KR101467673B1 - Novel Phenolic Acid Derivatives and Their Use for Antioxidant - Google Patents

Abstract

The present invention relates to a novel phenolic acid amide derivative or a pharmaceutically acceptable salt thereof, which exhibits excellent antioxidative activity because of its excellent radical scavenging activity and lipid peroxidation inhibitory activity, and thus can be usefully used for the prevention and treatment of oxidative diseases have.

Description

Novel Phenolic Acid Derivatives and Their Use as Antioxidants [

The present invention relates to a novel phenolic acid derivative and its use as an antioxidant based on its antioxidant activity.

Antioxidants are molecules that inhibit oxidation of other compounds. Antioxidants inhibit the oxidation of other compounds by themselves, by removing free radicals, which are the mediators of oxidation reactions, or by inhibiting other oxidation reactions.

Superoxide, nitric oxide, and reactive oxygen species (ROS), such as hydroxyl, peroxy, and alkoxy radicals, which are derived from oxygen in vivo, are naturally produced, used, and destroyed in intracellular metabolism. However, when ROS is present in excess, it causes toxicities such as cell membrane degradation, proteolysis, lipid oxidation, and DNA denaturation, thereby causing brain diseases such as stroke, Alzheimer's disease and Parkinson's disease and diseases such as diabetes, arteriosclerosis, inflammation, rheumatism and cancer . Therefore, efforts to develop a preventive and therapeutic agent for diseases by removing excess reactive oxygen species using an antioxidant have been actively conducted (Valko, M .; Leibfritz, D .; Moncol, J .; Cronin, MTD; Mazur, M .; Telser, J. The International Journal of Biochemistry & Cell Biology 2007, 39, 44.).

Efforts are being made to develop antioxidants using phenolic acid. These compounds are known to cleave radicals using hydrogen or electron donating properties and stabilizing properties of the resulting phenoxy radicals. Currently, commercially available phenolic acid derivatives include propyl gallate, octyl gallate, and dodecyl gallate, among which propyl gallate is most widely used. However, all of these have a disadvantage that their use is limited because they have a readily decomposable bond at high temperatures. Therefore, there is a need for a novel antioxidant with improved stability.

Accordingly, the present invention aims to provide novel phenolic acid compounds that are stable and have excellent antioxidant efficacy.

In order to solve the above-mentioned problems, the present invention provides a phenolic acid amide derivative represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

In Formula 1, n may be independently 0 or 1.

The present invention also provides a pharmaceutical composition for preventing or treating an oxidation-related disease, which comprises the phenolic acid amide derivative of 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 oxidation-related disease, which comprises the phenolic acid amide derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

The present invention also provides an antioxidant food composition comprising the phenolic acid amide derivative of formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

The novel phenolic acid amide derivative of the present invention has excellent radical scavenging activity and lipid peroxidation inhibitory activity and exhibits excellent antioxidative activity and thus can be effectively used for prevention and treatment of oxidation-related diseases.

The present invention provides a phenolic acid amide derivative represented by the following formula (I) or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1, n may be independently 0 or 1.

The inventors of the present invention have made extensive efforts to develop an antioxidant having a stable structure. As a result, they found a novel compound having a stable amide group and excellent antioxidant activity, thereby completing the present invention.

In one embodiment of the present invention, the phenolic acid amide derivative is N- (3,4-dihydroxybenzyl) -3,4,5-trihydroxybenzamide, N- (3,4-dihydroxyphenyl (3,4-dihydroxyphenethyl) -2- (3,4,5-trihydroxyphenyl) acetamide, but not limited thereto. It is not.

The phenolic acid amide derivatives represented by the above formula (1) can be used in the form of pharmaceutically acceptable salts, and acid addition salts formed by pharmaceutically acceptable free acids are useful as salts. As the free acid, inorganic acid and organic acid can be used. As the inorganic acid, hydrochloric acid, bromic acid, sulfuric acid, sulfurous acid, phosphoric acid and the like can be used. As the organic acid, citric acid, acetic acid, maleic acid, fumaric acid, , Acetic acid, glycolic acid, succinic acid, tartaric acid, 4-toluenesulfonic acid, galacturonic acid, embonic acid, glutamic acid, citric acid and arpartic acid. Preferably, hydrochloric acid is used as the inorganic acid, and methanesulfonic acid is used as the organic acid.

