CN118221690A - 一种色酮并哒嗪类化合物及其合成方法与应用 - Google Patents
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Abstract
本发明公开了结构式如下式所示的色酮并哒嗪类化合物，本发明以邻羟基芳基烯胺酮、芳基重氮盐为原料制得色酮并哒嗪类化合物，制备方法具有制备简单、反应温和、成本低、收率高的特点；将色酮并哒嗪类化合物应用在抗冠状病毒实验中，实验结果显示其具有抗冠状病毒活性，效果与阳性对照药阿比多尔(ARB)相当，而细胞毒性更低，其具有用于开发治疗、预防、缓解由冠状病毒引起的相关疾病的药物的潜力；
Description
技术领域
本发明属于有机合成技术与医药应用技术领域，具体涉及一种色酮并哒嗪类化合物、合成所述化合物的方法和使用所述化合物的抗冠状病毒的应用。
背景技术
色酮是最重要的一类天然杂环化合物，广泛存在于自然界中，其衍生物表现出多种生物和药物活性，如抗菌(Chem.Rev.2014,114,4960.)、抗氧化(Chem.Biol.DrugDes.2012,79,981.)、抗真菌(Cell Biochem.Funct.1991,9,79.)和抗癌特性(CancerLett.1997,114,153.)，以及出色的荧光特性(Spectrochim.Acta Part A 2006,65,397.)。此外，将两个或多个具有活性的骨架单元结合在一个化合物中，通过组合多个分子核心来发挥其生物活性，是药物设计的策略之一。因此，色酮及色酮衍生物的构建受到了化学家的广泛关注。
迄今为止，已经开发了大量的合成方法来制备色酮及其衍生物，包括经典的Claise缩合(Eur.J.Chem.2012,3,57.)、Baker-Venkatamara重排(J.Med.Chem.2011,54,7427.)、Kostanecki-Robinso反应(J.Heterocycl.Chem.2002,39,627.)。此外，还利用了金属催化(J.Org.Chem.2010,75,948.)、微波辅助(Tetrahedron Lett.2005,46,6315.)等其他的反应合成途径，例如，2014年，Zhang课题组报道的在碘及500w汞灯作用下通过N,N-二甲基邻羟基烯胺酮和苯衍生物反应合成异黄酮(Chem.Commun.2016,52,12306.)。但大多合成方法存在反应条件苛刻、使用过渡金属催化剂、底物预制备困难、结构多样性受限和产率低等局限性。因此，开发原料简单易得、反应条件温和、后处理简单、简洁高效地实现具有多功能结构的色酮衍生物具有重要意义。
另一方面，冠状病毒是单链RNA病毒，可感染人和多种脊柱动物。高致病性的冠状病毒传播与感染给社会公众健康造成了极大危害，而低致病性的冠状病毒也呈季节性散发，在一定程度上影响人类健康。虽然目前已研发出针对新型冠状病毒的疫苗，但对可感染人类的冠状病毒尚缺乏特异性药物，临床上仍以对症和支持治疗为主。为了更好地应对流行性病毒和新发传染病给人类带来的危害，亟需开发出更多的药物。因此，寻找有效抑制冠状病毒的候选药物是亟待解决的技术问题。
发明内容
为了解决现有技术不足，本发明提供了一种色酮并哒嗪类化合物以及简单高效的合成方法和抗冠状病毒应用。
为解决上述合成技术问题，本发明采用的技术方案是：在反应器中加入邻羟基芳基烯胺酮1、芳基重氮盐2、溶剂，在25℃～70℃油浴条件下反应，薄层色谱监测反应进程，直至反应完全；然后用乙酸乙酯和水萃取3～4次，收集合并有机相并用饱和食盐水洗涤，收集有机相后用无水硫酸钠干燥，减压浓缩，残渣用硅胶柱层析或者重结晶分离纯化得到色酮并哒嗪类化合物3，合成路线如下：
其中Ar1选自取代或未取代芳基，取代基为烷基、烷氧基、卤素、芳基、杂芳基；Ar2选自取代或未取代芳基，取代基为烷基、烷氧基、苄氧基、卤素、氰基、苯甲酰基、酰胺。
所述邻羟基芳基烯胺酮1和芳基重氮盐2的摩尔比为2～4:1。
制备色酮并哒嗪类化合物时，还可以添加添加剂，添加剂选自二氟乙酸、三氟乙酸、正丁酸、乙酸、氰基乙酸、异丁酸、丙二酸、对甲苯磺酸、三氟甲磺酸、丁二酸酐、异丁酸酐、苯甲酸酐、乙酸酐、三氟乙酸酐、丙酸酐、正戊酸酐；邻羟基芳基烯胺酮1与添加剂的摩尔比为2:1～3；溶剂选自1,4-二氧六环、二甲基亚砜、乙腈、甲苯、丙酮、二甲苯、二氯甲烷中。
上述合成反应在在惰性气氛、空气气氛或氧气气氛下进行。
所述邻羟基芳基烯胺酮按常规方法制备，例如参照Eur.J.Org.Chem.2011,2011,399文献中方法制得；芳基重氮盐按常规方法制备，例如参照文献Angew.Chem.Int.Ed.2015,54,7648-7652的方法制备。
所述产物结构经过核磁共振、高分辨质谱以及代表性产物的单晶衍射测试等确证。
目标产物色酮并哒嗪类化合物3为如下任一结构：
本发明所述的色酮并哒嗪类化合物或其药学上可接受的盐在制备抑制冠状病毒制剂中的应用，所述冠状病毒为HCoV-OC43冠状病毒。
