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WO2015026215A1 - Composition pharmaceutique pour prévenir ou traiter des maladies immunitaires ou des maladies inflammatoires, contenant un composé de dérivé de biguanide comme principe actif - Google Patents

Composition pharmaceutique pour prévenir ou traiter des maladies immunitaires ou des maladies inflammatoires, contenant un composé de dérivé de biguanide comme principe actif Download PDF

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Publication number
WO2015026215A1
WO2015026215A1 PCT/KR2014/007898 KR2014007898W WO2015026215A1 WO 2015026215 A1 WO2015026215 A1 WO 2015026215A1 KR 2014007898 W KR2014007898 W KR 2014007898W WO 2015026215 A1 WO2015026215 A1 WO 2015026215A1
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biguanide
disease
diseases
inflammatory
immune
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Korean (ko)
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WO2015026215A9 (fr
Inventor
조미라
양철우
신동윤
박민정
이선영
이성희
양은지
손혜진
김은경
김재경
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Industry Academic Cooperation Foundation of Catholic University of Korea
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Industry Academic Cooperation Foundation of Catholic University of Korea
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Priority to US15/502,981 priority Critical patent/US10369121B2/en
Priority claimed from KR1020140110919A external-priority patent/KR101642587B1/ko
Publication of WO2015026215A1 publication Critical patent/WO2015026215A1/fr
Publication of WO2015026215A9 publication Critical patent/WO2015026215A9/fr
Anticipated expiration legal-status Critical
Priority to US16/445,996 priority patent/US10716771B2/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)
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to biguanide derivative compounds capable of effectively preventing and treating immune diseases or inflammatory diseases.
  • Immune disease refers to a disease in which components of the immune system cause, mediate or otherwise contribute to pathology, in particular inflammatory disorders are one of the most important health problems worldwide. Inflammation generally refers to 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; Immune responses, such as allergies and autoimmune reactions, or conditions associated with oxidative stress.
  • Inflammation is characterized by symptoms such as pain, redness, swelling, fever and ultimate loss of function of the infected area. These symptoms are the result of a series of complex interactions that occur between cells of the immune system.
  • proteins eg cytokines, enzymes (eg proteases, peroxidases), major basic proteins, adhesion molecules (ICAM, VCAM), lipid mediators (eg For example, eicosanoids, prostaglandins, leukotriene, platelet activating factor (PAF), reactive oxygen species (e.g., hydroperoxide, superoxide anion O2- , nitric oxide (NO), etc.
  • the action network is created, but most of these mediators are also regulators of normal cellular activity, thus the host is compromised (ie, infected) uncontrolled due to lack of inflammatory response, and thus in part due to chronic inflammation. Overproduction of several of the aforementioned mediators results in inflammatory diseases mediated.
  • 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 rheumatoid disease, psoriasis, systemic dermatitis, multiple sclerosis, lupus erythematosus, or worsening of immune response by antigen, ie asthma, drug or food allergy. 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.
  • these drugs act against a variety of targets, and as a whole, may lower immune function.
  • long-term use of these pharmacological therapies may result in several cytotoxic effects, and by inhibiting the immune system in a nonspecific manner, may lead to infection or cancer in patients.
  • 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 present inventors while searching for a material that can effectively prevent or treat immune diseases or inflammatory diseases with little human side effects, synthesized various kinds of biguanide derivative compounds and confirmed the activity thereof, resulting in inflammatory cytokines IL Inhibits production of -17 and TNF- ⁇ ; As well as enhancing the activity of regulatory T cells with immunomodulatory functions;
  • the biguanide derivative compound of the present invention is applied to an inflammatory bowel disease animal model and an acute graft-versus-host disease animal model, the present invention was confirmed by showing a therapeutic effect in vivo .
  • compositions for the prevention or treatment of immune diseases or inflammatory diseases comprising a biguanide derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the biguanide derivative compound is 1- (3,5-dimethoxyphenyl) biguanide, 1- (4- (pentyloxy) biguanide, 1- (4-iso Propylphenyl) biguanide, 1- (2-fluorophenyl) biguanide, 1- (3-isopropylphenyl) biguanide, 1- (4-isopropoxyphenyl) biguanide, 1- ( 3,5-dimethoxyphenyl) biguanide, 1- (2-chlorophenyl) biguanide, 1- (4-fluorophenyl) biguanide, 1- (3-trifluoromethylphenyl) biguanide , 1- (3-fluorophenyl) biguanide, 1- (2,4-difluorophenyl) biguanide, 1- (2,3,4-trifluorofluorophenyl) biguanide, 1 -(2,5-difluorophenyl) biguanide
  • the biguanide derivative compound may exhibit a therapeutic effect through a mechanism to reduce or inhibit the production of inflammatory cytokines.
