Compositions and methods for treating autoimmune diseases

Abstract

This invention relates to pharmaceutical compositions and methods for treating or preventing autoimmune diseases in patients or subjects in need, said pharmaceutical compositions 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. Compositions comprising a 5-benzylaminosalicylic acid compound of chemical formula (I) or a pharmaceutically acceptable salt thereof can be used to treat autoimmune diseases.

Description

Technical Field

[0001] This application claims priority based on Korean Application No. 10-2023-0170944, filed November 30, 2023; Korean Application No. 10-2024-0120574, filed September 5, 2024; and Korean Application No. 10-2024-0143429, filed October 18, 2024, the entire contents of which are incorporated herein by reference.

[0002] This invention relates to pharmaceutical compositions and methods for treating or preventing autoimmune diseases, said pharmaceutical compositions comprising a 5-benzylaminosalicylic acid compound represented by chemical formula (I) or a pharmaceutically acceptable salt thereof. Background Technology

[0003] Autoimmune diseases are conditions caused by a dysfunction in the body's immune system, leading it to attack healthy endogenous tissues. To protect the body 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 include molecules that the immune system can recognize and that can stimulate a range of immune responses. These molecules are called antigens. Antigens can be contained inside or on the surface of cells (such as bacteria or cancer cells), or they may be part of a virus. Some antigens, such as pollen or food molecules, exist independently.

[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 main immune defenses against antigens is the production of antibodies by B cells. Antibodies bind tightly to specific antigens, either labeling them for attack or directly neutralizing them. The body produces a wide variety of antibodies. Each antibody has unique antigen specificity. When the immune system is exposed to the same antigen again, it remembers it, thus enabling it to attack more effectively.

[0005] Antigens are also present in the cells of a patient's or individual's own tissues. However, normally, the immune system does not react to antigens in a patient's or individual's own tissues, but only to antigens of foreign or dangerous substances. However, sometimes the immune system malfunctions, interpreting the body's own tissues as foreign substances and producing antibodies (called autoantibodies) that target and attack specific cells or tissues of the body. Nevertheless, because small amounts of autoantibodies do not cause autoimmune diseases, the presence of autoantibodies in the blood does not necessarily indicate the presence of an autoimmune disease.

[0006] The exact cause of autoimmune diseases remains unclear. Furthermore, the cause may vary depending on the specific type of autoimmune disease a patient has. Although the exact cause of autoimmune diseases is unknown, T-cell immune regulation is a common and important factor in their development. There are many types of T cells, the most well-known being helper T cells and cytotoxic T cells. [The text then abruptly shifts to a seemingly unrelated topic:] ...expressing CD4... + CD25 + and Foxp3 + Regulatory T cells (T cells) characterized by reg The importance of T has been confirmed. reg Cells support immune tolerance, also known as immune homeostasis, by reducing excessive immune responses and maintaining resistance to self-antigens. However, when due to T... reg When cellular imbalances lead to impaired immune function and the production of large amounts of autoantibodies, these can overwhelm anti-inflammatory mechanisms, resulting in severe inflammation and tissue damage.

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

[0008] Managing autoimmune diseases is far more difficult. Unlike cancer or infections, whose treatment aims to eliminate harmful cells in the body, autoimmune diseases require maintaining the immune system. The goal is to reduce inflammation by rebuilding tissues and organs damaged by inflammation and by resetting the immune system.

[0009] While there is no known cure for autoimmune diseases, symptoms can be managed. Therefore, traditional treatments for autoimmune diseases focus on reducing the signs and symptoms of the disease and limiting the autoimmune process. Some NSAIDs and TNF blockers are available for treating autoimmune diseases, but they primarily help alleviate pain in the joints, muscles, and bones. 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 treating autoimmune diseases, are largely associated with harmful side effects, and long-term use may increase the risk of fatal infections and cancer.

[0010] 5-Benzylaminosalicylic acid compounds or pharmaceutically acceptable salts thereof have been used to treat neurodegenerative diseases (US Patent No. 6,964,982). In previous studies, 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid is a potent spin-trapping molecule and nanomolar concentration inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) and has been shown to block neuronal death, lateral sclerosis, and autophagy formation in a mouse model of amyotrophic lateral sclerosis (ALS), as well as activate motor function and prolong lifespan. Summary of the Invention

[0011] Technical issues

[0012] 5-Benzylaminosalicylic acid compounds or pharmaceutically acceptable salts thereof have been used to treat autoimmune diseases in animal models of various autoimmune diseases. Surprisingly, administration of 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid has shown significant beneficial effects in various animal models of autoimmune diseases. In autoimmune disease-associated models of systemic lupus erythematosus (SLE) and multiple sclerosis (MS), effects such as improving behavioral changes, protecting against spleen and liver cell damage, restoring abnormal immune responses, and reducing inflammatory responses have been observed. In psoriasis animal models, effects such as inhibiting the increase in skin lesion severity, reducing epidermal thickness, compressing collagen patterns, and lowering spleen indices have been observed. Therefore, 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid may become a potential therapeutic option for treating autoimmune diseases by inhibiting oxidative stress and inflammation.

[0013] If an effective therapeutic substance is developed that can treat or prevent autoimmune diseases, it will greatly help patients by reducing pain and inflammation, regulating the immune system, and inhibiting cell apoptosis, without side effects.

[0014] Technical solution

[0015] This invention provides the use of compositions comprising a 5-benzylaminosalicylic acid compound represented by chemical formula (I) or a pharmaceutically acceptable salt thereof in the treatment and / or prevention of autoimmune diseases, such as 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 thrombocytopenic purpura, Sjogren's syndrome, autoimmune retinopathy, acute anterior uveitis, myasthenia gravis, autoimmune vasculitis, antiphospholipid syndrome, SAPHO syndrome, adult-onset Still's disease, and Behçet's disease.

