WO2021210799A1 - 피라졸 유도체의 폐섬유증 치료제 - Google Patents

피라졸 유도체의 폐섬유증 치료제 Download PDF

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WO2021210799A1
WO2021210799A1 PCT/KR2021/003537 KR2021003537W WO2021210799A1 WO 2021210799 A1 WO2021210799 A1 WO 2021210799A1 KR 2021003537 W KR2021003537 W KR 2021003537W WO 2021210799 A1 WO2021210799 A1 WO 2021210799A1
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Prior art keywords
pyrazol
pyridin
phenyl
hydrochloride
formula
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PCT/KR2021/003537
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English (en)
French (fr)
Korean (ko)
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문성환
이수진
유현경
고유경
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Aptabio Co Ltd
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Aptabio Co Ltd
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Priority claimed from KR1020210036863A external-priority patent/KR102386097B1/ko
Priority to BR112022020649A priority Critical patent/BR112022020649A2/pt
Priority to AU2021255160A priority patent/AU2021255160B2/en
Priority to CA3172596A priority patent/CA3172596A1/en
Priority to JP2022562440A priority patent/JP7539485B2/ja
Priority to CN202180028319.3A priority patent/CN115427039B/zh
Application filed by Aptabio Co Ltd filed Critical Aptabio Co Ltd
Priority to MX2022012726A priority patent/MX2022012726A/es
Priority to US17/918,497 priority patent/US12616684B2/en
Priority to EP21787824.8A priority patent/EP4137134A4/en
Publication of WO2021210799A1 publication Critical patent/WO2021210799A1/ko
Priority to CONC2022/0014273A priority patent/CO2022014273A2/es
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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a pyrazole derivative useful for preventing or treating pulmonary fibrosis, a method for preparing the same, and a pharmaceutical composition thereof.
  • Pulmonary fibrosis a type of chronic interstitial lung disease, is characterized by inflammatory cells such as lymphocytes and macrophages infiltrating the lung interstitial, fibroblast proliferation, and fibrous connective tissue deposition in the lung interstitial tissue. Pulmonary fibrosis is caused by various internal and external etiology, and it seriously threatens human health as a result of chronic lung damage or advanced disease.
  • the etiology of pulmonary fibrosis includes factors such as immune dysfunction, viral or bacterial infection, drugs and chemicals, radiation, and air pollution (smog, cigarette smoke, dust, etc.).
  • Idiopathic pulmonary fibrosis is a type of interstitial pneumonia in which fibrosis of the lung parenchyma is progressively progressing.
  • the 5-year survival rate is about 20%, similar to that of lung cancer.
  • the incidence and prevalence of pulmonary fibrosis are rapidly increasing with the aging of the population.
  • Pulmonary fibrosis is a complex pathological and physiological process.
  • a large amount of inflammatory cells infiltrate mainly pulmonary inflammation, the alveolar wall becomes chronically thick, and in the middle/late stage, extracellular matrix elements such as collagen fibroblasts Normal lung tissue structure is destroyed and function is lost due to overgrowth of lung tissue, alveolar deformation, hardening, and scarring caused by excessive deposition.
  • Fibroblasts play a role in the recruitment of immune cells to sites of inflammation and tissue damage.
  • fibroblasts produce and respond to many inflammatory cytokines.
  • fibroblasts may contribute to chronic inflammation, and conversely, inflammatory cytokines promote the conversion of fibroblasts to myofibroblasts, thereby promoting fibrosis. Therefore, injury or inflammation of the lung tissue can lead to pulmonary fibrosis.
  • Lung transplantation is the only way to repair lung tissue that has undergone fibrosis due to pulmonary fibrosis, and the 5-year survival rate after diagnosis is only 43%.
  • immunosuppressants which are steroids or cytotoxic drugs
  • steroids are used first, and a combination therapy of steroids and azathioprine or cyclophosphamide is currently being used.
