CN110386919B - 核转运调节剂及其用途 - Google Patents
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- CN110386919B CN110386919B CN201910389947.9A CN201910389947A CN110386919B CN 110386919 B CN110386919 B CN 110386919B CN 201910389947 A CN201910389947 A CN 201910389947A CN 110386919 B CN110386919 B CN 110386919B
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Abstract
本发明涉及核转运调节剂及其用途。具体来说,本发明涉及具有化学式(I)的化合物:
Description
本申请为国际申请PCT/US2014/043479进入中国国家阶段的中国专利申请(申请号为201480035555.8,申请日为2014年6月20日,发明名称为“核转运调节剂及其用途”)的分案申请。
相关申请
本申请要求于2013年6月21日提交的美国临时申请号61/838,172的权益。将本申请的全部传授内容通过引用结合在此。
发明背景
来自大部分主要人类实体和血液系统恶性肿瘤的细胞表现出多种致癌蛋白、肿瘤抑制蛋白、以及细胞周期调控子的异常细胞定位(Cronshaw等人,2004,Falini等人2006)。例如,某些p53突变可导致细胞基质定位,而非细胞核定位。这导致了正常生长调控的缺失,尽管肿瘤抑制功能是完整的。在其他肿瘤中,野生型p53被隔离在细胞质中或被迅速降解,再次导致其抑制因子功能的丧失。功能性p53蛋白的恰当的核定位的恢复可使肿瘤性细胞的一些特性正常化(Cai(蔡)等人,2008;Hoshino(星野)等人2008;Lain(莱恩)等人1999a;莱恩等人1999b;Smart(斯马特)等人1999),可恢复癌细胞对DNA损伤剂的敏感度(蔡等人,2008),并且可导致长成的肿瘤消退(Sharpless(沙普利斯)&DePinho(迪非欧)2007,Xue(薛)等人,2007)。从其他肿瘤抑制蛋白如叉头(forkhead)(Turner(特纳)和Sullivan(苏利文)2008)和c-Abl(Vignari(魏格纳瑞)和Wang(王)2001)中获得了类似数据。此外,一些肿瘤抑制因子和生长调控蛋白的异常定位可能与自身免疫性疾病的发病机理有关(Davis(戴维斯)2007,Nakahara(中原)2009)。CRM1抑制可在家族性癌症综合征中提供特别有意义的应用(例如,由一个p53等位基因缺失引起的李-佛美尼(Li-Fraumeni)综合征、BRCA1或BRCA2癌症综合征),其中特异的肿瘤抑制蛋白(TSP)被清除或具有功能障碍,并且其中通过系统的(或局部的)CRM1抑制剂的给予实现的TSP水平的提高能够帮助恢复正常的肿瘤抑制功能。
特异的蛋白和RNA由特异的转运分子输入和输出细胞核,若它们将分子输入细胞核,则这被分类为输入蛋白,若它们将分子输出细胞核,则被分类为输出蛋白(Terry(特里)等人,2007;Sorokin(索罗金)等人2007)。被输入或输出细胞核的蛋白质包含核输入/定位(NLS)或核输出(NES)序列,使它们与相关的转运因子相互作用。染色体区域稳定蛋白1(Crm1),也称作输出蛋白-1或Xpo1,为主要的输出蛋白。
据报道,在若干种肿瘤中Crm1过表达,这些肿瘤包括人类卵巢癌(Noske(诺斯克)等人,2008)、宫颈癌(van der Watt(范德瓦)等人,2009)、胰腺癌(Huang(黄)等人,2009)、肝细胞癌(Pascale(帕斯卡莱)等人,2005)及骨肉瘤(Yao((姚)等人,2009),并且Crm1的过表达独立地与这些肿瘤类型的不佳临床结果相互关联。
Crm1的抑制阻断肿瘤抑制蛋白和/或生长调控因子如p53、c-Abl、p21、p27、pRB、BRCA1、IkB、ICp27、E2F4、KLF5、YAP1、ZAP、KLF5、HDAC4、HDAC5或叉头蛋白(例如FOXO3a)的核输出,它们与基因表达、细胞增殖、血管生成以及表现遗传相关。有结果表明Crm1抑制因子可诱导癌细胞的凋亡,甚至是在致癌激活信号或生长激励信号存在的情况下,而不影响正常的(未被转化的)细胞。大多数关于Crm1抑制的研究应用了天然产物Crm1抑制剂来普霉素B(LMB)。LMB本身对肿瘤性细胞具有很高的毒性,但因显著的胃肠毒性很难被动物(Roberts(罗伯茨)等人,1986)和人(Newlands(纽兰兹)等人,1996)接受。衍生LMB来改善类药特性可得到保留抗肿瘤活性并且可被动物肿瘤模型更好地耐受的化合物(Yang(杨)等人,2007,杨等人,2008,Mutka(穆特卡)等人,2009)。因此,核输出抑制剂对肿瘤性紊乱及其他增生性紊乱可具有有益效果。然而至今,用于在体外和体内使用的小分子的类药Crm1抑制剂仍不常见。
除肿瘤抑制蛋白外,Crm1还输出若干与很多炎性过程相关的关键蛋白。这些蛋白包括IkB、NF-kB、Cox-2、RXRα、Commd1、HIF1、HMGB1、FOXO、FOXP等。因为能够引发免疫球蛋白κ基因表达的发现而得名的核因子κB(NF-kB/rel)族的转录激活因子可调控各种与炎症、增殖、免疫与细胞存活相关的基因的mRNA表达。在基本情况下,一种称为IkB的NF-kB蛋白抑制剂,在核内与NF-kB结合,且IkB-NF-kB复合物使NF-kB的转录功能失活。在炎症刺激的应答中,IkB从IkB-NF-kB复合物中解离,释放NF-kB,同时恢复其潜在的转录活性。很多激活NF-kB的信号就是通过靶向IkB蛋白水解来做到这些的(IkB的磷酸化可“标记”它进行泛素化并且然后蛋白水解)。核IkBa-NF-kB复合物可被Crm1输出到细胞质,在细胞质中该复合物解离,从而使NF-kB重新激活。泛素化的IkB还可以从NF-kB复合物上解离,恢复NF-kB的转录活性。通过LMB的在人嗜中性细胞和类巨噬细胞(U937)中Crm1诱导的输出的抑制不仅导致无转录活性的核IkBa-NF-kB复合物的累积,还防止了初始的NF-kB激活,甚至是在细胞刺激下(Ghosh(高希)2008,Huang(黄)2000)。在一项不同研究中,在肺毛微血管内皮细胞中,用LMB处理抑制了IL-1β诱导的NF-kB DNA结合(NF-kB转录激活的第一个步骤)、IL-8表达以及胞间黏附分子表达(Walsh(沃尔什)2008)。COMMD1是NF-kB和缺氧诱导因子1(HIF1)两者的转录活性的另一种核抑制剂。通过抑制Crm1阻断COMMD1的核输出可导致对NF-kB和HIF1的转录活性的抑制的增加(Muller(穆勒)2009)。
Crm1还介导类视黄醇X受体α(RXRα)运输。RXRα在肝脏中高度表达并且在调控胆汁酸、胆固醇、脂肪酸、类固醇和异生物质代谢以及内环境稳定中起到核心作用。在肝炎期间,核RXRα水平显著降低,主要归因于通过Crm1的炎症介导的RXRα核输出。在人肝源性细胞中,Lep B能够阻止IL-1β诱导的细胞质的RXRα水平增加(Zimmerman(齐默尔曼)2006)。
在NF-kB、HIF-1和RXRα信号转导中Crm1介导的核输出的作用表明阻断核输出对于很多跨多组织和器官的炎症过程可以有潜在的益处,包括脉管系统(血管炎、动脉炎、风湿性多肌痛、动脉粥样硬化)、皮肤病(见上文)、风湿病(类风湿及相关关节炎、银屑病关节炎、脊椎关节病、结晶性关节病、系统性红斑狼疮、混合性结缔组织病、肌炎综合征、皮肌炎、包涵体肌炎、未分化结缔组织病、干燥综合征、硬皮病以及重叠综合征等)。
抑制CRM1可通过抑制/激活一系列转录因子像ICp27、E2F4、KLF5、YAP1、ZAP来影响基因表达。
抑制Crm1对很多皮肤科综合征有潜在的治疗效果,包括炎性皮肤病(特应性、变应性皮炎、化学性皮炎、银屑病)、阳光损伤(紫外线/UV损伤)和感染。用LMB研究的最充分的CRM1抑制对正常的角质化细胞呈现最小的作用,且对在UV、TNFa或其他炎症刺激下的角质化细胞呈现抗炎活性(Kobayashi(小林)&Shinkai(新海)2005,Kannan(卡纳安)&Jaiswal(杰斯沃)2006)。抑制Crm1还可上调NRF2(核因子E2相关因子2)的活性,NRF2可保护角质化细胞(Schafer(谢弗)等人,2010,Kannan(卡纳安)&Jaiswal(杰斯沃)2006)及其他细胞类型(Wang(王)等人,2009)免于氧化损伤。LMB诱导被致癌性人乳头瘤病毒(HPV)毒株如HPV16感染的角质化细胞的凋亡,但不诱导未被感染的角质化细胞的凋亡(Jolly(乔利)等人,2009)。
Crm1还介导关键神经保护蛋白的转运,这些神经保护蛋白可能对神经退行性疾病包括帕金森氏病(PD)、阿尔茨海默病和肌萎缩性侧索硬化症有用。例如,(1)对关键神经保护调控因子如NRF2(Wang(王)2009)、FOXA2(Kittappa(凯塔巴)等人,2007)的强制核阻留,停泊在神经细胞中,和/或通过(2)将IκB隔离于神经胶质细胞的细胞核实现NFκB的转录活性的抑制,抑制Crm1可减缓或防止这些紊乱中发现的神经细胞死亡。还有证据表明,异常的神经胶质细胞增殖与CRM1水平或CR1功能的异常相关(Shen(沈)2008)。
很多病毒的完整的成熟也要求主要由CRM1介导的完整的核输出。生命周期里牵涉到核输出和/或CRM1自身的病毒包括人类免疫缺陷病毒(HIV)、腺病毒、猴I型逆转录病毒、波尔纳病(Borna disease)病毒、流感病毒(常规株以及H1N1和禽H5N1株)、乙型肝炎病毒(HBV)和丙型肝炎病毒(HCV)、人乳头瘤病毒(HPV)、呼吸道合胞体病毒(RSV)、Dungee、严重急性呼吸器官综合征冠状病毒、黄热病毒、西尼罗病毒、单纯疱疹病毒(HSV)、巨细胞病毒(CMV)以及默克尔(Merkel)细胞多瘤病毒(MCV)。(Bhuvanakantham(巴万科萨姆)2010,Cohen(科赫)2010,Whittaker(维特克尔)1998)。预期的是,依赖完整核输出的额外病毒感染在不久的将来将是无包被的。
穿过核仁并穿梭于细胞核与细胞质之间的HIV-1 Rev蛋白促使未剪接的和单剪接的含有Rev应答元件(RRE)RNA的HIV转录物的通过CRM1输出通路的输出。使用CRM1抑制剂如LepB或PKF050-638实现的Rev介导的RNA转运的抑制可以阻止HIV-1的转录过程,抑制新的HIV-1病毒粒子的产生,并且从而降低HIV-1的水平(Pollard(波拉德)1998,Daelemans(戴乐曼茨)2002)。
登革热病毒(DENV)为常见的节肢动物传播的病毒性疾病登革热(DF)及其更严重的和潜在致命的登革出血热(DHF)的病原体。DHF似乎是由对DENV的过旺的炎症应答导致的。NS5是DENV的最大的也是最保守的蛋白。CRM1调控NS5从细胞核到细胞质的转运,其中NS5的大部分功能是被介导的。抑制CRM1介导的NS5的输出可导致产病毒动力学改变,并且减少炎性趋化因子白细胞介素-8(IL-8)的诱导,为治疗DENV以及其他医学上重要的黄病毒包括丙型肝炎病毒引发的疾病提供了一个新的途径(Rawlinson(罗林森)2009)。
其他使用CRM1输出细胞核的病毒编码的RNA结合蛋白包括HSV I型间层蛋白(VP13/14或hUL47)、人CMV蛋白pp65、SARS冠状病毒ORF3b蛋白、以及RSV基质(M)蛋白(Williams(威廉姆斯)2008,Sanchez(桑切斯)2007,Freundt(弗兰德)2009,Ghildyal(吉友戴尔)2009)。
有趣的是,很多这些病毒与特定类型的人类癌症相关,这些癌症包括归因于慢性HBV或HCV感染的肝细胞癌(HCC)、归因于HPV的宫颈癌以及与MCV相关的默克尔细胞癌。因此CRM1抑制因子对病毒感染过程及这些病毒引起的肿瘤性转化过程均有益。
CRM1控制核定位,并且从而控制多种DNA代谢酶的活性,这些酶包括组蛋白脱乙酰基酶(HDAC)、组蛋白乙酰转移酶(HAT)和组蛋白甲基转移酶(HMT)。已被证明且公认的是,不可逆的CRM1抑制剂对心肌细胞肥大的抑制与HDAC5的核阻留(和激活)相关,HDAC5为一种已知抑制肥大遗传程序的酶(Monovich(莫纳维奇)等人,2009)。因此,CRM1抑制可对肥大综合征,包括特定形式的充血性心力衰竭和肥厚性心肌病,有有益效果。
CRM1也与其他紊乱相关。一种以视网膜神经节细胞的退化和视觉丧失为特征的遗传疾病-莱伯病(Leber’s disorder)与CRM1开关的无效相关(Gupta(古普塔)N 2008)。还有证据表明,神经退行性紊乱与异常的核转运相关。
鉴于上文,调节核转运的化合物的发现是令人希望的。
发明概述
本发明涉及作为核转运调节剂有用的化合物及其药学上可接受的盐;包含本发明的化合物或其药学上可接受的盐的药学上可接受的组合物;以及使用所述化合物、盐和组合物治疗各种紊乱的方法。
本发明的化合物具有通式I:
其中每个变量是如在此定义和描述的。
本发明的化合物及其药学上可接受的盐和组合物对于治疗多种与不当的核转运触发的异常细胞应答相关的疾病、紊乱或病症是有用的。因此,本发明的一个实施例是本发明的化合物或其药学上可接受的盐用于治疗多种与不当的核转运触发的异常细胞应答相关的疾病、紊乱或病症的用途。本发明的另一个实施例是一种用于治疗对其有需要的受试者的多种与CRM1活性相关的疾病、紊乱或病症的方法,该方法包括向该对其有需要的受试者给予治疗有效量的本发明的化合物或其药学上可接受的盐或组合物。此类疾病、紊乱或病症包括在此描述的那些。
本发明的化合物及其药学上可接受的盐和组合物在生产用于治疗多种与不当的核转运触发的异常细胞应答相关的疾病、紊乱或病症的药剂中也是有用的。此类疾病、紊乱或病症包括在此描述的那些。
由本发明提供的化合物对于生物学与病理学现象中的核转运调节的研究、由例如激酶介导的细胞内信号转导通路的研究、以及新的核转运调节剂的比较评价也是有用的。
附图简述
上述内容根据本发明的示例性实施例的以下更具体的描述应是显而易见的。
图1是蛋白质印迹的图像,并且显示用化合物124处理HT1080细胞导致CRM1的剂量依赖性降解。
图2是作为研究天数的函数的描述于实例3中的CAIA类风湿性关节炎小鼠模型的所有爪子的平均临床评分曲线图,并且示出了仅用运载体和化合物124处理对该研究中的小鼠的所有爪子的平均临床评分的影响。
图3A是作为时间的函数的平均肿瘤体积曲线图,并且示出了用化合物124或化合物149处理对携带MDA-MB-468异种移植物的小鼠的平均肿瘤体积的影响。
图3B是作为时间的函数的平均肿瘤体积曲线图,并且示出了用化合物124(5mg/kg或15mg/kg)或环磷酰胺处理对携带Z-138异种移植物的小鼠的平均肿瘤体积的影响。
图3C是作为时间的函数的平均肿瘤体积曲线图,并且示出了用化合物124(5mg/kg或15mg/kg)或阿霉素处理对携带Hep3B异种移植物的小鼠的平均肿瘤体积的影响。
图3D是作为时间的函数的平均肿瘤体积曲线图,并且示出了用化合物124(5mg/kg或15mg/kg)或5-FU处理对携带COLO 205异种移植物的小鼠的平均肿瘤体积的影响。
图3E是作为时间的函数的平均肿瘤体积曲线图,并且示出了用化合物124(5mg/kg或15mg/kg)或阿霉素处理对携带MOLT4异种移植物的小鼠的平均肿瘤体积的影响。
图4是U87MG和U251MG对照球状体和用1μM化合物124处理的U87MG和U251MG球状体的图像,并且示出了用化合物124处理对两种成胶质细胞瘤细胞系的影响。
发明详述
本发明的化合物
本发明的第一实施例是一种具有结构式I的化合物:
或其一种药学上可接受的盐,其中:
X是-C(H)-或-N-;
每个R1独立地选自卤素;卤代烷基;-(CH2)1-4R°;-(CH2)0-4OR°;-O-(CH2)0-4C(O)OR°;-(CH2)0-4CH(OR°)2;-(CH2)0-4SR°;可以被R°取代的-(CH2)0-4-碳环基;可以被R°取代的-(CH2)0-4-芳基;可以被R°取代的-(CH2)0-4-杂环基;可以被R°取代的-(CH2)0-4-杂芳基;可以被R°取代的-CH=CH-碳环基;可以被R°取代的-CH=CH-芳基;可以被R°取代的-CH=CH-杂环基;可以被R°取代的-CH=CH-杂芳基;-NO2;-CN;-N3;-(CH2)0-4N(R°)2;-(CH2)0-4N(R°)C(O)R°;-(CH2)0-4N(R°)C(S)R°;-(CH2)0-4N(R°)C(O)NR°2;-(CH2)0-4N(R°)C(S)NR°2;-(CH2)0-4N(R°)C(O)OR°;-(CH2)0-4N(R°)N(R°)C(O)R°;-(CH2)0-4N(R°)N(R°)C(O)NR°2;-(CH2)0-4N(R°)N(R°)C(O)OR°;-(CH2)0-4C(O)R°;-(CH2)0-4C(S)R°;-(CH2)0-4C(O)OR°;-(CH2)0-4C(O)SR°;-(CH2)0-4OC(O)R°;-(CH2)0-4OC(O)(CH2)0-4SR°,-(CH2)0-4SC(S)SR°;-(CH2)0-4SC(O)R°;-(CH2)0-4C(O)NR°2;-(CH2)0-4C(S)NR°2;-(CH2)0-4C(S)SR°;-(CH2)0-4OC(O)NR°2;-(CH2)0-4C(O)N(OR°)R°;-(CH2)0-4C(O)C(O)R°;-(CH2)0-4C(O)CH2C(O)R°;-(CH2)0-4C(NOR°)R°;-(CH2)0- 4SSR°;-(CH2)0-4S(O)2R°;-(CH2)0-4S(O)2OR°;-(CH2)0-4OS(O)2R°;-(CH2)0-4S(O)2NR°2;-(CH2)0-4S(O)R°;-(CH2)0-4N(R°)S(O)2NR°2;-(CH2)0-4N(R°)S(O)2R°;-(CH2)0-4N(OR°)R°;-(CH2)0-4C(NH)NR°2;-(CH2)0-4P(O)2R°;-(CH2)0-4P(O)R°2;-(CH2)0-4OP(O)R°2;-(CH2)0-4OP(O)(OR°)2;-(CH2)0-4ON(R°)2;以及-(CH2)0-4C(O)O-N(R°)2,其中:
每个R°独立地是氢、C1-6脂肪族、-CH2-碳环基、-CH2-芳基、-CH2-杂环基、-CH2-杂芳基、-O(CH2)0-1-碳环基、-O(CH2)0-1-芳基、-O(CH2)0-1-杂环基、-O(CH2)0-1-杂芳基、碳环基、芳基、杂环基或杂芳基,或者两个独立发生的R°连同它们的一个或多个插入原子一起形成一个3-12元碳环基、芳基、杂环基或杂芳基;并且
每个R°以及由两个独立发生的R°连同它们的一个或多个插入原子一起形成的每个环任选地并且独立地被一个或多个选自下组的取代基取代,该组由以下各项组成:卤素、CN、OH、未取代的C1-C3烷基、卤代-C1-C3烷基、-NH2、-NO2、-NH(未取代的C1-C3烷基)、-N(未取代的C1-C3烷基)2、-O-C1-C3烷基、-C(O)OH、-C(O)O-(未取代的C1-C3烷基)、-C(O)-(未取代的C1-C3烷基)、-O-(未取代的C1-C3烷基)以及-S-(未取代的C1-C3烷基);
R2选自任选取代的杂芳基和任选取代的芳基;
Ra和Rb之一是氢,并且另一个选自-C(O)-N(R5)(R6)、-CN、-C(O)-O-R3、-C(S)-O-R3、-C(S)-N(R5)(R6)、-C(O)-N(R7)-N(R5)(R6)、-C(S)-N(R7)-N(R5)(R6)、-C(O)-N(R7)-N(R7)-C(O)-R4、-C(S)-N(R7)-N(R7)-C(O)-R4、-C(O)-N(R7)-N(R7)-C(S)-R4、-C(S)-N(R7)-N(R7)-C(S)-R4、-C(O)-N(R7)-N(R7)-S(O)1-2-R4以及-C(S)-N(R7)-N(R7)-S(O)1-2-R4,其中:
R3选自氢、C1-C4烷基、C2-C4烯基、C2-C4炔基、碳环基、芳基、杂环基以及杂芳基;
R4选自-N(H)(C3-C6环烷基)、-N(C1-C4烷基)(C3-C6环烷基)、-C1-C6烷基、-(C0-C4亚烷基)-碳环基、-(C0-C4亚烷基)-杂环基、-(C0-C4亚烷基)-芳基以及-(C0-C4亚烷基)-杂芳基;
R5和R6各自独立地选自氢、C1-C4烷基、C2-C4烯基、C2-C4炔基、碳环基、芳基、杂环基以及杂芳基;或
R5和R6连同它们共同附接的氮原子一起形成一个杂环基或杂芳基;
每个R7独立地是氢或C1-C4烷基;并且
n是0、1、2、3、4或5;其中:
除非另外指定,每个烷基、烯基、炔基、亚烷基、碳环基、芳基、环烷基、杂环基以及杂芳基任选地并且独立地被取代。
在第一实施例的第一方面中,Ra和Rb之一是氢,并且另一个选自-C(O)-O-R3、-C(O)-N(R5)(R6)、-C(O)-N(R7)-N(R5)(R6)、-C(O)-N(R7)-N(R7)-C(O)-R4以及-C(O)-N(R7)-N(R7)-S(O)1-2-R4。剩余的变量的值是如第一实施例中所描述的。
在第一实施例的第二方面中,Ra和Rb之一是氢,并且另一个选自-C(O)-OH、-C(O)-NH2、-C(O)-N(R7)-N(R5)(R6)、-C(O)-N(R7)-N(R7)-C(O)-R4以及-C(O)-N(R7)-N(R7)-S(O)1-2-R4。剩余的变量的值是如第一实施例或其第一方面中所描述的。
在第一实施例的第三方面中,Ra和Rb之一是氢,并且另一个是-C(O)-OH;或-C(O)-NH2;或-C(O)-NH-NH(R6),并且R6是任选取代的杂芳基;或-C(O)-NH-NH-C(O)-R4或-C(O)-NH-NH-S(O)1-2-R4,并且R4选自任选取代的-N(H)(C3-C6环烷基)、-N(C1-C4烷基)(C3-C6环烷基)、-C1-C6烷基、-(C0-C4亚烷基)-杂环基以及-(C0-C4亚烷基)-杂芳基。剩余的变量的值是如第一实施例或其第一或第二方面中所描述的。
在第一实施例的第四方面中,Ra和Rb之一是氢并且另一个是-C(O)NH2。剩余的变量的值是如第一实施例或其第一至第三方面中所描述的。
在第一实施例的第五方面中,Ra是氢。剩余的变量的值是如第一实施例或其第一至第四方面中所描述的。
在第一实施例的第六方面中,R2是任选取代的C5-C15杂芳基。剩余的变量的值是如第一实施例或其第一至第五方面中所描述的。
在第一实施例的第七方面中,R2是具有1、2或3个独立地选自下组的杂原子的任选取代的5-6元杂芳基,该组由以下各项组成:氮、氧和硫。剩余的变量的值是如第一实施例或其第一至第六方面中所描述的。
在第一实施例的第八方面中,R2是具有1、2或3个独立地选自下组的杂原子的任选取代的5元杂芳基,该组由以下各项组成:氮、氧和硫。剩余的变量的值是如第一实施例或其第一至第七方面中所描述的。
在第一实施例的第九方面中,R2是任选取代的吡咯基、呋喃基、苯硫基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、三唑基、噻二唑基或噁二唑基。剩余的变量的值是如第一实施例或其第一至第八方面中所描述的。
在第一实施例的第十方面中,R2是具有1、2或3个独立地选自下组的杂原子的任选取代的6元杂芳基,该组由以下各项组成:氮、氧和硫。剩余的变量的值是如第一实施例或其第一至第九方面中所描述的。
在第一实施例的第十一方面中,R2是任选地取代的吡啶基、嘧啶基、吡嗪基、哒嗪基或三嗪基。剩余的变量的值是如第一实施例或其第一至第十方面中所描述的。
在第一实施例的第十二方面中,R2任选地被卤素、C1-C4烷基、C1-C4烷氧基、C1-C4硫代烷氧基、羟基、氨基、C1-C4烷基氨基、C1-C4二烷基氨基、巯基或氰基取代。剩余的变量的值是如第一实施例或其第一至第十一方面中所描述的。
在第一实施例的第十三方面中,R2任选被卤素、C1-C4烷基或C1-C4烷氧基取代。剩余的变量的值是如第一实施例或其第一至第十二方面中所描述的。
在第一实施例的第十四方面中,X是-C(H)-。剩余的变量的值是如第一实施例或其第一至第十三方面中所描述的。
在第一实施例的第十五方面中,n是0、1或2。剩余的变量的值是如第一实施例或其第一至第十四方面中所描述的。
在第一实施例的第十六方面中,每个R1独立地选自-CF3、-CN、卤素、-OH、C1-C3烷基、C3-C6环烷基、C3-C12杂环烷基、卤代-C1-C3烷基、-NH2、-NO2、-NH(C1-C3烷基)、-N(C1-C3烷基)(C1-C3烷基)、-C(O)OH、-C(O)O-(C1-C6烷基)、-C(O)-(C1-C3烷基)、-O-(C1-C3烷基)、-O-(C1-C3卤代烷基)以及-S-(C1-C3烷基),或者不存在。剩余的变量的值是如第一实施例或其第一至第十五方面中所描述的。
在第一实施例的第十七方面中,每个R1独立地选自卤素、-C1-C4烷基、-C1-C4卤代烷基以及-O-C1-C4烷基,或者不存在。剩余的变量的值是如第一实施例或其第一至第十六方面中所描述的。
在第一实施例的第十八方面中,Ra和Rb之一是氢,并且另一个是-C(O)OH;或-C(O)NH2;或-C(O)-NH-NH(R6),并且R6是任选取代的C5-C6杂芳基;或-C(O)-NH-NH-C(O)-R4或-C(O)-NH-NH-S(O)1-2-R4,并且R4选自任选取代的-N(H)(C3-C6环烷基)、-N(C1-C4烷基)(C3-C6环烷基)、-C1-C6烷基、-(C0-C4亚烷基)-(C3-C7)杂环基以及-(C0-C4亚烷基)-(C5-C6)杂芳基。剩余的变量的值是如第一实施例或其第一至第十七方面中所描述的。
在第一实施例的第十九方面中,每个R7都是氢。剩余的变量的值是如第一实施例或其第一至第十八方面中所描述的。
在第一实施例的第二十方面中,R5选自氢和C1-C4烷基;并且R6选自C1-C4烷基、碳环基、芳基、杂环基以及杂芳基。剩余的变量的值是如第一实施例或其第一至第十九方面中所描述的。
在第一实施例的第二十一方面中,R5和R6连同它们共同附接的氮原子一起形成一个杂环基或杂芳基。剩余的变量的值是如第一实施例或其第一至第二十方面中所描述的。
在第一实施例的第二十二方面中,R3选自任选取代的C1-C4烷基、碳环基、芳基、杂环基以及杂芳基。剩余的变量的值是如第一实施例或其第一至第二十一方面中所描述的。
在第一实施例的第二十三方面中,R4选自-N(R8)(C3-C6环烷基)、-C3-C6烷基、-(C0-C1亚烷基)-杂环基以及-(C0-C1亚烷基)-杂芳基,其中R8是氢或-C1-C4烷基;R4的任何烷基或亚烷基部分任选地并且独立地被一个或多个选自下组的取代基取代,该组由以下各项组成:氧和-N(R9)2,其中每个R9独立地选自氢和C1-C4烷基;R4的任何杂环基部分在环中包括至少一个氮原子,并且任选地被一个或多个选自下组的取代基取代,该组由以下各项组成:C1-C4烷基和氧;并且R4的任何杂芳基部分在环中包括至少一个氮原子并且任选地被一个或多个C1-C4烷基取代。剩余的变量的值是如第一实施例或其第一至第二十二方面中所描述的。
在第一实施例的第二十四方面中,R2任选地被1、2或3个独立地选自以下各项的取代基取代:卤素、C1-C4烷基、卤代-C1-C4烷基、C1-C4烷氧基、C1-C4硫代烷氧基、羟基、氨基、C1-C4烷基氨基、C1-C4二烷基氨基、巯基、氰基、C6芳基以及C5-C6杂芳基。这些变量的值是如第一实施例或其第一至第二十三方面中所描述的。
在第一实施例的第二十五方面中,R2任选地被1、2或3个独立地选自以下各项的取代基取代:氟、氯、C1-C4烷基、-CF3、氨基以及氰基。这些变量的值是如第一实施例或其第一至第二十四方面中所描述的。
