CN108218679B - 一种(z)型含氟1-苯基-1-芳基-二苯乙烯衍生物及其制备方法和应用 - Google Patents

一种(z)型含氟1-苯基-1-芳基-二苯乙烯衍生物及其制备方法和应用 Download PDF

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CN108218679B
CN108218679B CN201810052839.8A CN201810052839A CN108218679B CN 108218679 B CN108218679 B CN 108218679B CN 201810052839 A CN201810052839 A CN 201810052839A CN 108218679 B CN108218679 B CN 108218679B
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吴晶晶
梁俊清
王星
张天宇
吴范宏
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Abstract

本发明属于制药技术领域，具体为一种(Z)型含氟1‑苯基‑1‑芳基‑二苯乙烯衍生物及其制备方法和应用。本发明在1,1‑二苯乙烯A芳环的2',3',4'位用多种取代基进行化学结构修饰，同时B环固定为没有取代基的苯环。含氟1‑苯基‑1‑芳基‑二苯乙烯衍生物的结构如式(I)所示；含氟1‑苯基‑1‑芳基‑二苯乙烯衍生物具有较好的体外抗肿瘤活性，含氟部分取代基C和A环上取代基的不同对活性有较大的影响，氟原子的引入不仅改变了化合物本身的物理性质，同时增强了体外抗肿瘤活性，并对多种肿瘤细胞均有较好的抑制作用。

Description

一种(Z)型含氟1-苯基-1-芳基-二苯乙烯衍生物及其制备方 法和应用
技术领域
本发明涉及药物合成技术领域，尤其涉及一种(Z)型含氟1-苯基-1-芳基-二苯乙烯衍生物及其制备方法和应用。
背景技术
二苯乙烯类化合物通常是指含有两个苯环间由一个乙烯基相连接的二苯乙烯母体结构的化合物，其多种活性的不断发现及应用范围的不断拓展，已经引起了国内外有机合成研究人员的高度重视。
Combretastatin A-4(CA-4)是由Pettit等从南非灌木柳树皮combretumcaffrum中分离得到的一种二苯乙烯类化合物，它能够特异性地识别和破坏肿瘤血管，以致肿瘤细胞得不到足够的养分而“饿死”。通过作用于秋水仙碱结合位点，CA-4能够抑制微管蛋白的聚合从而阻止肿瘤血液流动。然而由于CA-4及其衍生物目前还存在许多缺陷，比如水溶性差、顺式结构不稳定、反式结构没有活性等，使其在临床试验中受到很大阻碍。所以，长久以来围绕CA-4类似物的结构改造做了大量的研究工作。多数情况下，在对CA-4结构改造中，往往只保留A环部分，对连接桥和B环进行改造。
Figure BDA0001552858090000011
近年来，含氟药物在临床治疗药物中占有很大的比重，在小分子药物中引入氟原子或含氟基团，是改善药物活性的重要策略之一。氟原子具有最大的元素电负性和与氢原子相近的原子半径，在小分子药物中引入氟原子或含氟基团后，对其分子体积几乎没有影响，但是对其理化性质包括电子效应和立体效应、生物活性、药代动力学性质、代谢稳定性和配体与靶标蛋白的相互作用力以及选择性等可能产生显著影响，而且还可以增强小分子的亲脂性，使其更容易透过细胞膜，进而提高生物活性。
发明内容
为了克服现有技术的不足，本发明的目的在于提供一种(Z)型含氟1-苯基-1-芳基-二苯乙烯衍生物及其制备方法和应用。
本发明的技术方案详细介绍如下。
一种(Z)型含氟1-苯基-1-芳基-二苯乙烯衍生物，其结构如通式(I)所示：
Figure BDA0001552858090000021
其中：R1为氢或氟，R2为单取代的甲基、甲氧基、氰基、氯、氟，或3,4,5-三甲氧基。
本发明中，R1为氟，R2为3-甲基、4-甲基、4-甲氧基、4-氯2-氯，或4-氟。
