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WO2018131924A1 - Dérivé de pyridinol ou sel pharmaceutiquement acceptable de ce dernier, et composition pharmaceutique pour prévenir ou traiter des maladies autoimmunes contenant ce dernier en tant que principe actif - Google Patents

Dérivé de pyridinol ou sel pharmaceutiquement acceptable de ce dernier, et composition pharmaceutique pour prévenir ou traiter des maladies autoimmunes contenant ce dernier en tant que principe actif Download PDF

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WO2018131924A1
WO2018131924A1 PCT/KR2018/000602 KR2018000602W WO2018131924A1 WO 2018131924 A1 WO2018131924 A1 WO 2018131924A1 KR 2018000602 W KR2018000602 W KR 2018000602W WO 2018131924 A1 WO2018131924 A1 WO 2018131924A1
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formula
carbon atoms
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substituted
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Korean (ko)
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정병선
김정애
장재훈
남태규
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Research Cooperation Foundation of Yeungnam University
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Research Cooperation Foundation of Yeungnam University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • 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
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • 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
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl

Definitions

  • the present invention relates to a pyridineol derivative or a pharmaceutically acceptable salt thereof and a pharmaceutical composition for preventing or treating autoimmune diseases containing the same as an active ingredient.
  • T cells are one of the cell populations that play a central role in the immune system, a biological defense system against various pathogens.
  • T cells are produced by the human thymus and undergo a series of differentiation processes to differentiate into unique T cells.
  • T cells that have completed differentiation are classified into CD8 T cells and CD4 T cells according to their function.
  • CD4 T cells are differentiated in detail according to environmental factors. The most representative ones are Th1, Th2, Th17 and Treg cells.
  • Th1 cells are involved in cell mediated immunity
  • Th2 cells are involved in humoral immunity
  • Th17 cells are involved in infectious and inflammatory diseases
  • Treg cells suppress immunity to maintain homeostasis.
  • these cell populations are balanced against each other so that they are not activated with each other.
  • immune diseases can be attributed to the imbalance between these immune cells.
  • abnormally increased activity of Th1 and Th17 cells may cause autoimmune diseases
  • abnormally increased activity of Th2 cells is known to cause immune diseases due to hypersensitivity.
  • Excessive immune suppression of Treg cells can also cause cancer.
  • Treg cells have the property of controlling the inflammatory response by inhibiting the function of abnormally activated immune cells. Many experiments have been reported to treat immune diseases through the action of increasing the activity of Treg cells.
  • Th1 cells and Th17 cells have been found to be involved in the forefront of the inflammatory response seen in immune diseases, maximizing the signal of the inflammatory response and accelerating disease progression. Therefore, in the case of autoimmune diseases that are not controlled by Treg cells among autoimmune diseases, development of therapeutic agents for autoimmune diseases that target inhibition of Th1 and Th17 cell activities has been highlighted.
  • immunosuppressive agents are immunosuppressants that block the signal transduction pathways in T cells. These immunosuppressive agents are toxic, infection, lymphoma, diabetes, tremor, headache, diarrhea, high blood pressure, nausea. Or side effects such as renal failure occurs.
  • the present inventors have completed the present invention by confirming that a pyridinol derivative of a specific structure or a pharmaceutically acceptable salt thereof has an excellent autoimmune disease treatment effect.
  • an object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of autoimmune diseases containing pyridinol derivatives or pharmaceutically acceptable salts thereof as an active ingredient.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of autoimmune diseases comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.
  • R 2 , R 3 and R 4 are each independently alkyl having 1 to 8 carbons
  • R 5 is hydrogen; halogen; Alkyl having 1 to 8 carbon atoms; -Si (R 6 ) 3 ; And it is any one selected from the group consisting of aryl having 6 to 18 carbon atoms,
  • alkyl of 1 to 8 carbon atoms or aryl of 6 to 18 carbon atoms of R 5 are each independently substituted or unsubstituted with alkyl of 1 to 8 carbon atoms or aryl of 6 to 18 carbon atoms,
  • R 6 is hydrogen, alkyl having 1 to 8 carbons; And it is any one selected from the group consisting of aryl having 6 to 18 carbon atoms,
  • R 1 is hydrogen; Sulfonyl; Carbonyl; Alkyl having 1 to 12 carbon atoms; And it is any one selected from the group consisting of aryl having 6 to 18 carbon atoms,
  • the sulfonyl or carbonyl of R 1 may be each independently substituted or unsubstituted alkyl having 1 to 8 carbon atoms; And one or more substituents selected from the group consisting of aryl having 6 to 18 carbon atoms unsubstituted or substituted with alkyl or halogen having 1 to 8 carbon atoms,
  • the alkyl of 1 to 12 carbon atoms or aryl of 6 to 18 carbon atoms of R 1 are each independently halogen; -NO 2 ; Alkyl having 1 to 8 carbon atoms which is unsubstituted or substituted with halogen; Alkoxy having 1 to 8 carbon atoms which is unsubstituted or substituted with halogen; And substituted or unsubstituted with one or more substituents selected from the group consisting of aryl having 6 to 18 carbon atoms unsubstituted or substituted with alkyl or halogen of 1 to 8 carbon atoms,
  • L represents -O- or a linking group represented by the following Chemical Formula 2 or 3,
  • Q is O or S
  • P is -NH- or -O-
  • Z is a single bond or -NH-.
