Treatment method using fused pyrimidine compound

Abstract

[Problem] To provide a treatment method capable of exerting a BTK inhibitory action while reducing side effects such as increase in blood pressure and bleeding. [Solution] A method for treating a disease involving BTK that includes administering a compound represented by the formula (1), which is (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-N-(benzo[d]oxazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide, or a pharmaceutically acceptable salt or cocrystal thereof as (R)-1-(1-acryloylpiperidin-3-yl)-4-amino-N-(benzo[d]oxazol-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide in a dose of 0.1 mg to less than 2.0 mg per day to a patient having a disease involving BTK. This method reduces blood pressure elevation and clinically significant increases in bleeding events in the patient.

Description

Therapeutic method using fused pyrimidine compound

[0001] The present invention relates to a therapeutic method using a Bruton's tyrosine kinase (BTK) inhibitor. More specifically, the present invention relates to a therapeutic method capable of providing a BTK inhibitory effect while reducing side effects such as elevated blood pressure and bleeding.

[0002] Bruton's tyrosine kinase (BTK) is a protein kinase belonging to the Tec kinase family, and is a non-receptor tyrosine kinase that plays an important role in the regulation of B cell proliferation, survival, differentiation, activation and the like downstream of B cell receptor (BCR) signaling (Non-Patent Document 1). Inhibitors capable of controlling BTK activity are useful as therapeutic agents for diseases associated with abnormal hyperactivation of the BTK signaling pathway (e.g., cancer) (Patent Document 1), and are also considered to be useful for allergic diseases and autoimmune diseases.

[0003] To date, compounds having BTK inhibitory activity have been used in clinical practice. Such compounds include, for example, Ibrutinib, Acalabrutinib, and Zanubrutinib (BGB-3111).

[0004] However, these BTK inhibitory compounds are known to cause other serious adverse cardiovascular events including bleeding, arrhythmia, myocardial infarction, stroke, heart failure, and cardiovascular death in patients with hypertension.

[0005] For example, Acalabrutinib and Ibrutinib are known to cause elevated blood pressure and bleeding upon administration. For these agents, discontinuation of administration is recommended depending on the degree and site of bleeding. When elevated blood pressure is caused, concomitant use of antihypertensive agents is one of the options, but it cannot be said that sufficient data regarding this countermeasure has been obtained (Non-Patent Documents 2 to 4).

[0006] Another BTK inhibitor, zanubrutinib, is known for its high selectivity in specifically inhibiting BTK, but it is also known to cause elevated blood pressure and bleeding (Non-patent documents 8-9).

[0007] Bleeding as a side effect of BTK inhibitors can occur in a variety of organs, including subcutaneous tissue, the oral cavity, and internal organs. In particular, bleeding in the brain can have a very serious impact on patients in any disease (Non-Patent Documents 14-15).

[0008] To address the resulting increase in blood pressure and bleeding, measures such as administering antihypertensive drugs in combination (Non-Patent Document 3) or reducing the dosage of BTK inhibitors (Non-Patent Document 10) have been taken, as described above.

[0009] However, it is known that the effects of BTK inhibitors diminish when the dosage is reduced, making dosage reduction an inappropriate treatment option (Non-Patent Documents 11-13).

[0010] As a compound having BTK inhibitory activity, the compound of the following formula (1), namely (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide (compound (1)) or a salt thereof is known (Patent Document 2).

[0011] Based on the results of previous clinical trials, compound (1) or a pharmaceutically acceptable salt thereof has been considered for administration at a dose of 2 mg to 4 mg per day. However, compound (1), like other BTK inhibitors, has been found to cause side effects such as bleeding events in hypertensive patients. For example, in cases where side effects occurred early after the start of administration, there was a case in which bleeding occurred on the second day after the start of administration. In addition, there was a case in which cerebellar hemorrhage occurred with administration at a daily dose of 4 mg (Non-Patent Literature 9).

[0012] Therefore, there is still a need for a treatment method that can induce BTK inhibition while reducing side effects such as elevated blood pressure and bleeding.

[0013] WO 2011 / 090760 publication WO 2015 / 022926 publication

[0014] Curr Opin Immunol., 2000 Jun;12(3):282-8.Curr Oncol Rep, (2021) 23(10) 113,Blood, 2022, 142(8) 687)J Hematol Oncol, 2022, 15(1 )92Blood Adv., 2022, 6(4), 1296-1308JACC CardioOncol, 2023, 5(5), 570Blood Adv., May 28, 2024; 8(10): 2478-2490Blood, 2015, 125, 2497-2506Ann Rheum Dis 2023;82:1025-1034Fac Rev., 2021, 10:22Journal of Hematology & Oncology, 2020, 13:66Blood, 2023, 142: 269-270Clinical Lymphoma, Myeloma & Leukemia, 2018, Vol. 19, No. 1, 41-7Bleeding in haemato-oncological diseases: how to score, treat, predict Ypma, PF, 2021

[0015] This invention provides a therapeutic method that can induce BTK inhibition while reducing side effects such as elevated blood pressure and bleeding.

[0016] As a result of diligent research, the present inventors have found that administering compound (1) or a pharmaceutically acceptable salt or cocrystal thereof (also known as "TAS5315") at a dose of 0.1 mg or more and less than 2.0 mg per day maintains high safety by reducing side effects such as elevated blood pressure and bleeding in patients with BTK-related diseases based on BTK inhibitory activity, while also maintaining high therapeutic efficacy against diseases based on the original BTK inhibitory activity. This led to the completion of the present invention.

[0017] In other words, the present invention includes the following embodiments.