  • the inflammatory cytokine may be IL-17 or TNF- ⁇ .
  • the biguanide derivative compound may exhibit a therapeutic effect through a mechanism for promoting or increasing the activity of Regulatory T cells.
  • the biguanide derivative compound may be included in the composition in a concentration of 1 ⁇ M ⁇ 1000 ⁇ M.
  • the immune disease may be selected from the group consisting of autoimmune disease, inflammatory immune disease and transplant rejection of cells, tissues or organs.
  • the inflammatory immune disease may be an inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • the transplant rejection disease may be a graft versus host disease.
  • the immune disease is Behcet's disease, polymyositis, cutaneous myositis, autoimmune cytopenia, autoimmune myocarditis, atopic dermatitis, asthma, primary cirrhosis, dermatitis, Goodfiction syndrome, autoimmunity Meningitis, Sjogren's syndrome, systemic lupus erythematosus, Addison's disease, alopecia areata, ankylosing myelitis, autoimmune hepatitis, autoimmune mumps, Crohn's disease, insulin-dependent diabetes, dystrophic epidermal detachment, epididymitis, glomerulonephritis, Graves' disease, Guillain Barre syndrome, Hashimoto's disease, hemolytic anemia, multiple sclerosis, myasthenia gravis, vulgaris, psoriasis, rheumatic fever, rheumatoid arthritis, sarcoidosis,
  • the inflammatory disease is gastritis, enteritis, nephritis, hepatitis, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, irritable bowel syndrome, inflammatory pain, migraine, headache, back pain, fibromyalgia, fascia Diseases, viral infections, bacterial infections, fungal infections, burns, wounds from surgical or dental surgery, PGE hyperplasia, atherosclerosis, gout, Hodgkin's disease, pancreatitis, conjunctivitis, iris, scleritis, uveitis and eczema It can be selected from the group.
  • COPD chronic obstructive pulmonary disease
  • the composition may be administered in an amount of 1 to 100mg per kg body weight (based on preclinical mouse animal model) for the subject in need thereof.
  • the biguanide derivative compounds of the present invention inhibit the production of the inflammatory cytokines IL-17 and TNF- ⁇ , enhance the activity of regulatory T cells with immunomodulatory functions, as well as for various animal models of cotton disease. Since it shows excellent therapeutic effect, it is useful as a pharmaceutical composition or immunosuppressant that can prevent or treat immune diseases or inflammatory diseases such as autoimmune diseases, inflammatory immune diseases and transplant rejection diseases caused by abnormal control of various immune responses. Can be used.
  • 1 is a result of analyzing the IL-17 production in the cells according to the concentration of the biguanide derivative compound of the present invention (2, 20, 200 ⁇ M) treatment in splenocytes isolated from the mouse by a sandwich ELISA method ( A: SD-196, B: SD-216, C: SD-217).
  • Figure 2 is a result of analyzing the TNF- ⁇ production in the cell according to the concentration of the biguanide derivative compound of the present invention (2, 20, 200 ⁇ M) treatment in splenocytes isolated from the mouse by a sandwich ELISA method ( A: SD-196, B: SD-216, C: SD-217).
  • Figure 3 is the result of observing the change in body weight according to administration of the biguanide derivative compound of the present invention in an animal model of inflammatory bowel disease.
  • a to C are the results of measuring the change in weight g (A: SD-196, B: SD-216, C: SD-217)
  • D to F are the results of measuring the change in weight% (D: SD -196, E: SD-216, F: SD-217).
  • Figure 4 is a result of observing the degree of tissue damage caused by inflammation in the colon tissue according to the administration of the biguanide derivative compound of the present invention in inflammatory bowel disease animal model through immunohistochemical staining.
  • Figure 5 is the result of observing the expression level of TNF- ⁇ in the colon tissue according to the administration of the biguanide derivative compound of the present invention in inflammatory bowel disease animal model through immunohistochemical staining method.
