CN103936667A - 新型3,5-双(芳香基次甲基)-1-甲基哌啶-4-酮类化合物,其合成方法及其作为抗癌药物的用途 - Google Patents
新型3,5-双(芳香基次甲基)-1-甲基哌啶-4-酮类化合物,其合成方法及其作为抗癌药物的用途 Download PDFInfo
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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Abstract
本发明提供了一类新型3,5-双(芳香基次甲基)-1-取代-4-哌啶酮类化合物,其合成方法及其作为抗癌药物的用途。所述新型3,5-双(芳香基次甲基)-1-取代-4-哌啶酮类化合物结构如式(I)所示,其中R1选自氢、丙基、苄基、2-苯乙基、乙酰基、乙氧基羰基;R2、R3和R4分别独立选自氟、氯、溴、C1-C12烯基、C1-C12烷基、C1-C12烷氧基、C1-C12羧酸、C1-C12羧酸酯、C1-C12羧酸对应的酰胺;n=0或1。该类型化合物有良好的抗癌活性,且合成方法简单,无毒副作用,适合用于制备治疗癌症的药物。
Description
技术领域
本发明涉及一类具有抗癌活性的化合物及其应用与合成方法,具体涉及一类新型3,5-双(芳香基次甲基)-1-取代-4-哌啶酮类化合物,其合成方法及其作为抗癌药物的用途。
背景技术
目前,癌症的主要治疗手段包括手术、放疗和化学药物治疗。一般根据病者的情况而选择适合的治疗方法,手术和放疗对病者的伤害性比较大。而目前临床应用的抗癌药物,大部分的毒副作用较大,再加上疗效的不稳定为病者带来精神上的折磨,治疗过程中给癌症患者带来巨大的痛苦。开发高效、低毒的抗癌药物既是征服癌症必不可缺的工作,也是拯救病人、帮助病人家属的人道主义精神体现。
姜黄素是天然存在的物质,其抗癌活性较高、抗癌谱较广,且毒副作用很低。姜黄素主要成分的结构式为
研究结果表明,连续三代喂饲姜黄素,未对大鼠表现出任何致畸性或致癌性;用较大剂量给大鼠连续口服80天,对大鼠的进食量和生长发育均无影响,病理学检查证实体内各器官未见损伤性改变;人每日口服1200mg/kg也是安全的。有不少这方面的研究报道,如:姜黄素可与多种信号蛋白互相作用抑制多种癌症的入侵、增殖和转移(Cancer Letters,199,2008,Bharat B.Aggarwal);姜黄素的免疫制剂及其治疗活性(International Immunopharmacology,331,2011,Ashok Khar);通过控制炎症通路的营养而控制肿瘤细胞的生存、繁殖、再生及转移(Cancer Metastasis Review,29:405,2010,Sahdeo Prasad);利用姜黄素调节人体氧化还原机能及抑制胆管肿瘤细胞(Biochemical Pharmacology,1658,2010,Veerapol Kukongviriyapan);异甲基姜黄素及其结构对应的氨 基酸在体外实验中显示出强氧化性,具有消炎和抑制炎症增殖作用(Biochemical Pharmacology,1658,2010,Bharat B.Aggarwal);新型4-芳基姜黄素化合物的合成及其作为抗癌药物KB信息通路的靶向因子的鉴定(J.Med.Chem.53,8260,2010,Xianzhang Bu);包含姜黄素和胆固醇的二价配体作为多功能β-低聚反应抑制剂的设计、合成、生物表征(J.Med.Chem.53,6198,2010,Shijun Zhang)。
发明内容
本发明提供了一类新型的3,5-双(芳香基次甲基)-1-取代-4-哌啶酮类化合物,结构式为式(Ⅰ)所示的化合物:
其中:
n=0或1;
R1选自氢、丙基、苄基、2-苯乙基、乙酰基、乙氧基羰基;
R2、R3和R4分别独立选自氟、氯、溴、C1-C12烯基、C1-C12烷基、C1-C12烷氧基、C1-C12羧酸、C1-C12羧酸酯、C1-C12羧酸对应的酰胺。
根据式(Ⅰ)中R1的不同,可将化合物分为A、B、C、D、E、F六个系列:
A系列化合物是3,5-双-(芳香基次甲基)-1-丙基哌啶-4-酮类化合物,其结构通式为式(Ⅲ):
其中R1为正丙基或异丙基;R2、R3和R4分别独立选自氟、氯、溴、C1-C12烯基、C1-C12烷基、C1-C12烷氧基、C1-C12羧酸、C1-C12羧酸酯、C1-C12羧酸对应的酰胺。
B系列化合物是3,5-双-(芳香基次甲基)-1-苄基哌啶-4-酮类化合物,其结构通式 为式(Ⅳ):
其中R1为苄基;R2、R3和R4分别独立选自氟、氯、溴、C1-C12烯基、C1-C12烷基、C1-C12烷氧基、C1-C12羧酸、C1-C12羧酸酯、C1-C12羧酸对应的酰胺。
C系列化合物是3,5-双-(芳香基次甲基)-1-乙氧基羰基哌啶-4-酮类化合物,其结构通式为式(Ⅴ):
其中R1为乙氧基羰基;R2、R3和R4分别独立选自氟、氯、溴、C1-C12烯基、C1-C12烷基、C1-C12烷氧基、C1-C12羧酸、C1-C12羧酸酯、C1-C12羧酸对应的酰胺。
D系列化合物是3,5-双-(芳香基次甲基)-1-乙酰基哌啶-4-酮类化合物,其结构通式为式(Ⅵ):
其中R1为乙酰基;R2、R3和R4分别独立选自氟、氯、溴、C1-C12烯基、C1-C12烷基、C1-C12烷氧基、C1-C12羧酸、C1-C12羧酸酯、C1-C12羧酸对应的酰胺。
E系列化合物是3,5-双-(芳香基次甲基)哌啶-4-酮类化合物,其结构通式为式(Ⅶ):
其中R1为氢基;R2、R3和R4分别独立选自氟、氯、溴、C1-C12烯基、C1-C12烷基、C1-C12烷氧基、C1-C12羧酸、C1-C12羧酸酯、C1-C12羧酸对应的酰胺。
F系列化合物是3,5-双-(芳香基次甲基)-1-(2-苯乙基)-4-酮类化合物,其结构通式为式(Ⅷ):
其中R1为2-苯乙基;R2、R3和R4分别独立选自氟、氯、溴、C1-C12烯基、C1-C12烷基、C1-C12烷氧基、C1-C12羧酸、C1-C12羧酸酯、C1-C12羧酸对应的酰胺。
本发明提供的新型的3,5-双(芳香基次甲基)-1-取代-4-哌啶酮类化合物,通过体外细胞活性测试结果证明,该类化合物显示出优良的抗癌活性,作为抗癌药物,具有明显的应用前景,适用于制备单方抗癌药物或与其他药物配伍成复方抗癌药物。经试验证明,该类化合物尤其对前列腺癌细胞株、结肠癌细胞株和肺癌细胞株有明显的抑制效力。因此,本发明还提供了所述式(Ⅰ)化合物用途用于制备单方或复方抗癌药物的用途,尤其是用于制备单方或复方前列腺癌、结肠癌和肺癌药物的用途。
另外,本发明还提供了一种式(Ⅰ)的化合物的合成方法,由2分子取代芳香醛和1分子1-取代-4-哌啶酮和/或其衍生物作为反应原料,在冰醋酸的氯化氢饱和溶液中,反应温度为20℃-100℃,反应生成1分子式(Ⅰ)的化合物;反应方程式如式(Ⅱ)所示:
其中,R1选自氢、丙基、苄基、2-苯乙基、乙酰基、乙氧基羰基;R2、R3和R4分别独立选自氟、氯、溴、C1-C12烯基、C1-C12烷基、C1-C12烷氧基、C1-C12羧酸、C1-C12羧酸酯、C1-C12羧酸对应的酰胺。
本发明提供了一种新型的抗癌化合物并提供了该化合物作为抗癌药物的活性测试结果,该化合物是姜黄素的衍生物,具有良好的抗癌活性,且无毒副作用;且本发明同时提供了该化合物的合成方法,该方法取材天然、合成条件简单,具有良好的应用前景。
具体实施方式
实施例1至实施例92为本发明给出3,5-双(芳香基次甲基)-1-取代-4-哌啶酮类化合物的实例,并提供对应实例的结构表征。按上述根据R1基团的不同分成的A、B、C、D、E、F六个系列,各类别均给出一定数量的例子,并按“类别+序号”的方式给予对应的化合物编号,以便与实施例93中表1的各个编号对应。
但本发明所述3,5-双(芳香基次甲基)-1-取代-4-哌啶酮类化合物的可实现结构不限于以下实施例子,可以是与该结构具有抗癌活性的异构体、取代物或衍生物。
