CN109503351A - 一种含有烯丙基结构的查尔酮衍生物及其应用 - Google Patents

一种含有烯丙基结构的查尔酮衍生物及其应用 Download PDF

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CN109503351A
CN109503351A CN201811451643.2A CN201811451643A CN109503351A CN 109503351 A CN109503351 A CN 109503351A CN 201811451643 A CN201811451643 A CN 201811451643A CN 109503351 A CN109503351 A CN 109503351A
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张婷婷
郑素清
钱建畅
邹鹏
刘志国
梁广
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Abstract

本发明公开了一种含有烯丙基结构的查尔酮衍生物及其应用，本发明合成了39种基于Licochalcone A和E作为前分子的新型烯丙基‑后代甾烷。作为PTP1B抑制剂，可以改善常见的2型糖尿病治疗。大多数合成化合物显示出对PTP1B的有效抑制。

Description

一种含有烯丙基结构的查尔酮衍生物及其应用
技术领域
本发明属于药物化学领域，具体涉及一种含烯丙基-反向查耳酮衍生物PTP1B抑制剂的设计与合成、生物评估与分子对接研究。
背景技术
糖尿病是一种进展性代谢性疾病，在目前医学水平无法根治的情况下，糖尿病患者需终生使用抗糖尿病调节药物。随着对糖尿病发病机制的深入研究，糖尿病药物研究也从对传统机制过渡到对新作用靶点和新作用机制的研究。遗憾的是，尽管大量研究已经表明胰岛素抵抗是T2M 的主要病理机制，但是目前临床使用的胰岛素增敏剂仅仅只有双胍类和噻唑烷二酮类。因此，新型胰岛素增敏剂是2型糖尿病治疗药物的研发重点。
蛋白酪氨酸磷酸酯酶1B是胰岛素信号中的关键负调控因子。PTP1B 抑制剂通过抑制PTP1B的活性，增加胰岛素刺激的受体IR的酪氨酸磷酸化，进而增加受体底物IRS磷酸化，通过PI3K和Akt通路，使细胞对胰岛素增敏，在GLUT4的转运下完成对葡萄糖的摄取。PTP1B抑制剂目前进入临床研究的只有三个。PTP1B抑制剂的开发一直受困于两点。一方面，高极性的A-site决定了竞争性抑制剂大都是高度负电荷的磷酸类似物，难以透过细胞膜而起效；另一方面，PTP各亚型的催化活性位点具有高度同源性，比如PTP1B与TCPTP的活性位点同源性高达94％。那么 PTP1B抑制剂若不能实现对亚型的高选择性，就很难避免副作用的产生。
发明内容
本发明提供给了一种含有烯丙基结构的查尔酮衍生物及其应用，试验结果表明，大多数合成的查尔酮衍生物显示出显着的PTP1B抑制活性。
为达到上述技术目的，本发明的技术方案为：
一种含烯丙基的查尔酮衍生物，结构通式如式(I)～(V)所示：
式(I)、(Ⅱ)、(Ⅲ)、(Ⅳ)、(Ⅴ)中R独立选自羟基、烷氧基、烃基、杂环、卤素及叔胺中的一个或者多个；
本发明中，所述的烷氧基，仅由碳与氢、氧原子组成，不含有不饱和性，例如：甲氧基、乙氧基等。
“卤素”为-Br。
所述的杂环为：吡啶、吡唑、吗啉或1,3-二氧戊环；
作为优选，所述的查尔酮衍生物为以下结构式中的一种：
本发明还提供了一种所述的查耳酮衍生物的应用，试验结果表明，大多数合成化合物显示出对PTP1B的有效抑制。PTP1B是治疗2型糖尿病和肥胖症的有吸引力的靶标。动物试验表明，PTP1B缺陷小鼠显示出增强的胰岛素敏感性，改善的血糖控制和对高脂肪饮食诱导的肥胖的抵抗。作为PTP1B抑制剂，这些化合物可以改善常见的2型糖尿病治疗。
同现有的蛋白酪氨酸磷酸酶抑制剂，本发明的查耳酮衍生物具有更好的抑制效果，可以用于开发新型胰岛素增敏剂。
附图说明
图1为本发明合成的化合物1-39对PTP1B酶的抑制活性。
图2黄色固体甘草素查尔酮A和E的结构
图3合成查耳酮衍生物的构效关系
图4预测活动对相应实验活动的散点图。
图5活性化合物23在体外减轻PA诱导的胰岛素抗性，并在体内缓解肝损伤的结构示意图。
图6化合物23在大鼠体内的药代动力学研究。
图7模拟过程中的构象转换。
图8构象转变前后的动态和能量变化。
具体实施方式
下面将结合附图和实施例进一步详细描述本发明。
实施例1～39化合物的合成：
本发明制备的含有烯丙基结构的查尔酮衍生物的方法，合成总路线如下式a：
类型I中的化合物(1,3-8,10-30)的合成步骤(步骤a-e)：
步骤a合成2a：将碳酸钾(68.1g，0.48mol)缓慢加入到4-羟基-2-甲氧基苯甲醛(1a；25.0g，0.16mol)和3-溴丙-1-烯(38.1g，0.32mol)的丙酮溶液中，将反应混合物回流6小时。过滤得到的混合物，减压浓缩滤液。然后将残余物溶于乙酸乙酯(50mL)中，用水(50mL)和盐水(50mL) 洗涤。有机层用MgSO4干燥，过滤，并在减压下浓缩。通过硅胶色谱法纯化残渣，得到化合物2a(27.95g，91％)，为浅黄色液体。
步骤b合成3a：将2a(25.0g，0.13mol)在N，N-二乙基苯胺(50mL) 中形成的溶液在200℃和氮气保护下加热10小时。通过硅胶色谱法纯化所得混合物，得到所需化合物3a(5.24g，21％)，呈棕褐色红色固体。熔点： 99.6-101.3℃。
步骤c合成4a：将60％氢化钠(2.2g，0.056mol)的无水THF(100mL) 溶液分批加入到3a(5.24g，0.028mol)的THF(10mL)溶液中，然后加入氯甲基甲基醚(4.3mL,0.056mol)在冰浴中。5小时后，将所得混合物用饱和氯化铵溶液淬灭，并用乙酸乙酯(3×100mL)萃取。将合并的有机层用水(150mL)洗涤，用MgSO4干燥，减压浓缩。通过硅胶色谱法进一步纯化残渣，得到所需的1-烯丙基-4-甲氧基-2-(甲氧基甲氧基)-5- 乙烯基苯(4a，5.24g，80％)，为黄色固体。熔点：85.3-87.9℃。
步骤d合成5a：将1.0Mol/L的KOH水溶液1mL缓慢滴加到4a(0.1g， 0.42mmol)与各种取代苯乙酮在无水乙醇和蒸馏水(9mL，v/v＝2：1)中的搅拌溶液中。将反应混合物在室温下搅拌4-24小时。将得到的混合物用水(15mL)稀释，并用乙酸乙酯(3×20mL)萃取。将合并的有机层用盐水(15mL)洗涤，用无水硫酸镁干燥，过滤，并减压浓缩。进一步将残渣通过硅胶色谱法纯化，得到所需化合物5a，产率为35-89％。
化合物1,3-8和10-30的一般制备方法。将10滴6N-HCl加入到5a (0.1mmol)的甲醇和水(10mL，v/v＝2：1)的几种溶液中。将反应混合物在室温下搅拌3-5小时，用饱和NH4Cl水溶液(10mL)淬灭，并用乙酸乙酯(3×10mL)萃取。合并的有机层用水(20mL)洗涤。用盐水(20mL) 洗涤，用硫酸镁干燥，过滤，并减压浓缩。通过硅胶色谱法纯化残余物，得到目标化合物，表征数据如下：
所合成的部分化合物的化学结构表征数据
化合物1：(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-(4-羟基苯基) 丙-2-烯-1-酮。黄色固体，产率42.64％，熔点：101.1-102.4℃.1H-NMR(500 MHz,acetone--d 6)δ(ppm):8.98(s,1H),8.73(s,1H),7.92(d,J＝15.7Hz, 1H),7.88(d,J＝8.6Hz,2H),7.55(d,J＝15.6Hz,1H),7.47(s,1H),6.82(d,J ＝8.5Hz,2H),6.47(s,1H),5.90(dd,J＝16.7,10.1Hz,1H),4.93(dd,J＝17.1, 1.7Hz,1H,--),4.87(d,J＝8.9Hz,1H),3.74(s,3H,-OCH3),3.22(d,J＝6.5 Hz,2H).13C-NMR(125MHz,acetone-d 6)δ(ppm):188.4,162.4,159.9,159.4,139.4,138.1,131.9,131.6×2,131.4,120.2,119.6,116.7,116.1×2, 115.4,99.9,56.0,34.2.ESI-MS m/z:311.18(M+H)+,calcd for C19H18O4。
化合物3：(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-(4-甲氧基苯基)丙-2-烯-1-酮.
