Application of fisotinib or pharmaceutically acceptable salt thereof in preparation of antiviral drugs

Abstract

The invention discloses an application of fisotinib or a pharmaceutically acceptable salt thereof in preparation of an antiviral drug. In-vitro drug experiments and in-vivo drug experiments of the invention find that the fesotinib or pharmaceutically acceptable salts, solvates, hydrates, prodrugs, isomers, analogues, derivatives or metabolites of the fesotinib can significantly inhibit the replication of various viruses, and especially show potent antiviral activity in certain virus infection models.

Description

Technical Field

[0001] The present invention belongs to the field of biomedicine, and particularly relates to the use of fostamatinib or a pharmaceutically acceptable salt thereof in the preparation of antiviral drugs. Background Art

[0002] In recent years, viral infections have become an important issue in global public health. In particular, the outbreak of novel viruses has posed a huge challenge to the world. Existing antiviral drugs have certain limitations, such as drug resistance, poor therapeutic effects, and significant side effects. Therefore, the development of novel antiviral drugs is one of the hotspots in current medical research. Summary of the Invention

[0003] To solve at least some of the above-mentioned problems in the prior art, the present invention provides the use of fostamatinib or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, isomer, analogue, derivative or metabolite thereof in the preparation of antiviral drugs. Specifically, the present invention includes the following contents.

[0004] In a first aspect of the present invention, there is provided the use of fostamatinib or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, isomer, analogue, derivative or metabolite thereof in the preparation of antiviral drugs.

[0005] In certain embodiments, according to the use described in the present invention, wherein the virus includes DNA virus and / or RNA virus.

[0006] In certain embodiments, according to the use described in the present invention, wherein the DNA virus includes at least one of herpes simplex virus, varicella-zoster virus, cytomegalovirus, smallpox virus, monkeypox virus, adenovirus, human papillomavirus, parvovirus, bocavirus, and hepatitis B virus.

[0007] In certain embodiments, according to the use described in the present invention, wherein the RNA virus includes at least one of vesicular stomatitis virus, influenza A virus, encephalomyocarditis virus, murine hepatitis virus, influenza A virus, influenza B virus, influenza C virus, dengue virus, Zika virus, Ebola virus, Marburg virus, Nipah virus, coronavirus, hepatitis A virus, hepatitis C virus, rotavirus, measles virus, human immunodeficiency virus, respiratory syncytial virus, and rabies virus.

[0008] In certain embodiments, according to the use described in the present invention, wherein the antiviral includes at least one of the following situations: (1) inhibiting virus entry into host cells; (2) inhibiting virus genome replication; (3) inhibiting virus protein processing or assembly; (4) Inhibiting virus release; (5) Reducing the amount or activity of the virus; (6) Increasing the survival rate.

[0009] In certain embodiments, for the application according to the present invention, antiviral is achieved by administering a therapeutically effective amount of the drug to a subject.

[0010] In certain embodiments, for the application according to the present invention, the subject includes mammals.

[0011] In certain embodiments, for the application according to the present invention, the mammal includes humans.

[0012] In certain embodiments, for the application according to the present invention, the therapeutically effective amount is 0.01 - 1000 mg / Kg.

[0013] In a second aspect of the present invention, there is provided the use of ficlatuzumab or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, isomer, analogue, derivative or metabolite thereof in combination with other drugs in the preparation of a combined antiviral drug.

[0014] Through in vitro and in vivo drug experiments, the present invention discovers that ficlatuzumab or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, isomer, analogue, derivative or metabolite thereof can significantly inhibit the replication of various viruses, and particularly exhibits potent antiviral activity in certain virus infection models. BRIEF DESCRIPTION OF THE DRAWINGS

[0015] Figure 1 It shows that ficlatuzumab can effectively reduce the viral load in RAW264.7 cells.

[0016] Figure 2 It shows the antiviral situation of ficlatuzumab detected by flow cytometry.

[0017] Figure 3 It shows the effect of ficlatuzumab on the survival rate of virus-infected mice.

[0018] Figure 4 It shows the inhibitory effect of ficlatuzumab on the expression of virus in the spleen and liver tissues of mice.