实施例1:(A1)
3,5-双-(4-氟苯基次甲基)-1-正丙基哌啶-4-酮
1HNMR(300MHz,DMSO):0.77(t,J=7.5Hz,3H,CH3),1.31-1.41(m,2H,CH2),2.46-2.50(m,2H,CH2),3.81(s,4H),7.61(d,J=8.4Hz,4H),7.63(s,2H,benzylidene),8.00(d,J=8.1Hz,4H).ESI-Ms,m/e354.1[M+H]+
实施例2:(A2)
3,5-双-(2,4-二氟苯基次甲基)-1-正丙基哌啶-4-酮
1HNMR(500MHz,DMSO):0.76(t,J=7.5Hz,3H),1.35(q,J=7.5Hz,2H),2.43(t,J=7.5Hz,2H),3.70(s,4H),7.19-7.23(m,2H),7.38-7.43(m,2H),7.53-7.58(m,2H),7.63(s,2H).13CNMR(125MHz, DMSO):12.0,20.1,54.2,58.4,105.0,112.4,119.4,126.7,132.8,135.6,160.3,162.3,186.6. 19FNMR(470MHz,DMSO):-107.0,-108.8
实施例3:(A3)
3,5-双-(3,4-二氟苯基次甲基)-1-正丙基哌啶-4-酮
1HNMR(300MHz,DMSO):0.79(s,3H,CH3),1.40(s,2H,CH2),2.51(s,2H,CH2),3.78(s,4H,2CH2),7.39(s,3H),7.56-7.64(m,6H)
实施例4:(A4)
3,5-双-(4-溴苯次甲基)-1-丙基哌啶-4-酮
1HNMR(DMSO):0.78(t,J=7.5Hz,3H,CH3),1.34-1.42(m,2H,CH2),2.50-2.51(m,2H,CH2),3.76(s,4H,2CH2),7.48(d,J=8.4Hz,4H,2Ar),7.57(s,2H,2benzylidene),7.69(d,J=8.1Hz,4H,2Ar),.13CNMR(75MHz,DMSO):11.5,19.6,53.9,58.2,122.7,131.7,132.2,133.6,133.7,134.4,186.4.ESI-Ms,m/e476.0[M+H]+.
实施例5:(A5)
3,5-双-(4-氯苯基次甲基)-1-丙基哌啶-4-酮
1HNMR(DMSO):0.78(t,J=7.5Hz,3H,CH3),1.32-1.45(m,2H,CH2),2.46-2.52(m,2H,CH2),3.77(s,4H,2CH2),7.54(s,8H,2Ar),7.60(s,2H,2benzylidene).13CNMR(75MHz,DMSO):11.5,19.6,53.9,58.2,128.8,132.2,133.4,133.5,133.9,134.2,186.7.ESI-Ms,m/e386.1[M+H]+.
实施例6:(A6)
3,5-双-((2-氯苯基)次甲基)-1-丙基哌啶-4-酮
1HNMR(DMSO):0.78(t,J=7.5Hz,3H,CH3),1.32-1.44(m,2H,CH2),2.45-2.50(m,2H,CH2),3.75(s,4H),7.26-7.31(m,4H),7.53-7.56(m,3H),7.58(s,3H).13CNMR(75MHz,DMSO):12.4,20.5,54.8,59.1,116.3,116.6,131.8,133.4,133.5,134.2,161.3,164.5,187.2.ESI-Ms,m/e386.1[M+H]+.
实施例7:(A7)
3,5-双-((2,3-二氯苯基)次甲基)-1-丙基哌啶-4-酮
1HNMR(DMSO):0.72(t,J=7.5Hz,3H,CH3),1.19-1.28(m,2H,CH2),2.37(t,J=7.2Hz,2H,CH2),3.64(s,4H),7.37-7.42(m,2H),7.47(d,J=7.8Hz,2H),7.69(dd,J1=7.8Hz,J2=1.8Hz,2H), 7.73(s,2H).-13CNMR(75MHz,DMSO):12.3,20.4,54.0,58.3,128.9,130.0,131.6,132.2,132.6,133.0,135.7,136.3,190.0.ESI-Ms,m/e456.0[M+H]+.
实施例8:(A8)
3,5-双-(2,4-二氯苯次甲基)-1-丙基哌啶-4-酮
1HNMR(300MHz,DMSO):0.74(t,J=7.2Hz,3H,CH3),1.29(s,2H,CH2),2.41(s,2H,CH2),3.68(s,4H,2CH2),7.49-7.53(m,4H),7.72(s,2H),7.79(s,2H).
实施例9:(A9)
3,5-双-((3,4-二氯苯基)次甲基)-1-丙基哌啶-4-酮
1HNMR(DMSO):0.78(t,J=7.5Hz,3H,CH3),1.33-1.38(m,2H,CH2),2.45-2.50(m,2H,CH2),3.77(s,4H),7.47(dd,J1=8.4Hz,J2=1.8Hz,2H),7.54(s,2H),7.71(d,J=8.1Hz,2H),7.77(d,J=1.8Hz,2H).
实施例10:(A10)
3,5-双-(4-三氟甲基苯基次甲基)-1-丙基哌啶-4-酮
1HNMR(300MHz,DMSO):0.79(t,J=7.2Hz,3H,CH3),1.39(s,2H,CH2),2.51(s,2H,CH2),3.84(s,4H,2CH2),7.59-7.82(m,10H).ESI-Ms,m/e454.1[M+H]+.
实施例11:(A11)
3,5-双-(4-羟基苯次甲基)-1-丙基哌啶-4-酮
1HNMR(300MHz,DMSO):0.81(t,J=7.2Hz,3H,CH3),1.38-1.46(m,2H,CH2),2.47-2.52(m,2H,CH2),3.73(s,4H,2CH2),6.89(d,J=8.7Hz,4H,2Ar),7.38(d,J=8.7Hz,4H,2Ar),7.52(s,2H,2benzylidene),10.04(s,2H,2OH);13CNMR(75MHz,DMSO):11.6,19.8,54.4,58.6,111.7,125.8,130.9,132.6,134.6,158.6,186.4.ESI-Ms,m/e350.1[M+H]+.
实施例12:(A12)
3,5-双-((3-羟基苯基)次甲基)-1-丙基哌啶-4-酮
1HNMR(300MHz,DMSO):0.80(t,J=7.2Hz,3H,CH3),1.33-1.43(m,2H,CH2),2.45-2.50(m,2H,CH2),3.75(s,4H,2CH2),6.79-6.91(m,6H,2Ar),7.22-7.27(m,2H,2Ar),7.48(s,2H,2benzylidene),9.58(s,2H,2OH);13CNMR(75MHz,DMSO):12.4,20.6,55.0,59.2,117.1,117.4,122.1,130.4,132.6, 134.3,135.5,136.5,158.0,187.3.ESI-Ms,m/e350.1[M+H]+.
实施例13:(A13)
3,5-双-((3,4-二羟基苯基)次甲基)-1-丙基哌啶-4-酮
1HNMR(DMSO):0.89(t,J=7.2Hz,3H,CH3),1.66-1.74(m,2H,CH2),3.24(s,2H,CH2),4.56(s,4H,2CH2),6.90(s,4H,2Ar),6.99(s,2H,2benzylidene),7.72(s,2H,2Ar),9.48(s,2H,2OH),9.90(s,2H,2OH).13CNMR(75MHz,DMSO):10.8,17.0,52.2,56.3,116.1,118.0,123.3,124.2,124.9,140.1,145.6,148.4,181.3.
