO-d6,75MHz),δ181.46;167.00;165.01;152.95;148.89;146.05;140.67;136.41;134.46;131.73;129.30;128.17;128.02;127.75;120.14;106.65;103.94;43.61;32.18;31.51;29.03;23.45;20.28.
实施例47
(S)3-苯基-2-[4-(5,6,7-三羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酰基氨基]-丙酸甲基酯
1H NMR(DMSO-d6,300MHz),δ12.74(s,1H);9.88(s,1H);9.13(br,1H);8.93(d,J=7.85Hz,1H);7.86(d,J=8.28Hz,2H);7.43(d,J=8.26Hz,2H);7.39~7.18(m,5H);4.70~4.68(m,1H);3.66(s,3H);3.19~3.12(m,2H);2.60(d,J=7.14Hz,2H);2.27(s,3H);1.98~1.89(m,1H);0.90(d,J=6.63Hz,6H);13C NMR(DMSO-d6,75MHz),δ181.07;172.85;166.84;164.63;152.62;148.52;145.71;138.40;136.34;133.41;131.34;129.73;128.92;127.79;127.16;119.75;106.30;103.58;54.96;52.65;36.85;31.85;22.72;19.93.
实施例48
5,6,7-三羟基-2-甲基-8-萘-2-基-3-(4-苯氧基-苯基)-色烯-4-酮
1H NMR(CDCl3,300MHz),δ13.10(s,1H);8.00~7.90(m,3H);7.63~7.50(m,2H);7.40~7.35(m,2H);7.28~7.18(m,4H);7.16~6.93(m,5H);6.22(br,1H);5.57(br,1H);2.25(s,3H);13C NMR(CDCl3,75MHz),δ181.61;164.70;157.36;156.60;147.85;145.50;133.37;132.81;131.79;130.01;129.82;128.63;128.17;128.09;127.93;127.74;127.40;126.37;126.21;123.68;120.69;119.46;118.46;107.51;104.66;19.50.
实施例49
8-环丁基甲基-5,6,7-三羟基-2-甲基-3-(4-苯氧基-苯基)-色烯-4-酮
1H NMR(CDCl3,300MHz),δ12.79(s,1H);7.41~7.03(m,7H);6.96(dd,J1=2.2Hz,J2=7.69Hz,1H);6.83(d,J=8.71Hz,1H);6.13(s,1H);5.39(s,1H);2.92(d,J=7.37Hz,2H);2.69~2.64(m,1H);2.38(s,3H);2.04~1.77(m,6H);13C NMR(CDCl3,75MHz),δ181.44;157.26;156.66;143.72;131.84;129.81;129.61;126.83;123.64;122.45;121.00;119.44;118.46;117.58;116.28;105.78;104.33;135.97;28.90;28.20;19.60;18.29.
实施例50
2-环丙基-5,6,7-三羟基-8-异丁基-3-(4-苯氧基-苯基)-色烯-4-酮
1H NMR(CDCl3,300MHz),δ12.93(s,1H);7.41~7.06(m,7H);6.97(dd,J=1.76,8.61Hz,1H);6.83(d,J=8.70Hz,1H);6.11(s,1H);5.43(s,1H);2.60(d,J=7.26Hz,2H);2.03~1.89(m,2H);1.35~1.29(m,2H);1.08~1.02(m,2H);0.98(d,J=6.64Hz,6H);13C NMR(CDCl3,75MHz),δ180.96;167.13;157.24;156.70;148.64;147.97;132.36;129.82;129.62;126.80;126.39;123.64;122.47;121.01;119.47;119.35;118.46;117.60;116.31;106.26;31.61;28.92;22.62;13.36;9.47.
实施例51
5,6,7-三羟基-8-异丁基-2-甲基-3-[4-(萘-2-基氧基)-苯基]-色烯-4-酮
1H NMR(CDCl3,300MHz),δ12.82(s,1H);7.87(dd,J=8.74,8.64Hz,1H);7.77(d,J=7.66Hz,1H);7.53~7.42(m,2H);7.38~7.28(m,5H);7.21~7.14(m,2H);6.15(s,1H);5.44(s,1H);2.71(d,J=7.25Hz,2H);2.36(s,3H);2.09~1.99(m,1H);0.99(d,J=6.63Hz,6H);13C NMR(CDCl3,75MHz),δ181.65;164.20;157.22;154.41;148.86;143.77;134.31;131.92;130.37;129.96;127.75;127.20;126.76;126.56;124.87;120.27;118.64;114.91;106.34;31.37;28.64;22.55;19.58.
