(1R,3S)-3-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid and its derivatives for use in the treatment of respiratory tract diseases

Abstract

The present invention relates to (1R,3S)-3-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid, its pharmaceutically acceptable salts and co-crystals thereof for use in the treatment of airway diseases, such as, inter alia, allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, and allergic rhinitis, in subjects with elevated peripheral blood eosinophil levels, and pharmaceutical compositions comprising the compounds; use of the compounds for the manufacture of a medicament for the treatment of airway diseases, such as, inter alia, allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, and allergic rhinitis, in subjects with elevated peripheral blood eosinophil levels; and methods of treating airway diseases, such as, inter alia, allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, and allergic rhinitis, in subjects with elevated peripheral blood eosinophil levels by administering the compounds.

Description

[Technical Field]

[0001] The present invention relates to (1R,3S)-3-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid, its pharmaceutically acceptable salts and co-crystals thereof, and pharmaceutical compositions comprising said compounds for use in the treatment of airway diseases such as allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, and allergic rhinitis, among others, in subjects with elevated peripheral blood eosinophil levels.

[0002] Another object of the present invention is to provide a method for the treatment of diseases by administering a compound of formula (I) or a pharmaceutical composition or combination preparation comprising a compound of formula (I) to a subject having elevated peripheral blood eosinophil levels. [Background technology]

[0003] Eosinophilia is a disorder that can occur in association with airway diseases such as asthma, COPD, and allergic rhinitis. Many of these diseases are treated with corticosteroids (topical or systemic), which target both eosinophils and other immune cells, such as lymphocytes, which may be the trigger cell population (Kuang, F. L, Approach to Patients with Eosinophilia, Med Clin N Am 104 (2020) 1-14).

[0004] In particular, blood eosinophils have been widely described as a potential surrogate biomarker of airway inflammation, a hallmark of asthma and COPD phenotypes in certain subjects. Recently, contemporaneous measurement of eosinophils in peripheral blood cells has been explored as a surrogate marker of bronchial and / or pulmonary inflammation. Most studies have established a blood eosinophil cutoff value of 300 cells / μL for classifying asthma patients as having eosinophilic asthma (Kostikas, K et al., Blood Eosinophils as Biomarkers to Drive Treatment Choices in Asthma and COPD, Curr Drug Targets. 2018 Dec; 19(16): 1882-1896).

[0005] Currently, eosinophil-targeting therapies have been shown to reduce disease frailty, and some have received national approval for severe eosinophilic asthma and eosinophilic granulomatosis with polyangiitis. These therapies involve the use of biologics such as monoclonal antibodies. Few small molecule drugs have been evaluated for various eosinophil-related conditions (Klion, A. D. et al., Contributions of Eosinophils to Human Health and Disease, Annu. Rev. Pathol. Mech. Dis. 2020.15:179-209).

[0006] Although eosinophils vary widely, blood eosinophilia secondary to atopy is common due to the high prevalence of atopy in the general population. Tissue eosinophils are thought to contribute to end-organ fibrosis and damage during uncontrolled atopic inflammation in diseases such as asthma and eosinophilic gastrointestinal disorders. Mild to moderate peripheral eosinophilia is a common finding in atopic diseases, but eosinophils in atopic disorders typically do not infiltrate tissues other than those primarily affected by the disorder. There is growing evidence that peripheral blood eosinophil counts may be used as a biomarker that may correlate with disease activity in some atopic disorders (Cafone, J et al., The Role of Eosinophils in Immunotherapy, Current Allergy and Asthma Reports (2020) 20:1).

[0007] asthma Asthma is a heterogeneous disease typically characterized by chronic airway inflammation. It is defined by a history of respiratory symptoms, including wheezing, shortness of breath, chest tightness, and cough, that vary in time and intensity, along with fluctuations in expiratory flow limitation. These variations are often triggered by factors such as exposure to allergens or irritants, viral respiratory infections, exercise, or weather changes.

[0008] An alternative treatment for allergic asthma is based on specific immunotherapy, i.e., repeated administration of increasing doses of an allergen induces hyposensitivity and thus reduces symptoms upon re-exposure to the allergen, but the efficacy of immunotherapy is still limited and is known to vary greatly between patients.

[0009] Yet another treatment for allergic asthma involves the use of biologics, such as monoclonal antibodies, which are most often administered parenterally / intravenously. Because antibodies themselves are proteins, their administration can cause allergic reactions or other side effects related to the antigens they target. Additionally, they are expensive, complex to administer and manage, and not widely used worldwide.

[0010] One antibody recently approved for the treatment of uncontrolled asthma is reslizumab, an anti-IL5 antibody for the treatment of moderate to severe eosinophilic asthma (usually treated with corticosteroids or other medications). Reslizumab blocks the proliferation and / or production of eosinophils. Patent application WO2016 / 040007A1 discloses treatment for asthma patients with elevated blood eosinophil levels (>400 cells / μL) and demonstrated that the efficacy of this antibody was related to baseline blood eosinophil levels (no statistically significant efficacy was observed below 400 cells / μL).

[0011] Another recently approved antibody is dupilumab, an interleukin-4 (IL-4) receptor α antagonist. It is a human monoclonal antibody of the immunoglobulin G4 subclass that inhibits IL-4 and interleukin-13 (IL-13) signaling by specifically binding to the IL-4 receptor α subunit shared by the IL-4 and IL-13 receptor complexes. However, unlike other eosinophil-targeting biologics, dupilumab's efficacy was observed not only in the subgroup of patients with eosinophil counts of ≥300 cells / μL, but also in the overall population and in the subgroup with eosinophil counts <300 cells / μL, with numerical and / or significant reductions in severe exacerbations, FEV1, and improvements in patient-reported outcomes (Kostikas K. et al., Blood Eosinophils as Biomarkers to Drive Treatment Choices in Asthma and COPD, Curr Drug Targets. 2018;19(16):1882-1896).

[0012] Regarding small molecule compounds, theophylline, a xanthine derivative, has been used to treat asthma for over 60 years; however, significant side effects have been observed at doses required for bronchodilation. Theophylline is a weak, nonselective adenosine antagonist and also an inhibitor of various phosphodiesterase families. Therefore, theophylline exhibits a narrow therapeutic index, and drug concentrations must be closely monitored (Scheiff AB et al., 2-Amino-5-benzoyl-4-phenylthiazoles: Development of potent and selective adenosine A1 receptor antagonists, Bioorg. Med. Chem. 18 (2010) 2195-2203).

[0013] Several adenosine A1 receptor antagonist compounds are selective, non-xanthine derivatives and have reached the stage of clinical development in humans for indications such as heart failure and renal insufficiency, but none have demonstrated therapeutic efficacy. Other compounds in this class have been proposed for other indications, such as liver fibrosis / steatosis, sepsis, neurodegenerative diseases, and movement disorders (A1). 2A / A1 dual activity antagonistic compound), but has not yet reached the clinical development stage (Giorg I et al, Adenosine A1 modulators: a patent update (2008 to present), Expert Opin. Ther. Patents (2013) 23(9)).

