Pharmaceutical composition for prevention or treatment of inflammatory diseases or autoimmune diseases comprising pyridine compounds as active ingredient

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of inflammatory diseases or autoimmune diseases, containing a pyridine compound as an active ingredient. The pyridine compound of the present invention used as the active ingredient of the pharmaceutical composition can significantly inhibit innate immune responses and inflammatory responses by inhibiting the activity of IRAK4 with very high efficacy, and thus can be effectively used for the prevention or treatment of inflammatory diseases or autoimmune diseases.

Description

Pharmaceutical composition for preventing or treating inflammatory diseases or autoimmune diseases containing a pyridine compound as an active ingredient

[0001] [Cross-reference with related applications]

[0002] This application claims the benefit of priority to Korean Patent Application No. 10-2024-0031574, filed March 5, 2024, the entire contents of which are incorporated herein by reference.

[0003] [Technical Field]

[0004] The present invention relates to a pharmaceutical composition for preventing or treating inflammatory diseases or autoimmune diseases, containing a pyridine compound as an active ingredient.

[0005] Immunity is the body's self-protection system against all foreign macromolecular substances (antigens) that invade or are injected into living tissue. A key component of the immune system are lymphocytes, white blood cells produced in the bone marrow and circulating in the bloodstream to lymphoid tissues and organs, primarily lymph nodes, spleen, and tonsils. B cells, when stimulated by an appropriate antigen, rapidly proliferate, forming clones that produce specific antibodies (immunoglobulins) to neutralize the antigen. These antibodies circulate in body fluids, carrying out humoral immunity. T cells, on the other hand, mature in the thymus and migrate to lymphoid tissues, where they are responsible for cell-mediated immunity, directly attacking antigens.

[0006] One of the most important characteristics of all normal organisms is the ability to recognize, respond to, and eliminate many non-self antigens, while not reacting harmfully to the antigenic substances that constitute the self. This lack of response to self-antigens is called immunological unresponsiveness or tolerance. If there is a problem in inducing or maintaining this self-tolerance, an immune response to self-antigens occurs, which leads to the attack of the body's own tissues, resulting in autoimmune diseases such as multiple sclerosis, type 1 diabetes, rheumatoid arthritis, and Hashimoto's thyroiditis. The primary cause of autoimmune diseases is believed to be the migration of lymphocytes into tissues, triggering an abnormality in the autoimmune system. However, the precise pathogenesis of each disease is still unknown.

[0007] Recently, research is being conducted to develop treatments for autoimmune diseases, focusing on effective immunosuppression at the cellular level (inhibiting the activation of lymphocytes and cell types responsible for the immune response in diseased tissues) and molecular levels. For example, combination therapy with various immunosuppressants such as steroids, cyclosporine, rapamycin, methotrexate, cyclophosphamide, IV immunoglobulins, azathioprine, and infliximab is currently being used for treatment. However, most of these treatments result in persistent inflammation and frequent relapses, and many systemic side effects occur due to the treatment. Therefore, there is an urgent need to research and develop treatments for autoimmune diseases that are effective and have minimal side effects.

[0008] Under these technical backgrounds, the inventors of the present invention have completed the present invention by confirming that the pyridine compound according to the present invention has a strong inhibitory activity against innate immune response and inflammatory response, while having low cytotoxicity and thus low risk of side effects.

[0009] The purpose of the present invention is to provide a pharmaceutical composition that can be used to prevent or treat inflammatory diseases or autoimmune diseases.

[0010] The purpose of the present invention is to provide a health functional food composition that can be used to prevent or improve inflammatory diseases or autoimmune diseases.

[0011] In order to achieve the above purpose, the present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease or an autoimmune disease, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[0012] [Chemical Formula 1]

[0013]

[0014] (In the above chemical formula, R 1 , R 2 , R 3 , R 4 and R 5 is as defined in the present invention).

[0015] In addition, the present invention provides a health functional food composition for preventing or improving inflammatory diseases or autoimmune diseases, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient:

[0016] [Chemical Formula 1]

[0017]

[0018] (In the above chemical formula, R 1 , R 2 , R 3 , R 4 and R 5is as defined in the present invention).

[0019] The compound represented by chemical formula 1 according to the present invention not only has DYRK1A inhibitory activity and can suppress adaptive immune responses such as T cell immune responses, but also has potent inhibitory activity against IRAK4, so it can effectively suppress innate immune responses and inflammatory responses. It was confirmed that it has higher efficacy and significantly lower cytotoxicity compared to anti-inflammatory or innate immune response suppressing drugs currently in clinical trials. Therefore, the compound represented by chemical formula 1 according to the present invention can be effectively used for the prevention or treatment of inflammatory diseases or autoimmune diseases.

[0020] Figure 1 shows the results of confirming the inhibition of DYRK1A, IRAK4 and IRAK1 substrate binding and kinase activity of drug P1.

[0021] Figure 2 shows the mechanism of action of the innate immune response suppression activity of drug P1.

[0022] Figure 3 shows the results of comparing the phosphorylation levels of TLR4 sub-kinases after treating THP-1 cells with LPS and P1 drugs or existing IRAK4 or DYRK1A / CLK inhibitory drugs.

[0023] Figure 4a shows the results of comparing the inflammatory gene expression patterns after treating THP-1 cells in which an innate immune response was induced by LPS with the pyridine compound (P1 drug) of the present invention and three control drugs.

[0024] Figure 4b shows the results of confirming the expression levels of genes related to the innate immune response after treating THP-1 cells in which the innate immune response was induced by LPS with the P1 drug.

[0025] Figure 5 shows the results of comparing gene expression patterns after treating THP-1 cells in which an innate immune response was induced by LPS with the P1 drug and the control drug Lorecivivint, respectively.

[0026] Figure 6 shows the results of comparing the CLK inhibitory activity of P1 drug and the control drug Lorecivivint by measuring the phosphorylation level of SR protein.

[0027] Figure 7 shows the results of comparing luciferase activity and cell viability when treated in a concentration-dependent manner with LPS and P1 drugs or competing drugs such as IRAK4 inhibitors (Zimlovisertib, Emavusertib, KT-474), JAK inhibitors (baricitinib), and DYRK1A / CLK inhibitors (Lorecivivint) in a cell system capable of quantitatively monitoring NF-κB signaling based on luciferase.

[0028] Figures 8a and 8b show the results comparing the changes in the amount of secreted cytokine proteins after treating THP-1 cells with LPS and P1 drug or a conventional IRAK4 inhibitory drug.

[0029] Figure 9 shows the results of comparing cell survival rates after treatment of CCD-18Co cells and GM14660 cells with P1 drug or Lorecivivint.

