Use of masitinib for the treatment of eosinophilic asthma

Abstract

The present invention relates to a 2-aminoarylthiazole derivative or a pharmaceutically acceptable salt or solvate thereof, particularly masitinib or a pharmaceutically acceptable salt or solvate thereof, for use in treating asthma in a subject in need thereof having a high level of eosinophils. In particular, the present invention relates to a 2-aminoarylthiazole derivative or a pharmaceutically acceptable salt or solvate thereof, particularly masitinib or a pharmaceutically acceptable salt or solvate thereof, for use in treating asthma in a subject in need thereof having a baseline eosinophil blood count in the range of 150 cells / μL to 300 cells / μL.

Description

[Technical Field]

[0001] The present invention relates to the treatment of asthma, particularly eosinophilic asthma, in subjects in need thereof. [Background technology]

[0002] Asthma is a chronic inflammatory disease of the airways, characterized by variable airflow obstruction, airway hyperresponsiveness and airway inflammation.As asthma is a chronic disease, the goal of asthma treatment is to achieve disease control, particularly to alleviate symptoms and reduce asthma exacerbations, thus improving quality of life.

[0003] Eosinophils are a type of inflammatory granulocyte and are involved in the pathophysiology of asthma. Increased eosinophil counts have been reported in bronchoalveolar lavage tests, sputum, and / or peripheral blood of subjects with asthma. The accumulation of eosinophils, particularly in the airways, can lead to airway inflammation and narrowing due to degranulation and release of inflammatory mediators such as eosinophil-derived neurotoxins, eosinophil cationic protein, eosinophil peroxidase, and major basic protein. Eosinophilic inflammation correlates with the severity of asthma, particularly the frequency of asthma exacerbations. Severe asthma is generally associated with difficulty in achieving disease control.

[0004] In many subjects, asthma is a disease that can be well controlled by maintenance medications, including corticosteroids, especially inhaled corticosteroids and / or bronchodilators.However, in some subjects with asthma, especially those with high eosinophilic levels and those with eosinophilic asthma, asthma is still not controlled by such maintenance medications.Therefore, in some subjects, asthma is not effective with generally effective maintenance medications, such as corticosteroids, especially inhaled corticosteroids and / or bronchodilators.Subjects with refractory asthma (also called uncontrolled asthma) usually receive high doses of corticosteroids, especially oral corticosteroids, and thus may become dependent on oral corticosteroids to achieve asthma control.However, oral corticosteroids may induce serious side effects, and therefore their long-term use should be avoided.In addition, in some subjects, asthma also responds poorly to oral corticosteroids.

[0005] Thus, there remains a need for effective treatments for asthma, particularly asthma that is difficult to treat with currently available maintenance medications, e.g., in subjects with eosinophilic inflammation and / or eosinophilic asthma. In particular, there is a need for effective treatments that achieve control of asthma, e.g., by reducing asthma exacerbations.

[0006] The present invention thus relates to a 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment of asthma in a subject in need thereof, wherein said subject has high levels of eosinophils, in particular said subject has a baseline eosinophil blood count of 150 cells / μL or greater, for example a baseline eosinophil blood count in the range of 150 cells / μL to 300 cells / μL. Summary of the Invention

[0007] The present invention relates to a 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in treating asthma in a subject in need thereof, wherein the subject has a baseline eosinophil blood count of 150 cells / μL or greater. The present invention also relates to a method for treating asthma in a subject in need thereof, wherein the subject has a baseline eosinophil blood count of 150 cells / μL or greater, the method comprising administering to the subject a 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0008] In one embodiment, a 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is for use in treating asthma in a subject in need thereof, wherein the subject has a baseline eosinophil blood count in the range of 150 cells / μL to 300 cells / μL. In one embodiment, a 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is for use in treating asthma in a subject in need thereof, wherein the subject has a baseline eosinophil blood count of 300 cells / μL or greater, preferably greater than 300 cells / μL.

[0009] Thus, in one embodiment, the present invention relates to a method for treating asthma in a subject in need thereof, the subject having a baseline eosinophil blood count in the range of 150 cells / μL to 300 cells / μL, comprising the step of administering to the subject a 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the present invention relates to a method for treating asthma in a subject in need thereof, the subject having a baseline eosinophil blood count of 300 cells / μL or greater, preferably greater than 300 cells / μL, comprising the step of administering to the subject a 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof.

[0010] In one embodiment, the asthma is asthma with type 2 inflammation, also known as type 2 asthma.

[0011] In one embodiment, the asthma is uncontrolled. In other words, in one embodiment, the asthma is refractory to maintenance medications such as corticosteroids and / or biologics. In one embodiment, the asthma is uncontrolled with inhaled corticosteroids and / or oral corticoids. In other words, in one embodiment, the asthma is refractory to inhaled corticosteroids and / or oral corticoids. In one embodiment, the asthma is uncontrolled with biologics. In other words, in one embodiment, the asthma is refractory to biologics.

[0012] In one embodiment, the 2-aminoarylthiazole derivative or a pharmaceutically acceptable salt or solvate thereof for use according to any one of claims 1 to 5 has the formula (II): [ka] (In the formula, R1 is independently selected from hydrogen, halogen, (C1 C10) alkyl, (C3 C10) cycloalkyl, trifluoromethyl, alkoxy, amino, alkylamino, dialkylamino, solubilizing groups, and (C1-C 10 ) alkyl; m is 0 to 5) It has.

[0013] In one preferred embodiment, the 2-aminoarylthiazole derivative, or a pharmaceutically acceptable salt or solvate thereof, is masitinib, or a pharmaceutically acceptable salt or solvate thereof. In one embodiment, the pharmaceutically acceptable salt or solvate of masitinib is the mesylate salt of masitinib.

[0014] In one embodiment, the 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered orally.

[0015] In one embodiment, the 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is for administration at a dose ranging from about 1 mg / kg / day to about 12 mg / kg / day, preferably from about 3 mg / kg / day to about 6 mg / kg / day. In one embodiment, the 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is for administration at a dose of about 3 mg / kg / day, 4.5 mg / kg / day, or 6 mg / kg / day. In one embodiment, the 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is for administration initially at a dose of about 3 mg / kg / day for at least four weeks, followed by a dose of about 4.5 mg / kg / day for at least four weeks, and then at a dose of about 6 mg / kg / day, with each dose increase being subject to toxicity control.

[0016] In one embodiment, the 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is for administration with at least another pharmaceutically effective agent. In one embodiment, the at least another pharmaceutically effective agent is selected from the group consisting of biologics, corticosteroids, bronchodilators (including LABAs), leukotriene modifiers, rescue medications, and any combination thereof. In one embodiment, the at least another pharmaceutically effective agent is a biologic selected from the group consisting of anti-IgE agents and anti-cytokine agents, e.g., an anti-IL-5 agent. In one embodiment, the biologic is an anti-IL-5 agent. In one embodiment, the at least another pharmaceutically effective agent is for administration as a first-line treatment, and the 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is for administration as a second-line treatment.

[0017] definition For the purposes of the present invention, the following terms have the following meanings:

[0018] The use of "about" preceding a number encompasses up to ±10% of the stated numerical value. It is to be understood that the value referred to by the term "about" is itself also specific and preferably disclosed.

[0019] An "asthma exacerbation" or "asthma attack" or "asthma episode" or "asthma flare-up" is defined as: Signs and / or progressive worsening of asthma symptoms (also called deterioration); Deterioration of lung function; Increased use of rescue medications are interchangeable expressions referring to an episode characterized by at least one of the following:

[0020] Examples of asthma symptoms include, but are not limited to, wheezing, coughing, shortness of breath (also known as dyspnea), and chest tightness. An asthma exacerbation may require medical visit and / or hospitalization. An asthma exacerbation may be moderate or severe. In one embodiment, a moderate asthma exacerbation is defined as a worsening of asthma symptoms, worsening lung function, and / or increased use of rescue medication, particularly lasting at least two days. In one embodiment, a moderate asthma exacerbation is defined as a worsening of asthma symptoms, worsening lung function, and / or increased use of rescue medication, particularly lasting at least two days, requiring a change in asthma treatment (other than an increase in the dose of systemic corticosteroids or hospitalization). In one embodiment, a severe asthma exacerbation is defined as an asthma exacerbation requiring hospitalization and / or an increase in control medication, such as a stable dose of corticosteroids, particularly lasting at least three days.

[0021] "Control of asthma" or "clinical control of asthma" refers to the clinical management of asthma, particularly with medications aimed at preventing or reducing airway inflammation, preventing or reducing asthma symptoms and / or asthma-related limitations, and preventing asthma exacerbations. For example, in a subject with controlled asthma, asthma induces little or no limitations, such as limitations on normal exercise and / or daily activities; little or no loss of sleep quality, such as nighttime awakenings; and does not frequently require life-saving treatment. Such control medications are also referred to as maintenance medications. Control medications may, for example, reduce airway inflammation or help maintain airway patency. Examples of control medications include, but are not limited to, corticosteroids (especially inhaled corticosteroids), leukotriene modifiers, long-acting beta-agonists (LABAs), combinations of corticosteroids and LABAs, and bronchodilators, such as theophylline.

[0022] "Baseline," as used herein, refers to the time preceding the initiation of treatment with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof. For example, a baseline eosinophil blood count for a given subject is the eosinophil blood count prior to administration of a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof to the subject.

[0023] "BID" as used herein in connection with the treatment of inhaled asthma means twice daily.

[0024] "Eosinophils" (sometimes known as acidophils) refer to a type of proinflammatory white blood cell (WBC), more precisely a granulocyte characterized by segmented nuclei and cytoplasmic granulation that stains easily, especially with eosin. Eosinophils play a role in inflammation, particularly airway inflammation.

[0025] "Eosinophil count" refers to a measurement of the number of eosinophils. For example, the number of eosinophils can be measured in tissue, bronchoalveolar lavage, sputum, or blood. As described hereinafter, the number of eosinophils measured in blood is known as the eosinophil blood count.

[0026] "Eosinophil blood count" (also known as absolute eosinophil count) refers to the number of white blood cells in the blood that are eosinophils. Methods for assessing a subject's eosinophil blood count are routinely used in clinical laboratories. For example, the measurement can be performed by counting the number of eosinophils per 100 cells and multiplying the resulting percentage by the white blood cell count (i.e., the total number of white blood cells). The eosinophil blood count is usually calculated per 1 μL of blood or 1 mm 3 It is expressed as the number of cells (i.e., eosinophils) per 1000 of blood.

[0027] An "exacerbation rate" refers to the number of asthma exacerbations that occur in a subject over a given period of time. For example, an annual or yearly exacerbation rate refers to the number of asthma exacerbations that occur in a subject over a year.

