Treatment of eosinophilic disorders with avapritinib

Abstract

To provide a method for the treatment of eosinophilic disorders, including hypereosinophilic syndrome.SOLUTION: Provided is a method for the treatment of eosinophilic disorders, including hypereosinophilic syndrome, the method comprising a step of administering a compound (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. Provisional Patent Application No. 62 / 910,931, filed October 4, 2019. No. 60 / 019,597, filed on Oct. 1, 2007. The entire contents of the aforementioned application are incorporated herein by reference. [Background technology]

[0002] Eosinophils play a beneficial role in host defense against infection, antitumor cytotoxicity, and wound healing. Eosinophils are bone marrow-derived granulocytes. They are involved in various diseases, including allergic diseases, and are associated with chronic respiratory It plays an important role in the development of allergic diseases such as bronchial asthma and atopic dermatitis. (Adv. Immunol., 39, 177 (1986), Immu Nol. Today, 13, 501 (1992)). In addition to the above diseases, eosinophils are also , hypereosinophilic syndrome (HES), eosinophilia, eosinophilic gastroenteritis, eosinophilic leukemia, eosinophil It is involved in diseases commonly referred to as granulomatous granulomatosis and Kimura's disease (Ann.Intern.Me d., 97, 78(1982)).

[0003] Eosinophils are divided into subgroups: normodense eosinophils and hypodense eosinophils. It has been shown that activation leads to low-density eosinophils (Immunology, 47, 531 (1982)). Low-density eosinophils are also called activated eosinophils. In addition to quantitative changes in peripheral blood eosinophils, qualitative changes have also been reported (Clin .Exp.Immunol., 24, 423 (1976)). Activated eosinophils are a cause of HES disease. It is involved in the severity of symptoms (Am. J. Cardiol., 52, 321 (1983)). Apart from HES patients, activated eosinophils are also present in the peripheral blood and trachea of ​​patients with bronchial asthma. It has also been found in bronchoalveolar lavage fluid (BALE) (Am. Rev. Respir. Dis , 132, 981 (1985)). Various receptors, such as cytokine receptors, are activated by It is expressed in eosinophils (low-density eosinophils) (J. Immunol., 142, 4416(19 89)). Compared with normodensity eosinophils, these low-density eosinophils have a high response to IL-5. (Clin. Exp. Immunol., 85, 312 (1991); J. .Exp.Med., 172, 1347(1990)).

[0004] Currently, treatment for patients with eosinophilic disorders consists of administering steroids. In particular, steroid administration is associated with side effects. If the administration is discontinued, the patient's condition may return to its original state, and long-term steroid administration However, it has some other problems, such as the possibility of inducing steroid resistance. Therefore, there is a need for safe and effective treatments for eosinophil-related disorders. Summary of the Invention [Means for solving the problem]

[0005] We have now discovered that Compound (I) shown below effectively reduces eosinophil levels in patients (see Examples). 1) Based on this finding, it was found that eosinophil levels in subjects who need to be reduced and a method for reducing eosinophil levels using Compound (I) or a pharmaceutically acceptable salt thereof. , as disclosed herein.

[0006] [ka]

[0007] One aspect of the present disclosure is a method for treating a patient with a rheumatoid arthritis, comprising administering a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof to a patient in need thereof. The present invention is a method for treating an eosinophilic disorder, comprising administering to a subject in need thereof Another aspect of the present disclosure is a method for the preparation of a compound (I) for the preparation of a medicament for treating an eosinophilic disorder. or a pharmaceutically acceptable salt thereof.

[0008] Another aspect of the present disclosure is the use of Compound (I) or its pharmaceutically acceptable salts for treating eosinophilic disorders. It is an acceptable salt. [Brief explanation of the drawings]

