CN110742892A - 一种12H-吲唑[2,1-a]噌啉-12-酮类化合物的应用 - Google Patents
一种12H-吲唑[2,1-a]噌啉-12-酮类化合物的应用 Download PDFInfo
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Abstract
本发明公开了一种12H‑吲唑[2,1‑a]噌啉‑12‑酮类化合物的应用,所述的12H‑吲唑[2,1‑a]噌啉‑12‑酮类化合物及其药学上可接受的盐或水合物在制备用于治疗恶性肿瘤药物中的应用。所述的化合物尤其对人前列腺癌PC‑3细胞和人胰腺癌PANC‑1细胞具有良好的抑制活性,并且能够剂量依耐性的抑制它们的增殖,具有重大应用前景。
Description
技术领域
本发明涉及一类12H-吲唑[2,1-a]噌啉-12-酮类化合物或其药学上可接受的盐或水合物在制备抗肿瘤药物中的应用。
背景技术
癌症是当前严重影响人类健康、威胁人类生命的主要疾病之一。世界卫生组织(WHO)和各国政府卫生部门都把攻克癌症列为一项首要任务。
前列腺癌是常见的男性恶性肿瘤之一。美国2017年新发前列腺癌病例161360人,占男性恶性肿瘤发病率第一位(19%);新增前列腺癌死亡人数26730人,占男性恶性肿瘤死亡率第三位(8%)。我国2015年新发前列腺癌病例60300人,且前列腺癌发病率以每年10%的速度增长。目前前列腺癌治疗以化疗和雄激素受体拮抗剂为主。阿比特龙是一种口服的CYP17抑制剂,属于孕烯醇酮类似物,可抑制依赖雄激素的前列腺癌的生长。但阿比特龙价格昂贵,并且使用一年左右可能会出现耐药,同时还会引起关节肿胀、高血压和心律失常等副作用,因此治疗依然有局限性。
胰腺癌是常见的消化道肿瘤,在全球范围内其死亡率已跃居所有肿瘤的前5位,并且发病率呈逐年上升趋势。我国的胰腺癌发病和死亡分别位居恶性肿瘤的第10位和第6位。但目前尚未开发出胰腺癌的特效治疗药物和策略,嘧啶核苷类似物吉西他滨仍是胰腺癌患者一线化疗的基础,其疗效有限,并且有较多的不良反应,因此临床对胰腺癌治疗的药物需求迫切。
因此,开发低毒高效的抗肿瘤新药尤其是针对前列腺癌和胰腺癌的新药仍然是当前亟待解决的问题。
发明内容
本发明的目的是提供一类通式I所示的12H-吲唑[2,1-a]噌啉-12-酮类化合物或其药学上可接受的盐或水合物在制备抗肿瘤药物中的应用。
为了实现上述目的,本发明采用如下技术方案:
一类12H-吲唑[2,1-a]噌啉-12-酮类化合物及其药学上可接受的盐或水合物在制备用于治疗各种恶性肿瘤药物中的应用,所述的12H-吲唑[2,1-a]噌啉-12-酮类化合物为下列之一:
本发明中的术语“药学上可接受的盐”是指与磷酸、硫酸、盐酸等无机酸,或醋酸、酒石酸、柠檬酸、苹果酸等有机酸,或天冬氨酸、谷氨酸等酸性氨基酸形成的盐,或与上述酸成酯或酰胺后再与无机碱形成的盐,如钠、钾、钙、铝盐和铵盐。
进一步,所述的恶性肿瘤优选为人前列腺癌或人胰腺癌。
再进一步,所述的12H-吲唑[2,1-a]噌啉-12-酮类化合物为化合物6、17、19或20。
本发明所述的式I所示的12H-吲唑[2,1-a]噌啉-12-酮类化合物按照如下方法进行制备:
将式A所示的2-苯基吲唑-3-酮类化合物和式B所示的重氮化合物和有机酸添加剂溶于有机溶剂中,在过渡金属催化剂的催化下,在0~150℃(优选为40~80℃)下反应1~5小时反应完全,得到的反应液经后处理得到式I所示的目标化合物;所述的有机溶剂为非质子性溶剂;过渡金属催化剂选自二价Ru催化体系或三价Rh催化体系;所述的式A所示的2-苯基吲唑-3-酮类化合物和式B所示的重氮化合物、过渡金属催化剂的物质的量之比为1:1.0~1.5:0.001~0.05;
反应式如下所示:
进一步,所述的二价Ru催化体系为“[Ru(p-cymene)(MeCN)3(SbF6)2]”或“[Ru(p-cymene)Cl2]2+银试剂”,其中p-cymene=对异丙基甲苯,[Ru(p-cymene)Cl2]2与银试剂的物质的量之比为1:4。
所述的三价Rh催化体系为“[Cp*Rh(MeCN)3(SbF6)2]”或“[Cp*RhCl2]2+银试剂”,其中Cp*=五甲基环戊二烯,[Cp*RhCl2]2与银试剂的物质的量之比为1:4。
进一步,所述的银试剂选自AgSbF6、AgBF4、AgNTf2、AgPF6、AgOTf或AgOCOCF3等含有较强吸电子作用酸根离子的银试剂。
本发明反应体系中加入有机酸添加剂可以促进反应进行,其中有机酸优选为AcOH、PivOH、PhCOOH、MesCOOH,有机酸与式A所示的化合物的物质的量之比为0.1~1.0:1。
进一步,所述的有机溶剂选自1,2-二氯乙烷、四氢呋喃、二氯甲烷、1,4-二氧六环、甲苯、氯仿等非质子性溶剂,优选为1,2-二氯乙烷和四氢呋喃,所述的有机溶剂的用量以式A所示化合物的物质的量计为0.5~1mL/mmol。
本发明所述反应液的后处理方法为:将反应液用硅胶拌样,经柱层析分离,以石油醚/乙酸乙酯=0.5~8:1(v/v)为洗脱剂,收集含目标产物的洗脱剂,蒸除溶剂即得目标产物。
本发明所述的式A所述的底物2-苯基吲唑-3-酮类化合物参考以下文献制备:a)H.A.Ardakani,et al.Tetrahedron Lett.49(1979)4765-4768;b)A.Y.Shaw,etal.Synth.Commun.39(2009)2647-2663;c)Z.Wang,et al.ChemCatChem 9(2017)3637-3640.
