WO2025116652A1 - Composition and method for treating autoimmune diseases - Google Patents

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

This application claims the benefit of 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, the entire contents of which are incorporated herein by reference.

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 autoimmune diseases.

An autoimmune disease is a condition in which the body's immune system malfunctions and attacks its own healthy endogenous tissues. In order to protect the body from foreign or dangerous substances, the immune system must be able to identify 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 identify and that can stimulate a series of immune responses. These molecules are called antigens. Antigens may be contained inside cells or on the surface of cells (such as bacteria or cancer cells), or they may be part of viruses. Some antigens exist on their own, such as pollen or food molecules.

When certain 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 immunological defenses against antigens is the production of antibodies by B cells. Antibodies bind tightly to specific antigens, tagging them for attack or neutralizing them directly. The body produces a wide range of antibodies. Each antibody has a distinct antigen-specificity. When the immune system is exposed to the same antigen again, it remembers it and can attack it much more effectively.

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

The exact cause of autoimmune diseases is unknown. Also, the cause may vary depending on the specific type of autoimmune disease that the patient has. Although the exact cause of autoimmune diseases is unknown, T cell immune regulation is a common 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. The importance of regulatory T cells (T _reg ), which are characterized by the expression of CD4 ⁺ , CD25 ⁺ , and Foxp3 ^{+ ,} has been elucidated. T _reg cells are known to support immunological tolerance, also known as immune homeostasis, by reducing exaggerated immune responses and preserving resistance to self-antigens. However, when an imbalance of T _reg cells causes a decrease in immune function, a large number of autoantibodies are produced, overwhelming the anti-inflammatory mechanisms and causing severe inflammation and tissue damage.

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 situations, autoimmune diseases can have potentially harmful consequences.

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

Autoimmune diseases have no known cure, but 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. Some NSAIDs and TNF blockers can be used to treat autoimmune diseases, but they are mainly helpful in reducing pain in 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, which are currently considered the gold standard for treating autoimmune diseases, are mostly associated with harmful side effects, and long-term use of these drugs can increase the risk of life-threatening infections and cancer.

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). In previous studies, 2-hydroxy-5-[2(4-trifluoromethyl-phenyl)ethylamino]benzoic acid was shown to be a potent spin-trapping molecule and microsomal prostaglandin E synthase-1 (mPGES-1) inhibitor at nanomolar concentrations, which exhibited blockade of neuronal apoptosis, lateral pathology, and autophagosome formation as well as increased motor function activity and lifespan in a mouse model of amyotrophic lateral sclerosis.

In various animal models of autoimmune diseases, 5-benzylaminosalicylic acid compounds or pharmaceutically acceptable salts thereof have been derived for the treatment of autoimmune diseases. Surprisingly, the 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) related to autoimmune diseases, it showed effects such as improving behavioral changes, protecting spleen and liver cell damage, restoring abnormal immune responses, and reducing inflammatory responses. In animal models of psoriasis, it showed effects such as suppressing the increase in the severity of skin lesions, reducing epidermal thickness, compacting collagen patterns, and reducing 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.

If a useful therapeutic substance that can treat or prevent autoimmune diseases is developed, it will be of great help in treating patients by reducing pain and inflammation, regulating the immune system, and inhibiting cell death without side effects.

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 The present invention provides 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.

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 said autoimmune disease.

Systemic lupus erythematosus (SLE) and multiple sclerosis (MS) are representative autoimmune diseases. Using the “experimental autoimmune encephalomyelitis (EAE) model,” which is an SLE animal model and an MS animal model, the effect of the 5-benzylamino salicylic acid compound of chemical 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, 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 decreased, and the T _reg cell population was significantly increased, confirming that compound 2 exhibits a therapeutic effect through not only anti-inflammatory and antioxidant effects but also immunomodulatory effects (maintaining the balance of T _reg cells). Therefore, the 5-benzylamino salicylic acid compound of chemical formula (I) (particularly, compound 2: 2-hydroxy-5-[2-(4-trifluoromethyl-phenyl)ethylamino]benzoic acid) can be usefully used for autoimmune diseases.