[0019] Figure 5 It shows the inhibitory effect of ficlatuzumab on the expression of cytokines in the spleen, liver tissues and blood of mice. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0020] The various exemplary embodiments of the present invention will be described in detail below. This detailed description should not be considered as a limitation on the present invention, but rather as a more detailed description of certain aspects, characteristics, and implementation schemes of the present invention.

[0021] It should be understood that the terms used in the present invention are only for describing specific embodiments and are not intended to limit the present invention. Additionally, for the numerical ranges in the present invention, it should be understood that the upper and lower limits of the range and each intermediate value therebetween are specifically disclosed. Intermediate values within any stated value or stated range, as well as each smaller range between any other stated value or intermediate value within the stated range, are also included in the present invention. The upper and lower limits of these smaller ranges may be independently included or excluded from the range.

[0022] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which the present invention pertains. Although the present invention only describes preferred methods and materials, any methods and materials similar or equivalent to those described herein may also be used in the implementation or testing of the present invention. All documents mentioned in this specification are incorporated by reference to disclose and describe the methods and / or materials related to the said documents. In case of conflict with any incorporated document, the content of this specification shall prevail.

[0023] Application In one aspect of the present invention, there is provided the use of Fisogatinib or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, isomer, analogue, derivative, or metabolite thereof in the preparation of an antiviral drug. Fisogatinib (also known as BLU-111362, BLU-554) is a small molecule chemical drug developed by Blueprint Medicines Corp. and is a highly effective, selective, and orally active FGFR4 inhibitor (IC 50 is 5 nM). As an FGFR4 antagonist, it can inhibit fibroblast growth factor receptor-4 and has significant anti-tumor activity in a hepatocellular carcinoma model dependent on FGFR4 signal transduction. It can also stimulate T cell infiltration into the tumor microenvironment. In the field of oncology, Fisogatinib, as a highly selective FGFR4 inhibitor, has been proven to have significant anti-tumor effects in a hepatocellular carcinoma (HCC) model. However, there is currently no relevant report on its antiviral effect.

[0024] In the present invention, the chemical name of Fisogatinib is N-((3S,4S)-3-((6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazolin-2-yl)amino)tetrahydro-2H-pyran-4-yl)acrylamide, and the chemical formula is C 24 H24 C l2 N4O4, with a molecular weight of 503.38, and its molecular structural formula is shown as the following formula (I): (I).

[0025] As used herein, the term "pharmaceutically acceptable" refers to those compounds, substances, compositions and / or dosage forms that are suitable for contact with human and animal tissues within the scope of reasonable medical judgment without excessive toxicity, irritation, allergic reaction or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0026] Examples of pharmaceutically acceptable salts of the compounds described herein include those salts derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, benzoate, benzenesulfonate, butyrate, citrate, digluconate, dodecyl sulfate, formate, fumarate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, lactate, maleate, malonate, mesylate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, toluenesulfonate and undecanoate. Salts derived from appropriate bases include alkali metal (e.g., sodium) salts, alkaline earth metal (e.g., magnesium) salts, ammonium salts and N-(alkyl)4 + salts.

[0027] As used herein, the term "solvate" refers to an association or complex formed by one or more solvent molecules with the compounds of the present invention. Solvents that form solvates include, but are not limited to: water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol, etc.

[0028] As used herein, the term "hydrate" refers to an association or complex formed by the compounds of the present invention when the solvent molecule is water.

[0029] As used herein, the term "isomer" includes enantiomeric forms, diastereomeric forms and geometric (or conformational) isomeric forms of a given structure. For example, the present invention includes the R and S configurations of each asymmetric center, Z and E double bond isomers, Z and E conformational isomers, single stereochemical isomers and mixtures of enantiomers, diastereomers and geometric (or conformational) isomers. Unless otherwise specified, the present invention includes all tautomeric forms of the structures disclosed by sunitinib.

[0030] As used herein, the term "prodrug" refers to a compound that is converted in vivo to a compound represented by the above formula (I). The term "prodrug" refers to a pharmacologically inactive derivative of the parent drug molecule that can undergo spontaneous or enzymatic biotransformation in a living organism to release the active drug. A prodrug is a variant or derivative of a compound of the present invention and has a group that is cleavable under metabolic conditions. When prodrugs undergo solvolysis or enzymatic degradation under physiological conditions, they become the compounds of the present invention that are pharmaceutically active in vivo. Prodrug forms generally offer advantages of solubility, tissue compatibility, or delayed release in mammalian organisms (see Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam 1985 and Silverman, The Organic Chemistry of Drug Design and Drug Action, pp. 352-401, Academic Press, San Diego, CA, 1992).