[0016] The present invention also provides the use of compositions comprising a 5-benzylaminosalicylic acid compound represented by chemical formula (I) or a pharmaceutically acceptable salt thereof in the preparation of medicaments for treating and / or preventing the aforementioned autoimmune diseases.

[0017] Beneficial effects

[0018] Systemic lupus erythematosus (SLE) and multiple sclerosis (MS) are representative autoimmune diseases. Using an experimental autoimmune encephalomyelitis (EAE) model, one of the animal models of SLE and MS, the effects of compound 5-benzylaminosalicylic acid of formula (I) (specifically compound 2: 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid) were confirmed. Results showed a significant reduction in spleen and splenic follicle size, and in the SLE model, a significant decrease in the titer of anti-dsDNA, a key biomarker of SLE; increased expression of CD206 (an anti-inflammatory marker in M2 macrophages); and decreased expression of iNOS (inducible nitric oxide synthase), tumor necrosis factor (TNF)-α, and IFN-γ (an anti-inflammatory marker), and T... reg The cell population increased significantly, confirming that compound 2 exerts its immunomodulatory effect (maintaining T cells). reg It exhibits therapeutic effects due to its cellular homeostasis, anti-inflammatory, and antioxidant properties. Therefore, the 5-benzylaminosalicylic acid compound of chemical formula (I) (specifically compound 2: 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid) can be effectively used for autoimmune diseases.

[0019] Furthermore, psoriasis is one of the representative autoimmune diseases. Using an imiquimod (IMQ)-induced mouse model of psoriasis, a known disease model, the efficacy of the 5-benzylaminosalicylic acid compound of formula (I) (specifically compound 2: 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid) was confirmed. Results confirmed its therapeutic effects on psoriasis, such as inhibiting the increase in skin lesion severity, reducing the thickness of thickened epidermis, compressing collagen patterns, and lowering the spleen index. Therefore, the 5-benzylaminosalicylic acid compound of formula (I) (specifically compound 2: 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid) can be effectively used to treat autoimmune diseases, particularly psoriasis. Attached Figure Description

[0020] Figure 1a and Figure 1b The spleen size and spleen index of systemic lupus erythematosus (SLE) mice are shown.

[0021] Figures 2a to 2c Histological assessment of the spleen in SLE mice is shown.

[0022] Figure 3 The results of the measurement of anti-double-stranded DNA (anti-dsDNA) antibodies in the serum of SLE mice are shown.

[0023] Figure 4 Clinical scores associated with an experimental autoimmune encephalomyelitis (EAE) mouse model are shown.

[0024] Figure 5 The spleen size of an EAE mouse is shown.

[0025] Figure 6 The expression of CD206, iNOS, tumor necrosis factor (TNF)-α and IFN-γ in the spleen of EAE mice is shown.

[0026] Figure 7 This shows regulatory T cells (T cells) in the spleen of EAE mice. reg The proportion of ).

[0027] Figure 8a and Figures 8b to 8e The images show keratinized lesions and the Psoriasis Area and Severity Index (PASI) in psoriasis mice.

[0028] Figure 9a and Figure 9b Histological assessment (H&E staining) and epidermal thickness of psoriasis mice are shown.

[0029] Figure 10Histological evaluation (Mason trichrome staining) of psoriatic mice is shown.

[0030] Figure 11a and Figure 11b The spleen size and spleen index of psoriasis mice are shown.

[0031] Best practice

[0032] This invention provides pharmaceutical compositions and methods for preventing, reducing the risk of developing, or treating autoimmune diseases, such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), celiac disease, type 1 diabetes, Graves' disease, inflammatory bowel disease, alopecia areata, Addison's disease, localized 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 thrombocytopenic purpura, Sjögren's syndrome, autoimmune retinopathy, acute anterior uveitis, myasthenia gravis, autoimmune vasculitis, antiphospholipid syndrome, SAPHO syndrome, adult-onset Still's disease, and Behçet's disease. The pharmaceutical compositions comprise: a 5-benzylaminosalicylic acid compound represented by chemical formula (I) or a pharmaceutically acceptable salt thereof.

[0033] <Chemical Formula (I)>

[0034]

[0035] in,

[0036] X is selected from CO, SO2, and (CH2). n ;

[0037] R1 is selected from hydrogen, C1 to C6 alkyl, and C1 to C6 alkanoyl;

[0038] R2 is hydrogen or a C1 to C6 alkyl group;

[0039] R3 is hydrogen or a C1 to C5 alkanoyl group; and

[0040] R4 is selected from phenyl, phenoxy, and 5- to 10-membered aryl, wherein the phenyl, phenoxy, and 5- to 10-membered aryl are optionally substituted by one or more of a number independently selected from nitro, halogen, C11 to C6 alkyl, C1 to C6 haloalkyl, C1 to C5 alkoxy, and C1 to C5 haloalkoxy.

[0041] n is an integer from 1 to 5;

[0042] Or its pharmaceutically acceptable salt.

[0043] This disclosure provides methods for treating and / or preventing autoimmune diseases such as systemic lupus erythematosus (SLE), multiple sclerosis (MS), celiac disease, type 1 diabetes, Graves' disease, inflammatory bowel disease, alopecia areata, Addison's disease, localized 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 thrombocytopenic purpura, Sjögren's syndrome, autoimmune retinopathy, acute anterior uveitis, myasthenia gravis, autoimmune vasculitis, antiphospholipid syndrome, SAPHO syndrome, adult-onset Still's disease, and Behçet's disease, the methods comprising administering a compound of formula (I) to a patient in need.

