CN110302205A - BCL-2/Bcl-xL抑制剂的医药用途及其药物组合物 - Google Patents
BCL-2/Bcl-xL抑制剂的医药用途及其药物组合物 Download PDFInfo
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- CN110302205A CN110302205A CN201910634742.2A CN201910634742A CN110302205A CN 110302205 A CN110302205 A CN 110302205A CN 201910634742 A CN201910634742 A CN 201910634742A CN 110302205 A CN110302205 A CN 110302205A
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- bcl
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- cancer
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Abstract
本发明公开了Bcl‑2/Bcl‑xL抑制剂在制备用于治疗有需要的个体中其中Bcl‑2或Bcl‑xL的抑制提供益处的疾病或病况(例如癌症)的药物中的用途。另外,本发明还公开了含有Bcl‑2/Bcl‑xL抑制剂的药物组合物。
Description
本申请是申请号为201480015733.0的专利申请的分案申请,该专利申请的申请日为2014年1月15日,其发明名称为《BCL-2/Bcl-xL抑制剂和使用所述抑制剂的治疗方法》。
发明领域
本发明涉及Bcl-2/Bcl-xL抑制剂和治疗其中Bcl-2/Bcl-xL的抑制提供益处的病况和疾病的治疗方法。
发明背景
细胞凋亡抵抗是人类癌症的标志(1-3)。癌细胞必须克服通过细胞应激的持续轰击,所述细胞应激例如DNA损伤、癌基因激活、细胞周期进行异常和残酷的微环境,其将引起正常细胞遭受细胞凋亡。癌细胞逃避细胞凋亡的主要方式之一是通过增量调节抗-细胞凋亡的Bcl-2家族的蛋白。靶向关键的细胞凋亡调节物以克服细胞凋亡-抵抗和促进肿瘤细胞的细胞凋亡是新的癌症治疗策略(4,5)。
Bcl-2蛋白在癌细胞和正常细胞两者中起细胞凋亡的关键调节物的作用(6-10)。Bcl-2蛋白作为细胞凋亡的核查,允许健康和有用的细胞存活。该蛋白家族包括抗-细胞凋亡的蛋白,例如Bcl-2、Bcl-xL和Mcl-1,和促-细胞凋亡的分子,包括Bid、Bim、Bad、Bak和Bax(6-10)。尽管正常细胞具有低表达水平的抗-细胞凋亡的Bcl-2和Bcl-xL蛋白,但发现这些蛋白在许多不同类型的人类肿瘤中高度过表达(6-10)。这些过表达与数种类型的癌症的预后差有关,和与对化学治疗剂和辐射的临床抵抗有关(6-10)。与临床观察一致的是,实验室研究已经确定在体外和体内,Bcl-2或Bcl-xL的过表达引起癌细胞变得对化学治疗剂更有抵抗力(6-10)。Bcl-2抑制细胞凋亡通过抑制细胞死亡而有助于癌症。因此,已寻求将靶向Bcl-2和/或Bcl-xL作为癌症治疗策略(11-34)。抑制癌细胞的Bcl-2活性可降低化学治疗抵抗和增加杀死癌细胞。
Bcl-2和Bcl-xL蛋白通过与促-细胞凋亡的Bcl-2家族蛋白例如Bak、Bax、Bim、Bid、Puma和Bad异二聚化而抑制细胞凋亡(6-10)。实验上确定的Bcl-xL和Bcl-2的三维结构已经表明,这些蛋白具有充分定义的沟,其与促-细胞凋亡的Bcl-2蛋白的BH3(Bcl-2同源性3)结构域相互作用(38-42)。已经提出,经设计以阻断Bcl-2/Bcl-xL蛋白与其促-死亡结合配偶体的异二聚化的非肽小分子可有效作为Bcl-2/Bcl-xL的拮抗剂,并且所述小分子抑制剂可具有治疗其中Bcl-2和/或Bcl-xL高度表达的人类癌症的极大治疗潜力(18-37)。
尽管已经报道Bcl-2/Bcl-xL的非肽小分子抑制剂,但大部分抑制剂对这些蛋白具有弱至中等的亲和力,并对其细胞活性缺乏完全明确的作用模式(18-37)。例外是ABT-737、ABT-263和其类似物(26-34)。ABT-737和ABT-263以非常高的亲和力结合Bcl-2、Bcl-xL和Bcl-w(Ki<1nM)和具有比Mcl-1和A1(两种其它的抗-细胞凋亡的Bcl-2蛋白)高的特异性(26,32,34)。ABT-263已经进入I/II期临床试验并显示临床上有前景的抗肿瘤活性(45)。
尽管发现了ABT-737和ABT-263,但Bcl-2/Bcl-xL的有效的非肽抑制剂的设计仍是现代药物发现中的重要挑战。因此,本领域仍对具有允许在治疗应用中使用抑制剂的物理和药理性质的Bcl-2/Bcl-xL抑制剂存在需要。本发明提供经设计以结合Bcl-2/Bcl-xL和抑制Bcl-2/Bcl-xL活性的化合物。
发明简述
本发明涉及Bcl-2/Bcl-xL的抑制剂,涉及包含所述抑制剂的组合物,和涉及在治疗性治疗其中Bcl-2/Bcl-xL活性的抑制提供益处的病况和疾病中使用所述抑制剂的方法。本发明的化合物是Bcl-2/Bcl-xL激活的有效抑制剂,并诱导表达Bcl-2和/或Bcl-xL的癌细胞的细胞凋亡。
更具体而言,本发明涉及具有结构式(I)、(II)或(III)的化合物或(I)、(II)或(III)的药学上可接受的盐:
其中A环是
取代或未取代的X选自亚烷基、亚烯基、环亚烷基、环亚烯基和杂环亚烷基;
Y选自(CH2)n-N(Ra)2和
Q选自O、O(CH2)1-3、NRc、NRc(C1-3亚烷基)、OC(=O)(C1-3亚烷基)、C(=O)O、C(=O)O(C1-3亚烷基)、NHC(=O)(C1-3亚烷基)、C(=O)NH和C(=O)NH(C1-3亚烷基);
Z是O或NRc;
R1和R2独立选自H、CN、NO2、卤素、烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基、杂环烷基、OR'、SR'、NR'R”、COR'、CO2R'、OCOR'、CONR'R”、CONR'SO2R”、NR'COR”、NR'CONR”R”'、NR'C=SNR”R”'、NR'SO2R”、SO2R'和SO2NR'R”;
R3选自H、烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基、杂环烷基、OR'、NR'R”、OCOR'、CO2R'、COR'、CONR'R”、CONR'SO2R”、C1-3亚烷基CH(OH)CH2OH、SO2R'和SO2NR'R”;
R'、R”和R”'独立地为H、烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基、C1-3亚烷基杂环烷基或杂环烷基;
R'和R”或R”和R”'可与它们所连接的原子一起形成3-7元环;
R4是氢、卤素、C1-3烷基、CF3或CN;
R5是氢、卤素、C1-3烷基、取代的C1-3烷基、羟基烷基、烷氧基或取代的烷氧基;
R6选自H、CN、NO2、卤素、烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基、杂环烷基、OR'、SR'、NR'R”、CO2R'、OCOR'、CONR'R”、CONR'SO2R”、NR'COR”、NR'CONR”R”'、NR'C=SNR”R”'、NR'SO2R”、SO2R'和SO2NR'R”;
取代或未取代的R7选自氢、烷基、烯基、(CH2)0-3环烷基、(CH2)0-3环烯基、(CH2)0-3杂环烷基、(CH2)0-3芳基,和(CH2)0-3杂芳基;
R8选自氢、卤素、NO2、CN、CF3SO2,和CF3;
Ra选自氢、烷基、杂烷基、烯基、羟基烷基、烷氧基、取代的烷氧基、环烷基、环烯基和杂环烷基;
Rb是氢或烷基;
Rc选自氢、烷基、取代的烷基、羟基烷基、烷氧基和取代的烷氧基;和
n、r和s独立地为1、2、3、4、5或6。
在一些实施方案中,R1和R2或R2和R3可一起形成环。在其它实施方案中,R'和R"或R"和R”'可与它们所连接的原子一起形成3-7元环。
在一个实施方案中,本发明提供通过给予有需要的个体治疗有效量的结构式(I)、(II)或(III)化合物来治疗病况或疾病的方法。目标疾病或病况可通过抑制Bcl-2和/或Bcl-xL治疗,例如癌症。
本发明的另一个实施方案是提供用于治疗其中Bcl-2/Bcl-xL的抑制提供益处的疾病或病况的包含以下的组合物:(a)结构式(I)、(II)或(III)的Bcl-2/Bcl-xL抑制剂和(b)赋形剂和/或药学上可接受的载体。
本发明的另一个实施方案是在治疗个体的其中Bcl-2/Bcl-xL的抑制提供益处的疾病或病况的方法中使用包含结构式(I)、(II)或(III)的化合物和第二种治疗活性剂的组合物。
在另一个实施方案中,本发明提供包含结构式(I)、(II)或(III)的Bcl-2/Bcl-xL抑制剂和任选的第二种治疗剂的组合物在制备用于治疗目标疾病或病况例如癌症的药物中的用途。
本发明的又一个实施方案是提供用于人类药用的药盒,其包含(a)容器,(b1)包装的组合物,其包含结构式(I)、(II)或(III)的Bcl-2/Bcl-xL抑制剂,和任选(b2)包装的组合物,其包含用于治疗目标疾病或病况的第二种治疗剂,和(c)包装插页(package insert),其包含在治疗疾病或病况中同时或序贯给予的所述一种或多种组合物的使用说明。
结构式(I)、(II)或(III)的Bcl-2/Bcl-xL抑制剂和第二种治疗剂可作为单一单位剂量一起给予,或作为多个单位剂量分开给予,其中结构式(I)、(II)或(III)的Bcl-2/Bcl-xL抑制剂在第二种治疗剂之前给予,或反之亦然。预期可给予一个或多个剂量的结构式(I)、(II)或(III)的Bcl-2/Bcl-xL抑制剂和/或一个或多个剂量的第二种治疗剂。
在一个实施方案中,同时给予结构式(I)、(II)或(III)的Bcl-2/Bcl-xL抑制剂和第二种治疗剂。在相关的实施方案中,结构式(I)、(II)或(III)的Bcl-2/Bcl-xL抑制剂和第二种治疗剂从单一组合物中给予或从分开的组合物中给予。在进一步的实施方案中,序贯给予结构式(I)、(II)或(III)的Bcl-2/Bcl-xL抑制剂和第二种治疗剂。本发明中使用的结构式(I)、(II)或(III)的Bcl-2/Bcl-xL抑制剂可以约0.005-约500毫克/剂量、约0.05-约250毫克/剂量或约0.5-约100毫克/剂量的量给予。
本发明的这些和其它实施方案和特征将从以下优选实施方案的详细描述中变得显而易见。
优选实施方案的详细描述
本发明结合优选的实施方案进行描述。然而,应理解,本发明不限于所公开的实施方案。要理解,鉴于本文中本发明实施方案的描述,本领域的技术人员可进行各种修改。下文的权利要求包括这样的修改。
本文所用的术语"Bcl-2/Bcl-xL"意指Bcl-2、Bcl-xL、或Bcl-2和Bcl-xL,即Bcl-2和/或Bcl-xL。
术语"其中Bcl-2和/或Bcl-xL的抑制提供益处的疾病或病况"属于其中Bcl-2和/或Bcl-xL,和/或Bcl-2和/或Bcl-xL的作用对于例如所述疾病或病况的发作、进展、表现是重要或必要的病况,或已知通过Bcl-2/Bcl-xL抑制剂例如ABT-737或ABT-263治疗的疾病或病况。这样的病况的实例包括但不限于癌症。本领域的普通技术人员能够容易确定一种化合物是否治疗对于任何特定细胞类型由Bcl-2/Bcl-xL介导的疾病或病况,例如,通过可方便地用于评价特定化合物的活性的测定法。
术语"第二种治疗剂"是指不同于结构式(I)、(II)和(III)的Bcl-2和/或Bcl-xL抑制剂的治疗剂,并且其已知治疗目标疾病或病况。例如,当癌症是目标疾病或病况时,第二种治疗剂可以是已知的化学治疗药,例如泰素或辐射。
术语"疾病"或“病况”表示按惯例被视为病理学状况或功能,并且可以具体征兆、症状和/或机能障碍的形式表现自身的失调和/或异常。如下文所示,结构式(I)、(II)和(III)的化合物是Bcl-2/Bcl-xL的有效抑制剂,并且可用于治疗其中Bcl-2/Bcl-xL的抑制提供益处的疾病和病况。
本文所用的术语"治疗(treat)"、"治疗(treating)"、"治疗(treatment)"等是指消除、减少或改善疾病或病况和/或与其相关的症状。尽管未排除,但治疗疾病或病况不要求所述疾病、病况或与其相关的症状被完全消除。本文所用的术语"治疗(treat)"、"治疗(treating)"、"治疗(treatment)"等可包括"预防性治疗",其是指在未患有疾病,但有风险或易于重新发生疾病或病况或所述疾病或病况有复发风险或易于复发的受试者中,减少重新发生疾病或病况的可能性,或减少之前控制的疾病或病况的复发的可能性。术语"治疗"和同义词预期给予需要所述治疗的个体治疗有效量的本发明化合物。
