CN101967127A - 一种喹唑啉衍生物及其制备方法和制备抗癌药物中的应用 - Google Patents
一种喹唑啉衍生物及其制备方法和制备抗癌药物中的应用 Download PDFInfo
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Abstract
本发明属于药物与化工领域,公开了一种喹唑啉衍生物及其制备方法和作为抗癌药物的用途。该喹唑啉衍生物的结构式为:,其中R1为NH(CH2)mNR5或NH(CH2)m-Ar;R2为NHCO(CH2)n NR5、NHCO(CH2)n-Ar、NHCO(CH2)nNH(CH2)nNR5或NHCO(CH2)nNH(CH2)n-Ar;R3为F、Cl、Br、I、H、CH3、SO2CH3或OCH3;R4为H、NHCO(CH2)nNR5、NHCO(CH2)n-Ar、NHCO(CH2)nNH(CH2)nNR5或NHCO(CH2)nNH(CH2)n-Ar。-Ar表示各种芳香环,包括各种芳香杂环;m=2、3或4;n=1、2、3、4或5;R5表示C1-6的烷基、C3-6的环烷基、哌啶基、吗啉基、哌嗪基或吡噁啉基等。本发明同时公开了该喹唑啉衍生物的制备方法及其作为抗癌药物的用途。实验证明,本发明所涉及的喹唑啉衍生物对端粒DNA表达有很强的抑制作用,对多种癌细胞株具有显著的抑制作用,且对正常细胞毒性小,在制备抗癌药物上有着广阔的应用空间。
Description
技术领域
本发明属于药物与化工领域,涉及一种喹唑啉衍生物及其制备方法,以及其在制备用于抗癌药物中的用途。
背景技术
癌症是威胁人类健康和生命安全的主要疾病之一。据统计,全世界每年新增癌症患者达400万人左右。抗癌药物的研究与开发一直是化学家和药物学家关注的热点。寻找高效、高选择性、毒副作用小的抗癌药物是药物研究开发的重要方向之一。
以DNA为靶点设计合成抗癌药物,特别是针对具有重要生理意义的端粒DNA及原癌基因DNA的特殊高级结构设计合成小分子抑制剂,是发展新型抗癌药物的重要方向。与端粒DNA相互作用的小分子化合物具有一些共同的结构特征:有三个或者更多的平面芳环结构;一条或则几条生理条件下带正电荷的侧链。它的抗癌作用机制主要是通过与端粒DNA的相互作用,抑制癌细胞的端粒酶活性,从而抑制癌细胞的复制。
吲哚喹啉类化合物是自然界中比较稀少的一种生物碱,具有四个平面芳环的结构,quindoline和cryptolepine是该类化合物的典型代表,这两种化合物分别于1977年和1929年从西非植物Cryptolepis sanguinolenta中首次分离出来。本研究小组先后报道了一系列11位氨基侧链取代的吲哚喹啉类衍生物(J.Med.Chem.2005,48,7315-7321;J.Med.Chem.2008,51,6381-6392)通过与端粒G-四链体DNA相互作用抑制端粒酶活性,对多种癌细胞株具有显著的抑制作用。
尽管吲哚喹啉类化合物的抗癌效果已经得到证实,但是由于目前已有的多种吲哚喹啉类化合物对G-四链体DNA的选择能力仍有待提高,同时由于自然界中吲哚喹啉类化合物的资源有限,目前,吲哚喹啉类化合物在抗癌方面的应用仍存在较大的限制。
发明内容
本发明的目的在于针对现有技术的不足,提供一种能更为有效抑制癌细胞且便于人工合成的喹唑啉衍生物。
本发明的另一个目的在于提供该喹唑啉衍生物的制备方法。
本发明还有一个目的在于提供该喹唑啉衍生物在制备抗癌药物中的应用。
本发明根据一些与端粒DNA相互作用的小分子化合物的结构特征,以11位取代的吲哚喹啉为先导化合物,在保留11位的氨基侧链的基础上,将吲哚喹啉四环母体中的五元环开环,利用电子等排原理将喹啉环4位-CH-换成-N-,得到2位苯基取代的喹唑啉为母体骨架,同时在取代苯环2位引入一条侧链,设计出一系列与端粒DNA相互作用的喹唑啉类衍生物。
本发明的上述技术目的是通过以下技术方案实现上述目的:
本发明提供了一种喹唑啉衍生物,其结构式为:
其中各基团可以为以下任一组合:
组合一:
R1为NH(CH2)mNR5或NH(CH2)m-Ar;R2为NHCO(CH2)n NR5、NHCO(CH2)n-Ar、NHCO(CH2)nNH(CH2)nNR5或NHCO(CH2)nNH(CH2)n-Ar;R3为F、C1、Br、I、H、CH3、SO2CH3或OCH3;R4为H。
其中,m=2、3或4;n=1、2、3、4或5;-Ar为芳香环或芳香杂环;R5为C1-6的烷基、C3-6的环烷基、哌啶基、吗啉基、哌嗪基或吡噁啉基。
组合二:
R1为NH(CH2)mNR5或NH(CH2)m-Ar;R2和R4相同,为NHCO(CH2)nNR5、NHCO(CH2)n-Ar、NHCO(CH2)nNH(CH2)nNR5或NHCO(CH2)nNH(CH2)n-Ar;R3为F、Cl、Br、I、H、CH3、SO2CH3或OCH3;
其中,m=2、3或4;n=1、2、3、4或5;-Ar为芳香环或芳香杂环;R5为C1-6的烷基、C3-6的环烷基、哌啶基、吗啉基、哌嗪基或吡噁啉基。
本发明同时提供了该喹唑啉衍生物的制备方法,其特征在于包括如下步骤:
(1)当R1=NH(CH2)mNR5或NH(CH2)m-Ar,m=2或3,R2=NHCO(CH2)nNR5、NHCO(CH2)n-Ar、NHCO(CH2)nNH(CH2)nNR5或NHCO(CH2)nNH(CH2)n-Ar,n=1、2、3、4或5,R3=F、Cl、Br、I、H、CH3、SO2CH3或OCH3,R4=H,R5为C1-6的烷基、C3-6的环烷基、哌啶基、吗啉基、哌嗪基或吡噁啉基时,合成过程为:
其步骤为:邻氨基苯甲酰胺与4位取代的邻硝基苯甲酰氯进行缩合反应,得到化合物Q-2,Q-2在碱性条件下(优选10%的KOH的醇水混合溶液)自身环合得到喹唑酮类化合物Q-3,将其进行氯代反应(反应物优选POCl3)得到喹唑啉类化合物Q-4,Q-4与脂肪胺链(NH2(CH2)mX,其中m=2或3,X=R5或Ar)发生取代反应,得到化合物Q-5,然后经还原反应(反应物优选Pd/C)得到化合物Q-6。Q-6与氯取代的烷基酰氯[Cl(CH2)nCOCl]进行烷基化反应得到烷基化中间体Q-7后,再与取代胺化合物(NHR5或NH(CH2)nNR5)作用,通过柱层析或者重结晶得到目标产物Q-8。
(2)当R1=NH(CH2)mNR5或NH(CH2)m-Ar,m=2或3,R2=R4=NHCO(CH2)nNR5、NHCO(CH2)n-Ar、NHCO(CH2)nNH(CH2)nNR5或NHCO(CH2)nNH(CH2)n-Ar,n=1、2、3、4或5,R3=F、Cl、Br、I、H、CH3、SO2CH3或OCH3,R5为C1-6的烷基、C3-6的环烷基、哌啶基、吗啉基、哌嗪基或吡噁啉基时,合成过程为:
其步骤为:2-氨基-5硝基苯甲酰胺与4位取代的邻硝基苯甲酰氯缩合,得到化合物Q-N-2,Q-N-2在碱性条件下(优选10%的KOH的醇水混合溶液)自身环合得到喹唑酮类化合物Q-3,将其进行氯代反应(反应物优选POCl3)得到喹唑啉类化合物Q-N-4,Q-N-4与脂肪胺链(NH2(CH2)mX,其中m=2或3,X=R5或Ar)发生取代反应,得到化合物Q-N-5,然后经还原反应(反应物优选Pd/C)得到化合物Q-N-6。Q-N-6与氯取代的烷基酰氯[Cl(CH2)nCOCl]进行烷基化反应得到烷基化中间体Q-N-7后,再与取代胺化合物(NHR5、NH(CH2)nNR5)作用,通过柱层析或者重结晶得到目标产物Q-N-8。
本发明的所涉及的喹唑啉衍生物与富含鸟嘌呤的端粒DNA具有很强的相互作用,实验显示对癌细胞中的端粒酶有良好的抑制活性的效果。进一步实验证明,本发明所涉及的喹唑啉衍生物对多种癌细胞株具有显著的抑制作用,因此可用于制备抗癌药物。
本发明的喹唑啉衍生物可与药学上可接受的辅助剂混合,制备各种剂型的抗肿瘤药物,如片剂、丸剂、胶囊、注射剂、悬浮剂或乳剂等。
本发明所涉及的2,4-二取代喹唑啉衍生物是根据小分子配体与G-四链体相互作用的结构特点合理设计的一系列具有双链取代能够形成潜在的分子内氢键半刚性平面的新型的G-四链体小分子配体。研究表明,能够诱导富含G序列DNA形成G-四链体或稳定G-四链体结构的小分子配体,可通过抑制端粒酶活性或降低癌基因转录表达而达到抑制肿瘤的效果。该类化合物以11位氨基侧链取代的吲哚喹啉类衍生物为先导化合物,在保留11位的氨基侧链的基础上,将吲哚喹啉四环母体中的五元环开环,利用电子等排原理将喹啉环4位-CH-换成-N-,使2位取代苯环上的氨基可与新的喹唑啉母环上两个氮原子都能形成潜在的氢键,从而获得“刚柔并济”母体芳环结构,希望能增加对G-四链体DNA的选择性。此外在取代苯环2位氨基再引入一条具氨基末端的侧链,以增加对G-四链体的沟槽结合力,从而提高对G-四链体DNA的结合能力和选择能力。
与现有技术相比,本发明具有以下有益效果:
