CN116332918A - 香豆素-喹啉衍生物及其制备方法与应用 - Google Patents
香豆素-喹啉衍生物及其制备方法与应用 Download PDFInfo
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- CN116332918A CN116332918A CN202310269294.7A CN202310269294A CN116332918A CN 116332918 A CN116332918 A CN 116332918A CN 202310269294 A CN202310269294 A CN 202310269294A CN 116332918 A CN116332918 A CN 116332918A
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- coumarin
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- synthesis
- hydroxyquinoline
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Abstract
Description
技术领域
本发明属于药物化学领域,特别涉及香豆素-喹啉衍生物及其制备方法与应用。
背景技术
阿尔茨海默症(AD),也称为老年痴呆,是一种慢性神经退行性疾病。老年性痴呆症已经是引发中老年人死亡的高发性疾病,而且耗资巨大,全球用于治疗和照顾老年痴呆症病人的费用占60岁以上疾病人口总支出的11.2%,远高于中风、心血管疾病和癌症,给患者家庭和社会带来很大负担。我国的老龄化人口逐年上升,现约有1000万AD患者,居世界首位。同时我国也是全球痴呆患者数量增速最快的国家之一。更严重的是,针对这一神经退行性疾病,目前还没找到特效药和治疗方法,只能通过药物缓解大脑萎缩。
目前临床上常用的抗AD药物类型和数量都比较有限,主要是胆碱酯酶抑制剂或NMDA受体拮抗剂,但这些药物只能在短期内改善患者的认知水平和生活质量,不能实质上逆转神经细胞的退化进程。
阿尔茨海默症致病原因复杂,包括遗传、外伤、病毒感染等,并且其发病机制涉及到多种信号通路的调节,如β-淀粉样蛋白(Aβ蛋白)的错误折叠和聚集、氧化应激、炎症等。并且这些因素之间相互影响,相互关联。针对包括AD这样的复杂疾病,国际上受广泛认可的多向药理学理念认为,复杂疾病产生的本质是多种因素共同作用的生物网络失衡,而并非仅仅源于某单一因素的影响。传统的“一药一靶一病”式治疗策略对复杂疾病往往很难达到治疗要求。
越来越多的研究表明,同时作用于与疾病相关的多个靶点的药物即多靶点药物可能治疗效果更好,这在治疗包括艾滋病、癌症和抑郁症等多种疾病方面已取得了一定成功。药物如果能同时干预诱发疾病的多个环节或多个节点蛋白,调控整个疾病机制网络,这将发挥更好的治疗效果。为此,人们提出了多靶点抗AD策略,即设计同时含有AD多个靶点药效团的多靶点药物,同时作用于AD致病机制中的多个靶点,产生协同效应,进而达到最佳治疗效果。多靶点抗AD策略符合AD复杂的病理情况,是一种具有前景的治疗策略。
发明内容
本发明意在针对现有技术的不足,提供一种香豆素-喹啉衍生物及其制备方法与应用。
本方案中的香豆素-喹啉衍生物,其结构式如式(I)或式(II)所示,
式(I)中,n为2或3或4或5;RR1为氢或甲基;R2为氢或氯;式(II)中,n为2或3或4或5;R2为氢或氯。
进一步,所述的香豆素-喹啉衍生物,选自如下式3n或3x:
本发明还提供了香豆素-喹啉衍生物的制备方法,将具有抗Aβ42蛋白聚集活性的香豆素结构与抗阿尔茨海默病药物的药效团喹啉环拼合,同时改变两个结构之间的长度。
具体的:其中所述式(I)的制备过程如下:
所述式(II)的制备过程如下:
优化的,将所得目标产物通过柱层析进行纯化。
进一步,所述溴烃烷为1,2-二溴乙烷,1,3-二溴丙烷,1,4-二溴丁烷或1,5-二溴戊烷。
进一步,所用缚酸剂B为碳酸钾、碳酸钠、碳酸铯、三乙胺、N,N-二异丙基乙胺中的一种或多种混合试剂。
本发明所述的香豆素-喹啉衍生物可应用于制备治疗阿尔茨海默病、脑血管痴呆或重症肌无力疾病的药物中,且药物剂型可选择片剂、丸剂、胶囊、注射剂、悬浮剂或乳剂。
本发明设计和合成所得香豆素-喹啉衍生物具有较好的抑制Aβ42蛋白聚集,抑制单胺氧化酶和丁酰胆碱酯酶的活性,并能透过血脑屏障,大部分化合物在10μM的浓度时对Aβ42蛋白聚集率达到40%以上。
其中化合物3x对Aβ42蛋白自聚集的抑制率达到61.2%,与阳性对照姜黄素和白藜芦醇相当;化合物3n抑制单胺氧化酶B的IC50达到0.77μM,显著优于阳性对照拉多替吉。
更进一步地,化合物3x抑制丁酰胆碱酯酶的IC50达到0.15μM,且能够透过血脑屏障,其Pe值为12.4,可作为潜在的多功能抗阿尔茨海默症药物。同时,3x能够通过抑制Aβ42蛋白的自聚集,诱导SYSH-5Y(神经母细胞瘤)细胞毒性,进而保护神经细胞;另外,在动物水平,3x可以改善APP/PS1((阿尔茨海默症)-神经类疾病模型)双转基因鼠的认知障碍。
本发明所提供的香豆素-喹啉衍生物具有抑制Aβ42蛋白的自聚集活性,制单胺氧化酶和丁酰胆碱酯酶的活性,并能透过血脑屏障。尤其适用,但不局限于制备治疗阿尔茨海默症、脑血管痴呆或重症肌无力疾病的药物。
与现有技术相比,本发明具有如下有益效果:
1.本发明提供了香豆素-喹啉衍生物,并且所述衍生物制备方法简单,易合成。
2.实验表明,本发明所述衍生物具有抑制Aβ42蛋白的自聚集活性,抑制与AD发病相关的乙酰胆碱酯酶、丁酰胆碱酯酶、单胺氧化酶的活性,并且能透过血脑屏障,具有很高的医学价值和广阔的市场开发前景。
附图说明
图1为本发明中化合物3x保护Aβ42蛋白诱导SYSH-5Y毒性;
图2为本发明中化合物3x改善APP/PS1转基因鼠认知障碍。