  • the present invention provides a method for preventing or treating autoimmune diseases, comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, and preventing autoimmune diseases.
  • a novel use of a compound represented by formula (1) or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for treatment comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, and preventing autoimmune diseases.
  • a novel use of a compound represented by formula (1) or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for treatment comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, and preventing autoimmune diseases.
  • a novel use of a compound represented by formula (1) or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for treatment comprising administering to a subject in need thereof a therapeutically effective amount of
  • the pyridinol derivatives or pharmaceutically acceptable salts thereof according to the present invention can inhibit the secretion of cytokines that exacerbate autoimmune diseases, and inhibit the autoimmune disease-induced cell differentiation that produces the cytokines.
  • the derivative may be usefully used as a medicament for the prevention or treatment of autoimmune diseases.
  • Figure 1 shows inhibition of Th1 and Th17 differentiation, inhibition of inflammatory cytokines secreted from T cells, IFN-g, IL-17, IL-4, IL-5 and IL-13, and no effect on Treg, an immunosuppressive T cell.
  • FACS data showing no giving and CBA result data for cytokine measurements.
  • FIG. 2 is a graph showing the results of testing the degree of cell division and cytotoxicity by decreasing the concentration of CFSE color by stimulating TSE-colored T cells.
  • Figure 3 is a graph confirming the effect of the drug in the process of inducing neurological autoimmune disease, and the Th1 and Th17 cells isolated from each organ of the mouse (spleen, lymph nodes, central nervous system) is a graph analyzed by FACS flow cytometry.
  • Figure 4 is a graph of the effect and cytotoxicity of the drug on the initial activity and division of T cells in vitro T cell stimulation test using antibodies.
  • Figure 6 is a graph of the results of confirming the effect of the drug in an animal model inducing autoimmune diseases using MOG antigen and the Th1 and Th17 cells isolated from each organ (brain, spinal cord, lymph nodes) of the mouse by FACS flow cytometry. .
  • T cell transplanted animal which is isolated from the T-cells induced autoimmune disease using MOG antigen and amplified in vitro, and transplanted into normal mice to induce inflammatory T cells to induce autoimmune diseases.
  • the result of confirming the effect of the drug to suppress the progression of the disease the graph of the analysis of the increase of Th1 and Th17 cells by flow cytometry.
  • the present invention provides a compound represented by Formula 1 below (compound 1) or a pharmaceutically acceptable salt thereof.
  • R 2 , R 3 and R 4 are each independently alkyl having 1 to 8 carbons
  • R 5 is hydrogen; halogen; Alkyl having 1 to 8 carbon atoms; -Si (R 6 ) 3 ; And it is any one selected from the group consisting of aryl having 6 to 18 carbon atoms,
  • alkyl of 1 to 8 carbon atoms or aryl of 6 to 18 carbon atoms of R 5 are each independently substituted or unsubstituted with alkyl of 1 to 8 carbon atoms or aryl of 6 to 18 carbon atoms,
  • R 6 is hydrogen, alkyl having 1 to 8 carbons; And it is any one selected from the group consisting of aryl having 6 to 18 carbon atoms,
  • R 1 is hydrogen; Sulfonyl; Carbonyl; Alkyl having 1 to 12 carbon atoms; And it is any one selected from the group consisting of aryl having 6 to 18 carbon atoms,
  • the sulfonyl or carbonyl of R 1 may be each independently substituted or unsubstituted alkyl having 1 to 8 carbon atoms; And one or more substituents selected from the group consisting of aryl having 6 to 18 carbon atoms unsubstituted or substituted with alkyl or halogen having 1 to 8 carbon atoms,
  • the alkyl of 1 to 12 carbon atoms or aryl of 6 to 18 carbon atoms of R 1 are each independently halogen; -NO 2 ; Alkyl having 1 to 8 carbon atoms which is unsubstituted or substituted with halogen; Alkoxy having 1 to 8 carbon atoms which is unsubstituted or substituted with halogen; And substituted or unsubstituted with one or more substituents selected from the group consisting of aryl having 6 to 18 carbon atoms unsubstituted or substituted with alkyl or halogen of 1 to 8 carbon atoms,
  • L represents -O- or a linking group represented by the following Chemical Formula 2 or 3,
  • Q is O or S
  • P is -NH- or -O-
  • Z may be a single bond or -NH-.
  • the compound of Formula 1 may be referred to as a pyridinol derivative.
  • Alkyl refers to a straight, branched or cyclic saturated hydrocarbon having the specified number of carbon atoms unless otherwise indicated.
  • Halogen refers to fluoro (F), chloro (Cl), bromo (Br) or iodo (I).
