CN111228252B - 丙炔胺类衍生物在制药中的应用 - Google Patents
丙炔胺类衍生物在制药中的应用 Download PDFInfo
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Abstract
本发明公开了一类丙炔胺类衍生物在制药中的应用。申请人的试验表明，该类衍生物能选择性的抑制MAO‑B且活性显著，可用于制备MAO‑B抑制剂以及预防和/或治疗AD病等相关神经退行性疾病的药物。其中所述的丙炔胺类衍生物为具有下述式(I)所示结构的化合物或其药学上可接受的盐：
其中：n＝1～10；R表示下述式(A)～(E)所示结构中的任意一种：
在式(A)～(E)所示结构中，R1表示任意位置取代的H、F、Cl、Br、OH、OCH3、NO2、CH3、CF3、COCH3、COOCH3或CH2OH，或者是C2～C5直连或支链烷烃；X表示O、N、S或C。
Description
技术领域
本发明涉及医药技术领域，具体涉及丙炔胺类衍生物在制药中的应用。
背景技术
阿尔茨海默病(Alzheimer’s disease,AD)又称老年痴呆，是一种临床表现为认知和记忆功能不断恶化，日常生活能力进行性衰退并伴有各种神经精神症状和行为障碍的神经退行性疾病。目前治疗AD的药物有限，开发新型有效的AD治疗药物具有重要的意义。
单胺氧化酶(Monoamine oxidase,MAO)是一种位于线粒体外膜的黄素蛋白酶。它能催化氧化生物体内的各种胺类物质最终生成相应的醛和过氧化氢。根据对底物和抑制剂的敏感性，单胺氧化酶分为A和B两种亚型。已有的研究发现，MAO-B在AD患者大脑中显著增加，增高的MAO-B水平，增加了对脑内胺类神经递质的催化，生成大量过氧化氢，从而诱导氧化应激(Oxidative stress,OS)导致一系列AD相关病理事件的发生。除此之外，MAO-B还可以通过多种途径影响AD的病理过程：(1)MAO-B直接调控γ-分泌酶和β-分泌酶的生成进而促进淀粉样前体蛋白(Amyloid precursor protein,APP)的分解生成Aβ；(2)激活的MAO-B可以破坏胆碱能神经元造成胆碱能神经系统紊乱；(3)MAO-B能促进tau蛋白的异常磷酸化，促进神经元纤维缠结的形成(NFTs)；(4)MAO-B水解过量的胺类神经递质导致脑内其它神经递质的再分布。
临床上，一些MAO-B选择性抑制剂的应用在一定程度上能缓解AD患者的认知症状。如司来吉兰(Selegiline)可以提高中重度AD患者的认知能力，拉扎贝胺(Lazabemide)则在II期临床试验中对比安慰剂组可以降低20-40％的认知下降。因此，开发新型有效的选择性MAO-B抑制剂成为AD治疗的有效途径。但目前尚未发现有丙炔胺类衍生物及其合成方法以及将其应用于治疗AD方面的相关报道。
发明内容
本发明要解决的技术问题是提供一系列结构新颖的丙炔胺类衍生物在制药中的应用。
本发明涉及丙炔胺类衍生物在制药中的多种应用，其中所述的丙炔胺类衍生物为具有下述式(I)所示结构的化合物或其药学上可接受的盐：
其中：
n＝1～10；
R表示下述式(A)～(E)所示结构中的任意一种：
上述式(A)～(E)所示结构中，R1表示任意位置取代的H、F、Cl、Br、OH、OCH3、NO2、CH3、CF3、COCH3、COOCH3或CH2OH，或者是C2～C5直连或支链烷烃；X表示O、N、S或C。
为方便描述，在本申请说明书的以下内容中出现的“丙炔胺类衍生物”可以理解为上述对R、R1和n进行限定的式(I)所示结构的化合物的简称。
本发明的第一个目的在于提供丙炔胺类衍生物或其药学上可接受的盐在制备单胺氧化酶B抑制剂中的应用。
本发明的第二个目的在于提供丙炔胺类衍生物或其药学上可接受的盐在制备治疗阿尔茨海默病、脑血管痴呆、青光眼或重症肌无力的药物中的应用。
本发明的第三个目的在于提供丙炔胺类衍生物或其药学上可接受的盐在制备改善阿尔茨海默病、脑血管痴呆、青光眼或重症肌无力的保健品中的应用。
本发明的第四个目的在于提供一种单胺氧化酶B抑制剂，它含有治疗上有效剂量的丙炔胺类衍生物或其药学上可接受的盐，以及药学上可接受的辅料。
本发明的第五个目的在于提供一种治疗阿尔茨海默病、脑血管痴呆、青光眼或重症肌无力的药物，它含有治疗上有效剂量的丙炔胺类衍生物或其药学上可接受的盐，以及药学上可接受的辅料。