实施例52
3-联苯基-4-基-5,6,7-三羟基-8-异丁基-2-甲基-色烯-4-酮
1H NMR(CDCl3,300MHz),δ12.82(s,1H);7.71~7.64(m,4H);7.51~7.39(m,5H);6.13(s,1H);5.35(s,1H);2.73(d,J=7.18Hz,2H);2.40(s,3H);2.06~2.02(m,1H);0.99(d,J=6.64Hz,6H);13C NMR(CDCl3,75MHz),δ181.60;164.12;148.81;143.82;140.89;140.80;130.98;130.83;128.80;127.41;127.32;127.18;126.84;123.58;120.64;106.35;31.38;28.65;22.56;19.59.
实施例53
3-(4-苯磺酰基-苯基)-5,6,7-三羟基-8-异丁基-2-甲基-色烯-4-酮
1H NMR(CDCl3,300MHz),δ12.52(s,1H);8.06~8.00(m,4H);7.61~7.45(m,5H);6.31(s,1H);5.84(s,1H);2.69(d,J=6.91Hz,2H);2.32(s,3H);2.05~1.95(m,1H);0.97(d,J=6.42Hz,6H)。
实施例54
N-金刚烷-1-基-4-(5,6,7-三羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酰胺
1H NMR(CDCl3,300MHz),δ12.71(s,1H);7.81(d,J=8.25Hz,2H);7.38(d,J=8.25Hz,2H);6.20(s,1H);5.83(s,1H);5.55(s,1H);2.70(d,J=7.23Hz,2H);2.28(s,3H);2.19~1.98(m,4H);1.76~1.66(m,12H);0.98(d,J=6.64Hz,6H);13C NMR(CDCl3,75MHz),δ181.03;166.57;163.89;148.75;148.74;135.87;135.02;130.67;126.90;120.16;106.08;103.82;52.34;41.66;36.35;31.36;29.47;28.63;22.53;19.47.
实施例55
3-(4-氯-苯基)-5,6,7-三羟基-8-异丁基-2-甲基-色烯-4-酮
1H NMR(CDCl3,300MHz),δ12.77(s,1H);7.45(d,J=8.40Hz,2H);7.26(d,J=8.40Hz,2H);6.35(s,1H);5.98(s,1H);2.69(d,J=7.11Hz,2H);2.33(s,3H);2.06~1.94(m,1H);0.97(d,J=6.63Hz,6H);13C NMR(CDCl3,75MHz),δ181.29;164.12;149.35;148.83;143.73;134.05;131.87;130.50;128.77;127.06;119.88;106.45;104.16;31.36;28.60;22.53;19.47.
实施例56
5,6,7-三羟基-3-(4-羟基-苯基)-8-异丁基-2-甲基-色烯-4-酮
1H NMR(DMSO-d6,300MHz),δ12.92(s,1);9.77(br,1H);9.53(br,1H);9.09(br,1H);7.10(d,J=8.52Hz,2H);6.81(d,J=8.55Hz,2H);2.58(d,J=6.99Hz,2H);2.26(s,3H);1.96~1.88(m,1H);0.90(d,J=6.63Hz,6H);13C NMR(DMSO-d6,75MHz),δ181.67;164.32;157.47;152.40;148.53;145.72;132.41;128.74;123.08;120.27;115.56;106.06;103.67;31.86;28.68;23.12;19.93.
实施例57
5,6,7-三羟基-8-异丁基-2-甲基-3-(4-苯氧基-苯基)-色烯-4-酮
1H NMR(DMSO-d6,300MHz),δ12.83(s,1H);9.83(br,1H);9.11(br,1H);7.46~7.33(m,4H);7.21~7.04(m,5H);2.59(d,J=7.18Hz,2H);2.3 0(s,3H);1.95~1.91(m,1H);0.90(d,J=6.61Hz,6H);13C NMR(DMSO-d6,75MHz),δ181.39;164.59;157.06;156.87;152.52;148.54;145.70;133.04;130.79;128.86;127.82;124.35;119.74;119.58;118.65;106.19;103.62;31.85;28.68;23.12;19.98.
