CN112375042A - 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 - Google Patents
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 Download PDFInfo
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Abstract
本发明公开了一种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,涉及抗炎类化合物技术领域,本发明所述三甲氧基苯乙烯基六元环类化合物和吡唑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。
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。
背景技术:
二苯乙烯化合物通常是指具有两个苯环和乙烯基连接的二苯乙烯母结构的化合物。作为天然黄芪化合物的单体,可分为顺式和反式两种。在天然植物中比较具有糖苷或多糖苷的反式结构,具有显著的抗氧化、抗肿瘤、抗炎、抗心血管疾病、增强免疫力、抗衰老、防辐射等作用。最具代表性的是白藜芦醇(Resveratrol)和己烯雌酚(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)具有抗老年痴呆、癌症、抗菌、抗氧化、降低血脂等重要的生物学功能;己烯雌酚(Diethylstilbestrol)是人工合成的非甾体***物质,能产生与天然***相同的所有药理与治疗作用;奥培米芬(Ospemifene)是托瑞米芬的活性代谢产物之一,也是新型选择性***受体调节剂,既具有***作用,也具有抗***作用,表现为组织选择性。由于新药靶点的不断更新,这类化合物的药物化学进展迅速,形成了苯乙烯化合物的一个新领域,是一种很有前途的化合物。苯乙烯化合物由于其独特的功效,引起了国内外学者的极大关注。
综上所述,基于二苯乙烯的骨架结构修饰具有潜在意义。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。
嘧啶是具有吸引力的稠合基团之一。很多药化文献研究报道的核心结构含有噻吩并嘧啶骨架,如美国Meadohnson公司1985年开发上市的盐酸丁螺环酮(BuspiHydro-chloride)具有良好的抗焦虑用途,可作为5-HTA部分的激动剂,被用于治疗急、慢性焦虑症。本品具有选择性高疗效确切,成瘾小等特点。日本洪制药株式会1980年开发上市的盐酸尼莫司汀创是一种疗效较好的抗肿瘤药,用于缓解脑肿瘤、消化道肿瘤(胃癌、肝癌、结直肠癌)、肺癌、恶性淋巴瘤及白血病等病症。
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;在前面的研究中,吡唑并嘧啶类化合物对佐剂诱导的炎症因子NO表达具有很好的抑制作用,对iNOS酶活性抑制效果显著。
基于,嘧啶骨架的结构修饰具有重要潜在的药用价值,因此,合成一种苯乙烯基嘧啶类化合物,提供一种高效抗炎药物,研究其对关节软骨细胞iNOS酶活性的抑制效果,对于构建一种新型iNOS抑制剂治疗骨关节炎的药物的意义重大。
发明内容:
本发明所要解决的技术问题在于合成一系列新型三甲氧基苯乙烯基六元环类和吡唑并嘧啶类化合物,用于开发高效抗炎药物。
本发明所要解决的技术问题采用以下的技术方案来实现:
一种三甲氧基苯乙烯基六元环类化合物,包括如式I所示结构的化合物:
其中,含有三种结构,(1):X=H,Y=CH;(2):X=Cl,Y=CH;(3):X=OH,Y=N;
R1和R2选自氢、烷基、取代烷基、环烷基、取代环烷基、苯基取代苯基中的任意一种。
上述三甲氧基苯乙烯基六元环类化合物的制备方法,将化合物1和胺类衍生物在异丙醇和三乙胺条件下制得化合物2,化合物2在盐酸条件下与三甲氧基苯甲醛反应,即得三甲氧基苯乙烯基六元环类化合物,反应过程如下:
本发明还提供了一种吡唑并嘧啶类化合物,包括如式II-a和式II-b所示结构的化合物:
R4和R5选自氢、烷基、取代烷基、环烷基、取代环烷基、吗啉基、取代吗啉基、苯基取代苯基中的任意一种;
R6选自氢、烷基、取代烷基、卤素中的任意一种;
Z=C、N或O;
n=1或2;
linker为CH2-CH2或CH=CH。
上述吡唑并嘧啶类化合物的制备方法,将化合物3和丙烯酸衍生物反应制得化合物4,化合物4在甲醇钠条件环合制得化合物5,中间体5用过量三氯氧磷发生氯化反应,制得关键的中间体6;中间体6和胺类衍生物进行取代反应即得所述吡唑并嘧啶类化合物,反应过程如下:
所述胺类衍生物选自异丙胺、环丙胺、吗啉、硫代吗啉、4-氯苯乙胺、4-氟苯乙胺、4-氟苄胺、2-氯苯乙胺中的任意一种。
上述三甲氧基苯乙烯基六元环类和吡唑并嘧啶类化合物,其结构式为:
本发明还提供了上述三甲氧基苯乙烯基六元环类和吡唑并嘧啶类化合物在制备抗炎药物中的应用。
本发明还提供了以上述三甲氧基苯乙烯基六元环类和吡唑并嘧啶类化合物为活性化合物的药物制剂。
所述药物制剂中活性化合物的剂量为0.01-500mg/kg。优选地,所述药物制剂中活性化合物的剂量为250mg/kg。
所述药物制剂为将活性化合物添加药剂学中能够接受的辅料制备成片剂、胶囊剂、锭剂、注射剂、悬浮剂、栓型或软膏剂。
所述辅料包括赋形剂和载体,赋形剂为碳酸钙、磷酸钙、糖类、淀粉、纤维素衍生物、明胶、植物油和聚乙二醇中的一种或多种,载体为稀释剂、崩解剂、粘合剂和润滑剂中的一种或多种。
本发明的有益效果是:
(1)本发明所述三甲氧基苯乙烯基六元环类和吡唑并嘧啶类化合物属于新型化合物,本发明首次合成了这些化合物,并进行了结构表征;
(2)本发明所述三甲氧基苯乙烯基六元环类和吡唑并嘧啶类化合物的制备方法简单、操作方便,能够快速合成这些化合物;
(3)经研究发现,本发明所述三甲氧基苯乙烯基六元环类和吡唑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
(E)-N-异丙基-2-(3,4,5-三甲氧基苯乙烯基)嘧啶-4-胺(结构如式I-1所示)的制备:
中间体2-1制备:
将化合物1-1(200mg,1.34mmol),异丙胺(0.115mL,1.34mmol)和TEA(0.556mL,4.02mmol)溶解在异丙醇(15mL)中并回流6h。反应完成后,除去溶剂,得到中间体2-1。
化合物I-1制备:
将化合物中间体2-1(77mg,0.51mmol)和3,4,5-三甲氧基苯甲醛(100mg,0.51mmol)加入盐酸(6mL)中并回流6h。反应完成后,减压除去溶剂,并将残余物通过柱色谱法纯化,得到化合物I-1。结构数据表征:1H NMR(400MHz,DMSO-d6)δ8.02(s,1H),7.70(d,J=15.9Hz,1H),7.18(d,J=7.5Hz,1H),6.98(s,2H),6.97(d,J=15.9Hz,1H),6.27(d,J=5.9Hz,1H),4.27(s,1H),3.84(s,6H),3.68(s,3H),1.18(d,J=6.5Hz,6H).HR-MS(ESI):calcd for C18H24N3O3[M+H]+,330.1812;found 330.1814.