在本发明的含义内,"治疗"还包括复发预防或阶段预防,以及治疗急性或慢性征兆、症状和/或机能障碍。治疗可以是针对症状的,例如,抑制症状。其可在短时期内起作用,针对中等时期内,或可以是长期治疗,例如在维持疗法的情况下。
本文所用的术语"治疗有效量"或"有效剂量"是指这样的活性成分的量,当通过本发明的方法给予时,其足以有效递送活性成分至有需要的个体用于治疗目标病况或疾病。在癌症或其它增殖病症的情况下,药剂的治疗有效量可减少(即,延缓至一定程度和优选停止)不需要的细胞增殖,减少癌细胞数,减少肿瘤大小;抑制(即,延缓至一定程度和优选停止)癌细胞侵润至周围器官;抑制(即,延缓至一定程度和优选停止)肿瘤转移;抑制肿瘤生长至一定程度;减少靶细胞中的Bcl-2/Bcl-xL信号转导;和/或缓解与癌症相关的一个或多个症状至一定程度。就所给予的化合物或组合物阻止生长和/或杀死存在的癌细胞的方面来说,它可以是细胞生长抑制的和/或细胞毒性的。
术语"容器"意指任何贮器和其闭合体(closure),适于储存、运输、分配和/或处理药物产品。
术语"插页"意指伴随药物产品的信息,其提供如何给予产品的描述,以及允许医师、药剂师和患者作出关于使用产品的基于可靠信息的决定所需要的安全性和功效数据。包装插页通常被认为是药物产品的"标签"。
"并发给予"、"组合给予"、"同时给予"和类似的词语意指两种或更多种药剂并发地给予待治疗的受试者。所谓"并发地"意指同时给予每种药剂,或者在不同的时间点以任何顺序序贯给予每种药剂。然而,如果不是同时给予,其意指将它们以某种顺序和足够接近的时间给予个体,以提供所需的治疗效果并可一致起作用。例如,结构式(I)、(II)或(III)的Bcl-2/Bcl-xL抑制剂可与第二种治疗剂同时给予或在不同时间点以任何顺序序贯给予。本发明的Bcl-2/Bcl-xL抑制剂和第二种治疗剂可以任何合适的形式和通过任何合适的途径分开给予。当本发明的Bcl-2/Bcl-xL抑制剂和第二种治疗剂不是并发给予时,应理解,它们可以任何顺序给予有需要的受试者。例如,本发明的Bcl-2/Bcl-xL抑制剂可在给予第二种治疗剂治疗形式(例如辐射疗法)之前(例如之前5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周或12周)给予有需要的个体,与给予第二种治疗剂治疗形式(例如辐射疗法)一起并发地给予有需要的个体,或在给予第二种治疗剂治疗形式(例如辐射疗法)之后(例如之后5分钟、15分钟、30分钟、45分钟、1小时、2小时、4小时、6小时、12小时、24小时、48小时、72小时、96小时、1周、2周、3周、4周、5周、6周、8周或12周)给予有需要的个体。在各种实施方案中,结构式(I)的Bcl-2/Bcl-xL抑制剂和第二种治疗剂分开1分钟、分开10分钟、分开30分钟、分开小于1小时、分开1小时、分开1小时至2小时、分开2小时至3小时、分开3小时至4小时、分开4小时至5小时、分开5小时至6小时、分开6小时至7小时、分开7小时至8小时、分开8小时至9小时、分开9小时至10小时、分开10小时至11小时、分开11小时至12小时、分开不超过24小时或分开不超过48小时给予。在一个实施方案中,组合疗法的各组分分开1分钟至24小时给予。
在描述本发明的背景下(尤其是在权利要求书的背景下),术语"一个"、"一种"、"所述"和类似的指示物的使用将解释为涵盖单数和复数两者,除非另有说明。本文数值范围的列举意指仅用作分别提及落入所述范围内的每个单独的值的速记方法,除非本文另有说明,和每个单独的值结合到本说明书中,如同其分别在本文中举出一样。本文提供的任何和所有实例或示例性语言(例如,"例如")的使用,意欲更好地说明本发明,并非对本发明的范围进行限制,除非另有要求保护。本说明书中不应有语言被解释为指出任何非要求保护的要素为本发明的实施所必需的。
在过去十年期间,对细胞凋亡的研究已确立,使用小分子抑制剂靶向Bcl-2和/或Bcl-xL是一种可行的癌症治疗策略(35-37)。ABT-737和ABT-263的发现以及关于ABT-263的早期临床数据已经证实,Bcl-2和/或Bcl-xL的非肽的小分子抑制剂具有用于治疗许多类型的人类癌症的极大的治疗潜力,在所述癌症中Bcl-2和/或Bcl-xL过表达,并且对于所述癌症,当前的抗癌药在很大程度上无效(26-36)。
尽管发现ABT-737和ABT-263,但几乎没有报道新类型的高度有效的Bcl-2/Bcl-xL的小分子抑制剂,其对Bcl-2/Bcl-xL的亲和力和细胞效能接近ABT-737/ABT-263所实现的。这是因为Bcl-2/Bcl-xL的小分子抑制剂的设计包括靶向和阻断Bcl-2/Bcl-xL蛋白与它们的促-细胞凋亡的结合配偶体的相互作用,这是一个已被证明因为至少3个主要原因而极具挑战性的任务。第一,与酶和受体中的典型结合位点相比,Bcl-2或Bcl-xL和它们的结合配偶体之间的界面非常大(38-42)。Bcl-2/Bcl-xL与其结合配偶体(例如BAD和Bim蛋白)的相互作用被BAD和Bim的20-25个残基BH3结构域以及Bcl-2/Bcl-xL的大的结合沟介导。第二,Bcl-2/Bcl-xL的结合沟在性质上非常疏水,这使得难以设计药物样小分子(26,38-42)。第三,Bcl-2和Bcl-xL在构象上非常柔韧,并且在无配体结构中和当结合至不同的配体时,可采用完全不同的构象(26,38-42)。在Bcl-xL与BAD(41)、Bim(43)和ABT-737(44)的复合物的晶体结构中对Bcl-xL所观察到的一些结合袋被配体结合诱导,并且不出现在无配体晶体结构中(38)。这三个因素使得Bcl-2/Bcl-xL的有效和药物样小分子抑制剂的设计成为现代药物发现中至关重大的挑战。
本发明涉及Bcl-2/Bcl-xL的新类型的有效和特异性抑制剂。本发明的化合物可结合Bcl-2和/或Bcl-xL,Ki值<10nM,和在无细胞功能测定法中作为Bcl-2和Bcl-xL的有效的拮抗剂起作用。所述化合物有效诱导癌细胞的细胞凋亡和具有与靶向Bcl-2和Bcl-xL高度一致的作用机制。所测试的化合物证实在肿瘤组织中稳健的体内细胞凋亡诱导和表明针对H146异种移植肿瘤的强的抗肿瘤活性。
因此,本发明的Bcl-2/Bcl-xL抑制剂可用于在需要所述治疗的受试者中治疗不需要的增值性细胞,包括癌症和初癌。还提供治疗具有不需要的增值性细胞的受试者的方法,包括给予需要所述治疗的受试者治疗有效量的本发明的化合物。还提供在受试者中预防不需要的增值性细胞(例如癌症和初癌)的增殖的方法,包括给予有发生特征为不需要的增值性细胞的病况的风险的受试者治疗有效量的结构式(I)的化合物的步骤。在一些实施方案中,结构式(I)、(II)和(III)的化合物通过诱导不需要的细胞的细胞凋亡来减少这些细胞的增殖。
本发明涉及具有结构式(I)、(II)或(III)的Bcl-2/Bcl-xL抑制剂:
其中A环是
取代或未取代的X选自亚烷基、亚烯基、环亚烷基、环亚烯基和杂环亚烷基;
Y选自(CH2)n-N(Ra)2和
Q选自O、O(CH2)1-3、NRc、NRc(C1-3亚烷基)、OC(=O)(C1-3亚烷基)、C(=O)O、C(=O)O(C1-3亚烷基)、NHC(=O)(C1-3亚烷基)、C(=O)NH和C(=O)NH(C1-3亚烷基);
Z是O或NRc;
R1和R2独立地选自H、CN、NO2、卤素、烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基、杂环烷基、OR'、SR'、NR'R”、COR'、CO2R'、OCOR'、CONR'R”、CONR'SO2R”、NR'COR”、NR'CONR”R”'、NR'C=SNR”R”'、NR'SO2R”、SO2R'和SO2NR'R”;
R3选自H、烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基、杂环烷基、OR'、NR'R”、OCOR'、CO2R'、COR'、CONR'R”、CONR'SO2R”、C1-3亚烷基CH(OH)CH2OH、SO2R'和SO2NR'R”;
R'、R”和R”'独立地是H、烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基、C1-3亚烷基杂环烷基或杂环烷基;
R'和R”或R”和R”'可与它们所连接的原子一起形成3-7元环;
R4是氢、卤素、C1-3烷基、CF3或CN;
R5是氢、卤素、C1-3烷基、取代的C1-3烷基、羟基烷基、烷氧基或取代的烷氧基;
R6选自H、CN、NO2、卤素、烷基、环烷基、烯基、环烯基、炔基、芳基、杂芳基、杂环烷基、OR'、SR'、NR'R”、CO2R'、OCOR'、CONR'R”、CONR'SO2R”、NR'COR”、NR'CONR”R”'、NR'C=SNR”R”'、NR'SO2R”、SO2R'和SO2NR'R”;
取代或未取代的R7选自氢、烷基、烯基、(CH2)0-3环烷基、(CH2)0-3环烯基、(CH2)0-3杂环烷基、(CH2)0-3芳基和(CH2)0-3杂芳基;
R8选自氢、卤素、NO2、CN、CF3SO2和CF3;
Ra选自氢、烷基、杂烷基、烯基、羟基烷基、烷氧基、取代的烷氧基、环烷基、环烯基和杂环烷基;
Rb是氢或烷基;
Rc选自氢、烷基、取代的烷基、羟基烷基、烷氧基和取代的烷氧基;和
n、r和s独立地是1、2、3、4、5或6;
或(I)、(II)或(III)的药学上可接受的盐。
结构式(I)、(II)和(III)的化合物抑制Bcl-2/Bcl-xL和可用于治疗各种疾病和病况。具体而言,结构式(I)、(II)和(III)的化合物用于治疗其中Bcl-2/Bcl-xL的抑制提供益处的疾病或病况(例如癌症)的方法。所述方法包括给予有需要的个体治疗有效量的结构式(I)、(II)或(III)的化合物。除了结构式(I)、(II)或(III)的化合物之外,本发明的方法还包括给予个体第二种治疗剂。第二种治疗剂选自已知用于治疗累及有需要的个体的疾病或病况的药物,例如已知用于治疗特定癌症的化学治疗剂和/或辐射。
本文所用的术语"烷基"是指直链和支链的饱和C1-10烃基,其非限制性实例包括甲基、乙基、和直链和支链的丙基、丁基、戊基、己基、庚基、辛基、壬基和癸基。术语Cn意指烷基具有"n"个碳原子。术语Cn-p意指烷基包含"n"至"p"个碳原子。术语"亚烷基"是指具有取代基的烷基。烷基例如甲基,或亚烷基例如—CH2—可以是未取代的或被例如卤素、三氟甲基、三氟甲氧基、羟基、烷氧基、硝基、氰基、烷基氨基或氨基取代。
术语"烯基"与"烷基"相同定义,除了含有碳-碳双键,例如乙烯基、丙烯基和丁烯基。术语"亚烯基"与"亚烷基"相同定义,除了含有碳-碳双键。术语"炔基"和"亚炔基"与"烷基"和"亚烷基"相同定义,除了所述基团含有碳-碳三键。
本文所用的术语"卤素"定义为氟、氯、溴和碘。
术语"羟基"定义为—OH。
术语"烷氧基"定义为—OR,其中R是烷基。
术语"氨基"定义为—NH2和术语"烷基氨基"定义为—NR2,其中至少一个R是烷基和另一个R是烷基或氢。
术语"硝基"定义为—NO2。
术语"氰基"定义为—CN。
术语"三氟甲基"定义为—CF3。
术语"三氟甲氧基"定义为—OCF3。
本文所用的基团例如是的缩写。
本文所用的术语"芳基"是指单环或多环的芳族基团,优选单环或二环的芳族基团,例如苯基或萘基。除非另外说明,否则芳基可以是未取代的或被一个或多个(并且特别是1-4个)基团取代,所述基团独立选自例如卤素、烷基、烯基、—OCF3、—CF3、—NO2、—CN、—NC、—OH、烷氧基、氨基、烷基氨基、—CO2H、—CO2烷基、—OCO烷基、芳基和杂芳基。
本文所用的术语"杂芳基"是指单环或二环的环系统,其包含一个或两个芳族环和在芳环中包含至少一个氮、氧或硫原子。除非另外说明,否则杂芳基可以是未取代的或被一个或多个(并且特别是1-4个)取代基取代,所述取代基选自例如卤素、烷基、烯基、—OCF3、—CF3、—NO2、—CN、—NC、—OH、烷氧基、氨基、烷基氨基、—CO2H、—CO2烷基、—OCO烷基、芳基和杂芳基。
本文所用的术语"环烷基"意指含有3-8个碳原子的单环脂肪族环。术语"杂环烷基"意指单环或二环的环系统,在环系统中含有至少一个氮、氧或硫原子。术语"杂芳基"和"杂环烷基"包括包含至少一个氧原子、氮原子或硫原子的环系统,和包括包含氧和氮原子;氧和硫原子;氮和硫原子;和氮、氧和硫原子的环系统。
在一些优选的实施方案中,X是亚烷基,和在优选的实施方案中,是C1-3亚烷基。
在一些实施方案中,Y是
在优选的实施方案中,n是2。在其它优选的实施方案中,Rb是氢或C1-3烷基。
在仍其它优选的实施方案中,Q是O、O(CH2)1-3、C(=O)O(CH2)1-3、OC(=O)(CH2)1-3或C(=O)O(C3H7)1-3。在一些实施方案中,Q是O、OCH2、C(=O)OCH2、C(=O)O(CH2)2、C(=O)O(CH2)3、OC(=O)CH2或C(=O)O(CH(CH3)CH2)。
在一些实施方案中,Z是O、NH或N(C1-3烷基)。在优选的实施方案中,Z是O、NH或NCH3。