本发明中，通式(I)结构中的连接R2的苯环用萘环代替。
本发明还提供一种上述的衍生物的制备方法，包括以下步骤：
(1)用对取代基的苯乙酮
Figure BDA0001552858090000022
和三氟乙酸乙酯在NaH条件下反应得到4,4,4-三氟-3-羟基-1-丁-2-烯-1-酮
Figure BDA0001552858090000023
(2)以4,4,4-三氟-3-羟基-1-丁-2-烯-1-酮
Figure BDA0001552858090000024
作为原料，使用选择性氟化试剂通过氟化反应得到2,2,4,4,4-五氟-3,3-二羟基-1-丁-1-酮
Figure BDA0001552858090000025
(3)以2,2,4,4,4-五氟-3,3-二羟基-1-丁-1-酮
Figure BDA0001552858090000026
作为原料，在溶剂中使用溴化锂，碘单质，三乙胺反应得到2-碘-2,2-二氟苯类化合物
Figure BDA0001552858090000027
(4)以2-碘-2,2-二氟苯类化合物
Figure BDA0001552858090000031
作为原料，与带有取代基的苯乙炔
Figure BDA0001552858090000032
和苯硼酸
Figure BDA0001552858090000033
在Pd(PPh3)4作为催化剂，K 3PO4作碱，50～70℃的温度，惰性气氛下反应10～15小时，得到含氟1-苯基-1-芳基-二苯乙烯衍生物。将衍生物的环分别命名为A、B,即为
Figure BDA0001552858090000034
以上，根据步骤(1)～(3)，2-碘-2,2-二氟苯类化合物
Figure BDA0001552858090000035
的合成路线如下式所示：
Figure BDA0001552858090000036
根据步骤(4)，含氟1-苯基-1-芳基-二苯乙烯类化合物的合成路线如下式所示：
Figure BDA0001552858090000037
本发明进一步提供一种上述的衍生物在制备抗肿瘤药物中的应用。
本发明中，抗肿瘤药物为预防或治疗胃癌、肝癌、肺癌、结肠癌或宫颈癌的药物。
本发明中，抗肿瘤药物的药物制剂，选自以下剂型：静脉注射形式给药的冻干粉剂、粉剂、注射剂、脂质体、乳剂、微囊、悬浮液或溶液；口服形式给药的颗粒剂、片剂、胶囊或糖浆；或是栓剂。
上述通式(I)上化合物药效评价，阳性对照物如下：
(Z)-3,4,5-三甲氧基-3'-羟基-4'-甲氧基二苯乙烯(CA-4)
Figure BDA0001552858090000041
上述通式(I)上化合物药效评价结果综述如下：
体外培养肿瘤细胞的抗肿瘤活性评价，结果表明实施例中的CA-4含氟类似物对HepG肝癌细胞株具有广泛的抑制活性，并且这些化合物的活性数值与对照药CA-4的活性数值相差不大，尤其化合物的A9IC50值为15.68μmol/mL小于CA-4的IC50值(16.04μmol/L)，说明在C部分用甲氧基的偕二氟基团有效地改善了化合物的抗肿瘤活性。而在对人宫颈癌细胞Hela细胞株的抑制中，化合物A9的IC50值为17.56μmol/mL表现出与CA-4相当的活性，CA-4的IC50值为1.76μmol/mL。
此外，其他的化合物对于人胃癌细胞MKN45、人肺癌细胞A549、人结肠癌细胞HTC-116、人胃癌细胞MGC803也具有较强的抑制活性，显示出广谱的抗肿瘤活性。
总体结果显示，本发明的经偕二氟取代的CA-4类似物对多数肿瘤细胞具有较好的抗肿瘤活性。
具体实施方式
下面结合实施例对本发明的技术方案进行详细介绍。
实施例1(Z)-2,2-二氟-1,4-二苯基-4-(对甲苯基)丁-3-烯-1-酮的制备
Figure BDA0001552858090000042
