CN110357901A - 芳香环乙烯基噻吩并嘧啶类化合物和制剂、该化合物的制备方法及应用 - Google Patents
芳香环乙烯基噻吩并嘧啶类化合物和制剂、该化合物的制备方法及应用 Download PDFInfo
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- CN110357901A CN110357901A CN201910689660.8A CN201910689660A CN110357901A CN 110357901 A CN110357901 A CN 110357901A CN 201910689660 A CN201910689660 A CN 201910689660A CN 110357901 A CN110357901 A CN 110357901A
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Abstract
本发明公开了一种芳香环乙烯基噻吩并嘧啶类化合物和制剂、该化合物的制备方法及应用，涉及抗炎类化合物技术领域，包含如下式A、式B和式C三种结构；本发明所述化合物具有良好的抗炎活性，在各种急慢性炎症的治疗中体现出良好的应用前景，在对如脓毒血症等急性炎症和以Ⅱ型糖尿病、阿尔海默茨病和动脉粥样硬化症为代表的慢性炎症的治疗中体现了良好的应用潜力。
Description
技术领域：
本发明涉及抗炎类化合物技术领域，具体涉及一种芳香环乙烯基噻吩并嘧啶类化合物和制剂、该化合物的制备方法及应用。
背景技术：
二苯乙烯的多种衍生物表现出一系列的生理活性，代表性化合物有白藜芦醇(Resveratrol)、己烯雌酚(Diethylstilbestrol)、紫檀芪(Pterostilbene)及奥培米芬(Ospemifene)等，其相应结构式分别如下：
其中，白藜芦醇(3，4’，5-三羟基二苯乙烯)具有预防心脏病，抑制血小板凝聚，调控脂质和脂蛋白代谢，抗氧化及对癌症的治疗等作用；己烯雌酚是人工合成的非甾体雌激素物质，能产生与天然雌二醇相同的所有药理与治疗作用；奥培米芬是托瑞米芬的活性代谢产物之一，也是新型选择性雌激素受体调节剂，既具有雌激素作用，也具有抗雌激素作用，表现为组织选择性。二苯乙烯衍生物多具有抗氧化、抗炎、抗肿瘤等多种药理活性。
综上所述，基于二苯乙烯的骨架结构修饰具有潜在意义。
噻吩和嘧啶类衍生物是具有广泛生物学活性的结构骨架，事实上，通过将这两种杂环骨架通过杂环融合设计得到的噻吩并嘧啶衍生物也具有广泛的生物活性。
噻吩并嘧啶是具有吸引力的稠合基团之一。很多文献研究报道的活性物质，其核心结构含有噻吩并嘧啶骨架，如Jeremy S.Disch,Ghotas Evindar等人用DNA编码分子库技术从120万杂环富集文库编码的小分子中筛选出的具有高效抗疟效果6-芳基噻吩并嘧啶片段。Dongwei Kang,Zengjun Fang等人通过基于结构的分子杂交策略和取代基修饰噻吩并嘧啶得到的高效的HIV-1抑制剂。
正是由于这种广泛的生物活性存在，药物化学家合成了大量的杂环拼合嘧啶衍生物。目前已知的几种稠合嘧啶衍生物，如吡唑并嘧啶，吡咯并嘧啶，噻唑并嘧啶和咪唑并嘧啶已显示出良好的抗菌活性。
基于噻吩并嘧啶骨架的结构修饰具有重要潜在的药用价值，因此，合成一种乙烯基噻吩并嘧啶类化合物，提供一种高效抗炎药物，对于开发抗炎药物的意义重大。
发明内容：
本发明所要解决的技术问题在于提供一种芳香环乙烯基噻吩并嘧啶类化合物，该化合物能够应用于制备抗炎药物，显示出良好的抗炎活性。
本发明所要解决的技术问题采用以下的技术方案来实现：
一种芳香环乙烯基噻吩并嘧啶类化合物，包含如下式A、式B和式C三种结构：
其中，
R2和R3选自氢、烷基、取代烷基、烷氧基、取代烷氧基、环烷基、取代环烷基、哌嗪基、取代哌嗪基、苯基取代苯基中的任意一种基团；
R4选自氢、烷基、取代烷基、烷氧基、取代烷氧基、环烷基、取代环烷基、哌嗪基、取代哌嗪基、苯基取代苯基中的任意一种基团；式B中X＝C、N、O或S，n＝1或2；
R5、R6、R7选自H、卤素、C1-C5烷基、硝基、C1-C3烷氧基、苯基、苯氧基、羟基、乙酰胺基、三氟甲基中的任意一种基团；式C中X＝O或C，Y＝N或C，m＝1或2，n＝0、1或2。
上述芳香环乙烯基噻吩并嘧啶类化合物的制备方法为：将芳香环基丙烯酸化合物I制酰氯得到中间体II，中间体II和氨基噻吩反应制得中间体III；中间体III在碱性条件下水解得到中间体IV，中间体IV制酰氯得到中间体V，中间体V和氨水反应得到中间体VI，中间体VI在碱性条件下经关环缩合得到中间体VII，中间体VII经氯化反应制得中间体VIII，中间体VIII和相应胺的衍生物经取代反应即得芳香环乙烯基噻吩并嘧啶类化合物，具体合成路线如下：
所述相应胺的衍生物选自对氨基酚、环丙胺、吗啉、2-氯苯乙胺、2-氯苄胺、2-甲氧基苄胺、3-甲氧基苄胺、4-甲氧基苄胺、4-溴苄胺、4-氟苄胺、4-甲氨基吡啶、N-吗啉基苯胺、糠胺、异丙胺、仲丁胺、4-三氟甲基苄胺、正丁胺中的任意一种。
上述芳香环乙烯基噻吩并嘧啶类化合物的结构式为：
上述化合物在制备抗炎药物中的应用。
本发明的有益效果是：
(1)本发明采用基于结构片段的药物设计方法，设计合成新型芳香环乙烯基噻吩并嘧啶类化合物，测定该组化合物的抗炎活性，并将这些化合物应用于开发抗炎药物及其制剂。
(2)本发明所述芳香环乙烯基噻吩并嘧啶类化合物的制备方法简单，操作方便，并对所有化合物进行了结构表征。