[0028] "Lung function," as used herein, reflects airflow, and a decrease in lung function reflects airflow limitation. In one embodiment, lung function, and thus airflow limitation, can be assessed through measurements of forced expiratory volume (FEV), forced expiratory volume in 1 second (FEV1), percentage of predicted FEV1 (as used herein, comparing how much a subject with asthma can exhale with how much a subject without asthma can exhale), peak expiratory flow (PEF), and / or forced vital capacity (FVC). Methods for assessing lung function, and thus airflow limitation, are well known and include, inter alia, spirometry.

[0029] A "pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to an excipient or carrier that does not produce adverse, allergic, or other undesirable reactions when administered to a mammal, preferably a human. This includes any solvents, such as dispersion media, coating agents, antibacterial and antifungal agents, isotonic and absorption delaying agents. A pharmaceutically acceptable excipient or carrier refers to any type of non-toxic solid, semisolid, or liquid filler, diluent, encapsulating material, or formulation aid. For human administration, formulations should meet sterility, pyrogenicity, general safety, and purity standards required by regulatory agencies such as the FDA (Food and Drug Administration) or EMA (European Medicines Agency).

[0030] "Rescue medication," as used herein, refers to a rapid-acting (or fast-acting) medication intended to provide immediate relief from asthma symptoms. In particular, rescue medication, as used herein, refers to a rapid-acting (or fast-acting) medication intended to relieve asthma exacerbations. Examples of rescue medications include, but are not limited to, bronchodilators, such as short-acting beta-agonists and ipratropium, and corticoids, such as oral or intravenous corticosteroids.

[0031] "Subject" refers to a mammal, preferably a human. In the present invention, the subject is a mammal, preferably a human, suffering from asthma. In one embodiment, the subject may be a "patient", i.e., a mammal, preferably a human, who is waiting to receive medical treatment, or is receiving medical treatment, or has been / is / may be a subject of medical treatment in the past / present / future, or is being monitored for the development of asthma. In one embodiment, the subject is a patient, i.e., a mammal, preferably a human, who is receiving medical treatment, particularly maintenance medication, and / or is being monitored for asthma.

[0032] A "therapeutically effective amount" or "therapeutically effective dose" is one that is effective to treat a subject in need of treatment without causing significant negative or adverse side effects, and is as follows: a reduction in asthma exacerbations, for example a reduction in moderate asthma exacerbations, a reduction in severe asthma exacerbations, and / or a reduction in overall asthma exacerbations; Prevention or reduction of one or more of the symptoms of asthma; Preventing or reducing airway inflammation; Preventing or reducing the deterioration of lung function; reduced need for rescue medications; Facilitating a steroid-sparing effect by reducing the required dose of inhaled and / or long-term oral corticosteroids; Prevention of the need for increased doses of maintenance medications; A reduction in the frequency of hospital visits and / or hospital admissions, i.e., a reduction in the frequency of hospitalization; A reduction in the length of hospital visits and / or hospital stays, i.e., a reduction in the length of hospital stays; and / or Improved quality of life The term "masitinib" refers to an amount or concentration of a 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, that is intended to provide at least one of the following:

[0033] In one embodiment, a therapeutically effective amount or therapeutically effective dose refers to an amount or concentration of a 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, as defined herein, aimed at reducing asthma exacerbations, particularly the rate of asthma exacerbations, e.g., the annual rate of asthma exacerbations, without causing significant negative or harmful side effects to a subject in need of treatment. In one embodiment, the asthma exacerbations are moderate asthma exacerbations and / or severe asthma exacerbations, and the rate of asthma exacerbations is the rate of moderate asthma exacerbations and / or the rate of severe asthma exacerbations (respectively), e.g., the annual rate of moderate asthma exacerbations and / or the annual rate of severe asthma exacerbations. In one embodiment, the asthma exacerbations are overall asthma exacerbations, including moderate asthma exacerbations and severe asthma exacerbations, and the asthma exacerbation rate is the overall asthma exacerbation rate, e.g., the overall asthma exacerbation yearly rate.

[0034] "Treating" or "treatment" refers to therapeutic, preventative (or prophylactic) treatment, or both therapeutic and preventative (or prophylactic) treatment, the purpose of which is to prevent, reduce, or delay (diminish) one or more of the symptoms or signs of asthma in a subject in need thereof, preferably the purpose is to reduce asthma exacerbations, e.g., moderate asthma exacerbations, severe asthma exacerbations, and / or overall asthma exacerbations. In one embodiment, the purpose of treatment according to the present application is to: a reduction in asthma exacerbations, for example a reduction in moderate asthma exacerbations, a reduction in severe asthma exacerbations, and / or a reduction in overall asthma exacerbations; Prevention or reduction of one or more of the symptoms of asthma; Preventing or reducing airway inflammation; Preventing or reducing the deterioration of lung function; reduced need for rescue medications; Facilitating a steroid-sparing effect by reducing the required dose of inhaled and / or long-term oral corticosteroids; Prevention of the need for increased doses of maintenance medications; A reduction in the frequency of hospital visits and / or hospitalizations, in other words, a reduction in the frequency of hospitalizations; A reduction in the length of hospital visits and / or hospital stays, i.e., a reduction in the length of hospital stays; and / or Improved quality of life The goal is to bring about at least one of the following.

[0035] Thus, a subject suffering from asthma may be administered a therapeutically effective amount of a 2-aminoarylthiazole derivative, particularly masitinib, as defined herein, or a pharmaceutically acceptable salt or solvate thereof, after which the subject experiences one of the following symptoms: a reduction in asthma exacerbations, particularly asthma exacerbation rates, such as moderate asthma exacerbations, severe asthma exacerbations, and / or overall asthma exacerbation rates; A decrease in one or more of the following asthma symptoms: wheezing, coughing, shortness of breath (also known as dyspnea), and chest tightness; reduced airway inflammation; reduced need for rescue medications; A reduction in the frequency of hospital visits and / or hospitalizations, in other words, a reduction in the frequency of hospitalizations; A reduction in the length of hospital visits and / or hospital stays, i.e., a reduction in the length of hospital stays; and / or Improved quality of life A "treatment" is considered successful if a patient benefits from at least one of the following:

[0036] "Type 2 asthma" or "asthma with type 2 inflammation" refers to a phenotype of asthma characterized by the production of cytokines such as interleukin (IL)-4, IL-5, and IL-13, which are often produced by the adaptive immune system after allergen recognition. Type 2 inflammation is often characterized by eosinophils and may be accompanied by atopy, whereas non-type 2 inflammation is often characterized by neutrophils. In subjects with mild or moderate asthma, type 2 inflammation improves rapidly with regular and precise administration of inhaled corticosteroids (ICS). In severe asthma, type 2 inflammation is relatively refractory to high doses of ICS. While severe type 2 asthma may respond to oral corticosteroids (OCS), their severe side effects mean that alternative treatments should be considered. If subjects are taking high-dose ICS or daily OCS and have blood eosinophils ≥ 150 / μL, the possibility of refractory type 2 inflammation is considered [Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2019. Available at www.ginasthma.org].

[0037] "Uncontrolled asthma," also known as "refractory asthma," refers to asthma that is not controlled by maintenance medications, particularly bronchodilators and / or corticoids, such as inhaled corticoids, or even, optionally, oral corticoids. In other words, in subjects with uncontrolled or refractory asthma, maintenance medications do not achieve their objectives, such as preventing or reducing airway inflammation, preventing or reducing asthma symptoms and / or asthma-related limitations, and preventing asthma exacerbations. In one embodiment, uncontrolled asthma is defined by the presence of at least one of the following: activity limitations, loss of sleep quality, especially nocturnal awakenings, and / or the need for life-saving treatment at least twice per week.

[0038] Detailed Description The present invention relates to a 2-aminoarylthiazole derivative, particularly masitinib, as described herein, or a pharmaceutically acceptable salt or solvate thereof, for use in treating elevated levels of eosinophils, particularly asthma in a subject in need thereof having elevated baseline levels of eosinophils.

[0039] In one embodiment, the level of eosinophils is the level or number or percentage of eosinophils in biological samples from subject.Examples of biological samples include but are not limited to tissue samples, blood samples, sputum samples, and bronchoalveolar lavage fluid.In one embodiment, the level of eosinophils is the level or number or percentage of eosinophils in sputum samples, tissue samples such as lung tissue samples or bronchial tissue samples, bronchoalveolar lavage fluid samples, or blood samples.

[0040] In the present invention, eosinophilic asthma (EA), sometimes referred to as severe eosinophilic asthma (SEA), represents a subtype of asthma characterized by high levels of eosinophils. Thus, one subject of the present invention is a 2-aminoarylthiazole derivative described herein, or a pharmaceutically acceptable salt or solvate thereof, for use in treating eosinophilic asthma (EA) in a subject in need thereof. Another subject of the present invention is a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, for use in treating severe eosinophilic asthma (SEA) in a subject in need thereof.

[0041] In one embodiment, the eosinophil level is an eosinophil blood cell count. In one embodiment, in the present application, a high level of eosinophils is an eosinophil blood cell count of 150 cells / μL or more (i.e., 150 eosinophils per μL of blood). In one embodiment, a high level of eosinophils is an eosinophil blood cell count in the range of 150 cells / μL to 300 cells / μL. In one embodiment, a high level of eosinophils is an eosinophil blood cell count of 300 cells / μL or more (i.e., 300 eosinophils per μL of blood), preferably an eosinophil blood cell count greater than 300 cells / μL.

[0042] One subject of the present invention is a 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, described herein for use in treating asthma in a subject in need thereof having a baseline eosinophil blood count of 150 cells / μL or greater. In one embodiment, the 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, described herein is for use in treating eosinophilic asthma in a subject in need thereof having a baseline eosinophil blood count of 150 cells / μL or greater.

[0043] One object of the present invention is a 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, described herein for use in treating asthma in a subject in need thereof having a baseline eosinophil blood count in the range of 150 cells / μL to 300 cells / μL. In one embodiment, a 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, described herein, is for use in treating eosinophilic asthma in a subject in need thereof having a baseline eosinophil blood count in the range of 150 cells / μL to 300 cells / μL.

[0044] One object of the present invention is a 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, as described herein, for use in treating asthma in a subject in need thereof having a baseline eosinophil blood count of 300 cells / μL or greater, preferably greater than 300 cells / μL. In one embodiment, the 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, as described herein, is for use in treating eosinophilic asthma in a subject in need thereof having a baseline eosinophil blood count of 300 cells / μL or greater, preferably greater than 300 cells / μL.

[0045] In one embodiment, the subject treated as described herein suffers from severe asthma, particularly severe eosinophilic asthma. The severity of asthma is traditionally classified according to the presence of clinical features prior to treatment initiation, airflow limitation, and / or the daily medication required for optimal treatment [Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 2007; http: / / www.ginasthma.org].

