Compositions and methods for treating pulmonary disorders

Abstract

The present invention relates to pharmaceutical compositions and methods comprising 2-hydroxybenzoic acid derivatives of formula (I) or pharma- ceutically acceptable salts thereof, useful for treating pulmonary disorders including asthma, chronic obstructive pulmonary disease (COPD), overlap syndrome of asthma and COPD (ACOD) or any other respiratory disease.Administration of 2-hydroxybenzoic acid derivatives of formula (I) significantly reduces airway tissue damage and inflammation in animal models of asthma and COPD.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 294,132, filed December 28, 2021, the entirety of which is incorporated herein by reference.

[0002] The present invention relates to pharmaceutical compositions and methods for aiding in the treatment of asthma, chronic obstructive pulmonary disease (COPD) and overlap syndrome of asthma and COPD (ACOD), comprising a 2-hydroxybenzoic acid derivative of formula (I) or a pharma- ceutically acceptable salt thereof. [Background technology]

[0003] asthma Asthma is the most common chronic condition worldwide, affecting over 300 million people worldwide with a prevalence rate ranging from 1% to 16% in 2018 in various countries ["The Global Asthma Report" from www.globalasthmanetwork.org]. Although it is rarely fatal, the economic burden associated with asthma is heavy due to direct and indirect medical costs, including the cost of prescription drugs, health care utilization and lost productivity.

[0004] Asthma is characterized by chronic airway inflammation, bronchial hyperreactivity, reversible airway obstruction and airway hyperresponsiveness to a variety of stimuli. Airway inflammation is the hallmark of asthma and underlines many of the pathophysiological changes seen in asthmatic airways, resulting in the characteristic symptoms of asthma, such as wheezing, shortness of breath, chest tightness and coughing.

[0005] Bronchodilators, such as beta2 agonists and anticholinergics, are prescribed to relieve symptoms by relaxing the muscles around the airways and clearing mucus from the lungs. Leukotriene receptor antagonists prevent breathing problems such as coughing, excess mucus in the chest and throat, and wheezing.

[0006] Airway inflammation in asthma patients can be controlled using inhaled corticosteroids (ICS). Patients with severe asthma respond poorly to ICS. In addition, some asthma patients are resistant to ICS. Oral administration of corticosteroids can be used to treat severe asthma, but they can cause side effects in most patients, leading to poor adherence and quality of life.

[0007] Cysteinyl leukotrienes are crucial proinflammatory lipid mediators of bronchial asthma formed through the 5-lipoxygenase pathway of arachidonic acid, which increase during asthma exacerbations and play a role in the pathogenesis of asthma by promoting bronchoconstriction, mucus secretion, tissue edema and leukocyte infiltration. In support of this, 5-lipoxygenase inhibitors and cysteinyl leukotriene receptor-1 antagonists (LTRAs) improve airflow function and reduce the frequency of asthma exacerbations.

[0008] Nonsteroidal anti-inflammatory drugs (NSAIDs) have potent anti-inflammatory activity through cyclooxygenase-2 (COX-2) inhibition. However, NSAIDs inhibit COX-1 and COX-2, causing severe side effects, such as gastrointestinal (GI) toxicity and myocardial infarction. In addition, NSAIDs can induce bronchospasm and exacerbate asthma symptoms. Selective inhibition of membrane-bound prostaglandin E synthase (mPGES)-1, a downstream PGE2-inducing synthesis enzyme, has emerged as a novel strategy to reduce side effects. Interestingly, LTRAs inhibit mPGES-1 activity and PGE2 production without affecting COX activity, suggesting that LTRAs may exert anti-inflammatory effects by inhibiting mPGES-1-mediated inflammatory pathways.

[0009] In asthmatics, oxidative stress is increased in the airways and systemic circulation, likely contributing to airway obstruction and inflammation that can increase mucus secretion, smooth muscle contraction, and vascular permeability. Oxidative stress likely interferes with glucocorticoid receptor (GR) signaling, resulting in ICS insensitivity [1].

[0010] COPD COPD is characterised by progressive airflow obstruction and is mainly caused by inhalation of tobacco and other pollutants. It caused 3.23 million deaths in 2019 and a substantial social and economic burden worldwide [www.who.int / news-room / fact-sheets / detail / the-top-10-causes-of-deathref].

[0011] Inhaled smoke and pollutant toxic particles induce various pathophysiological events in COPD, including abnormal airway inflammation, remodeling and thickening of airway wall tissue, genetic reprogramming in airway epithelial cells, senescence and death of lung structural cells, and oxidative stress [2-4]. Such pathological events are accompanied by symptoms of COPD, such as dyspnea, coughing, mucus production, and wheezing. Although COPD is not curable, its symptoms and complications are treatable. The current class of drugs used to treat COPD and asthma still relies on the use of bronchodilators and corticosteroids. Bronchodilators relieve dyspnea by reducing viscous resistive work and airway resistance. Although corticosteroids reduce inflammation to some extent in asthma patients, COPD patients respond poorly to them. Such insensitivity to corticosteroids is due to inactivation of histone deacetylase 2, which suppresses glucocorticoid receptor activity.

[0012] Roflumilast, a phosphodiesterase-4 (PDE-4) inhibitor that reduces airway inflammation, has been approved to reduce the risk of COPD exacerbations. Over the past two decades, pharmacological research has been directed toward finding new anti-inflammatory pharmacological approaches to more fully treat COPD patients. Unfortunately, with the exception of roflumilast, which inhibits the PDE-4 enzyme, most approaches targeting specific cytokines or chemokines have not reached the clinical development stage or have failed in clinical trials [5]. In fact, in COPD, there is no predominant cytokine or chemokine involved in the disease. Thus, no single target can be effective in all pathways. More studies are needed to correlate inflammatory endotypes with clinical outcomes and responses to more precise anti-inflammatory treatments that are currently under development [6]. Therefore, based on previous failures, there is an urgent need for effective and safe anti-inflammatory drugs to reduce COPD progression and exacerbations.

[0013] Oxidative stress is associated with corticosteroid resistance by suppressing glucocorticoid receptor activity, impeding responses to pathogens and exacerbating airway inflammation, thereby exacerbating COPD. Approaches targeting oxidative stress have beneficial effects in animal models of COPD and are considered as potential therapeutic candidates for treating COPD. Although the beneficial effects of thiol-based antioxidants, such as N-acetylcysteine, remain controversial in 12 clinical trials performed on COPD patients [7], COPD patients treated with N-acetylcysteine, erdosteine ​​and carbocisteine ​​showed reduced exacerbations and improved health status [8]. Antioxidant vitamins are positively and negatively associated with lung function in COPD patients (Rahman, 2009). Notably, due to heterogeneity in study populations, medications and additional treatments, targeted COPD patients sensitive to antioxidants were not identified. [Prior art documents] [Non-patent literature]

