CN111100116A - 一类新型的含甲基吲哚的以吡唑啉为骨架的苯胺衍生物的制备方法及应用 - Google Patents
一类新型的含甲基吲哚的以吡唑啉为骨架的苯胺衍生物的制备方法及应用 Download PDFInfo
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Abstract
Description
技术领域
本明属于药物化学技术领域,具体内容涉及一类含甲基吲哚的以吡唑啉为骨架的苯胺衍生物、其制备方法及其在抗结肠癌肿瘤方向的应用。
背景技术
近年来,以抗癌药物和治疗为主的蛋白-蛋白相互作用,因其对癌细胞增殖和迁移的调节而受到广泛的关注。研究发现,在结肠癌肿瘤细胞增殖和迁移过程中发挥重要作用的关键蛋白调控机制涉及到APC-Asef的相互作用。腺瘤样息肉病杆菌(adenomatouspolyposis coli,APC)是一种重要的抑制蛋白,根据临床研究,APC蛋白截短与85%以上的先天性结肠癌患者和80%的后天性结肠癌患者相关。其病理原因与病理APC信号被激活,阻断了Asef(APC受体)的负调控有关,从而导致人类结直肠癌的增殖和迁移。因此敲除APC或Asef均可防止二者的相互作用,从而减少结直肠癌的恶化。在治疗上,研究人员通过将外源性野生型APC基因转染到病理细胞中,恢复全长APC,阻断Asef与突变APC的结合,实现了外源性野生型APC基因的表达。然而,基因敲除、外源表达和基因诱导在体内难以控制。因此,阻断APC-Asef相互作用的小分子功能抑制剂引起了研究者的关注。
吡唑类是一类重要的五元氮杂环化合物,具有抗菌、解热镇痛、神经保护、抗肿瘤以及抗炎等作用,在医药领域内尤其是抗肿瘤方面具有重要的应用价值。本发明引入吡唑骨架,再结合与线粒体作用相关的吲哚结构,通过利用Discovery Studio软件将小分子和APC蛋白进行分子对接,并对其进行相应的修饰改造,发现其在APC-Asef相互作用方面表现出很好的抑制性。
因此,本发明设计了一类新型的含甲基吲哚的以吡唑啉为骨架的苯胺衍生物,并验证了化合物在抗结肠癌肿瘤中的应用。
发明内容
本发明的目的一在于提供一类含甲基吲哚的以吡唑啉为骨架的苯胺衍生物。
本发明的目的二在于提供目的一所述化合物的一种制备方法。
本发明的目的三在于提供目的一所述化合物在抗结肠癌肿瘤方向的应用。
本发明所述一类含甲基吲哚的以吡唑啉为骨架的苯胺衍生物,具有以下所示的结构:
其中,R1选自H、-CH3O;R2选自H、-CH3O;R3选自H、-CH3O、-CH3;R4选自H、-Br、-Cl、-NO2、-CF3、-F;R5选自H、-Cl、-F、-NO2;R6选自H、-CF3。
本发明所述一含甲基吲哚的以吡唑啉为骨架的苯胺衍生物,其制备方法如下:
其中,R1选自H、-CH3O;R2选自H、-CH3O;R3选自H、-CH3O、-CH3;R4选自H、-Br、-Cl、-NO2、-CF3、-F;R5选自H、-Cl、-F、-NO2;R6选自H、-CF3。
步骤i:在0℃下,将吲哚-5-甲醛(1.0mmol)溶解于无水DMF中,缓慢加入氢化钠(1.5mmol),搅拌30分钟,然后逐滴加入用DMF溶解的碘甲烷(1.5mmol),将反应转移至室温,继续搅拌12小时。TCL检测反应结束后,加入过量1N的盐酸淬灭,并用二氯甲烷萃取三次,收集有机层,用无水硫酸钠干燥过滤,真空旋干。以正己烷∶乙酸乙酯(4∶1 v∶v)为流动相,柱层析法纯化粗品,得到中间化合物2。
步骤ii:将化合物2(6mmol)溶解在10ml无水乙醇中,向反应体系中加入苯乙酮衍生物(6mmol),逐滴加入40%氢氧化钠溶液(9mmol)。反应在室温下搅拌4小时,过滤得到化合物3-4粗品。