  • Pirfenidone and nintedanib are the only approved drugs for the treatment of pulmonary fibrosis. Pirfenidone has a mild therapeutic effect and is used at a very high dose of about 2.4 g/day, but it has been reported that there is little or no significant improvement in survival. It tends to deteriorate the patient's quality of life due to severe side effects such as rash) and metabolic and malnutrition disorders (e.g., loss of appetite, loss of appetite), and it is difficult to continue administration because it weakens liver function.
  • Nintedanib is used at a dose of 200 to 400 mg/day and has been reported to reduce the incidence of acute exacerbation of mild to severe idiopathic pulmonary fibrosis, but continuous administration is difficult due to many side effects and gastrointestinal side effects.
  • Oxidative stress causes tissue damage caused by a relatively excessive production of reactive oxygen species (ROS) production and antioxidant defense mechanisms for biomolecules, cells, and tissues. refers to In particular, it has been reported that oxidative stress generated in lung tissue induces and worsens pulmonary fibrosis. It has been reported that TGF- ⁇ stimulation in lung tissue of patients undergoing pulmonary fibrosis induces an increase in the production of reactive oxygen species and increases the expression of collagen and ⁇ -SMA ( ⁇ -smooth muscle actin), which are important for fibrosis. In particular, it has been reported that pulmonary fibrosis worsens due to reactive oxygen species in the lung tissue of patients with idiopathic pulmonary fibrosis.
  • ROS reactive oxygen species
  • RNA virus or DNA virus infection also causes fatal lung damage through pneumonia and pulmonary fibrosis, leading to death.
  • single-stranded viruses corona virus, Influenza virus, Respiratory syncytial virus, Rhinovirus, Dengue virus, HIV, etc.
  • DNA viruses adenovirus, vaccinia virus, Herpes simplex virus, etc.
  • antiviral agents that inhibit the generation of reactive oxygen species and If antiviral agents are used in combination, viral pneumonia and pulmonary fibrosis can be treated more effectively.
  • antiviral agents that can be used in combination include Remdesivir, Ritonavir, Lopinavir, and Favilavir.
  • TGF- ⁇ stimulation in lung tissue of a patient undergoing pulmonary fibrosis induces an increase in the production of reactive oxygen species and increases the expression of collagen and ⁇ -SMA (a-smooth muscle actin), which are important for fibrosis. It has been reported that pulmonary fibrosis worsens due to reactive oxygen species in the lung tissue of patients with pulmonary fibrosis.
  • ⁇ -SMA smooth muscle actin
  • Patent Document 1 Republic of Korea Patent No. 10-1280160
  • Patent Document 2 Republic of Korea Patent Publication No. 10-2019-0122806
  • Patent Document 3 Republic of Korea Patent Publication No. 10-2019-0136079
  • Non-Patent Document 1 Gabriel Laghlai, et al. Respiratory 2019, 13629.
  • Non-Patent Document 2 Eunice E. To et al. Nature communications, 8(69), 1-17.
  • Non-Patent Document 3 Alessandro G. Fois, Panagiotis Paligiannis et al., Respir Res. 2018, 19:51.
  • An object of the present invention is to provide a pharmaceutical composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • An object of the present invention is to provide a pharmaceutical composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof, which effectively inhibits the generation of reactive oxygen species.
  • An object of the present invention is to provide a pharmaceutical composition for treating or preventing pulmonary fibrosis, comprising the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • An object of the present invention is to provide a method for preventing or treating pulmonary fibrosis by administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof to a subject.
  • An object of the present invention is to provide a use for preventing or treating pulmonary fibrosis of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • An 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, antifungal, antiviral, anti-inflammatory, or any combination thereof do it with
  • An object of the present invention is to provide a method for preventing or treating pulmonary fibrosis by further administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof and an antibiotic, antifungal, antiviral, anti-inflammatory, or any combination thereof to a subject. do it with
  • An object of the present invention is to provide a use for preventing or treating pulmonary fibrosis, further comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof and an antibiotic, antifungal, antiviral, anti-inflammatory, or combination thereof.