[0018] <1> A method for treating a disease involving BTK, comprising administering (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof to a patient having a disease involving BTK, in an amount of 0.1 mg or more and less than 2.0 mg per day as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide. <2> The method according to <1>, wherein the patient does not have uncontrollable hypertension. <3> The method according to <1>, wherein the patient has uncontrollable hypertension. <4> The method according to any one of <1> to <3>, wherein the daily dose of the compound of formula (1) or a pharmaceutically acceptable salt or cocrystal thereof as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide is 0.2 mg or more and 1.0 mg or less. <5> The method according to any one of <1> to <4>, wherein the daily dose of the compound of formula (1) or a pharmaceutically acceptable salt or cocrystal thereof as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide is 0.2 mg or more and 0.3 mg or less. <6> The method according to any one of <1> to <5>, wherein the daily dose of the compound of formula (1) or a pharmaceutically acceptable salt or cocrystal thereof is 0.25 mg as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide.<7> The method according to any one of <1> to <4>, wherein the daily dose of the compound of formula (1) or a pharmaceutically acceptable salt or cocrystal thereof is 1.0 mg as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide. <8> The method according to any one of <1> to <7>, wherein the compound of formula (1) or a pharmaceutically acceptable salt or cocrystal thereof is administered once daily, or in two or three divided doses daily. <9> The method according to any one of <1> to <8>, wherein the compound of formula (1) or a pharmaceutically acceptable salt or cocrystal thereof is administered once daily. <10> The method according to any one of <1> to <9>, wherein the administration comprises one or more treatment cycles, each of which comprises oral administration of the compound of formula (1) or a pharmaceutically acceptable salt or cocrystal thereof for 5 consecutive days, followed by a 2-day rest period. <11> The method according to any one of <1> to <10>, administered orally. <12> The method according to any one of <1> to <11>, wherein the disease in which BTK is involved is an immune disease. <13> The method according to <12>, wherein the immune disease is an allergic disease, an autoimmune disease, an inflammatory disease, or a tumor. <14> The method according to <13>, wherein the allergic disease is selected from the group consisting of atopic dermatitis, allergic rhinitis, contact dermatitis, urticaria, allergic conjunctivitis, bronchial asthma, anaphylaxis, food allergy, and drug allergy. <15> The method according to <14>, wherein the allergic disease is selected from the group consisting of atopic dermatitis, allergic rhinitis, contact dermatitis, urticaria, allergic conjunctivitis, and bronchial asthma. <16> The method according to <15>, wherein the allergic disease is selected from the group consisting of atopic dermatitis, contact dermatitis, urticaria, and bronchial asthma. <17> The method according to <16>, wherein the allergic disease is urticaria.<18> The method according to <13>, wherein the autoimmune disease is selected from the group consisting of serum sickness, systemic lupus erythematosus, rheumatoid arthritis, vasculitis, cryoglobulinemia, acute hypersensitivity pneumonitis, dermatomyositis, Sjögren's syndrome, Graves' disease, Hashimoto's disease, multiple sclerosis, myasthenia gravis, urticaria, pemphigus, bullous pemphigoid, hidradenitis suppurativa, scleroderma, lupus nephritis, idiopathic thrombocytopenic purpura, IgG4-related disease, warm autoimmune hemolytic anemia, primary membranous nephropathy, neuromyelitis optica, glomerulonephritis, interstitial pneumonia, and hypersensitivity pneumonitis. <19> The method according to <18>, wherein the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, multiple sclerosis, urticaria, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, IgG4-related disease, and warm autoimmune hemolytic anemia. <20> The inflammatory diseases mentioned above include appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, ulcerative colitis, Crohn's disease, irritable bowel disease, cystitis, dacryodenitis, contact dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, epididymitis, fasciitis, connective tissue inflammation, gastroenteritis, hepatitis, sweat gland abscess, laryngitis, mastitis, meningitis, myelitis, myocarditis, nephritis, oophoritis, orchitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, proctitis, prostatitis, pyelonephritis, eustitis, sinusitis, stomatitis, osteoarthritis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis. Preferably, the method according to <13>, selected from the group consisting of ulcerative colitis, Crohn's disease, irritable bowel disease, contact dermatitis, cystitis, and osteoarthritis. <21> The method according to <20>, wherein the inflammatory disease is selected from the group consisting of ulcerative colitis, Crohn's disease, irritable bowel disease, contact dermatitis, cystitis, and osteoarthritis. <22> The method according to <21>, wherein the inflammatory disease is selected from the group consisting of contact dermatitis, cystitis, and osteoarthritis. <23> The method according to <13>, wherein the tumor is selected from the group consisting of epithelial tumors, hematological tumors (hematopoietic tumors), and sarcomas. <24> The method according to <23>, wherein the tumor is a hematological tumor (hematopoietic tumor). <25> The method according to <24>, wherein the hematological tumor (hematopoietic tumor) is selected from the group consisting of lymphoma and leukemia.<26> The method according to <25>, wherein the hematological malignancy (hematopoietic malignancy) is lymphoma. <27> The method according to <25>, wherein the leukemia is lymphocytic leukemia. <28> The method according to <27>, wherein the lymphocytic leukemia is CLL (chronic lymphocytic leukemia). <29> The method according to any one of <1> to <28>, wherein in the patient, the systolic blood pressure before administration of the compound of formula (1) or a salt thereof is less than 140 mmHg and / or the diastolic blood pressure is less than 90 mmHg. <30> The method according to any one of <1> to <29>, characterized in that it reduces a clinically significant increase in blood pressure elevation or bleeding events in the patient. <31> A pharmaceutical product for use in any of the methods described in <1> to <30>, wherein the pharmaceutical product contains (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt thereof in an amount of 0.1 mg or more and less than 2.0 mg as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide. <31-1> The pharmaceutical product according to <31>, characterized in that it reduces a clinically significant increase in blood pressure or bleeding events in the patient. <32> A therapeutic agent for diseases involving BTK, comprising (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt thereof in an amount of 0.1 mg or more and less than 2.0 mg as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide. <32-1> The therapeutic agent according to <32>, characterized in that it reduces a clinically significant increase in blood pressure or bleeding events in the patient.<33> A pharmaceutical composition for the treatment of a disease involving BTK, comprising: a therapeutically effective amount of (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof; and a pharmaceutically acceptable excipient, wherein the therapeutically effective amount is 0.1 mg or more and less than 2.0 mg as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide. <33-1> The pharmaceutical composition according to <33>, characterized in that it reduces a clinically significant increase in blood pressure or bleeding events in the patient. <34> (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4- Use of (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof for the manufacture of a therapeutic agent for diseases involving BTK, comprising 0.1 mg or more and less than 2.0 mg of pyrimidine-3-carboxamide. <34-1> The use according to <34>, characterized in that it reduces a clinically significant increase in blood pressure or bleeding events in the patient.<35> For patients with BTK-related diseases, (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof, (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H- Use of (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof for the treatment of BTK-related diseases by administering a dose of 0.1 mg or more and less than 2.0 mg per day as pyrazolo[3,4-d]pyrimidine-3-carboxamide. <35-1> The use according to <35>, characterized in that it reduces a clinically significant increase in blood pressure or bleeding events in the patient. <36> A regimen comprising administering (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof in an amount of 0.1 mg or more and less than 2.0 mg per day as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide. <36-1> The regimen according to <36>, characterized in that it reduces a clinically significant increase in blood pressure or bleeding events in the patient.<37> A kit for the treatment of a disease involving BTK, comprising: a pharmaceutical preparation containing (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt thereof; and instructions for use, wherein the instructions for use include a statement instructing that (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide be administered in an amount of 0.1 mg or more and less than 2.0 mg per day. <37-1> The kit according to <37>, characterized in that it reduces a clinically significant increase in blood pressure or bleeding events in the patient.

[0019] This invention provides a treatment method for BTK-related diseases that can induce BTK inhibition while reducing side effects such as elevated blood pressure and bleeding. The treatment method of the present invention provides superior effects that could not be predicted from conventional techniques, such as improving safety while enhancing therapeutic efficacy.

[0020] This shows improvement in urticaria at 12 weeks of administration.

[0021] The present invention relates to a method for treating diseases involving Bruton's tyrosine kinase (BTK) using a BTK inhibitor. In embodiments of the present invention, a method for treating diseases involving BTK is provided that can induce BTK inhibitory effects while reducing side effects such as elevated blood pressure and bleeding.