In addition, psoriasis is one of the representative autoimmune diseases, and the effect of the 5-benzylamino salicylic acid compound of chemical 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 hypertrophied epidermis, compaction of collagen patterns, and reduction in spleen index. Therefore, the 5-benzylamino salicylic acid compound of chemical 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, particularly psoriasis.

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

Figures 2a to 2c show histological evaluation of the spleen in SLE mice.

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

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

Figure 5 shows the size of the spleen in EAE mice.

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

Figure 7 shows the proportion of regulatory T cells (T _reg ) in the spleen of EAE mice.

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

Figures 9a and 9b show histological evaluation (H&E staining) and epidermal thickness in psoriasis mice.

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

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

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, and Sjogren's disease. The present invention provides pharmaceutical compositions and methods comprising a compound of 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:

<Chemical formula (I)>

Here,

X is selected from CO, SO ₂ and (CH ₂ ) _n ;

R ₁ is selected from hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkanoyl;

R ₂ is hydrogen or C ₁ -C ₆ alkyl;

R ₃ is hydrogen and C ₁ -C ₅ alkanoyl group; and

R ₄ 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, C _{1 -C 6} alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C 5 alkoxy and C 1 -C ₅ haloalkoxy;

n contains integers from 1 to 5;

Or a pharmaceutically acceptable salt thereof.

The present disclosure 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 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).

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.

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

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 l7), 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.

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

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

In one embodiment, symptoms of an autoimmune disease include thickened erythema and keratin lesions of the skin, hypertrophy (acanthosis) and increased thickness of the epidermis, abnormal differentiation of keratinocytes, elongated rate 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 thickness of the epidermis, disorganization of collagen pattern, and increased spleen index.

In one embodiment, the treatment of the autoimmune disease is achieved by simultaneous pharmacological inhibition of oxidative stress and inflammation. In one embodiment, the treatment of the autoimmune disease is achieved by inhibiting oxidative stress and prostaglandin E ₂ synthesis. In one embodiment, the treatment of the autoimmune disease is achieved by inhibiting oxidative stress and microsomal prostaglandin E synthase-1.

In one embodiment, the animal exhibits a pathophysiological change. In one embodiment, the pathophysiological change is selected from increased follicle diameter, glomerular proliferation, leukocyte exudation, karyorrhexis and fibrinoid necrosis, decreased spleen follicles, cellular crescent, hyaline deposition on active index; interstitial inflammation, glomerular sclerosis, fibrous crescent, tubular atrophy, interstitial fibrosis. In one embodiment, the pathophysiological change is selected from increased macrophage size; increased macrophage number; and cell loss.

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 were 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.

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.

definition

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

The term "acetoxy" means a group represented by the general chemical formula hydrocarbylC(O)O-, preferably alkylC(O)O-.

An "alkyl" group (including the 'alkyl' in haloalkyl) or "alkane" is a fully saturated straight-chain or branched non-aromatic hydrocarbon. Typically, straight-chain or branched alkyl groups have from 1 to about 20 carbon atoms, unless otherwise defined, and preferably from 1 to about 10 carbon atoms. A C ₁ -C ₆ straight-chain or branched alkyl group is also referred to as a "lower alkyl group". In one embodiment, the alkyl is a C ₁ -C ₅ alkyl, and more preferably a C ₁ -C ₃ alkyl. More specifically, preferred alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl.

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., acyl such as carboxyl, alkoxycarbonyl, 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 an aromatic or heteroaromatic moiety. It will be appreciated by those skilled in the art that a moiety substituted on a hydrocarbon chain (chain) may itself be substituted, where appropriate. For example, substituents of a substituted alkyl can include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamido, sulfamoyl, and sulfonates), and silyl groups, as well as ethers, alkylthiols, carbonyl (including ketones, aldehydes, carboxylates, and esters), -CF ₃ , -CN, and the like. Illustrative examples of substituted alkyls are described below. Cycloalkyl can be further substituted with alkyl, alkenyl, alkoxy, alkylthio, aminoalkyl, carbonyl-substituted alkyl, -CF ₃ , -CN, and the like.

