Uses of compounds, pharmaceutical formulations, methods of treating asthma and / or COPD, and compounds

Abstract

The present invention is in the field of pharmacology and medicine and relates to the use of coumarin derivative compounds for treating asthma and / or chronic obstructive pulmonary disease (COPD). The inventors have found that inhaled Braylin has high therapeutic efficacy in treating asthma and COPD, and its efficacy is comparable to that of systemic dexamethasone, making it an unprecedented alternative to conventional treatments.

Description

[Technical field]

[0001] The present invention is in the field of pharmacology and medicine and relates to the use of coumarin derived compounds for the treatment of asthma and / or chronic obstructive pulmonary disease (COPD). [Background technology]

[0002] The most common diseases in society are those directly or indirectly linked to the respiratory system. The manifestations of these diseases are very wide and have various causes, which may be related to genetic factors, pollution, and bad habits (smoking). Of these respiratory diseases, asthma and chronic obstructive pulmonary disease (COPD) are the most common diseases in the world population (WHO, 2021).

[0003] Due to this high incidence, medical science is evolving with new treatment methods for respiratory diseases. Therefore, new drug formulations, including natural and synthetic compositions, are offered to people to improve the effectiveness of therapy.

[0004] Despite biotechnological advances in the treatment of respiratory diseases, there are still barriers to be overcome. In this sense, it is common for drug-based therapies to have side effects ranging from weight gain to cardiac problems.

[0005] In the early 1990s, asthma was defined as a syndrome characterized by variable and reversible airway obstruction with an abnormally increased response to various stimuli. However, despite the existence of definitions, there was still no consensus definition of the disease due to the variable causes, mechanisms, and response to therapy (Non-Patent Document 1). Currently, according to the National Heart, Lung, and Blood Institute (NHLBI), asthma is a chronic lung disease that causes inflammation and narrowing of the airways. In asthmatics, recurrent periods of wheezing, chest tightness, shortness of breath, and coughing are common (NIH, 2007). Guidelines for asthma management from the Brazilian Society of Pulmonology and Tisiology add to their definition that asthma chronicity and tissue inflammation are involved, as well as the involvement of many cells and cellular elements (SBPT, 2012).

[0006] Among other chronic respiratory diseases, asthma is an important public health problem that has a significant negative impact on the population (Non-Patent Document 2). The figures regarding the prevalence of asthma worldwide are impressive: according to the Global Asthma Network (2014), asthma affects 334 million people and is the 14th most important disease worldwide in terms of the degree and duration of the disability caused, in addition to being the most difficult to control in children and the elderly.

[0007] It is also known that expenditures on medical services and drug use by asthma patients are twice as high in patients with uncontrolled asthma than in patients with controlled asthma, with lack of asthma control being the factor with the greatest impact on the use of medical services, and expenditures increasing in proportion to the severity of the disease (SBPT, 2012).Regarding the impact of asthma on household income, expenditures currently reach 25% in low-income patients, which is 20% higher than the World Health Organization's recommendation that these costs should not exceed 20%.

[0008] Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease that causes blockages in the airways of the lungs. COPD is usually caused by prolonged exposure to particulate matter or irritating gases, often cigarette smoke. Emphysema and chronic bronchitis are the two most prominent clinical manifestations of COPD and usually occur together. People with COPD are at increased risk of developing heart disease, lung cancer, and various other conditions (Mayo Clinic, 2020).

[0009] Although asthma and COPD are distinct diseases, they share important pathophysiological similarities, including shared pharmacotherapy strategies. Both are chronic inflammatory diseases of the airways, causing airflow limitation characterized by excessive mucus production, airway hyperresponsiveness, and bronchoconstriction (Non-Patent Document 3, Non-Patent Document 4, Non-Patent Document 5). Increased mucus production due to goblet cell hyperplasia and mucus hypersecretion in the airways causes the process of airway narrowing in both diseases (Non-Patent Document 6). Common immunohistopathological features between asthma and COPD include common inflammatory cell activation and infiltration, and dysregulation of inflammatory mediators. For example, eosinophils, which are central effector cells in the development of asthma, are involved in the pathophysiology of COPD and are actively involved in the process, thus being a determinant of COPD exacerbations. Approximately 25% to 40% of COPD patients have an eosinophilic endotype (Non-Patent Document 7).

[0010] Asthma and COPD are closely associated with Th2-type immune responses accompanied by eosinophilia, mastocytosis, and elevated IgE levels induced by allergens (Non-Patent Document 8). When allergens come into contact with antigen-presenting cells, they are captured and processed, and are then expressed by CD4+ cells via MHCII. + This allows presentation to T lymphocytes, leading to their activation and differentiation into Th2 lymphocytes (Non-Patent Document 9).

[0011] Although inflammation is a relevant aspect of asthma and COPD, the chronic inflammatory process characteristic of these diseases is highly complex and distinct: unlike what is observed in acute inflammatory responses, all cells of the respiratory system are involved in the changes typical of asthma, including constituent cells such as epithelial and vascular endothelial cells that do not normally have inflammatory potential.

[0012] Acute inflammatory responses, such as those induced by tissue injury or chemical agents, involve vascular and cellular responses at the tissue level in which primary cytokines, such as IL1β, TNFα, and IL-6, are produced by inflammatory cells and are responsible for the generation of classic signs of inflammation, such as pain, redness, warmth, edema, and loss of function.

[0013] On the other hand, the lung inflammation seen in asthma involves the activation of lung inflammatory and structural cells. The products of these cells involved in typical asthmatic inflammation include cytokines of Th2 profile, such as interleukins IL-4, IL-5, and IL-13. The characteristics observed in lung inflammation and the physiological dysregulation observed in asthma are all the end result of the molecular and cellular events involved in sensitization, the development of Th2 cells, the production of Th2 cytokines, and the activation of the effector mechanisms of these cytokines, which are responsible for the initiation and maintenance of the pathophysiological process in asthma.

[0014] Based on this pathophysiology, drugs with potential therapeutic action in asthma should not only exert an anti-inflammatory effect but also be able to inhibit these events and certain pathophysiological pathways. This statement is mainly verified by the fact that nonsteroidal anti-inflammatory drugs, the most used class of anti-inflammatory drugs in the world with high efficacy in many diseases and inflammatory processes, have no clinical use in the treatment of asthma and COPD.

[0015] In this sense, compounds that have demonstrated anti-inflammatory properties, for example in local inflammation models, are unlikely to be useful for the treatment of asthma and COPD, given that anti-inflammatory and anti-asthmatic properties are distinct, independent and unpredictable.

[0016] When considering the treatment of patients with asthma or COPD, it must be taken into account that the aim is to improve the patient's quality of life, which can be achieved by controlling symptoms and improving or stabilizing lung function. Currently, treatment must necessarily include non-pharmacological measures accompanied by pharmacological therapy (Brazilian Ministry of Health, 2013).

[0017] Pharmacological treatment of asthma and COPD has evolved significantly over the last few years to include immunotherapy in the list of options alongside primarily corticosteroids and bronchodilators.

[0018] Among the main bronchodilators, a class of β2 adrenergic agonists can be pointed out, which act through selective interaction with β2 receptors present in bronchiolar smooth muscle, causing an increase in intracellular cAMP, which leads to relaxation of smooth muscle, an increase in the frequency of ciliary movement, and a decrease in the viscosity of mucus (Non-Patent Document 10). Thus, β2 agonists promote bronchiole dilation, relieve symptoms caused by bronchiole constriction, and reduce resistance to air entry during breathing (Non-Patent Document 11). However, the use of β2 agonists can cause tremors, nervous tension, headaches, tachycardia, and muscle spasms (NHS, 2019).

[0019] For 40 years, corticosteroids have been used to treat respiratory tract diseases, and today their superiority is undisputed and the results achieved by their use are scientifically difficult to dispute (Non-Patent Document 12). Corticosteroid-based treatments are the most effective due to their ability to reduce bronchial reactivity and restore airway integrity, and they act through various mechanisms of action, such as inhibition of cytokine and chemokine production, suppression of inflammatory protein and transcription factor production (Non-Patent Document 13, Non-Patent Document 14).

[0020] However, despite their potent effects when administered systemically, the toxicity associated with short-term and long-term use of systemic corticosteroids is extensive and well documented. Toxicity appears to be related to dose accumulation and duration of therapy. Patients treated with systemic corticosteroids are at increased risk of glucose intolerance, hypertension, development of cataracts, osteoporosis, and adrenal insufficiency (Non-Patent Document 15, Non-Patent Document 16). Furthermore, the degree of respiratory and peripheral muscle weakness correlates with the dose and duration of systemic steroid use in chronic treatment. The course of systemic steroids for COPD exacerbations is associated with hyperglycemia, weight gain, insomnia, anxiety, and depression (Non-Patent Document 17).

[0021] Thus, the justification for using inhaled corticosteroids involves a variety of factors, as they allow for direct drug delivery to target organs and allow for the use of lower cumulative doses of corticosteroids to reduce systemic absorption. Ideally, there would be no systemic absorption of inhaled corticosteroids at all, but this is not the case. However, due to first-pass metabolism in the liver, commonly used corticosteroids such as fluticasone propionate and budesonide are virtually not absorbed after passing through the gastrointestinal tract. Thus, most of the systemic absorption of inhaled corticosteroids occurs through the lungs. Despite the theoretical benefits of lower systemic corticosteroid levels, systemic side effects of inhaled corticosteroid use have been documented, including adrenal suppression, reduced bone mass density, and increased risk of fractures, glaucoma, and skin bruises (Non-Patent Document 18, Non-Patent Document 19).

[0022] Another disadvantage of inhaled corticosteroid treatment in asthma and COPD is the fact that their pharmacological effects disappear rapidly when treatment is discontinued (Non-Patent Document 20). Furthermore, continued use of corticosteroids may cause fluid retention, edema, elevated blood pressure, mood disorders, gastrointestinal disorders, and weight gain. Use of inhaled corticosteroids may also increase the incidence of oral fungal infections and hoarseness.

[0023] However, being effective via inhalation is a highly desirable property for potential new drugs intended to treat asthma and COPD.

[0024] Inhaled administration of drugs has proven to be a good therapeutic strategy since it allows to achieve high local concentrations of active ingredients in the lungs, reducing absorption and resulting in fewer side effects (Non-Patent Document 21). Indeed, the development of inhaled glucocorticoids has revolutionized the pharmacological treatment of asthma since the 1950s. Then, in 1956, thanks to metered-dose inhalers, this method of administration was incorporated into the management of asthma patients and is today considered a major part of the treatment of this disease (Non-Patent Document 22).

