CN115135321B - N-取代吡啶基苯并异硒唑酮化合物的应用 - Google Patents
N-取代吡啶基苯并异硒唑酮化合物的应用 Download PDFInfo
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Abstract
公开了一种N‑取代吡啶基苯并异硒唑酮化合物的应用。所述的应用具体为在制备治疗和/或预防冠状病毒引发的疾病的药物中的应用。N‑取代吡啶基苯并异硒唑酮化合物，如依布硒可显著抑制冠状病毒的主蛋白酶活性，且显著抑制SARS‑CoV‑2在细胞中的复制能力，可用于治疗冠状病毒引发的相关疾病。
Description
本申请要求申请日为2020年02月24日的PCT申请PCT/CN2020/076375的优先权。本申请引用上述PCT申请的全文。
技术领域
本发明属于生物医药技术领域，具体涉及N-取代吡啶基苯并异硒唑酮化合物的应用。
背景技术
冠状病毒是一类与人畜密切相关的病毒。冠状病毒HCoV-229E和HCoV-OC43会引起普通感冒(van der Hoek，L.，Pyrc，K.，Jebbink，M.et al.Identification of a newhuman coronavirus.Nat Med 2004，10，368-373)。2002至2003年期间由SARS冠状病毒引起的严重急性呼吸系统综合征(SARS)在全球造成8098人感染，774名患者死亡，致死率达到了10％(Stadler，K.，Masignani，V.，Eickmann，M.et al.SARS-beginning to understand anew virus.Nat Rev Microbiol 2003，1，209-218)。2004年鉴定出的HCoV-NL63同样能引起类似感冒的呼吸道疾病(van der Hoek，L.，Pyrc，K.，Jebbink，M.et al.Identificationof a new human coronavirus.Nat Med 2004，10，368-373)。2012年出现了中东呼吸综合征冠状病毒(MERS-CoV)，截至2016年4月26日，在27个国家造成1,728例感染，其中624人死亡(de Wit，E.，van Doremalen，N.，Falzarano，D.et al.SARS and MERS：recent insightsinto emerging coronaviruses.Nat Rev Microbiol 2016，14，523-534.)。最近流行的SARS-CoV-2病毒会引发COVID-19，临床表现为发烧，干咳和呼吸困难，重症会造成死亡(Jeannette Guarner，MD，Three Emerging Coronaviruses in Two Decades：The Storyof SARS，MERS，and Now COVID-19，American Journal of Clinical Pathology，，aqaa029)。冠状病毒对于畜牧业影响巨大：猪流行性腹泻病毒(PEDV)、肠胃炎病毒(TGEV)和猪丁型冠状病毒(Porcine delta coronavirus，PDCoV，也叫德尔塔病毒)，可引起猪的严重肠炎、腹泻、呕吐和脱水，给养猪业带来巨大的损失(Akimkin V，Beer M，Blome S，etal.New Chimeric Porcine Coronavirus in Swine Feces，Germany，2012.Emerg InfectDis.2016，22(7)：1314-1315)。猫传染性腹膜炎病毒(FIPV)可引起的猫科动物的致死性疾病。禽传染性支气管炎病毒(IBV)感染禽类，是一种分布广泛的家禽疾病，对家禽业造成了巨大的经济影响。
