CN106905280B - 一种酰胺基取代的橙皮素类衍生物及其制备方法和作为抗阿尔兹海默症的药物中的应用 - Google Patents
一种酰胺基取代的橙皮素类衍生物及其制备方法和作为抗阿尔兹海默症的药物中的应用 Download PDFInfo
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- CN106905280B CN106905280B CN201710103279.XA CN201710103279A CN106905280B CN 106905280 B CN106905280 B CN 106905280B CN 201710103279 A CN201710103279 A CN 201710103279A CN 106905280 B CN106905280 B CN 106905280B
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- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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Abstract
本发明属于药物化学和药物治疗学领域，公开了一种酰胺氨基取代的橙皮素类衍生物及其制备和作为治疗阿尔兹海默症的药物中的应用。研究证明，本发明所涉及的酰胺基取代的橙皮素类衍生物对乙酰胆碱酯酶具有很强的抑制性能及很好的抑制选择性，其对乙酰胆碱酯酶的抑制能力比对丁酰胆碱酯酶的抑制活性高出500多倍。表明该类化合物能够发展成为治疗阿尔茨海默症(Alzheimer’sdisease)的药物。
Description
技术领域
本发明属于药物化学和药物治疗学领域，具体涉及一种酰胺基取代的橙皮素类衍生物及其制备方法和作为抗阿尔兹海默症的药物中的应用。
背景技术
阿尔兹海默病(Alzheimer’s disease AD)是一种年龄相关性的神经退行性变的疾病，随着人口年龄的增长，发病率会显著增高在未来十年里。全世界，接近4千万人口患AD。AD是以逐渐的记忆缺失，语言功能的衰退和其他认知障碍为特征。尽管AD的机制尚未完全清楚，通常标志像β-淀粉样肽(Aβ)沉积，Tau蛋白聚集和氧化应激在疾病的机制中起到重要作用。此外，在AD患者中，胆碱能神经选择性缺失导致大脑特定区域乙酰胆碱的不足，从而影响学习和记忆功能。血清学以及多巴胺系统的改变也被认为是AD患者行为学改变的原因。
目前，有三种疗效较好的药物(多奈哌齐，加兰他敏和卡巴拉汀)旨在改变AD症状通过抑制乙酰胆碱酯酶(AChE)，从而提高突触的乙酰胆碱含量，乙酰胆碱酯酶能够水解乙酰胆碱。胆碱能药物除了具有抑制乙酰胆碱酯酶的性能外，但很少能抑制AD疾病的进程。因此，现在没有有效治疗，终止或延缓疾病的进程，因此有效的方法亟待被发现。现研究发现提高活性和选择性双位点抗AD药物，能有效的用于AD的治疗，通过设计不同药效团通过一定方式连接，得到能同时与AChE的中心催化位点和PAS结合，提高抑制AD疾病的活性。
发明内容
为实现上述目的，本发明提供一种酰胺基取代的橙皮素类衍生物。
本发明的另一个目的在于提供该酰胺基基取代的橙皮素类衍生物的制备方法。
本发明还有一个目的在于提供该酰胺基取代的橙皮素类衍生物作为抗阿尔兹海默症药物的应用。
本发明是通过以下技术方案实现的：
一种酰胺基取代的橙皮素类衍生物，其特征在于结构式为：
其中R表示对氯苄氨基，邻氯苄氨基，间甲氧基苄氨基，对氯苯乙氨基，邻氟苄氨基，对甲氧基苯乙氨基，对氯苯乙氨基，苄氨基，对氟苄氨基，邻氯苯乙氨基，4-甲氧基吡啶氨基，邻甲氧基苄氨基，邻氟苯乙氨基，间氯苯乙氨基，糠氨基，对溴苄氨基，对溴苯乙氨基，对甲氧基苄氨基，三氟甲基苄氨基，苯乙氨基中的一种。
所述的酰胺基取代的橙皮素类衍生物的制备方法，其特征在于，包括以下步骤：(1)将橙皮素类似物与2-3倍量的溴乙酸乙酯在弱碱作用下搅拌后得到产物
(2)将步骤(1)所得产物进行水解反应后，再与各种脂肪胺混合，酰胺基化反应得到终产物酰胺基取代的橙皮素类衍生物其中R为对氯苄氨基，邻氯苄氨基，间甲氧基苄氨基，对氯苯乙氨基，邻氟苄氨基，对甲氧基苯乙氨基，对氯苯乙氨基，苄氨基，对氟苄氨基，邻氯苯乙氨基，4-甲氧基吡啶氨基，邻甲氧基苄氨基，邻氟苯乙氨基，间氯苯乙氨基，糠氨基，对溴苄氨基，对溴苯乙氨基，对甲氧基苄氨基，三氟甲基苄氨基，苯乙氨基中的一种。
