CN110128325A - 取代苯基哌啶酮类化合物及其合成方法和应用 - Google Patents

取代苯基哌啶酮类化合物及其合成方法和应用 Download PDF

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CN110128325A
CN110128325A CN201910291185.9A CN201910291185A CN110128325A CN 110128325 A CN110128325 A CN 110128325A CN 201910291185 A CN201910291185 A CN 201910291185A CN 110128325 A CN110128325 A CN 110128325A
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易伟
周志
朱国勋
马磊
高辉
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Abstract

本发明公开了结构式如式(I)或(II)所示的3‑(2‑羟基苯甲酰基)‑4,4,6‑三甲基‑1‑苯基‑2‑哌啶酮类化合物、其合成方法和作为抗癌药物的应用：其中，R1、R2、R3和R4分别独立选自氢、烷基、卤素、烷氧基中的任一种；X为O或NH。

Description

取代苯基哌啶酮类化合物及其合成方法和应用
技术领域：
本发明涉及3-(2-羟基苯甲酰基)-4,4,6-三甲基-1-取代苯基-2-哌啶酮类化合物及其合成方法和应用。
背景技术：
癌症是人类死亡的主要“杀手”之一，过去30年，中国癌症死亡率增加了80％，每年因此去世的有180万人，占全球癌症死亡人数的1/4，且发病呈年轻化趋势。
癌症的主要治疗手段是手术、放疗和化学药物治疗。随着新型化学抗癌药物的不断面世，其疗效不断提高，抗癌药物在癌症治疗方面占据越来越重要的地位。目前临床应用的抗癌药物毒副作用均较大，再加上精神上的折磨，治疗过程中给癌症患者带来巨大的痛苦。开发高效、低毒的抗癌药物是亟需解决的问题。
发明内容：
本发明的目的是提供一种新型的3-(2-羟基苯甲酰基)-4,4,6-三甲基-1-取代苯基-2-哌啶酮类化合物及其合成方法和作为抗癌药物的应用。
本发明是通过以下技术方案予以实现的：
结构式如式(I)或(II)所示的3-(2-羟基苯甲酰基)-4,4,6-三甲基-1-苯基-2-哌啶酮类化合物：
其中，R1、R2、R3和R4分别独立选自氢、烷基、卤素、烷氧基中的任一种；X为O或NH。
R1、R2、R3和R4优选为C1-C12烷基、C1-C12烷氧基，最优选为甲烷、甲烷氧基。
优选地，3-(2-羟基苯甲酰基)-4,4,6-三甲基-1-苯基-2-哌啶酮类化合物选自表1中的化合物。
表1
本发明还保护式(I)所示的3-(2-羟基苯甲酰基)-4,4,6-三甲基-1-苯基-2-哌啶酮类化合物的制备方法，方程式如下：
包括以下步骤：将反应底物溶解于溶剂中，加入硼氢化钠及甲醇，反应完毕，加入盐酸猝灭反应用乙酸乙酯萃取，有机层用无水硫酸钠干燥，除去溶剂后得到粗品，经柱层析分离,得到产品，其中反应底物、甲醇与硼氢化钠的摩尔比为1：1：2-4。
式(II)所示的3-(2-羟基苯甲酰基)-4,4,6-三甲基-1-苯基-2-哌啶酮类化合物的制备方法，方程式如下：
包括以下步骤：将反应底物溶解于溶剂中，加入硼氢化钠及甲醇，反应完毕，加入盐酸猝灭反应用乙酸乙酯萃取，有机层用无水硫酸钠干燥，除去溶剂后得到粗品，经柱层析分离,得到产品，其中反应底物、甲醇与硼氢化钠的摩尔比为1：1：2-4。
式(I)或(II)所示的3-(2-羟基苯甲酰基)-4,4,6-三甲基-1-苯基-2-哌啶酮类化合物的反应底物的制备参考文献：Guoxun Zhu；Zhou Yi；Jie Zhou；Zhiyong Chen；PengranGuo；Yanying Huang；Jianghan Chen；Huacan Song；Wei Yi,Bran-New Four-Molecule andFive-Molecule Cascade Reactions for One-Pot Synthesis of Pyrano[3,2c]chromen-5-ones and Spiro[benzo[b][1,4]diazepine-2,2′-pyrano[3,2c]chromen]-5′-onesunder Catalyst-and Solvent-Free Conditions.ACS Omega 2018,3,13494-13502.