冠状病毒在系统分类上属套式病毒目(Nidovirales)冠状病毒科(Coronaviridae)冠状病毒亚科(Orthocoronavirinae)，日前SARS-CoV-2冠状病毒基因组序列已经公布，该序列与SARS-Cov的核苷酸相似度约为90％，蛋白质序列与SARS-CoV有约80％的序列相似性。冠状病毒的基因组为单股正链RNA，长度约28kb，主要编码病毒包装所需的结构蛋白以及与复制转录相关的非结构蛋白。开发治疗冠状病毒相关疾病的药物和疫苗主要针对上述两类蛋白。病毒基因组的三分之二的基因主要编码非结构蛋白。病毒编码了两种多聚酶蛋白pp1a和pp1ab，用于参与病毒的复制过程。pp1a和pp1ab通过两种由病毒编码的木瓜蛋白酶和主蛋白酶(main protease)可以将其切割成16个非结构蛋白nsp1-16，只有当这些功能亚基被病毒编码的蛋白酶切割成独立的蛋白单元，病毒才能完成正常的转录、复制功能，进而组装成复制转录复合物，完成病毒的复制和转录。其中，木瓜蛋白酶有3个酶切位点；主蛋白酶在pp1a和pp1ab上存在11个酶切位点。可见主蛋白酶在病毒的转录、复制过程中发挥关键的调节作用，因此成为研究的焦点(Ziebuhr，J.；Snijder，E.J.；Gorbalenya，A.E.Virus-encoded proteinases and proteolytic processing in theNidovirales.J Gen Virol 2000，81，853-79.；Ziebuhr，J.Molecular biology of severeacute respiratory syndrome coronavirus.Curr Opin Microbiol 2004，7，412-9.)。由于主蛋白酶对冠状病毒扩增复制的重要性，因此寻找针对主蛋白酶催化位点专一性强、安全性高的抑制剂对于药物开发显得尤其重要。
依布硒属于N-取代吡啶基苯并异硒唑酮化合物，是一种有机硒化合物，由于其类似谷胱甘肽过氧化物酶的特殊功能，可作为谷胱甘肽过氧化物酶调节剂或模拟化合物，具有良好的抗氧化功能。依布硒是多功效的化合物，可以保护细胞内重要组分免受氧化损伤目前发现依布硒可以抑制许多参与各种生物学过程的酶，包括锌指蛋白、脂氧合酶、一氧化氮合酶、NADPH氧化酶、H+-K+-ATPase、辣根过氧化物酶、谷氨酸脱氢酶以及乳酸脱氢酶等(Azad，G.K.&Tomar，R.SEbselen，a promising antioxidant drug：mechanisms ofactionand targets of biological pathways.Mol Biol Rep 2014，41，4865)。依布硒的分子式如下：
依布硒可以影响细胞内的多种生物反应过程，它不仅可以作为活性氧和自由基的清道夫，发挥抗氧化应激的功能，抑制细胞的凋亡，维持基因组的稳定性；它同样可以影响免疫系统，调节宿主的免疫系统并响应各种刺激而表现出抗炎作用(Azad，G.K.&Tomar，R.SEbselen，a promising antioxidant drug：mechanisms of actionand targets ofbiological pathways.Mol Biol Rep 2014，41，4865)。
依布硒在多种炎症模型中均表现出较好的抗炎活性，且没有非甾体抗炎药的胃肠道刺激作用。临床可用来治疗梅尼埃病和内淋巴水肿，治疗类风湿性关节炎、骨关节炎等(Azad，G.K.&Tomar，R.SEbselen，a promising antioxidant drug：mechanisms ofactionand targets of biological pathways.Mol Biol Rep 2014，41，4865.