CN113491703B - 苯乙醇苷类化合物及其组合物在制备防治新冠病毒感染的药物中的应用 - Google Patents
苯乙醇苷类化合物及其组合物在制备防治新冠病毒感染的药物中的应用 Download PDFInfo
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Abstract
本发明涉及苯乙醇苷类化合物及其组合物在制备防治新冠病毒感染药物中的应用。具体而言，本发明涉及苯乙醇苷类化合物及其药物组合物作为2019新型冠状病毒(SARS‑CoV‑2)3CL蛋白酶抑制剂在制备治疗和/或预防、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，具体地涉及苯乙醇苷类化合物及其组合物的新用途，尤其是苯乙醇葡萄糖苷类化合物及其组合物在抗冠状病毒(SARS-CoV-2或2019-nCoV)中用途。
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。
新型冠状病毒(SARS-CoV-2)感染可引起肺炎。SARS-CoV-2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。
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a、b、d及g四属。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(2019-nCoV)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。其中3CL蛋白酶(3 Chymotrypsin-like protease,3CLpro)是冠状病毒中负责切割前体蛋白的主蛋白酶(所以又称为Mpro)，对病毒的复制不可或缺。
3CLpro属于半胱氨酸水解酶，在各类冠状病毒中高度保守，与小RNA病毒中的3C蛋白酶也比较相似，而人体中却没有与其相似的蛋白酶，因而是研发广谱抗单正链RNA 病毒药物的理想靶点。2019n-CoV-3CLpro与SARS-CoV-3CLpro的序列等同性高达96%，而底物结合口袋部分更是100%保守。2003年SARS-CoV爆发后针对SARS-CoV-3CLpro设计和发现了多个抑制剂，其多为共价作用的类肽和多肽抑制剂，同时有少量杂环酯类、吡唑类及大环类的非共价抑制剂见报道。这些已知抑制剂的生物活性主要通过体外酶水平检测，少量抑制剂在细胞水平具有一定的抑制效率(EC50多为微摩尔级别)，鲜有具有动物药效的抑制剂见报道，也尚未有任何抑制剂进入系统的临床前研究或临床研究。
目前，针对SARS-CoV-2冠状病毒导致的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3CLpro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3CL蛋白酶的抑制剂用于治疗新型冠状病毒感染。
发明内容
本发明的目的是提供一种可有效抑制冠状病毒3CL蛋白酶的活性成分及其在抑制冠状病毒方面的新用途。
具体地，本发明提供了式I所示的苯乙醇苷类化合物及其组合物在抗冠状病毒尤其是新型冠状病毒(SARS-CoV-2)中的用途。
在本发明第一方面，提供了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化合物或其药学上可接受的盐或其前药：
(I)
式中，
R1选自：H，阿魏酰基、咖啡酰基、肉桂酰基、对羟基肉桂酰基、3,4,5-三甲氧基肉桂酰基；3-甲氧基-4,5-二羟基肉桂酰基；苯丙酰基、对羟基苯丙酰基、3,4-二羟基苯丙酰基、3,4,5-三羟基苯丙酰基、3-甲氧基-4,5-二羟基苯丙酰基、取代或未取代的C1-C6烷酰基、取代或未取代的苯甲酰基、磺酰基；
R2选自：H、L-鼠李糖基、咖啡酰基、阿魏酰基、肉桂酰基、对羟基肉桂酰基、3,4,5-三甲氧基肉桂酰基、3-甲氧基-4,5-二羟基肉桂酰基、苯丙酰基、对羟基苯丙酰基、3,4-二羟基苯丙酰基、3,4,5-三羟基苯丙酰基、3-甲氧基-4,5-二羟基苯丙酰基、取代或未取代的C1-C6烷酰基、取代或未取代的苯甲酰基、磺酰基；
R3选自：H、咖啡酰基、阿魏酰基、肉桂酰基、对羟基肉桂酰基、3,4,5-三甲氧基肉桂酰基、3-甲氧基-4,5-二羟基肉桂酰基、苯丙酰基、对羟基苯丙酰基、3,4-二羟基苯丙酰基、3,4,5-三羟基苯丙酰基、3-甲氧基-4,5-二羟基苯丙酰基、取代或未取代的C1-C6烷酰基、取代或未取代的苯甲酰基、磺酰基；
R4选自：芹糖基、鼠李糖基、木糖基、葡萄糖基、H、咖啡酰基，阿魏酰基；肉桂酰基、对羟基肉桂酰基、3,4,5-三甲氧基肉桂酰基、3-甲氧基-4,5-二羟基肉桂酰基、苯丙酰基、对羟基苯丙酰基、3,4-二羟基苯丙酰基、3,4,5-三羟基苯丙酰基、3-甲氧基-4,5-二羟基苯丙酰基、取代或未取代的C1-C6烷酰基、取代或未取代的苯甲酰基、磺酰基；
R5选自：H、OH、C1-C6烷氧基(如甲氧基)；
R6选自：H、C1-C6烷基(如甲基)；
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(SARS-CoV-2) 3CL蛋白酶的抑制剂；和/或(b)治疗和/或预防、缓解由2019新型冠状病毒(SARS-CoV-2)感染引起的相关疾病的药物。
在另一优选例中，所述的糖基包括L型、D型或其组合。
在另一优选例中，所述的糖基(如芹糖基、鼠李糖基、木糖基、葡萄糖基)中的任一个糖基包括α型糖基、β型糖基、或其组合。
在另一优选例中，所述由2019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，所述由2019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，R1选自：H、咖啡酰基；和/或
R2选自：H、α-L-鼠李糖、咖啡酰基；和/或
R3选自：H、咖啡酰基、阿魏酰基；和/或
R4选自：α-L-芹糖，α-L-鼠李糖，β-L-鼠李糖，β-D-木糖，β-D-葡萄糖；和/或
R5选自：H、OH、甲氧基；和/或
R6选自：H、甲基。
在另一优选例中，所述的式I化合物为3',4'-双羟基苯乙醇-1-葡萄糖苷类化合物。
在另一优选例中，所述的活性成分选自下组：
A(1) 连翘酯苷A (Forsythiaside A)；
A(2) 连翘酯苷B(Forsythiaside B)；
A(3) 连翘酯苷E(Forsythiaside E)；
A(4) 连翘酯苷H(Forsythiaside H)；
A(5) 连翘酯苷I(Forsythiaside I)；
A(6) 异连翘酯苷(Isoforsythiaside )；
A(7) 毛蕊花糖苷(Acteoside)；
A(8) 焦地黄苯乙醇苷A1(Jionoside A1)；
A(9) 异麦角甾苷(Isoacteoside)；
A(10) 松果菊苷(Echinacoside)；
A(11) 金石蚕苷(Poliumoside)；
A(12) 木通苯乙醇苷B(calceolarioside B)；
B 上述A(1)～A(12)的任意组合；
C 及其可接受的盐。
在另一优选例中，所述的活性成分选自下组：连翘酯苷A、连翘酯苷B、连翘酯苷H。
在另一优选例中，所述的药物还包括选自下组的额外组分：抗逆传录病毒的药物或增强免疫力的药物。
在另一优选例中，所述式(I)中，R5为OH，R6为H。
在另一优选例中，所述的组合物或药物包括：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，所述的第一活性成分为式I所示的苯乙醇苷类化合物或其药学上可接受的盐或其前药：
(I)
式中，
R1选自：H，阿魏酰基、咖啡酰基、肉桂酰基、对羟基肉桂酰基、3,4,5-三甲氧基肉桂酰基；3-甲氧基-4,5-二羟基肉桂酰基；苯丙酰基、对羟基苯丙酰基、3,4-二羟基苯丙酰基、3,4,5-三羟基苯丙酰基、3-甲氧基-4,5-二羟基苯丙酰基、取代或未取代的C1-C6烷酰基、取代或未取代的苯甲酰基、磺酰基；
