CN101732293B - 9,10-蒽醌类化合物的应用 - Google Patents
9,10-蒽醌类化合物的应用 Download PDFInfo
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- CN101732293B CN101732293B CN2008102031121A CN200810203112A CN101732293B CN 101732293 B CN101732293 B CN 101732293B CN 2008102031121 A CN2008102031121 A CN 2008102031121A CN 200810203112 A CN200810203112 A CN 200810203112A CN 101732293 B CN101732293 B CN 101732293B
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Classifications
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- A—HUMAN NECESSITIES
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Abstract
本发明公开了一类如式I所示的9，10-蒽醌类化合物或其药学上可接受的盐或含其的植物提取物在制备抗丙型肝炎病毒药物中的应用；其中，R1、R2、R3、R4、R5和R6各自独立的为氢，羟基、羧基、氰基、硝基、或者取代或未取代的下列基团：氨基、C1-C6链烃基，C3-C7环脂肪烃基，C1-C6烷氧基，C2-C7烷氧基羰基，C1-C4酰氧基，C6-C20芳香基，或者5-7元杂环或其苯并杂环；所述的取代的基团为卤素、C1-C6链烃基、氰基、硝基、氨基、羟基、羧基、C1-C4烷氧基、巯基、C1-C4酰氧基，以及C6-C20芳香基中的一个或多个。本发明所述的如式所示的化合物具有较好的抗丙型肝炎病毒的作用，其副作用小，大多来源于中药，廉价安全有效。
Description
技术领域
本发明涉及9，10-蒽醌类化合物的应用，具体涉及9，10-蒽醌类化合物在制备抗丙型肝炎病毒药物中的应用。
背景技术
据不完全统计，目前我国丙肝抗体阳性患者有4000万人之多，其中80％会患上慢性丙肝。丙肝是经血液、性接触、母婴及日常生活接触等途径传播的一种肝脏疾病。感染HCV后，和HBV感染一样，易发生慢性肝炎、肝硬化和肝癌。
目前，主要使用长效干扰素联合利巴韦林治疗肝功正常的丙肝患者，总体持续病毒学应答率为52％。但干扰素和利巴韦林在治疗过程中，有可能出现骨髓抑制以及情感抑郁、消化道症状等不良反应。并且，长效干扰素价格昂贵，一个疗程48周需花费人民币6万元左右。因此开发抗HCV疗效好、价格低，副作用较小的天然药物是目前医药行业的一个热点。
发明内容
本发明所要解决的技术问题是为提供疗效好、价格低，副作用较小的抗丙型肝炎病毒药物，而公开了一类如式I所示的9，10-蒽醌类化合物在制备抗丙型肝炎病毒药物中的应用。
本发明的公开了如式I所示的9，10-蒽醌类化合物或其药学上可接受的盐或含其的植物提取物在制备抗丙型肝炎病毒药物中的应用。
式I
其中，R1、R2、R3、R4、R5和R6各自独立的为氢，羟基、羧基、氰基、硝基、或者取代或未取代的下列基团：氨基、C1-C6链烃基，C3-C7环脂肪烃基，C1-C6烷氧基，C2-C7烷氧基羰基，C1-C4酰氧基，C6-C20芳香基，或者5-7元杂环或其苯并杂环。所述的取代的基团较佳的为卤素、C1-C6链烃基、氰基、硝基、氨基、羟基、羧基、C1-C4烷氧基、巯基、C1-C4酰氧基，以及C6-C20芳香基中的一个或多个。
其中，所述的5-7元杂环较佳的为含有1-3个选自氧、硫和氮的杂原子的5-7元杂环；所述的C6-C20芳香基较佳的为苯基、萘基、四氢萘基、2，3-二氢化茚基、联苯基、菲基、蒽基或者苊基。
较佳的，所述的R1、R2、R3、R4、R5和R6各自独立的为H、CH3、OH、OCH3、OC2H5、COOH、COOCH3、COOC2H5、CH2OH、三氟甲基、三氟甲氧基或苄基。
除非另有说明，在本发明说明书和权利要求书中出现的以下术语具有下述含义：
术语“链烃基”表示具有指定碳原子数目的支链或直链的饱和或不饱和的链状脂肪烃基。
术语“环脂肪烃基”表示具有指定碳原子数目的支链或直链的饱和或不饱和环脂肪烃基。
术语“烷氧基”表示通过氧桥连接的具有所述碳原子数目的环状或者非环状烷基。