向干燥的反应管中加入苯硼酸(1.0mmol，1.0当量,0.122g)，K3PO4(2.0mmol，2.0当量,0.424g)和Pd(PPh3)4(0.05mmol，5mol％,0.057g)。将管抽真空并用氮气回填(重复三次)。然后，将溶于甲苯(2.0mL)中的相应2-碘-2,2-二氟苯类化合物(1.0mmol，1.0当量)和对甲基苯乙炔(1.2mmol，1.2当量,0.139g)分别添加到管中。将反应混合物在60℃下搅拌12小时。反应完成后(如TLC所示)，反应混合物用乙酸乙酯(3×10mL)萃取。将合并的有机层用饱和盐水洗涤，用Na2SO4干燥，真空浓缩并将粗残余物通过硅胶柱色谱(石油醚/EtOAc＝100：1)纯化，得到淡黄色油状产物A1 0.289g。1H NMR(500MHz,CDCl3):δ7.82(d,J＝7.8Hz,2H),7.54(t,J＝7.4Hz,1H),7.42–7.21(m,7H),7.03(d,J＝7.8Hz,2H),6.86(d,J＝7.9Hz,2H),6.47(t,J＝12.2Hz,1H),2.35(s,3H)；13C NMR(125MHz,CDCl3):δ187.5(t,2'JC-F＝30.0Hz),151.3(t,3JC-F＝9.4Hz),140.9,138.5,134.2,133.7,129.9,129.7(t,3'JC-F＝1.9Hz),129.0,128.6,128.4,128.2,127.9,120.0(t,2JC-F＝27.5Hz),115.3(t,1JC-F＝245.6Hz),21.3；19F NMR(470MHz,CDCl3):δ-87.2(s,2F)；HRMS(ESI-FT)calculated[M+Na]+for C23H18F2O:371.1218,found:371.1221。反应产率83％。
实施例2(Z)-2,2-二氟-4-(4-甲氧基苯基)-1,4-二苯基丁-3-烯-1-酮的制备
Figure BDA0001552858090000051
按实施例1的方法进行，将合并的有机层用饱和盐水洗涤，用Na2SO4干燥，真空浓缩并将粗残余物通过硅胶柱色谱(石油醚/EtOAc＝100：1)纯化，得到期望的淡黄色油状产物A2 0.299g。1H NMR(500MHz,CDCl3):δ7.82(d,J＝7.8Hz,2H),7.55(t,J＝7.4Hz,1H),7.43–7.24(m,7H),6.89(d,J＝8.7Hz,2H),6.76(d,J＝8.7Hz,2H),6.48(t,J＝11.9Hz,1H),3.84(s,3H)；13C NMR(125MHz,CDCl3):δ187.4(t,2'JC-F＝30.0Hz),160.0,151.1(t,3JC-F＝9.4Hz),141.0,133.8,132.1,131.6,129.6,129.1,128.4,128.2,128.0,120.1(t,2JC-F＝27.5Hz),115.4(t,1JC-F＝213.8Hz),113.3,55.3；19F NMR(470MHz,CDCl3):δ-86.6(s,2F)；HRMS(ESI-FT)calculated[M+H]+for C32H18F2O2:365.1347,found:365.1347。反应产率82％。
实施例3(Z)-2,2-二氟-4-(4-氟苯基)-1,4-二苯基丁-3-烯-1-酮的制备
Figure BDA0001552858090000052
按实施例1的方法进行，将合并的有机层用饱和盐水洗涤，用Na2SO4干燥，真空浓缩并将粗残余物通过硅胶柱色谱(石油醚/EtOAc＝100：1)纯化，得到期望的淡黄色油状产物A30.275g。1H NMR(500MHz,CDCl3):δ7.86(d,J＝7.8Hz,2H),7.56(t,J＝7.4Hz,1H),7.45–7.19(m,7H),7.02–6.88(m,4H),6.52(t,J＝12.2Hz,1H)；13C NMR(125MHz,CDCl3):δ187.4(t,2'JC-F＝29.4Hz),163.9,161.9,150.2(t,3JC-F＝8.8Hz),140.5,134.0,133.0,131.9,131.8,129.8(t,3'JC-F＝1.9Hz),129.3,128.5,128.4,127.8,120.7(t,2JC-F＝26.9Hz),117.2,115.2(t,1JC-F＝245.6Hz),115.1,114.9；19F NMR(470MHz,CDCl3):δ-87.4(s,2F),-112.4(s,1F)；HRMS(ESI-FT)calculated[M+Na]+for C22H15F3O:375.0967,found:375.0970。反应产率78％。