本发明的第二实施例是一种具有结构式II的化合物:
或其一种药学上可接受的盐,其中:
R1a和R1b各自独立地选自卤素;卤代烷基;-(CH2)1-4R°;-(CH2)0-4OR°;-O-(CH2)0-4C(O)OR°;-(CH2)0-4CH(OR°)2;-(CH2)0-4SR°;可以被R°取代的-(CH2)0-4-碳环基;可以被R°取代的-(CH2)0-4-芳基;可以被R°取代的-(CH2)0-4-杂环基;可以被R°取代的-(CH2)0-4-杂芳基;可以被R°取代的-CH=CH-碳环基;可以被R°取代的-CH=CH-芳基;可以被R°取代的-CH=CH-杂环基;可以被R°取代的-CH=CH-杂芳基;-NO2;-CN;-N3;-(CH2)0-4N(R°)2;-(CH2)0-4N(R°)C(O)R°;-(CH2)0-4N(R°)C(S)R°;-(CH2)0-4N(R°)C(O)NR°2;-(CH2)0-4N(R°)C(S)NR°2;-(CH2)0-4N(R°)C(O)OR°;-(CH2)0-4N(R°)N(R°)C(O)R°;-(CH2)0-4N(R°)N(R°)C(O)NR°2;-(CH2)0-4N(R°)N(R°)C(O)OR°;-(CH2)0-4C(O)R°;-(CH2)0-4C(S)R°;-(CH2)0-4C(O)OR°;-(CH2)0-4C(O)SR°;-(CH2)0-4OC(O)R°;-(CH2)0-4OC(O)(CH2)0-4SR°,-(CH2)0-4SC(S)SR°;-(CH2)0-4SC(O)R°;-(CH2)0-4C(O)NR°2;-(CH2)0-4C(S)NR°2;-(CH2)0-4C(S)SR°;-(CH2)0-4OC(O)NR°2;-(CH2)0-4C(O)N(OR°)R°;-(CH2)0-4C(O)C(O)R°;-(CH2)0-4C(O)CH2C(O)R°;-(CH2)0-4C(NOR°)R°;-(CH2)0- 4SSR°;-(CH2)0-4S(O)2R°;-(CH2)0-4S(O)2OR°;-(CH2)0-4OS(O)2R°;-(CH2)0-4S(O)2NR°2;-(CH2)0-4S(O)R°;-(CH2)0-4N(R°)S(O)2NR°2;-(CH2)0-4N(R°)S(O)2R°;-(CH2)0-4N(OR°)R°;-(CH2)0-4C(NH)NR°2;-(CH2)0-4P(O)2R°;-(CH2)0-4P(O)R°2;-(CH2)0-4OP(O)R°2;-(CH2)0-4OP(O)(OR°)2;-(CH2)0-4ON(R°)2;以及-(CH2)0-4C(O)O-N(R°)2,其中:
每个R°独立地是氢、C1-6脂肪族、-CH2-碳环基、-CH2-芳基、-CH2-杂环基、-CH2-杂芳基、-O(CH2)0-1-碳环基、-O(CH2)0-1-芳基、-O(CH2)0-1-杂环基、-O(CH2)0-1-杂芳基、碳环基、芳基、杂环基或杂芳基,或者两个独立发生的R°连同它们的一个或多个插入原子一起形成一个3-12元碳环基、芳基、杂环基或杂芳基;并且
每个R°以及由两个独立发生的R°连同它们的一个或多个插入原子一起形成的每个环任选地并且独立地被一个或多个选自下组的取代基取代,该组由以下各项组成:卤素、CN、OH、未取代的C1-C3烷基、卤代-C1-C3烷基、-NH2、-NO2、-NH(未取代的C1-C3烷基)、-N(未取代的C1-C3烷基)2、-O-C1-C3烷基、-C(O)OH、-C(O)O-(未取代的C1-C3烷基)、-C(O)-(未取代的C1-C3烷基)、-O-(未取代的C1-C3烷基)以及-S-(未取代的C1-C3烷基);并且
m是0或1。
剩余的变量的值是如第一实施例或其任何方面中所描述的。
在第二实施例的第一方面中,m是1。剩余的变量的值是如第一实施例或其任何方面或者第二实施例中所描述的。
在第二实施例的第二方面中,R1a是卤素或-C1-C4卤代烷基。剩余的变量的值是如第一实施例或其任何方面或者第二实施例或其第一方面中所描述的。
在第二实施例的第三方面中,R1a是-C1-C4卤代烷基。剩余的变量的值是如第一实施例或其任何方面或者第二实施例或其第一或第二方面中所描述的。
在第二实施例的第四方面中,R1b是-C1-C4卤代烷基或-O-C1-C4烷基。剩余的变量的值是如第一实施例或其任何方面或者第二实施例或其第一至第三方面中所描述的。
在第二实施例的第五方面中,R1b是-C1-C4卤代烷基。剩余的变量的值是如第一实施例或其任何方面或者第二实施例或其第一至第四方面中所描述的。
在第二实施例的第六方面中,R1a是-CF3并且R1b是-CF3。剩余的变量的值是如第一实施例或其任何方面或者第二实施例或其第一至第五方面中所描述的。
本发明的第三实施例是一种具有结构式III的化合物:
或其一种药学上可接受的盐,其中:
Rb选自-C(O)OH、-C(O)NH2、-C(O)-N(R7)-N(R5)(R6)、-C(O)-N(R7)-N(R7)-C(O)-R4以及-C(O)-N(R7)-N(R7)-S(O)1-2-R4;其中:
R4选自-N(H)(C3-C6环烷基)、-N(C1-C4烷基)(C3-C6环烷基)、-C1-C6烷基、-(C0-C4亚烷基)-碳环基、-(C0-C4亚烷基)-杂环基、-(C0-C4亚烷基)-芳基以及-(C0-C4亚烷基)-杂芳基;
R5和R6各自独立地选自氢、C1-C4烷基、C2-C4烯基、C2-C4炔基、碳环基、芳基、杂环基以及杂芳基;或
R5和R6连同它们共同附接的氮原子一起形成一个杂环基或杂芳基;并且
每个R7独立地是氢或C1-C4烷基;并且
R2是任选取代的C5-C15杂芳基,其中:
除非另外指定,每个烷基、烯基、炔基、亚烷基、碳环基、芳基、环烷基、杂环基以及杂芳基任选地并且独立地被取代。
结构式III中的变量的替代值是如第一实施例或其任何方面中所描述的。
在第三实施例的第一方面中,Rb是-C(O)OH;或-C(O)NH2;或-C(O)-NH-NH(R6),并且R6是任选取代的杂芳基;或-C(O)-NH-NH-C(O)-R4或-C(O)-NH-NH-S(O)1-2-R4,并且R4选自任选取代的-N(H)(C3-C6环烷基)、-N(C1-C4烷基)(C3-C6环烷基)、-C1-C6烷基、-(C0-C4亚烷基)-杂环基以及-(C0-C4亚烷基)-杂芳基。剩余的变量的值是如第一实施例或其任何方面或者第三实施例中所描述的。
在第三实施例的第二方面中,Rb是-C(O)NH2。剩余的变量的值是如第一实施例或其任何方面或者第三实施例或其第一方面中所描述的。
在第三实施例的第三方面中,R2是具有1、2或3个独立地选自下组的杂原子的任选取代的5-6元杂芳基,该组由以下各项组成:氮、氧和硫。剩余的变量的值是如第一实施例或其任何方面或者第三实施例或其第一或第二方面中所描述的。
在第三实施例的第四方面中,R2是具有1、2或3个独立地选自下组的杂原子的任选取代的5元杂芳基,该组由以下各项组成:氮、氧和硫。剩余的变量的值是如第一实施例或其任何方面或者第三实施例或其第一至第三方面中所描述的。
在第三实施例的第五方面中,R2是任选取代的吡咯基、呋喃基、苯硫基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、三唑基、噻二唑基或噁二唑基。剩余的变量的值是如第一实施例或其任何方面或者第三实施例或其第一至第四方面中所描述的。
在第三实施例的第六方面中,R2是具有1、2或3个独立地选自下组的杂原子的任选取代的6元杂芳基,该组由以下各项组成:氮、氧和硫。剩余的变量的值是如第一实施例或其任何方面或者第三实施例或其第一至第五方面中所描述的。
在第三实施例的第七方面中,R2是任选地取代的吡啶基、嘧啶基、吡嗪基、哒嗪基或三嗪基。剩余的变量的值是如第一实施例或其任何方面或者第三实施例或其第一至第六方面中所描述的。
在第三实施例的第八方面中,R2任选地被卤素、C1-C4烷基、C1-C4烷氧基、C1-C4硫代烷氧基、羟基、氨基、C1-C4烷基氨基、C1-C4二烷基氨基、巯基或氰基取代。剩余的变量的值是如第一实施例或其任何方面或者第三实施例或其第一至第七方面中所描述的。
在第三实施例的第九方面中,R2任选被卤素、C1-C4烷基或C1-C4烷氧基取代。剩余的变量的值是如第一实施例或其任何方面或者第三实施例或其第一至第八方面中所描述的。
在第三实施例的第十方面中,Rb是-C(O)OH;或-C(O)NH2;或-C(O)-NH-NH(R6),并且R6是任选取代的C5-C6杂芳基;或-C(O)-NH-NH-C(O)-R4或-C(O)-NH-NH-S(O)1-2-R4,并且R4选自任选取代的-N(H)(C3-C6环烷基)、-N(C1-C4烷基)(C3-C6环烷基)、-C1-C6烷基、-(C0-C4亚烷基)-(C3-C7)杂环基以及-(C0-C4亚烷基)-(C5-C6)杂芳基。剩余的变量的值是如第一实施例或其任何方面或者第三实施例或其第一至第九方面中所描述的。
在第三实施例的第十一方面中,R2任选地被1、2或3个独立地选自以下各项的取代基取代:卤素、C1-C4烷基、卤代-C1-C4烷基、C1-C4烷氧基、C1-C4硫代烷氧基、羟基、氨基、C1-C4烷基氨基、C1-C4二烷基氨基、巯基、氰基、C6芳基以及C5-C6杂芳基。这些变量的值是如第一实施例或其任何方面或者第三实施例或其第一至第十方面中所描述的。
在第三实施例的第十二方面中,R2任选地被1、2或3个独立地选自以下各项的取代基取代:氟、氯、C1-C4烷基、-CF3、氨基以及氰基。这些变量的值是如第一实施例或其任何方面或者第三实施例或其第一至第十一方面中所描述的。
本发明的第四实施例是一种由结构式IV表示的化合物:
或其药学上可接受的盐,其中R2选自任选取代的杂芳基和任选取代的芳基。
在第四实施例的第一方面中,R2是任选取代的C5-C15杂芳基。
在第四实施例的第二方面中,R2是具有1、2或3个独立地选自下组的杂原子的任选取代的5-6元杂芳基,该组由以下各项组成:氮、氧和硫。
在第四实施例的第三方面中,R2是具有1、2或3个独立地选自下组的杂原子的任选取代的5元杂芳基,该组由以下各项组成:氮、氧和硫。
在第四实施例的第四方面中,R2是任选取代的吡咯基、呋喃基、苯硫基、吡唑基、咪唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、三唑基、噻二唑基或噁二唑基。
在第四实施例的第五方面中,R2是具有1、2或3个独立地选自下组的杂原子的任选取代的6元杂芳基,该组由以下各项组成:氮、氧和硫。
在第四实施例的第六方面中,R2是任选地取代的吡啶基、嘧啶基、吡嗪基、哒嗪基或三嗪基。
在第四实施例的第七方面中,R2任选地被1、2或3个独立地选自以下各项的取代基取代:卤素、C1-C4烷基、卤代-C1-C4烷基、C1-C4烷氧基、C1-C4硫代烷氧基、羟基、氨基、C1-C4烷基氨基、C1-C4二烷基氨基、巯基、氰基、C6芳基以及C5-C6杂芳基。R2的值和替代值是如第一至第三实施例或其任何方面或者第四实施例或其第一至第六方面中所描述的。
在第四实施例的第八方面中,R2任选地被1、2或3个独立地选自以下各项的取代基取代:氟、氯、C1-C4烷基、-CF3、氨基以及氰基。R2的值和替代值是如第一至第三实施例或其任何方面或者第四实施例或其第一至第七方面中所描述的。
示例性化合物列出于表A和表1中。
表A.
化合物和定义
本发明的化合物包括在上文中总体上描述的那些,并且通过在此披露的类别、子类别以及种类进一步描述。如如在此使用的,除非另外指明,应当使用下面的定义。出于本发明的目的,根据元素周期表,CAS版本,化学和物理手册(Handbook of Chemistry andPhysics),第75版对这些化学元素进行鉴定。此外,有机化学的一般原则描述于“OrganicChemistry(有机化学)”,Thomas Sorrell(托马斯·索雷尔),University Science Books(大学科学书籍出版社),索萨利托:1999,以及“March’s Advanced Organic Chemistry(马奇的高等有机化学)”,第5版,Smith(史密斯),M.B.与March(玛奇),J.编,John Wiley&Sons(约翰威利父子出版公司),纽约:2001中,将它们的全部内容通过引用结合在此。
在本说明书之内除非另外说明,在本说明书中使用的命名法总体上遵循在Nomenclature of Organic Chemistry(有机化学命名法),A、B、C、D、E、F、和H章节,Pergamon Press(帕加马出版社),牛津,1979中说明的实例和规则,对于它的示例性的化学结构命名及关于化学结构命名的规则,将它通过引用结合在此。任选地,可以使用一种化学命名程序(ACD/ChemSketch,5.09版/2001年9月,Advanced Chemistry Development,Inc.(高等化学发展有限公司),多伦多,加拿大)生成化合物的名称。
本发明的化合物可以具有不对称中心、手性轴以及手性平面(例如,如描述于E.L.Eliel(E.L.伊莱尔)与S.H.Wilen(S.H.威伦),Stereo-chemistry of CarbonCompounds(碳化合物的立体化学),John Wiley&Sons(约翰威利父子出版公司),纽约,1994,1119-1190页),并且作为外消旋体、外消旋混合物以及单个的非对映异构体或者对映异构体存在,其中全部可能的异构体及其混合物(包括旋光异构体)被包括在本发明中。
如在此使用的术语“脂肪族的”或“脂肪族基团”指代一种单价烃基,该烃基是直链(即非支链)、支链、或环状(包括稠合的、桥联的、以及螺稠合的多环的)。一种脂肪族基团可以是饱和的或包含一个或多个不饱和但不是芳香族的单元。除非另外说明,脂肪族基团包含1-12个碳原子。然而,在某些实施例中,一个脂肪族基团包含1-6或2-8碳原子。在某些实施例中,脂肪族基团包含1-4个碳原子,并且在另外的其他实施例中,脂肪族基团包含1-3个碳原子。适合的脂肪族基团包括但不限于直链的或支链的烷基、烯基和炔基及其杂化物,如(环烷基)烷基、(环烯基)烷基或(环烷基)烯基。
如在此使用的,除非另外指明,术语“烷基”意指直链的或支链的饱和单价烃基,典型地是C1-C12,优选C1-C6。因此,“C1-C6烷基”意指具有从一至六个碳原子(例如,1、2、3、4、5或6)的直链的或支链的饱和单价烃基。烷基的实例包括但不限于甲基、乙基、丙基、异丙基以及叔丁基。
如在此使用的,术语“烷氧基”意指“烷基-O-”基团,其中烷基是如以上定义的。烷氧基的实例包括甲氧基和乙氧基。
如在此使用的,术语“烯基”意指具有从2至12个碳原子并且具有至少一个碳-碳双键的饱和直链或支链非环烃。烯基可以任选地被一个或多个取代基取代。术语“烯基”囊括具有处于“顺式”与“反式”的或者可替代地处于“E”与“Z”构象的碳碳双键的基团。如果一个烯基包含多于一个碳碳双键,每个碳碳双键独立地是一种顺式或反式双键,或其一种混合物。
如在此使用的,术语“炔基”意指具有从2至12个碳原子并且具有至少一个碳-碳三键的饱和直链或支链非环烃。炔基可以任选地被一个或多个取代基取代。
如在此使用的,术语“亚烷基”是指具有从2至12个碳原子以及两个至化合物的其余部分的附接点的烷基。亚烷基的非限制性实例包括亚甲基(-CH2-)、亚乙基(-CH2CH2-)、亚正丙基(-CH2CH2CH2-)、亚异丙基(-CH2CH(CH3)-)等。亚烷基可以任选地被一个或多个取代基取代。
如在此使用的,术语“氨基”是指具有化学式-N(R)2的化学部分,其中每个R独立地选自氢和C1-C4烷基。
在此单独或者组合使用的术语“芳基”指的是一种碳环芳香族系统,该系统包含一个或多个环,该环能以一种悬着的方式附接在一起或者可以是稠合的。在具体实施例中,芳基是一个、两个或者三个环。在一个方面中,芳基具有六至十二个环原子。术语“芳基”包括芳香族基团,如苯基、萘基、四氢萘基、茚满基、联苯基、菲基、蒽基以及苊基(acenaphthyl)。芳基可以如在此定义和描述的任选地被取代。
单独使用的或作为一个更大部分的部分的术语“脂环族的”、“碳环基”、“碳环”和“碳环型的”是指一种饱和的或部分不饱和的环状脂肪族单环或双环的环系统,如在此说明的具有从3至12元,其中该脂肪族环系统可以如在此定义和描述的任选地被取代。脂环族基团包括但不限于环烷基(例如环丙基、环丁基、环戊基、环己基和环庚基)以及环烯基(例如环戊烯基、环己烯基、环庚烯基、环辛烯基和环辛二烯基)。术语“脂环族的”、“碳环基”、“碳环”、和“碳环型的”还包括脂肪族的环,这些环稠合至一个或多个芳香族的或非芳香族的环,如十氨萘基、四氢萘基、十氢化萘、或二环[2.2.2]辛烷。
如在此使用的,术语“环烷基”意指饱和环烃,即所有环原子都是碳的化合物。环烷基的实例包括但不限于环丙基、环丁基、环戊基、环己基以及环庚基。在一些实施例中,环烷基可以任选地被一个或多个选自以下各项的取代基取代:-OH、-SH、卤素、氨基、硝基、氰基、C1-C12烷基、C2-C12烯基或C2-C12炔基、C1-C12烷氧基、C1-C12卤代烷基以及C1-C12卤代烷氧基。
如在此使用的术语“卤代(halo)”或“卤素(halogen)”意指处于放射性的和非放射性的形式的卤素,并且包括例如但不限于氟、氯、溴、碘等。在一个优选实施例中,卤素选自下组,该组由以下各项组成:氟、氯和溴。
如在此使用的,术语“卤代烷基”包括被一个或多个F、Cl、Br或I取代的烷基,其中烷基是如以上定义的。
如在此使用的,术语“杂芳基”是指包含一个或多个杂原子(例如,一个或多个独立地选自O、S和N的杂原子)的芳香族基团。杂芳基可以是单环或多环的,例如稠合至一个或多个碳环芳香族基团或其他单环杂芳基的单环杂芳基。本发明的杂芳基还可以包括被一个或多个氧取代的环系统。在一个方面中,杂芳基具有五至十五个环原子,并且优选5或6个环原子。杂芳基的实例包括但不限于吡啶基、哒嗪基、咪唑基、嘧啶基、吡唑基、三唑基、吡嗪基、喹啉基、异喹啉基、四唑基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、喹啉基、异喹啉基、吲哚基、苯并咪唑基、苯并呋喃基、噌啉基、吲唑基、吲嗪基、酞嗪基、哒嗪基、三嗪基、异吲哚基、嘌呤基、噁二唑基、噻唑基、噻二唑基、呋咱基、苯并呋咱基、苯并苯硫基、苯并三唑基、苯并噻唑基、苯并噁唑基、喹唑啉基、喹喔啉基、萘啶基、二氢喹啉基、四氢喹啉基、二氢异喹啉基、四氢异喹啉基、苯并呋喃基、呋喃并吡啶基、吡咯并嘧啶基以及氮杂吲哚基。前述杂芳基可以是C-附连的或N-附连的(在这样可能的情况下)。例如,衍生自吡咯的基团可以是吡咯-1-基(N-附连的)或吡咯-3-基(C-附连的)。
“杂环基”意指包含1、2、3、4或5个杂原子(例如,一个或多个独立地选自O、S和N的杂原子)的环状3-12元饱和的或不饱和的脂肪族环。当一个杂原子是S时,它可以任选地是单-或二-氧合的(即-S(O)-或-S(O)2-)。杂环基可以是单环或多环的,在这种情况下这些环能以悬着方式附接在一起或者可以是稠合的或螺旋的。在一个方面中,杂环基是一个三-至七-元环系统。示例性杂环基包括例如但不限于哌啶基、哌嗪基、吡咯烷基、四氢呋喃基等。
“羟基”意指-OH。
“氧代”意指=O。
“硫代烷氧基”意指-S-烷基,其中烷基是如上所定义的。
应当理解的是在本发明的化合物上的取代基与取代模式可以由一个在本领域的普通技术人员选择,从而提供化合物,这些化合物是化学稳定的,并易于由本领域中已知的技术以及下文列举的那些方法合成。通常,不论是否由“任选地”在它之前面,术语“被取代的”指的是指定部分的一个或者多个氢被合适的取代基所替代。除非另外指明,一种“任选地被取代的基团”可以在该基团的每个可取代的位置上具有一种适当的取代基,并且在任何给定的结构中,当一个以上的位置被一个以上的选自一种指明的基团的取代基取代时,在每一位置的取代基可以是相同的或者不同的。可替代地,一种“任选地被取代的基团”可以是不经取代的。
本发明考虑的取代基的组合优选地是那些结果是形成稳定的或者化学上可行的化合物。如果一种取代基本身被多于一个基团取代,应当理解的是这些多个基团可以是在同一个碳原子上或者是在不同的碳原子上,只要结果是得到一种稳定的结构。如在此使用的术语“稳定的”是指这样的化合物,当经受它们的生产、检测所容许的条件,以及在某些实施例中,它们的回收、纯化以及用于在此披露的一个或多个目的时,它们大体上不改变。
“任选地被取代的基团”的可取代碳原子上的适合的单价取代基独立地是卤素;-(CH2)0-4R°;-(CH2)0-4OR°;-O(CH2)0-4R°,-O-(CH2)0-4C(O)OR°;-(CH2)0-4CH(OR°)2;-(CH2)0- 4SR°;可以被R°取代的-(CH2)0-4Ph;可以被R°取代的-(CH2)0-4O(CH2)0-1Ph;可以被R°取代的-CH=CHPh;可以被R°取代的-(CH2)0-4O(CH2)0-1-吡啶基;-NO2;-CN;-N3;-(CH2)0-4N(R°)2;-(CH2)0-4N(R°)C(O)R°;-N(R°)C(S)R°;-(CH2)0-4N(R°)C(O)NR°2;-N(R°)C(S)NR°2;-(CH2)0-4N(R°)C(O)OR°;-N(R°)N(R°)C(O)R°;-N(R°)N(R°)C(O)NR°2;-N(R°)N(R°)C(O)OR°;-(CH2)0-4C(O)R°;-C(S)R°;-(CH2)0-4C(O)OR°;-(CH2)0-4C(O)SR°;-(CH2)0-4C(O)OSiR°3;-(CH2)0-4OC(O)R°;-OC(O)(CH2)0-4SR-,SC(S)SR°;-(CH2)0-4SC(O)R°;-(CH2)0-4C(O)NR°2;-C(S)NR°2;-C(S)SR°;-SC(S)SR°,-(CH2)0-4OC(O)NR°2;-C(O)N(OR°)R°;-C(O)C(O)R°;-C(O)CH2C(O)R°;-C(NOR°)R°;-(CH2)0-4SSR°;-(CH2)0-4S(O)2R°;-(CH2)0-4S(O)2OR°;-(CH2)0-4OS(O)2R°;-S(O)2NR°2;-(CH2)0-4S(O)R°;-N(R°)S(O)2NR°2;-N(R°)S(O)2R°;-N(OR°)R°;-C(NH)NR°2;-P(O)2R°;-P(O)R°2;-OP(O)R°2;-OP(O)(OR°)2;SiR°3;-(C1-4直链的或支链的亚烷基)O-N(R°)2;或-(C1-4直链的或支链的亚烷基)C(O)O-N(R°)2,其中每个R°可以如以下定义地的被取代并且独立地是氢、C1-6脂肪族的、-CH2Ph、-O(CH2)0-1Ph、-CH2-(5-6元杂芳环)或具有0-4个独立地选自氮、氧和硫的杂原子的5-6-元饱和的、部分不饱和的或芳基的环,或者尽管以上定义,两个独立发生的R°连同它们的一个或多个插入原子一起形成一个具有0-4个独立地选自氮、氧和硫的杂原子的3-12元饱和的、部分不饱和的或芳基的单环的或双环的环,它们可以如以下所定义的被取代。
Rο(或通过将两个独立发生的Rο与它们的插入原子放在一起而形成的环)上的适合的单价取代基独立地是卤素,-(CH2)0-2R·,-(卤代R·),-(CH2)0-2OH,-(CH2)0-2OR·,-(CH2)0- 2CH(OR·)2;-O(卤代R·)、-CN、-N3、-(CH2)0-2C(O)R·、-(CH2)0-2C(O)OH、-(CH2)0-2C(O)OR·、-(CH2)0-2SR·、-(CH2)0-2SH、-(CH2)0-2NH2、-(CH2)0-2NHR·、-(CH2)0-2NR· 2、-NO2、-SiR· 3、-OSiR· 3、-C(O)SR·、-(C1-4直链的或支链的亚烷基)C(O)OR·或-SSR·,其中每个R·是未被取代的或者在其前有“卤代”的情况是仅被一个或多个卤素取代,并且是独立地选自C1-4脂肪族、-CH2Ph、-O(CH2)0-1Ph或具有0-4个独立地选自氮、氧和硫的杂原子的5-6-元饱和的、部分不饱和的或芳基的环。R°的饱和碳原子上的适合的二价取代基包括=O和=S。
“任选地被取代的基团”的饱和碳原子上的适合的二价取代基包括以下各项:=O、=S、=NNR* 2、=NNHC(O)R*、=NNHC(O)OR*、=NNHS(O)2R*、=NR*、=NOR*、-O(C(R* 2))2-3O-以及-S(C(R* 2))2-3S-,其中每个独立发生的R*选自氢、可以如以下所定义被取代的C1-6脂肪族或具有0-4个独立地选自氮、氧和硫的杂原子的未取代的5-6-元饱和的、部分不饱和的或芳基的环。结合至“任选地被取代的”基团的邻位可取代碳上的适合的二价取代基包括:-O(CR* 2)2-3O-,其中每个独立发生的R*选自氢、可以如以下所定义被取代的C1-6脂肪族或具有0-4个独立地选自氮、氧和硫的杂原子的未取代的5-6-元饱和的、部分不饱和的或芳基的环。
R*的脂肪族基团上的适合的取代基包括卤素、-R·、-(卤代R·)、-OH、-OR·、-O(卤代R·)、-CN、-C(O)OH、-C(O)OR·、-NH2、-NHR·、-NR· 2以及-NO2,其中每个R·是未被取代的或者在其前有“卤代”的情况是仅由一个或多个卤素取代,并且独立地是C1-4脂肪族、-CH2Ph、-O(CH2)0-1Ph或具有0-4个独立地选自氮、氧和硫的杂原子的5-6-元饱和的、部分不饱和的或芳基的环。
“任选地被取代的基团”的可取代氮上的适合的取代基包括 以及其中每个独立地是氢、可以如以下所定义被取代的C1-6脂肪族、未取代的-OPh或具有0-4个独立地选自氮、氧和硫的杂原子的未取代的5-6-元饱和的、部分不饱和的或芳基的环,或者尽管以上定义,两个独立发生的连同它们的一个或多个插入原子一起形成一个具有0-4个独立地选自氮、氧和硫的杂原子的未取代的3-12元饱和的、部分不饱和的或芳基的单环的或双环的环。
的脂肪族基团上的适合的取代基独立地是卤素、-R·、-(卤代R·)、-OH、-OR·、-O(卤代R·)、-CN、-C(O)OH、-C(O)OR·、-NH2、-NHR·、-NR· 2、或-NO2,其中每个R·是未被取代的或者在其前有“卤代”的情况是仅被一个或多个卤素取代,并且独立地是C1-4脂肪族、-CH2Ph、-O(CH2)0-1Ph或具有0-4个独立地选自氮、氧和硫的杂原子的5-6-元饱和的、部分不饱和的或芳基的环。
杂芳基上的优选取代基可以选自下组,该组由以下各项组成:-OH、-SH、硝基、卤素、氨基、氰基、C1-C12烷基、C2-C12烯基、C2-C12炔基、C1-C12烷氧基、C1-C12卤代烷基、C1-C12卤代烷氧基以及C1-C12硫代烷氧基。烷基、亚烷基和杂环基上的优选取代基包括杂芳基上的优选取代基和氧。在一个实施例中,烷基、亚烷基、杂环基或杂芳基上的取代基是具有化学式-N(R)2的氨基,其中每个R独立地选自氢和C1-C4烷基。
