新型吡唑并[3,4-d]嘧啶-4-酮类衍生物的结构表征和镇痛活性

doi:10.11938/cjmr20222995

波谱学杂志 ›› 2023, Vol. 40 ›› Issue (1): 1-9.doi: 10.11938/cjmr20222995

新型吡唑并[3,4-d]嘧啶-4-酮类衍生物的结构表征和镇痛活性

翟重钢^1,²,汪鹏程^1,²,单玉宝^1,²,兰昱^3,^#(),胡锐^1,^2,^*(),杨运煌^1,²

1.中国科学院生物磁共振分析重点实验室，波谱与原子分子物理国家重点实验室，武汉磁共振中心（中国科学院精密测量科学与技术创新研究院），湖北武汉 430071
2.中国科学院大学，北京 100049
3.武汉大学人民医院药学部，湖北武汉 430060

收稿日期:2022-04-07 出版日期:2023-03-05 在线发表日期:2022-05-12
通讯作者: 兰昱,胡锐 E-mail:lanthane@whu.edu.cn.;hurui@wipm.ac.cn
基金资助:
国家自然科学基金资助项目(21991080);国家自然科学基金资助项目(81602946);湖北省自然科学基金资助项目(2016CFB258)

Structure Characterization and Analgesic Activity of Novel Pyrazolo[3,4-d]pyrimidin-4-one Derivatives

ZHAI Chonggang^1,²,WANG Pengcheng^1,²,SHAN Yubao^1,²,LAN Yu^3,^#(),HU Rui^1,^2,^*(),YANG Yunhuang^1,²

1. CAS Key Laboratory of Magnetic Resonance in Biological System, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Center for Magnetic Resonance in Wuhan, Innovation Academy for Precision Measurement Science and Technology, Chinese Academy of Sciences, Wuhan 430071, China
2. University of Chinese Academy of Sciences, Beijing 100049, China
3. Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan 430060, China

Received:2022-04-07 Published:2023-03-05 Online:2022-05-12
Contact: LAN Yu,HU Rui E-mail:lanthane@whu.edu.cn.;hurui@wipm.ac.cn

1. 附件材料.pdf(1509KB)

摘要/Abstract

摘要：

本文以2-氰基-3-乙氧基丙烯酸乙酯与3,4-二甲基苯肼为原料，通过多步反应合成了三种新型吡唑并[3,4-d]嘧啶-4-酮类衍生物（A~C），通过核磁共振（NMR，包括¹H NMR、¹³C NMR）和液相色谱-质谱联用（LC-MS）技术表征确证了其结构，并完整归属了三种化合物的¹H NMR数据．对所合成的化合物1-(3,4-二甲基苯基)-6-甲基-5-[3-(哌啶-1-基)丙氧基]-1,5-二氢-4H-吡唑并[3,4-d]嘧啶-4-酮（A），通过小鼠脑部质谱成像和福尔马林实验进行了初步的体内镇痛活性评价，我们发现化合物A能透过血脑屏障，并产生显著且剂量依赖的镇痛活性．本研究为以吡唑并[3,4-d]嘧啶-4-酮为骨架的镇痛药物的研发提供了结构和体内活性的基础研究数据．

关键词: 吡唑并[3,4-d]嘧啶-4-酮, ¹H NMR, ¹³C NMR, 质谱成像, 镇痛活性

Abstract:

Three compounds of novel pyrazolo[3,4-d]pyrimidin-4-one derivatives (A~C) were synthesized through a multi-step reaction using ethyl-2-cyano-3-ethoxyacrylate and 3,4-dimethylphenylhydrazine. The structures of these compounds were identified by nuclear magnetic resonance (NMR, i.e., ¹H NMR, ¹³C NMR), and liquid chromatography-mass spectrum (LC-MS), and the ¹H NMR signals of each compound were fully assigned. The in vivo analgesic activity of synthesized compound A was preliminarily evaluated through mass spectrometry brain imaging and formalin induced pain model in mice. The imaging data and results showed that compound A could cross the blood-brain barrier and penetrate into the brain of mice, and produce a dose-dependent analgesic activity. This study provided a piece of fundamental research data on structural and in vivo activity for developing anti-pain drugs based on pyrazolo[3,4-d]pyrimidin-4-one scaffold.

Key words: pyrazolo[3,4-d]pyrimidin-4-one, ¹H NMR, ¹³C NMR, mass spectrometry imaging, analgesic activity

中图分类号:

O482.53

翟重钢,汪鹏程,单玉宝,兰昱,胡锐,杨运煌. 新型吡唑并[3,4-d]嘧啶-4-酮类衍生物的结构表征和镇痛活性[J]. 波谱学杂志, 2023, 40(1): 1-9.

ZHAI Chonggang,WANG Pengcheng,SHAN Yubao,LAN Yu,HU Rui,YANG Yunhuang. Structure Characterization and Analgesic Activity of Novel Pyrazolo[3,4-d]pyrimidin-4-one Derivatives[J]. Chinese Journal of Magnetic Resonance, 2023, 40(1): 1-9.

图/表 8

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参考文献 14

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编号	δ_H	氢原子个数	谱峰裂分(J/Hz)	归属
1	1.39	2	p (5.9)	H-20
2	1.49	4	p (5.5)	H-19, H-21
3	1.89	2	p (6.6)	H-14
4	2.28	3	s	H-16
5	2.31	3	s	H-17
6	2.33	4	t (6.8)	H-18, H-22
7	2.43	2	t (7.0)	H-15
8	2.62	3	s	H-12
9	4.25	2	t (6.2)	H-13
10	7.31	1	d (8.1)	H-2
11	7.71	1	dd (8.1/2.3)	H-1
12	7.74	1	d (2.3)	H-5
13	8.31	1	s	H-9

编号	δ_H	氢原子个数	谱峰裂分(J/Hz)	归属
1	1.91	2	p (6.5)	H-14
2	2.28	3	s	H-16
3	2.31	3	s	H-17
4	2.38	4	t (6.8)	H-18, H-21
5	2.48	2	t (7.0)	H-15
6	2.62	3	s	H-12
7	3.58	4	t (4.5)	H-19, H-20
8	4.27	2	t (6.3)	H-13
9	7.31	1	d (8.1)	H-2
10	7.71	1	dd (8.1/2.3)	H-1
11	7.75	1	d (2.3)	H-5
12	8.31	1	s	H-9

编号	δ_H	氢原子个数	谱峰裂分(J/Hz)	归属
1	1.95	2	p (6.6)	H-14
2	2.28	3	s	H-16
3	2.31	3	s	H-17
4	2.52	2	t (7.0)	H-15
5	2.55	4	t (6.8)	H-18, H-21
6	2.64	3	s	H-12
7	3.13	4	t (5.5)	H-19, H-20
8	4.29	2	t (6.2)	H-13
9	6.77	1	t (7.3)	H-25
10	6.93	2	d (8.1)	H-23, H-27
11	7.21	2	dd (8.7/7.2)	H-24, H-26
12	7.30	1	d (8.2)	H-2
13	7.71	1	dd (8.2/2.3)	H-1
14	7.75	1	d (2.3)	H-5
15	8.31	1	s	H-9

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新型吡唑并[3,4-d]嘧啶-4-酮类衍生物的结构表征和镇痛活性

Structure Characterization and Analgesic Activity of Novel Pyrazolo[3,4-d]pyrimidin-4-one Derivatives

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