WO2019004492A1 - Composition for preventing or treating obesity or lipid-related metabolic diseases containing acrylamide-based compounds as active ingredients - Google Patents

Composition for preventing or treating obesity or lipid-related metabolic diseases containing acrylamide-based compounds as active ingredients Download PDF

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Publication number
WO2019004492A1
WO2019004492A1 PCT/KR2017/006732 KR2017006732W WO2019004492A1 WO 2019004492 A1 WO2019004492 A1 WO 2019004492A1 KR 2017006732 W KR2017006732 W KR 2017006732W WO 2019004492 A1 WO2019004492 A1 WO 2019004492A1
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present
lipid
obesity
compound
methylacrylamide
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PCT/KR2017/006732
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French (fr)
Korean (ko)
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최상윤
김상희
최인욱
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한국식품연구원
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Priority to PCT/KR2017/006732 priority Critical patent/WO2019004492A1/en
Publication of WO2019004492A1 publication Critical patent/WO2019004492A1/en

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/121—Heterocyclic compounds containing oxygen or sulfur as hetero atom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • the present invention relates to the use of an acrylamide-based compound and its derivatives for preventing or treating or ameliorating obesity or lipid-related metabolic diseases, and more particularly to a method for preventing or treating (E) -3 Prevention or treatment of obesity or lipid-related metabolic diseases comprising, as an active ingredient, (benzo [d] [1,3] dioxol-5-yl) -N- (4-hydroxyphenethyl) acrylamide and derivatives thereof ≪ / RTI >
  • obesity is not only a major cause of heart disease, but also causes cancer, hypertension, diabetes, and degenerative arthritis.
  • health expenditures related to obesity amount to 16 trillion won.
  • the World Obesity Federation warned that within the next 20 years, one-third of the world's population would become obese (body mass index 30 kg / m 2 ) if the current obesity trend is increasing.
  • the body mass index is 25 kg
  • the obesity population of more than 2 / m 2 is 30.7% in 2008.
  • the proportion of highly obese people with a body mass index of 30 kg / m 2 or more increased from 2.3% in 1998 to 4.1% in 2008, nearly doubling.
  • the global anti-obesity material market is more than US $ 200 billion, and direct sales of medical anti-obesity drugs in the world's seven major markets such as the US, Europe and Japan are growing rapidly from US $ 512 million in 2010 to US $ 3.2 billion in 2018
  • the three most commonly used anti-obesity drugs, orlistat, sibutramine, and sertraline are all reported to have side effects. Development is proceeding fiercely.
  • Fat is composed of fatty acids and glycerol.
  • ACC acetyl-CoA carboxylase
  • an enzyme that plays an essential role in the early stage of fatty acid synthesis by cells induces carboxylation of acetyl-CoA Promotes the production of N-CoA (malonyl-CoA).
  • Fatty acid synthesis is carried out using malonyl-CoA as a raw material by an enzyme of molecular weight 250 kDa called FAS (fatty acid synthase). Therefore, FAS or ACC inhibitor can be expected to reduce obesity by reducing fat production.
  • PPAR- ⁇ is a glitazone receptor that regulates fatty acid storage and glucose metabolism
  • sirt-1 sirtuins
  • resveratrol is a kind of stilbene present in nature, and it is known that phytoalexin, which is naturally biosynthesized in order to combat the attack of pathogens such as bacteria and fungi in some plants, has anti-obesity effect ( European Journal of Pharmacology , Volume 635, Issues 1-3, 10 June 2010, Pages 1-8).
  • phytoalexin which is naturally biosynthesized in order to combat the attack of pathogens such as bacteria and fungi in some plants, has anti-obesity effect.
  • anti-obesity effect European Journal of Pharmacology , Volume 635, Issues 1-3, 10 June 2010, Pages 1-8.
  • Patent Document 0001 Korean Patent Publication No. 10-2010-0088887
  • Patent Document 0002 Korean Patent Publication No. 10-2004-0036112
  • Another object of the present invention is to provide a pharmaceutical composition, a health functional food, a cosmetic composition and a feed additive for preventing or treating / improving obesity and / or lipid-related metabolic diseases.
  • the present invention provides the use of an acrylamide-based compound and its derivatives for preventing or treating / improving obesity or lipid-related metabolic diseases.
  • the present invention provides a pharmaceutical composition for preventing or treating obesity or lipid-related metabolic diseases, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
  • R is , , , , , , , And ≪ / RTI >
  • the present invention also provides a health functional food for preventing or ameliorating an obesity or lipid-related metabolic disease comprising the compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a cosmetic composition for preventing or ameliorating an obesity or lipid-related metabolic disease, which comprises the compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a feed additive for preventing or ameliorating an obesity or lipid-related metabolic disease, which comprises the compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also provides a method for treating obesity or lipid-related metabolic diseases, comprising administering to a subject in need thereof a compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a use for a pharmaceutical composition for preventing or treating obesity or a lipid-related metabolic disease of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a use for a health functional food for preventing or ameliorating obesity or a lipid-related metabolic disease of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a use for a cosmetic composition for preventing or treating obesity or a lipid-related metabolic disease of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides a use for a feed additive for preventing or ameliorating obesity or lipid-related metabolic diseases of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
  • the present invention provides a novel material having an anti-obesity effect and a lipid-related metabolic disease prevention and treatment effect.
  • the acrylamide-based compound of the present invention inhibits adipocyte differentiation without cytotoxicity, inhibits the expression of FAS which is a factor associated with obesity and lipid metabolism, inhibits the activity and expression of PPAR- ⁇ , Fat mass, and blood triglyceride content without exhibiting toxicity, and has excellent anti-obesity effect and lipid metabolism improving effect. Therefore, the compound of the present invention is useful as a material capable of preventing, treating and improving obesity or lipid-related metabolic diseases, and can be used in various industrial fields such as medicines, health functional foods, cosmetics, feed additives and the like.
  • FIG. 1 shows the results of measuring the cell survival rate of 3T3-L1 cells treated with 50 ⁇ M of each of the compounds A, B and C in order to evaluate the cytotoxicity of the acrylamide compounds of the present invention.
  • FIG. 2 is a graph showing the inhibition of adipocyte differentiation according to treatment of 3T3-L1 cells at 50 ⁇ M concentration of each of the compounds A, B and C of the present invention in order to evaluate the effect of the acrylamide compound of the present invention on adipocyte differentiation This is a result.
  • FIG. 3 shows the result of measuring the degree of inhibition of adipocyte differentiation by treatment with 3T3-L1 cells of the compound A of the present invention (12.5, 25, 50 ⁇ M).
  • FIG. 4 shows photographs of 3T3-L1 cells stained with Oil Red O after treatment with 3T3-L1 cells of Compound A of the present invention (12.5, 25, 50 ⁇ M).
  • FIG. 5 shows the results of western blot analysis of the degree of intracellular FAS expression by treatment with 3T3-L1 cells of the compound A of the present invention (12.5, 25, 50 ⁇ M).
  • FIG. 6 shows the results of measuring the degree of PPAR- ⁇ activity by treatment with 3T3-L1 cells of Compound A of the present invention (12.5, 25, 50 ⁇ M).
  • FIG. 7 shows the results of Western blot analysis of intracellular PPAR-gamma expression by treatment with 3T3-L1 cells of the compound A of the present invention (12.5, 25, 50 ⁇ M).
  • FIG. 8 shows photographs of animals after 12 weeks of feeding Compound A of the present invention together with a high fat diet system (Low fat: a general diet group, high fat: high fat diet group, high fat + compound A: Compound A feed group).
  • a high fat diet system Low fat: a general diet group, high fat: high fat diet group, high fat + compound A: Compound A feed group.
  • FIG. 9A is a photograph showing a microscopic observation of the cell size of kidney fat tissue in a mouse fed with the compound A of the present invention in combination with a high fat diet system
  • FIG. 9B is a photograph of a mouse fed with Compound A of the present invention (Low fat: high fat: high fat + high fat + compound A).
  • FIG. 10 shows the result of measuring the concentration of triglycerides in the serum of mice fed with the compound A of the present invention together with the high fat diet (high fat: high fat: high fat + compound A, high fat + Resveratrol: Resveratrol with high fat diet.
  • FIG. 11 shows the results of measurement of ALT activity in blood of a mouse fed with Compound A of the present invention together with a high fat diet method (LF: general dietary group, HF: high fat dietary group, HF + compound A: Salary group, HF + resveratrol: resveratrol salary group with high fat diet).
  • LF general dietary group
  • HF high fat dietary group
  • HF + compound A Salary group
  • HF + resveratrol resveratrol salary group with high fat diet
  • FIG. 12 shows the results of measuring the AST activity in blood of a mouse fed with the compound A of the present invention in combination with the high fat diet method (LF: general dietary group, HF: high fat dietary group, HF + compound A: Salary group, HF + resveratrol: resveratrol salary group with high fat diet).
  • LF general dietary group
  • HF high fat dietary group
  • HF + compound A Salary group
  • HF + resveratrol resveratrol salary group with high fat diet
  • the present invention relates to a pharmaceutical composition for preventing or treating obesity or lipid-related metabolic diseases comprising an acrylamide-based compound or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the acrylamide-based compound of the present invention is a compound represented by the following general formula (1).
  • R is , , , , , , , And ≪ / RTI >
  • the acrylamide-based compound according to the present invention has an effect of preventing or treating obesity and / or lipid-related metabolic diseases.
  • an anti-obesity animal test is superior to resveratrol, which is a positive control, and has effects of reducing weight gain and decreasing weight of fat tissue in a concentration-dependent manner and thus has a therapeutic and preventive effect on obesity.
  • obesity which is a disease to be prevented or treated by the composition of the present invention, refers to a state in which fat cells multiply and multiply in the body due to metabolic disturbance and, as a result, fat accumulates excessively.
  • the number of adipocytes and the volume of the adipocytes increase, resulting in an increase in the mass of the adipose tissue.
  • Obesity at the cellular level means an increase in the number and volume of adipocytes due to promotion of proliferation and differentiation of adipocytes.
  • differentiation in the present invention refers to a phenomenon in which the structure or function of a cell is specialized and differentiated while it is growing and proliferating, that is, the cell or tissue of the organism is changed in shape or function It is said that.
  • a relatively simple system is separated into two or more qualitatively different systems. For example, there is a qualitative difference between the parts of a biological system that were almost homogeneous at first, such as the distinction of heads or trunks between the eggs that were homogeneous at first in the development of an individual, or the distinction of cells such as muscle cells or nerve cells
  • a state in which a difference occurs or is divided into qualitatively distinguishable zones or partial systems as a result is called eruption.
  • the compound according to the present invention reduces fatty acid synthase (FAS) expression in adipocytes, inhibits fatty acid production, and inhibits PPAR-gamma (peroxisome proliferator-activated receptor ) And the expression of the protein.
  • PPAR- ⁇ is a glitazone receptor that regulates fatty acid storage and glucose metabolism and promotes fat absorption to induce obesity. When it inhibits its activity, it treats obesity and lipid-related metabolic diseases . ≪ / RTI >
  • lipid-related metabolic diseases in the present invention refers to hyperlipidemia, dyslipidemia, arteriosclerosis, hepaticopathy, nonalcoholic fatty liver, type 2 diabetes and metabolic syndrome.
  • the compounds according to the present invention can be prepared by conducting an acid amide condensation method using (E) -3,4-methylenedioxincinamic acid ((E) -3,4- (methylenedioxy) cinnamic acid) have.
  • the compound is a compound (E) -3- (benzo [d] [1,3] dioxol-5-yl) -N- (4-hydroxyphenethyl ) Acrylamide (Compound A) (E) -3- (benzo [d] [1,3] dioxol-5-yl) -N- (4-hydroxyphenethyl) acrylamide.
  • the compound is (E) -3- (benzo [d] [1,3] dioxol-5-yl) -N- (p- tolyl) acrylamide (E) -3- (benzo [d] [1,3] dioxol-5-yl) -N- (p-tolyl) acrylamide (Compound B).
  • pharmaceutically acceptable salts thereof in the present specification means salts prepared from inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogenphosphate, phosphoric acid, Or a pharmaceutically acceptable salt thereof with an organic acid such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin) To form salts of these acids, or to react with alkali metal ions such as sodium and potassium to form metal salts thereof, or to form ammonium salts such as ammonium ions The reaction is also meant to form a pharmaceutically acceptable salt thereof of different types.
  • compositions of the present invention may be of various oral or parenteral formulations.
  • buffers e.g., saline or PBS
  • antioxidants e.g., bacteriostats
  • chelating agents e.g., EDTA or glutathione
  • fillers e.g., extenders, binders, adjuvants Aluminum hydroxide
  • suspending agents thickening agents, disintegrating agents or surfactants, diluents or excipients.
  • Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain one or more excipients such as starches (corn starch, wheat starch, rice starch, potatoes Starch and the like), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose, methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose - It is prepared by mixing cellulose or gelatin. For example, tablets or tablets may be obtained by combining the active ingredient with a solid excipient, then milling it, adding suitable auxiliaries, and processing the mixture into granules.
  • excipients such as starches (corn starch, wheat starch, rice starch, potatoes Starch and the like), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol,
  • lubricants such as magnesium stearate, talc, and the like may also be used.
  • Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups.
  • various excipients such as wetting agents, sweeteners, fragrances or preservatives are included .
  • crosslinked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may optionally be added as a disintegrant, and may further include an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and an antiseptic agent .
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations or suppositories.
  • non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like.
  • injectable esters such as ethyl oleate, and the like.
  • As a base for suppositories witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used.
  • composition of the present invention may be administered orally or parenterally, and may be administered externally for parenteral administration; Intraperitoneal, rectal, intravenous, intramuscular, subcutaneous, intrauterine, or intracerebral injection; Percutaneous administration agents; Or in the form of a nasal inhaler, according to methods known in the art.
  • suitable carriers for injectables include, but are not limited to, solvents or dispersion media containing water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycol, etc.), mixtures thereof and / or vegetable oils . More preferably, suitable carriers include isotonic solutions such as Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) containing triethanolamine, or sterile water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose Etc. may be used.
  • solvents or dispersion media containing water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycol, etc.), mixtures thereof and / or vegetable oils . More preferably, suitable carriers include isotonic solutions such as Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) containing triethanolamine, or
  • injections may in most cases additionally include isotonic agents, such as sugars or sodium chloride.
  • transdermal dosage forms examples include ointments, creams, lotions, gels, solutions for external use, pastes, liniments, and air lozenges.
  • transdermal administration means that the pharmaceutical composition is locally administered to the skin, so that an effective amount of the active ingredient contained in the pharmaceutical composition is delivered into the skin.
  • the compounds according to the invention can be prepared from the pressurized pack or sprayer using a suitable propellant, for example dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. It can be conveniently delivered in aerosol spray form.
  • a suitable propellant for example dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases.
  • the dosage unit may be determined by providing a valve that delivers a metered amount.
  • gelatin capsules and cartridges for use in an inhaler or insufflator may be formulated to contain a compound, and a powder mixture of a suitable powder base such as lactose or starch.
  • Formulations for parenteral administration are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, commonly known in all
  • composition of the present invention is administered in a pharmaceutically effective amount.
  • pharmaceutically effective amount means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including co-administered drugs, and other factors well known in the medical arts.
  • the composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses.
  • the total effective amount of the composition of the present invention may be administered to a patient in a single dose and administered by a fractionated treatment protocol administered over a long period in multiple doses . It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.
  • the dosage of the pharmaceutical composition of the present invention varies depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and disease severity.
  • the daily dosage is such that, when parenterally administered, it is preferably administered in an amount of 0.01 to 50 mg, more preferably 0.1 to 30 mg per kg of body weight per day on the basis of the compound according to the present invention,
  • the compound according to the present invention is preferably administered in an amount of 0.01 to 250 mg, more preferably 0.01 to 100 mg, and even more preferably 0.01 to 10 mg per kg of body weight per day on a daily basis, Lt; / RTI >
  • the dosage may be varied depending on the route of administration, the severity of obesity, sex, weight, age, etc. Therefore, the dosage is not limited to the scope of the present invention by any means.
  • the pharmaceutical composition of the present invention can also be provided as a formulation of the external preparation containing the compound according to the present invention as an active ingredient.
  • the pharmaceutical composition of the present invention may further contain at least one selected from the group consisting of fatty substances, organic solvents, solubilizers, thickening and gelling agents, softening agents, antioxidants, suspending agents, stabilizers, foaming agents, Such as water, an ionic emulsifier, a nonionic emulsifier, a filler, a sequestering agent, a chelating agent, a preservative, a vitamin, a blocker, a wetting agent, a necessary oil, a dye, a pigment, a hydrophilic activator, Such as any other ingredients conventionally used in the field of skin science.
  • the components can also be introduced in amounts commonly used in the field of dermatology.
  • the pharmaceutical composition of the present invention when provided as an external preparation for skin, it may be a formulation such as, but not limited to, an ointment, a patch, a gel, a cream or a spray.
  • the present invention provides a use for a pharmaceutical composition for preventing or treating obesity or a lipid-related metabolic disease of a compound represented by the formula 1 of the present invention or a pharmaceutically acceptable salt thereof, , A method for treating obesity or a lipid-related metabolic disease comprising administering to a subject in need thereof a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
  • the term " necessary entity" refers to a mammal that is the subject of treatment, observation or experimentation, preferably a human.
  • therapeutically effective amount refers to an amount of the active ingredient that induces a biological or medical response in a tissue system, animal or human, as contemplated by a researcher, veterinarian, refers to the amount of the pharmaceutical composition, which amount includes an amount that induces the relief of the symptoms of the disease or disorder being treated. It will be apparent to those skilled in the art that the therapeutically effective dose and the number of administrations of the active ingredient of the present invention will vary depending on the desired effect.
  • the optimal dosage to be administered can therefore be readily determined by those skilled in the art and will depend upon the nature of the disease, the severity of the disease, the amount of active and other ingredients contained in the composition, the type of formulation, and the age, , Sex and diet, time of administration, route of administration and rate of administration of the composition, duration of treatment, concurrent administration of the drug, and the like.
  • the treatment method of the present invention in the case of an adult, it is preferable to administer the compound of the present invention at a dose of 0.01 mg / kg to 250 mg / kg once to several times a day.
  • the composition comprising the compound of formula (I) of the present invention as an active ingredient can be administered orally, rectally, intravenously, intraarterially, intraperitoneally, intramuscularly, intrasternally, transdermally, topically, ≪ / RTI > can be administered in a conventional manner.
  • the present invention relates to a health functional food for preventing or ameliorating an obesity or lipid-related metabolic disease, which comprises a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the health functional food of the present invention can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, and circles for the purpose of preventing and improving obesity or lipid-related metabolic diseases.
  • health functional food used in the present invention refers to foods manufactured and processed using raw materials or ingredients having useful functions in accordance with Law No. 6727 on health functional foods, To be used for the purpose of obtaining a beneficial effect for health use such as controlling nutrients or physiological action.
  • the health functional foods of the present invention may contain conventional food additives and, unless otherwise specified, whether or not they are suitable as food additives are classified according to the General Rules for Food Additives approved by the Food and Drug Administration, Standards and standards.
  • Examples of the items listed in the above-mentioned "food additives” include chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; Natural additives such as persimmon extract, licorice extract, crystalline cellulose, high color pigment and guar gum; L-glutamic acid sodium preparations, noodle-added alkalis, preservative preparations, tar coloring preparations and the like.
  • the health functional food in the form of tablets may be prepared by granulating a mixture of the compound of Formula 1, which is an active ingredient of the present invention, with an excipient, a binder, a disintegrant, and other additives by a conventional method, Or the mixture can be directly compression-molded.
  • the health functional food of the tablet form may contain a mating agent or the like if necessary.
  • the hard capsule of the capsule-type health functional food can be prepared by filling a mixture of a compound of the above formula (1), which is an active ingredient of the present invention, with an additive such as an excipient, into a normal hard capsule, A compound obtained by mixing a compound with an additive such as an excipient, etc., into a capsule base such as gelatin.
  • the soft capsule may contain a plasticizer such as glycerin or sorbitol, a coloring agent, a preservative and the like, if necessary.
  • the ring-shaped health functional food can be prepared by molding a mixture of the compound of formula (1), the active ingredient of the present invention, excipient, binder, disintegrant and the like by a conventionally known method, It may be applied to the skin, or the surface may be coated with a substance such as starch or talc.
  • the granular health functional food may be prepared by granulating a mixture of the compound of formula (1), an active ingredient of the present invention, and excipients, binders, disintegrators, etc., into granules by a conventionally known method, And a mating agent.
  • the health functional food may be a beverage, a meat, a chocolate, a food, a confectionery, a pizza, a ramen, a noodle, a gum, a candy, an ice cream, an alcoholic beverage, a vitamin complex and a health supplement food.
  • the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof according to the present invention may also be provided as a cosmetic composition for preventing or ameliorating obesity or lipid-related metabolic diseases.
  • the cosmetic composition according to the present invention includes, but is not limited to lotions, ointments, gels, creams, patches or sprays.
  • the compound of the present invention may be added in an amount of 1 to 15 parts by weight, preferably 2 or 10 parts by weight, to a conventional composition for external application for skin.
  • the composition for external application for skin may further contain a lipid, an organic solvent, a solubilizer, a thickening agent and a gelling agent, a softening agent, an antioxidant, a suspending agent, a stabilizer, a foaming agent, It is generally used in ionic or nonionic emulsifiers, fillers, sequestering and chelating agents, preservatives, vitamins, barrier agents, wetting agents, essential oils, dyes, pigments, hydrophilic or lipophilic active agents, lipid vesicles or dermal topical compositions ≪ / RTI > any other ingredients that are commonly used in the skin sciences.
  • the components can also be introduced in amounts commonly used in the field of dermatology.
  • composition of the present invention may also be added to the feed composition for the purpose of preventing or ameliorating obesity or lipid-related metabolic diseases.
  • feed additive in the present invention means a substance added to feed for various purposes such as nutrient supplementation and weight loss prevention, promotion of digestive utilization of fibrin in feed, improvement of oil quality, prevention of reproductive disorder, improvement of conception rate, .
  • the feed additive of the present invention corresponds to an auxiliary feed in the feed control method and is a mineral preparation such as sodium hydrogencarbonate, bentonite, magnesium oxide and complex mineral, a mineral preparation such as zinc, copper, cobalt and selenium, , Vitamins such as vitamin AD, E, nicotinic acid and vitamin B complex, protective amino acids such as methionine and lysine, protective fatty acids such as calcium salt of fatty acid, live bacteria such as probiotics (lactic acid bacteria), yeast cultures, A yeast agent, and the like may be further included.
  • a mineral preparation such as sodium hydrogencarbonate, bentonite, magnesium oxide and complex mineral
  • a mineral preparation such as zinc, copper, cobalt and selenium
  • Vitamins such as vitamin AD, E, nicotin
  • feed in the context of the present invention refers to any natural or artificial diet, single meal, or the like formula for eating, ingesting, digesting,
  • the feed for purifying the composition for preventing or ameliorating disease may be manufactured in various forms known in the art, and preferably, it may include, but is not limited to, concentrated feed, forage and / or special feed.