[0046] The severity of asthma can be assessed, for example, by considering the frequency and intensity of asthma symptoms, such as wheezing, coughing, shortness of breath (also known as dyspnea), and chest tightness; the level of airflow limitation, which can be assessed, for example, via measurement of forced expiratory volume in 1 second (FEV1) and / or measurement of peak expiratory flow (PEF); the frequency of asthma exacerbations or the rate of asthma exacerbations; sleep quality and / or frequency of nocturnal asthma symptoms, such as nighttime awakenings; and limitations in physical activity. The severity of asthma can also be assessed by the intensity of maintenance treatment required to achieve good asthma control.

[0047] In one embodiment, severe asthma is defined as asthma that requires high-intensity treatment with maintenance medications, e.g., oral corticosteroids, to maintain good control, or asthma that has not achieved good control despite high-intensity treatment, e.g., oral corticosteroids.

[0048] In one embodiment, the severe asthma described herein is severe persistent asthma.

[0049] In one embodiment, severe persistent asthma refers to asthma that, despite optimal management, remains difficult to control for subject compliance with treatment and extensive reassessment of the diagnosis by an asthma specialist over an observation period of at least six months.

[0050] In one embodiment, severe persistent asthma is characterized by the presence of daily asthma symptoms (such as wheezing, coughing, shortness of breath (also known as dyspnea), and chest tightness), frequent asthma exacerbations (e.g., at least two asthma exacerbations per year), frequent nocturnal asthma symptoms such as nighttime awakenings, limited physical activity, FEV1 or PEF≦60% predicted FEV1 or PEF, and / or a variability in PEF or FEV1 >30%.

[0051] In one embodiment, the subject treated as described herein suffers from uncontrolled asthma, particularly severe and / or eosinophilic asthma. Thus, in one embodiment, the subject treated as described herein suffers from uncontrolled asthma, particularly uncontrolled severe and / or eosinophilic asthma. In other words, the subject treated as described herein suffers from asthma, particularly severe and / or eosinophilic asthma, that is refractory to maintenance medication.

[0052] Thus, in one embodiment, treatment of asthma with a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is a second (or further) choice of treatment.

[0053] In one embodiment, the maintenance medication is a corticosteroid. Thus, in one embodiment, the subject treated as described herein suffers from asthma that is not controlled with corticosteroids, particularly severe and / or eosinophilic asthma. In other words, in one embodiment, the subject treated as described herein suffers from asthma that is refractory to corticosteroids, particularly severe and / or eosinophilic asthma. Examples of corticosteroids used as maintenance medications for the treatment of asthma include, but are not limited to, fluticasone, budesonide, mometasone, beclomethasone, prednisone, prednisolone, betamethasone, and dexamethasone.

[0054] In one embodiment, if at any time two or more corticosteroids are administered simultaneously, then the corticosteroid dose contemplated during the overlap period is the sum of all individual prednisone equivalent doses.

[0055] Those skilled in the art will commonly recognize that published steroid conversion factors (dose equivalents) are used to normalize steroid doses to a common standard of prednisone, such as in Lefebvre et al. J Allergy Clin Immunol. 2015 Dec;136(6):1488-1495.

[0056] In one embodiment, the maintenance medication is an inhaled corticosteroid (ICS). Thus, in one embodiment, the subject treated as described herein suffers from asthma that is not controlled by inhaled corticosteroids (ICS), particularly severe and / or eosinophilic asthma. In other words, in one embodiment, the subject treated as described herein suffers from asthma that is refractory to ICS, particularly severe and / or eosinophilic asthma. Examples of ICS used as maintenance medications for the treatment of asthma include, but are not limited to, fluticasone, budesonide, mometasone, and beclomethasone.

[0057] In one embodiment, the maintenance medication is selected from the group including or consisting of fluticasone, budesonide, mometasone, beclomethasone, and any combination thereof.

[0058] In one embodiment, as used in this application, ICS also includes a combination of a corticoid and another agent, particularly a long-acting beta-agonist (LABA). Examples of ICS used as a maintenance medication for the treatment of asthma that comprise or consist of a corticoid in combination with a LABA include, but are not limited to, the combination of fluticasone and salmeterol, the combination of budesonide and formoterol, and the combination of mometasone and formoterol.

[0059] In one embodiment, the maintenance medication is a combination of fluticasone and salmeterol (e.g., a DPI (dry powder inhaler) formulation: 500 / 50 μg BID (BID means twice daily) or an MDI (metered dose inhaler) formulation: 460 / 42 μg breath-activated digital inhaler). inhaler: BID), a combination of budesonide and formoterol (e.g., 320 / 9 μg BID), and a combination of mometasone and formoterol (e.g., (400 / 10 μg BID). In one embodiment, the maintenance medication is a combination of fluticasone and salmeterol (e.g., DPI formulation: 500 / 50 μg BID or MDI formulation: 460 / 42 μg BID), a combination of budesonide and formoterol (e.g., 320 / 9 μg BID), or a combination of mometasone and formoterol (e.g., (400 / 10 μg BID), preferably administered for at least 6, 9, 12, 15, 18, or 24 months, more preferably for at least 12 months.

[0060] In one embodiment, the maintenance medication is an oral corticosteroid (OCS). Thus, in one embodiment, the subject treated as described herein suffers from asthma that is not controlled with oral corticosteroids (OCS), particularly severe and / or eosinophilic asthma. In other words, in one embodiment, the subject treated as described herein suffers from asthma that is refractory to OCS, particularly severe and / or eosinophilic asthma. Examples of OCS used as maintenance medications for the treatment of asthma include, but are not limited to, prednisone, prednisolone, betamethasone, and dexamethasone.

[0061] In one embodiment, the maintenance medication is selected from the group consisting of prednisone, prednisolone, betamethasone, dexamethasone, and any combination thereof. In one embodiment, the maintenance medication is prednisone. In one embodiment, the maintenance medication is prednisone, preferably administered at a daily dose of at least 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, or 20 mg for at least 1, 2, 3, 4, 5, or 6 months. In one embodiment, the maintenance medication is prednisone, preferably administered at a daily dose of at least 5 mg for at least 3 months. In one embodiment, the maintenance medication is prednisone, preferably administered at a daily dose of at least 7.5 mg for at least 3 months. In one embodiment, the maintenance medication is prednisone, preferably administered at a daily dose of at least 15 mg for at least 3 months.

[0062] In one embodiment, administration of a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, to a subject being treated as described herein enables the subject to reduce their intake of inhaled corticosteroids and / or long-term oral corticosteroids as described herein above; i.e., administration of a 2-aminoarylthiazole derivative described herein, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, promotes a steroid-sparing effect.

[0063] Other examples of maintenance medications may include, but are not limited to, biologics, bronchodilators, and leukotriene modifiers, non-limiting examples of which are listed herein.

[0064] In one embodiment, the maintenance medication is a biologic selected from the group including or consisting of dupilumab, mepolizumab, reslizumab, benralizumab, and any mixture thereof.

[0065] In one embodiment, the subject in need of treatment is male. In another embodiment, the subject in need of treatment is female. In one embodiment, the subject in need of treatment is an adult. In the present invention, an adult is a subject over 18, 19, 20, or 21 years of age. In one embodiment, the subject in need of treatment is over 20, 25, or 30 years of age. In one embodiment, the subject in need of treatment is a child. In the present invention, a child is a subject under 21, 20, 19, or 18 years of age.

[0066] In one embodiment, the subject is a patient, i.e., a human receiving medical treatment, particularly maintenance medication, and / or being monitored for asthma. In one embodiment, the subject is a patient, i.e., a human receiving medical treatment, particularly maintenance medication, and being monitored for asthma.

[0067] In one embodiment, the subject suffers from severe asthma as described herein above.

[0068] In one embodiment, before treatment with a 2-aminoarylthiazole derivative of the present invention (i.e., at baseline), the subject is receiving a corticoid, such as an inhaled corticoid (ICS), an ICS in combination with a long-acting beta-agonist (LABA), or an oral corticoid (OCS). In one embodiment, before treatment with a 2-aminoarylthiazole derivative of the present invention, the subject is receiving an OCS, such as prednisone, at a minimum daily dose of at least 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, or 20 mg, preferably at least 7.5 mg. In one embodiment, before treatment with a 2-aminoarylthiazole derivative of the present invention, the subject is receiving an OCS, such as prednisone, at a minimum daily dose of at least 100 μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 800 μg, 1,000 μg, or 1,200 μg. In one embodiment, prior to treatment with a 2-aminoarylthiazole derivative of the invention, the subject is receiving an ICS in combination with a LABA, such as a combination of fluticasone and salmeterol (e.g., a DPI (dry powder inhaler) formulation: 500 / 50 μg BID (BID means twice daily) or an MDI (metered dose inhaler) formulation: 460 / 42 μg breath-activated digital inhaler (BID)), a combination of budesonide and formoterol (e.g., 320 / 9 μg BID), or a combination of mometasone and formoterol (e.g., (400 / 10 μg BID)).

[0069] In one embodiment, prior to treatment with a 2-aminoarylthiazole derivative of the present invention, the subject has been receiving a corticoid, either an ICS, an ICS in combination with a LABA, or an OCS, for at least 1, 2, 3, 4, 5, or 6 months, preferably at least 3 months. In one embodiment, prior to treatment with a 2-aminoarylthiazole derivative of the present invention, the subject has been receiving an OCS, such as prednisone, for at least 1, 2, 3, 4, 5, or 6 months, preferably at least 3 months, at a minimum daily dose of at least 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, or 20 mg, preferably at least 7.5 mg. In one embodiment, prior to treatment with a 2-aminoarylthiazole derivative of the invention, the subject has been receiving ICS at a minimum daily dose of at least 100 μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 800 μg, 1,000 μg, or 1,200 μg for at least 1, 2, 3, 4, 5, or 6 months, preferably at least 3 months. In one embodiment, prior to treatment with a 2-aminoarylthiazole derivative of the invention, the subject has been receiving an ICS in combination with a LABA, such as a combination of fluticasone and salmeterol (e.g., DPI formulation: 500 / 50 μg BID or MDI formulation: 460 / 42 μg breath-activated digital inhaler (BID)), a combination of budesonide and formoterol (e.g., 320 / 9 μg BID), or a combination of mometasone and formoterol (e.g., (400 / 10 μg BID)) for at least 3, 6, 9, 12, 15, 18, or 24 months, preferably at least 12 months.

[0070] In one embodiment, in the year prior to treatment with a 2-aminoarylthiazole derivative of the present invention, the subject received a corticoid, either an ICS, an ICS in combination with a LABA, or an OCS, for at least one period of at least 7, 14, 21, 28, or 35 days, preferably at least 21 days. In one embodiment, in the year prior to treatment with a 2-aminoarylthiazole derivative of the present invention, the subject received an OCS, e.g., prednisone, with a minimum daily dose of at least 5 mg, 7.5 mg, 10 mg, 12.5 mg, 15 mg, 17.5 mg, or 20 mg, preferably at least 7.5 mg, for at least one period of at least 7, 14, 21, 28, or 35 days, preferably at least 21 days. In one embodiment, in the year prior to treatment with a 2-aminoarylthiazole derivative of the present invention, the subject received ICS at a minimum daily dose of at least 100 μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 800 μg, 1,000 μg, or 1,200 μg for at least one period of at least 7, 14, 21, 28, or 35 days, preferably at least 21 days.

