WO2021147236A1 - 取代氨基丙酸酯类化合物在治疗SARS-CoV-2感染中的应用 - Google Patents

取代氨基丙酸酯类化合物在治疗SARS-CoV-2感染中的应用 Download PDF

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WO2021147236A1
WO2021147236A1 PCT/CN2020/097421 CN2020097421W WO2021147236A1 WO 2021147236 A1 WO2021147236 A1 WO 2021147236A1 CN 2020097421 W CN2020097421 W CN 2020097421W WO 2021147236 A1 WO2021147236 A1 WO 2021147236A1
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pharmaceutical composition
pharmaceutically acceptable
preparation
cov
sars
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French (fr)
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WO2021147236A9 (zh
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钟武
曹瑞源
肖庚富
胡志红
王曼丽
张磊砢
李薇
李月香
赵磊
樊士勇
李松
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中国人民解放军军事科学院军事医学研究院
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • This application relates to substituted aminopropionate compounds represented by the following formula I, their geometric isomers or their pharmaceutically acceptable salts and/or both solvates and/or both hydrates, and those containing the above-mentioned compounds
  • the pharmaceutical composition is used for the treatment of SARS-CoV-2 infection.
  • Substituted aminopropionate compounds (compounds of formula I), chemical name 2-ethylbutyl (2S)-2-[[(2R, 3S, 4R, 5R)-5-(4-aminopyrrole [2, 1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyloxycycloalkan-2-yl]methoxyphenoxyphosphoryl]amino]propionic acid Ester (2-ethylbutyl(2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl) -5-cyano-3,4-dihydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate), also known as Remdesivir (GS-5734), is a viral RNA polymerase inhibitor whose in vivo active form is the parent drug The nu
  • Remdesivir exhibits antiviral activity against EBOV and other filovirus variants in cell-based assays.
  • GS-5734 also has broad-spectrum antiviral activity, such as Nipah virus, Middle East Respiratory Syndrome Coronavirus (MERS-CoV), Marburg virus and so on.
  • the 2019 Novel Coronavirus (2019-nCoV) is a new strain of coronavirus that has never been found in humans before.
  • ICTV International Commission for Classification of Viruses
  • SARS-CoV- 2 severe acute respiratory syndrome coronavirus 2
  • WHO World Health Organization
  • the symptoms of SARS-CoV-2 virus infection are mainly pneumonia, which can be divided into simple infection, mild pneumonia, severe pneumonia, acute respiratory distress syndrome, sepsis, septic shock, etc. according to the severity of the disease.
  • Patients with simple infections may have non-specific symptoms, such as fever, cough, sore throat, nasal congestion, fatigue, headache, muscle pain or discomfort, the elderly and immunosuppressed people may have atypical symptoms.
  • Patients with mild pneumonia mainly cough, dyspnea + shortness of breath. Severe pneumonia can be seen in adolescents, adults or children. The main symptoms are increased respiratory rate, severe respiratory failure or dyspnea, central cyanosis, lethargy, unconsciousness or convulsions, gas pumping, etc.
  • the lung images of acute respiratory distress syndrome are bilateral ground-glass shadows, but they cannot be completely explained by effusion, lobar exudation, atelectasis, or pulmonary block shadows. Pulmonary edema is the main symptom. Patients with sepsis often have fatal organ dysfunction, and septic shock is the most critical patient with a higher probability of death.
  • the purpose of this application is to discover a drug with antiviral activity against SARS-CoV-2, which can be used for the treatment of related diseases caused by its infection.
  • the compound of formula I has the function of inhibiting the replication of SARS-CoV-2, and has a good potential therapeutic effect in the treatment of diseases caused by SARS-CoV-2.
  • the pharmaceutically acceptable salt of the compound represented by formula I described in this application includes its inorganic or organic acid salts, and inorganic or organic base salts.
  • This application relates to all forms of the above-mentioned salts, including but Not limited to: sodium salt, potassium salt, calcium salt, lithium salt, meglumine salt, hydrochloride, hydrochloride, hydrocoholate, nitrate, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate , Acetate, Propionate, Butyrate, Oxalate, Trimethylacetate, Adipate, Alginate, Lactate, Citrate, Tartrate, Succinate, Maleate Acid salt, fumarate, picrate, aspartate, gluconate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and double Hydroxynaphate and so on.
  • the compound represented by formula I can inhibit SARS-CoV-2 virus replication on cells and reduce the SARS-CoV-2 viral nucleic acid load in cell culture.
  • the inventors of the present application have discovered the new function characteristics of the compound represented by formula I in cells after the creative invention research: the compound represented by formula I can reduce the viral nucleic acid of SARS-CoV-2 infected cells at a micromolar concentration. Load level.
  • This application also relates to the compound represented by formula I, its geometric isomers or pharmaceutically acceptable salts and/or solvates and/or hydrates thereof in preparation for the treatment of diseases caused by SARS-CoV-2 or Infections (such as respiratory diseases (such as simple infections such as fever, cough and sore throat, etc.), pneumonia, acute respiratory infections, severe acute respiratory infections (SARI), hypoxic respiratory failure and acute respiratory distress syndrome, sepsis and Septic shock, etc.)) in the use of drugs,
  • This application also relates to compounds represented by formula I, their geometric isomers or their pharmaceutically acceptable salts and/or their solvates and/or their hydrates in the preparation of drugs as SARS-CoV-2 inhibitors use.
  • This application also relates to the compound represented by formula I, its geometric isomers or its pharmaceutically acceptable salts and/or its solvates and/or its hydrates in preparation for inhibiting SARS-CoV-2 in cells (e.g. Mammalian cells) in the replication or reproduction of drugs.
