Pharmaceutical composition comprising 2-bromoaldisin for preventing or treating metabolic disease

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of metabolic diseases, and more specifically, to a pharmaceutical composition for the prevention or treatment of metabolic diseases that is effective for the prevention or treatment of metabolic diseases and is safe for the body with few side effects including adverse reactions, by including a compound represented by Formula 1, wherein R1 is H, F, Cl, Br, or a C1 to C5 alkyl and R2 is H, F, Cl, Br, or a C1 to C5 alkyl, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

Description

Technology Field

[0001] The present invention relates to a pharmaceutical composition for the prevention or treatment of metabolic diseases. Background Technology

[0003] The International Obesity Federation projects that the global obese population will exceed 1 billion by 2030, representing 18% of the total adult population. In Korea, one in three adults is obese, and childhood obesity affects one in nine, which is expected to cause serious social problems. Consequently, there is a growing demand for materials to prevent or treat obesity.

[0004] Childhood obesity is a major cause of diabetes and hypertension due to high levels of blood cholesterol and triglycerides, and 80% of obese children become obese adults, causing various metabolic diseases.

[0005] Obesity is a major cause of various metabolic diseases, such as hyperlipidemia, fatty liver, diabetes, and coronary artery disease (angina, myocardial infarction), and the need to address obesity is increasingly necessary to prevent various diseases.

[0006] Since dietary or exercise regimens recommended for obesity treatment require a lot of time and effort and are difficult to implement, obesity medications are used to ensure a definite weight loss effect. Widely known obesity medications include Xenical and Reductil.

[0007] Xenical is based on orlistat as its main ingredient and is the world's first obesity treatment drug. While it is effective in inhibiting fat absorption, it can cause gastrointestinal side effects such as steatorrhea and abdominal bloating.

[0008] Reductil uses sibutramine as its main ingredient and is effective in suppressing appetite and inducing a sense of fullness, but it causes side effects such as headaches, loss of appetite, and insomnia, and is a product banned in Korea.

[0009] Saxenda, an obesity treatment drug recently introduced in Korea, uses liraglutide as its main ingredient and has the effect of suppressing appetite and increasing satiety by acting similarly to GLP-1, one of the hormones in the body, but it has the problem of causing adverse reactions such as nausea, vomiting, diarrhea, and redness at the injection site.

[0010] As various side effects of synthetic obesity treatments have emerged, there is a demand for the development of obesity treatments utilizing natural active substances that are relatively safe in the body.

[0011] Meanwhile, AMP-activated protein kinase (AMPK) is an enzyme that acts as a sensor to maintain energy homeostasis within cells; it is activated by the binding of AMP when intracellular ATP decreases due to metabolic stress or exercise. Activated AMPK inhibits mechanisms that consume ATP and promotes mechanisms that produce ATP. More specifically, when AMPK is activated, lipolysis and lipogenesis in adipocytes are inhibited, fatty acid oxidation and glucose uptake are promoted in skeletal muscle, and fatty acid and cholesterol synthesis are inhibited while fatty acid oxidation is promoted in the liver. As such, AMPK is closely associated with metabolic diseases such as obesity, diabetes, and hyperlipidemia.

[0012] Accordingly, the inventors of the present invention completed the present invention by conducting research to find a natural bioactive substance that activates AMPK and discovering that 2-bromoaldicine regulates the activity of AMPK and exhibits therapeutic effects on various metabolic diseases. Prior art literature

[0014] (Patent Document 0001) KR 10-2023-0172930 A The problem to be solved

[0015] The present invention aims to provide a pharmaceutical composition for the prevention or treatment of metabolic diseases.

[0016] The present invention aims to provide a health functional food for the prevention or improvement of metabolic diseases.

[0017] The present invention aims to provide a health functional food for improving obesity.

[0018] The present invention aims to provide a health functional food for lowering blood sugar.

[0019] The present invention aims to provide a feed composition for the prevention or improvement of metabolic diseases.

[0020] The present invention aims to provide a feed composition for improving obesity.

[0021] The present invention aims to provide a feed composition for lowering blood sugar.

