Glutamic acid derivatives and compositions comprising the same
阅读说明：本技术 谷氨酸衍生物及包含其的组合物 (Glutamic acid derivatives and compositions comprising the same ) 是由 安镇熙 金珉希 裵银晶 苏瓦那·豪萨-哈瓦·帕雷 李多惠 豪沙包·史瓦吉·帕雷 李敦行 于 2018-10-30 设计创作，主要内容包括：本发明涉及一种发挥优秀抗氧化效果的新型化合物或包含其的抗氧化组合物,通过使用本发明组合物来提供抗氧化用化妆料组合物、抗氧化用功能性食品组合物、黑色素过度沉着疾病的预防或治疗用药物组合物或皮肤美白用化妆料组合物。(The present invention relates to a novel compound exhibiting an excellent antioxidant effect or an antioxidant composition comprising the same, and provides an antioxidant cosmetic composition, an antioxidant functional food composition, a pharmaceutical composition for preventing or treating a hypermelanosis disease, or a skin whitening cosmetic composition by using the composition of the present invention.)
1. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following formula 1:
[ formula 1 ]
In the above-mentioned formula 1, the compound,
R1is hydroxy or benzyloxy;
R2is hydrogen or benzyloxycarbonyl;
R3is selected from the group consisting of hydroxy, C1To C4Phenyl substituted with 1 to 3 substituents of the group consisting of alkyl, halogen, cyano and methanesulfonyl.
2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof,
said C is1To C4Alkyl is methyl, ethyl or isopropyl.
3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof,
the halogen is fluorine.
4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof,
R3any one selected from the group consisting of 4-cyanophenyl group, 3-cyanophenyl group, 2, 3-dimethylphenyl group, 2, 5-dimethylphenyl group, 2, 4-dihydroxyphenyl group, 3, 5-dihydroxyphenyl group, 2-fluoro-4- (methylsulfonyl) phenyl group, 4-isopropylphenyl group, 2-ethylphenyl group, o-tolyl group, m-tolyl group, p-tolyl group and 3-fluorophenyl group.
5. The compound or pharmaceutically acceptable salt thereof according to claim 1,
when R is1When it is hydroxy, R2Is hydrogen; when R is1When it is benzyloxy, R2Is benzyloxycarbonyl.
6. The compound or pharmaceutically acceptable salt thereof according to claim 1,
the compound represented by the formula 1 is selected from the group consisting of:
(1)N5- ((4-cyanophenyl) amino) -L-glutamine;
(2)N5- (p-toluylamino) -L-glutamine;
(3)N5- ((2, 4-dihydroxyphenyl) amino) -L-glutamine;
(4)N5- ((3, 5-dihydroxyphenyl) amino) -L-glutamine;
(5)N5- ((2-fluoro-4- (methylsulfonyl) phenyl) amino) -L-glutamine;
(6)N2- ((benzyloxy) carbonyl) -N5- ((4-cyanophenyl) amino) -D-glutaminebenzyl ester;
(7)N5- ((4-cyanophenyl) amino) -D-glutamine;
(8)N5- ((3-cyanophenyl) amino) -L-glutamine;
(9)N5- ((3-cyanophenyl) amino) -D-glutamine;
(10)N5- ((2, 4-dihydroxyphenyl) amino) -D-glutamine;
(11)N5- ((3, 5-dihydroxyphenyl) amino) -D-glutamine;
(12)N2- ((benzyloxy) carbonyl) -N5- ((4-cyanophenyl) amino) -L-glutaminebenzyl ester;
(13)N5- ((2-fluoro-4- (methylsulfonyl) phenyl) amino) -D-glutamine;
(14)N5- ((2, 3-dimethylphenyl) amino) -L-glutamine;
(15)N5- ((2, 3-dimethylphenyl) amino) -D-glutamine;
(16)N5- ((2, 5-dimethylphenyl) amino) -L-glutamine;
(17)N5- ((2, 5-dimethylphenyl) amino) -D-glutamine;
(18)N5- ((4-isopropylphenyl) amino) -L-glutamine;
(19)N5- ((4-isopropylphenyl) amino) -D-glutamine;
(20)N5- ((2-ethylphenyl) amino) -L-glutamine;
(21)N5- ((2-ethylphenyl) amino) -D-glutamine;
(22)N5- (o-tolylamino) -L-glutamine;
(23)N5- (o-tolylamino) -D-glutamine;
(24)N5- (m-tolylamino) -L-glutamine;
(25)N5- (m-tolylamino) -D-glutamine;
(26)N5- ((3-fluoro)Phenyl) amino) -L-glutamine;
(27)N5- ((4- (methylsulfonyl) phenyl) amino) -L-glutamine;
(28)N5- ((2-fluorophenyl) amino) -L-glutamine;
(29)N5- ((3-hydroxyphenyl) amino) -L-glutamine;
(30)N5- ((4-fluorophenyl) amino) -L-glutamine, and
(31)N5- ((2, 4-dimethylphenyl) amino) -L-glutamine.