本发明所述的式B所示的底物重氮类化合物参考以下文献制备:a)J.Rodriguez,et al.Synthesis 16(2011)2549-2552;b)P.Meffre,et al.Tetrahedron 58(2002)5159-5162.
与现有技术相比,本发明的有益效果在于:本发明所述的12H-吲唑[2,1-a]噌啉-12-酮类化合物及其药学上可接受的盐或水合物对人前列腺癌PC-3细胞和人胰腺癌PANC-1细胞具有良好的抑制活性,并且能够剂量依耐性的抑制它们的增殖,具有重大应用前景。
具体实施方式:
实施例旨在阐述而不是限制本发明的范围。
除非另有说明,本发明中采用的制备和测试方法以及设备等为本领域中常规的方法和设备。所用试剂均为分析纯或化学纯。
本发明所述的式A所述的底物2-苯基吲唑-3-酮类化合物参考以下文献制备:a)H.A.Ardakani,et al.Tetrahedron Lett.49(1979)4765-4768;b)A.Y.Shaw,etal.Synth.Commun.39(2009)2647-2663;c)Z.Wang,et al.ChemCatChem 9(2017)3637-3640.
本发明所述的式B所示的底物重氮类化合物参考以下文献制备:a)J.Rodriguez,et al.Synthesis 16(2011)2549-2552;b)P.Meffre,et al.Tetrahedron 58(2002)5159-5162.
实施例1.
称42mg(0.2mmol)2-苯基吲唑-3-酮,53mg(0.24mmol)苯甲酰乙酸乙酯重氮,12mg(0.2mmol)乙酸和5mg(0.006mmol)[Ru(p-cymene)(MeCN)3(SbF6)2]加入圆底反应瓶中,再加入2mL DCE溶解,在60℃下反应6小时。将反应液用硅胶拌样,硅胶柱层析(洗脱剂为石油醚:乙酸乙酯=4:1)分离得到72.6mg黄色固体,收率95%。
1H NMR(600MHz,CDCl3)δ9.05(d,J=8.4Hz,1H),8.00(d,J=7.8Hz,1H),7.59(d,J=7.8Hz,1H),7.55–7.49(m,3H),7.44(d,J=7.2Hz,2H),7.35(td,J=7.2,1.2Hz,1H),7.21(td,J=7.2,1.2Hz,1H),7.18(t,J=7.2Hz,1H),7.16–7.12(m,1H),5.61(d,J=8.4Hz,1H),3.94(q,J=7.2Hz,2H),0.84(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3)δ165.4,157.3,138.9,136.3,133.9,131.6,131.2,130.5,129.9,129.1,128.4,125.9,123.8,123.5,122.4,120.0,116.6,116.1,112.9,110.4,61.0,13.5.HRMS(ESI)calcd for[M+H]+[C24H19N2O3]+383.1390,found 383.1382.
实施例2.
采用2-苯基-5-氟吲唑-3-酮(45.6mg,0.2mmol)和苯甲酰乙酸乙酯重氮(53mg,0.24mmol)为原料,按照实施例1的方法制备得到70.4mg黄色固体(洗脱剂为石油醚:乙酸乙酯=4:1)。收率88%。
1H NMR(600MHz,CDCl3)δ9.02(dd,J=8.4,1.2Hz,1H),7.64–7.58(m,2H),7.53(m,3H),7.42(m,2H),7.39–7.33(m,1H),7.23(td,J=7.8,1.2Hz,1H),6.90(td,J=9.0,3.0Hz,1H),5.56(dd,J=9.6,4.2Hz,1H),3.94(q,J=7.2Hz,2H),0.84(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3)δ165.3,158.2(d,J=242.9Hz),156.5,138.8,133.6,132.8,131.4,130.7,129.9,129.3,128.4,126.2,123.9,120.2,120.0(d,J=2.3Hz),117.4(d,J=9.0Hz),116.3,114.7(d,J=7.8Hz),110.4,108.3(d,J=23.9Hz),61.0,13.5.HRMS(ESI)calcd for[M+H]+[C24H18FN2O3]+401.1296,found 401.1294.
实施例3.
采用2-苯基-5-甲氧基吲唑-3-酮(48.0mg,0.2mmol)和苯甲酰乙酸乙酯重氮(53mg,0.24mmol)为原料,按照实施例1的方法制备得到70.1mg黄色固体(洗脱剂为石油醚:乙酸乙酯=4:1)。收率85%。
1H NMR(600MHz,CDCl3)δ9.04(d,J=7.8Hz,1H),7.60(t,J=7.8Hz,1H),7.54(m,3H),7.42(d,J=7.8Hz,2H),7.38–7.33(m,2H),7.22(t,J=7.8Hz,1H),6.78(dd,J=9.6,3.0Hz,1H),5.50(d,J=9.6Hz,1H),3.93(q,J=7.2Hz,2H),3.83(s,3H),0.83(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3)δ165.5,157.1,155.7,139.4,133.6,131.8,131.3,130.5,129.9,129.2,128.2,125.9,123.8,122.3,120.3,117.3,116.3,114.4,109.3,102.8,60.9,55.8,13.5.HRMS(ESI)calcd for[M+H]+[C25H21N2O4]+413.1496,found 413.1501.
实施例4.
