CN104860847A - 利凡斯的明和咖啡酸、阿魏酸的二聚体,其制备方法及其药物组合物 - Google Patents
利凡斯的明和咖啡酸、阿魏酸的二聚体,其制备方法及其药物组合物 Download PDFInfo
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- CN104860847A CN104860847A CN201510083225.2A CN201510083225A CN104860847A CN 104860847 A CN104860847 A CN 104860847A CN 201510083225 A CN201510083225 A CN 201510083225A CN 104860847 A CN104860847 A CN 104860847A
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Abstract
本发明涉及合成一系列利凡斯的明的衍生物,结构式如式(I)所示。通过变换取代基,调节其抑制乙/丁酰胆碱酯酶、抑制谷氨酸诱导的氧化应激、降低H2O2等ROS对HT22细胞的损伤、抑制β-淀粉样蛋白自聚集和清除DPPH自由基的能力,使其能同时作用于多个靶点。它们可被制成适当的药物剂型用于治疗阿尔茨海默氏病(Alzheimer’s disease)。
Description
发明领域
本发明涉及合成一系列利凡斯的明的衍生物,结构式如式(I)所示。通过变换取代基,调节其抑制乙/丁酰胆碱酯酶、抑制谷氨酸诱导的氧化应激、降低H2O2等ROS对HT22细胞的损伤、抑制β-淀粉样蛋白自聚集和清除DPPH自由基的能力,使其能同时作用于多个靶点。它们可被制成适当的药物剂型用于治疗阿尔茨海默氏病(Alzheimer's disease)。
发明背景
德国精神病学家爱罗斯·阿兹海默于1907年最初报告了这一病症,并由此得名阿兹海默病(Alzheimer′s disease,AD)。阿尔茨海默氏病是一种以进行性认知功能障碍和记忆力损害为特征的神经退行性疾病,早期表现为短期记忆力缺失,随着疾病的发展,大脑神经细胞功能逐渐丧失,造成记忆力、判断力、方位感、注意力和语言能力的损伤,并伴有行为和人格方面的改变,最终在5-10年内导致病人死亡。
20世纪70年代初,人们发现胆碱能系统与学习记忆密切相关,其后大量的研究证实脑内胆碱能的减退是学习与记忆能力下降的主要发病原因之一。1982年,Bartus等(Science 1982,217:408-414)提出了记忆功能紊乱的“胆碱能假说”,该学说认为,AD患者致病的关键原因是由于突触间隙乙酰胆碱水平降低,大脑皮质区的信号传递受阻,导致神经元细胞的退变及凋亡,从而造成患者的记忆力水平下降、认知行为功能障碍。对AD患者的病理研究显示,AD患者脑内基地前脑胆碱能神经元90%发生了丢失,患者脑内乙酰胆碱水平过低,这些变化的程度与患者认知功能损害的程度呈正相关(Acta Neurol Scand Suppl 1993,149:42-45)。
在哺乳动物中,存在两种主要的胆碱酯酶——乙酰胆碱酯酶(AchE)和丁酰胆碱酯酶(BuchE)。在脑内,AchE主要分布于神经元的突触膜和突触间隙,控制细胞内的Ach水平;而BuchE则主要位于胶质细胞和血液,调控细胞外的Ach水平。传统观点认为,由于BuchE主要分布于外周,其中枢作用不明确,抑制BuchE可能会带来一定的外周副作用,因此该酶不适合作为AD药物的靶点。但随着研究的深入,人们发现,在疾病的进程中,BuchE酶活性增强,取代AchE对Ach的水解作用。在AchE基因敲除的小鼠脑中,BuchE可以替代AchE发挥对Ach的水解作用;当AD患者脑中的AchE随着病程的发展降至正常浓度的55-67%时,BuchE的浓度仍保持不变甚至升高至120%(Br Med J 1978;2:1457-9);皮层中,BuchE/AchE的比值也由0.5升高至11(Plenum Press,New York:1992,PP.19-34)。进一步的研究 表明,在老年斑形成的早期阶段,BuchE在Aβ的聚集中起到重要的作用。在组织培养中,BuchE能加强Aβ的毒性作用(Proc Soc Neurosci 1996;72:1172)。因此,BuchE作为抗AD药物的靶点逐渐被人们接受。
发明概述
