CN117624019A - 萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物及其制备方法和用途 - Google Patents
萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物及其制备方法和用途 Download PDFInfo
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Abstract
本发明公开了萘酚[1,8‑ef]异吲哚‑7,8,10(9H)‑三酮类衍生物及其制备方法和用途。所述萘酚[1,8‑ef]异吲哚‑7,8,10(9H)‑三酮类衍生物为通式(I)所示化合物或其药学上可接受的盐,其中R具有说明书中所定义的含义。本发明同时涉及通式(I)所示化合物或其药学上的盐及药物组合物用于制备PARP抑制剂、制备AKT抑制剂、制备用于预防和/或治疗与PARP相关的疾病的药物、制备用于预防和/或治疗与AKT相关的疾病的药物以及制备放疗或化疗药物的增敏剂中的用途。
Description
技术领域
本发明属于医药化学领域,具体涉及一系列可作为PARP抑制剂和/或AKT抑制剂的萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮衍生物及其制药用途。
背景技术
聚腺苷二磷酸核糖聚合酶(Poly(adenosine diphoshate[ADP]-ribose)polymerase,PARP)是一类存在于真核细胞中催化聚ADP核糖基化(poly(ADP-ribose),PAR)的细胞核酶,参与DNA复制和转录,在保持染色体结构完整、维持基因组稳定和细胞凋亡过程中发挥关键作用。
鉴于PARP在DNA损伤修复过程中的重要作用,PARP抑制剂最初被作为增敏剂与化疗药物联合应用用于提高化疗药物疗效。2005年,两个研究团队各自独立证实了PARP抑制剂与乳腺癌易感基因(BRCA)1/2突变之间存在“合成致死”效应,由此开启PARP抑制剂作为单药治疗与BRCA基因突变显著相关的癌症的研究热潮。2014年全世界第一个基于“合成致死”理念设计的PARP抑制剂Olaparib(奥拉帕利)被FDA批准用于治疗卵巢癌。随后PARP抑制剂Rucaparib(卢卡帕利)、Niraparib(尼拉帕利)、Talazoparib(他拉唑帕利)、Fluazolepali(氟唑帕利)和Pamiparib(帕米帕利)先后获批上市,治疗范围涵盖卵巢癌、乳腺癌、胰腺癌和前列腺癌等多种癌症。此外,由于其多功能作用,PARP抑制剂还可用于治疗心肌梗塞、心肌炎、神经退行性疾病、糖尿病等多种疾病。因此,开发PARP抑制剂对于多种疾病的临床治疗具有重要的意义。
PI3K/AKT/mTOR信号通路在细胞存活与生长中起着相当关键的作用,是肿瘤细胞抵御细胞死亡的重要通路之一。AKT(又称蛋白激酶B,PKB)是这一信号通路的关键节点蛋白,在胃癌、前列腺癌、卵巢癌、胰腺癌、乳腺癌等多种人类肿瘤中均存在过度表达的现象。AKT的功能失调或异常激活与这些肿瘤的发生、发展、转移以及对化疗产生耐药密切相关。抑制AKT活性既可避免抑制该通路上游PI3K(磷脂酰肌醇3-激酶)造成的严重副作用,也可避免抑制下游mTOR(哺乳动物雷帕霉素靶蛋白)引起的负反馈机制影响药效。因此,AKT是一个具有良好开发前景的抗肿瘤药物靶点,开发新颖、高效的AKT抑制剂是当前抗肿瘤药物开发的一个重要策略。
发明内容
本发明的目的是提供了萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物及其制备方法和用途,本发明的萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物能够用于制备PARP抑制剂和/或AKT抑制剂。
本发明解决其技术问题所采用的技术方案之一是:
一种萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物,为结构式如通式(Ⅰ)所示的化合物或其药学上可接受的盐:
通式(Ⅰ)中R选自以下取代基团:
(1)—(CH2)n-X,其中:n=1~6,X为羟基、氨基、巯基、卤素、—CN或羧基;
(2)其中:n=1~6,R1和R2各自独立地选自C1~C6的烷基中的一种,或R1+R2为至少含一个N的5~6元杂环;
(3)—X,其中:X为氢、硝基、羟基、氨基、巯基、氰基或—OR基其中R为C1~C6直链或支链的烷基、卤素或氨基酸;
(4)—X(CH2)n-Y,其中:X为NH或O时,n=0,Y=COR其中R为C1~C6直链或支链的烷基;X为NH、O或S时,n=1~6,Y为硝基、羟基、氨基、巯基、卤素、氨基酸或羧基;
(5)其中:X为NH、O或S,n=1~6,R3和R4各自独立地选自C1~C6的烷基中的一种,或R3+R4为至少含一个N的5~6元杂环。
优选地,所述的萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物,选自结构式如下式所示的化合物或其药学上可接受的盐:
本发明解决其技术问题所采用的技术方案之二是:
一种萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物的制备方法,包括:
1)苊醌、丙二腈和乙腈加热回流反应,得到1-二氰基亚甲基-2-氧-苊;
2)1-二氰基亚甲基-2-氧-苊、碳酸钾和乙腈加热回流反应,产物洗去残余碳酸钾,得到1-氧代-1H-非那烯-2,3-二甲腈;
3)1-氧代-1H-非那烯-2,3-二甲腈与硫酸在室温下反应,得到萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮;