本发明的第六个目的在于提供一种改善阿尔茨海默病、脑血管痴呆、青光眼或重症肌无力的保健品，它含有丙炔胺类衍生物或其药学上可接受的盐，以及药学上可接受的辅料。
上述提及的单胺氧化酶B抑制剂、治疗阿尔茨海默病、脑血管痴呆、青光眼或重症肌无力的药物或保健品的剂型可以是药学上可接受的任意剂型，具体可以是颗粒剂、片剂、丸剂、胶囊或注射剂等常规剂型。
本发明中涉及的丙炔胺类衍生物优选为包括下述式I-1～I-20所示结构中的至少一种化合物：
本发明中涉及的丙炔胺类衍生物的药学上可接受的盐，具体可以是上述式(I)所示结构化合物的盐酸盐、马来酸盐、枸橼酸盐、硫酸盐、马来酸盐、三氟乙酸盐、柠檬酸盐、酒石酸盐、苯磺酸盐、乙酸盐、丙酸盐、酒石酸盐、乙磺酸盐、苯甲酸盐或对甲苯磺酸盐等。式(I)所示化合物药学上可接受的盐具有与式(I)所示化合物同样或更好的药效活性。
本发明中涉及的丙炔胺类衍生物可以自行设计路线进行合成，优选按下述方法进行合成：
1)取下述式(A)～(E)所示结构中的任意一种化合物和过量的二溴烷烃置于有机溶剂中，加入缚酸剂，于加热或不加热条件下反应，所得反应物料固液分离，收集滤液，经纯化后得到相应的中间体；
上述式(A)～(E)所示结构中，R1表示任意位置取代的H、F、Cl、Br、OH、OCH3、NO2、CH3、CF3、COCH3、COOCH3或CH2OH，或者是C1～C5直连或支链烷烃；X表示O、N、S或C；
所述的二溴烷烃为Br(CH2)nBr，n＝1～10；
2)取中间体和N-甲基炔丙基胺置于有机溶剂中，加入缚酸剂，于加热或不加热条件下反应，得到相应的目标化合物粗品。
上述合成方法的步骤1)和2)中，所述的有机溶剂具体可以是选自丙酮、DMF、乙腈、四氢呋喃和二甲亚砜中的一种或两种以上的组合；所述有机溶剂的用量可以根据需要进行确定，通常情况下，以1mmol的式(A)～(E)所示结构中的一种化合物或中间体为基准计算，有机溶剂的用量一般为2-10mL。所述的缚酸剂为现有技术中的常规选择，具体可以是选自碳酸钾、碳酸铯、碳酸氢钠、碳酸钠、氢氧化钠、氢氧化钾、吡啶和三乙胺中的一种或两种以上的组合；缚酸剂的加入量为使得体系在碱性条件下反应，优选控制体系的pH＝8-12。
上述合成方法的步骤1)和2)中，当反应在不加热的条件下进行时，所得产物的产率较低，因此，优选反应在加热条件下进行，进一步优选反应在50℃至有机溶剂的沸点温度范围内进行，更优选反应在60～80℃条件下进行。反应是否完全可采用薄层层析跟踪检测。
上述合成方法的步骤1)中，所述的二溴烷烃为中n的取值优选为3～8；所述二溴烷烃的用量必须是过量的，其用量优选为式(A)～(E)所示结构中的任意一种化合物物质的量的10～30倍。该步骤1)中，收集的滤液可以采用硅胶柱层析或高效液相色谱纯化以得到相应的中间体。当收集的滤液经硅胶柱纯化时，采用由石油醚和乙酸乙酯组成的混合溶剂作为洗脱剂，其中石油醚可以用环己烷、正己烷、正戊烷、异戊烷、环戊烷或异辛烷代替，乙酸乙酯可以用丙酮、氯仿、二氧六环、四氢呋喃或二氯甲烷代替。在混合溶剂的组成中，石油醚(环己烷等)和乙酸乙酯(丙酮等)的体积比优选为5～30：1，更优选为5～20：1，最优选为10：1。
上述合成方法的步骤2)中，中间体和N-甲基炔丙基胺的摩尔比为化学计量比，在实际的操作过程中，N-甲基炔丙基胺可稍微过量。
由上述方法制得的是式(I)所示化合物的粗品，可采用现有常规的纯化方法对其进行纯化以提高式(I)所示化合物的纯度。通常是将制得的目标化合物粗品上硅胶柱或高效液相色谱层析以得到纯化后的目标化合物。当将目标化合物粗品上硅胶柱层析进行纯化时，采用由石油醚和乙酸乙酯组成的混合溶剂作为洗脱剂，其中石油醚可以用环己烷、正己烷、正戊烷、异戊烷、环戊烷或异辛烷代替，乙酸乙酯可以用丙酮、氯仿、二氧六环、四氢呋喃或二氯甲烷代替。在混合溶剂的组成中，石油醚(环己烷等)和乙酸乙酯(丙酮等)的体积比优选为1～20：1，更优选为1～10：1，最优选为4：1。
与现有技术相比，本发明提供了一系列结构新颖的丙炔胺类衍生物及其药学上可接受的盐在制药中的应用，申请人的实验结果表明，本发明所述的丙炔胺类衍生物能够选择性的抑制MAO-B，部分衍生物更是表现出极为显著的抑制活性，可用于制备MAO-B抑制剂以及预防或/和治疗阿尔茨海默病等相关神经退行性疾病的药物。
附图说明
图1为本发明所述目标化合物血脑屏障通透性相关参数曲线。
图2为本发明所述目标化合物I-10在不浓度下神经细胞SH-SY5Y的生存率柱状图。