实施例2
(E)-N-苯乙基-2-(3,4,5-三甲氧基苯乙烯基)嘧啶-4-胺(结构如式I-2所示)的制备:
采取化合物I-1同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.74(d,J=15.9Hz,1H),7.42(s,1H),7.34–7.28(m,4H),7.22(s,1H),7.03(d,J=15.9Hz,1H),6.98(s,2H),6.33(d,J=5.8Hz,1H),3.85(s,6H),3.69(s,3H),3.61(m,2H),2.89(t,J=7.5Hz,2H).13C NMR(101MHz,DMSO-d6)δ163.81,162.02,154.37,153.57(2C),140.11,138.57,136.35,132.09,129.24(2C),128.82(2C),128.71,126.60,105.17(2C),104.52,60.54,56.39(2C),41.96,35.30.HR-MS(ESI):calcd for C23H26N3O3[M+H]+,392.1969;found392.1962.
实施例3
(E)-N-(4-氟苯乙基)-2-(3,4,5-三甲氧基苯乙烯基)嘧啶-4-胺(结构如式I-3所示)的制备:
采取化合物I-1同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.72(d,J=15.9Hz,1H),7.40(s,1H),7.33(dd,J=8.5,5.7Hz,2H),7.13(t,J=8.9Hz,2H),7.01(d,J=15.9Hz,1H),6.98(s,2H),6.32(d,J=6.0Hz,1H),3.84(s,6H),3.68(s,3H),3.59(m,2H),2.88(t,J=7.3Hz,2H).13C NMR(101MHz,DMSO-d6)δ163.73,162.53,161.15(d,J=205.03Hz),154.23,153.55(2C),138.58,136.31,136.09,132.06,130.84(d,J=8.08Hz,2C),128.42,115.27(d,J=21.21Hz,2C),104.93(2C),104.46,60.31,56.14(2C),41.90,34.38.HR-MS(ESI):calcd for C23H25FN3O3[M+H]+,410.1874;found410.1876.
实施例4
(E)-N-(4-氯苯乙基)-2-(3,4,5-三甲氧基苯乙烯基)嘧啶-4-胺(结构如式I-4所示)的制备:
采取化合物I-1同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.72(d,J=15.9Hz,1H),7.45–7.23(m,5H),7.01(d,J=15.9Hz,1H),6.97(s,2H),6.32(d,J=5.9Hz,1H),3.85(s,6H),3.69(s,3H),3.59(s,2H),2.88(t,J=7.2Hz,2H).13CNMR(101MHz,DMSO)δ163.81,162.30,154.54,153.57(2C),139.15,138.65,136.36,132.09(2C),131.23,131.14(2C),129.22,128.81,128.69(2C),105.23(2C),60.54,56.42(2C),41.59,34.54.HR-MS(ESI):calcd for C23H24ClN3O3[M+H]+,426.1585;found 426.1579.
实施例5
(E)-6-氯-N-异丙基-2-(3,4,5-三甲氧基苯乙烯基)嘧啶-4-胺(结构如式I-5所示)的制备:
中间体2-2制备:
将化合物1-2(217mg,1.34mmol),异丙胺(0.115mL,1.34mmol)和TEA(0.556mL,4.02mmol)溶解在异丙醇(15mL)中并回流6h。反应完成后,除去溶剂,得到中间体2-2。
化合物I-5制备:
将化合物中间体2-2(95mg,0.51mmol)和3,4,5-三甲氧基苯甲醛(100mg,0.51mmol)加入盐酸(6mL)中并回流6h。反应完成后,减压除去溶剂,并将残余物通过柱色谱法纯化,得到化合物I-5。结构数据表征:1H NMR(400MHz,DMSO-d6)δ7.72(d,J=15.8Hz,1H),7.53(d,J=7.9Hz,1H),7.03(s,2H),6.99(d,J=15.8Hz,1H),6.30(s,1H),4.30(s,1H),3.84(s,6H),3.69(s,3H),1.18(d,J=6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ164.59,162.98,157.45,153.56(2C),138.91,138.17,131.59,127.13,105.52(2C),101.52,60.53,56.42(2C),42.10,22.81(2C).HR-MS(ESI):calcd for C18H23ClN3O3[M+H]+,364.1422;found 364.1422.
实施例6
(E)-6-氯-N-苯乙基-2-(3,4,5-三甲氧基苯乙烯基)嘧啶-4-胺(结构如式I-6所示)的制备:
采取化合物I-5同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ7.75(d,J=16.0Hz,1H),7.73(s,1H),7.36–7.26(m,4H),7.27–7.17(m,1H),7.03(s,2H),7.00(d,J=16.7Hz,1H),6.37(s,1H),3.85(s,6H),3.69(s,3H),3.65(m,2H),2.88(t,J=7.3Hz,2H).13C NMR(101MHz,DMSO-d6)δ164.61,163.68,157.50,153.58(2C),139.87,138.99,138.28,131.57,129.26(2C),128.82(2C),127.11,126.65,105.57,101.65,60.54(2C),56.44,42.24,35.23.HR-MS(ESI):calcd for C23H25ClN3O3[M+H]+,426.1579;found426.1578.
实施例7
(E)-6-氯-N-(4-氟苯乙基)-2-(3,4,5-三甲氧基苯乙烯基)嘧啶-4-胺(结构如式I-7所示)的制备:
采取化合物I-5同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ7.73(d,J=16.5Hz,1H),7.71(s,1H),7.36–7.27(m,2H),7.18–7.07(m,2H),7.03(s,2H),6.99(s,1H),6.36(s,1H),3.84(s,6H),3.69(s,3H),3.67–3.59(m,2H),2.86(t,J=7.3Hz,2H).13C NMR(101MHz,DMSO-d6)δ164.59,163.66,161.36(d,J=242.40Hz),157.49,153.57(2C),138.96,138.29,136.02,131.56,131.06(d,J=8.08Hz,2C),127.09,115.46(d,J=20.20Hz,2C),105.55(2C),101.64,60.54,56.42(2C),42.20,34.34.HR-MS(ESI):calcdfor C23H24ClFN3O3[M+H]+,444.1485;found 444.1504.
实施例8
(E)-4-(异丙基氨基)-6-(3,4,5-三甲氧基苯乙烯基)-1,3,5-三嗪-2-醇(结构如式I-8所示)的制备:
中间体2-3制备:
将化合物1-3(218mg,1.34mmol),异丙胺(0.115mL,1.34mmol)和TEA(0.556mL,4.02mmol)溶解在异丙醇(15mL)中并回流6h。反应完成后,除去溶剂,得到中间体2-3。
化合物I-8制备:
将化合物中间体2-3(95mg,0.51mmol)和3,4,5-三甲氧基苯甲醛(100mg,0.51mmol)加入盐酸(6mL)中并回流6h。反应完成后,减压除去溶剂,并将残余物通过柱色谱法纯化,得到化合物I-8。
结构数据表征:1H NMR(400MHz,DMSO-d6)δ11.43(s,1H),δ7.84(d,J=16.0Hz,1H),7.66(d,J=8.1Hz,1H),7.00(s,1H),6.90(s,2H),6.71(d,J=15.9Hz,1H),4.03(m,1H),3.84(s,6H),3.71(s,3H),1.13(d,J=6.6Hz,6H).13C NMR(101MHz,DMSO-d6)δ164.64,162.03,156.38,153.67(2C),141.61,140.05,130.33,119.10,105.90(2C),60.63,56.44(2C),42.22,22.47(2C).HR-MS(ESI):calcd for C17H23N4O4[M+H]+,347.1714;found347.1747.