1.本发明的新型喹唑啉衍生物与富含鸟嘌呤的端粒DNA具有很强的相互作用,显示对癌细胞中的端粒酶良好的抑制活性,从而对多种癌细胞株具有显著的抑制作用。
2.与传统的作用于激酶的喹唑啉类抗癌药物相比,本发明的新型喹唑啉衍生物作用于广泛存在人体基因组的G-四链体DNA,具有良好的靶向性。
3.本发明的新型喹唑啉衍生物对G-四链体DNA有着良好的结合能力和选择能力,有效降低了癌基因转录的表达,从而达到抑制肿瘤的良好效果。
4.本发明的新型喹唑啉衍生物对正常细胞毒性小,在制备抗癌药物的应用中安全性高。
5.本发明的新型喹唑啉衍生物可以可制成各种剂型的抗癌药物,具有很高的医学价值和广阔的市场前景。
具体实施方式
以下通过具体的实施例进一步说明本发明的技术方案。
实施例一:化合物QMC-2的合成
将549mmol干燥的4-氯-2-硝基苯甲酸溶于50ml氯化亚砜中,回流1.5h后蒸去氯化亚砜,得到的棕色液体在冰浴条件下缓慢缓慢滴加到溶有766mmol邻氨基苯甲酰胺和1532mmol三乙胺的氯仿(200ml)溶液中,室温条件下搅拌5h,过滤,乙醇洗涤,并用乙醇重结晶,得白色固体QMC-2。
产率:86%;1H NMR(400MHz,DMSO-d6)12.56(s,1H),8.44(d,J=8.2Hz,1H),8.39(s,1H),8.26(d,J=1.6Hz,1H),8.04-7.96(m,1H),7.93-7.85(m,2H),7.81(s,1H),7.59(t,J=7.8Hz,1H),7.24(t,J=7.6Hz,1H).ESI-MS m/z:320[M+H]+。
化合物QMC-2
实施例二:化合物Q-2的合成
化合物Q-2
方法同实施例一,所不同的是用2-硝基苯甲酸代替4-氯-2-硝基苯甲酸,得白色固体Q-2。
产率:88%;1H NMR(400MHz,DMSO)12.57(s,1H),8.53(d,J=8.2Hz,1H),8.43(s,1H),8.13(d,J=8.3Hz,1H),7.95-7.78(m,5H),7.62(dd,J=11.4,4.0Hz,1H),7.29-7.22(m,1H).ESI-MS m/z:286[M+H]+。
实施例三:化合物QMC-3的合成
将376mmol干燥的QMC-2与100ml 10%的氢氧化钾水溶液和100ml乙醇混匀后,在95℃反应4~5小时。结束反应后,蒸出乙醇,用盐酸调节溶液的pH值至1~3之间,析出大量白色固体,过滤并干燥,以石油醚/乙酸乙酯(体积比3/1)作为洗脱剂通过硅胶层析纯化,得到白色固体QMC-3。
产率:92%;1H NMR(400MHz,DMSO)12.87(s,1H),8.19(d,J=2.0Hz,1H),8.05(d,J=8.0Hz,1H),7.89(dd,J=8.4,2.0Hz,1H),7.78(d,J=8.4Hz,1H),7.71(t,J=7.8Hz,1H),7.51(d,J=8.2Hz,1H),7.44(t,J=7.7Hz,1H).ESI-MSm/z:302[M+H]+。
化合物QMC-3
实施例四:化合物Q-3的合成
方法同实施例三,所不同的是用Q-2代替QMC-2,得白色固体Q-3。
产率:95%;1H NMR(400MHz,DMSO)12.86(s,1H),8.27-8.16(m,2H),7.95-7.81(m,4H),7.67(d,J=7.8Hz,1H),7.62-7.56(m,1H).ESI-MS m/z:268[M+H]+。
化合物Q-3
实施例五:化合物QMC-4的合成
将33.2mmol干燥的QMC-3溶于100ml甲苯中,加入5倍摩尔量三氯氧磷和5倍摩尔量摩尔量的N,N-二乙基苯胺,在105℃回流反应5小时。反应结束后按顺序用等体积以下溶液洗涤:水、20%氢氧化钠水溶液(两次)、水、饱和食盐水、1M盐酸、水。滤出洗涤过程中析出的淡红色絮状固体,用少量乙醇洗涤,得大部分产物。滤液用无水硫酸镁干燥后蒸干甲苯,用乙醇洗涤析出的固体,得一部分产物。两部分产物加在一起为淡黄白色固体,以氯仿/甲醇(体积比15/1)作为洗脱剂通过硅胶层析纯化,得白色固体QMC-4。
产率:61%;1H NMR(400MHz,DMSO)8.36-8.31(m,1H),8.26(d,J=2.1Hz,1H),8.23-8.17(m,2H),8.10(d,J=8.1Hz,1H),7.96(ddd,J=9.1,5.9,2.2Hz,2H).ESI-MS m/z:321[M+H]+。
化合物QMC-4
实施例六:化合物Q-4的合成
方法同实施例五,所不同的是用Q-3代替QMC-3,得白色固体Q-4。
产率:72%;1H NMR(400MHz,DMSO)8.22(ddd,J=16.6,8.0,1.0Hz,2H),7.97-7.82(m,4H),7.69(d,J=7.7Hz,1H),7.63-7.58(m,1H).ESI-MSm/z:286[M+H]+。
化合物QMC-4
实施例七:化合物QMC-5的合成
将15.7mmol干燥的QMC-4溶于80ml四氢呋喃中,加入1.5倍摩尔量的3-二甲胺基丙胺,在68℃反应6小时。反应结束后蒸出四氢呋喃,加足量水与少量乙酸乙酯,超声震荡使析出固体呈小颗粒状。过滤,干燥,以氯仿/甲醇(体积比(30/1)作为洗脱剂通过硅胶层析纯化,得白色固体QMC-5。
产率:51%;1H NMR(400MHz,CDCl3)8.95(s,1H),8.21(d,J=8.4Hz,1H),7.84(d,J=8.3Hz,1H),7.75-7.66(m,2H),7.62-7.56(m,2H),7.45(t,J=7.3Hz,1H),3.66(dd,J=10.4,5.6Hz,2H),2.63-2.55(m,2H),2.38(s,6H),1.88-1.82(m,2H).ESI-MS m/z:386[M+H]+。
化合物QMC-5
实施例八:化合物QE-5的合成
方法同实施例七,所不同的是用Q-4代替QMC-4,用3-二乙胺基丙胺代替3-二甲胺基丙胺,反应时间减少至4h,得白色固体QE-5。
产率:76%;1H NMR(400MHz,CDCl3)8.97(s,1H),8.12(d,J=7.0Hz,1H),7.79(d,J=8.4Hz,1H),7.64(dd,J=8.7,6.3Hz,3H),7.56(t,J=7.4Hz,1H),7.44(t,J=7.6Hz,1H),7.36(t,J=7.4Hz,1H),3.61(dd,J=9.7,5.3Hz,2H),2.61(dt,J=14.2,6.2Hz,6H),1.81-1.75(m,2H),1.05(t,J=7.1Hz,6H).ESI-MS m/z:380[M+H]+。
化合物QE-5
实施例九:化合物QMC-6的合成将26mmol干燥的QMC-5溶于正丙醇中,加入1.5倍摩尔量的水合肼(80%)和催化量的Pd/C(10%),在80℃反应30分钟。反应结束后滤出Pd/C,蒸出正丙醇,加足量水,析出固体。过滤,干燥,得白色粉末状固体QMC-6。
产率:96%;1H NMR(400MHz,CDCl3)8.57(s,1H),8.51(d,J=8.7Hz,1H),7.78-7.73(m,1H),7.70-7.61(m,2H),7.41-7.35(m,1H),6.77(s,2H),6.71(dt,J=8.3,1.9Hz,2H),3.84(dd,J=10.5,5.8Hz,2H),2.69-2.62(m,2H),2.42(s,6H),1.96(dd,J=6.7,4.9Hz,2H).ESI-MS m/z:356[M+H]+。
化合物QMC-6
实施例十:化合物QE-6的合成
方法同实施例九,所不同的是用QE-5代替QMC-5,得白色固体QE-6。
产率:91%;1H NMR(400MHz,CDCl3)8.69(s,1H),8.49(dd,J=8.0,1.6Hz,1H),7.69(d,J=8.2Hz,1H),7.55(td,J=7.2,1.4Hz,2H),7.27-7.22(m,1H),7.10(ddd,J=8.2,7.1,1.7Hz,1H),6.68(ddd,J=8.1,7.2,1.2Hz,1H),6.64(dd,J=8.1,1.0Hz,1H),6.52(s,2H),3.74(dd,J=10.1,5.7Hz,2H),2.62-2.59(m,2H),2.55(q,J=7.1Hz,4H),1.79(dt,J=11.3,5.7Hz,2H),1.02(t,J=7.1Hz,6H).ESI-MS m/z:350[M+H]+。
化合物QE-6
实施例十一:化合物QMC-7A的合成
将8mmol干燥的QMC-6溶于50ml二氯甲烷中,加入0.5倍摩尔量的无水碳酸钾,再慢慢滴加2倍摩尔量的氯乙酰氯,室温搅拌反应过夜。反应完后滤出淡黄白色不溶物,蒸干二氯甲烷得深色固体,两部分固体加在一起用醇洗涤,得浅黄白色固体。产物柱层析纯化(洗脱剂梯度∶氯仿∶甲醇=50∶1,25∶1,10∶1,5∶1)得白色固体QMC-7A。