实施例58
N-萘-2-基-4-(5,6,7-三羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酰胺
1H NMR(DMSO-d6,300MHz),δ12.77(s,1H);10.54(s,1H);9.89(s,1H);8.51(br,1H);8.07(d,J=8.27Hz,2H);7.94~7.84(m,4H);7.54(d,J=8.30Hz,2H);7.89~7.84(m,2H);2.62(d,J=7.08Hz,2H);2.32(s,3H);1.98~1.90(m,1H);0.91(d,J=6.63Hz,6H);13C NMR(DMSO-d6,75MHz),δ181.12;166.26;164.69;152.65;148.56;145.74;137.48;136.49;134.76;134.00;131.49;130.65;128.98;128.85;128.14;128.10;127.07;125.46;121.58;119.78;117.16;106.33;103.62;31.87;28.70;23.13;19.99。
实施例59
(S)2-[4-(5,6,7-三羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酰基氨基]-琥珀酸二甲基酯
1H NMR(DMSO-d6,300MHz),δ12.74(s,1H);9.87(s,1H);9.14(br,1H);9.01(d,J=7.68Hz,1H);7.91(d,J=8.31Hz,2H);7.46(d,J=8.35Hz,2H);4.91~4.84(m,1H);3.68(s,3H);3.64(s,3H);3.03~2.82(m,2H);2.60(d,J=7.07Hz,2H);2.28(s,3H);1.98~1.86(m,1H);0.95(d,J=6.60Hz,6H)。
实施例60
5,6,7-三羟基-8-异丁基-3-(4-[4-(3-甲氧基-苯基)-哌嗪-1-羰基]-苯基}-2-甲基-色烯-4-酮(HCl)
1H NMR(DMSO-d6,300MHz),δ12.76(br,1H);9.90(br,1H);7.56(d,J=8.20Hz,2H);7.43(d,J=8.18Hz,2H);7.21(dd,J=8.13,8.16Hz,1H);6.75(s,1H);6.72(d,J=7.76Hz,1H);6.54(d,J=7.77Hz,1H);3.74(s,3H);3.90~3.57(m,8H);2.60(d,J=7.20Hz,2H);2.31(s,3H);2.00~1.90(m,1H);0.90(d,J=6.63Hz,6H)。
实施例61
N-(2,2-二苯基-乙基)-4-(5,6,7-三羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酰胺
1H NMR(DMSO-d6,300MHz),δ12.74(s,1H);9.87(s,1H);9.13(br,1H);8.50(t,J=5.15Hz,1H);7.76(d,J=8.24Hz,2H);7.39~7.17(m,12H);4.56(dd,J=8.03,7.77Hz,1H);3.93(dd,J=5.61,7.34Hz,2H);2.59(d,J=7.02Hz,2H);2.25(s,3H);1.97~1.87(m,1H);0.89(d,J=6.62Hz,6H);13C NMR(DMSO-d6,75MHz),δ181.08;166.72;164.58;152.60;148.51;145.50;143.55;135.84;134.35;131.22;129.07;128.93;128.60;127.48;126.99;119.77;106.28;103.57;50.50;44.46;31.84;28.67;23.09;19.92。
实施例62
3-[4-(4-苄基-[1,4]二氮杂_-1-羰基)-苯基]-5,6,7-三羟基-8-异丁基-2-甲基-色烯-4-酮盐酸化物
1H NMR(DMSO-d6,300MHz),δ12.75(s,1H);10.84(br,1H);9.89(s,1H);9.16(br,1H);7.64~7.41(m,9H);5.76(s,2H);4.41~3.15(m,8H);2.55(d,J=6.83Hz,2H);2.30(s,3H);2.20~2.00(m,2H);1.99~1.87(m,1H);0.90(d,J=6.67Hz,6H)。
实施例63
N-[1-苄基-2-(4-甲基-哌嗪-1-基)-2-氧代-乙基]-4-(5,6,7-三羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酰胺
1H NMR(DMSO-d6,300MHz),δ10.12(br,1H);9.50(br,1H);9.13(s,1H);8.93~8.87(m,1H);7.86(d,J=8.04Hz,2H);7.43(d,J=8.10Hz,2H);7.32~7.21(m,5H);4.68~4.58(m,1H);4.02(t,J=6.20Hz,1H);3.90~2.55(m,10H);2.80(s,3H);2.60(d,J=6.90Hz,2H);2.27(s,3H);1.95~1.91(m,1H);0.90(d,J=6.61Hz,6H)。
