CN112105360B - 用于癌症治疗的bcl-2蛋白降解剂 - Google Patents
用于癌症治疗的bcl-2蛋白降解剂 Download PDFInfo
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- CN112105360B CN112105360B CN201980021244.9A CN201980021244A CN112105360B CN 112105360 B CN112105360 B CN 112105360B CN 201980021244 A CN201980021244 A CN 201980021244A CN 112105360 B CN112105360 B CN 112105360B
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Abstract
本公开提供了用于选择性地杀死癌细胞的组合物和方法,其中所述组合物包含式(I)的化合物。与类似化合物相比,癌细胞的选择性杀死发生改进的效能和安全特性。特别是,本发明的组合物和方法显示降低的血小板毒性和在癌细胞中保留或改进的毒性。
Description
政府权利
本发明是在National Institutes of Health颁发的CA219836和CA223371的政府支持下完成的。政府对本发明享有一定权利。
相关申请的交叉引用
本申请要求2018年1月22日提交的美国临时申请号62/620,219的权益,其公开内容通过引用以其整体并入本文。
发明领域
本发明涉及诱导Bcl-2家族蛋白的降解的组合物及其在治疗各种癌症中的使用方法。
发明背景
由促凋亡成员和抗凋亡成员组成的B细胞淋巴瘤2 (Bcl-2)蛋白家族通过调节内在凋亡途径在确定细胞命运中起关键作用。抗凋亡Bcl-2家族蛋白(诸如Bcl-2、Bcl-xL、Bcl-W和Mcl-1)在许多癌症中被上调,并与肿瘤起始、进展和对化学疗法和靶向疗法的抗性相关。因此,这些抗凋亡Bcl-2蛋白是用于开发新型抗癌剂的有吸引力的靶(Lessene等人,Nat Rev Drug Discov 7: 989-1000, 2008;Vogler等人, Cell Death Differ 2009;16:360-367; Delbridge等人, Nat Rev Cancer 16: 99-109, 2016)。已报道多种Bcl-2小分子抑制剂(Bajwa等人, Expert Opin Ther Patents 22:37-55, 2012;Vogler, Adv Med.1-14, 2014;Ashkenazi等人, 16: 273-284, 2017)。以下是在药物开发的各个阶段已研究的Bcl-2小分子抑制剂中的一些:ABT-737 (US20070072860)、navitoclax (ABT-263,WO2009155386)、venetoclax (ABT-199,WO2010138588)、obatoclax (GX 15-070,WO2004106328)、(-)-棉酚(AT-101,WO2002097053)、sabutoclax (BI-97C1,WO2010120943)、TW-37 (WO2006023778)、BM-1252 (APG-1252)和A-1155463(WO2010080503)。
Venetoclax (一种选择性Bcl-2抑制剂)在2016年被FDA批准用于治疗具有17-p缺失的慢性淋巴细胞性白血病。Venetoclax被设计为比起Bcl-xL对Bcl-2具有高选择性,以避免靶向血小板毒性(Souers等人, Nat Med 19: 202-208, 2013)。血小板依赖Bcl-xL来维持其生存力,因此在用ABT-737 (Schoenwaelder等人, Blood 118: 1663-1674, 2011)、ABT-263 (Tse等人, Cancer Res 68: 3421-3428, 2008;Roberts等人, Bri J Haematol170: 669-678, 2015)、BM-1197 (Bai等人, PLoS ONE 9:e99404, 2014)或A-1155463(Tao等人, ACS Med Chem Lett 5:1088-1093,2014)治疗的动物和/或人中,由于它们的Bcl-xL的抑制,已经观察到剂量限制性血小板减少症。然而,许多CLL患者对venetoclax有抗性(Roberts等人, N Engl J Med 374: 311-322, 2016)并且通过微环境存活信号上调Bcl-xL已被鉴定为引起抗性的主要组分,与Bcl-2/Bcl-xL双重抑制剂ABT-263在杀死venetoclax抗性CLL细胞中的高功效一致(Oppermann等人, Blood 128: 934-947, 2016)。此外,Bcl-xL在实体瘤中通常比Bcl-2更频繁地过表达。重要的是,已经从ABT-263作为单一药剂或与其它抗肿瘤剂组合的临床前和临床研究记录了针对几种实体和血液恶性肿瘤的有希望的结果(Delbridge等人, Nat Rev Cancer 16: 99-109, 2016)。因此,非常需要开发一种策略,其可以保留Bcl-xL抑制剂的抗肿瘤通用性和功效,同时不受其靶向血小板毒性的影响。
因此,本领域需要开发能够保留Bcl-xL抑制剂的抗肿瘤通用性和功效,同时避免它们的靶向血小板毒性的化合物。
发明概述
本发明的一方面涵盖包含式(I)的化合物(以下)及其药学上可接受的盐和溶剂合物。这些化合物是抗凋亡Bcl-2蛋白降解剂,可用于治疗各种癌症。
本发明还涵盖杀死受试者的一种或多种癌症的方法。所述方法包括向需要其的受试者给予治疗有效量的本发明的化合物。
在另一方面,本发明涵盖降解受试者的抗凋亡Bcl-2蛋白的方法。所述方法包括向需要其的受试者给予治疗有效量的本发明的化合物。
在另一方面,本发明涵盖包含本发明的化合物和赋形剂和/或药学上可接受的载体的组合物,用于通过Bcl-2蛋白的降解治疗癌症。
在另一方面,本发明涵盖包含本发明的化合物和第二抗癌剂的组合物。
在另一方面,本发明涵盖包含本发明的化合物、第二癌症治疗剂和赋形剂和/或药学上可接受的载体的组合物,用于治疗癌症。
在另一方面,本发明涵盖本发明的化合物和抗癌剂的组合使用。
在再又一方面,本发明涵盖本发明的化合物和癌症放射疗法的组合使用。
附图简述
图1A、图1B、图1C、图1D、图1E和图1F描绘显示化合物#55降低Bcl-xL依赖性人肿瘤细胞的存活(图1A)、在MOLT4癌细胞系中诱导Bcl-xL降解,但在血小板中不诱导Bcl-xL降解(图1B和图1C)的说明。
图2显示化合物#55和ABT-263对Bcl-2、Bcl-xL和Bcl-w的结合亲和力以及化合物#55在多种肿瘤细胞中诱导Bcl-xL降解的说明。
图3A、图3B、图3C和图3D显示化合物#55以时间依赖性方式诱导Bcl-xL降解(图3A)并且在停掉化合物后该作用持续长时间(图3B)的说明。
图4A、图4B、图4C、图4D、图4E和图4F显示化合物#55对Bcl-xL的降解依赖于VHL表达和蛋白酶体活性,并且需要与Bcl-xL蛋白结合的说明。
图5显示化合物#55比ABT-263更有效地诱导PARP切割。
图6A和图6B显示化合物#55分别在Bcl-xL/Bcl-2和Bcl-xL/Mcl-1依赖性细胞系中与Bcl-2抑制剂ABT-199或McI1抑制剂S63845组合,协同降低细胞存活。
发明详述
本发明的化合物是能够促进抗凋亡Bcl-2家族蛋白的降解的二价化合物。这些二价化合物将Bcl-2小分子抑制剂或配体连接到E3连接酶结合部分,诸如von Hippel-Landau(VHL) E3连接酶接合部分(诸如HIF-1α衍生的含有(R)-羟脯氨酸的VHL E3连接酶配体)或cereblon (CRBN) E3连接酶结合部分(沙利度胺(thalidomide)衍生物,诸如泊马度胺(pomalidomide))。VHL为含有cullin-2 (CUL2)的E3泛素连接酶复合物延伸蛋白(elongin)BC-CUL2-VHL (称为CRL2VHL)的一部分,其负责转录因子HIF-1α的降解。已鉴定衍生自HIF-1α的含有(R)-羟脯氨酸的VHL E3连接酶配体具有高亲和力。CRBN是含有cullin-4 (CUL4)的E3泛素连接酶复合物CUL4-RBX1-DDB1-CRBN (称为CRL4CRBN)的一部分。沙利度胺及其衍生物(诸如来那度胺(lenalidomide)和泊马度胺)与该CRBN复合物特异性相互作用并且诱导必需IKAROS转录因子的降解。CC-122(沙利度胺的非邻苯二甲酰亚胺类似物)也与CRBNE3连接酶复合物相互作用但是诱导淋巴样转录因子Aiolos的降解。二价化合物可主动地将抗凋亡Bcl-2家族蛋白募集到E3泛素连接酶(诸如CRBN或VHL E3连接酶),导致它们通过泛素蛋白酶体系统降解。
血小板依赖Bcl-xL蛋白存活。因此,抑制血小板中的Bcl-xL蛋白引起血小板减少症,这限制了Bcl-xL抑制剂作为癌症治疗剂的应用。考虑到Bcl-xL在实体瘤中的充分记录的重要性及其对耐药性的贡献,设计使与Bcl-xL的抑制相关的靶向血小板毒性最小化的策略可以促进药物(如ABT-263,一种Bcl-2/Bcl-xL双重抑制剂)在癌症中的治疗应用。本发明的化合物被设计为募集E3连接酶(诸如CRBN或VHL E3连接酶),其在血小板中最低程度地表达,用于靶向降解Bcl-xL。
因此,与这些化合物相应的Bcl-2/Bcl-xL抑制剂相比,这些化合物具有降低的血小板毒性。因此,本公开提供了用于选择性地降解抗凋亡Bcl-2家族蛋白的组合物和方法。本发明的另外的方面在以下描述。
I.组合物
一方面,本发明的组合物包含式(I)的化合物。如与未修饰形式相比,可制备式(I)的衍生物,以改进效能、选择性、生物利用率、溶解度、稳定性、处理性质或其组合。
除式(I)的化合物之外,本发明的组合物可任选地包含一种或多种另外的药物或治疗活性剂。本发明的组合物可进一步包含药学上可接受的赋形剂、载体或稀释剂。此外,本发明的组合物可含有防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、增味剂、盐(本发明的物质本身可以药学上可接受的盐的形式提供)、缓冲液、包衣剂或抗氧化剂。
(a)
式(I)的化合物
本文提供包含式(I)的化合物:
其中
R1为卤素、CH3、CF3;
R2、R3、R4和R5独立地选自H、F、CH3、CHF2、CF3、CH2F、CH2OH、CH2OCH3或CH3O;
R6为C1-4烷基磺酰基、C1-4卤代烷基磺酰基、卤素、NO2或CN;
X为O或NH;
n为0-3的整数;
Y不存在、为-O-、-N(R7)-、、、、,、、、、、、,、、 、、、或;
其中R7为H、C1-4烷基或C1-4醇;
、、和的碳原子附着于L;
、、和的氮原子附着于L;
、、和的氧原子附着于L;
、、和的-N(R7)附着于L;
Z不存在、为-CH2-、-O-、-N(R8)-、-C(=O)N(R8)-、-N(R8)C(=O)(CH2)0-3O-或-N(R8)C(=O)(CH2)0-3N(R9)-;
其中R8和R9独立地为H或C1-4烷基;
-C(=O)N(R8)-的碳原子附着于L;
-N(R8)C(=O)(CH2)0-3O-和-N(R8)C(=O)(CH2)0-3N(R9)-的氮原子附着于L;
L为接头单元,其通过烷基、支链烷基、醚、硫醚、酯、胺、酰胺、氨基甲酸酯、脲、砜、芳基、杂芳基、羰基、环烷基或杂环基团共价地连接Y和Z,两端可以是相同的或不同的;接头单元可含有烷基、支链烷基、醚、硫醚、酯、胺、酰胺、氨基甲酸酯、脲、砜、芳基、杂芳基、羰基、环烷基和杂环基团中的两个或更多个基团的组合;最短长度的接头单元包含1-30个原子的长度;以及
A为E3泛素连接酶结合单元,其结合到E3泛素连接酶,在非限制性实例中,A为、、 、、、或,
其中R10为H、D、CH3或F。
在一个实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中R1为卤素、CH3、CF3。在优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中R1为Cl。
在另一个实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,R2、R3、R4和R5独立地选自H、F、CH3、CHF2、CF3、CH2F、CH2OH、CH2OCH3或CH3O。在优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中R2和R3为H。在另一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中R2和R3为CH3。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中R4和R5为H。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中R4和R5为CH3。在另一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中R2和R3为H,并且R4和R5为CH3。在另一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中R2和R3为CH3,并且R4和R5为H。
在再一个实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中R6选自C1-4烷基磺酰基、C1-4卤代烷基磺酰基、卤素、NO2或CN。在优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中R6为烷基磺酰基。在另一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中R6为C1-4卤代烷基磺酰基。在再一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中R6为-S(O2)CF3。
在再又一个实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中X为O或NH。在优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中X为NH。
在另一个实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中n为0-3的整数。在再又一个实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中n为2-3的整数。在另一个实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中n为3。在优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中n为1。
在另一个实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中Y选自-O-、-N(R7)-、、、、,、、、、、、,、、、、、和。在优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中Y选自-N(R7)-、、 、和,其中R7为H、C1-4烷基或C1-4醇。在另一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中Y为。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中Y为。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中Y为。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中Y为。在另一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中Y为-N(R7)-,其中R7选自CH3或CH2CH2OH。
在另一个实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为接头单元,其通过烷基、支链烷基、醚、硫醚、酯、胺、酰胺、氨基甲酸酯、脲、砜、芳基、杂芳基、羰基、环烷基或杂环基团共价地连接Y和Z,接头单元的两端可以是相同的或不同的;接头单元可含有烷基、支链烷基、醚、硫醚、酯、胺、酰胺、氨基甲酸酯、脲、砜、芳基、杂芳基、羰基、环烷基和杂环基团中的两个或更多个基团的组合;最短长度的接头单元包含1-30个原子的长度。在优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-C(=O)CH2CH2-。在另一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-C(=O)CH2(CH2)2CH2-。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-C(=O)CH2(CH2)3CH2-。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-C(=O)CH2(CH2)4CH2-。在另一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-C(=O)CH2(CH2)5CH2-。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-C(=O)CH2CH2CH2 CH2OCH2CH2OCH2CH2-。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-C(=O)CH2CH2CH2 CH2(OCH2CH2)2OCH2CH2-。在另一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-C(=O)CH2 CH2OCH2CH2OCH2CH2-。在另一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-C(=O)CH2OCH2CH2OCH2CH2-。在另一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-C(=O)CH2(OCH2CH2)2OCH2CH2-。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-C(=O)CH2(OCH2CH2)2OCH2CH2-。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-C(=O)CH2(OCH2CH2)3OCH2CH2-。在另一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-CH2CH2CH2-。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-CH2(CH2)2CH2-。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-CH2(CH2)3CH2-。在另一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-CH2(CH2)4CH2-。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-CH2(CH2)5CH2-。在另一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-CH2CH2OCH2CH2-。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-CH2CH2OCH2CH2OCH2CH2-。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-CH2CH2(OCH2CH2)2OCH2CH2-。在另一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-CH2CH2(OCH2CH2)3OCH2CH2-。在另一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-C(=O)CH2(CH2)4CH2 CH2OCH2CH2OCH2CH2-。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-C(=O)CH2(CH2)4CH2 CH2(OCH2CH2)2OCH2CH2-。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-CH2CH2(CH2)4CH2 CH2OCH2CH2OCH2CH2-。在另一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-CH2CH2(CH2)4CH2 CH2(OCH2CH2)2OCH2CH2-。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-CH2CH2OCH2-。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中L为-C(=O)CH2-。
