WO2020175597A1 - Médicament pour la prévention ou le traitement de maladies fibrotiques des tissus - Google Patents

Médicament pour la prévention ou le traitement de maladies fibrotiques des tissus Download PDF

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WO2020175597A1
WO2020175597A1 PCT/JP2020/007901 JP2020007901W WO2020175597A1 WO 2020175597 A1 WO2020175597 A1 WO 2020175597A1 JP 2020007901 W JP2020007901 W JP 2020007901W WO 2020175597 A1 WO2020175597 A1 WO 2020175597A1
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fibrosis
pharmaceutical composition
scleroderma
tissue
compound
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PCT/JP2020/007901
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English (en)
Japanese (ja)
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昇 芦田
周 成宮
良孝 平山
荒森　一朗
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国立大学法人京都大学
アステラス製薬株式会社
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Publication of WO2020175597A1 publication Critical patent/WO2020175597A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/14—Drugs for genital or sexual disorders; Contraceptives for lactation disorders, e.g. galactorrhoea
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a medicament for preventing or treating a disease caused by tissue fibrosis.
  • Tissue fibrosis is a bioadaptive reaction found in the healing process of damaged tissues, but when it occurs excessively, it destroys normal tissues and causes organ failure. It is believed that tissue fibrosis is mainly due to abnormal growth of connective tissue in the tissue and excessive deposition of extracellular matrix such as collagen produced by fibroblasts.
  • Scleroderma is a systemic disease centering on vascular disorders, mainly inflammatory and fibrotic changes.
  • changes in various organs such as pulmonary fibrosis.
  • various cytokines such as TGF-/S and IL-6 are involved in fibrosis (Non-patent Documents 1 and 2).
  • the skin fat layer is reduced in the skin of patients with scleroderma, but in recent years, skin adipocyte precursor cells control skin myofibroblasts and fibrosis in scleroderma (Non-patent document 3).
  • Adiponectin is one of the cytokines produced by adipocytes, and has various functions such as adipocyte differentiation promoting action, anti-inflammatory action, and anti-fibrotic action (Non-patent document 1, Non-patent document 5, and Non-patent document 6).
  • Non-patent Document 7 Non-patent Document 7
  • ⁇ 02020/175597 2 ⁇ (: 171-1? 2020 /007901
  • Non-Patent Document 8 As one of the mechanisms of tissue fibrosis, activation of Akt by phosphorylation of phosphatidylinositol-3-kinase (PI3K) leads to pulmonary fibrosis (Non-Patent Document 8) and renal fibrosis (Non-patent reference). Reference 9), it is disclosed that it is involved in skin fibrosis (Non-Patent Document 10).
  • a PI3K inhibitor can be used for the treatment of fibrosis, particularly idiopathic pulmonary fibrosis (Patent Document 1).
  • Patent Document 2 Patent Document 2 ⁇
  • PI3KS selective inhibitors various types of diseases associated with immune disorders are listed as uses of PI3KS selective inhibitors, and examples thereof include use for fibrosis, scleroderma, etc. There is no example showing the therapeutic effect on fibrosis and scleroderma.
  • Non-Patent Document 11 the PI3K/Akt/mT0R pathway is involved in scleroderma, and BEZ235, which inhibits PI3K/Akt/mTOR signaling activity and mTOR signaling activity, is reported in vitro and in vitro. It has been disclosed that in vivo experiments using a dermatosis model mouse (bleomycin induction model) showed anti-fibrotic activity.
  • Patent Document 7 discloses a compound having the following chemical formula as one of PI3K 8 (Phosphat i dy I i nos i to l-3-ki nase delta) selective inhibitors, [(3S)-3- ( ⁇ 6-[2-(Difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl ⁇ amino)pyrrolidin-1-yl](oxane-4 -Yl)methanone (Table 222, Ex. A 293) (hereinafter sometimes referred to as Compound 1) is disclosed, and rejection in organ transplantation, allergic disease, autoimmune disease, blood fluid is disclosed. It has been shown that it can be used for the prevention/treatment of tumors. However, Patent Document 7 does not describe a disease caused by fibrosis. ⁇ 0 2020/175597 3 ⁇ (: 171? 2020 /007901
  • Non-Patent Document 1 Nature Reviews Rheumatology, 2014; 10, 706-719
  • Non-Patent Document 2 Rheumatol., 2012; 39, 1120.
