CN106535894A - 用于癌症治疗的mcl‑1调节化合物 - Google Patents
用于癌症治疗的mcl‑1调节化合物 Download PDFInfo
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- CN106535894A CN106535894A CN201580011401.XA CN201580011401A CN106535894A CN 106535894 A CN106535894 A CN 106535894A CN 201580011401 A CN201580011401 A CN 201580011401A CN 106535894 A CN106535894 A CN 106535894A
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- pyridin
- methyl
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- pyridine
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract
本发明涉及式(I)的化合物,并且涉及它们在治疗癌症中的治疗用途:其中Y1、Y2、Ar1、Ar2、R1、R2、i、j、k、l如权利要求1所定义。
Description
本发明涉及用于治疗癌症和细胞增殖疾病的化合物、组合物和方法,并且更具体地涉及制备和使用调节Mcl-1的化合物的方法;所述化合物可包含于药物组合物中并用作治疗剂。
癌症在全球是头号死因。凋亡,也称为程序性细胞死亡,是多细胞生物体消除衰老或损伤细胞的天然过程,其在各种生理过程如形态发生和组织内稳态中也涉及。凋亡是涉及许多蛋白质的复杂、高度调节的过程。这些蛋白质中的一些促进细胞死亡(“促凋亡”蛋白质)而一些防止凋亡(“抗凋亡”蛋白质)。癌细胞往往过表达抗凋亡基因。抗凋亡基因的过表达与肿瘤形成、转移生长和化疗抗性相关,并且持续需要选择性杀死癌细胞的治疗策略。
更具体地,凋亡控制缺陷通常涉及血液恶性肿瘤和实体瘤中癌细胞的化学抗性,并且Bcl-2家族成员表达的下调构成最常见和重要的事件之一。这些蛋白质都有Bcl-2同源结构域(称为BH结构域)。抗凋亡蛋白质(Bcl-2,Bcl-xL...)含有BH1至BH4结构域,而促凋亡蛋白质含有BH1至BH3结构域(多结构域成员如Bax和Bak)或仅BH3结构域(仅BH3基团如Bim、Puma、Bid、Bad、Noxa和Hrk)(Adams,J.M.和Cory,S.(2007)Oncogene 26,1324-1337)。在细胞应激下,仅BH3-蛋白质通过阻断抗凋亡成员的活性或直接活化多结构域促凋亡成员来引发凋亡,其通过一个蛋白质的BH3结构域与另一个蛋白质的疏水性口袋的相互作用来介导(Shamas-Din等,(2011)Biochimica et Biophysica Acta 1813,508-520)。
对阻止抗凋亡成员如Bcl-2或Bcl-xL的活性付出持续努力,其中强效BH3-模拟分子的开发代表了一种理想方式。这些分子结合至Bcl-2家族的抗凋亡蛋白质的BH3-结合沟并通过释放促凋亡Bcl-2家族成员来促进细胞死亡(Zhang,Lin等,(2007)DrugResist.Updat.10,207-217)。ABT-737(和与ABT-737、ABT-263或Navitoclax相关的口服化合物)能高效抑制Bcl-2和Bcl-xL的抗凋亡活性。其已经显示能够在血液恶性肿瘤中以单一试剂诱导凋亡细胞死亡,并且在实体瘤细胞中以较低程度诱导。ABT-737也可使癌细胞对化疗敏感。然而,其活性的条件是Mcl-1的缺失或失活,而Mcl-1的强表达和活性与对ABT-737的响应缺失相关(Dai,Y.和Grant,S.(2007)Cancer Res.67(7),2908-2911)。因此,抗凋亡蛋白质Mcl-1的表达和活性构成ABT-737活性的主要障碍。
在卵巢癌中,发明人之前证明Bcl-xL与Mcl-1合作保护肿瘤细胞免于凋亡,并且对它们的共同抑制甚至在没有化疗的情况下导致大量凋亡,该情况中Bcl-xL或Mcl-1的下调仍然无效(Brotin等,(2010)Int J Cancer 126,885-895)。在这种情况中,它们也显示需要Mcl-1下调或失活来使卵巢癌细胞对Bcl-xL-靶向BH3-模拟分子如HA14-1(Simonin等,(2009)Mol Cancer Ther 8,3162-3170)或ABT-737(Simonin等,(2013)Apoptosis 18,492-508)敏感。
Mcl-1含有3个BH结构域(BH1-BH3)但在NH2末端处缺少清楚定义的BH4结构域。Mcl-1通过其COOH末端处的跨膜结构域定位于各种胞内膜,尤其是,线粒体外膜。与Bcl-2和Bcl-xL一样,Mcl-1可与Bax和/或Bak相互作用以抑制线粒体介导的凋亡。与Bcl-2和Bcl-xL不同的是,Mcl-1表达在接触细胞因子或生长因子后被迅速诱导。增加的Mcl-1表达促进了多种肿瘤细胞类型中的细胞活力,包括白血病、肝细胞癌、黑色素瘤、前列腺癌和乳腺癌细胞。此外,在多种癌症中,Mcl-1通过体拷贝数扩增在细胞固定和肿瘤发生中起作用。含Mcl-1扩增的癌细胞通常依赖Mcl-1存活(Beroukhim,R.等,(2010)Nature 463,899-905)。
Mcl-1在包括卵巢癌的多种癌细胞中过表达,并且其表达也与化学抗性相关(Shigemasa等,(2002)Jpn J Cancer Res 93,542-550)。重要的是,Mcl-1基因座是人类癌症中最频繁扩增的基因座之一,这进一步指向其在癌症发生中的中心性并增加了其作为高度有效的治疗靶标的重要性(Beroukhim等,(2010)Nature 463,899-905)。
因此,已经使用目标在于抑制Mcl-1的多种工具来敏化ABT-737,如:
-Mcl-1-靶向siRNA(Lin等,(2007)Oncogene 26,3972-3979),
-Noxa基因转移Wesarg等,(2007)Int J Cancer 121,2387-2394;Lucas等,(2012)Clin Cancer Res 18,783-795),
-信号转导通路抑制(Russo等,(2013)Biochem Pharmacol 85,927-936),或
-常规化疗(Mason等,(2009)Leukemia 23,2034-2041;Simonin等,(2013)Apoptosis 18,492-508)。
这些策略导致对Mcl-1表达本身的抑制,或通过激活其内源性抑制剂,即仅BH3-蛋白质,如Bim、Noxa或Puma导致其抗凋亡活性的间接抑制。如之前证明,基于铂化合物的化疗因此能够在卵巢癌中减少Mcl-1蛋白水平并诱导仅BH3-蛋白质,导致对ABT-737敏化(Simonin等,(2009)Molecular Cancer Therapeutics,8(11),3162-70和Simonin等,(2013)Apoptosis 18,492-508)。然而,这些策略在临床实践中难以应用,部分是由于累积毒性(常规化疗)或体内无效(siRNA,基因疗法),这激励研究者鉴定特异性且强效的Mcl-1抑制剂。
因此,本发明的目的是提供可用于调节,由其抑制Mcl-1活性的替代性化合物。
因此,本发明在一个方面涉及以下结构的各种化合物:
或其药学上可接受的盐形式,其中组分成员如下文定义。
本发明的另一个目的是提供包含本发明的化合物的药物组合物,其中该组合物包含一种或多种药学上可接受的赋形剂和治疗有效量的至少一种本发明的化合物,或其药学上可接受的盐。
本发明的另一个目的是提供式(I)的化合物与Bcl-2或Bcl-xL抑制剂的组合。
本发明的另一个目的是提供用于治疗癌症的式(I)的化合物。
本发明的另一个目的是提供制备式(I)的化合物和可用于制备式(I)的化合物的式(IIa)或(IIb)的具体化合物的方法。
式(I)的化合物的这些和其他目的、特征和优点公开于本发明的以下详述中。
式(I)的化合物
在第一目的中,本发明提供式(I)的化合物:
其中:
Y1,Y2各自独立地选自-S-、-C=C-、-N=C-,前提是当Y1,Y2之一是-S-时,则另一个是-N=C-;
Ar1,Ar2各自独立地选自C6-C10芳基或5-7元杂芳基,所述芳基和杂芳基任选地被1-3个R3基团取代,前提是:
-Ar1,Ar2不能同时表示选自4-吡啶基、未取代的2或3-苯硫基、3,4-二甲氧基苯基或3,4,5-三甲氧基苯基的相同基团,
i和j独立地是0或1,前提是:
-i+j≥1;并且
-当Y1,Y2都不是-S-时,则i+j=2;
R1,R2每次出现时,独立地选自C1-C6烷基、C6-C10芳基、(C6-C10)芳基(C1-C6)烷基、(C6-C10)芳基(C2-C6)烯基、(C6-C10)芳基羰基、(C6-C10)芳基(C1-C6)烷基羰基、C(=O)H、COOH、OH,所述烷基任选地被OH取代;
k和l独立地是0,1;
R3每次出现时,独立地选自C1-C6烷基、C1-C6烷氧基、OH、C(=O)H、(CH2)nCO2H、(CH2)pCN、(CH2)qC(=N(OH))NH2、I、Cl、Br、F、C6-C10芳基、和5-7元杂芳基、(C6-C10)芳基(C1-C6)烷基、(C6-C10)芳基(C2-C6)烯基,所述烷基任选地被OH取代;
n是0,1,2,3;