在一些实施方案中,R1是SO2R'、SO2NR'R"、NR'SOR"、H或烷基。在一些优选的实施方案中,R1是SO2(C1-3烷基)、SO2N(C1-3烷基)2、NHSO2(C1-3烷基)、H或C1-3烷基。R1的一个优选的实施方案是SO2CH3。
在一些实施方案中,R2和R3独立地是H、C1-3烷基或环烷基。R2也可以是卤素。在一些优选的实施方案中,R2和R3独立地是甲基、乙基、正丙基、异丙基、环戊基或环己基。R2也可以是Cl或F。
在一些实施方案中,R4是H、Cl或F。在其它实施方案中,R5是H、甲基、乙基、正丙基、异丙基、F或Cl。在其它实施方案中,R6是H、卤素、烷基或环烷基。在一些优选的实施方案中,R6是H、F、Cl、C1-3烷基、环戊基或环己基。
在一些实施方案中,R7是(CH2)0-3环烷基或(CH2)0-3杂环烷基。在优选的实施方案,R7是(CH2)0-3环烷基,任选被–OH取代。在一个实施方案中,R7是
在一些实施方案中,R8是CFSO2或CF3。在各种实施方案中,Ra、Rb和Rc独立地是H或C1-3烷基。
另外,本发明的化合物的盐、水合物和溶剂合物也包括在本发明中,和可用于本文公开的方法。本发明还包括结构式(I)、(II)和(III)的化合物的所有可能的立体异构体和几何异构体。本发明包括外消旋化合物和光学活性异构体两者。当结构式(I)、(II)或(III)的化合物需要作为单一的对映体时,其可通过终产物的解析或通过自异构纯的原料或使用手性辅助试剂的立体特异性合成获得,例如参见Z.Ma等,Tetrahedron:Asymmetry,8(6),第883-888页(1997)。终产物、中间体或原料的解析可通过本领域已知的任何合适的方法实现。此外,在其中结构式(I)、(II)或(III)的化合物的互变异构体是可能的情况下,本发明意欲包括所述化合物的所有互变异构体形式。
本发明的化合物可作为盐存在。在本发明的方法中,本发明的化合物的药学上可接受的盐通常是优选的。本文所用的术语"药学上可接受的盐"是指结构式(I)、(II)和(III)的化合物的盐或两性离子形式。式(I)、(II)和(III)的化合物的盐可在化合物的最终分离和纯化期间制备,或分别通过将所述化合物与具有合适的阳离子的酸反应制备。结构式(I)、(II)和(III)的化合物的药学上可接受的盐可以是与药学上可接受的酸形成的酸加成盐。可用于形成药学上可接受的盐的酸的实例包括无机酸例如硝酸、硼酸、盐酸、氢溴酸、硫酸和磷酸,和有机酸例如草酸、马来酸、琥珀酸和柠檬酸。本发明的化合物的盐的非限制性实例包括但不限于盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、2-羟基乙磺酸盐、磷酸盐、磷酸氢盐、乙酸盐、己二酸盐、藻酸盐、天冬氨酸盐、苯甲酸盐、硫酸氢盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、二葡糖酸盐、甘油磷酸盐、半硫酸盐、庚酸盐、己酸盐、甲酸盐、琥珀酸盐、延胡索酸盐、马来酸盐、抗坏血酸盐、羟乙基磺酸盐、水杨酸盐、甲磺酸盐、均三甲苯磺酸盐、萘磺酸盐、烟酸盐、2-萘磺酸盐、草酸盐、双羟萘酸盐、果胶酯酸盐、过硫酸盐、3-苯基丙酸盐、苦味酸盐、特戊酸盐、丙酸盐、三氯乙酸盐、三氟乙酸盐、磷酸盐、谷氨酸盐、碳酸氢盐、对甲苯磺酸盐、十一酸盐、乳酸盐、柠檬酸盐、酒石酸盐、葡糖酸盐、甲磺酸盐、乙二磺酸盐、苯磺酸盐和对甲苯磺酸盐。此外,本发明的化合物中存在的可用的氨基可被甲基、乙基、丙基和丁基氯化物、溴化物和碘化物;二甲基、二乙基、二丁基和二戊基硫酸酯;癸基、月桂基、肉豆蔻基和硬脂基氯化物、溴化物和碘化物;和苄基和苯乙基溴化物季胺化。根据前述,对本文出现的本发明的化合物的任何提及意欲包括结构式(I)、(II)和(III)的化合物以及其药学上可接受的盐、水合物或溶剂合物。
本发明的具体化合物包括但不限于具有下文所述结构的化合物。
本发明提供Bcl-2/Bcl-xL抑制剂,例如结构式(I)、(II)和(III)的化合物,用于治疗其中Bcl-2和/或Bcl-xL的抑制具有有益作用的各种疾病和病况。在一个实施方案中,本发明涉及治疗患有其中Bcl-2/Bcl-xL的抑制提供益处的疾病或病况的个体的方法,包括给予有需要的个体治疗有效量的结构式(I)、(II)或(III)化合物。
本发明的方法可通过给予作为纯的化合物或作为药物组合物的结构式(I)、(II)或(III)的化合物来实现。可在目标疾病或病况发作期间或之后进行药物组合物或纯的结构式(I)、(II)或(III)的化合物的给予。通常,药物组合物是无菌的,含有无毒性、无致癌性或无诱变性的化合物,当给予时所述化合物时将引起不良反应。还提供药盒,其包含分开或一起包装的结构式(I)、(II)或(III)的化合物和用于治疗其中Bcl-2/Bcl-xL的抑制提供益处的疾病和病况的任选第二种治疗剂,和带有这些活性剂的使用说明的插页。
在许多实施方案中,结构式(I)、(II)或(III)的化合物与用于治疗其中Bcl-2/Bcl-xL的抑制提供益处的疾病或病况的第二种治疗剂结合给予。第二种治疗剂不同于结构式(I)、(II)和(III)的化合物。结构式(I)、(II)或(III)的化合物和第二种治疗剂可同时或序贯给予以实现所需效果。此外,结构式(I)、(II)或(III)的化合物和第二种治疗剂可自单一的组合物或两种分开的组合物给予。
第二种治疗剂以提供其所需治疗效果的量给予。每种第二种治疗剂的有效剂量范围是本领域已知的,并且在这样的已确定的范围内给予有需要的个体第二种治疗剂。
结构式(I)、(II)或(III)的化合物和第二种治疗剂可作为单一-单位剂量一起给予或作为多-单位剂量分开给予,其中结构式(I)、(II)或(III)的化合物在第二种治疗剂之前给予或反之亦然。可给予一个或多个剂量的结构式(I)、(II)或(III)的化合物和/或一个或多个剂量的第二种治疗剂。因此,结构式(I)、(II)和(III)的化合物可与一种或多种的第二种治疗剂(例如但不限于抗癌剂)一起使用。
按照本发明可治疗的疾病和病况包括例如癌症。可治疗各种癌症,包括但不限于:癌,包括膀胱癌(包括加速的和转移的膀胱癌)、乳腺癌、结肠癌(包括结肠直肠癌)、肾癌、肝癌、肺癌(包括小和非小细胞肺癌以及肺腺癌)、卵巢癌、前列腺癌、睾丸癌、泌尿生殖道癌、淋巴系统癌、直肠癌、喉癌、胰腺癌(包括外分泌胰腺癌)、食管癌、胃癌、胆囊癌、宫颈癌、甲状腺癌、肾癌和皮肤癌(包括鳞状细胞癌);淋巴系的造血肿瘤,包括白血病、急性淋巴细胞性白血病、急性成淋巴细胞性白血病、B-细胞淋巴瘤、T-细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、毛细胞淋巴瘤、组织细胞淋巴瘤和Burketts淋巴瘤;骨髓系的造血肿瘤,包括急性和慢性骨髓性白血病、骨髓发育不良综合征、骨髓性白血病和早幼粒细胞性白血病;中枢和外周神经系统的肿瘤,包括星形细胞瘤、成神经细胞瘤、神经胶质瘤和神经鞘瘤;间质来源的肿瘤,包括纤维肉瘤、横纹肌肉瘤和骨肉瘤;和其它肿瘤,包括黑素瘤、着色性干皮病、角化棘皮瘤、精原细胞瘤、甲状腺滤泡癌、畸胎癌、肾细胞癌(RCC)、胰腺癌、骨髓瘤、骨髓性和成淋巴细胞性白血病、成神经细胞瘤和成胶质细胞瘤。
可通过本发明的Bcl-2/Bcl-xL抑制剂治疗的其它形式的癌症包括例如成人和儿科肿瘤、实体瘤/恶性肿瘤的生长、粘液样和圆形细胞癌、局部晚期肿瘤、转移性癌、人软组织肉瘤(包括尤因肉瘤)、癌转移(包括淋巴转移)、鳞状细胞癌(特别是头和颈、食管鳞状细胞癌)、口腔癌、血细胞恶性肿瘤(包括多发性骨髓瘤)、白血病(包括急性淋巴细胞性白血病、急性非淋巴细胞性白血病、慢性淋巴细胞性白血病、慢性髓细胞性白血病和毛细胞性白血病)、渗出淋巴瘤(基于体腔的淋巴瘤)、胸腺淋巴瘤、肺癌(包括小细胞癌)、皮肤T细胞淋巴瘤、霍奇金淋巴瘤、非霍奇金淋巴瘤、肾上腺皮质的癌症、产生ACTH的肿瘤、非小细胞癌、乳腺癌(包括小细胞癌和管癌)、胃肠癌症(包括胃癌、结肠癌、结肠直肠癌和与结肠直肠瘤形成有关的息肉)、胰腺癌、肝癌、泌尿道癌(包括膀胱癌,例如原发性表面膀胱肿瘤、膀胱的侵袭性移行细胞癌和肌肉侵袭性膀胱癌)、前列腺癌、女性生殖道的恶性肿瘤(包括卵巢癌、原发性腹膜上皮瘤、宫颈癌、子宫内膜癌、阴道癌、外阴癌症、子宫癌和卵泡中的实体瘤)、男性生殖道的恶性肿瘤(包括睾丸癌和阴茎癌)、肾癌(包括肾细胞癌)、脑癌(包括内在的脑肿瘤、成神经细胞瘤、星形细胞脑肿瘤、神经胶质瘤和中枢神经系统的转移性肿瘤细胞侵袭)、骨癌(包括骨瘤和骨肉瘤)、皮肤癌(包括恶性黑素瘤、人皮肤角质化细胞的肿瘤进展和鳞状细胞癌)、甲状腺癌、成视网膜细胞瘤、成神经细胞瘤、腹膜渗出物、恶性胸膜渗出物、间皮瘤、维尔姆斯肿瘤、胆囊癌、滋养层肿瘤、血管外皮细胞瘤和卡波西肉瘤。
可通过给予本发明的Bcl-2/Bcl-xL抑制剂治疗的其它疾病和病况(包括癌症)公开于美国专利公开号2007/0027135、美国专利号7,432,304、美国专利公开号2010/0278921和指定国为美国的WO 2012/017251,分别以其整体结合到本文中。
在本发明的方法中,将通常按照药学实践配制的治疗有效量的一种或多种化合物(I)、(II)或(III)给予对其有需要的人。是否需要这样的治疗取决于个别的病例,并进行医学评估(诊断),其考虑存在的征兆、症状和/或机能障碍,发展特定征兆、症状和/或机能障碍的风险,和其它因素。
结构式(I)、(II)或(III)的化合物可通过任何合适的途径给予,例如通过口服、含服、吸入、舌下、直肠、阴道、脑池内或经过腰椎刺穿的鞘内、经尿道、经鼻、经皮(即经皮肤)、或胃肠外(包括静脉内、肌肉内、皮下、冠状动脉内、皮内、乳房内、腹膜内、关节内、鞘内、眼球后、肺内注射和/或在特定位点的手术植入)给予。胃肠外给予可使用针头和注射器或使用高压技术完成。
药物组合物包括其中结构式(I)、(II)或(III)的化合物以有效实现其预期目的量给予的那些。准确的配制、给药途径和剂量根据诊断的病况或疾病通过个体医师确定。可分别调整给药量和间隔以提供足以保持治疗效果的结构式(I)、(II)或(III)的化合物的水平。
结构式(I)、(II)和(III)的化合物的毒性和治疗功效可通过标准制药程序在细胞培养物或实验动物中确定,例如用于确定化合物的最大耐受剂量(MTD),其定义为在动物中不引起毒性的最高剂量。在最大耐受剂量和治疗效果(例如抑制肿瘤生长)之间的剂量比是治疗指数。剂量可在该范围内变化,这取决于所用的剂型和所用的给药途径。治疗有效量的确定完全在本领域技术人员的能力范围内,特别是根据本文提供的详细公开内容。
治疗用途所需的治疗有效量的结构式(I)、(II)或(III)的化合物随正治疗的病况的性质、所需活性的时间长度和患者的年龄以及病况而变化,和最终通过主治医师来确定。可分别调整给药量和间隔以提供足以保持所需治疗效果的Bcl-2/Bcl-xL抑制剂的血浆水平。可以单一剂量或按以合适间隔给予的多次剂量方便地给予所需剂量,例如按1次、2次、3次、4次或更多次亚剂量/天。经常需要或要求多次剂量。例如,本发明的Bcl-2/Bcl-xL抑制剂可以以下频率给予:1次剂量/天,持续2天,休息5天,持续2周;1次剂量/天,持续3天,休息4天,持续3周;每周1次给药,持续2周;每周1次给药,持续4周;或者,对情况适当确定的任何剂量方案。
用于本发明的方法的结构式(I)、(II)或(III)的化合物可以约0.005-约500毫克/剂量、约0.05-约250毫克/剂量或约0.5-约100毫克/剂量的量给予。例如,结构式(I)、(II)或(III)的化合物可以每剂量约0.005、0.05、0.5、5、10、20、30、40、50、100、150、200、250、300、350、400、450或500毫克的量给予,包括在0.005和500毫克之间的所有剂量。
包含结构式(I)、(II)或(III)的Bcl-2/Bcl-xL抑制剂的组合物或包含所述抑制剂的组合物的剂量可以是约1ng/kg-约200mg/kg、约1μg/kg-约100mg/kg或约1mg/kg-约50mg/kg。组合物的剂量可以是以任何剂量,包括但不限于约1μg/kg。组合物的剂量可以是以任何剂量,包括但不限于约1μg/kg、10μg/kg、25μg/kg、50μg/kg、75μg/kg、100μg/kg、125μg/kg、150μg/kg、175μg/kg、200μg/kg、225μg/kg、250μg/kg、275μg/kg、300μg/kg、325μg/kg、350μg/kg、375μg/kg、400μg/kg、425μg/kg、450μg/kg、475μg/kg、500μg/kg、525μg/kg、550μg/kg、575μg/kg、600μg/kg、625μg/kg、650μg/kg、675μg/kg、700μg/kg、725μg/kg、750μg/kg、775μg/kg、800μg/kg、825μg/kg、850μg/kg、875μg/kg、900μg/kg、925μg/kg、950μg/kg、975μg/kg、1mg/kg、5mg/kg、10mg/kg、15mg/kg、20mg/kg、25mg/kg、30mg/kg、35mg/kg、40mg/kg、45mg/kg、50mg/kg、60mg/kg、70mg/kg、80mg/kg、90mg/kg、100mg/kg、125mg/kg、150mg/kg、175mg/kg或200mg/kg。上述剂量是平均情况的实例,但可存在个别情况,其中应该用更高或更低的剂量,并且这样的剂量在本发明的范围内。实践中,医师确定最适合于个体患者的实际的给药方案,其可随特定患者的年龄、体重和反应而改变。