  • Figure 6 shows the results of analyzing the degree of inhibition of allogeneic reaction of the derivative compound by treating the biguanide derivative compound of the present invention and measuring the T cell proliferation degree in splenocytes induced allogeneic reaction (alloresponse) ( A: SD-196 compound treatment result, B: SD-216 compound treatment result, C: SD-217 compound treatment result).
  • FIG. 7 is a graph showing the expression level of Treg cells (Foxp3 + CD25 + Treg cells) treated with the biguanide derivative compound of the present invention on splenocytes induced allogeneic reaction by FACS analysis (A), and Treg (B) shows the result of quantifying the number of cells (Foxp3 + CD25 + Treg cells) in a graph.
  • Figure 8 is a graph measuring the survival rate of animals over time after administration of the biguanide derivative compound of the present invention in an animal model of acute graft-versus-host disease.
  • Figure 9 is a cytotoxicity (MTT assay) (A), IgG production (B), IL-17 and TNF- ⁇ inflammatory cytokines in the rheumatoid arthritis animal model to evaluate the effect of the biguanide derivative compounds of the present invention It is the result of measuring (C).
  • Treg regulatory T cells
  • 11 is a result of measuring osteoclast differentiation (TRAP staining) in the animal model of rheumatoid arthritis in order to evaluate the arthritis treatment effect of the biguanide derivative compound of the present invention.
  • Figure 12 shows the cytotoxicity (MTT assay) (A), IL-17 inflammatory cytokine (B) expression in animal models to evaluate the therapeutic effect of rheumatoid arthritis with metabolic syndrome of the biguanide derivative compound of the present invention It is a result of a measurement.
  • Th17 and regulatory T cells are a result of measuring the expression of Th17 and regulatory T cells (Treg) in an animal model to evaluate the therapeutic effect of rheumatoid arthritis with metabolic syndrome of the biguanide derivative compound of the present invention.
  • Figure 14 shows the cytotoxicity (MTT assay) (A), IgG production (B), IL-17 and TNF- ⁇ inflammatory cytokines in the lupus animal model to evaluate the lupus therapeutic effect of the biguanide derivative compounds of the present invention C) It is the result of measuring a change of expression.
  • FIG. 16 shows the results of measuring cytotoxicity (MTT assay) (A) and TNF- ⁇ inflammatory cytokine expression change (B) of the biguanide derivative compounds of the present invention in normal cells.
  • the present invention was first identified that a biguanide derivative compound has an effect of preventing or treating an immune disease through an immunomodulatory action, and thus the biguanide derivative compound or a pharmaceutically acceptable salt thereof is an effective ingredient. It is characterized by providing a composition for the prevention or treatment of immune diseases, including.
  • the biguanide derivative compounds of the present invention are 1- (3,5-dimethoxyphenyl) biguanide, 1- (4- (pentyloxy) biguanide, 1- (4-isopropylphenyl) biguanide , 1- (2-fluorophenyl) biguanide, 1- (3-isopropylphenyl) biguanide, 1- (4-isopropoxyphenyl) biguanide, 1- (3,5-dimethoxy Phenyl) biguanide, 1- (2-chlorophenyl) biguanide, 1- (4-fluorophenyl) biguanide, 1- (3-trifluoromethylphenyl) biguanide, 1- (3- Fluorophenyl) biguanide, 1- (2,4-difluorophenyl) biguanide, 1- (2,3,4-trifluorofluoro) biguanide, 1- (2,5- Difluorophenyl) biguanide, 1-phenethyl
  • the present inventors paid attention to biguanide derivative compounds in order to develop new immunomodulators for the treatment of immune diseases, and the following experiments confirmed that the biguanide derivative compounds of the present invention can effectively regulate immunity.
  • Example 2 of the present invention the expression level of IL-17 was measured by ELISA analysis in order to examine the effect of the biguanide derivative compound on the production of the inflammatory cytokine IL-17.
  • IL-17 production was significantly reduced (see FIG. 1).
  • Example 3 the expression level of TNF- ⁇ was measured by ELISA analysis to examine the effect of the biguanide derivative compound on the production of inflammatory cytokine TNF- ⁇ .
  • the production amount is significantly reduced (see Fig. 2).
  • IBD inflammatory bowel disease
  • IBD ulcerative colitis
  • Crohn's disease affects larger areas of the digestive tract of the upper intestine and is more likely to cause malabsorption and chronic vitamin and nutritional deficiencies.