[0022] In the present invention, "BTK" includes human or non-human mammalian BTK, and preferably human BTK. The term "BTK" also includes isoforms. "BTK inhibitory activity" can be measured, for example, by the method of Test Example 1 described in WO 2015 / 022926.

[0023] In the present invention, compound (1) or a pharmaceutically acceptable salt or cocrystal thereof (TAS5315) is used as the BTK inhibitor. The compound used in the therapeutic method of the present invention, (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide (compound (1)) or a salt or cocrystal thereof (TAS5315), is a known compound and can be produced by known methods (see, for example, WO 2016 / 121953).

[0024] The salt of the compound of the present invention refers to a pharmaceutically acceptable salt, and may include a base addition salt or an acid addition salt.

[0025] "Pharmacologically acceptable salt" means a salt of a compound that has the desired pharmacological activity and is prepared from a pharmaceutically acceptable, non-toxic base or acid, including inorganic or organic bases and inorganic or organic acids.

[0026] Examples of such salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; acid addition salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, citric acid, tartaric acid, carbonic acid, picric acid, methanesulfonic acid, p-toluenesulfonic acid, and glutamic acid; salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts with organic bases such as methylamine, ethylamine, meglumine, and ethanolamine; or salts with basic amino acids such as lysine, arginine, and ornithine; and ammonium salts. Pharmaceutically acceptable salts can be synthesized, for example, by methods described in International Publication WO2016 / 121954.

[0027] The compounds of the present invention or their salts also include their prodrugs. Prodrugs are compounds that are converted into the compounds of the present invention or their salts by reactions with enzymes or gastric acid under physiological conditions in the body, that is, compounds that undergo enzymatic oxidation, reduction, hydrolysis, etc., to become the compounds of the present invention or their salts, or compounds that undergo hydrolysis, etc., by gastric acid, etc., to become the compounds of the present invention or their salts. They may also be compounds that are converted into the compounds of the present invention or their salts under physiological conditions as described in "Pharmaceutical Research and Development", Vol. 7, Molecular Design, pp. 163-198, published by Hirokawa Shoten, 1990.

[0028] The compounds of the present invention, or their salts or cocrystals, may be amorphous (non-crystalline) or crystalline, and the compounds or salts of the present invention are encompassed whether the crystalline form is single or a polymorphic mixture. As cocrystals of compound (1), various inorganic or organic bases and inorganic or organic acids, or other adducts can be considered, and examples include, but are not limited to, cocrystals with acids such as hydrochloric acid, oxalic acid, succinic acid, nicotinic acid, citric acid, boric acid, maleic acid, and fumaric acid as adducts.

[0029] Crystals can be produced by crystallization using known crystallization methods. The compounds or salts thereof of the present invention may be solvates (e.g., hydrates, etc.) or solvates, and both are included in the compounds or salts thereof of the present invention. Isotopes (e.g., ３ H, １４ C, ３５ S, １２５ Compounds labeled with 1, 1, or other markers are also included in the compounds or salts thereof of the present invention. Multiple crystals (crystalline polymorphs) with spatially regular atomic arrangements and different physicochemical properties may be formed, but the salt according to the present invention may be any of these crystalline polymorphs, a mixture of two or more crystalline polymorphs, or even a mixture of crystals and amorphous materials.

[0030] In one embodiment of the present invention, compound (1) or a pharmaceutically acceptable salt thereof is the fumarate of the compound represented by formula (1) above (the fumarate of the compound of the present invention). In a particular embodiment of the present invention, the compound or a salt thereof is the fumarate of compound (1). When "the fumarate of the compound of the present invention" is used, it may refer to any salt of compound (1) and fumaric acid, and includes mono-fumarate and 1 / 2-fumarate salts. Furthermore, it is used to mean that it includes both the crystalline form of the fumarate of compound (1) and the amorphous form of the fumarate of compound (1).

[0031] In one embodiment of the present invention, the compound or salt thereof is a fumarate of compound (1). Preferably, the fumarate of compound (1) is monofumarate of compound (1) (sometimes abbreviated as "compound 1, monofumarate"), or 1 / 2 fumarate of compound (1); more preferably, monofumarate of compound (1) (crystalline), 1 / 2 fumarate of compound (1) (crystalline), or monofumarate of compound (1) (amorphous); and particularly preferably, monofumarate of compound (1) (crystalline) or 1 / 2 fumarate of compound (1) (crystalline).

[0032] Although multiple crystals (crystalline polymorphs) with spatially regular atomic arrangements and different physicochemical properties may be formed, the salt according to the present invention may be any of these crystalline polymorphs, a mixture of two or more crystalline polymorphs, or even a mixture of crystals and amorphous materials.

[0033] Furthermore, labeled fumarate salts of the compounds of the present invention, i.e., compounds in which one or more atoms of the compounds of the present invention or fumaric acid are substituted with radioactive or non-radioactive isotopes, are also included in the present invention.

[0034] The specific crystalline form of the fumarate of the compound of the present invention and the method of production are described, for example, in International Publication WO 2016 / 121954.

[0035] In this specification, the term "effective amount" of the compound of the present invention refers to an amount of the compound (a therapeutically effective amount) that causes a target biological or medical response, such as a decrease or inhibition of enzyme or protein activity, or improves symptoms, alleviates a condition, slows or delays the progression of a disease, or prevents a disease.

[0036] In this specification, the term “Subject” encompasses both mammals and non-mammals. Examples of mammals include, but are not limited to, humans, chimpanzees, apes, monkeys, cattle, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, mice, guinea pigs, hedgehogs, kangaroos, moles, wild boars, bears, tigers, and lions. Examples of non-mammals include, but are not limited to, birds, fish, and reptiles. In one embodiment, the subject may be a human being diagnosed with a condition, state, or disease disclosed herein that requires treatment.

[0037] The age of the person to whom the therapeutic agent of the present invention is administered is not particularly limited. The therapeutic agent of the present invention can be used not only in adults, but also in the elderly or children.

[0038] The therapeutic agent of the present invention can be provided as an active ingredient alone. In addition to the active ingredient compound (1) of the present invention or a pharmaceutically acceptable salt or cocrystal thereof, pharmaceutically acceptable carriers, excipients, etc. may be added as needed. Thus, the therapeutic agent of the present invention can be prepared as a pharmaceutical composition consisting of one component or containing two or more components. One embodiment of the present invention provides a pharmaceutical composition comprising compound (1) of the present invention or a pharmaceutically acceptable salt or cocrystal thereof. A pharmaceutical composition of one embodiment of the present invention comprises compound (1) of the present invention or a pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable carrier and / or a pharmaceutically acceptable excipient. In another embodiment of the present invention, a pharmaceutical for use in the method of the present invention is provided. Furthermore, one embodiment of the present invention provides the use of compound (1) of the present invention or a pharmaceutically acceptable salt or cocrystal thereof for producing a therapeutic agent or pharmaceutical composition. Another embodiment of the present invention provides compound (1) of the present invention or a pharmaceutically acceptable salt or cocrystal thereof for use as a therapeutic agent or pharmaceutical.

