CN103420941B - 2-甲氧基苯基-二甲胺基甲酸酯衍生物及制备和用途 - Google Patents
2-甲氧基苯基-二甲胺基甲酸酯衍生物及制备和用途 Download PDFInfo
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Abstract
本发明提供2-甲氧基苯基-二甲胺基甲酸酯衍生物,本发明以利伐司替明为先导物,保留其中与AChE催化位点发生特异性结合的苄胺片段,以及与催化三联体发生反应的氨基甲酸酯药效团,创新性的在氨基甲酸酯邻位引入甲氧基,设计合成一系列具有AChE抑制活性以及金属离子螯合作用的多靶点化合物。体外AChE抑制实验表明,所合成的目标化合物均显示出一定的AChE抑制活性,而且进入体内后,二甲胺基甲酸酯片段可以经乙酰胆碱酯酶水解释放出邻甲氧基苯酚片段,具有金属离子螯合作用和抗氧化作用,因此该类衍生物具有多靶点治疗AD的特性,可用于早老性痴呆的治疗,可在制备AChE(乙酰胆碱酯酶)抑制剂中的应用。结构通式如下:
Description
技术领域
本发明属于化学领域,涉及2-甲氧基苯基-二甲胺基甲酸酯衍生物及其制备方法和用途。
背景技术
阿尔茨海默病(AD)是严重危害老年人健康的神经退行性疾病,其病因复杂,病理机制尚未完全清楚,仅针对单一靶点的 AD 治疗药物研发进展缓慢,目前多靶点 AD 治疗药物已经成为研究热点。
当前 AD 治疗的最重要药物是乙酰胆碱酯酶抑制剂,包括多奈哌齐、利伐司替明、加兰他敏和石杉碱甲,该类药物能够增加脑内乙酰胆碱的含量,延缓 AD的病程。另一方面,研究证明 AD 患者脑内金属离子(Cu2+, Zn2+)失衡可能是影响病程的重要因素。金属离子不但促进神经细胞外围淀粉样蛋白肽(Aβ)的聚集,还与 AD 患者脑内 Tau 蛋白发生积聚,造成患者脑细胞氧化损伤,加重 AD 患者病情,因此采用金属离子螯合剂以降低 AD 患者脑内金属离子水平,可能为 AD治疗研究提供新的契机和思路。寻找和发现能在脑内发挥金属离子螯合作用,并且拥有 AChE 抑制活性的多靶点 AD 治疗药物具有重要的应用前景。
发明内容
本发明的目的是提供2-甲氧基苯基-二甲胺基甲酸酯衍生物,不仅本身具有良好的AChE 抑制活性,而且进入体内后,二甲胺基甲酸酯片段可以经乙酰胆碱酯酶水解释放出邻甲氧基苯酚片段,具有金属离子螯合作用和抗氧化作用,因此该类衍生物具有多靶点治疗AD的特性,可用于早老性痴呆的治疗,结构通式如下:
其中:NR1R2取自哌啶基、吗啉基、吡咯烷基和二乙胺基,R3为氢或者甲基。
胺烷基片段在二甲氨基甲酸酯的邻位,NR1R2为哌啶基、吗啉基、吡咯烷基和二乙胺基。
胺烷基片段在二甲氨基甲酸酯的间位,NR1R2为哌啶基、吗啉基、吡咯烷基和二乙胺基。
胺烷基片段在二甲氨基甲酸酯的对位,NR1R2为哌啶基、吗啉基、吡咯烷基和二乙胺基。
本发明的另一个目的是提供所述2-甲氧基苯基-二甲胺基甲酸酯衍生物的制备方法,通过以下步骤获得:
(1) R3=H的目标分子的合成:
其中NR1R2 的定义同通式。
分别以异香兰素、香兰素、邻香兰素为原料,与N,N-二甲氨基甲酰氯反应生成二甲胺基甲酸酯中间体,然后经硼氢化钠还原醛基得到苄醇中间体,经二氯亚砜氯代得到苄氯中间体,最后与二级胺(哌啶、吗啉、吡咯烷和二乙胺)缩合得到R3为氢的目标化合物。
(2) R3为甲基的目标化合物的合成:
其中:。
异香兰素、香兰素生成的二甲胺基甲酸酯与甲基碘化镁反应得到分别得到甲基取代苄醇中间体7b和7c,然后经二氯亚砜氯代,与二级胺(哌啶、吗啉、二乙胺、吡咯烷等)反应生成R3为甲基的目标化合物8a-8e。
(3)化合物6a水解产物化合物9的制备:
香兰素与哌啶在甲醇中反应,然后经硼氢化钠还原得到化合物9。
本发明的再一个目的是提供所述2-甲氧基苯基-二甲胺基甲酸酯衍生物及其中间体在制备AChE(乙酰胆碱酯酶)抑制剂中的应用,以及在治疗早老性痴呆中的应用。AChE抑制剂是当前治疗早老性痴呆的最重要药物。
包括2-甲氧基苯基-二甲胺基甲酸酯衍生物的有机酸盐(包括酒石酸、富马酸、马来酸、樟脑磺酸)和无机酸盐(盐酸、氢溴酸)在制备治疗早老性痴呆药物中的应用。
本发明以利伐司替明为先导,根据药物设计中的前药原理,以AChE抑制剂利伐司替明为先导物,保留其中与AChE催化位点发生特异性结合的苄胺片段,以及与催化三联体发生反应的氨基甲酸酯药效团,创新性的在氨基甲酸酯邻位引入甲氧基,设计合成一系列具有AChE抑制活性以及金属离子螯合作用的多靶点化合物。体外AChE抑制实验表明,所合成的目标化合物均显示出一定的AChE抑制活性,其中有十个化合物对AChE的抑制活性优于阳性对照利伐司替明,构效关系研究表明,烷胺甲基处于氨基甲酸酯的对位有利于活性提高,哌啶基、吡咯基等脂溶性片段有利于分子与AChE的结合,其中活性最高的化合物6a的IC50为97.4nM,比利伐司替明强47倍,而且其氨基甲酸酯水解产物9具有较强的ABTS自由基清除能力,是一个具有多靶点特性AD治疗药物先导物,为后续的研究提供新的思路和先导物,进一步的研究工作正在开展之中。
附图说明
图1是实施例22的化合物9与美拉托宁清除ABTS自由基活性。