具体实施方式
下面结合具体实施例对本发明作进一步的详述，以更好地理解本发明的内容，但本发明并不限于以下实施例。
本发明所述目标化合物的合成路线如下：
其中，n＝1～10；
R表示下述式(A)～(E)所示结构中的任意一种：
上述式(A)～(E)所示结构中，R1表示任意位置取代的H、F、Cl、Br、OH、OCH3、NO2、CH3、CF3、COCH3、COOCH3或CH2OH，或者是C2～C5直连或支链烷烃；X表示O、N、S或C。
实施例1：中间体的制备
称取式(A)～(E)所示结构中的任意一种(6mmol)溶解于10mL有机溶剂(中间体A1～A4采用的有机溶剂为DMF，其余中间体采用的有机溶剂均为丙酮)中，溶解完全后，加入缚酸剂(中间体A1～A4及B1～B8采用的缚酸剂为碳酸钾，中间体C1～C4采用的缚酸剂为碳酸铯，中间体D1及E1～E3采用的缚酸剂为碳酸钠)(7.2mol,1.2当量)室温下搅拌1分钟，然后加入过量的二溴烷烃(120mmol，20当量)，于70℃下搅拌反应，TLC跟踪检测直至反应完全，反应结束，抽滤，滤液减压浓缩，残余物经硅胶柱层析分离(石油醚：乙酸乙酯＝10：1，体积比)，得到相应的中间体，其具体结构如表1所示。表1中间体的具体结构
实施例2：目标化合物I-1～I-20的制备
称取相应中间体(2mmol)溶解于10mL有机溶剂(目标化合物I-1～I-8采用的有机溶剂为乙腈，目标化合物I-9～I-15采用的有机溶剂为丙酮，目标化合物I-16～I-18采用的有机溶剂为四氢呋喃，目标化合物I-19采用的有机溶剂为DMF，目标化合物I-20采用的有机溶剂为二甲基亚砜)中，溶解完全后，加入缚酸剂(目标化合物I-1～I-15采用的缚酸剂为三乙胺，目标化合物I-16采用的缚酸剂为碳酸钠，目标化合物I-17采用的缚酸剂为吡啶，目标化合物I-18～I-20采用的缚酸剂为碳酸氢钠)(4mmol，2当量)和N-甲基炔丙基胺(2.2mmol)，加入完毕后，加热条件下回流反应(目标化合物I-1～I-5的反应温度为70℃，时间为8h；目标化合物I-6～I-15的反应温度为80℃，时间为6h；目标化合物I-16～I-19的反应温度为50℃，时间为10h；目标化合物I-20在常温条件下反应，时间为12h)，所得反应液减压浓缩，残余物经硅胶柱层析分离纯化(石油醚：乙酸乙酯＝4：1，体积比)，得相应的目标化合物，其结构如表2所示。
表2目标化合物I-1～I-20的具体结构
不同的目标产物及其表征如下：
I-1：产率83％,淡黄色油状物.1H NMR(500MHz,CDCl3)δ7.68–7.63(m,1H),6.87(d,J＝5.4Hz,2H),4.04(t,J＝6.3Hz,2H),3.36(d,J＝2.2Hz,2H),3.12–3.02(m,2H),2.69–2.61(m,2H),2.54–2.47(m,2H),2.32(s,3H),2.22(t,J＝2.2Hz,1H),1.89–1.80(m,2H),1.72–1.61(m,2H).13C NMR(126MHz,CDCl3)δ205.45,164.83,158.27,130.35,125.42,115.74,110.36,78.38,73.41,68.17,55.18,45.59,41.75,36.53,26.95,25.97,24.03.HRMS:calcd for C17H21NO2[M+H]+272.1645,found 272.1658.
I-2：产率87％,淡黄色油状物.1H NMR(500MHz,CDCl3)δ7.68–7.62(m,1H),6.89–6.83(m,2H),4.01(t,J＝6.4Hz,2H),3.34(d,J＝2.3Hz,2H),3.09–3.02(m,2H),2.68–2.60(m,2H),2.47–2.43(m,2H),2.31(s,3H),2.22(t,J＝2.3Hz,1H),1.88–1.77(m,2H),1.59–1.45(m,4H).13C NMR(126MHz,CDCl3)δ205.45,164.87,158.28,130.30,125.41,115.73,110.31,78.40,73.38,68.33,55.53,45.58,41.82,36.52,29.04,27.29,25.96,23.92.HRMS:calcd for C18H23NO2[M+H]+286.1802,found 286.1813.