R2选自：H、L-鼠李糖基、咖啡酰基、阿魏酰基、肉桂酰基、对羟基肉桂酰基、3,4,5-三甲氧基肉桂酰基、3-甲氧基-4,5-二羟基肉桂酰基、苯丙酰基、对羟基苯丙酰基、3,4-二羟基苯丙酰基、3,4,5-三羟基苯丙酰基、3-甲氧基-4,5-二羟基苯丙酰基、取代或未取代的C1-C6烷酰基、取代或未取代的苯甲酰基、磺酰基；
R3选自：H、咖啡酰基、阿魏酰基、肉桂酰基、对羟基肉桂酰基、3,4,5-三甲氧基肉桂酰基、3-甲氧基-4,5-二羟基肉桂酰基、苯丙酰基、对羟基苯丙酰基、3,4-二羟基苯丙酰基、3,4,5-三羟基苯丙酰基、3-甲氧基-4,5-二羟基苯丙酰基、取代或未取代的C1-C6烷酰基、取代或未取代的苯甲酰基、磺酰基；
R4选自：芹糖基、鼠李糖基、木糖基、葡萄糖基、H、咖啡酰基，阿魏酰基；肉桂酰基、对羟基肉桂酰基、3,4,5-三甲氧基肉桂酰基、3-甲氧基-4,5-二羟基肉桂酰基、苯丙酰基、对羟基苯丙酰基、3,4-二羟基苯丙酰基、3,4,5-三羟基苯丙酰基、3-甲氧基-4,5-二羟基苯丙酰基、取代或未取代的C1-C6烷酰基、取代或未取代的苯甲酰基、磺酰基；
R5选自：H、OH、C1-C6烷氧基(如甲氧基)；
R6选自：H、C1-C6烷基(如甲基)；
(a2)任选的第二活性成分，所述的第二活性成分选自下组：(Y1) RNA复制酶抑制剂(如Remdesivir(瑞德西韦或GS-5734))；(Y2) 洛匹那韦(Lopinavir)；(Y3) 利托那韦(Ritonavir)；(Y4) 法匹拉韦；(Y5) 氯喹(Chloroquine,Sigma-C6628)、羟氯喹、或其药学上可接受的盐(如磷酸氯喹)、(Y6)上述Y1～Y5的任意组合；
以及(b)药学上可接受的载体。
在另一优选例中，R5为OH，R6为H。
在另一优选例中，所述的第一活性成分选自下组：
A(1) 连翘酯苷A (Forsythiaside A)；
A(2) 连翘酯苷B(Forsythiaside B)；
A(3) 连翘酯苷E(Forsythiaside E)；
A(4) 连翘酯苷H(Forsythiaside H)；
A(5) 连翘酯苷I(Forsythiaside I)；
A(6) 异连翘酯苷(Isoforsythiaside )；
A(7) 毛蕊花糖苷(Acteoside)；
A(8) 焦地黄苯乙醇苷A1(Jionoside A1)；
A(9) 异麦角甾苷(Isoacteoside)；
A(10) 松果菊苷(Echinacoside)；
A(11) 金石蚕苷(Poliumoside)；
A(12) 木通苯乙醇苷B(calceolarioside B)；
B 上述A(1)～A(12)的任意组合；
C 及其可接受的盐。
在另一优选例中，所述的药物组合物为用于抑制2019新型冠状病毒(SARS-CoV-2)3CL蛋白酶的药物组合物。
在另一优选例中，所述的药物组合物用于制备(a)抑制2019新型冠状病毒(SARS-CoV-2) 3CL蛋白酶的抑制剂；和/或(b)治疗和/或预防、缓解由2019新型冠状病毒(SARS-CoV-2)感染引起的相关疾病的药物。
在本发明第三方面，提供了一种抑制2019新型冠状病毒(SARS-CoV-2) 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2019新型冠状病毒(SARS-CoV-2)的3CL蛋白酶接触，从而抑制所述3CL蛋白酶的活性；
其中，所述的第一活性成分为式I化合物或其药学上可接受的盐或其前药：
(I)
式中，
R1选自：H，阿魏酰基、咖啡酰基、肉桂酰基、对羟基肉桂酰基、3,4,5-三甲氧基肉桂酰基；3-甲氧基-4,5-二羟基肉桂酰基；苯丙酰基、对羟基苯丙酰基、3,4-二羟基苯丙酰基、3,4,5-三羟基苯丙酰基、3-甲氧基-4,5-二羟基苯丙酰基、取代或未取代的C1-C6烷酰基、取代或未取代的苯甲酰基、磺酰基；
R2选自：H、L-鼠李糖基、咖啡酰基、阿魏酰基、肉桂酰基、对羟基肉桂酰基、3,4,5-三甲氧基肉桂酰基、3-甲氧基-4,5-二羟基肉桂酰基、苯丙酰基、对羟基苯丙酰基、3,4-二羟基苯丙酰基、3,4,5-三羟基苯丙酰基、3-甲氧基-4,5-二羟基苯丙酰基、取代或未取代的C1-C6烷酰基、取代或未取代的苯甲酰基、磺酰基；
R3选自：H、咖啡酰基、阿魏酰基、肉桂酰基、对羟基肉桂酰基、3,4,5-三甲氧基肉桂酰基、3-甲氧基-4,5-二羟基肉桂酰基、苯丙酰基、对羟基苯丙酰基、3,4-二羟基苯丙酰基、3,4,5-三羟基苯丙酰基、3-甲氧基-4,5-二羟基苯丙酰基、取代或未取代的C1-C6烷酰基、取代或未取代的苯甲酰基、磺酰基；
R4选自：芹糖基、鼠李糖基、木糖基、葡萄糖基、H、咖啡酰基，阿魏酰基；肉桂酰基、对羟基肉桂酰基、3,4,5-三甲氧基肉桂酰基、3-甲氧基-4,5-二羟基肉桂酰基、苯丙酰基、对羟基苯丙酰基、3,4-二羟基苯丙酰基、3,4,5-三羟基苯丙酰基、3-甲氧基-4,5-二羟基苯丙酰基、取代或未取代的C1-C6烷酰基、取代或未取代的苯甲酰基、磺酰基；
R5选自：H、OH、C1-C6烷氧基(如甲氧基)；
R6选自：H、C1-C6烷基(如甲基)。
在另一优选例中，所述的第一活性成分选自下组：
A(1) 连翘酯苷A (Forsythiaside A)；
A(2) 连翘酯苷B(Forsythiaside B)；
A(3) 连翘酯苷E(Forsythiaside E)；
A(4) 连翘酯苷H(Forsythiaside H)；
A(5) 连翘酯苷I(Forsythiaside I)；
A(6) 异连翘酯苷(Isoforsythiaside )；
A(7) 毛蕊花糖苷(Acteoside)；
A(8) 焦地黄苯乙醇苷A1(Jionoside A1)；
A(9) 异麦角甾苷(Isoacteoside)；
A(10) 松果菊苷(Echinacoside)；
A(11) 金石蚕苷(Poliumoside)；
A(12) 木通苯乙醇苷B(calceolarioside B)；
B 上述A(1)～A(12)的任意组合；
C 及其可接受的盐。
在另一优选例中，与2019新型冠状病毒(SARS-CoV-2)的3CL蛋白酶接触的式I化合物或其药学上可接受的盐的浓度为0.5-20μM。
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显示了连翘酯苷A对SARS-CoV-2的3CL蛋白酶的抑制曲线。
图2显示了连翘酯苷B对SARS-CoV-2的3CL蛋白酶的抑制曲线。
图3显示了连翘酯苷H对SARS-CoV-2的3CL蛋白酶的抑制曲线。
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，首次意外地开发了一类可有效抑制2019新型冠状病毒(SARS-CoV-2)等冠状病毒的3CL蛋白酶的活性成分。实验表明，本发明的活性物质苯乙醇苷类化合物(如连翘酯苷A、连翘酯苷B、连翘酯苷E、连翘酯苷H、连翘酯苷I、异连翘酯苷、毛蕊花糖苷、焦地黄苯乙醇苷A1、松果菊苷、金石蚕苷、异麦角甾苷、木通苯乙醇苷B等或其药学上可接受的盐)可高效地抑制2019新型冠状病毒(SARS-CoV-2)等冠状病毒的3CL蛋白酶的活性，从而抑制SARS-CoV-2冠状病毒的复制和活力。在此基础上完成了本发明。
具体地，本发明揭示了翘酯苷A、连翘酯苷B连翘酯苷H及其组合物在抗冠状病毒的用途，尤其是在抗SARS-CoV-2病毒治疗中的用途。翘酯苷A、连翘酯苷B连翘酯苷H及其组合物对冠状病毒复制必不可少且高度保守的3CL水解酶具有优良的抑制作用，具有良好的临床应用前景。
术语
如本文所用，“本发明的活性化合物”、“本发明的活性成分”、“本发明的抑制3CL蛋白酶的活性化合物”可互换使用，指具有优异的3CL蛋白酶抑制活性的苯乙醇苷类化合物，包括式I所示的化合物，例如连翘酯苷A、连翘酯苷B、连翘酯苷H及其药学上可接受的盐、或其前药、或其组合。
如本文所用，“本发明的制剂”指含有本发明活性化合物的制剂。
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，并且造成新冠病毒感染(COVID-19)，是威胁全球人类健康的严重传染性疾病之一。
冠状病毒和3CL蛋白酶
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a、b、d及g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。