[0071] In one embodiment, prior to treatment with a 2-aminoarylthiazole derivative of the present invention (i.e., at baseline), the subject is receiving, has received, or was receiving corticosteroids at an annualized cumulative corticosteroid dose of greater than about 500 mg, 1000 mg, or 1500 mg.

[0072] As used herein, the cumulative annualized corticosteroid dose refers to the total corticosteroid dose received by a subject suffering from asthma over a continuous period of one year (i.e., 12 months). In one embodiment, the cumulative annualized corticosteroid dose is the cumulative prednisone-equivalent corticosteroid dose. Indeed, as described above, in one embodiment, when two or more corticosteroids are administered simultaneously, the intended corticosteroid dose during the overlapping period is the sum of all of the individual prednisone-equivalent doses.

[0073] The annualized cumulative corticosteroid dose may alternatively be expressed over different time periods, with appropriate dose adjustments. In one embodiment, the cumulative corticosteroid dose is determined retrospectively from medical history (e.g., from medical records and patient / caregiver recall of medical history) by adding up the daily corticosteroid doses administered on each day of a contemplated period (e.g., one year).

[0074] In one embodiment, before treatment with the 2-aminoarylthiazole derivative of the present invention (i.e., at baseline), the subject is receiving, has received, or has received systemic corticosteroids at a dose of more than about 500 mg, 1000 mg, or 1500 mg of cumulative annualized systemic corticosteroids. In one embodiment, before treatment with the 2-aminoarylthiazole derivative of the present invention (i.e., at baseline), the subject is receiving, has received, or has received systemic corticosteroids at a dose of more than about 500 mg, 1000 mg, or 1500 mg of cumulative annualized systemic corticosteroids equivalent to prednisone. In one embodiment, systemic corticosteroids include oral corticosteroids and intravenous corticosteroids. Thus, in one embodiment, systemic corticosteroids do not include inhaled corticosteroids.

[0075] In one embodiment, prior to treatment with a 2-aminoarylthiazole derivative of the present invention (i.e., at baseline), the subject is receiving, has received, or has received OCS at an annualized cumulative OCS dose of greater than about 500 mg, 1000 mg, or 1500 mg. In one embodiment, prior to treatment with a 2-aminoarylthiazole derivative of the present invention (i.e., at baseline), the subject is receiving, has received, or has received OCS at an OCS dose equivalent to greater than about 500 mg, 1000 mg, or 1500 mg of cumulative annualized prednisone.

[0076] In one embodiment, prior to treatment with a 2-aminoarylthiazole derivative of the present invention (i.e., at baseline), the subject is receiving maintenance medications, such as biologics, bronchodilators, and leukotriene modifiers. Non-limiting examples of biologics, bronchodilators, and leukotriene modifiers are listed herein.

[0077] In one embodiment, prior to treatment with a 2-aminoarylthiazole derivative of the invention (i.e., at baseline), the subject has received maintenance medications, such as biologics, bronchodilators, and leukotriene modifiers. In one embodiment, in the year prior to treatment with a 2-aminoarylthiazole derivative of the invention, the subject has received maintenance medications, such as biologics, bronchodilators, and leukotriene modifiers.

[0078] In one embodiment, prior to treatment with a 2-aminoarylthiazole derivative of the present invention (i.e., at baseline), the subject has an FEV1 in the range of 35% (inclusive) to 80% (exclusive) of predicted normal. Thus, in one embodiment, prior to treatment with a 2-aminoarylthiazole derivative of the present invention (i.e., at baseline), the subject has an FEV1 of 35%≦FEV1<80%.

[0079] In one embodiment, the subject has experienced at least two asthma exacerbations within 3, 6, 9, 12, 15, 18, or 24 months, preferably within 12 months, prior to treatment with a 2-aminoarylthiazole derivative of the present invention. In one embodiment, the subject has experienced at least two asthma exacerbations, including at least one severe asthma exacerbation, within 3, 6, 9, 12, 15, 18, or 24 months, preferably within 12 months, prior to treatment with a 2-aminoarylthiazole derivative of the present invention. In one embodiment, the subject has experienced at least two severe asthma exacerbations within 3, 6, 9, 12, 15, 18, or 24 months, preferably within 12 months, prior to treatment with a 2-aminoarylthiazole derivative of the present invention.

[0080] In one embodiment, the subject to be treated according to the present invention, in particular a subject with elevated levels of eosinophils as defined herein above, is a subject with type 2 asthma, i.e. a subject with asthma presenting with type 2 inflammation.

[0081] In the present invention, 2-aminoarylthiazole derivatives refer to compounds characterized by the presence of a thiazolyl group substituted at the 2-position (i.e., between the nitrogen and sulfur atoms of the heterocycle) with a secondary or tertiary amine, the nitrogen atom of this amine being substituted with at least one aryl group.

[0082] In one embodiment, the aryl group is substituted with an arylamido group (ie, --NH--CO-aryl).

[0083] In one embodiment, the 2-aminoarylthiazole derivative of the present invention has the following formula (I): [ka] (In the formula, R1 and R2 are independently selected from hydrogen, halogen, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl groups, trifluoromethyl, alkoxy, cyano, dialkylamino, solubilizing groups, and solubilizing group-substituted (C1-C 10 ) alkyl; m is 0 to 5; n is 0 to 4; R3 is: (i) optionally halogen, (C1-C 10 ) aryl groups (e.g., phenyl) substituted with one or more substituents such as alkyl groups, trifluoromethyl, cyano, and alkoxy; (ii) optionally halogen, (C1-C 10 ) heteroaryl groups (e.g., 2-, 3-, or 4-pyridyl groups) substituted with one or more substituents such as alkyl groups, trifluoromethyl, and alkoxy; (iii) optionally halogen, (C1-C 10) 5-membered aromatic heterocyclic groups (e.g., 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.) substituted with one or more substituents such as alkyl groups, trifluoromethyl, and alkoxy. (one of the It has.

[0084] In one embodiment, R and R of formula (I) are independently selected from hydrogen, halogen, (C-C 10 ) alkyl, (C3-C 10 ) selected from cycloalkyl groups, trifluoromethyl, alkoxy, cyano, dialkylamino, and solubilizing groups.

[0085] Thus, in one embodiment, the 2-aminoarylthiazole derivative or a pharmaceutically acceptable salt or solvate thereof of the present invention is a 2-aminoarylthiazole derivative of formula (I) as described hereinabove, or a pharmaceutically acceptable salt or solvate thereof.

[0086] In one embodiment, the 2-aminoarylthiazole derivative of the present invention has the following formula (II): [ka] (In the formula, R1 independently represents hydrogen, halogen, (C1-C 10 ) alkyl, (C3-C 10 ) cycloalkyl groups, trifluoromethyl, alkoxy, amino, alkylamino, dialkylamino, solubilizing groups, and solubilizing group-substituted (C1-C 10 ) alkyl; m is 0 to 5) It has.

[0087] In one embodiment, R1 in formula (I) is independently hydrogen, halogen, (C1-C 10 ) alkyl, (C3-C 10 ) selected from cycloalkyl groups, trifluoromethyl, alkoxy, amino, alkylamino, dialkylamino, and solubilizing groups.

[0088] In one embodiment, R1 of formula (I) is a solubilizing group. In one embodiment, R1 of formula (I) is a (C1-C 10 ) alkyl.

[0089] In one embodiment, R1 in formula (I) is (C1-C 10 )Alkyl-(C2-C 11 )heterocycloalkyl-(C1-C 10 In one embodiment, R1 in formula (I) is (C1-C4)alkyl-(C2-C 11 )heterocycloalkyl-(C1-C 10 ) alkyl-, preferably (C1-C2) alkyl-(C2-C 11 )heterocycloalkyl-(C1-C 10 In one embodiment, R1 in formula (I) is (C1-C 10 )Alkyl-(C2-C 11 )heterocycloalkyl-(C1-C4)alkyl-, preferably (C1-C 10 )Alkyl-(C2-C 11 In one embodiment, R1 in formula (I) is (C1-C2)heterocycloalkyl-(C1-C2)alkyl-. 10 ) alkyl-(C2-C6) heterocycloalkyl-(C1-C 10 ) alkyl-, preferably (C-C 10 ) alkyl-(C4) heterocycloalkyl-(C1-C 10) alkyl-. In one embodiment, R1 of formula (I) is (C1-C4) alkyl-(C2-C6)heterocycloalkyl-(C1-C4) alkyl-, preferably (C1-C2) alkyl-(C4)heterocycloalkyl-(C1-C2) alkyl-. In one embodiment, R1 of formula (I) is (C1-C4) alkyl-piperazinyl-(C1-C4) alkyl-, preferably (C1-C2) alkyl-piperazinyl-(C1-C2) alkyl-. In one embodiment, R1 of formula (I) is methylpiperazinyl-(C1-C2) alkyl-, preferably methylpiperazinyl-methyl-, more preferably 4-methylpiperazinyl-methyl-.

[0090] Thus, in one embodiment, the 2-aminoarylthiazole derivative or a pharmaceutically acceptable salt or solvate thereof of the present invention is a 2-aminoarylthiazole derivative of formula (II) as described herein above, or a pharmaceutically acceptable salt or solvate thereof.

[0091] As used herein, the term "aryl group" refers to a polyunsaturated aromatic hydrocarbyl group, typically containing 5 to 12 atoms, preferably 6 to 10 atoms, having a single aromatic ring (i.e., phenyl) or multiple aromatic rings fused together (e.g., naphthyl) or covalently linked, with at least one ring being aromatic. The aromatic ring may optionally contain one to two additional rings (cycloalkyl, heterocyclyl, or heteroaryl) fused thereto. Aryl is also intended to include partially hydrogenated derivatives of the carbocyclic ring systems described herein. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. Aryl groups can be unsubstituted or substituted with one or more substituents. In one embodiment, an aryl group is a single ring, where the ring contains 6 carbon atoms, referred to herein as "(C6)aryl."

[0092] As used herein, the term "alkyl group" refers to a saturated, straight-chain or branched, acyclic hydrocarbon having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Representative saturated straight-chain alkyls include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. Saturated branched alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, Examples include 3,3-dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and 3,3-diethylhexyl. The alkyl group contained in the compound of the present invention can be optionally substituted with one or more substituents.

[0093] As used herein, the term "alkoxy" refers to an alkyl group attached to another moiety by an oxygen atom. Examples of alkoxy groups include, but are not limited to, methoxy, isopropoxy, ethoxy, and tert-butoxy. An alkoxy group can be optionally substituted with one or more substituents.