The term "Cx-y" when used with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy means a group having 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 alkyl groups and branched-chain alkyl groups having 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 which are similar in length to the alkyl groups described above and which may be substituted, but which each contain one or more double or triple bonds.

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

The term "alkoxy" (including the 'alkoxy' in haloalkoxy) means an alkyl group having an oxygen attached thereto, preferably a lower alkyl group. In one embodiment, preferably the alkoxy is C ₁ -C ₅ alkoxy, more preferably C ₁ -C ₃ alkoxy. More specifically, preferred alkoxy includes, but is not limited to, methoxy, ethoxy and propanoxy. Halogen includes, but is not limited to, fluoride, chloride, bromide and iodide. Preferably, the alkanoyl is C ₂ -C ₁₀ alkanoyl, more preferably C ₃ -C ₅ alkanoyl. More specifically, preferred alkanoyl includes, but is not limited to, ethanoyl, propanoyl and cyclohexanecarbonyl.

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:

또는

or

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

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 rings can be 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, a halogen, a haloalkyl such as trifluoromethyl, a hydroxyl, a carbonyl (e.g., an acyl such as carboxyl, alkoxycarbonyl, formyl, or alkylC(O)), a thiocarbonyl (e.g., a thioester, thioacetate, or thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a silyl ether, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety.

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

The term "lower" when used in conjunction with a chemical moiety such as acyl, acyloxy, alkyl, alkenyl, alkynyl or alkoxy 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 a lower acyl, lower acyloxy, lower alkyl, lower alkenyl, lower alkynyl or lower alkoxy, respectively, as in the reference to hydroxyalkyl and aralkyl (in which case, for example, when counting carbon atoms of an alkyl substituent, the atoms in the aryl group are not counted).

The term "substituted" refers to a moiety having a substituent that replaces a hydrogen at one or more carbons of the skeleton. It will be understood that "substituted" or "substituted" includes the implicit condition that such substitution is in accordance with the permissible valences of the substituted atom and the substituent, and that the substitution results in a stable compound that is not spontaneously transformed, such as, for example, rearrangement, cyclization, elimination, etc. The term "substituted" as used herein 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 nonaromatic substituents of organic compounds. The permissible substituents may be one or more and may be the same or different for the appropriate organic compound. For purposes of the present invention, a heteroatom, such as nitrogen, may have any permissible substituent of the organic compounds described herein that satisfies the hydrogen substituent and/or the valence of the heteroatom. The substituent can include any of the substituents described herein, for example, halogen, haloalkyl, hydroxyl, carbonyl (e.g., carboxyl, alkoxycarbonyl, formyl, or acyl), thiocarbonyl (e.g., a 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 can 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.

As used herein, the term "pharmaceutically acceptable salt" means 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. 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, bromic, nitric, carbonic, monohydrocarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydrogeniodide and phosphorous. 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 or galactunoric.

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 method is provided by way of example and is not intended to limit the scope of the present disclosure.

<Reaction Formula 1>

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

More specifically, a diethylamine salt can be prepared by dissolving a compound in alcohol, adding diethylamine dropwise, stirring, distilling in a vacuum, adding ether, and crystallizing. An alkali metal salt can be prepared by adding an inorganic reagent such as lithium hydroxide, sodium hydroxide, or potassium hydroxide to a solvent such as alcohol, acetone, or acetonitrile, preparing a desired salt, and then freeze-drying. In addition, according to a similar method, a lithium salt can be prepared with lithium acetate, a sodium salt can be prepared with sodium 2-ethylhexanoate or sodium acetate, and a potassium salt can be prepared with potassium acetate.

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 according to the present disclosure may exist in crystalline or amorphous forms, and any physical form is included within the scope of the present disclosure. In addition, some of the compounds of the present disclosure may contain one or more asymmetric carbon atoms or double bonds and therefore exist in two or more stereoisomeric forms, such as racemates, enantiomers, diastereomers, geometric isomers, etc. The present disclosure includes these individual stereoisomers of the compounds.