In addition, the phenolic acid amide derivative represented by Formula 1 of the present invention includes not only pharmaceutically acceptable salts, but also all salts, hydrates and solvates which can be prepared by conventional methods.

The addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the compound of Chemical Formula 1 in a water-miscible organic solvent such as acetone, methanol, ethanol, acetonitrile, etc., And then precipitating or crystallizing the acid solution. Subsequently, in this mixture, a solvent or an excess acid is evaporated and dried to obtain an additional salt, or the precipitated salt may be produced by suction filtration.

The phenolic acid amide derivative of formula (1) according to the present invention can be prepared by reacting benzoic acid in which an alkoxy or hydroxy group is substituted at the 3,4,5-position as a starting material or phenylacetic acid substituted with an alkoxy or hydroxy group at the 3,4,5- With 3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride and 1-hydroxybenzotriazole in the presence of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride as the starting material, Can be, but are not limited to, N, N-dimethylformamide solvent. The reaction may be carried out at room temperature for 30 minutes to 5 hours under stirring, whereby an acid and an amine group react to form a stable amide bond. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the ethyl acetate layer was purified by column chromatography to obtain the target compound.

As described above, the novel phenolic acid amide derivatives prepared according to the present invention can be produced by a method such as infrared spectroscopy, nuclear magnetic resonance spectrum, mass spectrometry, liquid chromatography, X-ray crystallography, The molecular structure can be confirmed by comparing the calculated value with the measured value.

As can be seen from the following examples, the phenolic acid amide derivative of the formula (1) according to the present invention has excellent radical scavenging activity and lipid peroxidation inhibitory activity and thus exhibits excellent antioxidative activity, and can be used as an active ingredient of the oxidation- . Accordingly, the present invention relates to a pharmaceutical composition for preventing or treating an oxidation-related disease containing the phenolic acid amide derivative or a pharmaceutically acceptable salt thereof as an active ingredient, the use of the phenolic acid amide derivative for the production of an antioxidant, Comprising administering an acid amide derivative to a subject.

In one embodiment of the present invention, the pharmaceutical composition for prevention or treatment of an oxidation-related disease containing the phenolic acid amide derivative or a pharmaceutically acceptable salt thereof as an active ingredient is characterized in that, for 100 parts by weight of the pharmaceutical composition, Ruthenium compound or a pharmaceutically acceptable salt thereof may be contained in an amount of 0.01 to 90 parts by weight, 0.1 to 90 parts by weight, 1 to 90 parts by weight, or 10 to 90 parts by weight, but not limited thereto, Depending on the type and the progress of the process.

In another embodiment of the present invention, the pharmaceutical composition for preventing or treating an oxidation-related disease containing the phenolic acid amide derivative or a pharmaceutically acceptable salt thereof as an active ingredient is a carrier, an excipient, a disintegrant, a sweetener, One or more adjuvants selected from the group consisting of a lubricant, a lubricant, a lubricant, a flavoring agent, an antioxidant, a buffer, a bacteriostatic agent, a diluent, a dispersant, a surfactant, a binder and a lubricant.

Specific examples of carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methylcellulose, Cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. Solid formulations for oral administration may be in the form of tablets, pills, powders, granules, capsules These solid preparations can be prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., into the composition. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Examples of the liquid preparation for oral use include suspensions, solutions, emulsions, syrups and the like, and various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like may be included in addition to water and liquid paraffin which are commonly used simple diluents. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As the suppository base, witepsol, macrogol, tween 61, cacao paper, laurin, glycerogelatin and the like can be used.