在癌症的治疗中,结构式(I)、(II)或(III)的化合物可与化学治疗剂和/或辐射一起给予。
本发明的实施方案采用以下的电磁辐射:γ-辐射(10-20至10-13m)、X-射线辐射(10-12至10-9m)、紫外光(10nm至400nm)、可见光(400nm至700nm)、红外辐射(700nm至1mm)和微波辐射(1mm至30cm)。
当前,许多癌症治疗方案采用被电磁辐射例如X-射线激活的辐射致敏剂。X-射线激活的辐射致敏剂的实例包括但不限于甲硝哒唑、迷索硝唑、去甲基醚醇硝唑、哌莫硝唑、依他硝唑、尼莫唑、丝裂霉素C、RSU 1069、SR 4233、EO9、RB 6145、尼克酰胺、5-溴脱氧尿苷(BUdR)、5-碘-脱氧尿苷(IUdR)、溴脱氧胞苷、氟脱氧尿苷(FUdR)、羟基脲、顺铂和其治疗有效的类似物和衍生物。
癌症的光动力疗法(PDT)采用可见光作为致敏剂的辐射激活剂。光动力辐射致敏剂的实例包括以下,但不限于:血卟啉衍生物、苯并卟啉衍生物、NPe6、本卟啉锡(SnET2)、脱镁叶绿酸-a、细菌叶绿素-a、萘菁、酞菁、酞菁锌和其治疗有效量的类似物和衍生物。
除了本发明的Bcl-2/Bcl-xL抑制剂之外,辐射致敏剂还可以与治疗有效量的一种或多种化合物联合给予,所述化合物包括但不限于促进辐射致敏剂掺入靶细胞的化合物;控制治疗剂、营养素和/或氧流向靶细胞的化合物;与另外的辐射一起或不与另外的辐射一起对肿瘤起作用的化学治疗剂;或用于治疗癌症或其它疾病的其它治疗有效化合物。可与辐射致敏剂联合使用的另外的治疗剂的实例包括但不限于5-氟尿嘧啶(5-FU)、亚叶酸、氧、氧和5%二氧化碳的混合气(carbogen)、红细胞输注、全氟化碳(例如-DA)、2,3-DPG、BW12C、钙通道阻滞剂、己酮可可碱、血管生成抑制化合物、肼屈嗪和L-BSO。
化学治疗剂可以是诱导细胞凋亡的任何药理学作用剂或化合物。所述药理学作用剂或化合物可以是例如小的有机分子、肽、多肽、核酸或抗体。可使用的化学治疗剂包括但不限于烷基化剂、抗代谢物、激素和其拮抗剂、天然产物和其衍生物、放射性同位素、抗体以及天然产物和其组合。例如,本发明的Bcl-2/Bcl-xL抑制剂可与抗生素例如多柔比星和其它蒽环类抗生素类似物、氮芥例如环磷酰胺、嘧啶类似物例如5-氟尿嘧啶、顺铂、羟基脲、泰素和其天然和合成衍生物等一起给予。作为另一个实例,在混合肿瘤例如乳腺的腺癌(其中所述肿瘤包括促性腺素依赖性细胞和促性腺素非依赖性细胞)的情况下,所述化合物可与亮丙瑞林或戈舍瑞林(LH-RH的合成肽类似物)联合给予。其它抗瘤方案包括使用抑制剂化合物与另一种治疗形式,例如手术或辐射,本文亦称为"辅助抗瘤形式"。可用于本发明的其它化学治疗剂包括激素和其拮抗剂、放射性同位素、抗体、天然产物和其组合。
可用于本发明方法的化学治疗剂的实例列于下表中。
表1
微管作用剂干扰细胞有丝分裂,并且其细胞毒素活性是本领域众所周知的。可用于本发明的微管作用剂包括但不限于别秋水仙碱(NSC 406042)、软海绵素B(NSC 609395)、秋水仙碱(NSC 757)、秋水仙素衍生物(例如NSC 33410)、多拉司他汀10(NSC 376128)、美坦生(NSC 153858)、根霉素(NSC 332598)、紫杉醇(NSC 125973)、 衍生物(例如,NSC608832)、硫代秋水仙碱(NSC 361792)、三苯甲基半胱氨酸(NSC 83265)、硫酸长春碱(NSC49842)、硫酸长春新碱(NSC 67574)、天然和合成的epothilone包括但不限于epothiloneA、eopthilone B和discodermolide(参见Service,(1996)Science,274:2009);磷雌氮芥、诺考达唑、MAP4等。这样的作用剂的实例还描述于Bulinski(1997)J.Cell Sci.110:30553064;Panda(1997)Proc.Natl.Acad.Sci.USA 94:10560-10564;Muhlradt(1997)CancerRes.57:3344-3346;Nicolaou(1997)Nature 397:268-272;Vasquez(1997)Mol.Biol.Cell.8:973-985;和Panda(1996)J.Biol.Chem.271:29807-29812。
可使用的细胞生长抑制剂包括但不限于激素和类固醇(包括合成的类似物):17-α-炔雌醇、己烯雌酚、睾酮、泼尼松、氟甲睾酮、丙酸屈他雄酮、睾内酯、醋酸甲地孕酮、甲泼尼龙、甲基-睾酮、泼尼松龙、曲安西龙、氯烯雌醚、羟孕酮、氨鲁米特、雌莫司汀、醋酸甲羟孕酮、亮丙瑞林、氟他胺、托瑞米芬和诺雷德。
其它细胞生长抑制剂是抗血管生成药,例如基质金属蛋白酶抑制剂,和其它VEGF抑制剂,例如抗-VEGF抗体和小分子例如ZD6474和SU668。还可使用抗-Her2抗体。EGFR抑制剂是EKB-569(一种不可逆抑制剂)。还包括对EGFR和Src抑制剂具有免疫特异性的抗体C225。
作为细胞生长抑制剂还适合使用的是(比卡鲁胺,Astra Zeneca),其赋予雄激素依赖性的癌非增值性。细胞生长抑制剂的又一个实例是抗雌激素其抑制雌激素依赖性乳腺癌的增殖或生长。细胞增殖信号转导的抑制剂是细胞生长抑制剂。代表性实例包括表皮生长因子抑制剂、Her-2抑制剂、MEK-1激酶抑制剂、MAPK激酶抑制剂、PI3抑制剂、Src激酶抑制剂和PDGF抑制剂。
可与本发明的Bcl-2/Bcl-xL抑制剂一起给予的另外的第二种治疗剂公开于美国专利公开号2007/0027135、美国专利号7,432,304、美国专利公开号2010/0278921、指定国为美国的WO 2012/017251,各自通过引用结合到本文中。
本发明的化合物通常与药用载体混合给予,所述载体根据预期的给药途径和标准药学实践而选择。根据本发明使用的药物组合物使用一种或多种生理学可接受的载体以常规方式配制,所述载体包括促进结构式(I)、(II)和(III)的化合物处理的赋形剂和助剂。
这些药物组合物可通过例如常规的混合、溶解、制粒、制锭、乳化、包胶、捕获或冻干过程制备。合适的制剂取决于所选的给药途径。当治疗有效量的结构式(I)、(II)或(III)的化合物口服给予时,所述组合物通常呈片剂、胶囊剂、粉剂、溶液剂或酏剂的形式。当以片剂形式给予时,所述组合物可另外包含固体载体,例如明胶或辅剂。片剂、胶囊剂和粉剂含有约0.01%-约95%、和优选约1%-约50%的结构式(I)、(II)或(III)的化合物。当以液体形式给予时,可加入液体载体例如水、石油或动物或植物来源的油。液体形式的组合物可进一步含有生理盐水溶液、葡萄糖或其它糖溶液或甘油。当以液体形式给予时,所述组合物含有约0.1%-约90%、和优选约1%-约50%重量的结构式(I)、(II)或(III)的化合物。
当治疗有效量的结构式(I)、(II)或(III)的化合物通过静脉内、皮肤或皮下注射给予时,所述组合物呈无热源的胃肠外可接受的水溶液的形式。适当考虑pH、等渗性、稳定性等而制备这样的胃肠外可接受的溶液在本领域的技术范围内。用于静脉内、皮肤或皮下注射的优选的组合物通常含有等渗的溶媒。
结构式(I)、(II)和(III)的化合物可容易地与本领域众所周知的药学上可接受的载体组合。这样的载体使得活性剂能够作为片剂、丸剂、锭剂、胶囊剂、液体剂、凝胶剂、糖浆剂、膏剂、混悬剂等配制,用于由待治疗的患者口服摄取。用于口服使用的药物制剂可通过添加结构式(I)、(II)或(III)的化合物至固体赋形剂,任选研磨所得的混合,和在加入合适的助剂之后(如果需要),加工粒料混合物以得到片剂或锭剂核心而获得。合适的赋形剂包括例如填充剂和纤维素制剂。如果需要,可加入崩解剂。
结构式(I)、(II)和(III)的化合物可经配制通过注射用于胃肠外给予,例如通过推注或持续输注。注射制剂可以单位剂型提供,例如在安瓿中或在多剂量容器中,具有添加的防腐剂。所述组合物可呈这样的形式,例如在油性或水性溶媒中的混悬剂、溶液剂或乳剂,和可含有配制剂例如助悬剂、稳定剂和/或分散剂。
用于胃肠外给予的药物组合物包括呈水溶形式的活性剂的水性溶液。此外,结构式(I)、(II)或(III)的化合物的混悬剂可制备为合适的油性注射混悬剂。合适的亲脂溶剂或溶媒包括脂肪油或合成的脂肪酸酯。水性注射混悬剂可包含增加混悬剂的粘度的物质。任选地,混悬剂还可包含合适的稳定剂或增加化合物的溶解度并允许制备高度浓缩溶液的作用剂。或者,本发明的组合物可以呈粉末形式,用于在使用前与合适的溶媒例如无菌无热源水配制。
结构式(I)、(II)或(III)的化合物还可配制在直肠组合物中,例如栓剂或保留灌肠剂,例如含有常规的栓剂基料。除了前述制剂之外,结构式(I)、(II)或(III)的化合物还可配制为贮库制剂。这样的长效制剂可通过植入(例如皮下或肌肉内)或通过肌肉内注射给予。因此,例如,结构式(I)、(II)或(III)的化合物可与合适的聚合材料或疏水材料(例如作为在可接受的油中的乳剂)或离子交换树脂一起配制。
具体而言,结构式(I)、(II)和(III)的化合物可以含有赋形剂例如淀粉或乳糖的片剂的形式,或以单独或与赋形剂混合的胶囊剂或卵形剂(ovule)的形式,或以含有矫味剂或着色剂的酏剂或混悬剂的形式,口服、含服或舌下给予。这样的液体制剂可与药学上可接受的添加剂(例如助悬剂)一起配制。结构式(I)、(II)和(III)的化合物还可经胃肠外注射,例如静脉内、肌肉内、皮下或冠状动脉内。对于胃肠外给予,Bcl-2/Bcl-xL抑制剂最好以无菌水性溶液的形式使用,其可含有其它物质,例如盐或单糖,例如甘露糖醇或葡萄糖,以使所述溶液与血液等渗。
作为另外的实施方案,本发明包括药盒,其包括以促进其用于实施本发明方法的方式包装的一种或多种化合物或组合物。在一个简单的实施方案中,所述药盒包括用于方法实践的本文所述的化合物或组合物(例如,包含结构式(I)、(II)或(III)的化合物和任选第二种治疗剂的组合物),其包装在容器中,例如密封的瓶或管,容器上附有标签或药盒内包括标签,其描述使用所述化合物或组合物以实施本发明的方法。优选地,所述化合物或组合物以单位剂型包装。所述试剂盒可进一步包括适于根据预期给药途径而给予所述组合物的装置。
除了其在治疗药物中的用途之外,结构式(I)、(II)和(III)的化合物和其药学上可接受的盐还可用作在用于评价Bcl-2和/或Bcl-XL的抑制剂在实验动物(例如猫、狗、兔、猴、大鼠和小鼠)中的效果的体外和体内测试系统的开发和标准化中的药理学工具,作为新的治疗药的研究的一部分。
在先的Bcl-2/Bcl-xL抑制剂具有妨碍其开发作为治疗药的性质。根据本发明的重要特征,结构式(I)、(II)和(III)的化合物作为Bcl-2/Bcl-xL的抑制剂进行合成和评价。例如,本发明的化合物通常具有小于100nM的与Bcl-2/Bcl-xL的结合亲和力(IC50)。
化合物的合成
本发明的化合物如下制备。以下合成方案代表了用于合成结构式(I)、(II)和(III)的化合物的反应。制备本发明的Bcl-2/Bcl-xL抑制剂的变更和代替方案完全在本领域技术人员的能力范围内。
溶剂和试剂可市售获得,无需进一步纯化而使用。NMR光谱的化学位移(δ)报告为相对于内部标准的δ值(ppm)低磁场,以通常的方式报告多峰性。
除非另有说明,否则所有的温度以摄氏度计。
用于合成本发明的化合物的某些关键的中间体可通过指定国为美国的WO 2012/103059中所述的方法合成,所述专利通过引用以其整体结合到本文中,接着如下转化成其磷酸盐衍生物:
方案1:化合物1的合成
实验部分:(R)-1-(3-(4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基)-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)哌啶-4-基2-氨基乙酸酯(1)。将BM-1197(113mg,0.10mmol)和Fmoc-Gly-OSu(43mg,0.11mmol)在CH2Cl2(2mL)中的溶液在室温下搅拌1小时,直到通过TLC未观察到BM-1197。将溶液真空浓缩,提供1的粗制前体,其用于下一步骤而无需纯化。将得到的残余物溶于乙腈(5mL),接着加入二乙胺(0.2mL,2mmol)。将混合物在室温下搅拌过夜,直到通过TLC未观察到原料,和真空浓缩。残余物通过HPLC纯化,得到产物1(与TFA的盐,83mg,经2步收率70%)。梯度为在40min内60%的溶剂A和40%的溶剂B至20%的溶剂A和80%的溶剂B。MS(ESI)m/z 1189.08(M+H)+。