  • Non-Patent Document 3 Nature Reviews Rheumatology, 2017; 13, 71-72
  • Non-Patent Document 4 Clin. Med., 2019; 8, 1256
  • Non-Patent Document 5 Bi Lipid. Res., 2005; 46, 1369-1379
  • Non-Patent Document 6 Arthr i t i s. Res. Ther., 2012; 14, R229
  • Non-Patent Document 7 Exp. Dermatol., 2011; 20, 764-766.
  • Non-Patent Document 8 Int. ⁇ Mol. Sc i ., 2018; 19, 778
  • Non-Patent Document 9 Bowl Cell. Mol. Med., 2017; 21, 1248-1259
  • Non-Patent Document 10 Invest. Dermatol., 2006; 126, 551-560.
  • Non-Patent Document 11 ⁇ Dermatol Sc i ., 2014 Nov; 76(2): 104-111
  • Patent Document 1 International Publication WO2013/117503
  • Patent Document 2 Japanese Patent Laid-Open No. 2017-186378
  • Patent Document 3 International Publication WO2014/006572
  • Patent Document 4 International Publication WO2012/126901
  • Patent Document 5 International Publication WO2012/107465
  • Patent Document 6 International Publication WO2008/064018
  • Patent Document 7 International Publication WO2012/020762 ⁇ 0 2020/175597 4 (17 2020/007901 Summary of the invention
  • a pharmaceutical composition which includes, for example, a compound having a 131 ⁇ 5 inhibitory action or a salt thereof as an active ingredient, and is useful for preventing and/or treating a disease caused by tissue fibrosis.
  • the present invention was completed for the first time by discovering that a pharmaceutical composition containing 1 or a salt thereof suppresses tissue fibrosis in skin, lung, esophagus, kidney and the like.
  • the present invention consists of the following.
  • a pharmaceutical composition for preventing and/or treating a disease caused by tissue fibrosis is provided.
  • a pharmaceutical composition for preventing and/or treating a disease due to tissue fibrosis which comprises a compound having a 131 ⁇ 5 inhibitory action or a salt thereof as an active ingredient.
  • the compound or its salt is [(33)-3-( ⁇ 6-[2-(difluoromethyl)-1 benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidine-4- Il ⁇ amino)pyrrolidin-1-yl](oxan-4-yl)methanone or a salt thereof, the pharmaceutical composition according to the above (2).
  • the pharmaceutical composition according to the above (2) or (3) which is a pharmaceutical composition which further comprises a pharmaceutically acceptable excipient.
  • the pharmaceutical composition is [(33)-3-( ⁇ 6-[2-(difluoromethyl)-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidine-4- Ill ⁇ amino)pyrrolidin-1-yl](oxan-4-yl)methanone or a salt thereof is included in the preventive and/or therapeutic agent for diseases caused by tissue fibrosis.
  • Tissue fibrosis is caused by lung, skin, heart, esophagus, stomach, intestine, kidney, liver, blood vessel, spleen, bone marrow, mammary gland, muscle, peritoneum, pleura, thyroid, lymph node, joint, bladder, trachea
  • Scleroderma and/or diseases caused by fibrosis associated with organ failure include pulmonary fibrosis, pulmonary hypertension, skin sclerosis, reflux esophagitis, scleroderma renal crisis, and diffuse skin sclerosing systemic sclerosis.
  • the pharmaceutical composition according to (6) above which is one or more diseases selected from the group consisting of illness, localized systemic scleroderma and autoimmune diseases.
  • a method for preventing or treating a disease caused by tissue fibrosis is a human or other animal in need of prevention or treatment thereof, and in one embodiment, a human in need of prevention or treatment thereof.