采用2-苯基吲唑-3-酮(42.0mg,0.2mmol)和3-甲氧基苯甲酰乙酸甲酯重氮(56.2mg,0.24mmol)为原料,按照实施例1的方法制备得到62.8mg黄色固体(洗脱剂为石油醚:乙酸乙酯=4:1)。收率79%。
1H NMR(600MHz,CDCl3)δ9.05(dd,J=8.4,1.2Hz,1H),8.06–7.95(m,1H),7.47–7.41(m,2H),7.37–7.33(m,1H),7.24–7.16(m,3H),7.12(dd,J=8.4,2.4Hz,1H),7.01(d,J=7.2Hz,1H),6.98–6.91(m,1H),5.76–5.68(m,1H),3.81(s,3H),3.50(s,3H).13C NMR(150MHz,CDCl3)δ166.0,160.1,157.3,138.8,136.3,133.9,132.5,131.3,130.3,128.5,125.9,123.8,123.5,122.5,122.0,119.9,116.6,116.5,116.2,114.7,113.1,110.2,55.5,51.9.HRMS(ESI)calcd for[M+H]+[C24H19N2O4]+399.1339,found 399.1341.
实施例5.
采用2-苯基吲唑-3-酮(42.0mg,0.2mmol)和4-氟苯甲酰乙酸甲酯重氮(53.3mg,0.24mmol)为原料,按照实施例1的方法制备得到71.8mg黄色固体(洗脱剂为石油醚:乙酸乙酯=4:1)。收率93%。
1H NMR(600MHz,CDCl3)δ9.04(d,J=7.8Hz,1H),8.03(m,1H),7.49–7.40(m,3H),7.38(t,J=7.8Hz,1H),7.28(m,1H),7.25–7.18(m,4H),5.91–5.51(m,1H),3.53(s,3H).13CNMR(150MHz,CDCl3)δ165.8,163.8(d,J=250.7Hz),157.3,138.2,136.2,133.9,132.0(d,J=8.4Hz),131.4,128.6,127.4(d,J=3.5Hz),125.9,123.8(d,J=35.1Hz),122.7,119.8,116.7,116.6,116.4,116.1,112.7,110.8,51.9.HRMS(ESI)calcd for[M+H]+[C23H16FN2O3]+387.1139,found 387.1146.
实施例6.
采用2-苯基吲唑-3-酮(42.0mg,0.2mmol)和4-碘苯甲酰乙酸甲酯重氮(79.2mg,0.24mmol)为原料,按照实施例1的方法制备得到90.9mg黄色固体(洗脱剂为石油醚:乙酸乙酯=4:1)。收率92%。
1H NMR(600MHz,CDCl3)δ9.01(d,J=8.4Hz,1H),8.01(d,J=7.8Hz,1H),7.89(d,J=7.8Hz,2H),7.44(d,J=7.8Hz,1H),7.36(t,J=7.8Hz,1H),7.26–7.19(m,3H),7.17(d,J=8.4Hz,2H),5.75(d,J=7.8Hz,1H),3.51(s,3H).13C NMR(150MHz,CDCl3)δ165.7,157.3,138.4,138.2,136.3,134.0,131.5,131.4,130.9,128.7,125.9,124.0,123.8,122.7,119.8,116.7,116.1,112.8,110.7,96.9,52.0.HRMS(ESI)calcd for[M+H]+[C23H16IN2O3]+495.0200,found 495.0208.
实施例7.
采用2-苯基吲唑-3-酮(42.0mg,0.2mmol)和4-甲基苯甲酰乙酸甲酯重氮(52.3mg,0.24mmol)为原料,按照实施例1的方法制备得到72.6mg黄色固体(洗脱剂为石油醚:乙酸乙酯=4:1)。收率95%。
1H NMR(600MHz,CDCl3)δ9.05(d,J=7.8Hz,1H),8.05–7.92(m,1H),7.42(d,J=7.8Hz,1H),7.38–7.28(m,5H),7.22–7.12(m,3H),5.76–5.61(m,1H),3.49(s,3H),2.49(s,3H).13C NMR(150MHz,CDCl3)δ166.1,157.3,140.8,139.2,136.3,133.9,131.2,129.8,129.6,128.4,128.3,125.8,123.8,123.5,122.4,120.0,116.5,116.1,113.1,110.3,51.8,21.6.HRMS(ESI)calcd for[M+H]+[C24H19N2O3]+383.1390,found 383.1393.
实施例8.
采用2-(4-氯代苯基)-吲唑-3-酮(48.8mg,0.2mmol)和苯甲酰乙酸乙酯重氮(53mg,0.24mmol)为原料,按照实施例1的方法制备得到79.2mg黄色固体(洗脱剂为石油醚:乙酸乙酯=4:1)。收率95%。
1H NMR(600MHz,CDCl3)δ8.98(d,J=9.0Hz,1H),7.97(d,J=7.2Hz,1H),7.61(t,J=7.2Hz,1H),7.54(m,3H),7.42(d,J=7.2Hz,2H),7.27(dd,J=9.0Hz,2.4Hz,1H),7.18(m,1H),7.17–7.13(m,1H),5.58(d,J=8.4Hz,1H),3.93(q,J=7.2Hz,2H),0.82(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3)δ165.0,157.2,140.4,136.3,132.3,131.4,131.4,131.2,130.7,129.7,129.2,127.9,123.7,123.5,122.8,121.9,117.2,116.5,113.0,108.9,61.1,13.4.HRMS(ESI)calcd for[M+H]+[C24H18ClN2O3]+417.1000,found 417.0095.
实施例9.
