WO2017065495A2 - Composition utilisable en vue du traitement de la maladie intestinale inflammatoire et de la dermatite atopique - Google Patents

Composition utilisable en vue du traitement de la maladie intestinale inflammatoire et de la dermatite atopique Download PDF

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WO2017065495A2
WO2017065495A2 PCT/KR2016/011434 KR2016011434W WO2017065495A2 WO 2017065495 A2 WO2017065495 A2 WO 2017065495A2 KR 2016011434 W KR2016011434 W KR 2016011434W WO 2017065495 A2 WO2017065495 A2 WO 2017065495A2
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compound
atopic dermatitis
ips
ncs
active ingredient
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WO2017065495A3 (fr
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강인철
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주식회사 이노파마스크린
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Priority claimed from KR1020160131313A external-priority patent/KR101949451B1/ko
Application filed by 주식회사 이노파마스크린 filed Critical 주식회사 이노파마스크린
Priority to CN201680059836.6A priority Critical patent/CN108137490B/zh
Priority to JP2018519833A priority patent/JP6885607B2/ja
Priority to US15/768,374 priority patent/US10278931B2/en
Priority to EP16855712.2A priority patent/EP3363783B1/fr
Publication of WO2017065495A2 publication Critical patent/WO2017065495A2/fr
Publication of WO2017065495A3 publication Critical patent/WO2017065495A3/fr
Priority to HK18113385.6A priority patent/HK1254242A1/zh

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/43—Guanidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/46—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing sulfur
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
    • C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C233/06—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/20—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups containing any of the groups, X being a hetero atom, Y being any atom, e.g. acylguanidines
    • C07C279/24—Y being a hetero atom
    • C07C279/26—X and Y being nitrogen atoms, i.e. biguanides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/21—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring

Definitions

  • the present invention relates to a compound that inhibits the release of TSLP (Thymic Stromal Lymphopoietin) from mast cells, and the use of the compound for the treatment of inflammatory bowel disease and atopic dermatitis.
  • TSLP Thimic Stromal Lymphopoietin
  • Allergy is a phenomenon in which a living organism that is in contact with a foreign substance exhibits a different reaction from the normal. When an organism comes into contact with a foreign substance, it is suddenly caused by an antigen-antibody reaction. Changes in the ability to respond occur, called allergies. The living body produces antibodies and lymphocytes that specifically react to antigens of heterologous substances, and when they come into contact with antigens again, various immune reactions occur. This immune response or immune response is one of the important defense mechanisms for self-preservation of the living body, which usually acts protectively against the living body, but sometimes this mechanism adversely affects the living body and causes disorder. Allergy means "hypersensitivity" and the Greek word allos is from etymology, meaning "transformed”.
  • allergens that cause allergic reactions are called allergens.
  • Typical allergens include pollen, drugs, vegetable fibers, bacteria, food, dyes, and chemicals.
  • lymphocytes which are specialized for responding to specific antigens, such as B and T cells.
  • B cells produce antibodies, which are proteins that bind to and destroy antigens.
  • T cells stimulate direct attack by binding directly to antigens instead of producing antibodies. Allergic reactions are manifested as immediate or delayed allergy, depending on whether the antigen reacts with B or T cells.
  • Allergic diseases include various diseases including autoimmune diseases and collagen diseases, but in general, allergic diseases include anaphylactic shock, food allergy, allergic rhinitis, hay fever, and bronchial asthma. Drug allergies, plant allergies, urticaria, eczema, and allergic contact dermatitis. Although these are allergic diseases, the onset of the disease may require other biological conditions. The same symptoms may also be caused by non-allergic mechanisms.
  • Atopic dermatitis is a chronic, recurring inflammatory skin disease that usually begins in infancy or childhood, accompanied by pruritus (itch), dry skin, and characteristic eczema. In infancy, it begins with eczema on the flanks of the face and limbs, but as it grows, it is characteristic of eczema on the bends of the arms and behind the knees, and in many cases it tends to improve naturally as it grows. . In adults, the skin becomes thicker in lichenification when the skin is folded, and eczema is more common on the face than in infants. Atopic dermatitis is on the rise worldwide, with a prevalence rate of 20% of the population.
  • This phenomenon has limitations such as the current treatments, and the temporary improvement effect such as allergy disease is amplified by various other routes.
  • atopic dermatitis is a method of treating pruritus and restoring the damaged skin surface. Most of the side effects are recognized as immunosuppressants or steroids.
