Pharmaceutical composition for preventing or treating metabolic diseases or autoimmune diseases comprising novel terthiophene compound or pharmaceutically acceptable salt thereof

Abstract

One aspect provides a pharmaceutical composition for preventing or treating metabolic diseases or autoimmune diseases, the composition comprising a novel terthiophene derivative compound or a pharmaceutically acceptable salt thereof. The pharmaceutical composition effectively inhibits monoamine oxidase B (MAO-B), and thus can be used in various fields for the prevention or treatment of metabolic diseases, such as obesity and fatty liver, or autoimmune diseases, such as rheumatoid disease.

Description

A pharmaceutical composition for the prevention or treatment of metabolic or autoimmune diseases comprising a novel terthiophene compound or a pharmaceutically acceptable salt thereof

[0001] The present invention relates to a pharmaceutical composition for the prevention or treatment of metabolic or autoimmune diseases comprising a novel terthiophene compound or a pharmaceutically acceptable salt thereof.

[0002]

[0003] Eclipta prostrata is an annual herbaceous plant of the Asteraceae family that grows to a height of 10 to 70 cm and is commonly found in soybean fields in Jeju Island, the southern regions, and the central regions of Korea. It has long been known to be effective in promoting blood circulation, relieving pain, boosting immunity, treating dermatitis, promoting hair growth, and alleviating skin cracking; it is particularly known for its effectiveness in soothing skin irritation.

[0004] The human immune system plays the role of protecting the body from invading external antigens, but it possesses self-tolerance and does not attack its own tissues. However, when the immune system's self-tolerance is compromised, immune cells recognize proteins normally expressed by one's own genes as targets for attack, producing antibodies or triggering T-cell responses that destroy normal tissues; this condition is called autoimmunity, and when specific symptoms appear, it is referred to as an autoimmune disease.

[0005] Previous studies have disclosed that inhibiting MAO-B can be a major target for the treatment of rheumatoid arthritis, a representative immune inflammatory disease, and other prior studies have disclosed that inhibiting MAO-B can also be a major target for the treatment of obesity and fatty liver.

[0006] Accordingly, the inventors of the present invention isolated and purified six derivatives of terthiophene-based (2,2′:5′,2′′-Terthiophene, α-terthienyl) compounds derived from *Hyuncho*, and based on the derivative exhibiting the strongest MAO-B inhibitory activity among these derivatives, further synthesized four derivatives and confirmed their preventive or therapeutic effects against metabolic diseases such as obesity and fatty liver, and autoimmune diseases such as rheumatism.

[0007]

[0008] One aspect is to provide a compound represented by the following chemical formula 1 or a salt thereof:

[0009] [Chemical Formula 1]

[0010]

[0011] Another aspect is to provide a pharmaceutical composition for the prevention or treatment of metabolic or autoimmune diseases comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0012] Another aspect is to provide a health functional food for the prevention or improvement of metabolic or autoimmune diseases comprising a compound of Chemical Formula 1 or a food-grade acceptable salt thereof.

[0013] Another aspect is to provide a method for preventing or treating metabolic or autoimmune diseases, comprising the step of administering a compound of Formula 1 or a pharmaceutically acceptable salt thereof to an individual in need thereof.

[0014] Another aspect is to provide the use of the compound of Formula 1 or a pharmaceutically acceptable salt thereof for the manufacture of a drug for the prevention or treatment of metabolic or autoimmune diseases.

[0015]

[0016] The compounds described herein may contain one or more asymmetric centers and thus may exist in various isomer forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of a mixture of stereoisomers comprising a racemic mixture and a mixture rich in one or more stereoisomers. Isomers may be isolated from the mixture by methods known to those skilled in the art, including chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers may be prepared by asymmetric synthesis. The invention further comprises the compounds described herein as individual isomers that do not substantially contain other isomers, and alternatively as a mixture of various isomers. Furthermore, the invention is not intended to be limited in any way by the exemplary list of substituents described herein.

[0017] One aspect provides a compound represented by the following chemical formula 1 or a salt thereof:

[0018] [Chemical Formula 1]

[0019]

[0020] In the above chemical formula 1,

[0021] The above n is 0 or 1 and;

[0022] The above R 1 and R 3 Each independently consists of hydrogen, deuterium, halogen, hydroxyl, substituted or unsubstituted C1 to C10 alkyl and Selected from a group consisting of;

[0023] The above R 2 is hydrogen, deuterium, halogen and Selected from a group consisting of;

[0024] The above X is carbon;

[0025] The above X and Y are connected by a double or triple bond;

[0026] When the above X and Y are connected by a double bond, the above Y is carbon, nitrogen, or oxygen;

[0027] When the above X and Y are connected by a triple bond, the above Y is carbon or nitrogen;

[0028] When the above X and Y are connected by a double bond and the above Y is carbon, the above R 4 , R 5 and R 6 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups;

[0029] When the above X and Y are connected by a double bond and the above Y is nitrogen, the above R 4 and R 5 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups, and R 6 is not present;

[0030] When X and Y are connected by a double bond and Y is oxygen, R 4 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted alkyl groups having 1 to 10 carbon atoms, and R 5 and R 6 is not present;

[0031] When the above X and Y are connected by a triple bond and the above Y is carbon, the above R 4 and R 6 ...is not present, and the R5 is hydrogen, deuterium, hydroxyl, or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms;

[0032] When the above X and Y are connected by a triple bond and the above Y is nitrogen, the above R 4 , R 5 and R 6 is not present;

[0033] The above R 7 It is hydrogen, deuterium, a substituted or unsubstituted heterocycloalkyl having 2 to 10 carbon atoms, or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms.

[0034] Additionally, in this specification, the compound of Formula 1 or the pharmaceutically acceptable salt thereof includes their optical isomers, their hydrates, their solvates, or mixtures thereof.

[0035] In one embodiment, X and Y are connected by a double or triple bond;

[0036] When the above X and Y are connected by a double bond, the above Y is nitrogen or oxygen;

[0037] When the above X and Y are connected by a triple bond, the above Y is carbon;

[0038] When the above X and Y are connected by a double bond and the above Y is nitrogen, the above R 4 and R 5 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C5 alkyl groups, and R 6 is not present;

[0039] Where X and Y are connected by a double bond and Y is oxygen, R4 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C5 alkyls, and R 5 and R 6 is not present;

[0040] In the case where the above X and Y are connected by a triple bond, R 4 and R 6does not exist, and R 5 is a substituted or unsubstituted alkyl having 1 to 5 carbon atoms;

[0041] The above R 7 It may be a compound or a salt thereof, which is a substituted or unsubstituted heterocycloalkyl having 2 to 5 carbon atoms or a substituted or unsubstituted alkyl having 1 to 5 carbon atoms.

[0042] In one embodiment, n is 0 or 1, and R 1 and R 3 Each is independently hydrogen, deuterium, a substituted or unsubstituted C1 to C5 alkyl, -CH2OH, -I , , , and Selected from a group consisting of;

[0043] The above R 2 is hydrogen, deuterium and Selected from a group consisting of;

[0044] The above R 7 silver Or it could be -CH3.

[0045] In one embodiment, n is 0 or 1, and R 1 and R 3 Each independently consists of hydrogen, deuterium, and It is one selected from a group consisting of;

[0046] The above X and Y are connected by a double or triple bond;

[0047] When the above X and Y are connected by a double bond, Y is nitrogen;

[0048] When the above X and Y are connected by a triple bond, Y is carbon;

[0049] When the above X and Y are connected by a double bond, the above R 4 and R 5Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C5 alkyl groups, and R 6 is not present;

[0050] In the case where the above X and Y are connected by a triple bond, R 4 and R 6 does not exist, and R 5 is a substituted or unsubstituted alkyl having 1 to 5 carbon atoms;

[0051] The above R 7 It may be a substituted or unsubstituted heterocycloalkyl having 2 to 5 carbon atoms or a substituted or unsubstituted alkyl having 1 to 5 carbon atoms.

[0052] In one embodiment, n is 0 or 1, and R 1 and R 3 Each is independently hydrogen, deuterium, substituted or unsubstituted C1 to C5 alkyl, -I, , , and Selected from a group consisting of;

[0053] The above R 2 is hydrogen, deuterium and Selected from a group consisting of;

[0054] The above R 7 silver Or it could be -CH3.

[0055] The term "substituted" above may mean that at least one hydrogen connected to a carbon is substituted with a halogen element (e.g., F, Cl, Br, etc.), a hydroxyl group, a carboxyl group, etc., and specifically, the substituted alkyl group having 1 to 5 carbon atoms may be one or more selected from the group consisting of -CF3, -CCl3, and -CBr3.

[0056]

[0057] Another aspect provides a compound represented by the following chemical formula 19 or a salt thereof:

[0058] [Chemical Formula 19]

[0059] .

[0060] In the above chemical formula 19,

[0061] The above n is 0 or 1 and;

[0062] The above R 1 Silver consists of hydrogen, deuterium, substituted or unsubstituted C1 to C10 alkyl groups and Selected from a group consisting of;

[0063] The above R 2 Is And;

[0064] The above X is carbon;

[0065] The above X and Y are connected by a double or triple bond;

[0066] When the above X and Y are connected by a double bond, the above Y is nitrogen;

[0067] When the above X and Y are connected by a triple bond, the above Y is carbon;

[0068] When the above X and Y are connected by a double bond and the above Y is nitrogen, the above R 3 and R 4 Each is independently selected from the group consisting of hydrogen, deuterium, and hydroxy, and R 5 is not present;

[0069] When the above X and Y are connected by a triple bond and the above Y is carbon, the above R 3 and R 5 does not exist, and the above R 4 is a substituted or unsubstituted alkyl having 1 to 10 carbon atoms;

[0070] The above R 6It is a substituted or unsubstituted heterocycloalkyl having 2 to 10 carbon atoms or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms.

[0071]

[0072] Another aspect provides a compound represented by the following chemical formula 20 or a salt thereof:

[0073] [Chemical Formula 20]

[0074] .

[0075] In the above chemical formula 20,

[0076] The above R 1 silver And;

[0077] The above R 2 is a substituted or unsubstituted heterocycloalkyl having 2 to 10 carbon atoms or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms.

[0078]

[0079] Another aspect provides a compound represented by the following chemical formula 21 or a salt thereof:

[0080] [Chemical Formula 21]

[0081] .

[0082] In the above chemical formula 21,

[0083] The above n is 0 or 1 and;

[0084] The above R 1 Silver consists of hydrogen, deuterium, halogen, hydroxyl, substituted or unsubstituted alkyl groups having 1 to 10 carbon atoms, and Selected from a group consisting of;

[0085] The above X is carbon;

[0086] The above X and Y are connected by a double or triple bond;

[0087] When the above X and Y are connected by a double bond, the above Y is nitrogen or oxygen;

[0088] When the above X and Y are connected by a triple bond, the above Y is carbon or nitrogen;

[0089] When the above X and Y are connected by a double bond and the above Y is carbon, the above R 2 , R 3 and R 4 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups;

[0090] When the above X and Y are connected by a double bond and the above Y is nitrogen, the above R 2 and R 3 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups, and R 4 is not present;

[0091] When X and Y are connected by a double bond and Y is oxygen, R 2 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted alkyl groups having 1 to 10 carbon atoms, and R 3 and R 4 is not present;

[0092] When the above X and Y are connected by a triple bond and the above Y is carbon, the above R 2 and R 4 does not exist, and the above R 3 It is hydrogen, deuterium, hydroxyl, or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms;

[0093] When the above X and Y are connected by a triple bond and the above Y is nitrogen, the above R 2 , R 3 and R 4 does not exist.

[0094] The term "unsubstituted" above may mean that the hydrogen connected to the carbon is not replaced by another element.