4)萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮与含有R基团的物质及溶剂DMF在室温下反应,得到萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物。
进一步地,所述含有R基团的物质包括N,N-二甲基乙二胺、N,N-二乙氨基-乙二胺、N,N-二甲氨基-1,3-丙二胺、正丁胺、乙醇胺、氨甲基噻吩、哌啶、四氢吡咯、硫吗啉、吗啉或N-甲基哌嗪中的至少一种。
本发明解决其技术问题所采用的技术方案之三是:
一种萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物在制备PARP抑制剂中的用途。
本发明解决其技术问题所采用的技术方案之四是:
一种萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物在制备AKT抑制剂中的用途。
本发明解决其技术问题所采用的技术方案之五是:
一种萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物在制备用于预防和/或治疗与PARP相关的疾病的药物中的用途。
本发明解决其技术问题所采用的技术方案之六是:
一种萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物在制备用于预防和/或治疗与AKT蛋白激酶相关的疾病的药物中的用途。
本发明解决其技术问题所采用的技术方案之七是:
一种萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物在制备各种一般癌症的放疗或化疗药物的增敏剂中的用途。
本发明解决其技术问题所采用的技术方案之八是:
一种包括萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物的组合物的用途,所述用途包括以下的至少一种:
1)在制备PARP抑制剂中的用途;
2)在制备AKT抑制剂中的用途;
3)在制备用于预防和/或治疗与PARP相关的疾病的药物中的用途;
4)在制备用于预防和/或治疗与AKT蛋白激酶相关的疾病的药物中的用途;
5)在制备各种一般癌症的放疗或化疗药物的增敏剂中的用途。
本发明还提供了检测通式(Ⅰ)所示化合物、通式(Ⅰ)所示化合物药学上可接受的盐及包含通式(Ⅰ)所示化合物的药物组合物具有PARP抑制活性的方法。
本发明还提供了检测通式(Ⅰ)所示化合物、通式(Ⅰ)所示化合物药学上可接受的盐及包含通式(Ⅰ)所示化合物的药物组合物具有AKT抑制活性的方法。
本发明所指的“药学上可接受的盐”意指那些保留生物学有效性和母体化合物性质的盐。这种盐包括与无机酸或有机酸形成的酸加成盐,所述无机酸例如盐酸、氢溴酸、硝酸、磷酸、硫酸、高氯酸等,所述有机酸例如乙酸、抗坏血酸、三氟乙酸、丙酸、羟乙酸、(D)或(L)乳酸、(D)或(L)苹果酸、草酸、富马酸、马来酸、甲磺酸、乙磺酸、苯甲酸、对甲苯磺酸、水杨酸、肉桂酸、扁桃酸、酒石酸、柠檬酸、琥珀酸、羟乙磺酸和丙二酸。
本发明所述的“抑制剂”指的是可以用于科研实验工作的试剂,例如,在实验设计需要抑制PARP活性或者抑制AKT活性时,可以采用本发明的萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物抑制PARP活性或者抑制AKT活性进行实验;这类科研用抑制剂能够为相关科研工作者提供研究工具,具有重要的科研价值和应用前景。本发明所述的“抑制剂”也可以指的是作为药物使用的PARP抑制剂或AKT抑制剂,即可用于制备作为药物使用的PARP抑制剂或AKT抑制剂。
本发明所述的PARP相关的疾病包括癌症、中风、心机梗塞、炎症、高血压、动脉粥样硬化和糖尿病。优选地,所述疾病或疾病状态为癌症;更优选地,所述疾病或疾病状态为乳腺癌、前列腺癌或卵巢癌。
本发明所述的AKT蛋白激酶相关的疾病或疾病状态为癌症;更优选地,所述疾病或疾病状态为乳腺癌、前列腺癌或卵巢癌。
本发明的一种包括萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物的组合物在制备PARP抑制剂的用途中,通式(Ⅰ)所示的化合物或其药学上可接受的盐可以与其他抑制剂联合应用。同样地,本发明的一种包括萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物的组合物在制备AKT抑制剂的用途中,通式(Ⅰ)所示的化合物或其药学上可接受的盐可以与其他抑制剂联合应用。
本发明的一种包括萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物的组合物在制备预防和/或治疗与PARP相关的疾病的药物中的用途时,该组合物可进一步包括一种或多种预防和/或治疗PARP相关的疾病的药物,如针对癌症、中风、心机梗塞、炎症、高血压、动脉粥样硬化和糖尿病等的药物,如放疗或化疗药物等。
本发明的一种包括萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物的组合物在制备用于预防和/或治疗与AKT蛋白激酶相关的疾病的药物中的用途时,该组合物可进一步包括一种或多种预防和/或治疗AKT蛋白激酶相关的疾病的药物,如针对癌症等的药物,如放疗或化疗药物等。
本发明的一种包括萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物的组合物在制备各种一般癌症的放疗或化疗药物的增敏剂中的用途时,该组合物可进一步包括一种或多种放疗药物、化疗药物或增敏剂。