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。
除非特别说明,本发明采用的试剂、设备和方法为本技术领域常规市购的试剂、设备和常规使用的方法。
反应获得中间体的过程中以碳酸钾和丙酮存在的条件下反应为例,制备结构式(I)时,其合成过程如下:
反应获得中间体的过程中以碳酸钾和丙酮存在的条件下反应为例,制备结构式(II)时,其合成过程如下:
实施例1:中间体2a的合成
在100mL的烧瓶中加入7-羟基香豆素(2g,12.34mmol),K2CO3(5.11g,37mmol)、1,2-二溴乙烷(6.38mL,74.04mmol)以及20mL丙酮进行回流反应,用TLC检测反应进行情况。反应结束后,减压旋干丙酮,加入蒸馏水50mL,充分搅拌,抽滤,将滤饼晾干,再通过硅胶柱层析分离纯化,得到白色固体2.6g。产率为78.33%。
实施例2:中间体2b的合成
合成方法同2a,用1,3-二溴丙烷代替1,2-二溴乙烷。通过硅胶柱层析得到白色固体2.64g,产率为75.6%。
实施例3:中间体2c的合成
合成方法同2a,用1,4-二溴丁烷代替1,2-二溴乙烷;用二氯甲烷代替丙酮;用碳酸钠代替碳酸钾。通过硅胶柱层析得到白色固体2.58g,产率为70.4%。
实施例4:中间体2d的合成
合成方法同2a,用1,5-二溴戊烷代替1,2-二溴乙烷;用三氯甲烷代替丙酮;用碳酸铯代替碳酸钾。通过硅胶柱层析得到白色固体3.01g,产率78.4%。
实施例5:中间体2e的合成
合成方法同2a,用1,5-二溴戊烷代替1,2-二溴乙烷;用乙腈代替丙酮;用三乙胺代替碳酸钾。通过硅胶柱层析得到白色固体2.85g,产率88.7%。
实施例6:中间体2f的合成
合成方法同2a,用4-甲基伞形酮代替7-羟基香豆素;用四氢呋喃代替丙酮;用N,N-二异丙基乙胺代替碳酸钾,1,3-二溴丙烷代替1,2-二溴乙烷。通过硅胶柱层析得到白色固体2.1g,产率62.3%。
实施例7:中间体2g的合成
合成方法同2a,用4-甲基伞形酮代替7-羟基香豆素;用四氢呋喃代替丙酮;用碳酸钠代替碳酸钾,1,4-二溴丁烷代替1,2-二溴乙烷。通过硅胶柱层析得到白色固体2.32g,产率65.7%。
实施例8:中间体2h的合成
合成方法同2a,用4-甲基伞形酮代替7-羟基香豆素;用四氢呋喃代替丙酮,1,4-二溴戊烷代替1,2-二溴乙烷。通过硅胶柱层析得到白色固体2.93g,产率79.4%。
实施例9:中间体2i的合成
合成方法同2a,用4-羟基香豆素代替7-羟基香豆素;用乙腈代替丙酮。通过硅胶柱层析得到白色固体2.15g,产率64.77%。
实施例10:中间体2j的合成
合成方法同2a,用4-羟基香豆素代替7-羟基香豆素;用乙腈代替丙酮,1,3-二溴丙烷代替1,2-二溴乙烷。通过硅胶柱层析得到白色固体2.23g,产率63.8%。
实施例11:中间体2k的合成
合成方法同2a,用4-羟基香豆素代替7-羟基香豆素,1,4-二溴丁烷代替1,2-二溴乙烷。
通过硅胶柱层析得到白色固体2.58g,产率70.4%。
实施例12:中间体2l的合成
合成方法同2a,用4-羟基香豆素代替7-羟基香豆素,1,3-二溴戊烷代替1,2-二溴乙烷;用碳酸铯代替碳酸钾。通过硅胶柱层析得到白色固体2.18g,产率56.8%。
实施例13:化合物3a的合成
在50mL的烧瓶中加入5-氯-8-羟基喹啉(0.13g,0.74mmol),K2CO3(0.20g,1.48mmol)以及10mL乙腈进行回流,30min后再加入取代香豆素中间体2a(0.20g,0.74mmol),继续回流反应,用TLC检测反应进行情况。反应结束后,减压旋干乙腈,加入清水50mL,充分搅拌,抽滤,将滤饼晾干,再通过硅胶柱层析分离纯化,得到白色固体0.20g。产率为72.5%。1H NMR(500MHz,CDCl3)δ9.01(dd,J=4.2,1.7Hz,1H),8.55(dd,J=8.5,1.7Hz,1H),7.64(d,J=9.5Hz,1H),7.60–7.47(m,2H),7.41–7.35(m,1H),7.10(d,J=8.4Hz,1H),6.96–6.88(m,2H),6.27(d,J=9.5Hz,1H),4.65(dd,J=5.6,3.5Hz,2H),4.60(dd,J=5.6,3.5Hz,2H).13C NMR(126MHz,CDCl3)δ161.67,161.20,155.76,153.54,149.97,143.40,140.76,133.13,128.85,127.21,126.33,123.11,122.52,113.37,112.98,112.89,109.42,101.78,67.41,66.89.
实施例14:化合物3b的合成
合成方法同3a,所不同的是用香豆素中间体2b代替2a。通过柱层析分离纯化得到白色固体0.23g,产率为83.6%。1H NMR(500MHz,CDCl3)δ9.00(dd,J=4.2,1.7Hz,1H),8.54(dd,J=8.5,1.7Hz,1H),7.62(d,J=9.4Hz,1H),7.59–7.50(m,2H),7.39–7.32(m,1H),7.04(d,J=8.4Hz,1H),6.89–6.83(m,2H),6.24(d,J=9.4Hz,1H),4.80–4.76(m,1H),4.45(t,J=6.2Hz,2H),4.34(t,J=5.9Hz,2H),2.54(p,J=6.1Hz,2H),1.32–1.24(m,1H).13C NMR(126MHz,CDCl3)δ162.06,161.27,155.82,153.81,149.84,143.43,140.79,133.06,128.75,127.13,126.40,122.44,122.42,113.11,112.80,112.60,108.82,101.63,65.49,65.18,28.86.
