WO2015167243A1 - Nouveau composé ayant un effet thérapeutique sur les maladies immunitaires et utilisation de ce composé - Google Patents

Nouveau composé ayant un effet thérapeutique sur les maladies immunitaires et utilisation de ce composé Download PDF

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WO2015167243A1
WO2015167243A1 PCT/KR2015/004299 KR2015004299W WO2015167243A1 WO 2015167243 A1 WO2015167243 A1 WO 2015167243A1 KR 2015004299 W KR2015004299 W KR 2015004299W WO 2015167243 A1 WO2015167243 A1 WO 2015167243A1
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cells
disease
compound
immune
present
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PCT/KR2015/004299
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English (en)
Korean (ko)
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조미라
신동윤
박성환
양철우
최종영
박민정
손혜진
이성희
이선영
김은경
김재경
이승훈
박상혁
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가톨릭대학교 산학협력단
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Priority to EP15786179.0A priority Critical patent/EP3130582B8/fr
Priority to CN201580021720.9A priority patent/CN106458869A/zh
Priority to AU2015254037A priority patent/AU2015254037B2/en
Priority to ES15786179T priority patent/ES2702337T3/es
Priority to JP2016565203A priority patent/JP6462002B2/ja
Priority to CA2946516A priority patent/CA2946516C/fr
Priority claimed from KR1020150060182A external-priority patent/KR101705446B1/ko
Publication of WO2015167243A1 publication Critical patent/WO2015167243A1/fr
Priority to US15/339,410 priority patent/US20170114008A1/en
Priority to US15/819,758 priority patent/US10100006B2/en

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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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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

Definitions

  • the present invention relates to novel compounds having excellent therapeutic and prophylactic effects of immune diseases and their use.
  • Immune diseases are diseases in which components of the mammalian immune system cause, mediate or otherwise contribute to mammalian pathologies, in particular inflammatory disorders are one of the most important health problems in the world.
  • Inflammation is generally a localized protective response of body tissues to host invasion by foreign substances or harmful stimuli.
  • causes of inflammation include infectious causes such as bacteria, viruses and parasites; Physical causes such as burns or irradiation; Chemicals such as toxins, drugs or industrial preparations; It may be an immune response, such as an allergic and autoimmune response, or a condition associated with oxidative stress.
  • Inflammation is characterized by pain, redness, swelling, fever and ultimate loss of function of the infected area. These symptoms are the result of a series of complex interactions between cells of the immune system.
  • the response of the cell results in an interactive network of different groups of inflammatory mediators: proteins (eg cytokines, enzymes (eg proteases, peroxidases), major basic proteins, adhesion molecules (ICAM, VCAM), lipid mediators (e.g. eicosanoids, prostaglandins, leukotriene, platelet activating factor (PAF)), reactive oxygen species (e.g.
  • autoimmune disease one of immune diseases, is characterized by the immune system attacking its own organs and causing a spontaneous reaction. These responses are due to the recognition of auto-antigens by T lymphocytes, leading to humoral (autoantigen production) and cellular (increased lymphocyte and macrophage cytotoxic activity) immune responses.
  • autoimmune diseases include the following: rheumatic diseases, psoriasis, systemic dermatitis, multiple sclerosis, lupus erythematosus, or worsening of immune response by antigen, ie asthma, allergies to drugs or food, and the like. These diseases are all limited and chronic diseases, and in some cases fatal, to date there is no effective treatment method for treating the diseases. Therefore, any drug, medicine or medium that can alleviate or alleviate the disease during the course of the disease will be an important solution for the health of the patient.
  • autoimmune diseases mainly based on the use of immunosuppressive drugs such as glucocorticoids, calcineurin inhibitors and antiproliferatives-antimetabolites.
  • immunosuppressive drugs such as glucocorticoids, calcineurin inhibitors and antiproliferatives-antimetabolites.
  • pharmacological therapies act on a variety of targets, and as a whole, may lower immune function. Otherwise, long-term use of these pharmacological therapies poses a problem for various cytotoxic actions, which can expose the patient to risk of infection and cancer by inhibiting the immune system in a nonspecific manner. Since calcineurin and glucocorticoids present another problem due to their nephrotoxicity and diabetes-inducing properties, their use is limited for some clinical symptoms (eg renal failure, diabetes, etc.).
  • the inventors of the present invention have completed the present invention by finding that a newly synthesized novel compound can effectively treat immune diseases while searching for a material that can effectively prevent or treat immune diseases while reducing human side effects.
  • Another object of the present invention to provide a pharmaceutical composition for the prevention or treatment of immune diseases comprising the novel compound as an active ingredient.
  • Another object of the present invention is to provide a method for treating undifferentiated T cells with differentiating T cells in vitro and reducing the activity of Th17 cells by treating the novel compounds of the present invention in vitro.
  • Another object of the present invention is to provide a method for treating undifferentiated T cells with differentiating T cells and increasing the differentiation of undifferentiated T cells into Treg cells and increasing the activity of Treg cells in vitro.
  • the present invention provides novel biguanide derivative compounds.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of immune diseases comprising the novel compound of the present invention as an active ingredient.