[0030] Figure 10 shows the results of comparing the luciferase activity level, cell viability, and expression level of NF-κB downstream genes after transfecting THP-1 cells with an NF-κB-luciferase plasmid and treating them with LPS and three pyridine compounds of the present invention (P1 drug, P2 drug, or P3 drug), and comparing the cytotoxicity by measuring cell viability after treating HepG2 cells with each drug.

[0031] Figure 11 shows the molecular docking prediction results of drugs P1, P2, and P3 with IRAK4.

[0032] Figure 12 shows the results of in vitro ADME and in vivo PK evaluations of drug P1.

[0033] Figure 13 shows the results of evaluating the cardiac and genetic toxicity of drug P1.

[0034] Figures 14a and 14b show the results of evaluating non-GLP level toxicity after repeated administration of drug P1 to mice.

[0035] Figures 15a and 15b show the results of confirming the effect of improving rheumatoid arthritis symptoms after treating a rheumatoid arthritis mouse model with the P1 drug at different concentrations.

[0036] Figures 16a and 16b show the results of confirming the effect of improving rheumatoid arthritis symptoms after treating a rheumatoid arthritis mouse model with the P1 drug and a competing drug at different concentrations.

[0037] Hereinafter, the present invention will be described in detail.

[0038]

[0039] The present invention provides a compound represented by the following chemical formula 1.

[0040] [Chemical Formula 1]

[0041]

[0042] In the above chemical formula 1, R 1 is hydrogen or -NR 6 R 7 It can be. Here, R 6 and R 7 may independently be hydrogen, straight or branched chain alkyl of C1-C5 or benzyl, and specifically, R 6 and R 7 can be independently hydrogen or C1-C3 straight or branched chain alkyl.

[0043] In the above chemical formula 1, R 2 , R 3 and R 4 are independently hydrogen, halogen, C1-C5 straight or branched alkyl, -NR 8 R 9 , OR 8 , -CN, -NHC(O)R 8 , -SO2R 8 , -OS(O)2R 8 , pyrrolidine, piperidine or morpholine, and specifically the R 2 , R 3 and R 4 are independently hydrogen, -F, -Cl, -Br, -I, straight or branched chain alkyl of C1-C3, -NR 8 R 9 , OR 8 , -CN, -NHC(O)R 8 , -SO2R 8 , -OS(O)2R 8 , pyrrolidine, piperidine or morpholine, and more specifically the R 2 , R 3 and R 4 may independently be hydrogen, -F, -Cl, -Br, -I, C1-C3 straight or branched chain alkyl. Here, R 8 and R 9 are independently hydrogen, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkynyl, C1-C5 straight or branched alkenyl, C6-C 12 Aryl, C6-C substituted with halogen 12 C6-C substituted with aryl or trihalogenmethyl 12 It can be aryl of, and specifically R 8 and R 9 can be independently hydrogen, C1-C5 straight-chain or branched-chain alkyl.

[0044] In the above chemical formula 1, R 5may be hydrogen, straight or branched chain alkyl of C1-C5, unsubstituted 4-piperidine or acetyl substituted 4-piperidine, and specifically R 5 may be hydrogen, straight or branched chain alkyl of C1-C3, unsubstituted 4-piperidine or acetyl substituted 4-piperidine.

[0045] The compound represented by the above chemical formula 1 may be a compound represented by the following chemical formula 2, a compound represented by the following chemical formula 3, or a compound represented by the following chemical formula 4.

[0046] [Chemical Formula 2]

[0047]

[0048] [Chemical Formula 3]

[0049]

[0050] [Chemical Formula 4]

[0051]

[0052] The compound represented by Chemical Formula 1 of the present invention has the effect of strongly suppressing innate immune response and inflammatory response. In a specific embodiment of the present invention, it was confirmed that the compound represented by Chemical Formula 1 changes the gene expression pattern changed by LPS treatment in the opposite direction, and significantly reduces the expression of the genes CCL2, CCL4, CCL3, CXCL1, PTAFR, CCL8, CXCL11, CCL5, BCL6, CCL20, IL-6, IL-1β, TNF-α, and MyD88, which are innate immune response-related genes, and also significantly reduces the expression of NF-κB downstream genes. In addition, it was confirmed that these activities are caused by the compound represented by Chemical Formula 1 significantly inhibiting IRAK4, a master kinase that acts at the highest level in the TLR4 downstream signal transduction pathway. From the above results, it can be seen that the compound represented by the chemical formula 1 of the present invention can strongly suppress innate immune response and inflammatory response, and therefore can be used as an effective ingredient of a pharmaceutical composition for preventing or treating inflammatory diseases or autoimmune diseases.

[0053] Accordingly, the present invention provides a pharmaceutical composition for preventing or treating an inflammatory disease or an autoimmune disease, comprising a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0054] The compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof may have a strong inhibitory activity against IRAK4 (Interleukin-1 receptor associated kinase 4).

[0055] The term "prevention" as used herein refers to reducing the risk of developing a disease or disorder, i.e., preventing the progression of one or more clinical symptoms of a disease in a subject who is exposed to or susceptible to the disease but has not yet developed the disease or exhibited symptoms of the disease. The term "treatment" as used herein refers to alleviating a disease or disorder, i.e., preventing or reducing the progression of the disease or one or more clinical symptoms thereof.

[0056] The above inflammatory disease refers to a disease caused by a transmitter by an inflammatory reaction, that is, a disease that has inflammation as one of its causes, and may include, but is not limited to, pulmonary fibrosis, allergic disease, rhinitis, pneumonia, bronchitis, pharyngitis, chronic obstructive pulmonary disease, esophagitis, gastritis, hepatitis (non-alcoholic fatty liver disease, alcoholic hepatitis, hepatitis B, hepatitis C, etc.), pancreatitis, nephritis, cystitis, enteritis, dermatitis, myositis, vasculitis, arthritis, inflammatory eye disease, periodontitis, gout, inflammation after surgical trauma, etc. The above autoimmune disease refers to a disease caused by a pathological reaction to self-antigen, and examples thereof include, but are not limited to, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, Hashimoto's thyroiditis, chronic thyroiditis, ankylosing spondylitis, glomerulonephritis, chronic active infection, Behcet's disease, multiple sclerosis, systemic sclerosis, graft-versus-host disease, asthma, atopic dermatitis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes.

[0057] In a specific embodiment of the present invention, it was confirmed that the compound represented by Chemical Formula 1 of the present invention has higher efficacy and significantly lower cytotoxicity than anti-inflammatory or innate immune response suppressing drugs currently undergoing clinical trials, and it was confirmed that it can significantly improve symptoms compared to competing drugs in an animal model of rheumatoid arthritis. Therefore, it can be seen that the compound represented by Chemical Formula 1 of the present invention can be used as an active ingredient in a pharmaceutical composition for the prevention or treatment of inflammatory diseases or autoimmune diseases.