产率:85%;1H NMR(400MHz,CDCl3)14.29(s,1H),8.84(s,1H),8.81(d,J=2.1Hz,1H),8.62(d,J=8.6Hz,1H),7.95(d,J=8.7Hz,1H),7.84(d,J=8.3Hz,1H),7.73(ddd,J=8.3,7.0,1.3Hz,1H),7.50-7.44(m,1H),7.17(dd,J=8.6,2.2Hz,1H),4.29(s,2H),3.92(dd,J=11.0,5.4Hz,2H),2.86-2.76(m,2H),2.55(s,6H),2.09-2.02(m,2H).ESI-MS m/z:432[M+H]+。
化合物QMC-7A
实施例十二:化合物QMC-7B的合成
方法同实施例十一,所不同的是用3-氯丙酰氯代替氯乙酰氯,得白色固体QMC-7B。
产率:73%;1H NMR(400MHz,CDCl3)14.24(s,1H),8.79(s,1H),8.76(d,J=2.1Hz,1H),8.57(d,J=8.6Hz,1H),7.90(d,J=8.7Hz,1H),7.79(d,J=8.3Hz,1H),7.68(ddd,J=8.3,7.0,1.3Hz,1H),7.49-7.44(m,1H),7.12(dd,J=8.6,2.2Hz,1H),3.91(dd,J=10.7,5.5Hz,2H),3.72(t,J=6.2Hz,2H),2.76(t,J=5.9Hz,2H),2.75-2.70(m,2H),2.49(s,6H),2.06-1.96(m,2H).ESI-MS m/z:446[M+H]+。
化合物QMC-7B
实施例十三:化合物QMC-7C的合成
方法同实施例十一,所不同的是用4-氯丁酰氯代替3-氯丙酰氯,得白色固体QMC-7C。
产率:69%;1H NMR(400MHz,CDCl3)14.20(s,1H),8.94(s,1H),8.85(d,J=2.2Hz,1H),8.67(d,J=8.6Hz,1H),7.79-7.69(m,3H),7.50-7.44(m,1H),7.11(dd,J=8.6,2.2Hz,1H),3.90(dd,J=10.5,5.7Hz,2H),3.72(t,J=6.2Hz,2H),2.77(t,J=5.0Hz,2H),2.74(d,J=6.9Hz,2H),2.49(s,6H),2.30(dt,J=13.4,6.6Hz,2H),2.04-1.98(m,2H).ESI-MS m/z:460[M+H]+。
化合物QMC-7C
实施例十四:化合物QE-7A的合成
方法同实施例十一,所不同的是用QE-6代替QMC-6,得白色固体QE-7A。
产率:75%;1H NMR(400MHz,CDCl3)14.06(s,1H),9.03(s,1H),8.60(ddd,J=7.9,3.5,1.3Hz,2H),7.85(dd,J=8.7,1.0Hz,1H),7.64-7.59(m,2H),7.38-7.30(m,2H),7.15-7.10(m,1H),4.19(s,2H),3.77(dd,J=9.9,5.6Hz,2H),2.65-2.61(m,2H),2.58(q,J=7.1Hz,4H),1.80(dt,J=11.2,5.8Hz,2H),1.04(t,J=7.1Hz,6H).ESI-MS m/z:426[M+H]+。
化合物QE-7A
实施例十五:化合物QE-7B的合成
方法同实施例十一,所不同的是用QE-6代替QMC-6,用3-氯丙酰氯代替氯乙酰氯,得白色固体QE-7B。
产率:75%;1H NMR(400MHz,CDCl3)14.19(s,1H),9.18(s,1H),8.78-8.71(m,2H),7.74(dd,J=13.9,7.3Hz,3H),7.47-7.41(m,2H),7.20-7.14(m,1H),3.97(t,J=6.9Hz,2H),3.89(dd,J=10.0,5.5Hz,2H),3.02(t,J=6.9Hz,2H),2.78-2.74(m,2H),2.70(q,J=7.1Hz,4H),1.96-1.89(m,2H),1.15(t,J=7.1Hz,6H).ESI-MS m/z:440[M+H]+。
化合物QE-7B
实施例十六:化合物QMC-8A-1的合成
取1mmol干燥的QMC-7A加入到10ml无水六氢吡啶中,加热至回流,回流反应6小时,加入足量水和少量乙醚,超声震荡后静置,析出絮状白色固体,过滤,干燥,用乙醇-乙醚混合液重结晶得到白色固体QMC-8A-1。
产率:78%;1H NMR(400MHz,CDCl3)13.51(s,1H),9.00(s,1H),8.89(d,J=2.1Hz,1H),8.51(d,J=8.6Hz,1H),7.99(d,J=8.2Hz,1H),7.72(t,J=7.6Hz,1H),7.60(d,J=8.0Hz,1H),7.45(t,J=7.4Hz,1H),7.12(dd,J=8.6,2.1Hz,1H),3.86(dd,J=10.2,5.6Hz,2H),3.26(s,2H),2.67-2.61(m,2H),2.57-2.44(m,4H),2.41(s,6H),1.94-1.87(m,2H),1.46(dt,J=10.9,5.6Hz,4H),1.37-1.29(m,2H).13C NMR(100MHz,CDCl3)170.12,160.56,159.41,148.66,140.14,136.35,132.17,131.77,128.41,125.85,123.76,122.69,121.02,120.66,113.84,65.22,59.93,54.81,45.50,42.73,25.28,24.45,23.84.HRMS(ESI):Cacldfor(M-H)-(C26H33ClN6O)requires m/z 479.2326,found 479.2320.Anal.Cacld forC26H33ClN6O.H2O:C,62.57;H,7.07;N,16.84.Found:C,62.46;H,7.03;N,16.84。
化合物QMC-8A-1
实施例十七:化合物QMC-8A-2的合成
方法同实施例十六,所不同的是用四氢吡咯代替六氢吡啶,反应6h,得白色固体QMC-8A-2。
产率:74%;1H NMR(400MHz,CDCl3)13.84(s,1H),8.93(s,2H),8.57(d,J=8.1Hz,1H),7.92(d,J=7.8Hz,1H),7.69(d,J=6.6Hz,1H),7.60(d,J=7.5Hz,1H),7.43(t,J=6.9Hz,1H),7.12(d,J=8.1Hz,1H),3.86(dd,J=10.0,5.8Hz,2H),3.43(s,2H),2.68(t,J=7.0Hz,4H),2.65-2.52(m,2H),2.40(s,6H),1.97-1.84(m,2H),1.71(t,J=7.2Hz,4H).13C NMR(100MHz,CDCl3)170.55,160.50,159.38,148.72,140.36,136.42,131.99,131.76,128.01,125.79,123.54,122.66,121.01,120.69,113.80,62.22,59.78,54.52,45.44,42.53,24.51,23.93.HRMS(ESI):Cacld for(M-H)-(C25H31ClN6O)requires m/z 465.2170,found465.2162.Anal.Cacld for C25H31ClN6O·H2O:C,61.91;H,6.86;N,17.33.Found:C,61.88;H,6.53;N,17.38。
化合物QMC-8A-2
实施例十八:化合物QMC-8A-3的合成
方法同实施例十六,所不同的是用二乙胺代替六氢吡啶,反应5h,得白色固体QMC-8A-3。
产率:74%;1H NMR(400MHz,CDCl3)13.60(s,1H),8.92(d,J=2.1Hz,2H),8.53(d,J=8.6Hz,1H),7.90(d,J=8.3Hz,1H),7.71(t,J=7.3Hz,1H),7.60(d,J=8.0Hz,1H),7.43(t,J=7.5Hz,1H),7.13(dd,J=8.6,2.1Hz,1H),3.86(dd,J=10.3,5.5Hz,2H),3.30(s,2H),2.68(q,J=7.2Hz,4H),2.65-2.55(m,2H),2.40(s,6H),1.90(dd,J=16.7,5.9Hz,2H),0.99(t,J=7.1Hz,6H).13C NMR(100MHz,CDCl3)172.03,160.53,159.44,148.88,140.01,136.26,132.04,131.93,128.02,125.71,124.22,122.73,121.02,120.86,113.85,59.92,58.81,49.09,45.51,42.65,24.53,11.64.HRMS(ESI):Cacld for(M-H)-(C25H33ClN6O)requires m/z467.2326,found 467.2319.Anal.Cacld for C25H33ClN6O·H2O:C,61.65;H,7.24;N,17.26.Found:C,61.58;H,7.21;N,17.04。