化合物4：(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-(3-羟基苯基) 丙-2-烯-1-酮；(E)-3-(5-Allyl-4-hydroxy-2-methoxyphenyl)-1-(3-hydroxy phenyl)prop-2-en-1-one.黄色固体，产率47.98％，熔点：105.5-107.3℃.
化合物5:(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-(3-甲氧基苯基)丙-2-烯-1-酮；(E)-3-(5-Allyl-4-hydroxy-2-methoxyphenyl)-1- (3-methoxyphenyl)prop-2-en-1-one；黄色固体,产率45.8％,熔点： 139.0-141.5℃.1H NMR(500MHz,acetone-d 6)δ(ppm):8.91(s,1H),7.93 (d,J＝15.6Hz,1H),7.57(d,J＝1.8Hz,1H),7.51(d,J＝2.1Hz,1H),7.50(s, 1H),7.43(d,J＝1.6Hz,1H),7.31(t,J＝7.9Hz,1H),7.04(dd,J＝8.2,2.1Hz,1H),6.48(s,1H),5.90(dd,J＝16.7,6.5Hz,1H),4.93(dd,J＝17.1,1.7Hz, 1H),4.87(d,J＝8.9Hz,1H),3.74(s,6H),3.22(d,J＝6.5Hz,2H).13 C-NMR(125MHz,acetone-d 6)δ(ppm):190.0,160.9,160.4,159.8,141.2, 140.5,138.0,131.5,130.4,121.4,120.2,119.5,119.1,116.3,115.4,113.8, 99.8,56.0,55.7,34.1.ESI-MS m/z:325.32(M+H)+,calcd for C20H20O4: 324.14.
化合物6:(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-(2-羟基-4- 甲氧基苯基)丙-2-烯-1-酮；化合物7:(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-(4-乙氧基苯基)丙-2-烯-1-酮；(E)-3-(5-Allyl-4-hydroxy-2 -methoxyphenyl)-1-(4-ethoxyphenyl)prop-2-en-1-one黄色固体，49.5％收率， m.p：131.3-132.8℃。
化合物8:(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-[4-(烯丙氧基)苯基]丙-2-烯-1-酮,(E)-3-(5-Allyl-4-hydroxy-2-methoxyphenyl)-1- [4-(allyloxy)phenyl]prop-2-en-1-one.黄色固体，产率56.87％，熔点： 103.4-105.2℃.1H NMR(500MHz,acetone-d 6)δ(ppm):8.85(s,1H),7.94 (dd,J＝11.3,2.6Hz,3H),7.56(d,J＝15.6Hz,1H),7.48(s,1H),6.92(d,J＝ 8.2Hz,2H),6.47(s,1H),6.00-5.83(m,2H),5.30(d,J＝17.3Hz,1H),5.14(d, J＝10.4Hz,1H),4.93(dd,J＝17.1,1.7Hz,1H),4.87(d,J＝8.9Hz,1H),4.53 (d,J＝4.4Hz,2H),3.74(s,3H),3.22(d,J＝6.5Hz,2H).13C-NMR(125 MHz,acetone-d 6)δ(ppm):188.5,163.0,159.5,139.7,138.0,134.2,133.7, 131.9,131.4,131.3,129.6,120.2,119.4,117.8,116.6,115.5,115.3,99.9,69.3, 66.9,56.06,34.1.ESI-MS m/z:351.22(M+H)+,calcd for C22H22O4 350.15.
化合物10:(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-[4-(烯丙氧基)-2-羟基苯基]丙-2-烯-1-酮；(E)-3-(5-Allyl-4-hydroxy-2-methoxyphenyl)-1-[4-(allyloxy)-2-hydroxyphen yl]prop-2-en-1-one.Yellow solid,47.98％yield,m.p:129.1-132.2o℃. 1H-NMR(500MHz,acetone-d6)δ(ppm):8.07(d,J＝15.6Hz,1H),7.93(d,J ＝9.4Hz,1H),7.65(dd,J＝9.7,5.8Hz,1H),7.53(s,1H,Ar-H),6.50(s,1H), 6.43(d,J＝15.6Hz,1H),6.33(s,1H),6.01-5.80(m,2H),5.30(d,J＝17.2Hz, 1H),5.15(d,J＝9.1Hz,1H),4.93(dd,J＝17.1,1.7Hz,1H),4.87(d,J＝8.9 Hz,1H),4.53(d,J＝4.4Hz,2H),3.74(s,3H),3.22(d,J＝6.5Hz,2H), 13C-NMR(125MHz,acetone-d6)δ(ppm):193.3,187.4,160.6,160.1,140.8,138.0,134.9,132.9,132.5,131.9,120.3,118.0,117.7,116.2,115.4,109.3, 102.5,99.7,99.3,69.6,56.1,34.1.ESI-MS m/z:367.15(M+H)+,calcd for C22H22O5:366.15.
化合物11:(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-{4-[(3- 甲基丁-2-烯-1-基)氧基]苯基}丙-2-烯-1-酮； (E)-3-(5-Allyl-4-hydroxy-2-methoxyphenyl)-1-{4-[(3-methylbut-2-en-1-yl)ox y]phenyl}prop-2-en-1-one.黄色固体，45.2％收率，m.p：108.2-111.1℃。1H NMR(500MHz,acetone-d6)δ(ppm):8.92(s,1H),8.00(d,J＝8.5Hz,1H),7.98-7.95(m,2H),7.94(s,1H),7.63-7.58(m,1H),7.51(d,J＝4.9Hz,3H), 7.25(d,J＝8.5Hz,2H),6.44(s,1H),5.90(dd,J＝16.7Hz,6.5Hz,1H),4.93 (dd,J＝17.1,1.7Hz),4.87(d,J＝8.9Hz,1H),3.73(s,3H),3.22(d,J＝5.8 Hz,2H),1.80(s,3H,-CH3),1.68(s,3H,-CH3).13C-NMR(125MHz, acetone-d6)δ(ppm):188.8,165.2,160.1,159.7,158.4,155.3,140.4,137.9, 131.8,131.6,130.4,130.1,129.6,127.5,122.94,119.6,119.3,116.2,115.4, 99.8,56.0,41.5×2,34.1.ESI-MS m/z:379.18(M+H)+,calcd for C24H26O4:378.18.
化合物12：(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-{2-甲氧基-4 -[(3-甲基丁-2-烯-1-基)氧基]苯基}丙-2-烯-1-酮； (E)-3-(5-Allyl-4-hydroxy-2-methoxyphenyl)-1-{2-methoxy-4-[(3-methylbut-2- en-1-yl)oxy]phenyl}prop-2-en-1-one.黄色固体，47.4％收率，m.p： 116.3-118.2℃。1H-NMR(500MHz,acetone-d6)δ(ppm):8.75(s,1H),8.41(s, 1H),8.05(d,J＝15.6Hz,1H),7.77-7.73(m,2H),7.68-7.57(m,1H),6.92(d, J＝8.2Hz,1H),6.58(s,1H),5.89(dd,J＝16.7,6.5Hz,1H),5.23(m,1H), 4.93(dd,J＝17.1,1.7Hz,1H),4.87(d,J＝8.9Hz,1H),4.65(d,J＝6.4Hz, 2H),3.83(s,3H),3.22(d,J＝6.5Hz,2H),1.80(s,3H),1.68(s,3H). 13C-NMR(125MHz,acetone-d6)δ(ppm):188.4,159.8,159.4,152.0,148.5, 143.2,139.3,138.1,132.1,131.4,123.9,120.1,120.3,119.3,115.6,115.4, 115.3,112.1,99.8,66.9,56.5,41.5×2,34.1.ESI-MS m/z:395.18(M+H)+, calcd for C24H26O5:394.18.