实施例9
(E)-4-(苯乙氨基)-6-(3,4,5-三甲氧基苯乙烯基)-1,3,5-三嗪-2-醇(结构如式I-9所示)的制备:
采取化合物I-8同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ7.93–7.76(m,2H),7.36–7.16(m,5H),6.96(d,J=22.8Hz,2H),6.72(d,J=16.0Hz,1H),4.17–4.07(m,1H),3.84(s,6H),3.71(s,3H),3.55–3.43(m,2H),2.84(t,J=7.4Hz,2H).HR-MS(ESI):calcd for C22H25N4O4[M+H]+,409.1870;found 409.1864.
实施例10
(E)-4-((4-氟苯乙基)氨基)-6-(3,4,5-三甲氧基苯乙烯基)-1,3,5-三嗪-2-醇(结构如式I-10所示)的制备:
采取化合物I-8同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),7.94–7.79(m,2H),7.32–7.26(m,2H),7.17–7.06(m,2H),6.95(d,J=16.0Hz,1H),6.92(s,1H),6.72(d,J=16.0Hz,1H),3.84(s,6H),3.71(s,3H),3.51–3.41(m,2H),2.83(t,J=7.3Hz,2H).13C NMR(101MHz,DMSO-d6)δ165.49,162.26,160.30(d,J=242.40Hz),156.31,153.64(2C),141.77,140.02,136.02(d,J=3.03Hz),130.90(d,J=8.08Hz,2C),130.32,119.17,115.46(d,J=21.21Hz,2C),105.92(2C),60.62,56.42(2C),42.21,33.98.HR-MS(ESI):calcd for C22H24FN4O4[M+H]+,427.1776;found 427.1779.
实施例11
(E)-4-(环丙基氨基)-6-(3,4,5-三甲氧基苯乙烯基)-1,3,5-三嗪-2-醇(结构如式I-11所示)的制备:
采取化合物I-8同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ11.53(s,1H),7.94(s,1H),7.82(d,J=15.9Hz,1H),6.99(s,1H),6.90(s,2H),6.71(d,J=15.9Hz,1H),3.83(s,6H),3.71(s,3H),2.78(m,1H),0.69(m,2H),0.53(m,2H).HR-MS(ESI):calcd for C17H21N4O4[M+H]+,345.1557;found 345.1534.
实施例12
(E)-4-((4-氯苯乙基)氨基)-6-(3,4,5-三甲氧基苯乙烯基)-1,3,5-三嗪-2-醇(结构如式I-12所示)的制备:
采取化合物I-8同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ11.51(s,1H),7.83(d,J=16.0Hz,2H),7.34–7.21(m,5H),6.95(d,J=16.1Hz,1H),6.92(s,1H),6.71(d,J=16.1Hz,1H),3.83(s,6H),3.71(s,3H),3.46(q,J=6.8Hz,2H),2.84(t,J=7.1Hz,2H).13C NMR(101MHz,DMSO-d6)δ164.19,161.24,158.94,153.64(2C),141.77,140.01,138.95,131.21,131.04(2C),130.31,128.70(2C),119.07,105.91(2C),60.62,56.42(2C),41.97,34.09.HR-MS(ESI):calcd for C22H24ClN4O4[M+H]+,443.1481;found443.1477.
实施例13
(E)-N-环丙基-1-甲基-3-丙基-5-(2-(3,5,6-三甲基吡嗪-2-基)乙烯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(结构如式II-a-1所示)的制备:
中间体4-1制备:
将(E)-3-(3,5,6-三甲基吡嗪-2-基)丙烯酸(0.96g,5mmol),EDCI(1.434g,7.5mmol)和HOBT(1.103g,7.5mmol)溶解在干燥中DCM(10mL),将混合物在25℃下搅拌30min。加入化合物3(1.001g,5.5mmol)和TEA(2.073mL,15mmol),并将溶液在室温搅拌过夜。蒸发反应混合物,过滤沉淀物,用水洗涤并干燥,得到化合物4-1。
中间体5-1制备
将化合物4-1(1.715g,5mmol)和甲醇钠(30%,10mL)溶解在甲醇(20mL)中,并回流10h。将混合物在真空下浓缩。用2N HCl将残余物酸化至pH=7。过滤沉淀物,用水洗涤,干燥,得到化合物5-1。
中间体6-1制备
将化合物5-1(1.692g,5mmol)溶解在三氯氧化磷(POCl3,10mL)中,并在100℃下搅拌10h。反应完成后,将混合物真空浓缩,得到深色油状产物。将残余物用冷H2O洗涤,并用DCM(30mL×3)萃取。合并的有机层用饱和NaHCO3溶液,饱和盐水溶液洗涤,用无水Na2SO4干燥,浓缩,得到关键中间体6-1。
中间体II-a-1制备
将中间体6-1(100mg,0.281mmol),环丙胺(0.021mL,0.30mmol)和TEA(0.117mL,0.843mmol)溶于异丙醇(15mL)中,回流6h。反应完成后,除去溶剂,残余物通过柱色谱法纯化,得到化合物II-a-1。结构数据表征:1H NMR(400MHz,CDCl3)δ8.70(s,1H),8.29(d,J=14.9Hz,1H),7.79(d,J=14.9Hz,1H),4.25(s,3H),3.28–3.28(m,1H),2.90(t,J=7.5Hz,2H),2.61(s,3H),2.54–2.47(m,6H),1.75–1.66(m,2H),1.03–0.89(m,7H).13C NMR(101MHz,DMSO-d6)δ156.59,150.81,150.71,149.65,147.63,144.46,144.32,142.48,134.04,129.39,121.45,39.47,27.69,24.49,22.08,21.94,21.90,20.82,14.36,7.05(2C).HR-MS(ESI):calcd for C21H28N7[M+H]+,378.2041;found 378.2043.
实施例14
(E)-N-异丙基-1-甲基-3-丙基-5-(2-(3,5,6-三甲基吡嗪-2-基)乙烯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(结构如式II-a-2所示)的制备:
采取化合物II-a-1同样的合成方法。结构数据表征:1H NMR(400MHz,CDCl3)δ8.38(s,1H),8.23(d,J=14.9Hz,1H),7.79(d,J=14.9Hz,1H),4.86–4.77(m,1H),4.31(s,3H),2.91(t,J=7.5Hz,2H),2.63(s,3H),2.52(d,6H),1.75–1.66(m,2H),1.43(d,J=6.6Hz,6H),0.96(t,J=7.3Hz,3H).13C NMR(101MHz,DMSO-d6)δ156.55,150.76,149.61,149.13,147.56,144.45,144.32,142.47,134.23,129.02,121.33,42.80,39.49,27.68,22.21(2C),22.09,21.91,21.88,20.82,14.35.HR-MS(ESI):calcd for C21H30N7[M+H]+,380.2557;found 380.2559.