本发明所述的“药物”,除了具有药效的活性成分外,还可包括至少一种药学上可接受的辅料或载体。所述辅料包括但不限于稀释剂、溶剂、赋形剂、吸收剂、润湿剂、黏合剂、崩解剂、润滑剂、增溶剂、乳化剂、助悬剂、表面活性剂、成膜剂、抛射剂、抗氧剂、矫味剂、芳香剂、杀菌剂、防腐剂等;所述载体指能够担载化合物,并且具有改变化合物进入人体的方式和在体内的分布,控制释放速度达到控释或缓释,靶向输送至靶器官等作用的体系,包括但不限于脂质体、微球、微囊、固体分散体、胶束、微乳液、凝胶、缓释型载体、控释型载体、靶向型载体、纳米颗粒材料等。
采用公开的一般合成路线和实施方案,通过有机化学标准技术可以制备一些本发明中开发、使用的PARP抑制剂和/或AKT抑制剂。
本发明所涉及的设备、试剂、工艺、参数等,除有特别说明外,均为常规设备、试剂、工艺、参数等,不再作实施例。
本发明所列举的所有范围包括该范围内的所有点值。
本发明中,所述“室温”即常规环境温度,可以为10~30℃。
本技术方案与背景技术相比,它具有如下优点:
1.目前没有萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物作为PARP抑制剂或AKt抑制剂的相关研究报道。本发明所提供的通式(Ⅰ)所示化合物能够拓展PARP抑制剂和AKT抑制剂种类,为临床研究提供备选药物。
2.本发明所提供的通式(Ⅰ)所示化合物结构中含有易于通过氢键与PARP蛋白结合的取代基团,一方面可以提高所述化合物与PARP蛋白的结合能力,从而增强对PARP蛋白的抑制效果;另一方面也可以有效提高所述化合物的水溶性,从而使其更适用于制备药物。
3.本发明所提供的通式(Ⅰ)所示化合物合成路线简单,采用文献中公开的一般合成路线和实施方案,通过有机化学标准技术可以很容易地制备。
具体实施方式
下面结合实施例对本发明作进一步说明。
本发明实施例中,萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物的合成路线如式Ⅱ所示:
实施例1:萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮的合成(化合物4/化合物5-1)
1.中间体化合物2的合成:
在500mL单口烧瓶中,依次加入0.1mol苊醌,0.11mol丙二腈,150mL乙腈,加热至回流,反应4h,反应混合物由淡黄色浑浊变为橙红透明。冷至室温后,过滤,收集橙红色滤饼,得中间体2(1-二氰基亚甲基-2-氧-苊),粗产率96%。1H NMR(400MHz,DMSO):δ8.54-8.52(d,J=7.2Hz,1H),8.32-8.30(d,J=8.4Hz,2H),8.15-8.14(d,J=6.8Hz,1H),7.93-7.89(t,J=8.2Hz,2H);IR(KBr)cm-1:2221,1719,1595,1573,1463;ESI-MS:[M+Na]+(m/z 253).
2.中间体化合物3的合成:
在500mL单口烧瓶中,依次加入1-二氰基亚甲基-2-氧-苊粗品0.05mol,碳酸钾1g,200mL乙腈,加热至回流,反应4h,大量土黄色固体析出。冷至室温后,过滤,收集滤饼。将滤饼用大量温水洗,以除去残余的碳酸钾(此洗涤过程至关重要,若体系中仍有残留的碳酸钾,则在后面的目标化合物制备中会产生大量的深蓝色副产物,给产物的分离提纯增加困难,而且影响产率)。粗产品烘干,得亮黄色固体中间体3(1-氧代-1H-非那烯-2,3-二甲腈),产率95%。1H NMR(400M,DMSO):δ8.71-8.69(d,J=8.0Hz,1H),8.67-8.65(d,J=7.6Hz,1H),8.64-8.62(d,J=8.0Hz,1H),8.42-8.40(d,J=7.6Hz,1H),8.04-8.08(t,J=8.0Hz,1H),7.99-7.95(t,J=7.8Hz,1H);13C NMR(100M,DMSO):δ177.48,138.26,137.73,134.40,132.72,131.82,131.37,128.91,127.94,127.37,126.13,122.22,119.72,113.82,113.38;IR(KBr)cm-1:2231,1643,1577;ESI-MS:M+Na+(253,m/z).
3.萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮的合成(化合物4/化合物5-1即R为H):
在50mL单口烧瓶中,加入60mL浓硫酸或者25mL发烟硫酸,在0~5℃下,分批加入0.05mol中间体3,1h内加完,加完后在室温继续反应16h(如果是发烟硫酸的话,继续反应0.5h),反应混合物为粘稠的深棕红色。然后小心缓慢地将其滴入碎冰中,同时剧烈搅拌,滴完后,静置,过滤,滤饼用大量水洗涤,直至滤液呈中性,滤饼干燥后得深黄色固体萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮(化合物4/化合物5-1),产率95%。m.p.245℃ dec;1H NMR(400MHz,DMSO-d6)δ=11.41(s,1H,OH*),8.95(d,1H,J=7.2Hz),8.55(d,1H,J=8.0Hz),8.53(d,1H,J=7.2Hz),8.48(d,1H,J=8.0Hz),7.96(dd,1H,J1=8.0Hz,J2=7.2Hz),7.88(dd,1H,J1=8.0Hz,J2=7.2Hz).IR(KBr)cm-1:3208,1774,1700,1636,1583,1570.MS(API-ES)m/z(M-H)-248.1.