[0009] [Figure 1] 1 is a graph showing the absolute eosinophil change from baseline levels on C1D15 (Cycle 1, Day 15) after 2 weeks in adult patients treated with Compound (I) in a Phase 1 clinical trial. The dose range of Compound (I) was 30 mg to 400 mg. Patients with a baseline absolute eosinophil count >0.5. [Figure 2] Figure 1 shows the absolute eosinophil change from baseline levels on C1D15 (Cycle 1, Day 15) after 2 weeks in adult patients with KIT allele fraction <10% treated with Compound (I) in a Phase 1 clinical trial. The dose range of Compound (I) was 30 mg to 400 mg. Patients with baseline absolute eosinophil counts >0.5. [Figure 3] 1 is a graph showing the change in absolute eosinophils from baseline levels on C1D15 (Cycle 1, Day 15) in adult patients with KIT allele fractions between 10% and 40% treated with Compound (I) (300 mg dose) in a Phase 1 clinical trial after 2 weeks in patients with baseline absolute eosinophil counts >0.5. [Figure 4]Figure 1 shows the change in absolute eosinophils from baseline levels on C1D15 (Cycle 1, Day 15) after 2 weeks in adult patients with KIT allele fraction >40% treated with Compound (I) in a Phase 1 clinical trial. The dose range of Compound (I) was 200 mg to 300 mg. Patients with baseline absolute eosinophil counts >0.5. DETAILED DESCRIPTION OF THE INVENTION

[0010] Eosinophils are involved in the pathogenesis of many diseases and disorders. Eosinophils are a type of white blood cell. They help fight off infections and play a role in the body's immune response. and certain tissues, including the spleen, lymph nodes, and thymus, as well as the gastrointestinal, respiratory, and genitourinary tracts. Normal cellular components of the submucosal region. 0-450 eosinophils per cubic millimeter of blood The numbers are considered within the normal range.

[0011] If eosinophils are found in higher than normal amounts in various parts of the body, and / or A higher than normal ratio of low-density to normal-density eosinophils (e.g., >30%) is considered eosinophilic. The eosinophilic disorders described herein include excess eosinophils (eosinophilia) The increased number of eosinophils causes inflammation in the tissues and leads to organ damage. The lungs, skin and nervous system are most commonly affected, but any organ can be damaged. There is a possibility.

[0012] Eosinophilic disorders are diagnosed according to the location of elevated levels of eosinophils: Eosinophilic pneumonia (lungs) Eosinophilic cardiomyopathy (heart) Eosinophilic esophagitis (EoE) Eosinophilic gastritis (gastric-EG) Eosinophilic gastroenteritis (stomach and small intestine - EGE) Eosinophilic enteritis (small intestine) Eosinophilic colitis (colon-EC) Hypereosinophilic syndrome (blood and any organ - HES) Additionally, diseases and disorders in which eosinophils play a role (i.e., eosinophilic disorders) include, but are not limited to: Notable examples include asthma, immunoglobulin (IgE)-mediated food allergies, and eosinophilic esophagitis ( Inflammation of the esophagus), inflammatory bowel disease, COPD, allergic colitis, gastroesophageal reflux, eosinophilic gastrointestinal Enteric disease (EGID), eosinophilic gastroenteritis, endomyocardial fibrosis, Leffler's endocarditis, Davy S. disease, episodic angioedema associated with eosinophilia, eosinophilic myalgia syndrome / Spanish venom oil syndrome, cirrhosis, dermatitis herpetiformis, bullous pemphigoid, Churg-Strauss syndrome, acute myelopathy Acute eosinophilic leukemia, acute lymphoblastic eosinophilic leukemia, systemic mastocytosis with eosinophilia , allergic rhinitis, eczema, Wegener's granulomatosis, polyarteritis nodosa, eosinophilic fasciitis, and and rheumatoid arthritis.

[0013] Accordingly, one aspect of the present disclosure is a method for treating a patient suffering from atopic dermatitis, comprising administering a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof to a patient suffering from atopic dermatitis, the method ... and a method for treating an eosinophilic disorder, the method comprising administering to a subject a salt comprising: In this condition, eosinophilic disorders include hypereosinophilic syndrome, eosinophilia, eosinophilic gastroenteritis, and eosinophilic gastroenteritis. The disease is selected from eosinophilic leukemia, eosinophilic granuloma, and Kimura's disease.