如在此使用的,术语“药学上可接受的盐”是指在合理的医学判断范围内适合用于与人和低等动物的组织相接触,而无不当毒性、刺激、过敏反应等,并且与合理的益处/风险比相称的那些盐。这些药学上可接受的盐在本领域中是熟知的。例如,S.M.Berge等人在药物科学杂志(J.Pharmaceutical Sciences),1977,66,1-19中详细描述了药学上可接受的盐,将其通过引用结合在此。本发明化合物的药学上可接受的盐包括衍生自合适的无机和有机酸及碱的那些。药学上可接受的无毒酸加成盐的实例为氨基与无机酸(如盐酸、氢溴酸、磷酸、硫酸和高氯酸)或与有机酸(如乙酸、三氟乙酸(2,2,2-三氟乙酸)、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸)形成的盐或通过使用本领域中所用的其他方法(如离子交换法)形成的盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊丙酸盐、二葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡糖酸盐、半硫酸盐、庚酸盐、己酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖醛酸盐、乳酸盐、月桂酸盐、十二烷基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、扑酸盐、果胶酸盐、过硫酸盐、3-苯丙酸盐、磷酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、三氟乙酸盐(2,2,2-三氟乙酸盐)、十一烷酸盐、戊酸盐等。
衍生自适当的碱的盐包括碱金属盐、碱土金属盐、铵盐以及N+(C1-4烷基)4盐。代表性的碱或者碱土金属盐类包括钠、锂、钾、钙、镁等。此外的药学上可接受的盐包括,在适当的情况下,无毒的铵,季铵以及使用抗衡离子如卤化物、氢氧化物、羧酸盐、硫酸盐、磷酸盐、硝酸盐、低等烷基磺酸盐以及芳基磺酸盐形成的胺阳离子。
除非另外说明,在此描绘的结构还意在包括该结构的所有同分异构(例如,对映异构、非对映异构和几何(或构象))形式;例如,针对每个不对称中心的R和S构型,Z与E双键异构体以及Z和E构象异构体。因此,本发明化合物的单一立体异构体连同对映异构、非对映异构和几何(或构象)混合物都在本发明的范围之内。除非另行说明,本发明的化合物的所有互变异构形式在本发明的范围之内。
除非具体指出(例如,通过化学名称或指定双键几何形状的其他指示符),在此使用的每个结构式都意在包括具有碳-碳双键(例如,环外双键)的处于顺式(或Z)、反式(或E)或顺式和反式的混合物构型的化合物。例如,化学式I:意在指代以下两者:及其混合物。类似地,以下结构式:意在指代两者及其混合物。
已经通过x-射线晶体学确立化合物7、104、124以及153中的环外双键构型。实例通过指示与化合物7、104、124以及153相关的化学名称中的环外双键的构型反映出化合物7、104、125以及153中的环外双键是以顺式构型还是反式构型存在。
化合物7和化合物104在描述于实例中的其他化合物(例如,化合物115、123、124等)的合成中作为中间体。虽然不希望被任何具体理论所束缚,据信(并且得到x-射线晶体学的支持)用于将化合物7或化合物104转化为例如后续化合物(如例如化合物115、123和124)的反应以立体特异性方式进行。因此,可以为描述于实例中的许多化合物中的环外双键指定构型。在可能的情况下,实例通过指示与具体化合物相关的化学名称中的环外双键的构型反映出该化合物中的环外双键是以顺式构型还是反式构型存在。
如在此使用的,“顺式”或“顺式构型”是指主要为顺式的碳-碳双键,典型地是环外双键。在一些实施例中,化合物的混合物中大于85%的化合物分子具有顺式的碳-碳双键(例如,环外双键)。在一些实施例中,化合物的混合物中大于约90%、大于约95%、大于约98%、大于约99%、大于约99.5%或大于约99.8%的化合物分子具有顺式的碳-碳双键(例如,环外双键)。
如在此使用的,“反式”或“反式构型”是指主要为反式的碳-碳双键,典型地是环外双键。在一些实施例中,化合物的混合物中大于85%的化合物分子具有顺式的碳-碳双键(例如,环外双键)。在一些实施例中,化合物的混合物中大于约90%、大于约95%、大于约98%、大于约99%、大于约99.5%或大于约99.8%的化合物分子具有顺式的碳-碳双键(例如,环外双键)。
此外,除非另外说明,在此描绘的结构还意在包括不同之处仅在于存在一个或多个同位素富集的原子的化合物。例如,具有本发明结构(包括氢被氘或氚置换,或碳被富集13C或14C的碳置换)的化合物在本发明的范围之内。此类化合物作为,例如,分析的工具,在生物学测定中的探针,或者依照本发明的治疗剂是有用的。
术语“药学上可接受的盐”是指与患者的治疗兼容的酸加成盐亦或碱加成盐。
在一些实施例中,形成适当的盐的示例性的无机酸包括但不限于,盐酸、氢溴酸、硫酸与磷酸以及酸金属盐如磷酸氢二钠与硫酸氢钾。形成适当的盐的说明性的有机酸包括单羧酸、双羧酸以及三羧酸。说明性的此类酸是例如乙酸、三氟乙酸(2,2,2-三氟乙酸)、乙醇酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、马来酸、羟基马来酸、苯甲酸、羟基苯甲酸、苯乙酸、肉桂酸、水杨酸、2-苯氧基苯甲酸、对甲苯磺酸以及其他磺酸如甲磺酸与2-羟基乙磺酸。可以形成单酸盐或二酸盐,并且此类盐能以水合、溶剂化或大体上无水形式存在。通常,这些化合物的酸加成盐与它们的游离碱形式相比较,在水中以及不同的亲水的有机溶剂中是更加易溶的,并且通常展示了更高的熔点。例如,在分离在此描述的化合物用于实验室使用或用于随后转化为药学上可接受的酸加成盐中可以使用其他非药学上可接受的盐(例如,草酸盐)。
“药学上可接受的碱加成盐”是在此描述的酸性化合物的任何无毒的有机或无机碱加成盐或其任何中间体。形成适当的盐的示例性的无机碱包括但不限于,锂、钠、钾、钙、镁或者钡的氢氧化物。形成适当的盐的示例性的有机碱包括,脂肪族的、脂环族的或者芳香族的有机胺,如甲胺、三甲基胺以及甲基吡啶或者氨。适当的盐的选择可能是重要的,使得酯官能度(如果有的话)在分子中的其他地方是不水解的。用于适当的盐的选择标准是本领域内普通技术人员熟知的。
在此描述的化合物的酸加成盐最合适地形成自药学上可接受的酸,并且包括例如与无机酸(例如,盐酸、硫酸或磷酸)以及有机酸(例如,琥珀酸、马来酸、乙酸、三氟乙酸或富马酸)形成的那些。例如,在分离在此描述的化合物用于实验室使用或用于随后转化为药学上可接受的酸加成盐中可以使用其他非药学上可接受的盐(例如,草酸盐)。碱加成盐(如钠、钾以及铵盐)、本发明的化合物的溶剂化物以及水合物也包括在本发明的范围之内。通过应用本领域内普通技术人员熟知的标准技术可以完成从一种给定的化合物的盐到一种希望的化合物的盐的转化。
术语“立体异构体”是用于仅在其空间中原子的取向存在差异的单个分子的所有异构体的一般性术语。它包括镜像异构体(对映异构体)、几何(顺/反)异构体以及具有多于一个彼此不为镜像的手性中心的化合物的异构体(非对映异构体)。
术语“治疗(treat或treating)”是指减轻症状,在暂时性亦或永久性基础上消除症状起因,或阻止或减缓名为紊乱或病症的症状的出现。
如在此使用的,“促进伤口愈合”意指治疗具有伤口的受试者并且部分或完全地实现伤口愈合。促进伤口愈合可以意指例如以下一项或多项:促进表皮闭合;促进真皮迁移;促进真皮中的表皮闭合;减少伤口愈合并发症,例如表皮增生和粘连;减少伤口开裂;以及促进正确结痂。
术语“治疗有效量”是指治疗或减轻紊乱或病症的一个或多个症状的严重性中有效的一个化合物的量。在伤口愈合的情况下,治疗有效量是促进伤口愈合的量。
术语“药学上可接受的载体”意指一种无毒的溶剂、分散剂、赋形剂、佐剂或者其他与活性成分混合以便于容许药物组合物(即,能够给予受试者的剂型)的形成的材料。这样一种载体的一个实例是典型地用于肠胃外投药的药学上可接受的油。这些药学上可接受的载体在本领域中是熟知的。
当引入在此披露的要素时,冠词“一个(a或an)”、“该”以及“所述”旨在指存在这些要素的一个或多个。术语“包括(comprising)”、“具有(having)”、“包括(including)”旨在是开放式的并且意指除列出的要素之外还可以存在另外的要素。
用途、配制品以及给药
药学上可接受的组合物
根据另一个实施例,本发明提供了一种组合物,该组合物包括本发明的化合物或其药学上可接受的衍生物以及一种药学上可接受的载体、佐剂或运载体。本发明组合物中的化合物的量是这样,使得其在生物样品或患者中有效地适度抑制CRM1。在某些实施例中,配制用于向需要此类组合物的患者给药的本发明的一种组合物。如在此使用的,术语“患者”意指一种动物。在一些实施例中,该动物是一种哺乳动物。在某些实施例中,该患者是一种兽用患者(即,非人类哺乳动物患者)。在一些实施例中,该患者是狗。在其他的实施例中,该患者是人类。
术语“药学上可接受的载体、佐剂或运载体”是指不会破坏与其一起配制的化合物的药理学活性的无毒载体、佐剂或运载体。可以在本发明的组合物中使用的药学上可接受的载体、佐剂或运载体包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐)、胶体二氧化硅、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯嵌段聚合物、聚乙二醇以及羊毛脂。
本发明的组合物可以经口给药、肠胃外(包括皮下、肌内、静脉内以及真皮内)给药、通过吸入喷雾给药、局部给药、直肠给药、鼻腔给药、口腔含化给药、阴道给药或者经由植入型储器给药。在一些实施例中,提供的化合物或者组合物是可以静脉内给药的和/或向腹膜内给药的。
如在此使用的术语“肠胃外的”包括皮下的、静脉内的、肌内的、眼内的、玻璃体内的、关节内的、滑膜内的、胸骨内的、鞘内的、肝内的、腹膜内的、病灶内的以及颅内的注射或注入技术。优选地,将该组合物经口给药、皮下给药、腹腔内给药或者静脉给药。本发明的组合物的无菌注射可以是水的或者油性悬浮液的形式。这些悬浮液可以根据本领域中已知的技术,使用适当的分散或者湿润剂以及悬浮剂来配制。无菌可注射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中的无菌可注射溶液或悬浮液,例如作为在1,3-丁二醇中的溶液。其中可以采用的可接受的运载体和溶剂是水,林格氏溶液(Ringer's solution)和等渗氯化钠溶液。此外,无菌固定油惯例上用作溶剂或悬浮介质。
本发明的药学上可接受的组合物能以任何经口可接受的剂型经口给药,该剂型包括但不局限于,胶囊、片剂、水性悬浮液或溶液。在用于口服使用的片剂的情况下,常用的载体包括乳糖和玉米淀粉。典型地还加入润滑剂,如硬脂酸镁。对于以胶囊形式口服给药,有用的稀释剂包括乳糖与干玉米淀粉。当要求用于口服使用的水悬浮液时,将该活性成分与乳化剂和悬浮剂组合。如果希望的话,还可以加入某些甜化剂、香料或者着色剂。在一些实施例中,一种提供的口服配制品被配制成用于立即释放或者持续的/延迟的释放。在一些实施例中,适用于口腔含化或者舌下给药的组合物包括片剂、锭剂和软锭剂。一种提供的化合物还可以是处于微囊化形式。
可替代地,对于直肠给药,本发明的药学上可接受的组合物能以栓剂的形式进行给药。还可以将本发明的药学上可接受的组合物局部地给药,尤其是当治疗靶点包含局部施用易于接近的区域或者器官时,包括眼部、皮肤或者低位肠道的疾病。用于这些区域或者器官的每一个的适当的局部的配制品是易于制备的。
用于低位肠道的局部施用能以直肠栓剂配制品(见上文)或适当的灌肠剂配制品完成。还可以使用局部透皮贴剂。
对于眼科使用,可以将提供的药学上可接受的组合物配制为微粉化悬浮液或配制在软膏如凡士林中。
本发明的药学上可接受的组合物还可以通过鼻用气溶胶或吸入物来给药。
在一些实施例中,本发明的药学上可接受的组合物被配制为用于腹膜内给药。
可以与载体材料组合以便产生处于单一剂型的组合物的本发明的化合物的量将取决于被治疗的宿主、具体的给予方式而变化。在一个实施例中,提供的组合物应当这样进行配制,使得可以向接受这些组合物的患者给予在0.01mg-100mg/kg体重/天之间的抑制剂剂量。在另一个实施例中,该剂量是每4至120小时从大约0.5至大约100mg/kg体重,或在1mg以及1000mg/剂之间,或者根据特定的药物要求而定。典型地,本发明的药用组合物将从每天大约1次至大约6次给药。
还应理解,针对任何具体患者的特定剂量与治疗方案将取决于多种因素,包括采用的特定化合物的活性、年龄、体重、一般健康状况、性别、饮食、给药时间、排泄率、药物组合、以及治疗医生的判断和正治疗的具体疾病的严重性。在该组合物中的本发明的化合物的量还将取决于在该组合物中的特定的化合物。
在患者病症改善时,如果需要的话,可以给药本发明化合物、组合物或其组合的一个维持剂量。随后,当这些症状已经被减轻到希望水平时,可以随着症状的变化减少给药的剂量或频率,或两者至保持改善的病症的水平。然而,患者可能需要针对疾病症状的任何复发进行长期的间歇式治疗。
化合物和药学上可接受的组合物的使用
通常在此描述的化合物和组合物对抑制CRM1是有用的,并且因此对于治疗一种或多种与CRM1活性相关的紊乱是有用的。因此,在某些实施例中,本发明提供了一种用于治疗CRM1介导的紊乱的方法,该方法包括以下步骤:向对其有需要的患者给予本发明的化合物或其药学上可接受的组合物。还可以将在此描述的化合物和组合物给予培养中的细胞(例如,在体外或离体地),或者给予受试者(例如,在体内),从而治疗、预防和/或诊断多种紊乱,包括在下文描述的那些。
可以在体外、在体内或在细胞系中测定在本发明中用作CRM1抑制剂的化合物的活性。用于测定在本发明中使用的作为CRM1抑制剂的化合物的详细条件列于下文实例中。
如在此使用的,术语“CRM1介导的”紊乱或病症,如在此使用的,意指已知CRM1在其中起作用的任何疾病或其他有害病症。因此,本发明的另一个实施例涉及已知CRM1在其中起作用的一种或多种疾病的治疗或其严重性缓解。在一些实施例中,本发明提供了治疗受试者的与p53、p73、p21、pRB、p27、IκB、NFκB、c-Abl、FOXO蛋白、COX-2或HDAC(组蛋白脱乙酰酶)的表达或活性相关的疾病的方法,这些方法包括向该患者给予治疗有效量的在此描述的化合物。在另一个实施例中,本发明涉及一种治疗选自增生性紊乱(例如,癌症)、炎症性紊乱、自身免疫性紊乱、病毒感染、眼科紊乱或神经变形紊乱的疾病或病症或者减轻其严重性的方法,其中所述方法包括向对其有需要的患者给予根据本发明的化合物或组合物。在一个更具体的实施例中,本发明涉及一种治疗癌症或减轻其严重性的方法。以上紊乱的具体实例在下文详细列出。
通过本发明的化合物可治疗的癌症包括但不限于恶性血液病(白血病、淋巴瘤、骨髓瘤包括多发性骨髓瘤、骨髓增生异常综合征和骨髓增生综合征)以及实体瘤(癌如前列腺癌、乳腺癌、肺癌、结肠癌、胰腺癌、肾癌、卵巢癌以及软组织和骨肉瘤和间质瘤)。乳腺癌(BC)可包括基底样乳腺癌(BLBC)、三阴性乳腺癌(TNBC)以及是BLBC又是TNBC的乳腺癌。另外,乳腺癌可包括侵入性的或非侵入性的导管癌或小叶癌,乳腺的管状癌、髓质癌、粘液癌、乳头状癌、筛状癌,男性乳腺癌,复发性或转移性乳腺癌,乳腺叶状瘤,以及乳头佩吉特病(Paget’s disease)。
通过本发明的化合物可治疗的炎症性紊乱包括但不限于多发性硬化症、类风湿性关节炎、变性关节病、系统性红斑狼疮、系统性硬化病、血管炎综合征(小血管、中血管和大血管)、动脉粥样硬化、炎症性肠病、肠道易激综合征、克罗恩病、粘液性结肠炎、溃疡性结肠炎、胃炎、败血症、银屑病和其他皮肤炎症性紊乱(如湿疹、特应性皮炎、接触性皮炎、荨麻疹、硬皮病和具有急性炎症性组分的皮肤病、天疱疮、类天疱疮、变应性皮炎)以及荨麻疹综合征。
通过本发明的化合物可治疗的病毒性疾病包括但不限于急性发热性咽炎、咽结膜热、流行性角膜结膜炎、幼儿肠胃炎、柯萨奇病毒感染、传染性单核细胞增多、伯基特淋巴瘤、急性肝炎、慢性肝炎、肝硬化、肝细胞癌、原发性HSV-1感染(primary HSV-1infection)(例如,儿童龈口炎、成人扁桃腺炎和咽炎、角膜结膜炎)、潜伏性HSV-1感染(latent HSV-1infection)(例如,唇疱疹以及感冒疮)、原发性HSV-2感染、潜伏性HSV-2感染、无菌性脑膜炎、传染性单核细胞增多、巨细胞包涵体病、卡波西氏肉瘤、多中心卡斯特莱曼病(multicentric Castleman disease)、原发性渗出性淋巴瘤、AIDS、流感、雷氏综合征(Reyesyndrome)、麻疹、感染后脑脊髓炎、腮腺炎、增生性上皮病变(例如,常见的、平坦的、跖和肛门生殖器疣,喉乳头状瘤,疣状表皮发育不良)、宫颈癌、鳞状细胞癌、义膜性喉炎、肺炎、细支气管炎、普通感冒、脊髓灰质炎、狂犬病、流感样综合征、严重的细支气管炎与肺炎、德国麻疹、先天性风疹、水痘、以及带状疱疹。通过本发明的这些化合物可治疗的病毒性疾病还包括慢性病毒感染,包括乙型肝炎和丙型肝炎。
示例性眼科紊乱包括但不限于黄斑水肿(糖尿病的和非糖尿病的黄斑水肿)、与年龄有关的黄斑湿性和干性变性、年龄性盘状黄斑变性、囊样黄斑水肿、眼睑水肿、视网膜水肿、糖尿病性视网膜病变、脉络膜视网膜病变、新生血管性黄斑病变、新生血管性青光眼、葡萄膜炎、虹膜炎、视网膜脉管炎、眼内炎、全眼球炎、转移性眼炎、脉络膜炎、视网膜色素上皮炎、结膜炎、睫状体炎、巩膜炎、巩膜外层炎、视神经炎、球后视神经炎、角膜炎、睑炎、渗出性视网膜脱离、角膜溃疡、结膜溃疡、慢性钱币状角膜炎、与组织缺氧或局部缺血相关的眼科疾病、早产儿视网膜病变、糖尿病增生性视网膜病变、息肉状脉络膜血管病变、视网膜血管瘤样增生、视网膜动脉闭塞、视网膜静脉闭塞、科茨氏病(Coats'disease)、家族性渗出性玻璃体视网膜病变、无脉病(高安氏病(Takayasu's disease))、视网膜静脉周围炎、抗磷脂抗体综合征、白血病性视网膜病变、血液高粘滞综合征、巨球蛋白血症、干扰素相关的视网膜病变、高血压性视网膜病变、放射性视网膜病变、角膜上皮干细胞缺乏或白内障。
通过具有化学式I的化合物可治疗的神经退行性疾病包括但不限于帕金森氏病、阿尔茨海默病和亨廷顿氏病以及肌萎缩性侧索硬化症(ALS/卢·格里克(Lou Gehrig)病)。
在此描述的化合物以及组合物还可以用于治疗异常组织生长和纤维化的紊乱,包括膨胀性心肌症、肥厚性心肌病、限制性心肌病、肺纤维化、肝纤维化、肾小球肾炎、多囊肾紊乱(PKD)以及其他肾病。
在此描述的化合物和组合物还可以用于治疗与食物摄取有关的紊乱,如肥胖和饮食过多。
在另一个实施例中,在此描述的化合物或组合物可以用于治疗或者预防过敏以及呼吸紊乱,包括哮喘、支气管炎、肺纤维化、过敏性鼻炎、氧中毒、肺气肿、慢性支气管炎、急性呼吸窘迫综合征以及任何慢性阻塞性肺病(COPD)。
在一些实施例中,与CRM1活性相关的紊乱或病症是肌肉萎缩、关节炎(例如骨关节炎和类风湿性关节炎)、强直性脊柱炎、外伤性脑损伤、脊髓损伤、败血症、风湿性疾病、癌性动脉粥样硬化、1型糖尿病、2型糖尿病、钩端螺旋体肾病、青光眼、视网膜疾病、老化、头痛、疼痛、复杂区域疼痛综合征、心脏肥大、肌肉耗损、分解代谢紊乱、肥胖、胎儿生长迟缓、血胆固醇过多、心脏病、慢性心力衰竭、局部缺血/再灌注、中风、脑动脉瘤、心绞痛、肺病、囊性纤维化、酸源性肺损伤、肺动脉高压、哮喘、慢性阻塞性肺病、干燥综合征、透明膜病、肾病、肾小球疾病、酒精性肝病、肠疾病、腹膜性子宫内膜异位、皮肤病、鼻窦、间皮瘤、无汗型外胚层性发育异常-ID、贝切特氏病(behcet’s disease)、色素失调症、结核病、哮喘、克罗恩病、结肠炎、眼部过敏、阑尾炎、佩吉特病、胰腺炎、齿根骨膜炎、子宫内膜异位、炎症性肠病、炎症性肺病、硅源性疾病、睡眠呼吸暂停、AIDS、HIV-1、自身免疫性疾病、抗磷脂综合征、狼疮、狼疮肾炎、家族性地中海热、遗传性周期性发热综合征、心理社会应激性疾病、神经病理学疾病、家族性淀粉样多神经病、炎症性神经病、帕金森氏病、多发性硬化症、阿尔茨海默病、肌萎缩性脊髓侧索硬化症、亨廷顿氏病、白内障、或听力损失。
在其他实施例中,与CRM1活性相关的紊乱或病症是头部伤害、葡萄膜炎、炎性疼痛、过敏原诱发哮喘、非过敏原诱发哮喘、肾小球肾炎、溃疡性结肠炎、坏死性肠结肠炎、具有反覆性发烧的高免疫球蛋白血症D(HIDS)、TNF受体相关周期性综合征(TRAPS)、隐热蛋白-相关周期综合征、穆-韦综合征(荨麻疹耳聋淀粉样变性),家族性冷性荨麻疹、新生儿多系统炎症性疾病(NOMID)、周期性发热、口疮性口炎、咽炎和腺炎(PFAPA综合征)、布劳综合征、化脓性无菌性关节炎、坏疽性脓皮病、痤疮(PAPA)、白细胞介素-1受体拮抗因子缺乏(DIRA)、蛛网膜下腔出血、多囊肾病、移植、器官移植、组织移植、骨髓增生异常综合征、刺激物诱发炎症、植物刺激物诱发炎症、野葛/漆酚原油诱发炎症、化学刺激物诱发炎症、蜂蜇伤诱发炎症、昆虫叮咬诱发炎症、日晒病、烧伤、皮炎、内毒素血症、肺损伤、急性呼吸窘迫综合征、酒精性肝炎、或由寄生虫感染引起的肾损伤。
在另外的方面中,本发明提供了在此描述的化合物用于生产以下药剂的用途,该药剂用于治疗受试者的与p53、p73、p21、pRB、p27、IκB、NFκB、c-Abl、FOXO蛋白、COX-2或HDAC的表达或活性相关的疾病。在一些实施例中,本发明提供了在此描述的化合物在生产以下药剂中的用途,该药剂用于治疗癌症和/或肿瘤性紊乱、血管生成、自身免疫性紊乱、炎症性紊乱和/或疾病、表观遗传、激素紊乱和/或疾病、病毒性疾病、神经退行性紊乱和/或疾病、伤口以及眼科紊乱中的任何。
在一些实施例中,本发明提供了一种用于在生物样品中抑制CRM1的方法,该方法包括使本发明的化合物的药学上可接受的盐或其药学上可接受的组合物与该生物样品接触或者给予该患者。
肿瘤性紊乱
在此描述的化合物或者组合物可以用以治疗肿瘤性紊乱。“肿瘤性紊乱”是一种疾病或者紊乱,其特征为具有自主生长或者复制能力的细胞,例如,一种异常状态或者特征为增殖性细胞生长的病症。示例性肿瘤性紊乱包括:癌,肉瘤,转移性紊乱,例如,起于前列腺、脑、骨头、结肠、肺、乳腺、卵巢以及肝脏起源的肿瘤,造血肿瘤性紊乱,例如,白血病,淋巴瘤,骨髓瘤以及其他的恶性浆细胞紊乱和转移性肿瘤。常见癌症包括:乳腺癌、前列腺癌、结肠癌、肺癌、肝癌以及胰腺癌。使用该化合物的治疗可以处于一种有效量值,从而改善肿瘤性紊乱的至少一种症状,例如,减少细胞增殖、降低肿瘤质量,等。
这些披露的方法在癌症(包括例如实体瘤、软组织瘤及其转移)连同在家族性癌症综合征(如李-佛美尼综合征、家族性乳癌与卵巢癌(BRCA1或BRAC2突变)综合征)等的预防和治疗中是有用的。这些披露的方法在治疗非实体癌中也是有用的。示例性实体瘤包括不同器官系统的恶性肿瘤(例如,肉瘤、腺癌以及癌),如肺、乳腺、淋巴、胃肠道(例如,结肠)以及泌尿生殖器道(例如,肾脏、泌尿道上皮或者睾丸肿瘤)、咽喉癌、前列腺癌以及卵巢癌。示例性腺癌包括结肠直肠癌、肾细胞癌、肝癌、非小细胞肺癌以及小肠癌。
由美国国家癌症研究所(National Cancer Institute)描述的示例性癌症包括:急性成淋巴细胞性白血病,成人;急性成淋巴细胞性白血病,儿童;急性髓性白血病,成人;肾上腺皮质癌;肾上腺皮质癌,儿童;AIDS相关的淋巴瘤;AIDS相关的恶性肿瘤;肛门癌;儿童小脑星形细胞瘤;儿童大脑星形细胞瘤;胆管癌,肝外的;膀胱癌;膀胱癌,儿童;骨癌,骨肉瘤/恶性纤维组织细胞瘤;脑干神经胶质瘤,儿童;脑肿瘤,成人;脑肿瘤,脑干神经胶质瘤,儿童;脑肿瘤,小脑星形细胞瘤,儿童;脑肿瘤,大脑星形细胞瘤/恶性胶质瘤,儿童;脑肿瘤,室管膜瘤,儿童;脑肿瘤,成神经管细胞瘤,儿童;脑肿瘤,幕上原始神经外胚层肿瘤,儿童;脑肿瘤,视神经通路和下丘脑胶质瘤,儿童;脑肿瘤,儿童(其他);乳腺癌;乳腺癌和妊娠;乳腺癌,儿童;乳腺癌,男性;支气管腺瘤/类癌瘤,儿童;类癌肿瘤,儿童;类癌肿瘤,胃肠的;癌,肾上腺皮质的;癌,胰岛细胞;原发灶不明癌;中枢神经系统淋巴瘤,原发性;小脑星形细胞瘤,儿童;大脑星形细胞瘤/恶性胶质瘤,儿童;宫颈癌;儿童癌症;慢性淋巴细胞性白血病;慢性粒细胞性白血病;慢性骨髓增生障碍;腱鞘透明细胞肉瘤;结肠癌;结肠直肠癌,儿童;皮肤T细胞淋巴瘤;子宫内膜癌;室管膜瘤,儿童;上皮癌,卵巢;食管癌;食管癌,儿童;尤因氏家族肿瘤;颅外生殖细胞瘤,儿童;性腺外生殖细胞瘤;肝外胆道癌;眼癌,眼内黑色素瘤;眼癌,成视网膜细胞瘤;胆囊癌;胃(Gastric,Stomach)癌;胃(Gastric,Stomach)癌,儿童;胃肠类癌肿瘤;生殖细胞瘤,颅外的,儿童;生殖细胞瘤,性腺外的;生殖细胞瘤,卵巢的;妊娠性滋养细胞肿瘤;神经胶质瘤,儿童脑干;神经胶质瘤,儿童视神经通路和下丘脑;毛细胞白血病;头颈癌;肝细胞(肝)癌,成人(原发性);肝细胞(肝)癌,儿童(原发性);何杰金氏淋巴瘤,成人;何杰金氏淋巴瘤,儿童;妊娠期间的何杰金氏淋巴瘤;下咽癌;下丘脑和视神经通路神经胶质瘤,儿童;眼内黑色素瘤;胰岛细胞癌(内分泌胰腺);卡波西氏肉瘤;肾癌;喉癌;喉癌,儿童;白血病,急性成淋巴细胞性的,成人;白血病,急性成淋巴细胞性的,儿童;白血病,急性髓性的,成人;白血病,急性髓性的,儿童;白血病,慢性淋巴细胞性的;白血病,慢性粒细胞性的;白血病,毛细胞;唇及口腔癌;肝癌,成人(原发性);肝癌,儿童(原发性);肺癌,非小细胞;肺癌,小细胞;成淋巴细胞性白血病,成人急性;成淋巴细胞性白血病,儿童急性;淋巴细胞性白血病,慢性;淋巴瘤,AIDS相关的;淋巴瘤,中枢神经系统(原发性);淋巴瘤,皮肤T细胞;淋巴瘤,何杰金氏,成人;淋巴瘤,何杰金氏,儿童;淋巴瘤,妊娠期间的何杰金氏;淋巴瘤,非何杰金氏,成人;淋巴瘤,非何杰金氏,儿童;淋巴瘤,妊娠期间的非何杰金氏;淋巴瘤,原发性中枢神经系统;巨球蛋白血症,沃尔德斯特罗姆氏(Waldenstrom's);男性乳腺癌;恶性间皮瘤,成人;恶性间皮瘤,儿童;恶性胸腺瘤;成神经管细胞瘤,儿童;黑色素瘤;黑色素瘤,眼内的;默克尔细胞癌;间皮瘤,恶性的;隐匿原发性转移性鳞状颈癌;多发性内分泌腺瘤综合征,儿童;多发性骨髓瘤/浆细胞赘生物;蕈样霉菌病;骨髓增生异常综合征;粒细胞性白血病,慢性;髓性白血病,儿童急性;骨髓瘤,多发性;骨髓增生障碍,慢性;鼻腔和副鼻窦癌;鼻咽癌;鼻咽癌,儿童;成神经细胞瘤;非何杰金氏淋巴瘤,成人;非何杰金氏淋巴瘤,儿童;妊娠期间的非何杰金氏淋巴瘤;非小细胞肺癌;口腔癌,儿童;口腔和唇癌;口咽癌;骨肉瘤/骨恶性纤维组织细胞瘤;卵巢癌,儿童;卵巢上皮癌;卵巢的生殖细胞瘤;卵巢低度恶性潜能的肿瘤;胰腺癌;胰腺癌,儿童;胰腺癌,胰岛细胞;副鼻窦和鼻腔癌;甲状旁腺癌;阴茎癌;嗜铬细胞瘤;松果体和幕上原始神经外胚层肿瘤,儿童;垂体瘤;浆细胞赘生物/多发性骨髓瘤;胸膜肺母细胞瘤;妊娠及乳腺癌;妊娠及何杰金氏淋巴瘤;妊娠及非何杰金氏淋巴瘤;原发性中枢神经系统淋巴瘤;原发性肝癌,成人;原发性肝癌,儿童;前列腺癌;直肠癌;肾细胞(肾)癌;肾细胞癌,儿童;肾盂和输尿管,过渡细胞癌;成视网膜细胞瘤;横纹肌肉瘤,儿童;唾液腺癌;唾液腺癌,儿童;肉瘤,尤因氏家族肿瘤;肉瘤,卡波西氏;肉瘤(骨肉瘤)/骨恶性纤维组织细胞瘤;肉瘤,横纹肌肉瘤,儿童;肉瘤,软组织,成人;肉瘤,软组织,儿童;塞扎里(Sezary)综合征;皮肤癌;皮肤癌,儿童;皮肤癌(黑色素瘤);皮肤癌,默克尔细胞;小细胞肺癌;小肠癌;软组织肉瘤,成人;软组织肉瘤,儿童;隐匿原发性鳞状颈癌,转移性;胃(Stomach,Gastric)癌;胃(Stomach,Gastric)癌,儿童;幕上原始神经外胚层肿瘤,儿童;T细胞淋巴瘤,皮肤的;睾丸癌;胸腺瘤,儿童;胸腺瘤,恶性的;甲状腺癌;甲状腺癌,儿童;肾盂和输尿管过渡细胞癌;滋养细胞肿瘤,妊娠性的;原发灶不明癌,儿童;罕见儿童癌症;输尿管和肾盂,过渡细胞癌;尿道癌;子宫肉瘤;阴道癌;视神经通路和下丘脑胶质瘤,儿童;外阴癌;沃尔德斯特罗姆氏巨球蛋白血症;以及维尔姆斯瘤。
另外的示例性癌症包括弥散性大B细胞淋巴瘤(DLBCL)和套细胞淋巴瘤(MCL)。又另外的示例性癌症包括宫颈癌、B细胞ALL、T细胞ALL、B细胞或T细胞淋巴瘤、肥大细胞癌症、成胶质细胞瘤、成神经细胞瘤、滤泡性淋巴瘤以及里克特氏综合征(Richter’s syndrome)。
示例性肉瘤包括纤维肉瘤、腺泡状软组织肉瘤(ASPS)、脂肪肉瘤、平滑肌肉瘤、软骨肉瘤、滑膜肉瘤、脊索瘤、梭形细胞肉瘤、组织细胞瘤、横纹肌肉瘤、尤因氏肉瘤、神经外胚层肉瘤、叶状/骨原性肉瘤以及成软骨细胞骨肉瘤。