实施例64
N-(1-苄基-2-氧代-2-{4-[5-(2-氧代-六氢-噻吩并[3,4-d]咪唑-6-基)-戊酰基]-哌嗪-1-基}-乙基)-4-(5,6,7-三羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酰胺
1H NMR(DMSO-d6,300MHz),δ12.75(br,1H),9.86(br,1H);8.90(m,1H);7.89(d,J=7.75Hz,2H);7.42(d,J=7.74Hz,2H);7.34~7.22(m,5H);6.44(br,2H);5.12(br,1H);4.37~2.60(m,16H);2.56(d,J=6.93Hz,2H);2.60~2.30(m,2H);2.27(s,3H);1.93(m,1H);1.60~1.20(m,6H);0.90(d,J=6.00Hz,6H)。
实施例65
3-苯基-2-[4-(5,6,7-三羟基-8-异丁基-2-甲基-4-氧代-4H-色烯-3-基)-苯甲酰基氨基]-丙酸
1H NMR(DMSO-d6,300MHz),δ12.75(s,1H);9.88(s,1H);9.13(s,1H);8.78(m,1H);7.85~7.15(m,9H);4.64(m,1H);3.41~3.09(m,2H);2.59(d,J=7.00Hz,2H);2.27(s,3H);1.93(m,1H);0.90(d,J=6.40Hz,6H)。
实施例66
5,6,7-三羟基-8-异丁基-2-甲基-3-[4-(4-苯基-哌嗪-1-羰基)-苯基]-色烯-4-酮
1H NMR(DMSO-d6,300MHz),δ12.74(br,1H);9.86(br,1H);7.54~6.95(m,9H);4.07~3.34(m,8H);2.60(d,J=6.90Hz,2H);2.31(s,3H);1.98~1.90(m,1H);0.90(d,J=6.60Hz,6H);13C NMR(DMSO-d6,75MHz),δ181.18;169.57;164.74;152.62;148.55;145.76;134.47;131.48;129.97;129.00;127.55;119.82;118.02;106.34;103.65;31.89;31.65;28.71;25.46;23.14;22.75;20.02;14.66.
实施例67
3-[4-(4-苄基-哌啶-1-羰基)-苯基]-5,6,7-三羟基-8-异丁基-2-甲基-色烯-4-酮
1H NMR(DMSO-d6,300MHz),δ12.75(s,1H);9.86(br,1H);9.13(br,1H);7.43~7.13(m,9H);4.46~2.90(m,4H);2.61~2.51(m,4H);2.31(s,3H);1.98~1.81(m,2H);1.80~1.15(m,4H);0.90(d,J=6.64Hz,6H);13C NMR(DMSO-d6,75MHz),δ181.34;169.56;164.90;152.80;148.74;145.89;140.89;136.47;134.20;131.57;129.89;129.05;127.28;126.71;120.04;106.49;103.81;42.94;39.78;38.38;31.82;28.88;23.31;22.93;20.18;14.84.
实施例68
1H NMR(CDCl3,300MHz),δ12.83(b,2H),7.34(s,4H),4.04(s,6H),3.93(s,6H),2.65(d,J=7.2Hz,4H),2.39(s,6H),1.94(m,2H),0.96(d,J=6.6Hz,12H);13C NMR(CDCl3,75MHz),δ181.88,164.59,157.54,152.24,150.34,136.32,131.69,130.62,120.79,112.59,107.04,61.30,60.66,32.0,29.09,22.67,19.74.
实施例69
1H NMR(CO(CD3)2,300MHz),δ8.8(b,2H),7.42(s,4H),2.86(m,4H),2.43(s,6H),1.72(m,2H),1.49(m,4H),0.99(d,J=7.0Hz,12H);13C NMR(CO(CD3)2,75MHz),δ176.31,161.50,155.71,151.44,151.09,143.97,132.50,130.56,123.31,120.74,114.91,39.28,28.36,22.60,21.61,19.37.
实施例70
1H NMR(CO(CD3)2,300MHz),δ8.6(b,2H),7.56(t,J=7.0Hz,1H),7.42(t,J=1.5Hz,1H),7.38(m,2H),2.85(t,J=7.7Hz,4H),2.44(s,6H),1.61(m,2H),1.53(m,4H),0.99(d,J=6.4Hz,12H);13C NMR(CO(CD3)2,75MHz),δ181.09,164.21,150.43,148.24,144.64,133.19,132.49,130.05,127.74,120.26,106.94,103.82,38.36,22.02,20.19,18.79.