[0022] The present invention aims to provide a feed composition for reducing body fat. means of solving the problem

[0024] 1. A pharmaceutical composition for the prevention or treatment of metabolic diseases comprising a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0025] [Chemical Formula 1]

[0026]

[0027] In the formula, R1 is H, F, Cl, Br, or a C1 to C5 alkyl, and R2 is H, F, Cl, Br, or a C1 to C5 alkyl.

[0028] 2. A pharmaceutical composition for the prevention or treatment of a metabolic disease, wherein the metabolic disease in 1 above is obesity, diabetes mellitus, hyperlipidemia, hypertension, hypercholesterolemia, hyperinsulinemia, arteriosclerosis, or fatty liver.

[0029] 3. A pharmaceutical composition for the prevention or treatment of metabolic diseases, wherein R1 of Chemical Formula 1 is H or Br and R2 is H.

[0030] 4. A pharmaceutical composition for the prevention or treatment of metabolic diseases, wherein the compound represented by Chemical Formula 1 in 3 above is derived from Stylissa sp. or Callyspongia sp.

[0031] 5. A health functional food for the prevention or improvement of metabolic diseases comprising a compound represented by the following chemical formula 1, a stereoisomer thereof, or a food science-acceptable salt thereof:

[0032] [Chemical Formula 1]

[0033]

[0034] In the formula, R1 is H, F, Cl, Br, or a C1 to C5 alkyl, and R2 is H, F, Cl, Br, or a C1 to C5 alkyl.

[0035] 6. A health functional food for the prevention or improvement of metabolic diseases, wherein the metabolic disease in 5 above is obesity, diabetes, hyperlipidemia, hypertension, hypercholesterolemia, hyperinsulinemia, arteriosclerosis, or fatty liver.

[0036] 7. A health functional food for the prevention or improvement of metabolic diseases, wherein R1 of Chemical Formula 1 is H or Br and R2 is H.

[0037] 8. In the above 7, the compound represented by Chemical Formula 1 is a health functional food for the prevention or improvement of metabolic diseases, derived from Stilisa sponge or pretty sponge.

[0038] 9. A feed composition for the prevention or improvement of metabolic diseases comprising a compound represented by the following chemical formula 1, a stereoisomer thereof, or a feed-grade salt thereof:

[0039] [Chemical Formula 1]

[0040]

[0041] In the formula, R1 is H, F, Cl, Br, or a C1 to C5 alkyl, and R2 is H, F, Cl, Br, or a C1 to C5 alkyl.

[0042] 10. A feed composition for the prevention or improvement of metabolic diseases, wherein the metabolic disease in 9 above is obesity, diabetes mellitus, hyperlipidemia, hypertension, hypercholesterolemia, hyperinsulinemia, arteriosclerosis, or fatty liver.

[0043] 11. A feed composition for the prevention or improvement of metabolic diseases, wherein R1 of Chemical Formula 1 is H or Br and R2 is H.

[0044] 12. A feed composition for the prevention or improvement of metabolic diseases, wherein the compound represented by Chemical Formula 1 in 11 above is derived from a Stillis sponge or a Pretty sponge. Effects of the invention

[0046] The pharmaceutical composition of the present invention is effective in preventing or treating metabolic diseases such as obesity, diabetes, hyperlipidemia, hypertension, hypercholesterolemia, hyperinsulinemia, arteriosclerosis, or fatty liver.

[0047] The pharmaceutical composition of the present invention, by including a natural active substance as an active ingredient, is not only effective in preventing or treating metabolic diseases but is also safe for the body and has few side effects, including adverse reactions.

[0048] The compound represented by Formula 1 of the present invention, its stereoisomers, and pharmaceutically acceptable salts thereof can act as activators of AMPK to regulate metabolism-related mechanisms.

[0049] The compound represented by Formula 1 of the present invention, its stereoisomers, and pharmaceutically acceptable salts thereof can inhibit the differentiation of fat cells and promote the breakdown of fat.

[0050] The health functional food of the present invention is effective in preventing or improving metabolic diseases.

[0051] The health functional food of the present invention is effective in improving obesity and / or lowering blood sugar.

[0052] The health functional food of the present invention is effective in improving obesity and / or lowering blood sugar by including natural active substances as active ingredients, and is also relatively safe for the body.

[0053] The feed composition of the present invention is effective in preventing or improving metabolic diseases.

[0054] The feed composition of the present invention is effective in improving obesity and / or lowering blood sugar.