[0031] As used herein, the term "metabolite" refers to a product obtained by the metabolism of the above compound or its salt in vivo. The metabolites of a compound can be identified by techniques well known in the art, and their activities can be characterized by methods known in the art. Such products can be obtained by methods such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic cleavage, etc. of the administered compound.

[0032] In the present invention, the term "derivative" refers to a product derived by substituting an atom or functional group in the compound of formula (I) with another atom or functional group, and its derivatives are not specifically limited, including but not limited to esters, acylates, or metal complexes of the compound of formula (I), etc.

[0033] In the present invention, the compound can be administered as a pharmaceutical composition together with a pharmaceutically acceptable carrier. Examples of pharmaceutically acceptable carriers include: (1) saccharides such as lactose, glucose, and sucrose; (2) starches such as corn starch and potato starch; (3) celluloses and their derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) diols such as propylene glycol; (11) polyols such as glycerol, sorbitol, mannitol, and polyethylene glycol; (12) esters such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethanol; (20) phosphate buffer solution; (21) cyclodextrins such as Captisol ® ; targeting ligands attached to the nanoparticles, such as Accurins TM ; and (22) other non-toxic compatible substances for pharmaceutical formulations, such as polymer-based compositions.

[0034] In the present invention, examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite, etc.; (2) oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, α-tocopherol, etc.; and (3) metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, etc. Solid dosage forms (e.g., capsules, tablets, pills, dragees, powders, granules, etc.) may include one or more pharmaceutically acceptable carriers such as sodium citrate or calcium phosphate dibasic, and / or any of the following: (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders such as carboxymethyl cellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or gum arabic; (3) humectants such as glycerol; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution blockers such as paraffin wax; (6) absorption promoters such as quaternary ammonium compounds; (7) wetting agents such as cetyl alcohol and glycerol monostearate; (8) adsorbents such as kaolin and bentonite; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and (10) coloring agents. Liquid dosage forms may include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, liquid dosage forms may contain inert diluents commonly used in the art (such as water or other solvents), solubilizers, and emulsifying agents (such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, oils (such as cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of dehydrated sorbitol, and mixtures thereof.

[0035] In the present invention, in addition to the active compound, suspensions may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum hydroxide, bentonite, agar, and tragacanth, and mixtures thereof.

[0036] In the present invention, in addition to the active compound, ointments, pastes, creams, and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffin wax, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0037] In the present invention, in addition to the active compound, the powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures of these substances. The sprays may additionally contain conventional propellants (such as chlorofluorocarbons) and volatile unsubstituted hydrocarbons (such as butane and propane).

[0038] In the present invention, the formulations may be conveniently presented in unit dosage forms and may be prepared by any methods well known in the pharmaceutical art. The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending on the host to be treated and the specific mode of administration. The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will generally be the amount at which the compound produces a therapeutic effect.

[0039] In the present invention, the dosage forms of the compounds of the present invention for topical or transdermal administration include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0040] When the compounds disclosed herein are administered as a medicine to humans or animals, they may be given either alone or as a pharmaceutical composition containing, for example, 0.1% to 99.5% (more preferably, 0.5% to 90%) of the active ingredient in combination with a pharmaceutically acceptable carrier.

[0041] In the present invention, the formulations may be administered topically, orally, transdermally, rectally, vaginally, parenterally, intranasally, intrapulmonary, intraocularly, intravenously, intramuscularly, intraarterially, intrathecally, intracapsularly, intradermally, intraperitoneally, subcutaneously, subepidermally, or by inhalation.