实施例2:4-(2-(二甲氨基)乙基)氨基)萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮(化合物5-2)
化合物2~4按照实施例1中所述方法获得。在10mL单口烧瓶中,依次加入0.5mmol化合物4(萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮),220μL(2mmol)N,N-二甲基乙二胺,5mL的DMF作溶剂,在室温下搅拌反应2小时。TLC(薄层层析板)跟踪,直至反应完全,反应混合物由开始的棕黄色浑浊变为紫黑色。减压蒸除溶剂后,粗产物经两次硅胶柱柱层析分离、精制,得到目标产物,为黑紫色粉末状固体,产率45%。mp>300℃;1H NMR(400MHz,DMSO-d6)δ(ppm)10.92(s,1H)8.81(t,2H,J=8.8Hz)8.59(d,1H,J=8.0Hz)7.83(t,1H,J=7.6Hz)6.98(d,1H,J=8.0Hz)3.68(t,2H,J=6.4Hz)2.78(br,2H)2.36(s,6H);13C NMR(100MHz,DMSO-d6)δ(ppm)175.9,171.0,169.1,155.1,141.7,137.9,133.7,131.8,130.8,130.3,126.2,123.6,115.8,108.7,107.8,56.8,45.4;IR(KBr cm-1)3237,3081,1710,1614,1573;HRMS(ESI)m/z(M-H)-calcd for C19H16N3O3 334.1192,found:334.1205.
实施例3:4-(2-(二乙氨基)乙基)氨基)萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮(化合物5-3)
依照实施例2中的合成方法,在10mL单口烧瓶中,依次加入0.5mmol化合物4,281μL(2mmol)N,N-二乙氨基-乙二胺,5mL的DMF作溶剂,在室温下搅拌反应2小时。TLC(薄层层析板)跟踪,直至反应完全,反应混合物由开始的棕黄色浑浊变为紫黑色。减压蒸除溶剂后,粗产物经两次硅胶柱柱层析分离、精制,得到目标产物,为黑紫色粉末状固体,产率40%。mp239-239.5℃;1H NMR(500MHz,DMSO-d6)δ(ppm)8.79(d,2H,J=8.4Hz)8.58(d,1H,J=8.2Hz)7.83(t,1H,J=8.0Hz)6.98(d,1H,J=8.2Hz)3.63(t,2H,J=6.0Hz)2.80(br,2H)2.61(br,4H)0.99(t,6H,J=7.0Hz);13C NMR(125MHz,DMSO-d6)δ(ppm)175.4,170.6,168.4,154.8,141.2,137.5,133.4,131.4,130.5,129.6,125.8,123.2,15.2,108.1,107.3,50.6,46.6,11.6;IR(KBr cm-1)3251,3049,2977,1740,1703;HRMS(ESI)m/z(M-H)-calcd for C21H20N3O3362.1505,found:362.1511.
实施例4:4-(3-二甲氨基-丙胺)-萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮(化合物5-4)
依照实施例2中的合成方法,在10mL单口烧瓶中,依次加入0.5mmol化合物4,252μL(2mmol)N,N-二甲氨基-1,3-丙二胺,5mL的DMF作溶剂,在室温下搅拌反应2小时。TLC(薄层层析板)跟踪,直至反应完全,反应混合物由开始的棕黄色浑浊变为紫黑色。减压蒸除溶剂后,粗产物经两次硅胶柱柱层析分离、精制,得到目标产物,为黑紫色粉末状固体,产率40.3%。mp>300℃;1H NMR(500MHz,DMSO-d6)δ(ppm)8.78-8.76(m,2H)8.57(d,1H,J=8.0Hz)7.82(t,1H,J=7.0Hz)6.94(d,1H,J=8.0Hz)3.58(t,2H,J=7.0Hz)2.57(br,2H)2.33(s,6H)1.94-1.91(m,2H);13C NMR(125MHz,DMSO-d6)δ(ppm)175.5,170.7,168.6,154.9,141.3,137.7,133.5,131.5,130.5,129.8,126.0,123.3,115.2,108.1,107.2,56.3,44.6,25.2;IR(KBr cm-1)3259,3059,1751,1717,1559;HRMS(ESI)m/z(M-H)-calcd for C20H18N3O3348.1348,found:348.1337.
