CN105693662A - 一种乙酰胆碱酯酶抑制剂组合物及其制备方法与应用 - Google Patents

一种乙酰胆碱酯酶抑制剂组合物及其制备方法与应用 Download PDF

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CN105693662A
CN105693662A CN201510987620.3A CN201510987620A CN105693662A CN 105693662 A CN105693662 A CN 105693662A CN 201510987620 A CN201510987620 A CN 201510987620A CN 105693662 A CN105693662 A CN 105693662A
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CN105693662B (zh
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杨利民
韩梅
蔡恩博
屠书梅
赵岩
王超卓
张永刚
杨莉
邢静静
郭蒙
刘德民
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Jilin Agricultural University
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Abstract

本发明涉及一种乙酰胆碱酯酶抑制剂苯丙二苄基丁内酯组合物及其制备方法与作为乙酰胆碱酯酶活性抑制剂，用于提高老年痴呆病人记忆力的应用。其结构通式如式I所示，R为Boc-L-Gly,Boc-L-Ala,Boc-L-Val,Boc-L-Leu,Boc-L-Ile氨基酸侧链。

Description

一种乙酰胆碱酯酶抑制剂组合物及其制备方法与应用
技术领域
本发明属于医药技术领域，尤其涉及乙酰胆碱酯酶抑制剂——苯丙二苄基丁内酯组合物及其制备方法与作为乙酰胆碱酯酶活性抑制剂的用途，以及应用于提高老年痴呆病人记忆力。
背景技术
老年痴呆(AD)是一种渐进性神经退化性疾病，其主要表现为记忆功能衰退及识别能力障碍，同时伴有各种神经症状和行为障碍，具有非常高的发病率，目前市场批准治疗AD的药物大多是抑制乙酰胆碱酶活性的药物，主要包括他格林（tacrine)，多奈哌齐（donepezil)，氨基甲酸酯，石杉碱甲等。随着全球人口老龄化的到来，其发病人数将不断增加，抗老年痴呆药物的需求将有广阔的增长空间。因此，抗老年痴呆药物的研发尤为迫切，寻找和发现新的乙酰胆碱酯酶抑制剂就显得尤为重要。
牛蒡子苷元（ARG），一种苯丙二苄基丁内酯木脂素，是菊科(Compositae)植物牛蒡(ArctiumIappaL.)的干燥成熟果实牛蒡子（FructusArctii）的主要活性成分，具有抗肿瘤、抗糖尿病等药理活性。但其口服生物利用度低，严重制约了在临床上的应用。本发明将氨基酸引入到药物分子中，形成苯丙二苄基丁内酯组合物，研究发现其具有较好的抑制乙酰胆碱酯酶活性。
发明内容
本发明涉及具有乙酰胆碱酯酶抑制活性的苯丙二苄基丁内酯组合物的制备。
具体而言，本发明内容如下：本发明提供了组合物，见通式I
通式I
其中，通式I中的R为Boc-L-Gly,Boc-L-Ala,Boc-L-Val,Boc-L-Leu,Boc-L-Ile氨基酸侧链。
具体实施方式
下面的实施例可以对本发明进一步的描述，然而，这些实施例不应该作为对本发明的范围的限制。
下述制备实施例中，NMR（核磁共振）用BrukerAvance-300M仪器测定。
实施例14-(4-(3,4-二甲氧苯甲基)-2-羰基)四氢呋喃甲基-2-甲氧基苯酚2-(N-叔丁氧羰基)氨基-乙酸酯(ARG1)的合成。
称取0.20g(0.54mmol)牛蒡子苷元,0.19g(1.08mmol)BOC-L-甘氨酸,0.21g(1.08mmol)1-乙基-(3-二甲基氨基丙基)碳二亚胺盐酸盐(EDCI)，0.03g(0.27mmol)4-二甲氨基吡啶（DMAP）置于100ml旋瓶中，加入10ml乙腈溶液，冰水浴下搅拌溶解，再室温反应1-2小时，TLC检测反应至反应完毕，减压蒸去溶剂，得到浅黄色粘稠物。将粘稠物用YMC反相填料进行柱层析分离，用乙腈/水(55:45)混合溶剂洗脱，收集所需组分，减压蒸去有机溶剂，冷冻干燥，得白色粉末状化合物ARG1。