实施例71
1H NMR(CO(CD3)2,300MHz),δ7.44(s,4H),2.86(q,J=7.4Hz,4H),2.42(s,6H),1.22(t,J=7.4Hz,6H);13C NMR(CO(CD3)2,75MHz),δ181.13,167.16,151.23,149.16,145.21,132.13,131.24,128.34,121.04,106.78,104.23,21.41,18.42,16.43.
实施例72
1H NMR(CD3OD,300MHz),δ7.29-7.32(m,12H),7.20(m,2H),4.23(s,4H),2.33(s,6H);13C NMR(CD3OD,75MHz),δ175.95,161.39,155.66,151.71,151.28,143.78,140.24,132.28,130.33,128.41,125.96,123.17,118.43,114.70,31.23,20.15.
实施例73
1H NMR(CO(CD3)2,300MHz),δ7.45(s,4H),2.73-2.77(m,8H),2.06(m,2H),1.34(t,J=7.5Hz,6H),0.99(d,J=6.7Hz,12H);13C NMR(CO(CD3)2,75MHz),δ176.43,165.16,155.96,151.54,151.11,143.61,132.28,130.32,122.48,119.20,114.56,32.42,28.92,25.82,22.62,16.74.
实施例74
1H NMR(CO(CD3)2,300MHz),δ7.46(s,4H),2.71-2.77(m,8H),2.06(m,2H),1.84(hex,J=7.4Hz,4H),0.99(d,J=6.6Hz,12H),0.96(t,J=7.4Hz,6H);13C NMR(CO(CD3)2,75MHz),δ176.47,164.17,156.0,151.57,151.14,143.65,132.31,130.45,123.29,119.23,114.61,34.03,32.49,28.99,22.68,20.47,13.66。
实施例75
1H NMR(CO(CD3)2,300MHz),δ7.43(s,4H),2.73(t,J=7.2Hz,4H),2.61(d,J=7.3Hz,4H),2.23(m,J=6.8Hz,2H),2.04(m,2H),0.90-0.99(m,24H);13C NMR(CO(CD3)2,75MHz),δ176.38,163.59,155.89,151.49,151.04,143.54,132.21,130.48,123.87,119.23,114.48,40.78,32.40,28.88,26.88,22.56,22.25.
实施例76
棉酚及类似物与Bcl-xL结合的模型
用15N异核单量相干性光谱(HSQC)NMR法确定棉酚与Bcl-xL的结合。根据在Jansson等,J.Biomol.NMR,7:131(1996)和Cai等,J.Biomol.NMR,11:97(1998)中所述的方法,用15N将用于NMR研究的蛋白质样品均匀地标记以进行筛选,并用15N和13C均匀地双标记以表征结构特征。由于在pH7.2和脉冲梯度场(PFG)中进行NMR试验,可以在水翻动转回(flip back)下使用HSQC来使信号强度最大(Grzesiek等,J.Am.Chem.Soc.,115:12593(1993);和Sheppard等,Abstracts of Papers of the Amer.Chem.Soc.,213:81(1997))并使水信号的破坏最小。在加入浓的抑制剂溶液前(不含Bcl-xL)和后记录Bcl-xL的HSQC谱。比较这两个谱来鉴别由于加入抑制剂而诱导的化学位移。用nmrPipe,pipp和nmrDraw软件来进行数据处理(参见Garrett等,J.Magn.Reson.Ser.B,95:214(1991);和Delaglio等,J.Biomol.NMR,6:277(1995))。位移的峰值与指定表互相参照以显示受棉酚化合物存在影响的残留物。
棉酚/Bcl-xL复合物的3-D NMR光谱表明,棉酚结合到Bcl-xL蛋白的表面袋上,在此细胞凋亡前体蛋白的BH3结构域结合(附图1)。棉酚/Bcl-xL复合结构的近距离检查表明,这两种分子之间有几种决定性的相互作用。棉酚分子的-半(附图1的右部)占据了主要由Phe101,Leu103,Tyr105,Gly142,Arg143,Ile145和Tyr199限定的腔体。多个羟基和醛基与Arg143和Tyr199形成了氢键网络;而萘环与其上的疏水取代基(异丙基和甲基)嵌入到该腔体的疏水性底部。对于棉酚的另-半(附图1的左部),萘环是作为巨大的疏水基,并嵌入到由Ala108,Leu112,Leu134和Ala146形成的腔体中。