p是0,1,2,3;
q是0,1,2,3;
排除以下化合物:
2-(吡啶-3-基)-5-(5-(吡啶-3-基)-3-苯乙烯基吡啶-2-基)吡啶
3-(5-甲基-6-(5-甲基-6-(吡啶-3-基)吡啶-3-基)吡啶-3-基)吡啶
3-(6-(5-甲基-6-(吡啶-3-基)吡啶-3-基)吡啶-3-基)吡啶
及其药学上可接受的盐。
在某些方面中,包括式(I)的化合物,其中Y1和Y2都是-N=C-。
在特定方面中,包括式(I)的化合物,其中Ar1,Ar2如上定义,前提是Ar1,Ar2中的至少一个是5-7元杂芳基。
在另一个方面中,包括式(I)的化合物,其中当Y1和Y2都是-N=C-时,Ar1,Ar2中的至少一个是苯基。
在另一个方面中,包括式(I)的化合物,其中Ar1和/或Ar2选自苯基、吡啶基、嘧啶基、咪唑基、吡唑基、苯硫基、三唑基,尤其选自苯基、3-吡啶基、5-嘧啶基、2-咪唑基、3-吡唑基、2-苯硫基、4-三唑基。
在另一个方面中,包括式(I)的化合物,其中Ar1,Ar2中的至少一个是含有氮原子的5-7元杂芳基,优选吡啶基,尤其是3-吡啶基。
在另一个方面中,包括式(I)的化合物,其中Ar1是3-吡啶基或苯基。
在另一个方面中,包括式(I)的化合物,其中Ar2是3-吡啶基或苯基。
在某些方面中,包括式(I)的化合物,其中R1,R2独立地选自C1-C6烷基、(C6-C10)芳基(C2-C6)烯基,优选地选自甲基和苯乙烯基。
在另一个方面中,包括式(I)的化合物,其中R1是5-甲基。
在另一个方面中,包括式(I)的化合物,其中R2是5-苯乙烯基。
在一个优选的方面中,包括式(I)的化合物,其中R1是5-甲基且R2是5-苯乙烯基。
在另一个方面中,包括式(I)的化合物,其中Y1是-S-并且Y2是-N=C-。
在某些方面中,包括式(I)的化合物,其中Ar1是5-7元杂芳基,尤其是吡啶基,更具体是3-吡啶基。
在某些方面中,包括式(I)的化合物,其中Ar1是5-7元杂芳基,尤其是苯硫基,更具体是3-苯硫基。
在另一个方面中,包括式(I)的化合物,其中Ar2是5-7元杂芳基,尤其是吡啶基或苯硫基,更具体是3-吡啶基、2-苯硫基或3-苯硫基。
在其他方面中,包括式(I)的化合物,其中R1选自C1-C6烷基、(C6-C10)芳基(C2-C6)烯基,尤其选自甲基、异丙基或萘基-CH2-。
在其他方面中,包括式(I)的化合物,其中药学上可接受的盐是盐酸盐。
在其他方面中,包括式(I)的化合物,其选自式(Ia)、(Ib)、(Ic)和(Id)的化合物:
其中:
X1,X2,X3每次出现时,独立地选自C或N;
R1,R2,R3每次出现时,独立地如上定义。
在其他方面中,包括式(I)的化合物,其选自:
-5,6’-二(吡啶-3-基)-5′-甲基-3-((E)-苯乙烯基)-2,3′-二吡啶(MR29072)
-5,6”-二(吡啶-3-基)-3,5”-双-((E)-苯乙烯基)-[2,3’;6’,3”]三联吡啶(MR29075)
-3,5”,5”-三甲基-5,6”-二苯基-[2,3’;6’,3”]-三联吡啶(MR30802)
-5’-溴-3’,5-二甲基-6-(3-甲基-4-吡啶-3-基苯基)-3,2’-二吡啶(MR30804)
-5’-(2-甲基-4-吡啶-3-基苯基)-3’,5-二甲基-6-(2-甲基-4-吡啶-3-基苯基)-3,2’-二吡啶(MR30811)
-2-(吡啶-3-基)-5-(3-甲基-4-吡啶-3-基苯基)-(E)苯乙烯基苯(MR 30820)
-3-(4-甲基-5-(吡啶-3-基)噻吩-2-基)吡啶(MR31327)
-3-(4-((萘-3-基)甲基)-5-(吡啶-3-基)噻吩-2-基)吡啶(MR31328)
-3-(4-异丁基-5-(吡啶-3-基)噻吩-2-基)吡啶(MR31330)
-2-(5-甲基-6-(吡啶-3-基)吡啶-3-基)-5-苯基-3-苯乙烯基吡啶(MR31348)
-2-(5-甲基-6-苯基吡啶-3-基)-5-(吡啶-3-基)-3-苯乙烯基吡啶(MR31349)
-5-(3-苄基吡啶-2-基)-2-(5-苄基吡啶-3-基)吡啶(MR31397)
及其药学上可接受的盐。
在优选的方面中,式(I)的化合物是:
-5,6’-二(吡啶-3-基)-5′-甲基-3-((E)-苯乙烯基)-2,3′-二吡啶(MR29072)
及其盐酸盐。
式(I)的化合物的制备方法
本发明的化合物可以本领域技术人员所熟知的多种方法制备,包括,但不限于下述的那些,或通过应用有机合成领域技术人员所知的标志技术对这些方法进行修改。试剂和起始材料市售可得,或易于由本领域普通技术人员熟知的技术合成。除非另有说明,所有的取代基如前所述定义。本发明相关公开的所有过程可考虑以任意规模实施,包括毫克、克、多克或工业规模。
易于理解的是,式I的化合物上存在的功能基团可含有保护基团。保护基团本身已知是可选择性依附官能团并从中去除的化学功能基团,如羟基和羧基。这些基团存在于化学化合物中以赋予这些官能团对化合物接触的化学反应条件的惰性。本发明可采用多种保护基团中的任意。本发明的其他优选保护基团可发现于Greene,T.W.和Wuts,P.G.M.,《有机合成中的保护性基团》(“Protective Groups in Organic Synthesis”),第二版,威利父子公司(Wiley&Sons),1991或P.J.Kocienski,《保护基团》(“Protecting Groups”),第3版,蒂姆出版社(Thieme),纽约州斯图加特,2004。
可通过常规手段从反应混合物中回收如此制备的化合物。例如,化合物可在提取后从溶剂混合物中蒸馏,或者,如果需要,在从溶剂混合物中蒸馏之后,将残留物倒入水中,之后用水不互溶有机溶剂提取并从溶剂混合物中蒸馏。另外,如果需要,产物可通过各种熟知的技术,如重结晶、沉淀或各种色谱技术,尤其是柱色谱或制备型薄层色谱,尤其是高效液相色谱(HPLC)进一步纯化。
在另一个目的中,本发明涉及制备本文所述的式(I)的化合物的方法,包括以下步骤:
i)按照Suzuki-Miyaura偶联法,在钯(Pd0)催化剂和碱存在下使化合物(IIa)与Ar2B(OH)2反应;
其中Y1、Y2、Ar1、Ar2、R1、R2、i、j、k、l如上定义,并且Hal2是I或Br;并且任选地
ii)回收所得的式(I)的化合物。
在其他方面中,按照一定过程制备式(IIa)的化合物,该过程包括以下步骤:
i)按照Suzuki-Miyaura偶联法,在钯(Pd0)催化剂和碱存在下使式(IV)的化合物与硼酸(III)反应;
其中Y1、Y2、Ar1、Ar2、R1、R2、i、j、、k、1如上定义,并且Hal1是I或Br;并且Hal2是C1;并且任选地
ii)回收所得的式(IIa)的化合物。
在另一个目的中,本发明涉及制备上述定义的式(I)的化合物的方法,包括以下步骤:
i)按照Suzuki-Miyaura偶联法,在钯(Pd0)催化剂和碱存在下使化合物(IIb)与Ar2B(OH)2反应;
其中Y1、Y2、Ar1、Ar2、R1、R2、k、1如上定义,Ar1和Ar2相同,并且Hal2是I或Br;并且任选地
ii)回收所得的式(I)的化合物。
可用于制备式(I)的化合物的合成中间体
在其他目的中,本发明涉及式(IIa)的化合物:
其中,
Y1、Y2、Ar1、Ar2、R1、R2、i、j、k、1如上述定义,并且
Hal2是I、Br或Cl。
例如,式(IIa)的化合物可选自:
-2-(6-溴-5-甲基吡啶-3-基)-5-(5-氯-1-甲基-1H-咪唑-2-基)-3-苯乙烯基吡啶(MR31352)
-2-溴-3-甲基-5-(5-(吡啶-3-基)-3-苯乙烯基吡啶-2-基)吡啶(MR31360)
-5-(6-(6-溴-5-甲基吡啶-3-基)-5-苯乙烯基吡啶-3-基)嘧啶(MR31362)
-3-(6-(6-溴-5-甲基吡啶-3-基)-5-苯乙烯基吡啶-3-基)苯酚(MR31377)
-2-(3-(6-(6-溴-5-甲基吡啶-3-基)-5-苯乙烯基吡啶-3-基)苯基)乙腈(MR31380)
在其他目的中,本发明涉及式(IIb)的化合物:
Y1、Y2、Ar1、Ar2、R1、R2、i、j、k、1如上述定义,并且Hal2是I或Br。
例如,式(IIb)的化合物可选自:
-5-溴-2-(6-溴-5-甲基吡啶-3-基)-3-苯乙烯基吡啶(MR29061)
-5-溴-2-(6-碘-5-甲基吡啶-3-基)-3-苯乙烯基吡啶(MR29069)
药物组合物
在另一个目的中,本发明涉及包含式(I)的化合物的药物组合物:
其中,
Y1、Y2、Ar1、Ar2、R1、R2、i、j、k和1如上述定义,
及其药学上可接受的盐,
排除以下化合物:
-2-(吡啶-3-基)-5-(5-(吡啶-3-基)-3-苯乙烯基吡啶-2-基)吡啶
-3-(5-甲基-6-(5-甲基-6-(吡啶-3-基)吡啶-3-基)吡啶-3-基)吡啶
-3-(5-甲基-6-(5-甲基-6-(吡啶-3-基)吡啶-3-基)吡啶-3-基)吡啶,与至少一种药学上可接受的赋形剂或运载体混合。
在一个具体方面中,包括上述定义的药物组合物,其中排除式(I)的以下化合物:
-3,3’-二甲基-2,5”-二吡啶-3-基-[2,5’;2’.5”]三联吡啶
-3,3’,3”-三甲基-2,5”-二吡啶-3-基-[2,5’;2’,5”]三联吡啶
-3,3’,3”,3”’-四甲基-2,5”-二吡啶-3-基-[2,5’;2’,5”;2”,5”’]四联吡啶
-3’,3”,3”’-三甲基-2,5”-二吡啶-3-基-[2,5’;2’,5”;2”,5”’]四联吡啶