In another embodiment of the present invention, the pharmaceutical composition for preventing or treating an oxidation-related disease containing the phenolic acid amide derivative or a pharmaceutically acceptable salt thereof as an active ingredient is a granule, a powder, a tablet, a tablet, Pills, capsules, suppositories, gels, syrups, juices, suspensions, emulsions, drops, or liquids.

According to one embodiment of the present invention, the pharmaceutical composition may be administered orally, intraarterally, intraperitoneally, intramuscularly, intraarterally, intraperitoneally, intrasternally, transdermally, nasally, inhaled, topically, rectally, ≪ / RTI > can be administered to the subject in a conventional manner.

A preferable dosage of the pharmaceutical composition for preventing or treating an oxidation-related disease containing the phenolic acid amide derivative or a pharmaceutically acceptable salt thereof as an active ingredient is not particularly limited and may be appropriately determined depending on the condition and body weight of the patient, The route and the period, and can be appropriately selected by those skilled in the art. According to one embodiment of the present invention, the daily dose may be 0.01 to 1,000 mg / kg, specifically 0.1 to 1,000 mg / kg, more specifically 0.1 to 100 mg / kg, though it is not limited thereto. The administration may be performed once a day or divided into several times, and thus the scope of the present invention is not limited thereto.

In the present invention, the 'subject' may be a mammal including a human, but is not limited thereto.

In one embodiment of the present invention, the oxidative-related disease may be, but is not limited to, aging, cancer, diabetes, arteriosclerosis, epilepsy or neurodegenerative diseases, and the neurodegenerative diseases include stroke, paralysis, memory loss, Parkinson's disease, Alzheimer's disease, Pick's disease, Creutzfeld-Kacob disease, Huntington's disease or Lou Gehrig's disease, but are not limited thereto.

The present invention also provides a cosmetic composition comprising the phenolic acid amide derivative of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

As can be seen from the following examples, the phenolic acid amide derivatives are excellent in antioxidative effect and can be used as a cosmetic composition for preventing or improving oxidation-related diseases.

In one embodiment of the invention, the oxidative related disease may be, but is not limited to, skin aging, skin pigmentation, wrinkles, psoriasis or eczema.

In one embodiment of the present invention, the cosmetic composition may contain, in addition to the phenolic acid amide derivatives represented by the general formula (1), additives commonly used in cosmetics such as vitamins, surfactants, emulsifiers, perfumes, colorants, stabilizers, An ultraviolet screening agent, a pH adjusting agent, and a chelating agent.

According to one embodiment of the present invention, the cosmetic composition in which the cosmetic composition is used is not limited to the formulation, but may be, for example, a softener, a nutritional lotion, a massage cream, a nutritional cream, a pack, a gel, Base, foundation, lotion, ointment, gel, cream, cleansing, cleanser, soap, shampoo, rinse, treatment and serum. Such cosmetics may contain conventional ingredients such as aqueous vitamins, oily vitamins, high molecular weight peptides, polymeric polysaccharides, sphingolipids and the like, and may be easily prepared according to techniques well known to those skilled in the art.

According to one embodiment of the present invention, the content of the phenolic acid amide derivative may be 0.001 to 20% by weight, 0.001 to 5% by weight, or 0.001 to 1% by weight based on the total weight of the cosmetic composition, though not limited thereto.

The present invention also provides an antioxidant food composition comprising the phenolic acid amide derivative of formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. The phenolic acid amide derivative of the present invention is excellent in antioxidative effects such as radical scavenging activity and lipid peroxidation inhibitory activity, and can be used as a functional food composition for preventing or improving oxidation-related diseases or as a food additive for preventing food from decaying.

In one embodiment of the present invention, the food composition containing the phenolic acid amide derivative or a pharmaceutically acceptable salt thereof as an active ingredient may contain 0.01 to 90 parts by weight of the ginsenoside, 0.1 to 90 parts by weight, 1 to 90 parts by weight, or 10 to 90 parts by weight, but is not limited thereto.

