Agent for treating or preventing severe asthma

Abstract

To provide an agent for treating or preventing severe asthma, steroid-resistant asthma, and chronic obstructive disease.SOLUTION: The present disclosure relates to an agent for treating or preventing severe asthma and other respiratory diseases, which contains, as an active ingredient, a specific dihydropyrimidin-2-one compound or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to an agent for treating or preventing respiratory diseases such as severe asthma, which contains a specific dihydropyrimidin-2-one compound or a pharmaceutically acceptable salt thereof as an active ingredient. [Background technology]

[0002] Bronchial asthma (hereafter referred to as asthma) is a disease in which the airways become chronically inflamed and hypersensitive to various stimuli, resulting in paroxysmal symptoms such as dyspnea, coughing, and wheezing. Inhaled corticosteroids (ICS), which are used for long-term management of asthma, have become widespread due to the development of various drugs and improvements in devices. Furthermore, the use of long-acting β2 agonists (LABAs), leukotriene receptor antagonists (LTRAs), and long-acting muscarinic antagonists (LAMAs) has significantly improved asthma control (Non-Patent Document 1).

[0003] However, even with the use of high doses of inhaled steroids, there is little improvement in asthma symptoms, and approximately 5 to 10% of patients experience frequent attacks (Non-Patent Document 2). How to treat such patients with intractable asthma (severe asthma) is an important issue in asthma treatment today.

[0004] The pathology of severe asthma can be broadly classified into type 2 inflammation and non-type 2 inflammation (Non-Patent Document 2). Type 2 inflammation involves Th2 cells with antigen-specific T cell receptors and type 2 innate lymphoid cells (ILC2s) that lack antigen specificity, and these cells produce cytokines such as IL-4, IL-5, and IL-13 upon activation (Non-Patent Document 3). IL-4 induces the production of antigen-specific IgE by B cells, IL-5 increases eosinophils, and IL-13 enhances mucin production (Non-Patent Document 4). Furthermore, thymic stromal lymphopoietin (TSLP) produced by airway epithelial cells acts on dendritic cells to promote the differentiation of Th2 cells (Non-Patent Document 4). As the relationship between these cytokines and asthma became clearer, the introduction of biological agents for the treatment of poorly controlled severe asthma began to be considered, and in recent years, a number of biological agents targeting type 2 inflammation have been developed, including anti-IgE antibodies, anti-IL-4Rα antibodies, anti-IL-5 antibodies, anti-IL-5Rα antibodies, and anti-TSLP antibodies.

[0005] As asthma is a heterogeneous pathology, and efficacy varies depending on the type of disease, blood eosinophil counts, exhaled nitric oxide (FeNO) levels, serum total IgE levels, and allergen-specific IgE antibodies are measured when selecting medications (Non-Patent Document 5). On the other hand, treatment for severe asthma due to non-type 2 inflammation, which is not accompanied by type 2 inflammation or increased eosinophils, involves long-term administration of low-dose macrolides or bronchial thermoplasty (Non-Patent Document 5), and there are fewer drug options than for severe asthma due to type 2 inflammation.

[0006] Chronic obstructive pulmonary disease (COPD) is a general term for diseases primarily known as chronic bronchitis and emphysema, and is thought to be caused by the long-term inhalation of irritants. Unlike asthma, COPD constantly presents with airflow obstruction and is a progressive disease. As the disease progresses, the lungs of COPD patients show increased inflammation and increased numbers of lymphocytes, neutrophils, and macrophages (Non-Patent Document 6). LABAs, LAMAs, and ICS are used for drug treatment (Non-Patent Document 7), but have not yet been effective in suppressing disease progression. While the pathological mechanisms of COPD are not fully understood, steroid-resistant chronic inflammation and oxidative stress are known to accelerate lung aging and disrupt repair mechanisms (Non-Patent Document 6). [Prior art documents] [Patent documents]

[0007] [Patent Document 1] WO2016093342 [Non-patent literature]

[0008] [Non-Patent Document 1] Journal of the Japanese Society of Internal Medicine, Vol. 108, No. 9 [Non-patent document 2] Immune Netw. 2022 Dec 5;22(6):e45. [Non-patent document 3] Nat Immunol. 2015 Jan;16(1):45-56. [Non-patent document 4] Respirology. 2023 Aug;28(8):709-721. [Non-patent document 5] Asthma Treatment Practice Guidelines 2023 (Kyowa Kikaku Co., Ltd.) [Non-patent document 6] Nat Rev Dis Primers. 2015 Dec 3;1:15076. [Non-Patent Document 7] Int J Chron Obstruct Pulmon Dis. 2023 May 5;18:745-754. Summary of the Invention [Problem to be solved by the invention]

[0009] An object of the present invention is to provide a novel drug for treating and / or preventing respiratory diseases such as severe asthma. [Means for solving the problem]

[0010] As a result of extensive investigations, the present inventors have found that compounds of the following structural formula, which are known retinoid-related orphan receptor gamma (RORγ) antagonists, may be effective in treating respiratory diseases such as severe asthma, and have thus completed the present invention.

[0011] Specific embodiments of the present invention are exemplified below.