[0014] L-97-1 is an adenosine A1 receptor antagonist described several years ago but has not yet reached clinical development. The compound was studied in an allergic rabbit asthma model to evaluate early and late allergic responses after house dust mite (HDM) challenge, as well as bronchial hyperresponsiveness to histamine and airway inflammation. In this study, L-97-1 reduced the number of eosinophils in the animals' bronchoalveolar lavage fluid (BALF) only up to 6 hours after HDM challenge (Nadeem A. et al., Adenosine A1 receptor antagonist versus montelukast on airway reactivity and inflammation, European Journal of Pharmacology 551 (2006) 116-124). This reference does not disclose or suggest the potential of L-97-1 to reduce blood eosinophil levels.

[0015] COPD Other chronic lung diseases also present that may accompany eosinophilic airway inflammation, e.g., in some patients with chronic obstructive pulmonary disease (COPD). Two observational studies have shown that blood eosinophil count is a significant biomarker of COPD exacerbations, with elevated sputum eosinophil counts and a positive response to prednisolone (Pavord, ID, Blood Eosinophil-Directed Management of Airway Disease: The Past, Present and Future, AJRCCM Articles in Press. Published May 01, 2020).

[0016] International diagnostic and treatment guidelines for chronic obstructive pulmonary disease (COPD) do not incorporate recommendations for the treatment of allergies. This lack of recommendation is primarily due to insufficient knowledge about the role of atopy in the pathogenesis and outcome of COPD. However, it has been reported that approximately 18% of COPD patients have atopy, and atopy is a potential risk factor for the development of COPD. Therefore, there is growing interest in discovering the relationship between atopy and COPD and its impact on the outcome of this disease.

[0017] The European Respiratory Society on Chronic Obstructive Pulmonary Disease (EUROSCOP) conducted a large-scale, multicenter study to evaluate the effect of three years of inhaled budesonide treatment on pulmonary function decline in smoking COPD patients and concluded that atopy is present in COPD patients and is associated with a high prevalence and incidence of respiratory symptoms. This study points out that atopic status should not be forgotten in routine COPD workup (Fattahi, F. et al., Atopy is a risk factor for respiratory symptoms in COPD patients: results from the EUROSCOP study, Respiratory Research 2013, 14:10).

[0018] Patent application US2015 / 0104447A1 discloses benralizumab, a humanized, afucosylated monoclonal antibody targeting the IL5-receptor α-chain, which depletes eosinophils by antibody-dependent, cell-mediated cytotoxicity via activated natural killer cell-induced apoptosis of eosinophils.

[0019] The first trial of the anti-IL5R antibody benralizumab in COPD patients with high baseline sputum eosinophils (≥3%) showed numerical improvements in exacerbation rate, SGRQ-C and Self-Report Chronic Respiratory Questionnaire (CRQ-SAS) scores, and FEV1, but these improvements were not statistically significant (Kostikas K. et al., Blood Eosinophils as Biomarkers to Drive Treatment Choices in Asthma and COPD, Current Drug Targets, 2018, 19, 1882-1896).

[0020] Similarly, mepolizumab, another anti-IL-5 monoclonal antibody, significantly reduced sputum and blood eosinophil counts compared with placebo in COPD patients with high baseline eosinophil counts, but again, these differences did not translate into significant between-group differences in lung function parameters, exacerbation rates, and health-related quality of life (Kostikas K. et al, Blood Eosinophils as Biomarkers to Drive Treatment Choices in Asthma and COPD, Current Drug Targets, 2018, 19, 1882-1896).

[0021] Among small molecule compounds, roflumilast, a long-acting oral PDE-4 inhibitor, has shown significant effects on inflammation, airway remodeling, and bronchoconstriction caused by eosinophils and neutrophils, and has shown good results in the treatment of patients with COPD and asthma (Zhang X. et al., Pharmacological mechanism of roflumilast in the treatment of asthma-COPD overlap, Drug Des Devel Ther. 2018; 12: 2371-2379).

[0022] In a study to evaluate the anti-inflammatory potential of oral roflumilast, antigen-induced cellular infiltration, total protein, and TNFα concentrations were measured in the bronchoalveolar lavage fluid (BALF) of Brown Norway rats. Roflumilast suppressed eosinophilia in rat bronchoalveolar lavage fluid (BALF) and abolished lipopolysaccharide (LPS)-induced circulating TNFα, suggesting that it may be a potential new drug for the treatment of asthma and chronic obstructive pulmonary disease. However, even in this case, there was no indication that roflumilast could reduce blood eosinophil levels (BUNDSCHUH DS et al., In Vivo Efficacy in Airway Disease Models of Roflumilast, a Novel Orally Active PDE4 Inhibitor, The Journal of Pharmacology and Experimental Therapeutics (JPET) 297:280-290, 2001).

[0023] However, the ROBERT (Roflumilast Biopsy European Research Trial; NCT01509677) trial showed a significant reduction in eosinophils in sputum and bronchial biopsy samples, but not in blood eosinophils, providing evidence that it acts solely through modulation of lung eosinophil counts (Rabe KF et al, Anti-inflammatory effects of roflumilast in chronic obstructive pulmonary disease (ROBERT): a 16-week, randomized, placebo-controlled trial, The Lancet: Respiratory Medicine, Volume 6, Issue 11, November 2018, Pages 827-836).

[0024] IPF Idiopathic pulmonary fibrosis (IPF) encompasses a group of interstitial lung diseases and is a significant cause of death worldwide. Few studies have been published on the association between sputum eosinophilia and idiopathic pulmonary fibrosis. One study demonstrated that the mean sputum eosinophil percentage was higher in IPF patients (2.1%) compared with normal controls (0.3%; p<0.001), but was comparable to levels in COPD patients. Furthermore, eosinophil cationic protein (EOP) was found to be higher in IPF patients (1.1 mg / ml) than normal controls (0.2 mg / ml), and even higher than COPD patients (0.4 mg / ml), suggesting active inflammation and suggesting a possible relationship between eosinophilic inflammation and cough in IPF. Other studies have reported that eosinophils are important in advanced IPF and correlate with adverse outcomes (Eltboli O. et al, Eosinophils as diagnostic tools in chronic lung disease, Expert Rev. Respir. Med. 7(1), (2013)).

[0025] Allergic rhinitis Allergic rhinitis can present with mild peripheral eosinophilia. In this cohort, peripheral eosinophils were superior to total IgE levels in predicting mucosal disease, with a positive predictive value of 89% and a negative predictive value of 99% (Cafone, J et al, The Role of Eosinophils in Immunotherapy, Current Allergy and Asthma Reports (2020) 20:1).

[0026] obstructive sleep apnea Obstructive sleep apnea (OSA) refers to repeated episodes of breathing cessation during sleep despite continuous breathing efforts. Clinically, OSA is characterized by excessive daytime sleepiness, disruptive snoring, and nocturnal hypoxemia. This condition is a common sleep-disordered breathing disorder affecting approximately 4.0% of middle-aged men and 2.0% of middle-aged women in developed countries. Numerous studies have shown that OSA is a significant cause of morbidity and mortality and is associated with serious health consequences, primarily affecting the cardiovascular and cerebrovascular systems. Research has shown that inflammation associated with allergic rhinitis may exacerbate the severity of OSA (Gadi, G et al., The prevalence of allergic rhinitis and atopic markers in obstructive sleep apnea, Journal of Epidemiology and Global Health, Volume 7, Issue 1, March 2017, Pages 37-44).

