Pulmonary fibrosis drugs containing pyrazole derivatives

Abstract

The present invention provides a pharmaceutical composition or an antiviral agent for treating pulmonary fibrosis, comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof as a pyrazole derivative.

Description

Technical Field

[0001] This application claims the benefit of Korean Patent Application No. 10-2020-0044598 filed on April 13, 2020, and Korean Patent Application No. 10-2021-0036863 filed on March 22, 2021, in the Korean Intellectual Property Office, the disclosures of which are incorporated herein by reference in their entirety.

[0002] The present invention relates to a pyrazole derivative for preventing or treating pulmonary fibrosis, a method for preparing the pyrazole derivative and a pharmaceutical composition of the pyrazole derivative. Background Art

[0003] Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by infiltration of inflammatory cells such as lymphocytes and macrophages into the lung interstitium, proliferation of fibroblasts, and deposition of fibrous connective tissue into the lung interstitium. Pulmonary fibrosis is caused by various internal and external causes of the lungs, is the final result of chronic lung damage or disease progression, and seriously threatens human health.

[0004] Causes of pulmonary fibrosis include factors such as immune dysfunction, viral or bacterial infection, drugs and chemicals, radiation, and air pollution (smog, cigarette smoke, dust, etc.).

[0005] As mentioned above, some patients can be diagnosed with a clear cause of pulmonary fibrosis, but there are also cases where the cause cannot be determined, which is called idiopathic pulmonary fibrosis (IPF). Idiopathic pulmonary fibrosis is an interstitial pneumonia with progressive fibrosis of the lung parenchyma, and is known to have a high risk of death due to respiratory failure within a few years of diagnosis and an extremely poor prognosis. The 5-year survival rate is about 20%, which is similar to that of lung cancer. In addition, the incidence and prevalence of pulmonary fibrosis are rapidly increasing as the population ages.

[0006] Pulmonary fibrosis is a complex pathophysiological process in which, in the early stages, a large number of inflammatory cells infiltrate around the inflammatory sites of the lungs, causing the alveolar walls to become chronically thickened. In the middle / late stages, excessive deposition of extracellular matrix elements such as collagen by fibroblasts causes lung tissue hyperplasia, alveolar deformation, hardening and scarring, thereby destroying the normal lung tissue structure and leading to loss of function.

[0007] Fibroblasts play a role in attracting immune cells to sites of inflammation and tissue damage. In addition, fibroblasts produce and respond to many inflammatory cytokines. Therefore, fibroblasts contribute to chronic inflammation, and in turn, inflammatory cytokines promote the transformation of fibroblasts to myofibroblasts, thereby promoting fibrosis. Therefore, damage or inflammation of lung tissue can cause pulmonary fibrosis.

[0008] Lung transplantation is the only way to repair the progressively fibrotic lung tissue caused by pulmonary fibrosis, and the five-year survival rate after diagnosis is only 43%.

[0009] Although many clinical studies are being conducted to develop a therapeutic agent for pulmonary fibrosis, there is still no therapeutic agent for pulmonary fibrosis, and immunosuppressants of steroids or cytotoxic drugs are mainly used as first-line drugs. Among steroids and cytotoxic drugs, steroids are used first, and combined treatment of steroids with azathioprine or cyclophosphamide is currently being used.

[0010] In addition, pirfenidone and nintedanib are the only approved drugs for the treatment of pulmonary fibrosis. It is reported that the therapeutic effect of pirfenidone is mild, and is used at a very high dose of about 2.4g / day, but the survival rate is almost not improved or not significantly improved, and due to serious side effects such as gastrointestinal diseases (nausea, diarrhea, indigestion), skin diseases (photosensitive rash), metabolism and nutritional disorders (anorexia, loss of appetite) and weakening liver function, it tends to reduce the quality of life of patients, therefore, continuous administration is difficult. It is reported that the dosage of nintedanib is 200 to 400mg / day, and reduces the incidence of acute exacerbation of mild to severe idiopathic pulmonary fibrosis, but is difficult to continuous administration due to many side effects and gastrointestinal side effects.

[0011] Therefore, there is an urgent need to develop new drugs that can treat the underlying causes rather than alleviate the progression of disease symptoms.

[0012] Although many studies are being conducted on the causes of pulmonary fibrosis, the pathogenesis remains unclear, making it difficult to develop therapeutic agents, but research results have reported that excessive reactive oxygen species are produced according to changes in the redox homeostasis in the body, and oxidative stress caused thereby plays an important role in the progression and exacerbation of pulmonary fibrosis.

[0013] Oxidative stress refers to the tissue damage caused by relatively excessive production of reactive oxygen species (ROS) due to the balance between the production of reactive oxygen species (ROS) and the antioxidant defense mechanisms of biomolecules, cells and tissues. In particular, it is reported that the oxidative stress produced in lung tissue induces and worsens pulmonary fibrosis. It is reported that in the lung tissue of patients with progressive pulmonary fibrosis, TGF-β stimulation induces an increase in the production of reactive oxygen species and increases the expression of collagen and α-smooth muscle actin (α-SMA), which are important for fibrosis. In particular, it is reported that due to the reactive oxygen species in the lung tissue of patients with idiopathic pulmonary fibrosis, pulmonary fibrosis worsens.

[0014] Infection with RNA or DNA viruses can also cause fatal lung damage through pneumonia and pulmonary fibrosis, leading to death. It is reported that when single-stranded viruses (coronavirus, influenza virus, respiratory syncytial virus, rhinovirus, dengue virus, HIV, etc.) and DNA viruses (adenovirus, vaccinia virus, herpes simplex virus, etc.) invade cells and form endosomes, reactive oxygen species are generated to promote viral replication, and the rapidly amplified viruses penetrate into lung tissues to cause lung damage, while promoting inflammation and fibrosis.