称取45mg(0.2mmol)2-(4-甲基苯基)-吲唑-3-酮,53mg(0.24mmol)苯甲酰乙酸乙酯重氮,12mg(0.2mmol)乙酸和5mg(0.006mmol)[Cp*Rh(MeCN)3(SbF6)2]加入圆底反应瓶中,再加入2mL DCE溶解,在40℃下反应3小时。将反应液用硅胶拌样,硅胶柱层析(洗脱剂为石油醚:乙酸乙酯=4:1)分离得到75.3mg黄色固体。收率95%。
1H NMR(600MHz,CDCl3)δ8.94(d,J=8.4Hz,1H),7.99(d,J=7.8Hz,1H),7.60(t,J=7.8Hz,1H),7.53(t,J=7.8Hz,2H),7.45–7.41(m,2H),7.30(s,1H),7.17(t,J=7.8Hz,2H),7.13(t,J=7.8Hz,1H),5.60(d,J=8.4Hz,1H),3.94(q,J=7.2Hz,2H),2.35(s,3H),0.83(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3)δ165.6,157.0,138.6,136.1,135.7,131.7,131.5,131.0,130.5,130.0,129.1,128.9,124.2,123.5,122.4,119.8,116.6,116.1,112.9,110.4,61.0,21.2,13.5.HRMS(ESI)calcd for[M+H]+[C25H21N2O3]+397.1552,found397.1551.
实施例10.
采用2-(4-溴代苯基)-吲唑-3-酮(57.8mg,0.2mmol)和苯甲酰乙酸乙酯重氮(53mg,0.24mmol)为原料,按照实施例1的方法制备得到83.9mg黄色固体(洗脱剂为石油醚:乙酸乙酯=4:1)。收率91%。
1H NMR(600MHz,CDCl3)δ8.94(d,J=9.0Hz,1H),7.99(d,J=7.2Hz,1H),7.70(d,J=2.4Hz,1H),7.62(t,J=7.2Hz,1H),7.54(t,J=7.2Hz,2H),7.43(m,3H),7.20(t,J=7.2Hz,1H),7.18–7.14(m,1H),5.59(d,J=8.4Hz,1H),3.93(q,J=7.2Hz,2H),0.82(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3)δ165.0,157.3,140.4,136.3,132.9,131.5,131.4,130.9,130.7,129.8,129.2,126.6,123.6,122.8,122.1,119.0,117.5,116.6,113.1,108.9,61.1,13.4.HRMS(ESI)calcd for[M+H]+[C24H18BrN2O3]+461.0495,found 461.0493.
实施例11.
在一个圆底烧瓶中相继加入实施例10(46.1mg,0.1mmol),Zn(CN)2(7.1mg,0.06mmol)和Pd(PPh3)4(4.6mg,0.004mmol),随后加入1.0mL DMF,置换氮气后于100℃反应过夜,冷却至室温后,加入水和乙酸乙酯萃取,有机相拌样过硅胶柱(洗脱剂为石油醚:乙酸乙酯=3:1)纯化得到目标化合物38.6mg(黄色固体),收率95%。
1H NMR(600MHz,CDCl3)δ9.13(d,J=8.4Hz,1H),8.00(dd,J=7.2,1.8Hz,1H),7.88(d,J=1.8Hz,1H),7.64(t,J=7.2Hz,1H),7.59(dd,J=9.0,1.8Hz,1H),7.56(t,J=7.8Hz,2H),7.45–7.40(m,2H),7.25–7.16(m,2H),5.59(d,J=8.4Hz,1H),3.94(q,J=7.2Hz,2H),0.82(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3)δ164.7,157.7,141.4,137.2,136.7,132.2,132.1,131.1,130.9,129.6,129.3,127.4,123.9,123.2,121.3,118.4,116.2,116.1,113.1,109.3,108.1,61.3,13.4.HRMS(ESI)calcd for[M+H]+[C25H18N3O3]+408.1343,found408.1350.
实施例12.
在一个圆底烧瓶中相继加入实施例10(46.1mg,0.1mmol),苯硼酸(15.9mg,0.13mmol),Na2CO3(77.4mg,0.73mmol)和Pd(PPh3)4(4.6mg,0.004mmol),随后加入2.2mL溶剂(toluene/H2O/EtOH=5/5/1),置换氮气后回流反应过夜,冷却至室温后,加入水和乙酸乙酯萃取,有机相拌样过硅胶柱(洗脱剂为石油醚:乙酸乙酯=6:1)纯化得到目标化合物41.5mg(黄色固体),收率91%。
1H NMR(600MHz,CDCl3)δ9.13(d,J=8.4Hz,1H),8.01(d,J=7.2Hz,1H),7.76(d,J=2.4Hz,1H),7.64–7.60(m,3H),7.59(dd,J=8.4,2.4Hz,1H),7.55(t,J=7.8Hz,2H),7.48–7.42(m,4H),7.36(t,J=7.8Hz,1H),7.21–7.14(m,2H),5.62(d,J=8.4Hz,1H),3.96(q,J=7.2Hz,2H),0.85(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3)δ165.5,157.2,140.1,139.2,138.7,136.3,133.1,131.6,131.3,130.6,129.9,129.2,128.8,127.5,126.9,126.9,123.6,122.6,122.4,120.4,116.5,116.5,113.0,110.2,61.1,13.5.HRMS(ESI)calcd for[M+H]+[C30H23N2O3]+459.1703,found 459.1711.
实施例13.
在一个圆底烧瓶中相继加入实施例10(46.1mg,0.1mmol),吗啉(10.5mg,0.12mmol),Cs2CO3(65.2mg,0.2mmol),Pd(OAc)2(0.9mg,0.004mmol)和BINAP(2.5mg,0.004mmol),随后加入2.0mL甲苯,置换氮气后反应过夜,冷却至室温后,旋干溶剂,拌样过硅胶柱(洗脱剂为石油醚:乙酸乙酯=2:1)纯化得到目标化合物28.0mg(黄色固体),收率60%。
1H NMR(600MHz,CDCl3)δ8.96(d,J=9.0Hz,1H),7.98(d,J=7.8Hz,1H),7.60(t,J=7.8Hz,1H),7.53(t,J=7.8Hz,2H),7.44–7.40(m,2H),7.17(t,J=7.2Hz,1H),7.14(d,J=3.0Hz,1H),7.12(ddd,J=8.4,7.2,1.2Hz,1H),6.89(dd,J=9.0,2.4Hz,1H),5.58(d,J=8.4Hz,1H),3.91(q,J=7.2Hz,2H),3.89–3.84(m,4H),3.26–3.12(m,4H),0.80(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3)δ165.7,156.6,149.1,139.4,136.0,131.9,130.8,130.5,129.9,129.1,126.8,123.4,122.5,120.9,117.2,116.9,114.9,113.0,110.8,110.0,66.8,60.9,49.2,13.4.HRMS(ESI)calcd for[M+H]+[C28H26N3O4]+468.1918,found468.1920.