所述的酰胺基取代的橙皮素类衍生物的制备方法，其特征在于：步骤(1)中弱碱为K2CO3，搅拌时间为18-22min，反应溶剂为DMF。
所述的酰胺基取代的橙皮素类衍生物的制备方法，其特征在于步骤(2)中水解在碱性条件下，催化剂为氢氧化钠，溶剂为乙醇；氨基取代化反应温度为室温，在HOBT和EDC盐酸盐的催化下进行，溶剂为氯仿。
所述的酰胺基取代的橙皮素类衍生物的应用，其特征在于作为制备抗阿尔兹海默症的药物中的应用。
所述的应用，所述的药物为注射剂、片剂、丸剂、胶囊剂、悬浮剂或乳剂。
本发明所述的该酰胺基取代的橙皮素类衍生物的制备方法，主要合成路线为：
其具体步骤为：
(1)将橙皮素类似物与15倍量的DMF溶剂混合，加入2-3倍量的溴乙酸乙酯，在K2CO3的作用下搅拌20min后，得到产物
(2)将上述产物溶于乙醇中，将反应装置放于冰浴条件，加入适量NaOH调PH到2到3左右，反应2h，终止反应，加水析出，抽滤得到水解产物，用氯仿溶解，再加5倍量的脂肪胺，适量的HOBT和EDC盐酸盐，搅拌反应过夜。停止反应，干燥，中性氧化铝珠层析，得到最终产物酰胺基取代的橙皮素衍生物R为对氯苄氨基，邻氯苄氨基，间甲氧基苄氨基，对氯苯乙氨基，邻氟苄氨基，对甲氧基苯乙氨基，对氯苯乙氨基，苄氨基，对氟苄氨基，邻氯苯乙氨基，4-甲氧基吡啶氨基，邻甲氧基苄氨基，邻氟苯乙氨基，间氯苯乙氨基，糠氨基，对溴苄氨基，对溴苯乙氨基，对甲氧基苄氨基，三氟甲基苄氨基，苯乙氨基中的一种。
与现有技术相比，本发明具有如下有益效果：
本发明通过体外乙酰胆碱酯酶和丁酰胆碱酯酶的抑制实验，证明本发明的酰胺基取代的橙皮素类衍生物对乙酰胆碱酯酶具有较强的抑制活性和较高的选择性，可以作为乙酰胆碱酯酶抑制剂药物应用。表明本发明所述的衍生物可用于制备治疗阿尔兹海默症的药物。
本发明公开了一种酰胺基取代的橙皮素类衍生物及其制备和作为治疗阿尔兹海默症的药物中的应用。研究证明，本发明所涉及的酰胺基取代的橙皮素类衍生物对乙酰胆碱酯酶具有很强的抑制性能及很好的抑制选择性，其对乙酰胆碱酯酶的抑制能力比对丁酰胆碱酯酶的抑制活性高出1200多倍。表明该类化合物能够发展成为治疗阿尔茨海默症(Alzheimer’sdisease)的药物。
具体的实施方式：
下面结合具体实施例进一步详细说明本发明。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。
实施例一：化合物3的合成
将化合物2，即橙皮素(5.72g，约0.02mol)溶于100mL无水DMF中，加入1.5倍摩尔量的K2CO3，随后加入2倍量的溴乙酸乙酯，常温搅拌20min。终止反应，用乙酸乙酯萃取，反复用饱和食盐水萃取，洗去DMF,干燥，减压回收乙酸乙酯，浓缩至油状后，加水，析出黄色固体，依次用甲醇、二氯甲烷重结晶，得到白色晶体，产率68％，
化合物3的化学式如下：
实施例二：化合物5a的合成
化合物3(3.72g，10mmol)，溶于乙醇中，滴加10％NaOH，调PH至12到13左右，反应2h，加稀盐酸调PH至2到3左右，终止反应，加水析出，抽滤得粗制淡黄色固体化合物4。取化合物4的粗制品0.33g，溶于氯仿，加3倍量的苄胺，加适量HOBT和EDC盐酸盐，室温搅拌过夜。停止反应，将反应液转移至萃取瓶中，调PH至弱酸，用饱和食盐水洗涤(40mL×3)，有机相用无水氯化钙干燥，过滤，滤液减压蒸馏的浅黄色油状物。用硅胶柱层析[V(三氯甲烷)：V(石油醚)＝3：1]得白色固体5a。1H NMR(400MHz,CDCl3)δ11.97(s,1H,5-OH),7.37–7.27(m,5H,Ar-H),7.02(d,J＝2.0Hz,1H,2’-H),6.92(dd,J＝8.4,1.9Hz,1H,5’-H),6.88(d,J＝8.3Hz,1H,4’-H),6.74(t,J＝5.0Hz,1H,NH),6.07(d,J＝2.4Hz,1H,8-H),6.05(d,J＝2.4Hz,1H,6-H),5.33(dd,J＝12.8,3.1Hz,1H,2-H),4.54(d,J＝5.1Hz,2H,NCH2),4.54(s,2H,C＝OCH2O),3.92(s,3H,OCH3),3.08(dd,J＝17.2,12.8Hz,1H,3-H),2.81(dd,J＝17.2,3.1Hz,1H,3-H).TOF-HRMS m/z:472.1236[M+Na]+，