步骤iii:将4-肼基苯甲酸(4.0mmol)、化合物3-4(2.0mmol)溶于甲醇中,加入冰醋酸(0.2mmol)。在室温下搅拌30min,加热至回流温度,搅拌过夜。TCL检测反应结束后,以正己烷∶乙酸乙酯(2∶1 v∶v)为洗脱剂,柱层析纯化得到相应化合物5-6。
步骤iv:0℃下,将化合物5-6(1mmol)溶于无水二氯甲烷(30ml)中,然后将EDC(1.6mmol),HOBt(0.6mmol)依次加入到反应液中,搅拌30分钟,之后将苯胺衍生物(0.6mmol)加入到反应液中,将反应混合液转移到常温,搅拌反应过夜。TLC监测反应结束后,用10%碳酸氢钠水溶液对反应进行猝灭,用二氯甲烷(3×100m1)萃取。用10%碳酸氢钠水溶液清洗有机层三次,无水硫酸钠除水干燥过滤,真空蒸干。得到的粗品以正己烷∶乙酸乙酯(6∶1 v∶v)为洗脱液,柱层析纯化得到目的化合物Q1-Q20。
具体实施方式:
实施例一:
4-(3-(4-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)-N-苯基苯甲酰胺(Q1)的制备:
在0℃下,将吲哚-5-甲醛(1.0mmol)溶解于无水DMF中,缓慢加入氢化钠(1.5mmol),搅拌30分钟,然后逐滴加入用DMF溶解的碘甲烷,将反应转移至室温,继续搅拌12小时。TCL检测反应结束后,加入过量1N的盐酸淬灭,并用二氯甲烷萃取三次,收集有机层,用无水硫酸钠干燥过滤,真空旋干。以正己烷/乙酸乙酯(4∶1 v∶v)为流动相,柱层析法纯化粗品,得到中间化合物2粗品。将化合物2(6mmol)溶解在10ml无水乙醇中,向反应体系中加入对甲氧基苯乙酮(6mmol),逐滴加入40%氢氧化钠溶液(9mmol)。反应在室温下搅拌4小时,过滤得到化合物3粗品。将4-肼基苯甲酸(4.0mmol)、化合物3(2.0mmol)溶于甲醇中,加入冰醋酸(0.2mmol)。在室温下搅拌30min,加热至回流温度,搅拌过夜。用薄层色谱法测定反应过程。反应结束后,以正己烷/乙酸乙酯(2∶1 v∶v)为洗脱剂,柱层析纯化得到相应化合物5。0℃下,将化合物5(1mmol)溶于无水二氯甲烷(30ml)中,然后将EDC(1.6mmol),HOBt(0.6mmol)依次加入到反应液中,搅拌30分钟,之后将苯胺(0.6mmol)加入到反应液中,将反应混合液转移到常温,搅拌反应过夜。TLC监测反应结束后,用10%碳酸氢钠水溶液对反应进行猝灭,用二氯甲烷(3×100ml)萃取。用10%碳酸氢钠水溶液清洗有机层三次,无水硫酸钠除水干燥过滤,真空蒸干。得到的粗品以正己烷/乙酸乙酯(6∶1 v∶v)为洗脱液,柱层析纯化得到目的化合物4-(3-(4-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)-N-苯基苯甲酰胺(Q1)。黄色固体,产率:80.6%,m.p.204-212℃.1H NMR(400MHz,DMSO-d6)δ9.82(s,1H),7.76(s,1H),7.74(s,1H),7.71(s,2H),7.69(s,2H),7.46(s,1H),7.39(d,J=8.4Hz,1H),7.31-7.25(m,5H),7.11(s,1H),7.09(s,1H),7.08-7.00(m,2H),6.37(d,J=3.0Hz,1H),5.67(dd,J=12.1,5.3Hz,1H),3.98(dd,J=17.7,12.1Hz,1H),3.74(s,3H),3.19(dd,J=17.6,5.4Hz,1H),2.35(s,3H).HRMS(ESI-TOF)Calcd.for C32H28N4O2[M+H]+501.2265;Found 501.2267.