  • Aryl means monovalent and divalent aromatic groups each containing a 5-membered and 6-membered monocyclic aromatic group, unless otherwise noted.
  • a “pharmaceutical composition” is a compound according to the present invention or a mixture of physiological / pharmaceutically acceptable salts or prodrugs thereof, together with other chemical components such as physiologically / pharmaceutically acceptable carriers and excipients.
  • a pharmaceutical composition is to facilitate administration of a compound to an organism.
  • Prodrugs may act as prodrugs.
  • Prodrug refers to a substance that is converted into the parent drug in the body. Prodrugs are often useful because, in some cases, they are easier to administer than the parent drug. For example, prodrugs may be bioavailable upon oral administration, even if the parent drug is not bioavailable upon oral administration. Prodrugs may also exhibit improved solubility over the parent drug in pharmaceutical compositions.
  • a “physiologically / pharmaceutically acceptable carrier” refers to a carrier or diluent that does not cause significant irritation to the organism and does not eliminate the biological activity and properties of the administered compound.
  • Physiologically / pharmaceutically acceptable excipient refers to a stable substance added to make administration of the compound easier.
  • excipients include calcium carbonate, calcium phosphate, various sugar and starch varieties, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols.
  • Treating refers to a method of alleviating or eliminating a disease or accompanying symptoms in accordance with the present invention.
  • Organism or “subject” means all living beings composed of at least one cell. Living organisms can be as simple as eukaryotic single cells, but complex to mammals, including humans.
  • a “therapeutically effective amount” means the amount of an active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue system, animal or human, as contemplated by a researcher, veterinarian, physician or other clinician, which may be Amounts that induce alleviation of the symptoms of the disorder.
  • R 2 , R 3 and R 4 are each independently alkyl having 1 to 4 carbon atoms
  • R 5 is hydrogen; Alkyl having 1 to 4 carbon atoms unsubstituted or substituted with aryl having 6 to 12 carbon atoms; And -Si (R 6 ) 3 , which is selected from the group consisting of
  • R 6 is alkyl having 1 to 6 carbon atoms or aryl having 6 to 12 carbon atoms
  • L is -O-, -NH-C (O) -NH-, -NH-C (S) -NH-, -NH-C (O) -O-, -NH-S (O) 2 -NH- Or -NH-S (O) 2- .
  • R 2 , R 3 and R 4 are each independently methyl
  • R 5 is hydrogen; Methyl unsubstituted or substituted with phenyl; And -Si (R 6 ) 3 , which is selected from the group consisting of
  • R 6 may be butyl or phenyl.
  • R 1 is hydrogen; Sulfonyl; Carbonyl; Alkyl having 1 to 10 carbon atoms; And it is any one selected from the group consisting of aryl having 6 to 12 carbon atoms,
  • the sulfonyl or carbonyl is each independently alkyl having 1 to 4 carbon atoms; And it is substituted or unsubstituted with one or more substituents selected from the group consisting of aryl having 6 to 12 carbon atoms,
  • the alkyl having 1 to 10 carbon atoms is halogen; Alkoxy having 1 to 4 carbon atoms; And one or more substituents selected from the group consisting of aryl having 6 to 12 carbon atoms or unsubstituted or substituted with alkyl or halogen having 1 to 6 carbon atoms,
  • the aryl having 6 to 12 carbon atoms is halogen; -NO 2 ; Alkyl of 1 to 4 carbon atoms unsubstituted or substituted with halogen; And it may be substituted or unsubstituted with one or more substituents selected from the group consisting of alkoxy having 1 to 4 carbon atoms unsubstituted or substituted with halogen.
  • the sulfonyl or carbonyl is substituted with phenyl
  • the alkyl having 1 to 8 carbon atoms is halogen; Methoxy; Ethoxy; Propoxy; And unsubstituted or substituted with one or more substituents selected from the group consisting of phenyl unsubstituted or substituted with alkyl or halogen having 1 to 4 carbon atoms,
  • the aryl having 6 to 10 carbon atoms is halogen; -NO 2 ; Alkyl of 1 to 4 carbon atoms unsubstituted or substituted with halogen; And it may be substituted or unsubstituted with one or more substituents selected from the group consisting of alkoxy having 1 to 4 carbon atoms which is unsubstituted or substituted with halogen.
  • R 2 , R 3 and R 4 are each independently methyl
  • R 5 is hydrogen; Methyl unsubstituted or substituted with phenyl; Or silyl substituted with phenyl and butyl,
  • R 1 is hydrogen; Carbonyl substituted with phenyl; Sulfonyl substituted with phenyl; Alkyl having 1 to 8 carbon atoms unsubstituted or substituted with one or more substituents selected from the group consisting of chloro, methoxy, phenyl, chlorophenyl, and butylphenyl; Or phenyl or naphthyl which may be unsubstituted or substituted with one or more substituents selected from the group consisting of chloro, fluoro, bromo, methyl, ethyl, propyl, butyl, trifluoromethyl, nitro, methoxy and trifluoromethoxy have.