  • the compound may reduce or inhibit the production of inflammatory cytokines, inhibit the production of autoantibodies, and inhibit the differentiation of osteoclasts.
  • the inflammatory cytokine may be IL-17, IL-6, TNF-a, IFN-r, MMP-9 or STAT-3.
  • the antibody may be IgG, IgG1 or IgG2a.
  • the compound may promote or increase the activity of regulatory T cells (regulatory T cells), and may reduce or inhibit the activity of Th17 cells that are pathogens.
  • the compound may be included in a concentration of 0.1mM ⁇ 10mM in the composition.
  • the immune disease is an autoimmune disease; Inflammatory diseases; And it may be selected from the group consisting of transplant rejection (transplantation rejection) disease of cells, tissues or organs.
  • the immune disease is rheumatoid arthritis, Behcet's disease, multiple myositis or skin myositis, autoimmune hematopoiesis, autoimmune myocarditis, atopic dermatitis, asthma, primary cirrhosis, dermatitis, Goodfitz syndrome , Autoimmune meningitis, Sjogren's syndrome, lupus, Addison's disease, alopecia areata, ankylosing myelitis, autoimmune hepatitis, autoimmune mumps, Crohn's disease, insulin dependent diabetes mellitus, dystrophic epidermal detachment, epididymitis, glomerulonephritis, Graves' disease, Guillain Barre syndrome, Hashimoto's disease, hemolytic anemia, multiple sclerosis, myasthenia gravis, vulgaris, psoriasis, rheumatic fever, sarcoidosis, scler
  • the transplant rejection disease may be a graft versus host disease.
  • the present invention also provides an immunomodulator comprising the novel compound of the present invention as an active ingredient.
  • the present invention provides a method of treating undifferentiated T cells with differentiation of Th17 cells and reducing the activity of Th17 cells by treating the novel compounds of the present invention in vitro.
  • the present invention also provides a method for treating undifferentiated T cells with differentiating T cells in vitro and increasing the differentiation of undifferentiated T cells into Treg cells and the activity of Treg cells in vitro.
  • the present invention relates to novel compounds and their use which can effectively prevent and treat immune diseases.
  • the novel compounds of the present invention inhibit the production of inflammatory cytokines, not only increase the activity of regulatory T cells with immunomodulatory functions, but also inhibit the production of autoantibodies to control excessive immune responses and to differentiate osteoclasts.
  • immune diseases such as autoimmune diseases, inflammatory diseases and transplant rejection diseases caused by the regulation of various immune responses.
  • Figure 1 shows the results of analyzing the cytotoxicity, autoantibody production, inflammatory cytokine production and inflammatory gene expression according to the SD-281 compound treatment at each concentration in normal mouse spleen cells. At this time, observe whether osteoclast differentiation is regulated by SD-281 compound treatment.
  • Figure 2 shows the results of analysis of Th17 inhibitory and Treg activation, over-activated Th17 inhibitory according to the treatment of SD-281 compound at each concentration in normal mouse spleen cells and osteoclasts derived from bone marrow cells (BM) of the mouse The result of analyzing the differentiation inhibitory ability is shown.
  • Figure 3 shows the results of analyzing cytotoxicity, autoantibody production, inflammatory cytokine production and inflammatory gene expression according to SD-281 compound treatment at each concentration in the spleen cells of rheumatoid arthritis-induced mice. .
  • Figure 4 shows the results of analyzing the degree of Th17 inhibition and Treg activation, osteoclast differentiation inhibition according to the treatment of SD-281 compound at each concentration in the spleen cells of rheumatoid arthritis induced mice.
  • Figure 5 shows the results of analyzing the cytotoxicity, autoantibody production, the production of inflammatory cytokines and inflammatory gene expression according to the treatment of SD-281 compound at each concentration in the spleen cells of Lupus-infected mice.
  • Figure 6 shows the results of analyzing the degree of Th17 inhibition and Treg activation in accordance with the treatment of SD-281 compound at each concentration in splenocytes of mice with Lupus.
  • Figure 7 shows the results of analyzing the cytotoxicity and inflammatory cytokine production in accordance with the SD-281 compound treatment at each concentration in lymphocytes isolated from human peripheral blood.
  • Figure 8 shows the results of analyzing the cytotoxicity, autoantibody production, the production of inflammatory cytokines and inflammatory gene expression according to the treatment of SD-282 compound at each concentration in normal mouse splenocytes.
  • FIG. 9 shows the results of analysis of Th17 inhibition and Treg activation, osteoclast differentiation inhibition, and hyperactivated Th17 inhibition in normal mouse splenocytes according to SD-282 compound treatment at each concentration.
  • FIG. 10 shows the results of analyzing cytotoxicity, autoantibody production, inflammatory cytokine production and inflammatory gene expression according to SD-282 compound treatment at each concentration in spleen cells of rheumatoid arthritis-induced mice. .
  • Figure 11 shows the results of the analysis of the degree of Th17 inhibition and Treg activation, osteoclast differentiation inhibition according to the treatment of SD-282 compound at each concentration in the spleen cells of rheumatoid arthritis induced mice.