化合物13：(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-[4-(烯丙氧基)-2-甲氧基苯基]丙-2-烯-1-酮； (E)-3-(5-Allyl-4-hydroxy-2-methoxyphenyl)-1-[4-(allyloxy)-2-methoxyphenyl ]prop-2-en-1-one.Yellow solid,56.3％yield,m.p:120.7-122.8℃.1H-NMR (500MHz,acetone--d6)δppm:8.92(s,1H),8.46(s,1H),8.05(d,J＝15.6Hz, 1H),7.76-7.75(m,2H),7.65-7.57(m,2H),6.92(d,J＝8.2Hz,1H),6.58(s, 1H),5.89(dd,J＝16.7,6.5Hz,1H),5.23(m,1H),4.93(dd,J＝17.1,1.7Hz, 1H),4.87(d,J＝8.9Hz,1H),4.65(d,J＝6.4Hz,2H),3.91(s,3H),3.83(s, 3H),3.22(d,J＝6.5Hz,2H),1.80(s,3H),1.68(s,3H).13C-NMR(125MHz, acetone-d6)δ(ppm):188.4,159.8,159.4,152.0,148.5,139.3,138.1,132.1, 131.4,123.9,120.1,119.4,116.6,115.3,115.3,112.1,108.7,106.3,102.3, 99.8,66.9,56.5,56.0,34.1,31.2.ESI-MS m/z:409.19(M+H)+,calcd for C25H28O5:408.19.
化合物14：(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-(3-烯丙基 -4-甲氧基苯基)丙-2-烯-1-酮；(E)-3-(5-Allyl-4-hydroxy-2-methoxyphenyl)-1-
-(3-allyl-4-methoxyphenyl)prop-2-en-1-one.黄绿色固体，产率60.43％，熔点：119.7-121.9℃。1H-NMR(125MHz,acetone-d6)δ(ppm):8.83(s,1H), 7.92(d,J＝15.6Hz,1H),7.87(dd,J＝8.5,2.1Hz,1H),7.77(s,1H),7.56(d, J＝15.6Hz,1H),7.44(s,1H),6.92(d,J＝8.6Hz,1H),6.46(s,1H),5.97-5.78 (m,2H),4.98-4.91(m,2H),4.88(dd,J＝16.6,10.7Hz,2H),3.77(s,3H),3.72 (s,3H),3.23(d,J＝5.8Hz,4H).13C-NMR(125MHz,acetone-d6)δ(ppm): 189.8,161.7,159.8,159.5,139.6,138.0,137.4,132.4,131.4,130.8,129.6,129.4,120.1,119.6,116.5,116.1,115.4,110.8,99.9,56.1,56.0,34.8,34.1. ESI-MS m/z:365.17(M+H)+,calcd for C23H24O4:364.17.
化合物15:(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-[4-甲氧基-3-(3-甲基丁-3-烯-2-基)苯基〕丙-2-烯-1-酮； (E)-3-(5-Allyl-4-hydroxy-2-methoxyphenyl)-1-[4-methoxy-3-(3-methylbut-3-e n-2-yl)phenyl]prop-2-en-1-one.黄色固体，产率45.33％，熔点： 123.5-125.1℃。1H-NMR(500MHz,acetone-d6)δ(ppm):8.90(s,1H),7.88(d,J＝8.6Hz,2H),7.87(dd,J＝8.5,2.1Hz,1H),7.77(s,1H),7.56(d,J＝15.6 Hz,1H),7.44(s,1H),6.92(d,J＝8.6Hz,1H),6.46(s,1H),5.90(dd,J＝16.7, 6.5Hz,1H),4.98-4.91(m,2H),4.88(dd,J＝16.6,10.7Hz,2H),3.77(s,3H), 3.72(s,3H),3.23(d,J＝5.8Hz,2H),1.82(s,3H),1.75(s,3H).13C-NMR (125MHz,acetone-d6)δ(ppm):189.7,161.7,159.8,159.3,149.00,139.4, 138.0,137.2,132.4,131.4,130.8,129.7,120.1,119.6,116.4,116.1,115.4, 111.2,99.9,56.2,56.0,34.3,34.1,21.2,20.1.ESI-MS m/z:393.20(M+H)+,calcd for C25H28O4:392.20.
化合物16:(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-[4-甲氧基 -3-(3-甲基丁-2-烯-1-基)苯基]丙-2-烯-1-酮； (E)-3-(5-Allyl-4-hydroxy-2-methoxyphenyl)-1-[4-methoxy-3-(3-methylbut-2-e n-1-yl)phenyl]prop-2-en-1-one.黄色固体，产率34.33％，熔点： 139.2-141.5℃。1H-NMR(500MHz,acetone-d6)δ(ppm):8.79(s,1H),7.89(d,J＝8.5Hz,2H),7.85(dd,J＝8.4,2.6Hz,1H),7.74(s,1H),7.56(d,J＝15.6 Hz,1H),7.41(s,1H),6.91(d,J＝8.5Hz,1H),6.48(s,1H),5.90(dd,J＝16.7, 6.5Hz,1H),5.78(s,1H)4.98-4.91(m,2H),4.88(dd,J＝16.6,10.7Hz,2H), 3.77(s,3H),3.72(s,3H),3.23(d,J＝5.8Hz,2H),1.85(s,3H),1.72(s,3H). 13C-NMR(125MHz,acetone-d6)δ(ppm):189.6,162.5,159.4,140.7,138.4, 138.0,132.4,131.4,130.8,129.7,121.6,120.1,119.6,116.3,116.1,114.4, 111.1,99.9,56.2,56.0,34.3,34.1,25.3,20.1,14.6.ESI-MS m/z:393.20(M+H)+,calcd for C25H28O4:392.20.
化合物17:(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-[4-(哌啶 -1-基)苯基]丙-2-烯-1-酮.(E)-3-(5-Allyl-4-hydroxy-2-methoxyphen
yl)-1-[4-(piperidin-1-yl)phenyl]prop-2-en-1-one.Yellow solid,36.97.％yield,m.p:179.1-181.2℃.1H NMR(500MHz,DMSO-d6)δ(ppm):10.12(s, 1H),7.97(d,J＝8.8Hz,2H),7.91(d,J＝15.6Hz,1H),7.64(d,J＝6.0Hz, 1H),7.62(s,1H),6.99(d,J＝7.8Hz,2H),6.54(s,1H),5.90(dd,J＝16.7,6.5 Hz,1H),4.93(dd,J＝17.1,1.7Hz,1H),4.87(d,J＝8.9Hz,1H),3.82(s,3H), 3.40(d,J＝19.4Hz,4H),3.22(d,J＝6.5Hz,2H),1.62-1.33(m,6H). 13C-NMR(125MHz,DMSO-d6)δ(ppm):186.4,159.4,158.2,153.5,137.2×2, 137.2,130.2,129.9×2,119.9,118.0,114.9×2,114.4,113.1,99.8,65.0,55.5 ×2,47.9,33.1,24.9,23.8.ESI-MS m/z:378.22(M+H)+,calcd for C24H27NO3: 377.20.