  • An object of the present invention is to provide an antiviral agent comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • An object of the present invention is to provide a method for preventing or treating a viral disease by administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof to an individual.
  • An object of the present invention is to provide a use for preventing or treating a viral disease, including the compound of Formula 1 or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical composition for the prevention and improvement or treatment of pulmonary fibrosis or antiviral disease, comprising a pyrazole-based compound represented by the following formula (1), or a pharmaceutically acceptable salt thereof .
  • R is a linear or pulverized alkyl group having 1 to 10 carbon atoms.
  • the pyrazole-based compound according to the present invention can effectively inhibit the generation of reactive oxygen species produced in the lungs, and thus can be usefully used for the prevention or treatment of pulmonary fibrosis induced by oxidative stress without any special side effects. have.
  • the pyrazole-based compound according to the present invention or a pharmaceutically acceptable salt thereof, has antiviral activity, and thus can be usefully used for the prevention or treatment of viral diseases.
  • Figure 1 shows the result that the expression of reactive oxygen species induced by PMA stimulation in human lung fibroblasts (NHLF) is effectively inhibited when compound 1 is treated.
  • Figure 2 shows the results of inhibition of the expression of ⁇ SMA by Compound 1 during myofibroblast differentiation of human lung fibroblasts by TGF- ⁇ 1.
  • Figure 4 shows the result that the LPS treatment-induced IL-1 ⁇ expression in human lung fibroblasts was effectively inhibited when compound 1 was treated.
  • Figure 5 is a photograph of H&E staining of alveoli (alveolar) and bronchiole (bronchiole) when treated with nintedanib or compound 1 in an animal model of pulmonary fibrosis by bleomycin (BLM) administration, alveoli when treated with compound 1 And it shows the result of decreasing the amount of immune cells infiltrating into the capillaries.
  • BBM bleomycin
  • Figure 6 is a photograph of collagen deposition staining of the capillaries (bronchiole) when treated with nintedanib or Compound 1 in an animal model of pulmonary fibrosis by bleomycin (BLM) administration. show the results
  • FIG. 7 is a photograph of staining of ⁇ SMA when treated with nintedanib or compound 1 in an animal model of pulmonary fibrosis by bleomycin (BLM) administration, showing a decrease in the expression of ⁇ SMA when treated with compound 1.
  • FIG. 8 is a photograph of collagen I staining when treated with nintedanib or compound 1 in an animal model of pulmonary fibrosis by bleomycin (BLM) administration, showing a decrease in the expression of collagen I when treated with compound 1.
  • Figure 10 shows that the antiviral efficacy is excellent and the cytotoxicity is low when the compound 1 is treated in human lung epithelial cells.
  • Pulmonary fibrosis is caused by fibrosis of the lung parenchyma due to pulmonary interstitial infiltration, fibroblast proliferation, and fibrous connective tissue deposition in the lung interstitial due to inflammation of the lung, and the normal lung tissue structure is destroyed and lung function is lost. That is, pulmonary fibrosis is caused by various internal and external causes of the lungs, and as a result of chronic lung injury or disease progressing until the end, the incidence and prevalence are rapidly increasing in line with the recent aging trend. Recently, in particular, idiopathic pulmonary fibrosis of unknown cause has become a problem.
  • Lung transplantation is the only method that can repair lung tissue that has undergone fibrosis due to pulmonary fibrosis, and Pirfenidon and Nintedanib are the only approved drugs for pulmonary fibrosis, but both drugs have many side effects. And there is a problem that continuous administration is difficult due to gastrointestinal disorders.
  • symptomatic therapy to relieve symptoms using steroids or immunosuppressive agents is generally used, but a fundamental treatment is required.
  • the present inventors have focused on the development of a therapeutic agent for pulmonary fibrosis disease by effectively inhibiting the occurrence of oxidative stress in the lung tissue.
  • the pyrazole derivative of the present invention reduces lung damage caused by bleomycin administration, ⁇ SMA and collagen I
  • the present invention was completed by confirming that it can be used as a therapeutic agent for pulmonary fibrosis by discovering that pulmonary fibrosis is reduced by inhibiting pulmonary fibrosis due to accumulation.
