Composition and method for treating autoimmune diseases

Abstract

The present invention relates to a pharmaceutical composition and method for treating or preventing autoimmune diseases in a patient or subject in need thereof, the pharmaceutical composition comprising: a 5-benzylaminosalicylic acid compound represented by Chemical Formula (I) or a pharmaceutically acceptable salt thereof; and, for example, a pharmaceutically acceptable carrier suitable for oral, intraperitoneal, or intravenous administration. The composition comprising the 5-benzylaminosalicylic acid compound of chemical formula (I) or a pharmaceutically acceptable salt thereof can be used for the treatment of autoimmune diseases.

Description

Compositions and methods for treating autoimmune diseases

[0001] This application claims priority to Republic of Korea Application No. 10-2023-0170944, filed November 30, 2023, Republic of Korea Application No. 10-2024-0120574, filed September 5, 2024, and Republic of Korea Application No. 10-2024-0143429, filed October 18, 2024, all of which are hereby incorporated by reference in their entirety.

[0002] The present invention relates to a composition and method comprising a 5-benzylaminosalicylic acid compound of formula (I) or a pharmaceutically acceptable salt thereof for treating an autoimmune disease.

[0003] An autoimmune disease is a condition in which the body's immune system malfunctions, causing it to attack its own healthy tissues. To protect itself from foreign or dangerous substances, the immune system must be able to recognize them. These substances include bacteria, viruses, parasites (such as worms), some cancer cells, and even transplanted organs and tissues. These substances contain molecules that the immune system can recognize and trigger a series of immune responses. These molecules are called antigens. Antigens can be present inside cells or on the surface of cells (such as bacteria or cancer cells), or they can be part of viruses. Some antigens, such as pollen or food molecules, exist on their own.

[0004] When specific lymphocytes (B cells and T cells) encounter an antigen, they learn how to attack it, thus protecting the body from potentially harmful antigens. One of the body's primary immunological defenses against antigens is the production of antibodies by B cells. Antibodies bind tightly to specific antigens, tagging them for attack or directly neutralizing them. The body produces a wide variety of antibodies, each with distinct antigen-specific properties. When the immune system is exposed to the same antigen again, it remembers it and can attack it more effectively.

[0005] Cells within a patient's or individual's own tissues also contain antigens. However, the immune system generally does not respond to antigens within the patient's or individual's own tissues, but only to antigens from foreign or dangerous substances. However, sometimes the immune system malfunctions, interpreting the body's own tissues as foreign and producing antibodies (called autoantibodies) that target and attack specific cells or tissues. However, autoantibodies produced in small quantities do not cause autoimmune diseases, so the presence of autoantibodies in the blood does not necessarily indicate the presence of an autoimmune disease.

[0006] The exact cause of autoimmune diseases is unknown. Furthermore, the cause may vary depending on the specific type of autoimmune disease a patient has. While the exact cause of autoimmune diseases remains unknown, T cell immune regulation is a common and important factor in the development of autoimmune diseases. There are several types of T cells, the most well-known being helper T cells and cytotoxic T cells. CD4 + , CD25 + , and Foxp3 + Regulatory T cells (T) characterized by the expression of reg ) has been revealed to be important. T reg T cells are known to support immunological tolerance, also known as immune homeostasis, by reducing exaggerated immune responses and preserving resistance to self-antigens. However, Treg This cellular imbalance compromises immune function, leading to the production of numerous autoantibodies that overwhelm anti-inflammatory mechanisms, causing severe inflammation and tissue damage.

[0007] Symptoms may vary depending on the specific type of autoimmune disease a patient has. However, many types share similar symptoms, one of which is fatigue. Other common symptoms include redness and swelling, and many patients report muscle pain. Hair loss is also a side effect of some autoimmune diseases. Fever and numbness or tingling in the hands and feet are also common symptoms. In some circumstances, autoimmune diseases can have potentially harmful consequences.

[0008] Managing autoimmune diseases is much more challenging. Unlike cancer or infections, where the goal of treatment is to eliminate harmful cells from the body, autoimmune diseases require the immune system to function properly. The goal is to rebuild tissues and organs damaged by inflammation and reset the immune system to reduce inflammation.

[0009] While autoimmune diseases have no known cure, their symptoms can be controlled. Therefore, traditional treatments for autoimmune diseases focus on reducing the signs and symptoms of the disease and limiting the autoimmune process. While some nonsteroidal anti-inflammatory drugs (NSAIDs) and tumor necrosis factor (TNF) blockers can be used to treat autoimmune diseases, they primarily help reduce joint, muscle, and bone pain. Immunosuppressants, such as corticosteroids, are often recommended to reduce the severity of damage caused by abnormal immune system function. However, immunosuppressants, currently considered the gold standard for autoimmune disease treatment, are often associated with harmful side effects, and long-term use can increase the risk of life-threatening infections and cancer.

[0010] 5-Benzylaminosalicylic acid compounds or pharmaceutically acceptable salts thereof have been used in the treatment of neurodegenerative diseases (U.S. Patent No. US 6,964,982). Previous studies have shown that 2-hydroxy-5-[2(4-trifluoromethyl-phenyl)ethylamino]benzoic acid, at nanomolar concentrations, is a potent spin-trapping molecule and microsomal prostaglandin E synthase-1 (mPGES-1) inhibitor, which blocks neuronal cell death, lateral pathology, and autophagosome formation, as well as increases motor function activity and lifespan in a mouse model of amyotrophic lateral sclerosis.

[0011] 5-Benzylaminosalicylic acid compounds or pharmaceutically acceptable salts thereof have been derived for the treatment of autoimmune diseases in various animal models of autoimmune diseases. Surprisingly, administration of 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid showed remarkable beneficial effects in various animal models of autoimmune diseases. In models of systemic lupus erythematosus (SLE) and multiple sclerosis (MS), which are related to autoimmune diseases, it was shown to improve behavioral changes, protect spleen and liver cell damage, restore abnormal immune responses, and reduce inflammatory responses. In animal models of psoriasis, it was shown to suppress the increase in skin lesion severity, reduce epidermal thickness, compactify collagen patterns, and reduce spleen index. Therefore, it is proposed that 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid may be a potential therapeutic option for treating autoimmune diseases by suppressing both oxidative stress and inflammation.