[0044] In one embodiment, a variety of compounds of formula (I) were prepared and evaluated. In one embodiment, the composition and method comprise a 5-benzylaminosalicylic acid compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0045] In one embodiment, the 5-benzylaminosalicylic acid compound is 5-benzylaminosalicylic acid itself.

[0046] Preferred examples of 5-benzylaminosalicylic acid compounds include, but are not limited to: 2-hydroxy-5-phenylethylamino-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]-ethylamino]-benzoic acid (compound 5), 2-hydroxy-5-[2-(2-nitro-phenyl)-ethylamino]-benzoic acid (compound 5), 5-[2-(4-chloro-phenyl)-ethylamino]-ethylamino]-[2-(4-chloro-phenyl) ... 5-[2-(3,4-difluoro-phenyl)-ethylamino]-2-hydroxy-benzoic acid (compound 6), 5-[2-(3,4-dichloro-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,Compounds 26, 27, 28, 29, 20, 30, 31, 32, 33, and 33, are 6-pentafluorobenzyl)aminosalicylic acid (compound 26), 5-(4-nitrobenzyl)amino-2-hydroxybenzoic acid (compound 27), 5-(4-nitrobenzyl)-N-acetamino-2-hydroxybenzoic acid (compound 28), 5-(4-nitrobenzyl)-N-acetamino-2-acetoxybenzoic acid (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-nitrophenyl)-n-propyl]aminosalicylic acid (compound 33). In a specific preferred embodiment, the compound of formula (I) is compound 2, namely 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid or a pharmaceutically acceptable salt thereof.

[0047] The 5-benzylaminosalicylic acid compound disclosed herein, or a pharmaceutically acceptable salt thereof, can be prepared by, but is not limited to, the reaction scheme described in U.S. Patent No. 6,573,402.

[0048] In one implementation, altered inflammatory responses, aberrant immune responses, multi-organ cell damage, and behavioral dysfunctions, such as tail paralysis and unsteady gait, are symptoms of autoimmune diseases. In one implementation, the compound of formula (I) reduces and / or inhibits aberrant immune responses, multi-organ cell damage, and behavioral dysfunctions.

[0049] In one implementation, thickened erythema and keratotic lesions of the skin, epidermal hypertrophy (acanthosis) and increased thickness, abnormal keratinocyte differentiation, elongation of the epidermal reticulum ridges, immune cell infiltration into the epidermis and dermis, irregular, fragmented and disordered collagen fiber structure, and increased spleen size and weight are symptoms of autoimmune disease. In one implementation, the compound of formula (I) reduces and / or inhibits these abnormal immune responses, increased severity of skin lesions, increased epidermal thickness, disordered collagen patterns, and increased spleen index.

[0050] In one embodiment, treatment of autoimmune diseases is achieved by simultaneously pharmacologically inhibiting oxidative stress and inflammation. In another embodiment, treatment of autoimmune diseases is achieved by inhibiting oxidative stress and prostaglandin E2 synthesis. In yet another embodiment, treatment of autoimmune diseases is achieved by inhibiting oxidative stress and microsomal prostaglandin E synthase-1.

[0051] In one implementation, the animal exhibits pathophysiological changes. In one implementation, these pathophysiological changes are selected from: increased follicle diameter, glomerular proliferation, leukocyte exudation, nuclear fragmentation, and fibrinoid necrosis; decreased splenic follicles, cellular crescents, and clear deposits for activity index; interstitial inflammation, glomerular sclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis. In one implementation, these pathophysiological changes are selected from: increased macrophage size; increased macrophage number; and cell loss.

[0052] In one implementation, human patients are selected from those suffering from the following diseases: systemic lupus erythematosus (SLE), multiple sclerosis (MS), celiac disease, type 1 diabetes, Graves' disease, inflammatory bowel disease, alopecia areata, Addison's disease, localized 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 thrombocytopenic purpura, Sjögren's syndrome, autoimmune retinopathy, acute anterior uveitis, myasthenia gravis, autoimmune vasculitis, antiphospholipid syndrome, SAPHO syndrome, adult-onset Still's disease, and Behçet's disease.

[0053] In one implementation, the animals are selected from cattle, horses, sheep, cats, chinchillas, dogs, ferrets, gerbils, pigs, and hamsters.

[0054] definition

[0055] The definitions of the following terms apply to situations where the term is used alone or in combination with other terms.

[0056] The term "acetoxy" refers to a group represented by the general chemical formula hydrocarbon C(O)O-, preferably alkyl C(O)O-.

[0057] The term "alkyl" (including 'alkyl' in haloalkyl) or "alkane" refers to a fully saturated straight-chain or branched non-aromatic hydrocarbon. Generally, unless otherwise defined, a straight-chain alkyl or branched alkyl has 1 to about 20 carbon atoms, preferably 1 to about 10 carbon atoms. C1 to C6 straight-chain or branched alkyl is also referred to as "lower alkyl". In one embodiment, the alkyl is a C1 to C5 alkyl, more preferably a C1 to C3 alkyl. More specifically, preferred alkyls are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, and tert-butyl, but are not limited thereto.