实施例14.
采用2-(3,5-二甲氧基苯基)-吲唑-3-酮(54.0mg,0.2mmol)和苯甲酰乙酸乙酯重氮(53mg,0.24mmol)为原料,按照实施例1的方法制备得到80.5mg黄色固体(洗脱剂为石油醚:乙酸乙酯=3:1)。收率91%。
1H NMR(600MHz,CDCl3)δ8.49(d,J=2.4Hz,1H),7.94(m,1H),7.53(t,J=7.2Hz,1H),7.47(t,J=7.2Hz,2H),7.45–7.41(m,2H),7.15–7.08(m,2H),6.35(d,J=2.4Hz,1H),5.72–5.63(m,1H),3.96(q,J=7.2Hz,2H),3.92(s,3H),3.79(s,3H),1.02(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3)δ166.7,160.9,157.5,155.0,136.8,136.4,134.7,131.3,131.1,130.4,130.3,128.7,123.4,121.9,116.2,112.8,109.9,103.2,97.1,93.8,60.9,56.1,55.8,13.9.HRMS(ESI)calcd for[M+H]+[C26H23N2O5]+443.1601,found 443.1598.
实施例15.
采用2-(3,4-亚甲二氧基苯基)-吲唑-3-酮(51.0mg,0.2mmol)和苯甲酰乙酸乙酯重氮(53mg,0.24mmol)为原料,按照实施例1的方法制备得到79.2mg黄色固体(洗脱剂为石油醚:乙酸乙酯=3:1)。收率93%。
1H NMR(600MHz,CDCl3)δ8.57(d,J=9.0Hz,1H),7.96(d,J=7.8Hz,1H),7.59(t,J=7.8Hz,1H),7.52(t,J=7.8Hz,2H),7.45(m,2H),7.16(t,J=7.2Hz,1H),7.14–7.09(m,1H),6.79(d,J=9.0Hz,1H),5.99(s,2H),5.61(d,J=8.4Hz,1H),4.00(q,J=7.2Hz,2H),1.00(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3)δ165.3,157.0,145.5,141.6,137.9,136.6,131.2,130.7,130.5,130.3,129.0,128.1,123.5,122.5,116.7,112.8,110.0,107.1,105.2,101.7,61.36,13.68.HRMS(ESI)calcd for[M+H]+[C25H19N2O5]+427.1288,found427.1287.
实施例16.
采用2-(4-氟代苯基)-吲唑-3-酮(45.6mg,0.2mmol)和苯甲酰乙酸乙酯重氮(53mg,0.24mmol)为原料,按照实施例1的方法制备得到75.3mg黄色固体(洗脱剂为石油醚:乙酸乙酯=4:1)。收率94%。
1H NMR(600MHz,CDCl3)δ9.03(dd,J=9.0,5.4Hz,1H),7.99(d,J=7.8Hz,1H),7.62(t,J=7.8Hz,1H),7.54(t,J=7.8Hz,2H),7.42(d,J=7.2Hz,2H),7.34(dd,J=9.6,3.0Hz,1H),7.19(t,J=7.2Hz,1H),7.17–7.12(m,1H),7.01(ddd,J=9.0,7.8,2.4Hz,1H),5.58(d,J=9.0Hz,1H),3.92(q,J=7.2Hz,2H),0.81(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3)δ165.1,160.1(d,J=243.6Hz),157.1,140.7,136.1,131.4,131.3,130.7,130.0(d,J=2.1Hz),129.7,129.2,123.5,122.9,122.4(d,J=9.2Hz),117.7(d,J=8.1Hz),116.7,114.4(d,J=22.5Hz),113.1,111.1(d,J=26.1Hz),109.0,61.1,13.4.HRMS(ESI)calcdfor[M+H]+[C24H18FN2O3]+401.1296,found 401.1297.
实施例17.
采用2-(4-甲氧基苯基)-吲唑-3-酮(48.0mg,0.2mmol)和苯甲酰乙酸乙酯重氮(53mg,0.24mmol)为原料,按照实施例1的方法制备得到75.9mg黄色固体(洗脱剂为石油醚:乙酸乙酯=4:1)。收率92%。
1H NMR(600MHz,CDCl3)δ9.00(d,J=9.0Hz,1H),7.99(d,J=7.8Hz,1H),7.60(t,J=7.2Hz,1H),7.53(t,J=7.2Hz,2H),7.43(d,J=7.2Hz,2H),7.18(t,J=7.2Hz,1H),7.16–7.08(m,2H),6.88(dd,J=9.0,2.4Hz,1H),5.59(d,J=9.0Hz,1H),3.93(q,J=7.2Hz,2H),3.84(s,3H),0.83(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3)δ165.4,157.3,156.7,139.6,136.0,131.7,130.9,130.5,129.9,129.1,127.5,123.4,122.6,121.5,117.5,116.9,113.0,112.9,109.9,109.6,61.0,55.5,13.5.HRMS(ESI)calcd for[M+H]+[C25H21N2O4]+413.1496,found 413.1499.
实施例18.
采用2-苯基吲唑-3-酮(42.0mg,0.2mmol)和乙酰乙酸乙酯重氮(37.4mg,0.24mmol)为原料,按照实施例1的方法制备得到55.5mg黄色固体(洗脱剂为石油醚:乙酸乙酯=3:1)。收率87%。
1H NMR(600MHz,CDCl3)δ8.92(d,J=8.4Hz,1H),8.07(d,J=8.4Hz,1H),7.63(m,2H),7.34(t,J=7.2Hz,1H),7.32–7.28(m,1H),7.26(dd,J=7.2,1.2Hz,1H),7.21–7.17(m,1H),4.42(q,J=7.2Hz,2H),2.68(s,3H),1.41(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3)δ166.7,157.0,138.1,136.9,133.3,131.9,127.8,125.8,124.1,123.6,122.9,120.3,117.3,116.2,113.7,109.6,61.5,18.4,14.3.HRMS(ESI)calcd for[M+H]+[C19H17N2O3]+321.1234,found 321.1228.