[0058] The above “pharmaceutically acceptable salt” refers to a salt of the compound of the present invention that is pharmaceutically acceptable and has the desired pharmacological activity of the parent compound. These salts can be prepared by methods conventional in the art, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sodium hydrogen sulfate, phosphoric acid, nitric acid, carbonic acid, etc.; salts with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, benzoic acid, citric acid, maleic acid, malonic acid, tartaric acid, gluconic acid, lactic acid, gestic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin); salts with amino acids such as glycine, alanine, vanillin, isoleucine, serine, cysteine, cystine, aspartic acid, glutamine, lysine, arginine, tyrosine, proline, etc.; salts with sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, etc.; salts with alkali metals such as sodium and potassium. Includes metal salts formed by reaction, or salts with ammonium ions.

[0059] The pharmaceutical composition according to the present invention can be formulated by adding non-toxic and pharmaceutically acceptable carriers, adjuvants, excipients, etc. according to a conventional method, and can be manufactured as a preparation for oral administration such as a tablet, capsule, troche, liquid, suspension, or a preparation for parenteral administration.

[0060] In addition, excipients that can be used in the pharmaceutical composition according to the present invention include sweeteners, binders, solubilizers, solubilizers, wetting agents, emulsifiers, isotonic agents, adsorbents, disintegrants, antioxidants, preservatives, lubricants, fillers, fragrances, etc., and examples thereof include lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, glycine, silica, talc, stearic acid, sterin, magnesium stearate, magnesium aluminum silicate, starch, gelatin, gum tragacanth, alginic acid, sodium alginate, methylcellulose, sodium carboxymethylcellulose, agar, water, ethanol, polyethylene glycol, polyvinylpyrrolidone, sodium chloride, calcium chloride, orange essence, strawberry essence, vanilla flavor, etc.

[0061] The compound of the present invention may be included in a concentration level ranging from 0.1% to 95% by weight based on the total weight of the pharmaceutical composition, i.e., in an amount sufficient to obtain the desired effect.

[0062] The pharmaceutical composition of the present invention can be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories, or sterile injection solutions according to conventional methods.

[0063] A pharmaceutical composition comprising the compound of the present invention may further comprise a suitable carrier, excipient, or diluent according to a conventional method. Specifically, when formulating, the composition may be prepared using diluents or excipients such as fillers, bulking agents, binders, wetting agents, disintegrating agents, and surfactants that are commonly used. Solid preparations for oral administration include tablets, pills, powders, granules, and capsules, and these solid preparations may be prepared by mixing the compound with at least one excipient, such as starch, calcium carbonate, sucrose, lactose, or gelatin. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral administration include suspensions, oral solutions, emulsions, and syrups, and in addition to commonly used simple diluents such as water and liquid paraffin, various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives may be included. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions and suspensions can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include withepsol, macrogol, Tween 61, cocoa butter, laurin, and glycerogelatin.

[0064] The pharmaceutical composition of the present invention can be administered to mammals such as rats, mice, livestock, and humans via various routes. All routes of administration can be administered, for example, by skin, oral, rectal, intravenous, intraperitoneal, intramuscular, subcutaneous, intrauterine, or intracerebroventricular injection, and preferably, by either oral or intravenous route, but are not limited thereto.

[0065] The pharmaceutical composition of the present invention can be administered in a pharmaceutically effective amount. The term "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dosage level can be determined according to factors including the type and severity of the individual, age, sex, activity of the drug, sensitivity to the drug, time of administration, route of administration and excretion rate, duration of treatment, concurrently used drugs, and other factors well known in the medical field. For example, the pharmaceutical composition can be administered at a dosage of 0.0001 to 1,000 mg / kg per day, specifically 0.01 to 100 mg / kg, and the administration can be administered once a day or in several divided doses.

[0066] The pharmaceutical composition of the present invention can be administered as an individual treatment or in combination with other inflammatory or autoimmune disease treatments. It can also be administered sequentially or simultaneously with conventional inflammatory or autoimmune disease treatments. It can be administered singly or in multiple doses. Taking all of the above factors into account, it is important to administer the dose that achieves maximum efficacy with the minimum amount possible without causing side effects, a determination readily made by those skilled in the art.

[0067]

[0068] In addition, the present invention provides a health functional food composition for preventing or improving inflammatory diseases or autoimmune diseases, which comprises a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0069] In the present invention, food refers to a natural or processed product containing one or more nutrients, and specifically refers to a product that has undergone a certain degree of processing to become directly edible. In its general meaning, it is used to mean all kinds of foods, functional foods, beverages, food additives, and beverage additives. Examples of the above foods include various foods, beverages, gum, tea, vitamin complexes, and functional foods. In addition, the food of the present invention includes, but is not limited to, special nutritional foods (e.g., formulated milk, infant food, baby food, etc.), processed meat products, fish products, tofu, starch jelly, noodles (e.g., ramen, noodles, etc.), health supplements, seasoned foods (e.g., soy sauce, soybean paste, red pepper paste, mixed sauce, etc.), sauces, confectionery (e.g., snacks), dairy products (e.g., fermented milk, cheese, etc.), other processed foods, kimchi, pickled foods (various kimchi, pickled vegetables, etc.), beverages (e.g., fruit and vegetable beverages, soy milk, fermented beverages, ice cream, etc.), natural seasonings (e.g., ramen soup, etc.), vitamin complexes, alcoholic beverages, liquors, and other health supplements. The functional foods, beverages, food additives, or beverage additives can be manufactured by conventional manufacturing methods.

[0070] The term "health functional food" used in the present invention refers to a food manufactured and processed in the form of tablets, capsules, powders, granules, liquids, pills, etc. using raw materials or ingredients with useful functionality for the human body. Here, "function" means obtaining a useful effect for health purposes, such as regulating nutrients for the structure and function of the human body or physiological functions. The health functional food composition of the present invention can be manufactured by a method commonly used in the art, and during the manufacturing process, raw materials and ingredients commonly added in the art can be added. In addition, the formulation of the health functional food composition can also be manufactured without limitation as long as it is a formulation recognized as a health functional food. The health functional food composition of the present invention can be manufactured in various forms of formulations, and unlike general drugs, it has the advantage of not having side effects that may occur with long-term administration of drugs using food as a raw material, and is highly portable. Therefore, the health functional food composition of the present invention can be taken as a supplement for preventing or improving inflammatory diseases or autoimmune diseases.

[0071] In addition, the health functional food composition may include a food additive acceptable from a food science perspective, and may further include appropriate carriers, excipients, and diluents commonly used in the manufacture of functional foods.