在另一个实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中Z选自-CH2-、-O-、-N(R8)-、-C(=O)N(R8)-、-N(R8)C(=O)(CH2)0-3O-或-N(R8)C(=O)(CH2)0-3N(R9)-,其中R8为H或C1-4烷基。在优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中Z为-N(R8)-,其中R8为H。
在另一个实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中A选自
、、、、、或,
其中R10为H、D、CH3或F。在优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中A为,其中R10为H。在另一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中A为,其中R10为H。在再一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中A为。在又一个优选的实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其中A为。
在示例性实施方案中,式(I)的化合物包含前述式(I)的化合物中的任一种,其选自:
。
(b)
组合物的组分
本公开还提供药物组合物。所述药物组合物包含式(I)的化合物作为活性成分以及至少一种药学上可接受的赋形剂。
所述药学上可接受的赋形剂可以是稀释剂、粘结剂、填充剂、缓冲剂、pH调节剂、崩解剂、分散剂、防腐剂、润滑剂、味道掩蔽剂、调味剂或着色剂。用于形成药物组合物的赋形剂的量和类型可根据药物科学的已知原理来选择。
在一个实施方案中,赋形剂可以是稀释剂。稀释剂可以是可压缩的(即,塑性可变形的)或研磨脆性的。合适的可压缩稀释剂的非限制性实例包括微晶纤维素(MCC)、纤维素衍生物、纤维素粉末、纤维素酯(即,乙酸酯和丁酸酯混合酯)、乙基纤维素、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、玉米淀粉、磷酸化玉米淀粉、预胶化玉米淀粉、大米淀粉、马铃薯淀粉、木薯淀粉、淀粉-乳糖、淀粉-碳酸钙、淀粉羟基乙酸钠、葡萄糖、果糖、乳糖、乳糖一水合物、蔗糖、木糖、乳糖醇、甘露醇、麦芽糖醇、山梨糖醇、木糖醇、麦芽糖糊精和海藻糖。合适的研磨脆性稀释剂的非限制性实例包括磷酸氢钙(无水或二水合物)、磷酸钙、碳酸钙和碳酸镁。
在另一个实施方案中,赋形剂可以是粘结剂。合适的粘结剂包括但不限于淀粉、预胶化淀粉、明胶、聚乙烯吡咯烷酮、纤维素、甲基纤维素、羧甲基纤维素钠、乙基纤维素、聚丙烯酰胺、聚乙烯噁唑烷酮、聚乙烯醇、C12-C18脂肪酸醇、聚乙二醇、多元醇、糖类、寡糖、多肽、寡肽及其组合。
在另一个实施方案中,赋形剂可以是填充剂。合适的填充剂包括但不限于碳水化合物、无机化合物和聚乙烯吡咯烷酮。通过非限制性实例的方式,填充剂可以是硫酸钙(二碱式和三碱式两者)、淀粉、碳酸钙、碳酸镁、微晶纤维素、磷酸氢钙、碳酸镁、氧化镁、硅酸钙、滑石、改性淀粉、乳糖、蔗糖、甘露醇或山梨糖醇。
在再一个实施方案中,赋形剂可以是缓冲剂。合适的缓冲剂的代表性实例包括但不限于磷酸盐、碳酸盐、柠檬酸盐、tris缓冲液和缓冲盐水盐(例如,Tris缓冲盐水或磷酸盐缓冲盐水)。
在各种实施方案中,赋形剂可以是pH调节剂。通过非限制性实例的方式,pH调节剂可以是碳酸钠、碳酸氢钠、柠檬酸钠、柠檬酸或磷酸。
在进一步的实施方案中,赋形剂可以是崩解剂。崩解剂可以是非泡腾的或泡腾的。非泡腾崩解剂的合适的实例包括但不限于淀粉(诸如玉米淀粉、马铃薯淀粉及其预胶化的和改性淀粉)、甜味剂、粘土(诸如膨润土)、微晶纤维素、海藻酸盐、淀粉羟基乙酸钠、胶(诸如琼脂、瓜尔胶、槐豆胶、卡拉亚胶、果胶和黄芪胶)。合适的泡腾崩解剂的非限制性实例包括与柠檬酸组合的碳酸氢钠和与酒石酸组合的碳酸氢钠。
在又一个实施方案中,赋形剂可以是分散剂或分散增强剂。合适的分散剂可包括但不限于淀粉、海藻酸、聚乙烯吡咯烷酮、瓜尔胶、高岭土、膨润土、纯化的木纤维素、淀粉羟基乙酸钠、同形的(isoamorphous)硅酸盐和微晶纤维素。
在另一个替代实施方案中,赋形剂可以是防腐剂。合适的防腐剂的非限制性实例包括抗氧化剂,诸如BHA、BHT、维生素A、维生素C、维生素E或棕榈酸视黄酯、柠檬酸、柠檬酸钠;螯合剂,诸如EDTA或EGTA;以及抗微生物剂,诸如对羟基苯甲酸酯、氯丁醇或苯酚。
在进一步的实施方案中,赋形剂可以是润滑剂。合适的润滑剂的非限制性实例包括矿物,诸如滑石或二氧化硅;以及脂肪,诸如植物脂、硬脂酸镁或硬脂酸。
在又一个实施方案中,赋形剂可以是味道掩蔽剂。味道掩蔽材料包括纤维素醚;聚乙二醇;聚乙烯醇;聚乙烯醇和聚乙二醇共聚物;单甘油酯或三甘油酯;丙烯酸类聚合物;丙烯酸类聚合物与纤维素醚的混合物;乙酸邻苯二甲酸纤维素酯;及其组合。
在一个替代实施方案中,赋形剂可以是调味剂。调味剂可选自合成风味油和调味香料和/或天然油,来自植物、叶、花、果实的提取物及其组合。
在再进一步的实施方案中,赋形剂可以是着色剂。合适的颜色添加剂包括但不限于食品、药物和化妆品色素(FD&C)、药物和化妆品色素(D&C)或外用药物和化妆品色素(Ext. D&C)。
组合物中的赋形剂或赋形剂的组合的重量分数可以是组合物的总重量的约99%或更少、约97%或更少、约95%或更少、约90%或更少、约85%或更少、约80%或更少、约75%或更少、约70%或更少、约65%或更少、约60%或更少、约55%或更少、约50%或更少、约45%或更少、约40%或更少、约35%或更少、约30%或更少、约25%或更少、约20%或更少、约15%或更少、约10%或更少、约5%或更少、约2%、或约1%或更少。
所述组合物可配制成各种剂型并且通过递送治疗有效量的活性成分的多种不同的方式给予。这样的组合物可根据需要以含有常规的非毒性的药学上可接受的载体、佐剂和媒介物的剂量单位制剂口服、肠胃外或局部给予。局部给予还可涉及使用经皮给予,诸如经皮贴片或离子电渗装置。如本文所用,术语肠胃外包括皮下、静脉内、肌内或胸骨内注射或输注技术。药物的配制在例如Gennaro, A. R., Remington's PharmaceuticalSciences, Mack Publishing Co., Easton, Pa.(第18版, 1995)以及Liberman, H. A.和Lachman, L.编辑, Pharmaceutical Dosage Forms, Marcel Dekker Inc., New York,N.Y.(1980)中讨论。在一个具体实施方案中,组合物可以是食品补充剂或者组合物可以是化妆品。
用于口服给予的固体剂型包括胶囊、片剂、囊片、丸剂(pill)、粉末、丸粒(pellet)和颗粒剂。在这样的固体剂型中,活性成分通常与一种或多种药学上可接受的赋形剂(其实例在以上详述)组合。口服制剂还可作为水性悬浮液、酏剂或糖浆给予。为此,活性成分可与以下组合:各种甜味剂或调味剂、着色剂和(如果需要的话)乳化剂和/或悬浮剂以及稀释剂(诸如水、乙醇、甘油及其组合)。
对于肠胃外给予(包括皮下、真皮内、静脉内、肌内和腹膜内),所述制剂可以是水性溶液或基于油的溶液。水性溶液可包括无菌稀释剂(诸如水、盐水溶液)、药学上可接受的多元醇(诸如甘油、丙二醇)或其它合成溶剂;抗细菌剂和/或抗真菌剂,诸如苄醇、对羟基苯甲酸甲酯、氯丁醇、酚、硫柳汞(thimerosal)等;抗氧化剂,诸如抗坏血酸或亚硫酸氢钠;螯合剂,诸如乙二胺四乙酸;缓冲液,诸如乙酸盐、柠檬酸盐或磷酸盐;和/或用于调整张力的试剂,诸如氯化钠、右旋糖或多元醇(诸如甘露醇或山梨糖醇)。水性溶液的pH可用酸或碱(诸如盐酸或氢氧化钠)调节。基于油的溶液或悬浮液可进一步包含芝麻油、花生油、橄榄油或矿物油。
所述组合物可呈现在单位剂量或多剂量容器(例如密封的安瓿和小瓶)中,并且可在即将使用之前仅需要加入携带例如用于注射的水的无菌液体的冷冻干燥(冻干)的条件中储存。临时注射溶液和悬浮液可由无菌粉末、颗粒剂和片剂制备。
对于局部(例如,经皮或经粘膜)给予,通常在制剂中包括适用于待穿透的屏障的渗透剂。适于局部给予的药物组合物可配制为膏剂、乳膏、悬浮液、洗剂、粉末、溶液、糊剂、凝胶、喷雾剂、气溶胶或油。在一些实施方案中,药物组合物作为局部膏剂或乳膏施加。当以膏剂配制时,活性成分可与石蜡或水混溶性膏剂基质一起采用。可替代地,活性成分可与水包油乳膏基质或油包水基质一起配制在乳膏中。适于局部给予到眼睛的药物组合物包括滴眼剂,其中将活性成分溶解或悬浮在合适的载体(尤其是水性溶剂)中。适于在口中局部给予的药物组合物包括锭剂(lozenge)、锭剂(pastille)和漱口剂。经粘膜给予可通过使用鼻喷雾剂、气溶胶喷雾剂、片剂或栓剂来实现,并且经皮给予可通过如本领域通常已知的膏剂、药膏、凝胶、贴片或乳膏来实现。
在某些实施方案中,将包含式(I)的化合物的组合物包封在合适的媒介物中,以帮助将化合物递送到靶细胞,增加组合物的稳定性或使组合物的潜在毒性最小化。如技术人员所认识到的,各种媒介物适于递送本发明的组合物。合适的结构化流体递送系统的非限制性实例可包括纳米颗粒、脂质体、微乳液、胶束、树状分子和其它含有磷脂的系统。将组合物并入到递送媒介物中的方法在本领域中是已知的。
在一个可替代的实施方案中,可利用脂质体递送媒介物。依赖于实施方案,考虑到其结构和化学性质,脂质体适于递送式(I)的化合物。一般来讲,脂质体是具有磷脂双层膜的球形囊泡。脂质体的脂质双层可与其它双层(例如,细胞膜)融合,因此将脂质体的内容物递送到细胞。采用这种方式,包含式(I)的化合物可通过包封在与靶向细胞的膜融合的脂质体中来选择性地递送到细胞。
脂质体可包含各种不同类型的具有变化的烃链长度的磷脂。磷脂通常包含两个脂肪酸,其通过磷酸甘油连接至多种极性基团中的一个。合适的磷脂包括磷脂酸(PA)、磷脂酰丝氨酸(PS)、磷脂酰肌醇(PI)、磷脂酰甘油(PG)、双磷脂酰甘油(DPG)、磷脂酰胆碱(PC)和磷脂酰乙醇胺(PE)。包含磷脂的脂肪酸链的长度可在约6至约26个碳原子的范围内,并且脂质链可以是饱和的或不饱和的。合适的脂肪酸链包括(通用名呈现在括号中)正十二酸酯(月桂酸酯)、正十四酸酯(豆蔻酸酯)、正十六酸酯(棕榈酸酯)、正十八酸酯(硬脂酸酯)、正二十酸酯(花生酸酯)、正二十二酸酯(山嵛酸酯)、正二十四酸酯(木蜡酸酯)、顺-9-十六碳烯酸酯(棕榈油酸酯)、顺-9-十八酸酯(油酸酯)、顺,顺-9,12-十八碳二烯酸酯(亚油酸酯)、全顺-9,12,15-十八碳三烯酸酯(亚麻酸酯)以及全顺-5,8,11,14-二十碳四烯酸酯(花生四烯酸酯)。磷脂的两个脂肪酸链可以是相同的或不同的。可接受的磷脂包括二油酰基PS、二油酰基PC、二硬脂酰基PS、二硬脂酰基PC、二豆蔻酰基PS、二豆蔻酰基PC、二棕榈酰基PG、硬脂酰基、油酰基PS、棕榈酰基、亚麻酰基PS等。
磷脂可来自任何天然来源,并且由此可包含磷脂的混合物。例如,蛋黄富含PC、PG和PE,大豆含有PC、PE、PI和PA,以及动物脑或脊髓富含PS。磷脂还可来自合成来源。可使用具有变化比率的单个磷脂的磷脂混合物。不同磷脂的混合物可产生具有活性性质的有利活性或稳定性的脂质体组合物。以上提及的磷脂可与阳离子脂质以最佳比率混合,所述阳离子脂质诸如N-(1-(2,3-二油酰氧基)丙基)-N,N,N-三甲基氯化铵、1,1’-二(十八烷基)-3,3,3’,3’-四甲基吲哚羰花青高氯酸盐、3,3’-二庚基氧杂羰花青碘化物、1,1’-十二烷基-3,3,3’,3’-四甲基吲哚羰花青高氯酸盐、1,1’-二油烯基-3,3,3’,3’-四甲基吲哚羰花青甲磺酸盐、N-4-(二亚油基氨基苯乙烯基)-N-甲基吡啶碘化物或1,1-二亚油基-3,3,3’,3’-四甲基吲哚羰花青高氯酸盐。
脂质体可任选地包含鞘脂,其中鞘氨醇是甘油和磷酸甘油酯或胆固醇(动物细胞膜的主要组分)的一种脂肪酸中的一种的结构对应物。脂质体可任选地含有聚乙二醇化脂质,其是共价地连接到聚乙二醇(PEG)的聚合物的脂质。PEG的大小可在约500至约10,000道尔顿的范围内。
脂质体可进一步包含合适的溶剂。所述溶剂可以是有机溶剂或无机溶剂。合适的溶剂包括但不限于二甲亚砜(DMSO)、甲基吡咯烷酮、N-甲基吡咯烷酮、乙腈、醇、二甲基甲酰胺、四氢呋喃或其组合。
具有式(I)的化合物的脂质体可通过任何已知的制备用于药物递送的脂质体的方法来制备,所述方法例如详述于美国专利号4,241,046、4,394,448、4,529,561、4,755,388、4,828,837、4,925,661、4,954,345、4,957,735、5,043,164、5,064,655、5,077,211和5,264,618中,其公开内容通过引用以其整体并入本文。例如,脂质体可通过在水性溶液中对脂质声处理、溶剂注射、脂质水合、逆蒸发或通过重复冷冻和融化而冷冻干燥来制备。在优选的实施方案中,脂质体通过声处理形成。脂质体可以是多层的,其具有许多层像洋葱,或者是单层的。脂质体可以是大的或小的。连续的高剪切声处理倾向于形成较小的单层脂质体。
如对于普通技术人员显而易见的,控制脂质体形成的所有参数可变化。这些参数包括但不限于温度、pH、甲硫氨酸化合物的浓度、脂质的浓度和组成、多价阳离子的浓度、混合速率、溶剂的存在和浓度。
在另一个实施方案中,本发明的组合物可作为微乳液递送到细胞。微乳液通常是透明的热力学稳定的溶液,其包含水性溶液、表面活性剂和“油”。在此情况下,“油”是超临界流体相。表面活性剂位于油水界面处。各种表面活性剂中的任一种适于在微乳液制剂中使用,包括本文所述或本领域其它已知的那些。适于在本发明中使用的水性微区通常具有约5 nm至约100 nm的特征性结构尺寸。这种大小的聚集体是较差的可见光散射体,并且因此这些溶液是光学上透明的。如技术人员所认识到的,微乳液可具有并且将具有多种不同的微观结构,包括球形、棒状或圆盘状聚集体。在一个实施方案中,所述结构可以是胶束,其是通常为球形或圆柱形物体的最简单的微乳液结构。胶束类似于水中的油滴,并且反胶束类似于油中的水滴。在一个可替代的实施方案中,微乳液结构是薄层。它包含通过表面活性剂层分开的水和油的连续层。微乳液的“油”最佳地包含磷脂。针对脂质体的以上所详述的磷脂中的任一种适于涉及微乳液的实施方案。包含式(I)的化合物可通过本领域通常已知的任何方法包封在微乳液中。
(c)
另外的化合物
一方面,所述组合物进一步包含至少一种或多种抗癌治疗剂。
化疗剂是指用于治疗癌症的化合物。所述化合物可以是一般来讲影响快速分裂细胞的细胞毒性剂,或者它可以是影响癌细胞的失调蛋白质的靶向治疗剂。化疗剂可以是烷基化剂、抗代谢物、抗肿瘤抗生素、抗细胞骨架剂、拓扑异构酶抑制剂、抗激素剂、靶向治疗剂、光动力治疗剂或其组合。
合适的烷基化剂的非限制性实例包括六甲蜜胺、苯并多巴(benzodopa)、白消安、卡铂、卡波醌、卡莫司汀(BCNU)、苯丁酸氮芥、萘氮芥、氯磷酰胺(cholophosphamide)、氯脲霉素、顺铂、环磷酰胺、达卡巴嗪(DTIC)、雌氮芥、福莫司汀、异环磷酰胺、英丙舒凡、lipoplatin、洛莫司汀(CCNU)、马磷酰胺、甘露舒凡、氮芥、盐酸氧氮芥(mechlorethamineoxide hydrochloride)、美法仑、美妥替哌(meturedopa)、氮芥(氮芥(mechlorethamine))、二溴甘露醇、尼莫司汀、新恩比兴(novembichin)、奥沙利铂、苯芥胆甾醇(phenesterine)、哌泊舒凡、泼尼莫司汀、雷莫司汀、赛特铂(satraplatin)、司莫司汀(semustine)、替莫唑胺(temozolomide)、噻替派(thiotepa)、苏消安、三亚胺醌、曲他胺(triethylenemelamine)、三乙烯磷酰胺(triethylenephosphoramide, TEPA)、三乙烯硫代磷酰胺(triethylenethiophosphaoramide) (噻替派)、三羟甲蜜胺(trimethylolomelamine)、曲磷胺(trofosfamide)、乌拉莫司汀(uracil mustard)和uredopa。
合适的抗代谢物包括但不限于氨基蝶呤、环胞苷(ancitabine)、阿扎胞苷、8-氮杂鸟嘌呤、6-氮杂尿苷、卡培他滨(capecitabine)、卡莫氟(1-己基氨基甲酰基-5-氟尿嘧啶)、克拉屈滨(cladribine)、氯法拉滨(clofarabine)、阿糖胞苷(阿糖胞苷(Ara-C))、地西他滨、二甲叶酸、双脱氧尿苷(dideoxyuridine)、脱氧氟尿苷(doxifluridine)、依诺他宾(enocitabine)、氟尿苷、氟达拉滨(fludarabine)、5-氟尿嘧啶、吉西他滨(gemcetabine)、羟基脲(羟基尿素)、甲酰四氢叶酸(亚叶酸)、6-巯嘌呤、甲氨蝶呤、萘福昔定(nafoxidine)、奈拉滨(nelarabine)、奥利默森(oblimersen)、培美曲塞、蝶罗呤、雷替曲塞、替加氟(tegofur)、噻唑呋林(tiazofurin)、硫咪嘌呤(thiamiprine)、硫鸟嘌呤(tioguanine) (硫鸟嘌呤(thioguanine))和三甲曲沙(trimetrexate)。