  • People with IBD suffer from symptoms such as chronic visceral inflammation, diarrhea, bleeding, abdominal pain, fever, joint pain, and weight loss. These symptoms can range from mild to severe. IBD may develop initially from mild discomfort gradually and unknowingly, or suddenly appear acute.
  • Example 2 confirmed in vitro through Example 2 and Example 3, the decrease in the production / expression of inflammatory bowel disease-related cytokines (IL-17 and TNF- ⁇ ) following treatment with the biguanide derivative compounds of the present invention.
  • the biguanide derivative compound of the present invention is effective in treating inflammatory bowel disease.
  • Example 4 of the present invention an inflammatory bowel disease animal model was prepared using DSS (dextran sodiumsulfate), and the weight of the animal model of inflammatory bowel disease was significantly improved as a result of applying (administering) a biguanide derivative compound thereto. It was confirmed (see FIG. 3).
  • the biguanide derivative compound of the present invention to an animal model of inflammatory bowel disease, it was confirmed that the degree of cellular inflammation in the colon tissue of the mouse was reduced and the damage in the colon tissue was low and the cell penetration was low. (See Figure 4).
  • the biguanide derivative compounds of the present invention can treat immune diseases through mechanisms such as effectively reducing the amount / expression of inflammatory cytokines (IL-17 and TNF- ⁇ ). .
  • Example 5 the alloresponse inhibitory effect of the biguanide derivative compound was examined, and as a result, alloresponse was remarkably suppressed when the biguanide derivative compound of the present invention was treated (FIG. 6).
  • Example 6 of the present invention the effect on the activity of the regulator T cells (hereinafter, abbreviated as 'Treg') of the biguanide derivative compound was examined.
  • Treatment of iguanide derivative compounds was found to significantly increase the activity of Treg cells (see FIG. 7).
  • Example 7 of the present invention acute graft-versus-host disease was prepared, and whether or not there was actually an improvement or treatment effect according to the application (administration) of the biguanide derivative compound was investigated. Treatment with the biguanide derivative compound of the present invention was confirmed to significantly increase the survival of mice induced with acute graft-versus-host disease (see FIG. 8).
  • the biguanide derivative compound of the present invention is excellent in regulating immunity through the mechanism of inhibiting alloresponse and increasing the activity of Treg cells, graft-versus-host disease as a kind of immune disease Experiments proved that can be treated.
  • the present invention can provide a composition for preventing or treating immune diseases, including a biguanide derivative compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the biguanide derivative compound of the present invention may be at least one compound selected from compounds represented by Formulas 1 to 22 shown in Table 1 above.
  • the compound represented by the formula according to the present invention may be used in the form of a salt, preferably a pharmaceutically acceptable salt.
  • 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 that are isolated from nature or prepared by chemical synthesis known in the art.
  • 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 TNF- ⁇ (tumor necrosis factor- ⁇ ) and IL-1 (excessively stimulated the human immune system due to harmful stimuli such as inflammation-induced factors or irradiation and secreted by immune cells such as macrophages).
  • interleukin-1), IL-6, prostaglandin (prostagladin), luecotriene or nitric oxide (nitric oxide, NO) refers to a disease caused by proinflammatory substances (inflammatory cytokines).
  • T cell which is induced by the T cell receptor to recognize the major histocompatibility complex (MHC) expressed in the graft.
  • 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.
  • Graft-versus-host disease (GVDH) is also known that the donor's T lymphocytes respond to the patient's histocompatibility antigens, whereas the donor's T lymphocytes respond to the donor's histocompatibility antigens. 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 type of immune disease in the present invention is not limited to this, Behcet's disease, multiple myositis, cutaneous myositis, autoimmune cytopenia, autoimmune myocarditis, atopic dermatitis, asthma, primary cirrhosis, dermatitis, gut pie Syndrome, autoimmune meningitis, Sjogren's syndrome, systemic lupus erythematosus, Addison's disease, alopecia areata, ankylosing myelitis, autoimmune hepatitis, autoimmune mumps, Crohn's disease, insulin-dependent diabetes mellitus, dystrophic bullous epidermal detachment, epididymitis, glomerulonephritis , Graves' disease, Guillain-Barré syndrome, Hashimoto's disease, hemolytic anemia, multiple sclerosis, myasthenia gravis, vulgaris, psoriasis, rheumatic fever, rheumatoi
  • the inflammatory disease is gastritis, enteritis, nephritis, hepatitis, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, irritable bowel syndrome, inflammatory pain, migraine, headache, back pain, fibromyalgia, fascia disease, viral infection , Bacterial infections, fungal infections, burns, surgical or dental wounds, PGE hyperplasia, atherosclerosis, gout, Hodgkin's disease, pancreatitis, conjunctivitis, iris, scleritis, uveitis and eczema, and the like. .