[0027] There is an unmet medical need to obtain an effective and safe treatment for airway diseases in subjects with elevated peripheral blood eosinophil levels, which ensures control of these diseases in this group of subjects, improves the clinical condition and quality of life of these patients, all with a simple administration procedure. For this purpose, oral treatment and a minimal daily dose would be a desirable option.

[0028] WO2009 / 044250A1 discloses a group of 5-cyanothiazol-2-ylacetamide derivatives as adenosine A1 receptor antagonists and their use in the treatment of conditions or diseases that can be improved by antagonizing said adenosine receptors. The treatment of airway diseases in subjects with elevated levels of eosinophils in the peripheral blood is not specifically mentioned in WO2009 / 044250A1.

[0029] In summary, experts believe that biologics and small molecules have strong and distinct biochemical, pharmacological, and clinically effective, as well as therapeutic performance-limiting, characteristics that, when used together, can create powerful combinations.

[0030] Furthermore, patient stratification is recognized as a prerequisite for the success of targeted approaches, as some compounds have failed in later development stages, likely due to a lack of phenotype-based patient selection (Franziska Roth-Walter et al, Comparing biologicals and small molecule drug therapies for chronic respiratory diseases: An EAACI Taskforce on Immunopharmacology position paper, Allergy. 2019;74:432-448).

[0031] Analyzing all of the above, it is impossible to predict the effect of small molecules on the mechanism of action of specific targets in complex diseases such as asthma and COPD. Results obtained in animal models are inconclusive and cannot predict efficacy in human populations, let alone provide information for patient stratification, which is necessary to avoid inappropriate or ineffective treatments.

[0032] Currently, no selective adenosine A1 receptor ligands have been approved for the market. Furthermore, none have been tested in human clinical trials for the treatment of airway diseases, such as allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, and allergic rhinitis. However, several adenosine A1 antagonists, such as rolofylline (CAS No. 136199-02-5), tonapophilline (CAS No. 340021-17-2), and adentri (CAS No. 166374-48-7), have been tested in humans for the treatment of cardiovascular and renal conditions, such as chronic or acute heart failure and renal failure. To the best of our knowledge, there have been no reports demonstrating the effects or side effects of treatment with these adenosine A1 antagonists on blood eosinophils.

[0033] There is no precedent in the current state of the art to suggest that treatment with an adenosine A1 antagonist, let alone a compound of formula (I), will significantly reduce blood eosinophil counts or significantly improve lung function in human subjects with airway diseases such as asthma who have peripheral blood eosinophil levels of 300 cells / μL or greater.

[0034] There is a precedent that treatment with the adenosine A1 antagonist L-97-1 reduced eosinophils in bronchoalveolar lavage fluid (BALF) in allergic rabbits (Nadeem A. et al, Adenosine A1 receptor antagonist versus montelukast on airway reactivity and inflammation, European Journal of Pharmacology 551 (2006) 116-124). However, a study with roflumilast (Rabe KF et al, Anti-influmatory effects of roflumilast in chronic obstructive pulmonary disease (ROBERT): a 16-week, randomized, placebo-controlled trial, The Lancet: Respiratory Medicine, Volume 6, Issue 11, November 2018, Pages 827-836) clearly demonstrated that a reduction in BALF eosinophils does not necessarily translate into a reduction in blood eosinophils.

[0035] Furthermore, Nadeem A. et al. only demonstrated that a specific adenosine A1 antagonist (L-97-1) was able to reduce eosinophil counts in bronchoalveolar lavage fluid (BALF), and there is no reason for experts to believe that the effects of L-97-1 can be extrapolated to the entire class of adenosine A1 antagonists. In fact, the same paper reported that montelukast, a leukotriene receptor antagonist rather than an adenosine A1 antagonist, also had the ability to reduce eosinophil counts in BALF, indicating that this ability to reduce eosinophil counts in bronchoalveolar lavage fluid is not necessarily related to the adenosine A1 antagonist.

[0036] The inventors of the present patent application have studied the efficacy of Compound (I) in treating airway diseases, particularly in patients with mild to moderate allergic asthma, and have shown that in a 15-day study, human subjects treated with Compound (I) experienced a significant reduction in peripheral blood eosinophil counts, as well as a significant decrease in trough forced expiratory volume (trough FEV1) and corresponding FEV1 AUC 30min-23h 30min An unexpected finding was the significant increase in eosinophil counts (EOCs) associated with improvements in Asthma Control Questionnaire-7 (ACQ-7) scores. This improvement was particularly pronounced in patients with elevated peripheral blood eosinophil levels, particularly those with eosinophil levels of 300 cells / μL.

[0037] Therefore, there is growing interest in developing once-daily oral medications to further simplify treatment regimens for airway diseases and improve patient compliance.

[0038] The inventors of the present invention have now surprisingly discovered that a compound of formula (I) [ka] They have found that (1R,3S)-3-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid is particularly effective in treating airway diseases, and results in a significant reduction in peripheral blood eosinophil counts in human subjects with high peripheral blood eosinophil levels before treatment, particularly peripheral blood eosinophil levels of 300 cells / μL.

[0039] In one aspect, the present invention provides (1R,3S)-3-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid of formula (I), its pharmaceutically acceptable salts, and cocrystals thereof, for use in treating airway diseases in human subjects with pre-treatment peripheral blood eosinophil levels of 300 cells / μL or greater. The compound of formula (I) has the ability to reduce blood eosinophil counts. Another advantage is provided by the superior toxicity profile of the compound tested in humans compared to other agents for the treatment of airway eosinophilic diseases, such as corticoids and biologics, as well as other adenosine A1 antagonists known in the state of the art. Another difference is that it can be administered orally. Summary of the Invention

[0040] The present invention relates to (1R,3S)-3-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid, its pharmaceutically acceptable salts and co-crystals thereof, pharmaceutical compositions containing said compounds, and combinations of said compounds with one or more agents useful in the treatment of airway diseases, such as allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, and allergic rhinitis, among others, in human subjects with elevated pre-treatment peripheral blood eosinophil levels, particularly peripheral blood eosinophil levels of 300 cells / μL.

[0041] In one aspect, the present invention provides a compound of formula (I) for use in the treatment of airway diseases such as allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, and allergic rhinitis in a human subject having a pre-treatment peripheral blood eosinophil level of 300 cells / μL or greater. [ka] The present invention relates to (1R,3S)-3-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid (compound (I)) of the formula (I), a pharmaceutically acceptable salt thereof, or a cocrystal thereof.

[0042] In another aspect, the present invention relates to (1R,3S)-3-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid of formula (I) (Compound (I), a pharmaceutically acceptable salt thereof, or a co-crystal thereof) for the manufacture of a medicament for the treatment of an airway disease, such as allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, or allergic rhinitis, in a human subject having a pre-treatment peripheral blood eosinophil level of 300 cells / μL or more.