[0025] However, only a small proportion of compounds that are active systemically (e.g., via the intraperitoneal route) are effective via inhalation, since this depends on the specific physicochemical properties of the compound. The administration of drugs by inhalation is relatively complex. Firstly, the respiratory tract has developed defense mechanisms aimed not only at preventing inhaled substances from entering the lungs, but also at removing or inactivating these substances if they do deposit themselves.

[0026] In addition, other attributes of a compound must be observed for proper inhalation administration. For example, the compound must have an ionization constant (pKa) and LogP that can cross the cell membrane and distribute into the lung tissue, but with a limited systemic absorption rate. The compound must have chemical stability and low binding affinity to P-glycoprotein so that it remains in the lung tissue long enough to exert its local therapeutic effect without being degraded or removed from the tissue into the circulating bloodstream (Non-Patent Document 23, Non-Patent Document 24, Non-Patent Document 25). Therefore, demonstrating the pharmacological properties of a systemically administered compound cannot predict its effect via inhalation.

[0027] As an example, the majority of compounds that activate the glucocorticoid receptor are not active via inhalation. This is illustrated by the fact that there are few inhaled glucocorticoids available for clinical use (beclomethasone, fluticasone, budesonide, ciclesonide, and mometasone), while there are dozens of systemic glucocorticoids. Having activity via inhalation is a property of a compound, not a class, that depends on the bioavailability of the drug in lung tissue after administration via this route.

[0028] Despite the various strategies to treat and improve the quality of life of asthma and COPD patients, the multifactorial nature that can lead to the development of these diseases makes them increasingly challenging for researchers. As a result, new efforts are continually being made to control them, whether in the discovery of new active molecules, new biological strategies, or even new drug delivery systems. [Prior art documents] [Non-patent literature]

[0029] [Non-Patent Document 1] BOUSQUET, J.; CHANEZ, P.; LACOSTE, JY; BARNEON, G. et al. "Eosinophilic inflammation in asthma." N Engl J Med, 323, n. 15, p. 1033-1039, Oct 11, 1990. [Non-Patent Document 2] BOUSQUET, J.; BOUSQUET, PJ; GODARD, P.; DAURES, J.-P. "The public health implications of asthma." Bulletin of the World Health Organization, 83, 2005. [Non-Patent Document 3] Jeffery PK. "Comparison of the structural and inflammatory characteristics of COPD and asthma." Giles F. Filley Lecture. Chest. 2000 May;117(5 Suppl 1):251S-60S. doi: 10.1378 / chest.117.5_suppl_1.251s. PMID: 10843939. [Non-Patent Document 4] BUIST AS. "Similarities and differences between asthma and chronic obstructive pulmonary disease: treatment and early outcomes." Eur Respir J Suppl. 2003 Jan; 39:30s-35s. doi: 10.1183 / 09031936.03.00404903. PMID: 12572699. [Non-Patent Document 5] WIDDICOMBE JG (2003) “Overview of neural pathways in allergy and asthma.” Pulm Pharmacol Ther 16(23):30. https: / / doi. org / 10. 1016 / s1094- 5539(02) 00178-5 [Non-Patent Document 6] Athanazio R. “Airway disease: similarities and differences between asthma, COPD and bronchiectasis.” Clinics (Sao Paulo). 2012;67(11):1335-1343. doi:10.6061 / clinics / 2012(11)19. [Non-Patent Document 7] Li A, Chan HP, Gan PXL, Liew MF, Wong WSF, Lim HF. "Eosinophilic endotype of chronic obstructive pulmonary disease: similarities and differences from asthma." Korean J Intern Med. 2021 Nov;36(6):1305-1319. doi: 10.3904 / kjim.2021.180. Epub 2021 Oct 12. PMID: 34634855; PMCID: PMC8588979. [Non-Patent Document 8] SILVEIRA, MR; NUNES, KP; FACE, DC; SOUZA, DG et al. 「Infection with Strongyloides venezuelensis induces transient airway eosinophilic inflammation, an increase in immunoglobulin E, and hyperresponsiveness in rats.」 Infect Immun, 70, n. 11, p. 6263-6272, Nov. 2002.

Outdoor Tools9

Outdoor Tools 10

Outdoor Content11

Outdoor Tools 12

Outdoor Content13

Outdoor Tools 14

Outdoor Tools20

Direct Environment21

Outdoor Tools22

Optional Trademark23

[0030] In a first aspect, the present invention provides a compound according to formula I: [ka] (I) (In the formula, Any one of R1, R2, R3, R4, R5, and R6 is independently selected from the group consisting of H, OH, O, S, N, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, optionally aromatic C3-C7 cycloalkyl, C1-C5 heteroalkyl, and optionally aromatic C3-C7 heterocycloalkyl, wherein C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, optionally aromatic C3-C7 cycloalkyl, C1-C5 heteroalkyl, and optionally aromatic C3-C7 heterocycloalkyl are independently selected from the group consisting of H, OH, O, S, N, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, optionally aromatic C3-C7 cycloalkyl, C1-C5 heteroalkyl, and optionally aromatic C3-C7 heterocycloalkyl. Any of the chloroalkyls may be optionally substituted with one or more substituents selected from OH, O, S, N, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, optionally aromatic C3-C7 cycloalkyl, C1-C5 heteroalkyl, and optionally aromatic C3-C7 heterocycloalkyl, and the C1-C5 heteroalkyl and optionally aromatic C3-C7 heterocycloalkyl contain 1 to 3 heteroatoms in their chain selected from F, O, N, Cl, Br, I, S, and / or R3 and R4, R4 and R5, R5 and R6 independently and together form an optionally aromatic 3- to 7-membered cyclic group which may contain 1 to 3 heteroatoms selected from O, N, S as ring members, and where the cyclic group is optionally substituted with one or more substituents selected from OH, O, S, N, C1-C5 alkyl, C2-C5 alkenyl, C2-C5 alkynyl, optionally aromatic C3-C7 cycloalkyl, C1-C5 heteroalkyl, and optionally aromatic C3-C7 heterocycloalkyl, wherein C1-C5 heteroalkyl and optionally aromatic C3-C7 heterocycloalkyl contain 1 to 3 heteroatoms in their chain selected from F, O, N, Cl, Br, I, S), or salts, prodrugs, stereoisomers, hydrates, dimeric derivatives, equivalents, bioisosteres, and polymorphs thereof.

[0031] In a first embodiment, the compound has formula II: [ka] (II) or a salt, prodrug, stereoisomer, hydrate, dimeric derivative, equivalent, bioisostere, and polymorph thereof. In a preferred embodiment, the compound is Braylin or a pharma- ceutically acceptable salt thereof.

[0032] In another embodiment, the therapeutic agent is formulated in a form suitable for administration via inhalation.

[0033] In another embodiment, the therapeutic agent comprises between 1 mg and 1000 mg of the compound of formula I.

[0034] In yet another embodiment, the therapeutic agent is in the form of a powder, granules, solution, or suspension. In an alternative embodiment, the medicament is formulated in a form suitable for administration via capsule, spray, or aerosol.

[0035] In a second aspect, the present invention relates to a pharmaceutical formulation comprising a compound of formula I and at least one pharma- ceutically acceptable excipient.

[0036] In a first embodiment, the pharmaceutical formulation comprises a compound of formula II, or salts, prodrugs, stereoisomers, hydrates, dimeric derivatives, equivalents, bioisosteres, and polymorphs thereof. In a preferred embodiment, the compound is Braylin or a pharma- ceutically acceptable salt thereof.

[0037] In another embodiment, the pharmaceutical formulation is in a form suitable for administration via inhalation.

[0038] In yet another embodiment, the pharmaceutical formulation is for the treatment of asthma and / or COPD.

[0039] In another embodiment, the pharmaceutical formulation of the present invention is in the form of a powder, granules, solution, or suspension.

[0040] In yet another embodiment, the pharmaceutical formulation is in the form of a capsule, spray, or aerosol.

[0041] In a further embodiment, the pharmaceutical formulation comprises from 1 mg to 1000 mg of the compound of formula I.

[0042] In a third aspect, the present invention relates to a method of treating asthma and / or COPD comprising administering a therapeutically effective amount of a compound of formula I to a patient in need thereof.

[0043] In a first embodiment, the compound is selected from a compound of formula II, or a salt, prodrug, stereoisomer, hydrate, dimeric derivative, equivalent, bioisostere, and polymorph thereof. In a preferred embodiment, the compound is Braylin or a pharma- ceutically acceptable salt thereof.

[0044] In one embodiment, the compound is administered at a dose of 1 mg / kg to 100 mg / kg. In a preferred embodiment, the compound is administered at a dose of 50 mg / kg.

[0045] In another embodiment, the compound is administered via inhalation.

[0046] In another embodiment, the compound is administered in the form of a powder, granules, solution, or suspension, hi alternative embodiments, the compound is administered by capsule, spray, or aerosol.

[0047] In another aspect, the invention relates to a compound of formula I for use in the treatment of asthma and / or COPD.