[0042] Indications In the present invention, ficotinib or a pharmaceutically acceptable salt thereof can be used to treat viral infections, including DNA viruses and / or RNA viruses. Among them, examples of the DNA viruses include, but are not limited to, herpes simplex virus type 1, herpes simplex virus type 2, varicella-zoster virus, cytomegalovirus, smallpox virus, monkeypox virus, adenovirus, human papillomavirus, parvovirus, bocavirus, hepatitis B virus, etc.; examples of the RNA viruses include, but are not limited to, vesicular stomatitis virus, influenza A virus, encephalomyocarditis virus, murine hepatitis virus, influenza A virus, influenza B virus, influenza C virus, dengue virus, Zika virus, Ebola virus, Marburg virus, Nipah virus, coronavirus, hepatitis A virus, hepatitis C virus, rotavirus, measles virus, human immunodeficiency virus, respiratory syncytial virus, rabies virus, etc.

[0043] In the present invention, "antiviral" means improving the condition after viral infection or before or after the occurrence of a dysfunction. Compared with an untreated reference group under the same conditions, the degree of alleviation or improvement is at least 5%, 10%, 20%, 40%, 50%, 60%, 80%, 90%, 95% or 100% as measured by any standard technique. Beneficial or desired clinical outcomes include, but are not limited to, the following outcomes whether detectable or undetectable, including alleviation of symptoms, reduction in the degree of disease, stabilization of the disease state (i.e., no worsening), delay or slowing of disease progression, improvement or mitigation of the disease state, and alleviation (whether partial or complete).

[0044] In a preferred embodiment, the antiviral scenarios include, but are not limited to: (1) inhibiting viral entry into host cells; (2) inhibiting viral genome replication; (3) inhibiting viral protein processing or assembly; (4) inhibiting viral release; (5) reducing the amount or activity of the virus; (6) increasing survival rate or viability.

[0045] In the present invention, the antiviral effect is achieved by administering a therapeutically effective amount of the said drug to a subject. Subjects include, but are not limited to, mammals, examples of mammals including, but not limited to, humans, mice, rabbits, cats, dogs, cows, sheep, pigs, etc.

[0046] The therapeutically effective amount described in the present invention refers to the pharmaceutically recognized effective dosage, that is, the amount of the active compound (i.e., ficotinib or its pharmaceutically acceptable salt, solvate, hydrate, prodrug, isomer, analogue, derivative or metabolite) is sufficient to significantly improve the condition without causing serious side effects. The daily dosage of ficotinib or its pharmaceutically acceptable salt, solvate, hydrate, prodrug, isomer, analogue, derivative or metabolite is usually 0.01 - 1000 mg / Kg, preferably 0.01 - 500 mg / Kg, or 0.01 - 400 mg / Kg, or 0.01 - 300 mg / Kg, or 0.01 - 200 mg / Kg, or 0.01 - 150 mg / Kg, or 0.01 - 100 mg / Kg, or 0.01 - 50 mg / Kg, or 0.01 - 40 mg / Kg, or 0.01 - 30 mg / Kg, and most preferably 0.01 - 20 mg / Kg. Exemplary effective dosages are for example 0.01 mg / Kg, 0.05 mg / Kg, 0.1 mg / Kg, 0.2 mg / Kg, 0.3 mg / Kg, 0.4 mg / Kg, 0.5 mg / Kg, 0.75 mg / Kg, 0.95 mg / Kg, 1 mg / Kg, 1.25 mg / Kg, 1.5 mg / Kg, 1.75 mg / Kg, 2 mg / Kg, 2.5 mg / Kg, 2.75 mg / Kg, 3 mg / Kg, 3.25 mg / Kg, 3.5 mg / Kg, 3.75 mg / Kg, 4 mg / Kg, 4.25 mg / Kg, 4.5 mg / Kg, 4.75 mg / Kg, 5 mg / Kg, 5.25 mg / Kg, 5.5 mg / Kg, 5.75 mg / Kg, 6 mg / Kg, 6.25 mg / Kg, 6.5 mg / Kg, 6.75 mg / Kg, 7 mg / Kg, 7.25 mg / Kg, 7.5 mg / Kg, 7.75 mg / Kg, 8 mg / Kg, 8.25 mg / Kg, 8.5 mg / Kg, 8.75 mg / Kg, 9 mg / Kg, 9.25 mg / Kg, 9.5 mg / Kg, 9.75 mg / Kg, 10 mg / Kg, 11 mg / Kg, 12 mg / Kg, 13 mg / Kg, 14 mg / Kg, 15 mg / Kg, 16 mg / Kg, 17 mg / Kg, 18 mg / Kg, 19 mg / Kg, 20 mg / Kg. It can be administered as a single dose once a day, in multiple doses per day, or at intervals.