[0043] In yet another aspect, the present invention relates to use of a pharmaceutical composition comprising (1R,3S)-3-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid of Formula (I), a pharmaceutically acceptable salt thereof, or a co-crystal thereof for use in treating an airway disease such as allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, or allergic rhinitis in a human subject having a pre-treatment peripheral blood eosinophil level of 300 cells / μL or more.

[0044] In yet another aspect, the present invention relates to a combination preparation comprising (1R,3S)-3-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid of formula (I), a pharmaceutically acceptable salt thereof, or a cocrystal thereof, and one or more agents useful for the treatment of airway diseases such as allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, and allergic rhinitis in a human subject having a pre-treatment peripheral blood eosinophil level of 300 cells / μL or more.

[0045] In yet another aspect, the invention relates to a combination as described in the preceding paragraph for use in the treatment of an airway disease, such as allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, allergic rhinitis, and the like, in a human subject having a pre-treatment peripheral blood eosinophil level of 300 cells / μL or greater.

[0046] In yet another aspect, the present invention relates to a method for treating a human subject having a pre-treatment peripheral blood eosinophil level of 300 cells / μL or greater. a compound of formula (I) or a pharmaceutically acceptable salt or co-crystal thereof; a pharmaceutical composition comprising a compound of formula (I); or a pharmaceutically acceptable salt thereof or a co-crystal thereof; The present invention relates to a method for treating airway diseases such as allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, and allergic rhinitis by administering a combination preparation containing a compound of formula (I) or a pharmaceutically acceptable salt or cocrystal thereof.

[0047] As mentioned above, the compounds of formula (I) of the present invention are useful for treating airway diseases such as allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, and allergic rhinitis.

[0048] Thus, the compound of formula (I) of the present invention, its pharmaceutically acceptable salt, or co-crystal thereof, pharmaceutical composition comprising such compound and / or its salt or co-crystal, and combined preparations comprising such compound, its salt, or co-crystal can be used in a method for treating airway diseases such as allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, allergic rhinitis, etc., which comprises administering an effective amount of the compound of formula (I) of the present invention or its pharmaceutically acceptable salt, or co-crystal to a human subject in need of said treatment and having a peripheral blood eosinophil level of 300 cells / μL or more before treatment.

[0049] In a preferred embodiment, (1R,3S)-3-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid of formula (I), a pharmaceutically acceptable salt thereof, or a co-crystal thereof, a combination comprising said compound and one or more agents useful for the treatment of airway diseases, such as allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, allergic rhinitis, and the like, in a human subject having a pre-treatment peripheral blood eosinophil level of 300 cells / μL or greater.

[0050] In a preferred embodiment, (1R,3S)-3-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid of formula (I) is administered in a therapeutically effective amount for the treatment of airway diseases such as allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, and allergic rhinitis to a human subject having a peripheral blood eosinophil level of 300 cells / μL or greater before treatment, and reduces blood eosinophil levels after administration.

[0051] Some embodiments are directed to a method of treating a condition characterized by elevated peripheral eosinophil levels in a human subject, comprising administering to the human subject in need thereof a therapeutically effective amount of (1R,3S)-3-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid of Formula (I) or a pharmaceutically acceptable salt thereof, wherein blood eosinophil levels are reduced.

[0052] In a preferred embodiment, (1R,3S)-3-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid of Formula (I) is administered to treat a condition characterized by elevated blood eosinophil levels. In a more preferred embodiment, the eosinophilic disorder is characterized by elevated peripheral blood eosinophil levels of 300 cells / μL or greater.

[0053] In one embodiment, the methods of the present invention provide a therapeutic effect such that a 5% to 30% reduction in a patient's peripheral eosinophil count is achieved within 4 weeks, preferably within 2 weeks, of initiating treatment.

[0054] In a preferred embodiment, the airway disease is asthma selected from atopic asthma, allergic asthma, mild asthma, moderate asthma, severe asthma, eosinophilic asthma, and combinations thereof. In a preferred embodiment, the compound of formula (I) or a pharmaceutically acceptable salt or co-crystal thereof is for the treatment of asthma, wherein the allergic asthma is selected from mild, moderate, and severe asthma.

[0055] In a preferred embodiment, the condition is COPD.

[0056] In a preferred embodiment, the condition is IPF.

[0057] In a preferred embodiment, the compound of formula (I) or a pharmaceutically acceptable salt or co-crystal thereof for use in the treatment of respiratory tract diseases is for administration by the oral route.

[0058] In a preferred embodiment, the compound of formula (I) or a pharmaceutically acceptable salt or co-crystal thereof for use in the treatment of allergic asthma is administered once daily or twice daily. In a more preferred embodiment, the compound of formula (I) is administered once daily.

[0059] In a preferred embodiment, the compound of formula (I) or a pharmaceutically acceptable salt or co-crystal thereof in the treatment of respiratory tract diseases is administered at a dose of 5 mg to 40 mg. In a more preferred embodiment, the compound of formula (I) is administered at a dose of 5 mg to 20 mg.

[0060] In a preferred embodiment, the pharmaceutical composition comprises an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt or co-crystal thereof and a pharmaceutically acceptable vehicle or carrier.

[0061] In a preferred embodiment, the combination formulation comprises the compound of formula (I) or a pharmaceutically acceptable salt or co-crystal thereof and one or more agents selected from the group consisting of corticosteroids such as budesonide, fluticasone, beclomethasone, mometasone, etc., bronchodilators such as salmeterol and formoterol, and biologics selected from dupilumab, reslizumab, mepolizumab, imatinib, lebrikizumab, AK002, benralizumab, tralokinuvam, and antifibrotic agents such as pirfenidone and nintedanib. The components of the combination formulation are in the same formulation or in different formulations.

[0062] In one embodiment of the present invention, the compound of formula (I), a pharmaceutically acceptable salt thereof, or a co-crystal thereof and an agent useful in the treatment of allergic asthma form part of the same composition.

[0063] In another embodiment of the invention, the compound of formula (I), a pharmaceutically acceptable salt thereof or a co-crystal thereof and the agent useful in the treatment of allergic asthma form part of separate compositions for simultaneous or sequential administration.

[0064] In a preferred embodiment, the treatment method for allergic asthma has an effect that can be measured by any suitable metric selected from peripheral eosinophil count and trough forced expiratory volume in 1 second (FEV1).Methods for measuring peripheral eosinophil count and trough FEV1 are known in the art.These and other methods for determining the effect of treatment on patients can be used alone or in combination.

[0065] Eosinophil count Peripheral blood eosinophil counts were obtained from standard complete blood counts performed at all centers participating in this study, e.g., using standardized methods on Beckman Coulter LH series analyzers (Beckman Coulter Ltd, Brea, CA, USA; Negewo, NA et al, Peripheral blood eosinophils: a surrogate marker for airway eosinophilia in stable COPD, Int J Chron Obstruct Pulmon Dis. 2016;11:1495-1504).

[0066] SI units (10 9 / L) eosinophils are 1 × 10 9 The cells / μL were converted to cells / μL using a conversion factor of 1000 cells / μL. The primary endpoint for each protocol population was stratified into two subgroups based on hematological test eosinophil counts (cells / μL) at Visit V1 (low <300 cells / μL and high ≥300 cells / μL). Trough FEV1 values ​​on Day 16 (with a 4-day margin) were summarized by treatment group and eosinophil count at Visit V1. FEV1 measurements on Day 16 (23 hours 15 minutes and 23 hours 45 minutes post-dose) were fitted with a mixed model, with treatment group and eosinophil count as fixed effects, location as a random effect, and baseline FEV1 at Visit V5 as a covariate.