  • cells e.g. Mammalian cells
  • This application also relates to a pharmaceutical composition, which comprises a compound represented by formula I, its geometric isomers or pharmaceutically acceptable salts and/or solvates and/or hydrates thereof,
  • the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or auxiliary material.
  • the pharmaceutical composition is a solid preparation, an injection, an external preparation, a spray, a liquid preparation, or a compound preparation.
  • This application also relates to the pharmaceutical composition or the compound compound represented by formula I, containing the compound represented by formula I, its geometric isomer or its pharmaceutically acceptable salt and/or its solvate and/or its hydrate, Its geometric isomers and their pharmaceutically acceptable salts and/or their solvates and/or their hydrates are used in the preparation for the treatment of respiratory diseases but not limited to respiratory diseases (simple infections such as fever, cough and sore throat). Etc., pneumonia, acute respiratory infection, severe acute respiratory infection (SARI), hypoxic respiratory failure and acute respiratory distress syndrome, sepsis and septic shock, etc.).
  • respiratory diseases simple infections such as fever, cough and sore throat.
  • Etc. pneumonia, acute respiratory infection, severe acute respiratory infection (SARI), hypoxic respiratory failure and acute respiratory distress syndrome, sepsis and septic shock, etc.
  • This application also relates to the preparation of the pharmaceutical composition comprising the compound represented by formula I, its geometric isomers or its pharmaceutically acceptable salts and/or its solvates and/or its hydrates for the treatment of SARS-CoV -2 Diseases or infections (such as respiratory diseases (such as simple infections such as fever, cough and sore throat, etc.), pneumonia, acute respiratory infections, severe acute respiratory infections (SARI), hypoxic respiratory failure, and acute respiratory distress syndrome Symptoms, sepsis and septic shock, etc.)).
  • SARS-CoV -2 Diseases or infections such as respiratory diseases (such as simple infections such as fever, cough and sore throat, etc.), pneumonia, acute respiratory infections, severe acute respiratory infections (SARI), hypoxic respiratory failure, and acute respiratory distress syndrome Symptoms, sepsis and septic shock, etc.)).
  • This application also relates to the preparation of the pharmaceutical composition containing the compound of formula I, its geometric isomers or its pharmaceutically acceptable salts and/or its solvates and/or its hydrates as SARS-CoV-2 inhibitors Use in medicines.
  • This application also relates to the pharmaceutical composition
  • the pharmaceutical composition comprising the compound of formula I, its geometric isomers or its pharmaceutically acceptable salts and/or its solvates and/or its hydrates in preparation for inhibiting SARS-CoV-2 Use in drugs for replication or reproduction in cells (e.g., mammalian cells).
  • This application also relates to a method for treating and/or preventing diseases in a mammal in need or a method for inhibiting SARS-CoV-2 replication or reproduction in a mammal in need, and the method includes giving a mammal in need A therapeutically and/or prophylactically effective amount of the pharmaceutical composition or the pharmaceutical composition comprising the compound represented by formula I, its geometric isomer or its pharmaceutically acceptable salt and/or its solvate and/or its hydrate is administered The compound of formula I, its geometric isomers, or pharmaceutically acceptable salts and/or solvates and/or hydrates thereof, wherein the diseases include diseases caused by SARS-CoV-2, such as SARS-CoV- 2 Viral infectious diseases (such as respiratory diseases, including simple infections such as fever, cough and sore throat, etc., pneumonia, acute respiratory infections, severe acute respiratory infections (SARI), hypoxic respiratory failure and acute respiratory distress syndrome) Symptoms, sepsis and septic shock, etc.).
  • SARS-CoV-2 such as SARS-
  • This application also relates to the compound represented by Formula I, its geometric isomers or its pharmaceutically acceptable salts and/or its solvates and/or its hydrates, which serve as SARS-CoV-2 inhibitors.
  • This application also relates to the compound represented by formula I, its geometric isomers or its pharmaceutically acceptable salts and/or its solvates and/or its hydrates, which are used to inhibit SARS-CoV-2 in cells (such as lactating Reproduction or reproduction in animal cells).
  • This application also relates to the pharmaceutical composition
  • the pharmaceutical composition comprising the compound represented by formula I, its geometric isomers or its pharmaceutically acceptable salts and/or its solvates and/or its hydrates, which are referred to as SARS-CoV-2 Inhibitor.
  • This application also relates to the pharmaceutical composition
  • the pharmaceutical composition comprising the compound represented by formula I, its geometric isomers or its pharmaceutically acceptable salts and/or its solvates and/or its hydrates, which are used to inhibit SARS-CoV- 2 Reproduction or reproduction in cells (such as mammalian cells).
  • the diseases caused by SARS-CoV-2 described in this application include, but are not limited to, respiratory diseases, such as simple infections such as fever, cough and sore throat, pneumonia, acute respiratory infections, severe acute respiratory infections, etc. Infection (SARI), hypoxic respiratory failure and acute respiratory distress syndrome, sepsis and septic shock, etc.
  • respiratory diseases such as simple infections such as fever, cough and sore throat, pneumonia, acute respiratory infections, severe acute respiratory infections, etc.
  • Infection SARI
  • hypoxic respiratory failure and acute respiratory distress syndrome Sepsis and septic shock, etc.
  • the disease caused by SARS-CoV-2 described in this application is COVID-19.
  • 2019-nCoV 2019-nCoV
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • the mammals include bovines, equines, ovines, swines, canines, felines, rodents, primates, among which mammals are preferred Being human, cat, dog or pig.
  • the pharmaceutical composition described in this application can be prepared into various forms according to different administration routes.