实施例二:
N-(4-甲氧基苯基)-4-(3-(4-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)苯甲酰胺(Q2)的制备
制备方法参考实施例一。白色固体,产率:86.3%,m.p.112-117℃.1H NMR(600MHz,DMSO-d6)δ9.00(s,1H),8.14(d,J=8.4Hz,1H),8.01(d,J=8.8Hz,1H),7.82-7.78(m,1H),7.75(t,J=9.1Hz,2H),7.70(d,J=7.9Hz,1H),7.62(t,J=7.7Hz,1H),7.51(t,J=7.7Hz,1H),7.45(s,1H),7.41(dd,J=16.7,8.5Hz,1H),7.34-7.29(m,2H),7.27(d,J=8.0Hz,1H),7.10(dd,J=8.1,5.9Hz,1H),7.06(ddt,J=8.4,4.0,1.7Hz,1H),6.95-6.90(m,1H),6.38(dd,J=10.0,3.1Hz,1H),5.81(dd,J=11.8,4.6Hz,1H),4.01(ddd,J=45.2,17.7,12.0Hz,1H),3.80(s,3H),3.75(d,J=5.6Hz,3H),3.22(ddd,J=53.3,17.7,5.0Hz,1H),2.36(d,J=8.5Hz,3H).HRMS(ESI-TOF)Calcd.for C33H30N4O3[M+H]+531.2373;Found531.2371.
实施例三:
N-(3-溴苯基)-4-(3-(4-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)苯甲酰胺(Q3)的制备
制备方法参考实施例一。白色固体,产率:76.5%,m.p.110-115℃.1H NMR(600MHz,DMSO-d6)δ9.98(s,1H),8.04(s,1H),7.94(d,J=8.6Hz,0.5H),7.86(d,J=7.9Hz,0.5H),7.73(dd,J=19.4,8.3Hz,3H),7.68(d,J=8.4Hz,1H),7.48-7.44(m,1H),7.40(d,J=8.5Hz,1H),7.33-7.20(m,5H),7.12-7.08(m,2H),7.06(dd,J=8.5,1.4Hz,1H),6.37(d,J=3.0Hz,1H),5.69(dd,J=12.1,5.3Hz,1H),3.98(dd,J=17.5,12.1Hz,1H),3.81(s,1H),3.74(s,2H),3.19(dd,J=17.5,5.3Hz,1H),2.36(d,J=5.3Hz,3H).HRMS(ESI-TOF)Calcd.for C32H27BrN4O2[M+H]+579.1379;Found 579.1377.
实施例四:
N-(4-氯苯基)-4-(3-(4-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)苯甲酰胺(Q4)的制备
制备方法参考实施例一。黄色固体,产率:60%,m.p.142-149℃.1H NMR(600MHz,DMSO-d6)δ8.14(d,J=8.6Hz,1H),8.00(dd,J=8.4,6.4Hz,2H),7.80(d,J=8.3Hz,1H),7.76(d,J=8.2Hz,2H),7.64-7.58(m,1H),7.54-7.48(m,1H),7.46(d,J=1.7Hz,1H),7.41(dd,J=14.4,8.5Hz,2H),7.33(d,J=3.1Hz,1H),7.30(s,1H),7.29(s,1H),7.23(s,1H),7.07(dd,J=8.5,1.8Hz,1H),6.39(d,J=3.1Hz,1H),5.81(dd,J=11.9,4.6Hz,1H),4.04(dd,J=17.8,11.9Hz,1H),3.75(s,3H),3.26(dd,J=17.8,4.6Hz,1H),2.36(s,3H).HRMS(ESI-TOF)Calcd.for C32H27ClN4O2[M+H]+535.1813;Found 535.1812.
实施例五:
N-(4-氟苯基)-4-(3-(4-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)苯甲酰胺(Q5)的制备
制备方法参考实施例一。白色固体,产率:83.3%,m.p.128-135℃.1H NMR(600MHz,DMSO-d6)δ9.68(s,1H),7.97(d,J=8.5Hz,1H),7.86(d,J=8.0Hz,1H),7.76(d,J=8.6Hz,1H),7.71(d,J=8.0Hz,1H),7.62-7.57(m,1H),7.54(t,J=7.9,1H),7.47(dd,J=8.6,2.9Hz,1H),7.45(d,J=1.6Hz,1H),7.39(d,J=8.0Hz,1H),7.31(d,J=3.2Hz,1H),7.27(t,J=6.4Hz,2H),7.23-7.20(m,1H),7.17(t,J=7.5,1.7Hz,1H),7.09(d,J=10.5Hz,1H),7.05(t,J=9.3Hz,1H),6.37(d,J=3.0Hz,1H),5.69(dd,J=12.1,5.2Hz,1H),3.98(dd,J=17.6,12.1Hz,1H),3.77(d,J=39.8Hz,3H),3.19(dd,J=17.6,5.2Hz,1H),2.36(d,J=6.8Hz,3H).HRMS(ESI-TOF)Calcd.for C32H27FN4O2[M+H]+519.2217;Found 519.2216.