3CL蛋白酶(3 Chymotrypsin-like protease, 3CLpro)是冠状病毒中负责切割前体蛋白的主蛋白酶(所以又称为Mpro)，对病毒的复制不可或缺。
3CLpro属于半胱氨酸水解酶，在各类冠状病毒中高度保守，与小RNA病毒中的3C蛋白酶也比较相似，而人体中却没有与其相似的蛋白酶，因而是研发广谱抗单正链RNA病毒药物的理想靶点。
本发明的活性成分
在本发明中，提供了一种可有效抑制2019新型冠状病毒(SARS-CoV-2)等冠状病毒复制的活性成分。
该活性成分为式I化合物或其药学上可接受的盐或其前药：
(I)
式中，R1、R2、R3、R4、R5、和R6的定义如上所述。
在另一优选例中，该活性成分选自下组，且对应结构为：
本发明的活性成分(苯乙醇苷类化合物)包括人工合成的或天然形成的。
一些苯乙醇苷类化合物是广泛存在于双子叶植物中的天然产物。马鞭草科、苦苣苔科、唇形科、玄参科、木犀科、列当科、木通科、车前科等多科的药用植物中均有该类成分的。该类化合物以β-葡萄糖为母核，分别与苯丙烯酸酯化、苯乙醇或α-羟基苯乙醇苷化；中心葡萄糖基上常连有乙酰基、咖啡酰基、阿魏酰基、香豆酰基、桂皮酰基、香草酰基或鼠李糖、阿拉伯糖、芹糖、葡萄糖等糖基。已有的研究报道该类化合物具有抗菌、抗炎等活性。
实验表明，本发明的活性成分可高效地抑制2019新型冠状病毒(2019-nCov)等冠状病毒的3CL蛋白酶的活性，从而抑制2019-nCov冠状病毒的复制和活，进而预防、治疗和/或缓解SARS-CoV-2相关疾病。通过分析总结化合物的结构与活性之间的关系，发明人意外地发现：3',4'-双羟基苯乙醇-1-葡萄糖苷结构为活性的核心骨架，葡萄糖结构上的其余羟基上的不同取代基，如糖基(包括葡萄糖、鼠李糖、芹糖、木糖等)、酰基(咖啡酰基、阿魏酰基等)对3CL蛋白酶的抑制活性无影响，即核心骨架为3',4'-双羟基苯乙醇-1-葡萄糖苷的结构衍生物均对3CL蛋白酶有抑制作用，从而抑制2019-nCov冠状病毒的复制和活力。
如本文所用，“本发明的活性化合物”、“本发明的抑制3CL蛋白酶的活性化合物”可互换使用，指具有优异的3CL蛋白酶抑制活性的化合物，包括连翘酯苷A、连翘酯苷B、连翘酯苷H或其药学上可接受的盐、或其晶体、或其溶剂化物。
应理解，本发明的活性成分包括本发明的抑制3CL蛋白酶的活性化合物、或其药学上可接受的盐、对映异构体、非对映异构体或外消旋体、或其前药。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、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。
此外，本发明的活性成分还特别适合与其他抗病毒的药物联用。代表性的其他的抗病毒药物包括(但并不限于)：逆转录酶抑制剂、蛋白酶抑制剂、辅助受体拮抗剂、逆转录病毒整合酶抑制剂、病毒吸附抑制剂、特异性病毒转录抑制剂、抗体、或其组合。
本发明的活性成分可抑制SARS-CoV-2等新型冠状病毒的感染活性。因此，当在治疗上施用或给予本发明的的活性成分时，可抑制3CL蛋白酶活性，从而抑制2019新型冠状病毒(SARS-CoV-2)的感染，进而达到抗病毒作用。
药物组合物和应用
本发明还提供了以本发明的抑制3CL蛋白酶的活性化合物、或其药学上可接受的盐、或其前药、或其提取物、或其药材中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0.01-400 mg/kg体重，一次性服用，或0.01-200 mg/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。
本发明的主要优点包括：
(a)本发明活性化合物可高效地抑制SARS-CoV-2 3CL蛋白酶，优选的连翘酯苷A、连翘酯苷B、连翘酯苷H的IC50值可以达到个位数微摩尔级别，最优的连翘酯苷A的IC50值为约6.26μM。
(b)本发明活性化合物对2019-nCoV-3CLpro具有浓度依赖的抑制作用，为抗2019-nCoV提供了潜在候选药物。
(c)本发明活性化合物的毒副作用低，成药性好。这提示着本发明的苯乙醇苷类化合物在抗新冠病毒感染领域有很好的药用前景。
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，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1：连翘中苯乙醇苷类化合物的分离与结构鉴定
1.1.方法
购自上海同仁堂的连翘果实(5 Kg)粉碎后用70%的工业乙醇 (50 L)室温浸泡3次，每次7天。乙醇提取液合并浓缩后所得流浸膏(约1 Kg)加15 L的蒸馏水混悬后用乙酸乙酯(10 L)萃取3次，除去中低极性成分；水层浓缩至3 L后上大孔树脂柱层析(AB-8, 3 Kg)依次用水、10%乙醇、40%乙醇、70%乙醇和95%乙醇各洗脱25 L。经HPLC-MS分析，连翘酯苷类成分主要集中于40%乙醇洗脱部位。40%洗脱液浓缩后所得浸膏取10 g用OSD拌样后上ODS(RP-C18, 60 μM, 1 Kg)柱层析后依次用20%甲醇、30%甲醇、40%甲醇、50%甲醇、60%甲醇和100%甲醇洗脱，得馏分F1-F6，馏分F2经制备型高效液相色谱纯化 (15% ～ 25% 乙腈/水)得连翘酯苷E (10 mg)；馏分F3经制备型高效液相色谱纯化 (15% ～ 25% 乙腈/水)得连翘酯苷B (40 mg)和连翘酯苷A (50 mg)；馏分F4经制备型高效液相色谱纯化 (20% ～ 35%乙腈/水)纯化得连翘酯苷A (60 mg)、连翘酯苷H (20 mg)、连翘酯苷I (10 mg)、异连翘酯苷 (8 mg)、毛蕊花糖苷 (17 mg)。
1.2.结果
上述化合物的理化性质与波谱数据如下：
连翘酯苷A (Forsythoside A)：白色粉末，ESI-MS m/z 622.9 [M-H]+; 1H NMR(600 MHz, MeOH-d4) 苯乙醇片段：δ 6.69 (1H, d, J = 2.1 Hz, H-2), 6.68 (1H, d, J= 8.0 Hz, H-5), 6.56 (1H, dd, J = 2.1, 8.0 Hz, H-6), 2.80 (2H, m, H-7), 3.66and 3.98 (each 1H, m, H-8a, 8b), 咖啡酰基片段：δ 7.05 (1H, d, J = 2.1 Hz, H-2'), 6.78 (1H, d, J = 8.2 Hz, H-5'), 6.96 (1H, dd, J = 2.1, 8.2 Hz, H-6'),6.30 and 7.60 (each 1H, d, J = 15.8 Hz, H-7',8'), 葡萄糖片段：δ 4.36 (1H, d, J= 7.8 Hz, H-1''), 3.29 (1H, dd, J = 7.8, 9.3 Hz, H-2''),3.62 (1H, m, H-3''),4.92 (1H, t, J = 9.6 Hz, H-4''), 3.61 (1H, m, H-5''), 3.48 (1H, dd, J = 5.8,11.4 Hz, H-6''a) and 3.73 (1H, m, H-6''a); 鼠李糖片段：δ 4.64 (1H, d, J = 1.7Hz, H-1'''), 3.83 (1H, dd, J = 1.7, 3.5Hz, H-2'''), 3.66 (1H, m, H-3'''),3.34 (1H, t, J = 9.5 Hz, H-4'''), 3.59 (1H, m, H-5'''), 1.20 (3H, d, J = 6.2Hz, H-6'''); 13C NMR (150 MHz, MeOH-d4): 苯乙醇片段：δ 146.1, 144.7, 131.4 ,121.3, 117.1, 116.3, 72.4, 36.7; 咖啡酰基片段：δ 168.2, 149.7, 147.6, 146.7,127.7, 123.1, 116.5, 115.2, 114.7; 葡萄糖片段：δ 104.5, 75.8, 75.2, 74.8,73.9, 67.7; 鼠李糖片段：δ 102.3, 72.3, 72.3, 72.0, 69.9, 18.0.
