CN114983993B - 杨梅素和二氢杨梅素磷酸酯类化合物在防治新冠肺炎药物中的应用 - Google Patents
杨梅素和二氢杨梅素磷酸酯类化合物在防治新冠肺炎药物中的应用 Download PDFInfo
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- CN114983993B CN114983993B CN202110231565.0A CN202110231565A CN114983993B CN 114983993 B CN114983993 B CN 114983993B CN 202110231565 A CN202110231565 A CN 202110231565A CN 114983993 B CN114983993 B CN 114983993B
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- myricetin
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- dihydromyricetin
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Abstract
本发明涉及一类杨梅素、二氢杨梅素磷酸酯类前药化合物的制备及其在防治新冠肺炎药物中的应用。具体而言,本发明涉及杨梅素磷、二氢杨梅素酸酯类前药化合物及其药物组合物在(a)制备2019新型冠状病毒(SARS‑CoV‑2)3CL蛋白酶抑制剂;(b)制备治疗和/或预防和/或缓解由2019新型冠状病毒感染引起的呼吸道感染、肺炎等相关疾病的药物中的用途。
Description
技术领域
本发明涉及医药领域,具体地涉及一类杨梅素和二氢杨梅素磷酸酯类前药化合物的制备及其在防治新冠肺炎药物中的应用
背景技术
在急性传染病中,绝大部分都是病毒性传染病,病毒性传染病的发病率高,死亡率也很高。由于检测和诊断手段有限,导致新病毒引发的新疫情爆发往往具有突发性、随机性和不可预测性等特点,一旦爆发,如无有效的防治手段,极易造成大规模流行,严重威胁人民健康生命安全。
冠状病毒(Coronaviruses)是单股正链RNA病毒,属于巢病毒目(Nidovirales)冠状病毒科(Coronaviridae)正冠状病毒亚科(Orthocoronavirinae),可以感染人、蝙蝠、猪、老鼠、牛、马、山羊、猴子等多种物种。已知感染人的冠状病毒(HCoV)有6种,包括中东呼吸综合征相关冠状病毒(MERSr-CoV)和严重急性呼吸综合征相关冠状病毒(SARSr-CoV)。
新型冠状病毒2019-nCoV(SARS-CoV-2)是第7种感染人的冠状病毒,可以引起严重肺炎。2019-nCoV病毒传播途径未完全掌握,已知能通过飞沫和接触传播,且存在人传人、医务人员感染,一定社区传播风险,且病毒存在变异的可能。目前对于新型冠状病毒所致疾病没有特异的预防和治疗方法。
2019-nCoV冠状病毒属于冠状病毒科冠状病毒属,为具有包膜的单链正义RNA病毒。和其他已知冠状病毒类似,2019-nCoV冠状病毒也经过吸附、穿入、脱壳、生物合成、子代病毒的组装与释放等几个过程完成子代病毒的增殖。2019-nCoV冠状病毒感染宿主细胞起始于病毒包膜表面的刺突糖蛋白与宿主细胞表面的受体结合,随后发生膜融合,病毒进入宿主细胞,在细胞溶酶体等细胞器作用下,释放出病毒的遗传物质单链正义RNA,在宿主细胞的线粒体、核糖体等蛋白质合成元件以及必须的原料等作用下,翻译产生多聚蛋白,之后,2019-nCoV冠状病毒的两大必需半胱氨酸蛋白酶:木瓜样蛋白酶(papain-likeprotease,PLpro)和3C样蛋白酶(3C-like protease,3CLpro)在特定位点切割加工多聚蛋白前体,产生多个对病毒生命周期非常重要的非结构蛋白。在这些非结构蛋白的作用下,病毒RNA复制出子代病毒核酸物质,并大量翻译出所需的结构蛋白,完成子代病毒的组装和释放。2019-nCoV冠状病毒感染细胞的生命周期的任何环节或关键酶均可以作为抗病毒药物的研究靶点,如水解切割多聚蛋白前体的半胱氨酸蛋白酶PLpro和3CLpro,负责完成子代病毒遗传物质复制的RNA聚合酶等。
目前,针对SARS-CoV-2冠状病毒导致的严重肺炎疾病尚无特效的疫苗和抗病毒药物。这些感染性疾病严重影响了人们的生命健康,研发效果好的抗病毒药物迫在眉睫。针对SARS-CoV-2冠状病毒开发出低毒高效的抗病毒药物,以满足国内外SARS-CoV-2冠状病毒感染患者的临床需求,具有重大的社会意义。
综上所述,本领域迫切需要开发针对SARS-CoV-2冠状病毒的抑制剂以用于治疗新型冠状病毒感染引起的肺炎。
发明内容
本发明的目的是提供杨梅素磷酸酯类化合物在抗新型冠状病毒中的新用途。
具体地,本发明提供了以杨梅素3’-O-磷酸二异丙基酯、杨梅素7-O-2,2-二甲基-1,3丙二醇基磷酸酯、杨梅素7-O-磷酸二苯基酯、杨梅素7-O-磷酸双(对氯苯基)酯为代表的一类杨梅素磷酸酯类化合物在制备新型冠状病毒3CL蛋白酶抑制剂,以及治疗、预防、缓解由新型冠状病毒引起的相关疾病的药物中的用途。
在本发明的第一方面,一种活性成分或含所述活性成分的制剂的用途,所述的活性成分为式I所示化合物或其溶剂化物或其前药或其组合物;
式中,为单键或双键;
R1和R2各自独立地选自:OH、-O-C1-C6烷基、-O-C3-C6环烷基、且R1、R2中至少一个为/>
R8、R9各自独立地选自:H、取代或未取代的C1-C6烷基、取代或未取代的C3-C6环烷基、取代或未取代的苯基;其中,所述的取代表示被一个或多个选自下组的取代基取代:卤素、C1-C3烷基、C1-C3卤代烷基、C3-C6环烷基;
或者R8、R9与相连的-O-P-O-共同构成取代或未取代的6-7元杂环,所述的杂环含有2个O杂原子、1个P杂原子和0-1个N杂原子,所述的取代表示被一个或多个选自下组的取代基取代:卤素、C1-C3烷基、C1-C3卤代烷基、C3-C6环烷基、苄基、卤代苄基、烷(氧)基取代的苄基;