[0067] FEV1Briefly, spirometry measurements are performed using spirometry equipment that meets or exceeds the minimum performance recommendations of the ATS / ERS standard (Miller M. R et al, Standardisation of spirometry, Eur Respir J 2005; 26: 319-338). Calibration and quality control should be performed prior to facility start-up: a. Use a 3L syringe to check the accuracy of the spirometer. b. Syringe accuracy must be certified within the past 12 months and have an accuracy of ±15 ml. c. Before use, keep the syringe at the same temperature as the spirometer to ensure volume stability. d. Volumetric spirometers must be calibrated and leak checked before each testing session according to manufacturer guidelines. Calibration reports, kept as facility source documents, are required to verify adherence to guidelines. Examples of spirometry devices used in testing: Jaeger and ERT Spirosphere

[0068] The present invention is used in human subjects. [Brief explanation of the drawings]

[0069] [Figure 1]Study Design. The study included a screening visit (V1), a withdrawal protocol for asthma maintenance therapy (Visits 2–V4), a two-arm treatment period (Visits V5–V7, with V5 being the randomization visit R), and a follow-up visit (V8, FU). Subjects entered screening and then entered the withdrawal phase of asthma treatment through three alternative pathways (A, B, or C) depending on their asthma medication at study entry: a1, b1, and c1: Visit V1 for Pathways A, B, and C, respectively. Subjects receiving a medium-dose ICS concomitantly with at least one additional asthma controller entered the withdrawal phase from Pathway A through the following steps: (a2) withdrawal of non-ICS medications (LABA, LTRA) at Visit V2, (a3) ​​reduction of ICS to a low dose at Visit V3, and (a4) withdrawal of low-dose ICS at Visit V4. Subjects receiving a low-dose ICS concomitantly with at least one additional asthma controller or subjects receiving a medium-dose ICS as monotherapy entered Pathway B as follows: (b2) Withdrawal of non-ICS medications (LABA, LTRA) or, if applicable, reduction of ICS monotherapy from a medium dose to a low dose, and (b3) Withdrawal of low-dose ICS. These subjects skip Visit V4 and proceed directly to randomization at V3 (step b3). Subjects who entered the study on low-dose ICS monotherapy take Route C, which involves withdrawal of ICS at Visit V2 (single step c2) and skipping Visits V3 and V4, and proceeding to randomization. Intranasal rhinitis / rhinosinusitis medication, if applicable, is discontinued at Visit V2 for all subjects. The period before randomization (R) refers to the period between visits. For Visits V5 (randomization), V6, and V7, the exact visit dates and leeway are indicated. (*Waiting time for Visit V5: Visit V5 must be scheduled within 7 days (± 2 days) after Visit V4 for Route A, after V3 for Route B, and after V2 for Route C.) For subjects who do not meet spirometric enrollment criterion #10, Visit V5 procedures may be discontinued and an unscheduled visit may be designated for spirometric follow-up within a maximum of 7 days. A complete Visit V5 may be rescheduled up to 14 days after the initial V5 discontinuation, with at least one follow-up visit in between. The time period between Visits V7 and V8 (FU, follow-up) is also applicable to PSW (early subject withdrawal) visits after the discontinuation date.Route A: Subjects entering the study taking a medium-dose ICS and at least one additional asthma controller (e.g., LABA or LTRA). All withdrawal visits: V1 → V4. Route B: Subjects entering the study with both a low-dose ICS and at least one additional asthma controller, or medium-dose ICS alone. Withdrawal visits V1 → V3 (no V4). Route C: Subjects entering the study with low-dose ICS as asthma monotherapy. ICS is withdrawn at visit V2 (no V3, V4). Rescue medication: Subjects may use short-acting beta2-adrenergic rescue bronchodilators during the entire study period. [Figure 2] Effect of Compound (I) administration on eosinophil counts. V5 / D0: Visit 5, day 0. V7 / D15: Visit 7, day 15. V8 / FU: Visit 8, follow-up. [Figure 3] Difference in FEV1 relative to baseline after 15 days of Compound (I) / placebo treatment (serial spirometry). [Figure 4] AUC of FEV1 after 15 days of administration. [Figure 5] Difference in ACQ-7 scores relative to baseline after Compound (I) / placebo treatment. [Figure 6-1] Summary of associated adverse events by organ system type and preferred term worst grade per patient (safety population). [Figure 6-2] Summary of associated adverse events by organ system type and preferred term worst grade by patient (safety population) (continuation of Figure 6-1).

[0070] As used herein, the term allergic asthma is used to describe a type of asthma that causes symptoms when the person is around certain triggers (allergens). These allergens cause an immune system response that affects the lungs, making breathing difficult. (https: / / www.medicalnewstoday.com / articles / 324476)

[0071] As used herein, the term atopic asthma, like allergic asthma, is generally associated with an increased immune response to inhaled allergens.

[0072] As used herein, the term mild asthma refers to asthma that is well controlled with regular daily low-dose ICS treatment with SABAs as needed, which is effective in reducing asthma symptoms and the risk of asthma-related exacerbations, hospitalizations, and death, but where adherence to ICS is poor. Additionally, in adult and adolescent patients with mild asthma, treatment with low-dose ICS-formoterol as needed reduced the risk of severe exacerbations by approximately two-thirds compared with SABAs alone and was non-inferior to daily low-dose ICS for severe exacerbations (Global Strategy for Asthma Management and Prevention. 2020. Available at www.ginasthma.org).

[0073] As used herein, the term moderate asthma refers to asthma that can be managed with low-dose ICS-LABA as maintenance therapy and rescue SABA as needed, and low-dose ICS-formoterol as both maintenance and rescue therapy. It also includes alternative treatments for moderate asthma, such as a medium-dose ICS with a SABA as needed, or a low-dose ICS-LABA combination with a SABA as needed (Global Strategy for Asthma Management and Prevention. 2020. Available at www.ginasthma.org).

[0074] As used herein, the term severe asthma refers to asthma that is not controlled despite GINA Step 4 or 5 treatment, or asthma that requires such treatment to maintain good symptom control and reduce exacerbations. Approximately 3-10% of asthma patients have severe asthma (Global Strategy for Asthma Management and Prevention. 2020. Available at www.ginasthma.org).

[0075] As used herein, the term pharmaceutically acceptable salts is used to refer to salts with pharmaceutically acceptable bases such as alkali metal hydroxides (e.g., sodium or potassium), alkaline earth metal hydroxides (e.g., calcium or magnesium), and organic bases, e.g., alkylamines, arylalkylamines, and heterocyclic amines.

[0076] Other preferred salts according to the invention are those containing the anion (X - ) is a quaternary ammonium compound in which the equivalent of X is associated with a positive charge on the N atom. - X may be an anion of various mineral acids, such as chloride, bromide, iodide, sulfate, nitrate, phosphate, or an anion of organic acids, such as acetate, maleate, fumarate, citrate, oxalate, sulfate, tartrate, malate, mandelate, trifluoroacetate, methanesulfonate, and p-toluenesulfonate. - is preferably an anion selected from chloride, bromide, iodide, sulfate, nitrate, acetate, maleate, oxalate, succinate or trifluoroacetate.