[0047] Combined application In one aspect of the present invention, there is provided the use of fisogatinib or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, isomer, analogue, derivative or metabolite thereof in combination with other drugs in the preparation of a combined antiviral drug.

[0048] In the present invention, the other drugs include but are not limited to remdesivir, ribavirin, favipiravir, acyclovir, valacyclovir, famciclovir, ganciclovir, bromovinyldeoxyuridine, interferon, oseltamivir phosphate, peramivir, zanamivir, baloxavir marboxil, favipiravir, arbidol, etc.

[0049] Example 1 The inhibitory effect of fisogatinib on viruses is exemplarily shown below.

[0050] 1. Experimental method 1.1 Inhibitory effect of Fisogatinib on viral load in cells (1) After RAW264.7 cells (2×10 5 cells) were cultured in a 24-well plate for 16 hours, MOI = 0.1 Vesicular Stomatitis Virus (VSV), which is a non-pathogenic, enveloped negative-strand RNA rhabdovirus, was added, and then the small molecule compound Fisogatinib was added at a final concentration of 50 nM. After co-culturing for 12 hours, the viral load was detected by RT-qPCR. The positive control group was VSV + DMSO, and the negative control group was DMSO. Actb was used as an internal reference to calculate the relative expression value.

[0051] (2) After RAW264.7 cells (2×10 5 cells) were cultured in a 24-well plate for 16 hours, herpes simplex virus (HSV) with MOI = 0.1, which is a double-stranded linear DNA virus, was added, and then the small molecule compound Fisogatinib was added at a final concentration of 50 nM. After co-culturing for 12 hours, the viral load was detected by RT-qPCR. The positive control group was HSV + DMSO, and the negative control group was DMSO. Actb was used as an internal reference to calculate the relative expression value.

[0052] (3) RAW264.7 cells (2×10 5(0) After culturing in 24-well plates for 16 hours, encephalomyocarditis virus (EMCV) with an MOI of 0.1 was added. EMCV is an unencapsulated single-stranded positive-sense RNA virus. Then, the small molecule compound Fisogatinib was added at a final concentration of 50 nM. After co-culturing for 12 hours, the viral load was detected by RT-qpcr. The positive control group was EMCV + DMSO, and the negative control group was DMSO. Actb was used as an internal reference to calculate the relative expression value.

[0053] 1.2 Antiviral effect of Fisogatinib detected by flow cytometry RAW264.7 cells (2 * 10 5 (0) After culturing in 24-well plates for 16 hours, the cells were infected with VSV-GFP with an MOI of 0.1 for 12 hours. Then, the virus infection and the antiviral effect of the small molecule drug were detected by the GFP channel of the flow cytometry.

[0054] 2. Experimental results As Figure 1 shown, the small molecule compound Fisogatinib can effectively reduce the viral load in RAW264.7 cells, significantly inhibit the replication of various DNA viruses or RNA viruses, and exhibit potent antiviral activity.

[0055] As Figure 2 shown, the results of flow cytometry detection prove that, compared with the control group, the VSV-GFP fluorescence signal in the experimental group treated with Fisogatinib was significantly weakened. The experiment shows that the ability of virus infection and replication in the cells of the Fisogatinib group was weakened, which illustrates the antiviral efficacy of Fisogatinib.

[0056] Example 2 The following exemplarily shows the virus inhibitory effect of Fisogatinib in a virus infection model.

[0057] In this example, experiments were conducted in a virus infection model. Mice infected with the virus were treated with Fisogatinib. The results showed that the drug could significantly reduce the viral load and improve the survival rate of the mice, as follows: 1. Experimental method Six-week-old male C57BL / 6J wild-type mice with matched body weights and from the same litter were selected. All mice were housed in a specific pathogen-free (SPF) animal facility. The virus solution was diluted with sterile PBS to a final infection dose of 1 × 10 8 PFU / 100 μL and stored in an ice bath at 4°C to avoid repeated freezing and thawing.