[0014] In one embodiment, the eosinophilic disorder is hypereosinophilic syndrome. In one embodiment, the hypereosinophilic syndrome is idiopathic hypereosinophilic syndrome. The eosinophilic disorder is eosinophilic leukemia. In a specific embodiment, the eosinophilic leukemia is In another embodiment, the eosinophilic disorder is chronic eosinophilic leukemia. In a specific embodiment, the tumor is resistant to treatment with rituximab and / or regorafenib. In this case, the eosinophilic disorder is resistant to treatment with imatinib.

[0015] Another aspect of the present disclosure is a method for reducing the number of eosinophils in a subject in need thereof. The method comprises administering a therapeutically effective amount of Compound (I) or a pharmaceutically acceptable salt thereof to a subject. The method comprises the step of administering.

[0016] In one embodiment, the disclosed method is directed to the blood, bone marrow, gastrointestinal tract (e.g., esophagus, stomach, small intestine, etc.). In another embodiment, the present invention provides a method for treating atopic dermatitis, comprising administering to a subject a therapeutically effective amount of ... The method disclosed in reduces the number of eosinophils in the blood. In yet a further embodiment, the methods disclosed herein reduce the number of lung eosinophils. The methods disclosed herein reduce the number of eosinophil progenitor cells.

[0017] In another embodiment, the disclosed method provides for increasing (after administration) the number of eosinophils to at least about 10 %, at least about 20%, at least about 30%, at least about 40%, at least about 50 %, at least about 60%, at least about 70%, at least about 80%, at least about 90 %, at least about 95%, or at least about 99%. Thus, the methods disclosed herein reduce the number of eosinophils below the limit of detection.

[0018] In another embodiment, the disclosed method comprises increasing (after administration) the number of eosinophil precursors by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least About 50%, at least about 60%, at least about 70%, at least about 80%, at least A reduction of about 90%, at least about 95%, or at least about 99%. In the present invention, the method disclosed reduces the number of eosinophil precursors below the limit of detection. .

[0019] In further embodiments, the disclosed methods comprise administering to a patient a compound of formula (I) or a pharmaceutically acceptable salt thereof. In a specific embodiment, the eosinophil count is reduced below the limit of detection after a single administration of the salt. A single administration of Compound (I) or a pharmaceutically acceptable salt thereof reduces eosinophils to below the limit of detection. At least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least at least about 5 days, at least about 6 days, at least about 7 days, at least about 2 weeks, at least about 3 weeks, at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks weeks, at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 12 weeks, at least about 14 weeks, at least about 16 weeks, at least about 20 weeks, or Reduce for at least about 25 weeks.

[0020] In further embodiments, the disclosed methods comprise administering to a patient a compound of formula (I) or a pharmaceutically acceptable salt thereof. In a specific embodiment, the compound A single administration of (I) or a pharmaceutically acceptable salt thereof reduces eosinophil precursors to levels below the detection limit. At least about 1 day, at least about 2 days, at least about 3 days, at least about 4 days, at least About 5 days, at least about 6 days, at least about 7 days, at least about 2 weeks, at least about 3 weeks at least about 4 weeks, at least about 5 weeks, at least about 6 weeks, at least about 7 weeks at least about 8 weeks, at least about 9 weeks, at least about 10 weeks, at least about 1 2 weeks, at least about 14 weeks, at least about 16 weeks, at least about 20 weeks or less It will reduce the risk of heart disease by at least about 25 weeks.

[0021] The present disclosure provides a dose of 30 mg to 400 mg (e.g., 100 mg to 300 mg, or 200 mg Compound (I) and / or a pharmaceutically acceptable salt thereof in an amount of about 1000 mg to about 300 mg (about 1000 mg to about 300 mg) The present invention provides a method for treating an eosinophilic disorder, comprising administering to a subject in need thereof once daily In some embodiments, the amount is 25 mg, 30 mg, 35 mg, 40 mg, 45 mg. g, 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85m g, 90mg, 95mg, 100mg, 125mg, 150mg, 175mg, 200m g, 225mg, 250mg, 275mg, 300mg, 325mg, 350mg, 37 5 mg, 400 mg, 425 mg, or 450 mg once daily. In some embodiments, the amount is 25 mg once daily. In some embodiments, the amount is 50 mg once daily. In some embodiments, the amount is 75 mg once daily. The amount is 100 mg once daily. In some embodiments, the amount is 150 mg once daily. In some embodiments, the amount is 200 mg once daily. In some embodiments, the amount is 250 mg once daily. In some embodiments, the amount is 300 mg once daily. be.