7. An antioxidant cosmetic composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
8. A functional food composition for antioxidation comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
9. A pharmaceutical composition for preventing or treating a hypermelanosis disease, which comprises the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
10. The pharmaceutical composition for preventing or treating a hypermelanosis disease according to claim 9,
the hypermelanotic disease is selected from the group consisting of chloasma, freckles, age spots, lentigo, cafe é, beck nevus, mottle, mongolian spot, nevus of taetia, acquired bilateral taetitana-like nevus, ita nevus, blue nevus, junction nevus, compound nevus, intradermal nevus, carsickness, congenital melanocyte nevus, spiculatus, dysplastic nevus, sunburn and hand-foot syndrome.
11. A skin whitening cosmetic composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
Technical Field
The invention relates to a glutamic acid derivative and an antioxidant composition containing the same.
Background
The human body is in close contact with the environment and is susceptible to exposure to ultraviolet rays or environmental pollutants, chemicals, detergents, pollen, etc. Skin exposed to the external environment is easily exposed to reactive oxygen species, which attack normal cellular tissues or cell membranes, ultimately leading to skin inflammation. The inflammatory tissue destroys proteins, genetic materials, and the like of the skin, resulting in skin aging (formation of wrinkles and the like in the skin).
In general, there are several theories explaining skin aging, but the most reasonable one of them is the free radical theory, i.e., skin aging occurs due to free radicals generated by various causes in vivo. Free radicals, which are very chemically reactive chemicals, are also produced during the exposure of the skin to ultraviolet radiation or the respiration of cells within the skin. The majority of free radicals involved in skin aging are Reactive Oxygen Species (ROS), which include superoxide radicals (Superoxidases), hydrogen peroxide (H)2O2) Hydroxyl Radical (Hydroxy Radical), singlet Oxygen (Single Oxygen), and the like.
Such active oxygen is generated during irradiation with ultraviolet rays or respiration, and induces peroxidation of lipids, which are constituents of cell membranes, through a multi-step chain reaction. Peroxidation of lipids generates various active species, for example, radicals, peroxides, aldehydes (Aldehyde), epoxy compounds (epoxides), etc., and destroys DNA, RNA, proteins, cell membranes and cell structures. The toxicity of these reactive oxygen species is believed to be the major cause of cancer, tissue damage and aging (Black HS, Photochem photobiol,46(2),213,1987).
In order to neutralize these active oxygen, antioxidants, for example, tocopherol, polyphenols, Coenzyme (coenzymes) Q10, BHT (Butylated hydroxytoluene), and BHA (Butylated hydroxyanisole) are widely used, but further development of more excellent antioxidants is still required.
Throughout the specification, reference is made to a number of papers and patent documents, and citations thereof are indicated. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to more clearly describe the state of the art to which this invention pertains and the contents of this invention.
Disclosure of Invention
Problems to be solved by the invention
The present inventors have made an effort to develop a novel compound having antioxidant activity. As a result, the present invention has been completed by elucidating that a prescribed glutamic acid derivative compound has excellent antioxidant activity.
Accordingly, an object of the present invention is to provide a glutamic acid derivative compound or a pharmaceutically acceptable salt thereof.
Another object of the present invention is to provide an antioxidant cosmetic composition.
Another object of the present invention is to provide a functional food composition for antioxidation.
Another object of the present invention is to provide a pharmaceutical composition for preventing or treating a hypermelanosis disease.
Another object of the present invention is to provide a cosmetic composition for skin whitening.
Other objects and advantages of the present invention will become more fully apparent from the following detailed description of the invention, the appended claims and the accompanying drawings.
Means for solving the problems
According to an aspect of the present invention, there is provided a compound represented by the following formula 1 or a pharmaceutically acceptable salt thereof.
In the above-mentioned formula 1, the compound,
R1is hydroxy or benzyloxy;
R2is hydrogen or benzyloxycarbonyl;
R3is selected from the group consisting of hydroxy, C1To C4Phenyl substituted with 1 to 3 substituents of the group consisting of alkyl, halogen, cyano and methanesulfonyl.
According to another aspect of the present invention, there is provided an antioxidant cosmetic composition comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient.
