CN107898786A - 取代芳酰胺类化合物在制备单胺氧化酶抑制剂中的应用 - Google Patents

取代芳酰胺类化合物在制备单胺氧化酶抑制剂中的应用 Download PDF

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CN107898786A
CN107898786A CN201711268288.0A CN201711268288A CN107898786A CN 107898786 A CN107898786 A CN 107898786A CN 201711268288 A CN201711268288 A CN 201711268288A CN 107898786 A CN107898786 A CN 107898786A
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王宇光
朱冰春
吴中礼
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Zhejiang University of Technology ZJUT
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Abstract

本发明公开了取代芳酰胺类化合物在制备单胺氧化酶抑制剂中的应用，所述取代芳酰胺类化合物的结构式如式(III)所示：式(III)中，n为0或1，R8为或其中R9为氨基，R10为C1‑C4的烷基。

Description

取代芳酰胺类化合物在制备单胺氧化酶抑制剂中的应用
(一)技术领域
本发明涉及取代芳酰胺类化合物在制备单胺氧化酶抑制剂中的应用。
(二)背景技术
帕金森病(Parkinson’s disease，PD)是一种常见的神经系统变性疾病和运动障碍慢性疾病，常合并有行为或心理的异常，严重影响患者的生活质量(Dauer W，Przedborski S，Parkinson's disease:mechanisms and models.Neuron,2003,39(6):889-909.)。每年4月11日是世界卫生组织确定的世界帕金森病日。当前全球有一半以上的帕金森病人在中国，总数超过200万。我国60岁以上的老年人发病率超过1％，但从近年来发病及就诊的患者年龄来看，正呈现低龄化趋势，“青少年型帕金森病”患者占总人数的10％。抑郁症是一种常见的精神病理状态或综合征，其程度可以从轻度的忧伤到重度的绝望、自杀企图等；其引发的主要原因是中枢去甲肾上腺素和5-羟色胺、多巴胺这些特定的神经递质的水平过低及其受体功能低下。它有发病率高和发病年龄广泛的特点，给人们的工作和生活造成了严重的影响。
单胺氧化酶抑制剂是临床上用于治疗多种疾病的一类药物：其中单胺氧化酶A抑制剂主要用于治疗抑郁症，而单胺氧化酶B抑制剂主要用于治疗帕金森病。单胺氧化酶抑制剂可分为可逆性和不可逆性抑制剂，像早期的不可逆性抑制剂闷可乐、苯乙肼这些药物有很强的副作用。因此，寻求抑制性强、选择性高、毒副作用小的单胺氧化酶抑制剂已成为改领域的热点问题。
单胺氧化酶(Monoamine oxidase,MAO,EC1.4.3.4)全名为单胺氧化还原酶，它在大脑和周围神经组织中催化一些生物体产生的胺，氧化脱氨产生过氧化氢。根据底物选择性和对抑制剂的灵敏度，单胺氧化酶被分为A和B两种。单胺氧化酶A对底物血清素(52HT)、去甲肾上腺素(NE)、多巴胺(DA)具有高亲和性；而单胺氧化酶B则对苯乙基胺(PEA)和苯甲胺具有高亲和性。研究表明它与人的多种行为和疾病有关，如抑郁症、帕金森氏综合症等(Brunner H G,Nelen M,Breakefield X O，et al.Abnormal behavior associated witha point mutation in the structural gene for monoamine oxidase A.Science,1993,262(5133):578-580)。