本发明提供一种药物组合物，包含至少一种所述的式(I)或式(II)化合物作为活性成分，单独或结合一种或几种药学上可接受的、惰性的、无毒的赋形剂或载体。
本发明还保护式(I)或式(II)所示的3-(2-羟基苯甲酰基)-4,4,6-三甲基-1-苯基-2-哌啶酮类化合物或所述药物组合物作为抗癌药物特别是抗人肝癌、乳腺癌、人肺癌、神经母细胞瘤药物的应用。
本发明的有益效果如下：
本发明提供了一种新型的3-(2-羟基苯甲酰基)-4,4,6-三甲基-1-苯基-2-哌啶酮类化合物并提供了该化合物的合成方法，并提供了其作为抗癌药物的活性测试结果，该化合物具有良好的抗癌活性，且无毒副作用；且合成条件简单，具有良好的应用前景。
具体实施方式：
以下是对本发明的进一步说明，而不是对本发明的限制。
下面实施例1-15中的反应底物的制备参考文献：Guoxun Zhu；ZhouYi；Jie Zhou；Zhiyong Chen；Pengran Guo；Yanying Huang；Jianghan Chen；Huacan Song；Wei Yi,Bran-New Four-Molecule and Five-Molecule Cascade Reactions for One-Pot Synthesisof Pyrano[3,2c]chromen-5-ones and Spiro[benzo[b][1,4]diazepine-2,2′-pyrano[3,2c]chromen]-5′-ones under Catalyst-and Solvent-Free Conditions.ACS Omega2018,3,13494-13502.
实施例1：3-(2-羟基苯甲酰基)-4,4,6-三甲基-1-苯基-2-哌啶酮(化合物1)
在50mL圆底烧瓶中加入2,4,4-三甲基-2-苯氨基-3,4-二氢-2H-吡喃并[3,2-c]-5-色酮(670mg,2mmol)，溶解于四氢呋喃(15mL)中，加入硼氢化钠(226mg,6mmol)及甲醇(64mg,2mmol)，室温反应2小时。反应完毕，加入1M盐酸(20mL)猝灭反应，反应液用乙酸乙酯(20mL×3)萃取，有机层用无水硫酸钠干燥，除去溶剂后得到粗品，经柱层析分离,使用洗脱剂PE：EA＝3：1洗脱得到产品525.1mg。产率：78％；熔点：151.7-152.0℃。
1H NMR(400MHz,Chloroform-d)δ12.47(s,1H),7.83(dd,J＝8.2,1.5Hz,1H),7.46(ddd,J＝8.5,7.3,1.6Hz,1H),7.40(d,J＝15.4Hz,2H),7.29(t,J＝7.6Hz,1H),7.23–7.17(m,2H),6.99(dd,J＝8.3,1.0Hz,1H),6.95–6.89(m,1H),4.54(s,1H),4.05(dp,J＝12.0,6.1Hz,1H),1.98(dd,J＝13.8,5.3Hz,1H),1.39(s,3H),1.10(s,3H),1.07(d,J＝6.3Hz,3H).
13C NMR(101MHz,Chloroform-d)δ203.5,167.8,162.8,140.0,136.5,130.9,129.2,128.1,127.4,121.6,118.9,118.6,57.8,5.54,46.6,34.1,29.7,22.76,22.29.
HRMS-ESI,m/z:338.1750[M+H]+(Calcd.for C21H24NO3 +,338.1751).