本发明所述抑制冠状病毒制剂是以色酮并哒嗪类化合物作为有效成分，还可以加入一种或多种药剂学上可接受的辅料，以改善药物的吸收效果或便于使用，如制成胶囊或丸剂、粉剂、片剂、粒剂、口服液和注射液等，即制成适宜的使用剂型，用于治疗、预防、缓解由冠状病毒引起的相关疾病。
本发明所述制剂，包含有效量的所述的色酮并哒嗪类化合物或其药学上可接受的盐、立体异构体、活性代谢物、前药、溶剂化物或结晶形式，以及药学上可以接受的赋形剂。
与现有技术相比，本发明具有如下优点：
本发明公开了全新结构的色酮并哒嗪类化合物，并提供了一种具有多官能结构、结构多样的色酮并哒嗪类化合物的高通用性合成方法，该合成方法的起始原料是通过来源广泛、结构多样、价廉易得的简单合成得到；合成方法简洁高效，反应条件温和，操作简便，环境友好，产率高等特点，合成方法适合工业放大，有良好的产业应用前景；
本发明色酮并哒嗪类化合物通过抗冠状病毒药效试验，证实其具有抗冠状病毒活性，效果与阳性对照瑞德西韦药阿比多尔(ARB)相当，且细胞毒性比ARB更低，具有非常好的抗冠状病毒效果，可以用于开发治疗、预防、缓解由冠状病毒引起的相关疾病的药物。
附图说明
图1为化合物3s的单晶结构图。
具体实施方式
下面通过实施例对本发明作进一步详细说明，但本发明保护范围不局限于所述内容，实施例中试剂如无特殊说明，均为常规市售试剂或按常规方法制得的试剂。
实施例1：
在15mL反应管中依次加入(E)-3-(二甲氨基)-1-(2-羟基苯基)丙-2-烯-1-酮1(0.21mmol)、丁二酸酐(0.1mmol)、乙腈(2mL)、对甲氧基苯基重氮四氟硼酸盐2(0.1mmol)，在氮气气氛、25℃下反应，TLC监测反应，待原料点完全消失后，反应产物用乙酸乙酯和水萃取3次，收集合并有机相并用饱和食盐水洗涤，收集有机相后有机相用无水Na2SO4进行干燥，将经过干燥的液体45℃下旋蒸浓缩，之后浓缩蒸干物进行硅胶柱层析分离纯化，柱色谱分离采用的溶剂为石油醚-乙酸乙酯的混合溶剂，收集洗脱液，45℃下旋蒸干燥，得黄色固体3a，收率93％，反应如下：
产品3a的结构、形态、熔点、核磁、高分辨质谱数据如下：
V石油醚/V乙酸乙酯＝10:1,Rf＝0.25；黄色固体:40mg产率93％；熔点＝143-144℃；1H NMR(600MHz,CDCl3):δ＝11.82(s,1H,OH),8.20(s,1H,C＝CH),7.99(s,2H,ArH),7.57(t,J＝7.4Hz,1H,ArH),7.52(t,J＝7.3Hz,1H,ArH),7.37(d,J＝8.8Hz,2H,ArH),7.09(t,J＝8.9Hz,2H,ArH),6.99-6.93(m,4H,ArH),6.41(s,1H,C-CH),3.83(s,3H,ArOCH3)；13C NMR(150MHz,CDCl3)δ＝193.2,181.2,163.8,158.3,157.6,140.3,137.1,136.6,136.0,133.2,129.0,127.3,123.4,122.3,120.3,120.3,118.9,118.5,118.5,118.4,114.7,114.7,109.5,64.2,55.6；HRMS(TOF ES+):m/z calcd for C25H19N2O5[(M+H)+],427.1288,found,427.1309.
下述实施例制备方法同实施例1；
实施例2：不同在于化合物1为(E)-3-(二甲氨基)-1-(2-羟基-5-甲基苯基)丙-2-烯-1-酮，所得产品3b的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝10:1,Rf＝0.25；黄色固体:42mg产率92％；熔点＝178-179℃；1H NMR(600MHz,CDCl3):δ＝11.63(s,1H,OH),8.00(d,J＝9.4Hz,2H,ArH),7.78(s,1H,C＝CH),7.38(t,J＝9.0Hz,3H,ArH),7.32(d,J＝8.4Hz,1H,ArH),6.99(d,J＝8.5Hz,1H,ArH),6.95(d,J＝9.0Hz,2H,ArH),6.84(d,J＝8.4Hz,1H,ArH),6.35(s,1H,C-CH),3.83(s,3H,ArOCH3),2.34(s,3H,ArCH3),2.33(s,3H,ArCH3)；13C NMR(150MHz,CDCl3):δ＝193.2,181.3,161.7,158.2,155.6,140.4,138.2,137.7,136.1,132.9,131.8,128.9,127.9,126.9,123.0,120.2,120.2,118.3,118.2,118.1,114.7,114.7,109.6,64.1,55.6,20.6,20.5；HRMS(TOF ES+):m/z calcd for C27H23N2O5[(M+H)+],455.1601,found,455.1603.