[0055] The feed composition of the present invention is effective in reducing body fat.

[0056] The feed composition of the present invention is effective in improving obesity, lowering blood sugar, and / or reducing body fat by including natural active substances as active ingredients, and is also relatively safe for the body. Brief explanation of the drawing

[0058] Figure 1 shows the results of confirming molecular docking between 2-bromoaldicine and the AMPK α2 subunit using a molecular modeling tool. Figure 2 shows the fat accumulation inhibitory effect of 2-bromoaldicine. Figure 3 shows the results of observing the interaction between the binding site residue of AMPK and 2-bromoaldicine using a 2D interaction map. Specific details for implementing the invention

[0059] The present invention relates to a pharmaceutical composition for the prevention or treatment of metabolic diseases. More specifically, the invention relates to a pharmaceutical composition for the prevention or treatment of metabolic diseases that is effective for the prevention or treatment of metabolic diseases and is safe for the body, with few side effects including adverse reactions, by comprising a compound represented by Formula 1, wherein R1 is H, F, Cl, Br, or a C1 to C5 alkyl and R2 is H, F, Cl, Br, or a C1 to C5 alkyl, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

[0060] In the present invention, metabolic disease (metabolic syndrome) is a general term for diseases caused by lifestyle habits such as obesity, lack of exercise, or overnutrition, and refers to various diseases related to metabolism. Specifically, the metabolic disease of the present invention includes, but is not limited to, obesity, diabetes, hyperlipidemia, hypertension, hypercholesterolemia, hyperinsulinemia, arteriosclerosis, fatty liver, and complications thereof. The metabolic disease of the present invention may refer to obesity, and may refer to complications such as diabetes, hyperlipidemia, hypertension, hypercholesterolemia, hyperinsulinemia, arteriosclerosis, or fatty liver caused by obesity.

[0061] The compound represented by Formula 1 of the present invention has the following structure:

[0062] [Chemical Formula 1]

[0063]

[0064] In the formula, R1 may be H, F, Cl, Br, or a C1 to C5 alkyl, and R2 may be H, F, Cl, Br, or a C1 to C5 alkyl. Preferably, in the formula, R1 may be H, F, Cl, Br, or methyl, and R2 may be H, F, Cl, Br, or methyl.

[0065] More specifically, Formula 1 of the present invention may have the substituents of Table 1 below.

[0066] 순번 R 1 R 2 1 H H 2 H F 3 H Cl 4 H Br 5 H methyl 6 H ethyl 7 H n-propyl 8 H isopropyl 9 H n-butyl 10 H sec-butyl 11 H tert-butyl 12 H isobutyl 13 F H 14 F F 15 F Cl 16 F Br 17 F methyl 18 F ethyl 19 F n-propyl 20 F isopropyl 21 F n-butyl 22 F sec-butyl 23 F tert-butyl 24 F isobutyl 25 Cl H 26 Cl F 27 Cl Cl 28 Cl Br 29 Cl methyl 30 Cl ethyl 31 Cl n-propyl 32 Cl isopropyl 33 Cl n-butyl 34 Cl sec-butyl 35 Cl tert-butyl 36 Cl isobutyl 37 Br H 38 Br F 39 Br Cl 40 Br Br 41 Br methyl 42 Br ethyl 43 Br n-propyl 44 Br isopropyl 45 Br n-butyl 46 Br sec-butyl 47 Br tert-butyl 48 Br isobutyl 49 methyl H 50 methyl F 51 methyl Cl 52 methyl Br 53 methyl methyl 54 methyl ethyl 55 methyl n-propyl 56 methyl isopropyl 57 methyl n-butyl 58 methyl sec-butyl 59 methyl tert-butyl 60 methyl isobutyl 61 ethyl H 62 ethyl F 63 ethyl Cl 64 ethyl Br 65 ethyl methyl 66 ethyl ethyl 67 ethyl n-propyl 68 ethyl isopropyl 69 ethyl n-butyl 70 ethyl sec-butyl 71 ethyl tert-butyl 72 ethyl isobutyl 73 n-propyl H 74 n-propyl F 75 n-propyl Cl 76 n-propyl Br 77 n-propyl methyl 78 n-propyl ethyl 79 n-propyl n-propyl 80 n-propyl isopropyl 81 n-propyl n-butyl 82 n-propyl sec-butyl 83 n-propyl tert-butyl 84 n-propyl isobutyl 85 isopropyl H 86 isopropyl F 87 isopropyl Cl 88 isopropyl Br 89 isopropyl methyl 90 isopropyl ethyl 91 isopropyl n-propyl 92 isopropyl isopropyl 93 isopropyl n-butyl 94 isopropyl sec-butyl 95 isopropyl tert-butyl 96 isopropyl isobutyl 97 n-butyl H 98 n-butyl F 99 n-butyl Cl 100 n-butyl Br 101 n-butyl methyl 102 n-butyl ethyl 103 n-butyl n-propyl 104 n-butyl isopropyl 105 n-butyl n-butyl 106 n-butyl sec-butyl 107 n-butyl tert-butyl 108 n-butyl isobutyl 109 sec-butyl H 110 sec-butyl F 111 sec-butyl Cl 112 sec-butyl Br 113 sec-butyl methyl 114 sec-butyl ethyl 115 sec-butyl n-propyl 116 sec-butyl isopropyl 117 sec-butyl n-butyl 118 sec-butyl sec-butyl 119 sec-butyl tert-butyl 120 sec-butyl isobutyl 121 tert-butyl H 122 tert-butyl F 123 tert-butyl Cl 124 tert-butyl Br 125 tert-butyl methyl 126 tert-butyl ethyl 127 tert-butyl n-propyl 128 tert-butyl isopropyl 129 tert-butyl n-butyl 130 tert-butyl sec-butyl 131 tert-butyl tert-butyl 132 tert-butyl isobutyl 133 isobutyl H 134 isobutyl F 135 isobutyl Cl 136 isobutyl Br 137 isobutyl methyl 138 isobutyl ethyl 139 isobutyl n-propyl 140 isobutyl isopropyl 141 isobutyl n-butyl 142 isobutyl sec-butyl 143 isobutyl tert-butyl 144 isobutyl isobutyl