实施例15:化合物3c的合成
合成方法同3a,所不同的是用香豆素中间体2c代替2a。通过柱层析分离纯化得到白色固体0.23g,产率为88.6%。
实施例16:化合物3d的合成
合成方法同3a,所不同的是用香豆素中间体2d代替2a。通过柱层析分离纯化得到白色固体0.23g,产率为87.6%。1H NMR(500MHz,CDCl3)δ9.00(dd,J=4.2,1.7Hz,1H),8.54(dd,J=8.6,1.7Hz,1H),7.64(d,J=9.4Hz,1H),7.59–7.50(m,2H),7.35(d,J=8.6Hz,1H),6.99(d,J=8.4Hz,1H),6.83(dd,J=8.5,2.4Hz,1H),6.80(d,J=2.4Hz,1H),6.25(d,J=9.5Hz,1H),4.27(t,J=6.7Hz,2H),4.07(t,J=6.3Hz,2H),2.12(p,J=6.9Hz,2H),2.00–1.91(m,2H),1.82–1.72(m,2H).13C NMR(126MHz,CDCl3)δ162.29,161.35,155.87,153.98,149.78,143.50,140.84,133.01,128.73,127.11,126.43,122.34,122.07,112.96,112.91,112.44,108.54,101.36,68.91,68.33,28.78,28.65,22.73.
实施例17:化合物3e的合成
合成方法同3a,所不同的是用香豆素中间体2e代替2a。通过柱层析分离纯化得到白色固体0.20g,产率为73.8%。1H NMR(500MHz,CDCl3)δ9.03(dd,J=4.2,1.7Hz,1H),8.56(dd,J=8.5,1.7Hz,1H),7.56(td,J=8.5,4.7Hz,2H),7.50(dd,J=8.5,2.4Hz,1H),7.17–7.09(m,1H),6.96–6.89(m,2H),6.18–6.14(m,1H),4.65(dd,J=5.8,3.6Hz,2H),4.61(dt,J=5.7,2.6Hz,2H),2.40(d,J=1.4Hz,3H).13C NMR(126MHz,CDCl3)δ161.53,161.26,155.17,153.58,152.52,150.00,140.79,133.11,127.21,126.33,125.60,123.10,122.51,113.92,112.62,112.20,109.45,101.79,67.46,66.83.
实施例18:化合物3f的合成
合成方法同3a,所不同的是用香豆素中间体2f代替2a。通过柱层析分离纯化得到白色固体0.25g,产率为93.2%。1H NMR(500MHz,CDCl3)δ9.02(dt,J=3.0,1.6Hz,1H),8.54(ddt,J=7.2,3.4,1.6Hz,1H),7.55(dddd,J=18.0,9.7,3.6,1.4Hz,2H),7.47(dt,J=8.7,2.0Hz,1H),7.04(dt,J=8.4,1.6Hz,1H),6.91–6.83(m,2H),6.13(q,J=1.7Hz,1H),4.49–4.43(m,2H),4.34(t,J=5.9Hz,2H),2.54(p,J=6.1Hz,2H),2.39(dt,J=2.5,1.5Hz,3H).13C NMR(126MHz,CDCl3)δ161.87,161.31,155.21,153.84,152.51,149.87,140.83,133.03,127.13,126.38,125.51,122.43,122.41,113.65,112.44,112.01,108.83,101.66,65.53,65.13,28.88.
实施例19:化合物3g的合成
合成方法同3a,所不同的是用香豆素中间体2g代替2a。通过柱层析分离纯化得到白色固体0.22g,产率为82.1%。1H NMR(500MHz,CDCl3)δ9.01(dd,J=4.2,1.7Hz,1H),8.51(dd,J=8.5,1.7Hz,1H),7.59–7.48(m,2H),7.44(d,J=9.1Hz,1H),6.99(d,J=8.4Hz,1H),6.81(d,J=7.9Hz,2H),6.13(d,J=1.4Hz,1H),4.34(t,J=6.4Hz,2H),4.18(t,J=6.2Hz,2H),2.39(d,J=1.2Hz,3H),2.24(dq,J=7.8,6.4Hz,2H),2.13(dt,J=8.6,6.1Hz,2H).13CNMR(126MHz,CDCl3)δ161.99,161.38,155.20,153.82,152.61,149.84,140.83,132.91,127.08,126.38,125.41,122.35,122.14,113.43,112.66,111.84,108.53,101.30,68.70,68.17,26.05,25.49,18.68.
实施例20:化合物3h的合成
合成方法同3a,所不同的是用香豆素中间体2h代替2a。通过柱层析分离纯化得到白色固体0.22g,产率为82.7%。1H NMR(500MHz,CDCl3)δ9.01(dd,J=4.2,1.6Hz,1H),8.54(dd,J=8.5,1.7Hz,1H),7.59–7.50(m,2H),7.47(d,J=8.8Hz,1H),6.99(d,J=8.4Hz,1H),6.84(dd,J=8.8,2.5Hz,1H),6.80(d,J=2.5Hz,1H),6.13(q,J=1.3Hz,1H),4.28(t,J=6.7Hz,2H),4.07(t,J=6.3Hz,2H),2.40(d,J=1.3Hz,3H),2.17–2.08(m,2H),1.95(dt,J=14.8,6.5Hz,2H),1.82–1.71(m,2H).13C NMR(126MHz,CDCl3)δ162.09,161.39,155.26,153.99,152.61,149.80,140.86,133.00,127.11,126.43,125.49,122.33,122.06,113.47,112.57,111.86,108.54,101.38,68.93,68.27,28.80,28.65,22.74,18.69.
实施例21:化合物3i的合成
合成方法同3a,所不同的是用香豆素中间体2i代替2a。通过柱层析分离纯化得到黄色固体0.21g,产率为78.6%。1H NMR(500MHz,CDCl3)δ9.02(dd,J=4.2,1.7Hz,1H),8.57(dd,J=8.6,1.6Hz,1H),7.77(dd,J=8.0,1.6Hz,1H),7.56(dddd,J=19.1,8.7,6.7,1.9Hz,3H),7.34–7.26(m,1H),7.26–7.19(m,1H),7.15(d,J=8.4Hz,1H),5.79(s,1H),4.76(dd,J=5.8,3.5Hz,2H),4.70(dd,J=5.7,3.5Hz,2H).13C NMR(126MHz,CDCl3)δ165.39,162.74,153.53,153.30,150.09,140.91,133.18,132.52,127.32,126.27,123.88,123.59,123.24,122.59,116.74,115.42,110.13,90.99,67.65,67.15.