化合物18:(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-[2-(哌啶 -1-基)苯基]丙-2-烯-1-酮；(E)-3-(5-Allyl-4-hydroxy-2-methoxyphen
yl)-1-[2-(piperidin-1-yl)phenyl]prop-2-en-1-one.黄色固体，收率29.34％，熔点：175.3-177.1℃。1H-NMR(500MHz,acetone--d6)δ(ppm):9.00 (s,1H),7.83(d,J＝16.0Hz,1H),7.60(d,J＝2.4Hz,1H),7.50(d,J＝3.2Hz, 1H),7.41(d,J＝17.0Hz,1H),7.28(d,J＝28.6Hz,1H),7.01(s,1H),6.89(s, 1H),6.49(s,1H),5.90(dd,J＝16.7,6.5Hz,1H),4.92(dd,J＝17.1,1.7Hz, 1H),4.87(d,J＝8.9Hz,1H),3.74(s,3H),3.22(d,J＝6.5Hz,2H),2.88(d,J ＝2.1Hz,4H),1.64-1.48(m,6H),13C-NMR(125MHz,DMSO-d6)δ(ppm): 193.4,167.9,159.6,136.7,133.4,132.4,131.9,130.3,129.5×2,120.2,116.3,115,5,99.9,66.8,56.0×2,55.2,34.0,32.6,31.3,26.9,24.7,23.3.ESI-MS m/z: 378.22(M+H)+,calcd for C24H27NO3:377.20.
化合物19:(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-[3-(哌啶 -1-基)苯基]丙-2-烯-1-酮；(E)-3-(5-Allyl-4-hydroxy-2-methoxyp
henyl)-1-[3-(piperidin-1-yl)phenyl]prop-2-en-1-one黄色固体，产率45.89％，熔点：178.3-179.8℃。1H NMR(500MHz,acetone-d6)δ(ppm):9.03 (s,1H),7.88(d,J＝16.0Hz,1H),7.61(d,J＝2.4Hz,1H),7.51(d,J＝3.2Hz, 1H),7.41(d,J＝17.0Hz,1H),7.33(d,J＝18.6Hz,1H),7.01(s,1H),6.91(s, 1H),6.51(s,1H),5.90(dd,J＝16.7,6.5Hz,1H),4.93(dd,J＝17.1,1.7Hz, 1H),4.87(d,J＝8.9Hz,1H),3.71(s,3H),3.22(d,J＝6.5Hz,2H),2.88(d,J ＝2.1Hz,4H),1.64-1.48(m,6H).13C-NMR(125MHz,DMSO-d6)δ(ppm):194.6,167.9,159.6,133.4,132.5,131.9,130.3,129.6,128.5,120.2,116.4, 115,5,114.4,99.9,66.9,56.0,55.1×2,34.0,32.6,31.3,26.9,24.7,23.3. ESI-MS m/z:378.22(M+H)+,calcd for C24H27NO3:377.20.
化合物20:(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-(4-吗啉代苯基)丙-2-烯-1-酮；(E)-3-(5-Allyl-4-hydroxy-2-methoxyphenyl) -1-(4-morpholinophenyl)prop-2-en-1-one.黄色固体，产率45.84％，熔点： 163.7-165.0℃。1H-NMR(500MHz,DMSO--d6)δ(ppm):10.13(s,1H),8.01 (d,J＝8.8Hz,2H),7.92(d,J＝15.6Hz,1H),7.72(s,1H),7.66(d,J＝4.6Hz, 1H),7.02(d,J＝8.8Hz,2H),6.53(s,1H),5.90(dd,J＝16.7,6.5Hz,1H), 4.93(dd,J＝17.1,1.7Hz,1H),4.87(d,J＝8.9Hz,1H),3.82(s,3H), 3.77-3.70(m,4H),3.32-3.29(m,4H),3.22(d,J＝6.5Hz,2H),13C-NMR(125 MHz,DMSO-d6)δ(ppm):186.5,159.8,158.2,153.7,137.4,131.4,130.1, 129.9,128.2,118.9,117.9,114.9,113.3,112.9,98.8,66.8,64.9,56.5,46.8, 33.1,29.9,19.6,13.4.ESI-MS m/z:380.18(M+H)+,calcd for C23H25NO4: 379.18.
化合物21:(E)-1-[4-(1H-吡唑-1-基)苯基]-3-(5-烯丙基-4-羟基 -2-甲氧基苯基)丙-2-烯-1-酮；(E)-1-[4-(1H-pyrazol-1-yl)phenyl] -3-(5-allyl-4-hydroxy-2-methoxyphenyl)prop-2-en-1-one.棕黄色固体，产率 42.1％，熔点：135.4-137.6℃。1HNMR(500MHz,acetone-d6)δ(ppm):8.78 (s,1H),7.89(d,J＝8.5Hz,2H),7.85(dd,J＝8.7,2.6Hz,1H),7.78(s,1H), 7.56(d,J＝15.6Hz,1H),7.41(s,1H),7.29(d,J＝8.5Hz,2H),6.92(d,J＝ 8.2Hz,1H),6.91(d,J＝8.5Hz,1H),6.48(s,1H),5.90(dd,J＝16.7,6.5Hz,1H),4.93(dd,J＝17.1,1.7Hz,1H),4.87(d,J＝8.9Hz,1H),3.72(s,3H), 3.22(d,J＝6.5Hz,2H),13C-NMR(125MHz,acetone-d6)δ(ppm):188.79, 167.25,160.21,159.57,158.42,155.35,140.34,138.99,134.57,131.89, 130.43,130.16,129.63,122.94,119.68,119.27,116.22,115.42,109.35,99.89, 56.03,34.13.ESI-MS m/z:361.15(M+H)+,calcd for C22H20N2O3:360.15.
化合物22:(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-[4-(二甲基氨基)苯基]丙-2-烯-1-酮；(E)-3-(5-Allyl-4-hydroxy-2-methoxy
yl)-1-[4-(dimethylamino)phenyl]prop-2-en-1-one.黄色固体，48.3％收率，m.p：151.6-153.1℃。
化合物23:(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-[3-(二甲基氨基)苯基]丙-2-烯-1-酮；(E)-3-(5-Allyl-4-hydroxy-2-methoxyphen
yl)-1-[3-(dimethylamino)phenyl]prop-2-en-1-one.黄色固体，产率 59.36％，熔点：159.8-162.8℃.1H NMR(500MHz,CDCl3)δ(ppm):8.91(s, 1H),8.05(s,1H),8.03(d,J＝2.6Hz,1H),8.01(d,J＝6.4Hz,1H),7.71(d,J ＝15.6Hz,1H),7.61(s,1H),6.80(d,J＝8.9Hz,2H),6.61(s,1H),5.90(dd,J ＝16.7,6.5Hz,1H),4.93(dd,J＝17.1,1.7Hz,1H),4.87(d,J＝8.9Hz,1H), 3.88(s,3H),3.22(d,J＝6.5Hz,2H),3.10(s,6H).13C-NMR(125MHz,acetone-d6)δ(ppm):188.2,168.7,168.3,142.5,141.0,139.4,135.6,129.7, 129.4,127.1,122.1,118.4,118.2,115.9,113.4,113.9,97.0,64.0,53.7,44.2, 31.7.ESI-MS m/z:338.17(M+H)+,calcd for C21H23NO3:337.17.