[0015] At present, in the case of viral infection, rapid expansion in the human body causes rapid lung damage, making treatment difficult. Therefore, if a therapeutic agent that inhibits the production of reactive oxygen and an antiviral agent are used in combination to treat and alleviate lung damage caused by viral infection and rapid expansion, viral pneumonia and pulmonary fibrosis may be more effectively treated. In this case, as antiviral agents that can be used in combination, representative drugs include remdesivir, ritonavir, lopinavir, favipiravir, etc.

[0016] It has been reported that in the lung tissues of patients with progressive pulmonary fibrosis, TGF-β stimulation induces an increase in the production of reactive oxygen species and increases the expression of collagen and α-smooth muscle actin (α-SMA), which are important for fibrosis, and that reactive oxygen species in the lung tissues of patients with idiopathic pulmonary fibrosis cause worsening of pulmonary fibrosis.

[0017] On the other hand, none of the prior art documents discloses that the pyrazole compounds of the present invention are effective in preventing and treating pulmonary fibrosis.

[0018] [Prior art literature]

[0019] (Patent Document 1) Korean Patent No. 10-1280160

[0020] (Patent Document 2) Korean Patent Application Publication No. 10-2019-0122806

[0021] (Patent Document 3) Korean Patent Application Publication No. 10-2019-0136079

[0022] (Non-patent document 1) Gabriel Laghlali, et al. Respiratory 2019, 13629.

[0023] (Non-patent document 2) Eunice E. To et al. Nature communications, 8(69), 1-17.

[0024] (Non-patent document 3) Alessandro G. Fois, Panagiotis Paligiannis et al., Respir Res. 2018, 19: 51. Summary of the invention

[0025] Technical issues

[0026] An object of the present invention is to provide a pharmaceutical composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0027] Another object of the present invention is to provide a pharmaceutical composition that effectively inhibits the generation of active oxygen, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0028] Another object of the present invention is to provide a pharmaceutical composition for treating or preventing pulmonary fibrosis, comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0029] Another object of the present invention is to provide a method for preventing or treating pulmonary fibrosis by administering the compound of Formula 1 or a pharmaceutically acceptable salt thereof to a subject.

[0030] Another object of the present invention is to provide a use of the compound of formula 1 or a pharmaceutically acceptable salt thereof for preventing or treating pulmonary fibrosis.

[0031] Another object of the present invention is to provide a pharmaceutical composition for treating and preventing pulmonary fibrosis, further comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof, and an antibiotic, an antifungal agent, an antiviral agent, an anti-inflammatory agent or any combination thereof.

[0032] Another object of the present invention is to provide a method for preventing or treating pulmonary fibrosis, which further comprises administering to an individual a compound of Formula 1 or a pharmaceutically acceptable salt thereof, and an antibiotic, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or any combination thereof.

[0033] Another object of the present invention is to provide a compound of formula 1 or a pharmaceutically acceptable salt thereof and an antibiotic, an antifungal agent, an antiviral agent, an anti-inflammatory agent or any combination thereof for preventing or treating pulmonary fibrosis.

[0034] Another object of the present invention is to provide an antiviral agent comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0035] Another object of the present invention is to provide a method for preventing or treating viral diseases by administering the compound of Formula 1 or a pharmaceutically acceptable salt thereof to a subject.

[0036] Another object of the present invention is to provide a use of the compound of formula 1 or a pharmaceutically acceptable salt thereof for preventing or treating viral diseases.

[0037] Technical Solution

[0038] In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing, improving or treating pulmonary fibrosis or viral diseases, comprising a pyrazole compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof:

[0039] <Formula 1>

[0040]

[0041] Here, R is a straight or branched chain alkyl group having 1 to 10 carbon atoms.

[0042] Beneficial Effects

[0043] The pyrazole compound or a pharmaceutically acceptable salt thereof according to the present invention can effectively inhibit the generation of reactive oxygen species generated in the lung, and thus can be effectively used for preventing or treating oxidative stress-induced pulmonary fibrosis without any particular side effects.

[0044] Furthermore, the pyrazole compound or the pharmaceutically acceptable salt thereof according to the present invention has antiviral activity and thus can be effectively used for preventing or treating viral diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 The results show that when compound 1 is treated, the expression of reactive oxygen species induced by PMA stimulation is effectively inhibited in normal human lung fibroblasts (NHLF).

[0046] Figure 2 The results show that Compound 1 inhibited the expression of αSMA mediated by TGF-β1 during the differentiation of normal human lung fibroblasts into myofibroblasts.

[0047] Figure 3 The results show that Compound 1 inhibits the expression of collagen I by TGF-β1 during the differentiation of normal human lung fibroblasts into myofibroblasts.

[0048] Figure 4 The results show that when treated with Compound 1, IL-1β expression induced by LPS treatment was effectively inhibited in normal human lung fibroblasts.

[0049] Figure 5The present invention is a photograph showing H&E staining of alveoli and bronchioles when treated with nintedanib or compound 1 in the bleomycin administration-induced pulmonary fibrosis (BLM) animal model, and shows the results that the amount of immune cells infiltrated into the alveoli and bronchioles is reduced when treated with compound 1.

[0050] Figure 6 are photographs showing staining of collagen deposition of bronchioles when treated with nintedanib or compound 1 in a bleomycin administration-induced pulmonary fibrosis (BLM) animal model, and show the results that when compound 1 was treated, collagen deposition was reduced.

[0051] Figure 7 are photographs showing staining of αSMA when treated with nintedanib or compound 1 in a bleomycin administration-induced pulmonary fibrosis (BLM) animal model, and show that when treated with compound 1, the expression of αSMA is reduced.

[0052] Figure 8 are photographs showing staining of collagen I when treated with nintedanib or compound 1 in a bleomycin administration-induced pulmonary fibrosis (BLM) animal model, and show that when treated with compound 1, the expression of collagen I is reduced.

[0053] Fig. 9 The results are of quantifying the degree of lung fibrosis using the modified Ashcroft scale when treated with nintedanib or compound 1 in the bleomycin administration-induced lung fibrosis (BLM) animal model, and show that lung fibrosis is effectively improved when treated with compound 1 compared with nintedanib.