[0014] [Non-Patent Document 1] Lewis, BW, et al., Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD. Antioxidants (Basel), 2021. 10(9). [Non-Patent Document 2] Crystal, RG, Airway basal cells. The "smoking gun" of chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2014. 190(12): p. 1355-62. [Non-Patent Document 3] Pauwels, RA, et al., Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: National Heart, Lung, and Blood Institute and World Health Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD): executive summary. Respir Care, 2001. 46(8): p. 798-825. [Non-Patent Document 4] Walters, EH, et al., Fully integrating pathophysiological insights in COPD: an updated working disease model to broaden therapeutic vision. Eur Respir Rev, 2021. 30(160). [Non-Patent Document 5] Rabe, KF, et al., Effect of roflumilast in patients with severe COPD and a history of hospitalisation. Eur Respir J, 2017. 50(1). [Non-Patent Document 6] Barnes, PJ, Inflammatory endotypes in COPD. Allergy, 2019. 74(7): p. 1249-1256. [Non-Patent Document 7] Fowdar, K., et al., The effect of N-acetylcysteine ​​on exacerbations of chronic obstructive pulmonary disease: A meta-analysis and systematic review. Heart Lung, 2017. 46(2): p. 120-128. [Non-Patent Document 8] Rogliani, P., et al., Efficacy and safety profile of mucolytic / antioxidant agents in chronic obstructive pulmonary disease: a comparative analysis across erdosteine, carbocysteine, and N-acetylcysteine. Respir Res, 2019. 20(1): p. 104. [Non-Patent Document 9] Ryu, BR, et al., The novel neuroprotective action of sulfasalazine through blockade of NMDA receptors. J Pharmacol Exp Ther, 2003. 305(1): p. 48-56. [Non-Patent Document 10] Vane, JR and RM Botting, The mechanism of action of aspirin. Thromb Res, 2003. 110(5-6): p. 255-8. [Non-Patent Document 11] Wu, KK, Aspirin and other cyclooxygenase inhibitors: new therapeutic insights. Semin Vasc Med, 2003. 3(2): p. 107-12. [Non-Patent Document 12] Lee, JH, et al., Prevention effects of ND-07, a novel drug candidate with a potent antioxidative action and anti-inflammatory action, in animal models of severe acute pancreatitis. Eur J Pharmacol, 2012. 687(1-3): p. 28-38. [Non-Patent Document 13] Hosseini, M., et al., Global prevalence of asthma-COPD overlap (ACO) in the general population: a systematic review and meta-analysis. Respir Res, 2019. 20(1): p. 229. Summary of the Invention [Means for solving the problem]

[0015] 2-Acetoxy-5-(2-4-(trifluoromethyl)-phenethylamino)-benzoic acid (ATPB) and its derivatives ATPB is a novel compound synthesized from lead structures based on sulfasalazine [9], which has antioxidant and anti-inflammatory activities, and aspirin [10, 11], which has anti-inflammatory, antipyretic and anti-pain activities. ATPB [also codenamed "ND-07" and chemical name 2-acetoxy-5-(2-4-(trifluoromethyl)-phenethylamino)-benzoic acid] exhibits potent anti-inflammatory effects by inhibiting mPGES-1, the terminal enzyme in prostaglandin-E2 (PGE2) biosynthesis, and antioxidant effects by scavenging hydroxyl radicals

[12] .

[0016] ATPB Effectively Reduces Airway Tissue Damage and Inflammation in Rodent Models of Asthma and COPD The present invention relates to pharmacological compositions and methods for treating pulmonary diseases, such as asthma, COPD and ACOD.

[0017] The present invention provides ATPB or a derivative thereof as a modulator for the treatment of pulmonary diseases, such as asthma or COPD. The present invention also provides ATPB or a derivative thereof for complement steroid treatment or replace corticosteroid treatment during exacerbations of asthma or COPD.

[0018] Accordingly, a first aspect of the present invention includes a composition for treating a pulmonary disease comprising a pharma- ceutically acceptable excipient and a therapeutically effective amount of a compound represented by Formula 1 or a pharma- ceutically acceptable salt thereof.

[0019] A second aspect of the present invention includes a method of treating a pulmonary disease in a subject suffering from a pulmonary disease, comprising administering to the patient a therapeutically effective amount of a compound represented by Formula 1 or a pharma- ceutically acceptable salt thereof.

[0020] In some embodiments, Formula 1 is as set forth below: [ka] (Wherein, X is CO, SO2 and (CH2) n is selected from R1 is selected from hydrogen, C1-C6 alkyl and C1-C6 alkanoyl; R2 is selected from hydrogen and C1-C6 alkyl; R3 is selected from hydrogen and a C1-C5 alkanoyl group; R4 is selected from phenyl, phenoxy, and 5-10 membered aryl groups unsubstituted or substituted with one or more groups independently selected from nitro, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C5 alkoxy, and C1-C5 haloalkoxy; n is an integer between 1 and 5, inclusive. or a pharma- ceutically acceptable salt thereof.

[0021] In some embodiments, the airway disorder is asthma and ATPB is used to treat asthma, hi another embodiment, the airway disorder is COPD and ATPB is used to treat COPD.

[0022] In another embodiment, the airway disorder is an airway exacerbation and ATPB is used to treat or control the airway exacerbation or disease.

[0023] Asthma and COPD are the most widely recognized chronic respiratory diseases and have been increasing over recent decades. These two diseases have many similarities and differences that can hinder their diagnosis and management. Asthma-COPD ACOD appears when a patient has features of both asthma and COPD. The global prevalence of asthma, COPD and ACOD is estimated to be 6.2%, 4.9% and 2.0%, respectively

[13] .

[0024] Currently, there is no cure for asthma and COPD, and only drugs for some degree of symptomatic management are available. Therefore, new treatments with better efficacy and safety for patients with asthma, COPD and ACOD remain an unmet medical need.

[0025] The present invention will be better understood by reference to the following description of some specific embodiments thereof, as illustrated in the accompanying drawings. [Brief description of the drawings]

[0026] [Figure 1] FIG. 1 is a graph showing the effect of ATPB on ovalbumin (OVA)-induced upregulation of serum immunoglobulin E (IgE) levels. Serum was collected 24 hours after the final OVA aerosol challenge. OVA-specific IgE and total IgE levels were analyzed by enzyme-linked immunosorbent assay (ELISA). ATPB significantly reduced OVA-specific IgE levels, indicating OVA-specific inhibition of Th2 responses. [Diagram 2] Figure 1 shows the effect of ATPB on cytokine levels in OVA-induced bronchoalveolar lavage fluid (BALF) collected 24 hours after the final OVA aerosol challenge. Interleukin (IL)-4 and IL-5 levels were analyzed using ELISA. [Diagram 3] Graph showing the effect of ATPB on BALF cell infiltration. Inflammatory cell counts in BALF were obtained after saline aerosol or 1-0 mg / mL OVA challenge. ATPB significantly reduced OVA-induced inflammatory cell counts. Cell counts were performed in minicells to identify eosinophils (EO), monocytes (MO), neutrophils (NE), and lymphocytes (LY). [Figure 4] Figure 1 shows the effect of ATPB on lung tissue eosinophilia and mucus production. Histological assessment of lung tissue eosinophilia after final challenge with saline OVA aerosol or OVA aerosol + 10 mg / kg ATPB (upper panel, hematoxylin and eosin (H&E) staining, magnification). [Diagram 5] 1 is a graph showing the effect of ATPB on BALF cell infiltration. [Figure 6]Figure 1 shows the effect of ATPB on lung tissue eosinophilia and mucus production. Histological investigation of lung tissue eosinophilia (upper panel, H&E staining, magnification x400) and mucus secretion (right panel, PAS staining, magnification x400) in smoking-induced COPD and smoking-induced COPD + ATPB 10 mg / kg after 3 months. [Figure 7] Graph showing the effect of ATPB on cytokine and chemokine levels in lung tissue. Lung tissue was collected 3 months after smoking. IL-1β, TNFα and chemotactic protein-1 (MCP-1) levels were analyzed using quantitative polymerase chain reaction (PCR). [Figure 8] FIG. 1 shows the effect of post-treatment with ATPB on BALF cell infiltration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] Airway disorders, such as COPD and asthma, involve multiple inflammatory cells and various mediators. ATPB effectively reduces smoking-induced inflammatory cell recruitment to BALF, as well as TNF-α levels, IL-6 levels and MCP-1 gene expression in lung tissue, pulmonary eosinophilia and mucus hypersecretion in a rat COPD model. ATPB attenuated OVA-induced inflammatory cell recruitment to BALF, IL-4, IL-5, eotaxin production, serum IgE synthesis, pulmonary eosinophilia and mucus hypersecretion in a mouse asthma model. Our findings support the novel therapeutic use of ATPB to treat airway disorders.

[0028] The present invention provides ATPB as a modulator for the treatment of airway disorders, such as asthma or COPD. This study provides ATPB for complement steroid treatment or steroid replacement treatment during exacerbations of asthma or COPD.

