WO2020004404A1 - IL-1β INHIBITOR - Google Patents

IL-1β INHIBITOR Download PDF

Info

Publication number
WO2020004404A1
WO2020004404A1 PCT/JP2019/025204 JP2019025204W WO2020004404A1 WO 2020004404 A1 WO2020004404 A1 WO 2020004404A1 JP 2019025204 W JP2019025204 W JP 2019025204W WO 2020004404 A1 WO2020004404 A1 WO 2020004404A1
Authority
WO
WIPO (PCT)
Prior art keywords
disease
syndrome
active ingredient
inhibitor
medicament
Prior art date
Application number
PCT/JP2019/025204
Other languages
French (fr)
Japanese (ja)
Inventor
龍佑 沈
直樹 外角
昭徳 西
Original Assignee
学校法人 久留米大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 学校法人 久留米大学 filed Critical 学校法人 久留米大学
Priority to JP2020527548A priority Critical patent/JP7290223B2/en
Publication of WO2020004404A1 publication Critical patent/WO2020004404A1/en

Links

Images

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • 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
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • 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
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • A61P37/08—Antiallergic agents
    • 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
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to an IL-1 ⁇ inhibitor, a medicament for treating a disease caused by IL-1 ⁇ , a medicinal composition for treatment, a treatment method, and the like, which comprise a low molecular compound as an active ingredient.
  • compositions containing low-molecular-weight compounds as active ingredients have a simpler manufacturing process than pharmaceutical products such as antibodies, can reduce drug costs, and can be orally administered as tablets, capsules, etc. It is. Therefore, at least the problems 2) and 4) of the above-mentioned biological preparation can be solved by using a low molecular weight compound as an active ingredient. Therefore, development of an IL-1 ⁇ inhibitor containing a low molecular weight compound as an active ingredient is required.
  • IL-1 ⁇ increases in peripheral blood and acts on IL-1 ⁇ receptor of cerebrovascular endothelial cells in the brain. It is considered that one of the causes is invasion of macrophages and inflammatory cytokines (Non-patent Document 3). Therefore, it is considered that an IL-1 ⁇ inhibitor can also be used as a therapeutic agent for depression.
  • Non-muscle Mlck is required for ⁇ -catenin- and FoxO1-dependent downregulation of Cldn5 in IL-1 ⁇ -mediated barrier dysfunction in brain endothelial cells, J Cell Sci. 2014 Apr 15; 127 (8): 1840-1853.
  • An object of the present invention is to provide an IL-1 ⁇ inhibitor, a medicament for treating a disease caused by IL-1 ⁇ , a pharmaceutical composition for treatment, a treatment method, and the like, which comprise a low molecular compound as an active ingredient.
  • a medicament for treating a disease caused by IL-1 ⁇ comprising 6-fluoro-3-[(1E) -2- (3-pyridinyl) ethenyl] -1H-indole as an active ingredient.
  • IL-1 ⁇ -induced diseases include familial Mediterranean fever, cryopyrin-associated periodic fever syndrome, NLRP12-associated periodic fever syndrome, IL-1 receptor antagonist deficiency, purulent aseptic arthritis, Majeed syndrome, Nakajo-Nishimura syndrome, CARD14 abnormality, juvenile-onset sarcoidosis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, Behcet's disease, Crohn's disease, gout / pseudogout, asbestosis / Silicosis, type 2 diabetes, Schnitzler syndrome, arteriosclerosis, stroke, depression, multiple sclerosis, Alzheimer's disease, rheumatic disease, malignancy, autoimmune disease, collagen disease, arteriosclerotic disease and allergic disease
  • the medicament according to [3] which is selected from the group consisting of:
  • FIG. 1 shows the effect of 680C91 on cytokine gene expression in Raw264.7 cells stimulated with LPS.
  • FIG. 2 shows the effect of 680C91 on cytokine gene expression in primary cultured macrophages from TDO wild type mice stimulated with LPS.
  • FIG. 3 shows the effect of 680C91 on cytokine gene expression of primary cultured macrophages from TDO gene deficient mice stimulated with LPS.
  • FIG. 4 shows the effect of 680C91 on weight loss in an inflammatory bowel disease model created by oral administration of dextran sodium sulfate (DSS).
  • FIG. 5 shows the effect of 680C91 on colon length shortening in an inflammatory bowel disease model created by oral administration of DSS.
  • FIG. 6 shows the effect of 680C91 on cytokine gene expression in colon tissue of an inflammatory bowel disease model created by oral administration of DSS.
  • FIG. 7 shows the effect of 680C91 on increasing the expression of IL-1 ⁇ protein in large intestine tissue of an inflammatory bowel disease model created by oral administration of DSS.
  • the present invention relates to an IL-1 ⁇ inhibitor comprising 6-fluoro-3-[(1E) -2- (3-pyridinyl) ethenyl] -1H-indole (680C91) as an active ingredient, and a disease caused by IL-1 ⁇ .
  • the present invention relates to a medicament for treatment, a pharmaceutical composition for treatment, a treatment method and the like.
  • the 680C91 has the following structural formula: Which is commercially available as a TDO inhibitor. 680C91 is known to have an antitumor effect. Hereinafter, 680C91 is also referred to as “the present compound”.
  • the compound may be a solvate, amorphous, crystal, polymorph, co-crystal or the like. Further, the present compound may be a compound in which one or more atoms are substituted with one or more isotope atoms. Examples of isotope atoms include deuterium ( 2 H), tritium ( 3 H), 13 C, 15 N, 18 O and the like.
  • the compound can suppress IL-1 ⁇ gene expression.
  • This IL-1 ⁇ inhibitory action is clearly different from the TDO inhibitory action. Therefore, the present invention provides an IL-1 ⁇ inhibitor comprising the present compound as an active ingredient.
  • the “IL-1 ⁇ inhibitor” in the present invention means an agent that suppresses gene expression of IL-1 ⁇ .
  • the present invention provides a medicament for treating a disease caused by IL-1 ⁇ , comprising the present compound as an active ingredient.
  • ⁇ disease caused by IL-1 ⁇ '' in the present invention a disease in which the involvement of IL-1 ⁇ is confirmed or indicated in the onset or progression, or a disease associated with overproduction of IL-1 ⁇ or abnormal activity expression
  • examples thereof include an autoinflammatory syndrome, a chronic inflammatory disease and the like (see YAKUGAKU ZASSHI 133 (6) 645-660 (2013) and the like). It is known that in these diseases, the pathology of hypercytokinemia (particularly hyperIL-1 ⁇ blood) can be observed.
  • Autoinflammatory syndromes include, for example, familial Mediterranean fever, cryopyrin-associated periodic fever syndrome, NLRP12-associated periodic fever syndrome, IL-1 receptor antagonist deficiency, purulent aseptic arthritis, Majeed syndrome, Nakajo-Nishimura Syndrome, CARD14 abnormality, juvenile-onset sarcoidosis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, Behcet's disease, Crohn's disease, gout / pseudogout, asbestosis / silicosis, type 2 Examples include diabetes, Schnitzler syndrome, arteriosclerosis, stroke, depression, multiple sclerosis, Alzheimer's disease, rheumatic diseases (rheumatoid arthritis, etc.).
  • various malignant tumors rectal cancer, colon cancer, renal cell carcinoma, non-small cell lung cancer, etc.
  • various autoimmune diseases glomerulonephritis, dilated cardiomyopathy, myocardium after infection with Cocksaki virus) Disease
  • collagen diseases scleroderma, etc.
  • various arteriosclerotic diseases arteriosclerotic diseases (atherosclerosis, etc.)
  • various allergic diseases allergic rhinitis, bronchitis, etc.
  • treatment includes prophylactic and therapeutic treatments, and includes any management measures such as prevention, treatment, alleviation of symptoms, reduction of symptoms, suppression of progression, and the like. .
  • the present invention also provides a method for treating a disease caused by IL-1 ⁇ , comprising administering an effective amount of the present compound to a subject.
  • the subject includes any mammal such as a human, monkey, dog, cat, rat, rat and the like.
  • the compounds may be administered systemically or locally.