实施例19.
采用2-苯基吲唑-3-酮(42.0mg,0.2mmol)和乙酰乙酸甲酯重氮(34.1mg,0.24mmol)为原料,按照实施例1的方法制备得到51.5mg黄色固体(洗脱剂为石油醚:乙酸乙酯=3:1)。收率84%。
1H NMR(600MHz,CDCl3)δ8.91(dd,J=8.4,0.6Hz,1H),8.07(d,J=7.8Hz,1H),7.62(m,2H),7.36–7.32(m,1H),7.32–7.28(m,1H),7.23(dd,J=7.8,1.2Hz,1H),7.20–7.16(m,1H),3.94(s,3H),2.66(s,3H).13C NMR(150MHz,CDCl3)δ167.2,157.0,138.6,136.9,133.3,131.9,127.8,125.8,124.1,123.7,122.9,120.2,117.4,116.2,113.7,109.3,52.3,18.4.HRMS(ESI)calcd for[M+H]+[C18H15N2O3]+307.1077,found 307.1073.
实施例20.
采用2-(2-甲氧基苯基)-吲唑-3-酮(48.0mg,0.2mmol)和乙酰乙酸乙酯重氮(37.4mg,0.24mmol)为原料,按照实施例1的方法制备得到56.8mg黄色固体(洗脱剂为石油醚:乙酸乙酯=3:1)。收率81%。
1H NMR(600MHz,CDCl3)δ8.01(d,J=7.8Hz,1H),7.60(ddd,J=8.4,7.2,1.2Hz,1H),7.51(d,J=7.8Hz,1H),7.40(t,J=7.2Hz,1H),7.24(dd,J=16.2,8.4Hz,1H),6.94(d,J=7.8Hz,1H),6.87(dd,J=7.8,0.6Hz,1H),4.36(q,J=7.2Hz,2H),3.94(s,3H),2.50(s,3H),1.36(t,J=7.2Hz,3H).13C NMR(150MHz,CDCl3)δ166.7,157.7,151.2,144.1,141.3,131.2,128.1,126.9,124.7,123.7,120.5,119.5,116.0,115.5,112.5,110.3,61.3,56.3,17.6,14.2.HRMS(ESI)calcd for[M+H]+[C20H19N2O4]+351.1339,found 351.1346.
实施例21.
采用2-苯基吲唑-3-酮(44.0mg,0.2mmol)和丙酰乙酸甲酯重氮(37.4mg,0.24mmol)为原料,按照实施例9的方法制备得到58.3mg黄色固体(洗脱剂为石油醚:乙酸乙酯=4:1)。收率91%。
1H NMR(500MHz,CDCl3)δ8.92(d,J=8.5Hz,1H),8.09(d,J=7.5Hz,1H),7.69–7.63(m,1H),7.58(d,J=8.5Hz,1H),7.36(t,J=7.5Hz,1H),7.33–7.28(m,1H),7.22–7.16(m,2H),3.94(s,3H),2.99(q,J=7.5Hz,2H),1.46(t,J=7.5Hz,3H).13C NMR(150MHz,CDCl3)δ167.1,157.1,143.2,136.3,133.3,132.3,127.8,125.9,124.2,123.6,122.9,120.4,117.3,116.3,113.1,108.7,52.3,23.4,13.3.HRMS(ESI)calcd for[M+H]+[C19H17N2O3]+321.1234,found 321.1231.
实施例22.
采用2-苯基吲唑-3-酮(44.0mg,0.2mmol)和3-环丙基-3-氧代丙酸甲酯重氮(40.3mg,0.24mmol)为原料,按照实施例9的方法制备得到59.8mg黄色固体(洗脱剂为石油醚:乙酸乙酯=4:1)。收率90%。
1H NMR(600MHz,CDCl3)δ8.98(d,J=7.8Hz,1H),8.06(d,J=7.8Hz,1H),7.94(d,J=8.4Hz,1H),7.60(t,J=7.8Hz,1H),7.35–7.28(m,2H),7.24(d,J=7.8Hz,1H),7.17(t,J=7.8Hz,1H),3.95(s,3H),2.24–2.10(m,1H),1.20–1.11(m,2H),0.77(m,2H).13C NMR(150MHz,CDCl3)δ167.4,157.1,141.3,136.5,133.5,131.4,128.2,125.8,123.7,123.2,122.5,119.9,116.6,116.1,114.2,111.6,52.3,13.7,10.2.HRMS(ESI)calcd for[M+H]+[C20H17N2O3]+333.1234,found 333.1233.
实施例23.
采用2-苯基吲唑-3-酮(44.0mg,0.2mmol)和呋喃-2-甲酰乙酸甲酯重氮(46.6mg,0.24mmol)为原料,按照实施例1的方法制备得到66.5mg黄色固体(洗脱剂为石油醚:乙酸乙酯=4:1)。收率93%。
1H NMR(600MHz,CDCl3)δ8.99(dd,J=8.4,1.2Hz,1H),8.01(d,J=7.8Hz,1H),7.66(d,J=1.2Hz,1H),7.48(dd,J=7.8,1.2Hz,1H),7.36(t,J=7.8Hz,2H),7.24(t,J=7.2Hz,1H),7.19(td,J=7.8,1.2Hz,1H),6.74(d,J=3.0Hz,1H),6.63(dd,J=3.3,1.8Hz,1H),5.73(d,J=8.4Hz,1H),3.63(s,3H).13C NMR(150MHz,CDCl3)δ165.6,157.6,144.3,144.2,142.7,136.3,134.7,132.0,131.8,129.3,129.1,125.9,124.5,123.6,122.7,119.4,116.4,116.1,114.5,113.4,112.0,111.5,52.3.HRMS(ESI)calcd for[M+H]+[C21H15N2O4]+359.1026,found 359.1031.