  • the pharmaceutical composition of the present invention showed an excellent therapeutic effect in a fibrosis model animal from the viewpoint of evaluation of skin score and fat layer ratio. Furthermore, histologically, for example, it showed an excellent improving effect on skin fibrosis, esophageal submucosal fibrosis, and renal glomerulosclerosis. It also showed an excellent improvement effect on the circumference of the right ventricle. Furthermore, it was shown that the pharmaceutical composition of the present invention was directly applied to fibroblasts of animal models of fibrosis and humans to differentiate into adipocytes. From this, it was confirmed that the pharmaceutical composition of the present invention exhibits an excellent effect on tissue fibrosis in various organs.
  • FIG. 1 shows IKK /S f m. x Sm22 a -Cre +/ _ mouse (hereinafter, in the specification or figures,
  • FIG. 2 is a diagram showing the results of confirming the ratio of the fat layer in the epidermis when the compound 1 was orally administered to K0 mice. (Example 1)
  • FIG. 3 is a photograph showing the results of confirming the proportion of the fat layer in the epidermis when the compound 1 was orally administered to K0 mice. (Example 1)
  • FIG. 4 is a diagram showing the results of evaluation by the circumference of the right ventricle, which reflects the degree of pulmonary hypertension when Compound 1 was orally administered to K0 mice. (Example 2)
  • FIG. 5 shows the effect of oral administration of Compound 1 to K0 mice on the fibrosis of the submucosa of the esophagus, which was stained with Masson Trichrome. ⁇ 0 2020/175597 7 ⁇ (: 171-1?2020/007901
  • FIG. 6 shows the improving effect on renal glomerulosclerosis when Compound 1 is orally administered to 1 ⁇ 0 mice. It is a stained tissue chart, and the arrow shows a glomerulus. (Example 3)
  • FIG. 7 shows the degree of lung fibrosis when compound 1 was administered to a lung fibrosis model mouse (bleomycin-induced) by 831 ((" ⁇ 1 : 1; score evaluation results. It is a diagram (Example 4)
  • FIG. 8 shows the results obtained when Compound 1 was applied to skin fibroblasts of 1 ⁇ 0 mice.
  • FIG. 3 is a diagram showing the results of Western plot showing increased expression of H. (Example 5)
  • FIG. 9 shows compounds in human dermal fibroblasts.
  • FIG. 3 is a diagram showing the results of Western blot showing increased expression. (Example 6)
  • Fig. 10 shows the results obtained when Compound 1 was applied to skin fibroblasts of scleroderma patients. It is a figure which shows the result of G. (Example 7)
  • tissue fibrosis refers to abnormal growth of connective tissue in a tissue. For example, it is the bioadaptive response seen in the healing process of damaged tissues. However, excessive accumulation of extracellular matrix such as collagen fiber (collagen) causes the tissue to harden, destroys normal tissue, and causes organ failure. The phenomenon that the structure becomes hard like this is also called hardening.
  • tissue fibrosis is applied as long as fibrosis is observed in a tissue, at which site fibrosis is caused, which disease is caused by fibrosis, or which disease is caused. There is no particular limitation as to whether or not It is also called fibrosis rather than tissue fibrosis, and there is no particular limitation regarding fibrosis and hardening.
  • disease due to tissue fibrosis means autoimmune disease, collagen disease, skin disease, heart disease, respiratory system disease, esophageal disease, gastrointestinal disease, liver disease, renal disease. ⁇ 0 2020/175597 8 ⁇ (: 171? 2020 /007901
  • Cranial nerve diseases Cranial nerve diseases, eye diseases, bone marrow diseases, cancer, arteriosclerosis, obesity, diabetes and the like. Examples include scleroderma and fibrosis associated with organ failure. Tissue fibrosis in the present specification is not limited to these diseases as long as the tissue has fibrosis.
  • tissue in which "tissue fibrosis" occurs is not particularly limited, and examples thereof include lung, skin, heart, esophagus, stomach, intestine, kidney, liver, blood vessel, and spleen. , Bone marrow, mammary gland, muscle, peritoneum, pleura, thyroid, lymph node, joint, bladder, tracheal wall, adipose tissue, connective tissue, and/or one or more types of tissue. In one aspect, it refers to fibrosis in any tissue of lung, skin and heart.
  • the cause of tissue fibrosis and diseases associated with tissue fibrosis in the present specification are not particularly limited.
  • Scleroderma is classified into, for example, systemic scleroderma (system i c scleros i s: SSc) and localized scleroderma.