[0054] Fig.10 It was shown that when treated with compound 1 in human lung epithelial cells, the antiviral efficacy was excellent and the cytotoxicity was low. DETAILED DESCRIPTION

[0055] Hereinafter, the present invention will be described in more detail with reference to embodiments.

[0056] However, the present invention is not limited to the embodiments shown by way of example, and the present invention is limited only by the scope of the appended claims. In addition, even if it is a composition necessary for implementing the present invention, a detailed description of a composition that can be easily implemented by a person skilled in the art will be omitted.

[0057] The terms and words used in this specification and claims should not be understood as limited to the conventional or dictionary meanings, but should be understood as meanings and concepts consistent with the technical concept of the present invention based on the principle that inventors can appropriately define the concepts of terms in order to describe their inventions in the best manner.

[0058] The terms used in the present invention are only used for the purpose of describing specific embodiments and are not intended to limit the present invention. Unless the context clearly states otherwise, singular expressions include plural expressions. In the present invention, terms such as "including" and "having" are intended to indicate the presence of features, numbers, steps, operations, components, parts or combinations thereof described in this specification, and it should be understood that these terms do not preclude the possibility of the presence or addition of one or more other features, numbers, steps, operations, components, parts or combinations thereof.

[0059] Pulmonary fibrosis is the fibrosis of the lung parenchyma, which is caused by the infiltration of inflammatory cells caused by lung inflammation into the lung interstitium, the proliferation of fibroblasts and the deposition of fibrous connective tissue into the lung interstitium, and the normal lung tissue structure is destroyed, so that the lung function is lost. That is, pulmonary fibrosis is caused by various internal and external causes of the lung, and is the result of chronic lung injury or disease progression to the end, and with the aging trend in recent years, the incidence and prevalence rate are rapidly increasing. Recently, in particular, idiopathic pulmonary fibrosis of unknown cause has become a problem.

[0060] Lung transplantation is the only way to repair progressive fibrotic lung tissue due to pulmonary fibrosis, and pirfenidone and nintedanib are the only approved drugs for pulmonary fibrosis, but both drugs have the problem of difficulty in continuous administration due to many side effects and gastrointestinal disorders.

[0061] Therefore, treatment for pulmonary fibrosis is usually symptomatic treatment using steroids or immunosuppressants to relieve symptoms, but a radical cure is needed.

[0062] As a result of research focusing on the fact that a therapeutic agent for pulmonary fibrosis can be developed if the generation of oxidative stress in lung tissue is effectively suppressed, the present inventors have completed the present invention by finding that the pyrazole derivatives of the present invention reduce lung damage induced by bleomycin administration and inhibit lung fibrosis induced by accumulation of αSMA and collagen I, thereby reducing lung fibrosis, and confirming that they can be used as a therapeutic agent for pulmonary fibrosis.

[0063] Therefore, the present invention provides a pharmaceutical composition capable of preventing or treating pulmonary fibrosis, comprising one or more compounds selected from the pyrazole compounds represented by Formula 1 or pharmaceutically acceptable salts thereof.

[0064] In addition, the present invention provides a pharmaceutical composition capable of preventing or treating idiopathic pulmonary fibrosis, comprising one or more compounds selected from the pyrazole compounds represented by Formula 1 or pharmaceutically acceptable salts thereof.

[0065] The pyrazole compound used in the present invention is represented by the following formula 1:

[0066] <Formula 1>

[0067]

[0068] Here, R is a straight or branched chain alkyl group having 1 to 10 carbon atoms.

[0069] The pharmaceutically acceptable salt of the pyrazole compound contained in the pharmaceutical composition of the present invention refers to a salt which retains the biological effectiveness and properties of the parent compound when administered in a single dose and is biologically or otherwise harmless. In addition, it refers to a salt commonly used in the pharmaceutical industry.

[0070] Specifically, pharmaceutically acceptable addition salts can be prepared from inorganic bases and organic bases. Salts from inorganic bases can include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts and magnesium salts. Salts from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines; substituted amines, including naturally occurring substituted amines; and isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucosamine, theobromine, purine, piperazine, piperidine and / or cyclic amines, including N-ethylpiperidine.

[0071] It should also be understood that other carboxylic acid derivatives, specifically, carboxylic acid amides, including formamide, lower alkyl formamides, di(lower alkyl) formamides, and the like, may also be used in the practice of the present invention.

[0072] In addition, pharmaceutically acceptable acid addition salts can be prepared by inorganic acid and organic acid. Salts from inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, iodic acid, tartaric acid, etc. Salts from organic acid can include, but are not limited to, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, lactic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid and / or salicylic acid, etc.

[0073] The pharmaceutically acceptable salt may be a hydrochloride.

[0074] The pyrazole compound represented by Formula 1 or a pharmaceutically acceptable salt thereof contained in the pharmaceutical composition of the present invention is specifically exemplified as follows:

[0075] 3-phenyl-4-methyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol or its hydrochloride;

[0076] 3-phenyl-4-ethyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol or its hydrochloride;

[0077] 3-phenyl-4-n-propyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol or its hydrochloride;

[0078] 3-phenyl-4-isopropyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol or its hydrochloride;

[0079] 3-phenyl-4-n-butyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol or its hydrochloride;

[0080] 3-phenyl-4-tert-butyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol or its hydrochloride;

[0081] 3-phenyl-4-n-pentyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol or its hydrochloride;

[0082] 3-phenyl-4-n-hexyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol or its hydrochloride.

[0083] Specifically, the pyrazole compound contained in the pharmaceutical composition of the present invention can be 3-phenyl-4-n-propyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol or its hydrochloride.

[0084] The compound of Formula 1 of the present invention can inhibit the generation of active oxygen.