连翘酯苷B (Forsythoside B)：白色粉末，ESI-MS m/z 754.9 [M-H]+; 1H NMR(600 MHz, MeOH-d4) 苯乙醇片段：δ 6.70 (1H, d, J = 2.0 Hz, H-2), 6.68 (1H, d, J= 8.0 Hz, H-5), 6.57 (1H, dd, J = 2.0, 8.0 Hz, H-6), 2.80 (2H, m, H-7), 3.71and 4.01 (each 1H, m, H-8a, 8b), 咖啡酰基片段：δ 7.06 (1H, d, J = 2.1 Hz, H-2'), 6.78 (1H, d, J = 8.2 Hz, H-5'), 6.96 (1H, dd, J = 2.1, 8.2 Hz, H-6'),6.28 and 7.59 (each 1H, d, J = 15.8 Hz, H-7',8'), 葡萄糖片段：δ 4.37 (1H, d, J= 7.9 Hz, H-1''), 3.38 (1H, dd, J = 7.9, 9.2 Hz, H-2''), 3.80 (1H, t, J = 9.3Hz, H-3''), 4.94 (1H, t, J = 9.3 Hz, H-4''), 3.73 (1H, m, H-5''), 3.49 and3.74 (each 1H, m, H-6''); 鼠李糖片段：δ 5.19 (1H, d, J = 1.8 Hz, H-1'''), 3.91(1H, m, H-2'''), 3.56 (1H, m, H-3'''), 3.29 (1H, t, J = 9.5 Hz, H-4'''), 3.57(1H, m, H-5'''), 1.08 (3H, d, J = 6.2 Hz, H-6'''); 芹糖片段: δ 4.92 (1H, d, J= 2.3 Hz, H-1''''), 3.87 (1H, d, J = 2.3 Hz, H-2''''), 3.92 (1H, J = 9.8 Hz,H-4a''''), 3.74 (1H, m, H-4b''''), 3.54 (2H, s, H-5''''); 13C NMR (150 MHz,MeOH-d4): 苯乙醇片段：δ 146.1, 144.7, 131.4, 121.3 , 117.1, 116.3, 72.4, 36.7;咖啡酰基片段：δ 168.1, 149.8, 148.0, 146.8, 127.7, 123.2, 116.5, 115.2, 114.8;葡萄糖片段：δ 104.3, 81.7, 76.2, 74.6, 70.9, 68.5; 鼠李糖片段：δ 103.6, 73.8,72.4, 72.1, 70.4, 18.5; 芹糖片段：δ 111.1, 80.6, 78.1, 75.1, 65.7.
连翘酯苷E (Forsythoside E)：白色粉末，ESI-MS m/z 622.9 [M-H]+; 1H NMR(600 MHz, MeOH-d4) 苯乙醇片段：δ 6.69 (1H, d, J = 1.8 Hz, H-2), 6.67 (1H, d, J= 8.6 Hz, H-5), 6.55 (1H, dd, J = 1.8, 8.6 Hz, H-6), 2.79 (2H, m, H-7), 3.68and 3.98 (each 1H, m, H-8a, 8b), 咖啡酰基片段：δ 7.05 (1H, d, J = 2.0 Hz, H-2'), 6.76 (1H, d, J = 8.0 Hz, H-5'), 6.95 (1H, dd, J = 2.0, 8.0 Hz, H-6'),6.32 and 7.58 (each 1H, d, J = 15.6 Hz, H-7',8'), 葡萄糖片段：δ 4.37 (1H, d, J= 7.8 Hz, H-1''), 3.62 (1H, m, H-2''), 3.28 (1H, m, H-3''), 4.92 (1H, m, H-4''), 3.61 (1H, m, H-5''), 3.49 and 3.74 (each 1H, m, H-6''); 鼠李糖片段：δ4.65 (1H, d, J = 7.8 Hz, H-1'''), 3.85 (1H, m, H-2'''), 3.69 (2H, m, H-3'''),3.33 (1H, m, H-4'''), 3.59 (1H, m, H-5'''), 1.21 (3H, d, J = 6.2 Hz, H-6''');13C NMR (150 MHz, MeOH-d4): 苯乙醇片段：δ 144.7, 143.3, 130.0 , 119.0, 115.8,115.2, 70.9, 35.3; 咖啡酰基片段：δ 166.9, 148.3, 146.3, 145.4, 126.3, 121.8,115.0, 113.9, 113.4; 葡萄糖片段：δ 103.1, 74.4, 73.8, 73.4, 70.9, 66.3; 鼠李糖片段：δ 100.9, 72.6, 71.0, 70.6, 68.5, 18.5.
连翘酯苷H (Forsythoside H)：白色粉末，ESI-MS m/z 622.9 [M-H]+; 1H NMR(600 MHz, MeOH-d4) 苯乙醇片段：δ 6.61 (1H, d, J = 2.0 Hz, H-2), 6.59 (1H, d, J= 8.0 Hz, H-5), 6.49 (1H, dd, J = 2.0, 8.0 Hz, H-6), 2.68 (2H, t, J = 7.1 Hz,H-7), 3.95 and 3.63 (each 1H, m, H-8), 咖啡酰基片段：δ 7.07 (1H, d, J = 2.0Hz, H-2'), 6.79 (1H, d, J = 8.2 Hz, H-5'), 6.97 (1H, dd, J = 2.0, 8.2 Hz, H-6'), 6.28 and 7.57 (each 1H, d, J = 15.7 Hz, H-7',8'), 葡萄糖片段：δ 4.50 (1H,d, J = 8.0 Hz, H-1''), 4.81 (1H, dd, J = 8.0, 9.4 Hz, H-2''), 3.57 (1H, t, J= 9.4 Hz , H-3''), 3.38 (1H, t, J = 9.4 Hz, H-4''), 3.45 (1H, m, H-5''), 3.66(1H, m, H-6a'') and 4.00 (1H, dd, J = 1.6, 11.1 Hz, H-6b''); 鼠李糖片段：δ4.76 (1H, d, J = 1.4 Hz, H-1'''), 3.85 (1H, m, H-2'''), 3.70 (2H, m, H-3'''),3.37 (1H, m, H-4'''), 3.69 (1H, m, H-5'''), 1.27 (3H, d, J = 6.3 Hz, H-6''');13C NMR (150 MHz, MeOH-d4): 苯乙醇片段：δ 146.5, 145.0, 131.9, 121.8, 117.5,116.8, 72.5, 37.2; 咖啡酰基片段：δ 168.9, 150.0, 147.6, 147.3, 128.3, 123.5,117.0, 115.7, 115.7; 葡萄糖片段：δ 102.9, 77.4, 76.7, 75.6, 72.2, 68.4; 鼠李糖片段：δ 102.7, 74.5, 72.9, 72.7, 70.3, 18.6.
连翘酯苷I (Forsythoside I)：白色粉末，ESI-MS m/z 622.9 [M-H]+; 1H NMR(600 MHz, MeOH-d4) 苯乙醇片段：δ 6.69 (1H, d, J = 2.1 Hz, H-2), 6.68 (1H, d, J= 8.0 Hz, H-5), 6.57 (1H, dd, J = 2.0, 8.0 Hz, H-6), 2.80 (2H, m, H-7), 3.72and 3.37 (each 1H, m, H-8), 咖啡酰基片段：δ 7.04 (1H, d, J = 2.1 Hz, H-2'),6.78 (1H, d, J = 8.1 Hz, H-5'), 6.96 (1H, dd, J = 2.1, 8.1 Hz, H-6'), 6.33and 7.59 (each 1H, d, J = 15.9 Hz, H-7',8'), 葡萄糖片段：δ 4.41 (1H, d, J =7.8 Hz, H-1''), 3.97 (1H, t, J = 7.8 Hz, H-2''), 5.04 (1H, m, H-3''), 4.00(1H, m, H-4''), 3.74 (1H, m, H-5''), 3.39 (1H, m, H-6a'') and 3.73 (1H, m, H-6b''); 鼠李糖片段：δ 4.75 (1H, d, J = 1.7 Hz, H-1'''), 3.85 (1H, m, H-2'''),3.52-3.70 (1H, m, H-3''',4''',5'''), 1.27 (3H, d, J = 6.2 Hz, H-6'''); 13CNMR (150 MHz, MeOH-d4): 苯乙醇片段：δ 146.1, 144.7, 131.4, 121.3, 117.1,116.3, 72.3, 36.7; 咖啡酰基片段：δ 169.1, 149.5, 146.9, 146.8, 127.9, 122.9,116.5, 115.4, 115.1; 葡萄糖片段：δ 104.4, 78.9, 76.7, 73.5, 69.9, 67.8; 鼠李糖片段：δ 102.2, 74.0, 72.3, 72.3, 70.0, 18.1.