实施例5:4-丁氨基-萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮(化合物5-5)
依照实施例2中的合成方法,在10mL单口烧瓶中,依次加入0.5mmol化合物4,198μL(2mmol)正丁胺,5mL的DMF作溶剂,在室温下搅拌反应1.5小时。TLC(薄层层析板)跟踪,直至反应完全,反应混合物由开始的棕黄色浑浊变为紫黑色。减压蒸除溶剂后,粗产物经两次硅胶柱柱层析分离、精制,得到目标产物,为黑紫色粉末状固体,产率52.1%。mp>300℃;1HNMR(500MHz,DMSO-d6)δ(ppm)10.91(s,1H)8.87(d,1H,J=7.9Hz)8.79(d,1H,J=9.0Hz)8.59(d,1H,J=7.9Hz)7.83(t,1H,J=7.5Hz)6.96(d,1H,J=9.0Hz)3.56-3.52(m,2H)3.33(br,1H)1.75-1.69(m,2H)1.48-1.40(m,2H)0.96(t,3H,J=7.3Hz);13C NMR(125MHz,DMSO-d6)δ(ppm)175.3,170.5,168.4,154.7,141.2,137.6,133.4,131.4,130.4,129.8,125.7,123.1,115.0,107.9,107.1,42.9,32.1,19.6,13.6;IR(KBr cm-1)3259,2955,1751,1717;HRMS(ESI)m/z(M-H)-calcd for C19H15N2O3 319.1083,found:319.1074.
实施例6:4-(2-羟乙基)氨基)-萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮(化合物5-6)
依照实施例2中的合成方法,在10mL单口烧瓶中,依次加入0.5mmol化合物4,120μL(2mmol)乙醇胺,5mL的DMF作溶剂,在室温下搅拌反应2小时。TLC(薄层层析板)跟踪,直至反应完全,反应混合物由开始的棕黄色浑浊变为紫黑色。减压蒸除溶剂后,粗产物经两次硅胶柱柱层析分离、精制,得到目标产物,为黑紫色粉末状固体,产率48.1%。mp>300℃;1H NMR(400M,DMSO):δ11.02(s,1H)9.545(br s,1H),8.87-8.85(d,J=8.0Hz,1H),8.51-8.49(d,J=7.6Hz,1H),7.88-7.85(d,J=9.2Hz,1H),7.80-7.84(t,J=7.8Hz,1H),6.98-7.00(d,J=9.2Hz,1H),4.99(s,1H)3.755(br s,2H),3.66-3.69(t,J=4.2Hz);13C NMR(100M,DMSO):δ176.14,156.14,138.22,132.12,130.82,129.38,127.72,126.65,125.22,121.89,115.90,114.12,111.14,108.23,103.80,58.94,46.37;IR(KBr)cm-1:3457,3309,2215,1656,1623,1571,1494;HRMS(ESI)m/z(M-H)-calcd for C17H11N2O4 307.0845,found:307.0831.
实施例7:4-[(噻吩-2-甲基)氨基]-萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮(化合物5-7)
依照实施例2中的合成方法,在10mL单口烧瓶中,依次加入0.5mmol化合物4,206μL(2mmol)氨甲基噻吩,5mL的DMF作溶剂,在室温下搅拌反应8小时。TLC(薄层层析板)跟踪,直至反应完全,反应混合物由开始的棕黄色浑浊变为紫黑色。减压蒸除溶剂后,粗产物经两次硅胶柱柱层析分离、精制,得到目标产物,为黑紫色粉末状固体,产率38%。mp>300℃;1HNMR(400MHz,DMSO-d6)δ(ppm)10.15(d,1H,J=6.0Hz)9.00(d,1H,J=8.0Hz)8.64(d,1H,J=7.2Hz)8.04(d,1H,J=8.8Hz)7.95(t,1H,J=8.0Hz)7.46(d,1H,J=4.8Hz)7.22(s,1H)7.15(d,1H,J=9.2Hz)7.03-7.01(m,1H)5.03(d,2H,J=6.0Hz);13C NMR(100MHz,DMSO-d6)δ(ppm)177.4,155.9,140.1,139.4,133.3,131.8,130.2,128.7,127.9,127.5,127.2,127.1,126.4,122.7,116.4,114.8,112.4,108.8,106.0,42.4;IR(KBr cm-1)3318,1624,1576,1483;HRMS(ESI)m/z(M-H)-calcd for C20H11N2O3S 359.0490,found:359.0506.
实施例8:4-哌啶基-萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮(化合物5-8)
依照实施例2中的合成方法,在10mL单口烧瓶中,依次加入0.5mmol化合物4,198μL(2mmol)哌啶,5mL的DMF作溶剂,在室温下搅拌反应2小时。TLC(薄层层析板)跟踪,直至反应完全,反应混合物由开始的棕黄色浑浊变为紫黑色。减压蒸除溶剂后,粗产物经两次硅胶柱柱层析分离、精制,得到目标产物,为黑紫色粉末状固体,产率62.2%。mp>300℃;1H NMR(500MHz,DMSO-d6)δ(ppm)11.11(s,1H)8.77(d,1H,J=8.5Hz)8.53(dd,1H,J=1.0and7.5Hz)8.46(dd,1H,J=1.0and 7.5Hz)7.84(t,1H,J=8.0Hz)7.27(d,1H,J=8.5Hz)3.55(t,4H,J=5.0Hz)1.83-1.81(m,4H)1.73-1.72(m,2H);13C NMR(125MHz,DMSO-d6)δ(ppm)176.7,170.3,168.1,159.5,141.9,135.0,133.2,132.6,131.1,130.7,126.0,125.9,119.2,115.0,112.2,54.2,25.6,23.6;IR(KBr cm-1)3170,3036,1740,1691;HRMS(ESI)m/z(M-H)-calcd for C20H15N2O3 331.1083,found:331.1089.