利凡斯的明作为第二代乙酰胆碱酯酶抑制剂,能同时作用于乙酰胆碱酯酶和丁酰胆碱酯酶,抑制两者对胆碱酯酶的水解作用,提高体内胆碱酯酶的水平,改善AD的症状。咖啡酸(3,4-二羟基肉桂酸,Caffeic acid)是一类重要的酚酸,普遍存在于各类食物中,如咖啡、苹果等,具有多方面的生物活性,如抗氧化和抗炎症等。阿魏酸(4-羟基-3-甲氧基苯丙烯酸,Ferulic acid)最初在植物的种子和叶子中发现,是一种广泛存在于植物中的酚酸,在细胞壁中与多糖和蛋白质结合成为细胞壁的骨架。阿魏酸被公认为天然安全的自由基淬灭剂和抗氧化剂,对过氧化氢、超氧自由基、羟自由基、过氧化亚硝基都有强烈的清除作用。一项体内研究表明,给小鼠长期经口使用阿魏酸,能有效抵抗Aβ12-42所产生的神经细胞毒性,对智力有一定的改善作用。基于此,将利凡斯的明和咖啡酸或阿魏酸相连,以达到调节乙酰胆碱酯酶和丁酰胆碱酯酶的活性、抑制AchE诱导的的β-淀粉样蛋白自聚集和清除自由基的能力,使其能同时作用于诱使AD的多个靶点。
本发明涉及式(I)的化合物或其互变异构体,药用盐,前药或溶剂化物。
其中,n=0~2;R1=O,NH;R2=H,CH3。
除非另外指明,本发明的化合物还意欲包括区别仅在于存在一个或多个同位素富集的原子的化合物。例如,用氘或氚替换氢,或者用13C或14C-富集的碳原子替换碳原子,或15N-富集的氮原子替换氮原子的化合物属于本发明的范围内。
属于“药用盐,衍生物,溶剂化物,前药”是指任何药用盐,酯,溶剂化物,或经施用于接受者后能够提供(直接或间接)本文所述化合物的其他化合物。然而,应当理解非药用盐也属于本发明的范围内,因为那些可能用于植被药用盐,盐,前药和衍生物的植被可以通过本领域已知的方法进行。例如,本发明提供的化合物的药用盐可以通过常规方法由母体化合物合成,该母体化合物含有碱或酸部分。通常,该盐例如通过将游离酸或碱形式的这些化合物与化学计算量的适当碱或酸在水中或在有机溶剂中或在两者的混合物中制备。通常,非水 性介质如乙醚,乙酸乙酯,乙醇,异丙醇或乙腈是优选的。酸加成盐的实例包括无机酸加成盐例如,盐酸盐,氢溴酸盐,氢碘酸盐,硫酸盐,硝酸盐,和有机酸加成盐,如例如乙酸盐,马来酸盐,富马酸盐,柠檬酸盐,草酸盐,琥珀酸盐,酒石酸盐,苹果酸盐,扁桃酸盐和对甲苯磺酸盐。碱加成盐的实例包括无机盐如例如钠,钾,钙,铵,镁,铝和锂盐;和有机碱如例如乙二胺,乙醇胺,N,N-二烷基乙醇胺,三乙醇胺,葡糖胺和碱性氨基酸盐。
优选的衍生物或前药是相对于母体物质,当将这些化合物使用于患者时提高本发明化合物的生物利用度(例如通过使得口服给药的化合物更容易被吸收到血液中)或增强母体化合物向生物区室(例如脑或淋巴系统)的传递的那些。
式(I)化合物前药的任何化合物属于本发明的范围内,术语“前药”以其最广泛的意义使用并且包括在体内转化为本发明化合物的那些衍生物。这些衍生物对于本领域技术人员是显而易见的,并且根据分子中存在的官能团,包括不限于本发明化合物的下列衍生物:酯;氨基酸酯;磷酸;金属盐硫酸;氨基甲酸酯和酰胺。
本发明的化合物可以是作为有利化合物或作为溶剂化物的晶体形式,意欲将两种形式都包括在本发明的范围内。溶剂化的方法是本领域公知的。适当的溶剂化物是药用溶剂化物。在一个具体实施方案中,溶剂化物是水合物。
反应路线列举了制备本发明的化合物的方法。
反应路线1
反应路线2
将胺(0.93mmol)溶解于THF(5mL)中,再加入到羧酸(0.93mmol)和DCC(192mg,0.93mmol)的THF(10mL)混合物中。将混合物在回流温度下搅拌7小时。反应完毕,除去溶剂后,通过快速色谱法纯化粗产物得目标化合物。
对于接头中含有胺,酯或其他单元的化合物的备选方法对于本领域技术人员是显而易见 的。
如果需要,可以通过常规方法如结晶法或色谱法纯化反应产物。当用于制备本发明化合物的上述方法产生立体异构体的混合物时,这些异构体可以通过常规技术如制备色谱法分离。如果存在手性中心,化合物可能以外消旋形式制备,或者可以通过对映特异性合成或通过拆分来制备单个的对映异构体。
一种优选的药用形式是结晶形式,包括药物组合物中的这种形式。如果是盐和溶剂化物,另外的离子或溶剂部分也应当是非毒性。本发明的化合物可以存在不同的多晶型物,意欲本发明包括所有这些形式。
上文所述药学上可接受的载体、辅剂或赋形剂,是指药学领域常规的药物载体,例如:稀释剂,赋形剂如水等,填充剂如淀粉、蔗糖等;黏合剂如纤维素衍生物、藻酸盐、明胶和聚乙烯吡咯烷酮;湿润剂如甘油;崩解剂如琼脂、碳酸钙和碳酸氢钠;吸收促进剂如季胺化合物;表面活性剂如滑石粉、硬脂酸镁和钙和聚乙二醇。另外还可以以组合物中加入其它辅料如香味剂、甜味剂等。