化合物5a的化学式如下：
实施例三：化合物5b的合成
方法同实施例二，所不同的是用对氯苄胺代替苄胺，得白色固体化合物5b。1H NMR(400MHz,CDCl3)δ11.98(s,5-OH),7.33–7.28(m,2H,Ar-H),7.25–7.20(m,2H,Ar-H),7.03(d,J＝2.0Hz,1H,2’-H),6.92(dd,J＝8.4,1.9Hz,1H,5’-H),6.88(d,J＝8.3Hz,1H,4’-H),6.74(t,J＝5.7Hz,1H,NH),6.07(d,J＝2.4Hz,1H,8-H),6.04(d,J＝2.4Hz,1H,6-H),5.34(dd,J＝12.8,3.1Hz,1H,2-H),4.53(s,2H,C＝OCH2O),4.50(d,J＝6.1Hz,2H,NCH2),3.92(s,3H,OCH3),3.09(dd,J＝17.2,12.8Hz,1H,3-H),2.82(dd,J＝17.2,3.1Hz,1H,3-H).TOF-HRMS m/z:509.0977[M+Na]+，
化合物5b的化学式如下：
实施例四：化合物5c的合成
方法同实施例二，所不同的是用对氟苄胺代替苄胺，得白色固体5c。1H NMR(400MHz,CDCl3)δ11.98(s,1H,5-OH),7.29–7.23(m,2H,Ar-H),7.06–6.98(m,3H,Ar-H,2’-H),6.91(dd,J＝8.3,1.9Hz,1H,5’-H),6.88(d,J＝8.3Hz,1H,4’-H),6.74(t,J＝5.0Hz,1H,NH),6.07(d,J＝2.4Hz,1H,8-H),6.04(d,J＝2.4Hz,1H,6-H),5.33(dd,J＝12.8,3.1Hz,1H,2-H),4.53(s,2H,C＝OCH2O),4.50(d,J＝6.0Hz,2H,Ar-CH2N),3.92(s,3H,OCH3),3.08(dd,J＝17.2,12.8Hz,1H,3-H),2.81(dd,J＝17.2,3.1Hz,1H,3-H).TOF-HRMS m/z:490.1273[M+Na]+，
化合物5c的化学式如下：
实施例五：化合物5d的合成
方法同实施例二，所不同的是用对溴苄氨代替苄胺，得白色固体5d。1H NMR(400MHz,CDCl3)δ11.98(s,1H,5-OH),7.48–7.43(m,2H,Ar-H),7.16(d,J＝8.3Hz,2H,Ar-H),7.03(d,J＝1.9Hz,1H,2’-H),6.92(dd,J＝8.3,2.0Hz,1H,5’-H),6.88(d,J＝8.3Hz,1H,4’-H),6.76(t,J＝5.6Hz,1H,NH),6.07(d,J＝2.3Hz,1H,8-H),6.04(d,J＝2.2Hz,1H,6-H),5.33(dd,J＝12.8,3.0Hz,1H,2-H),4.53(s,2H,C＝OCH2O),4.48(d,J＝6.1Hz,2H,NCH2),3.92(s,3H,OCH3),3.08(dd,J＝17.2,12.8Hz,1H,3-H),2.81(dd,J＝17.2,3.1Hz,1H,3-H).TOF-HRMS m/z:550.0725[M+Na]+，
化合物5d的化学式如下：
实施例六：化合物5e的合成
方法同实施例二，所不同的是用对甲氧基苄胺代替苄氨，得白色固体5e。1H NMR(400MHz,CDCl3)δ11.97(s,1H,5-OH),7.24–7.19(m,2H,Ar-H),7.02(d,J＝1.9Hz,1H,2’-H),6.91(dd,J＝8.3,1.9Hz,1H,5’-H),6.88(d,J＝8.4Hz,1H,4’-H),6.88–6.85(m,2H,Ar-H),6.67(t,J＝4.7Hz,1H,NH),6.06(d,J＝2.3Hz,1H,8-H),6.03(d,J＝2.3Hz,1H,6-H),5.33(dd,J＝12.8,3.0Hz,1H,2-H),4.51(s,2H,C＝OCH2O),4.47(d,J＝5.8Hz,2H,Ar-CH2N),3.92(s,3H,OCH3),3.80(s,3H,OCH3),3.08(dd,J＝17.2,12.9Hz,1H,3-H),2.80(dd,J＝17.2,3.1Hz,1H,3-H).TOF-HRMS m/z:502.1472[M+Na]+，