[0068] Among the compounds represented by Chemical Formula 1 of the present invention, the compounds in which R1 and R2 are H may be referred to as aldisin or 6,7-dihydropyrrolo[2,3-c]azepine-4,8(1H,5H)-dione.

[0069] Among the compounds represented by Chemical Formula 1 of the present invention, the compound in which R1 is H and R2 is Br may be referred to as 2-bromoaldisin or 2-bromo-6,7-dihydropyrrolo[2,3-c]azepine-4,8(1H,5H)-dione.

[0070] Aldicin or 2-bromoaldicin can be chemically synthesized or extracted from natural products such as Stylissa sp. or Callyspongia sp. When extracted from natural products, extraction can be performed by conventional methods known in the art. More specifically, extraction can be performed using water or an organic solvent, and the organic solvent may be, but is not limited to, methanol, ethanol, isopropanol, butanol, ethylene, acetone, hexane, ether, chloroform, ethyl acetate, butyl acetate, dichloromethane, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), 1,3-butylene glycol, propylene glycol, or a mixture thereof. Since the degree of extraction and loss of active ingredients may vary depending on the organic solvent used for extraction, an appropriate organic solvent may be selected and used based on basic knowledge in the art. The extraction method is not particularly limited and, for example, cold maceration extraction, ultrasonic extraction, reflux cooling extraction, etc., can all be used. In addition, a separation process by various types of chromatography (chromatography based on size, charge, hydrophobicity, or affinity) may be additionally included.

[0071] A pharmaceutically acceptable salt of the compound of the present invention refers to a salt in a form that can be used pharmaceutically among salts in which cations and anions are bonded by electrostatic attraction, and which has the desirable pharmacological activity of the parent compound. The pharmaceutically acceptable salt of the compound of the present invention may be an acid addition salt or a metal salt.

[0072] Acid addition salts can be formed from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromide, hydroiodide, nitrous acid, or phosphoric acid, and non-toxic organic acids such as aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxyalkanoates and alkandioates, aromatic acids, and aliphatic and aromatic sulfonic acids. These pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, fluorides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprates, heptanoates, propyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, malieates, butin-1,4-dioate, nucleus-1,6-dioate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, It may include terephthalate, benzenesulfonate, ethylsulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, or mandelate. For example, an acid addition salt may be obtained by dissolving a compound in an excess amount of aqueous acid solution and precipitating the salt using an aqueous organic solvent, such as methanol, ethanol, acetone, or acetonitrile.