化合物QMC-8A-3
实施例十九:化合物QMC-8A-4的合成
方法同实施例十六,所不同的是用1-甲基哌嗪代替六氢吡啶,反应8h,得白色固体QMC-8A-4。
产率:66%;1H NMR(400MHz,CDCl3)13.51(s,1H),8.98(s,1H),8.86(d,J=2.1Hz,1H),8.49(d,J=8.6Hz,1H),7.95(d,J=8.2Hz,1H),7.77-7.67(m,2H),7.47(t,J=7.5Hz,1H),7.13(dd,J=8.6,2.1Hz,1H),3.87(dd,J=10.4,5.5Hz,2H),3.31(s,2H),2.72-2.67(m,2H),2.67-2.51(m,4H),2.46(s,6H),2.40-2.24(m,4H),2.12(s,3H),2.01-1.91(m,2H).13C NMR(100MHz,CDCl3)169.36,160.52,159.45,148.55,139.93,136.37,132.42,131.75,128.46,126.01,123.79,122.85,121.29,120.67,113.86,64.20,59.29,54.15,53.35,45.80,45.20,42.04,24.31.HRMS(ESI):Cacld for(M-H)-(C26H34ClN7O)requires m/z 494.2435,found 494.2421.Anal.Cacld for C26H34ClN7O·H2O:C,60.75;H,7.06;N,19.07.Found:C,60.66;H,6.97;N,18.89。
化合物QMC-8A-4
实施例二十:化合物QMC-8A-5的合成
方法同实施例十六,所不同的是用吗啡啉代替六氢吡啶,反应4h,得白色固体QMC-8A-5。
产率:78%;1H NMR(400MHz,CDCl3)13.67(s,1H),9.09(s,1H),8.88(d,J=2.1Hz,1H),8.53(d,J=8.6Hz,1H),7.92(d,J=8.2Hz,1H),7.77-7.69(m,1H),7.62(d,J=8.1Hz,1H),7.46(t,J=7.6Hz,1H),7.13(dd,J=8.6,2.2Hz,1H),3.86(dd,J=10.2,5.6Hz,2H),3.64-3.53(m,4H),3.32(s,2H),2.68-2.62(m,2H),2.63-2.53(m,4H),2.42(s,6H),1.94-1.85(m,2H).13C NMR(100MHz,CDCl3)168.97,160.56,159.40,148.43,140.04,136.45,132.35,131.83,128.02,126.02,123.51,122.86,121.22,120.55,113.89,66.34,64.81,59.95,53.78,45.51,42.80,24.41.HRMS(ESI):Cacld for(M-H)-(C25H31ClN6O2)requires m/z481.2119,found 481.2107.Anal.Cacld for C25H31ClN6O2:C,62.17;H,6.47;N,17.40.Found:C,62.24;H,6.36;N,17.55。
化合物QMC-8A-5
实施例二十一:化合物QMC-8A-6的合成
方法同实施例十六,所不同的是用1-(2-氨乙基)吡咯烷代替六氢吡啶,反应12h,得白色固体QMC-8A-6。
产率:44%;1H NMR(400MHz,CDCl3)14.04(s,1H),8.94(s,1H),8.90(s,1H),8.60(d,J=8.6Hz,1H),7.95(d,J=8.2Hz,1H),7.68(t,J=7.5Hz,1H),7.58(d,J=8.1Hz,1H),7.41(t,J=7.5Hz,1H),7.10(d,J=8.5Hz,1H),3.84(dd,J=9.9,5.2Hz,2H),3.58(s,2H),2.76(t,J=6.1Hz,2H),2.63-2.57(m,2H),2.51(t,J=6.1Hz,2H),2.42(t,J=5.9Hz,4H),2.37(s,6H),1.96-1.88(m,2H),1.80-1.67(m,4H).13C NMR(100MHz,CDCl3)171.48,160.57,159.36,148.62,140.53,136.60,132.36,131.85,128.03,125.83,123.16,122.67,121.06,120.49,113.91,59.93,55.63,54.79,54.11,48.42,45.51,42.71,24.54,23.49.HRMS(ESI):Cacld for(M-H)-(C27H36ClN7O)requires m/z 508.2592,found 508.2585.Anal.Cacld for C27H36C1N7O·H2O:C,61.41;H,7.25;N,18.57.Found:C,61.22;H,7.21;N,18.50。
化合物QMC-8A-6
实施例二十二:化合物QMC-8A-7的合成
方法同实施例十六,所不同的是用1-(2-氨基乙基)哌啶代替六氢吡啶,反应12h,得白色固体QMC-8A-7。
产率:47%;1H NMR(400MHz,CDCl3)14.04(s,1H),8.95(s,1H),8.91(d,J=1.9Hz,1H),8.61(d,J=8.6Hz,1H),7.96(d,J=8.3Hz,1H),7.69(t,J=7.6Hz,1H),7.59(d,J=8.0Hz,1H),7.43(t,J=7.5Hz,1H),7.11(dd,J=8.6,1.9Hz,1H),3.86(dd,J=9.9,5.3Hz,2H),3.59(s,2H),2.75(t,J=6.1Hz,2H),2.66-2.60(m,2H),2.40(s,6H),2.38-2.34(m,2H),2.34-2.13(m,4H),1.90(dt,J=10.7,5.5Hz,2H),1.55(dt,J=10.6,5.2Hz,4H),1.44-1.35(m,2H).13C NMR(100MHz,CDCl3)171.55,160.49,159.30,148.58,140.48,136.50,132.25,131.83,127.97,125.78,123.17,122.61,121.04,120.43,113.87,59.90,58.24,54.84,54.59,46.56,45.50,42.68,26.01,24.53,24.46.HRMS(ESI):Cacld for(M-H)-(C28H38ClN7O)requires m/z 522.2748,found 522.2745.Anal.Cacld forC28H38ClN7O·H2O:C,62.03;H,7.44;N,18.09.Found:C,62.14;H,7.45;N,18.17。
化合物QMC-8A-7
实施例二十三:化合物QMC-8A-8的合成
方法同实施例十六,所不同的是用3-二甲胺基丙胺代替六氢吡啶,反应10h,得白色固体QMC-8A-8。
产率:55%;1H NMR(400MHz,CDCl3)14.05(s,1H),8.99(s,1H),8.89(d,J=2.1Hz,1H),8.62(d,J=8.6Hz,1H),7.88(d,J=8.2Hz,1H),7.71(t,J=7.6Hz,1H),7.60(d,J=8.0Hz,1H),7.44(t,J=7.5Hz,1H),7.12(dd,J=8.6,2.1Hz,1H),3.87(dd,J=10.2,5.5Hz,2H),3.60(s,2H),2.74(t,J=7.1Hz,2H),2.67-2.61(m,2H),2.41(s,6H),2.29(t,J=7.2Hz,2H),2.15(s,6H),1.93-1.90(m,2H),1.70-1.62(m,2H).13C NMR(100MHz,CDCl3)171.21,160.47,159.25,148.37,140.47,136.55,132.41,131.83,127.74,125.87,122.90,122.66,121.12,120.34,113.86,65.85,59.89,57.78,54.59,48.45,45.51,45.43,42.72,27.88,24.44,15.27.HRMS(ESI):Cacld for(M-H)-(C26H36ClN7O)requires m/z 496.2592,found496.2588.Anal.Cacld for C26H36ClN7O·H2O:C,60.51;H,7.42;N,19.00.Found:C,60.47;H,7.45;N,19.03。