[0048] In a first embodiment, the compound includes a compound of formula II, or salts, prodrugs, stereoisomers, hydrates, dimeric derivatives, equivalents, bioisosteres, and polymorphs thereof. In a preferred embodiment, the compound is Braylin or a pharma- ceutically acceptable salt thereof. [Brief description of the drawings]

[0049] [Figure 1]Figure 1 shows the effect of Braylin administered by various routes in an airway hyperresponsiveness model in mice. The X-axis represents the groups tested: mice not subjected to any experimental manipulation (Naive), mice induced with an airway hyperresponsiveness model treated with vehicle (Ve, 10% propylene glycol in saline), mice induced with an airway hyperresponsiveness model treated intraperitoneally with dexamethasone (30 mg / kg / ip, gold standard), mice induced with an airway hyperresponsiveness model treated intraperitoneally with 50 mg / kg Braylin (50 ip), and mice induced with an airway hyperresponsiveness model treated by inhalation with 50 mg / kg Braylin (50 in). The Y-axis represents the amount of total inflammatory cells counted in the bronchoalveolar lavage fluid (x104). Treatment was performed on 5 consecutive days, 2 hours before ovalbumin challenge. Bronchoalveolar lavage fluid was collected 24 hours after the last challenge and quantified. Cells in bronchoalveolar lavage fluid were quantified using a Neubauer chamber under a light microscope. *Statistically significant difference between treated and vehicle groups (p<0.05). #Statistically significant difference vs. naive group (p<0.05). Data are expressed as mean ± standard deviation with n=5 animals per group. One-way ANOVA test followed by Tukey's multiple comparison post-hoc test. [Diagram 2]Figure 1 shows the dose-response curve of inhaled Braylin in an airway hyperresponsiveness model in mice. The X-axis represents the groups tested, i.e., mice not subjected to any experimental manipulation (Naive), mice induced to an airway hyperresponsiveness model treated with vehicle (Ve, 10% propylene glycol in saline), and mice induced to an airway hyperresponsiveness model treated by inhalation with Braylin (12.5 mg / kg to 100 mg / kg). Intraperitoneal dexamethasone (30 mg / kg) was the gold standard. The Y-axis represents the amount of total inflammatory cells counted in the bronchoalveolar lavage fluid (x104). Treatment was performed for 5 consecutive days, 2 hours before the challenge with ovalbumin. Quantification was performed by collecting bronchoalveolar lavage fluid 24 hours after the last challenge. Cells in the bronchoalveolar lavage fluid were quantified with the aid of a Neubauer chamber under a light microscope. *Statistically significant difference (p<0.05) vs. vehicle group. #Statistically significant difference (p<0.05) versus naive group. Data are expressed as mean ± standard deviation with n=5 animals per group. One-way ANOVA test followed by Tukey's multiple comparison post-hoc test. [Diagram 3] Figure 1 shows the effect of Braylin on the fractional number of inflammatory cells in bronchoalveolar lavage fluid in an airway hyperresponsiveness model in mice. Panels show representative images of cells in bronchoalveolar lavage fluid from (A) naive animals, (B) animals induced in the airway hyperresponsiveness model and treated with vehicle, (C) animals induced in the model and treated with dexamethasone (30 mg / kg / ip), and (D) animals induced in the model and treated with Braylin (50 mg / kg / in). Material stained with hematoxylin and eosin, magnification (100x). Differential quantification of monocytes (E), neutrophils (F), and eosinophils (G) in bronchoalveolar lavage fluid. Data are expressed as percentages of the total number. #Statistically significant difference (p<0.05) relative to the naive group. *Statistically significant difference (p<0.05) between treated and vehicle groups. Data are expressed as mean ± SD with n = 5 animals per group. One-way ANOVA test followed by Tukey's multiple comparison post-hoc test. [Figure 4]FIG. 1 shows the effect of Braylin on cytokine levels in bronchoalveolar lavage fluid of mice with airway hyperresponsiveness. Panels show levels of cytokines (A) IL-4, (B) IL-5, and (C) IL-13 in bronchoalveolar lavage fluid of mice as determined by ELISA. X-axis represents the tested groups: mice not subjected to experimental manipulation (Naive), mice induced in the airway hyperresponsiveness model treated with vehicle (Ve, 10% propylene glycol in saline), mice induced in the airway hyperresponsiveness model treated with dexamethasone (30 mg / Kg / ip, gold standard), and mice induced in the airway hyperresponsiveness model treated via inhalation with Braylin (12.5 mg / kg, 50 mg / kg, and 100 mg / kg). Treatment was performed for 5 consecutive days, 2 hours before ovalbumin challenge. Bronchoalveolar lavage fluid was collected 24 hours after the last challenge for quantification. *Statistically significant difference (p<0.05) versus vehicle group. #Statistically significant difference (p<0.05) versus naive group. Data are expressed as mean ± standard deviation with n=6 animals per group. One-way ANOVA test followed by Tukey's multiple comparison post-hoc test. [Diagram 5] Figure 1. Effect of Braylin on lung tissue and cellular parameters. Panels show representative images of mice treated with vehicle (C-D), dexamethasone (E-F, 30 mg / kg / ip), or Braylin (G-H, 50 mg / kg / in). Naive animals constitute the naive group (A-B). Lungs stained with HE (A, C, E, G). Lungs stained with Periodic Acid Schiff (PAS) (B, D, F, H). Arrows indicate cells of the inflammatory infiltrate. Arrows indicate PAS-labeled goblet cells. Magnification x40, bar 50 μm. Panel I shows the number of cells in the inflammatory infiltrate of the various experimental groups, while panel J shows the quantification of PAS-labeled mucus-producing goblet cells. *Statistically significant difference (p<0.05) vs. vehicle group. #Statistically significant difference (p<0.05) vs. naive group. Data are expressed as mean ± SD with n = 5 animals per group. One-way ANOVA test followed by Tukey's multiple comparison post-hoc test. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0050] Unless otherwise specified, all technical and scientific terms used herein have the same meaning as understood by those skilled in the art to which the present invention belongs. Conventional techniques of molecular biology and immunology are familiar to those skilled in the art. This specification also provides definitions of terms that aid in the interpretation of the contents described in the specification and claims. Unless otherwise indicated, all numbers expressing amounts, percentages, and proportions, as well as other numerical values ​​used in the specification and claims, are to be understood as being modified in all cases by the term "about". Thus, unless otherwise indicated, the numerical parameters set forth in the specification and claims are approximations that may vary depending on the properties obtained.

[0051] In an attempt to find new drugs with reduced side effects in the treatment of asthma and COPD, the present investigators developed a characterization study to examine the pharmacological potential of compounds from the coumarin group.

[0052] The inventors confirmed that Braylyn has high therapeutic efficacy comparable to dexamethasone (the gold standard drug) in the treatment of asthma and COPD. The therapeutic effect was dose-dependent. In models of airway sensitization and chronic inflammation, the compounds of the present invention, via inhalation, reduced important tissue, biochemical, and cellular parameters involved in the pathophysiology of asthma and COPD. That is, these compounds reduced the number of inflammatory cells in bronchoalveolar lavage fluid, reduced the levels of the cytokines IL4, IL-5, and IL-13 in bronchoalveolar lavage fluid, reduced inflammatory infiltration in lung tissue, and reduced mucus production by goblet cells of the bronchiolar epithelium.

[0053] The compounds of formula I according to the present invention can be synthesized or isolated by any available method and chemical route known to those skilled in the art.

[0054] Alternatively, the compound of formula I of the present invention is extracted and isolated from the roots of Z. tingoassuiba St. Hil according to the method described by Costa and coworkers (COSTA, 2018).

[0055] The present invention may also include pharma- ceutically acceptable salts of the compounds of formula I. Examples of pharma- ceutically acceptable salts that may be formed by the compounds of the present invention include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, diphosphate, and the like; organic acid salts such as succinate, fumarate, acetate, methanesulfonate, toluenesulfonate, and the like; alkali metal salts such as sodium salt, potassium salt, and the like; alkaline earth metal salts such as magnesium salt, calcium salt, and the like; ammonium salts such as ammonium salt, alkylammonium salt, and the like.

[0056] Additionally, the present application includes solvates of the compounds of formula I or their pharma- ceutically acceptable salts. Examples of solvents include water, methanol, ethanol, isopropanol, acetone, ethyl acetate, and the like.

[0057] Thus, in a first embodiment, the present invention relates to the use of a compound of formula I for the manufacture of a medicament for the treatment of asthma and chronic obstructive pulmonary disease (COPD).

[0058] The compounds of the present invention, as well as their salts, hydrates and solvates, can also be used as the active ingredients of the pharmaceuticals of the present invention.The administration route of the pharmaceuticals of the present invention is not particularly limited, and the pharmaceuticals can be administered orally, pulmonary or parenterally.Preferably, the administration route of the pharmaceuticals of the present invention is the inhalation route.

[0059] As used herein, the terms "administer", "administration" and similar terms refer to any method, in good medical practice, of delivering a subject compound to an individual to produce a therapeutic effect. Certain aspects of the invention provide for the administration by inhalation of a therapeutically effective amount of a compound of the invention to a patient in need thereof.

[0060] In one embodiment, the compound of the present invention is administered via inhalation. "Inhalation administration" or "inhalation administration" refers to a method of administration of a compound that can release or deliver the compound to any part of the respiratory tract of an individual. Any part of the respiratory tract means, for example, the mouth, trachea, bronchi, bronchioles, lungs, among others. Preferably, the compound of interest reaches the trachea, bronchi, bronchioles, and / or lungs.

[0061] Just like the pharmaceutical preparations of the present invention, the compounds of the present invention can be administered directly to a patient. However, the compounds of the present invention should preferably be administered as a preparation in the form of a pharmaceutical composition containing the active ingredient and at least one pharma- ceutically and pharmacologically acceptable excipient.

[0062] Thus, in a second aspect, the present invention relates to a pharmaceutical formulation comprising at least one compound according to the invention and at least one pharma- ceutically acceptable excipient.

[0063] The subject compositions may be formulated to be compatible with the desired route of administration. The compositions may be formulated as tablets, capsules, solutions, powders, inhalants, lotions, tinctures, lozenges, suppositories, or transdermal patches. Preferably, the compositions are formulated as capsules, solutions, powders, or inhalants.

[0064] As used herein, pharma- ceutically and pharmacologically acceptable additives can be listed as, for example, excipients, disintegrants or disintegration aids, binders, coating agents, dyes, diluents, bases, solubilizers or solubilization aids, isotonicity agents, pH adjusters, stabilizers, propellants, adhesives, etc. Examples of preparations suitable for parenteral administration include powder inhalants, capsules, powders, fine granules, solutions, suspensions, aerosols, sprays, and nebulizers.However, the form of preparations should not be limited thereto.

[0065] For administration by the inhalation route, the compounds may or may not be delivered in the form of an aerosol spray, for example from a pressurized container dispenser, which may contain a suitable propellant, e.g., gas, or may be delivered by other known methods. Examples of suitable devices include metered dose inhalers, pressurized metered dose inhalers, and pressurized metered dose inhalers.

[0066] Other types of devices may be suitable for administering the compounds according to the present application, for example, the compounds of the present invention may be administered by ultrasonic inhalers, dry powder inhalers, soft mist inhalers, nebulizers, capsule inhalers, and any other method suitable for administering a compound by inhalation.

[0067] Preparations suitable for solid preparations may contain, as additives, excipients such as glucose, lactose, lactose monohydrate, D-mannitol, starch, cellulose, crystalline cellulose, etc.; disintegrants or disintegration aids such as carboxymethylcellulose, starch, carboxymethylcellulose calcium, silicon dioxide, etc.; binders such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, gelatin, etc.; lubricants such as magnesium stearate, talc, etc.; and bases such as hydroxypropylmethylcellulose, sucrose, polyethylene glycol, gelatin, kaolin, glycerol, purified water, hard fat, etc.