[0073] Metal salts can be sodium, potassium, or calcium salts. Metal salts can be prepared using a base, for example, alkali metal or alkaline earth metal salts can be obtained by dissolving a compound in an excess amount of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved compound salt, and evaporating and / or drying the filtrate.

[0074] These salts can be prepared by conventional chemical methods from compounds having a base or acid function, and the corresponding acid or base.

[0075] The pharmaceutical composition of the present invention may be provided as a pharmaceutical composition comprising an active ingredient alone or comprising one or more pharmaceutically acceptable carriers, excipients, or diluents. The carriers, excipients, or diluents that may be included in the pharmaceutical composition of the present invention may be, but are not limited to, lactose, dextrose, sucrose, dextrin, maltodextrin, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, or mineral oil.

[0076] The route of administration of the pharmaceutical composition of the present invention may be oral, intravenous, intramuscular, intra-arterial, intramedullary, intradural, intracardiac, transdermal, subcutaneous, intraperitoneal, intranasal, intestinal, local, sublingual, or rectal, but is not limited thereto.

[0077] The composition of the present invention can be administered orally or parenterally.

[0078] When administering the composition of the present invention parenterally, it is preferable to select an injection method such as topical application to the skin, intraperitoneal injection, rectal injection, subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection, but is not limited thereto.

[0079] The pharmaceutical composition of the present invention may be a solid dosage form for oral administration, such as a tablet, pill, powder, granule, or capsule.

[0080] The pharmaceutical composition of the present invention may be a liquid formulation for oral administration, such as a suspension, liquid formulation, emulsion, or syrup.

[0081] The pharmaceutical composition of the present invention may be a formulation for parenteral administration, such as a sterile aqueous solution, a non-aqueous solvent, a suspension, an emulsion, a lyophilized formulation, or a suppository.

[0082] The pharmaceutical composition of the present invention may be administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment.

[0083] The pharmaceutically effective amount of the pharmaceutical composition of the present invention can be determined based on factors including the type and severity of the disease, the activity of the drug, the patient's sensitivity to the drug, the time of administration, the route of administration and elimination rate, the duration of treatment, and concomitant drugs, as well as other factors well known in the medical field, and can be appropriately selected by those skilled in the art.

[0084] The pharmaceutical composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered as a single or multiple doses, which can be easily determined by a person skilled in the art.

[0086] The present invention provides a health functional food for the prevention or improvement of metabolic diseases comprising a compound represented by Formula 1, a stereoisomer thereof, or a food-grade acceptable salt thereof.

[0087] The health functional food for the prevention or improvement of metabolic diseases according to the present invention may specifically be a health functional food for the improvement of obesity.

[0088] The health functional food for the prevention or improvement of metabolic diseases according to the present invention may specifically be a health functional food for lowering blood sugar.

[0089] The health functional food of the present invention refers to a food manufactured and / or processed in various forms to provide functional benefits useful to the human body.

[0090] The health functional food of the present invention may be included in various foods or medicines known in the art.

[0091] There are no specific restrictions on the types of food that may include the health functional food of the present invention. For example, the health functional food of the present invention may be included in meat, sausage, bread, chocolate, candies, snacks, confectionery, pizza, ramen, other noodles, chewing gum, dairy products including ice cream, various soups, beverages, tea, drinks, alcoholic beverages, and vitamin complexes.

[0092] The health functional food of the present invention includes all forms such as functional food, nutritional supplement, health food, and food additives, and these types of food can be manufactured in various forms according to conventional methods known in the art. For example, as a health food, it may be manufactured in the form of a liquid drink for consumption, or consumed by granulation, encapsulation, spherical tablet (pill, etc.), and powdering, or may be manufactured in the form of powder, capsule, soft capsule, tablet, gum, or adhesive type liquid composition for consumption. In addition, the health functional food of the present invention may be added to functional foods such as beverages (including alcoholic beverages), fruits and their processed foods (e.g., canned fruit, bottled fruit, jam, marmalade, etc.), fish, meat and their processed foods (e.g., ham, sausage, corned beef, etc.), breads and noodles (e.g., udon, buckwheat noodles, ramen, spaghetti, macaroni, etc.), fruit juice, various drinks, cookies, malt syrup, dairy products (e.g., butter, cheese, etc.), edible vegetable oils and fats, margarine, vegetable protein, retort foods, frozen foods, medicines, and various seasonings (e.g., soybean paste, soy sauce, sauces, etc.).