(3)本发明所述芳香环乙烯基噻吩并嘧啶类化合物具有良好的抗炎活性，在各种急慢性炎症的治疗中体现出良好的应用前景，在对如脓毒血症等急性炎症和以Ⅱ型糖尿病、阿尔海默茨病和动脉粥样硬化症为代表的慢性炎症的治疗中体现了良好的应用潜力。
具体实施方式：
为了使本发明实现的技术手段、创作特征、达成目的与功效易于明白了解，下面结合具体实施例，进一步阐述本发明。
实施例1
中间体1-VIII的制备
1.1中间体1-II制备：
在0℃下向含有溶解在二氯甲烷(15mL)中的中间体1-I肉桂酸(1g，6.75mmol)和DMF(0.05mL，0.65mmol)的溶液中滴加草酰氯(1.15mL，13.50mmol)。在室温下搅拌反应混合物后。保持3h，将溶液在减压下浓缩，得到相应的1-II。
1.2中间体1-III制备：
在0℃下，向溶解在二氯甲烷(10mL)中的由3-胺基-2-噻吩甲酸甲酯(1.06g，6.75mmol)和三乙胺(0.94mL，6.8mmol)组成的溶液中滴加预先溶解的二氯甲烷(10mL)的相应中间体1-II(1.12g，6.75mmol)的溶液。在室温下搅拌3h后，将混合物用饱和柠檬酸洗涤三次。然后将合并的有机层用无水硫酸钠干燥，然后在减压下浓缩。然后将残余物用乙醇结晶，得到纯产物中间体1-III。
1.3中间体1-IV制备：
将得到的中间体1-III(1g，3.48mmol)溶解在甲醇(15mL)中。加入5N氢氧化钠溶液，并将反应加热至60℃。反应2h后，通过加入2N盐酸将pH值调节至1。在减压下除去有机溶剂后，抽滤得到产物中间体1-IV。
1.4中间体1-V制备：
在0℃下，向含有溶解在二氯甲烷(20mL)中的中间体1-IV(1g，3.66mmol)和DMF(0.05mL，0.65mmol)的溶液中滴加草酰氯(0.62mL，7.32mmol)。在室温下搅拌反应混合物后。保持3h，将溶液在减压下浓缩，得到相应的酰氯中间体1-V。
1.5中间体1-VI制备：
在0℃下，向氨水(8mL，208mmol)中滴加预先溶解的丙酮(20mL)的相应中间体1-V(1g，3.43mmol)的溶液。在室温下搅拌3h后，减压下除去有机溶剂后，通过加入2N盐酸酸化pH至6-7，过滤干燥得到纯产物中间体1-VI。
1.6中间体1-VII制备：
在90℃下，向溶解在甲醇中的中间体1-VI(1g，3.67mmol)滴加甲醇钠溶液(5mL)，回流3h，在减压下除去有机溶剂后，通过加入2N盐酸酸化pH至5-6，过滤干燥得到纯产物中间体1-VII。
1.7中间体1-VIII制备：
向装有磁力搅拌和回流冷凝器的圆底烧瓶中放入三氯氧磷(5mL，53.75mmol)，中间体VII(1g，3.93mmol)。隔绝湿气条件下，反应约6-12h，TLC监控；反应完成后，冷却至室温，然后将反应溶液倾入约50g冰水混合物中，充分搅拌待碎冰完全消失，用乙酸乙酯萃取，有机层用水，饱和碳酸氢钠洗涤，干燥，浓缩干，即得中间体1-VIII。
实施例2
(E)-N-(4-氟苄基)-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-1所示)的制备
反应瓶中，加入中间体1-VIII(100mg，0.37mmol)(制备方法见实施例1)，加入10mL异丙醇，再加入4-氟苄胺(0.37mmol)，回流反应约6-12h，TLC监控，反应完成后，冷却至室温，减压浓缩至干，用异丙醇重结晶，得到白色固体，即(E)-N-(4-氟苄基)-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺。结构数据表征：1H NMR(600MHz,DMSO-d6)δ10.27(s,1H),8.43(d,J＝5.4Hz,1H),8.21(d,J＝15.8Hz,1H),7.75(d,J＝6.9Hz,2H),7.56–7.46(m,6H),7.27(dd,J＝15.8,2.0Hz,1H),7.23–7.19(m,2H),4.94(d,J＝5.8Hz,2H).HR-MS:calcd for C21H16FN3S[M+H]+,334.1350；found 334.1350.
实施例3
(E)-N-(4-甲氧基苯基)-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-2所示)的制备
采取化合物1-1同样的合成方法。结构数据表征：1H NMR(600MHz,DMSO-d6)δ11.21(s,1H),8.43(s,1H),8.05(d,J＝15.7Hz,1H),7.74–7.60(m,4H),7.57(d,J＝4.5Hz,1H),7.47–7.50(m,3H),7.32(d,J＝15.8Hz,1H),7.09(d,J＝8.6Hz,2H),3.82(s,3H).HR-MS:calcd for C21H17N3OS[M+H]+,348.1165；found 348.1165.
实施例4
(E)-N-甲基-N-苯基-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-3所示)的制备
采取化合物1-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ8.32(d,J＝15.8Hz,1H),7.87(d,J＝5.5Hz,1H),7.76–7.73(m,2H),7.65–7.78(m,2H),7.63–7.58(m,3H),7.46–7.41(m,5H),3.84(s,3H).HR-MS:calcd for C21H17N3S[M+H]+,332.1216；found 332.1216.