实施例六:
4-(3-(4-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)-N-(o-甲苯基)苯甲酰胺(Q6)的制备
制备方法参考实施例一。白色固体,产率:76.9%,m.p.112-115℃.1H NMR(600MHz,DMSO-d6)δ10.13(s,1H),8.18(d,J=8.5Hz,1H),8.13(d,J=9.1Hz,2H),8.00(d,J=9.4Hz,1H),7.87(d,J=8.4Hz,1H),7.83-7.80(m,3H),7.67(ddd,J=8.1,6.9,0.9Hz,1H),7.54(ddd,J=8.2,6.9,1.0Hz,1H),7.46(s,1H),7.43(d,J=8.6Hz,1H),7.07(dd,J=8.5,1.8Hz,1H),7.05-7.03(m,1H),7.00(d,J=2.2Hz,1H),6.99(d,J=2.1Hz,1H),6.39(d,J=3.1Hz,1H),5.80(td,J=11.6,4.5Hz,1H),4.05(ddd,J=17.6,11.8,5.2Hz,1H),3.82(s,1.5H),3.80(s,3H),3.76(s,1.5H),3.26(dd,J=17.8,4.6Hz,1H),2.34(s,3H).HRMS(ESI-TOF)Calcd.for C33H30N4O2[M+H]+515.2480;Found 515.2478.
实施例七:
N-(3,4-二氯苯基)-4-(3-(4-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑)苯甲酰胺(Q7)的制备
制备方法参考实施例一。黄色固体,产率:59.8%,m.p.114-119℃.1H NMR(600MHz,DMSO-d6)δ8.14(d,J=8.5Hz,1H),8.01(d,J=9.4Hz,2H),7.81(d,J=8.4Hz,1H),7.76(d,J=8.2Hz,2H),7.62(ddd,J=8.1,6.9,0.9Hz,1H),7.51(ddd,J=8.2,7.0,1.0Hz,1H),7.46(d,J=1.7Hz,1H),7.43(d,J=8.5Hz,1H),7.33(d,J=3.1Hz,1H),7.30(d,J=8.1Hz,2H),7.23(d,J=9.8Hz,1H),7.06(dt,J=9.2,2.8Hz,1H),6.39(dd,J=3.1,0.8Hz,1H),5.81(dd,J=11.8,4.6Hz,1H),4.05(dd,J=17.8,11.8Hz,1H),3.75(d,J=9.6Hz,3H),3.26(dd,J=17.8,4.6Hz,1H),2.36(s,3H).HRMS(ESI-TOF)Calcd.for C32H26Cl2N4O2[M+H]+569.1464;Found 569.1463.
实施例八:
N-(3,4-二硝基苯基)-4-(3-(4-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)苯甲酰胺(Q8)的制备
制备方法参考实施例一。白色固体,产率:85.5%,m.p.135-142℃.1H NMR(600MHz,DMSO-d6)δ8.14(d,J=8.5Hz,1H),8.01(s,1H),7.99(s,1H),7.83-7.78(m,3H),7.61(t,J=7.6Hz,1H),7.51(t,J=7.2Hz,1H),7.45(d,J=1.7Hz,1H),7.43(d,J=8.5Hz,1H),7.33(d,J=3.1Hz,1H),7.21(s,1H),7.07(dd,J=8.5,1.8Hz,1H),7.05(s,1H),7.03(s,1H),6.39(dd,J=3.1,0.8Hz,1H),5.79(dd,J=11.8,4.5Hz,1H),4.04(dd,J=17.8,11.8Hz,1H),3.82(s,3H),3.76(s,3H),3.26(dd,J=17.8,4.5Hz,1H).HRMS(ESI-TOF)Calcd.for C32H26N6O6[M+H]+591.1967;Found 591.1866.
实施例九:
N-(3,5-二-(三氟甲基)苯基)-4-(3-(4-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)苯甲酰胺(Q9)的制备
制备方法参考实施例一。白色固体,产率:90.6%,m.p.128-140℃.1H NMR(600MHz,DMSO-d6)δ8.14(d,J=8.5Hz,1H),8.00(d,J=9.3Hz,2H),7.80(dd,J=8.5,6.6Hz,3H),7.61(ddd,J=8.1,6.9,0.9Hz,1H),7.51(ddd,J=8.1,6.9,1.0Hz,1H),7.46(s,1H),7.42(d,J=8.4Hz,1H),7.33(d,J=3.1Hz,1H),7.21(s,1H),7.07(dd,J=8.5,1.7Hz,1H),7.05(s,1H),7.03(s,1H),6.40-6.35(d,J=3.0Hz,1H),5.78(dd,J=11.8,4.5Hz,1H),4.03(dd,J=17.8,11.8Hz,1H),3.82(s,3H),3.75(s,3H),3.26(dd,J=17.8,4.5Hz,1H).HRMS(ESI-TOF)Calcd.for C34H26F6N4O2[M+H]+637.2044;Found 637.2043.