[0058] Furthermore, the term "alkyl" (or "lower alkyl") as used throughout the specification, examples, and claims is intended to include both "unsubstituted alkyl" and "substituted alkyl," the latter referring to an alkyl residue having a substituent that replaces a hydrogen atom on one or more carbons of the hydrocarbon backbone. Unless otherwise stated, these substituents may comprise halogens, hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl such as alkyl C(O)), thiocarbonyl groups (e.g., thioesters, thioacetic acids, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphate groups, phosphonates, phosphinates, amino groups, amide groups, amido groups, imino groups, cyano groups, nitro groups, azide groups, silyl ethers, mercapto groups, alkylthio groups, sulfates, sulfonates, aminosulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, aralkyl groups, or aromatic or heteroaromatic residues. Those skilled in the art will understand that substituted residues on a hydrocarbon chain can be self-substituted where appropriate. For example, substituents in substituted alkyl groups can include substituted and unsubstituted forms, such as amino, azide, imino, amide, phosphoryl (including phosphonates and hypophosphonates), sulfonyl (including sulfates, sulfonamides, aminosulfonyls, and sulfonates), and silyl, as well as ethers, alkylthiols, carbonyl (including ketones, aldehydes, carboxylic esters, and esters), -CF3, -CN, etc. Exemplary examples of substituted alkyl groups are described below. Cycloalkyl groups can also be substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl groups, -CF3, -CN, etc.

[0059] Term "C" x-y "When used with chemical residues such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, it indicates that the group contains x to y carbon atoms in the chain. For example, the term 'C'..." x-y "Alkyl" refers to a substituted or unsubstituted saturated hydrocarbon group, including straight-chain alkyl and branched alkyl groups, containing x to y carbon atoms in the chain, including haloalkyls such as trifluoromethyl and 2,2,2-trifluoroethyl. When the group is at the terminal position, C0 alkyl indicates hydrogen; when it is internal, it indicates a bond. The term "C"... 2-y "Alkenyl" and "C" 2-y "Alkyne" refers to an unsaturated aliphatic group, whether substituted or unsubstituted, which is similar in length to the alkyl group mentioned above and is substituted, but contains one or more double or triple bonds.

[0060] The term "alkanoyl" refers to a hydrocarbon group -C(O)-, preferably an alkyl group -C(O)-.

[0061] The term "alkoxy" (including 'alkoxy' in haloalkoxy) refers to an oxygen-linked alkyl group, preferably a lower alkyl group. In one embodiment, preferably, the alkoxy group is a C1 to C5 alkoxy, more preferably a C1 to C3 alkoxy. More specifically, preferred alkoxy groups include, but are not limited to, methoxy, ethoxy, and propoxy groups. Halogens include, but are not limited to, fluorides, chlorides, bromides, and iodides. Preferably, the alkanoyl group is a C2 to C5 alkoxy group. 10 Alkyl group, more preferably C3 to C5 alkyl group. More specifically, the desired alkyl group includes, but is not limited to, acetyl, propionyl, and cyclohexanecarbonyl.

[0062] The terms "amine" and "amino" are generally accepted in the art to refer to unsubstituted and substituted amines and their salts, for example, to portions that can be represented as follows:

[0063]

[0064] Among them, each R 10 Independently representing a hydrogen or hydrocarbon group, or two Rs 10 They connect with the N atoms to form a heterocycle with 4 to 8 atoms within the ring structure.

[0065] As used in this specification, the term "aryl" includes a substituted or unsubstituted monocyclic aromatic group, wherein each atom of the ring is a carbon atom. 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 a polycyclic system having two or more rings, wherein two or more carbons are shared by two adjacent rings, and wherein at least one ring is aromatic, and for example, the other ring may be a cycloalkyl, cycloalkenyl, cycloynyl, aryl, heteroaryl, and / or heterocyclic group. Aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, etc. Exemplary substituents of the aryl group may include, for example: halogen, haloalkyl such as trifluoromethyl, hydroxyl, carbonyl (e.g. carboxyl, alkoxycarbonyl, formyl or acyl such as alkyl C(O)), thiocarbonyl (e.g. thioester, thioacetate or thiocarbamate), alkoxy, phosphoryl, phosphate, phosphonate, hypophosphonate, amino, amide, amido, imino, cyano, nitro, azide, silyl ether, mercapto, alkylthio, sulfate, sulfonate, aminosulfonyl, sulfonamide, sulfonyl, heterocyclic, aralkyl, or aromatic or heteroaromatic residues.

[0066] The terms “halogenated” and “halogen” used in this specification refer to halogens, including chlorine, fluorine, bromine and iodine.

[0067] When the term "lower" is used with chemical residues such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, it indicates that the group contains 10 or fewer, preferably 6 or fewer, non-hydrogen atoms in the substituent. For example, "lower alkyl" refers to an alkyl group containing 10 or fewer, preferably 6 or fewer carbon atoms. In some embodiments, the acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy substituents as defined herein are each lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl, or lower alkoxy, whether they occur alone or in combination with other substituents. For example, as in hydroxyalkyl and aralkyl groups (e.g., in this case, atoms within the aryl group are not counted when calculating the carbon atoms of the alkyl substituent).

[0068] The term "substituted" refers to a portion having a substituent that replaces a hydrogen atom on one or more carbons in the backbone. "Substitution" or "substituted" should be understood to include the implicit condition that such substitution must meet the permissible valence states of the substituted atom and the substituent, and that the substitution produces a stable compound that does not spontaneously undergo modifications such as rearrangement, cyclization, or elimination. As used herein, the term "substituted" is considered to include all permissible substituents in organic compounds. Broadly speaking, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic types of organic compounds. For suitable organic compounds, there may be one or more permissible substituents, and they may be the same or different. For the purposes of this invention, for example, a nitrogen heteroatom may have a hydrogen substituent and / or any permissible substituent in organic compounds satisfying the heteroatom valence states described herein. Substituents may include any substituents described herein, such as halogens, haloalkyl groups, hydroxyl groups, carbonyl groups (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl groups (e.g., thioesters, thioacetates, or thiocarbamates), alkoxy groups, phosphoryl groups, phosphate esters, phosphonates, hypophosphonates, amino groups, amide groups, amido groups, imino groups, cyano groups, nitro groups, azide groups, mercapto groups, alkylthio groups, sulfate esters, sulfonates, aminosulfonyl groups, sulfonamide groups, sulfonyl groups, heterocyclic groups, aralkyl groups, or aromatic or heteroaromatic residues. Those skilled in the art will understand that substituents themselves may be substituted where appropriate. Unless specifically stated as “unsubstituted,” references to chemical residues herein are to be understood to include substituted variants. For example, references to “aryl” groups or residues implicitly include both substituted and unsubstituted variants.