并且,所述的活性成分或含所述活性成分的药物组合物的制剂被用于制备(a)抑制新型冠状病毒3CL蛋白酶活性的抑制剂;和/或(b)治疗和/或预防、缓解由新型冠状病毒感染引起的相关疾病的药物。
在另一优选例中,R8和R9各自独立地选自下组:Cl取代的苯基、Br取代的苯基、I取代的苯基。
在另一优选例中,所述由新型冠状病毒感染引起的相关疾病选自下组:呼吸道感染、肺炎及其并发症、或其组合。
在另一优选例中,当式I中为单键,所述活性成分为如式II所示化合物或其溶剂化物或其前药或其组合物:
式中,R1、R2如上定义。
在另一优选例中,含所述含活性成分的制剂还可以含有其他抗病毒药。
在另一优选例中,所述的含活性成分的制剂还包括选自下组的额外组分:抗肺损伤的药物、抗炎药物或具有免疫调节作用的药物。
在另一优选例中,所述的含活性成分的制剂还包括选自下组的额外组分:锌(Zinc)、芬戈莫德(Fingolimod)、维生素C(Vitamin C)、奥美沙坦酯(OlmesartanMedoxomil)、缬沙坦(valsartan)、氯沙坦(Losartan)、沙利度胺(Thalidomide)、甘草酸(glycyrrhizic acid)、青蒿素(Artemisinin)、双氢青蒿素(dihydroartemisinin)、青蒿琥酯(Artesunate)、青蒿酮(Artemisone)、阿奇霉素(Azithromycin)、七叶皂苷(Escin)、萘普生(Naproxen)、或其组合。
在另一优选例中,所述的活性成分选自下组:
A3杨梅素7-O-磷酸二苯基酯
A5二氢杨梅素7-O-磷酸二苯基酯
A7 A1-A6的组合。
在另一优选例中,所述的制剂包括:口服制剂和非口服制剂。
在另一优选例中,所述的制剂包括:粉剂、颗粒剂、胶囊剂、注射剂、酊剂、口服液、片剂、含片、或滴丸。
在本发明的第二方面,提供了一种药物组合物,所述的药物组合物含有:
(a1)第一活性成分,所述第一活性成分为式I所示化合物或其溶剂化物或其前药或其组合物;
(a2)任选的第二活性成分,所述的第二活性成分为抗病毒药物,其选自下组:干扰素、RNA依赖的RNA聚合酶抑制剂(如Remdesivir(瑞德西韦或GS-5734)、法匹拉韦(favipiravir)、Galidesivir、GS-441524);3CL蛋白酶抑制剂(如GC-376)、洛匹那韦(Lopinavir)、利托那韦(Ritonavir)、奈非那韦(Nelfinavir);氯喹(Chloroquine,Sigma-C6628)、羟氯喹(hydroxychloroquine)、环孢菌素(cyclosporine)、可利霉素(Carrimycin)、黄芩苷(baicalin)、黄芩素(baicalein)、萘酚喹(Naphthoquine)、环索奈德(Ciclesonide)、利巴韦林(Ribavirin)、喷昔洛韦(Penciclovir)、来氟米特(Leflunomide)、特立氟胺(Teriflunomide)、萘莫司他(nafamostat)、硝唑尼特(nitazoxanide)、达芦那韦(Darunavir)、阿比多尔(Arbidol)、卡莫司他(Camostat)、氯硝柳胺(Niclosamide)、巴瑞替尼(baricitinib)、芦可替尼(Ruxolitinib)、达沙替尼(Dasatinib)、沙奎那韦(Saquinavir)、Beclabuvir、司美匹韦(Simeprevir)、或其药学上可接受的盐、或其组合;
和/或所述的第二活性成分选自下组:锌(Zinc)、芬戈莫德(Fingolimod)、维生素C(Vitamin C)、奥美沙坦酯(Olmesartan Medoxomil)、缬沙坦(valsartan)、氯沙坦(Losartan)、沙利度胺(Thalidomide)、甘草酸(glycyrrhizic acid)、青蒿素(Artemisinin)、双氢青蒿素(dihydroartemisinin)、青蒿琥酯(Artesunate)、青蒿酮(Artemisone)、阿奇霉素(Azithromycin)、七叶皂苷(Escin)、萘普生(Naproxen)、或其组合;
及(b)药学上可接受的载体。
在另一优选例中,所述第一活性成分为式II所示化合物或其溶剂化物或其前药或其组合物。
在另一优选例中,所述第一活性成分选自:
A3杨梅素7-O-磷酸二苯基酯
A5二氢杨梅素7-O-磷酸二苯基酯
A7 A1-A6的组合。
在另一优选例中,所述的药物组合物用于抑制新型冠状病毒3CL蛋白酶活性。
在本发明的第三方面,提供了一种第二方面所述的药物组合物的用途,用于制备(a)抑制新型冠状病毒3CL蛋白酶抑制剂;和/或(b)治疗和/或预防、缓解由新型冠状病毒感染引起的相关疾病的药物。
在本发明的第四方面,提供了一种活性成分,所述活性成分为式II所示的化合物或其或其溶剂化物或其前药或其组合物,其中式II如上定义。
在另一优选例中,所述活性成分为
二氢杨梅素7-O-磷酸二苯基酯
在本发明的第五方面,提供了一种体外的抑制新型冠状病毒3CL蛋白酶的方法,包括步骤:
将第一活性成分或含所述第一活性成分的制剂与冠状病毒(SARS-CoV-2)接触,抑制所述冠状病毒3CL蛋白酶的活性,从而抑制冠状病毒的复制;
其中,所述的第一活性成分为式I所示化合物或其溶剂化物或其组合物。
在另一优选例中,所述一活性成分为式II所示化合物或其溶剂化物或其组合物,其中式II如上定义。
在另一优选例中,所述的第一活性成分选自下组:
A3杨梅素7-O-磷酸二苯基酯
A5二氢杨梅素7-O-磷酸二苯基酯
A7 A1-A4的组合。
在另一优选例中,所述方法是体外方法。
在另一优选例中,所述方法是非治疗性和非诊断性的。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