实施例22:化合物3j的合成
合成方法同3a,所不同的是用香豆素中间体2j代替2a。通过柱层析分离纯化得到浅黄色固体0.10g,产率为35.7%。1H NMR(500MHz,CDCl3)δ9.01(dd,J=4.2,1.7Hz,1H),8.54(dd,J=8.5,1.7Hz,1H),7.81(dd,J=7.9,1.6Hz,1H),7.60–7.50(m,3H),7.31(d,J=8.3Hz,1H),7.28–7.21(m,1H),7.04(d,J=8.4Hz,1H),5.75(s,1H),4.48(dt,J=11.6,6.0Hz,4H),2.64(p,J=6.0Hz,2H).13C NMR(126MHz,CDCl3)δ165.44,162.84,153.67,153.30,149.96,140.81,133.06,132.40,127.19,126.32,123.86,122.90,122.74,122.50,116.81,115.62,108.92,90.81,66.13,65.37,28.46,0.02.
实施例23:化合物3k的合成
合成方法同3a,所不同的是用香豆素中间体2k代替2a。通过柱层析分离纯化得到浅黄色固体0.24g,产率为89.7%。1H NMR(500MHz,CDCl3)δ9.04(dd,J=4.2,1.7Hz,1H),8.52(dd,J=8.5,1.7Hz,1H),7.73(dd,J=8.0,1.6Hz,1H),7.60–7.47(m,3H),7.32–7.27(m,1H),7.25–7.18(m,1H),6.99(d,J=8.4Hz,1H),5.76(s,1H),4.36(dt,J=8.0,5.7Hz,4H),2.26(ttd,J=16.4,7.5,4.7Hz,4H).13C NMR(126MHz,CDCl3)δ165.54,163.01,153.68,153.26,149.98,140.77,132.96,132.28,127.10,126.31,123.78,122.89,122.52,122.34,116.72,115.63,108.50,90.65,69.17,68.59,25.92,25.38.
实施例24:化合物3l的合成
合成方法同3a,所不同的是用香豆素中间体2l代替2a。通过柱层析分离纯化得到白色固体0.16g,产率为60.2%。1H NMR(500MHz,CDCl3)δ8.99(dd,J=4.2,1.7Hz,1H),8.54(dd,J=8.5,1.7Hz,1H),7.81(dd,J=7.9,1.7Hz,1H),7.58–7.50(m,3H),7.31(dd,J=8.4,1.1Hz,1H),7.24(ddd,J=8.1,7.4,1.1Hz,1H),6.99(d,J=8.4Hz,1H),5.67(s,1H),4.29(t,J=6.6Hz,2H),4.18(t,J=6.3Hz,2H),2.15(dt,J=14.4,6.8Hz,2H),2.04(dq,J=8.2,6.4Hz,2H),1.87–1.77(m,2H).13C NMR(126MHz,CDCl3)δ165.65,163.00,153.93,153.32,149.83,140.87,133.00,132.35,127.12,126.40,123.83,123.01,122.35,122.16,116.77,115.74,108.56,90.43,69.13,68.77,28.59,28.34,22.79.
实施例25:化合物3m的合成
合成方法同3a,所不同的是用8-羟基喹啉代替5-氯-8-羟基喹啉。通过柱层析分离纯化得到白色固体0.19g,产率为78.0%。1H NMR(500MHz,CDCl3)δ8.99(dd,J=4.2,1.8Hz,1H),8.16(dd,J=8.2,1.8Hz,1H),7.65(d,J=9.5Hz,1H),7.52–7.44(m,3H),7.41–7.35(m,1H),7.19(dd,J=7.3,1.6Hz,1H),6.92(d,J=7.6Hz,2H),6.27(d,J=9.5Hz,1H),4.67(dd,J=5.9,4.0Hz,2H),4.61(dd,J=5.8,4.0Hz,2H).13C NMR(126MHz,CDCl3)δ161.81,161.21,155.79,154.29,149.54,143.41,140.25,136.09,129.61,128.82,126.61,121.78,120.54,113.31,112.96,112.82,109.50,101.80,67.11,66.95.
实施例26:化合物3n的合成
合成方法同3a,所不同的是用香豆素中间体2b代替2a,8-羟基喹啉代替5-氯-8-羟基喹啉。通过柱层析分离纯化得到白色固体0.19g,产率为78.0%。1H NMR(500MHz,CDCl3)δ8.96(dd,J=4.2,1.7Hz,1H),8.13(dd,J=8.3,1.8Hz,1H),7.61(d,J=9.5Hz,1H),7.47–7.32(m,4H),7.11(dd,J=7.6,1.3Hz,1H),6.88–6.82(m,2H),6.23(d,J=9.4Hz,1H),4.46(t,J=6.2Hz,2H),4.33(t,J=6.0Hz,2H),2.54(p,J=6.1Hz,2H).13C NMR(126MHz,CDCl3)δ162.12,161.26,155.83,154.57,149.43,143.43,140.33,135.98,129.54,128.74,126.65,121.67,119.91,113.08,112.77,112.56,108.92,101.67,65.33,65.21,28.92.
实施例27:化合物3o的合成
合成方法同3a,所不同的是用香豆素中间体2c代替2a,8-羟基喹啉代替5-氯-8-羟基喹啉。通过柱层析分离纯化得到白色固体0.22g,产率为90.4%。1H NMR(500MHz,CDCl3)δ8.97(dd,J=4.2,1.7Hz,1H),8.13(dd,J=8.3,1.8Hz,1H),7.62(d,J=9.4Hz,1H),7.50–7.31(m,4H),7.08(dd,J=7.7,1.3Hz,1H),6.83(dq,J=4.3,2.4Hz,2H),6.25(d,J=9.5Hz,1H),4.35(t,J=6.4Hz,2H),4.19(t,J=6.3Hz,2H),2.25(dq,J=8.1,6.5Hz,2H),2.13(dq,J=9.3,6.4Hz,2H).13C NMR(126MHz,CDCl3)δ162.28,161.31,155.87,154.62,149.43,143.47,140.37,135.91,129.52,128.68,126.65,121.65,119.68,112.95,112.93,112.41,108.66,101.42,68.42,68.32,26.12,25.61.