实施例14:(A14)
3,5-双-(3-甲氧基-4-羟基苯次甲基)-1-丙基哌啶-4-酮
1HNMR(300MHz,DMSO):0.81(t,J=7.2Hz,3H,CH3),1.38-1.45(m,2H,CH2),2.50-2.51(m,2H,CH2),3.77(s,4H,2CH2),3.82(s,6H,2OCH3),6.89(d,J=8.1Hz,2H,2Ar),6.98(d,J=7.8Hz,2H,2Ar),7.08(s,2H,2Ar),7.55(s,2H,2benzylidene),9.66(s,2H,2OH);13CNMR(75MHz,DMSO):11.7,19.8,54.3,55.6,58.5,114.9,115.7,124.1,126.2,131.1,135.1,147.5,148.1,186.3.ESI-Ms,m/e410.2[M+H]+.
实施例15:(A15)
3,5-双-((3-乙氧基-4-羟基苯基)次甲基)-1-丙基哌啶-4-酮
1HNMR(DMSO):0.81(t,J=7.5Hz,3H,CH3),1.32-1.42(m,8H,CH2+2CH3),2.46-2.50(m,2H,CH2),3.74(s,4H),4.05(q,J=6.9Hz,2H,CH2),7.37-7.42(m,2H),7.47(d,J=7.8Hz,2H),7.69(dd,J1=7.8Hz,J2=1.8Hz,2H),7.73(s,2H);13CNMR(75MHz,DMSO):12.5,15.5,20.6,55.1,59.3,64.6,116.5,116.9,124.9,126.9,131.7,135.8,149.1,186.8.ESI-Ms,m/e438.2[M+H]+.
实施例16:(A16)
3,5-双-(3,4-二甲氧基苯次甲基)-1-丙基哌啶-4-酮
1HNMR(300MHz,DMSO):0.81(t,J=7.5Hz,3H,CH3),1.37-1.45(m,2H,CH2),2.50-2.51(m,2H,CH2),3.79-3.87(m,16H,2CH2+4CH3),7.07(s,4H,2Ar),7.11(s,2H,2Ar),7.59(s,2H,2benzylidene); 13CNMR(75MHz,DMSO):11.7,19.8,54.2,55.5,58.4,111.6,114.2,123.7,127.4,131.9,134.9,148.5,149.8,186.4.ESI-Ms,m/e438.2[M+H]+.
实施例17:(A17)
3,5-双-(2,3,4-三甲氧基苯次甲基)-1-丙基哌啶-4-酮
1HNMR(DMSO):0.78(t,J=7.5Hz,3H,CH3),1.32-1.39(m,2H,CH2),2.43(t,J=7.5Hz,2H,CH2),3.70(s,4H,2CH2),3.78(s,3H,CH3O),3.81(s,3H,CH3O),3.86(s,3H,CH3O),6.93(d,J=8.7Hz,2H,2Ar),7.09(d,J=8.7Hz,2H,2Ar),7.76(s,2H,2benzylidene).13CNMR(75MHz,DMSO):11.6,19.7,54.2,55.9,58.2,60.4,61.4,107.8,121.1,125.2,129.8,132.4,141.7,154.7,186.3.ESI-Ms,m/e498.2[M+H]+.
实施例18:(A18)
3,5-双-((3,4,5-三甲氧基苯基)次甲基)-1-丙基哌啶-4-酮
1HNMR(300MHz,DMSO):0.81(t,J=7.2Hz,3H),1.37-1.45(m,2H),2.49-2.54(m,2H,N-CH2),3.72(s,6H,2OCH3),3.83(s,16H,4OCH3+2CH2),6.81(s,4H,2Ar),7.59(s,2H,benzylidene); 13CNMR(75MHz,DMSO):11.7,19.8,53.9,55.9,58.2,60.1,108.0,130.2,133.0,135.1,138.4,152.7,186.6.ESI-Ms,m/e498.2[M+H]+.
实施例19:(A19)
3,5-双-(4-吡啶基次甲基)-1-丙基哌啶-4-酮
1HNMR(DMSO):0.74-0.80(m,3H,CH3),1.36-1.37(m,2H,CH2),2.49-2.51(m,2H,CH2),3.81(s,4H,2CH2),7.47(s,4H,2Ar),7.54(s,2H,2benzylidene),8.67(s,4H,2Ar).13CNMR(75MHz,DMSO):11.5,19.5,53.7,58.0,124.2,132.3,137.2,141.6,150.0,186.8.ESI-Ms,m/e320.2[M+H]+.
实施例20:(A20)
3,5-双-(3-吡啶基次甲基)-1-丙基哌啶-4-酮
1HNMR(DMSO):0.78(t,J=7.5Hz,3H,CH3),1.35-1.42(m,2H,CH2),2.46-2.52(m,2H,CH2),3.82(s,4H,2CH2),7.49-7.52(m,2H,2Ar),7.64(s,2H),7.95(d,J=7.5Hz,2H),8.59-8.60(m,2H),8.73(s,2H).13CNMR(75MHz,DMSO):11.5,19.5,53.8,58.1,123.7,130.5,131.6,135.5,137.1,149.6,151.2,186.5.ESI-Ms,m/e320.2[M+H]+.
实施例21:(A21)
3,5-双-(2-萘次甲基)-1-丙基哌啶-4-酮
1HNMR(300MHz,DMSO):0.77(t,J=7.5Hz,3H,CH3),1.34-1.42(m,2H,CH2),2.50-2.52(m,2H,CH2),3.96(s,4H),7.58-7.68(m,6H),7.82(s,2H),7.97-8.01(m,6H),8.11(s,2H,benzylidene).
实施例22:(A22)
3,5-双-(1-萘次甲基)-1-丙基哌啶-4-酮
1HNMR(300MHz,DMSO):0.61(t,J=7.2Hz,3H,CH3),1.09-1.16(m,2H,CH2),2.31(t,J=7.2Hz,2H,CH2),3.69(s,4H),7.53(d,J=7.2Hz,2H),7.59-7.66(m,6H),8.01-8.04(m,6H),8.34(s,2H,benzylidene).13CNMR(75MHz,DMSO):11.4,19.6,54.0,57.8,123.0,125.4,126.4,127.0,127.4,128.7,129.5,131.3,133.1,133.2,135.2,187.4.ESI-Ms,m/e418.2[M+H]+.
实施例23:(A23)
3,5-双-(3-苯亚烯丙基)-1-丙基哌啶-4-酮
1HNMR(300MHz,DMSO):0.91(t,J=7.5Hz,3H,CH3),1.59-1.67(m,2H,CH2),2.51-2.56(m,2H,CH2),3.71(s,4H,2CH2),7.12-7.19(m,2H,2Ar),7.22-7.29(m,4H,2Ar),7.32-7.43(m,6H,2Ar),7.70(d,J=7.5Hz,4H);13CNMR(75MHz,DMSO):11.8,19.6,52.9,58.8,123.4,127.5,128.7,129.0,133.0,134.4,136.3,141.4,185.7.ESI-Ms,m/e370.2[M+H]+.
实施例24:(A24)
3,5-双-((2-噻吩基)次甲基)-1-丙基哌啶-4-酮
1HNMR(300MHz,DMSO):0.89(t,J=7.2Hz,3H),1.48-1.61(m,2H),2.59(t,J=7.5Hz,2H,N-CH2),3.78(s,4H,2CH2),7.27(dd,J1=5.1Hz,J2=3.9Hz,2H,2Ar),7.60(d,J=3.3Hz,2H,2Ar),7.81(s,1H),7.94(d,J=5.1Hz,2H,2Ar);13CNMR(75MHz,DMSO):11.6,19.9,53.7,58.5,127.3,128.4,130.4,132.0,134.2,137.8,185.6.ESI-Ms,m/e330.1[M+H]+.
实施例25:(B1)
3,5-双-(4-氟苯基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):3.71(s,2H,CH2),3.82(s,4H,2CH2),7.21-7.30(m,9H),7.49-7.54(m,4H),7.64(s,2H).13CNMR(75MHz,DMSO):53.6,60.4,115.5,127.2,128.1,128.8,131.0,132.7,133.3,134.0,137.6,160.6,163.9,186.5.
实施例26:(B2)
3,5-双-(3-氟苯基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):3.72(s,2H),3.83(s,4H),7.18-7.31(m,11H),7.46-7.50(m,2H),7.62(s,2H).