合适的抗肿瘤抗生素的非限制性实例包括阿克拉霉素(aclacinomysin)、阿柔比星(aclarubicin)、放线菌素、阿霉素、奥瑞斯他汀(aurostatin) (例如,单甲基奥瑞斯他汀(auristatin) E)、安曲霉素(authramycin)、重氮丝氨酸、博来霉素、放线菌素、加利车霉素(calicheamicin)、卡柔比星(carabicin)、洋红霉素(caminomycin)、carzinophilin、色霉素、更生霉素、柔红菌素、地托比星(detorubicin)、6-重氮-5-氧代-L-正亮氨酸、多柔比星(doxorubicin)、表柔比星、环氧霉素(epoxomicin)、依索比星、伊达比星、麻西罗霉素、丝裂霉素、光辉霉素、霉酚酸、诺加霉素、橄榄霉素(olivomycins)、培洛霉素(peplomycin)、普卡霉素、泊非霉素(potfiromycin)、嘌呤霉素、三铁阿霉素(quelamycin)、罗多比星、稀疏霉素、链黑菌素、链脲霉素、杀结核菌素(tubercidin)、戊柔比星、乌苯美司、净司他丁(zinostatin)和佐柔比星。
合适的抗细胞骨架剂的非限制性实例包括卡巴他赛(cabazitaxel)、秋水仙碱(colchicines)、秋水仙胺(demecolcine)、多西他赛(docetaxel)、埃博霉素(epothilones)、伊沙匹隆(ixabepilone)、巨毛霉素(macromycin)、高三尖杉酯碱(omacetaxine mepesuccinate)、奥他赛(ortataxel)、紫杉醇(例如,DHA-紫杉醇)、紫杉烷、替西他赛(tesetaxel)、长春花碱、长春新碱、长春地辛和长春瑞滨(vinorelbine)。
合适的拓扑异构酶抑制剂包括但不限于安吖啶(amsacrine)、依托泊苷(VP-16)、伊立替康、米托蒽醌、RFS 2000、替尼泊苷和托泊替康。
合适的抗激素剂的非限制性实例诸如氨鲁米特、抗雌激素(antiestrogen)、芳香酶抑制性4(5)-咪唑、比卡鲁胺(bicalutamide)、非那雄胺、氟他胺(flutamide)、氟维司群(fluvestrant)、戈舍瑞林(goserelin)、4-羟三苯氧胺、keoxifene、亮丙瑞林(leuprolide)、LY117018、米托坦、尼鲁米特(nilutamide)、奥那斯酮(onapristone)、雷洛昔芬(raloxifene)、三苯氧胺、托瑞米芬(toremifene)和曲洛司坦(trilostane)。
靶向治疗剂的实例包括但不限于单克隆抗体,诸如阿伦单抗、卡妥莫单抗(cartumaxomab)、依决洛单抗(edrecolomab)、依帕珠单抗(epratuzumab)、吉妥珠单抗(gemtuzumab)、吉妥珠单抗奥佐米星(gemtuzumab ozogamicin)、吉妥木单抗维多汀(glembatumumab vedotin)、替伊莫单抗(ibritumomab tiuxetan)、瑞妥昔(reditux)、利妥昔单抗(rituximab)、托西莫单抗(tositumomab)和曲妥珠单抗(trastuzumab);蛋白激酶抑制剂,诸如贝伐珠单抗(bevacizumab)、西妥昔单抗(cetuximab)、克唑替尼(crizonib)、达沙替尼(dasatinib)、厄洛替尼(erlotinib)、吉非替尼(gefitinib)、伊马替尼(imatinib)、拉帕替尼(lapatinib)、莫立替尼(mubritinib)、尼罗替尼(nilotinib)、帕尼单抗(panitumumab)、帕唑帕尼(pazopanib)、索拉非尼(sorafenib)、舒尼替尼(sunitinib)、托西尼布(toceranib)和凡德他尼(vandetanib);
血管生成抑制剂,诸如血管抑素(angiostatin)、贝伐珠单抗、地尼白介素(denileukin diftitox)、内皮抑素(endostatin)、依维莫司(everolimus)、染料木黄酮(genistein)、干扰素α、白细胞介素-2、白细胞介素-12、帕唑帕尼、培加尼布(pegaptanib)、雷珠单抗(ranibizumab)、雷帕霉素(西罗莫司)、坦西莫司(temsirolimus)和沙利度胺;以及生长抑制多肽,诸如硼替佐米(bortazomib)、促红细胞生成素、白细胞介素(例如IL-1、IL-2、IL-3、IL-6)、白血病抑制因子、干扰素、罗米地辛、血小板生成素、TNF-α、CD30配体、4-1BB配体和Apo-1配体。
光动力治疗剂的非限制性实例包括氨基乙酰丙酸、氨基乙酰丙酸甲酯、类视黄醇(阿利维甲酸(alitretinon)、他米巴罗汀(tamibarotene)、维甲酸(tretinoin))和替莫泊芬。
其它抗肿瘤剂包括阿那格雷(anagrelide)、三氧化二砷、天门冬酰胺酶、贝沙罗汀(bexarotene)、溴匹立明(bropirimine)、塞来昔布(celecoxib)、化学连接的Fab、乙丙昔罗(efaproxiral)、依托格鲁(etoglucid)、铁锈醇(ferruginol)、氯尼达明(lonidamide)、masoprocol、米替福新(miltefosine)、米托胍腙(mitoguazone)、talapanel、曲贝替定(trabectedin)和伏立诺他(vorinostat)。
还包括以上列出的药剂中的任一种的药学上可接受的盐、酸或衍生物。化疗剂的给予模式可以并且将根据药剂以及肿瘤或赘生物的类型而变化。合适的给予模式在以下部分II(d)中详述。熟练的从业人员将能够确定化疗剂的适当剂量。
II.方法
本发明还涵盖杀死受试者的一种或多种癌症的方法。所述方法包括向需要其的受试者给予治疗有效量的本发明的化合物。
在另一个实施方案中,本发明提供了治疗哺乳动物的癌症的方法,所述方法包括向其给予治疗可接受量的具有式(I)的化合物。
在另一方面,本发明涵盖降解受试者的Bcl-2蛋白的方法。所述方法包括向需要其的受试者给予治疗有效量的本发明的化合物。
在另一方面,本发明涵盖向需要其的受试者给予包含本发明的化合物和赋形剂和/或药学上可接受的载体的组合物的方法,用于通过Bcl-2蛋白的降解治疗癌症。
在另一方面,本发明涵盖给予包含本发明的化合物和第二癌症治疗剂的组合物。
在另一方面,本发明涵盖给予包含本发明的化合物、第二癌症治疗剂和赋形剂和/或药学上可接受的载体的组合物,用于治疗癌症。
在另一方面,本发明涵盖本发明的化合物和癌症治疗剂的组合使用。
在再又一方面,本发明涵盖本发明的化合物和癌症放射疗法的组合使用。
本公开涵盖选择性地杀死样品中的一种或多种癌细胞的方法,所述方法包括使包含有效量的式(I)的化合物的组合物与所述样品接触。在另一方面,本公开涵盖选择性地杀死需要其的受试者的一种或多种癌细胞的方法,所述方法包括向所述受试者给予包含治疗有效量的式(I)的化合物的组合物。
选择性地杀死一种或多种癌细胞意指本发明的组合物在相同浓度下不明显地杀死非癌细胞。在一个实施方案中,当与类似的BCL-2抑制剂相比时,本发明的组合物具有降低的血小板毒性和在癌细胞中保留或改进的毒性。因此,抑制剂在非癌细胞中的半数致死量或LD50可以是抑制剂在癌细胞中的LD50的约5至约50倍。如本文所用,LD50是杀死细胞样品中的一半细胞所需的抑制剂的浓度。例如,抑制剂在非癌细胞中的LD50可以是抑制剂在癌细胞中的LD50的大于约5倍、约6倍、约7倍、约8倍、约9倍或约10倍。可替代地,抑制剂在非癌细胞中的LD50可以是抑制剂在癌细胞中的LD50的大于约10倍、约15倍、约20倍、约25倍、约30倍、约35倍、约40倍、约45倍或约50倍。此外,抑制剂在非癌细胞中的LD50可以是抑制剂在癌细胞中的LD50的大于50倍。在一个具体实施方案中,抑制剂在非癌细胞中的LD50是抑制剂在癌细胞中的LD500的大于10倍。在另一个具体实施方案中,抑制剂在非癌细胞中的LD50是抑制剂在癌细胞中的LD50的大于20倍。
在前述实施方案的任一种中,受试者可以被诊断为患有癌症或可以不被诊断为患有癌症。在某些实施方案中,受试者可能未被诊断为患有癌症,但基于症状怀疑患有癌症。可导致诊断的癌症症状取决于癌症,并且是本领域技术人员已知的。在其它实施方案中,受试者可能未被诊断为患有癌症,但处于患有癌症的风险中。癌症的风险因素取决于癌症,并且是本领域技术人员已知的。在其它实施方案中,受试者没有癌症症状和/或没有癌症风险因素。诊断癌症的方法取决于癌症并且是本领域技术人员已知的。例如,NCCN指南提供了检测、预防和风险降低的全面公开(nccn.org)。
受试者可以是啮齿动物、人、家畜动物、伴侣动物或动物园动物。在一个实施方案中,受试者可以是啮齿动物(例如,小鼠、大鼠、豚鼠等)。在另一个实施方案中,受试者可以是家畜动物。合适的家畜动物的非限制性实例可包括猪、牛、马、山羊、绵羊、美洲鸵和羊驼。在再一个实施方案中,受试者可以是伴侣动物。伴侣动物的非限制性实例可包括宠物,诸如狗、猫、兔和鸟。在又一个实施方案中,受试者可以是动物园动物。如本文所用,“动物园动物”是指可存在于动物园中的动物。这样的动物可包括非人灵长类、大型猫科动物、狼和熊。在优选的实施方案中,受试者是人。
本公开提供了选择性地杀死患有癌症的受试者的一种或多种癌症杀死的方法。因此,本公开的方法可用于治疗衍生自赘生物或癌症的肿瘤。所述赘生物可以是恶性的或良性的,所述癌症可以是原发性或转移性的;赘生物或癌症可以是早期或晚期的。可治疗的赘生物或癌症的非限制性实例包括急性淋巴细胞性白血病、急性骨髓性白血病、肾上腺皮质癌、AIDS相关癌症、AIDS相关淋巴瘤、肛门癌、阑尾癌、星形细胞瘤(儿童小脑或大脑)、基底细胞癌、胆管癌、膀胱癌、骨癌、脑干胶质瘤、脑肿瘤(小脑星形细胞瘤、大脑星形细胞瘤/恶性胶质瘤、室管膜瘤、髓母细胞瘤、幕上原始神经外胚层肿瘤、视觉通路和下丘脑胶质瘤、乳腺癌、支气管腺瘤/类癌瘤、伯基特淋巴瘤、类癌瘤(儿童、胃肠)、未知的原发性癌、中枢神经系统淋巴瘤(原发性)、小脑星形细胞瘤、大脑星形细胞瘤/恶性胶质瘤、宫颈癌、儿童癌症、绒毛膜癌、慢性淋巴细胞性白血病、慢性骨髓性白血病、慢性骨髓增生性病症、结肠癌、皮肤T细胞淋巴瘤、促结缔组织增生小圆细胞瘤、子宫内膜癌、室管膜瘤、食管癌、肿瘤的尤因家族中的尤因氏肉瘤、颅外生殖细胞肿瘤(儿童)、性腺外生殖细胞肿瘤、肝外胆管癌、眼癌(眼内黑色素瘤、成视网膜细胞瘤)、胆囊癌、胃的(胃)癌、胃肠类癌瘤、胃肠基质肿瘤、生殖细胞肿瘤(儿童颅外、性腺外、卵巢)、妊娠滋养细胞肿瘤、成胶质细胞瘤、胶质瘤(成人、儿童脑干、儿童大脑星形细胞瘤、儿童视觉通路和下丘脑)、胃类癌瘤、毛细胞白血病、头颈癌、肝细胞(肝)癌、霍奇金淋巴瘤、下咽癌、下丘脑和视觉通路胶质瘤(儿童)、眼内黑色素瘤、胰岛细胞癌、卡波西肉瘤、肾癌(肾细胞癌)、喉癌、白血病(急性成淋巴细胞性、急性骨髓性、慢性淋巴细胞性、慢性骨髓性、毛细胞)、唇和口腔癌、肝癌(原发性)、肺癌(非小细胞、小细胞)、淋巴瘤(AIDS相关的、伯基特、皮肤T细胞、霍奇金、非霍奇金、原发性中枢神经系统)、巨球蛋白血症(瓦尔登斯特伦)、骨的恶性纤维组织细胞瘤/骨肉瘤、髓母细胞瘤(儿童)、黑色素瘤、眼内黑色素瘤、Merkel细胞癌、间皮瘤(成人恶性、儿童)、具有潜隐原发性的转移性鳞状颈癌、口癌、多发性内分泌瘤形成综合征(儿童)、多发性骨髓瘤/浆细胞赘生物、蕈样霉菌病、脊髓发育不良综合征、脊髓发育不良/骨髓增生性疾病、骨髓性白血病(慢性)、骨髓性白血病(成人急性、儿童急性)、多发性骨髓瘤、骨髓增生性病症(慢性)、鼻腔和鼻旁窦癌、鼻咽癌、成神经细胞瘤、非霍奇金淋巴瘤、非小细胞肾盂移行细胞癌、尿道癌、子宫癌(子宫内膜)、子宫肉瘤、阴道癌、视觉通路和下丘脑胶质瘤(儿童)、外阴癌、瓦尔登斯特伦巨球蛋白血症和Wilms肿瘤(儿童)。在某些实施方案中,癌症选自滑液肉瘤、伯基特淋巴瘤、霍奇金淋巴瘤、多发性骨髓瘤、成神经细胞瘤、成胶质细胞瘤、小细胞肺癌、胰腺癌、肝细胞(肝)癌、子宫内膜癌、卵巢癌、宫颈癌、乳腺癌、前列腺癌、膀胱癌、黑色素瘤、横纹肌肉瘤、骨肉瘤/骨的恶性纤维组织细胞瘤、绒毛膜癌、肾癌(肾细胞癌)、甲状腺癌和白血病(急性淋巴细胞、急性骨髓性、慢性淋巴细胞性和慢性骨髓性)。
当与以下组合给予时,预期具有式(I)的化合物是有用的:烷基化剂、血管生成抑制剂、抗体、抗代谢物、抗有丝分裂剂、抗增殖剂、抗病毒剂、极光激酶抑制剂、其它凋亡促进剂(例如Bcl-xL、Bcl-w和Bfl-1)抑制剂、死亡受体途径激活剂、Bcr-Abl激酶抑制剂、BiTE(双特异性T细胞衔接器)抗体、抗体药物缀合物、生物应答改性剂、细胞周期蛋白依赖性激酶抑制剂、细胞周期抑制剂、环氧合酶-2抑制剂、DVDs、白血病病毒致癌基因同源物(ErbB2)受体抑制剂、生长因子抑制剂、热休克蛋白(HSP)-90抑制剂、组蛋白脱乙酰酶(HDAC)抑制剂、激素疗法、免疫药(immunologicals)、凋亡蛋白抑制剂(IAP)抑制剂、嵌入抗生素、激酶抑制剂、驱动蛋白抑制剂、Jak2抑制剂、雷帕霉素抑制剂的哺乳动物靶、microRNA、有丝分裂原激活的细胞外信号调节的激酶抑制剂、多价结合蛋白、非甾体抗炎药物(NSAID)、聚ADP(二磷酸腺苷)-核糖聚合酶(PARP)抑制剂、铂化疗剂、polo-样激酶(Plk)抑制剂、磷酸肌醇-3激酶(PI3K)抑制剂、蛋白酶体(proteosome)抑制剂、嘌呤类似物、嘧啶类似物、受体酪氨酸激酶抑制剂、etinoids/三角肌植物生物碱(deltoids plant alkaloids)、小的抑制核糖核酸(siRNAs)、拓扑异构酶抑制剂、泛素连接酶抑制剂等以及与这些药剂中的一种或多种的组合。
本发明的化合物也可用作增强放射疗法功效的放射增敏剂。放射疗法的实例包括外束(external beam)放射疗法、远距放射疗法、近距放射疗法以及密封、非密封源放射疗法等。
在某些方面,可向受试者给予治疗有效量的本发明的组合物。给予使用标准有效技术来执行,包括在外周(即,不通过给予到中枢神经系统中)或局部给予到中枢神经系统。外周给予包括但不限于口服、吸入、静脉内、腹膜内、关节内、皮下、肺部、经皮、肌内、鼻内、口腔、舌下或栓剂给予。局部给予(包括直接给予到中枢神经系统(CNS)中)包括但不限于通过腰部、心室内或实质内导管或使用手术植入的受控释放制剂。给予途径可通过待治疗的癌症或肿瘤的类型来决定。基于待治疗的疾病或病况来确定给予途径是在本领域的技术人员的能力范围内。在一个具体实施方案中,本发明的组合物口服给予。
用于有效给予的药物组合物有意地被设计成适用于所选的给予模式,并且在适当时使用药学上可接受的赋形剂,诸如相容的分散剂、缓冲液、表面活性剂、防腐剂、增溶剂、等渗剂、稳定剂等。Remington's Pharmaceutical Sciences, Mack Publishing Co.,Easton Pa., 第16版ISBN: 0-912734-04-3 (最新版本,其通过引用以其整体并入本文)提供如从业人员通常已知的配制技术的纲要。
对于治疗性应用,向受试者给予治疗有效量的本发明的组合物。“治疗有效量”是足以产生可测量的响应(例如,衰老细胞的细胞死亡、抗老化响应、与退行性疾病相关联的症状的改进或与功能降低的病症相关联的症状的改进)的治疗组合物的量。本发明的治疗组合物中的活性成分的实际剂量水平可变化,以给予有效实现对于特定受试者的所需治疗响应的一种或多种活性化合物的量。所选的剂量水平将取决于各种因素,包括治疗组合物的活性、配制、给予途径、与其它药物或治疗的组合、年龄、年龄相关疾病或病况、退行性疾病、功能降低的病症、症状以及正在治疗的受试者的身体状况和先前的病史。在一些实施方案中,给予最小剂量,并且在剂量限制毒性不存在的情况下逐步增加剂量。治疗有效剂量的确定和调整以及对于何时并且如何做出这样的调整的评价对于医学领域的普通技术人员是已知的。
根据有效治疗症状的需要,给药的频率可以是每天给药或每周或每月一次、两次、三次或更多次。相对于疾病本身的治疗的给予时间安排和治疗的持续时间将通过病例周围的环境确定。治疗可诸如在损伤地点处立即开始,如紧急医务人员所给予的。治疗可在医院或诊所本身开始,或在出院之后晚点时间开始,或在门诊患者诊所看过之后开始。治疗持续时间可在一次基础上给予的单一剂量至治疗性治疗的终身疗程的范围内。
典型剂量水平可使用标准临床技术确定和优化,并且将取决于给予模式。
定义
可用于所述组合物和方法的化合物包括本文所述的呈其药学上可接受的形式中的任一种的那些化合物,包括异构体(诸如非对映体和对映体)、盐、溶剂化物和多晶型物以及本文所述的化合物的外消旋混合物和纯异构体(在适用的情况下)。
本文所述的化合物具有不对称中心。含有不对称取代原子的本公开的化合物可以光学活性或外消旋形式分离。意图指所有手性、非对映、外消旋形式和所有几何异构体形式的结构,除非具体地指示特定的立体化学或异构体形式。
当引入本文所述的实施方案的元素时,冠词“一个”、“一种”、“所述”和“该”意图意指存在一种或多种该元素。术语“包含”、“包括”和“具有”意图是包含性的并且意指可能存在除所列的元素以外的另外的元素。
如本文单独使用或作为或作为组的一部分的“Bcl-2”是指Bcl-2家族蛋白的成员,包括以下:Bcl-xL、MCL-1、Bcl-W、BFL-1/A1、Bcl-B、BAX、BAK和BOK。
术语“治疗(treat)”、“治疗(treating)”和“治疗(treatment)”是指减轻或消除疾病和/或其伴随症状的方法。
术语“治疗有效量”是指足以防止所治疗的病况或病症的一种或多种症状的发展或将其减轻至一定程度的化合物的给予量。
如本文单独使用或作为组的一部分的“烷基”是指具有直链或支链烃链或在存在至少3个碳原子的情况下具有环烃或其组合的饱和单价烃基团,并且含有1-20个碳原子(C1-C20烷基)、合适地1-10个碳原子(C1-C10烷基)、优选地1-8个碳原子(C1-C8烷基)、更优选地1-6个碳原子(C1-C4烷基)以及甚至更优选地1-4个碳原子(C1-C4烷基)。烷基基团的实例包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、戊基、异戊基、己基、环丙基、环丁基、环戊基、环己基等。
如本文单独使用或作为组的一部分的“芳基”包括通过去除一个氢而衍生自芳香烃的有机基团,并且包括单环和多环基团,诸如苯基、联苯基、萘基。
如本文单独或组合使用的“环烷基”意指饱和或部分饱和的单环、双环或三环烷基基团,其中每个环部分含有约3至约8个碳原子、更优选地约3至约6个碳原子。这样的环烷基基团的实例包括环丙基、环丁基、环戊基、环己基等。
“杂原子”意指例如在杂环基团的环或杂基团(heterogeneous group)的链中的除碳以外的原子。优选地,杂原子选自由硫、磷、氮和氧原子组成的组。含有多于一个杂原子的基团可含有不同的杂原子。