[0012] If a useful therapeutic agent is developed that can treat or prevent autoimmune diseases, it would be of great help in treating patients by reducing pain and inflammation, regulating the immune system, and inhibiting apoptosis without side effects.

[0013] The present invention relates to a method for treating systemic lupus erythematosus (SLE), multiple sclerosis (MS), celiac disease, type 1 diabetes, Graves' disease, inflammatory bowel disease, alopecia areata, Addison's disease, local or systemic scleroderma, psoriasis, atopic dermatitis, dermatomyositis, vitiligo, primary biliary cirrhosis, psoriatic arthritis, ankylosing spondylitis, reactive arthritis or Reiter's syndrome, rheumatoid arthritis, chronic thyroiditis (Hashimoto's thyroiditis or autoimmune thyroiditis), autoimmune hemolytic anemia, and immune-mediated inflammatory bowel disease. Provided is the use of a composition comprising a 5-benzylamino salicylic acid compound of formula (I) or a pharmaceutically acceptable salt thereof for the treatment and / or prevention of autoimmune diseases such as thrombocytopenia, Sjogren's syndrome, autoimmune retinopathy, acute anterior uveitis, myasthenia gravis, autoimmune vasculitis, antiphospholipid antibody syndrome, SAPHO syndrome, adult-onset Still's disease, and Behcet's disease.

[0014] Also provided is the use of a composition comprising a 5-benzylamino salicylic acid compound of formula (I) or a pharmaceutically acceptable salt thereof for the production of a medicament for the treatment and / or prevention of the above autoimmune disease.

[0015] Systemic lupus erythematosus (SLE) and multiple sclerosis (MS) are representative autoimmune diseases. Using the “experimental autoimmune encephalomyelitis (EAE) model,” which is one of the SLE animal models and MS animal models, the effect of the 5-benzylamino salicylic acid compound of formula (I) (particularly, compound 2: 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid) was confirmed. As a result, the size of the spleen and spleen follicles was significantly alleviated, and in the SLE model, the anti-dsDNA titer, which is a key biomarker of SLE, was significantly reduced, and the expression of CD206 (an anti-inflammatory phase marker of M2 macrophages) was increased, and inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α, and The expression of IFN (Interferon)-γ (inflammatory stage marker) was reduced, and T reg The cell population was significantly increased, indicating that compound 2 had anti-inflammatory and antioxidant effects as well as immunomodulatory effects (T reg It was confirmed that it exhibits a therapeutic effect through (maintaining cell balance). Therefore, the 5-benzylamino salicylic acid compound of formula (I) (particularly, compound 2: 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid) can be usefully used for autoimmune diseases.

[0016] In addition, psoriasis is one of the representative autoimmune diseases, and the effect of the 5-benzylamino salicylic acid compound of formula (I) (particularly, compound 2: 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid) was confirmed using the imiquimod (IMQ)-induced psoriasis mouse model known as a psoriasis disease model. As a result, it was confirmed to exhibit psoriasis treatment effects such as suppression of the increase in the severity of skin lesions, reduction in the thickness of hypertrophic epidermis, compaction of collagen pattern, and reduction in spleen index. Therefore, the 5-benzylamino salicylic acid compound of formula (I) (particularly, compound 2: 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid) can be usefully used in the treatment of autoimmune diseases, especially psoriasis.

[0017] Figures 1a and 1b show the spleen size and spleen index of systemic lupus erythematosus (SLE) mice.

[0018] Figures 2a and 2c show histological evaluation of the spleen in SLE mice.

[0019] Figure 3 shows the results of measuring anti-double-stranded DNA (anti-dsDNA) antibodies in SLE mouse serum.

[0020] Figure 4 shows clinical scores associated with an experimental autoimmune encephalomyelitis (EAE) mouse model.

[0021] Figure 5 shows the size of the spleen in EAE mice.

[0022] Figure 6 shows the expression of CD206, iNOS, tumor necrosis factor (TNF)-α, and IFN-γ in the spleen of EAE mice.

[0023] Figure 7 shows regulatory T cells (T) in the spleen of EAE mice. reg ) shows the ratio.

[0024] Figures 8a and 8b and 8e show the keratin lesions and the Psoriasis Area and Severity Index (PASI) of psoriatic mice.

[0025] Figures 9a and 9b show histological evaluation (H&E staining) and epidermal thickness in psoriatic mice.

[0026] Figure 10 shows histological evaluation (Masson's trichrome staining) in psoriatic mice.

[0027] Figures 11a and 11b show spleen size and spleen index in psoriatic mice.

[0028] The present invention relates to a method for treating systemic lupus erythematosus (SLE), multiple sclerosis (MS), celiac disease, type 1 diabetes, Graves' disease, inflammatory bowel disease, alopecia areata, Addison's disease, local or systemic scleroderma, psoriasis, atopic dermatitis, dermatomyositis, vitiligo, primary biliary cirrhosis, psoriatic arthritis, ankylosing spondylitis, reactive arthritis or Reiter's syndrome, rheumatoid arthritis, chronic thyroiditis (Hashimoto's thyroiditis or autoimmune thyroiditis), autoimmune hemolytic anemia, immune thrombocytopenia, Sjogren's disease. Provided are pharmaceutical compositions and methods comprising a compound of the following formula (I) or a pharmaceutically acceptable salt thereof for preventing, reducing the risk of developing, or treating autoimmune diseases such as Sjogren's syndrome, autoimmune retinopathy, acute anterior uveitis, Myasthenia gravis, autoimmune vasculitis, antiphospholipid antibody syndrome, SAPHO syndrome, adult-onset Still's disease, and Behcet's disease:

[0029] <Chemical formula (I)>

[0030]

[0031] Here,

[0032] X is CO, SO2 and (CH2) n are selected from;

[0033] R1 is selected from hydrogen, C1-C6 alkyl and C1-C6 alkanoyl;

[0034] R2 is hydrogen or C1-C6 alkyl;

[0035] R3 is hydrogen and C1-C5 alkanoyl group; and

[0036] R4 is selected from a phenyl group, a phenoxy group and a 5- to 10-membered aryl group, which is unsubstituted or substituted with one or more substituents each independently selected from nitro, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C5 alkoxy and C1-C5 haloalkoxy;

[0037] n contains integers from 1 to 5;

[0038] or a pharmaceutically acceptable salt thereof.