[0012] [Section 1] The chemical structure is as follows: [ka] 10. A therapeutic or preventive agent for a disease selected from the group consisting of severe asthma, steroid-resistant asthma, and chronic obstructive pulmonary disease, comprising as an active ingredient a compound represented by the formula: [Section 2] Item 1. The therapeutic or prophylactic agent according to Item 1, wherein the disease is severe asthma or steroid-resistant asthma. [Section 3] Item 3. The therapeutic or preventive agent according to Item 2, wherein the severe asthma or steroid-resistant asthma is accompanied by non-type 2 inflammation. [Section 4] Item 4. The therapeutic or prophylactic agent according to Item 2 or 3, wherein the severe asthma or steroid-resistant asthma is not accompanied by an increase in blood eosinophil count. [Section 5] Item 5. The therapeutic or prophylactic agent according to Item 4, wherein the blood eosinophil count is less than 300 cells / μL. [Section 6] Item 6. The therapeutic or prophylactic agent according to any one of Items 2 to 5, wherein the severe asthma or steroid-resistant asthma is mediated by Th17 cells. [Section 7] Item 1. The therapeutic or prophylactic agent according to Item 1, wherein the disease is chronic obstructive pulmonary disease. [Section 8] Item 8. The therapeutic or preventive agent according to Item 7, wherein the chronic obstructive pulmonary disease is accompanied by non-type 2 inflammation. [Section 9] Item 9. The therapeutic or prophylactic agent according to Item 7 or 8, wherein the chronic obstructive pulmonary disease is not accompanied by an increase in blood eosinophil count. [Section 10] Item 10. The therapeutic or prophylactic agent according to Item 9, wherein the blood eosinophil count is less than 300 cells / μL. [Section 11] Item 11. The therapeutic or prophylactic agent according to any one of Items 7 to 10, wherein the chronic obstructive pulmonary disease is mediated by Th17 cells. [Section 12] Item 12. The therapeutic or prophylactic agent according to any one of Items 1 to 11, wherein the disease is accompanied by an increase in blood neutrophil count. [Section 13] The blood neutrophil count is 5 x 10 9 Item 13. The therapeutic or prophylactic agent according to Item 12, wherein the total amount of the therapeutic or prophylactic agent is 100 cells / L or more. [Section 14] Item 14. The therapeutic or prophylactic agent according to any one of Items 1 to 13, wherein the disease is accompanied by an increase in blood IL-17A, IL-17F, and / or IL-22. [Section 15] Item 15. The therapeutic or preventive agent according to any one of Items 1 to 14, wherein the disease is accompanied by an increase in the number of neutrophils in sputum. [Section 16] Item 16. The therapeutic or prophylactic agent according to any one of Items 1 to 15, wherein the disease is accompanied by an increase in IL-17A, IL-17F, and / or IL-22 in sputum. [Section 17] Item 17. The therapeutic or prophylactic agent according to any one of Items 1 to 16, which is to be administered to a subject having an increased blood neutrophil count. [Section 18] The subject's blood neutrophil count is 5 x 10 9 Item 18. The therapeutic or prophylactic agent according to Item 17, wherein the total amount of the therapeutic or prophylactic agent is 100 cells / L or more. [Section 19] Item 19. The therapeutic or prophylactic agent according to any one of Items 1 to 18, which is to be administered to a subject in which increased levels of IL-17A, IL-17F, and / or IL-22 in the blood are observed. [Section 20] 20. The therapeutic or prophylactic agent according to any one of items 1 to 19, for administration to a subject with an increased neutrophil count in sputum. [Section 21] Item 21. The therapeutic or prophylactic agent according to any one of Items 1 to 20, for administration to a subject in which increased levels of IL-17A, IL-17F, and / or IL-22 in sputum have been observed. [Section 22] A therapeutically effective amount of the following chemical structure: [ka] A method for treating or preventing a disease selected from the group consisting of severe asthma, steroid-resistant asthma, and chronic obstructive pulmonary disease, comprising administering to a subject a compound represented by the following formula (I): [Section 23] 1. A compound having the following chemical structural formula: [ka] or a pharmaceutically acceptable salt thereof. [Section 24] 2. The method for producing a medicament for treating or preventing a disease selected from the group consisting of severe asthma, steroid-resistant asthma, and chronic obstructive pulmonary disease, comprising administering to a subject a compound having the following chemical structural formula: [ka] or a pharmaceutically acceptable salt thereof. [Effects of the Invention]

[0013] The present invention provides an agent for treating or preventing respiratory diseases such as severe asthma, which comprises a specific dihydropyrimidin-2-one compound or a pharmaceutically acceptable salt thereof as an active ingredient. [Brief explanation of the drawings]

[0014] [Figure 1] Effect of Compound A on airway hyperresponsiveness [airway resistance: lung resistance (RL)] in Th17 cell-transfected asthma model mice. Data are shown as mean ± SD (n = 10). Statistical analysis was performed on the data for 6.25 mg / mL methacholine, which showed nearly the maximum response and the largest difference between the sham group and the vehicle group. The following statistical analysis was performed using a closed procedure: ††, p < 0.01; Sham group vs. Vehicle group (Student's t-test); *, p < 0.05; Vehicle group vs. Compound A group (Dunnett's test). [Figure 2] Effect of Compound A on airway hyperresponsiveness [dynamic lung compliance (Cdyn)] in Th17 cell-transferred asthma model mice. Data are shown as mean ± SD (n = 10). Statistical analysis was performed on the data for 6.25 mg / mL methacholine, which showed nearly the maximum response and the largest difference between the sham group and the vehicle group. The following statistical analysis was performed using a closed procedure: ††, p < 0.01; Sham group vs. Vehicle group (Student's t-test); *, p < 0.05; Vehicle group vs. Compound A group (Dunnett's test). DETAILED DESCRIPTION OF THE INVENTION

[0015] The present disclosure provides a compound of formula [I]: [ka] [I] or a pharmaceutically acceptable salt thereof (hereinafter, may be referred to as "the compound of the present invention") in the treatment or prevention of a disease selected from the group consisting of severe asthma, steroid-resistant asthma, and chronic obstructive pulmonary disease.

[0016] The following formula [I]: [ka] [I] The compound represented by the following formula (1) is disclosed in Patent Document 1 as a method for producing the compound represented by the following formula (1):

[0017] As used herein, the term "pharmaceutically acceptable salt" refers to any salt known in the art that is not excessively toxic. Specific examples include salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases. Various forms of pharmaceutically acceptable salts are well known in the art and are described, for example, in the following references: (a) Berge et al., J. Pharm. Sci., 66, pp. 1-19 (1977), (b) Stahl et al., "Handbook of Pharmaceutical Salt: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002), (c) Paulekuhn et al., J. Med. Chem., 50, p6665-6672 (2007). According to a method known per se, the compound of formula [I] can be reacted with an inorganic acid, an organic acid, an inorganic base or an organic base to obtain a pharmaceutically acceptable salt thereof.

[0018] Examples of salts with inorganic acids include salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid. Preferred examples include salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and hydrobromic acid.

[0019] Salts with organic acids include acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylene citric acid, benzoic acid, benzenesulfonic acid, calcium edetate, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, edetic acid, ethane-1,2-disulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycolylarsanilic acid, hexylresorcylic acid, hydroxy-naphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, and lactobionic acid. , malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitrate, methylenebis(salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1,5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectinic acid, picric acid, propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, teoclic acid, thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid, or glutamic acid. Preferred examples include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or 2-hydroxy-1-ethanesulfonic acid.

[0020] Examples of salts with inorganic bases include salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, or ammonium, and preferably salts with sodium, potassium, calcium, magnesium, or zinc.

[0021] Examples of salts with organic bases include salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris(hydroxymethyl)methylamine, arginine, or lysine. Preferably, salts with tris(hydroxymethyl)methylamine, N-methylglucamine, or lysine are used.

[0022] The compound of the present invention may exist as a solvate. A solvate is, for example, a compound of formula [I] or a pharmaceutically acceptable salt thereof in which solvent molecules are coordinated. The solvate may be any pharmaceutically acceptable solvate, and examples thereof include a hydrate, ethanolate, and dimethyl sulfoxide solvate of a compound of formula [I] or a pharmaceutically acceptable salt thereof. Specific examples include a hemihydrate, monohydrate, dihydrate, or monoethanolate of a compound of formula [I], or a monohydrate or 2 / 3 ethanolate of the sodium salt or dihydrochloride of a compound of formula [I]. These solvates can be obtained according to known methods.