本发明利凡斯的明的衍生物及其互变异构体、药用盐类、前药或溶剂化物可以给病人口服或、皮下或静脉注射、或用植入体内的方法给药,因此可以制备成常规的口服制剂、注射剂。所述的利凡斯的明的衍生物室温溶于水或部分溶于水,可以制备水溶液或悬浮剂型。药物学上也可以液体或固型剂来口服,例如水性悬浮液、乙醇溶液,片剂或胶囊。如果需要,也可以将其制成缓释剂型或控释剂型。
由上述发明式(I)表示的典型化合物,其盐能有效抑制BuchE和AchE的活性,抑制Aβ的自聚集,清除DPPH自由基,保护谷氨酸和H2O2诱导的细胞死亡。因此,本发明另一方面涉及治疗、改善或预防相关疾病或病症的方法,该方法包含向需要这种治疗的患者施用治疗有效量的式(I)的化合物或其药物组合物。在可以治疗的疾病中有认知障碍如老年性痴呆,脑血管痴呆,轻度认知损伤,注意缺损障碍,和/或带有异常蛋白聚集的神经变性痴呆症,如特别是阿尔茨海默症或病症,及其它氧化应激参与的痴呆症。
本发明另外提供药物组合物,其包含本发明的化合物,或其药用盐,衍生物,前药或立体异构体,以及药用载体,辅剂,或赋形剂,以用于向患者给药。
本发明的化合物和组合物可以与其它药物一起使用以提供联合治疗。其它药物可以形成相同组合物的一部分,或者可以作为同时或不同时给药的分开的组合物提供。
总之,本发明包括一系列列利凡斯的明的衍生物,其制备方法以及其在老年痴呆症中的应用。尽管以上的描述具有许多特性,但其只是本发明的一些优选实施方案,并非用于限制本发明的范围。提供下列实施例进一步举例说明本发明,它们不应当认为是对本发明范围的 限定。本发明的范围应由所附的权利要求和其等效的诠释决定,而不是由所举的实施例来界定。
附图说明
附图1待测化合物对HT22细胞的细胞毒性。
附图2LDH法检测待测化合物对HT22细胞的细胞毒性。
附图3待测化合物对L-glutamate诱导HT22细胞死亡的保护作用。
附图4对H2O2诱导HT22细胞死亡的保护作用。
实施例
实施例1:
(2E)-3-(3,4-二羟基苯基)-N-(3-{[乙基(甲基)氨基甲酰基]氨基}苯基)-2-丙烯酰胺
试剂:咖啡酸(109mg,0.53mmol),3-(3-氨基苯基)-1-乙基-1-甲基脲(111mg,0.53mmol)。
纯化:CHCl3/MeOH(9.5∶0.5).硅胶柱层析法,使用CHCl3/MeOH(9.5∶0.5)。黄色固体,产率:81mg(43%)。
mp 110-112℃;
1H NMR(CD3OD)δ:1.17(t,3H,J=7.2Hz,CH3),3.01(s,3H,CH3),3.43(q,1H,J=7.2Hz,CH2),6.55(d,1H,J=15.4Hz,CH=),6.78(d,1H,J=8.0Hz,Ar),6.95(dd,1H,J=1.6,8.0Hz,Ar),7.05(d,1H,J=1.6Hz,Ar),7.11(d,1H,J=8.0Hz,Ar),7.22(t,1H,J=8.0Hz,Ar),7.34(d,1H,J=8.0Hz,Ar),7.51(d,1H,J=15.4Hz,CH=),7.70(s,1H,Ar)ppm;
13C NMR(Acetone-d6)δ:165.03,156.18,148.19,146.30,141.96,140.62,129.31,128.23,121.84,119.79,116.37,115.86,114.98,114.10,111.84,43.94,34.11,13.19ppm.Anal.(C19H21N3O4)Calc%:C 64.21,H 5.96,N 11.82;Trov%:C 64.47,H 6.08,N 11.69。
实施例2:
(2E)-N-(3-{[乙基(甲基)氨基甲酰基]氨基}苯基)-3-(4-羟基-3-甲氧基苯基)-2-丙烯 酰胺
试剂:阿魏酸(92mg,0.48mmol),3-(3-氨基苯基)-1-乙基-1-甲基脲(100mg,0.48mmol)。
纯化:硅胶柱层析法,使用CHCl3/MeOH(9.8∶0.2)。黄色固体,产率:71mg(40%)。mp 112-115℃;