  • FIG. 12 shows the results of analyzing cytotoxicity, autoantibody production, inflammatory cytokine production, and inflammatory gene expression according to SD-282 compound treatment at each concentration in spleen cells of lupus-infected mice.
  • Figure 13 shows the results of analyzing the degree of Th17 inhibition and Treg activation in accordance with the treatment of SD-282 compound at each concentration in splenocytes of mice suffering from Lupus.
  • Figure 14 shows the results of analysis of the cytotoxicity and inflammatory cytokine production according to the treatment of SD-282 compound at each concentration in lymphocytes isolated from human peripheral blood.
  • FIG. 15 shows the results of analysis of cytotoxicity, autoantibody production, inflammatory cytokine production and inflammatory gene expression according to SD-283 compound treatment at each concentration in normal mouse spleen cells.
  • FIG. 16 shows the results of analysis of Th17 inhibition and Treg activation, osteoclast differentiation inhibition, and hyperactivation of Th17 inhibition in normal mouse splenocytes according to SD-283 compound treatment.
  • FIG. 17 shows the results of analysis of cytotoxicity, autoantibody production, inflammatory cytokine production and inflammatory gene expression according to SD-283 compound treatment at each concentration in splenocytes induced by rheumatoid arthritis. .
  • Figure 18 shows the results of analyzing the degree of Th17 inhibition and Treg activation, osteoclast differentiation inhibition according to the treatment of SD-283 compound at each concentration in the spleen cells of rheumatoid arthritis induced mice.
  • FIG. 19 shows the results of analyzing cytotoxicity, autoantibody production, inflammatory cytokine production, and inflammatory gene expression according to SD-283 compound treatment at each concentration in spleen cells of lupus-infected mice.
  • Figure 20 shows the results of analyzing the degree of Th17 inhibition and Treg activation in accordance with the SD-283 compound treatment at each concentration in the spleen cells of the mice affected by Lupus.
  • Figure 21 shows the results of analyzing the cytotoxicity and inflammatory cytokine production according to the treatment of SD-283 compound at each concentration in lymphocytes isolated from human peripheral blood.
  • Figure 22 shows the results of analyzing the cytotoxicity, the production of inflammatory cytokines and the Th17 inhibitory and Treg activity of the splenocytes of normal mice according to the SD-284 compound treatment at each concentration.
  • FIG. 23 shows the results of analysis of cytotoxicity and inflammatory cytokine production according to SD-284 compound treatment at each concentration in lymphocytes isolated from human peripheral blood.
  • Figure 24 shows the results of analyzing the inhibitory activity of the inflammatory cytokines TNF-a and IL-17 of the novel compounds of the present invention.
  • the present invention is characterized by the first finding that the following novel compounds can be used as novel therapeutic agents that can effectively prevent or treat immune diseases.
  • the present invention can provide a novel compound represented by the following formula or a pharmaceutically acceptable salt thereof.
  • X is one or more F, Cl, Br or H; R is hydrogen or alkyl.
  • the compound of the formula may be any one compound selected from the 24 compounds listed in the following table.
  • the present inventors conducted experiments to determine whether the novel compounds synthesized in the present invention can treat immune diseases. According to one embodiment of the present invention, all of the compounds reduce or inhibit the production of inflammatory cytokines, It has been shown to inhibit autologous antibody production and inhibit osteoclast differentiation, wherein the inflammatory cytokines include, but are not limited to, thyIL-17, IL-6, TNF-a, and IFN-r. , MMP-9 or STAT-3.
  • the present invention was found that the compounds have the ability to regulate the suppression of excessive immune response by inhibiting the production of IgG, IgG1 or IgG2a autoantibodies.
  • the compounds of the present invention were able to promote or increase the activity of regulatory T cells (regulatory T cells), it was confirmed that the activity of the pathogen cell Th17 cells decrease or inhibit.
  • the present inventors were able to confirm the possibility that the new compounds synthesized in the present invention as a novel therapeutic agent that can effectively treat immune diseases.
  • T cells are one of a group of cells that play a central role in the immune system as a biological defense system against various pathogens.
  • T cells are produced in the thymus of the human body and undergo a series of differentiation processes to differentiate into T cells with unique characteristics.
  • T cells which have completed differentiation, are largely divided into type 1 helper cells (Th1) and type 2 according to their function. It is divided into helper cells (Th2).
  • Th1 cells the main function of Th1 cells is involved in cell mediated immunity
  • Th2 cells are involved in humoral immunity
  • these two cell populations are balanced with each other so that they are not activated with each other.
  • Tregs immunoregulatory T cells
  • Th17 cells are known to be formed through a process similar to the differentiation of Treg cells during the differentiation of undifferentiated T cells. That is, differentiation of Treg cells and Th17 cells is performed in the presence of TGF- ⁇ in common but does not require IL-6 in Treg cells, whereas IL-6 is present in combination with TGF- ⁇ in Th17 cells. Differentiate in situations In addition, differentiated Th17 cells are characterized by the secretion of IL-17.