[0022] As used herein, "Compound (I)" has the chemical name (S)-1-(4-fluorophenyl)- )-1-(2-(4-(6-(1-methyl-1H-pyrazol-4-yl)pyrrolo[2, 1-f][1,2,4]triazin-4-yl)piperazin-yl)pyrimidin-5-yl ) ethan-1-amine, having the following structure:

[0023] [ka]

[0024] It refers to a compound having the formula: Compound (I) is disclosed in WO2015 / 057873, the entire teachings of which are incorporated by reference. The preparation of compound (I) is described in WO2015 / 057873. As described in Example 7.

[0025] Compound (I) selects for the D816V mutation of KIT and other KIT exon 17 mutations. This antibody was developed to specifically target KIT D816V and demonstrates potent and selective activity against the D816V variant in KIT in vitro. activity in a tyrosine kinase inhibitor (TKI)-resistant mast cell tumor model in vivo demonstrated potent growth inhibition in 100% of patients with cerebrospinal fluid-containing steroids and was well tolerated at active doses in toxicology and safety pharmacology studies. Ongoing Phase 3 Study of Compound (I) in Patients with Advanced Systemic Mastocytosis (AdvSM) A phase 1 trial (NCT02561988) is evaluating safety and preliminary efficacy. The phase 2 dose (RP2D) to be administered was identified as 300 mg once daily (QD) and is included in this study. The expansion cohort will further confirm the efficacy and safety of this dose in a larger cohort of patients. Further evaluation of the effect of Compound (I) on symptom improvement in patients with AdvSM Validated AdvSM Symptom Assessment Form (AdvSM-SAF) developed to assess Based on new safety and efficacy data from patients treated with 300 mg QD , an additional cohort of patients treated with 200 mg QD was added.

[0026] Activating mutations at position D816 are found in eosinophilic disorders, with the most common mutation being D The D816V mutation is located in the activation loop of the kinase domain. which results in constitutive activation of KIT kinase.

[0027] First-line treatment with KIT inhibitors such as imatinib may also be beneficial in the initial treatment of eosinophilic disorders. Specifically, imatinib has been shown to be effective in treating idiopathic hypereosinophilic syndrome. However, resistance to imatinib may develop over several months through somatic mutations. These imatinib-resistant secondary mutations occur within exons 11, 13, 14, and 17. or 18. Patients with eosinophilic disorders, specifically exon There is a need for therapeutic agents to treat patients with the 17 mutation.

[0028] Compound (I) or a pharmaceutically acceptable salt thereof is selected from the group consisting of one or more K IT mutations (e.g., D816V, D816Y, D816F, D816K, D816H, D 816A, D816G, D820A, D820E, D820G, N822K, N822H , Y823D, and A829P), but not wild-type KIT. Very low.

[0029] In one embodiment, compound (I) or a pharmaceutically acceptable salt thereof is an exon of KIT. In a specific embodiment, D In another specific embodiment, the D816 mutation is D816V. It's 6Y.

[0030] As used herein, the term "pharmaceutically acceptable salts" refers to non-toxic salts of the compounds of the present disclosure. The pharmaceutically acceptable salts of Compound (I) include those prepared from suitable inorganic and organic acids. Pharmaceutically acceptable salts include those derived from hydroxyl groups and bases. Suitable pharmaceutically acceptable salts are described, for example, in Berge, SM et al., J. Pha This is disclosed in Rma. Sci. 66:1-19 (1977). Non-limiting examples of pharmaceutically acceptable salts disclosed include acetate; benzenesulfonate; Salts; Benzoates; Bicarbonates; Hydrogen Tartrates; Bromides; Calcium Edetate; Camsylate Salt;Carbonate;Chloride;Citrate;Dihydrochloride;Edetate;Edisylate;Estolic Acid Salts; Esylate; Fumarate; Gluceptate; Gluconate; Glutamate; Glyco Lylarsanilate;Hexylresorcinate;Hydrabamine;Hydrobromide;Hydrogenate; Hydroxynaphthoate;Iodide;Isethionate;Lactate;Lactobionate;Phosphorus Methyl nitrate; Methyl maleate; Methyl mandelate; Methyl mesylate; Methyl bromide; Methyl nitrate; Methyl Sulfates; mucoates; napsylates; nitrates; pamoates (embaonates) );Pantothenate;Phosphate / Diphosphate;Polygalacturonate;Salicylate;S tearates;basic acetates;succinates;sulfates;tannates;tartrates;teocl Acid salt; Triethiodide; Benzathine; Chloroprocaine; Choline; Diethanolamine ;Ethylenediamine;Meglumine;Procaine;Aluminum;Calcium;Lithium; Magnesium; potassium; sodium and zinc.