实施例3：不同在于化合物1为(E)-1-(5-氯-2-羟基苯基)-3-(二甲氨基)丙-2-烯-1-酮，所得产品3c的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝10:1,Rf＝0.25；黄色固体:33mg产率67％；熔点＝140-141℃；1H NMR(600MHz,CDCl3):δ＝11.68(s,1H,OH),8.28(d,J＝2.4Hz,1H,ArH),7.99(s,1H,C＝CH),7.95(d,J＝2.4Hz,1H,ArH),7.53-7.50(m,1H,ArH),7.48-7.46(m,1H,ArH),7.38(d,J＝8.9Hz,2H,ArH),7.04(d,J＝8.9Hz,1H,ArH),6.98(d,J＝8.9Hz,2H,ArH),6.92(d,J＝8.8Hz,1H,ArH),6.39(s,1H,C-CH),3.85(s,3H,ArOCH3)；13C NMR(150MHz,CDCl3):δ＝191.7,180.0,162.2,158.6,155.9,139.8,136.8,136.5,135.8,132.4,129.6,127.9,126.8,124.1,123.7,120.6,120.6,120.3,120.1,118.8,114.9,114.9,109.4,64.1,55.7；HRMS(TOF ES+):m/z calcd for C25H17Cl2N2O5[(M+H)+],495.0509,found,495.0507.
实施例4：不同在于化合物1为(E)-1-(5-溴-2-羟基苯基)-3-(二甲氨基)丙-2-烯-1-酮，所得产品3d的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝10:1,Rf＝0.25；黄色固体:24mgg产率41％；熔点＝201-202℃；1HNMR(600MHz,CDCl3):δ＝11.68(s,1H,OH),8.45(s,1H,C＝CH),8.04(d,J＝73.8Hz,2H,ArH),7.59(s,2H,ArH),7.38(s,2H,ArH),6.98(s,3H,ArH),6.85(s,1H,ArH),6.38(s,1H,C-CH),3.84(s,3H,ArOCH3)；13C NMR(150MHz,CDCl3):δ＝189.8,178.2,160.9,156.9,154.6,137.9,137.7,137.5,134.0,133.7,128.1,127.8,122.8,118.8,118.8,118.8,118.7,117.7,113.4,113.1,113.1,108.8,107.7,62.3,53.9；HRMS(TOF ES+):m/z calcd forC25H17Br2N2O5[(M+H)+],582.9499,found,582.9494.
实施例5：不同在于化合物1为(E)-3-(二甲氨基)-1-(4-羟基-[1，1’-联苯基]-3-基)丙-2-烯-1-酮，所得产品3e的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝8:1,Rf＝0.25；黄色固体:45mg产率77％；熔点＝195-196℃；1H NMR(600MHz,CDCl3):δ＝11.91(s,1H,OH),8.58(s,1H,ArH),8.23(s,1H,ArH),8.00(s,1H,C＝CH),7.83-7.77(m,2H,ArH),7.61(d,J＝7.3Hz,2H,ArH),7.52(d,J＝7.3Hz,2H,ArH),7.44(t,J＝7.4Hz,2H,ArH),7.41-7.33(m,6H,ArH),7.17(d,J＝8.6Hz,1H,ArH),7.04(d,J＝8.5Hz,1H,ArH),6.89(d,J＝8.6Hz,2H,ArH),6.46(s,1H,C-CH),3.82(s,3H,ArOCH3)；13CNMR(150MHz,CDCl3):δ＝192.7,181.3,163.3,158.4,157.0,140.3,139.9,139.5,136.1,135.8,135.3,135.3,132.2,131.8,129.2,128.9,128.9,128.9,128.9,127.5,127.2,126.8,126.8,126.7,126.7,125.4,123.5,120.7,120.7,119.1,118.9,118.5,114.7,114.7,110.1,64.2,55.7；HRMS(TOF ES+):m/zcalcd for C37H27N2O5[(M+H)+],579.1914,found,579.1917.
实施例6：不同在于化合物1为(E)-3-(二甲氨基)-1-(2-羟基-6-甲氧基苯基)丙-2-烯-1-酮，所得产品3f的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝10:1,Rf＝0.25；黄色固体:35mg产率72％；熔点＝165-166℃；1H NMR(600MHz,CDCl3):δ＝11.26(s,1H,OH),8.79(s,1H,C＝CH),7.75(s,1H,ArH),7.71(s,1H,ArH),7.46(t,J＝8.3Hz,1H,ArH),7.36(t,J＝8.3Hz,1H,ArH),6.90(d,J＝8.4Hz,1H,ArH),6.85(d,J＝8.9Hz,1H,ArH),6.70(d,J＝8.2Hz,1H,ArH),6.61(s,1H,ArH),6.49(d,J＝8.3Hz,1H,ArH),6.35(d,J＝8.2Hz,1H,ArH),5.61(s,1H,C-CH),3.84(s,3H,ArOCH3),3.77(s,3H,ArOCH3),3.59(s,3H,ArOCH3)；13C NMR(150MHz,CDCl3):δ＝195.3,192.9,176.3,160.8,159.9,158.4,157.8,157.5,152.9,138.8,137.1,136.5,133.6,123.4,119.8,119.8,114.5,114.5,110.6,109.9,106.4,102.8,101.8,56.3,55.9,55.6,29.9；HRMS(TOFES+):m/z calcd for C27H23N2O7[(M+H)+],487.1500,found,487.1500.