[0095] The term "alkyl" refers to a radical of a straight-chain or branched saturated hydrocarbon group having 1 to 10 carbon atoms ("C 1-10 It refers to an alkyl group. In some embodiments, the alkyl group has 1 to 9 carbon atoms ("C 1-9 alkyl"). In some embodiments, the alkyl group has 1 to 8 carbon atoms ("C 1-8 alkyl"). In some embodiments, the alkyl group has 1 to 7 carbon atoms ("C 1-7 alkyl"). In some embodiments, the alkyl group has 1 to 6 carbon atoms ("C 1-6 alkyl"). In some embodiments, the alkyl group has 1 to 5 carbon atoms ("C 1-5 alkyl"). In some embodiments, the alkyl group has 1 to 4 carbon atoms ("C 1-4 alkyl"). In some embodiments, the alkyl group has 1 to 3 carbon atoms ("C 1-3 alkyl"). In some embodiments, the alkyl group has 1 to 2 carbon atoms ("C 1-2 alkyl"). In some embodiments, the alkyl group has one carbon atom ("C1alkyl"). In some embodiments, the alkyl group has two to six carbon atoms ("C 2-6 Alkyl"). C 1-6 Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert-butyl, sec-butyl, isobutyl), pentyl (C5) (e.g., n-pentyl, 3-fentanyl, amyl, neopentyl, 3-methyl-2-butanyl, tertiary amyl), and hexyl (C6) (e.g., n-hexyl). Additional examples of alkyl groups include n-heptyl (C7), n-octyl (C8), etc. Unless otherwise specified, each example of an alkyl group is independently unsubstituted (“unsubstituted alkyl”) or substituted with one or more substituents (e.g., a halogen such as F) (“substituted alkyl”).

[0096] The term "salt" above refers to a salt prepared using a specific compound according to one aspect and a relatively non-toxic acid or base. Additionally, the "salt" may be a "pharmaceutically acceptable salt."

[0097] In one embodiment, the compound may be selected from the group represented by the following chemical formulas 2 to 18:

[0098]

[0099] [Chemical Formula 2]

[0100] ,

[0101]

[0102] [Chemical Formula 3]

[0103] ,

[0104]

[0105] [Chemical Formula 4]

[0106] ,

[0107]

[0108] [Chemical Formula 5]

[0109] ,

[0110]

[0111] [Chemical Formula 6]

[0112] ,

[0113]

[0114] [Chemical Formula 7]

[0115] ,

[0116]

[0117] [Chemical Formula 8]

[0118] ,

[0119]

[0120] [Chemical Formula 9]

[0121] ,

[0122]

[0123] [Chemical Formula 10]

[0124] .

[0125]

[0126] [Chemical Formula 11]

[0127] ,

[0128]

[0129] [Chemical Formula 12]

[0130] ,

[0131]

[0132] [Chemical Formula 13]

[0133] ,

[0134]

[0135] [Chemical Formula 14]

[0136] ,

[0137]

[0138] [Chemical Formula 15]

[0139] ,

[0140]

[0141] [Chemical Formula 16]

[0142] ,

[0143]

[0144] [Chemical Formula 17]

[0145] ,

[0146]

[0147] [Chemical Formula 18]

[0148] .

[0149]

[0150] Another aspect provides a pharmaceutical composition for the prevention or treatment of metabolic or autoimmune diseases comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof:

[0151] [Chemical Formula 1]

[0152] .

[0153] In the above chemical formula 1,

[0154] The above n is 0 or 1 and;

[0155] The above R 1 and R 3 Each independently consists of hydrogen, deuterium, halogen, hydroxyl, substituted or unsubstituted C1 to C10 alkyl and Selected from a group consisting of;

[0156] The above R 2 is hydrogen, deuterium, halogen and Selected from a group consisting of;

[0157] The above X is carbon;

[0158] The above X and Y are connected by a double or triple bond;

[0159] When the above X and Y are connected by a double bond, the above Y is carbon, nitrogen, or oxygen;

[0160] When the above X and Y are connected by a triple bond, the above Y is carbon or nitrogen;

[0161] When the above X and Y are connected by a double bond and the above Y is carbon, the above R 4 , R 5 and R 6 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups;

[0162] When the above X and Y are connected by a double bond and the above Y is nitrogen, the above R 4 and R 5Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups, and R 6 is not present;

[0163] When X and Y are connected by a double bond and Y is oxygen, R 4 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted alkyl groups having 1 to 10 carbon atoms, and R 5 and R 6 is not present;

[0164] When the above X and Y are connected by a triple bond and the above Y is carbon, the above R 4 and R 6 ...is not present, and the R5 is hydrogen, deuterium, hydroxyl, or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms;

[0165] When the above X and Y are connected by a triple bond and the above Y is nitrogen, the above R 4 , R 5 and R 6 is not present;

[0166] The above R 7 It is hydrogen, deuterium, a substituted or unsubstituted heterocycloalkyl having 2 to 10 carbon atoms, or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms.

[0167] The above "compound of Chemical Formula 1" may be within the aforementioned range.

[0168] The term "pharmaceuticalally acceptable" above means exhibiting a characteristic that is not toxic to cells or humans exposed to a specific compound according to one aspect.

[0169] When the above compound contains relatively acidic functional groups, a base addition salt can be obtained by contacting a sufficient amount of base with the neutral form of the compound in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include salts of sodium, potassium, calcium, ammonium, organic amines, or magnesium, or similar salts. When the above compound contains relatively basic functional groups, an acid addition salt can be obtained by contacting a sufficient amount of acid with the neutral form of the compound in a pure solution or a suitable inert solvent. Pharmaceutically acceptable acid addition salts include salts of inorganic acids such as hydrochloric acid, hydrobromide, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, or phosphoric acid, and salts of organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, souveric acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, and methanesulfonic acid, and further include salts of amino acids (e.g., arginine) and salts of organic acids such as glucuronic acid.

[0170] The above pharmaceutically acceptable salts can be synthesized by conventional chemical methods from parent compounds containing an acidic or basic portion. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometrically appropriate amount of base or acid in water, an organic solvent, or a mixture of both. Generally, the medium may be a non-aqueous medium such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile.

[0171] In one embodiment, the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be derived from nature or synthesized using known organic synthesis methods. Additionally, the compound of Formula 1 or a pharmaceutically acceptable salt thereof may be a non-protein compound, a peptide, an extract of a plant-derived tissue or cell, or a product obtained from the culture of microorganisms (e.g., bacteria or fungi, and particularly yeast).

[0172] In one embodiment, the compound of Formula 1 or a pharmaceutically acceptable salt thereof may inhibit monoamine oxidase B (MAO-B) and may not inhibit monoamine oxidase A (MAO-A) or hydrogen peroxide.

[0173] The above term "prevention" may refer to any act of suppressing or delaying metabolic diseases or autoimmune diseases in an individual by administering a pharmaceutical composition according to one aspect.

[0174] The term "treatment" above may refer to any act in which symptoms of a metabolic disease or autoimmune disease in an individual are improved or beneficially altered by the administration of a pharmaceutical composition according to one aspect.

[0175] Additionally, the above pharmaceutical composition may be provided as a pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, excipients, or diluents.

[0176] Specifically, the carrier may be, for example, a colloidal suspension, powder, saline solution, lipid, liposome, microsphere, or nano-spherical particle. These may form a complex with or be associated with a transport means and may be transported in vivo using a transport system known in the art, such as lipids, liposomes, microparticles, gold, nanoparticles, polymers, condensation agents, polysaccharides, polyamino acids, dendrimers, saponins, adsorption-enhancing substances, or fatty acids.

[0177] When the above pharmaceutical composition is formulated, it may be prepared using diluents or excipients such as commonly used lubricants, sweeteners, flavorings, emulsifiers, suspending agents, preservatives, fillers, volume expanders, binders, wetting agents, disintegrants, and surfactants. Solid dosage forms for oral administration may include tablets, pills, powders, granules, capsules, etc., and these solid dosage forms may be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., with the above composition. In addition, lubricants such as magnesium stearate and talc may also be used in addition to simple excipients. Liquid formulations for oral administration include suspensions, oral liquids, emulsions, syrups, etc., and may contain various excipients, such as humectants, sweeteners, flavorings, and preservatives, in addition to commonly used simple diluents like water and liquid paraffin. Formulations for parenteral administration may include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations, and suppositories. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspensions. Witepsol, macrogol, Tween 61, cacao oil, laurin oil, glycerogelatin, etc. may be used as bases for suppositories, and known diluents or excipients may be used when manufactured in the form of ophthalmic preparations.

[0178] In one embodiment, the metabolic disease is a general term for diseases caused by an imbalance of carbohydrates, lipids, proteins, vitamins, minerals, and water, and among these, lipid-related metabolic disease refers to a disease caused by excessive lipid accumulation in the body, and specifically, it may be one or more selected from the group consisting of obesity, fatty liver disease, diabetes, hyperlipidemia, hypertension, hypercholesterolemia, and glucose intolerance.

[0179] The aforementioned "fatty liver disease" refers to a condition in which triglycerides are excessively accumulated in liver cells, amounting to more than 5% of the liver's weight. If the cause is non-alcoholic fatty liver disease, it is a disease that includes fat accumulation, steatohepatitis, liver fibrosis, and cirrhosis, which progress despite the absence of alcohol intake recognized as harmful to the liver. In particular, if the disease continues to progress, there is a high probability of it developing into liver cancer, so it requires active treatment. Furthermore, excessive fat accumulation can promote inflammatory responses within blood vessels through an increase in triglycerides and the overproduction of low-density lipoproteins; these inflammatory responses contribute to blood clot formation, which can lead to elevated blood pressure and atherosclerosis.

[0180] The above "fatty liver disease" may be one or more selected from the group consisting of alcoholic fatty liver disease (AFLD), non-alcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH).

[0181] The above "non-alcoholic fatty liver" may be one or more selected from the group consisting of simple fatty liver, nutritional fatty liver, starvation fatty liver, obese fatty liver, diabetic fatty liver, liver fibrosis, and liver cirrhosis.

[0182] The aforementioned "simple fatty liver (steatosis)" is a type of non-alcoholic fatty liver disease and is considered a benign disease with a good clinical prognosis.

[0183] In one embodiment, the autoimmune disease may be one or more selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, septic shock, allergic asthma, allergic rhinitis, atopic dermatitis, ulcerative colitis, lacrimation, Alzheimer's disease, stroke, arteriosclerosis, restenosis, type 1 diabetes, type 2 diabetes, urticaria, conjunctivitis, psoriasis, systemic inflammatory plaque syndrome, polymyositis, dermatomyositis, polyarthritis nodularis, mixed connective tissue disease, Sjögren's syndrome, gout, Parkinson's disease, amyotrophic lateral sclerosis, diabetic retinopathy, multiple sclerosis, Crohn's disease, chronic thyroiditis, Ceriak's disease, myasthenia gravis, pemphigus vulgaris, viral disease, bacterial disease, radiation-induced disorder, arteriosclerosis, hemangioma, angiofibroma, reperfusion impairment, and cardiac hypertrophy.

[0184] Another aspect provides a pharmaceutical composition for the prevention or treatment of metabolic or autoimmune diseases comprising a compound represented by the following chemical formula 19 or a pharmaceutically acceptable salt thereof:

[0185] [Chemical Formula 19]

[0186] .

[0187] The above "pharmaceuticalally acceptable salt," "metabolic disease," "autoimmune disease," "prevention," "treatment," and "pharmaceutical composition," etc., may be within the scope described above.

[0188] In the above chemical formula 19,

[0189] The above n is 0 or 1 and;

[0190] The above R 1 Silver consists of hydrogen, deuterium, substituted or unsubstituted C1 to C10 alkyl groups and Selected from a group consisting of;

[0191] The above R 2 Is And;

[0192] The above X is carbon;

[0193] The above X and Y are connected by a double or triple bond;

[0194] When the above X and Y are connected by a double bond, the above Y is nitrogen;

[0195] When the above X and Y are connected by a triple bond, the above Y is carbon;

[0196] When the above X and Y are connected by a double bond and the above Y is nitrogen, the above R 3 and R 4 Each is independently selected from the group consisting of hydrogen, deuterium, and hydroxy, and R 5 is not present;

[0197] When the above X and Y are connected by a triple bond and the above Y is carbon, the above R 3 and R 5 does not exist, and the above R 4 is a substituted or unsubstituted alkyl having 1 to 10 carbon atoms;

[0198] The above R 6 It is a substituted or unsubstituted heterocycloalkyl having 2 to 10 carbon atoms or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms.

[0199] Another aspect provides a compound represented by the following chemical formula 20 or a salt thereof:

[0200] [Chemical Formula 20]

[0201] .

[0202] The above "pharmaceuticalally acceptable salt," "metabolic disease," "autoimmune disease," "prevention," "treatment," and "pharmaceutical composition," etc., may be within the scope described above.

[0203] In the above chemical formula 20,

[0204] The above R 1 silver And;

[0205] The above R 2is a substituted or unsubstituted heterocycloalkyl having 2 to 10 carbon atoms or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms.