实施例28:化合物3p的合成
合成方法同3a,所不同的是用香豆素中间体2d代替2a,8-羟基喹啉代替5-氯-8-羟基喹啉。通过柱层析分离纯化得到白色固体0.22g,产率为92.5%。1H NMR(500MHz,CDCl3)δ8.95(dt,J=3.1,1.5Hz,1H),8.12(dd,J=8.2,1.8Hz,1H),7.61(d,J=9.4Hz,1H),7.49–7.30(m,4H),7.07(dd,J=7.7,1.2Hz,1H),6.85–6.74(m,2H),6.23(d,J=9.4Hz,1H),4.28(t,J=6.7Hz,2H),4.05(t,J=6.4Hz,2H),2.12(p,J=7.0Hz,2H),1.94(p,J=6.7Hz,2H),1.81–1.71(m,2H).13C NMR(126MHz,CDCl3)δ162.32,161.31,155.87,154.73,149.35,143.49,140.35,135.95,129.52,128.76,128.74,126.69,121.58,119.56,112.92,112.88,112.41,108.65,101.37,68.64,68.37,28.82,28.74,22.76.
实施例29:化合物3q的合成
合成方法同3a,所不同的是用香豆素中间体2e代替2a,8-羟基喹啉代替5-氯-8-羟基喹啉。通过柱层析分离纯化得到白色固体0.20g,产率为80.7%。1H NMR(500MHz,CDCl3)δ8.99(dd,J=4.2,1.7Hz,1H),8.17(dd,J=8.3,1.7Hz,1H),7.58–7.44(m,5H),6.97–6.90(m,2H),6.16(q,J=1.2Hz,1H),4.70–4.65(m,2H),4.65–4.59(m,2H),2.41(d,J=1.2Hz,3H).13C NMR(126MHz,CDCl3)δ161.62,161.33,155.18,154.27,152.57,149.50,136.15,129.62,126.64,125.61,124.48,124.00,121.80,120.51,112.65,112.15,109.46,101.80,67.10,66.88,18.71.
实施例30:化合物3r的合成
合成方法同3a,所不同的是用香豆素中间体2f代替2a,8-羟基喹啉代替5-氯-8-羟基喹啉。通过柱层析分离纯化得到白色固体0.17g,产率为68.4%。1H NMR(500MHz,CDCl3)δ8.97(dd,J=4.2,1.7Hz,1H),8.14(dd,J=8.3,1.8Hz,1H),7.49–7.39(m,4H),7.14(ddd,J=7.6,6.2,1.9Hz,1H),6.92–6.84(m,2H),6.13(q,J=1.3Hz,1H),4.48(t,J=6.2Hz,2H),4.35(t,J=6.0Hz,2H),2.55(p,J=6.1Hz,2H),2.39(d,J=1.2Hz,3H).13C NMR(126MHz,CDCl3)δ161.94,161.35,155.22,154.58,152.54,149.43,140.33,135.97,129.54,126.65,125.50,121.67,119.90,113.61,112.43,111.96,108.92,101.71,65.28,65.24,28.94,18.69.
实施例31:化合物3s的合成
合成方法同3a,所不同的是用香豆素中间体2g代替2a,8-羟基喹啉代替5-氯-8-羟基喹啉。通过柱层析分离纯化得到白色固体0.20g,产率为83.9%。1H NMR(500MHz,CDCl3)δ8.98(dq,J=5.2,2.2Hz,1H),8.14(dt,J=8.4,2.1Hz,1H),7.51–7.35(m,4H),7.18–7.06(m,1H),6.85(ddt,J=9.5,5.0,2.4Hz,2H),6.17–6.12(m,1H),4.36(td,J=6.3,2.7Hz,2H),4.20(td,J=6.3,2.6Hz,2H),2.26(ddt,J=9.4,6.8,4.8Hz,2H),2.15(dt,J=9.3,6.2Hz,2H).13C NMR(126MHz,CDCl3)δ162.09,161.44,155.26,154.62,152.62,149.41,135.94,129.53,126.67,125.45,121.65,119.66,113.46,112.65,111.86(2C),108.66,101.44,68.41,68.26,26.09,25.65,18.71.
实施例32:化合物3t的合成
合成方法同3a,所不同的是用香豆素中间体2h代替2a,8-羟基喹啉代替5-氯-8-羟基喹啉。通过柱层析分离纯化得到浅黄色固体0.18g,产率为73.4%。1H NMR(500MHz,CDCl3)δ8.97(dq,J=4.2,1.4Hz,1H),8.15(dq,J=8.3,1.7Hz,1H),7.53–7.35(m,4H),7.09(dt,J=7.7,1.3Hz,1H),6.91–6.78(m,2H),6.14(q,J=1.5Hz,1H),4.30(td,J=6.9,1.4Hz,2H),4.08(tt,J=6.4,1.6Hz,2H),2.41(dt,J=3.1,1.3Hz,3H),2.20–2.09(m,2H),2.01–1.90(m,2H),1.83–1.73(m,3H).13C NMR(126MHz,CDCl3)δ162.14,161.42,155.28,154.76,152.62,149.38,140.39,135.94,129.53,126.68,125.49,121.59,119.57,113.47,112.59,111.86,108.65,101.41,68.66,68.34,28.85,28.75,22.78,18.71.
实施例33:化合物3u的合成
合成方法同3a,所不同的是用香豆素中间体2i代替2a,8-羟基喹啉代替5-氯-8-羟基喹啉。通过柱层析分离纯化得到浅黄色固体0.09g,产率为36.1%。1H NMR(500MHz,CDCl3)δ8.97(dd,J=4.2,1.7Hz,1H),8.17(dd,J=8.3,1.8Hz,1H),7.80(dd,J=7.9,1.6Hz,1H),7.56–7.42(m,4H),7.33–7.28(m,1H),7.24–7.19(m,2H),5.78(s,1H),4.77(dd,J=5.8,3.7Hz,2H),4.70(dd,J=5.8,3.7Hz,2H).13C NMR(126MHz,CDCl3)δ165.46,162.78,154.26,153.29,149.62,140.39,136.08,132.47,129.69,126.53,123.85,123.34,121.84,120.96,116.69,115.48,110.11,90.92,67.74,66.79.