图 2是化合物9以及化合物9+Cu2+的紫外吸收图谱,图中粗线为化合物9+Cu2+,细线为化合物9。
图 3是化合物9以及化合物9+Fe2+的紫外吸收图谱,图中粗线为化合物9+Fe2+,细线为化合物9。
图 4是化合物9以及化合物9+Zn2+的紫外吸收图谱,图中粗线为化合物9+Zn2+,细线为化合物9。
具体实施方式
本发明结合附图和实施例作进一步的说明。
实施例1:2-甲氧基-6-甲酰基-苯基-二甲氨基甲酸酯 (2a)
将邻香兰素(3.04g, 20mmol)、NaH(0.96g, 40mmol)和DMF(10mL)加入单口瓶中,0℃下搅拌10分钟,缓慢滴加N、N二甲基甲酰氯(3.23g, 30mmol),加毕,撤去冰浴,室温搅拌40分钟,加入80mL水,乙酸乙酯萃取(30mL×2),合并有机层,饱和食盐水洗涤,无水硫酸钠干燥,减压回收溶剂得到白色固体2a 3.91g,收率87.6%,mp 84-86℃; 1H NMR (500 MHz, CDCl3): δ 10.19 (s, 1H, CHO), 7.46 (dd, 1H, J 1 = 8.0 Hz, J 2 = 1.5 Hz, H-3), 7.29 (m,1H, H-4), 7.19 (dd, 1H, J 1 = 8.0Hz, J 2 = 1.5 Hz, H-5), 3.87 (s, 3H, OCH3), 3.18 (s, 3H, N-CH3), 3.04 (s, 3H, N-CH3); ESI-MS: m/z = 224.3 [M+H]+.
实施例2:5-甲酰基-2-甲氧基苯基-二甲氨基甲酸酯 (2b)
方法同实施例1,以异香兰素替代邻香兰素,得到白色固体2.88g,收率64.6%,mp 85-86℃; 1H NMR (500MHz, CDCl3): δ 9.85 (s, 1H, CHO), 7.74 (dd, 1H, J 1 = 8.0 Hz, J 2 = 2.0 Hz, H-4), 7.61 (d, 1H, J = 2.0 Hz, H-6), 7.06 (d, 1H, J = 8.0 Hz, H-3), 3.91 (s, 3H, OCH3), 3.15 (s, 3H, N-CH3), 3.04 (s, 3H, N-CH3); ESI-MS:m/z= 224.3 [M+H]+.
实施例3:4-甲酰基-2-甲氧基苯基-二甲氨基甲酸酯(2c)
方法同实施例1,以香兰素替代邻香兰素,得到白色固体4.13g,收率92.6%,mp 69-70℃;1H NMR (500 MHz, CDCl3): δ 9.93 (s, 1H, CHO), 7.47-7.44 (m, 2H, H-3,H-5), 7.26-7.25 (d, 1H, J = 8.0 Hz, H-6), 3.90 (s, 3H, OCH3), 3.12 (s, 3H, N-CH3), 3.01(s, 3H, N-CH3); ESI-MS: m/z = 224.3[M+H]+; 13C NMR (CDCl3, 125 Hz):δ 191.1, 153.8, 152.4, 145.9, 134.6, 124.8, 123.7, 110.7, 56.1, 36.8, 36.6.
实施例4: 2-甲氧基-6-(羟甲基)-苯基-二甲基氨基甲酸酯(3a)
将化合物2a(0.22g, 1.0 mmol)溶于甲醇(10mL)中,分次加入NaBH4 (0.076g, 2.0 mmol),加毕,室温搅拌30分钟。减压回收溶剂,加入稀盐酸调节PH < 4;水层用二氯甲烷萃取,合并有机层,经饱和食盐水洗涤,无水硫酸钠干燥后减压回收溶剂,得到无色油状物3a 0.19g,收率 85%;1H NMR (500 MHz, CDCl3): δ 7.21 (t, J = 8.0 Hz, 1H, H-4), 7.05 ( dd, 1H, J 1 = 7.5 Hz, J 2 = 1.5 Hz, H-3), 6.92 ( dd, 1H, J 1 = 7.5 Hz, J 2 = 1.5 Hz, H-5), 4.57 (s, 2H, benzylic-CH2), 3.83 (s, 3H, OCH3), 3.17 (s, 3H, N-CH3), 3.03 (s, 3H, N-CH3); ESI-MS: m/z = 225.1[M+H]+.
实施例5:5 –(羟甲基)-2-甲氧基苯基二甲基氨基甲酸酯 (3b)
方法同实施例4, 5-甲酰基-2-甲氧基苯基二甲基氨基甲酸酯(2b)还原得到白色固体0.18g (3b),收率80%, mp 59-61℃; 1H NMR (500 MHz, CDCl3): δ 7.16 (dd, 1H, J 1 = 8.5 Hz, J 2 = 2.0 Hz, H-4), 7.09 (d, 1H, J = 2.0 Hz, H-6), 7.06 (d, 1H, J = 8.5 Hz, H-3), 4.59 (s, 2H, benzylic-CH2), 3.83 (s, 3H, OCH3), 3.11 (s, 3H, N-CH3), 3.00 (s, 3H, N-CH3); ESI-MS: m/z = 225.1[M+H]+.