  • Systemic scleroderma is a systemic disease centering on vascular disorders, mainly inflammatory and fibrotic changes, and in addition to sclerotic lesions of the skin starting from the fingers, lesions of various organs such as pulmonary fibrosis are also present.
  • Systemic scleroderma is a diffuse skin-curing systemic scleroderma (diffuse cut aneous SSc: dcSSc) in which skin fibrosis (hardening) extends to the forearm and trunk, and is localized to the fingers and face. It is classified as skin-curing systemic scleroderma (limited cutaneous SSc: IcSSc).
  • Symptoms of systemic scleroderma include, for example, skin swelling, finger swelling, skin hardening, pigmentation and loss, and peripheral circulatory disorders such as Raynaud's phenomenon, finger ulcers, organ disorders such as pulmonary arterial hypertension. , Myocardial disorders such as heart fibrosis, gastrointestinal dysfunction, interstitial lung disease, and renal crisis.
  • liver fibrosis examples include liver fibrosis and inflammatory diseases that predispose it.
  • liver fibrosis examples include liver fibrosis and inflammatory diseases that predispose it.
  • inflammatory diseases that predispose it.
  • acute or chronic hepatitis, biliary tract disease and toxic liver damage nephrosclerosis due to diabetic nephropathy, myelofibrosis, fibroid fibrosis, post-wound scar, post-angioplasty restenosis, arteriosclerosis, Aneurysm, arterial calcification, aortic valve stenosis, ischemic heart disease, cardiomyopathy, arthritis, mammary fibrosis, muscle fibrosis, retroperitoneal fibrosis, thyroid fibrosis, lymph node fibrosis, bladder fibrosis, Pleural line ⁇ 0 2020/175597 9 ⁇ (: 171-1? 2020 /007901
  • an active ingredient of a pharmaceutical composition applicable to the prevention and/or treatment of tissue fibrosis includes a PI3KS selective inhibitor.
  • Specific examples of the PI3K S selective inhibitor as an active ingredient include Compound 1 or a salt thereof.
  • the present invention includes a pharmaceutically acceptable prodrug of Compound 1 or a salt thereof.
  • the pharmaceutically acceptable prodrug is a compound having a group which can be converted into an amino group, a hydroxyl group, a carboxyl group or the like by solvolysis or under physiological conditions.
  • groups that form prodrugs include the groups described in Prog. Med., 5, 2157-2161 (1985) and “Development of pharmaceuticals” (Hirokawa Shoten, 1990) Volume 7 Molecular Design 163-198. Can be mentioned.
  • the salt of Compound 1 is a pharmaceutically acceptable salt of Compound 1, and specifically, an acid addition salt (inorganic acid salt (hydrochloride, hydrobromide, hydrogen iodide, Acid salts, sulfates, phosphates, nitrates, etc.), organic acid salts (formic acid, propionic acid, acetate, trifluoroacetate, lactate, malonic acid, succinic acid, malic acid, mandelic acid, dibenzoyltartaric acid, Tartrate, ditoluoyl tartaric acid, oxalate, fumarate, maleate, benzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, Glucuronate, gluconate, aspartic acid, glutamic acid, etc.) and the like.
  • an acid addition salt inorganic acid salt (hydrochloride
  • Compound 1 or a salt thereof contained as an active ingredient in the pharmaceutical composition of the present invention has a function as a PI3K5 selective inhibitor.
  • the compound 1 or a salt thereof can be produced by using the method described in Patent Document 7, a method obvious to those skilled in the art, or a modified method thereof.
  • the "PI3K S selective inhibitor” means that the PI3K S inhibitory activity is 10 times or more in IC 50 value as compared to the PI3K a inhibitory activity, and in another embodiment, Double ⁇ 0 2020/175597 10 ⁇ (: 171-1? 2020 /007901
  • Still another embodiment means an inhibitor showing a strong activity with 100 times or more selectivity.
  • the amount of Compound 1 or a salt thereof contained in the pharmaceutical composition of the present invention varies depending on the route of administration, dosage form, administration site, kinds of excipients and additives, but is 0.01 to 100% by weight.
