CN108295074B - 一种噻二唑并三嗪类化合物在制备单胺氧化酶抑制剂中的用途 - Google Patents

一种噻二唑并三嗪类化合物在制备单胺氧化酶抑制剂中的用途 Download PDF

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CN108295074B
CN108295074B CN201810103226.2A CN201810103226A CN108295074B CN 108295074 B CN108295074 B CN 108295074B CN 201810103226 A CN201810103226 A CN 201810103226A CN 108295074 B CN108295074 B CN 108295074B
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monoamine oxidase
compound
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thiadiazolo
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CN108295074A (zh
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孔德信
王栋
左之利
王雅琪
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Huazhong Agricultural University
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    • A—HUMAN NECESSITIES
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
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Abstract

本发明公开了结构如式(Ⅰ)所示的噻二唑并三嗪类化合物在制备单胺氧化酶抑制剂中的用途，经过体外酶活性实验测试，该类化合物对单胺氧化酶‑B具有良好的抑制活性，从而为开发新型MAO抑制剂提供参考和启发新思路。

Description

一种噻二唑并三嗪类化合物在制备单胺氧化酶抑制剂中的 用途
技术领域
本发明属于医药技术领域，涉及一种噻二唑并三嗪类化合物的制药新用途，尤其是在制备单胺氧化酶抑制剂中的新用途。
背景技术
单胺类神经递质包括去甲肾上腺素、肾上腺素、多巴胺和五羟色胺，是神经递质中最重要的一类。这些神经递质及其代谢产物的表达水平与诸多疾病密切相关，影响着人类的注意力、情感和行为。例如，人体内5-HT浓度的降低会引起抑郁症；神经系统中多巴胺浓度的降低会诱发帕金森综合症和阿尔茨海默症。这些单胺类神经递质的降解调节主要通过单胺氧化酶(monoamine oxidase,MAO)来完成，因此，抑制MAO的活性就能够提高单胺类神经递质的表达水平并减少有害的胺代谢产物的生成。由此可见，MAO是一类重要的药物发现靶标。
单胺氧化酶是一类重要的氧化还原酶。人体内存在两种MAO亚型，MAO-A和MAO-B。这两个亚型之间具有高度的相似性，但是它们对底物的选择性有较大的差别。MAO-A通常催化五羟色胺、去甲肾上腺素、肾上腺素。MAO-B亚型则对苯甲胺、苯乙胺等神经递质具有高度的亲和力。由于它们底物的选择性不同，因此目前临床上使用这两个亚型的抑制剂治疗不同的疾病。例如MAO-A抑制剂主要用于治疗抑郁症、社交恐惧症、疼痛、偏头痛；而MAO-B抑制剂主要用于治疗阿尔茨海默症和帕金森综合症。
发明内容
本发明的目的是提供一种噻二唑并三嗪类化合物在制备单胺氧化酶抑制剂中的新用途。
为了实现上述目的，本发明采用了如下技术方案：
所述噻二唑并三嗪类化合物的结构式如下：
Figure BDA0001566953370000021
其中，R1为卤素、H或甲基；
R2为H或甲基。
下表列出的是五种具体化合物。
表1化合物种类及其取代基
No. R1 R2
1 Br H
2 Cl H
3 F H
4 CH<sub>3</sub> CH<sub>3</sub>
5 H H
本发明首次发现并通过活性测试，验证了式(Ⅰ)所示的噻二唑并三嗪类化合物具有单胺氧化酶抑制活性，尤其是对单胺氧化酶MAO-B的抑制活性，因此提供了该类化合物作为单胺氧化酶抑制剂的新用途，有望被开发成阿尔茨海默症、帕金森综合症等疾病的治疗药物。
具体实施方式
下面用本发明的下列实施例对本发明的实质性内容进行详细叙述，但并不以此来限定本发明。实施例中所使用到的化合物均可购自荷兰specs公司(http://www.specs.com)，均为specs公司化合物库中的化合物。
实施例1：本发明化合物对单胺氧化酶抑制剂活性的测试
1.实验试剂
本发明化合物、MAO-A(Active Motif,Cat.No.31502)、MAO-B(Active Motif,Cat.No.31503)、氯吉兰Clorgyline(Sigma,Cat.No.M3778)、司里吉兰R(-)-deprenyl(Abcam,Cat.No.ab120604)、384孔板(from Perkin Elmer,Cat.No.6007299)
2.实验方法
1)用100％的DMSO将本发明化合物溶解至100mM，在多孔板中加入HEPES位缓冲液，将化合物转移至多孔板中，使DMSO的浓度降低至1％。
2)将酶和底物分别溶解到缓冲溶液中，移入10μL的底物溶液，启动反应，静置60分钟，加入20μL的荧光素，混匀，室温下静置20分钟，测量并记录荧光信号的相对亮度，分别在10个浓度条件下测定化合物对酶的百分抑制率。
3)实验中，分别以氯吉兰、司里吉兰为对照，实验重复2-3次，分别计算最大荧光值和最小荧光值及其标准差，以最大荧光值和最小荧光值之比计算每一组多孔版数据的可靠性。
3.数据处理
1)使用Excel按照那个公式一计算每个化合物的抑制率
Inh％＝(Max-Signal)/(Max-Min)*100 Equation(1)
2)采用GraphPad Prism5将各个化合物在10个浓度条件下所得的酶的百分抑制率按照公式二进行拟合，计算化合物的IC50值，式中Y和X分别是百分抑制率和化合物浓度。
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*Hill Slope)) Equation(2)
4.实验结果
本发明化合物经单胺氧化酶抑制活性筛选，并测得相应半数有效抑制浓度(IC50)。选自式(Ⅰ)的5个化合物的化学结构及其对单胺氧化酶的抑制率和IC50活性如下表所示。
表2化合物对单胺氧化酶的抑制活性
No. MAOA％ A_IC50/μM MAOB％ B_IC50/μM
1 46 >50 85 0.9
2 51 >50 87 0.68
3 4 >100 91 0.79
4 29 >100 93 0.4
5 34 >100 76 1.2
从上表结果可以看出，本发明化合物1-5均对MAO-B表现出良好的抑制活性，而对MAO-A的抑制活性很差。

Claims (1)

1.结构如式(Ⅰ)所示的化合物在制备单胺氧化酶-B抑制剂中的用途，
Figure FDA0002312419520000011
R1为卤素、H或甲基；
R2为H或甲基。
CN201810103226.2A 2018-02-01 2018-02-01 一种噻二唑并三嗪类化合物在制备单胺氧化酶抑制剂中的用途 Expired - Fee Related CN108295074B (zh)

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