实施例5
(E)-N-(甲基哌嗪-1-基)-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-4所示)的制备
采取化合物1-1同样的合成方法。结构数据表征：1H NMR(600MHz,DMSO-d6)δ8.28(d,J＝5.4Hz,1H),7.92(d,J＝15.9Hz,1H),7.72(d,J＝7.9Hz,2H),7.50(d,J＝5.4,1H),7.42(t,J＝7.6Hz,2H),7.35(t,J＝7.3Hz,1H),7.18(d,J＝15.9Hz,1H),3.35(d,8H),2.74(s,3H).HR-MS:calcd for C19H20FN4S[M+H]+,325.1481；found 325.1481.
实施例6
(E)-N-苯基-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-5所示)的制备
采取化合物1-1同样的合成方法。结构数据表征：1H NMR(600MHz,DMSO-d6)δ11.31(s,1H),8.48(d,J＝4.5Hz,1H),8.04(d,J＝15.8Hz,1H),7.80(d,J＝4.4Hz,2H),7.69(d,J＝7.0Hz,2H),7.60(d,J＝5.4Hz,1H),7.46–7.54(m,5H),7.35(d,J＝15.8Hz,2H).HR-MS:calcd for C20H15N3S[M+H]+,318.1059；found 318.1059.
实施例7
(E)-N-(4-溴苯基)-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-6所示)的制备
采取化合物1-1同样的合成方法。结构数据表征：1H NMR(600MHz,DMSO-d6)δ11.17(s,1H),8.48(d,J＝5.3Hz,1H),8.01(d,J＝15.9Hz,1H),7.84(d,J＝7.7Hz,2H),7.71–7.74(m,4H),7.60(d,J＝5.4Hz,1H),7.46–7.51(m,3H),7.32(d,J＝15.9Hz,1H).HR-MS:calcdfor C20H14BrN3S[M+H]+,396.0165；found 396.0165.
实施例8
(E)-N-(4-溴苄基)-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-7所示)的制备
采取化合物1-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.93(d,J＝15.9Hz,1H),7.70(d,J＝5.3Hz,1H),7.61(d,J＝7.5Hz,2H),7.47–7.36(m,5H),7.36–7.29(m,3H),7.21(d,J＝15.9Hz,1H),5.24(t,J＝4.4Hz,1H),4.94(d,J＝5.7Hz,2H).HR-MS:calcd for C21H18BrN3S[M+H]+,411.0399；found 411.0399.
实施例9
(E)-N-异丙基-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-8所示)的制备
采取化合物1-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.95(d,J＝15.9Hz,1H),7.67(d,J＝5.3Hz,1H),7.63(d,J＝7.6Hz,2H),7.42–7.36(m,3H),7.30(t,J＝7.3Hz,1H),7.21(d,J＝15.9Hz,1H),4.73(d,J＝7.1Hz,1H),4.70–4.62(m,1H),1.38(d,J＝6.4Hz,6H).HR-MS:calcd for C17H19N3S[M+H]+,285.1294；found 285.1294.
实施例10
(E)-N-吗啉-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-9所示)的制备
采取化合物1-1同样的合成方法。结构数据表征：1H NMR(600MHz,DMSO-d6)δ8.55(d,J＝5.5Hz,1H),8.23(d,J＝15.9Hz,1H),7.75(d,J＝7.0Hz,2H),7.63(d,J＝5.5Hz,1H),7.53–7.45(m,3H),7.28(d,J＝15.9Hz,1H),4.19(t,J＝4.2Hz,4H),3.86(t,J＝4.8Hz,4H).HR-MS:calcd for C18H19N3OS[M+H]+,323.4162；found 323.4162。
实施例11
(E)-N-(4-氟苯乙基)-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-10所示)的制备
采取化合物1-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.99(d,J＝15.9Hz,1H),7.67(d,J＝5.3Hz,1H),7.63(d,J＝7.7Hz,2H),7.45–7.37(m,3H),7.32(t,J＝7.3Hz,1H),7.27–7.20(m,3H),7.03(t,J＝8.6Hz,2H),4.91(s,1H),3.98(q,J＝6.7Hz,2H),3.05(t,J＝7.1Hz,2H).HR-MS:calcd for C22H18FN3S[M+H]+,364.1278；found364.1278.
实施例12
(E)-N-(2-氟苯乙基)-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-11所示)的制备
采取化合物1-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ8.01(d,J＝15.9Hz,1H),7.67(d,J＝5.3Hz,1H),7.64(d,J＝7.3Hz,2H),7.42–7.37(m,3H),7.31(t,J＝7.3Hz,1H),7.28–7.19(m,3H),7.12–7.05(m,2H),5.00(s,1H),4.01(q,J＝6.8Hz,2H),3.13(t,J＝7.1Hz,2H).HR-MS:calcd for C22H18FN3S[M+H]+,364.1278；found364.1278.
实施例13
(E)-N-(3-溴苯基)-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-12所示)的制备
采取化合物1-1同样的合成方法。结构数据表征：1H NMR(600MHz,DMSO-d6)δ11.14(s,1H,NH),8.48(d,J＝5.4Hz,1H,ArH),8.35(s,1H,ArH),8.01(d,J＝15.8Hz,1H,＝CH),7.79(s,1H,ArH),7.71(d,J＝7.7Hz,2H,ArH),7.59(d,J＝5.4Hz,1H,ArH),7.46-7.52(m,5H,ArH),7.33(d,J＝15.8Hz,1H,＝CH).HR-MS:calcd for C22H18FN3S[M+H]+,396.0165；found 396.0165.
实施例14
(E)-N-(2-氯苄基)-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-13所示)的制备
采取化合物1-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.97(d,J＝15.9Hz,1H),7.69(d,J＝5.3Hz,1H),7.63(d,J＝7.5Hz,2H),7.57(dd,J＝5.6,3.7Hz,1H),7.43–7.37(m,4H),7.32(t,J＝7.3Hz,1H),7.26–7.20(m,3H),5.38(s,1H),5.06(d,J＝6.0Hz,2H).HR-MS:calcd for C23H25ClN5O[M+H]+,366.0826；found 366.0826.