化合物5e的化学式如下：
实施例七：化合物5f的合成
方法同实施例二，所不同的是用4-三氟甲基苄氨代替苄氨，得白色固体5f。1H NMR(400MHz,DMSO)δ12.07(s,1H,5-OH),9.08(s,1H,3’-OH),8.77(t,J＝6.1Hz,1H,NH),7.66(d,J＝8.1Hz,2H,Ar-H),7.47(d,J＝8.0Hz,2H,Ar-H),6.94(m,2H,2’-H,4’-H),6.88(dd,J＝8.4,2.0Hz,1H,5’-H),6.14(d,J＝2.3Hz,1H,8-H),6.12(d,J＝2.3Hz,1H,6-H),5.50(dd,J＝12.4,3.0Hz,1H,2-H),4.65(s,2H,C＝OCH2O),4.42(d,J＝6.0Hz,2H,Ar-CH2N),3.78(s,3H,OCH3),3.27(dd,J＝17.2,12.5Hz,1H,3-H),2.77(dd,J＝17.2,3.1Hz,1H,3-H).TOF-HRMS m/z:540.1348[M+Na]+，
化合物5f的化学式如下：
实施例八：化合物5g的合成
方法同实施例二，所不同的是用邻氯苄氨代替苄氨，得白色固体5g。1H NMR(400MHz,CDCl3)δ11.97(s,1H,5-OH),7.34(td,J＝7.4,1.5Hz,1H,Ar-H),7.31–7.25(m,2H,Ar-H),7.11(td,J＝7.5,1.1Hz,1H,Ar-H),7.09–7.03(m,1H,Ar-H),7.03(d,J＝2.0Hz,1H,2’-H),6.92(dd,J＝8.4,1.9Hz,1H,5’-H),6.88(d,J＝8.3Hz,1H,4’-H),6.81(t,J＝5.5Hz,1H,NH),6.08(d,J＝2.4Hz,1H,8-H),6.05(d,J＝2.4Hz,1H,6-H),5.33(dd,J＝12.8,3.0Hz,1H,2-H),4.59(d,J＝6.1Hz,2H,NCH2),4.51(s,2H,C＝OCH2O),3.92(s,3H,OCH3),3.08(dd,J＝17.2,12.9Hz,1H,3-H),2.81(dd,J＝17.2,3.1Hz,1H,3-H).TOF-HRMS m/z:506.1123[M+Na]+，
化合物5g的化学式如下：
实施例九：化合物5h的合成
方法同实施例二，所不同的是用邻氟苄氨代替苄氨，得白色固体5h。1H NMR(400MHz,CDCl3)δ11.97(s,1H,5-OH),7.37–7.27(m,2H,Ar-H),7.11(td,J＝7.5,1.1Hz,2H,Ar-H),7.03(d,J＝2.0Hz,1H,2’-H),6.92(dd,J＝8.3,2.0Hz,1H,5’-H),6.88(d,J＝8.3Hz,1H,4’-H),6.81(t,J＝5.5Hz,1H,NH),6.08(d,J＝2.4Hz,1H,8-H),6.05(d,J＝2.4Hz,1H,6-H),5.33(dd,J＝12.8,3.0Hz,1H,2-H),4.59(d,J＝6.1Hz,2H,NCH2),4.51(s,2H,C＝OCH2O),3.92(s,3H,OCH3),3.08(dd,J＝17.2,12.9Hz,1H,3-H),2.81(dd,J＝17.2,3.1Hz,1H,3-H).TOF-HRMS m/z:468.1453[M+H]+，
化合物5h的化学式如下：
实施例十：化合物5i的合成
方法同实施例二，所不同的是用2-甲氧基苄氨代替苄氨，得白色固体5i。1H NMR(400MHz,DMSO)δ12.07(s,1H,5-OH),9.09(s,1H,3’-OH),8.43(t,J＝5.9Hz,1H,NH),7.26–7.19(m,1H,Ar-H),7.15–7.10(m,1H,Ar-H),6.99–6.92(m,3H,2’-H,Ar-H),6.87(m,2H,4’-H,5’-H),6.12(d,J＝2.3Hz,1H,8-H),6.11(d,J＝2.3Hz,1H,6-H),5.49(dd,J＝12.5,3.0Hz,1H,2-H),4.64(s,2H,C＝OCH2O),4.30(d,J＝5.9Hz,2H,Ar-CH2N),3.79(s,3H,OCH3),3.78(s,3H,OCH3),3.27(dd,J＝17.2,12.6Hz,1H,3-H),2.76(dd,J＝17.2,3.1Hz,1H,3-H).TOF-HRMS m/z:480.1653[M+H]+，