[0093] The health functional food of the present invention may further include ingredients that are typically added during food manufacturing, provided that such addition does not fall outside the scope of the ultimate purpose of the present invention, and may further include, for example, proteins, carbohydrates, fats, nutrients, seasonings, and flavorings.

[0094] The health functional food of the present invention may additionally contain various nutritional supplements, vitamins, electrolytes, flavoring agents, coloring agents, 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.

[0095] The health functional food of the present invention may contain fruit pulp for the production of natural fruit juice, fruit juice beverages, and vegetable beverages. These ingredients may be used independently or in combination.

[0097] The present invention provides a feed composition for the prevention or improvement of metabolic diseases comprising a compound represented by Formula 1, a stereoisomer thereof, or a feed-grade salt thereof.

[0098] The feed composition for the prevention or improvement of metabolic diseases of the present invention may specifically be a feed composition for the improvement of obesity.

[0099] The feed composition for the prevention or improvement of metabolic diseases of the present invention may specifically be a feed composition for lowering blood sugar.

[0100] The feed composition for the prevention or improvement of metabolic diseases of the present invention may specifically be a feed composition for reducing body fat.

[0101] The feed composition of the present invention refers to a prescribed diet or a single meal for animals to consume and digest, or the components thereof.

[0102] The feed composition of the present invention may be intended for feeding to animals, specifically reptiles, fish, birds, or mammals.

[0103] The feed composition of the present invention may be intended for feeding to livestock or aquatic organisms that are suitable for rearing due to their domesticated wild habits and can contribute to increasing farm income, as defined in Article 2, Paragraph 1 of the Livestock Act and each subparagraph of Article 2 of the Enforcement Rule of the same Act.

[0104] The feed composition of the present invention may be intended for feeding to pets.

[0106] Examples

[0107] Experimental Example 1: In silico molecular docking experiment between 2-bromoaldicine and AMPK α2 subunit

[0108] Molecular docking is a method for simulating intermolecular interactions that can reproduce the three-dimensional movement and interactions between molecules in an aqueous solution in silico. Additionally, by calculating the binding energies between molecules, it is possible to predict sites with a high probability of binding between molecular structures.

[0109] The stereostructure of the AMPK α2 subunit was obtained from the Protein Data Bank (PDB) database, and the stereostructure of 2-bromoaldicine was obtained from the PubChem database. Molecular docking between the AMPK α2 subunit and 2-bromoaldicine was performed using a molecular modeling tool. As a result, as shown in Figure 1, it was verified that 2-bromoaldicine stably binds within the binding site of the AMPK α2 subunit, and the docking energy value was measured to be -7.12 kcal / mol.

[0111] Experimental Example 2: Measurement of the fat accumulation inhibitory effect of 2-bromoaldicine

[0112] To analyze the inhibitory effect of 2-bromoaldicin on fat accumulation, adipocyte progenitor cells were differentiated, and then Oil Red O staining was performed.

[0113] To evaluate the effect of 2-bromoaldicine on the differentiation and growth of adipocytes induced by MDI (Methylisobutylxanthine), 3T3-L1 adipocyte precursor cells were seeded into a 24-well plate and cultured in DMEM (Dulbecco-modified Eagle medium) supplemented with 10% Bovine Calf Serum (BCS) and 10 ml / L of Antibiotic-Antimycotic at 37°C in a 10% CO2 incubator until they grew to a confluent state.

[0114] To differentiate confluent 3T3-L1 cells into adipocytes, they were cultured for 48 hours in DMEM medium supplemented with MDI {0.5 mM isobutylmethylxanthine, 1 μM dexamethasone, and 10 μg / ml insulin}, then cultured for 48 hours in DMEM medium mixed with 10 μg / ml insulin, and then cultured for 48 hours in a culture medium supplemented with 10% fetal bovine serum.