  • the content can be 0.01 to 50% by weight.
  • the pharmaceutical composition of the present invention may also include various hydrates or solvates of Compound 1 or a salt thereof, and crystalline polymorphic substances.
  • the solvate include solvates with water and alcoholic solvents (eg, ethanol).
  • the pharmaceutical composition of the present invention includes all pharmaceutically acceptable compounds 1 or salts thereof labeled with one or more radioactive or non-radioactive isotopes.
  • suitable isotopes used for the isotope labeling of the compound which is the active ingredient of the pharmaceutical composition of the present invention include hydrogen (and 3 H etc.), carbon ("0, 13 (: and 14 etc.)) , nitrogen (1 3 1 ⁇ 1 and the like), oxygen ( '5 ⁇ , 17 0 and 18 0, etc.), Ru isotopes of fluorine ⁇ equality) is wrapped.
  • the compound which is an isotope-labeled active ingredient of the pharmaceutical composition of the present invention, can be used in studies such as tissue distribution studies of drugs and/or substrates.
  • radioactive isotopes such as tritium () and carbon 14 ( 140 ) can be used for this purpose because of the ease of labeling and the ease of detection.
  • substitution with a heavier isotope for example, substitution of hydrogen with deuterium (), has a therapeutic advantage due to improved metabolic stability (eg, The increase in half-life at ⁇ , decrease in required dose, decrease in drug interaction) may occur.
  • the pharmaceutical composition of the present invention is orally administered by tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intravenous, intramuscular, etc., suppositories, transdermal solutions, It may be administered in any form of parenteral administration such as ointment, transdermal patch, transmucosal solution, transmucosal patch, and inhalant.
  • the pharmaceutical composition of the present invention is a solid composition for oral administration, tablets, powders, granules and the like are used.
  • the active ingredient is mixed with at least one inert excipient.
  • the composition is according to a conventional method. ⁇ 0 2020/175597 1 1 ⁇ (: 171-1? 2020 /007901
  • the tablets or pills may be coated with sugar or a film of a gastric or enteric substance.
  • the pharmaceutical composition of the present invention is a liquid composition for oral administration, it contains a pharmaceutically acceptable emulsion, solution, suspension, syrup or elixir, etc. It may contain a diluent used conventionally.
  • the liquid composition may contain a solubilizing agent, a wetting agent, an auxiliary agent such as a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent, and a preservative, in addition to the diluent.
  • the pharmaceutical composition of the present invention when it is an injection, it may contain a sterile aqueous or non-aqueous solvent, a suspension, or an emulsion.
  • aqueous solvent include distilled water for injection and physiological saline.
  • non-aqueous solvents include plant oils and alcohols.
  • Such a composition may further contain a tonicity agent, a preservative, a wetting agent, an emulsifying agent, a dispersing agent, a stabilizing agent, or a solubilizing agent. These are sterilized by, for example, filtration through a bacteria-retaining filter, addition of a sterilizing agent, or irradiation. In addition, these can also be used by producing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before use.
  • the pharmaceutical composition of the present invention may also include an ointment, a plaster, a cream, a jelly, a poultice, a spray, a lotion and the like.
  • an ointment a plaster, a cream, a jelly, a poultice, a spray, a lotion and the like.
  • the pharmaceutical composition of the present invention is a transmucosal agent such as an inhalant or a nasal agent
  • a solid, liquid or semisolid one is used and can be produced according to a conventionally known method.
  • known excipients, and further, regulators, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be appropriately added.
  • a device can be used as appropriate.
  • the compound may be dispensed alone or as a powder in a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier.
  • the dry powder inhaler and the like may be those for single or multiple administration, and dry powder or powder-containing capsules can be used.
  • the pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
  • the daily dose is about 0.0001 to 100 mg/kg of body weight, preferably 0.01 to 30 mg/kg, and more preferably 0.1.
  • a suitable dose is 03 to 10 mg/kg, which can be administered once or in 1 to 4 divided doses.
  • a suitable daily dose is about 0.00001-10 mg/kg of body weight, and the daily dose should be administered once or in multiple doses.
  • as a transmucosal agent about 0.0001 to 100 mg/kg of body weight can be administered once to multiple times a day. The dose is appropriately determined according to each case in consideration of symptoms, age, sex and the like.