  • Concentrated feeds include seeds containing cereals such as wheat, oats, and corn, and by-products such as rice bran, wheat bran, barley, etc., (Fish), which is a concentrate of fresh liquids obtained from fish meal, fish meal, fish residue, and fish, which are by-products such as residual oats, which are the main components of starch residues, yeast, chlorella, and seaweed, such as wheat germ, soluble wheat flour, wheat flour, wheat flour, skimmed milk powder, cheese from milk, dry whey that is the balance when casein is manufactured from skimmed milk, But is not limited thereto.
  • cereals such as wheat, oats, and corn
  • by-products such as rice bran, wheat bran, barley, etc., (Fish), which is a concentrate of fresh liquids obtained from fish meal, fish meal, fish residue, and fish, which are by-products such as residual oats, which are the main components of starch residues, yeast, chlorella, and seaweed,
  • Roughage includes root vegetables such as wild grasses, grasses and fodder, raw turnip for feed, turnip for feed, feed bit, turnip root, Silage, which is filled with lactic acid and fermented by lactic acid, hay, dried hay, herbage straw, straw of leguminous crops, leaves of leguminous plants, and the like.
  • Special feeds include mineral feeds such as oyster shells and rock salt, urea feeds such as urea and its derivatives diuret isobutane, supplemented with ingredients that are insufficient when mixed with natural feed ingredients, or mixed feeds to improve the storage stability of the feed.
  • Feed additive, dietary supplement which is a substance to be added in a trace amount.
  • the feed additive for preventing or ameliorating an obesity or lipid-related metabolic disease can be produced by various feed preparation methods known in the art in the range of an effective effective concentration, such as fucose terol, mungbean mung bean mung bean crushed mung bean mung bean extract, It can be prepared by adding crushed material or top extract.
  • the feed additive according to the present invention can be applied to any object for the purpose of preventing or improving obesity or lipid-related metabolic diseases without limitation.
  • it can be applied to any non-human animal such as a dog, a cat, a monkey, a rabbit, a guinea pig, a rat, a mouse, a cattle, a sheep, a pig,
  • Compound B of the following formula (3) was synthesized by the method of condensation of an acide amine of Example 1-1, similarly to Compound A.
  • the target compound was obtained by using p-toluidine (Sigma Aldrich, 110 mg, 1 eq) instead of 4- (2-aminoethyl) phenol as an amine part
  • the title compound was prepared in the form of a white solid.
  • Compound F of the following formula (7) was synthesized using the method of condensation of an acide amine of Example 1-1 in a manner similar to that of Compound (A). At this time, 2- (3,4-dimethoxy) phenethylamine was used instead of 4- (2-aminoethyl) phenol, (Sigma Aldrich, 181 mg, 1 eq) as an amine part, the target compound was prepared in the form of a white solid.
  • Compound I of the following formula (10) was synthesized using the method of condensation of an acide amine of Example 1-1, similarly to Compound (A). At this time, instead of 4- (2-aminoethyl) phenol, 2,3-dihydrobenzo [b] [1,4] dioxin-6- [b] [1,4] dioxin-6-amine) (Sigma Aldrich, 151 mg, 1 eq) as an amine part, the target compound was prepared in the form of a white solid.
  • the cytotoxicity of the acrylamide compounds of the present invention prepared in Example 1 was evaluated as follows.
  • 3T3-L1 cells were cultured in DMEM medium containing 10% FBS at 37 ° C and 5% CO 2 .
  • 3T3-L1 cells were inoculated on a 48-well plate and treated with the compounds A, B and C of the present invention and resveratrol (Sigma-Aldrich Co) at a concentration of 50 ⁇ M, dimethylthiazol-2yl) -2,5-diphenyl tetrazolium bromide (Sigma-Aldrich Co.). Resveratrol was used as a positive control.
  • Example 1 In order to confirm the effect of the acrylamide compounds according to the present invention on adipocyte differentiation, the compounds prepared in Example 1 were tested as follows.
  • 3T3-L1 cells were cultured in DMEM medium containing 10% FBS at 37 ° C and 5% CO 2 .
  • 3T3-L1 cells were inoculated into 48-well plates and then incubated with 50 [mu] M of the compounds A, B, C and resveratrol (positive control) of the present invention together with a hormone mixture (10 ⁇ g / mL insulin, 0.5 ⁇ M dexamethasone and 0.5 mM IBMX) Respectively, and cultured for 48 hours. Then, each sample was treated with DMEM medium containing insulin for 8 days to observe adipocyte differentiation.
  • the cells were washed twice with PBS, fixed with 3.7% formaldehyde, and cultured with Oil Red O dye for 1 hour. After staining, the differentiation from 3T3-L1 cells into adipocytes was confirmed by adding isopropanol and measuring the amount of triglyceride by measuring the absorbance at 510 nm.
  • the compounds A, B, and C of the present invention all showed an effect of inhibiting the induction of differentiation.
  • Compounds A and B showed better inhibitory effects on adipocyte differentiation than resveratrol, which is a positive control, and their inhibitory effects on differentiation were lower than those of untreated (non-differentiated) .
  • 3T3-L1 cells were cultured in DMEM medium containing 10% FBS at 37 ° C and 5% CO 2 .
  • 3T3-L1 cells were filled in a 60-well plate and incubated with Compound A (12.5, 25, 50 ⁇ M) of the present invention together with a hormone mixture (10 ⁇ g / mL insulin, 0.5 ⁇ M dexamethasone and 0.5 mM IBMX) After each treatment, they were incubated at 48-hour intervals for 8 days and exchanged with DMEM medium containing insulin.
  • the thus-cultured 3T3-L1 cells were washed twice with cold PBS and lysed in a lysis buffer (50 mM Tris-HCl, 1% Triton X-100, 0.5% sodium deoxycholate, 150 mM NaCl, 1 mM PMSF, 1 mM sodium orthovanadate, 1 mM NaF, and 0.2% protease inhibitor cocktail, pH 7.2).
  • a lysis buffer 50 mM Tris-HCl, 1% Triton X-100, 0.5% sodium deoxycholate, 150 mM NaCl, 1 mM PMSF, 1 mM sodium orthovanadate, 1 mM NaF, and 0.2% protease inhibitor cocktail, pH 7.2.
  • Compound A of the present invention decreased the expression level of FAS in 3T3-L1 cells in a concentration-dependent manner.
  • FAS is a fatty acid synthase, and substances that inhibit it are expected to have an effect of reducing fat production and inhibiting obesity.
  • the above experimental results show that Compound A of the present invention decreases the expression amount of FAS and inhibits fatty acid production , Indicating that the compounds according to the present invention are useful for the prevention and treatment of obesity and lipid-related metabolic diseases.
  • PPAR- ⁇ is a glitazone receptor that regulates fatty acid storage and glucose metabolism and promotes fat absorption to induce obesity. When it inhibits its activity, it is useful as a therapeutic agent for obesity and metabolic diseases Lt; / RTI >
  • PPAR- ⁇ peroxisome proliferator-activated receptor ⁇
  • PPAR- ⁇ transcription factor analysis was performed using the PPAR- ⁇ transcription factor assay kit (cayman, cat10006855) according to the manufacturer's instructions to measure the activation of PPAR- ⁇ .
  • the compound 3 and the resveratrol of the present invention were treated with the concentrations of (12.5, 25, and 50 [mu] M) in the cultured 3T3-L1 cells and then the cells were disrupted and the cell extracts were coated with the dsDNA sequence- plate, and reacted with the PPAR- ⁇ antibody and the secondary antibody in order.
  • the detection reagent was added and absorbance was measured at 450 nm.
  • Compound A of the present invention inhibited the activation of PPAR-y due to rosiglitazone in a concentration-dependent manner, and showed a higher inhibition rate than the positive control, resveratrol .
  • Example ⁇ 3-2> The experiment was conducted in a manner similar to that of Example ⁇ 3-2>. Specifically, 3T3-L1 cells were washed twice with cold PBS and then lysed in lysis buffer (50 mM Tris-HCl, 1% Triton X-100, 0.5% sodium deoxycholate, 150 mM NaCl, 1 mM EDTA, 1 mM sodium orthovanadate, 1 mM NaF, and 0.2% protease inhibitor cocktail, pH 7.2). The collected protein was centrifuged at 12,000 rpm for 20 minutes, and the supernatant was taken to quantify the protein. 30 ⁇ g of the protein was electrophoresed on 10% SDS-PAGE, transferred to nitrocellulose membrane, and reacted with PPAR- ⁇ antibody (1: 500) and secondary anti-mouse antibody (1: 1000).
  • lysis buffer 50 mM Tris-HCl, 1% Triton X-100, 0.5% sodium deoxycholate, 150 mM NaCl, 1
  • the compound A of the present invention decreased the amount of PPAR-gamma expression in 3T3-L1 cells in a concentration-dependent manner.
  • Example 1 In order to measure the weight loss effect of the acrylamide compounds according to the present invention, the compound A prepared in Example 1 was subjected to an anti-obesity animal experiment as follows.
  • mice Fiveweek-old C57BL / 6J mice (about 20 g) were fed from a central laboratory animal and were adapted for 1 week. Then, eight mice per group were divided into two groups, and a rodent diet with 10 kcal% Were supplied with Rodent diet with 60 kcal% Fat. In the sample intake group, Compound (A) or resveratrol (0.05% (w / w)) was added to Rodent diet with 60 kcal% Fat for 12 weeks. There was no animal in each group that died during the experiment, and the feed intake and body weight gain of the mice belonging to each group raised for 12 weeks were examined.
  • the body weight gain was the highest in the high fat diet group and the resveratrol group was not significant.
  • the body weight gain See Table 1 and Fig. 8 below.
  • Feed intake and weight gain of dietary mice Feed intake (g / day) Weight gain (g / 12 weeks) A normal diet 2.83 ⁇ 0.33 10.04 + - 1.70 High fat diet 2.48 ⁇ 0.28 25.43 + - 3.41 High Fat Diet + Compound A 2.64 ⁇ 0.28 19.55 + 2.66 * High fat diet + resveratrol 2.68 ⁇ 0.36 23.37 + - 2.53
  • the amount of peripheral fat, epididymal fat and brown fat in the experimental animal groups of Example 4-1 was measured.
  • adipose tissue and epididymal adipose tissue of the kidney were extracted and the size of adipocytes was observed under a microscope.
  • mice of the test group to which the compound A of the present invention was administered decreased the amounts of the peripheral fat, epididymal fat and brown fat of the kidneys compared with the mice belonging to the high fat diet group, which is superior to the positive control group, resveratrol.
  • the sizes of adipose tissue and epididymal adipose tissue of the kidney were significantly reduced compared with those of the high fat diet group.
  • resveratrol See Figs. 9A and 9B).
  • the content of triglyceride in the serum of the experimental animal groups of Example 4-1 was measured using a commercial measurement kit (Pureauto S TG-N, Daiichi, Japan).
  • the blood triglyceride content was very high, while in the high fat dietary group and the compound group of the present invention, the triglyceride content in the blood was markedly decreased .
  • the effect of reducing the content of triglyceride in blood according to the administration of the compound A of the present invention was higher than that of the general dietary group (LF), and the effect was more excellent than that of the test group administered with resveratrol could know.
  • AST and ALT activity in the test group administered with the compound A of the present invention showed AST activity and ALT activity similar to those of the normal dietary group (LF) and the high fat dietary group (HF) And did not induce liver toxicity.
  • the compound of the present invention 300 mg
  • the above components are mixed and filled in airtight bags to prepare powders.
  • tablets are prepared by tableting according to the usual preparation method of tablets.
  • the compound of the present invention 50 mg
  • the above components are mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.
  • the compound of the present invention 100 mg
  • Each component was added to purified water in accordance with the usual preparation method of the liquid preparation and dissolved, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed and then purified water was added thereto. The whole was adjusted to 100 ml with purified water, And sterilized to prepare a liquid preparation.
  • composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.
  • compositional ratio is relatively mixed with a component suitable for a favorite drink, it is also possible to arbitrarily modify the compounding ratio according to the regional or national preference such as the demand class, the demanding country, and the use purpose.
  • Methylpolysiloxane 0.4 parts by weight
  • Glycerin monostearate having a proline type 1.8 parts by weight
  • the inventors of the present invention prepared the feed additive with the following composition using the acrylamide-based compound of the present invention as an active ingredient.
  • the compound according to the present invention 0.1 to 20% by weight

Abstract

The present invention relates to use of acrylamide-based compounds and derivatives thereof for the prevention or treatment/improvement of obesity or lipid-related metabolic diseases. Since the acrylamide-based compounds of the present invention inhibited adipocyte differentiation without cytotoxicity, inhibited the expression of FAS, a factor associated with obesity and lipid metabolism, inhibited the activity and expression of PPAR-γ, and reduced feed intake and body weight gain, fat cell size, and blood triglyceride content without exhibiting liver toxicity in vivo, the compounds have an excellent anti-obesity effect and lipid metabolism improving effect. Therefore, the compounds of the present invention are very useful as these compounds can be used in various industrial fields such as in medicines, health functional foods, cosmetics, feed additives, and the like as a material capable of preventing, treating, and improving obesity or lipid-related metabolic diseases.

Description

아크릴아미드계 화합물을 유효성분으로 함유하는 비만 또는 지질관련 대사성 질환의 예방 또는 치료용 조성물A composition for preventing or treating obesity or a lipid-related metabolic disease containing an acrylamide-based compound as an active ingredient
본 발명은 아크릴아미드계 화합물 및 이의 유도체들의 비만 또는 지질관련 대사성 질환의 예방 또는 치료/개선용 용도에 관한 것으로, 보다 상세하게는 항비만 및 지질관련 대사를 개선하는 효과를 가지는 (E)-3-(벤조[d][1,3]디옥솔-5-일)-N-(4-하이드록시페네틸)아크릴아미드 및 이의 유도체들을 유효성분으로 포함하는 비만 또는 지질 관련 대사성 질환의 예방 또는 치료용 조성물에 관한 것이다. The present invention relates to the use of an acrylamide-based compound and its derivatives for preventing or treating or ameliorating obesity or lipid-related metabolic diseases, and more particularly to a method for preventing or treating (E) -3 Prevention or treatment of obesity or lipid-related metabolic diseases comprising, as an active ingredient, (benzo [d] [1,3] dioxol-5-yl) -N- (4-hydroxyphenethyl) acrylamide and derivatives thereof ≪ / RTI >
산업의 발달과 더불어 인스턴트 음식물 섭취와 육식 위주의 식생활로의 변화는 비만 인구 증가의 주요 원인이 되고 있다. 비만은 과다한 지방 섭취로 인한 호르몬의 변화 및 불균형적인 에너지 대사로 인한 지방세포(adipocyte) 분화에 의하여 유발된다. 체내에서의 지방생성은 지방전구세포(preadipocyte)로부터 지방세포가 분화되어 지방이 축적되는 과정으로서, 성숙한 지방세포는 섬유아세포(fibroblast)와 같은 미성숙 지방세포로부터 분화되어 궁극적으로 세포 내에 지방방울(lipid droplet)을 형성하게 된다. 비만인 사람의 관상동맥질환 발생 위험은 정상인에 비해 2~3배 높은 것으로 알려져 있다.Along with the development of the industry, changes in the diet of instant food and flesh-eating have become the main causes of the increase in the obese population. Obesity is caused by hormone changes due to excessive fat intake and adipocyte differentiation due to unbalanced energy metabolism. Fat production in the body is a process in which adipocytes differentiate from preadipocytes and accumulate fat. Mature adipocytes differentiate from immature adipocytes such as fibroblasts and ultimately produce lipid droplets. The risk of developing coronary artery disease in obese people is two to three times higher than in normal people.
이와 같이, 비만은 심장질환의 주요한 원인일 뿐만 아니라 암, 고혈압, 당뇨, 퇴행성관절염을 일으키며 미국의 경우 비만과 관련된 의료비 지출이 16조 원에 이르고 있다. 세계 비만 연맹은 현재의 비만 인구 증가추세라면 향후 20년 안에 전 세계 인구의 3분의 1이 비만환자 (체질량지수 30 kg/m2)가 될 것이라고 경고하였으며, 국내의 경우도 체질량지수가 25 kg/m2 이상인 비만 인구는 2008년 30.7%에 이른다. 특히, 체질량지수 30 kg/m2 이상인 고도비만 인구비율이 1998년 2.3%에서 2008년 4.1%로 2배 가까이 증가하였다.Thus, obesity is not only a major cause of heart disease, but also causes cancer, hypertension, diabetes, and degenerative arthritis. In the United States, health expenditures related to obesity amount to 16 trillion won. The World Obesity Federation warned that within the next 20 years, one-third of the world's population would become obese (body mass index 30 kg / m 2 ) if the current obesity trend is increasing. In Korea, the body mass index is 25 kg The obesity population of more than 2 / m 2 is 30.7% in 2008. In particular, the proportion of highly obese people with a body mass index of 30 kg / m 2 or more increased from 2.3% in 1998 to 4.1% in 2008, nearly doubling.
전 세계의 항비만 소재시장 규모는 2000억 달러를 상회하고 미국, 유럽, 일본 등 세계 7대 시장에서 직접의료 항비만제 매출규모가 2010년 5억 1200만 달러에서 2018년 32억 달러 규모까지 급성장할 것으로 전망되고 있으나 현재 사용되고 있는 3대 항비만제인 '올리스타트'(orlistat), '시부트라민'(sibutramine), '설트랄린'(sertraline)이 모두 부작용이 보고되고 있어 이를 대체할 항비만 소재 연구개발이 치열하게 진행되고 있다.The global anti-obesity material market is more than US $ 200 billion, and direct sales of medical anti-obesity drugs in the world's seven major markets such as the US, Europe and Japan are growing rapidly from US $ 512 million in 2010 to US $ 3.2 billion in 2018 However, the three most commonly used anti-obesity drugs, orlistat, sibutramine, and sertraline are all reported to have side effects. Development is proceeding fiercely.
지방은 지방산과 글리세롤로 이루어져 있으며 세포에 의한 지방산합성의 초기 단계에서 필수적인 역할을 담당하는 효소인 ACC(acetyl-CoA carboxylase)는 아세틸-CoA(acetyl-CoA)의 카복시화(carboxylation)를 유도하여 말로닐-CoA(malonyl-CoA)의 생산을 촉진시킨다. 지방산 합성은 FAS(fatty acid synthase) 라는 분자량이 250 kDa의 엔자임에 의하여 말로닐-CoA를 원료로 사용하여 진행된다. 따라서 FAS 또는 ACC 저해물질은 지방 생산을 감소시켜 비만을 억제하는 효과를 기대할 수 있다. 또한, PPAR-γ는 글리타존(glitazone) 수용체로, 지방산 저장과 글루코오스 대사를 조절한다고 알려져 있으며, sirt-1(sirtuins)은 PPAR-γ의 탈아세틸화를 함으로서 지방세포 분화에 관여한다고 알려져 있다 (J. Agric . Food Chem., 2012, 60 (4), pp 1094-1101).Fat is composed of fatty acids and glycerol. ACC (acetyl-CoA carboxylase), an enzyme that plays an essential role in the early stage of fatty acid synthesis by cells, induces carboxylation of acetyl-CoA Promotes the production of N-CoA (malonyl-CoA). Fatty acid synthesis is carried out using malonyl-CoA as a raw material by an enzyme of molecular weight 250 kDa called FAS (fatty acid synthase). Therefore, FAS or ACC inhibitor can be expected to reduce obesity by reducing fat production. It is also known that PPAR-γ is a glitazone receptor that regulates fatty acid storage and glucose metabolism, and sirt-1 (sirtuins) is known to be involved in adipocyte differentiation by deacetylating PPAR-γ ( J. Agric . Food Chem ., 2012, 60 (4), pp 1094-1101).
한편, 레스베라트롤은 천연에 존재하는 스틸벤(stilbene)의 일종으로서, 일부 식물체에서 박테리아나 균류와 같은 병원균의 공격에 대항하기 위하여 자연적으로 생합성 되는 피토알렉신(phytoalexin)이며 항비만 효과가 있다고 알려져 있다 (European Journal of Pharmacology, Volume 635, Issues 1-3, 10 June 2010, Pages 1-8). 그러나, 이러한 레스베라트롤은 비정상적인 혈액의 응집을 방해한다는 부작용이 보고되고 있으며, 레스베라트롤 보다 더욱 우수한 항비만 소재 연구개발이 여전히 필요한 실정이다.On the other hand, resveratrol is a kind of stilbene present in nature, and it is known that phytoalexin, which is naturally biosynthesized in order to combat the attack of pathogens such as bacteria and fungi in some plants, has anti-obesity effect ( European Journal of Pharmacology , Volume 635, Issues 1-3, 10 June 2010, Pages 1-8). However, such side effects of resveratrol have been reported to prevent abnormal blood aggregation, and research and development of anti-obesity materials, which are superior to resveratrol, are still needed.
이에 본 발명자들은 독성 없이 우수한 항비만 효과 및/또는 지질관련 대사성 질환 예방 및 치료 효과를 가지는 새로운 화합물 소재를 개발하고자 예의 노력한 결과, (E)-3-(벤조[d][1,3]디옥솔-5-일)-N-(4-하이드록시페네틸)아크릴아미드 및 이의 유도체가 세포의 독성이 없이 항비만 및 지질관련 대사를 개선하는 효과를 제공함을 확인하고, 본 발명을 완성하였다.Accordingly, the present inventors have made intensive efforts to develop a new compound material having an excellent anti-obesity effect and / or a lipid-related metabolic disease prevention and treatment effect without toxicity. As a result, it has been found that (E) -3- (benzo [ Oxo-5-yl) -N- (4-hydroxyphenethyl) acrylamide and its derivatives provide an effect of improving anti-obesity and lipid-related metabolism without toxicity of cells.
본 배경기술 부분에 기재된 상기 정보는 오직 본 발명의 배경에 대한 이해를 향상시키기 위한 것이며, 이에 본 발명이 속하는 기술분야에서 통상의 지식을 가지는 자에게 있어 이미 알려진 선행기술을 형성하는 정보를 포함하지 않을 수 있다.The information described in the Background section is intended only to improve the understanding of the background of the present invention and thus does not include information forming a prior art already known to those skilled in the art .
[선행기술문헌][Prior Art Literature]
(특허문헌 0001) 한국공개특허 제10-2010-0088887호(Patent Document 0001) Korean Patent Publication No. 10-2010-0088887
(특허문헌 0002) 한국공개특허 제10-2004-0036112호(Patent Document 0002) Korean Patent Publication No. 10-2004-0036112
본 발명의 목적은 우수한 항비만 효과 및/또는 지질 관련 대사성 질환의 예방 및/또는 치료 효과를 나타내는 새로운 화합물 소재를 제공하는데 있다. It is an object of the present invention to provide a new compound material showing an excellent anti-obesity effect and / or a preventive and / or therapeutic effect of a lipid-related metabolic disease.