方案2:2的合成
实验部分:(R)-2-(1-(3-(4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基)-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)哌啶-4-基氧基)-2-氧代乙酸(2)。向BM-1197(113mg,0.10mmol)、DMAP(2mg,0.02mmol)、Et3N(42uL,0.3mmol)在CH2Cl2(2mL)的溶液中加入2-氯-2-氧代乙酸叔丁酯(33mg,0.2mmol)。将溶液在室温下搅拌1小时,直到通过TLC未观察到BM-1197,和真空浓缩。将粗制残余物在硅胶上用5%MeOH/CH2Cl2快速色谱分离,提供2的前体。将前体溶于CH2Cl2(3mL),接着加入TFA(3mL)。将混合物在室温下搅拌1小时,直到通过TLC未观察到原料,和真空浓缩。残余物通过HPLC纯化,得到产物2(与TFA的盐,66mg,经2步收率55%)。梯度为在40min内60%的溶剂A和40%的溶剂B至20%的溶剂A和80%的溶剂B。MS(ESI)m/z 1189.08(M+H)+。
方案3:关键中间体B和D的制备
实验部分:N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基)-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)-4-氟-3-(三氟甲基磺酰基)苯磺酰胺(B)。向A(3.0g,4.9mmol)在150mL甲醇中的溶液加入10%wt.Pd/C(300mg,0.1eq.m/m)。将溶液在氢气氛下在室温下搅拌约20min,直到通过TLC未观察到A。将反应混合物过滤,和将滤液真空浓缩。将残余物直接用于下一步骤而无需纯化。在0℃向该苯胺在吡啶中的溶液中加入4-氟-3-(三氟甲基磺酰基)苯-1-磺酰氯(1.8g,5.4mmol)。将混合物在0℃至室温搅拌1小时,直到通过TLC未观察到苯胺。加入水(10mL)和用乙酸乙酯(200mL*2)萃取。合并的乙酸乙酯溶液用盐水(150mL)洗涤,经硫酸钠干燥和真空浓缩。浓缩物在硅胶上用40%EtOA/己烷快速色谱分离,提供中间体B(3.2g,经2步收率75%)。MS(ESI)m/z 931.75(M+K)+。
通用流程I:(R)-(9H-芴-9-基)甲基4-氧代-1-(苯基硫代)丁-2-基氨基甲酸酯(D)。在-10℃在氩气氛下向C(5.0g,11.5mmol)在THF(100mL)中的溶液中加入三乙胺(4.8mL,34.5mmol)和氯甲酸乙酯(3.3mL,34.5mmol)。将混合物在-10℃搅拌1h,和在-10℃滴加含NaBH4(1.7g,46.1mmol)的水(60mL)。将混合物在-10℃搅拌1h,然后在室温下搅拌2h。用1M含水KHSO4(200mL)将反应淬灭,混合物用EtOAc(3×200mL)萃取。萃取物用盐水(200mL)洗涤,经无水硫酸钠干燥,过滤和真空浓缩。浓缩物在硅胶上用50%EtOA/己烷快速色谱分离,提供相应的醇(4.3g,收率90%)。在-78℃向草酰氯(2.6mL,31.1mmol)在DCM(100mL)中的溶液中加入二甲基亚砜(3.7mL,51.8mmol)。将溶液升温至-40℃5min和再次冷却至-78℃,然后滴加前一步骤的所得醇(4.3g,10.4mmol)在DCM(50mL)中的溶液。将溶液搅拌另外40min,接着加入过量三乙胺(25mL)和搅拌另外30min。将反应混合物升温至室温,接着加入饱和氯化铵水溶液(100mL),和用DCM(2×200mL)萃取。合并的DCM溶液用盐水(150mL)洗涤,经硫酸钠干燥和真空浓缩。残余物在硅胶上用20%EtOA/己烷快速色谱分离,提供中间体D(3.7g,收率85%)。MS(ESI)m/z418.25(M+H)+。
方案4:3的合成
实验部分:二-叔丁基哌啶-4-基磷酸酯(F)。将二-叔丁基二-异丙基亚磷酰胺(832mg,3.0mmol)和四唑(6.6mL,0.45M,在乙腈中)在THF(15mL)中的溶液在N2下在室温下搅拌大约10min。然后经15分钟将在无水THF(2mL)中的化合物E(626mg,2.0mmol)加入至反应物,在室温下在N2下搅拌2小时,直到通过TLC未观察到E。然后将反应温度冷却至0℃和加入叔丁基过氧化物(3.0mL,4.6mmol)的14%水溶液。然后将温度升至室温,将混合物搅拌过夜。用饱和NaHCO3水溶液(2mL)淬灭反应。添加水(50mL)至反应混合物中,然后将其用乙酸乙酯(2×50mL)萃取。合并的乙酸乙酯溶液用盐水(50mL)洗涤,经硫酸钠干燥和真空浓缩,得到粗制产物,其用于下一步骤而无需纯化。将得到的残余物溶于乙腈(20mL),然后加入二乙胺(4.1mL,40mmol)。将混合物在室温下搅拌过夜,直到通过TLC未观察到原料,和真空浓缩。残余物在硅胶上用5%MeOH/DCM快速色谱分离,提供中间体F(452mg,经2步收率77%)。MS(ESI)m/z 295.17(M+H)+。
通用程序II:(R)-1-(3-氨基-4-(苯基硫代)丁基)哌啶-4-基二-叔丁基磷酸酯(G)。向F(293mg,1.0mmol)和中间体D(500mg,1.2mmol)在DCE(10mL)中的溶液中加入NaBH(OAc)3(636mg,3.0mmol),将混合物在室温下搅拌过夜,直到通过TLC未观察到F。混合物用DCM(50mL)洗涤,用盐水(50mL)洗涤和经硫酸钠干燥。真空除去溶剂,得到粗制产物,其用于下一步骤而无需纯化。将得到的残余物溶于乙腈(10mL),接着加入二乙胺(2.1mL,20mmol)。将混合物在室温下搅拌过夜,直到通过TLC未观察到原料和真空浓缩。残余物在硅胶上用10%MeOH/DCM快速色谱分离,提供中间体G(307mg,经2步收率65%)。MS(ESI)m/z 474.00(M+H)+。
通用程序III:(R)-1-(3-(4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基)-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)哌啶-4-基二氢磷酸酯(3)。向B(100mg,0.11mmol)和G(65mg,0.14mmol)在DMF(2mL)中的溶液中加入DIPEA(1mL)。将溶液在室温下搅拌4小时,直到通过TLC未观察到B。将反应混合物真空浓缩,得到粗制产物,其用于下一步骤而无需纯化。将得到的残余物溶于DCM(5mL),接着加入TFA(2.5mL)。将溶液在室温下搅拌1h,直到通过TLC未观察到原料。将反应混合物真空浓缩和残余物通过HPLC纯化,得到纯的产物3(与TFA的盐,88mg,经2步收率66%)。梯度为在40min内60%的溶剂A和40%的溶剂B至20%的溶剂A和80%的溶剂B。1H NMR(300M Hz,CD3OD):δ7.96(s,1H),7.73(d,J=8.9Hz,1H),7.32-7.07(m,13H),6.93-6.41(m,4H),4.61-4.41(m,2H),3.99(s,1H),3.55-3.11(m,16H),2.84(s,3H),2.74(s,3H),2.26-1.80(m,6H),1.43(d,J=7.0Hz,6H).MS(ESI):m/z 1212.67(M+H)+。
方案5:4的合成
实验部分:4-(甲基硫代甲氧基)哌啶(H)。在0℃向醇E(1.0g,3.1mmol)和硫化甲基(1.8mL,24.8mmol)在乙腈(31mL)中的溶液中经10min分4等份加入苯甲酰过氧化物(3.0g,12.4mmol),在0℃将混合物搅拌1h,然后在室温下搅拌1h,直到通过TLC未观察到E。混合物用乙酸乙酯(100mL)稀释,用10%Na2CO3(100mL)洗涤,然后用盐水(100mL)洗涤,经硫酸钠干燥。真空除去溶剂,得到粗制产物,其用于下一步骤而无需纯化。将得到的残余物溶于乙腈(10mL),接着加入二乙胺(6.2mL,60mmol)。将混合物在室温下搅拌过夜,直到通过TLC未观察到原料和真空浓缩。残余物在硅胶上用5%MeOH/DCM快速色谱分离,提供中间体H(270mg,经2步收率54%)。MS(ESI)m/z 162.83(M+H)+。
(R)-4-(4-(甲基硫代甲氧基)哌啶-1-基)-1-(苯基硫代)丁-2-胺(I)。根据通用程序II自H和D制备I。MS(ESI)m/z 341.58(M+H)+。
(R)-(1-(3-(4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基)-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)哌啶-4-基氧基)甲基二氢磷酸酯(4)。向B(200mg,0.23mmol)和I(86mg,0.25mmol)在DMF(4mL)中的溶液中加入DIPEA(2mL)。将溶液在室温下搅拌4小时,直到通过TLC未观察到B。将反应混合物在真空浓缩。残余物在硅胶上用5%MeOH/DCM快速色谱分离,得到相应的硫醚(241mg,收率88%)。在0℃向来自第一步骤的硫醚(200mg,0.17mmol)、磷酸(117mg,1.2mmol)和分子筛(500mg)在THF(6mL)中的溶液加入N-碘代琥珀酰亚胺(57mg,0.26mmol),将混合物在室温下搅拌1h,直到通过TLC未观察到原料。将反应混合物通过硅藻土过滤,固体用甲醇洗涤。滤液经真空浓缩,残余物通过HPLC纯化,得到纯的产物4(与TFA的盐,93mg,收率44%)。梯度为在40min内60%的溶剂A和40%的溶剂B至20%的溶剂A和80%的溶剂B。MS(ESI):m/z 1242.08(M+H)+。
方案6:化合物5、6、7的合成
实验部分:通用程序IV。(R)-3-((5-(4-氯苯基)-1-乙基-4-(3-(4-(4-(4-((4-(4-羟基哌啶-1-基)-1-(苯基硫代)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基磺酰胺基)苯基)哌嗪-1-基)苯基)-2-甲基-1H-吡咯-3-羰基)氧基)丙酸(5)。向957(100mg,0.09mmol)、DIC(18mg,0.14mmol)和DMAP(20mg,0.14mmol)在DCM(2mL)中的溶液中加入3-羟基丙酸叔丁酯(41mg,0.28mmol)。将溶液在室温下搅拌6小时,直到通过TLC未观察到BM-957。反应混合物用乙酸乙酯(50mL)稀释,用饱和NaHCO3溶液(50mL)、盐水(50mL)洗涤和经硫酸钠干燥。真空除去溶剂得到粗制产物,其用于下一步骤而无需纯化。将得到的残余物溶于DCM(5mL),接着添加TFA(2.5mL)。将溶液在室温下搅拌3h,直到通过TLC未观察到原料。将反应混合物在真空浓缩,残余物通过HPLC纯化,得到纯的产物5(与TFA的盐,75mg,经2步收率70%)。梯度为在40min内60%的溶剂A和40%的溶剂B至20%的溶剂A和80%的溶剂B。MS(ESI):m/z1238.17(M+H)+。
(R)-4-((5-(4-氯苯基)-1-乙基-4-(3-(4-(4-(4-((4-(4-羟基哌啶-1-基)-1-(苯基硫代)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基磺酰胺基)苯基)哌嗪-1-基)苯基)-2-甲基-1H-吡咯-3-羰基)氧基)苯甲酸(6)。6根据通用程序IV自BM-957和4-羟基苯甲酸叔丁酯制备。MS(ESI):m/z 1186.00(M+H)+。
(R)-4-((5-(4-氯苯基)-1-乙基-4-(3-(4-(4-(4-((4-(4-羟基哌啶-1-基)-1-(苯基硫代)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基磺酰胺基)苯基)哌嗪-1-基)苯基)-2-甲基-1H-吡咯-3-羰基)氧基)环己烷甲酸(7)。7根据通用程序IV自BM-957和4-羟基环己烷甲酸叔丁酯制备。MS(ESI):m/z 1192.25(M+H)+。
方案7:8、9的合成
实验部分:
通用程序V:(R)-(((5-(4-氯苯基)-1-乙基-4-(3-(4-(4-(4-((4-(4-羟基哌啶-1-基)-1-(苯基硫代)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基磺酰胺基)苯基)哌嗪-1-基)苯基)-2-甲基-1H-吡咯-3-羰基)氧基)甲基)膦酸(8)。向BM-957(100mg,0.09mmol)、DIC(18mg,0.14mmol)和DMAP(20mg,0.14mmol)在DCM(2mL)中的溶液中加入二甲基(羟基甲基)膦酸酯(40mg,0.28mmol)。将溶液在室温下搅拌6小时,直到通过TLC未观察到BM-957。将反应混合物用乙酸乙酯(50mL)稀释,用饱和NaHCO3溶液(50mL)、盐水(50mL)洗涤和经硫酸钠干燥。真空除去溶剂得到粗制产物,其用于下一步骤而无需纯化。将得到的残余物溶于DCM(5mL),接着加入TMSBr(248uL,1.9mmol)。将溶液在室温下搅拌20h,直到通过MS未观察到原料。将反应混合物在真空浓缩,残余物通过HPLC纯化,得到纯的产物8(与TFA的盐,74mg,经2步收率68%)。梯度为在40min内60%的溶剂A和40%的溶剂B至20%的溶剂A和80%的溶剂B。1H NMR(300M Hz,CD3OD):δ7.92(s,1H),7.73-7.70(m,2H),7.34-6.82(m,17H),4.28(d,J=8.6Hz,2H),4.06-3.35(m,14H),3.20-2.92(m,5H),2.65(s,3H),2.24-1.67(m,6H),1.10(t,J=7.0Hz,3H).MS(ESI):m/z 1259.50(M+H)+。
(R)-(2-((5-(4-氯苯基)-1-乙基-4-(3-(4-(4-(4-((4-(4-羟基哌啶-1-基)-1-(苯基硫代)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基磺酰胺基)苯基)哌嗪-1-基)苯基)-2-甲基-1H-吡咯-3-羰基)氧基)乙基)膦酸(9)。9根据通用程序V自BM-957和二甲基(2-羟基乙基)膦酸酯制备。MS(ESI):m/z 1173.42(M+H)+。
方案8:10的合成
((R)-4-(5-(4-氯苯基)-1-乙基-4-(3-(4-(4-(4-(4-(4-羟基哌啶-1-基)-1-(苯基硫代)丁-2-基氨基)-3-(三氟甲基磺酰基)苯基磺酰胺基)苯基)哌嗪-1-基)苯基)-2-甲基-1H-吡咯-3-甲酰胺基)环己烷甲酸(10)。向BM-957(100mg,0.09mmol)、EDCI(27mg,0.14mmol)和HOBT(19mg,0.14mmol)在DCM(2mL)中的溶液中加入4-氨基环己烷甲酸甲酯(44mg,0.28mmol)。将溶液在室温下搅拌2小时,直到通过TLC未观察到BM-957。反应混合物用乙酸乙酯(50mL)稀释,用饱和NaHCO3溶液(50mL)、盐水(50mL)洗涤和经硫酸钠干燥。真空除去溶剂,得到粗制产物,其用于下一步骤而无需纯化。将得到的残余物溶于H2O和MeOH(分别5mL和5mL),接着加入NaOH(76mg,1.9mmol)。将溶液在室温下搅拌20h,直到通过TLC未观察到原料。将反应混合物在真空浓缩,残余物通过HPLC纯化,得到纯的产物10(与TFA的盐,61mg,经2步收率55%)。梯度为在40min内60%的溶剂A和40%的溶剂B至20%的溶剂A和80%的溶剂B。MS(ESI):m/z 1191.17(M+H)+。
方案9:11的合成
实验部分:
(R)-(((5-(4-氯苯基)-4-(3-(4-(4-(4-((4-(4-羟基哌啶-1-基)-1-(苯基硫代)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基磺酰胺基)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羰基)氧基)甲基)膦酸(11)。11根据通用程序V自BM-962和二甲基(羟基甲基)膦酸酯制备。1HNMR(300M Hz,CD3OD):δ8.00(s,1H),7.80-7.71(m,2H),7.38-6.83(m,17H),4.50-4.41(m,1H),4.29(d,J=8.7Hz,2H),4.11-3.59(m,12H),3.25-3.01(m,6H),2.77(s,3H),2.28-1.70(m,6H),1.47(d,J=7.1Hz,6H).MS(ESI):m/z 1174.25(M+H)+。
方案9:12的合成
实验部分:
(R)-(2-((1-(3-((4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基)-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)氨磺酰基)-2-((三氟甲基)磺酰基)苯基)氨基)-4-(苯基硫代)丁基)哌啶-4-基)氧基)-2-氧代乙基)膦酸(12)。12根据通用程序V自BM-1197和2-(二乙氧基磷酰基)乙酸制备。1H NMR(300M Hz,CD3OD):δ7.99(s,1H),7.75(d,J=8.6Hz,1H),7.36-7.13(m,12H),6.92-6.43(m,5H),5.10(s,1H),4.51-4.44(m,1H),4.10(s,1H),3.56-2.93(m,18H),2.87(s,3H),2.76(s,3H),2.29-1.90(m,6H),1.46(d,J=7.3Hz,6H).MS(ESI):m/z1253.36(M+H)+。
方案10:13的合成
实验部分:
(R)-1-(3-氨基-4-(苯基硫代)丁基)哌啶-4-甲酸叔丁酯(K)。K根据通用程序II自哌啶-4-甲酸叔丁酯和D制备。MS(ESI):m/z 365.50(M+H)+。
(R)-1-(3-(4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基)-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)哌啶-4-甲酸(13)。13根据通用程序III自K和B制备。MS(ESI):m/z365.50(M+H)+。
方案11:14、15、16、17的合成
实验部分:
(R)-(1-(3-(4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基)-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)哌啶-4-羰基氧基)甲基膦酸(14)。14根据通用程序V自13和二甲基(2-羟基甲基)膦酸酯制备。1H NMR(300M Hz,CD3OD):δ7.94(s,1H),7.72(d,J=9.1Hz,1H),7.30-7.09(m,13H),6.91-6.42(m,4H),4.49-4.40(m,1H),3.99(s,1H),3.55-2.90(m,16H),2.84(s,3H),2.72(s,3H),2.63-2.55(m,1H),2.23-1.81(m,6H),1.41(d,J=4.3Hz,6H).MS(ESI):m/z 1160.34(M+H)+。
(R)-2-(1-(3-(4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基)-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)哌啶-4-羰基氧基)乙基膦酸(15)。15根据通用程序V自13和二甲基(2-羟基乙基)膦酸酯制备。1H NMR(300M Hz,CD3OD):δ7.93(d,J=1.9Hz,1H),7.72(dd,J=9.2,1.8Hz,1H),7.30-7.12(m,12H),6.83-6.42(m,5H),4.46-4.33(m,3H),3.96(s,1H),3.54-2.93(m,16H),2.82(s,3H),2.72(s,3H),2.71-2.55(m,1H),2.24-1.65(m,8H),1.41(d,J=7.1Hz,6H).MS(ESI):m/z 1268.58(M+H)+。
(R)-3-(1-(3-(4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基)-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)哌啶-4-羰基氧基)丙基膦酸(16)。16根据通用程序V自13和二甲基3-羟基丙基膦酸酯制备。1H NMR(300M Hz,CD3OD):δ7.95(d,J=2.0Hz,1H),7.73(dd,J=9.2,2.1Hz,1H),7.33-7.12(m,12H),6.92-6.43(m,5H),4.51-4.41(m,1H),4.18-3.98(m,3H),3.56-2.92(m,16H),2.85(s,3H),2.73(s,3H),2.67-2.50(m,1H),2.25-1.70(m,10H),1.43(d,J=7.1Hz,6H).MS(ESI):m/z 1282.34(M+H)+。
2-(1-((R)-3-(4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基)-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)哌啶-4-羰基氧基)丙基膦酸(17)。17根据通用程序V自13和二甲基2-羟基丙基膦酸酯制备。1H NMR(300M Hz,CD3OD):δ7.97(d,J=2.1Hz,1H),7.73(d,J=9.2Hz,1H),7.36-7.08(m,13H),6.85-6.43(m,4H),5.26(s,1H),4.54-4.44(m,1H),4.01(s,1H),3.58-2.92(m,16H),2.87(s,3H),2.76(s,3H),2.70-2.55(m,1H),2.26-1.85(m,8H),1.46(d,J=7.1Hz,6H),1.38(d,J=5.9Hz,3H).MS(ESI):m/z 1281.34(M+H)+。
方案12:18的合成
实验部分:
(R)-1-(3-氨基-4-(苯基硫代)丁基)-4-甲基哌啶-4-甲酸甲酯(M)。M根据通用程序II自4-甲基哌啶-4-甲酸甲酯和D制备。MS(ESI):m/z 337.55(M+H)+。
(R)-1-(3-(4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基)-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)-4-甲基哌啶-4-甲酸(18)。向B(100mg,0.11mmol)和M(47mg,0.14mmol)在DMF(2mL)中的溶液中加入DIPEA(1mL)。将溶液在室温下搅拌4小时,直到通过TLC未观察到B。将反应混合物在真空浓缩,得到粗制产物,其用于下一步骤而无需纯化。将得到的残余物溶于H2O和MeOH(分别5mL和5mL),接着加入NaOH(88mg,2.2mmol)。将溶液在室温下搅拌20h,直到通过TLC未观察到原料。将反应混合物在真空浓缩,残余物通过HPLC纯化得到纯的产物18(与TFA的盐,75mg,经2步收率58%)。梯度为在40min内60%的溶剂A和40%的溶剂B至20%的溶剂A和80%的溶剂B。1H NMR(300MHz,CD3OD):δ7.99(d,J=1.6Hz,1H),7.76(dd,J=9.1,1.9Hz,1H),7.37-6.84(m,14H),6.68-6.45(m,3H),4.55-4.45(m,1H),4.02(s,1H),3.58-2.92(m,17H),2.88(s,3H),2.77(s,3H),2.41-1.86(m,5H),1.47(d,J=7.1Hz,6H),1.31(s,3H).MS(ESI):m/z 1173.73(M+H)+。
方案13:19的合成
实验部分:
(R)-2-(1-(3-(4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基)-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)-4-甲基哌啶-4-羰基氧基)乙基膦酸(19)。19根据通用程序V自18和二甲基(2-羟基乙基)膦酸酯制备。1H NMR(300M Hz,CD3OD):δ7.98(d,J=1.6Hz,1H),7.73(dd,J=9.2,2.0Hz,1H),7.35-6.83(m,14H),6.65-6.44(m,3H),4.52-4.38(m,3H),4.01(s,1H),3.44-2.92(m,17H),2.87(s,3H),2.77(s,3H),2.45-2.11(m,5H),1.71(t,J=14.4Hz,2H),1.46(d,J=7.1Hz,6H),1.30(s,3H).MS(ESI):m/z 1281.92(M+H)+。
方案14:化合物20的合成
实验部分:
(R)-3-(((9H-芴-9-基)甲氧基)羰基氨基)-4-(2-氟苯基硫代)丁酸(O)。Bu3P(0.8mL,3.3mmol)和ADDP(833mg,3.3mmol)在THF(30mL)中的溶液用N(1.2g,3.0mmol)和硫代苯酚(320uL,3.0mmol)处理,搅拌4h直到通过TLC未观察到N。混合物用乙酸乙酯(100mL)稀释,用1M HCl水溶液(100mL)、盐水(100mL)洗涤和经硫酸钠干燥。真空除去溶剂得到粗制产物,其用于下一步骤而无需纯化。将得到的残余物溶于DCM(10mL),接着加入TFA(5mL)。将溶液在室温下搅拌1h,直到通过TLC未观察到原料。将反应混合物在真空浓缩,残余物在硅胶上用5%MeOH/DCM快速色谱分离,提供中间体O(840mg,经2步收率62%)。MS(ESI)m/z 452.86(M+H)+。