  • the pharmaceutical composition can be administered in any of the following ways: oral administration, spray inhalation, rectal administration, nasal administration, buccal administration, vaginal administration, topical administration, parenteral administration such as subcutaneous, intravenous, intramuscular , Intraperitoneal, intrathecal, intraventricular, intrasternal and intracranial injection or infusion, or medication with the aid of an explanted reservoir.
  • oral, intraperitoneal or intravenous administration is preferred.
  • the compound represented by formula I, its geometric isomers or its pharmaceutically acceptable salts and/or its solvates and/or its hydrates can be made into any orally acceptable formulations, including But not limited to tablets, capsules, aqueous solutions or suspensions.
  • the carriers commonly used in tablets include lactose and corn starch, and lubricants such as magnesium stearate can also be added.
  • Diluents commonly used in capsule preparations include lactose and dried corn starch.
  • Aqueous suspension formulations usually mix the active ingredients with suitable emulsifiers and suspending agents. If necessary, some sweeteners, fragrances or coloring agents can be added to the above oral preparations.
  • the compound represented by formula I can generally be prepared in the form of suppositories, which can be used to form a suppository. It is prepared by mixing with a suitable non-irritating excipient.
  • the excipient presents a solid state at room temperature, but melts at the rectal temperature to release the drug.
  • excipients include cocoa butter, beeswax and polyethylene glycol.
  • the compound represented by formula I When applied locally to the eye, the compound represented by formula I, its geometric isomers or pharmaceutically acceptable salts and/or solvates and/or hydrates thereof can be formulated into a micronized suspension or solution
  • the carrier used is isotonic sterile saline with a certain pH, which may or may not be added with preservatives such as chlorinated benzyl alkanolate.
  • the compound can also be made into an ointment form such as petrolatum.
  • the compound represented by formula I, its geometric isomers or its pharmaceutically acceptable salts and/or its solvates and/or its hydrates can be made into appropriate ointments, lotions or creams A dosage form in which the active ingredient is suspended or dissolved in one or more carriers.
  • the carriers that can be used for the ointment here include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; the carriers that can be used for lotions or creams include but are not limited to: Mineral oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecenyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compound represented by formula I When administered locally in the lower intestinal tract, the compound represented by formula I, its geometric isomers or pharmaceutically acceptable salts and/or solvates and/or hydrates thereof can be prepared into rectal suppository formulations as described above Or a suitable enema preparation form, and a topical transdermal patch can also be used.
  • the compound represented by formula I can also be administered in the form of sterile injection preparations, including sterile injection water or oil suspensions Solution, or sterile injection solution.
  • usable carriers and solvents include water, Ringer's solution and isotonic sodium chloride solution.
  • sterilized non-volatile oils can also be used as solvents or suspension media, such as monoglycerides or diglycerides.
  • the term "therapeutically effective amount” or “prophylactically effective amount” refers to an amount that is sufficient to treat or prevent the patient's disease but is low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of reasonable medical judgment.
  • the therapeutically effective amount of the compound will depend on the specific compound selected (for example, considering the potency, effectiveness and half-life of the compound), the route of administration selected, the disease to be treated, the severity of the disease to be treated, and the patient's condition to be treated. Factors such as age, size, weight, and physical disease, the medical history of the patient being treated, the duration of treatment, the nature of concurrent therapy, the desired therapeutic effect and other factors have changed, but they can still be routinely determined by those skilled in the art.
  • the specific dosage and method of use of the compound represented by formula I, its geometric isomers, or pharmaceutically acceptable salts and/or its solvates and/or its hydrates for different patients are determined by many Factors include the patient’s age, weight, gender, natural health status, nutritional status, active strength of the drug, taking time, metabolic rate, severity of the disease, and the subjective judgment of the physician.
  • the preferred dosage here is between 0.001-1000 mg/kg body weight/day.
  • Remdesivir effectively reduces the viral nucleic acid load on veroE6 cells infected with SARS-CoV-2 virus.
  • Remdesivir can inhibit the viral RNA load on the cell 48h after the cell is infected with the SARS-CoV-2 virus, and the drug concentration of 33 ⁇ M can reduce the nucleic acid load of the virus by an order of magnitude.
  • the ordinate is the copy number of the viral RNA in the sample, and the abscissa is the drug concentration;
  • Remdesivir treated the test cells at the test concentration for 48 hours, and no cytotoxicity was observed.
  • the ordinate is the percentage of cell viability relative to the negative control group (only cells, no drug), and the abscissa is the drug concentration.
  • Example 1 Remdesivir reduces the viral nucleic acid load of SARS-CoV-2 infected cells
  • Vero E6 cells purchased from ATCC, article number 1586
  • 2% cell maintenance solution formula: FBS (purchased from Gibco company, article number 16000044)
  • MEM purchased from Gibco, article number 10370021
  • SARS-CoV-2 2019-nCoV
  • SARS-CoV-2019BetaCoV/Wuhan/WIV04/2019 strain was diluted from the Wuhan Institute of Virology, CAS provided to the appropriate concentration and added 24 per well plates containing viral manipulation amount 100TCID 50.
  • RNA extraction kit was purchased from Qiagen Company, catalog number 74106.
  • the consumables spin column, 2ml collection tube without RNase, etc.
  • reagents RLT, RW1, RPE, RNase-free water, etc.
  • the following extraction steps are recommended steps in the kit instructions.
  • the reverse transcription kit (PrimeScript TM RT reagent Kit with gDNA Eraser, article number RR047Q) produced by TaKaRa was used for RNA reverse transcription.