[0039] The present disclosure relates to a method for treating or preventing systemic lupus erythematosus (SLE), multiple sclerosis (MS), celiac disease, type 1 diabetes, Graves' disease, inflammatory bowel disease, alopecia areata, Addison's disease, local or systemic scleroderma, psoriasis, atopic dermatitis, dermatomyositis, vitiligo, primary biliary cirrhosis, psoriatic arthritis, ankylosing spondylitis, reactive arthritis or Reiter's syndrome, rheumatoid arthritis, chronic thyroiditis (Hashimoto's thyroiditis or autoimmune thyroiditis), autoimmune hemolytic anemia, immune thrombocytopenia, Sjogren's syndrome. (Sjogren's syndrome), autoimmune retinopathy, acute anterior uveitis, myasthenia gravis, autoimmune vasculitis, antiphospholipid antibody syndrome, SAPHO syndrome, adult-onset Still's disease, and Behcet's disease, comprising administering to a patient in need thereof a compound of formula (I).

[0040] In one embodiment, a number of compounds of formula (I) are prepared and evaluated. In one embodiment, the compositions and methods comprise a 5-benzylaminosalicylic acid compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0041] In one embodiment, the 5-benzylaminosalicylic acid compound is 5-benzylaminosalicylic acid itself.

[0042] Preferred examples of 5-benzylaminosalicylic acid compounds include 2-hydroxy-5-phenethylamino-benzoic acid (compound 1), 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid (compound 2), 2-hydroxy-5-[2-(3-trifluoromethyl-phenyl)-ethylamino]-benzoic acid (compound 3), 5-[2-(3,5-bis-trifluoromethyl-phenyl)-ethylamino]-2-hydroxy-benzoic acid (compound 4), 2-hydroxy-5-[2-(2-nitro-phenyl)-ethylamino]-benzoic acid (compound 5), 5-[2-(4-chloro-phenyl)-ethylamino]-2-hydroxy-benzoic acid (compound 6), 5-[2-(3,4-difluoro-phenyl)-ethylamino]-2-hydroxy-benzoic acid (Compound 7), 5-[2-(3,4-dichloro-phenyl)-ethylamino]-2-hydroxy-benzoic acid (Compound 8), 5-[2-(4-fluoro-2-trifluoromethyl-phenyl)-ethylamino]-2-hydroxy-benzoic acid (Compound 9), 5-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-hydroxy-benzoic acid (Compound 10), 2-hydroxy-5-[2-(4-methoxy-phenyl)-ethylamino]-benzoic acid (Compound 11), 2-hydroxy-5-(2-o-tolyl-ethylamino)-benzoic acid (Compound 12), 2-Hydroxy-5-(3-phenyl-propylamino)-benzoic acid (Compound 13), 2-Hydroxy-5-[3-(4-trifluoromethyl-phenyl)-propylamino]-benzoic acid (Compound 14), 5-[3-(4-fluoro-phenyl)-propylamino]-2-hydroxy-benzoic acid (Compound 15), 5-[3-(3,4-dichloro-phenyl)-propylamino]-2-hydroxy-benzoic acid (Compound 16), 2-Hydroxy-5-(3-p-tolyl-propylamino)-benzoic acid (Compound 17), 2-Acetoxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid (Compound 18), 5-[2-(2-chloro-phenyl)-ethylamino]-2-hydroxy-benzoic acid (Compound 19), 5-benzylaminosalicylic acid (Compound 20), 5-(4-nitrobenzyl)aminosalicylic acid (Compound 21), 5-(4-chlorobenzyl)aminosalicylic acid (Compound 22),5-(4-Trifluoromethylbenzyl)aminosalicylic acid (Compound 23), 5-(4-fluorobenzyl)aminosalicylic acid (Compound 24), 5-(4-methoxybenzyl)aminosalicylic acid (Compound 25), 5-(2,3,4,5,6-pentafluorobenzyl)aminosalicylic acid (Compound 26), 5-(4-nitrobenzyl)amino-2-hydroxy ethylbenzoate (Compound 27), 5-(4-nitrobenzyl)-N-acetylamino-2-hydroxy ethylbenzoate (Compound 28), 5-(4-nitrobenzyl)-N-acetylamino-2-acetoxy ethylbenzoate (Compound 29), 5-(4-nitrobenzoyl)aminosalicylic acid (Compound 30), 5-(4-nitrobenzenesulfonyl)aminosalicylic acid (Compound 31), 5-[2-(4-nitrophenyl)-ethyl]aminosalicylic acid (Compound 32), and 5-[3-(4-nitro-phenyl)-n-propyl]aminosalicylic acid (Compound 33). In certain preferred embodiments, the compound of formula (I) is Compound 2, 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid or a pharmaceutically acceptable salt thereof.

[0043] The 5-benzylaminosalicylic acid compound of the present disclosure or a pharmaceutically acceptable salt thereof can be prepared by, but is not limited to, the reaction scheme described in U.S. Patent No. US 6,573,402.

[0044] In one embodiment, altered inflammatory responses, abnormal immune responses, cell damage in multiple organs, and behavioral dysfunction, such as tail paralysis and a waddling gait, are symptoms of an autoimmune disease. In one embodiment, the compound of formula (I) reduces and / or suppresses the abnormal immune responses, cell damage in multiple organs, and behavioral dysfunction.

[0045] In one embodiment, symptoms of an autoimmune disease include thickened erythema and keratin lesions of the skin, epidermal thickening (acanthosis) and increased thickness, abnormal keratinocyte differentiation, elongated reticular ridges of the epidermis, infiltration of immune cells into the epidermis and dermis, irregular, fragmented, and disorganized collagen fiber structure, and increased spleen size and weight. In one embodiment, the compound of formula (I) reduces and / or inhibits these abnormal immune responses, increased severity of skin lesions, increased epidermal thickness, disorganized collagen pattern, and increased spleen index.

[0046] In one embodiment, the treatment of an autoimmune disease is achieved through the simultaneous pharmacological suppression of oxidative stress and inflammation. In one embodiment, the treatment of an autoimmune disease is achieved through the suppression of oxidative stress and prostaglandin E2 synthesis. In one embodiment, the treatment of an autoimmune disease is achieved through the suppression of oxidative stress and microsomal prostaglandin E synthase-1.