异连翘酯苷(Isoforsythoside)：白色粉末，ESI-MS m/z 622.9 [M-H]+; 1H NMR(600 MHz, MeOH-d4) 苯乙醇片段：δ 6.69 (1H, d, J = 2.0 Hz, H-2), 6.68 (1H, d, J= 8.0 Hz, H-5), 6.56 (1H, dd, J = 1.8, 8.0 Hz, H-6), 2.80 (2H, m, H-7), 3.75and 4.00 (each 1H, m, H-8a, 8b), 咖啡酰基片段：δ 7.05 (1H, d, J = 2.0 Hz, H-2'), 6.78 (1H, d, J = 8.2 Hz, H-5'), 6.95 (1H, dd, J = 2.0, 8.2 Hz, H-6'),6.33 and 7.59 (each 1H, d, J = 15.9 Hz, H-7',8'), 葡萄糖片段：δ 4.41 (1H, d, J= 7.8 Hz, H-1''), 3.37 (1H, m, H-2''), 3.38 (1H, m, H-3''), 5.03 (1H, m, H-4''), 3.51 (1H, m, H-5''), 3.67 and 3.99 (each 1H, m, H-6''); 鼠李糖片段：δ4.75 (1H, d, J = 1.7 Hz, H-1'''), 3.85 (1H, m, H-2'''), 3.65-3.71 (3H, m, H-3''', 4''' 5'''), 1.26 (3H, d, J = 6.0 Hz, H-6'''); 13C NMR (125 MHz, MeOH-d4): 苯乙醇片段：δ 146.1, 144.7, 131.4 , 121.3, 117.1, 116.3, 72.3, 37.1; 咖啡酰基片段：δ 169.0, 149.6, 148.6, 147.0, 127.9, 123.4, 116.8, 115.9, 115.0; 葡萄糖片段：δ 104.4, 79.5, 76.7, 73.5, 70.0, 67.8; 鼠李糖片段：δ 102.2, 74.0,72.4, 72.2, 69.9, 18.5.
毛蕊花糖苷(Acteoside)：白色粉末，ESI-MS m/z 622.9 [M-H]+; 1H NMR (400MHz, MeOH-d4) 苯乙醇片段：δ 6.69 (1H, d, J = 1.8 Hz, H-2), 6.67 (1H, d, J =8.0 Hz, H-5), 6.56 (1H, dd, J = 1.8, 8.0 Hz, H-6), 2.80 (2H, m, H-7), 3.71and 4.03 (each 1H, m, H-8a, 8b), 咖啡酰基片段：δ 7.05 (1H, d, J = 1.8 Hz, H-2'), 6.78 (1H, d, J = 8.1 Hz, H-5'), 6.96 (1H, dd, J = 2.0, 8.2 Hz, H-6'),6.27 and 7.59 (each 1H, d, J = 15.9 Hz, H-7',8'), 葡萄糖片段：δ 4.38 (1H, d, J= 7.9 Hz, H-1''), 3.38 (1H, m, H-2''), 3.81 (1H, t, J = 9.2 Hz, H-3''), 4.92(1H, t, J = 9.2 Hz, H-4''), 3.54 (1H, m, H-5''), 3.52 and 3.62 (each 1H, m,H-6''); 鼠李糖片段：δ 5.19 (1H, d, J = 1.2 Hz, H-1'''), 3.91 (1H, m, H-2'''),3.58 (1H, m, H-3'''), 3.29 (1H, m, H-4'''), 3.56 (1H, m, H-5'''), 1.09 (3H,d, J = 6.2 Hz, H-6'''); 13C NMR (100 MHz, MeOH-d4): 苯乙醇片段：δ 146.1,144.7, 131.5, 121.3, 117.1, 116.3, 72.3, 36.6; 咖啡酰基片段：δ 168.2, 149.8,148.0, 146.8, 127.7, 123.2, 116.5, 115.2, 114.7; 葡萄糖片段：δ 104.2, 81.6,76.2, 76.1, 70.6, 62.4; 鼠李糖片段：δ 103.0, 73.8, 72.4, 72.3, 70.4, 18.4.
实施例2：连翘酯苷类化合物对2019-nCoV-3CLpro的抑制作用
利用荧光共振能量转移方法评价测定连翘中的苯乙醇苷类化合物对2019-nCoV3CLpro酶活的抑制活性。整个酶促反应体系的体积为120 µL，蛋白酶的终浓度为30 nM，底物终浓度为20 µM。反应体系的缓冲液包括50mM Tris pH7.3、1mM EDTA。在96孔板中加入2019-nCoV 3CLpro蛋白酶和不同浓度的化合物或混合物等样品，30℃孵育10 min，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340 nM和405 nM。测试时间为10 min，每隔30s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、图2、图3分别是连翘酯苷A、连翘酯苷B、连翘酯苷H对SARS-CoV-2蛋白酶的抑制曲线
将不同苯乙醇苷类化合物对2019-nCoV-3CLpro抑制的IC50值列在表中，实验结果如表1所示。
表1：连翘中苯乙醇苷类化合物对2019-nCoV-3CLpro的抑制作用
-: 无效，IC50>100 uM； +: 弱效，50 uM ≥ IC50≥ 100 uM； ++: 中效，10 uM ≥IC50>50 uM；+++ 强效：1 uM ≥ IC50>10 uM。
上述活性结果表明，连翘中苯乙醇苷类化合物均对2019-nCoV-3CLpro具有不同程度的抑制作用。由于各种冠状病毒中3CLpro及其底物结合口袋的高度保守性，连翘中苯乙醇苷类化合物有望抑制其他冠状病毒3CLpro而发挥广谱的抗病毒活性。
图1、图2、图3分别是连翘酯苷A、连翘酯苷B、连翘酯苷H对SARS-CoV-2蛋白酶的抑制曲线，由图可知，连翘酯苷A、连翘酯苷B、连翘酯苷H的IC50值可以达到个位数微摩尔级别，最优的连翘酯苷A的IC50值为约6.26μM，是是潜在的抗2019-nCoV候选药物。
根据上述活性化合物的结构与活性之间的关系可以看出，羟基取代的苯乙醇葡萄糖苷(3',4'-双羟基苯乙醇-1-葡萄糖苷)是抑制2019-nCoV-3CLpro核心结构单元，葡萄糖结构上的取代基(包括咖啡酰基、鼠李糖、芹糖等)不同或者位置不同，仅影响活性的强弱，但均对2019-nCoV-3CLpro具有不同程度的抑制作用，是潜在的抗2019-nCoV候选药物。
实施例3：其它苯乙醇苷类化合物的分离与结构鉴定
参照文献以及上述制备方法，红景天苷(Salidroside)、焦地黄苯乙醇苷A1(Jionoside A1)和B1(Jionoside B1)、异麦角甾苷(Isoacteoside)和松果菊苷(Echinacoside)和肉苁蓉苷A(Cistanoside A)、金石蚕苷(Poliumoside)、安格洛苷C(Angoroside C)、木通苯乙醇苷B(calceolarioside B)、去鼠李糖地黄苷(Desrhamnosylmartynoside)分别从红景天(Rhodiola rosea)、熟地黄(Radix RehmanniaePraeparata)、肉苁蓉(Cistanche tubulosa )、广东紫株(Callicarpa kwangtungensis)、玄参(Scrophularia ningpoensis)、木通(Akebia quinata)、平卧黄芩(Scutellariaprostrata)中分离得到。化合物的结构通过1H NMR、13C NMR和质谱鉴定。
红景天苷(Salidroside)：白色粉末，ESI-MS m/z 299.3 [M-H]+; 1H NMR (400MHz, MeOH-d4) 苯乙醇片段：δ 7.06 (2H, d, J = 8.6 Hz, H-2,6), 6.69 (2H, d, J =8.6 Hz, H-3,5), 2.83 (2H, m, H-7), 3.70 and 4.03 (each 1H, m, H-8a, 8b), 葡萄糖片段：δ 4.29 (1H, d, J = 7.8 Hz, H-1'), 3.18 (1H, dd, J = 7.8, 8.6 Hz, H-2'), 3.35 (1H, t, J = 8.6 Hz, H-3'), 3.30 (1H, m, H-4'), 3.28 (1H, m, H-5''),3.86 (1H, brd, J = 11.8 Hz, H-6'a), 3.66 (1H, dd, J = 5.6, 11.8 Hz, H-6'b);13C NMR (100 MHz, MeOH-d4): 苯乙醇片段：δ 156.8, 131.0, 131.0, 130.8, 116.3,116.3, 71.8, 36.4; 葡萄糖片段：δ 104.2, 78.1, 77.9, 75.2, 72.1, 62.9.