[0023] Any one or more of the compounds of the present invention 1 H 2 Deuterium-converted derivatives converted to H(D) are also encompassed in the compounds of the present invention.

[0024] The compound of the present invention obtained as a crystal may exist in the form of a crystalline polymorph, and such crystalline polymorphs are also included in the present invention.

[0025] The compound of the present invention is preferably substantially purified, and more preferably the compound of formula [I] or a pharmaceutically acceptable salt thereof, which has been purified to a purity of 80% or more.

[0026] The compound of the present invention can be administered orally or parenterally (topical, rectal, intravenous, intramuscular, subcutaneous, nasal, pulmonary, etc.) to non-human mammals (mouse, rat, hamster, guinea pig, rabbit, cat, dog, pig, cow, horse, sheep, monkey, etc.) and humans. The daily dose varies depending on the subject, disease, symptoms, dosage form, administration route, etc. For example, in the case of oral administration, the compound can be administered in a dose of about 0.01 mg to 100 mg (e.g., about 0.25 mg to 50 mg, about 0.5 mg to 25 mg, or about 1 mg to 12.5 mg) per kg body weight of a human or mammal, once or in divided doses. Specifically, the daily dose for an adult patient is about 0.6 mg to 6000 mg (e.g., about 15 mg to 3000 mg, about 30 mg to 1500 mg, or about 60 mg to 750 mg). In the case of inhalation administration, for example, the daily dose for an adult patient is about 1 μg to 5,000 μg (eg, about 5 μg to 4,000 μg, about 10 μg to 3,000 μg, about 30 μg to 1,000 μg).

[0027] As used herein, the frequency of administration of each drug, medicament, and pharmaceutical composition may be once, twice, three times, or more times per day.

[0028] Pharmaceutical compositions (including therapeutic and prophylactic agents) containing the compounds of the present invention may be prepared by appropriately mixing a therapeutically effective amount of each contained drug with at least one or more pharmaceutically acceptable carriers, etc., according to methods known in the technical field of pharmaceutical formulation. The content of the compound of the present invention in the pharmaceutical composition varies depending on the dosage form, dosage, etc., but is, for example, 0.01 to 85% by weight based on the total weight of the composition.

[0029] Dosage forms of the pharmaceutical composition containing the compound of the present invention include oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions, and suspensions, and parenteral preparations such as topical preparations, suppositories, injections, eye drops, nasal preparations, and pulmonary preparations such as inhalants. Inhalation capsules are also possible, and for example, inhalation capsules can be used as inhalants using a dedicated device.

[0030] Pharmaceutically acceptable carriers include various organic or inorganic carrier substances commonly used as formulation materials, such as excipients, disintegrants, binders, fluidizing agents, lubricants, etc. in solid preparations, solvents, solubilizing agents, suspending agents, isotonicity agents, buffers, soothing agents, surfactants, pH adjusters, etc. in liquid preparations, and bases, emulsifiers, wetting agents, stabilizers, dispersants, plasticizers, pH adjusters, absorption enhancers, gelling agents, preservatives, fillers, solubilizers, solubilizing agents, suspending agents, etc. in semi-solid preparations. Furthermore, additives such as preservatives, antioxidants, colorants, sweeteners, etc. may be added as necessary.

[0031] Examples of excipients include lactose, sucrose, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carmellose, carmellose calcium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and gum arabic. Examples of disintegrants include carmellose, carmellose calcium, carmellose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, hydroxypropylmethyl cellulose, and crystalline cellulose. Examples of binders include hydroxypropyl cellulose, hydroxypropylmethyl cellulose, povidone, crystalline cellulose, sucrose, dextrin, starch, gelatin, carmellose sodium, and gum arabic. Examples of the fluidizing agent include light anhydrous silicic acid and magnesium stearate. Lubricants include, for example, magnesium stearate, calcium stearate, and talc. Examples of solvents include purified water, ethanol, propylene glycol, macrogol, sesame oil, corn oil, and olive oil. Examples of solubilizing agents include propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, and sodium citrate. Suspending agents include, for example, benzalkonium chloride, carmellose, hydroxypropyl cellulose, propylene glycol, povidone, methylcellulose, and glyceryl monostearate. Examples of isotonic agents include glucose, D-sorbitol, sodium chloride, and D-mannitol. Examples of buffering agents include sodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate. An example of a soothing agent is benzyl alcohol. Examples of surfactants include polyoxyethylene hydrogenated castor oils such as polyoxyethylene hydrogenated castor oil 60, polyethylene glycol monostearate, polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, alkyldiaminoethylglycine, alkylbenzenesulfonate, and benzethonium chloride. Examples of pH adjusters include hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, sodium hydrogen carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, monoethanolamine, and triethanolamine. Examples of bases include water, animal and vegetable oils (olive oil, corn oil, peanut oil, sesame oil, castor oil, etc.), lower alcohols (ethanol, propanol, propylene glycol, 1,3-butylene glycol, phenol, etc.), higher fatty acids and their esters, waxes, higher alcohols, polyhydric alcohols, hydrocarbons (white petrolatum, liquid paraffin, paraffin, etc.), hydrophilic petrolatum, purified lanolin, absorbent ointment, hydrous lanolin, hydrophilic ointment, starch, pullulan, gum arabic, tragacanth gum, gelatin, dextran, cellulose derivatives (methylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, etc.), synthetic polymers (carboxyvinyl polymer, sodium polyacrylate, polyvinyl alcohol, polyvinylpyrrolidone, etc.), propylene glycol, macrogols (macrogol 200 to 600, etc.), and combinations of two or more thereof. Examples of preservatives include ethyl parahydroxybenzoate, chlorobutanol, benzyl alcohol, sodium dehydroacetate, sorbic acid, and sodium edetate. Antioxidants include, for example, sodium sulfite and ascorbic acid. Examples of coloring agents include food dyes (food red No. 2 or No. 3, food yellow No. 4 or No. 5, etc.), and β-carotene. Examples of sweeteners include sodium saccharin, dipotassium glycyrrhizinate, and aspartame.

[0032] When the inhalant is an aerosol, it can be prepared using a propellant selected as needed from, for example, 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, and the like. Capsules for inhalation can be prepared using excipients selected as needed, such as lactose anhydrous and magnesium stearate.