1H NMR(CD3OD)δ:1.18(t,3H,J=7.2Hz,CH3),3.02(s,3H,CH3),3.44(q,1H,J=7.2Hz,CH2),3.91(s,3H,OCH3),6.55(d,1H,J=15.6Hz,CH=),6.82(d,1H,J=8.2Hz,Ar),7.09(dd,1H,J=1.8,8.2Hz,Ar),7.12(d,1H,J=8.0Hz,Ar),7.17(d,1H,J=1.8Hz,Ar),7.22(t,1H,J=8.0Hz,Ar),7.35(d,1H,J=8.0Hz,Ar),7.57(d,1H,J=15.6Hz,CH=),7.70(s,1H,Ar)ppm;
13C NMR(Acetone-d6)δ:164.87,156.00,149.44,148.65,142.15,141.75,140.68,129.29,128.09,122.77,120.15,116.20,115.61,113.88,111.48,56.23,43.90,34.08,13.20ppm.Anal.(C20H23N3O4)Calc%:C 65.03,H 6.28,N 11.37;Trov%:C 65.32,H 6.44,N 11.53。
实施例3:
3-{[(2E)-3-(3,4-二羟基苯基)-2-丙烯酰基]氨基}苯基乙基(甲基)氨基甲酸
试剂:咖啡酸(167mg,0.93mmol),3-氨基苯基乙基(甲基)氨基甲酸(180mg,0.93mmol)。
纯化:硅胶柱层析法,使用CHCl3/MeOH(9.5∶0.5)最为洗脱剂,再从乙酸乙酯/正己烷中沉淀。黄色固体,产率:278mg(84%)。
mp 193-195℃;
1H NMR(Acetone-d6)δ:1.15(t,1.5H,J=7.0Hz,CH3rotamer),1.24(t,1.5H,J=7.0Hz,CH3rotamer),2.95(s,1.5H,CH3rotamer),3.08(s,1.5H,CH3rotamer),3.37(q,1H,J=7.0Hz,CH2rotamer),3.49(q,1H,J=7.0Hz,CH2rotamer),6.59(d,1H,J=15.4Hz,CH=),6.81-6.84(m,1H,Ar),6.87(d,1H,J=8.0Hz,Ar),6.99(dd,1H,J=8.0,2.1Hz,Ar),7.10(d,1H,J=2.1Hz,Ar),7.28(dd,1H,J=8.4,8.0Hz,Ar),7.47(d,1H,J=8.4Hz,Ar),7.54(d,1H,J=15.4Hz,CH=),7.73(s,1H,Ar)ppm;
13C NMR(Acetone-d6)δ:164.18,153.83,152.21,147.33,145.39,141.44,140.52,128.97,127.30,121.11,118.61,116.60,115.58,115.51,114.10,112.98,43.68,33.46(NCH2rotamer),33.30(NCH2rotamer),12.63(CH3rotamer),11.81(CH3rotamer)ppm.Anal.(C19H20N2O5)Calc%:C 64.04,H 5.66,N 7.86;Trov%:C 64.32,H 5.71,N 7.59。
实施例4:
3-{[(2E)-3-(4-羟基-3-甲氧基苯基)丙-2-烯酰基]氨基}苯基乙基(甲基)氨基甲酸
试剂:阿魏酸(142mg,0.73mmol),3-氨基苯基乙基(甲基)氨基甲酸(142mg,0.73mmol)。
纯化:硅胶柱层析法,使用CHCl3/MeOH(9.5∶0.5)最为洗脱剂,再从乙酸乙酯/正己烷中沉淀。黄色固体,产率:124mg(46%)。
mp 133-135℃;
1H NMR(Acetone-d6)δ:1.15(t,1.5H,J=6.8Hz,CH3rotamer),1.24(t,1.5H,J=6.8Hz,CH3rotamer),2.95(s,1.5H,CH3rotamer),3.08(s,1.5H,CH3rotamer),3.38(q,1H,J=6.8Hz,CH2rotamer),3.49(q,1H,J=6.8Hz,CH2rotamer),3.90(s,3H,CH3O),6.66(d,1H,J=15.4Hz,CH=),6.81-6.85(m,1H,Ar),6.86(d,1H,J=8.0Hz,Ar),7.11(dd,1H,J=8.0,2.0Hz,Ar),7.21(d,1H,J=2.0Hz,Ar),7.28(dd,1H,J=8.4,8.0Hz,Ar),7.48(d,1H,J=8.0Hz,Ar),7.60(d,1H,J=15.4Hz,CH=),7.74(s,1H,Ar)ppm.