术语“卤素”表示氟、氯、溴或碘。
术语“芳香基”表示任何稳定的在各环中可高达7个原子的单环、双环或者多个碳环，其中至少一个环是芳香环。在芳香取代基为二环或多环取代基，且其中一个或几个环是非芳香环的情况时，与中心分子的连接是通过芳环进行。
其中，所述的其药学上可接受的盐较佳的为如式I所示的9，10-蒽醌类化合物与有机酸，或酸性氨基酸形成酯后，再与无机碱或有机碱形成的盐；或者为如式I所示的9，10-蒽醌类化合物与碱性氨基酸形成酯后，再与酸形成的加成盐。
所述的有机酸较佳的为丙酸、草酸或丙二酸；所述的酸性氨基酸较佳的为天冬氨酸或谷氨酸；所述的再与无机碱或有机碱形成的盐较佳的为钠盐、钾盐、铵盐、甲胺盐或乙胺盐；所述的碱性氨基酸较佳的为赖氨酸、精氨酸或鸟氨酸；所述的酸较佳的为盐酸、硫酸、硝酸或磷酸等无机酸，或甲酸、乙酸或甲磺酸等有机酸。
本发明中，经研究发现，如式I所示的9，10-蒽醌类化合物中，R1、R3、R4和R6均为氢时，即有如式A所示的母核结构的蒽醌类化合物或含其的植物提取物，该物质具有更佳的抗丙型肝炎病毒活性。
式A
其中，R2为H或CH3，R5为H、OH、OCH3、OC2H5、COOH、COOCH3、COOC2H5或CH2OH。
本发明中，所述的如式A所示的蒽醌类化合物更优选下述五种化合物：
(1)如式B所示的大黄素，即式A化合物中R2为CH3、R5为OH，其分子式为C15H10O5；分子量270.25，化学名为1，3，8-二羟基-6-甲基蒽醌，英文名称为Emodin，CAS编号为518-82-1。
式B
(2)如式C所示的大黄酚，即式A化合物中R2为CH3、R5为H，其分子式为C15H10O4；分子量254.24，化学名为1，8-二羟基-6-甲基蒽醌，英文名称为Chrysophanic acid，CAS编号为481-74-3。
式C
(3)如式D所示的大黄素甲醚，即式A化合物中R2为CH3、R5为OCH3，其分子式为C16H12O5；分子量284.27，化学名为1，8-二羟基-3-甲氧基-6-甲基蒽醌，英文名称为Physcion，CAS编号为521-61-9。
式D
(4)如式E所示的芦荟大黄素，即式A化合物中R2为H、R5为CH2OH，其分子式为C15H10O5；分子量270.24，化学名为1，8-二羟基-3-羟甲基蒽醌，英文名称为Aloe-emodin，CAS编号为481-72-1。
式E
(5)如式F所示的大黄酸，即式A化合物中R2为H、R5为COOH，其分子式为C15H8O6；分子量284.22，化学名为1，8-二羟基-3-羧基蒽醌，英文名称为Rhein，CAS编号为478-43-3。
式F
本发明中，所述的蒽醌类化合物现较佳的为从天然植物(如大黄等)中提取分离制得，其不仅包括市售单体纯品，也包括从天然植物中提取的粗品或纯品，还包括以这些蒽醌类化合物为有效成份的植物提取物，更佳的为由中药大黄、决明子、茜草、芦荟或番泻叶采用丙酮、甲醇、乙醇、正丁醇、乙酸乙酯、石油醚、氯仿、二氯甲烷和水等溶剂的一种或多种提取的提取物。
本发明的所有原料和药品均市售可得。
本发明的积极进步效果在于：本发明所述的蒽醌类化合物具有较好的抗丙型肝炎病毒的作用，其副作用小，其来源于中药，廉价安全有效。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。
实施例中所用的大黄素、大黄酚、大黄素甲醚、芹菜素、芦荟大黄素和大黄酸购自上海中药标准化中心。HCV-E2抗体取自美国Scripps研究所。对照药物α干扰素以及其它所用试剂和原料均国内市售可得。
大黄、决明子、茜草、芦荟及番泻叶提取物为水或75％(V/V)乙醇水溶液的提取物，自制。
取大黄、决明子、茜草、芦荟及番泻叶药材两份各1kg，用水(5kg)和75％(V/V)乙醇水溶液(5kg)分别提取，浓缩至干，即得提取物。
效果实施例 体外细胞试验
1、样品制备
用DMSO将样品溶解成浓度为20mg/ml的母液，4℃保存。检测时，再用DMSO将贮存母液分别稀释为5mg/ml和2mg/ml的溶液。
2、细胞、病毒及细胞培养
本试验采用Huh7衍生细胞系和HCV病毒株，该病毒株能在该细胞中产生高滴度、有感染能力的HCV病毒颗粒。
将细胞以1×104个/100μl/孔接种于96孔细胞培养板中，培养过夜。用完全培养基(DMEM中含10％胎牛血清，100U/ml青霉素，100μg/ml链霉素)将HCV病毒上清稀释到1×103ffu/ml，按50ffu/孔感染细胞。
3、HCV病毒集落减少实验