实施例15
(E)-N-(3-甲氧基苄基)-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-14所示)的制备
采取化合物1-1同样的合成方法。结构数据表征：1H NMR(600MHz,DMSO-d6)δ10.17(s,1H,NH),8.42(d,J＝5.4Hz,1H,ArH),8.19(d,J＝15.8Hz,1H,＝CH),7.75(d,J＝7.0Hz,2H,ArH),7.56–7.45(m,4H,ArH),7.29(t,J＝7.9Hz,1H,ArH),7.24(d,J＝15.8Hz,1H,＝CH),7.10(s,1H,ArH),7.05(d,J＝7.7Hz,1H,ArH),6.86(dd,J＝8.2,2.4Hz,1H,ArH),4.92(d,J＝5.8Hz,2H,ArH),3.73(s,3H,CH3).HR-MS:calcd for C22H18FN3S[M+H]+,362.1322；found362.1322.
实施例16
(E)-N-甲基-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-15所示)的制备
采取化合物1-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.99(d,J＝15.9Hz,1H),7.67(d,J＝5.3Hz,1H),7.63(d,J＝7.4Hz,2H),7.41(d,J＝5.3Hz,1H),7.38(t,J＝7.6Hz,2H),7.31(t,J＝7.3Hz,1H),7.22(d,J＝15.9Hz,1H),3.29(d,J＝4.9Hz,3H).HR-MS:calcd for C22H18FN3S[M+H]+,269.0981；found 269.0981.
实施例17
(E)-N,N-二甲基-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-16所示)的制备
采取化合物1-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.93(d,J＝15.9Hz,1H),7.70(d,J＝5.5Hz,1H),7.62(d,J＝7.7Hz,2H),7.42–7.35(m,3H),7.30(t,J＝7.3Hz,1H),7.18(d,J＝15.9Hz,1H),3.48(s,6H).HR-MS:calcd for C22H18FN3S[M+H]+,283.1138；found283.1138.
实施例18
(E)-N-正丁基-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-17所示)的制备
采取化合物1-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.96(d,J＝15.9Hz,1H),7.67(d,J＝5.3Hz,1H),7.63(d,J＝7.5Hz,2H),7.41(d,J＝5.3Hz,1H),7.38(t,J＝7.6Hz,2H),7.30(t,J＝7.3Hz,1H),7.21(d,J＝15.9Hz,1H),4.90(s,1H),3.76(dd,J＝13.0,7.1Hz,2H),1.76–1.71(m,2H),1.54–1.46(m,2H),1.02(t,J＝7.4Hz,3H).HR-MS:calcd for C18H19N3S[M+H]+,310.1372；found 310.1372.
实施例19
(E)-N-异丁基-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-18所示)的制备
采取化合物1-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.95(d,J＝15.9Hz,1H),7.68(d,J＝5.3Hz,1H),7.63(d,J＝7.5Hz,2H),7.42(d,J＝5.3Hz,1H),7.38(t,J＝7.6Hz,2H),7.31(t,J＝7.3Hz,1H),7.20(d,J＝15.9Hz,1H),4.96(s,1H),3.58(t,J＝6.4Hz,2H),2.06(dt,J＝13.4,6.7Hz,1H),1.06(d,J＝6.7Hz,6H).HR-MS:calcdfor C18H19N3S[M+H]+,310.1372；found 310.1372.
实施例20
(E)-N-(三氟甲基苯基)-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式1-19所示)的制备
采取化合物1-1同样的合成方法。结构数据表征：1H NMR(600MHz,DMSO-d6)δ11.04(s,1H,NH),8.48(d,J＝5.4Hz,1H,ArH),8.17(d,J＝8.4Hz,2H,ArH),8.01(d,J＝15.9Hz,1H,＝CH),7.88(d,J＝8.6Hz,2H,ArH),7.76(d,J＝7.3Hz,2H,ArH),7.60(d,J＝5.4Hz,1H,ArH),7.44–7.50(m,3H,ArH),7.33(d,J＝15.9Hz,1H,＝CH).HR-MS:calcd for C18H19N3S[M+H]+,398.0933；found 398.0933.
实施例21
采取实施例1中中间体1-VIII同样的方法制备呋喃乙烯基噻吩并嘧啶类中间体2-VIII。
实施例22
(E)-N-甲基-5-(2-(呋喃-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式2-1所示)的制备
反应瓶中，加入中间体2-VIII(100mg，0.38mmol)(制备方法见实施例3)，加入10mL异丙醇，再加入甲胺(0.37mmol)，回流反应约6-12h，TLC监控，反应完成后，冷却至室温，减压浓缩至干，残余物经柱层析纯化，洗脱剂为石油醚：乙酸乙酯(4:1，v/v)，得到白色固体，即(E)-N-甲基-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.77(d,J＝15.7Hz,1H),7.65(d,J＝5.3Hz,1H),7.46(d,J＝1.3Hz,1H),7.39(d,J＝5.3Hz,1H),7.11(d,J＝15.7Hz,1H),6.52(d,J＝3.2Hz,1H),6.45(dd,J＝3.3,1.8Hz,1H),4.93(s,1H),3.26(d,J＝4.9Hz,3H).HR-MS:calcd forC13H11N3OS[M+H]+,259.0744；found 259.0744.
实施例23
(E)-N-(甲基哌嗪-1-基)-5-(2-(呋喃-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式2-2所示)的制备
采取化合物2-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.70(d,J＝1.4Hz,1H),7.68(d,J＝8.7Hz,1H),7.45(d,J＝1.3Hz,3H),7.41(d,J＝5.5Hz,3H),7.07(d,J＝15.7Hz,3H),6.52(d,J＝3.3Hz,3H),6.45(dd,J＝3.3,1.8Hz,3H),4.10–4.02(m,4H),2.61–2.55(m,4H),2.37(s,3H).HR-MS:calcd for C17H18N4OS[M+H]+,313.1243；found 313.1243.