  • the compound according to the present invention may be any one selected from the group consisting of compounds represented by the following formula.
  • Pyridinol-urea derivatives may be represented by the following formula.
  • Pyridinol-thiourea derivatives may be represented by the following formula.
  • Pyridinol-carbamate derivatives may be represented by the following formula.
  • Pyridinol-sulfonamide derivatives may be represented by the following formula.
  • Pyridinol-sulfamide derivatives may be represented by the following formula.
  • pyridinol-alkoxide derivatives may be represented by the following formula.
  • the pharmaceutically acceptable salt in the present invention is an organic acid selected from the group consisting of oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid and benzoic acid, or is formed by an inorganic acid selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid. It may be in the form of acid addition salts.
  • the present invention also provides a method for preparing the compound of formula (1).
  • the preparation is for example,
  • the present invention is to react the compound of formula 4 with a compound of formula 5 or a compound of formula 6;
  • the compound of formula 4 may be converted to a compound of formula 10, and the compound of formula 10 may be prepared by reacting the compound of formula 10 with the compound of formula 11.
  • R 1 to R 5 , Q, and L may use the aforementioned compounds, R may represent carbonyl or sulfonyl, and X may be halogen.
  • the compound of Formula 1 may be prepared by a preparation method such as Scheme 1 or 2.
  • the compound of Scheme 1 or 2 may be prepared by the preparation method according to Examples 1 to 16.
  • the present invention relates to a pharmaceutical composition for preventing or treating autoimmune diseases comprising the above-described compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • autoimmune diseases include Behcet's disease, multiple myositis / skin myositis, autoimmune cytopenia, autoimmune myocarditis, atopic dermatitis, asthma, primary cirrhosis, dermatitis, fibromyalgia, Goodfiction syndrome, autoimmune meningitis, Sjogren Syndrome, systemic lupus erythematosus, Addison's disease, alopecia areata, ankylosing myelitis, autoimmune hepatitis, autoimmune mumps, insulin dependent diabetes mellitus, dystrophic epidermal detachment, epididymitis, glomerulonephritis, Graves' disease, celiac disease, Guillain-Barré syndrome, Hashimoto's disease, hemolytic anemia, multiple sclerosis, myasthenia gravis, myotrophic lateral sclerosis, vulgaris ulcer, psoriasis, rheumatic fever, rhe
  • the compound of formula 1 or a pharmaceutically acceptable salt thereof according to the present invention may be administered to a patient by itself or in a pharmaceutical composition mixed with a suitable carrier or excipient.
  • a suitable carrier or excipient suitable carrier or excipient.
  • administering means the delivery of a pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof or a compound of formula 1 to the organism for the treatment or prevention of the above-mentioned diseases. I say that.
  • Suitable routes of administration may be oral, rectal, mucosal or enteral administration or intramuscular, subcutaneous, intramedullary, intravesical, direct intraventricular, intravascular, intraocular intravitreal, intraperitoneal, intranasal, or eye, etc. have.
  • Preferred routes of administration may be oral and parenteral administration.
  • compositions of the present invention are well known processes such as conventional mixing, dissolving, granulating, dragging-making, levigating, emulsifying, encapsulating, entrapping and lyophilizing processes in the art. It can be prepared by.
  • the pharmaceutical composition according to the invention may be formulated with an active compound into a formulation which can be used pharmaceutically. Suitable formulations may vary depending on the choice of route of administration.
  • the compounds of the present invention may be formulated in aqueous solutions, preferably in physiologically suitable buffers such as Hanks' solution, Ringer's solution or physiological saline.
  • a surface penetrant may be used in the formulation that allows penetration of the barrier.
  • Such surface penetrants may use those generally known in the art.
  • the compounds may be formulated in combination with a pharmaceutically acceptable carrier.
  • Carriers are formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, so that the patient can take them orally. can do.
  • Pharmaceutical formulations for oral administration can be prepared using solid excipients, with the addition of other suitable auxiliaries as necessary, to make the tablets or the core of the tablets containing. At this time, optionally, the resulting mixture may be ground and the mixture may be granulated.
  • Useful excipients include sugars, including lactose, sucrose, mannitol or sorbbitol; Fibrous preparations such as corn starch, wheat starch, rice starch and potato starch; Fillers such as gelatin, gum, gum sap, methylcellulose, hydroxypropylmethyl-cellulose, and / or polyvinyl-pyrrolidone (PVP). If necessary, disintegrating agents such as crosslinked polyvinyl-pyrrolidone, agar or alginic acid may be added. It is also possible to add salts such as sodium alginate.
  • sugars including lactose, sucrose, mannitol or sorbbitol
  • Fibrous preparations such as corn starch, wheat starch, rice starch and potato starch
  • Fillers such as gelatin, gum, gum sap, methylcellulose, hydroxypropylmethyl-cellulose, and / or polyvinyl-pyrrolidone (PVP).
  • disintegrating agents such as crosslinked polyvinyl-pyr
  • the central part of the dragee can be made by appropriate coating.