在一个具体方面中,包括药物组合物,其中式(I)的化合物如上述定义,前提是:
当Y1,Y2都是N=C,或Y1,Y2之一是N=C并且另一个是C=C,并且Ar1,Ar2都是吡啶基时,则R1,R2中至少一个存在并且不是H或CH3。
在其他方面中,包括药物组合物,还包含Bcl-xL抑制剂,尤其是BH3-模拟抑制剂,如HA 14-1、ABT-737或ABT-263。
对于本领域普通技术人员显而易见的是,所述药物组合物的具体制剂可基于受治疗的癌症类型选择。本发明的组合物可与改善它们的稳定性和/或提供体内控释或缓释的物质配制用于给予患者。
这些组合物可根据药学领域熟知的方法制备,可以各种途径施用,视需要局部或系统性治疗和要治疗的区域而定。
给予可以是局部(包括皮肤、眼部和粘膜,包括鼻内、阴道和直肠递送),肺(例如,通过粉末或气溶胶吸入或吹入,包括通过喷雾器;气管内,鼻内,表皮和透皮),眼部,口服或胃肠外形式。眼部给药的方法包括外用(滴眼剂)、结膜下、眼周、或通过球导管来玻璃体内注射或引入,或手术置于结膜囊内的眼科插入物。胃肠外给药包括静脉内、动脉内、皮下、腹膜内或肌肉内注射或输液;或颅内如鞘内或心室内给药。
通过采用本领域公知的方法,可将药物组合物配制成能够在给予患者后提供活性成分的速释、缓释或延迟释放。
药物组合物通常包含药学上可接受的无机或有机运载体、防腐剂、增溶剂、稳定剂、润湿剂、乳化剂、甜味剂、着色剂、风味剂、用于改变渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂。它们也可含有其他有治疗价值的物质。这些成分根据给药模式和途径选择。合适的药物成分,以及药物配制中使用的药物必要物质描述于《雷明顿药物科学》(Remington′sPharmaceutical Sciences)(E.W.Martin)。
本发明的化合物的治疗剂量可根据,例如,进行治疗的具体应用、化合物的给药方式、患者的健康和病情、以及临床医师的判断变化。在药物组合物中本发明的化合物的比例或浓度可根据许多因素变化,包括剂量、化学性质(例如疏水性)、以及给药途径。
组合
在一些实施方式中,本发明的化合物可与至少一种第二治疗剂结合。
化合物因此可与另一种治疗剂一起给予,如细胞毒剂或癌症化疗剂。并行给予两种或多种治疗剂不需要同时、在相同时间期中或通过同一途径给予药剂,只要这些药剂发挥其疗效的时间期有所重叠即可。考虑同时或依次给药,也考虑在不同日或不同周给药。
可与本发明的化合物一起给予的其他可用治疗剂包括靶向Bcl-2家族的其他成员的药剂。抗-Bcl-2药剂可以是调节Bcl-2活性的任何药剂并且可包括抗-Bcl-2寡核苷酸、抗-Bcl-2抗体和小分子抑制剂。示例性的小分子抑制剂包括棉子酚和棉子酚类似物(例如,AT-101);苯磺酰基衍生物,TW37;阿朴棉子酚衍生物,Sabutoclax;ABT系列化合物,包括ABT-199、ABT-737和口服类似物,ABT-263;Obatoclax;和HA14-1。
本发明优选涉及包含式(I)的化合物与Bcl-xL抑制剂,尤其是BH3-模拟抑制剂,如HA14-1、ABT-737或ABT-263的组合。
用于治疗癌症的式(I)的化合物
本文公开的化合物和组合物一般并且多方面地用于治疗癌症。
因此,在另一目的中,本发明涉及式(I)的化合物,
其中:
Y1、Y2、Ar1、Ar2、R1、R2、i、j、k和1如上述定义,
及其药学上可接受的盐,
其用于治疗癌症,尤其是响应Mcl-1调节的癌症。
适用于本发明的治疗方法的癌症可以是响应Mcl-1调节的癌症;因此,与Mcl-1的误调节(例如,过表达或改变的结合或活性)相关的任意形式的癌症在本发明的范围内。
癌症或肿瘤病症包括,例如,但不限于,乳腺癌,血液癌如骨髓瘤,白血病和淋巴瘤(例如,伯基特淋巴瘤、非霍奇金淋巴瘤、霍奇金淋巴瘤、和急性T细胞白血病),神经肿瘤如脑瘤,例如,胶质瘤,包括星形细胞瘤或胶质母细胞瘤,黑色素瘤,肺癌,头颈癌,甲状腺癌,胃肠瘤如胃癌、结肠或直肠癌,肝癌,胰腺癌,泌尿生殖系统肿瘤如卵巢癌、阴道癌、外阴癌、子宫内膜癌、膀胱癌、肾癌、睾丸癌、前列腺癌、或阴茎癌,骨癌,血管肿瘤,和皮肤癌如基底细胞癌,鳞状细胞癌和黑色素瘤。
优选地,式(I)的化合物可用于治疗血液恶性肿瘤,例如,淋巴瘤、白血病、多发性骨髓瘤;和实体瘤如卵巢癌、间皮瘤、黑色素瘤、胰腺癌、肺癌、乳腺癌、肾癌和肝癌。就对于Bcl-xL靶向策略的响应而言,血液恶性肿瘤已经描述为对Mcl-1成瘾(Dai等,(2007)CancerRes.,67(7),2908-11;Yecies等,(2010)Blood,115(16),3304-13)。
在一个具体方面中,式(I)的化合物与Bcl-xL抑制剂,尤其是BH3-模拟抑制剂一起给予,如:
-2-氨基-6-溴-α-氰基-3-(乙氧基羰基)-4H-1-苯并吡喃-4-乙酸乙酯(也称为HA14-1),
-4-[4-[[2-(4-氯苯基)苯基]甲基]哌嗪-1-基]-N-[4-[[(2R)-4-(二甲基氨基)-1-苯基巯基丁-2-基]氨基]-3-硝基苯基]磺酰基苯甲酰胺(也称为ABT-737)
或
-4-[4-[[2-(4-氯苯基)-5,5-二甲基环己烯-1-基]甲基]哌嗪-1-基]-N-[4-[[(2R)-4-吗啉-4-基-1-苯基巯基丁-2-基]氨基]-3-(三氟甲基磺酰基)苯基]磺酰基苯甲酰胺(也称为ABT-263)。
在另一个方面中,包括式(I)的化合物,其用于诱导Mcl-1蛋白介导的凋亡。
无论何时只要出现临床上有益的结果,则称患者得到有效治疗。这可表示,例如,疾病症状的完全解决,疾病症状严重性下降,或疾病发展减缓。
可向需要治疗的个体给予有效量的本文提供的任意化合物。本文使用的术语“有效”是指患者中诱导所需的响应但不诱导明显毒性的量。这种量可通过评价给予已知量的特定组合物后患者的响应来确定。
治疗对Mcl-1的调节有响应的癌症的方法
本发明还涉及给予组合物以治疗癌症的方法、杀死癌细胞的方法和调节细胞中Mcl-1水平的方法。本文所述的治疗方法可与其他细胞毒性治疗(例如,化疗、激素治疗、放疗和基于抗体的治疗)结合进行。
在优选的实施方式中,本发明的化合物和组合物可用于预防或减少转移或进一步遏制患有Mcl-1表达癌症的患者;更具体地,它们可用于增加这类患者的存活时间,增加这类患者的无进展存活,增加响应持续时间,导致通过测量存活持续时间、无进展存活、响应率或响应持续时间确定的受治疗患者统计上显著并且临床上有意义的改善。在一个优选的实施方式中,该药物可用于增加患者群中的响应率。
在附图和以下描述中详细说明了本发明的一种或多种实施方式。本发明的其他特征、目的和优势通过描述、附图以及权利要求书将是显而易见的。
定义
本文所含的以下数据和表达如下定义:
本文所用术语“烷基”是指具有1-8个碳原子的直链或支链基团,如甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、戊基、异戊基酯、新戊基、1-乙基丙基、3-甲基戊基、2,2-二甲基丁基、2,3-二甲基丁基、己基、辛基等。含烷基基团(如烷氧基和烷氧基羰基)的烷基部分具有与上述定义的烷基相同的含义。优选的低级烷基是上述定义的烷基基团,其含1-4个碳。名称如“C1-C6烷基”是指含1-6个碳原子的烷基。
本文所用术语“烯基”指直链或支链的2-6个碳原子的烃链,其具有至少一个碳碳双键。名称“C2-C6烯基”是指含2-6个碳原子的烯基。烯基的示例包括乙烯基、丙烯基、异丙烯基、2,4-戊二烯基。特别优选“C2-C4烯基”。
本文中所用的术语“烷氧基”指的是烷基-O-基团,其中所述烷基基团如本文所述。示例性的烷氧基包括甲氧基、乙氧基、正丙氧基、异丙氧基、和正丁氧基。
本文所用术语“芳基”指取代或未取代的具有6-16个环碳原子的单环或二环烃芳环系统。示例包括苯基和萘基。
本文所用术语“芳烷基”是指被芳基取代的烷基。芳烷基的示例包括但不限于苄基、溴代苄基、苯乙基、二苯甲基、二苯甲基、三苯甲基、二苯基乙基、萘基甲基。
本文所用术语“芳基烯基”是指被芳基取代的烯基。芳基烯基的示例包括但不限于苯乙烯基。
本文中所用的术语“芳基羰基”指的是芳基-C(=O)-基团,其中所述芳基基团如本文所述。
本文中所用的术语“芳烷基羰基”指的是芳烷基-C(=O)-基团,其中所述芳烷基基团如本文所述。
本文所用术语“杂芳基”是指含5-10个,优选5-7个环碳原子的芳基,其中一个或多个环原子被至少一个杂原子如-O-、-N-、或-S-取代。杂芳基的示例包括吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噻唑基、异噻唑基、异噁唑基、噁唑基、噁硫醇基、噁二唑基、三唑基、噁三唑基、呋咱基、四唑基、吡啶基、吡嗪基、嘧啶基、哒嗪基、三嗪基、吲哚即、异吲哚基、吲唑基、苯并呋喃基、异苯并呋喃基、嘌呤基、喹唑啉基、喹啉基、异喹啉基、苯并咪唑基、苯并噻唑基、苯并苯硫基、硫茚基(thianaphthenyl)、苯并噁唑基、苯并异噁唑基、噌啉、酞嗪基、萘啶基、和喹喔啉基。“杂芳基”的定义内包括稠合环系统,包括,例如,其中芳环与杂环烷基环稠合的环系统。这类稠合的环系统的示例包括,例如,邻苯二甲酰胺、邻苯二甲酸酐、二氢吲哚、异二氢吲哚、四氢异喹啉、苯并二氢吡喃、异苯并二氢吡喃、苯并吡喃、和异苯并吡喃。
本文所用术语“对象”是指恒温动物,如哺乳动物,优选人类或人类儿童,其患有或有可能患有一种或多种本文所述的疾病或病症。
本文所用“治疗有效量”是指有效预防或治疗特定疾病的症状的本发明的化合物的量。这类疾病包括但不限于与本文所述的受体的异常活性相关的病理性和神经性疾病,其中治疗或预防包括通过使受体与本发明的化合物接触来抑制、诱导或增强其活性。