实施例4(Z)-4-(4-氯苯基)-2,2-二氟-1,4-二苯基丁-3-烯-1-酮的制备
Figure BDA0001552858090000061
按实施例1的方法进行，将合并的有机层用饱和盐水洗涤，用Na2SO4干燥，真空浓缩并将粗残余物通过硅胶柱色谱(石油醚/EtOAc＝100：1)纯化，得到期望的淡黄色油状产物A40.291g。1H NMR(500MHz,CDCl3):δ7.87(d,J＝6.9Hz,2H),7.64–7.15(m,10H),7.01–6.90(m,2H),6.51(t,J＝12.4Hz,1H)；13C NMR(125MHz,CDCl3):δ187.6(t,2'JC-F＝29.4Hz),150.0(t,3JC-F＝8.8Hz),140.3,135.6,134.8,134.1,131.9,131.2,129.8,129.3,128.5,128.4,128.2,127.8,120.6(t,2JC-F＝26.9Hz),115.2(t,1JC-F＝246.9Hz)；19F NMR(470MHz,CDCl3):δ-87.7(d,J＝4.7Hz,2F)；HRMS(ESI-FT)calculated[M+Na]+for C22H15ClF2O:391.0672,found:391.0675。反应产率79％。
实施例5(Z)-4-(3,3-二氟-4-氧代-1,4-二苯基丁-1-烯-1-基)苄腈的制备
Figure BDA0001552858090000062
按实施例1的方法进行，将合并的有机层用饱和盐水洗涤，用Na2SO4干燥，真空浓缩并将粗残余物通过硅胶柱色谱(石油醚/EtOAc＝100：1)纯化，得到期望的无色油状产物A50.270g。1H NMR(500MHz,CDCl3):δ7.91(d,J＝7.8Hz,2H),7.63–7.16(m,12H),6.56(t,J＝12.8Hz,1H)；13C NMR(125MHz,CDCl3):δ187.5(t,2'JC-F＝30.0Hz),149.3(t,3JC-F＝8.1Hz),142.2,139.5,134.4,131.7,130.5,129.9,129.6,128.7,128.6,127.7,121.0(t,2JC-F＝26.3Hz),118.5,115.2(t,1JC-F＝248.1Hz),112.4；19F NMR(470MHz,CDCl3):δ-88.4(s,2F)；HRMS(ESI-FT)calculated[M+Na]+for C23H15F2NO:382.1014,found:382.1015。
反应产率75％。
实施例6(Z)-2,2-二氟-1,4-二苯基-4-(间甲苯基)丁-3-烯-1-酮的制备
Figure BDA0001552858090000071
按实施例1的方法进行，将合并的有机层用饱和盐水洗涤，用Na2SO4干燥，真空浓缩并将粗残余物通过硅胶柱色谱(石油醚/EtOAc＝100：1)纯化，得到期望的无色油状产物A60.265g。1H NMR(500MHz,CDCl3):δ7.81(d,J＝7.8Hz,2H),7.54(t,J＝7.4Hz,1H),7.42–7.24(m,7H),7.13(d,J＝4.8Hz,2H),6.83(d,J＝3.8Hz,1H),6.65(s,1H),6.52(t,J＝11.9Hz,1H),2.21(s,3H)；13C NMR(125MHz,CDCl3):δ187.3(t,2'JC-F＝28.8Hz),151.3(t,3JC-F＝10.0Hz),140.7,137.5,136.9,133.8,132.1,130.5,129.6,129.4,129.1,128.4,128.2,127.9,127.8,127.2,120.4(t,2JC-F＝27.5Hz),115.2(t,1JC-F＝245.0Hz),21.3；19FNMR(470MHz,CDCl3):δ-87.0(s,2F)；HRMS(ESI-TOF)calculated[M+Na]+for C23H18F2O:371.1223,found:371.1222。反应产率76％。