[0068] Preparations suitable for liquid preparations may contain additives such as a solubilizer or solubilization aid that can constitute an aqueous preparation or a composition that is dissolved in water, distilled water for injection, physiological saline solution, propylene glycol, or the like when used; an isotonicity agent such as glucose, sodium chloride, D-mannitol, glycerol, or the like; a pH adjuster such as an inorganic acid, an organic acid, an inorganic base, or an organic base, or the like.

[0069] The active agent is preferably administered in an effective amount.As used herein, the phrase "effective amount" refers to the amount of an ingredient that is sufficient to produce desired therapeutic response without excessive side effects (such as toxicity, irritation, or allergic reaction) when used in the manner described herein, and is commensurate with a reasonable benefit / risk ratio.For example, "therapeutically effective amount" can be the amount of active agent that is sufficient to cause regression, control, or prevent the progression of asthma, chronic obstructive pulmonary disease, and / or symptoms associated with these diseases.

[0070] The actual amount administered, as well as the rate and duration of administration, will depend on the nature and severity of the condition being treated. The determination of treatment regimen, such as dosage, timing, etc., is within the responsibility of ordinary skilled artisans and specialists, which typically take into account the disorder being treated, the condition of the individual patient, the site of release, the method of administration, and other factors known to those skilled in the art. Examples of techniques and protocols can be found, for example, in Remington's Pharmaceutical Sciences.

[0071] The dosage of the pharmaceutical of the present invention should vary depending on the condition of the patient, such as the type of disease to be applied, age, weight, symptoms, etc., but the unit dosage is generally about 50 mg to about 1000 mg of active ingredient per administration. More specifically, the unit dosage may be 150 mg to 900 mg, 200 mg to 800 mg, and 400 mg to 600 mg. In general, the above-mentioned dosage may be administered once or in divided doses per day, or every few days. In particular, the dosage of the compound of the present invention is in the range of 1 mg / kg to 100 mg / kg. Preferably, the dosage is 50 mg / kg.

[0072] Although the term "comprising" is used throughout this application in describing various embodiments, it will be understood by those of skill in the art that in some specific cases, the embodiments may instead be described using the phrases "consisting essentially of" or "consisting of."

[0073] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this subject matter belongs.

[0074] For the purpose of improving understanding of the present disclosure, and not intended in any way to limit the scope of the present disclosure, all numbers expressing quantities, percentages or proportions, as well as other numerical values ​​used in the specification and claims, unless otherwise indicated, shall be understood to be modified in all instances by the term "about". Accordingly, unless otherwise indicated, the numerical parameters set forth in the specification and appended claims are approximations that may vary depending on the desired properties sought to be obtained. At the very least, each numerical parameter should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

[0075] The present invention is also described by the following non-limiting examples, which are merely illustrative. Various changes and modifications to the embodiments will be apparent to those skilled in the art without departing from the spirit and scope of the present invention.

[0076] Numerous variations are permitted which affect the scope of protection of the present application, thus emphasizing the fact that the present invention is not limited to the specific configurations / embodiments described above. EXAMPLES

[0077] Example 1 Materials and Methods Extraction, isolation, and characterization of braylin The specimen of Z. chingoa sorrel St.Hil was collected on August 12, 2009, in the Jaiba district (12°12′52.560″S, 38°52′46.205″W), in the municipality of Feira de Santana, Bahia. The identification of the specimen was carried out by Professor Maria Lenise da Silva Guedes. It was deposited in the Alexandre Leal Costa Herbarium (ALCB) under number 88005, from Eccata. The procedure for the extraction, purification and identification of braillin from the roots of Z. chingoa sorrel St.Hil was described by Costa and co-workers (COSTA, 2018). The formula was established by mass spectrometry and nuclear magnetic resonance (NMR) analysis, which confirmed its chemical structure with a purity of more than 99% (YOO, 2002). animal

[0078] Male mice of BALB / c lineage weighing between 20 and 25 g from the breeding facility of the Gonzalo Moniz Research Center (FIOCRUZ / BA). Animals were housed under controlled temperature conditions (22 ± 2 °C) with a 12-h light / dark cycle with water and food available ad libitum. All protocols and procedures were approved by the Ethical Committee for Animal Experiments of FIOCRUZ (CEUA / FIOCRUZ / L-IGM-015 / 2013). Airway hyperresponsiveness models and treatments

[0079] The ovalbumin-induced airway hyperresponsiveness model (BOLANDI et al., 2021) used as the basis for these findings induces pathophysiological and structural changes that characterize respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD).

[0080] Mice were divided into groups of 6 animals and immunized with a subcutaneous injection of 10 μg ovalbumin (Sigma, St. Louis, MO) diluted in 2 mg / ml alum (AlumImject, Pierce, Rockford, IL), followed by a booster injection 14 days later. From day 28 onwards, mice were placed in acrylic boxes and subjected to inhalation exposure to ovalbumin (1%) for 15 min per day for 5 consecutive days. The ovalbumin solution was nebulized using an ultrasonic inhaler (RespiraMax, Brazil). The protocol used to induce airway hyperresponsiveness was performed as previously described (POSSA, 2013). The naïve group was challenged with saline only. To administer the treatment, mice were treated with Braylyn (100 mg / kg, 50 mg / kg, 25.5 mg / kg, and 12.5 mg / kg, via inhalation), dexamethasone (30 mg / kg, via intraperitoneal), or vehicle (10% propylene glycol in saline, via inhalation) 2 hours prior to each challenge via inhalation. Collection of bronchoalveolar lavage specimens

[0081] 24 hours after the last challenge, animals were euthanized with lethal doses of ketamine and xylazine (300mg / Kg and 30mg / Kg, respectively, via intraperitoneal route) and bronchoalveolar lavage (BAL) was collected. An intratracheal instillation of 1ml of ice-cold PBS was performed, followed by collection of BAL, and the procedure was repeated. The first lavage was centrifuged, the supernatant was stored at -70°C, and cytokines were then quantified by ELISA. The second lavage was centrifuged, the supernatant was discarded, the pellet was resuspended in 1ml of saline, and total white blood cells were counted using a Neubauer chamber. To perform differential cell counts, 10,000 cells were collected from the previous resuspension, centrifuged in a Cytospin®, and stained with hematoxylin and eosin (VASCONCELOS, 2009). Histopathological and morphometric analyses

[0082] After collection of bronchoalveolar lavage, lungs were perfused intratracheally with 1 ml of formalin (4%), after which the right lobe of the lung of each animal was removed and fixed in the same solution for histological and morphometric analysis. Sections were stained with hematoxylin and eosin to quantify inflammatory cells according to the number of cores present in the field containing the greatest number of cells by light microscopy. To quantify mucus production, staining was performed with Periodic Acid Schiff (PAS) and the marked areas were quantified. Areas of lung tissue labeled with PAS were considered positive for mucus produced by goblet cells (SOUTHAM, 2008). For a total of 5 animals, 10 fields (400x) per animal were analyzed and the data were used to calculate the inflammatory cell counts per mm. 2 The average number of cells per well or the area stained with PAS was calculated. The program used to assist in cell counting and area determination was Image-Pro PLUS version 4.5 (Media Cybernetics, Silver Spring, USA). Quantification of cytokines in bronchoalveolar lavage fluid

[0083] Bronchoalveolar lavage supernatants stored at -70°C were thawed and used to quantify the cytokines IL-4, IL-5, and IL-13 by ELISA using specific mouse kits (R&D System, MN, USA) according to the manufacturer's instructions ( VASCONCELOS, 2009 ). statistical analysis

[0084] Results were expressed as mean ± standard deviation. Statistical differences were determined by one-way ANOVA test followed by Tukey's post-hoc test, where the significance level was established a priori at p<0.05. Analyses were performed using the GraphPad Prism 5.0 program (Los Angeles, CA, USA). result

[0085] Effect of route of administration on the biological activity of Braylin in a mouse model of airway hyperresponsiveness. In order to establish whether Braylin has pharmacological activity when administered via inhalation, we compared the effects of inhaled or intraperitoneal administration of this coumarin on inflammatory cell numbers in bronchoalveolar lavage (BAL).

[0086] Mice induced with ovalbumin and treated with vehicle showed an increase in the total number of inflammatory cells in the BAL compared to naive animals. In both diseased animals treated intraperitoneally and by inhalation with Braylin (50 mg / kg), the number of inflammatory cells in the BAL was significantly lower (p<0.05). A significant inhibition of this parameter was also observed in mice treated intraperitoneally with the gold standard drug dexamethasone at a dose of 30 mg / kg (Figure 1). Dose-response curve of inhaled Braylin in a mouse model of airway hyperresponsiveness

[0087] The dose-dependent relationship of the effect of Braylin administered via inhalation in the dose range of 12.5 mg / kg to 100 mg / kg was then evaluated (Figure 2). Inhaled Braylin at doses of 25 mg / kg, 50 mg / kg, and 100 mg / kg non-dose-dependently reduced the number of inflammatory cells in the BAL of mice with airway hyperresponsiveness compared to vehicle-treated mice (p<0.05). At the 12.5 mg / kg dose, Braylin had no effect. The effect of inhaled Braylin was similar in efficacy to systemic treatment with dexamethasone (30 mg / kg / ip), which is considered the gold standard in this study. Braylyn reduces the presence of eosinophils and neutrophils in bronchoalveolar lavage.

[0088] In addition to quantifying the total number of inflammatory cells in the bronchoalveolar lavage fluid, we also quantified the differential between eosinophils, neutrophils, and mononuclear cells in these samples (Figure 3). Inhalation treatment with Braylin (50 mg / Kg) reduced the amount of eosinophils and neutrophils present in the BAL compared to lavage fluid from vehicle-treated animals (p<0.05). The amount of mononuclear cells in animals treated with Braylin approached the values ​​seen in naive mice that had not been induced with airway hyperresponsiveness. Dexamethasone (30 mg / kg / ip) caused an effect with a similar profile to Braylin, reducing the number of eosinophils and neutrophils in the BAL. Braylin regulates the cytokines IL-4, IL-5, and IL-13.

[0089] The levels of cytokines involved in Th2 responses were quantified in bronchoalveolar lavage fluids of mice from the various experimental groups. Mice induced to the airway hyperresponsiveness model showed increased levels of IL4, IL-5, and IL-13 cytokines in the BAL compared to naive mice (p<0.05). Inhaled Braylin at doses of 25 mg / kg and 50 mg / kg reduced the levels of IL4, IL-5, and IL-13 in the BAL (p<0.05). However, Braylin at a dose of 12.5 mg / kg caused a significant reduction in IL-5 and IL-13, but not IL-4, in the BAL of mice. Animals treated with systemic dexamethasone (30 mg / kg / ip) showed a reduction in the levels of all quantified cytokines in the BAL (Figure 4), which was comparable to that obtained with inhaled Braylin. Braylin reduces the incidence of pulmonary inflammatory infiltrates and goblet cell metaplasia.