[0206]

[0207] Another aspect provides a compound represented by the following chemical formula 21 or a salt thereof:

[0208] [Chemical Formula 21]

[0209] .

[0210] The above "pharmaceuticalally acceptable salt," "metabolic disease," "autoimmune disease," "prevention," "treatment," and "pharmaceutical composition," etc., may be within the scope described above.

[0211] In the above chemical formula 21,

[0212] The above n is 0 or 1 and;

[0213] The above R 1 Silver consists of hydrogen, deuterium, halogen, hydroxyl, substituted or unsubstituted alkyl groups having 1 to 10 carbon atoms, and Selected from a group consisting of;

[0214] The above X is carbon;

[0215] The above X and Y are connected by a double or triple bond;

[0216] When the above X and Y are connected by a double bond, the above Y is nitrogen or oxygen;

[0217] When the above X and Y are connected by a triple bond, the above Y is carbon or nitrogen;

[0218] When the above X and Y are connected by a double bond and the above Y is carbon, the above R 2 , R 3 and R 4 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups;

[0219] When the above X and Y are connected by a double bond and the above Y is nitrogen, the above R 2 and R 3 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups, and R 4 is not present;

[0220] When X and Y are connected by a double bond and Y is oxygen, R 2 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted alkyl groups having 1 to 10 carbon atoms, and R 3 and R 4 is not present;

[0221] When the above X and Y are connected by a triple bond and the above Y is carbon, the above R 2 and R 4 does not exist, and the above R 3 It is hydrogen, deuterium, hydroxyl, or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms;

[0222] When the above X and Y are connected by a triple bond and the above Y is nitrogen, the above R 2 , R 3 and R 4 does not exist.

[0223] Another aspect provides a health functional food for the prevention or improvement of metabolic or autoimmune diseases comprising a compound of the following chemical formula 1 or a food-grade acceptable salt thereof:

[0224] [Chemical Formula 1]

[0225]

[0226] In the above chemical formula 1,

[0227] The above n is 0 or 1 and;

[0228] The above R 1 and R 3Each independently consists of hydrogen, deuterium, halogen, hydroxyl, substituted or unsubstituted C1 to C10 alkyl and Selected from a group consisting of;

[0229] The above R 2 is hydrogen, deuterium, halogen and Selected from a group consisting of;

[0230] The above X is carbon;

[0231] The above X and Y are connected by a double or triple bond;

[0232] When the above X and Y are connected by a double bond, the above Y is carbon, nitrogen, or oxygen;

[0233] When the above X and Y are connected by a triple bond, the above Y is carbon or nitrogen;

[0234] When the above X and Y are connected by a double bond and the above Y is carbon, the above R 4 , R 5 and R 6 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups;

[0235] When the above X and Y are connected by a double bond and the above Y is nitrogen, the above R 4 and R 5 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups, and R 6 is not present;

[0236] When X and Y are connected by a double bond and Y is oxygen, R 4 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted alkyl groups having 1 to 10 carbon atoms, and R 5 and R 6 is not present;

[0237] When the above X and Y are connected by a triple bond and the above Y is carbon, the above R 4 and R 6 ...is not present, and the R5 is hydrogen, deuterium, hydroxyl, or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms;

[0238] When the above X and Y are connected by a triple bond and the above Y is nitrogen, the above R 4 , R 5 and R 6 is not present;

[0239] The above R 7 It is hydrogen, deuterium, a substituted or unsubstituted heterocycloalkyl having 2 to 10 carbon atoms, or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms.

[0240] The above "compound of Chemical Formula 1," "pharmaceutically acceptable," "prevention," "treatment," etc. may be within the aforementioned range.

[0241] The term “improvement” may refer to any action that at least reduces parameters related to the condition being treated, such as the severity of symptoms. In this case, the health functional food may be used for the prevention or improvement of metabolic diseases or autoimmune diseases, either simultaneously with or separately from a drug for treatment, either before or after the onset of the disease.

[0242] The term "functional food" is synonymous with "food for special health use (FosHU)," and refers to a food with high medical or health effects that is processed to efficiently exhibit bio-regulatory functions in addition to providing nutrition. Here, "functional" means obtaining useful effects for health purposes, such as regulating nutrients or physiological actions regarding the structure and function of the human body.

[0243] In addition, the above "health functional food" includes health functional foods, health foods, and health supplement foods. "Health food" refers to a food that has an active effect of maintaining or promoting health compared to general food, and "health supplement food" refers to a food intended for the purpose of health support.

[0244] In the above-mentioned health functional food, the compound of Formula 1 or its food-grade acceptable salt may be added directly to the food or mixed with other foods or food ingredients and used appropriately according to conventional methods. The amount of the compound of Formula 1 or its food-grade acceptable salt mixed may be appropriately determined according to the purpose of its use (for prevention or improvement). Generally, when manufacturing food or beverages, the compound of Formula 1 or its food-grade acceptable salt may be added in an amount of about 15% by weight or less, specifically about 10% by weight or less, with respect to the raw materials. However, in the case of long-term consumption for the purpose of health and hygiene or health control, the above amount may be less than the above range.

[0245] The above-mentioned health functional food may be formulated into one selected from the group consisting of tablets, pills, powders, granules, powders, capsules, and liquid formulations, by further including one or more of a carrier, a diluent, an excipient, and an additive. Foods to which a compound according to one aspect may be added include various types of food, powders, granules, tablets, capsules, syrups, beverages, gum, tea, vitamin complexes, health functional foods, etc.

[0246] Specific examples of the above carrier, excipient, diluent, and additive may be one or more selected from the group consisting of lactose, dextrose, sucrose, sorbitol, mannitol, erythritol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium phosphate, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, polyvinylpyrrolidone, methylcellulose, water, sugar syrup, methylcellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil.

[0247] The above-mentioned health functional food may contain other ingredients as essential components without special limitations, in addition to containing the compound of Formula 1 or a food-grade acceptable salt thereof. For example, it may contain various flavoring agents or natural carbohydrates as additional ingredients, such as in ordinary beverages. Examples of the above-mentioned natural carbohydrates may be monosaccharides, e.g., glucose, fructose, etc.; disaccharides, e.g., maltose, sucrose, etc.; polysaccharides, e.g., dextrin, cyclodextrin, etc., common sugars; and sugar alcohols such as xylitol, sorbitol, erythritol, etc. As flavoring agents other than those mentioned above, natural flavoring agents (thaumatin, stevia extract (e.g., rebaudioside A, glycyrrhizin, etc.)) and synthetic flavoring agents (saccharin, aspartame, etc.) may be advantageously used. The proportion of the above-mentioned natural carbohydrates may be appropriately determined by the choice of a person skilled in the art.

[0248] In addition to the above, a health functional food according to one aspect may contain various nutritional supplements, vitamins, minerals (electrolytes), flavoring agents such as synthetic and natural flavoring agents, coloring agents and thickening agents (cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohol, carbonating agents used in carbonated beverages, etc. These ingredients may be used independently or in combination, and the proportion of these additives may also be appropriately selected by a person skilled in the art.

[0249] In another aspect, a method for preventing or treating a metabolic disease or an autoimmune disease is provided, comprising the step of administering to an individual in need a compound of the following chemical formula 1 or a pharmaceutically acceptable salt thereof.

[0250] [Chemical Formula 1]

[0251]

[0252] In the above chemical formula 1,

[0253] The above n is 0 or 1 and;

[0254] The above R 1 and R 3 Each independently consists of hydrogen, deuterium, halogen, hydroxyl, substituted or unsubstituted C1 to C10 alkyl and Selected from a group consisting of;

[0255] The above R 2 is hydrogen, deuterium, halogen and Selected from a group consisting of;

[0256] The above X is carbon;

[0257] The above X and Y are connected by a double or triple bond;

[0258] When the above X and Y are connected by a double bond, the above Y is carbon, nitrogen, or oxygen;

[0259] When the above X and Y are connected by a triple bond, the above Y is carbon or nitrogen;

[0260] When the above X and Y are connected by a double bond and the above Y is carbon, the above R 4 , R 5 and R 6 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups;

[0261] When the above X and Y are connected by a double bond and the above Y is nitrogen, the above R 4 and R 5 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups, and R 6 is not present;

[0262] When X and Y are connected by a double bond and Y is oxygen, R 4 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted alkyl groups having 1 to 10 carbon atoms, and R 5 and R 6 is not present;

[0263] When the above X and Y are connected by a triple bond and the above Y is carbon, the above R 4 and R 6 ...is not present, and the R5 is hydrogen, deuterium, hydroxyl, or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms;

[0264] When the above X and Y are connected by a triple bond and the above Y is nitrogen, the above R 4 , R 5 and R 6 is not present;

[0265] The above R 7It is hydrogen, deuterium, a substituted or unsubstituted heterocycloalkyl having 2 to 10 carbon atoms, or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms.

[0266] The above "compound of Chemical Formula 1," "pharmaceutically acceptable," "prevention," "treatment," etc. may be within the aforementioned range.

[0267]

[0268] In another aspect, the use of a compound of Formula 1 below or a pharmaceutically acceptable salt thereof is provided for the manufacture of a drug for the prevention or treatment of metabolic diseases or autoimmune diseases.

[0269] [Chemical Formula 1]

[0270]

[0271] In the above chemical formula 1,

[0272] The above n is 0 or 1 and;

[0273] The above R 1 and R 3 Each independently consists of hydrogen, deuterium, halogen, hydroxyl, substituted or unsubstituted C1 to C10 alkyl and Selected from a group consisting of;

[0274] The above R 2 is hydrogen, deuterium, halogen and Selected from a group consisting of;

[0275] The above X is carbon;

[0276] The above X and Y are connected by a double or triple bond;

[0277] When the above X and Y are connected by a double bond, the above Y is carbon, nitrogen, or oxygen;

[0278] When the above X and Y are connected by a triple bond, the above Y is carbon or nitrogen;

[0279] When the above X and Y are connected by a double bond and the above Y is carbon, the above R4 , R 5 and R 6 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups;

[0280] When the above X and Y are connected by a double bond and the above Y is nitrogen, the above R 4 and R 5 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups, and R 6 is not present;

[0281] When X and Y are connected by a double bond and Y is oxygen, R 4 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted alkyl groups having 1 to 10 carbon atoms, and R 5 and R 6 is not present;

[0282] When the above X and Y are connected by a triple bond and the above Y is carbon, the above R 4 and R 6 ...is not present, and the R5 is hydrogen, deuterium, hydroxyl, or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms;

[0283] When the above X and Y are connected by a triple bond and the above Y is nitrogen, the above R 4 , R 5 and R 6 is not present;

[0284] The above R 7 It is hydrogen, deuterium, a substituted or unsubstituted heterocycloalkyl having 2 to 10 carbon atoms, or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms.

[0285] The above "compound of Chemical Formula 1," "pharmaceutically acceptable," "prevention," "treatment," etc. may be within the aforementioned range.

[0286]

[0287] One aspect provides a pharmaceutical composition for the prevention or treatment of metabolic or autoimmune diseases comprising a novel terthiophene compound or a pharmaceutically acceptable salt thereof. The pharmaceutical composition inhibits monoamine oxidase B (MAO-B), thereby exhibiting a preventive or therapeutic effect against metabolic diseases such as obesity and fatty liver or autoimmune diseases such as rheumatic diseases.

[0288]

[0289] Figure 1 is a schematic diagram showing the extract fractionation process.

[0290] FIG. 2a is a diagram showing the process of preparing compounds 3 and 7 to 10 from terthiophene.

[0291] Figure 2b is of compound 3 1 This is the H-NMR spectrum.

[0292] Figure 2c is of compound 7 1 This is the H-NMR spectrum.

[0293] Figure 2d is of compound 8 1 This is the H-NMR spectrum.

[0294] Figure 2e is of compound 9 1 This is the H-NMR spectrum.

[0295] Figure 2f is of compound 10 1 This is the H-NMR spectrum.

[0296] Figure 2g is of compound 11 1 This is the H-NMR spectrum.

[0297] Figure 2h is of compound 12 1 This is the H-NMR spectrum.

[0298] Fig. 2i is of compound 12 19 This is the F-NMR spectrum.

[0299] Fig. 2j is of compound 13 1 This is the H-NMR spectrum.