  • the present compounds can be administered by oral administration, nasal administration, inhalation administration, intravenous injection (including infusion), subcutaneous injection, rectal administration, vaginal administration, transdermal administration, and the like.
  • the dose may vary depending on the type, age, body weight, symptom to be treated, desired therapeutic effect, administration route, treatment period and the like of the target mammal.
  • a satisfactory effect can be obtained by systemically or continuously administering an amount of 0.00001 to 500 mg / kg body weight per day, more preferably 0.0001 to 100 mg / kg body weight one to four times a day.
  • the pharmaceutical composition of the present invention may further contain a physiologically acceptable additive.
  • the additives include components used in combination with the present compound, and include, for example, excipients, diluents, extenders, solvents, lubricants, auxiliaries, binders, disintegrants, coating agents, encapsulating agents, ointments.
  • Base suppository base, aerosolizing agent, emulsifier, dispersing agent, suspending agent, thickener, isotonic agent, buffer, soothing agent, preservative, antioxidant, flavoring agent, fragrance
  • coloring agents include coloring agents, functional substances such as cyclodextrin, biodegradable polymers, and stabilizers.
  • the amount of the compound in the pharmaceutical composition of the present invention may vary depending on the formulation of the composition, and can generally be 0.000001 to 10.0%, more preferably 0.00001 to 5.0%, and most preferably 0.0001 to 1%.
  • Solid compositions for oral administration include tablets, troches, sublingual tablets, capsules, pills, powders, granules and the like.
  • Solid compositions may be prepared by mixing one or more active ingredients with at least one inert diluent.
  • the composition may further include additives other than the inert diluent, for example, lubricants, disintegrants and stabilizers.
  • Tablets and pills can be coated with enteric or gastrointestinal films, if necessary. Tablets and pills may be coated with two or more layers. They may be adsorbed on sustained release materials or may be microencapsulated.
  • the composition may be encapsulated with a readily degradable substance such as gelatin. They may be further dissolved in a suitable solvent such as a fatty acid or its mono-, di- or triglycerides to form soft capsules. If immediate action is required, sublingual tablets may be used.
  • liquid compositions for oral administration include emulsions, solutions, suspensions, syrups and elixirs.
  • the composition may further comprise a conventionally used inert diluent, for example, purified water or ethyl alcohol.
  • the compositions may also contain additives other than inert diluents, for example, adjuvants such as wetting or suspending agents, sweetening, flavoring, flavoring and preserving agents.
  • the pharmaceutical composition of the present invention may be in the form of a spray composition, which can be prepared according to a known method.
  • nasal formulations may be aqueous or oily solutions, suspensions, or emulsions.
  • the compositions may be in the form of a suspension, solution or emulsion capable of providing an aerosol, or in the form of a powder suitable for dry powder inhalation.
  • Compositions for administration by inhalation may additionally contain conventional propellants.
  • injectable compositions for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • Diluents for aqueous solutions or suspensions include, for example, distilled water for injection, saline and Ringer's solution.
  • Non-aqueous diluents for solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbates.
  • the composition may further include additives such as preservatives, wetting agents, emulsifiers, dispersants and the like.
  • compositions may be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating a sterilizing agent, or by gas or radioisotope irradiation sterilization.
  • injectable compositions may be presented as sterile powder compositions that are dissolved in a sterile vehicle for injection before use.
  • external preparations include all external preparations used in the fields of dermatology and otolaryngology, and include, for example, ointments, creams, lotions and sprays.
  • the present invention also provides the present compounds for use in inhibiting IL-1 ⁇ or for treating a disease caused by IL-1 ⁇ .
  • the present invention also provides the use of the present compound for producing an IL-1 ⁇ inhibitor or for producing a medicament or a pharmaceutical composition for treating a disease caused by IL-1 ⁇ .
  • the present invention provides a medicament or a pharmaceutical composition containing the present compound as an active ingredient, and the medicament or the pharmaceutical composition can be used for inhibiting IL-1 ⁇ , or treating a disease caused by IL-1 ⁇ .
  • Example 1 ⁇ Method ⁇ Raw264.7 cells were spread on a 35 mm culture plate, and the following day, the medium was replaced with a medium containing 680C91 (1, 10 ⁇ M). After 30 minutes, lipopolysaccharide (LPS; Lipopolysaccharide (from E. coli o26), Wako BioWindow (Osaka, 0.1 ⁇ g / ml was added to the medium. Five hours later, total RNA was collected from the cells, and the gene expression of inflammatory cytokines IL-1 ⁇ , IL-6, and TNF- ⁇ was measured by real-time PCR.
  • LPS lipopolysaccharide
  • Wako BioWindow Osaka, 0.1 ⁇ g / ml
  • cDNA was purified from total RNA using the QuantiTect Reverse Transcription Kit (Qiagen, Valencia, USA) and real-time PCR was performed using LightCycler 480 System II (Roche, Basel, Switzerland) and GeneAce SYBR qPCR MIX ⁇ No. This was performed using ROX (NIPPON GENE, Toyama, Japan).
  • Example 2 ⁇ Method ⁇ 680C91 target molecule TDO wild type mouse and gene-deficient mouse (male, 9-11 weeks old, Molecular Brain 2009, 2: 8 doi: 10.1186 / 1756-6606-2-8, prepared by the method described in Asahikawa Intraperitoneal macrophages were collected from each of the medical devices according to a standard method. After intraperitoneal administration of 4% thioglycolate, 3-4 days later, macrophages infiltrating into the intraperitoneal cavity were collected and spread on a culture plate, and then 680C91 (1, 10, 50 ⁇ M) and LPS were added in the same manner as in Example 1. Added to the medium. Five hours later, total RNA was recovered from the cells, and the gene expression of inflammatory cytokines IL-1 ⁇ , IL-6, and TNF- ⁇ was measured by real-time PCR as in Example 1.
  • Example 3 ⁇ Method ⁇ C57BL / 6N mice (male, 10 weeks old, Japan SLC, Inc.) were used for the test of ulcerative colitis model.
  • the mice were divided into a DSS + 680C91 group, a DSS group, and a control group (6 mice per group).
  • a DSS + 680C91 group and the DSS group 3% dextran sulfate sodium (hereinafter, referred to as DSS; molecular weight: 36.000 to 50.000, MP bio) was allowed to freely drink to prepare an ulcerative colitis model.
  • the control group was allowed to freely drink tap water.
  • DSS + 680C91 680C91 dissolved in a vehicle was subcutaneously injected at a dose of 8 mg / kg once a day for 8 days (day 8) from the first day of DSS drinking (day 1).
  • the vehicle was similarly administered to the DSS group and the control group.
  • the vehicle was prepared by dissolving 0.2% DMSO (dimethyl sulfoxide) and 40% PEG400 (polyethylene glycol 400) in physiological saline.
  • mice After the treatment period (day 8), the mice were weighed and then dissected, the large intestine was collected, and the length was measured. The change in body weight was evaluated as the ratio of the weight loss after administration to that before the start of DSS administration (weight after 8 days / body weight before administration ⁇ 100).
  • cDNA was collected from the collected large intestine and purified from total RNA using the QuantiTect Reverse Transcription Kit (Qiagen, Valencia, USA), and the inflammatory cytokines IL-1 ⁇ , IL-6, and TNF were used as in Example 1.
  • - ⁇ gene expression was measured by real-time PCR.
  • protein expression was measured by Western blotting.
  • Protein was extracted from the collected large intestine, subjected to polyacrylamide electrophoresis (SDS-PAGE), transferred to a Nitrocellulose membrane, and detected using an antibody against Pro IL-1 ⁇ (IL-1 ⁇ precursor). Note that ⁇ -actin was used as an internal standard.