化合物5i的化学式如下：
实施例十一：化合物5j的合成
方法同实施例二，所不同的是用3-甲氧基苄氨代替苄氨，得白色固体5j。1H NMR(400MHz,CDCl3)δ11.97(s,1H,5-OH),7.28–7.22(m,1H,Ar-H),7.02(d,J＝2.0Hz,1H,2’-H),6.92(dd,J＝8.3,2.0Hz,1H,5’-H),6.88(d,J＝8.2Hz,1H,4’-H),6.88–6.80(m,3H,Ar-H),6.72(t,J＝5.5Hz,1H,NH),6.07(d,J＝2.4Hz,1H,8-H),6.05(d,J＝2.4Hz,1H,6-H),5.33(dd,J＝12.8,3.0Hz,1H,2-H),4.54(s,2H,C＝OCH2O),4.51(d,J＝5.9Hz,2H,NCH2),3.92(s,3H,OCH3),3.79(s,3H,OCH3),3.08(dd,J＝17.2,12.9Hz,1H,3-H),2.81(dd,J＝17.2,3.1Hz,1H,3-H).TOF-HRMS m/z:502.1472[M+Na]+，
化合物5j的化学式如下：
实施例十二：化合物5k的合成
方法同实施例二，所不同的是用苯乙胺代替苄氨，得白色固体5k。1H NMR(400MHz,CDCl3)δ11.99(s,1H,5-OH),7.32–7.27(m,2H,Ar-H),7.25–7.21(m,1H,Ar-H),7.19–7.15(m,2H,Ar-H),7.04(d,J＝2.0Hz,1H,2’-H),6.92(dd,J＝8.4,2.0Hz,1H,5’-H),6.89(d,J＝8.3Hz,1H,4’-H),6.45(t,J＝5.3Hz,1H,NH),6.02(d,J＝2.4Hz,1H,8-H),5.99(d,J＝2.4Hz,1H,6-H),5.34(dd,J＝12.8,3.0Hz,1H,2-H),4.45(s,2H,C＝OCH2N),3.92(s,3H,OCH3),3.60(dd,J＝13.0,6.9Hz,2H,NCH2),3.09(dd,J＝17.2,12.8Hz,1H,3-H),2.88–2.78(m,3H,Ar-CH2,3-H).TOF-HRMS m/z:486.1523[M+Na]+，
化合物5k的化学式如下：
实施例十三：化合物5l的合成
方法同实施例二，所不同的是用对甲氧基苯乙胺代替苄氨，得白色固体5l。1H NMR(400MHz,CDCl3)δ11.99(s,1H,5-OH),7.10–7.05(m,2H,Ar-H),7.04(d,J＝2.0Hz,1H,2’-H),6.93(dd,J＝8.3,2.0Hz,1H,5’-H),6.89(d,J＝8.3Hz,1H,4’-H),6.86–6.81(m,2H,Ar-H),6.41(t,J＝5.3Hz,1H,NH),6.01(d,J＝2.3Hz,1H,8-H),5.99(d,J＝2.3Hz,1H,8-H),5.35(dd,J＝12.8,3.0Hz,1H,2-H),4.45(s,2H,C＝OCH2O),3.92(s,3H,OCH3),3.78(s,3H,OCH3),3.56(q,J＝6.8Hz,2H,NCH2),3.10(dd,J＝17.2,12.8Hz,1H,3-H),2.80(dt,J＝10.7,5.0Hz,3H,Ar-CH2,3-H).TOF-HRMS m/z:516.1629[M+Na]+，
化合物5l的化学式如下：
实施例十四：化合物5m的合成