In another embodiment of the present invention, the food composition may further comprise at least one additive selected from the group consisting of organic acids, phosphates, antioxidants, lactose casein, dextrin, glucose, sugar and sorbitol. The organic acid can be, but is not limited to, citric acid, fumaric acid, adipic acid, lactic acid or malic acid, and the phosphate can be sodium phosphate, potassium phosphate, acid pyrophosphate or polyphosphate (polymeric phosphate) But are not limited to, natural antioxidants such as polyphenols, catechins, alpha-tocopherol, rosemary extract, licorice extract, chitosan, tannic acid or phytic acid.

In another embodiment of the present invention, the antioxidant food composition containing the phenolic acid amide derivative or a pharmaceutically acceptable salt thereof as an active ingredient may be used in combination with various nutrients, vitamins, minerals (electrolytes), synthetic (Such as cheese, chocolate, etc.), pectic acid and its salts, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusting agents, stabilizers, preservatives, glycerin, Alcohols, carbonating agents used in carbonated drinks, and the like. In addition, the food composition according to one embodiment of the present invention may contain flesh for the production of natural fruit juice, fruit juice drink and vegetable drink. The proportion of such an additive is generally, but not limited to, 0 to 20 parts by weight, 5 to 20 parts by weight, or 5 to 15 parts by weight per 100 parts by weight of the composition of the present invention.

According to one embodiment of the invention, the formulation of the food composition may be in the form of solid, powder, granule, tablet, capsule, liquid or drink, although not limited thereto.

In addition, the food composition may be selected from the group consisting of confectionery, saccharides, ice cream products, dairy products, meat products, fish products, tofu or glue, edible oils, noodles, Dried products of ginseng products, kimchi pickles, dried fruits, fruits, vegetables, fruits or vegetables, cutting products, fruit juices, vegetable juices, mixed juice thereof, nuts, noodles, processed livestock products, processed marine products, , Fermented milk food, bean curd food, cereal food, fermented microorganism food, confectionery bakery, condiments, meat processing, acidic beverage, licorice, herb.

According to one embodiment of the present invention, when an antioxidative food composition containing the phenolic acid amide derivative or a pharmaceutically acceptable salt thereof as an active ingredient is used for the production of a health functional food, 0.01 to 15 wt% %, Or 0.1 to 10% by weight of the total beverage, and when used in the manufacture of beverages, 0.02 to 10% by weight or 0.3 to 1% by weight of the total beverage can be used.

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are intended to illustrate the contents of the present invention, but the scope of the present invention is not limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

In the following preparations and examples, unless otherwise stated, all temperatures are expressed in degrees Celsius. All parts and percentages are by weight unless otherwise stated. Solids / solids (weight / weight) (Weight / volume) or%, and liquid / liquid is (volume / volume) or%.

The reactions shown below were generally carried out in an anhydrous solvent under positive pressure of argon or nitrogen at ambient temperature (unless otherwise stated) or using a drying tube, and the reaction flask was equipped with a rubber The diaphragm was fitted. The glassware was oven or thermally dried. The reaction was analyzed by TLC and terminated as judged by consumption of the starting material. The hydrogen gas reduction was carried out at the pressure mentioned in the examples or at ambient pressure.

¹ H-NMR spectra were recorded on a Bruker instrument operating at 400 Hz and ¹³ C-NMR spectra were recorded on a machine operating at 100 Hz. NMR spectra were obtained as CDCl ₃ solution (recorded in ppm) using chloroform (7.25 ppm and 77.00 ppm) as reference or optionally tetramethylsilane (0.00 ppm) internally. Other NMR solvents were used as needed. The following abbreviations are used when recording peak multiplicity: s (single line), d (double line), t (triple line), m (multiline), dd (double line of double line), td (double line triple line) , qd (double line quadrature), and coupling constant are given in hertz (Hz) given.