13C NMR(Acetone-d6)δ:165.00,154.50,153.15,149.56,148.67,142.25,141.46,129.86,127.99,122.96,119.75,117.50,116.45,116.21,113.86,111.47,56.26,44.58,34.57(CH2rotamer),34.20(CH2rotamer),13.56(CH3rotamer),12.80(CH3rotamer)ppm.Anal.(C20H22N2O5)Calc%:C 64.85,H 5.99,N 7.56;Trov%:C 64.90,H 5.87,N 7.62。
实施例5:
3-(2-{[(2E)-3-(3,4-二羟苯基)丙-2-烯酰基]氨基}乙基)苯基乙基(甲基)氨基甲酸
试剂:咖啡酸(81mg,0.45mmol)和3-(2-氨基乙基)苯基乙基(甲基)氨基甲酸(100mg,0.45mmol)。
纯化:硅胶柱层析法,使用CHCl3/MeOH(9.5∶0.5)最为洗脱剂,再从乙酸乙酯/正己烷中沉淀。黄色固体,产率:66mg(38%)。
mp 78-80℃;
1H NMR(Acetone-d6)δ:1.13(t,1.5H,J=6.7Hz,CH3rotamer),1.21(t,1.5H,J=6.7Hz,CH3rotamer),2.85(t,2H,J=7.2Hz,ArCH2),2.94(s,1.5H,CH3rotamer),3.06(s,1.5H,CH3 rotamer),3.36(q,1H,J=6.7Hz,CH2rotamer),3.46(q,1H,J=6.7Hz,CH2rotamer),3.52-3.57(m,2H,CH2N),6.43(d,1H,J=15.8Hz,CH=),6.82(d,1H,J=8.4Hz,Ar),6.92(dd,1H,J=1.6,7.9Hz,Ar),6.97(d,1H,J=8.4Hz,Ar),7.01(s,1H,Ar),7.07-7.08(m,2H,Ar),7.27(t,1H,J=7.9Hz,Ar),7.42(d,1H,J=15.8Hz,CH=)ppm.
13C NMR(Acetone-d6)δ:166.80(CO rotamer),166.72(CO rotamer),152.87,147.94,146.29,141.91,140.74,129.82,128.34,126.18,123.05,121.54,120.5l,119.56,116.32,114.89,44.55,41.49(CH3rotamer),41.36(CH3rotamer),36.25,34.34(CH2rotamer),34.02(CH2rotamer),13.46(CH3rotamer),12.69(CH3rotamer)ppm.Anal.(C21H24N2O5)Calc%:C 65.61,H 6.29,N 7.29;Trov%:C 65.35,H 6.12,N 7.41。
实施例6:
3-(2-{[(2E)-3-(4-羟基-3-甲氧基苯基)丙-2-烯酰基]氨基}乙基)苯基-乙基(甲基)氨基甲酸
试剂:阿魏酸(52mg,0.27mmol)和3-(2-氨基乙基)苯基乙基(甲基)氨基甲酸(60.00mg,0.27mmol)。
纯化:硅胶柱层析法,使用CHCl3/MeOH(9.5∶0.5)为洗脱剂,再从乙酸乙酯/正己烷中沉淀。
黄色固体,产率:43mg(40%)。
mp 63-65℃;
1H NMR(Acetone-d6)δ:1.13(t,1.5H,J=6.7Hz,CH3rotamer),1.21(t,1.5H,J=6.7Hz,CH3rotamer),2.86(t,2H,J=7.2Hz,ArCH2),2.94(s,1.5H,CH3rotamer),3.06(s,1.5H,CH3rotamer),3.36(q,1H,J=6.7Hz,CH2rotamer),3.47(q,1H,J=6.7Hz,CH2rotamer),3.52-3.58(m,2H,CH2N),3.87(s,3H,CH3O),6.49(d,1H,J=15.6Hz,CH=),6.83(d,1H,J=8.1Hz,Ar),6.99(d,1H,J=8.2Hz,Ar),7.03(s,1H,Ar),7.06(dd,1H,J=1.6,8.1Hz,Ar),7.08(d,1H,J=7.6Hz,Ar),7.15(d,1H,J=1.6Hz,Ar),7.28(dd,1H,J=7.6,8.2Hz,Ar),7.44(d,1H,CH=,J=15.6Hz)ppm.