  • composition according to the present invention can be used as a pharmaceutical composition that can prevent or treat immune diseases or inflammatory 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 preventing or treating an immune disease according to the present invention may include a pharmaceutically effective amount of one or more compounds of the compounds represented by Formulas 1 to 22 (see Table 1 above) or salts thereof alone or in one or more pharmaceutical forms. And an acceptable carrier, excipient or diluent.
  • the pharmaceutically effective amount herein refers to an amount sufficient to prevent, ameliorate and treat the symptoms of an immune disease or an inflammatory disease.
  • a pharmaceutically effective amount of a biguanide derivative compound or a salt thereof according to the present invention may be appropriately changed depending on the degree of symptoms of an immune disease, the age, weight, health condition, sex, route of administration and duration of treatment of the patient.
  • the pharmaceutically acceptable refers to a composition that is physiologically acceptable and does not cause an allergic reaction such as gastrointestinal disorders, dizziness or the like when administered to humans.
  • 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 biguanide derivative compound as an active ingredient for the manufacture of a medicament for the prevention or treatment of immune diseases or inflammatory diseases.
  • the composition of the present invention comprising a biguanide derivative compound as an active ingredient can be used for the manufacture of a medicament for the prevention or treatment of immune diseases or inflammatory diseases.
  • the present invention also provides a method of preventing or treating an immune disease or inflammatory 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.
  • biguanide derivatives (biguanide) derivative 1 to derivative 22 represented by the formula of Table 1 was prepared by the following method.
  • SD-000171, SD-000172, SD-000173, SD-000174, SD-000175, SD-000177, SD-000178 Synthesis: After dissolving each aniline in acetonitrile, 1M hydrochloric acid was added by 1 equivalent. After the addition of dicyano diamide, the reaction was heated to 100 ° C. and purified through column chromatography.
  • the expression level of IL-17 is measured by ELISA analysis. It was.
  • Spleen cells were obtained from normal mice of C57BL / 6 (Orient, Korea). That is, the spleen extracted from the mouse was chopped the spleen tissue using a glass slide (teasing slide), and then removed the red blood cells in the spleen with a erythrocyte hemolysis solution, after which the splenocytes were washed by adding PBS buffer solution and centrifugation. Obtained.
  • the mouse prepared in Example ⁇ 2-1> was used to dispense splenocytes 1 ⁇ 10 6 into a 24-well plate coated with 0.5 g / mL of anti-CD3 antibody and stimulate Th17 cells.
  • the cells were treated with the anti-CD28 antibody 1 ⁇ g / mL, TGF- ⁇ 2ng / ml, IL-6 20ng / ml, anti-IL-4 2 ⁇ g / ml, and anti-IFNr 2 ⁇ g / ml simultaneously.
  • the biguanide derivative compound of the present invention (SD-000196: 1-isopropylbiguanide, SD-000216: 1- (3-fluorophenyl) biguanide, SD-000217: 1- (2,4-difluorophenyl) Each biguanide) was incubated at a concentration of 2 ⁇ M, 20 ⁇ M, and 200 ⁇ M. Positive control group was used instead of the compound of the present invention metformin (meformin), a biguanide-based compound that is currently used in the treatment of diabetes.
  • metformin meformin
  • IL-17 cytokines In order to measure the amount of IL-17 cytokines produced, the supernatants in which the cells were cultured were collected and the degree of IL-17 expression was examined by using a sandwich ELISA. To this end, monoclonal anti-IL-17 was first reacted in a 96 well plate at 2 ° C / mL overnight at 4 ° C, and then nonspecific binding was blocked with a blocking solution (1% BSA / PBST). IL-17 recombinant was serially diluted by 1/2 and used as a standard. Cell culture supernatant was added and reacted at room temperature for 2 hours.
  • biotinylated anti-IL-17 was 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.
  • IL-17 an inflammatory cytokine produced from Th17 cells, which are pathogenic cells, was found to be significantly reduced when the biguanide derivative compound was treated at a concentration of 200 ⁇ M. there was.