  • IBD Inflammatory bowel disease
  • ulcerative colitis ulcerative colitis
  • Crohn's disease Activation is known to be an important etiology. Sustained or improper activation of the immune system plays an important role in the pathophysiology of chronic mucosal inflammation.
  • Infiltrated and activated neutrophils are an important cause of reactive nitric oxide species, which are cytotoxic substances that induce cellular oxidative stress by cross-linking proteins, lipids and nucleic acids and lead to epithelial dysfunction and damage.
  • Inflammatory diseases result in the release of various inflammatory cytokines from the intestinal mucosa.
  • TNF- ⁇ is highly expressed in colon lumen and colon epithelial cells of ulcerative colitis patients, and recent studies have shown that TNF- ⁇ plays an important role in the pathogenesis of ulcerative colitis.
  • Infliximab an anti-TNF- ⁇ antibody, is known to be effective not only in the treatment of boils, but also in the treatment of Crohn's disease.
  • these therapies are costly and in some patients cause side effects such as fluid response or infectious complications.
  • 5-aminosalicylic acid 5-ASA
  • sulfasalazine sulfasalazine
  • steroidal immunosuppressants for example, sulfasalazine, or steroidal immunosuppressants.
  • Sulfasalazine is prone to side effects or adverse effects, such as fullness, headache, rash, liver disease, leukopenia, agranulocytosis, male infertility, and the like. It is also unclear whether sulfasalazine has a sufficient relapse inhibitory effect in patients with incisions in the intestine or in patients with remission.
  • Steroid immunosuppressants are adrenal corticosteroids, which have been recognized for their short-term effects, but cannot improve their long-term prognosis, induced infectious diseases, secondary corticosteroids, peptic ulcers, diabetes, mental disorders, steroidal kidney disease, etc. There are limitations that should be used only in acute cases in terms of the same side effects.
  • the present invention solves the above problems and the object of the present invention is to provide a novel allergic atopic dermatitis candidates.
  • Another object of the present invention is to provide a novel candidate for treating inflammatory bowel disease.
  • the present invention provides one compound or a pharmaceutically acceptable salt thereof selected from the compounds of Formulas 1 to 4 below.
  • the compound preferably inhibits TSLP (Thymic Stromal Lymphopoietin) secretion from mast cells, but is not limited thereto.
  • TSLP Thimic Stromal Lymphopoietin
  • the compound preferably has an effect on atopic dermatitis, but is not limited thereto.
  • the compound preferably has an effect on inflammatory bowel disease, but is not limited thereto.
  • Pharmaceutically acceptable salts of the invention include salts derived from inorganic bases such as Li, Na, K, Ca, Mg, Fe, Cu, Zn, Mn; Salts of organic bases such as N, N'-diacetylethylenediamine, glucamine, triethylamine, chlorine, hydroxide, dicyclohexylamine, metformin, benzylamine, trialkylamine, thiamine, and equivalents thereof; Chiral bases such as alkylphenylamine, glycinol, phenyl glycinol and their equivalents, glycine, alanine, varine, leucine, isoleucine, norleucine, tyrosine, cystine, cysteine, methiotin, proline, hydroxyproline, Natural amino acid salts such as histidine, omitin, lysine, arginine, serine, and equivalents thereof; Quaternary ammonium salts of the compounds of the present invention with
  • Salts may include salts with acid added, and suitable ones include sulfates, nitrates, phosphates, perchlorates, borates, hydrohalides, acetates, tartrates, maleates, citrates, fumarates, succinates, palmoates, Methanesulfonate, benzoate, salicylate, benzenesulfonate, ascorbate, glycerophosphate, ketoglutarate and equivalents thereof.
  • Pharmaceutically acceptable solvates include crystallization solvents such as hydroxides or alcohols.
  • the present invention also provides a pharmaceutical composition for preventing and treating atopic dermatitis, comprising the compound of the present invention as an active ingredient.
  • the present invention provides a pharmaceutical composition for allergy and treatment comprising the compound of the present invention as an active ingredient.
  • the present invention provides a pharmaceutical composition for treating inflammatory bowel disease comprising the compound of the present invention as an active ingredient.
  • Single unit dosage forms of the invention may be administered orally to a patient, mucosal (eg, nasal, sublingual, vaginal, oral, or rectal), parenteral (eg subcutaneous, intravenous, bolus injection, intramuscular). , Intraarterial) or transdermal administration.
  • mucosal eg, nasal, sublingual, vaginal, oral, or rectal
  • parenteral eg subcutaneous, intravenous, bolus injection, intramuscular.