[0039] The therapeutic agent of the present invention can be manufactured in various dosage forms by known methods using a pharmaceutically acceptable carrier as needed.

[0040] The dosage form may be either oral or parenteral. Oral administration is preferred. In one embodiment of the oral embodiment, compound (1) or a pharmaceutically acceptable salt or cocrystal thereof is administered orally.

[0041] There are no particular restrictions on the form of such formulations, and examples include oral preparations such as tablets, coated tablets, pills, powders, granules, capsules, disintegrants, liquids, suspensions, and emulsions; parenteral preparations such as injections, suppositories, and inhalants; and topical preparations such as sprays and patches.

[0042] The therapeutic agent of the present invention is appropriately determined according to various preparation forms, the age, sex and other conditions of the patient, the degree of symptoms of the patient, and the like. For example, tablets, pills, powders, granules, capsules, solutions, suspensions and emulsions are administered orally. Injections are administered intravenously alone or in admixture with conventional replenishing fluids such as glucose and amino acids, and if necessary, are further administered alone intraarterially, intramuscularly, intradermally, subcutaneously or intraperitoneally. Suppositories are administered intrarectally.

[0043] When forming into a tablet form, examples of pharmaceutically acceptable carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, and silicic acid; binders such as water, ethanol, propanol, corn starch, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, potassium phosphate, and polyvinylpyrrolidone; disintegrants such as dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, and lactose; disintegration inhibitors such as sucrose, stearic acid, cocoa butter, and hydrogenated oil; absorption promoters such as quaternary ammonium salts and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; lubricants such as purified talc, stearate, boric acid powder, and polyethylene glycol can be used. Further, the tablets can be made into coated tablets with a conventional coating as needed, for example, sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, multi-layered tablets and the like.

[0044] When forming into a pill form, examples of pharmaceutically acceptable carriers include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc; binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol; disintegrants such as laminaran and agar can be used. Capsules are prepared according to a conventional method by mixing with the various pharmaceutically acceptable carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules and the like.

[0045] When preparing an oral liquid formulation, for example, flavoring and odor-masking agents, buffering agents, stabilizers and the like can be used as pharmaceutically acceptable carriers, and an oral liquid preparation, syrup, elixir and the like can be produced by a conventional method. In this case, examples of the flavoring and odor-masking agent include white sugar, orange peel, citric acid, tartaric acid and the like, examples of the buffering agent include sodium citrate and the like, and examples of the stabilizer include tragacanth, gum arabic, gelatin and the like. Liquid formulations include solutions, suspensions, and emulsions.

[0046] When forming into a suppository form, for example, polyethylene glycol, cacao butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like can be used as pharmaceutically acceptable carriers.

[0047] In the case of preparing an injection, solutions, emulsions and suspensions are preferably sterilized and isotonic with blood. In addition, when forming these forms, a diluent can be used as a pharmaceutically acceptable carrier, and examples of such a diluent include water, lactic acid aqueous solution, ethyl alcohol, propylene glycol, macrogol, ethoxylated isostearyl alcohol, polyoxyethylenated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like. In this case, a sufficient amount of sodium chloride, glucose or glycerin to prepare an isotonic solution may be contained in the pharmaceutical preparation, and usual solubilizing agents, buffering agents, soothing agents and the like may also be added.

[0048] In the case of preparing an inhalant, various forms such as aerosols, powdery inhalants, and liquid inhalants can be mentioned.

[0049] Furthermore, if necessary, colorants, preservatives, fragrances, flavoring agents, sweetening agents and the like, as well as other pharmaceutical agents may be incorporated into each of the above formulations as pharmaceutically acceptable carriers.

[0050] One embodiment of the present invention provides a method for treating a disease involving BTK, which comprises administering an effective amount of Compound (1), or a pharmaceutically acceptable salt or co-crystal thereof, to a subject in need thereof.

[0051] In this invention, the patients targeted for treatment are those with diseases involving BTK, based on its BTK inhibitory effect.

[0052] In the present invention, "diseases involving BTK" include immune diseases. In one embodiment of the present invention, the disease involving BTK is an immune disease.

[0053] In embodiments of the present invention, "immune disease" refers to immunodeficiency diseases characterized by an excessive immune response, such as allergic diseases, autoimmune diseases, inflammatory diseases, and tumors. In one embodiment of the present invention, the immune disease is an allergic disease, an autoimmune disease, an inflammatory disease, or a tumor. In a preferred embodiment of the present invention, the immune disease is an allergic disease or an autoimmune disease.

[0054] Allergic diseases are immunodeficiency disorders characterized by an excessive immune response primarily to exogenous antigens, and are classified into types I, II, III, and IV, any of which are acceptable. Alternatively, allergic diseases include, for example, inhalation allergies, food allergies, and contact allergies, but in embodiments of the present invention, allergic diseases are preferably food allergies and contact allergies. In embodiments of the present invention, allergic diseases are selected from the group consisting of atopic dermatitis, allergic rhinitis (e.g., hay fever), contact dermatitis, urticaria, allergic conjunctivitis, bronchial asthma, anaphylaxis, food allergies, and drug allergies. In preferred embodiments of the present invention, allergic diseases are selected from the group consisting of atopic dermatitis, allergic rhinitis, contact dermatitis, urticaria, allergic conjunctivitis, and bronchial asthma. In more preferred embodiments of the present invention, allergic diseases are selected from the group consisting of atopic dermatitis, contact dermatitis, urticaria, and bronchial asthma. In a more preferred embodiment of the present invention, the allergic disease is urticaria. The urticaria is preferably idiopathic urticaria, more preferably idiopathic chronic urticaria that is inadequately controlled by existing treatments, and particularly preferably idiopathic chronic urticaria resistant to antihistamines.

[0055] Autoimmune diseases are immunodeficiency diseases characterized by an excessive immune response primarily to self-antigens. These include systemic autoimmune diseases and organ-specific autoimmune diseases, and either is acceptable, with systemic autoimmune diseases and organ-specific autoimmune diseases being preferred. In embodiments of the present invention, the autoimmune disease is selected from the group consisting of serum sickness, systemic lupus erythematosus, rheumatoid arthritis, vasculitis, cryoglobulinemia, acute hypersensitivity pneumonitis, dermatomyositis, Sjögren's syndrome, Graves' disease, Hashimoto's disease, multiple sclerosis, myasthenia gravis, urticaria, pemphigus, bullous pemphigoid, hidradenitis suppurativa, scleroderma, lupus nephritis, idiopathic thrombocytopenic purpura, IgG4-related disease, warm autoimmune hemolytic anemia, primary membranous nephropathy, neuromyelitis, glomerulonephritis, interstitial pneumonia, and hypersensitivity pneumonitis. In a preferred embodiment of the present invention, the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, multiple sclerosis, urticaria, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, IgG4-related disease, and warm autoimmune hemolytic anemia. In a more preferred embodiment of the present invention, the autoimmune disease is rheumatoid arthritis or urticaria.