[0031] Non-limiting examples of pharmaceutically acceptable salts derived from appropriate acids include hydrochloric acid, hydrobromic acid, Salts formed with inorganic acids such as phosphoric, sulfuric or perchloric acid; acetic acid, oxalic acid, maleic salts formed with organic acids such as tartaric acid, citric acid, succinic acid or malonic acid; and and salts formed using other methods used in the art, such as ion exchange. Additional non-limiting examples of physiologically acceptable salts include adipates, alginates, aspartates, and the like. Corbate, aspartate, benzenesulfonate, benzoate, hydrogen sulfate, phosphatase Salt, butyrate, camphorate, camphorsulfonate, citrate, cyclopentasilate propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, Malate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, hepta Phosphate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactate Bionate, lactate, laurate, lauryl sulfate, malate, maleate, malo Phosphate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, o Leylate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-fluorouracil Phenylpropionate, phosphate, picrate, pivalate, propionate, stearate Phosphate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate Pharmaceutically acceptable salts derived from suitable bases include benzoyl methyl esters, ... Non-limiting examples of suitable salts include alkali metal, alkaline earth metal, ammonium and N + (C1-4 alkyl)4 salts. The present disclosure also provides compounds disclosed herein. The quaternization of any basic nitrogen-containing groups of is contemplated. Alkali metal salts and alkaline earth metal salts Non-limiting examples of salts include sodium, lithium, potassium, calcium, and magnesium. Further non-limiting examples of pharmaceutically acceptable salts include halogens. Chlorides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and ammonium, quaternary, formed with counterions such as arylsulfonates. Other non-limiting examples of pharmaceutically acceptable salts include ammonium and amine cations. Suitable examples include the besylate and glucosamine salts.

[0032] As used herein, a "therapeutically effective amount" of a compound disclosed herein is an amount that is effective in treating a biological eliciting a therapeutic or medical response, e.g., reducing or inhibiting enzyme or protein activity to harm, ameliorate symptoms, alleviate the condition, or slow the progression of the disease or It refers to the amount of compound that retards.

[0033] As used herein, the term "patient" or "subject" refers to a living individual or group of individuals who are treated by the methods of the present disclosure. Non-limiting exemplary organisms include mammals, such as mice, monkeys, horses, In some embodiments, the organism is a human. .

[0034] As used herein, the term "treat" when used in conjunction with a disorder or condition is "reat," "treating," or "treatment" " refers to any effect that results in improvement of a disease or condition, e.g., mitigation, reduction, modulation, amelioration, and Improving or alleviating the severity of any symptom of a disease or condition. The sum can be readily evaluated according to standard methods and techniques known in the art.

[0035] Hypereosinophilic syndrome is a condition characterized by high numbers of eosinophils, white blood cells that play an important role in the immune system. Over time, excess eosinophils invade various tissues, causing Ultimately, it damages organs.

[0036] The current classification of HES is (1) idiopathic HES, where the cause of HE remains unknown; (2) (3) primary (tumor-induced) HES with eosinophil clonality, and (4) cytokine-driven This includes secondary (reactive) HES due to the presence of non-clonal HES. ES is called lymphocytic, and abnormal T cells can be identified in the blood.

[0037] Pharmaceutical Composition Compound (I) and / or its pharmaceutically acceptable salts described herein are useful in the treatment of various conditions, including as a medicament for the treatment of rheumatoid arthritis, as well as for the treatment of rheumatoid arthritis. The active ingredient (API) and one or more pharmaceutically acceptable excipients are incorporated into the These compounds are useful as materials for preparing pharmaceutical compositions suitable for administration to human subjects.