实施例7：不同在于化合物1为(E)-3-(二甲氨基)-1-(4-氟-2-羟基苯基)丙-2-烯-1-酮，所得产品3g的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝10:1,Rf＝0.25；红色固体:40mg产率86％；熔点＝196-197℃；1H NMR(600MHz,CDCl3):δ＝12.15(s,1H,OH),8.27-8.23(m,1H,ArH),8.03-8.00(m,1H,ArH),7.98(s,1H,C＝CH),7.35(d,J＝8.9Hz,2H,ArH),6.96(d,J＝8.9Hz,2H,ArH),6.81(t,J＝7.3Hz,1H,ArH),6.76(d,J＝10.2Hz,1H,ArH),6.69(t,J＝8.5Hz,1H,ArH),6.65(d,J＝9.6Hz,1H,ArH),6.43(s,1H,C-CH),3.83(s,3H,ArOCH3)；13C NMR(150MHz,CDCl3):δ＝191.7,179.9,167.9(C-F,J＝258.2Hz),167.9(C-F,J＝256.7Hz),166.5(C-F,J＝15.1Hz),159.3(C-F,J＝13.6Hz),158.4,139.9,135.9,135.7(C-F,J＝11.7Hz),129.9(C-F,J＝11.4Hz),129.2,120.4,120.4,120.2(C-F,J＝2.5Hz),115.5(C-F,J＝1.5Hz),114.8,114.8,110.7(C-F,J＝22.7Hz),109.1,107.5(C-F,J＝22.6Hz),105.4(C-F,J＝24.5Hz),105.1(d,J＝23.6Hz),64.7,55.6；HRMS(TOF ES+):m/z calcd for C25H17F2N2O5[(M+H)+],463.1100,found,436.1104.
实施例8：不同在于化合物1为(E)-3-(二甲氨基)-1-(4-溴-2-羟基苯基)丙-2-烯-1-酮，所得产品3h的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝10:1,Rf＝0.25；黄色固体:27mg产率47％；熔点＝210-211℃；1H NMR(600MHz,CDCl3):δ＝11.87(s,1H,OH),8.07(d,J＝8.7Hz,1H,ArH),7.97(s,1H,C＝CH),7.84(d,J＝8.4Hz,1H,ArH),7.34(d,J＝8.9Hz,2H,ArH),7.28(s,1H,ArH),7.23(d,J＝8.5Hz,1H,ArH),7.17(s,1H,ArH),7.11(d,J＝8.6Hz,1H,ArH),6.96(d,J＝8.9Hz,2H,ArH),6.40(s,1H,C-CH),3.84(s,3H,ArOCH3)；13C NMR(150MHz,CDCl3):δ＝192.3,180.4,164.2,158.5,157.7,139.9,135.8,134.0,131.9,131.1,129.3,128.6,125.9,122.7,122.3,121.7,121.7,120.4,120.4,117.3,114.9,114.9,109.3,64.5,55.7；HRMS(TOF ES+):m/zcalcd for C25H17Br2N2O5[(M+H)+],582.9499,found,582.9493.
实施例9：不同在于化合物1为(E)-3-(二甲氨基)-1-(2-羟基-4-(噻吩-2-基)苯基)丙-2-烯-1-酮，所得产品3i的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝7:1,Rf＝0.25；黄色固体:22mg产率37％；熔点＝194-195℃；1H NMR(600MHz,CDCl3):δ＝12.03(s,1H,OH),8.23(d,J＝9.7Hz,1H,C＝CH),8.01(s,1H,C＝CH),8.00(d,J＝8.5Hz,1H,C＝CH),7.52(d,J＝2.8Hz,1H,C＝CH),7.43(s,2H,ArH),7.39(d,J＝8.9Hz,2H,ArH),7.37(s,1H,ArH),7.34(d,J＝8.2Hz,2H,ArH),7.24(d,J＝6.7Hz,1H,C＝CH),7.21(s,1H,ArH),7.15(t,J＝3.0Hz,1H,C＝CH),7.11(t,J＝4.5Hz,1H,C＝CH),6.97(d,J＝9.1Hz,2H,ArH),6.45(s,1H,C-CH),3.84(s,3H,ArOCH3)；13C NMR(150MHz,CDCl3):δ＝192.2,180.5,164.4,158.3,157.9,142.5,142.5,142.5,142.3,140.3,136.1,133.9,128.9,128.5,128.4,128.1,127.5,127.1,125.7,125.3,122.1,120.3,120.3,119.8,117.4,116.6,114.8,114.8,114.7,114.5,109.5,64.4,55.7；HRMS(TOF ES+):m/z calcdfor C33H23N2O5S2[(M+H)+],591.1043,found,591.1049.
实施例10：不同在于化合物1为(E)-3-(二甲氨基)-1-(5-氯-2-羟基-4-甲基苯基)丙-2-烯-1-酮，所得产品3j的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝10:1,Rf＝0.25；黄色固体:44mg产率84％；熔点＝200-201℃；1H NMR(600MHz,CDCl3):δ＝11.69(s,1H,OH),8.28(s,1H,C＝CH),7.95(d,J＝19.8Hz,2H,ArH),7.38(d,J＝9.2Hz,2H,ArH),6.97(d,J＝9.8Hz,3H,ArH),6.86(s,1H,ArH),6.34(s,1H,C-CH),3.84(s,3H,ArOCH3),2.42(s,3H,ArCH3),2.37(s,3H,ArCH3)；13C NMR(150MHz,CDCl3):δ＝191.3,179.9,162.2,158.5,155.7,146.4,145.9,139.9,135.9,132.7,129.3,128.5,127.0,124.4,122.3,120.5,120.4,120.4,120.4,117.1,114.8,114.8,109.5,64.1,55.6,20.9,20.9；HRMS(TOF ES+):m/z calcd for C27H21Cl2N2O5[(M+H)+],523.0822,found,523.0829.