如本文单独或组合使用的“杂芳基”包括通过去除一个氢而衍生自芳香烃的有机基团,并且包括至少一个杂原子。杂芳基的实例包括吡咯、噻吩、呋喃、吲哚、吡嗪、吡啶、三唑、咪唑、噻唑、噁唑等。
“取代的”意指结合到链或环中的碳原子的氢原子中的一个或多个被其它取代基替换。合适的取代基包括:单价烃基,包括烷基基团,诸如甲基基团;以及单价杂基团,包括烷氧基基团,诸如甲氧基基团。“未取代的”意指碳链或环不含有除碳和氢以外的其它取代基。
“支链的”意指碳链不是简单的直链。“非支链的”意指碳链是直链碳链。
“杂原子”意指例如在杂环基团的环或杂基团的链中的除碳以外的原子。优选地,杂原子选自硫、磷、氮和氧原子。含有多于一个杂原子的基团可含有不同的杂原子。
“杂环基团”意指在环中含有碳原子和一个或多个杂原子的饱和或不饱和环结构。杂环基团不是芳族的。杂环基团是单环的或多环的。多环的杂芳族基团可以是稠合的、螺接或桥接的环系统。单环的杂环基团在环中含有4-10个原子(即,包括碳原子和至少1个杂原子两者)、合适地4-7个并且更合适地5-6个原子。双环杂环基团在环中含有8-18个原子、合适地9个或10个原子。
如本文所用,“异构体”、“异构体形式”、“立体化学异构体形式”或“立体异构体形式”定义所有可能的异构体以及构象形式,其由通过相同的键序列结合的相同原子构成但是可能具有具有不可互换的在所述方法期间获得的化合物或中间体的不同三维结构。除非另外提及或指示,否则化合物的化学名称涵盖所述化合物可能具有的所有可能的立体化学异构体形式的混合物。所述混合物可含有所述化合物的基本分子结构的所有非对映异构体、差向异构体、对映体和/或构象异构体。更具体地,立体中心可具有R-构型或S-构型,非对映异构体可具有顺式构型或反式构型,二价环状饱和基团上的取代基可具有顺式构型或反式构型,并且烯基基团可具有E构型或Z构型。呈纯形式或呈与彼此的混合物形式两者的所述化合物的所有立体化学异构体形式意图包括在本发明的范围内。
实施例
包括以下实施例以证明本公开的各种实施方案。本领域技术人员应理解以下实施例中公开的技术表示由本发明人发现的在本发明实践中发挥良好作用的技术,并且因此可被认为构成本发明实践的优选模式。然而,根据本公开,本领域的技术人员应理解,在不脱离本发明的精神和范围的情况下可在已公开并仍获得类似或相似结果的具体实施方案中做出许多改变。
本发明的化合物可以有机合成领域的技术人员熟知的多种方法制备。更具体地,本发明的新型化合物可使用本文所述的反应和技术(例如在以下实施例中描述的那些)制备。在以下所述的合成方法的描述中,应理解所有提出的反应条件(包括溶剂、反应气氛、反应温度、实验持续时间和制定程序的选择)被选择为对于该反应标准的条件。有机合成领域的技术人员应理解,各种分子部分上存在的官能度必须与所提出的试剂和反应相容。对于取代基(其对于反应条件是不相容的)的这样的限制将对于本领域的技术人员是显而易见的,并且然后必须使用替代方法。除非另外声明,否则本文含有的实施例的起始材料是市售可得的或者易于由已知材料通过标准方法制备。式(I)的化合物可通过使用市售可得的起始材料和试剂通过对于有机合成领域训练的技术人员已知的标准有机化学方法和纯化来合成。
实施例1:化合物#1-5的制备
用于制备1a-e的一般程序:将2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮(1.0当量)、适当的氨基酸(1.2当量)和DIPEA (2.0当量)在DMF中的混合物在90℃下搅拌过夜。然后将反应混合物真空浓缩,并且通过硅胶柱色谱法纯化粗产物。
4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酸(1a):1HNMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.50 (dd, J = 8.5, 7.1 Hz, 1H), 7.11(dd, J = 7.1, 0.6 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.36-6.25 (m, 1H), 4.92(dd, J = 12.1, 5.3 Hz, 1H), 3.43-3.29 (m, 2H), 2.97-2.67 (m, 3H), 2.49 (t, J= 7.0 Hz, 2H), 2.16-2.08 (m, 1H), 2.03-1.96 (m, 2H) ppm。
5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酸(1b):1HNMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.49 (dd, J = 8.5, 7.1 Hz, 1H), 7.10(dd, J = 7.1, 0.6 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 6.36-6.25 (m, 1H), 4.92(dd, J = 12.1, 5.3 Hz, 1H), 3.30-3.20 (m, 2H), 2.97-2.67 (m, 3H), 2.45-2.35(m, 2H), 2.16-2.05 (m, 1H), 1.80-1.65 (m, 4H) ppm。
6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己酸(1c):1HNMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.54-7.44 (m, 1H), 7.09 (dd, J = 7.2,0.6 Hz, 1H), 6.86 (d, J = 8.5 Hz, 1H), 6.27-6.10 (m, 1H), 4.91 (dd, J = 12.2,5.3 Hz, 1H), 3.36-3.16 (m, 2H), 2.99-2.63 (m, 3H), 2.39 (t, J = 7.4 Hz, 2H),2.18-2.06 (m, 1H), 1.82-1.62 (m, 4H), 1.52-1.39 (m, 2H) ppm。
7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酸(1d):1HNMR (400 MHz, CDCl3) δ 8.39 (s, 1H), 7.48 (dd, J = 8.5, 7.1 Hz, 1H), 7.07(dd, J = 7.1, 0.6 Hz, 1H), 6.87 (d, J = 8.5 Hz, 1H), 6.31-6.10 (m, 1H), 4.91(dd, J = 12.0, 5.4 Hz, 1H), 3.32-3.18 (m, 2H), 2.97-2.66 (m, 3H), 2.35 (t, J= 7.4 Hz, 2H), 2.17-2.09 (m, 1H), 1.73-1.59 (m, 4H), 1.51-1.34 (m, 4H) ppm。
8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)辛酸(1e):1HNMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.49 (dd, J = 8.5, 7.1 Hz, 1H), 7.08 (d,J = 7.1 Hz, 1H), 6.88 (d, J = 8.5 Hz, 1H), 6.32-6.16 (m, 1H), 4.92 (dd, J =12.1, 5.4 Hz, 1H), 3.31-3.20 (m, 2H), 3.02-2.65 (m, 3H), 2.35 (t, J = 7.4 Hz,2H), 2.19-2.08 (m, 1H), 1.73-1.57 (m, 4H), 1.50-1.32 (m, 6H) ppm。
用于制备化合物#1-5、XZ-15766、XZ-15754、XZ-15765和XZ-15762的一般程序:将(R)-4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((1-(苯硫基)-4-(哌嗪-1-基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(1.0当量)、1 (1.0当量)、HATU (1.05当量)和DIPEA (2.0当量)在DCM中的混合物在室温下搅拌1小时。然后将反应混合物倒入水中并用DCM萃取。合并的有机层用NH4Cl水溶液洗涤,盐水洗涤,经Na2SO4干燥,并真空浓缩。通过硅胶柱色谱法纯化粗产物。
4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-(4-(4-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)丁酰基)哌嗪-1-基)-1-(苯硫基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(化合物#1):1H NMR (400 MHz, CDCl3) δ 8.65-8.31 (m, 2H), 8.13-7.98 (m,1H), 7.76-7.63 (m, 2H), 7.47 (dd, J = 8.5, 7.1 Hz, 1H), 7.41-7.26 (m, 6H),7.13-6.90 (m, 5H), 6.81-6.56 (m, 3H), 6.36-6.22 (m, 1H), 4.99-4.80 (m, 1H),3.98-2.70 (m, 18H), 2.50-1.91 (m, 20H), 1.72-1.57 (m, 1H), 1.49-1.42 (m, 2H),0.97 (s, 6H) ppm。
4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-(4-(5-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)戊酰基)哌嗪-1-基)-1-(苯硫基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(化合物#2):1H NMR (400 MHz, CDCl3) δ 8.57-8.26 (m, 2H), 8.13-8.04 (m,1H), 7.72-7.64 (m, 2H), 7.47 (dd, J = 8.5, 7.1 Hz, 1H), 7.40-7.26 (m, 6H),7.11-6.95 (m, 4H), 6.87 (d, J = 8.5 Hz, 1H), 6.80-6.71 (m, 2H), 6.59 (dd, J =9.6, 2.6 Hz, 1H), 6.29-6.20 (m, 1H), 4.97-4.80 (m, 1H), 3.97-2.64 (m, 18H),2.51-1.97 (m, 18H), 1.79-1.43 (m, 7H), 0.98 (s, 6H) ppm。
4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-(4-(6-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)己酰基)哌嗪-1-基)-1-(苯硫基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(化合物#3):1H NMR (400 MHz, CDCl3) δ 8.60-8.26 (m, 2H), 8.09 (t, J =8.6 Hz, 1H), 7.71-7.59 (m, 2H), 7.51-7.45 (m, 1H), 7.42-7.27 (m, 6H), 7.16-6.94 (m, 4H), 6.87 (d, J = 8.5 Hz, 1H), 6.80-6.54 (m, 3H), 6.23 (s, 1H),4.97-4.82 (m, 1H), 3.95-2.69 (m, 18H), 2.47-1.96 (m, 18H), 1.79-1.39 (m, 9H),0.99 (s, 6H) ppm。
4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-(4-(7-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)庚酰基)哌嗪-1-基)-1-(苯硫基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(化合物#4):1H NMR (400 MHz, CDCl3) δ 8.62-8.49 (m, 1H), 8.36 (d, J =2.1 Hz, 1H), 8.17-8.04 (m, 1H), 7.72-7.64 (m, 2H), 7.47 (dd, J = 8.5, 7.1 Hz,1H), 7.40-7.27 (m, 6H), 7.14-6.95 (m, 4H), 6.86 (d, J = 8.5 Hz, 1H), 6.74 (d,J = 8.7 Hz, 2H), 6.59 (dd, J = 9.5, 4.1 Hz, 1H), 6.26-6.15 (m, 1H), 4.96-4.85(m, 1H), 3.94-2.69 (m, 18H), 2.52-1.98 (m, 18H), 1.74-1.36 (m, 11H), 0.98 (s,6H) ppm。
4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-(4-(8-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)辛酰基)哌嗪-1-基)-1-(苯硫基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(化合物#5):1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.37 (s, 1H), 8.10(d, J = 9.2 Hz, 1H), 7.63 (d, J = 8.5 Hz, 2H), 7.48 (t, J = 7.8 Hz, 1H),7.42-7.27 (m, 6H), 7.13-6.95 (m, 4H), 6.87 (d, J = 8.6 Hz, 1H), 6.74 (d, J =8.6 Hz, 2H), 6.61 (d, J = 9.3 Hz, 1H), 6.28-6.15 (m, 1H), 4.98-4.84 (m, 1H),4.04-2.65 (m, 18H), 2.61-1.97 (m, 18H), 1.74-1.32 (m, 13H), 0.98 (s, 6H) ppm。
实施例2:化合物#23-26的制备
用于制备3a和3b的一般程序:将(R)-4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((4-(甲基氨基)-1-(苯硫基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(1.0当量)、酸2a或2b (1.1当量)、HATU(1.05当量)和TEA (5.0当量)在DCM中的混合物在室温下搅拌1小时,随后倒入水中并用DCM萃取。合并的有机层用NH4Cl水溶液和盐水洗涤,经Na2SO4干燥,并真空浓缩。通过硅胶柱色谱法纯化粗产物。
(R)-N-((4-((4-(4-叠氮基-N-甲基丁酰氨基)-1-(苯硫基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)-4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺(3a):1H NMR (400 MHz, CDCl3和CD3OD) δ 8.49-8.35 (m, 1H), 8.23-8.12 (m, 1H), 7.75 (d, J = 8.5 Hz, 2H), 7.48-7.33 (m, 5H),7.31-7.25 (m, 1H), 7.08-6.75 (m, 5H), 6.59-6.33 (m, 1H), 3.85-2.82 (m, 16H),2.56-1.74 (m, 14H), 1.57-1.46 (m, 2H), 1.03 (s, 6H) ppm。
(R)-N-((4-((4-(7-叠氮基-N-甲基庚酰氨基)-1-(苯硫基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)-4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺(3b):1H NMR (400 MHz, CDCl3和CD3OD) δ 8.40-8.29 (m, 1H), 8.11 (dd, J = 9.2, 2.3 Hz, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.49-7.27 (m, 5H), 7.24-7.18 (m, 1H), 7.09-6.92 (m, 3H), 6.81-6.71 (m, 2H), 6.56-6.25 (m, 1H), 3.77-2.85 (m, 16H), 2.52-1.15 (m, 22H), 0.96 (s, 6H) ppm。
用于制备化合物#23-26的一般程序:在氩气下,向叠氮化物3a/3b (1.0当量)和炔4a/4b (1.0当量)在t-BuOH/THF (1:1, v/v)中的混合物中加入在水中的CuSO4·5H2O (0.2当量)和抗坏血酸钠(0.2当量)。将混合物在50℃下搅拌3小时并用DCM萃取。合并的有机相用盐水洗涤,经Na2SO4干燥,过滤,并蒸发至干燥。使用DCM和MeOH作为洗脱液通过硅胶柱色谱法纯化粗产物。
4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-(4-(4-((2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)甲基)-1H-1,2,3-三唑-1-基)-N-甲基丁酰氨基)-1-(苯硫基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(化合物#23):1H NMR (400MHz, CDCl3) δ 9.26 (s, 1H), 8.35 (s, 1H), 8.08 (d, J = 9.0 Hz, 1H), 7.82-7.27(m, 7H), 7.26-7.15 (m, 3H), 7.11-6.81 (m, 5H), 6.78-6.36 (m, 4H), 5.00-4.86(m, 1H), 4.73-4.56 (m, 2H), 4.39-4.17 (m, 2H), 3.85-2.64 (m, 25H), 2.47-1.95(m, 14H), 1.83-1.66 (m, 1H), 1.51-1.40 (m, 2H), 0.97 (s, 6H) ppm。
