CN111170877A - 丙炔胺类衍生物及其合成方法 - Google Patents
丙炔胺类衍生物及其合成方法 Download PDFInfo
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- CN111170877A CN111170877A CN202010071196.9A CN202010071196A CN111170877A CN 111170877 A CN111170877 A CN 111170877A CN 202010071196 A CN202010071196 A CN 202010071196A CN 111170877 A CN111170877 A CN 111170877A
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
- C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
- C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
- C07C217/22—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted by carbon atoms having at least two bonds to oxygen atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
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Abstract
本发明公开了一系列丙炔胺类衍生物及其合成方法。该衍生物的合成方法主要包括：1)取下述式(A)～(E)所示结构中的任一种和过量的二溴烷烃置于有机溶剂中，加入缚酸剂反应，得到中间体；2)取中间体和N‑甲基炔丙基胺置于有机溶剂中，加入缚酸剂进行取代反应，得到相应的目标化合物粗品。本发明所述方法简单易操作，产率高；所得目标化合物能选择性的抑制MAO‑B。所述的式(A)～(E)所示结构为：
其中R1为任意位置取代的H、F、Cl、Br、OH、OCH3、NO2、CH3、CF3、COCH3、COOCH3、CH2OH或者是C2～C5直连或支链烷烃；X为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及其合成方法。
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，我国是世界上AD发病人数最多的国家，约有1000万人，占全球总患病人数的四分之一，并且随着老龄化社会的到来，这一数字将急剧增加。此病严重影响老年人的独立生活能力，需要长期的护理和看护，消耗大量人力、财力和物力，同时其较高的致死率已成为继心血管病、癌症和脑卒中之后的“第四大杀手”。目前治疗AD的药物有限且疗效欠佳，因此开发新型有效的AD治疗药物，对我国未来经济发展和社会稳定有着及其重要的意义。
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。研究发现，MAO-B在AD病人大脑中显著增加，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且能够抑制单胺氧化酶B的丙炔胺类衍生物及其合成方法。
本发明涉及具有下述式(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。
上述技术方案中，n优选为3～8，在式(A)～(E)所示结构中，R1优选为任意位置取代的H、OCH3或CH3，X优选为O或C。
更进一步的，上述式(I)所示结构的丙炔胺类衍生物具体优选为下述式I-1～I-20所示结构的化合物：
上述式(I)所示结构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。
上述式(I)所示结构的丙炔胺类衍生物的合成方法，主要包括以下步骤：
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合成方法，所述的合成方法简单易操作，产率高，质量稳定；合成得到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。
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,found300.1961.
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,found286.1815.
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,found304.1908.
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,found304.1921.
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(0.05MKH2PO4/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。
Claims (10)
1.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。
2.根据权利要求1所述的化合物，其特征在于：
n＝3～8；
在式(A)～(E)所示结构中，R1表示任意位置取代的H、OCH3或CH3，X表示O或C。
3.权利要求1所述化合物的合成方法，其特征在于：主要包括以下步骤：
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C2-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。
4.根据权利要求3所述的合成方法，其特征在于：步骤1)和2)中，所述的有机溶剂为选自丙酮、DMF、乙腈、四氢呋喃和二甲亚砜中的一种或两种以上的组合。
5.根据权利要求3所述的合成方法，其特征在于：步骤1)和2)中，所述的反应在50℃至有机溶剂的沸点温度范围内进行。
6.根据权利要求3所述的合成方法，其特征在于：步骤1)中，收集的滤液经硅胶柱或高效液相色谱纯化后得到相应的中间体。
7.根据权利要求6所述的合成方法，其特征在于：当收集的滤液经硅胶柱纯化时，采用由选自石油醚、环己烷、正己烷、正戊烷、异戊烷、环戊烷和异辛烷中的任意一种和选自乙酸乙酯、丙酮、氯仿、二氧六环、四氢呋喃和二氯甲烷中的任意一种组成的混合溶剂作为洗脱剂。
8.根据权利要求3～7中任一项所述的制备方法，其特征在于：还包括将制得的目标化合物粗品进行纯化的步骤。
9.根据权利要求8所述的合成方法，其特征在于：所述的纯化步骤为：将制得的目标化合物粗品上硅胶柱或高效液相色谱层析，得到纯化后的目标化合物。
10.根据权利要求9所述的合成方法，其特征在于：所述的纯化步骤为：当目标化合物粗品上硅胶柱层析时，采用由选自石油醚、环己烷、正己烷、正戊烷、异戊烷、环戊烷和异辛烷中的任意一种和选自乙酸乙酯、丙酮、氯仿、二氧六环、四氢呋喃和二氯甲烷中的任意一种组成的混合溶剂作为洗脱剂。
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| CN106187858A (zh) * | 2016-07-07 | 2016-12-07 | 浙江工业大学 | 一种β‑碘‑N‑烷氧基胺类化合物的合成方法 |
| CN109251155A (zh) * | 2017-07-14 | 2019-01-22 | 广东东阳光药业有限公司 | α-氨基酰胺衍生物及其用途 |
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