[0047] In one embodiment, the animal exhibits pathophysiological changes. In one embodiment, the pathophysiological changes are selected from increased follicle diameter, glomerular proliferation, leukocyte exudation, karyorrhexis and fibrinoid necrosis, decreased spleen follicles, cellular crescents, hyaline deposition on the activity index, interstitial inflammation, glomerulosclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis. In one embodiment, the pathophysiological changes are selected from increased macrophage size; increased macrophage number; and cell loss.

[0048] In one embodiment, the human patient is suffering from systemic lupus erythematosus (SLE), multiple sclerosis (MS), celiac disease, type 1 diabetes, Graves' disease, inflammatory bowel disease, alopecia areata, Addison's disease, local or systemic scleroderma, psoriasis, atopic dermatitis, dermatomyositis, vitiligo, primary biliary cirrhosis, psoriatic arthritis, ankylosing spondylitis, reactive arthritis or Reiter's syndrome, rheumatoid arthritis, chronic thyroiditis (Hashimoto's thyroiditis or autoimmune thyroiditis), autoimmune hemolytic anemia, immune thrombocytopenia, Sjogren's disease. Patients are selected from patients with Sjogren's syndrome, autoimmune retinopathy, acute anterior uveitis, myasthenia gravis, autoimmune vasculitis, antiphospholipid antibody syndrome, SAPHO syndrome, adult-onset Still's disease, and Behcet's disease.

[0049] In one embodiment, the animal is selected from a cow, a horse, a sheep, a cat, a chinchilla, a dog, a ferret, a gerbil, a pig, and a hamster.

[0050] definition

[0051] The definitions of terms set forth below apply whether the term is used alone or in combination with other terms.

[0052] The term "acetoxy" refers to a group represented by the general chemical formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

[0053] An "alkyl" group (including the "alkyl" in haloalkyl) or "alkane" is a fully saturated straight-chain or branched-chain non-aromatic hydrocarbon. Typically, a straight-chain or branched-chain alkyl group has from 1 to about 20 carbon atoms, and preferably from 1 to about 10 carbon atoms, unless otherwise defined. A C1-C6 straight-chain or branched-chain alkyl group is also referred to as a "lower alkyl group." In one embodiment, the alkyl is a C1-C5 alkyl, and more preferably a C1-C3 alkyl. More specifically, preferred alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl.

[0054] Additionally, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to encompass both "unsubstituted alkyl" and "substituted alkyl," the latter referring to an alkyl moiety having a substituent replacing a hydrogen at one or more carbons of the hydrocarbon backbone. Such substituents may include, unless otherwise specified, halogen, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, acyl such as formyl or alkylC(O)), thiocarbonyl (e.g., thioester, thioacetate or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, silyl ether, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be appreciated by those skilled in the art that moieties substituted on the hydrocarbon chain may themselves be substituted, where appropriate. For example, substituents of a substituted alkyl can include amino, azido, imino, amido, phosphoryl (including phosphonate and phosphinate), sulfonyl (including sulfate, sulfonamido, sulfamoyl, and sulfonate), and silyl groups, as well as substituted and unsubstituted forms of ether, alkylthiol, carbonyl (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, and the like. Illustrative examples of substituted alkyl are described below. Cycloalkyl can be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF3, -CN, and the like.

[0055] The term "Cx-y" when used with chemical moieties such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy means a group containing carbons x through y in the chain. For example, the term "Cx-y alkyl" means a substituted or unsubstituted saturated hydrocarbon group including straight-chain and branched-chain alkyl groups containing carbons x through y in the chain, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl. C0 alkyl represents hydrogen when the group is terminal and a bond when it is internal. The terms "C2-y alkenyl" and "C2-y alkynyl" mean substituted or unsubstituted unsaturated aliphatic groups similar in length to alkyl as described above and which may be substituted, but which contain one or more double or triple bonds, respectively.

[0056] The term "alkanoyl" means a group represented by the general formula hydrocarbyl-C(O)-, preferably alkyl-C(O)-.

[0057] The term "alkoxy" (including the "alkoxy" in haloalkoxy) means an alkyl group, preferably a lower alkyl group, having an oxygen atom attached thereto. In one embodiment, the alkoxy is preferably C1-C5 alkoxy, more preferably C1-C3 alkoxy. More specifically, preferred alkoxy groups include, but are not limited to, methoxy, ethoxy, and propaneoxy. Halogens include, but are not limited to, fluoride, chloride, bromide, and iodide. Preferably, the alkanoyl group is C2-C 10 Alkanoyl, more preferably C3-C5 alkanoyl. More specifically, preferred alkanoyl groups include, but are not limited to, ethanoyl, propanoyl, and cyclohexanecarbonyl.

[0058] The terms "amine" and "amino" are art-recognized and refer to unsubstituted and substituted amines and salts thereof, for example, moieties which may be represented by:

[0059] or

[0060] Here each R 10 independently represents hydrogen or hydrocarbyl group, or two R 10 They complete a heterocycle with 4 to 8 atoms within the ring structure together with the N atom to which they are attached.

[0061] The term "aryl" as used herein includes substituted or unsubstituted single ring aromatic groups wherein each atom of the ring is carbon. Preferably, the ring is a 5- to 10-membered ring, more preferably a 6- to 10-membered ring or a 6-membered ring. The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, wherein at least one of the rings is aromatic, for example, the other cyclic ring may be a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Exemplary substitutions of an aryl group can include, for example, halogen, haloalkyl such as trifluoromethyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl such as alkylC(O)), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, silyl ether, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety.

[0062] The terms “halo” and “halogen” as used herein mean halogen, including chloro, fluoro, bromo and iodo.

[0063] When the term "lower" is used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy, it is meant to include groups having 10 or fewer, and preferably 6 or fewer, non-hydrogen atoms in the substituent. For example, "lower alkyl" refers to an alkyl group containing 10 or fewer, and preferably 6 or fewer, carbon atoms. In certain embodiments, an acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy substituent as defined herein, whether appearing alone or in combination with other substituents, is lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl or lower alkoxy, respectively. , as in reference to hydroxyalkyl and aralkyl (in which case, for example, atoms within an aryl group are not counted when counting carbon atoms of an alkyl substituent).