化合物QMC-8A-8
实施例二十四:化合物QMC-8A-9的合成
方法同实施例十六,所不同的是用3-二乙胺基丙胺代替六氢吡啶,反应10h,得白色固体QMC-8A-9。
产率:57%;1H NMR(400MHz,CDCl3)14.05(s,1H),9.00(s,1H),8.89(d,J=2.2Hz,1H),8.62(d,J=8.6Hz,1H),7.89(d,J=8.3Hz,1H),7.75-7.68(m,1H),7.61(d,J=8.1Hz,1H),7.48-7.41(m,1H),7.13(dd,J=8.6,2.2Hz,1H),3.87(dd,J=10.2,5.7Hz,2H),3.60(s,2H),2.74(t,J=6.9Hz,2H),2.68-2.62(m,2H),2.51(dd,J=13.2,6.7Hz,6H),2.42(d,J=5.6Hz,6H),1.91(dd,J=11.2,5.6Hz,2H),1.73-1.63(m,2H),0.99(t,J=7.2Hz,6H).13C NMR(100MHz,CDCl3)171.33,160.50,159.28,148.46,140.48,136.53,132.34,131.83,127.82,125.82,123.01,122.63,121.06,120.38,113.87,59.94,54.64,51.13,48.84,46.79,45.51,42.75,27.13,24.49,11.68.HRMS(ESI):Cacld for(M-H)-(C28H40ClN7O)requiresm/z 524.2905,found 524.2900.Anal.Cacld for C28H40ClN7O·H2O:C,61.80;H,7.78;N,18.02.Found:C,61.62;H,7.61;N,17.93。
化合物QMC-8A-9
实施例二十五:化合物QMC-8B-1的合成
方法同实施例十六,所不同的是用QMC-7B代替QMC-7A,反应6h,得白色固体QMC-8B-1。
产率:69%;1H NMR(400MHz,CDCl3)14.06(s,1H),9.06(s,1H),8.85(d,J=2.0Hz,1H),8.66(d,J=8.6Hz,1H),7.79-7.68(m,2H),7.59(d,J=8.1Hz,1H),7.48-7.40(m,1H),7.08(dd,J=8.6,2.1Hz,1H),3.84(dd,J=10.2,5.5Hz,2H),2.92-2.82(m,2H),2.80-2.71(m,2H),2.67-2.58(m,2H),2.54-2.42(m,4H),2.40(s,6H),1.96-1.85(m,2H),1.61-1.53(m,4H),1.46-1.37(m,2H).13CNMR(100MHz,CDCl3)170.93,160.60,159.11,148.02,141.16,136.75,132.58,131.74,127.45,125.93,122.33,121.79,121.21,120.01,113.86,59.94,54.99,54.42,45.51,42.83,36.52,25.97,24.39,24.30.HRMS(ESI):Cacld for(M-H)-(C27H35ClN6O)requires m/z 493.2483,found 493.2472.Anal.Cacld forC27H35ClN6O:C,65.51;H,7.13;N,16.98.Found:C,65.70;H,7.24;N,16.86。
化合物QMC-8B-1
实施例二十六:化合物QMC-8B-2的合成
方法同实施例十六,所不同的是用QMC-7B代替QMC-7A,用四氢吡咯代替六氢吡啶,反应6h,得白色固体QMC-8B-2。
产率:71%;1H NMR(400MHz,CDCl3)14.12(s,1H),9.07(s,1H),8.86(d,J=2.0Hz,1H),8.67(d,J=8.6Hz,1H),7.74(dt,J=14.9,7.6Hz,2H),7.60(d,J=8.1Hz,1H),7.45(dd,J=11.0,3.9Hz,1H),7.10(dd,J=8.6,2.1Hz,1H),3.87(dd,J=10.2,5.5Hz,2H),3.01(t,J=7.5Hz,2H),2.82(t,J=7.5Hz,2H),2.74-2.55(m,6H),2.41(s,6H),1.97-1.88(m,2H),1.86-1.74(m,4H).13C NMR(100MHz,CDCl3)170.62,160.68,159.16,148.07,141.15,136.84,132.64,131.73,127.50,125.94,122.39,121.81,121.19,120.09,113.88,59.96,54.18,52.08,45.51,42.84,38.41,24.40,23.52.HRMS(ESI):Cacld for(M-H)-(C26H33ClN6O)requiresm/z 479.2326,found 479.2318.Anal.Cacld for C26H33ClN6O:C,64.92;H,6.91;N,17.47.Found:C,65.02;H,6.68;N,17.55。
化合物QMC-8B-2
实施例二十七:化合物QMC-8B-3的合成
方法同实施例十六,所不同的是用QMC-7B代替QMC-7A,用二乙胺代替六氢吡啶,反应4h,得白色固体QMC-8B-3。
产率:60%;1H NMR(400MHz,CDCl3)14.08(s,1H),9.07(s,1H),8.86(d,J=2.1Hz,1H),8.67(d,J=8.6Hz,1H),7.77-7.68(m,2H),7.59(d,J=8.1Hz,1H),7.44(ddd,J=8.1,6.1,2.0Hz,1H),7.09(dd,J=8.6,2.2Hz,1H),3.86(dd,J=10.2,5.6Hz,2H),3.07-2.95(m,2H),2.76-2.68(m,2H),2.64(t,J=4.1Hz,2H),2.63-2.56(m,4H),2.41(s,6H),1.97-1.85(m,2H),1.05(t,J=7.1Hz,6H).13C NMR(100MHz,CDCl3)171.05,160.60,159.10,147.99,141.19,136.74,132.56,131.74,127.35,125.93,122.31,121.74,121.24,119.95,113.87,59.90,48.93,47.01,45.49,42.73,36.64,24.41,11.90.HRMS(ESI):Cacld for(M-H)-(C26H35ClN6O)requires m/z 481.2483,found 481.2472.Anal.Cacld forC26H35ClN6O·H2O:C,62.32;H,7.44;N,16.77.Found:C,62.15;H,7.57;N,16.63。
化合物QMC-8B-3
实施例二十八:化合物QMC-8B-4的合成
方法同实施例十六,所不同的是用QMC-7B代替QMC-7A,用1-甲基哌嗪代替六氢吡啶,反应8h,得白色固体QMC-8B-4。
产率:44%;1H NMR(400MHz,CDCl3)14.07(s,1H),9.07(s,1H),8.85(d,J=1.5Hz,1H),8.66(d,J=8.6Hz,1H),7.72(d,J=3.9Hz,2H),7.60(d,J=8.1Hz,1H),7.45(dt,J=8.1,4.0Hz,1H),7.09(dd,J=8.6,1.8Hz,1H),3.86(dd,J=10.2,5.3Hz,2H),2.92(t,J=7.4Hz,2H),2.75(t,J=7.4Hz,2H),2.67-2.63(m,2H),2.59(dd,J=19.2,11.0Hz,4H),2.49-2.41(m,4H),2.41(s,6H),2.26(s,3H),1.95-1.87(m,2H).13C NMR(100MHz,CDCl3)170.62,160.71,159.19,148.08,141.12,136.87,132.69,131.77,127.40,125.98,122.46,121.85,121.28,120.12,113.92,59.92,55.08,54.20,52.99,46.01,45.51,42.80,36.39,24.42.HRMS(ESI):Cacld for(M-H)-(C27H36ClN7O)requires m/z 508.2592,found 508.2588.Anal.Cacld for C27H36ClN7O:C,63.58;H,7.11;N,19.22.Found:C,63.49;H,7.26;N,19.36。