[0077] As used herein, the term co-crystal is used to refer to a crystalline material consisting of two or more molecules in the same crystal lattice, more particularly a co-crystal formed by molecules of (1R,3S)-3-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid of formula (I) and a pharmaceutically acceptable conformer. The present invention is as follows. [1] A compound of formula (I) for use in treating an airway disease in a human subject having a pre-treatment peripheral blood eosinophil level of 300 cells / μL or greater, said treatment comprising administering to said subject a therapeutically effective amount of said compound. [2] The compound according to [1] above, wherein the eosinophilic airway disease is selected from allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, and allergic rhinitis. [3] The compound according to [2] above, wherein the allergic asthma is selected from mild, moderate and severe asthma. [4] The compound according to any one of the above [1] to [3], which is administered orally. [5] The compound according to any one of [1] to [4] above, which is administered once a day or twice a day. [6] The compound according to [5] above, which is administered once a day. [7] The compound according to any one of [1] to [6] above, which is administered at a dose of 5 to 40 mg. [8] The compound according to [7] above, administered at a dose of 5 to 20 mg. [9] The compound according to any one of the above [1] to [8], wherein administration of compound (I) reduces peripheral blood eosinophil levels by 5% to 30% from baseline.

[10] The compound according to any one of the above [1] to [9], wherein administration of compound (I) increases trough FEV1 by 110 to 200 mL.

[11] The compound according to [1] above, wherein compound (I) is present in a combined formulation comprising the compound of formula (I) or a pharmaceutically acceptable salt or cocrystal thereof and one or more agents selected from the group consisting of corticosteroids such as budesonide, fluticasone, beclomethasone, mometasone, etc., bronchodilators such as salmeterol and formoterol, and biologics selected from dupilumab, reslizumab, mepolizumab, imatinib, lebrikizumab, AK002, benralizumab, tralokinuvam, and antifibrotic agents such as pirfenidone and nintedanib.

[12] Use of a compound of formula (I) for the manufacture of a medicament for the treatment of an airway disease in a human subject having a pre-treatment peripheral blood eosinophil level of 300 cells / μL or more, wherein the treatment comprises administering to the subject a therapeutically effective amount of the compound.

[13] The use according to

[12] above, wherein the eosinophilic airway disease is selected from allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, and allergic rhinitis.

[14] The use according to

[13] above, wherein the allergic asthma is selected from mild, moderate and severe asthma.

[15] The use according to any one of the above

[12] to

[14] , wherein the compound is administered orally.

[16] The use according to any one of

[12] to

[15] above, wherein the compound is administered once a day or twice a day.

[17] The use according to

[16] above, wherein the compound is administered once a day.

[18] The use according to any one of

[12] to

[17] above, wherein the compound is administered at a dose of 5 to 40 mg.

[19] The use according to

[18] above, wherein the compound is administered at a dose of 5 to 20 mg.

[20] The use according to any one of the above

[12] to

[19] , wherein administration of compound (I) reduces peripheral blood eosinophil levels by 5% to 30% from baseline.

[21] The use according to any one of the above

[12] to

[20] , wherein administration of compound (I) increases trough FEV1 by 110 to 200 mL.

[22] The use according to

[12] above, wherein compound (I) is present in a combined formulation comprising the compound of formula (I) or a pharmaceutically acceptable salt or cocrystal thereof and one or more agents selected from the group consisting of corticosteroids such as budesonide, fluticasone, beclomethasone, mometasone, etc., bronchodilators such as salmeterol and formoterol, and biologics selected from dupilumab, reslizumab, mepolizumab, imatinib, lebrikizumab, AK002, benralizumab, tralokinuvam, and antifibrotic agents such as pirfenidone and nintedanib.

[23] A method for treating an airway disease in a human subject having a pre-treatment peripheral blood eosinophil level of 300 cells / μL or more, comprising administering to the subject a therapeutically effective amount of a compound of formula (I).

[24] The method according to

[23] above, wherein the eosinophilic airway disease is selected from allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea, and allergic rhinitis.

[25] The method according to

[24] above, wherein the allergic asthma is selected from mild, moderate and severe asthma.

[26] The method according to any one of the above

[23] to

[25] , wherein the compound is administered orally.

[27] The method according to any one of

[23] to

[26] above, wherein the compound is administered once a day or twice a day.

[28] The method according to

[27] above, wherein the compound is administered once a day.

[29] The method according to any one of

[23] to

[28] above, wherein the compound is administered at a dose of 5 to 40 mg.

[30] The method according to

[29] above, wherein the compound is administered at a dose of 5 to 20 mg.

[31] The method according to any one of the above

[23] to

[30] , wherein administration of compound (I) reduces peripheral blood eosinophil levels by 5% to 30% from baseline.

[32] The method according to any one of the above

[23] to

[31] , wherein administration of compound (I) increases trough FEV1 by 110 to 200 mL.

[33] The method according to

[23] above, wherein compound (I) is present in a combined formulation comprising the compound of formula (I) or a pharmaceutically acceptable salt or cocrystal thereof and one or more agents selected from the group consisting of corticosteroids such as budesonide, fluticasone, beclomethasone, mometasone, etc., bronchodilators such as salmeterol and formoterol, and biologics selected from dupilumab, reslizumab, mepolizumab, imatinib, lebrikizumab, AK002, benralizumab, tralokinuvam, and antifibrotic agents such as pirfenidone and nintedanib. [Example]

[0078] Example 1: Adenosine A on forced expiratory volume in 1 second (FEV1) in patients with mild to moderate persistent atopic asthma 1 A study to investigate the effects of the receptor antagonist (1R,3S)-3-((5-cyano-4-phenylthiazol-2-yl)carbamoyl)cyclopentane-1-carboxylic acid the purpose This exploratory study aims to evaluate the safety, tolerability, and efficacy of Compound (I) 10 mg administered once daily for 15 days in subjects with mild-to-moderate persistent atopic asthma. Regarding exploratory efficacy, the primary objective of this study is to determine whether Compound (I) improves FEV1 compared to placebo and to provide comparative safety data from this asthma patient population. Additionally, measurements obtained in this study will be used to determine whether this treatment improves other variables related to asthma control and lung function.