4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-(4-(4-((2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)甲基)-1H-1,2,3-三唑-1-基)-N-甲基丁酰氨基)-1-(苯硫基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(化合物#24):1H NMR (400 MHz, CDCl3) δ 9.19 (s, 1H), 8.47-8.29 (m, 1H), 8.16-7.99 (m, 1H),7.82-7.27 (m, 8H), 7.26-7.17 (m, 2H), 7.12-6.36 (m, 9H), 5.00-4.81 (m, 1H),4.70-4.52 (m, 2H), 4.35-4.13 (m, 2H), 3.88-2.67 (m, 29H), 2.46-1.94 (m, 14H),1.81-1.66 (m, 1H), 1.50-1.41 (m, 2H), 0.97 (s, 6H) ppm。
4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-(7-(4-((2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)甲基)-1H-1,2,3-三唑-1-基)-N-甲基庚酰氨基)-1-(苯硫基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(化合物#25):1H NMR (400MHz, CDCl3) δ 8.78 (s, 1H), 8.43-8.32 (m, 1H), 8.16-7.96 (m, 1H), 7.71 (d, J= 8.5 Hz, 2H), 7.58-7.27 (m, 6H), 7.26-7.18 (m, 2H), 7.11-6.85 (m, 5H), 6.78-6.68 (m, 2H), 6.56-6.31 (m, 2H), 4.96-4.84 (m, 1H), 4.68 (d, J = 7.8 Hz, 2H),4.24 (dt, J = 28.9, 7.2 Hz, 2H), 3.84-2.63 (m, 25H), 2.45-1.66 (m, 15H), 1.36(dt, J = 74.8, 6.4 Hz, 8H), 0.98 (s, 6H) ppm。
4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-(7-(4-((2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)甲基)-1H-1,2,3-三唑-1-基)-N-甲基庚酰氨基)-1-(苯硫基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(化合物#26):1H NMR (400 MHz, CDCl3) δ 9.04-8.81 (m, 1H), 8.45-8.33 (m, 1H), 8.17-7.98 (m,1H), 7.71 (d, J = 8.6 Hz, 2H), 7.57-7.27 (m, 6H), 7.26-7.19 (m, 2H), 7.11-6.83 (m, 5H), 6.79-6.68 (m, 2H), 6.55-6.27 (m, 2H), 4.98-4.87 (m, 1H), 4.72-4.60 (m, 2H), 4.34-4.11 (m, 2H), 3.84-2.67 (m, 29H), 2.43-1.21 (m, 23H), 0.98(s, 6H) ppm。
实施例3:化合物#27和#28的制备
(R)-(4-(甲基氨基)-1-(苯硫基)丁-2-基)氨基甲酸叔丁酯(5)的制备:将在MeOH(7.5 mg)中的(R)-(4-氧代-1-(苯硫基)丁-2-基)氨基甲酸叔丁酯(450 mg)、2.0 M MeNH2和在50 mL THF中MgSO4 (3.0 g)的混合物在室温下搅拌过夜。然后加入NaBH(OAc)3 (143mg)。将所得的混合物在室温下搅拌30分钟,随后倒入水中并用DCM萃取。合并的有机相用盐水洗涤,经Na2SO4干燥,过滤,并蒸发至干燥。使用DCM和MeOH作为洗脱液通过硅胶柱色谱法纯化粗产物,以得到280 mg化合物5。产率56%。1H NMR (400 MHz, CDCl3) δ 7.45-7.28 (m,4H), 7.27-7.23 (m, 1H), 5.09 (d, J = 8.1 Hz, 1H), 4.52-4.31 (m, 1H), 3.86-3.66 (m, 1H), 3.27-2.81 (m, 3H), 2.67 (s, 3H), 2.30-2.17 (m, 1H), 1.88-1.72(m, 1H), 1.44 (s, 9H) ppm。
(R)-(3-((叔丁氧基羰基)氨基)-4-(苯硫基)丁基)(甲基)氨基甲酸-2,2,2-三氯乙酯(6)的制备:将化合物5 (280 mg)、Troc-Cl (137 μL)和TEA (250 μL)在10 mL DCM中的混合物在室温下搅拌3小时。然后将反应混合物倒入水中并用DCM萃取。合并的有机相用盐水洗涤,经Na2SO4干燥,过滤,并蒸发至干燥。使用EA和己烷作为洗脱液通过硅胶柱色谱法纯化粗产物,以得到6。1H NMR (400 MHz, CDCl3) δ 7.44-7.16 (m, 5H), 4.87-4.59 (m,3H), 3.89-3.71 (m, 1H), 3.59-3.40 (m, 1H), 3.33-3.01 (m, 3H), 3.00-2.91 (m,3H), 2.11-1.88 (m, 1H), 1.86-1.68 (m, 1H), 1.46-1.37 (m, 9H) ppm。
(R)-(3-氨基-4-(苯硫基)丁基)(甲基)氨基甲酸-2,2,2-三氯乙酯(7)的制备:向化合物6在10 mL DCM中的混合物中加入0.7 mL TFA。将混合物在室温下搅拌3小时并在减压下去除溶剂。用Et2O洗涤固体,以得到13,其直接用于下一步骤。
(R)-甲基(4-(苯硫基)-3-((4-氨磺酰基-2-((三氟甲基)磺酰基)苯基)氨基)丁基)氨基甲酸-2,2,2-三氯乙酯(8)的制备:将化合物7、4-氟-3-((三氟甲基)磺酰基)苯磺酰胺和TEA在乙腈中的混合物回流过夜。将溶剂在减压下蒸发,并且使用EA和己烷作为洗脱液通过硅胶柱色谱法纯化粗产物,以得到220 mg化合物8。3步产率36%。1H NMR (400 MHz,CDCl3) δ 8.25 (d, J = 2.3 Hz, 1H), 7.81 (dd, J = 9.1, 2.3 Hz, 1H), 7.45-7.29(m, 5H), 7.03-6.94 (m, 1H), 6.41 (dd, J = 27.3, 9.2 Hz, 1H), 4.92 (s, 2H),4.83-4.55 (m, 2H), 3.81-3.61 (m, 1H), 3.56-3.24 (m, 2H), 3.19-2.90 (m, 5H),2.46-2.19 (m, 1H), 1.93-1.71 (m, 1H) ppm。
(R)-(3-((4-(N-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-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-(苯硫基)丁基)(甲基)氨基甲酸-2,2,2-三氯乙酯(9)的制备:将化合物8 (220 mg)、4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酸(174 mg)、EDCI (151 mg)和DMAP (96 mg)在15 mL DCM中的混合物在室温下搅拌过夜。将混合物倒入水中并用DCM萃取。合并的有机层用1N HCl (水溶液)洗涤1次,盐水洗涤1次,经Na2SO4干燥,过滤,并蒸发至干燥。使用DCM和MeOH作为洗脱液通过柱色谱法纯化粗产物,以得到标题化合物。1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 2.2 Hz, 1H), 8.13 (dd, J = 9.2,2.3 Hz, 1H), 7.66 (d, J = 8.7 Hz, 2H), 7.45-7.28 (m, 6H), 7.08-6.95 (m, 3H),6.77 (d, J = 8.7 Hz, 2H), 6.42 (dd, J = 29.2, 9.3 Hz, 1H), 4.83-4.50 (m, 2H),3.82-3.61 (m, 1H), 3.48-3.26 (m, 6H), 3.22-2.88 (m, 7H), 2.60-2.19 (m, 7H),2.12-2.06 (m, 2H), 1.93-1.74 (m, 1H), 1.54-1.41 (m, 2H), 0.99 (s, 6H) ppm。
(R)-4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((4-(甲基氨基)-1-(苯硫基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(10)的制备:将锌粉加入到化合物9和乙酸在THF中的混合物中。将反应混合物在室温下搅拌过夜。通过过滤去除固体并将滤液倒入水中,并用乙酸乙酯萃取。合并的有机相用盐水洗涤一次,经Na2SO4干燥,过滤,并蒸发至干燥。使用DCM、MeOH和TEA作为洗脱液通过硅胶柱色谱法纯化粗产物,以得到180 mg化合物10。2步产率60%。1H NMR (400MHz, CDCl3和CD3OD) δ 8.25 (s, 1H), 8.00 (d, J = 8.6 Hz, 1H), 7.83 (d, J = 8.3Hz, 2H), 7.44-7.10 (m, 7H), 7.06-6.95 (m, 2H), 6.77 (d, J = 8.5 Hz, 2H), 6.70(d, J = 9.3 Hz, 1H), 4.03-3.90 (m, 1H), 3.21-2.91 (m, 7H), 2.65 (s, 3H),2.58-2.42 (m, 4H), 2.35-2.18 (m, 3H), 2.15-1.97 (m, 5H), 1.53-1.44 (m, 2H),1.42-1.31 (m, 2H), 0.99 (s, 6H) ppm。
(R)-N-((4-((4-((7-叠氮庚基)(甲基)氨基)-1-(苯硫基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)-4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)苯甲酰胺(11)的制备:将10 (1.0当量)、4-甲基苯磺酸7-叠氮庚酯(5.0当量)、K2CO3 (2.0当量)和NaI (0.2当量)在ACN中的混合物在80℃下搅拌过夜。然后将反应混合物倒入水中并用DCM萃取。合并的有机层用NH4Cl水溶液和盐水洗涤,经Na2SO4干燥,并真空浓缩。通过硅胶柱色谱法纯化粗产物。1H NMR (400 MHz, CDCl3) δ 8.28 (d,J = 2.2 Hz, 1H), 7.93-7.78 (m, 3H), 7.37-7.27 (m, 3H), 7.26-7.18 (m, 3H),7.05-6.88 (m, 3H), 6.75 (d, J = 8.6 Hz, 2H), 6.56 (d, J = 9.3 Hz, 1H), 3.96-3.79 (m, 1H), 3.29-3.15 (m, 6H), 3.11-2.95 (m, 2H), 2.87-2.67 (m, 6H), 2.55(s, 3H), 2.45-2.31 (m, 4H), 2.30-2.08 (m, 3H), 2.05-1.84 (m, 3H), 1.64-1.39(m, 6H), 1.36-1.18 (m, 6H), 0.97 (s, 6H) ppm。
用于制备化合物#27和#28的一般程序:在氩气下,向化合物5 (1.0当量)、化合物4a/4b (1.0当量)在t-BuOH-THF (1:1, v/v)中的混合物中加入在水中的CuSO4·5H2O (0.2当量)和抗坏血酸钠(0.2当量)。将混合物在50℃下搅拌2小时并用DCM萃取。有机相用盐水洗涤一次,经Na2SO4干燥,过滤,并蒸发至干燥。使用DCM和MeOH作为洗脱液通过柱色谱法纯化粗产物,以得到纯产物。
4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-((7-(4-((2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)甲基)-1H-1,2,3-三唑-1-基)庚基)(甲基)氨基)-1-(苯硫基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(化合物#27):1H NMR(400 MHz, CDCl3) δ 8.79 (s, 1H), 8.30 (s, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.84(d, J = 8.4 Hz, 2H), 7.60 (s, 1H), 7.50-7.39 (m, 1H), 7.36-7.27 (m, 3H),7.25-7.15 (m, 3H), 7.08-6.95 (m, 4H), 6.88 (d, J = 8.6 Hz, 1H), 6.71 (d, J =8.5 Hz, 2H), 6.58 (d, J = 9.3 Hz, 1H), 6.51-6.44 (m, 1H), 4.93-4.85 (m, 1H),4.66 (s, 2H), 4.31-4.19 (m, 2H), 3.97-3.83 (m, 1H), 3.75-3.61 (m, 6H), 3.47-3.38 (m, 2H), 3.26-3.15 (m, 4H), 3.11-2.96 (m, 2H), 2.89-2.46 (m, 10H), 2.43-2.20 (m, 9H), 2.18-1.96 (m, 4H), 1.88-1.71 (m, 3H), 1.52-1.37 (m, 4H), 1.27-1.09 (m, 6H), 0.97 (s, 6H) ppm。
4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-((7-(4-((2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙氧基)甲基)-1H-1,2,3-三唑-1-基)庚基)(甲基)氨基)-1-(苯硫基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(化合物#28):1H NMR (400 MHz, 丙酮-d 6) δ 10.00 (s, 1H), 8.31 (s, 1H), 8.12-7.97 (m,2H), 7.93-7.80 (m, 2H), 7.61-7.52 (m, 1H), 7.46-7.31 (m, 4H), 7.31-7.23 (m,2H), 7.22-6.99 (m, 6H), 6.92-6.81 (m, 2H), 6.66-6.58 (m, 1H), 5.16-5.00 (m,1H), 4.75-4.51 (m, 2H), 4.46-4.19 (m, 3H), 3.82-3.48 (m, 12H), 3.45-3.22 (m,6H), 3.11-2.65 (m, 13H), 2.55-2.13 (m, 9H), 1.94-1.55 (m, 5H), 1.52-1.44 (m,2H), 1.39-1.15 (m, 6H), 1.00 (s, 6H)。
实施例4:化合物#29的制备
3-(2-甲基-4-氧代-5-((2-(2-(丙-2-炔-1-基氧基)乙氧基)乙基)氨基)喹唑啉-3(4H)-基)哌啶-2,6-二酮(12)的制备:将3-(2,5-二甲基-4-氧代喹唑啉-3(4H)-基)哌啶-2,6-二酮(150 mg)、2-(2-(丙-2-炔-1-基氧基)乙氧基)乙-1-胺(112 mg)和DIPEA (172 μL)在2 mL DMF中在90℃下搅拌过夜。将水加入到反应混合物中,并用EtOAc萃取。有机相用水洗涤,盐水洗涤,经Na2SO4干燥,过滤,并蒸发至干燥。使用DCM和MeOH作为洗脱液通过柱色谱法纯化所得的混合物,以得到标题化合物,为白色固体。1H NMR (600 MHz, DMSO-d 6) δ10.99 (s, 1H), 8.43 (t, J = 5.4 Hz, 1H), 7.49 (t, J = 8.1 Hz, 1H), 6.66 (d, J= 7.8 Hz, 1H), 6.55 (d, J = 8.4 Hz, 1H), 5.18 (dd, J = 11.6, 5.8 Hz, 1H),4.19-4.09 (m, 2H), 3.67-3.56 (m, 6H), 3.40-3.38 (m, 1H), 3.36-3.34 (m, 2H),2.91-2.77 (m, 1H), 2.68-2.54 (m, 5H), 2.19-2.09 (m, 1H)。
4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-((7-(4-((2-(2-((3-(2,6-二氧代哌啶-3-基)-2-甲基-4-氧代-3,4-二氢喹唑啉-5-基)氨基)乙氧基)乙氧基)甲基)-1H-1,2,3-三唑-1-基)庚基)(甲基)氨基)-1-(苯硫基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(化合物#29)的制备:在氩气下,向化合物11 (1.0当量)、化合物12 (1.0当量)在t-BuOH-THF (1:1, v/v)中的混合物中加入在水中的CuSO4·5H2O (0.2当量)和抗坏血酸钠(0.2当量)。将混合物在50℃下搅拌2小时并用DCM萃取。有机相用盐水洗涤一次,经Na2SO4干燥,过滤,并蒸发至干燥。使用DCM和MeOH作为洗脱液通过柱色谱法纯化粗产物,以得到纯产物。1H NMR (400MHz, 丙酮-d 6) δ 9.99 (s, 1H), 8.61 (t, J = 5.3 Hz, 1H), 8.32 (d, J = 2.2 Hz,1H), 8.10-7.99 (m, 1H), 7.92-7.82 (m, 3H), 7.50-7.31 (m, 5H), 7.30-7.00 (m,7H), 6.86 (d, J = 9.0 Hz, 2H), 6.69 (dd, J = 7.9, 1.0 Hz, 1H), 6.53 (dd, J =8.4, 0.9 Hz, 1H), 5.32-5.18 (m, 1H), 4.61 (s, 2H), 4.40-4.19 (m, 3H), 3.77-3.58 (m, 6H), 3.43-3.22 (m, 8H), 3.04-2.51 (m, 17H), 2.41-2.21 (m, 8H), 2.18-2.10 (m, 1H), 1.84-1.73 (m, 2H), 1.66-1.53 (m, 2H), 1.48 (t, J = 6.5 Hz, 2H),1.27-1.13 (m, 6H), 1.00 (s, 6H)。