  • the present invention provides a pharmaceutical composition capable of preventing or treating pulmonary fibrosis comprising at least one compound selected from the pyrazole compound represented by Formula 1, or a pharmaceutically acceptable salt thereof.
  • the present invention provides a pharmaceutical composition capable of preventing or treating idiopathic pulmonary fibrosis comprising at least one compound selected from the pyrazole compound represented by Formula 1, or a pharmaceutically acceptable salt thereof.
  • the pyrazole-based compound used in the present invention is represented by the following formula (1).
  • R is a linear or pulverized alkyl group having 1 to 10 carbon atoms.
  • the pharmaceutically acceptable salt of the pyrazole compound contained in the pharmaceutical composition of the present invention retains the biological effectiveness and properties of the parent compound, and when administered in a single dose, biologically or in other directions may mean harmless salts. In addition, it refers to a salt commonly used in the pharmaceutical industry.
  • salts derived from inorganic bases may include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, primary, secondary and tertiary amines; substituted amines, including naturally occurring substituted amines; And isopropylamine (isopropylamine), trimethylamine (trimethylamine), diethylamine (diethylamine), triethylamine (triethylamine), tripropylamine (tripropylamine), ethanolamine (ethanolamine), 2-dimethylaminoethanol (2-dimethylaminoethanol) ), tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylendiamine, glucosamine , N-alkylglucamine, theobromine,
  • carboxylic acid derivatives specifically carboxylic acid amides, including carboxamides, lower alkyl carboxamides, di(lower alkyl) carboxamides, and the like, are also useful in the practice of the present invention. It should be
  • salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, perchloric acid, iodic acid, tartaric acid and the like.
  • Salts derived from organic acids are 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, hydroio Dixic 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, and the like, but may not be limited thereto.
  • the pharmaceutically acceptable salt may be a hydrochloride salt.
  • the pyrazole-based 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.
  • the pyrazole-based compound contained in the pharmaceutical composition of the invention is 3-phenyl-4-n-1- (pyridin-2-yl) -1 H - pyrazol-5-ol or may be a hydrochloride thereof.
  • the compound of Formula 1 of the present invention can inhibit the generation of reactive oxygen species.
  • oxidative stress is caused by a relatively excessive production of reactive oxygen species (ROS) production and antioxidant defense mechanisms for biomolecules, cells, and tissues. refers to tissue damage.
  • ROS reactive oxygen species
  • reactive oxygen species may be referred to as active oxygen, active oxygen, or active oxygen species, and refers to the same substance.
  • Pyrazoline-based compounds of the present invention in particular 3-phenyl-4-n-1- (pyridin-2-yl) -1 H - pyrazol-5-ol hydrochloride (Compound 1) is effectively active in human lung epithelial cells Oxygen species were reduced, and when lung fibroblasts were differentiated into myofibroblasts, the expression of ⁇ SMA and collagen I, which are markers of myofibroblast differentiation, was effectively suppressed.
  • the compound of the present invention reduced the infiltration of inflammatory cells in the lung tissue, and decreased lung epithelial cell hypertrophy, compared to nintedanib, which was previously approved as a therapeutic agent for pulmonary fibrosis. Deformation of the lung structure and the site of abnormal tissue deposition were reduced.
  • the compound of the present invention decreased the expression and accumulation of collagen 1 and aSMA in the lung tissue, and also decreased the expression of reactive oxygen species in the lung tissue, compared to nintedanib. Based on these results, when the severity of fibrosis was quantified with the improved Ashcroft score, it showed a significant improvement in pulmonary fibrosis compared to nintenadib, which was previously approved as a treatment for pulmonary fibrosis.
  • the compound of the present invention not only suppresses the inflammatory response by inhibiting reactive oxygen species in the lung tissue in human lung cells and lung fibrosis models, but also reduces the expression and accumulation of collagen I and ⁇ SMA, thereby preventing or alleviating pulmonary fibrosis. effect was confirmed.