  • Th17 cells Unlike Treg cells, Th17 cells have been found to be involved in the forefront of inflammatory reactions seen in immune diseases, maximizing the signal of inflammatory responses and accelerating disease progression. Therefore, in the case of autoimmune diseases which are not controlled by Treg cells among autoimmune diseases, development of therapeutic agents for autoimmune diseases that target the inhibition of Th17 cell activity has been highlighted.
  • immunotherapeutic agents that block signal transduction pathways in T cells are the most commonly used immunosuppressive agents, such as toxicity, infection, lymphoma, diabetes, tremor, headache, diarrhea, high blood pressure, There are problems such as side effects such as nausea, renal failure.
  • novel compounds provided by the present invention have the ability to simultaneously operate the action of inhibiting inflammatory cytokine production, inhibiting Th17 cells and Treg cell activity, and thus may be able to treat immune diseases more effectively than conventional therapeutics. .
  • the results of one embodiment of the present invention was confirmed that the compounds of the present invention have the activity of inhibiting the gene expression of STAT3, recently, the active forms of STAT1, STAT3 and STAT5 have been found in various carcinomas, STAT3 is an important anticancer target because it is active in various solid cancers such as breast cancer, head and neck cancer, melanoma, ovarian cancer, lung cancer, pancreatic cancer and prostate cancer, as well as blood cancers such as leukemia (Hua Yu and Richard Jove, Nature Review). Cancer., 2004, 8, 945).
  • STAT3 has been known to inhibit apoptosis, induce angiogenesis, and induce immune evasion (Wang T. et al., Nature Medicine., 2004, 10, 48). Therefore, inhibition of STAT3 activity is effective in controlling tumors by a complex anti-cancer mechanism, and since STAT3 protein is involved in various intracellular functions as well as tumors, its inhibitor discovery can be developed as an immunosuppressive agent.
  • the immune system controls specific immune responses to autologous antigens in a normal state, and also suppresses immune responses to external antigens.
  • a pregnant woman's response to a fetus and a chronically infected microorganism may be used.
  • Immune response These phenomena are known to be induced by clonal deletion, clone anergy and active control by immunoregulatory T cells (Treg) as a mechanism by which antigen specific immunotolerance can be induced.
  • Treg immunoregulatory T cells
  • the immunoregulatory T cells ie immunoregulatory T lymphocytes (Tregs), which have recently been identified, can be largely divided into natural and adaptive Treg cells, and CD4 + CD25 + T cells, which are natural Tregs, are referred to as thymus It is given immunosuppressive function when it is newly created in, and is present in 5 ⁇ 10% of peripheral CD4 + T lymphocytes of normal individuals.
  • the mechanism of immunosuppression of this cell is not yet known, but it has recently been discovered that the expression control factor of the gene, Foxp3, plays an important role in the differentiation and activity of the cell.
  • peripheral natural T cells can be differentiated into cells that exhibit immunosuppressive effects when stimulated by autologous or external antigens under certain circumstances, which are called adaptive or inducible Tregs and secrete IL-10. These include Tr1, Th3 and CD8 Ts that secrete TGF- ⁇ .
  • Th17 cells are differentiated into Th17 cells through differentiation in addition to Treg cells.
  • Th17 cells are formed in the presence of TGF- ⁇ in common with Treg cells, but Treg cells do not require IL-6, Th17 cells are characterized by differentiating in the presence of IL-6 with TGF- ⁇ and secreting IL-17.
  • Th17 cells are characterized by having cytotoxicity that maximizes the signal of the inflammatory response to accelerate disease progression. Therefore, inhibition of differentiation or activity into Th17 cells is one of the ways to treat immune diseases.
  • Treg cells express Foxp3, which is mainly present in regulatory T cells derived from the thymus and transcriptional factors present in cells with CD4 + CD25 + labeled antigens.
  • the function may cause autoimmunity among CD4 + CD25- T cells that do not express Foxp3 differentiated from the thymus while having low reactivity to the antigen upon antigen recognition against T cells expressing Foxp3. It has a role as a suppressor T cell that inhibits the production and division of IL-2 against T cells.
  • Foxp3 is not only IL-2, but also IL-4, which is influenced by the transcription factor NFAT on CD25-T cells through regulatory T cells expressing Foxp3 and cell-cell contact therewith.
  • T cells expressing Foxp3 having such a function, it is applied to the treatment of immune diseases through the action of inhibiting or regulating the immune response, and furthermore, the CD4 T cells expressing Foxp3 present in humans.
  • self-antigen specific T cell clones to cell therapy by increasing their number through high concentration of IL-2 cytokine and combination treatment with anti-CD3 and anti-CD28 antibodies There have been attempts.
  • the novel compounds provided by the present invention show a more effective pharmacological effect with the solution of the problems that have not been solved in the past, and thus may be very useful as therapeutic agents for the immunological diseases.
  • the pharmaceutical composition for preventing or treating the immune disease provided by the present invention may include the novel compound or a pharmaceutically acceptable salt thereof according to the present invention.
  • the salt is preferably an acid addition salt formed by a pharmaceutically acceptable free acid, and an organic acid and an inorganic acid may be used as the free acid.