实施例27:(B3)
3,5-双-(2,4-二氟苯基次甲基)-1-苄基哌啶-4-酮
1HNMR(500MHz,DMSO):3.66(s,2H),3.75(s,4H),7.14-7.19(m,7H),7.36-7.40(m,2H),7.43-7.47(m,2H),7.66(s,2H).13CNMR(125MHz,DMSO):53.7,60.1,105.0,112.5,119.3,127.6,128.6,129.3,132.6,135.5,137.9,160.2,162.2,164.3,186.5.19FNMR(470MHz,DMSO):-108.7,-107.0
实施例28:(B4)
3,5-双-(3,4-二氟苯基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):3.73(s,2H),3.82(s,4H),7.24(s,5H),7.30-7.33(m,2H),7.46-7.60(m,6H).
实施例29:(B5)
3,5-双-(4-氯苯基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):3.70(s,2H,CH2),3.81(s,4H,2CH2),7.20-7.21(m,6H),7.23-7.25(m,7H),7.61(s,2H).
实施例30:(B6)
3,5-双-(2氯苯基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):3.62(s,2H),3.73(s,4H),7.17(s,5H),7.34-7.40(m,6H),7.57(s,2H),7.82(s,2H).
实施例31:(B7)
3,5-双-(2,3-二氯苯基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):3.59(s,2H),3.69(s,4H),7.14(s,5H),7.27(d,J=7.5Hz,2H),7.34-7.39(m,2H),7.69(d,J=7.5Hz,2H),7.77(s,2H).
实施例32:(B8)
3,5-双-(2,4-二氯苯基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):3.61(s,2H),3.71(s,4H),7.17(s,5H),7.36(d,J=8.4Hz,2H),7.46(dd,J1=8.4Hz,J2=1.4Hz,2H),7.74-7.77(m,4H).
实施例33:(B9)
3,5-双-(3,4-二氟苯基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):3.75-3.82(m,6H),7.25(s,5H),7.44(d,J=8.1Hz,2H),7.62(s,2H),.72(d,J=8.4Hz,2H),7.74(s,2H).13CNMR(75MHz,DMSO):52.7,58.5,122.1,127.4,128.1,128.7,129.3,131.3,131.5,131.8,134.4,134.8,135.4,187.2.ESI-Ms,m/e503.9,[M+H]+.
实施例34:(B10)
3,5-双-(4-溴苯基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):3.70(s,2H,CH2),3.80(s,4H,2CH2),7.20-7.25(m,5H),7.41(d,J=8.4Hz,4H),7.58(s,2H),7.64(d,J=8.4Hz,4H).13CNMR(75MHz,DMSO):53.6,60.3,122.7,127.2,128.2,128.8,131.6,132.3,133.7,133.9,134.2,137.5,186.6.
实施例35:(B11)
3,5-双-(4-吡啶基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):3.71(s,2H,CH2),3.85(s,4H,2CH2),7.40(d,J=6.0Hz,4H),7.58(s,2H),8.64(d,4H),7.64(d,J=6.0Hz,4H).
实施例36:(B12)
3,5-双-(3-吡啶基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):3.73(s,2H,CH2),3.86(s,4H,2CH2),7.16-7.26(m,5H),7.44-7.48(m,2H),7.66(s,2H),7.84-7.87(m,2H),8.57(d,J=3.6Hz,2H),8.67(s,2H).
实施例37:(B13)
3,5-双-(3,4-二羟基苯基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):4.18-4.29(m,6H),6.89(d,J=8.4Hz,4H,2Ar),7.31-7.34(m,7H),7.69(s,2H),7.80(br,2H,2-OH),39(br,2H,2-OH);
实施例38:(B14)
3,5-双-(3-甲氧基-4-羟基苯基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):3.80(s,12H),6.87(d,J=8.1Hz,2H),6.95(d,J=8.4Hz,2H),7.01(s,2H),7.27-31(m,5H),7.56(s,2H),9.70(s,-OH,1H).13CNMR(75MHz,DMSO):54.0,55.5,61.1,114.5,115.7,124.6,126.0,127.5,128.3,129.2,130.6,135.0,147.5,148.3,186.2.
实施例39:(B15)
3,5-双-(3-乙氧基-4-羟基苯基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):1.34-1.36(m,6H),3.74-3.77(m,6H),4.01-4.03(m,4H),6.85-6.91(m,4H),6.97(s,2H),7.24-7.29(m,5H),7.53(s,2H),9.58(s,2H,OH).13CNMR(75MHz,DMSO):14.7,54.2,61.2,63.7,115.6,115.7,124.6,126.1,127.2,128.1,129.0,130.7,135.1,137.6,146.6,148.4,186.1.
实施例40:(B16)
3,5-双-(3,4-二甲氧基苯基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):3.75(s,4H,CH2),3.75-3.80(m,14H,6-OCH3),7.02(s,6H),7.27-7.30(m,5H),7.58(s,2H).13CNMR(75MHz,DMSO):54.0,55.4,55.5,61.1,111.6,113.7,124.1,127.2,127.3,128.2,129.0,131.6,134.9,137.5,148.5,149.8,186.2.
实施例41:(B17)
3,5-双-(2,5-二-甲氧基苯基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):3.66(s,2H),3.71(s,10H),3.78(s,6H),6.74(s,2H),6.93-7.01(m,4H),7.17-7.22(m,5H),7.83(s,2H).13CNMR(75MHz,DMSO):53.9,55.4,55.8,60.6,112.2,115.1,115.9,123.6,127.1,128.1,128.9,130.5,133.3,137.5,152.2,152.5,186.4.
实施例42:(B18)
3,5-双-(3,4,5-三甲氧基苯基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):3.70(s,12H),3.85(s,12H),6.75(d,J=3.6Hz,4H),7.23-7.27(m,5H),7.81(s,2H).
实施例43:(B19)
3,5-双-(2,3,4-三甲氧基苯基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):3.60(s,2H),3.74-3.76(m,10H),3.81-3.83(m,12H),6.86(d,J=9.0Hz,4H),6.99(d,J=8.4Hz,4H),7.20-7.24(m,5H),7.78(s,2H).13CNMR(75MHz,DMSO):54.0,55.9,60.4,61.3,107.7,121.1,125.0,127.1,128.1,128.7,130.1,132.3,137.8,141.7,152.9,154.7,186.3.
实施例44:(B20)
3,5-双-(1-萘基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):3.54(s,2H),3.74(s,4H),7.01(s,5H),7.41(s,2H),7.53-7.63(m,6H),7.99(s,6H),8.34(s,2H).
实施例45:(B21)
3,5-双-(2-萘基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):377(s,2H),4.00(s,4H),7.04-7.21(m,5H),7.30(d J=6.3Hz,2H),7.60(d,J=6.9Hz,6H),7.83(s,2H),7.95-8.04(m,8H).
实施例46:(B22)
3,5-双-(4-异丙基苯基次甲基)-1-苄基哌啶-4-酮
1HNMR(300MHz,DMSO):1.21(d,J=6.9Hz,6H),2.86-2.95(m,2H),3.71(s,2H),3.82(s,4H),7.19-7.27(m,5H),7.31(d,J=8.4Hz,4H),7.38(d,J=8.1Hz,4H),7.60(s,2H).13CNMR(75MHz,DMSO):23.6,33.3,54.0,60.6,61.3,126.7,127.1,128.1,128.8,130.6,132.2,133.0,134.8,137.7,149.8,186.7.
实施例47:(C1)
3,5-双-(4-氟苯基次甲基)-1-乙氧基羰基哌啶-4-酮
1HNMR(300MHz,DMSO):0.90-0.95(m,3H),3.91(s,2H),4.77(s,4H),7.78-7.80(m,10H).
实施例48:(C2)
3,5-双-(2,4-二氟苯基次甲基)-1-乙氧基羰基哌啶-4-酮
1HNMR(500MHz,DMSO):0.97(t,J=7.0Hz,3H),3.93(q,J=7.0Hz,2H),4.63(s,4H),7.24-7.29(m,2H),7.44-7.48(m,2H),7.60-7.62(m,2H),7.67(s,2H).13CNMR(125MHz,DMSO):14.6,45.2,61.8,105.1,112.7,119.1,128.1,132.9,134.6,155.0,164.6,185.9.19FNMR(470MHz,DMSO):-106.4,-108.5
实施例49:(C3)
3,5-双-(3,4-二氟苯基次甲基)-1-乙氧基羰基哌啶-4-酮
1HNMR(500MHz,DMSO):1.00(t,J=7.0Hz,3H),3.95(q,J=7.0Hz,2H),4.73(s,4H),7.41(s,2H),7.54-7.59(m,2H),7.65-7.69(m,4H).13CNMR(125MHz,DMSO):14.6,45.1,61.9,118.5,119.9,128.2,132.3,133.6,134.7,148.9,150.8,155.0,186.2.19FNMR(470MHz,DMSO):-136.1,-137.7
实施例50:(C4)
3,5-双-(4-氯苯基次甲基)-1-乙氧基羰基哌啶-4-酮
1HNMR(300MHz,DMSO):0.98(t,J=6.9Hz,3H),3.90-4.00(m,2H),4.74(s,4H),7.57(s,8H),7.69(s,2H).13CNMR(75MHz,DMSO):14.2,44.7,61.3,128.4,129.1,132.1,133.1,134.3,135.0,154.5,185.7.