[0029] Compositions and methods of the present invention To this end, the present invention provides a composition for treating at least one pulmonary disease selected from asthma, COPD and / or ACOD in a patient suffering therefrom, the composition comprising a pharma- ceutical acceptable excipient and a therapeutically effective amount of a compound represented by formula 1 or a pharma- ceutical acceptable salt thereof. [ka] (Wherein, X is CO, SO2 and (CH2) n is selected from R1 is selected from hydrogen, C1-C6 alkyl and C1-C6 alkanoyl; R2 is selected from hydrogen and C1-C6 alkyl; R3 is selected from hydrogen and a C1-C5 alkanoyl group; R4 is selected from a phenoxy group and a 5-10 membered aryl group that is unsubstituted or substituted with one or more groups independently selected from nitro, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C5 alkoxy, and C1-C5 haloalkoxy; n is an integer from 1 to 5. The present invention provides a composition comprising:

[0030] In certain embodiments, X is (CH2) n and R1 is C1-C6 alkanoyl; R2 is hydrogen; R3 is hydrogen; R4 is a 5-10 membered aryl group that is unsubstituted or substituted with one or more groups independently selected from nitro, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C5 alkoxy, and C1-C5 haloalkoxy; n is an integer from 1 to 5, inclusive.

[0031] In certain embodiments, the 5-10 membered aryl group is a phenyl group. In certain embodiments, the phenyl is substituted. In other embodiments, the phenyl is unsubstituted.

[0032] In certain embodiments, n is 2.

[0033] In certain embodiments, R2 is hydrogen.

[0034] In certain embodiments, R1 is hydrogen or -C(O)alkyl. In other embodiments, R1 is hydrogen. In other embodiments, R1 is -C(O)alkyl. In other embodiments, R1 is -C(O)CH3. Several compounds of this formula (I) have been prepared and evaluated. In certain embodiments, the compositions and methods include 5-benzylaminosalicylic acid, a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0035] In certain embodiments, the 5-benzylaminosalicylic acid compound is 5-benzylaminosalicylic acid.

[0036] Preferred examples of 5-benzylaminosalicylic acid compounds include 2-hydroxy-5-phenethylamino-benzoic acid (compound 1), 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid (compound 2), 2-hydroxy-5-[2-(3-trifluoromethyl-phenyl)-ethylamino]-benzoic acid (compound 3), 5-[2-(3,5-bistrifluoromethyl-phenyl)-ethylamino]-2-hydroxy-benzoic acid (compound 4), 2-hydroxy-5-[2-(2-nitro-phenyl)-ethylamino]-benzoic acid (compound 5), 5-[2-(4-chloro-phenyl)-ethylamino]-2-hydroxy-benzoic acid (compound 6), 5-[2-(3,4-difluoro-phenyl)-ethylamino]-2-hydroxy-benzoic acid (compound 7), 5-[2-(3,4-dichloro-phenyl)-ethylamino]-2-hydroxy-benzoic acid (compound 8), ethylamino]-2-hydroxy-benzoic acid (compound 8), 5-[2-(4-fluoro-2-trifluoromethylphenyl)-ethylamino]-2-hydroxy-benzoic acid (compound 9), 5-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-hydroxy-benzoic acid (compound 10), 2-hydroxy-5-[2-(4-methoxy-phenyl)-ethylamino]-benzoic acid (compound 11), 2-hydroxy-5-(2-o-tolylethylamino)-benzoic acid (compound 12), 2-hydroxy-5-(3-phenyl-propylamino)-benzoic acid (compound 13), 2-hydroxy-5-[3-(4-trifluoromethyl-phenyl)-propylamino]-benzoic acid (compound 14), 5-[3-(4-fluoro-phenyl)-propylamino]-2-hydroxy-benzoic acid (compound 15), 5-[3-(3,4-Dichloro-phenyl)-propylamino]-2-hydroxy-benzoic acid (Compound 16), 2-hydroxy-5-(3-p-tolyl-propylamino)-benzoic acid (Compound 17), 2-acetoxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid (Compound 18), 5-[2-(2-chloro-phenyl)-ethylamino]-2-hydroxy-benzoic acid (Compound 19), 5-benzylaminosalicylic acid (Compound 20), 5-(4-nitrobenzyl)aminosalicylic acid (Compound 21), 5-(4-chlorobenzyl)aminosalicylic acid (Compound 22), 5-(4-trifluoromethylbenzyl)aminosalicylic acid (Compound 23), 5-(4-fluorobenzyl)aminosalicylic acid (Compound 24), 5-(4-methoxybenzyl)aminosalicylic acid Acid (Compound 25), 5-(2,3,4,5,6-pentafluorobenzyl)aminosalicylic acid (Compound 26), 5-(4-nitrobenzyl)amino-2-hydroxyethyl benzoate (Compound 27), 5-(4-nitrobenzyl)-N-acetylamino-2-hydroxymethyl benzoate (Compound 28), 5-(4-nitrobenzyl)-N-acetylamino-2-acetoxyethyl benzoate (Compound 29), 5-(4-nitrobenzoyl)aminosalicylic acid (Compound 30), 5-(4-nitrobenzenesulfonyl)aminosalicylic acid (Compound 31), 5-[2-(4-nitrophenyl)-ethyl]aminosalicylic acid (Compound 32) and 5-[3-(4-nitro-phenyl)-n-propyl]aminosalicylic acid (Compound 33).

[0037] In certain preferred embodiments, the compound of formula (I) is compound 18, 2-acetoxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid, or a pharma- ceutically acceptable salt thereof, as a therapeutic agent for treating asthma, COPD, and ACOD. In some embodiments, the compound having formula (I) is the structure 2-acetoxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid (compound 18). [ka] has.

[0038] In certain preferred embodiments, the compound of formula (I) is 2,2-hydroxy-5-[2-(4-trifluoromethylphenyl)ethylamino]benzoic acid (Compound 2) or a pharma- ceutically acceptable salt thereof. In some embodiments, the compound of formula (I) has the following structure:

[0039] [ka]

[0040] In certain embodiments, the compound of formula (I) is selected from 2-acetoxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino-benzoic acid (Compound 18, ATPB) and 2-hydroxy-5-2-(4-trifluoromethyl-phenyl)-ethylamino-benzoic acid (Compound 2), and the at least one pulmonary disease is selected from asthma, COPD, and ACOD.

[0041] In certain embodiments, the compound of formula (I) is 2-acetoxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino-benzoic acid (ATPB) and the at least one pulmonary disease is selected from asthma, COPD, and AOCD.

[0042] In certain embodiments, the compound of formula (I) is a pharma- ceutically acceptable salt.

[0043] In certain embodiments, the composition is in the form of a powder.

[0044] In certain embodiments, the composition is suitable for oral administration.

[0045] In certain embodiments, the composition is a pharmaceutical composition.

[0046] The present invention relates to a method for treating at least one pulmonary disease selected from asthma, COPD, ACOD, pulmonary fibrosis, pneumonia, and lung cancer in a subject suffering therefrom, comprising administering to a patient having at least one pulmonary disease a therapeutically effective amount of a compound represented by formula 1. [ka] (Wherein, X is CO, SO2 and (CH2) n is selected from R1 is selected from hydrogen, C1-C6 alkyl and C1-C6 alkanoyl; R2 is selected from hydrogen and C1-C6 alkyl; R3 is selected from hydrogen and a C1-C5 alkanoyl group; R4 is selected from a phenoxy group and a 5-10 membered aryl group that is unsubstituted or substituted with one or more groups independently selected from nitro, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C5 alkoxy, and C1-C5 haloalkoxy; n is an integer of 1 to 5, inclusive, or a pharma- ceutically acceptable salt thereof. The method includes administering

[0047] In certain embodiments, X is (CH2) n and R1 is C1-C6 alkanoyl; R2 is hydrogen; R3 is hydrogen; R4 is a 5-10 membered aryl group that is unsubstituted or substituted with one or more groups independently selected from nitro, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C5 alkoxy, and C1-C5 haloalkoxy; n is an integer from 1 to 5, inclusive.

[0048] In certain embodiments, the 5-10 membered aryl group is a phenyl group. In certain embodiments, the phenyl is substituted. In other embodiments, the phenyl is unsubstituted.