实施例7(Z)-4-(2-氯苯基)-2,2-二氟-1,4-二苯基丁-3-烯-1-酮的制备
Figure BDA0001552858090000072
按照实施例6的方法进行，将合并的有机层用饱和盐水洗涤，用Na2SO4干燥，真空浓缩，通过硅胶柱色谱法(石油醚/EtOAc＝100：1)纯化粗残余物，得到最期望的淡黄色油状产物A70.280g。1H NMR(500MHz,CDCl3):δ7.96(d,J＝7.8Hz,2H),7.58(t,J＝7.4Hz,1H),7.44(t,J＝7.8Hz,2H),7.36–7.24(m,9H),6.63(t,J＝12.5Hz,1H)；13C NMR(125MHz,CDCl3):δ187.4(t,2'JC-F＝30.6Hz),148.2(t,3JC-F＝11.9Hz),138.6,135.7,134.2,133.5,131.9,130.1,129.9,129.6,129.2,128.6,128.5,126.9,126.3,121.2(t,2JC-F＝26.3Hz),115.3(t,1JC-F＝247.5Hz)；19F NMR(470MHz,CDCl3):δ-90.5(d,J＝89.3Hz,2F)；HRMS(ESI-TOF)calculated[M+Na]+for C22H15ClF2O:391.0677,found:391.0671。反应产率76％。
实施例8(Z)-2,2-二氟-4-(6-甲氧基萘-2-基)-1,4-二苯基丁-3-烯-1-酮的制备
Figure BDA0001552858090000073
按照实施例6的方法进行，将合并的有机层用饱和盐水洗涤，用Na2SO4干燥，真空浓缩，通过硅胶柱色谱法(石油醚/EtOAc＝100：1)纯化粗残余物，得到最期望的淡黄色油状产物A8 0.265g。1H NMR(500MHz,CDCl3):δ7.68–7.41(m,6H),7.40–7.29(m,7H),7.22–7.10(m,2H),6.90(dd,J＝8.4,1.4Hz,1H),6.59(t,J＝11.8Hz,1H),3.97(s,3H)；13C NMR(125MHz,CDCl3):δ187.3(t,2'JC-F＝28.8Hz),158.4,151.3(t,3JC-F＝9.4Hz),140.7,134.4,133.7,132.3,132.1,129.9,129.8,129.1,128.4,128.1,128.0,127.9,127.7,126.4,120.6(t,2JC-F＝28.1Hz),119.2,115.3(t,1JC-F＝245.0Hz),105.7,55.4；19F NMR(470MHz,CDCl3):δ-86.6(s,2F)；HRMS(ESI-FT)calculated[M+H]+for C27H20F2O2:415.1504,found:415.1507。反应产率64％。
实施例9(Z)-2,2-二氟-1-(4-氟苯基)-4-苯基-4-(3,4,5-三甲氧基苯基)丁-3-烯-1-酮的制备
Figure BDA0001552858090000081
按照实施例6的方法进行，将合并的有机层用饱和盐水洗涤，用Na2SO4干燥，真空浓缩，通过硅胶柱色谱法(石油醚/EtOAc＝100：1)纯化粗残余物，得到最期望的淡黄色油状产物A90.305g。