实施例2：3-(2-羟基苯甲酰基)-1-(甲氧基苯基)-4,4,6-三甲基哌啶-2-酮(化合物2)
制备方法参考实施例1，以2,4,4-三甲基-2-(4-甲氧基苯基)氨基-3,4-二氢-2H-吡喃并[3,2-c]-5-色酮为反应底物，还原后得到目标化合物580.2mg。产率：79％；熔点：153.2-153.6℃。
1H NMR(400MHz,Chloroform-d)δ12.42(s,1H),7.81(dd,J＝8.2,1.6Hz,1H),7.52–7.43(m,1H),7.14–7.06(m,2H),7.02–6.96(m,1H),6.92(dd,J＝8.3,6.6Hz,3H),4.51(s,1H),4.01(dt,J＝11.4,5.8Hz,1H),3.81(s,3H),2.00(dd,J＝13.7,5.4Hz,1H),1.74(dd,J＝13.7,10.5Hz,1H),1.38(s,3H),1.12(s,3H),1.10(d,J＝6.3Hz,3H).
13C NMR(101MHz,Chloroform-d)δ203.5,168.0,162.8,158.6,136.4,132.7,130.9,129.0,121.6,118.9,118.6,114.4,57.9,55.5,52.7,46.5,34.1,29.7,22.8,22.3.
HRMS-ESI,m/z:368.1856[M+H]+(Calcd.for C22H26NO4 +,368.1856).
实施例3：3-(2-羟基苯甲酰基)-1-(甲基苯基)-4,4,6-三甲基哌啶-2-酮(化合物3)
制备方法参考实施例1，以2,4,4-三甲基-2-(4-甲基苯基)氨基-3,4-二氢-2H-吡喃并[3,2-c]-5-色酮为反应底物，还原后得到目标化合物565.1mg。产率：80％；熔点：149.1-149.7℃。
1H NMR(400MHz,Chloroform-d)δ12.41(s,1H),7.81(dd,J＝8.1,1.6Hz,1H),7.48(ddd,J＝8.5,7.2,1.5Hz,1H),7.21(d,J＝7.9Hz,2H),7.07(d,J＝8.1Hz,2H),6.99(dd,J＝8.4,1.1Hz,1H),6.95–6.89(m,1H),4.51(s,1H),4.11–3.98(m,1H),2.36(s,3H),2.01(dd,J＝13.7,5.4Hz,1H),1.74(dd,J＝13.7,10.4Hz,1H),1.39(s,3H),1.13(s,3H),1.10(d,J＝6.3Hz,3H).
13C NMR(101MHz,Chloroform-d)δ203.5,167.8,162.8,137.3,137.1,136.4,130.9,129.8,127.8,121.7,118.9,118.6,57.9,52.5,46.5,34.1,29.7,22.8,22.3,21.1.
HRMS-ESI,m/z:352.1906[M+H]+(Calcd.for C22H26NO3 +,352.1907).
实施例4：3-(2-羟基苯甲酰基)-1-(氟苯基)-4,4,6-三甲基哌啶-2-酮(化合物4)
制备方法参考实施例1，以2,4,4-三甲基-2-(4-氟苯基)氨基-3,4-二氢-2H-吡喃并[3,2-c]-5-色酮为反应底物，还原后得到目标化合物526.0mg。产率：74％；熔点：110.5-111.0℃。
1H NMR(400MHz,Chloroform-d)δ12.38(s,1H),7.83–7.77(m,1H),7.53–7.45(m,1H),7.39(d,J＝8.5Hz,2H),7.14(d,J＝8.5Hz,2H),7.00(d,J＝8.3Hz,1H),6.93(t,J＝7.6Hz,1H),4.51(s,1H),4.05(dt,J＝11.2,5.9Hz,1H),2.02(dd,J＝13.8,5.4Hz,1H),1.76(dd,J＝13.8,10.4Hz,1H),1.37(s,3H),1.13(s,3H),1.10(d,J＝6.3Hz,3H).
13C NMR(101MHz,Chloroform-d)δ203.4,168.1,162.9,162.8,160.3,136.6,135.9,135.9,130.9,129.8,129.7,121.5,118.9,118.7,116.2,116.0,57.7,52.7,46.5,34.1,29.7,26.9,22.8,22.2.HRMS-ESI,m/z:356.1655[M+H]+(Calcd.for C21H23FNO3 +,356.1656).