实施例6: 4-(羟甲基)-2-甲氧基苯基-二甲基氨基甲酸酯(3c)
方法同实施例4,4 -甲酰基-2-甲氧基苯基二甲基氨基甲酸酯(2c)还原得到白色固体0.19g (3c),收率85% , mp 55-57 ℃; 1H NMR (500 MHz, CDCl3): δ 7.05 (d, 1H, J = 8.0 Hz, H-6), 7.00 (d, 1H, J = 1.5 Hz, H-3), 6.90 (dd, 1H, J 1 = 8.0 Hz, J 2 = 2.0 Hz,H-5), 4.65 (s, 2H, CH2), 3.84 (s, 3H, OCH3), 3.13 (s, 3H, N-CH3), 3.02 (s, 3H, N-CH3); ESI-MS: m/z=225.1[M+H]+.
实施例6:2 -甲氧基-6-(哌啶-1-基甲基)苯基-二甲基氨基甲酸酯(4)
将3a (0.12g, 0.53mmol)溶于5mL二氯甲烷中,加入二氯亚砜 (0.06 mL, 0.83mmol),室温搅拌30分钟,加入10mL饱和NaHCO3溶液淬灭反应,二氯甲烷萃取(10mL×2),合并有机层,经饱和食盐水洗涤、无水硫酸钠干燥后减压回收溶剂得到氯代物,不经处理直接用于下一步反应。将氯代物与哌啶(0.052g,0.62 mmol)和K2CO3 (0.085g, 0.62mmol) 溶于15mL乙腈中,升温回流1h,抽滤除去固体,减压回收溶剂。残留物用20mL 2N HCl/15mL乙酸乙酯分液,弃去有机层,水层用20mL 3N NaOH溶液碱化,乙酸乙酯萃取(10mL×2),减压回收溶剂,残留物经柱层析纯化得到淡黄色固体4 50.6 mg, 收率 32.7%,mp 78-80℃; IR (KBr, cm-1): 3025, 2934, 1720, 1588, 1483, 1439 , 1314, 1203, 1164, 845; 1H NMR (500 MHz, CDCl3): δ 7.19 (m, 2H, H-3and H-5), 6.92 (m, 1H, H-4), 3.84 (s, 3H, OCH3), 3.15 (s, 2H, benzylic-CH2), 3.15 (s, 3H, N-CH3), 3.03 (s, 3H, N-CH3), 2.55 (m, 4H, piperidine-CH2, H-2'and H-6'), 1.70-1.67 (m, 4H, piperidine-CH2, H-3' and H-5'), 1.49-1.46 (m, 2H, piperidine-CH2, H-4');13C NMR (125 MHz, CDCl3):154.1, 151.9, 139.9, 125.9, 123.0, 111.9, 56.5, 56.1, 53.8, 36.9, 36.6, 24.8, 24.6, 23.4; ESI-MS: m/z = 293.5 [M+H]+.
实施例7: 2 -甲氧基-5-(哌啶-1-基甲基)苯基-二甲基-氨基甲酸酯(5a)
用3b替代3a,方法同实施例6,得到 5a黄色固体51.4mg,收率 33%, mp 70-72℃; IR(KBr, cm-1): 3023, 2925, 2853, 1713, 1619, 1516, 1456, 1126, 1025, 825; 1H NMR ( 500 MHz, CDCl3): δ 7.12 (d, 1H, J = 8.0 Hz, H-4), 7.04 (d, 1H, J = 1.5 Hz, H-6), 6.89 (d, 1H, J = 8.0 Hz, H-3), 3.82 (s, 3H, OCH3), 3.42 (s, 2H, benzylic-CH2), 3.11(s, 3H, N-CH3), 3.00(s, 3H, N-CH3), 2.38-2.36 (m, 4H, piperidine-CH2, H-2'and H-6'), 1.57-1.55 (m, 4H, piperidine-CH2, H-3'and H-5'), 1.42-1.40 (m, 2H, piperidine-CH2, H-4'). 13C NMR (125 MHz, CDCl3): δ154.7,150.7,140.2,130.5,127.0,124.2,112.0,62.8,56.0,54.2,36.7,36.6,29.7, 25.7, 24.2; ESI-MS: m/z = 293.4 [M+H]+.
实施例8:2-甲氧基-5-(吗啉-1-基甲基)苯基-二甲基氨基甲酸酯 (5b)
方法同实施例6,用3b替代3a,用吗啉代替哌啶,得到5b 黄色油状物54.5mg,收率 35.0%; IR(液膜法,cm-1):3020, 2926, 2855, 1719, 1618, 1515,1457, 1388, 1273, 1167, 1119, 856, 824;1H NMR (500 MHz, CDCl3): δ 7.13 (dd, 1H, J 1 = 8.5 Hz, J 2 = 2.0 Hz,H-4), 7.07 (d, 1H, J = 2.0 Hz, H-6), 6.90 (d, 1H, J = 8.5 Hz, H-3), 3.83 (s, 3H, OCH3), 3.72 (t, 4H, J 2 = 5.0 Hz, morpholine-CH2, H-3'and H-5'), 3.43 (s, 2H, benzylic-CH2), 3.12 (s, 3H, N-CH3), 3.01 (s, 3H, N-CH3), 2.44-2.40 (m, 4H, morpholine-CH2, H-2'and H-6'). 13C NMR (125 MHz, CDCl3) :δ154.5, 152.2, 140.5, 128.6, 125.5, 125.4, 112.5, 65.0, 61.4, 56.0, 52.2, 36.8, 36.6, 29.7; ESI-MS: m/z = 295.4 [M+H]+.