实施例9:4-吡咯基-萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮(化合物5-9)
依照实施例2中的合成方法,在10mL单口烧瓶中,依次加入0.5mmol化合物4,165μL(2mmol)四氢吡咯,5mL的DMF作溶剂,在室温下搅拌反应2小时。TLC(薄层层析板)跟踪,直至反应完全,反应混合物由开始的棕黄色浑浊变为紫黑色。减压蒸除溶剂后,粗产物经两次硅胶柱柱层析分离、精制,得到目标产物,为黑紫色粉末状固体,产率57%。mp>300℃;1H NMR(400MHz,CDCl3)δ11.09(s,1H)8.68(d,1H,J=7.6Hz),8.50(d,1H,J=8.4Hz),8.12(d,1H,J=8.4Hz),7.82(dd,1H,J=8.4Hz,7.6Hz),7.06(d,1H,J=8.4Hz),3.67(t,4H,J=4.6Hz),2.77(t,4H,J=4.6Hz),2.45ppm(s,3H).IR(KBr)cm-1:3423,2941,2214,1623,1572.HRMS(ESI)m/z(M-H)-calcd for C19H13N2O3 319.1014,found 319.1015.
实施例10:4-硫吗啉基-萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮(化合物5-10)
依照实施例2中的合成方法,在10mL单口烧瓶中,依次加入0.5mmol化合物4,190μL(2mmol)硫吗啉,5mL的DMF作溶剂,在室温下搅拌反应8小时。TLC(薄层层析板)跟踪,直至反应完全,反应混合物由开始的棕黄色浑浊变为紫黑色。减压蒸除溶剂后,粗产物经两次硅胶柱柱层析分离、精制,得到目标产物,为黑紫色粉末状固体,产率43%。mp>300℃;1H NMR(500MHz,DMSO-d6)δ(ppm)11.20(s,1H)8.87(d,1H,J=8.5Hz)8.58-8.55(m,2H)7.91(t,1H,J=8.5Hz)7.39(d,1H,J=8.5Hz)3.72-3.70(m,4H)2.98-2.96(m,4H);13C NMR(125MHz,DMSO-d6)δ(ppm)206.3,177.4,170.4,168.1,159.1,142.5,134.8,133.1,132.3,131.1,130.4,126.6,120.9,116.2,113.9,55.5,30.6,26.9;IR(KBr cm-1)3229,3055,1771,1709;HRMS(ESI)m/z(M-H)-calcd for C19H13N2O3S 349.0647;found:349.0652.
实施例11:4-吗啉基-萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮(化合物5-11)
依照实施例2中的合成方法,在10mL单口烧瓶中,依次加入0.5mmol化合物4,175μL(2mmol)吗啉,5mL的DMF作溶剂,在室温下搅拌反应2小时。TLC(薄层层析板)跟踪,直至反应完全,反应混合物由开始的棕黄色浑浊变为紫黑色。减压蒸除溶剂后,粗产物经两次硅胶柱柱层析分离、精制,得到目标产物,为黑紫色粉末状固体,产率47.5%。mp>300℃;1H NMR(500MHz,DMSO-d6)δ(ppm)11.19(s,1H)8.86(d,1H,J=8.5Hz)8.59(d,1H,J=8.5Hz)8.56(d,1H,J=8.0Hz)7.89(t,1H,J=7.8Hz)7.36(d,1H,J=8.0Hz)3.92(t,4H,J=4.5Hz)3.50(t,4H,J=4.5Hz);13C NMR(125MHz,DMSO-d6)δ(ppm)177.3 170.4 168.1 158.3 142.4134.9 133.1 132.4 131.1 130.5 126.5 126.0 120.6 115.3 113.6 66.0 53.4;IR(KBrcm-1)3152,3060,1760,1730,1221;HRMS(ESI)m/z(M-H)-calcd for C19H13N2O4 333.0875;found:333.0861.
实施例12:4-(4-甲基-哌嗪基)-萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮(化合物5-12)
依照实施例2中的合成方法,在10mL单口烧瓶中,依次加入0.5mmol化合物4,222μL(2mmol)N-甲基哌嗪,5mL的DMF作溶剂,在室温下搅拌反应2小时。TLC(薄层层析板)跟踪,直至反应完全,反应混合物由开始的棕黄色浑浊变为紫黑色。减压蒸除溶剂后,粗产物经两次硅胶柱柱层析分离、精制,得到目标产物,为黑紫色粉末状固体,50.5%。mp>300℃;1H NMR(500MHz,DMSO-d6)δ(ppm)11.16(s,1H)8.83(d,1H,J=8.5Hz)8.56(dd,1H,J=1.0and8.5Hz)8.53(dd,1H,J=1.0and 8.5Hz)7.88(t,1H,J=8.0Hz)7.34(d,1H,J=8.5Hz)3.55(t,4H,J=4.7Hz)2.66(br,4H)2.32(s,3H);13C NMR(125MHz,DMSO-d6)δ(ppm)177.1,170.4,168.1,158.5,142.3,134.9,133.1,132.5,131.1,130.6,126.3,125.9,120.1,115.3,113.1,54.4,52.9,45.4,30.6;IR(KBr cm-1)3537,1745,1704;HRMS(ESI)m/z(M-H)-calcd for C20H16N3O3 346.1192;found:346.1203.