[0300] Figure 2k is of compound 13 19 This is the F-NMR spectrum.

[0301] Figures 2l and 2m show the Liquid Chromatography-Mass Spectrometry (LC-MS) of compound 13.

[0302] Figure 2n is of compound 15 1 This is the H-NMR spectrum.

[0303] Figure 20 is of compound 15 19 This is the F-NMR spectrum.

[0304] Figures 2p and 2q show the Liquid Chromatography-Mass Spectrometry (LC-MS) of compound 16.

[0305] Figures 2r and 2s show the Liquid Chromatography-Mass Spectrometry (LC-MS) of compound 17.

[0306] Figure 2t is of compound 17 1 This is the H-NMR spectrum.

[0307] Figure 3 is a schematic diagram showing the experimental procedure for measuring the monoamine oxidase B inhibitory activity of a compound.

[0308] Figure 4 is a figure showing the results of measuring the monoamine oxidase B inhibitory activity of compounds 1 to 6.

[0309] Figures 5 to 9b show the results of measuring the oxidase B inhibitory activity of compounds 3, 4 and 7 to 10.

[0310] Figure 10 is a schematic diagram showing the experimental procedure for measuring the monoamine oxidase A inhibitory activity of a compound.

[0311] Figure 11 shows the results of measuring the monoamine oxidase A inhibitory activity of compound 9.

[0312] Figure 12 shows the results of comparing the selective monoamine oxidase B inhibitory activity of compound 9 against the control group.

[0313] Figures 13a to 13g show the results of confirming the selective inhibitory ability of compounds 11 to 17 on monoamine oxidase B.

[0314] Figure 14 is a schematic diagram showing the experimental process for evaluating the hydrogen peroxide scavenging ability of a compound.

[0315] Figure 15 shows the measurement results of the hydrogen peroxide scavenging ability of the control group KDS12025 and compound 9.

[0316] Figure 16 is a schematic diagram showing the experimental process of the PAMPA test to confirm whether compound 9 penetrates the BBB.

[0317] Figure 17 is a figure showing the PAMPA test results of compound 9.

[0318] Figure 18 is a figure showing the results of the reversibility test of compound 9.

[0319] Figure 19 is a figure showing the timeline of the Dose Lethality test experiment of compound 9.

[0320] Figure 20 is a figure showing the experimental results of the Dose Lethality test of compound 9.

[0321] Figure 21 is a figure showing the experimental timeline to confirm the rheumatoid arthritis relief effect of compound 9.

[0322] Figures 22 to 27 show the rheumatoid arthritis-relieving effect of compound 9.

[0323] Figure 28 is a figure showing the experimental timeline to confirm the fatty liver alleviating effect of compound 9.

[0324] Figures 29 to 31 show the fatty liver alleviating effect of compound 9.

[0325] Figure 32 shows the results of the genotoxicity evaluation of compound 9.

[0326]

[0327] The present invention will be explained in more detail below through examples. However, these examples are intended to illustrate the invention and the scope of the invention is not limited to these examples.

[0328]

[0329] Reference Example

[0330] Compounds 1 to 17 shown in Table 1 below were prepared according to Reference Examples 1 to 3.

[0331] Compound No. Chemical Formula No. Compound Structure Korean Name 12 3'-hydroxy-2,2':5',2''-terthiophene-3'-O-β-D-glucopyranoside(3'-hydroxy-2,2':5',2"-terthiophene-3'-O-β-d-glucopyranoside)23 2,2':5',2''-terthiophene(2,2':5',2"-terthiophene)34 5-formyl-2,2':5',2''-terthiophene(5-formyl-2,2':5',2"-terthiophene)45 5-hydroxymethyl-2,2':5',2''-terthiophene 3'-methoxy-2,2':5',2''-terthiophene(3'-methoxy-2,2':5',2"-terthiophene)67 5-(3",4"-dihydroxy-1"-butynyl)-2,2'-bithiophene(5-(3",4"-dihydroxy-1"-butynyl)-2,2'-bithiophene)78 (E)-[2,2':5',2''-terthiophene]-5-carbaldehyde oxime((E)-[2,2':5',2'-terthiophene]-5-carbaldehyde oxime)89 (Z)-[2,2':5',2''-terthiophene]-5-carbaldehyde oxime((Z)-[2,2':5',2''-terthiophene]-5-carbaldehyde oxime)910 [2,2':5',2''-terthiophene]-5,5''-dicarbaldehyde ([2,2':5',2''-terthiophene]-5,5''-dicarbaldehyde)1011 [2,2':5',2''-Terthiophene]-5,5''-Diyldimethanol 2,2′:5′,2′′-Terthiophene-5,5′′-diyldimethanol 1112 5''-iodo-[2,2':5',2''-terthiophene]-5-carbaldehyde1213 5''-(trifluoromethyl)-[2,2':5',2''-terthiophene]-5-carbaldehyde 5''-(trifluoromethyl)-[2,2':5',2''-terthiophene]-5-carbaldehyde 1314 5-iodo-5''-(trifluoromethyl)-[2,2':5',2''-terthiophene]5-iodo-5''-(trifluoromethyl)-[2,2':5',2''-terthiophene]1415 5,5''-diiodod-[2, 2': 5',2''-terthiophene]5,5''-diiodod-[2,2':5',2''-terthiophene]1516 5,5"-bis(trifluoromethyl)-[2,2':5′',2″"-terthiophene]5,5"-bis(trifluoromethyl)-[2,2':5′',2″"-terthiophene]1617 5'-(5-carboxy-2-thienyl)-[2,2':5′',2″"-terthiophene]-5"-carbaldehyde1718 2-[5-(trifluoromethyl)thiophene-2-yl]-5-[5-carboxythiophen-2-yl]thiophene

[0332]

[0333] Reference Example 1. Extract Fractionation and Compound Preparation

[0334] The compounds used in the experiments of the following examples were prepared through the following process.

[0335] 4.2 kg of dried *Hyundai* was extracted by leaching it three times repeatedly in ethanol at room temperature. The extracted solution was filtered through a Whatman No. 2 filter and concentrated in a vacuum concentrator to produce 750 g of extract (ECPR2). The extract was fractionated with ethyl acetate, and silica gel column chromatography was performed on it to produce a total of 15 fractions (E1 to E15).

[0336] Silica gel column chromatography (n-hexane / MC=19 / 1, v / v) was performed again on subfraction E1 to obtain compound 2 (149 mg) and compound 5 (8.6 mg).

[0337] of the above-mentioned obtained compound 2 (chemical formula 3 below) 1 As a result of confirming the H NMR, the following data was obtained:

[0338] [Chemical Formula 3]

[0339]

[0340] 1 H NMR (500 MHz, CDCl₃): δ 7.34 (dd, J = 5.2, 1.2 Hz, 2H), 7.15 (dd, J = 3.6, 1.2 Hz, 2H), 7.10 (dd, J = 5.2, 3.6 Hz, 2H), 6.98 (dd, J = 3.6, 1.2 Hz, 2H), 6.93 (dd, J = 5.2, 3.6 Hz, 2H).

[0341]

[0342] of the above-mentioned obtained compound 5 (chemical formula 6 below) 1 As a result of confirming the H NMR, the following data was obtained:

[0343] [Chemical Formula 6]

[0344]

[0345] 1 H NMR (500 MHz, CDCl₃): δ 7.35 (dd, J = 5.0, 1.0 Hz, 2H), 7.20 (dd, J = 3.5, 1.0 Hz, 2H), 7.12 (dd, J = 5.0, 3.5 Hz, 2H), 7.00 (dd, J = 3.5, 1.0 Hz, 2H), 6.95 (dd, J = 5.0, 3.5 Hz, 2H), 3.85 (s, 3H).

[0346]

[0347] Silica gel column chromatography (n-hexane / MC=9 / 1~7 / 3, v / v) was performed on subfraction E3 to obtain compound 3 (8.8 mg) and compound 6 (16.6 mg).

[0348] of the above-mentioned obtained compound 6 (chemical formula 7 below) 1 As a result of confirming the H NMR, the following data was obtained:

[0349] [Chemical Formula 7]

[0350]

[0351] 1H NMR (500 MHz, CDCl₃): δ 7.24 (dd, J = 5.1, 1.2 Hz, 2H), 7.17 (dd, J = 3.6, 1.2 Hz, 2H), 7.13 (dd, J = 5.1, 3.6 Hz, 2H), 7.02 (dd, J = 3.6, 1.2 Hz, 2H), 7.00 (dd, J = 5.1, 3.6 Hz, 2H), 4.31 (t, J = 5.7 Hz, 1H), 3.82 (d, J = 5.7 Hz, 1H).

[0352] Reverse-phase column chromatography (YMC C18, MeOH / W = 4 / 1, v / v) was performed on subfraction E5 to obtain compound 4 (48.4 mg).

[0353] of the above-mentioned obtained compound 4 (chemical formula 5 below) 1 As a result of confirming the H NMR, the following data was obtained:

[0354] [Chemical Formula 5]

[0355]

[0356] 1 H NMR (500 MHz, CDCl₃): δ 7.25 (dd, J = 5.2, 1.2 Hz, 2H), 7.15 (dd, J = 3.6, 1.2 Hz, 2H), 7.10 (dd, J = 5.2, 3.6 Hz, 2H), 7.00 (dd, J = 3.6, 1.2 Hz, 2H), 6.95 (dd, J = 5.2, 3.6 Hz, 2H), 4.75 (s, 2H), 2.50 (br s, 1H).

[0357] Sephadex LH-20 column chromatography (MC / M = 1 / 1, v / v) was performed on subfraction E9 to obtain 8 subfractions, and then reverse-phase MPLC (Redi Sep-C18 43 g, MeOH / W = 50 / 50~65 / 35 v / v) was performed on subfraction E9-3 to obtain compound 1 (15.2 mg) (Fig. 1).

[0358] of the above-mentioned obtained compound 1 (chemical formula 2 below). 1 As a result of confirming the H NMR, the following data was obtained:

[0359] [Chemical Formula 2]

[0360]

[0361] 1 H NMR (500 MHz, Chloroform-d): δ 7.37 (dd, J = 3.5, 1.0 Hz, 1H), 7.30 (dd, J = 5.0, 1.0 Hz, 1H), 7.25 (s, 1H), 7.25 (dd, J = 3.5, 1.0 Hz, 1H), 7.04 (dd, J = 5.0, 3.5 Hz, 1H), 7.03 (dd, J = 5.0, 3.5 Hz, 1H), 7.35 (dd, J = 5.0, 1.0 Hz, 1H), 5.04 (d, J = 7.5 Hz, 1H), 3.56 (dd, J = 9.0, 7.5 Hz, 1H), 3.49 (t, J = 9.0 Hz, 1H), 3.41 (t, J = 9.0 Hz, 1H),

[0362] 3.48 (ddd, J = 9.5, 6.0, 2.5 Hz, 1H), 3.91 (dd, J = 12.0, 2.0 Hz, 1H), 3.71 (dd, J = 12.0, 6.0 Hz, 1H).

[0363]

[0364] Reference Example 2. Synthesis of Terthiophene derivative (ecliptal, TTA)

[0365] Compounds 3, 7 to 10 were prepared via the following reaction scheme 1:

[0366] [Reaction Equation 1]

[0367] .

[0368]

[0369] Step 1: Compound 3 Synthesis Process

[0370] The process for synthesizing compound 3 from terthiophene was carried out. Terthiophene was dissolved in 0.6 M dichloromethane (DCM), and dimethylformamide (DMF) was added. Then, phosphoryl chloride (POCl3) dissolved in DCM was added dropwise at 0°C. After stirring for 5 minutes at room temperature, the reaction was carried out at 60°C. After the reaction was completed, the solution was stopped with an aqueous sodium bicarbonate solution, extracted with MC, and dehydrated with magnesium sulfate (MgSO4). Subsequently, the solution was separated and purified by flash column chromatography (EtOAc:Hex = 1:80) to obtain a yellow solid derivative, compound 3 (TTA), with a yield of 72%.

[0371] of the above-mentioned obtained compound 3 (chemical formula 4 below) 1 As a result of confirming the ¹H NMR, the following data was obtained (Fig. 2b):

[0372] [Chemical Formula 4]

[0373]

[0374] 1 H NMR (500 MHz, Chloroform-d):δ9.87 (s, 1H), 7.68 (d,J= 4.0 Hz, 1H), 7.29 - 7.27 (m, 2H), 7.25 - 7.22 (m, 2H), 7.14 (d,J= 3.8 Hz, 1H), 7.08 - 7.03 (m, 1H).