[0049] In certain embodiments, n is 2.

[0050] In certain embodiments, R2 is hydrogen.

[0051] In certain embodiments, R1 is hydrogen or -C(O)alkyl. In other embodiments, R1 is hydrogen. In other embodiments, R1 is -C(O)alkyl. In other embodiments, R1 is -C(O)CH3.

[0052] Several such compounds of formula (I) have been prepared and evaluated. In certain embodiments, the compositions and methods include 5-benzylaminosalicylic acid, a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0053] In certain embodiments, the compound of formula (I) is 2-hydroxy-5-phenethylamino-benzoic acid, 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid, 2-hydroxy-5-[2-(3-trifluoromethylphenyl)-ethylamino]-benzoic acid, 5-[2-(3,5-bis(-trifluoromethyl-phenyl)-ethylamino]-2-hydroxy-benzoic acid, 2-hydroxy-5-[2-(2-nitro-phenyl)-ethylamino]-benzoic acid, 5-[2-(4-chlorophenyl)-ethylamino]-benzoic acid, -phenyl)-ethylamino]-2-hydroxy-benzoic acid, 5-[2-(3,4-difluoro-phenyl)-ethylamino]-2-hydroxy-benzoic acid, 5-[2-(3,4-dichloro-phenyl)-ethylamino]-2-hydroxy-benzoic acid, 5-[2-(4-fluoro-2-trifluoromethyl-phenyl)-ethylamino]-2-hydroxybenzoic acid, 5-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-hydroxy-benzoic acid, 2-hydroxy-5-[2-(4-methoxy- 2-Hydroxy-5-(2-o-tolyl-ethylamino)-benzoic acid, 2-Hydroxy-5-(3-phenyl-propylamino)-benzoic acid, 2-Hydroxy-5-[3-(4-trifluoromethyl-phenyl)-propylamino]-benzoic acid, 5-[3-(4-fluorophenyl)-propylamino]-2-hydroxy-benzoic acid, 5-[3-(3,4-dichloro-phenyl)-propylamino]-2-hydroxy-benzoic acid, 2-Hydroxy-5-(3-p-tolyl-propyla amino)-benzoic acid, 2-acetoxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid, 5-[2-(2-chloro-phenyl)-ethylamino]-2-hydroxy-benzoic acid, 5-benzylaminosalicylic acid, 5-(4-nitrobenzyl)aminosalicylic acid, 5-(4-chlorobenzyl)aminosalicylic acid, 5-(4-trifluoromethylbenzyl)aminosalicylic acid, 5-(4-fluorobenzyl)aminosalicylic acid, 5-(4-methoxybenzyl)aminosalicylic acid, 5-(2,3,4,5,6-pentafluorobenzyl)aminosalicylic acid, 5-(4-nitrobenzyl)amino-2-hydroxyethyl benzoate, 5-(4-nitrobenzyl)-N-acetylamino-2-hydroxyethyl benzoate, 5-(4-nitrobenzyl)-N-acetylamino-2-acetoxyethyl benzoate, 5-(4-nitrobenzoyl)aminosalicylic acid, 5-(4-nitrobenzenesulfonyl)aminosalicylic acid, 5-[2-(4-nitrophenyl)-ethyl]aminosalicylic acid and 5-[3-(4-nitrophenyl)-n-propyl]aminosalicylic acid. In certain embodiments, the compound of formula (I) is selected from 2-acetoxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino-benzoic acid (Compound 18, ATPB) and 2-hydroxy-5-2-(4-trifluoromethyl-phenyl)-ethylamino-benzoic acid (Compound 2), and the at least one pulmonary disease is selected from asthma, COPD, and ACOD.

[0054] In certain embodiments, the compound of formula (I) is 2-acetoxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino-benzoic acid (ATPB) and the at least one pulmonary disease is selected from asthma, COPD, and AOCD.

[0055] In certain embodiments, the compound of formula (I) is a pharma- ceutically acceptable salt.

[0056] In certain embodiments of the methods, the compound is present in a composition that also includes a pharma- ceutically acceptable excipient.

[0057] In certain embodiments, the composition is in the form of a powder.

[0058] In certain embodiments, the composition is administered orally.

[0059] In certain embodiments, the at least one pulmonary disease is asthma.

[0060] In certain embodiments, the asthma is selected from glucocorticoid-resistant asthma and childhood asthma.

[0061] In certain embodiments, a composition for treating asthma in combination with one or more additional therapeutic agents for treating asthma in a patient.

[0062] In certain embodiments, the methods further comprise the step of conjointly or simultaneously administering to the patient one or more additional therapeutic agents for treating asthma.

[0063] In certain embodiments, the one or more additional therapeutic agents for treating asthma are selected from corticosteroids (e.g., hydrocortisone, budesonide, methylprednisolone, fluticasone, mometasone, and dexamethasone).

[0064] In certain embodiments, the one or more additional therapeutic agents for treating asthma are selected from β2 agonists (e.g., short-acting or long-acting bronchodilators, such as formoterol and salmeterol).

[0065] In certain embodiments, the one or more additional therapeutic agents for treating asthma are selected from anticholinergics (eg, ipratropium, oxitropium, and tiotropium).

[0066] In certain embodiments, the one or more additional therapeutic agents for treating asthma are selected from a leukotriene receptor antagonist (e.g., montelukast, zafirlukast) or a 5-lipoxygenase inhibitor (e.g., zileuton).

[0067] In certain embodiments, the one or more additional therapeutic agents for treating asthma are selected from oral xanthines (eg, theophylline and aminophylline).

[0068] In certain embodiments, the one or more additional therapeutic agents for treating asthma are selected from antihistamines (e.g., levocetirizine, fexofenadine).

[0069] In certain embodiments, the one or more additional therapeutic agents for treating asthma are selected from anti-IgE antibody therapy (e.g., omalizumab).

[0070] In certain embodiments, the one or more additional therapeutic agents for treating asthma are selected from anti-interleukin-5 therapies (e.g., benralizumab, mepolizumab, reslizumab).

[0071] In certain embodiments, the one or more additional therapeutic agents for treating asthma are selected from corticosteroids, beta 2 agonists, anticholinergics, leukotriene receptor antagonists, 5-lipoxygenase inhibitors, oral xanthines, antihistamines, anti-IgE antibody therapy, and anti-interleukin-5 therapy.

[0072] In certain embodiments, the at least one pulmonary disease is COPD and ACOD.

[0073] In certain embodiments, a composition for treating COPD or ACOD in combination with one or more additional therapeutic agents for COPD or ACOD in a patient.

[0074] In certain embodiments, the methods further comprise the step of concurrently or simultaneously administering to the patient one or more additional therapeutic agents for treating COPD or ACOD.

[0075] In certain embodiments, the one or more additional therapeutic agents for treating COPD or ACOD are selected from corticosteroids (e.g., beclomethasone, ciclesonide, budesonide, fluticasone).

[0076] In certain embodiments, the one or more additional therapeutic agents for treating COPD or ACOD are selected from β2 agonists with short-acting or long-acting bronchodilation (e.g., fenoterol, salbutamol, formoterol, salmeterol, and indacaterol).

[0077] In certain embodiments, the one or more additional therapeutic agents for treating COPD or ACOD are selected from anticholinergics (e.g., ipratropium).

[0078] In certain embodiments, the one or more additional therapeutic agents for treating COPD or ACOD are selected from long-acting muscarinic receptor antagonists (LAMAs) (e.g., tiotropium bromide, glycopyrronium bromide, and aclidinium bromide).

[0079] In certain embodiments, the one or more additional therapeutic agents for treating COPD or ACOD are selected from phosphodiesterase 4 (PDE4) inhibitors (e.g., roflumilast).

[0080] In certain embodiments, the one or more additional therapeutic agents for treating COPD or ACOD are selected from corticosteroids, beta 2 agonists with short or long acting bronchodilation, anticholinergics, LAMAs, and PDE4 inhibitors (e.g., fluticasone / salmeterol, budesonide / formoterol, and ipratropium / beta 2 agonist).