  • Pulmonary fibrosis can be caused by pulmonary inflammatory fibrosis disease, chronic obstructive pulmonary disease combined pulmonary fibrosis (COPD combined pulmonary fibrosis), idiopathic pulmonary fibrosis (IPF) or asthma.
  • COPD combined pulmonary fibrosis chronic obstructive pulmonary disease combined pulmonary fibrosis
  • IPF idiopathic pulmonary fibrosis
  • pneumonia the main cause of pulmonary fibrosis, is viral pneumonia, bacterial pneumonia, fungal pneumonia, hypersensitivity pneumonitis, aspiration pneumonia, interstitial pulmonary disease, pneumoconiosis ( pneumoconiosis), etc.
  • the viral pneumonia is adenovirus, vaccinia virus, herpes simplex virus, parainfluenza virus, rhinovirus, varicella Zoster Virus, Measle virus, respiratory syncytial virus, Dengue virus, human immunodeficiency virus (HIV), influenza virus, coronavirus, severe acute respiratory syndrome syndrome-related coronavirus (SARS-CoV), severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV2), middle east respiratory syndrome coronavirus (MERS-CoV), or Variants of these viruses can be caused by viruses.
  • HIV human immunodeficiency virus
  • influenza virus coronavirus
  • SARS-CoV severe acute respiratory syndrome-related coronavirus
  • SARS-CoV2 severe acute respiratory syndrome-related coronavirus 2
  • MERS-CoV middle east respiratory syndrome coronavirus
  • the pharmaceutical composition of the present invention may further include an antibiotic, an antifungal agent, an antiviral agent, an anti-inflammatory agent, or any combination thereof as a second therapeutic agent in addition to the compound of Formula 1 or a salt thereof.
  • antibiotics included in the second therapeutic agent include gentamycin, kanamycin, streptomycin, amikacin, neomycin, and the like among aminoglycoside antibiotics; Among macrolide antibiotics, erythromycin, azithromycin, clarithromycin, and the like; Among the beta-lactam antibiotics, penicillin, cephalosporin, carbapenem, monobactam, and the like; lincomycin-based antibiotics such as clindamycin; oxazolidinone antibiotics such as linezolid; Ciprocloxacin, leboploxacin, moxifloxacin, fluoroquinone, etc.
  • sulfonamide-based antibiotic is trimethoprime/sulfamethoxazole (TMX/SMX) or a combination thereof.
  • Antiviral agents included as second therapeutic agents include thiosemicarbazone, metisazone, acyclovir, remdecivir, ritonavir, and lopinavir. , faviravir, idoxuridine, vidarabine, ribavirin, ganciclovir, famciclovir, valaciclovir, cidofovir , valganciclovir, brivudine, ribavirin, rimantadine, tromantadine, foscarnet, saquinavir, indinavir ( indinavir, nelfinavir, amprenavir, fosamprenavir, atazanavir, tipranavir, zidovudine, didanosine, zalsi Tabine, stavudine, lamivudine, abacavir, tenofovir disoproxil, adefovir disoproxil, emtricit
  • Antifungal agents included as second therapeutic agents include allylamine, terbinafine, 5-fluoro cytosine, fluconazole, itraconazole, ketoconazole, ravuconazole ), posaconazole (posaconazzole); voriconazole, caspofungin, micafungin, anidulafungin, amphotericin B , amphotericin B lipid complex (ABLC) , amphotericin B colloidal dispersion ABCD, liposome-amphotericin B (L-AMB); liposome nystatin, griseofulvin, or a combination thereof
  • the compound of Formula 1 of the present invention since the compound of Formula 1 of the present invention has antiviral activity against various viruses, the compound of the present invention can be used as an antiviral agent by itself. Accordingly, the compound of Formula 1 of the present invention may be effective in preventing or treating viral diseases.