본 발명의 다른 목적은, 비만 및/또는 지질 관련 대사성 질환의 예방 또는 치료/개선용 약학 조성물, 건강기능식품, 화장료 조성물 및 사료 첨가물을 제공하는데 있다. Another object of the present invention is to provide a pharmaceutical composition, a health functional food, a cosmetic composition and a feed additive for preventing or treating / improving obesity and / or lipid-related metabolic diseases.
상기 목적을 달성하기 위해, 본 발명은 아크릴아미드계 화합물 및 그 유도체들의 비만 또는 지질관련 대사성 질환의 예방 또는 치료/개선용 용도를 제공한다. In order to achieve the above object, the present invention provides the use of an acrylamide-based compound and its derivatives for preventing or treating / improving obesity or lipid-related metabolic diseases.
구체적으로, 본 발명은 하기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용되는 염을 유효성분으로 포함하는, 비만 또는 지질관련 대사성 질환의 예방 또는 치료용 약학 조성물을 제공한다:Specifically, the present invention provides a pharmaceutical composition for preventing or treating obesity or lipid-related metabolic diseases, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
[화학식 1][Chemical Formula 1]
Figure PCTKR2017006732-appb-I000001
Figure PCTKR2017006732-appb-I000001
상기 화학식 1에서, R은
Figure PCTKR2017006732-appb-I000002
,
Figure PCTKR2017006732-appb-I000003
,
Figure PCTKR2017006732-appb-I000004
,
Figure PCTKR2017006732-appb-I000005
,
Figure PCTKR2017006732-appb-I000006
,
Figure PCTKR2017006732-appb-I000007
,
Figure PCTKR2017006732-appb-I000008
,
Figure PCTKR2017006732-appb-I000009
및
Figure PCTKR2017006732-appb-I000010
로 이루어진 군에서 선택되는 어느 하나임. In the above formula (1), R is
Figure PCTKR2017006732-appb-I000002
,
Figure PCTKR2017006732-appb-I000003
,
Figure PCTKR2017006732-appb-I000004
,
Figure PCTKR2017006732-appb-I000005
,
Figure PCTKR2017006732-appb-I000006
,
Figure PCTKR2017006732-appb-I000007
,
Figure PCTKR2017006732-appb-I000008
,
Figure PCTKR2017006732-appb-I000009
And
Figure PCTKR2017006732-appb-I000010
≪ / RTI >
본 발명은 또한, 상기 화학식 1로 표시되는 화합물 또는 이의 식품학적으로 허용되는 염을 유효성분으로 포함하는, 비만 또는 지질관련 대사성 질환의 예방 또는 개선용 건강기능식품을 제공한다. The present invention also provides a health functional food for preventing or ameliorating an obesity or lipid-related metabolic disease comprising the compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명은 또한, 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용되는 염을 유효성분으로 포함하는, 비만 또는 지질관련 대사성 질환의 예방 또는 개선용 화장료 조성물을 제공한다. The present invention also provides a cosmetic composition for preventing or ameliorating an obesity or lipid-related metabolic disease, which comprises the compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명은 또한, 상기 화학식 1로 표시되는 화합물 또는 이의 식품학적으로 허용되는 염을 유효성분으로 포함하는, 비만 또는 지질관련 대사성 질환의 예방 또는 개선용 사료 첨가물을 제공한다. The present invention also provides a feed additive for preventing or ameliorating an obesity or lipid-related metabolic disease, which comprises the compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명은 또한, 필요한 개체에 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용되는 염을 투여하는 단계를 포함하는, 비만 또는 지질관련 대사성 질환의 치료방법을 제공한다.The present invention also provides a method for treating obesity or lipid-related metabolic diseases, comprising administering to a subject in need thereof a compound represented by the above-mentioned formula (1) or a pharmaceutically acceptable salt thereof.
본 발명은 또한, 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용되는 염의 비만 또는 지질관련 대사성 질환의 예방 또는 치료용 약학적 조성물에 사용하기 위한 용도를 제공한다. The present invention also provides a use for a pharmaceutical composition for preventing or treating obesity or a lipid-related metabolic disease of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
본 발명은 또한, 상기 화학식 1로 표시되는 화합물 또는 이의 식품학적으로 허용되는 염의 비만 또는 지질관련 대사성 질환의 예방 또는 개선용 건강기능식품에 사용하기 위한 용도를 제공한다. The present invention also provides a use for a health functional food for preventing or ameliorating obesity or a lipid-related metabolic disease of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
본 발명은 또한, 상기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용되는 염의 비만 또는 지질관련 대사성 질환의 예방 또는 치료용 화장료 조성물에 사용하기 위한 용도를 제공한다. The present invention also provides a use for a cosmetic composition for preventing or treating obesity or a lipid-related metabolic disease of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
본 발명은 또한, 상기 화학식 1로 표시되는 화합물 또는 이의 식품학적으로 허용되는 염의 비만 또는 지질관련 대사성 질환의 예방 또는 개선용 사료첨가물에 사용하기 위한 용도를 제공한다. The present invention also provides a use for a feed additive for preventing or ameliorating obesity or lipid-related metabolic diseases of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
본 발명은 항비만 효과 및 지질 관련 대사성 질환 예방 및 치료 효과를 가지는 새로운 소재를 제공한다. The present invention provides a novel material having an anti-obesity effect and a lipid-related metabolic disease prevention and treatment effect.
본 발명의 아크릴아미드계 화합물은 세포 독성 없이 지방세포분화를 억제하고 비만 및 지질 대사 관련 인자인 FAS의 발현을 억제하며, PPAR-γ의 활성 및 발현을 억제하였고, 인 비보(in vivo) 상에서도 간 독성을 나타내지 않으면서 사료섭취량 및 체중 증가량, 지방세포크기, 및 혈중 중성지방 함량을 감소시키는바 우수한 항비만 효과 및 지질 대사 개선 효과를 가진다. 따라서 본 발명의 화합물은 비만 또는 지질 관련 대사성 질환을 예방, 치료 및 개선할 수 있는 소재로서 의약품, 건강기능식품, 화장료, 사료 첨가제 등 다양한 산업 분야에 사용될 수 있어 매우 유용하다. The acrylamide-based compound of the present invention inhibits adipocyte differentiation without cytotoxicity, inhibits the expression of FAS which is a factor associated with obesity and lipid metabolism, inhibits the activity and expression of PPAR-γ, Fat mass, and blood triglyceride content without exhibiting toxicity, and has excellent anti-obesity effect and lipid metabolism improving effect. Therefore, the compound of the present invention is useful as a material capable of preventing, treating and improving obesity or lipid-related metabolic diseases, and can be used in various industrial fields such as medicines, health functional foods, cosmetics, feed additives and the like.
도 1은 본 발명의 아크릴아미드계 화합물의 세포독성 평가를 위해 화합물 A, B, C 각각을 50μM 농도로 3T3-L1 세포에 처리에 따른 세포 생존율을 측정한 결과이다.FIG. 1 shows the results of measuring the cell survival rate of 3T3-L1 cells treated with 50 μM of each of the compounds A, B and C in order to evaluate the cytotoxicity of the acrylamide compounds of the present invention.
도 2는 본 발명의 아크릴아미드계 화합물의 지방세포 분화에 미치는 영향을 평가하기 위하여 본 발명의 화합물 A, B, C 각각을 50μM 농도로 3T3-L1 세포에 처리에 따른 지방세포 분화 억제 정도를 측정한 결과이다.FIG. 2 is a graph showing the inhibition of adipocyte differentiation according to treatment of 3T3-L1 cells at 50 μM concentration of each of the compounds A, B and C of the present invention in order to evaluate the effect of the acrylamide compound of the present invention on adipocyte differentiation This is a result.
도 3은 본 발명의 화합물 A의 3T3-L1 세포에 농도별(12.5, 25, 50 μM) 처리에 따른 지방세포의 분화 억제 정도를 측정한 결과이다.FIG. 3 shows the result of measuring the degree of inhibition of adipocyte differentiation by treatment with 3T3-L1 cells of the compound A of the present invention (12.5, 25, 50 μM).
도 4는 본 발명의 화합물 A의 3T3-L1 세포에 농도별(12.5, 25, 50 μM) 처리 후 Oil Red O로 염색된 3T3-L1 세포 사진을 나타낸 것이다.FIG. 4 shows photographs of 3T3-L1 cells stained with Oil Red O after treatment with 3T3-L1 cells of Compound A of the present invention (12.5, 25, 50 μM).
도 5는 본 발명의 화합물 A의 3T3-L1 세포에 농도별(12.5, 25, 50 μM) 처리에 따른 세포 내 FAS 발현 정도를 웨스턴 블랏으로 확인한 결과이다.FIG. 5 shows the results of western blot analysis of the degree of intracellular FAS expression by treatment with 3T3-L1 cells of the compound A of the present invention (12.5, 25, 50 μM).
도 6은 본 발명의 화합물 A의 3T3-L1 세포에 농도별(12.5, 25, 50 μM) 처리에 따른 PPAR-γ 활성 정도를 측정한 결과이다.FIG. 6 shows the results of measuring the degree of PPAR-γ activity by treatment with 3T3-L1 cells of Compound A of the present invention (12.5, 25, 50 μM).
도 7은 본 발명의 화합물 A의 3T3-L1 세포에 농도별(12.5, 25, 50 μM) 처리에 따른 세포 내 PPAR-γ 발현 정도를 웨스턴 블랏으로 확인한 결과이다.FIG. 7 shows the results of Western blot analysis of intracellular PPAR-gamma expression by treatment with 3T3-L1 cells of the compound A of the present invention (12.5, 25, 50 μM).
도 8은 고지방식이와 함께 본 발명의 화합물 A를 마우스에 공급하여 12주 후 동물사진을 나타낸 것이다(Low fat: 일반 식이군, High fat: 고지방 식이군, High fat+화합물 A: 고지방 식이와 함께 화합물 A 급여군).FIG. 8 shows photographs of animals after 12 weeks of feeding Compound A of the present invention together with a high fat diet system (Low fat: a general diet group, high fat: high fat diet group, high fat + compound A: Compound A feed group).
도 9a는 고지방식이와 함께 본 발명의 화합물 A를 공급한 마우스에서 신장지방조직의 세포 크기를 현미경으로 측정한 사진이며, 도 9b는 고지방식이와 함께 본 발명의 화합물 A를 공급한 마우스에서 부고환 지방조직의 세포 크기를 현미경으로 측정한 사진이다(Low fat: 일반 식이군, High fat: 고지방 식이군, High fat+화합물 A).FIG. 9A is a photograph showing a microscopic observation of the cell size of kidney fat tissue in a mouse fed with the compound A of the present invention in combination with a high fat diet system, FIG. 9B is a photograph of a mouse fed with Compound A of the present invention (Low fat: high fat: high fat + high fat + compound A).
도 10은 고지방식이와 함께 본 발명의 화합물 A를 공급한 마우스의 혈청 중 중성지방 농도를 측정한 결과이다(Low fat: 일반 식이군, High fat: 고지방 식이군, High fat+화합물 A, High fat+Resveratrol: 고지방식이와 함께 레스베라트롤 급여군).FIG. 10 shows the result of measuring the concentration of triglycerides in the serum of mice fed with the compound A of the present invention together with the high fat diet (high fat: high fat: high fat + compound A, high fat + Resveratrol: Resveratrol with high fat diet.
도 11은 고지방식이와 함께 본 발명의 화합물 A를 공급한 마우스의 혈중 ALT활성을 측정한 결과이다(LF: 일반 식이군, HF: 고지방 식이군, HF+화합물 A: 고지방식이와 함께 화합물 A 급여군, HF+레스베라트롤: 고지방식이와 함께 레스베라트롤 급여군).FIG. 11 shows the results of measurement of ALT activity in blood of a mouse fed with Compound A of the present invention together with a high fat diet method (LF: general dietary group, HF: high fat dietary group, HF + compound A: Salary group, HF + resveratrol: resveratrol salary group with high fat diet).
도 12는 고지방식이와 함께 본 발명의 화합물 A를 공급한 마우스의 혈중 AST활성을 측정한 결과이다(LF: 일반 식이군, HF: 고지방 식이군, HF+화합물 A: 고지방식이와 함께 화합물 A 급여군, HF+레스베라트롤: 고지방식이와 함께 레스베라트롤 급여군).FIG. 12 shows the results of measuring the AST activity in blood of a mouse fed with the compound A of the present invention in combination with the high fat diet method (LF: general dietary group, HF: high fat dietary group, HF + compound A: Salary group, HF + resveratrol: resveratrol salary group with high fat diet).
다른 식으로 정의되지 않는 한, 본 명세서에서 사용된 모든 기술적 및 과학적 용어들은 본 발명이 속하는 기술분야에서 숙련된 전문가에 의해서 통상적으로 이해되는 것과 동일한 의미를 갖는다. 일반적으로, 본 명세서에서 사용된 명명법은 본 기술분야에서 잘 알려져 있고 통상적으로 사용되는 것이다.Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. In general, the nomenclature used herein is well known and commonly used in the art.
이하, 구체적으로 본 발명을 설명한다.Hereinafter, the present invention will be specifically described.
본 발명은 일 관점에서, 아크릴아미드계 화합물 또는 이의 약제학적으로 허용되는 염을 유효성분으로 포함하는 비만 또는 지질관련 대사성 질환의 예방 또는 치료용 약학 조성물에 관한 것이다. In one aspect, the present invention relates to a pharmaceutical composition for preventing or treating obesity or lipid-related metabolic diseases comprising an acrylamide-based compound or a pharmaceutically acceptable salt thereof as an active ingredient.
구체적으로는 본 발명의 아크릴아미드계 화합물은 하기 화학식 1로 표시되는 화합물임을 특징으로 할 수 있다. Specifically, the acrylamide-based compound of the present invention is a compound represented by the following general formula (1).
[화학식 1][Chemical Formula 1]
Figure PCTKR2017006732-appb-I000011
Figure PCTKR2017006732-appb-I000011
상기 화학식 1에서, R은
Figure PCTKR2017006732-appb-I000012
,
Figure PCTKR2017006732-appb-I000013
,
Figure PCTKR2017006732-appb-I000014
,
Figure PCTKR2017006732-appb-I000015
,
Figure PCTKR2017006732-appb-I000016
,
Figure PCTKR2017006732-appb-I000017
,
Figure PCTKR2017006732-appb-I000018
,
Figure PCTKR2017006732-appb-I000019
및
Figure PCTKR2017006732-appb-I000020
로 이루어진 군에서 선택되는 어느 하나임. In the above formula (1), R is
Figure PCTKR2017006732-appb-I000012
,
Figure PCTKR2017006732-appb-I000013
,
Figure PCTKR2017006732-appb-I000014
,
Figure PCTKR2017006732-appb-I000015
,
Figure PCTKR2017006732-appb-I000016
,
Figure PCTKR2017006732-appb-I000017
,
Figure PCTKR2017006732-appb-I000018
,
Figure PCTKR2017006732-appb-I000019
And
Figure PCTKR2017006732-appb-I000020
≪ / RTI >
본 발명에 따른 아크릴아미드계 화합물은 비만 및/또는 지질관련 대사성 질환을 예방 또는 치료하는 효과를 나타낸다. The acrylamide-based compound according to the present invention has an effect of preventing or treating obesity and / or lipid-related metabolic diseases.
본 발명의 일 실시예에서는 본 발명에 따른 화합물이 양성대조군인 레스베라트롤보다 우수한 것은 물론, 분화를 유도하지 않은 무처리군과 비교하여서도 이와 유사한 수준으로 지방세포로의 분화를 억제하는 것으로 확인되었으며, 본 발명의 다른 실시예에서는 항비만 동물 실험에서 양성대조군인 레스베라트롤에 비하여 우수하고 농도의존적으로 체중 증가량 감소 효과 및 지방 조직 무게 감소 효과를 나타내어 비만의 치료 및 예방 효과를 가짐을 제시하였다. In one embodiment of the present invention, it was confirmed that the compound according to the present invention was superior to the positive control group, resveratrol, and inhibited the differentiation into adipocytes in a similar level to the untreated group that did not induce differentiation, In another embodiment of the present invention, an anti-obesity animal test is superior to resveratrol, which is a positive control, and has effects of reducing weight gain and decreasing weight of fat tissue in a concentration-dependent manner and thus has a therapeutic and preventive effect on obesity.
본 발명의 조성물에 의한 예방 또는 치료 대상 질병인 "비만 (obesity)"은 대사 장애로 인하여 체내에 지방세포가 증식 분화하고, 이로 인하여 지방이 과잉으로 축적된 상태를 의미하며, 에너지 흡수량이 소비량에 비해 상대적으로 증가하는 경우, 지방세포의 수와 부피가 증가되는 과정을 거쳐 결과적으로 지방조직의 질량이 증가된다. 세포 수준에서의 비만은 지방세포의 증식 및 분화의 촉진으로 인한 지방세포의 수와 부피의 증가를 의미한다.The term " obesity ", which is a disease to be prevented or treated by the composition of the present invention, refers to a state in which fat cells multiply and multiply in the body due to metabolic disturbance and, as a result, fat accumulates excessively. , The number of adipocytes and the volume of the adipocytes increase, resulting in an increase in the mass of the adipose tissue. Obesity at the cellular level means an increase in the number and volume of adipocytes due to promotion of proliferation and differentiation of adipocytes.
본 발명에서의 용어 "분화(differentiation)"는 세포가 분열 증식하여 성장하는 동안에 서로 구조나 기능이 특수화하는 현상, 즉 생물의 세포, 조직 등이 각각에게 주어진 일을 수행하기 위하여 형태나 기능이 변해가는 것을 말한다. 일반적으로 비교적 단순한 계(系)가 둘 이상의 질적으로 다른 부분계(部分系)로 분리되는 현상이다. 예를 들면, 개체 발생에서 처음에 동질적이었던 알 부분 사이에 머리나 몸통 등의 구별이 생기거나 세포에도 근세포 또는 신경세포 등의 구별이 생기는 것과 같이 처음에 거의 동질이었던 어떤 생물계의 부분 사이에 질적인 차이가 생기는 것, 또는 그 결과로서 질적으로 구별할 수 있는 구역 또는 부분계로 나누어져 있는 상태를 분화라고 한다. The term " differentiation " in the present invention refers to a phenomenon in which the structure or function of a cell is specialized and differentiated while it is growing and proliferating, that is, the cell or tissue of the organism is changed in shape or function It is said that. In general, a relatively simple system is separated into two or more qualitatively different systems. For example, there is a qualitative difference between the parts of a biological system that were almost homogeneous at first, such as the distinction of heads or trunks between the eggs that were homogeneous at first in the development of an individual, or the distinction of cells such as muscle cells or nerve cells A state in which a difference occurs or is divided into qualitatively distinguishable zones or partial systems as a result is called eruption.
한편, 본 발명의 다른 실시예에서는, 본 발명에 따른 화합물이 지방세포에서 FAS(fatty acid synthase)의 발현량을 감소시켜 지방산 생성을 억제하며, 농도의존적으로 PPAR-γ(peroxisome proliferators- activated receptror γ)의 활성화 및 발현을 억제시키는 것을 확인할 수 있었다. PPAR-γ는 지방산 저장과 글루코오즈 대사를 조절하고 지방 흡수를 촉진하여 비만을 유발하는 것으로 알려진 글리타존 수용체(glitazone receptor)에 해당하는바, 이의 활성을 억제하는 경우 비만 및 지질관련 대사질환 치료제로 유용하게 사용될 수 있다.In another embodiment of the present invention, the compound according to the present invention reduces fatty acid synthase (FAS) expression in adipocytes, inhibits fatty acid production, and inhibits PPAR-gamma (peroxisome proliferator-activated receptor ) And the expression of the protein. PPAR-γ is a glitazone receptor that regulates fatty acid storage and glucose metabolism and promotes fat absorption to induce obesity. When it inhibits its activity, it treats obesity and lipid-related metabolic diseases . ≪ / RTI >
본 발명에서의 용어 "지질 관련 대사성 질환"은 고지혈증, 이상지질혈증, 동맥경화, 간지방증, 비알콜성 지방간, 2형 당뇨병 및 대사증후군 등을 나타낸다. The term " lipid-related metabolic diseases " in the present invention refers to hyperlipidemia, dyslipidemia, arteriosclerosis, hepaticopathy, nonalcoholic fatty liver, type 2 diabetes and metabolic syndrome.
본 발명에 따른 화합물은 (E)-3,4-메틸렌다이옥시시나믹 액시드 ((E)-3,4-(methylenedioxy)cinnamic acid)를 이용하여 액시드 아민 축합 방법을 수행하여 제조될 수 있다. The compounds according to the present invention can be prepared by conducting an acid amide condensation method using (E) -3,4-methylenedioxincinamic acid ((E) -3,4- (methylenedioxy) cinnamic acid) have.
본 발명의 일 구현예에서, 상기 화합물은 하기 화학식 2로 나타내는 화합물 (E)-3-(벤조[d][1,3]디옥솔-5-일)-N-(4-하이드록시페네틸)아크릴아미드 ((E)-3-(benzo[d][1,3]dioxol-5-yl)-N-(4-hydroxyphenethyl)acrylamide) (화합물 A)일 수 있다.In one embodiment of the invention, the compound is a compound (E) -3- (benzo [d] [1,3] dioxol-5-yl) -N- (4-hydroxyphenethyl ) Acrylamide (Compound A) (E) -3- (benzo [d] [1,3] dioxol-5-yl) -N- (4-hydroxyphenethyl) acrylamide.
[화학식 2] (2)
Figure PCTKR2017006732-appb-I000021
Figure PCTKR2017006732-appb-I000021
본 발명의 다른 구현예에서, 상기 화합물은 하기 화학식 3으로 나타내는 (E)-3-(벤조[d][1,3]디옥솔-5-일)-N-(p-톨릴)아크릴아미드 ((E)-3-(benzo[d][1,3]dioxol-5-yl)-N-(p-tolyl)acrylamide) (화합물 B)일 수 있다.In another embodiment of the present invention, the compound is (E) -3- (benzo [d] [1,3] dioxol-5-yl) -N- (p- tolyl) acrylamide (E) -3- (benzo [d] [1,3] dioxol-5-yl) -N- (p-tolyl) acrylamide (Compound B).
