CN113248518A - 嘧啶哌嗪类衍生物及其制备方法与应用 - Google Patents
嘧啶哌嗪类衍生物及其制备方法与应用 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 16
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- 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
- C07D513/04—Ortho-condensed systems
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Abstract
本发明提供了一种嘧啶哌嗪类衍生物，具有如下通式I所示的结构。本发明还涉及该类衍生物的制备方法及其作为CHIKV抑制剂在制备抗基孔肯雅热药物中的应用。
Description
技术领域
本发明涉及一种衍生物及其制备方法，具体涉及嘧啶哌嗪类衍生物的制备及其在抗 CHIKV药物领域的应用，属于有机合成与医药应用技术领域。
背景技术
基孔肯雅热(Chikungunya fever，CHIKF)是由基孔肯雅病毒(Chikungunyavirus，CHIKV) 引起的急性传染性疾病，以发热、皮疹及关节疼痛为主要特征。尽管CHIKV致死率很低，但在蚊媒密度较高的地区容易形成大规模的流行和暴发，是21世纪初严重影响人类公共卫生安全的虫媒传染病之一。目前，针对CHIKV的研究主要集中于疫苗领域，包括灭活病毒疫苗、减毒活病毒疫苗、嵌合病毒疫苗、重组病毒疫苗、重组亚单位疫苗以及最近出现的一种类病毒疫苗。尽管针对CHIKV疫苗的研究正在不断进行，但是到目前为止依旧没有取得突破性进展，全世界仍然面临着CHIKV感染迅速蔓延的威胁。因此，针对开发安全有效、具有临床应用价值的抗CHIKV药物显得尤为重要。
为发现新一代CHIKV抑制剂，本发明公开了一类全新结构的嘧啶哌嗪类CHIKV抑制剂，现有技术中未见相关报道。
发明内容
本发明提供了嘧啶哌嗪类衍生物及其制备方法，本发明还提供了上述化合物的部分活性筛选结果及其制药用途。
本发明的技术方案如下：
一、嘧啶哌嗪类衍生物
本发明的嘧啶哌嗪类衍生物，具有如下通式I所示的结构：
其中，
R为取代苯环、取代芳杂环、烷烃；所述的取代基选自卤素、甲基、硝基、氨基、甲氧基；
A环为苯环、六元杂环、五元杂环。
根据本发明优选的，通式I中，R为卤代苯基、吡啶基、乙基、丙基、二甲胺基；A环为噻吩环、呋喃环、吡咯环、噻唑环、苯环。
进一步优选的，嘧啶哌嗪类衍生物，是下列之一：
二、嘧啶哌嗪类衍生物的制备方法
本发明嘧啶哌嗪类衍生物的制备方法，以2,4-二氯稠环并[3,2-d]嘧啶为初始原料，与对甲苯胺反应得中间体2，再与4-Boc-哌嗪经亲核取代反应制得3；3在三氟乙酸中脱去Boc 保护基团得到白色中间体4，最后再与各种不同取代的磺酰氯反应得到目标产物5(a-c)；
合成路线如下：
反应试剂与条件：i)对甲苯胺，K2CO3，DMF，室温；ii)4-Boc-哌嗪，K2CO3，DMF， 110℃；iii)三氟乙酸、二氯甲烷，室温；iv)取代磺酰氯，三乙胺，二氯甲烷，室温。
其中，R同上述通式I中所述。
本发明嘧啶哌嗪类衍生物的制备方法，具体步骤如下：
(1)将对甲基苯胺和碳酸钾置于二甲基甲酰胺溶液中，室温搅拌，然后加入2,4-二氯稠环并[3,2-d]嘧啶，继续室温搅拌；此时有大量白色固体生成，慢慢地向其中加入冰水，过滤，真空干燥，DMF-H2O中重结晶得到中间体2；