  • SD-000196 (1-isopropylbiguanide) compound IL-17 production amount was decreased depending on the treatment concentration, and it was confirmed that the production of IL-17 was completely inhibited at the concentration of 200 ⁇ M (see FIG. 1A). ).
  • Metformin which is currently used as a diabetic drug in the market, is known to have a negligible effect of blocking the inflammatory cytokine TNF- ⁇ .
  • the biguanide derivative compound of the present invention reduces the production of TNF- ⁇ .
  • the expression level of TNF- ⁇ was measured by ELISA analysis.
  • the biguanide derivative compound of the present invention (SD-000196: 1-isopropylbiguanide, SD-000216: 1- (3-fluorophenyl) biguanide) in mouse spleen cells 1 ⁇ 10 6 prepared according to Example ⁇ 2-1>.
  • SD-000217: 1- (2,4-difluorophenyl) biguanide) was treated at concentrations of 2 ⁇ M, 20 ⁇ M, and 200 ⁇ M, and then treated with LPS (lipopolysaccharide) at a concentration of 100 ng / ml and incubated in a 37 ° C. incubator for 3 days. Induced inflammatory response in splenocytes.
  • Positive control group was used instead of the compound of the present invention metformin (meformin), a biguanide-based compound that is currently used in the treatment of diabetes.
  • TNF- ⁇ cytokine In order to measure the amount of TNF- ⁇ cytokine produced, the supernatant cultured with the cells was collected and examined for the production of TNF- ⁇ by ELISA. Monoclonal anti-TNF- ⁇ was reacted in a 96-well plate at 2 ⁇ g / mL overnight at 4 ° C, and non-specific binding was blocked with a blocking solution (1% BSA / PBST) after the reaction. TNF- ⁇ recombinant was used as standard by diluting serially by 1/2, and the cell culture supernatant was added and reacted at room temperature for 2 hours. Thereafter, the biotinylated anti-TNF- ⁇ was reacted at room temperature for 2 hours and washed four times.
  • ExtraAvidin-Alkaline Phosphatase conjugate was diluted and added and reacted at room temperature for 2 hours. Thereafter, PNPP / DEA solution was added, followed by color development, and absorbance at 405 nm was measured.
  • the biguanide derivative according to the present invention 1 mg of compound (SD-000196: 1-isopropylbiguanide, SD-000216: 1- (3-fluorophenyl) biguanide, and SD-000217: 1- (2,4-difluorophenyl) biguanide) was orally administered, and 2 mg rectally. administered to the rectal.
  • the change in weight was measured every day while observing the progress of inflammatory bowel disease over time every day, and the weight of the disease was converted into% to evaluate the treatment / improvement effect of the disease.
  • the positive control group used metformin (sigma aldrich, animal experimental dose: 1 mg oral administration, 2 mg rectal administration), a biguanide compound currently used as a diabetes treatment in the market, instead of the compound of the present invention.
  • DSS corresponds to a chemical administered by drinking water that kills the epithelial cells of the colon and causes colon inflammation
  • DSS colitis model corresponds to an established model of experimental Inflammatory bowel disease (IBD).
  • Immunohistochemical staining was performed by the following procedure.
  • the colon tissues of the mouse experimental group of Table 1 were separated, fixed in 10% neutral buffered formalin and embedded in paraffin, and then 7 mm thick sections were made and attached to slides. After passing through the deparaffinization process using xylene before the basic staining, ethanol was hydrated from high to low concentrations. The staining process was performed by hematoxylin / eosin (hematoxylin / eosin) staining and analyzed by light microscopy.
  • the large intestine tissue of the inflammatory bowel disease mouse experimental group ingested DSS can be observed that the cell penetrates a lot, while the guaganide derivative compound of the present invention to the inflammatory bowel disease mouse Colon tissue of the experimental group administered was confirmed that the damage is low and the penetration of cells is low.
  • Immunohistochemical staining was performed in the same manner as in Example ⁇ 4-2>, and reacted with TNF- ⁇ antibody to develop DAB and analyzed by light microscopy.
  • the biguanide derivative compounds of the present invention (SD-000196: 1-isopropylbiguanide, SD-000216: 1- (3-fluorophenyl) biguanide, SD-000217: 1- (2,4-difluorophenyl) biguanide) or metformin
  • the degree of T cell proliferation reaction in the cultured cells was analyzed using the 3H incorporation method for the effect on the homologous reaction of the biguanide derivative compounds of the present invention.