[0072] The health functional food composition of the present invention may contain, in addition to the active ingredient, a sweetener, a flavoring agent, a physiologically active ingredient, minerals, etc. The sweetener may be used in an amount that imparts an appropriate sweetness to the food, and may be natural or synthetic. Specifically, natural sweeteners are used. Examples of natural sweeteners include sugar sweeteners such as corn syrup solids, honey, sucrose, fructose, lactose, and maltose. Flavoring agents may be used to enhance taste or aroma, and may be either natural or synthetic. Specifically, natural sweeteners are used. When natural sweeteners are used, they may also serve the purpose of enhancing nutrition in addition to flavor. Natural flavoring agents may include those obtained from apples, lemons, tangerines, grapes, strawberries, and peaches, or from green tea leaves, Polygonum multiflorum, bamboo leaves, cinnamon, chrysanthemum leaves, and jasmine. Furthermore, those obtained from ginseng (red ginseng), bamboo shoots, aloe vera, and ginkgo biloba may be used. Natural flavoring agents can be liquid concentrates or solid extracts. In some cases, synthetic flavoring agents can be used, such as esters, alcohols, aldehydes, and terpenes. Physiologically active substances can include catechins such as catechin, epicatechin, gallocatechin, and epigallocatechin, and vitamins such as retinol, ascorbic acid, tocopherol, calciferol, thiamine, and riboflavin. Minerals can include calcium, magnesium, chromium, cobalt, copper, fluoride, germanium, iodine, iron, lithium, magnesium, manganese, molybdenum, phosphorus, potassium, selenium, silicon, sodium, sulfur, vanadium, and zinc.

[0073] In addition, the health functional food composition of the present invention may contain, in addition to the sweetener, etc., a preservative, an emulsifier, an acidulant, a thickener, etc., as necessary. It is preferable that such preservatives, emulsifiers, etc. be added and used in an extremely small amount as long as the purpose for which they are added can be achieved. The extremely small amount, when expressed numerically, means a range of about 0.0005 wt% to about 0.5 wt% based on the total weight of the food composition. Examples of preservatives that can be used include sodium calcium sorbate, sodium sorbate, potassium sorbate, calcium benzoate, sodium benzoate, potassium benzoate, EDTA (ethylenediaminetetraacetic acid), etc. Examples of emulsifiers that can be used include acacia gum, carboxymethylcellulose, xanthan gum, pectin, etc. Examples of acidulants that can be used include lactic acid, malic acid, fumaric acid, adipic acid, phosphoric acid, gluconic acid, tartaric acid, ascorbic acid, acetic acid, and phosphoric acid. In addition to enhancing flavor, these acidulants can be added to food compositions to maintain an appropriate acidity level for the purpose of inhibiting microbial growth. Examples of thickeners that can be used include suspending agents, sedimentation agents, gelling agents, and bulking agents.

[0074]

[0075] In addition, the present invention provides a method for preventing, improving or treating an inflammatory disease or an autoimmune disease, comprising a step of administering to a subject a compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0076] In addition, the present invention provides a use of the compound represented by the above chemical formula 1 or a pharmaceutically acceptable salt thereof for preventing, improving or treating an inflammatory disease or an autoimmune disease.

[0077]

[0078] Hereinafter, the present invention will be described in detail by the following experimental examples.

[0079] However, the following experimental examples are merely illustrative of the present invention and the scope of the invention is not limited by the experimental examples.

[0080]

[0081] [Experimental Example 1] Analysis of the Innate Immune Response Suppression Effect of Pyridine Compounds

[0082] The compound represented by chemical formula 2 (drug P1) has been previously shown to potently inhibit DYRK1A, which promotes adaptive immune responses such as T cell immune responses. In the present invention, experiments were conducted to determine whether the drug P1 can also participate in innate immune responses in addition to adaptive immunity.

[0083] First, in vitro kinase profiling was performed on 460 kinases for P1 drug. As a result, among the top 20 kinases with high inhibitory activity, IRAK4 and IRAK1 were identified in addition to DYRK1A. Specifically, for IRAK4 and IRAK1, the substrate binding was confirmed to be inhibited by 99.6% and 99.1%, respectively, at a concentration of 1 μM, and the substrate binding was confirmed to be inhibited by 80% and 78%, respectively, at a concentration of 0.1 μM. This tendency was similarly observed in the kinase activity evaluation, with IC for IRAK4 50 =27nM level, and IC for IRAK1 50 =153 nM (Fig. 1). Given that IRAK4 and IRAK1 are kinases that act at the highest level of the TLR4 downstream signaling pathway, it can be interpreted that the P1 drug can significantly suppress the overall innate immune response by inhibiting IRAK4 and IRAK1 (Fig. 2).

[0084]

[0085] [Experimental Example 2] Analysis of the mechanism of action of pyridine compounds in suppressing the innate immune response.

[0086] [2-1] Comparison of the innate immune response suppression activity of pyridine compounds

[0087] In Experimental Example 1 above, we confirmed that the P1 drug has the potential to significantly suppress the overall innate immune response by inhibiting IRAK4 and IRAK1. To confirm the inhibition of IRAK4 and IRAK1 at the cellular level, THP-1 cells were treated with LPS and the P1 drug or existing IRAK4 inhibitory drugs (Emavusertib and Zimlovisertib), and after 30 minutes, the phosphorylation levels of downstream kinases of TLR4 were analyzed by Western blotting. As a result, it was shown that the phosphorylation levels of IRAK4 and the phosphorylation levels of p38 and JNK, which are downstream kinases of IRAK4, were suppressed by the P1 drug in a concentration-dependent manner (Fig. 3). In particular, the JNK inhibition effect by the P1 drug was greater than that by Zimlovisertib.

[0088] Through the above experiments, it was confirmed that the potent inhibitory activity of drug P1 on the innate immune response is due to inhibition of IRAK4, a master kinase that acts at the highest level of the TLR4 downstream signaling pathway.

[0089]

[0090] [2-2] Analysis of gene expression patterns related to innate immune response and inflammatory response

[0091] To confirm the inhibitory activity of drug P1 on the innate immune response, human monocyte lineage THP-1 cells were first treated with LPS at a concentration of 0.1 μg / mL to induce an innate immune response. Then, the cells were treated with drug P1 and three control drugs at a concentration of 3 μM each for 12 hours, and RNA was obtained and RNA-seq was performed to analyze the changes in the expression patterns of 1,499 genes related to the innate immune response and inflammatory response among a total of 24,424 genes. As control drugs, two DYRK1A / CLK inhibitors (Lorecivivint and B-02) that are in clinical trials for autoimmune and inflammatory diseases, and Aristolactam BIII, a natural DYRK1A inhibitor, were used.