  • the viral disease is adenovirus, vaccinia virus, herpes simplex virus, parainfluenza virus, rhinovirus, varicella Zoster Virus, Measle virus, respiratory syncytial virus, Dengue virus, HIV (human immunodeficiency virus), influenza virus, coronavirus, severe acute respiratory syndrome 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 these Variant of the virus It may be caused by a virus, but is not limited thereto.
  • compound 1 of the present invention can effectively inhibit the proliferation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), and thus also inhibit the proliferation of related viruses, SARS-CoV, MERS-CoV, or variant viruses of these coronaviruses. can do.
  • SARS-CoV2 severe acute respiratory syndrome coronavirus 2
  • MERS-CoV MERS-CoV
  • variant viruses of these coronaviruses can do.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier within a range that does not impair the effects of the present invention.
  • the "pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (antibacterial or antifungal agents), isotonic agents, diluents, absorption delaying agents, salts, preservatives, stabilizers, binders, excipients, disintegrants, lubricants, sweetening agents, sweetening agents, flavoring agents, dyes, and the like, and combinations thereof. Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.
  • the diluent may be selected from the group consisting of microcrystalline cellulose, lactose monohydrate, lactose anhydride, lactose, starch, mannitol, carboxymethylcellulose, sorbitol, and combinations thereof, but is not limited thereto.
  • the disintegrant may be selected from the group consisting of low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, sodium starch glycolate, F-melt, and combinations thereof, but is not limited thereto.
  • the binder is hydroxypropylcellulose, hydroxypropylmethylcellulose, hypromellose, polyvinylacetic acid, povidone, polyvinylpyrrolidone, copovidone, macrogol, sodium lauryl sulfate, light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate. or silicate derivatives such as magnesium metasilicate aluminate, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, pregelatinized starches, gums such as acacia gum, gelatin, cellulose derivatives such as ethyl cellulose, and mixtures thereof It may be selected from, but is not limited thereto.
  • the lubricant may be selected from the group consisting of magnesium stearate, silicon dioxide, talc, light anhydrous silicic acid, sodium stearyl fumarate, and combinations thereof, but is not limited thereto.
  • pH adjusters include acidifying agents such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium etheric acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid (citric acid), aqueous ammonia, sodium carbonate, magnesium oxide, magnesium carbonate, A basifying agent such as sodium citrate or tribasic calcium phosphate may be used.
  • acidifying agents such as acetic acid, adipic acid, ascorbic acid, sodium ascorbate, sodium etheric acid, malic acid, succinic acid, tartaric acid, fumaric acid, citric acid (citric acid), aqueous ammonia, sodium carbonate, magnesium oxide, magnesium carbonate,
  • a basifying agent such as sodium citrate or tribasic calcium phosphate may be used.
  • antioxidant dibutyl hydroxy toluene, butylated hydroxyanisole, tocopherol acetate, tocopherol, propyl gallate, sodium hydrogen sulfite, sodium pyrosulfite and the like may be used.
  • the scope of the additive is not limited to using the additive, and the additive may be selected and formulated to contain a dose within a normal range.
  • the pharmaceutical composition according to the present invention may be formulated in the form of oral dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, external preparations, suppositories, or sterile injection solutions according to conventional methods. have.
  • the active ingredient is contained in the range of 0.00001 to 100% by weight, 0.0001 to 95% by weight, or 0.001 to 90% by weight based on the total weight of the pharmaceutical composition for preventing, improving or treating pulmonary fibrosis It may be a pharmaceutical composition.
  • the dosage of the pyrazole-based compound represented by Formula 1 or a pharmaceutically acceptable salt thereof can be appropriately changed depending on the age, weight, symptom, administration route, etc. of the patient do.
  • the dosage of the pyrazole compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof is 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, or 0.001 mg/kg/day to 80 mg/kg/day day or 0.01 mg/kg/day to 70 mg/kg/day.
  • the content of the pyrazole compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof is 0.00001 to 100% by weight, 0.0001 to 95% by weight, 0.0001 to 90% by weight, 0.001 to 70% by weight, or 0.001 to 50 per unit dosage form. % by weight.