根据在此描述的方法还可以治疗或预防上述癌症的转移。
联合疗法
在一些实施例中,在此描述的化合物与一种另外的“第二”治疗剂或治疗一起给药。可以从在一种典型地在治疗指定疾病或病症的单一疗法中使用的任一种剂中进行第二治疗剂的选择。如在此使用的,术语“一起给药”以及相关的术语指的是依照本发明的治疗剂的同时的或者连续的给药。例如,可以将本发明的一种化合物与另一种治疗剂同时地或者以分开的单位剂型顺序地或者以单一的单位剂型一起地进行给药。因此,本发明提供一种单一的单位剂型,该剂型包括本发明的化合物、一种另外的治疗剂以及一种药学上可接受的载体、佐剂或者运载体。
在本发明的一个实施例中,当将一种第二治疗剂给予受试者时,本发明的化合物的有效量小于当不给予该第二治疗剂时其应有的有效量。在另一个实施例中,该第二治疗剂的有效量小于当不给予本发明的化合物时其应有的有效量。以此方式,可以将与两个试剂任何一个的高剂量相关的所不希望的副反应减少到最小。其他潜在的优点(包括但不限于改进的给药方案和/或降低的药物成本)对于本领域普通技术人员应是显而易见的。额外的药剂可以与本发明的化合物分开地、作为多剂量疗法的一部分进行给药。可替代地,这些药剂可以是单剂型的一部分,与本发明的化合物一起混合到一个单一组合物中。
癌症联合疗法
在一些实施例中,在此描述的化合物与一种另外的癌症治疗一起给药。另外的示例性癌症治疗包括,例如:化学疗法,标靶疗法(如抗体疗法、激酶抑制剂、免疫疗法和激素疗法)、表观遗传疗法、蛋白酶体抑制剂以及抗血管生成疗法。在下面提供这些治疗的每个的实例。如在此使用的,术语“联合”、“联合的”以及相关的术语指的是依照本发明的治疗剂的同时的或者连续的给药。例如,可以将本发明的一种化合物与另一种治疗剂同时地或者以分开的单位剂型顺序地或者以单一的单位剂型一起地进行给药。因此,本发明提供一种单一的单位剂型,该剂型包括本发明的化合物、一种另外的治疗剂以及一种药学上可接受的载体、佐剂或者运载体。
一种本发明的化合物以及一种另外的治疗剂两者(在包括一种如在上文中描述的另外的治疗剂的那些组合物中)可以与载体材料组合从而产生一种单一剂型的量将取决于治疗的主体以及特定的给药方式而变化。优选地,应当将本发明的组合物配制成这样以便于可以按在0.01-100mg/kg体重/天之间的本发明的化合物的剂量给药。
化学疗法
在一些实施例中,将在此描述的化合物与一种化学疗法一起进行给药。化学疗法是用药物治疗癌症,这些药物可以破坏癌细胞。“化学疗法”通常是指总体上影响迅速分裂的细胞的细胞毒性药物,与靶向疗法形成对比。化疗药物以不同的可能方式干扰细胞分裂,例如干扰DNA的复制或新形成的染色体的分离。虽然某种程度的特异性可以来自许多癌细胞没有正常细胞通常具有的修复DNA损伤的能力,但是化学疗法的大多数形式都靶向所有迅速分裂的细胞并且不特异性针对癌细胞。
用于癌症疗法中的化疗剂的实例包括例如抗代谢物(例如,叶酸、嘌呤和嘧啶衍生物)以及烷化剂(例如,氮芥、亚硝基脲、铂、磺酸烷基酯、肼、三氮烯、氮丙啶、纺锤体毒剂、细胞毒剂、拓扑异构酶抑制剂等)。示例性药剂包括阿柔比星、放线菌素、阿利维甲酸、六甲蜜胺、氨基蝶呤、氨基乙酰丙酸、氨柔比星、安吖啶、阿那格雷、三氧化二砷、天冬酰胺酶、阿曲生坦、贝洛替康、蓓萨罗丁、苯达莫司汀、博来霉素、硼替佐米、白消安、喜树碱、卡培他滨、卡铂、卡波醌、卡莫氟、卡莫司汀、塞来昔布、苯丁酸氮芥、氮芥、顺铂、克拉屈滨、氯法拉滨、克立他酶、环磷酰胺、阿糖胞苷、达卡巴嗪、更生霉素、道诺霉素、地西他滨、秋水仙胺、多烯紫杉醇、阿霉素、乙丙昔罗、伊利司莫、依沙芦星、依诺他滨、表柔比星、雌莫司汀、依托格鲁、依托泊苷、氟尿苷、氟达拉滨、氟尿嘧啶(5FU)、福莫司汀、吉西他滨、格立得(Gliadel)植入剂、羟基脲(Hydroxycarbamide)、羟基脲(Hydroxyurea)、伊达比星、异环磷酰胺、伊立替康、伊洛福芬、伊沙匹隆、拉洛他赛、亚叶酸、阿霉素脂质体、道诺霉素脂质体、氯尼达明、洛莫司汀、硫蒽酮、甘露舒凡、马索罗酚、美法仑、巯基嘌呤、美司钠、甲氨蝶呤、氨基酮戊酸甲酯、二溴甘露醇、米托胍腙、米托坦、丝裂霉素、米托蒽醌、奈达铂、尼莫司汀、奥利默森、奥马西他辛、奥他赛、奥沙利铂、紫杉醇、培门冬酶、培美曲塞、喷司他丁、吡柔比星、匹杉琼、普卡霉素、卟吩姆钠、泼尼莫司汀、丙卡巴肼、雷替曲赛、雷莫司汀、鲁比替康、沙帕他滨、司莫司汀、塞西马集、赛特铂、链佐星、他拉泊芬、替加氟-尿嘧啶、替莫泊芬、替莫唑胺、替尼泊苷、替司他赛、睾内酯、四硝酸酯、塞替派、噻唑呋林、硫鸟嘌呤、替吡法呢、拓扑替康、曲贝替定、三亚胺醌、曲他胺、三合铂(Triplatin)、维甲酸、曲奥舒凡、曲磷胺、乌拉莫司汀、戊柔比星、维替泊芬、长春花碱、长春新碱、长春地辛、长春氟宁、长春瑞滨、伏立诺他、佐柔比星以及在此描述的其他细胞生长抑制剂或细胞毒性剂。
由于一些药物一起使用的作用大于单独使用,因此经常同时给出两种或者更多种药物。经常地,将两种或者更多种化学治疗剂用作联合化学疗法。在一些实施例中,这些化学治疗剂(包括组合化学疗法)可以与在此描述的一种化合物联合使用。
靶向疗法
靶向疗法包括使用对于癌细胞的下调蛋白特异性的药剂。小分子靶向疗法药物通常是关于癌细胞内的突变的、过表达的或者另外的关键性蛋白的酶结构域的抑制剂。突出的实例是酪氨酸激酶抑制剂,如阿西替尼、博舒替尼、西地尼布、达沙替尼、厄洛替尼(erolotinib)、伊马替尼、吉非替尼、拉帕替尼、来他替尼、尼洛替尼、司马沙尼、索拉非尼、舒尼替尼及凡德他尼,以及周期蛋白依赖性激酶抑制剂,如阿伏西地(Alvocidib)和塞立西布(Seliciclib)。单克隆抗体疗法是另外一种策略,其中,该治疗剂是一种抗体,该抗体特异性地结合到在癌细胞表面的一种蛋白。实例包括典型地用于乳腺癌的抗HER2/neu抗体曲妥珠单抗以及典型地用于多种B细胞恶性肿瘤的抗CD20抗体利妥昔单抗和托西莫单抗。其他示例性抗体包括西妥昔单抗、帕尼单抗、曲妥珠单抗、阿仑单抗、贝伐单抗、依决洛单抗以及吉姆单抗。示例性融合蛋白包括阿柏西普和地尼白介素(Denileukindiftitox)。在一些实施例中,靶向疗法可以与在此描述的化合物,例如,格列卫(Vignari(维格纳里)和Wang(王),2001)组合使用。
靶向疗法还可以涉及作为“导归器(homing device)”的小肽,该小肽可以结合到细胞表面受体或者影响肿瘤周围的细胞外基质。如果核素在细胞附近衰变,那么附接到这些肽(例如,RGD)上的放射性核素最终杀死癌细胞。此类疗法的一个实例包括血管生成
在此描述的化合物可以被用以治疗或者预防与血管生成相关的疾病或者紊乱。与血管生成相关的疾病包括癌症、心血管疾病以及黄斑变性。
血管生成是一种生理学过程,涉及新血管从已有血管中的生长。血管生成是一种在生长和发育,连同在创伤愈合以及在肉芽组织中的正常的且至关重要的过程。然而,它也是肿瘤细胞从休眠状态转变为恶性状态的一个基本步骤。血管生成可以是用于对抗疾病的一个目标,这些疾病的特征为很少的血管化作用或者不正常的血管系统。
可以抑制或者诱导在体内的新血管建立的特异性化合物的施用可以帮助对抗此类疾病。在不应当存在的部位存在的血管可以影响一种组织的力学特性,增加衰竭的可能性。在损伤修复或者另外的代谢活跃组织中的血管的缺乏能抑制修复或者其他的基本功能。若干疾病,如局部缺血性慢性创伤是衰竭或者血管生成不足的结果,并且能通过局部血管扩张进行治疗,由此给这些部位带来新的营养素,从而促进修复。其他疾病(如年龄相关的黄斑变性)可以通过局部血管扩张引起,从而干扰正常的生理学过程。
血管内皮生长因子(VEGF)已经被证明是血管生成从而在给定的血管网中增加毛细血管数目的主要贡献者。VEGF上调是对运动的生理应答的主要部分,并且它在血管生成中的作用被怀疑是在血管损伤中的一种可能的治疗。体外研究清楚地证明,VEGF是一种血管生成的有效刺激物,因为在此生长因子的存在下,盘状内皮细胞将会增殖并迁移,最终形成类似毛细血管的管状结构。
肿瘤通过分泌不同的生长因子(例如,VEGF),诱导血管生长(血管生成)。生长因子(如bFGF和VEGF)可以诱导毛细血管生长进入肿瘤中,一些研究者猜测,这供应所需要的营养素,从而允许肿瘤扩张。
血管生成代表用于心血管疾病治疗的一个极好治疗目标。这是一种基于自然方式的有效的生理学过程,以这样的方式,我们的身体响应于供给到至关重要的器官血液的减少,换句话说,生成新的并行管从而克服缺血性的损伤。
除刺激血管生成外,VEGF的过表达在血管中引起渗透性增强。在湿性黄斑变性中,VEGF引起毛细血管增生进入视网膜中。由于血管生成的增加还引起浮肿,血液以及其他视网膜流体渗漏进入视网膜,从而引起失明。
抗血管生成疗法可以包括靶向血管内皮生长因子(VEGF)的激酶抑制剂如舒尼替尼、索拉非尼,或者针对VEGF或VEGF受体的单克隆抗体或受体“诱饵”包括贝伐单抗或VEGF-Trap,或者沙利度胺或其类似物(来那度胺、珀玛力度胺(pomalidomide)),或者靶向非VEGF血管生成靶标的药剂如成纤维细胞生长因子(FGF)、血管生成素,或者血管抑素或内皮抑素。
表观遗传学
在此描述的化合物可以被用以治疗或者预防与表观遗传学相关的疾病或者紊乱。表观遗传学是由除基础DNA序列的改变外的机制引起的表型或基因表达的遗传改变的研究。在真核生物中的表观遗传变化的一个实例是细胞分化的过程。在形态建成过程中,干细胞成为胚的不同细胞系,并进而成为完全分化的细胞。换言之,一个单一的受精卵细胞变为许多种细胞类型,包括神经元、肌细胞、上皮细胞、血管等,正如它继续分裂的那些。它通过激活一些基因同时抑制另一些基因来实现该分化。
当细胞分裂时,表观遗传变化被保持。大多数的表观遗传变化仅发生在个体生物体的生命周期过程中,但是,如果已经引起在精子或卵细胞中的导致受精的DNA突变,那么一些表观遗传变化将会由一代遗传到下一代。具体的表观遗传过程包括副突变、加书签(bookmarking)、加印迹、基因沉默、X染色体失活、位置效应、重编程、反式效应(transvection)、母体效应、致癌作用的过程、致畸因子的多种效应、组蛋白修饰和异染色质的调节以及影响孤雌生殖和克隆的技术限制。
与表观遗传学相关的示例性疾病包括ATR-综合征、脆性X染色体综合征、ICF综合征、天使人综合征(Angelman’s syndrome)、普瑞德-威利氏综合征(Prader-Willssyndrome)、BWS、Rett综合征、α-地中海贫血、癌症、白血病、鲁宾斯坦-泰比(Rubinstein-Taybi)综合征和考费因-劳里(Coffin-Lowry)综合征。
第一个与表观遗传学相关的人类疾病是癌症。研究者发现来自患有结肠直肠癌的患者的病变组织具有比来自相同患者的正常组织更少的DNA甲基化。由于甲基化的基因被典型地关闭,DNA甲基化的缺失可以通过改变染色质的排列而导致反常的高的基因激活。另一方面,过多的甲基化会取消保护性的肿瘤抑制基因的工作。
DNA甲基化发生在CpG位点,并且在哺乳动物中,大部分CpG胞嘧啶被甲基化。然而,在启动子附近区域存在DNA区段,这些区段在正常细胞中具有集中度更高的、未甲基化的CpG位点(称为CpG岛)。这些CpG岛在癌细胞中变为极度甲基化,由此导致不应当沉默的基因的关闭。这种异常是在肿瘤中发生的表观遗传变化的标志并且在癌症发育早期发生。CpG岛的超甲基化可以通过关闭肿瘤抑制基因而引起肿瘤。事实上,这些类型的改变在人类癌症中比DNA序列突变更加普遍。
此外,尽管表观遗传变化不会改变DNA序列,但它们能导致突变。这些导致癌症的家族性的或者遗传性的基因的大约一半通过甲基化被关闭。这些基因的大多数正常地抑制肿瘤形成并且帮助修复DNA,包括O6-甲基鸟嘌呤-DNA甲基转移酶(MGMT)、MLH1周期蛋白依赖性激酶抑制剂2B(CDKN2B)以及RASSF1A。例如,MGMT启动子的超甲基化导致G-到A-突变数目的增加。
超甲基化还可导致微卫星的不稳定,微卫星是重复的DNA序列。微卫星在正常个体中普遍存在,并且它们通常由重复的二核苷酸CA组成。DNA修复基因MLH1的启动子过度甲基化能使微卫星不稳定并且将其延长或者缩短。微卫星的不稳定性与许多癌症有关,包括结肠直肠癌、子宫内膜癌、卵巢癌以及胃癌。
脆性X染色体综合征是最常遗传的智力障碍,尤其是在男性中。两种性别都会受到这种病症的影响,但是由于男性仅有一条X染色体,一条脆性的X对他们的影响将更严重。确实,脆性X染色体综合征发生率大致在男性中1/4000,且在女性中1/8000。患有这种综合征的人具有严重的智力障碍,延迟的言语发育,以及“类自闭症”行为。
脆性X综合征从包含基因异常的X染色体部分在显微镜下看起来的样子得名;它通常呈现出似乎由一根线悬挂着并且易于破碎。该综合征是由一种在FMR1(脆性X综合征1)基因中的异常导致的。未患脆性X综合征的人在他们的FMR1基因中具有6至50个三核苷酸CGG的重复。然而,具有超过200个重复的个体具有一种完全突变,并且他们通常表现出该综合征的症状。过多的CGG导致在FMR1基因启动子区的CpG岛变为甲基化的;而正常情况下,它们是非甲基化的。这种甲基化关闭该基因,使该FMR1基因停止产生一种称作脆性X综合征蛋白的重要的蛋白。这种特异性蛋白的缺失导致了脆性X染色体综合征。虽然已经给予脆性X导致的CGG扩增突变很多的关注,与FMR1甲基化相关的表观遗传变化是该综合征的真正的原因。
脆性X染色体综合征不是唯一的涉及表观遗传变化的智力迟钝相关的的紊乱。其他此类病症包括鲁泰二氏(Rubenstein-Taybi)、科芬-劳里(Coffin-Lowry)、普瑞德-威利(Prader-Willi)、天使人、贝威二氏(Beckwith-Wiedemann)、ATR-X以及雷特(Rett)综合征。
表观遗传学疗法包括控制表观修饰的酶,特别是DNA甲基转移酶以及组蛋白脱乙酰基酶的抑制剂,它们对于一些恶性肿瘤表现出良好的抗肿瘤发生效果,连同反义寡核苷酸以及siRNA。
免疫疗法
在一些实施例中,将在此描述的化合物与一种免疫疗法一起进行给药。肿瘤免疫疗法指的是被设计成诱导患者自身免疫系统对抗肿瘤的一组不同的治疗策略。用于产生免疫应答对抗肿瘤的现代的方法包括用于浅表性膀胱癌的血管内BCG免疫疗法、前列腺癌疫苗普罗文奇(Provenge)、以及使用干扰素和其他细胞因子在肾细胞癌和黑色素瘤患者体内诱导免疫应答。
同种异体造血干细胞移植可以视为免疫疗法的一种形式,因为供体的免疫细胞通常将以移植物抗肿瘤效应攻击肿瘤。在一些实施例中,这些免疫疗法剂可以与在此描述的一种化合物组合使用。
激素疗法
在一些实施例中,将在此描述的化合物与一种激素疗法一起进行给药。一些癌症的生长可以通过提供或阻断某些激素来抑制。激素敏感型肿瘤的常见实例包括某些类型的乳腺癌和前列腺癌,连同某些类型的响应于某些视黄醇/视黄酸的白血病。去除或者阻断雌激素或睾酮常常是一种重要的附加的治疗。在某些癌症中,给予激素激动剂(如孕激素)可以是治疗有益的。在一些实施例中,这些激素疗法剂可以与在此描述的一种化合物组合使用。
激素治疗剂包含给予激素促效剂或激素拮抗剂,并包含类视黄醇/视黄酸,抑制雌激素或睾丸素的化合物,以及给予孕激素类。
炎症和自身免疫性疾病
在此描述的化合物可以在尤其人类和其他的哺乳动物中被用以治疗或者预防与炎症相关的疾病或者紊乱。在此描述的化合物可以在炎症开始发病之前、之时或者之后给药。当预防性地使用时,这些化合物优选地在任何炎症应答或者症状之前被提供。给予这些化合物能预防或者减弱炎症应答或者症状。示例性炎性病症包括,例如,多发性硬化症、类风湿性关节炎、银屑病关节炎、变性关节病、脊椎关节病、其他的血清反应阴性的炎性关节炎、风湿性多肌病、各种脉管炎(例如,巨细胞动脉炎、ANCA+脉管炎)、痛风性关节炎、系统性红斑狼疮、幼年型关节炎、青少年类风湿性关节炎、骨关节炎、骨质疏松症、糖尿病(例如,胰岛素依赖型糖尿病或者青少年型糖尿病)、经期痉挛、纤维囊泡症、炎性肠病、过敏性肠综合征、克罗恩病、粘液性结肠炎、溃疡性结肠炎、胃炎、食道炎、胰腺炎、腹膜炎、阿尔茨海默病、休克、强直性脊椎炎、胃炎、结膜炎、胰腺炎(急性或者慢性)、多器官损伤综合征(例如,继发性败血症或创伤)、心肌梗塞、动脉粥样硬化、中风、再灌注损伤(例如,由于心肺分流术或者肾透析)、急性肾小球肾炎、热损伤(即,晒伤)、坏死性小肠结肠炎、粒细胞输注相关的综合征、和/或斯耶格伦氏综合征(Sjogren's syndrome)。示例性皮肤炎性病症包括例如湿疹、特应性皮炎、接触性皮炎、荨麻疹、硬皮病、银屑病以及具有急性炎症性组分的皮肤病。
在另一个实施例中,在此描述的一种化合物或者方法可以用于治疗或者预防变态反应过敏以及呼吸病症,包括哮喘、支气管炎、肺纤维化、过敏性鼻炎、氧中毒、肺气肿、慢性支气管炎、急性呼吸窘迫综合征以及任何慢性阻塞性肺病(COPD)。这些化合物可以被用于治疗慢性肝炎感染,包括乙型肝炎以及丙型肝炎。
此外,在此描述的化合物或者方法可以用于治疗自身免疫疾病和/或与自身免疫疾病相关的炎症如器官-组织自身免疫性疾病(例如,雷诺氏综合征(Raynaud'ssyndrome))、硬皮病、重症肌无力、移植排斥、内毒素休克、败血病、银屑病、湿疹、皮炎、多发性硬化症、自身免疫性甲状腺炎、葡萄膜炎、系统性红斑狼疮、阿狄森氏病(Addison'sdisease)、自身免疫多腺病(也称作自身免疫性多腺体综合征)以及格雷弗氏病(Grave'sdisease)。
在一个具体的实施例中,此处所述的这些化合物可用于治疗多发性硬化症。
联合疗法
在某些实施例中,一种在此描述的化合物可以单独地或者与其他的有用于治疗或者预防炎症的化合物组合地给药。示例性抗炎剂包括,例如,类固醇(例如,氢化可的松、可的松、氟氢可的松、泼尼松、6[α]-甲泼尼龙、曲安西龙、倍他米松或地塞米松)、非甾体抗炎药物(NSAIDS)(例如阿司匹林、扑热息痛、托美汀、布洛芬、甲芬那酸、吡罗昔康、萘丁美酮、罗非考昔、塞来昔布、依托度酸或尼美舒利)。在另一个实施例中,其他的治疗剂是抗生素(例如,万古霉素、盘尼西林、阿莫西林、氨比西林、头孢噻肟、头孢曲松、头孢克肟、利福平甲硝唑、多西环素或者链霉素)。在另一个实施例中,其他的治疗剂是PDE4抑制剂(例如,罗氟司特或者咯利普兰)。在另一个实施例中,其他的治疗剂是抗组织胺剂(例如,赛克力嗪、羟嗪、普鲁米近或者苯海拉明)。在另一个实施例中,其他的治疗剂是抗疟药(例如,青蒿素、蒿甲醚、青蒿琥酯、磷酸氯喹、盐酸甲氟喹、盐酸多西环素、盐酸氯胍、阿托伐醌或者卤泛群)。在一个实施例中,其他的化合物是屈曲克凝α。
抗炎剂的另外的实例包括例如醋氯芬酸、阿西美辛、e-乙酰氨基己酸、扑热息痛、醋氨沙洛、乙酰苯胺、乙酰水杨酸、S-腺苷甲硫氨酸、阿氯芬酸、阿氯米松、阿芬太尼、阿尔孕酮、烯丙罗定、阿明洛芬、阿洛普令、阿法罗定、阿司匹林铝、安西奈德、氨芬酸、氨氯苯噁嗪、3-氨基-4-羟丁酸、2-氨基-4-甲基吡啶、氨丙吡酮、氨基比林、阿米西群、水杨酸铵、安吡昔康、呱氨托美丁、阿尼利定、安替比林、安曲非宁、阿扎丙宗、丙酸倍氯米松、苄达酸、贝诺酯、苯噁洛芬、苄哌吡酮、苄达明、苄吗啡、柏莫洛芬、倍他米松、倍他米松-17-戊酸盐、贝齐米特、[α]-没药醇、溴芬酸、对溴乙酰苯胺、5-溴水杨酸酯、溴水杨醇、布西丁、布氯酸、布可隆、布地奈德、丁苯羟酸、丁丙二苯肼、丁丙诺啡、布他西丁、布替布芬、布托啡诺、卡马西平、卡比芬、卡洛芬、卡沙兰、三氯叔丁醇、氯泼尼松、氯乙苯噁嗪酮、水杨酸胆碱、辛可芬、桂美辛、西拉马朵、环氯茚酸、氯倍他索、氯可托龙、氯美辛、氯尼他秦、氯尼辛、氯吡酸、氯泼尼醇、丁香(clove)、可待因、溴甲可待因、磷酸可待因、硫酸可待因、可的松、可的伐唑、克罗丙胺、克罗乙胺、环佐辛、地夫可特、去氢睾酮、地素吗啡、地奈德、去羟米松、地塞米松、地塞米松-21-异烟酸盐、右奥沙屈、右吗拉胺、右丙氧芬、去氧皮质酮、地佐辛、地恩丙胺、二醋吗啡、双氯芬酸、二苯米唑、联苯吡胺、二氟拉松、二氟可龙、二氟尼柳、二氟泼尼酯、双氢可待因、双氢可待因酮烯醇乙酸酯、双氢吗啡、乙酰水杨酸二羟铝、地美沙朵、地美庚醇、二甲噻丁、吗苯丁酯、地匹哌酮、diprocetyl、安乃近、地他唑、屈噁昔康、依莫法宗、恩芬那酸、甘草次酸、依匹唑、依他佐辛、依特柳酯、乙水杨胺、依索庚嗪、依托沙秦、乙甲噻丁、乙基吗啡、依托度酸、依托芬那酯、依托尼秦、丁香酚、联苯乙酸、芬布芬、芬克洛酸、芬度柳、非诺洛芬、芬太尼、芬替酸、非普地醇、非普拉宗、夫洛非宁、氟扎可特、氟氯奈德、氟芬那酸、二氟美松、氟尼缩松、氟尼辛、氟诺洛芬、氟轻松、醋酸氟轻松、氟轻松、氟可丁酯、氟考龙、氟苯乙砜、氟米龙、氟培龙、氟吡汀、氟泼尼定、氟泼尼龙、氟丙喹宗、氟氢缩松、氟比洛芬、氟替卡松、福莫可他、磷柳酸、龙胆酸、格拉非宁、葡美辛、水杨酸乙二醇酯、愈创蓝油烃、哈西奈德、乌倍他索、卤米松、卤泼尼松、海洛因、氢可酮、氢可他酯、氢化可的松、乙酸氢化可的松、琥珀酸氢化可的松、半琥珀酸氢化可的松、氢化可的松21-赖氨酸盐、环戊丙酸氢化可的松、氢吗啡酮、羟哌替啶、异丁芬酸、布洛芬、异丁普生、水杨酸咪唑、吲哚美辛、吲哚洛芬、三苯唑酸、异氟泼尼龙、醋酸异氟泼尼龙、isoladol、异美沙酮、异尼辛、伊索克酸、伊索昔康、凯托米酮、酮洛芬、酮咯酸、对乳酰乙氧苯胺、利非他明、左洛啡烷、左啡诺、左芬啡烷、洛芬太尼、氯那唑酸、氯诺昔康、洛索洛芬、赖氨酸乙酰水杨酸、马泼尼酮、甲氯芬那酸、甲羟松、甲芬那酸、美洛昔康、哌替啶、甲泼尼松、美普他酚、氨基水杨酸、美他佐辛、美沙酮、左美丙嗪、甲基氢化泼尼松、醋酸甲基氢化泼尼松、甲泼尼龙琥珀酸钠、甲基氢化泼尼松suleptnate、甲嗪酸、甲氧夫啉、美托酮、莫非布宗、莫苯唑酸、莫米松、吗拉宗、吗啡、盐酸吗啡、硫酸吗啡、水杨吗啉、麦罗啡、萘丁美酮、纳布啡、烯丙吗啡、水杨酸1-萘酯、萘普生、罂粟碱、奈福泮、尼可吗啡、烟胺比林、尼氟灭酸、尼美舒利、5'-硝基-2'-丙氧基乙酰苯胺、去甲左啡诺、去甲美沙酮、去甲吗啡、诺匹哌酮、奥沙拉秦、阿片、奥沙西罗、奥沙美辛、奥沙普秦、羟考酮、羟吗啡酮、羟布宗、阿片全碱、帕拉米松、瑞尼托林、帕沙米特、喷他佐辛、哌立索唑、非那西丁、苯吗庚酮、非那佐辛、盐酸非那吡啶、非诺可、苯哌利定、非诺吡酮、非诺吗烷、乙酰水杨酸苯酯、保泰松、水杨酸苯酯、非尼拉朵、吡酮洛芬、匹米诺定、哌布宗、哌立酮、吡拉唑酸、哌腈米特、吡罗昔康、吡洛芬、普拉洛芬、泼尼卡酯、氢化波尼松、泼尼松、泼尼松龙戊酸酯、泼尼立定、丙谷美辛、普罗庚嗪、二甲哌替啶、丙帕他莫、丙哌利定、丙吡兰、右丙氧芬、异丙安替比林、普罗喹宗、丙替嗪酸、普罗沙唑、雷米那酮、瑞芬太尼、甲硫利马唑、醋水杨胺、水杨苷、水杨酰胺、水杨酰胺O-乙酸、水杨酸、水杨基硫酸、双水杨酯、沙维林、西美曲特、舒芬太尼、柳氮磺吡啶、舒林酸、超氧化物歧化酶、舒洛芬、琥布宗、他尼氟酯、替尼达普、替诺昔康、特罗芬那酯、粉防己碱、噻唑丁炎酮、噻洛芬酸、噻拉米特、替利定、替诺立定、替可的松、托芬那酸、托美丁、曲马多、曲安西龙、曲安奈德、托培辛、维米醇、联苯丁酸、希莫洛芬、扎托洛芬以及佐美酸。
在一个实施例中,一种在此描述的化合物可以与一种用于治疗或者预防炎症的选择性COX-2抑制剂一起给药。示例性的选择性COX-2抑制剂包括例如地拉考昔、帕瑞考昔、塞来考昔、伐地考昔、罗非考昔、艾托考昔以及芦米考昔。
在一些实施例中,提供的化合物与一种蒽环类化合物或Topo II抑制剂组合给药。在某些实施例中,提供的化合物与阿霉素(Dox)组合给药。在某些实施例中,提供的化合物与硼替佐米(并且更广泛地包括carfilzomib)组合给药。出人意料地,已经发现提供的化合物与Dox或者硼替佐米联合致使一种协同效应(亦即,大于相加的)。
病毒感染
在此描述的化合物和方法可以被用以治疗或者预防尤其在人类和其他哺乳动物中的病毒感染相关的疾病或者紊乱。在此描述的化合物可以在病毒感染开始发病之前、之时或者之后给药。当预防性地使用时,这些化合物优选地在任何病毒感染或其症状之前被提供。
示例性病毒性疾病包括急性发热性咽炎、咽结膜热、流行性角膜结膜炎、幼儿肠胃炎、柯萨奇病毒感染、传染性单核细胞增多、伯基特淋巴瘤、急性肝炎、慢性肝炎、肝硬化、肝细胞癌、原发性HSV-1感染(例如,儿童龈口炎、成人扁桃腺炎和咽炎、角膜结膜炎)、潜伏性HSV-1感染(例如,唇疱疹以及感冒疮)、原发性HSV-2感染、潜伏性HSV-2感染、无菌性脑膜炎、传染性单核细胞增多、巨细胞包涵体病、卡波西氏肉瘤、多中心卡斯特莱曼病、原发性渗出性淋巴瘤、AIDS、流感、雷氏综合征、麻疹、感染后脑脊髓炎、腮腺炎、增生性上皮病变(例如,常见的、平坦的、跖和肛门生殖器疣,喉乳头状瘤,疣状表皮发育不良)、宫颈癌、鳞状细胞癌、义膜性喉炎、肺炎、细支气管炎、普通感冒、脊髓灰质炎、狂犬病、流感样综合征、严重的细支气管炎与肺炎、德国麻疹、先天性风疹、水痘、以及带状疱疹。
示例性甲型流感病毒毒株包括H1N1、H3N2、H5N1、H7N3、H7N9。在此描述的化合物还可以用于治疗或预防乙型流感。
示例性病毒病原体包括腺病病、柯萨奇病毒、登革热病毒、脑炎病毒、EB病毒、甲型肝炎病毒、乙型肝炎病毒、丙型肝炎病毒、1型单纯疱疹病毒、2型单纯疱疹病毒、巨细胞病毒、8型人类疱疹病毒、人类免疫缺陷病毒、流感病毒、麻疹病毒、腮腺炎病毒、人乳头瘤病毒、副流感病毒、脊髓灰质炎病毒、狂犬病病毒、呼吸道合胞病毒、风疹病毒、水痘带状疱疹病毒、西尼罗病毒、Dungee以及黄热病毒。病毒病原体还可以包括那些引起抗性病毒感染的病毒。
抗病毒药是一类特异性地用于治疗病毒感染的药剂。抗病毒作用通常分为三种机制之一:干扰病毒侵袭靶细胞的能力(例如,金刚烷胺、金刚乙胺和普拉康纳利),病毒合成的抑制(例如,核苷类似物,例如阿昔洛韦和齐多夫定(AZT))以及病毒释放的抑制(例如,扎那米韦和奥塞米韦)。
眼科
在此描述的化合物和方法可以用来治疗或预防眼科紊乱。示例性眼科紊乱包括黄斑水肿(糖尿病的和非糖尿病的黄斑水肿)、与年龄有关的黄斑湿性和干性变性、年龄性盘状黄斑变性、囊样黄斑水肿、眼睑水肿、视网膜水肿、糖尿病性视网膜病变、脉络膜视网膜病变、新生血管性黄斑病变、新生血管性青光眼、葡萄膜炎、虹膜炎、视网膜脉管炎、眼内炎、全眼球炎、转移性眼炎、脉络膜炎、视网膜色素上皮炎、结膜炎、睫状体炎、巩膜炎、巩膜外层炎、视神经炎、球后视神经炎、角膜炎、睑炎、渗出性视网膜脱离、角膜溃疡、结膜溃疡、慢性钱币状角膜炎、与组织缺氧或局部缺血相关的眼科疾病、早产儿视网膜病变、糖尿病增生性视网膜病变、息肉状脉络膜血管病变、视网膜血管瘤样增生、视网膜动脉闭塞、视网膜静脉闭塞、科茨氏病、家族性渗出性玻璃体视网膜病变、无脉病(高安氏病)、视网膜静脉周围炎、抗磷脂抗体综合征、白血病性视网膜病变、血液高粘滞综合征、巨球蛋白血症、干扰素相关的视网膜病变、高血压性视网膜病变、放射性视网膜病变、角膜上皮干细胞缺乏以及白内障。
使用在此描述的化合物和方法可治疗的其他眼科紊乱包括增生性玻璃体视网膜病变和慢性视网膜脱离。
炎性眼病使用在此描述的化合物和方法也是可治疗的。
神经退行性疾病
神经退行性变是针对神经元的结构或功能的逐渐丧失,包括神经元死亡的涵盖性术语。包括帕金森症、阿尔茨海默氏症以及亨廷顿氏症的许多神经退行性疾病的发生是神经退行性过程的结果。随着研究进展,与这些疾病有关的疾病在亚细胞水平上彼此显示出许多相似性。这些发现的相似性为可以同时改善许多疾病的进一步治疗提供了希望。在包括非典型性蛋白质装配连同诱导性细胞死亡的不同的神经退行性紊乱之间存在许多相似之处。
阿尔茨海默病的特征为在脑皮层以及某些皮层下区域的神经元以及突触的损失。这种丧失导致患部的严重萎缩,包括颞叶和顶叶,以及部分额皮质与扣带回的退行性变。
亨廷顿氏病导致星形胶质细胞增生以及中棘神经元的损失。脑区域根据它们的结构以及它们所包含的神经元的类型,因为它们累积地失去细胞而减少的大小而受损。受影响区域主要是在纹状体,但是在额皮质以及颞皮质中也有。该纹状体的丘脑下神经核传递控制信号至该苍白球,该苍白球开始并调节运动。来自丘脑下神经核的信号越弱,由此导致运动开始与调节的减少,从而导致典型性的运动紊乱。示例性的用于亨廷顿氏病的治疗包括丁苯那嗪、神经镇定药、苯并二氮杂卓、金刚烷胺、瑞马西胺、丙戊酸、选择性5羟色胺再吸收抑制剂(SSRIs)、米氮平以及抗紧张剂。