  • Intraarterial intradermal administration.
  • dosage formulations include, but are not limited to, the examples listed below, tablets; caplets (caffeine); capsules such as soft elastic gelatin capsules; cassettes; troches; lozenges (lozenges); dispersions; suppositories; Ointments; poultices (papants); pastes; powders; dressings; creams; gypsum; solutions; adherents; sprays (eg nasal sprays or inhalers); gels; suspensions (eg aqueous or non-aqueous liquid suspensions)
  • Liquid dosage forms suitable for oral or mucosal administration of a patient including tangible oilin-water emulsions, or water-in-oil liquid emulsions, solutions, and elixirs; Liquid dosage forms suitable for administration; sterile solids which can be processed into liquid and dosage forms suitable for parenteral administration in patients and patients. (Eg, crystalline, amorphous solids).
  • compositions, shape, and type of dosage forms of the invention will typically vary depending on their use.
  • dosage forms suitable for mucosal administration may comprise smaller amounts of active ingredient than dosage forms suitable for oral administration used to treat the same disease.
  • This aspect of the invention will be quite apparent to those skilled in the art. (Remington's Pharmaceutical Sciences (1990) 18th ed., Mack Publishing, Easton PA.)
  • Typical pharmaceutical compositions and dosage forms comprise one or more excipients.
  • Suitable excipients will be apparent to those skilled in the pharmaceutical arts and the suitable excipient examples described in the present invention are not limited in this respect.
  • Whether or not a particular excipient is suitable for use in a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including but not limited to, methods of dosage form to be administered to a patient.
  • Oral dosage forms such as, for example, tablets, may contain excipients that are not suitable for use in parenteral dosage forms.
  • the suitability of a particular excipient may also depend on the specific active ingredient of the dosage form. For example, degradation of certain active ingredients can be accelerated by excipients such as lactose or when exposed to aqueous solutions. Active ingredients comprising primary or secondary amines (eg N-desmethylvenlafaxine and N, N-didesmethylvenlafaxine) are particularly sensitive to such accelerated degradation.
  • active ingredients comprising primary or secondary amines (eg N-desmethylvenlafaxine and N, N-didesmethylvenlafaxine) are particularly sensitive to such accelerated degradation.
  • the present invention also provides pharmaceutical compositions and dosage forms comprising one or more compounds that reduce the rate at which the active ingredient degrades.
  • Such compounds include, but are not limited to, the following examples, including antioxidants such as ascorbic acid, pH buffers, salt buffers.
  • the amount and type of active ingredient in the dosage form will vary depending on factors such as but not limited to the examples below.
  • typical dosage forms of the present invention include a compound of the present invention in an amount of about 1 mg to about 1000 mg, preferably from about 50 mg to about 500 mg, most preferably from about 75 mg to about 350 mg, or a pharmaceutically acceptable salt thereof. do. Determination of dosage or dosage formulation appropriate for a particular patient is within the skill of the art.
  • the present invention also provides a cosmetic composition for improving and alleviating atopic dermatitis comprising the compound of the present invention as an active ingredient.
  • the present invention provides a cosmetic composition for allergy and alleviation comprising the compound of the present invention as an active ingredient.
  • Cosmetic compositions of the present invention can be prepared in a variety of forms, including emulsions, lotions, creams (oil-in-water, water-in-oil, multiphase), solutions, suspensions (anhydrous and water-based), anhydrous products (oils and glycols) ), Gels, masks, packs, powders, and the like.
  • the present invention provides a food composition for improving and alleviating atopic dermatitis comprising the compound of the present invention as an active ingredient.
  • the present invention provides a food composition for allergy and alleviation comprising the compound of the present invention as an active ingredient.
  • the compounds of the present invention was found to significantly inhibit TSLP secretion from mast cells, and thus candidates for treatment and prevention of atopic dermatitis and / or allergic dermatitis and inflammatory bowel disease. There is an effect that can be used as a substance.