根据这些观察,5,6,7-三羟基-3-(6-羟基-5-异丙基-萘-2-基)-8-异丁基-2-甲基-色烯-4-酮(化合物2)可以被设计以模拟棉酚和Bcl-2和Bcl-xL之间的相互作用。这清楚地表明,化合物2具有与棉酚类似的结构几何学。化合物2的4位的酮基象棉酚的1-羟基-样,在与Bcl-xL的相互作用中发挥相同作用。与棉酚的结构相比,已有几处其他的改变。棉酚的醛基(其与体内毒性有关)用羟基取代。分子模型表明,该羟基也能与Bcl-xL上的Arg143形成决定性的氢键。对棉酚/Bcl-xL复合结构的分析表明,适度较大的疏水性基团可以被容纳在腔体中,在此棉酚的异丙基结合(附图1的右部),因此它可以被相对较大的异丁基取代。由于棉酚的左半部分用作较大的疏水性基团嵌入到左边的疏水袋(附图1),因此可以移除所有不希望的取代基。这些改变也可以使得它更适于合成所设计的化合物。为了研究结合亲和力的决定性因素,也可以在左侧萘环和核心结构上进行-些改变。
基于结构的模型表明,化合物2可以非常相似地模拟棉酚以实现与Bcl-xL的相互作用。异黄酮部分上的羰基和另外三个羟基与残基Arg139和Tyr195-起形成了氢键网络,同时该部分的疏水性部分与该结合腔的疏水性底部接触。总之,化合物2的该半部分与棉酚的结合方式是非常相似的。至于萘基部分,它嵌入到了由Ala104,Leu108,Leu112,Leu130和Ala142形成的疏水性腔中。与棉酚相比,化合物2在萘基部分少-个甲基,这使得两个主要部分相对旋转成为可能。结果,化合物2比棉酚更为柔韧,并且它的萘基部分可以更好地嵌入到由Ala104,Leu108,Leu112,Leu130和Ala142形成的疏水性腔中,并保持着积极有利的构象。
实施例77
结合和细胞活性
基于棉酚和Bcl-xL之间结合的NMR研究,及其后的基于计算结构的模型,设计和合成出了异黄酮类似物(化合物15a-15e和15j)作为新的Bcl2/Bcl-xL抑制剂。
这些化合物和化合物2与Bcl-2和Bcl-xL的结合亲和力可以通过基于荧光极化的结合分析来确定。
Bcl-2结合分析
使用6-羧基荧光素琥珀酰亚胺酯(FAM)在N-末端标记的21-残基Bid BH3肽(QEDIIRNIARHLAQVGDSMDR)(SEQ ID NO:1)作为荧光标记(Flu-Bid-21)。据显示,该荧光肽具有Kd为15.74nM的高结合亲和力。在该分析中使用的Bcl-2是重组His-融合的可溶性蛋白。
将溶解于DMSO中的受试化合物的5μl样品和用在分析缓冲液(100mM磷酸钾,pH7.5;100μg/ml牛血清丙种球蛋白;0.02%叠氮化钠,购自Invitrogen Corporation,Life Technologies)中的Flu-Bid-21肽(0.010μM)预培养的Bcl-2蛋白(0.120μM)加入到Dynex96-孔、黑色圆底培养皿(plate)中(Fisher Scientific),以达到最终体积为125μl。对于每个分析,在每个分析培养皿中包括包含Bcl-2和Flu-Bid-21肽(相当于0%抑制作用)的结合肽对照品和仅包含游离Flu-Bid-21(相当于100%抑制作用)的游离肽对照品。当培养4小时结合达到平衡时,用Ultra面板读数器(Tecan U.S.Inc.,Research Triangle Park,NC)在485nm的激发波长和530nm的发射波长下测定单位为毫极化单位(mP)的极化值。50%的结合肽被取代时的抑制剂浓度IC50是由非线性最小二乘法分析的绘图和用GraphPadPrism_软件拟合的曲线确定的。用未标记的Bid肽作为阳性对照。用我们开发出来的用于FP分析的等式(Nikolovska-Coleska等,Anal.Biochem.332:261(2004))来计算Ki值。计算Ki值的程序可以通过互联网在http://sw16.im.med.umich.edu/software/calc_ki/上免费获得。
Bcl-xL结合分析
为了确定与Bcl-xL蛋白的结合亲和力,使用的是不含C-末端疏水尾部的人Bcl-xL重组His-标记蛋白和6-羧基荧光素琥珀酰亚胺酯(FAM)标记的Bak-16mer BH3肽。该肽显示的结合亲和力是Kd=9.79nM。以与Bcl-2蛋白相同的方式,用采用含有50mM Tris-Bis,pH7.4;0.01%牛血清丙种球蛋白的60nM Bcl-xL和5nM Flu-Bak肽的分析缓冲液预培养的复合物进行竞争性结合分析。
这些异黄酮类似物的结合亲和力如表2所示。
表2.