实施例9: 2-甲氧基-5-(吡咯烷-1-基甲基)苯基-二甲基氨基甲酸酯(5c)
方法同实施例6,用3b替代3a,用吡咯烷代替哌啶,得到5c 黄色固体56.0mg,收率 37.7% , mp 51-53℃; IR (KBr, cm-1): 3020, 2958,2784,1716,1619,1514,1391, 1265,1024, 895,841;1H NMR (500 MHz, CDCl3): δ 7.13 (dd, 1H, J 1 = 8.5 Hz, J 2 = 2.0 Hz, H-4), 7.05(d, 1H, J = 2.0 Hz, H-6), 6.89 (d, 1H, J = 8.5 Hz, H-3), 3.82 (s, 3H, OCH3), 3.54 (s, 2H, benzylic-CH2), 3.10 (s, 3H, N-CH3), 3.00 (s, 3H, N-CH3), 2.49 (s, 4H, pyrrolidine-CH2, H-2'and H-5'), 1.78-1.75 (m, 4H, pyrrolidine-CH2, H-3'and H-4'); 13C NMR (125 MHz, CDCl3) :δ154.7, 150.6, 140.2, 131.8, 126.5, 123.9, 112.1, 59.7, 56.0, 54.0, 36.7, 36.5, 23.4; ESI-MS: m/z = 279.4 [M+H]+.
实施例10:2-甲氧基-5-(二乙基氨基甲基)苯基-二甲基氨基甲酸酯 (5d)
方法同实施例6,用3b替代3a,用二乙胺代替哌啶,得到5d 浅黄色油状物56.9mg,收率 38.1%;IR (液膜法, cm-1): 3025, 2967, 2839, 2802, 1718, 1618, 1513, 1386, 1267, 1166, 1027,891, 810; 1H NMR (500 MHz, CDCl3): δ 7.13 (dd, 1H, J 1 = 8.0 Hz, J 2 = 2.0 Hz, H-4), 7.07 (d, 1H, J = 2.0 Hz, H-6), 6.89 (d, 1H, J = 8.0 Hz, H-3), 3.83 (s, 3H, OCH3), 3.51 (s, 2H, benzylic-CH2), 3.12 (s, 3H, N-CH3), 3.01 (s, 3H, N-CH3), 2.54 (q, 4H, J = 7.0 Hz, 2×CH2), 1.05 (t, 6H, J = 7.0 Hz, 2×CH3); 13C NMR (125 MHz, CDCl3) :δ154.6,151.5,140.4,127.6,124.7,112.4,56.0,55.9,46.2,36.7,36.6,29.7; ESI-MS: m/z = 281.4[M+H]+.
实施例11:2-甲氧基-4-(哌啶-1-基甲基)苯基二甲基氨基甲酸酯(6a) 及其盐
用4 -(羟甲基)-2-甲氧基苯基二甲基氨基甲酸酯3c (0.12g, 0.53mmol)代替3b, 先与二氯亚砜反应生成氯代物,然后与哌啶缩合得到6a,具体方法同5a的制备(实施例6),得到59.8mg无色油状物,收率 38.4%; IR (液膜法, cm-1): 3023, 2934, 2852, 2793, 1719, 1605, 1510, 1490, 1037, 1010, 865, 806; 1H NMR (500 MHz, CDCl3): δ 6.97 (s, 1H, H-3), 6.92 (d, 1H, J = 8.0 Hz, H-6), 6.78 (dd, 1H, J 1 = 8.0 Hz, J 2 = 2.0 Hz, H-5), 3.77 (s, 3H, OCH3), 3.42 (s, 2H, benzylic-CH2), 3.04 (s, 3H, N-CH3), 2.93 (s, 3H, N-CH3), 2.35-2.33 (m, 4H, piperidine-CH2, H-2'and H-6'),1.55-1.51 (m, 4H, piperidine-CH2, H-3'andH-5'), 1.39-1.36 (m, 2H, piperidine-CH2, H-4'); 13C NMR (125 MHz, CDCl3) : δ 154.9, 151.4, 139.4, 137.0, 122.6,121.2, 113.0,63.6,55.9,54.4,36.7,36.5,25.9, 24.4; ESI-MS:m/z = 293.2 [M+H]+.
将化合物200mg 6a溶于5mL氯化氢饱和的乙酸乙酯,回收溶剂,用甲醇/乙酸乙酯重结晶得到2-甲氧基-4-(哌啶-1-基甲基)苯基二甲基氨基甲酸酯盐酸盐155mg。
将200mg 6a与5mL 45%氢溴酸混合,再加入5mL甲醇,回收溶剂,得到的固体用乙醇/乙酸乙酯重结晶得到2-甲氧基-4-(哌啶-1-基甲基)苯基二甲基氨基甲酸酯氢溴酸盐175mg。
将200mg 6a与166mg左旋樟脑磺酸、5mL甲醇混合,加热溶解,回收溶剂,得到的固体用甲醇/乙酸乙酯重结晶得到2-甲氧基-4-(哌啶-1-基甲基)苯基二甲基氨基甲酸酯樟脑磺酸盐210mg。
将200mg 6a与100mg富马酸、5mL乙醇混合,加热溶解,回收溶剂,得到的固体用甲醇/乙酸乙酯重结晶得到2-甲氧基-4-(哌啶-1-基甲基)苯基二甲基氨基甲酸酯富马酸盐192mg。
将200mg 6a与100mg马来酸、5mL乙醇混合,加热溶解,回收溶剂,得到的固体用甲醇/乙酸乙酯重结晶得到2-甲氧基-4-(哌啶-1-基甲基)苯基二甲基氨基甲酸酯马来酸盐198mg。
将化合物200mg 6a,100mg D-酒石酸与10mL乙醇混合,升温至60度,反应1小时,回收溶剂,残留物用乙醇/水重结晶得到2-甲氧基-4-(哌啶-1-基甲基)苯基二甲基氨基甲酸酯酒石酸盐218mg。
实施例12:2-甲氧基-4-(吗啉-1-基甲基)苯基二甲基氨基甲酸酯(6b)
用吗啉代替哌啶,方法同实施例11,得到无色透明油状物(6b) 70.5mg, 收率45.0%; IR (液膜法, cm-1): 3010, 2956, 2925, 2818, 1713, 1601, 1514, 1390, 1207, 1117, 1034, 867, 819; 1H NMR (500 MHz, CDCl3):δ 6.99 (d, 1H, J = 8.0Hz, H-6), 6.96 (s, 1H, H-3), 6.86 (dd, 1H, J 1 = 8.0 Hz, J 2 = 1.5 Hz, H-5), 3.83 (s, 3H, OCH3), 3.68-3.66 (m, 4H, morpholine-CH2, H-3'and H-5'), 3.45 (s, 2H, benzylic-CH2), 3.11 (s, 3H, N-CH3), 3.01 (s, 3H, N-CH3), 2.46-2.35 (m, 4H, morpholine-CH2, H-2'and H-6'); 13C NMR (125 MHz, CDCl3) : δ 154.8,151.5,139.6,136.1,122.8,121.1,113.0, 66.9, 63.2, 56.0, 53.6, 36.7, 36.5; ESI-MS:m/z = 295.2 [M+H]+..