将不同浓度(2mg/ml和1mg/ml)的样品溶液分别以体积比1:50的比例稀释于完全培养基中，使之浓度相应为40μg/ml和20μg/ml，分别吸取适量样品溶液与等体积病毒稀释液混和均匀，制备成浓度为20μg/ml和10μg/ml的样品。室温孵育1小时。弃去96孔细胞培养板中的培养基，每孔加入100μl上述混和液，置37℃、5％CO2培养箱中培养8小时。弃去上清，用无钙镁离子的磷酸盐缓冲液(DPBS)洗1次，每孔加入150μl新鲜的完全培养基，置37℃、5％CO2培养箱中培养64小时。每孔加入150μl4％多聚甲醛(PFA)，室温固定15分钟。弃去上清，用DPBS洗涤3次，用抗HCV-E2人源单克隆抗体和免疫荧光素标记的抗人二抗进行免疫荧光染色。荧光显微镜观察记录病毒集落数量。
4、阴性对照组设定
阴性对照组以DMSO代替样品溶液，其余同样品检测。
5、α干扰素对照组设定
用完全培养基将干扰素溶液分别稀释至5，50，500IU/ml。与细胞孵育1小时，加入病毒稀释液，其余同提取物检测。
抑制率＝(阴性对照组病毒集落数量—实验组的病毒集落数量)/阴性对照组病毒集落数量×100％。
实验结果
实验测试显示大黄素甲醚的IC50是8ng/ml，活性优于其他化合物。
细胞毒性说明：
无细胞毒性＝实验组细胞密度/阴性对照组细胞密度≥80％
有细胞毒性＝实验组细胞密度/阴性对照组细胞密度<80％
实验结果显示大黄素甲醚、大黄素、芦荟大黄素、大黄酸和大黄酚等蒽醌类化合物，以及大黄、决明子、茜草、芦荟及番泻叶植物提取物对丙型肝炎病毒有显著的抑制作用。
综上所述，各项实验结果表明大黄素甲醚、大黄酚、大黄素、芦荟大黄素和大黄酸，以及含其的植物提取物均具有抗丙型肝炎病毒活性，其中大黄素甲醚抑制丙型肝炎病毒的活性最强。
Claims (4)
1.一类如式I所示的9，10-蒽醌类化合物或其药学上可接受的盐作为唯一活性成分在制备抗丙型肝炎病毒药物中的应用：
其中，R1、R3、R4和R6为氢，R2为CH3，R5为H，即所述的如式I所示的蒽醌类化合物为如式C所示的大黄酚：
或者，R1、R3、R4和R6为氢，R2为CH3，R5为OCH3，即所述的如式I所示的蒽醌类化合物为如式D所示的大黄素甲醚：
或者，R1、R3、R4和R6为氢，R2为H，R5为COOH，即所述的如式I所示的蒽醌类化合物为如式F所示的大黄酸：
2.如权利要求1所述的应用，其特征在于：所述的其药学上可接受的盐为如式I所示的9，10-蒽醌类化合物与有机酸，或酸性氨基酸形成酯后，再与无机碱或有机碱形成的盐；或者为如式I所示的9，10-蒽醌类化合物与碱性氨基酸形成酯后，再与酸形成的加成盐。
3.如权利要求2所述的应用，其特征在于：所述的有机酸为丙酸、草酸或丙二酸；所述的酸性氨基酸为天冬氨酸或谷氨酸；所述的再与无机碱或有机碱形成的盐为钠盐、钾盐、铵盐、甲胺盐或乙胺盐；所述的碱性氨基酸为赖氨酸、精氨酸或鸟氨酸；所述的酸为盐酸、硫酸、硝酸、磷酸、甲酸、乙酸或甲磺酸。
4.如权利要求1所述的应用，其特征在于：所述的抗丙型肝炎病毒药物为治疗病毒性丙型肝炎的药物。
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| Application Number | Priority Date | Filing Date | Title |
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| CN2008102031121A CN101732293B (zh) | 2008-11-21 | 2008-11-21 | 9,10-蒽醌类化合物的应用 |
| PCT/CN2009/075075 WO2010057443A1 (zh) | 2008-11-21 | 2009-11-23 | 9,10-蒽醌类化合物的应用 |
| US13/130,130 US8895725B2 (en) | 2008-11-21 | 2009-11-23 | Use of 9, 10-anthraquinone compounds |
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| CN2008102031121A CN101732293B (zh) | 2008-11-21 | 2008-11-21 | 9,10-蒽醌类化合物的应用 |
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| CN101732293A CN101732293A (zh) | 2010-06-16 |
| CN101732293B true CN101732293B (zh) | 2012-05-23 |