化合物 | 结合亲和力Ki(μM) | 细胞活性IC50(μM) | ||
Bcl-xL | Bcl-2 | PC3 | 2LMP | |
2 | 1.49±0.18 | 0.088±0.003 | 1.82 | 1.54 |
15a | 1.78±0.13 | 0.13±0.01 | 3.09 | 1.44 |
15b | 1.71±0.22 | 0.17±0.02 | 5.07 | 2.55 |
15c | 2.32±0.26 | 0.39±0.17 | 3.62 | 2.08 |
15d | >14 | 1.24±0.13 | 20.61 | >30 |
15e | >14 | >12 | >40 | >30 |
15f | 4.27±0.84 | 0.79±0.03 | 23.7 | 9.3 |
15j | >14 | 4.63±0.16 | 20.1 | >30 |
棉酚 | 1.97±0.39 | 0.23±0.05 | 9.7 | 6.00 |
为了测试本发明的化合物对于抑制人癌细胞中细胞生长的作用,将这些化合物施用于两种不同的癌细胞系。将PC-3前列腺癌细胞和2LMP乳腺癌细胞分别植入96孔板中,并增加抑制剂化合物的浓度。然后将细胞在37℃下用5%CO2培养5天,然后用MTT检测细胞的生存能力,用未处理的细胞作为100%生长。细胞生长的抑制结果如表1所示。
由于与棉酚具有高度的结构相似性,化合物2显示出与棉酚非常相似的与Bcl-xL(Ki值1.49μM)和Bcl-2(Ki值0.088μM)的结合亲和力。至于对细胞生长的抑制活性,在2LMP和PC3细胞系中,化合物2比棉酚强3到4倍。
当化合物2的异丙基被较小的基团例如甲基或氢(15a和15b)取代时,它们与Bcl-2和Bcl-xL的结合亲和力几乎没有改变。这些结果表明,化合物2中的异丙基对于与Bcl-2和Bcl-xL的结合亲和力没有贡献。这些结果证明了先前对棉酚进行的NMR研究,其证明左侧的异丙基(附图1)是在结合袋之外的。尽管除去6′位(15c)的羟基,该化合物与Bcl-xL的结合亲和力几乎没有改变,但是降低了该化合物与Bcl-2的结合亲和力约2倍,其表明,羟基可以与特定的氨基酸残基形成氢键相互作用。在核结构(15d)中羟基的阻断使得与两种蛋白质的结合亲和力引人注目地降低(将化合物15b与15d相比,降低超过10倍)。这表明,这些羟基和蛋白质(Bcl-xL中的Arg143和Tyr199)之间的氢键相互作用对于结合相互作用是必需的。同时,对PC3和2LMP细胞系的细胞生长抑制活性显著地降低,其表明,该化合物的细胞活性和它们与Bcl-2/Bcl-xL蛋白的结合亲和力有关。用乙基(15e)阻断化合物15d中的6′羟基使得该化合物在结合和细胞分析中几乎完全失活(Ki值或IC50>10μM)。
用较小的芳香环(苯基;15f)或氢原子(15j)替代取代的萘环会使结合亲和力显著降低。特别是对于单体(15j),除去大的疏水基使与Bcl-xL和Bcl-2的结合亲和力分别降低了10倍和50倍以上,同时细胞活性降低。这表明,占据蛋白质表面上的疏水腔的大疏水基对于结合亲和力也是必需的。
由于已经完整地描述了本发明,所以本领域技术人员可以理解,可以在不影响本发明范围或其任意实施方案的情况下,可在较宽和等同范围的条件、陈述和其它参数范围内实施本发明。将本文中引述的所有专利、专利申请和出版物的全部内容完整地引入本文作为参考。
Claims (28)
4.权利要求2的化合物,具有通式IV:
或其药学上可接受的盐或前药。
7.药物组合物,包含权利要求1的化合物和药学可接受的载体。
8.在细胞中抑制抗细胞凋亡的Bcl-2家族成员的方法,包括将所述细胞与权利要求1的化合物接触。
9.在细胞中诱导细胞凋亡的方法,包括将该细胞与权利要求1的化合物接触。
10.使细胞对细胞凋亡诱导剂敏感的方法,包括将所述细胞与权利要求1的化合物接触。
11.权利要求10的方法,进一步包含将所述细胞与细胞凋亡诱导剂接触。
12.权利要求11的方法,其中所述细胞凋亡诱导剂是化学治疗剂。
13.权利要求11的方法,其中所述细胞凋亡诱导剂是放射。
14.在动物中治疗、改善或预防对细胞凋亡的诱导应答的障碍的方法,包括给予所述动物治疗有效量的权利要求1的化合物。
15.权利要求14的方法,进一步包含给予细胞凋亡诱导剂。
16.权利要求15的方法,其中所述细胞凋亡诱导剂是化学治疗剂。
17.权利要求15的方法,其中所述细胞凋亡的诱导剂是放射。
18.权利要求14的方法,其中所述对细胞凋亡的诱导应答的障碍是过度增殖性疾病。
19.权利要求18的方法,其中所述过度增殖性疾病是癌症。