< Comparative Example  1 > N- ( Benzo [d] [1,3] dioxole -5- Yl methyl ) -3,4,5-trihydroxybenzamide &lt; / RTI &gt;

, 0.10 g (0.53 mmol) of 3,4,5-trihydroxybenzoic acid and 0.15 g (1.0 mmol) of N- (3-dimethylaminopropyl) -N'- ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole 53 μL (0.43 mmol) of 0.14 g (1.1 mmol) of (1,3-benzodioxol-5-yl) methylamine was added to 10 mL of N, N-dimethylformamide and the mixture was stirred at room temperature for 2 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the organic layer was washed with 5% citric acid, sodium bicarbonate, and distilled water. The ethyl acetate layer was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography using a mixed solvent of dichloromethane: methanol (93: 7) to give N- ( benzo [d] [1,3] dioxol -5- ylmethyl ) -3,4,5-trihydroxybenzene Amide ( Comparative Example 1) was obtained in a yield of 44.3%.

_{^{1 H NMR (400MHz, CD 3}} OD): δ (ppm) 6.89 (s, 2H), 6.85 (d, J = 6.2 Hz, 1H), 6.82 (s, 1H), 6.73 (s, 1H), 5.90 ( s, 2 H), 4.45 (s, 2 H)

^{13 C NMR (100 MHz, CDCl} 3 + CD 3 OD): δ (ppm) 168.9, 147.8, 146.7, 145.2, 136.7, 132.8, 128.8, 124.7, 120.4, 109.9, 107.7, 107.8, 106.6, 43.0

ESI MS: m / z = 304 [M + H] &lt; ⁺ &gt;.

< Example  1 > N- (3,4- Dihydroxybenzyl ) -3,4,5- Of trihydroxybenzamide  Produce

79 mg (0.26 mmol) of N- ( benzo [d] [1,3] dioxol -5- ylmethyl ) -3,4,5 -trihydroxybenzamide of Comparative Example 1 was dissolved in 5 mL of dichloromethane After adding 1.5 mL of boron tribromide in a 0 ° C ice bath, the mixture was stirred at room temperature for 2 hours. Water was added and stirred for 5 minutes. The solvent was removed by distillation under reduced pressure, then ethyl acetate was added, and the organic layer was washed with water. The ethyl acetate layer was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure. The crude product was purified by column chromatography using a mixed solvent of chloroform: methanol: formic acid (90: 20: 1) to obtain N- (3,4 -dihydroxybenzyl ) -3,4,5-trihydroxybenzamide ( Example 1) was obtained in a yield of 20.7%.

_{^{1 H NMR (400MHz, CDCl 3}} + CD 3 OD): δ (ppm) 6.86 (s, 2H), 6.80 (d, J = 2 Hz 1H), 6.78 (dd, J = 2 Hz, 1H), 6.75 ( s, J = 8 Hz, 1H), 4.40 (d, J = 4.4, 2H)

< Comparative Example  2 > N- (3,4- Dimethoxyphenethyl ) -3,4,5- Of trihydroxybenzamide  Produce

, 0.10 g (0.53 mmol) of 3,4,5-trihydroxybenzoic acid and 0.15 g (1.0 mmol) of N- (3-dimethylaminopropyl) -N'- ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole 0.070 mL (0.43 mmol) of 0.14 g (1.1 mmol) of 2- (3,4-dimethoxyphenyl) ethanamine was added to 10 mL of N, N-dimethylformamide and the mixture was stirred at room temperature for 2 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the organic layer was washed with 5% citric acid, sodium bicarbonate, and distilled water. The ethyl acetate layer was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography using a mixed solvent of dichloromethane: methanol (90:10) to obtain 91 mg of N- (3,4 -dimethoxyphenethyl ) -3,4,5-trihydroxybenzamide ( Comparative Example 2) Was obtained in a yield of 55.3%.