Abstract

Provided are an IL-1β inhibitor, and a medicine, a pharmaceutical composition and a method each for treating a disease associated with IL-1β, and others, in each of which a low-molecular-weight compound is used as an active ingredient. The present invention relates to an IL-1β inhibitor containing 6-fluoro-3-[(1E)-2-(3-pyridinyl)ethenyl]-1H-indole as an active ingredient.

Description

ＩＬ－１β阻害薬IL-1β inhibitor
　本発明は、低分子化合物を有効成分とする、IL-1β阻害薬、IL-1βに起因する疾患の処置用医薬、処置用医薬組成物、処置方法等に関する。 The present invention relates to an IL-1β inhibitor, a medicament for treating a disease caused by IL-1β, a medicinal composition for treatment, a treatment method, and the like, which comprise a low molecular compound as an active ingredient.
　先天性の慢性自己免疫症候群の治療に、抗IL-1βモノクローナル抗体のカナキヌマブ（Canakinumab）や、IL-1分子結合部分をヒトIgG1のFc部分と結合させたキメラ蛋白のリロナセプト(Rilonacept)が、IL-1β阻害薬として使用されている。しかしながら、これらの生物学的製剤には、以下のような問題点がある（非特許文献１、２）：
　1) 感染症のリスクを高める可能性がある、
　2) 薬剤費が高い、
　3) 有効でない症例がある、
　4) 煩雑さがある（経口薬ではない、点滴に時間がかかる、自己注射への抵抗、指導・投薬・管理における医療側の負担も増）、
　5) 悪性腫瘍のリスクを高める可能性がある。 For the treatment of congenital chronic autoimmune syndrome, the anti-IL-1β monoclonal antibody canakinumab (Canakinumab) and the chimeric protein Rilonacept (Rilonacept), which binds the IL-1 molecule-binding portion to the Fc portion of human IgG1, have been developed by IL. It is used as a -1β inhibitor. However, these biologics have the following problems (Non-Patent Documents 1 and 2):
1) may increase the risk of infectious disease,
2) High drug cost,
3) Some cases are not valid,
4) There are complications (not oral drugs, it takes a long time for infusion, resistance to self-injection, and the medical burden on guidance, medication and management increases),
5) May increase the risk of malignancy.
　低分子化合物を有効成分とする医薬は、抗体等の生物学的製剤に比べて、製造工程が簡素であり、薬剤費を低く抑えることができ、また、錠剤、カプセル剤等として経口投与が可能である。したがって、低分子化合物を有効成分とすることで、少なくとも、上記生物学的製剤の問題点2)および4)を解消することができる。このため、低分子化合物を有効成分とするIL-1β阻害薬の開発が求められている。 Pharmaceuticals containing low-molecular-weight compounds as active ingredients have a simpler manufacturing process than pharmaceutical products such as antibodies, can reduce drug costs, and can be orally administered as tablets, capsules, etc. It is. Therefore, at least the problems 2) and 4) of the above-mentioned biological preparation can be solved by using a low molecular weight compound as an active ingredient. Therefore, development of an IL-1β inhibitor containing a low molecular weight compound as an active ingredient is required.
　また、炎症性うつ病は、末梢血でIL-1βが増加して、脳内血管内皮細胞のIL-1β受容体に作用することで、血液脳関門のバリヤー機能が破綻して、脳内にマクロファージや炎症性サイトカインが侵入することが原因の一つと考えられている（非特許文献３）。したがって、IL-1β阻害薬は、うつ病治療薬としても使用できると考えられる。 In addition, in inflammatory depression, IL-1β increases in peripheral blood and acts on IL-1β receptor of cerebrovascular endothelial cells in the brain. It is considered that one of the causes is invasion of macrophages and inflammatory cytokines (Non-patent Document 3). Therefore, it is considered that an IL-1β inhibitor can also be used as a therapeutic agent for depression.
　本発明は、低分子化合物を有効成分とする、IL-1β阻害薬、IL-1βに起因する疾患の処置用医薬、処置用医薬組成物、処置方法等を提供することを課題とする。 と す る An object of the present invention is to provide an IL-1β inhibitor, a medicament for treating a disease caused by IL-1β, a pharmaceutical composition for treatment, a treatment method, and the like, which comprise a low molecular compound as an active ingredient.
　本発明者らは、上記課題を解決するために鋭意検討した結果、トリプトファン-2,3-ジオキシゲナーゼ(TDO)の阻害剤として既知の6-フルオロ-3-[(1E)-2-(3-ピリジニル)エテニル]-1H-インドール(680C91)が、IL-1β産生を著しく低下させることを初めて見出し、本発明を完成させるに至った。
　本発明は、以下の態様を含む：
[１]　有効成分として6-フルオロ-3-[(1E)-2-(3-ピリジニル)エテニル]-1H-インドールを含む、IL-1β阻害薬。
[２]　有効成分として6-フルオロ-3-[(1E)-2-(3-ピリジニル)エテニル]-1H-インドールを含む、IL-1βに起因する疾患の処置用医薬。
[３]　IL-1βに起因する疾患が、自己炎症症候群および慢性炎症性疾患から選択される、[２]記載の医薬。
[４]　IL-1βに起因する疾患が、家族性地中海熱、クリオピリン関連周期熱症候群、NLRP12関連周期熱症候群、IL-1受容体アンタゴニスト欠損症、化膿性無菌性関節炎、マジード（Majeed）症候群、中条－西村症候群、CARD14異常症、若年発症サルコイドーシス、全身型若年性特発性関節炎、成人発症スティル（Still）病、ベーチェット（Behcet）病、クローン（Crohn）病、通風／偽痛風、石綿肺／珪肺、2型糖尿病、シュニッツラー（Schnitzler）症候群、動脈硬化症、脳卒中、うつ病、多発性硬化症、アルツハイマー病、リウマチ性疾患、悪性腫瘍、自己免疫疾患、膠原病、動脈硬化性疾患およびアレルギー疾患から選択される、[３]記載の医薬。 The present inventors have conducted intensive studies in order to solve the above-described problems, and as a result, as a tryptophan-2,3-dioxygenase (TDO) inhibitor, 6-fluoro-3-[(1E) -2- (3 -Pyridinyl) ethenyl] -1H-indole (680C91) was found for the first time to significantly reduce IL-1β production, leading to the completion of the present invention.
The invention includes the following aspects:
[1] An IL-1β inhibitor comprising 6-fluoro-3-[(1E) -2- (3-pyridinyl) ethenyl] -1H-indole as an active ingredient.
[2] A medicament for treating a disease caused by IL-1β, comprising 6-fluoro-3-[(1E) -2- (3-pyridinyl) ethenyl] -1H-indole as an active ingredient.
[3] The medicament according to [2], wherein the disease caused by IL-1β is selected from autoinflammatory syndrome and chronic inflammatory disease.
[4] IL-1β-induced diseases include familial Mediterranean fever, cryopyrin-associated periodic fever syndrome, NLRP12-associated periodic fever syndrome, IL-1 receptor antagonist deficiency, purulent aseptic arthritis, Majeed syndrome, Nakajo-Nishimura syndrome, CARD14 abnormality, juvenile-onset sarcoidosis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, Behcet's disease, Crohn's disease, gout / pseudogout, asbestosis / Silicosis, type 2 diabetes, Schnitzler syndrome, arteriosclerosis, stroke, depression, multiple sclerosis, Alzheimer's disease, rheumatic disease, malignancy, autoimmune disease, collagen disease, arteriosclerotic disease and allergic disease The medicament according to [3], which is selected from the group consisting of:
図１は、LPSで刺激したRaw264.7細胞のサイトカイン遺伝子発現に対する680C91の効果を示す。FIG. 1 shows the effect of 680C91 on cytokine gene expression in Raw264.7 cells stimulated with LPS. 図２は、LPSで刺激した、TDO野生型マウス由来の初代培養マクロファージのサイトカイン遺伝子発現に対する680C91の効果を示す。FIG. 2 shows the effect of 680C91 on cytokine gene expression in primary cultured macrophages from TDO wild type mice stimulated with LPS. 図３は、LPSで刺激した、TDO遺伝子欠損マウス由来の初代培養マクロファージのサイトカイン遺伝子発現に対する680C91の効果を示す。FIG. 3 shows the effect of 680C91 on cytokine gene expression of primary cultured macrophages from TDO gene deficient mice stimulated with LPS. 図４は、デキストラン硫酸ナトリウム（DSS）経口投与により作成した炎症性腸疾患モデルにおける体重減少に対する680C91の効果を示す。FIG. 4 shows the effect of 680C91 on weight loss in an inflammatory bowel disease model created by oral administration of dextran sodium sulfate (DSS). 図５は、DSS経口投与により作成した炎症性腸疾患モデルにおける大腸長短縮に対する680C91の効果を示す。（A）は、各処置群における大腸の長さの比較であり、（B）は、その大腸の長さを示すグラフ（B）である。FIG. 5 shows the effect of 680C91 on colon length shortening in an inflammatory bowel disease model created by oral administration of DSS. (A) is a comparison of the colon length in each treatment group, and (B) is a graph (B) showing the colon length. 図６は、DSS経口投与により作成した炎症性腸疾患モデルの大腸組織におけるサイトカイン遺伝子発現に対する680C91の効果を示す。FIG. 6 shows the effect of 680C91 on cytokine gene expression in colon tissue of an inflammatory bowel disease model created by oral administration of DSS. 図７は、DSS経口投与により作成した炎症性腸疾患モデルの大腸組織におけるIL-1βタンパク質発現上昇に対する680C91の効果を示す。FIG. 7 shows the effect of 680C91 on increasing the expression of IL-1β protein in large intestine tissue of an inflammatory bowel disease model created by oral administration of DSS.