  • the administration concentration of the pyrazole compound represented by Formula 1 of the present invention or a pharmaceutically acceptable salt thereof is 0.0001 to 500 ⁇ M, 0.001 to 300 ⁇ M, 0.001 to 150 ⁇ M, 0.001 to 130 ⁇ M, 0.001 to 100 ⁇ M, 0.001 to 80 ⁇ M or 0.01 to 70 ⁇ M.
  • composition of the present invention may be administered through a general route, and specifically, it may be formulated for intramuscular, intrathecal, gastrointestinal, cardiovascular, intrarenal, or intravenous administration.
  • Formulation methods employ conventional methods known to those skilled in the art.
  • a typical composition for intramuscular or intrathecal administration may consist of, for example, but not limited to, the active ingredient and dextrose or sodium chloride, or a sterile isotonic aqueous solution containing dextrose and sodium chloride.
  • Other examples include, but are not limited to, lactated Ringer's injection, lactated Ringer's injection + dextrose injection, Normosol-M and dextrose, Isolyte E, acylated Ringer's injection, etc. does not optionally, a cosolvent such as polyethylene glycol; chelating agents such as ethylenediamine tetraacetic acid; Antioxidants such as sodium metabisulphite may be included in the formulation, but are not limited thereto.
  • the solution may be lyophilized and then reconstituted with a suitable solvent immediately prior to administration, but is not limited thereto.
  • Each cell was suspended in a culture medium containing 10% FBS, aliquoted in a 96-well plate, and incubated at 5% CO 2 , 37° C. for 24 hours. After pretreatment with Compound 1 for 30 minutes to 1 hour, TGF- ⁇ 1 or PMA (Phorbol 12-myristate 13-acette) stimulation was applied to each well including cells and drugs.
  • TGF- ⁇ 1 or PMA Phorbol 12-myristate 13-acette
  • Example 2 Expression pattern of aSMA and type I collagen induced by TGF- ⁇ 1 in human lung fibroblasts
  • NHLF cells were suspended in culture medium (FGM-2 Bulletkit media, Lonza) and inoculated at a concentration of 1x10 4 cells/well on a 4-well chamber slide (Nunc).
  • aSMA and collagen I expression was observed using a fluorescence microscope.
  • IL-1 ⁇ was confirmed using RT-PCR.
  • the base sequence for the target primer is as follows.
  • IL-1 ⁇ forward: 5′-CCACAGACCTTCCAGGAGAATG-3′, reverse: 5′-GTGCAGTTCAGTGATCGTACAGG-3′
  • GAPDH forward: 5'-GTGGCTGGCTCAGAAAAAGG-3', reverse: 5'-GTGGGTCCAGGGGTCTTACT-3'
  • ⁇ -actin forward: 5'-CACCATTGGCAATGAGCGGTTC-3', reverse: 5'-AGGTCTTTGCGGATGTCCACGT-3'.
  • the PCR product was confirmed by electrophoresis on 1.5% agarose gel.
  • mice For the mouse model of bleomycin-induced pulmonary fibrosis, C57BL/6J male mice aged 5 weeks and before and after body weight 20 g were used. C57BL/6J mice were intraperitoneally injected with pentobarbital (40 mg/kg) and under anesthesia, the skin of the anterior region was incised, the trachea was exposed with an opener, and a micro syringe was inserted from the occipital side to the lungs. While checking the state of respiration, bleomycin (2 mg/kg) was slowly administered. Immediately after injection, the skin of the incised anterior region was sutured and bred in a sterile animal room at constant temperature (22 ⁇ 26°C) and constant humidity (55 ⁇ 60%). With this method, significant fibrosis occurred in the lungs, usually after 3 weeks of treatment.