_{^{1 H NMR (400MHz, CDCl 3}} + CD 3 OD): δ (ppm) 6.82 (d, J = 7.2 Hz, 3H), 6.78 (d, J = 1.6 2H), 3.85 (d, J = 3.2 Hz, 2H ), 3.55 (t, J = 8 Hz, 2H), 2.83 (t, J = 7.6 Hz,

^{13 C NMR (100 MHz, CDCl} 3 + CD 3 OD): δ (ppm) 168.5, 148.8, 147.4, 145.0, 136.5, 131.9, 124.9, 120.8, 112.2, 111.5, 106.5, 55.5, 41.5, 35.0

ESI MS: m / z = 334 [M + H] &lt; ⁺ &gt;.

< Example  2 > N- (3,4- Dihydroxyphenethyl ) -3,4,5- Of trihydroxybenzamide  Produce

0.080 g (0.24 mmol) of N- (3,4 -dimethoxyphenethyl ) -3,4,5-trihydroxybenzamide of Comparative Example 2 was added to 5 mL of dichloromethane, 1.5 mL of boron tribromide was added thereto, and the mixture was stirred at room temperature for 2 hours. Water was added and stirred for 5 minutes. The solvent was removed by distillation under reduced pressure, then ethyl acetate was added, and the organic layer was washed with water. The ethyl acetate layer was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure. The crude product was purified by column chromatography using a mixed solvent of chloroform: methanol: formic acid (90: 20: 1) to obtain N- (3,4 -dihydroxyphenethyl ) -3,4,5 -trihydroxybenzene Amide ( Example 2) in a yield of 58.1%.

_{^{1 H NMR (400MHz, CDCl 3}} + CD 3 OD): δ (ppm) 8.20 (s, 1H), 6.80 (d, J = 8.8 Hz, 4H), 6.90 (s, 2H), 6.85 (s, 4H) , 6.30 (d, J = 8 Hz, 1 H), 3.80 (s, 6 H)

< Example  3 > N- (3,4- Dihydroxyphenethyl ) -2- (3,4,5-trihydroxyphenyl) Acetamide  Produce

, 0.20 g (0.88 mmol) of 3,4,5-trimethoxyphenylacetic acid, 0.25 g (1.3 mmol) of N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride, 0.24 g (1.8 mmol) of the sol and 0.16 mL (0.97 mmol) of homo veratrylamine were added to 5 mL of N, N-dimethylformamide, followed by stirring at room temperature for 2 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the organic layer was washed with 5% citric acid, saturated sodium bicarbonate, and distilled water. The ethyl acetate layer was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure to give N- (3,4 -dimethoxyphenethyl ) -2- (3,4,5 -trihydroxyphenyl ) acetamide quantitatively .

0.34 g (0.88 mmol) of the above compound was added to 5 mL of dichloromethane, and 1 mL of boron tribromide was added thereto at 0 ° C on an ice bath. The mixture was stirred at room temperature for 2 hours. Water was added and the solvent was removed by distillation under reduced pressure. Ethyl acetate was then added and the organic layer was washed with water. The ethyl acetate layer was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure. Unextracted solids were filtered and combined with the extracted product. (3 , 4-dihydroxyphenethyl ) -2- (3,4,5- tri (pyridin - 2-yl) phenol ) of the present invention was obtained by purification by column chromatography using a mixed solvent of chloroform: methanol: formic acid Hydroxyphenyl ) acetamide ( Example 3) in a yield of 25.8%.

_{^{1 H NMR (DMSO-d 6}} ): δ 8.73 (s, 3H), 7.90 (t, J = 5.6 Hz, 1H), 6.62 (d, J = 8 Hz, 1H), 6.56 (d, J = 2 Hz , 6.40 (dd, J = 8 Hz, 2 Hz, 1H), 6.17 (s, 2H), 3.11 (m, 4H), 2.48 (m, 2H).

_{^{13 C NMR (DMSO-d 6}} ): δ 170.88, 146.27, 145.52, 143.98, 131.91, 130.63, 126.81, 119.65, 116.33, 115.94, 108.27, 42.61, 41.25, 35.27.

ESI MS: m / z = 320 [M + H] &lt; ⁺ &gt;.

