CN110128325B - 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

Info

Publication number
CN110128325B
CN110128325B CN201910291185.9A CN201910291185A CN110128325B CN 110128325 B CN110128325 B CN 110128325B CN 201910291185 A CN201910291185 A CN 201910291185A CN 110128325 B CN110128325 B CN 110128325B
Authority
CN
China
Prior art keywords
formula
compound
reaction
substituted
solvent
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active
Application number
CN201910291185.9A
Other languages
English (en)
Other versions
CN110128325A (zh
Inventor
易伟
周志
朱国勋
马磊
高辉
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Guangzhou Medical University
Original Assignee
Guangzhou Medical University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Guangzhou Medical University filed Critical Guangzhou Medical University
Priority to CN201910291185.9A priority Critical patent/CN110128325B/zh
Publication of CN110128325A publication Critical patent/CN110128325A/zh
Application granted granted Critical
Publication of CN110128325B publication Critical patent/CN110128325B/zh
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)

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：
Figure DDA0002024960950000011
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：
Figure BDA0002024960940000021
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
Figure BDA0002024960940000022
Figure BDA0002024960940000031
Figure BDA0002024960940000041
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：
Figure BDA0002024960940000042
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：
Figure BDA0002024960940000043
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
Figure BDA0002024960940000161
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 (8)

1.结构式如式(I)或(II)所示的取代苯基哌啶酮类化合物：
Figure FDA0002682366160000011
其中，R1、R2、R3和R4分别独立选自氢、C1-C12烷基、卤素、C1-C12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分别独立选自甲基、甲氧基中的任一种。
3.取代苯基哌啶酮类化合物，其特征在于，选自以下化合物：
Figure FDA0002682366160000012
Figure FDA0002682366160000021
4.权利要求1所述式(I)所示的取代苯基哌啶酮类化合物的制备方法，其特征在于，方程式如下：
Figure FDA0002682366160000022
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。
5.权利要求1所述式(II)所示的取代苯基哌啶酮类化合物的制备方法，其特征在于，方程式如下：
Figure FDA0002682366160000023
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。
6.一种药物组合物，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，结合一种或几种药学上可接受的惰性无毒的赋形剂或载体。
7.权利要求1所述式(I)或式(II)所示的取代苯基哌啶酮类化合物在制备抗人肝癌、乳腺癌、人肺癌、神经母细胞瘤药物的应用。
8.权利要求6所述药物组合物的应用，其特征在于，所述组合物在制备抗人肝癌、乳腺癌、人肺癌、神经母细胞瘤药物的应用。
CN201910291185.9A 2019-04-11 2019-04-11 取代苯基哌啶酮类化合物及其合成方法和应用 Active CN110128325B (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201910291185.9A CN110128325B (zh) 2019-04-11 2019-04-11 取代苯基哌啶酮类化合物及其合成方法和应用

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201910291185.9A CN110128325B (zh) 2019-04-11 2019-04-11 取代苯基哌啶酮类化合物及其合成方法和应用

Publications (2)

Publication Number Publication Date
CN110128325A CN110128325A (zh) 2019-08-16
CN110128325B true CN110128325B (zh) 2021-01-05

Family

ID=67569672

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201910291185.9A Active CN110128325B (zh) 2019-04-11 2019-04-11 取代苯基哌啶酮类化合物及其合成方法和应用

Country Status (1)

Country Link
CN (1) CN110128325B (zh)

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3472678D1 (de) * 1983-07-18 1988-08-18 Beecham Group Plc Benzazepine and benzoxazepine derivatives
US4808720A (en) * 1986-06-09 1989-02-28 Stauffer Chemical Company Certain 3-benzoyl-4-oxolactams
WO2004101529A1 (ja) * 2003-05-19 2004-11-25 Ono Pharmaceutical Co., Ltd. 含窒素複素環化合物およびその医薬用途
CN103570721A (zh) * 2012-07-19 2014-02-12 中国医学科学院药物研究所 三唑并吡嗪（酮）以及异噁唑并哌啶酮类化合物

Also Published As

Publication number Publication date
CN110128325A (zh) 2019-08-16

Similar Documents

Publication Publication Date Title
US5770605A (en) Method for treating leukemia with a hexa-cyclic compound
WO1994011376A1 (en) Camptothecin analogues and methods of preparation thereof
CN1955183B (zh) 20-位酯化的喜树碱衍生物、其制法和其药物组合物与用途
KR100756113B1 (ko) 당뇨병 및 비만을 치료하기 위한 5ｈｔ2ｃ 수용체 작용물질
CN113527335A (zh) 作为egfr抑制剂的大环类化合物及其应用
JP7485661B2 (ja) カンプトテシン誘導体およびその調製方法並びに用途
AU2021105895A4 (en) Lycoline B-aryl acrylate derivatives, preparation method and application thereof
WO2013107428A1 (zh) 7-位取代的汉防己乙素衍生物、及其制备方法和应用
CN110872253A (zh) 一种具有镇痛活性的高乌甲素衍生物及其制备方法
CN110128325B (zh) 取代苯基哌啶酮类化合物及其合成方法和应用
JP2001505922A (ja) 新規なカンプトテシン類縁体、その医薬としての使用及びそれを含有する医薬組成物
JP3652708B2 (ja) シクロアルカ［ｂ］ピリジン−３−カルボニルグアニジン誘導体、その製造法およびそれを含有する医薬品
CZ2000711A3 (cs) Opticky čisté analogy kamptothecinu, meziprodukty syntézy a způsob přípravy
TWI275588B (en) 1-trifluoromethyl-4-hydroxy-7-piperidinylaminomethylchroman derivatives
CN113024557B (zh) 一种Peganumine A生物碱结构简化物及其应用
US20140011833A1 (en) Camptothecin derivatives having anti-tumor activity
US6187783B1 (en) Phenanthridinium derivatives
CN111533753A (zh) 氨基甲酸酯类氟代喜树碱类化合物及其应用
CN111116551A (zh) 1-氮杂螺[5.5]十一烷-3-酮类及1-氮杂螺[5.5]十一烷-3-醇类化合物
JP3600248B2 (ja) ２０（ｓ）−カンプトテシンの新規な水溶性ｃ−環類似体
KR20070097535A (ko) 캄토테신의 입체선택적 방법 및 결정성 형태
CN113493456B (zh) 一类含中环四氢咔啉-四氢异喹啉化合物的制备和用途
CN111138361B (zh) 取代苯氧基-2-氮杂双环[3.2.1]辛烷类化合物及其制备方法和应用
JPH05504345A (ja) 新規ジヒドロピリジン
CN111393416B (zh) 含1-甲基吡啶-3-(4-氯苯基)吡唑单元的吡唑化合物的制备方法和应用

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
GR01 Patent grant
GR01 Patent grant