实施例5:化合物#31-33的制备
用于制备14a-c的一般程序:将2-(2,6-二氧代哌啶-3-基)-4-氟异吲哚啉-1,3-二酮(1.0当量)、化合物13a/13b/13c (1.5当量)和DIPEA (3.0当量)在2 mL DMF中在90℃下搅拌过夜。将水加入到反应混合物中并用EtOAc萃取之。有机相用水洗涤一次,盐水洗涤一次,经Na2SO4干燥,过滤,并蒸发至干燥。使用DCM和MeOH作为洗脱液通过柱色谱法纯化所得的混合物,以得到14a-c。
2-(2,6-二氧代哌啶-3-基)-4-((2-(2-(2-羟基乙氧基)乙氧基)乙基)氨基)异吲哚啉-1,3-二酮(14a):1H NMR (400 MHz, CDCl3) δ 8.19 (br s, 1H), 7.55-7.44 (m,1H), 7.10 (d, J = 7.1 Hz, 1H), 6.91 (d, J = 8.5 Hz, 1H), 6.57 (t, J = 5.2 Hz,1H), 4.91 (dd, J = 12.0, 5.4 Hz, 1H), 3.85-3.65 (m, 8H), 3.64-3.59 (m, 2H),3.51-3.43 (m, 2H), 2.92-2.68 (m, 3H), 2.57 (br s, 1H), 2.18-2.07 (m, 1H) ppm。
2-(2,6-二氧代哌啶-3-基)-4-((2-(2-(2-(2-羟基乙氧基)乙氧基)乙氧基)乙基)氨基)异吲哚啉-1,3-二酮(14b):1H NMR (400 MHz, CDCl3) δ 8.23 (br s, 1H), 7.58-7.40 (m, 1H), 7.10 (d, J = 7.1 Hz, 1H), 6.92 (d, J = 8.6 Hz, 1H), 6.52 (t, J= 5.5 Hz, 1H), 4.92 (dd, J = 12.0, 5.4 Hz, 1H), 3.77-3.65 (m, 12H), 3.63-3.58(m, 2H), 3.52-3.44 (m, 2H), 3.00-2.59 (m, 4H), 2.24-2.04 (m, 1H) ppm。
2-(2,6-二氧代哌啶-3-基)-4-((14-羟基-3,6,9,12-四氧杂十四烷基)氨基)异吲哚啉-1,3-二酮(14c):1H NMR (400 MHz, CDCl3) δ 8.53 (br s, 1H), 7.49 (dd, J =8.5, 7.1 Hz, 1H), 7.11 (d, J = 6.8 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 4.90(dd, J = 12.0, 5.4 Hz, 1H), 3.76-3.58 (m, 18H), 3.50-3.43 (m, 2H), 2.92-2.74(m, 3H), 2.18-2.07 (m, 1H)。
用于制备15a-c的一般程序:将DMSO (3.0当量)在DCM中冷却至-78℃,并逐滴加入(COCl)2 (1.5当量)。将混合物搅拌10分钟,并将14a/14b/14c (1.0当量)在DCM中逐滴加入到溶液中。10分钟后,加入三乙胺(6.0当量),并将所得的混合物在-78℃下保持30分钟,并加热至室温。将混合物倒入水中并用DCM萃取。有机相用水洗涤,盐水洗涤,经Na2SO4干燥,过滤,并蒸发至干燥。使用DCM和MeOH作为洗脱液通过柱色谱法纯化粗产物,以得到15a-c。
用于制备化合物#31-33的一般程序:将化合物10 (1.0当量)和15a/15b/15c (1.5当量)在DCM中的混合物用三乙胺(4.0当量)和NaBH3CN (2.0当量)处理。将混合物在室温下搅拌过夜。然后将溶液倒入水中并用DCM萃取。有机相用水洗涤,盐水洗涤,经Na2SO4干燥,过滤,并蒸发至干燥。使用DCM和MeOH作为洗脱液通过柱色谱法纯化粗产物,以得到纯产物。
4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((2R)-4-((2-(2-(2-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)乙氧基)乙氧基)乙基)(甲基)氨基)-1-(苯硫基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(化合物#31):1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H),8.07-7.93 (m, 1H), 7.77 (d, J = 8.5 Hz, 2H), 7.48-7.39 (m, 1H), 7.33-7.27 (m,3H), 7.25-7.13 (m, 3H), 7.09-6.91 (m, 4H), 6.87-6.77 (m, 1H), 6.76-6.54 (m,3H), 6.48-6.34 (m, 1H), 5.00-4.82 (m, 1H), 3.93 (s, 1H), 3.80-3.43 (m, 10H),3.43-3.16 (m, 6H), 3.07-2.66 (m, 9H), 2.59-2.00 (m, 13H), 1.95-1.83 (m, 1H),1.45 (t, J = 6.5 Hz, 2H), 0.97 (s, 6H)。
4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((15R)-1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-12-甲基-16-(苯硫基)-3,6,9-三氧杂-12-氮杂十六烷-15-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(化合物#32):1H NMR (400 MHz, CDCl3) δ 8.38-8.26 (m,1H), 8.06-7.97 (m, 1H), 7.77 (d, J = 8.7 Hz, 2H), 7.50-7.41 (m, 1H), 7.38-7.27 (m, 3H), 7.26-7.17 (m, 3H), 7.15-7.04 (m, 2H), 7.02-6.96 (m, 2H), 6.87(d, J = 8.5 Hz, 1H), 6.72 (d, J = 8.8 Hz, 2H), 6.61 (d, J = 9.4 Hz, 1H),6.49-6.38 (m, 1H), 4.95-4.82 (m, 1H), 3.96-3.82 (m, 1H), 3.68-3.39 (m, 14H),3.29-3.17 (m, 4H), 3.09-3.00 (m, 2H), 2.89-2.60 (m, 9H), 2.43-1.97 (m, 13H),1.89-1.76 (m, 1H), 1.45 (t, J = 6.5 Hz, 2H), 0.97 (s, 6H)。
4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-(((18R)-1-((2-(2,6-二氧代哌啶-3-基)-1,3-二氧代异吲哚啉-4-基)氨基)-15-甲基-19-(苯硫基)-3,6,9,12-四氧杂-15-氮杂十九烷-18-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(化合物#33):1H NMR (400 MHz, CDCl3) δ 8.41-8.31 (m,1H), 8.13-8.01 (m, 1H), 7.79-7.68 (m, 2H), 7.50-7.27 (m, 5H), 7.24-7.11 (m,3H), 7.08 (d, J = 7.1 Hz, 1H), 7.03-6.96 (m, 2H), 6.87 (d, J = 8.5 Hz, 1H),6.79-6.64 (m, 3H), 6.45 (t, J = 5.6 Hz, 1H), 4.95-4.84 (m, 1H), 4.05-3.90 (m,1H), 3.76-3.36 (m, 18H), 3.31-3.17 (m, 4H), 3.08 (t, J = 4.9 Hz, 2H), 2.91-2.48 (m, 9H), 2.45-1.96 (m, 13H), 1.87-1.72 (m, 1H), 1.46 (t, J = 6.4 Hz,2H), 0.98 (s, 6H)。
实施例6:化合物#41-44的制备
用于制备17a-c的一般程序:将(R)-4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((1-(苯硫基)-4-(哌嗪-1-基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(1.0当量)、甲苯磺酸酯16a/16b/16c(5.0当量)、K2CO3 (2.0当量)和NaI (0.2当量)在DMSO中的混合物在80℃下搅拌过夜。然后将反应混合物倒入水中并用DCM萃取。合并的有机层用NH4Cl水溶液洗涤,盐水洗涤,经Na2SO4干燥,并真空浓缩。通过硅胶柱色谱法纯化粗产物,以得到纯的酯,将其溶解在MeOH-THF中并用LiOH (水溶液)处理。1小时后,通过加入NH4Cl水溶液猝灭反应并用DCM萃取。合并的有机层用盐水洗涤,经Na2SO4干燥,并真空浓缩。粗产物直接用于下一步骤。
用于制备化合物#41-44的一般程序:将酸17 (1.0当量)、胺18 (1.0当量)、HATU(1.1当量)和TEA (5.0当量)在DCM中的混合物在室温下搅拌过夜。然后将反应混合物倒入水中并用DCM萃取。合并的有机层用NH4Cl水溶液洗涤,经Na2SO4干燥,并真空浓缩。通过硅胶柱色谱法纯化粗产物。
(2S,4R)-1-((S)-2-(2-(2-(4-((R)-3-((4-(N-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-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-(苯硫基)丁基)哌嗪-1-基)乙氧基)乙酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(化合物#41):1HNMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.37 (d, J = 2.1 Hz, 1H), 8.09 (d, J =8.9 Hz, 1H), 7.91-7.79 (m, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.46-7.28 (m, 11H),7.25-7.16 (m, 1H), 6.99 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 8.6 Hz, 2H), 6.70-6.57 (m, 1H), 5.20-5.00 (m, 1H), 4.91-4.77 (m, 1H), 4.67 (d, J = 9.3 Hz, 1H),4.47 (s, 1H), 4.04-2.65 (m, 21H), 2.60-1.43 (m, 26H), 1.05 (s, 9H), 1.00 (s,6H) ppm。
(2S,4R)-1-((S)-2-(2-(2-(2-(4-((R)-3-((4-(N-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-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-(苯硫基)丁基)哌嗪-1-基)乙氧基)乙氧基)乙酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(化合物#42):1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.40 (d, J = 2.2 Hz, 1H),8.01 (d, J = 9.3 Hz, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 7.4 Hz, 1H),7.43-7.27 (m, 12H), 6.99 (d, J = 8.5 Hz, 2H), 6.78 (d, J = 8.7 Hz, 2H), 6.70-6.61 (m, 1H), 5.15-5.03 (m, 1H), 4.83-4.73 (m, 1H), 4.67 (d, J = 9.3 Hz, 1H),4.45 (s, 1H), 4.18-2.65 (m, 25H), 2.61-1.43 (m, 26H), 1.05 (s, 9H), 0.99 (s,6H) ppm。
(2S,4R)-1-((S)-2-(叔丁基)-14-(4-((R)-3-((4-(N-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-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-(苯硫基)丁基)哌嗪-1-基)-4-氧代-6,9,12-三氧杂-3-氮杂十四烷-1-酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(化合物#43):1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 8.37 (d, J = 2.1 Hz, 1H),8.09 (d, J = 8.9 Hz, 1H), 7.91-7.79 (m, 1H), 7.71 (d, J = 8.4 Hz, 2H), 7.46-7.28 (m, 11H), 7.25-7.16 (m, 1H), 6.99 (d, J = 8.1 Hz, 2H), 6.77 (d, J = 8.6Hz, 2H), 6.70-6.57 (m, 1H), 5.20-5.00 (m, 1H), 4.91-4.77 (m, 1H), 4.67 (d, J= 9.3 Hz, 1H), 4.47 (s, 1H), 4.04-2.65 (m, 29H), 2.60-1.43 (m, 26H), 1.05 (s,9H), 1.00 (s, 6H) ppm。
(2S,4R)-1-((S)-2-(叔丁基)-14-(4-((R)-3-((4-(N-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-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-(苯硫基)丁基)哌嗪-1-基)-4-氧代-6,9,12-三氧杂-3-氮杂十四烷-1-酰基)-4-羟基-N-(4-(4-甲基噻唑-5-基)苄基)吡咯烷-2-甲酰胺(化合物#44):1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 8.35 (s, 1H), 8.16-7.95 (m, 2H), 7.72(d, J = 8.3 Hz, 2H), 7.47-7.28 (m, 11H), 7.23-7.13 (m, 1H), 7.00 (d, J = 8.0Hz, 2H), 6.82-6.56 (m, 3H), 4.92-4.78 (m, 1H), 4.72-4.29 (m, 4H), 4.02-2.86(m, 29H), 2.84-1.46 (m, 23H), 1.02 (s, 6H), 1.00 (s, 9H) ppm。
实施例7:化合物#45、 #46、#48和#50的制备
用于制备20a-d的一般程序:将(R)-4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((1-(苯硫基)-4-(哌嗪-1-基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(1.0当量)、溴化物19 (5.0当量)、K2CO3(2.0当量)和NaI (0.2当量)在DMSO中的混合物在80℃下搅拌过夜。然后将反应混合物倒入水中并用DCM萃取。合并的有机层用NH4Cl水溶液洗涤,盐水洗涤,经Na2SO4干燥,并真空浓缩。通过硅胶柱色谱法纯化粗产物,以得到纯的酯,将其溶解在MeOH-THF中并用LiOH (水溶液)处理。1小时后,通过加入NH4Cl水溶液猝灭反应。将混合物用DCM萃取,并且合并的有机层用盐水洗涤,经Na2SO4干燥,并真空浓缩。粗产物直接用于下一步骤。
用于制备化合物#45, #46, #48和#50的一般程序:将酸20 (1.0当量)、胺18a(1.0当量)、HATU (1.1当量)和三乙胺(5.0当量)在DCM中的混合物在室温下搅拌过夜。然后将混合物倒入水中并用DCM萃取。合并的有机层用NH4Cl水溶液和盐水洗涤,经Na2SO4干燥,并真空浓缩。通过硅胶柱色谱法纯化粗产物。
(2S,4R)-1-((S)-2-(5-(4-((R)-3-((4-(N-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-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-(苯硫基)丁基)哌嗪-1-基)戊酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(化合物#45):1H NMR (400MHz, CDCl3和CD3OD) δ 8.64 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 7.99 (dd, J =9.2, 2.3 Hz, 1H), 7.78 (d, J = 8.6 Hz, 2H), 7.56 (d, J = 7.7 Hz, 1H), 7.41-7.29 (m, 6H), 7.25-7.15 (m, 5H), 7.00-6.83 (m, 4H), 6.73 (d, J = 8.6 Hz, 2H),6.54 (d, J = 9.3 Hz, 1H), 5.08-4.95 (m, 1H), 4.65-4.55 (m, 1H), 4.52 (d, J =9.0 Hz, 1H), 4.42 (s, 1H), 3.95 (d, J = 11.3 Hz, 1H), 3.84-3.69 (m, 1H), 3.56(dd, J = 11.3, 3.4 Hz, 1H), 3.11-1.92 (m, 36H), 1.70-1.37 (m, 10H), 0.99 (s,9H), 0.94 (s, 6H) ppm。