；JonathanKil，Edward Lobarinas，Christopher Spankovich，et.al.Safety and efficacy ofebselen for the prevention of noise-induced hearing loss：a randomised，double-blind，placebo-controlled，phase 2 trial.The Lancet 2017，390，969-979.；J·奇尔.梅尼埃病的治疗；中国专利：CN109475518A，2019-03-15.)。依布硒大量口服会引起急性毒性：大鼠经口致死剂量：＞4600mg/kg；小鼠经口致死剂量：＞2150mg/kg。在一项2019年关于梅尼埃病治疗的专利中，Sound Pharmaceuticals Inc进行了依布硒对于梅尼埃病治疗的II期临床实验，结果显示依布硒安全性和耐受性较好，未观测到明显的毒副作用，少数有轻微头痛症状但停药后很快恢复(Jeannette Guarner，MD，Three Emerging Coronavirusesin Two Decades：The Story of SARS，MERS，and Now COVID-19，American Journal ofClinical Pathology，，aqaa029；Akimkin V，Beer M，Blome S，et al.New ChimericPorcine Coronavirus in Swine Feces，Germany，2012.Emerg Infect Dis.2016，22(7)：1314-1315.)。临床试验证实了依布硒具有较高的安全性。
现有技术中(CN 1615883A)有依布硒抑制HBV病毒、治疗HBV病毒相关的疾病的记载，然该专利中依布硒主要是起到免疫调节的作用，与主蛋白酶的作用无关，与病毒复制或病毒蛋白合成无关，且依布硒是和其他药物连用。目前为止尚未发现依布硒可用于治疗冠状病毒引发的相关疾病。
发明内容
本发明所要解决的技术问题是针对现有技术中尚无有效治疗和/或预防冠状病毒所引发的疾病的药物的缺陷，提供一种N-取代吡啶基苯并异硒唑酮化合物的应用，具体为在制备治疗冠状病毒引发的疾病的药物中的应用。
本发明主要通过以下技术方案解决上述技术问题。
本发明的第一方面提供N-取代吡啶基苯并异硒唑酮化合物在制备治疗和/或预防冠状病毒引发的疾病的药物中的应用，所述N-取代吡啶基苯并异硒唑酮化合物的通式I如下式所示：
该通式中R1选自氢，卤素，C1-C4的直链或支链烷基或烷氧基；R1的取代位置是3-、4-、5-或6-位；
R2选自氢，卤素，C1-C4的直链或支链烷基或烷氧基；R2的取代位置是2-位吡啶环上任一碳原子；
X代表氮原子，其取代位置是2-，3-或4-位。
所述N-取代吡啶基苯并异硒唑酮化合物较佳地包括以下如通式(Ia)所示的化合物：
其中，R1和R2的定义同上；
通式(Ib)所示的化合物：
R1和R2的定义同上；以及通式(Ic)所示的化合物：
其中，R1和R2的定义同上。
所述N-取代吡啶基苯并异硒唑酮化合物更佳地为如下式所示的依布硒：
较佳地，所述的疾病为哺乳动物或者禽类疾病。
较佳地，所述的哺乳动物包括人、猪和猫。
本发明所述的冠状病毒，其定义为本领域熟知，在系统分类上属套式病毒目(Nidovirales)冠状病毒科(Coronaviridae)冠状病毒亚科(Orthocoronavirinae)。冠状病毒是具有囊膜(envelope)、基因组为单股正链的RNA病毒，是自然界广泛存在的一大类病毒。
本发明的目的是提供冠状病毒感染引起的疾病的潜在治疗方案。本发明所述的冠状病毒较佳地属于正冠状病毒亚科(Orthocoronavirinae)，更佳地属于Alpha冠状病毒属、Beta冠状病毒属、Gamma冠状病毒属或者Delta冠状病毒属。