[0038] In some embodiments, the present disclosure provides Compound (I) and / or its pharmaceutically acceptable salts. and at least one additional pharmaceutically acceptable excipient. As used herein, the term "pharmaceutically acceptable excipient" refers to a liquid or solid filler. pharmaceutically acceptable materials, such as fillers, diluents, excipients, solvents, or encapsulating materials; Each excipient is compatible with the subject composition and its components. and must be "pharmaceutically acceptable" in the sense that they are not harmful to the patient. Any conventional pharmaceutically acceptable excipient may produce some undesirable biological effects. by combining or otherwise interacting with any other component of the pharmaceutically acceptable composition. Compound (I) and / or its pharmaceutically acceptable salts, e.g., by interacting in a harmful manner. Except where incompatible with the salts disclosed herein, their use is contemplated within the scope of this disclosure. .

[0039] Some non-limiting examples of materials that can act as pharmaceutically acceptable excipients include: (1) sugars such as lactose, glucose, and sucrose; (2) corn starch and Starch such as potato starch; (3) sodium carboxymethylcellulose, e.g. Cellulose and its derivatives, such as cellulose acetate and cellulose acetate; (4) Traga (5) Malt; (6) Gelatin; (7) Talc; (8) Cocoa butter and suppository powder (9) peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, oils such as corn oil and soybean oil; (10) glycols such as propylene glycol; (1 1) Polyesters such as glycerin, sorbitol, mannitol, and polyethylene glycol (12) Esters such as ethyl oleate and ethyl laurate; (13) (14) Buffers such as magnesium hydroxide and aluminum hydroxide; (15) Al (16) Pyrogen-free water; (17) Isotonic saline; (18) Ringer's solution; ( 19) Ethyl alcohol; (20) Phosphate buffer solution; and (21) A compound used in pharmaceutical preparations. Other non-toxic compatible materials may be used.

[0040] Remington:The Science and Practice of P harmacy, 21st edition, 2005, edited by DBTroy, Lippincott Williams & Wilkins, Philadelphia, and Ency clopedia of Pharmaceutical Technology, J. Swarbrick and J.C. Boylan, eds., 1988–1999, Marcel Dekker, New York, the contents of each of which are incorporated herein by reference. This also provides additional non-limiting examples of pharmaceutically acceptable excipients, as well as methods for preparing and using the same. This application discloses known techniques for using

[0041] The pharmaceutical compositions disclosed herein can be administered orally, parenterally, by inhalation spray, topically, rectally, orally. It can be administered intravenously, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, In some embodiments, the method includes intrahepatic, intralesional, and intracranial injection or infusion techniques. The compositions of the present disclosure may be administered orally, intraperitoneally, or intravenously. Injectable forms may be aqueous or oily suspensions. These suspensions may be prepared by dispersing the or wetting agents and suspending agents according to techniques known in the art. The sterile injectable preparations may also be prepared by sterilization in a non-toxic parenterally acceptable diluent or solvent. It can be an injectable solution or suspension, for example, a solution in 1,3-butanediol. Non-limiting examples of acceptable vehicles and solvents that can be used include water, Ringer's solution, and the like. In addition, sterile, fixed oils are commonly used as solvents or suspending media. I can.

[0042] For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives, are useful in the preparation of injectables. as well as natural pharmaceutically acceptable oils such as olive oil or castor oil, among others. Polyoxyethylated versions of these are also useful. Solutions or suspensions of these oils may be Also, a long-chain alcohol diluent or dispersant such as carboxymethyl cellulose, or The same compounds commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions, Other commonly used dispersing agents such as Tweens, Spans and other emulsifiers may also be included. surfactants used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms; Commonly used bioavailability enhancers may also be used for the formulation.