附图说明
图1:化合物1对2019-nCoV-3CLpro的抑制活性曲线图。
图2:化合物2对2019-nCoV-3CLpro的抑制活性曲线图。
图3:化合物3对2019-nCoV-3CLpro的抑制活性曲线图。
图4:化合物4对2019-nCoV-3CLpro的抑制活性曲线图。
图5:杨梅素对2019新型冠状病毒复制抑制活性曲线图。
图6:化合物3对2019新型冠状病毒复制抑制活性曲线图。
图7:二氢杨梅素对2019新型冠状病毒复制抑制活性曲线图。
图8:化合物5对2019新型冠状病毒复制抑制活性曲线图。
具体实施方式
本发明人经过广泛而深入的研究,通过大量筛选,首次意外地发现杨梅素磷酸酯类化合物在抑制新型冠状病毒中的作用。在此基础上完成了本发明。
具体地,本发明通过制备以杨梅素3’-O-磷酸二异丙基酯、杨梅素7-O-2,2-二甲基-1,3丙二醇基磷酸酯、杨梅素7-O-磷酸二苯基酯、杨梅素7-O-磷酸双(对氯苯基)酯、二氢杨梅素7-O-磷酸二苯基酯、二氢杨梅素7-O-磷酸双(对氯苯基)酯为代表的杨梅素和二氢杨梅素磷酸酯类化合物,发现这类化合物能有效抑制新型冠状病毒的3CL蛋白酶的活性,并且能够抑制新型冠状病毒的复制。此外该类化合物的细胞渗透性也非常有益,具有良好的药用前景。
术语
如本文所用,“本发明的药物活性成分”、“本发明的活性成分”、“本发明的抑制新型冠状病毒3CL蛋白霉的活性成分”、可互换使用均指的是杨梅素磷酸酯类化合物。
如本文所用,“本发明的制剂”指含有本发明活性成分的制剂。
如本文所用,术语“包括”或其变换形式如“包含”或“包括有”等等,被理解为包括所述的元件或组成部分,而并未排除其它元件或其它组成部分。
如本文所用,术语“新型冠状病毒”、“2019-nCov”或“SARS-CoV-2”可互换使用,该2019新型冠状病毒是已知感染人的第7种冠状病毒,并且造成新冠肺炎(COVID-19),是威胁全球人类健康的严重传染性疾病之一。
冠状病毒
冠状病毒(Coronavirus,CoV)属于套式病毒目(Nidovirales)冠状病毒科(Coronaviridae),是一种有包膜的正链RNA病毒,其亚科包含α、β、δ及γ四属。
目前已知的感染人的冠状病毒中,HCoV-229E和HCoV-NL63属于α属冠状病毒,HCoV-OC43、SARS-CoV、HCoV-HKU1、MERS-CoV和SARS-CoV-2均为β属冠状病毒。SARS-CoV-2也被称为2019-nCov。
2003年和2012年分别爆发的高致病性冠状病毒“非典”SARS-CoV和“中东呼吸综合征”MERS-CoV均属于β属冠状病毒。2019年年底爆发的新型冠状病毒(SARS-CoV-2)与SARS-CoV有约80%相似性、与MERS-CoV有40%的相似性,也属于β属冠状病毒。
该类病毒的基因组是一条单股正链RNA,是基因组最大的RNA病毒之一,编码包括复制酶、刺突蛋白、囊膜蛋白、包膜蛋白和核壳蛋白等。在病毒复制的初始阶段,基因组被翻译成两条长达几千个氨基酸的肽链即前体多聚蛋白(Polyprotein),随后前体蛋白被蛋白酶切割生成非结构蛋白(如RNA聚合酶和解旋酶)和结构蛋白(如刺突蛋白)及辅助蛋白。
本发明的活性化合物和活性成分
在本发明中,提供了可有效抑制冠状病毒3CL蛋白酶活性的活性成分。该活性成分为杨梅素磷酸酯类化合物或其溶剂化物或其组合物。
优选地,本发明的活性成分选自:
A3杨梅素7-O-磷酸二苯基酯
A5二氢杨梅素7-O-磷酸二苯基酯
A7 A1-A4的组合。
实验表明,本发明的活性成分可有效地抑制新型冠状病毒的3CL蛋白酶活性,从而预防、治疗和/或缓解新型冠状病毒的相关疾病。
如本文所用,“本发明的药物活性成分”“本发明的活性成分”“本发明的活性化合物”、“本发明的抑制冠状病毒复制的活性化合物”可互换使用,指具有优异的抑制冠状病毒复制的活性的化合物。
应理解,本发明的活性成分包括杨梅素磷酸酯类化合物或其溶剂化物或其组合物。
应理解,本发明的活性成分还包括本发明的活性化合物的晶型、无定形化合物、以及氘代化合物等形式。
所述“药学上可接受的盐”为本发明的活性化合物与无机酸或有机酸反应形成常规的无毒盐。例如,常规的无毒盐可通过本发明的活性化合物与无机酸或有机酸反应制得,所述无机酸包括盐酸、氢溴酸、硫酸、硝酸、胺基磺酸和磷酸等,所述有机酸包括柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、苯磺酸、对甲苯磺酸、甲磺酸、萘磺酸、乙磺酸、萘二磺酸、马来酸、苹果酸、丙二酸、富马酸、琥珀酸、丙酸、草酸、三氟乙酸、硬酯酸、扑酸、羟基马来酸、苯乙酸、苯甲酸、水杨酸、谷氨酸、抗坏血酸、对胺基苯磺酸、2-乙酰氧基苯甲酸和羟乙磺酸等;或者本发明的活性化合物与丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、天冬氨酸或谷氨酸形成酯后再与无机碱形成的钠盐、锌盐、钾盐、钙盐、铝盐或铵盐;或者本发明的活性化合物与赖氨酸、精氨酸、鸟氨酸形成酯后再与盐酸、氢溴酸、氢氟酸、硫酸、硝酸或磷酸形成的对应的无机酸盐或与甲酸、乙酸、苦味酸、甲磺酸或乙磺酸形成的对应的有机酸盐;或者本发明的活性化合物分子中的羧基/酚羟基与无机碱形成的钠盐、锌盐、钾盐、钙盐、铝盐或铵盐。