实施例十:
N-(3,4-二氟苯基)-4-(3-(4-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)苯甲酰胺(Q10)的制备
制备方法参考实施例一。黄色固体,产率:78.2%,m.p.130-138℃.1H NMR(600MHz,DMSO-d6)δ8.14(d,J=8.5Hz,1H),8.00(d,J=8.8Hz,2H),7.80(dd,J=8.4,5.8Hz,3H),7.61(t,J=7.6Hz,1H),7.51(t,J=8.6Hz,1H),7.46(s,1H),7.43(d,J=8.5Hz,1H),7.33(d,J=3.1Hz,1H),7.21(s,1H),7.05(dd,J=15.5,8.7Hz,3H),6.39(d,J=3.1Hz,1H),5.79(dd,J=11.8,4.5Hz,1H),4.04(dd,J=17.8,11.8Hz,1H),3.82(s,3H),3.75(s,3H),3.26(dd,J=17.8,4.5Hz,1H).HRMS(ESI-TOF)Calcd.for C32H26F2N4O2[M+H]+536.2052;Found 536.2050.
实施例十一:
4-(3-(3-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)-N-苯基苯甲酰胺(Q11)的制备
制备方法参考实施例一。白色固体,产率:85.2%,m.p.145-150℃.1H NMR(600MHz,DMSO-d6)δ9.85(s,1H),7.75(d,J=8.5Hz,2H),7.70(d,J=8.0Hz,2H),7.46(s,1H),7.39(dd,J=16.3,9.4Hz,3H),7.34(s,1H),7.32-7.27(m,3H),7.12(d,J=8.5Hz,2H),7.07(d,J=8.6Hz,1H),7.03(t,J=7.4Hz,1H),6.99(d,J=7.8Hz,1H),6.37(d,J=3.0Hz,1H),5.71(dd,J=12.2,5.4Hz,1H),3.99(dd,J=17.5,12.1Hz,1H),3.83(s,3H),3.74(s,3H),3.22(dd,J=17.6,5.4Hz,1H).HRMS(ESI-TOF)Calcd.for C32H28N4O2[M+H]+501.2325;Found 501.2325.
实施例十二:
N-(2-甲氧基苯基)-4-(3-(3-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)苯甲酰胺(Q12)的制备
制备方法参考实施例一。白色固体,产率:93.6%,m.p.158-163℃.1H NMR(600MHz,DMSO-d6)δ9.01(s,1H),7.81(d,J=7.9Hz,1H),7.76(d,J=8.6Hz,2H),7.46(s,1H),7.42-7.34(m,4H),7.31(d,J=3.1Hz,1H),7.11(dd,J=10.4,7.7Hz,3H),7.05(dd,J=13.9,8.4Hz,2H),6.98(d,J=7.4Hz,1H),6.92(t,J=7.6Hz,1H),6.37(d,J=3.1Hz,1H),5.69(dd,J=12.1,5.4Hz,1H),3.98(dd,J=17.6,12.2Hz,1H),3.82(s,3H),3.80(s,3H),3.74(s,3H),3.21(dd,J=17.6,5.4Hz,1H).HRMS(ESI-TOF)Calcd.for C33H30N4O3[M+H]+530.2451;Found 530.2450.
实施例十三:
N-(3-溴苯基)-4-(3-(3-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)苯甲酰胺(Q13)的制备
制备方法参考实施例一。黄色固体,产率:79.2%,m.p.135-142℃.1H NMR(600MHz,DMSO-d6)δ10.00(s,1H),8.11(d,J=55.5Hz,1H),8.02(d,J=9.4Hz,1H),7.76(d,J=8.8Hz,1H),7.62(t,J=8.0Hz,1H),7.53-7.48(m,1H),7.44(t,J=7.4Hz,2H),7.39(t,J=7.7Hz,2H),7.37-7.21(m,4H),7.13(d,J=8.7Hz,1H),7.07(ddd,J=8.6,3.8,1.8Hz,1H),7.05-6.95(m,1H),6.38(ddd,J=11.0,3.1,0.8Hz,1H),5.77(ddd,J=72.1,12.1,5.0Hz,1H),4.02(ddd,J=41.7,17.8,12.1Hz,1H),3.83(d,J=5.2Hz,3H),3.75(d,J=7.8Hz,3H),3.27(ddd,J=43.9,17.7,5.0Hz,1H).HRMS(ESI-TOF)Calcd.for C32H27BrN4O2[M+H]+578.1347;Found 578.1346.