[0069] In this invention, a "pharmaceutically acceptable salt" refers to a salt produced from a non-toxic or nearly toxic acid or base. If the compound of this disclosure is acidic, a base addition salt of the compound can be prepared by reacting the free base of the compound with a sufficient amount of a preferred base in a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to, salts made from sodium, potassium, calcium, ammonium, magnesium, or organic amino acids. If the compound of this invention 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 preferred acid in a suitable inert solvent. Pharmaceutically acceptable acid addition salts include, but are not limited to, propionic acid, isobutyric acid, oxalic acid, malic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogenated carbonic acid, phosphoric acid, monohydrogenated phosphoric acid, dihydrogenated phosphoric acid, sulfuric acid, monohydrogenated sulfuric acid, hydrogen iodide, and phosphoric acid. Furthermore, pharmaceutically acceptable salts of the present invention include, but are not limited to, amino acid salts such as alginate, and organic acid analogs such as glucuronic acid or galacturonic acid.

[0070] For example, a pharmaceutically acceptable salt of 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)-ethylamino]-benzoic acid (compound 2), a preferred example of the present invention, can be prepared by the following reaction scheme. However, the following reaction method is provided by way of example and is not intended to limit the scope of this disclosure.

[0071] <Reaction Scheme 1>

[0072]

[0073] In the above reaction scheme, M is a pharmaceutically acceptable metal or basic organic compound, such as diethylamine, lithium, sodium, and potassium.

[0074] More specifically, diethylamine salts can be prepared by dissolving the compound in an alcohol, adding diethylamine dropwise, stirring, vacuum distilling, and then adding diethyl ether to crystallize. Alkali metal salts can be prepared by adding inorganic reagents such as lithium hydroxide, sodium hydroxide, or potassium hydroxide to a solvent such as ethanol, acetone, or acetonitrile to produce the desired salt, followed by freeze-drying. Furthermore, lithium salts can be prepared from lithium acetate, sodium salts from 2-ethylhexanoate or sodium acetate, and potassium salts from potassium acetate, according to similar methods.

[0075] Some compounds disclosed herein may be in hydrated form, or may exist in solvated or desolvated form. Some compounds according to this disclosure may exist in crystalline or amorphous form, and any physical form is included within the scope of this disclosure. Furthermore, some compounds of this disclosure may contain one or more asymmetric carbon atoms or double bonds, and may exist in two or more stereoisomers, such as racemates, enantiomers, diastereomers, geometric isomers, etc. This disclosure includes all stereoisomers of the compounds.

[0076] The present invention also provides a food composition for improving symptoms of autoimmune diseases, comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0077] The present disclosure is described in more detail below to aid those skilled in the art in understanding. However, the following embodiments are illustrative and not intended to limit the scope of the disclosure. It will be apparent that various modifications may be made without departing from the spirit and scope of the disclosure or without sacrificing all its substantial advantages.

[0078] Example 1. Evaluation of the symptom-improving effect of compound 2 in a mouse model of SLE

[0079] Compound 2, namely 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid, is used as a representative compound.

[0080] The purpose of this embodiment is to study the effect of compound 2 in an imiquimod (IMQ)-induced lupus model, which is widely used as one of the induced SLE models.

[0081] Experimental Design

[0082] Female BALB / c mice weighing 18g to 20g were provided by Saeron Bio Co., Ltd. (Korea) and acclimatized for 7 days. Animals were housed individually with free access to laboratory feed and water. During the experiment, animals were kept at 23±3℃, 50±10% relative humidity, and a 12-hour light-dark cycle. Animals were treated according to protocols approved by the GNT Pharmaceuticals Animal Ethics Committee. Mice were randomly assigned to four groups: normal control (n=6), control SLE group (loader 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 treatment groups received topical application of 5% imiquimod cream (Aldara cream, Dong-A Pharmaceutical Co., Ltd.) at a dose of 1.25mg to the right ear every two days for 4 weeks. The IMQ + compound 2 group received oral administration of compound 2 (5mg / kg, twice daily) for 4 weeks, followed by IMQ treatment. The IMQ+NAC group received intraperitoneal administration of N-acetylcysteine ​​(150 mg / kg, once daily, pH adjusted to 7.5 to 8.0) for 4 weeks, while also undergoing IMQ treatment.

[0083] Mice were anesthetized with pentobarbital at the end of the experiment. Blood was collected via cardiac aspiration. Within 30 minutes of collection, serum was separated from whole blood by centrifugation at 12000g for 10 minutes using EDTA. Spleens were extracted and weighed, then the tissue was heated to 60°C, washed with xylene, and immersed in ethanol of varying concentrations. Sections were stained with H&E (BBC Biochemical, Washington State, Mount Vernon) and then imaged under a microscope. Observation was performed through five fields of view at 10x magnification, and the number of splenic alba pulp (follicles) was counted. Additionally, the diameter of the splenic alba pulp was observed using a micrometer. The diameter of the alba pulp was measured vertically and horizontally, and the average value was calculated. Serum anti-dsDNA (IgG specific) concentration was analyzed using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (LBIS Mouse Anti-dsDNA ELISA, Fujifilm Wako Shibayagi Co., Ltd., Richmond, Virginia, USA).