此外,本发明的活性成分还特别适合与其他抗冠状病毒的药物联用。代表性的其他的抗冠状病毒药物包括(但并不限于):干扰素、RNA依赖的RNA聚合酶抑制剂(如Remdesivir(瑞德西韦或GS-5734)、法匹拉韦(favipiravir)、Galidesivir、GS-441524);3CL蛋白酶抑制剂(如GC-376)、洛匹那韦(Lopinavir)、利托那韦(Ritonavir)、奈非那韦(Nelfinavir);氯喹(Chloroquine,Sigma-C6628)、羟氯喹、环孢菌素(cyclosporine)、可利霉素(Carrimycin)、黄芩苷(baicalin)、黄芩素(baicalein)、萘酚喹(Naphthoquine)、环索奈德(Ciclesonide)、利巴韦林(Ribavirin)、喷昔洛韦(Penciclovir)、来氟米特(Leflunomide)、特立氟胺(Teriflunomide)、萘莫司他(nafamostat)、硝唑尼特(nitazoxanide)、达芦那韦(Darunavir)、阿比多尔(Arbidol)、卡莫司他(Camostat)、氯硝柳胺(Niclosamide)、巴瑞替尼(baricitinib)、芦可替尼(Ruxolitinib)、达沙替尼(Dasatinib)、沙奎那韦(Saquinavir)、Beclabuvir、司美匹韦(Simeprevir)、或其药学上可接受的盐、或其组合。所述干扰素包括干扰素α-2a、干扰素α-2b、干扰素α-n1、干扰素α-n3、干扰素β-1a、干扰素β-1b中的一种或多种。
此外,由于SARS-CoV-2感染可引起急性肺损伤、炎症反应甚至细胞因子风暴,本发明的活性成分还特别适合与具有改善急性肺损伤、抗炎作用或调节免疫作用的药物联用。代表性的药物包括但不限于锌(Zinc)、芬戈莫德(Fingolimod)、维生素C(Vitamin C)、奥美沙坦酯(Olmesartan Medoxomil)、缬沙坦(valsartan)、氯沙坦(Losartan)、沙利度胺(Thalidomide)、甘草酸(glycyrrhizic acid)、青蒿素(Artemisinin)、双氢青蒿素(dihydroartemisinin)、青蒿琥酯(Artesunate)、青蒿酮(Artemisone)、阿奇霉素(Azithromycin)、七叶皂苷(Escin)、萘普生(Naproxen)。
药物组合物和应用
本发明还提供了以本发明的抑制冠状病毒复制的活性化合物、或其药学上可接受的盐、或其前药的一种或多种的混合物为有效成分,在制备治疗和/或预防、缓解由2019新型冠状病毒等冠状病毒感染引起的呼吸道感染、肺炎等相关疾病的药物中的用途。
本发明所提供的药物组合物优选含有重量比为0.001-99wt%的活性成份,优选的比例是本发明的活性化合物作为活性成分占总重量的0.1wt%~90wt%或1wt%~50wt%,其余部分为药学可接受的载体、稀释液或溶液或盐溶液。
需要的时候,在本发明药物中还可以加入一种或多种药学上可接受的载体。所述载体包括药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂等。
本发明所提供的化合物和药物组合物可以是多种形式,如片剂、胶囊、粉剂、糖浆、溶液状、悬浮液和气雾剂等,并可以存在于适宜的固体或液体的载体或稀释液中和适宜的用于注射或滴注的消毒器具中。
本发明的药物组合物的各种剂型可按照药学领域的常规制备方法制备。其制剂配方的单位计量中通常包含0.05-400mg本发明的活性化合物,优选地,制剂配方的单位计量中包含1mg-500mg本发明的活性化合物。
本发明的化合物和药物组合物可对哺乳动物临床使用,包括人和动物,可以通过口、鼻、皮肤、肺或者胃肠道等的给药途径。最优选为口服。最优选日剂量为0.01-400mg/kg体重,一次性服用,或0.01-200mg/kg体重分次服用。不管用何种服用方法,个人的最佳剂量应依据具体的治疗而定。通常情况下是从小剂量开始,逐渐增加剂量一直到找到最适合的剂量。
本发明的药物或抑制剂可通过各种不同方式施用,例如可通过注射、喷射、滴鼻、滴眼、渗透、吸收、物理或化学介导的方法导入机体如肌肉、皮内、皮下、静脉、粘膜组织;或是被其他物质混合或包裹导入机体。
典型地,本发明活性成分或含有它的药物组合物可以单位剂量形式给药,给药途径可为肠道或非肠道,如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等;固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等;半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明活性成分可以被制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
为了将本发明活性成分被制成片剂,可以广泛使用本领域公知的各种赋形剂,包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等;润湿剂可以是水、乙醇、异丙醇等;黏合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等;崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等;润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片,例如糖包衣片、薄膜包衣片、肠溶包衣片,或双层片和多层片。
为了将给药单元制成胶囊剂,可以将有效成分本发明活性成分与稀释剂、助流剂混合,将混合物直接置于硬胶囊或软胶囊中。也可将有效成分先与稀释剂、黏合剂、崩解剂制成颗粒或微丸,再置于硬胶囊或软胶囊中。用于制备本发明片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明的胶囊剂。
为将本发明活性成分制成注射剂,可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、PH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等;PH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等;渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂,还可加入甘露醇、葡萄糖等作为支撑剂。