化合物24:(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-[2-(二甲基氨基)苯基]丙-2-烯-1-酮；(E)-3-(5-Allyl-4-hydroxy-2-methoxy
phenyl)-1-[2-(dimethylamino)phenyl]prop-2-en-1-one.黄色固体，产率60.15％，熔点：148.6-150.2℃。
化合物25:(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-[3-(二甲基氨基)苯基]丙-2-烯-1-酮；(E)-3-(5-Allyl-4-hydroxy-2-methoxyphen
yl)-1-[3-(dimethylamino)phenyl]prop-2-en-1-one.黄色固体，产率 59.36％，熔点：167.3-169.5℃。
化合物26:(E)-3-(5-烯丙基-4-羟基-2-异丙氧基苯基)-1-[3-(二甲基氨基)苯基〕丙-2-烯-1-酮；(E)-3-(5-Allyl-4-hydroxy-2--isopr
opoxyphenyl)-1-[3-(dimethylamino)phenyl]prop-2-en-1-one.黄色固体，产率48.98％，熔点：137.4-139.6℃。
化合物27:E)-N-{3-[3-(5-烯丙基-4-羟基-2-甲氧基苯基)丙烯酰基] 苯基}甲磺酰胺；(E)-N-{3-[3-(5-Allyl-4-hydroxy-2- methoxyphenyl)acryloyl]phenyl}methanesulfonamide.黄色固体，产率 45.92％，熔点：167.4-169.8℃。
化合物28:E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-[6-(二甲基氨基)苯并[d][1,3]二氧杂环戊烯-5-基]丙-2-烯-1--酮； (E)-3-(5-Allyl-4-hydroxy-2-methoxyphenyl)-1-[6-(dimethylamino)benzo[d][1, 3]dioxol-5-yl]prop-2-en-1-one.Yellow solid,49.76％yield,m.p:159.3-162.1 ℃.1H-NMR(500MHz,acetone-d6)δ(ppm):8.99(s,1H),8.05(d,J＝15.6 Hz,1H),7.83(s,1H),7.63(s,1H),7.56(d,J＝15.6Hz,1H),7.41(s,1H),6.49 (s,1H),6.03(s,2H)5.90(dd,J＝16.7,6.5Hz,1H),4.93(dd,J＝17.1,1.7Hz, 1H),4.87(d,J＝8.9Hz,1H),3.72(s,3H),3.20(dd,J＝14.2,6.5Hz,2H), 3.02(s,6H).13C-NMR(125MHz,acetone-d6)δ(ppm):186.4,158.3,158.0, 150.2,144.1,138.3,136.7,130.3,129.8,129.0,121.5,121.0,121.0,115.2, 113.4,113.2,110.6,101.2,99.4,54.9,32.7.ESI-MS m/z:382.60(M+H)+, calcd for C22H23NO5:381.16.
化合物29:(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-[3-(二烯丙基氨基)苯基〕丙-2-烯-1-酮；(E)-3-(5-Allyl-4-hydroxy-2-methoxyp
henyl)-1-[3-(diallylamino)phenyl]prop-2-en-1-one.黄色固体，产率59.36％，熔点：145.7-147.3℃。1H-NMR(500MHz,acetone-d6)δ(ppm):8.90 (s,1H),7.90(d,J＝15.6Hz,1H),7.46(d,J＝15.7Hz,1H),7.42(d,J＝14.2 Hz,1H),7.23(s,1H),7.19(d,J＝7.5Hz,1H),7.16(d,J＝7.9Hz,1H),6.80 (dd,J＝7.9,1.8Hz,1H),6.47(s,1H),5.90(dd,J＝16.7,6.5Hz,1H), 5.84-5.71(m,2H),5.13-4.99(m,4H),4.93(dd,J＝17.1,1.7Hz,1H),4.87(d, J＝8.9Hz,1H),3.90(d,J＝4.5Hz,4H),3.73(s,3H),3.21(dd,J＝14.0,6.6 Hz,2H).13C-NMR(125MHz,acetone-d6)δ(ppm):190.9,187.3,163.5,159.9, 159.6,149.69,140.6,140.0,139.0,135.0,131.5,130.3,129.9,120.2,117.0, 116.4,116.3,115.8,115.4,112.5,99.8,99.4,56.0,53.6,34.1.ESI-MSm/z: 390.29(M+H)+,calcd forC25H27NO3:389.20.
化合物30:(E)-3-(5-烯丙基-4-羟基-2-甲氧基苯基)-1-[4-(二烯丙基氨基)苯基〕丙-2-烯-1-酮；(E)-3-(5-Allyl-4-hydroxy-2-methoxyp
henyl)-1-[4-(diallylamino)phenyl]prop-2-en-1-one.黄色固体，产率62.50％，熔点：141.2-142.9℃。1H NMR(500MHz,acetone--d6)δ(ppm):8.90 (s,1H),7.90(d,J＝15.7Hz,1H),7.46(d,J＝15.7Hz,1H),7.41(d,J＝11.3 Hz,1H),7.23(s,1H),7.19(d,J＝7.5Hz,1H),7.16(d,J＝7.9Hz,1H),6.80 (dd,J＝7.8,1.6Hz,1H),6.47(s,1H),5.90(dd,J＝16.7,6.5Hz,1H), 5.84-5.71(m,2H),5.13-4.99(m,4H),4.93(dd,J＝17.1,1.7Hz,1H),4.87(d, J＝8.9Hz,1H),3.90(d,J＝4.5Hz,4H),3.72(s,3H),3.20(dd,J＝14.2,6.5Hz,2H).13C-NMR(125MHz,acetone-d6)δ(ppm):191.9,187.4,159.9,159.6, 149.6,140.6,138.0,135.0×2,131.5,130.3,129.9,120.2,117.0,116.4,116.3, 115.8,115.4,112.5,99.4,99.4,56.0,53.6,53.1,34.1.ESI-MS m/z:390.29 (M+H)+,calcd for C25H27NO3:389.20.
类型Ⅱ中的化合物2,9的合成步骤(步骤a-d,f)；
化合物2,9与上述化合物5a的方法相同
实施例29所合成的化合物2的化学结构表征数据
化合物2:(E)-3-{5-烯丙基-2-甲氧基-4-[(四氢-2H-吡喃-2-基)氧基]苯基}-1-(4-羟基苯基)丙-2-烯-1-酮； (E)-3-{5-Allyl-2-methoxy-4-[(tetrahydro-2H-pyran-2-yl)oxy]phenyl}-1-(4-hyd roxyphenyl)prop-2-en-1-on.黄色液体，产率45.3％，1H NMR(500MHz, acetone--d6)δ(ppm):8.98(s,1H),8.71(s,1H),7.90(d,J＝15.7Hz,1H),7.88(d,J＝8.6Hz,2H),7.50(d,J＝15.6Hz,1H),7.47(s,1H),6.8(d,J＝8.5Hz, 1H),6.47(s,1H),5.90(ddt,J＝16.7,10.1,6.5Hz,1H),5.76(m,1H),4.93(dd, J＝17.1,1.7Hz,1H),4.87(d,J＝8.9Hz,1H),3.74(s,3H),3.60(t,J＝8.6Hz, 2H),3.22(d,J＝6.5Hz,2H),2.22(m,2H),1.93(m,2H),1.71(m,2H). 13C-NMR(125MHz,acetone--d6)δ(ppm):188.4,162.3,159.7,159.2,139.2, 138.1,131.7,131.5×2,131.4,120.1,119.5,116.6,116.0×2,102.3,115.4,99.9, 62.4,56.0,34.2,30.4,24.6,20.4.ESI-MS m/z:395.18(M+H)+,calcdfor C24H26O5:394.18.