　本発明は、6-フルオロ-3-[(1E)-2-(3-ピリジニル)エテニル]-1H-インドール(680C91)を有効成分とする、IL-1β阻害薬、IL-1βに起因する疾患の処置用医薬、処置用医薬組成物、処置方法等に関する。
　上記680C91は、以下の構造式：
Figure JPOXMLDOC01-appb-C000001
 で表される化合物であり、TDO阻害剤として市販されている。また、680C91は、抗腫瘍効果を有することが知られている。
　以下、680C91を「本化合物」とも称する。 The present invention relates to an IL-1β inhibitor comprising 6-fluoro-3-[(1E) -2- (3-pyridinyl) ethenyl] -1H-indole (680C91) as an active ingredient, and a disease caused by IL-1β. The present invention relates to a medicament for treatment, a pharmaceutical composition for treatment, a treatment method and the like.
The 680C91 has the following structural formula:
Figure JPOXMLDOC01-appb-C000001
 Which is commercially available as a TDO inhibitor. 680C91 is known to have an antitumor effect.
Hereinafter, 680C91 is also referred to as “the present compound”.
　本化合物は、溶媒和物、非晶質、結晶、結晶多形、共結晶等であってもよい。また、本化合物は、１つ又は複数の原子を１つ又は複数の同位体原子で置換された化合物であってもよい。同位体原子の例としては重水素（２Ｈ）、三重水素（３Ｈ）、１３Ｃ、１5Ｎ、１８Ｏ等が挙げられる。 The compound may be a solvate, amorphous, crystal, polymorph, co-crystal or the like. Further, the present compound may be a compound in which one or more atoms are substituted with one or more isotope atoms. Examples of isotope atoms include deuterium ( 2 H), tritium ( 3 H), 13 C, 15 N, 18 O and the like.
　本化合物は、IL-1βの遺伝子発現を抑制することができる。このIL-1β阻害作用は、TDO阻害作用とは明確に異なる作用である。
　したがって、本発明は、有効成分として本化合物を含むIL-1β阻害薬を提供する。本発明における「IL-1β阻害薬」は、IL-1βの遺伝子発現を抑制する薬剤を意味する。 The compound can suppress IL-1β gene expression. This IL-1β inhibitory action is clearly different from the TDO inhibitory action.
Therefore, the present invention provides an IL-1β inhibitor comprising the present compound as an active ingredient. The “IL-1β inhibitor” in the present invention means an agent that suppresses gene expression of IL-1β.
　また、本化合物は、IL-1β阻害作用を有するので、IL-1βに起因する疾患の処置に有用である。したがって、本発明は、有効成分として本化合物を含む、IL-1βに起因する疾患の処置用医薬を提供する。 本 In addition, since the present compound has an IL-1β inhibitory action, it is useful for treating a disease caused by IL-1β. Therefore, the present invention provides a medicament for treating a disease caused by IL-1β, comprising the present compound as an active ingredient.
　本発明における「IL-1βに起因する疾患」としては、発症または進行にIL-1βの関与が確認または指摘されている疾患や、IL-1βの過剰産生や異常活性発現を伴う疾患であれば特に限定されないが、例えば、自己炎症症候群、慢性炎症性疾患等が挙げられる（YAKUGAKU ZASSHI 133(6) 645-660 (2013)等参照）。これらの疾患では、高サイトカイン血症（特に高IL-1β血症）の病態が観察され得ることが知られている。
　自己炎症症候群としては、例えば、家族性地中海熱、クリオピリン関連周期熱症候群、NLRP12関連周期熱症候群、IL-1受容体アンタゴニスト欠損症、化膿性無菌性関節炎、マジード（Majeed）症候群、中条－西村症候群、CARD14異常症、若年発症サルコイドーシス、全身型若年性特発性関節炎、成人発症スティル（Still）病、ベーチェット（Behcet）病、クローン（Crohn）病、通風／偽痛風、石綿肺／珪肺、2型糖尿病、シュニッツラー（Schnitzler）症候群、動脈硬化症、脳卒中、うつ病、多発性硬化症、アルツハイマー病、リウマチ性疾患（関節リウマチ等）等が挙げられる。
　慢性炎症性疾患としては、例えば、各種悪性腫瘍（直腸癌、結腸癌、腎細胞癌、非小細胞肺癌等）、各種自己免疫疾患（糸球体腎炎，拡張型心筋症、コックサキーウイルス感染後心筋症等）、膠原病(強皮症等)、各種動脈硬化性疾患（アテローム性動脈硬化症等）、各種アレルギー疾患（アレルギー性鼻炎・気管支炎等）等が挙げられる。 As the `` disease caused by IL-1β '' in the present invention, a disease in which the involvement of IL-1β is confirmed or indicated in the onset or progression, or a disease associated with overproduction of IL-1β or abnormal activity expression Although not particularly limited, examples thereof include an autoinflammatory syndrome, a chronic inflammatory disease and the like (see YAKUGAKU ZASSHI 133 (6) 645-660 (2013) and the like). It is known that in these diseases, the pathology of hypercytokinemia (particularly hyperIL-1β blood) can be observed.
Autoinflammatory syndromes include, for example, familial Mediterranean fever, cryopyrin-associated periodic fever syndrome, NLRP12-associated periodic fever syndrome, IL-1 receptor antagonist deficiency, purulent aseptic arthritis, Majeed syndrome, Nakajo-Nishimura Syndrome, CARD14 abnormality, juvenile-onset sarcoidosis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, Behcet's disease, Crohn's disease, gout / pseudogout, asbestosis / silicosis, type 2 Examples include diabetes, Schnitzler syndrome, arteriosclerosis, stroke, depression, multiple sclerosis, Alzheimer's disease, rheumatic diseases (rheumatoid arthritis, etc.).
As chronic inflammatory diseases, for example, various malignant tumors (rectal cancer, colon cancer, renal cell carcinoma, non-small cell lung cancer, etc.), various autoimmune diseases (glomerulonephritis, dilated cardiomyopathy, myocardium after infection with Cocksaki virus) Disease), collagen diseases (scleroderma, etc.), various arteriosclerotic diseases (atherosclerosis, etc.), various allergic diseases (allergic rhinitis, bronchitis, etc.), and the like.
　本明細書における「処置」または「処置すること」なる用語は、予防的および治療的な処置を含み、予防、治療、症状の軽減、症状の減弱、進行の抑止等の任意の管理手段を含む。 As used herein, the term "treatment" or "treating" includes prophylactic and therapeutic treatments, and includes any management measures such as prevention, treatment, alleviation of symptoms, reduction of symptoms, suppression of progression, and the like. .
　本発明はまた、本化合物を対象に有効量投与することを含む、IL-1βに起因する疾患の処置方法を提供する。該対象としては、ヒト、サル、イヌ、ネコ、ラット、ネズミ等の任意の哺乳動物が挙げられる。 The present invention also provides a method for treating a disease caused by IL-1β, comprising administering an effective amount of the present compound to a subject. The subject includes any mammal such as a human, monkey, dog, cat, rat, rat and the like.
　本化合物は、全身にまたは局所的に投与されてよい。通常、本化合物は、経口投与、経鼻投与、吸入投与、静脈内注射（点滴を含む）、皮下注入、直腸内投与、膣内投与、経皮投与等によって投与され得る。 The compounds may be administered systemically or locally. Generally, the present compounds can be administered by oral administration, nasal administration, inhalation administration, intravenous injection (including infusion), subcutaneous injection, rectal administration, vaginal administration, transdermal administration, and the like.
　投与量は、対象となる哺乳動物の種類、年齢、体重、処置すべき症状、所望の治療効果、投与経路、処置期間等に応じて変化しうる。１日に0.00001～500mg/kg体重、より好ましくは0.0001～100mg/kg体重の量を、１日に1～4回全身投与または連続投与することにより、満足のいく効果を得ることができる。 The dose may vary depending on the type, age, body weight, symptom to be treated, desired therapeutic effect, administration route, treatment period and the like of the target mammal. A satisfactory effect can be obtained by systemically or continuously administering an amount of 0.00001 to 500 mg / kg body weight per day, more preferably 0.0001 to 100 mg / kg body weight one to four times a day.
　本化合物は、そのままで対象に投与することもできるが、従来法により投与に適した医薬組成物として製剤化するのが好ましい。該医薬組成物は、経口投与、経鼻投与、吸入投与、注射またはかん流に適したもの、ならびに外用剤、坐剤または腟坐剤でありうる。 The present compound can be administered to a subject as it is, but is preferably formulated into a pharmaceutical composition suitable for administration by a conventional method. The pharmaceutical compositions may be those suitable for oral, nasal, inhalation, injection or perfusion, as well as topical, suppository or vaginal suppositories.