实施例51:(C5)
3,5-双-(2-氯苯基次甲基)-1-乙氧基羰基哌啶-4-酮
1HNMR(300MHz,DMSO):0.94(t,J=6.9Hz,3H),3.90(q,J=7.2Hz,2H),4.62(s,4H),7.50(s,6H),7.61(s,2H),7.82(s,2H).
实施例52:(C6)
3,5-双-(2,3-二氯苯基次甲基)-1-乙氧基羰基哌啶-4-酮
1HNMR(300MHz,DMSO):0.93(t,J=7.8Hz,3H),3.91(q,J=7.2Hz,2H),4.77(s,4H),7.64-7.81(m,8H).ESI-Ms,m/e486.6[M+H]+.
实施例53:(C7)
3,5-双-(2,4-二氯苯基次甲基)-1-乙氧基羰基哌啶-4-酮
1HNMR(300MHz,DMSO):0.97(t,J=7.2Hz,3H),3.93(q,J=7.2Hz,2H),4.59(s,4H),7.51-7.61(m,4H),7.73(s,2H),7.83(s,2H).ESI-Ms,m/e486.7[M+H]+.
实施例54:(C8)
3,5-双-(3,4-二氯苯基次甲基)-1-乙氧基羰基哌啶-4-酮
1HNMR(300MHz,DMSO):0.99(t,J=6.9Hz,3H),3.93-3.95(m,2H),4.72(s,4H),7.52-7.54(m, 2H),7.66(s,2H),7.79(d,J=8.1Hz,2H),7.85(s,2H).
实施例55:(C9)
3,5-双-(4-溴苯基次甲基)-1-乙氧基羰基哌啶-4-酮
1HNMR(300MHz,DMSO):0.98(t,J=7.2Hz,3H),3.94(q,J=7.2Hz,2H),4.72(s,4H),7.51(d,J=8.4Hz,4H),7.66(s,2H),7.72(d,J=8.4Hz,4H).
实施例56:(C10)
3,5-双-(4-三氟甲基苯基次甲基)-1-乙氧基羰基哌啶-4-酮
1HNMR(300MHz,DMSO):0.94(t,J=7.2Hz,3H),3.90(s,2H),4.62(s,4H),7.49(s,6H),7.61(s,2H),7.82(s,2H).13CNMR(75MHz,DMSO):14.2,44.7,61.3,116.0,130.8,132.2,132.9,135.2,154.5,160.9,164.2,185.8.
实施例57:(C11)
3,5-双-(4-吡啶基次甲基)-1-乙氧基羰基哌啶-4-酮
1HNMR(300MHz,DMSO):0.97(t,J=6.3Hz,3H),3.90-3.94(m,2H),4.75(s,4H),7.50(s,4H),7.65(s,2H),8.71(s,4H).
实施例58:(C12)
3,5-双-(3-甲氧基-4-羟基苯基次甲基)-1-乙氧基羰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.04(t,J=6.9Hz,3H),3.83(s,6H,2-OCH3),3.99(s,2H),4.77(s,4H),6.93(s,2H),7.00(s,2H),7.13(s,2H),7.66(s,2H),9.74(s,2H,2-OH).13CNMR(75MHz,DMSO):14.3,44.9,55.6,61.2,115.0,115.7,124.3,125.9,129.6,136.6,147.6,148.5,154.6,185.3.
实施例59:(C13)
3,5-双-(3-乙氧基-4-羟基苯基次甲基)-1-乙氧基羰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.03(t,J=7.2Hz,3H),1.36(t,J=6.9Hz,3H),3.98(q,J=7.2Hz,2H),4.10(q,J=7.2Hz,2H),4.75(s,4H),6.93(d,J=8.1Hz,2H),7.01(d,J=8.1Hz,2H),7.09(s,2H),7.62(s,2H),9.67(s,2H,2OH).
实施例60:(C14)
3,5-双-(3,4-二甲氧基苯基次甲基)-1-乙氧基羰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.03(t,J=7.2Hz,3H),3.82(s,6H),3.83(s,6H),3.98(q,J=7.2Hz,2H),4.78(s,4H),7.10(s,4H),7.15(s,2H),7.68(s,2H).13CNMR(75MHz,DMSO):12.5,43.1,53.8,59.5,109.9,112.5,122.0,125.3,128.6,134.6,146.8,148.3,152.8,183.6.
实施例61:(C15)
3,5-双-(2,5-二甲氧基苯基次甲基)-1-乙氧基羰基哌啶-4-酮
1HNMR(300MHz,DMSO):0.99(t,J=7.2Hz,3H),3.76(s,6H),3.81(s,6H),3.94(q,J=7.2Hz,2H),4.65(s,4H),6.88(s,2H),7.01-7.08(m,4H),7.82(s,2H).13CNMR(75MHz,DMSO):14.2,44.8,55.5,55.9,61.2,112.3,115.6,116.0,123.4,131.8,132.4,152.2,152.6,154.5,185.9.
实施例62:(C16)
3,5-双-(3,4,5-三甲氧基苯基次甲基)-1-乙氧基羰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.00-1.05(m,3H),3.73(s,6H,2-OCH3),3.84(s,12H,4-OCH3),3.95-3.98(m,2H),4.81(s,4H),6.85(s,4H),7.67(s,2H).13CNMR(75MHz,DMSO):14.2,44.8,56.0,60.1,61.3,108.1,129.9,131.7,136.6,138.8,152.8,154.6,185.6.
实施例63:(C17)
3,5-双-(2,3,4-三甲氧基苯基次甲基)-1-乙氧基羰基哌啶-4-酮
1HNMR(300MHz,DMSO):0.99(t,J=7.2Hz,3H),3.79(s,6H,2-OCH3),3.81(s,6H,2-OCH3),3.87(s,6H,2-OCH3),3.92(q,J=6.9Hz,2H),4.66(s,4H),6.96(d,J=8.7Hz,2H),7.12(d,J=8.4Hz,2H),7.80(s,2H).
实施例64:(D1)
3,5-双-(4-氟苯基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.90(s,3H),4.80(s,4H),7.35(t,J=8.4Hz,4H),7.64(d,J=3.9Hz,2H),7.70(s,2H).13CNMR(75MHz,DMSO):20.7,42.1,46.8,116.0,130.9,132.3,133.0,135.1,160.9,164.2,168.7,186.0.ESI-Ms,m/e354.1[M+H]+.
实施例65:(D2)
3,5-双-(3-氟苯基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(500MHz,DMSO):1.90(s,3H),4.82(s,4H),7.30-7.33(m,2H),7.39-7.44(m,4H),7.53-7.58(m,2H),7.69(d,J=5.5Hz,2H).13CNMR(125MHz,DMSO):21.3,42.6,47.3,117.4,127.1,131.3,134.1,135.4,137.1,161.6,163.6,169.3,186.6.19FNMR(470MHz,DMSO):-112.2,-112.4.
实施例66:(D3)
3,5-双-(2,4-二氟苯基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(500MHz,DMSO):1.88(s3H),4.70(s,4H),7.25(t,J=8.5Hz,2H),7.42-7.46(m,2H),7.62-7.68(m,4H).13CNMR(125MHz,DMSO):21.2,42.6,47.3,105.1,112.7,119.1,128.0,132.9,134.6,162.3,164.5,169.3,186.0.19FNMR(470MHz,DMSO):-106.5,(-108.3,108.4)
实施例67:(D4)
3,5-双-(3,4-二氟苯基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(500MHz,DMSO):1.92(s,2H),4.79(s,4H),7.45(s,2H),7.54-7.59(m,2H),7.63-7.64(m,2H),7.67-7.72(m,2H).13CNMR(125MHz,DMSO):21.3,42.5,47.2,118.5,119.9,128.5,132.4,133.7,134.6,148.8,150.9,169.3,186.5.19FNMR(470MHz,DMSO):-113.6.