[0081] In certain embodiments, a composition for treatment, wherein the treatment comprises reducing any pathologically increased TH2 cytokines (e.g., TNF-α, IL-6, and / or MCP-1) in a patient.

[0082] In certain embodiments, the method, wherein the treatment comprises reducing any pathologically elevated TH2 cytokines (e.g., TNF-α, IL-6, and / or MCP-1) in the patient.

[0083] In certain embodiments, a composition for treatment, wherein the treatment comprises reducing any pathologically increased TH2 cytokines (e.g., IL-4 and / or IL-5) in a patient.

[0084] In certain embodiments, the method, wherein the treatment comprises reducing any pathologically elevated TH2 cytokines (e.g., IL-4 and / or IL-5) in the patient.

[0085] In certain embodiments, a composition for treatment, wherein the dosage of the compound for treating a patient is from about 1 μg / kg to about 200 mg / kg per day.

[0086] In certain embodiments, the method, wherein a dosage of about 1 μg / kg to about 200 mg / kg of the compound is administered to the patient per day.

[0087] The 5-benzylaminosalicylic acid compounds or pharma- ceutically acceptable salts thereof of the present disclosure can be prepared by, but not limited to, the reaction schemes shown in U.S. Pat. No. 6,573,402, which is incorporated herein by reference.

[0088] A preferred embodiment of the present invention, 2-acetoxy-5-2-(4-trifluoromethyl-phenyl)-ethylamino-benzoic acid (compound 18), can be prepared by, but is not limited to, the reaction schemes shown in U.S. Pat. Nos. 8,598,383 and 8,686,185, each of which is incorporated herein by reference.

[0089] A preferred example of the present invention, 2-hydroxy-5-2-(4-trifluoromethyl-phenyl)-ethylamino-benzoic acid (compound 2), can be prepared by, but is not limited to, the reaction scheme shown in U.S. Pat. No. 8,598,383, which is incorporated herein by reference.

[0090] Next, pharmaceutical compositions for treating or preventing COPD and asthma, and methods for treating or preventing COPD and asthma will be described in more detail.

[0091] definition The definitions of terms set forth below apply to the use of the terms individually or in combination with other terms.

[0092] The term "acetoxy" refers to a group represented by the general formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0093] The term "acetyl" refers to a group represented by the general formula CH3C(O). An "alkyl" group (including the "alkyl" of haloalkyl) or "alkane" is a fully saturated straight or branched chain non-aromatic hydrocarbon. Typically, a straight or branched chain alkyl group has from 1 to about 20, preferably from 1 to about 10 carbon atoms, unless otherwise defined. A C1-C6 straight or branched chain alkyl group is referred to as a "lower alkyl" group. In some embodiments, the alkyl is a C1-C5 alkyl, preferably a C1-C3 alkyl. More specifically, preferred alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

[0094] Furthermore, the term "alkyl" (or "lower alkyl"), as used throughout the specification, examples, and claims, is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter of which refers to alkyl moieties having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone. Unless otherwise specified, such substituents can include, for example, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl, e.g., alkyl C(O), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, silyl ether, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. Where appropriate, the substituted moieties on the hydrocarbon chain may be selected from the group consisting of aryl, ... It will be understood by those skilled in the art that it may itself be substituted. For example, the substituents of substituted alkyl may include substituted and unsubstituted amino, azido, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamides, sulfamoyls and sulfonates) and silyl groups, as well as ethers, alkylthiols, carbonyls (including ketones, aldehydes, carboxylates and esters), -CF3 and -CN. Representative substituted alkyls are described below. Cycloalkyls may be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, etc.

[0095] The term "Cx-y" when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, refers to the inclusion of groups containing from x to y carbons in the chain. For example, "Cx-y alkyl" refers to substituted or unsubstituted saturated hydrocarbon groups including straight-chain alkyl and branched-chain alkyl groups containing from x to y carbons in the chain, including, for example, haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. C0 alkyl refers to a hydrogen if the group is in a terminal position, or a bond if internal. The terms "C2-alkenyl" and "C2-alkynyl" refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but containing at least one double or triple bond, respectively.

[0096] The term "alkanoyl" refers to a group represented by the general formula hydrocarbyl-C(O), preferably alkyl-C(O)-.

[0097] The term "alkoxy" (including the "alkoxy" of haloalkoxy) refers to an alkyl group, preferably a lower alkyl group, having an oxygen bonded thereto. In some embodiments, preferably, alkoxy is a C1-C5 alkoxy, more preferably a C1-C3 alkoxy. More specifically, preferred alkoxy includes, but is not limited to, methoxy, ethoxy, and propanoxy. Halogen includes, but is not limited to, fluoride, chloride, bromide, and iodide. Preferably, alkanoyl is a C2-C5 alkoxy, more preferably a C1-C3 alkoxy. 10 Alkanoyl, more preferably C3 to C5 alkanoyl. More specifically, preferred alkanoyl includes, but is not limited to, ethanoyl, propanoyl and cyclohexanecarbonyl.

[0098] The terms "amine" and "amino" are art-recognized and refer to both unsubstituted and substituted amines and their salts, e.g., [ka] (In the formula, each R 10 R independently represents a hydrogen or a hydrocarbyl group, or two R 10 together with the N atom to which they are attached complete a heterocycle having 4-8 atoms in the ring structure) It refers to a portion that can be replaced by:

[0099] The term "aryl" as used herein includes substituted or unsubstituted monocyclic aromatic groups in which each atom of the ring is carbon. Preferably, the ring is 5-10 membered, more preferably 6-10 membered or 6 membered. The term "aryl" also includes polycyclic systems having two or more cyclic rings, in which two or more carbons are shared between two adjacent rings, at least one of the rings is aromatic, for example, the other cyclic rings can be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Representative substituents on an aryl group include, for example, halogen, haloalkyl, such as trifluoromethyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl, such as alkyl C(O)), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azide, silyl ether, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamide, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.

[0100] The terms "halo" and "halogen" as used herein mean halogen and include chloro, fluoro, bromo and iodo.

[0101] The term "lower" when used in conjunction with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy includes groups in which there are 10 or fewer non-hydrogen atoms in the substituent, preferably 6 or fewer. "Lower alkyl" refers to alkyl groups, for example, containing 10 or fewer carbon atoms, preferably 6 or fewer. In certain preferred embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents defined herein are lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, respectively, occurring either alone or in combination with other substituents in the list, such as hydroxyalkyl and aralkyl (where, for example, atoms in aryl groups are not counted when counting carbon atoms in an alkyl substituent).

[0102] The term "substituted" refers to a moiety that contains a substituent replacing a hydrogen atom on one or more carbon atoms of the backbone. The terms "substituted" and "substituted with" are implicit so long as such substitution is in accordance with the permissible valences of the substituted atom and the substituent, and so long as the substitution results in a stable compound, e.g., one that does not spontaneously change by rearrangement, cyclization, or elimination, etc. As used herein, "substituted" includes all permissible substituents in organic compounds. In a broad aspect, permissible substituents include acyclic or cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Permissible substituents can be one or more and the same or different for appropriate organic compounds. For the present invention, heteroatoms, e.g., nitrogen, may have hydrogen substituents or any permissible substituent of organic compounds described herein that satisfies the valence of the heteroatom. The substituents may include any of the substituents described herein, such as halogen, haloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, aryl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that, where appropriate, the substituents may themselves be substituted. Unless specifically indicated as "unsubstituted," references to chemical moieties herein include substituted variants. For example, references to "aryl" groups or moieties implicitly include substituted and unsubstituted variants.

[0103] The phrase "conjoint administration" as used herein refers to any form of administration of two or more different therapeutic agents, such that the second agent is administered while the previously administered therapeutic agent is still effective in the body (e.g., the two agents are effective simultaneously in the patient, which may involve a synergistic effect of the two agents). For example, the different therapeutic compounds can be administered simultaneously or sequentially in the same or separate formulations. Thus, an individual undergoing such treatment can benefit from the combined effect of the different therapeutic agents.