在本发明一较佳实施例中，所述的N-取代吡啶基苯并异硒唑酮化合物，如依布硒可用于治疗SARS-CoV-2(Beta冠状病毒属)引发的疾病以外，还应可治疗其他冠状病毒SARS-CoV(Beta冠状病毒属)和MERS-CoV等引起的重大传染病，亦可作为普通感冒药，治疗HCoV-HKU1(Human coronavirus HKU1；Beta冠状病毒属)、HCoV-NL63(Human coronavirusNL63；Alpha冠状病毒属)、HCoV-OC43(Human coronavirus OC43)以及HCoV-229E(Humancoronavirus 22E；Alpha冠状病毒属)等冠状病毒引起的疾病；还可作为兽药，治疗猪传染性胃肠炎病毒(Transmissible gastroenteritis virus，TGEV；Alpha冠状病毒属)、猪流行性腹泻病毒(Porcine epidemic diarrhea virus，PEDV；Alpha冠状病毒属)、猪丁型冠状病毒(Porcine delta coronavirus，PDCoV；Delta冠状病毒属)、猫传染性腹膜炎病毒(Felineinfectious peritonitis virus，FIPV；Alpha冠状病毒属)、禽传染性支气管炎病毒(Infectious bronchitis virus，IBV；Gamma冠状病毒属)等动物疾病。
因此，本发明所述冠状病毒的较佳地选自SARS-CoV-2、SARS-CoV、MERS-CoV、HCoV-HKU1、HCoV-NL63、HCoV-OC43、HCoV-229E、TGEV、PEDV、PDCoV、FIPV或者IBV。
任何药物在供给临床使用前，均必须制成适合于医疗和预防应用的形式，这种形式称为药物的剂型，简称药剂。药物制成不同的剂型后，患者使用方便，易于接受，不仅药物用量准确，同时增加了药物的稳定性，有时还可减少毒副作用，也便于药物的贮存、运输和携带。药物剂型有几十种之多，比较常用的也有二三十种，如口服剂型、注射剂型等。
本发明中，所述的药物的剂型较佳地为口服剂型。
本发明的第二方面提供一种使用N-取代吡啶基苯并异硒唑酮化合物或包含其的药物组合物治疗冠状病毒引发的疾病的方法，所述N-取代吡啶基苯并异硒唑酮化合物的通式I如下式所示：
该通式中R1选自氢，卤素，C1-C4的直链或支链烷基或烷氧基；R1的取代位置是3-、4-、5-或6-位；
R2选自氢，卤素，C1-C4的直链或支链烷基或烷氧基；R2的取代位置是2-位吡啶环上任一碳原子；
X代表氮原子，其取代位置是2-，3-或4-位。
所述N-取代吡啶基苯并异硒唑酮化合物较佳地包括以下如通式(Ia)所示的化合物：
其中，R1和R2的定义同上；
通式(Ib)所示的化合物：
R1和R2的定义同上；以及通式(Ic)所示的化合物：
其中，R1和R2的定义同上。
所述N-取代吡啶基苯并异硒唑酮化合物更佳地为如下式所示的依布硒：
其中，所述药物组合物的剂型较佳地为口服剂型。
本发明的第三方面提供一种通过向患有冠状病毒引发的疾病的动物施用N-取代吡啶基苯并异硒唑酮化合物或包含其的药物组合物治疗冠状病毒引发的疾病的方法，所述N-取代吡啶基苯并异硒唑酮化合物的通式I如下式所示：
该通式中R1选自氢，卤素，C1-C4的直链或支链烷基或烷氧基；R1的取代位置是3-、4-、5-或6-位；
R2选自氢，卤素，C1-C4的直链或支链烷基或烷氧基；R2的取代位置是2-位吡啶环上任一碳原子；
X代表氮原子，其取代位置是2-，3-或4-位。
所述N-取代吡啶基苯并异硒唑酮化合物较佳地包括以下如通式(Ia)所示的化合物：
其中，R1和R2的定义同上；
通式(Ib)所示的化合物：
R1和R2的定义同上；以及通式(Ic)所示的化合物：
其中，R1和R2的定义同上。
所述N-取代吡啶基苯并异硒唑酮化合物更佳地为如下式所示的依布硒：
所述的动物较佳地为能够患冠状病毒引发的疾病的动物，如哺乳动物和禽类。本发明中所述的哺乳动物较佳地包括人、猪和猫。
对于本发明第二方面和第三方面中的所述冠状病毒、所述N-取代吡啶基苯并异硒唑酮化合物、所述疾病的具体限定同以上第一方面中对冠状病毒、N-取代吡啶基苯并异硒唑酮化合物、疾病的限定。