  • 1gDNA removal Collect RNA samples of each experimental group, and take 1 ⁇ g for reverse transcription. First, add 2 ⁇ l 5 ⁇ gDNA Eraser Buffer to the RNA of each experimental group, fill up the reaction system to 10 ⁇ l with RNase Free water, mix well, and remove the g DNA that may exist in the sample in a water bath at 42°C for 2 minutes;
  • Fluorescence quantitative PCR was used to detect the number of copies per milliliter of the original virus solution.
  • RBD-qR CTCAAGTGTCTGTGGATCACG
  • Cycle parameters 95°C for 15 seconds, 54°C for 15 seconds, 72°C for 30 seconds, a total of 40 cycles.
  • MEM medium purchased from Gibco, product number 10370021
  • FBS Gibco company, product number 10370021
  • Cell viability (%) (A (drug treatment group) -A (blank control) )/(A (negative control) -A (blank control) ) ⁇ 100%
  • test compound can effectively inhibit the replication of the SARS-CoV-2 virus genome in the infection supernatant at the concentrations of 100 ⁇ M, 33 ⁇ M, 11.1 ⁇ M and 3.7 ⁇ M (Table 1 and Figure 1)

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Abstract

本申请涉及式I所示取代氨基丙酸酯类化合物，及其药学上可接受的盐和/或其溶剂化物和/或其水合物，及含有此化合物的药物组合物，用于治疗SARS-CoV-2引起的疾病或感染。

Description

取代氨基丙酸酯类化合物在治疗SARS-CoV-2感染中的应用
本申请是以CN申请号为202010071087.7，申请日为2020年1月21日的申请为基础，并主张其优先权，该CN申请的公开内容在此作为整体引入本申请中。
技术领域
本申请涉及下面式I所示的取代氨基丙酸酯类化合物，其几何异构体或其药学上可接受的盐和/或两者溶剂化物和/或两者水合物，及含上述化合物的药物组合物，用于治疗SARS-CoV-2感染方面的用途。
Figure PCTCN2020097421-appb-000001
背景技术
取代氨基丙酸酯类化合物(式I化合物),化学名为2-乙基丁基(2S)-2-[[(2R，3S，4R，5R)-5-(4-氨基吡咯[2,1-f][1,2,4]三嗪-7-基)-5-氰基-3,4-二羟氧环烷-2-基]甲氧基苯氧磷酰基]氨基]丙酸酯(2-ethylbutyl(2S)-2-[[[(2R,3S,4R,5R)-5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-5-cyano-3,4-dihydroxyoxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate)，又名Remdesivir(GS-5734)，是一种病毒RNA聚合酶抑制剂，其体内活性形式为母体药物的核苷三磷酸酸(NTP)。该药化合物目前已完成临床治疗埃博拉病毒感染的III期临床试验，对埃博拉病毒感染显示出良好的治疗效果。
Remdesivir在基于细胞的测定中表现出针对EBOV和其它丝状病毒的多种变体的抗病毒活性。在埃博拉病毒感染的恒河猴模型中，即使在病毒暴露后三天开始治疗(在六只处理的动物中的两只中检测到全身病毒RNA)，每天静脉内施用10mg/kg的GS-5734，持续给药12天，可非常明显的抑制EBOV的复制，100％的保护EBOV感染的动物免受于死亡，并改善临床疾病征象和病理生理标志物。除了埃博拉病毒外，GS-5734还具有广谱的抗病毒活性，比如尼帕病毒(Nipah virus)、中东呼吸综合症冠状病毒(MERS-CoV)、马尔 堡病毒(Marburg virus)等。
2019新型冠状病毒(2019-nCoV)是以前从未在人类中发现的冠状病毒新毒株。2020年2月11日，国际病毒分类委员会(ICTV)宣布，2019新型冠状病毒(2019-nCoV)的正式分类名为严重急性呼吸综合征冠状病毒2(severe acute respiratory syndrome coronavirus 2，SARS-CoV-2)。同日，世界卫生组织(WHO)宣布，由这一病毒导致的疾病的正式名称为COVID-19。SARS-CoV-2病毒感染的症状主要以肺炎为主，依据病情的轻重程度可分为单纯性感染、轻症肺炎、重症肺炎、急性呼吸窘迫综合症、脓毒症、脓毒症休克等。单纯性感染的患者可能有非特异性症状，例如发热、咳嗽、咽痛、鼻塞、乏力、头痛、肌肉疼痛或不适，老年人和免疫抑制者可能会出现非典型症状。轻症肺炎的患者主要以咳嗽、呼吸困难+呼吸急促为主。重症肺炎可见于青少年、成人或儿童，主要症状为呼吸频率增加，严重的呼吸衰竭或呼吸困难，中心型发绀、嗜睡、意识不清或惊厥、抽气等。急性呼吸窘迫综合症的肺部影像为双侧磨玻璃影，但不能完全由积液、大叶渗出或者肺不张或者肺部块影解释，以肺水肿为主要症状。脓毒症患者往往有致命的器官功能障碍，脓毒性休克是最为危重的患者，死亡可能性较高。
目前，针对SARS-CoV-2病毒感染，临床上以支持治疗为主，无抗病毒药物可用。
申请内容
本申请目的是发现对SARS-CoV-2有抗病毒活性的药物，可用于其感染引起相关疾病的救治。本申请通过创造性的研究发现式I化合物具有抑制SARS-CoV-2复制方面的功能，在治疗SARS-CoV-2引起的疾病方面具有很好的潜在的治疗效果。
本申请提供式I所示的化合物，其几何异构体，及其药学上可接受的盐和/或其溶剂化物或其水合物:
Figure PCTCN2020097421-appb-000002
在某些实施方案中，本申请所述式I所示化合物的药学上可接受的盐包括其无机或有机酸盐，以及无机或有机碱盐，本申请涉及上述盐的所有形式，其中包括但不限于:钠盐、 钾盐、钙盐、锂盐、葡甲胺盐、盐酸盐，氢澳酸盐，氢腆酸盐，硝酸盐，硫酸盐，硫酸氢盐，磷酸盐，磷酸氢盐，乙酸盐，丙酸盐，丁酸盐，草酸盐，三甲基乙酸盐，己二酸盐，藻酸盐，乳酸盐，柠檬酸盐，酒石酸盐，琥珀酸盐，马来酸盐，富马酸盐，苦味酸盐，天冬氨酸盐，葡糖酸盐，苯甲酸盐，甲磺酸盐，乙磺酸盐，苯磺酸盐，对甲苯磺酸盐和双羟萘酸盐等。
式I所示化合物可在细胞上抑制SARS-CoV-2病毒复制，减少细胞培养物中SARS-CoV-2病毒核酸载量。
本申请的发明人在经过创造性发明研究后，发现了式I所示化合物在细胞内的新作用特点：式I所示化合物可以在微摩尔级浓度下降低SARS-CoV-2感染的细胞病毒核酸载量水平。
本申请还涉及式I所示的化合物，其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物在制备用于治疗SARS-CoV-2引起的疾病或感染(例如呼吸系统疾病(例如单纯性感染如发热、咳嗽和咽痛等、肺炎、急性呼吸道感染、严重急性呼吸道感染(SARI)、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症和脓毒性休克等))的药物中的用途，
Figure PCTCN2020097421-appb-000003
本申请还涉及式I所示的化合物，其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物在制备作为SARS-CoV-2抑制剂的药物中的用途。
本申请还涉及式I所示的化合物，其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物在制备用于抑制SARS-CoV-2在细胞(例如哺乳动物细胞)中复制或繁殖的药物中的用途。
本申请还涉及一种药物组合物，其包含式I所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物，
优选地，所述的药物组合物还包含药学上可接受的载体或辅料，具体地，所述药物组合物为固体制剂、注射剂、外用制剂、喷剂、液体制剂、或复方制剂。
本申请还涉及所述包含式I所示化合物、其几何异构体或其药学上可接受的盐和/ 或其溶剂化物和/或其水合物的药物组合物或式I所示化合物化合物、其几何异构体及其药学上可接受的盐和/或其溶剂化物和/或其水合物在制备用于治疗呼吸系统疾病但不限于呼吸系统疾病(单纯性感染如发热、咳嗽和咽痛等、肺炎、急性呼吸道感染、严重急性呼吸道感染(SARI)、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症和脓毒性休克等)的药物中的用途。
本申请还涉及所述包含式I所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物的药物组合物在制备用于治疗SARS-CoV-2引起的疾病或感染(例如呼吸系统疾病(例如单纯性感染如发热、咳嗽和咽痛等、肺炎、急性呼吸道感染、严重急性呼吸道感染(SARI)、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症和脓毒性休克等))的药物中的用途。
本申请还涉及所述包含式I化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物的药物组合物在制备作为SARS-CoV-2抑制剂的药物中的用途。
本申请还涉及所述包含式I化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物的药物组合物在制备用于抑制SARS-CoV-2在细胞(例如哺乳动物细胞)中复制或繁殖的药物中的用途。
本申请还涉及一种在有需要的哺乳动物中治疗和/或预防疾病的方法或者在有需要的哺乳动物中抑制SARS-CoV-2复制或繁殖的方法，该方法包括给有需要的哺乳动物施用治疗和/或预防有效量的所述包含式I所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物的药物组合物或所述式I化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物，其中所述的疾病包括SARS-CoV-2引起的疾病，例如SARS-CoV-2引起的病毒感染性疾病(例如呼吸系统疾病，包括单纯性感染如发热、咳嗽和咽痛等、肺炎、急性呼吸道感染、严重急性呼吸道感染(SARI)、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症和脓毒性休克等)。
本申请还涉及式I所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物，其作为SARS-CoV-2抑制剂。
本申请还涉及式I所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物，其用于抑制SARS-CoV-2在细胞(例如哺乳动物细胞)中复制或繁殖。
本申请还涉及所述包含式I所示化合物、其几何异构体或其药学上可接受的盐和/ 或其溶剂化物和/或其水合物的药物组合物，其作为SARS-CoV-2抑制剂。
本申请还涉及所述包含式I所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物的药物组合物，用于抑制SARS-CoV-2在细胞(例如哺乳动物细胞)中复制或繁殖。
在某些实施方案中，本申请所述的SARS-CoV-2引起的疾病包括但不限于呼吸系统疾病，例如单纯性感染如发热、咳嗽和咽痛等、肺炎、急性呼吸道感染、严重急性呼吸道感染(SARI)、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症和脓毒性休克等。
在某些实施方案中，本申请所述的SARS-CoV-2引起的疾病为COVID-19。
本申请中，所用术语“2019新型冠状病毒(2019-nCoV)”的正式分类名为严重急性呼吸综合征冠状病毒2(severe acute respiratory syndrome coronavirus 2，SARS-CoV-2)。
本申请中，所用术语“2019新型冠状病毒(2019-nCoV)引起的疾病”的正式名称为COVID-19。
在某些实施方案中，所述哺乳动物包括牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物，其中优选的哺乳动物为人、猫、狗或猪。