(2S,4R)-1-((S)-2-(6-(4-((R)-3-((4-(N-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-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-(苯硫基)丁基)哌嗪-1-基)己酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(化合物#46):1H NMR (400MHz, CDCl3和CD3OD) δ 8.67 (s, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.01 (dd, J =9.1, 2.2 Hz, 1H), 7.83 (d, J = 8.6 Hz, 2H), 7.57 (d, J = 7.7 Hz, 1H), 7.42-7.32 (m, 6H), 7.28-7.19 (m, 5H), 7.03-6.90 (m, 3H), 6.82-6.72 (m, 3H), 6.54(d, J = 9.3 Hz, 1H), 5.11-5.00 (m, 1H), 4.72-4.61 (m, 1H), 4.57 (d, J = 9.1Hz, 1H), 4.45 (s, 1H), 4.01 (d, J = 11.4 Hz, 1H), 3.87-3.71 (m, 1H), 3.58(dd, J = 11.2, 3.3 Hz, 1H), 3.13-1.94 (m, 36H), 1.75-1.18 (m, 12H), 1.02 (s,9H), 0.97 (d, J = 1.8 Hz, 6H) ppm。
(2S,4R)-1-((S)-2-(7-(4-((R)-3-((4-(N-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-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-(苯硫基)丁基)哌嗪-1-基)庚酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(化合物#48):1H NMR (400MHz, CDCl3和CD3OD) δ 8.75 (s, 1H), 8.33 (d, J = 2.2 Hz, 1H), 8.25 (d, J = 7.6Hz, 1H), 8.07 (dd, J = 9.2, 2.3 Hz, 1H), 7.81 (d, J = 8.7 Hz, 2H), 7.56 (s,1H), 7.41-7.17 (m, 11H), 7.13-7.00 (m, 3H), 6.84 (d, J = 9.0 Hz, 2H), 6.69(d, J = 9.4 Hz, 1H), 5.09-4.98 (m, 1H), 4.46 (s, 3H), 3.92 (d, J = 11.3 Hz,2H), 3.77-3.65 (m, 1H), 3.39-2.92 (m, 12H), 2.75-1.95 (m, 24H), 1.86-1.21 (m,14H), 1.04 (s, 9H), 1.02 (s, 6H) ppm。
(2S,4R)-1-((S)-2-(8-(4-((R)-3-((4-(N-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-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-(苯硫基)丁基)哌嗪-1-基)辛酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(化合物#50):1H NMR (400MHz, CDCl3和CD3OD) δ 8.75 (s, 1H), 8.34 (d, J = 2.2 Hz, 1H), 8.20 (d, J = 7.6Hz, 1H), 8.08 (dd, J = 9.2, 2.3 Hz, 1H), 7.78 (d, J = 8.7 Hz, 2H), 7.56 (s,1H), 7.46-7.19 (m, 11H), 7.13 (d, J = 8.4 Hz, 1H), 7.07-6.99 (m, 2H), 6.88-6.80 (m, 2H), 6.68 (d, J = 9.4 Hz, 1H), 5.11-4.98 (m, 1H), 4.61-4.41 (m, 3H),3.92 (t, J = 10.9 Hz, 2H), 3.78-3.67 (m, 1H), 3.37-2.91 (m, 12H), 2.65-1.99(m, 24H), 1.85-1.30 (m, 16H), 1.04 (s, 9H), 1.01 (s, 6H) ppm。
实施例8:化合物#51-55和57的制备
用于制备22a-f的一般程序:将化合物18a (1.0当量)、酸21 (1.3当量)、HATU(1.1当量)和TEA (5.0当量)在DCM中的混合物在室温下搅拌1小时。将反应混合物倒入水中并用DCM萃取。合并的有机层用NH4Cl水溶液和盐水洗涤,经Na2SO4干燥,并真空浓缩。将残余物溶解在MeOH中并用LiOH (水溶液)处理。2小时后,将反应在真空下进行浓缩。通过硅胶柱色谱法纯化粗产物。
3-(((S)-1-((2S,4R)-4-羟基-2-(((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-3-氧代丙酸(22a):1H NMR(400 MHz, CDCl3) δ 9.26 (s, 1H), 8.65 (s, 1H), 7.90 (s, 1H), 7.43-7.29 (m,4H), 5.13-4.98 (m, 1H), 4.83-4.67 (m, 1H), 4.55-4.36 (m, 2H), 4.15 (d, J =11.4 Hz, 1H), 3.64-3.49 (m, 1H), 3.27-3.09 (m, 2H), 2.50 (s, 3H), 2.43-2.23(m, 1H), 2.21-2.06 (m, 1H), 1.45 (d, J = 7.0 Hz, 3H), 1.06 (s, 9H) ppm。
4-(((S)-1-((2S,4R)-4-羟基-2-(((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-4-氧代丁酸(22b):1H NMR(400 MHz, CDCl3) δ 8.67 (s, 1H), 7.94 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 7.7Hz, 1H), 7.44-7.34 (m, 4H), 5.13-5.03 (m, 1H), 4.81-4.73 (m, 1H), 4.51-4.38(m, 2H), 4.15 (d, J = 11.4 Hz, 1H), 3.54 (dd, J = 11.4, 3.5 Hz, 1H), 2.64-2.37 (m, 8H), 2.16-2.06 (m, 1H), 1.47 (d, J = 6.9 Hz, 3H), 1.05 (s, 9H) ppm。
5-(((S)-1-((2S,4R)-4-羟基-2-(((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-5-氧代戊酸(22c):1H NMR(400 MHz, CDCl3) δ 8.67 (s, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.45-7.32 (m, 4H),7.19 (s, 1H), 5.15-5.02 (m, 1H), 4.80-4.69 (m, 1H), 4.57 (d, J = 8.4 Hz, 1H),4.46 (s, 1H), 4.16-4.03 (m, 1H), 3.60 (dd, J = 11.1, 3.8 Hz, 1H), 2.52 (s,3H), 2.47-1.84 (m, 8H), 1.47 (d, J = 6.9 Hz, 3H), 1.05 (s, 9H) ppm。
6-(((S)-1-((2S,4R)-4-羟基-2-(((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-6-氧代己酸(22d):1H NMR(400 MHz, CDCl3) δ 8.67 (s, 1H), 7.67 (d, J = 7.7 Hz, 1H), 7.43-7.32 (m, 4H),6.85 (d, J = 8.9 Hz, 1H), 5.09 (t, J = 7.2 Hz, 1H), 4.72 (t, J = 8.1 Hz, 1H),4.63 (d, J = 9.0 Hz, 1H), 4.46 (s, 1H), 4.06 (d, J = 11.3 Hz, 1H), 3.61 (dd,J = 11.2, 3.6 Hz, 1H), 2.52 (s, 3H), 2.41-2.05 (m, 6H), 1.73-1.52 (m, 4H),1.47 (d, J = 6.9 Hz, 3H), 1.03 (s, 9H) ppm。
(((S)-1-((2S,4R)-4-羟基-2-(((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-7-氧代庚酸(22e):1H NMR(400 MHz, CDCl3和CD3OD) δ 8.72 (s, 1H), 8.05-7.89 (m, 1H), 7.43-7.33 (m, 4H),7.24-7.08 (m, 1H), 5.14-4.95 (m, 1H), 4.73-4.40 (m, 3H), 4.00-3.93 (m, 1H),3.76-3.59 (m, 1H), 2.52 (s, 3H), 2.38-2.05 (m, 6H), 1.71-1.49 (m, 9H), 1.04(s, 9H) ppm。
8-(((S)-1-((2S,4R)-4-羟基-2-(((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)氨基)-8-氧代辛酸(22f):1H NMR(400 MHz, CDCl3) δ 8.72 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.40-7.33 (m, 4H),6.92 (d, J = 8.7 Hz, 1H), 5.15-4.98 (m, 1H), 4.76-4.67 (m, 1H), 4.62 (d, J =8.9 Hz, 1H), 4.52 (s, 1H), 4.04 (d, J = 11.2 Hz, 1H), 3.74-3.59 (m, 1H), 2.51(s, 3H), 2.39-2.10 (m, 6H), 1.66-1.45 (m, 7H), 1.35-1.27 (m, 4H), 1.03 (s,9H) ppm。
用于制备化合物#51-55和57的一般程序:将(R)-4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-基)甲基)哌嗪-1-基)-N-((4-((1-(苯硫基)-4-(哌嗪-1-基)丁-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺酰基)苯甲酰胺(1.0当量)、酸22 (1.1当量)、HATU (1.05当量)和TEA (5.0当量)在DCM中的混合物在室温下搅拌1小时。然后将反应混合物倒入水中并用DCM萃取。合并的有机层用NH4Cl水溶液和盐水洗涤,经Na2SO4干燥,并真空浓缩。通过硅胶柱色谱法纯化粗产物。
(2S,4R)-1-((S)-2-(3-(4-((R)-3-((4-(N-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-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-(苯硫基)丁基)哌嗪-1-基)-3-氧代丙酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(化合物#51):1H NMR(400 MHz, CDCl3) δ 8.74-8.54 (m, 2H), 8.35 (d, J = 2.2 Hz, 1H), 8.10 (dd, J =9.3, 2.3 Hz, 1H), 7.79-7.58 (m, 3H), 7.41-7.27 (m, 10H), 7.26-7.19 (m, 1H),7.06 (d, J = 8.5 Hz, 1H), 7.01-6.94 (m, 2H), 6.75 (d, J = 8.7 Hz, 2H), 6.64(d, J = 9.4 Hz, 1H), 5.13-5.01 (m, 1H), 4.80-4.71 (m, 1H), 4.54-4.44 (m, 2H),4.19-4.04 (m, 1H), 3.97-3.84 (m, 1H), 3.72-2.88 (m, 15H), 2.59-2.02 (m, 20H),1.66 (d, J = 13.1 Hz, 1H), 1.45 (d, J = 6.9 Hz, 5H), 1.08 (s, 9H), 0.98 (s,6H) ppm。
(2S,4R)-1-((S)-2-(4-(4-((R)-3-((4-(N-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-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-(苯硫基)丁基)哌嗪-1-基)-4-氧代丁酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(化合物#52):1H NMR(400 MHz, CDCl3) δ 8.67 (s, 1H), 8.37 (d, J = 2.2 Hz, 1H), 8.09 (dd, J = 9.2,2.3 Hz, 1H), 7.68 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 7.8 Hz, 1H), 7.43-7.28(m, 10H), 7.26-7.21 (m, 1H), 7.11-6.89 (m, 4H), 6.76 (d, J = 8.8 Hz, 2H),6.62 (d, J = 9.4 Hz, 1H), 5.14-5.01 (m, 1H), 4.81-4.74 (m, 1H), 4.53 (d, J =8.5 Hz, 1H), 4.47 (s, 1H), 4.06 (d, J = 11.5 Hz, 1H), 3.97-3.83 (m, 1H),3.63-2.84 (m, 13H), 2.62-1.99 (m, 24H), 1.74-1.61 (m, 1H), 1.51-1.43 (m, 5H),1.06 (s, 9H), 0.98 (s, 6H) ppm。
(2S,4R)-1-((S)-2-(5-(4-((R)-3-((4-(N-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-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-(苯硫基)丁基)哌嗪-1-基)-5-氧代戊酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(化合物#53):1H NMR(400 MHz, CDCl3) δ 8.67 (s, 1H), 8.34 (d, J = 2.2 Hz, 1H), 8.09 (dd, J = 9.3,2.3 Hz, 1H), 7.71 (d, J = 8.7 Hz, 2H), 7.52 (d, J = 7.8 Hz, 1H), 7.41-7.27(m, 9H), 7.26-7.21 (m, 2H), 7.12-6.95 (m, 3H), 6.89 (d, J = 8.3 Hz, 1H), 6.76(d, J = 8.8 Hz, 2H), 6.61 (d, J = 9.5 Hz, 1H), 5.14-5.02 (m, 1H), 4.79-4.68(m, 1H), 4.58-4.44 (m, 2H), 4.12 (d, J = 11.3 Hz, 1H), 3.96-3.81 (m, 1H),3.68-2.85 (m, 13H), 2.54-2.00 (m, 24H), 1.87 (p, J = 7.2 Hz, 2H), 1.78-1.60(m, 1H), 1.46 (dd, J = 6.7, 3.6 Hz, 5H), 1.06 (s, 9H), 0.97 (s, 6H) ppm。
(2S,4R)-1-((S)-2-(6-(4-((R)-3-((4-(N-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-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-(苯硫基)丁基)哌嗪-1-基)-6-氧代己酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(化合物#54):1H NMR(400 MHz, CDCl3) δ 8.67 (s, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.09 (dd, J = 9.3,2.3 Hz, 1H), 7.70 (d, J = 8.6 Hz, 2H), 7.45-7.27 (m, 10H), 7.26-7.22 (m, 2H),7.12-6.94 (m, 3H), 6.76 (d, J = 8.7 Hz, 2H), 6.62 (d, J = 9.4 Hz, 1H), 6.56(d, J = 8.7 Hz, 1H), 5.14-5.01 (m, 1H), 4.80-4.69 (m, 1H), 4.61 (d, J = 8.8Hz, 1H), 4.49 (s, 1H), 4.10 (d, J = 11.4 Hz, 1H), 3.98-3.84 (m, 1H), 3.70-2.85 (m, 13H), 2.54-2.00 (m, 24H), 1.45 (d, J = 6.7 Hz, 10H), 1.05 (s, 9H),0.97 (s, 6H) ppm。
(2S,4R)-1-((S)-2-(7-(4-((R)-3-((4-(N-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-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-(苯硫基)丁基)哌嗪-1-基)-7-氧代庚酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(化合物#55):1H NMR(400 MHz, CDCl3) δ 8.67 (s, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.08 (d, J = 9.1Hz, 1H), 7.69 (d, J = 8.6 Hz, 2H), 7.46-7.27 (m, 12H), 7.14-6.93 (m, 3H),6.76 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 9.4 Hz, 1H), 6.34 (d, J = 8.7 Hz, 1H),5.13-5.00 (m, 1H), 4.79-4.69 (m, 1H), 4.60 (d, J = 8.7 Hz, 1H), 4.49 (s, 1H),4.10 (d, J = 11.4 Hz, 1H), 3.96-3.83 (m, 1H), 3.72-2.81 (m, 13H), 2.55-2.00(m, 24H), 1.77-1.30 (m, 12H), 1.03 (s, 9H), 0.97 (s, 6H) ppm。