实施例24
(E)-N-吗啉-5-(2-(呋喃-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式2-3所示)的制备
采取化合物2-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.71(d,J＝5.5Hz,1H),7.69(d,J＝15.7Hz,1H),7.46(d,J＝1.1Hz,1H),7.42(d,J＝5.5Hz,1H),7.08(d,J＝15.7Hz,1H),6.52(d,J＝3.2Hz,1H),6.45(dd,J＝3.2,1.8Hz,1H),4.04–4.02(m,4H),3.89–3.87(m,4H).HR-MS:calcd for C16H15N3O2S[M+H]+,314.0958；found314.0958.
实施例25
(E)-N-(4-氟苄基)-5-(2-(呋喃-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式2-4所示)的制备
采取化合物2-1同样的合成方法。结构数据表征：1H NMR(600MHz,DMSO-d6)δ8.40(t,J＝5.8Hz,1H),8.09(d,J＝5.3Hz,1H),7.76(s,1H),7.63(d,J＝15.8Hz,1H),7.46(dd,J＝8.3,5.8Hz,2H),7.37(d,J＝5.3Hz,1H),7.15(t,J＝8.9Hz,2H),6.83(d,J＝15.8Hz,1H),6.77(d,J＝3.2Hz,1H),6.59(dd,J＝3.0,1.8Hz,1H),4.76(d,J＝5.8Hz,2H).HR-MS:calcdfor C18H12FN3OS[M+H]+,314.0958；found 314.0958.
实施例26
(E)-N-环丙基-5-(2-(呋喃-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式2-5所示)的制备
采取化合物2-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.76(d,J＝5.4Hz,1H),7.70(d,J＝15.7Hz,1H),7.45(s,1H),7.40(d,J＝5.4Hz,1H),7.06(d,J＝15.7Hz,1H),6.50(d,J＝3.2Hz,1H),6.44(dd,J＝3.2,1.8Hz,1H),5.48(s,1H),3.11–3.04(m,1H),1.00(d,J＝5.3Hz,2H),0.80(d,J＝2.1Hz,2H).HR-MS:calcd forC15H13N3OS[M+H]+,284.0852；found 284.0852.
实施例27
(E)-N-(4-异丙基苯基)-5-(2-(呋喃-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式2-6所示)的制备
采取化合物2-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.74(d,J＝15.7Hz,1H),7.68(d,J＝5.4Hz,1H),7.55(d,J＝8.3Hz,2H),7.47(s,1H),7.40(d,J＝5.3Hz,1H),7.29(d,J＝8.4Hz,2H),7.13(d,J＝15.7Hz,1H),6.79(s,1H),6.53(d,J＝3.2Hz,1H),6.46(dd,J＝3.2,1.7Hz,1H),2.97(dt,J＝13.8,6.9Hz,1H),1.31(s,3H),1.30(s,3H).HR-MS:calcd for C21H19N3OS[M+H]+,378.1271；found 378.1271.
实施例28
(E)-N-(2-氟苄基)-5-(2-(呋喃-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式2-7所示)的制备
采取化合物2-1同样的合成方法。结构数据表征：1H NMR(600MHz,DMSO-d6)δ8.38(s,1H),8.08(d,J＝3.5Hz,1H),7.75(s,1H),7.63(d,J＝15.8Hz,1H),7.46(t,J＝6.4Hz,2H),7.36(d,J＝5.2Hz,1H),7.15(t,J＝8.2Hz,2H),6.85(d,J＝15.8Hz,1H),6.76(s,1H),6.58(d,J＝1.2Hz,1H),4.77(d,J＝5.5Hz,2H).HR-MS:calcd for C15H13N3OS[M+H]+,314.0958；found 314.0958.
实施例29
(E)-N-苄基-5-(2-(呋喃-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式2-8所示)的制备
采取化合物2-1同样的合成方法。结构数据表征：1H NMR(600MHz,DMSO-d6)δ8.37(t,J＝5.8Hz,1H),8.04(d,J＝5.3Hz,1H),7.71(d,J＝1.0Hz,1H),7.62(d,J＝15.8Hz,1H),7.42(d,J＝7.4Hz,2H),7.34(d,J＝5.3Hz,1H),7.31(t,J＝7.6Hz,2H),7.22(t,J＝7.3Hz,1H),6.84(d,J＝15.8Hz,1H),6.71(d,J＝3.3Hz,1H),6.55(dd,J＝3.2,1.8Hz,1H),4.79(d,J＝5.9Hz,2H).HR-MS:calcd for C19H17N3OS[M+H]+,334.1009；found 334.1009.
实施例30
(E)-N-(吡啶-4-甲基)-5-(2-(呋喃-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式2-9所示)的制备
采取化合物2-1同样的合成方法。结构数据表征：1H NMR(600MHz,DMSO-d6)δ8.50(d,J＝5.5Hz,2H),8.48(s,1H),8.12(d,J＝5.4Hz,1H),7.74(s,1H),7.53(d,J＝15.8Hz,1H),7.39(s,1H),7.38(d,J＝4.6Hz,2H),6.79(d,J＝15.8Hz,1H),6.74(d,J＝3.2Hz,1H),6.58(dd,J＝3.1,1.7Hz,1H),4.79(d,J＝5.8Hz,2H).HR-MS:calcd for C19H17N3OS[M+H]+,311.0961；found 311.0961.
实施例31
采取实施例1中中间体1-VIII同样的方法制备3,4,5-三甲氧基苯乙烯基噻吩并嘧啶类中间体3-VIII。
实施例32
(E)-N-吗啉基-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-1所示)的制备
反应瓶中，加入中间体3-VIII(100mg，0.28mmol)(制备方法见实施例1)，加入10mL异丙醇，再加入吗啉(0.37mmol)，回流反应约6-12h，TLC监控，反应完成后，冷却至室温，减压浓缩至干，残余物经柱层析纯化，洗脱剂为石油醚：乙酸乙酯(2:1，v/v)，得到白色固体，即(E)-N-吗啉基-5-(2-(苯-2-基)乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺。结构数据表征：1H NMR(600MHz,DMSO-d6)δ7.80(d,J＝15.8Hz,1H,＝CH),7.71(d,J＝5.4Hz,1H,ArH),7.41(d,J＝5.5Hz,1H,ArH),7.09(d,J＝15.8Hz,1H,＝CH),6.85(s,2H,ArH),4.06–4.03(m,4H),3.91–3.86(m,13H).HR-MS:calcd for C21H23N3O4S[M+H]+,414.1482；found 414.1482.