  • the compound as an active ingredient contained in the pharmaceutical composition of the present invention is compound 1 or a salt thereof, as well as a compound as an active ingredient for use in the known prevention and/or treatment of tissue fibrosis. May be administered simultaneously, or separately and continuously, or at desired time intervals.
  • the preparation for co-administration may be a combination drug or may be separately formulated.
  • the method for evaluating the efficacy of a compound as an active ingredient for use in the prevention and/or treatment of tissue fibrosis includes evaluation for the prevention and/or treatment of tissue fibrosis.
  • the evaluation system described in International Publication WO2014/069597 can be applied.
  • the degree of fibrosis is decreased or suppressed, increased or accelerated, or there is no change such as increase or decrease, and the condition is measured and evaluated.
  • a non-human model animal that strongly reflects the pathological condition of human scleroderma as described in International Publication WO2014/069597, visual observation, histological prayer, biochemical analysis, image analysis, etc. It can be performed and can be appropriately determined by those skilled in the art.
  • a five-point score can be evaluated for the face and frontal area, occipital area, occipital area, left and right hindlimbs, and caudal area.
  • the skin score is ( ⁇ : no lesion, 1: erosion, 2: wide range).
  • Erosion 3 Ulcer ⁇ 0 2020/175597 13 ⁇ (: 171-1? 2020 /007901
  • the test for scleroderma can be applied to the test for scleroderma patients in addition to the above-described measurement of fibrosis.
  • autoantibody test, skin biopsy, visceral test, etc. are performed.
  • autoantibodies specific to scleroderma include antinuclear antibodies, particularly anti-antibodies 70 antibodies (anti-topoisomerase 1 antibody), anti-centromere antibodies, anti-1 ⁇ 18 polymerase III antibodies, anti-nucleolar antibodies, etc. Is It can be detected by the method.
  • anti-antibodies 70 antibodies anti-topoisomerase 1 antibody
  • anti-centromere antibodies anti-1 ⁇ 18 polymerase III antibodies
  • anti-nucleolar antibodies etc. Is It can be detected by the method.
  • the antibody and kit used for these the above-mentioned commercially available products and the like can be appropriately used.
  • Compound 1 [(35) -3-( ⁇ 6-[2-(difluoromethyl)- Benzimidazole-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl ⁇ amino)pyrrolidin-1-yl](oxan-4-yl)methanone) has a therapeutic effect on fibrosis. confirmed.
  • the fibrosis model mouse shown in Example 1 described in International Publication ⁇ 2014/069597 was produced. Specifically, it was produced by the following method.
  • mice 6 tenths / -mouse (hereinafter, "1 ⁇ 0 mouse” 311122 A mouse (hereinafter, “1 ⁇ mouse”) was obtained. 1 ⁇ 0 mice were born at a rate according to Mendelian's law, and their growth such as change in body weight was not different from that of town mice. All of the ⁇ O mice obtained in the present invention were obtained by mating mice with a pure animal strain 0578176 as a genetic background.
  • the skin score is a 5-step score (0: no lesion, 1: erosion, 2: extensive erosion, 3: ulceration, 4: on the face and frontal region, occipital region, right and left hind limbs, and tail region. It was calculated as the total value of 5): moderate ulcer and 5: widespread and serious ulcer).
  • the therapeutic effect was evaluated by calculating the value obtained by subtracting the score before administration from the score after administration of the preparation containing Compound 1.
  • erosion refers to a defect extending to the epidermal layer
  • ulcer refers to a defect extending to the dermal layer.
  • Compound 1 compared to administration group 6 1 Rei_16 group, 0.03 1 ⁇ / 1 ⁇ are suppressed increase in skin score from low dose, the symptoms of scleroderma-like is suppressed (Fig. 1).
  • the skin pathological sections were stained with Masson-Trichrome.
  • the stained image was digitally photographed under a microscope, and the ratio of the fat layer in the epidermis was measured using image analysis software 1! 11 3 96".
  • the solvent was orally administered 10 11 117 twice a day! ⁇ 0 mice were set as ⁇ 6 ⁇ 0 4 groups.