在帕金森氏症中脑细胞损失的机制可以包括在受损细胞中的结合至泛素的蛋白α-突触核蛋白的异常累积。该α-突触核蛋白-泛素复合体不可以导向蛋白酶体。这种蛋白累积形成了称为路易体的蛋白质细胞质内含物。最新的疾病发病机理研究表明通过α-突触核蛋白的多巴胺能神经元的死亡取决于在两种主要的细胞器-内质网(ER)与高尔基体之间的蛋白转运的结构缺陷。在动物模型中,某些蛋白质(如Rab1)可以逆转这种由α-突触核蛋白引起的缺陷。示例性的帕金森氏病疗法包括左旋多巴,多巴胺激动药如包括溴麦角环肽、硫丙麦角林、普拉克索、罗匹尼罗、吡贝地尔、卡麦角林、阿扑吗啡和麦角乙脲,多巴脱羧基抑制剂,MAO-B抑制剂如司来吉兰(selegilene)和雷沙吉兰(rasagilene),抗胆碱能类以及金刚烷胺。
肌萎缩性侧索硬化症(ALS/卢·格里克病)是一种运动神经元选择性地定向退行性变的疾病。示例性的ALS疗法包括利鲁唑、巴氯芬、地西泮、苯海索以及阿米替林。
其他的示例性的神经退行疗法包括反义寡核苷酸以及干细胞。
伤口愈合
伤口是由细胞或组织损伤表征的病症类型。伤口愈合是一个动态途径,它最佳地导致恢复组织完整性和功能。伤口愈合过程由三个重叠阶段组成。第一阶段是发炎期,它由内环境稳定、血小板聚集和脱粒表征。作为第一应答的血小板释放多种生长因子,以募集免疫细胞、上皮细胞和内皮细胞。发炎期典型地发生在第0-5天。伤口愈合的第二阶段是增生期,在此期间巨噬细胞和粒细胞侵入伤口。浸润性成纤维细胞开始产生胶原。此阶段的主要特征是上皮形成、血管生成、肉芽组织形成以及胶原产生。增生期典型地发生在第3-14天。第三阶段是重塑期,此时发生基质形成。成纤维细胞、上皮细胞和内皮细胞继续产生用于重塑的胶原和胶原酶连同基质金属蛋白酶(MMP)。发生胶原交联并且伤口经历收缩。重塑期典型地发生从第7天至一年。
在此描述的化合物和组合物可以用于促进伤口愈合(例如,促进或加速伤口闭合和/或伤口愈合,减轻伤口和/或围绕伤口的组织的瘢痕纤维化,抑制伤口周围或附近的细胞凋亡)。因此,在某些实施例中,本发明提供了一种用于促进受试者的伤口愈合的方法,该方法包括向该受试者给予治疗有效量的化合物(例如,CRM1抑制剂)或其药学上可接受的盐或组合物。该方法不需要实现完全愈合或闭合伤口;该方法足以促进任何程度的伤口闭合。在此方面中,该方法可以单独应用或作为用于愈合受伤组织的其他方法的辅助物。
在此描述的化合物和组合物可以用于治疗发炎(或早期)阶段期间、增生(或中期)伤口愈合阶段期间和/或重塑(或晚期)伤口愈合阶段期间的伤口。
在一些实施例中,对伤口愈合有需要的受试者是人或动物,例如,狗、猫、马、猪或啮齿动物(如小鼠)。
在一些实施例中,有用于伤口愈合的在此描述的化合物和组合物局部地给药(例如至伤口部位附近)或全身地给药。
更确切地说,可以通过包衣伤口或应用用在此描述的化合物或组合物包衣或处理的绷带、填料、缝线等来向伤口部位给予治疗有效量的在此描述的化合物或组合物(任选地与其他药剂组合)。因此,在此描述的化合物和组合物可以被配制用于局部给药来治疗表面伤口。局部配制品包括经由口腔(颊)递送并且递送至皮肤,使得一层皮肤(即,表皮、真皮和/或皮下层)与在此描述的化合物或组合物接触的那些。局部递送系统可以用于给予在此描述的化合物和组合物的局部配制品。
可替代地,可以通过例如注射溶液、注射延长释放配制品或引入生物可降解的植入物在伤口部位处或靠近伤口部位给予在此描述的化合物和组合物,该溶液、配制品或植入物包括在此描述的化合物或组合物。
在此描述的化合物和组合物可以用于治疗急性伤口或慢性伤口。当正常修复性过程中断时产生慢性伤口。慢性伤口可以从无法识别的持续感染或不适当的初级处理导致的急性损伤发展而来。然而,在大多数情况下,慢性损害是归因于静脉、动脉或代谢血管疾病、压疮、辐射损伤或肿瘤的进行性组织分解的终末期。
在慢性伤口中,出于多种原因不会发生愈合,包括糖尿病溃疡中的不当循环、显著坏死(如在烧伤中)和感染。在这些慢性伤口中,生存能力或恢复期通常是限速步骤。这些细胞不再能生存,并且因此,由不利的伤口床环境延长了初始恢复期。
慢性伤口包括但不限于以下各项:慢性局部缺血皮肤损害;硬皮病溃疡;动脉溃疡;糖尿病足溃疡;压迫性溃疡;静脉溃疡;未愈合的下肢伤口;归因于炎性病症的溃疡;和/或长久性伤口。慢性伤口的其他实例包括慢性溃疡,糖尿病伤口,由糖尿病性神经病、静脉机能不全和动脉机能不全引起的伤口,以及压力伤口和冷热烧伤。慢性伤口的另外的其他实例包括慢性溃疡,糖尿病伤口,由糖尿病性神经病、静脉机能不全、动脉机能不全引起的伤口,以及压力伤口。
急性伤口包括但不限于术后伤口、撕裂、痔疮以及裂伤。
在一个具体实施例中,在受试者中,在此描述的化合物和组合物可以用于糖尿病伤口愈合或加速继发于糖尿病或局部缺血的腿和足溃疡的愈合。
在一个实施例中,该伤口是表面伤口。在另一个实施例中,该伤口是手术伤口(例如,腹部或胃肠手术伤口)。在一个另外的实施例中,该伤口是烧伤。在又另一个实施例中,该伤口是辐射暴露的结果。
在此描述的化合物和组合物还可以用于糖尿病伤口愈合、胃肠伤口愈合或愈合归因于例如手术的粘连。
在此描述的化合物和组合物还可以用于愈合继发于另一种疾病的伤口。例如,在炎性皮肤病(如银屑病和皮炎)中,存在众多继发于该疾病并且由皮肤深层开裂或皮肤抓伤引起的皮肤损害事件。在此描述的化合物和组合物可以用于愈合继发于这些疾病(例如,炎性皮肤病,如银屑病和皮炎)的伤口。
在一个另外的实施例中,该伤口是内部伤口。在一个具体方面中,该内部伤口是慢性伤口。在另一个具体方面中,该伤口是血管伤口。在又另一个具体方面中,该内部伤口是溃疡。内部伤口的实例包括但不限于瘘以及与整容手术、内部适应症、克罗恩病、溃疡性结肠炎、内部手术缝合线和骨骼固定相关的内部伤口。内部伤口的其他实例包括但不限于瘘以及与整容手术、内部适应症、内部手术缝合线和骨骼固定相关的内部伤口。
伤口的实例包括但不限于擦伤、撕脱伤、开放性气胸(blowing wound)(即,开放性气胸(open pneumothorax))、烧伤、挫伤、枪伤、切伤、开放性伤口、穿透伤、穿孔伤、穿刺伤、挂线(séton)伤口、戳刺伤、手术伤口、皮下伤口、糖尿病病变或切线伤口。可以通过在此描述的化合物和组合物治疗的另外的伤口实例包括急性病症或伤口,如热烧伤、化学烧伤、辐射烧伤、由过度暴露于紫外线辐射引起的烧伤(例如,晒伤);对身体组织的损伤,如由劳动和分娩导致的会阴伤;医疗过程(如会阴切开术)期间遭受的损伤;创伤引起的损伤,包括割口(cut)、切口(incision)、表皮脱落;由于偶发事故而遭受的损伤;术后损伤,以及慢性病症,如压疮、褥疮、与糖尿病和循环不良有关的病症和所有类型的痤疮。此外,该伤口可以包括皮炎,如脓疱疮、擦烂、毛囊炎和湿疹;牙科手术之后的伤口;牙周病;创伤之后的伤口;以及肿瘤相关的伤口。伤口的另外的其他实例包括动物咬伤、动脉疾病、昆虫叮咬、骨感染、受损皮肤/肌肉移植物、坏疽、皮肤撕裂或撕裂伤、皮肤老化、手术切口(包括缓慢或未愈合的手术切口)、脑内出血、动脉瘤、皮薄弱症以及术后感染。
在优选实施例中,该伤口选自下组,该组由以下各项组成:烧伤、切伤、开放性伤口、手术或术后伤口、糖尿病病变、热烧伤、化学烧伤、辐射烧伤、压疮、褥疮以及与糖尿病或循环不良有关的病症。在更优选的实施例中,该伤口选自下组,该组由以下各项组成:切伤、开放性伤口、手术或术后伤口、糖尿病病变、压疮、褥疮以及与糖尿病或循环不良有关的病症或伤口。
在一些实施例中,该伤口选自下组,该组由以下各项组成:非辐射烧伤、切伤、开放性伤口、手术或术后伤口、糖尿病病变、热烧伤、化学烧伤、压疮、褥疮以及与糖尿病或循环不良有关的病症。在一些实施例中,该伤口选自下组,该组由以下各项组成:切伤、开放性伤口、手术或术后伤口、糖尿病病变、压疮、褥疮以及与糖尿病或循环不良有关的病症。
本披露还涉及减少受试者在伤口愈合期间瘢痕形成的方法和组合物。在此描述的化合物和组合物可以按有效减少伤口中和/或围绕伤口的瘢痕形成的量直接给予至伤口或给予至伤口附近的细胞。因此,在一些实施例中,提供了一种减少受试者在伤口愈合期间瘢痕形成的方法,该方法包括向该受试者给予治疗有效量的在此描述的化合物(例如,CRM1抑制剂)或其药学上可接受的盐。
该伤口可以包括受试者的身体的任何部分的任何损伤。根据实施例,提供了用于改善、减少或降低已经遭受烧伤的受试者的瘢痕形成的方法。根据优选实施例,提供了用于治疗已经遭受急性或慢性伤口或损伤的受试者的肥厚性瘢痕、减少肥厚性瘢痕的出现或降低肥厚性瘢痕的发生概率的方法。
其他紊乱
在此描述的化合物以及组合物还可以用于治疗异常组织生长以及纤维化的紊乱,包括膨胀性心肌症、肥厚性心肌病、限制性心肌病、肺纤维化、肝纤维化、肾小球肾炎以及其他的肾病症。
联合放射疗法
在此描述的化合物和组合物作为放射致敏剂是有用的。因此,在此描述的化合物和组合物可以与放射疗法组合给予。放射疗法是医学应用高能辐射(例如,x-射线、γ射线、带电粒子)来缩小肿瘤和杀死恶性细胞,并且通常被用作癌症治疗的一部分。放射疗法通过破坏恶性细胞的DNA来杀死它们。
放射疗法可以按若干方式递送给患者。例如,辐射可以从外源(如患者身体外的机器)来递送,如在外照射放射疗法中。用于治疗癌症的外照射放射疗法使用在患者外部的辐射源,典型地是放射性同位素(如60Co、137Cs)或高能x-射线源(如直线加速器)。该外部源产生准直射束导向患者中到达肿瘤部位。外源放射疗法避免了内源放射疗法的一些问题,但是它在辐射束的路径中不令人希望地且必然地连同肿瘤性组织一起照射显著体积的非肿瘤性或健康组织。
通过将外部辐射束以各种“机架(gantry)”角度投射到患者体内并且这些射束会聚在肿瘤部位上,可降低照射健康组织的不良影响,同时在肿瘤性组织中保持给定的辐射剂量。沿着辐射束路径的健康组织的具体体积单元改变,从而减少整个治疗期间给每个这样的健康组织单元的总剂量。
还可以通过将辐射束紧紧对准垂直于辐射束的轴所取的肿瘤的总横截面来降低健康组织的辐射。存在众多系统用于产生这样的周边对准,其中有一些使用多个滑动遮挡板,它们可逐片产生任意轮廓的不透辐射的屏蔽。
对于给予外照射辐射,该量可以是对治疗区至少约1戈瑞(Gy)的份量,至少每隔一天一次。在一个具体实施例中,该辐射以至少每天一次至少约2戈瑞(Gy)的份量给予治疗区。在另一个具体实施例中,该辐射以至少每天一次至少约2戈瑞(Gy)的份量给予治疗区,每周连续五天。在另一个具体实施例中,辐射每隔一天以10Gy的份量给予治疗区,每周三次。在另一个具体实施例中,向对其有需要的患者给予总计至少约20Gy。在另一个具体实施例中,向对其有需要的患者给予至少约30Gy。在另一个具体实施例中,向对其有需要的患者给予至少约40Gy。
典型地,患者一周接受四次或五次外照射疗法。整个治疗过程通常根据癌症的类型和治疗目标而持续从一至七周。例如,患者可以在30天内接受2Gy/天的剂量。
内照射疗法是定位放射疗法,意指辐射源放在肿瘤或患区的部位。内照射疗法可以通过在需要治疗的区域内或靠近该区域放置辐射源来递送。内照射治疗法也称为近距离疗法。近距离疗法包括腔内治疗和间质治疗。在腔内治疗中,容纳放射源的容器被放在肿瘤中或靠近肿瘤。这些源被放入体腔中。在间质治疗中,仅放射源被放入肿瘤中。这些放射源可长久停留在患者体内。典型地,放射源在若干天之后从患者取出。这些放射源位于容器中。
存在许多用于给予放射性药剂的方法。例如,放射性药剂可以通过靶向递送或通过全身性递送靶向放射性缀合物(如放射性标记的抗体、放射性标记的肽和脂质体递送系统)来给予。在靶向递送的一个具体实施例中,该放射性标记的药剂可以是放射性标记的抗体。参见例如,Ballangrud A.M.(巴兰格鲁德A.M.)等人Cancer Res(癌症研究).,2001;61:2008-2014和Goldenber,D.M.(戈登比尔,D.M.)J.Nucl.Med.(核医学杂志),2002;43(5):693-713,将其内容通过引用结合在此。
在靶向递送的另一个具体实施例中,该放射性药剂能以脂质体递送系统(如小单层囊泡、大单层囊泡和多层囊泡)的形式给予。脂质体可以由多种磷脂(如胆固醇、硬脂胺或磷脂酰胆碱)形成。参见例如,Emfietzoglou D(艾姆伏特佐罗D)、Kostarelos K(科斯他拉洛斯K)、Sgouros G(斯古洛斯G).An analytical dosimetry study for the use ofradionuclide-liposome conjugates in internal radiotherapy(在内部放射疗法中使用放射性核素-脂质体缀合物的分析剂量学研究).J Nucl Med(核医学杂志)2001;42:499-504,将其内容通过引用结合在此。
在靶向递送的又另一个具体实施例中,该放射性标记的药剂可以是放射性标记的肽。参见例如,Weiner RE(韦纳RE)、Thakur ML(塔库尔ML).Radiolabeled peptides inthe diagnosis and therapy of oncological diseases(肿瘤疾病的诊断和治疗中的放射性标记的肽).Appl Radiat Isot(实用放射与同位素)2002年11月;57(5):749-63,将其内容通过引用结合在此。
除了靶向递送之外,近距离疗法还可以用于向靶部位递送该放射性药剂。近距离疗法是将辐射源放得尽可能靠近肿瘤部位的技术。通常,该源直接插入肿瘤中。放射源可以处于丝、粒或棒的形式。通常,使用铯、铱或碘。
全身性放射疗法是另一种类型的放射疗法并且涉及在血液中使用放射性物质。全身性放射疗法是靶向疗法的一种形式。在全身性放射疗法中,患者典型地摄取或接受放射性物质的注射液,例如放射性碘或与单克隆抗体结合的放射性物质。
如在此定义的,“放射性药剂”是指包含至少一种发出辐射的放射性同位素的药剂。放射性药剂常规用于核医学中以诊断和/或治疗各种疾病。放射性标记的药剂(例如,放射性标记的抗体)包含作为辐射源的放射性同位素(RI)。如在此所考虑的,术语“放射性同位素”包括金属和非金属放射性同位素。基于放射性标记的药剂的医疗应用来选择放射性同位素。当放射性同位素是金属放射性同位素时,典型地使用螯合剂将该金属放射性同位素与分子的其余部分结合起来。当放射性同位素是非金属放射性同位素时,该非金属放射性同位素典型地与分子的其余部分直接连接,或通过连接物连接。
如在此使用的,“金属放射性同位素”是有用于体内或体外治疗或诊断程序的任何适合的金属放射性同位素。适合的金属放射性同位素包括但不限于:锕-225、锑-124、锑-125、砷-74、钡-103、钡-140、铍-7、铋-206、铋-207、铋-212、铋-213、镉-109、镉-115m、钙-45、铈-139、铈-141、铈-144、铯-137、铬-51、钴-55、钴-56、钴-57、钴-58、钴-60、钴-64、铜-60、铜-62、铜-64、铜-67、铒-169、铕-152、镓-64、镓-67、镓-68、钆-153、钆-157、金-195、金-199、铪-175、铪-175-181、钬-166、铟-110、铟-111、铱-192、铁-55、铁-59、氪-85、铅-203、铅-210、镥-177、锰-54、汞-197、汞-203、钼-99、钕-147、镎-237、镍-63、铌-95、锇-185+191、钯-103、钯-109、铂-195m、镨-143、钷-147、钷-149、镤-233、镭-226、铼-186、铼-188、铷-86、钌-97、钌-103、钌-105、钌-106、钐-153、钪-44、钪-46、钪-47、硒-75、银-110m、银-111、钠-22、锶-85、锶-89、锶-90、硫-35、钽-182、锝-99m、碲-125、碲-132、铊-204、钍-228、钍-232、铊-170、锡-113、锡-114、锡-117m、钛-44、钨-185、钒-48、钒-49、镱-169、钇-86、钇-88、钇-90、钇-91、锌-65、锆-89以及锆-95。
如在此使用的,“非金属放射性同位素”是有用于体内或体外治疗或诊断程序的任何适合的非金属放射性同位素(nonmetallic radioisotope,non-metallicradioisotope)。适合的非金属放射性同位素包括但不限于:碘-131、碘-125、碘-123、磷-32、砹-211、氟-18、碳-11、氧-15、溴-76以及氮-13。
确定放疗最适合的同位素需要权衡各种因素。这些因素包括放射性同位素的肿瘤摄取和保留、血液清除率、辐射递送速率、半衰期和比活性,以及以经济的方式大规模生产放射性同位素的可行性。治疗用放射性药物的关键点是向肿瘤细胞递送必需量的辐射剂量并达到细胞毒或杀肿瘤效应,同时不引起难以控制的副作用。
优选的是,治疗用放射性同位素的物理半衰期与放射性药物在肿瘤部位的生物半衰期相似。例如,如果放射性同位素的半衰期过短,那么在放射性药物已经达到最大的靶标/背景比之前将已经发生大量衰减。另一方面,半衰期太长可导致向正常组织的不必要的辐射剂量。理想地,放射性同位素应该具有足够长的半衰期以达到最低剂量率并在细胞周期的辐射最敏感阶段期间照射所有这些细胞。此外,放射性同位素的半衰期必须足够长以允许足够的时间来生产、释放和运输。
在肿瘤治疗中选择用于给定应用的放射性同位素的其他实际考虑是可利用性和质量。纯度必须足够并且可再现,因为痕量的杂质可影响放射性药物的放射性标记和放射化学纯度。
肿瘤中的靶受体部位典型地是数量有限的。因此,优选的是放射性同位素具有高比活性。比活性主要取决于产生方法。痕量金属污染物必须最小化,因为它们经常与放射性同位素竞争螯合剂并且它们的金属络合物与放射性标记的螯合剂竞争受体结合。
适于在本发明的方法中使用的辐射类型可以变化。例如,辐射可以本质上是电磁辐射或微粒辐射。有用于实践本发明的电磁辐射包括但不限于x-射线和γ射线。有用于实践本发明的微粒辐射包括但不限于电子束(β粒子)、质子束、中子束、α粒子以及负π介子。可以使用常规放射性治疗仪器和方法并且通过手术中和立体定向方法递送辐射。关于适于在实践本发明中使用的辐射治疗的另外的讨论可在整个Steven A.Leibel(史蒂芬A.利贝尔)等人,Textbook of Radiation Oncology(放射肿瘤学教科书)(1998)(W.B.SaundersCompany(W.B.桑德斯公司)出版)中找到,并且特别是在第13和14章中。辐射也可以通过其他方法递送,如靶向递送,例如通过放射性“种子(seed)”,或通过全身性递送靶向放射性缀合物。J.Padawer(J.帕达威尔)等人,Combined Treatment with Radioestradiollucanthone in Mouse C3HBA Mammary Adenocarcinoma and with Estradiollucanthone in an Estrogen Bioassay(在小鼠C3HBA乳腺癌中用放射性雌二醇硫蒽酮进行组合治疗以及在雌激素生物测定中用雌二醇硫蒽酮进行组合治疗),Int.J.Radiat.Oncol.Biol.Phys.(放射肿瘤生物于物理学国际期刊)7:347-357(1981)。其他辐射递送方法可以用于本发明的实践中。
为了肿瘤治疗,α和β-粒子发射体二者都已被研究。α粒子是特别好的细胞毒性剂,因为它们在一或两个细胞直径内消散大量能量。β-粒子发射体根据能量水平具有比较长的穿透范围(在组织中为2mm-12mm)。长程穿透对于具有不均匀的血流和/或受体表达的实体瘤尤为重要。β-粒子发射体产生更均匀的剂量分布,即使当它们在靶组织内不均匀分布时。
在一个具体实施例中,治疗有效量的在此描述的化合物和组合物与治疗有效量的放射疗法组合地给予来治疗癌症(例如肺癌,如非小细胞肺癌)。必要的辐射量可由本领域普通技术人员基于用于具体癌症类型的已知剂量来确定。参见例如,Cancer Medicine(癌症医学)第5版,由R.C.Bast(R.C.巴斯特)等人编辑,2000年7月,BC Decker(BC德克尔)。
上文的披露总体上描述了本发明。通过参照以下的具体实例可以获得更完整的理解。这些实例仅仅是作为说明性的目的而描述的,并且不旨在限制本发明的范围。随着建议或者赋予方便的情况,考虑形式的变化以及等值的替代。尽管已经在此使用了特定的术语,这些术语旨在说明性的意义并且不是出于限制性的目的。
实例
缩写
aq. 水性
DMF N,N-二甲基甲酰胺
DMSO 二甲亚砜
eq. 当量
Et 乙基
EtOAc 乙酸乙酯
g 克
h 小时
HPLC 高效液相色谱法
LCMS 液相色谱质谱法
Me 甲基
mg 毫克
min 分钟
mL 毫升
NMM N-甲基吗啉
NMR 核磁共振
Ph 苯基
THF 四氢呋喃
tR 保留时间
通过此类过程在下文中的描述,应当理解的是,在适当的情况下,将加入适合的保护基团,并且随后以易于被有机合成领域的普通技术人员所理解的方式从不同的反应物和中间体中去除。用于使用此类保护基团的常规程序连同适合的保护基团的实例描述于例如“Protective Groups in Organic Synthesis(有机合成中的保护基团)”,T.W.Green(T.W.格林),P.G.M.Wuts(P.G.M.瓦茨),Wiley-Interscience(威利出版社),纽约,(1999)中。还应理解的是,通过化学操作将一个基团或者取代基转化为另一个基团或者取代基,可以在任何中间体或者终产物上,在形成终产物的合成途径下实施,其中,可能的转化类型仅受在该阶段的分子所带的官能度与该转化中使用的条件或者试剂的固有不相容性的限制。此类固有的不相容性以及通过以适当的顺序进行适当的转化以及合成步骤从而避免它们发生的方法将是易于被有机合成领域的普通技术人员所理解的。在下文给出了转化的实例,并且应当理解的是,所描述的转化不仅限制于针对其举例转化的通用基团或者取代基。关于其他适合的转化的参考和描述在“Comprehensive Organic Transformations-A Guide toFunctional Group Preparations(综合有机转化-官能团制备指南)”,R.C.Larock(R.C.拉洛克),VHC出版公司(1989)中给出。其他的适当的反应的参考和描述在有机化学教科书,例如“Advanced Organic Chemistry(高等有机化学)”March(玛奇),March,第4版,McGrawHill(1992)或者,“Organic Synthesis(有机合成)”,Smith(史密斯),McGraw Hill,(1994))中给出。用于纯化中间体和终产物的技术包括例如在柱上或旋转板上的正相和反相色谱法、重结晶、蒸馏以及液-液或固-液萃取,它们应易于被在本领域的普通技术人员所理解。除非进行不同地定义,取代基和基团的定义是如在化学式I中的。除非另外说明,术语“室温”和“环境温度”应当意指在16℃与25℃之间的温度。除非另外说明,术语“回流”应当意指关于在指定的溶剂沸点或其之上温度下使用一种溶剂。
实例1.合成程序
3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-2-基)丙烯腈(100)的合成:
3-乙氧基-2-(吡啶-2-基)丙烯腈(2)的合成:
在室温下,将2-吡啶基乙腈(1)(1.00g,8.46mmol)和原甲酸三乙酯(1.25g,8.46mmol)添加至乙酸酐(1.73g,16.93mmol)中。将所得反应混合物在100℃下加热3h,冷却至室温,用水(500mL)稀释,并且用乙酸乙酯(100mL x3)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥,并且在减压下浓缩,以给出800mg的粗品3-乙氧基-2-(吡啶-2-基)丙烯腈(2),将其不经进一步纯化而用于以下步骤中。收率(34%),LCMS:m/z 175.20[M+H]+,tR=1.52min。
3-肼基-2-(吡啶-2-基)丙烯腈(3)的合成:
在室温下,将3-乙氧基-2-(吡啶-2-基)丙烯腈(2)(800mg,4.59mmol)和水合肼(230mg,4.59mmol)添加至水(8mL)中。将反应混合物在80℃下加热1h,冷却至室温,用水(500mL)稀释并且用乙酸乙酯(3x 100mL)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥,并且在减压下浓缩,以给出435mg的粗品3-肼基-2-(吡啶-2-基)丙烯腈(3),将其不经进一步纯化而用于以下步骤中。收率(42%),LCMS:m/z 161.18[M+H]+,tR=0.24min。
甲基3,5-双(三氟甲基)苯并咪唑硫代酸酯(benzimidothioate)(5)的合成:
在0℃下,3,5-双(三氟甲基)苯并硫代酰胺(4)(15.0g,54.91mmol)和碘甲烷(38.97g,274.53mmol,17.1mL)添加至二乙醚(120mL)中。将反应混合物在室温下搅拌12h。将固体产物过滤并干燥,以给出甲基3,5-双(三氟甲基)苯并咪唑硫代酸酯(5)。收率(8g,51%),1H NMR(400MHz,DMSO-d6)δ8.51(s,1H),8.44(s,2H),2.72(s,3H)。
甲基-N'-(2-氰基-2-(吡啶-2-基)乙烯基)-3,5-双(三氟甲基)苯并咪唑酰肼(6)的合成:
在室温下,将甲基3,5-双(三氟甲基)苯并咪唑硫代酸酯(5)(300mg,1.04mmol)和3-肼基-2-(吡啶-2-基)丙烯腈(3)(184mg,1.15mmol)添加至二甲基甲酰胺(1.5mL)中。在室温下搅拌1h后,将反应混合物用水(500mL)稀释并用乙酸乙酯(3x 100mL)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥,并且在减压下浓缩,以给出400mg的粗品N'-(2-氰基-2-(吡啶-2-基)乙烯基)-3,5-双(三氟甲基)苯并咪唑酰肼(6),将其不经进一步纯化而用于以下步骤中。收率(96%)。
3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-2-基)丙烯腈(100)的合成:
在室温下,将N'-(2-氰基-2-(吡啶-2-基)乙烯基)-3,5-双(三氟甲基)苯并咪唑酰肼(6)(400mg,1.00mmol)和原甲酸三乙酯(148mg,1.00mmol)添加至乙酸(2mL)中。将反应混合物在100℃下加热30min。冷却至室温后,将反应混合物用水(500mL)稀释并用乙酸乙酯(2x50mL)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥,在减压下浓缩并通过硅胶色谱法纯化,以提供3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-2-基)丙烯腈(100)。收率(100mg,24%)。1H NMR(400MHz,DMSO-d6)δ10.11(s,1H),9.05-9.01(m,3H),8.68-8.67(m,1H),8.47-8.45(m,2H),8.05-8.00(m,1H),7.36-7.33(m,1H)。LCMS:m/z 410.29[M+H]+,tR=2.71min。
(E)-异丙基3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-3-基)丙烯酸酯(101)的合成:
通用程序1:铃木(Suzuki)交叉偶联