[0375]

[0376] Step 2: Synthesis process of Compounds 7 and 8

[0377] An experiment was conducted to synthesize compounds 7 and 8 from the material obtained in Step 1 above. 0.3 M pyridine was added to TTA, followed by the addition of hydroxylamine hydrochloric acid (HONH2HCl), and the reaction was carried out at 115°C. After reacting for 3 hours, the reaction was stopped with a 2 N aqueous solution of hydrochloric acid (HCl). Subsequently, the mixture was extracted with ethyl acetate, and the organic layer was dehydrated with magnesium sulfate (MgSO4). The resulting compounds were then separated and purified by flash column chromatography (EtOAc:Hex = 1:80 ~ 1:40 (tans) ~ 1:10 (cis)) to obtain yellow solid compounds 7 and 8 corresponding to chemical formulas 8 and 9 with yields of 26% (trans) and 15% (cis), respectively.

[0378] of the above-mentioned obtained compounds 7 (Chemical Formula 8) and 8 (Chemical Formula 9). 1 As a result of confirming the 1H NMR, the following data were obtained (Figs. 2c and 2d):

[0379] [Chemical Formula 8]

[0380]

[0381] 1 H NMR (500 MHz, DMSO-d6): δ11.32 (s, 1H), 8.31 (d,J= 6.6 Hz, 1H), 7.55 (dd,J= 5.1, 1.2 Hz, 1H), 7.37 (dd,J= 3.6, 1.2 Hz, 1H), 7.34 (d,J= 3.8 Hz, 1H), 7.32 - 7.28 (m, 2H), 7.26 (d,J= 3.8 Hz, 1H), 7.11 (dd,J= 5.1, 3.6 Hz, 1H),

[0382] [Chemical Formula 9]

[0383]

[0384] 1H NMR (500 MHz, DMSO-d6): δ12.09 (s, 1H), 7.86 (s, 1H), 7.55 (dd,J= 5.1, 1.3 Hz, 1H), 7.43 (d,J= 4.0 Hz, 1H), 7.37 (dq,J= 10.7, 5.1, 4.4 Hz, 3H), 7.30 (q,J= 4.1, 3.5 Hz, 1H), 7.12 (dd,J= 5.0, 3.6 Hz, 1H).

[0385]

[0386] Step 3: Compound 9 Synthesis Process

[0387] An experiment was conducted to synthesize Compound 9 from terthiophene. Terthiophene was dissolved in 0.5 M DMF (Dimethylformamide) and replaced with argon gas, after which phosphoryl chloride (POCl3) was added dropwise at room temperature. Subsequently, the reaction was carried out at 100°C for 3 hours, after which an aqueous sodium acetate solution was added. The precipitate was filtered and separated and purified by flash column chromatography (MC:Hex = 1:1–3:1, MC:EA = 40:1) to obtain Compound 9 in the form of a yellow solid with a yield of 26%.

[0388] of the above-mentioned obtained compound 9 (Chemical Formula 10) 1 As a result of confirming the H NMR, the following data was obtained (Fig. 2e):

[0389] [Chemical Formula 10]

[0390]

[0391] 1 H NMR (500 MHz, Chloroform-d) δ 9.89 (s, 2H), 7.70 (d,J= 4.0 Hz, 2H), 7.33 (s, 2H), 7.30 (d,J= 3.9 Hz, 2H).

[0392]

[0393] Step 4: Compound 10 Synthesis Process

[0394] An experiment was conducted to synthesize Compound 10 from Compound 9 obtained in Step 3 above. Compound 9 and sodium borohydride (NaBH4) were dissolved in 0.1M Tetrahydrofuran (THF), replaced with argon gas, and the reaction was carried out at room temperature while stirring. After the reaction was completed, the solution was extracted with ethyl acetate, and the organic layer was dehydrated with sodium sulfate (NaSO4). Subsequently, the mixture was separated and purified by flash column chromatography (EtOAc:MC = 1:10 ~ 1:1) to obtain Compound 10, a pale yellow solid corresponding to Chemical Formula 11, with a yield of 33%.

[0395] of the above-mentioned obtained compound 10 (Chemical Formula 11) 1 As a result of confirming the H NMR, the following data was obtained (Fig. 2f):

[0396] [Chemical Formula 11]

[0397]

[0398] 1 H NMR (500 MHz, Methanol-d4): δ7.07 (s, 2H), 7.05 (d,J= 3.6 Hz, 2H), 6.89 (dt,J= 3.6, 0.9 Hz, 2H), 4.69 (d,J= 0.9 Hz, 4H).

[0399]

[0400] Reference Example 3: Synthesis of Terthiophene Derivative (Ecliptal, TTA)

[0401] Compounds 11 to 13 and 15 to 17 were prepared according to the following steps, and in the case of compound 14, it was purchased from Sigma Aldrich and used.

[0402] [Chemical Formula 15]

[0403]

[0404]

[0405] Step 1: Compound 11 Synthesis Process

[0406] Compound 11 was prepared via the following reaction scheme 2:

[0407] [Reaction Equation 2]

[0408] .

[0409] 2,2':5',2''-Terthiophene-5-carboxaldehyde was dissolved in AcOH / DCM (1:1, 0.3 M), and NIS (1.1 eq) dissolved in DCM was added dropwise while stirring in an ice bath at 0°C. After stirring overnight, the precipitate was washed with an excess amount of MeOH. Subsequently, the mixture was filtered using a MeOH filter, and the filter cake was dried under high vacuum to obtain Compound 11, an orange solid corresponding to Chemical Formula 12, with a yield of 97%.

[0410] of the above-mentioned obtained compound 11 (Chemical Formula 12) 1 As a result of confirming the ¹H NMR, the following data was obtained (Fig. 2g):

[0411] [Chemical Formula 12]

[0412]

[0413] 1 H NMR (400 MHz, DMSO-d6) δ 9.89 (s, 1H), 8.00 (d,J= 4.0 Hz, 1H), 7.57 (dd,J= 6.4, 3.9 Hz, 2H), 7.36 (d,J= 3.9 Hz, 2H), 7.15 (d,J= 3.8 Hz, 1H).

[0414]

[0415] Step 2: Compound 12 Synthesis Process

[0416] Compound 12 was prepared via the following reaction scheme 3:

[0417] [Reaction Equation 3]

[0418] .

[0419] Methyldifluoro(fluorosulfonyl)aceate (5.0 eq) and CuI (1.5 eq) were added to Compound 11 obtained in Step 1 above, and then dissolved in NMP (0.83 M) and DMF (0.1 M). After stirring overnight at 100°C, the mixture was cooled and then quenched with an aqueous NH4Cl solution. The mixture was filtered through a Celite filter, extracted with EtOAc and H2O, and the organic layer was dehydrated with MgSO4. Subsequently, the mixture was separated and purified by flash column chromatography (EtOAc:Hex = 1:99 ~ 9:91) to obtain Compound 12, a pale yellow solid corresponding to Chemical Formula 13, with a yield of 67%.

[0420] of the above-mentioned obtained compound 12 (Chemical Formula 13) 1 H NMR and 19 As a result of confirming the F NMR, the following data were obtained (Figs. 2h and 2i):

[0421] [Chemical Formula 13]

[0422]

[0423] 1 H NMR (400 MHz, Chloroform-d) δ 9.88 (s, 1H), 7.69 (d,J= 4.0 Hz, 1H), 7.40 - 7.34 (m, 1H), 7.28 (dd,J= 10.3, 3.9 Hz, 2H), 7.22 - 7.12 (m, 2H), 19 F NMR (376 MHz, Chloroform-d) δ -55.48.

[0424]

[0425] Step 3: Compound 13 Synthesis Process

[0426] Compound 13 was prepared via the following reaction scheme 4:

[0427] [Reaction Equation 4]

[0428] .

[0429] 3-(Trifluoromethyl)-2,2:5′',2″"-terthiophene was dissolved in a mixed solvent of AcOH / DCM (1:1, 0.3 M), and NIS (1.0 eq) dissolved in DCM was slowly added while stirring in an ice bath at 0°C. After stirring the reaction mixture at room temperature for a certain period, an excess amount of MeOH was added to form a precipitate. The resulting precipitate was purified by preparative high-performance liquid chromatography (0.1% formic acid in water:0.1% formic acid in acetonitrile = 1:9 ~ 9:1) to obtain compound 13 in the form of a yellow solid with a yield of 80%.

[0430] of the above-mentioned obtained compound 13 (Chemical Formula 14) 1 H NMR and 19 As a result of confirming the F NMR, the following data were obtained (2j and 2k):

[0431] [Chemical Formula 14]

[0432]

[0433] 1 H NMR (500 MHz, Acetone-d6) δ 7.58 (dq,J= 4.0 and 1.5 Hz, 1H), 7.38 (d,J= 4.0 Hz, 1H), 7.36 (dq,J= 4.0 and 1.5 Hz, 1H), 7.31 (d,J= 4.0 Hz, 1H), 7.26 (d,J= 4.0 Hz, 1H), 7.06 (d,J= 4.0 Hz, 1H), 19 F NMR (470 MHz, , Acetone-d6) δ -55.87.

[0434]

[0435] Step 4: Compound 15 Synthesis Process

[0436] Compound 15 was prepared via the following reaction scheme 5:

[0437] [Reaction Equation 5]

[0438] .

[0439] Specifically, Compound 14 was dissolved in DMF (0.66 mL, 0.3 M), and then methyl difluoro(fluorosulfonyl)acetate (0.126 mL, 1.0 mmol), CuI (76.2 mg, 0.4 mmol), and NMP (0.25 mL, 0.8 M) were added. Subsequently, the mixture was irgonized and stirred overnight in an oil bath at 100 °C. After cooling the stirred mixture, it was filtered through a Celite filter, extracted with EtOAc and H2O, and the organic layer was dehydrated with Na2SO4. Subsequently, by preparative high-performance liquid chromatography (0.1% formic acid in water:0.1% formic acid in acetonitrile = 1:9 ~ 9:1), compound 15 in the form of a yellow solid corresponding to chemical formula 16 was obtained with a yield of 52%.

[0440] of the above-mentioned obtained compound 15 (Chemical Formula 16) 1 H NMR and 19 As a result of confirming the F NMR, the following data were obtained (Figs. 2l and 2m):

[0441] [Chemical Formula 16]

[0442]

[0443] 1 H NMR (500 MHz, Acetone-d6) δ 7.58 (dq,J= 4.0 and 1.5 Hz, 2H), 7.41 (br s, 2H), 7.37 (dq,J= 4.0 and 1.5 Hz, 2H), 19F NMR (470 MHz, , Acetone-d6) δ -55.91.

[0444]

[0445] Step 5: Compound 16 Synthesis Process

[0446] Compound 16 was prepared via the following reaction scheme 6:

[0447] [Reaction Equation 6]

[0448]

[0449] Specifically, 0.05 mmol of compound 9 and 0.5 mL of tBuOH (0.1 M) and 2-methyl-2-butene (0.5 M) (1:1, 0.3 M, for impurity removal) were all dissolved in 0.5 mL of THF 0.1 M. Subsequently, NaClO2 (10 eq) was dissolved in 2.5 mL of NaH2PO4 (0.5 M), added dropwise over 5 minutes at 0°C, and stirred overnight at room temperature. The stirred solution was quenched with a saturated aqueous solution of Na2SO3 to acidify it to a pH of approximately 3, extracted with EtOAc and H2O, and the organic layer was dehydrated with Na2SO4. Subsequently, by purification using preparative high-performance liquid chromatography (0.1% formic acid in water:0.1% formic acid in acetonitrile = 1:9 ~ 9:1), compound 16 in the form of a pale yellow solid corresponding to chemical formula 17 was obtained with a yield of 2%.