实施例11：不同在于化合物1为(E)-3-(二甲氨基)-1-(2-羟基-4,5-二甲基苯基)丙-2-烯-1-酮，所得产品3k的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝10:1,Rf＝0.25；黄色固体:42mg产率87％；熔点＝186-187℃；1H NMR(600MHz,CDCl3):δ＝11.95(s,1H,OH),7.98(s,1H,C＝CH),7.87(s,1H,ArH),7.62(s,1H,ArH),7.37(d,J＝9.0Hz,2H,ArH),7.27(s,1H,ArH),7.19(s,1H,ArH),6.96-6.92(m,2H,ArH),6.29(s,1H,C-CH),3.83(s,3H,ArOCH3),2.32(s,3H,ArCH3),2.30(s,6H,ArCH3),2.07(s,3H,ArCH3)；13C NMR(150MHz,CDCl3):δ＝193.4,181.7,160.1,158.1,153.9,140.6,139.1,138.6,136.2,131.1,130.5,128.8,127.7,127.2,127.1,124.4,122.9,120.1,120.1,117.6,114.7,114.7,109.6,64.2,55.6,20.7,20.6,15.6,15.5；HRMS(TOF ES+):m/zcalcd for C29H27N2O5[(M+H)+],483.1914,found,483.1911.
实施例12：不同在于化合物1为(E)-3-(二甲氨基)-1-(1-羟基萘-2-基)丙-2-烯-1-酮，所得产品3l的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝10:1,Rf＝0.25；黄色固体:48mg产率91％；熔点＝180-181℃；1H NMR(600MHz,CDCl3):δ＝8.57(d,J＝8.3Hz,1H,ArH),8.26(d,J＝8.9Hz,1H,ArH),8.18(s,1H,C＝CH),8.09(d,J＝8.3Hz,1H,ArH),7.99(d,J＝8.8Hz,1H,ArH),7.83-7.78(m,2H,ArH),7.70(t,J＝7.7Hz,1H,ArH),7.60(s,2H,ArH),7.49(d,J＝8.7Hz,1H,ArH),7.45(t,J＝7.7Hz,1H,ArH),7.35(d,J＝8.4Hz,2H,ArH),7.10(s,2H,ArH),6.83(d,J＝8.4Hz,1H,ArH),6.57(s,1H,C-CH),3.84(s,3H,ArOCH3)；13C NMR(150MHz,CDCl3):δ＝192.5,180.8,164.9,160.7,155.7,143.6,140.1,137.8,137.6,130.8,130.5,129.9,128.1,127.8,127.5,126.7,126.5,126.1,125.2,124.9,124.6,123.8,122.0,121.9,118.3,117.9,112.4,112.1,110.1,109.6,104.2,65.1,55.5；HRMS(TOF ES+):m/z calcd for C33H23N2O5[(M+H)+],527.1601,found,527.1597.
实施例13：不同在于化合物1为(E)-3-(二甲氨基)-1-(2-羟基苯基)丙-2-烯-1-酮，所得产品3m的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝10:1,Rf＝0.25；黄色固体:33mg产率82％；熔点＝163-164℃；1H NMR(600MHz,CDCl3):δ＝11.80(s,1H,OH),8.21(d,J＝8.1Hz,1H,ArH),8.10(s,1H,C＝CH),8.00(d,J＝7.9Hz,1H,ArH),7.58(t,J＝7.9Hz,1H,ArH),7.52(t,J＝7.8Hz,1H,ArH),7.45(d,J＝8.1Hz,4H,ArH),7.31-7.27(m,1H,ArH),7.10(d,J＝7.6Hz,2H,ArH),6.99(t,J＝7.2Hz,1H,ArH),6.95(d,J＝8.1Hz,1H,ArH),6.40(s,1H,C-CH)；13C NMR(150MHz,CDCl3):δ＝193.3,181.1,163.9,157.7,142.4,140.7,137.2,136.7,133.3,129.8,129.8,128.5,127.4,126.6,123.4,122.4,119.1,118.6,118.5,118.5,118.3,118.3,109.9,64.2；HRMS(TOF ES+):m/z calcd for C24H17N2O4[(M+H)+],397.1183,found,397.1188.
实施例14：不同在于化合物2为4-甲基苯基重氮四氟硼酸盐，所得产品3n的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝10:1,Rf＝0.25；黄色固体:23mg产率56％；熔点＝175-176℃；1H NMR(600MHz,CDCl3):δ＝11.82(s,1H,OH),8.21(d,J＝7.8Hz,1H,ArH),8.06(s,1H,C＝CH),8.00(d,J＝7.5Hz,1H,ArH),7.58(t,J＝7.5Hz,1H,ArH),7.52(t,J＝7.1Hz,1H,ArH),7.34(d,J＝8.2Hz,2H,ArH),7.23(d,J＝8.1Hz,2H,ArH),7.09(d,J＝8.1Hz,2H,ArH),6.99-6.93(m,2H,ArH),6.41(s,1H,C-CH),2.37(s,3H,ArCH3)；13C NMR(150MHz,CDCl3):δ＝193.2,181.2,163.8,157.6,140.4,140.2,137.1,136.6,136.6,133.3,130.2,130.2,128.6,127.4,123.4,122.3,118.9,118.5,118.5,118.4,118.4,118.4,109.7,64.2,20.9；HRMS(TOF ES+):m/z calcd for C25H19N2O4[(M+H)+],411.1339,found,411.1332.