[화학식 3](3)
Figure PCTKR2017006732-appb-I000022
Figure PCTKR2017006732-appb-I000022
본 발명의 또 다른 구현예에서, 상기 화합물은 하기 화학식 4로 나타내는 화합물 (E)-3-(벤조[d][1,3]디옥솔-5-일)-N-(4-부톡시페닐)아크릴아미드 ((E)-3-(benzo[d][1,3]dioxol-5-yl)-N-(4-butoxyphenyl)acrylamide) (화합물 C)일 수 있다.In another embodiment of the present invention, the compound is a compound (E) -3- (benzo [d] [1,3] dioxol-5-yl) -N- (4-butoxyphenyl (4-butoxyphenyl) acrylamide (Compound C). ≪ RTI ID = 0.0 >
[화학식 4][Chemical Formula 4]
Figure PCTKR2017006732-appb-I000023
Figure PCTKR2017006732-appb-I000023
한편, 화합물이 비만 및 지질관련 대사질환에 대한 예방 및 치료 효과를 가지는 경우 이의 약제학적으로 허용되는 염 역시 동일한 효과를 가짐은 당업계에서 통상의 지식을 가진 자에게 있어 자명하며, 이때, 본 발명에서의 용어 "약제학적으로 허용 가능한 이의 염"은 당해 기술분야에서 통상적인 방법에 의해 제조될 수 있는 것으로, 예를 들면, 염산, 브롬화수소, 황산, 황산수소나트륨, 인산, 탄산 등의 무기산과의 염 또는 개미산, 초산, 옥살산, 벤조산, 시트르산, 타르타르산, 글루콘산, 게스티스산, 푸마르산, 락토비온산, 살리실릭산, 또는 아세틸살리실릭산(아스피린)과 같은 유기산과 함께 약제학적으로 허용 가능한 이들의 산의 염을 형성하거나, 또는 나트륨, 칼륨 등의 알칼리금속이온과 반응하여 이들의 금속염을 형성하거나, 또는 암모늄 이온과 반응하여 또 다른 형태의 약제학적으로 허용 가능한 그의 염을 형성하는 것을 의미한다.Meanwhile, it is apparent to those skilled in the art that the compound has prophylactic and therapeutic effects on obesity and lipid-related metabolic diseases, and its pharmaceutically acceptable salts also have the same effect. The term " pharmaceutically acceptable salts thereof " in the present specification means salts prepared from inorganic acids such as hydrochloric acid, hydrogen bromide, sulfuric acid, sodium hydrogenphosphate, phosphoric acid, Or a pharmaceutically acceptable salt thereof with an organic acid such as formic acid, acetic acid, oxalic acid, benzoic acid, citric acid, tartaric acid, gluconic acid, gestic acid, fumaric acid, lactobionic acid, salicylic acid, or acetylsalicylic acid (aspirin) To form salts of these acids, or to react with alkali metal ions such as sodium and potassium to form metal salts thereof, or to form ammonium salts such as ammonium ions The reaction is also meant to form a pharmaceutically acceptable salt thereof of different types.
본 발명의 조성물은 경구 또는 비경구의 여러 가지 제형일 수 있다. 상기 조성물을 제형화할 경우에는 하나 이상의 완충제(예를 들어, 식염수 또는 PBS), 항산화제, 정균제, 킬레이트화제(예를 들어, EDTA 또는 글루타치온), 충진제, 증량제, 결합제, 아쥬반트(예를 들어, 알루미늄 하이드록사이드), 현탁제, 농후제 습윤제, 붕해제 또는 계면활성제, 희석제 또는 부형제를 사용하여 조제될 수 있다.The compositions of the present invention may be of various oral or parenteral formulations. When formulating the composition, one or more buffers (e.g., saline or PBS), antioxidants, bacteriostats, chelating agents (e.g., EDTA or glutathione), fillers, extenders, binders, adjuvants Aluminum hydroxide), suspending agents, thickening agents, disintegrating agents or surfactants, diluents or excipients.
경구투여를 위한 고형제제에는 정제, 환제, 산제, 과립제, 캡슐제 등이 포함되며, 이러한 고형제는 하나 이상의 화합물에 적어도 하나 이상의 부형제 예를 들면, 전분(옥수수 전분, 밀 전분, 쌀 전분, 감자 전분 등 포함), 칼슘카보네이트(calcium carbonate), 수크로스(sucrose), 락토오스(lactose), 덱스트로오스, 솔비톨, 만니톨, 자일리톨, 에리스리톨 말티톨, 셀룰로즈, 메틸 셀룰로즈, 나트륨 카르복시메틸셀룰로오즈 및 하이드록시프로필메틸-셀룰로즈 또는 젤라틴 등을 섞어 조제된다. 예컨대, 활성성분을 고체 부형제와 배합한 다음 이를 분쇄하고 적합한 보조제를 첨가한 후 과립 혼합물로 가공함으로써 정제 또는 당의정제를 수득할 수 있다. Solid formulations for oral administration include tablets, pills, powders, granules, capsules and the like, which may contain one or more excipients such as starches (corn starch, wheat starch, rice starch, potatoes Starch and the like), calcium carbonate, sucrose, lactose, dextrose, sorbitol, mannitol, xylitol, erythritol maltitol, cellulose, methylcellulose, sodium carboxymethylcellulose and hydroxypropylmethylcellulose - It is prepared by mixing cellulose or gelatin. For example, tablets or tablets may be obtained by combining the active ingredient with a solid excipient, then milling it, adding suitable auxiliaries, and processing the mixture into granules.
또한, 단순한 부형제 이외에 스테아린산 마그네슘, 탈크 등과 같은 윤활제들도 사용된다. 경구투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 또는 시럽제 등이 해당되는데, 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제 또는 보존제 등이 포함될 수 있다. 또한, 경우에 따라 가교결합 폴리비닐피롤리돈, 한천, 알긴산 또는 나트륨 알기네이트 등을 붕해제로 첨가할 수 있으며, 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다.In addition to simple excipients, lubricants such as magnesium stearate, talc, and the like may also be used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. In addition to water and liquid paraffin which are commonly used simple diluents, various excipients such as wetting agents, sweeteners, fragrances or preservatives are included . In addition, crosslinked polyvinylpyrrolidone, agar, alginic acid, or sodium alginate may optionally be added as a disintegrant, and may further include an anticoagulant, a lubricant, a wetting agent, a flavoring agent, an emulsifying agent and an antiseptic agent .
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁용제, 유제, 동결건조제제 또는 좌제 등이 포함된다. 비수성용제 및 현탁용제로는 프로필렌글리콜(propylene glycol), 폴리에틸렌 글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈(tween) 61, 카카오지, 라우린지, 글리세롤, 젤라틴 등이 사용될 수 있다.Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations or suppositories. Examples of non-aqueous solvents and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used.
본 발명의 조성물은 경구 또는 비경구로 투여될 수 있으며, 비경구 투여시 피부외용; 복강내, 직장, 정맥, 근육, 피하, 자궁내 경막 또는 뇌혈관내 주사하는 주사제; 경피 투여제; 또는 비강 흡입제의 형태로 당업계에 공지된 방법에 따라 제형화할 수 있다.The composition of the present invention may be administered orally or parenterally, and may be administered externally for parenteral administration; Intraperitoneal, rectal, intravenous, intramuscular, subcutaneous, intrauterine, or intracerebral injection; Percutaneous administration agents; Or in the form of a nasal inhaler, according to methods known in the art.
상기 주사제의 경우에는 반드시 멸균되어야 하며 박테리아 및 진균과 같은 미생물의 오염으로부터 보호되어야 한다. 주사제의 경우 적합한 담체의 예로는 이에 한정되지는 않으나, 물, 에탄올, 폴리올(예를 들어, 글리세롤, 프로필렌 글리콜 및 액체 폴리에틸렌 글리콜 등), 이들의 혼합물 및/또는 식물유를 포함하는 용매 또는 분산매질일 수 있다. 보다 바람직하게는, 적합한 담체로는 행크스 용액, 링거 용액, 트리에탄올 아민이 함유된 PBS (phosphate buffered saline) 또는 주사용 멸균수, 10% 에탄올, 40% 프로필렌 글리콜 및 5% 덱스트로즈와 같은 등장 용액 등을 사용할 수 있다. 상기 주사제를 미생물 오염으로부터 보호하기 위해서는 파라벤, 클로로부탄올, 페놀, 소르빈산, 티메로살 등과 같은 다양한 항균제 및 항진균제를 추가로 포함할 수 있다. 또한, 상기 주사제는 대부분의 경우 당 또는 나트륨 클로라이드와 같은 등장화제를 추가로 포함할 수 있다.In the case of such injections, they must be sterilized and protected against contamination of microorganisms such as bacteria and fungi. Examples of suitable carriers for injectables include, but are not limited to, solvents or dispersion media containing water, ethanol, polyols (e.g., glycerol, propylene glycol and liquid polyethylene glycol, etc.), mixtures thereof and / or vegetable oils . More preferably, suitable carriers include isotonic solutions such as Hanks' solution, Ringer's solution, phosphate buffered saline (PBS) containing triethanolamine, or sterile water for injection, 10% ethanol, 40% propylene glycol and 5% dextrose Etc. may be used. In order to protect the injection from microbial contamination, various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like may be further included. In addition, the injections may in most cases additionally include isotonic agents, such as sugars or sodium chloride.
경피 투여제의 경우 연고제, 크림제, 로션제, 겔제, 외용액제, 파스타제, 리니멘트제, 에어롤제 등의 형태가 포함된다. 상기에서 경피 투여는 약학 조성물을 국소적으로 피부에 투여하여 약학 조성물에 함유된 유효한 양의 활성성분이 피부 내로 전달되는 것을 의미한다. Examples of transdermal dosage forms include ointments, creams, lotions, gels, solutions for external use, pastes, liniments, and air lozenges. In the above, transdermal administration means that the pharmaceutical composition is locally administered to the skin, so that an effective amount of the active ingredient contained in the pharmaceutical composition is delivered into the skin.
흡입 투여제의 경우, 본 발명에 따른 화합물은 적합한 추진제, 예를 들면, 디클로로플루오로메탄, 트리클로로플루오로메탄, 디클로로테트라플루오로에탄, 이산화탄소 또는 다른 적합한 기체를 사용하여, 가압 팩 또는 연무기로부터 에어로졸 스프레이 형태로 편리하게 전달할 수 있다. 가압 에어로졸의 경우, 투약 단위는 계량된 양을 전달하는 밸브를 제공하여 결정할 수 있다. 예를 들면, 흡입기 또는 취입기에 사용되는 젤라틴 캡슐 및 카트리지는 화합물, 및 락토즈 또는 전분과 같은 적합한 분말 기제의 분말 혼합물을 함유하도록 제형화할 수 있다. 비경구 투여용 제형은 모든 제약 화학에 일반적으로 공지된 처방서인 문헌(Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour)에 기재되어 있다.In the case of inhalation dosage forms, the compounds according to the invention can be prepared from the pressurized pack or sprayer using a suitable propellant, for example dichlorofluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. It can be conveniently delivered in aerosol spray form. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve that delivers a metered amount. For example, gelatin capsules and cartridges for use in an inhaler or insufflator may be formulated to contain a compound, and a powder mixture of a suitable powder base such as lactose or starch. Formulations for parenteral administration are described in Remington's Pharmaceutical Science, 15th Edition, 1975. Mack Publishing Company, Easton, Pennsylvania 18042, Chapter 87: Blaug, Seymour, commonly known in all pharmaceutical chemistries.
본 발명의 조성물은 약제학적으로 유효한 양으로 투여한다. 본 발명에 있어서, "약제학적으로 유효한 양"은 의학적 치료에 적용 가능한 합리적인 수혜/위험 비율로 질환을 치료하기에 충분한 양을 의미하며, 유효용량 수준은 환자의 질환의 종류, 중증도, 약물의 활성, 약물에 대한 민감도, 투여 시간, 투여 경로 및 배출 비율, 치료기간, 동시 사용되는 약물을 포함한 요소 및 기타 의학 분야에 잘 알려진 요소에 따라 결정될 수 있다. 본 발명의 조성물은 개별 치료제로 투여하거나 다른 치료제와 병용하여 투여될 수 있고 종래의 치료제와는 순차적 또는 동시에 투여될 수 있으며, 단일 또는 다중 투여될 수 있다. 즉, 본 발명의 조성물의 총 유효량은 단일 투여량(single dose)으로 환자에게 투여될 수 있으며, 다중 투여량(multiple dose)으로 장기간 투여되는 분할 치료 방법(fractionated treatment protocol)에 의해 투여될 수 있다. 상기한 요소들을 모두 고려하여 부작용없이 최소한의 양으로 최대 효과를 얻을 수 있는 양을 투여하는 것이 중요하며, 이는 당업자에 의해 용이하게 결정될 수 있다.The composition of the present invention is administered in a pharmaceutically effective amount. In the present invention, " pharmaceutically effective amount " means an amount sufficient to treat a disease at a reasonable benefit / risk ratio applicable to medical treatment, and the effective dose level will depend on the type of disease, severity, , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including co-administered drugs, and other factors well known in the medical arts. The composition of the present invention can be administered as an individual therapeutic agent or in combination with other therapeutic agents, and can be administered sequentially or simultaneously with conventional therapeutic agents, and can be administered singly or in multiple doses. That is, the total effective amount of the composition of the present invention may be administered to a patient in a single dose and administered by a fractionated treatment protocol administered over a long period in multiple doses . It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.
본 발명의 약학적 조성물의 투여량은 환자의 체중, 연령, 성별, 건강상태, 식이, 투여시간, 투여방법, 배설율 및 질환의 중증도에 따라 그 범위가 다양하다. 일일 투여량으로는, 비경구 투여 시 본 발명에 따른 화합물을 기준으로 하루에 체중 1 kg당 바람직하게 0.01 내지 50 mg, 더 바람직하게는 0.1 내지 30 mg의 양으로 투여되도록, 그리고 경구 투여 시는 본 발명에 따른 화합물은 을 기준으로 하루에 체중 1 kg당 바람직하게는 0.01 내지 250㎎, 더 바람직하게는 0.01 내지 100 mg, 더욱 바람직하게는 0.01 내지 10 mg의 양으로 투여되도록 1 내지 수회에 나누어 투여할 수 있다. 그러나 투여 경로, 비만의 중증도, 성별, 체중, 연령 등에 따라서 증감될 수 있으므로 상기 투여량이 어떠한 방법으로도 본 발명의 범위를 한정하는 것은 아니다.The dosage of the pharmaceutical composition of the present invention varies depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate, and disease severity. The daily dosage is such that, when parenterally administered, it is preferably administered in an amount of 0.01 to 50 mg, more preferably 0.1 to 30 mg per kg of body weight per day on the basis of the compound according to the present invention, The compound according to the present invention is preferably administered in an amount of 0.01 to 250 mg, more preferably 0.01 to 100 mg, and even more preferably 0.01 to 10 mg per kg of body weight per day on a daily basis, Lt; / RTI > However, the dosage may be varied depending on the route of administration, the severity of obesity, sex, weight, age, etc. Therefore, the dosage is not limited to the scope of the present invention by any means.
본 발명의 약학 조성물은 또한 본 발명에 따른 화합물을 유효성분으로 포함하는 외용제의 제형으로 제공할 수 있다. 본 발명의 약학 조성물을 피부외용제로 사용하는 경우, 추가로 지방 물질, 유기 용매, 용해제, 농축제 및 겔화제, 연화제, 항산화제, 현탁화제, 안정화제, 발포제(foaming agent), 방향제, 계면활성제, 물, 이온형 유화제, 비이온형 유화제, 충전제, 금속이온봉쇄제, 킬레이트화제, 보존제, 비타민, 차단제, 습윤화제, 필수 오일, 염료, 안료, 친수성 활성제, 친유성 활성제 또는 지질 소낭 등 피부 외용제에 통상적으로 사용되는 임의의 다른 성분과 같은 피부 과학 분야에서 통상적으로 사용되는 보조제를 함유할 수 있다. 또한 상기 성분들은 피부 과학 분야에서 일반적으로 사용되는 양으로 도입될 수 있다.The pharmaceutical composition of the present invention can also be provided as a formulation of the external preparation containing the compound according to the present invention as an active ingredient. When the pharmaceutical composition of the present invention is used as an external preparation for skin, it may further contain at least one selected from the group consisting of fatty substances, organic solvents, solubilizers, thickening and gelling agents, softening agents, antioxidants, suspending agents, stabilizers, foaming agents, Such as water, an ionic emulsifier, a nonionic emulsifier, a filler, a sequestering agent, a chelating agent, a preservative, a vitamin, a blocker, a wetting agent, a necessary oil, a dye, a pigment, a hydrophilic activator, Such as any other ingredients conventionally used in the field of skin science. The components can also be introduced in amounts commonly used in the field of dermatology.
본 발명의 약학 조성물이 피부 외용제로 제공될 경우, 이에 제한되는 것은 아니나, 연고, 패취, 겔, 크림 또는 분무제 등의 제형일 수 있다.When the pharmaceutical composition of the present invention is provided as an external preparation for skin, it may be a formulation such as, but not limited to, an ointment, a patch, a gel, a cream or a spray.
이때, 본 발명의 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용되는 염의 비만 또는 지질관련 대사성 질환의 예방 또는 치료용 약학적 조성물에 사용하기 위한 용도를 제공하며, 따라서, 본 발명은 다른 관점에서, 필요한 개체에 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용되는 염을 투여하는 단계를 포함하는, 비만 또는 지질관련 대사성 질환의 치료방법을 제공한다. Herein, the present invention provides a use for a pharmaceutical composition for preventing or treating obesity or a lipid-related metabolic disease of a compound represented by the formula 1 of the present invention or a pharmaceutically acceptable salt thereof, , A method for treating obesity or a lipid-related metabolic disease comprising administering to a subject in need thereof a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof.
본 발명에서 사용된 용어 "필요한 개체"는 치료, 관찰 또는 실험의 대상인 포유동물을 말하며, 바람직하게는 인간을 말한다. As used herein, the term " necessary entity " refers to a mammal that is the subject of treatment, observation or experimentation, preferably a human.
투여는 치료상 유효량으로 투여될 수 있으며, 여기에서 사용된 용어 "치료상 유효량"은 연구자, 수의사, 의사 또는 기타 임상에 의해 생각되는 조직계, 동물 또는 인간에서 생물학적 또는 의학적 반응을 유도하는 유효 성분 또는 약제학적 조성물의 양을 의미하는 것으로, 이는 치료되는 질환 또는 장애의 증상의 완화를 유도하는 양을 포함한다. 본 발명의 유효 성분에 대한 치료상 유효 투여량 및 투여횟수는 원하는 효과에 따라 변화될 것임은 당업자에게 자명하다. 그러므로 투여될 최적의 투여량은 당업자에 의해 쉽게 결정될 수 있으며, 질환의 종류, 질환의 중증도, 조성물에 함유된 유효성분 및 다른 성분의 함량, 제형의 종류, 및 환자의 연령, 체중, 일반 건강 상태, 성별 및 식이, 투여 시간, 투여 경로 및 조성물의 분비율, 치료기간, 동시 사용되는 약물을 비롯한 다양한 인자에 따라 조절될 수 있다. 본 발명의 치료방법에 있어서, 성인의 경우, 본 발명의 화합물을 1일 1회 내지 수회 투여시, 0.01㎎/kg~250㎎/kg의 용량으로 투여하는 것이 바람직하다.The term " therapeutically effective amount ", as used herein, refers to an amount of the active ingredient that induces a biological or medical response in a tissue system, animal or human, as contemplated by a researcher, veterinarian, Refers to the amount of the pharmaceutical composition, which amount includes an amount that induces the relief of the symptoms of the disease or disorder being treated. It will be apparent to those skilled in the art that the therapeutically effective dose and the number of administrations of the active ingredient of the present invention will vary depending on the desired effect. The optimal dosage to be administered can therefore be readily determined by those skilled in the art and will depend upon the nature of the disease, the severity of the disease, the amount of active and other ingredients contained in the composition, the type of formulation, and the age, , Sex and diet, time of administration, route of administration and rate of administration of the composition, duration of treatment, concurrent administration of the drug, and the like. In the treatment method of the present invention, in the case of an adult, it is preferable to administer the compound of the present invention at a dose of 0.01 mg / kg to 250 mg / kg once to several times a day.
본 발명의 치료방법에서 본 발명의 화학식 1의 화합물을 유효 성분으로 포함하는 조성물은 경구, 직장, 정맥내, 동맥내, 복강내, 근육내, 흉골내, 경피, 국소, 안구내 또는 피내 경로를 통해 통상적인 방식으로 투여할 수 있다.In the therapeutic method of the present invention, the composition comprising the compound of formula (I) of the present invention as an active ingredient can be administered orally, rectally, intravenously, intraarterially, intraperitoneally, intramuscularly, intrasternally, transdermally, topically, ≪ / RTI > can be administered in a conventional manner.
본 발명은 다른 관점에서, 화학식 1로 표시되는 화합물 또는 이의 식품학적으로 허용되는 염을 유효성분으로 포함하는, 비만 또는 지질관련 대사성 질환의 예방 또는 개선용 건강기능식품에 대한 것이다. In another aspect, the present invention relates to a health functional food for preventing or ameliorating an obesity or lipid-related metabolic disease, which comprises a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 건강기능식품은 비만 또는 지질관련 대사성 질환의 예방 및 개선을 목적으로, 정제, 캅셀, 분말, 과립, 액상, 환 등의 형태로 제조 및 가공할 수 있다.The health functional food of the present invention can be manufactured and processed in the form of tablets, capsules, powders, granules, liquids, and circles for the purpose of preventing and improving obesity or lipid-related metabolic diseases.
본 발명에서 사용된 용어 "건강기능식품"이라 함은 건강기능식품에 관한 법률 제6727호에 따른 인체에 유용한 기능성을 가진 원료나 성분을 사용하여 제조 및 가공한 식품을 말하며, 인체의 구조 및 기능에 대하여 영양소를 조절하거나 생리학적 작용 등과 같은 보건 용도에 유용한 효과를 얻을 목적으로 섭취하는 것을 의미한다.The term " health functional food " used in the present invention refers to foods manufactured and processed using raw materials or ingredients having useful functions in accordance with Law No. 6727 on health functional foods, To be used for the purpose of obtaining a beneficial effect for health use such as controlling nutrients or physiological action.
본 발명의 건강기능식품은 통상의 식품 첨가물을 포함할 수 있으며, 식품 첨가물로서의 적합 여부는 다른 규정이 없는 한, 식품의약품안전청에 승인된 식품 첨가물 공전의 총칙 및 일반시험법 등에 따라 해당 품목에 관한 규격 및 기준에 의하여 판정한다.The health functional foods of the present invention may contain conventional food additives and, unless otherwise specified, whether or not they are suitable as food additives are classified according to the General Rules for Food Additives approved by the Food and Drug Administration, Standards and standards.
상기 "식품 첨가물 공전"에 수재된 품목으로는 예를 들어, 케톤류, 글리신, 구연산칼슘, 니코틴산, 계피산 등의 화학적 합성물; 감색소, 감초 추출물, 결정셀룰로오스, 고량색소, 구아검 등의 천연첨가물; L-글루타민산나트륨제제, 면류첨가알칼리제, 보존료제제, 타르색소제제 등의 혼합제제류 등을 들 수 있다.Examples of the items listed in the above-mentioned "food additives" include chemical compounds such as ketones, glycine, calcium citrate, nicotinic acid, and cinnamic acid; Natural additives such as persimmon extract, licorice extract, crystalline cellulose, high color pigment and guar gum; L-glutamic acid sodium preparations, noodle-added alkalis, preservative preparations, tar coloring preparations and the like.