实施例15
(E)-1-甲基-N-苯乙基-3-丙基-5-(2-(3,5,6-三甲基吡嗪-2-基)乙烯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(结构如式II-a-3所示)的制备:
采取化合物II-a-1同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ8.80(s,1H),8.14(d,J=14.9Hz,1H),7.71(d,J=14.9Hz,1H),7.32(dd,J=13.0,5.6Hz,4H),7.23(t,J=7.0Hz,1H),4.26(s,3H),3.98-3.92(m,2H),3.08-3.00(m,2H),2.85(t,J=7.5Hz,2H),2.61(s,3H),2.51(s,6H),1.75-1.66(m,2H),0.95(t,J=7.3Hz,3H).13C NMR(101MHz,DMSO-d6+Pyridine-d5)δ156.44,150.85,149.58,149.54,147.64,144.30,144.17,141.48,140.07,133.68,129.59,129.09(2C),128.85(2C),126.62,121.42,42.72,39.58,35.23,27.74,22.16,21.83(2C),20.82,14.27.HR-MS(ESI):calcd for C26H32N7[M+H]+,442.2714;found442.2713.
实施例16
(E)-N-(3-氯苯乙基)-1-甲基-3-丙基-5-(2-(3,5,6-三甲基吡嗪-2-基)乙烯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(结构如式II-a-4所示)的制备:
采取化合物II-a-1同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ7.92(d,J=15.2Hz,1H),7.55(d,J=15.2Hz,1H),7.49(s,1H),7.42–7.25(m,4H),4.16(s,3H),3.87–3.81(m,2H),3.08–3.00(m,2H),2.80(t,J=7.5Hz,2H),2.56(s,3H),2.49(s,3H),2.46(s,3H),1.79–1.71(m,2H),0.95(t,J=7.3Hz,3H).13C NMR(101MHz,DMSO-d6+Pyridine-d5)δ156.67,150.71,149.53,149.50,147.60,144.49,144.43,142.69,142.31,134.22,133.64,130.55,129.25,128.97,127.84,126.61,121.43,42.18,39.50,34.79,27.76,22.15,21.79(2C),20.88,14.26.HR-MS(ESI):calcd for C26H31ClN7[M+H]+,476.2324;found 476.2321.
实施例17
(E)-N-)4-氟苄基)-1-甲基-3-丙基-5-(2-(3,5,6-三甲基吡嗪-2-基)乙烯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(结构如式II-a-5所示)的制备:
采取化合物II-a-1同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ7.93(t,J=5.9Hz,1H),7.76(d,J=15.2Hz,1H),7.55(dd,J=8.4,5.6Hz,2H),7.47(d,J=15.2Hz,1H),7.15(t,J=8.9Hz,2H),4.79(d,J=5.7Hz,2H),4.25(s,3H),2.80(t,J=7.5Hz,2H),2.53(s,3H),2.47(s,3H),2.45(s,3H),1.80–1.71(m,2H),0.94(t,J=7.3Hz,3H).13C NMR(101MHz,DMSO-d6)δ162.50(d,J=242.40Hz),156.46,150.81,149.60,149.13,147.56,144.47,144.25,142.47,136.65(d,J=3.03Hz),134.04,129.60(d,J=8.08Hz,2C),129.15,121.23,115.36(d,J=21.21Hz,2C),43.61,39.63,27.69,22.12,21.91,21.88,20.86,14.36.HR-MS(ESI):calcd for C25H29FN7[M+H]+,446.2463;found 446.2458.
实施例18
(E)-N-环丙基-1-甲基-3-丙基-5-(2-(吡啶-3-基)乙烯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(结构如式II-a-6所示)的制备:
中间体4-2制备:
将(E)吡啶丙烯酸(0.745g,5mmol),EDCI(1.434g,7.5mmol)和HOBT(1.103g,7.5mmol)溶解在干燥中DCM(10mL),将混合物在25℃下搅拌30分钟。加入化合物3(1.001g,5.5mmol)和TEA(2.073mL,15mmol),并将溶液在室温搅拌过夜。蒸发反应混合物,过滤沉淀物,用水洗涤并干燥,得到化合物4-2。
中间体5-2制备
将化合物4-2(1.567g,5mmol)和甲醇钠(30%,10mL)溶解在甲醇(20mL)中,并回流10h。将混合物在真空下浓缩。用2N HCl将残余物酸化至pH=7。过滤沉淀物,用水洗涤,干燥,得到化合物5-2。
中间体6-2制备
将化合物5-2(1.477g,5mmol)溶解在三氯氧化磷(POCl3,10mL)中,并在100℃下搅拌10h。反应完成后,将混合物真空浓缩,得到深色油状产物。将残余物用冷H2O洗涤,并用DCM(30mL×3)萃取。合并的有机层用饱和NaHCO3溶液,饱和盐水溶液洗涤,用无水Na2SO4干燥,浓缩,得到关键中间体6-2。
中间体II-a-6制备
将中间体6-2(88mg,0.281mmol),环丙胺(0.021mL,0.30mmol)和TEA(0.117mL,0.843mmol)溶于异丙醇(15mL)中,回流6h。反应完成后,除去溶剂,残余物通过柱色谱法纯化,得到化合物II-a-6。结构数据表征:1H NMR(400MHz,CDCl3)δ9.17(s,1H),8.82(d,J=5.2Hz,1H),8.60(d,J=7.9Hz,2H),8.20(d,J=15.8Hz,1H),7.93(dd,J=8.1,5.3Hz,1H),7.81(d,J=15.9Hz,1H),4.26(s,3H),3.42-3.36(m,1H),2.94(t,J=7.5Hz,2H),1.77-1.68(m,2H),1.07-0.87(m,7H).13C NMR(101MHz,DMSO-d6)δ156.61,150.74,149.49,149.37,144.34,142.34,133.88,132.52,131.55,131.41,124.35,121.45,39.48,27.69,24.54,22.16,14.36,7.01(2C).HR-MS(ESI):calcd for C19H23N6[M+H]+,335.1979;found335.1977.
实施例19
(E)-N-异丙基-1-甲基-3-丙基-5-(2-(吡啶-3-基)乙烯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(结构如式II-a-7所示)的制备:
采取化合物II-a-6同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ8.83(d,J=2.2Hz,1H),8.49(dd,J=4.7,1.6Hz,1H),8.16(dt,J=8.1,2.0Hz,1H),7.73(d,J=16.0Hz,1H),7.40(dd,J=8.0,4.7Hz,1H),7.26(d,J=16.0Hz,1H),6.69(d,J=7.7Hz,1H),4.71-4.66(m,1H),4.19(s,3H),2.80(t,J=7.5Hz,2H),1.80-1.70(m,2H),1.34(d,J=6.6Hz,6H),0.94(t,J=7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ156.60,149.47,149.33,149.15,144.33,142.38,133.89,132.52,131.73,131.05,124.33,121.32,42.50,39.51,27.69,22.36,22.17(2C),14.35.HR-MS(ESI):calcd for C19H25N6[M+H]+,337.2135;found337.2133.