[0033] The compound of the present invention may be used in combination with other drugs for the purpose of enhancing its effects and / or reducing side effects, etc. When the compound of the present invention is used in combination with other drugs, the compound of the present invention and the other drugs may be formulated as separate preparations and administered to a subject in any order, or may be administered together as a single combined preparation. Examples of other drugs that can be used in combination with the compound of the present invention include the following drugs. For example, the compound of the present invention can be used in combination with one or more drugs selected from the following drugs. Inhaled corticosteroids (ICS): for example, ciclesonide, beclomethasone propionate, fluticasone propionate, fluticasone furoate, budesonide, and mometasone furoate; Long-acting beta2 agonists (LABAs): for example, salmeterol xinafoate, formoterol fumarate hydrate, vilanterol triphenylacetate, indacaterol acetate, indacaterol maleate, and olodaterol hydrochloride; Long-acting muscarinic antagonists (LAMAs): for example, tiotropium bromide hydrate, umeclidinium bromide, glycopyrronium bromide, and aclidinium bromide; Leukotriene receptor antagonists (LTRAs): such as pranlukast hydrate, and montelukast sodium; Short-acting β2 agonists (SABAs): for example, procaterol hydrochloride hydrate, and salbutamol sulfate; Short-acting muscarinic antagonist (SAMA): e.g., ipratropium bromide hydrate; Biologics: for example, omalizumab (anti-IgE antibody), mepolizumab (anti-IL-5 antibody), benralizumab (anti-IL-5Rα antibody), dupilumab (anti-IL-4Rα antibody), and tezepelumab (anti-TSLP antibody); Theophylline.

[0034] In some embodiments, the compounds of the present invention may be used in combination with one or more of the following agents to treat or prevent severe asthma or steroid-resistant asthma: Inhaled corticosteroids (ICS): for example, ciclesonide, beclomethasone propionate, fluticasone propionate, fluticasone furoate, budesonide, and mometasone furoate; Long-acting beta2 agonists (LABAs): for example, salmeterol xinafoate, formoterol fumarate hydrate, vilanterol triphenylacetate, and indacaterol acetate; Long-acting muscarinic antagonists (LAMAs): for example, tiotropium bromide hydrate, umeclidinium bromide, and glycopyrronium bromide; Leukotriene receptor antagonists (LTRAs): such as pranlukast hydrate, and montelukast sodium; Short-acting β2 agonists (SABAs): for example, procaterol hydrochloride hydrate, and salbutamol sulfate; Short-acting muscarinic antagonist (SAMA): e.g., ipratropium bromide hydrate; Biologics: for example, omalizumab (anti-IgE antibody), mepolizumab (anti-IL-5 antibody), benralizumab (anti-IL-5Rα antibody), dupilumab (anti-IL-4Rα antibody), and tezepelumab (anti-TSLP antibody); Theophylline.

[0035] In some embodiments, for the treatment or prevention of chronic obstructive pulmonary disease, the compounds of the present invention may be used in combination with one or more of the following agents: Inhaled corticosteroids (ICS): for example, fluticasone propionate, fluticasone furoate, and budesonide; Long-acting beta2 agonists (LABAs): for example, salmeterol xinafoate, formoterol fumarate hydrate, vilanterol triphenylacetate, indacaterol maleate, and olodaterol hydrochloride; Long-acting muscarinic antagonists (LAMAs): for example, tiotropium bromide hydrate, umeclidinium bromide, glycopyrronium bromide, and aclidinium bromide; Leukotriene receptor antagonists (LTRAs): such as pranlukast hydrate, and montelukast sodium; Short-acting β2 agonists (SABAs): for example, procaterol hydrochloride hydrate, and salbutamol sulfate; Short-acting muscarinic antagonist (SAMA): e.g., ipratropium bromide hydrate; Theophylline.

[0036] In some embodiments, the compounds of the present invention are used as the sole active ingredient for the treatment or prevention of severe asthma, steroid-resistant asthma, or chronic obstructive pulmonary disease.

[0037] In some embodiments, compositions containing a compound of the present invention as the sole active ingredient are provided.

[0038] In certain embodiments, the compounds of the present invention may be provided in the form of kits (e.g., administration, treatment, and / or prevention kits), packages (e.g., wrapping), and pharmaceutical sets (and / or containers) containing the compounds of the present invention along with written material describing that the compounds can or should be used for treatment and / or prevention. Such kits, packages, and pharmaceutical sets may include one or more containers filled with the compounds of the present invention and other pharmaceuticals or drugs (or ingredients). Examples of such kits, packages, and pharmaceutical sets include commercial kits, commercial packages, and commercial pharmaceutical sets suitable for the treatment and / or prevention of a target disease. The written material included in such kits, packages, and pharmaceutical sets may include notices or inserts in the form mandated by a governmental agency regulating the manufacture, use, or sale of pharmaceutical or biological products, indicating the agency's approval of the manufacture, use, or sale of the product for administration to humans. The above kits, packages, and pharmaceutical sets include packaged products, and may also include structures configured for appropriate administration steps, or structures configured to achieve more desirable medical treatment and / or prevention, including treatment and / or prevention of a target disease.

[0039] Asthma is a disease in which the airways become chronically inflamed and hypersensitive to various stimuli, resulting in attacks of symptoms such as difficulty breathing, coughing, and wheezing.

[0040] Chronic obstructive pulmonary disease (COPD) is a general term for diseases formerly known as chronic bronchitis and emphysema, and is thought to be caused by long-term inhalation of irritants. Unlike asthma, COPD is characterized by constant airflow obstruction and a progressive disease.

[0041] In the present disclosure, the "severity of asthma" can be determined by a specialist such as a physician in accordance with standard guidelines, etc. For example, the severity of asthma is determined based on the treatment required to maintain good asthma control for at least four weeks.

[0042] In the present disclosure, "good asthma control" may refer to a state that is judged to be "good asthma control" by a doctor or other specialist in accordance with standard guidelines, etc. For example, it may refer to a state in which there are no asthma symptoms, no use of exacerbation (attack) medications, no activity restrictions including exercise, no exacerbations, and respiratory function (forced expiratory volume in 1 second (FEV1)) maintained at 80% or more of the predicted value or personal best value. Alternatively, it may refer to a state in which the Asthma Control Test (ACT) score is maintained at 20 or more.

[0043] In this disclosure, FEV1 may refer to the volume of air exhaled in 1 second from maximum expiration.

[0044] In the present disclosure, the predicted FEV1 value may refer to the predicted forced expiratory volume in one second of a healthy individual calculated in advance based on age, sex, and physique. Calculation methods include the Berglund formula (FEV1-B formula) and the formula (FEV1-J formula) of the Japanese Respiratory Society (JRS) Pulmonary Physiology Specialist Committee, and either method may be used. According to the Berglund formula, the predicted FEV1 value can be calculated by the following formula: Male: FEV1(L) = 3.44 x height (m) - 0.033 x age - 1.00 Female: FEV1(L) = 2.67 x height (m) - 0.027 x age - 0.54 According to the formula of the Japanese Respiratory Society (JRS) Pulmonary Physiology Specialist Committee, if the subject is 18 years of age or older, the predicted FEV1 value can be calculated using the following formula. Male: FEV1(L) = 0.036 x height (cm) - 0.028 x age - 1.178 Female: FEV1(L) = 0.022 x height (cm) - 0.022 x age - 0.005

[0045] In the present disclosure, the best personal FEV1 value may refer to the highest FEV1 value measured from the patient.