예를 들어, 정제 형태의 건강기능식품은 본 발명의 유효성분인 상기 화학식 1의 화합물을 부형제, 결합제, 붕해제 및 다른 첨가제와 혼합한 혼합물을 통상의 방법으로 과립화한 다음, 활택제 등을 넣어 압축성형하거나, 상기 혼합물을 직접 압축 성형할 수 있다. 또한 상기 정제 형태의 건강기능식품은 필요에 따라 교미제 등을 함유할 수도 있다.For example, the health functional food in the form of tablets may be prepared by granulating a mixture of the compound of Formula 1, which is an active ingredient of the present invention, with an excipient, a binder, a disintegrant, and other additives by a conventional method, Or the mixture can be directly compression-molded. In addition, the health functional food of the tablet form may contain a mating agent or the like if necessary.
캅셀 형태의 건강기능식품 중 경질 캅셀제는 통상의 경질 캅셀에 본 발명의 유효성분인 상기 화학식 1의 화합물을 부형제 등의 첨가제와 혼합한 혼합물을 충진하여 제조할 수 있으며, 연질 캅셀제는 상기 화학식 1의 화합물을 부형제 등의 첨가제와 혼합한 혼합물을 젤라틴과 같은 캅셀기제에 충진하여 제조할 수 있다. 상기 연질 캅셀제는 필요에 따라 글리세린 또는 소르비톨 등의 가소제, 착색제, 보존제 등을 함유할 수 있다.The hard capsule of the capsule-type health functional food can be prepared by filling a mixture of a compound of the above formula (1), which is an active ingredient of the present invention, with an additive such as an excipient, into a normal hard capsule, A compound obtained by mixing a compound with an additive such as an excipient, etc., into a capsule base such as gelatin. The soft capsule may contain a plasticizer such as glycerin or sorbitol, a coloring agent, a preservative and the like, if necessary.
환 형태의 건강기능식품은 본 발명의 유효성분인 상기 화학식 1의 화합물과 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 성형하여 조제할 수 있으며, 필요에 따라 백당이나 다른 제피제로 제피할 수 있으며, 또는 전분, 탈크와 같은 물질로 표면을 코팅할 수도 있다.The ring-shaped health functional food can be prepared by molding a mixture of the compound of formula (1), the active ingredient of the present invention, excipient, binder, disintegrant and the like by a conventionally known method, It may be applied to the skin, or the surface may be coated with a substance such as starch or talc.
과립 형태의 건강기능식품은 본 발명의 유효성분인 상기 화학식 1의 화합물과 부형제, 결합제, 붕해제 등을 혼합한 혼합물을 기존에 공지된 방법으로 입상으로 제조할 수 있으며, 필요에 따라 착향제, 교미제 등을 함유할 수 있다. The granular health functional food may be prepared by granulating a mixture of the compound of formula (1), an active ingredient of the present invention, and excipients, binders, disintegrators, etc., into granules by a conventionally known method, And a mating agent.
상기 건강기능식품은 음료류, 육류, 초코렛, 식품류, 과자류, 피자, 라면, 기타 면류, 껌류, 사탕류, 아이스크림류, 알코올 음료류, 비타민 복합제 및 건강보조식품류 등일 수 있다.The health functional food may be a beverage, a meat, a chocolate, a food, a confectionery, a pizza, a ramen, a noodle, a gum, a candy, an ice cream, an alcoholic beverage, a vitamin complex and a health supplement food.
이때, 본 발명에 따른 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용되는 염은 비만 또는 지질관련 대사성 질환의 예방 또는 개선용 화장료 조성물로도 제공될 수 있다. The compound represented by the formula (1) or a pharmaceutically acceptable salt thereof according to the present invention may also be provided as a cosmetic composition for preventing or ameliorating obesity or lipid-related metabolic diseases.
본 발명에 따른 화장료 조성물은 로션, 연고, 겔, 크림, 패치 또는 분무제 등을 포함하나 여기에 국한되는 것은 아니다. 본 발명에 따른 화장료 조성물을 제조함에 있어서, 통상적으로 함유되는 피부 외용제 조성물에 본 발명의 화합물을 1 내지 15 중량부, 바람직하게는 2 또는 10 중량부로 첨가할 수 있다. 상기 피부 외용제 조성물에는 본 발명의 화합물에 추가로 지방 물질, 유기 용매, 용해제, 농축제 및 겔화제, 연화제, 항산화제, 현탁화제, 안정화제, 발포제(foaming agent), 방향제, 계면활성제, 물, 이온형 또는 비이온형 유화제, 충전제, 금속이온봉쇄제 및 킬레이트화제, 보존제, 비타민, 차단제, 습윤화제, 필수 오일, 염료, 안료, 친수성 또는 친유성 활성제, 지질 소낭 또는 피부 외용제 조성물에 통상적으로 사용되는 임의의 다른 성분과 같은 피부 과학 분야에서 통상적으로 사용되는 보조제를 함유할 수 있다. 또한 상기 성분들은 피부 과학 분야에서 일반적으로 사용되는 양으로 도입될 수 있다.The cosmetic composition according to the present invention includes, but is not limited to lotions, ointments, gels, creams, patches or sprays. In preparing the cosmetic composition according to the present invention, the compound of the present invention may be added in an amount of 1 to 15 parts by weight, preferably 2 or 10 parts by weight, to a conventional composition for external application for skin. In addition to the compound of the present invention, the composition for external application for skin may further contain a lipid, an organic solvent, a solubilizer, a thickening agent and a gelling agent, a softening agent, an antioxidant, a suspending agent, a stabilizer, a foaming agent, It is generally used in ionic or nonionic emulsifiers, fillers, sequestering and chelating agents, preservatives, vitamins, barrier agents, wetting agents, essential oils, dyes, pigments, hydrophilic or lipophilic active agents, lipid vesicles or dermal topical compositions ≪ / RTI > any other ingredients that are commonly used in the skin sciences. The components can also be introduced in amounts commonly used in the field of dermatology.
본 발명의 조성물은 또한, 비만 또는 지질관련 대사성 질환의 예방 또는 개선 목적으로 사료 조성물에 첨가할 수 있다.The composition of the present invention may also be added to the feed composition for the purpose of preventing or ameliorating obesity or lipid-related metabolic diseases.
본 발명에서 용어, "사료첨가제"는 영양소 보충 및 체중감소 예방, 사료 내 섬유소의 소화 이용성 증진, 유질개선, 번식장애 예방 및 수태율 향상, 하절기 고온 스트레스 예방 등 다양한 효과를 목적으로 사료에 첨가하는 물질을 포함한다. 본 발명의 사료첨가제는 사료관리법상의 보조사료에 해당하며, 탄산수소나트륨, 벤토나이트(bentonite), 산화마그네슘, 복합광물질 등의 광물질제제, 아연, 구리, 코발트, 셀레늄 등의 미량 광물질인 미네랄제제, 케로틴, 비타민 A D, E, 니코틴산, 비타민 B 복합체 등의 비타민제, 메티오닌, 라이신 등의 보호아미노산제, 지방산 칼슘염 등의 보호지방산제, 생균제(유산균제), 효모배양물, 곰팡이 발효물 등의 생균, 효모제 등이 추가로 포함될 수 있다.The term " feed additive " in the present invention means a substance added to feed for various purposes such as nutrient supplementation and weight loss prevention, promotion of digestive utilization of fibrin in feed, improvement of oil quality, prevention of reproductive disorder, improvement of conception rate, . The feed additive of the present invention corresponds to an auxiliary feed in the feed control method and is a mineral preparation such as sodium hydrogencarbonate, bentonite, magnesium oxide and complex mineral, a mineral preparation such as zinc, copper, cobalt and selenium, , Vitamins such as vitamin AD, E, nicotinic acid and vitamin B complex, protective amino acids such as methionine and lysine, protective fatty acids such as calcium salt of fatty acid, live bacteria such as probiotics (lactic acid bacteria), yeast cultures, A yeast agent, and the like may be further included.
본 발명에서 용어 "사료"는, 동물이 먹고, 섭취하며, 소화시키기 위한 또는 이에 적당한 임의의 천연 또는 인공 규정식, 한끼식 등 또는 상기 한끼식의 성분으로, 본 발명에 따른 비만 또는 지질관련 대사성 질환 예방 또는 개선용 조성물을 유효성분으로 푸함하는 사료는 당업계에 공지된 다양한 형태의 사료로 제조가능하며, 바람직하게는 농후 사료, 조사료 및/또는 특수사료가 포함될 수 있으나, 이로 한정되지 않는다.The term " feed " in the context of the present invention refers to any natural or artificial diet, single meal, or the like formula for eating, ingesting, digesting, The feed for purifying the composition for preventing or ameliorating disease may be manufactured in various forms known in the art, and preferably, it may include, but is not limited to, concentrated feed, forage and / or special feed.
농후사료에는 밀, 귀리, 옥수수 등의 곡류를 포함하는 종자열매류, 곡물을 정제하고 얻는 부산물로서 쌀겨, 밀기울, 보릿겨 등을 포함하는 겨류, 콩, 유체, 깨, 아마인, 코코야자 등을 채유하고 얻는 부산물인 깻묵류와 고구마, 감자 등에서 녹말을 뺀 나머지인 녹말찌꺼기의 주성분인 잔존녹말질류 등의 찌꺼기류, 어분, 물고기찌꺼기, 어류에서 얻은 신선한 액상물을 농축시킨 것인 피시솔루블(fish soluble), 육분(肉粉), 혈분, 우모분, 탈지분유, 우유에서 치즈, 탈지유에서 카제인을 제조할 때의 잔액인 훼이(whey)를 건조한 건조훼이 등의 동물질사료, 효모, 클로렐라, 해조류가 있으나 이에 제한되지 않는다.Concentrated feeds include seeds containing cereals such as wheat, oats, and corn, and by-products such as rice bran, wheat bran, barley, etc., (Fish), which is a concentrate of fresh liquids obtained from fish meal, fish meal, fish residue, and fish, which are by-products such as residual oats, which are the main components of starch residues, yeast, chlorella, and seaweed, such as wheat germ, soluble wheat flour, wheat flour, wheat flour, skimmed milk powder, cheese from milk, dry whey that is the balance when casein is manufactured from skimmed milk, But is not limited thereto.
조사료에는 야초, 목초, 풋베기 등의 생초(生草)사료, 사료용 순무, 사료용 비트, 순무의 일종인 루터베어거 등의 뿌리채소류, 생초, 풋베기작물, 곡실(穀實) 등을 사일로에 채워 놓고 젖산발효시킨 저장사료인 사일리지(silage), 야초, 목초를 베어 건조시킨 건초, 종축용(種畜用) 작물의 짚, 콩과 식물의 나뭇잎이 있으며, 이에 제한되지 않는다. 특수사료에는 굴껍데기, 암염 등의 미네랄 사료, 요소나 그 유도체인 디우레이드이소부탄 등의 요소사료, 천연사료원료만을 배합했을 때 부족하기 쉬운 성분을 보충하거나, 사료의 저장성을 높이기 위해서 배합사료에 미량으로 첨가하는 물질인 사료첨가물, 식이보조제가 있으나 이에 제한되지 않는다.Roughage includes root vegetables such as wild grasses, grasses and fodder, raw turnip for feed, turnip for feed, feed bit, turnip root, Silage, which is filled with lactic acid and fermented by lactic acid, hay, dried hay, herbage straw, straw of leguminous crops, leaves of leguminous plants, and the like. Special feeds include mineral feeds such as oyster shells and rock salt, urea feeds such as urea and its derivatives diuret isobutane, supplemented with ingredients that are insufficient when mixed with natural feed ingredients, or mixed feeds to improve the storage stability of the feed. Feed additive, dietary supplement, which is a substance to be added in a trace amount.
본 발명에 따른 비만 또는 지질 관련 대사성 질환의 예방 또는 개선용 사료 첨가제는 당업계에 공지된 다양한 사료 제조방법에 따라 적절한 유효 농도 범위에서 퓨코스테롤, 모자반, 모자반 분쇄물, 모자반 추출물, 톳, 톳 분쇄물 또는 톳 추출물을 첨가하여 제조 가능하다.The feed additive for preventing or ameliorating an obesity or lipid-related metabolic disease according to the present invention can be produced by various feed preparation methods known in the art in the range of an effective effective concentration, such as fucose terol, mungbean mung bean mung bean crushed mung bean mung bean extract, It can be prepared by adding crushed material or top extract.
본 발명에 따른 사료 첨가제는 비만 또는 지질 관련 대사성 질환의 예방 또는 개선을 목적으로 하는 개체이면 제한없이 적용가능하다. 예를 들면, 개, 고양이, 원숭이, 토끼, 모르모트, 랫트, 마우스, 소, 양, 돼지, 염소 등과 같은 비인간동물, 조류 및 어류 등 어느 개체에도 적용이 가능하다.The feed additive according to the present invention can be applied to any object for the purpose of preventing or improving obesity or lipid-related metabolic diseases without limitation. For example, it can be applied to any non-human animal such as a dog, a cat, a monkey, a rabbit, a guinea pig, a rat, a mouse, a cattle, a sheep, a pig,
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 예시하기 위한 것으로서, 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지는 않는 것은 당업계에서 통상의 지식을 가진 자에게 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these examples are for illustrative purposes only and that the scope of the present invention is not construed as being limited by these examples.
<실시예><Examples>
<실시예 1> 본 발명에 따른 아크릴아미드계 화합물의 제조 &Lt; Example 1 > Preparation of acrylamide-based compounds according to the present invention
<1-1> 화합물 A ((E)-3-(<1-1> Compound A ((E) -3- ( benzo[d][1,3]dioxolbenzo [d] [1,3] dioxole -5--5- ylyl )-N-(4-hydroxyphenethyl)acrylamide)의 제조) -N- (4-hydroxyphenethyl) acrylamide)
액시드 아민 축합 방법을 이용하여, 하기의 화학식 2의 화합물 A를 합성하였다. Compound A of the following formula (2) was synthesized using an acid amide condensation method.
먼저, 화합물 A의 합성을 위해 (E)-3,4-메틸렌다이옥시시나믹 액시드 ((E)-3,4-(methylenedioxy)cinnamic acid) (sigma aldrich, 200mg, 1eq)와 4-(2-아미노에틸)페놀 (4-(2-aminoethyl)phenol) (sigma aldrich, 143 mg, 1eq) 축합반응을 진행하였다. 두 시료를 넣고 메틸렌 클로라이드 5 ml과 N-(3-다이메틸아미노프로필)-N-에틸카보다이이마이드 염산염 (N-(3-dimethylaminopropyl)-N-ethylcarbodiimidehydrochloride) (TCI chemicals, 380 mg, 2 eq)과 1-하이드록시벤조트리아졸 수화물 (1-hydroxybenzotriazole hydrate) (Sigma Aldrich, 150 mg, 1eq), N,N-다이아이소프로필에틸아민 (N,N-diisopropylethylamine) (Sigma Aldrich, 0.15 ml, 1eq)을 넣은 뒤 상온에서 5 시간 동안 반응을 돌려 원하는 화합물을 얻을 수 있었다. 반응이 진행된 이후에는 aqueous work-up과 컬럼 크로마토그래피 (hexane/EtOAc, 4:1) 를 통해 물질의 정제를 진행하여 하기의 화학식 2의 화합물 A를 수득하였다.(E) -3,4-methylenedioxy cinnamic acid (sigma aldrich, 200 mg, 1 eq) and 4- ( (2-aminoethyl) phenol) (sigma aldrich, 143 mg, 1 eq). Two samples were added, and 5 ml of methylene chloride and N- (3-dimethylaminopropyl) -N-ethylcarbodiimidehydrochloride (TCI chemicals, 380 mg, 2 eq) N-diisopropylethylamine (Sigma Aldrich, 0.15 ml, 1 eq) and 1-hydroxybenzotriazole hydrate (Sigma Aldrich, 150 mg, 1 eq) And the reaction was carried out at room temperature for 5 hours to obtain the desired compound. After the reaction had proceeded, the material was purified through aqueous work-up and column chromatography (hexane / EtOAc, 4: 1) to give compound A of the following formula (2).
[화학식 2](2)
Figure PCTKR2017006732-appb-I000024
Figure PCTKR2017006732-appb-I000024
<1-2> 화합물 B ((E)-3-(benzo[d][1,3]dioxol-5-yl)-N-(ptolyl)acrylamide)의 제조Preparation of Compound B ((E) -3- (benzo [d] [1,3] dioxol-5-yl) -N- (ptolyl) acrylamide
화합물 A와 유사하게 실시예 1-1의 액시드 아민 축합 방법을 이용하여 하기 화학식 3의 화합물 B를 합성하였다. 이때, 4-(2-아미노에틸)페놀 (4-(2-aminoethyl)phenol)을 대신하여 p-톨루이딘 (p-toluidine)(Sigma Aldrich, 110 mg, 1eq)을 아민 파트로 사용하여 목적 화합물을 흰색 고체의 형태로 제조하였다.Compound B of the following formula (3) was synthesized by the method of condensation of an acide amine of Example 1-1, similarly to Compound A. At this time, the target compound was obtained by using p-toluidine (Sigma Aldrich, 110 mg, 1 eq) instead of 4- (2-aminoethyl) phenol as an amine part The title compound was prepared in the form of a white solid.
[화학식 3](3)
Figure PCTKR2017006732-appb-I000025
Figure PCTKR2017006732-appb-I000025
<1-3> 화합물 C ((E)-3-(<1-3> Compound C ((E) -3- ( benzo[d][1,3]dioxolbenzo [d] [1,3] dioxole -5--5- ylyl )-N-(4-butoxyphenyl)acrylamide)의 제조) -N- (4-butoxyphenyl) acrylamide)
화합물 A와 유사하게 실시예 1-1의 액시드 아민 축합 방법을 이용하여 하기의 화학식 4의 화합물 C를 합성하였다. 이때, 4-(2-아미노에틸)페놀 (4-(2-aminoethyl)phenol)을 대신하여 4-부톡시아닐린 (4-butoxyaniline) (Sigma Aldrich, 170mg, 1eq)을 아민 파트로 사용하여 목적 화합물을 흰색 고체의 형태로 제조하였다.Compound C of the following formula (4) was synthesized by using the method of condensation of an acide amine of Example 1-1, similarly to Compound A. At this time, 4-butoxyaniline (Sigma Aldrich, 170 mg, 1 eq) was used as an amine part in place of 4- (2-aminoethyl) phenol, Was prepared in the form of a white solid.
[화학식 4][Chemical Formula 4]
Figure PCTKR2017006732-appb-I000026
Figure PCTKR2017006732-appb-I000026
<1-4> 화합물 D ((E)-3-(<1-4> Compound D ((E) -3- ( benzo[d][1,3]dioxolbenzo [d] [1,3] dioxole -5--5- ylyl )-N-(4-methoxybenzyl)acrylamide)의 제조) -N- (4-methoxybenzyl) acrylamide
화합물 A와 유사하게 실시예 1-1의 액시드 아민 축합 방법을 이용하여 하기의 화학식 5의 화합물 D를 합성하였다. 이때, 4-(2-아미노에틸)페놀 (4-(2-aminoethyl)phenol)을 대신하여 4-메톡시벤질아민 (4-methoxybenzylamine) (Sigma Aldrich, 137mg, 1eq)을 아민 파트로 사용하여 목적 화합물을 흰색 고체의 형태로 제조하였다.Compound D of the following formula (5) was synthesized using the method of condensation of an acide amine of Example 1-1 in a similar manner to Compound (A). At this time, 4-methoxybenzylamine (Sigma Aldrich, 137 mg, 1 eq) was used as an amine part instead of 4- (2-aminoethyl) phenol, The compound was prepared in the form of a white solid.
[화학식 5][Chemical Formula 5]
Figure PCTKR2017006732-appb-I000027
Figure PCTKR2017006732-appb-I000027
<1-5> 화합물 E ((E)-3-(<1-5> Compound E ((E) -3- ( benzo[d][1,3]dioxolbenzo [d] [1,3] dioxole -5--5- ylyl )-N-(4-methoxyphenethyl)acrylamide)의 제조) -N- (4-methoxyphenethyl) acrylamide)
화합물 A와 유사하게 실시예 1-1의 액시드 아민 축합 방법을 이용하여 하기의 화학식 6의 화합물 E를 합성하였다. 이때, 4-(2-아미노에틸)페놀 (4-(2-aminoethyl)phenol)을 대신하여 4-메톡펜에틸아민 (4-methoxyphenethylamine)(Sigma Aldrich, 151mg, 1eq)을 아민 파트로 사용하여 목적 화합물을 흰색 고체의 형태로 제조하였다.Compound E of the following formula (6) was synthesized using the method of condensation of an acide amine of Example 1-1 in a similar manner to Compound (A). At this time, 4-methoxyphenethylamine (Sigma Aldrich, 151 mg, 1 eq) was used as an amine part in place of 4- (2-aminoethyl) phenol, The compound was prepared in the form of a white solid.
[화학식 6][Chemical Formula 6]
Figure PCTKR2017006732-appb-I000028
Figure PCTKR2017006732-appb-I000028
<1-6> 화합물 F ((E)-3-(<1-6> Compound F ((E) -3- ( benzo[d][1,3]dioxolbenzo [d] [1,3] dioxole -5--5- ylyl )-N-(3,4-dimethoxyphenethyl)acrylamide)의 제조) -N- (3,4-dimethoxyphenethyl) acrylamide)
화합물 A와 유사하게 실시예 1-1의 액시드 아민 축합 방법을 이용하여 하기의 화학식 7의 화합물 F를 합성하였다. 이때, 4-(2-아미노에틸)페놀 (4-(2-aminoethyl)phenol)을 대신하여 2-(3,4-다이메톡시)페닐에틸아민 (2-(3,4-dimethoxy)phenethylamine) (Sigma Aldrich, 181mg, 1eq)을 아민 파트로 사용하여 목적 화합물을 흰색 고체의 형태로 제조하였다. Compound F of the following formula (7) was synthesized using the method of condensation of an acide amine of Example 1-1 in a manner similar to that of Compound (A). At this time, 2- (3,4-dimethoxy) phenethylamine was used instead of 4- (2-aminoethyl) phenol, (Sigma Aldrich, 181 mg, 1 eq) as an amine part, the target compound was prepared in the form of a white solid.
[화학식 7](7)
Figure PCTKR2017006732-appb-I000029
Figure PCTKR2017006732-appb-I000029
<1-7> 화합물 G ((E)-3-(<1-7> Compound G ((E) -3- ( benzo[d][1,3]dioxolbenzo [d] [1,3] dioxole -5--5- ylyl )-N-) -N- benzylacrylamidebenzylacrylamide )의 제조)
화합물 A와 유사하게 실시예 1-1의 액시드 아민 축합 방법을 이용하여 하기의 화학식 8의 화합물 G를 합성하였다. 이때, 4-(2-아미노에틸)페놀 (4-(2-aminoethyl)phenol)을 대신하여 벤질아민 (benzylamine) (Sigma Aldrich, 107mg, 1eq)을 아민 파트로 사용하여 목적 화합물을 흰색 고체의 형태로 제조하였다.Compound 8 of the following formula (8) was synthesized using the method of condensation of an acide amine of Example 1-1 in a manner similar to that of Compound A. Benzylamine (Sigma Aldrich, 107 mg, 1 eq) was used as an amine part in place of 4- (2-aminoethyl) phenol to obtain the title compound as a white solid .