[0094] As used herein, the term "cycloalkyl" refers to a saturated cyclic alkyl radical having 3 to 10 carbon atoms. Representative cycloalkyl groups include cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Cycloalkyl groups can be optionally substituted with one or more substituents.

[0095] As used herein, the term "halogen" refers to -F, -Cl, -Br, or -I.

[0096] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic heteroaromatic ring containing carbon atom ring members and one or more heteroatom ring members (e.g., oxygen, sulfur, or nitrogen). Typically, heteroaryl groups contain from 1 to about 5 heteroatom ring members and from 1 to about 14 carbon atom ring members. Representative heteroaryl groups include, but are not limited to, pyridyl, 1-oxo-pyridyl, furanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, Examples of heteroaryl groups include benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, imidazo[1,2-a]pyridyl, and benzo(b)thienyl. Heteroatoms may be substituted with protecting groups known to those skilled in the art; for example, the hydrogen on a nitrogen atom may be substituted with a tert-butoxycarbonyl group. Heteroaryl groups may optionally be substituted with one or more substituents. Additionally, the nitrogen or sulfur heteroatom ring members may be oxidized. In one embodiment, the heteroaromatic ring is selected from 5- to 8-membered monocyclic heteroaryl rings. The point of attachment of a heteroaromatic or heteroaryl ring to another group can be at a carbon atom or a heteroatom of the heteroaromatic or heteroaryl ring.

[0097] As used herein, the term "heterocycle" collectively refers to heterocycloalkyl and heteroaryl groups.

[0098] As used herein, the term "heterocycloalkyl" refers to a monocyclic or polycyclic group having at least one heteroatom selected from O, N, or S, having 2 to 11 carbon atoms, which may be saturated or unsaturated, but which is not aromatic. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 4-piperidonyl, pyrrolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiopyranyl sulfone, tetrahydrothiopyranyl sulfoxide, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane, tetrahydrofuranyl, dihydrofuranyl-2-one, tetrahydrothienyl, and tetrahydro-1,1-dioxothienyl. Typically, monocyclic heterocycloalkyl groups have 3 to 7 members. Preferred 3- to 7-membered monocyclic heterocycloalkyl groups are those having 5 to 6 ring atoms. The heteroatom may be substituted with a protecting group known to those skilled in the art; for example, the hydrogen on a nitrogen may be substituted with a tert-butoxycarbonyl group. Furthermore, the heterocycloalkyl group may be optionally substituted with one or more substituents. Furthermore, the point of attachment of the heterocycle to another group may be either a carbon atom or a heteroatom of the heterocycle. Only stable isomers of such substituted heterocyclic groups are contemplated by this definition.

[0099] As used herein, the term "substituent" or "substituted" means that a hydrogen radical on a compound or group is replaced with any desired group that is substantially stable to the reaction conditions, either in unprotected form or when protected with a protecting group. Examples of preferred substituents include, but are not limited to, halogen (chloro, iodo, bromo, or fluoro); alkyl; alkenyl; alkynyl; hydroxy; alkoxy; nitro; thiol; thioether; imine; cyano; amide; phosphonate; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen (-O); haloalkyl (e.g., trifluoromethyl); cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which may be monocyclic or fused or non-fused polycyclic, or heterocycloalkyl (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or aryl), which may be monocyclic or fused or non-fused polycyclic. or thiazinyl), monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary, or tertiary); COCH; CONH; OCHCONH; NH; SONH; OCHF; CF; OCF, which moieties may also be optionally substituted with fused ring structures or bridges, e.g., —OCHO—. These substituents may optionally be further substituted with substituents selected from the group. In certain embodiments, the term "substituent" or the adjective "substituted" refers to any group including alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, haloalkyl, -C(O)NR 11 R12 , -NR 13 C(O)R 14 , halo, -OR 13 , cyano, nitro, haloalkoxy, -C(O)R 13 , -NR 11 R 12 , -SR 13 , -C(O)OR 13 , -OC(O)R 13 , -NR 13 C(O)NR 11 R 12 , -OC(O)NR 11 R 12 , -NR 13 C(O)OR 14 , -S(O)rR 13 , -NR 13 S(O)rR 14 , -OS(O)rR 14 , S(O)rNR 11 R 12 , -O, -S, and -NR 13 where r is 1 or 2; R 11 and R 12 is each occurrence independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; or R 11 and R 12 together with the nitrogen to which it is attached, is optionally substituted heterocycloalkyl or optionally substituted heteroaryl; R 13 and R 14is independently, at each occurrence, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl. In certain embodiments, the term "substituent" or the adjective "substituted" refers to a solubilizing group.

[0100] As used herein, the term "solubilizing group" refers to any group that can be substantially ionized and that can solubilize a compound in a desired solvent, such as water or a water-containing solvent ("water-solubilizing group"). Additionally, the solubilizing group can be a group that increases the lipophilicity of the compound or complex. In one embodiment, the solubilizing group is selected from an alkyl group substituted with one or more heteroatoms, such as N, O, S (each of which is optionally substituted independently with an alkoxy, amino, alkylamino, dialkylamino, carboxyl, cyano-substituted, or cycloheteroalkyl- or heteroaryl-substituted alkyl group), or a phosphate or sulfate, or a carboxylic acid. In one embodiment, the solubilizing group is one of the following: alkyl, cycloalkyl, aryl, heteroaryl groups containing at least one nitrogen or oxygen heteroatom and / or substituted with at least one amino or oxo group (including, but not limited to, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 4-piperidonyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydropyranyl, morpholinyl, 1,3-dioxolane, tetrahydrofuranyl, and dihydrofuranyl-2-one); an amino group which may be a saturated cyclic amino group (including but not limited to piperidinyl, piperazinyl, and pyrrolidinyl) which may be substituted with the group consisting of alkyl, alkoxycarbonyl, halogen, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylcarbamoyl, and dialkylcarbamoyl (including but not limited to methyl-piperidinyl, methyl-piperazinyl, and methyl-pyrrolidinyl); One of the structures a) to i) shown below (where the wavy line and arrowed line correspond to the point of attachment to the core structure of a 2-aminoarylthiazole derivative of the invention, e.g., formula (I) or (II): [ka]

[0101] In one embodiment, the solubilizing group is one of the following: alkyl, cycloalkyl, aryl, heteroaryl groups containing at least one nitrogen or oxygen heteroatom or groups substituted with at least one amino or oxo group; an amino group which may be a saturated cyclic amino group which may be substituted with the group consisting of alkyl, alkoxycarbonyl, halogen, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylcarbamoyl, and dialkylcarbamoyl; One of the structures a)-i) shown above, where the wavy line and arrowed line correspond to the point of attachment to the core structure of a 2-aminoarylthiazole derivative of the invention, e.g., formula (I) or (II).

[0102] In one embodiment, the solubilizing group is a saturated cyclic amino group (including but not limited to piperidinyl, piperazinyl, and pyrrolidinyl) which may be substituted with the group consisting of alkyl, alkoxycarbonyl, halogen, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylcarbamoyl, and dialkylcarbamoyl (including but not limited to methyl-piperidinyl, methyl-piperazinyl, and methyl-pyrrolidinyl).

[0103] In one embodiment, the solubilizing group is structure c) shown above, where the wavy line corresponds to the point of attachment to the core structure of a 2-aminoarylthiazole derivative of the invention, such as formula (I) or (II).

[0104] As used herein, "pharmaceutically acceptable salt" refers to a salt of a free acid or free base that is not biologically undesirable and is generally prepared by reacting the free base with a suitable organic or inorganic acid or by reacting the free acid with a suitable organic or inorganic base. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, and malate. , maleate, malonate, mesylate, methylsulfate, naphthylate, napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen, phosphate / dihydrogen, phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinofoate salts. Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine; potassium, sodium, tromethamine, 2(diethylamino)ethanol, ethanolamine, morpholine, 4(2hydroxyethyl)morpholine, and zinc salts. Heme salts of acids and bases, such as hemisulfate and hemicalcium salts, can also be formed.

[0105] In one embodiment, the pharmaceutically acceptable salt is a pharmaceutically acceptable acid addition salt with an inorganic acid such as, for example, hydrochloric acid, sulfuric acid, or phosphoric acid, or a suitable organic carboxylic or sulfonic acid, for example, an aliphatic mono- or dicarboxylic acid such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid, or oxalic acid, or an amino acid such as arginine or lysine, an aromatic carboxylic acid such as benzoic acid, 2-phenoxy-benzoic acid, 2-acetoxy-benzoic acid, salicylic acid, 4-aminosalicylic acid, an aromatic-aliphatic carboxylic acid such as mandelic acid or cinnamic acid, a heteroaromatic carboxylic acid such as nicotinic acid or isonicotinic acid, an aliphatic sulfonic acid such as methane-, ethane-, or 2-hydroxyethane-sulfonic acid, in particular methanesulfonic acid, or an aromatic sulfonic acid such as benzene-, p-toluene-, or naphthalene-2-sulfonic acid.

[0106] In one embodiment, a pharmaceutically acceptable salt of a 2-aminoarylthiazole derivative of the present invention is a mesylate salt.

[0107] Unless otherwise specified, the term "mesylate" is used herein to refer to the salt of a named pharmaceutical agent (such as a 2-aminoarylthiazole derivative of Formula (I) or (II)) with methanesulfonic acid. The use of mesilate rather than mesylate is in accordance with the International Nonproprietary Names Modified (INNM) published by the WHO (e.g., World Health Organization (February 2006). International Nonproprietary Names Modified. INN Working Document 05.167 / 3. WHO).

[0108] As used herein, a "pharmaceutically acceptable solvate" refers to a molecular complex comprising a 2-aminoarylthiazole derivative of the present invention with stoichiometric or sub-stoichiometric amounts of one or more pharmaceutically acceptable solvent molecules, such as ethanol. The term "hydrate" refers to when the solvent is water.

[0109] In one particular embodiment, the 2-aminoarylthiazole derivative or a pharmaceutically acceptable salt or solvate thereof of the present invention is masitinib or a pharmaceutically acceptable salt or solvate thereof.

[0110] The chemical name of masitinib is 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3ylthiazol-2-ylamino)phenyl]benzamide - CAS number 790299-79-5: [ka]

[0111] Masitinib was first described in US Pat. No. 7,423,055 and European Patent Publication No. 1 525 200.

[0112] In one embodiment, the 2-aminoarylthiazole derivative of the present invention, or a pharmaceutically acceptable salt or solvate thereof, is a mesylate salt of masitinib. Thus, in one embodiment, the pharmaceutically acceptable salt of masitinib described hereinabove is a mesylate salt of masitinib. In other words, as described hereinabove, the pharmaceutically acceptable salt of masitinib is a methanesulfonate salt of masitinib.