According to another aspect of the present invention, there is provided a functional food composition for antioxidation comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient.
According to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating a hypermelanosis disease, comprising the above compound or a pharmaceutically acceptable salt thereof as an active ingredient.
According to an aspect of the present invention, there is provided a cosmetic composition for skin whitening comprising the above compound or a pharmaceutically acceptable salt thereof as an active ingredient.
Effects of the invention
The present invention provides a novel compound exhibiting an excellent antioxidant effect, and provides an antioxidant cosmetic composition, an antioxidant functional food composition, a pharmaceutical composition for preventing or treating a hypermelanosis disease, or a skin-whitening cosmetic composition using the same.
Drawings
FIG. 1 is a graph showing the results of the cytotoxicity test in test example 2.
Fig. 2 is a graph showing the NO analysis results of test example 3.
Fig. 3a and 3b are a graph and a graph, respectively, showing the results of the in vivo anti-inflammatory activity test of test example 5.
Detailed Description
Hereinafter, the present invention will be described in detail.
According to an aspect of the present invention, there is provided a compound represented by formula 1 or a pharmaceutically acceptable salt thereof.
[ formula 1 ]
In the above-mentioned formula 1, the compound,
R1is hydroxy or benzyloxy;
R2is hydrogen or benzyloxycarbonyl;
R3is selected from the group consisting of hydroxy, C1To C4Phenyl substituted with 1 to 3 substituents of the group consisting of alkyl, halogen, cyano and methanesulfonyl.
The present inventors have made an effort to develop a novel compound having antioxidant activity. As a result, it was clarified that the specified glutamic acid derivative compound has excellent antioxidant activity.
The term "pharmaceutically acceptable salt" of the invention refers to a salt as defined herein that is pharmaceutically acceptable and retains the desired pharmaceutical activity of a compound.
The term "hydroxy" in the present invention refers to an-OH substituent.
The term "C" according to the invention1To C4Alkyl "is represented by a straight or branched chain (straight or branched chain) alkyl group containing from 1 to 4 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and the like.
The term "halogen" in the present invention denotes a halogen substituent and denotes a substituent of-F, -Cl, -Br or-I.
The term "cyano" in the context of the present invention refers to the-CN substituent.
The term "benzyl" in the present invention refers to the-Bn substituent.
The term "methanesulfonyl" according to the present invention meansAnd (4) a substituent.
According to an embodiment of the present invention, C1To C4The alkyl group may be methyl, ethyl or isopropyl.
According to an embodiment of the invention, R3The halogen in the substituent may be fluorine.
According to an embodiment of the invention, R3Can be selected from 4-cyanophenyl, 3-cyanophenyl, 2, 3-dimethylphenyl, 2, 5-dimethylphenyl, 2, 4-dihydroxyphenyl, 3, 5-dihydroxyphenyl, 2-fluoro-4- (methylsulfonyl) phenyl, 4-cyanophenyl, 3-dimethylphenyl, 2, 3-dimethylphenyl, 4-dimethylphenyl, 2-fluoro-4- (methylsulfonyl) phenyl, and mixtures thereof-isopropylphenyl group, 2-ethylphenyl group, o-tolyl group, m-tolyl group, p-tolyl group, and 3-fluorophenyl group.
According to an embodiment of the present invention, when R1When it is hydroxy, R2May be hydrogen; when R is1When it is benzyloxy, R2May be benzyloxycarbonyl.