　本発明の医薬組成物は、生理学的に許容しうる添加剤をさらに含んでいてもよい。該添加剤には本化合物と併用される成分が含まれ、例えば、賦形剤、希釈剤、増量剤、溶剤、潤滑剤、補助剤、結合剤、崩壊剤、被覆剤、カプセル化剤、軟膏基剤、坐薬用基剤、エアゾール化剤、乳化剤、分散剤、懸濁剤、増粘剤、等張化剤、緩衝剤、無痛化剤、防腐剤、抗酸化剤、矯味剤、芳香剤、着色剤、機能性物質、例えばシクロデキストリン、生分解性高分子、安定剤が挙げられる。これらの添加剤は当該技術分野で周知であり、製剤学に関する一般書籍に記載されているものから選択してよい。 医 薬 The pharmaceutical composition of the present invention may further contain a physiologically acceptable additive. The additives include components used in combination with the present compound, and include, for example, excipients, diluents, extenders, solvents, lubricants, auxiliaries, binders, disintegrants, coating agents, encapsulating agents, ointments. Base, suppository base, aerosolizing agent, emulsifier, dispersing agent, suspending agent, thickener, isotonic agent, buffer, soothing agent, preservative, antioxidant, flavoring agent, fragrance, Examples include coloring agents, functional substances such as cyclodextrin, biodegradable polymers, and stabilizers. These additives are well known in the art and may be selected from those described in general books on pharmaceuticals.
　本発明の医薬組成物における本化合物の量は、組成物の処方に応じて変化させてよく、一般に0.000001～10.0％、より好ましくは0.00001～5.0％、最も好ましくは0.0001～1％であり得る。 量 The amount of the compound in the pharmaceutical composition of the present invention may vary depending on the formulation of the composition, and can generally be 0.000001 to 10.0%, more preferably 0.00001 to 5.0%, and most preferably 0.0001 to 1%.
　経口投与のための固体組成物の例としては、錠剤、トローチ剤、舌下錠剤、カプセル剤、丸剤、散剤、顆粒剤等が挙げられる。固体組成物は１つ以上の活性成分と少なくとも１つの不活性希釈剤を混合して調製してもよい。組成物はさらに、不活性希釈剤以外の添加剤、例えば、潤滑剤、崩壊剤および安定剤を含んでよい。錠剤および丸剤は、必要であれば、腸溶性または胃腸溶性フィルムによって被覆してもよい。錠剤および丸剤は２つ以上の層によって被覆してもよい。それらは徐放性物質に吸着させても、またはマイクロカプセル化してもよい。さらに、該組成物は、ゼラチン等の易分解性物質を用いてカプセル化してもよい。それらは、脂肪酸またはそのモノ、ジもしくはトリグリセリドのような適切な溶媒にさらに溶解させて軟カプセルとしてもよい。即効性が必要な場合は舌下錠を用いてもよい。 固体 Examples of solid compositions for oral administration include tablets, troches, sublingual tablets, capsules, pills, powders, granules and the like. Solid compositions may be prepared by mixing one or more active ingredients with at least one inert diluent. The composition may further include additives other than the inert diluent, for example, lubricants, disintegrants and stabilizers. Tablets and pills can be coated with enteric or gastrointestinal films, if necessary. Tablets and pills may be coated with two or more layers. They may be adsorbed on sustained release materials or may be microencapsulated. Further, the composition may be encapsulated with a readily degradable substance such as gelatin. They may be further dissolved in a suitable solvent such as a fatty acid or its mono-, di- or triglycerides to form soft capsules. If immediate action is required, sublingual tablets may be used.
　経口投与のための液体組成物の例としては、乳剤、液剤、懸濁剤、シロップ剤およびエリキシル剤等が挙げられる。該組成物は、常套的に用いられる不活性希釈剤、例えば精製水またはエチルアルコールをさらに含んでもよい。組成物は、不活性希釈剤以外の添加剤、例えば湿潤剤や懸濁剤のような補助剤、甘味剤、香味剤、芳香剤および防腐剤を含んでいてもよい。 Examples of liquid compositions for oral administration include emulsions, solutions, suspensions, syrups and elixirs. The composition may further comprise a conventionally used inert diluent, for example, purified water or ethyl alcohol. The compositions may also contain additives other than inert diluents, for example, adjuvants such as wetting or suspending agents, sweetening, flavoring, flavoring and preserving agents.
　本発明の医薬組成物は、噴霧用組成物の形態であってもよく、これは公知の方法にしたがって調製し得る。 医 薬 The pharmaceutical composition of the present invention may be in the form of a spray composition, which can be prepared according to a known method.
　経鼻製剤の例は、水性もしくは油性の液剤、懸濁剤、または乳剤であってよい。
　本化合物を吸入により投与するため組成物は、エアロゾルを提供できる懸濁剤、液剤または乳剤の形態であるか、または、ドライパウダー吸入に適した散剤の形態でありうる。吸入投与用の組成物はさらに、慣用される噴霧剤を含んでいてよい。 Examples of nasal formulations may be aqueous or oily solutions, suspensions, or emulsions.
For administration of the compounds by inhalation, the compositions may be in the form of a suspension, solution or emulsion capable of providing an aerosol, or in the form of a powder suitable for dry powder inhalation. Compositions for administration by inhalation may additionally contain conventional propellants.
　非経口投与用の注射用組成物の例としては、滅菌した水性もしくは非水性液剤、懸濁剤および乳剤が挙げられる。水溶液剤または懸濁剤用の希釈剤としては、例えば、注射用蒸留水、生理食塩水およびリンゲル液が挙げられる。
　液剤および懸濁剤用の非水性希釈剤としては、例えば、プロピレングリコール、ポリエチレングリコール、オリーブ油のような植物油、エタノールのようなアルコールおよびポリソルベートが挙げられる。
　該組成物は、防腐剤、湿潤剤、乳化剤、分散剤等の添加剤をさらに含んでもよい。それらは、例えば細菌保留フィルターを通して濾過することによって、滅菌剤を配合することによって、またはガスもしくは放射性同位体照射滅菌によって滅菌してよい。
　注射用組成物は、使用前に注射用の滅菌溶媒に溶解させる滅菌粉末組成物として提供してもよい。 Examples of injectable compositions for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Diluents for aqueous solutions or suspensions include, for example, distilled water for injection, saline and Ringer's solution.
Non-aqueous diluents for solutions and suspensions include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbates.
The composition may further include additives such as preservatives, wetting agents, emulsifiers, dispersants and the like. They may be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating a sterilizing agent, or by gas or radioisotope irradiation sterilization.
Injectable compositions may be presented as sterile powder compositions that are dissolved in a sterile vehicle for injection before use.
　外用剤の例には、皮膚科学および耳鼻咽頭学の分野で用いられる全ての外用製剤が含まれ、例えば、軟膏剤、クリーム剤、ローション剤およびスプレー剤が挙げられる。 Examples of external preparations include all external preparations used in the fields of dermatology and otolaryngology, and include, for example, ointments, creams, lotions and sprays.
　本発明の医薬組成物の他の形態は、坐剤または膣坐剤であり、これらは、有効成分を慣用の基剤、例えば体温で軟化するカカオバターに混合することによって製剤でき、適度な軟化温度を有する非イオン性の界面活性剤は、吸収性を改善するのに用いうる。 Another form of the pharmaceutical composition of the present invention is a suppository or vaginal suppository, which can be formulated by mixing the active ingredient with a conventional base, such as cocoa butter, which softens at body temperature. Nonionic surfactants having a temperature can be used to improve absorption.
　また、本発明は、IL-1βの阻害に使用するための、またはIL-1βに起因する疾患の処置に使用するための、本化合物を提供する。 本 The present invention also provides the present compounds for use in inhibiting IL-1β or for treating a disease caused by IL-1β.
　本発明はまた、IL-1β阻害薬を製造するための、またはIL-1βに起因する疾患の処置用医薬もしくは医薬組成物を製造するための、本化合物の使用を提供する。 The present invention also provides the use of the present compound for producing an IL-1β inhibitor or for producing a medicament or a pharmaceutical composition for treating a disease caused by IL-1β.
　さらに、本発明は、有効成分として本化合物を含む医薬または医薬組成物、ならびに当該医薬または医薬組成物を、IL-1βの阻害に使用することができる、またはIL-1βに起因する疾患の処置に使用することができる、あるいは使用すべきであることを記載した当該医薬または医薬組成物に関する記載物を含む、商業パッケージを提供する。 Furthermore, the present invention provides a medicament or a pharmaceutical composition containing the present compound as an active ingredient, and the medicament or the pharmaceutical composition can be used for inhibiting IL-1β, or treating a disease caused by IL-1β. A commercial package containing a description of the medicament or pharmaceutical composition stating that it can or should be used.
　本発明のさらなる詳細は、以下の実施例を参照に記載するが、これは本発明の範囲を限定することを意図するものではない。 さ ら な る Further details of the present invention are described with reference to the following examples, which are not intended to limit the scope of the present invention.
実施例１
〔方法〕