本文中所用的术语“药学上可接受的”是指合理医疗判断范围内的这些化合物、材料、组合物和/或剂型,其适用于接触人体和动物组织、与合理的效益/风险比相适应的、不会产生过度毒性、刺激性、过敏反应或其它问题或并发症。
本发明的说明书中使用的所有其他数据的含义为本领域所熟知。
在另一个方面中,本发明涉及上述化合物的药学上可接受的盐。本文所用的“药学上可接受的盐”包括本发明的化合物的盐,其衍生自这类化合物与无毒性酸或碱加成盐的组合。
酸加成盐包括无机酸如盐酸、氢溴酸、氢碘酸、硫酸、硝酸和磷酸,以及有机酸如乙酸、柠檬酸、丙酸、酒石酸、谷氨酸、水杨酸、草酸、甲磺酸、对甲苯磺酸、琥珀酸和苯甲酸,以及相关的无机和有机酸。
碱加成盐包括衍生自无机碱的那些,如铵和碱金属或碱土金属氢氧化物、碳酸盐、碳酸氢盐等,以及衍生自有机胺的盐,如脂族胺和芳族胺、脂族二胺、羟基氨基醇等。因此,可用于制备本发明的盐的这类碱包括氢氧化铵、碳酸钾、碳酸氢钠、氢氧化钙、甲胺、二乙胺、乙二胺、环己胺、乙醇胺等。
除了药学上可接受的盐以外,本发明包括其他盐。它们可用作化合物纯化、其他盐制备、或化合物或中间体的鉴定和表征中的中间体。
附图说明
图1显示了BRET试验中Pyridoclax和ABT-737对Mcl-1/Puma和Noxa/Mcl-1相互作用的效果(分别是图1A和1B);Pyridoclax能够破坏Mcl-1/Puma和Noxa/Mcl-1相互作用,其中ABT-737不能调整这些相互作用。
图2显示了Pyridoclax单独或与Bcl-xL靶向siRNA(siXL1)组合对IGROV1-R10卵巢癌细胞的效果。在接触25μM Pyridoclax持续24小时(A,B,C,D)或2、4、6小时(E)前用10nMsiRNA转染细胞48小时。[A]细胞形态,DNA含量柱形图和膜联蛋白V/碘化丙啶双参数柱形图。[B]:台盼蓝排除试验。[C]:通过Western印迹评价的Bcl-xL表达以及PARP和胱冬酶3切割。[D]:DAPI染色后研究的核形态学(上部)和通过电子显微镜研究的细胞形态学。[E]:联合Pyridoclax/siXL1(开始接触Pyridoclax后2、4和6小时评价)的短时间效果。细胞形态和DNA含量柱形图(左图)和通过Western印迹评价的PARP和胱冬酶3切割(右图)。
图3显示了Pyridoclax单独或与Bcl-xL靶向siRNA(siXL1)的组合对卵巢癌、肺癌和间皮癌细胞系的效果。在接触25μμM Pyridoclax持续24小时之前用10nM siRNA转染细胞48小时。在卵巢癌细胞[A]和肺癌或间皮癌细胞[B]细胞脱落和DNA柱形图上亚G1部分比例分别通过观察细胞形态和流式细胞术进行。
图4表示Pyridoclax与ABT-737的结合对抗化疗卵巢癌细胞IGROVl-R10(上部)和SKOV3(下部)的效果。细胞同时(A,E)或依次(B)接触25μM Pyridoclax和5μM ABT-737,并且纵向(A、B、E)或24小时后(C、D、F)评价细胞效果。同时接触(A,E)或依次接触(B;24小时Pyridoclax,然后ABT-737)后的[A,B,E]实时细胞活性由阻抗计(xCELLigence科技公司(xCELLigence technology))评价。[C]:24小时同时接触后的细胞形态和DNA含量柱形图。[D和F]:24小时同时接触后的PARP和胱冬酶3切割。
实施例
I.式(I)的化合物的合成
材料和方法如下所述。
材料
市售试剂直接使用而无需额外纯化。在Kofler加热台(Kofler heating bench)上确定熔点。在Perkin Elmer BX FT-IR分光光度计上记录IR光谱。以厘米的倒数(cm-1)给出带位置。在JEOL Lambda 400光谱仪上记录1H NMR(400MHz)和13C NMR(100MHz)。化学位移表示为相对于作为内标的四甲基硅烷低磁场方向的ppm,并且偶联常数表示为赫兹。化学位移报告为相对于溶剂共振的ppm。在使用快速硅胶60Merck(0.063-0.200mm)作为稳定相的柱上进行色谱。通过在0.2mm预包被的硅胶板60F-264(默克公司(Merck))上进行的波层色谱(TCL)确定各纯化的洗脱溶剂并且使用紫外灯观察点。进行对新化合物的元素分析,并且对于所有最终化合物,C、H和N的数据在预定值的±0.4以内。
方法
按照用于从5-溴-2-羟基吡啶1、反式-苯基乙烯基硼酸4和6-溴-5-甲基吡啶-3-基硼酸7获得MR29072的相同过程合成本发明的(杂)芳寡系统((Het)aromaticoligosystem),并且其示于下面的方案1和实施例1中。
方案1
实施例1:5,6’-二(吡啶-3-基)-5′-甲基-3-((E)-苯乙烯基)-2,3′-二吡啶(MR29072)
向5-溴-2-羟基吡啶1(5g,29mmol)中加入乙腈(120mL)中的固体N-碘代琥珀酰亚胺(7.1g,32mmol)。溶液回流搅拌4小时并通过TLC跟踪。溶液冷却至室温,过滤并用甲醇洗涤。获得粉色固体的5-溴-2-羟基-3-碘代吡啶2(产率:83%)。
2(9g,30mmol)溶解在90%苯基膦酰二氯(100mL,0.3mol)中。混合物搅拌并加热(160℃)4小时并通过TLC跟踪。在室温下,在1L充满水的瓶中滴加引入并在0℃下冷却。通过加入NH4OH溶液中和溶液。在乙酸乙酯中萃取该混合物。获得白色固体,5-溴-2-氯-3-碘代吡啶3(产率:82%)。
在氮气氛围中,向含3(5g,15.7mmol)的反应容器(100mL)中加入1,4-二噁烷(100mL)中的碳酸钠(4.2g,39mmol)、反式-苯基乙烯基硼酸4(2.7g,18mmol)、四(三苯基膦)(907mg,0.8mmol)。混合物回流搅拌24小时直至TLC跟踪起始物质被消耗。产物冷却至室温;其在硅藻土上过滤。溶液在MgSO4上干燥、过滤并蒸发。残留物通过色谱(环己烷∶乙酸乙酯=99∶1,然后98∶2)纯化以得到5-溴-2-氯-3-((E)-苯乙烯基)-吡啶5(产率:93%)。
向5(200mg,0.7mmol)中加入碘化钠(1g,6.8mmol)、乙酰氯(0.07mL,1mmol)、和乙腈(10mL)。在100℃下,溶液在微波辐射下搅拌1小时。室温下,用NaHCO3溶液中和混合物。在萃取和用亚硫酸氢钠/水洗涤后,有机层用MgSO4干燥、过滤并蒸发。产物通过色谱(环己烷∶乙酸乙酯=98∶2,然后95∶5)纯化以得到5-溴-2-碘-3-((E)-苯乙烯基)-吡啶6(产率:84%)。
在氮气氛围中向含6(1.4g,3.6mmol)的反应容器(100mL)中加入1,2-二甲氧基乙烷(30mL)中的磷酸钾(2.1g,9mmol)、6-溴-5-甲基吡啶-3-基硼酸7(978mg,4.5mmol)、四(三苯基膦)(210mg,0.18mmol)的。混合物回流搅拌20小时直至TLC跟踪起始物质被消耗。在室温下,用乙酸乙酯萃取溶液。有机层在MgSO4上干燥、过滤并蒸发。残留物通过色谱(环己烷∶乙酸乙酯=95∶5,然后9∶1和8∶2)纯化并得到5,6′-二溴-5′-甲基-3-((E)-苯乙烯基)-2,3′-二吡啶8(产率:86%)。
在氮气氛围中,向含8(320mg,0.7mmol)的反应容器(100mL)中加入1,4-二噁烷(20mL)中的碳酸钠(355mg,3.35mmol)、吡啶-3-基硼酸9(156mg,1.7mmol)、四(三苯基膦)(78mg,0.07mmol)、。混合物回流搅拌24小时直至TLC跟踪消耗起始物质。在室温下,悬浮液在硅藻土上过滤并且用乙酸乙酯萃取溶液。有机层在MgSO4上干燥、过滤并蒸发。产物通过色谱(环己烷∶乙酸乙酯=8∶2,然后7∶3和50∶50)纯化以得到白色固体的5,6’-二(吡啶-3-基)-5′-甲基-3-((E)-苯乙烯基)-2,3′-二吡啶MR29072(产率:86%)(Mp 158℃)。IR(KBr):2957,1727,1575,1274,1125,1014,967,801,770,688em-1.1H NMR(400MHz,CDCl3):δ8.98(d,4J=1.9Hz,1H),8.91(d,4J=1.9Hz,1H),8.87(m,2H),8.72(dd,3J=4.9Hz,4J=1.9Hz,2H),8.68(dd,3J=4.9Hz,4J=1.9Hz,1H),8.24(d,4J=1.9Hz,1H),8.00(m,3H),7.48(d,3J=7.8Hz,3H),7.44(dd,3J=7.8Hz,4J=1.9Hz,1H),7.36(d,3J=7.8Hz,1H),7.31(d,3J=7.8Hz,1H),7.28(d,3J=16.6Hz,1H),7.23(d,3J=16.6Hz,1H),2.51(s,3H).13C NMR(100MHz,CDCl3):δ155.3,153.4,149.9,149.6,149.2,148.2,148.0,146.9,139.8,136.5,136.3,135.8,134.4,134.1,133.1,133.0,132.9,132.6,132.0,131.1,128.8(2C),128.5,126.8(2C),124.6,123.8,123.2,20.0.LCMS(EI):m/z(%)=[M+H]+理论:427.53,实验:427.32.C29H22N4的分析计算值:C,81.67;H,5.20;N,13.14.实际值:C,81.65;H,5.25;N,13.23.