[0085] In the present invention, oxidative stress refers to tissue damage caused by relatively excessive production of reactive oxygen species (ROS) when the balance between the production of reactive oxygen species (ROS) and the antioxidant defense mechanisms of biomolecules, cells and tissues is disrupted. In this case, "reactive oxygen" may refer to activated oxygen, active oxygen and activated oxygen species, which refer to the same substance.

[0086] The pyrazole compounds of the present invention, particularly the hydrochloride of 3-phenyl-4-n-propyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol (Compound 1), effectively reduce reactive oxygen species in human lung epithelial cells and effectively inhibit the expression of αSMA and collagen I, which are myofibroblast differentiation markers, when lung fibroblasts differentiate into myofibroblasts.

[0087] In addition, as demonstrated in an animal model experiment of pulmonary fibrosis administered with bleomycin, the compound of the present invention reduces the infiltration of inflammatory cells into lung tissue, reduces the hypertrophy of lung epithelial cells, reduces the deformation of lung structure, and reduces the site of abnormal tissue deposition compared to nintedanib, which is approved as a conventional therapeutic agent for pulmonary fibrosis.

[0088] Compared with nintedanib, the compound of the present invention reduces the expression and accumulation of collagen I and αSMA in lung tissue, and also reduces the expression of reactive oxygen species in lung tissue. Based on these results, when the severity of fibrosis is quantified using the modified Ashcroft scale, it shows a significantly improved effect in lung fibrosis compared with nintedanib, which is approved as a conventional therapeutic agent for pulmonary fibrosis.

[0089] Therefore, it was confirmed that the compound of the present invention not only inhibits inflammatory response by inhibiting reactive oxygen species in lung tissues in human lung cells and pulmonary fibrosis models, but also prevents or alleviates pulmonary fibrosis by reducing the expression and accumulation of collagen I and αSMA.

[0090] Pulmonary fibrosis may be caused by pulmonary fibrosis, chronic obstructive pulmonary disease (COPD) with pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), or asthma.

[0091] In addition, pneumonia, which is said to be the main cause of pulmonary fibrosis, may be caused by viral pneumonia, bacterial pneumonia, fungal pneumonia, allergic pneumonia, aspiration pneumonia, interstitial lung disease, pneumoconiosis, and the like.

[0092] Viral pneumonia may be caused by a virus selected from adenovirus, vaccinia virus, herpes simplex virus, parainfluenza virus, rhinovirus, varicella-zoster virus, measles virus, respiratory syncytial virus, dengue virus, human immunodeficiency virus (HIV), influenza virus, coronavirus, severe acute respiratory syndrome-related coronavirus (SARS-CoV), severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV2), Middle East respiratory syndrome coronavirus (MERS-CoV), or a variant of these viruses.

[0093] In addition to the compound of Formula 1 or a salt thereof, the pharmaceutical composition of the present invention may further comprise an antibiotic, an antifungal agent, an antiviral agent, an anti-inflammatory agent or any combination thereof as a second therapeutic agent.

[0094] Specifically, the antibiotics contained in the second therapeutic agent are: gentamicin, kanamycin, streptomycin, amikacin, neomycin and the like in the aminoglycoside antibiotics; erythromycin, azithromycin, clarithromycin and the like in the macrolide antibiotics; penicillin, cephalosporin, carbapenem, monobactam and the like in the β-lactam antibiotics; clindamycin and the like as lincomycin antibiotics; linezolid and the like as oxazolidinone antibiotics; ciprofloxacin, levofloxacin, moxifloxacin, fluoroquinolone and the like as quinolone antibiotics; tetracycline, doxycycline, tigecycline and the like as tetracycline antibiotics; trimethoprim / sulfamethoxazole (TMX / SMX) as sulfonamide antibiotics; or a combination thereof.

[0095] The antiviral agent contained in the second therapeutic agent is thiosemicarbazone, metixazone, acyclovir, remdesivir, ritonavir, lopinavir, favipiravir, iodoxuridine, vidarabine, ribavirin, ganciclovir, famciclovir, valacyclovir, cidofovir, valganciclovir, brivudine, ribavirin, rimantadine, tromantine, foscarnet, saquinavir, indinavir, nelfinavir, amprenavir, fosamprenavir, atazanavir, tipranavir, zidovudine, didanosine, zalcitabine, stavudine, lamivudine, abacavir, tenofovir disoproxil, adefovir dipivoxil, emtricitabine, entecavir, nevirapine, delavirdine, efavirenz, zanamivir, oseltamivir, isoprenoid, pleconaril, enfuvirtide or a combination thereof.

[0096] The antifungal agent contained in the second therapeutic agent is allylamine, terbinafine, 5-flucytosine, fluconazole, itraconazole, ketoconazole, ravuconazole, posaconazole, voriconazole, caspofungin, micafungin, anidulafungin, amphotericin B, amphotericin B lipid complex (ABLC), amphotericin B colloidal dispersion (ABCD), liposome-amphotericin B (L-AMB), liposomal nystatin, griseofulvin or a combination thereof.

[0097] The compound of formula 1 of the present invention has antiviral activity against various viruses, and therefore, the compound of the present invention itself can be used as an antiviral agent. Therefore, the compound of formula 1 of the present invention can effectively prevent or treat viral diseases. Viral diseases may be caused by a virus selected from adenovirus, vaccinia virus, herpes simplex virus, parainfluenza virus, rhinovirus, varicella zoster virus, measles virus, respiratory syncytial virus, dengue virus, human immunodeficiency virus (HIV), influenza virus, coronavirus, severe acute respiratory syndrome coronavirus (SARS-CoV), severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV2), Middle East respiratory syndrome coronavirus (MERS-CoV) or variant viruses of these viruses, but not limited thereto. In particular, compound 1 of the present invention can effectively inhibit the reproduction of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV2), and therefore, the reproduction of variant viruses of its related viruses SARS-CoV, MERS-CoV or these coronaviruses can also be inhibited.