[0058] The experimental mice were randomly grouped, and their initial weights were recorded by weighing before the experiment. The mice were gently restrained in a fixing device, and the abdomen was wiped with 75% ethanol to ensure that the injection site was free of contamination. A 1 mL insulin syringe (30 G needle) was used to aspirate 100 μL of the VSV suspension, which was slowly injected intraperitoneally in the inguinal region. The needle was inserted to a depth of about 3 - 5 mm to ensure uniform distribution of the virus suspension and avoid accidental puncture of the intestine or bladder. After the injection, the injection site was gently pressed for 5 seconds to prevent fluid leakage. After infection, the mice were weighed at a fixed time every day, and their mental state, activity ability, hair condition, and neurological symptoms (such as hind limb paralysis and ataxia) were observed, and the survival rate was calculated.

[0059] Before infection and 1 day after infection, mouse blood samples were collected by tail vein blood sampling. The mice were fixed in a fixing device, and the tail was disinfected with 75% ethanol. After the tail vein was fully dilated, a 28 G blood sampling needle was used to slowly puncture along the vein, and 100 μL of blood was collected into an EDTA anticoagulant tube. 48 hours after infection, the mice were anesthetized (anesthetized by intraperitoneal injection of sodium pentobarbital), and then the spleen and liver tissues were collected under sterile conditions for subsequent RNA extraction.

[0060] The virus-infected model mice were divided into a control group and a Fisogatinib drug treatment group to observe the comparison of their survival rate changes over time, as well as the expression of the virus and cytokines in the spleen, liver tissues, and blood of the mice.

[0061] 2. Experimental Results The results of the mouse survival rate are as Figure 3 shown. The results indicate that Fisogatinib can effectively inhibit the virus in the virus infection model, thus greatly improving the survival rate of the mice.

[0062] The expression of the virus in the spleen and liver tissues of the mice is as Figure 4 shown. The results indicate that Fisogatinib can effectively inhibit the expression of the virus in the virus infection model.

[0063] The expression of cytokines in the spleen, liver tissues, and blood of the mice is as Figure 5 shown. The results indicate that Fisogatinib can effectively inhibit the virus in the virus infection model, thereby inhibiting the expression of inflammatory cytokines.

[0064] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those of ordinary skill in the art should understand that they can still modify the technical solutions recorded in the foregoing embodiments or perform equivalent replacements for some of the technical features. These modifications or replacements do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. Use of ficotinib or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, isomer, analogue, derivative or metabolite thereof in the preparation of an antiviral drug.

2. The application according to claim 1, characterized in that, The virus includes DNA virus and / or RNA virus.

3. The application according to claim 2, wherein The DNA virus includes at least one of herpes simplex virus, varicella-zoster virus, cytomegalovirus, smallpox virus, monkeypox virus, adenovirus, human papillomavirus, parvovirus, bocavirus and hepatitis B virus.

4. The application according to claim 2, wherein The RNA virus includes at least one of vesicular stomatitis virus, influenza A virus, encephalomyocarditis virus, murine hepatitis virus, influenza A virus, influenza B virus, influenza C virus, dengue virus, Zika virus, Ebola virus, Marburg virus, Nipah virus, coronavirus, hepatitis A virus, hepatitis C virus, rotavirus, measles virus, human immunodeficiency virus, respiratory syncytial virus and rabies virus.

5. The application according to claim 1, wherein The antiviral includes at least one of the following situations: (1) Inhibiting virus entry into host cells; (2) Inhibiting virus genome replication; (3) Inhibiting virus protein processing or assembly; (4) Inhibiting virus release; (5) Reducing the amount or activity of the virus; (6) Increasing the survival rate.

6. The application according to claim 1, characterized in that, Antiviral is achieved by administering a therapeutically effective amount of the ficotinib or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, isomer, analogue, derivative or metabolite thereof to a subject.

7. The application according to claim 6, wherein The subject includes mammals.

8. The application according to claim 7, wherein The mammal includes humans.

9. The application according to claim 6, wherein The therapeutically effective amount is 0.01 - 1000 mg / Kg.

10. Use of ficotinib or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, isomer, analogue, derivative or metabolite thereof in combination with other drugs in the preparation of a combined antiviral drug.

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