  • the present inventors have found that the biguanide derivative compounds of the present invention can effectively inhibit allogeneic reactions that may occur during the transplantation process and thus can successfully induce allografts.
  • Treg cells are characterized by inhibiting the function of abnormally activated immune cells and controlling the inflammatory response, and many experiments have been shown to effectively treat immune diseases and inflammatory diseases by increasing the activity of Treg cells. It is becoming. Therefore, the experiment was conducted to demonstrate the possibility that the biguanide derivative compounds of the present invention can be used as an immunotherapeutic agent through the action of increasing the activity of Tregs.
  • Treg cell activity was performed using flow cytometry. Specifically, 2 ⁇ 10 5 of the top grantor CD4 + T cell with 2 ⁇ 10 5 of can was irradiated in women (homologous homozygous) or a donor (C57BL / 6 of (Balb / c, responder) per 96well in In vitro , stimulator, allogeneic) -derived T cell removal splenocytes were mixed and cultured to induce alloresponse.
  • the biguanide derivative compound of the present invention (SD-000196: 1-isopropylbiguanide, SD-000216: 1- (3-fluorophenyl) biguanide, SD-000217: 1- (2,4-difluorophenyl) biguanide) Metformin was treated together and incubated together for 4 days, and differentiated regulatory T cells were analyzed by flow cytometry using anti-CD4-percp, anti-CD25-APC, and anti Foxp3-Pe fluorescent antibodies.
  • the biguanide derivative compound of the present invention can increase the Treg activity at the same time as inhibiting the Alloresponse response, and has an ideal immune regulatory function.
  • Examples 5 and 6 confirmed that the biguanide derivative compound of the present invention has the effect of inhibiting alloresponse and at the same time increasing the Treg activity.
  • the derivative compounds of the present invention were acute grafts. We investigated whether symptoms of major host disease can be improved and treated.
  • aGVHD acute Graft Versus Host Disease
  • TBI Whole-body radiotherapy
  • H-2k / d the recipient mouse Balb / c (H-2k / d) at 800 cGy was performed and the donor mouse C57BL / 6 (H Hematopoietic and splenocytes were isolated from femur and tibia of -2k / b), and hematopoietic stem cells 5 ⁇ 10 6 and splenocytes 8 ⁇ 10 6 were transplanted into recipient Balb / c (H-2k / d).
  • Splenocytes before transplantation may be metformin or the biguanide derivative compound of the present invention (SD-000196: 1-isopropylbiguanide, SD-000216: 1- (3-fluorophenyl) biguanide, SD-000217: 1- (2,4). -difluorophenyl) biguanide) was treated for 2 hours at a concentration of 5 mM, and then the survival rate of mice induced with acute graft-versus-host disease was evaluated.
  • SD-000196 1-isopropylbiguanide
  • SD-000216 1- (3-fluorophenyl) biguanide
  • SD-000217 1- (2,4).
  • -difluorophenyl) biguanide was treated for 2 hours at a concentration of 5 mM, and then the survival rate of mice induced with acute graft-versus-host disease was evaluated.
  • the experimental group treated with the biguanide derivative compound of the present invention significantly increased the survival of the mice compared to the acute graft-versus-host disease mouse group and metformin-treated acute graft-versus-host mouse group I could confirm that.
  • cytotoxicity In order to evaluate the arthritis therapeutic effect of the biguanide derivative compound of the present invention, cytotoxicity, autoantibody production, inflammatory cytokine and regulatory T cell (Treg) expression, and osteoclast differentiation were measured in a rheumatoid arthritis animal model.
  • Metformin was used as a control as in the above examples.
  • MTT assay was performed to investigate the cytotoxicity of the biguanide derivative compounds of the present invention.
  • Cells were isolated from the spleen of the normal mouse group, and the isolated cells were incubated for 3 days at a concentration of anti-CD3 0.5ug / ml or LPS 100ng / ml, with metformin, SD-196, SD-216 or SD- Each of 217 was incubated for 3 days with concentration.
  • a concentration of cytotoxicity by treating MTT 4 hours before harvest it was confirmed that there was no cytotoxicity of SD-196, 216 and 217 (FIG. 9A).
  • the cultured supernatant was collected and examined for the level of IgG expression using ELISA.
  • Monoclonal anti-IgG was reacted in a 96-well plate at 4 ° C. overnight, and then non-specific binding was blocked with a blocking solution.