[0104] The term "pharmaceutically acceptable salts" as used in this disclosure refers to salts prepared with non-toxic or slightly toxic acids or bases. Pharmaceutically acceptable base addition salts include, but are not limited to, salts prepared with sodium, potassium, calcium, ammonium, magnesium, or organic amino. If the compound of the present disclosure is basic, an acid addition salt of the compound can be prepared by reacting the free base of the compound with a sufficient amount of the desired acid and a sufficient inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, propionic acid, isobutyric acid, oxalic acid, malic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, hydrochloric acid, bromic acid, nitric acid, carboxylic acid, monohydrogen carboxylic acid, phosphoric acid, monohydrogen-phosphoric acid, dihydrogen-phosphoric acid, sulfuric acid, monohydrogen-sulfuric acid, hydrogen iodide, and phosphorous acid. In addition, pharma- ceutically acceptable salts of the present disclosure include, but are not limited to, salts of amino acids, such as arginate salts, and organic acid analogs, such as glucuronic acid or galacturonic acid.

[0105] For example, a pharma- ceutically acceptable salt of 2-hydroxy-5-[2-(4-trifluoromethylphenyl)-ethylamino]-benzoic acid (compound 2), which is a preferred example of the present disclosure, can be prepared using the method described in U.S. Patent No. 8,598,383, which is incorporated herein by reference. However, the following reaction methods are provided by way of example and are not intended to limit the scope of the present disclosure.

[0106] Some of the compounds of the present disclosure may be hydrated and may exist in solvated or nonsolvated form. According to the present disclosure, some of the compounds may exist in crystalline or amorphous form, and any physical form is included within the scope of the present disclosure. Furthermore, some of the compounds of the present disclosure may contain one or more asymmetric carbon atoms or double bonds. Therefore, they may exist in two or more stereoisomeric forms, such as racemates, enantiomers, diastereomers, and geometric isomers. The present disclosure includes these individual stereoisomers.

[0107] composition The present disclosure also provides a composition for asthma, COPD and ACOD, comprising a 5-benzylaminosalicylic acid derivative represented by the above formula (I) or a pharma- ceutically acceptable salt thereof and a pharma-ceutically acceptable excipient or additive. The 5-benzylaminosalicylic acid derivative represented by the above formula (I) or a pharma-ceutically acceptable salt thereof of the present disclosure may be administered alone. In some embodiments, the composition comprising the compound of formula (I) is administered together with a convenient carrier, diluent, etc.

[0108] In some embodiments, the dosage of the composition is in the range of about 1 μg / kg to 200 mg / kg of the compound of formula (I) per day. In some embodiments, the dosage of the composition is in the range of about 10 μg / kg to 10 mg / kg of the compound of formula (I) per day. However, the dosage may vary depending on the condition or characteristics of the patient (age, sex, weight, etc.), the severity of the patient in need thereof, the active ingredient used, and the diet. The compounds of the present invention may be administered once a day, or several times a day in divided doses if necessary.

[0109] In some embodiments, the formulation may be administered as a single dose or multiple dose units. In some embodiments, the composition comprises a single dose unit. In some embodiments, the composition comprises multiple dose units. The compositions for oral administration of the present disclosure may be formulated in solid or liquid form. Solid formulations include, but are not limited to, powders, granules, tablets, capsules, and suppositories. In addition, solid formulations may further include, but are not limited to, diluents, flavors, binders, preservatives, disintegrants, lubricants, fillers, plasticizers, and the like. Liquid formulations include, but are not limited to, liquids, such as aqueous solutions and propylene glycol solutions, suspensions, and emulsions, which may be prepared by adding suitable additives, such as colorants, flavors, stabilizers, and thickeners. In some embodiments, the compositions are administered in a form selected from capsules, tablets, powders, and solutions. In some embodiments, the compositions are administered by mixing with a dietary supplement. In some embodiments, the compositions are administered as a dietary supplement. In some embodiments, the compositions are administered by mixing with a food. In some embodiments, the compositions are administered as a food composition. In some embodiments, the compositions are administered by dissolving in water. In some embodiments, the compositions are administered as a capsule with water. In some embodiments, the compositions are administered as a chewable tablet.

[0110] For example, powders can be prepared by mixing the 5-benzylaminosalicylic acid derivatives of the present disclosure with pharma- ceutically acceptable excipients, such as lactose, starch, and microcrystalline cellulose. Granules can be prepared by mixing the compounds with pharma- ceutically acceptable excipients. In some embodiments, the pharma- ceutically acceptable excipients include diluents and / or pharma- ceutically acceptable binders. In some embodiments, the binders are polyvinylpyrrolidone, hydroxypropyl cellulose, and the like.

[0111] In some embodiments, the composition is formed by wet granulation using sufficient solvent, such as water, ethanol, and isopropanol. In some embodiments, the composition is formed by direct compression using compression power. Additionally, tablets can be prepared by mixing the granules with a pharma- ceutically acceptable lubricant, such as magnesium stearate, and compressing the mixture.

[0112] The pharmaceutical composition of the present disclosure may be administered in the form of, but is not limited to, oral preparations, injectable preparations (e.g., intramuscular, intraperitoneal, intravenous, drip, subcutaneous, implant), inhalation, intranasal, vaginal, rectal, sublingual, transdermal, topical, etc., depending on the disorder to be treated and the condition of the animal. The composition of the present disclosure may be formulated in an appropriate dosage unit containing non-toxic pharmaceutically acceptable carriers, additives and / or vehicles commonly used in the art, all of which are suitable for the route of administration. Depot-type preparations capable of continuously releasing drugs at a desired time are also included within the scope of the present disclosure. EXAMPLES

[0113] The present invention will now be described with reference to the following examples. These examples are provided for illustrative purposes only, and the present invention should in no way be construed as being limited to these examples, but rather as embracing any and all variations that become evident as a result of the teachings provided herein. The materials and methods used in these examples are as follows:

[0114] Materials and Methods asthma Seven-week-old female Balb / C mice were sensitized by intraperitoneal injection (IP, 200 μL / mouse) of 100 μg OVA complexed with aluminum potassium sulfate on days 0, 7, and 14. Mice were challenged with 5% aerosolized OVA in 48 mL of sterile phosphate-buffered saline (PBS) on days 26, 27, and 28. The control group received sterile PBS with aluminum potassium sulfate by IP route on days 0, 7, and 14, and 48 mL of aerosolized sterile PBS on days 26, 27, and 28. On days 22, 27, 28, and 29, mice in the ATPB group were orally administered 10 mg / kg ATPB twice daily.

[0115] COPD A rat model of COPD was established by smoke exposure and intratracheal instillation of lipopolysaccharide (LPS) as previously described. Experimental rats, including COPD and drug-treated groups (10 mg / kg ATPB), were subjected to daily whole-body exposure to tobacco smoke from 10 cigarettes with a 2-h smoke-free interval twice a day in a cigarette smoke chamber (90 × 40 × 30 cm, Plexiglas) for 12 weeks.

[0116] Animals from the two smoke-exposed groups were intratracheally administered 180 μg / 180 μL LPS solution on two occasions, on the first and 14th days of cigarette smoke exposure. In addition, rats in the ATPB group were orally administered ATPB (10 mg / kg ATPB). All rats were sacrificed on the 91st day.

[0117] A porcine pancreatic elastase (PPE)-induced emphysema model was used to measure the effect of post-treatment with ATPB in COPD model mice. C57BL / 6J mice were intratracheally injected with PPE (0.8 U per mouse) in PBS with a micropipette. Mice were randomly divided into four groups: (A) emphysema group exposed to intratracheal PPE, (B) emphysema + ATPB (5 mg / kg ATPB, PO, twice daily), (C) emphysema + ATPB (10 mg / kg ATPB, PO, twice daily), (D) emphysema + roflumilast (10 mg / kg, PO, once daily), and (E) emphysema + prednisolone (1 mg / kg, PO, once daily). All treatments were started 3 days after PPE injection. Mice were sacrificed 21 days after PPE injection.