化合物9:(E)-3-{5-烯丙基-2-甲氧基-4-[(四氢-2H-吡喃-2-基)氧基]苯基}-1-[4-(烯丙氧基)-2-羟基苯基]丙-2-烯-1- 酮；(E)-3-{5-Allyl-2-methoxy-4-[(tetrahydro-2H-pyran-2-yl)oxy]phenyl}-1-[4- (allyloxy)-2-hydroxyphenyl]prop-2-en-1-one.黄色液体，产率49.78％类型Ⅲ中的化合物31-33的合成步骤(步骤a,b,e)
步骤a合成7a:化合物4a到7a合成方法与上述化合物5a的合成方法相同。(E)-3-[5-烯丙基-2-甲氧基-4-(甲氧基甲氧基)苯基]-1-{4-[2-(三甲基硅烷基)乙氧基]甲氧基}丙-2-烯-1-酮， (E)-3-[5-allyl-2-methoxy-4-(methoxymethoxymethoxy)phenyl]-1-{4-[2-(trime thylsilyl)thoxy]methoxy}prop-2-en-1-one.7a：收率85.0％，为黄色油状物。1H-NMR(500MHz,dmso--d6)δ(ppm):8.15(d,J＝8.6Hz,2H),8.02(d,J＝ 15.6Hz,1H),7.86–7.75(m,2H),7.18(d,J＝8.6Hz,2H),7.18(d,J＝8.6Hz, 1H),6.03(ddd,J＝13.2,12.7,6.3Hz,1H),5.37(s,2H),5.07(d,J＝17.3Hz, 2H),3.92(s,3H),3.80–3.68(m,2H),3.45(s,3H),3.37(d,J＝6.0Hz,2H), 0.95–0.91(m,2H),0..05(s,9H)ESI-MS m/z:484.86(M+H)+,calcd forC27H36O6Si:484.23
步骤a合成8a:将Et 3N(4.8g，80.97mmol)分批加入到7a(2.6g， 5.4mmol)的THF(30mL)溶液中，然后逐滴加入四丁基氟化铵(21.0g， 80.97mmol)。将反应混合物在65℃下回流20分钟。将反应混合物用水(30mL)嚼干并减压浓缩。然后将混合物用乙酸乙酯(3×30mL)萃取。将合并的有机层用盐水(50mL)洗涤，经硫酸镁干燥并减压浓缩。通过硅胶色谱法进一步纯化残余物，得到化合物8a(5.24g，80％)，为黄色液体。(E)-3-[5-烯丙基-2-甲氧基-4-(甲氧基甲氧基)苯基]-1-(4-羟基苯基)丙-2-烯-1-酮， (E)-3-[5-allyl-2-methoxy-4-(methoxymethoxy)phenyl]-1-(4-hydroxyphenyl)pr op-2-en-1-one，1H-NMR(500MHz,acetone--d6)δ(ppm):8.08(t,J＝2.1Hz, 2H),8.06–8.05(m,1H),7.80–7.75(m,1H),7.71(s,1H),7.00(d,J＝2.0Hz, 1H),6.98(d,J＝2.0Hz,1H),6.89(s,1H),6.05(ddt,J＝16.6,10.0,6.5Hz, 1H),5.37(s,1H),5.09(ddd,J＝17.1,3.6,1.6Hz,1H),5.03(ddd,J＝10.0,3.4, 1.3Hz,1H),3.97(s,3H),3.51(s,3H),3.40(d,J＝6.4Hz,2H).ESI-MS m/z:355.28(M+H)+,C21H22O5:354.15
化合物31-33的合成：向8a(100mg，0.28mmol)的THF(10mL) 溶液中加入不同的苯甲酰氯(0.85mmol)，然后滴加Et 3N(0.15mL， 1.2mmol)。将反应混合物在室温下搅拌8小时，将所得混合物用水(20mL) 淬灭，用乙酸乙酯(3×30mL)萃取。将合并的有机层用盐水(50mL) 洗涤，经MgSO 4干燥并减压浓缩。将残余物进一步溶解在MeOH和H 2 O(15mL，v/v2：1)中，将6N-HCl滴入溶液中。将反应混合物在室温下搅拌3-5小时，然后用饱和NH4Cl水溶液(20mL)淬灭，并用乙酸乙酯(3×20mL)萃取。将合并的有机层用盐水(50mL)洗涤，经MgSO4干燥，过滤并减压浓缩。通过硅胶色谱法纯化残余物，得到目标化合物 31-33，产率48.1-78％。
化合物31：(E)-4-[3-(5-烯丙基-4-羟基-2-甲氧基苯基)丙烯酰基] 苯基4-(叔丁基)苯甲酸酯；(E)-4-[3-(5-Allyl-4-hydroxy-2-methoxy
phenyl)acryloyl]phenyl 4-(tert-butyl)benzoate.黄色固体，78％收率， m.p：170.2-172.9℃。1H-NMR(500MHz,acetone-d6)δ(ppm):8.95(s,1H), 8.06(d,J＝8.5Hz,2H),8.04-7.98(m,2H),7.98(s,1H),7.65-7.58(m,1H), 7.53(d,J＝4.9Hz,3H),7.32(d,J＝8.5Hz,2H),6.48(s,1H),5.95-5.83(m, 1H),4.93(dd,J＝17.1,1.7Hz,1H),4.87(d,J＝8.9Hz,1H),3.75(s,3H), 3.23(d,J＝5.8Hz,2H),1.24(s,9H).13C-NMR(125MHz,acetone-d6)δ (ppm):189.1,165.1,160.1,159.8,158.5,155.3,140.6,138.0,137.4,134.80,131.9,131.6,130.8,130.6,129.7,129.6,127.5,126.6,122.9,120.3,119.3, 116.3,115.4,99.8,56.0,35.8,34.1,31.3×3.ESI-MS m/z:471.21(M+H)+, calcd for C30H30O5:470.21.
化合物31:(E)-4-[3-(5-烯丙基-4-羟基-2-甲氧基苯基)丙烯酰基] 苯基苯甲酸酯；(E)-4-[3-(5-Allyl-4-hydroxy-2-methoxyphenyl) acryloyl]phenyl benzoate.黄色固体，收率48.1％，熔点：150.8-152.4℃。1H-NMR(500MHz,acetone-d6)δ(ppm):8.95(s,1H),8.05(d,J＝8.5Hz, 2H),8.04-7.98(m,3H),7.98(s,1H),7.63-7.58(m,1H),7.51(d,J＝4.9Hz, 3H),7.29(d,J＝8.5Hz,2H),6.48(s,1H),5.90(dd,J＝16.7,6.5Hz,1H), 4.93(dd,J＝17.1,1.7Hz,1H),4.87(d,J＝8.9Hz,1H),3.75(s,3H),3.23(d, J＝5.8Hz,2H).13C-NMR(125MHz,acetone-d6)δ(ppm):189.1,165.0,160.1, 159.7,158.4,155.3,140.5,138.0,137.9,134.6,131.9,131.6,130.8,130.6, 129.6,127.5,122.9,120.3,119.3,116.3,115.4,99.8,56.0,35.8,34.1.ESI-MS m/z:415.15(M+H)+,calcd for C26H22O5:414.15.
化合物33:E)-4-[3-(5-烯丙基-4-羟基-2-甲氧基苯基)丙烯酰基]苯基4-溴苯甲酸酯；(E)-4-[3-(5-Allyl-4-hydroxy-2-methoxyphenyl) acryloyll]phenyl 4-bromobenzoate.黄色固体，64％收率，m.p： 173.1-175.2℃。1H-NMR(500MHz,acetone-d6)δ(ppm):8.92(s,1H),8.00(d, J＝8.5Hz,2H),7.98.04-7.95(m,2H),7.94(s,1H),7.63-7.58(m,1H),7.51(d, J＝4.9Hz,3H),7.25(d,J＝8.5Hz,2H),6.44(s,1H),5.90(dd,J＝16.7,6.5 Hz,1H),4.93(dd,J＝17.1,1.7Hz,1H),4.87(d,J＝8.9Hz,1H),3.73(s,3H), 3.22(d,J＝5.8Hz,2H),13C-NMR(125MHz,acetone-d6)δ(ppm):188.8, 165.2,160.1,159.7,158.4,155.3,140.4,138.0,137.9,134.5,131.8,131.6, 130.4,130.1,129.6,127.5,122.9,119.6,119.3,116.2,115.4,99.8,56.0,35.7, 34.1.ESI-MS m/z:493.06(M+H)+,calcdfor C26H21BrO5:492.06.
化合物34,36和38的合成。向8a(100mg，0.28mmol)的丙酮(20mL) 溶液中加入2-溴乙酸乙酯，4-溴丁酸乙酯或5-溴戊酸乙酯(0.56mmol)，然后加入室温下K2CO3(77.5mg，1.13mmol)。然后将反应混合物回流8小时。过滤所得混合物，滤饼用丙酮(20mL)洗涤。减压浓缩滤液，将残余物溶于MeOH和H 2O(20mL，v/v 2：1)中，将6N-HCl滴入沸液中。将反应混合物在室温下搅拌3-5小时，然后用饱和NH4Cl水溶液 (20mL)淬灭，并用乙酸乙酯(3×20mL)萃取。将合并的有机层用盐水(50mL)洗涤，经无水硫酸镁干燥，过滤并减压浓缩。通过硅胶色谱法纯化残余物，分别得到所需化合物34,36和38。
化合物38：(E)-2-{4-[3-(5-烯丙基-羟基-2-甲氧基苯基)丙烯酰基]苯氧基}乙酸乙酯；(E)-Ethyl2-{4-[3-(5-allyl-hydroxy-2- methoxyphenyl)acryloyl]phenoxy}acetate.Yellow solid,56.32％yield.m.p: 166.7-168.9℃.1H-NMR(500MHz,acetone-d6)δ(ppm):8.03(d,J＝8.0Hz, 2H),7.71(d,J＝3.3Hz,1H),7.52(d,J＝15.7Hz,1H),7.36(s,1H),6.98(d,J ＝8.5Hz,2H),6.49(s,1H),5.90(dd,J＝16.7,6.5Hz,1H),4.95(s,2H),4.93(dd,J＝17.1,1.7Hz,1H),4.87(d,J＝8.9Hz,1H),4.15-4.13(m,2H),3.74(s, 3H),3.22(d,J＝6.5Hz,2H),1.72(s,3H)13C-NMR(125MHz,acetone-d6)δ (ppm):189.6,169.2,163.9,158.9,140.7,136.4,130.9×2,130.6,130.5,121.3, 116.0,115.7×2,114.8,108.2,107.3,102.4,65.3,61.2,56.1,34.1,14.1. ESI-MS m/z:397.16(M+H)+,calcd forC23H24O6:396.16.