  • the organic acid is not limited thereto, citric acid, acetic acid, lactic acid, tartaric acid, maleic acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, benzoic acid, gluconic acid, metasulfonic acid, glycolic acid, succinic acid, 4-toluenesulfonic acid, Glutamic acid and aspartic acid.
  • the inorganic acid includes, but is not limited to, hydrochloric acid, bromic acid, sulfuric acid and phosphoric acid.
  • the compounds according to the invention can be used isolated from nature or prepared by chemical synthesis known in the art, and the inventors have synthesized these compounds by the methods described in the Examples below.
  • the "immune disease” refers to a disease in which components of the mammalian immune system cause, mediate or otherwise contribute to the pathology of a mammal.
  • stimulation or interruption of an immune response may include any disease that has a compensatory effect on the progression of the disease, and in the present invention may include diseases caused by an overactive immune response.
  • immune diseases include, but are not limited to, autoimmune diseases; Inflammatory diseases; And transplant rejection of cells, tissues, or organs.
  • one of the most important traits of all normal individuals is that they do not deleteriously react with the antigenic substances that make up self, while non-self antigens can recognize and react to eliminate them.
  • Have the ability to The non-response of the body to autoantigens is called immunologic unresponsiveness or tolerance.
  • inflammatory disease refers to tumor necrosis factor- ⁇ (TNF- ⁇ ) and IL-1 (excessively stimulated in the immune system such as macrophages due to excessive stimulation of the body's immune system due to harmful stimuli such as inflammation-inducing factors or irradiation).
  • interleukin-1 interleukin-1
  • IL-6 prostaglandin
  • prostagladin prostaglandin
  • luecotriene nitric oxide
  • NO nitric oxide
  • T cell The major mediator of GCC is T cell, which is induced by the T cell receptor to recognize the major histocompatibility complex (MHC) expressed in the graft. The reaction will occur.
  • MHC major histocompatibility complex
  • the major histocompatibility component is determined by the type of glycoprotein antigen.
  • the immune response caused by the mismatch of the histocompatibility antigens is a barrier to successful transplantation, and the investigation of the accuracy and agreement of the histocompatibility antigen test is a very important factor.
  • Class I antigens include HLA-A, -B, and -C and Class II antigens including HLA-DR, -DP and -DQ.
  • the biological function of these antigens delivers antigens to T lymphocytes, and Class I antigens are expressed in most nucleated cells, and antigens delivered through them are recognized by CD8 + cytotoxic T lymphocytes.
  • Class II antigens are expressed in dendritic cells, B lymphocytes, activated T lymphocytes, macrophages, and the like, which are known as antigen presenting cells, and function to deliver antigens to CD4 + T lymphocytes.
  • Antigens delivered to T lymphocytes bind to T lymphocyte receptors so that the T lymphocytes recognize antigens.
  • tissue antigens from other than their own are recognized at high frequency.
  • About 1 to 10% of the donor or patient's total T lymphocytes recognize histocompatibility antigens derived from the patient or donor and proliferate in response to them, causing a series of immune responses, called “Alloresponse.” do.
  • a donor's T lymphocytes that cause an immune response to a patient's histocompatibility antigens are called "graft versus host disease (GVDH)". (graft rejection) ".
  • immunosuppressive agents are used to reduce abnormal reactions caused by the immune response occurring in the transplantation process.
  • a common purpose of these immunosuppressive agents is to suppress T cell-mediated immune responses against the graft. Attempts have been made to treat transplant rejection by suppressing immune responses.
  • the kind of the immune disease that can be prevented and treated in the present invention is not limited thereto, but rheumatoid arthritis, Behcet's disease, multiple myositis or skin myositis, autoimmune cytopenia, autoimmune myocarditis, atopic dermatitis, asthma, primary Liver Cirrhosis, Dermatitis, Goodfiction Syndrome, Autoimmune Meningitis, Sjogren's Syndrome, Lupus, Addison's Disease, Alopecia areata, Ankylosing myelitis, Autoimmune Hepatitis, Autoimmune Mumps, Crohn's Disease, Insulin-Dependent Diabetes, Dystrophic Epidermolysis , Epididymitis, glomerulonephritis, Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, hemolytic anemia, multiple sclerosis, myasthenia gravis, vulgaris, psoriasis, rheumatoid arthritis,
  • composition according to the present invention can be used as a pharmaceutical composition that can prevent or treat immune diseases.
  • treatment means to reverse, alleviate, inhibit the progression of, or prevent the disease or condition to which the term applies, or one or more symptoms of the disease or condition.
  • treatment refers to the act of treating when “treating” is defined as above.
  • treatment or “therapy” of an immune disease in a mammal may include one or more of the following:
  • a composition for the prophylaxis or treatment of an immune disease according to the present invention comprises a pharmaceutically effective amount of one or more of the compounds or salts thereof, or one or more pharmaceutically acceptable carriers, excipients or diluents in the present novel compounds. It may include.
  • the pharmaceutically effective amount herein refers to an amount sufficient to prevent, ameliorate and treat the symptoms of an immune disease.
  • the pharmaceutically effective amount of the novel compound or salt thereof according to the present invention may be appropriately changed depending on the degree of symptoms of immune disease, the age, weight, health condition, sex, route of administration and duration of treatment of the patient.