在室温下,将(Z)-异丙基3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酸酯(7)(1.0g,2.0mmol)、吡啶3-硼酸(0.39g,3.20mmol)和水(5mL)中的碳酸铯(1.38g,4.0mmol)溶液添加至二噁烷(20mL)中,脱气并用N2吹扫。将四(三苯基膦)钯(0)(0.23g,0.2mmol)添加至反应混合物中并且将所得混合物脱气,并且用N2吹扫。将反应混合物在50℃下搅拌12h。将反应混合物用水(150mL)稀释并用乙酸乙酯(3x50mL)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥并在减压下浓缩。将粗产物使用(己烷中的10%EtOAc)通过硅胶色谱法纯化,以给出(E)-异丙基3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-3-基)丙烯酸酯(101)。收率(0.399g,40%),1H NMR(400MHz,DMSO-d6)δ9.16(s,1H),8.58(s,2H),8.48(s,1H),8.23(s,1H),8.06(s,2H),7.74(d,J=7.2Hz,1H),7.48-7.45(m,1H),5.12-5.06(m,1H),1.28-1.26(m,6H)。LCMS:m/z 471.37[M+H]+,tR=2.73min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-3-基)丙烯腈(102)、(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-3-基)丙烯酸(103)和(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-3-基)丙烯酰胺(104)的合成:
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-3-基)丙烯酸(103)的合成。
通用程序2:酯水解
在0℃下,将异丙基(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-3-基)丙烯酸酯(101)(1.1g,2.3mmol)溶解于THF:H2O(1:1)(11mL)和LiOH.H2O(0.29g,7.0mmol)的溶液中。将该反应混合物在室温下搅拌4h。将反应混合物转移进冰水中并使用3M HCl溶液(10mL)中和并用乙酸乙酯(50mL x3)萃取。将合并的有机层用盐水洗涤并经无水Na2SO4干燥。将有机层在减压下浓缩并且将粗产物通过硅胶色谱法纯化(CH2Cl2中的6%MeOH),以给出(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-3-基)丙烯酸(103)。收率(0.42g,42%),1H NMR(400MHz,DMSO-d6)δ13.33(s,1H),9.12(s,1H),8.59-8.56(m,2H),8.46(s,1H),8.23(s,1H),8.07(s,2H),7.74-7.70(m,1H),7.47-7.43(m,1H)。LCMS:m/z 429.29[M+H]+,tR=2.17min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-3-基)丙烯酰胺(104)的合成。
通用程序3:将羧酸转化为伯酰胺
将(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基-2-(吡啶-3-基)丙烯酸(103)(1g,2.3mmol)溶解于THF(10mL)中并冷却至0℃。向溶液中添加氯甲酸异丁酯(0.49g,3.64mmol)、N-甲基吗啉(0.33g,3.26mmol)。将反应混合物在室温下搅拌30min。在0℃下,将反应混合物过滤并且使氨气吹扫通过滤液持续15min。将反应混合物转移进冰水中并且将化合物用乙酸乙酯(3x50mL)萃取。将合并的有机层用盐水洗涤并经无水Na2SO4干燥。将有机层在减压下浓缩并且将粗产物通过硅胶色谱法纯化,以给出0.370g的(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-3-基)丙烯酰胺(104)。收率(0.370g,37%),1H NMR(400MHz,DMSO-d6)δ8.99(s,1H),8.61-8.59(m,1H),8.45(s,1H),8.30(s,1H),8.22(s,1H),8.09(s,2H),7.71-7.69(m,1H),7.61(s,1H),7.48-7.45(m,1H),7.23(s,1H)。LCMS:m/z428.30[M+H]+,tR=2.31min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-3-基)丙烯腈(102)的合成。
通用程序4:将伯酰胺转化为腈
将(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-3-基)丙烯酰胺(104)(260mg,0.60mmol)溶解于二甲基甲酰胺(5mL)中并冷却至0℃,向其中添加三氯氧磷(110mg,1.21mmol)。将反应混合物在0℃下搅拌1h,转移进冰水中并用乙酸乙酯(3x50mL)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥,在减压下浓缩。将粗产物通过硅胶色谱法纯化,以给出(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-3-基)丙烯腈(102)。收率(0.08g,32%),1H NMR(400MHz,DMSO-d6)δ9.04(s,1H),8.73(s,1H),8.68-8.67(m,1H),8.59(s,1H),8.28(s,1H),8.13(s,2H),8.00-7.97(m,1H),7.55-7.52(m,1H)。LCMS:m/z 410.0[M+H]+,tR=2.37min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-4-基)丙烯腈(105)、异丙基(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-4-基)丙烯酸酯(106)、(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-4-基)丙烯酸(107)以及(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-4-基)丙烯酰胺(108)的合成:
异丙基(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-4-基)丙烯酸酯(106)的合成:
使用通用程序1合成异丙基(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-4-基)丙烯酸酯(106)。收率(9%),1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.63-8.61(m,2H),8.54(s,1H),8.24(s,1H),8.06(s,2H),7.34-7.32(m,2H),5.10-5.06(m,1H),1.27-1.25(m,6H)。LCMS:m/z 471.5[M+H]+,tR=2.73min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-4-基)丙烯酸(107)的合成:
使用通用程序2合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-4-基)丙烯酸(107)。收率(52%),1H NMR(400MHz,DMSO-d6)δ13.38(s,1H),9.12-9.08(m,1H),8.63-8.53(m,3H),8.25-8.22(m,1H),8.10-8.06(m,2H),7.35-7.31(m,2H)。LCMS:m/z 429.11[M+H]+,tR=2.01min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-4-基)丙烯酰胺(108)的合成。
使用通用程序3合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-4-基)丙烯酰胺(108)。收率(33%),1H NMR(400MHz,DMSO-d6)δ8.95(s,1H),8.66-8.62(m,2H),8.24-8.23(m,2H),8.09(s,2H),7.63(s,1H),7.31-7.29(m,2H),7.18(s,1H)。LCMS:m/z 428.16[M+H]+,tR=2.10min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-4-基)丙烯腈(105)的合成:
使用通用程序4合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-4-基)丙烯腈(105)。收率(58%),1H NMR(400MHz,DMSO-d6)δ9.16(s,1H),9.04(s,1H),8.77-8.75(m,2H),8.61(s,2H),8.38(s,1H),7.72-7.70(m,2H)。LCMS:m/z 410.1[M+H]+,tR=2.64min。
异丙基(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(噻唑-2-基)丙烯酸酯(109)、(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(噻唑-2-基)丙烯腈(110)和(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(噻唑-2-基)丙烯酰胺(111)的合成
异丙基(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(噻唑-2-基)丙烯酸酯(109)的合成:
使用通用程序5合成异丙基(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(噻唑-2-基)丙烯酸酯(109),针对(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-N,N-二甲基-2-(吡啶-4-基)丙烯酰胺(113)的合成详细描述通用程序5。收率(54%)。1H NMR(400MHz,DMSO-d6)δ9.27(s,1H),9.12(s,1H),8.59(s,1H),8.27(s,1H),8.22(s,2H),7.88(s,1H),5.13-5.01(m,1H),1.25(d,J=6Hz,6H)。LCMS:m/z 477.18[M+H]+,tR=2.94min。
(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(噻唑-2-基)丙烯酸(8)的合成:
使用通用程序2合成(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(噻唑-2-基)丙烯酸(8)并且将粗产物不经纯化而用于下一步骤中。
(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(噻唑-2-基)丙烯酰胺(111)的合成:
使用通用程序3合成(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(噻唑-2-基)丙烯酰胺(111)。收率(55%)。1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),9.97(s,1H),8.26-8.22(m,4H),7.87(s,1H),7.70(s,1H),7.50(s,1H)。LCMS:m/z 434.21[M+H]+,tR=2.28min。
(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(噻唑-2-基)丙烯腈(110)的合成:
使用通用程序4合成(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(噻唑-2-基)丙烯腈(110)。收率(30%)。1H NMR(400MHz,DMSO-d6)δ9.36(s,1H),9.36(s,1H),9.09(s,1H),8.53(s,1H),8.42(s,2H),8.35(s,1H),8.30(s,1H)。LCMS:m/z 416.01[M+H]+,tR:2.69min。
(E)-(3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-N,N-二甲基-2-(吡啶-3-基)丙烯酰胺(112)的合成:
在室温下,将(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(吡啶-3-基)丙烯酸(103)(0.15g,0.35mmol)溶解于THF(5mL)中。将反应混合物冷却至0℃并且滴加氯甲酸异丁酯(0.067mL,0.525mmol)。然后添加4-甲基吗啉(0.04mL,0.52mmol)。允许将反应混合物加温至室温并搅拌30min。将反应混合物过滤并且将滤液冷却至0℃。将二甲胺(2N,在THF中,2mL)滴加至反应混合物中。将反应混合物在0℃下搅拌15min,加温至室温,转移进冰水中,并且用乙酸乙酯(3x30mL)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥,并且在减压下浓缩,以给出粗产物,将其通过硅胶色谱法纯化(0-5%MeOH:CH2Cl2),以获得(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-N,N-二甲基-2-(吡啶-3-基)丙烯酰胺(12)。(收率:0.040g,25%)。1H NMR(400MHz,DMSO-d6)δ8.82(s,1H),8.57(s,1H),8.56(s,1H),8.23(s,1H),8.21(s,2H),7.80(d,J=11.6Hz,1H),7.68(s,1H),7.45-7.42(m,1H),2.97(s,3H),2.88(s,3H)。LCMS:m/z 456.61[M+H]-,tR=2.30min。
(E)-(3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-N,N-二甲基-2-(吡啶-4-基)丙烯酰胺(113)的合成:
(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴-N,N-二甲基丙烯酰胺(9)的合成:
在室温下,将(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酸(7)(0.5g,1.16mmol)溶解于THF(10mL)中。将反应混合物冷却至0℃并且滴加氯甲酸异丁酯(0.22mL,1.74mmol)。然后将N-甲基吗啉(0.19mL,1.74mmol)添加至反应混合物中并搅拌5min。允许将反应混合物加温至室温,搅拌30min并过滤。将滤液冷却至0℃并且滴加二甲胺(2N,在THF中,2mL)并搅拌15min。允许将反应混合物加温至室温,转移进冰水中并用乙酸乙酯(3x50mL)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥并在减压下浓缩,以给出粗产物,将其通过硅胶色谱法纯化(0-5%MeOH:CH2Cl2),以获得(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴-N,N-二甲基丙烯酰胺(9)。(收率:0.2g,37%)。1HNMR(400MHz,DMSO d6)δ9.41(s,1H),8.70(s,1H),8.57(s,2H),8.32(s,1H),2.97(s,3H),2.88(s,3H)。LCMS:m/z 457.17[M+H]-,tR=2.55min。
(E)-(3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-N,N-二甲基-2-(吡啶-4-基)丙烯酰胺(113)的合成:
通用程序5:斯蒂莱(Stille)偶联
在室温下,将(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴-N,N-二甲基丙烯酰胺(9)(0.2g,0.437mmol)溶解于干1,4-二噁烷(10mL)中并使用N2脱气30min。添加4-(三丁基甲锡烷基)吡啶(0.19g,0.524mmol)和四(三苯基膦)钯(0)(0.05g,0.0437mmol)并且将反应混合物在90℃下加热2h并且然后冷却至室温。将反应混合物转移进冰水中并用乙酸乙酯(3x25mL)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥并在减压下浓缩,以给出粗合物,将其使用(0-5%MeOH:CH2Cl2)通过柱硅胶色谱纯化,以获得(E)-(3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-N,N-二甲基-2-(吡啶-4-基)丙烯酰胺(113)。(收率:0.05g,25%)。1H NMR(400MHz,DMSO-d6)δ9.02(s,1H),8.67(d,J=5.6Hz,2H),8.52(s,2H),8.33(s,1H),8.21(s,1H),7.49(d,J=6Hz,2H),3.10(s,3H),2.85(s,3H)。LCMS:m/z 456.31[M+H]+,tR=2.20min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(1-甲基-1H-吡唑-4-基)丙烯酰胺(114)的合成:
使用通用程序3合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(1-甲基-1H-吡唑-4-基)丙烯酰胺(114)。(收率:0.01g,33%)。1H NMR(400MHz,DMSO-d6)δ8.79(s,1H),8.45(s,2H),8.28(s,1H),7.84(s,1H),7.75(s,1H),7.57(s,1H),7.48(s,1H),7.27(s,1H),3.84(s,3H)。LCMS:m/z 431.21[M+H]+,tR=2.22min。
异丙基(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(嘧啶-5-基)丙烯酸酯(115)的合成:
通用程序6:铃木偶联-方法2
在室温下,将异丙基-(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酸酯(7)(0.7g,1.48mmol)、嘧啶5-硼酸(0.22g,1.77mmol)和水(3.0mL)中的乙酸钾(0.43g,4.4mmol)溶液添加进二噁烷中,脱气并用N2吹扫。添加双(三苯基膦)二氯化钯(II)(0.1g,0.14mmol)并且将反应混合物脱气,并且用N2吹扫。将反应混合物在100℃下搅拌12h,用水(150mL)稀释并用乙酸乙酯(3x50mL)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥并在减压下浓缩。将粗产物通过硅胶色谱法纯化(己烷中的30%EtOAc),以给出异丙基-(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(嘧啶-5-基)丙烯酸酯(115)(收率:0.2g,20%)。1H NMR(400MHz,DMSO-d6)δ9.26(s,1H),9.20(s,1H),8.79(s,2H),8.68(s,1H),8.26(s,1H),8.07(s,2H),5.13-5.07(m,1H),1.27(d,J=6Hz,6H)。LCMS:m/z472.22[M+H]+,tR=2.73min。
异丙基(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(3,5-二甲基异噁唑-4-基)丙烯酸酯(116)的合成:
使用通用程序6合成异丙基(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(3,5-二甲基异噁唑-4-基)丙烯酸酯(116)。(收率:0.2g,20%)。1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.63(s,1H),8.29(s,3H),5.10-5.07(m,1H),2.16(s,3H),1.98(s,3H),1.27(d,J=6Hz,6H)。LCMS:m/z 489.22[M+H]+,tR=2.95min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(3,5-二甲基异噁唑-4-基)丙烯酸(117)的合成
使用通用程序2合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(3,5-二甲基异噁唑-4-基)丙烯酸(117)。(收率:0.1g,50%)。1H NMR(400MHz,DMSO-d6)δ13.37(s,1H),9.17(s,1H),8.63(s,1H),8.29(s,3H),2.15(s,3H),1.98(s,3H)。LCMS:m/z447.23[M+H]+,tR=2.46min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(3,5-二甲基异噁唑-4-基)丙烯酰胺(118)的合成:
使用通用程序3合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(3,5-二甲基异噁唑-4-基)丙烯酰胺(118)。(收率:0.015g,15%)。1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.39(s,1H),8.30(s,2H),8.27(s,1H),7.53(s,1H),7.37(s,1H)2.33(s,3H),2.17(s,3H)。LCMS:m/z 490.27[M+45]+,tR=2.37min。
异丙基(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(5-氟吡啶-3-基)丙烯酸酯(119)的合成:
使用通用程序6合成异丙基(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(5-氟吡啶-3-基)丙烯酸酯(119)。(收率:0.2g,19%)。1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),8.63(s,1H),8.60(s,1H),8.37(s,1H),8.25(s,1H),8.07(s,2H),7.83-7.80(m,1H)5.10-5.07(m,1H),1.27(d,J=6Hz,6H)。LCMS:m/z 489.32[M+H]+,tR=2.91min。
异丙基(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(6-甲氧基吡啶-3-基)丙烯酸酯(120)的合成:
使用通用程序6合成异丙基(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(6-甲氧基吡啶-3-基)丙烯酸酯(120)。(收率:0.14g,20%)。1H NMR(400MHz,DMSO-d6)δ9.12(s,1H),8.51(s,1H),8.23(s,1H),8.14(s,2H),8.07(s,1H),7.62(dd,J1,J2=2.4Hz,1H),6.87(d,J=8.4Hz,1H),5.09-5.06(m,1H)。3.89(s,3H),1.27(d,J=6Hz,6H)。LCMS:m/z 501.33[M+H]+,tR=3.06min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(6-甲氧基吡啶-3-基)丙烯酸(121)的合成:
使用通用程序2合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(6-甲氧基吡啶-3-基)丙烯酸(121)。(收率:0.1g,71%)。1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),9.09(s,1H),8.52(s,1H),8.23(s,1H),8.14(s,2H),8.06(s,1H),7.60(dd,J1,J2=2.4Hz,1H),6.86(dd,J1,J2=0.8Hz,1H),3.89(s,3H)。LCMS:m/z 459.21[M+H]+,tR=2.53min。
异丙基(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(呋喃-3-基)丙烯酸酯(122)的合成:
使用通用程序6合成异丙基(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(呋喃-3-基)丙烯酸酯(122)。(收率:0.2g,21%)。1H NMR(400MHz,DMSO-d6)δ8.93(s,1H),8.42(s,2H),8.26(d,J=10Hz,2H),7.86(s,1H),7.73(s,1H),6.41(dd,J1,J2=0.8Hz,1H),5.10-5.07(m,1H),1.30(d,J=6Hz,6H)。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(嘧啶-5-基)丙烯酸(123)的合成:
使用通用程序2合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(嘧啶-5-基)丙烯酸(123)。(收率:0.15g,19%)。1H NMR(400MHz,DMSO-d6)δ13.52(s,1H),9.23(s,1H),9.18(s,1H),8.77(s,2H),8.69(s,1H),8.26(s,1H),8.07(s,2H)。LCMS:m/z430.0[M+H]+,tR=2.21min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(嘧啶-5-基)丙烯酰胺(124)的合成:
使用通用程序3合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(嘧啶-5-基)丙烯酰胺(124)(收率:0.03g,30%)。1H NMR(400MHz,DMSO-d6)δ9.21(s,1H),9.14(s,1H),8.73(s,2H),8.43(s,1H),8.24(s,1H),8.06(s,2H),7.65(s,1H),7.40(s,1H)。LCMS:m/z 429.13[M+H]+,tR=2.14min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(5-氟吡啶-3-基)丙烯酸(125)的合成:
使用通用程序2合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(5-氟吡啶-3-基)丙烯酸(125)(收率:0.07g,64%)。1H NMR(400MHz,DMSO d6)δ13.46(s,1H),9.18(s,1H),8.63(s,1H),8.58(s,1H),8.35(t,J=3.5Hz,1H),8.25(s,1H),8.07(s,2H),7.81-7.77(m,1H)。LCMS:m/z 447.3[M+H]+,tR=2.43min。
3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(5-氟吡啶-3-基)丙烯酰胺(126)的合成:
使用通用程序3合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(5-氟吡啶-3-基)丙烯酰胺(126)(收率:0.04g,66%)。1H NMR(400MHz,DMSO d6)δ9.08(s,1H),8.60(d,J=2.8Hz,1H),8.37(s,1H),8.43(t,J=1.6Hz,1H),8.23(s,1H),8.08(s,2H),7.78-7.74(m,1H),7.65(s,1H),7.24(s,1H)。LCMS:m/z 446.3[M+H]-,tR=2.32min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(6-甲氧基吡啶-3-基)丙烯酰胺(127)的合成:
使用通用程序3合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(6-甲氧基吡啶-3-基)丙烯酰胺(127)(收率:0.05g,36%)。1H NMR(400MHz,DMSO-d6)δ8.97(s,1H),8.23(d,J=10Hz,2H),8.16(s,2H),8.04(d,J=0.8Hz,1H),7.57(dd,J1=2.4Hz,J2=2.4Hz,2H),7.17(s,1H),6.88(d,J=8Hz,1H),3.90(s,3H)。LCMS:m/z 458.36[M+H]+。tR=2.44min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(呋喃-3-基)丙烯酸(128)的合成:
使用通用程序2合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(呋喃-3-基)丙烯酸(128)(收率:0.11g,81%)。1H NMR(400MHz,DMSO-d6)δ13.31(s,1H),8.91(s,1H),8.42(s,2H),8.27(d,J=3.2Hz,2H),7.84(s,1H),7.70(s,1H),6.40(s,1H)。LCMS:m/z 416.25[M-H]-,tR=2.57min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(呋喃-3-基)丙烯酰胺(129)的合成:
使用通用程序3合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(呋喃-3-基)丙烯酰胺(129)(收率:0.05g,50%)。1H NMR(400MHz,DMSO-d6)δ8.77(s,1H),8.43(s,2H),8.27(s,1H),7.91(s,1H),7.83(s,1H),7.74(s,1H),7.60(s,1H),7.46(s,1H)。6.29(s,1H)。
异丙基(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(1-甲基-1H-吡唑-4-基)丙烯酸酯(130)的合成:
使用通用程序1合成异丙基(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(1-甲基-1H-吡唑-4-基)丙烯酸酯(130)(收率:0.32g,13%)。1H NMR(400MHz,DMSO-d6)δ8.96(s,1H),8.43(s,2H),8.29(s,1H),8.13(s,1H),7.92(s,1H),7.41(s,1H),5.10-5.07(m,1H),3.86(s,3H),1.31-1.24(m,6H)。LCMS:m/z 474.37[M+H]+,tR=2.86min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(1-甲基-1H-吡唑-4-基)丙烯酸(131)的合成:
使用通用程序2合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(1-甲基-1H-吡唑-4-基)丙烯酸(131)(收率:0.08mg,88%)。1H NMR(400MHz,DMSO-d6)δ13.25(s,1H),8.93(s,1H),8.43(s,2H),8.28(s,1H),8.16(s,1H),7.90(s,1H),7.38(s,1H),3.86(s,3H)。LCMS:m/z 432.29[M+H]+,tR=2.32min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(5-氟吡啶-3-基)丙烯酰胺(132)的合成:
异丙基3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2,3-二溴丙酸酯(12)的合成:在室温下,将(Z)-异丙基3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)丙烯酸酯(11)(100g,254.4mmol)溶解于二氯甲烷(500mL)中。在0℃下,经40min滴加溴(80g,500mmol)。允许该反应混合物加热至室温并搅拌6h。将反应混合物转移进冰水中并用CH2Cl2(500mL X3)萃取。将合并的有机层用饱和亚硫酸氢钠水溶液(500mL)洗涤,随后用盐水洗涤,经无水Na2SO4干燥并在减压下浓缩,以给出异丙基3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2,3-二溴丙酸酯(12),将其不经进一步纯化而用于下一步骤中。(130g,93%收率)。LCMS:m/z 554.09[M+H]+,tR=1.95min。
(Z)-异丙基3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酸酯(13)的合成:将异丙基3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2,3-二溴丙酸酯(12)(120g,217mmol)溶解于四氢呋喃(350mL)中并冷却至0℃。添加三乙胺(44g,434mmol)并且将混合物在室温下搅拌16h。将反应混合物用水(120mL)稀释并用乙酸乙酯(200mL X3)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥并在减压下浓缩。将粗产物通过从石油醚中的8%EtOAc中重结晶而纯化,以得到呈白色固体的(Z)-异丙基3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酸酯(13)(90g,88%收率)。1H NMR(400MHz,DMSO-d6)δ9.46(s,1H),8.92(s,1H),8.56(s,2H),8.32(s,1H),5.13-5.07(m,1H),1.33(d,J=6Hz,6H)。LCMS:m/z 472.0[M+H]+,tR=2.10min。
(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酸(14)的合成:将(Z)-异丙基3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酸酯(13)(40g,85mmol)溶解于四氢呋喃(350mL)和水(85mL)中。在0℃下,将氢氧化锂水溶液(20mL,254mmol,12.7N)滴加至混合物中。将反应混合物在0℃下搅拌1h,并且倾倒进水(100mL)中,用HCl(3N)酸化直到pH=3,用乙酸乙酯(200mL X3)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥,在减压下浓缩,并且通过从石油醚中的20%EtOAc中重结晶而纯化,以提供呈白色固体的(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酸(14)(27g,75%收率)。1H NMR(400MHz,DMSO-d6)δ9.43(s,1H),8.89(s,1H),8.56(s,2H),8.31(s,1H)。LCMS:m/z 431.9[M+H]+,tR=1.85min。
(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酰胺(15)的合成:在0℃下,将(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酸(14)(50g,34.9mmol)溶解于THF(400mL)中并且添加氯甲酸异丁酯(31.7g,224mmol)、N-甲基吗啉(17.8g,175.5mmol)。将反应混合物在0℃下搅拌1h。在0℃下,氨气吹扫40min。将反应混合物转移进冰水中并用乙酸乙酯(300mL X3)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥并在减压下浓缩,以给出粗产物,将其通过从EtOAc中重结晶而纯化,以给出42g的(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酰胺(15)。收率:85%。1H NMR(400MHz,DMSO-d6)δ9.40(s,1H),8.70(s,1H),8.54(s,2H),8.29(s,1H),8.0-7.95(m,2H)。LCMS:m/z429.0[M+H]+,tR=1.78min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(5-氟吡啶-3-基)丙烯酰胺(132)的合成:根据通用程序6合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(5-氟吡啶-3-基)丙烯酰胺(132)。收率:6%。1H NMR(400MHz,DMSO-d6)δ9.08(s,1H),8.60(d,J=3Hz,1H),8.37(s,1H),8.32(s,1H),8.22(s,1H),8.08(s,2H),7.76(d,J=9Hz,1H),7.63(s,1H),7.24(s,1H)。LCMS:m/z 446.1[M+H]+,tR=1.70min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(哒嗪-4-基)丙烯酰胺(133)的合成:
根据通用程序6合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(哒嗪-4-基)丙烯酰胺(133)。收率:2%。
1H NMR(400MHz,DMSO-d6)δ9.28(dd,J1=5Hz,J2=1Hz,1H),9.17-9.09(m,2H),8.40(s,1H),8.22(s,1H),8.02(s,2H),7.70-7.61(m,2H),7.36(s,1H)。LCMS:m/z 429.1[M+H]+,tR=1.54min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(6-氟吡啶-2-基)丙烯酰胺(134)的合成:
根据通用程序6合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(6-氟吡啶-2-基)丙烯酰胺(134)。收率:40%。1H NMR(400MHz,DMSO-d6)δ9.17(s,1H),8.54(s,2H),8.32-8.23(m,2H),8.14-8.00(m,2H),7.91(s,1H),7.47-7.39(m,1H),7.24-7.17(m,1H)。LCMS:m/z 446.1[M+H]+,tR=1.84min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(2-氟吡啶-3-基)丙烯酰胺(135)的合成:
根据通用程序2合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(2-氟吡啶-3-基)丙烯酰胺(135)。收率:14%。1H NMR(400MHz,CD3OD)δ8.90(s,1H),8.42(s,1H),8.34(d,J=4Hz,1H),8.19(s,2H),8.02(s,1H),7.97-7.88(m,1H),7.52-7.42(m,1H)。LCMS:m/z 446.1[M+H]+,tR=1.82min。
(E)-2-(2-氨基嘧啶-5-基)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)丙烯酰胺(136)的合成。
(E)-2-(2-氨基嘧啶-5-基)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)丙烯酰胺(136)。收率:25%。1H NMR(400MHz,DMSO-d6)δ9.01(s,1H),8.30(s,2H),8.25(s,1H),8.14(s,1H),8.07(s,2H),7.52(s,1H),7.40(s,1H),6.79(s,2H)。LCMS:m/z 444.1[M+H]+,tR=1.64min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(2-氟嘧啶-5-基)丙烯酰胺(137)的合成:
根据通用程序6合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(2-氟嘧啶-5-基)丙烯酰胺(137)。收率:18%。1H NMR(400MHz,DMSO-d6)δ9.19(s,1H),8.75(s,2H),8.48(s,1H),8.25(s,1H),8.09(s,2H),7.67(s,1H),7.36(s,1H)。LCMS:m/z447.1[M+H]+,tR=1.81min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(3-氟吡啶-4-基)丙烯酰胺(138)的合成:
根据通用程序6合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(3-氟吡啶-4-基)丙烯酰胺(138)。收率:3%。
1H NMR(400MHz,CD3OD)δ8.78(s,1H),8.48(s,1H),8.41(d,J=5Hz,1H),8.34(s,1H),8.06(s,2H),7.92(s,1H),7.43-7.37(m,1H)。LCMS:m/z 446.0[M+H]+,tR=1.69min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(6-氟吡啶-3-基)丙烯酰胺(139)的合成。
根据通用程序6合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(6-氟吡啶-3-基)丙烯酰胺(139)。收率:15%。1H NMR(400MHz,CD3OD)δ8.80(s,1H),8.37(s,1H),8.24(s,2H),8.19(d,J=2Hz,1H),8.03(s,1H),7.98-7.90(m,1H),7.27-7.19(m,1H)。LCMS:m/z 446.1[M+H]+,tR=1.84min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(2-氟吡啶-4-基)丙烯酰胺(140)的合成。
根据通用程序6合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(2-氟吡啶-4-基)丙烯酰胺(140)。收率:29%。
1H NMR(400MHz,CD3OD)δ8.79(s,1H),8.36-8.30(m,2H),8.23(s,2H),8.03(s,1H),7.33(d,J=5Hz,1H),7.17(s,1H)。LCMS:m/z 446.1[M+H]+,tR=1.84min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(5-氯吡啶-3-基)丙烯酰胺(141)的合成。
根据通用程序6合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(5-氯吡啶-3-基)丙烯酰胺(141)。收率:31%。
1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),8.65(d,J=2Hz,1H),8.40(d,J=2Hz,1H),8.37(s,1H),8.22(s,1H),8.08(s,2H),7.98-91(m,1H),7.62(s,1H),7.27(s,1H)。
LCMS:m/z 462.0[M+H]+,tR=1.76min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(6-氯吡啶-3-基)丙烯酰胺(143)的合成:
根据通用程序6合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(6-氯吡啶-3-基)丙烯酰胺(143)。收率:24%。1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.35(s,1H),8.30(d,J=2.0Hz,1H),8.22(s,1H),8.10(s,2H),7.80-7.74(m,1H),7.65-7.55(m,2H),7.24(s,1H)。LCMS:m/z 462.0[M+H]+,tR=1.77min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(2-氯吡啶-3-基)丙烯酰胺(144)的合成:
根据通用程序6合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(2-氯吡啶-3-基)丙烯酰胺(144)。收率:4%。1H NMR(400MHz,CD3OD)δ8.89(s,1H),8.54-8.49(m,1H),8.42(s,1H),8.17(s,2H),8.03(s,1H),7.88-7.83(m,1H),7.57-7.52(m,1H)。LCMS:m/z 462.0[M+H]+,tR=1.70min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(2,6-二氟吡啶-3-基)丙烯酰胺(145)的合成:
根据通用程序6合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(2,6-二氟吡啶-3-基)丙烯酰胺(145)。收率:5%。1H NMR(400MHz,CD3OD)δ8.80(s,1H),8.32(s,1H),8.12(s,2H),7.95-7.86(m,2H),7.01(dd,J1=8Hz,J2=2Hz,1H)。LCMS:m/z464.0[M+H]+,tR=1.74min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-苯基丙烯酰胺(146)的合成:
根据通用程序6合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-苯基丙烯酰胺(146)。收率:32%。1H NMR(400MHz,CD3OD)δ8.24(s,2H),8.11(s,1H),8.04(s,1H),7.90(s,1H),7.49-7.40(m,3H),7.30-7.21(m,2H)。LCMS:m/z 427.1[M+H]+,tR=2.10min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(2-(三氟甲基)吡啶-4-基)丙烯酰胺(147)的合成:
根据通用程序6合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(2-(三氟甲基)吡啶-4-基)丙烯酰胺(147)。收率:11%。1H NMR(400MHz,DMSO-d6)δ9.13(s,1H),8.81(d,J=5Hz,1H),8.36(s,1H),8.20(s,1H),8.00(s,2H),7.88(s,1H),7.66(s,1H),7.61(d,J=5Hz,1H),7.25(s,1H)。LCMS:m/z 496.0[M+H]+,tR=1.79min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(5-氰基吡啶-3-基)丙烯酰胺(148)的合成:
根据通用程序6合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(5-氰基吡啶-3-基)丙烯酰胺(148)。收率:20%。1H NMR(400MHz,DMSO-d6)δ9.14(s,1H),9.06(d,J=2Hz,1H),8.75(d,J=2Hz,1H),8.43(s,1H),8.37-8.32(m,1H),8.23(s,1H),8.03(s,2H),7.66(s,1H),7.27(s,1H)。
LCMS:m/z 453.1[M+H]+,tR=1.79min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(喹啉-3-基)丙烯酰胺(149)的合成:
根据通用程序6合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(喹啉-3-基)丙烯酰胺(149)。收率:80%。1H NMR(400MHz,DMSO-d6)δ9.09(s,1H),8.75(d,J=2Hz,1H),8.42(s,1H),8.29(d,J=2Hz,1H),8.12-7.97(m,3H),7.88(s,2H),7.82(t,J=7Hz,1H),7.63(t,J=7Hz,2H),7.31(s,1H)。LCMS:m/z 478.1[M+H]+,tR=1.64min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(2-氟联苯基-4-基)丙烯酰胺(150)的合成:
根据通用程序6合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(2-氟联苯基-4-基)丙烯酰胺(150)。收率:30%。1H NMR(400MHz,DMSO-d6)δ8.89(s,1H),8.23-8.18(m,4H),7.63-7.56(m,4H),7.54-7.48(m,2H),7.47-7.40(m,1H),7.31-7.25(m,1H),7.20-7.14(m,2H)。LCMS:m/z 521.1[M+H]+,tR=2.06min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(4-(吡啶-3-基)苯基)丙烯酰胺(151)的合成:
根据通用程序6合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(4-(吡啶-3-基)苯基)丙烯酰胺(151)。收率:11%。1H NMR(400MHz,CD3OD)δ9.19(s,1H),8.84-8.74(m,2H),8.52(s,1H),8.31-8.26(m,3H),8.07-7.95(m,4H),7.59(d,J=8Hz,2H)。LCMS:m/z 504.1[M+H]+,tR=1.55min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(1H-吲唑-6-基)丙烯酰胺(152)的合成:
根据通用程序6合成(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(1H-吲唑-6-基)丙烯酰胺(152)。收率:46%。1H NMR(400MHz,DMSO-d6)δ8.54(s,1H),8.20-8.10(m,3H),8.06(s,2H),7.85(d,J=8Hz,1H),7.47(s,1H),6.98(d,J=8Hz,1H)。LCMS:m/z 467.1[M+H]+,tR=1.67min。
(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(嘧啶-5-基)丙烯酰胺(153)的合成:
(E)-异丙基3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酸酯(16)的合成:将异丙基3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2,3-二溴丙酸酯(12)(6.2g,11.3mmol)溶解于四氢呋喃(40mL)中并冷却至0℃。添加三乙胺(2.3g,22.5mmol)并且将混合物在室温下搅拌16h。将反应混合物用水(20mL)稀释并用乙酸乙酯(30mL X3)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥并在减压下浓缩。将粗产物通过硅胶色谱法纯化,以提供呈白色固体的(E)-异丙基3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酸酯(16)(3.1g,59%收率)。1H NMR(400MHz,DMSO-d6)δ8.95(s,1H),8.46(s,1H),8.29(s,2H),8.09(s,1H),5.13-5.07(m,1H),1.26(d,J=6Hz,6H)。LCMS:m/z 472.0[M+H]+,tR=2.02min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酸(17)的合成:将(E)-异丙基3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酸酯(16)(2.36g,5mmol)溶解于四氢呋喃(25mL)中。在0℃下,滴加水(25mL)中的氢氧化锂(1.05g,25mmol)溶液。将反应混合物在0℃下搅拌3h,并且倾倒进水(30mL)中,用HCl(3 N)酸化直到pH=5,用乙酸乙酯(200mL X3)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥,在减压下浓缩,并且通过从石油醚中的20%EtOAc中重结晶而纯化,以提供呈白色固体的(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酸(17)(1.2g,56%收率)。1H NMR(400MHz,DMSO-d6)δ8.98(s,1H),8.49(s,1H),8.29(s,2H),8.00(s,1H)。LCMS:m/z 433.0[M+H]+,tR=1.81min。