本申请所述药物组合物可以根据不同给药途径而制备成各种形式。
根据本申请，所述的药物组合物可以以下面的任意方式施用：口服、喷雾吸入、直肠用药、鼻腔用药、颊部用药、阴道用药、局部用药、非肠道用药如皮下、静脉、肌内、腹膜内、鞘内、心室内、胸骨内和颅内注射或输入、或借助一种外植储器用药。其中优选口服、腹膜内或静脉内用药方式。
当口服用药时，所述式I所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊、水溶液或水悬浮液。其中，片剂一般使用的载体包括乳糖和玉米淀粉，另外也可加入润滑剂如硬质酸镁。胶囊制剂一般使用的稀释剂包括乳糖和干燥玉米淀粉。水悬浮液制剂则通常是将活性成分与适宜的乳化剂和悬浮剂混合使用。如果需要，以上口服制剂形式中还可加入一些甜味剂、芳香剂或着色剂。
当直肠用药时，所述式I所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物一般可制成栓剂的形式，其通过将药物与一种适宜的非刺激性赋形剂混合而制得。该赋形剂在室温下呈现固体状态，而在直肠温度下熔化释 出药物。该类赋形剂包括可可脂、蜂蜡和聚乙二醇。
当局部用药时，特别是治疗局部外敷容易达到的患面或器官，如眼睛、皮肤或下肠道神经性疾病时，所述式I所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物可根据不同的患面或器官制成不同的局部用药制剂形式，具体说明如下：
当眼部局部施用时，所述式I所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物可配制成一种微粉化悬浮液或溶液的制剂形式，所使用载体为等渗的一定pH的无菌盐水，其中可加入也可不加防腐剂如氯化苄基烷醇盐。此外对于眼用，也可将化合物制成膏剂形式如凡士林膏。
当皮肤局部施用时，所述式I所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物可制成适当的软膏、洗剂或霜剂制剂形式，其中活性成分悬浮或溶解于一种或多种载体中。这里软膏即可使用的载体包括但不限于：矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水；洗剂或霜剂可使用的载体包括但不限于：矿物油、脱水山梨糖醇单硬脂酸酯、吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。
当下肠道局部施用时，所述式I所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物可制成如上所述的直肠栓剂制剂或适宜的灌肠制剂形式，另外也可使用局部透皮贴剂。
所述式I所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液，或无菌注射溶液。其中，可使用的载体和溶剂包括水，林格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。
上述各种剂型的药物均可以按照药学领域的常规方法制备。
本申请中，术语“治疗有效量”或“预防有效量”是指在合理的医学判断范围内，足以治疗或预防患者疾病但足够低地避免严重副作用(在合理的利益/风险比)的量。化合物的治疗有效量将根据所选择的具体化合物(例如考虑化合物的效力、有效性和半衰期)、所选择的给药途径、所治疗的疾病、所治疗的疾病的严重性、所治疗的患者的年龄、大小、体重和身体疾病、所治疗的患者的医疗史、治疗持续时间、并行疗法的性质、所需的治疗效果等因素发生变化，但仍可以由本领域技术人员常规确定。
另外需要指出，所述式I所示化合物、其几何异构体或其药学上可接受的盐和/ 或其溶剂化物和/或其水合物针对不同患者的特定使用剂量和使用方法决定于诸多因素，包括患者的年龄，体重，性别，自然健康状况，营养状况，药物的活性强度，服用时间，代谢速率，病症的严重程度以及诊治医师的主观判断。这里优选使用剂量介于0.001-1000mg/kg体重/天。
附图说明
图1.显示Remdesivir有效降低SARS-CoV-2病毒感染的veroE6细胞上病毒核酸载量。其中(a)Remdesivir在细胞感染SARS-CoV-2病毒48h后能够抑制细胞上的病毒RNA载量，其中33μM的药物浓度可使得病毒的核酸载量降低一个数量级。纵坐标为样品中病毒RNA的拷贝数，横坐标为药物浓度；(b)Remdesivir在受试浓度下对受试细胞处理48h，观察不到细胞毒性。纵坐标为相对于阴性对照组(只有细胞，未加药物)的细胞活力百分比，横坐标为药物浓度。
具体实施方式
下面的实施例是本申请说明性优选实施方案，对本申请不构成任何限制。
实施例1：Remdesivir降低SARS-CoV-2病毒感染的细胞病毒核酸载量实验
(1)药物处理感染病毒的细胞
将Vero E6细胞(购自ATCC，货号1586)接种至24孔板，培养24h；然后进行病毒感染，具体的，用2％细胞维持液(配方为：将FBS(购自Gibco公司，货号16000044)按照2％的体积比加入MEM(购自Gibco公司，货号10370021)，即为2％细胞维持液)将SARS-CoV-2(2019-nCoV)病毒(nCoV-2019BetaCoV/Wuhan/WIV04/2019株，由中国科学院武汉病毒研究所提供)稀释成相应浓度，然后加入24孔板中使每孔含有病毒量为100TCID 50。接下来，再用2％细胞维持液将Remdesivir(购自MedChemExpress，货号HY-104077)分别稀释成相应浓度，加入到对应的孔中，使药物最终浓度分别为100μM、33μM、11μM、3.7μM、1.23μM、0.41μM、0.14μM，然后放37℃、5％CO 2孵箱继续培养48h，细胞对照组只加不含有任何受试药物的2％细胞维持液。
(2)RNA提取
RNA提取试剂盒购自Qiagen公司，货号74106。下述RNA提取步骤中所涉及的耗材(离心柱、无RNA酶的2ml收集管等)及试剂(RLT、RW1、RPE、无RNA酶水等)均为试剂盒的组成部分。下述提取步骤均为试剂盒说明书所推荐的步骤。
1)取受试培养板的上清液100μL，加入无核酸酶EP管中，然后每孔加入350μL Buffer RLT，用移液枪吹吸混匀使其充分裂解后，离心取上清；
2)向1)中所得上清液加入等体积的70％乙醇，混匀；
3)将上述2)中所得混合液转入无RNA酶的离心柱中，12000rpm离心15s，弃废液；
4)加入700μL Buffer RW1,12000rpm离心15s清洗离心柱，弃废液；