[0098] The pharmaceutical composition of the present invention may contain a pharmaceutically acceptable carrier within the range not impairing the effects of the present invention.

[0099] "Pharmaceutically acceptable carriers" include any and all types of solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (antibacterial or antifungal agents), isotonic agents, diluents, absorption delaying agents, salts, preservatives, stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavoring agents, dyes, etc., and combinations thereof, as known to those skilled in the art. Except where any conventional carrier is incompatible with the active ingredient, its use in the treatment or pharmaceutical composition is contemplated.

[0100] The diluent may be selected from, but not limited to, microcrystalline cellulose, lactose monohydrate, anhydrolactose, lactose, starch, mannitol, carboxymethyl cellulose, sorbitol, and combinations thereof.

[0101] The disintegrant may be selected from, but not limited to, low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, F-melt, and combinations thereof.

[0102] The binder can be selected from, but is not limited to, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose, polyvinyl acetate, povidone, polyvinyl pyrrolidone, copovidone, polyethylene glycol, sodium lauryl sulfate, light anhydrous silicic acid, synthetic aluminum silicate; silicate derivatives, such as calcium silicate or magnesium aluminate metasilicate; phosphates, such as calcium hydrogen phosphate; carbonates, such as calcium carbonate; pregelatinized starch; gums, such as gum arabic; gelatin; cellulose derivatives, such as ethyl cellulose, and mixtures thereof.

[0103] The lubricant may be selected from, but not limited to, magnesium stearate, silicon dioxide, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof.

[0104] As the pH adjuster, acidulants such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium etherate, malic acid, succinic acid, tartaric acid, fumaric acid and citric acid, and alkalizing agents such as ammonia water, sodium carbonate, magnesium oxide, magnesium carbonate, sodium citrate and tricalcium phosphate can be used.

[0105] As the antioxidant, butylated hydroxytoluene, butylated hydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, sodium hydrogen sulfite, sodium pyrosulfite and the like can be used.

[0106] In addition, the preparation of the present invention can be formulated by selectively using various additives selected from coloring agents and flavorings as pharmaceutically acceptable additives.

[0107] In the present invention, the range of the additives is not limited to the use additives, and may be formulated to selectively contain a dosage within a normal range of the use additives.

[0108] The pharmaceutical composition according to the present invention can be formulated and used in the following dosage forms: oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols; external preparations, suppositories or sterile injections.

[0109] In one aspect of the present invention, the present invention may be a pharmaceutical composition for preventing, improving or treating pulmonary fibrosis, which contains an active ingredient in the range of 0.00001 wt % to 100 wt %, 0.0001 wt % to 95 wt % or 0.001 wt % to 90 wt %, based on the total weight of the pharmaceutical composition.

[0110] In the preventive or therapeutic agent for pulmonary fibrosis according to the present invention, the dosage of the pyrazole compound represented by Formula 1 or a pharmaceutically acceptable salt thereof can be appropriately changed according to the patient's age, weight, symptoms, administration route, and the like.

[0111] The dosage of the pyrazole compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof can be 0.00001 mg / kg / day to 2000 mg / kg / day, 0.0001 mg / kg / day to 1000 mg / kg / day, 0.001 mg / kg / day to 800 mg / kg / day, 0.001 mg / kg / day to 500 mg / kg / day, 0.001 mg / kg / day to 100 mg / kg / day, 0.001 mg / kg / day to 80 mg / kg / day or 0.01 mg / kg / day to 70 mg / kg / day.

[0112] The content of the pyrazole compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof may be 0.00001 to 100 weight %, 0.0001 to 95 weight %, 0.0001 to 90 weight %, 0.001 to 70 weight % or 0.001 to 50 weight % per unit dosage form.

[0113] The pyrazole compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof may be administered at a concentration of 0.0001 μM to 500 μM, 0.001 μM to 300 μM, 0.001 μM to 150 μM, 0.001 μM to 130 μM, 0.001 μM to 100 μM, 0.001 μM to 80 μM or 0.01 μM to 70 μM.

[0114] The pharmaceutical composition of the present invention can be administered by conventional routes and can be specifically formulated for intramuscular, intrathecal, intradigestive, intracardiovascular, intrarenal or intravenous administration. The formulation method adopts conventional methods known to those skilled in the art.

[0115] Conventional compositions for intramuscular or intrathecal administration may consist of, for example, an active ingredient and a sterile isotonic aqueous solution containing glucose, sodium chloride, or both glucose and sodium chloride, but are not limited thereto. Other examples include, but are not limited to, lactated Ringer's injection, lactated Ringer's injection + glucose injection, Normosol-M and glucose, Isolyte E, acylated Ringer's injection, and the like. Optionally, the formulations of the present invention may include, but are not limited to, cosolvents such as polyethylene glycol; chelating agents such as ethylenediaminetetraacetic acid; and antioxidants such as sodium metabisulfite. Optionally, the solution may be lyophilized and then reconstituted with a suitable solvent immediately before administration, without limitation thereto.

[0116] Preferred embodiments are provided to help understand the present invention. The following embodiments are provided not to limit the present invention but to facilitate understanding of the present invention.

[0117] <Synthesis Example 1> Synthesis of 3-phenyl-4-ethyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol

[0118]

[0119] In a round bottom flask, 2-ethyl-3-oxo-3-phenylpropionic acid ethyl ester (10.7 g, 49 mmol) and 2-hydrazinopyridine (5.6 g, 51.4 mmol) were heated to reflux for 1 day under nitrogen without solvent. The obtained solid was purified with hexane and ethyl acetate and then dried in vacuo to obtain the title compound in 70% yield.