化合物QMC-8B-4
实施例二十九:化合物QMC-8B-5的合成
方法同实施例十六,所不同的是用QMC-7B代替QMC-7A,用吗啡啉代替六氢吡啶,反应3h,得白色固体QMC-8B-5。
产率:67%;1H NMR(400MHz,CDCl3)14.10(s,1H),9.08(s,1H),8.84(d,J=2.0Hz,1H),8.67(d,J=8.6Hz,1H),7.75-7.69(m,2H),7.62(d,J=8.1Hz,1H),7.45(ddd,J=8.2,5.2,2.9Hz,1H),7.10(dd,J=8.6,2.1Hz,1H),3.86(dd,J=10.2,5.4Hz,2H),3.69-3.61(m,4H),2.89(t,J=7.1Hz,2H),2.75(t,J=7.2Hz,2H),2.68-2.62(m,2H),2.58-2.48(m,4H),2.42(s,6H),1.95-1.89(m,2H).13C NMR(100MHz,CDCl3)170.52,160.59,159.12,147.94,141.04,136.77,132.63,131.77,127.20,125.99,122.46,121.80,121.34,120.02,113.88,66.88,59.72,54.61,53.53,45.46,42.61,36.28,24.44.HRMS(ESI):Cacld for(M-H)-(C26H33ClN6O2)requires m/z 495.2275,found 495.2271.Anal.Cacld for C26H33ClN6O2 ·H2O:C,60.63;H,6.85;N,16.32.Found:C,60.51;H,6.92;N,16.36。.
化合物QMC-8B-5
实施例三十:化合物QMC-8C-1的合成
方法同实施例十六,所不同的是用QMC-7C代替QMC-7A,反应6h,得白色固体QMC-8C-1。
产率:73%;1H NMR(400MHz,CDCl3)14.04(s,1H),9.03(s,1H),8.86(d,J=2.2Hz,1H),8.68(d,J=8.6Hz,1H),7.80-7.70(m,2H),7.61(d,J=8.0Hz,1H),7.45(ddd,J=8.2,6.2,2.0Hz,1H),7.10(dd,J=8.6,2.2Hz,1H),3.87(dd,J=10.2,5.7Hz,2H),2.69-2.62(m,2H),2.59(t,J=7.3Hz,2H),2.53-2.46(m,2H),2.46-2.41(m,4H),2.41(s,6H),2.04(dt,J=14.8,7.4Hz,2H),1.92(dt,J=11.3,5.8Hz,2H),1.56(dt,J=11.0,5.5Hz,4H),1.45-1.36(m,2H).13C NMR(100MHz,CDCl3)171.94,160.74,159.20,148.17,141.29,136.90,132.64,131.77,127.54,125.94,122.33,121.81,121.23,120.05,113.92,60.00,58.70,54.56,45.53,42.86,36.90,25.95,24.45,22.94.HRMS(ESI):Cacld for(M-H)-(C28H37ClN6O)requires m/z 507.2639,found 507.2629.Anal.Cacld forC28H37ClN6O:C,66.06;H,7.33;N,16.51.Found:C,66.10;H,7.49;N,16.32。
化合物QMC-8C-1
实施例三十一:化合物QMC-8C-4的合成
方法同实施例十六,所不同的是用QMC-7C代替QMC-7A,用1-甲基哌嗪代替六氢吡啶,反应9h,得白色固体QMC-8C-4。
产率:58%;1H NMR(400MHz,CDCl3)δ14.04(s,1H),9.03(s,1H),8.87(d,J=2.1Hz,1H),8.68(t,J=6.8Hz,1H),7.94-7.64(m,2H),7.62(d,J=8.1Hz,1H),7.45(ddd,J=8.2,5.4,2.8Hz,1H),7.10(dd,J=8.6,2.2Hz,1H),3.87(dd,J=10.2,5.5Hz,2H),2.72-2.63(m,2H),2.59(t,J=7.3Hz,2H),2.55-2.44(m,4H),2.42(s,6H),2.37-2.27(m,4H),2.22(s,3H),2.01(dt,J=14.5,7.3Hz,2H),1.97-1.89(m,2H),1.89-1.76(m,2H).13C NMR(100MHz,CDCl3)δ171.86,160.64,159.12,148.05,141.26,136.80,132.60,131.75,127.42,125.91,122.26,121.71,121.26,119.95,113.89,59.89,57.81,55.10,53.11,45.99,45.49,42.76,36.75,24.41,22.93.HRMS(ESI):Cacld for(M-H)-(C28H38ClN7O)requiresm/z 522.2748,found 522.2747.Anal.Cacld for C28H38ClN7O:C,64.17;H,7.31;N,18.71.Found:C,64.03;H,7.26;N,18.59。
化合物QMC-8C-4
实施例三十二:化合物QMC-8C-5的合成
方法同实施例十六,所不同的是用QMC-7C代替QMC-7A,用1-甲基哌嗪代替六氢吡啶,反应4h,得白色固体QMC-8C-5。
产率:65%;1H NMR(400MHz,CDCl3)14.07(s,1H),9.03(s,1H),8.87(d,J=2.2Hz,1H),8.68(d,J=8.6Hz,1H),7.78-7.69(m,2H),7.65(d,J=8.2Hz,1H),7.46(ddd,J=8.2,5.0,3.2Hz,1H),7.10(dd,J=8.6,2.2Hz,1H),3.88(dd,J=10.3,5.6Hz,2H),3.70-3.56(m,4H),2.73-2.64(m,2H),2.61(t,J=7.2Hz,2H),2.47(t,J=6.3Hz,2H),2.44(s,6H),2.08-1.99(m,2H),1.98-1.91(m,2H),1.86-1.72(m,4H).13C NMR(100MHz,CDCl3)171.82,160.65,159.12,148.02,141.24,136.83,132.60,131.77,127.30,125.96,122.32,121.68,121.32,119.93,113.89,66.97,59.81,58.27,53.67,45.48,42.68,36.62,24.43,22.52.HRMS(ESI):Cacld for(M-H)-(C27H35ClN6O2)requires m/z 509.2432,found 509.2429.Anal.Cacld for C27H35ClN6O2:C,63.45;H,6.90;N,16.44.Found:C,63.31;H,7.05;N,16.51。
化合物QMC-8C-5
实施例三十三:化合物QE-8A-1的合成
方法同实施例十六,所不同的是用QE-7A代替QMC-7A,反应6h,得白色固体QE-8A-1。
产率:61%;1H NMR(400MHz,CDCl3)13.20(s,1H),9.02(s,1H),8.77-8.71(m,1H),8.50(dd,J=7.9,1.6Hz,1H),7.99(d,J=8.0Hz,1H),7.80(d,J=7.8Hz,1H),7.74-7.69(m,1H),7.43(td,J=7.8,1.3Hz,2H),7.19-7.14(m,1H),3.89(dd,J=10.3,5.4Hz,2H),3.23(s,2H),2.77(dt,J=14.1,6.2Hz,6H),2.49(s,4H),1.98(s,2H),1.43(dt,J=10.8,5.6Hz,4H),1.35-1.28(m,2H),1.18(t,J=7.2Hz,6H).13C NMR(101MHz,CDCl3)169.84,161.42,159.40,148.93,138.95,132.09,130.58,128.49,126.01,125.43,122.73,121.30,121.04,113.74,65.21,54.82,53.79,47.11,43.15,25.29,24.29,23.86,11.61.HRMS(ESI):Cacld for(M-H)-(C28H38N6O)requires m/z 473.3029,found 473.3021.Anal.Calcd forC28H38N6O:C,70.85;H,8.07;N,17.71.Found:C,70.79;H,8.11;N,17.66。