方法同实施例二，所不同的是用对氯苯乙胺代替苄氨，得白色固体5m。1H NMR(400MHz,CDCl3)δ12.00(s,1H,5-OH),7.26–7.23(m,2H,Ar-H),7.12–7.07(m,2H,Ar-H),7.04(d,J＝2.0Hz,1H,2’-H),6.93(dd,J＝8.4,2.0Hz,2H.5’-H),6.89(d,J＝8.3Hz,1H,4’-H),6.41(t,J＝5.6Hz,1H,NH),6.02(d,J＝2.4Hz,1H,8-H),6.00(d,J＝2.4Hz,1H,6-H),5.35(dd,J＝12.8,3.1Hz,1H,2-H),4.46(s,2H,C＝OCH2O),3.92(s,3H,OCH3),3.58(q,J＝6.6Hz,2H,NCH2),3.10(dd,J＝17.2,12.8Hz,1H,3-H),2.86–2.78(m,3H,Ar-CH2,3-H).TOF-HRMS m/z:520.1134[M+Na]+，
化合物5m的化学式如下：
实施例十五：化合物5n的合成
方法同实施例二，所不同的是用对溴苯乙胺代替苄氨，得白色固体5n。1H NMR(400MHz,CDCl3)δ12.00(s,1H,5-OH),7.43–7.38(m,2H,Ar-H),7.07–7.01(m,3H,Ar-H,2’-H),6.93(dd,J＝8.4,2.0Hz,1H,5’-H),6.89(d,J＝8.3Hz,1H,4’-H),6.41(t,J＝5.5Hz,1H,NH),6.03(d,J＝2.4Hz,1H,8-H),6.00(d,J＝2.4Hz,1H,6-H),5.35(dd,J＝12.8,3.1Hz,1H,2-H),4.46(s,2H,C＝OCH2O),3.92(s,3H,OCH3),3.57(q,J＝6.3Hz,2H,NCH2),3.10(dd,J＝17.2,12.8Hz,1H,3-H),2.87–2.78(m,3H,Ar-CH2,3-H).TOF-HRMS m/z:564.0628[M+Na]+，
化合物5n的化学式如下：
实施例十六：化合物5o的合成
方法同实施例二，所不同的是用对氟苯乙胺代替苄氨，得白色固体5o。1H NMR(400MHz,CDCl3)δ12.00(s,1H,5-OH),7.15–7.09(m,2H,Ar-H),7.04(d,J＝2.0Hz,1H,2’-H),6.97(ddd,J＝10.8,5.8,2.5Hz,2H,Ar-H),6.93(dd,J＝8.5,2.0Hz,1H,5’-H),6.89(d,J＝8.3Hz,1H,4’-H),6.42(t,J＝5.5Hz,1H,NH),6.02(d,J＝2.4Hz,1H,8-H),5.99(d,J＝2.4Hz,1H,6-H),5.34(dd,J＝12.8,3.1Hz,1H,2-H),4.45(s,2H,C＝OCH2O),3.92(s,3H,OCH3),3.57(dd,J＝13.2,6.9Hz,2H,NH),3.10(dd,J＝17.2,12.8Hz,1H,3H),2.85–2.79(m,3H,Ar-CH2,3-H).TOF-HRMS m/z:482.1610[M+H]+，
化合物5o的化学式如下：
实施例十七：化合物5p的合成
方法同实施例二，所不同的是用邻氯苯乙胺代替苄氨，得白色固体5p。1H NMR(400MHz,CDCl3)δ11.99(s,1H,5-OH),7.38–7.33(m,1H,Ar-H),7.21–7.16(m,3H,Ar-H),7.04(d,J＝2.0Hz,1H,2’-H),6.92(dd,J＝8.4,2.0Hz,1H,5’-H),6.89(d,J＝8.3Hz,1H,4’-H),6.51(t,J＝5.5Hz,1H,NH),6.03(d,J＝2.4Hz,1H,8-H),6.01(d,J＝2.4Hz,1H,6-H),5.34(dd,J＝12.8,3.1Hz,1H,2-H),4.45(s,2H,C＝OCH2O),3.92(s,3H,OCH3),3.63(dd,J＝12.9,6.8Hz,2H,NCH2),3.09(dd,J＝17.2,12.8Hz,1H,3-H),3.01(t,J＝6.9Hz,2H,Ar-CH2),2.82(dd,J＝17.2,3.1Hz,1H,3-H).TOF-HRMS m/z:520.1134[M+Na]+，化合物5p的化学式如下：
实施例十八：化合物5q的合成