[화학식 8][Chemical Formula 8]
Figure PCTKR2017006732-appb-I000030
Figure PCTKR2017006732-appb-I000030
<1-8> 화합물 H ((E)-3-(<1-8> Compound H ((E) -3- ( benzo[d][1,3]dioxolbenzo [d] [1,3] dioxole -5--5- ylyl )-N-) -N- phenethylacrylamide피 에ethylacrylamide )의 제조)
화합물 A와 유사하게 실시예 1-1의 액시드 아민 축합 방법을 이용하여 하기의 화학식 9의 화합물 H를 합성하였다. 이때, 4-(2-아미노에틸)페놀 (4-(2-aminoethyl)phenol)을 대신하여 페닐에틸아민 (phenylethylamine) (Sigma Aldrich, 121mg, 1eq)을 아민 파트로 사용하여 목적 화합물을 흰색 고체의 형태로 제조하였다.Compound H of the following formula (9) was synthesized using the method of condensation of an acide amine of Example 1-1 in a similar manner to Compound (A). At this time, phenylethylamine (Sigma Aldrich, 121 mg, 1 eq) was used as an amine part in place of 4- (2-aminoethyl) phenol to obtain the target compound as a white solid Lt; / RTI &gt;
[화학식 9][Chemical Formula 9]
Figure PCTKR2017006732-appb-I000031
Figure PCTKR2017006732-appb-I000031
<1-9> 화합물 I ((E)-3-(<1-9> Compound I ((E) -3- ( benzo[d][1,3]dioxolbenzo [d] [1,3] dioxole -5--5- ylyl )-N-(2,3-dihydrobenzo[b][1,4]dioxin-6- ) -N- (2,3-dihydrobenzo [b] [1,4] dioxin-6- ylyl )) acrylamideacrylamide )의 제조)
화합물 A와 유사하게 실시예 1-1의 액시드 아민 축합 방법을 이용하여 하기의 화학식 10의 화합물 I를 합성하였다. 이때, 4-(2-아미노에틸)페놀 (4-(2-aminoethyl)phenol)을 대신하여 2,3-다이하이드로벤조[b][1,4]다이옥신-6-아민(2,3-dihydrobenzo[b][1,4] dioxin-6-amine) (Sigma Aldrich, 151mg, 1eq)을 아민 파트로 사용하여 목적 화합물을 흰색 고체의 형태로 제조하였다.Compound I of the following formula (10) was synthesized using the method of condensation of an acide amine of Example 1-1, similarly to Compound (A). At this time, instead of 4- (2-aminoethyl) phenol, 2,3-dihydrobenzo [b] [1,4] dioxin-6- [b] [1,4] dioxin-6-amine) (Sigma Aldrich, 151 mg, 1 eq) as an amine part, the target compound was prepared in the form of a white solid.
[화학식 10][Chemical formula 10]
Figure PCTKR2017006732-appb-I000032
Figure PCTKR2017006732-appb-I000032
<실시예 2> 본 발명 화합물의 독성 분석<Example 2> Toxicity analysis of the compound of the present invention
상기 실시예 1에서 제조한 본 발명의 아크릴아미드계 화합물들의 세포 독성을 다음과 같이 평가하였다. The cytotoxicity of the acrylamide compounds of the present invention prepared in Example 1 was evaluated as follows.
먼저, 3T3-L1세포(한국세포주은행)는 10% FBS가 함유된 DMEM 배지를 사용하여 37℃, 5% CO2 조건에서 배양하였다. 48-웰 플레이트에 3T3-L1세포를 가득 배양한 후 본 발명의 화합물 A, B 및 C와 레스베라트롤(Sigma-Aldrich Co)을 50 μM의 농도로 각각 처리한 뒤 MTT (3-(4,5-dimethylthiazol-2yl)-2,5-diphenyl tetrazolium bromide) (Sigma-Aldrich Co.) 분석 방법으로 세포 생존율을 확인하였다. 이때 레스베라트롤은 양성대조군으로 이용하였다.First, 3T3-L1 cells (Korean Cell Line Bank) were cultured in DMEM medium containing 10% FBS at 37 ° C and 5% CO 2 . 3T3-L1 cells were inoculated on a 48-well plate and treated with the compounds A, B and C of the present invention and resveratrol (Sigma-Aldrich Co) at a concentration of 50 μM, dimethylthiazol-2yl) -2,5-diphenyl tetrazolium bromide (Sigma-Aldrich Co.). Resveratrol was used as a positive control.
그 결과 도 1에서 나타낸 바와 같이, 양성대조군인 레스베라트롤이 50 μM 에서 28.9%의 세포독성을 나타내는데 비하여, 본 발명에 따른 화합물 A, B, C는 세포독성을 거의 나타내지 않는 것을 확인할 수 있었다.As a result, as shown in FIG. 1, it was confirmed that the compounds A, B, and C according to the present invention show little cytotoxicity, while the positive control group resveratrol showed 28.9% cytotoxicity at 50 μM.
<실시예 3> 본 발명 화합물의 항비만 세포 실험Example 3: Anti-obesity cell experiment of the compound of the present invention
<3-1> 지방세포 분화 억제 효과 확인<3-1> Confirmation of inhibitory effect on adipocyte differentiation
본 발명에 따른 아크릴아미드계 화합물들의 지방세포 분화에의 영향을 확인하기 위하여, 실시예 1에서 제조한 화합물들에 대하여 다음과 같이 실험을 수행하였다. In order to confirm the effect of the acrylamide compounds according to the present invention on adipocyte differentiation, the compounds prepared in Example 1 were tested as follows.
먼저, 3T3-L1 세포(한국세포주은행)는 10% FBS가 함유된 DMEM 배지를 사용하여 37℃, 5% CO2 조건에서 배양하였다. 48-웰 플레이트에 3T3-L1 세포를 가득 배양한 후 호르몬 혼합물(10 ㎍/mL 인슐린, 0.5 μM 덱사메타손 및 0.5 mM IBMX)과 함께 본 발명의 화합물 A, B, C 및 레스베라트롤(양성대조군) 50 μM씩을 각각 처리한 뒤 48시간 동안 배양하였다. 그 후, 인슐린이 포함된 DMEM 배지로 교환하여 각각의 샘플을 8일 동안 처리하면서 지방세포(adipocytes)로의 분화를 관찰하였다. 분화가 완료된 후 세포를 PBS로 2회 세척한 후 3.7% 포름알데하이드로 세포를 고정시켰고, 1시간 동안 Oil Red O dye를 처리하여 배양하였다. 염색 후, 이소프로판올을 가하고 510nm에서 흡광도를 측정을 통해 트리글리세라이드(triglyceride)의 양을 측정함으로써 3T3-L1 세포에서 지방세포로의 분화를 확인하였다.First, 3T3-L1 cells (Korean Cell Line Bank) were cultured in DMEM medium containing 10% FBS at 37 ° C and 5% CO 2 . 3T3-L1 cells were inoculated into 48-well plates and then incubated with 50 [mu] M of the compounds A, B, C and resveratrol (positive control) of the present invention together with a hormone mixture (10 쨉 g / mL insulin, 0.5 袖 M dexamethasone and 0.5 mM IBMX) Respectively, and cultured for 48 hours. Then, each sample was treated with DMEM medium containing insulin for 8 days to observe adipocyte differentiation. After completion of the differentiation, the cells were washed twice with PBS, fixed with 3.7% formaldehyde, and cultured with Oil Red O dye for 1 hour. After staining, the differentiation from 3T3-L1 cells into adipocytes was confirmed by adding isopropanol and measuring the amount of triglyceride by measuring the absorbance at 510 nm.
그 결과 도 2에서 나타낸 바와 같이, 본 발명의 화합물 A, B 및 C는 모두 분화유도를 억제하는 효과를 보였다. 특히, 화합물 A 및 B는 양성대조군인 레스베라트롤보다 더 우수한 지방세포 분화 억제 효과를 보였으며, 그 분화 유도 억제 효과는 무처리군(분화유도 하지 않은 군)과 유사한 정도로 낮게 나타나 매우 우수한 지방세포 분화 억제 효과를 가지는 것으로 나타났다. As a result, as shown in Fig. 2, the compounds A, B, and C of the present invention all showed an effect of inhibiting the induction of differentiation. In particular, Compounds A and B showed better inhibitory effects on adipocyte differentiation than resveratrol, which is a positive control, and their inhibitory effects on differentiation were lower than those of untreated (non-differentiated) .
추가적으로, 이러한 지방세포 분화 억제 효과가 농도의존적인지 확인하기 위하여, 본 발명의 화합물들 중에 세포생존율 대비 지방세포분화억제 활성이 가장 뛰어난 화합물 A의 농도별 (12.5, 25, 50μM) 지방세포 분화 억제 효과를 상기와 동일한 방법으로 확인하였다.In order to confirm that the inhibitory effect of adipocyte differentiation was dose-dependent, addition of compounds of the present invention (12.5, 25, 50 μM) inhibiting adipocyte differentiation Was confirmed by the same method as described above.
그 결과 도 3 및 도 4에서 나타낸 바와 같이, 화합물 A가 농도 의존적으로 지방세포의 분화를 억제하며, 각 농도별(12.5, 25, 50μM) 지방세포 분화 억제 효과가 양성대조군인 레스베라트롤 보다도 우수한 것을 확인할 수 있었다.As a result, as shown in FIG. 3 and FIG. 4, Compound A inhibited the differentiation of adipocytes in a concentration-dependent manner, confirming that the effect of inhibiting adipocyte differentiation by each concentration (12.5, 25, 50 μM) was superior to the positive control, resveratrol I could.
이는 본 발명에 따른 화합물들이 우수한 항비만 효과를 보임을 제시한다. This suggests that the compounds according to the present invention show an excellent anti-obesity effect.
<3-2> FAS 발현 억제 효과 확인<3-2> Confirmation of inhibitory effect on FAS expression
본 발명에 따른 아크릴아미드계 화합물들의 비만 및 지질관련 대사성 질환을 억제하는 주요한 인자에 해당하는 FAS(fatty acid synthase)의 단백질 발현에 미치는 영향을 측정하기 위하여, 실시예 1에서 제조한 화합물들에 대하여 다음과 같이 실험을 수행하였다. In order to measure the effect of the acrylamide compounds according to the present invention on protein expression of FAS (fatty acid synthase), which is a major factor inhibiting obesity and lipid-related metabolic diseases, the compounds prepared in Example 1 The following experiment was conducted.
먼저, 3T3-L1 세포는 10% FBS가 함유된 DMEM 배지를 사용하여 37℃, 5% CO2 조건에서 배양하였다. 60파이 플레이트에 3T3-L1 세포를 가득 배양한 후, 호르몬 혼합물(10 ㎍/mL 인슐린, 0.5 μM 덱사메타손 및 0.5 mM IBMX) 과 함께 본 발명의 화합물 A를 농도별(12.5, 25, 50 μM )로 각각 처리한 후, 48시간 간격으로 8일 동안 배양하면서 인슐린이 포함된 DMEM 배지로 교환하였다. First, 3T3-L1 cells were cultured in DMEM medium containing 10% FBS at 37 ° C and 5% CO 2 . 3T3-L1 cells were filled in a 60-well plate and incubated with Compound A (12.5, 25, 50 μM) of the present invention together with a hormone mixture (10 μg / mL insulin, 0.5 μM dexamethasone and 0.5 mM IBMX) After each treatment, they were incubated at 48-hour intervals for 8 days and exchanged with DMEM medium containing insulin.
이렇게 배양된 3T3-L1 세포를 냉각된 PBS로 2번 세척한 다음 용해 버퍼(lysis buffer) (50 mM Tris-HCl, 1% Triton X-100, 0.5% sodium deoxycholate, 150 mM NaCl, 1 mM EDTA, 1 mM PMSF, 1 mM sodium orthovanadate, 1 mM NaF, and 0.2% protease inhibitor cocktail, pH 7.2)로 용해시켰다. 세포 파쇄물에서 단백질을 모은 후 14,000 rpm에서 5분 동안 원심분리하여 상등액을 취해 96 웰 플레이트에 분리된 단백질 1㎕를 증류수로 10배 희석한 뒤, protein assay dye reagent concentrate(Bio-rad) 시약과 혼합하여 595 ㎚에서 흡광도를 측정하여 단백질 정량을 수행하였다. 30 ㎍의 단백질을 10% SDS-PAGE에 로딩하여 전기영동한 후 니트로셀룰로오스 멤브레인(nitrocellulose membrane)에 트랜스퍼한 뒤 1차 항체 항-FAS 항체 (1:1000, Cell signaling Co)와 4℃에서 하룻밤 동안 반응시키고, 2차 항-래빗 (Cell signaling)항체 (1:2000)와 실온에서 한 시간 동안 반응시켜 ECL로 검출하였다.The thus-cultured 3T3-L1 cells were washed twice with cold PBS and lysed in a lysis buffer (50 mM Tris-HCl, 1% Triton X-100, 0.5% sodium deoxycholate, 150 mM NaCl, 1 mM PMSF, 1 mM sodium orthovanadate, 1 mM NaF, and 0.2% protease inhibitor cocktail, pH 7.2). After collecting the proteins from the cell lysates, centrifuge at 14,000 rpm for 5 minutes, take the supernatant, dilute 10-fold of the separated protein in 96-well plate with distilled water, and mix with protein assay dye reagent concentrate (Bio-rad) reagent And the absorbance was measured at 595 nm to quantitate the protein. 30 μg of protein was loaded on 10% SDS-PAGE, electrophoresed, transferred to nitrocellulose membrane, and incubated with primary antibody anti-FAS antibody (1: 1000, Cell signaling Co) overnight at 4 ° C And reacted with secondary anti-rabbit (1: 2000) antibody at room temperature for 1 hour to detect ECL.
그 결과 도 5에서 나타낸 바와 같이, 본 발명의 화합물 A는 3T3-L1 세포 내 FAS의 발현량을 농도 의존적으로 감소시키는 것을 확인할 수 있었다.As a result, as shown in FIG. 5, it was confirmed that Compound A of the present invention decreased the expression level of FAS in 3T3-L1 cells in a concentration-dependent manner.
FAS는 지방산 합성 효소로서 이를 저해하는 물질은 지방 생산을 감소시켜 비만을 억제하는 효과를 기대할 수 있는 바, 상기와 같은 실험 결과는 본 발명의 화합물 A가 FAS의 발현량을 감소시켜 지방산 생성을 억제하는 것임을 제시하며, 이는 본 발명에 따른 화합물이 비만 및 지질관련 대사성 질환의 예방 및 치료에 도움이 됨을 나타낸다. FAS is a fatty acid synthase, and substances that inhibit it are expected to have an effect of reducing fat production and inhibiting obesity. The above experimental results show that Compound A of the present invention decreases the expression amount of FAS and inhibits fatty acid production , Indicating that the compounds according to the present invention are useful for the prevention and treatment of obesity and lipid-related metabolic diseases.
<3-3> <3-3> PPARPPAR -γ 활성 억제 효과 확인(1)-γ activation inhibitory effect (1)
PPAR-γ는 지방산 저장과 글루코오즈 대사를 조절하고 지방 흡수를 촉진하여 비만을 유발하는 것으로 알려진 글리타존 수용체(glitazone receptor)에 해당하는 바, 이의 활성을 억제하는 경우 비만 및 대사성 질환 치료제로 유용하게 사용될 수 있다. 이에 본 발명에 따른 아크릴아미드계 화합물들이 PPAR-γ(peroxisome proliferators- activated receptror γ)의 활성에 어떠한 영향을 미치는지 확인하기 위하여, 실시예 1에서 제조한 화합물 A에 대하여 다음과 같이 실험을 수행하였다. PPAR-γ is a glitazone receptor that regulates fatty acid storage and glucose metabolism and promotes fat absorption to induce obesity. When it inhibits its activity, it is useful as a therapeutic agent for obesity and metabolic diseases Lt; / RTI &gt; Thus, in order to examine the influence of the acrylamide compounds according to the present invention on the activity of PPAR-γ (peroxisome proliferator-activated receptor γ), Compound A prepared in Example 1 was tested as follows.
즉, PPAR-γ의 활성화를 측정하기 위하여 PPAR-γ transcription factor assay kit (cayman, cat10006855)를 이용하여 제조자의 지시에 따라 PPAR-γ 전사인자 분석을 실시하였다. 구체으로는, 배양된 3T3-L1 세포에 본 발명의 화합물 A와 레스베라트롤을 농도별(12.5, 25, 50 μM)로 각각 처리한 후, 세포를 파쇄하여 세포추출물을 키트에 포함된 dsDNA sequence-coated plate에 첨가하고 PPAR-γ 항체와 이차 항체(secondary antibody)와 차례로 반응시킨 후 검출 시약(detection reagent)를 가하고 450 nm에서 흡광도를 측정하였다.That is, PPAR-γ transcription factor analysis was performed using the PPAR-γ transcription factor assay kit (cayman, cat10006855) according to the manufacturer's instructions to measure the activation of PPAR-γ. As the sphere, the compound 3 and the resveratrol of the present invention were treated with the concentrations of (12.5, 25, and 50 [mu] M) in the cultured 3T3-L1 cells and then the cells were disrupted and the cell extracts were coated with the dsDNA sequence- plate, and reacted with the PPAR-γ antibody and the secondary antibody in order. The detection reagent was added and absorbance was measured at 450 nm.
그 결과 도 6에서 나타낸 바와 같이, 본 발명의 화합물 A는 로지-글리타존(rosi-glitazone)으로 인한 PPAR-γ의 활성화를 농도 의존적으로 억제하였으며, 양성 대조군인 레스베라트롤보다 높은 억제도를 나타내었다. As a result, as shown in Fig. 6, Compound A of the present invention inhibited the activation of PPAR-y due to rosiglitazone in a concentration-dependent manner, and showed a higher inhibition rate than the positive control, resveratrol .
<3-4> <3-4> PPARPPAR -γ 발현 억제 효과 확인(2)-γ expression inhibition (2)
추가적으로 본 발명에 따른 아크릴아미드계 화합물들이 PPAR-γ(peroxisome proliferators- activated receptror γ)의 단백질 발현에 미치는 영향을 확인하기 위하여, 실시예 1에서 제조한 화합물 A에 대하여 다음과 같이 웨스턴 블롯을 수행하였다. Furthermore, in order to confirm the effect of the acrylamide compounds according to the present invention on the protein expression of PPAR-y (peroxisome proliferator-activated receptor gamma), western blotting was performed on Compound A prepared in Example 1 as follows .
실험방법은 상기 실시예 <3-2>와 유사한 방식으로 진행하였다. 구체적으로는 3T3-L1세포를 냉각된 PBS로 2번 세척한 후 lysis buffer (50 mM Tris-HCl, 1% Triton X-100, 0.5% sodium deoxycholate, 150 mM NaCl, 1 mM EDTA, 1 mM PMSF, 1 mM sodium orthovanadate, 1 mM NaF, and 0.2% protease inhibitor cocktail, pH 7.2)로 lysis 시켰다. 모아진 단백질은 12,000 rpm에서 20분간 원심분리하여 상등액을 취한 후 단백질을 정량하였다. 30 ug 의 단백질을 10% SDS-PAGE 에 loading 하여 전기영동한 후 nitrocellulose membrane에 옮기고 PPAR-γ antibody (1:500), 2차 anti-mouse antibody (1:1000)와 반응시켜 ECL로 검출하였다.The experiment was conducted in a manner similar to that of Example <3-2>. Specifically, 3T3-L1 cells were washed twice with cold PBS and then lysed in lysis buffer (50 mM Tris-HCl, 1% Triton X-100, 0.5% sodium deoxycholate, 150 mM NaCl, 1 mM EDTA, 1 mM sodium orthovanadate, 1 mM NaF, and 0.2% protease inhibitor cocktail, pH 7.2). The collected protein was centrifuged at 12,000 rpm for 20 minutes, and the supernatant was taken to quantify the protein. 30 μg of the protein was electrophoresed on 10% SDS-PAGE, transferred to nitrocellulose membrane, and reacted with PPAR-γ antibody (1: 500) and secondary anti-mouse antibody (1: 1000).
그 결과 도 7에서 나타낸 바와 같이, 본 발명의 화합물 A가 3T3-L1 세포에서의 PPAR-γ 발현량을 농도 의존적으로 감소시키는 것을 확인할 수 있었다.As a result, as shown in Fig. 7, it was confirmed that the compound A of the present invention decreased the amount of PPAR-gamma expression in 3T3-L1 cells in a concentration-dependent manner.
이러한 실험 결과들은 본 발명에 따른 화합물이 PPAR-γ의 활성을 억제하여 비만 및 대사성 질환 치료제로 유용하게 사용될 수 있음을 의미한다.These experimental results indicate that the compounds according to the present invention inhibit the activity of PPAR-y and thus can be usefully used as a therapeutic agent for obesity and metabolic diseases.
<실시예 4> 항비만 동물 실험Example 4: An anti-obesity animal experiment
<4-1> 사료 섭취량과 체중 증가량 감소 효과 확인<4-1> Effect of reducing feed intake and weight gain
본 발명에 따른 아크릴아미드계 화합물들의 체중 감소 효과를 측정하기 위하여, 실시예 1에서 제조한 화합물 A에 대하여 다음과 같이 항비만 동물실험을 진행하였다. In order to measure the weight loss effect of the acrylamide compounds according to the present invention, the compound A prepared in Example 1 was subjected to an anti-obesity animal experiment as follows.
먼저, 20 g 내외의 5주령 C57BL/6J 마우스를 (주)중앙실험동물로부터 공급받아 1주일간 적응시킨 후 군 당 8마리씩 분류하여 일반식이군은 Rodent diet with 10 kcal% Fat을 공급하고 고지방 식이군은 Rodent diet with 60 kcal% Fat을 공급하였다. 시료 섭취군은 Rodent diet with 60 kcal% Fat에 화합물 A 또는 레스베라트롤을 0.05% (w/w)씩 섞어 12주 동안 공급하였다. 실험기간 중 사망한 실험동물은 모든 군에서 1마리도 없었으며, 12주 동안 사육한 각각의 군에 속하는 마우스들의 사료 섭취량 및 체중 증가량을 확인하였다.First, 5-week-old C57BL / 6J mice (about 20 g) were fed from a central laboratory animal and were adapted for 1 week. Then, eight mice per group were divided into two groups, and a rodent diet with 10 kcal% Were supplied with Rodent diet with 60 kcal% Fat. In the sample intake group, Compound (A) or resveratrol (0.05% (w / w)) was added to Rodent diet with 60 kcal% Fat for 12 weeks. There was no animal in each group that died during the experiment, and the feed intake and body weight gain of the mice belonging to each group raised for 12 weeks were examined.