实施例5：3-(2-羟基苯甲酰基)-1-(氯苯基)-4,4,6-三甲基哌啶-2-酮(化合物5)
制备方法参考实施例1，以2,4,4-三甲基-2-(4-氯苯基)氨基-3,4-二氢-2H-吡喃并[3,2-c]-5-色酮为反应底物，还原后得到目标化合物533.4mg。产率：72％；熔点：143.5-144.4℃。
1H NMR(400MHz,Chloroform-d)δ12.38(s,1H),7.83–7.77(m,1H),7.53–7.45(m,1H),7.39(d,J＝8.5Hz,2H),7.14(d,J＝8.5Hz,2H),7.00(d,J＝8.3Hz,1H),6.93(t,J＝7.6Hz,1H),4.51(s,1H),4.05(dt,J＝11.2,5.9Hz,1H),2.02(dd,J＝13.8,5.4Hz,1H),1.76(dd,J＝13.8,10.4Hz,1H),1.37(s,3H),1.13(s,3H),1.10(d,J＝6.3Hz,3H).
13C NMR(101MHz,Chloroform-d)δ203.3,167.9,162.9,138.6,136.6,133.1,130.8,129.5,129.4,121.5,119.0,118.7,57.8,52.5,46.4,34.1,29.7,22.8,22.2.
HRMS-ESI,m/z:372.1360[M+H]+(Calcd.for C21H23ClNO3 +,372.1361).
实施例6：3-(2-羟基苯甲酰基)-1-(溴苯基)-4,4,6-三甲基哌啶-2-酮(化合物6)
制备方法参考实施例1，以2,4,4-三甲基-2-(4-溴苯基)氨基-3,4-二氢-2H-吡喃并[3,2-c]-5-色酮为反应底物，还原后得到目标化合物540.2mg。产率：65％；熔点：144.8-145.7℃。
1H NMR(400MHz,Chloroform-d)δ12.38(s,1H),7.80(d,J＝7.9Hz,1H),7.51(dd,J＝23.6,7.9Hz,3H),7.09(s,2H),7.00(d,J＝8.3Hz,1H),6.92(t,J＝7.5Hz,1H),4.51(s,1H),4.05(dp,J＝11.8,6.0Hz,1H),2.01(dd,J＝13.7,5.3Hz,1H),1.75(dd,J＝13.8,10.4Hz,1H),1.36(s,3H),1.13(s,3H),1.09(d,J＝6.2Hz,3H).
13C NMR(101MHz,Chloroform-d)δ203.3,167.9,162.9,139.1,136.6,132.3,130.6,129.8,121.5,121.1,119.0,118.7,57.8,52.5,46.4,34.1,29.7,22.8,22.2.
HRMS-ESI,m/z:416.0855[M+H]+(Calcd.for C21H23BrNO3 +,416.0856).
实施例7：3-(2-羟基苯甲酰基)-4,4,6-三甲基-1-(3-甲基苯基)哌啶-2-酮(化合物7)
制备方法参考实施例1，以2,4,4-三甲基-2-(3-甲基苯基)氨基-3,4-二氢-2H-吡喃并[3,2-c]-5-色酮为反应底物，还原后得到目标化合物494.1mg。产率：70％；熔点：115.9-116.7℃。
1H NMR(400MHz,Chloroform-d)δ12.46(s,1H),7.83(dd,J＝8.1,1.6Hz,1H),7.47(ddd,J＝8.6,7.2,1.6Hz,1H),7.29(t,J＝7.7Hz,1H),7.11(d,J＝7.6Hz,1H),7.04–6.96(m,3H),6.92(ddd,J＝8.2,7.1,1.2Hz,1H),4.53(s,1H),4.04(dp,J＝11.9,6.1Hz,1H),2.36(s,3H),1.99(dd,J＝13.8,5.3Hz,1H),1.75(dd,J＝13.8,10.6Hz,1H),1.40(s,3H),1.12(s,3H),1.08(d,J＝6.3Hz,3H).
13C NMR(101MHz,Chloroform-d)δ203.68,167.84,162.77,139.95,139.04,136.47,130.97,128.91,128.62,128.19,125.12,121.69,118.95,118.55,57.82,52.58,46.53,34.09,29.63,22.72,22.27,21.34.