5)加入500μL Buffer RPE,12000rpm离心15s清洗离心柱，弃废液；
6)加入500μL Buffer RPE,12000rpm离心2min清洗离心柱，弃废液；
7)换新的无RNA酶的2ml收集管，12000rpm离心1min，干燥离心柱，然后将离心柱整体转移至步骤8)的1.5ml收集管中；
8)换上新的1.5ml收集管，放入步骤7)中干燥后的离心柱，并向离心柱中加入30μl不含RNA酶的水，12000rpm离心2min，洗脱液即含有相应的RNA，加入RNA酶抑制剂(购自NEB公司，货号M0314L)，用Nano Drop(购自Thermo scientific，型号Nano Drop One)检测各RNA浓度。
(3)RNA反转录
实验采用TaKaRa公司生产的反转录试剂盒(PrimeScript TM RT reagent Kit with gDNA Eraser，货号RR047Q)进行RNA反转录，步骤如下。
①gDNA去除：收集各实验组RNA样品，分别取1μg进行反转录。首先，向各实验组RNA中加入2μl 5×gDNA Eraser Buffer，用RNase Free水补足反应体系至10μl，充分混匀，42℃水浴2min去除样品中可能存在的g DNA；
②逆转录：向①所得样品中加入适量的酶和引物Mix及反应缓冲液，用RNase Free水补足体积至20μl，37℃水浴反应15min，之后投入85℃水中5sec，既可转录得到cDNA。
(4)Real-time PCR
采用荧光定量PCR检测原病毒液每毫升所含拷贝数。
采用TB Green Premix(Takara，Cat#RR820A)混好反应体系，在StepOne Plus Real-time PCR仪(品牌：ABI)进行扩增反应和读数。计算原病毒液每毫升所含拷贝数。步骤如下：
①首先建立标准品：将质粒pMT-RBD(质粒由中国科学院武汉病毒研究所提供)稀释成5×10 8copies/μL,5×10 7copies/μL,5×10 6copies/μL,5×10 5copies/μL,5×10 4copies/μL,5×10 3copies/μL,5×10 2copies/μL。取2μL标准品或cDNA 模板用于qPCR反应。
②实验过程中所用引物序列如下(均为5’-3’方向表示)：
RBD-qF:CAATGGTTTAACAGGCACAGG
RBD-qR:CTCAAGTGTCTGTGGATCACG
③反应程序如下：
预变性：95℃5分钟；
循环参数：95℃15秒，54℃15秒，72℃30秒，共40个循环。
(5)药物对细胞毒性测试
药物对细胞毒性的检测利用CCK-8试剂盒(Beoytime)测定。具体步骤如下：
①96孔板中接种1×10 4个Vero E6(ATCC)细胞，37℃培养8小时。
②将药物用DMSO稀释到合适的母液浓度，再用含2％FBS(购自Gibco公司，货号16000044)的MEM培养基(购自Gibco公司，货号10370021)稀释到与药物处理同样的浓度，弃96孔板中原培养基，取100μL含药物的MEM培养基加入到细胞中，每个浓度做三个复孔。设置阴性对照(细胞孔中加DMSO和培养基，而不加药物)和空白对照(不含细胞，加DMSO和培养基)。加药完毕，细胞37℃培养48小时。
③向待测孔中加入20μL CCK-8溶液(Beoytime)，轻轻混匀，不要产生气泡，37℃继续培养2小时。在酶标仪(购自Molecular Devices公司，型号SpectraMax M5)上读取OD 450，计算细胞活性：
细胞活性(％)＝(A (药物处理组)-A (空白对照))/(A (阴性对照)-A (空白对照))×100％
其中A为酶标仪读数。
(6)实验结果
病毒增殖抑制实验的结果显示，受试化合物在100μM，33μM，11.1μM以及3.7μM的浓度下，均能够有效抑制感染上清中SARS-CoV-2病毒基因组的复制(表1和图1)
表1.受试化合物(Remdesivir)的体外抗病毒实验
Figure PCTCN2020097421-appb-000004
细胞毒性结果显示，在所有受试浓度下，受试化合物(Remdesivir)的处理均未改变细胞活力，即受试化合物在所有浓度下对细胞均无毒性作用(表2和图1)。
表2.受试化合物(Remdesivir)的细胞毒性实验
Figure PCTCN2020097421-appb-000005

Claims (18)

  1. 式I所示的化合物，其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物在制备用于治疗SARS-CoV-2引起的疾病或感染(例如呼吸系统疾病(例如单纯性感染如发热、咳嗽和咽痛等、肺炎、急性呼吸道感染、严重急性呼吸道感染(SARI)、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症和脓毒性休克等))的药物中的用途，
    Figure PCTCN2020097421-appb-100001
  2. 药物组合物在制备用于治疗SARS-CoV-2引起的疾病或感染(例如呼吸系统疾病(例如单纯性感染如发热、咳嗽和咽痛等、肺炎、急性呼吸道感染、严重急性呼吸道感染(SARI)、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症和脓毒性休克等))的药物中的用途，其中所述药物组合物包含式Ⅰ所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物，
    Figure PCTCN2020097421-appb-100002
    优选地，所述的药物组合物还包含药学上可接受的载体或辅料，具体地，所述药物组合物为固体制剂、注射剂、外用制剂、喷剂、液体制剂、或复方制剂。
  3. 式I所示的化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物在制备作为SARS-CoV-2抑制剂的药物中的用途，
    Figure PCTCN2020097421-appb-100003
  4. 式I所示的化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物在制备用于抑制SARS-CoV-2在细胞(例如哺乳动物细胞)中复制或繁殖的药物中的用途，
    Figure PCTCN2020097421-appb-100004
  5. 药物组合物在制备作为SARS-CoV-2抑制剂的药物中的用途，
    Figure PCTCN2020097421-appb-100005