[0064] The term "substituted" refers to a moiety having a substituent that replaces a hydrogen at one or more carbon atoms of the skeleton. It will be understood that "substituted" or "substituted" includes the implicit condition that such substitution is dependent on the permissible valences of the substituted atom and the substituent, and that the substitution results in a stable compound that does not undergo spontaneous transformations such as rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad sense, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Permissible substituents may be one or more and may be the same or different for appropriate organic compounds. For purposes of the present invention, a heteroatom, such as nitrogen, may have a hydrogen substituent and / or any permissible substituent of the organic compounds described herein that satisfies the valences of the heteroatoms. The substituent may include any of the substituents described herein, for example, halogen, haloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphate, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by those skilled in the art that the substituents themselves may be substituted, where appropriate. Unless specifically stated as "unsubstituted," references to a chemical moiety herein are to be understood to include substituted variations. For example, reference to an “aryl” group or moiety implicitly includes both substituted and unsubstituted variants.

[0065] As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by a non-toxic or substantially non-toxic acid or base. When the compound of the present disclosure is acidic, a base addition salt of the compound of the present disclosure can be prepared by reacting the free base of the compound with a sufficient amount of a desired base and a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, salts made with sodium, potassium, calcium, ammonium, magnesium, or organic amino acids. When the compound of the present disclosure is basic, an acid addition salt of the compound can be prepared by reacting the free base of the compound with a sufficient amount of a desired acid and a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, propionic, isobutyric, oxalic, malic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydrogeniodide, and phosphorous acids. Pharmaceutically acceptable salts of the present invention also include, but are not limited to, amino acid salts such as alginates, organic acid analogs such as glucuronic acid or galactunoric.

[0066] For example, a pharmaceutically acceptable salt of 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid (Compound 2), which is a preferred embodiment of the present invention, can be prepared by the following reaction scheme. However, the following reaction scheme is provided as an example and is not intended to limit the scope of the present disclosure.

[0067] <Reaction Scheme 1>

[0068]

[0069] In the above reaction formula, M is a pharmaceutically acceptable metal or basic organic compound such as diethylamine, lithium, sodium and potassium.

[0070] More specifically, diethylamine salts can be prepared by dissolving a compound in alcohol, adding diethylamine dropwise, stirring, distilling in a vacuum, and adding ether to crystallize. Alkali metal salts can be prepared by adding inorganic reagents such as lithium hydroxide, sodium hydroxide, and potassium hydroxide to a solvent such as alcohol, acetone, or acetonitrile, preparing the desired salt, and then freeze-drying. In addition, according to a similar method, lithium salts can be prepared with lithium acetate, sodium salts can be prepared with sodium 2-ethylhexanoate or sodium acetate, and potassium salts can be prepared with potassium acetate.

[0071] Some of the compounds of the present disclosure may be in hydrated forms, and may exist in solvated or unsolvated forms. Some of the compounds of the present disclosure may exist in crystalline or amorphous forms, and any physical form is included within the scope of the present disclosure. Furthermore, some of the compounds of the present disclosure may contain one or more asymmetric carbon atoms or double bonds, and thus exist in two or more stereoisomeric forms, such as racemates, enantiomers, diastereomers, geometric isomers, etc. The present disclosure encompasses these individual stereoisomers of the compounds.

[0072] The present invention also provides a food composition for improving symptoms of an autoimmune disease, comprising a compound of the above formula (I) or a pharmaceutically acceptable salt thereof.

[0073]

[0074] Hereinafter, the present disclosure will be described in more detail to assist those skilled in the art in understanding the present disclosure. However, the following examples are illustrative and are not intended to limit the scope of the present disclosure. It will be apparent that various modifications can be made without departing from the spirit and scope of the present disclosure or sacrificing all of its material advantages.

[0075]

[0076] Example 1. Evaluation of the symptom improvement effect of compound 2 in an SLE mouse model.

[0077] Compound 2, 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid was used as a representative compound.

[0078] The aim of this example was to investigate the effect of compound 2 in the imiquimod (IMQ)-induced lupus model, a widely used model of induced SLE.

[0079] Experimental design

[0080] Female BALB / C mice weighing 18–20 g were supplied by Saeron Bio (Korea) and acclimated for 7 days. Animals were housed in separate cages with free access to laboratory food and water. During the experiment, animals were maintained at 23±3°C and 50±10% relative humidity with a 12-h light / dark cycle. Animals were handled according to a protocol approved by the Institutional Animal Care and Use Committee of GNT Pharmaceuticals. Mice were randomly divided into four groups: normal group (Normal group, n=6), control SLE group (vehicle group, n=8), IMQ + Compound 2 group (Compound 2 treatment group, n=4), and IMQ + N-acetylcysteine ​​group (NAC treatment group, n=8). All IMQ-treated mice received topical 5% imiquimod cream (Aldara cream, Dong-A Pharmaceutical) at a dose of 1.25 mg / day, every other day, for 4 weeks, administered to the right ear. Compound 2 (5 mg / kg, twice daily) was administered orally to the IMQ+Compound 2 group for 4 weeks, followed by IMQ treatment. N-acetyl cysteine ​​(150 mg / kg, once daily, pH adjusted to 7.5-8.0) was administered intraperitoneally to the IMQ+NAC group for 4 weeks, along with IMQ treatment.

[0081] At the end of the experiment, mice were anesthetized with pentobarbital. Blood was collected via cardiac puncture. Within 30 minutes of collection, whole blood was centrifuged at 12,000 g for 10 minutes, and serum was separated from the whole blood with EDTA. The extracted spleens were weighed, and the tissue was heated to 60°C, washed with xylene, and then immersed in a gradient of ethanol. Sections were stained with H&E (BBC Biochemical, Mount Vernon, Washington) and imaged under a microscope. Five fields of view were observed at ×10 magnification, and the number of spleen alba pulp (follicles) was counted. The diameter of the spleen alba pulp was also measured using a micrometer. The diameter of the spleen alba pulp was measured vertically and horizontally, and the average was calculated. Serum anti-dsDNA (IgG-specific) concentrations were analyzed using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (LBIS Mouse anti-dsDNA ELISA, Fujifilm Wako Shibayagi Co., Ltd., Richmond, VA, USA).