[0079] Registration Criteria 1. Written informed consent must be obtained before any study evaluations are conducted. Subjects must be able to communicate satisfactorily with the investigator and staff to ensure they understand and comply with the requirements of the study. 2. Male and female subjects aged 18-70 years. 3. Subjects with a history of mild to moderate persistent allergic asthma diagnosed according to the GINA 2017 guidelines, with maintenance therapy limited to low / medium doses of ICS in treatment steps 2-3, or medium doses of ICS and LABA and / or leukotriene antagonists in treatment step 4. Maintenance asthma therapy must be stable for at least 3 months before participation in this study. Subjects with allergic rhinitis or chronic rhinosinusitis receiving intranasal medication with or without nasal polyposis are permitted to participate in the study. The use of oral antihistamines as rescue medication for allergic rhinitis is permitted after a protocol-specified washout period. 4. A positive skin prick test or specific serum IgE to airborne allergens, such as house dust mites, tree or grass pollens, pet dander, or cockroach antigens. Additionally, any allergens specific to the country / region may be included. A history of skin prick test or serum IgE within the 12 months prior to screening is acceptable (supported by source), except for subjects who have received specific immunotherapy within the past 12 months (see Exclusion Criteria No. 18). For such subjects, a positive airborne allergen skin prick test or specific serum IgE is required at Visit V1. 5. Females of childbearing potential must agree to use effective contraception from Visit 1 through the FU visit unless they are surgically sterilized (i.e., bilateral tubal ligation, bilateral salpingectomy, or total hysterectomy), postmenopausal for at least 2 years, or abstinent. Acceptable contraceptive methods are oral, transdermal, or implantable contraceptives, intrauterine devices, spermicide-loaded female condoms, spermicide-loaded diaphragms, or use of spermicide-loaded condoms by sexual partners. Surgically sterilized female subjects must have undergone surgery at least 6 months prior to the first dose of study drug. Surgical sterilization must be supported by clinical documentation available to the sponsor. 6. All female subjects must have a negative pregnancy test result at screening and baseline. 7. Male subjects agree to use two acceptable methods of contraception (e.g., spermicidal gel and condoms) throughout the entire study and until the end-of-study visit, and to refrain from fathering within 3 months of the last study drug dose. Cyclic abstinence and withdrawal are not acceptable methods of contraception. 8. Subjects weigh at least 45 kg and have a body mass index (BMI) ≥ 17 kg / m 2 That is. 9. Subjects must demonstrate an increase in FEV1 of ≥ 12% and ≥ 200 mL above pre-bronchodilator values ​​within 30 minutes after inhaling a total of 400 μg of salbutamol (reversibility test). Reversibility can be determined at screening or during the withdrawal period leading up to Visit V5. Alternatively, subjects who do not have a positive "reversibility test" but whose pre-bronchodilator FEV1 declines by ≥ 200 mL from the baseline FEV1 at Visit V1 are also eligible. 10. At Visit V5, upon completion of asthma maintenance therapy withdrawal, subjects must have a pre-bronchodilator FEV1 of ≥60% and ≤90% of predicted normal upon completion of LABA and ICS withdrawal. Alternatively, subjects with a pre-bronchodilator FEV1 of ≥90% at Visit V5 must have a pre-bronchodilator FEV1 decrease of ≥200 mL from baseline FEV1 at Visit V1. 11. Subjects must have an ACQ-7 score ≥ 1.5 upon completion of LABA and ICS withdrawal at Visit V5. 12. Subjects must achieve 80% or greater compliance with morning and evening electronic / PEF recordings during the withdrawal period from asthma maintenance therapy (i.e., Visit V2 through Visit V5). 13. Withdrawal from asthma maintenance therapy (i.e., from Visit V2 to Visit V5).

[0080] Exclusion criteria 1. Use of other investigational drugs at the time of enrollment, or within 30 days or 5 half-lives of enrollment, whichever is longer. 2. History of hypersensitivity to the test drug or drugs of a similar chemical class (A1 adenosine receptor antagonists). 3. History of clinically significant ECG abnormalities or recent history of autonomic dysfunction (e.g., syncope, recurrent arrhythmias, etc.). 4. History of malignant tumor of any organ system (excluding localized basal cell carcinoma of the skin) within the past 5 years, whether treated or untreated. 5. Pregnant or lactating women. 6. Smoking within the past 6 months or smoking history of more than 10 pack-years (1 pack-year is defined as smoking the equivalent of 20 cigarettes (1 pack) per day for 1 year). 7. Subjects with severe persistent asthma managed at GINA treatment step 4 (excluding restrictive tolerance in inclusion criterion 3) or 5 according to the GINA 2017 guidelines. This criterion includes subjects treated with high-dose ICS, systemic corticosteroids, tiotropium bromide, theophylline, or monoclonal antibody-based biologic therapies such as omalizumab, mepolizumab, and reslizumab. Subjects receiving immunosuppressant therapy or systemic corticosteroid therapy for conditions other than asthma are excluded. Also excluded are subjects requiring daily use of antihistamines. 8. Current or past use of a biologic (e.g., monoclonal antibody) for the treatment of asthma. Have used a biologic for any other condition within the past 6 months. 9. Use of systemic corticosteroids for treatment of an asthma exacerbation or other condition within 4 weeks prior to Visit V1. 10. History of life-threatening asthma, defined as an asthma episode requiring intubation and / or involving hypercarbia, respiratory arrest, and / or hypoxic attacks. History of asthma exacerbation requiring hospitalization or emergency room stay of 48 hours or more within the 5 years prior to Visit 1. 11. Any disease or illness other than asthma that may require the use of systemic corticosteroids during the study period. 12. Occupational exposure to allergens / irritants that may exacerbate asthma symptoms during the study period. 13. Respiratory infection requiring antibiotic use within 4 weeks prior to Visit V1 or pneumonia within 6 months prior to Visit V1. 14. Asthma exacerbation requiring treatment or use of any medical resource within 4 weeks prior to Visit V1. This includes asthma exacerbations managed with a transient increase in the subject's usual asthma maintenance medication, and exacerbations self-managed using an "action plan." 15. Subjects with other underlying conditions that may compromise safety or interfere with efficacy outcomes (e.g., tuberculosis, clinically relevant bronchiectasis, diffuse pulmonary interstitial disease, pulmonary hypertension, emphysema, chronic bronchitis, α1-antitrypsin deficiency, systemic immune-driven diseases). 16. Use of prescription or over-the-counter medications is subject to protocol-defined restrictions (non-permitted drugs). 17. Surgical or medical conditions that may significantly alter drug absorption, distribution, metabolism, or excretion or that may place the subject at risk if they participate in this study. The investigator must determine this based on the subject's medical history and / or clinical or laboratory evidence of the following conditions: inflammatory bowel disease, gastrointestinal ulcer, gastrointestinal or rectal bleeding, major gastrointestinal surgery such as gastrectomy or intestinal resection, pancreatic injury or pancreatitis, liver disease or injury as indicated by abnormalities in liver function assays such as SGOT (AST), SGPT (ALT), γ-GT, or alkaline phosphatase. 18. Subjects currently receiving or have received within the past 5 years any specific immunotherapy.

[0081] Test Plan A phase II, double-blind, randomized, parallel-group, placebo-controlled, multicenter study to investigate the effect of an adenosine A1 receptor antagonist compound (I) on forced expiratory volume in 1 second (FEV1) in patients with mild to moderate persistent atopic asthma.

[0082] The primary objective was to demonstrate that 15 days of Compound (I) improves trough FEV1 compared with placebo in patients with mild-to-moderate asthma who were on GINA Step 2-3 (excluding high-dose inhaled corticosteroids (ICS)) or Step 4 at baseline and whose maintenance therapy was limited to medium-dose ICS and long-acting beta-agonist (LABA) bronchodilators and / or leukotriene receptor antagonists (LTRAs). Secondary objectives included determination of the area under the FEV1 curve (AUC), FEV1 assessments before and after bronchodilator administration, and patient-reported outcomes (PROs) including the Asthma Control Questionnaire-7 (ACQ-7) and the standard Asthma Quality of Life Questionnaire (AQLQ(S)).