实施例13:2-甲氧基-4-(吡咯烷-1-基甲基)苯基二甲基氨基甲酸酯(6c)
用吡咯烷代替哌啶,方法同实施例11,得到无色透明油状物(6c) 59.5mg,收率40.1%;
IR(液膜法, cm-1): 3011, 2964, 2931, 2795, 1714, 1604, 1512, 1445, 1390, 1281, 1168, 1032, 858; 1H NMR (500 MHz, CDCl3): δ 6.99 (s, 1H, H-3), 6.97 (d, 1H, J = 8.5Hz, H-6), 6.86 (dd, 1H, J 1 = 8.0Hz, J 2 = 1.5 Hz, H-5), 3.83 (s, 3H, OCH3), 3.58 (s, 2H, benzylic-CH2), 3.11 (s, 3H, N-CH3), 3.00 (s, 3H, N-CH3), 2.50(s, 4H, pyrrolidine-CH2, H-2'and H-5'), 1.78 (s, 4H, pyrrolidine-CH2, H-3' and H-4'); 13C NMR (125 MHz, CDCl3) : δ 154.8,151.5,139.4,137.6,122.7,120.8,112.9, 60.5,56.0,54.1,36.8,36.5,23.5; ESI-MS:m/z = 279.2[M+H]+.
实施例14:2-甲氧基-4-(二乙胺基-1-基甲基)苯基-二甲基氨基甲酸酯(6d)
用二乙胺代替哌啶,方法同实施例11,得到无色透明油状物(6d) 64.6mg,收率43.3%;IR (液膜法, cm-1):3025, 2969,2936,2802,1733,1606,1513,1388,1278,1166,1119,1038,862, 805; 1H NMR (500 MHz, CDCl3): δ 6.99 (s, 1H, H-6), 6.97 (s, 1H, H-3), 6.86 (dd, 1H, J 1 = 8.0Hz, J 2 =1.5 Hz, H-5), 3.83 (s, 3H, OCH3), 3.52 (s, 2H, benzylic-CH2), 3.11 (s, 3H, N-CH3), 3.00 (s, 3H, N-CH3), 2.51 (q, 4H, J = 7.0 Hz, 2×CH2), 1.02 (t, 6H, J = 7.0 Hz, 2×CH3); 13C NMR (125 MHz, CDCl3) :δ154.8,151.5,139.2,138.3,122.6,120.6,112.7,57.4,55.9,46.7,36.7,36.4,11.7; ESI-MS: m/z = 281.4[M+H]+.
实施例15:2-甲氧基-5-(1-羟乙基)-苯基-二甲基氨基甲酸酯 (7b)
室温下将碘甲烷(1.94 g, 13.7mmol) 缓慢滴加镁(0.33g, 13.7mmol) 10mL无水乙醚中,加毕,继续回流2h直到镁屑消失,制得CH3MgI溶液备用。5-甲酰基-2-甲氧基苯基二甲基氨基甲酸酯(2b, 2.55g, 11.4mmol)溶解在20mL THF中,在0℃下加入CH3MgI溶液,然后回流过夜。加入10ml水和30ml乙酸乙酯,分出有机层,水层用乙酸乙酯萃取,合并有机层,用饱和食盐水洗涤,无水硫酸钠干燥。减压回收溶剂得到2-甲氧基-5-(1-羟乙基)苯基-二甲基氨基甲酸酯(7b) 2.51g,收率92.7%, mp 63-65℃; 1H NMR (500 MHz, CDCl3): δ 7.16 (dd, 1H, J 1= 7.5 Hz, J 2 = 2.0 Hz, H-4), 7.09 (d, 1H, J = 2.0 Hz, H-6), 6.92 (d, 1H, J = 7.5 Hz, H-3), 4.80-4.82 (m, 1H, CH), 3.83 (s, 3H, OCH3), 3.11 (s, 3H, N-CH3), 3.00 (s, 3H, N-CH3), 2.0 (brs, 1H, OH), 1.46 (d, 1H, J = 6.5 Hz, CH3);
实施例16:2-甲氧基4-(1-羟乙基)-苯基-二甲基氨基甲酸酯 (7c)
将3c替代3b, 方法同实施例15,制备得到1.98克白色固体(7c),收率73.4%, mp 134-135℃; 1H NMR(CDCl3, 500MHz):δ 7.03 (d,1H, J= 8.5 Hz, H-6 ), 7.00 (d, 1H, J= 1.5 Hz, H-3) 6.89 (dd, 1H, J 1 = 8.5 Hz, J 2 = 1.5 Hz, H-5 ), 4.86 (q, 1H, J = 6.5 Hz, CH), 3.82 (s, 3H, OCH3), 3.12 (s, 3H, N-CH3), 3.01 (s, 3H, N-CH3), 2.24 (s, 1H, OH), 1.47 (d, 3H, J = 6.5 Hz, CH3). 13C NMR (CDCl3, 125MHz):δ 154.8, 151.6, 144.3, 139.6, 123.0, 117.4, 109.5, 70.0, 55.9, 36.7, 36.5, 25.1.