< Comparative Example  3> 3,4,5- Trihydroxy -N- (4- Hydroxyphenethyl ) Benzamide  Produce

, 0.10 g (0.53 mmol) of 3,4,5-trihydroxybenzoic acid and 0.15 g (1.0 mmol) of N- (3-dimethylaminopropyl) -N'- ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole 58 mg (0.43 mmol) of 4- (2-aminoethyl) phenol (0.14 g, 1.1 mmol) was added to 10 mL of N, N-dimethylformamide and the mixture was stirred at room temperature for 2 hours. The solvent was removed by distillation under reduced pressure, ethyl acetate was added, and the organic layer was washed with 5% citric acid, sodium bicarbonate, and distilled water. The ethyl acetate layer was dried over magnesium sulfate and the solvent was removed by distillation under reduced pressure. 32 mg of 3,4,5 -trihydroxy- N- (4-hydroxyphenethyl) benzamide ( Comparative Example 3) was dissolved in 20.9 ml of a mixture of dichloromethane: methanol (90:10) %. &Lt; / RTI &gt;

^{1 H NMR (400 MHz, CDCl} 3 + CD 3 OD): δ (ppm) 7.80 (d, J = 8.4 Hz, 2H), 6.82 (s, 2H), 6.75 (d, J = 8.8 Hz, 2H), 3.50 (q, J = 6 Hz, 2H), 2.28 (t, J = 7.6 Hz, 2H)

¹³ C NMR (100 MHz, CDCl ₃ + CD ₃ OD):? (Ppm) 160.9, 155.3, 145.1, 136.5, 130.1, 129.6, 124.9, 115.1, 108.9, 34.6, 29.5

ESI MS: m / z = 290 [M + H] &lt; ⁺ &gt;.

< Experimental Example  1> DPPH  analysis

Each sample was dissolved in 99% methanol, and 40 μL of a 0.15 mM DPPH solution dissolved in methanol was added to 160 μL of the diluted solution. The absorbance was measured at 517 nm after 30 minutes at room temperature. The radical scavenging activity of each compound was expressed as the EC ₅₀ value, which is the concentration of the sample required to reduce the absorbance of the control without addition of the sample in half. Vitamin C, Trolox, gallic acid, and propyl gallate were used as a control for the activity comparison. The results are shown in Table 1 below.

< Experimental Example  2> ABTS  analysis

After the addition of 7 mM ABTS and 2.45 mM potassium persulfate, the mixture was allowed to stand in the dark for 24 hours to produce ABTS + ·, and then diluted with phosphate buffer saline (PBS, pH 7.4) so that the absorbance value became 0.70 (± 0.02) Respectively. To 180 μL of the diluted solution, 20 μL of the sample was added, and the sample was allowed to stand for exactly one minute, and the absorbance was measured. Galactan, propyl gallate, and trolox were used as a control for the activity comparison. The results are shown in Table 1 below.

< Experimental Example  3> Ferric thiocyanate ( FTC ) Experiment

Previous studies (Kikuzaki, H. & Nakatani, N., Antioxidant Effects of Some Ginger Constituents. Journal of Food Science , 1993, 58, 1407-1410). The reaction mixture was mixed with 1 mL of 2.52% linoleic acid, 2 mL of 0.05 M phosphate buffer (pH 7.0), and 1 mL of distilled water in 1 mL of the sample prepared in absolute ethanol at a final concentration of 50 μM. 50 μL of the reaction sample solution was diluted with 4.85 mL of 75% ethanol, and mixed with 50 μL of 30% ammonium thiocyanate and 50 μL of 0.02 M ferrous chloride dissolved in 3.5% HCl. Then, the absorbance at 500 nm Were measured. The experiment proceeded until the absorbance of the control reached its maximum. The activity of the sample was determined by the inhibition of the lipid peroxidation of the sample in the control without addition of the sample. Propyl gallate and gallic acid were used as the positive control. The results are shown in Table 1 below.