　Raw264.7細胞を35mmの培養プレートに撒き、翌日に680C91(1、10μM)を含む培地に交換し、30分後にリポポリサッカリド（LPS; Lipopolysaccharide (from E.coli o26)、Wako BioWindow（大阪、日本）から購入）0.1 μg/mlを培地に添加した。5時間後に細胞からtotal RNAを回収し、炎症性サイトカインであるIL-1β、IL-6、TNF-αの遺伝子発現をリアルタイムPCR法で測定した。具体的には、cDNAを、QuantiTect Reverse Transcription Kit（Qiagen、バレンシア、アメリカ合衆国）を使用してtotal RNAから精製し、リアルタイムPCRを、LightCycler 480 System II（Roche、バーゼル、スイス国）とGeneAce SYBR qPCR MIXαNo ROX（NIPPON GENE、富山、日本）を用いて実行した。 Example 1
〔Method〕
Raw264.7 cells were spread on a 35 mm culture plate, and the following day, the medium was replaced with a medium containing 680C91 (1, 10 μM). After 30 minutes, lipopolysaccharide (LPS; Lipopolysaccharide (from E. coli o26), Wako BioWindow (Osaka, 0.1 μg / ml was added to the medium. Five hours later, total RNA was collected from the cells, and the gene expression of inflammatory cytokines IL-1β, IL-6, and TNF-α was measured by real-time PCR. Specifically, cDNA was purified from total RNA using the QuantiTect Reverse Transcription Kit (Qiagen, Valencia, USA) and real-time PCR was performed using LightCycler 480 System II (Roche, Basel, Switzerland) and GeneAce SYBR qPCR MIXαNo. This was performed using ROX (NIPPON GENE, Toyama, Japan).
〔結果〕
　その結果、680C91(10 μM)は、LPSにより誘導されるIL-1βの遺伝子発現を有意に抑制した（図１）。IL-6遺伝子の発現については抑制傾向を示したが、有意な差は認められなかった。また、TNFα遺伝子の発現は抑制されなかった。 〔result〕
As a result, 680C91 (10 μM) significantly suppressed IL-1β gene expression induced by LPS (FIG. 1). Although the expression of the IL-6 gene tended to be suppressed, no significant difference was observed. In addition, the expression of the TNFα gene was not suppressed.
実施例２
〔方法〕
　680C91の標的分子であるTDOの野生型マウスおよび遺伝子欠損マウス（雄、９-11週齢、Molecular Brain 2009, 2:8 doi:10.1186/1756-6606-2-8に記載の方法により作製、旭川医科大学 船越研究所より提供）から、それぞれに、常法に従って腹腔内マクロファージを採取した。4%チオグリコレートを腹腔内投与し、3～4日後に腹腔内に浸潤したマクロファージを回収し、培養プレートに撒き、次いで実施例１と同様に680C91(1、10、50 μM)とLPSを培地に添加した。5時間後に細胞からtotal RNAを回収し、実施例１と同様に炎症性サイトカインであるIL-1β、IL-6、TNF-αの遺伝子発現をリアルタイムPCR法で測定した。 Example 2
〔Method〕
680C91 target molecule TDO wild type mouse and gene-deficient mouse (male, 9-11 weeks old, Molecular Brain 2009, 2: 8 doi: 10.1186 / 1756-6606-2-8, prepared by the method described in Asahikawa Intraperitoneal macrophages were collected from each of the medical devices according to a standard method. After intraperitoneal administration of 4% thioglycolate, 3-4 days later, macrophages infiltrating into the intraperitoneal cavity were collected and spread on a culture plate, and then 680C91 (1, 10, 50 μM) and LPS were added in the same manner as in Example 1. Added to the medium. Five hours later, total RNA was recovered from the cells, and the gene expression of inflammatory cytokines IL-1β, IL-6, and TNF-α was measured by real-time PCR as in Example 1.
〔結果〕
　その結果、野生型マウスから採取した腹腔内マクロファージにおいて、680C91(50 μM)はIL-1βの遺伝子発現を顕著に抑制した（図２）。TDOの遺伝子欠損マウスから採取した腹腔内マクロファージにおいても、680C91(50 μM)はIL-1βの遺伝子発現を顕著に抑制した（図３）。TDOの遺伝子欠損マウスでも野生型マウスと同様の結果が示されたことから、680C91は、TDO抑制とは異なる機序によりIL-1β発現を抑制すると考えられた。 〔result〕
As a result, in intraperitoneal macrophages collected from wild-type mice, 680C91 (50 μM) significantly suppressed IL-1β gene expression (FIG. 2). 680C91 (50 μM) also markedly suppressed IL-1β gene expression in intraperitoneal macrophages collected from TDO gene-deficient mice (FIG. 3). Since the results similar to those of wild-type mice were shown in the TDO gene-deficient mice, 680C91 was considered to suppress IL-1β expression by a mechanism different from TDO suppression.
実施例３
〔方法〕
　C57BL/6Nマウス（雄、10週齢、日本エスエルシー株式会社）を潰瘍性大腸炎モデルの試験に用いた。マウスをDSS＋680C91群とDSS群とコントロール群に分けた（各群6匹）。DSS＋680C91群とDSS群には、3％デキストラン硫酸ナトリウム（以下、DSSと称する。分子量36.000～50.000、MPバイオ）を自由飲水させて潰瘍性大腸炎モデルを作成した。コントロール群には、水道水を自由飲水させた。また、DSS＋680C91群には、ビヒクル中に溶解させた680C91を8mg/kgの用量で1日1回、DSS飲水開始日（1日目）から8日間（8日目）皮下注射した。DSS群およびコントロール群には、ビヒクルを同様に投与した。なお、ビヒクルは生理食塩水中に0.2％DMSO（ジメチルスルホキシド）および40％PEG400（ポリエチレングリコール400）を溶解させて調製した。 Example 3
〔Method〕
C57BL / 6N mice (male, 10 weeks old, Japan SLC, Inc.) were used for the test of ulcerative colitis model. The mice were divided into a DSS + 680C91 group, a DSS group, and a control group (6 mice per group). For the DSS + 680C91 group and the DSS group, 3% dextran sulfate sodium (hereinafter, referred to as DSS; molecular weight: 36.000 to 50.000, MP bio) was allowed to freely drink to prepare an ulcerative colitis model. The control group was allowed to freely drink tap water. In the DSS + 680C91 group, 680C91 dissolved in a vehicle was subcutaneously injected at a dose of 8 mg / kg once a day for 8 days (day 8) from the first day of DSS drinking (day 1). The vehicle was similarly administered to the DSS group and the control group. The vehicle was prepared by dissolving 0.2% DMSO (dimethyl sulfoxide) and 40% PEG400 (polyethylene glycol 400) in physiological saline.
　処置期間終了後（8日目）、マウスの体重を測定後、解剖し、大腸を採取して、その長さを測定した。体重変化については、DSS投与開始前に対する投与後の体重減少の比（8日後の体重／投与前の体重×100）として評価した。
　また、採取した大腸からcDNAを、QuantiTect Reverse Transcription Kit（Qiagen、バレンシア、アメリカ合衆国）を使用してtotal RNAから精製し、実施例1と同様に炎症性サイトカインであるIL-1β、IL-6、TNF-αの遺伝子発現をリアルタイムPCR法で測定した。
　さらに、ウエスタンブロット法によりタンパク質発現を測定した。採取した大腸からタンパク質を抽出し、ポリアクリルアミド電気泳動（SDS-PAGE）を行い、Nitrocellulose膜に転写後、Pro IL-1β（IL-1β前駆体）に対する抗体を用いて検出した。なお、内部標準としてβ-アクチンを用いた。 After the treatment period (day 8), the mice were weighed and then dissected, the large intestine was collected, and the length was measured. The change in body weight was evaluated as the ratio of the weight loss after administration to that before the start of DSS administration (weight after 8 days / body weight before administration × 100).
In addition, cDNA was collected from the collected large intestine and purified from total RNA using the QuantiTect Reverse Transcription Kit (Qiagen, Valencia, USA), and the inflammatory cytokines IL-1β, IL-6, and TNF were used as in Example 1. -α gene expression was measured by real-time PCR.
Furthermore, protein expression was measured by Western blotting. Protein was extracted from the collected large intestine, subjected to polyacrylamide electrophoresis (SDS-PAGE), transferred to a Nitrocellulose membrane, and detected using an antibody against Pro IL-1β (IL-1β precursor). Note that β-actin was used as an internal standard.
〔結果〕
　その結果、DSSの摂取（DSS群）によりマウスの体重減少および大腸長の短縮がみられたが、680C91の投与（DSS＋680C91群）により体重減少および大腸長の短縮のいずれも有意に抑制された（図4、5）。
　また、PCR法によるmRNA測定の結果、コントロール群と比較して、DSS群ではIL-1β、IL-6およびTNFαの遺伝子発現は亢進したが、680C91の投与（DSS＋680C91群）によりいずれも改善された（図6）。
　さらに、ウエスタンブロット法によるタンパク質測定の結果、DSS群と比較して、DSS＋680C91群において、IL-1βタンパク質の産生が680C91によって顕著に抑制された（図7）。 〔result〕
As a result, ingestion of DSS (DSS group) reduced the body weight and shortened colon length of mice, but administration of 680C91 (DSS + 680C91 group) significantly suppressed both body weight loss and shortened colon length ( Figures 4 and 5).
As a result of mRNA measurement by PCR, gene expression of IL-1β, IL-6 and TNFα was enhanced in the DSS group compared to the control group, but all were improved by administration of 680C91 (DSS + 680C91 group) (Figure 6).
Furthermore, as a result of protein measurement by Western blotting, production of IL-1β protein was significantly suppressed by 680C91 in the DSS + 680C91 group as compared with the DSS group (FIG. 7).