[0120] 1H NMR(300MHz,DMSO-d6)δ8.25-8.24(1H,d),8.00-7.97(1H,d),7.84-7.82(1H,t),7.73-7.71(2H,m ),7.46-7.37(3H,m)7.12-7.11(1H,t),2.62-2.57(2H,m),1.23-1.17(3H,m); ESI(m / z)266.1[M+H] +

[0121] <Synthesis Example 2> Synthesis of 3-phenyl-4-butyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol

[0122]

[0123] In a round bottom flask, 2-butyl-3-oxo-3-phenylpropionic acid ethyl ester (12.1 g, 49 mmol) and 2-hydrazinopyridine (5.6 g, 51.4 mmol) were heated to reflux for 1 day under nitrogen without solvent. The obtained solid was purified with hexane and ethyl acetate and then dried in vacuo to obtain the title compound in 75% yield.

[0124] 1H NMR(300MHz,DMSO-d6)δ8.25-8.24(1H,d),8.03-8.02(1H,d),7.85-7.83(1H,t),7.70-7.69(2H,m),7.44-7.35(3H,m )7.12-7.11(1H,t),2.56-2.53(2H,t),1.58-1.52(2H,m),1.38-1.24(2H,m),0.89-0.86(3H,t); ESI(m / z)294.0[M+H] +

[0125] <Synthesis Example 3> Synthesis of 3-phenyl-4-propyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol

[0126]

[0127] 2-propyl-3-oxo-3-phenylpropionic acid ethyl ester (2.52 g, 10.7 mmol) and 10 ml of ethanol were placed in a round-bottom flask, and then a solution of 2-hydrazinopyridine (1.29 g, 1.18 mmol) diluted in 3 ml of ethanol was slowly added dropwise thereto at 0° C. The mixture was heated to reflux for 3 days at 100° C. The solvent was removed by distillation under reduced pressure, and the obtained solid was washed with hexane and ethyl acetate, and then vacuum dried to obtain the title compound in a yield of 82%.

[0128] 1H NMR (300MHz, CDCl3) δ12.50(1H,s),8.27-8.25(1H,m),8.01(1H,d,J=8.5Hz),7.81(1H,m),7.69(2H,m),7.48- 7.34(3H,m),7.12-7.10(1H,m),2.54(2H,d,J=7.5Hz),1.64(2H,m),0.93(3H,t,J=7.3Hz); EIMS(70eV)m / z(rel intensity)279(M+,37),250(100)

[0129] <Synthesis Example 4> Synthesis of 3-phenyl-4-propyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol hydrochloride (Compound 1)

[0130]

[0131] 3-Phenyl-4-propyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol (280 mg, 1.0 mmol) prepared in the above Synthesis Example 3 was dissolved in 4 ml of diethyl ether in a round-bottom flask, and then 0.55 ml of diethyl ether dissolved in 2M HCl was slowly added dropwise thereto at 0° C. The solid produced by the reaction solution was filtered under reduced pressure, the solvent was removed, washed with hexane and ethyl acetate, and then dried in vacuo to obtain the title compound (270 mg, 0.85 mmol).

[0132] 1H NMR(300MHz, CDCl3)δ8.44(1H,d,J=4.2Hz),8.0-8.03(2H,m),7.66-7.64(2H,m),7.48-7.42(3H ,m),7.34-7.30(1H,m),2.49(2H,brs),2.43(2H,t,J=7.5Hz),1.48(2H,m),0.48(3H,t,J=7.3Hz)

[0133] <Example 1> Analysis of changes in reactive oxygen species production in normal human lung fibroblasts

[0134] In order to confirm the effect of the compound of Synthesis Example on the generation of reactive oxygen species in lung fibroblasts, the generation of reactive oxygen species was induced in normal human lung fibroblasts (NHLFs, Lonza) by PMA stimulation, and the inhibitory effect of Compound 1 on the generation of reactive oxygen species was observed under this condition.

[0135] Each cell was suspended in a medium containing 10% FBS, seeded in a 96-well plate, and cultured for 24 hours under 5% CO2 and 37°C. After pretreatment with compound 1 for 30 minutes to 1 hour, TGF-β1 or phorbol 12-myristate 13-acetate (PMA) stimulation was applied to each well including cells and drugs. After culturing for another 30 minutes or 48 hours, 8-amino-5-chloro-7-phenyl-2,3-dihydro-pyridine [3,4-d] pyridazine-1,4-dione (L-012) or 2',7'-dichlorodihydrofluorescein diacetate (DCF-DA) was used to confirm the degree of reactive oxygen generation.

[0136] It was confirmed that when treated with compound 1, the generation of reactive oxygen species induced by PMA stimulation was inhibited in a concentration-dependent manner ( Figure 1 ).

[0137] <Example 2> Expression patterns of αSMA and type I collagen induced by TGF-β1 in normal human lung fibroblasts

[0138] In order to analyze the effect of compound 1 on the differentiation of lung fibroblasts into myofibroblasts, the inhibitory effect of compound 1 on the increase of TGF-β1-induced α-smooth muscle actin (αSMA) and type I collagen (collagen I) expression in normal human lung fibroblasts (NHLFs, Lonza) was observed. NHLF cells were suspended in culture medium (FGM-2 Bulletkit media, Lonza) and cultured at 1×10 4 The concentrations of cells / well were plated on 4-well chamber slides (Nunc).

[0139] After culturing in a CO2 incubator for 24 hours, the medium was replaced with a serum-free medium and further cultured for 12 hours. Then, the vehicle and 2 mM compound 1 were pretreated in the corresponding wells for 1 hour, and then 10 ng / ml TGF-β1 was treated in each well except the negative control (vehicle group) for 72 hours.

[0140] The expression of αSMA and collagen I in the prepared cells was confirmed by immunocytochemistry as follows. The cells were fixed in 4% paraformaldehyde for 10 minutes, infiltrated with 0.1% Triton X-100, and sequentially treated with the primary antibody (antibody-αSMA Ab, 1:200; type I collagen antibody Ab, 1:500, reacted at room temperature for 3 hours) and the secondary antibody (Alexa-594-coupled Ab, 1:1000, reacted at room temperature for 1 hour), and then the expression of αSMA and collagen I was observed using a fluorescence microscope.