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.

Hereinafter, the present disclosure will be described in more detail to help those skilled in the art understand 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 without sacrificing all of the material advantages of the present disclosure.

Example 1. Evaluation of the symptom improvement effect of compound 2 in a SLE mouse model

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

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.

Experimental design

Female BALB/C mice weighing 18–20 g were supplied by Saeron Bio (Korea) and were acclimated for 7 days. The animals were housed in separate cages with free access to laboratory food and water. During the experiment, the animals were maintained at 23±3°C and 50±10% relative humidity with a 12-h light/dark cycle. The animals were handled according to the protocol approved by the Institutional Animal Care and Use Committee of GNT Pharmaceuticals. The 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 groups were administered 1.25 mg of 5% imiquimod cream (Aldara cream, Dong-A Pharmaceutical) topically to the right ear every other day for 4 weeks. 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, adjusted to pH 7.5-8.0) was administered intraperitoneally to the IMQ+NAC group together with IMQ treatment for 4 weeks.

At the end of the experiment, mice were anesthetized with pentobarbital. Blood was collected by cardiac puncture. Within 30 minutes after blood collection, whole blood was centrifuged at 12,000 g for 10 minutes, and serum was separated from the whole blood with EDTA. The extracted spleen was weighed, and the tissue was heated to 60°C, washed with xylene, and immersed in ethanol at a gradient concentration. The sections were stained with H&E (BBC Biochemical, Mount Vernon, WA) and imaged under a microscope. Five fields of view were observed at ×10 magnification, and the number of spleen alba pulp (follicles) was counted. In addition, the diameter of the spleen alba pulp was observed using a micrometer. The diameter of the 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).

The control SLE group had a larger spleen size than the normal group, whereas the Compound 2-treated group had a smaller spleen size 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 x100%) was significantly higher in the control SLE group than in the normal group, but the spleen index of the Compound 2-treated group was significantly lower than that in 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).

H&E stained sections of the spleen from the control SLE group showed rarefied and enlarged white pulp, indicating lymphatic 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 had a cytoprotective effect against abnormal autoimmune-related spleen damage (Fig. 2b-2c, ^**** P <0.0001). However, the N-acetylcysteine-treated group did not show any beneficial effect.

The control SLE group showed a significant increase in anti-dsDNA concentration compared with the normal group. Compound 2 significantly reduced the anti-dsDNA titer in SLE mice, whereas NAC had no effect (Fig. 3; ^** P <0.01, ^*** P <0.001 ^**** P <0.0001).

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

Multiple sclerosis (MS) is a neurological autoimmune disease in which the body's immune system attacks the cells of the myelin sheath that surrounds the ganglia of the brain and spinal cord. EAE has been well known as a preclinical model related to multiple sclerosis. Therefore, the EAE mouse model was used to confirm the effect of compound 2 on autoimmune diseases.

Experimental design

EAE mouse model was induced in 6-week-old female C57BL/6 mice. The mice were divided into three groups, six mice in the normal group (Normal group), eight mice in the control EAE group (Vehicle group) and EAE + Compound 2 group (Compound 2 treatment group), respectively. The 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 emulsified solution was injected into both flanks of each mouse. After that, 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 from 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 waddle gait; grade 1.5, partial tail paralysis and waddle gait; grade 2, tail paralysis and waddle gait; grade 2.5, partial paralysis of all four limbs; 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.

On day 25 after EAE induction, mice were euthanized by _CO2 exposure and their 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) on 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 the control EAE group. To evaluate the effect of compound 2 on T _reg , mouse spleen cell preparations were stained with a T _reg detection kit (CD4/CD25/FoxP3) (Miltenyi Biotech, Germany) according to the manufacturer's instructions, and the T _reg population was evaluated using flow cytometry. Data were analyzed using FlowJo™10.8.1 software.

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 compound 2-treated group. Clinical signs were effectively alleviated in the compound 2-treated group (Fig. 4; ^*** P <0.001).

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).