实施例34:化合物3v的合成
合成方法同3a,所不同的是用香豆素中间体2j代替2a,8-羟基喹啉代替5-氯-8-羟基喹啉。通过柱层析分离纯化得到白色固体0.15g,产率为60.4%。1H NMR(500MHz,CDCl3)δ8.98(dd,J=4.1,1.7Hz,1H),8.15(dd,J=8.3,1.7Hz,1H),7.83(dd,J=7.9,1.6Hz,1H),7.55(ddd,J=8.8,7.4,1.7Hz,1H),7.50–7.40(m,3H),7.32(d,J=8.3Hz,1H),7.29–7.22(m,1H),7.13(dd,J=7.4,1.5Hz,1H),5.75(s,1H),4.51(t,J=6.1Hz,2H),4.48(t,J=6.0Hz,2H),2.65(p,J=6.1Hz,2H).13C NMR(126MHz,CDCl3)δ165.50,162.89,154.42,153.32,149.49,140.27,136.04,132.37,129.58,126.60,123.86,122.97,121.77,120.17,116.79,115.68,109.01,90.79,66.28,65.08,28.54.
实施例35:化合物3w的合成
合成方法同3a,所不同的是用香豆素中间体2k代替2a,8-羟基喹啉代替5-氯-8-羟基喹啉。通过柱层析分离纯化得到白色固体0.18g,产率为74.9%。
实施例36:化合物3x的合成
合成方法同3a,所不同的是用香豆素中间体2l代替2a,8-羟基喹啉代替5-氯-8-羟基喹啉。通过柱层析分离纯化得到白色固体0.14g,产率为58.0%。1H NMR(500MHz,CDCl3)δ8.96(dd,J=4.3,1.8Hz,1H),8.15(dd,J=8.3,1.8Hz,1H),7.83(dd,J=7.9,1.6Hz,1H),7.55(ddd,J=8.7,7.2,1.6Hz,1H),7.52–7.35(m,3H),7.33(dd,J=8.4,1.0Hz,1H),7.29–7.22(m,1H),7.09(dd,J=7.6,1.3Hz,1H),5.68(s,1H),4.32(t,J=6.6Hz,2H),4.19(t,J=6.3Hz,2H),2.17(p,J=6.8Hz,2H),2.11–2.01(m,2H),1.89–1.79(m,2H).13C NMR(126MHz,CDCl3)δ165.69,163.05,154.69,153.34,149.38,140.36,135.98,132.34,129.55,126.66,123.85,123.07,121.62,119.66,116.77,115.78,108.68,90.43,77.31,77.05,76.80,69.18,68.49,28.66,28.37,22.82.
实施例37:本发明所述喹啉衍生物对Aβ自聚集的抑制作用:
选择实施例13~34制备的化合物,采用ThT法进行Aβ自聚集抑制活性测定。
1.溶液的配制
(1)10mM pH 7.4磷酸盐缓冲溶液(PBS):取3.618g Na2HPO4和0.603g KH2PO4于烧杯中,超纯水定容至100mL作为储备液。取4mL储备液用超纯水稀释至100mL,调pH至7.4,4℃保存备用。
(3)Aβ42蛋白溶液:1mg蛋白加入500μL六氟异丙醇,室温放置过夜,等蛋白完全溶解并使聚集的Aβ42全部打散,平均分装到10个200μL EP管中,-80℃冻过夜,随后用冷冻干燥机冻干,冻干粉末贮存于-20℃备用。使用时用DMSO溶解为5mM,再用PBS缓冲液稀释为100μM。
(4)50mM甘氨酸-NaOH缓冲液:称取0.938g甘氨酸于烧杯中,加入250mL超纯水使其溶解完全,用NaOH溶液调pH至8.5,保存于4℃备用。
(5)5μM硫磺素T溶液:称取3.1mg ThT粉末于1.5mL EP管中,加入970μL甘氨酸-NaOH溶液,使其浓度为10mM作为储备液,-20℃避光保存。临用前取3μL储备液用6mL甘氨酸-NaOH溶液稀释至5μM,该溶液现配现用。
(7)10.0mM样品溶液:称取一定量各种待分析样品用适量DMSO溶解,配成10.0mM样品溶液,再用10mM pH 7.4的PBS稀释为40μM。
2.Aβ42蛋白自聚集抑制活性测试
取10μL 50μM的Aβ1-42蛋白与10μL 20μM的化合物溶液于200μL EP管中37℃孵育48小时。10μL蛋白与10μL PBS设置为空白对照,阳性对照为10μL蛋白与10μL姜黄素或白藜芦醇或多奈哌齐。48小时后,在200μL EP管中加180μL 5μM的ThT溶液混匀,室温下避光反应5分钟。用排枪吸出180μL于黑色96孔板中用多功能酶标仪(INFINITE M1000)测量荧光吸收值,其中激发波长为450nm,吸收波长为482nm,以空白对照的荧光吸收值为对照,按以下公式求得化合物对Aβ42蛋白自聚集抑制率。
抑制率=(1-IFi/IFc)×100%,其中IFi为含有化合物样品的荧光值减去背景,IFc为空白对照的荧光吸收值减去背景。
结果如表1所示。结果表明在化合物与Aβ比值为1:2.5的情况下,本发明所述大部分化合物对Aβ42蛋白具有一定的抑制作用,其中化合物3x表现出最强的抑制活性,达到69.0%,与阳性对照姜黄素(Curcumin)和白藜芦醇(Resveratrol)相当。因此本发明所述的香豆素-8-羟基喹啉类衍生物极具有开发前景,可用于制备抗阿尔茨海默症的药物。
表1香豆素-8-羟基喹唑啉类衍生物对Aβ42自聚集的抑制活性
实施例36:本发明所述喹啉衍生物对单胺氧化酶的抑制作用:
选择实施例13~34制备的化合物,采用荧光法进行单胺氧化酶A和单胺氧化酶B的抑制活性测定,以氯吉兰(Clorgyline)作为单胺氧化酶A阳性对照,以拉多替吉(Ladostigil)作为单胺氧化酶B阳性对照。
(1)药物溶液的配制:
称取一定量的各种待分析样品溶于二甲亚砜(DMSO,dimethylsulfoxide),配成10mM浓度,-20℃低温冰箱保存,临用时用磷酸盐缓冲液(50mM/L,pH 7.4)稀释至所需浓度。
(2)反应溶液的配制:
单胺氧化酶A(M7316-1VL,recombinant,expressed in baculovirus infectedBTI insect cells)从Sigma公司购买;吸取一定体积单胺氧化酶A,用去离子水稀释至75μg/mL。
单胺氧化酶B(M7441-1VL,recombinant,expressed in baculovirus infectedBTI insect cells)从Sigma公司购买;吸取一定体积单胺氧化酶B,用去离子水稀释至12.5μg/mL。
辣根过氧化物酶(SRE0082-5KU,horseradish peroxidase)从Sigma公司购买,称取一定量Amplex Red reagent,用磷酸盐缓冲溶液(50mM/L,pH 7.4)配制成10U/mL的溶液,4℃遮光保存。
Amplex红试剂(Amplex Red reagent)从Sigma公司购买,称取一定量Amplex Redreagent,用磷酸盐缓冲溶液((50mM/L,pH 7.4)配制成200μM/L的溶液,4℃遮光保存。
酪胺从Sigma公司购买,称取一定量Amplex Red reagent,用磷酸盐缓冲溶液((50mM/L,pH 7.4)配制成10mM/L的溶液,4℃保存。
苄胺从Sigma公司购买,称取一定量Amplex Red reagent,用磷酸盐缓冲溶液((50mM/L,pH 7.4)配制成10mM/L的溶液,4℃保存。
(3)单胺氧化酶测试:
在黑色96孔板中分别加入80μL MAO-A或MAO-B酶溶液,以及20μL待测化合物溶液,在37℃孵育15min,立即加入20μL辣根过氧化物酶溶液、20μL Amplex红试剂溶液及酪胺(用于测试MAO-A)或苄胺(用于测试MAO-B),40μL磷酸缓冲溶液的混合液共100μL,在37℃孵育20min后,激发波545nm,发射波590nm读取荧光值。实验结果见表2所示,结果表明本发明所述的部分化合物具有一定的单胺氧化酶抑制活性,其中3a,3g,3h,3n,3q,3t对MAO-B的抑制活性显著好于阳性对照,且3n对氧化酶B的选择性指数达到25.9。可用于制备抗阿尔茨海默症的药物。
表2香豆素-8-羟基喹唑啉类衍生物对单胺氧化酶的抑制活性
a化合物20μM情况下,单胺氧化酶的抑制活性.