[0082] The control SLE group had a larger spleen than the normal group, whereas the Compound 2-treated group had a smaller spleen than the control SLE group. However, the spleen size of the NAC-treated group was similar to that of the control SLE group (Fig. 1a). The spleen index (organ weight / body weight x 100%) of the control SLE group was significantly higher than that of the normal group, but the spleen index of the Compound 2-treated group was significantly lower than that of the control SLE group. However, there was no significant difference between the NAC-treated group and the control SLE group (Fig. 1b; * P<0.05, ** P<0.01, *** P<0.001).

[0083] H&E stained sections of the spleen from the control SLE group showed splenic hyperplasia and enlarged white pulp, indicative of lymphoid hyperplasia due to autoimmune disease (Fig. 2a). In the compound 2-treated group, the number of splenic follicles significantly increased and the follicle diameter significantly decreased, indicating that compound 2 has a cytoprotective effect against abnormal autoimmune-related splenic damage (Figs. 2b-2c). **** P<0.0001). However, the N-acetylcysteine ​​treatment group did not show any beneficial effect.

[0084] The control SLE group showed a significantly increased anti-dsDNA concentration compared to the normal group. In SLE mice, compound 2 significantly reduced anti-dsDNA titer, whereas NAC had no effect (Fig. 3; ** P<0.01, *** P<0.001 **** P<0.0001).

[0085]

[0086] Example 2. Evaluation of the symptom improvement effect of compound 2 in an EAE mouse model.

[0087] Multiple sclerosis (MS) is a neurological autoimmune disease in which the body's immune system attacks myelin cells, the protective sheath surrounding the brain and spinal cord's ganglia. EAE has been a well-known preclinical model for MS. Therefore, we used the EAE mouse model to examine the effects of compound 2 on autoimmune diseases.

[0088] Experimental design

[0089] The EAE mouse model was induced in 6-week-old female C57BL / 6 mice. The mice were divided into three groups: the normal group (6 mice), the vehicle control EAE group (8 mice), and the EAE + compound 2 group (8 mice treated with compound 2). The mice were each inoculated with 200 μg of oligodendrocyte glycoprotein peptide myelin oligodendrocyte glycoprotein 35-55 (MOG35-55, Prospecbio, Israel) emulsified in 400 μg of complete Freund's adjuvant (CFA, Sigma, USA). The emulsion was injected into both flanks of each mouse. Subsequently, 200 ng of pertussis toxin (Sigma, USA) was injected intraperitoneally on days 0 and 2. Compound 2 was injected intraperitoneally at 3.3 mg / kg every 24 hours for 7 days, starting on day 9. In the control EAE group, PBS was injected intraperitoneally. Clinical signs associated with EAE were monitored daily and graded from 0 to 5: grade 0, no obvious clinical symptoms; grade 0.5, partial tail paralysis; grade 1, tail paralysis or waddling gait; grade 1.5, partial tail paralysis and waddling gait; grade 2, tail paralysis and waddling gait; grade 2.5, partial quadriplegia; grade 3, paralysis of one limb; grade 3.5, paralysis of one limb and partial paralysis of the other limb; grade 4, paralysis of both limbs; grade 4.5, coma; grade 5, death.

[0090] On the 25th day after EAE induction, mice were euthanized by exposure to CO2, and spleens were extracted. RNA expression in the spleen was analyzed using AMPIGENE qPCR Green Mix Hyrox (Thermofisher, USA) containing 400 nm forward and reverse primers (Korea Bionics) and SYBR Green dye (Enzo Life Sciences, Farmingdale, NY, USA) in an Applied Biosystems™QuantStudio 5 qPCR system (Thermofisher, USA). The expression level of each gene was normalized to glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and compared with the expression in the normal group or control EAE group. Compound 2 was T reg To evaluate the effect on T, mouse spleen cell preparations were prepared according to the manufacturer's instructions. reg Staining with the detection kit (CD4 / CD25 / FoxP3) (Miltenyi Biotech, Germany) and flow cytometry were used to detect T reg The groups were evaluated. Data were analyzed using FlowJo™10.8.1 software.

[0091] EAE-related neurological signs began on day 9, and symptom severity peaked on day 16. The onset dates were similar in the control EAE group and the compound 2-treated group. Clinical signs were effectively alleviated in the compound 2-treated group (Figure 4; *** P<0.001).

[0092] In the control EAE group, the spleen size was enlarged, whereas the spleen size in the compound 2-treated group was similar to that in the normal group (Fig. 5).

[0093] The expression of CD206 decreased in the control EAE group, but significantly increased in the compound 2-treated group compared to the control EAE group. The compound 2-treated group showed significantly lower expression of iNOS compared to the control EAE group. The expression of inflammatory cytokines TNF-α and IFN-γ was lower in the compound 2-treated group compared to the control EAE group (Fig. 6). * P<0.05, *** P<0.001).

[0094] CD4 in the control EAE group + CD25 + Foxp3 + T reg The percentage of cells was significantly lower than that of the control group. However, the compound 2-treated group had a higher T reg The cell number was significantly higher (Fig. 7, * P<0.05).

[0095]

[0096] Conclusions of Examples 1 and 2

[0097] To evaluate the therapeutic potential of compound 2, splenic leukemia (SLE) and EAE, which are representative models of autoimmune diseases, were used in this experiment. The size of the spleen and spleen follicles was significantly reduced in the compound 2-treated group. In the SLE model, anti-dsDNA titer, a key biomarker of SLE, was significantly reduced in the compound 2-treated group. The expression of CD206 (M2 anti-inflammatory phase marker) increased, and the expression of iNOS, TNF-α, and IFN-γ (inflammatory phase markers) decreased in the compound 2-treated group. T reg The cell population was significantly increased in the compound 2 treatment group. These results indicate that compound 2 has anti-inflammatory and antioxidant effects as well as immunomodulatory effects (T reg (maintaining cellular balance) to have beneficial therapeutic effects. Taken together, these findings strongly suggest that compound 2 may be applied to the treatment of autoimmune diseases.

[0098]

[0099] Example 3. Evaluation of the skin lesion improvement effect of compound 2 in a mouse psoriasis model.

[0100] The aim of this example was to investigate the effect of compound 2 in the imiquimod (IMQ)-induced psoriasis model, which is widely used as one of the induced psoriasis models.