13C NMR(Acetone-d6)δ:165.47,152.02,148.00,147.70,141.20,139.44,128.89,127.42,125.23,122.13,121.64,119.61,119.18,115.18,110.38,55.33,43.64,40.47,35.39,12.60ppm.Anal.(C22H26N2O5)Calc%:C 66.32,H 6.58,N 7.03;Trov%:C 66.07,H 6.73,N 6.95。
实施例7:
3-({[(2E)-3-(3,4-二羟苯基)丙-2-烯酰基]氨基}甲基)苯基乙基(甲基)氨基甲酸
试剂:咖啡酸(86mg,0.48mmol)和3-(氨基甲基)苯基乙基(甲基)氨基甲酸(100mg,0.48mmol)。
纯化:硅胶柱层析法,使用CHCl3/MeOH(9.5∶0.5)为洗脱剂,得到黄色固体,产率:66mg(37%)。
mp 188-190℃;
1H NMR(CD3OD)δ:1.17(t,1.5H,J=7.0Hz,CH3rotamer),1.24(t,1.5H,J=7.0Hz,CH3rotamer),2.96(s,1.5H,CH3rotamer),3.08(s,1.5H,CH3rotamer),3.38(q,1H,J=7.0Hz,CH2rotamer),3.49(q,1H,J=7.0Hz,CH2rotamer),4.48(s.2H,CH2NH),6.40(d,1H,J=15.8Hz,CH=),6.76(d,1H,J=8.2Hz,Ar),6.91(dd,1H,J=2.0,8.2Hz,Ar),6.98-7.02(m,2H,Ar),7.06(s,1H,Ar),7.18(d,1H,J=7.8Hz,Ar),7.34(dd,1H,J=7.8,8.0Hz,Ar),7.43(d,1H,J=15.8Hz,CH=)ppm;
13C NMR(CD3OD)δ:169.18,156.39,153.01,148.86,146.74,142.69,141.80,130.46,128.25,125.68,122.19,122.08,121.72,118.13,116.46,115.07,45.15,43.85,34.53(CH2rotamer),34.27(CH2rotamer),13.40(CH3rotamer),12.61(CH3rotamer)ppm.Anal.(C20H22N2O5)Calc%:C64.85,H 5.99,N 7.56;Trov%:C 64.78,H 5.86,N 7.62。
实施例8:
3-({[(2E)-3-(3,4-二羟苯基)丙-2-烯酰基]氨基}甲基)苯基乙基(甲基)氨基甲酸
试剂:阿魏酸(93mg,0.48mmol)和3-(氨基甲基)苯基乙基(甲基)氨基甲酸(100mg,0.48mmol)。
纯化:硅胶柱层析法,使用CHCl3/MeOH(9.5∶0.5)为洗脱剂,再从氯仿/正己烷中沉淀。黄色固体,产率:65mg(35%)。
mp 138-140℃;
1H NMR(CDCl3)δ:1.19-1.26(m,3H,CH3),2.98(s,1.5H,CH3rotamer),3.06(s,1.5H,CH3 rotamer),3.37-3.49(m,2H,CH2),3.91(s,3H,OCH3),4.56(d,2H,J=5.2Hz,CH2NH),6.27(d,1H,J=15.6Hz,CH=),6.90(d,1H,J=8.2Hz,Ar),7.00-7.08(m,4H,Ar),7.15(d,1H,J=7.6Hz,Ar)7.32(dd,1H,J=7.6,8.2Hz,Ar),7.58(d,1H,J=15.6Hz,CH=)ppm;
13C NMR(CD3OD)δ:169.02,156.27,152.97,149.88,149.23,142.49,141.73,130.41,128.17,125.60,123.23,121.99,121.67,118.48,116.45,111.62,56.35,45.09,43.82,34.48(CH2rotamer),34.22(CH2rotamer),13.37(CH3rotamer),12.58(CH3rotamer)ppm.Anal.(C21H24N2O5)Calc%:C 65.61,H 6.29,N 7.29;Trov%:C 65.52,H 6.12,N 7.35。
实施例9:生物学评估
待测化合物的细胞毒性