实施例20
(E)-1-甲基-N-苯乙基-3-丙基-5-(2-(吡啶-3-基)乙烯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(结构如式II-a-8所示)的制备:
采取化合物II-a-6同样的合成方法。结构数据表征:1H NMR(400MHz,CDCl3)δ8.82(d,J=2.4Hz,1H),8.53(d,J=4.3Hz,1H),7.97(d,J=8.0Hz,1H),7.88(d,J=15.9Hz,1H),7.44–7.35(m,2H),7.37–7.26(m,5H),5.15(t,J=5.6Hz,1H),4.06–4.01(m,2H),4.03(s,3H),3.11(t,J=6.7Hz,2H),2.95(t,J=7.7Hz,2H),1.89-1.82(m,2H),1.04(t,J=7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ156.61,149.48,149.45,149.21,144.37,142.36,140.13,133.81,132.50,131.74,131.08,129.16(2C),128.86(2C),126.59,124.34,121.31,42.57,39.45,35.17,27.70,22.09,14.34.HR-MS(ESI):calcd for C24H27N6[M+H]+,399.2292;found 399.2291.
实施例21
(E)-N-(3-氯苯乙基)-1-甲基-3-丙基-5-(2-(吡啶-3-基)乙烯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(结构如式II-a-9所示)的制备:
采取化合物II-a-6同样的合成方法。结构数据表征:1H NMR(400MHz,CDCl3)δ8.82(s,1H),8.53(d,J=3.9Hz,1H),7.98(d,J=7.9Hz,1H),7.87(d,J=15.9Hz,1H),7.36–7.28(m,5H),7.19(d,J=7.0Hz,1H),5.20(t,J=5.8Hz,1H),4.11(s,3H),4.02(m,2H),3.10(t,J=6.9Hz,2H),2.95(t,J=7.7Hz,2H),1.88–1.86(m,2H),1.04(t,J=7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ156.59,149.53,149.39,149.34,144.37,142.77,142.36,133.83,133.45,132.48,131.64,131.17,130.67,129.09,128.04,126.61,124.35,121.28,42.15,39.47,34.75,27.71,22.16,14.38.HR-MS(ESI):calcd for C24H26ClN6[M+H]+,433.1902;found 433.1905.
实施例22
(E)-N-(4-氟苄基)-1-甲基-3-丙基-5-(2-(吡啶-3-基)乙烯基)-1H-吡唑并[4,3-d]嘧啶-7-胺(结构如式II-a-10所示)的制备:
采取化合物II-a-6同样的合成方法。结构数据表征:1H NMR(400MHz,CDCl3)δ8.78(d,J=2.2Hz,1H),8.52(dd,J=4.8,1.6Hz,1H),7.93(dt,J=7.9,2.0Hz,1H),7.80(d,J=15.9Hz,1H),7.49–7.40(m,2H),7.35–7.27(m,2H),7.13–7.05(m,2H),5.48(t,J=5.5Hz,1H),4.94(d,J=5.4Hz,2H),4.24(s,3H),3.01–2.92(m,2H),1.91–1.83(m,2H),1.04(t,J=7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ161.55(d,J=243.41Hz),156.52,149.52,149.34,149.16,144.36,142.43,136.69(d,J=3.03Hz),133.84,132.48,131.48,131.40,129.87(d,J=8.08Hz,2C),124.35,121.24,115.35(d,J=21.21Hz,2C),43.54,39.63,27.70,22.18,14.36.HR-MS(ESI):calcd for C23H24FN6[M+H]+,403.2041;found 403.2042.
实施例23
(E)-3-(2-(7-(环丙基氨基)-1-甲基-3-丙基-1H-吡唑并[4,3-d]嘧啶-5-基)乙烯基)吡啶1-氧化物(结构如式II-a-11所示)的制备:
化合物II-a-11制备:
将化合物II-a-6(100mg,0.297mmol)溶解于丙酮(6mL)和水(3mL)中。在1小时内将NaHCO3(749mg,8.918mmol)和KHSO5(912mg,2.97mmol)添加3次。将混合物在室温搅拌4h。反应完成后,除去溶剂。残余物通过柱色谱法纯化,得到化合物II-a-11。结构数据表征:1HNMR(600MHz,DMSO-d6)δ8.59(s,1H),8.14(d,J=6.5Hz,1H),7.75(d,J=8.2Hz,1H),7.71(d,J=15.7Hz,1H),7.44–7.39(m,1H),7.33(d,J=15.9Hz,1H),7.28(d,J=3.0Hz,1H),4.15(s,3H),3.13–3.06(m,1H),2.80(t,J=7.5Hz,2H),1.81–1.70(m,2H),0.94(t,J=7.3Hz,3H),0.92–0.88(m,2H),0.73–0.66(m,2H).13C NMR(101MHz,DMSO-d6)δ156.18,150.74,144.46,142.30,138.21,137.93,136.35,133.73,129.49,126.86,123.39,121.48,39.52,27.69,24.58,22.14,14.36,6.98(2C).HR-MS(ESI):calcd for C19H23N6O[M+H]+,351.1928;found 351.1931.
实施例24
(E)3-(2-(7-(异丙基氨基)-1-甲基-3-丙基-1H-吡唑并[4,3-d]嘧啶-5-基)乙烯基)吡啶1-氧化物(结构如式II-a-12所示)的制备:
采取化合物II-a-11同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ8.59(t,J=1.7Hz,1H),8.14(dd,J=6.3,1.0Hz,1H),7.75(d,J=8.4Hz,1H),7.63(d,J=15.9Hz,1H),7.41(dd,J=8.0,6.4Hz,1H),7.30(d,J=16.0Hz,1H),6.72(d,J=7.8Hz,1H),4.72–4.64(m,1H),4.20(s,3H),2.79(t,J=7.5Hz,2H),1.79–1.70(m,2H),1.33(d,J=6.5Hz,6H),0.93(t,J=7.3Hz,3H).13C NMR(101MHz,DMSO-d6)δ156.18,149.14,144.44,142.30,138.18,137.90,136.37,133.85,129.19,126.85,123.47,121.34,42.47,39.50,27.68,22.39(2C),22.15,14.35.HR-MS(ESI):calcd for C19H25N6O[M+H]+,353.2084;found353.2083.