该第一过程应用于以下化合物:3-甲基-5-(3-(E)-苯乙烯基-5-(噻吩-3-基)吡啶-2-基)-2-(噻吩-3-基)吡啶(MR31322)、3-甲基-2-(3-甲基噻吩-2-基)-5-(5-(3-甲基噻吩-2-基)-3-(E)-苯乙烯基吡啶-2-基)吡啶(MR31336)、3-甲基-5-(3-(E)-苯乙烯基-5-(噻吩-2-基)吡啶-2-基)-2-(噻吩-2-基)吡啶(MR31321)、2-(5-甲基-6-(1H-吡唑-5-基)吡啶-3-基)-5-(1H-吡唑-5-基)-3-苯乙烯基吡啶(MR31363)、5-(2-氯-1-甲基-1H-咪唑-5-基)-2-(6-(2-氯-1-甲基-1H-咪唑-5-基)-5-甲基吡啶-3-基)-3-苯乙烯基吡啶(MR31351)、3-甲基-2-(4-氰基苯基)-5-(5-(4-氰基苯基)-3-苯乙烯基吡啶-2-基)吡啶(MR30854)、5-(3,4,5-三甲氧基苯基)-2-(6-(3,4,5-三甲氧基苯基)-5-甲基吡啶-3-基)-3-苯乙烯基吡啶(MR30847)、2-(3,4-二甲氧基苯基)-5-(5-(3,4-二甲氧基苯基)-3-苯乙烯基吡啶-2-基)-3-甲基吡啶(MR30846)、4-(3-甲基-5-(5-(吡啶-4-基)-3-苯乙烯基吡啶-2-基)吡啶-2-基)吡啶(MR31350)、3-甲基-2-苯基-5-(5-苯基-3-苯乙烯基吡啶-2-基)吡啶(MR30814)、5-(3-甲基-5-(5-(嘧啶-5-基)-3-苯乙烯基吡啶-2-基)吡啶-2-基)嘧啶(MR31361)。
从氮气氛围中在反应容器中(100mL)引入的5,6′-二溴-5′-甲基-3-((E)-苯乙烯基)-2,3′-二吡啶8,和1,4-二噁烷(20mL)中的碳酸钠、噻吩-3-硼酸、3-甲基-噻吩-2-硼酸、噻吩-2-硼酸、1-(四氢-2H-吡喃-2-基)-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-吡唑、2-氯-1-甲基-5-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)-1H-咪唑、4-氰基苯基硼酸、3,4,5-三甲氧基苯基硼酸、3,4-二甲氧基苯基硼酸、4-(4,4,5,5-四甲基-1,3,2-二氧杂环戊硼烷-2-基)吡啶、苯硼酸、嘧啶-5-基硼酸、四(三苯基膦)的,我们分别得到MR31322、MR31336、MR31321、MR31363、MR31351、MR30854、MR30847、MR30846、MR31350、MR30814、MR31361。
实施例2:3-甲基-5-(3-(E)-苯乙烯基-5-(噻吩-2-基)吡啶-2-基)-2-(噻吩-2-基)吡啶(MR31321)
1H-NMR(CDCl3)δ8.90(d,1H,H6’,J=1.96Hz),8.73(d,1H,H6,J=1.96Hz),8.18(d,1H,H4’,J=1.96Hz),7.95(d,1H,H4,J=1.96Hz),7.58(d,1H,H3”’,J=3.87Hz),7.49-7.46(m,4H,2H邻Ph,H5”和H5”’),7.43(d,1H,H3”,J=3.87Hz),7.38-7.34(dd,2H间Ph,J=7Hz),7.30(m,1H对Ph,J=7Hz),7.20(s,2H,CH=CH),7.19-7.17(m,2H,H4”和H4”’),2.68(3H,CH3).
MS(EI):437[M+]*.
实施例3:3-甲基-5-(3-(E)-苯乙烯基-5-(噻吩-3-基)吡啶-2-基)-2-(噻吩-3-基)吡啶(MR31321)
1H-NMR(CDCl3)δ8.89(d,1H,H6,J=1.92Hz),8.77(d,1H,H6’,J=1.92Hz),8.21(d,1H,H4,J=1.92Hz),7.96(1H,H4’,J=1.92Hz),7.68-7.66(dd,2H,H5”和H5”’,J=2.92Hz,J=7.4Hz),7.57(d,1H,H对Ph,J=7Hz),7.51(d,2H,H2”和H5”’,J=2.92Hz),7.47(d,2H邻Ph,J=7Hz),7.43-7.41(dd,2H,H4”和H4”’,J=2.92Hz),7.38-7.34(dd,2H间Ph,J=7Hz),7.26-7.21(m,2H,CH=CH),2.68(s,3H,CH3).
MS(EI):437[M+]*.
实施例4:3-甲基-2-(3-甲基噻吩-2-基)-5-(5-(3-甲基噻吩-2-基)-3-(E)-苯乙烯基吡啶-2-基)吡啶(MR31336)
1H-NMR(CDCl3):8.68(d,1H,H6,J=1.92Hz),8.59(d,1H,H6’,J=1.92Hz),8.07(d,1H,H4,J=1.92Hz),7.95(d,1H,H4’,J=1.92Hz),7.52-7.28(m,7H),7.25-7.6.95(m,4H),2.41(s,3H,CH3),2.16(s,3H,CH3),2.03(s,3H,CH3).
MS(EI):466[M++H,100].
实施例5:2-(5-甲基-6-(1H-吡唑-5-基)吡啶-3-基)-5-(1H-吡唑-5-基)-3-苯乙烯基吡啶(MR31363)
1H-NMR(d6-DMSO):δ9.08(d,1H,J=1.7Hz),8.65(d,1H,J=1.7Hz),8.58(d,1H,J=1.7Hz),7.98(d,1H,J=1.6Hz),7.86(d,1H,J=1.5Hz),7.76(bs,1H),7.55(d,2H,J=7.8Hz),7.45(d,1H,CH=CH,J=16.4Hz),7.40-7.36(m,2H),7.31-7.27(m,1H),7.22(d,1H,CH=CH,J=16.4Hz,),7.02(d,1H,J=2.16),6.86(m,1H),6.53(bs,1H),2.65(s,3H,CH3).
MS(EI):405.60[M+]+.
实施例6:5-(2-氯-1-甲基-1H-咪唑-5-基)-2-(6-(2-氯-1-甲基-1H-咪唑-5-基)-5-甲基吡啶-3-基)-3-苯乙烯基吡啶(MR31351)
1H-NMR(CDCl3):δ8.82(d,1H,J=2.2Hz),8,66(d,1H,J=2.2Hz),8.04(d,1H,J=2.2Hz),7.99(d,1H,J=2.2Hz),7.39(d,2H,J=7.3Hz),7.32-7.25(m,3H),7.18(s,1H),7.14(d,1H,J=16Hz),7.12(s,1H),7.10(d,1H,J=16Hz),3.69(s,3H,CH3),3.65(s,3H,CH3),2.47(s,3H,CH3).
MS(EI):501.13[M+]*,503.12[M++2]*,505.32[M++4]*.
实施例7:3-甲基-2-(4-氰基苯基)-5-(5-(4-氰基苯基)-3-苯乙烯基吡啶-2-基)吡啶(MR30854)
1H NMR(400MHz,CDCl3):δ8.88(d,J=2.2,1H,H2′),8.85(d,J=2.2,1H,H6),8.24(d,J=2.2,1H,H4),8.04(d,J=2.2,1H,H4′),7.79(dd,J=8.3,1.9,4H),7.74(dd,J=8.5,2.0,4H),7.45(d,J=8.0,2H,Hstyr),7.35(d,J=8.1,2H,Hstyr),7.31(d,J=7.3,1H,Hstyr),7.17(d,J=16.3,2H,CH=CH),2.49(s,3H,CH3).
实施例8:5-(3,4,5-三甲氧基苯基)-2-(6-(3,4,5-三甲氧基苯基)-5-甲基吡啶-3-基)-3-苯乙烯基吡啶(MR30847)
1H NMR(400MHz,CDCl3):δ8.83(s,1H,H6),8.80(s,1H,H2′),8.16(s,1H,H4),7.99(s,1H,H4′),7.49(d,J=7.1,2H,Hstyr),7.35(dd,J=7.6,6.8,2H,Hstyr),7.31(d,J=7.3,1H,Hstyr),7.28(d,J=15.6,1H,CH=CH),7,21(d,J=15.6,1H,CH=CH),6.86(s,2H),6,84(s,2H),3.99(s,6H,CH3O-间),3,93(s,3H,CH3O-对),3,91(s,6H,CH3O-间’),3,82(s,3H,CH3O-对’),2,50(s,3H,CH3).
实施例9:2-(3,4-二甲氧基苯基)-5-(5-(3,4-二甲氧基苯基)-3-苯乙烯基吡啶-2-基)-3-甲基吡啶(MR30846)
1H NMR(400MHz,CDCl3):δ8.84(s,1H,H6),8.80(s,1H,H2′),8.17(s,1H,H4),7.98(s,1H,H4′),7.48(d,J=6.8,2H,Hstyr),7.36(dd,J=7.8,7.1,2H,Hstyr),7.30(d,J=8.3,1H,Hstyr),7.28(d,J=16.4,1H,CH=CH),7,27-7.21(m,4H),7.18(d,J=15.9,1H,CH=CH),7.04(d,J=8.3,1H),6.98(d,J=8.3,1H),4.01(s,3H,CH3O-间’),3,97(s,9H),2,50(s,3H,CH3).