< Experimental Example  4> Thiobarbituric acid ( TBA ) Experiment

The reaction sample solution was prepared in the same manner as the FTC, and 500 μL of 20% trichloroacetic acid and 500 μL of 0.8% 2-thiobarbituric acid (TBA) were added to 250 μL of the reaction sample solution every 48 hours. Minute and then cooled. After centrifugation at 3000 rpm for 10 minutes, the supernatant was measured for absorbance at 532 nm. The experiment proceeded until the end of the TBA reaction of the control. The activity of the sample was determined as a percentage of the lipid peroxidation inhibitory ability of the sample in the control without addition of the sample, and propyl gallate and gallic acid were used as the positive control. The results are shown in Table 1 below.

The results of the DPPH and ABT experiments show the radical scavenging ability as EC ₅₀ , and the FTC and TBAR results show the% inhibition at the sample concentration of 10 μM.

compound DPPH
EC ₅₀ ([mu] M) ABTS
EC ₅₀ ([mu] M) FTC
% Low performance
(10 [mu] M) TBAR
% Low performance
(10 [mu] M) Example 1 3.1 16.4 73 74 Example 2 2.4 13.3 <58 64 Example 3 3.8 17.2 62 70 Comparative Example 1 3.5 14.9 - - Comparative Example 2 2.8 13.2 24 48 Comparative Example 3 3.1 9.2 33 47 Vit C 23.9 - - - Trolox 27.2 29.9 - - Gallic acid 2.9 4.3 0 17 Propyl gallate 3.0 14.7 73 73

As shown in Table 1, the compounds of Examples 1 to 3 of the present invention exhibited not only a radical scavenging activity but also a lipid peroxidation inhibitory activity of 60% or more as compared with the compounds of the comparative examples. Lt; / RTI &gt;

Meanwhile, the compound according to the present invention can be formulated into various forms depending on the purpose. The following examples illustrate some formulations containing the compound according to the present invention as an active ingredient, but the present invention is not limited thereto.

< Formulation example  1> Purification (direct pressurization)

After 5.0 mg of the active ingredient was sieved, 14.1 mg of lactose, 0.8 mg of crospovidone USNF and 0.1 mg of magnesium stearate were mixed and pressed to prepare tablets.

< Formulation example  2> Purification (wet assembly)

After 5.0 mg of the active ingredient was sieved, 16.0 mg of lactose and 4.0 mg of starch were mixed. 0.3 mg of Polysorbate 80 was dissolved in pure water, and an appropriate amount of this solution was added, followed by atomization. After drying, the granules were sieved and mixed with 2.7 mg of colloidal silicon dioxide and 2.0 mg of magnesium stearate. The fine particles were pressed to prepare tablets.

< Formulation example  3> Powder and Capsule

5.0 mg of the active ingredient was sieved and then mixed with 14.8 mg of lactose, 10.0 mg of polyvinylpyrrolidone and 0.2 mg of magnesium stearate. The mixture was extruded through a hard No. 5 &lt; / RTI &gt; gelatin capsules.

< Formulation example  4> injection

100 mg of the active ingredient, 180 mg of mannitol, 26 mg of Na ₂ HPO _{4 12} H ₂ O and 2974 mg of distilled water were mixed. The mixed solution was filled in an ampoule made of transparent glass, sealed in an upper lattice by dissolving the glass, sterilized by autoclaving at 120 DEG C for 15 minutes or longer, and injected.

While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that such detail is solved by the person skilled in the art without departing from the scope of the invention. will be. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (8)

N- (3,4-dihydroxybenzyl) -3,4,5-trihydroxybenzamide or a pharmaceutically acceptable salt thereof. delete delete delete delete An antioxidative cosmetic composition comprising N- (3,4-dihydroxybenzyl) -3,4,5-trihydroxybenzamide or a pharmaceutically acceptable salt thereof as an active ingredient. delete An antioxidative food composition comprising N- (3,4-dihydroxybenzyl) -3,4,5-trihydroxybenzamide or a pharmaceutically acceptable salt thereof as an active ingredient.