实施例33
(E)-N-(4-氯苄基)-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-2所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,DMSO-d6)δ10.28(s,1H),8.42(d,J＝5.3Hz,1H),8.09(d,J＝15.7Hz,1H),7.54(d,J＝5.2Hz,1H),7.52(d,J＝8.2Hz,2H),7.43(d,J＝8.2Hz,2H),7.22(dd,J＝15.7,2.6Hz,1H),7.04(s,2H),4.96(d,J＝5.5Hz,3H),3.87(s,6H),3.73(s,2H).HR-MS:calcd for C24H22ClN3O3S[M+H]+,460.1456；found 460.1456.
实施例34
(E)-N-(三氟甲基苯基)-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-3所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,DMSO-d6)δ11.49(s,1H,NH),8.49(d,J＝5.3Hz,1H,ArH),8.19(d,J＝8.4Hz,2H,ArH),8.00(d,J＝15.8Hz,1H,＝CH),7.85(d,J＝8.6Hz,2H,ArH),7.62(d,J＝5.4Hz,1H,ArH),7.34(d,J＝15.9Hz,1H,＝CH),7.03(s,2H,ArH),3.85(s,6H,CH3),3.72(s,3H,CH3).HR-MS:calcd for C24H20F3N3O3S[M+H]+,480.1563；found 480.1563.
实施例35
(E)-N-(吡啶-4-甲基)-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-4所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ8.54(d,J＝4.8Hz,2H,ArH),7.72(d,J＝15.8Hz,1H,＝CH),7.70(s,1H,ArH),7.41(d,J＝5.2Hz,1H,ArH),7.33(d,J＝4.8Hz,2H,ArH),7.08(d,J＝15.8Hz,1H,＝CH),6.79(s,2H,ArH),5.84(t,J＝5.2Hz,1H,NH),4.97(d,J＝5.6Hz,2H,CH2),3.87(s,6H,CH3),3.86(s,3H,CH3).HR-MS:calcd for C23H22N4O3S[M+H]+,427.1798；found 427.1798.
实施例36
(E)-N-吡咯-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-5所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.85(d,J＝15.7Hz,1H),7.71(d,J＝5.4Hz,1H),7.41(d,J＝5.4Hz,1H),7.10(d,J＝15.8Hz,1H),6.86(s,2H),3.98(s,4H),3.91(s,6H),3.88(s,3H),2.09(s,4H).HR-MS:calcdfor C21H23N3O3S[M+H]+,401.1455；found 401.1455.
实施例37
(E)-N-(4-羟基苯基)-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-6所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,DMSO-d6)δ10.63(s,1H,OH),9.72(s,1H,NH),8.32(s,1H,ArH),7.93(d,J＝15.6Hz,1H,＝CH),7.47(d,J＝5.0Hz,3H,ArH),7.18(d,J＝15.8Hz,1H,＝CH),7.01(s,2H,ArH),6.90(d,J＝8.6Hz,2H,ArH),3.87(s,6H,CH3),3.72(s,3H,CH3).HR-MS:calcd for C23H21N3O4S[M+H]+,439.1560；found 439.1560.
实施例38
(E)-N-环丙基-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-7所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.83(d,J＝15.8Hz,1H),7.79(d,J＝5.4Hz,1H),7.41(d,J＝5.3Hz,1H),7.08(d,J＝15.8Hz,1H),6.85(s,2H),5.81–5.70(m,1H),3.89(s,6H),3.87(s,3H),3.09(d,J＝2.8Hz,1H),1.01(q,J＝6.4Hz,2H),0.83–0.79(m,2H).HR-MS:calcd for C20H21N3O3S[M+H]+,386.1533；found 386.1533.
实施例39
(E)-N-(2-氯苄胺)-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-8所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.87(d,J＝15.8Hz,1H),7.69(d,J＝5.3Hz,1H),7.56–7.52(m,1H),7.43–7.41(m,1H),7.40(s,1H),7.25–7.22(m,2H),7.12(d,J＝15.8Hz,1H),6.86(s,2H),5.39(t,J＝5.7Hz,1H),5.07(d,J＝5.9Hz,2H),3.91(s,6H),3.88(s,3H).HR-MS:calcd for C24H22ClN3O3S[M+H]+,460.1456；found460.1456.
实施例40
(E)-N-(4-甲氧基苄胺)-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-9所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.89(d,J＝15.8Hz,1H),7.67(dd,J＝5.3,2.3Hz,1H),7.41–7.39(m,1H),7.37(d,J＝8.4Hz,2H),7.14(d,J＝15.8Hz,1H),6.92–6.88(m,2H),6.86(s,2H),5.19(d,J＝4.7Hz,1H),4.90(d,J＝5.3Hz,2H),3.90(d,J＝1.9Hz,6H),3.88(s,3H),3.80(d,J＝2.3Hz,3H).HR-MS:calcd for C25H25N3O4S[M+H]+,466.1795；found 466.1795.
实施例41
(E)-N-(呋喃-2-甲基)-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-10所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.90(d,J＝15.8Hz,1H),7.68(d,J＝5.3Hz,1H),7.43–7.37(m,2H),7.14(d,J＝15.7Hz,1H),6.87(s,2H),6.40–6.32(m,2H),5.26(s,1H),4.97(d,J＝5.4Hz,2H),3.90(s,6H),3.88(s,3H).HR-MS:calcd for C22H21N3O4S[M+H]+,426.1482；found 426.1482.