(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酰胺(18)的合成:在0℃下,将(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酸(17)(0.9g,2.1mmol)溶解于THF(20mL)中并且添加氯甲酸异丁酯(0.57g,4.2mmol)、N-甲基吗啉(0.32g,3.1mmol)。将反应混合物在0℃下搅拌1h。在0℃下,氨气吹扫40min。将反应混合物转移进冰水中并用乙酸乙酯(20mL X3)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥并在减压下浓缩,以给出粗产物,将其通过从EtOAc中重结晶而纯化,以给出0.8g的(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酰胺(18)。收率:90%。1H NMR(400MHz,DMSO-d6)δ8.88(s,1H),8.49(s,1H),8.29(s,2H),8.01(s,1H),7.87(s,1H),7.81(s,1H)。LCMS:m/z 429.0[M+H]+,tR=1.80min。
(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(嘧啶-5-基)丙烯酰胺(153)的合成。在氮气氛下,将二噁烷(60mL)和水(5mL)中的(E)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-溴丙烯酰胺(18)(600mg,1.4mmol)、嘧啶-5-基硼酸(261mg,2.1mmol)、乙酸钾(277mg,2.8mmol)、[1,1'-双(二苯基膦基)二茂铁]氯化钯-(II)(91mg,0.11mmol)的混合物在80℃下加热45分钟。将混合物倾倒进30mL的水中并用乙酸乙酯(10mL X3)萃取。将合并的有机层用盐水洗涤,经无水Na2SO4干燥,在减压下浓缩并通过制备型HPLC纯化,以提供(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(嘧啶-5-基)丙烯酰胺(153)(130mg,22%收率)。1H NMR(400MHz,DMSO-d6)δ9.22(s,1H),8.96(s,3H),8.54(s,2H),8.31(s,1H),8.10(s,1H),8.01(s,1H),7.94(s,1H)。LCMS:m/z 429.1[M+H]+,tR=1.67min。
(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(6-氟吡啶-3-基)丙烯酰胺(154)的合成:
根据通用程序6合成(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(6-氟吡啶-3-基)丙烯酰胺(154)。收率:7%。
1H NMR(400MHz,CD3OD)δ8.70(s,1H),8.56(s,2H),8.34(d,J=3Hz,1H),8.11-8.03(m,1H),7.97(s,1H),7.64(s,1H),7.11-7.05(m,1H)。LCMS:m/z 446.1[M+H]+,tR=1.68min。
(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(2-氟吡啶-4-基)丙烯酰胺(155)的合成:
根据通用程序6合成(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(2-氟吡啶-4-基)丙烯酰胺(155)。收率:30%。1H NMR(400MHz,CD3OD)δ8.75(s,1H),8.57(s,2H),8.18(d,J=5Hz,1H),7.99(s,1H),7.93(s,1H),7.47-7.40(m,1H),7.19(s,1H)。LCMS:m/z 446.1[M+H]+,tR=1.79min。
(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(6-氯吡啶-3-基)丙烯酰胺(156)的合成。
根据通用程序6合成(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(6-氯吡啶-3-基)丙烯酰胺(156)。收率:7%。1H NMR(400MHz,DMSO-d6)δ8.94(s,1H),8.60(d,J=2Hz,1H),8.54(s,2H),8.30(s,1H),8.06(s,1H),8.02-7.97(m,1H),7.93(s,1H),7.89(s,1H),7.65(d,J=8Hz,1H)。LCMS:m/z462.1[M+H]+,tR=1.82min。
(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(2-氟吡啶-3-基)丙烯酰胺(157)的合成:
根据通用程序6合成(Z)-3-(3-(3,5-双(三氟甲基)苯基)-1H-1,2,4-三唑-1-基)-2-(2-氟吡啶-3-基)丙烯酰胺(157)。收率:29%。1H NMR(400MHz,DMSO-d6)δ9.06(s,1H),8.60(s,2H),8.38-8.33(m,2H),8.20-8.11(m,1H),8.03(s,1H),7.86-7.81(m,2H),7.60-7.51(m,1H)。LCMS:m/z 446.1[M+H]+,tR=1.69min。
实例2.测定
在不同测定中测试本发明的某些化合物。
核输出的抑制-Rev-GFP测定
在RevGFP测定中确定本发明的化合物对CRM1介导的核输出的抑制。Rev是一种来自人类免疫缺陷病毒1(HIV-1)的蛋白并且在其C-末端结构域包含一种核输出信号(NES)以及在其N-末端结构域包含一种核定位信号(NLS)。Rev蛋白的核输出依赖于经典NES/CRM1途径(Neville(内维尔)等人,1997,Kau(卡乌)等人,2003)。在用特异性CRM1抑制剂(如LMB)处理的细胞中观察到Rev的核和核仁累积(Kau(卡乌)等人,2003)。
在此测定中,在实验的前一天,将U2OS-RevGFP细胞接种于透明底、黑色、384孔板上。在分开的384孔板中,从40μM起始,在DMEM中连续地将化合物进行1:2稀释,并且然后转移到细胞上。在用3.7%甲醛固定以及用Hoechst 33258进行细胞核染色之前,将细胞与化合物一起孵育大约1小时。测量细胞核中的GFP量并且确定化合物IC50(Kau(卡乌)等人,2003)。此测定的结果示于表1中。
在一个单独的实验中,将U2OS Rev-GFP细胞用化合物124(从10μM起始,将其以1:3连续稀释)或DMSO处理4小时。4小时后,将细胞用多聚甲醛(PFA)固定并用核染料DAPI复染。使用剂量-反应曲线,在U2OS Rev-GFP测定中确定化合物124的IC50为约40nM。因此,化合物124重演了使用LMB观察到的CRM1抑制,并且用化合物124处理产生核Rev-GFP。
MTT细胞增殖测定
MTT细胞增殖测定用于研究这些化合物的细胞毒特性。根据由罗氏分子生物化学(Roche Molecular Biochemical)(进行了少许修饰)所述的方法来进行该测定。该测定是基于在电子耦合试剂的存在下,四唑鎓盐MTT的切割。必须将产生的水不溶性甲臜盐在另外的步骤中溶解。将在96孔组织培养板上生长的细胞与该MTT溶液一起孵育大约4小时。此孵育时间之后,水不溶性甲臜染料形成。溶解之后,使用扫描多孔分光光度计(酶标仪(ELISAreader))对甲臜染料进行定量。吸光度揭示直接与细胞数目相关。以96孔板每孔5,000-10,000个细胞将这些细胞接种于100μL的新鲜培养基中并且允许其贴壁过夜。在100μL细胞培养基中对这些化合物的储备溶液进行稀释,以获得每种测试化合物的八种浓度,范围从1nM至30μM。孵育大约64-72小时之后,将20μL的CellTiter96水性单溶液试剂(Aqueous OneSolution Reagent)(普洛麦格(Promega),G358B)添加至每个孔中并且将板返回培养箱(37℃;5%CO2),直到对照细胞的绝对OD达到1.5。使用Vmax动力学酶标仪(MicroplateReader)(分子设备公司(Molecular Devices))在490nm下测量所有光密度。在大多数情况下,该测定以一式两份进行并且结果作为对于阴性对照±SE的平均抑制百分比而呈现。使用下式计算抑制百分比:抑制(%)=(1-(ODo/OD))X 100。
针对Z138、MM1S和3T3细胞测试这些化合物。Z138细胞系是一种来源于患有急性淋巴细胞性白血病的患者的成熟B细胞急性成淋巴细胞性白血病细胞系。MM1S细胞系建立自人类多发性骨髓瘤患者的外周血。3T3细胞是标准的成纤维细胞;它们最初分离自瑞士小鼠胚胎组织。
MTT测定的结果报告于表1中。
表1.示例性化合物的测定结果(A=<100nM;B=100nM至<5μM;C=5μM至30μM;D=>30μM;NT=未测试)。
在MTT测定中,针对一组选择的实体和血液学癌症细胞系和选择的正常细胞系进一步测试化合物124。简言之,在第1天,将以上各种细胞系以不同密度铺板。生长24小时之后,在一式二份的行中用化合物124的剂量曲线(10μM起始,以1:3稀释)处理细胞。将细胞和化合物124在37℃培养箱中孵育72小时。将Cell Titer AQueous One添加至每个孔中,并且将板在读板机中于OD 495下读数。
测试的血液学癌症细胞系包括MOLT-4、Z-138、THP1、MO7E、OCIAML-5、AML-193、道迪(Daudi)、托莱多(Toledo)、TF-1、法拉奇(Farage)、菲弗尔(Pfieffer)、MV-4-11、MINO、HEL.92.1.7、KG-1、BL-2、MM1R、HS-Sultan、RL、U-937、DB、BL-40、U-266以及ANBL-6。测试的实体癌细胞系包括PATU-8902、SK-CO-1、NCI-H2170、PL-45、NCI-H1650、TFK-1、NCI-H520、RKO、U118 MG、海拉(HeLa)、HuCCT-1、CAPAN-1、NCI-H889、NCI-H187、L3.6pl、HEP3B、MS751、NCI-H69、AU-565、SHSY5Y、Tera-1、SW-620、PC3、LS-180、SW-48、NCI-H1299、Colo-205、NCI-H28、HT1080、SHP-77、MSTO-211H、LoVo、HCT-15、NCI-H2030、Calu-6、Calu-3、SW-403、HPAC、NCI-H1563、PATU-8988T、PATU-8988S、HPAF-II、Colo-201、NCI-H747、SW-837、HCC-4006、NCI-H358、HCC-827、PANC-10.05、SW-948、SW-480、SW-1417、DLD-1、SW-1116、MDA-MB-231、NCI-H508、MCF7、LN-18、NCI-H820、HCC-2935、SNU-398、NCI-H2122、NCI-H226、LS-174T、HCT116、MDA-MB-361、SW-900、NCI-H1993、HCT116.1、C6、MHCC97H以及SKOV3。测试的正常细胞系包括IMR-90和3T3。将化合物124的进一步测试结果报告于表2中。
表2.
Cys 528突变测定
用表达野生型CRM1或突变型CRM1-Cys528Ser的构建体将U2OS(骨肉瘤)细胞瞬时转染36小时,这些细胞稳定地表达融合至cAMP依赖性蛋白激酶抑制剂(PKI)核输出信号的GFP标记的HIV-Rev(Rev-GFP)。估计在实验中的瞬时转染效率为约50%。当在这些细胞中共表达Rev-GFP和野生型CRM1并且将这些细胞用30μM化合物124处理4小时时,Rev-GFP定位于细胞核和核仁。然而,当在这些细胞中共表达Rev-GFP和突变型CRM-Cys528Ser时,用30μM化合物124处理细胞不诱导Rev-GFP的核定位。将30μM化合物124处理选择用于最大化对这些转染细胞的药物暴露。这些结果证明了在化合物124对CRM1的抑制中Cys528的重要性。
洗脱测定
使用U2OS细胞评估在处理后洗脱或不洗脱化合物124的情况下CRM1抑制的水平以及该化合物的所得IC50,这些细胞稳定地表达融合至cAMP依赖性PKI核输出信号的绿色荧光蛋白标记的HIV-Rev(Rev-GFP)。将U2OS Rev-GFP细胞的三个96孔板用化合物124(在10μM处,已经将其以1:3连续稀释)或DMSO处理4小时。4小时后,将这些板之一用PFA固定(未洗脱,条件A)。从其他两个板中除去培养基,并且将这些细胞用新鲜培养基洗涤两次并且在不包含化合物124的培养基进一步孵育。4小时洗脱之后将第二板用PFA固定(4hr洗脱,条件B)并且24小时洗脱之后将第三板用PFA固定(24h洗脱,条件C)。将细胞用核染料DAPI复染。确定化合物124在条件A、条件B和条件C下的IC50,并且报告于表3中。表3显示化合物124在4小时洗脱之后仍是非常有效的,并且在24小时洗脱之后仅降低6倍。这些结果证实化合物124与XPO1共价结合。
表3.
XPO1货物(Cargo)定位测定
将U2OS细胞用500nM化合物124处理4至24小时并且,或者用100%冰冷甲醇(MeOH)固定并用0.1%Tween20、0.3 M甘氨酸和1%BSA在PBS中透化/封闭,或者用PFA(3%多聚甲醛和2%蔗糖,在PBS中)并用0.1%Triton-X100和1%BSA在PBS中透化/封闭。通过免疫荧光(IF)分析被固定细胞的以下XPO1货物蛋白的核定位:p53、IKB、Foxo1A、PP2A、p21以及p27。将细胞核用DAPI染色。在20X放大下拍照。用化合物124处理的细胞的图像示出了XPO1货物的增加或完整的核定位。
XPO1降解测定
将HT1080(纤维肉瘤)细胞用五个不同浓度的化合物124处理24小时。使用经处理的细胞的细胞溶解产物的蛋白质印迹分析确定XPO1的蛋白质表达。将β-肌动蛋白用作上样对照。图1是从此实验获得的蛋白质印迹的图像,并且显示化合物124以剂量依赖性方式降解XPO1。
实例3.胶原抗体诱导的关节炎(CAIA)小鼠模型
在抗胶原抗体诱导的类风湿性关节炎小鼠模型中评估化合物124。确切地说,将二十四只(24)6至7周龄的雄性Balb/c小鼠随机分为3个将接受运载体、20mg/kg的化合物124或40mg/kg的化合物124的组。在研究的第0天(研究开始),对所有小鼠静脉注射4mg的ArthritoMAbTM抗体混合物(MD生物科学(MD Biosciences)#51306001),随后在研究的第3天腹膜内注射LPS(50μg/只小鼠)。当平均临床评分达到2时,在第6天开始处理小鼠。PO给予用化合物124进行的处理,每周两次(周一和周三),直到第17天。
在研究的第0天检查这些动物的所有爪子(左前爪和右前爪,左后爪和右后爪)的关节炎征象。将在研究的第0天的关节炎征象作为关节炎临床评分参数的基线。从第3直至第8天每天,并且在第10、12、15和18天(研究终止)检查关节炎应答。如表4所示,根据0-4标度按严重性升序报告每只爪子的关节炎反应。
表4.关节炎临床评分
临床征象数据被表示为平均值±SEM(平均标准误)。使用单向ANOVA检验,随后使用图基(后测Tukey post-test),将处理组2-3与运载体组1进行比较。认为<0.05的p值表示显著性差异。
在研究的第6天,88%的用运载体处理的动物显示出关节炎的临床征象。在研究结束时,此值降至75%。显现关节炎的临床征象的并且以20mg/kg的剂量用化合物124进行处理的动物的百分比从研究第6天的78%减至研究第18天的22%。显现关节炎的临床征象的并且以40mg/kg的剂量用化合物124进行处理的动物的百分比从研究第6天的88%减至研究第18天的13%。
图2是作为研究天数的函数的CAIA类风湿性关节炎小鼠模型的所有爪子的平均临床评分曲线图。图1显示与运载体处理相比,用化合物124进行处理降低该研究中的小鼠的关节炎评分。
总之,在此项研究中,用20mg/kg或40mg/kg化合物124进行处理减少表现疾病的动物的数目并且降低这些动物的关节炎评分。
实例4.异种移植物模型
在小鼠中于若干异种移植物模型中评估化合物124和化合物149。
在CB-17 SCID小鼠中使用MDA-MB-468(三阴性乳腺癌)异种移植物模型评估化合物124和化合物149的肿瘤学影响。MDA-MB-468(ATCC#HTB-102)乳腺癌细胞获得自ATCC。使这些细胞在补充有10%胎牛血清、1%青霉素和链霉素及2mM L-谷氨酰胺的高葡萄糖DMEM培养基中生长。通过以1:4的比率稀释将这些细胞进行继代培养。通过胰酶消化收获MDA-MB-468细胞并且使用血球计数器进行计数。将细胞以4x 108个细胞/mL的浓度再悬浮于PBS中。将细胞置于冰上并与等体积的基质胶(BD生物科学(BD Biosciences)CB-40234)混合。用4x 107个MDA-MB-468细胞皮下接种二十二只(22)CB-17 SCID小鼠的左肋部。当肿瘤达到约100mm3的平均体积时启动处理。将小鼠分为三个(3)组,八只(8)小鼠用于运载体并且七只(7)小鼠用于每个处理组-化合物124和化合物149-这样使得每组中的平均肿瘤体积为约100mm3。将小鼠用运载体、化合物124或化合物149处理。口服地(PO)给予化合物124(10mg/kg)和化合物149(10mg/kg),逐日地每周每天一次。每天记录动物的体重和情况,并且在周一、周三和周五测量肿瘤。
图3A是作为时间的函数的平均肿瘤体积曲线图,并且显示与携带MDA-MB-468异种移植物并用运载体处理的小鼠相比,携带MDA-MB-468异种移植物并用化合物124或化合物149处理的小鼠的平均肿瘤体积减小。
在另一项研究中,在SCID小鼠中使用Z-138套细胞淋巴瘤癌异种移植物模型测试化合物124对肿瘤生长的影响。Z-138(ATCC#CRL-3001)套细胞淋巴瘤细胞获得自ATCC。使这些细胞在补充有10%马血清、1%青霉素和链霉素及2mM L--谷氨酰胺的IMEM培养基中生长。通过以1:5至1:10的比率稀释将这些细胞进行继代培养。通过离心收获Z-138细胞并且使用血球计数器进行计数。将细胞以2x 108个细胞/mL的浓度再悬浮于PBS中。将细胞置于冰上并与等体积的基质胶(BD生物科学(CB-40234)混合。将此混合物保持在冰上并且以0.2mL的体积注入小鼠的左肋部,相当于2x 107个细胞/只小鼠。用2x 107个Z-138细胞皮下接种三十二只(32)CB-17 SCID小鼠的左肋部。当肿瘤达到125.2mm3的平均体积时启动处理。将小鼠分为每组八只(8)小鼠的四个(4)组,这样使得每组中的平均肿瘤体积在106.5mm3至138.8mm3的范围内。将小鼠用运载体、护理/阳性对照药物标准品(环磷酰胺)或化合物124(5mg/kg或15mg/kg)处理。从第1天开始每天口服地(PO)给予化合物124(5mg/kg或15mg/kg)。每天记录动物的体重和情况,并且在周一、周三和周五测量肿瘤。
图3B是作为时间的函数的平均肿瘤体积曲线图,并且显示与携带Z-138异种移植物并用运载体处理的小鼠相比,携带Z-138异种移植物并用化合物124处理的小鼠的平均肿瘤体积减小。特别地,获得自15mg/kg剂量的化合物124的结果有利地与使用环磷酰胺获得的结果进行比较。
在又另一项研究中,在SCID小鼠中使用Hep3B肝细胞癌异种移植物模型评估化合物124对肿瘤生长的影响。Hep3B细胞(ATCC#HTB-8064)肝细胞癌细胞获得自ATCC。使这些细胞在补充有10%胎牛血清、1%青霉素和链霉素的DMEM培养基中生长。通过以1:4的比率稀释将这些细胞进行继代培养。通过离心收获Hep3B细胞并且使用血球计数器进行计数。将细胞以5x107个细胞/mL的浓度再悬浮于PBS中。将细胞置于冰上并且然后与等体积的基质胶TM(BD生物科学CB-40234)混合。将此混合物保持在冰上并且以0.2mL的体积注入小鼠的左肋部,相当于5x 106个细胞/只小鼠。用5x 106个Hep3B细胞皮下接种三十二只(32)SCID小鼠的左肋部。当肿瘤达到103.7mm3(标准差±30mm3,范围17mm3-183mm3)的平均体积时启动处理。将小鼠分为每组八只(8)小鼠的四个(4)组,这样使得每组中的平均肿瘤体积在95mm3至104mm3的范围内。将小鼠用运载体、护理对照标准品(阿霉素)或化合物124(5mg/kg或15mg/kg)处理。除阿霉素之外(将其IP给予),所有化合物都通过口服强饲法给予。每天口服地(PO)给予化合物124(5mg/kg或15mg/kg)。每天记录动物的体重和情况,并且在周一、周三和周五测量肿瘤。
图3C是作为时间的函数的平均肿瘤体积曲线图,并且显示与携带Hep3B异种移植物并用运载体处理的小鼠相比,携带Hep3B异种移植物并用化合物124处理的小鼠的平均肿瘤体积减小。获得自用化合物124(特别是15mg/kg剂量的化合物124)进行处理的结果有利地与使用阿霉素获得的结果进行比较。
在另一项研究中,在SCID小鼠中使用COLO 205结肠直肠癌异种移植物模型评估化合物124对肿瘤生长的影响。COLO 205(CCL-222)结肠直肠癌细胞获得自ATCC。使这些细胞在补充有10%胎牛血清、1%青霉素和链霉素的RPMI-1640培养基中生长。通过将漂浮细胞转移至新的烧瓶中并且在以1:4的比率进行继代培养之前胰酶消化贴壁细胞而将细胞进行继代培养。通过离心收获COLO 205细胞并且使用血球计数器进行计数。将细胞以5x 107个细胞/mL的浓度再悬浮于PBS中。将细胞置于冰上并且然后与等体积的基质胶TM(BD生物科学CB-40234)混合。将此混合物保持在冰上并且以0.2mL的体积注入小鼠的左肋部,相当于5x106个细胞/只小鼠。用5x 106个COLO 205细胞皮下接种三十二只(32)SCID小鼠的左肋部。当肿瘤达到103.7mm3(标准差±30mm3,范围17mm3-183mm3)的平均体积时启动处理。将小鼠分为每组八只(8)小鼠的四个(4)组,这样使得每组中的平均肿瘤体积在95mm3至104mm3的范围内。将小鼠用运载体、护理对照标准品(5-FU,5-氟尿嘧啶)或化合物124(5mg/kg或15mg/kg)处理。除5-FU之外(在第1天和第3天,将其IP给予),所有化合物都通过口服强饲法给予。每天口服地(PO)给予化合物124(5mg/kg或15mg/kg)。每天记录动物的体重和情况,并且在周一、周三和周五测量肿瘤。
图3D是作为时间的函数的平均肿瘤体积曲线图,并且显示与携带COLO 205异种移植物并用运载体处理的小鼠相比,携带COLO 205异种移植物并用化合物124处理的小鼠的平均肿瘤体积减小。获得自用化合物124(特别是15mg/kg剂量的化合物124)进行处理的结果有利地与使用5-FU获得的结果进行比较。
在另一项研究中,在SCID小鼠中使用MOLT4急性成淋巴细胞性白血病异种移植物模型评估化合物124对肿瘤生长的影响。MOLT4(CRL-1582)急性成淋巴细胞性白血病细胞获得自ATCC。使这些细胞在补充有10%胎牛血清、1%青霉素和链霉素的RPMI-1640培养基中生长。通过将漂浮细胞转移至新的烧瓶中并且在以1:4的比率进行继代培养之前胰酶消化贴壁细胞而将细胞进行继代培养。通过离心收获MOLT4细胞并且使用血球计数器进行计数。将细胞以5x 107个细胞/mL的浓度再悬浮于PBS中。将细胞置于冰上并且然后与等体积的基质胶TM(BD生物科学CB-40234)混合。将此混合物保持在冰上并且以0.2mL的体积注入小鼠的左肋部,相当于5x 106个细胞/只小鼠。用5x 106个MOLT 4细胞皮下接种三十二只(32)SCID小鼠的左肋部。当肿瘤达到106.5mm3(标准差±33.9mm3,CV31.9%,范围43mm3-181mm3)的平均体积时启动处理。将小鼠分为每组八只(8)小鼠的四个(4)组,具有5只小鼠的一组以及具有四只小鼠的一组,这样使得每组中的平均肿瘤体积在102mm3至111mm3的范围内。将小鼠用运载体、护理对照标准品(阿霉素,5mg/kg IP,在第1天和第15天)或化合物124(5mg/kg或15mg/kg)处理。除阿霉素之外(将其IP给予),所有化合物都通过口服强饲法给予。每天口服地(PO)给予化合物124(5mg/kg或15mg/kg)。每天记录动物的体重和情况,并且在周一、周三和周五测量肿瘤。
图3E是作为时间的函数的平均肿瘤体积曲线图,并且显示与携带MOLT4异种移植物并用运载体处理的小鼠相比,携带MOLT4异种移植物并用化合物124处理的小鼠的平均肿瘤体积减小。
实例5.成胶质细胞瘤
将细胞(U87MG和U251MG)分离并以1x 105个细胞/mL再悬浮。将5,000个细胞装入悬滴板(3D生物基质(Biomatrix),目录号:HDP1096)中并孵育5天(37℃;5%CO2),以形成球状体。在24孔板的每个孔中铺300μL的基质胶(康宁基质胶(Corning Matrigel),目录号354234;批号3330622)并孵育30分钟。从悬滴板上取出球状体并接种进基质胶TM(每个孔1个球状体)中。将球状体孵育15分钟并且然后加入460μL培养基。将球状体孵育过夜之后,添加1μM化合物124,至最终体积为1mL/孔。使用40X和20X相差显微镜在若干时间点分析这些板,并且对球状体拍照。
图4是U87MG和U251MG对照球状体和用1μM化合物124处理的U87MG和U251MG球状体的图像,并且示出了用化合物124处理对两种成胶质细胞瘤细胞系的影响。与对照相比,用化合物124(1μM)处理的U87MG球状体在细胞生长方面展示出显著降低,没有显示出细胞从该球体的任何扩散或生长。然而,在用化合物124处理的U251球状体中,除与对照相比细胞生长的显著降低之外,注意到该球状体缩小,其中从该球体的任何细胞生长完全消除。基于显微镜分析,观察到这些细胞的完全破坏。
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在此引用的全部专利、公开的申请以及参考文献的传授内容通过引用以其全文进行结合。
虽然本发明参考其示例性的实施例已经进行了具体显示和描述,本领域的技术人员应当理解的是,在不偏离由所附权利要求书所包括的本发明的范围下,可以在其中做出在形式和细节方面的多种改变。
Claims (8)
2.根据权利要求1所述的用途,其中所述紊乱选自白血病、淋巴瘤和骨髓瘤。
3.根据权利要求2所述的用途,其中所述紊乱是选自毛细胞白血病、急性成淋巴细胞性白血病、慢性粒细胞性白血病、急性髓性白血病和慢性淋巴细胞性白血病的白血病。
4.根据权利要求2所述的用途,其中所述紊乱是选自皮肤T细胞淋巴瘤、弥散性大B细胞淋巴瘤、套细胞淋巴瘤、伯基特淋巴瘤和滤泡性淋巴瘤的淋巴瘤。
5.根据权利要求1所述的用途,其中所述实体瘤是前列腺癌。
6.根据权利要求1所述的用途,其中所述实体瘤是结肠癌。
7.根据权利要求1所述的用途,其中所述紊乱是骨髓增生异常综合征。
8.根据权利要求1-7中任一项所述的用途,其中所述化合物适于口服递送。
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