化合物36:E)-Ethyl4-{4-[3-(5-烯丙基-4-羟基-2-甲氧基苯基)丙烯酰基]苯氧基}丁酸乙酯,(E)-Ethyl4-{4-[3-(5-allyl-4-hydroxy-2-me
thoxyphenyl)acryloyl]phenoxy}butanoate.黄色固体，产率62.50％，熔点：156.6-158.3℃。
化合物38:(E)-5-{4-[3-(5-烯丙基-4-羟基-2-甲氧基苯基)丙烯酰基]苯氧基}戊酸乙酯；(E)-Ethyl 5-{4-[3-(5-allyl-4-hydroxy-2-meth
oxyphenyl)acryloyl]phenoxy}pentanoate.黄色固体，产率50.66％，熔点：178.3-180.3℃。1H NMR(500MHz,acetone-d6)δ(ppm):8.89(s,1H), 7.97-7.91(m,3H),7.56(d,J＝15.6Hz,1H),7.48(s,1H),6.91(d,J＝8.8Hz, 2H),6.47(d,J＝19.5Hz,1H),5.90(dd,J＝16.7,6.5Hz,1H),4.93(dd,J＝ 17.1,1.7Hz,1H),4.87(d,J＝8.9Hz,1H),3.96(dt,J＝14.2,6.5Hz,4H), 3.73(s,3H),3.22(d,J＝6.5Hz,2H),2.25(t,J＝7.2Hz,2H),1.75–1.60(m, 4H),1.32(s,3H).13C-NMR(125MHz,acetone-d6)δ(ppm):188.4,173.4, 163.5,159.9,159.5,139.5,138.1×2,132.5,131.5,131.3,120.1,119.3,116.5, 115.3,115.0×2,99.8,68.5,60.5,56.0,34.2,34.1,22.3,14.5×2.ESI-MS m/z: 439.20(M+H)+,calcdfor C26H30O6:438.20.
化合物35,37和39的合成。向34,36或38(0.3mmol)的MeOH(10mL) 溶液中逐滴加入10％NaOH(5mL)，将反应混合物在室温下搅拌3小时。将所得混合物用水(20mL)淬灭，并用6N-HCl酸化至pH＝2。用EtOAc (3×20mL)萃取混合物。将合并的有机层用盐水(50mL)洗涤，经MgSO 4干燥，过滤并减压浓缩。通过硅胶色谱法纯化残余物，分别得到目标化合物35,37和39。
化合物35：(E)-2-{4-{3-{5-烯丙基-2-甲氧基-4-[(四氢-2H-吡喃-2- 基)氧基]苯基}丙烯酰基}苯氧基}乙酸； (E)-2-{4-{3-{5-Allyl-2-methoxy-4-[(tetrahydro-2H-pyran-2-yl)oxy]phenyl}acr yloyl}phenoxy}acetic acid.黄色液体，产率60.3％.1H-NMR(500MHz, acetone-d6)δ(ppm):8.87(s,1H),7.96(d,J＝2.7Hz,2H),7.56(d,J＝15.6Hz,1H),7.49(s,1H),6.93(d,J＝8.8Hz,2H),6.48(s,1H),5.90(dd,J＝16.7, 6.5Hz,1H),4.93(dd,J＝17.1,1.7Hz,1H),4.87(d,J＝8.9Hz,1H),4.71(s, 2H),3.76(s,3H),3.71(s,2H),3.22(d,J＝6.5Hz,2H).13C-NMR(125MHz, acetone-d6)δ(ppm):188.4,169.9,162.4,159.9,139.7,138.0,133.3,131.4, 131.2×2,120.1,119.3,115.5,115.2×2,99.8,65.8,61.6,56.0,34.1,14.4. ESI-MS m/z:352.13(M+H)+,calcd for C21H20O5:352.13.
化合物37:(E)-4-{4-[3-(5-烯丙基-4-羟基-2-甲氧基苯基)丙烯酰基]苯氧基}丁酸；(E)-4-{4-[3-(5-Allyl-4-hydroxy-2-methoxyphenyl) acryloyl]phenoxy}butanoicacid.黄色液体，产率64.6％。
化合物39：(E)-5-{4-[3-(5-烯丙基-4-羟基-2-甲氧基苯基)丙烯酰基]苯氧基}戊酸；(E)-5-{4-[3-(5-Allyl-4-hydroxy-2-methoxy phenyl))acryloy]phenoxy}pentanoicacid。黄色液体，产率64.6％。1H NMR (500MHz,acetone-d6)δ(ppm):8.79(s,1H),7.97-7.91(m,3H),7.56(d,J＝ 15.6Hz,1H),7.48(s,1H),6.90(d,J＝8.8Hz,2H),6.47(d,J＝19.5Hz,1H), 5.90(dd,J＝16.7,6.5Hz,1H),4.93(dd,J＝17.1,1.7Hz,1H),4.87(d,J＝8.9 Hz,1H),3.96(dt,J＝14.2,6.5Hz,4H),3.73(s,3H),3.22(d,J＝6.5Hz,2H), 2.25(t,J＝7.2Hz,1H),1.75-1.60(m,4H),13C-NMR(125MHz,acetone-d6)δ (ppm):188.4,178.1,165.3,159.1,159.0,140.8,139.5,138.1×2,131.3,120.7, 119.1,116.5,115.3,115.0×2,99.8,68.5,60.5,56.0,34.2,34.1,22.3,17.8. ESI-MS m/z:411.17(M+H)+,calcd forC24H26O6:410.17.