[0113] Detailed procedures for the synthesis of the mesylate salt of masitinib are provided in WO 2008 / 098949.

[0114] In one embodiment, "masitinib mesylate salt" refers to the orally bioavailable mesylate salt of masitinib -CAS1048007-93-7(MsOH);C 28 H 30 N6OS.CH3SO3H; MW 594.76: [ka]

[0115] In one embodiment, the 2-aminoarylthiazole derivative described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered in a therapeutically effective dose.

[0116] In one embodiment, the 2-aminoarylthiazole derivatives described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, are administered at a dose ranging from about 1 to about 12 mg / kg / day (mg per kg of body weight per day). In one embodiment, the 2-aminoarylthiazole derivatives described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, are administered at a dose ranging from about 1.5 to about 7.5 mg / kg / day. In one embodiment, the 2-aminoarylthiazole derivatives described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, are administered at a dose ranging from about 3 to about 12 mg / kg / day, preferably from about 3 to about 6 mg / kg / day.

[0117] In one embodiment, the 2-aminoarylthiazole derivative described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 mg / kg / day. In one embodiment, the 2-aminoarylthiazole derivative described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 1.5, 3, 4.5, 6, 7.5, 9, 10.5, or 12 mg / kg / day.

[0118] In one embodiment, the 2-aminoarylthiazole derivative described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered at a dose of about 3, 4.5, or 6 mg / kg / day.

[0119] In one embodiment, the 2-aminoarylthiazole derivatives described hereinabove, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, may be administered in doses increasing in increments of about 1.5 mg / kg / day to reach a maximum of about 7.5 mg / kg / day, more preferably about 4.5 or about 6 mg / kg / day, with each dose increase being subject to toxicity control to allow the dose increase to occur without any toxic events.

[0120] In one embodiment, the dose escalation of the 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, occurs at least 4 weeks after administration of the first dose and any time before 26 weeks after administration of the first dose, for example, 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, or 24 weeks after administration of the first dose. Each dose escalation is subject to toxicity control, including, but not limited to, a prior 4-week treatment period at a fixed dose of study treatment, in which no suspected serious adverse events are reported, no suspected adverse events result in treatment discontinuation, and no suspected adverse events, regardless of severity, are ongoing at the time the dose is increased.

[0121] In one embodiment, the 2-aminoarylthiazole derivative described hereinabove, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered at an initial dose of about 3 mg / kg / day for 6 weeks, followed by a dose of about 4.5 mg / kg / day. In another embodiment, the 2-aminoarylthiazole derivative described hereinabove, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered at an initial dose of about 3 mg / kg / day for 12 weeks, followed by a dose of about 4.5 mg / kg / day.

[0122] In one embodiment, the 2-aminoarylthiazole derivatives described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, are administered at an initial dose of about 3 mg / kg / day for at least 4 weeks, followed by a dose of about 4.5 mg / kg / day for at least 4 weeks, and then at a dose of about 6 mg / kg / day, with each dose increase subject to toxicity control. In another embodiment, the 2-aminoarylthiazole derivatives described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, are administered at an initial dose of about 4.5 mg / kg / day for at least 6 weeks, followed by a dose of about 6 mg / kg / day, with each dose increase subject to toxicity control.

[0123] In one embodiment, all dosages described herein refer to the amount of the active ingredient itself, not its pharmaceutically acceptable salt or solvate forms. Thus, variations in the composition of the 2-aminoarylthiazole derivatives of the present invention, particularly the pharmaceutically acceptable salts or solvates of masitinib, do not affect the administered dosage.

[0124] In one embodiment, the 2-aminoarylthiazole derivatives described hereinabove, preferably masitinib, or a pharmaceutically acceptable salt or solvate thereof, can be administered orally, intravenously, parenterally, topically, by inhalation, particularly by inhalation spray, rectally, nasally, or bucally. In one embodiment, the 2-aminoarylthiazole derivatives described hereinabove, preferably masitinib, or a pharmaceutically acceptable salt or solvate thereof, are administered orally.

[0125] In one embodiment, the 2-aminoarylthiazole derivative described herein above, preferably masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered at least once a day, preferably twice a day. In one embodiment, the 2-aminoarylthiazole derivative described herein above, preferably masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered for a long period of time, for example, for at least 1, 2, 3, 6, 9, or 12 months.

[0126] In one embodiment, the 2-aminoarylthiazole derivative, preferably masitinib, or its pharmaceutically acceptable salt or solvate described hereinabove is in a form suitable for oral administration. Examples of forms suitable for oral administration include, but are not limited to, liquid, paste, or solid compositions, more specifically, tablets, pills, capsules, liquids, gels, syrups, slurries, and suspensions.

[0127] In one embodiment, the 2-aminoarylthiazole derivative described herein above, preferably masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered as a tablet, preferably a 100 mg or 200 mg tablet.

[0128] In one embodiment, the 2-aminoarylthiazole derivatives described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, are administered together with at least another pharmaceutically active agent.

[0129] In the present invention, the 2-aminoarylthiazole derivatives described hereinabove, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, can be administered simultaneously, separately, or sequentially with the at least another pharmaceutically effective agent. In one embodiment, the 2-aminoarylthiazole derivatives described hereinabove, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, are administered in combination with the at least another pharmaceutically effective agent, preferably in a combined formulation, pharmaceutical composition, or medicament.

[0130] Examples of other pharmaceutically effective agents that may be administered to a subject with asthma described herein include, but are not limited to, biologics such as anti-IgE agents and anti-cytokine agents, corticosteroids, bronchodilators including long-acting beta-agonists (LABAs), rescue medications, and any combination thereof. In one embodiment, the at least another pharmaceutically effective agent is selected from the group including or consisting of: biologics, corticosteroids, bronchodilators including LABAs, rescue medications, and any combination thereof.

[0131] In one embodiment, the at least another pharmaceutically effective agent is a biologic. As used herein, a "biological drug" or simply "biologic" is a compound produced from or containing components of a living organism. Thus, examples of biologics include antibodies, recombinant proteins, cells, and blood components.

[0132] In one embodiment, the biologic is selected from an anti-IgE agent and an anti-cytokine agent, e.g., an anti-IL-5 agent. In one embodiment, the biologic is an antibody selected from an anti-IgE antibody and an anti-cytokine antibody, e.g., an anti-IL-5 antibody.

[0133] In one embodiment, the biologic is an anti-IgE agent. An example of an anti-IgE agent includes, but is not limited to, the monoclonal antibody omalizumab. In one embodiment, the anti-IgE agent is omalizumab.

[0134] In one embodiment, the biologic is an anti-cytokine agent, preferably an anti-cytokine antibody. Examples of anti-cytokine agents include, but are not limited to, dupilumab, mepolizumab, reslizumab, and benralizumab. In one embodiment, the anti-cytokine agent is selected from the group including or consisting of dupilumab, mepolizumab, reslizumab, benralizumab, and any mixture thereof.

[0135] In one embodiment, the anti-cytokine agent is an anti-IL-5 agent. Thus, in one embodiment, the biologic is an anti-IL-5 agent. The anti-IL-5 agent is a monoclonal antibody that targets IL-5 (interleukin-5) or its receptor (IL-5R). Examples of anti-IL-5 agents include, but are not limited to, mepolizumab, reslizumab, and benralizumab. In one embodiment, the anti-IL-5 agent is selected from the group including or consisting of mepolizumab, reslizumab, benralizumab, and any mixture thereof.

[0136] In one embodiment, the at least another pharmaceutically active agent is a biologic selected from the group comprising or consisting of omalizumab, dupilumab, mepolizumab, reslizumab, benralizumab, and any mixtures thereof. In one embodiment, the at least another pharmaceutically active agent is a biologic selected from the group comprising or consisting of dupilumab, mepolizumab, reslizumab, benralizumab, and any mixtures thereof. In one embodiment, the at least another pharmaceutically active agent is a biologic selected from the group comprising or consisting of mepolizumab, reslizumab, benralizumab, and any mixtures thereof.

[0137] In one embodiment, at least another pharmaceutically effective agent is a corticosteroid. Corticosteroids are anti-inflammatory compounds that are administered to reduce airway inflammation. Examples of corticosteroids include, but are not limited to, fluticasone, budesonide, mometasone, beclomethasone, prednisone, prednisolone, betamethasone, and dexamethasone.

[0138] In one embodiment, the corticosteroid is an inhaled corticosteroid and / or an oral corticosteroid, hi one embodiment, the corticosteroid is selected from the group comprising or consisting of fluticasone, budesonide, mometasone, beclomethasone, prednisone, prednisolone, betamethasone, dexamethasone, and any mixture thereof.

[0139] In one embodiment, the corticosteroid is an inhaled corticosteroid (ICS). Examples of ICS include, but are not limited to, fluticasone, budesonide, mometasone, and beclomethasone. In one embodiment, the ICS is selected from the group comprising or consisting of fluticasone, budesonide, mometasone, beclomethasone, and any mixture thereof.

[0140] In one embodiment, the corticosteroid is an oral corticosteroid (OCS). Examples of OCS include, but are not limited to, prednisolone, betamethasone, and dexamethasone. In one embodiment, the OCS is selected from the group comprising or consisting of prednisolone, betamethasone, dexamethasone, and any mixture thereof.

[0141] In one embodiment, at least another pharmaceutically effective agent is a bronchodilator. Bronchodilators help keep airways open by relaxing the muscles around the airways. Examples of bronchodilators include but are not limited to theophylline and LABA described herein. In one embodiment, the bronchodilator is selected from the group comprising or consisting of the LABA and theophylline described herein.

[0142] In one embodiment, the bronchodilator is a LABA. Thus, in one embodiment, at least another pharmaceutically effective agent is a LABA. LABAs are administered to open narrow airways and prevent asthma exacerbations. Examples of LABAs (also known as long-acting beta 2 agonists or long-acting beta 2 adrenergic receptor agonists) include, but are not limited to, salmeterol, formoterol, arformoterol, and vilanterol.

[0143] In one embodiment, the LABA is selected from the group comprising or consisting of salmeterol, formoterol, arformoterol, vilanterol, and any mixtures thereof. In one embodiment, the LABA is selected from the group comprising or consisting of salmeterol, formoterol, arformoterol, and any mixtures thereof.

[0144] In one embodiment, the at least another pharmaceutically active agent is a bronchodilator selected from the group including or consisting of theophylline, salmeterol, formoterol, arformoterol, vilanterol, and any mixture thereof.

[0145] In one embodiment, at least another pharmaceutically effective agent is a combination of corticosteroid and LABA.In one embodiment, LABA is administered together with corticosteroid, particularly inhaled corticosteroid.The example of the combination of LABA and inhaled corticosteroid includes but is not limited to the combination of fluticasone and salmeterol, the combination of budesonide and formoterol, the combination of mometasone and formoterol, the combination of fluticasone and vilanterol.In one embodiment, the combination of LABA and inhaled corticosteroid comprises or is selected from the group consisting of the combination of fluticasone and salmeterol, the combination of budesonide and formoterol, the combination of mometasone and formoterol, the combination of fluticasone and vilanterol, and any mixture thereof.