实施例15：不同在于化合物2为3,5-二甲基苯基重氮四氟硼酸盐，所得产品3o的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝10:1,Rf＝0.25；黄色固体:29mg产率70％；熔点＝166-167℃；1H NMR(600MHz,CDCl3):δ＝11.83(s,1H,OH),8.23(d,J＝7.8Hz,1H,ArH),8.05(s,1H,C＝CH),8.00(d,J＝7.5Hz,1H,ArH),7.57(t,J＝7.5Hz,1H,ArH),7.51(t,J＝7.3Hz,1H,ArH),7.23(s,1H,ArH),7.18(s,2H,ArH),7.10(t,J＝7.7Hz,2H,ArH),6.98(t,J＝7.6Hz,1H,ArH),6.94(d,J＝8.3Hz,1H,ArH),6.40(s,1H,C-CH),2.30(s,3H,ArCH3),2.27(s,3H,ArCH3)；13CNMR(150MHz,CDCl3):δ＝193.3,181.2,163.8,157.6,140.4,140.3,138.2,137.1,136.6,135.3,133.4,130.6,128.8,127.3,123.39,122.3,119.6,118.9,118.5,118.5,118.4,115.9,109.6,64.3,20.1,19.3；HRMS(TOF ES+):m/z calcd for C26H21N2O4[(M+H)+],425.1496,found,425.1496.
实施例16：不同在于化合物2为3,5-二甲氧基苯基重氮四氟硼酸盐，所得产品3p的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝10:1,Rf＝0.25；黄色固体:33mg产率72％；熔点＝130-131℃；1H NMR(600MHz,CDCl3):δ＝11.84(s,1H,OH),8.27(d,J＝9.0Hz,1H,ArH),7.99(d,J＝7.7Hz,1H,ArH),7.85(s,1H,C＝CH),7.56-7.49(m,2H,ArH),7.10-7.05(m,2H,ArH),6.97-6.92(m,4H,ArH),6.89-6.86(m,1H,ArH),6.41(s,1H,C-CH),3.88(s,3H,ArOCH3),3.77(s,3H,ArOCH3)；13C NMR(150MHz,CDCl3):δ＝193.4,181.3,163.8,157.7,153.7,146.5,140.4,137.0,136.5,133.5,132.8,132.0,127.4,123.6,122.2,118.8,118.6,118.5,118.4,114.3,113.2,111.0,108.1,63.9,56.4,55.9；HRMS(TOF ES+):m/z calcd for C26H21N2O6[(M+H)+],457.1394,found,457.1398.
实施例17：不同在于化合物2为2-(苄氧基)苯基重氮四氟硼酸盐，所得产品3q的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝8:1,Rf＝0.25；黄色固体:18mg产率35％；熔点＝200-201℃；1H NMR(600MHz,CDCl3):δ＝8.30(d,J＝7.5Hz,1H,ArH),8.09(s,1H,C＝CH),8.03(d,J＝7.3Hz,1H,ArH),7.70(t,J＝7.4Hz,1H,ArH),7.57(d,J＝7.4Hz,2H,ArH),7.49(d,J＝8.4Hz,2H,ArH),7.44(t,J＝7.6Hz,3H,ArH),7.37-7.32(m,2H,ArH),7.11(t,J＝7.5Hz,1H,ArH),7.00(d,J＝8.2Hz,1H,ArH),6.90(d,J＝6.9Hz,2H,ArH),6.84-6.80(m,1H,ArH),6.57(s,1H,C-CH),5.25(s,2H,CH2)；13C NMR(150MHz,CDCl3):δ＝178.3,176.1,159.1,156.3,154.9,146.0,136.7,135.8,133.9,132.3,128.8,128.7,128.7,127.9,127.6,126.9,126.9,126.2,125.5,124.1,123.5,123.2,122.9,122.4,121.7,118.3,118.3,113.9,112.4,75.5,70.4；HRMS(TOF ES+):m/z calcd for C31H23N2O5[(M+H)+],503.1601,found,503.1604.
实施例18：不同在于化合物2为2-氟苯基重氮四氟硼酸盐，所得产品3r的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝10:1,Rf＝0.25；黄色固体:16mg产率39％；熔点＝202-203℃；1H NMR(600MHz,CDCl3):δ＝11.78(s,1H,OH),8.21(d,J＝7.3Hz,1H,ArH),7.99(d,J＝6.9Hz,1H,ArH),7.84(s,1H,C＝CH),7.56(t,J＝7.6Hz,1H,ArH),7.52(t,J＝7.7Hz,1H,ArH),7.44(t,J＝7.7Hz,1H,ArH),7.34(q,J＝7.2Hz,1H,ArH),7.26-7.20(m,2H,ArH),7.11-7.06(m,2H,ArH),6.98-6.93(m,2H,ArH),6.40(s,1H,C-CH)；13C NMR(150MHz,CDCl3):δ＝193.2,180.92,163.9,157.7,155.0(C-F,J＝251.3Hz),141.1,137.3,136.6,133.3,131.5(C-F,J＝5.1Hz),130.9(C-F,J＝9.6Hz),129.3(C-F,J＝7.7Hz),127.4,125.1(C-F,J＝3.9Hz),124.9,123.4,122.4,119.1,118.5,118.4,118.4,117.3(C-F,J＝19.9Hz),109.1,63.8；HRMS(TOF ES+):m/z calcd for C24H16FN2O4[(M+H)+],415.1089,found,415.1090.