1H NMR(500MHz,CDCl3):δ7.79(dd,J＝8.4,5.6Hz,2H),7.36-7.29(m,5H),7.02(t,J＝7.5Hz,2H),6.46(t,J＝12.5Hz,1H),6.06(s,2H),3.87(s,3H),3.64(s,6H)；13C NMR(125MHz,CDCl3):δ185.4(t,2'JC-F＝28.8Hz),167.0,164.9,152.6,151.1(t,3JC-F＝10.6Hz),139.9,138.6,132.1,132.0,131.9,129.4,128.7,128.5,128.0,120.6(t,2JC-F＝28.8Hz),115.5,115.3,115.0(t,1JC-F＝242.5Hz),107.6,60.9,55.9；19F NMR(470MHz,CDCl3):δ-85.7(s,2F),-103.3(s,1F)；HRMS(ESI-FT)calculated[M+H]+for C25H21F3O4:443.1464,found:443.1465。反应产率69％。
实施例10 CCK-8法测试化合物对多种肿瘤细胞的抗肿瘤活性
1、试验方法
取活细胞比例达90％以上的细胞进行实验。细胞增殖抑制试验采用EnoGeneCellTMCounting Kit-8(CCK-8)细胞活力检测试剂盒。细胞消化、计数、制成浓度为1×105个/mL的细胞悬液，96孔板中每孔加入100μL细胞悬液(每孔1×104个细胞)；96孔板置于37℃，5％CO2培养箱中培养24小时；每孔加入100μL相应的含药物的培养基，同时设阴性对照组，溶媒对照组，阳性对照组，每组5复孔；96孔板置于37℃，5％CO2培养箱中培养72h后；每孔加入10μL CCK-8溶液,将培养板在培养箱内孵育4小时，用酶标仪测定在450nm处的OD值，计算目标化合物对人肝癌细胞HepG2、人肺癌细胞A549、人胃癌细胞MGC-803、人宫颈癌细胞Hela等细胞的抑制率及IC50值。
2、试验结果
表1部分实施例化合物对多种肿瘤细胞株的体外抗肿瘤活性评价(CKK-8法)
Figure BDA0001552858090000091
以上所述仅为本发明的较佳实施例而已，并非用以限定本发明的实质技术内容范围，本发明的实质技术内容是广义地定义于申请的权利要求范围中，任何他人完成的技术实体或方法，若是与申请的权利要求范围所定义的完全相同，也或是一种等效的变更，均将被视为涵盖于该权利要求范围之中。

Claims (2)

1.一种(Z)型含氟1,1-二苯乙烯衍生物，其特征在于，其结构如通式(I)所示：
Figure FDA0003165497160000011
其中：R1为氟，R2为3-甲基、4-甲基、4-甲氧基、4-氯、2-氯或4-氟；
所述衍生物的制备方法，包括以下步骤：
(1)用对取代基的苯乙酮
Figure FDA0003165497160000012
和三氟乙酸乙酯在NaH条件下反应得到4,4,4-三氟-3-羟基-1-丁-2-烯-1-酮
Figure FDA0003165497160000013
(2)以4,4,4-三氟-3-羟基-1-丁-2-烯-1-酮
Figure FDA0003165497160000014
作为原料，使用选择性氟化试剂通过氟化反应得到2,2,4,4,4-五氟-3,3-二羟基-1-丁-1-酮
Figure FDA0003165497160000015
(3)以2,2,4,4,4-五氟-3,3-二羟基-1-丁-1-酮
Figure FDA0003165497160000016
作为原料，在溶剂中使用溴化锂，碘单质，三乙胺反应得到2-碘-2,2-二氟苯类化合物
Figure FDA0003165497160000017
(4)以2-碘-2,2-二氟苯类化合物
Figure FDA0003165497160000018
作为原料，与带有取代基的苯乙炔
Figure FDA0003165497160000021
和苯硼酸
Figure FDA0003165497160000022
在Pd(PPh3)4作为催化剂，K3PO4作碱，50～70℃的温度，惰性气氛下反应10～15小时，得到含氟1,1-二苯乙烯衍生物。
2.一种根据权利要求1所述的衍生物在制备抗肿瘤药物中的应用，抗肿瘤药物为预防或治疗胃癌、肝癌、肺癌、结肠癌或宫颈癌的药物。
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