[0146] In one embodiment, the at least another pharmaceutically effective agent is a leukotriene modifier. The leukotriene modifier is administered to help alleviate asthma symptoms. Examples of leukotriene modifiers include, but are not limited to, montelukast, zafirlukast, and zileuton. In one embodiment, the leukotriene modifier is selected from the group including or consisting of montelukast, zafirlukast, zileuton, and any mixture thereof.

[0147] In one embodiment, the at least another pharmaceutically effective agent is a rescue medication. In one embodiment, the at least another pharmaceutically effective agent is an agent described above and a rescue medication described herein below.

[0148] Rescue medications may be administered as needed for short-term, rapid symptom relief during an asthma exacerbation. Examples of rescue medications include, but are not limited to, bronchodilators, such as short-acting beta-agonists and ipratropium, and corticoids, such as oral or intravenous corticosteroids.

[0149] Examples of short-acting beta-agonists (also known as short-acting beta-2 agonists) include, but are not limited to, albuterol (also known as salbutamol) and levalbuterol. Examples of oral or intravenous corticosteroids include, but are not limited to, prednisone and methylprednisolone.

[0150] In one embodiment, the rescue medication is selected from the group including or consisting of albuterol, levalbuterol, ipratropium, prednisone, methylprednisolone, and any mixture thereof.

[0151] In one embodiment, the at least another pharmaceutically active agent is selected from the group comprising or consisting of omalizumab, dupilumab, mepolizumab, reslizumab, benralizumab, fluticasone, budesonide, mometasone, beclomethasone, prednisone, prednisolone, betamethasone, dexamethasone, theophylline, salmeterol, formoterol, arformoterol, vilanterol, a combination of fluticasone and salmeterol, a combination of budesonide and formoterol, a combination of mometasone and formoterol, a combination of fluticasone and vilanterol, montelukast, zafirlukast, zileuton, albuterol, levalbuterol, and any mixture thereof. In one embodiment, the at least another pharmaceutically active agent is selected from the group comprising or consisting of omalizumab, dupilumab, mepolizumab, reslizumab, benralizumab, fluticasone, budesonide, mometasone, prednisone, prednisolone, a combination of fluticasone and salmeterol, a combination of budesonide and formoterol, a combination of mometasone and formoterol, theophylline, albuterol, levalbuterol, and any mixture thereof.

[0152] In one embodiment, the at least another pharmaceutically active agent is selected from the group including or consisting of omalizumab, dupilumab, mepolizumab, reslizumab, benralizumab, prednisone, prednisolone, a combination of fluticasone and salmeterol, a combination of budesonide and formoterol, a combination of mometasone and formoterol, and any mixture thereof.

[0153] In one embodiment, the 2-aminoarylthiazole derivatives described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, are administered as a first line treatment.

[0154] In one embodiment, the 2-aminoarylthiazole derivatives described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, are administered after and / or simultaneously with treatment with at least another pharmaceutically active agent described herein above. In one embodiment, the 2-aminoarylthiazole derivatives described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, are administered after and / or simultaneously with treatment with a biologic described herein above. In one embodiment, the 2-aminoarylthiazole derivatives described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, are administered after and / or simultaneously with treatment with an anti-IL-5 agent described herein above.

[0155] In one embodiment, the 2-aminoarylthiazole derivatives described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, are administered as a second-line treatment. In one embodiment, the 2-aminoarylthiazole derivatives described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, are administered as a second-line treatment after and / or simultaneously with the first-line treatment. In one embodiment, the 2-aminoarylthiazole derivatives described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, are administered as a second-line treatment after and / or simultaneously with the first-line treatment comprising the administration of at least another pharmaceutically active agent described herein above. In one embodiment, the 2-aminoarylthiazole derivatives described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, are administered as a second-line treatment after and / or simultaneously with the first-line treatment comprising the administration of the biologic described above. In one embodiment, the 2-aminoarylthiazole derivative described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, is administered as a second line treatment following and / or concurrently with a first line treatment comprising administration of an anti-IL-5 agent described herein above.

[0156] Another object of the present invention is a method for treating asthma in a subject in need thereof having high levels of eosinophils, particularly high levels of eosinophils at baseline as described herein above, comprising the step of administering to the subject a 2-aminoarylthiazole derivative, particularly masitinib, as described herein above, or a pharmaceutically acceptable salt or solvate thereof.

[0157] The present invention relates to a method for treating asthma, particularly severe and / or eosinophilic asthma as described hereinabove, in a subject in need thereof having a baseline eosinophil blood count of 150 cells / μL or greater, the method comprising the step of administering to the subject a 2-aminoarylthiazole derivative, particularly masitinib, as described hereinabove, or a pharmaceutically acceptable salt or solvate thereof.

[0158] The present invention also relates to a method for treating asthma, particularly severe and / or eosinophilic asthma as described herein above, in a subject in need thereof having a baseline eosinophil blood count in the range of 150 cells / μL to 300 cells / μL, the method comprising the step of administering to the subject a 2-aminoarylthiazole derivative, particularly masitinib, as described herein above, or a pharmaceutically acceptable salt or solvate thereof.

[0159] The present invention also relates to a method for treating asthma, particularly severe and / or eosinophilic asthma as described hereinabove, in a subject in need thereof having a baseline eosinophil blood count of 300 cells / μL or greater, preferably more than 300 cells / μL, comprising the step of administering to the subject a 2-aminoarylthiazole derivative, particularly masitinib, as described hereinabove, or a pharmaceutically acceptable salt or solvate thereof.

[0160] In one embodiment, the method of the present invention comprises the step of administering to a subject a therapeutically effective dose, as described herein above, of a 2-aminoarylthiazole derivative, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, as described herein above.

[0161] In one embodiment, the method of the present invention comprises administering to the subject at least another pharmaceutically active agent as described herein above.

[0162] Another object of the present invention is a pharmaceutical composition comprising a 2-aminoarylthiazole derivative as described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, for use in treating asthma in a subject in need thereof who has a high level of eosinophils, particularly a high baseline level of eosinophils as described herein above.The present invention also relates to a pharmaceutical composition for use in treating asthma in a subject in need thereof who has a high level of eosinophils, particularly a high baseline level of eosinophils as described herein above, the pharmaceutical composition comprising a 2-aminoarylthiazole derivative as described herein above, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0163] In one embodiment, the pharmaceutical composition of the present invention is for use in combination with at least another pharmaceutically active agent as described herein above.

[0164] Another object of the present invention is a pharmaceutical composition comprising a 2-aminoarylthiazole derivative as described hereinabove, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient, for use in treating asthma in a subject in need thereof who has a high level of eosinophils, particularly a high baseline level of eosinophils as described hereinabove.The present invention also relates to a pharmaceutical composition for treating asthma in a subject in need thereof who has a high baseline level of eosinophils, particularly a high baseline level of eosinophils as described hereinabove, comprising a 2-aminoarylthiazole derivative as described hereinabove, particularly masitinib, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0165] In one embodiment, the present invention relates to a pharmaceutical composition comprising a 2-aminoarylthiazole derivative, particularly masitinib, as described herein above, or a pharmaceutically acceptable salt or solvate thereof, in combination with at least another pharmaceutically active agent, as described herein above, for the treatment of high levels of eosinophils, particularly asthma in a subject in need thereof having high baseline levels of eosinophils as described herein above, and at least one pharmaceutically acceptable excipient.

[0166] Another object of the present invention is the use of a 2-aminoarylthiazole derivative, particularly masitinib, as described herein above, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of high levels of eosinophils, particularly asthma, as described herein above, in a subject in need thereof having high levels of eosinophils at baseline, as described herein above.

[0167] In one embodiment, the present invention relates to the use of a 2-aminoarylthiazole derivative, particularly masitinib, as described herein above, or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of high levels of eosinophils, particularly asthma, as described herein above, in a subject in need thereof having high levels of eosinophils, particularly asthma, as described herein above, in combination with at least another pharmaceutically active agent, as described herein above.

[0168] In one embodiment, the present invention relates to the use of a 2-aminoarylthiazole derivative, particularly masitinib, as described herein above, or a pharmaceutically acceptable salt or solvate thereof, in combination with at least another pharmaceutically active agent, as described herein above, for the manufacture of a medicament for the treatment of high levels of eosinophils, particularly asthma, in a subject in need thereof having high levels of eosinophils at baseline, as described herein above.

[0169] Example The invention is further illustrated by the following examples.

[0170] Working Example: A prospective, multicenter, randomized, double-blind, placebo-controlled, two-parallel group phase 3 study was conducted to compare the efficacy and safety of masitinib 6 mg / kg / day versus placebo in the treatment of subjects with severe persistent asthma treated with oral corticosteroids.The clinical trial (reference number AB07015) is registered under EudraCT number: 2010-020803-63 and ClinicalTrials.gov identifier: NCT01449162.

[0171] method patient Patients were randomized into two groups with a 2:1 masitinib:placebo randomization ratio: Group 1: Patients who received masitinib at 6 mg / kg / day Group 2: Patients who received placebo.

[0172] The main entry criteria are: Patients with severe asthma who were already treated with oral corticosteroids at a minimum daily dose of 7.5 mg prednisone or equivalent for at least 3 months prior to the screening visit; Patients with no significant change in usual asthma medication and no severe asthma exacerbations for at least 4 weeks prior to the screening visit; patients who previously consumed less than 10 packs / year of cigarettes and have quit smoking for at least 1 year; Patients who had a history of asthma for at least one year prior to the screening visit and also met the following criteria: A predicted normal value of 35 or less than 80% of baseline FEV1, demonstrated at least 6 hours after a short-acting beta-agonist or at least 12 hours after a long-acting beta-agonist (LABA). At least two asthma exacerbations within the year prior to the screening visit, including one severe asthma exacerbation per protocol definition Uncontrolled asthma (ACQ (Asthma Control Questionnaire) items) defined as two or more of the following characteristics within 1 week prior to the screening visit: Daytime symptoms more than twice per week Symptoms that limit any activity Any nighttime symptoms / awakenings Need for palliative / life support medications more than twice per week.

[0173] The main exclusion criteria were: patients with active lung disease other than asthma (e.g., chronic bronchitis); Asthmatic patients who have already been exposed to allergens or triggers that affect asthma control; and / or Patients with a history of acute infectious sinusitis or respiratory tract infection within 4 weeks prior to the screening visit.

[0174] Study Design & Treatment Administration The study consisted of the following periods: Run-In Period: Patients who met the inclusion / exclusion criteria were entered into a 2-week, single-blind, placebo-controlled run-in period, which served as a reference period for assessing patient status, including symptoms, need for rescue medications, and treatment compliance.