[0450] As a result of verifying the LC-MS values ​​of the above-mentioned compound 16 (Chemical Formula 17), data as shown in Fig. 2n was obtained:

[0451] [Chemical Formula 17]

[0452]

[0453]

[0454] Step 6: Compound 17 Synthesis Process

[0455] Compound 17 was prepared via the following reaction scheme 7:

[0456] [Reaction Equation 7]

[0457]

[0458] Specifically, terthiophene, 0.5 mL of tBuOH (0.1 M), and 2-methyl-2-butene (0.5 M) (1:1, 0.3 M, for removing impurities) were all dissolved in 0.5 mL of THF (0.1 M). Subsequently, NaClO2 (10 eq) was dissolved in 2.5 mL of NaH2PO4 (0.5 M), added dropwise over 5 minutes at 0°C, and stirred overnight at room temperature. The stirred solution was quenched with a saturated aqueous solution of Na2SO3 to acidify it to a pH of approximately 3, and the organic layer was dehydrated with Na2SO4 by extraction with EtOAc and H2O. Subsequently, by separation and purification using preparative high-performance liquid chromatography (0.1% formic acid in water:0.1% formic acid in acetonitrile = 1:9 ~ 9:1), compound 17 in the form of a pale yellow solid corresponding to chemical formula 18 was obtained with a yield of 85%.

[0459] As a result of confirming the LC-MS values ​​of the above-mentioned compound 17 (Chemical Formula 18), data as shown in Fig. 20 was obtained, and 1 As a result of confirming the ¹H NMR, the following data was obtained (Fig. 2p):

[0460] [Chemical Formula 18]

[0461]

[0462] 1H NMR (500 MHz, Methanol-d4) δ 7.70 (d, J = 4.0 Hz, 1H), 7.50 (m, 1H), 7.36 (dd, J = 8.5 and 5.0 Hz, 2H), 7.32 (d, J = 4.0 Hz, 2H).

[0463]

[0464] Examples

[0465] Example 1. Analysis of Monoamine Oxidase B (MAO-B) Inhibitory Activity

[0466] To determine the extent to which each compound inhibits monoamine oxidase B (MAO-B), an analysis was performed using HRP (Horseradish peroxidase). HRP (Invitrogen, 31490-10 mg) enzyme, MAO-B enzyme (Sigma-Aldrich, M7441), Benzyl amine (Sigma-Aldrich, B5136), and Amplex Red reagent (Invitrogen A12222) were purchased and used.

[0467] 49 µl of MAO-B enzyme solution was added to each well, and 1 µl of a test inhibitor compound dissolved in dimethyl sulfoxide was added. After inhibition for 10 minutes, the result solution (50 µl) was treated with a mixed solution (50 µl) of benzylamine (100 mM, 200 µl in 10 ml of phosphate buffer; final concentration, 1 mM), Amplex Red reagent (20 mM, 100 µl in 10 ml of phosphate buffer; final concentration, 0.1 mM), and HRP (200 U / ml, 100 µl in 10 ml of phosphate buffer; final concentration, 2 U / ml) in 9.6 ml of 50 mM phosphate buffer (pH 7.4). Afterwards, after incubating at 37°C for 60 minutes, the amount of resorufin produced by Amplex Red was measured using a microplate fluorescence reader (SpectraMax i3 reader, Molecular Devices).

[0468] As a result of the experiment, as disclosed in Figures 9a and 9b, compound 10 is IC 50 3.809 nM, Compound 9 is IC 50 Compound 9 showed the best MAO-B inhibitory activity at 1.970 nM.

[0469]

[0470] Example 2. Analysis of Monoamine Oxidase A (MAO-A) Inhibitory Activity

[0471] To determine the extent of monoamine oxidase A (MAO-A) inhibition by compound 9, an analysis using HRP (Horseradish peroxidase) was performed. HRP (Invitrogen, 31490-10 mg), MAO-A enzyme (Sigma-Aldrich, M7316), Tyramine (Sigma-Aldrich, T2879), and Amplex Red reagent (Invitrogen, A12222) were purchased and used. Clorgiline, Selegiline, and KDS2010 were used as controls.

[0472] 49 µl of MAO-A enzyme solution (2.5 mg / mL, 10 µl in 10 mL, final concentration: 12.5 µg / mL) was added to each well, and 1 µl of a test inhibitor compound dissolved in dimethyl sulfoxide was added. After inhibition for 10 minutes, the result solution (50 µl) was treated with a mixed solution (50 µl) of tyramine (100 mM, 200 µl in 10 mL phosphate buffer; final concentration, 1 mM), Amplex Red reagent (20 mM, 100 µl in 10 mL phosphate buffer; final concentration, 0.1 mM), and HRP (200 U / mL, 100 µl in 10 mL phosphate buffer; final concentration, 2 U / mL) in 9.6 mL of 50 mM phosphate buffer (pH 7.4). Afterwards, after incubating at 37°C for 160 minutes, the amount of resorufin produced by Amplex Red was measured using a microplate fluorescence reader (SpectraMax i3 reader, Molecular Devices).

[0473] As a result of the experiment, as disclosed in Figure 11, it was confirmed that compound 9 has a negligible inhibitory effect on MAO-A and selectively inhibits only MAO-B.

[0474]

[0475] Example 3. Comparison of the selective inhibitory activity of Compound 9 on Monoamine Oxidase B (MAO-B).

[0476] Experiments were conducted to confirm the selective inhibitory activity of compound 9 against each enzyme by comparing its MAO-B selective inhibitory activity with existing MAO-B inhibitors and its MAO-A inhibitory activity with existing MAO-A inhibitors.

[0477] The specific experimental method was the same as in Examples 1 and 2 above, but compound 9 was reacted with the MAO-B enzyme for 2 hours to inhibit it. Selegiline and KDS2010 were used as conventional MAO-B inhibitors, and Clogiline was used as an MAO-A inhibitor.

[0478] Confirmation results showed that, as previously known, clozylin completely inhibited MAO-A enzyme activity but barely inhibited MAO-B. Seligilin and KDS2010 selectively inhibited MAO-B, and IC 50 The values ​​were found to be 6.77 nM and 9.34 nM, respectively. In contrast, Compound 9 had an IC50 of 0.41 nM. 50 Showing values, it exhibited MAO-B inhibitory activity approximately 15 times stronger than selegiline and 20 times stronger than KDS2010, while showing almost no inhibitory activity against MAO-A enzyme. In other words, Compound 9 showed a selectivity ratio for MAO-B (MAO-A IC₀). 50 / MAO-B IC 50 ) is approximately 1.17 x 10 6 It was confirmed that while the inhibitory ability against MAO-A is significantly low, it has a significantly superior MAO-B inhibitory ability compared to selegiline and KDS2010, which are known as existing MAO-B inhibitors (Fig. 12).

[0479]

[0480] Example 4. Analysis of the selective inhibitory activity of compounds 11 to 17 on monoamine oxidase B (MAO-B)

[0481] To determine the degree to which compounds 11 to 17 selectively inhibit monoamine oxidase B (MAO-B), an analysis was performed using HRP (Horseradish peroxidase). The experimental method was carried out in the same manner as in Examples 1 and 2 above, but similar to Example 3, the compounds were reacted with the MAO-B enzyme for 2 hours to inhibit it, and to confirm whether only MAO-B was selectively inhibited, the inhibition of MAO-A was also checked.

[0482] Experimental results for confirming the MAO-A inhibitory effect as disclosed in compounds 13a to 13g IC 50The values ​​were very high, ranging from a minimum of 16,701 nM to a maximum of 1,316,837 nM, but the IC to confirm the MAO-B inhibitory effect 50 The value was significantly lower in comparison, and in particular, in the case of compound 11, it was found to be 0.2803 nM, confirming that compounds 11 to 17 have excellent efficacy in selectively inhibiting only MAO-B.

[0483]

[0484] Example 4. Analysis of hydrogen peroxide scavenging ability

[0485] To evaluate the efficacy of each compound as a hydrogen peroxide scavenger, an analysis was performed using HRP (Horseradish peroxidase). HRP (Invitrogen, 31490-10 mg) enzyme, H2O2 9.79 M solution (Sigma-Aldrich, H1009-5 mL), and Amplex Red reagent (Invitrogen A12222) were purchased and used.

[0486] After diluting hydrogen peroxide to 4 μM in 50 mM sodium phosphate buffer (pH 7.4), 49 μL and 2 μM of H2O2 solution were added to each well, and 1 μL of a test inhibitor compound dissolved in dimethyl sulfoxide was added.

[0487] The result solution (50 µl) was treated with a mixed solution (50 µl) of Amplex Red reagent (20 mM in 10 ml of phosphate buffer, 100 µl; final concentration, 0.1 mM) and HRP (200 U / ml in 10 ml of phosphate buffer, 100 µl; final concentration, 2 U / ml) in 9.8 ml of aqueous solution of 50 mM phosphate buffer (pH 7.4).

[0488] After incubating at 37°C for 60 minutes, the amount of resorufin produced by Amplex Red was measured using a microplate fluorescence reader (SpectraMax i3 reader, Molecular Devices).

[0489] As a result of the experiment, compound 9 was found to have a negligible hydrogen peroxide removal effect compared to a control group well known as a hydrogen peroxide remover, as disclosed in Fig. 15.

[0490] The evaluation of MAO-B and MAO-A inhibitory activity is based on hydrogen peroxide measurements using peroxidase and Amplex Red. Therefore, under these conditions, if a compound has hydrogen peroxide scavenging activity, it is difficult to conclude that it has MAO-B or MAO-A inhibitory activity. However, as shown in the above example, it can be seen that Compound 9 has a minimal degree of inhibition of MAO-A and hydrogen peroxide, while having an effect of selectively inhibiting only MAO-B.

[0491]

[0492] Example 4. Analysis of BBB penetration

[0493] To analyze whether Compound 9 permeates the BBB, a PAMPA test was performed using brain-derived lipids. The overall experimental procedure is shown in Figure 16. The materials used in the experiment were PRISMA HT (#110151, Pion Inc., USA), Brain sink buffer (#110674, Pion Inc., USA), Stirwell PAMPA sandwich (#110243, Pion Inc., USA), and BBB-1-lipid (#110672, Pion Inc., USA).

[0494] The test solution, PRISMA HT, was diluted with distilled water at a ratio of 1:40 and adjusted to pH 7.4 to be used as the donor buffer. Compound 9 was diluted to 5 μM in the donor buffer and used as the initial sample, while brain sink buffer was used as the acceptor buffer. The absorbance of the donor buffer was measured after dispensing it onto a UV plate at a rate of 150 μL / well and used as the blank value, while the absorbance of Compound 9 diluted to 5 μM was measured after dispensing it at a rate of 150 μL / well and used as the initial value. Next, the prepared initial sample was dispensed at a rate of 200 μL / well onto the donor plate of a Stirwell PAMPA sandwich, and after coating the membrane of the acceptor plate with 5 μL of BBB-1-lipid, brain sink buffer was dispensed at a rate of 200 μL / well. To confirm the permeability of the substance, the acceptor plate and donor plate were combined as shown in Fig. 16 and reacted at 25°C for 4 hours. After the reaction, the acceptor and donor plates were separated and transferred to UV plates at a rate of 150 µL / well. The absorbance was measured and used as the donor and acceptor values, respectively. The PAMPA transmittance (Pe) values ​​were analyzed using the PAMPA explorer program (Ver 3.8, Pion Inc., USA) after measuring the absorbance of each sample using a microplate reader. The experiment was repeated three times, and the mean and standard deviation were calculated.

[0495] As a result of the experiment, it can be confirmed that the likelihood of compound 9 penetrating the BBB is very low when compared to the values ​​of the positive control (Progesterone) and negative control (Ranitidine) shown in Table 2 below.

[0496]

[0497] Test(concentration)pHP e (10 -6 cm / sec)1st2nd3rdAvgSD Progesterone (50 μM)7.44 1.59 43.31 42.24 42.38 0.87 Ranitidine (50 μM)7.40000- Compound 9 (5 μM)7.40000-

[0498]

[0499] Example 5. CYP isoenzyme inhibition test

[0500] A CYP isoenzyme inhibition test was performed to determine whether compound 9 inhibits CYP isoenzymes, which are major drug metabolizing enzymes in human liver microsomes. Materials used in the experiment include NADPH Regeneration system (Promega, V9510), Terfenadine (internal reference material for test evaluation, Sigma Aldrich, T9562), Potassium Phosphate pH 7.4 (Corning, #451201), Human liver microsomes (Corning, #452117), Phenacetin (50 μM, CYP1A2 Substrate, Sigma Aldrich, 77440), Acetaminophen (CYP1A2 Metabolite, Sigma Aldrich, A7085), Diclofenac (10 μM, CYP2C9 Substrate, Sigma Aldrich, D6899), 4'-hydroxydiclofenac (CYP2C9 Metabolite, TRC, H825225), S-Mephenytoin (100 μM, CYP2C19 Substrate, Sigma) Aldrich, UC175), 4'-hydroxymephenytoin (CYP2C19 Metabolite, Santacruz, sc210197), Dextromethorphan (5 μM, CYP2D6 Substrate, Sigma Aldrich, 81091), Dextrophan (CYP2D6 Metabolite, Sigma Aldrich, UC205), Midazolam (2.5 μM, CYP3A4 Substrate, KFDA), 1'-hydroxymidazolam (CYP3A4 Metabolite, Sigma Aldrich, UC430), and Ketoconazole (Sigma Aldrich, K1003), a CYP3A4 specific inhibitor, were used as positive controls.