[0046] In this disclosure, the Asthma Control Test (ACT) may refer to a questionnaire developed to accurately grasp the current control state and severity of asthma. Specifically, for subjects aged 12 years or older, the following questionnaire may be used, and if the total score of questions 1 to 5 is "20 points or more," it can be determined that the asthma is well controlled. [Table 1]

[0047] In the present disclosure, improvement of disease symptoms may be comprehensively assessed by a specialist such as a physician, or may be determined based on changes in various disease parameters. For example, when evaluating the effect of the compound of the present invention, improvement may be determined based on the difference between the baseline value of a disease parameter of a subject before administration of the compound of the present invention and the value of the parameter at a specific time point after the start of treatment, where the difference is an increase or decrease depending on the type of parameter. Measurement of the parameter after initiation of treatment may be measured at about day 1, about day 2, about day 3, about day 4, about day 5, about day 6, about day 7, about day 8, about day 9, about day 10, about day 11, about day 12, about day 14, or at about week 3, about week 4, about week 5, about week 6, about week 7, about week 8, about week 9, about week 10, about week 11, about week 12, about week 13, about week 14, about week 15, about week 16, about week 17, about week 18, about week 19, about week 20, about week 21, about week 22, about week 23, about week 24, or more after the first treatment. In some embodiments, measurement of the parameter after initiation of treatment is measured at about day 5 after the first treatment.

[0048] In the present disclosure, various disease parameters for asthma and chronic obstructive pulmonary disease include, for example, blood eosinophil count, exhaled nitric oxide (FeNO), serum total IgE level, allergen-specific IgE antibody, blood neutrophil count, forced expiratory volume in one second (FEV1), asthma control test (ACT), blood IL-17A, blood IL-17F, blood IL-22, sputum IL-17A, sputum IL-17F, and / or sputum IL-22. These can be measured and / or evaluated by conventional methods.

[0049] In the present disclosure, the "baseline" of various disease parameters used to evaluate therapeutic effects can mean the value of the various disease parameters in a subject before administration of the compound of the present invention.

[0050] In the present disclosure, the "baseline" of a disease parameter described in relation to a disease phenotype may refer to the value of the disease parameter in a subject before administration of the compound of the present invention, but in cases where the subject has already been treated with another drug before receiving treatment with the compound of the present invention and the disease parameter may have changed from before the treatment, it may also refer to the value of various disease parameters in a subject before treatment with the compound of the present invention and the other drug.

[0051] In some embodiments, the compounds of the invention are used to lower exhaled nitric oxide (FeNO), for example, to less than 25 ppb, or to between 5 ppb and less than 25 ppb.

[0052] In some embodiments, the compounds of the invention are administered to reduce blood neutrophil counts, e.g., 5×10 9 cells / L, less than 6 × 10 9 cells / L, less than 7 × 10 9 cells / L, less than 1.8 × 10 9 More than 5 x 10 cells 9 cells / L, less than 1.8 × 10 9 More than 6 x 10 cells 9 cells / L or less than 1.8 × 10 9 More than 7 x 10 cells 9Used to reduce the concentration to less than cells / L.

[0053] In some embodiments, compounds of the invention are used to increase forced expiratory volume in 1 second (FEV1), for example, to 80% or greater of predicted or personal best.

[0054] In this disclosure, "mild asthma" refers to asthma that can be determined to be mild by a doctor in accordance with standard guidelines, etc. For example, it refers to asthma that can be well controlled with low-dose ICS, or low-dose ICS and LABA.

[0055] In this disclosure, "moderate asthma" refers to asthma that can be determined as moderate by a doctor in accordance with standard guidelines, etc. For example, it refers to asthma that can be well controlled with the addition of a LAMA and / or LTRA to a medium-dose ICS and a LABA or a low-dose ICS and a LABA.

[0056] In this disclosure, "severe asthma" refers to asthma that can be determined to be severe by a physician in accordance with standard guidelines. For example, it refers to asthma that can be well controlled by combining high-dose ICS and LABA with multiple other medications (e.g., LAMA, LTRA, theophylline), or asthma that cannot be well controlled even with these. In addition, "severe asthma" in this disclosure is sometimes referred to as "refractory asthma."

[0057] In the present disclosure, low-dose ICS, medium-dose ICS, and high-dose ICS can be classified based on conventional criteria. For example, if the subject is an adult, they can be classified based on the table below. [Table 2]

[0058] In the present disclosure, "steroid-resistant asthma" refers to asthma in which steroids do not improve asthma symptoms. For example, even if asthma is determined to be mild or moderate asthma, if ICS does not improve the symptoms, the asthma may be steroid-resistant asthma. The compounds of the present invention may be useful for steroid-resistant asthma and may improve asthma symptoms without the administration of ICS. In some embodiments, steroid-resistant asthma includes asthma that is inadequately controlled by administration of medium- to high-dose ICS alone or in combination with other medications (e.g., LABA, LAMA, LTRA, theophylline, etc.). In some embodiments, steroid-resistant asthma includes asthma that is inadequately controlled with medium- to high-dose ICS in combination with a LABA, an LTRA, and / or a sustained-release theophylline formulation and experiences two or more exacerbations per year.

[0059] In the present disclosure, "exacerbation" may refer to a case where asthma symptoms correspond to at least one of the following (1) to (3): (1) When oral or systemic steroids are administered (2) If you visit an emergency room (3) If you are hospitalized

[0060] In some embodiments, the compounds of the invention are used to treat or prevent severe asthma associated with non-type 2 inflammation or steroid-resistant asthma.

[0061] In some embodiments, the compounds of the present invention are used to treat or prevent chronic obstructive pulmonary disease associated with non-type 2 inflammation.

[0062] Type 2 inflammation is inflammation involving Th2 cells and / or type 2 innate lymphoid cells (ILC2s), whereas non-type 2 inflammation refers to inflammation in which Th2 cells and / or ILC2s are not clearly involved. Examples of non-type 2 inflammation include elevated blood neutrophil counts (e.g., baseline blood neutrophil counts of 5 × 10 9 Cells / L or more, 6×10 9cells / L or more, or 7 × 10 9 Examples of non-type 2 inflammation include elevated blood levels of IL-17A, IL-17F, and / or IL-22, for example, when the blood concentrations of these cytokines are higher than those of healthy subjects. Examples of non-type 2 inflammation include elevated neutrophil counts in sputum, for example, when the proportion of neutrophils in sputum is higher than that of healthy subjects. Examples of non-type 2 inflammation include elevated IL-17A, IL-17F, and / or IL-22 in sputum, for example, when the sputum concentrations of these cytokines are higher than those of healthy subjects.