实施例十四:
N-(4-氯苯基)-4-(3-(3-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)苯甲酰胺(Q14)的制备
制备方法参考实施例一。黄色固体,产率:74.3%,m.p.135-142℃.1H NMR(600MHz,DMSO-d6)δ8.14(d,J=8.5Hz,1H),8.02(d,J=9.3Hz,2H),7.81(d,J=8.4Hz,1H),7.62(t,J=7.6Hz,1H),7.51(ddd,J=8.2,7.0,1.0Hz,1H),7.46(d,J=1.7Hz,1H),7.45-7.42(m,2H),7.43-7.37(m,3H),7.33(d,J=3.1Hz,1H),7.26(s,1H),7.07(dd,J=8.5,1.8Hz,1H),7.04(ddd,J=8.1,2.6,1.1Hz,1H),6.39(dd,J=3.1,0.8Hz,1H),5.84(dd,J=11.9,4.6Hz,1H),4.06(dd,J=17.9,11.9Hz,1H),3.83(d,J=9.5Hz,3H),3.75(d,J=9.8Hz,3H),3.30(dd,J=17.9,4.6Hz,1H).HRMS(ESI-TOF)Calcd.for C32H27ClN4O2[M+H]+534.1894;Found 534.1892.
实施例十五:
N-(4-氟苯基)-4-(3-(3-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)苯甲酰胺(Q15)的制备
制备方法参考实施例一。白色固体,产率:80.2%,m.p.129-137℃.1H NMR(600MHz,DMSO-d6)δ9.71(s,1H),8.14(d,J=8.4Hz,1H),8.02(s,1H),8.01(s,1H),7.79(dd,J=17.5,8.7Hz,1H),7.62(t,J=7.6Hz,1H),7.50(dd,J=16.3,8.2Hz,2H),7.47-7.35(m,5H),7.33(d,J=3.1Hz,1H),7.26(s,1H),7.07(dd,J=8.5,1.7Hz,1H),7.04(dd,J=7.6,2.2Hz,1H),6.39(d,J=3.0Hz,1H),5.83(dd,J=11.9,4.6Hz,1H),4.06(dd,J=17.9,12.0Hz,1H),3.84(s,3H),3.76(s,3H),3.30(dd,J=17.9,4.6Hz,1H).HRMS(ESI-TOF)Calcd.for C32H27FN4O2[M+H]+518.2189;Found 518.2188.
实施例十六:
4-(3-(3-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)-N-(O-甲苯基)苯甲酰胺(Q16)的制备
制备方法参考实施例一。黄色固体,产率:70.5%,m.p.130-144℃.1H NMR(600MHz,DMSO-d6)δ10.13(s,1H),8.14(dd,J=8.8,5.7Hz,2H),8.00(d,J=9.4Hz,2H),7.81(dd,J=8.8,3.3Hz,3H),7.61(t,J=7.7Hz,1H),7.51(t,J=7.2Hz,1H),7.46-7.42(m,3H),7.33(d,J=3.1Hz,1H),7.07(dd,J=8.5,1.8Hz,1H),7.05(d,J=2.3Hz,1H),7.03(d,J=2.6Hz,1H),6.39(dd,J=3.0,0.8Hz,1H),5.79(dd,J=11.8,4.5Hz,1H),4.04(dd,J=17.8,11.8Hz,1H),3.82(s,3H),3.80(s,3H),3.76(s,3H),3.26(dd,J=17.8,4.5Hz,1H).HRMS(ESI-TOF)Calcd.for C33H30N4O2[M+H]+514.2495;Found 514.2495.