[0115] Starting from the first day of differentiation of 3T3-L1 cells with the addition of MDI, 2-bromoaldicin was added to the culture medium at concentrations of 5 to 40 μM whenever the medium was changed at 48-hour intervals. 2-bromoaldicin was dissolved in DMSO for use. After culturing for a total of 6 days, the culture medium was removed upon completion of differentiation, and lipid globules contained in the differentiated adipocytes were stained. For this purpose, cells were fixed with a 10% formalin solution for 15 minutes, washed with PBS, and stained with Oil Red O solution for 20 minutes. After staining was complete, the cells were washed four times with PBS, dissolved in isopropanol (2-propanol), and the Optical Density (OD) value was measured at 515 nm.

[0116] As a result of treating 3T3-L1 cells, which are preadipocytes, with 2-bromoaldicin, it was confirmed that the amount of intracellular lipid accumulation decreased in a concentration-dependent manner due to 2-bromoaldicin treatment, as shown in Figure 2. In Figure 2, Lane 1 represents the untreated control group, Lane 2 represents the MDI-treated group, Lane 3 represents the group treated with MDI and 2-bromoaldicin 5 μM, Lane 4 represents the group treated with MDI and 2-bromoaldicin 10 μM, Lane 5 represents the group treated with MDI and 2-bromoaldicin 20 μM, and Lane 6 represents the group treated with MDI and 2-bromoaldicin 40 μM.

[0118] Experimental Example 3: Confirmation of intermolecular interactions formed within the binding structure of 2-bromoaldicine and AMPK

[0119] To confirm the intermolecular interactions formed within the binding structure of 2-bromoaldicine and AMPK, the interactions between the binding site residues of AMPK and 2-bromoaldicine were observed using a 2D interaction map after molecular docking. As a result, as shown in Figure 3, it was found that the carbonyl group of 2-bromoaldicine forms hydrogen bonds with the LYS29 and LYS31 residues of the AMPK protein, and the hydrogen bonded to the oxygen of the lactam group and the nitrogen of the pyrrole group of 2-bromoaldicine forms hydrogen bonds with the ARG83 and ASP88 residues of the AMPK protein, respectively. Additionally, it was found that the pyrrole group of 2-bromoaldicine further forms pi-cation interactions with the ARG83 residue of the AMPK protein. From this, it was confirmed that the main reason for the strong binding affinity between 2-bromoaldicine and AMPK is the hydrogen bond formed between the carbonyl group and the pyrrole group of 2-bromoaldicine, and that Br and neighboring hydrogens that do not interact with the AMPK protein can be substituted with other functional groups.

Claims

Claim 1 A pharmaceutical composition for the prevention or treatment of metabolic diseases comprising a compound represented by the following chemical formula 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the metabolic disease is obesity, diabetes mellitus, hyperlipidemia, hypertension, hypercholesterolemia, hyperinsulinemia, arteriosclerosis, or fatty liver: [Chemical Formula 1] In the formula, R1 is Br and R2 is H. Claim 2 delete Claim 3 delete Claim 4 A pharmaceutical composition according to claim 1, wherein the compound represented by Chemical Formula 1 is derived from Stylissa sp. or Callyspongia sp. Claim 5 A food composition for the prevention or improvement of metabolic diseases comprising a compound represented by the following chemical formula 1, a stereoisomer thereof, or a food-grade salt thereof, wherein the metabolic disease is obesity, diabetes mellitus, hyperlipidemia, hypertension, hypercholesterolemia, hyperinsulinemia, arteriosclerosis, or fatty liver; food composition: [Chemical Formula 1] In the formula, R1 is Br and R2 is H. Claim 6 delete Claim 7 delete Claim 8 A food composition according to claim 5, wherein the compound represented by Chemical Formula 1 is derived from a Stilisa sponge or a pretty sponge. Claim 9 A feed composition for the prevention or improvement of metabolic diseases comprising a compound represented by the following chemical formula 1, a stereoisomer thereof, or a feed-grade salt thereof, wherein the metabolic disease is obesity, diabetes mellitus, hyperlipidemia, hypertension, hypercholesterolemia, hyperinsulinemia, arteriosclerosis, or fatty liver; feed composition: [Chemical Formula 1] In the formula, R1 is Br and R2 is H. Claim 10 delete Claim 11 delete Claim 12 A feed composition according to claim 9, wherein the compound represented by Chemical Formula 1 is derived from a Stillis sponge or a Pretty sponge.

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