化合物QE-8A-1
实施例三十四:化合物QE-8A-2的合成
方法同实施例十六,所不同的是用QE-7A代替QMC-7A,用四氢吡咯代替六氢吡啶,反应4h,得白色固体QE-8A-2。
产率:63%;1H NMR(400MHz,CDCl3)13.58(s,1H),9.00(s,1H),8.78(dd,J=8.3,0.8Hz,1H),8.57(dd,J=7.9,1.6Hz,1H),7.93(d,J=8.1Hz,1H),7.76(d,J=8.2Hz,1H),7.72-7.67(m,1H),7.45-7.40(m,2H),7.19-7.14(m,1H),3.89(dd,J=10.3,5.4Hz,2H),3.41(s,2H),2.79-2.70(m,6H),2.66(t,J=5.9Hz,4H),1.99-1.92(m,2H),1.69(dt,J=6.5,3.2Hz,4H),1.16(t,J=7.1Hz,6H).13CNMR(101MHz,CDCl3)170.27,161.34,159.35,148.92,139.25,131.89,130.63,128.10,125.68,125.37,122.66,121.28,121.05,113.70,62.23,54.53,53.83,47.12,43.15,24.34,23.92,11.63.HRMS(ESI):Cacld for(M-H)-(C27H36N6O)requiresm/z 459.2872,found 459.2873.Anal.Calcd for C27H36N6O:C,70.40;H,7.88;N,18.25.Found:C,70.38;H,7.94;N,18.21。
化合物QE-8A-2
实施例三十五:化合物QE-8A-3的合成
方法同实施例十六,所不同的是用QE-7A代替QMC-7A,用二乙胺代替六氢吡啶,反应5h,得白色固体QE-8A-3。
产率:45%;1H NMR(400MHz,CDCl3)13.28(s,1H),8.85(s,1H),8.69(d,J=8.3Hz,1H),8.44(dd,J=7.9,1.6Hz,1H),7.83(d,J=8.2Hz,1H),7.74(d,J=7.4Hz,1H),7.66-7.61(m,1H),7.35(dd,J=11.2,4.2Hz,2H),7.12-7.07(m,1H),3.83(dd,J=10.6,5.2Hz,2H),3.21(s,2H),2.71(dt,J=14.0,6.2Hz,6H),2.59(q,J=7.1Hz,4H),1.92(d,J=3.8Hz,2H),1.11(t,J=7.1Hz,6H),0.90(t,J=7.1Hz,6H).13C NMR(101MHz,CDCl3)171.71,161.37,159.44,149.08,138.85,131.94,130.82,130.42,128.11,126.40,125.29,122.74,121.28(d,J=5.1Hz),113.74,58.77,53.79,49.02,47.11,43.06,24.37,11.61.HRMS(ESI):Cacldfor(M-H)-(C27H38N6O)requires m/z 461.3029,found 461.3021.Anal.Calcd forC27H38N6O:C,70.10;H,8.28;N,18.17.Found:C,70.03;H,8.34;N,18.14。
化合物QE-8A-3
实施例三十六:化合物QE-8A-4的合成
方法同实施例十六,所不同的是用QE-7A代替QMC-7A,用1-甲基哌嗪代替六氢吡啶,反应9h,得白色固体QE-8A-4。
产率:48%;1H NMR(400MHz,CDCl3)13.20(s,1H),9.03(s,1H),8.73(d,J=8.3Hz,1H),8.48(dd,J=7.9,1.5Hz,1H),7.97(d,J=8.1Hz,1H),7.87(d,J=6.9Hz,1H),7.74(t,J=7.2Hz,1H),7.45(ddd,J=13.6,9.6,4.4Hz,2H),7.20-7.15(m,1H),3.91(dd,J=10.4,5.2Hz,2H),3.29(s,2H),2.86-2.75(m,6H),2.61(s,4H),2.29(s,4H),2.10(s,3H),2.02(s,2H),1.21(t,J=7.1Hz,6H).13C NMR(101MHz,CDCl3)169.11,161.48,159.45,148.91,138.77,132.28,130.62,128.66,126.08,125.50,122.87,121.41,121.04,113.80,64.29,54.24,53.79,53.45,47.11,45.86,43.13,24.25,11.56.HRMS(ESI):Cacld for(M-H)-(C28H39N7O)requires m/z488.3138,found 488.3143.Anal.Calcd for C28H39N7O:C,68.68;H,8.03;N,20.02.Found:C,68.74;H,7.99;N,20.07。
化合物QE-8A-4
实施例三十七:化合物QE-8A-5的合成
方法同实施例十六,所不同的是用QE-7A代替QMC-7A,用吗啡啉代替六氢吡啶,反应6h,得白色固体QE-8A-5。
产率:73%;1HNMR(400MHz,CDCl3)13.41(s,1H),9.09(s,1H),8.74(d,J=8.1Hz,1H),8.53(dd,J=7.9,1.5Hz,1H),7.94(d,J=8.2Hz,1H),7.81(d,J=8.1Hz,1H),7.73(dd,J=11.3,4.0Hz,1H),7.48-7.41(m,2H),7.20-7.15(m,1H),3.90(dd,J=10.4,5.3Hz,2H),3.59-3.56(m,4H),3.30(s,2H),2.77(dt,J=14.2,6.2Hz,6H),2.60-2.56(m,4H),1.98(d,J=3.6Hz,2H),1.18(t,J=7.1Hz,6H).13C NMR(101MHz,CDCl3)168.69,161.43,159.41,148.71,138.90,132.27,130.69,128.14,125.64,122.89,121.49,120.94,113.78,66.36,64.84,53.81,47.12,43.23,24.27,11.61.HRMS(ESI):Cacld for(M-H)-(C27H36N6O2)requiresm/z 475.2821,found 475.2815.Anal.Calcd for C27H36N6O2:C,68.04;H,7.61;N,17.63.Found:C,68.11;H,7.57;N,17.68。
化合物QE-8A-5
实施例三十八:化合物QE-8B-1的合成
方法同实施例十六,所不同的是用QE-7B代替QMC-7A,反应6h,得白色固体QE-8B-1。
产率:65%;1H NMR(400MHz,CDCl3)13.88(s,1H),9.14(s,1H),8.74-8.70(m,2H),7.80(d,J=7.9Hz,1H),7.74(dt,J=11.3,6.2Hz,2H),7.45-7.40(m,2H),7.17-7.12(m,1H),2.92-2.87(m,2H),2.85-2.62(m,10H),2.50(s,4H),1.95(dd,J=10.4,5.5Hz,2H),1.57(dd,J=11.1,5.5Hz,4H),1.43(dd,J=10.8,5.6Hz,2H),1.16(t,J=7.1Hz,6H).13C NMR(101MHz,CDCl3)170.72,161.48,159.12,148.32,140.26,132.50,131.02,130.64,127.61,125.51,123.79,122.34,121.49,120.39,113.77,55.14,54.40,53.85,47.13,43.27,36.54,25.98,24.29,11.62.HRMS(ESI):Cacld for(M-H)-(C29H40N6O)requires m/z 487.3185,found 487.3180.Anal.Calcd for C29H40N6O:C,71.28;H,8.25;N,17.20.Found:C,71.35;H,8.21;N,17.24。
化合物QE-8B-1
实施例三十九:化合物QE-8B-2的合成