实施例17:2 -甲氧基-5 –(1 –(哌啶-1-基)乙基苯基-二甲基氨基甲酸酯(8a)
5-(1-羟乙基)-2-甲氧基苯基-二甲基氨基甲酸酯 7b (0.54g, 2.26mmol) 与二氯亚砜反应生成氯代物,再与哌啶缩合制备化合物8a, 具体方法同化合物4的制备,得到235 mg浅黄色固体,收率 34.1%, mp 72-74℃; IR (KBr, cm-1): 3018, 2964, 2930, 2853, 2753, 1716, 1620, 1516, 1393, 1174, 1114, 1029, 842; 1H NMR (500 MHz, CDCl3): δ 7.08 (dd, 1H, J 1 = 8.5 Hz, J 2 = 2.0 Hz, H-4), 7.01(d, 1H, J = 2.0 Hz, H-6), 6.88 (d, 1H, J = 8.5 Hz, H-3), 3.81 (s, 3H, OCH3), 3.38 (q, 1H, J =7.0 Hz, benzylic-CH), 3.11 (s, 3H, N-CH3), 3.00 (s, 3H, N-CH3), 2.34-2.32 (m, 4H, piperidine-CH2, H-2'and H-6'), 1.54-1.51 (m, 4H, piperidine-CH2, H-3'and H-5'), 1.34-1.32 (m, 5H, CH3 and piperidine-CH2, H-4'); 13C NMR (125 MHz, CDCl3) :δ 154.7,150.7,140.2, 126.9,124.2,112.0,62.8,56.1,54.3,36.8,36.6,25.8,24.3; ESI-MS: m/z = 307.5 [M+H]+.
实施例18:2 -甲氧基-5 –(1-吗啉乙基)苯基-二甲基氨基甲酸酯(8b)
用吗啉代替哌啶,方法同实施例17,得到214 mg黄色油状物,收率 30.7%; IR (液膜法, cm-1) 3027, 2956, 2857, 1713, 1682, 1514, 1455, 1390, 1281, 1117, 1034, 842; 1H NMR (500 MHz, CDCl3): δ 7.10 (dd, 1H, J 1 = 8.5 Hz, J 2 = 2.0 Hz, H-4), 7.03(d, 1H, J = 2.5 Hz, H-6), 6.89 (d, 1H, J = 8.5 Hz, H-3), 3.82(s, 3H, OCH3), 3.6-3.66 (m, 4H, morpholine-CH2, H-3' and H-5'), 3.26 (q, 1H, J = 6.5Hz, benzylic-CH), 3.12 (s, 3H, N-CH3), 3.01 (s, 3H, N-CH3), 2.45-2.35 (m, 4H, morpholine-CH2, H-2' and H-6'), 1.32-1.25 (d, 3H, J = 6.5 Hz, CH3); 13C NMR (125 MHz, CDCl3) :δ154.6,151.3,140.4,125.8,123.0,112.3,66.2, 65.1, 56.0, 50.7, 36.8, 36.6, 18.6; ESI-MS: m/z = 309.2 [M+H]+.
实施例19:2 -甲氧基-5 –(1-(吡咯烷-1 -基)乙基)-苯基-二甲基氨基甲酸酯(8c)
用吡咯烷代替哌啶得到240 mg 黄色固体,收率 36.4%, mp 67-69℃; IR (KBr, cm-1): 3072, 2969, 2778, 1714, 1619, 1514, 1392, 1265, 1022, 842; 1H NMR (500 MHz, CDCl3): δ 7.12 (dd, 1H, J 1 = 8. 0 Hz, J 2 = 2.0 Hz, H-4), 7.05 (d, 1H, J = 2.0 Hz, H-6), 6.89 (d, 1H, J = 8.0 Hz, H-3), 3.81 (s, 3H, OCH3), 3.10 (m, 4H, benzylic-CH and N-CH3), 2.99 (s, 3H, N-CH3), 2.54-2.36 (m, 4H, pyrrolidine-CH2, H-2'and H-5'), 1.75-1.72 (m, 4H, pyrrolidine-CH2, H-3'and H-4'), 1.38-1.36 (d, J = 6.5 Hz, 3H, CH3); 13C NMR (125 MHz, CDCl3) :δ154.7, 150.5, 140.3, 123.9, 122.2, 112.1, 64.9, 56.1, 52.8, 36.8, 36.6, 23.4,22.9; ESI-MS: m/z = 293.4 [M+H]+.