(2)称取中间体2、4-Boc-哌嗪与碳酸钾置于二甲基甲酰胺中，加热回流；待反应冷却到室温以后，慢慢地将反应液滴加到水溶液中，搅拌，有大量的黄色固体生成；过滤，干燥得粗品3；将3溶于二氯甲烷中，然后慢慢地向其中加入三氟乙酸，室温搅拌；向反应液中加入水，用饱和的碳酸氢钠溶液调pH为9，二氯甲烷萃取，饱和氯化钠溶液洗涤，分取有机层，无水硫酸钠干燥；然后进行快速柱层析分离得中间体4；
(3)将化合物4置于二氯甲烷中，冰浴条件下依次加入三乙胺与取代的苯磺酰氯，转移至室温，搅拌反应；减压蒸出溶剂，然后向残留底物中加入饱和食盐水，乙酸乙酯洗涤，分取有机层，无水硫酸钠干燥，过滤，浓缩；快速柱层析分离得到目标化合物，进而在乙酸乙酯-石油醚体系中重结晶得到目标化合物。
所得目标化合物5(a-c)结构见表1。
表1 目标化合物的结构式
三、嘧啶哌嗪类衍生物的应用
活性测试结果表明，嘧啶哌嗪类衍生物是一系列结构新颖的CHIKV抑制剂，3个目标化合物均表现出显著的CHIKV抑制活性，其中，化合物5a(IC50＝2.7μM)活性最优，且细胞毒性较低，说明该类化合物具有进一步研究的价值。
因此，本发明所提供的嘧啶哌嗪类衍生物可作为CHIKV抑制剂用于制备抗基孔肯雅热药物。
一种抗CHIKV的药物组合物，含有上述的嘧啶哌嗪类衍生物及其药学上可接受的盐与药用辅料，制成不同剂型的药物。
具体实施方式
下面结合实施例对本发明做进一步说明，所有目标化合物的编号与表1相同，所述百分比数均为质量百分比。
实施例1：中间体2-氯-N-(对甲苯基)噻吩[2,3-d]嘧啶-4-胺(2a)的制备
称取对甲基苯胺(0.15g,1mmol)和碳酸钾(0.17g,1.2mmol)于50mL圆底烧瓶中，加入5mLN,N-二甲基甲酰胺溶液溶解，室温搅拌15min，然后加入2,4-二氯噻吩并[3,2-d]嘧啶(0.21g,1mmol)继续室温搅拌2h(TLC监测反应完毕)。此时有大量白色固体生成，慢慢地向其中加入25mL冰水，过滤，真空干燥，DMF-H2O中重结晶得到中间体2a。产率： 76％，mp：103-104℃。1H NMR(400MHz,DMSO-d6)δ8.73(s,1H),7.71(d,J＝6.9Hz,1H), 7.55(d,J＝7.1Hz,1H),7.41–7.35(m,2H),7.21(dq,J＝7.6,0.7Hz,2H),2.35(s,3H).ESI-MS: m/z 276.14[M+1]+.C13H10ClN3S(275.03).
实施例2：中间体2-(哌嗪-1-基)-N-(对甲苯基)噻吩并[2,3-d]嘧啶-4-胺(4a)的制备
称取化合物2a(1.0g,3.17mmol)，4-Boc-哌嗪(0.83g,3.80mmol)与碳酸钾(0.87g,6.33 mmol)于50mL圆底烧瓶中，加入5mL的N,N-二甲基甲酰胺溶解，然后加热回流12h。待反应冷却到室温以后，慢慢地将反应液滴加到20mL水溶液中，搅拌，有大量黄色固体生成。过滤，干燥得粗品3。称取3(1.26g,2.53mmol)溶于4mL二氯甲烷中，然后慢慢地向其中加入三氟乙酸(2.22mL,30mmol)，室温条件下搅拌6h(TLC检测反应完毕)。向反应液中加入10mL水，用饱和的碳酸氢钠溶液调pH为9，二氯甲烷萃取(3×5mL)，饱和氯化钠溶液洗涤，分取有机层，无水硫酸钠干燥。然后进行快速柱层析分离得白色固体粉末。产率：81％，mp：156-157℃。1H NMR(400MHz,DMSO-d6)δ8.71(s,1H),7.67(d,J＝7.1Hz,1H), 7.55(d,J＝7.1Hz,1H),7.41–7.35(m,2H),7.21(dq,J＝7.7,0.8Hz,2H),3.71(ddd,J＝13.2, 6.3,3.5Hz,4H),2.78(dt,J＝6.5,3.4Hz,4H),2.35(s,3H),1.81(p,J＝3.2Hz,1H).ESI-MS:m/z 326.18[M+1]+.C17H19N5S(325.14).