  • HMC-1 Cell human mast cells
  • HMC-1 cell human mast cells
  • FIG. 4 TSLP measurement and mRNA expression in human mast cells (HMC-1 cell) by IPS-07001 (5182436). 1) TSLP volume measurement by IPS-07001. 2) measuring mRNA expression by IPS-07001,
  • FIG. 5 activity in human mast cells (HMC-1 cells) by IPS-07001 (5182436) 1) measuring the caspas-1 activity efficacy of IPS-07001. 2) changes in activity caspase-1 expression of IPS-07001 by western blot,
  • Figure 6 shows the measurement of caspase-1 activity inhibition by IPS-07001 (# 5182436)
  • Figure 13 is the histological characteristics of the dorsal skin stained with H & E. 1) Determination of epidermal thickness values 2) balb / c mice (epidermal depth) with DNCB-induced atopic dermatitis (## p ⁇ 0.01 normal control vs DNCB; * p ⁇ 0.01 DNCB vs 0.01, 0.1, 1 uM treated) , ** p ⁇ 0.01 DNCB vs 0.01, 0.1, 1 uM respectively),
  • Figure 15 shows IgE measurements in serum of AD balb / c mice induced by DNCB (## p ⁇ 0.01 normal control vs DNCB; * p ⁇ 0.01 DNCB vs 0.01, 0.1, 1 uM treated, ** p ⁇ 0.01 DNCB vs 0.01, 0.1, 1 uM respectively),
  • Control is a skin tissue sample treated with 1% DNCB only.
  • IPS-07001 is a skin tissue sample treated with 1% DNCB and 1 ⁇ M IPS-07001.
  • red color means increased expression
  • green color means reduced expression
  • INR results above 1.1 indicate increased expression, below 0.9 indicate decreased expression,
  • Figure 23 shows the inhibitory effect of IPS-07001 (Formula 1) and IPS-07004 (Formula 4) on human recombinant caspase-1 activity
  • FIG. 28 shows the inhibitory effect of IPS-07004 (Formula 4) on diarrhea scores in DSS-induced animal models.
  • Protein preparation The initial structure of the target protein was used as the structure of Protein Data Bank (PDB) Caspase-1 (PDB id 2HBQ), and the modeling software was used to compensate for the missing hydrogen atoms and to prepare non-crystal water molecules. By removing, we completed the molecular model of the target protein. The completed protein model was used for simulation after stabilizing through energy minimization.
  • PDB Protein Data Bank
  • Caspase-1 PDB id 2HBQ
  • Receptor Grid generation docking site is limited to 30 boxes near 3- [2- (2-benzyloxycarbonylamino-3-methyl-butyrylamino) -propionylamino] -4-oxo-pentanoic acid (z-VAD-FMK) binding site
  • the software used for the calculation is Schrodinger's Glide program. Glide's own function was used as the scoring function, and the Glide Score for the final result was obtained.
  • Ligand docking Up to 10 docked poses were calculated for each ligand compound, and the output files were obtained by deriving the results in the order of high score. The structure search was performed in Glide-SP mode, and the results of the compounds were calculated in the order of highest final score corrected by Docking calculation.
  • Example 2 allergy Of active ingredients in in vitro models of atopic dermatitis Atopic Factors Regulatory Efficacy Study
  • HMC-1 Human mast cell line
  • Enzyme Immunoassay After stabilizing mast cells (3 ⁇ 10 6 cells / ml) for 1 hour, candidates were treated with 0.1, 1, 10 ⁇ M concentrations, and then treated with PMACI for 8 hours. Centrifugation was performed to obtain supernatant. Enzyme immunoassay was used to measure the amount of TSLP secreted from the cells. Enzyme immunoassay was performed on 96-well plates coated with 1 ⁇ g / well TSLP capture Ab. Wipe the coated plates twice with PBS. Treat for 2 hours with PBS containing 10% FBS. Thereafter, PBS washed with 0.05% Tween-20 (Sigma) and a recombinant TSLP were used to draw a standard curve. The plates were then exposed to an ABTS substrate containing biotinylated-TSLP antibody, Avidin peroxidase, solution 30% H2O2 and measured at 405 nm.
  • ELISA Enzyme Immunoassay
  • RT-PCR reverse transcription-polymerase chain reaction
  • mice Male BALB / c mice, 5 weeks old, were supplied from Daehan Biolink (negative Chungbuk), temperature 22 ⁇ 3 °C, relative humidity 50 ⁇ 20%, ventilation frequency 10-15 times / hour, lighting 12 hours, illumination 150 It was used for experiment after adapting for 2 weeks in clean animal breeding room (small animal room 2-302) of Hoseo University safety evaluation center set at ⁇ 300 Lux.
  • Daehan Biolink negative Chungbuk
  • temperature 22 ⁇ 3 °C relative humidity 50 ⁇ 20%
  • ventilation frequency 10-15 times / hour lighting 12 hours
  • illumination 150 It was used for experiment after adapting for 2 weeks in clean animal breeding room (small animal room 2-302) of Hoseo University safety evaluation center set at ⁇ 300 Lux.