그 결과 하기의 표 1에서 나타낸 바와 같이, 사료섭취량은 고지방 식이군이 일반식이군 보다 약간 감소하는 경향을 나타내었고 고지방 식이군과 고지방식이에 시료를 첨가한 군간의 차이는 거의 없는 것을 확인할 수 있었다. 따라서 시료가 사료 섭취량에 미치는 영향은 미비한 것으로 판단되었다. As a result, as shown in the following Table 1, the feed intake tended to be slightly lower in the high fat dietary group than in the normal dietary group, and it was found that there was almost no difference between the high fat dietary group and the high fat dietary supplement group there was. Therefore, it was concluded that the effect of the sample on the feed intake was insignificant.
한편, 체중 증가량은 고지방 식이군이 가장 높았고 레스베라트롤(resveratrol) 군은 유의성은 없는 것으로 나타난 반면, 고지방 식이와 함께 본 발명의 화학물 A를 시료로 공급한 실험군에서 고지방 식이군 대비 유의성 있게 체중이 감소된 것을 확인할 수 있었다(하기 표 1 및 도 8 참조).On the other hand, the body weight gain was the highest in the high fat diet group and the resveratrol group was not significant. On the other hand, in the experiment group in which the chemical A of the present invention was fed with the high fat diet, the body weight gain (See Table 1 and Fig. 8 below).
식이별 마우스의 사료섭취량 및 체중증가량Feed intake and weight gain of dietary mice
사료 섭취량(g/day)Feed intake (g / day) 체중 증가량 (g/12주)Weight gain (g / 12 weeks)
일반 식이A normal diet 2.83 ± 0.332.83 ± 0.33 10.04 ± 1.7010.04 + - 1.70
고지방 식이High fat diet 2.48 ± 0.282.48 ± 0.28 25.43 ± 3.4125.43 + - 3.41
고지방 식이 + 화합물 AHigh Fat Diet + Compound A 2.64 ± 0.282.64 ± 0.28 19.55 ± 2.66*19.55 + 2.66 *
고지방 식이 + 레스베라트롤High fat diet + resveratrol 2.68 ± 0.362.68 ± 0.36 23.37 ± 2.5323.37 + - 2.53
*P<0.05* P < 0.05
<4-2> 지방조직 무게 감소 효과 확인<4-2> Confirmation of weight reduction effect of fat tissue
본 발명에 따른 아크릴아미드계 화합물들의 지방조직의 양에 미치는 영향을 확인하기 위하여, 실시예 4-1의 실험동물군들의 신장 주변 지방, 부고환 지방 및 갈색 지방의 양을 측정하였다. 또한, 신장 주변 지방 조직과 부고환 지방 조직을 적출하여 현미경으로 지방세포의 크기를 관찰하였다.In order to confirm the effect of the acrylamide compounds according to the present invention on the amount of adipose tissue, the amount of peripheral fat, epididymal fat and brown fat in the experimental animal groups of Example 4-1 was measured. In addition, adipose tissue and epididymal adipose tissue of the kidney were extracted and the size of adipocytes was observed under a microscope.
그 결과 하기 표 2에서 나타낸 바와 같이, 본 발명의 화합물 A를 투여한 실험군의 마우스들이 고지방 식이군에 속하는 마우스들보다 신장 주변 지방, 부고환 지방 및 갈색 지방의 양을 모두 감소시켰으며, 그 효과는 양성대조군인 레스베라트롤에 비해 우수한 것을 확인할 수 있었다.As a result, as shown in Table 2 below, the mice of the test group to which the compound A of the present invention was administered decreased the amounts of the peripheral fat, epididymal fat and brown fat of the kidneys compared with the mice belonging to the high fat diet group, Which is superior to the positive control group, resveratrol.
또한, 본 발명의 화합물 A를 투여한 실험군에서 신장 주변 지방 조직과 부고환 지방 조직의 지방 세포의 크기가 고지방 식이군에 비하여 현저히 줄어들었으며, 양성대조군인 레스베라트롤 투여군과 비교할 때 지방 세포 크기의 감소효과가 우수하였다 (도 9a 및 9b 참조).In addition, in the test group administered with the compound A of the present invention, the sizes of adipose tissue and epididymal adipose tissue of the kidney were significantly reduced compared with those of the high fat diet group. Compared with the positive control group, resveratrol, (See Figs. 9A and 9B).
식이별 마우스의 신장주변 지방, 부고환 지방 및 갈색지방 무게Weight of dietary peripartum, epididymal fat and brown fat in mice
신장 주변 지방 (g) Fat around the kidney (g) 부고환 지방 (g)Epididymis fat (g) 갈색 지방 (g)Brown fat (g)
일반 식이A normal diet 0.333 ± 0.1030.333 + - 0.103 0.839 ± 0.2350.839 + 0.235 0.124 ± 0.0180.124 + 0.018
고지방 식이High fat diet 1.260 ± 0.1561.260 + - 0.156 2.635 ± 0.4272.635 + 0.427 0.232 ± 0.0220.232 + 0.022
고지방 식이 + 화합물 AHigh Fat Diet + Compound A 0.931 ± 0.109*0.931 + - 0.109 * 2.342 ± 0.3952.342 + - 0.395 0.195 ± 0.0440.195 + 0.044
고지방 식이 + 레스베라트롤High fat diet + resveratrol 1.176 ± 0.0951.176 + 0.095 2.758 ± 0.3012.758 0.301 0.227 ± 0.0430.227 0.043
*P<0.05* P < 0.05
<4-3> 혈청 중 중성지방 농도 감소 효과 확인<4-3> Confirming the effect of reducing triglyceride concentration in serum
본 발명에 따른 아크릴아미드계 화합물들의 혈청 중 중성지방 함량에 미치는 영향을 확인하기 위하여, 실시예 4-1의 실험동물군들의 혈청 중 중성지방 함량을 상업용 측정키트(Pureauto S TG-N, Daiichi, 일본)를 이용하여 측정하였다.In order to confirm the effect of the acrylamide compounds according to the present invention on the triglyceride content in the serum, the content of triglyceride in the serum of the experimental animal groups of Example 4-1 was measured using a commercial measurement kit (Pureauto S TG-N, Daiichi, Japan).
그 결과 도 10에서 나타낸 바와 같이, 고지방 식이군(HF)의 경우 혈중 중성지방 함량이 매우 높게 나타난 반면, 고지방 식이와 함께 본 발명의 화합물 A를 급여한 실험군에서는 혈중 중성지방 함량이 두드러지게 감소되어 있는 것을 확인할 수 있었다. 특히, 이러한 본 발명의 화합물 A의 투여에 따른 혈중 중성지방의 함량 감소 효과는 일반식이군(LF) 보다 높았으며, 또한 고지방식이와 함께 레스베라트롤 투여한 실험군과 비교해서도 그 효과가 매우 우수한 것을 알 수 있었다.As a result, as shown in FIG. 10, in the case of the high fat dietary group (HF), the blood triglyceride content was very high, while in the high fat dietary group and the compound group of the present invention, the triglyceride content in the blood was markedly decreased . Particularly, the effect of reducing the content of triglyceride in blood according to the administration of the compound A of the present invention was higher than that of the general dietary group (LF), and the effect was more excellent than that of the test group administered with resveratrol Could know.
<4-4> 혈중 <4-4> Serum ASTAST /ALT 활성도 확인/ Check ALT activity
본 발명의 화합물 A가 in vivo에서 독성을 나타내는지 확인하기 위하여, 독성 물질에 의한 간 손상시 급격히 증가하는 것으로 알려진 혈중 AST 및 ALT 활성도를 상기 실시예 4-1의 실험동물군들에서 측정하였다. 혈중 ALT(alanine aminotransferase) 및 AST(aspartate aminotransferase) 양은 IFCC UV 방법으로 AST, ALT분석시약(Siemens, 미국)를 사용하여 측정하였다.In order to confirm that the compound A of the present invention shows toxicity in vivo , blood AST and ALT activities, which are known to be abruptly increased upon liver damage caused by toxic substances, were measured in the experimental animal groups of the above Example 4-1. Serum ALT (alanine aminotransferase) and AST (aspartate aminotransferase) levels were measured by IFCC UV method using AST and ALT assay reagents (Siemens, USA).
그 결과 도 11 및 도 12에서 나타낸 바와 같이, 본 발명의 화합물 A을 투여한 실험군에서의 AST 및 ALT 활성도는 일반 식이군(LF) 및 고지방 식이군 (HF)과 유사한 AST 활성도 및 ALT 활성도를 나타내어 간 독성을 유발하지 않는 것을 확인할 수 있었다.As a result, as shown in FIG. 11 and FIG. 12, AST and ALT activity in the test group administered with the compound A of the present invention showed AST activity and ALT activity similar to those of the normal dietary group (LF) and the high fat dietary group (HF) And did not induce liver toxicity.
<제조예 1> 약학제제 제조예&Lt; Preparation Example 1 >
<1-1> <1-1> 산제의Sanje 제조 Produce
본 발명의 화합물 ----------------------------- 300 mgThe compound of the present invention 300 mg
유당 ------------------------------ 100mgLactose ------------------------------ 100mg
탈크 ------------------------------ 10 mgTalc ------------------------------ 10 mg
상기의 성분들을 혼합하고 기밀포에 충진하여 산제를 제조한다.The above components are mixed and filled in airtight bags to prepare powders.
<1-2> 정제의 제조<1-2> Preparation of tablets
본 발명의 화합물 ------------------------------- 50 mgCompound of the present invention 50 mg
옥수수전분 ------------------------------ 100mgCorn Starch ------------------------------ 100mg
유당 ------------------------------ 100 mgLactose ------------------------------ 100 mg
스테아린산 마그네슘 -------------------------- 2 mgMagnesium stearate -------------------------- 2 mg
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above components, tablets are prepared by tableting according to the usual preparation method of tablets.
<1-3> 캡슐제의 제조&Lt; 1-3 > Preparation of capsules
본 발명의 화합물 ----------------------------- 50 mgThe compound of the present invention - 50 mg
옥수수전분 ------------------------------ 100mgCorn Starch ------------------------------ 100mg
유당 ------------------------------ 100 mgLactose ------------------------------ 100 mg
스테아린산 마그네슘 ------------------------- 2 mgMagnesium stearate ------------------------- 2 mg
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.The above components are mixed according to a conventional capsule preparation method and filled in gelatin capsules to prepare capsules.
<1-4> 주사제의 제조&Lt; 1-4 > Preparation of injection
본 발명의 화합물 ------------------------------- 50 mgCompound of the present invention 50 mg
주사용 멸균 증류수 --------------------------- 적량Sterile sterilized distilled water for injection ---------------------------
pH 조절제 ----------------------------- 적량pH adjusting agent -----------------------------
통상의 주사제의 제조방법에 따라 1 앰플당 (2㎖) 상기의 성분 함량으로 제조한다.(2 ml) per 1 ampoule according to the usual injection preparation method.
<1-5> <1-5> 액제의Liquid 제조 Produce
본 발명의 화합물 ----------------------------------- 100mgThe compound of the present invention - 100 mg
이성화당 ------------------------------------ 10 gIsing Party ------------------------------------ 10 g
만니톨 ------------------------------------- 5 gMannitol ------------------------------------- 5 g
정제수 -------------------------------------적량Purified water -------------------------------------
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100 ㎖로 조절한 후 갈색병에 충진하여 멸균시켜 액제를 제조한다.Each component was added to purified water in accordance with the usual preparation method of the liquid preparation and dissolved, and the lemon flavor was added in an appropriate amount. Then, the above components were mixed and then purified water was added thereto. The whole was adjusted to 100 ml with purified water, And sterilized to prepare a liquid preparation.
<제조예 2> 건강 식품의 제조&Lt; Preparation Example 2 > Preparation of health food
<2-1> 기능성 식품의 제조<2-1> Production of functional food
본 발명의 화합물 -------------------------------- 1000 ㎎1000 mg of the compound of the present invention
비타민 혼합물 ------------------------------ 적량Vitamin mixture ------------------------------
비타민 A 아세테이트 -------------------------- 70 ㎍Vitamin A Acetate -------------------------- 70 g
비타민 E ------------------------------ 1.0 ㎎Vitamin E ------------------------------ 1.0 mg
비타민 B1 ------------------------------ 0.13 ㎎Vitamin B1 ------------------------------ 0.13 mg
비타민 B2 ------------------------------- 0.15 ㎎Vitamin B2 ------------------------------- 0.15 mg
비타민 B6 ------------------------------ 0.5 ㎎Vitamin B6 ------------------------------ 0.5 mg
비타민 B12 ------------------------------ 0.2 ㎍Vitamin B12 ------------------------------ 0.2 g
비타민 C ------------------------------ 10 ㎎Vitamin C ------------------------------ 10 mg
비오틴 ------------------------------- 10 ㎍Biotin ------------------------------- 10 μg
니코틴산아미드 ------------------------------ 1.7 ㎎Nicotinic amide ------------------------------ 1.7 mg
엽산 ---------------------------------------- 50㎍Folic acid ----------------------------------------
판토텐산 칼슘 ------------------------------ 0.5 ㎎Calcium pantothenate ------------------------------ 0.5 mg
무기질 혼합물 ------------------------------- 적량Inorganic mixture -------------------------------
황산제1철 ------------------------------ 1.75 ㎎Ferrous sulfate ------------------------------ 1.75 mg
산화아연 ------------------------------ 0.82 ㎎Zinc oxide ------------------------------ 0.82 mg
탄산마그네슘 ------------------------------ 25.3 ㎎Magnesium carbonate ------------------------------ 25.3 mg
제1인산칼륨 -------------------------------- 15 ㎎Potassium phosphate monohydrate 15 mg
제2인산칼 --------------------------------- 55 ㎎Second phosphoric acid knife - 55 mg
구연산칼륨 --------------------------------- 90㎎Potassium citrate --------------------------------- 90 mg
탄산칼슘 --------------------------------- 100 ㎎Calcium carbonate --------------------------------- 100 mg
염화마그네슘 ------------------------------- 24.8 ㎎Magnesium Chloride ------------------------------- 24.8 mg
상기의 비타민 및 미네랄 혼합물의 조성비는 비교적 건강식품에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만, 그 배합비를 임의로 변형 실시하여도 무방하며, 통상의 건강식품 제조방법에 따라 상기의 성분을 혼합한 다음, 과립을 제조하고, 통상의 방법에 따라 건강식품 조성물 제조에 사용할 수 있다.Although the composition ratio of the above-mentioned vitamin and mineral mixture is comparatively mixed with a composition suitable for health food as a preferred embodiment, the compounding ratio may be arbitrarily modified, and the above ingredients are mixed according to a conventional method for producing healthy foods , Granules can be prepared and used in the manufacture of health food compositions according to conventional methods.
<2-1> 기능성 건강 음료의 제조<2-1> Preparation of functional health drinks
본 발명의 화합물 -----------------------------------1000 ㎎The compounds of the present invention - 1000 mg
구연산 ----------------------------------- 1000㎎Citric acid ----------------------------------- 1000㎎
올리고당 -------------------------------------100 gOligosaccharides ------------------------------------- 100 g
매실농축액 --------------------------------------- 2 gPlum concentrate --------------------------------------- 2 g
타우린 ---------------------------------------1 gTaurine --------------------------------------- 1 g
정제수를 가하여 전체 ----------------------------900 ㎖Purified water was added to the whole to 900 ml
통상의 건강음료 제조방법에 따라 상기의 성분을 혼합한 다음, 약 1시간 동안 85℃에서 교반 가열한 후, 만들어진 용액을 여과하여 멸균된 2ℓ용기에 취득하여 밀봉 멸균한 뒤 냉장 보관한 다음 본 발명의 건강음료 조성물 제조에 사용한다. 상기 조성비는 비교적 기호음료에 적합한 성분을 바람직한 실시예로 혼합 조성하였지만 수요계층이나, 수요국가, 사용용도 등 지역적, 민족적 기호도에 따라서 그 배합비를 임의로 변형 실시하여도 무방하다.The above components were mixed according to a conventional health drink manufacturing method, and the mixture was heated for about 1 hour at 85 DEG C with stirring, and the solution thus prepared was filtered to obtain a sterilized 2-liter container, which was sealed and sterilized, &Lt; / RTI &gt; Although the compositional ratio is relatively mixed with a component suitable for a favorite drink, it is also possible to arbitrarily modify the compounding ratio according to the regional or national preference such as the demand class, the demanding country, and the use purpose.
<제조예 3> 화장료 조성물의 제조&Lt; Preparation Example 3 > Preparation of cosmetic composition
<3-1> 크림의 제조<3-1> Production of cream
본 발명에 따른 화합물 ------------------------------ 4.6 중량부Compound according to the present invention 4.6 parts by weight
세토스테아릴알코올 ------------------------------ 2.8 중량부Cetostearyl alcohol ------------------------------ 2.8 parts by weight
밀납 ------------------------------ 2.6 중량부Wax ------------------------------ 2.6 parts by weight
스테아린산 ------------------------------ 1.4 중량부Stearic acid 1.4 parts by weight
친유형모노스테아린산글리세린 ------------------------------ 2 중량부Choline type glycerin monostearate ------------------------------ 2 parts by weight
피이지-100 스테아레이트 ------------------------------ 1 중량부&Lt; tb &gt; &lt; tb &gt; &lt; tb &gt;
세스퀴올레인산소르비탈 ------------------------------ 1.4 중량부Sorbitol sesquioleate ------------------------------ 1.4 parts by weight
호호바오일 ------------------------------ 4 중량부Jojoba oil ------------------------------ 4 parts by weight
스쿠알란 ------------------------------ 3.8 중량부Squalane ------------------------------ 3.8 parts by weight
폴리소르베이트 60 ------------------------------ 1.1 중량부 Polysorbate 60 ------------------------------ 1.1 parts by weight
마카다이아오일 ------------------------------ 2 중량부Macadia oil ------------------------------ 2 parts by weight
초산토코페롤 ------------------------------ 0.2 중량부Tocopheryl acetate ------------------------------ 0.2 parts by weight
메칠폴리실록산 ------------------------------ 0.4 중량부Methylpolysiloxane 0.4 parts by weight
에칠파라벤 ------------------------------ 0.1 중량부Ethyl paraben 0.1 part by weight
프로필파라벤 ------------------------------ 0.1 중량부Propyl paraben 0.1 part by weight
Euxyl K-400 ------------------------------ 0.1 중량부Euxyl K-400 ------------------------------ 0.1 part by weight
1,3-부칠렌글리콜 ------------------------------ 7 중량부1,3-butylene glycol - 7 parts by weight
메칠파라벤 ------------------------------ 0.05 중량부Methylparaben 0.05 part by weight
글리세린 ------------------------------ 6 중량부Glycerin 6 parts by weight
d-판데놀 ------------------------------ 0.2 중량부d-Pandenol ------------------------------ 0.2 parts by weight
트리에탄올아민 ------------------------------ 0.2 중량부Triethanolamine ------------------------------ 0.2 parts by weight
pt 41891 ------------------------------ 0.2 중량부pt 41891 ------------------------------ 0.2 parts by weight
p-H2O ------------------------------ 46.05 중량부p-H 2 O - 46.05 parts by weight
<3-2> 로션의 제조<3-2> Production of Lotion
본 발명에 따른 화합물 ------------------------------ 3.5 중량부Compound according to the present invention 3.5 parts by weight
세토스테아릴알코올 ------------------------------ 1.6 중량부Cetostearyl alcohol ------------------------------ 1.6 parts by weight
스테아린산 ------------------------------ 1.4 중량부Stearic acid 1.4 parts by weight
친유형모노스테아린산글리세린 ---------------------------- 1.8 중량부Glycerin monostearate having a proline type 1.8 parts by weight
피이지-100 스테아레이트 ------------------------------ 2.6 중량부&Lt; tb &gt; &lt; tb &gt; &lt; tb &gt;
세스퀴올레인산소르비탈 ------------------------------ 0.6 중량부Sorbitol sesquioleate ------------------------------ 0.6 parts by weight
스쿠알렌 ------------------------------ 4.8 중량부Squalane ------------------------------ 4.8 parts by weight
마카다이아오일 ------------------------------ 2 중량부Macadia oil ------------------------------ 2 parts by weight
호호바오일 ------------------------------ 2 중량부Jojoba oil ------------------------------ 2 parts by weight
초산토코페롤 ------------------------------ 0.4 중량부Tocopheryl acetate ------------------------------ 0.4 parts by weight
메칠폴리실록산 ------------------------------ 0.2 중량부Methylpolysiloxane - 0.2 part by weight
에칠파라벤 ------------------------------ 0.1 중량부Ethyl paraben 0.1 part by weight
프로필파라벤 ------------------------------ 0.1 중량부Propyl paraben 0.1 part by weight
1,3-부칠렌글리콜 ------------------------------ 4 중량부1,3-butylene glycol 4 parts by weight
메칠파라벤 ------------------------------ 0.1 중량부Methylparaben 0.1 part by weight
산탄검 ------------------------------ 0.1 중량부Xanthan gum ------------------------------ 0.1 part by weight
글리세린 ------------------------------ 4 중량부Glycerin 4 parts by weight
d-판데놀 ------------------------------ 0.15 중량부d-Pandenol ------------------------------ 0.15 parts by weight
알란토인 ------------------------------ 0.1 중량부Allantoin ------------------------------ 0.1 part by weight
카르보머(2% aq. Sol) ------------------------------ 4 중량부Carbomer (2% aq. Sol) - 4 parts by weight
트리에탄올아민 ------------------------------ 0.15 중량부Triethanolamine ------------------------------ 0.15 parts by weight
에탄올 ------------------------------ 3 중량부Ethanol - 3 parts by weight
pt 41891 ------------------------------ 0.1 중량부pt 41891 ------------------------------ 0.1 part by weight
p-H20 ------------------------------ 48.3 중량부p-H 2 O - 48.3 parts by weight
<제조예 4> 사료첨가제의 제조&Lt; Preparation Example 4 > Production of feed additive
본 발명자들을 본 발명의 아크릴아미드계 화합물을 유효성분으로 하여 하기와 같은 조성으로 사료첨가제를 제조하였다.The inventors of the present invention prepared the feed additive with the following composition using the acrylamide-based compound of the present invention as an active ingredient.