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| CN (1) | CN101732293B (zh) |
| WO (1) | WO2010057443A1 (zh) |
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| EP2872474B1 (en) * | 2012-07-10 | 2022-01-19 | Georgia State University Research Foundation, Inc. | Anthraquinone analogs and methods of making and using thereof |
| CN102838530A (zh) * | 2012-09-19 | 2012-12-26 | 陕西师范大学 | 芦荟大黄素衍生物及其制备方法 |
| US9801898B2 (en) | 2015-02-06 | 2017-10-31 | Emory University | Glutamate dehydrogenase 1 inhibitors and methods of treating cancer |
| CN107129428B (zh) * | 2017-05-18 | 2020-06-16 | 云南中烟工业有限责任公司 | 一种蒽醌类化合物及其制备方法和应用 |
| CN107032976B (zh) * | 2017-05-18 | 2020-06-16 | 云南中烟工业有限责任公司 | 一种具有抗氧化活性的蒽醌类化合物及其制备方法和应用 |
| CN108938772B (zh) * | 2017-05-25 | 2021-09-03 | 江苏康缘药业股份有限公司 | 一种茜草有效部位及其制备方法与应用 |
| CN109745302B (zh) * | 2017-11-03 | 2022-09-20 | 上海医药工业研究院 | 大黄素衍生物、其制备方法及应用 |
| CN109748810B (zh) * | 2017-11-03 | 2021-09-03 | 上海医药工业研究院 | 2-胺甲基-9,10-蒽醌衍生物、其制备方法及应用 |
| CN109748828B (zh) * | 2017-11-03 | 2021-09-03 | 上海医药工业研究院 | 1，8-二羟基-9，10-蒽醌衍生物、其制备方法及应用 |
| CN109745306B (zh) * | 2017-11-03 | 2022-03-22 | 上海医药工业研究院 | 9，10-蒽醌衍生物、其制备方法及应用 |
| CN110305496B (zh) * | 2019-07-17 | 2021-02-12 | 衡水学院 | 一种高稳定性决明子色素提取方法 |
| US20230278957A1 (en) * | 2020-08-04 | 2023-09-07 | Wake Forest University Health Sciences | Trex1 inhibitors and uses thereof |
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| US20100256217A1 (en) * | 2006-05-22 | 2010-10-07 | The Trustees Of The University Of Pennsylvania | Antiviral inhibition of casein kinase ii |
| PL381714A1 (pl) * | 2007-02-07 | 2008-08-18 | Instytut Biotechnologii i Antybiotyków | Nowe zastosowanie medyczne pochodnych antybiotyków antracyklinowych |
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| US8895725B2 (en) | 2014-11-25 |
| US20110224414A1 (en) | 2011-09-15 |
| CN101732293A (zh) | 2010-06-16 |
| WO2010057443A1 (zh) | 2010-05-27 |
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