According to an embodiment of the present invention, the compound represented by formula 1 above may be selected from the group consisting of:
(1)N5- ((4-cyanophenyl) amino) -L-glutamine;
(2)N5- (p-toluylamino) -L-glutamine;
(3)N5- ((2, 4-dihydroxyphenyl) amino) -L-glutamine;
(4)N5- ((3, 5-dihydroxyphenyl) amino) -L-glutamine;
(5)N5- ((2-fluoro-4- (methylsulfonyl) phenyl) amino) -L-glutamine;
(6)N2- ((benzyloxy) carbonyl) -N5- ((4-cyanophenyl) amino) -D-glutaminebenzyl ester (Benzyl N)2-((benzyloxy)carbonyl)-N5-((4-cyanophenyl)amino)-D-glutaminate)；
(7)N5- ((4-cyanophenyl) amino) -D-glutamine;
(8)N5- ((3-cyanophenyl) amino) -L-glutamine;
(9)N5- ((3-cyanophenyl) amino) -D-glutamine;
(10)N5- ((2, 4-dihydroxyphenyl) amino) -D-glutamine;
(11)N5- ((3, 5-dihydroxyphenyl) amino) -D-glutamine;
(12)N2- ((benzyloxy) carbonyl) -N5- ((4-cyanophenyl) amino) -L-Glutamine Benzyl ester (Benzyl N2-((benzyloxy)carbonyl)-N5-((4-cyanophenyl)amino)-L-glutaminate)；
(13)N5- ((2-fluoro-4- (methylsulfonyl) phenyl) amino) -D-glutamine;
(14)N5- ((2, 3-dimethylphenyl) amino) -L-glutamine;
(15)N5- ((2, 3-dimethylphenyl) amino) -D-glutamine;
(16)N5- ((2, 5-dimethylphenyl) amino) -L-glutamine;
(17)N5- ((2, 5-dimethylphenyl) amino) -D-glutamine;
(18)N5- ((4-isopropylphenyl) amino) -L-glutamine;
(19)N5- ((4-isopropylphenyl) amino) -D-glutamine;
(20)N5- ((2-ethylphenyl) amino) -L-glutamine;
(21)N5- ((2-ethylphenyl) amino) -D-glutamine;
(22)N5- (o-tolylamino) -L-glutamine;
(23)N5- (o-tolylamino) -D-glutamine;
(24)N5- (m-tolylamino) -L-glutamine;
(25)N5- (m-tolylamino) -D-glutamine;
(26)N5- ((3-fluorophenyl) amino) -L-glutamine;
(27)N5- ((4- (methylsulfonyl) phenyl) amino) -L-glutamine;
(28)N5- ((2-fluorophenyl) amino) -L-glutamine;
(29)N5- ((3-hydroxyphenyl) amino) -L-glutamine;
(30)N5- ((4-fluorophenyl) amino) -L-glutamine, and
(31)N5- ((2, 4-dimethylphenyl) amino) -L-glutamine.
According to another aspect of the present invention, there is provided an antioxidant cosmetic composition comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient.
The cosmetic composition of the present invention may also be manufactured in any dosage form conventionally manufactured in the art. For example, the composition may be formulated into a solvent, suspension, emulsion, cream, gel, cream, emulsion, powder, soap, surfactant-containing cleanser, oil, foundation emulsion, wax-like foundation, spray, or the like, but is not limited thereto. More specifically, it can be made into emollient lotion, nourishing lotion, emulsion, nourishing cream, massage cream, essence, eye cream, cleansing foam, cleansing water, facial mask, spray or powder.
When the formulation of the present invention is a paste, cream, emulsion or gel, animal oil, vegetable oil, wax, paraffin, starch, traganth (traganth), cellulose derivatives, polyethylene glycol, silicon, bentonite, silica, talc, zinc oxide, etc. may be used as a carrier component.
When the dosage form of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, polyamide powder may be used as a carrier component, and particularly in the case of a spray, a propellant such as chlorofluorocarbon, propane/butane or dimethyl ether may be further contained.
When the formulation of the present invention is a solution or emulsion, a solvent, a dissolving agent or an emulsifier can be used as a carrier component. For example, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butyl glycol oil, glycerin fatty ester, polyethylene glycol, and fatty acid ester of sorbitan can be used.
When the dosage form of the present invention is a suspension, a liquid phase diluent such as water, ethanol or propylene glycol; suspensions such as ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters; microcrystalline cellulose; aluminum metahydroxide (Aluminum metahydroxide); bentonite; agar or traganth, and the like.
When the formulation of the present invention is a surfactant-containing detergent, fatty alcohol sulfate, fatty alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazoline derivative, methyltaurate, sarcosinate, fatty acid amide ether sulfate, alkylamide betaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative, ethoxylated glycerin fatty acid ester, and the like can be used as a carrier component.
The ingredients contained in the cosmetic composition of the present invention may include ingredients conventionally used in cosmetic compositions in addition to the active ingredient and the carrier ingredient. For example, adjuvants such as antioxidants, stabilizers, solubilizers, vitamins, pigments and perfumes may be included.
According to another aspect of the present invention, there is provided a functional food composition for antioxidation comprising the above compound as an effective ingredient.
The functional food composition of the present invention contains ingredients that are conventionally added in food production, and may contain, for example, protein, carbohydrate, fat, nutrients, seasonings, and the like. For example, in the case of a beverage, a flavoring agent or a natural carbohydrate may be contained as an additional component in addition to the active ingredient. For example, the natural carbohydrates may comprise monosaccharides (e.g., glucose, fructose, etc.), disaccharides (e.g., maltose, sucrose, etc.), oligosaccharides, polysaccharides (e.g., dextrins, cyclodextrins, etc.), sugar alcohols (e.g., xylitol, sorbitol, erythritol, etc.).