(R)-(9H-芴-9-基)甲基1-(2-氟苯基硫代)-4-氧代丁-2-基氨基甲酸酯(P)。P根据通用程序I自O制备。MS(ESI)m/z 437.00(M+H)+。
(R)-1-(3-氨基-4-(2-氟苯基硫代)丁基)哌啶-4-甲酸叔丁酯(Q)。Q根据通用程序II自P和J制备。MS(ESI)m/z 383.38(M+H)+。
(R)-1-(3-(4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基)-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(2-氟苯基硫代)丁基)哌啶-4-甲酸(20)。20根据通用程序III自Q和B制备。1H NMR(300MHz,CD3OD):δ7.97(d,J=1.9Hz,1H),7.76(dd,J=9.2,2.0Hz,1H),7.39-6.87(m,13H),6.65-6.43(m,3H),4.54-4.45(m,1H),4.01(s,1H),3.67-2.93(m,17H),2.87(s,3H),2.77(s,3H),2.29-1.86(m,6H),1.46(d,J=7.1Hz,6H).MS(ESI):m/z 1177.92(M+H)+。
方案15:21的合成
实验部分:
(R)-2-(1-(3-(4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基)-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(2-氟苯基硫代)丁基)哌啶-4-羰基氧基)乙基膦酸(21)。21根据通用程序V自20和二甲基(2-羟基乙基)膦酸酯制备。1H NMR(300M Hz,CD3OD):δ7.95(d,J=1.7Hz,1H),7.77(dd,J=9.0,2.0Hz,1H),7.36-6.86(m,13H),6.66-6.44(m,3H),4.51-4.33(m,3H),4.01(s,1H),3.58-2.93(m,16H),2.85(s,3H),2.74(s,3H),2.70-2.58(m,1H),2.27-1.84(m,8H),1.43(d,J=7.1Hz,6H).MS(ESI):m/z 1286.58(M+H)+。
方案16:22的合成
实验部分:
(R)-1-(4-(苯基硫代)-3-(4-氨磺酰基-2-(三氟甲基磺酰基)苯基氨基)丁基)哌啶-4-甲酸叔丁酯(S)。向K(1.1g,3.0mmol)和R(922mg,3.0mmol)在DMF(15mL)中的溶液中加入DIPEA(3mL)。将溶液在室温下搅拌4小时,直到通过TLC未观察到K。将反应混合物在真空浓缩,残余物在硅胶上用5%MeOH/DCM快速色谱分离,提供中间体S(1.7g,经2步收率88%)。MS(ESI)m/z 653.21(M+H)+。
(R)-1-(3-(4-(N-(4-(4-((2-(4-氯苯基)-5,5-二甲基环己-1-烯基)甲基)哌嗪-1-基)苯甲酰基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)哌啶-4-甲酸(22)。向T(438mg,1.0mmol)、EDCI(386mg,2.0mmol)和DMAP(121mg,1.0mmol)在DCM(10mL)中的溶液中加入S(718mg,1.1mmol)。将溶液在室温下搅拌2小时,直到通过TLC未观察到T。将反应混合物用乙酸乙酯(50mL)稀释,用饱和NaHCO3溶液(50mL)、盐水(50mL)洗涤和经硫酸钠干燥。真空除去溶剂,得到粗制产物,其用于下一步骤而无需纯化。将得到的残余物溶于DCM(10mL),接着加入TFA(5mL)。将溶液在室温下搅拌1h,直到通过TLC未观察到原料。将反应混合物在真空浓缩,残余物通过HPLC纯化,得到纯的产物22(与TFA的盐,742mg,经2步收率73%)。梯度为在40min内60%的溶剂A和40%的溶剂B至20%的溶剂A和80%的溶剂B。1H NMR(300M Hz,CD3OD):δ8.30(d,J=2.1Hz,1H),8.02(dd,J=9.2,2.5Hz,1H),7.70(d,J=8.9Hz,2H),7.40-6.88(m,12H),4.04(s,1H),3.67-2.82(m,19H),2.58(t,J=14.4Hz,1H),2.37-1.81(m,10H),1.53(t,J=6.2Hz,2H),1.03(s,6H).MS(ESI):m/z1017.50(M+H)+。
方案17:23、24、25的合成
实验部分:
(R)-(1-(3-(4-(N-(4-(4-((2-(4-氯苯基)-5,5-二甲基环己-1-烯基)甲基)哌嗪-1-基)苯甲酰基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)哌啶-4-羰基氧基)甲基膦酸(23)。23根据通用程序V自22和二甲基(2-羟基甲基)膦酸酯制备。1H NMR(300M Hz,CD3OD):δ8.35(s,1H),8.09(d,J=6.7Hz,1H),7.79(d,J=7.7Hz,2H),7.44-6.82(m,12H),4.30-4.10(m,3H),3.74-2.73(m,19H),2.43-1.44(m,12H),1.10(s,6H).MS(ESI):m/z 1110.58(M+H)+。
(R)-2-(1-(3-(4-(N-(4-(4-((2-(4-氯苯基)-5,5-二甲基环己-1-烯基)甲基)哌嗪-1-基)苯甲酰基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)哌啶-4-羰基氧基)乙基膦酸(24)。24根据通用程序V自22和二甲基(2-羟基乙基)膦酸酯制备。1HNMR(300M Hz,CD3OD):δ8.29(d,J=2.0Hz,1H),8.02(dd,J=9.2,2.0Hz,1H),7.71(d,J=8.8Hz,2H),7.37-6.84(m,12H),4.34-4.30(m,2H),4.03(s,1H),3.66-2.88(m,18H),2.62(t,J=14.4Hz,1H),2.36-1.82(m,12H),1.53(t,J=6.1Hz,2H),1.03(s,6H).MS(ESI):m/z1025.64(M+H)+。
(R)-3-(1-(3-(4-(N-(4-(4-((2-(4-氯苯基)-5,5-二甲基环己-1-烯基)甲基)哌嗪-1-基)苯甲酰基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)哌啶-4-羰基氧基)丙基膦酸(25)。25根据通用程序V自22和二甲基3-羟基丙基膦酸酯制备。1HNMR(300M Hz,CD3OD):δ7.95(d,J=2.0Hz,1H),7.73(dd,J=9.2,2.1Hz,1H),7.33-7.12(m,12H),6.92-6.43(m,5H),4.51-4.41(m,1H),4.18-3.98(m,3H),3.56-2.92(m,16H),2.85(s,3H),2.73(s,3H),2.67-2.50(m,1H),2.25-1.70(m,10H),1.43(d,J=7.1Hz,6H).MS(ESI):m/z 1282.34(M+H)+。
5-(4-氯苯基)-4-(3-(4-(4-(4-氟-3-(三氟甲基磺酰基)苯基磺酰胺基)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-N-(甲基磺酰基)-1H-吡咯-3-甲酰胺(V)。V根据所述用于制备化合物B的流程自U制备。
(R)-1-(3-(4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基氨基甲酰基)-1H-吡咯-3-基)苯基)哌嗪-1-基)苯基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)哌啶-4-甲酸(26)(BM-1077):26根据通用程序III自K和V制备。1HNMR(300M Hz,CD3OD):δ7.94(d,J=1.7Hz,1H),7.71(dd,J=2.0,9.2Hz,1H),7.39-7.28(m,4H),7.26-7.14(m,6H),7.09-6.96(m,5H),6.93-6.85(m,2H),6.81(d,J=9.3Hz,1H),6.75(d,J=7.6Hz,1H),4.41(五重峰,J=7.0Hz,1H),4.06-3.88(m,1H),3.66-3.33(m,8H),3.25-2.79(m,10H),2.63(s,3H),2.36-1.71(m,8H),1.43(d,J=7.1Hz,6H).MS(ESI):m/z1184.42(M+H)+。
(R)-2-(1-(3-(4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基氨基甲酰基)-1H-吡咯-3-基)苯基)哌嗪-1-基)苯基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)哌啶-4-羰基氧基)乙基膦酸(27)(BM-1080):27根据通用程序V自26和二甲基(2-羟基乙基)膦酸酯制备。1H NMR(300M Hz,CD3OD):δ7.95(d,J=1.9Hz,1H),7.69(dd,J=1.8,9.3Hz,1H),7.39-7.28(m,4H),7.27-7.12(m,6H),7.08-6.76(m,8H),6.70(d,J=7.5Hz,1H),4.49-4.27(m,3H),4.04-3.89(m,1H),3.65-3.48(m,2H),3.29-2.84(m,15H),2.63(s,3H),2.37-1.74(m,11H),1.43(d,J=7.1Hz,6H).MS(ESI):m/z 1292.00(M+H)+。
(R)-1-(3-氨基-4-(苯基硫代)丁基)-3-甲基氮杂环丁烷-3-甲酸甲酯(X)。X根据通用程序II自3-甲基氮杂环丁烷-3-甲酸甲酯(W)和D制备。
(R)-1-(3-(4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基)-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)-3-甲基氮杂环丁烷-3-甲酸(28)(BM-1082):28根据所述用于制备化合物18的程序自X和B制备。1H NMR(300M Hz,CD3OD):δ7.94(d,J=1.9Hz,1H),7.70(dd,J=2.1,9.1Hz,1H),7.35-7.24(m,4H),7.23-7.12(m,5H),7.07-6.91(m,4H),6.87(d,J=9.0Hz,1H),6.81(d,J=9.3Hz,1H),6.63-6.47(m,2H),6.41(d,J=9.0Hz,1H),4.55-4.38(m,2H),3.97(br.s.,3H),3.29-3.08(m,13H),2.84(s,3H),2.74(s,3H),2.12-1.81(m,2H),1.56(br.s.,3H),1.43(d,J=7.1Hz,6H).MS(ESI):m/z 1144.75(M+H)+。
(R)-2-(1-(3-(4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基)-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)-3-甲基氮杂环丁烷-3-羰基氧基)乙基膦酸(29)(BM-1083):29根据通用程序V自28和二甲基(2-羟基乙基)膦酸酯制备。1H NMR(300M Hz,CD3OD):δ7.94(d,J=1.8Hz,1H),7.72(dd,J=2.0,9.1Hz,1H),7.36-7.26(m,4H),7.25-7.15(m,5H),7.10-7.00(m,4H),6.92-6.83(m,1H),6.63(s,1H),6.57(d,J=12.0Hz,1H),6.42(d,J=9.2Hz,1H)4.58-4.35(m,5H),4.12-3.82(m,3H),3.29-3.05(m,11H),2.84(s,3H),2.74(s,3H),2.25-1.83(m,5H),1.50(br.s.,3H),1.43(d,J=7.1Hz,6H).MS(ESI):m/z 1252.83(M+H)+。