    其中所述药物组合物包含式Ⅰ所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物，
    优选地，所述的药物组合物还包含药学上可接受的载体或辅料，具体地，所述药物组合物为固体制剂、注射剂、外用制剂、喷剂、液体制剂、或复方制剂。
  6. 药物组合物在制备用于抑制SARS-CoV-2在细胞(例如哺乳动物细胞)中复制或繁殖的药物中的用途，
    Figure PCTCN2020097421-appb-100006
    其中所述药物组合物包含式Ⅰ所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物，
    优选地，所述的药物组合物还包含药学上可接受的载体或辅料，具体地，所述药物组合物为固体制剂、注射剂、外用制剂、喷剂、液体制剂、或复方制剂。
  7. 权利要求1或2所述的用途，其中所述SARS-CoV-2引起的疾病为COVID-19。
  8. 权利要求4或6所述的用途，其中所述哺乳动物包括牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物，例如是人，猫，狗或猪。
  9. 一种在有需要的哺乳动物中治疗和/或预防疾病的方法，该方法包括给有需要的哺乳动物施用治疗和/或预防有效量的所述包含式I所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物的药物组合物或所述式I化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物，
    Figure PCTCN2020097421-appb-100007
    其中所述的疾病包括SARS-CoV-2引起的疾病，例如SARS-CoV-2引起的病毒感染性疾病(例如呼吸系统疾病，包括单纯性感染如发热、咳嗽和咽痛等、肺炎、急性呼吸道感染、严重急性呼吸道感染(SARI)、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症和脓毒性休克等)，
    优选地，所述的药物组合物还包含药学上可接受的载体或辅料，具体地，所述药物组合物为固体制剂、注射剂、外用制剂、喷剂、液体制剂、或复方制剂。
  10. 一种在有需要的哺乳动物中抑制SARS-CoV-2复制或繁殖的方法，该方法包括给有需要的哺乳动物施用治疗和/或预防有效量的所述包含式I所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物的药物组合物或所述式I化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物，
    Figure PCTCN2020097421-appb-100008
    优选地，所述的药物组合物还包含药学上可接受的载体或辅料，具体地，所述药物组合物为固体制剂、注射剂、外用制剂、喷剂、液体制剂、或复方制剂。
  11. 式I所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物，
    Figure PCTCN2020097421-appb-100009
    其作为SARS-CoV-2抑制剂。
  12. 式I所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物，
    Figure PCTCN2020097421-appb-100010
    其用于抑制SARS-CoV-2在细胞(例如哺乳动物细胞)中复制或繁殖。
  13. 式I所示的化合物，其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物，
    Figure PCTCN2020097421-appb-100011
    其用于治疗SARS-CoV-2引起的疾病或感染(例如呼吸系统疾病(包括单纯性感染如发热、咳嗽和咽痛等、肺炎、急性呼吸道感染、严重急性呼吸道感染(SARI)、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症和脓毒性休克等))。
  14. 药物组合物，其用于治疗SARS-CoV-2引起的疾病或感染(例如呼吸系统疾病(例如单纯性感染如发热、咳嗽和咽痛等、肺炎、急性、呼吸道感染、严重急性呼吸道感染(SARI)、低氧性呼吸衰竭及急性呼吸窘迫综合征、脓毒症和脓毒性休克等))，其中所述药物组合物包含式Ⅰ所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物，
    Figure PCTCN2020097421-appb-100012
    优选地，所述的药物组合物还包含药学上可接受的载体或辅料，具体地，所述药 物组合物为固体制剂、注射剂、外用制剂、喷剂、液体制剂、或复方制剂。
  15. 药物组合物，其作为SARS-CoV-2抑制剂，其中所述药物组合物包含式Ⅰ所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物，
    Figure PCTCN2020097421-appb-100013
    优选地，所述的药物组合物还包含药学上可接受的载体或辅料，具体地，所述药物组合物为固体制剂、注射剂、外用制剂、喷剂、液体制剂、或复方制剂。
  16. 药物组合物，用于抑制SARS-CoV-2在细胞(例如哺乳动物细胞)中复制或繁殖，其中所述药物组合物包含式Ⅰ所示化合物、其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物，
    Figure PCTCN2020097421-appb-100014
    优选地，所述的药物组合物还包含药学上可接受的载体或辅料，具体地，所述药物组合物为固体制剂、注射剂、外用制剂、喷剂、液体制剂、或复方制剂。
  17. 权利要求9所述的方法、权利要求13所述的化合物，其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物或权利要求14所述的药物组合物，其中所述SARS-CoV-2引起的疾病为COVID-19。
  18. 权利要求10所述的方法、权利要求12所述的化合物，其几何异构体或其药学上可接受的盐和/或其溶剂化物和/或其水合物或权利要求16所述的药物组合物，其中所述 哺乳动物包括牛科动物、马科动物、羊科动物、猪科动物、犬科动物、猫科动物、啮齿类动物、灵长类动物，例如是人，猫，狗或猪。
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