[0083] The study consisted of (i) a minimum 5-day screening period to assess subjects' clinical stability and overall eligibility for the study, (ii) a 7-day withdrawal period during which asthma medications were gradually tapered, (iii) a randomized parallel-group treatment period, and (iv) a follow-up visit after study completion. The asthma medication withdrawal period consisted of three visits to adjust each subject's asthma therapy at study initiation. The study was administered as described for the study objectives and included a primary analysis population of 58 stable asthma patients who met all inclusion and exclusion criteria and completed a complete and valid dataset for the primary variables. Figure 1 shows the study design.

[0084] Data Analysis Distributions of the primary efficacy variable and secondary outcomes will be analyzed by treatment using repeated measures models as appropriate. Additional analyses will include datasets generated from baseline characteristics and safety assessments, pharmacokinetics, and any analyses to evaluate the effect of baseline and clinical covariates on the primary variable. Factor-tailored subanalyses can be performed according to adaptive data analysis plans.

[0085] result Of 107 subjects screened, 63 (58.9%) met the eligibility criteria and were randomized. Of the 63 randomized patients, 63 (100%) completed the study (32 and 31 in the Compound (I) and placebo groups, respectively). There were no adverse events leading to discontinuation. The safety population included 63 patients (placebo: n=31, Compound (I): n=32). Results were based on the per-protocol population (placebo: n=27, Compound (I): n=31).

[0086] Patient demographics and baseline characteristics of the safety population are summarized in Table 1 .

[0087] [Table 1]

[0088] - Change from baseline in blood eosinophil count Blood eosinophil count (10 9 The overall change from baseline in blood eosinophil count (p<0.01) / L demonstrated a treatment difference (reduction in blood eosinophil count) in the Compound (I) group compared to placebo. Table 2 and Figure 2.

[0089] [Table 2]

[0090] As can be seen from the table above, the reduction in eosinophil counts in subjects treated with Compound (I) was statistically and clinically significant and was associated with improved clinical outcomes during the study.

[0091] Administration of Compound (I) reduced peripheral blood eosinophil levels by 5% to 30% from baseline.

[0092] Analysis of peripheral blood eosinophil levels by patient subgroups

[0093] [Table 3]

[0094] [Table 4]

[0095] As can be seen in Table 4, patients with high V1 eosinophil levels (≥300 cells / μL) showed a statistically significant improvement in trough FEV1 compared to matched placebo (0.38 L; p=0.0164), while patients with low V1 eosinophil levels (<300 cells / μL) showed a non-statistically significant improvement in trough FEV1 of 0.04 L (p=0.7778) with this treatment compared to matched placebo.

[0096] - Change from baseline in trough FEV1 Analysis of the primary efficacy variable, overall change from baseline in trough FEV1 over 15 days of treatment, showed a significant improvement (increase) in patients in the Compound (I) group compared with the placebo group (Table 5 and Figure 3). A mixed model was fitted with FEV1 measurements on Day 16 (23 hours 15 minutes and 23 hours 45 minutes post-dose) including treatment group as a fixed effect, site as a random effect, and baseline FEV1 at Visit V5 as a covariate. The treatment effect was greater in the Compound (I) group compared with the placebo group, with a 180 mL increase in FEV1 (p=0.0816).

[0097] [Table 5]

[0098] Specifically, administration of Compound (I) increases trough FEV1 by 110 to 200 mL.

[0099] FEV1 AUC after 15-16 days of administration 30min-23h30min Change from baseline in Secondary efficacy variables: post-dose FEV1 AUC 15-16 days after treatment 30min-23h30min Analysis of the overall change from baseline in showed a significant improvement (increase) in patients in the Compound (I) group compared to the placebo group (Table 6 and Figure 4).

[0100] [Table 6]

[0101] - Change from baseline in Asthma Control Questionnaire-7 (ACQ-7) Analysis of the overall mean change from baseline in ACQ-7 scores at 15 days of treatment showed improvement (decrease) in patients in the Compound (I) group compared to the placebo group (p=0.0430). Table 7 and Figure 5. Visit and study group as covariates. * Similar trends were observed when comparing visits.

[0102] [Table 7]

[0103] -Safety profile In conjunction with the above data, Compound (I) exhibits a very favorable safety profile in patients with allergic / atopic asthma. This data highlights the potential of Compound (I), an adenosine A1 receptor antagonist, as a promising oral asthma treatment. See Figure 6. The safety set included all randomized patients who received at least one dose of study drug.

[0104] Overall, 63 patients completed the study (safety population), and 58 patients, excluding non-compliant subjects, were evaluated in the per-protocol (pp) population. In the pp population, significant differences were observed between compound (I) and placebo with regard to peripheral eosinophil count, trough forced expiratory volume in 1 second (FEV1), and Asthma Control Questionnaire-7 (ACQ-7). Patients treated with compound (I) demonstrated significant improvements in trough FEV1 compared to placebo, resulting in a significant reduction in blood eosinophils after 15 days of treatment.

[0105] Most adverse events (AEs) were mild / moderate in both groups, and no severe AEs were reported. Compound (I) demonstrated an excellent safety profile in patients with allergic / atopic asthma.

Claims

1. 1. A compound of formula (I): 【Chemistry 1】 wherein said treatment comprises administering to said subject a therapeutically effective amount of said compound of formula (I).

2. The pharmaceutical composition described in claim 1, wherein the airway disease is selected from allergic asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), obstructive sleep apnea and allergic rhinitis.

3. 3. The pharmaceutical composition according to claim 2, wherein the allergic asthma is selected from mild, moderate and severe asthma.

4. 3. The pharmaceutical composition according to claim 1 or 2, which is administered by oral route.

5. 3. The pharmaceutical composition of claim 1 or 2, which is administered once a day or twice a day.

6. 6. The pharmaceutical composition of claim 5, which is administered once daily.

7. The pharmaceutical composition of claim 1 or 2, administered at a dose of 5 to 40 mg.

8. 8. The pharmaceutical composition of claim 7, administered at a dose of 5 to 20 mg.

9. The pharmaceutical composition of claim 1, wherein administration of a compound of formula (I) reduces peripheral blood eosinophil levels by 5% to 30% from baseline.

10. The pharmaceutical composition of claim 1 or 2, wherein administration of a compound of formula (I) increases trough FEV1 by 110 to 200 mL.

11. The pharmaceutical composition of claim 1, wherein the compound of formula (I) is present in a combination formulation comprising the compound of formula (I) or a pharmaceutically acceptable salt or co-crystal thereof and one or more agents selected from the group consisting of corticosteroids such as budesonide, fluticasone, beclomethasone, mometasone, etc., bronchodilators such as salmeterol and formoterol, and biologics selected from dupilumab, reslizumab, mepolizumab, imatinib, lebrikizumab, AK002, benralizumab, traloquinovam, and antifibrotic agents such as pirfenidone and nintedanib.

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