[0101] Model Description: Imiquimod (IMQ)-induced psoriasis model

[0102] Psoriasis was induced using imiquimod (IMQ) for this experiment. The IMQ-induced psoriasis mouse model is one of the most widely used models for studying psoriasis. IMQ is a Toll-like receptor-7 / 8 (TLR-7 / 8) agonist used to treat actinic keratosis and basal cell carcinoma. Topical application of IMQ cream to mouse skin is known to recruit immune cells and activate macrophages, monocytes, and dendritic cells, leading to the secretion of inflammatory cytokines. The IMQ-induced psoriasis mouse model is known to closely resemble human psoriasis in terms of skin erythema, scaliness, epidermal changes (acanthosis), and inflammatory infiltrates composed of T cells, neutrophils, and dendritic cells.

[0103] Experimental design

[0104] Male BALB / C mice weighing 20–22 g were supplied by Saeron Bio (Korea) and acclimated for 7 days. Animals were housed in separate cages with free access to laboratory food and water. During the experiment, animals were maintained at 23±3°C and 50±10% relative humidity with a 12-h light / dark cycle. Animals were handled according to a protocol approved by the GNT Pharmaceutical Institutional Animal Care and Use Committee. Mice were randomly divided into three groups: normal group (Normal group, n=5), control psoriasis group (Vehicle group, n=8), and IMQ + Compound 2 group (Compound 2 treatment group, n=9). All IMQ-treated groups received topical 5% imiquimod cream (Aldara cream, Dong-A Pharmaceutical) at a dose of 62.5 mg / day for 6 days on the shaved back. Compound 2 (5 mg / kg, twice daily) was administered orally to the IMQ+Compound 2 group for 6 days, followed by concurrent IMQ treatment.

[0105] Experimental results

[0106] To evaluate the antipsoriatic effect of compound 2, the severity of psoriasis was monitored using an IMQ-induced psoriasis mouse model. The psoriasis skin PASI score is used to evaluate the severity of skin lesions in mice. Mice treated with IMQ showed significantly thicker erythema and scale lesions compared to normal mice after 7 days (Fig. 8a). The PASI score of the normal group was 0, whereas the control psoriasis group treated only with IMQ showed an increase in the score (Figs. 8b-8e, * P<0.05 and control psoriasis group, # P<0.05 and compound 2 treatment group). However, the compound 2 treatment group showed a significant decrease in scores compared to the control psoriasis group. Compound 2 treatment was shown to suppress the increase in the severity of skin lesions caused by IMQ by reducing keratin and thickness.

[0107]

[0108] Example 4. Histopathological changes following compound 2 treatment in IMQ-induced psoriasis mice.

[0109] After confirming the therapeutic effect of Compound 2 on psoriasis-like symptoms in mice, histological analysis was performed to identify histological changes occurring in psoriatic skin and methods for improvement. IMQ-induced inflammation exhibits histological characteristics of psoriasis, including increased epidermal proliferation, abnormal keratinocyte differentiation, and elongated, reticular ridges in the epidermis.

[0110] In the H&E-stained sections of the dorsal skin of the IMQ-induced control psoriasis group, epidermal hyperplasia, acanthosis, and elongated reticular ridges of the epidermis were increased (Fig. 9a). The epidermal thickness was also increased in the control psoriasis group compared to the normal group (Fig. 9b, **** P<0.0001). In contrast, the compound 2-treated group showed a significant decrease in epidermal thickness. This increased epidermal thickness was attributed to the proliferation of basal cells and keratinocytes. In contrast to the IMQ-only treated group (control psoriasis group), the histopathological manifestations of skin lesions in the compound 2 group significantly suppressed epidermal thickening (acanthosis) and proliferation-induced elongation of reticular ridges.

[0111] Infiltration of immune cells into the epidermis and dermis is another pathological hallmark of psoriasis. MT (Masson's trichrome) staining demonstrated that IMQ application significantly stimulated the proliferation of epidermal keratinocytes and induced inflammatory cell infiltration (Figure 10). These features were not observed in the control group. Compound 2 treatment reduced IMQ-induced epidermal thickness and hyperkeratosis and potently suppressed psoriasis-like inflammation. Furthermore, the control group exhibited long, regular reticular fiber structures, whereas the control psoriasis group exhibited irregular, fragmented, and disorganized collagen fiber structures. However, mice treated with compound 2 exhibited a significantly more compact collagen pattern in the dermis (HF: Hair follicle; Open arrow: epidermal thickness; Black arrow: inflammatory cell infiltration).

[0112] The above results indicate that compound 2 can alleviate symptoms that may occur in the skin of an imiquimod-induced psoriasis model and improve skin histopathological changes.

[0113]

[0114] Example 5. Evaluation of the effects of compound 2 on spleen changes and spleen index in IMQ-induced psoriasis mice.

[0115] The spleen, an immune organ, contains various types of immune cells and plays a crucial role in maintaining the immune system. To determine the systemic effects of IMQ, which induces splenomegaly, and the effect of compound 2 on systemic immune responses, the spleen index was assessed.

[0116] At the end of the experiment, mice were anesthetized with pentobarbital. Blood was collected via cardiac puncture. Within 30 minutes of collection, whole blood was centrifuged at 12,000 g for 10 minutes, and serum was separated from the blood using EDTA. The weight of the extracted spleen was measured.

[0117] IMQ application increased the spleen size and weight of IMQ-induced psoriasis mice (Fig. 11a). In contrast, compound 2 treatment reduced the spleen size and weight of IMQ-induced psoriasis mice. As a result, the spleen index was reduced in the compound 2 group compared to the control psoriasis group, suggesting the anti-inflammatory effect of compound 2 (Fig. 11b). * P<0.05 and control psoriasis group, # P<0.05 and compound 2 treatment group).

[0118]

[0119] The foregoing description of the present invention is for illustrative purposes only, and those skilled in the art will readily appreciate that the present invention can be readily modified into other specific forms without altering the technical spirit or essential characteristics of the present invention. Therefore, the embodiments described above should be understood as illustrative in all respects and not restrictive. For example, each component described as a single entity may be implemented in a distributed manner, and similarly, components described as distributed may be implemented in a combined manner.

[0120]

[0121] The scope of the present invention is indicated by the claims set forth below, and all changes or modifications derived from the meaning and scope of the claims and their equivalent concepts should be interpreted as being included in the scope of the present invention.