(R)-3-(1-(3-(4-(N-(4-(4-(3-(2-(4-氯苯基)-1-异丙基-5-甲基-4-(甲基磺酰基)-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)氨磺酰基)-2-(三氟甲基磺酰基)苯基氨基)-4-(苯基硫代)丁基)-3-甲基氮杂环丁烷-3-羰基氧基)丙基膦酸(30)(BM-1084):30根据通用程序V自28和二甲基(3-羟基丙基)膦酸酯制备。1H NMR(300M Hz,CD3OD):δ7.94(s,1H),7.71(dd,1.5,9.0Hz,1H),7.36-7.26(m,4H),7.24-7.15(m,5H),7.08-6.97(m,4H),6.90-6.79(m,2H),6.62(s,1H),6.56(d,J=11.8Hz,1H),6.41(d,J=8.8Hz,1H),4.54-4.37(m,3H),4.33-4.21(m,2H),3.99(br.s.,3H),3.28-3.05(m,11H),2.84(s,3H),2.74(s,3H),2.15-1.71(m,7H),1.57(s,3H),1.43(d,J=7.0Hz,6H).MS(ESI):m/z 1266.92(M+H)+。
用于Bcl-2/Bcl-xL/Mcl-1蛋白的基于荧光偏振的结合测定法
灵敏和定量的基于荧光偏振(FP)的测定法经开发和优化以确定Bcl-2家族蛋白抑制剂与重组Bcl-2、Bcl-xL和Mcl-1蛋白的结合亲和力。
确定荧光探针与蛋白的Kd值
自制的荧光素标记的BIM(81-106)、Bak(72-87)和BID(79-99)肽,称为Flu-BIM、Flu-BAK和Flu-BID,用作在FP测定法中分别针对Bcl-2、Bcl-xL和Mcl-1的荧光探针。通过监测由固定浓度的荧光探针和具有递增浓度直至完全饱和的蛋白组成的混合物的总荧光偏振,Flu-BIM与Bcl-2、Flu-BAK与Bcl-xL和Flu-BID与Mcl-1的Kd值分别确定为0.55±0.15nM、4.4±0.8和6.8±1.5nM。使用Infinite M-1000多模式读板器(Tecan U.S.,ResearchTriangle Park,NC)在Microfluor 2 96-孔黑色圆底板(Thermo Scientific)上测量荧光偏振值。向各孔中添加1nM的Flu-BIM或2nM的Flu-BAK或2nM的Flu-BID和递增浓度的Bcl-2或Bcl-xL或Mcl-1至在测定缓冲液(100mM磷酸钾,pH 7.5,100μg/ml牛γ-球蛋白,0.02%叠氮化钠,Invitrogen,含0.01%Triton X-100和4%DMSO)中的125μl终体积。将板在室温下孵育2小时,同时温和振荡以确保平衡。在激发波长为485nm和发射波长为530nm时测量以毫偏振单位(mP)计的偏振值。然后通过使用Graphpad Prism 5.0软件(Graphpad Software,San Diego,CA)拟合S形剂量依赖性FP增加作为蛋白浓度的函数,计算平衡离解常数(Kd)。
确定Bcl-2家族蛋白抑制剂的Ki值
Bcl-2家族蛋白抑制剂与Bcl-2/Bcl-xL/Mcl-1蛋白的Ki值通过抑制剂剂量依赖性竞争结合实验来确定,其中连续稀释的抑制剂针对固定浓度的荧光探针竞争结合至固定浓度的蛋白。将在DMSO中的5μl受试抑制剂和在测定缓冲液中的120μl预孵育蛋白/探针复合物的混合物加入至测定板并在室温下孵育2小时,同时温和振荡。对于Bcl-2测定,蛋白和探针的终浓度分别是1.5nM和1nM,对于Bcl-xL测定为10nM和2nM,和对于Mcl-1测定为20nM和2nM。仅含蛋白/探针复合物的阴性对照(等于0%抑制)和仅含游离探针的阳性对照(等于100%抑制)包括在每个测定板中。如上所述测量FP值。通过竞争曲线的非线性回归拟合测定IC50值。基于得到的IC50值(探针与蛋白的Kd值)和竞争测定中的蛋白与探针的浓度,使用前述的自推导的方程式计算抑制剂的Ki值(Z.Nikolovska-Coleska等,AnalyticalBiochemistry,2004,332,261-273.)。Ki值还通过使用文献中提供的另一经常使用的方程式计算(X.Y.Huang,Journal of Biomolecular Screening,2003,8,34-38.),其结果与我们的结果非常一致。
细胞生长测定法
RS4;11和H146细胞以10,000个细胞/孔的密度与连续稀释的化合物一起接种在96-孔细胞培养板中和在37℃在95%空气和5%CO2的气氛中孵育4天。根据制造商的说明书,使用基于WST-8(2-(2-甲氧基-4-硝基苯基)-3-(4-硝基苯基)-5-(2,4-二磺基苯基)-2H-四唑单钠盐)的Cell Counting-8Kit(Dojindo Molecular Technologies,Inc.,Rockville,MD)确定细胞成活力。简言之,将WST-8以终浓度10%(v/v)加入各孔,然后将板在37℃孵育1-2小时以显色。使用SPECTRAmax PLUS读板器(Molecular Devices,Sunnyvale,CA)在450nm测量吸光度。使用GraphPad Prism 5软件(GraphPad Software,La Jolla,CA)计算半最大抑制浓度(IC50)。
细胞死亡测定法
使用细胞成活力的锥虫蓝排除试验进行细胞死亡测定法。将一百万个细胞接种在6-孔板中,在37℃在95%空气和5%CO2的气氛中与或不与化合物一起孵育指定的时间点。在处理结束时,收集细胞和在1000rpm离心5分钟。将细胞沉淀重悬浮于PBS中,与0.4%锥虫蓝(Invitrogen)以1:1稀释混合,以使用Olympus CKX41显微镜(Olympus,Center Valley,PA)确定细胞成活力。
细胞凋亡测定法
按照制造商的说明书,使用Annexin-V-FLUOS Staining试剂盒(Roche Diagnostics,Indianapolis,IN)进行细胞凋亡测定法。简言之,细胞用化合物处理指定的时间点,收获并用PBS洗涤。在室温下在暗室中,细胞用Annexin V-FITC和碘化丙锭染色15分钟,然后用BDBiosciences FACSCaliburs(Becton Dickinson)分析。
蛋白印迹分析
细胞用补充蛋白酶抑制剂(α-完整,Roche)的裂解缓冲液(含1%NP40、0.5%脱氧胆酸钠和0.1%SDS的PBS)裂解。使用量热测定法(Bradford Reagent)(BioRad,Hercules,CA)定量测定蛋白提取物。蛋白在4-20%SDS-PAGE凝胶(Invitrogen)上进行电泳,然后转移到偏聚二氟乙烯膜(Bio-Rad)上。在5%牛奶中封闭后,将膜与特异性第一抗体一起孵育,洗涤,然后与辣根过氧化物酶连接的第二抗体(Pierce)一起孵育。将信号用化学发光辣根过氧化物酶抗体检测试剂(Denville Scientific)可视化。
细胞色素c和Smac释放测定法
将四百万个H146或RS4;11细胞在37℃用化合物在95%空气和5%CO2的气氛中处理指定的时间点,用PBS洗涤和重悬浮于100μl的毛地黄皂苷缓冲液(75mM NaCl,8mMNa2HPO4,1mM NaH2PO4,1mM EDTA,350μg/ml毛地黄皂苷和250mM蔗糖)中。通过在13,000rpm离心1min将细胞溶质级分与细胞器膜级分分离。将细胞溶质级分在12%SDS-PAGE上解析,使用抗-细胞色素c抗体(BD Biosciences)和抗-Smac(Cell Signaling Technology,Danvers,MA)抗体探测。
具体而言,测定本发明的化合物与Bcl-2、Bcl-xL和Mcl-1的亲和力。测定结果与针对ABT-737(一种已知的专利Bcl-2/Bcl-xL抑制剂)的测定结果相比较,并与这些肽相比较。结果在表1中概述。
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Claims (19)
1.Bcl-2/Bcl-xL抑制剂在制备用于治疗有需要的个体中其中Bcl-2或Bcl-xL的抑制提供益处的疾病或病况的药物中的用途,其中,所述Bcl-2/Bcl-xL抑制剂是具有以下结构式(I)的化合物或其药学上可接受的盐:
其中Y为
Q是C(=O)O(C1-3亚烷基);
R1是SO2(C1-3烷基);
R2是C1-3烷基;
R3是C1-3烷基;
R4是卤素;
R5是卤素;
R6是H或卤素;
Rb是氢或C1-3烷基。
2.权利要求1的用途,其中,所述Bcl-2/Bcl-xL抑制剂是具有以下结构的化合物:
3.权利要求1的用途,其中,所述治疗进一步包括给予治疗有效量的用于治疗所述疾病或病况的第二种治疗剂。
4.权利要求3的用途,其中,同时给予权利要求1-2中任一项的用途中的化合物和第二种治疗剂。
5.权利要求3的用途,其中分开给予权利要求1-2中任一项的用途中的化合物和第二种治疗剂。
6.权利要求1的用途,其中所述疾病或病况是癌症。
7.权利要求3的用途,其中所述疾病是癌症,而且第二种治疗剂是化学治疗剂和辐射的一种或多种。
8.权利要求3的用途,其中所述疾病是癌症,和第二种治疗剂选自段落[0125]-[0131]中公开的药剂。
9.权利要求3的用途,其中所述第二种治疗剂包括辐射,和所述辐射任选与本文段落[0122]-[0124]中公开的辐射致敏剂和/或治疗剂结合给予。
10.权利要求6的用途,其中所述癌症选自本文段落[0110]-[0112]中公开的癌症。
11.权利要求3的用途,其中权利要求1-2中任一项的用途中的化合物和第二种治疗剂从单一组合物中给予。
12.权利要求3的用途,其中权利要求1-2中任一项的用途中的化合物和第二种治疗剂从分开的组合物中给予。
13.权利要求5的用途,其中权利要求1-2中任一项的用途中的化合物在第二种治疗剂之前给予。
14.权利要求5的用途,其中权利要求1-2中任一项的用途中的化合物在第二种治疗剂之后给予。
15.组合物,其包含:(a)Bcl-2/Bcl-xL抑制剂,(b)用于治疗其中Bcl-2或Bcl-xL的抑制提供益处的疾病或病况的第二种治疗剂,和(c)任选的赋形剂和/或药学上可接受的载体,其中,所述Bcl-2/Bcl-xL抑制剂是具有以下结构式(I)的化合物或其药学上可接受的盐:
其中Y为
Q是C(=O)O(C1-3亚烷基);
R1是SO2(C1-3烷基);
R2是C1-3烷基;
R3是C1-3烷基;
R4是卤素;
R5是卤素;
R6是H或卤素;
Rb是氢或C1-3烷基。
16.权利要求15的组合物,其中,所述Bcl-2/Bcl-xL抑制剂是具有以下结构的化合物:
17.权利要求15的组合物,其中第二种治疗剂包括用于治疗癌症的化学治疗剂。
18.药物组合物,其包含Bcl-2/Bcl-xL抑制剂和药学上可接受的载体或溶媒,其中,所述Bcl-2/Bcl-xL抑制剂是具有以下结构式(I)的化合物或其药学上可接受的盐:
其中Y为
Q是C(=O)O(C1-3亚烷基);
R1是SO2(C1-3烷基);
R2是C1-3烷基;
R3是C1-3烷基;
R4是卤素;
R5是卤素;
R6是H或卤素;
Rb是氢或C1-3烷基。
19.权利要求18的药物组合物,其中,所述Bcl-2/Bcl-xL抑制剂是具有以下结构的化合物:
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KR102210316B1 (ko) | 2021-01-29 |
CA2897055A1 (en) | 2014-07-24 |
CN110305162A (zh) | 2019-10-08 |
SG11201505525UA (en) | 2015-08-28 |
ZA201504902B (en) | 2016-07-27 |
US9403856B2 (en) | 2016-08-02 |
AU2014207716A1 (en) | 2015-07-23 |
WO2014113413A1 (en) | 2014-07-24 |
EP3689886A1 (en) | 2020-08-05 |
EP2945940A1 (en) | 2015-11-25 |
CN110302205B (zh) | 2020-06-09 |
US9096625B2 (en) | 2015-08-04 |
HK1219734A1 (zh) | 2017-04-13 |
KR20150104631A (ko) | 2015-09-15 |
AU2014207716B2 (en) | 2017-07-27 |
EP2945940B1 (en) | 2020-07-15 |
JP6347793B2 (ja) | 2018-06-27 |
ES2819232T3 (es) | 2021-04-15 |
CA2897055C (en) | 2021-04-20 |
CN105246882A (zh) | 2016-01-13 |
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