[0063] In the present disclosure, a "healthy subject" refers to a subject in whom no symptoms or signs of a disease are observed. The "healthy subject concentration" of a disease parameter can be determined by a conventional method, for example, based on a sufficient number of samples from healthy subjects, for example, 100 or more, 150 or more, or 200 or more.

[0064] Asthma with non-type 2 inflammation may also be associated with type 2 inflammation, and chronic obstructive pulmonary disease with non-type 2 inflammation may also be associated with type 2 inflammation. In some embodiments, the compounds of the present invention are used to treat or prevent severe asthma associated with non-type 2 inflammation and type 2 inflammation or steroid-resistant asthma. In some embodiments, the compounds of the present invention are used to treat or prevent chronic obstructive pulmonary disease associated with non-type 2 inflammation and type 2 inflammation. Biomarkers of type 2 inflammation include blood eosinophil count, exhaled nitric oxide (FeNO), serum total IgE levels, and allergen-specific IgE antibodies. At least one of these biomarkers can be used to determine whether a patient has type 2 inflammation.

[0065] In some embodiments, the compounds of the invention are used to treat or prevent severe or steroid-resistant asthma that is not accompanied by elevated blood eosinophil counts (e.g., the subject has a baseline blood eosinophil count of less than 300 cells / μL, less than 150 cells / μL, greater than or equal to 50 cells / μL but less than 300 cells / μL, or greater than or equal to 50 cells / μL but less than 150 cells / μL).

[0066] In some embodiments, the compounds of the invention are used to treat or prevent chronic obstructive pulmonary disease that is not accompanied by an elevated blood eosinophil count (e.g., the subject has a baseline blood eosinophil count of less than 300 cells / μL, less than 150 cells / μL, at least 50 cells / μL but less than 300 cells / μL, or at least 50 cells / μL but less than 150 cells / μL).

[0067] In some embodiments, the compounds of the invention are administered to subjects with a baseline blood eosinophil count of less than 300 cells / μL, less than 150 cells / μL, at least 50 cells / μL but less than 300 cells / μL, or at least 50 cells / μL but less than 150 cells / μL.

[0068] In some embodiments, the compounds of the invention are used to treat or prevent Th17 cell-mediated severe asthma or steroid-resistant asthma.

[0069] In the present disclosure, Th17 cell-mediated severe asthma or steroid-resistant asthma includes, for example, severe asthma or steroid-resistant asthma accompanied by neutrophilic airway inflammation, increased mucus production, and / or airway remodeling due to Th17-associated cytokines (e.g., IL-17A, IL-17F, IL-22) produced by Th17 cells.

[0070] In some embodiments, the compounds of the invention are used to treat or prevent Th17 cell-mediated chronic obstructive pulmonary disease.

[0071] The determination of whether or not the asthma is Th17 cell-mediated severe asthma or steroid-resistant asthma, and whether or not the asthma is Th17 cell-mediated chronic obstructive pulmonary disease, is not particularly limited. For example, if an increase in the blood concentration of at least one Th17-associated cytokine (e.g., IL-17A, IL-17F, IL-22) (e.g., higher than that in healthy individuals) is observed, the condition can be determined to be Th17 cell-mediated. Furthermore, since these Th17-associated cytokines induce neutrophils, an increase in blood neutrophils (e.g., baseline blood neutrophil count of 5×10 9 Cells / L or more, 6×10 9 Cells / L or more, 7×10 9 Cells / L or more, 5×10 9 cells / L or more 11×10 9 cells / L, less than 6 × 10 9 cells / L or more 11×10 9 cells / L or less than 7 × 10 9 cells / L or more 11×10 9 Cases involving pulmonary embolism (<100 cells / L) may also be considered Th17 cell-mediated asthma or chronic obstructive pulmonary disease.

[0072] In some embodiments, the compounds of the invention may be used to increase blood neutrophil counts (e.g., to increase blood neutrophil counts above 5×10 9 Cells / L or more, 6×10 9 Cells / L or more, 7×10 9 Cells / L or more, 5×10 9 cells / L or more 11×10 9 cells / L, less than 6 × 10 9 cells / L or more 11×10 9 cells / L or less than 7 × 10 9 cells / L or more 11×10 9 It is used to treat or prevent severe asthma with pulmonary embolism (<100 cells / L) or steroid-resistant asthma.

[0073] In some embodiments, the compounds of the invention may be used to increase blood neutrophil counts (e.g., to increase blood neutrophil counts above 5×10 9 Cells / L or more, 6×10 9 Cells / L or more, 7×10 9 Cells / L or more, 5×109 cells / L or more 11×10 9 cells / L, less than 6 × 10 9 cells / L or more 11×10 9 cells / L or less than 7 × 10 9 cells / L or more 11×10 9 It is used to treat or prevent chronic obstructive pulmonary disease (COPD) associated with pulmonary embolism (<100 cells / L).

[0074] In some embodiments, the compounds of the present invention are useful in subjects with elevated blood neutrophil counts, e.g., subjects with a baseline blood neutrophil count of 5×10 9 Cells / L or more, 6×10 9 Cells / L or more, 7×10 9 Cells / L or more, 5×10 9 cells / L or more 11×10 9 cells / L, less than 6 × 10 9 cells / L or more 11×10 9 cells / L or less than 7 × 10 9 cells / L or more 11×10 9 The compound of the present invention is used for the treatment or prevention of severe asthma, steroid-resistant asthma, or chronic obstructive pulmonary disease in subjects with an elevated blood neutrophil count or less than 100 cells / L. For example, administering the compound of the present invention to a patient with mild or moderate asthma who has an elevated blood neutrophil count can prevent the asthma from becoming severe.

[0075] In some embodiments, the compounds of the present invention are used to treat or prevent severe asthma, steroid-resistant asthma, or chronic obstructive pulmonary disease in subjects with elevated sputum neutrophil counts (e.g., baseline values ​​are higher than those of healthy subjects). For example, administering the compounds of the present invention to subjects with mild or moderate asthma who have elevated sputum neutrophil counts can prevent the asthma from becoming severe.

[0076] In some embodiments, the compounds of the present invention are used to treat or prevent severe asthma, steroid-resistant asthma, or chronic obstructive pulmonary disease in subjects with elevated sputum levels of IL-17A, IL-17F, and / or IL-22 (e.g., elevated baseline levels compared to healthy subjects). For example, administering the compounds of the present invention to subjects with mild or moderate asthma who have elevated sputum levels of IL-17A, IL-17F, and / or IL-22 can prevent the asthma from becoming severe.

[0077] In some embodiments, the compounds of the invention are effective in treating patients with a baseline blood eosinophil count of less than 300 cells / μL, less than 150 cells / μL, greater than or equal to 50 cells / μL but less than 300 cells / μL, or greater than or equal to 50 cells / μL but less than 150 cells / μL, and a baseline blood neutrophil count of 5×10 9 Cells / L or more, 6×10 9 Cells / L or more, 7×10 9 Cells / L or more, 5×10 9 cells / L or more 11×10 9 cells / L, less than 6 × 10 9 cells / L or more 11×10 9 cells / L or less than 7 × 10 9 cells / L or more 11×10 9 for the treatment or prevention of severe asthma, steroid-resistant asthma, or chronic obstructive pulmonary disease in subjects with less than 100 cells / L.