[0118] Preparation of BALF and cell counts Rats and mice were sacrificed, and BALF was obtained by cannulating the trachea and lavaging three times with 2 mL of DPBS. BALF cells were centrifuged at 1000×g for 10 min at 4° C. The supernatant was collected and stored at −80° C. to measure inflammatory factors. Pelleted BALF cells were resuspended in 1 mL of PBS and quantified using a hematology analyzer (Mindray Medical International Ltd., Shenzhen, China).

[0119] RNA isolation and real-time PCR for gene expression Total RNA from lung tissues was extracted using TRIzol reagent (Invitrogen) according to the manufacturer's instructions. cDNA was synthesized using a cDNA synthesis kit (Life Technologies). SYBR Green Master Mix (Thermo Fisher) was used for PCR amplification on a StepOnePlus real-time PCR system (Applied Biosystems, Foster City, CA, USA). Specific primers were designed as shown in Table 1.

[0120] histopathology The lungs of the rats were removed at week 12 and fixed in 10% neutral buffered formalin for histopathological analysis. The formalin-fixed tissues were embedded in paraffin, sectioned at 3–5 mm, and stained with hematoxylin and eosin (HE) and alcian blue periodic acid-Schiff (AB-PAS) to reveal histopathological lesions.

[0121] statistical analysis GraphPad Prism 5.0 was used for all statistical analyses. Differences between groups were analyzed using one-way analysis of variance (ANOVA) followed by Tukey's multiple comparison test (for multiple groups). All data are presented as mean ± standard error of the mean.

[0122] result Treatment with ATPB attenuates serum IgE production ELISA was performed to evaluate the effect of ATPB on IgE production. The results revealed that the production of IgE in serum was higher in OVA-challenged mice than in normal control mice (Figure 1). However, the increase in the level of IgE was significantly reduced in ATPB-treated mice compared with OVA-challenged mice.

[0123] Treatment with ATPB reduces the levels of Th2 cytokines in BALF Because Th2 cytokines are involved in the airway inflammatory response in allergic asthma, we used ELISA to examine the production of Th2 cytokines, including IL-4 and IL-5. OVA-challenged mice showed a significant increase in IL-4 and IL-5 production compared with normal control mice. However, this level was significantly downregulated in the ATPB-treated group (Figure 2).

[0124] Treatment with ATPB attenuated inflammatory cells in the BALF of asthmatic mice The OVA group had significantly increased numbers of inflammatory cells, including WBC, LY, MO, and EO, in BALF (p<.05) compared to the normal group (Figure 3). The ATPB group showed a significant decrease in the cell counts of WBC, LY, MO, and EO, especially eosinophils, compared to the vehicle group.

[0125] Treatment with ATPB inhibits inflammatory cell influx and mucus hypersecretion in the lungs H&E staining was performed to determine whether ATPB influenced OVA-induced inflammatory cell recruitment. In OVA-challenged mice, cellular infiltration into peribranchial lung lesions was significantly increased. However, this cellular infiltration was markedly downregulated in ATPB-treated mice. PAS staining was performed to evaluate the effect of ATPB on mucus production. The results revealed mucus hypersecretion in the bronchial airways of OVA-challenged mice. Notably, this level was attenuated in the lungs of ATPB-treated mice compared with that of OVA-challenged mice (Figure 4). These results indicate that ATPB may be useful in airway inflammation by suppressing inflammatory cell recruitment and mucus production (Figure 4).

[0126] ATPB reduces the number of inflammatory cells in BALF To evaluate whether ATPB affected inflammation in the lung, the number of inflammatory cells in BALF was analyzed. As shown in Figure 5, LPS and CS (chronic smoking) challenge caused an increase in the total WBC number in BALF compared with the control group. Compared with the vehicle group, the ATPB group showed a significantly decreased WBC number.

[0127] ATPB reduces pulmonary inflammatory responses in a rat COPD model The effect of chronic smoking on the destruction of alveolar structure was evaluated. Histopathological examination of hematoxylin and eosin stained lung sections revealed necrosis of bronchial mucosal epithelial cells in the chronic smoking group. The alveolar sacs and alveolar spaces were enlarged, and the alveolar walls were thickened (Figure 6). After treatment with ATPB, the alveolar sacs and spaces were restored compared with those in the COPD group (Figure 6). ATPB protected against chronic smoking-induced pathological destruction and inflammatory infiltration in the lungs.

[0128] Goblet products in the tracheal epithelium were stained with PAS, and then the positive PAS stained area was measured and analyzed as goblet metaplasia and mucus secretion. Histological evaluation showed that goblet cell proliferation and mucus obstruction induced by cigarette smoke were significantly increased in the chronic smoking-induced rat model compared with the ATPB group (Figure 6). However, rats treated with ATPB (10 mg / kg) showed a decreased level of mucus secretion and decreased goblet cell proliferation (PAS+ cells) compared with COPD rats (Figure 6).

[0129] ATPB treatment reduces the mRNAs of TNF-α, IL-1β and MCP-1 Gene expression of TNF-α, IL-6 and MCP-1 in the lung was evaluated using RT-PCR. In the COPD group, the mRNA expression levels of genes encoding TNF-α, IL-6 and MCP-1 were significantly higher than those in the control group (Figure 7, P<0.01 or P<0.05). Compared with the COPD group, the gene expression levels of TNF-α, IL-6 and MCP-1 were reduced in all ATPB-treated groups and the prednisolone group (Figure 7, P<0.01 or P<0.05).

[0130] ATPB posttreatment reduces pulmonary inflammatory responses in a mouse COPD model The number of WBCs in BALF was compared to compare the effect of post-treatment with ATPB, roflumilast, or prednisolone after induction of emphysema in PPE-induced COPD (Figure 8, P<0.05). Each drug was administered from d days after PPE treatment, and mice were sacrificed on day 21. Compared with the vehicle group, the 10 mg / kg ATPB group showed a significantly decreased WBC count. Neither roflumilast nor prednisolone decreased the WBC count. [Industrial Applicability]

[0131] This study identifies compounds, including compound 18 (ATPB), and methods of administering a therapeutically effective amount of compound 18 to treat respiratory diseases, such as asthma, COPD, and ACOD. The compositions and methods of the disclosure are useful for treating tissue damage in pulmonary diseases.

[0132] Incorporation by Reference All publications and patents mentioned in this specification are herein incorporated by reference in their entirety as if each individual publication or patent was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control.

[0133] Equivalent While specific embodiments of the subject invention have been discussed, the above detailed description is illustrative and not restrictive. Many variations of the invention will become apparent to those skilled in the art upon review of this specification and the claims that follow. The full scope of the invention should be determined by reference to the claims, along with their equivalents and the full scope of the specification and such variations.

[0134] References 1. Lewis, BW, et al., Oxidative Stress Promotes Corticosteroid Insensitivity in Asthma and COPD. Antioxidants (Basel), 2021. 10(9). 2. Crystal, R.G., Airway basal cells. The "smoking gun" of chronic obstructive pulmonary disease. Am J Respir Crit Care Med, 2014. 190(12): p. 1355-62. 3. Pauwels, R.A., et al., Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: National Heart, Lung, and Blood Institute and World Health Organization Global Initiative for Chronic Obstructive Lung Disease (GOLD): executive summary. Respir Care, 2001. 46(8): p. 798-825. 4. Walters, E.H., et al., Fully integrating pathophysiological insights in COPD: an updated working disease model to broaden therapeutic vision. Eur Respir Rev, 2021. 30(160). 5. Rabe, K.F., et al., Effect of roflumilast in patients with severe COPD and a history of hospitalisation. Eur Respir J, 2017. 50(1). 6. Barnes, P.J., Inflammatory endotypes in COPD. Allergy, 2019. 74(7): p. 1249-1256. 7. Fowdar, K., et al., The effect of N-acetylcysteine on exacerbations of chronic obstructive pulmonary disease: A meta-analysis and systematic review. Heart Lung, 2017. 46(2): p. 120-128. 8. Rogliani, P., et al., Efficacy and safety profile of mucolytic / antioxidant agents in chronic obstructive pulmonary disease: a comparative analysis across erdosteine, carbocysteine, and N-acetylcysteine. Respir Res, 2019. 20(1): p. 104. 9. Ryu, B.R., et al., The novel neuroprotective action of sulfasalazine through blockade of NMDA receptors. J Pharmacol Exp Ther, 2003. 305(1): p. 48-56. 10. Vane, J.R. and R.M. Botting, The mechanism of action of aspirin. Thromb Res, 2003. 110(5-6): p. 255-8. 11. Wu, K.K., Aspirin and other cyclooxygenase inhibitors: new therapeutic insights. Semin Vasc Med, 2003. 3(2): p. 107-12. 12. Lee, J.H., et al., Prevention effects of ND-07, a novel drug candidate with a potent antioxidative action and anti-inflammatory action, in animal models of severe acute pancreatitis. Eur J Pharmacol, 2012. 687(1-3): p. 28-38. 13. Hosseini, M., et al., Global prevalence of asthma-COPD overlap (ACO) in the general population: a systematic review and meta-analysis. Respir Res, 2019. 20(1): p. 229.