[0141] At this time, in order to quantitatively confirm the expression degree of αSMA and collagen I, the number of DAPI (nuclear staining marker)-positive cells and αSMA- and collagen I-positive cells in each field of view was counted, and then the percentage of the number of αSMA- and collagen I-positive cells was calculated and compared using the following equation:

[0142] %αSMA (or collagen I)-positive cells / field of view = αSMA (or collagen I)-positive cells / DAPI-positive cells × 100 / field of view

[0143] like Figure 2 and Figure 3 As shown in , it can be observed that when NHLFs were treated with 10 ng / ml of TGF-β1, the expression of αSMA and collagen I was significantly increased compared with the control group, and when treated with compound 1, the increase in the expression of both markers was significantly inhibited.

[0144] These results demonstrate that compound 1 can effectively inhibit the differentiation of lung fibroblasts into myofibroblasts induced by TGF-β1 treatment (see Figure 2 and Figure 3 ).

[0145] <Example 3> Analysis of changes in LPS-induced IL-1β expression

[0146] In order to confirm the effect of the compounds of the synthesis examples of the present invention on the inflammatory response of normal human lung fibroblasts (NHLFs, Lonza), it was observed whether Compound 1 inhibited the increase in IL-1β expression caused by LPS treatment.

[0147] 2×10 5 Cells were seeded in 6-well plates, cultured for 24 hours, and further cultured in serum-free medium for 16 hours, and then pretreated with compound 1 for 30 minutes according to each condition and induced inflammatory response with LPS for 6 hours. IL-1β expression was confirmed using RT-PCR. Total RNA was isolated from cells using the RNeasy mini kit (Qiagen) and PrimeScript TM II 1 st cDNA was synthesized from 2 μg of isolated RNA using the strand cDNA synthesis kit (TaKaRa) and then PCR PreMix (Bioneer) was used to amplify the gene. The base sequences of the target primers were as follows: IL-1β (forward: 5'-CCACAGACCTTCCAGGAGAATG-3', reverse: 5'-GTGCAGTTCAGTGATCGTACAGG-3'); GAPDH (forward: 5'-GTGGCTGGCTCAGAAAAAGG-3', reverse: 5'-GGTGGTCCAGGGGTCTTACT-3'); β-actin (forward: 5'-CACCATTGGCAATGAGCGGTTC-3', reverse: 5'-AGGTCTTTGCGGATGTCCACGT-3'). The PCR product was confirmed by electrophoresis on 1.5% agarose gel.

[0148] As a result of the experiment, Figure 4 As can be seen in Figure 2, it was observed that when treated with compound 1, LPS-induced IL-1β was effectively inhibited in a concentration-dependent manner (see Figure 4 ).

[0149] <Example 4> Confirmation of therapeutic effect on pulmonary fibrosis in a mouse model of bleomycin-induced pulmonary fibrosis

[0150] For the mouse model of bleomycin-induced pulmonary fibrosis, 5-week-old C57BL / 6J male mice weighing around 20 g were used. C57BL / 6J mice were anesthetized by intraperitoneal injection of pentobarbital (40 mg / kg), the skin of the front neck or midline was cut, the trachea was exposed with an automatic retractor, and then a micro-syringe was inserted from the occipital side to the lungs to slowly inject bleomycin (2 mg / kg) while checking the respiratory state. The cut skin of the front neck or midline was sutured immediately after injection, and then raised in a sterile animal room with constant temperature (22°C to 26°C) and constant humidity (55% to 60%). By this method, obvious fibrosis usually occurs in the lungs after 3 weeks of treatment.

[0151] The experimental animals were 7 in each group, and the experiment was conducted by dividing them into the following groups: a control group (Control) that was orally administered with distilled water; a group with bleomycin-induced pulmonary fibrosis (BLM); an experimental group that was orally administered with 100 mg / kg of nintedanib daily after taking bleomycin for 3 weeks, serving as a positive control group (BLM+nintedanib); and an experimental group that was orally administered with 60 mg / kg of compound 1 daily after taking bleomycin for 3 weeks (BLM+compound 1).

[0152] Nintedanib and Compound 1 were orally administered once a day for 28 days. On the day after the last administration of Nintedanib or Compound 1, each animal was anesthetized and then bled by cardiac puncture and sacrificed.

[0153] Lung tissues were removed from all animals for histopathological examination. The removed lung tissues were fixed in 10% neutral buffered formalin (NBF). The fixed lung tissues were embedded in paraffin and cut into 4 μm thickness to prepare tissue slides.

[0154] Tissue slides were stained with hematoxylin & eosin (H&E), i.e., cell staining, and Masson's trichrome (MT) to confirm fibrosis. Histopathological examination of prepared tissue slides was confirmed using an optical microscope (Carl Zeiss, Oberkochen, Germany). The severity of fibrosis was assessed using the modified Ashcroft scale as a semiquantitative histopathological score.

[0155] For immunohistochemical staining, the tissue slides prepared above were dewaxed, and then rabbit anti-α-smooth muscle actin (SMA) antibody or rabbit anti-type I collagen antibody was used as the primary antibody, and the Vectastatin ABC kit (Vector Laboratories, Inc, Burlingame, CA) was used to confirm the expression of the antigen reactive with each antibody.

[0156] After 5 minutes of reaction using 3,3'-diaminobenzidine (DAB) as a substrate for peroxidase, the cells were observed under a light microscope at a magnification of 400. When the staining results were read, if all or part of the cytoplasm was reddish brown, it was considered to be an immune reaction and thus judged as positive.

[0157] According to the experimental results, the mean values ​​and standard deviations were obtained using SPSS ver. 22.0 statistical program (SPSS Inc., Chicago, IL, USA), and the significance of the differences between the experimental groups was verified by Student's t-test at the p < 0.05 level.