I-3：产率78％,淡黄色固体.1H NMR(500MHz,CDCl3)δ7.68–7.64(m,1H),6.87(d,J＝4.9Hz,2H),4.01(t,J＝6.5Hz,2H),3.34(d,J＝2.2Hz,2H),3.10–3.03(m,2H),2.69–2.60(m,2H),2.48–2.38(m,2H),2.30(s,3H),2.21(t,J＝2.2Hz,1H),1.87–1.76(m,2H),1.49(dq,J＝14.5,7.2Hz,4H),1.39(dd,J＝14.3,7.5Hz,2H).13C NMR(126MHz,CDCl3)δ205.43,164.92,158.27,130.30,125.41,115.74,110.34,78.48,73.31,68.41,55.64,45.57,41.84,36.52,29.12,27.53,27.19,26.02,25.96.HRMS:calcd for C19H25NO2[M+H]+300.1958,found 300.1961.
I-4：产率86％,黄色油状物.1H NMR(500MHz,CDCl3)δ7.55(d,J＝8.6Hz,1H),6.63(dd,J＝8.6,1.7Hz,1H),6.51(d,J＝1.5Hz,1H),4.61(s,2H),4.01(t,J＝6.4Hz,2H),3.41(s,2H),2.55–2.47(m,2H),2.37(s,3H),2.27(s,1H),1.86–1.77(m,2H),1.55(dd,J＝15.0,7.5Hz,2H),1.51–1.46(m,2H),1.43–1.36(m,2H).13C NMR(126MHz,CDCl3)δ196.72,175.69,166.88,124.18,113.28,111.20,95.88,74.67,73.06,67.77,54.53,44.44,40.66,27.96,26.20,26.12,24.97.HRMS:calcd for C18H23NO3[M+H]+302.1751,found 302.1764.
I-5：产率91％,淡黄色油状物.1H NMR(500MHz,CDCl3)δ7.96(d,J＝8.7Hz,1H),6.78(dd,J＝8.7,1.9Hz,1H),6.67(s,1H),4.01(t,J＝6.3Hz,2H),3.34(d,J＝1.8Hz,2H),2.88(t,J＝6.0Hz,2H),2.60–2.54(m,2H),2.47(t,J＝7.3Hz,2H),2.30(s,3H),2.21(s,1H),2.12–2.04(m,2H),1.86–1.77(m,2H),1.68–1.57(m,2H).13C NMR(126MHz,CDCl3)δ197.30,163.10,147.00,129.66,126.22,113.50,113.18,78.46,77.16,73.30,67.87,55.16,45.57,41.73,38.96,30.22,26.95,24.02,23.45.HRMS:calcd for C18H23NO2[M+H]+286.1801,found 286.1815.
I-6：产率76％,淡黄色油状物.1H NMR(500MHz,CDCl3)δ7.96(d,J＝8.7Hz,1H),6.77(dd,J＝8.7,2.1Hz,1H),6.66(d,J＝1.4Hz,1H),3.98(t,J＝6.4Hz,2H),3.32(d,J＝2.1Hz,2H),2.88(t,J＝6.0Hz,2H),2.59–2.54(m,2H),2.42(t,J＝7.1Hz,2H),2.29(s,3H),2.21(t,J＝2.0Hz,1H),2.11–2.03(m,2H),1.85–1.75(m,2H),1.56–1.42(m,4H).13C NMR(126MHz,CDCl3)δ197.31,163.14,147.00,129.65,126.18,113.48,113.14,78.47,73.27,68.02,55.50,45.55,41.79,38.94,30.20,29.03,27.28,23.88,23.43.HRMS:calcd forC19H25NO2[M+H]+300.1958,found 300.1970.
I-7：产率74％,淡黄色油状物.1H NMR(500MHz,CDCl3)δ7.97(d,J＝8.7Hz,1H),6.78(dd,J＝8.7,2.4Hz,1H),6.67(d,J＝2.2Hz,1H),3.98(t,J＝6.5Hz,2H),3.34(d,J＝2.3Hz,2H),2.89(t,J＝6.1Hz,2H),2.58(t,J＝6.5Hz,2H),2.42(t,J＝6.5Hz,2H),2.30(s,3H),2.21(t,J＝2.3Hz,1H),2.14–2.04(m,2H),1.84–1.74(m,2H),1.48(m,4H),1.38(m,2H).13C NMR(126MHz,CDCl3)δ197.35,163.21,147.02,129.68,126.19,113.50,113.19,78.45,73.31,68.11,55.63,45.54,41.81,38.98,30.24,29.13,27.50,27.18,26.00,23.47.HRMS:calcd for C20H27NO2[M+H]+314.2114,found 314.2127.