[0090] To characterize the tissue changes caused by induction of the airway hyperresponsiveness model and the possible effect of Braylin on inflammatory cell migration, HE-stained lung sections were examined. In animals induced in this model and treated with vehicle, a large cellular infiltrate was observed, including lymphocytes, macrophages, and eosinophils. Mice treated with inhaled Braylin at 50 mg / kg showed a reduced presence of inflammatory cells along with reduced lung inflammation compared to vehicle-treated animals (p<0.05, Figure 5I). Systemic treatment with dexamethasone (30 mg / kg / ip) was also able to reduce pulmonary inflammatory infiltrates. The occurrence of goblet cell metaplasia in the bronchiolar epithelium was determined by staining of tissues with Periodic Acid Schiff (PAS), which shows increased mucus formation. Lungs from mice with airway hyperresponsiveness treated with vehicle showed a larger area stained with PAS (p<0.05, Figure 5J). Braylin treatment reduced goblet cell labeling in the bronchiolar epithelium of animals with induced airway hyperresponsiveness (p<0.05), indicating its ability to modulate mucus production. As expected, systemic dexamethasone also reduced the presence of mucus in PAS-stained goblet cells. References

[0091] ABRAMSON, MJ; WALTERS, J.; WALTERS, EH “Adverse effects of beta-agonists: are they clinically relevant?” Am J Respir Med, 2, no. 4, p. 287-297, 2003.

[0092] ALAN, IS; ALAN, B. “Side Effects of Glucocorticoids” In: Pharmacokinetics and Adverse Effects of Drugs, December 20, 2017

[0093] ALI, M. 「CHAPTER 9 - Pulmonary Drug Delivery.」 In: MALANGU, N. Handbook of Non-Invasive Drug Delivery Systems, 2010, p. 209-246 (Exploitation 24)

[0094] ALLEN, DB 「Inhaled Corticosteroids and Endocrine Effects in Childhood」, Endocrinology and Metabolism Clinics of North America, vol. 49, n. 4, p. 651-665, December 2020(Update 19)

[0095] ANEJA, R.; MUKERJEE, SK; SESHADRI, TR 「Synthesis of benzo-furan derivatives-I.」 Tetrahedron, 2, n. 3-4, p. 203-210,

[0096] AROOJ, M.; SAKKIAH, S.; CAO, G.; LEE, KW 「An innovative strategy for dual inhibitor design and its application in dual inhibition of human thymidylate synthase and dihydrofolate reductase enzymes.」 PLoS One, 8, no. 4, p. e60470 , 2013 .

[0097] Athanazio R. 「Airway disease: similarities and differences between asthma, COPD and bronchiectasis.」 Clinics (Sao Paulo). 2012;67(11):1335-1343. doi:10.6061 / clinics / 2012(11)19. (Non-patent Document 6)

[0098] AZAB, A.; NASSAR, A.; AZAB, A. N. 「Anti-Inflammatory Activity of Natural Products.」 Molecules, 21, n. 10, Oct 1, 2016.

[0099] BABU, S.; NUTMAN, T. B. 「Proinflammatory cytokines dominate the early immune response to filarial parasites.」 J Immunol, 171, n. 12, p. 6723-6732, Dec 15, 2003.

[0100] BANSAL, Y.; SETHI, P.; BANSAL, G. 「Coumarin: a potential nucleus for anti-inflammatory molecules.」 Medicinal Chemistry Research, 22, no. 7, p. 3049-3060, 2012.

[0101] BARNES, P. J. 「Th2 cytokines and asthma: an introduction.」 Respir Res, 2, n. 2, p. 64-65, 2001. (Non-patent Document 13)

[0102] BARREIRO, E. J.; BOLZANI, V. d. S. 「Biodiversidade: fonte potencial para a descoberta de farmacos (Biodiversity: potential source for drug discovery).」 Quimica Nova, 32, n. 3, p. 679-688, 2009.

[0103] BARRIOS, R.J., et al., 「Asthma: Pathology and Pathophysiology.」 Arch Pathol Lab Med, 2006. 130(4): p. 447-51.

[0104] BARROS, T. A.; DE FREITAS, L. A.; FILHO, J.M.; NUNES, X. P. et al. 「Antinociceptive and anti-inflammatory properties of 7-hydroxycoumarin in experimental animal models: therapeutic potential for the control of inflammatory chronic pain.」 J Pharm Pharmacol, 62, n. 2, p. 205-213, Feb 2010.

[0105] BATEMAN, E. D.; O'BYRNE, P. M.; BUSSE, W. W.; LOTVALL, J. et al. 「Once-daily fluticasone furoate (FF) / vilanterol reduces risk of severe exacerbations in asthma versus FF alone.」 Thorax, 69, n. 4, p. 312-319, Apr 2014.

[0106] BAUMER, W.; HOPPMANN, J.; RUNDFELDT, C.; KIETZMANN, M. 「Highly selective phosphodiesterase 4 inhibitors for the treatment of allergic skin diseases and psoriasis.」 Inflamm Allergy Drug Targets, 6, n. 1, p. 17-26, Mar 2007.

[0107] BENDER, A. T.; BEAVO, J. A. 「Cyclic nucleotide phosphodiesterases: molecular regulation to clinical use.」 Pharmacol Rev, 58, n. 3, p. 488-520, Sep 2006.

[0108] Bolandi SM, Abdolmaleki Z, Assarehzadegan MA. 「Bevacizumab regulates inflammatory cytokines and inhibits VEGFR2 signaling pathway in an ovalbumin-induced rat model of airway hypersensitivity.」 Inflammopharmacology. 2021 Jun;29(3):683-694. doi: 10.1007 / s10787-021-00798-8. Epub 2021 Mar 19. PMID: 33742375.

[0109] BOUSQUET, J.; BOUSQUET, P.J.; GODARD, P.; DAURES, J.-P. 「The public health implications of asthma.」 Bulletin of the World Health Organization, 83, 2005.(Non-patent Document 2)

[0110] BOUSQUET, J.; CHANEZ, P.; LACOSTE, JY; BARNEON, G. et al. “Eosinophilic inflammation in asthma.” N Engl J Med, 323, n. 15, p. 1033-1039, Oct 11, 1990.(Open Note 1)

[0111] BOYTON , RJ ; ALTMANN, DM 「Asthma: new developments in cytokine regulation.」 Clin Exp Immunol, 136, n. 1, p. 13-14, Apr 2004.

[0112] BUIST AS. 「Similarities and differences between asthma and chronic obstructive pulmonary disease: treatment and early outcomes.」 Eur Respir J Suppl. 2003 Jan; 39:30s-35s. doi: 10.1183 / 09031936.03.00404903. PMID: 12572699.(Special Edition 4)

[0113] CALHOUN, KH 「Asthma treatments: new and emerging therapies.」 Int Forum Allergy Rhinol, 5 Suppl 1, p. S76-81, Sep

[0114] CARDOSO, T. A.; RONCADA, C.; SILVA, E. R. D.; PINTO, L. A. et al. 「The impact of asthma in Brazil: a longitudinal analysis of data from a Brazilian national database system.」 J Bras Pneumol, 43, n. 3, p. 163-168, May-Jun 2017.

[0115] CAZZOLA, M.; MATERA, M. G. 「The effect of doxofylline in asthma and COPD.」 Respir Med, 164, p. 105904, Apr 2020.

[0116] CAZZOLA, M.; PAGE, C. P.; ROGLIANI, P.; MATERA, M. G. 「Beta2-agonist therapy in lung disease.」 Am J Respir Crit Care Med, 187, n. 7, p. 690-696, Apr 1 2013.

[0117] CHARRIOT, J.; VACHIER, I.; HALIMI, L.; GAMEZ, A. S. et al. 「Future treatment for asthma.」 Eur Respir Rev, 25, n. 139, p. 77-92, Mar 2016.

[0118] CHEAH J. T. L. et al. 「The patient's perspective of the adverse effects of glucocorticoid use: A systematic review of quantitative and qualitative studies.」 From an OMERACT working group, Seminars in Arthritis and Rheumatism, v. 50, no. 5, p. 996-1005, October 2020(Non-patent Document 16)

[0119] CHEENPRACHA, S.; PARK, E.J.; YOSHIDA, W. Y.; BARIT, C. et al. 「Potential anti-inflammatory phenolic glycosides from the medicinal plant Moringa oleifera fruits.」 Bioorg Med Chem, 18, n. 17, p. 6598-6602, Sep 1 2010.

[0120] CHEN et al 2018. 「Inflammatory responses and inflammation-associated diseases in organs」 Oncotarget, 2018, 9(6), 7204-7218.

[0121] CHIANG, C.Y., et al., 「Osthole treatment improves Th2-mediated allergic asthma and exerts immunomodulatory effects on dendritic cell maturation and function.」 Cell Mol Immunol, 2017.

[0122] CORRY, D.B., et al., 「Requirements for allergen-induced airway hyperreactivity in T and B cell-deficient mice.」 Mol Med, 1998. 4(5): p. 344-55.

[0123] COSTA, R.S., et al., 「In vitro antileishmanial and antitrypanosomal activity of compounds isolated from the roots of Zanthoxylum tingoassuiba.」 Brazilian Journal of Pharmacognosy, 2018. 28(5): p. 551-558.

[0124] COUTINHO, A. E.; CHAPMAN, K. E. 「The anti-inflammatory and immunosuppressive effects of glucocorticoids, recent developments and mechanistic insights.」 Mol Cell Endocrinol, 335, n. 1, p. 2-13, Mar 15, 2011.

[0125] CROMPTON, G., 「A brief history of inhaled asthma therapy over the last fifty years.」 Prim Care Respir J, 2006. 15(6): p. 326-31.(Non-patent Document 22)

[0126] CURRAN, D.R. and L. Cohn, 「Advances in mucous cell metaplasia: a plug for mucus as a therapeutic focus in chronic airway disease.」 Am J Respir Cell Mol Biol, 2010. 42(3): p. 268-75.

[0127] DAHL, R. 「Systemic side effects of inhaled corticosteroids in patients with asthma.」 Respir Med, 100, n. 8, p. 1307-1317, Aug 2006.

[0128] DAUGHERTY, J.; LIN, X.; BAXTER, R.; SURUKI, R. et al. 「The impact of long-term systemic glucocorticoid use in severe asthma: A UK retrospective cohort analysis.」 J Asthma, 55, n. 6, p. 651-658, Jun 2018.