实施例20:2 -甲氧基-5-(1 –(二乙基氨基)乙基)-苯基-二甲基氨基甲酸酯(8d)及其酒石酸盐
用二乙胺代替哌啶得到204 mg黄色油状物,收率 30.7%; IR (液膜法, cm-1): 3035, 2968, 2934, 2840, 1728, 1616, 1514, 1445, 1386, 1265, 1166, 1023, 895, 816; 1H NMR (500 MHz, CDCl3): δ 7.14 (dd, 1H, J 1 = 8.5 Hz, J 2 = 2.0 Hz, H-4), 7.07 (d, 1H, J = 2.0 Hz, H-6), 6.89 (d, 1H, J = 8.0 Hz, H-3), 3.81 (s, 3H, OCH3), 3.74 (q, 1H,J = 7.0 Hz, benzylic-CH), 3.11 (s, 3H, N-CH3), 3.00 (s, 3H, N-CH3), 2.56-2.52 ( m, 4H, 2×CH2), 1.30 (d, 3H, J = 6.5 Hz, CH3), 0.98 (t, 6H, J = 7.0 Hz, 2×CH3); 13C NMR (125 MHz, CDCl3) :δ 154.6, 151.3, 140.4, 125.9, 123.2, 112.3, 59.8, 56.0, 43.3, 36.8, 36.5, 17.7, 10.8; ESI-MS: m/z = 295.3 [M+H]+.
将化合物200mg 8d,100mg D-酒石酸与10mL乙醇混合,升温至60度,反应1小时,回收溶剂,残留物用乙醇/水重结晶得到白色固体150mg 2 -甲氧基-5-(1 –(二乙基氨基)乙基)-苯基-二甲基氨基甲酸酯酒石酸盐)。
实施例21:2 -甲氧基-4-(1 -哌啶基乙基)苯基-二甲基氨基甲酸酯(8e)及马来酸盐
以化合物7c为原料,经二氯亚砜氯代,哌啶缩合得到化合物8e;得到281mg黄色油状物,收率 40.7%; IR: 3020 2932, 2852, 2793, 2751, 1730, 1604, 1507, 1455, 1386, 1270, 1160, 861, 818 cm-1; 1H NMR (CDCl3, 500Hz):δ 6.98 (d, J= 8.5 Hz, 1H), 6.94 (d, J = 1.5 Hz, 1H), 6.83 (dd, J 1 = 8.0 Hz, J 2 = 2.0 Hz, 1H), 3.83 (s, 3H), 3.33 (q, J = 6.5 Hz. 1H), 3.10 (s, 3H), 2.99 (s, 3H), 2.38-2.33 (m, 4H), 1.53-1.52 (m, 4H), 1.39-1.36 (m, 2H), 1.33 (d, J = 6.5 Hz. 3H). 13C NMR(CDCl3, 125MHz):δ 154.8, 151.3, 142.6, 139.1, 122.5, 119.7, 111.6, 65.1, 56.0, 51.6, 36.7, 36.5, 26.2, 24.5, 19.5.
按照实施例20的方法,制备得到8e的马来酸盐160mg。
实施例 22:化合物6a的水解产物(9)
将化合物香兰素(0.50g, 3.29 mmol)溶于甲醇(10mL)中,滴加(0.72ml,7.24mmol)哌啶,室温搅拌15分钟后,分批次加入NaBH4 (0.19g, 4.9 mmol)加毕,室温搅拌30分钟,减压回收溶剂,加入2N盐酸20mL和乙酸乙酯(20mL),弃去有机层,水层用浓氨水调至pH > 10,乙酸乙酯萃取(20mL×3),饱和食盐水洗涤,无水硫酸钠干燥,减压回收溶剂,得到白色固体0.16g,收率21.9% , mp:85-87℃; IR(KBr, cm-1): 3417, 3132, 3000, 2950, 2801, 2718, 1611, 1521, 1468, 1342, 1271, 1161, 862;1H NMR (500 MHz, CDCl3): δ 6.87 (s, 1H, H-3), 6.82 (d, 1H, J = 8.0 Hz, H-6), 6.76 (d, 1H, J = 8.0 Hz, H-5), 3.86 (s, 3H, OCH3), 3.49 (s, 2H, benzylic-CH2), 2.36 (m, 4H, piperidine-CH2, H-2' and H-6'), 1.59-1.55 (m, 4H, piperidine-CH2, H-3' and H-5'), 1.43 (m, 2H, piperidine-CH2, H-4') ; 13C NMR (125 MHz, CDCl3) : δ 146.5, 144.7, 130.2, 130.1, 122.2, 113.8, 111.8, 64.0, 55.9, 54.3, 25.8, 24.4; ESI-MS: m/z = 222.2 [M+H]+.