  • the experiment was conducted using 10 cases in each group.
  • the proportion of the fat layer in the epidermis was 0.3 in the compound 1-administered group compared with the 611 _1 ( ⁇ 6 group.
  • the rate was high in the treated group (Figs. 2 and 3).
  • Compound 1 has an inhibitory effect on skin ulcer of scleroderma, an inhibitory effect on reduction of fat layer, and a concomitant normalizing effect on skin tissue.
  • Scleroderma may be associated with pulmonary fibrosis and pulmonary hypertension, resulting in dilation of the right ventricle and hypertrophy of the right ventricular wall. Therefore, Compound 1 monohydrochloride was suspended in a solvent (0.5% solution), and 0.003 to 0.1 Of the fibrosis model mouse prepared in 1 of Example 1 ( ⁇ ⁇ 0 mouse) from 16 weeks to 30 weeks of age, and the preparation containing Compound 1 was administered twice a day. by oral administration in 11117, the compound was administered 1 0.0 3-1 111 9 9. After euthanasia, the heart was removed.
  • a formulation containing Compound 1 was prepared. To a fibrosis model mouse prepared in 1 of Example 1 (0 ⁇ 0 mouse), a formulation containing Compound 1 was orally administered twice a day from 16 weeks to 30 weeks of age at 10 11117. , 0.1 to 5 111 9 9 Compound 1 was administered to the esophageal mucosa ⁇ 02020/175597 16 ⁇ (: 171-1? 2020 /007901
  • Fibrosis of the lower layer and renal glomerulosclerosis were confirmed.
  • the group to which only the solvent was administered was defined as the Vehicle group.
  • fibrosis in the submucosa of the esophagus (Fig. 5) and renal glomerulosclerosis (Fig. 6) were suppressed in the compound 1-administered group as compared to the Vehicle group.
  • mice were anesthetized with sodium pentobarbital, and bleomycinin physiological saline solution (1.2 mg/mL) was administered intratracheally once at 50 ML/head using Microsprayer (registered trademark) (Penn-Century). did.
  • Compound 1 monohydrochloride was suspended in a solvent (0.5% MC solution) to give a preparation containing 0.01 to 0.5 mg/mL of Compound 1.
  • the bleomycin-induced pulmonary fibrosis model mouse prepared in 1. of the present Example was orally administered with a formulation containing Compound 1 at 10 mL/kg for 21 days including the day of bleomycin administration.
  • Compound 1 at 5 mg/kg was administered twice daily.
  • Dexamethasone (Dex: 0.25 mg/kg) as a control (positive control) was orally administered once daily.
  • the vehicle group was a group in which 10 mL/kg of the solvent alone was orally administered twice a day to bleomycin-administered mice for 21 days.
  • mice not administered with bleomycin were used as a control group.
  • Control group 14 cases Vehicle group 14 cases, Compound 1 0.1 mg/kg administration group 13 cases, 0.5 mg/kg administration group 14 cases, 1 mg/kg administration group 12 cases, 5 mg/kg administration group 13 cases, Dex group 11
  • Mice were euthanized on day 22 after bleomycin administration, lungs were removed and fixed with formalin, and tissue sections were stained with Masson's Trichrome to show the degree of fibrosis. Ashcroft score (Ashcroft TA et a 1., J Clin Pathol, 19 88; 41 (4), 467-70) was calculated to evaluate lung tissue fibrosis.
  • Ashcroft score is obtained by dividing the degree of fibrosis of the lung into 0 to 8 grades in each field under a microscope in a lung tissue sample, and scoring the score from 20 to 8 fields in each section. ⁇ 02020/175597 17 ⁇ (: 171-1? 2020 /007901
  • the median value was used as the score of each individual.
  • the compound 1 at 5 mg/kg was shown to have the same pulmonary fibrosis inhibitory effect as the positive control dexamethasone. It was considered that Compound 1 could be expected to be effective in diseases involving fibrosis of the lung, such as interstitial pneumonia associated with scleroderma and idiopathic pulmonary fibrosis (Fig. 7).