实施例24.
在一个圆底烧瓶中相继加入实施例1(38.2mg,0.1mmol),KOH(22.4mg,0.4mmol)和1.0mL乙二醇。随后在110℃反应3小时,冷却至室温后,加入3mL冰水,析出固体,过滤干燥之后过硅胶柱纯化(洗脱剂为石油醚:乙酸乙酯=2:1)得到目标化合物35.1mg(黄色固体),收率88%。
1H NMR(500MHz,DMSO-d6)δ8.93(dd,J=8.3,0.9Hz,1H),7.90(d,J=7.2Hz,1H),7.69–7.64(m,1H),7.59(t,J=7.6Hz,2H),7.56–7.51(m,2H),7.48–7.39(m,2H),7.32–7.21(m,3H),5.53(d,J=8.5Hz,1H),4.72(t,J=5.4Hz,1H),3.87(t,J=5.4Hz,2H),3.25(q,J=5.4Hz,2H).13C NMR(125MHz,DMSO-d6)δ164.8,156.4,139.0,136.0,133.5,131.6,130.8,130.7,129.8,129.1,128.2,125.9,123.8,123.1,122.6,119.8,115.8,115.2,112.6,109.5,66.2,58.3.HRMS(ESI)calcd for[M+Na]+[C24H18N2NaO4]+421.1164,found 421.1161.
实施例25.
在一个圆底烧瓶中相继加入实施例18(32.0mg,0.1mmol),KOH(22.4mg,0.4mmol)和1.0mL乙二醇。随后在110℃反应3小时,冷却至室温后,加入3mL冰水,析出固体,过滤干燥之后过硅胶柱(洗脱剂为石油醚:乙酸乙酯=1:1)纯化得到目标化合物30.6mg(黄色固体),收率91%。
1H NMR(500MHz,DMSO-d6)δ8.78(d,J=8.2Hz,1H),7.97(d,J=9.0Hz,2H),7.78–7.73(m,1H),7.43(t,J=7.5Hz,1H),7.38–7.32(m,2H),7.27–7.22(m,1H),4.97(t,J=5.3Hz,1H),4.42–4.28(m,2H),3.70(q,J=5.1Hz,2H),2.68(s,3H).13C NMR(125MHz,DMSO-d6)δ166.1,156.38,139.3,136.9,132.8,132.4,127.4,125.9,123.7,123.1,123.1,120.2,116.3,115.2,115.0,108.4,66.9,58.8,17.9.HRMS(ESI)calcd for[M+Na]+[C19H16N2NaO4]+359.1008,found 359.1003.
实施例26.
采用2-(4-氟代苯基)-吲唑-3-酮(45.6mg,0.2mmol)和1,3-环己二酮重氮(33.1mg,0.24mmol)为原料,按照实施例9的制备方法得到61.5mg黄色固体(洗脱剂为石油醚:乙酸乙酯=0.5:1)。收率96%。
1H NMR(600MHz,CDCl3)δ8.84(dd,J=9.0,5.4Hz,1H),8.53(dd,J=11.4,3.0Hz,1H),8.09(d,J=7.8Hz,1H),7.74–7.65(m,2H),7.44(dd,J=10.5,3.9Hz,1H),6.97(ddd,J=9.0,7.8,3.0Hz,1H),3.3(t,J=6.2Hz,2H),2.70–2.55(m,2H),2.33–2.20(m,2H).13C NMR(100MHz,CDCl3)δ194.1,160.06(d,J=243.7Hz),156.5,151.6,136.3,132.3,129.2,124.4,121.7(d,J=10.0Hz),118.7,117.1(d,J=8.3Hz),114.4,113.9(d,J=23.2Hz),113.3(d,J=27.6Hz),108.5,37.7,28.2,20.9.HRMS(ESI)calcd for[M+H]+[C19H14FN2O2]+321.1039,found 321.1037.
实施例27.
采用2-(4-碘代苯基)-吲唑-3-酮(67.2mg,0.2mmol)和1,3-环戊二酮重氮(29.8mg,0.24mmol)为原料,按照实施例9的方法制备得到76.2mg黄色固体(洗脱剂为石油醚:乙酸乙酯=0.5:1)。收率92%。
1H NMR(500MHz,DMSO-d6)δ8.65(d,J=8.5Hz,1H),8.57(d,J=2.0Hz,1H),8.03(d,J=8.0Hz,1H),7.97(d,J=8.5Hz,1H),7.87(t,J=8.0Hz,1H),7.71(dd,J=8.5,2.0Hz,1H),7.53(t,J=7.5Hz,1H),3.46–3.41(m,2H),2.69–2.63(m,2H).13C NMR(125MHz,DMSO-d6)δ198.2,161.8,156.3,136.0,135.2,133.3,131.7,129.5,124.5,123.4,120.2,117.1,116.2,113.1,108.1,90.5,34.0,25.0.HRMS(ESI)calcd for[M+H]+[C18H12IN2O2]+414.9943,found 414.9936.
实施例28.
采用2-(2-氟代苯基)-吲唑-3-酮(45.6mg,0.2mmol)和1,3-环戊二酮重氮(29.8mg,0.24mmol)为原料,按照实施例9的方法制备得到52.1mg黄色固体(洗脱剂为石油醚:乙酸乙酯=0.5:1)。收率85%。
1H NMR(500MHz,CD2Cl2)δ8.10(d,J=7.0Hz,1H),8.04(d,J=8.0Hz,1H),7.81–7.75(m,1H),7.60(d,J=8.5Hz,1H),7.53(t,J=7.5Hz,1H),7.30(td,J=8.0,5.0Hz,1H),7.16–7.09(m,1H),3.23–3.15(m,2H),2.72–2.65(m,2H).13C NMR(125MHz,CD2Cl2)δ198.6,165.5,157.8,152.9(d,J=256.8Hz),139.6,133.4,129.1(d,J=8.1Hz),126.2(d,J=13.1Hz),126.0,124.6,124.2,118.7(d,J=30.0Hz),117.9(d,J=12.6Hz),117.2(d,J=20.5Hz),113.5,34.6,25.6.HRMS(ESI)calcd for[M+H]+[C18H12FN2O2]+307.0883,found307.0879.