The expression of CD206 was decreased in the control EAE group, but significantly increased in the compound 2-treated group compared to the control EAE group. The expression of iNOS was significantly lower in the compound 2-treated group 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).

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

Conclusions of Examples 1 and 2

To evaluate the therapeutic potential of compound 2, SLE and EAE, which are representative models of autoimmune diseases, were used in this experiment. The size of the spleen and spleen follicles were significantly alleviated in the compound 2 treatment group. In the SLE model, the anti-dsDNA titer, a key biomarker of SLE, was significantly reduced in the compound 2 treatment group. The expression of CD206 (M2 anti-inflammatory phase marker) was increased in the compound 2 treatment group, and the expression of iNOS, TNF-α, and IFN-γ (inflammatory phase markers) was decreased. The T _reg cell population was significantly increased in the compound 2 treatment group. These results indicate that compound 2 has beneficial therapeutic effects not only through anti-inflammatory and antioxidant effects but also through immunomodulatory effects (maintaining the balance of T _reg cells). Taken together, these findings strongly suggest that compound 2 can be applied to the treatment of autoimmune diseases.

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

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

Model description: Imiquimod (IMQ)-induced psoriasis model

Psoriasis was induced using imiquimod (IMQ) for the experiment. IMQ-induced psoriasis mouse model is one of the most widely used models to study psoriasis. IMQ is a Toll-like receptor-7/8 (TLR-7/8) agonist used in the treatment of actinic keratosis and basal cell carcinoma. Topical application of IMQ cream to the skin of mice is known to recruit immune cells and activate macrophages, monocytes, and dendritic cells to secrete inflammatory cytokines. IMQ-induced psoriasis mouse model is known to be very similar to human psoriasis in terms of skin erythema, keratinization, epidermal changes (acanthosis), and inflammatory infiltrates consisting of T cells, neutrophils, and dendritic cells.

Experimental design

Male BALB/C mice weighing 20–22 g were supplied by Saeron Bio (Korea) and were acclimated for 7 days. The animals were housed in separate cages with free access to laboratory food and water. During the experiment, the animals were maintained at 23±3°C, 50±10% relative humidity, and a 12-h light/dark cycle. The animals were handled according to the protocol approved by the GNT Pharmaceutical Institutional Animal Care and Use Committee. The 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 treatment groups were administered 62.5 mg of 5% imiquimod cream (Aldara cream, Dong-A Pharmaceutical) topically to the shaved back once a day for 6 days. Compound 2 (5 mg/kg, twice daily) was orally administered to the IMQ+Compound 2 group for 6 days, followed by concurrent IMQ treatment.

Experimental Results

To evaluate the antipsoriatic effect of compound 2, the severity of psoriasis was monitored using an IMQ-induced psoriasis mouse model. 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 than normal mice after 7 days (Fig. 8a). In the PASI score, the normal group had 0 points, whereas the control psoriasis group treated only with IMQ showed an increase in the score (Figs. 8b-8e, ^* P <0.05 and the control psoriasis group, ^# P <0.05 and the compound 2-treated group). However, the compound 2-treated group showed a significant decrease in the score compared to the control psoriasis group. Compound 2 treatment was shown to inhibit the increase in the severity of skin lesions induced by IMQ by reducing scales and thickness.

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

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 ways to improve them. IMQ-induced inflammation exhibits histological characteristics of psoriasis, including increased epidermal proliferation, abnormal keratinocyte differentiation, and elongated reticular ridges in the epidermis.

In the H&E-stained sections of the back skin of the control psoriasis group induced by IMQ, 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 with the normal group (Fig. 9b, ^**** P <0.0001). In contrast, the epidermal thickness was significantly reduced in the compound 2-treated group. This increased epidermal thickness was due to the proliferation of basal cells and keratinocytes. In contrast to the IMQ alone-treated group (the control psoriasis group), the histopathological manifestations of skin lesions of compound 2 significantly suppressed epidermal hyperplasia (acanthosis) and elongation of reticular ridges due to proliferation.