本发明设计与合成了吡啶芳酰胺类化合物，经生物活性检测发现它们具有极好的单胺氧化酶抑制活性，是一类高活性的单胺氧化酶抑制剂。
(三)发明内容
本发明的目的是提供取代芳酰胺类化合物在制备单胺氧化酶抑制剂中的应用。
本发明采用如下技术方案：
本发明提供了取代芳酰胺类化合物在制备单胺氧化酶抑制剂中的应用，所述取代芳酰胺或含氮杂环类化合物的结构式如式(III)所示：
式(III)中，n为0或1，R8为其中R9为氨基，R10为C1-C4的烷基。
本发明中，所述的C1～C4烷基可以是甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基。所述的C1～C4烷氧基可以是甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基。
进一步，R9为p-氨基。
进一步，R10为甲基。
本发明具体优选式(III)选自下列之一：
上述化合物中，化合物(III-1)-(III-2)对单胺氧化酶A有较强抑制活性，特别是化合物(III-2)有极强的抑制活性；化合物(Ⅲ-1)、(Ⅲ-2)对单胺氧化酶B有较强抑制活性。
本发明所述的取代芳酰胺类化合物均可按照现有文献公开的方法进行制备。
与现有技术相比，本发明的有益效果在于本发明提供的取代芳酰胺类化合物都具有良好的的单胺氧化酶抑制活性。
(四)具体实施方式
下面结合具体实施例对本发明进行进一步描述，但本发明的保护范围并不仅限于此：
本发明实施例中使用的Ru/C购自沈阳展宇科技开发有限公司，型号为REASB，其中Ru含量为5％(g/g)。
实施例1N-(3,4-二甲氧基苯乙基)-3-(三氟甲基)苯甲酰胺(Ⅰ-1)的合成
将0.93g(5mmol)化合物(IX-1)、0.91g(5mmol)化合物物(X-1)、Ru/C催化剂(0.05g)，和20mL四氢呋喃(THF)加入到反应瓶中，30℃下敞口搅拌反应20小时，TLC监测反应，待反应完全，将反应液过滤，滤渣用二氯甲烷洗涤两次，合并滤液，用二氯甲烷和水体系萃取，收集有机相，干燥，浓缩，层析柱分离，制得N-(3,4-二甲氧基苯乙基)-3-(三氟甲基)苯甲酰胺(I-1)。
化合物(I-1)的表征数据如下：
1H NMR(600MHz,CDCl3):δ7.98(s,1H),7.88(d,J＝7.8Hz,1H),7.74(d,J＝7.8Hz,1H),7.55-7.52(t,J＝7.8Hz,1H),6.83(d,J＝7.8Hz,1H),6.77-6.74(m,2H),6.57(s,1H),3.87(d,6H),3.68(t,J＝6.6Hz,2H),2.92-2.90(t,J＝6.6Hz,2H)；GC-MS(EI):m/z 353[M+].
实施例2N-(4-4-氨基苄基)-6-氯烟酰胺(Ⅲ-1)的合成
实验方法同实施例1，这里就不再赘述。化合物(Ⅲ-1)的表征数据如下：
1H NMR(600MHz,CDCl3)δ8.70(d,J＝8.4Hz,1H),8.07-8.05(m,1H),7.37(d,J＝8.4Hz,1H),7.11(d,J＝7.8Hz,2H),6.64-6.63(t,2H),6.59(s,1H),4.48(d,J＝5.4Hz,2H),3.74(s,2H)；GC-MS(EI):m/z 261[M+].
实施例3 6-氯-N-(6-甲基吡啶-2-基)烟酰胺(Ⅲ-2)的合成
实验方法同实施例1，这里就不再赘述。化合物(Ⅲ-2)的表征数据如下：