实施例25
(E)-3-(2-(1-甲基-7-(苯乙基氨基)-3-丙基-1H-吡唑并[4,3-d]嘧啶-5-基)乙烯基)吡啶1-氧化物(结构如式II-a-13所示)的制备:
采取化合物II-a-11同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ8.56(s,1H),8.16(d,J=6.3Hz,1H),7.72(d,J=8.1Hz,1H),7.66(d,J=15.9Hz,1H),7.46–7.37(m,2H),7.39–7.29(m,5H),7.27–7.16(m,1H),4.16(s,3H),3.88–3.78(m,2H),3.06–2.98(m,2H),2.79(t,J=7.6Hz,2H),1.82–1.68(m,2H),0.94(t,J=7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ156.20,149.46,144.47,142.25,140.13,138.23,137.75,136.33,133.87,129.25(2C),129.21,128.87(2C),126.93,126.61,123.50,121.32,42.49,39.51,35.17,27.70,22.14,14.38.HR-MS(ESI):calcd for C24H27N6O[M+H]+,415.2241;found415.2239.
实施例26
(E)-3-(2-(7-((3-氯苯乙基)氨基)-1-甲基-3-丙基-1H-吡唑并[4,3-d]嘧啶-5-基)乙烯基)吡啶1-氧化物(结构如式II-a-14所示)的制备:
采取化合物II-a-11同样的合成方法。结构数据表征:1H NMR(600MHz,DMSO-d6)δ8.57(s,1H),8.14(d,J=6.5Hz,1H),7.73(d,J=8.0Hz,1H),7.65(d,J=15.9Hz,1H),7.42(m,2H),7.39–7.23(m,5H),4.15(s,3H),3.88–3.85(m,2H),3.03(t,J=7.4Hz,2H),2.79(t,J=7.6Hz,2H),1.75(m,2H),0.94(t,J=7.3Hz,3H).13C NMR(101MHz,DMSO-d6)δ156.16,149.41,144.48,142.74,142.30,138.21,137.81,136.34,133.80,133.43,130.56,129.23,129.16,128.06,126.85,126.55,123.39,121.29,42.00,39.47,34.81,27.70,22.14,14.37.HR-MS(ESI):calcd for C24H26ClN6O[M+H]+,449.1851;found 449.1856.
实施例27
(E)-3-(2-(7-((4-氟苄基)氨基)-1-甲基-3-丙基-1H-吡唑并[4,3-d]嘧啶-5-基)乙烯基)吡啶1-氧化物(结构如式II-a-15所示)的制备:
采取化合物II-a-11同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ8.57(t,J=1.7Hz,1H),8.14(dd,J=6.3,1.0Hz,1H),7.94(t,J=5.9Hz,1H),7.71(d,J=8.2Hz,1H),7.63–7.51(m,3H),7.41(dd,J=8.0,6.4Hz,1H),7.27(d,J=16.0Hz,1H),7.20–7.11(m,2H),4.82(d,J=5.7Hz,2H),4.24(s,3H),2.79(t,J=7.5Hz,2H),1.79–1.69(m,2H),0.93(t,J=7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ161.57(d,J=243.41Hz),156.07,149.18,144.49,142.37,138.23,137.81,136.63(d,J=3.03Hz),136.30,133.61,130.01(d,J=8.08Hz,2C),129.41,126.90,123.48,121.27,115.32(d,J=21.21Hz,2C),43.42,39.64,27.68,22.15,14.35.HR-MS(ESI):calcd for C23H24FN6O[M+H]+,419.1990;found419.1989.
实施例28
N-环丙基-1-甲基-3-丙基-5-(2-(吡啶-3-基)乙基)-1H-吡唑并[4,3-d]嘧啶-7-胺(结构如式II-a-16所示)的制备:
将化合物II-a-6(100mg,0.297mmol)和5%Pd/C(3.14mg,0.0297mmol)的THF(6mL)混合物在氢气(2atm)下于室温搅拌10h。反应完成后,将混合物过滤,在真空下浓缩,并将残余物通过柱色谱法纯化,得到化合物II-a-16。结构数据表征:1H NMR(600MHz,DMSO-d6)δ8.44(d,J=2.2Hz,1H),8.34(dd,J=4.7,1.6Hz,1H),7.65(d,J=7.8,1H),7.25(dd,J=7.8,4.7Hz,1H),7.12(d,J=2.9Hz,1H),4.09(s,3H),3.14(t,J=7.3Hz,2H),3.06(t,J=7.7Hz,2H),2.96–2.94(m,1H),2.73(t,J=7.5Hz,2H),1.73–1.66(m,2H),0.89(t,J=7.3Hz,3H),0.83–0.75(m,2H),0.65–0.61(m,2H).13C NMR(101MHz,DMSO-d6)δ161.14,151.00,150.18,147.37,143.46,142.14,137.74,136.33,123.70,121.25,39.78,39.34,31.13,27.63,24.45,22.09,14.27,6.99(2C).HR-MS(ESI):calcd for C19H25N6[M+H]+,337.2135;found 337.2130.
实施例29
N-异丙基-1-甲基-3-丙基-5-(2-(吡啶-3-基)乙基)-1H-吡唑并[4,3-d]嘧啶-7-胺(结构如式II-a-17所示)的制备:
采取化合物II-a-16同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ8.41(d,J=1.4Hz,1H),8.34(dd,J=4.8,1.7Hz,1H),7.64(dt,J=7.8,2.0Hz,1H),7.27–7.23(m,1H),6.58(d,J=7.8Hz,1H),4.53–4.41(m,1H),4.14(s,3H),3.09(t,J=6.8Hz,2H),3.05–2.97(m,2H),2.73(t,J=7.5Hz,2H),1.74–1.65(m,2H),1.26(d,J=6.6Hz,6H),0.89(t,J=7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ161.17,150.09,149.43,147.40,143.48,142.21,137.67,136.29,123.73,121.09,42.35,39.78,39.40,31.26,27.64,22.34(2C),22.10,14.30.HR-MS(ESI):calcd for C19H27N6[M+H]+,339.2292;found 339.2293.
实施例30
1-甲基-N-苯乙基-3-丙基-5-(2-(吡啶-3-基)乙基)-1H-吡唑并[4,3-d]嘧啶-7-胺(结构如式II-a-18所示)的制备:
采取化合物II-a-16同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ8.43(s,1H),8.34(d,J=3.1Hz,1H),7.64(d,J=7.8Hz,1H),7.36–7.24(m,5H),7.25–7.20(m,2H),4.11(s,3H),3.76–3.66(m,2H),3.13(t,J=6.7Hz,2H),3.04(t,J=6.7Hz,2H),2.98–2.90(m,2H),2.74(t,J=7.5Hz,2H),1.77–1.61(m,2H),0.90(t,J=7.4Hz,3H).13CNMR(101MHz,DMSO-d6)δ161.23,150.09,149.72,147.45,143.50,142.17,140.13,137.70,136.29,129.15(2C),128.87(2C),126.59,123.76,121.07,42.50,39.53,39.37,35.19,31.33,27.67,22.10,14.34.HR-MS(ESI):calcd for C24H29N6[M+H]+,401.2448;found401.2450.