实施例10:4-(3-甲基-5-(5-(吡啶-4-基)-3-苯乙烯基吡啶-2-基)吡啶-2-基)吡啶(MR31350)
1H-NMR(CDCl3):δ8.85(d,1H,J=2.2Hz),8,80(d,1H,J=1.9Hz),8.73-8.71(dd,2H,J=1.7Hz,J=4.5Hz),8.70-8.68(dd,2H,J=1.7Hz,J=4.5Hz),8.21(d,1H,J=2.2Hz),7.97(d,1H,J=1.9Hz),7.58-7.57(dd,2H,J=1.7Hz,J=4.5Hz),7.48-7.47(dd,2H,J=1.7Hz,J=4.5Hz),7.41(d,2H,J=6.8Hz),7.32-7.29(m,2H),7.26-7.25(m,1H),7.23-7.16(m,2H,CH=CH),2.43(s,3H,CH3).
MS(EI):427.37[M+]+
实施例11:3-甲基-2-苯基-5-(5-苯基-3-苯乙烯基吡啶-2-基)吡啶(MR30814)
13C NMR(100MHz,CDCl3):δ158.4,153.1,146.9,146.2,140.3,139.7,137.5,136.8,135.9,133.3,132.5(2C),131.7,130.6,129.3(2C),129.2(2C),128.8(2C),128.3(2C),128.2(2C),128.1,127.2(2C),126.8(2C),125.4,20.1.
LCMS(ESI)(m/z):424.55;[M+H+]425.27.
实施例12:5-(3-甲基-5-(5-(嘧啶-5-基)-3-苯乙烯基吡啶-2-基)吡啶-2-基)嘧啶(MR31361)
1H-NMR(CDCl3):δ9.33(s,1H),9.30(s,1H),9.10(s,2H),9.07(s,2H),8.90(d,1H,J=1.9Hz),8.88(d,1HJ=2.2Hz),8.25(d,1H,J=2.2Hz),8.07(d,1H,J=1.9Hz),7.48(d,2H,J=7Hz),7.40-7.32(m,3H),7.27(d,1H,J=16Hz,CH=CH),7.22(d,1H,J=16Hz,CH=CH),2.53(s,3H,CH3).
MS(EI):429.58[M+]*.
第二和第三过程(方案2)应用于以下化合物:3-甲基-5-(5-苯基-3-苯乙烯基吡啶-2-基)-2-(吡啶-3-基)吡啶(MR31348)、3-(6-(5-甲基-6-苯基吡啶-3-基)-5-苯乙烯基吡啶-3-基)吡啶(MR31349)、3-(3-甲基-5-(5-(吡啶-3-基)-3-苯乙烯基吡啶-2-基)吡啶-2-基)苯酚(MR31364)、3-(3-甲基-5-(5-(吡啶-3-基)-3-苯乙烯基吡啶-2-基)吡啶-2-基)苯酚(MR31366)、(1Z)-N′-羟基-2-(3-(3-甲基-5-(5-(吡啶-3-基)-3-苯乙烯基吡啶-2-基)吡啶-2-基)苯基)乙脒(MR31367)、5-(3,4-二甲氧基苯基)-2-(6-(3,4,5-三甲氧基苯基)-5-甲基吡啶-3-基)-3-苯乙烯基吡啶(MR30849)、5-(3,4,5-三甲氧基苯基)-2-(6-(3,4-二甲氧基苯基)-5-甲基吡啶-3-基)-3-苯乙烯基吡啶(MR30850)。
方案2
实施例13:5-(3,4,5-三甲氧基苯基)-2-(6-(3,4-二甲氧基苯基)-5-甲基吡啶-3-基)-3-苯乙烯基吡啶(MR30850)
1H NMR(400MHz,CDCl3):δ8.83(d,J=2.2,1H,H6),8.80(d,J=2.2,1H,H2′),8.16(d,J=2.4,1H,H4),7.98(d,J=1.7,1H,H4′),7.49(d,J=7.1,2H,Ha),7.36(dd,J=7,6,7.1,2H,Hb),7.30(d,J=6.8,1H,Hc),7.21(d,J=17.8,1H,CH=CH),7.20(d,J=17.8,1H,CH=CH),7.20(d,J=8.3,1H),7.19(d,J=8.0,1H),6.98(d,J=8.3,1H),6.86(s,2H),3.99(s,6H),3.97(s,3H),3.96(s,3H),3.94(s,3H),2.50(s,3H,CH3).
实施例14:5-(3,4-二甲氧基苯基)-2-(6-(3,4,5-三甲氧基苯基)-5-甲基吡啶-3-基)-3-苯乙烯基吡啶(MR30849)
1H NMR(400MHz,CDCl3):δ8.84(d,J=2.2,1H,H6),8.79(d,J=2.2,1H,H2′),8.17(d,J=2.2,1H,H4),7.99(d,J=2.0,1H,H4′),7.48(d,J=7.3,2H,Hstyr),7.35(dd,J=7.8,6.8,2H,Hstyr),7.30(d,J=7.1,1H,Hstyr),7.27(d,J=2.2,1H),7.27(d,J=16,1H,CH=CH),7.23(d,J=16.2,1H,CH=CH),7.19(d,J=2.2,1H),6.84(s,3H),4.01(s,3H),3.97(s,3H),3.93(s,6H),3.91(s,3H),2.50(s,3H,CH3).
实施例15:(1Z)-N′-羟基-2-(3-(3-甲基-5-(5-(吡啶-3-基)-3-苯乙烯基吡啶-2-基)吡啶-2-基)苯基)乙脒(MR31367)
1H-NMR(CDCl3):δ8.98(d,1H,J=1.96Hz),8.87(d,1H,J=2.2Hz),8.82(d,1H,J=2.2Hz),8.72(d,1H,J=1.96Hz),8.24(d,1H,J=2.2Hz),8.02-8.00(m,2H),7.55-7.43(m,7H),7.36-7.20(m,4H),4.58(bs,1H,NH2),3.56(s,2H,CH2),2.46(s,3H,CH3).
MS(EI):498.55[M+]+
实施例16:3-(3-甲基-5-(5-(吡啶-3-基)-3-苯乙烯基吡啶-2-基)吡啶-2-基)苯酚(MR31366)
1H-NMR(CD3OD):δ10.5(bs,1H,COOH),9.02(d,1H,J=1.96Hz),8.90(d,1H,J=2.2Hz),8.68(d,1H,J=2.2Hz),8.66-8.64(dd,1H,J=1.2Hz,J=4.6Hz),8.56(d,1H,J=2.2Hz),8.33-8.31(dd,1H,J=1.3Hz,J=4.6Hz),8.07(d,1H,J=2.2Hz),7.63-7.62(m,1H),7.53-7.48(m,5H),7.37-7.33(m,2H),7.29-7.21(m,2H),3.71(s,2H,CH2),2.44(s,3H,CH3).
MS(EI):484.54[M+]+
实施例17:3-(3-甲基-5-(5-(吡啶-3-基)-3-苯乙烯基吡啶-2-基)吡啶-2-基)苯酚(MR31364)
1H-NMR(CDCl3):δ8.98(d,1H,J=1.96Hz),8.86(d,1H,J=1.96Hz),8.78(d,1H,J=1.96Hz),8.72-8.71(m,1H)8.26(d,1H,J=2.2Hz),8.03-7.99(m,3H),7.51-7.46(m,3H),7.35-7.32(m,2H),7.31-7.20(m,4H),7.07(d,1H,J=7.56Hz),6.93(s,1H),6-84-6.81(dd,1H,J=1.6Hz,J=7.56Hz),2.45(s,CH3),1.77(bs,1H,OH)
MS(EI):442.41[M+]*
实施例18:3-(6-(5-甲基-6-苯基吡啶-3-基)-5-苯乙烯基吡啶-3-基)吡啶(MR31349)
1H-NMR(CDCl3):δ8.90(d,1H,J=1.9Hz),8,79(d,1H,J=2.2Hz),8.75(d,1H,J=2.2Hz),8.64-8.62(dd,1H,J=1.2Hz,J=4.7Hz),8.15(d,1H,J=2.2Hz),7.94-7.91(m,2H),7.55(d,2H,J=7Hz),7.44-7.33(m,6H),7.29-7.26(m,2H),7.23-7.19(m,2H),7.14(d,1H,J=16Hz,CH=CH),2.42(s,3H,CH3).
MS(EI):426.42[M+]*
实施例19:3-甲基-5-(5-苯基-3-苯乙烯基吡啶-2-基)-2-(吡啶-3-基)吡啶(MR31348)
1H-NMR(CDCl3):δ8.90(d,1H,J=1.9Hz),8,88(d,1H,J=2.2Hz),8.86(d,1H,J=1.9Hz),8.68-8.67(dd,1H,J=1.7Hz,J=4.8Hz),8.24(d,1H,J=1.9Hz),8.03(d,1H,J=1.7Hz),7.98-7.97(m,1H),7.72(d,2H,J=8.3Hz),7.57-7.53(m,2H),7.49-7.46(m,4H),7.38-7.34(m,2H),7.31-7.29(m,1H),7.27(d,1H,J=16.6Hz),7.22(d,1H,J=16.6Hz),2.50(s,3H,CH3).