[0078] In the present disclosure, treatment may include improvement of symptoms, suppression of disease progression, suppression of acute exacerbations, prevention of aggravation such as status asthmaticus, maintenance of remission, prevention of exacerbation, and prevention of recurrence. Treatment herein may also include improvement of various disease parameters of asthma and / or chronic obstructive pulmonary disease, such as blood eosinophil count, exhaled nitric oxide (FeNO), serum total IgE level, allergen-specific IgE antibody, blood neutrophil count, forced expiratory volume in 1 second (FEV1), asthma control test (ACT), blood IL-17A, blood IL-17F, blood IL-22, sputum IL-17A, sputum IL-17F, and / or sputum IL-22. In the present disclosure, prevention of severe asthma includes, for example, preventing mild or moderate asthma from worsening to severe asthma. In the present disclosure, prevention of steroid-resistant asthma includes, for example, preventing a patient with steroid-sensitive asthma from developing steroid-resistant asthma due to a decrease in steroid sensitivity. In the present disclosure, preventing chronic obstructive pulmonary disease includes, for example, preventing the onset of symptoms of chronic obstructive pulmonary disease.

[0079] In the present disclosure, a therapeutically effective amount refers to an amount of a compound of the present invention that may be effective in preventing or treating severe asthma, steroid-resistant asthma, or chronic obstructive pulmonary disease. [Example]

[0080] The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. The method for obtaining the compound of the present invention used here (hereinafter referred to as "Compound A") is shown below. Compound A: [ka] Obtained from Japan Tobacco Inc.

[0081] Evaluation of airway hyperresponsiveness in a mouse asthma model transfected with Th17 cells

[0082] [Test Example 1] Preparation of mouse CD4-positive naive T cells Spleens collected from female DO11.10 mice (12 weeks old, Jackson Laboratory) were placed on a 100 μm cell strainer and crushed with the rubber part of a syringe in ice-cold RPMI 1640 medium (Thermo Fisher Scientific). The spleen suspension was passed through the 100 μm cell strainer and collected in a 50 mL polypropylene tube. After further washing with ice-cold RPMI 1640 medium, the spleen was centrifuged (300 × g, 5 minutes, 4°C; the same centrifugation conditions were used below) to remove the supernatant. HLB solution (Immunobiology Laboratories) was added and the spleen was left to stand at room temperature for 1 minute. The hemolysis reaction was stopped with ice-cold RPMI 1640 medium, and the spleen was then passed through a 70 μm cell strainer and collected in a 50 mL polypropylene tube. The supernatant was removed by centrifugation, and the cells were resuspended in ice-cold RPMI 1640 medium containing 10% fetal bovine serum (FBS) and passed through a 40 μm cell strainer into a 50 mL polypropylene tube. After counting the number of viable cells, the supernatant was removed by centrifugation and the cells were resuspended at 2.5 × 10 in ice-cold MACS Buffer [0.5% bovine serum albumin (BSA) / Dulbecco's phosphate-buffered saline (DPBS), 2 mM ethylenediaminetetraacetic acid]. 8 The resulting suspension was prepared at 100 cells / mL. This was used as a splenocyte suspension. Naive CD4 + A CD4-positive naive T cell suspension was prepared from the splenocyte suspension using a T Cell Isolation Kit (MiliTeny Biotech Co., Ltd.).

[0083] [Test Example 2] Th17 cell differentiation and preparation of transfected cell suspension To prepare antigen-presenting cells, a portion of the splenocyte suspension prepared in Test Example 1 was used. The cells were cultured at 1 × 10 in a culture medium (Iscove's modified Dulbecco's medium containing 10% FBS, 2.5 μM 2-mercaptoethanol, 100 U / mL penicillin, and 100 mg / mL streptomycin). 7 After adding mitomycin C to a final concentration of 25 μg / mL, the cells were cultured at 37°C, 5% CO2 for 30 minutes. After washing twice with culture medium, the cells were used as an antigen-presenting cell suspension. 6cells / mL of CD4+ naive T cell suspension and 4 x 10 6 A suspension of antigen-presenting cells at 5 × 10 cells / mL was co-cultured for 3 days with a Th17 cell differentiation-inducing stimulus solution (Table 1). After further culturing for 3 days with an equal volume of the Th17 cell differentiation-inducing stimulus solution, the supernatant was removed by centrifugation and the cells were diluted to 5 × 10 cells / mL with cold DPBS. 6 This was used as the transfection cell suspension. [Table 3]

[0084] [Test Example 3] Preparation of Th17 cell-transferred asthma model On Day 1, female SCID mice (7 weeks old, Jackson Laboratory Japan) were anesthetized by intraperitoneal administration of 10 mL / kg of a triple anesthetic mixture (medetomidine hydrochloride, midazolam, and butorphanol tartrate). Under deep anesthesia, ovalbumin (OVA) was administered intratracheally at 50 μg / 50 μL / mouse. On Day 1, 5 × 10 6 The transfection cell suspension was adjusted to 1 × 10 cells / mL. 6 On days 2, 3, and 4, mice were anesthetized with a triple anesthetic mixture, and OVA was administered intratracheally at 50 μg / 50 μL / mouse.