此外,如需要,也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其他添加剂。
本发明的活性成分或组合物可单独服用,或与其他治疗药物或对症药物合并使用。
当本发明的活性成分与其他治疗药物存在协同作用时,应根据实际情况调整它的剂量。
本发明的主要优点包括:
(a)本发明活性成分能有效抑制新型冠状病毒的3CL蛋白酶的活性。杨梅素3’-O-磷酸二异丙基酯、杨梅素7-O-磷酸2,2-二甲基-1,3-丙二醇基酯、杨梅素7-O-磷酸二苯基酯、杨梅素7-O-磷酸双(对氯苯基)酯、二氢杨梅素7-O-磷酸二苯基酯、二氢杨梅素7-O-磷酸双(对氯苯基)酯抑制SARS-CoV-2 3CLpro的IC50值分别为27.58μM、6.14μM、2.70μM、2.11μM、1.88μM、8.59μM。
(b)本发明活性成分能有效抑制新型冠状病毒的复制。代表化合物杨梅素7-O-磷酸二苯基酯抑制新型冠状病毒的EC50值约为2.98μM。
(c)本发明活性成分的细胞渗透性好。代表化合物杨梅素7-O-磷酸二苯基酯的平均吸收生物利用度为82%,渗透性较好。
(d)本发明活性成分的口服暴露量更高。代表化合物二氢杨梅素7-O-磷酸二苯基酯(5)在30mg/kg的口服剂量下,其释放出来的二氢杨梅素最大血药浓度(Cmax)和药时曲线下面积(AUClast)与二氢杨梅素以100mg/kg口服形式给药所达到的最大血药浓度(Cmax)和药时曲线下面积(AUClast)相当。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件,例如Sambrook等人,分子克隆:实验室手册(New York:Cold Spring HarborLaboratory Press,1989)中所述的条件,或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数是重量百分比和重量份数。
实施例一、杨梅素磷酸酯类化合物的合成
1.1合成杨梅素3’-O-磷酸二异丙基酯(1)
于25ml的圆底烧瓶中加入318mg的杨梅素(1.0mmol)和10ml的无水THF,待杨梅素完全溶解后加入146μL的无水三乙胺(1.05mmol,1.05当量),反应瓶置于0度冰水浴中10min后加入氯磷酸二异丙酯(192μL,1.05mmol,1.05当量),反应液于室温下搅拌3h,然后过滤除去三乙胺的盐酸盐,滤液减压蒸馏除去THF,所得剩余物通过制备型高效液相色谱【乙腈-水(含0.1%甲酸),30-45%,0-35min】制备纯化,杨梅素3’-O-磷酸二异丙基酯120mg(得率25%)。化合物的质谱和波谱数据如下:ESI-MS m/z 483.02[M+H]+,481.00[M-H]-;1H NMR(Acetone-d6,500MHz)δ12.07(1H,s,5-OH),7.77and 7.68(each 1H,br.s,H-2’,6’),6.50and 6.25(each 1H,d,J=2.0Hz,H-5,7),4.85(2H,m,OCH-×2),1.40and 1.36(each3H,d,J=6.3Hz,CH3×2);13C NMR(Acetone-d6,125MHz)δ175.7,164.3,161.4,156.8,147.2,144.8,139.2(139.1),138.6(138.5),136.4,122.3,112.5(112.5),111.7,103.3,98.4,93.6,74.2,74.2,23.0,23.0,22.9,22.9;31P NMR(Acetone-d6,125MHz)δ-5.9.
1.2合成杨梅素7-O-2,2-二甲基-1,3丙二醇基磷酸酯(2)
于25ml的圆底烧瓶中加入318mg的杨梅素(1.0mmol)和10ml的无水THF,待杨梅素完全溶解后加入146μL的无水三乙胺(1.05mmol,1.05当量),反应瓶置于0度冰水浴中10min后加入2-氯-5,5-二甲基-1,3,2-二氧杂磷化氢烷2-氧化物(136.8μL,1.05mmol,1.05当量),反应液于室温下搅拌3h,然后过滤除去三乙胺的盐酸盐,滤液减压蒸馏除去THF,所得剩余物通过制备型高效液相色谱【乙腈-水(含0.1%甲酸),25-45%,0-60min】制备,得化合物杨梅素7-O-5,5-二甲基-1,3丙二醇基磷酸酯50mg(得率11%),化合物的质谱和波谱数据如下:ESI-MS m/z 467.00[M+H]+,464.94[M-H]-;1H NMR(Acetone-d6,500MHz)δ12.07(1H,s,5-OH),7.30(2H,s,H-2’,6’),7.05and 6.25(each 1H,d,J=3.1Hz,H-5,7),4.35(2H,d,J=10.6Hz,OCH2-),4.07(2H,dd,J=10.8and 10.6Hz,OCH2-),1.20and0.87(each 3H,s,CH3×2);13C NMR(Acetone-d6,125MHz)δ176.5,161.1,155.4,155.0(154.9),148.8,146.3,146.3,137.2,136.9,120.8,107.9,107.9,107.3,102.3(102.2),98.9(98.8),79.0,78.9,32.4,21.4,19.5;31P NMR(Acetone-d6,125MHz)δ-14.6
1.3合成杨梅素7-O-磷酸二苯基酯(3)