Claims

1. A pharmaceutical composition for treating or preventing an autoimmune disease, comprising a compound of the following chemical formula (I) or a pharmaceutically acceptable salt thereof: <Chemical formula (I)> Here, X is CO, SO 2 and (CH 2 ) n are selected from; R 1 Silver hydrogen, C 1 -C 6 Alkyl and C 1 -C 6 Selected from alkanoyl; R 2 is hydrogen or C 1 -C 6 It is alkyl; R 3 is hydrogen or C 1 -C 5 It is an alkanoic acid; and R 4 is nitro, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 5 Alkoxy and C 1 -C 5 A phenyl group, a phenoxy group and a 5- to 10-membered aryl group, each unsubstituted or substituted with one or more substituents independently selected from haloalkoxy; n contains integers from 1 to 5.

2. In the first paragraph, the compound of the formula (I) is 2-hydroxy-5-phenethylamino-benzoic acid, 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid, 2-hydroxy-5-[2-(3-trifluoromethyl-phenyl)-ethylamino]-benzoic acid, 5-[2-(3,5-bis-trifluoromethyl-phenyl)-ethylamino]-2-hydroxy-benzoic acid, 2-hydroxy-5-[2-(2-nitro-phenyl)-ethylamino]-benzoic acid, 5-[2-(4-chloro-phenyl)-ethylamino]-2-hydroxy-benzoic acid, 5-[2-(3,4-difluoro-phenyl)-ethylamino]-2-hydroxy-benzoic acid, 5-[2-(3,4-dichloro-phenyl)-ethylamino]-2-hydroxy-benzoic acid, 5-[2-(4-fluoro-2-trifluoromethyl-phenyl)-ethylamino]-2-hydroxy-benzoic acid, 5-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-hydroxy-benzoic acid, 2-hydroxy-5-[2-(4-methoxy-phenyl)-ethylamino]-benzoic acid, 2-hydroxy-5-(2-o-tolyl-ethylamino)-benzoic acid, 2-hydroxy-5-(3-phenyl-propylamino)-benzoic acid, 2-hydroxy-5-[3-(4-trifluoromethyl-phenyl)-propylamino]-benzoic acid, 5-[3-(4-fluoro-phenyl)-propylamino]-2-hydroxy-benzoic acid, 5-[3-(3,4-dichloro-phenyl)-propylamino]-2-hydroxy-benzoic acid, 2-hydroxy-5-(3-p-tolyl-propylamino)-benzoic acid, 2-acetoxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid, 5-[2-(2-chloro-phenyl)-ethylamino]-2-hydroxy-benzoic acid, 5-benzylaminosalicylic acid, 5-(4-nitrobenzyl)aminosalicylic acid, 5-(4-chlorobenzyl)aminosalicylic acid, 5-(4-trifluoromethylbenzyl)aminosalicylic acid, 5-(4-fluorobenzyl)aminosalicylic acid, 5-(4-methoxybenzyl)aminosalicylic acid, 5-(2,3,4,5,6-pentafluorobenzyl)aminosalicylic acid, 5-(4-nitrobenzyl)amino-2-hydroxyethylbenzoate, 5-(4-nitrobenzyl)-N-acetylamino-2-hydroxyethylbenzoate, 5-(4-nitrobenzyl)-N-acetylamino-2-acetoxyethylbenzoate,A pharmaceutical composition selected from the group consisting of 5-(4-nitrobenzoyl)aminosalicylic acid, 5-(4-nitrobenzenesulfonyl)aminosalicylic acid, 5-[2-(4-nitrophenyl)-ethyl]aminosalicylic acid, and 5-[3-(4-nitro-phenyl)-n-propyl]aminosalicylic acid.

3. A pharmaceutical composition in the second paragraph, wherein the compound of the chemical formula (I) is 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid or 2-acetoxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid.

4. A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition comprises a capsule, a tablet including an orally disintegrating tablet, an orally disintegrating film, and an injection including intraperitoneal and intravenous administration.

5. In the first paragraph, the autoimmune disease is systemic lupus erythematosus (SLE), multiple sclerosis (MS), celiac disease, type 1 diabetes, Graves' disease, inflammatory bowel disease, alopecia areata, Addison's disease, local or systemic scleroderma, psoriasis, atopic dermatitis, dermatomyositis, vitiligo, primary biliary cirrhosis, psoriatic arthritis, ankylosing spondylitis, reactive arthritis or Reiter's syndrome, rheumatoid arthritis, chronic thyroiditis (Hashimoto's thyroiditis or autoimmune thyroiditis), autoimmune hemolytic anemia, immune thrombocytopenia, A pharmaceutical composition selected from the group consisting of Sjogren's syndrome, autoimmune retinopathy, acute anterior uveitis, myasthenia gravis, autoimmune vasculitis, antiphospholipid antibody syndrome, SAPHO syndrome, adult-onset Still's disease, and Behcet's disease.

6. A pharmaceutical composition according to claim 1, wherein the autoimmune disease is treated through simultaneous pharmacological inhibition of oxidative stress and inflammation.

7. In the first paragraph, the autoimmune disease is caused by oxidative stress and prostaglandin E. 2 A pharmaceutical composition which is treated by inhibiting synthesis.

8. A pharmaceutical composition according to claim 1, wherein the autoimmune disease is treated through inhibition of oxidative stress and microsomal prostaglandin E synthase-1.

9. In the first paragraph, the autoimmune disease is T reg A pharmaceutical composition which is capable of treating through cell control.

10. A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is for human or companion animal use.

11. A pharmaceutical composition according to claim 10, wherein the companion animal is selected from the group consisting of cows, horses, sheep, cats, chinchillas, dogs, ferrets, geese, pigs, and hamsters.

12. A food composition for improving symptoms of an autoimmune disease, comprising a compound of the following chemical formula (I) or a pharmaceutically acceptable salt thereof: <Chemical formula (I)> Here, X is CO, SO 2 and (CH 2 ) n are selected from; R 1 Silver hydrogen, C 1 -C 6 Alkyl and C 1 -C 6 Selected from alkanoyl; R 2 is hydrogen or C 1 -C 6 It is alkyl; R 3 is hydrogen or C 1 -C 5 It is an alkanoic acid; and R 4 is nitro, halogen, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 5 Alkoxy and C 1 -C 5 A phenyl group, a phenoxy group and a 5- to 10-membered aryl group, each unsubstituted or substituted with one or more substituents independently selected from haloalkoxy; n contains integers from 1 to 5.

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