实施例29.
采用2-(3,5-二甲氧基苯基)-吲唑-3-酮(54.0mg,0.2mmol)和1,3-环戊二酮重氮(29.8mg,0.24mmol)为原料,按照实施例9的方法制备得到62.7mg黄色固体(洗脱剂为石油醚:乙酸乙酯=0.5:1)。收率90%。
1H NMR(500MHz,DMSO-d6)δ8.14(d,J=2.5Hz,1H),7.97(d,J=8.0Hz,1H),7.93(d,J=8.5Hz,1H),7.83(t,J=8.0Hz,1H),7.48(t,J=7.5Hz,1H),6.58(d,J=2.0Hz,1H),3.83(s,3H),3.82(s,3H),3.36–3.28(m,2H),2.58–2.54(m,2H).13C NMR(125MHz,DMSO-d6)δ194.4,160.0,156.4,136.3,134.7,133.1,124.0,123.4,116.8,113.4,112.4,100.9,97.0,94.5,56.1,55.5,34.1,24.3.HRMS(ESI)calcd for[M+H]+[C20H17N2O4]+349.1188,found349.1184.
实施例30.
采用2-苯基吲唑-3-酮(42.0mg,0.2mmol)和丙酮基膦酸二甲酯重氮(46.1mg,0.24mmol)为原料,按照实施例1的方法制备得到69.3mg黄色固体(洗脱剂为石油醚:乙酸乙酯=0.5:1)。收率97%。
1H NMR(600MHz,CDCl3)δ8.76(d,J=8.4Hz,1H),8.07(d,J=7.8Hz,1H),7.73(dd,J=7.8,1.2Hz,1H),7.71(d,J=8.4Hz,1H),7.65(td,J=7.8,1.2Hz,1H),7.38(t,J=7.8Hz,1H),7.29(td,J=7.8,1.2Hz,1H),7.20(td,J=7.8,1.2Hz,1H),3.77(s,3H),3.76(s,3H),3.11(d,J=2.4Hz,3H).13C NMR(150MHz,CDCl3)δ157.2,149.9(d,J=24.7Hz),137.5,133.4(d,J=11.1Hz),132.1,127.4,125.9,125.4,124.1,123.7,121.3(d,J=8.8Hz),118.5,115.8,115.1,99.2(d,J=200.5Hz),52.3(d,J=16.8Hz),18.6.HRMS(ESI)calcd for[M+H]+[C18H18N2O4P]+357.0999,found 357.1002.
体外抗肿瘤活性实验
采用CCK-8法并选取人前列腺癌PC-3细胞(源于日本癌症研究基金会)进行体外抗肿瘤活性评价(采用雷公藤甲素作为阳性对照),操作如下:
1、在96孔板中接种100μL PC-3细胞悬液,每孔细胞密度为1×104个,设不含细胞的空白对照,将96孔板在培养箱预培养24小时(37℃,5%CO2)使细胞贴壁;
2、向培养孔中加入10μL不同浓度的待测化合物,每个浓度设3个平行孔(设不含药物的对照组)。在培养箱中孵育72小时后,向每孔加入10μL CCK-8溶液,将96孔板在培养箱内孵育1-4小时;
3、用酶标仪测定在450nM处的吸光度:
细胞活力(%)=(A加药-A空白)/(A0加药-A空白)×100%
A加药:含有细胞悬液、CCK-8溶液和待测化合物溶液的孔的吸光度
A空白:不含细胞悬液,含有培养基溶液、CCK-8溶液和待测化合物溶液的孔的吸光度
A0加药:不含待测化合物溶液,含有细胞悬液、CCK-8溶液和培养基溶液的孔的吸光度
细胞抑制率(%)=(A0加药-A加药)/(A0加药-A空白)×100%
表1、化合物在三种浓度下对PC-3细胞的抑制率
表1的结果表明:所测的30个化合物中有26个化合物在50μM时对PC-3细胞的抑制率大于50%,有12个化合物在5μM时对PC-3细胞的抑制率大于50%,有3个化合物在0.5μM时对PC-3细胞的抑制率大于50%。可见,这一类12H-吲唑[2,1-a]噌啉-12-酮类化合物具有良好的抗肿瘤活性,代表所述的化合物具有显著的抗肿瘤活性。
进一步选取活性较好的化合物6、8、13、15、17、19和20测试它们对人前列腺癌PC-3细胞和人胰腺癌PANC-1细胞(源于日本癌症研究基金会)的半数抑制浓度IC50。结果如表2所示:化合物6、13、15、17、19和20对PC-3细胞的IC50均小于10μM,其中6、17、19和20对PC-3细胞的IC50均小于5μM,并且化合物20对PC-3细胞的IC50为216nM。化合物6、17、19和20对PANC-1细胞的IC50均小于10μM,其中17、19和20对PANC-1细胞的IC50均小于5μM,并且化合物19和20对PANC-1细胞的IC50均小于1μM,分别为551nM和216nM。这些良好的结果进一步说明这类化合物具有显著的抗肿瘤活性。
表2、部分化合物对PC-3和PANC-1细胞的抑制活性
a每个实验采用9个浓度且至少重复三遍
上述实例只为说明本发明的技术构思及特点,其目的在于让熟悉此项技术的人员能够了解本发明的内容并据以实施,并不能以此限制本发明的保护范围。凡根据本发明精神实质所做的等效变换或修饰,都应涵盖在本发明的保护范围之内。
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