焦地黄苯乙醇苷A1 (Jionoside A1)：灰白色无定形粉末, ESI-MS m/z 799.3[M-H]-; 1H NMR (600 MHz, MeOH-d4) 苯乙醇片段：δ 6.76 (1H, d, J = 2.1 Hz, H-2),6.72 (1H, d, J = 8.0 Hz, H-5), 6.61 (1H, dd, J = 2.1, 8.1 Hz, H-6), 2.84 (2H,m, H-7); 咖啡酰基片段：δ 7.24 (1H, d, J = 2.0 Hz, H-2'), 6.85 (1H, d, J = 8.2Hz, H-5'), 7.13 (1H, dd, J = 2.0, 8.2 Hz, H-6'), 6.42 and 7.71 (each 1H, d, J= 15.9 Hz, H-7', 8'); 葡萄糖片段：δ 4.42 (1H, d, J = 7.9 Hz, H-1''), 5.03 (1H,t, J = 9.7 Hz H-4''); 鼠李糖片段：δ 5.23 (1H, d, J = 1.8 Hz, H-1'''), 1.13(3H, d, J = 6.2 Hz, H-6'''); 半乳糖片段：δ 4.30 (1H, d, J = 7.4 Hz, H-1'''')；3.32-4.08 (17H, m) , 3.98 (3H, s, OMe); 13C NMR (150 MHz, MeOH-d4): 苯乙醇片段：δ 146.1, 144.7, 131.6, 121.3, 117.1, 116.5, 72.4, 36.6; 咖啡酰基片段：δ168.4, 150.9, 149.4, 148.1, 127.7, 124.4, 116.3, 115.1, 111.9; 葡萄糖片段：δ104.2, 76.2, 81.5, 70.5, 75.0, 69.2; 鼠李糖片段：δ 103.1, 72.1, 72.4, 73.8,70.3, 18.4; 半乳糖片段：δ 105.3, 72.6, 74.8, 70.4, 76.7, 62.5.
焦地黄苯乙醇苷B1 (Jionoside B1)：灰白色无定形粉末, ESI-MS m/z 813.2[M-H]-; 1H NMR (600 MHz, MeOH-d4) 苯乙醇片段：δ 6.77 (1H, d, J = 2.1 Hz, H-2),6.84 (1H, t, J = 7.9 Hz, H-5), 6.72 (1H, dd, J = 2.1, 8.2 Hz, H-6), 2.84 (2H,td, J = 2.4, 7.2 Hz, H-7); 咖啡酰基片段：δ 7.22 (1H, d, J = 2.0 Hz, H-2'),6.84 (1H, t, J = 7.9 Hz, H-5'), 7.11 (1H, dd, J = 2.0, 8.2 Hz, H-6'), 6.40and 7.68 (each 1H, d, J = 15.9 Hz, H-7', 8'); 葡萄糖片段：δ 4.41 (1H, d, J =7.9 Hz, H-1''), 5.01 (1H, t, J = 9.7 Hz H-4''); 鼠李糖片段：δ 5.20 (1H, d, J =1.8 Hz, H-1'''), 1.11 (3H, d, J = 6.2 Hz, H-6'''); 半乳糖片段：δ 4.28 (1H, d,J = 7.7 Hz, H-1'''')；3.30-4.07 (17H, m) , 3.91, 3.83 (each, 3H, s, OMe); 13CNMR (150 MHz, MeOH-d4): 苯乙醇片段：δ 147.5, 147.3, 133.0, 121.2, 116.5,112.9, 72.2, 56.5, 36.5; 咖啡酰基片段：δ 168.4, 150.8, 149.4, 148.1, 127.6,124.4, 117.1, 115.1, 111.8, 56.5; 葡萄糖片段：δ 104.1, 76.1, 81.6, 70.5, 75.0,69.2; 鼠李糖片段：δ 103.0, 72.0, 72.3, 73.7, 70.2, 18.4; 半乳糖片段：δ 105.3,72.6, 74.8, 70.4, 76.7, 62.5.
异麦角甾苷(又称异毛蕊花糖苷)(Isoacteoside)：淡黄色无定形粉末，ESI-MS m/z 623 [M - H]+; 1H NMR (600 MHz, MeOH-d4) 苯乙醇片段：δ 6.71 (1H, d, J = 2.0Hz, H-2), 6.67 (1H, d, J = 8.0 Hz, H-5), 6.57 (1H, dd, J = 2.1, 8.1 Hz, H-6),2.82 (2H, ddd, J = 2.0, 7.0, 8.5 Hz, H-7), 3.76 and 4.05 (each 1H, m, H-8a,8b); 咖啡酰基片段：δ 7.08 (1H, d, J = 2.1 Hz, H-2'), 6.81 (1H, d, J = 8.2 Hz,H-5'), 6.93 (1H, dd, J = 2.1, 8.3 Hz, H-6'), 6.33 and 7.60 (each 1H, d, J =15.9 Hz, H-7', 8'); 葡萄糖片段：δ 4.37 (1H, d, J = 7.9 Hz, H-1''), 3.39 (1H,m, H-2''), 3.56 (1H, m, H-3''), 3.45 (1H, m, H-4''), 3.59 (1H, m, H-5''),4.40 (1H, m, H-6a'')and 4.54 (1H, dd, J = 2.2, 11.9 Hz, H-6b''); 鼠李糖片段：δ5.22 (1H, d, J = 1.7 Hz, H-1'''), 3.98 (1H, m, H-2'''), 3.73 (1H, m, H-3'''),3.43 (1H, m, H-4'''), 4.01 (1H, m, H-5'''), 1.29 (3H, d, J = 6.2 Hz, H-6''');13C NMR (150 MHz, MeOH-d4): 苯乙醇片段：δ 146.1, 144.7, 131.4, 121.3, 117.1,116.3, 72.4, 36.7; 咖啡酰基片段：δ 169.1, 149.6, 147.2, 146.8, 127.7, 123.1,116.5, 115.1, 114.8; 葡萄糖片段：δ 104.4, 83.9, 75.7, 75.4, 70.4, 64.6; 鼠李糖片段：δ 102.7, 74.0, 72.4, 72.3, 70.0, 17.9.
松果菊苷 (Echinacoside)：白色粉末，ESI-MS m/z 785.3 [M-H]-; 1H NMR (600MHz, MeOH-d4) 苯乙醇片段：δ 6.70 (1H, d, J = 2.1 Hz, H-2), 6.68 (1H, d, J =8.0 Hz, H-5), 6.57 (1H, dd, J = 8.0, 2.1 Hz, H-6), 2.79 (2H, m, H-7), 3.72and 4.03 (each 1H, m, H-8); 咖啡酰基片段：δ 7.05 (1H, d, J = 2.1 Hz, H-2'),6.78 (1H, d, J = 8.2 Hz, H-5'), 6.96 (1H, dd, J = 8.2, 2.1 Hz, H-6'), 7.59and 6.27 (each 1H, d, J = 15.9 Hz, H-7',8'), 葡萄糖片段(inner)：δ 4.39 (1H, d,J = 7.9 Hz, H-1''), 3.39 (1H, dd, J = 7.9, 9.4 Hz, H-2''), 3.81 (1H, t, J =9.4 Hz, H-3''), 5.01 (1H, t, J = 9.4 Hz, H-4''), 3.77 (1H, m, H-5''), 3.94(1H, dd, J = 2.3, 11.6 Hz, H-6''a), 3.64 (1H, dd, J = 5.4, 11.6, H-6''b), 鼠李糖片段：δ 5.18 (1H, d, J = 1.8 Hz, H-1'''), 3.91 (1H, dd, J = 3.3, 1.8 Hz,H-2'''), 3.57 (1H, m, H-3'''), 3.28 (1H, m, H-4'''), 3.55 (1H, m, H-5'''),1.08 (3H, d, J = 6.2 Hz, H-6'''), 葡萄糖片段(outer)：δ 4.30 (1H, d, J = 7.7Hz, H-1''''), 3.20 (1H, dd, J = 7.7, 9.2 Hz, H-2''''), 3.34 (1H, t, J = 9.2Hz, H-3''''), 3.28 (1H, m, H-4'''') , 3.23 (1H, m, H-5''''), 3.83 (1H, dd, J= 2.3, 11.4 Hz, H-6''''a), 3.64 (1H, dd, J = 5.4, 11.4 Hz, H-6''''b); 13C NMR(150 MHz, MeOH-d4): 苯乙醇片段：δ 146.1, 144.7, 131.4, 121.3, 117.1, 116.3,72.4, 36.6；咖啡酰基片段：δ 168.5, 149.8, 148.2, 146.8, 127.6, 123.3, 116.5,115.2, 114.7; 葡萄糖片段(inner)：δ 104.2, 81.6, 76.2, 74.8, 70.6, 69.4; 鼠李糖片段：δ 103.1, 73.8, 72.4, 72.0, 70.5, 18.5；葡萄糖片段(outer)：δ 104.7, 77.9,77.8, 75.1, 71.5, 62.6.