[0129] DE BOSSCHER, K. 「Mechanisms of anti-inflammatory action and of immunosuppression by glucocorticoids: negative interference of activated glucocorticoid receptor with transcription factors.」 Journal of Neuroimmunology, 109, no. 1, p. 16-22, 2000.

[0130] DE LIMA, F. O.; NONATO, F. R.; COUTO, R. D.; BARBOSA FILHO, J. M. et al. 「Mechanisms involved in the antinociceptive effects of 7-hydroxycoumarin.」 J Nat Prod, 74, n. 4, p. 596-602, Apr 25 2011.

[0131] DESAI, J. T.; DESAI, C. K.; DESAI, K. R. 「A convenient, rapid and eco-friendly synthesis of isoxazoline heterocyclic moiety containing bridge at 2°-amine as potential pharmacological agent.」 Journal of the Iranian Chemical Society, 5, no. 1, p. 67-73, 2008.

[0132] DINARELLO, C. A. 「Overview of the IL-1 family in innate inflammation and acquired immunity.」 Immunol Rev, 281, n. 1, p. 8-27, Jan 2018.

[0133] 「IV Diretrizes Brasileiras para o Manejo da Asma (IV Brazilian Guidelines for Asthma Management).」 J Bras Pneumol. 2006;32(Suppl 7):S 447-S 474

[0134] DONAHUE, J. G.; WEISS, S. T.; LIVINGSTON, J. M.; GOETSCH, M. A. et al. 「Inhaled steroids and the risk of hospitalization for asthma.」 JAMA, 277, n. 11, p. 887-891, Mar 19, 1997.

[0135] DRAY, A.; URBAN, L.; DICKENSON, A. 「Pharmacology of chronic pain.」 Trends in Pharmacological Sciences, 15, n. 6, p. 190-197, 1994.

[0136] DUMONDE, D. C.; WOLSTENCROFT, R. A.; PANAYI, G. S.; MATTHEW, M. et al. 「"Lymphokines": non-antibody mediators of cellular immunity generated by lymphocyte activation.」 Nature, 224, n. 5214, p. 38-42, Oct 4, 1969.

[0137] FIREMAN, P. 「B2 Agonists and Their Safety in the Treatment of Asthma.」 Allergy Proceedings, 16, no. 5, 1995.(Non-Patent Document 11)

[0138] FISCHER, P. M. 「Computational chemistry approaches to drug discovery in signal transduction.」 Biotechnol J, 3, n. 4, p. 452-470, Apr 2008.

[0139] FRANCO, R.; NASCIMENTO, H. F.; CRUZ, A. A.; SANTOS, A. C. et al. 「The economic impact of severe asthma on low-income families.」 Allergy, 64, n. 3, p. 478-483, Mar 2009.

[0140] FYLAKTAKIDOU, K. C.; HADJIPAVLOU-LITINA, D. J.; LITINAS, K. E.; NICOLAIDES, D. N. 「Natural and synthetic coumarin derivatives with anti-inflammatory / antioxidant activities.」 Curr Pharm Des, 10, n. 30, p. 3813-3833, 2004.

[0141] GIBSON, P. G.; POWELL, H.; WILSON, A.; ABRAMSON, M. J. et al. 「Self-management education and regular practitioner review for adults with asthma.」 Cochrane Database of Systematic Reviews, 2002.

[0142] GOMEZ-OUTES, A.; SUAREZ-GEA, M. L.; CALVO-ROJAS, G.; LECUMBERRI, R. et al. 「Discovery of anticoagulant drugs: a historical perspective.」 Curr Drug Discov Technol, 9, n. 2, p. 83-104, Jun 1 2012.

[0143] GUILBERT, T. W.; MORGAN, W.J.; ZEIGER, R. S.; MAUGER, D. T. et al. 「Long-term inhaled corticosteroids in preschool children at high risk for asthma.」N Engl J Med, 354, n. 19, p. 1985-1997, May 11, 2006. (Non-Patent Document 20)

[0144] HADDAD, J. J. 「On the enigma of pain and hyperalgesia: A molecular perspective.」 Biochem Biophys Res Commun, 353, no. 2, p. 217-224, Feb 9, 2007.

[0145] HALDAR, P.; BRIGHTLING, C. E.; SINGAPURI, A.; HARGADON, B. et al. 「Outcomes after cessation of mepolizumab therapy in severe eosinophilic asthma: a 12-month follow-up analysis.」 J Allergy Clin Immunol, 133, n. 3, p. 921-923, Mar 2014.

[0146] HARVEY, A. L.; EDRADA-EBEL, R.; QUINN, R. J. 「The re-emergence of natural products for drug discovery in the genomics era.」 Nat Rev Drug Discov, 14, n. 2, p. 111-129, Feb 2015.

[0147] HEFFLER, E. et al. 「Inhaled Corticosteroids Safety and Adverse Effects in Patients with Asthma」, The Journal of Allergy and Clinical Immunology: In Practice, vol. 6, no. 3, p. 776 - 781, February 02, 2018. (Non-Patent Document 18)

[0148] EIXARCH, H.; HALTNER-UKOMADU, H.; BEISSWENGER, C.; BOCK, U. 「Drug Delivery to the Lung: Permeability and Physicochemical Characteristics of Drugs as the Basis for a Pulmonary Biopharmaceutical Classification System (pBCS)」, J Epithel Biol Pharmacol, v. 3, p. 1-14, 2010. (Non-Patent Document 25)

[0149] Hisbello S. Campos. 「Asthma: its origins, inflammatory mechanisms and the role of the corticosteroid.」 Rev Bras Pneumol Sanit 2007; 15(1):47-60.

[0150] HOUSLAY, M. D.; SCHAFER, P.; ZHANG, K. Y. J. 「Keynote review: Phosphodiesterase-4 as a therapeutic target.」 Drug Discovery Today, 10, no. 22, p. 1503-1519, 2005.

[0151] HUSCHER, D.; THIELE, K.; GROMNICA-IHLE, E.; HEIN, G. et al. 「Dose-related patterns of glucocorticoid-induced side effects.」 Ann Rheum Dis, 68, n. 7, p. 1119-1124, Jul 2009.

[0152] IZUHARA, K.; Ohta, S.; SHIRAISHI, H.; SUZUKI, S. et al. 「The mechanism of mucus production in bronchial asthma.」 Curr Med Chem, 16, n. 22, p. 2867-2875, 2009.

[0153] JANKOWSKA, A.; SWIERCZEK, A.; CHLON-RZEPA, G.; PAWLOWSKI, M. et al. 「PDE7-Selective and Dual Inhibitors: Advances in Chemical and Biological Research.」 Curr Med Chem, 24, n. 7, p. 673-700, 2017.

[0154] Jeffery PK. 「Comparison of the structural and inflammatory characteristics of COPD and asthma.」 Giles F. Filley Lecture. Chest. 2000 May;117(5 Suppl 1):251S-60S. doi: 10.1378 / chest.117.5_suppl_1.251s. PMID: 10843939. (Non-Patent Document 3)

[0155] JI, H. F.; LI, X.J.; ZHANG, H. Y. 「Natural products and drug discovery. Can thousands of years of ancient medical knowledge lead us to new and powerful drug combinations in the fight against cancer and dementia?」 EMBO Rep, 10, n. 3, p. 194-200, Mar 2009.

[0156] KELLER, A. C.; RODRIGUEZ, D.; RUSSO, M. 「Nitric oxide paradox in asthma.」 Mem Inst Oswaldo Cruz, 100 Suppl 1, p. 19-23, Mar 2005.

[0157] KELLY, H.; NELSON, H. 「Potential adverse effects of the inhaled corticosteroids.」 Journal of Allergy and Clinical Immunology, 112, no. 3, p. 469-478, 2003.

[0158] KELSO, A. 「Cytokines: principles and prospects.」 Immunol Cell Biol, 76, no. 4, p. 300-317, Aug 1998.

[0159] KIM, H. P.; SON, K.H.; CHANG, H.W.; KANG, S. S. 「Anti-inflammatory plant flavonoids and cellular action mechanisms.」 J Pharmacol Sci, 96, n. 3, p. 229-245, Nov 2004.

[0160] KITCHEN, D. B.; DECORNEZ, H.; FURR, J.R.; BAJORATH, J. 「Docking and scoring in virtual screening for drug discovery: methods and applications.」 Nat Rev Drug Discov, 3, n. 11, p. 935-949, Nov 2004.

[0161] KONTOGIORGIS, C. A.; HADJIPAVLOU-LITINA, D. J. 「Synthesis and antiinflammatory activity of coumarin derivatives.」 J Med Chem, 48, n. 20, p. 6400-6408, Oct 6, 2005.

[0162] KUMAR, R.K., et al., 「Inhibition of inflammation and remodeling by roflumilast and dexamethasone in murine chronic asthma.」 J Pharmacol Exp Ther, 2003. 307(1): p. 349-55.

[0163] KUPELI AKKOL, E.; GENC, Y.; KARPUZ, B.; SOBARZO-SANCHEZ, E. et al. 「Coumarins and Coumarin-Related Compounds in Pharmacotherapy of Cancer.」 Cancers (Basel), 12, no. 7, Jul 19, 2020.

[0164] Li A, Chan HP, Gan PXL, Liew MF, Wong WSF, Lim HF. "Eosinophilic endotype of chronic obstructive pulmonary disease: similarities and differences from asthma." Korean J Intern Med. 2021 Nov;36(6):1305-1319. doi: 10.3904 / kjim.2021.180. Epub 2021 Oct 12. PMID: 34634855; PMCID: PMC8588979. (Non-patent literature 7)

[0165] LI, D. and L. WU, "Coumarins from the roots of Angelica dahurica cause anti-allergic inflammation." Exp Ther Med, 2017. 14(1): p. 874-880

[0166] LIN, E.; CALVANO, S. E.; LOWRY, S. F. "Inflammatory cytokines and cellular response in surgery." Surgery, 127, n. 2, p. 117-126, Feb 2000.

[0167] LIN, T. T.; HUANG, Y. Y.; TANG, G.H.; CHENG, Z. B. et al. "Prenylated coumarins: natural phosphodiesterase-4 inhibitors from Toddalia asiatica." J Nat Prod, 77, n. 4, p. 955-962, Apr 25 2014.

[0168] LIPWORTH, B.J., "Pharmacokinetics of inhaled drugs." Br J Clin Pharmacol, 1996. 42(6): p. 697-705. (Non-Patent Document 21)

[0169] LIPWORTH, B. J. "Phosphodiesterase-4 inhibitors for asthma and chronic obstructive pulmonary disease." The Lancet, 365, no. 9454, p. 167-175, 2005.