[0092] The analysis results showed that when treated with P1 drug, almost all gene expression patterns changed by LPS treatment were reversed (Fig. 4a). This can be interpreted as because P1 drug fundamentally inhibits the TLR4 innate immune response induced by LPS. In contrast, when treated with Lorecivivint, the gene expression patterns changed by LPS treatment were reversed, but for about 40% of genes, the gene expression changed by LPS treatment was confirmed to be further aggravated. On the other hand, the B-02 treatment group and the Aristolactam BIII treatment group were confirmed to have a minimal effect on the gene expression patterns changed by LPS treatment.

[0093] Thereafter, among the genes related to the innate immune response identified through RNA-seq analysis as described above, highly representative genes were selected and their gene expression levels were analyzed through RT-PCR. As a result, it was confirmed that the expression levels of all CCL2, CCL4, CCL3, CXCL1, PTAFR, CCL8, CXCL11, CCL5, BCL6, CCL20, IL-6, IL-1β, TNF-α, and MyD88 genes were dose-dependently reduced by P1 drug treatment (Fig. 4b).

[0094] Meanwhile, Lorecivivint further aggravated the expression of some genes altered by LPS treatment, a pattern observed in gene groups other than those related to inflammation (Figure 5). This suggests that Lorecivivint does not specifically suppress the innate immune response, but rather induces changes in gene expression through various mechanisms, one of which is an anti-inflammatory response.

[0095] To analyze the mechanism of action of P1 and Lorecivivint in more detail, we compared their inhibitory activity against cdc2-like kinase (CLK) by measuring the phosphorylation level of SR protein. Previous studies have reported that part of Lorecivivint's anti-inflammatory effect is due to CLK inhibition. As a result, Lorecivivint showed a marked CLK inhibitory activity, whereas P1 showed no CLK inhibitory activity at all (Fig. 6). This suggests that Lorecivivint's anti-inflammatory effect may be related to its CLK inhibitory activity, and that P1's potent innate immune response suppression activity is not derived from its CLK inhibitory activity. Furthermore, since both P1 and Lorecivivint have DYRK1A inhibitory activity, it suggests that P1's innate immune response suppression activity is not based on DYRK1A inhibitory activity.

[0096] Through the above experiments, it was confirmed that the compound represented by Chemical Formula 2 (drug P1) can significantly suppress the overall expression of genes related to innate immune responses and inflammatory responses. Furthermore, it was confirmed that the innate immune response suppression activity of drug P1 is significantly superior to that of existing DYRK1A inhibitory drugs, and that it has innate immune response suppression activity through a different mechanism of action than that of existing DYRK1A inhibitory drugs.

[0097]

[0098] [2-3] Comparison of the innate immune response suppression activity of pyridine compounds and competing drugs

[0099] To evaluate the innate immune response suppression activity of P1 drug at the cellular level comparatively with that of competing drugs, a cell system (THP1-Lucia™ NF-κB cells, InvivoGen) capable of quantitatively monitoring NF-κB signaling, which is key to regulating the expression of downstream genes of the innate immune response, based on luciferase was used. After treating the cells with LPS to induce an inflammatory response, the cells were treated with P1 drug or competing drugs such as IRAK4 inhibitors (Zimlovisertib, Emavusertib, KT-474), JAK inhibitors (baricitinib), and DYRK1A / CLK inhibitors (Lorecivivint) for 12 hours, and luciferase activity was measured for comparative analysis.

[0100] As a result, it was found that the expression of luciferase was increased by LPS treatment, but when each drug was treated in a concentration-dependent manner, the expression of luciferase was significantly reduced, and in particular, when the P1 drug was treated, the expression of luciferase was found to be reduced the most (Fig. 7A).

[0101] Next, to confirm the cytotoxicity of each drug, THP1-Lucia™ NF-κB cells were treated with each drug for 12 hours, and the cell viability was measured using Cell-Titer Glo. As a result, it was confirmed that the cytotoxicity was the lowest compared to the decrease in luciferase expression when P1 drug was treated in particular (B in Figure 7).

[0102] Through the above experiment, it was confirmed that the P1 drug with IRAK4 inhibitory activity has innate immune response suppression activity in immune cells, and in particular, it was confirmed that the P1 drug has significantly higher innate immune response suppression activity compared to toxicity compared to competing drugs such as IRAK4 inhibitors (Zimlovisertib, Emavusertib, KT-474), JAK inhibitors (baricitinib), and DYRK1A / CLK inhibitors (Lorecivivint).

[0103]

[0104] [Experimental Example 3] Analysis of secreted cytokine expression by pyridine compounds

[0105] To compare the potent innate immune response suppression efficacy of P1 drug with that of competing drugs, cytokine production and secretion were analyzed using the Olink assay, a state-of-the-art proteomics technique. Specifically, THP-1 cells were treated with LPS to induce an inflammatory response. Then, P1 drug or competing drugs (zimlovisertib, emavusertib, and lorecivivint) were treated. Cell cultures were collected and the relative abundances of approximately 80 cytokine proteins were analyzed.

[0106] As a result, LPS treatment significantly increased the amount of about 30 cytokine proteins, and the tested drugs exhibited inhibitory effects. In particular, in the case of P1 drugs, Zimlovisertib and Emavusertib, which have IRAK4 inhibitory effects, an overall decrease in about 30 genes was observed, clearly showing a pattern opposite to that in the case of LPS treatment alone (Figures 8a and 8b). Among the three drugs, P1 drug was confirmed to have the most concentration-dependent and relatively highest inhibitory effect. On the other hand, Lorecivivint, which is mechanistically distinct from P1 drug, was found to induce non-specific changes in the expression level of cytokines, showing a similar trend to the results of mRNA levels observed above.

[0107]

[0108] [Experimental Example 4] Cytotoxicity Analysis of Pyridine Compounds

[0109] Through the above Experimental Examples 1, 2, and 3, it was confirmed that the P1 drug not only effectively suppresses the adaptive immune response by inhibiting DYRK1A, but also effectively suppresses the innate immune response by inhibiting IRAK4. In the following experiment, the cytotoxicity of this P1 drug and Lorecivivint, an existing DYRK1A inhibitor currently in clinical trials, were compared and evaluated.

[0110] After treating colon fibroblasts CCD-18Co and lymphoblasts GM14660 with P1 drug or Lorecivivint, cell viability was measured, and it was confirmed that the cytotoxicity of P1 drug was significantly lower than that of Lorecivivint in both cell lines (Fig. 9).