[0056] In embodiments of the present invention, inflammatory diseases include appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, ulcerative colitis, Crohn's disease, irritable bowel disease, cystitis, dacryodenitis, contact dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, epididymitis, fasciitis, connective tissue inflammation, gastroenteritis, hepatitis, sweat gland abscess, laryngitis, mastitis, meningitis, myelitis, myocarditis, nephritis, oophoritis, orchitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, proctitis, prostatitis, pyelonephritis, eustitis, sinusitis, stomatitis, osteoarthritis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis. Preferably, the inflammatory disease is selected from the group consisting of ulcerative colitis, Crohn's disease, irritable bowel disease, contact dermatitis, cystitis, and osteoarthritis. In a preferred embodiment of the present invention, the inflammatory disease is selected from the group consisting of ulcerative colitis, Crohn's disease, irritable bowel disease, contact dermatitis, cystitis, and osteoarthritis. In a more preferred embodiment of the present invention, the inflammatory disease is selected from the group consisting of contact dermatitis, cystitis, and osteoarthritis.

[0057] In embodiments of the present invention, the tumor is selected from the group consisting of epithelial tumors, hematological tumors (hematopoietic tumors), and sarcomas. In a preferred embodiment of the present invention, the tumor is a hematological tumor (hematopoietic tumor). Examples of hematological tumors include lymphoma and leukemia, which are further classified into acute myeloid leukemia, acute promyelocytic leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, multiple myeloma, Hodgkin lymphoma, non-Hodgkin lymphoma, myelodysplastic syndrome, adult T-cell leukemia / lymphoma, etc. In a more preferred embodiment of the present invention, the hematological tumor (hematopoietic tumor) is selected from the group consisting of lymphoma and leukemia. In a yet more preferred embodiment of the present invention, the hematological tumor (hematopoietic tumor) is lymphoma. In another yet more preferred embodiment of the present invention, the leukemia is lymphocytic leukemia. In an even more preferred embodiment of the present invention, the lymphocytic leukemia is chronic lymphocytic leukemia.

[0058] In embodiments of the present invention, the daily dose was set as an effective amount of compound (1) or a pharmaceutically acceptable salt or cocrystal thereof that can exert a BTK inhibitory effect while reducing side effects such as elevated blood pressure and bleeding.

[0059] In the present invention, the dose of TAS5315 can be administered as the free form (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide in a dose of 0.1 mg or more and 4.0 mg or less per day, preferably 0.1 mg or more and less than 2.0 mg per day, more preferably 0.2 mg or more and 1.0 mg or less per day, even more preferably 0.2 mg or more and 0.3 mg or less, and particularly preferably 0.25 mg per day.

[0060] One embodiment of the present invention provides a method for treating a BTK-related disease, comprising administering to a patient having the disease, a compound of the following formula (1), which is (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide, or a pharmaceutically acceptable salt or cocrystal thereof, in an amount of 0.1 mg or more and less than 2.0 mg per day as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide. In a preferred embodiment, the method is provided to reduce a clinically significant increase in blood pressure or bleeding events in the patient.

[0061] In a preferred embodiment of the present invention, the above method is provided, wherein the daily dose of the compound of formula (1) or a pharmaceutically acceptable salt or cocrystal thereof as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide is 0.2 mg or more and 1.0 mg or less.

[0062] A more preferred embodiment of the present invention provides the above method, wherein the daily dose of the compound of formula (1) or a pharmaceutically acceptable salt or cocrystal thereof as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide is 0.2 mg or more and 0.3 mg or less.

[0063] A more preferred embodiment of the present invention provides the above method, wherein the daily dose of the compound of formula (1) or a pharmaceutically acceptable salt or cocrystal thereof is 0.25 mg as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide.

[0064] In a more preferred embodiment of the present invention, the above method is provided, wherein the daily dose of the compound of formula (1) or a pharmaceutically acceptable salt or cocrystal thereof is 1.0 mg as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide.

[0065] Compound (1) or a pharmaceutically acceptable salt or cocrystal may be administered once daily, or in two or three divided doses. In one embodiment of the present invention, compound (1) or a pharmaceutically acceptable salt or cocrystal may be administered twice daily. In another embodiment of the present invention, compound (1) or a pharmaceutically acceptable salt or cocrystal may be administered once daily.

[0066] In the present invention, TAS5315 may be administered daily, preferably for two or more consecutive days, preferably for seven or more consecutive days, more preferably for 14 or more consecutive days, even more preferably for 28 or more consecutive days, particularly preferably for 84 or more consecutive days, even more preferably for 180 or more consecutive days, and most preferably for 360 or more consecutive days.

[0067] In one embodiment of the present invention, the method is provided wherein the administration comprises one or more treatment cycles, each of which comprises oral administration of the compound of formula (1) or a pharmaceutically acceptable salt or cocrystal thereof for five consecutive days, followed by a two-day rest period.

[0068] In the present invention, TAS5315 can be administered at any time at a predetermined frequency, but it is preferably administered on an empty stomach.

[0069] The method of the present invention reduces a clinically significant increase in blood pressure elevation or bleeding events in the patient. In the present invention, the target patient may be either a patient without uncontrollable hypertension or a patient with uncontrollable hypertension. In one embodiment of the present invention, the target patient does not have uncontrollable hypertension. Here, a patient without uncontrollable hypertension may be either a patient without concomitant hypertension or a patient with concomitant hypertension whose blood pressure is controlled by the use of antihypertensive drugs or the like. In another embodiment of the present invention, the target patient has uncontrollable hypertension.

[0070] More specifically, in the present invention, a patient with controllable hypertension, i.e., a patient without uncontrollable hypertension, means a patient whose systolic blood pressure is less than 140 mmHg and diastolic blood pressure is less than 90 mmHg before initiating administration of compound (1) or a pharmaceutically acceptable salt or cocrystal thereof, or a patient whose systolic blood pressure is less than 140 mmHg and diastolic blood pressure is less than 90 mmHg by the use of antihypertensive drugs or the like. In one embodiment of the present invention, the above method is provided, wherein in the patient, the systolic blood pressure is less than 140 mmHg and / or the diastolic blood pressure is less than 90 mmHg before initiating administration of the compound of formula (1) or a salt or cocrystal thereof.

[0071] In the present invention, a patient with uncontrolled hypertension, i.e., a patient with uncontrolled hypertension, means a patient who, before initiating administration of compound (1) or a pharmaceutically acceptable salt or cocrystal thereof, is unable to maintain a systolic blood pressure of less than 140 mmHg and a diastolic blood pressure of less than 90 mmHg by taking antihypertensive drugs.