  • concentrated sugar solutions may optionally be used containing Arabian gum, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol and / or titanium dioxide, lacquer solutions.
  • compositions that can be used orally may include push-fit capsules made of gelatin, as well as soft sealing capsules made of gelatin and plasticizers such as glycerol or sorbitol.
  • soft capsules the active compounds may be dissolved or suspended in suitable solutions, such as fatty oils, liquid paraffin or liquid polyethylene glycols.
  • stabilizers may be added to the composition.
  • compositions that can be used can include hard gelatin capsules.
  • Capsules can be filled in brown glass or plastic bottles to protect the active compound from light.
  • Containers containing the active compound capsule formulation can be stored at controlled room temperature (15-30 ° C.).
  • the compounds according to the present invention may be compressed into compression vessels, nebulizers and suitable propellants such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane and carbon dioxide. It can be easily administered in the form of a used aerosol spray.
  • the compounds may be formulated for parenteral administration, for example, by bolus injection or continuous intravenous infusion.
  • Formulations for infusion may be provided in the form of unit doses with preservatives added, such as, for example, ampoules or multidose containers.
  • the compositions take the form of suspensions, solutions or emulsions as carriers that are oily or aqueous and may comprise formulating materials such as suspending, stabilizing and / or dispersing agents.
  • compositions for parenteral administration include water-soluble aqueous solutions, for example, water-soluble aqueous solutions of active compounds such as salts.
  • suspensions of the active compounds may be formulated with lipophilic carriers.
  • Suitable lipophilic carriers can include substances such as liposomes, synthetic fatty acid esters such as fatty oils, ethyl oleate and triglycerides.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxy methyl cellulose, sorbitol or dextran.
  • the suspension may optionally contain a suitable stabilizer and / or material that increases the solubility of the compound to allow for the preparation of high concentration solutions.
  • the compounds may also be formulated in rectal dosage compounds, such as suppositories or retention enemas, using bases of conventional suppositories, such as cocoa butter or other glycerides.
  • the compounds may be formulated in the form of depot preparations. Such long acting formulations are administered by implantation (eg subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds of the present invention are very insoluble in water, such as, but not limited to, suitable polymeric or hydrophobic materials (e.g., emulsions made from pharmaceutically acceptable oils), ion exchange resins, or salts that are not very soluble in water. Derivatives may be formulated for administration of this route.
  • the pharmaceutical composition according to the present invention the above-described diseases, for example, Behcet's disease, multiple myositis / skin myositis, autoimmune hematopoiesis, autoimmune myocarditis, atopic dermatitis, asthma, primary cirrhosis, dermatitis, fibromyalgia, gut Future syndrome, autoimmune meningitis, Sjogren's syndrome, systemic lupus erythematosus, Addison's disease, alopecia areata, ankylosing myelitis, autoimmune hepatitis, autoimmune mumps, insulin dependent diabetes mellitus, dystrophic epidermal detachment, epididymitis, glomerulonephritis, Graves Illness, celiac disease, Guillain-Barré syndrome, Hashimoto's disease, hemolytic anemia, multiple sclerosis, myasthenia gravis, amyotrophic lateral sclerosis, vulgaris ulcer,
  • the therapeutically effective amount means a dose that can prevent, alleviate or ameliorate the symptoms of the disease, or prolong the survival of the prescribed patient.
  • the pyridinol derivatives or pharmaceutically acceptable salts thereof according to the present invention can inhibit the secretion of cytokines that exacerbate autoimmune diseases in an autoimmune disease model, and inhibit the differentiation of autoimmune disease-causing cells that produce these cytokines. have. Therefore, the derivative may be usefully used as a medicament for the prevention or treatment of autoimmune diseases.
  • the pharmaceutical composition according to the present invention may comprise 0.1 to 50% by weight of the pyridinol derivative or pharmaceutically acceptable salt thereof based on the total weight of the composition.
  • the amount of pyridinol derivatives or pharmaceutically acceptable salts thereof according to the present invention may vary depending on the age, sex and weight of the patient, but the amount of 0.001 to 100 mg / kg, preferably 0.01 to 10 mg / kg per day It may be administered several times to several times.
  • the dosage of the pyridinol derivatives or pharmaceutically acceptable salts thereof may be increased or decreased depending on the route of administration, the severity of the disease, sex, weight, age and the like. Therefore, the above dosage does not limit the scope of the present invention in any aspect.
  • the pharmaceutical composition may be administered to mammals such as mice, mice, livestock, humans, and the like by various routes. All modes of administration can be expected, for example, by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
  • the pyridinol derivatives or pharmaceutically acceptable salts thereof according to the present invention have a 50% lethal amount (LC 50 ) of 2 g / kg or more and can be used in the pharmaceutical composition of the present invention.
  • the present invention also provides a method for preventing or treating an autoimmune disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof.
  • the optimal dosage to be administered can be readily determined by one skilled in the art and includes the type of disease, the severity of the disease, the amount of active ingredients and other ingredients contained in the composition, the type of formulation, and the age, weight, general health of the patient. It may be adjusted according to various factors including the condition, sex and diet, time of administration, route of administration and the rate of secretion of the composition, the duration of treatment, and the drugs used simultaneously.