[0175] To be eligible for randomization, each patient must demonstrate good study treatment (i.e., placebo) compliance (≥80%); a mean daily symptom score of ≥2; and no asthma exacerbations (moderate or severe) during the 2-week run-in period.

[0176] First treatment period (W0-W36): During the 36-week treatment period, patients received a fixed dose of 6 mg / kg / day masitinib or matching placebo.

[0177] Oral corticosteroid weaning period (W36-W44): At week 36, patients treated with more than 15 mg / day of prednisone entered an 8-week follow-up oral corticosteroid-sparing period. During this period, the initial oral corticosteroid dose was reduced by 25% each week until an asthma exacerbation occurred. As soon as the patient experienced an asthma exacerbation, the investigators reintroduced corticosteroids at the previous week's dose. Thereafter, no further corticosteroid dose reductions were made.

[0178] Extension period: At week 36 for patients on ≤15 mg / day prednisone or week 44 for patients on >15 mg / day prednisone, patients could enter directly into the treatment extension phase if deemed medically appropriate by the investigator.

[0179] Enrolled subjects received a total daily dose of 6 mg / kg masitinib or matching placebo, taken with meals, as described in Table 1.

[0180] [Table 1]

[0181] Permitted concomitant asthma treatments are: long-acting beta-agonists (washout requirement: 12 hours before each study visit); a short-acting beta-agonist (salbutamol) as rescue medication reimbursed by the sponsor (washout requirement: 6 hours before each study visit); Inhaled corticosteroids at stable doses; Stable doses of oral corticosteroids during the first 36 weeks of treatment It was.

[0182] Efficacy analysis The statistical analysis plan for study AB07015 (version 1.0, date: October 18, 2019) defined the overall evaluable population as "all patients in the full analysis set (FAS) with severe asthma who were already treated with oral corticosteroids at a minimum daily dose of >5 mg prednisone or equivalent for at least 3 months prior to screening."

[0183] The full analysis set (FAS) included patients with: a) Patients originating from sites with significant Good Clinical Practice (GCP) violations; b) Patients not treated with the investigational product; c) patients with incorrect randomization (randomized twice at two different locations); d) Patients who were not receiving reference oral corticosteroids (OCS) at screening and baseline. This is defined as all randomized patients except

[0184] Subgroup analyses were performed on cohorts of severe asthma patients classified by baseline eosinophil blood count.

[0185] The primary endpoint was defined as the severe asthma exacerbation rate adjusted for available person-hours (time to end of treatment) over the complete exposure (main period + extension / weaning period).

[0186] The rate of severe asthma exacerbations was analyzed by applying a Poisson regression (log link function and Poisson distribution) model.

[0187] In the primary analysis, an inclusive cutoff was applied at the end of study AB07015, defined as 36 weeks after the last randomization.

[0188] Secondary endpoints included: Severe asthma exacerbation rate at week 36; time to first severe asthma exacerbation; the percentage of patients who experienced at least one severe asthma exacerbation at week 36 and throughout the study; overall (severe and moderate) asthma exacerbation rates at week 36 and throughout the study; time to first asthma exacerbation (severe or moderate); the percentage of patients who experienced at least one severe or moderate asthma exacerbation at week 36 and throughout the study; ACQ score at week 36; AQLQ at 36 weeks; FEV1 at 36 weeks; forced vital capacity (FVC) at 36 weeks; Change in oral corticosteroid dose after baseline at week 36.

[0189] result A total of 419 patients were randomized into Study AB07015. The full analysis set (FAS) included 402 patients, of whom 269 were in the masitinib-treated arm and 133 in the placebo arm. The evaluable population for the primary endpoint analysis (i.e., patients with severe asthma who had already been treated with oral corticosteroids at a minimum daily dose of more than 5 mg prednisone or equivalent for at least 3 months prior to screening) included 355 patients; of whom 240 were in the masitinib-treated arm and 115 in the placebo arm. Of these, a total of 268 patients, 181 in the masitinib-treated arm and 87 in the placebo arm, had elevated blood eosinophil levels of 150 cells / μL or greater.

[0190] Mean drug exposure between treatment arms (masitinib or placebo) was well matched across the entire population and all subgroups (i.e., approximately 1:1). At a 2:1 masitinib:placebo randomization ratio, overall study exposure (years) was also approximately 2:1, e.g., 273 vs. 132.5 years in the primary analysis population and 198.6 vs. 97.8 years in the cohort with elevated blood eosinophil levels (≥150 cells / μL).

[0191] Because eosinophil inflammation correlates with asthma severity, it was of interest to perform subgroup analyses by blood eosinophil levels. Table 2 below presents results regarding the effect of treatment with masitinib versus placebo (ratio of rates of asthma exacerbations requiring steroid therapy) in cohorts defined by various blood eosinophil levels and their supplementary cohorts (according to the primary efficacy analysis population). Rates of asthma exacerbations were analyzed using Poisson regression with treatment group (masitinib, placebo) as the primary variable of interest (covariate).

[0192] In the cohort with blood eosinophils ≥150 cells / μL (181 vs. 87 patients in the masitinib and placebo-treated arms, respectively), the exacerbation rate for patients receiving masitinib was 0.34 severe exacerbations per year compared with 0.48 severe exacerbations per year for patients receiving placebo. The corresponding rate ratio for asthma exacerbations was 0.66, representing a 33% reduction (improvement) in severe exacerbations for patients receiving masitinib versus placebo. In comparison, the supplemental cohort, i.e., the subgroup with blood eosinophils <150 cells / μL (59 vs. 28 patients in the masitinib and placebo-treated arms, respectively), showed no discernible difference in exacerbation rate (0.36 vs. 0.37 severe exacerbations per year, respectively). The corresponding rate ratio for asthma exacerbations was 0.97, which corresponds to a 3% reduction in severe exacerbations in patients receiving masitinib versus those treated with placebo.

[0193] Further analysis utilized the severe asthma phenotype subgroup of type 2 inflammation. In the cohort with blood eosinophils in the 150-300 cells / µL range (89 vs. 35 patients in the masitinib-treated and placebo-treated arms, respectively), the exacerbation rate for patients receiving masitinib was 0.38 severe exacerbations per year, compared with 0.53 severe exacerbations per year for patients receiving placebo. The corresponding rate ratio for asthma exacerbations was 0.72, corresponding to a 28% reduction (improvement) in severe exacerbations in patients receiving masitinib versus those receiving placebo. Similarly, in the cohort with blood eosinophils of 300 cells / μL or more (95 vs. 52 patients in the masitinib-treated and placebo-treated arms, respectively), the exacerbation rate for patients receiving masitinib was 0.29 severe exacerbations per year compared with 0.50 severe exacerbations per year for patients receiving placebo. The corresponding rate ratio for asthma exacerbations was 0.59, corresponding to a 41% reduction (improvement) in severe exacerbations for patients receiving masitinib versus placebo. In comparison, the subgroup described above with blood eosinophils below 150 cells / μL showed no discernible difference in exacerbation rate.

[0194] These results suggest that masitinib may be suitable for patients with severe asthma associated with high eosinophil levels, which corresponds to asthma with type 2 inflammation. Notably, masitinib significantly improved the treatment of this severe asthma phenotype, including the difficult-to-treat subgroup with eosinophil counts in the range of 150-300 cells / µL.

[0195] [Table 2]

Claims

1. 1. A pharmaceutical composition for use in treating asthma in a subject in need thereof, said pharmaceutical composition comprising masitinib or a pharmaceutically acceptable salt or solvate thereof, wherein said subject has a baseline eosinophil blood count of greater than 300 cells / μL.

2. The pharmaceutical composition according to claim 1, wherein the asthma is asthma accompanied by type 2 inflammation.

3. The pharmaceutical composition according to claim 1 or 2, wherein the asthma is uncontrolled.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the asthma is not controlled with inhaled corticosteroids.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the asthma is not controlled with oral corticosteroids.

6. 6. The pharmaceutical composition of any one of claims 1-5, wherein prior to treatment with masitinib or the pharmaceutically acceptable salt or solvate thereof, the subject was receiving oral corticosteroids (OCS) at a cumulative annualized OCS dose of greater than about 500 mg.

7. 7. The pharmaceutical composition of any one of claims 1-6, wherein prior to treatment with masitinib or the pharmaceutically acceptable salt or solvate thereof, the subject was receiving oral corticosteroids (OCS) at a dose of OCS equivalent to greater than about 500 mg of cumulative annualized prednisone.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the asthma is not controlled with a biological agent.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutically acceptable salt of masitinib is a mesylate salt of masitinib.

10. The pharmaceutical composition of any one of claims 1 to 9, wherein masitinib or the pharmaceutically acceptable salt or solvate thereof is administered orally.

11. 11. The pharmaceutical composition of any one of claims 1 to 10, wherein masitinib or a pharmaceutically acceptable salt or solvate thereof is administered at a dose ranging from about 1 mg / kg / day to about 12 mg / kg / day.

12. 12. The pharmaceutical composition of any one of claims 1 to 11, wherein masitinib or a pharmaceutically acceptable salt or solvate thereof is administered at a dose ranging from about 3 mg / kg / day to about 6 mg / kg / day.

13. 13. The pharmaceutical composition of any one of claims 1-12, wherein masitinib or a pharmaceutically acceptable salt or solvate thereof is administered at a dose of about 3 mg / kg / day, 4.5 mg / kg / day, or 6 mg / kg / day.

14. The pharmaceutical composition of any one of claims 1 to 13, wherein masitinib or a pharmaceutically acceptable salt or solvate thereof is administered together with at least another pharmaceutically active agent.

15. The at least another pharmaceutically active agent is selected from the group consisting of a biologic, a corticosteroid, a bronchodilator, a leukotriene modifier, a rescue medication, and any combination thereof, wherein the biologic is selected from the group consisting of omalizumab, dupilumab, mepolizumab, reslizumab, benralizumab, and mixtures thereof, and the corticosteroid is selected from the group consisting of fluticasone, budesonide, mometasone, beclomethasone, prednisone, prednisolone, betamethasone, dexamethasone, and mixtures thereof.

15. The pharmaceutical composition of claim 14, wherein the bronchodilator is selected from the group consisting of theophylline, salmeterol, formoterol, arformoterol, vilanterol, and mixtures thereof; the leukotriene modifier is selected from the group consisting of montelukast, zafirlukast, zileuton, and mixtures thereof; and the rescue medication is selected from the group consisting of albuterol, levalbuterol, ipratropium, prednisone, methylprednisolone, and mixtures thereof.

16. 16. The pharmaceutical composition of claim 14 or 15, wherein the at least another pharmaceutically active agent is administered as a first-line treatment and masitinib or the pharmaceutically acceptable salt or solvate thereof is administered as a second-line treatment.

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