  • the experimental animals were housed in four polycarbonate breeding boxes (270 ⁇ 500 ⁇ 200 mm, Gyeryong Science). Feed (5053-Picolab Rodent 20, PMI Nutrition International) and negative water (ultraviolet sterilized filtered water) were taken freely. All procedures were performed with the approval of the Ethics Committee of Hoseo University Safety Evaluation Center (HTRC-15-19).
  • DNCB 2,4-Dinitrochlorobenzene
  • mice were divided into 6 groups and 0.5% DMSO was applied to the control animals, and 200 ⁇ l of test substance 0.01, 0.1, and 1 uM were applied to the animals of the test group for 3 weeks every day. Animals of the positive control group were applied with 50 ul of 0.1% Dexamethasone dissolved in stock alcohol at 2 days intervals.
  • Test group Test substance Number of animals Treatment concentration Group 1 Control (0.5% DMSO) 6 0 Group 2 DNCB 6 0 Group 3 DNCB + Dexamethasone 6 0.1% 4th group DNCB + Test Substance 6 0.01 uM 5 groups DNCB + Test Substance 6 0.1 uM 6 groups DNCB + Test Substance 6 1 uM
  • IgE level measurement Plasma Ig E concentration was measured using plasma collected at necropsy (SHIBAYAGI, Japan). After the reaction was carried out for 2 hours, 50 ⁇ L of IgE standard solution and sample were added to the 96 well to which the antibody was attached. After 1 hour of HRP-avidin solution and 20 minutes of chromogenic substrare (TBM) reagent, the reaction was stopped using a reaction stopper. Absorbance was measured at 450 nm using ELISA (Molecular devices Emax).
  • Feed and negative water The feed was freely fed PMI Nutrition International's rat animal feed (5053-Picolab Rodent 20), and the negative water was freely supplied with UV sterilized filtered water (R / O water).
  • Test group Test substance castle Animal number (two heads) Dosage ( ⁇ M / kg / 4ml bw) Group 1 IPS-07001 cock 1101-1105 (5) 0 female 2101-2105 (5) Group 2 cock 1206-1210 (5) 200 female 2206-2210 (5)
  • Transdermal administration was chosen at the request of the sponsor. Number of doses : 1 time / day, 24 hours after single dose Dose calculation : Dosage per dose (mg / kg) was calculated based on body weight on the day of administration.
  • test substance was sufficiently wetted with solvent, and then the test substance was applied to the range of about 10% (about 44 cm) of the total surface area.
  • test substance was maintained in contact with the skin using porous gauze, non-irritating tape and bandages during the 24-hour exposure period.
  • Tissue Sample Preparation Mouse skin tissue was frozen in liquid nitrogen and finely ground in a mortar and pestle. Medium medium liquid nitrogen was added to prevent the tissue from melting. Finely divided skin tissue was placed in lysis M buffer to make tissue sample lysate.
  • Fluorescent labeling of tissue lysate The protein is extracted from the treated tissue lysate and the untreated tissue lysate (Lysis M Extract Solution, Roche) for a period of time and labeled with fluorescent material (Cy3 or Cy5) (GE health care). First, adjust the amount of protein in each tissue lysate to at least 1mg, and then mix well by adding a coupling buffer (0.1M sodium carbonate buffer, pH9.3). Add Cy3 and Cy5 dye to each tissue lysate with coupling buffer, mix well, and label at 4 ° C for at least 16 hours. The control group was treated with only DNCB and labeled with Cy3 and Cy5, and the experimental group treated with the sample was also labeled with Cy3 and Cy5. After dyeing with a fluorescent die, free dye was removed using a Post-reactive Spin column (Sigma).
  • ProteoChip TM Proteogen, Inc., Seoul, Korea was used as a protein chip and spotted antibodies against 26 intracellular proteins on a substrate on which Protein A 200 ⁇ g / ml was immobilized on ProteoChip TM .
  • the antibodies are first diluted to 100 ⁇ g / ml with phosphate buffer containing 30% glycerol and the antibody array is fixed at 4 ° C. overnight.
  • the antibody chip is washed three times with PBST and blocked with 3% BSA at room temperature for 1 hour in a stirrer.
  • the chip is washed with PBST solution (phosphate buffer containing 0.05% Tween 20) to remove excess BSA after blocking and dried with N2 gas.