[0501] Compound 9 was added at concentrations of 0, 0.1, 0.5, 2, and 10 μM to a mixture of human liver microbody (0.25 mg / mL), 0.1 M Potassium Phosphate buffer, and a Substrate cocktail of five types of drug metabolizing enzymes, and pre-incubated at 37 °C for 5 minutes. Then, NADPH generation system solution was added and incubated at the same temperature for 15 minutes. Afterward, to terminate the reaction, an acetonitrile solution containing an internal standard (terfenadine) was added, and after centrifugation (15,000 rpm, 4 °C) for 5 minutes, the supernatant was injected into an LC-MS / MS system (Nexera XR system, Shimadzu, Japan; TSQ vantage, Thermo Scientific, USA) to simultaneously analyze the Substrate and Metabolite. A Kinetex C18 column (2.1 x 100 mm, 2.6 μm particle size, Phenomenex, USA) was used for the HPLC column, and distilled water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid were used as the mobile phase. The elution condition was analyzed using a gradient, and the generated metabolites were analyzed using the Xcalibur (ver 4.4) program in MRM (Multiple Reaction Monitoring) quantitative mode.

[0502] Repeated experiments were performed twice, and the activity of each CYP isoenzyme metabolite, quantified after reacting for 15 minutes at different concentrations, was calculated as a % by comparing it to a control group without added inhibitor. The evaluation was made according to the criteria shown in Table 4 below, and as shown in Table 3 below, it was confirmed that compound 9 does not inhibit CYP isoenzymes.

[0503]

[0504] InhibitionIC 50 Potent inhibition IC50 <1 μMModerate inhibition1 μM <IC 50 < 10 μMNo or Weak inhibition10 μM < IC 50

[0505] CompoundIC 50 (μM)CYP1A2CYP2C9CYP2C19CYP2D6CYP3A4Compound 9> 10> 1010.1> 10> 10Ketoconazole(Reference)94.195.1> 10092.731.5

[0506]

[0507] Example 6. Reversibility test using dialysis

[0508] To determine whether the binding of compound 9 to a protein is reversible, a reversibility experiment using dialysis was performed as shown in Figure 16. The materials used in the experiment were GeBaFlex-Tube MIDI (D020, 8kDA MWCO, GeBa, Israel), 50 mM Sodium Phosphate buffer (pH 7.4), HRP (Invitrogen, 31490-10 mg) enzyme, MAO-B enzyme (Sigma-Aldrich, M7441), Benzyl amine (Sigma-Aldrich, B5136), Amplex Red reagent (Invitrogen™ A12222), and KDS2010 and Selegiline were used as controls.

[0509] First, 500 µl of MAO-B enzyme (125 µg / ml) was mixed with a 1 µm control or Compound 9, respectively, in an EP tube and incubated on wet ice for 30 minutes. Subsequently, half of the reaction mixture was placed in a GeBaFlex tube and dialysis was performed for 6 hours in 300 ml of sodium phosphate buffer at 4°C, ensuring the semipermeable membrane was submerged. The sodium phosphate buffer was replaced after 3 hours of dialysis. The remaining reaction mixture was used as the non-dialysis group. Before the assay, both the dialysis and non-dialysis groups were diluted 1 / 10 for use in the assay.

[0510] 100 µl of diluted reaction product was added to each well, and 100 µl of a mixed solution of benzylamine (100 mM, 200 µl in 10 ml phosphate buffer; final concentration, 1 mM), Amplex Red reagent (20 mM, 100 µl in 10 ml phosphate buffer; final concentration, 0.1 mM), and HRP (200 U / ml, 100 µl in 10 ml phosphate buffer; final concentration, 2 U / ml) was added to 9.6 ml of 50 mM phosphate buffer (pH 7.4). Afterward, the wells were incubated at 37°C for 60 minutes, and the amount of resorufin produced by Amplex Red was measured using a microplate fluorescence reader (SpectraMax i3 reader, Molecular Devices).

[0511] Experimental results showed that, unlike the KDS2010 substance used as a control, compound 9 did not recover its activity even after dialysis, confirming that it was irreversible (Fig. 18).

[0512]

[0513] Example 7. Dose Lethality Analysis

[0514] To confirm the Dose Lethality of Compound 9, an experiment was performed as shown in Figure 18. Compound 9 used in the experiment was dissolved using two excipients (Excipient 1 and Excipient 2). Excipient 1 was prepared by mixing 10% (w / w) of Labrafil M2125 CS solution with Labrafac lipophile WL1349 solution and sonicating at 30°C for 30 minutes, while 5 mg / mL Methyl Cellulose was used for Excipient 2. The drug calculated based on mg / kg was added to Excipient 1, which accounted for 35% of the total volume, and bath sonicated in a glass vial for 10 minutes. Subsequently, Excipient 2 was added to account for 65% of the total volume and sonicated using an ultrasonic homogenizer.

[0515] As a result of the experiment, as shown in Figure 20, it was confirmed that compound 9 was not fatal for 6 to 10 days after a single oral administration of 10 mpk, 100 mpk, 300 mpk, and 1000 mpk.

[0516]

[0517] Example 8. Analysis of Rheumatoid Arthritis Alleviation Effect

[0518] To confirm the rheumatoid arthritis-relieving effect of compound 9, an experiment was performed as shown in Figure 21.

[0519] Rheumatoid arthritis induction was carried out through two immunization processes. Bovine type II collagen was dissolved in 10 mM acetic acid to a concentration of 2 mg / mL, then emulsified with 2 mg / mL of Complete Freund's adjuvant (CFA) and bovine type II collagen in a 1:1 (v / v) ratio, and 100 µL was injected intradermally into the tails of DBA / 1J mice (first immunization). After 21 days, incomplete Freund's adjuvant (IFA) and bovine type II collagen were emulsified with a 1:1 (v / v) ratio, and 100 µL was injected intradermally into the tails of mice (second immunization). Compound 9 was dissolved in the same excipient as in Example 7 and administered orally daily. After confirming the increase in foot volume, mice were sacrificed, fixed with 10% neutral buffered formalin solution, decalcified, and paraffin embedding to produce 3 μm thick sections. The prepared sections were evaluated by two or more researchers for foot volume increase, synovial proliferation, pannus formation, cartilage damage, and bone erosion using hematoxylin and eosin staining.

[0520] As a result of the experiment, as shown in Figures 22 to 27, daily oral administration of Compound 9 resulted in a weight reduction of approximately 10%, but there was no significant difference between the experimental groups. In addition, it was confirmed that Compound 9 at 0.1 mpk and 1 mpk significantly alleviated symptoms of foot volume increase, synovial proliferation, pannus formation, cartilage damage, and bone erosion caused by rheumatism.

[0521]

[0522] Example 9. Analysis of the effect of alleviating fatty liver symptoms

[0523] To analyze the degree of alleviation of fatty liver symptoms by compound 9, an experiment was conducted as shown in Figure 27.

[0524] First, hepatic fat accumulation was induced in B6 / J mice by feeding them a high-fat diet (Research Diets Inc, D12492) for 7 weeks. Subsequently, compound 9 was dissolved in an excipient as in Example 7 and orally administered at doses of 1 mpk and 10 mpk for 7 days.

[0525] Experimental results, as shown in Figures 29 to 31, confirmed that oral administration of 1 mpk and 10 mpk of Compound 9 resulted in a weight reduction effect of approximately 2%, but no significant difference was observed. When liver tissue perfused with a 4% paraformaldehyde solution was observed using Hematoxylin and Eosin staining, it was confirmed that the area of ​​lipid droplets accumulated in the liver was significantly reduced, and a decreasing trend in the number of droplets was also observed. Through this, the fatty liver alleviating effect of Compound 9 was confirmed.

[0526]

[0527] Example 10. Analysis of liver microbody stability

[0528] To evaluate the metabolic stability of compound 9, a liver microsomal stability test was performed. The materials used in the experiment were NADPH Regeneration system (Promega, V9510), Potassium Phosphate pH 7.4 (Corning, #451201), Human liver microsomes (Corning, #452117), Dog liver microsomes (Corning, #452601), Rat liver microsomes (Corning, #452501), Mouse liver microsomes (Corning, #452701), Chlorpromamide (TRC, C424800) as an internal standard, and Verapamil as a control.

[0529] Four types of liver microsomes (Human, Dog, Rat, Mouse, 0.5 mg / mL) were pre-incubated with 0.1 M phosphate buffer (pH 7.4) at 37°C for 5 minutes. Then, Compound 9 was added at a concentration of 1 μM along with NADPH Regeneration System solution and incubated at 37°C for 30 minutes. Subsequently, to terminate the reaction, an acetonitrile solution containing an internal standard was added, followed by centrifugation (15,000 rpm, 4°C) for 5 minutes. The supernatant was then injected into an LC-MS / MS system for substrate drug analysis. The analysis was performed using an Agilent 1290 infinity series LC system (Agilent, USA) and a Triple Quad 5500 MS (Applied Biosystems, USA). A Kinetex Polar C18 column (2.1 x 100 mm, 2.6 μm particle size, Phenomenex, USA) was used for the HPLC column, and distilled water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid were used as the mobile phase. The elution condition was analyzed using a gradient, and the analysis was performed in the MRM (Multiple Reaction Monitoring) quantitative mode using Analyst software (ver 1.6.3). The evaluation criteria are as shown in Table 5 below.

[0530]

[0531] % Remaining Microsomal Stability Evaluation Criteria > 90% Very stable compounds with a half-life of 3 hours or more 70–90% Stable compounds with a half-life of approximately 1–3 hours 50–70% Relatively stable compounds with a half-life of approximately 30–60 minutes 30–50% Relatively unstable compounds with a half-life of approximately 15–30 minutes Less than 30% Unstable compounds with a half-life of 15 minutes or less that are expected to be rapidly metabolized

[0532] As shown in Table 6 below, the experimental results confirmed that the microbody stability of compound 9 was 9.2%, 10.1%, 6.3%, and 9.9% in Human, Dog, Rat, and Mouse, respectively, with a half-life of less than 15 minutes, indicating very rapid metabolism.

[0533]

[0534] Compound Human-Rat-Mouse Compound 99.210.16.39.9Verapamil(Reference)18.1---

[0535]

[0536] Example 11. Plasma stability analysis

[0537] A plasma stability test was performed to evaluate the stability of compound 9 in plasma. The materials used in the experiment were human plasma (Biochemed, BC23024PSC (Lot number), 3.8% sodium citrate), Chlorpromamide (TRC, C424800) as an internal standard, and procaine and enalapril as controls.

[0538] For the experiment, Compound 9 was added to Human Plasma at a concentration of 10 μM and incubated at 37°C for 0, 30, and 120 minutes, respectively. At each time point, the tube containing the plasma was removed, an acetonitrile solution containing an internal standard was added, and the mixture was vortexed for 5 minutes followed by centrifugation (15,000 rpm, 4°C). The supernatant was then injected into an LC-MS / MS system to evaluate the stability of the drug at each time point based on the amount of remaining substrate. The analysis was performed using an Agilent 1290 infinity series LC system (Agilent, USA) and a Triple Quad 5500 MS (Applied Biosystems, USA). A Kinetex Polar C18 column (2.1 x 100 mm, 2.6 μm particle size, Phenomenex, USA) was used for the HPLC column, and distilled water containing 0.1% formic acid and acetonitrile containing 0.1% formic acid were used as the mobile phase. The elution condition was analyzed using a gradient, and the analysis was performed in MRM (Multiple Reaction Monitoring) quantitative mode using Analyst software (ver 1.6.3).

[0539] As a result of the experiment, as shown in Table 7 below, it was confirmed that compound 9 decomposes in the plasma very quickly (Fig. 33).