实施例42
(E)-N-二甲基-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-11所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.82(d,J＝15.8Hz,1H),7.69(d,J＝5.5Hz,1H),7.38(d,J＝5.5Hz,1H),7.08(d,J＝15.8Hz,1H),6.85(s,2H),3.90(s,6H),3.87(s,3H),3.47(s,6H).HR-MS:calcd forC19H21N3O3S[M+H]+,374.1533；found 374.1533.
实施例43
(E)-N-甲基-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-12所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.89(d,J＝15.8,1H),7.67(d,J＝5.2Hz,1H),7.39(d,J＝5.2,1H),7.13(d,J＝15.8Hz,1H),6.86(d,J＝2.8Hz,2H),5.01(s,1H),3.90(s,6H),3.87(s,3H),3.26(s,3H).HR-MS:calcd for C18H19N3O3S[M+H]+,360.1376；found 360.1376.
实施例44
(E)-N-甲基-N-苯基-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-13所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.94(d,J＝15.8Hz,1H),7.51–7.46(m,4H),7.41–7.38(m,2H),7.27(d,J＝5.4Hz,1H),7.18(d,J＝15.8Hz,1H),6.90(s,2H),3.93(s,6H),3.89(s,3H),3.74(s,3H).HR-MS:calcd forC24H23N3O3S[M+H]+,436.1689；found 436.1689.
实施例45
(E)-N-苄基-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-14所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.88(d,J＝15.8Hz,1H),7.70(d,J＝5.3Hz,1H),7.46(d,J＝7.3Hz,2H),7.42(d,J＝5.3Hz,1H),7.39(t,J＝7.5Hz,2H),7.33(s,1H),7.14(d,J＝15.8Hz,1H),6.87(s,2H),5.18–5.14(m,1H),4.99(d,J＝5.5Hz,2H),3.91(s,6H),3.88(s,3H).HR-MS:calcd for C24H23N3O3S[M+H]+,436.1689；found 436.1689.
实施例46
(E)-N-(4-甲基苯胺)-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-15所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,DMSO-d6)δ10.49(s,1H),8.34(d,J＝4.9Hz,1H),7.89(d,J＝15.8Hz,1H),7.68(d,J＝7.1Hz,2H),7.49(d,J＝5.3Hz,1H),7.30(d,J＝8.0Hz,2H),7.19(d,J＝15.8Hz,1H),7.02(s,2H),3.87(s,6H),3.71(s,3H),2.36(s,3H).HR-MS:calcd for C24H23N3O3S[M+H]+,437.1768；found437.1768.
实施例47
(E)-N-(N-乙基哌嗪)-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-16所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.81(d,J＝15.8Hz,1H),7.70(d,J＝5.5Hz,1H),7.40(d,J＝5.5Hz,1H),7.09(d,J＝15.7Hz,1H),6.86(s,2H),4.12–4.08(m,4H),3.90(s,6H),3.88(s,3H),2.67–2.62(m,4H),2.50(q,J＝7.2Hz,2H),1.15(t,J＝7.2Hz,3H).HR-MS:calcd for C23H26N4O3S[M+H]+,440.1877；found 440.1877.
实施例48
(E)-N-(4-甲氧基苯基)-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-17所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.86(d,J＝15.8Hz,1H),7.65(d,J＝5.4Hz,1H),7.47–7.43(m,2H),7.37(d,J＝5.4Hz,1H),7.13(d,J＝15.8Hz,1H),7.03(s,1H),6.96(d,J＝8.7Hz,2H),6.85(s,2H),3.90(s,6H),3.88(s,3H),3.86(s,3H).HR-MS:calcd for C24H23N3O4S[M+H]+,453.1717；found453.1717.
实施例49
(E)-N-(4-异丙基苯基)-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-18所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.88(d,J＝15.8Hz,1H),7.70(d,J＝5.4Hz,1H),7.53(d,J＝8.3Hz,2H),7.40(d,J＝5.4Hz,1H),7.30(d,J＝8.3Hz,2H),7.15(d,J＝15.8Hz,1H),6.87(s,2H),6.85(s,1H),3.91(s,6H),3.89(s,3H),1.31(s,3H),1.30(s,3H).HR-MS:calcd for C26H27N3O3S[M+H]+,465.2081；found 465.2081.
实施例50
(E)-N-(4-甲基哌嗪)-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-19所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.79(d,J＝15.8Hz,1H),7.69(d,J＝5.5Hz,1H),7.39(d,J＝5.5Hz,1H),7.07(d,J＝15.8Hz,1H),6.84(s,2H),4.09–4.04(m,4H),3.90–3.83(m,9H),2.60–2.55(m,4H),2.35(s,3H).HR-MS:calcd for C22H22N4O3S[M+H]+,430.2033；found 430.2033.
实施例51
(E)-N-(4-甲基苄胺)-5-(3,4,5-三甲氧基苯乙烯基)-1H-二氢噻吩并[3,2-d]嘧啶-7-胺(结构如式3-20所示)的制备
采取化合物3-1同样的合成方法。结构数据表征：1H NMR(600MHz,Chloroform-d)δ7.89(d,J＝15.8Hz,1H),7.69(d,J＝5.3Hz,1H),7.41(d,J＝5.3Hz,1H),7.35(d,J＝7.9Hz,2H),7.20(d,J＝7.8Hz,2H),7.14(d,J＝15.8Hz,1H),6.87(s,2H),5.12(t,J＝5.2Hz,1H),4.94(d,J＝5.5Hz,2H),3.91(s,6H),3.88(s,3H),2.37(s,3H).HR-MS:calcd forC25H27N3O3S[M+H]+,451.1924；found 451.1924.