  • PBST solution phosphate buffer containing 0.05% Tween 20
  • Hybridization of Antibody Arrays Tissue lysates labeled with fluorescent material were quantified (Brad ford method), and each fluorescently labeled sample was mixed in 30 ml of 10 ml reaction solution. The antibody chip is immersed in a buffer containing a fluorescently labeled sample and reacted at 30 ° C. for 1 hour. After the reaction, the antibody chip was washed twice with PBST solution and dried with nitrogen gas. Each slide was analyzed using a fluorescence microarray scanner. The PMT value was scanned so that the main peak of Cy3 and Cy5 was about 10000. The ratio of Cy5 to Cy3 at each spot is calculated using software (Genepix 6.0).
  • the INR value was calculated as sample-Cy5 / control-Cy3 * sample-Cy3 / control-Cy5. If there is no difference in expression, the ideal INR value is 1, a value of 1 or more means an increase in expression, a value of 1 or less means a decrease in expression.
  • TSLP a causative agent of atopic dermatitis.
  • PKC activator PMA and calcium ionophore A23187 (PMACI) are stimulated with PKC activator PMA and calcium ionophore A23187 (PMACI). From the stimulated mast cells, TSLP secretion was found to be significantly increased compared to the non-stimulated cells (Blank), and the efficacy of various candidates was searched. As a result, it was confirmed that 5182436, 5211084, and 5356744 substances significantly inhibit TSLP secretion from mast cells (FIG. 2).
  • MTT-assay was carried out to confirm the cytotoxicity of the effective substances, and showed no cytotoxicity at 10 ⁇ M of IPS-07002 (5211084) and IPS-07003 (5356744). However, it was confirmed that the cytotoxicity appeared at 10 ⁇ M of IPS-07001 (5182436). IPS-07001 (5182436) was not cytotoxic up to 1 ⁇ M as a result of repeated experiments at various concentrations (Fig. 3).
  • IPS-07001 was repeated to control the production of TSLP in a non-toxic concentration. It was found that IPS-07001 significantly regulates TSLP production at 0.011 ⁇ M. IPS-07001 also significantly inhibited TSLP mRNA expression (FIG. 4).
  • IPS-07001 was found to significantly inhibit caspase-1 activity in a concentration-dependent manner (Fig. 6).
  • IPS-07001 (# 5182436) significantly inhibited the production of various inflammatory cytokine and mRNA expression (FIG. 7).
  • Histamine, IL-4, and IgE levels were measured in DNCB-coated balb / c mice serum. It was confirmed that serum histamine, IL-4, and IgE levels were significantly regulated at IPS-07001 (# 5182436) 0.011 ⁇ M concentration (FIG. 8).
  • caspase-1 assay was performed with dorsal skin of DNCB-coated balb / c mice to investigate the regulatory effect of IPS-07001 (# 5182436) on caspase-1 activity.
  • IPS-07001 (# 5182436) was found to significantly inhibit caspase-1 activity in a concentration-dependent manner (Fig. 9).
  • Inflammatory cytokine levels were analyzed in dorsal skin of DNCB-coated balb / c mice. It was confirmed that IL-4 and IL-6 levels were significantly regulated at IPS-07001 (# 5182436) 0.011 ⁇ M concentration (FIG. 10).
  • IPS-07001 (# 5182436) regulates TARC, TNF-a, and IL-6 mRNA expression in atopic skin lesions. It could be seen (Fig. 11).
  • Psoriasis and atopic dermatitis are known as typical diseases that cause skin dryness.
  • atopic dermatitis is characterized by epidermal hyperplasia (hyperkeratosis), erythema, edema, severe pruritus, exudation and scab, as well as skin dryness.
  • epidermal hyperplasia hyperkeratosis
  • erythema erythema
  • edema severe pruritus
  • exudation and scab as well as skin dryness.
  • It is a dermatological disease with various symptoms such as dermatitis, which causes blisters in the chronic phase and thickening of the skin (Bieber T. Atopic dermatitis. N Engl J Med. 2008; 358: 1483-94). Therefore, the clinical symptoms of erythema, dry skin, edema and excoriation, erosion, and lichenification were observed in this study.
  • the DNCB alone group showed noticeable dryness, erythema, hematoma, and mammary gland compared to the normal control group.
  • DNCB-induced skin symptoms, except erythema were mostly lost.
  • the test substance treatment group no significant visual observation change was observed in 0.01 uM and 0.1 uM, but erythema, hematoma, and mammary glands were decreased in 1 uM compared to the DNCB group (FIG. 12).