方法同实施例二，所不同的是用邻氟苯乙胺代替苄氨，得白色固体5q。1H NMR(400MHz,DMSO)δ12.07(s,1H,5-OH),9.09(s,1H,3’-OH),8.22(t,J＝5.7Hz,1H,NH),7.33–7.20(m,3H,Ar-H),7.19–7.04(m,2H,Ar-H,2’-OH),6.98–6.86(m,2H,4’-H,5’-H),6.09–6.07(m,2H,6-H,8-H),5.49(dd,J＝12.4,2.9Hz,1H,2-H),4.52(s,2H,C＝OCH2O),3.78(s,3H,OCH3),3.35(dd,J＝13.0,6.8Hz,2H,NCH2),3.26(dd,J＝17.2,12.3Hz,1H,3-H),2.81–2.73(dd,J＝17.0,3.0Hz,1H,3-H).TOF-HRMS m/z:504.1429[M+Na]+，化合物5q的化学式如下：
实施例十九：化合物5r的合成
方法同实施例二，所不同的是用间氯苯乙胺代替苄氨，得白色固体5r。1H NMR(400MHz,CDCl3)δ11.99(s,1H,5-OH),7.25–7.13(m,2H,Ar-H),7.10–7.00(m,3H,Ar-H,2’-H),6.93(dd,J＝8.3,2.0Hz,1H,5’-H),6.89(d,J＝8.3Hz,1H,4’-H),6.52(t,J＝5.3Hz,1H,NH),6.03(d,J＝2.3Hz,1H,8-H),6.01(d,J＝2.3Hz,1H,6-H),5.34(dd,J＝12.8,3.0Hz,1H,2-H),4.45(s,2H,C＝OCH2O),3.92(s,3H,OCH3),3.61(dd,J＝12.9,6.7Hz,2H,NCH2),3.09(dd,J＝17.2,12.8Hz,1H,3-H),2.91(t,J＝6.8Hz,1H,Ar-CH2),2.82(dd,J＝17.2,3.1Hz,1H,3-H).TOF-HRMSm/z:520.1134[M+Na]+，化合物5r的化学式如下：
实施例二十：化合物5s的合成
方法同实施例二，所不同的是用4-甲氨基吡啶代替苄氨，得白色固体5s。1H NMR(400MHz,DMSO)δ12.07(s,1H,5-OH),9.09(s,1H,3’-OH),8.75(t,J＝6.1Hz,1H,NH),8.47(dd,J＝4.4,1.6Hz,2H,Py-H),7.24(d,J＝6.0Hz,2H,Py-H),6.96–6.92(m,2H,2’-H,4’-H),6.91–6.86(m,1H,5’-H),6.14(d,J＝2.3Hz,1H,8-H),6.13(d,J＝2.3Hz,1H,6-H),5.50(dd,J＝12.4,3.0Hz,1H,2-H),4.68(s,2H,C＝OCH2O),4.36(d,J＝6.1Hz,2H,Py-CH2),3.78(s,3H,OCH3),3.27(dd,J＝17.0,12.2Hz,1H,3-H),2.77(dd,J＝17.2,3.1Hz,1H,3-H).TOF-HRMS m/z:451.1500[M+H]+，化合物5s的化学式如下：
实施例二十一：化合物5t的合成
方法同实施例二，所不同的是用糠胺代替苄氨，得白色固体5t。1H NMR(400MHz,CDCl3)δ11.98(s,1H,5-oh),7.37(dd,J＝1.8,0.8Hz,1H,Fu-H),7.03(d,J＝2.0Hz,1H,2’-H),6.92(dd,J＝8.4,2.0Hz,1H,5’-H),6.88(d,J＝8.3Hz,1H,4’-H),6.76(t,J＝4.6Hz,1H,NH),6.33(dd,J＝3.2,1.9Hz,1H,Fu-H),6.26(dd,J＝3.2,0.6Hz,1H,Fu-H),6.08(d,J＝2.4Hz,1H,8-H),6.05(d,J＝2.4Hz,1H,6-H),5.34(dd,J＝12.8,3.0Hz,1H,2-H),4.53(d,J＝5.8Hz,2H,NCH2),4.51(s,2H,C＝OCH2O),3.92(s,3H,OCH3),3.08(dd,J＝17.2,12.8Hz,1H,3-H),2.81(dd,J＝17.2,3.1Hz,1H,3-H).TOF-HRMS m/z:460.1159[M+Na]+，
化合物5t的化学式如下：
实验测试实施例制得的化合物对乙酰胆碱酯酶和丁酰胆碱酯酶的抑制作用(Biochemical Pharmacology 1961,7,88-95.)