[0043] The pharmaceutical compositions disclosed herein also include capsules, tablets, aqueous suspensions or solutions. The pharmaceutical composition may be orally administered in any orally acceptable dosage form, including, but not limited to, aqueous suspensions. When a suspension is required for oral use, the active ingredient is typically combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added. In some embodiments, a pharmaceutical composition comprising Compound (I) and / or a pharmaceutically acceptable salt thereof is provided. The pharmaceutical composition is a tablet prepared using methods known in the art. In some embodiments, the tablet is an immediate release tablet for oral administration. Compound (I) and / or its pharmaceutically acceptable salts may be mixed with the compound (I) to form an immediate release tablet. In some embodiments, the excipients that make up the tablet are finely divided. Crystalline cellulose, copovidone, croscarmellose sodium and magnesium stearate In some embodiments, the formulation blend is roller compacted and compressed to form a It is made into round tablets and film-coated for aesthetic purposes. [Example]

[0044] The following examples are intended to be illustrative and not to broaden the scope of the present disclosure in any way. It is not intended to be legally limiting. Example 1 This is a common symptom of advanced systemic mastocytosis (AdvSM) and relapsed or refractory myeloid malignancies. Safety, tolerability, PK, PD and steroid use of orally administered Compound (I) in adult patients with This is a Phase 1, open-label study designed to evaluate the efficacy and safety of EGFR-1 inhibitors in treating rheumatoid arthritis and preliminary antitumor activity.

[0045] The study consists of two parts: dose escalation (Part 1) and dose expansion (Part 2). Part 1 patients will receive approximately 2 There were 5 patients in the first part and approximately 55 patients in the second part. Diagnostic confirmation of systemic mastocytosis for study eligibility was required for diagnosis and subclassification. Evaluated using WHO criteria. Evaluable according to modified IWG-MRT-ECNM criteria. C findings are used to assess response.

[0046] The treatment cycle is 28 days. Patients receive the first dose of the study drug and receive serial PK samples. PD sample collection, vital signs measurement, electrocardiogram (ECG) monitoring, patient symptom assessment, Global Impression of Severity of Symptoms (PGIS) and European Organization for Research and Treatment of Cancer Core Quality of Life Scales questionnaire (EORTC QLQ-C30), safety monitoring and adverse event (AE) records The patient visited the research center on C1D1 for this reason.

[0047] Progressive SM responses were assessed using C3D1, C5D1 (imaging only), C7D1, C11D1 and C1 Imaging (magnetic resonance imaging [MRI] or computed tomography [CT]) at 8D1 and After C18, AdvSM response was assessed by chemotherapy and bone marrow (BM) evaluation. Evaluated.

[0048] All patients participated in an end-of-treatment (EOT) visit within 14 (±7) days after their last dose of study drug. The EOT visit must occur within 21 days after the last dose of study drug. Part 1 (dose escalation) Patients with AdvSM or relapsed or refractory myeloid malignancies will be included in the dose escalation study A 3+3 dose escalation design with cohorts of 3 patients was used.

[0049] Patients in the first cohort will receive Compound (I) at a starting dose of 30 mg once daily (QD). Dose escalation was initiated if ≥1 patient treated at a given dose level developed Grade 2 or greater Non-hematological AE or Grade 4 hematological AE, and AE (non-hematological or hematological) (e.g., GI) is not clearly attributable to a cause other than compound (I), or the dose is Ongoing Compound (I) First-in-Human (FIH) Study in ST, BLU-285-1101 The dose progressed in increments of up to 100% until the maximum dose determined to be safe was exceeded.

[0050] Three patients were initially enrolled in each cohort, and the cohorts were discontinued due to dose-limiting toxicity (DLT). If further expansion was required, three more patients (six total) were enrolled. Dose escalation was limited to a maximum of Until the tolerated dose (MTD) or the recommended phase 2 dose (RP2D) below the MTD is determined It continued.

[0051] Part 2 (enlarged) Once the MTD or RP2D is determined, up to three groups of patients with the following AdvSM diagnoses will be included: were enrolled in Part 2 and treated with Compound (I) at RP2D. Patients with ASM. Patients with SM-AHN. Patients with MCL.

[0052] Based on available efficacy, PK, and long-term safety data, Compound (I) 200 mg Q D was selected as the starting dose for the remainder of the study; all newly enrolled patients in the second part of the study Patients were given a starting dose of 200 mg.