[0111] Through the above experiments, we confirmed that drug P1 possesses potent innate immune response suppression activity and, based on its DYRK1A inhibitory activity, has a high potential for adaptive immune modulation, particularly T-cell immunomodulation. However, it exhibits significantly lower cytotoxicity compared to Lorecivivint, which is currently in Phase 3 clinical trials for the treatment of inflammatory diseases. Consequently, drug P1 exhibits excellent anti-inflammatory effects while exhibiting lower cytotoxicity compared to existing drugs, and is expected to be highly competitive as a drug for inflammatory or autoimmune diseases.

[0112]

[0113] [Experimental Example 5] Comparison of the innate immune suppressive activity of pyridine compounds

[0114] Next, the innate immune response suppression activity of other pyridine compounds having a similar structure to the compound represented by Chemical Formula 2 (P1 drug) was compared. As other pyridine compounds, the compound represented by Chemical Formula 3 (P2 drug) and the compound represented by Chemical Formula 4 (P3 drug), which were reported to have inhibitory activity against DYRK1A in previous studies, were used.

[0115] The innate immune response suppression activity was compared by transfecting THP-1 cells with the NF-κB-luciferase plasmid, a downstream gene expression reporter of the TLR4 signaling pathway, and then simultaneously treating them with LPS and each drug for 6 hours to measure the activity of luciferase.

[0116] As a result, it was found that the expression of luciferase increased by LPS treatment, but the expression of luciferase was significantly reduced when each drug was treated, and in particular, the expression of luciferase was found to be reduced the most when the P1 drug was treated (Fig. 10A).

[0117] Next, to confirm the cytotoxicity of each drug, THP-1 cells were treated with each drug and cell viability was measured using Cell-Titer Glo. As a result, no significant change in cell viability was observed due to treatment with each drug (B in Figure 10).

[0118] In addition, after simultaneously treating THP-1 cells with LPS and each drug for 6 hours, total RNA was obtained and the expression of several NF-κB sub-genes was analyzed through RT-PCR. As a result, the expression of NF-κB sub-genes increased by LPS treatment, but when each drug was additionally treated, the gene expression was significantly reduced, and in particular, the expression of NF-κB sub-genes was significantly reduced in the P1 drug treatment group and the P2 drug treatment group (Fig. 10C).

[0119] Meanwhile, when pyridine drugs were treated for 72 hours on hepatoma cells (HepG2) rather than immune cells, cytotoxicity was analyzed, and it was confirmed that the cytotoxicity of drug P1 was relatively lower than that of drug P2 (Fig. 10D).

[0120] Next, to determine whether the innate immunosuppressive activity of pyridine-based drugs is mediated through interactions with IRAK4, a molecular docking prediction program was used to analyze the activity. The results confirmed that all three pyridine-based compounds inhibit IRAK4 activity by forming hydrogen bonds with surrounding amino acid residues in the ATP-binding pocket of IRAK4 (Figure 11).

[0121] Through the above experiments, it was confirmed that the compounds represented by the chemical formula 2 (drug P1), the compound represented by the chemical formula 3 (drug P2), and the compound represented by the chemical formula 4 (drug P3) all have DYRK1A inhibitory activity and have innate immune response suppression activity, which is achieved through interaction with IRAK4. In particular, it was confirmed that the innate immune response suppression activity of drug P1 is remarkably high, and that none of drugs P1 to P3 exhibits significant cytotoxicity.

[0122]

[0123] [Experimental Example 6] Drug metabolism and pharmacokinetic evaluation of pyridine compounds

[0124] To evaluate the basic pharmacological properties of P1 drug, which has potent innate immune response suppression activity and low cytotoxicity, various pharmacodynamic and pharmacokinetic evaluation experiments were performed as follows.

[0125]

[0126] [6-1] In vitro ADME evaluation

[0127] In performing in vitro ADME (absorption, distribution, metabolism, excretion) on drug P1, the following six evaluations were conducted.

[0128] First, the physicochemical properties of the P1 drug were confirmed to satisfy all criteria of Lipinski's rule of five (Fig. 12A).

[0129] Second, we performed a metabolic stability analysis of drug P1. The metabolic stability of drug P1 was assessed using liver microsomes from mice, rats, dogs, and humans, with busporine used as a positive control. The results showed that more than 50% of drug P1 remained in all liver microsomes, even after the longest test period of 60 minutes (Figure 12A). This indicates that the half-life of drug P1 in liver microsomes is more than 1 hour, indicating good metabolic stability.

[0130] Third, the stability of P1 drug in plasma was evaluated, with procaine used as a positive control. The results showed that even after the longest test period of 2 hours, P1 drug remained nearly 100%, demonstrating excellent plasma stability (Figure 12A). In contrast, procaine was barely detectable in human serum after 2 hours.

[0131] Fourth, plasma protein binding assay of drug P1 was performed using plasma proteins of humans, mice, rats, and dogs. The evaluation results showed that the drug (f) did not bind to plasma proteins. u , unbound fraction) was measured as 25.18% in humans, 20.91% in mice, 22.14% in rats, and 38.85% in dogs (Fig. 12A). This suggests that drugs that do not bind to plasma proteins may be distributed to tissues and exhibit the efficacy of the P1 drug.

[0132] Fifth, a Caco-2 assay was performed to analyze and predict the intestinal absorption rate of the P1 drug. As a result of the assessment, the efflux ratio (ER) of the P1 drug was 1.89 at 1 μM and 1.51 at 10 μM, confirming that the drug was absorbed normally in the intestine (Fig. 12A).

[0133] Finally, the inhibitory efficacy against seven CYP (Cytochrome P450) enzymes (1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 3A4) that account for more than 90% of metabolism among the CYP enzymes important for drug metabolism in the liver was evaluated. The evaluation results showed that drug P1 had an intermediate level of inhibitory activity against CYP 2C9 (IC 50 =1.52 μM), it was confirmed that it had no inhibitory activity against the remaining six CYP enzymes (Fig. 12A).

[0134]

[0135] [6-2] In vivoPK evaluation

[0136] An in vivoPK (pharmacokinetics) evaluation was performed to evaluate how much the P1 drug is absorbed, distributed, metabolized, and excreted in the body.

[0137] P1 drug was dissolved in a 1:1:8 mixture of DMAC, CremophorEL, and 0.1 M citrate buffer, and administered intravenously or orally to mice and rats, and serum drug concentrations were measured hourly. The intravenous dose was 1 mg / kg, and the oral dose was 10 mg / kg.

[0138] The measurement results showed that the half-life was short and the bioavailability was low when administered intravenously, but when administered orally, the half-life was 1.26 hours and the bioavailability was 6.7% in mice, and the half-life was 5.9 hours and the bioavailability was approximately 40% in rats, which were very good (B in Figure 12).

[0139]

[0140] [6-3] Acute toxicity assessment

[0141] Cardiac and genetic toxicity assessments were performed to determine the acute toxicity level of the P1 drug.