实施例19：不同在于化合物2为3-氯苯基重氮四氟硼酸盐，所得产品3s的结构、形态、熔点、核磁、高分辨质谱数据如下，化合物3s的单晶结构图见图1；
V石油醚/V乙酸乙酯＝10:1,Rf＝0.25；黄色固体:35mg产率81％；熔点＝215-216℃；1H NMR(600MHz,CDCl3):δ＝8.30(d,J＝7.6Hz,1H,ArH),8.13(s,1H,C＝CH),8.00(d,J＝7.5Hz,1H,ArH),7.72(t,J＝7.3Hz,1H,ArH),7.52(t,J＝8.0Hz,2H,ArH),7.46(t,J＝7.6Hz,1H,ArH),7.16-7.11(m,3H,ArH),7.03(d,J＝8.2Hz,1H,ArH),6.93(d,J＝7.0Hz,2H,ArH),6.48(s,1H,C-CH)；13C NMR(150MHz,CDCl3):δ＝179.2,176.1,159.5,156.3,154.6,143.7,136.4,135.3,134.1,130.3,129.3,127.5,126.2,125.6,124.0,123.4,122.8,122.7,122.6,118.3,118.3,114.7,112.9,75.8；HRMS(TOF ES+):m/z calcd for C24H16ClN2O4[(M+H)+],431.0793,found,437.0787.
实施例20：不同在于化合物2为4-氯苯基重氮四氟硼酸盐，所得产品3t的结构、形态、熔点、核磁、高分辨质谱数据如下；
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V石油醚/V乙酸乙酯＝10:1,Rf＝0.25；黄色固体:34mg产率78％；熔点＝194-195℃；1H NMR(600MHz,CDCl3):δ＝11.75(s,1H,OH),8.15(d,J＝7.6Hz,1H,ArH),8.05(s,1H,C＝CH),7.99(d,J＝7.1Hz,1H,ArH),7.61-7.58(m,1H,ArH),7.53-7.50(m,1H,ArH),7.40(s,4H,ArH),7.13-7.09(m,2H,ArH),7.00-6.97(m,1H,ArH),6.94(d,J＝8.2Hz,1H,ArH),6.37(s,1H,C-CH)；13C NMR(150MHz,CDCl3):δ＝193.1,180.9,163.9,157.7,140.9,137.3,136.7,133.1,131.9,129.8,129.8,127.9,127.4,123.2,122.4,119.3,119.3,119.1,118.6,118.5,118.4,115.8,110.0,64.1；HRMS(TOF ES+):m/z calcd for C24H16ClN2O4[(M+H)+],431.0793,found,431.0793.
实施例21：不同在于化合物2为3-溴苯基重氮四氟硼酸盐，所得产品3u的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝10:1,Rf＝0.25；黄色固体:42mg产率88％；熔点＝174-175℃；1H NMR(600MHz,CDCl3):δ＝11.75(s,1H,OH),8.15(d,J＝7.7Hz,1H,ArH),8.06(s,1H,C＝CH),8.00(d,J＝7.5Hz,1H,ArH),7.64(s,1H,ArH),7.62-7.58(m,1H,ArH),7.54-7.51(m,1H,ArH),7.40(d,J＝7.3Hz,2H,ArH),7.32-7.29(m,1H,ArH),7.11(d,J＝6.7Hz,2H,ArH),7.02-6.99(m,1H,ArH),6.95(d,J＝8.1Hz,1H,ArH),6.37(s,1H,C-CH)；13C NMR(150MHz,CDCl3):δ＝193.0,180.9,163.9,157.7,143.3,141.1,137.4,136.7,133.1,130.9,129.4,127.8,127.4,123.4,123.2,122.5,121.3,119.1,118.5,118.5,118.4,116.5,110.2,64.1；HRMS(TOF ES+):m/z calcd for C24H16BrN2O4[(M+H)+],475.0288,found,475.0294.
实施例22：不同在于化合物2为3-氰基苯基重氮四氟硼酸盐，所得产品3v的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝5:1,Rf＝0.25；黄色固体:37mg产率89％；熔点＝186-187℃；1H NMR(600MHz,CDCl3):δ＝8.29(d,J＝7.8Hz,1H,ArH),8.16(s,1H,C＝CH),8.00(d,J＝7.7Hz,1H,ArH),7.73(t,J＝7.7Hz,1H,ArH),7.53(t,J＝8.3Hz,2H,ArH),7.48(t,J＝7.4Hz,1H,ArH),7.34(s,1H,ArH),7.30(t,J＝7.9Hz,1H,ArH),7.24-7.21(m,2H,ArH),7.14(t,J＝7.4Hz,1H,ArH),7.03(d,J＝8.2Hz,1H,ArH),6.43(s,1H,C-CH)；13C NMR(150MHz,CDCl3):δ＝178.4,174.9,158.7,155.3,153.6,142.3,135.6,133.2,129.4,129.1,126.6,125.5,124.9,124.8,122.9,121.6,121.5,121.5,117.7,117.4,117.3,117.2,116.4,112.3,74.9；HRMS(TOF ES+):m/z calcd for C25H16N3O4[(M+H)+],422.1135,found,422.1129.
实施例23：不同在于化合物2为2-(4-氟苯甲酰基)苯基重氮四氟硼酸盐，所得产品3w的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝7:1,Rf＝0.25；黄色固体:21mg产率40％；熔点＝203-204℃；1H NMR(600MHz,CDCl3):δ＝8.30(d,J＝7.6Hz,1H,ArH),8.13(d,J＝7.8Hz,1H,ArH),8.11(s,1H,C＝CH),7.80-7.77(m,2H,ArH),7.71(d,J＝7.3Hz,1H,ArH),7.65(d,J＝8.3Hz,1H,ArH),7.52-7.44(m,4H,ArH),7.37(t,J＝7.5Hz,1H,ArH),7.16-7.09(m,3H,ArH),7.01(d,J＝8.2Hz,1H,ArH),6.96(t,J＝7.3Hz,1H,ArH),6.56(s,1H,C-CH)；13C NMR(150MHz,CDCl3):δ＝196.30,178.16,175.98,165.15(C-F,J＝253.8Hz),159.47,156.34,154.77,144.84,136.28,134.95(C-F,J＝3.0Hz),134.06(C-F,J＝14.6Hz),133.14,132.63(C-F,J＝9.1Hz),131.23,128.17,126.15,125.55,124.04,122.87(C-F,J＝26.9Hz),122.57,121.24,121.12,118.30,118.27,115.33(d,J＝21.8Hz),115.31,75.78；HRMS(TOF ES+):m/z calcd for C31H20FN2O5[(M+H)+],519.1351,found,519.1353.