b单胺氧化酶B选择性指数=IC50(hMAO-A)/IC50(hMAO-B).
cno determined.
实施例37:本发明所述喹啉衍生物对丁酰胆碱酯酶的抑制作用:
应用Ellman(Biochemical Pharmacology 1961,7,88-95.)的方法测试实施例13~34制备的化合物对丁酰胆碱酯酶的抑制作用,结果用IC50值表示,以Tacrine作为阳性对照。所有的测试均在PowerWave XS2型全波长酶标仪上进行,在37℃的条件下测定。数据分析利用软件Origin进行处理。
(1)药物溶液的配制:
称取一定量的各种待分析样品溶于二甲亚砜(DMSO,dimethylsulfoxide),配成10mM浓度,-20℃低温冰箱保存,临用时用磷酸盐缓冲液(0.1mol/L,pH 8.0)稀释至所需浓度,使DMSO终浓度小于或等于0.5%(v/v)。
(2)酶储备液的配制:
丁酰胆碱酯酶(E.C.3.1.1.8,from equine serum)从Sigma公司购买;称取一定量丁酰胆碱酯酶,用去离子水稀释至合适活力范围。
(3)底物储备液的配制:
硫代丁酰胆碱(Butylthiocholine,BTC)从Sigma公司购买;称取一定量BTC,用磷酸盐缓冲溶液(0.1mol/L,pH 8.0)配制成0.01mol/L的溶液,4℃遮光保存。
(4)显色剂储备液的配制:
显色剂5,5-二硫代双(2-硝基苯甲酸)(DTNB)从Sigma公司购买;称取一定量DTNB,用磷酸盐缓冲溶液(0.1mol/L,pH 8.0)配制成0.01mol/L,4℃遮光保存。
(5)测试:
在96孔板中选取6个孔,分别加入10μL酶溶液,以及0,5,10,20,35,50μL待测化合物溶液,加入0.1mol/L pH8.0磷酸缓冲溶液使总体积为100μL,在37℃全波长酶标仪中孵育15min,立即加入10μL BTC溶液、10μL DTNB溶液及80μL磷酸缓冲溶液的混合液共100μL,在λ=412nm扫描2min测定吸光度变化。实验结果见表3所示,结果表明本发明所述的部分化合物具有一定的丁酰胆碱酯酶的抑制活性,可用于制备抗阿尔茨海默症的药物。
表3.化合物对丁酰胆碱酯酶的抑制活性
a化合物5μM情况下,丁酰胆碱酯酶的抑制活性.
实施例38:本发明所述喹啉衍生物血脑屏障透过能力:
选择实施例13~34制备的化合物,采用PAMPA-BBB法进行血脑屏障透过性预测1.试剂准备
(1)配制2%的猪脑提取物(Porcine brain lipid,PBL):称取10mg猪脑提取物加入500μl的正十二烷,使其充分溶解。使用前配制。
(2)配制50mM的PBS:称取1.36g K2HPO4于200mL超纯水中,KOH调pH至7.4。
(3)配制5mg/mL对照药物储备液:称取5mg对照药物加入1mL DMSO溶解,-20℃保存。(4)配制100μg/mL待测样品液:取储备液20μL于1.5mL的EP管中,加入980μl缓冲液(pH7.4PBS:乙醇=70:30)。
2.测试
(1)小心吸取4μL 2%的猪脑提取液加入作为给药池的96孔板疏水膜上。
(2)迅速吸取200μL待测样品液于96孔板中作为给药池,接收池加入300μL缓冲液(pH7.4PBS:乙醇:DMSO=68:30:2)。
(3)小心的将给药池平放于接收池上,并使膜与接收液充分接触。
(4)室温静止10小时,小心移去给药池。用多功能酶标仪测试接收池内化合物在其最大吸收峰处的OD值。
(5)吸取200μL待测样品液于300μL缓冲液(pH 7.4PBS:乙醇:DMSO=68:30:2)中混匀,作为理论平衡溶液,测其化合物在最大吸收峰处的OD值。
(6)以含2%的DMSO缓冲液作为空白对照。
(7)根据公式计算出Pe值
Pe=-Vd×Va/[(Vd+Va)A×t]×ln(1-OD接收池内待测样品/OD理论平衡溶液待测样品)
Vd为给药池体积,Vd为接收池体积,A为渗透面积,t为渗透时间。
实验结果见表4所示,结果表明本发明所述的大部分化合物Pe值大于3.8,具透过血脑屏障的能力。可用于制备抗阿尔茨海默症的药物。
表4香豆素-8-羟基喹唑啉类衍生物Pe值及血脑屏障透过能力的预测
化合物 | Pe(×10-6cm/s) | predictiona | 化合物 | Pe(×10-6cm/s) | predictiona |
3a | 3.3±0.5 | CNS± | 3m | 10.1±0.4 | CNS+ |
3b | 14.2±1.5 | CNS+ | 3n | 5.0±0.3 | CNS+ |
3c | 14.5±1.1 | CNS+ | 3o | 16.5±1.0 | CNS+ |
3d | 0.8±0.1 | CNS- | 3p | 3.8±1.0 | CNS± |
3e | 4.5±0.4 | CNS+ | 3q | 5.4±0.5 | CNS+ |
3f | 5.5±0.0 | CNS+ | 3r | 13.1±0.2 | CNS+ |
3g | 7.5±0.2 | CNS+ | 3s | 22.2±1.8 | CNS+ |
3h | 1.3±0.0 | CNS- | 3t | 7.7±0.5 | CNS+ |
3i | 14.0±0.8 | CNS+ | 3u | 19.7±1.5 | CNS+ |
3j | 4.8±0.5 | CNS+ | 3v | 10.6±0.4 | CNS+ |
3k | 13.6±1.3 | CNS+ | 3w | 5.7±0.5 | CNS+ |
3l | 13.6±0.8 | CNS+ | 3x | 12.4±0.7 | CNS+ |
aCompounds with permeabilities Pe>3.8×10-6cm/s could cross the BBBby passive diffusion,CNS+,high brain penetration;CNS-,low brainpenetrationn.d.,no determined.