结果用IC50值表示，以Tacrine作为阳性对照。所有的测试均在PowerWaveXS2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。
实验步骤：
1)化合物溶液的配制：
将测试化合物配成10mM浓度(溶剂：DMSO)，-20℃低温冰箱保存，使时用磷酸盐缓冲液(0.1mol/L，pH8.0)稀释至所需浓度。
2)酶储备液的配制：
从Sigma公司购买乙酰胆碱酯酶(E.C.3.1.1.7,from electric ell.)和丁酰胆碱酯酶(E.C.3.1.1.8,from equine serum)；乙酰胆碱酯酶储备液配制为0.1mg/ml，丁酰胆碱酯酶储备液配制为0.2mg/ml。
3)底物储备液的配制：
从Sigma公司购买硫代乙酰胆碱(Acetylthiocholine，ATC)和硫代丁酰胆碱(Butylthiocholine,BTC)；称取一定量ATC或BTC，用磷酸盐缓冲溶液(0.1mol/L，pH8.0)配制成0.01mol/L的溶液，备用。
4)显色剂储备液的配制：
从Sigma公司购买的显色剂5,5-二硫代双(2-硝基苯甲酸)用磷酸盐缓冲溶液(0.1mol/L，pH8.0)配制成0.01mol/L，4℃遮光保存,备用。
5)化合物酶抑制能力检测：
每一种化合物在96孔板中选取6个孔测试；分别加入10μL酶溶液；0，5，10，20，35，50μL待测化合物溶液；加入0.1mol/LpH8.0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10μLATC溶液(或BTC)、10μLDTNB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。
6)结果计算：
IC50值的计算：以没有加入抑制剂时测得的吸光度变化(斜率)为100个活力单位(Acontrol)，相对酶活力＝(加入抑制剂的吸光度变化/没有加入抑制剂的吸光度变化)×100，当相对酶活力达到50时，即为抑制剂的IC50值。
实验结果为三次独立实验的平均值。
7)实验结果：
表1化合物5a-5t及Tacrine对乙酰胆碱酯酶和丁酰胆碱酯酶抑制作用的IC50值及抑制选择性
a对乙酰胆碱酯酶的选择性＝IC50(丁酰胆碱酯酶)/IC50(乙酰胆碱酯酶)
8)结论：从表1发现所有的橙皮素衍生物对乙酰胆碱酯酶均有较好的抑制活性，活性达到49.2～207.3nM，而对丁酰胆碱酯酶的抑制活性较弱，对乙酰胆碱酯酶的选择性较高，选择性范围达到135.2～581.8。化合物5f表现出最好的乙酰胆碱酯酶抑制活性(IC50为49.2nM)，同时具有最好的乙酰胆碱酯酶抑制选择性(581.8)。
Claims (4)
1.一种酰胺基取代的橙皮素类衍生物，其特征在于，结构式为：
其中R表示对氯苄胺基，邻氯苄胺基，间甲氧基苄胺基，对氯苯乙胺基，邻氟苄胺基，对甲氧基苯乙胺基，对氯苯乙胺基，苄胺基，对氟苄胺基，邻氯苯乙胺基，(4-吡啶基)甲胺基，邻甲氧基苄胺基，邻氟苯乙胺基，间氯苯乙胺基，糠胺基，对溴苄胺基，对溴苯乙胺基，对甲氧基苄胺基，三氟甲基苄胺基，苯乙胺基中的一种。
2.一种如权利要求1所述的酰胺基取代的橙皮素类衍生物的制备方法，其特征在于，主要合成路线为：
其具体步骤为：
将橙皮素类似物与2-3倍量的溴乙酸乙酯在弱碱作用下搅拌后得到产物；
（2）将步骤（1）所得产物进行水解反应后，再与各种RH混合，在HOBt和EDC催化下缩合，得到终产物酰胺基取代的橙皮素类衍生物，其中，R为对氯苄胺基，邻氯苄胺基，间甲氧基苄胺基，对氯苯乙胺基，邻氟苄胺基，对甲氧基苯乙胺基，对氯苯乙胺基，苄胺基，对氟苄胺基，邻氯苯乙胺基，(4-吡啶基)甲胺基，邻甲氧基苄胺基，邻氟苯乙胺基，间氯苯乙胺基，糠胺基，对溴苄胺基，对溴苯乙胺基，对甲氧基苄胺基，三氟甲基苄胺基，苯乙胺基中的一种；
步骤（1）中弱碱为K2CO3，搅拌时间为18-22min，反应溶剂为DMF；
步骤（2）中水解反应条件为NaOH催化，pH为12-13，溶剂为乙醇；
冰浴条件；缩合反应在HOBt和EDC的催化下，溶剂为氯仿。
3.一种如权利要求1所述的酰胺基取代的橙皮素类衍生物的应用，其特征在于：作为制备抗阿尔兹海默症的药物中的应用。
4.如权利要求3所述的应用，其特征在于：所述的药物为注射剂、片剂、丸剂、胶囊剂、悬浮剂或乳剂。
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