实施例 23:体外抑制乙酰胆碱酯酶活性的测定:
乙酰胆碱酯酶酶源采用大鼠大脑皮层,以利伐司替明为阳性对照,采用Ellman 方法(Ellman, G.L. Courtney, K.D. Andres, V. Featherstone, R.M. A new and rapid colormetric determination of acetylcholinesterase activity. Biochem Pharmacol. 1961, 7, 88-95.),实验结果(为三次测试的平均值)参见表1。
表1 2-甲氧基苯基-二甲胺基甲酸酯衍生物的AChE抑制活性
实施例24 化合物6a经乙酰胆碱酯酶水解为化合物9
将少量的化合物6a溶于0.1M pH=7.4磷酸缓冲液中, 并加入过量的大鼠脑匀浆(AChE),37度孵育4小时后,代谢产物用乙酸乙酯提取,经LC-MS测定,确定化合物6a已经水解为化合物9。
实施例25 自由基清除活性研究
采用ABTS+.方法测定水解化合物的抗氧化作用,在96 微孔板中,加入50μl不同终浓度的样品或参比溶液(pH7.4的PBS液),再加入150μl的ABTS+液,振荡摇匀,于室温下避光静置6min,测定溶液在415 nm处的吸光值。以美拉托宁为对照,实施例22制备的化合物9对不同浓度的ABTS自由基清除活性参见图1。
图1显示,化合物6a的水解产物9显示出较强的ABTS自由基清除能力,IC50为2.91μM,与美拉托宁的IC50为1.92μM接近,说明其具有较高的抗氧化活性。
实施例26 化合物9 的金属离子螯合能力
采用紫外分光光度法对化合物9开展金属离子螯合能力的测定,考察其对Cu2+,Fe2+和Zn2+三种金属离子的螯合能力。以甲醇为溶剂,使用紫外分光光度计检测化合物、金属离子(Cu2+, Fe2+和Zn2+)以及化合物-金属离子混合溶液的紫外光谱。结果参见图2-4,当化合物9的溶液中加入了铜离子和铁离子后,紫外吸收有明显变化(图2, 图3),说明化合物9对铜离子表明和铁离子产生了较好的螯合作用,而图4说明化合物9对锌离子的螯合能力较弱。
Claims (5)
1.一种2-甲氧基苯基-二甲胺基甲酸酯衍生物,其结构通式如下:
其中:NR1R2取自哌啶基、吗啉基、吡咯烷基和二乙胺基,R3为氢或者甲基;
当胺烷基片段在二甲氨基甲酸酯的邻位时,NR1R2为哌啶基、吗啉基、吡咯烷基和二乙胺基;胺烷基片段在二甲氨基甲酸酯的间位时,NR1R2为哌啶基、吗啉基、吡咯烷基和二乙胺基;胺烷基片段在二甲氨基甲酸酯的对位时,NR1R2为哌啶基、吗啉基、吡咯烷基和二乙胺基。
2.一种2-甲氧基苯基-二甲胺基甲酸酯衍生物的制备方法,其特征在于,通过以下步骤获得:分别以异香兰素、香兰素、邻香兰素为原料,与N,N-二甲氨基甲酰氯反应生成二甲胺基甲酸酯中间体,然后经硼氢化钠还原醛基得到苄醇中间体,经二氯亚砜氯代得到苄氯中间体,最后与二级胺:哌啶、吗啉、吡咯烷或二乙胺缩合得到目标化合物;
反应式:
其中:NR1R2 的定义同权利要求1。
3.一种2-甲氧基苯基-二甲胺基甲酸酯衍生物的制备方法,其特征在于,通过以下步骤获得:异香兰素、香兰素生成的二甲胺基甲酸酯与甲基碘化镁反应分别得到甲基取代苄醇中间体7b和7c,然后经二氯亚砜氯代,与二级胺:哌啶、吗啉、二乙胺、吡咯烷反应生成目标化合物8a-8e;反应式:
。
4.根据权利要求1所述的一种2-甲氧基苯基-二甲胺基甲酸酯衍生物在制备乙酰胆碱酯酶抑制剂中的应用。
5.根据权利要求4所述的应用,其特征在于,所述的2-甲氧基苯基-二甲胺基甲酸酯衍生物包括其有机酸盐和无机酸盐在制备治疗早老性痴呆药物中的应用,所述的有机酸为酒石酸、富马酸、马来酸、樟脑磺酸,所述的无机酸为盐酸、氢溴酸。
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Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5585378A (en) * | 1991-12-18 | 1996-12-17 | Aktiebolaget Astra | Composition containing an oxoindole compound |
CN1863536A (zh) * | 2003-08-05 | 2006-11-15 | 萨马里坦药品公司 | 具有乙酰胆碱酯酶抑制特性的σ-1受体配体 |
EP1746092A1 (en) * | 2005-07-22 | 2007-01-24 | Exonhit Therapeutics SA | Compounds and methods for treatment of amyloid-B-peptide related disorders |
CN101134738A (zh) * | 2007-09-29 | 2008-03-05 | 暨南大学 | 一种(s)-卡巴拉汀的不对称合成方法 |
CN101311171A (zh) * | 2007-05-22 | 2008-11-26 | 中国医学科学院药物研究所 | 对乙、丁酰胆碱酯酶具有双重抑制活性的化合物及其用途 |
CN101707952A (zh) * | 2007-04-16 | 2010-05-12 | 上海特化医药科技有限公司 | 一种制备利伐斯的明的方法及其中间体 |
CN102603675A (zh) * | 2012-02-06 | 2012-07-25 | 江苏先声药物研究有限公司 | 哌嗪类化合物及其应用 |
-
2013
- 2013-08-26 CN CN201310373861.XA patent/CN103420941B/zh not_active Expired - Fee Related
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5585378A (en) * | 1991-12-18 | 1996-12-17 | Aktiebolaget Astra | Composition containing an oxoindole compound |
CN1863536A (zh) * | 2003-08-05 | 2006-11-15 | 萨马里坦药品公司 | 具有乙酰胆碱酯酶抑制特性的σ-1受体配体 |
EP1746092A1 (en) * | 2005-07-22 | 2007-01-24 | Exonhit Therapeutics SA | Compounds and methods for treatment of amyloid-B-peptide related disorders |
CN101707952A (zh) * | 2007-04-16 | 2010-05-12 | 上海特化医药科技有限公司 | 一种制备利伐斯的明的方法及其中间体 |
CN101311171A (zh) * | 2007-05-22 | 2008-11-26 | 中国医学科学院药物研究所 | 对乙、丁酰胆碱酯酶具有双重抑制活性的化合物及其用途 |
CN101134738A (zh) * | 2007-09-29 | 2008-03-05 | 暨南大学 | 一种(s)-卡巴拉汀的不对称合成方法 |
CN102603675A (zh) * | 2012-02-06 | 2012-07-25 | 江苏先声药物研究有限公司 | 哌嗪类化合物及其应用 |
Non-Patent Citations (2)
Title |
---|
乙酰胆碱酯酶抑制剂的构效关系研究;邵东 等;《药学进展》;20041031;第28卷(第10期);433-437 * |
治疗阿尔茨海默病的乙酰胆碱酯酶抑制剂的分子设计:从多位点抑制剂到一药多靶;杨文超 等;《药学学报》;20120331;第47卷(第3期);313-321 * |
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