[0072] In this invention, the severity of side effects is as follows: • Mild: Requires minimal treatment or no treatment at all, and does not interfere with the patient's daily living activities. • Moderate: Causes minor inconvenience or concern regarding the treatment method. Moderate events may cause some impairment to daily living activities. • Severe: Impairs the patient's daily living activities and may require systemic drug therapy or other treatment. In many cases, severe side effects can be life-threatening and cause dysfunction. The term "severe" is not necessarily synonymous with "critical."

[0073] In the present invention, "side effect" means what is commonly used in the art and refers to unfavorable events (unfavorable effects or adverse effects) that occur in connection with the use of a drug. In the present invention, "side effect" more preferably refers to unfavorable events or adverse events (treatment-related adverse events; TRAEs or adverse reactions) that have a direct causal relationship with the administration of the drug.

[0074] In the present invention, increasing blood pressure or bleeding events as a side effect means causing a significant increase in blood pressure or an increase in bleeding events during the administration period.

[0075] Here, an increase in blood pressure as a side effect refers to a significant increase in blood pressure, the need for additional treatment, or a condition that further interferes with the patient's daily activities.

[0076] Furthermore, bleeding as a side effect can be varied, including that caused by human actions such as the patient's behavior or medical procedures, as well as that caused by factors other than such human actions.

[0077] Bleeding caused by patient actions includes, for example, bleeding from the skin and ear, nose, and throat area due to scratching or friction by the patient themselves. More specifically, this includes auricular bleeding, nosebleeds, and gum bleeding.

[0078] Examples of bleeding resulting from medical procedures include bleeding at the site of vascular puncture, which is a result of surgical procedures.

[0079] Bleeding caused by factors other than human intervention can be categorized into bleeding based solely on the patient's chief complaint and bleeding that can be objectively measured. Examples of bleeding based solely on the patient's chief complaint include menorrhagia and intermenstrual bleeding. These types of bleeding, based solely on the patient's chief complaint, are difficult for a physician to confirm during an examination.

[0080] Objectively measurable bleeding includes conditions that are not solely based on the patient's chief complaint, such as subcutaneous bleeding, hematuria, positive urine occult blood, gastrointestinal bleeding, intracerebral hemorrhage, and respiratory tract bleeding.

[0081] In the present invention, bleeding events can be determined more specifically by indicators such as the frequency of bleeding, the size and shape of bleeding (punctate, purpura, macula), the number of bleeding lesions, the duration of bleeding, the amount of bleeding, the extent of bleeding (local, systemic), and the site of bleeding.

[0082] In the present invention, when evaluating bleeding as a side effect, it is undesirable to use bleeding caused by artificial actions (events caused by the patient's actions, bleeding caused by medical procedures) or bleeding that cannot be measured by objective indicators (bleeding based solely on the patient's chief complaint), and it is preferable to use bleeding that can be objectively measured. The dose used in the present invention is the dose at which objectively measurable bleeding is reduced, more preferably the dose at which subcutaneous bleeding, hematuria, positive urine occult blood, gastrointestinal bleeding, intracerebral bleeding, and respiratory bleeding are reduced, and even more preferably the dose at which hematuria, positive urine occult blood, intracerebral bleeding, gastrointestinal bleeding, and respiratory bleeding are reduced, and particularly preferably the dose at which cerebral bleeding, gastrointestinal bleeding, and respiratory bleeding are reduced.

[0083] Subcutaneous hemorrhage can be classified by measuring the size of the bleeding, for example, into petechiae (less than 4 mm in diameter), purpura (4 mm to less than 10 mm), and ecchymosis (10 mm or more) (Reference: Mount Sinai Hospital Health Library; https: / / www.mountsinai.org / health-library / symptoms / purpura#:~:text=Purpura%20occurs%20when%20small%20blood,diameter%2C%20they%20are%20called%20petechiae). The dose used in this invention is an indicator of side effects, preferably the dose at which purpura and ecchymosis are reduced, and more preferably the dose at which ecchymosis is reduced.

[0084] More preferably, the dose used is the dose administered when side effects such as intracerebral hemorrhage, gastrointestinal bleeding, and respiratory bleeding have been reduced, and is a dose of 0.25 mg of TAS5315 per day.

[0085] The severity of bleeding can also be evaluated by the name of the bleeding event, and criteria for the severity of bleeding (e.g., WHO criteria) can be used as a reference (Non-Patent Documents 14-15).

[0086] According to the WHO criteria described in these examples, the severity is as follows: Grade 0: No bleeding; Grade 1 (milder bleeding): Petechiae, purpura (≤1 inch), oropharyngeal bleeding and / or epistaxis (≤30 minutes), positive urine occult blood, temporary abnormal vaginal bleeding, etc.; Grade 2 (mild bleeding): Bleeding that does not require a blood transfusion, such as purpura (>1 inch), oropharyngeal bleeding or epistaxis (>30 minutes), hematuria, bloody stool, hemoptysis, hematemesis, retinal hemorrhage (without visual field defects), etc.; Grade 3 (moderate bleeding): Bleeding that requires a blood transfusion with moderate hemodynamic instability, especially those related to the treatment of bleeding (less than 24 hours), etc.; Grade 4 (severe bleeding): Bleeding that requires a blood transfusion with severe hemodynamic instability, such as fatal bleeding, central nervous system bleeding (cerebral hemorrhage), retinal hemorrhage (with visual impairment), etc.

[0087] In the present invention, preferably, the dose is one in which there is no Grade 4 of the criteria for bleeding severity; more preferably, the dose is one in which there is no Grade 3 or higher of the criteria; even more preferably, the dose is one in which there is no Grade 2 or higher of the criteria; and particularly preferably, the dose is one in which there is no Grade 1 or higher.

[0088] More preferably, the dose is 0.25 mg of TAS5315 per day, provided that no side effects of Grade 2 or higher occur.

[0089] In this invention, administration of TAS5315 0.25 mg to patients with chronic idiopathic urticaria who were not adequately controlled by antihistamines showed excellent efficacy without causing serious side effects related to elevated blood pressure or bleeding. Furthermore, in the TAS5315 0.5 mg and 1 mg groups, there were no occurrences of large petechial hemorrhages (diameter of 10 mm or more), and considering that the bleeding-related side effects other than subcutaneous hemorrhage that occurred in the 0.5 mg group were events attributable to the patient's behavior or medical procedures (auricular bleeding, epistaxis, bleeding at the vascular puncture site) or events that could not be objectively captured based solely on the patient's chief complaint (menorrhagia, intermenstrual bleeding), it was suggested that 0.5 mg and 1 mg, like 0.25 mg, do not cause elevated blood pressure, and if bleeding occurs, it is limited, suggesting that they may be safe and highly effective treatment methods.

[0090] According to the present invention, by administering (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide (compound (1)) or a pharmaceutically acceptable salt or cocrystal thereof in an amount of 0.1 mg or more and less than 2.0 mg per day as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide, it is possible to reduce a clinically significant increase in side effects (especially elevated blood pressure or bleeding events) and to provide excellent treatment for patients with diseases involving BTK.