  • pharmaceutically acceptable refers to a composition that is physiologically acceptable and does not normally cause an allergic reaction, such as gastrointestinal disorders, dizziness, or the like when administered to a human.
  • carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • fillers, anti-coagulants, lubricants, wetting agents, fragrances, emulsifiers and preservatives may be further included.
  • compositions of the present invention may be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal.
  • the formulations may be in the form of powders, granules, tablets, emulsions, syrups, aerosols, soft or hard gelatin capsules, sterile injectable solutions, sterile powders.
  • composition for preventing or treating immune diseases according to the present invention may be administered through various routes including oral, transdermal, subcutaneous, intravenous or intramuscular, and the dosage of the active ingredient is determined by the route of administration, age, sex, It may be appropriately selected according to various factors such as the weight and the severity of the patient, and the composition for preventing or treating an immune disease according to the present invention is combined with a known compound having the effect of preventing, ameliorating or treating the symptoms of an immune disease. May be administered.
  • the present invention also provides the use of a composition comprising the compound as an active ingredient for the manufacture of a medicament for the prevention or treatment of immune diseases.
  • the composition of the present invention comprising the compound of the present invention as an active ingredient can be used for the manufacture of a medicament for the prevention or treatment of immune diseases.
  • the present invention also provides a method for preventing or treating an immune disease comprising administering to a mammal a therapeutically effective amount of a pharmaceutical composition of the present invention.
  • mammal refers to a mammal that is the subject of treatment, observation or experimentation, preferably human.
  • the term “therapeutically effective amount” means an amount of an active ingredient or pharmaceutical composition that induces a biological or medical response in a tissue system, animal or human, as thought by a researcher, veterinarian, doctor or other clinician, which Amounts that induce alleviation of the symptoms of the disease or disorder being treated. It will be apparent to those skilled in the art that the therapeutically effective dosages and frequency of administrations for the active ingredients of the present invention will vary depending on the desired effect. Therefore, 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 present invention can provide an immunomodulator comprising the compound provided by the present invention as an active ingredient.
  • the present invention can provide a method for reducing the activity of Th17 cells in cells by treating the cells of the compounds of the present invention in vitro, and by treating the cells with a novel compound of the present invention in vitro It may also provide a method for increasing the activity of Treg cells in the.
  • each aniline compound (1.0 mmol) was dissolved in an acetonitrile solvent in a sealed reactor, then dicyano diamide (1.0 mmol) and concentrated sulfuric acid (1.0 mmol) were added and sealed, followed by 1 hour at 175 ° C. Stirred. After cooling to room temperature to produce a white solid, the solvent was removed and washed with hexane and isopropyl alcohol to synthesize the following compounds in the form of a white solid.
  • the present inventors performed the following experiment based on the following experimental group to confirm whether each of the compounds newly synthesized herein can treat and prevent immune diseases.
  • the normal mouse group was activated 72 h cultured under anti-CD3 0.5ug / ml stimulation conditions before activating the cells of splenocytes obtained from DBA / 1J-based normal mice after activating the cells Used.
  • mice were prepared using DBA / 1J-based normal mice, in which normal type 2 collagen (Cll) was dissolved in 0.1N acetic acid solution to 4 mg / ml, and then dialysis buffer (50mM Tris). , 0.2 N Nacl) and mixed in the same amount with complete Freund's adjuvant (CFA, Chondrex) containing M. tuberculosis, subcutaneously injected into the base of the mouse, 100 ⁇ l per animal (ie 100 ⁇ l) / 100 ⁇ g) (first injection).
  • CFA complete Freund's adjuvant
  • the lupus-onset mouse model used sanroque mice which are used as a lupus model in the art
  • the human P.B group used lymphocytes obtained from human peripheral blood. Isolation of splenocytes and lymphocytes from each mouse and human peripheral blood was carried out using a general method well known in the art, and all obtained cells were cultured for 72 h under anti-CD3 0.5ug / ml stimulation conditions. It was used after activation.
  • MTT analysis was performed. Each cell was divided into cells at 96 ⁇ well plates at 2 ⁇ 10 5 cells per well. Compounds of the present invention were treated at each concentration and incubated for 72 hours, and then cells were treated with MTT solution (0.5% 3-4,5-dimethyl thiazol-2-yl) -2,5-diphenyl-2H-tetrazolium bromide). After 4 hours of incubation, the absorbance was measured at 540 nm using an ELISA (enzymelinked immunospecific assay) test to observe the presence of cytotoxicity.
  • Enzyme-linked immunoassay was performed to determine whether the novel compounds of the present invention affect the production of total IgG and total IgG1 and IgG2a antibodies in serum. Therefore, total IgG and antibody specific IgG1 and IgG2a were measured by using a sandwich ELISA in the cells treated with the compound of the present invention.
  • Each monoclonal anti-mouse IgG and CII were reacted at room temperature for 1 hour in a 96 well plate, and then non-specific binding was blocked with a blocking solution (1% BSA / PBST).