  • the compound of Formula 1 is administered at a dose of 0.001 to 100 mg / kg, preferably 0.01 to 10 mg / kg, once or several times a day. It is preferable.
  • the composition comprising the compound of formula 1 of the present invention as an active ingredient is administered in a conventional manner through oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection. can do.
  • the present invention also provides the use of a compound of formula 1 or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical composition for the prevention or treatment of autoimmune diseases.
  • Phenyl isocyanate (47.5 ⁇ l, 0.289 mmol) was added to a suspension of compound 7a (70 mg, 0.289 mmol) in CH 2 Cl 2 (3 mL), and the mixture was stirred at room temperature for 7 hours.
  • Example 17-4> 1- (5- Hydroxy -3,4,6- trimethylpyridin -2- yl ) -3- phenylurea (16-2) manufacturing
  • Example 17-5> 1- (5- Benzyloxy -3,4,6- trimethylpyridin -2- yl Manufacture) -3- (4-chlorophenyl) urea (15-3)
  • Example 17-7> 1- (5- Benzyloxy -3,4,6- trimethylpyridin -2- yl ) -3- (2- tert -butyl-6-methylphenyl) urea (15-4) manufacturer
  • Methanesulfonyl chloride (47.8 ⁇ l, 0.618 mmol) was added to a suspension of pyridine (2 mL) of compound 7a (50 mg, 0.206 mmol), followed by stirring at room temperature for 24 hours.
  • the reaction solution was concentrated and the residue was diluted with CH 2 Cl 2 and washed with water and saturated brine.
  • the CH 2 Cl 2 solution was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure.
  • the aqueous layer was extracted with CH 2 Cl 2 , the CH 2 Cl 2 solution was washed with saturated brine, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure to give the target compound 26 (1.95 g, 98%) as a yellow solid.
  • CD4 T cells were isolated from the spleen of B57BL / 6 mice using a magnetic instrument called MACS. In order to stimulate CD4 T cells, CD3 antibody (5 mg / ml) was coated on the plate where the cells were grown, CD4 T cells were added and another stimulant CD28 antibody (1 mg / ml) was added.
  • T cells There are several types of inflammatory cells in T cells, the most representative of which are Th1, Th2 or Th17 cells. These inflammatory cells differ in their methods of differentiation.
  • Th1 cells 10% FBS and 1% penicillin / streptomycin (PS) were included in RPMI-1640 medium, and the isolated CD4 T cells were incubated under 37 ° C. and 5% CO 2 conditions. When cultured, the cell stimulant CD3 antibody and CD28 antibody were added as before. To differentiate into Th1 cells, IL-12 (10 ng / ml) was added to the cytokine and grown for 4 days. At this time, pyridinol derivative compounds (10 ⁇ M) (treatment group) were included to confirm the inhibitory ability of the drug.
  • IL-12 10 ng / ml
  • tofacitinib 10 ⁇ M
  • T cell inhibitor of rheumatoid arthritis disease was used.
  • Th17 cells which are other inflammatory cells
  • IL-12 as a cytokine
  • anti- IFN- ⁇ antibody 5 mg / ml
  • anti-IL-4 antibody 5 mg / ml
  • IL-4 (10 ng / ml) was added to the cytokine.
  • Regulatory T cells which are inflammation inhibitory cells, were prepared in the same manner as above, but IL-2 (10 ng / ml) and TGF- ⁇ (10 ng / ml) were added as cytokines.
  • Table 7 shows Th1 differentiation inhibitory effect (10 uM compound concentration), and Table 8 shows Th17 differentiation inhibitory effect (10 uM compound concentration).
  • 18-1, 18-3, 18-13, 20-5, 22-4, and 28 showed that the pyridinol derivative compounds inhibited the in vitro differentiation of Th1 and Th17 cells.
  • -6 showed over 40% inhibition of differentiation in both Th1 and Th17 cells.
  • the compounds with high inhibition rate and no cytotoxicity under the conditions of stimulating T cell differentiation were 18-13 and 28-6.
  • Th1 cell differentiation was measured by flow cytometry 3 days after cytokine treatment. Th1 differentiation by cytokines was about 50% (FIG. 1). The degree of cytokine-induced Th1 cell differentiation by the administration of the compound was found to be 30% or less for the compound 28-6, and tofacitinib used as the positive control group was about 20% (FIG. 1A). In addition, Compound 28-6 and tofacitinib showed similar inhibitory effects on the differentiation of Th17 cells (FIG. 1B).
  • tofacitinib also inhibited the differentiation of immunosuppressive cells (FoxP3 +, Treg cells), whereas compound 28-6 inhibited the differentiation of Th1 and Th17 cells and did not affect the differentiation of Treg cells, which are immunosuppressive cells.
  • Compound 28-6 specifically reacts to inflammatory cells (FIG. 1C).