实施例3：终产物5a-c的通用制法
称取化合物4(a-c)于10mL二氯甲烷中，冰浴条件下依次加入三乙胺与取代的苯磺酰氯(0.6mmol)，转移至室温，搅拌4-12h(TLC检测反应完毕)。减压蒸出溶剂，然后加入饱和食盐水20mL,乙酸乙酯洗涤(3×10mL)，分取有机层，无水硫酸钠干燥，过滤，浓缩。快速柱层析分离得到目标化合物，进而在乙酸乙酯-石油醚体系中重结晶得到目标化合物。。
2-(4-((4-氯苯基)磺酰基)哌嗪-1-基)-N-(对甲苯基)噻吩并[2,3-d]嘧啶-4-胺(5a). 白色粉末状固体，产率：76％，mp：120-121℃。1H NMR(400MHz,DMSO-d6)δ9.24(s,1H),7.68(d,J＝8.6Hz,2H),7.60(d,J＝8.5Hz,2H),7.52(dd,J＝9.6,7.1Hz,3H),7.08(dd,J＝11.2, 7.1Hz,3H),3.74(t,J＝4.9Hz,4H),2.90(t,J＝5.0Hz,4H),2.22(s,3H).13C NMR(100MHz, DMSO-d6)δ169.56,158.72,155.19,138.76,137.15,134.33,132.37,130.06,129.93,129.41, 121.77,119.84,117.66,110.17,46.11,43.67,20.94.ESI-MS:m/z499.09[M+1]+.C23H22ClN5O2S2 (500.03).
5-(4-(吡啶-3-基磺酰基)哌嗪-1-基)-N-(对甲苯基)噻唑并[4,5-d]嘧啶-7-胺(5b). 白色粉末状固体，产率：79％，mp：139-141℃。1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.86(d,J＝2.3Hz,1H),8.79(d,J＝4.8Hz,2H),8.10(dt,J＝8.1,2.0Hz,1H),7.60(d,J＝8.5Hz, 3H),7.07(d,J＝8.2Hz,2H),3.78(t,J＝5.0Hz,4H),2.99(t,J＝5.0Hz,4H),2.21(s,3H).13C NMR(100MHz,DMSO-d6)δ164.60,158.76,154.29,153.62,148.26,146.92,136.87,136.13, 132.47,132.30,129.31,125.29,124.97,121.78,46.00,43.81,20.94.ESI-MS:m/z 468.09[M+1]+. C21H21N7O2S2(467.57).
5-(4-(吡啶-3-基磺酰基)哌嗪-1-基)-N-(对甲苯基)噻唑并[5,4-d]嘧啶-7-胺(5c). 白色固体粉末，产率：73％，mp：126-127℃。1H NMR(400MHz,DMSO-d6)δ9.68(s,1H),8.86 (d,J＝2.3Hz,1H),8.79(d,J＝4.9Hz,2H),8.10(dt,J＝8.1,2.0Hz,1H),7.59(t,J＝7.3Hz,3H), 7.08(d,J＝8.2Hz,2H),3.78(t,J＝5.1Hz,4H),2.99(t,J＝4.8Hz,4H),2.21(s,3H).13C NMR (100MHz,DMSO-d6)δ164.60,158.76,154.29,153.62,148.26,146.91,136.87,136.13,132.47, 132.30,129.31,125.29,124.97,121.78,46.00,43.81,20.94.ESI-MS:m/z 468.09[M+1]+. C21H21N7O2S2(467.57).