Claims (4)

  1. 　有効成分として6-フルオロ-3-[(1E)-2-(3-ピリジニル)エテニル]-1H-インドールを含む、IL-1β阻害薬。 (4) An IL-1β inhibitor comprising 6-fluoro-3-[(1E) -2- (3-pyridinyl) ethenyl] -1H-indole as an active ingredient.
  2. 　有効成分として6-フルオロ-3-[(1E)-2-(3-ピリジニル)エテニル]-1H-インドールを含む、IL-1βに起因する疾患の処置用医薬。 (4) A medicament for treating a disease caused by IL-1β, comprising 6-fluoro-3-[(1E) -2- (3-pyridinyl) ethenyl] -1H-indole as an active ingredient.
  3. 　IL-1βに起因する疾患が、自己炎症症候群および慢性炎症性疾患から選択される、請求項２記載の医薬。 3. The medicament according to claim 2, wherein the disease caused by IL-1β is selected from autoinflammatory syndrome and chronic inflammatory disease.
  4. 　IL-1βに起因する疾患が、家族性地中海熱、クリオピリン関連周期熱症候群、NLRP12関連周期熱症候群、IL-1受容体アンタゴニスト欠損症、化膿性無菌性関節炎、マジード（Majeed）症候群、中条－西村症候群、CARD14異常症、若年発症サルコイドーシス、全身型若年性特発性関節炎、成人発症スティル（Still）病、ベーチェット（Behcet）病、クローン（Crohn）病、通風／偽痛風、石綿肺／珪肺、2型糖尿病、シュニッツラー（Schnitzler）症候群、動脈硬化症、脳卒中、うつ病、多発性硬化症、アルツハイマー病、リウマチ性疾患、悪性腫瘍、自己免疫疾患、膠原病、動脈硬化性疾患およびアレルギー疾患から選択される、請求項３記載の医薬。 IL-1β-induced diseases include familial Mediterranean fever, cryopyrin-associated periodic fever syndrome, NLRP12-associated periodic fever syndrome, IL-1 receptor antagonist deficiency, purulent aseptic arthritis, Majeed syndrome, Nakajo- Nishimura syndrome, CARD14 abnormality, juvenile-onset sarcoidosis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, Behcet's disease, Crohn's disease, gout / pseudogout, asbestosis / silicosis, 2 Selected from type diabetes, Schnitzler syndrome, arteriosclerosis, stroke, depression, multiple sclerosis, Alzheimer's disease, rheumatic disease, malignant tumor, autoimmune disease, collagen disease, atherosclerotic disease and allergic disease The medicament according to claim 3, wherein
PCT/JP2019/025204 2018-06-26 2019-06-25 IL-1β INHIBITOR WO2020004404A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2020527548A JP7290223B2 (en) 2018-06-26 2019-06-25 IL-1β inhibitor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2018121098 2018-06-26
JP2018-121098 2018-06-26