본 발명에 따른 화합물 ------------------------------0.1 ~ 20% 중량부The compound according to the present invention 0.1 to 20% by weight
지방분해효소(Lipase) ---------------------------0.001 ~ 0.01% 중량부Lipase 0.001 to 0.01% by weight
제 3 인산칼슘 ------------------------------ 1 ~ 20% 중량부Calcium tertiary phosphate - 1 to 20% by weight
비타민 E ------------------------------ 0.01 ~ 0.1% 중량부Vitamin E ------------------------------ 0.01 to 0.1% by weight
효소 분말 ------------------------------ 1 ~ 10% 중량부Enzyme powder ------------------------------ 1 ~ 10% by weight
유산균 ------------------------------ 0.1 ~ 10% 중량부Lactic acid bacteria ------------------------------ 0.1 ~ 10% by weight
바실러스(Bacillus) 배양액 -------------------------0.01 ~ 10% 중량부Bacillus culture solution - 0.01 to 10% by weight
포도당 ------------------------------ 20 ~ 90% 중량부Glucose - 20 to 90% by weight
이상으로 본 발명의 내용의 특정한 부분을 상세히 기술하였는바, 당업계의 통상의 지식을 가진 자에게 있어서, 이러한 구체적 기술은 단지 바람직한 실시양태일 뿐이며, 이에 의해 본 발명의 범위가 제한되는 것이 아닌 점은 명백할 것이다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항들과 그것들의 등가물에 의하여 정의된다고 할 것이다.While the present invention has been particularly shown and described with reference to specific embodiments thereof, those skilled in the art will appreciate that such specific embodiments are merely preferred embodiments and that the scope of the invention is not limited thereby. It will be obvious. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (14)

  1. 하기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용되는 염을 유효성분으로 포함하는, 비만 또는 지질관련 대사성 질환의 예방 또는 치료용 약학 조성물:A pharmaceutical composition for preventing or treating obesity or lipid-related metabolic diseases, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
    [화학식 1][Chemical Formula 1]
    Figure PCTKR2017006732-appb-I000033
    Figure PCTKR2017006732-appb-I000033
    상기 화학식 1에서, R은
    Figure PCTKR2017006732-appb-I000034
    ,
    Figure PCTKR2017006732-appb-I000035
    ,
    Figure PCTKR2017006732-appb-I000036
    ,
    Figure PCTKR2017006732-appb-I000037
    ,
    Figure PCTKR2017006732-appb-I000038
    ,
    Figure PCTKR2017006732-appb-I000039
    ,
    Figure PCTKR2017006732-appb-I000040
    ,
    Figure PCTKR2017006732-appb-I000041
    및
    Figure PCTKR2017006732-appb-I000042
    로 이루어진 군에서 선택되는 어느 하나임.     In the above formula (1), R is
    Figure PCTKR2017006732-appb-I000034
    ,
    Figure PCTKR2017006732-appb-I000035
    ,
    Figure PCTKR2017006732-appb-I000036
    ,
    Figure PCTKR2017006732-appb-I000037
    ,
    Figure PCTKR2017006732-appb-I000038
    ,
    Figure PCTKR2017006732-appb-I000039
    ,
    Figure PCTKR2017006732-appb-I000040
    ,
    Figure PCTKR2017006732-appb-I000041
    And
    Figure PCTKR2017006732-appb-I000042
    &Lt; / RTI &gt;
  2. 제1항에 있어서, The method according to claim 1,
    상기 화학식 1로 표시되는 화합물은 (E)-3-(4-(tert-부틸)페닐)-N-이소부틸-2-메틸아크릴아미드((E)-3-(4-(tertbutyl)phenyl)-N-isobutyl-2-methylacrylamide); (E)-3-(4-(tert-부틸)페닐)2-메틸-N-펜에틸아크릴아미드 ((E)-3-(4-(tert-butyl)phenyl)2-methyl-N-phenethylacrylamide); 및 (E)-3-(4-(tert-부틸)페닐)-N-(4-하이드록시펜에틸)-2-메틸아크릴아미드 ((E)-3-(4-(tert-butyl)phenyl)-N-(4-hydroxyphenethyl)-2-methylacrylamide)로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 비만 또는 지질관련 대사성 질환의 예방 또는 치료용 약학 조성물. (E) -3- (4- (tertbutyl) phenyl) -N-isobutyl-2-methylacrylamide (E) -N-isobutyl-2-methylacrylamide); (E) -3- (4- (tert-butyl) phenyl) 2-methyl-N-phenethylacrylamide ); (E) -3- (4- (tert-butyl) phenyl) -N- (4-hydroxyphenyl) -2-methylacrylamide ) -N- (4-hydroxyphenethyl) -2-methylacrylamide). &Lt; / RTI &gt;
  3. 제1항에 있어서, The method according to claim 1,
    상기 지질관련 대사성 질환은 고지혈증, 이상지질혈증, 동맥경화, 간지방증, 비알콜성 지방간, 2형 당뇨병 및 대사증후군으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 비만 또는 지질관련 대사성 질환의 예방 또는 치료용 약학 조성물. Wherein said lipid-related metabolic diseases are selected from the group consisting of hyperlipidemia, dyslipidemia, arteriosclerosis, hepaticopathy, non-alcoholic fatty liver, type 2 diabetes and metabolic syndrome. &Lt; / RTI &gt;
  4. 하기 화학식 1로 표시되는 화합물 또는 이의 식품학적으로 허용되는 염을 유효성분으로 포함하는, 비만 또는 지질관련 대사성 질환의 예방 또는 개선용 건강기능식품:A health functional food for preventing or ameliorating an obesity or lipid-related metabolic disease comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
    [화학식 1][Chemical Formula 1]
    Figure PCTKR2017006732-appb-I000043
    Figure PCTKR2017006732-appb-I000043
    상기 화학식 1에서, R은
    Figure PCTKR2017006732-appb-I000044
    ,
    Figure PCTKR2017006732-appb-I000045
    ,
    Figure PCTKR2017006732-appb-I000046
    ,
    Figure PCTKR2017006732-appb-I000047
    ,
    Figure PCTKR2017006732-appb-I000048
    ,
    Figure PCTKR2017006732-appb-I000049
    ,
    Figure PCTKR2017006732-appb-I000050
    ,
    Figure PCTKR2017006732-appb-I000051
    및
    Figure PCTKR2017006732-appb-I000052
    로 이루어진 군에서 선택되는 어느 하나임.     In the above formula (1), R is
    Figure PCTKR2017006732-appb-I000044
    ,
    Figure PCTKR2017006732-appb-I000045
    ,
    Figure PCTKR2017006732-appb-I000046
    ,
    Figure PCTKR2017006732-appb-I000047
    ,
    Figure PCTKR2017006732-appb-I000048
    ,
    Figure PCTKR2017006732-appb-I000049
    ,
    Figure PCTKR2017006732-appb-I000050
    ,
    Figure PCTKR2017006732-appb-I000051
    And
    Figure PCTKR2017006732-appb-I000052
    &Lt; / RTI &gt;
  5. 제4항에 있어서, 5. The method of claim 4,
    상기 화학식 1로 표시되는 화합물은 (E)-3-(4-(tert-부틸)페닐)-N-이소부틸-2-메틸아크릴아미드((E)-3-(4-(tertbutyl)phenyl)-N-isobutyl-2-methylacrylamide); (E)-3-(4-(tert-부틸)페닐)2-메틸-N-펜에틸아크릴아미드 ((E)-3-(4-(tert-butyl)phenyl)2-methyl-N-phenethylacrylamide); 및 (E)-3-(4-(tert-부틸)페닐)-N-(4-하이드록시펜에틸)-2-메틸아크릴아미드 ((E)-3-(4-(tert-butyl)phenyl)-N-(4-hydroxyphenethyl)-2-methylacrylamide)로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 비만 또는 지질관련 대사성 질환의 예방 또는 개선용 건강기능식품.(E) -3- (4- (tertbutyl) phenyl) -N-isobutyl-2-methylacrylamide (E) -N-isobutyl-2-methylacrylamide); (E) -3- (4- (tert-butyl) phenyl) 2-methyl-N-phenethylacrylamide ); (E) -3- (4- (tert-butyl) phenyl) -N- (4-hydroxyphenyl) -2-methylacrylamide ) -N- (4-hydroxyphenethyl) -2-methylacrylamide). &Lt; / RTI &gt;
  6. 하기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용되는 염을 유효성분으로 포함하는, 비만 또는 지질관련 대사성 질환의 예방 또는 개선용 화장료 조성물:A cosmetic composition for preventing or ameliorating an obesity or lipid-related metabolic disease, comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
    [화학식 1][Chemical Formula 1]
    Figure PCTKR2017006732-appb-I000053
    Figure PCTKR2017006732-appb-I000053
    상기 화학식 1에서, In Formula 1,
    R은
    Figure PCTKR2017006732-appb-I000054
    ,
    Figure PCTKR2017006732-appb-I000055
    ,
    Figure PCTKR2017006732-appb-I000056
    ,
    Figure PCTKR2017006732-appb-I000057
    ,
    Figure PCTKR2017006732-appb-I000058
    ,
    Figure PCTKR2017006732-appb-I000059
    ,
    Figure PCTKR2017006732-appb-I000060
    ,
    Figure PCTKR2017006732-appb-I000061
    및
    Figure PCTKR2017006732-appb-I000062
    로 이루어진 군에서 선택되는 어느 하나임.     R is
    Figure PCTKR2017006732-appb-I000054
    ,
    Figure PCTKR2017006732-appb-I000055
    ,
    Figure PCTKR2017006732-appb-I000056
    ,
    Figure PCTKR2017006732-appb-I000057
    ,
    Figure PCTKR2017006732-appb-I000058
    ,
    Figure PCTKR2017006732-appb-I000059
    ,
    Figure PCTKR2017006732-appb-I000060
    ,
    Figure PCTKR2017006732-appb-I000061
    And
    Figure PCTKR2017006732-appb-I000062
    &Lt; / RTI &gt;
  7. 제6항에 있어서, The method according to claim 6,
    상기 화학식 1로 표시되는 화합물은 (E)-3-(4-(tert-부틸)페닐)-N-이소부틸-2-메틸아크릴아미드((E)-3-(4-(tertbutyl)phenyl)-N-isobutyl-2-methylacrylamide); (E)-3-(4-(tert-부틸)페닐)2-메틸-N-펜에틸아크릴아미드 ((E)-3-(4-(tert-butyl)phenyl)2-methyl-N-phenethylacrylamide); 및 (E)-3-(4-(tert-부틸)페닐)-N-(4-하이드록시펜에틸)-2-메틸아크릴아미드 ((E)-3-(4-(tert-butyl)phenyl)-N-(4-hydroxyphenethyl)-2-methylacrylamide)로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 비만 또는 지질관련 대사성 질환의 예방 또는 개선용 화장료 조성물.(E) -3- (4- (tertbutyl) phenyl) -N-isobutyl-2-methylacrylamide (E) -N-isobutyl-2-methylacrylamide); (E) -3- (4- (tert-butyl) phenyl) 2-methyl-N-phenethylacrylamide ); (E) -3- (4- (tert-butyl) phenyl) -N- (4-hydroxyphenyl) -2-methylacrylamide ) -N- (4-hydroxyphenethyl) -2-methylacrylamide). &Lt; / RTI &gt;
  8. 하기 화학식 1로 표시되는 화합물 또는 이의 식품학적으로 허용되는 염을 유효성분으로 포함하는, 비만 또는 지질관련 대사성 질환의 예방 또는 개선용 사료 첨가물:A feed additive for preventing or ameliorating an obesity or lipid-related metabolic disease comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient:
    [화학식 1][Chemical Formula 1]
    Figure PCTKR2017006732-appb-I000063
    Figure PCTKR2017006732-appb-I000063
    상기 화학식 1에서, R은
    Figure PCTKR2017006732-appb-I000064
    ,
    Figure PCTKR2017006732-appb-I000065
    ,
    Figure PCTKR2017006732-appb-I000066
    ,
    Figure PCTKR2017006732-appb-I000067
    ,
    Figure PCTKR2017006732-appb-I000068
    ,
    Figure PCTKR2017006732-appb-I000069
    ,
    Figure PCTKR2017006732-appb-I000070
    ,
    Figure PCTKR2017006732-appb-I000071
    및
    Figure PCTKR2017006732-appb-I000072
    로 이루어진 군에서 선택되는 어느 하나임.     In the above formula (1), R is
    Figure PCTKR2017006732-appb-I000064
    ,
    Figure PCTKR2017006732-appb-I000065
    ,
    Figure PCTKR2017006732-appb-I000066
    ,
    Figure PCTKR2017006732-appb-I000067
    ,
    Figure PCTKR2017006732-appb-I000068
    ,
    Figure PCTKR2017006732-appb-I000069
    ,
    Figure PCTKR2017006732-appb-I000070
    ,
    Figure PCTKR2017006732-appb-I000071
    And
    Figure PCTKR2017006732-appb-I000072
    &Lt; / RTI &gt;
  9. 제8항에 있어서, 9. The method of claim 8,
    상기 화학식 1로 표시되는 화합물은 (E)-3-(4-(tert-부틸)페닐)-N-이소부틸-2-메틸아크릴아미드((E)-3-(4-(tertbutyl)phenyl)-N-isobutyl-2-methylacrylamide); (E)-3-(4-(tert-부틸)페닐)2-메틸-N-펜에틸아크릴아미드 ((E)-3-(4-(tert-butyl)phenyl)2-methyl-N-phenethylacrylamide); 및 (E)-3-(4-(tert-부틸)페닐)-N-(4-하이드록시펜에틸)-2-메틸아크릴아미드 ((E)-3-(4-(tert-butyl)phenyl)-N-(4-hydroxyphenethyl)-2-methylacrylamide)로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 비만 또는 지질관련 대사성 질환의 예방 또는 개선용 사료 첨가물.(E) -3- (4- (tertbutyl) phenyl) -N-isobutyl-2-methylacrylamide (E) -N-isobutyl-2-methylacrylamide); (E) -3- (4- (tert-butyl) phenyl) 2-methyl-N-phenethylacrylamide ); (E) -3- (4- (tert-butyl) phenyl) -N- (4-hydroxyphenyl) -2-methylacrylamide ) -N- (4-hydroxyphenethyl) -2-methylacrylamide). &Lt; / RTI &gt;
  10. 필요한 개체에 하기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용되는 염을 투여하는 단계를 포함하는, 비만 또는 지질관련 대사성 질환의 치료방법:A method for the treatment of obesity or a lipid-related metabolic disease comprising administering to a subject in need thereof a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof:
    [화학식 1][Chemical Formula 1]
    Figure PCTKR2017006732-appb-I000073
    Figure PCTKR2017006732-appb-I000073
    상기 화학식 1에서, R은
    Figure PCTKR2017006732-appb-I000074
    ,
    Figure PCTKR2017006732-appb-I000075
    ,
    Figure PCTKR2017006732-appb-I000076
    ,
    Figure PCTKR2017006732-appb-I000077
    ,
    Figure PCTKR2017006732-appb-I000078
    ,
    Figure PCTKR2017006732-appb-I000079
    ,
    Figure PCTKR2017006732-appb-I000080
    ,
    Figure PCTKR2017006732-appb-I000081
    및
    Figure PCTKR2017006732-appb-I000082
    로 이루어진 군에서 선택되는 어느 하나임.     In the above formula (1), R is
    Figure PCTKR2017006732-appb-I000074
    ,
    Figure PCTKR2017006732-appb-I000075
    ,
    Figure PCTKR2017006732-appb-I000076
    ,
    Figure PCTKR2017006732-appb-I000077
    ,
    Figure PCTKR2017006732-appb-I000078
    ,
    Figure PCTKR2017006732-appb-I000079
    ,
    Figure PCTKR2017006732-appb-I000080
    ,
    Figure PCTKR2017006732-appb-I000081
    And
    Figure PCTKR2017006732-appb-I000082
    &Lt; / RTI &gt;
  11. 하기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용되는 염의 비만 또는 지질관련 대사성 질환의 예방 또는 치료용 약학적 조성물에 사용하기 위한 용도:Use of a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof for use in a pharmaceutical composition for preventing or treating obesity or a lipid-related metabolic disease:
    [화학식 1][Chemical Formula 1]
    Figure PCTKR2017006732-appb-I000083
    Figure PCTKR2017006732-appb-I000083
    상기 화학식 1에서, R은
    Figure PCTKR2017006732-appb-I000084
    ,
    Figure PCTKR2017006732-appb-I000085
    ,
    Figure PCTKR2017006732-appb-I000086
    ,
    Figure PCTKR2017006732-appb-I000087
    ,
    Figure PCTKR2017006732-appb-I000088
    ,
    Figure PCTKR2017006732-appb-I000089
    ,
    Figure PCTKR2017006732-appb-I000090
    ,
    Figure PCTKR2017006732-appb-I000091
    및
    Figure PCTKR2017006732-appb-I000092
    로 이루어진 군에서 선택되는 어느 하나임.     In the above formula (1), R is
    Figure PCTKR2017006732-appb-I000084
    ,
    Figure PCTKR2017006732-appb-I000085
    ,
    Figure PCTKR2017006732-appb-I000086
    ,
    Figure PCTKR2017006732-appb-I000087
    ,
    Figure PCTKR2017006732-appb-I000088
    ,
    Figure PCTKR2017006732-appb-I000089
    ,
    Figure PCTKR2017006732-appb-I000090
    ,
    Figure PCTKR2017006732-appb-I000091
    And
    Figure PCTKR2017006732-appb-I000092
    &Lt; / RTI &gt;
  12. 하기 화학식 1로 표시되는 화합물 또는 이의 식품학적으로 허용되는 염의 비만 또는 지질관련 대사성 질환의 예방 또는 개선용 건강기능식품에 사용하기 위한 용도:Use of a compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof for use in a health functional food for preventing or ameliorating obesity or a lipid-related metabolic disease:
    [화학식 1][Chemical Formula 1]
    Figure PCTKR2017006732-appb-I000093
    Figure PCTKR2017006732-appb-I000093
    상기 화학식 1에서, R은
    Figure PCTKR2017006732-appb-I000094
    ,
    Figure PCTKR2017006732-appb-I000095
    ,
    Figure PCTKR2017006732-appb-I000096
    ,
    Figure PCTKR2017006732-appb-I000097
    ,
    Figure PCTKR2017006732-appb-I000098
    ,
    Figure PCTKR2017006732-appb-I000099
    ,
    Figure PCTKR2017006732-appb-I000100
    ,
    Figure PCTKR2017006732-appb-I000101
    및
    Figure PCTKR2017006732-appb-I000102
    로 이루어진 군에서 선택되는 어느 하나임.     In the above formula (1), R is
    Figure PCTKR2017006732-appb-I000094
    ,
    Figure PCTKR2017006732-appb-I000095
    ,
    Figure PCTKR2017006732-appb-I000096
    ,
    Figure PCTKR2017006732-appb-I000097
    ,
    Figure PCTKR2017006732-appb-I000098
    ,
    Figure PCTKR2017006732-appb-I000099
    ,
    Figure PCTKR2017006732-appb-I000100
    ,
    Figure PCTKR2017006732-appb-I000101
    And
    Figure PCTKR2017006732-appb-I000102
    &Lt; / RTI &gt;
  13. 하기 화학식 1로 표시되는 화합물 또는 이의 약제학적으로 허용되는 염의 비만 또는 지질관련 대사성 질환의 예방 또는 치료용 화장료 조성물에 사용하기 위한 용도:Use of a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof for use in a cosmetic composition for preventing or treating obesity or a lipid-related metabolic disease:
    [화학식 1][Chemical Formula 1]
    Figure PCTKR2017006732-appb-I000103
    Figure PCTKR2017006732-appb-I000103
    상기 화학식 1에서, R은
    Figure PCTKR2017006732-appb-I000104
    ,
    Figure PCTKR2017006732-appb-I000105
    ,
    Figure PCTKR2017006732-appb-I000106
    ,
    Figure PCTKR2017006732-appb-I000107
    ,
    Figure PCTKR2017006732-appb-I000108
    ,
    Figure PCTKR2017006732-appb-I000109
    ,
    Figure PCTKR2017006732-appb-I000110
    ,
    Figure PCTKR2017006732-appb-I000111
    및
    Figure PCTKR2017006732-appb-I000112
    로 이루어진 군에서 선택되는 어느 하나임.     In the above formula (1), R is
    Figure PCTKR2017006732-appb-I000104
    ,
    Figure PCTKR2017006732-appb-I000105
    ,
    Figure PCTKR2017006732-appb-I000106
    ,
    Figure PCTKR2017006732-appb-I000107
    ,
    Figure PCTKR2017006732-appb-I000108
    ,
    Figure PCTKR2017006732-appb-I000109
    ,
    Figure PCTKR2017006732-appb-I000110
    ,
    Figure PCTKR2017006732-appb-I000111
    And
    Figure PCTKR2017006732-appb-I000112
    &Lt; / RTI &gt;
  14. 하기 화학식 1로 표시되는 화합물 또는 이의 식품학적으로 허용되는 염의 비만 또는 지질관련 대사성 질환의 예방 또는 개선용 사료첨가물에 사용하기 위한 용도:Use of a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof for use in a feed additive for preventing or ameliorating obesity or a lipid-related metabolic disease:
    [화학식 1][Chemical Formula 1]
    Figure PCTKR2017006732-appb-I000113
    Figure PCTKR2017006732-appb-I000113
    상기 화학식 1에서, R은
    Figure PCTKR2017006732-appb-I000114
    ,
    Figure PCTKR2017006732-appb-I000115
    ,
    Figure PCTKR2017006732-appb-I000116
    ,
    Figure PCTKR2017006732-appb-I000117
    ,
    Figure PCTKR2017006732-appb-I000118
    ,
    Figure PCTKR2017006732-appb-I000119
    ,
    Figure PCTKR2017006732-appb-I000120
    ,
    Figure PCTKR2017006732-appb-I000121
    및
    Figure PCTKR2017006732-appb-I000122
    로 이루어진 군에서 선택되는 어느 하나임.     In the above formula (1), R is
    Figure PCTKR2017006732-appb-I000114
    ,
    Figure PCTKR2017006732-appb-I000115
    ,
    Figure PCTKR2017006732-appb-I000116
    ,
    Figure PCTKR2017006732-appb-I000117
    ,
    Figure PCTKR2017006732-appb-I000118
    ,
    Figure PCTKR2017006732-appb-I000119
    ,
    Figure PCTKR2017006732-appb-I000120
    ,
    Figure PCTKR2017006732-appb-I000121
    And
    Figure PCTKR2017006732-appb-I000122
    &Lt; / RTI &gt;
PCT/KR2017/006732 2017-06-26 2017-06-26 Composition for preventing or treating obesity or lipid-related metabolic diseases containing acrylamide-based compounds as active ingredients WO2019004492A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001139550A (en) * 1999-11-17 2001-05-22 Shionogi & Co Ltd New use of amide compound
US20090143397A1 (en) * 2006-08-07 2009-06-04 Lotus Pharmaceutical Co., Ltd. Catechol-based derivatives for treating or preventing diabetics
KR20140109273A (en) * 2013-02-25 2014-09-15 서울대학교산학협력단 Piper amide derivatives as bombesin receptor subtype-3 modulators
KR20170028640A (en) * 2015-09-04 2017-03-14 서울대학교산학협력단 A composition comprising of Piper amide derivative for skin whitening
KR101729078B1 (en) * 2015-10-23 2017-04-21 한국식품연구원 Composition for anti-obesity containing enmides

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001139550A (en) * 1999-11-17 2001-05-22 Shionogi & Co Ltd New use of amide compound
US20090143397A1 (en) * 2006-08-07 2009-06-04 Lotus Pharmaceutical Co., Ltd. Catechol-based derivatives for treating or preventing diabetics
KR20140109273A (en) * 2013-02-25 2014-09-15 서울대학교산학협력단 Piper amide derivatives as bombesin receptor subtype-3 modulators
KR20170028640A (en) * 2015-09-04 2017-03-14 서울대학교산학협력단 A composition comprising of Piper amide derivative for skin whitening
KR101729078B1 (en) * 2015-10-23 2017-04-21 한국식품연구원 Composition for anti-obesity containing enmides

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