实施例52
抗炎活性验证实验：
为测试本发明公开的芳香环乙烯基噻吩并嘧啶类化合物的抗炎活性，选取上述实施例制备得到的芳香环乙烯基噻吩并嘧啶类化合物化合物进行活性实验。
1、实验原理：实验采用NO含量测定法，利用硝酸还原酶还原硝酸盐为亚硝酸盐，然后通过Griess Reagent试剂检测亚硝酸盐，从而计算出总的NO含量。
2、实验步骤如下：
(1)取处于对数生长期的RAW264.7细胞，收集细胞，利用细胞计数板进行计数；利用培养基进行稀释细胞使浓度为1.4*105/mL，接种细胞在24孔板内，每孔加入体积为500μL，培养过夜；
(2)24孔板分为三组：空白组(只有细胞)、模型组(细胞+LPS)、实验组(细胞+LPS+化合物)；
(3)隔夜后换液，空白组、模型组直接换新鲜培养基500μL，实验组每孔加入含有不同浓度(40、20、10、5、2.5μM)的化合物溶液500μL；
(4)1h后加入LPS进行刺激，使LPS的终浓度为1μg/mL(一般可以把高浓度的LPS用少量培养基进行稀释，再进行滴加)；
(5)24h后观察细胞提细胞上清液，用碧云天生产的一氧化氮检测试剂盒检测并计算细胞上清NO的浓度；
(6)配置标准曲线：用新鲜培养基稀释标准品浓度为1、5、10、20、40、60、100μM；
(7)按50μL每孔，在96孔板中分别加入标准品及细胞上清；
(8)每孔分别先加50μL Griess ReagentⅠ，再加50μL Griess ReagentⅡ；
(9)使用酶标仪在540nm测定吸光度，带入标准曲线算出NO含量。
(10)以上实验均重复三次，结果用SPSS17.0统计分析软件进行分析作图。
3、实验结果：实验结果如表1所示：
表1各实施例中相应编号化合物的抗炎活性数据统计表
注：IC50值单位为：μmol/L，“--”表示IC50值大于50μmol/L，没有进行复筛，“/”表示未测试活性。
由表1可知，本发明提供的芳香环乙烯基噻吩并嘧啶类化合物具有良好的抗炎活性，在各种急慢性炎症的治疗中体现出良好的应用前景，在对如脓毒血症等急性炎症和以Ⅱ型糖尿病、阿尔茨海默病和动脉粥样硬化症为代表的慢性炎症的治疗中体现了良好的应用潜力。
以上显示和描述了本发明的基本原理和主要特征和本发明的优点。本行业的技术人员应该了解，本发明不受上述实施例的限制，上述实施例和说明书中描述的只是说明本发明的原理，在不脱离本发明精神和范围的前提下，本发明还会有各种变化和改进，这些变化和改进都落入要求保护的本发明范围内。本发明要求保护范围由所附的权利要求书及其等效物界定。
Claims (4)
1.一种芳香环乙烯基噻吩并嘧啶类化合物，其特征在于，包含如下式A、式B和式C三种结构：
其中，
R2和R3选自氢、烷基、取代烷基、烷氧基、取代烷氧基、环烷基、取代环烷基、哌嗪基、取代哌嗪基、苯基取代苯基中的任意一种基团；
R4选自氢、烷基、取代烷基、烷氧基、取代烷氧基、环烷基、取代环烷基、哌嗪基、取代哌嗪基、苯基取代苯基中的任意一种基团；式B中X＝C、N、O或S，n＝1或2；
R5、R6、R7选自H、卤素、C1-C5烷基、硝基、C1-C3烷氧基、苯基、苯氧基、羟基、乙酰胺基、三氟甲基中的任意一种基团；式C中X＝O或C，Y＝N或C，m＝1或2，n＝0、1或2。
2.权利要求1所述的化合物的制备方法，其特征在于：将芳香环基丙烯酸化合物I制酰氯得到中间体II，中间体II和氨基噻吩反应制得中间体III；中间体III在碱性条件下水解得到中间体IV，中间体IV制酰氯得到中间体V，中间体V和氨水反应得到中间体VI，中间体VI在碱性条件下经关环缩合得到中间体VII，中间体VII经氯化反应制得中间体VIII，中间体VIII和相应胺的衍生物经取代反应即得芳香环乙烯基噻吩并嘧啶类化合物，具体合成路线如下：
3.根据权利要求2所述的制备方法，其特征在于：所述相应胺的衍生物选自对氨基酚、环丙胺、吗啉、2-氯苯乙胺、2-氯苄胺、2-甲氧基苄胺、3-甲氧基苄胺、4-甲氧基苄胺、4-溴苄胺、4-氟苄胺、4-甲氨基吡啶、N-吗啉基苯胺、糠胺、异丙胺、仲丁胺、4-三氟甲基苄胺、正丁胺中的任意一种。
4.权利要求1所述的化合物在制备抗炎药物中的应用。
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| CN108503648A (zh) * | 2018-04-27 | 2018-09-07 | 安徽医科大学 | 苯乙烯基吡唑并嘧啶类化合物、药物组合物及制备方法与用途 |
| CN109206427A (zh) * | 2018-09-25 | 2019-01-15 | 安徽医科大学 | 芳香杂环乙烯基吡唑并嘧啶类化合物、药物制剂及制备方法与应用 |
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| DE2039663A1 (de) * | 1970-08-10 | 1972-02-17 | Karl Twomae Gmbh Dr | Neue 2-(5-Nitro-2-furyl)-vinyl-thieno-[3,2-d]-pyrimidine |
| CN108503648A (zh) * | 2018-04-27 | 2018-09-07 | 安徽医科大学 | 苯乙烯基吡唑并嘧啶类化合物、药物组合物及制备方法与用途 |
| CN109206427A (zh) * | 2018-09-25 | 2019-01-15 | 安徽医科大学 | 芳香杂环乙烯基吡唑并嘧啶类化合物、药物制剂及制备方法与应用 |
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| CN112375042A (zh) * | 2020-10-27 | 2021-02-19 | 安徽医科大学 | 三甲氧基苯乙烯基六元环类和吡唑并嘧啶类化合物、制剂及其制备与应用 |
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