实施例68:(D5)
3,5-双-(4-氯苯基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.88(s,3H),4.79(s,4H),7.55-7.62(m,8H),7.67(s,2H).ESI-Ms,m/e386.1[M+H]+.
实施例69:(D6)
3,5-双-(2,3-二氯苯基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.82(J=4.5Hz,3H),4.63(s,4H),7.50(s,4H),7.75(d,J=3.0Hz,4H).
实施例70:(D7)
3,5-双-(2,4-二氯苯基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.84(s,3H),4.68(d,J=6.9Hz,4H),7.58(s,4H),7.76(d,J=11.1Hz,2H),7.81(s,2H).
实施例71:(D8)
3,5-双-(3,4-二氯苯基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.90(s,3H),4.78(s,4H),7.56(d,J=8.4Hz,2H),7.64(s,2H),7.78(d,J=8.7Hz,2H),7.87(s,2H).
实施例72:(D9)
3,5-双-(4-三氟甲基苯基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.88(s,3H),4.83(s,4H),7.79(d,J=9.6Hz,6H),7.84-7.87(m,4H). 13CNMR(75MHz,DMSO):20.7,42.1,46.8,122.1,125.6,128.6,129.4,131.1,134.6,138.3,168.8,186.1.ESI-Ms,m/e454.1[M+H]+.
实施例73:(D10)
3,5-双-(4-吡啶基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.90(s,3H),4.82(s,4H),7.54(d,J=4.5Hz,4H),7.64(s,2H),8.72(d,J=5.4Hz,4H).13CNMR(75MHz,DMSO):20.8,41.9,46.8,124.2,133.6,135.9,141.4,150.1,168.8,186.0.
实施例74:(D11)
3,5-双-(3-吡啶基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.91(s,3H),4.84(d,J=4.8Hz,4H),7.52-7.57(m,2H),7.73(d,J=4.8Hz,2H),7.98-8.03(m,2H),8.65(d,J=4.8Hz,2H),8.80(d,J=3.9Hz,3H).13CNMR(75MHz,DMSO):20.8,42.0,46.9,123.8,130.2,133.0,134.2,137.3,149.9,151.2,168.8,185.8.
实施例75:(D12)
3,5-双-(4-羟基-3-甲氧基苯基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.92(s,3H),3.84(s,6H),4.81(s,4H),6.92(d J=6.9Hz,2H),7.03(s,2H),7.14(s,2H),7.63(s,2H),9.74(s,2H,2-OH).
实施例76:(D13)
3,5-双-(4-羟基-3-乙氧基苯基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.36(t,J=6.9Hz,6H),1.91(s,3H),4.09(t,J=6.3Hz,4H),4.80(d,J= 1.8Hz,4H),6.92(d,J=8.4Hz,2H),7.00-7.04(m,2H),7.12(d,J=3.0Hz,2H),7.61(s,2H),9.65(s,2H,2-OH).13CNMR(75MHz,DMSO):14.7,20.8,42.3,47.0,63.9,115.8,116.6,124.4,125.9,129.8,136.6,146.7,148.8,168.6,185.6.
实施例77:(D14)
3,5-双-(3,4-二甲氧基苯基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.92(s,3H),3.83(s,12H),4.83(s,4H),7.07-7.18(m,6H),7.67(s,2H).
实施例78:(D15)
3,5-双-(2,5-二甲氧基苯基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.85(s,3H),3.76(J=1.2Hz,6H),3.81(s,6H),4.71(d,J=5.4Hz,4H),6.94(d J=9.3Hz,2H),7.05(s,4H),7.78(s,1H),7.83(s,1H).13CNMR(75MHz,DMSO):20.7,42.2,46.9,55.5,56.0,112.4,115.6,116.2,123.4,131.7,132.6,152.3,152.6,168.6,186.2.
实施例79:(D16)
3,5-双-(3,4,5-三甲氧基苯基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.96(s,3H),3.74(s,6H),3.84(s,6H),3.86(s,6H),4.87(d J=3.0Hz,4H),6.88(d,J=6.0Hz,4H),7.67(s,2H).
实施例80:(D17)
3,5-双-(2,4,5-三甲氧基苯基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.87(s,3H),3.82(s,18H),4.72(s,4H),6.95(s,2H),7.16(s,2H),7.81(s,2H).ESI-Ms,m/e497.6[M+H]+.
实施例81:(D18)
3-双-(2,3,4-三甲氧基苯基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.89(s,3H),3.76(s,3H),3.79(s,3H),3.88(s,12H),4.73(s,4H),6.79(s,2H),6.91(s,1H),6.97(s,1H),7.85(d,J=12.3Hz,2H).13CNMR(75MHz,DMSO):20.8,42.3,47.2,55.8,56.3,97.6,114.0,130.2,131.4,142.2,151.6,153.8,168.6,185.9.
实施例82:(D19)
3,5-双-(4-醛基苯基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.88(s,3H),4.85(s,4H),7.71(s,6H),7.96-8.12(m,4H),10.01-10.14(m,2H).
实施例83:(D20)
3,5-双-(4-羧基苯基次甲基)-1-乙酰基哌啶-4-酮
1HNMR(300MHz,DMSO):1.86(s,3H),4.81(s,4H),7.66(d,J=4.8Hz,2H),7.71(s,2H),8.02-8.05(m,2H).
实施例84:(E1)
3,5-双-(3-氟苯基次甲基)哌啶-4-酮
1HNMR(500MHz,DMSO):4.16(s,4H),7.27-7.31(m,2H),7.34-7.38(m,4H),7.51-7.56(m,2H),7.67(s,2H).13CNMR(125MHz,DMSO):46.7,116.7,117.4,127.1,131.2,134.9,137.2,161.6,163.5,186.4.19FNMR(470MHz,DMSO):-112.5
实施例85:(E2)
3,5-双-(3,4-二氟苯基次甲基)哌啶-4-酮
1HNMR(500MHz,DMSO):3.98(s,4H),7.37(s,2H),7.51-7.56(m,4H),7.59-7.63(m,2H). 13CNMR(125MHz,DMSO):47.7,118.3,119.8,128.2,132.2,133.0,137.2,148.8,150.8,187.9. 19FNMR(470MHz,DMSO):-1136.1.
实施例86:(E3)
3,5-双-(2,4-二氯苯基次甲基)哌啶-4-酮
1HNMR(300MHz,DMSO):4.16(s,4H),7.73(s,4H),7.83(s,4H).
实施例87:(E4)
3,5-双-(3,4-二氯苯基次甲基)哌啶-4-酮
1HNMR(300MHz,DMSO):4.16(s,4H),7.73(s,4H),7.83(s,4H).
实施例88:(E5)
3,5-双-(4-三氟甲基苯基次甲基)哌啶-4-酮
1HNMR(300MHz,DMSO):4.06(s,4H),7.70(t,J=8.4Hz,4H),7.84(d,J=8.1Hz,2H),7.89(d,J=8.4Hz,2H),8.15(d,J=8.1Hz,2H).ESI-Ms,m/e412.1[M+H]+.
实施例89:(E6)
3,5-双-(3,4-二甲氧基苯基次甲基)哌啶-4-酮
1HNMR(300MHz,DMSO):3.81(s,12H),4.01(s,4H),7.05(s,4H),7.07(s,2H),7.55(s,2H).
实施例90:(F1)
3,5-双-(4-氟苯基次甲基)-1-(2-苯乙基)哌啶-4-酮
1HNMR(300MHz,DMSO):2.71(t,J=6.9Hz,2H),2.82(t,J=7.8Hz,2H),3.85(s,4H),7.14-7.22(m,5H),7.28(t,J=8.7Hz,4H),7.55-7.60(m,6H).
实施例91:(F2)
3,5-双-(4-氯苯基次甲基)-1-(2-苯乙基)哌啶-4-酮
1HNMR(300MHz,DMSO):2.70(t,J=7.2Hz,2H),2.81(t,J=7.5Hz,2H),3.84(s,4H),7.14-7.22(m,5H),7.53(s,8H),7.58(s,2H).