实施例十七:
N-(3,4-二氯苯基)-4-(3-(3-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)苯甲酰胺(Q17)的制备
制备方法参考实施例一。白色固体,产率:93.3%,m.p.100-112℃.1H NMR(600MHz,DMSO-d6)δ8.14(d,J=8.4Hz,1H),8.02(d,J=8.9Hz,2H),7.81(d,J=8.3Hz,1H),7.62(t,J=7.4Hz,1H),7.51(t,J=7.7Hz,1H),7.46(s,1H),7.44(t,J=7.6Hz,2H),7.41-7.38(m,2H),7.33(d,J=3.1Hz,1H),7.26(s,1H),7.07(dd,J=8.5,1.7Hz,1H),7.04(dd,J=8.0,2.5Hz,1H),6.39(d,J=3.1Hz,1H),5.84(dd,J=11.9,4.6Hz,1H),4.06(dd,J=17.9,11.9Hz,1H),3.84(s,3H),3.76(s,3H),3.30(dd,J=17.9,4.6Hz,1H).HRMS(ESI-TOF)Calcd.for C32H26Cl2N4O2[M+H]+568.1433;Found 568.1431.
实施例十八:
4-(3-(3-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)-N-(4-硝基苯基)苯甲酰胺(Q18)的制备
制备方法参考实施例一。白色固体,产率:75.5%,m.p.105-110℃.1H NMR(600MHz,DMSO-d6)δ8.14(d,J=8.4Hz,1H),8.02(d,J=9.3Hz,2H),7.81(d,J=8.4Hz,2H),7.62(t,J=7.6Hz,1H),7.51(t,J=7.4Hz,1H),7.46(s,1H),7.44(t,J=7.0Hz,1H),7.42-7.38(m,3H),7.33(d,J=3.1Hz,1H),7.26(s,1H),7.07(dd,J=8.5,1.7Hz,1H),7.04(dd,J=8.1,2.7Hz,1H),6.39(d,J=3.1Hz,1H),5.84(dd,J=12.0,4.6Hz,1H),4.06(dd,J=17.9,11.9Hz,1H),3.84(s,3H),3.76(s,3H),3.30(dd,J=17.9,4.6Hz,1H).HRMS(ESI-TOF)Calcd.for C32H27N5O4[M+H]+545.2179;Found 545.2178.
实施例十九:
N-(3,5-二-(三氟甲基)苯基)-4-(3-(3-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)苯甲酰胺(Q19)的制备
制备方法参考实施例一。白色固体,产率:80.4%,m.p.138-147℃.1H NMR(600MHz,DMSO-d6)δ8.14(d,J=8.4Hz,1H),8.02(d,J=8.8Hz,2H),7.81(d,J=8.3Hz,1H),7.62(t,J=7.7Hz,1H),7.51(t,J=7.0Hz,1H),7.46(s,1H),7.44(t,J=7.1Hz,2H),7.41-7.38(m,2H),7.33(d,J=3.0Hz,1H),7.26(s,1H),7.07(d,J=8.2Hz,1H),7.04(dd,J=8.1,2.3Hz,1H),6.39(d,J=3.1Hz,1H),5.84(dd,J=11.9,4.6Hz,1H),4.06(dd,J=17.9,11.9Hz,1H),3.84(s,3H),3.76(s,3H),3.30(dd,J=17.9,4.6Hz,1H).HRMS(ESI-TOF)Calcd.for C34H26F6N4O2[M+H]+636.2058;Found 636.2056.
实施例二十:
N-(3,4-二氟苯基)-4-(3-(3-甲氧基苯基)-5-(1-甲基-1H-吲哚-5-基)-4,5-二氢-1H-吡唑-1-基)苯甲酰胺(Q20)的制备
制备方法参考实施例一。白色固体,产率:85.7%,m.p.125-140℃.1H NMR(600MHz,DMSO-d6)δ8.14(d,J=8.5Hz,1H),8.02(d,J=9.2Hz,2H),7.81(d,J=8.4Hz,1H),7.62(t,J=7.8Hz,1H),7.51(t,J=7.7Hz,1H),7.47(s,1H),7.44(t,J=7.3Hz,2H),7.41-7.38(m,2H),7.33(d,J=3.1Hz,1H),7.26(s,1H),7.07(d,J=7.0Hz,1H),7.04(dd,J=7.8,2.1Hz,1H),6.39(d,J=2.9Hz,1H),5.83(dd,J=11.9,4.6Hz,1H),4.06(dd,J=17.9,11.9Hz,1H),3.83(d,J=9.4Hz,3H),3.75(d,J=9.8Hz,3H),3.30(dd,J=17.9,4.6Hz,1H).HRMS(ESI-TOF)Calcd.for C32H26F2N4O2[M+H]+536.2082;Found 536.2081.