白色固体，产率80%。1H-NMR(CDCl3,300MHz)δppm:6.97(1H,d,7.8HZ,C6 H 5),6.77(1H,d,2.1HZ,C6 H 5),6.74(1H,d,8.1HZ,C6 H 5),6.67(1H,dd,2.1HZ,7.8HZ,C6 H 5),6.54(1H,dd,2.1HZ,8.1HZ,C6 H 5),6.49(1H,d,2.1HZ,C6 H 5),5.09(1H,m,NH),4.20(m,-NH-CH-COO-),3.914.14(m,-COOCH 2-),3.83(3H,s,-OCH 3)2.912.97(m,CH 2),2.68(m,CH),2.59(m,CH),2.53,2.61(m,CH 2),1.45(3H,s,CH 3)。
实施例24-(4-(3,4-二甲氧苯甲基)-2-羰基)四氢呋喃甲基-2-甲氧基苯酚2-(N-叔丁氧羰基)氨基-丙酸酯(ARG2)的合成。
制备方法同实施例1，所不同用Boc-L-丙氨酸，得到化合物ARG2。
白色固体，产率81%。1H-NMR(CDCl3,300MHz)δppm:6.98(1H,d,7.8HZ,C6 H 5),6.79(1H,d,8.1HZ,C6 H 5),6.76(1H,d2.1HZ,C6 H 5),6.70(1H,dd,2.1HZ,7.8HZ,C6 H 5),6.56(1H,dd,2.1HZ,8.1HZ,C6 H 5),6.51(1H,d,2.1HZ,C6 H 5),5.12(NH)4.61(m,-NH-CH-COO-),3.93,4.21(m,-COOCH 2-),3.86(3H,s,OCH 3),3.83(3H,s,OCH 3),3.76(3H,s,OCH 3),2.973.00(m,CH 2),2.70(m,CH),2.60(m,CH),2.54,2.63(m,CH 2),1.58(3H,s,CH 3),1.47(3H,s,CH 3)。
实施例34-(4-(3,4-二甲氧苯甲基)-2-羰基)四氢呋喃甲基-2-甲氧基苯酚2-(N实施例34-(4-(3,4-二甲氧苯甲基)-2-羰基)四氢呋喃甲基-2-甲氧基苯酚2-(N-叔丁氧羰基)氨基-3-甲基丁酸酯(ARG3)的合成。
制备方法同实施例1，所不同用Boc-L-缬氨酸，得到化合物ARG3。
白色固体，产率83%。1H-NMR(CDCl3,300MHz)δppm:6.98(1H,d,8.1HZ,C6 H 5),6.76(1H,d,2.1HZ,C6 H 5),6.79(1H,d,8.4HZ,C6 H 5),6.70(1H,dd,1.8HZ,8.1HZ,C6 H 5),6.56(1H,dd,1.2HZ,8.4HZ,C6 H 5),6.51(1H,d,2.1HZ,C6 H 5),5.12(NH),4.54(m,-NH-CH-COO-),3.94,4.21(m,-COOCH 2-)，3.86(3H,s,OCH 3),3.83(3H,s,OCH 3),3.76(3H,s,OCH 3),2.99,3.03(m,CH 2),2.70(m,CH)，2.54,2.63(m,CH 2),2.60(m,CH),2.44(m,CH),1.48(3H,s,CH 3),1.11(d,CH 3)。
实施例44-(4-(3,4-二甲氧苯甲基)-2-羰基)四氢呋喃甲基-2-甲氧基苯酚4-甲基-2-(N-叔丁氧羰基)氨基-戊酸酯(ARG4)的合成。
制备方法同实施例1，所不同用Boc-L-亮氨酸，得到化合物ARG4。
白色固体，产率71%。1H-NMR(CDCl3,300MHz)δppm:6.99(1H,d,8.1HZ,C6 H 5),6.78(1H,d,8.4HZ,C6 H 5),6.75(1H,d,2.1HZ,C6 H 5),6.70(1H,dd,1.8HZ,8.1HZ,C6 H 5),6.55(1H,dd,1.2HZ,8.4HZ,C6 H 5),6.51(1H,d,2.1HZ,C6 H 5),4.99(NH),4.59(m,-NH-CH-COO-),3.94,4.21(m,-COOCH 2-),3.86(3H,s,OCH 3),3.83(3H,s,OCH 3),3.75(3H,s,OCH 3),2.97,3.00(m,CH 2),2.69(m,CH),2.54,2.63(m,CH 2),2.60(m,CH),1.66,1.87(m,CH 2),1.49(m,CH),1.47(3H,s,CH 3),1.03(3H,s,CH 3)。