实施例92:(F3)
3,5-双-(4-羟基-3-乙氧基苯基次甲基)-1-(2-苯乙基)哌啶-4-酮
1HNMR(300MHz,DMSO):1.36(t,J=6.9Hz,3H),2.74(t,J=6.6Hz,2H),2.81(t,J=7.2Hz,2H),3.84(s,4H),4.10(q,J=6.9Hz,2H),6.87(d,J=8.1Hz,2H),6.97(d,J=8.1Hz,2H),7.07(s,2H),7.15-7.23(m,5H),7.53(s,6H),9.57(s,2H).
实施例93:
本发明对所述3,5-双(芳香基次甲基)-1-取代-4-哌啶酮类化合物进行抗癌活性试验,现给出该试验的操作过程和性能描述:
1、样品抗癌活性试验操作过程:
细胞培养:肿瘤细胞株按常规方法培养传代,均培养于RPMI1640,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。
MTT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(姜黄素),空白对照组(即只加培养液,不加细胞以调零),每组均设4复孔。共同培养48h后,每孔加入20μL MTT(5mg/mL PBS液,pH7.2),再培养4h,弃上清液,每孔加入150μL DMSO,振荡10min,应用酶标仪于570nm处测吸光度值(A)。
数据处理:把MTT法测得的吸光度值,用SPSS11.0软件进行统计学分析,计算出样品相对姜黄素为参考的IC50值。3,5-双(芳香基次甲基)-1-取代-4-哌啶酮类化合物的IC50值见表1。
2、试验结果:
表1新型3,5-双(芳香基次甲基)-1-取代-4-哌啶酮类化合物的抗癌活性(IC50值,μM)
注:a:PC-3,前列腺癌细胞株;b:HT-29,结肠癌细胞株;c:H1299,肺癌细胞株(肺癌);d:“—”,表示没有测试结果。
从表1中看出,大部分新合成出的新型3,5-双(芳香基次甲基)-1-取代-4-哌啶酮类化合物的抗癌活性均比姜黄素本身高,说明其结构改造效果很明显,其中A1、A9、A11、A12、A14、A19、A22、C2、C7、C11、D1、D5、D7、D11、D19、E2、E4、E5、18个(IC50值带“*”表示)化合物对前列腺癌细胞株的IC50值低于1.0μM,有很高的潜在应用价值。
上述结果证明,该类化合物显示出优良的抗癌活性,作为抗癌药物,具有明显的应用前景,适用于制备单方抗癌药物或与其他药物配伍成复方抗癌药物,尤其是可以针对性的用于制备单方或复方抗前列腺癌、结肠癌、肺癌等癌症的药物。
实施例94:
本发明提供了一种3,5-双(芳香基次甲基)-1-取代-4-哌啶酮类化合物的合成方法,具体的合成操作方法如下:
按照常用方法制备出冰醋酸的饱和氯化氢溶液。
取1-取代-4-哌啶酮10.0毫摩尔,相应的芳香醛20.0毫摩尔,冰醋酸饱和氯化氢溶液40-60mL,于150mL干燥的反应瓶中,(若醛是固体,超声振荡使其溶解),密封后25-100℃放置32-72小时。
搅拌下把反应混合物慢慢倒入250mL冰水中,用25%的氢氧化钠水溶液中和至中性,静置、过滤,收集固体产物。干燥后研碎,利用超声振荡技术用乙醇洗涤固体,过滤、干燥后得到纯品。
Claims (10)
1.一种式(Ⅰ)的化合物:
其中:
n=0或1;
R1选自氢、丙基、苄基、2-苯乙基、乙酰基、乙氧基羰基;
R2、R3和R4分别独立选自氟、氯、溴、C1-C12烯基、C1-C12烷基、C1-C12烷氧基、C1-C12羧酸、C1-C12羧酸酯、C1-C12羧酸对应的酰胺。
2.如权利要求1所述的式(Ⅰ)的化合物,其特征在于:式(Ⅰ)的化合物是3,5-双-(芳香基次甲基)-1-丙基哌啶-4-酮类化合物;
所述R1为正丙基或异丙基;
所述R2、R3和R4分别独立选自氟、氯、溴、C1-C12烯基、C1-C12烷基、C1-C12烷氧基、C1-C12羧酸、C1-C12羧酸酯、C1-C12羧酸对应的酰胺;
可实现的式(Ⅰ)化合物至少有:3,5-双-(4-氟苯基次甲基)-1-正丙基哌啶-4-酮;3,5-双-(2,4-二氟苯基次甲基)-1-正丙基哌啶-4-酮;3,5-双-(3,4-二氟苯基次甲基)-1-正丙基哌啶-4-酮;3,5-双-(4-溴苯次甲基)-1-丙基哌啶-4-酮;3,5-双-(4-氯苯基次甲基)-1-丙基哌啶-4-酮;3,5-双-((2-氯苯基)次甲基)-1-丙基哌啶-4-酮;3,5-双-((2,3-二氯苯基)次甲基)-1-丙基哌啶-4-酮;3,5-双-(2,4-二氯苯次甲基)-1-丙基哌啶-4-酮;3,5-双-((3,4-二氯苯基)次甲基)-1-丙基哌啶-4-酮;3,5-双-(4-三氟甲基苯基次甲基)-1-丙基哌啶-4-酮;3,5-双-(4-羟基苯次甲基)-1-丙基哌啶-4-酮;3,5-双-((3-羟基苯基)次甲基)-1-丙基哌啶-4-酮;3,5-双-((3,4-二羟基苯基)次甲基)-1-丙基哌啶-4-酮;3,5-双-(3-甲氧基-4-羟基苯次甲基)-1-丙基哌啶-4-酮;3,5-双-((3-乙氧基-4-羟基苯基)次甲基)-1-丙基哌啶-4-酮;3,5-双-(3,4-二甲氧基苯次甲基)-1-丙基哌啶-4-酮;3,5-双-(2,3,4-三甲氧基苯次甲基)-1-丙基哌啶-4-酮;3,5-双-((3,4,5-三甲氧基苯基)次甲基)-1-丙基哌啶-4-酮;3,5-双-(4-吡啶基次甲基)-1-丙基哌啶-4-酮;3,5-双-(3-吡啶基次甲基)-1-丙基哌啶-4-酮;3,5-双-(2-萘次甲基)-1-丙基哌啶-4-酮;3,5-双-(1-萘次甲基)-1-丙基哌啶-4-酮;3,5-双-(3-苯亚烯丙基)-1-丙基哌啶-4-酮;3,5-双-((2-噻吩基)次甲基)-1-丙基哌啶-4-酮。
3.如权利要求1所述的式(Ⅰ)的化合物,其特征在于:式(Ⅰ)的化合物是3,5-双-(芳香基次甲基)-1-苄基哌啶-4-酮类化合物;
所述R1为苄基;
所述R2、R3和R4分别独立选自氟、氯、溴、C1-C12烯基、C1-C12烷基、C1-C12烷氧基、C1-C12羧酸、C1-C12羧酸酯、C1-C12羧酸对应的酰胺;