小鼠海马神经元细胞株HT22,用含10%胎牛血清的DMEM完全培养基,在37℃,饱和湿度,含体积分数为5%CO2的二氧化碳培养箱中常规培养。取对数生长期细胞,以0.25%胰酶消化后,完全培养基重悬,显微镜下细胞计数板计数并调整细胞浓度为10×104个/ml,接种96孔细胞培养板,100μL/孔,培养过夜,使细胞贴壁。将96孔板中培养基吸走,待测化合物用DMSO溶解,用完全培养基稀释成10、30和100μM,加到96孔板中,100μL/孔。孵育24h后,每孔加入10μL 5mg/mL MTT,孵育2h,弃去上清,加DMSO 100μL/孔,振荡使生成物formazan充分溶解,在酶标仪上测定各孔吸光度值,测定波长570nm。计算化合物导致细胞的死亡率(%)=100%*(A待测化合物-A空白)/(A模型组-A空白)。结果在图1中显示。
实施例10:生物学评估
LDH法检测待测化合物对细胞的毒性
小鼠海马神经元细胞株HT22,用含10%胎牛血清的DMEM完全培养基,在37℃,饱和湿度,含体积分数为5%CO2的二氧化碳培养箱中常规培养。取对数生长期细胞,以0.25%胰酶消化后,完全培养基重悬,显微镜下细胞计数板计数并调整细胞浓度为10×104个/ml,接种96孔细胞培养板,100μL/孔,培养过夜,使细胞贴壁。吸取10μM上清液,按照LDH试剂盒说明书(南京建成)依次加入20μL 0.2mmol/L丙酮酸标准液、20μL待测样本、25μL基质缓冲液和5μL辅酶I,混均后,37℃温浴15min,再加入25μL 2,4-二硝基苯肼,混均,37℃温浴15min,加入250μL0.4mol/LNaOH溶液,混均,室温放置5min,酶标仪测定450nm处的吸光度。上清液中LDH的活性=(测定OD值-对照OD值)/(标准OD值-空白OD值)*100%。结果在图2中显示。
实施例11:生物学评估
对L-glutamate诱导HT22细胞死亡的保护作用
小鼠海马神经元细胞株HT22,用含10%胎牛血清的DMEM完全培养基,在37℃,饱和湿度,含体积分数为5%CO2的二氧化碳培养箱中常规培养。取对数生长期细胞,以0.25%胰酶消化后,完全培养基重悬,显微镜下细胞计数板计数并调整细胞浓度为10×104个/ml,接种96孔细胞培养板,100μL/孔,培养过夜,使细胞贴壁。将96孔板中培养基吸走,待测化合物用DMSO溶解,用完全培养基稀释成10和30μM,加到96孔板中,100μL/孔。预孵育30min后,加入2μL 100mM L-glutamate。模型组不加待测化合物,直接加入2μL 100mML-glutamate。孵育24h后,每孔加入10μL 5mg/mL MTT,孵育2h,弃去上清,加DMSO 100μL/孔,振荡使生成物formazan充分溶解,在酶标仪上测定各孔吸光度值,测定波长570nm。计算细胞存活率:对L-glutamate诱导HT22细胞死亡的保护作用(%)=100%*(A待测化合物-A空白)/(A模型组-A空白)。结果在图3中显示。
实施例12:生物学评估
对H2O2诱导HT22细胞死亡的保护作用
小鼠海马神经元细胞株HT22,用含10%胎牛血清的DMEM完全培养基,在37℃,饱和湿度,含体积分数为5%CO2的二氧化碳培养箱中常规培养。取对数生长期细胞,以0.25%胰酶消化后,完全培养基重悬,显微镜下细胞计数板计数并调整细胞浓度为10×104个/ml,接种96孔细胞培养板,100μL/孔,培养过夜,使细胞贴壁。将96孔板中培养基吸走,待测化合物用DMSO溶解,用完全培养基稀释成10和30μM,加到96孔板中,100μL/孔。预孵育30min后,加入6μL 10mM H2O2。模型组不加待测化合物,直接加入6μL 10mM H2O2。孵育24h后,每孔加入10μL 5mg/mL MTT,孵育2h,弃去上清,加DMSO 100μL/孔,振荡使生成物formazan充分溶解,在酶标仪上测定各孔吸光度值,测定波长570nm。计算细胞存活率:对H2O2诱导HT22细胞死亡的保护作用(%)=100%*(A待测化合物-A空白)/(A模型组-A空白)。结果在图4中显示。
实施例13:生物学评估
有机自由基(DPPH)消除能力的测定