  • Mouse contorl serum was serially diluted by 1/2 and used as a standard. Cell culture supernatants were added and reacted at room temperature for 1 hour. Thereafter, anti-mouse IgG-HRP and anti-mouse IgG2a-HRP were allowed to react at room temperature for 1 hour and washed four times, followed by color development using a TMB system.
  • inflammatory cytokines which are the causative agents of inflammation and immune diseases
  • the present inventors studied IL-17, IL-6, TNF-a, IFN in each experimental group.
  • the production of -r, MMP-9 and STAT-3 and the expression of these cytokine mRNAs were analyzed.
  • the production of inflammatory cytokines was obtained by treating the cells of the present invention with supernatants of the cultured cells. Afterwards, it was analyzed by enzyme-linked immunoassay (ELISA).
  • each cytokine (anti-IL-17, anti-IL-6, anti-TNF-a, anti-IFN- r, anti-MMP-9, anti-STAT-3) was reacted overnight at 4, followed by blocking the nonspecific binding with blocking solution (1% BSA / PBST). Thereafter, each of the biotinylated antibodies were reacted at room temperature for 2 hours, washed four times, and then diluted with an ExtraAvidin-Alkaline Phosphatase conjugate, followed by reaction at room temperature for 2 hours. Thereafter, PNPP / DEA solution was added, followed by color development, and absorbance at 405 nm was measured.
  • analysis of the expression level of inflammatory cytokines was performed by obtaining total RNA from the cells to be analyzed and then using RT-PCR using primers that specifically bind to IL-17, IL-6, TNF-a and IFN-r. was performed to analyze the amount of mRNA.
  • the present inventors analyzed using a flow cytometer to determine whether the novel compounds of the present invention can inhibit the differentiation and activity of Th17 cells associated with inflammation, and at the same time promote the activity of immunoregulatory Treg cells. It was. That is, after culturing the cells in T 17 cells or Treg cell differentiation conditions for T cells, the number of Foxp3 + Treg cells or il-17 + Th 17 cells were analyzed by flow cytometry.
  • mouse bone marrow cells were obtained and induced to differentiate into bone marrow cells in the presence of macrophage colony-stimulating factor (MCSF) and soluble RANKL (Sugatani et al. 2003, J. Cell.Biochem. 90, 59-67 method).
  • MCSF macrophage colony-stimulating factor
  • RANKL soluble RANKL
  • Example 1 In order to confirm whether the novel compounds synthesized in Example 1 are cytotoxic, the cell viability of the cells of each experimental group described in Table 3 was confirmed by MTT analysis. That is, cells of each experimental group were divided into 2 ⁇ 105 cells per well, and the new synthetic compounds of the present invention were treated for each concentration, and then cell viability was analyzed.
  • the compounds of the SD-281, SD-282, SD-283, and SD-284 were not found to have cytotoxicity according to the treatment according to the cell concentration when compared with the control or metformin treatment group. It was found that there is no cytotoxicity according to diseased cells.
  • Example 1 In order to investigate whether the novel compounds synthesized in Example 1 affect the immune response by the production of autoantibodies, blood was obtained from each mouse group through orbital blood collection from the four groups of mice described above, and serum was isolated. The amount of IgG, IgG1, IgG2a was measured.
  • the compounds of the present invention all showed that the amount of immunoglobulins (total IgG, IgG1, IgG2) in autoantibody production state in the disease conditions decreased by the treatment concentration of the compounds, the compounds described in Table 4 below are excessive immune response It was found that the immunomodulatory function of inhibiting is excellent.
  • the novel compounds synthesized in the present invention all process both the production of inflammatory cytokines IL-17, IL-6, TNF-a, IFN-r, MMP-9, STAT-3 and expression at the gene level. It was shown to inhibit concentration dependently. Therefore, these results indicate that the novel compounds of the present invention can prevent and treat immune diseases through inhibition of the production of inflammatory cytokines.
  • the inventors of the present invention investigated whether the differentiation and activity of Treg cells having immunomodulatory ability together with the differentiation and activity of Th17 cells secreting the inflammatory cytokine IL-17 against the novel compounds of the present invention. Th17 cell inhibition and Treg cell induction activity assays described in> were performed.
  • the present inventors found that the novel compounds of the present invention can regulate Th17 and Tregs independently, but at the same time, thereby inducing immunomodulatory ability, and thus, more efficient immunomodulators or immunity. It was found that these compounds could be used as a therapeutic agent for diseases.
  • the degree of inhibition of osteoclast differentiation by the compound of the present invention in the cells stimulated with M-CSF and RANKL was determined by TRAP staining, an osteoclast differentiation factor. Confirmed.
  • the inventors of the present invention in order to evaluate the effectiveness of the inhibitory effect of inflammatory cytokines on each compound synthesized in the embodiment of the present invention, 0.5ug of Anti mouse CD3 to cells obtained from the spleen of DBA1 / J normal mouse group After treatment at a concentration of / ml and co-stimulated each compound at a concentration of 200 and 500uM, the degree of inhibition of inflammatory cytokines IL-17 and TNFa was confirmed by ELISA technique.