实施例13:本发明实施例1~12的化合物对PARP的抑制作用
实验试剂:(1)实施例1~12中描述的萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮衍生物;(2)PARP通用显色方法试剂盒:(TREVIGEN,ME,USA,R&D Catalog Number 4677-096-K)。
测试具体步骤:
A.核糖基化反应:
(1)每孔加入50μL 1×PARP buffer,再水化组蛋白,室温孵育30min。用滤纸吸净每孔内的液体。
(2)每孔加入10μL梯度稀释后的抑制剂。
(3)加入稀释的PARP-HAS酶(每孔0.5U)到含有抑制剂的孔里,室温下孵育10min。
(4)对照:①活性对照:每孔0.5U PARP-HAS酶,无抑制剂,提供100%活性参照点;②阴性对照:含有不同浓度抑制剂的孔,无PARP-HAS酶,检测背景吸光度。
(5)每孔加入25μL 1×PARP Cocktail,室温下孵育60min。
B.检测
(1)用1×PBS+0.1%Triton X-100,清洗平板两次,每孔200μL,随后用1×PBS,清洗平板两次,每孔200μL,确保清洗结束后用滤纸将每孔的液体吸净。
(2)每孔加入50μL稀释的Strep-HRP,室温下孵育60min。
(3)用1×PBS+0.1%Triton X-100,清洗平板两次,每孔200μL,随后用1×PBS,每孔200μL,清洗两次,确保清洗结束后用滤纸将每孔的液体吸净。
(4)每孔加入50μL预热好的TACS-Sapphire,室温避光显色15min。
(5)每孔加入50μL 0.2M HCl,终止反应,并在450n m下读取吸光度。
表1本发明部分化合物对PARP-1的抑制活性(IC50值μM)
化合物 | 5-1 | 5-2 | 5-3 | 5-4 | 5-5 | 5-6 | 5-7 |
IC50 | 2.15 | 0.39 | 0.84 | 25.6 | >200 | 0.18 | >200 |
化合物 | 5-8 | 5-9 | 5-10 | 5-11 | 5-12 | 4AN | |
IC50 | 0.34 | >200 | 13.5 | 18.9 | 0.42 | 0.36 |
4AN代表4-氨基-1,8-萘酰亚胺,一个已知的中等强度PARP抑制剂,常用来研究PARP蛋白相关机理或者作为新开发的PARP抑制剂阳性对照物,在本实施例中用作阳性对照物。
由表1数据可以发现,本发明的化合物具有对PARP-1的抑制作用,其中化合物5-2、5-3、5-6、5-8和5-12具有与4AN接近的对PARP的抑制作用。此外,本发明的化合物对某些化疗药物具有增效作用。
实施例14:本发明实施例1~12的化合物对AKT的抑制作用
实验试剂:(1)实施例1~12中描述的萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮衍生物;(2)HTRF试剂盒(德国Cisbio公司)、200ng/μL AKT1酶(日本Carna Biosciences公司)、ATP(美国Sigma-Aldrich公司)、MgCl2水溶液(美国Sigma-Aldrich公司)、DTT(美国Sigma-Aldrich公司)。2μL
测试具体步骤:
冰浴条件下,将4μL化合物(用激酶缓冲液稀释),2μL底物KinEASE STKS3(AKT1底物)和2μL AKT1激酶依次加入到384孔板上,混匀,离心,加入2μL ATP混匀离心,37℃下孵育40分钟。加入10μL anti-Eu(K)STK抗体溶液和treptavidin-XL665缓冲液等体积的混合液(含有的乙二胺四乙酸(EDTA)可终止酶反应),37℃孵育2h,采用BioTeK多功能酶标仪Synnergy 2TM检测发射波长620nm和665nm的荧光值。实验中,分别设有阳性对照组(P),阴性对照组(N)和实验组(C)。各组别加样量及加样顺序按照HTRF试剂盒说明书执行。
抑制率与IC50值计算:
抑制率的计算公式为:
其中C为测试组,P为阳性对照组,N为阴性对照组。采用软件Graghpad Prism 5.0以抑制率为纵坐标,浓度的对数为横坐标,拟合曲线,计算IC50值。
表2本发明部分化合物对AKT1的抑制活性(IC50值μM)
化合物 | 5-1 | 5-2 | 5-3 | 5-4 | 5-5 | 5-6 | 5-7 |
IC50 | 25.2 | 10.6 | >30 | >30 | >30 | 1.8 | 4.7 |
化合物 | 5-8 | 5-9 | 5-10 | 5-11 | 5-12 | GSK690693 | |
IC50 | 2.3 | >30 | 7.5 | >30 | 4.2 | 19.5 |
由表2数据可以发现本发明的化合物具有对AKT的抑制作用,其中化合物5-1、5-2、5-3、5-6、5-7、5-8、5-10和5-12具有与阳性对照GSK690693接近的抑制作用。
实施例15:实施例1~12的化合物体外抑制肿瘤细胞生长活性测定
用四氮唑盐(microculture tetrozolium,MTT)还原法评价实施例中描述化合物对HeLa(人宫颈癌细胞),HL-60(人血病细胞),HCT-8(人盲肠癌细胞),A375(人黑色素瘤细胞)和MCF-7(人乳腺癌细胞)肿瘤细胞的体外生长抑制情况,测试结果列于表3。