[0084] Compared to the normal (Sham) group, the spleen size was increased in the control SLE group, while the spleen size in the compound 2 treated group was smaller than that in the control SLE group. However, the spleen size in the NAC treated group was similar to that in the control SLE group. Figure 1aRegarding the spleen index (organ weight / body weight × 100%), the spleen index in the control SLE group was significantly higher than that in the normal group, while the spleen index in the compound 2 treatment group was significantly lower than that in the control SLE group. However, there was no significant difference between the NAC treatment group and the control SLE group. Figure 1b ; * P < 0.05, ** P < 0.01, *** P < 0.001).

[0085] H&E-stained transverse sections of the spleen from the SLE group showed sparse and enlarged white pulp, indicating lymphoid hyperplasia caused by autoimmune disease. Figure 2a In the compound 2 treatment group, the number of spleen follicles increased significantly and the follicle diameter decreased significantly, indicating that compound 2 has a cytoprotective effect against abnormal autoimmune-related spleen damage. Figures 2b to 2c , **** P < 0.0001). However, no beneficial effect was observed in the N-acetylcysteine ​​treatment group.

[0086] Compared with the normal group, the concentration of anti-dsDNA was significantly increased in the control SLE group. In SLE mice, compound 2 significantly reduced the anti-dsDNA titer, while NAC had no effect. Figure 3 ; ** P < 0.01, *** P < 0.001 **** P < 0.0001).

[0087] Example 2. Evaluation of the symptom-improving effect of compound 2 in an EAE mouse model

[0088] Multiple sclerosis (MS) is a neurological autoimmune disease in which the body's immune system attacks myelin cells, the protective sheaths that surround the ganglia of the brain and spinal cord. EAE (extracorporeal membrane oxygenation) is, to date, a well-known preclinical model associated with multiple sclerosis. Therefore, the EAE mouse model was used to confirm the effects of compound 2 on autoimmune diseases.

[0089] Experimental Design

[0090] An EAE mouse model was induced in 6-week-old female C57BL / 6 mice. Mice were divided into three groups: 6 mice in the normal control group, 8 mice in the control EAE group (loador group), and 8 mice in the EAE + compound 2 group (compound 2 treatment group). Mice were 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 bilaterally into each mouse. Subsequently, 200 ng of pertussis toxin (Sigma, USA) was injected intraperitoneally on days 0 and 2. Starting on day 9, compound 2 was injected intraperitoneally every 24 hours at a dose of 3.3 mg / kg for 7 days. In the control EAE group, PBS was injected intraperitoneally. Daily monitoring for clinical signs related to EAE, graded on a scale of 0 to 5: 0, no obvious clinical symptoms; 0.5, partial tail paralysis; 1, tail paralysis or staggering gait; 1.5, partial tail paralysis and staggering gait; 2, tail paralysis and staggering gait; 2.5, partial quadriplegia; 3, unilateral limb paralysis; 3.5, unilateral paralysis and partial paralysis of the other limb; 4, bilateral paralysis; 4.5, coma; 5, death.

[0091] On day 25 after EAE induction, mice were euthanized by exposure to CO2, and spleens were harvested. Applied Biosystems was used. TM RNA expression in the spleen was analyzed using the QuantStudio 5 qPCR system (Thermofisher, USA) and the AMPGENE qPCR GreenMix Hyrox system (Thermofisher, USA), including 400 nm forward and reverse primers (Bionics Korea) and SYBR Green dye (Enzo Life Sciences, Farmingdale, NY, USA). Expression levels of each gene were measured using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as a standard and compared with those in the normal or control EAE groups. To evaluate the effect of compound 2 on T... reg The effect, using T reg The assay kit (CD4 / CD25 / FoxP3) (Miltenyi Biotech, Germany) was used to stain mouse spleen cells according to the manufacturer's instructions, and T cells were assessed using flow cytometry. reg Group. Using FlowJo TM 10.8.1 Software analysis of data.

[0092] Neurological signs associated with EAE began to appear on day 9, with symptom severity peaking on day 16. The onset dates were similar in the control EAE group and the compound 2 treatment group. Clinical signs in the compound 2 treatment group were effectively relieved. Figure 4 ; *** P < 0.001).

[0093] In the control EAE group, spleen size increased, while in the compound 2 treatment group, spleen size was similar to that of the normal group. Figure 5 ).

[0094] CD206 expression was decreased in the control EAE group, but significantly increased in the compound 2 treatment group compared to the control EAE group. iNOS expression was significantly decreased in the compound 2 treatment group compared to the control EAE group. The expression of inflammatory cytokines TNF-α and IFN-γ was lower in the compound 2 treatment group compared to the control EAE group. Figure 6 , * P < 0.05, *** P < 0.001).

[0095] Compared with the normal group, the control EAE group had CD4 + CD25 + FoxP3 + T reg The proportion of cells was significantly reduced. However, compared with the control EAE group, the T cells in the compound 2 treatment group were significantly lower. reg The number of cells was significantly higher. Figure 7 , * P < 0.05).

[0096] Conclusions of Examples 1 and 2

[0097] To evaluate the therapeutic potential of compound 2, this study used representative autoimmune disease models SLE and EAE. In the compound 2 treatment group, spleen and splenic follicle size were significantly reduced. In the SLE model, the anti-dsDNA titer, a key biomarker of SLE, was significantly decreased in the compound 2 treatment group. In the compound 2 treatment group, CD206 expression (a marker of the M2 anti-inflammatory phase) was increased, while the expression of iNOS, TNF-α, and IFN-γ (markers of the inflammatory phase) was decreased. The T... reg The cell population increased significantly. These results indicate that compound 2 exerts its immunomodulatory effect (maintaining T cells). reg The compound exhibits beneficial therapeutic effects, including cellular homeostasis, anti-inflammatory, and antioxidant properties. In summary, these findings strongly suggest that compound 2 may be applicable to the treatment of autoimmune diseases.