20.权利要求15的方法,其中所述权利要求1的化合物是在所述细胞凋亡诱导剂之前给予。
21.权利要求15的方法,其中所述权利要求1的化合物是在所述细胞凋亡诱导剂之后给予。
22.权利要求15的方法,其中所述权利要求1的化合物与所述细胞凋亡诱导剂同时给予。
23.试剂盒,包含权利要求1的化合物。
24.权利要求23的试剂盒,还包含给予动物所述化合物的说明。
25.权利要求23的试剂盒,还包含细胞凋亡诱导剂。
26.权利要求25的试剂盒,其中所述细胞凋亡诱导剂是化学治疗剂。
27.权利要求24的试剂盒,其中所述说明用于将所述化合物给予具有过度增殖性疾病的动物。
28.权利要求27的试剂盒,其中所述过度增殖性疾病是癌症。
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- 2006-03-13 EP EP06748344A patent/EP1856083A4/en not_active Withdrawn
- 2006-03-13 CN CNA2006800148318A patent/CN101171241A/zh active Pending
- 2006-03-13 AU AU2006223257A patent/AU2006223257A1/en not_active Abandoned
- 2006-03-13 CA CA002600797A patent/CA2600797A1/en not_active Abandoned
- 2006-03-13 US US11/373,898 patent/US20060247305A1/en not_active Abandoned
- 2006-03-13 JP JP2008500984A patent/JP2008533039A/ja not_active Withdrawn
Cited By (9)
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CN102438452A (zh) * | 2009-05-08 | 2012-05-02 | 乔治亚州大学研究基金会 | 包含cdk抑制剂的化合物和组合物以及用于癌症治疗的方法 |
CN102438452B (zh) * | 2009-05-08 | 2015-02-25 | 乔治亚州大学研究基金会 | 包含cdk抑制剂的化合物和组合物以及用于癌症治疗的方法 |
CN103450142A (zh) * | 2013-09-04 | 2013-12-18 | 浙江大学 | 一种色满化合物及其提取方法和应用 |
CN108619488A (zh) * | 2017-03-21 | 2018-10-09 | 中国科学院上海生命科学研究院 | 一种治疗肿瘤的联合用药方法 |
CN108619488B (zh) * | 2017-03-21 | 2020-12-01 | 中国科学院脑科学与智能技术卓越创新中心 | 一种治疗肿瘤的联合用药方法 |
CN115093388A (zh) * | 2022-07-27 | 2022-09-23 | 湖南正清制药集团股份有限公司 | 一种黄酮类化合物及其制备方法和应用 |
CN115093388B (zh) * | 2022-07-27 | 2023-12-05 | 湖南正清制药集团股份有限公司 | 一种黄酮类化合物及其制备方法和应用 |
CN115490661A (zh) * | 2022-08-09 | 2022-12-20 | 海南师范大学 | 红树来源真菌中抗氧化活性化合物及其制备方法 |
CN115490661B (zh) * | 2022-08-09 | 2023-09-08 | 海南师范大学 | 红树来源真菌中抗氧化活性化合物及其制备方法 |
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WO2006099193A2 (en) | 2006-09-21 |
EP1856083A4 (en) | 2009-05-27 |
AU2006223257A1 (en) | 2006-09-21 |
JP2008533039A (ja) | 2008-08-21 |
WO2006099193A3 (en) | 2007-01-11 |
US20060247305A1 (en) | 2006-11-02 |
EP1856083A2 (en) | 2007-11-21 |
CA2600797A1 (en) | 2006-09-21 |
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