HRMS-ESI,m/z:352.1907[M+H]+(Calcd.for C22H26NO3 +,352.1907).
实施例8：1-(3-氯苯基)-3-(2-羟基苯甲酰基)-4,4,6-三甲基哌啶-2-酮(化合物8)
制备方法参考实施例1，以2,4,4-三甲基-2-(3-氯苯基)氨基-3,4-二氢-2H-吡喃并[3,2-c]-5-色酮为反应底物，还原后得到目标化合物502.8mg。产率：68％；熔点：116.5-117.3℃。
1H NMR(400MHz,Chloroform-d)δ12.38(s,1H),7.80(d,J＝8.1Hz,1H),7.49(t,J＝7.8Hz,1H),7.34(dd,J＝16.5,8.8Hz,3H),7.22(s,1H),7.10(d,J＝7.7Hz,1H),7.00(d,J＝8.4Hz,1H),6.93(t,J＝7.7Hz,1H),4.52(s,1H),4.07(dp,J＝12.0,6.3Hz,1H),2.02(dd,J＝13.9,5.4Hz,1H),1.76(dd,J＝13.8,10.4Hz,1H),1.38(s,3H),1.13(s,3H),1.10(d,J＝6.2Hz,3H).
13C NMR(101MHz,Chloroform-d)δ203.30,167.89,162.87,141.26,136.65,134.59,130.83,130.09,128.45,127.70,126.53,121.50,118.97,118.68,57.74,52.57,46.42,34.11,29.65,22.74,22.21.
HRMS-ESI,m/z:372.1360[M+H]+(Calcd.for C21H23ClNO3 +,372.1361).
实施例9：1-(3,5-二甲基苯基)-3-(2-羟基苯甲酰基)-4,4,6-三甲基哌啶-2-酮(化合物9)
制备方法参考实施例1，以2,4,4-三甲基-2-(3-氯苯基)氨基-3,4-二氢-2H-吡喃并[3,2-c]-5-色酮为反应底物，还原后得到目标化合物605.1mg。产率：83％；熔点：142.5-143.1℃。
1H NMR(400MHz,Chloroform-d)δ12.41(s,1H),7.82(dd,J＝8.3,1.6Hz,1H),7.52–7.44(m,1H),6.99(d,J＝8.3Hz,1H),6.96–6.90(m,2H),6.79(s,2H),4.51(s,1H),4.03(dq,J＝11.3,6.0Hz,1H),2.32(s,6H),2.00(dd,J＝13.7,5.4Hz,1H),1.72(d,J＝10.4Hz,1H),1.40(s,3H),1.13(s,3H),1.10(d,J＝6.3Hz,3H).
13C NMR(101MHz,Chloroform-d)δ203.59,167.83,162.76,139.77,138.78,136.42,130.91,129.16,125.64,121.68,118.89,118.58,57.78,52.55,46.58,34.07,29.67,22.78,22.32,21.23.HRMS-ESI,m/z:366.2063[M+H]+(Calcd.for C23H28NO3 +,366.2064).
实施例10：3-(2-羟基-5-甲基苯甲酰基)-4,4,6-三甲基-1-苯基哌啶-2-酮(化合物10)
制备方法参考实施例1，以2,4,4,9四甲基-2-(苯基氨基)-3,4-二氢-2H，-5H-吡喃并[3,2-c]苯并吡喃-5-酮为反应底物，还原后得到目标化合物550.5mg。产率：78％；熔点：143.3-143.8℃。
1H NMR(400MHz,Chloroform-d)δ12.23(s,1H),7.61–7.56(m,1H),7.41(t,J＝7.7Hz,2H),7.33–7.29(m,2H),7.22–7.17(m,2H),6.90(d,J＝8.5Hz,1H),4.52(s,1H),4.12–4.04(m,1H),2.34(s,3H),2.08–1.99(m,1H),1.79(dd,J＝13.7,10.4Hz,1H),1.40(s,3H),1.14(s,3H),1.11(d,J＝6.3Hz,3H).