[0540]

[0541] % Remaining Compound Human 30 min 120 min Compound 929.95.7 Procaine(Reference)1.6 (5 min)< 1 (10 min) Enalapril(Reference)98.693.1

[0542]

[0543] Example 12. Cardiotoxicity evaluation (hERG assay)

[0544] A cardiotoxicity assessment was performed to confirm the cardiac safety of compound 9. This measured the potential for inhibition of the Human Ether-a-go-go-Related Gene (hERG) potassium channel. The materials used in the experiment were the hERG Fluorescence Polarization Assay (PV5365, Thermofisher Scientific, USA), DMSO (Sigma-Aldrich, USA) as a solvent control, and E-4031 (Invitrogen, USA) as a positive control.

[0545] E-4031 and the test substance were serially diluted (Dilution factor = 3, 16 doses) and dispensed into 384 wells, respectively. Subsequently, Predicto TM The hERG membrane and the Predictor-hERG Tracer mixture solution were added and reacted for 4 hours. The gain setting and the Z-position (optimal distance between the assay plate and the instrument optics) were set using the negative control well, and the G-Factor was fixed by applying a value of 50 mP to the Free Tracer Control wells and setting buffer blanks. The fluorescence intensity at each concentration (Ex: 530 nm / Em: 590 nm) was measured using Synergy Neo (Biotek, USA).

[0546] As a result of verification, the IC of Compound 9 is as shown in Table 8 below. 50 It was confirmed that the value exceeded 75 μM and did not have cardiotoxicity.

[0547]

[0548] Test Material Polarization (mP) IC 50(μM)hERG channel inhibitory potential compounds 9-> 75-

[0549] -: Low inhibition potential, IC 50 ≥ 10 μM or normalized fluorescence intensity over the baseline ≥ 50%+: High potential for inhibition, IC50 50 < 10 μM or normalized fluorescence intensity over the baseline < 50%

[0550] N / A: not applicable

[0551]

[0552] Example 13. Genotoxicity Evaluation (Ames Test)

[0553] To confirm the mutagenic potential of compound 9, a genotoxicity evaluation (Ames assay) was performed by determining whether the test substance induced reverse mutation. For the experiment, the Ames MPF Pneta 2 Mutagenecity Assay Kit (B10-513-S2-P, Xenometrix, Switzerland) and TA (Salmonella typhimurium) strains 98 and 100 (Xenometrix, Switzerland) were used.

[0554] Prior to the experiment, the TA strain was first added to a culture medium supplemented with 1% (v / v) Penicillin / Streptomycin. Subsequently, the strain was cultured for 12–16 hours in a shaking incubator set at 37°C and 250 rpm. Compound 9 was added to six test concentrations (5.1, 15.4, 46.2, 138.8, 416.6, and 1250 μg / mL) in exposure medium containing or without Rat S9 liver extract (metabolic activating enzyme) and reacted at 37°C for 90 minutes. After adding indicator medium and dispensing into 384-well plates, the samples were incubated at 37°C for 24–48 hours. The potential for inducing reversible mutagenicity was evaluated by determining the number of reversible mutations at different concentrations of the test substance, relative to a baseline established by the test substance solvent (solvent control).

[0555] As a result of the experiment, compound 9 did not induce mutations in both TA98 and TA100 strains across most test concentration ranges, regardless of the presence of S9 (Rat S9 liver extract). However, in TA100 (S9+), there is a possibility of inducing genotoxicity at concentrations of 15.4 μg / mL or higher. Therefore, compound 9 was found not to be genotoxic at concentrations below a certain level (Fig. 32).

Claims

1. A compound represented by the following chemical formula 1 or a salt thereof: [Chemical Formula 1] In the above chemical formula 1, The above n is 0 or 1 and; The above R 1 and R 3 Each independently consists of hydrogen, deuterium, halogen, hydroxyl, substituted or unsubstituted C1 to C10 alkyl and Selected from a group consisting of; The above R 2 is hydrogen, deuterium, halogen and Selected from a group consisting of; The above X is carbon; The above X and Y are connected by a double or triple bond; When the above X and Y are connected by a double bond, the above Y is carbon, nitrogen, or oxygen; When the above X and Y are connected by a triple bond, the above Y is carbon or nitrogen; When the above X and Y are connected by a double bond and the above Y is carbon, the above R 4 , R 5 and R 6 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups; When the above X and Y are connected by a double bond and the above Y is nitrogen, the above R 4 and R 5 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups, and R 6 is not present; When X and Y are connected by a double bond and Y is oxygen, R 4 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted alkyl groups having 1 to 10 carbon atoms, and R 5 and R 6 is not present; When the above X and Y are connected by a triple bond and the above Y is carbon, the above R 4 and R 6 ...is not present, and the R5 is hydrogen, deuterium, hydroxyl, or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms; When the above X and Y are connected by a triple bond and the above Y is nitrogen, the above R 4 , R 5 and R 6 is not present; The above R 7 It is hydrogen, deuterium, a substituted or unsubstituted heterocycloalkyl having 2 to 10 carbon atoms, or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms.

2. In Claim 1, The above X and Y are connected by a double or triple bond; When the above X and Y are connected by a double bond, the above Y is nitrogen or oxygen; When the above X and Y are connected by a triple bond, the above Y is carbon; When the above X and Y are connected by a double bond and the above Y is nitrogen, the above R 4 and R 5 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C5 alkyl groups, and R 6 is not present; Where X and Y are connected by a double bond and Y is oxygen, R4 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C5 alkyls, and R 5 and R 6 is not present; In the case where the above X and Y are connected by a triple bond, R 4 and R 6 does not exist, and R 5 is a substituted or unsubstituted alkyl having 1 to 5 carbon atoms; The above R 7 A compound or a salt thereof, which is a substituted or unsubstituted heterocycloalkyl having 2 to 5 carbon atoms or a substituted or unsubstituted alkyl having 1 to 5 carbon atoms.

3. In Claim 1, The above R 1 and R 3 Each independently consists of hydrogen, deuterium, -CH2OH, -I, substituted or unsubstituted C1 to C5 alkyl groups, , , , and Selected from a group consisting of; The above R 2 is hydrogen, deuterium and Selected from a group consisting of; The above R 7 silver or a compound or salt thereof that is -CH3.

4. In Claim 1, The above R 1 and R 3 Each is independently hydrogen, deuterium, substituted or unsubstituted C1 to C5 alkyl and It is one selected from a group consisting of; The above X and Y are connected by a double or triple bond; When the above X and Y are connected by a double bond, Y is nitrogen; When the above X and Y are connected by a triple bond, Y is carbon; When the above X and Y are connected by a double bond, the above R 4 and R 5 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C5 alkyl groups, and R 6 is not present; In the case where the above X and Y are connected by a triple bond, R 4 and R 6 does not exist, and R 5 is a substituted or unsubstituted alkyl having 1 to 5 carbon atoms; The above R 7 A compound or a salt thereof, which is a substituted or unsubstituted heterocycloalkyl having 2 to 5 carbon atoms or a substituted or unsubstituted alkyl having 1 to 5 carbon atoms.

5. In Claim 1, The above R 1 and R 3 Each is independently hydrogen, deuterium, substituted or unsubstituted C1 to C5 alkyl, -I, , , and Selected from a group consisting of; The above R 2 is hydrogen, deuterium and Selected from a group consisting of; The above R 7 silver or a compound or salt thereof that is -CH3.

6. A pharmaceutical composition for the prevention or treatment of metabolic or autoimmune diseases comprising a compound represented by the following chemical formula 1 or a pharmaceutically acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, The above n is 0 or 1 and; The above R 1 and R 3 Each independently consists of hydrogen, deuterium, halogen, hydroxyl, substituted or unsubstituted C1 to C10 alkyl and Selected from a group consisting of; The above R 2 is hydrogen, deuterium, halogen and Selected from a group consisting of; The above X is carbon; The above X and Y are connected by a double or triple bond; When the above X and Y are connected by a double bond, the above Y is carbon, nitrogen, or oxygen; When the above X and Y are connected by a triple bond, the above Y is carbon or nitrogen; When the above X and Y are connected by a double bond and the above Y is carbon, the above R 4 , R 5 and R 6 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups; When the above X and Y are connected by a double bond and the above Y is nitrogen, the above R 4 and R 5 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups, and R 6 is not present; When X and Y are connected by a double bond and Y is oxygen, R 4 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted alkyl groups having 1 to 10 carbon atoms, and R 5 and R 6 is not present; When the above X and Y are connected by a triple bond and the above Y is carbon, the above R 4 and R 6 ...is not present, and the R5 is hydrogen, deuterium, hydroxyl, or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms; When the above X and Y are connected by a triple bond and the above Y is nitrogen, the above R 4 , R 5 and R 6 is not present; The above R 7 It is hydrogen, deuterium, a substituted or unsubstituted heterocycloalkyl having 2 to 10 carbon atoms, or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms.

7. A pharmaceutical composition according to claim 6, wherein the compound of Formula 1 or a pharmaceutically acceptable salt thereof inhibits monoamine oxidase B (MAO-B).

8. A pharmaceutical composition according to claim 7, wherein the compound of Formula 1 or a pharmaceutically acceptable salt thereof is not capable of inhibiting monoamine oxidase A (MAO-A) or hydrogen peroxide.

9. A pharmaceutical composition according to claim 6, wherein the metabolic disease is one or more selected from the group consisting of obesity, fatty liver disease, diabetes, hyperlipidemia, hypertension, hypercholesterolemia, and glucose intolerance.

10. A pharmaceutical composition according to claim 9, wherein the fatty liver disease is one or more selected from the group consisting of alcoholic fatty liver (AFLD), non-alcoholic fatty liver (NAFLD), and non-alcoholic steatohepatitis (NASH).

11. In claim 6, the autoimmune disease is one selected from the group consisting of rheumatoid arthritis, systemic lupus erythematosus, septic shock, allergic asthma, allergic rhinitis, atopic dermatitis, ulcerative colitis, lacrimation, Alzheimer's disease, stroke, arteriosclerosis, restenosis, type 1 diabetes, type 2 diabetes, urticaria, conjunctivitis, psoriasis, systemic inflammatory plaque syndrome, polymyositis, dermatomyositis, nodular polyarthritis, mixed connective tissue disease, Sjögren's syndrome, gout, Parkinson's disease, amyotrophic lateral sclerosis, diabetic retinopathy, multiple sclerosis, Crohn's disease, chronic thyroiditis, Ceriak's disease, myasthenia gravis, pemphigus vulgaris, viral disease, bacterial disease, radiation-induced disorder, arteriosclerosis, hemangioma, angiofibroma, reperfusion impairment, and cardiac hypertrophy. A pharmaceutical composition.

12. A health functional food for the prevention or improvement of metabolic or autoimmune diseases comprising a compound represented by the following chemical formula 1 or a food-grade acceptable salt thereof: [Chemical Formula 1] In the above chemical formula 1, The above n is 0 or 1 and; The above R 1 and R 3 Each independently consists of hydrogen, deuterium, halogen, hydroxyl, substituted or unsubstituted C1 to C10 alkyl and Selected from a group consisting of; The above R 2 is hydrogen, deuterium, halogen and Selected from a group consisting of; The above X is carbon; The above X and Y are connected by a double or triple bond; When the above X and Y are connected by a double bond, the above Y is carbon, nitrogen, or oxygen; When the above X and Y are connected by a triple bond, the above Y is carbon or nitrogen; When the above X and Y are connected by a double bond and the above Y is carbon, the above R 4 , R 5 and R 6 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups; When the above X and Y are connected by a double bond and the above Y is nitrogen, the above R 4 and R 5 Each is independently selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted C1 to C10 alkyl groups, and R 6 is not present; When X and Y are connected by a double bond and Y is oxygen, R 4 is selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, and substituted or unsubstituted alkyl groups having 1 to 10 carbon atoms, and R 5 and R 6 is not present; When the above X and Y are connected by a triple bond and the above Y is carbon, the above R 4 and R 6 ...is not present, and the R5 is hydrogen, deuterium, hydroxyl, or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms; When the above X and Y are connected by a triple bond and the above Y is nitrogen, the above R 4 , R 5 and R 6 is not present; The above R 7 It is hydrogen, deuterium, a substituted or unsubstituted heterocycloalkyl having 2 to 10 carbon atoms, or a substituted or unsubstituted alkyl having 1 to 10 carbon atoms.

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