实施例40活性测试
以对硝基苯磷酸酯(pNPP)为底物，测定本发明实施例1～39制备出的化合物对PTP1B的抑制活性，结果总结在图1中。已知的PTP1B抑制剂熊果酸(IC50＝3.1M)用作阳性对照。除化合物4,9,27和37外，所有合成化合物剂量依赖性地抑制PTP1B活性，IC50值范围为0.5至 24.8μM。大多数这些化合物显示出比甘草查耳酮更好的活性。其中，化合物1与甘草查耳酮A相比显示出两倍的抑制活性。化合物7(IC50＝5.3 ×M)，8(IC50＝5.4×M)和11(IC50＝5.8×M)，与化合物1相比，抑制活性增加约2倍。随着4-羟基取代长度的增加，对PTP1B显示出比例增加的抑制效力(特别是带有异戊二烯基的化合物12)，表现出特别好的活性(IC50＝3.0μM)。用THP保护基保护B环上2'-羟基位置的化合物1 和10得到化合物2和9，其显示没有PTP1B抑制活性。通过在3-C位置插入各种烯丙基，化合物14,15和16提供与化合物3相似的效力(IC 50 ＝7.4μM)。在用哌啶取代的化合物17-19中，间-和对-取代的衍生物表现出比邻位取代的化合物18更有效的PTP1B抑制作用(IC50＝9.5μ M)。在C-4位置插入吗啉中的化合物20(IC50＝6.3μM)显示出比化合物21(IC50＝12.3μM)两倍更显著的活性，如吡唑取代的反向查尔酮。在化合物22-27中，具有间-或对-二甲氨基取代基的化合物比具有邻- 二甲氨基取代基的化合物更有效。在这些化合物中显示出对PTP1B最显着的抑制活性并且具有0.57μM的低IC50值的间位取代的化合物23显示出比阳性对照熊果酸高6倍的活性。在2'-羟基位置掺入苄基和异丙基，得到化合物25(IC50＝5.0μM)和26(IC50＝6.9μM)导致抑制作用降低。对于化合物27，甲烷磺酰胺在C-3位置的掺入导致效力的完全丧失。然而，用二烯丙基保护的化合物29和30显示出与化合物8中的对-烯丙基类似的强抑制作用(IC50＝5.4×M)。化合物1在4-羟基上分别苯甲酰化成不同的反向查耳酮衍生物31-33，所有这些都显示出比初始化合物1高约两倍的活性。羧酸残基的引入，如化合物35和37，导致几乎完全丧失活性。然而，化合物39表现出中等效力。此外，其他酯(化合物34,36和 38)显示出不同的相应活性程度，具有高达两倍的更好的抑制活性。特别是，化合物38显示出与阳性对照熊果酸类似的有效PTP1B抑制作用。图 1显示了这些烯丙基-后代甾烷的结构-活性关系。
实施例41构效关系的定量评估
为了将PTP1B抑制活性与合成的烯丙基-后代糖的结构构象相关联，进行了结构活性关系(QSAR)研究的定量评估。我们的数据集由33 种活性烯丙基-后代炔醇组成，其在图1中显示其50％抑制浓度(IC 50)。我们使用了总共39种合成新抑制剂中的37种化合物，因为六种烯丙基- 后代甙(化合物4,6,9,27,36和37)由于IC50浓度不精确而被排除，因此不能用于多元回归分析。用PTP1B活性的三个变量获得统计学上显着的模型。预测值与实验值的散点图如图4所示。
实施例42作用机理研究
筛选活性化合物23.葡萄糖向细胞的流入受胰岛素受体(IR)转导途径的调节。其下游分子(例如胰岛素受体底物1和Akt)的失调导致肝脏中的胰岛素抵抗。考虑到PTP1B是胰岛素信号传导途径的负调节剂性,化合物23将激活胰岛素受体底物-1(IRS-1)和蛋白激酶B(Akt)以恢复胰岛素抗性。因此，23用于评估棕榈酸(PA)诱导的胰岛素抗性HepG2细胞。如图5A所示，与单胰岛素刺激相比，HepG2与PA的孵育显着下调磷酸化IRS-1(P-IRS-1)和磷酸化Akt(P-Akt)。然而，用化合物23处理分别在5和10μM浓度下显着增强P-IRS1和P-Akt。结果表明,合物23 可以减轻PA诱导的肝脏胰岛素抵抗。然后，我们研究了化合物23对2 型糖尿病db/db小鼠的高血糖诱导的肝损伤的潜在保护作用。胰岛素抵抗与肝损伤之间存在密切关联.图5B所示，db/db小鼠中碱性磷酸酶(AKP) 和丙氨酸氨基转移酶(ALT)(肝功能和完整性的经典标志物)显着增加。在以10和20mg/kg的剂量用化合物23处理后，AKP和ALT含量显着降低。此外，化合物23的给药有效地下调了血清中总胆固醇(TCH)的水平，具有统计学意义。组织学检查显示db/db小鼠肝组织中弥漫性脂质积聚和散发性大脂滴，而化合物23(10和20mg/kg)治疗显着减弱脂肪变性程度，如图5C所示。这些脂滴的大小和数量也显着降低了肝脏，表明化合物23有效抑制肝脏中的脂质积累并具有显着的保肝作用。同时，肝脏提取物中IRS-1的磷酸化水平与肝脏中观察到的IR信号传导的激活密切相关(图5D)。这些数据表明化合物23激活IR信号通路可保护小鼠免受肝损伤。
实施例43药代动力学研究
化合物23分别通过静脉或口服以2mg/kg，20mg/kg的剂量给予雄性 SD大鼠。药代动力学参数总结在图6A中，对所显示的大鼠静脉内给药 23具有延长的半衰期(21.12小时)和低清除率(1.41mL/分钟/千克)。以 20mg/kg口服给予小鼠产生中度口服暴露(AUC0-∞＝1620.78h·ng/mL)，半衰期(8.85h)和高Cmax(2148.83ng/mL)。有趣的是，在胃内后4小时存在第二个峰值(图6B-6C)，这可能是由于肝肠循环导致部分药物再次在肠道中被吸收。由于尚不知道该化合物是否特异性地靶向催化位点附近的催化位点或第二个磷酸酪氨酸结合口袋(已被提议作为促进选择性和亲和力的相当大的结合位点)，我们采用PTP1B与选择性的复合物阻断剂穿过两个结合口袋(PDB ID 1Q1M)作为参考结构。对接结果清楚地表明活性化合物23是催化位点特异性抑制剂，因为前20个位置都富含在这个口袋和附近区域。
实施例44分子动力学模拟
为了进一步了解分子间结合模式，我们进行了50ns的分子动力学模拟。如图7A所示，受体和配体在20ns后会聚，并且骨架原子的均方根偏差(RMSD)分别为约1.6和2.0。配体显示出从10到13ns的突然构象转变，表明对接结果不是真实的最终构象，因为在半刚性对接中不考虑蛋白质受体的柔韧性。通过对轨迹的分析，我们发现在配体的构象转变过程中，催化袋的构型也开始改变。图7A和7B清楚地表明，从闭合(水解主管) 转化的一个保守的蛋白质循环(WPD环)到打开(水解无能)位置的移动，而蛋白酪氨酸磷酸酶(PTP)循环，它包含了催化半胱氨酸CYS215，无显著变化。以前的研究表明，WPD环在PTP1B催化机制中起着重要作用。在apo形式中，WPD环通常处于“开放”构象，而在配体结合时它在活性位点上闭合，并且其运动是水解的限速步骤。该模拟工作的结果与实验观察结果非常一致，表明我们的化合物在PTP1B的催化位点具有良好的亲和力和合理的结合模式。为了进一步了解分子间结合模式，我们进行了50ns的分子动力学模拟。如图7A所示，受体和配体在20ns后会聚，并且骨架原子的均方根偏差(RMSD)分别为约1.6和2.0。配体显示出从 10到13ns的突然构象转变，表明对接结果不是真实的最终构象，因为在半刚性对接中不考虑蛋白质受体的柔韧性。

Claims (9)

1.一种含有烯丙基结构的查尔酮衍生物，其特征在于，结构如通式(I)～(V)任一所示：
式(I)～(Ⅴ)中，R独立地选自羟基、烷氧基、烃基、杂环、卤素及叔胺中的一个或者多个；
n＝0～5。
2.根据权利要求1所述的查尔酮衍生物，其特征在于，式(I)～(Ⅴ)中，R为羟基、甲氧基、C1～C5烃基、Br、杂环及叔胺中的一个或者多个。
3.根据权利要求1所述的查尔酮衍生物，其特征在于，选自以下化合物中任一个：
4.一种如权利要求1～3任一项所述的查尔酮衍生物的应用，其特征在于，所述的查尔酮衍生物的用于制备胰岛素增敏剂。
5.根据权利要求4所述的查尔酮衍生物的应用，其特征在于，所述的胰岛素增敏剂作为PTP1B的特异性抑制剂，能够在活动站点中将WPD循环从“关闭”转换为“打开”。
6.根据权利要求4所述的查尔酮衍生物的应用，其特征在于，所述的胰岛素增敏剂用于治疗糖尿病和/或肥胖症。
7.根据权利要求6所述的查尔酮衍生物的应用，其特征在于，所述的胰岛素增敏剂用于治疗2型糖尿病。
8.一种药物制剂，包括有效成分和药用辅料，其特征在于，所述的有效成分包括权利要求1～3任一项所述的查尔酮衍生物。
9.根据权利要求8所述的药物制剂，其特征在于，所述的药物制剂为注射剂、片剂、胶囊剂、气雾剂、栓剂、膜剂、滴丸剂、软膏剂、控释剂、缓释剂或纳米制剂的任一种。
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