13C NMR(101MHz,Chloroform-d)δ203.51,167.98,160.75,140.06,137.64,130.62,129.14,128.11,127.96,127.37,121.32,118.34,57.67,52.59,46.44,34.09,29.65,22.77,22.23,20.68.HRMS-ESI,m/z:352.1906[M+H]+(Calcd.for C22H26NO3 +,352.1907).
实施例11：3-(2-羟基-5-甲基苯甲酰基)-1-(甲氧基苯基)-4,4,6-三甲基哌啶-2-酮(化合物11)
制备方法参考实施例1，以2-((4-甲氧基苯基)氨基)-2,4,4,9四甲基-3,4-二氢-2H,-5H-吡喃并[3,2-c]苯并吡喃-5-酮为反应底物，还原后得到目标化合物595.8mg。产率：78％；熔点：
158.7-159.0℃。
1HNMR(400MHz,Chloroform-d)δ12.23(s,1H),7.57(s,1H),7.31-7.29(m,1H),7.10(d,J＝8.4Hz,2H),6.91(dd,J＝11.9,8.5Hz,3H),4.50(s,1H),4.02(dp,J＝12.5,6.3Hz,1H),3.82(s,3H),2.34(s,3H),2.01(dd,J＝13.8,5.5Hz,1H),1.76(dd,J＝13.8,10.4Hz,1H),1.38(s,3H),1.17–1.06(m,6H).
13C NMR(101MHz,Chloroform-d)δ203.38,168.13,160.75,158.56,137.53,132.76,130.56,129.05,127.84,121.34,118.38,114.44,57.74,55.45,52.72,46.48,34.03,29.75,22.91,22.31,20.66.
HRMS-ESI,m/z:382.2012[M+H]+(Calcd.for C23H28NO4 +,382.2013).
实施例12：3-(2-羟基-3-甲基苯甲酰基)-1-(甲氧基苯基)-4,4,6-三甲基哌啶-2-酮(化合物12)
制备方法参考实施例1，以2-((4-甲氧基苯基)氨基)-2,4,4,7四甲基-3,4-二氢-2H,-5H-吡喃并[3,2-c]苯并吡喃-5-酮为反应底物，还原后得到目标化合物510.3mg。产率：67％；熔点：148.2-148.9℃。
1H NMR(400MHz,Chloroform-d)δ12.72(s,1H),7.67(d,J＝8.1Hz,1H),7.35(d,J＝7.3Hz,1H),7.10(d,J＝8.3Hz,2H),6.93(d,J＝8.3Hz,2H),6.82(t,J＝7.9Hz,1H),4.52(s,1H),4.02(dt,J＝11.4,5.8Hz,1H),3.82(s,3H),2.28(s,3H),2.00(dd,J＝13.8,5.3Hz,1H),1.74(t,J＝12.1Hz,1H),1.38(s,3H),1.18–1.06(m,6H).
13C NMR(101MHz,Chloroform-d)δ203.69,168.08,161.33,158.53,137.17,132.81,129.06,128.53,127.58,120.91,118.09,114.42,57.89,55.45,52.66,46.55,34.04,29.79,22.87,22.33,15.58.
HRMS-ESI,m/z:382.2012[M+H]+(Calcd.for C23H28NO4 +,382.2013).
实施例13：10-(2-羟基苯甲酰基)-6,6,9,9四甲基6,7,7a，8,9,10六氢11H苯并[b]吡啶并[1,2-d][1,4]氧氮杂-11-酮(化合物13)
制备方法参考实施例1，以2,2,4',4'-四甲基2,3,3',4'-四氢-5H-,5'H-螺[苯并[b][1,4]氧氮杂--4,2'-吡喃并并[3,2-c]苯并吡喃]-5'-酮为反应底物，还原后得到目标化合物510.3mg。产率：69％；熔点：178.7-179.0℃。
1H NMR(400MHz,Chloroform-d)δ12.32(s,1H),8.05(dd,J＝8.1,1.6Hz,1H),7.48(ddd,J＝8.6,7.2,1.6Hz,1H),7.39(dd,J＝7.8,1.8Hz,1H),7.14(dtd,J＝21.9,7.5,1.8Hz,2H),7.00(ddd,J＝8.4,2.8,1.4Hz,2H),6.92(ddd,J＝8.3,7.2,1.2Hz,1H),4.44(s,1H),4.24–4.12(m,1H),2.15(dd,J＝13.5,6.7Hz,1H),2.10–2.00(m,1H),1.72(dd,J＝14.9,1.8Hz,1H),1.66(s,2H),1.39(s,3H),1.36(s,3H),1.26(s,3H),1.23(s,3H).