  • Mouse control serum was serially diluted by 1/2 and used as a standard.
  • Cell culture supernatant was added and reacted at room temperature for 2 hours.
  • HRP-anti-IgG was reacted at room temperature for 2 hours, and washed four times after the reaction, and then diluted with HRP-conjugate, and reacted at room temperature for 2 hours.
  • As a result of absorbance measurement at 405 nm wavelength after color development it was confirmed that SD-196, 216 and 217 significantly inhibited the expression of IgG than metformin (FIG. 9B).
  • the cultured supernatants were collected and examined for expression of mouse IL-17 and TNF- ⁇ using sandwich ELISA.
  • monoclonal anti-IL-17 or anti-TNF ⁇ 2g / mL were reacted overnight at 4 ° C. After the reaction, non-specific binding was blocked with blocking solution (1% BSA / PBST).
  • Serial dilutions of IL-17 or TNF- ⁇ recombinant by 1/2 were used as standard, and the cell culture supernatant was added and reacted at room temperature for 2 hours.
  • biotinylated anti-IL-17 or anti-TNF- ⁇ was added and reacted at room temperature for 2 hours.
  • the cells were washed four times, and diluted with ExtraAvidin-Alkaline Phosphatase conjugate, and reacted at room temperature for 2 hours.
  • the PNPP / DEA solution was added and developed, and then the absorbance was measured at 405 nm. As a result, it was confirmed that IL-17 and TNF- ⁇ inflammatory cytokines were significantly inhibited by SD-196, 216 and 217 (FIG. 9C).
  • the cultured cells were treated with anti-CD4-percp, anti-CD25-APC, anti-Foxp3-Pe fluorescent antibodies (ab
  • As a result of flow cytometry analysis it was confirmed that SD-196, 216 and 217 activated Foxp3 + Treg cells (FIG. 10).
  • osteoclasts are differentiated by treating MCSF (10ng / ml) and RANKL (50ng / ml) in bone marrow extracted from the leg of animal model of arthritis. While, metformin, SD-196, SD-216 and SD-217 were treated together to evaluate the degree of differentiation of osteoclasts. Evaluation was performed using TRAP staining. As a result, it was confirmed that SD-196, 216 and 217 can significantly inhibit the differentiation of osteoclasts (FIG. 11).
  • cytotoxicity, autoantibody production, inflammatory cytokine production and Th17 regulation in the lupus animal model were measured by the same method as in Example 8.
  • FIG. 14A As a result, it was confirmed that there was no cytotoxicity of SD-196, 216 and 217 (FIG. 14A), and SD-196, 216 and 217 significantly inhibited the expression of IgG than metformin (FIG. 14B), IL-17 and Inhibition of TNF- ⁇ inflammatory cytokine expression and Th17 activity was confirmed (Fig. 14C, 15).

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Abstract

La présente invention concerne un composé de dérivé de biguanide pouvant prévenir et traiter efficacement des maladies immunitaires. Le composé de dérivé à base de biguanide selon la présente invention empêche la génération de IL-17 et TNF-α, qui sont des cytokines inflammatoires, augmente l'activité de lymphocytes T régulateurs ayant une fonction immunomodulatrice, et présente d'excellents effets thérapeutiques chez des modèles animaux atteints de maladies immunitaires. Par conséquent, le composé de dérivé à base de biguanide peut être utilisé efficacement comme immunosuppresseur ou comme composition pharmaceutique pouvant prévenir ou traiter diverses maladies immunitaires, telles que des maladies auto-immunes, des maladies inflammatoires et un rejet de greffe, causées par le dérèglement des réponses immunitaires.
PCT/KR2014/007898 2013-08-23 2014-08-25 Composition pharmaceutique pour prévenir ou traiter des maladies immunitaires ou des maladies inflammatoires, contenant un composé de dérivé de biguanide comme principe actif Ceased WO2015026215A1 (fr)

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CN114681438A (zh) * 2022-05-17 2022-07-01 中国医学科学院基础医学研究所 二甲双胍及其它含胍化合物在逆转Gal-10结晶趋势并缓解相关疾病中应用
CN114681438B (zh) * 2022-05-17 2024-03-19 中国医学科学院基础医学研究所 二甲双胍及其它含胍化合物在逆转Gal-10结晶趋势并缓解相关疾病中应用

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