四氮唑盐(MTT)还原法的具体操作是:按不同肿瘤生长速率,将一定数量处于对数生长期的肿瘤细胞90μL/孔接种于96孔微量培养板内,培养24h后加入药液10μL/孔,对每个细胞株,每个浓度均为三个复孔。另设无细胞调零孔、如果药物有颜色要做相应药物浓度无细胞调零孔。肿瘤细胞在37℃、5%CO2条件下培养24h后,加MTT(Sigma)液5mg/mL用生理盐水配制20μL/孔;继续培养4h后,加入三联液(10%SDS-5%异丁醇-0.01mol/L HCl)50μL/孔,于CO2培养箱中过夜。然后用酶标仪测OD570值。
按下列公式计算被测物对癌细胞生长的抑制率:
肿瘤抑制率=(对照组OD值-治疗组OD值)/对照组OD值×100%。
表3.本发明部分化合物体外抗肿瘤活性测试结果
由表3数据可以发现本发明的多数化合物具有良好的体外抑制肿瘤细胞生长活性,其中化合物5-2、5-3、5-6、5-8和5-12活性较好。
以上所述,仅为本发明较佳实施例而已,故不能依此限定本发明实施的范围,即依本发明专利范围及说明书内容所作的等效变化与修饰,皆应仍属本发明涵盖的范围内。
Claims (10)
1.一种萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物,为结构式如通式(Ⅰ)所示的化合物或其药学上可接受的盐:
通式(Ⅰ)中R选自以下取代基团:
(1)-(CH2)n-X,其中:n=1~6,X为羟基、氨基、巯基、卤素、—CN或羧基;
(2)其中:n=1~6,R1和R2各自独立地选自C1~C6的烷基中的一种,或R1+R2为至少含一个N的5~6元杂环;
(3)—X,其中:X为氢、硝基、羟基、氨基、巯基、氰基或—OR基其中R为C1~C6直链或支链的烷基、卤素或氨基酸;
(4)-X-(CH2)n-Y,其中:X为NH或O时,n=0,Y=COR其中R为C1~C6直链或支链的烷基;X为NH、O或S时,n=1~6,Y为硝基、羟基、氨基、巯基、卤素、氨基酸或羧基;
(5)其中:X为NH、O或S,n=1~6,R3和R4各自独立地选自C1~C6的烷基中的一种,或R3+R4为至少含一个N的5~6元杂环。
2.根据权利要求1所述的萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物,其特征在于:为结构式如下式所示的化合物或其药学上可接受的盐:
3.一种权利要求1或2所述的萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物的制备方法,其特征在于:包括:
1)苊醌、丙二腈和乙腈加热回流反应,得到1-二氰基亚甲基-2-氧-苊;
2)1-二氰基亚甲基-2-氧-苊、碳酸钾和乙腈加热回流反应,产物洗去残余碳酸钾,得到1-氧代-1H-非那烯-2,3-二甲腈;
3)1-氧代-1H-非那烯-2,3-二甲腈与硫酸在室温下反应,得到萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮;
4)萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮与含有R基团的物质及溶剂DMF在室温下反应,得到萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物。
4.根据权利要求3所述的制备方法,其特征在于:所述含有R基团的物质包括N,N-二甲基乙二胺、N,N-二乙氨基-乙二胺、N,N-二甲氨基-1,3-丙二胺、正丁胺、乙醇胺、氨甲基噻吩、哌啶、四氢吡咯、硫吗啉、吗啉或N-甲基哌嗪中的至少一种。
5.一种权利要求1或2所述的萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物在制备PARP抑制剂中的用途。
6.一种权利要求1或2所述的萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物在制备AKT抑制剂中的用途。
7.一种权利要求1或2所述的萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物在制备用于预防和/或治疗与PARP相关的疾病的药物中的用途。
8.一种权利要求1或2所述的萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物在制备用于预防和/或治疗与AKT相关的疾病的药物中的用途。
9.一种权利要求1或2所述的萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物在制备放疗或化疗药物的增敏剂中的用途。
10.一种包括权利要求1或2所述的萘酚[1,8-ef]异吲哚-7,8,10(9H)-三酮类衍生物的组合物的用途,所述用途包括以下的至少一种:
1)在制备PARP抑制剂中的用途;
2)在制备AKT抑制剂中的用途;
3)在制备用于预防和/或治疗与PARP相关的疾病的药物中的用途;
4)在制备用于预防和/或治疗与AKT相关的疾病的药物中的用途;
5)在制备放疗或化疗药物的增敏剂中的用途。
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