Infiltration of immune cells into the epidermis and dermis is another pathological feature of psoriasis. MT (Masson's trichrome) staining showed that IMQ application significantly stimulated the proliferation of epidermal keratinocytes and induced the infiltration of inflammatory cells (Fig. 10). These features were not observed in the normal group. Treatment with compound 2 reduced IMQ-induced epidermal thickness and keratosis and potently inhibited psoriasis-like inflammation. In addition, the normal group showed long and regular reticular fiber structures, whereas the control psoriasis group showed irregular, fragmentary, and disorganized collagen fiber structures. However, mice treated with compound 2 showed a much more compact collagen pattern in the dermis (HF: Hair follicle, Open arrow: epidermal thickness, black arrow: inflammatory cell infiltration)

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.

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

The spleen is an immune organ that contains various types of immune cells and plays an important role in maintaining the immune system. To determine the systemic effect of IMQ that induces splenomegaly and the effect of compound 2 on the systemic immune response, the spleen index was evaluated.

At the end of the experiment, mice were anesthetized with pentobarbital. Blood was collected by cardiac puncture. Within 30 minutes after blood collection, serum was separated from whole blood by centrifugation at 12,000 g for 10 minutes with EDTA. The weight of the extracted spleen was measured.

IMQ application increased the spleen size and weight of IMQ-induced psoriasis mice (Fig. 11a). In contrast, compound 2 treatment decreased the spleen size and weight of IMQ-induced psoriasis mice. As a result, the spleen index was decreased 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 the control psoriasis group, ^# P <0.05 and the compound 2 treatment group).

The above description of the present invention is for illustrative purposes, and those skilled in the art will understand that the present invention can be easily modified into other specific forms without changing the technical idea or essential characteristics of the present invention. Therefore, it should be understood that the embodiments described above are exemplary in all respects and not restrictive. For example, each component described as a single component may be implemented in a distributed manner, and likewise, components described as distributed may be implemented in a combined form.

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 (12)

A pharmaceutical composition for treating or preventing an autoimmune disease, comprising a compound of the following formula (I) or a pharmaceutically acceptable salt thereof: <Chemical formula (I)>

Here, X is selected from CO, SO ₂ and (CH ₂ ) _n ; R ₁ is selected from hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkanoyl; R ₂ is hydrogen or C ₁ -C ₆ alkyl; R ₃ is hydrogen or a C ₁ -C ₅ alkanoyl group; and R ₄ 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, C _{1 -C 6} alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C 5 alkoxy and C 1 -C ₅ haloalkoxy; n contains integers from 1 to 5. 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, A pharmaceutical composition selected from the group consisting of 5-(4-nitrobenzyl)amino-2-hydroxyethylbenzoate, 5-(4-nitrobenzyl)-N-acetylamino-2-hydroxyethylbenzoate, 5-(4-nitrobenzyl)-N-acetylamino-2-acetoxyethylbenzoate, 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. A pharmaceutical composition in 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. 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. In claim 1, 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, Sjogren's disease. 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. A pharmaceutical composition according to claim 1, wherein the autoimmune disease is treated through simultaneous pharmacological inhibition of oxidative stress and inflammation. A pharmaceutical composition according to claim 1, wherein the autoimmune disease is treated by inhibiting oxidative stress and prostaglandin E ₂ synthesis. A pharmaceutical composition according to claim 1, wherein the autoimmune disease is treated through inhibition of oxidative stress and microsomal prostaglandin E synthase-1. A pharmaceutical composition according to claim 1, wherein the autoimmune disease is treated by controlling T _reg cells. A pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is for humans or companion animals. 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. 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 selected from CO, SO ₂ and (CH ₂ ) _n ; R ₁ is selected from hydrogen, C ₁ -C ₆ alkyl and C ₁ -C ₆ alkanoyl; R ₂ is hydrogen or C ₁ -C ₆ alkyl; R ₃ is hydrogen or a C ₁ -C ₅ alkanoyl group; and R ₄ 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, C _{1 -C 6} alkyl, C ₁ -C ₆ haloalkyl, C ₁ -C 5 alkoxy and C 1 -C ₅ haloalkoxy; n contains integers from 1 to 5.

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