  • compound 28-6 and tofacitinib showed excellent inhibitory ability against Th2 inflammatory cells causing atopy or allergy (FIGS. 1D, E and F).
  • CD4 T cells were isolated from the spleen of B57BL / 6 mice as in Experiment 1. The isolated cells were stained with CFSE stain, and stimulated with the differentiation conditions of Th1 (adding IL-12 to cytokines) or Th17 (adding IL-6 and TGF- ⁇ to cytokines) by the above-described method, The concentration of compound 28-6 was added to confirm that the staining concentration was released from the T cells to confirm cell division. (When the cells divide and divide, the dye concentration decreases in half.)
  • the cells were stimulated for 3 days under inflammatory cell stimulation conditions, and then stained with PI and Annexin V to confirm the cytotoxicity by distinguishing between dying or dead cells.
  • toxicity tests were conducted at various concentrations and the results are shown in FIG. 2.
  • Compound 28-6 had a minimal ( ⁇ 5%) effect on T cell division at high concentrations (20 ⁇ M) (FIGS. 2A and B).
  • Tofacitinib a positive control drug, is well known to inhibit cell division itself, affecting both differentiation and division, resulting in poor drug specificity.
  • compound 28-6 shows only inhibitory ability to T cell differentiation and does not affect T cell division, and thus is evaluated as a drug having high specificity for T cell differentiation.
  • compound 28-6 showed no cytotoxicity even at high concentrations (FIG. 2C).
  • Animals were 8-12 weeks old B57BL / 6 mice. Feed and water were freely fed during the breeding period, and the room temperature was 25 ⁇ 1 °C and relative humidity was maintained at 50 ⁇ 10%. Lighting control was controlled by a 12 hour contrast cycle by an automatic light controller.
  • the experimental group was divided into 2 groups (control group, drug administration group) by randomized block design with 5 animals in each group.
  • EAE experimentalal autoimmune encephalomyelitis
  • the spleen, lymph node (LN), brain and spinal cord (CNS) were extracted from the mouse to calculate the number of immune cells, and the immune cells obtained from each organ to check the distribution of Th1 and Th17 cells.
  • LN lymph node
  • CNS spinal cord
  • CD4 T cells were isolated from the spleen of B57BL / 6 mice as in Experiment 1. The isolated cells were stimulated with compound 18-13 for 24 hours under inflammatory cell stimulation conditions, and stained PI and Annexin V to distinguish between dying cells or dead cells to confirm cytotoxicity.
  • the markers were stained with CD44 and CD69 to confirm the expression level by flow cytometry.
  • the cells were stimulated with the differentiation conditions of Th1 (adding IL-12 as a cytokine) or Th17 (adding IL-6 and TGF-b as a cytokine) to various concentrations. Compound 18-13 was added to confirm that the staining concentration was released from T cells to confirm cell division.
  • the cells were stimulated with Th1 differentiation conditions, and stained with BrdU and Ki-67, which are markers, on T cells to which Compound 18-13 was added, and confirmed by flow cytometry.
  • the results are shown in FIG.
  • CD4 T cells were isolated from the spleen of B57BL / 6 mice as in Experiment 1. The isolated cells were stimulated under the differentiation conditions of Th1 (adding IL-12 to cytokines) or Th17 (adding IL-6 and TGF- ⁇ to cytokines) in the same manner as above, and treated with Compound 18-13 for 3 days. After growing for a while, the ability of the drug to inhibit T cell differentiation was confirmed. After 3 days, restimulated with PMA / ionomycin and golgi stop for 4 hours as in Experiment 1, washed twice with PBS, and then punctured the cell surface using Fix / Perm buffer. To identify Th1 cells secreting IFN- ⁇ and Th17 cells secreting IL-17, PE-anti-IFN- ⁇ antibody and APC-anti-IL-17 antibody were stained and confirmed by flow cytometry.
  • CD1 T cells were isolated from the spleen of transgenic OT-II mice as in Experiment 1 and then Th1 (addition of IL-12 cytokine) or Th17 ( Addition of IL-6 and TGF-b cytokines) was stimulated under differentiation conditions, and the compound 18-13 was grown for 3 days to confirm the drug's ability to inhibit differentiation.
  • Th1 differentiation Three days after the differentiation of Th1 was induced by flow cytometry, the cytokine addition resulted in more than 30% of Th1 differentiated cells, whereas Th1 differentiation when treated with compounds 18-13 was 10%. To a significant extent (FIG. 5A). In addition, Th17 differentiation was similarly reduced by more than 20% when cytokine was added, but decreased to about 12% when Compounds 18-13 were treated (FIG. 5B). When antigen-specific differentiation was measured using OT-II mice, the differentiation of Th1 (FIG. 5C) and Th17 (FIG. 5D) was reduced when Compound 18-13 was treated. Comparing compound 18-13 and compound 28-6, it was confirmed that inhibiting differentiation to a similar level.
  • the control group was intraperitoneally injected with PBS every other day, and the drug administration group was injected with compound 18-13 intraperitoneally every other day in an amount of 3 mg / kg.