[0091] In one embodiment of the present invention, a dosage regimen for the treatment of a BTK-related disease is provided, comprising administering a compound of the following formula (1), which is (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide, or a pharmaceutically acceptable salt or cocrystal thereof, in an amount of 0.1 mg or more and less than 2.0 mg per day as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide. In a preferred embodiment, the dosage regimen is provided that reduces a clinically significant increase in blood pressure or bleeding events in the patient.

[0092] In one embodiment of the present invention, to a patient having a disease involving BTK, (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof is administered to (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl) The use of (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof is provided for the treatment of BTK-related diseases by administering it in an amount of 0.1 mg or more and less than 2.0 mg per day as -1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide. In a preferred embodiment, the use is provided to reduce a clinically significant increase in blood pressure or bleeding events in the patient.

[0093] A kit for the treatment of a disease involving BTK, comprising: a pharmaceutical preparation containing (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide, which is (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof; and instructions for use. A kit is provided in which the instructions for use include a statement instructing that the compound of formula (1) or a pharmaceutically acceptable salt or cocrystal thereof be administered at a dose of (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide of 0.1 mg or more and less than 2.0 mg per day. In a preferred embodiment, the kit is provided to reduce in patients an increase in blood pressure or a clinically significant increase in bleeding events.

[0094] In patients with chronic idiopathic urticaria (CSU) who were inadequately controlled with antihistamines (H1RAs), the efficacy and safety of TAS5315 (fumarate cocrystal; equivalent to 4 mg, 2 mg, 1 mg, 0.5 mg, or 0.25 mg per day) or placebo were administered orally once daily for up to 12 weeks. The primary efficacy endpoint was the change from baseline in the weekly urticaria activity score (UAS7) at 12 weeks of treatment.

[0095] The main criteria for patient inclusion were as follows: • Age between 18 and 75 years at the time of consent; • Ability to take the investigational drug orally; • Continuous use of a chronic stress unit (CSU) for at least 6 months (180 days) prior to consent; • Presence of itching and wheals for at least 6 weeks (42 days) prior to consent, despite treatment with currently approved doses of H1RA.

[0096] The main criteria for excluding patients were as follows: • A history or co-existence of bleeding disorders (e.g., thrombocytopenic purpura, bleeding tendency due to vascular disorders, hemophilia, or other blood coagulation disorders); • Poorly controlled hypertension (e.g., systolic pressure of 140 mmHg or higher or diastolic pressure of 90 mmHg or higher) [however, patients whose hypertension is controlled by antihypertensive drugs, etc. (systolic pressure less than 140 mmHg and diastolic pressure less than 90 mmHg) do not violate the exclusion criteria].

[0097] The primary endpoint, the change from baseline (95% confidence interval) of UAS7 at 12 weeks of treatment, was -17.31 (-21.66 - -12.97), -15.39 (-19.61 - -11.18), -14.99 (-19.23 - -10.76), -11.71 (-16.08 - -7.34), -17.35 (-21.62 - -13.08), and -8.91 (-13.19 - -4.63) for the TAS5315 4 mg, 2 mg, 1 mg, 0.5 mg, 0.25 mg, and placebo groups, respectively, in the Full Analysis Set (FAS) (Table 1 and Figure 1). The estimated difference in the change from baseline in UAS7 at week 12 compared to the placebo group in the TAS5315 group showed that the upper limit of the 95% confidence interval was below 0 for the TAS5315 4 mg, 2 mg, 1 mg, and 0.25 mg groups.

[0098]

[0099] Table 2 shows the incidence rate of bleeding events among the safety (adverse reactions) evaluation items. No bleeding events were observed in the TAS5315 0.25 mg group. The most common adverse reaction was petechiae, with incidence rates of 9.5% in the TAS5315 4 mg group, 33.3% in the TAS5315 2 mg group, 9.5% in the TAS5315 1 mg group, and 14.3% in the TAS5315 0.5 mg group. It did not occur in the TAS5315 0.25 mg group or the placebo group, and there was no clear dose-dependent increase in incidence. In this study, subcutaneous bleeding events were diagnosed based on their size, and large petechiae (diameter of 10 mm or more) did not occur in the TAS5315 1 mg and 0.5 mg groups. Table 3 shows the incidence rates of all adverse reactions, including bleeding events. Even when considering all adverse events, including bleeding events, no adverse events were observed in the 0.25 mg group.

[0100] In the TAS5315 0.5mg group, in addition to subcutaneous hemorrhage, one case each of the following side effects was reported: auricular bleeding (due to mask rubbing), epistaxis (due to blowing the nose), menorrhagia, irregular bleeding, and bleeding at the vascular puncture site (due to blood sampling). All of these occurred during oral administration of TAS5315 and were judged as side effects by the clinical trial physician. However, only events attributable to the patient's actions or medical procedures (auricular bleeding, epistaxis, bleeding at the vascular puncture site) or events whose presence or severity could not be objectively determined based solely on the patient's chief complaint (menorrhagia, intermenstrual bleeding).

[0101] In the TAS5315 1mg group, no bleeding events other than subcutaneous hemorrhage were observed.

[0102] In all TAS5315 dosage groups, no elevated blood pressure or other cardiovascular side effects related to cardiac disorders were observed. In particular, the 0.25 mg to 1.0 mg dosage groups showed even better results, with no bleeding events or other cardiovascular side effects.

[0103]

[0104]

[0105] Table 4 shows the baseline changes in systolic and diastolic blood pressure. No clinically significant changes were observed in any of the treatment groups.

[0106]

[0107] Based on the above, administration of TAS5315 0.25 mg to patients with chronic idiopathic urticaria who were not adequately controlled by antihistamines showed excellent efficacy without causing serious side effects related to elevated blood pressure or bleeding. Furthermore, in the 0.5 mg and 1 mg groups of TAS5315, there were no occurrences of large petechial hemorrhages (diameter of 10 mm or more), and considering that the bleeding-related side effects other than subcutaneous hemorrhage that occurred in the 0.5 mg group were events attributable to the patient's behavior or medical procedures (auricular bleeding, epistaxis, bleeding at the vascular puncture site) or events that could not be objectively captured based solely on the patient's chief complaint (menorrhagia, intermenstrual bleeding), it is suggested that 0.5 mg and 1 mg, like 0.25 mg, may be safe and effective treatment methods that do not cause elevated blood pressure.

[0108] Furthermore, all references and publications mentioned herein, regardless of their purpose, shall be incorporated herein by reference in their entirety.

[0109] While several embodiments of the present invention have been described, these embodiments are presented as examples only and are not intended to limit the scope of the invention. These novel embodiments can be carried out in a variety of other forms, and various omissions, substitutions, and modifications can be made without departing from the spirit of the invention. These embodiments and their variations are included in the scope and spirit of the invention, as well as in the claims of the invention and its equivalents.