[0170] MADORE, A. M.; LAPRISE, C. "Immunological and genetic aspects of asthma and allergy." J Asthma Allergy, 3, p. 107-121, Aug 20 2010.

[0171] MALIKOV, V. M.; SAIDKHODZHAEV, A. I.; ARIPOV, K. N. "Coumarins: Plants, structure, properties." Chemistry of Natural Compounds, 34, no. 2, p. 202-264, 1998.

[0172] Mattos MS, Ferrero MR, Kraemer L, Lopes GAO, Reis DC, Cassali GD, Oliveira FMS, Brandolini L, Allegretti M, Garcia CC, Martins MA, Teixeira MM, Russo RC. 「CXCR1 and CXCR2 Inhibition by Ladarixin Improves Neutrophil-Dependent Airway Inflammation in Mice.」 Front Immunol. 2020 Oct 2;11:566953. doi: 10.3389 / fimmu.2020.566953. PMID: 33123138; PMCID: PMC7566412.

[0173] MCBRIEN, C. N.; MENZIES-GOW, A. 「The Biology of Eosinophils and Their Role in Asthma.」 Front Med (Lausanne), 4, p. 93, 2017.

[0174] MEDZHITOV, R. 「Inflammation 2010: new adventures of an old flame.」 Cell, 140, no. 6, p. 771-776, Mar 19 2010.

[0175] MENG, X. Y.; ZHANG, H.X.; MEZEI, M.; CUI, M. 「Molecular Docking: A powerful approach for structure-based drug discovery.」 Curr Comput Aided Drug Des, 7, no. 2, p. 146-157, Jun 2011.

[0176] MENZIES-GOW, A.; FLOOD-PAGE, P.; SEHMI, R.; BURMAN, J. et al. 「Anti-IL-5 (mepolizumab) therapy induces bone marrow eosinophil maturational arrest and decreases eosinophil progenitors in the bronchial mucosa of atopic asthmatics.」 J Allergy Clin Immunol, 111, n. 4, p. 714-719, Apr 2003.

[0177] MIGUEL, M. G. 「Antioxidant and anti-inflammatory activities of essential oils: a short review.」 Molecules, 15, n. 12, p. 9252-9287, Dec 15, 2010.

[0178] MIRAVITLLES, M. et al. 「Systematic review on long-term adverse effects of inhaled corticosteroids in the treatment of COPD」, European Respiratory Review, 30: 210075, 2021(Non-Patent Document 17)

[0179] MORE, D. H.; MAHULIKAR, P. P. 「Microwave assisted one-pot synthesis of nitrogen and oxygen containing heterocycles from acyl meldrum’s acid.」 Indian Journal of Chemistry, 50, 2011.

[0180] NEWMAN, D. J.; CRAGG, G. M. 「Natural Products as Sources of New Drugs over the Nearly Four Decades from 01 / 1981 to 09 / 2019.」 J Nat Prod, 83, n. 3, p. 770-803, Mar 27 2020.

[0181] OGUNGBE, I. V.; ERWIN, W. R.; SETZER, W. N. 「Antileishmanial phytochemical phenolics: molecular docking to potential protein targets.」 J Mol Graph Model, 48, p. 105-117, Mar 2014.

[0182] OKIN, D.; MEDZHITOV, R. 「Evolution of inflammatory diseases.」 Curr Biol, 22, n. 17, p. R733-740, Sep 11, 2012.

[0183] ORTEGA, H. G.; LIU, M. C.; PAVORD, I. D.; BRUSSELLE, G. G. et al. 「Mepolizumab treatment in patients with severe eosinophilic asthma.」 N Engl J Med, 371, n. 13, p. 1198-1207, Sep 25, 2014.

[0184] PAGE, C. P. 「An explanation of the asthma paradox.」 Am Rev Respir Dis, 147, n. 6 Pt 2, p. S29-32, Jun 1993.

[0185] PATRIDGE, E.; GAREISS, P.; KINCH, M.S.; HOYER, D. 「An analysis of FDA-approved drugs: natural products and their derivatives.」 Drug Discov Today, 21, n. 2, p. 204-207, Feb 2016.

[0186] PATYAR, S.; PRAKASH, A.; MEDHI, B. 「Dual inhibition: a novel promising pharmacological approach for different disease conditions.」 J Pharm Pharmacol, 63, n. 4, p. 459-471, Apr 2011.

[0187] PAWANKAR, R. 「Mast cell function modulating IgE-mediated allergy.」 Allergology International, 48, no. 3, p. 171-182, 1999.

[0188] POSSA, S.S., et al., 「Eosinophilic inflammation in allergic asthma.」 Front Pharmacol, 2013. 4: p. 46.

[0189] PUNCHARD, N. A.; WHELAN, C.J.; ADCOCK, I. 「The Journal of Inflammation.」 J Inflamm (Lond), 1, n. 1, p. 1, Sep 27, 2004.

[0190] R. Hays, S. and J.V. Fahy, 「The role of mucus in fatal asthma.」 The American Journal of Medicine, 2003. 115(1): p. 68-69.

[0191] RAKOTOARISON, O.; RABENAU, I.; LOBSTEIN, A.; UM, B. H. et al. 「Vasorelaxing properties and bio-guided fractionation of Cedrelopsis strikei.」 Planta Med, 69, n. 2, p. 179-181, Feb 2003.

[0192] RATHER, L. J. 「Disturbance of function (functio laesa): the legendary fifth cardinal sign of inflammation, added by Galen to the four cardinal signs of Celsus.」 Bull N Y Acad Med, 47, n. 3, p. 303-322, Mar 1971.

[0193] ROIFMAN, I.; BECK, P. L.; ANDERSON, T.J.; EISENBERG, M. J. et al. 「Chronic inflammatory diseases and cardiovascular risk: a systematic review.」 Can J Cardiol, 27, n. 2, p. 174-182, Mar-Apr 2011.

[0194] RUGE, A. C.; KIRCH, J.; LEHR, C. M. "Pulmonary drug delivery: from generating aerosols to overcoming biological barriers - therapeutic possibilities and technological challenges", The Lancet Respiratory Medicine, v. 1, i. 5, p. 402-413, July 1, 2013 (Non-Patent Document 23)

[0195] SALARI, P.; ABDOLLAHI, M. "Phosphodiesterase inhibitors in inflammatory bowel disease." Expert Opin Investig Drugs, 21, n. 3, p. 261-264, Mar 2012.

[0196] SANTOS, W. A.; DOURADO, K. M. C.; ARAUJO, F. A.; JESUS, R. L. C. et al. "Braylin induces a potent vasorelaxation, involving distinct mechanisms in superior mesenteric and iliac arteries of rats." Naunyn Schmiedebergs Arch Pharmacol, Oct 9, 2020.

[0197] SCHOFIELD, M. L. "Asthma pharmacotherapy." Otolaryngol Clin North Am, 47, n. 1, p. 55-64, Feb 2014.

[0198] SCIO, E.; RIBEIRO, A.; ALVES, TM; ROMANHA, AJ et al. “New bioactive coumarins from Kielmeyera albopunctata.” J Nat Prod, 66, n. 5, p. 634-637, May 2003.

[0199] SEREZANI, CH; BALLINGER, MN; ARONOFF , DM ; PETERS-GOLDEN, M. “Cyclic AMP: a master regulator of innate immune cell function.” Am J Respir Cell Mol Biol, 39, n. 2, p. 127-132, Aug

[0200] SHUBAYEV, VI; KATO, K.; MYERS, RR 「Translational Pain Research: From Mouse to Man.」 Boca Raton (FL): CRC Press / Taylor & Francis, 2010.

[0201] SILVEIRA, MR; NUNES, KP; FACE, DC; SOUZA, DG et al. 「Infection with Strongyloides venezuelensis induces transient airway eosinophilic inflammation, an increase in immunoglobulin E, and hyperresponsiveness in rats.」 Infect Immun, 70, n. 11, p. 6263-6272, Nov 2002. (Special Note 8)

[0202] SOUTHAM, D.S., et al., 「Goblet cell rebound and airway dysfunction with corticosteroid withdrawal in a mouse model of asthma.」 Am J Respir Crit Care Med, 2008. 178(11): p. 1115-22.

[0203] STRAND, V.; FIORENTINO, D.; HU, C.; DAY, R. M. et al. 「Improvements in patient-reported outcomes with apremilast, an oral phosphodiesterase 4 inhibitor, in the treatment of moderate to severe psoriasis: results from a phase IIb randomized, controlled study.」 Health Qual Life Outcomes, 11, p. 82, May 10 2013.

[0204] SUISSA, S.; ERNST, P.; BENAYOUN, S.; BALTZAN, M. et al. 「Low-dose inhaled corticosteroids and the prevention of death from asthma.」 N Engl J Med, 343, n. 5, p. 332-336, Aug 3 2000.(Non-Patent Document 12)

[0205] SUN, C.; ZHAO, W.; WANG, X.; SUN, Y. et al. 「A pharmacological review of dicoumarol: An old natural anticoagulant agent.」 Pharmacol Res, 160, p. 105193, Oct 2020.

[0206] TRACY, R. P. 「The five cardinal signs of inflammation: Heat, Pain, Flushing, Tumor and Penuria (Apologies to Aulus Cornelius Celsus, De Medicina, c. A.D. 25).」 J Gerontol A Biol Sci Med Sci, 61, n. 10, p. 1051-1052, Oct 2006.

[0207] TSAI, I.-L.; WUN, M.-F.; TENG, C.-M.; ISHIKAWA, T. et al. 「Anti-platelet aggregation constituents from formosan Toddalia asiatica.」 Phytochemistry, 48, n. 8, p. 1377-1382, 1998.

[0208] VASCONCELOS, J.F., et al., 「Effects of umbelliferone in a murine model of allergic airway inflammation.」 Eur J Pharmacol, 2009. 609(1-3): p. 126-31.

[0209] VERRI, W. A., Jr.; CUNHA, T. M.; PARADA, C. A.; POOLE, S. et al. 「Hypernociceptive role of cytokines and chemokines: targets for analgesic drug development?」 Pharmacol Ther, 112, n. 1, p. 116-138, Oct 2006.

[0210] WANG, J., et al., 「Anti-asthmatic activity of osthole in an ovalbumin-induced asthma murine model.」 Respir Physiol Neurobiol, 2017. 239: p. 64-69.

[0211] WATZL, B. 「Anti-inflammatory effects of plant-based foods and of their constituents.」 Int J Vitam Nutr Res, 78, n. 6, p. 293-298, Dec 2008.