实施例31
N-(3-氯苯乙基)-1-甲基-3-丙基-5-(2-(吡啶-3-基)乙基)-1H-吡唑并[4,3-d]嘧啶-7-胺(结构如式II-a-19所示)的制备:
采取化合物II-a-16同样的合成方法。结构数据表征:1H NMR(600MHz,DMSO-d6)δ8.40(d,J=2.3Hz,1H),8.32(dd,J=4.8,1.6Hz,1H),7.61(dt,J=7.8,2.1Hz,1H),7.35–7.26(m,2H),7.25–7.19(m,4H),4.08(s,3H),3.73–3.67(m,2H),3.09(t,J=7.7Hz,2H),3.05–2.98(m,2H),2.92(t,J=7.3Hz,2H),2.71(t,J=7.5Hz,2H),1.68(m,2H),0.88(t,J=7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ161.21,150.09,149.68,147.44,143.53,142.78,142.20,136.28,133.40,130.63,129.15,129.05,127.97,126.55,123.74,121.05,42.02,39.53,39.35,34.71,31.37,27.66,22.09,14.34.HR-MS(ESI):calcd for C24H28ClN6[M+H]+,435.2058;found 435.2060.
实施例32
N-(4-氟苄基)-1-甲基-3-丙基-5-(2-(吡啶-3-基)乙基)-1H-吡唑并[4,3-d]嘧啶-7-胺(结构如式II-a-20所示)的制备:
采取化合物II-a-16同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ8.32(dd,J=4.8,1.7Hz,1H),8.28(dd,J=2.3,0.9Hz,1H),7.81(t,J=5.9Hz,1H),7.51–7.42(m,3H),7.21–7.17(m,1H),7.16–7.09(m,2H),4.70(d,J=5.8Hz,2H),4.19(s,3H),3.01–2.92(m,4H),2.72(t,J=7.5Hz,2H),1.73–1.63(m,2H),0.89(t,J=7.4Hz,3H).13CNMR(101MHz,DMSO-d6)δ161.54(d,J=243.41Hz),161.02,150.04,149.51,147.37,143.51,142.24,137.59,136.59(d,J=3.03Hz),136.23,129.85(d,J=8.08Hz,2C),123.66,121.02,115.29(d,J=21.21Hz,2C),43.30,39.89,39.53,31.11,27.64,22.10,14.31.HR-MS(ESI):calcd for C23H26FN6[M+H]+,405.2197;found 405.2196.
实施例33
(E)-4-(1-甲基-3-丙基-5-(2-(3,5,6-三甲基吡嗪-2-基)乙烯基)-1H-吡唑并[4,3-d]嘧啶-7-基)吗啉(结构如式II-b-1所示)的制备:
采取化合物II-a-1同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ8.18(d,J=15.0Hz,1H),7.81(d,J=15.0Hz,1H),4.12(s,3H),3.99–3.96(m,4H),3.83–3.81(m,4H),2.96(t,J=7.5Hz,2H),2.65(s,3H),2.52(d,6H),1.78–1.69(m,2H),0.98(t,J=7.3Hz,3H).13C NMR(101MHz,DMSO-d6+Pyridine-d5)δ156.08,153.63,150.95,149.60,147.76,146.06,144.67,144.16,133.35,129.82,123.96,66.12(2C),49.98(2C),39.21,27.76,21.97,21.83,21.80,20.82,14.29.HR-MS(ESI):calcd for C22H30N7O[M+H]+,408.2506;found 408.2510.
实施例34
(E)-4-(1-甲基-3-丙基-5-(2-(3,5,6-三甲基吡嗪-2-基)乙烯基)-1H-吡唑并[4,3-d]嘧啶-7-基硫吗啉1,1-二氧化物(结构如式II-b-2所示)的制备:
采取化合物II-a-1同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ8.07(d,J=15.1Hz,1H),7.74(d,J=15.1Hz,1H),4.18-4.15(m,4H),4.14(s,3H),3.47-3.73(m,4H),2.93(t,J=7.5Hz,2H),2.64(s,3H),2.52(d,6H),1.82-1.73(m,2H),0.97(t,J=7.3Hz,3H).13C NMR(101MHz,DMSO-d6)δ155.78,152.55,151.12,149.69,147.84,146.02,145.09,144.00,132.97,129.95,123.66,50.70(2C),48.10(2C),39.38,27.70,21.97,21.92(2C),20.89,14.38.HR-MS(ESI):calcd for C22H30N7O2S[M+H]+,456.2176;found456.2178.
实施例35
(E)-4-(1-甲基-3-丙基-5-(2-(吡啶-3-基)乙烯基)-1H-吡唑并[4,3-d]嘧啶-7-基)吗啉(结构如式II-b-3所示)的制备:
采取化合物II-a-6同样的合成方法。结构数据表征:1H NMR(400MHz,CDCl3)δ9.14(s,1H),8.73(d,J=3.9Hz,1H),8.67(d,J=8.2Hz,1H),7.94(d,J=16.0Hz,1H),7.84(dd,J=8.1,5.3Hz,1H),7.59(d,J=16.0Hz,1H),4.10(s,3H),3.85–3.82(m,4H),3.67–3.66(m,4H),2.89(t,J=7.5Hz,2H),1.83-1.74(m,2H),0.97(t,J=7.3Hz,3H).13C NMR(101MHz,DMSO-d6)δ156.06,153.68,149.63,149.40,145.94,144.56,133.93,132.32,131.94,130.72,124.31,123.93,66.15(2C),50.00(2C),39.27,27.75,22.02,14.38.HR-MS(ESI):calcd for C20H25N6O[M+H]+,365.2084;found 365.2088.
实施例36
(E)-4-(1-甲基-3-丙基-5-(2-(吡啶-3-基)乙烯基)-1H-吡唑并[4,3-d]嘧啶-7-基)硫代吗啉1,1-二氧化物(结构如式II-b-4所示)的制备:
采取化合物II-a-6同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ8.88(d,J=2.2Hz,1H),8.52(dd,J=4.8,1.6Hz,1H),8.21(dt,J=8.0,2.0Hz,1H),7.82(d,J=16.0Hz,1H),7.46-7.43(m,1H),7.40(d,J=16.0Hz,1H),4.12(s,3H),4.05-4.02(m,4H),3.44–3.41(m,4H),2.88(t,J=7.5Hz,2H),1.84-1.75(m,2H),0.97(t,J=7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ155.90,152.63,149.76,149.54,145.89,144.99,134.04,132.27,132.24,130.48,124.37,123.69,50.76(2C),48.12(2C),39.41,27.72,22.04,14.39.HR-MS(ESI):calcd for C20H25N6O2S[M+H]+,413.1754;found 413.1779.