肉苁蓉苷A(Cistanoside A)：白色粉末，ESI-MS m/z 799.3 [M-H]-; 1H NMR(600 MHz, MeOH-d4) 苯乙醇片段：6.88 (1H, d, J = 1.7 Hz, H-2), 6.72-6.68 (2H,m, H-5, 6), 2.87 (2H, m, H-7), 3.64 and 4.07 (each 1H, m, H-8a,8b), 3.85 (3H,s, 3-OCH3), 咖啡酰基片段：δ 7.06 (1H, d, J = 2.1 Hz, H-2'), 6.78 (1H, d, J =8.2 Hz, H-5'), 6.96 (1H, dd, J = 8.2, 2.0 Hz, H-6'), 6.28 and 7.60 (each 1H,d, J = 15.9 Hz, H-7', 8'), 葡萄糖片段(inner)：δ 4.40 (1H, d, J = 7.9 Hz, H-1''), 3.40 (1H, dd, J = 7.9, 9.2 Hz, H-2''), 3.84-3.82 (1H, m, H-3''), 5.01(1H, t, J = 9.7 Hz, H-4''), 3.76 (1H, m, H-5''), 3.95 (1H, dd, J = 11.5, 2.1Hz, H-6''a), 3.78 (m, 1H, H-6''b) , 鼠李糖片段：δ 5.19 (1H, d, J = 1.6 Hz, H-1'''), 3.92 (dd, J = 3.2, 1.6 Hz, 1H, H-2'''), 3.57 (1H, m, H-3'''), 3.28(1H, m, H-4'''), 3.55 (1H, m, H-5'''), 1.09 (3H, d, J = 6.2 Hz, H-6'''), 葡萄糖片段(outer)：δ 4.28 (1H, d, J = 7.7 Hz, H-1''''), 3.19 (1H, m, H-2''''),3.32 (1H, m, H-3''''), 3.22 (1H, m, H-4'''') , 3.20 (1H, m, H-5''''), 3.86(1H, m, H-6''''a), 3.62 (m, 1H, H-6''''b); 13C NMR (150 MHz, MeOH-d4): 苯乙醇片段：δ 148.8, 145.9, 131.6, 122.4, 116.1, 113.8, 56.5, 36.7; 咖啡酰基片段：δ168.5, 149.9, 148.2, 146.9, 127.6, 123.3, 116.5, 115.2, 114.7,; 葡萄糖片段(inner)：δ 104.2, 81.6, 76.2, 74.7, 70.5, 69.4; 鼠李糖片段：δ 103.1, 73.8,72.4, 72.1, 70.6, 18.5; 葡萄糖片段(outer)：δ 104.7, 77.9, 77.8, 75.1, 71.5,62.6.
金石蚕苷(Poliumoside)：白色粉末，ESI-MS m/z 769.3 [M-H]-; 1H NMR (400MHz, MeOH-d4) 苯乙醇片段：δ 6.69 (1H, d, J = 1.71 Hz, H-2), 6.68 (1H, d, J =7.87 Hz, H-5), 6.57 (1H, dd, J = 2.1, 8.0 Hz, H-6), 2.80 (2H, m, H-7), 3.67and 3.99 (each 1H, m, H-8a, 8b)；咖啡酰基片段: δ 7.06 (1H, d, J = 2.07 Hz, H-2'), 6.78 (1H, d, J = 8.16 Hz, H-5'), 6.96 (1H, dd, J = 2.13, 8.24 Hz, H-6'),6.27 and 7.60 (each 1H, d, J = 15.86 Hz, H-7',8')；葡萄糖片段：δ 4.37 (1H, d, J= 7.90 Hz, H-1''), 3.38 (1H, m, H-2''), 3.81 (1H, t, J = 9.23 Hz, H-3''),4.99 (1H, t, J = 9.66 Hz, H-4''), 3.69 (1H, m, H-5''), 3.47 and 3.74 (each1H, m, H-6'');鼠李糖片段(3位)：δ 5.19 (1H, d, J = 1.76 Hz, H-1'''), 3.91 (1H,dd, J = 1.82,3.34 Hz, H-2'''), 3.71 (1H, m, H-3'''), 3.38 (1H, d, J = 9.13Hz, H-4'''), 3.61 (1H, m, H-5'''), 1.08 (3H, d, J = 6.18 Hz, H-6'''); 鼠李糖片段(6位)：δ 4.63 (1H, d, J = 1.76 Hz, H-1''''), 3.84 (1H, dd, J = 1.69,3.41Hz, H-2''''), 3.58 (1H, m, H-3''''), 3.34 (1H, t, J = 9.48 Hz, H-4''''), 3.61(1H, m, H-5''''), 1.20 (3H, d, J = 6.26 Hz, H-6'''')；13C NMR (100 MHz, MeOH-d4): 苯乙醇片段：δ 146.1, 144.7, 131.4, 121.3, 117.1, 116.5, 72.3, 36.7; 咖啡酰基片段：δ 168.0, 149.8, 148.0, 146.8, 127.7, 123.2, 116.4, 115.2, 114.7; 葡萄糖片段：δ 104.4, 81.6, 76.2, 74.7, 70.4, 67.6; 鼠李糖片段(3位)：δ 103.1,74.0, 72.4, 72.1, 70.4, 18.4；鼠李糖片段(6位)：δ 102.3, 73.8, 72.4, 72.0, 69.9,18.0.
安格洛苷C(Angoroside C)：白色粉末，ESI-MS m/z 783.3 [M-H]-; 1H NMR (400MHz, MeOH-d4) 苯乙醇片段：δ 6.75 (1H, d, J = 2.1 Hz, H-2), 6.82 (1H, d, J =8.2 Hz, H-5), 6.70 (1H, dd, J = 2.1, 8.2 Hz, H-6), 2.83 (2H, m, H-7), 3.74and 4.05 (each 1H, m, H-8a, 8b), 3.82 (3H, s, 4-OMe)；咖啡酰基片段: δ 7.20(1H, d, J = 2.0 Hz, H-2'), 6.82 (1H, d, J = 8.2Hz, H-5'), 7.09 (1H, dd, J =2.0, 8.2 Hz, H-6'), 6.38 and 7.67 (each 1H, d, J = 15.9 Hz, H-7',8'), 3.89(3H, s, 3'-OMe)；葡萄糖片段：δ 4.38 (1H, d, J = 7.9 Hz, H-1''), 3.40 (1H, t, J= 7.9 Hz, H-2''), 3.84 (1H, m, H-3''), 4.97 (1H, t, J = 9.7 Hz, H-4''), 3.74(1H, m, H-5''), 3.59 (1H, m, H-6''a), 3.87 (1H, dd, J = 11.6, 1.95 Hz, H-6''b);鼠李糖片段：δ 5.20 (1H, d, J = 1.8 Hz, H-1'''), 3.91 (1H, dd, J = 1.8, 3.4Hz, H-2'''), 3.58 (1H, m, H-3'''), 3.29 (1H, t, J = 9.7 Hz, H-4'''), 3.57(1H, m, H-5'''), 1.10 (3H, d, J = 6.2 Hz, H-6''')；木糖片段：δ 4.24 (1H, d, J =7.8 Hz, H-1'''')；3.88, 3.84, 3.59, 3.49 and 3.47 (each 1H, m, H-2''''-6'''''); 13C NMR (100 MHz, MeOH-d4): 苯乙醇片段：δ 147.5, 147.4, 133.0, 121.2,117.1, 112.9, 56.5, 36.6; 咖啡酰基片段：δ 168.3, 150.9, 149.4, 148.1, 127.7,124.4, 116.5, 115.1, 111.9, 56.5; 葡萄糖片段：δ 104.2, 81.5, 76.2, 75.0, 69.0;鼠李糖片段(3位)：δ 103.0, 74.1, 72.4, 72.2, 70.4, 18.4；木糖片段(6位)：δ 105.1,73.8, 72.4, 69.5, 66.7.