[0142] Specifically, the drug P1 was prepared by dissolving it in DMSO, and the human ether-a-go-go-related gene (hERG) potassium channel inhibitory activity was evaluated to confirm the cardiotoxicity of the drug. As a result of the evaluation, the toxicity of the drug P1 to the hERG channel was confirmed to be low in the hERG manual-patch clamp (IC 50 = 265.2 μM), it was also confirmed that the possibility of hERG channel inhibition was low in the hERG fluorescence polarization assay (IC 50 > 75 μM) (Fig. 13).

[0143] Next, to confirm the genotoxicity of the P1 drug, the mutant strains Salmonella typhimurium (TA98, TA100, TA1535, TA1537) and Escherichia coli (uvrA[pKM101]) were used to confirm whether the P1 drug induced reverse mutations using the Ames test. As a result, the possibility of the P1 drug inducing reverse mutations was very low in all strains in the tested concentration range (Fig. 13).

[0144] Through the above experiment, it was confirmed that the compound represented by chemical formula 2 (drug P1) is a safe drug with a very low possibility of causing cardiac and genotoxicity.

[0145]

[0146] [6-4] Non-GLP toxicity assessment

[0147] Next, a non-GLP level toxicity assessment was performed in mice to determine the biotoxicity level of the P1 drug.

[0148] First, the drug P1 was dissolved in distilled water to prepare the drug, and to determine the optimal concentration range of the drug, a single oral administration was given to mice at concentrations of 250, 500, or 1,000 mg / kg, and the survival rate was observed for one week. As a result, no deaths occurred at concentrations up to 500 mg / kg, but about 70% of the animals died at concentrations of 1,000 mg / kg, which is an approximate LD 50 The values ​​were found to be in the range of 500 to 1,000 mg / kg.

[0149] Based on the above results, the maximum administration concentration was set at 500 mg / kg, and concentrations of 160 mg / kg and 50 mg / kg, which are one-third of this concentration, were added. After oral administration to mice once daily for two weeks, the survival rate of the mice was observed. As a result, no deaths were observed at concentrations up to 160 mg / kg, but at a concentration of 500 mg / kg, approximately 60% of the mice died.

[0150] In addition, when we analyzed and evaluated indicators other than survival rate (body weight change, feed intake, general symptoms, ophthalmological symptoms, hematological tests, blood biochemical tests, organ weights, autopsy findings, etc.) during the two-week repeated administration experiment, it was found that at a concentration of 500 mg / kg, not only did approximately 60% of the animals die, but abnormal findings were confirmed in various biomarkers. On the other hand, at a concentration of 160 mg / kg, statistically significant changes and autopsy abnormalities were confirmed in some indicators, but at a concentration of 50 mg / kg, no abnormal findings were observed at all in all indicators (Figs. 14a and 14b). Therefore, the maximum non-toxic dose was considered to be 50 mg / kg.

[0151]

[0152] [Experimental Example 7] Confirmation of the efficacy of pyridine compounds in treating autoimmune diseases.

[0153] In Experimental Examples 1 to 3, it was confirmed that drug P1 could potently suppress innate immune responses by inhibiting IRAK4, and that it could also modulate adaptive immunity by inhibiting DYRK1A. In the following experiments, an in vivo efficacy evaluation was performed to confirm whether drug P1 actually has therapeutic efficacy against autoimmune diseases.

[0154] As an autoimmune disease model, we used a mouse model of rheumatoid arthritis, a representative autoimmune disease. Specifically, mice were administered Type II collagen and complete Freud's adjuvant (CFA), followed by Type II collagen and incomplete Freud's adjuvant (IFA) to establish a collagen-induced arthritis (CIA) model. Two days after IFA administration, the P1 drug was administered orally daily, and the severity of arthritis symptoms was assessed using the CAI index. Methotrexate, a first-line treatment for autoimmune diseases, was administered as a positive control.

[0155] As a result of the experiment, clinical rheumatic symptoms appeared 3 weeks after administration of Type II collagen and CFA, and the symptoms were found to worsen over time. However, when the P1 drug was administered, the symptom score (CAI index) was confirmed to be reduced to 60% compared to the vehicle-administered group, which was the negative control group. This symptom improvement effect was evident even in the lowest administration concentration of 1 mg / kg, and the symptom improvement effect of the P1 drug-administered group was confirmed to be similar to that of the methotrexate-administered group, which was the positive control group (Figures 15a and 15b).

[0156] In addition, histomorphological evaluation of mouse paws showed that treatment with P1 drug had excellent therapeutic effects in terms of quantitative indicators of inflammatory activity of arthritic tissue and severity of cartilage and bone damage (synovial hyperplasia, pannus formation, cartilage destruction, bone erosion) and quantitative indicators of cartilage damage in the joint (matrix staining, surface regularity, cartilage thickness). This symptom improvement effect in the P1 drug administration group was dose-dependent, and the therapeutic activity in the P1 drug 10 mg / kg administration group was confirmed to be similar to that in the methotrexate drug administration group, which was the positive control group (Figs. 15a and 15b).

[0157] Next, the administration concentration of the P1 drug was lowered, and the IRAK4 inhibitor Zimlovisertib, which is currently in clinical trials for rheumatoid arthritis, and the JAK1 / 2 inhibitor Baricitinib, which is currently on the market as a treatment for rheumatoid arthritis, were selected as positive control drugs, and an in vivo efficacy comparison evaluation was performed.

[0158] The experimental results showed that clinical rheumatic symptoms appeared 3 weeks after administration of Type II collagen and CFA, and the symptoms worsened over time. However, when the P1 drug was administered, the symptom score (CAI index) was confirmed to be reduced to 60% compared to the vehicle-administered group, which was the negative control group. This symptom improvement effect was evident even in the lowest administration concentration of 0.1 mg / kg, and the symptom improvement effect of the P1 drug administration group was confirmed to be superior to that of the Zimlovisertib 10 mg / kg administration group with a similar inhibitory mechanism. In contrast, the Baricitinib 5 mg / kg administration group with a different inhibitory mechanism was confirmed to be superior to the P1 drug administration group in symptom improvement effect (Figures 16a and 16b).

[0159] In addition, histomorphological evaluation of mouse paws revealed that treatment with P1 drug had excellent therapeutic effects in terms of quantitative indicators of inflammatory activity and severity of cartilage and bone damage in arthritic tissue (synovial hyperplasia, pannus formation, cartilage destruction, bone erosion) and quantitative indicators of cartilage damage in the joint (matrix staining, surface regularity, cartilage thickness). This symptom improvement effect in the P1 drug administration group was shown to be dose-dependent (Figs. 16a and 16b).