于25ml的圆底烧瓶中加入318mg的杨梅素(1.0mmol)和10ml的无水THF,待杨梅素完全溶解后加入146μL的无水三乙胺(1.05mmol,1.05当量),反应瓶置于0度冰水浴中10min后加入氯磷酸二苯酯(218μL,1.05mmol,1.05当量),反应液于室温下搅拌3h,然后过滤除去三乙胺的盐酸盐,滤液减压蒸馏除去THF,所得剩余物通过制备型高效液相色谱【乙腈-水(含0.1%甲酸),45-65%,0-35min】制备,得化合物杨梅素7-O-磷酸二苯基酯42mg(得率8%),化合物的质谱和波谱数据如下:ESI-MS m/z 551.20[M+H]+,549.17[M-H]-;1H NMR(Acetone-d6,500MHz)δ12.37(1H,s,5-OH),7.47(4H,d,J=7.5Hz,H-1a,6a×2),7.45(2H,s,H-2’,6’),7.35(4H,dd,J=7.5and 1.1Hz,H-2a,5a×2),7.30(2H,dt,J=7.5and 1.1Hz,H-3a×2),7.10and 6.67(each 1H,d,J=1.3Hz,H-5,7);13C NMR(Acetone-d6,125MHz)δ176.0,161.3,155.7,155.2(155.1),150.0,150.0,147.9,145.7,145.7,136.8,136.1,120.8,130.1,130.1,129.1,129.1,126.0,123.3,120.3,120.2,120.1,120.1,107.9,107.9,107.1,102.0(102.0),99.1(99.0);31P NMR(Acetone-d6,125MHz)δ-18.5
1.4合成杨梅素7-O-磷酸双(对氯苯基)酯(4)
于25ml的圆底烧瓶中加入318mg的杨梅素(1.0mmol)和10ml的无水THF,待杨梅素完全溶解后加入146μL的无水三乙胺(1.05mmol,1.05当量),反应瓶置于0度冰水浴中10min后加入氯磷酸二苯酯(242μL,1.05mmol,1.05当量),反应液于室温下搅拌3h,然后过滤除去三乙胺的盐酸盐,滤液减压蒸馏除去THF,所得剩余物通过制备型高效液相色谱【乙腈-水(含0.1%甲酸),52-72%,0-35min】制备,得化合物杨梅素7-O-磷酸双(对氯苯基)酯32mg(得率5%),化合物的质谱和波谱数据如下:ESI-MS m/z 619.11[M+H]+,617.09[M-H]-;1HNMR(Acetone-d6,500MHz)δ12.38(1H,s,5-OH),7.62(2H,dt,J=1.4,8.3Hz,H-2a,6a),6.59(each 2H,dt,J=1.6,8.1Hz,H-2b,6b),7.47(2H,s,H-2’,6’),7.5(2H,dt,J=1.6,8.1Hz,H-3b,5b),7.34(2H,dt,J=1.4,8.3Hz,H-3a,5a),7.17and 6.74(each 1H,d,J=1.4Hz,H-5,7);13C NMR(Acetone-d6,125MHz)δ176.9(C-3),162.2(C-5),156.5,155.7(155.7),148.7,147.2,147.1,146.4,146.4,137.8,136.9,131.8,131.8,129.5,129.5,128.2,128.2,126.1,126.0,122.7,122.7,122.2,108.6(C-2’),108.6(C-5’),108.1,103.1(103.0),100.1(100.0);31P NMR(Acetone-d6,125MHz)δ-5.9.
1.5合成杨梅素7-O-磷酸双苯酯(5)
二氢杨梅素7-O-磷酸双苯酯(5)的合成参照杨梅素7-O-磷酸双苯酯(3)即得。化合物的质谱和波谱数据如下:ESI-MS m/z 553.3[M+H]+,1H NMR(Acetone-d6,500MHz)δ11.69(1H,s,5-OH),7.46(4H,dd,J=7.5Hz,H-2a,6a;2b,6b),7.34(4H,dd,J=7.5and 1.1Hz,H-3a,5a;3b,5b),7.30(2H,dt,J=8.5and 1.1Hz,H-4a;4b),6.64(2H,s,H-2’,6’),6.46and6.44(each 1H,d,J=2.1Hz,H-5,7),5.10and 4.73(each 1H,d,J=11.6Hz,H-2,H-3);13CNMR(Acetone-d6,125MHz)δ199.9,164.2,163.8,158.6(158.5),151.3(151.2),146.4,146.5,134.4,131.0,131.0,131.0,131.0,128.5,126.9,126.9,126.9,121.1,121.1,120.9,120.9,108.1,108.1,105.4,101.7(101.6),100.6(100.5),85.0,73.4;31P NMR(Acetone-d6,125MHz)δ-18.7.
1.6合成二氢杨梅素7-O-磷酸双(对氯苯基)酯(6)
二氢杨梅素7-O-磷酸双(对氯苯基)酯(6)的合成参照杨梅素7-O-磷酸双(对氯苯基)酯(4)即得,化合物的质谱和波谱数据如下:ESI-MS m/z 621.3[M+H]+,1H NMR(Acetone-d6,600MHz)δ11.70(1H,s,5-OH),7.59(4H,dd,J=7.8Hz,H-2a,6a;2b,6b),7.45(2H,dt,J=1.6,7.8Hz,H-3a,5a),7.34(2H,brt,J=7.8Hz,H-3b,5b),6.64(2H,s,H-2’,6’),6.52and6.49(each 1H,d,J=2.3Hz,H-5,7);13C NMR(Acetone-d6,125MHz)δ200.0,164.2,163.8,158.2(158.2),147.1(147.1),146.4,146.4,146.4,134.5,131.9,131.9,129.6,129.6,128.5,128.3,128.3,126.1,126.0,122.7,122.7,108.2,108.2,105.6,101.9(101.8),100.8(100.7),85.0,73.5;31P NMR(Acetone-d6,125MHz)δ-19.2.