木通苯乙醇苷B(Calceolarioside B): 白色粉末，ESI-MS m/z 476.9 [M-H]-;1H NMR (500 MHz, MeOH-d4) 苯乙醇片段：δ 6.67 (1H, d, J = 2.0 Hz, H-2), 6.63(1H, d, J = 8.0 Hz, H-5), 6.54 (1H, dd, J = 8.0, 2.0 Hz, H-6), 2.78 (2H, m,H-7), 3.75 and 3.96 (each 1H, m, H-8); 咖啡酰基片段：δ 7.03 (1H, d, J = 2.0Hz, H-2'), 6.77 (1H, d, J = 8.2 Hz, H-5'), 6.89 (1H, dd, J = 8.2, 2.0 Hz, H-6'), 7.56 and 6.29 (each 1H, d, J = 15.9 Hz, H-7',8'), 葡萄糖片段：δ 4.33 (1H,d, J = 7.8 Hz, H-1''), 3.21 (1H, t, J = 7.8 Hz, H-2''), 3.38 (2H, m, H-3'',4''), 3.52 (1H, m, H-5''), 4.50 (1H, dd, J = 2.1, 11.9 Hz, H-6''a), 4.33 (1H,dd, J = 6.0, 11.9, H-6''b); 13C NMR (125 MHz, MeOH-d4): 苯乙醇片段：δ 146.1,144.7, 131.4, 121.2, 117.1, 116.3, 72.4, 36.7; 咖啡酰基片段：δ 169.1, 149.6,147.2, 146.8, 127.7, 123.1, 116.5, 115.1, 114.9; 葡萄糖片段：δ 104.6, 77.9,75.6, 75.1, 71.7, 64.6。
去鼠李糖地黄苷(Desrhamnosylmartynoside)：白色粉末，ESI-MS m/z 504.9 [M-H]-; 1H NMR (600 MHz, MeOH-d4) 苯乙醇片段：δ 6.74 (1H, d, J = 2.2 Hz, H-2),6.81 (1H, d, J = 8.2 Hz, H-5), 6.69 (1H, dd, J = 8.2, 2.2 Hz, H-6), 2.83 (2H,m, H-7), 3.74 and 4.07 (each 1H, m, H-8), 3.83 (3H, s, OCH3-4); 咖啡酰基片段：δ 7.20 (1H, d, J = 2.0 Hz, H-2'), 6.82 (1H, d, J = 8.2 Hz, H-5'), 7.09 (1H,dd, J = 8.2, 2.0 Hz, H-6'), 7.66 and 6.40 (each 1H, d, J = 15.9 Hz, H-7',8'),3.89 (3H, s, OCH3-3'), 葡萄糖片段：δ 4.37 (1H, d, J = 7.8 Hz, H-1''), 3.31(1H, m, overlap, H-2''), 3.64 (1H, m, H-3''), 4.87 (1H, overlap, H-4''), 3.55(1H, m, H-5''), 3.52 and 3.62 (each 1H, m, H-6''a, 6''b); 13C NMR (150 MHz,MeOH-d4): 苯乙醇片段：δ 146.3, 146.1, 131.5, 119.6, 115.6, 111.3, 70.6, 55.0,35.1；咖啡酰基片段：δ 167.0, 149.4, 148.0, 146.0, 126.2, 122.8, 115.0, 113.7,110.4, 55.0; 葡萄糖片段：δ 103.0, 74.8, 74.3, 73.9, 71.1, 761.0.
实施例4：其它苯乙醇苷类化合物对2019-nCoV-3CLpro抑制作用的评价
采用实施例2中建立的2019-nCoV-3CLpro抑制剂发现方法，对从不同植物中分离得到的天然苯乙醇苷类化合物红景天苷(Salidroside)、焦地黄苯乙醇苷A1(JionosideA1)和B1(Jionoside B1)、异麦角甾苷(Isoacteoside)、松果菊苷(Echinacoside)、肉苁蓉苷A(Cistanoside A)、金石蚕苷(Poliumoside)、安格洛苷C(Angoroside C)、木通苯乙醇苷B(calceolarioside B)、去鼠李糖地黄苷(Desrhamnosylmartynoside)的2019-nCoV-3CLpro抑制活性进行评价，化合物不同浓度对2019-nCoV-3CLpro的抑制率及IC50如表2所示。
表2：其它植物中苯乙醇苷类化合物对2019-nCoV-3CLpro的抑制作用
-: 无效，IC50>100 uM； +: 弱效，50 uM ≥ IC50≥ 100 uM； ++: 中效，10 uM ≥IC50>50 uM；+++ 强效：1 uM ≥ IC50>10 uM。
有表2 结果可知当取代基R5为OH，R6为H时，即苯乙醇葡萄糖苷的3,4为皆为OH时，对应苯乙醇苷类化合物对于2019-nCoV-3CLpro的抑制更为有效。
上述结构与活性之间的关系进一步表明，苯乙醇苷结构中需具有相邻的2个或多个酚羟基(例如3',4'-双羟基苯乙醇-1-葡萄糖苷)才能维持其对2019-nCoV-3CLpro的高抑制活性。
讨论
在本发明之前，苯乙醇苷类化合物或其药学上可接受的盐对2019新型冠状病毒(SARS-CoV-2) 3CL水解酶的抑制作用尚未见报道。
在本发明中，本发明人首次公开了连翘酯苷A、连翘酯苷B、连翘酯苷H或其药学上可接受的盐对SARS-CoV-2的3CLpro具有显著的抑制作用，IC50达到个位数微摩尔级别，尤其是连翘酯苷A的IC50值为约6.26μM。因此，连翘酯苷A、连翘酯苷B、连翘酯苷H或其药学上可接受的盐具有优异的抗2019新型冠状病毒(SARS-CoV-2)活性，具有良好的临床应用前景。
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 (8)
1.一种活性成分的用途，其特征在于，所述的活性成分为式I化合物或其药学上可接受的盐：
(I)
式中，
R1选自：H、咖啡酰基；
R2选自：H、L-鼠李糖基、咖啡酰基；
R3选自：H、咖啡酰基；
R4选自：芹糖基、鼠李糖基、葡萄糖基、H、咖啡酰基；
R5为OH；
R6为H；
附加条件是，所述的活性成分不包括：连翘酯苷A (Forsythiaside A)和连翘酯苷B(Forsythiaside B)；
并且，所述的活性成分被用于制备抑制2019新型冠状病毒(SARS-CoV-2) 3CL蛋白酶的抑制剂。
2. 如权利要求1所述的用途，其特征在于，
R1选自：H、咖啡酰基；和/或
R2选自：H、α-L-鼠李糖、咖啡酰基；和/或
R3选自：H、咖啡酰基；和/或
R4选自：α-L-芹糖，α-L-鼠李糖、β-L-鼠李糖、β-D-葡萄糖。
3.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：
A(3) 连翘酯苷E(Forsythiaside E)；
A(4) 连翘酯苷H(Forsythiaside H)；
A(5) 连翘酯苷I(Forsythiaside I)；
A(6) 异连翘酯苷(Isoforsythiaside )；
A(7) 毛蕊花糖苷(Acteoside)；
A(8) 焦地黄苯乙醇苷A1(Jionoside A1)；
A(9) 异麦角甾苷(Isoacteoside)；
A(10) 松果菊苷(Echinacoside)；
A(11) 金石蚕苷(Poliumoside)；
A(12) 木通苯乙醇苷B(calceolarioside B)；
B 上述A(3)～A(12)的任意组合；
C 及其可接受的盐。
4.如权利要求1所述的用途，其特征在于，所述的活性成分还包括选自下组的额外组分：抗逆传录病毒的药物或增强免疫力的药物。
5.一种药物组合物用于制备抑制2019新型冠状病毒(SARS-CoV-2) 3CL蛋白酶的抑制剂的用途，其特征在于，所述的药物组合物含有：
(a1)第一活性成分，所述的第一活性成分为式I所示的苯乙醇苷类化合物或其药学上可接受的盐：
(I)
式中，
R1选自：H、咖啡酰基；
R2选自：H、L-鼠李糖基、咖啡酰基；
R3选自：H、咖啡酰基；
R4选自：芹糖基、鼠李糖基、葡萄糖基、H、咖啡酰基；
R5为OH；
R6为H；
附加条件是，所述的活性成分不包括：连翘酯苷A (Forsythiaside A)和连翘酯苷B(Forsythiaside B)；
(a2)任选的第二活性成分，所述的第二活性成分选自下组：(Y1) RNA复制酶抑制剂；(Y2) 洛匹那韦；(Y3) 利托那韦；(Y4) 法匹拉韦；(Y5) 氯喹、羟氯喹、或其药学上可接受的盐、(Y6)上述Y1～Y5的任意组合；
以及(b)药学上可接受的载体。
6.如权利要求5所述的用途，其特征在于，所述的RNA复制酶抑制剂为瑞德西韦。
7.一种体外非诊断的非治疗性的抑制2019新型冠状病毒(SARS-CoV-2) 3CL蛋白酶的方法，其特征在于，包括步骤：将第一活性成分与2019新型冠状病毒(SARS-CoV-2)的3CL蛋白酶接触，从而抑制所述3CL蛋白酶的活性；
其中，所述的第一活性成分为式I化合物或其药学上可接受的盐：
(I)
式中，
R1选自：H、咖啡酰基；
R2选自：H、L-鼠李糖基、咖啡酰基；
R3选自：H、咖啡酰基；
R4选自：芹糖基、鼠李糖基、葡萄糖基、H、咖啡酰基；
R5为OH；
R6为H；
附加条件是，所述的活性成分不包括：连翘酯苷A (Forsythiaside A)和连翘酯苷B(Forsythiaside B)。
8.如权利要求7所述的方法，其特征在于，与2019新型冠状病毒(SARS-CoV-2)的3CL蛋白酶接触的式I化合物或其药学上可接受的盐的浓度为0.5-20μM。
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