MS(EI):426.58[M+]*
II.式(I)的化合物的生物活性
II.A.材料和方法
测试的化合物
(杂)芳寡系统如实施例I所述合成并通过色谱(使用快速硅胶60Merck[0.063-0.200mm]作为稳定相的柱)纯化。
ABT-737获自Selleckchem(美国得克萨斯州休斯顿)并且二甲亚砜(DMSO)获自西格玛-奥德里奇公司(Sigma-Aldrich)(法国圣屈昂坦法拉维耶(Saint-QuentinFallavier))。
这些化合物通常在-20℃下储存在DMSO中的母液中。
细胞培养
从人卵巢腺癌中建立人卵巢癌OAW42细胞系并且获自ECACC(法国圣屈昂坦法拉维耶的西格玛-奥德里奇公司)。其在补充4500mg/l葡萄糖、2mM Glutamax、1mM丙酮酸钠、10%胎牛血清、33mM碳酸氢钠(法国里昂的吉布可BRL公司(Gibco BRL))和20IU/l重组人胰岛素(法国苏雷斯尼(Suresnes)的礼来公司(Lilly))的DMEM培养基中生长。
人卵巢癌SKOV3细胞系从人卵巢腺癌中建立并获自美国典型培养物保藏中心(美国弗吉尼亚州玛纳萨斯),人恶性间皮瘤细胞系NCI-H28和人肺癌细胞系A549也是如此。
由J.Bénard博士(法国维勒瑞夫的G鲁西研究所(Institut G.Roussy,Villejuif))友情提供IGROV1细胞系。这些细胞系在补充2mM GlutamaxTM,25mM HEPES,10%胎牛血清和33mM碳酸氢钠的RPMI1640培养基(法国伊尔基希的费舍尔科学公司(Fisher Scientific,Illkirch))中生长。
之前通过模拟顺铂给药的临床方案获得IGROV1(IGROV1-R10)和OVW42(OAW42-R)细胞系的体外抗化疗模型(Poulain等,(1998)Int J Cancer 78,454-463;Villedieu等,(2007)Gynecol Oncol.105(1),31-44)。
细胞保持在37℃下的5%CO2湿润气氛中并且通过胰蛋白酶处理每周分配2次。
处理
如下所述,用siRNA转染指数生长的细胞,并且在48小时后,细胞连续接触DMSO中溶解(<0.1%总体积)的(杂)芳基寡系统(10,25或50μM)另外持续4-24小时。
基因沉默
siRNA由欧基公司(Eurogentec)(比利时列日(Liege,Belgium))合成并退火。引物如下:
Bcl-xL siRNA反义(siXL1):5’-auuggugagucggaucgcatt-3’(SEQ.ID.N1);
Mcl-1 siRNA(siMCL1):5’-gugccuuuguggcuaaacatt-3’(SEQ.ID.N2);
对照siRNA(siCONT):5’-gacguaaacggccacaagutt-3’(SEQ.ID.N 3)。
对照siRNA不含与相关人基因的任何同源性。细胞在前一天接种在25cm2烧瓶中以在转染时达到30-50%融合。向在血清减少培养基(法国蓬多瓦兹的英杰公司(Invitrogen,Cergy-Pontoise))中稀释的siRNA中加入转染INTERFERinTM试剂(法国斯特拉斯堡的Polyplus转染公司(Polyplus Transfection,Strasbourg)),并且在室温下进行复合物形成持续15分钟,然后施加至细胞。烧瓶中的最终siRNA浓度为20nM。
BRET试验
Hela细胞接种在6-孔板上并用200ng/孔的编码BRET供体质粒的pRLuc-Bax、pRLuc-Puma或pRLuc-Noxa和1μg/孔的编码BRET受体的peYFP-Bcl-xL或peYFP-Mcl-1转染(或用pCMV-Bcl-xL或pCMV-Mcl-1转染作为对照)。转染后24小时,细胞用胰蛋白酶消化并且重新接种到96孔平板底部,再孵育一天,然后用10μM的药物处理16小时。在加入终浓度5μM的复立玛津H(Uptima公司)、荧光素酶底物之后,用Mithras荧光-发光检测器LB 940(伯赫公司(Berthold))连续测量485nm和530nm处的光发射。如所述计算BRET比率(Terrillon等,(2003)Mol Endocrinol 17,677-691,Vo等,(2012)Eur J Med Chem,286-93)。
实时细胞活性试验
使用实时细胞分析仪多板(RTCA MP)设备、xCELLigence系统(德国曼海姆的罗氏应用科学公司(Roche Applied Science,Mannheim))来监测化合物介导的细胞毒性。该系统实时监测细胞事件,测量跨在组织培养E-板观测物(E-plage View)(罗氏公司(Roche))上相间错杂的的微电极的阻抗。与电极传感器粘附的细胞的数量和尺寸增加导致阻抗增加,从而驱使在图上显示细胞指数值(CI)。因此,该指数反映了Ke等所述的细胞活力变化(2011,Methods Mol Biol 740,33-43)。简言之,以3x103个细胞/孔接种96-孔E-板并且置于位于组织培养孵育器内的RTCA MP上,其中细胞在处理之前生长24小时。连续测量阻抗直至处理结束。用RTCA软件分析孔重复物的标准偏差。
凋亡试验
通过用DAPI的核染色的凋亡细胞的形态表征
处理后,脱落和粘附的细胞在胰蛋白酶处理后收集、通过细胞离心施加到聚赖氨酸包被的玻璃载玻片,并且用乙醇/氯仿/乙酸(6∶3∶1)的溶液固定。然后,制备物在室温下用1μg/ml DAPI溶液(德国曼海姆的宝灵曼-罗氏公司(Boehringer Mannheim-Roche))孵育15分钟,在蒸馏水中洗涤,在盖玻片下在Mowiol(卡巴开公司(Calbiochem))中固定并且在荧光显微镜(BX51,法国伦吉斯的奥林巴斯公司(Olympus,Rungis))下分析。
通过流式细胞术的细胞周期分析
收集粘附和浮游细胞,用1XPBS洗涤并在200g下离心5分钟,之后用膜联蛋白V,碘化丙啶或两者同时染色,如生产商(美国印第安纳波利斯的罗氏诊断公司(RocheDiagnostic,Indianapolis))所推荐。简言之,100μl的膜联蛋白V-FITC或碘化丙啶或两者同时加到细胞团块(106个细胞)上并在室温下静置孵育15分钟。然后向悬浮液上加入500μl的样品缓冲液,其之后使用Gallios流式细胞仪(法国鲁瓦西的贝克曼库尔特公司(BeckmanCoulter,Roissy))分析,并且使用Kaluza采集软件(贝克曼库尔特公司)确定细胞周期分布。
细胞提取物的制备和Western印迹分析
细胞用冰冷PBS冲洗,在裂解缓冲液(RIPA:NaCl 150mM,Tris(pH8)50mM,曲通X1001%,PMSF 4mM,EDTA 5mM,NaF 10mM,NaPPi10mM,Na3OV41mM,抑肽酶0.5μl/ml和4.6ml超纯水)中悬浮并在冰上孵育30分钟。离心(13200g,10分钟,4℃)后收集裂解液并且使用Bradford试验(美国赫尔克里斯的伯乐公司(Bio-Rad,Hercules))测定蛋白质浓度。20μg蛋白质通过4-12%梯度聚丙烯酰胺凝胶(法国蓬多瓦兹的英杰公司)上的SDS-PAGE分离并且转移至Hybond-PVDF膜(法国奥尔赛的安玛西亚公司(Amersham,Orsay))。在室温下用含5%(w/v)脱脂奶粉的含0.1%(v/v)吐温20的TBS(T-TBS)封闭非特异性结合位点1小时后,膜用以下兔单克隆抗体在4℃下孵育过夜:PARP,胱冬酶-3和Bcl-xL,Bim(法国圣康丁市的细胞信号转导技术公司(Cell Signaling Technology,Ozyme,Saint-Quentin-en-Yvelines)),Mcl-1(法国Le Perray-en-Yvelines的圣克鲁兹公司(Santa Cruz,Le Perray-en-Yvelines)),HSP-70,Noxa(法国Fontenay-sous-Bois的卡巴开公司(Calbiochem,Fontenay-sous-Bois)),(细胞信号转导)和肌动蛋白(法国圣康丁市的西格玛-奥德里奇公司(Sigma-Aldrich,Saint-Quentin Fallavier))。膜然后用T-TBS洗涤并用合适的辣根过氧化物酶偶联的抗-兔或抗-小鼠二抗(法国奥尔赛的安玛西亚公司(Amersham,Orsay))孵育1小时。使用荧光图像分析仪(法国奥尔赛的GE医疗公司(GE Healthcare,Orsay))来进行解析。
透射电子显微术
细胞用含2.5%戊二醛的PBS缓冲液固定,包含在琼脂中,并在Sorensen缓冲液中漂洗,在含1%四氧化锇的Sorensen缓冲液中后固定,并包埋在EPON树脂中。切下超薄切片并用乙酸铀酰和柠檬酸铅染色,并用JEOL1011透射电子显微镜检查。
II.B.结果
II.B.1.Pyridoclax(MR29072)的活性
Pyridoclax扰乱Mcl-1/Puma相互作用
如图1A和1B所示,Pyridoclax能够在Hela细胞中进行的细胞试验(BRET)中扰乱Mcl-1/Puma和Mcl-1/Noxa相互作用。ABT-737不能改变该相互作用,但Pyridoclax诱导对Mcl-1/Puma相互作用的强烈抑制(约50%)。
Pyridoclax作为单一药剂或与siRNA-介-导的Bcl-x
L
抑制联合的效果
为了证明对Pyridoclax作为Mcl-1抑制剂的兴趣,使用对Bcl-xL和Mcl-1选择性成瘾的模型,其中在接触前48小时通过RNA干扰使Bcl-xL表达沉默。选择卵巢癌细胞系IGROV1-R10来进行这些试验,因为之前已经证明该细胞系对Bcl-xL和Mcl-1的共同抑制高度敏感(Brotin等,(2010)Int J Cancer 126,885-895),但在仅抑制这些靶标之一时保留活性。
如预期那样,Pyridoclax或Bcl-xL靶向siRNA(siXL1)本身都没有诱导大量细胞死亡。观察到减缓的增殖,但是在这些情况中没有观察到细胞脱落,或强亚G1峰,胱冬酶3激活以及收缩或片段化的核(图2A、B、C)。
相反,它们的联合导致大量细胞死亡,如强细胞脱落,在DNA含量柱形图上出现强亚G1峰(超过50%)和擦后果60%比例的膜联蛋白V阳性细胞所证明(图2A)。此外,活性评价显示,这种联合导致活细胞数量的显著减少以及死亡细胞的同时增加(图2B),并且Western印迹显示PARP和胱冬酶3的完全切割。DAPI染色和电子显微术显示,这种联合导致核收缩和片段化(仅在2种药剂组合时),高度激发凋亡性细胞死亡(图2D)。