[0160] Through the above experiment, it was confirmed that the P1 drug, which has a strong inhibitory activity on innate and adaptive immune responses, has an excellent symptom improvement effect in a rheumatoid arthritis disease model, which is an actual autoimmune disease. Therefore, it is expected that the P1 drug can be usefully utilized as a drug for inflammatory diseases or autoimmune diseases.

[0161]

[0162] Although the preferred embodiments of the present invention have been described above as examples, the scope of the present invention is not limited to the specific embodiments described above, and those skilled in the art will be able to make appropriate changes within the scope described in the claims of the present invention.

Claims

1. A pharmaceutical composition for preventing or treating inflammatory diseases or autoimmune diseases, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: [Chemical Formula 1] (In the above chemical formula 1, R 1 is hydrogen or -NR 6 R 7 and here R 6 and R 7 are independently hydrogen, straight or branched chain alkyl of C1-C5 or benzyl; R 2 , R 3 and R 4 are independently hydrogen, halogen, C1-C5 straight or branched alkyl, -NR 8 R 9 , OR 8 , -CN, -NHC(O)R 8 , -SO2R 8 , -OS(O)2R 8 , pyrrolidine, piperidine or morpholine, wherein R 8 and R 9 are independently hydrogen, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkynyl, C1-C5 straight or branched alkenyl, C6-C 12 Aryl, C6-C substituted with halogen 12 C6-C substituted with aryl or trihalogenmethyl 12 is the aryl of; R 5 is hydrogen, straight or branched chain alkyl of C1-C5, unsubstituted 4-piperidine, acetyl substituted 4-piperidine).

2. In claim 1, The above R 1 is hydrogen or -NR 6 R 7 and here R 6 and R 7 are independently hydrogen, C1-C3 straight or branched chain alkyl; R 2 , R 3 and R 4 are independently hydrogen, -F, -Cl, -Br, -I, straight or branched chain alkyl of C1-C3, -NR 8 R 9 , OR 8 , -CN, -NHC(O)R 8 , -SO2R 8 , -OS(O)2R 8 , pyrrolidine, piperidine or morpholine, wherein R 8 and R 9 are independently hydrogen, C1-C5 straight or branched chain alkyl; R 5 A pharmaceutical composition comprising hydrogen, C1-C3 straight or branched alkyl, unsubstituted 4-piperidine or acetyl substituted 4-piperidine.

3. In claim 1, The above R 1 is hydrogen or -NR 6 R 7 and here R 6 and R 7 are independently hydrogen, C1-C3 straight or branched chain alkyl; R 2 , R 3 and R 4 are independently hydrogen, -F, -Cl, -Br, -I, C1-C3 straight or branched chain alkyl; R 5 A pharmaceutical composition comprising hydrogen, C1-C3 straight or branched alkyl, unsubstituted 4-piperidine or acetyl substituted 4-piperidine.

4. In claim 1, The above R 1 is -NH2; R 2 , R 3 and R 4 are independently hydrogen; R 5 A pharmaceutical composition comprising hydrogen, C1-C3 straight or branched alkyl, unsubstituted 4-piperidine or acetyl substituted 4-piperidine.

5. In claim 4, The above R 5 A pharmaceutical composition wherein the pharmaceutical composition is hydrogen, C1 alkyl, unsubstituted 4-piperidine or acetyl substituted 4-piperidine.

6. In claim 1, A pharmaceutical composition, wherein the autoimmune disease is at least one disease selected from the group consisting of inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, Hashimoto's thyroiditis, chronic thyroiditis, ankylosing spondylitis, glomerulonephritis, chronic active infection, Behcet's disease, multiple sclerosis, systemic sclerosis, graft-versus-host disease, asthma, atopic dermatitis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes.

7. A health functional food composition for preventing or improving inflammatory diseases or autoimmune diseases, comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient: [Chemical Formula 1] (In the above chemical formula 1, R 1 is hydrogen or -NR 6 R 7 and here R 6 and R 7 are independently hydrogen, straight or branched chain alkyl of C1-C5 or benzyl; R 2 , R 3 and R 4 are independently hydrogen, halogen, C1-C5 straight or branched alkyl, -NR 8 R 9 , OR 8 , -CN, -NHC(O)R 8 , -SO2R 8 , -OS(O)2R 8 , pyrrolidine, piperidine or morpholine, wherein R 8 and R 9 are independently hydrogen, C1-C5 straight or branched alkyl, C1-C5 straight or branched alkynyl, C1-C5 straight or branched alkenyl, C6-C 12 Aryl, C6-C substituted with halogen 12 C6-C substituted with aryl or trihalogenmethyl 12 is the aryl of; R 5 is hydrogen, straight or branched chain alkyl of C1-C5, unsubstituted 4-piperidine, acetyl substituted 4-piperidine).

8. In claim 7, The above R 1 is hydrogen or -NR 6 R 7 and here R 6 and R 7 are independently hydrogen, C1-C3 straight or branched chain alkyl; R 2 , R 3 and R 4 are independently hydrogen, -F, -Cl, -Br, -I, straight or branched chain alkyl of C1-C3, -NR 8 R 9 , OR 8 , -CN, -NHC(O)R 8 , -SO2R 8 , -OS(O)2R 8 , pyrrolidine, piperidine or morpholine, wherein R 8 and R 9 are independently hydrogen, C1-C5 straight or branched chain alkyl; R 5 A health functional food composition comprising hydrogen, C1-C3 straight or branched alkyl, unsubstituted 4-piperidine or acetyl substituted 4-piperidine.

9. In claim 7, The above R 1 is hydrogen or -NR 6 R 7 and here R 6 and R 7 are independently hydrogen, C1-C3 straight or branched chain alkyl; R 2 , R 3 and R 4 are independently hydrogen, -F, -Cl, -Br, -I, C1-C3 straight or branched chain alkyl; R 5 A health functional food composition comprising hydrogen, C1-C3 straight or branched alkyl, unsubstituted 4-piperidine or acetyl substituted 4-piperidine.

10. In claim 7, The above R 1 is -NH2; R 2 , R 3 and R 4 are independently hydrogen; R 5 A health functional food composition comprising hydrogen, C1-C3 straight or branched alkyl, unsubstituted 4-piperidine or acetyl substituted 4-piperidine.

11. In claim 10, The above R 5 A health functional food composition comprising hydrogen, C1 alkyl, unsubstituted 4-piperidine or acetyl substituted 4-piperidine.

12. In claim 7, A health functional food composition, wherein the autoimmune disease is at least one disease selected from the group consisting of inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, Hashimoto's thyroiditis, chronic thyroiditis, ankylosing spondylitis, glomerulonephritis, chronic active infection, Behcet's disease, multiple sclerosis, systemic sclerosis, graft-versus-host disease, asthma, atopic dermatitis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes.

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