I-8：产率81％,黄色固体.1H NMR(500MHz,CDCl3)δ7.81(d,J＝8.8Hz,1H),6.56(dd,J＝8.8,2.2Hz,1H),6.39(d,J＝2.2Hz,1H),4.49(t,J＝6.4Hz,2H),4.03(t,J＝6.3Hz,2H),3.36(d,J＝2.2Hz,2H),2.73(t,J＝6.4Hz,2H),2.60(t,J＝7.1Hz,2H),2.33(s,3H),2.23(t,J＝2.3Hz,1H),1.95(p,J＝6.6Hz,2H).13C NMR(126MHz,CDCl3)δ190.65,165.49,163.87,128.93,115.29,110.33,101.37,78.27,73.52,67.46,66.47,52.13,45.75,41.76,37.53,27.14.HRMS:calcd for C16H19NO3[M+H]+274.1438,found 274.1438.
I-9：产率71％,淡黄色油状物.1H NMR(500MHz,CDCl3)δ7.82(d,J＝8.8Hz,1H),6.56(dd,J＝8.8,2.4Hz,1H),6.38(d,J＝2.3Hz,1H),4.50(t,J＝6.3Hz,2H),4.00(t,J＝6.3Hz,2H),3.37(d,J＝2.3Hz,2H),2.74(t,J＝5.0Hz,2H),2.50(t,J＝5.0Hz,2H),2.33(s,3H),2.23(t,J＝2.4Hz,1H),1.87–1.77(m,2H),1.64(m,2H).13C NMR(126MHz,CDCl3)δ190.77(s),165.63(s),163.78(s),128.95(s),115.29(s),110.31(s),101.28(s),78.01(s)73.69(s),68.09(s),67.43(s),55.06(s),45.73(s),42.00(s),37.29(s),27.07(s),23.98(s).HRMS:calcd for C17H21NO3[M+H]+288.1594,found 288.1568.
I-10：产率89％,黄色油状物.1H NMR(500MHz,CDCl3)δ7.82(d,J＝8.8Hz,1H),6.55(dd,J＝8.8,2.4Hz,1H),6.38(d,J＝2.3Hz,1H),4.50(t,J＝6.4Hz,2H),3.98(t,J＝6.4Hz,2H),3.37(d,J＝2.3Hz,2H),2.74(t,J＝5.0Hz 2H),2.47(t,J＝5.0Hz,2H),2.33(s,3H),2.24(t,J＝2.4Hz,1H),1.81(q,J＝6.6Hz,2H),1.60–1.52(m,2H),1.48(m,2H).13C NMR(126MHz,CDCl3)δ190.76,165.61,163.90,128.97,115.30,110.32,101.29,78.27,73.69,68.35,67.49,55.53,45.59,41.82,37.57,28.98,27.38,23.92.HRMS:calcd for C18H23NO3[M+H]+302.1751,found 302.1745.
I-11：产率73％,淡黄色油状物.1H NMR(500MHz,CDCl3)δ7.82(d,J＝8.8Hz,1H),6.56(dd,J＝8.8,2.3Hz,1H),6.38(d,J＝2.3Hz,1H),4.58–4.45(m,2H),3.97(t,J＝6.4Hz,2H),3.46(s,2H),2.79–2.70(m,2H),2.62–2.51(m,2H),2.42(s,3H),2.31(s,1H),1.86–1.73(m,2H),1.58(dt,J＝15.0,7.6Hz,2H),1.52–1.45(m,2H),1.40(dd,J＝15.1,8.1Hz,2H).13C NMR(126MHz,CDCl3)δ190.69,165.63,163.92,128.98,115.26,110.39,101.31,68.37,67.50,55.47,45.34,41.52,37.57,29.01,27.07,25.94,26.93.HRMS:calcd forC19H25NO3[M+H]+316.1907,found 316.1913.
I-12：产率89％,淡黄色油状物.1H NMR(500MHz,CDCl3)δ7.82(d,J＝8.8Hz,1H),6.56(dd,J＝8.8,2.3Hz,1H),6.38(d,J＝2.3Hz,1H),4.50(t,J＝6.4Hz,2H),3.97(t,J＝6.5Hz,2H),3.39(d,J＝2.1Hz,2H),2.74(t,J＝5.0Hz,2H),2.46(t,J＝5.0Hz,2H),2.35(s,3H),2.25(t,J＝2.3Hz,1H),1.77(m,2H),1.55–1.40(m,4H),1.33(br,6H).13C NMR(126MHz,CDCl3)δ190.68,165.69,163.91,128.95,115.21,110.41,101.29,77.90,73.84,68.52,67.48,55.73,45.47,41.71,37.57,29.50,29.34,29.07,27.37,26.01.HRMS:calcd forC21H29NO3[M+H]+344.2220,found 344.2221.