[0053] Part 2 enrolled two cohorts: those with modified IWG- at baseline due to SM; Patients without measurable C findings according to MRT-ECNM criteria were enrolled in Cohort 1. At baseline, there were fewer cases according to the modified IWG-MRT-ECNM criteria due to SM. Patients with at least one measurable C finding were enrolled in Cohort 2. The person is to be determined by the Response Assessment Committee (RAC) of the revised IWG-MRT-ECNM Based on this, the population was evaluable for the primary purpose of determining ORR.

[0054] Eosinophil measurement Patients' eosinophils were measured by routine blood testing on C1D15 (Cycle 1, Day 15). For example, see LaGow B et al., PDR Lab Advisor. A Comprehensive hensive Point-of-Care Guide for Over 600 Lab Tests. 1st edition, Montvale, NJ: Thomson PDR, 2. 007;Pagana K, Pagana TJ, Mosby's Manual o f Diagnostic and Laboratory Tests. 5th edition, St. Louis, Missouri.2014;https: / / www.ebmco nsult.com / articles / lab-test-eosinophil-c ount, and https: / / www.cancer.net / cancer-types / leuk See emia-eosinophilic / diagnosis.

[0055] The entire teachings of the above references and web pages are incorporated herein by reference. . The test results are shown in Figures 1 to 4. This shows that administration of Compound (I) significantly increased the absolute eosinophil count of patients. This indicates a significant reduction.

Claims

1. a therapeutically effective amount of Compound (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof to a subject in need thereof. A method for treating an eosinophilic disorder.

2. Eosinophilic disorders include hypereosinophilic syndrome, eosinophilia, eosinophilic gastroenteritis, and eosinophilic leukemia.

2. The method of claim 1, wherein the disease is selected from eosinophilic granulomatosis and Kimura's disease.

3. 2. The method of claim 1, wherein the eosinophilic disorder is hypereosinophilic syndrome.

4. 10. The method of claim 1, wherein the eosinophilic disorder is eosinophilic leukemia.

5. 5. The method of claim 4, wherein the eosinophilic leukemia is chronic eosinophilic leukemia.

6. Eosinophilic disorders respond to treatment with imatinib, sunitinib, and / or regorafenib The method of any one of claims 1 to 5, wherein the strain is resistant to the genotype.

7. The method according to any one of claims 1 to 6, wherein the subject has a mutation in exon 17 of KIT. Law.

8. The method according to any one of claims 1 to 7, wherein the subject has a D816 mutation in exon 17 of KIT.

1. The method according to claim 1.

9. The method of claim 8, wherein the D816 mutation is D816V.

10. 10. The method of claim 9, wherein the D816 mutation is D816Y.

11. The method according to any one of claims 1 to 10, wherein the therapeutically effective amount is 30 to 400 mg. 。

12. Any one of claims 1 to 10, wherein the therapeutically effective amount is 100 to 300 mg per day. The method described below.

13. The therapeutically effective amount of any one of claims 1 to 10 is 100 mg per day. method.

14. The therapeutically effective amount of any one of claims 1 to 10 is 200 mg per day. method.

15. The therapeutically effective amount of any one of claims 1 to 10 is 300 mg per day. method.

16. a therapeutically effective amount of Compound (I): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof to a subject in need of a reduction in the number of eosinophils. A method for reducing the number of eosinophils in a subject, comprising administering to said subject a therapeutically effective amount of eosinophils.

17. 17. The method of claim 16, wherein a post-administration reduction in absolute eosinophil count of at least about 20% is observed. method.

18. 17. The method of claim 16, wherein a post-administration reduction in absolute eosinophil count of at least about 30% is observed. method.

19. 17. The method of claim 16, wherein a post-administration reduction in absolute eosinophil count of at least about 40% is observed. method.

20. 17. The method of claim 16, wherein a post-administration reduction in absolute eosinophil count of at least about 50% is observed. method.

21. 17. The method of claim 16, wherein a post-administration reduction in absolute eosinophil count of at least about 60% is observed. method.

22. 17. The method of claim 16, wherein there is a post-administration reduction in absolute eosinophil count of at least about 70%. method.

23. 17. The method of claim 16, wherein there is a post-administration reduction in absolute eosinophil count of at least about 80%. method.

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