13C NMR(101MHz,Chloroform-d)δ202.50,167.65,162.89,149.78,136.70,134.00,131.57,128.76,127.50,125.20,124.05,121.18,119.05,118.46,77.71,60.01,51.38,47.81,44.74,34.16,31.08,29.38,25.17,24.58.
HRMS-ESI,m/z:394.2012[M+H]+(Calcd.for C24H28NO4 +,394.2013).
实施例14：10-(2-羟基苯甲酰基)-3,6,6,9,9五甲基6,7,7a,8,9,10六氢11H苯并[b]吡啶并[1,2-d][1,4]氧氮杂-11-酮(化合物14)
制备方法参考实施例1，以2,2,4',4',8-五甲基-2,3,3',4'-四氢-5H-,5'H-螺[苯并[b][1,4]氧氮杂-4,2'吡喃并[3,2-c]苯并吡喃]-5'-酮为反应底物，还原后得到目标化合物510.3mg。产率：69％；熔点：179.3-179.6℃。
1H NMR(400MHz,Chloroform-d)δ12.31(s,1H),8.06(d,J＝8.2Hz,1H),7.48(t,J＝7.9Hz,1H),7.18(s,1H),7.04–6.84(m,4H),4.43(s,1H),4.18(q,J＝9.5Hz,1H),2.32(s,3H),2.15(dd,J＝13.6,6.7Hz,1H),2.03(dd,J＝14.9,10.8Hz,1H),1.75–1.58(m,2H),1.37(d,J＝3.6Hz,6H),1.24(d,J＝7.8Hz,6H).
13C NMR(101MHz,Chloroform-d)δ202.37,167.45,162.89,147.27,136.66,133.68,133.40,131.63,128.84,128.19,124.82,121.18,119.03,118.44,60.29,51.40,44.79,34.13,31.25,29.18,25.21,24.76,20.78.
HRMS-ESI,m/z:408.2168[M+H]+(Calcd.for C25H30NO4 +,408.2169).
实施例15：10-(2-羟基苯甲酰基)-6,6,9,9四甲基6,7,7a,8,9,10六氢苯并[b]吡啶并[1,2-d][1,4]二氮杂-11(5H)-酮(化合物15)
制备方法参考实施例1，以4,4,4',4',7-五甲基-1,3,3-',4,4',5-六氢5'H-螺[苯并[b][1,4]二氮-2,2'-吡喃并[3,2-c]苯并吡喃]-5'-酮为反应底物，还原后得到目标化合物510.3mg。产率：70％；熔点：182.8-183.7℃。
1H NMR(400MHz,Chloroform-d)δ12.37(s,1H),7.86(d,J＝8.1Hz,1H),7.46(dd,J＝15.5,1.5Hz,1H),7.30–7.24(m,1H),7.12–7.05(m,1H),6.97(t,J＝8.2Hz,2H),6.90(t,J＝7.6Hz,1H),6.80(d,J＝7.8Hz,1H),4.38(s,1H),3.94–3.81(m,1H),2.91(s,1H),2.15(dd,J＝13.7,7.9Hz,1H),1.98(dd,J＝14.0,11.1Hz,1H),1.77–1.68(m,1H),1.61(dd,J＝13.7,8.2Hz,1H),1.44(s,3H),1.35(s,3H),1.17(s,3H),1.07(s,3H).
13C NMR(101MHz,Chloroform-d)δ203.23,167.81,162.69,142.32,136.41,133.14,131.23,129.29,127.71,123.44,122.40,121.55,118.95,118.45,58.13,52.83,51.66,51.48,45.33,34.74,32.19,29.88,26.29,23.48.
HRMS-ESI,m/z:393.2172[M+H]+(Calcd.for C24H29N2O3 +,393.2173).