实施例24：不同在于化合物2为(-)-樟脑酸衍生重氮四氟硼酸盐，所得产品3x的结构、形态、熔点、核磁、高分辨质谱数据如下；
V石油醚/V乙酸乙酯＝5:1,Rf＝0.25；黄色固体:20mg产率33％；熔点＝196-198℃；1H NMR(600MHz,CDCl3):δ＝13.97(s,1H,OH),8.28(d,J＝7.9Hz,1H,ArH),8.12(s,1H,NH),8.04(s,1H,C＝CH),7.99(d,J＝7.8Hz,1H,ArH),7.72(s,1H,ArH),7.53-7.42(m,4H,ArH),7.16-6.99(m,5H,ArH),6.50(s,1H,C-CH),2.58(d,J＝8.9Hz,1H,CH2),1.98(t,J＝11.6Hz,2H,CH2),1.74(d,J＝11.3Hz,1H,CH2),1.14(s,6H,CH3),0.95(s,3H,CH3)；13C NMR(150MHz,CDCl3):δ＝178.8,177.9,175.9,164.9,159.3,156.3,154.7,139.4,136.1,133.9,132.6,128.4,127.4,126.1,125.5,123.9,122.9,122.7,122.5,121.0,121.0,118.2,118.2,115.2,115.2,92.4,75.5,55.4,54.4,30.4,29.0,16.7,16.6,9.7；HRMS(TOF ES+):m/zcalcd for C34H30N3O7[(M+H)+],592.2078,found,592.2077.
实施例25：体外抗冠状病毒活性实验
盐酸阿比多尔片剂(ARB,0.1g/片)(欧意制药有限公司)，主要适应症是A类、B类流感病毒引起的流行性感冒，同时对其他一些呼吸道病毒感染可能也有抗病毒活性；
HCoV-OC43细胞(由昆明理工大学生命科学与技术学院夏雪山分子病毒学课题组培养)；
本发明实施例制备的试验药品作体外抗冠状病毒药效评价试验，步骤参考文献Phytomedicine,2021,93,153808.；选择代表性色酮并哒嗪类化合物进行了抗冠状病毒测试，结果见表1；
表1抗冠状病毒活性测试
由表1可以看出，化合物3b和3g表现出较高的抗冠状病毒活性，相较市场上抗对照药阿比多尔的抗病毒活性近似，而且细胞毒性更低，可以用于开发治疗、预防、缓解由冠状病毒引起的相关疾病的药物。
Claims (9)
1.结构式如下式所示的色酮并哒嗪类化合物：
其中，Ar1选自取代或未取代芳基，取代基为烷基、烷氧基、卤素、芳基、杂芳基；Ar2选自取代或未取代芳基，取代基为烷基、烷氧基、苄氧基、卤素、氰基、苯甲酰基、酰胺。
2.根据权利要求1所述的色酮并哒嗪类化合物，其特征在于，化合物为如下任一结构：
3.根据权利要求1所述的色酮并哒嗪类化合物，其特征在于：还包括色酮并哒嗪类化合物药学上可接受的盐、立体异构体。
4.权利要求1所述的色酮并哒嗪类化合物的合成方法，其特征在于：在溶剂存在条件下，邻羟基芳基烯胺酮、芳基重氮盐在25℃～70℃下反应，薄层色谱监测反应进程，直至反应完全；然后用乙酸乙酯和水萃取3～4次，收集合并有机相并用饱和食盐水洗涤，收集有机相后用无水硫酸钠干燥，减压浓缩，浓缩物用硅胶柱层析或者重结晶分离纯化得到色酮并哒嗪类化合物；
5.根据权利要求4所述的色酮并哒嗪类化合物的合成方法，其特征在于：合成时还添加添加剂，添加剂选自二氟乙酸、三氟乙酸、正丁酸、乙酸、氰基乙酸、异丁酸、丙二酸、对甲苯磺酸、三氟甲磺酸、丁二酸酐、异丁酸酐、苯甲酸酐、乙酸酐、三氟乙酸酐、丙酸酐、正戊酸酐，邻羟基芳基烯胺酮与添加剂的摩尔比为2:1～3。
6.根据权利要求4所述的色酮并哒嗪类化合物的合成方法，其特征在于：溶剂选自1,4-二氧六环、二甲基亚砜、乙腈、甲苯、丙酮、二甲苯、二氯甲烷中。
7.根据权利要求4所述的色酮并哒嗪类化合物的合成方法，其特征在于：邻羟基芳基烯胺酮与芳基重氮盐的摩尔比为2～4:1。
8.根据权利要求4所述的色酮并哒嗪类化合物的合成方法，其特征在于：反应在惰性气氛、空气气氛或氧气气氛下进行。
9.权利要求1所述的色酮并哒嗪类化合物在制备抑制冠状病毒制剂中的应用。
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