(2S,4R)-1-((S)-2-(8-(4-((R)-3-((4-(N-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-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-(苯硫基)丁基)哌嗪-1-基)-8-氧代辛酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(化合物#57):1H NMR(400 MHz, CDCl3) δ 8.67 (s, 1H), 8.34 (d, J = 2.3 Hz, 1H), 8.14-8.05 (m, 1H),7.71 (d, J = 8.5 Hz, 2H), 7.49-7.27 (m, 11H), 7.25-7.18 (m, 1H), 7.13-6.94(m, 3H), 6.75 (d, J = 8.6 Hz, 2H), 6.61 (d, J = 9.4 Hz, 1H), 6.32 (d, J = 8.7Hz, 1H), 5.14-5.02 (m, 1H), 4.77-4.67 (m, 1H), 4.60 (d, J = 8.8 Hz, 1H), 4.49(s, 1H), 4.10 (d, J = 11.4 Hz, 1H), 3.97-3.84 (m, 1H), 3.74-2.85 (m, 13H),2.54-1.99 (m, 24H), 1.76-1.23 (m, 14H), 1.04 (s, 9H), 0.97 (s, 6H) ppm。
实施例9:化合物#61的制备
N1-((R)-3-((4-(N-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-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-(苯硫基)丁基)-N7-((S)-1-((2S,4R)-4-羟基-2-(((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)氨基甲酰基)吡咯烷-1-基)-3,3-二甲基-1-氧代丁-2-基)-N1-甲基庚二酰胺(化合物#61)的制备:将10 (1.0当量)、酸22e (1.1当量)、HATU (1.05当量)和TEA (5.0当量)在DCM和DMSO中的混合物在室温下搅拌2小时,随后倒入水中并用DCM萃取。合并的有机层用NH4Cl水溶液洗涤,经Na2SO4干燥,并真空浓缩。通过硅胶柱色谱法纯化粗产物,以得到标题化合物。1HNMR (400 MHz, CDCl3和CD3OD) δ 8.69 (s, 1H), 8.44-8.30 (m, 1H), 8.10-7.96 (m,1H), 7.92-7.57 (m, 3H), 7.43-7.34 (m, 6H), 7.31-7.18 (m, 4H), 7.08-6.73 (m,6H), 6.56-6.26 (m, 1H), 5.12-4.94 (m, 1H), 4.72-4.40 (m, 3H), 4.12-3.88 (m,1H), 3.81-2.77 (m, 16H), 2.51 (s, 3H), 2.45-1.93 (m, 15H), 1.83-1.16 (m,12H), 1.08-0.94 (m, 15H) ppm。
实施例10:化合物#65的制备
(R)-7-((3-((4-(N-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-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-(苯硫基)丁基)(甲基)氨基)庚酸(23)的制备:将10 (1.0当量)、7-溴庚酸甲酯(5.0当量)、K2CO3(2.0当量)和NaI (0.2当量)在DMSO中的混合物在80℃下搅拌过夜。然后将反应混合物倒入水中并用DCM萃取。合并的有机层用NH4Cl水溶液和盐水洗涤,经Na2SO4干燥,并真空浓缩。通过硅胶柱色谱法纯化粗产物。将酯溶解在MeOH-THF中并用LiOH (水溶液)处理。1小时后,通过加入NH4Cl水溶液猝灭反应。将混合物用DCM萃取。合并的有机层用盐水洗涤,经Na2SO4干燥,并真空浓缩。粗产物直接用于下一步骤。
(2S,4R)-1-((S)-2-(7-(((R)-3-((4-(N-(4-(4-((4'-氯-4,4-二甲基-3,4,5,6-四氢-[1,1'-联苯基]-2-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-(苯硫基)丁基)(甲基)氨基)庚酰氨基)-3,3-二甲基丁酰基)-4-羟基-N-((S)-1-(4-(4-甲基噻唑-5-基)苯基)乙基)吡咯烷-2-甲酰胺(化合物#65)的制备:将23(1.0当量)、18a (1.1当量)、HATU (1.05当量)和TEA (5.0当量)在DCM中的混合物在室温下搅拌1小时。然后将混合物倒入水中并用DCM萃取。合并的有机层用NH4Cl水溶液和盐水洗涤,经Na2SO4干燥,并真空浓缩。通过硅胶柱色谱法纯化粗产物。1H NMR (400 MHz, CDCl3和CD3OD) δ 8.69 (s, 1H), 8.36 (d, J = 2.2 Hz, 1H), 8.16-8.06 (m, 1H), 7.89 (d,J = 7.7 Hz, 1H), 7.77 (d, J = 8.6 Hz, 2H), 7.40-7.37 (m, 4H), 7.36-7.33 (m,2H), 7.32-7.17 (m, 5H), 7.09-6.96 (m, 3H), 6.92-6.77 (m, 3H), 5.05-4.93 (m,1H), 4.67-4.57 (m, 2H), 4.49-4.41 (m, 1H), 4.21-4.06 (m, 1H), 3.96 (d, J =11.3 Hz, 1H), 3.65 (dd, J = 11.2, 3.5 Hz, 1H), 3.40-3.35 (m, 2H), 3.22-2.59(m, 12H), 2.50 (s, 3H), 2.48-1.92 (m, 15H), 1.72-1.19 (m, 13H), 1.04 (s, 9H),1.00 (s, 6H) ppm。
实施例11:化合物#55在杀死癌细胞中的选择性。
将来自不同组织来源的癌细胞(包括急性淋巴细胞性白血病(MOLT4和RS4;11)、小细胞肺癌(NCI-H146或简单地H146)和多发性骨髓瘤(EJM和H929))与增加浓度的化合物#55或ABT-263一起孵育72小时。通过基于四唑鎓的MTS测定测量细胞生存力,并将IC50计算为用媒介物处理的细胞的百分比。
在测试的肿瘤细胞中,Bcl-xL依赖性MOLT4细胞对化合物#55处理最敏感,其IC50为52 nM,其效能是ABT-263的约4倍。化合物#55还在Bcl-2依赖性RS4;11和Bcl-2/Bcl-xL依赖性H146细胞中诱导细胞生存力的丧失;其IC50分别为230 nM和160 nM。然而,化合物#55在这些细胞中的作用不如ABT-263显著。化合物#55在EJM和H929细胞中未显示任何显著的细胞活性,这主要取决于Mcl-1 (图1A)。此外,它在高达3 μM时没有诱导任何显著的血小板毒性(数据未显示),表明对Bcl-xL依赖性癌细胞的高选择性。
实施例12:在MOLT4细胞和人血小板中的剂量依赖性蛋白质降解测定。
将MOLT4细胞和人血小板与增加浓度的化合物#55一起孵育16小时。收获细胞并在补充了蛋白酶和磷酸酶抑制剂混合物的RIPA裂解缓冲液中裂解。在预浇铸的4-20% SDS-PAGE凝胶上解析等量的蛋白质(20 μg/泳道)。随后通过电泳将蛋白质转移至NOVEX PVDF膜。将膜在封闭缓冲液(在TBS-T中5%脱脂奶粉)中封闭,并与一抗(在最佳浓度下)在4℃下孵育过夜。在TBS-T中洗涤三次后,将膜与适当的HRP缀合的二抗在室温下孵育1小时。在充分洗涤三次之后,用ECL蛋白印迹(western blotting)检测试剂检测感兴趣的蛋白质并且用放射自显影(Pierce Biotech,Rockford,IL,USA)记录。用于Bcl-xL (目录号2762)、Bcl-2抗体(目录号2872S)、Mcl-1 (目录号5453)和β-肌动蛋白(目录号4970)的一抗购自CellSignaling technology。使用ImageJ软件测量相对条带强度,并对β-肌动蛋白归一化。使用GraphPad Prism计算DC50(50%降解的浓度)。化合物#55剂量依赖性地诱导Bcl-xL在MOLT4细胞中的降解,其中DC50和Dmax (最大降解)分别为0.063 μM和90.8%。在MOLT4细胞中未检测到Bcl-2水平,而Mcl-1未受化合物#55处理的影响(图1B和1D)。化合物#55不影响人血小板中的Bcl-xL水平,而未检测到Bcl-2和Mcl-1 (图1C)。化合物#55在血小板中的DC50和Dmax值分别为>3 μM和26% (图1E)。
接着,我们寻求确定在这些肿瘤细胞和血小板中E3连接酶VHL的相对蛋白质水平,以解释化合物#55的选择性。与血小板相比,肿瘤细胞中的VHL水平显著更高,这解释了肿瘤细胞对化合物#55更敏感的原因(图1E)。
实施例13:化合物#55对Bcl-2家族蛋白的结合亲和力的评价。
为了评价化合物#55对Bcl-2家族蛋白的结合亲和力,在室温下进行AlphaLISA竞争性测定,并将试剂在含有250 mM HEPES(pH 7.5)、1 M NaCl、1% BSA和0.05% Tween-20的缓冲液中稀释。将纯化的重组His-标记的Bcl-xL/Bcl-2/Bcl-w (Sigma-Aldrich, St.Louis, MO)与增加浓度的化合物#55和固定浓度的生物素标记的Bad (对于Bcl-xL)或BIM肽(对于Bcl-2和Bcl-w) (AnaSpec, Fremont, CA)在96孔PCR板中孵育至最终体积为40 μL。孵育24小时后,将5 μL 6 x His-受体珠(His-Acceptor beads) (最终浓度20 μg/mL)(PerkinElmer, Houston, TX)加入到每个孔中并孵育1小时。之后,将5 μL链霉亲和素-供体珠(最终浓度20 μg/mL) (PerkinElmer)加入到每个孔中并孵育0.5小时,在孵育期结束时,将17 μL各样品转移到384孔替代板的相邻孔中。使用Alpha程序在Biotek’s SynergyNeo2多模式读板机上扫描板。使用非线性回归、一个位点、竞争性结合、基于对于每个蛋白质/肽对通过实验测定的Kd在GraphPad Prism上的拟合Ki函数,计算抑制常数(Ki)。
化合物#55显示对Bcl-xL和Bcl-2具有纳摩尔结合亲和力,其相对低于ABT263。对Bcl-xL/Bcl-2的结合亲和力显著高于Bcl-w (见表2)。
表2
实施例14:在另外的癌细胞中的蛋白质降解测定。
将肿瘤细胞与固定浓度的化合物#55一起孵育16小时(RS4;11、EJM、H929)或48小时(H146),并且使用如上所述的蛋白质印迹分析确定Bcl-2/Bcl-xL/Mcl-1水平。
化合物#55能够在所有这些细胞系中降解Bcl-xL,而不降解Bcl-2和Mcl-1 (图2)。
实施例15:在MOLT4细胞中时间依赖性Bcl-xL降解。
将MOLT4细胞与固定浓度的化合物#55孵育增加的时间点。在另一个实验中,将细胞处理16小时,随后停药,并在收获它们用于Bcl-xL降解测定之前进一步培养增加的时间点。使用如上所述的蛋白质印迹分析测量Bcl-xL水平。使用ImageJ软件测量相对条带强度,并将其归一化为相等负载的对照β-肌动蛋白。
化合物#55时间依赖性地降解Bcl-xL,其中在早至处理2小时时就开始显著降解(图3A和3B)。此外,化合物#55在停药后能够维持其Bcl-xL降解活性达延长的时间段(图3C和3D)。
实施例16:化合物#55诱导的Bcl-xL降解的VHL和蛋白酶体依赖性的验证。
首先,我们寻求证实在VHL-配体(VHL-L)与Bcl-xL配体(ABT263)之间需要接头用于Bcl-xL降解和更有效的细胞杀死。将MOLT4细胞与1 μM的ABT-263或10 μM的VHL-L或两者的组合孵育16小时,随后蛋白质印迹分析Bcl-xL表达。用增加浓度的ABT263(用或不用1 μM和2 μM VHL-L)处理MOLT4细胞72小时,使用MTS测定测量细胞生存力。
单个配体或两者的组合都不能降解Bcl-xL,这表明为了降解Bcl-xL,在两个配体之间存在接头是必需的(图4A)。类似地,在VHL-L存在下,ABT-263不能进一步诱导细胞杀死,这进一步验证了该概念(图4B)。
第二,我们寻求证实游离VHL的存在对于化合物#55诱导的Bcl-xL降解是必需的。MOLT4细胞用VHL-L预处理以封闭VHL,且然后用化合物#55处理16小时,随后通过蛋白质印迹进行Bcl-xL表达分析。MOLT4细胞未经处理或用1 μM和2μM VHL-L预处理1小时,且然后用增加浓度的化合物#55处理72小时。通过MTS 测定测量细胞生存力。
化合物#55在VHL-L预处理的细胞中不诱导Bcl-xL降解,这证实Bcl-xL降解是VHL依赖性的(图4C)。此外,化合物#55诱导的细胞杀死在VHL-L存在下消除(图4D)。
第三,我们寻求证实化合物#55诱导的Bcl-xL降解依赖于蛋白酶体活性。MOLT4细胞未经处理或用1 μM的蛋白酶体抑制剂MG132预处理,且然后用或不用化合物#55 (0.1 μM和1 μM)如所说明地处理6小时,随后蛋白质印迹分析Bcl-xL。
化合物#55在MG132预处理的细胞中不诱导Bcl-xL降解,这证实了蛋白酶体依赖性Bcl-xL降解(图4E)。
第四,我们寻求证实通过化合物#55的Bcl-xL降解需要与Bcl-xL蛋白结合。MOLT4细胞未经处理或用1 μM的ABT-263预处理,且然后用或不用化合物#55 (0.1 μM和1 μM)如所说明地处理16小时,随后蛋白质印迹分析Bcl-xL。
化合物#55在ABT263预处理的细胞中不诱导Bcl-xL降解,这证实了化合物#55的Bcl-xL降解需要与Bcl-xL蛋白结合(图4F)。
实施例17:化合物#55的下游凋亡机制的阐述。
将MOLT4细胞与0.1 μM和0.3 μM的化合物#55或ABT-263一起孵育24小时。孵育结束时,收获细胞用于切割的和全长胱天蛋白酶(caspase)-3和聚(ADP)核糖聚合酶(PARP)的蛋白质印迹分析。切割的胱天蛋白酶-3 (目录号9661)、全长胱天蛋白酶-3 (目录号9662)和PARP (目录号9532)的抗体购自Cell Signaling Technology。所用的单一抗PARP抗体可检测切割的和全长PARP两者。
化合物#55诱导胱天蛋白酶-3和PARP的切割,且该作用比ABT263更显著(图5)。
实施例18:化合物#55与Bcl-2抑制剂ABT-199或Mcl-1抑制剂S63845组合的细胞活性。
将小细胞肺癌H146细胞与500 nM ABT-199 (Bcl-2抑制剂)或125 nM化合物#55或两者的组合一起孵育72小时。使用MTS测定测量细胞生存力。使用式CI = AB/(A×B)计算组合指数(CI);其中AB是组合的细胞抑制百分比,而A和B是单独试剂的细胞抑制百分比。CI<1表示协同作用,而CI<0.3表示强协同作用。
ABT-199和化合物#55的组合协同诱导Bcl-2/Bcl-xL依赖性肿瘤细胞中细胞生存力的丧失(图6A)。
将多发性骨髓瘤EJM细胞与250 nM S63845 (Mcl-1抑制剂)或125 nM化合物#55或两者的组合一起孵育72小时。使用MTS测定测量细胞生存力。使用式CI = AB/(A×B)计算组合指数(CI);其中AB是组合的细胞抑制百分比,而A和B是单独试剂的细胞抑制百分比。CI<1表示协同作用,而CI<0.3表示强协同作用。
Mcl-1抑制剂(S63845)和化合物#55的组合协同诱导Bcl-xL/Mcl-1依赖性肿瘤细胞中细胞生存力的丧失(图6A)。
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Claims (16)
1.包含式(I)的化合物:
其中
A为结合到E3泛素连接酶的E3泛素连接酶结合单元,其具有以下结构:
其中R1为卤素;
其中R2和R3为H;
其中R4和R5为CH3;
其中R6为SO2CF3;
其中X为NH;
其中Y为
其中L为-C(=O)CH2-,-C(=O)CH2CH2-,-C(=O)CH2(CH2)2CH2-,-C(=O)CH2(CH2)3CH2-,-C(=O)CH2(CH2)4CH2-或-C(=O)CH2(CH2)5CH2-;和
其中Z不存在;
并且n为0-3的整数。
2.权利要求1所述的化合物,其中A是
3.权利要求1所述的化合物,其中A是
4.权利要求1-3中任一项所述的化合物,其中R1为Cl。
5.权利要求1-3中任一项所述的化合物,其中n是1。
6.权利要求1-3中任一项所述的化合物,其中L为-C(=O)CH2(CH2)3CH2-。
7.权利要求1所述的化合物,其中所述式(I)的化合物选自:
8.权利要求1-7中任一项所述的化合物在制备用于选择性地杀死需要其的受试者的一种或多种癌细胞的组合物中的用途。
9.权利要求1-7中任一项所述的化合物在制备用于治疗哺乳动物癌症的药物中的用途。
10.权利要求1-7中任一项所述的化合物在制备用于降解需要其的受试者的Bcl-2蛋白的组合物中的用途。
11.权利要求1-7中任一项所述的化合物在制备用于需要其的受试者中通过Bcl-2蛋白的降解来治疗癌症的组合物中的用途,所述组合物包含所述化合物以及赋形剂和/或药学上可接受的载体。
12.组合物,其包含权利要求1-7中任一项所述的化合物和第二癌症治疗剂。
13.组合物,其包含权利要求1-7中任一项所述的化合物、第二癌症治疗剂和赋形剂和/或药学上可接受的载体。
14.权利要求12或权利要求13所述的组合物,其中所述第二癌症治疗剂选自:烷基化剂、抗代谢物、抗肿瘤抗生素、抗细胞骨架剂、抗激素剂、靶向治疗剂或其组合。
15.权利要求12或权利要求13所述的组合物,其中所述第二癌症治疗剂选自:拓扑异构酶抑制剂、光动力治疗剂或其组合。
16.权利要求12-15中任一项所述的组合物在制备用于治疗需要其的受试者的癌症的药物中的用途。
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