[0098] Example 3. Evaluation of the effect of compound 2 on improving skin lesions in a mouse model of psoriasis.

[0099] The purpose of this embodiment is to study the effect of compound 2 in an imiquimod (IMQ)-induced psoriasis model, which is widely used as one of the induced psoriasis models.

[0100] Model Description: Imiquimod (IMQ)-induced psoriasis model

[0101] In this experiment, imiquimod (IMQ) was used to induce psoriasis. The IMQ-induced mouse model of psoriasis 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 to secrete inflammatory cytokines. The IMQ-induced mouse model of psoriasis is known to be very similar to human psoriasis in terms of skin erythema, keratosis, epidermal changes (acanthosis), and inflammatory infiltration composed of T cells, neutrophils, and dendritic cells.

[0102] Experimental Design

[0103] Male BALB / c mice weighing 20-22g were provided by Saeron Bio Co., Ltd. (Korea) and acclimatized for 7 days. Animals were housed individually with free access to laboratory feed and water. During the experiment, animals were kept at 23±3℃, 50±10% relative humidity, and a 12-hour light-dark cycle. Animals were treated according to protocols approved by the GNT Pharmaceutical Company Animal Ethics Committee. Mice were randomly assigned to three groups: a normal control group (n=5), a control psoriasis group (loader group, n=8), and an IMQ + compound 2 group (compound 2 treatment group, n=9). All IMQ treatment groups received topical application of 5% imiquimod cream (Aldara cream, Dong-A Pharmaceutical Co., Ltd.) at a dose of 62.5 mg once daily to the shaved back for 6 days. The IMQ + compound 2 group received oral administration of compound 2 (5 mg / kg, twice daily) for 6 days, followed by simultaneous IMQ treatment.

[0104] Experimental results

[0105] To evaluate the anti-psoriasis effect of compound 2, the severity of psoriasis was monitored using an IMQ-induced psoriasis mouse model. The PASI skin score was used to assess the severity of skin lesions in mice. Compared with normal mice, mice treated with IMQ showed significantly thickened erythema and scales after 7 days. Figure 8aRegarding PASI scores, the normal group scored 0, while the control psoriasis group treated with IMQ alone showed an increase in score. Figures 8b to 8e , * P <0.05 compared with the control psoriasis group, # P < 0.05 compared to the compound 2 treatment group. However, the compound 2 treatment group showed significantly lower scores than the control psoriasis group. The results indicate that compound 2 treatment showed an inhibitory effect on the increase in skin lesion severity caused by IMQ by reducing scales and thickness.

[0106] Example 4. Histopathological changes in IMQ-induced psoriatic mice after treatment with compound 2

[0107] After confirming the therapeutic effect of compound 2 on psoriasis-like symptoms in mice, histological analysis was performed to determine the histological changes occurring in psoriatic skin and methods for improvement. IMQ-induced inflammation exhibited histological features of psoriasis, such as increased epidermal proliferation, abnormal keratinocyte differentiation, and elongation of the epidermal reticular ridges.

[0108] In the H&E-stained areas of the dorsal skin of the IMQ-induced control psoriasis group, increased epidermal hyperplasia, acanthosis, and elongation of the epidermal reticular ridges were observed. Figure 9a In the control psoriasis group, the epidermal thickness was also increased compared to the normal group. Figure 9b , **** (P < 0.0001). In contrast, the epidermal thickness was significantly reduced in the compound 2 treatment group. This increase in epidermal thickness was due to the proliferation of basal cells and keratinocytes. Compared with the IMQ treatment group alone (control psoriasis group), the histopathological manifestations of skin lesions in the compound 2 treatment group showed a significant inhibition of epidermal thickening (acanthosis) and elongation of reticular ridges caused by proliferation.

[0109] Immune cell infiltration into the epidermis and dermis is another pathological feature of psoriasis. Masson's trichrome (MT) staining showed that administration of IMQ significantly stimulated the proliferation of epidermal keratinocytes and induced the infiltration of inflammatory cells. Figure 10 These features were not observed in the normal group. Compound 2 treatment reduced IMQ-induced epidermal thickness and keratinization and effectively suppressed psoriatic inflammation. Furthermore, the normal group showed long and regular reticular fiber structures, while the control psoriasis group showed irregular, fragmented, and disordered collagen fiber structures. However, mice treated with compound 2 showed a more compressed collagen pattern in the dermis (HF: hair follicle, open arrow: epidermal thickness, black arrow: inflammatory cell infiltration).

[0110] 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.

[0111] Example 5. Evaluation of the effects of compound 2 on spleen changes and spleen index in IMQ-induced psoriatic mice.

[0112] The spleen is an immune organ containing various immune cells and plays a vital role in maintaining the immune system. To confirm the systemic effects of IMQ-induced splenomegaly and the influence of compound 2 on the systemic immune response, the spleen index was assessed.

[0113] Mice were anesthetized with pentobarbital at the end of the experiment. Blood was collected via cardiac sampling. Within 30 minutes of collection, serum was separated from whole blood by centrifugation at 12000g for 10 minutes using EDTA. The weight of the extracted spleen was measured.