实施例16：
对实施例1-15得到的3-(2-羟基苯甲酰基)-4,4,6-三甲基-1-取代苯基-2-哌啶酮类化合物进行抗癌活性试验。
1.样品抗癌活性试验
(1)样品抗癌活性试验操作过程：
细胞培养：肿瘤细胞株(MCF-7，A549，HepG2，SH-SH5Y)按常规方法培养传代，均培养于RPMI 1640或DMEM，补充10％热灭活胎牛血清，2μmol/L谷氨酰胺，105U/L青霉素，100mg/L 860链霉素，37℃、5％CO2培养箱中饱和湿度下培养，取对数生长期细胞用于实验。
CCK-8法比色实验：取对数生长期细胞，调整细胞浓度为1×105个/mL接种于96孔培养板，100μL/孔，培养24h后，加入不同浓度的样品；同时设阴性对照组、阳性对照组(5-氟尿嘧啶)，空白对照组(即只加培养液，不加细胞以调零)，每组均设3复孔。共同培养48h后，每孔加入10μL CCK-8再培养1h，应用酶标仪于450nm处测吸光度值(A)。
数据处理：把CCK-8法测得的吸光度值，用SPSS11.0软件进行统计学分析，计算出样品相对5-氟尿嘧啶为参考的IC50值。本专利所涉及的哌啶类衍生物的IC50值见表2。
表2
其中HepG2为人肝癌细胞系，MCF-7为乳腺癌细胞系A549为人肺癌细胞系，SH-SH5Y为神经母细胞瘤系，5-FU为5-氟尿嘧啶。

Claims (10)

1.结构式如式(I)或(II)所示的3-(2-羟基苯甲酰基)-4,4,6-三甲基-1-苯基-2-哌啶酮类化合物：
其中，R1、R2、R3和R4分别独立选自氢、烷基、卤素、烷氧基中的任一种；X为O或NH。
2.根据权利要求1所述的化合物，其特征在于，R1、R2、R3和R4分别独立选自C1-C12烷基、C1-C12烷氧基中的任一种。
3.根据权利要求1所述的化合物，其特征在于，R1、R2、R3和R4分别独立选自甲烷、甲烷氧基中的任一种。
4.根据权利要求1所述的化合物，其特征在于，选自以下化合物：
5.权利要求1所述式(I)所示的3-(2-羟基苯甲酰基)-4,4,6-三甲基-1-苯基-2-哌啶酮类化合物的制备方法，其特征在于，方程式如下：
包括以下步骤：将反应底物溶解于溶剂中，加入硼氢化钠及甲醇，反应完毕，加入盐酸猝灭反应，用乙酸乙酯萃取，有机层用无水硫酸钠干燥，除去溶剂后得到粗品，经柱层析分离,得到产品，其中反应底物、甲醇与硼氢化钠的摩尔比为1：1：2-4。
6.权利要求1所述式(II)所示的3-(2-羟基苯甲酰基)-4,4,6-三甲基-1-苯基-2-哌啶酮类化合物的制备方法，其特征在于，方程式如下：
包括以下步骤：将反应底物溶解于溶剂中，加入硼氢化钠及甲醇，反应完毕，加入盐酸猝灭反应，用乙酸乙酯萃取，有机层用无水硫酸钠干燥，除去溶剂后得到粗品，经柱层析分离,得到产品，其中反应底物、甲醇与硼氢化钠的摩尔比为1：1：2-4。
7.一种药物组合物，其特征在于，包含至少一种权利要求1所述的式(I)或式(II)化合物作为活性成分，单独或结合一种或几种药学上可接受的、惰性的、无毒的赋形剂或载体。
8.权利要求1所述式(I)或式(II)所示的3-(2-羟基苯甲酰基)-4,4,6-三甲基-1-苯基-2-哌啶酮类化合物作为抗癌药物的应用。
9.根据权利要求8所述的应用，其特征在于，所述化合物作为抗人肝癌、乳腺癌、人肺癌、神经母细胞瘤药物的应用。
10.权利要求7所述药物组合物的应用，其特征在于，所述组合物作为抗人肝癌、乳腺癌、人肺癌、神经母细胞瘤药物的应用。
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