可实现的式(Ⅰ)化合物至少有:3,5-双-(4-氟苯基次甲基)-1-苄基哌啶-4-酮;3,5-双-(3-氟苯基次甲基)-1-苄基哌啶-4-酮;3,5-双-(2,4-二氟苯基次甲基)-1-苄基哌啶-4-酮;3,5-双-(3,4-二氟苯基次甲基)-1-苄基哌啶-4-酮;3,5-双-(4-氯苯基次甲基)-1-苄基哌啶-4-酮;3,5-双-(2氯苯基次甲基)-1-苄基哌啶-4-酮;3,5-双-(2,3-二氯苯基次甲基)-1-苄基哌啶-4-酮;3,5-双-(2,4-二氯苯基次甲基)-1-苄基哌啶-4-酮;3,5-双-(3,4-二氟苯基次甲基)-1-苄基哌啶-4-酮;3,5-双-(4-溴苯基次甲基)-1-苄基哌啶-4-酮;3,5-双-(4-吡啶基次甲基)-1-苄基哌啶-4-酮;3,5-双-(3-吡啶基次甲基)-1-苄基哌啶-4-酮;3,5-双-(3,4-二羟基苯基次甲基)-1-苄基哌啶-4-酮;3,5-双-(3-甲氧基-4-羟基苯基次甲基)-1-苄基哌啶-4-酮;3,5-双-(3-乙氧基-4-羟基苯基次甲基)-1-苄基哌啶-4-酮;3,5-双-(3,4-二甲氧基苯基次甲基)-1-苄基哌啶-4-酮;3,5-双-(2,5-二-甲氧基苯基次甲基)-1-苄基哌啶-4-酮;3,5-双-(3,4,5-三甲氧基苯基次甲基)-1-苄基哌啶-4-酮;3,5-双-(2,3,4-三甲氧基苯基次甲基)-1-苄基哌啶-4-酮;3,5-双-(1-萘基次甲基)-1-苄基哌啶-4-酮;3,5-双-(2-萘基次甲基)-1-苄基哌啶-4-酮;3,5-双-(4-异丙基苯基次甲基)-1-苄基哌啶-4-酮。
4.如权利要求1所述的式(Ⅰ)的化合物,其特征在于:式(Ⅰ)的化合物是3,5-双-(芳香基次甲基)-1-乙氧基羰基哌啶-4-酮类化合物;
所述R1为乙氧基羰基;
所述R2、R3和R4分别独立选自氟、氯、溴、C1-C12烯基、C1-C12烷基、C1-C12烷氧基、C1-C12羧酸、C1-C12羧酸酯、C1-C12羧酸对应的酰胺;
可实现的式(Ⅰ)化合物至少有:3,5-双-(4-氟苯基次甲基)-1-乙氧基羰基哌啶-4-酮;3,5-双-(2,4-二氟苯基次甲基)-1-乙氧基羰基哌啶-4-酮;3,5-双-(3,4-二氟苯基次甲基)-1-乙氧基羰基哌啶-4-酮;3,5-双-(4-氯苯基次甲基)-1-乙氧基羰基哌啶-4-酮;3,5-双-(2-氯苯基次甲基)-1-乙氧基羰基哌啶-4-酮;3,5-双-(2,3-二氯苯基次甲基)-1-乙氧基羰基哌啶-4-酮;3,5-双-(2,4-二氯苯基次甲基)-1-乙氧基羰基哌啶-4-酮;3,5-双-(3,4-二氯苯基次甲基)-1-乙氧基羰基哌啶-4-酮;3,5-双-(4-溴苯基次甲基)-1-乙氧基羰基哌啶-4-酮;3,5-双-(4-三氟甲基苯基次甲基)-1-乙氧基羰基哌啶-4-酮;3,5-双-(4-吡啶基次甲基)-1-乙氧基羰基哌啶-4-酮;3,5-双-(3-甲氧基-4-羟基苯基次甲基)-1-乙氧基羰基哌啶-4-酮;3,5-双-(3-乙氧基-4-羟基苯基次甲基)-1-乙氧基羰基哌啶-4-酮;3,5-双-(3,4-二甲氧基苯基次甲基)-1-乙氧基羰基哌啶-4-酮;3,5-双-(2,5-二甲氧基苯基次甲基)-1-乙氧基羰基哌啶-4-酮;3,5-双-(3,4,5-三甲氧基苯基次甲基)-1-乙氧基羰基哌啶-4-酮;3,5-双-(2,3,4-三甲氧基苯基次甲基)-1-乙氧基羰基哌啶-4-酮。
5.如权利要求1所述的式(Ⅰ)的化合物,其特征在于:式(Ⅰ)的化合物是3,5-双-(芳香基次甲基)-1-乙酰基哌啶-4-酮类化合物;
所述R1为乙酰基;
所述R2、R3和R4分别独立选自氟、氯、溴、C1-C12烯基、C1-C12烷基、C1-C12烷氧基、C1-C12羧酸、C1-C12羧酸酯、C1-C12羧酸对应的酰胺;
可实现的式(Ⅰ)化合物至少有:3,5-双-(4-氟苯基次甲基)-1-乙酰基哌啶-4-酮;3,5-双-(3-氟苯基次甲基)-1-乙酰基哌啶-4-酮;3,5-双-(2,4-二氟苯基次甲基)-1-乙酰基哌啶-4-酮;3,5-双-(3,4-二氟苯基次甲基)-1-乙酰基哌啶-4-酮;3,5-双-(4-氯苯基次甲基)-1-乙酰基哌啶-4-酮;3,5-双-(2,3-二氯苯基次甲基)-1-乙酰基哌啶-4-酮;3,5-双-(2,4-二氯苯基次甲基)-1-乙酰基哌啶-4-酮;3,5-双-(3,4-二氯苯基次甲基)-1-乙酰基哌啶-4-酮;3,5-双-(4-三氟甲基苯基次甲基)-1-乙酰基哌啶-4-酮;3,5-双-(4-吡啶基次甲基)-1-乙酰基哌啶-4-酮;3,5-双-(3-吡啶基次甲基)-1-乙酰基哌啶-4-酮;3,5-双-(4-羟基-3-甲氧基苯基次甲基)-1-乙酰基哌啶-4-酮;3,5-双-(4-羟基-3-乙氧基苯基次甲基)-1-乙酰基哌啶-4-酮;3,5-双-(3,4-二甲氧基苯基次甲基)-1-乙酰基哌啶-4-酮;3,5-双-(2,5-二甲氧基苯基次甲基)-1-乙酰基哌啶-4-酮;3,5-双-(3,4,5-三甲氧基苯基次甲基)-1-乙酰基哌啶-4-酮;3,5-双-(2,4,5-三甲氧基苯基次甲基)-1-乙酰基哌啶-4-酮;3-双-(2,3,4-三甲氧基苯基次甲基)-1-乙酰基哌啶-4-酮;3,5-双-(4-醛基苯基次甲基)-1-乙酰基哌啶-4-酮;3,5-双-(4-羧基苯基次甲基)-1-乙酰基哌啶-4-酮。
6.如权利要求1所述的式(Ⅰ)的化合物,其特征在于:式(Ⅰ)的化合物是3,5-双-(芳香基次甲基)哌啶-4-酮类化合物;
所述R1为氢基;
所述R2、R3和R4分别独立选自氟、氯、溴、C1-C12烯基、C1-C12烷基、C1-C12烷氧基、C1-C12羧酸、C1-C12羧酸酯、C1-C12羧酸对应的酰胺;
可实现的式(Ⅰ)化合物至少有:3,5-双-(3-氟苯基次甲基)哌啶-4-酮;3,5-双-(3,4-二氟苯基次甲基)哌啶-4-酮;3,5-双-(2,4-二氯苯基次甲基)哌啶-4-酮;3,5-双-(3,4-二氯苯基次甲基)哌啶-4-酮;3,5-双-(4-三氟甲基苯基次甲基)哌啶-4-酮;3,5-双-(3,4-二甲氧基苯基次甲基)哌啶-4-酮。
7.如权利要求1所述的式(Ⅰ)的化合物,其特征在于:式(Ⅰ)的化合物是3,5-双-(芳香基次甲基)-1-(2-苯乙基)哌啶-4-酮类化合物;
所述R1为2-苯乙基;
所述R2、R3和R4分别独立选自氟、氯、溴、C1-C12烯基、C1-C12烷基、C1-C12烷氧基、C1-C12羧酸、C1-C12羧酸酯、C1-C12羧酸对应的酰胺;
可实现的式(Ⅰ)化合物至少有:3,5-双-(4-氟苯基次甲基)-1-(2-苯乙基)哌啶-4-酮;3,5-双-(4-氯苯基次甲基)-1-(2-苯乙基)哌啶-4-酮;3,5-双-(4-羟基-3-乙氧基苯基次甲基)-1-(2-苯乙基)哌啶-4-酮。
8.权利要求1至7之任一所述的式(Ⅰ)化合物用途用于制备单方或复方抗癌药物的用途。
9.权利要求1至7之任一所述的式(Ⅰ)化合物的合成方法,其特征在于:由2分子取代芳香醛和1分子1-取代-4-哌啶酮和/或其衍生物作为反应原料,在冰醋酸的氯化氢饱和溶液中,反应温度为25℃-100℃,反应生成1分子式(Ⅰ)的化合物。
10.如权利要求9所述的式(Ⅰ)化合物的合成方法,其特征在于反应方程式如式(Ⅱ)所示:
其中,R1选自氢、丙基、苄基、2-苯乙基、乙酰基、乙氧基羰基;R2、R3和R4分别独立选自氟、氯、溴、C1-C12烯基、C1-C12烷基、C1-C12烷氧基、C1-C12羧酸、C1-C12羧酸酯、C1-C12羧酸对应的酰胺。
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