[0212] WIDDICOMBE JG (2003) 「Overview of neural pathways in allergy and asthma.」 Pulm Pharmacol Ther 16(23):30. https: / / doi. org / 10. 1016 / s1094- 5539(02) 00178-5(Non-patent Document 5)

[0213] WITAICENIS, A.; SEITO, L. N.; DA SILVEIRA CHAGAS, A.; DE ALMEIDA, L. D., Jr. et al. 「Antioxidant and intestinal anti-inflammatory effects of plant-derived coumarin derivatives.」 Phytomedicine, 21, n. 3, p. 240-246, Feb 15 2014.

[0214] XIONG, Y., et al., 「The effects of nodakenin on airway inflammation, hyper-responsiveness and remodeling in a murine model of allergic asthma.」 Immunopharmacol Immunotoxicol, 2014. 36(5): p. 341-8.

[0215] YOO, S.W., et al., 「Constituents of the fruits and leaves of Euodia daniellii.」 Arch Pharm Res, 2002. 25(6): p. 824-30.

[0216] ZHANG, J. M.; AN, J. 「Cytokines, inflammation, and pain.」 Int Anesthesiol Clin, 45, n. 2, p. 27-37, Spring 2007.

Claims

1. Formula I: 【Chemistry 1】 (I) (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ Any one of the following is H, OH, O, S, N, or C １ ~C ５ Alkyl, C ２ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, optionally aromatic C ３ ~C ７ Cycloalkyl, C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ heterocycloalkyl, wherein C １ ~C ５ Alkyl, C ２ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, optionally aromatic C ３ ~C ７ Cycloalkyl, C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ Any of the heterocycloalkyls may be OH, O, S, N, C, １ ~C ５ Alkyl, C ２ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, optionally aromatic C ３ ~C ７ Cycloalkyl, C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ heterocycloalkyl, and C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ Heterocycloalkyls contain 1 to 3 heteroatoms in their chain selected from F, O, N, Cl, Br, I, S, and / or R ３ and R ４ , R ４ and R ５ , R ５ and R ６ independently, taken together, form an optionally aromatic 3- to 7-membered cyclic group which may contain 1 to 3 heteroatoms selected from O, N, and S as ring members, wherein said cyclic group is selected from OH, O, S, N, C １ ~C ５ Alkyl, C ２ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, optionally aromatic C ３ ~C ７ Cycloalkyl, C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ Heterocycloalkyl is optionally substituted with one or more substituents selected from １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ 2. Use of an active compound of the formula (I) (heterocycloalkyl contains 1 to 3 heteroatoms in their chain selected from F, O, N, Cl, Br, I, S), or salts, prodrugs, stereoisomers, hydrates, dimeric derivatives, equivalents, bioisosteres, and polymorphs thereof, for the manufacture of a medicament for the treatment of asthma or chronic obstructive pulmonary disease (COPD).

2. The active compound has the formula II: 【Chemistry 2】 (II) or its salts, prodrugs, stereoisomers, hydrates, dimeric derivatives, isomers, bioisosteres and polymorphs thereof.

3. The use according to claim 1 or 2, characterized in that the active compound is Braylin or a pharma- ceutically acceptable salt thereof.

4. The use according to any one of claims 1 to 3, characterized in that the therapeutic agent is formulated in a form suitable for administration via inhalation.

5. The use according to any one of claims 1 to 4, characterized in that the therapeutic agent contains from 1 mg to 1000 mg of the active compound.

6. The use according to any one of claims 1 to 5, characterized in that the therapeutic agent is in the form of a powder, granules, solution or suspension.

7. 7. The use according to claim 6, characterized in that the therapeutic agent is formulated in a form suitable for administration by capsule, spray or aerosol.

8. Formula I: 【Chemistry 3】 (I) (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ Any one of the following is H, OH, O, S, N, or C １ ~C ５ Alkyl, C ２ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, optionally aromatic C ３ ~C ７ Cycloalkyl, C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ heterocycloalkyl, wherein C １ ~C ５ Alkyl, C ２ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, optionally aromatic C ３ ~C ７ Cycloalkyl, C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ Any of the heterocycloalkyls may be OH, O, S, N, C, １ ~C ５ Alkyl, C ２ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, optionally aromatic C ３ ~C ７ Cycloalkyl, C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ heterocycloalkyl, and C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ Heterocycloalkyls contain 1 to 3 heteroatoms in their chain selected from F, O, N, Cl, Br, I, S, and / or R ３ and R ４ , R ４ and R ５ , R ５ and R ６ independently, taken together, form an optionally aromatic 3- to 7-membered cyclic group which may contain 1 to 3 heteroatoms selected from O, N, and S as ring members, wherein said cyclic group is selected from OH, O, S, N, C １ ~C ５ Alkyl, C ２ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, optionally aromatic C ３ ~C ７ Cycloalkyl, C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ Heterocycloalkyl is optionally substituted with one or more substituents selected from １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ Heterocycloalkyls contain 1 to 3 heteroatoms in their chain selected from F, O, N, Cl, Br, I, S), or salts, prodrugs, stereoisomers, hydrates, dimeric derivatives, isomers, bioisomers, and polymorphs thereof, and at least one pharmaceutically acceptable excipient.

9. The active compound has the formula II: 【Chemistry 4】 (II) 9. The pharmaceutical formulation according to claim 8, characterized in that it is selected from the group consisting of the compounds of the formula (I) and (II) or their salts, prodrugs, stereoisomers, hydrates, dimeric derivatives, isomers, bioisosteres and polymorphs.

10. 10. The pharmaceutical formulation according to claim 8 or 9, characterized in that the active compound is Braylin or a pharma- ceutically acceptable salt thereof.

11. A pharmaceutical formulation according to any one of claims 8 to 10, characterized in that it is in a form suitable for administration via inhalation.

12. A pharmaceutical formulation according to any one of claims 8 to 11, characterized in that it is for the treatment of asthma and / or COPD.

13. A pharmaceutical formulation according to any one of claims 8 to 12, characterized in that it is in the form of a powder, granules, solution or suspension.

14. A pharmaceutical formulation according to any one of claims 8 to 13, characterized in that it is in the form of a capsule, a spray or an aerosol.

15. A pharmaceutical formulation according to any one of claims 8 to 14, characterized in that it contains between 1 mg and 1000 mg of the compound of formula I.

16. A method for treating asthma and / or COPD comprising administering a therapeutically effective amount of a compound of formula I: 【Chemistry 5】 (I) (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ Any one of the following is H, OH, O, S, N, or C １ ~C ５ Alkyl, C ２ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, optionally aromatic C ３ ~C ７ Cycloalkyl, C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ heterocycloalkyl, wherein C １ ~C ５ Alkyl, C ２ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, optionally aromatic C ３ ~C ７ Cycloalkyl, C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ Any of the heterocycloalkyls may be OH, O, S, N, C, １ ~C ５ Alkyl, C ２ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, optionally aromatic C ３ ~C ７ Cycloalkyl, C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ heterocycloalkyl, and C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ Heterocycloalkyls contain 1 to 3 heteroatoms in their chain selected from F, O, N, Cl, Br, I, S, and / or R ３ and R ４ , R ４ and R ５ , R ５ and R ６ independently, taken together, form an optionally aromatic 3- to 7-membered cyclic group which may contain 1 to 3 heteroatoms selected from O, N, and S as ring members, wherein said cyclic group is selected from OH, O, S, N, C １ ~C ５ Alkyl, C ２ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, optionally aromatic C ３ ~C ７ Cycloalkyl, C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ Heterocycloalkyl is optionally substituted with one or more substituents selected from １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ and heterocycloalkyl contain 1 to 3 heteroatoms in their chain selected from F, O, N, Cl, Br, I, S), or salts, prodrugs, stereoisomers, hydrates, dimeric derivatives, equivalents, bioisosteres, and polymorphs thereof, to a patient in need thereof.

17. The compound has formula II: 【Chemistry 6】 (II) or a salt, prodrug, stereoisomer, hydrate, dimeric derivative, isomer, bioisostere, or polymorph thereof.

18. 18. The method of claim 16 or 17, wherein the compound is braylin or a pharma- ceutically acceptable salt thereof.

19. The method according to any one of claims 16 to 18, characterized in that the compound is administered at a dose between 1 mg / kg and 100 mg / kg.

20. The method according to any one of claims 16 to 19, characterized in that the compound is administered at a dose of 50 mg / kg.

21. The method according to any one of claims 16 to 20, characterized in that the compound is administered via inhalation.

22. The method according to any one of claims 16 to 21, characterized in that the compound is administered in the form of a powder, granules, a solution or a suspension.

23. The method according to any one of claims 16 to 22, characterized in that the compound is administered by capsule, spray or aerosol.

24. A compound of formula I: 【Chemistry 7】 (I) (In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ Any one of the following is H, OH, O, S, N, or C １ ~C ５ Alkyl, C ２ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, optionally aromatic C ３ ~C ７ Cycloalkyl, C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ heterocycloalkyl, wherein C １ ~C ５ Alkyl, C ２ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, optionally aromatic C ３ ~C ７ Cycloalkyl, C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ Any of the heterocycloalkyls may be OH, O, S, N, C, １ ~C ５ Alkyl, C ２ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, optionally aromatic C ３ ~C ７ Cycloalkyl, C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ heterocycloalkyl, and C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ Heterocycloalkyls contain 1 to 3 heteroatoms in their chain selected from F, O, N, Cl, Br, I, S, and / or R ３ and R ４ , R ４ and R ５ , R ５ and R ６ independently, taken together, form an optionally aromatic 3- to 7-membered cyclic group which may contain 1 to 3 heteroatoms selected from O, N, and S as ring members, wherein said cyclic group is selected from OH, O, S, N, C １ ~C ５ Alkyl, C ２ ~C ５ Alkenyl, C ２ ~C ５ Alkynyl, optionally aromatic C ３ ~C ７ Cycloalkyl, C １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ Heterocycloalkyl is optionally substituted with one or more substituents selected from １ ~C ５ Heteroalkyl and optionally aromatic C ３ ~C ７ Heterocycloalkyl contains 1 to 3 heteroatoms in its chain selected from F, O, N, Cl, Br, I, S), or salts, prodrugs, stereoisomers, hydrates, dimeric derivatives, isomers, bioisomers, and polymorphs thereof.

25. Formula II: 【Chemistry 8】 (II) 25. The compound according to claim 24, characterized in that it is a compound of the formula:

26. 26. The compound according to claim 24 or 25, characterized in that the compound is braylin or a pharma- ceutically acceptable salt thereof.

Images