实施例二、杨梅素磷酸酯类化合物对SARS-CoV-2 3CLpro抑制活性的测试
利用荧光共振能量转移方法评价测定杨梅素及其磷酸酯类化合物对SARS-CoV-23CLpro酶活的抑制活性。整个酶促反应体系的体积为120μL,蛋白酶的终浓度为30nM,底物终浓度为20μM。反应体系的缓冲液包括50mM Tris pH7.3、1mM EDTA。在96孔板中加入SARS-CoV-2 3CLpro蛋白酶和不同浓度的化合物,30℃孵育10min,加入底物并迅速放入酶标仪中读数。激发光和发射光分别为320nM和405nM。测试时间为3.5min,每隔35s读一次荧光值。最终结果取前2min的读值拟合出反应速率,并与对照组(DMSO)比较,计算抑制率。利用软件GraphPad Prism 8拟合得到IC50值以及抑制率曲线。图1-4分别是杨梅素磷酸酯类化合物1-4对SARS-CoV-2 3CLpro的抑制曲线图。
将杨梅素磷酸酯类化合物对SARS-CoV-2 3CLpro抑制的IC50值列在表中,实验结果如表1所示。
表1:杨梅素磷酸酯类化合物对SARS-CoV-2 3CLpro的抑制作用
*杨梅素对SARS-CoV-2 3CLpro抑制IC50值引自专利CN202010153446.3
实施例三、杨梅素和杨梅素-7-O-磷酸双苯基酯(3)Caco-2细胞渗透性测试
Caco-2细胞用高糖DMEM培养基,置于37℃、5%CO2、空气相对湿度90%的培养箱中培养,培养基中添加10%胎牛血清、10mmol/L HEPES、1mmol/L丙酮酸钠、1%谷氨酰胺、1%非必需氨基酸、100U/mL青霉素和100μg/mL链霉素。每隔7天传一代,传代比率1:10。实验使用40至60代之间的细胞。培养21天以后,用TEER值检测细胞单层的紧密程度(须大于400Ω·cm2)。同时考察从细胞顶层(A侧)到基底层(B侧)和B侧到A侧的药物转运。试验方法如下:用HBSS洗细胞三次以后,20μM的化合物以及化合物加抑制剂(GF120918)分别加到对应的细胞孔中(A侧pH6.8,B侧pH7.4)。在37℃培养箱中培养95分钟,分别在5分钟和95分钟时给药侧取样,在35分钟和95分钟时接收侧取样。用LC-MS/MS检测样品的浓度。测定被试化合物杨梅素和杨梅素-7-O-磷酸双苯基酯(3)的Papp和Efflux值。杨梅素和杨梅素磷酸酯类化合物(3)Caco-2细胞渗透性的测试结果如表2所示。
表2:杨梅素和杨梅素-7-O-磷酸双苯基酯(3)细胞渗透性测试结果
渗透性判定标准:Fab%>70%,渗透性较好;30%<Fab%<70%,渗透性中等;Fab%<30%,渗透性较差。
实验结果显示在杨梅素结构中引入前药基团磷酸酯基明显提高了化合物的渗透性。
实施例四、二氢杨梅素及其磷酸酯前药的药代动力学参数比较
1、色谱条件
色谱柱:ACQUITY UPLC BEH Phenyl(2.1*50mm,1.7μm)
流速:0.5mL/min
A:0.1%FA in H2O
B:ACN
2、给药方案
ICR小鼠6只,雄性,体重18-22g,分别随机分成2组,每组各3只。按照如下方案灌胃给予受试化合物。
试验前禁食12h,自由饮水。给药后2h统一进食。
3、实验分组、采血时间点及样品处理
每个时间点3只动物,分组及采血时间点见下表:
灌胃给药溶液以DMSO/0.5%HPMC(5/95,v/v)配制到最终浓度。给药溶液留样(分别在给药前及给药后,取50μL药液与50μL DMSO混匀)待测。
按上述给药剂量给予药物,记录给药时间,并在以上设定的时间点经小鼠股脉丛取血40μL,置肝素化试管中。立即于4摄氏度下离心5min(转速11000rpm),之后立即准确吸取20μL血浆并加入2μL的20%维生素C水溶液,再加入200μL的乙腈(含1%甲酸)溶液沉淀混匀,冻存于-60℃待测。
4、标准溶液的配制
分别精密称取二氢杨梅素对照品适量,用DMSO溶解稀释配制成二氢杨梅素浓度为3、10、30、100、300、1000、3000和10000ng/mL的标准系列溶液,4℃冰箱保存备用。
5、血浆样品标准曲线的绘制
取小鼠空白血浆18μL,加入二氢杨梅素标准系列溶液2μL和2μL的20%维生素C水溶液,加入加入200μL的乙腈(含1%甲酸)溶液沉淀混匀.于4℃下离心5min(转速11000rpm),冻存于-60℃待测。
6、血药浓度数据处理
运用WinNonlin 6.4软件对血药浓度数据进行分析处理,采用非房室模型计算药动学参数,实验结果如表3所示。
表3:二氢杨梅素与二氢杨梅素7-O-磷酸二苯基酯(5)口服PK参数比较
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实验结果表明,二氢杨梅素的磷酸酯前药二氢杨梅素7-O-磷酸二苯基酯(5)在30mg/kg的口服剂量下,其释放出来的二氢杨梅素最大血药浓度(Cmax)和药时曲线下面积(AUClast)与二氢杨梅素以100mg/kg口服形式给药所达到的最大血药浓度(Cmax)和药时曲线下面积(AUClast)相当。
因此,在二氢杨梅素结构中引入前药基团磷酸酯基明显提高了化合物的暴露量。
实施例五、杨梅素和杨梅素-7-O-磷酸双苯基酯(3)、二氢杨梅素和二氢杨梅素-7-O-磷酸双苯基酯(5)对2019新型冠状病毒复制抑制活性评价
将Vero E6细胞提前一天铺于48孔板中(50000/孔),随后每孔加入不同浓度的小分子化合物,1小时后以MOI=0.01的感染复数加入SARS-CoV-2,孵育一小时后吸走上清,并加入含不同浓度小分子化合物的培养基。感染24小时后,取上清,提取上清中病毒RNA并进行反转,随后利用实时荧光定量PCR方法对上清中病毒RNA拷贝数进行定量,计算不同浓度化合物对病毒RNA的抑制率,利用软件GraphPad Prism 8计算IC50值并拟合抑制曲线图。杨梅素和杨梅素磷酸酯类化合物(3)、二氢杨梅素和二氢杨梅素磷酸酯(5)对2019新型冠状病毒复制抑制活性测试结果如表3所示,杨梅素及其磷酸酯化合物3、二氢杨梅素及其磷酸酯化合物5对2019新型冠状病毒复制抑制的曲线图分别如图5-8所示。