  • Hyperkeratosis was confirmed in the skin tissue of mice by histological observation in the atopic dermatitis group.
  • the epidermal thickness of the DNCB group was 87.1 ⁇ 13.0 ⁇ m, which was more pronounced than the 24.5 ⁇ 10.3 ⁇ m of the normal control group, indicating hyperkeratosis in atopic dermatitis.
  • the group treated with Dexamethasone, a positive control showed a marked decrease in epidermal thickness of 39.9 ⁇ 9.4 ⁇ m.
  • the thickness was reduced to 70.8 ⁇ 4.3 ⁇ m, 74.4 ⁇ 7.1 ⁇ m and 60.0 ⁇ 8.2 ⁇ m for each concentration (Fig. 13).
  • Ig E Increasing serum Ig E is known as an atopic dermatitis index, in particular Ig E correlates closely with clinical severity (M. Ban and D. Hetich, Toxicol. Lett, 118, 129 (2001). Sexual dermatitis increases the IgE antibody response (Matsuda, H., Watanabe, N., Geba, GP, Sperl, J., Tsudzuki, M. and Hiroi, J .: Int. Immunol. 9, 461 (1997).
  • Ig E production leads to increased antibody response and increased histamine secretion by increasing the activity of the Ig E dependent histamine vitreous, which is known to induce infiltration of eosinophils and cause acute hypersensitivity and pruritus ( HC Sung, WJ Lee, SJ Lee, and DW Kim, Kor.J. Dermatol, 44, 1051 (2006) .Reduction of Ig E is therefore considered a major indicator of improvement in atopic dermatitis.
  • Table 7 shows mortality after test substance treatment
  • Table 8 shows clinical symptoms induced by treatment of test substances.
  • Table 9 shows weight change in test rats treated male rats.
  • Table 10 shows weight change in test rats treated female rats.
  • Table 11 shows the features and findings in rats treated with test substances.
  • the LD50 by transdermal administration of test substance in rats was more than 200 ⁇ M / kg / 4 ml bw for both male and female.
  • Antibody microarray protein chip analysis was performed with reference to the antibody map immobilized on ProteoChip. Fluorescence images comparing the expression levels on the antibody chip immobilized with 26 kinds of antibodies are shown in FIG. The graph of the INR result analyzing the result is shown in Fig. 16-2.
  • IL-6 is secreted in Th2 cells, which has been reported to be increased in T cells of patients with atopic dermatitis (Toshitani, Akito, et al. J Invest Dermatol 100.3 (1993): 299-304).
  • IL-22 is produced in Th17 cells and contributes to the development of inflammatory skin diseases and is known to play a key role in inflammatory diseases. It has also been reported that IL-22 is increased in atopic dermatitis (Cho, Kyung-Ah, et al. International immunology 24.3 (2012): 147-158).
  • IL-33 is a recently known cytokine belonging to the IL-1 family, associated with Th2 type immune responses and expressed in cells of the barrier tissue.
  • IL-6, IL-22, and IL-33 have been reported to increase expression in atopic dermatitis skin and are closely related to the progression of atopic dermatitis.
  • the three cytokine is believed to be reduced by alleviating the symptoms of atopic dermatitis.
  • Example 6 IPS -07004 (Formula 4) and its atopic dermatitis experiment
  • IPS-07004 is a screening of 07001 (Formula 1), followed by a literature search to find a material with a structure similar to 07001 (07004), where 07004 is purchased from Key Organics (London, UK).
  • HaCat cells Human skin cell lines (HaCat cells) were cultured at 37 ° C. and 5% CO 2 with 10% FBS in RPMI. Candidates were dissolved in DMSO and filtered using a 0.22 ⁇ m filter. Diluted with DMSO and treated to cells.
  • dextran sodium sulfate (cat no 160110 by Mpbio.com) was diluted to 3% in drinking water and orally administered to mice to induce enteritis.
  • the mice were divided into 6 groups and DW was added to control animals. Animals were orally administered 1.0 mg / kg of test substance and 10 mg / kg once daily for 5 weeks. Positive control animals were orally administered with Sulfasalazine (100 mg / kg) dissolved in undiluted olive oil once daily.
  • Sulfasalazine 100 mg / kg
  • the disease progression was confirmed after 5 days of administration.
  • chronic cases the disease progression was checked 15 and 30 days after 5 days of administration. (Ref .: Toxicology Reports 2 (2015) 10391045- colon inflammation)
  • Body weight was measured at least once / 5 days during the test period.