实施例7：CHIKV抑制活性测试实验
实验材料：
Vero E6细胞；96孔微孔板；2％胎牛血清；抗生素抗真菌溶液；3-(4,5-二甲基-2-噻唑基(MTT)；DMEM低葡萄糖培养基。
实验步骤：
首先，将Vero E6细胞以2×104个细胞/孔接种在96孔微孔板中，并在37℃和5％CO2条件下培养。然后，汇合细胞单层，加入浓度为10μM的化合物，在含有2％胎牛血清和抗生素抗真菌溶液的DMEM低葡萄糖中培养48小时。最后，使用MTT法评估细胞活力。
实验结果：
对表1所示3个化合物进行抗CHIKV活性筛选，活性数据见表2。
表2 目标化合物对CHIKV的抑制活性
如表2所示，3个目标化合物对于CHIKV表现出较强的抑制活性，IC50值在2.70～6.75 μM之间。其中，尤其以化合物5a的活性最高(IC50＝2.70)，其细胞毒性较低(CC50>80.00)，具有进一步研究的价值。
Claims (7)
1.本发明的嘧啶哌嗪类衍生物，具有如下通式I所示的结构：
其中，
R为取代苯环、取代芳杂环、烷烃；所述的取代基选自卤素、甲基、硝基、氨基、甲氧基；A环为苯环、六元杂环、五元杂环。
2.如权利要求1所述的嘧啶哌嗪类衍生物，其特征在于，通式I中，R为卤代苯基、吡啶基、乙基、丙基、二甲胺基；A环为噻吩环、呋喃环、吡咯环、噻唑环、苯环。
3.如权利要求2所述的嘧啶哌嗪类衍生物，其特征在于，化合物为下列之一：
4.如权利要求1或2所述的嘧啶哌嗪类衍生物的制备方法，其特征在于，包括步骤：
以2,4-二氯稠环并[3,2-d]嘧啶为初始原料，与对甲苯胺反应得中间体2，再与4-Boc-哌嗪经亲核取代反应制得3；3在三氟乙酸中脱去Boc保护基团得到白色中间体4，最后再与各种不同取代的磺酰氯反应得到目标产物5(a-c)；
合成路线如下：
反应试剂与条件：i)对甲苯胺，K2CO3，DMF，室温；ii)4-Boc-哌嗪，K2CO3，DMF，110℃；iii)三氟乙酸、二氯甲烷，室温；iv)取代磺酰氯，三乙胺，二氯甲烷，室温；
其中，R同上述通式I中所述。
5.如权利要求4所述的嘧啶哌嗪类衍生物的制备方法，具体步骤如下：
(1)将对甲基苯胺和碳酸钾置于二甲基甲酰胺溶液中，室温搅拌，然后加入2,4-二氯稠环并[3,2-d]嘧啶，继续室温搅拌；此时有大量白色固体生成，慢慢地向其中加入冰水，过滤，真空干燥，DMF-H2O中重结晶得到中间体2；
(2)称取中间体2、4-Boc-哌嗪与碳酸钾置于二甲基甲酰胺中，加热回流；待反应冷却到室温以后，慢慢地将反应液滴加到水溶液中，搅拌，有大量的黄色固体生成；过滤，干燥得粗品3；将3溶于二氯甲烷中，然后慢慢地向其中加入三氟乙酸，室温搅拌；向反应液中加入水，用饱和的碳酸氢钠溶液调pH为9，二氯甲烷萃取，饱和氯化钠溶液洗涤，分取有机层，无水硫酸钠干燥；然后进行快速柱层析分离得中间体4；
(3)将化合物4置于二氯甲烷中，冰浴条件下依次加入三乙胺与取代的苯磺酰氯，转移至室温，搅拌反应；减压蒸出溶剂，然后向残留底物中加入饱和食盐水，乙酸乙酯洗涤，分取有机层，无水硫酸钠干燥，过滤，浓缩；快速柱层析分离得到目标化合物，进而在乙酸乙酯-石油醚体系中重结晶得到目标化合物。
6.如权利要求1-3所述的嘧啶哌嗪类衍生物作为CHIKV抑制剂在制备抗基孔肯雅热药物中的应用。
7.一种抗CHIKV药物组合物，其特征在于，包括权利要求1-3所述的嘧啶哌嗪类衍生物或其可药用盐和一种或多种药学上可接受载体或赋形剂。
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114621204A (zh) * | 2022-01-06 | 2022-06-14 | 山东大学 | 一种含有嘧啶二酮酰基多取代哌嗪类衍生物及其制备方法与应用 |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006111549A1 (de) * | 2005-04-21 | 2006-10-26 | Boehringer Ingelheim International Gmbh | Dihydrothienopyrimidine zur behandlung von entzündlichen erkrankungen |
| WO2013082476A1 (en) * | 2011-11-30 | 2013-06-06 | Emory University | Antiviral jak inhibitors useful in treating or preventing retroviral and other viral infections |
| CN104926829A (zh) * | 2015-06-08 | 2015-09-23 | 山东大学 | 一种噻吩并嘧啶类衍生物及其制备方法和应用 |
| CN106536538A (zh) * | 2014-04-24 | 2017-03-22 | 共晶制药股份有限公司 | 用于治疗黄病毒家族病毒和癌症的2’‑双取代核苷类似物 |
| US20180185372A1 (en) * | 2015-07-04 | 2018-07-05 | Emory University | Use of trem-1 inhibitors for treatment, elimination and eradication of hiv-1 infection |
| WO2019043177A1 (en) * | 2017-09-01 | 2019-03-07 | Janssen Pharmaceutica Nv | NUCLEOSIDES OF SPIROTHIETANE |