1H NMR(600MHz,CDCl3)δ9.04(d,1H),8.31-8.29(m,1H),7.54-7.52(m,2H),7.35(d,1H),6.50-6.49(m,2H),2.55(s,3H)；13C NMR(150MHz,CDCl3)δ171.2,156.1,153.4,151.5,149.6,142.6,139.9,130.4,123.5,111.9,19.5；GC-MS(EI):m/z 247[M+].
实施例4所合成化合物单胺氧化酶抑制活性的测试
(1)样品配制
将实施例2～3制备的化合物(Ⅲ-1)～(Ⅲ-2)溶于二甲基亚砜(DMSO)中，分别配成0.5，1，10，25，50，100，200，400，800，1600μmol/L浓度梯度的样品液，记为样品1～2。
(2)所合成化合物对单胺氧化酶-A抑制活性测试检测方法
分别向2份装有371μL硼酸缓冲液(pH＝8.4)的EP管中加入15μL单胺氧化酶-A和10μL步骤(1)配制的样品1～2混合，再将混合物在38℃水浴中反应3h，然后分别向上述22份EP管中加入2μL下式所示的探针7-(3-氨基丙氧基)-4-甲基香豆素(20mmol/ml)和2μL的牛血清蛋白(BSA，20mg/mL)，并各个EP管置于38℃水浴中继续反应1.5h。与其同时需检测未加抑制剂的MAO-A的酶活，即向装有381μL硼酸缓冲液(pH＝8.4)的EP管中加入15μL单胺氧化酶-A(MAO-A)，在38℃水浴中反应3h，再加入2μL探针(20mmol/ml)和2μL的BSA同样也在38℃水浴中反应1.5h。
最后在每个EP管(微量离心管)中取出100μL加入96孔板中并用全功能荧光分光光度计(λex/λem＝365/460nm)(spectraMax M,美国分子仪器公司)检测样品。根据所测的荧光值计算样品1～2的IC50，化合物(Ⅲ-1)～(Ⅲ-2)对单胺氧化酶-A活性抑制测试结果见表1。
化合物的抑制效果用半数抑制浓度(IC50)来表示。IC50是指“反应”被抑制一半时抑制剂的浓度，化合物抑制能力越强，该数值越低。
IC50可以用以下方法计算：
1)检测并计算只加酶与探针缓冲液的平均荧光强度(FM)；
2)计算含有不同浓度梯度抑制剂的各组分酶的荧光强度(要扣除背景值)；
3)根据不同浓度梯度抑制剂的各组分酶的荧光强度做抑制剂的浓度(C)与荧光强度(F)
之间关系的直线回归，建立得到方程：F＝aC+b(通过回归直线确定方程系数a和截踞b)；
4)根据方程，求F＝1/2FM下的对应的抑制剂浓度，即可求出抑制率为50％时的抑制剂浓度，即为IC50
(3)所合成化合物对单胺氧化酶-B抑制活性测试
将单胺氧化酶A换成单胺氧化酶B，样品配制及操作同步骤(2)，结果如表1所示。
表1实施例2～3制备的化合物(Ⅲ-1)～(Ⅲ-2)对单胺氧化酶A和B的抑制活性[a]
[a]抑制剂的活性用IC50表示，每个样品做5个浓度梯度，每组3个平行；[b]对酶的选择性用SI表示，SI:selectivity index＝IC50(MAO-A)/IC50(MAO-B)；[c]ND表示活性很小。
从表1可以看出，化合物(III-1)-(III-2)对单胺氧化酶A有较强抑制活性，特别是化合物(III-2)有极强的抑制活性；化合物(Ⅲ-1)、(Ⅲ-2)对单胺氧化酶B有较强抑制活性。

Claims (5)

1.取代芳酰胺类化合物在制备单胺氧化酶抑制剂中的应用，其特征在于：所述取代芳酰胺类化合物的结构式如式(III)所示：
式(III)中，n为0或1，R8为或其中R9为氨基，R10为C1-C4的烷基。
2.如权利要求1所述的应用，其特征在于：R9为p-氨基，R10为甲基。
3.如权利要求1所述的应用，其特征在于：式(III)选自下列之一：
4.如权利要求3所述的应用，其特征在于：化合物(III-1)-(III-2)在制备单胺氧化酶A抑制剂中的应用。
5.如权利要求3所述的应用，其特征在于：化合物(Ⅲ-1)、(Ⅲ-2)在制备单胺氧化酶B抑制剂中的应用。
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