Publications (1)

Publication Number Publication Date
WO2020004404A1 true WO2020004404A1 (en) 2020-01-02

Family

ID=68986658

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2019/025204 WO2020004404A1 (en) 2018-06-26 2019-06-25 IL-1β INHIBITOR

Country Status (2)

Country Link
JP (1) JP7290223B2 (en)
WO (1) WO2020004404A1 (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021162650A1 (en) * 2020-02-12 2021-08-19 Istanbul Universitesi 5-fluoro/5-trifluoromethoxy-1h-indole-2,3-dione 3-(4-phenylthiosemicarbazone) derivatives as interleukin 1 (il-1) antagonists and anti-pyretic and/or anti-inflammatory agents for use in treating e.g. behçet's disease

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
BABAK, M. ET AL.: "Engagement of the aryl hydrocarbon receptor in M. tuberculosis-infected macrophages has pleiotropic effects on innate immune signaling", INFLAMMATION RESEARCH, vol. 64, no. 2, 2015, pages S188, XP055667965 *
BOSTIAN, A. ET AL.: "Aberrant activation of the kynurenine pathway in gliomas increases polymerase kappa expression and promotes genomic instability and chemoresistance", FASEB J, vol. 30, 2016, [retrieved on 20190821] *
BREDA, C. ET AL.: "Tryptophan-2, 3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites", PNAS, vol. 113, no. 19, 2016, pages 5435 - 5440, XP055667970 *
GIBNEY, S. M. ET AL.: "Inhibition of stress- induced hepatic tryptophan 2, 3-dioxygenase exhibits antidepressant activity in an animal model of depressive behavior", INT J NEUROPSYCHOPHARMACOL, vol. 17, no. 6, 2014, pages 917 - 928, XP055667967 *
HSU, Y. L. ET AL.: "Lung cancer-derived galectin-1 contributes to cancer associated fibroblast- mediated cancer progression and immune suppression through TD02/kynurenine axis", ONCOTARGET, vol. 7, no. 19, 2016, pages 27584 - 27598, XP055667975 *
REED, M. R. ET AL.: "Inhibition of kynurenine signaling decreases glioblastoma multiforme genomic instability and sensitizes cells to chemotherapeutic treatment", FASEB J, vol. 31, 2017, pages 754, [retrieved on 20190821] *
URAIA, Y. ET AL.: "IL -Ibeta increases expression of tryptophan 2,3-dioxygenase and stimulates tryptophan catabolism in endometrioma stromal cells", AM J REPROD IMMUNOL, vol. 72, no. 5, 2014, pages 496 - 503 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021162650A1 (en) * 2020-02-12 2021-08-19 Istanbul Universitesi 5-fluoro/5-trifluoromethoxy-1h-indole-2,3-dione 3-(4-phenylthiosemicarbazone) derivatives as interleukin 1 (il-1) antagonists and anti-pyretic and/or anti-inflammatory agents for use in treating e.g. behçet's disease

Also Published As

Publication number Publication date
JPWO2020004404A1 (en) 2021-07-08
JP7290223B2 (en) 2023-06-13

Similar Documents

Publication Publication Date Title
JP2019518071A (en) Compounds and compositions for treating conditions associated with NLRP activity
EP3672591B1 (en) Synergistic antitumor effect of bcl-2 inhibitor combined with rituximab and/or bendamustine or bcl-2 inhibitor combined with chop
CN107087409A (en) Benzoheterocyclic compounds and its application
WO2002036592A1 (en) Remedies for arachidonic acid-induced skin diseases
TWI821235B (en) Methods of treating generalized pustular psoriasis with an antagonist of ccr6 or cxcr2
Qi et al. Advances of CCR5 antagonists: From small molecules to macromolecules
KR102091464B1 (en) Composition for anti-inflammation
JP2022116304A (en) PPAR-γ AGONIST FOR TREATMENT OF BLOOD CANCERS
IL287470B1 (en) 6-METHYL-1,6-DIHYDRO-7H-PYRROLO[2,3-c]PYRIDIN-7-ONE DERIVATIVES OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF AND PHARMACEUTICAL COMPOSITIONS COMPRISING THEM
Wang et al. Trichinella spiralis—A potential anti-tumor agent
CN107530309A (en) Eutectic composition and its medicinal usage
BRPI0616659A2 (en) antituberculosis therapeutic drug, drug, and tuberculosis treatment kit
WO2021194991A1 (en) Use of losmapimod for treatment of covid-19
AU2022256212A1 (en) Glutarimide derivative for overcoming resistance to steriods
WO2014208354A1 (en) Pharmaceutical composition for treatment or prophylaxis of inflammatory diseases
WO2020004404A1 (en) IL-1β INHIBITOR
JP2021102624A (en) Treatment of cyr61- and vegf-mediated conditions
US20230114408A1 (en) Methods of modulating t-cell activation using estrogen receptor beta (erb) agonists
TW201000098A (en) Combination of a bisthiazolium salt or a precursor thereof and artemisinin or a derivative thereof for the treatment of severe malaria
WO2021256547A1 (en) Composition for treating, preventing, or alleviating sars-cov-2 infectious disease
JP2024504002A (en) how to treat cancer
JP2024500874A (en) how to treat cancer
JP2024500877A (en) how to treat cancer
WO2016117666A1 (en) Agent for killing hiv-1-infected cell and application thereof
CN107617101B (en) Zoledronic acid-containing and interleukin-containing medium pharmaceutical combination of element 2 and application thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19827466

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2020527548

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19827466

Country of ref document: EP

Kind code of ref document: A1