| US20190106425A1 (en) * | 2016-04-15 | 2019-04-11 | Cancer Research Technology Limited | Heterocyclic compounds as ret kinase inhibitors |
| CN111285882A (zh) * | 2018-12-07 | 2020-06-16 | 四川科伦博泰生物医药股份有限公司 | 稠环化合物、包含其的药物组合物及其制备方法和用途 |
| WO2020142748A1 (en) * | 2019-01-03 | 2020-07-09 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Methods and materials for increasing transcription factor eb polypeptide levels |
-
2021
- 2021-06-21 CN CN202110684929.0A patent/CN113248518B/zh active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006111549A1 (de) * | 2005-04-21 | 2006-10-26 | Boehringer Ingelheim International Gmbh | Dihydrothienopyrimidine zur behandlung von entzündlichen erkrankungen |
| WO2013082476A1 (en) * | 2011-11-30 | 2013-06-06 | Emory University | Antiviral jak inhibitors useful in treating or preventing retroviral and other viral infections |
| CN106536538A (zh) * | 2014-04-24 | 2017-03-22 | 共晶制药股份有限公司 | 用于治疗黄病毒家族病毒和癌症的2’‑双取代核苷类似物 |
| CN104926829A (zh) * | 2015-06-08 | 2015-09-23 | 山东大学 | 一种噻吩并嘧啶类衍生物及其制备方法和应用 |
| US20180185372A1 (en) * | 2015-07-04 | 2018-07-05 | Emory University | Use of trem-1 inhibitors for treatment, elimination and eradication of hiv-1 infection |
| US20190106425A1 (en) * | 2016-04-15 | 2019-04-11 | Cancer Research Technology Limited | Heterocyclic compounds as ret kinase inhibitors |
| WO2019043177A1 (en) * | 2017-09-01 | 2019-03-07 | Janssen Pharmaceutica Nv | NUCLEOSIDES OF SPIROTHIETANE |
| CN111285882A (zh) * | 2018-12-07 | 2020-06-16 | 四川科伦博泰生物医药股份有限公司 | 稠环化合物、包含其的药物组合物及其制备方法和用途 |
| WO2020142748A1 (en) * | 2019-01-03 | 2020-07-09 | University Of Pittsburgh - Of The Commonwealth System Of Higher Education | Methods and materials for increasing transcription factor eb polypeptide levels |
Non-Patent Citations (3)
| Title |
|---|
| JULIA MOESSLACHER ET AL.: "Identification of 2-(4-(Phenylsulfonyl)piperazine-1-yl)pyrimidine Analogues as Novel Inhibitors of Chikungunya Virus", 《ACS MED. CHEM. LETT.》 * |
| TSUI-FEN CHOU ET AL.: "Structure–Activity Relationship Study Reveals ML240 and ML241 as Potent and Selective Inhibitors of p97 ATPase", 《CHEMMEDCHEM》 * |
| 姜向毅 等: "基孔肯雅病毒抑制剂研究进展", 《药学学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114621204A (zh) * | 2022-01-06 | 2022-06-14 | 山东大学 | 一种含有嘧啶二酮酰基多取代哌嗪类衍生物及其制备方法与应用 |
| CN114621204B (zh) * | 2022-01-06 | 2024-04-02 | 山东大学 | 一种含有嘧啶二酮酰基多取代哌嗪类衍生物及其制备方法与应用 |
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