I-13：产率81％,淡黄色油状物.1H NMR(500MHz,DMSO)δ7.91(d,J＝8.8Hz,2H),7.02(d,J＝8.8Hz,2H),4.06(t,J＝6.5Hz,2H),3.29(s,3H),3.10(s,1H),2.39(t,J＝7.1Hz,2H),2.19(s,3H),1.78–1.68(m,2H),1.53(dt,J＝14.6,7.3Hz,2H),1.34(s,2H).13CNMR(126MHz,DMSO)δ196.32,162.55,130.51,129.75,114.28,75.77,67.70,54.45,44.89,41.18,29.80,26.42,26.31,23.24.HRMS:calcd for C16H21NO2[M+H]+260.1645,found260.1651.
I-14：产率74％,淡黄色油状物.1H NMR(500MHz,DMSO)δ8.00–7.80(m,2H),7.09–6.93(m,2H),4.04(t,J＝6.5Hz,2H),3.27(s,3H),3.09(s,1H),2.32(t,J＝7.1Hz,2H),2.17(s,3H),1.77–1.68(m,2H),1.43–1.36(m,4H),1.35–1.27(m,4H).13C NMR(126MHz,DMSO)δ196.31,162.58,130.50,129.74,114.26,75.68,67.85,54.87,44.90,41.29,28.53,26.79,26.55,26.42,25.36.HRMS:calcd for C18H25NO2[M+H]+288.1958,found 288.1966.
I-15：产率84％,淡黄色油状物.1H NMR(500MHz,DMSO)δ7.15(t,J＝8.2Hz,1H),6.50(t,J＝2.5Hz,1H),6.48(t,J＝2.4Hz,1H),6.46(t,J＝2.3Hz,1H),3.92(t,J＝6.5Hz,2H),3.72(s,3H),3.10(s,1H),2.35(s,2H),2.18(s,3H),1.69(dd,J＝12.8,5.9Hz,2H),1.46–1.38(m,4H),1.35(d,J＝2.6Hz,2H).13C NMR(126MHz,DMSO)δ160.94,160.39,130.37,107.03,106.61,101.07,67.81,55.51,55.28,45.33,30.24,29.00,23.83.HRMS:calcd forC16H23NO2[M+H]+262.1801,found 266.1809.
I-16：产率75％,淡黄色固体.1H NMR(500MHz,CDCl3)δ7.54(dd,J＝8.3,2.0Hz,1H),7.50(d,J＝2.0Hz,1H),6.87(d,J＝8.4Hz,1H),4.10(t,J＝6.6Hz,2H),3.90(s,3H),3.35(d,J＝2.4Hz,2H),2.55(s,3H),2.51–2.45(m,2H),2.31(s,3H),2.21(t,J＝2.4Hz,1H),1.89(dd,J＝14.9,6.8Hz,2H),1.65(dt,J＝15.0,7.5Hz,2H).13C NMR(126MHz,CDCl3)δ196.71,152.70,149.08,130.14,123.09,111.01,110.25,78.27,72.91,68.39,55.86,54.81,45.35,41.50,26.60,25.99,23.59.HRMS:calcd for C17H23NO3[M+H]+290.1751,found 290.1749.
I-17：产率79％,黄色固体.1H NMR(500MHz,CDCl3)δ7.54(dd,J＝8.3,2.0Hz,1H),7.50(d,J＝2.0Hz,1H),6.87(d,J＝8.4Hz,1H),4.10(t,J＝6.6Hz,2H),3.90(s,3H),3.35(d,J＝2.4Hz,2H),2.55(s,3H),2.51–2.45(m,2H),2.31(s,3H),2.21(t,J＝2.4Hz,1H),1.89(dd,J＝14.9,6.8Hz,2H),1.65(dt,J＝15.0,7.5Hz,2H).13C NMR(126MHz,CDCl3)δ196.98,152.98,149.29,130.28,123.49,111.09,110.55,78.51,73.31,68.97,56.13,55.54,45.61,41.84,28.96,27.30,26.34,23.88.HRMS:calcd for C18H25NO3[M+H]+304.1907,found 304.1908.
I-18：产率79％,红色固体.1H NMR(500MHz,CDCl3)δ10.26(s,1H),7.78(d,J＝8.7Hz,1H),6.52(dd,J＝8.7,1.9Hz,1H),6.43(d,J＝2.0Hz,1H),4.04(t,J＝6.3Hz,2H),3.88(s,3H),3.36(s,2H),2.53–2.47(m,2H),2.32(s,3H),2.22(t,J＝2.3Hz,1H),1.88–1.79(m,2H),1.70–1.60(m,2H).13C NMR(126MHz,CDCl3)δ188.48,165.80,163.71,130.85,119.01,106.28,98.45,78.38,73.42,68.17,55.71,55.16,45.60,41.77,26.96,24.02.HRMS:calcd for C16H21NO3[M+H]+276.1594,found 276.1601.