表3:杨梅素和杨梅素-7-O-磷酸双苯基酯(3)对2019新型冠状病毒复制抑制活性测试结果
实验结果显示在杨梅素、二氢杨梅素结构中引入前药基团磷酸酯基有助于提高化合物对新型冠状病毒复制抑制活性。
讨论
在化合物中引入磷酸酯或磷酸及其钠盐作为前药在药物研究与开发中是一个极其重要的策略。在前述发明中,我们发现杨梅素和二氢杨梅素对新冠病毒主蛋白酶SARS-CoV-2 3CLpro有明显的抑制作用,IC50值分别为0.64和1.14μM。但由于杨梅素结构上有6个羟基,造成杨梅素渗透性仅为中等。本发明通过在杨梅素的结构中引入磷酸酯基团,意外的发现所得杨梅素磷酸酯,尤其是杨梅素7-O-磷酸二苯基酯的渗透性有了明显的改善,化合物对细胞膜的通透性得到了提高,从而提高了化合物对新型冠状病毒复制抑制活性。对于二氢杨梅素,本发明通过在二氢杨梅素的结构中引入磷酸酯基团,意外的发现所得二氢杨梅素磷酸酯,尤其是二氢杨梅素7-O-磷酸二苯基酯的口服暴露量和对新型冠状病毒复制抑制活性均有了明显的改善。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (14)
1.一种活性成分或含所述活性成分的制剂的用途,其特征在于,所述的活性成分为式I所示化合物、或其药学上可接受的盐;
式中,
为单键或双键;
R1为:OH;
R2为:
R8、R9各自独立地选自:取代或未取代的苯基;其中,所述的取代表示被一个或多个选自下组的取代基取代:卤素、C1烷基;
或者R8、R9与相连的-O-P-O-共同构成取代或未取代的6-7元杂环,所述的杂环含有2个O杂原子和1个P杂原子,所述的取代表示被一个或多个选自下组的取代基取代:卤素、C1-C3烷基;
并且,所述的活性成分或含所述活性成分的制剂被用于制备(a)抑制2019新型冠状病毒3CL蛋白酶活性的抑制剂;和/或(b)抑制2019新型冠状病毒复制的药物。
2.如权利要求1所述的用途,R8和R9各自独立地选自下组:Cl取代的苯基、Br取代的苯基、I取代的苯基。
3.如权利要求1所述的用途,其特征在于,当式I中为单键,所述活性成分为如式II所示化合物,或其组合物:
式中,R1、R2如权利要求1定义。
4.如权利要求1所述的用途,其特征在于,所述的活性成分选自下组:
5.如权利要求1所述的用途,其特征在于,所述的制剂包括:口服制剂和非口服制剂。
6.一种药物组合物,其特征在于,所述的药物组合物含有:
(a1)第一活性成分,所述第一活性成分为式I所示化合物,或其组合物,
其中,
R1、R2如权利要求1所定义;
(a2)第二活性成分,所述的第二活性成分为抗病毒药物,其选自下组:干扰素、RNA依赖的RNA聚合酶抑制剂;3CL蛋白酶抑制剂;氯喹(Chloroquine,Sigma-C6628)、羟氯喹(hydroxychloroquine)、环孢菌素(cyclosporine)、可利霉素(Carrimycin)、黄芩苷(baicalin)、黄芩素(baicalein)、萘酚喹(Naphthoquine)、环索奈德(Ciclesonide)、利巴韦林(Ribavirin)、喷昔洛韦(Penciclovir)、来氟米特(Leflunomide)、特立氟胺(Teriflunomide)、萘莫司他(nafamostat)、硝唑尼特(nitazoxanide)、达芦那韦(Darunavir)、阿比多尔(Arbidol)、卡莫司他(Camostat)、氯硝柳胺(Niclosamide)、巴瑞替尼(baricitinib)、芦可替尼(Ruxolitinib)、达沙替尼(Dasatinib)、沙奎那韦(Saquinavir)、Beclabuvir、司美匹韦(Simeprevir),或其组合;
及(b)药学上可接受的载体。
7.一种药物组合物,其特征在于,所述的药物组合物含有:
(a1)第一活性成分,所述第一活性成分为式I所示化合物,或其组合物,
其中,
R1、R2如权利要求1所定义;
(a2)第二活性成分,所述的第二活性成分选自下组:锌(Zinc)、芬戈莫德(Fingolimod)、维生素C(Vitamin C)、奥美沙坦酯(Olmesartan Medoxomil)、缬沙坦(valsartan)、氯沙坦(Losartan)、沙利度胺(Thalidomide)、甘草酸(glycyrrhizic acid)、青蒿素(Artemisinin)、双氢青蒿素(dihydroartemisinin)、青蒿琥酯(Artesunate)、青蒿酮(Artemisone)、阿奇霉素(Azithromycin)、七叶皂苷(Escin)、萘普生(Naproxen),或其组合;
及(b)药学上可接受的载体。
8.如权利要求6所述的药物组合物,其特征在于,所述的RNA依赖的RNA聚合酶抑制剂为瑞德西韦、法匹拉韦(favipiravir)、Galidesivir、GS-441524。
9.如权利要求6所述的药物组合物,其特征在于,所述的3CL蛋白酶抑制剂是GC-376、洛匹那韦(Lopinavir)、利托那韦(Ritonavir)、奈非那韦(Nelfinavir)。
10.如权利要求6或7所述的药物组合物,其特征在于,所述的第一活性成分为式II所示化合物,或其组合物,其中式II如权利要求3所定义。
11.一种权利要求6或7所述的药物组合物的用途,其特征在于,用于制备(a)抑制2019新型冠状病毒3CL蛋白酶抑制剂;和/或(b)抑制2019新型冠状病毒复制的药物。
12.一种活性成分,其特征在于,所述活性成分为式II所示的化合物,或其组合物,其中式II如权利要求3所定义。
13.一种体外的抑制2019新型冠状病毒3CL蛋白酶的方法,其特征在于,包括步骤:
将第一活性成分或含所述第一活性成分的制剂与2019新型冠状病毒接触,抑制所述2019新型冠状病毒3CL蛋白酶的活性,从而抑制2019新型冠状病毒的复制;
其中,所述的第一活性成分为权利要求1所述的式I所示的化合物,或其组合物。
14.如权利要求13所述的方法,其特征在于,所述的第一活性成分选自下组:
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