这些效果在接触5μM的Pyridoclax之后最优,但是也在响应10μM中以较低程度观察到(数据未显示)。
这种组合效果的动力学研究显示,在开始接触后2-4小时就观察到凋亡(4小时后37%的亚G1事件比例),这一观察与通过BH3-模拟活性的药理学Mcl-1抑制相符(图2E)。
综上,这些元素显示Pyridoclax使卵巢癌抗化疗IGROV1-R10细胞对Bcl-xL靶向siRNA强烈敏化,它们的组合导致大量凋亡。
Pyridoclax使各种癌细胞类型对Bcl-x
L
靶向siRNA敏化
已经研究了Pyridoclax与siXL1的组合在其他卵巢癌细胞系(图3A)和其他癌细胞类型(图3B)中的效果。
在所有的卵巢癌细胞系,以及肺癌(A549)和间皮瘤(NCI-H28和MSTO-211H)细胞系中都观察到对这种联合的类似响应。
Pvridoclax使抗化疗卵巢癌细胞系对ABT-737敏化
ABT-737仍然是最强效的Bcl-xL抑制BH3-模拟分子之一,并且通过抑制Mcl-1调节对卵巢癌细胞的响应,已经观察到ABT-737与Pyridoclax的组合的效果(图4)。如之前与siXL1所述,观察到作为单一药剂的ABT-737或Pyridoclax都没有诱导细胞死亡,而它们的组合在IGROV1-R10和SKOV3抗化疗卵巢癌细胞系中导致大量凋亡性细胞死亡。事实上,如通过阻抗(xCELLigence科技公司)评价,当组合2种分子时,细胞活性在2种细胞系中都明显下降(图4A和4D);此外,观察到强细胞脱离和重要的亚G1分数(图4B)以及完全PRAP和胱冬酶3切割(图4C和4D右图)。应注意到这些效果在同时接触实验和依次接触(Pyridoclax 24小时,然后ABT-737)中相似。此外,在细胞刚一接触Pyridoclax和ABT-737时观察到的凋亡是类似中间体,表明有利于BH3-模拟活性。
II.B.2.本发明的其他化合物的活性
已经测试了基于它们在BRET试验中扰乱Mcl-1/Puma相互作用的能力选择的化合物在细胞形态、细胞周期、PRAP切割和核形态上的活性,结果示于下表I:
表I
不同标准评价:
细胞脱离:
“-”表示未处理的细胞和用测试化合物处理的细胞之间没有差异;
“±”表示几乎没有细胞从支持物上脱离(少于10%);
“+”表示约20%的细胞从支持物上脱离;
“++”表示约一半的细胞从支持物上脱离;
“+++”表示约大部分细胞从支持物上脱离。
PRAP切割:
“+”表示在Western印迹上可观察到从PRAP切下的对应于85kDa的小条带。当细胞未受处理时,该条带通常缺失或弱,因此可观察到的唯一条带是110kDa条带;
“++”表示在Western印迹上可清楚地观察到从PRAP切下的对应于85kDa的条带。未切割的条带(110kDa)通常与切割的条带共存;
“+++”表示PRAP几乎完全被切割。100kDa条带通常已经消失以促使85kDa形式形成。
凋亡性核特征:
“+”表示在DAPI染色后观察到一些收缩或片段化的核;
“++”表示在DAPI染色后观察到多个收缩或片段化的核(20-50%);
“+++”表示大多数核收缩或片段化。
Claims (18)
1.一种药物组合物,其包含式(I)的化合物:
其中:
Y1,Y2是-N=C-;
Ar1,Ar2各自独立地选自C6-C10芳基或5-7元杂芳基,所述芳基和杂芳基任选地被1-3个R3基团取代,前提是:
Ar1,Ar2不能同时相同地表示4-吡啶基、未取代的2或3-苯硫基、或3,4-二甲氧基苯基或3,4,5-三甲氧基苯基,
i和j独立地是0或1,前提是:
-i+j≥1;并且
-当Y1,Y2都不是-S-时,则i+j=2;
并且
R1,R2每次出现时,独立地选自C1-C6烷基、C6-C10芳基、(C6-C10)芳基(C1-C6)烷基、(C6-C10)芳基(C2-C6)烯基、(C6-C10)芳基羰基、(C6-C10)芳基(C1-C6)烷基羰基、C(=O)H、COOH、OH,所述烷基任选地被OH取代;
k和l独立地是0,1;
R3每次出现时,独立地选自C1-C6烷基、C1-C6烷氧基、OH、C(=O)H、(CH2)nCO2H、(CH2)pCN、(CH2)qC(=N(OH))NH2、I、Cl、Br、F、C6-C10芳基、和5-7元杂芳基、(C6-C10)芳基(C1-C6)烷基、(C6-C10)芳基(C2-C6)烯基,所述烷基任选地被OH取代;
n是0,1,2,3;
p是0,1,2,3;
q是0,1,2,3;
排除以下化合物:
2-(吡啶-3-基)-5-(5-(吡啶-3-基)-3-苯乙烯基吡啶-2-基)吡啶
3-(5-甲基-6-(5-甲基-6-(吡啶-3-基)吡啶-3-基)吡啶-3-基)吡啶
3-(6-(5-甲基-6-(吡啶-3-基)吡啶-3-基)吡啶-3-基)吡啶
及其药学上可接受的盐,与至少一种药学上可接受的赋形剂或运载体混合。
2.如权利要求1所述的药物组合物,其特征在于,Ar1和/或Ar2选自苯基、吡啶基、嘧啶基、咪唑基、吡唑基、苯硫基、三唑基,尤其选自苯基、3-吡啶基、5-嘧啶基、2-咪唑基、3-吡唑基、2-苯硫基、5-三唑基。
3.如权利要求2所述的药物组合物,其特征在于,Ar1,Ar2中的至少一个是含有氮原子的5-7元杂芳基,优选吡啶基,尤其是3-吡啶基。
4.如权利要求2或3所述的药物组合物,其特征在于,Ar1是3-吡啶基或苯基。
5.如权利要求2-4中任一项所述的药物组合物,其特征在于,Ar2是3-吡啶基或苯基。
6.如权利要求1-5中任一项所述的药物组合物,其特征在于,R1,R2独立地选自C1-C6烷基、(C6-C10)芳基(C2-C6)烯基,优选地选自甲基和苯乙烯基。
7.如权利要求1-6中任一项所述的药物组合物,其特征在于,R1是5-甲基。
8.如权利要求1-7中任一项所述的药物组合物,其特征在于,R2是5-苯乙烯基。
9.如权利要求1-8中任一项所述的药物组合物,其选自式(Ia)的化合物:
其中:
X1,X2每次出现时,独立地选自C或N;
R1,R2,R3每次出现时如权利要求1-8中任一项定义。
10.如权利要求1-9中任一项所述的药物组合物,其中式(I)的化合物选自:
-5,6’-二(吡啶-3-基)-5′-甲基-3-((E)-苯乙烯基)-2,3′-二吡啶
-5,6”-二(吡啶-3-基)-3,5”-双-((E)-苯乙烯基)-[2,3’;6’,3”]三联吡啶
-3,5”,5”-三甲基-5,6”-二苯基-[2,3’;6’,3”]-三联吡啶
-5’-溴-3’,5-二甲基-6-(3-甲基-4-吡啶-3-基苯基)-3,2’-二吡啶
-5’-(2-甲基-4-吡啶-3-基苯基)-3’,5-二甲基-6-(2-甲基-4-吡啶-3-基苯基)-3,2’-二吡啶
-2-(5-甲基-6-(吡啶-3-基)吡啶-3-基)-5-苯基-3-苯乙烯基吡啶
-2-(5-甲基-6-苯基吡啶-3-基)-5-(吡啶-3-基)-3-苯乙烯基吡啶
-5-(3-苄基吡啶-2-基)-2-(5-苄基吡啶-3-基)吡啶。
11.如权利要求1-10中任一项所述的药物组合物,其特征在于,所述组合物还包含Bcl-XL抑制剂,尤其是BH3-模拟抑制剂,如2-氨基-6-溴-α-氰基-3-(乙氧基羰基)-4H-1-苯并吡喃-4-乙酸乙酯(HA 14-1)或4-[4-[[2-(4-氯苯基)苯基]甲基]哌嗪-1-基]-N-[4-[[(2R)-4-(二甲基氨基)-1-苯基巯基丁-2-基]氨基]-3-硝基苯基]磺酰基苯甲酰胺(ABT-737)。
12.一种组合,包含权利要求1-10中任一项所述的式(I)的化合物,其联合Bcl-XL抑制剂,尤其是BH3-模拟抑制剂,如HA 14-1或ABT-737。
13.如权利要求1-10中任一项所述的式(I)的化合物,其用于治疗癌症,尤其是血液恶性肿瘤,如淋巴瘤、白血病、多发性骨髓瘤,和/或实体瘤如卵巢癌、间皮瘤、黑色素瘤、胰腺癌、肺癌、乳腺癌、肾癌和肝癌。
14.如权利要求13所述用途的式(I)的化合物,其特征在于,所述式(I)的化合物与Bcl-XL抑制剂,尤其是BH3-模拟抑制剂,如2-氨基-6-溴-α-氰基-3-(乙氧基羰基)-4H-1-苯并吡喃-4-乙酸乙酯(HA 14-1)、4-[4-[[2-(4-氯苯基)苯基]甲基]哌嗪-1-基]-N-[4-[[(2R)-4-(二甲基氨基)-1-苯基巯基丁-2-基]氨基]-3-硝基苯基]磺酰基苯甲酰胺(ABT-737)或4-[4-[[2-(4-氯苯基)-5,5-二甲基环己烯-1-基]甲基]哌嗪-1-基]-N-[4-[[(2R)-4-吗啉-4-基-1-苯基巯基丁-2-基]氨基]-3-(三氟甲基磺酰基)苯基]磺酰基苯甲酰胺(ABT-263)一起给予。
15.如权利要求13或14中任一项所述的式(I)的化合物,其用于诱导由Mcl-1蛋白介导的凋亡。
16.一种式(I)的化合物:
其中:
Y1、Y2、Ar1、Ar2、R1、R2、i、j、k、l如权利要求1所定义,
前提是,当k=l=1时:
-则R1,R2中的至少一个不是H;并且
-如果R1,R2之一是CH3,则另一个不是H或CH3,
排除以下化合物:
2-(吡啶-3-基)-5-(5-(吡啶-3-基)-3-苯乙烯基吡啶-2-基)吡啶
-3-(5-甲基-6-(5-甲基-6-(吡啶-3-基)吡啶-3-基)吡啶-3-基)吡啶
-3-(6-(5-甲基-6-(吡啶-3-基)吡啶-3-基)吡啶-3-基)吡啶
及其药学上可接受的盐。
17.如权利要求16所述的式(I)的化合物,其特征在于R1之一是甲基并且R2是苯乙烯基。
18.如权利要求17所述的式(I)的化合物,其特征在于,R1是5-甲基并且R2是5-苯乙烯基。
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ES2739508T3 (es) | 2020-01-31 |
PT3114119T (pt) | 2019-07-30 |
CA2940504C (en) | 2022-09-06 |
WO2015132727A1 (en) | 2015-09-11 |
JP6674381B2 (ja) | 2020-04-01 |
CA2940504A1 (en) | 2015-09-11 |
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