实施例54-(4-(3,4-二甲氧苯甲基)-2-羰基)四氢呋喃甲基-2-甲氧基苯酚3-甲基-2-(N-叔丁氧羰基)氨基-戊酸酯(ARG5)的合成。
制备方法同实施例1，所不同用Boc-L-异亮氨酸，得到化合物ARG5。
白色固体，产率80%。1H-NMR(CDCl3,300MHz)δppm:6.96(1H,d,7.8HZ,C6 H 5),6.78(1H,d,8.4HZ,C6 H 5),6.75(1H,d,2.1HZ,C6 H 5),6.69(1H,dd,1.8HZ,8.1HZ,C6 H 5),6.55(1H,dd,2.1HZ,8.4HZ,C6 H 5),6.50(1H,d,2.1HZ,C6 H 5),5.13(NH),4.20(m,-NH-CH-COO-),3.924.52(m,-COOCH 2-),3.85(3H,s,OCH 3),3.82(3H,s,OCH 3),3.74(3H,s,OCH 3),2.97,3.02(m,CH 2),2.68(m,),2.53,2.61(m,CH 2),2.57(m,CH),2.47(m,CH),1.46(3H,s,CH 3),1.43(m,CH 2),1.07(3H,d,6.9HZ,CH 3),0.99(3H,s,CH 3)。
实施例6乙酰胆碱酯酶抑制活性测试
（1）药品与试剂
乙酰胆碱酶（AChE,Sigma公司），200mmol/L、pH8.0的磷酸缓冲盐溶液（PBS），1mmol/L5,5-二硫代-2-硝基苯甲酸（dithiobis-nitrobenzoicacid，DTNB）溶液（Sigma公司）（用200mmol/L，pH8.0PBS配制），1mmol/L硫代乙酰胆碱（Acetylthiocholine,ATCI，Sigma公司,用200mmol/L，pH8.0PBS配制），阳性对照石杉碱甲（中国药品生物制品检定所），甲醇。
（2）实验方法
参照文献（Choo,C.Y.;Hirasawa,Y.;Karimata,C.;Koyama,K.;Sekiguchi,M.;Kobayashi,J.;Morita,H.Bioorg.Med.Chem.2007,15,1703.）的方法做适当改进。化合物体外AChE抑制活性检测对照品为石杉碱甲。样品及对照品用DMSO配成8mg/ml和1mg/ml。酶标仪法测样品的体外AChE抑制活性的具体步骤如下：样品按表1在96孔板中依次加入待测液20ul，140ulPH=8.0的PBS,加15ul1mMAChE溶液，混合，震荡，4℃培养20min,然后加10ul1mM的DTNB，最后加10ul1mM的ATCI开始反应，37℃培养20min，样品做三个平行，在波长405nm下检测OD值。阴性是用DMSO代替待测液，阴性对照是在阴性中不加AChE，样品对照是在样品中不加AChE。按如下公式计算抑制率：
抑制率/%=[(OD阴性-OD阴性对照)-(OD样品-OD样品对照)]/(OD阴性-OD阴性对照)*100%
化合物ARG、ARG1-5及对照品石杉碱甲的活性测定：
将ARG及ARG1-5分别溶于DMSO中，配成8mg/ml，再分别稀释成1.6mg/ml,0.32mg/m,0.064mg/ml,0.0128mg/ml,0.0256mg/ml；石杉碱甲溶于DMSO中，配成1mg/ml，再分别稀释为0.1mg/ml、0.01mg/ml、0.001mg/ml、0.0001mg/ml、0.00001mg/ml，测OD值，计算抑制率（表2、表3），使用SPSS16.0软件计算其IC50值（表4）。
表2ARG、ARG1-5不同浓度的AChE抑制活性结果
表3石杉甲不同浓度的AChE抑制活性结果
表4ARG、ARG1-5及石杉碱甲的抑制IC50值

Claims (2)

1.一种乙酰胆碱酯酶抑制剂，具有增强老年痴呆病人记忆力的作用，其特征在于：该抑制剂为具有通式I结构的化合物，
通式I
其中，式I中的R为
Boc-L-Gly,Boc-L-Ala,Boc-L-Val,Boc-L-Leu,Boc-L-Ile氨基酸侧链。
2.权利要求1所述的抑制剂具有明显的抑制乙酰胆碱酯酶活性的作用。
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