  • the measured weight result is 0 point if there is no difference compared to the normal control group, 15% for weight loss rate is 1 point, 510% is 2 points, 1015% is 3 points, > 15% were quantified with 4 points.
  • Fecal observation was performed to determine the degree of diarrhea and the results were quantified and displayed. (0, normal stool; 1, mildly softstool; 2, very soft stool; 3, very soft stool (no regular shape); 4, watery stool)
  • Rectal tissue and blood were collected at each autopsy period. Yuhan ketamine 50 r (Yuhan Corporation, Korea) and lump (bayer, USA) were mixed 3: 1 and then anesthetized by intramuscular injection. The anesthetized animal was opened and blood was collected from the abdominal aorta. After the blood was collected, the abdominal aorta was cut and lethaled and rectal tissues were collected. The weight and the weight of the tissue was calculated by measuring the length and weight of the collected tissue. The collected tissues were partially biopsied, others were frozen in liquid nitrogen and stored at -70 ° C until analysis.
  • tissue of the rectum were fixed in 4% neutral buffered formalin (4% NBF), subjected to a general biopsy procedure, and then cut to 4 um thickness using a microtome, followed by haematoxylin & eosin staining.
  • the degree of inflammation was divided into 5 stages (normal-0, minimal-1, mild-2, moderate-3, severe-4) using an optical microscope.
  • the inhibitory effect of enteritis on IPS-07001 and IPS-07004 was observed using a DSS-induced animal model constructed by the above experimental method. Dosage was divided into 1.0 mg / kg and 10 mg / kg, the administration was oral. Efficacy was evaluated by the ratio of intestinal weight to intestinal length (wt / cm), and additionally by weight change, diarrhea and bleeding. As a result of the experiment, both substances were observed to have superior enteritis inhibitory effect compared to the DSS control group at the 10 mg / kg dose (see FIGS. 18 to 20, 25, and 27 to 28, etc.). The change in body weight was shown to be similar to that of the normal group, and it was observed that the bleeding was significantly reduced compared to the DSS-induced group (see FIGS. 20, 26 to 27, etc.). The inhibitory mechanism of enteritis is thought to control the mechanism of inflammation by inhibiting Caspase-1, a key protein of Inflammasome.

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Abstract

La présente invention concerne un composé visant à inhiber la sécrétion de lymphopoïétine stromale thymique (TSLP) par les mastocytes, et son utilisation. Il a été confirmé que le composé de la présente invention inhibe significativement la sécrétion de TSLP par les mastocytes, si bien que le composé peut être utilisé en tant que substance candidate pour traiter et prévenir la dermatite atopique, la dermatite allergique et/ou la maladie intestinale inflammatoire.
PCT/KR2016/011434 2015-10-13 2016-10-12 Composition utilisable en vue du traitement de la maladie intestinale inflammatoire et de la dermatite atopique WO2017065495A2 (fr)

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CN201680059836.6A CN108137490B (zh) 2015-10-13 2016-10-12 用于治疗炎性肠病和异位性皮炎的组合物
JP2018519833A JP6885607B2 (ja) 2015-10-13 2016-10-12 炎症性腸疾患およびアトピー性皮膚炎の処置のための組成物
US15/768,374 US10278931B2 (en) 2015-10-13 2016-10-12 Composition for treatment of inflammatory bowel disease and atopic dermatitis
EP16855712.2A EP3363783B1 (fr) 2015-10-13 2016-10-12 Composition pour le traitement de la maladie intestinale inflammatoire et de la dermatite atopique
HK18113385.6A HK1254242A1 (zh) 2015-10-13 2018-10-18 用於治療炎性腸病和異位性皮炎的組合物

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EP4178558A4 (fr) * 2020-06-08 2024-09-04 Elevaid Therapeutics Inc Utilisation d'atovaquone et de proguanil pour le traitement de maladies gastro-intestinales et de l'inflammation

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WO2003037346A1 (fr) * 2001-10-31 2003-05-08 Cell Therapeutics, Inc. Derives de 6-phenyl-n-phenyl-(1,3,5)-triazine-2,4-diamine et composes apparentes ayant un effet inhibiteur de l'acide lysophosphatidique acyltransferase beta (lpaat-beta) et destines a etre utilises pour traiter le cancer
JPWO2004005509A1 (ja) * 2002-07-02 2005-11-04 株式会社ジェノックス創薬研究所 アレルギー性疾患の検査方法、および治療のための薬剤
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