实施例37
(E)-3-(2-(1-甲基-7-吗啉代-3-丙基-1H-吡唑并[4,3-d]嘧啶-5-基)乙烯基)吡啶1-氧化物(结构如式II-b-5所示)的制备:
采取化合物II-a-11同样的合成方法。结构数据表征:1H NMR(400MHz,CDCl3)δ8.43(s,1H),8.17(d,J=6.3Hz,1H),7.68(d,J=15.9Hz,1H),7.57(d,J=8.0Hz,1H),7.37(d,J=15.9Hz,1H),7.32(dd,J=8.1,6.4Hz,1H),4.14(s,3H),4.00–3.93(m,4H),3.63(t,J=4.7Hz,4H),3.05–2.97(m,2H),1.94–1.85(m,2H),1.06(t,J=7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ155.66,153.62,146.02,144.50,138.37,138.04,136.17,132.86,130.14,126.89,123.95,123.42,66.14(2C),49.96(2C),39.40,27.75,22.01,14.39.HR-MS(ESI):calcd for C20H25N6O2[M+H]+,381.2034;found 381.2038.
实施例38
(E)-3-(2-(7-(1,1-二氧化硫代吗啉代)-1-甲基-3-丙基-1H-吡唑并[4,3-d]嘧啶-5-基)乙烯基)吡啶1-氧化物(结构如式II-b-6所示)的制备:
采取化合物II-a-11同样的合成方法。结构数据表征:1H NMR(400MHz,DMSO-d6)δ8.64(t,J=1.8Hz,1H),8.15(dd,J=6.3,1.0Hz,1H),7.79(d,J=8.8Hz,1H),7.71(d,J=16.0Hz,1H),7.47–7.40(m,2H),4.11(s,3H),4.05–4.03(m,4H),3.43–3.38(m,4H),2.87(t,J=7.5Hz,2H),1.83–1.74(m,2H),0.96(t,J=7.4Hz,3H).13C NMR(101MHz,DMSO-d6)δ155.30,152.61,146.10,144.65,138.40,137.91,136.14,132.53,130.19,127.16,125.23,123.71,50.69(2C),47.99(2C),39.01,27.54,22.01,14.26.HR-MS(ESI):calcd forC20H25N6O3S[M+H]+,429.1703;found 429.1703.
实施例39
4-(1-甲基-3-丙基-5-(2-(吡啶-3-基)乙基)-1H-吡唑并[4,3-d]嘧啶-7-基)吗啉(结构如式II-b-7所示)的制备:
采取化合物II-a-16同样的合成方法。结构数据表征:1H NMR(400MHz,CDCl3)δ8.50(d,J=2.3Hz,1H),8.44(dd,J=4.9,1.6Hz,1H),7.68–7.65(m,1H),7.25(dd,J=7.4,5.2Hz,1H),4.08(s,3H),3.92–3.86(m,4H),3.55–3.48(m,4H),3.32–3.18(m,4H),3.02–2.92(m,2H),1.89–1.80(m,2H),1.02(t,J=7.3Hz,3H).13C NMR(101MHz,CDCl3)δ160.99,153.75,149.74,146.91,146.83,144.90,137.39,136.33,124.20,123.34,66.38(2C),49.88(2C),39.54,38.43,31.64,27.79,22.16,14.05.HR-MS(ESI):calcd for C20H27N6O[M+H]+,367.2242;found 367.2236.
实施例40
4-(1-甲基-3-丙基-5-(2-(吡啶-3-基)乙基)-1H-吡唑并[4,3-d]嘧啶-7-基)硫代吗啉1,1-二氧化物(结构如式II-b-8所示)的制备:
采取化合物II-a-16同样的合成方法。结构数据表征:1H NMR(400MHz,CDCl3)δ8.46(dd,J=4.9,1.6Hz,1H),8.42(d,J=2.2Hz,1H),7.68(dt,J=7.8,2.0Hz,1H),7.34–7.27(m,1H),4.11–4.02(m,4H),4.08(s,3H),3.32–3.29(m,2H),3.24–3.22(m,2H),3.17(t,J=5.3Hz,4H),3.01–2.93(m,2H),1.90–1.81(m,2H),1.04(t,J=7.4Hz,3H).13C NMR(101MHz,CDCl3)δ160.80,151.88,149.32,147.31,146.88,145.91,137.19,136.66,123.66,123.56,50.54(2C),47.76(2C),39.42,38.43,31.71,27.76,22.09,14.06.HR-MS(ESI):calcd forC20H27N6O2S[M+H]+,415.1911;found 415.1915.
实施例41
以上述实施例制备得到的三甲氧基苯乙烯基六元环类和吡唑并嘧啶类化合物为活性化合物,按照药物制剂常规的制备方法,将上述活性化合物制备成片剂、胶囊剂、锭剂、注射剂、悬浮剂、栓型、软膏剂中的一种或多种剂型。其中,制剂中包括活性化合物本身以及药学上能够接受的辅料,辅料为载体或赋形剂。
其中,上述药物制剂中活性化合物的剂量为0.01-500mg/kg。
其中,赋形剂为碳酸钙、磷酸钙、糖类、淀粉、纤维素衍生物、明胶、植物油或聚乙二醇;载体为稀释剂、崩解剂、粘合剂或润滑剂。
抗炎活性验证实验:
为了验证本发明公开的三甲氧基苯乙烯基六元环类和吡唑并嘧啶类化合物具有抗炎活性,选取上述实施例制备得到的三甲氧基苯乙烯基六元环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)每孔分别先加室温50μL Griess Reagent,Ⅰ再加50μL Griess ReagentⅡ;
(9)使用酶标仪在540nm测定吸光度,带入标曲算出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。
以平衡毒性和抗炎活性的关系为指导,设计和合成具有有效的类药物抗炎活性的新型分子,部分化合物表现出强大的NO生成和iNOS抑制活性,对人正常干细胞细胞的细胞毒性较低。口服药物通过被动扩散渗透时,log P值在0-3范围是最佳,这些化合物的log P此范围内。
由表1可知,本实施例提供的三甲氧基苯乙烯基六元环类和吡唑并嘧啶类化合物对LPS诱导的RAW 264.7细胞模型中,显示出良好的抗炎活性,表明其对各种急慢性炎症的治疗可能具有良好的应用前景,在对脓毒血症等急性炎症和类风湿关节炎,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。
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 (10)
5.根据权利要求2或4所述的制备方法,其特征在于:所述胺类衍生物选自异丙胺、环丙胺、吗啉、硫代吗啉、4-氯苯乙胺、4-氟苯乙胺、4-氟苄胺、2-氯苯乙胺中的任意一种。
6.权利要求1所述的三甲氧基苯乙烯基六元环类化合物在制备抗炎药物中的应用。
7.权利要求3所述的吡唑并嘧啶类化合物在制备抗炎药物中的应用。
8.以权利要求1所述的三甲氧基苯乙烯基六元环类化合物为活性化合物的药物制剂。
9.以权利要求3所述的吡唑并嘧啶类化合物为活性化合物的药物制剂。
10.根据权利要求8或9所述的药物制剂,其特征在于:所述药物制剂为将活性化合物添加药剂学中能够接受的辅料制备成片剂、胶囊剂、锭剂、注射剂、悬浮剂、栓型或软膏剂;所述辅料包括赋形剂和载体,赋形剂为碳酸钙、磷酸钙、糖类、淀粉、纤维素衍生物、明胶、植物油和聚乙二醇中的一种或多种,载体为稀释剂、崩解剂、粘合剂和润滑剂中的一种或多种。
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