本发明通过体外酶活实验和体外细胞病毒实验，发现依布硒可用于治疗冠状病毒引发的相关疾病。
本发明的积极进步效果在于：
本发明通过体外酶活实验和体外细胞病毒实验，发现N-取代吡啶基苯并异硒唑酮化合物，如依布硒可用于治疗冠状病毒引发的相关疾病。目前尚无已批准上市的针对人类冠状病毒的特效药，依布硒治疗方案可填补现有技术的不足，毒副作用低，口服给药易实施。
附图说明
图1显示依布硒对新型冠状病毒(SARS-CoV-2)主蛋白酶有很强的抑制活性。
图2为分子对接显示依布硒是靶向新型冠状病毒的主蛋白酶活性口袋的抑制剂。
图3为依布硒可防止新型冠状病毒感染引起的细胞病变(a：加入依布硒，b：感染新型冠状病毒的细胞，c：MOCK对照，加入0.1％的DMSO)。
图4为细胞水平的抗病毒试验。
图5为不同种属冠状病毒主蛋白酶结构叠加图；图中显示其底物/抑制剂(绿色)结合口袋非常保守(比对了12种冠状病毒的结构，包括SARS-CoV-2、SARS-CoV、MERS-CoV、HCoV-HKU1、BtCoV-HKU4、MHV-A59、PEDV、FIPV、TGEV、HCoV-NL63、HCoV-229E和IBV)。
具体实施方式
实施例1
通过体外酶活实验发现依布硒可显著抑制新型冠状病毒(SARS-CoV-2)的主蛋白酶活性，IC50值为0.48μM(图1)。分子对接显示依布硒是靶向新型冠状病毒的主蛋白酶活性口袋的抑制剂(图2)。
通过体外细胞病毒实验，发现依布硒可防止新型冠状病毒感染引起的细胞病变(图3)，依布硒显著抑制SARS-CoV-2在细胞中的复制能力(图4)。同时临床试验证实了依布硒具有较高的安全性，因此依布硒可用于治疗冠状病毒引发的相关疾病。
以上体外酶活实验和体外细胞病毒实验的详细实验方法详见Wang，M.etal.Remdesivir and chloroquine effectively inhibit the recently emerged novelcoronavirus(2019-nCoV)in vitro.Cell Research，doi：10.1038/s41422-020-0282-0(2020)。
因冠状病毒主要蛋白酶的底物结合口袋高度保守(图5)，因此靶向其结合口袋的抑制剂(依布硒等)会具有广谱抗冠状病毒的作用。由此可知，本发明的依布硒可用于治疗SARS-CoV-2引发的疾病以外，还应可治疗其他冠状病毒SARS-CoV和MERS-CoV等引起的重大传染病，亦可作为普通感冒药，治疗HCoV-HKU1、HCoV-NL63、HCoV-OC43以及HCoV-229E等冠状病毒引起的疾病；还可作为兽药，治疗猪传染性胃肠炎病毒(TGEV)、猪流行性腹泻病毒(PEDV)、猪丁型冠状病毒(Porcine delta coronavirus，PDCoV)、猫传染性腹膜炎病毒(FIPV)、禽传染性支气管炎病毒(IBV)等动物疾病。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。
Claims (5)
1.一种N-取代吡啶基苯并异硒唑酮化合物在制备治疗和/或预防冠状病毒引发的疾病的药物中的应用，所述N-取代吡啶基苯并异硒唑酮化合物为如下式所示的依布硒：
所述的冠状病毒选自SARS-CoV-2和SARS-CoV；
所述N-取代吡啶基苯并异硒唑酮化合物为唯一的活性成分，并且具有靶向冠状病毒的主蛋白酶的抑制活性。
2.如权利要求1所述的应用，其特征在于，所述的疾病为哺乳动物或者禽类疾病。
3.如权利要求2所述的应用，其特征在于，所述的哺乳动物包括人、猪和猫。
4.如权利要求2所述的应用，其特征在于，所述的药物的剂型为口服剂型。
5.如权利要求2所述的应用，其特征在于，所述的药物为感冒药或者兽药。
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