[0114] Administration of IMQ increased spleen size and weight in IMQ-induced psoriatic mice. Figure 11a Conversely, treatment with compound 2 reduced spleen size and weight in IMQ-induced psoriatic mice. As a result, the spleen index was lower in the compound 2 group compared to the control psoriatic group, indicating that compound 2 has anti-inflammatory effects. Figure 11b , * P <0.05 compared with the control psoriasis group, # P<0.05 compared to the compound 2 treatment group).

[0115] The foregoing description of the invention is for illustrative purposes only, and those skilled in the art will understand that modifications to other specific forms can be readily made without altering the technical spirit or essential characteristics of the invention. Therefore, the above embodiments should be understood as illustrative in all respects and not restrictive. For example, each component described as a single unit can be implemented in a distributed manner; similarly, components described as distributed can also be implemented in a combined manner.

[0116] The scope of this invention is defined by the following claims, and all modifications or variations derived from the meaning and scope of the claims and their equivalents shall be construed as being included within the scope of this invention.

Claims

1. A pharmaceutical composition for the prevention or treatment of autoimmune diseases, comprising a compound represented by the following chemical formula (I) or a pharmaceutically acceptable salt thereof: <Chemical Formula (I)> in, X is selected from CO, SO2, and (CH2). n ; R1 is selected from hydrogen, C1 to C6 alkyl, and C1 to C6 alkanoyl; R2 is hydrogen or a C1 to C6 alkyl group; R3 is hydrogen or a C1 to C5 alkanoyl group; and R4 is selected from phenyl, phenoxy, and 5- to 10-membered aryl, wherein the phenyl, phenoxy, and 5- to 10-membered aryl are optionally substituted by one or more of a single group selected from nitro, halogen, C1 to C6 alkyl, C1 to C6 haloalkyl, C1 to C5 alkoxy, and C1 to C5 haloalkoxy. n is an integer from 1 to 5.

2. The pharmaceutical composition according to claim 1, wherein the compound of formula (I) is selected from 2-hydroxy-5-phenylethylaminobenzoic 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-hydroxybenzoic acid, 2-hydroxy-5-[2-(2-nitro-phenyl)-ethylamino]-benzoic acid, 5-[2-(4-chloro-phenyl)-ethylamino]-2-hydroxybenzoic acid, 5-[2-(3,4-difluoro- [Phenyl)-ethylamino]-2-hydroxybenzoic acid, 5-[2-(3,4-dichloro-phenyl)-ethylamino]-2-hydroxybenzoic acid, 5-[2-(4-fluoro-2-trifluoromethyl-phenyl)-ethylamino]-2-hydroxybenzoic acid, 5-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-hydroxybenzoic 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)-ethylamino]-benzoic acid [-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-)-propyl ... 5-(4-Fluorobenzyl)aminosalicylic acid, 5-(2,3,4,5,6-pentafluorobenzyl)aminosalicylic acid, ethyl 5-(4-nitrobenzyl)amino-2-hydroxybenzoate, ethyl 5-(4-nitrobenzyl)-N-acetamino-2-hydroxybenzoate, ethyl 5-(4-nitrobenzyl)-N-acetamino-2-acetoxybenzoate, ethyl 5-(4-nitrobenzoyl)aminosalicylic acid, 5-(4-nitrobenzenesulfonyl)aminosalicylic acid, 5-[2-(4-nitrophenyl)-ethyl]aminosalicylic acid, and 5-[3-(4-nitrophenyl)-n-propyl]aminosalicylic acid.

3. The pharmaceutical composition according to claim 2, wherein the compound of 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. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises capsules, tablets including orally disintegrating tablets, orally disintegrating films, and injections including intraperitoneal and intravenous administration.

5. The pharmaceutical composition according to claim 1, wherein the autoimmune disease is selected from systemic lupus erythematosus (SLE), multiple sclerosis (MS), celiac disease, type 1 diabetes, Graves' disease, inflammatory bowel disease, alopecia areata, Addison's disease, localized 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 thrombocytopenic purpura, Sjögren's syndrome, autoimmune retinopathy, acute anterior uveitis, myasthenia gravis, autoimmune vasculitis, antiphospholipid syndrome, SAPHO syndrome, adult-onset Still's disease, and Behçet's disease.

6. The pharmaceutical composition of claim 1, wherein the autoimmune disease is treated by simultaneously pharmacologically inhibiting oxidative stress and inflammation.

7. The pharmaceutical composition of claim 1, wherein the autoimmune disease is treated by inhibiting oxidative stress and prostaglandin E2 synthesis.

8. The pharmaceutical composition of claim 1, wherein the autoimmune disease is treated by inhibiting oxidative stress and microsomal prostaglandin E synthase-1.

9. The pharmaceutical composition of claim 1, wherein the autoimmune disease is controlled by T... reg Cellular therapy.

10. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used for human or associated animal.

11. The pharmaceutical composition according to claim 10, wherein the associated animal is selected from cattle, horses, sheep, cats, chinchillas, dogs, ferrets, gerbils, pigs, and hamsters.

12. A food composition for improving symptoms of an autoimmune disease, comprising a compound represented by the following chemical formula (I) or a pharmaceutically acceptable salt thereof: <Chemical Formula (I)> in, X is selected from CO, SO2, and (CH2). n ; R1 is selected from hydrogen, C1 to C6 alkyl, and C1 to C6 alkanoyl; R2 is hydrogen or a C1 to C6 alkyl group; R3 is hydrogen or a C1 to C5 alkanoyl group; and R4 is selected from phenyl, phenoxy, and 5- to 10-membered aryl, wherein the phenyl, phenoxy, and 5- to 10-membered aryl are optionally substituted by one or more of a single group selected from nitro, halogen, C1 to C6 alkyl, C1 to C6 haloalkyl, C1 to C5 alkoxy, and C1 to C5 haloalkoxy. n is an integer from 1 to 5.

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