Claims

1. A composition for treating at least one pulmonary disease selected from asthma, COPD, ACOD, pulmonary fibrosis, pneumonia, and lung cancer in a patient suffering therefrom, the composition comprising a pharmaceutically acceptable excipient and a therapeutically effective amount of a compound represented by formula 1. 【Chemistry 1】 (In the formula, X is CO, SO 2 and (CH 2 ) n is selected from R 1 is hydrogen, C 1 ~C 6 Alkyl and C 1 ~C 6 alkanoyl, R 2 is hydrogen and C 1 ~C 6 alkyl, R 3 is hydrogen and C 1 ~C 5 alkanoyl groups, R 4 is a phenoxy group, and is unsubstituted or substituted with nitro, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 5 Alkoxy and C 1 ~C 5 haloalkoxy; wherein n is an integer from 1 to 5, inclusive), or a pharmaceutically acceptable salt thereof.

2. X is (CH 2 ) n and R 1 C 1 ~C 6 is alkanoyl, R 2 is hydrogen, R 3 is hydrogen, R 4 is unsubstituted or is selected from nitro, halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 5 Alkoxy and C 1 ~C 5 a 5- to 10-membered aryl group substituted with one or more groups independently selected from haloalkoxy; 2. The composition of claim 1, wherein n is an integer from 1 to 5, inclusive.

3. 2. The composition of claim 1, wherein the 5- to 10-membered aryl group is a phenyl group.

4. The compound of formula (I) is 2-hydroxy-5-phenethylamino-benzoic acid, 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid, 2-hydroxy-5-[2-(3-trifluoromethylphenyl)-ethylamino]-benzoic acid, 5-[2-(3,5-bis(-trifluoromethyl-phenyl)-ethylamino]-2-hydroxy-benzoic acid, 2-hydroxy-5-[2-(2-nitro-phenyl)-ethylamino]-benzoic acid, 5-[2-(4-chloro-phenyl)-ethylamino]-benzoic acid, ethylamino]-2-hydroxy-benzoic acid, 5-[2-(3,4-difluoro-phenyl)-ethylamino]-2-hydroxy-benzoic acid, 5-[2-(3,4-dichloro-phenyl)-ethylamino]-2-hydroxy-benzoic acid, 5-[2-(4-fluoro-2-trifluoromethyl-phenyl)-ethylamino]-2-hydroxy-benzoic acid, 5-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-hydroxy-benzoic acid, 2-hydroxy-5-[2-(4-methoxy-phenyl) -ethylamino]-benzoic acid, 2-hydroxy-5-(2-o-tolyl-ethylamino)-benzoic acid, 2-hydroxy-5-(3-phenyl-propylamino)-benzoic acid, 2-hydroxy-5-[3-(4-trifluoromethyl-phenyl)-propylamino]-benzoic acid, 5-[3-(4-fluorophenyl)-propylamino]-2-hydroxy-benzoic acid, 5-[3-(3,4-dichloro-phenyl)-propylamino]-2-hydroxy-benzoic acid, 2-hydroxy-5-(3-p-tolyl-propylamino) -benzoic acid, 2-acetoxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid, 5-[2-(2-chloro-phenyl)-ethylamino]-2-hydroxy-benzoic acid, 5-benzylaminosalicylic acid, 5-(4-nitrobenzyl)aminosalicylic acid, 5-(4-chlorobenzyl)aminosalicylic acid, 5-(4-trifluoromethylbenzyl)aminosalicylic acid, 5-(4-fluorobenzyl)aminosalicylic acid, 5-(4-methoxybenzyl)aminosalicylic acid, 5-(2,3,4,5,6-pentafluorobenzyl)aminosalicylic acid, 5-(4-nitrobenzyl)amino-2-hydroxyethyl benzoate, 5-(4-nitrobenzyl)-N-acetylamino-2-hydroxyethyl benzoate, 5-(4-nitrobenzyl)-N-acetylamino-2-acetoxyethyl benzoate, 5-(4-nitrobenzoyl)aminosalicylic acid, 5-(4-nitrobenzenesulfonyl)aminosalicylic acid, 5-[2-(4-nitrophenyl)-ethyl]aminosalicylic acid, and 5-[3-(4-nitrophenyl)-n-propyl]aminosalicylic acid.

5. 5. The composition of claim 4, wherein the compound of formula (I) is selected from 2-acetoxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino-benzoic acid (Compound 18, ATPB) and 2-hydroxy-5-2-(4-trifluoromethyl-phenyl)-ethylamino-benzoic acid (Compound 2), and the at least one pulmonary disease is selected from asthma, COPD, and ACOD.

6. 6. The composition of claim 5, wherein the compound of formula (I) is 2-acetoxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino-benzoic acid (ATPB) and the at least one pulmonary disease is selected from asthma, COPD, and AOCD.

7. 10. The composition of claim 1, wherein the compound of formula (I) is a pharmaceutically acceptable salt.

8. 10. The composition of claim 1 in the form of a powder.

9. 10. The composition of claim 1, suitable for oral administration.

10. 7. The composition of claim 1, wherein the composition is in the form of a powder.

11. 10. The composition of any one of claims 1 to 9, wherein the at least one pulmonary disease is asthma.

12. 12. The composition of claim 11, wherein the asthma is selected from glucocorticoid-resistant asthma and childhood asthma.

13. 10. The composition of any one of claims 1 to 9, further comprising the step of co-administering to the patient one or more additional therapeutic agents for treating asthma.

14. The one or more additional therapeutic agents for treating asthma include corticosteroids, beta 2 14. The composition of claim 13, wherein the antihistamine is selected from an agonist, an anticholinergic, a leukotriene receptor antagonist, a 5-lipoxygenase inhibitor, an oral xanthine, an antihistamine, an anti-IgE antibody therapy, and an anti-interleukin-5 therapy.

15. 10. The composition of any one of claims 1 to 9, further comprising the step of co-administering to the patient one or more additional therapeutic agents for treating COPD or ACOD.

16. The one or more additional therapeutic agents for treating COPD or ACOD may be corticosteroids, beta-2 agonists with short- or long-acting bronchodilators, anticholinergics, LAMAs and PDE4 inhibitors (e.g., fluticasone / salmeterol, budesonide / formoterol, and ipratropium / beta-agonists). 2 16. The composition of claim 15, wherein the compound is selected from the group consisting of a hydroxybenzoate (hydroxybenzoate) and a hydroxybenzoate agonist.

17. 10. The composition of any one of claims 1 to 9, wherein the treatment comprises reducing any pathologically elevated TH2 cytokines (e.g., TNF-α, IL-6, and / or MCP-1) in the patient.

18. 10. The composition of any one of claims 1 to 9, wherein the treatment comprises reducing any pathologically elevated TH2 cytokines (e.g., IL-4 and / or IL-5) in the patient.

19. 10. The composition of any one of claims 1 to 9, wherein the dosage of the compound for treating the patient is from about 1 μg / kg to about 200 mg / kg per day.

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