实施例二十一:
上述实施例一到实施例二十化合物抗结肠癌细胞活性测试:
采用MTT[3-(4,5)-双甲基-2-噻唑-(2,5)-苯基溴化四氮唑蓝]法来测定一类含甲基吲哚的以吡唑啉为骨架的苯胺衍生物对HCT116(人结肠癌肿瘤细胞)、SW480(人结肠癌细胞)、HT-29(人结肠癌细胞)、CT26(小鼠结肠癌细胞),HeLa(人宫颈癌细胞)抑制率达到50%时的药物浓度(IC50)。
具体方案:选定五种细胞置于37℃,5%CO2培养箱中培养至对数期,其后将细胞消化、计数,混匀加入96孔培养板中(100μL/孔),使待测细胞密度达到5000-8000/孔,同时设立空白组、阴性对照组。37℃,5%CO2培养箱中培养12h;用2%的培养液配制待测化合物及阳性对照药至所需浓度梯度,每个化合物五个浓度梯度,每个浓度三个平行孔,每孔加入100μL相应的含药培养液;给药后96孔板置于37℃,5%CO2培养箱中培养48h;随后,向96孔板中,加入MTT(5mg/mL)5μL/孔,置于37℃,5%CO2培养箱中4h,移除上清液,加DMSO 150μL/孔,振荡至formazan结晶全部溶解,用自动酶标仪在570nm波长处检测各孔的光密度(OD值),计算IC50值。结果见表1:
表1:一类含甲基吲哚的以吡唑啉为骨架的苯胺衍生物对肿瘤细胞的IC50值
本发明所述一类含甲基吲哚的以吡唑啉为骨架的苯胺衍生物对HCT116(人结肠癌肿瘤细胞)、SW480(人结肠癌细胞)、HT-29(人结肠癌细胞)、CT26(小鼠结肠癌细胞),HeLa(人宫颈癌细胞)均具备抑制细胞恶性增殖的作用,所述的化合物Q19的抗结肠癌细胞增殖效果优于Regorafenib。因此,本发明所述的含甲基吲哚的以吡唑啉为骨架的苯胺衍生物具有作为抗肿瘤药物的潜力。
Claims (4)
2.权利要求1中所述的一类含甲基吲哚的以吡唑啉为骨架的苯胺衍生物的制备方法,其特征在于,步骤如下:
其中,R1选自H、-CH3O;R2选自H、-CH3O;R3选自H、-CH3O、-CH3;R4选自H、-Br、-Cl、-NO2、-CF3、-F;R5选自H、-Cl、-F、-NO2;R6选自H、-CF3。
步骤i:在0℃下,将吲哚-5-甲醛(1.0mmol)溶解于无水DMF中,缓慢加入氢化钠(1.5mmol),搅拌30分钟,然后逐滴加入用DMF溶解的碘甲烷(1.5mmol),将反应转移至室温,继续搅拌12小时。TCL检测反应结束后,加入过量1N的盐酸淬灭,并用二氯甲烷萃取三次,收集有机层,用无水硫酸钠干燥过滤,真空旋干。以正己烷∶乙酸乙酯(4∶1 v∶v)为流动相,柱层析法纯化粗品,得到中间化合物2。
步骤ii:将化合物2(6mmol)溶解在10ml无水乙醇中,向反应体系中加入苯乙酮衍生物(6mmol),逐滴加入40%氢氧化钠溶液(9mmol)。反应在室温下搅拌4小时,过滤得到化合物3-4粗品。
步骤iii:将4-肼基苯甲酸(4.0mmol)、化合物3-4(2.0mmol)溶于甲醇中,加入冰醋酸(0.2mmol)。在室温下搅拌30min,加热至回流温度,搅拌过夜。TCL检测反应结束后,以正己烷∶乙酸乙酯(2∶1 v∶v)为洗脱剂,柱层析纯化得到相应化合物5-6。
步骤iv:0℃下,将化合物5-6(1mmol)溶于无水二氯甲烷(30ml)中,然后将EDC(1.6mmol),HOBt(0.6mmol)依次加入到反应液中,搅拌30分钟,之后将苯胺衍生物(0.6mmol)加入到反应液中,将反应混合液转移到常温,搅拌反应过夜。TLC监测反应结束后,用10%碳酸氢钠水溶液对反应进行猝灭,用二氯甲烷(3×100ml)萃取。用10%碳酸氢钠水溶液清洗有机层三次,无水硫酸钠除水干燥过滤,真空蒸干。得到的粗品以正己烷∶乙酸乙酯(6∶1 v∶v)为洗脱液,柱层析纯化得到目的化合物Q1-Q20。
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