  • the spleen, lymph node, brain and spinal cord were removed from the mouse as in Experiment 3 to calculate the number of immune cells.
  • the immune cells obtained from each organ were stimulated with PMA / Ionomycin and golgi stop, and then anti-IFN- ⁇ antibodies capable of identifying Th1 and anti-IL capable of identifying Th17. Staining was performed using -17 antibody and flow cytometry was used to determine the specific gravity of inflammatory cells in the whole immune cells. The results are shown in FIG.
  • spleen and lymph nodes were extracted 10 days after EAE-induced mice, as in Experiment 3, and then Th1 (MOG 35 -55 (25 ⁇ g / ml), IL-12 (10 ng). / ml)) or Th17 (MOG 35 -55 (25 ⁇ g / ml), IL-23 (10 ng / ml)) differentiation conditions were stimulated and raised for 3 days.
  • Th1 MOG 35 -55 (25 ⁇ g / ml), IL-12 (10 ng). / ml)
  • Th17 MOG 35 -55 (25 ⁇ g / ml), IL-23 (10 ng / ml)
  • compounds 18-13 do not affect the differentiation of other T cells and only affect the activity of Th1 and Th17 cells that cause autoimmune diseases.
  • Another indicator, the T cell activator factor CD62L low CD44 hi was also significantly reduced, reaffirming that it had an inhibitory effect on T cell activity (FIGS. 7A and B).
  • autoimmune diseases such as EAE occur, which represents the progression of the disease, not the initial model of the disease, as shown in FIG. It is a model that can be Treatment of compounds 18-13 at this time can be shown to be able to mitigate ongoing EAE (FIGS. 7C and D).
  • the spleen and central nerve were also analyzed and the results of the compound 18-13 administration group showed a decrease in CD4 and CD8 cells and Th1 and Th17 cells significantly decreased (Fig. 7E and F). Therefore, it was confirmed that Compound 18-13 may have a drug effect even in an advanced state of autoimmune disease.
  • the pyridinol derivatives or pharmaceutically acceptable salts thereof according to the present invention can inhibit the secretion of cytokines that exacerbate autoimmune diseases, and inhibit the autoimmune disease-induced cell differentiation that produces the cytokines.
  • the derivative may be usefully used as a medicament for the prevention or treatment of autoimmune diseases.

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Abstract

La présente invention concerne une composition pharmaceutique pour prévenir ou traiter des maladies autoimmunes, contenant comme principe actif un dérivé de pyridinol ou un sel pharmaceutiquement acceptable de ce dernier. Un dérivé de pyridinol représenté par la formule chimique 1 ou un sel pharmaceutiquement acceptable de ce dernier inhibe la différenciation des cellules Th1 et Th17, lesquelles sont des cellules T pro-inflammatoires, et inhibe remarquablement bien la sécrétion de cytokines pro-inflammatoires par les cellules, permettant ainsi d'atténuer la progression de la maladie. De plus, le dérivé de pyridinol ou un sel pharmaceutiquement acceptable de ce dernier agit de manière spécifique uniquement sur les cellules T pro-inflammatoires, sans affecter les cellules Treg à rôle d'inhibition immunitaire, permettant son utilisation en tant que médicament pour prévenir ou traiter des maladies auto-immunes.
PCT/KR2018/000602 2017-01-13 2018-01-12 Dérivé de pyridinol ou sel pharmaceutiquement acceptable de ce dernier, et composition pharmaceutique pour prévenir ou traiter des maladies autoimmunes contenant ce dernier en tant que principe actif Ceased WO2018131924A1 (fr)

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EP4008718A4 (fr) * 2019-09-24 2022-08-17 Innovo Therapeutics Inc. Dérivé d'hétéroarylamidopyridinol et composition pharmaceutique le comprenant en tant que principe actif pour prévenir ou traiter une maladie auto-immune
JP2022551431A (ja) * 2019-09-24 2022-12-09 イノボ テラピュティクス インク ヘテロアリールアミドピリジノール誘導体、および自己免疫疾患の予防または処置のための活性成分として同誘導体を含む医薬組成物
AU2020354138B2 (en) * 2019-09-24 2023-07-13 Innovo Therapeutics Inc. Heteroarylamidopyridinol derivative and pharmaceutical composition comprising same as active ingredient for prevention or treatment of autoimmune disease
JP7353683B2 (ja) 2019-09-24 2023-10-02 イノボ テラピュティクス インク ヘテロアリールアミドピリジノール誘導体、および自己免疫疾患の予防または処置のための活性成分として同誘導体を含む医薬組成物
US12398117B2 (en) 2019-09-24 2025-08-26 Innovo Therapeutics Inc. Heteroarylamidopyridinol derivative and pharmaceutical composition comprising same as active ingredient for prevention or treatment of autoimmune disease
IL291168B1 (en) * 2019-09-24 2025-11-01 Innovo Therapeutics Inc Heteroarylamidopyridinol derivative and pharmaceutical preparation containing it as an active ingredient for the prevention or treatment of autoimmune disease

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