I-19：产率82％,黄色固体.1H NMR(500MHz,CDCl3)δ10.24(s,1H),7.76(d,J＝8.7Hz,1H),6.49(dd,J＝8.7,1.8Hz,1H),6.41(d,J＝1.9Hz,1H),4.00(t,J＝6.4Hz,2H),3.87(s,3H),3.33(d,J＝2.2Hz,2H),2.43(t,J＝7.1Hz,2H),2.37(s,1H),2.29(s,3H),2.21(t,J＝2.2Hz,1H),1.87–1.76(m,2H),1.50(t,J＝11.4Hz,4H).13C NMR(126MHz,CDCl3)δ188.44,165.82,163.68,130.79,118.92,106.24,98.38,78.48,73.29,68.33,55.66,55.50,45.56,41.81,29.02,27.29,23.89.HRMS:calcd for C17H23NO3[M+H]+290.1751,found 290.1764.
I-20：产率73％,黄色粉末.1H NMR(500MHz,CDCl3)δ10.26(s,1H),7.77(d,J＝8.7Hz,1H),6.51(dd,J＝8.7,1.5Hz,1H),6.42(d,J＝1.8Hz,1H),4.00(t,J＝6.5Hz,2H),3.88(s,3H),3.34(d,J＝2.1Hz,2H),2.48–2.38(m,2H),2.30(s,3H),2.21(t,J＝2.2Hz,1H),1.85–1.74(m,2H),1.55–1.44(m,4H),1.39(dd,J＝14.5,7.6Hz,2H).13C NMR(126MHz,CDCl3)δ188.44,165.87,163.70,130.82,118.94,106.26,98.41,78.47,73.31,68.41,55.64,45.57,41.83,29.14,27.53,27.19,26.01.HRMS:calcd for C18H25NO3[M+H]+304.1907,found 304.1921.
实验例1：对按本发明所述目标化合物对单胺氧化酶A和B的抑制活性测定
采用Amplex red荧光法测定单胺氧化酶抑制活性。重组人单胺氧化酶A(E.C.1.4.3.4)和单胺氧化酶B(E.C.1.4.3.4)用作活性测试用酶源。异丙烟肼(Iproniazid)和雷沙吉兰(Rasagiline)用作阳性对照。
实验方法：将所测试化合物溶解于DMSO中，用缓冲液(0.05M KH2PO4/K2HPO4buffer,pH＝7.4)稀释到所需浓度。在96孔黑色酶标板中，依次加入20μL待测化合物和80μL单胺氧化酶A，轻拍使其混匀后，于37℃下避光孵育15min。孵育结束后，依次加入终浓度为200μM的Amplex Red试剂,2U/mL的辣根过氧化物酶和2mM的对酪胺。加入完成后，立即转入酶标仪中，于37℃下，测定其在30min内的荧光强度变化(excitation,545nm；emission,590nm)。在孵育过程中，MAO-A可催化底物酪胺氧化并释放过氧化氢，释放的过氧化氢作用于Amplex red并将其转化为具有荧光的物质试卤灵。为了避免化合物对辣根过氧化物酶的干扰，以3％的过氧化氢为代替酶进行平行对照试验。
测定结束后，根据其荧光强度变化并按照以下公式计算抑制率(％)：抑制率(％)＝{1-[(IF实验组-IF平行对照组)/(IF空白组-IF平行对照组)]}×100％。实验重复三次取平均值，利用GraphPad软件计算化合物对单胺氧化酶A的半数抑制浓度(IC50)；单胺氧化酶B的抑制活性测定方法同MAO-A抑制活性相同只是将所用的单胺氧化酶A替换为单胺氧化酶B，同时调整酶反应速率相同。测定结果如表3所示。
表3各目标化合物对MAO-A和MAO-B的抑制活性结果
b表示化合物在100μM浓度下的抑制率。
由表3可知，本发明所述各目标化合物都表现出了对MAO-B显著的抑制活性，而对MAO-A的抑制活性较弱，显示出本发明所述目标化合物对MAO-B良好的选择性。其中，化合物I-10为本系列最优化合物其对MAO-A的抑制率在100μM下为6.04％，而对MAO-B的抑制IC50值达4nM，远高于阳性对照药物雷沙吉兰，是一种有效选择性MAO-B抑制剂。
实验例2：本发明所述目标化合物的血脑屏障透过性
采用PAMPA-BBB人工膜法测定。采用猪脑磷脂构建体外透膜模型。通过测定9个具有不同血脑屏障透过性的药物，建立当前血脑屏障透过性曲线。
具体方法：PAMPA模型实验在96孔滤板中进行，配制浓度为2％的牛脑磷脂/十二烷(V/V)的溶液，超声溶解直至混合均匀。吸取该溶液5μL加在PAMPA供给板各孔中的亲脂性滤膜上，对照孔加入5μL的十二烷溶液。在接收板各孔中加入300μL的缓冲液(PBS/EtOH＝70:30，V/V，pH＝7.4)，在供给板各孔中加入150μL待测药液(每个药物在人工膜及对照膜均重复3次)，整个加药过程在10min内完成。将供给板放在接收板上，盖上盖子，将整个96孔滤板装置放置恒温培养箱中(25℃)孵育16h，孵育结束后，收集供体板和接收板的溶液，测定浓度，依照下述公式计算透过率Pe：Pe＝{-VdVa/[(Vd+Va)At]}ln(1-drugacceptor/drugequilibrium)，其中Vd为供体孔体积(mL)，Va为接收孔体积(mL)，A为滤膜面积(cm2)，t为渗透时间(s)，drugacceptor为t时间接收板溶液浓度，drugequilibrium为理论平衡吸收浓度。通过将已知标准药物的文献Pe值和实测Pe值比较建立的标准曲线，求出此次血脑屏障透过Pe值范围，判定化合物的透过性。结果如下述表4所示。
表4 PAMPA-BBB人工膜法测定的9个对比药物的渗透系数Pe(×106cm/s).