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Abstract

L'invention concerne un nouveau composé permettant de prévenir et de traiter efficacement des maladies immunitaires, ainsi que l'utilisation de ce composé. Le nouveau composé selon l'invention présente des effets d'inhibition de la production de cytokines inflammatoires, d'augmentation de l'activité de lymphocytes T régulateurs dotés de fonctions immunorégulatrices, d'inhibition de la production d'auto-anticorps pour réguler les réactions immunitaires excessives, et d'inhibition de la différenciation d'ostéoclastes. Ce composé peut ainsi être utilisé dans le traitement des maladies immunitaires, telles qu'une maladie auto-immune, une maladie inflammatoire et les maladies de rejet du greffon, qui sont provoquées par une régulation anormale de divers types de réactions immunitaires.
PCT/KR2015/004299 2014-04-29 2015-04-29 Nouveau composé ayant un effet thérapeutique sur les maladies immunitaires et utilisation de ce composé WO2015167243A1 (fr)

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EP15786179.0A EP3130582B8 (fr) 2014-04-29 2015-04-29 Composé ayant un effet thérapeutique sur les maladies immunitaires et utilisation de ce composé
CN201580021720.9A CN106458869A (zh) 2014-04-29 2015-04-29 具有免疫疾病治疗效果的新型化合物及其应用
AU2015254037A AU2015254037B2 (en) 2014-04-29 2015-04-29 Novel compound having immune disease treatment effect and use thereof
ES15786179T ES2702337T3 (es) 2014-04-29 2015-04-29 Compuesto que tiene un efecto terapéutico en las enfermedades inmunitarias y uso del mismo
JP2016565203A JP6462002B2 (ja) 2014-04-29 2015-04-29 免疫疾患治療効果を有する新規化合物およびその使用
CA2946516A CA2946516C (fr) 2014-04-29 2015-04-29 Compose ayant un effet de traitement des maladies immunitaires et utilisation connexe
US15/339,410 US20170114008A1 (en) 2014-04-29 2016-10-31 Novel compound having immune disease treatment effect and use thereof
US15/819,758 US10100006B2 (en) 2014-04-29 2017-11-21 Compound having immune disease treatment effect and use thereof

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WO2019047866A1 (fr) * 2017-09-05 2019-03-14 1Globe Biomedical Co., Ltd. Nouveaux agents thérapeutiques destinés pour des troubles du système nerveux central
WO2020096371A1 (fr) * 2018-11-07 2020-05-14 가톨릭대학교 산학협력단 Composition pour prévenir et traiter un rejet de greffe ou des maladies liées à un rejet de greffe, comprenant un nouveau composé et un inhibiteur de la calcineurine
KR20220069855A (ko) * 2020-11-20 2022-05-27 가톨릭대학교 산학협력단 바이구아나이드를 유효성분으로 포함하는 smile 발현이 저하된 대사이상 난치 류마티스관절염 또는 염증성 장질환의 예방 또는 치료용 약학적 조성물
WO2022108390A1 (fr) * 2020-11-20 2022-05-27 가톨릭대학교 산학협력단 Composition pharmaceutique pour la prévention ou le traitement de troubles immunitaires dans lesquels l'expression de smile est réduite, contenant du biguanide en tant que principe actif

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JP2018536638A (ja) * 2015-10-13 2018-12-13 インノファーマスクリーン インコーポレイテッド 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
WO2019047866A1 (fr) * 2017-09-05 2019-03-14 1Globe Biomedical Co., Ltd. Nouveaux agents thérapeutiques destinés pour des troubles du système nerveux central
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WO2020096371A1 (fr) * 2018-11-07 2020-05-14 가톨릭대학교 산학협력단 Composition pour prévenir et traiter un rejet de greffe ou des maladies liées à un rejet de greffe, comprenant un nouveau composé et un inhibiteur de la calcineurine
KR20200052743A (ko) * 2018-11-07 2020-05-15 가톨릭대학교 산학협력단 신규 화합물 및 칼시뉴린 억제제를 포함하는 이식 거부 반응 또는 이식 거부 질환의 예방 및 치료용 조성물
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CN113194936A (zh) * 2018-11-07 2021-07-30 加图立大学校产学协力团 含新型化合物和钙调磷酸酶抑制剂的用于预防和治疗移植排斥反应或移植排斥疾病的组合物
KR20220069855A (ko) * 2020-11-20 2022-05-27 가톨릭대학교 산학협력단 바이구아나이드를 유효성분으로 포함하는 smile 발현이 저하된 대사이상 난치 류마티스관절염 또는 염증성 장질환의 예방 또는 치료용 약학적 조성물
WO2022108390A1 (fr) * 2020-11-20 2022-05-27 가톨릭대학교 산학협력단 Composition pharmaceutique pour la prévention ou le traitement de troubles immunitaires dans lesquels l'expression de smile est réduite, contenant du biguanide en tant que principe actif
KR102504468B1 (ko) * 2020-11-20 2023-02-28 가톨릭대학교 산학협력단 바이구아나이드를 유효성분으로 포함하는 smile 발현이 저하된 대사이상 난치 류마티스관절염 또는 염증성 장질환의 예방 또는 치료용 약학적 조성물

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