  • mice were treated with 7 animals in each group, a control group that was orally administered with distilled water (Control), a group that induced pulmonary fibrosis with bleomycin (BLM), and three weeks after administration of bleomycin, 100 mg/kg of nintedanib ( nintedanib) was administered orally daily (BLM + Nintedanib), and three weeks after administration of bleomycin, 60 mg/kg of Compound 1 was orally administered daily (BLM + Compound 1).
  • 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 blood was drawn by cardiac puncture and sacrificed.
  • Lung tissues were harvested from all animals for histopathological examination.
  • the extracted lung tissue was fixed in 10% neutral buffered formalin (NBF).
  • NBF neutral buffered formalin
  • the fixed lung tissue was embedded in paraffin and sliced to a thickness of 4 ⁇ m to prepare a tissue slide.
  • the tissue slides were subjected to Hematoxylin & Eosin (H&E) staining, which is cell staining, and Masson's trichrome (MT) staining to confirm fibrosis. Histopathological examination of the prepared tissue slides was confirmed using an optical microscope (Carl Zeiss, Oberkochen, Germany). The severity of fibrosis was assessed with the modified Ashcroft scale, a semi-quantitative histopathological scoring.
  • H&E Hematoxylin & Eosin
  • MT Masson's trichrome
  • tissue slide prepared above was de-paraffinized and then rabbit anti- ⁇ -SMA (smooth muscle actin) antibody or rabbit anti-collagen type 1 antibody was used as a primary antibody. and Vectastatin ABC kit (Vector Laboratories, Inc, Burlingame, CA) was used to confirm the expression of the antigen reacted with each antibody.
  • ⁇ -SMA smooth muscle actin
  • Vectastatin ABC kit Vector Laboratories, Inc, Burlingame, CA
  • DAB 3,3'-diaminobenzidine
  • control negative control group
  • experimental group BLM
  • positive control group BLM + Nintedanib
  • compound 1 administration group BLM + compound 1
  • the score was 0 in the negative control group (PBS) showing normal findings, and the experimental group (BLM) in which pulmonary fibrosis was induced by bleomycin was 5.5 ⁇ 0.8.
  • the improved Ashcroft score of the positive control group administered with nintedanib (BLM + Nintedanib) was reduced to 5.2 ⁇ 0.45, and the improved Ashcroft score in the experimental group administered with Compound 1 (BLM + Compound 1) was 4.0 ⁇ 1.1, according to the present invention. was confirmed to effectively improve pulmonary fibrosis compared to nintedanib, which has been used as a conventional treatment for idiopathic pulmonary fibrosis.
  • the antiviral efficacy exhibited an IC 50 1.67 ⁇ M at 48 hours, and the cytotoxicity was CC 50 164.5 ⁇ M at 48 hours, indicating a very low cytotoxicity. Therefore, it was confirmed that Compound 1 could inhibit the replication of SARS-CoV-2, and it was confirmed that the drug had very low cytotoxicity.

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EP21787824.8A EP4137134A4 (en) 2020-04-13 2021-03-23 MEDICATION AGAINST PULMONARY FIBROSIS CONTAINING A PYRAZOLE DERIVATIVE
AU2021255160A AU2021255160B2 (en) 2020-04-13 2021-03-23 Pulmonary fibrosis medicine containing pyrazole derivative
CA3172596A CA3172596A1 (en) 2020-04-13 2021-03-23 Pulmonary fibrosis medicine containing pyrazole derivative
JP2022562440A JP7539485B2 (ja) 2020-04-13 2021-03-23 ピラゾール誘導体の肺線維症治療剤
CN202180028319.3A CN115427039B (zh) 2020-04-13 2021-03-23 包含吡唑衍生物的肺纤维化药物
BR112022020649A BR112022020649A2 (pt) 2020-04-13 2021-03-23 Remédio para fibrose pulmonar contendo derivativo de pirazol
MX2022012726A MX2022012726A (es) 2020-04-13 2021-03-23 Medicamentos para fibrosis pulmonar que contienen derivado de pirazol.
US17/918,497 US12616684B2 (en) 2020-04-13 2021-03-23 Pulmonary fibrosis medicine containing pyrazole derivative
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