a数据来源于文献Eur.J.Med.Chem.2003,38:223–232。
b三次独立实验平均值，表示为平均值±SD，溶剂配比为PBS:EtOH＝70:30。
对比实验测定的9个药物Pe值(表4)和文献报道数值作线性回归(如图1所示)，得到的一个良好的线性关系公式：Pe(exp.)＝0.9707Pe(bibl.)-0.1043(R2＝0.9573)。根据文献报道的血脑屏障透过数值结合当前计算公式，得到当Pe(×106cm/s)>3.78时化合物可以很好的透过血脑屏障。如表5所示，本发明所述目标化合物Pe值均大于3.78，说明这些化合物均能很好的透过血脑屏障。
表5目标化合物在PAMPA-BBB测定中的Pe(×106cm/s)值。
a三次独立实验平均值，表示为平均值±SD，溶剂配比为PBS:EtOH＝70:30，体积比。
bCNS+代表化合物可以透过血脑屏障。
实验例3：本发明所述目标化合物的抗Aβ1-42聚集作用
采用硫代硫磺素T(ThT)法测定化合物的抗Aβ1-42聚集作用。
具体方法：称取Aβ1-42溶解于六氟异丙醇中，充分溶解后，分装，放置通风橱中过夜，挥发掉六氟异丙醇后冻存。实验之前，取一份样品溶解于DMSO中，再用PBS缓冲液稀释至25μM。化合物用DMSO配置，并用缓冲液稀释，控制最后DMSO含量不高于10％。然后依次向黑色酶标板中加入1μL待测样品和9μLAβ1-42缓冲液，加入完毕后，轻拍使其混合均匀，用盖板膜将96孔板盖好，于室温下静置46-48h。静置结束，加入50mM ThT溶液200μL并于激发波长446nm和吸收波长490nm下测定其荧光吸收。其抑制率(％)计算公式为：抑制率(％)＝1-(IFi/IFo*100)，其中IFi代表抑制剂存在下的荧光吸收；IFo代表无抑制剂存在下的荧光吸收。每个实验重复三次，结果表达为平均值±SD。结果如表6所示
表6目标化合物的抗Aβ聚集作用
a药物浓度在25μM浓度下，对Aβ1-42自身聚集的抑制率。
如表6所示，化合物I-1、I-9、I-10、I-15、I-16表现出了较好的抗Aβ聚集作用，I-2、I-5、I-6、I-7、I-14、I-15、I-16表现出了中等强度的抗Aβ聚集作用，表明本发明所述目标化合物可以一定程度的抗Aβ聚集。
实验例4：目标化合物I-10的神经细胞毒性
采用MTT法测定化合物对神经细胞的毒性，上市药物雷沙吉兰(rasagiline)选做阳性对照。
具体方法：人神经母细胞瘤细胞(SH-SY5Y)培养在含有10％胎牛血清的EMEM和F-12(1:1)混合培养基中，并加入110U/mL青霉素和100μg/mL链霉素作为双抗。待细胞生长满培养瓶约80％后，将细胞以10000个/孔转入96孔板中培养。24h后，换液，加入相应浓度的测试化合物，继续孵育48h。孵育结束后，加入20μL MTT。4h后，移去培养基加入200μL DMSO，溶解生成的甲瓒，并在570nm下测定吸光度计算生存率。结果如图2所示。
由图2可知，对比雷沙吉兰，目标化合物I-10在100和50μM浓度下有一定的神经毒性，但在25、12.5和6.25μM浓度下则较为安全，由于目标化合物I-10对MAO-B的抑制在4nM，因此在有效浓度范围内I-10具有良好的安全性。
Claims (3)
1.具有下述式I-13～I-20所示结构的化合物或其药学上可接受的盐在制备治疗阿尔茨海默病药物中的应用；
2.一种治疗阿尔茨海默病的药物，其特征在于：它含有治疗上有效剂量的下述式I-13～I-20所示结构的化合物或其药学上可接受的盐以及药学上可接受的辅料；
3.根据权利要求2所述的药物，其特征在于：所述药物的剂型为药学上可接受的剂型。
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