Claims

1. A method for treating a disease involving BTK, comprising administering (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof to a patient having a disease involving BTK, in an amount of 0.1 mg or more and less than 2.0 mg per day as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide.

2. The method according to claim 1, wherein the patient does not have uncontrolled hypertension.

3. The method according to claim 1, wherein the patient has uncontrolled hypertension.

4. The method according to any one of claims 1 to 3, wherein the daily dose of (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof is 0.2 mg or more and 1.0 mg or less.

5. The method according to any one of claims 1 to 4, wherein the daily dose of (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof is 0.2 mg or more and 0.3 mg or less.

6. The method according to any one of claims 1 to 5, wherein the daily dose of (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof is 0.25 mg.

7. The method according to any one of claims 1 to 4, wherein the daily dose of (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof is 1.0 mg.

8. The method according to any one of claims 1 to 7, wherein (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof is administered once daily, or in two or three divided doses daily.

9. The method according to any one of claims 1 to 8, comprising administering (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof once daily.

10. The method according to any one of claims 1 to 9, wherein the administration comprises one or more therapeutic cycles, each of which comprises oral administration of (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof for 5 consecutive days, followed by a 2-day rest period.

11. The method according to any one of claims 1 to 10, administered orally.

12. The method according to any one of claims 1 to 11, wherein the disease in which BTK is involved is an immune disease.

13. The method according to claim 12, wherein the immune disease is an allergic disease, an autoimmune disease, an inflammatory disease, or a tumor.

14. The method according to claim 13, wherein the allergic disease is selected from the group consisting of atopic dermatitis, allergic rhinitis, contact dermatitis, urticaria, allergic conjunctivitis, bronchial asthma, anaphylaxis, food allergy, and drug allergy.

15. The method according to claim 14, wherein the allergic disease is selected from the group consisting of atopic dermatitis, allergic rhinitis, contact dermatitis, urticaria, allergic conjunctivitis, and bronchial asthma.

16. The method according to claim 15, wherein the allergic disease is selected from the group consisting of atopic dermatitis, contact dermatitis, urticaria, and bronchial asthma.

17. The method according to claim 16, wherein the allergic disease is urticaria.

18. The method according to claim 13, wherein the autoimmune disease is selected from the group consisting of serum sickness, systemic lupus erythematosus, rheumatoid arthritis, vasculitis, cryoglobulinemia, acute hypersensitivity pneumonitis, dermatomyositis, Sjögren's syndrome, Graves' disease, Hashimoto's disease, multiple sclerosis, myasthenia gravis, urticaria, pemphigus, bullous pemphigoid, hidradenitis suppurativa, scleroderma, lupus nephritis, idiopathic thrombocytopenic purpura, IgG4-related disease, warm autoimmune hemolytic anemia, primary membranous nephropathy, neuromyelitis optica, glomerulonephritis, interstitial pneumonia, and hypersensitivity pneumonitis.

19. The method according to claim 18, wherein the autoimmune disease is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, multiple sclerosis, urticaria, hidradenitis suppurativa, idiopathic thrombocytopenic purpura, IgG4-related disease, and warm autoimmune hemolytic anemia.

20. The aforementioned inflammatory diseases include appendicitis, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, ulcerative colitis, Crohn's disease, irritable bowel disease, cystitis, dacryodenitis, contact dermatitis, dermatomyositis, encephalitis, endocarditis, endometritis, epididymitis, fasciitis, connective tissue inflammation, gastroenteritis, hepatitis, sweat gland abscess, laryngitis, mastitis, meningitis, myelitis, myocarditis, nephritis, oophoritis, orchitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleurisy, phlebitis, pneumonia, proctitis, prostatitis, pyelonephritis, eustitis, sinusitis, stomatitis, osteoarthritis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis, and vulvitis. Preferably, the method according to claim 13, selected from the group consisting of ulcerative colitis, Crohn's disease, irritable bowel disease, contact dermatitis, cystitis, and osteoarthritis.

21. The method according to claim 20, wherein the inflammatory disease is selected from the group consisting of ulcerative colitis, Crohn's disease, irritable bowel disease, contact dermatitis, cystitis, and osteoarthritis.

22. The method according to claim 21, wherein the inflammatory disease is selected from the group consisting of contact dermatitis, cystitis, and osteoarthritis.

23. The method according to claim 13, wherein the tumor is selected from the group consisting of epithelial tumors, hematological tumors (hematopoietic malignancies), and sarcomas.

24. The method according to claim 23, wherein the tumor is a hematological malignancy (hematopoietic malignancy).

25. The method according to claim 24, wherein the hematological malignancy (hematopoietic malignancy) is selected from the group consisting of lymphoma and leukemia.

26. The method according to claim 25, wherein the hematological tumor (hematopoietic tumor) is a lymphoma.

27. The method according to claim 25, wherein the leukemia is lymphocytic leukemia.

28. The method according to claim 27, wherein the lymphocytic leukemia is chronic lymphocytic leukemia (CLL).

29. The method according to any one of claims 1 to 28, wherein, in the patient, the systolic blood pressure before initiation of administration of (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof is less than 140 mmHg and / or the diastolic blood pressure is less than 90 mmHg.

30. The method according to any one of claims 1 to 29, characterized in that it reduces a clinically significant increase in blood pressure or bleeding events in the patient.

31. A pharmaceutical product for use in the method described in any one of claims 1 to 30, wherein the pharmaceutical product contains (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof in an amount of 0.1 mg or more and less than 2.0 mg as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide.

32. A therapeutic agent for diseases involving BTK, comprising (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof in an amount of 0.1 mg or more and less than 2.0 mg as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide.

33. A pharmaceutical composition for the treatment of a disease involving BTK, comprising a therapeutically effective amount of (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof, and a pharmaceutically acceptable excipient, wherein the therapeutically effective amount is 0.1 mg or more and less than 2.0 mg as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide.

34. (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4- Use of (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof for the manufacture of a therapeutic agent for diseases involving BTK, comprising an amount of 0.1 mg or more and less than 2.0 mg as [d]pyrimidine-3-carboxamide.

35. For patients with BTK-related diseases, (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof, (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H- Use of (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof for the treatment of BTK-related diseases, administered in an amount of 0.1 mg or more and less than 2.0 mg per day as pyrazolo[3,4-d]pyrimidine-3-carboxamide.

36. A regimen for the treatment of BTK-related diseases, comprising administering (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof in an amount of 0.1 mg or more and less than 2.0 mg per day as (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide.

37. A kit for the treatment of a disease involving BTK, comprising: a pharmaceutical preparation containing (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide or a pharmaceutically acceptable salt or cocrystal thereof; and instructions for use, wherein the instructions for use include a statement instructing that (R)-1-(1-acryloylpiperidine-3-yl)-4-amino-N-(benzo[d]oxazole-2-yl)-1H-pyrazolo[3,4-d]pyrimidine-3-carboxamide be administered in an amount of 0.1 mg or more and less than 2.0 mg per day.

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