The flavoring agent may be natural flavoring agent (e.g., thaumatin, stevia extract, etc.) or synthetic flavoring agent (e.g., saccharin, aspartame, etc.).
According to another aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating a hypermelanosis disease, comprising the above compound or a pharmaceutically acceptable salt thereof as an active ingredient.
The "hyperpigmentation disorder" of the present invention may specifically include chloasma, freckles, age spots (liverspots), spots (blephish), Cafe é (Cafe's auratus macules), Becker's Nevus (Becker's Nevus), Nevus spilus (Nevus spilus), Mongolian spots (Mongolian spot), Nevus of Ota, Acquired bilateral pachymal Nevus (Acquired bilateral Nevus of Ota-like macules), orienavine Nevus (Nevus of Ito), Blue Nevus (Blue Nevus), junction Nevus (Junctional Nevus), Compound Nevus (Compound Nevus), Intradermal Nevus (Intradermal Nevus), Halo (Halo Nevus), melanocyte Nevus (connective Nevus), lentigo (Nevus), and Nevus (Nevus flavus) and Nevus (Nevus-Nevus), but is not limited to these.
The pharmaceutical composition of the present invention comprises a pharmaceutically acceptable carrier in addition to the active ingredient. The pharmaceutically acceptable carrier contained in the pharmaceutical composition of the present invention is generally used in formulation and includes lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, mineral oil, and the like, but is not limited thereto. The pharmaceutical composition of the present invention may further comprise a lubricant, a wetting agent, a sweetener, a flavoring agent, an emulsifier, a suspending agent, a preservative, and the like, in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in the literature [ Remington's Pharmaceutical Sciences (1995, 19 th edition) ].
The appropriate dose of the pharmaceutical composition of the present invention can be determined in various ways depending on factors such as formulation methods, administration methods, patient's age, body weight, sex, disease state, food, administration time, administration route, excretion rate, and reaction sensitivity. In addition, the pharmaceutical composition of the present invention is preferably administered in an amount of 0.001mg/kg to 1000mg/kg (body weight) per day.
The pharmaceutical composition of the present invention can be administered orally or parenterally, and in the case of parenteral administration, it can be administered by topical application to the skin, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal injection, nasal administration, and the like. In view of the suitability of the pharmaceutical composition of the present invention for the treatment of hyper-melanin disorders, the mode of administration is preferably a mode in which the skin is coated topically.
The pharmaceutical composition of the present invention can be prepared into a unit volume form or can be contained in a large-volume container by formulating the pharmaceutical composition with a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily carried out by those skilled in the art to which the present invention pertains. In this case, the formulation may be an oil; or in solution, suspension or emulsion in an aqueous medium; or in the form of an extract, powder, granule, tablet or capsule, and may further comprise a dispersing agent or a stabilizer.
The pharmaceutical composition of the present invention may be prepared in the form of a skin external preparation. The present invention is not particularly limited to the above external skin preparation, but is preferably in the form of powder, gel, ointment, cream, liquid or aerosol.
As the gel base of the external skin preparation of the present invention, one or more selected from Carbopol (Carbopol), Carbomer (Carbomer), polyethylene glycol (polyethylene glycol), Polypropylene glycol (Polypropylene glycol), Polyacrylic acid (Polyacrylic acid), carboxymethylcellulose (carboxymethylcellulose), hydroxymethylcellulose (hydroxymethylcellulose), Polyvinylpyrrolidone (Polyvinylpyrrolidone), gelatin (Gelatine), Alginate (Alginate Salt), Chitin (Chitin) derivative or Chitosan (Chitosan) derivative, Hyaluronic acid (Hyaluronic acid), collagen (collagen) may be used, but not limited thereto.
According to another aspect of the present invention, there is provided a skin whitening cosmetic composition comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient. The skin whitening effect of the cosmetic composition of the present invention is the antioxidant effect using the compound of the present invention described above with respect to the antioxidant cosmetic of another aspect of the present invention, and reference may be made to the above contents of the cosmetic composition for the formulation of the cosmetic composition, the carrier according to the above formulation, the auxiliary ingredients further included, and the like, and repeated contents will be omitted to avoid over-complicating the description of the present specification.
Best mode for carrying out the invention
Hereinafter, the present invention will be described in more detail by way of examples. These examples are only intended to illustrate the present invention in more detail, and it is obvious to those skilled in the art that the scope of the present invention is not limited by these examples in light of the gist of the present invention.