  • adipocytes Two days later, cells were collected, and the differentiation state of adipocytes was confirmed by Western blot using an anti-PPAR ⁇ antibody (manufactured by CeU Signaling Technology) and an anti-FABP4 antibody (manufactured by CeU Signaling Technology). In addition, /S-actin was used as a control. As shown in Fig. 8, in the fibrosis model mouse, the expression of adipocyte markers PPAR ⁇ and FABP4 was increased by compound 1, and compound 1 was directly applied to dermal fibroblasts and It was found to differentiate into.
  • Skin fibroblasts (2X10 5 cells) were prepared from the skin of a scleroderma patient, and 5%C0 was added in Dulbecco's modified Eagle medium (DMEM, FUJIFILM Wako Pure Chemical Industries, Ltd.) containing 10% fetal bovine serum (FBS). Culture was performed at 37°C in 2 atmospheres.
  • DMEM Dulbecco's modified Eagle medium
  • FBS fetal bovine serum
  • the medium was replaced with DME M medium containing nant human insulin (1 yu, g/ml) % 10% FBS and 10 nM compound 1.
  • DME M medium containing nant human insulin (1 yu, g/ml) % 10% FBS and 10 nM compound 1.
  • nant human insulin (1 yu, g/ml) % 10% FBS and 10 nM compound 1.
  • GAPHD was used as a control.
  • the expression of PerUipin which is a marker for adipocytes, was increased by Compound 1, and it was revealed that Compound 1 also induces differentiation of dermal fibroblasts of scleroderma patients into adipocytes.
  • the pharmaceutical composition of the present invention showed excellent therapeutic effect in the fibrosis model animal from the viewpoints of skin score and evaluation of fat layer ratio. Furthermore, histologically, it showed an excellent improving effect on, for example, skin fibrosis, lower esophageal fibrosis, and renal glomerulosclerosis. It also showed an excellent effect on the perimeter of the right ventricle. From this, it was confirmed that the pharmaceutical composition of the present invention has an excellent effect on tissue fibrosis in various organs and has industrial applicability.

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Abstract

L'invention concerne une composition médicinale destinée à être utilisée pour prévenir et/ou traiter des maladies fibrotiques des tissus. La composition médicinale selon la présente invention, qui comprend un inhibiteur de la PI3Kδ en tant que principe actif, présente d'excellents effets sur la fibrose tissulaire dans divers organes et, de ce fait, peut prévenir et/ou traiter des maladies fibrotiques des tissus. A titre d'exemple d'inhibiteur de la PI3Kδ, on peut citer le [(3S)-3-({6-[2-(difluorométhyl)-1H-benzoimidazol-1-yl]-2-(morpholine-4-yl)pyrimidine-4-yl}amino)pyrrolidine-1-yl](oxan-4-yl)méthanone ou un sel de celui-ci.
PCT/JP2020/007901 2019-02-28 2020-02-27 Médicament pour la prévention ou le traitement de maladies fibrotiques des tissus WO2020175597A1 (fr)

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WO2012020762A1 (fr) * 2010-08-10 2012-02-16 アステラス製薬株式会社 Composé hétérocyclique
JP2012523429A (ja) * 2009-04-09 2012-10-04 オンコシレオン，インコーポレイテッド 線維症を処置するための方法およびｐｉ−３キナーゼインヒビターの組成物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012523429A (ja) * 2009-04-09 2012-10-04 オンコシレオン，インコーポレイテッド 線維症を処置するための方法およびｐｉ−３キナーゼインヒビターの組成物
WO2012020762A1 (fr) * 2010-08-10 2012-02-16 アステラス製薬株式会社 Composé hétérocyclique

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HASELMAYER, PHILIPP ET AL.: "Characterization of novel PI3Kdelta inhibitors as potential therapeutics for SLE and lupus nephritis in pre-clinical studies", IMMUNOLOGY, vol. 5, 2014, pages 1 - 15, XP055712279, DOI: 10.3389/fimmu.2014.00233 *
KASIVISWANATH, ROUTHU ET AL.: "Pre-clinical evaluation of a novel and selective PI3K delta/gamma inhibitor in pulmonary fibrosis", EUROPEAN RESPIRATORY JOURNAL, vol. 44, no. 58, 2014, pages 1507 *

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