方法同实施例十六,所不同的是用QE-7B代替QMC-7A,用四氢吡咯代替六氢吡啶,反应6h,得白色固体QE-8B-2。
产率:61%;1H NMR(400MHz,CDCl3)13.91(s,1H),9.15(s,1H),8.77-8.70(m,2H),7.80-7.76(m,1H),7.74-7.69(m,2H),7.42(dd,J=11.1,4.2Hz,2H),7.17-7.12(m,1H),3.88(dd,J=9.9,5.5Hz,2H),3.00(t,J=7.6Hz,2H),2.83-2.78(m,2H),2.77-2.73(m,2H),2.69(q,J=7.1Hz,4H),2.61(d,J=5.2Hz,4H),1.95-1.89(m,2H),1.79(dt,J=6.5,3.1Hz,4H),1.14(t,J=7.1Hz,6H).13C NMR(101MHz,CDCl3)170.44,161.46,159.11,148.29,140.28,132.52,131.02,130.64,127.57,125.51,123.75,122.33,121.49,120.38,113.77,54.17,53.84,52.24,47.12,43.26,38.52,24.28,23.52,11.63.HRMS(ESI):Cacld for(M-H)-(C28H38N6O)requires m/z 473.3029,found 473.3025.Anal.Calcd for C28H38N6O:C,70.85;H,8.07;N,17.71.Found:C,70.9l;H,8.11;N,17.66。
化合物QE-8B-2
实施例四十:化合物QE-8B-3的合成
方法同实施例十六,所不同的是用QE-7B代替QMC-7A,用二乙胺代替六氢吡啶,反应4h,得白色固体QE-8B-3。
产率:39%;1H NMR(400MHz,CDCl3)13.84(s,1H),9.06(s,1H),8.65(dd,J=12.9,4.9Hz,2H),7.71-7.61(m,3H),7.36(dd,J=11.1,4.2Hz,2H),7.10-7.04(m,1H),3.81(dd,J=9.9,5.4Hz,2H),2.97-2.92(m,2H),2.69-2.59(m,8H),2.54(q,J=7.1Hz,4H),1.89-1.82(m,2H),1.07(t,J=7.1Hz,6H),0.98(t,J=7.1Hz,6H).13C NMR(101MHz,CDCl3)170.79,161.43,159.14,148.27,140.27,132.51,131.02,130.64,127.49,125.55,123.73,122.34,121.59,120.34,113.78,53.54,48.96,46.98,42.97,36.53,24.23,11.43.HRMS(ESI):Cacld for(M-H)-(C28H38N6O)requires m/z 475.3185,found 475.3186.Anal.Calcd forC28H40N6O:C,70.55;H,8.46;N,17.63.Found:C,70.51;H,8.44;N,17.68。
化合物QE-8B-3
实施例四十一:化合物QE-8B-4的合成
方法同实施例十六,所不同的是用QE-7B代替QMC-7A,用1-甲基哌嗪代替六氢吡啶,反应8h,得白色固体QE-8B-4。
产率:47%;1H NMR(400MHz,CDCl3)13.87(s,1H),9.14(s,1H),8.71(dd,J=10.4,4.1Hz,2H),7.77-7.69(m,3H),7.43(dd,J=8.2,7.0Hz,2H),7.15(dd,J=11.2,4.1Hz,1H),3.88(dd,J=10.0,5.3Hz,2H),2.92(t,J=7.4Hz,2H),2.72(ddd,J=21.5,12.5,7.3Hz,8H),2.58(s,4H),2.42(s,4H),2.25(s,3H),1.96-1.89(m,2H),1.15(t,J=7.1Hz,6H).13C NMR(101MHz,CDCl3)170.38,161.43,159.12,148.25,140.20,132.53,131.00,130.65,127.44,125.54,123.77,122.38,121.57,120.37,113.77,55.06,54.34,53.67,52.96,47.05,45.98,43.10,36.44,24.23,11.53.HRMS(ESI):Cacld for(M-H)-(C29H41N7O)requires m/z502.3294,found 502.3295.Anal.Calcd for C29H41N7O:C,69.15;H,8.20;N,19.47.Found:C,69.21;H,8.17;N,19.51。
化合物QE-8B-4
实施例四十二:化合物QE-8B-5的合成
方法同实施例十六,所不同的是用QE-7B代替QMC-7A,用吗啡啉代替六氢吡啶,反应4.5h,得白色固体QE-8B-5。
产率:69%;1H NMR(400MHz,CDCl3)13.92(s,1H),9.16(s,1H),8.72(d,J=8.1Hz,2H),7.74(dd,J=9.2,7.6Hz,3H),7.47-7.40(m,2H),7.16(t,J=7.6Hz,1H),3.90(dd,J=10.0,5.3Hz,2H),3.67-3.62(m,4H),2.90(t,J=7.2Hz,2H),2.74(tt,J=14.4,7.1Hz,8H),2.55-2.49(m,4H),1.95(s,2H),1.16(t,J=7.1Hz,6H).13C NMR(101MHz,CDCl3)170.29,161.50,159.13,148.25,140.19,132.54,131.07,130.68,127.38,125.57,123.78,122.45,121.61,120.41,113.80,66.95,54.78,53.83,53.56,47.12,43.25,36.40,24.26,11.61.HRMS(ESI):Cacldfor(M-H)-(C28H38N6O2)requires m/z 489.2978,found 489.2975.Anal.Calcd forC28H38N6O2:C,68.54;H,7.81;N,17.13.Found:C,68.58;H,7.85;N,17.09。
化合物QE-8B-5
实施例四十三:本专利所述喹唑啉衍生物对端粒酶的抑制作用
选择施例十六~三十二制备的化合物,采用TRAP法进行无细胞体系端粒酶活性测定。从人乳腺癌细胞株MCF-7中提取总蛋白(内含端粒酶),将一定量的总蛋白提取液与待测药物混合加入TRAP反应混合液中,PCR反应后利用荧光凝胶成像仪或荧光酶标仪进行检测,结果如表1所示。结果表明,本专利所述的化合物在浓度为10μmol/L时,在体外对端粒酶有明显抑制作用。因此本发明的新型喹唑啉衍生物可用于制备以端粒酶为靶点的抗癌药物。
表2QMC系列化合物在10μmol/L时对端粒酶活性的抑制作用
实施例四十四:本专利所述喹唑啉衍生物对肿瘤细胞生长的抑制作用
选择实施例十六~三十二制备的化合物,以三种肿瘤细胞株CNE-2(人鼻咽癌细胞株)、PC-3(人前列腺癌细胞株)、SMMC-7721(人肝癌细胞株),采用MTT法进行体外细胞毒测定。对数生长期细胞加入不同浓度的新型喹唑啉衍生物,作用48小时后,测定其吸光度。分别计算抑制细胞生长达50%时的化合物浓度,以IC50值表示,结果如表2所示。结果表明本专利所述化合物在体外对这三种肿瘤细胞株均具有较强的抑制作用。因此本发明所述的双取代喹唑啉类衍生物极具有开发前景,可用于制备抗癌的药物。
表1QMC系列化合物对肿瘤细胞株生长的抑制作用(IC50/μM)
实施例四十五:本专利所述喹唑啉衍生物急性毒性试验
选择部分具有代表性的化合物(如QMC-8B-4),进行急性毒性试验。取18-22克小鼠随机分六组,每组10只小鼠,分别用生理盐水、DMSO 2.5ml/kg、QMC-8B-4 500mg/kg、QMC-8B-4 200mg/kg、QMC-8B-4 100mg/kg、QMC-8B-4 50mg/kg处理,观察14天,结果可见QMC-8B-4对小鼠的急性毒性LD50值大约为480mg/kg。因此本发明所述的喹唑啉衍生物的具有弱毒性,可用于制备抗癌药物。
Claims (7)
5.如权利要求3-4所述的制备方法,其特征在于所述反应获得的喹唑啉衍生物经过柱层析纯化或者重结晶得到纯品。
6.如权利要求1~2所述的喹唑啉衍生在制备抗癌药物中的用途。
7.如权利要求6所述的用途,其特征在于所述的药物剂型为片剂、丸剂、胶囊、注射剂、悬浮剂或乳剂。
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