实施例39:本发明所述喹啉衍生物3x对Aβ诱导SYSH-5Y细胞毒性的保护作用
选择实施例34制备的化合物,采用MTT法进行化合物对Aβ诱导SYSH-5Y细胞毒性的保护作用评价。
1.药物的孵育
(1)将Aβ42用DMSO溶解为5mM,再用DMEM培养基稀释至20μM备用
(2)取适当体积20μM Aβ42,加入不同体积10mM 3x,使其终浓度分别为2,5,10μM,37℃孵育24小时
2.操作流程
取对数生长期SYSH-5Y细胞,以0.25%胰酶消化后,离心收集细胞,用DMEM培养基(10%胎牛血清,1%双抗)重新悬浮,细胞计数板计数,接种于96孔细胞培养板中,每孔100μL,5000个/孔。培养24小时,使细胞贴壁后,吸去原培养基,加入孵育后的Aβ42和3x,每孔100μL,设3个复孔。继续培养24小时。空白及对照组加入含有相同量DMSO的培养基代替。24小时后除空白组孔外,每孔加入含5mg/mL MTT的培养基,继续培养4小时。然后弃去培养基,每孔加100μL DMSO。待生成物充分溶解后,在全波长酶标仪上测定各孔在波长570nm处的OD值。各样品中的细胞存活率以下列公式计算:细胞存活率(%)=(OD样品-OD空白)/(OD对照-OD空白)。结果如图1所示。结果表明本发明所述化合物3x具有较强的对Aβ42诱导SYSH-5Y细胞损伤的保护能力,可用于制备抗阿尔茨海默症的药物。
实施例40:本发明所述喹啉衍生物3x对APP/PS1转基因鼠认知能力的影响
选择实施例34制备的化合物,采用水迷宫法评价化合物对APP/PS1转基因鼠认知能力的影响
1.动物
18只SPF级6月龄APPsw/PSEN1双转基因雄性小鼠,6只同种属野生型小鼠C57BL/6J,购买于华阜康生物科技股份有限公司。将新购买的小鼠分笼喂养于室温控制在23℃左右的室内,12小时光照,湿度60-70%,自由进食进水,在实验动物中心适应环境一周。所有试验遵守实验动物使用和爱护准则,经遵义医科大学动物实验伦理道德委员会批准,实验动物使用许可证编号SYXK(黔)2021-0004。
2.分组
6只同种属野生型小鼠C57BL/6J作为野生型对照组,18只APPsw/PSEN1双转基因小鼠随机分为三组,每组6只,分别为生理盐水组,阳性对照多奈哌齐组,3x处理组。
3.水迷宫定位航行实验
灌胃24天后执行水迷宫定位航行试验。预先在水池(直径120厘米,深45厘米)里注入深32厘米左右的清水,使水面高出平台(直径9厘米,高30厘米)2厘米,水温控制在20℃左右,加入二氧化钛使水成乳白色,水中不能明显见到安全平台。水池等分为4个象限(从东,南,西,北分别是一至四象限)。将平台放在第三象限中间,在四个象限任选一点面向水池池壁将小鼠放入水中。试验历时5天。每天4次训练,小鼠分别从4个不同的入水点入水,每次90秒。仪器自动记录小鼠寻找并爬上平台的路线图、小鼠从入水到找到水下隐蔽平台并立于其上所需时间(潜伏期)以及游行路程。如果小鼠在90秒内未找到平台,需将其引至平台,这时潜伏期以90秒计。让小鼠停留10秒,再放回笼中。
4.水迷宫空间探索实验
定位航行试验结束24小时后,撤除平台。小鼠在原平台象限的对侧象限入水,记录小鼠90秒内的穿越平台次数,并进行比较分析。数据搜集和处理由Morris软件完成。结果如图2所示。结果表明本发明所述化合物3x能够显著的缩短AD鼠寻找平台的时间及增加穿过虚拟平台的次数,提高AD鼠的空间认知能力,可用于制备抗阿尔茨海默症的药物。
Claims (8)
3.根据权利要求1所述的香豆素-喹啉衍生物的制备方法,其特征在于:将具有抗Aβ42蛋白聚集活性的香豆素结构与抗阿尔茨海默病药物的药效团喹啉环拼合,同时改变两个结构之间的长度。
6.根据权利要求4或5所述的香豆素-喹啉衍生物的制备方法,其特征在于:所述溴烃烷为1,2-二溴乙烷,1,3-二溴丙烷,1,4-二溴丁烷,1,5-二溴戊烷。
7.根据权利要求4或5所述的香豆素-喹啉衍生物的制备方法,其特征在于:所用缚酸剂B为碳酸钾、碳酸钠、碳酸铯、三乙胺、N,N-二异丙基乙胺中的一种或多种混合试剂。
8.根据权利要求1所述的香豆素-喹啉衍生物在制备治疗阿尔茨海默病、脑血管痴呆或重症肌无力疾病的药物中的应用。
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