[0085] [Test Example 4] Administration and evaluation of test substance According to the group composition in Table 2, the test substance was orally administered once daily from Day 1 to Day 4. The dose was calculated based on body weight on Day -1. On Day 1, the substance was orally administered before Th17 cell transfer, and on Days 2, 3, and 4, it was orally administered 2 hours before intratracheal OVA administration. On Day 5, methacholine-induced airway hyperresponsiveness was measured using a FlexiVent (emka). A triple anesthetic mixture was administered intraperitoneally at 10 mL / kg. After incision of the airway under deep anesthesia, a cannula was inserted into the airway and connected to the FlexiVent. Subsequently, gallamine (1 mg / kg) was administered intravenously at 5 mL / kg to suppress spontaneous breathing. After stable suppression of spontaneous breathing, the animals were sequentially inhaled with methacholine solutions (1.5625, 3.125, 6.25, 12.5, and 25 mg / mL) to measure airway hyperresponsiveness (lung resistance (RL) and dynamic lung compliance (Cdyn)). After measurement, the abdominal aorta and caudal vena cava were cut, and after confirming death by exsanguination, a syringe filled with 1 mL of 2% BSA / DPBS was attached to the cannula, and the lungs were lavaged to collect bronchoalveolar lavage fluid (BALF). This procedure was repeated twice more. The bronchoalveolar lavage fluid was centrifuged (190 × g, 5 min, 4°C), and the cell pellet was resuspended in 200 μL of 2% BSA / DPBS. The total white blood cell (WBC) count and inflammatory cell counts [macrophages (MONO), neutrophils (NEUT), lymphocytes (LYMPH), eosinophils (EO), and basophils (BASO)] in the resuspended samples were counted using a multiparameter automated hematology analyzer (Sysmex Corporation). Statistical analysis of airway hyperresponsiveness (RL and Cdyn) and total WBC and inflammatory cell counts in BALF was performed using a closed procedure. Statistical analysis of airway hyperresponsiveness was performed using the methacholine concentration of 6.25 mg / mL, which showed the greatest difference between the sham and vehicle groups and demonstrated the highest methacholine-induced airway hyperresponsiveness. Equality of variance was confirmed between the sham and vehicle groups using the F test. Student's t-test was used to confirm equality of variance, and the Aspin-Welch t-test was used to confirm unequal variance.If a statistically significant difference was observed between the Sham group and the Vehicle group, the equality of variance between the Vehicle group and the Compound A group was confirmed by Bartlett's test for equality of variance. If the variances were equal, Dunnett's multiple comparison was performed, and if the variances were unequal, Steel's multiple comparison was performed. The results of measuring RL at a methacholine concentration of 6.25 mg / mL are shown in Figure 1. The RL measured before administration of the methacholine solution was taken as the baseline (100%). The results of measuring Cdyn at a methacholine concentration of 6.25 mg / mL are shown in Figure 2. The measured value of Cdyn before administration of the methacholine solution was taken as the baseline (100%). The measurement results for BALF are shown in Table 3.

[0086] [Table 4]

[0087] [Table 5]

[0088] Regarding airway responsiveness to various concentrations of inhaled methacholine, the vehicle group showed a concentration-related increase in RL and a decrease in Cdyn compared with the sham group. Airway hyperresponsiveness to methacholine was nearly maximal at 6.25 mg / mL methacholine, which showed the largest difference between the sham and vehicle groups, but the DEX group showed no effect on RL or Cdyn. On the other hand, the 3 mg / kg and 30 mg / kg compound A groups significantly suppressed the increase in RL and the decrease in Cdn. These results indicate that compound A suppresses airway hyperresponsiveness to methacholine. In BALF analysis, the number of neutrophils in the vehicle group was dramatically increased compared to the number of eosinophils, indicating that this model exhibits neutrophilic inflammation. The number of neutrophils tended to decrease in the 30 mg / kg compound A administration group. These findings indicate that Compound A may be useful in treating or preventing severe asthma, steroid-resistant asthma, and chronic obstructive pulmonary disease. [Industrial Applicability]

[0089] The compounds of the present invention can be used as therapeutic or preventive agents for severe asthma, steroid-resistant asthma, and chronic obstructive pulmonary disease.

Claims

1. The following chemical structure: 【Chemistry 1】 10. A therapeutic or preventive agent for a disease selected from the group consisting of severe asthma, steroid-resistant asthma, and chronic obstructive pulmonary disease, comprising as an active ingredient a compound represented by the formula:

2. The therapeutic or prophylactic agent according to claim 1, wherein the disease is severe asthma or steroid-resistant asthma.

3. The therapeutic or preventive agent according to claim 2, wherein the severe asthma or steroid-resistant asthma is accompanied by non-type 2 inflammation.

4. 4. The therapeutic or prophylactic agent according to claim 2 or 3, wherein the severe asthma or steroid-resistant asthma is not accompanied by an increase in blood eosinophil count.

5. The therapeutic or prophylactic agent according to claim 4, wherein the blood eosinophil count is less than 300 cells / μL.

6. The therapeutic or prophylactic agent according to any one of claims 2 to 5, wherein the severe asthma or steroid-resistant asthma is mediated by Th17 cells.

7. The therapeutic or prophylactic agent according to claim 1, wherein the disease is chronic obstructive pulmonary disease.

8. The therapeutic or preventive agent according to claim 7, wherein the chronic obstructive pulmonary disease is accompanied by non-type 2 inflammation.

9. The therapeutic or preventive agent according to claim 7 or 8, wherein the chronic obstructive pulmonary disease is not accompanied by an increase in blood eosinophil count.

10. The therapeutic or prophylactic agent according to claim 9, wherein the blood eosinophil count is less than 300 cells / μL.

11. The therapeutic or prophylactic agent according to any one of claims 7 to 10, wherein the chronic obstructive pulmonary disease is mediated by Th17 cells.

12. The therapeutic or prophylactic agent according to any one of claims 1 to 11, wherein the disease is accompanied by an increase in blood neutrophil count.

13. The blood neutrophil count is 5 x 10 ９ The therapeutic or prophylactic agent according to claim 12, wherein the concentration is 1000 cells / L or more.

14. The therapeutic or prophylactic agent according to any one of claims 1 to 13, wherein the disease is accompanied by an increase in blood IL-17A, IL-17F, and / or IL-22.

15. The therapeutic or preventive agent according to any one of claims 1 to 14, wherein the disease is accompanied by an increase in the number of neutrophils in sputum.

16. The therapeutic or prophylactic agent according to any one of claims 1 to 15, wherein the disease is accompanied by an increase in IL-17A, IL-17F, and / or IL-22 in sputum.

17. The therapeutic or prophylactic agent according to any one of claims 1 to 16, for administration to a subject in whom an increase in blood neutrophil count has been observed.

18. The subject's blood neutrophil count is 5 x 10 ９ The therapeutic or prophylactic agent according to claim 17, wherein the concentration is 1000 cells / L or more.

19. The therapeutic or prophylactic agent according to any one of claims 1 to 18, for administration to a subject in whom increased levels of IL-17A, IL-17F, and / or IL-22 in the blood have been observed.

20. The therapeutic or prophylactic agent according to any one of claims 1 to 19, for administration to a subject in whom an increase in sputum neutrophil count has been observed.

21. The therapeutic or prophylactic agent according to any one of claims 1 to 20, for administration to a subject in whom increased levels of IL-17A, IL-17F, and / or IL-22 in sputum have been observed.

22. A therapeutically effective amount of the following chemical structure: 【Chemistry 2】 A method for treating or preventing a disease selected from the group consisting of severe asthma, steroid-resistant asthma, and chronic obstructive pulmonary disease, comprising administering to a subject a compound represented by the following formula (I):

23. 1. A compound having the following chemical structural formula: 【Transformation 3】 or a pharmaceutically acceptable salt thereof.

24. 1. A method for producing a medicament for treating or preventing a disease selected from the group consisting of severe asthma, steroid-resistant asthma, and chronic obstructive pulmonary disease, comprising administering to a patient having the following chemical structural formula: 【Chemistry 4】 or a pharmaceutically acceptable salt thereof.

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