[0158] As a result of histological analysis by H&E staining, in the experimental group (BLM) of bleomycin-induced pulmonary fibrosis, the positive control group (BLM+nintedanib) administered with nintedanib, and the group (BLM+compound 1) administered with compound 1, it was confirmed that the degree of infiltration of inflammatory cells into the alveoli and bronchioles in the group (BLM+compound 1) administered with compound 1 was significantly lower than that in the experimental group and the positive control group. In addition, it was confirmed that hypertrophic epithelial cells decreased, the deformation of the lung structure decreased, and the sites of abnormal tissue deposition decreased (see Figure 5 ).

[0159] exist Figure 6In the experiment, the degree of pulmonary fibrosis of the group administered with compound 1 (BLM + compound 1) was compared with the degree of pulmonary fibrosis of the experimental group (BLM) of bleomycin-induced pulmonary fibrosis and the positive control group (BLM + nintedanib) administered with nintedanib by Masson's trichrome (MT) staining for pulmonary fibrosis. The results confirmed that the size of the fibrotic area and the collagen deposition caused by fibrosis were significantly reduced in the group administered with compound 1 (BLM + compound 1) compared with the experimental group and the positive control group.

[0160] exist Figure 7 and Figure 8 In the experiment, it was confirmed that the expression of α-SMA in the group administered with compound 1 (BLM+compound 1) was reduced compared with the experimental group of bleomycin-induced pulmonary fibrosis (BLM) and the positive control group administered with nintedanib (BLM+nintedanib) ( Figure 7 ), and it can be confirmed that the expression of type I collagen (collagen I) in the group administered with compound 1 (BLM + compound 1) was also significantly reduced compared with the experimental group (BLM) and the positive control group (BLM + nintedanib) ( Figure 8 ).

[0161] Comprehensively, after quantifying the histological and immunological results with the modified Ashcroft scale widely used in the field of pulmonary fibrosis histology, the severity of pulmonary fibrosis in the group administered with compound 1 (BLM + compound 1) was evaluated compared with the negative control group (Control), the experimental group (BLM) and the positive control group (BLM + nintedanib), respectively.

[0162] like Fig. 9 As shown in, the score of the negative control group (PBS) was 0, indicating a normal result, and the score of the bleomycin-induced pulmonary fibrosis experimental group (BLM) was 5.5 ± 0.8. The modified Ashcroft score of the positive control group (BLM + nintedanib) administered with nintedanib was reduced to 5.2 ± 0.45, and the modified Ashcroft score of the experimental group (BLM + compound 1) administered with compound 1 was 4.0 ± 1.1, thus, it can be confirmed that the compound of the present invention effectively improves pulmonary fibrosis compared with nintedanib used as a conventional therapeutic agent for idiopathic pulmonary fibrosis.

[0163] <Example 5> Confirmation of viral inhibition in human lung epithelial cells

[0164] In order to analyze the antiviral activity of the compounds of the synthesis examples, real-time qRT-PCR (quantitative RT-PCR) was performed using severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) and Calu-3 cells as human lung epithelial cells. Human lung epithelial cells (Calu-3) were cultured in Dulbecco's modified Eagle medium (DMEM) at 37°C and 5% CO2. The concentrations of compound 1 were 15 μM, 12.5 μM, 6.25 μM, 3.125 μM, 1.563 μM, 0.781 μM, 0.391 μM, 0.195 μM, 0.098 μM, 0.049 μM, 0.024 μM, and 0.012 μM. After treating the cells for 24 hours and 48 hours according to the concentration, the antiviral efficacy (IC 50 ; 50% inhibitory concentration) and cytotoxicity (CC 50 ; 50% cytotoxic concentration), and are shown in Tables 1 and Fig.10 middle.

[0165] [Table 1]

[0166]

[0167]

[0168] From Table 1 and Fig.10 It can be seen that the antiviral efficacy is manifested as IC 50 was 1.67 μM, and the cytotoxicity showed very low cytotoxicity, that is, CC 50 It is 164.5 μM. Therefore, it can be confirmed that compound 1 can inhibit the replication of SARS-CoV-2 and is a drug with very low cytotoxicity.

Claims

1. Use of a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for preventing or treating pulmonary fibrosis: <Formula 1> in, The compound of formula 1 is 3-phenyl-4-n-propyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol.

2. The use according to claim 1, wherein The pulmonary fibrosis is caused by pulmonary fibrosis, chronic obstructive pulmonary disease combined with pulmonary fibrosis, idiopathic pulmonary fibrosis or asthma.

3. The use according to claim 2, wherein The pulmonary fibrosis is caused by any one or a combination of viral pneumonia, bacterial pneumonia, fungal pneumonia, mycoplasma pneumonia, hypersensitivity pneumonitis, aspiration pneumonia, interstitial lung disease and pneumoconiosis.

4. The use according to claim 3, wherein The viral pneumonia is caused by a virus selected from adenovirus, vaccinia virus, herpes simplex virus, parainfluenza virus, rhinovirus, varicella zoster virus, measles virus, respiratory syncytial virus, dengue virus, human immunodeficiency virus, influenza virus, and coronavirus.

5. The use according to claim 4, wherein The coronavirus is selected from severe acute respiratory syndrome-related coronavirus 2 and Middle East respiratory syndrome coronavirus.

6. The use according to claim 2, wherein The pulmonary fibrosis is caused by idiopathic pulmonary fibrosis.

7. The use according to claim 1, wherein The pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.

8. The use according to claim 1, wherein The compound of Formula 1 is used together with a second therapeutic agent, wherein the second therapeutic agent is an antibiotic, an antifungal agent, an antiviral agent, an anti-inflammatory agent or any combination thereof.

9. Use of the compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof in the preparation of an antiviral agent, in, The antiviral agent has antiviral activity against severe acute respiratory syndrome-associated coronavirus 2: <Formula 1> Wherein, the compound of formula 1 is 3-phenyl-4-n-propyl-1-(pyridin-2-yl)-1H-pyrazol-5-ol.

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