利用DPPH溶液的特征紫红色团的吸收峰,以分光光度法测定加入抗氧化剂后,在517nm处吸光度减少值,表示其对有机自由基消除能力。在反应管中加入250μL 0.2mM DPPH的甲醇溶液,再加入250μL的目标化合物终浓度为(10μM),混合均匀,室温避光反应60min后在 517nm处读取吸光度。设250μL DPPH+250μL化合物溶液为实验组,同时以250μL DPPH+250μL甲醇混合后的吸光度为对照组。计算清除率(%)=[(对照组A517-实验组As17)/对照组A517]×100%。结果在表1中显示。
实施例14:生物学评估
乙酰胆碱酯酶(ACHE)活性抑制
Ellman(Ellman,G.L.;et al.Biochem.Pharmaco1.1961.)报道的比色法在37℃评估AChE抑制活性。测试溶液由以下各项组成:0.1M磷酸盐缓冲液pH 8.0,0.5mM 5,5’-二硫代双(2-硝基苯甲酸)(DTNB,Ellman's试剂),0.03单位AChE(Sigma,来源于电鳗),和0.5mM乙酰硫代胆碱碘化物作为酶促反应的底物。将待检测的化合物加入测定溶液中并与酶在37℃下预温育20分钟后,加入底物。用分光光度计测量在412nm处5分钟内的吸光度变化,比较反应速率,计算由于测试化合物的存在导致反应速率抑制的百分比。用至少一式三份的测量值计算分应速率,计算相对于不含化合物的对照,由于测试化合物的存在导致的百分比抑制。结果在表2中显示。
实施例15:生物学评估
丁酰胆碱酯酶(BuChE)抑制
通过Ellman报道的比色法在37℃评估BuChE抑制活性。测定溶液由以下各项组成:0.05单位来源于人血清的BuChE,0.1M磷酸盐缓冲液(pH 8.0),0.3mM 5,5’-二硫代双(2-硝基苯甲酸)(DTNB,Ellman's试剂),和0.5mM丁酰硫代胆碱碘化物作为酶促反应的底物。将待检测的化合物加入测定溶液中并与酶在37℃下预温育20分钟后,加入底物。用分光光度计测量在412nm处5分钟内的吸光度变化,比较反应速率,计算由于测试化合物的存在导致反应速率抑制的百分比。用至少一式三份的测量值计算分应速率,计算相对于不含化合物的对照,由于测试化合物的存在导致的百分比抑制。结果在表3中显示。
实施例16:生物学评估
抑制Aβ自身诱导聚集作用
取已用六氟异丙醇(HFIP)使单体化后冻干的Aβ1-42和待测化合物溶解于DMSO,用0.215M PBS(pH 8.0)稀释。测试溶液由以下各项组成:10μLAβ1-42溶液和10μL待测化合物(终浓度为10μM)或10μL 0.215M PBS(pH8.0)。37℃孵育24h后,加入180μL1.5μM硫磺素T溶液,混匀,采用300秒的荧光强度扫描(λexc=446nm;λem=490nm)。采用公式:抑制率 =100-(IFi/IF0*100)计算待测化合物对Aβ1-42自身诱导聚集的抑制率。其中IF0和IFi分别为Aβ1-42组、Aβ1-42给予待测化合物组的测量值。结果在表4中显示。
附表1.待测化合物对DPPH的消除能力
附表2.待测化合物对AChE活性的抑制作用
附表3.待测化合物对BuchE活性的抑制作用
附表4.抑制Aβ自身诱导聚集作用
Claims (10)
1.一种具有下述结构式的化合物或其互变异构体、药用盐类、前药或溶剂化合物。
其中,n=0~2;R1=O,NH;R2=H,CH3。
2.一种药物组合物,包括如权利1所述化合物或其药用盐类、前药或溶剂化合物,以及药用载体、辅剂或赋形剂。
3.权利要求1的化合物在制备药物中的应用,所述药物用于治疗AChE/BuchE介导的疾病。
4.按照权利要求3的应用,其中所述药物用于治疗认知障碍如老年性痴呆,脑血管性痴呆,轻度认知损伤,注意缺损障碍,和/或带有异常蛋白聚集的神经变性痴呆症,如特别是阿尔茨海默氏病或病症,及其他氧化应激参与的痴呆症。
5.按照权利要求4的应用,其中所述药物用于治疗阿尔茨海默氏病或病症。
6.根据权利要求4的应用,其中所述药物包括治疗有效量的权利要求1的化合物。
7.用有效量的如权利要求1中任何一项所定义的化合物治疗需要治疗的患者的方法。
8.按照权利要求7的方法,其用于治疗认知障碍如老年性痴呆,脑血管性痴呆,轻度认知损伤,注意缺损障碍,和/或带有异常蛋白聚集的神经变性痴呆症,如特别是阿尔茨海默氏病或病症,及其他氧化应激参与的痴呆症。
9.按照权利要求7或8的方法,其用于治疗阿尔茨海默氏病或病症。
10.根据权利要求4的应用,其中所述药物被放入贮药器植入体内施用。
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