KR102393317B1 - Glutamic acid derivatives and a composition comprising the same - Google Patents
Glutamic acid derivatives and a composition comprising the same Download PDFInfo
- Publication number
- KR102393317B1 KR102393317B1 KR1020170144088A KR20170144088A KR102393317B1 KR 102393317 B1 KR102393317 B1 KR 102393317B1 KR 1020170144088 A KR1020170144088 A KR 1020170144088A KR 20170144088 A KR20170144088 A KR 20170144088A KR 102393317 B1 KR102393317 B1 KR 102393317B1
- Authority
- KR
- South Korea
- Prior art keywords
- amino
- glutamine
- nevus
- compound
- cyanophenyl
- Prior art date
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- 150000002306 glutamic acid derivatives Chemical class 0.000 title abstract description 5
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- 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
- A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
- A61K8/44—Aminocarboxylic acids or derivatives thereof, e.g. aminocarboxylic acids containing sulfur; Salts; Esters or N-acylated derivatives thereof
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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Abstract
본 발명은 우수한 항산화 효과를 발휘하는 신규한 글루탐산 유도체 또는 이를 포함하는 항산화 조성물에 관한 것으로서, 본 발명의 조성물을 사용함으로써, 항산화용 화장료 조성물, 항산화용 기능성 식품 조성물, 멜라닌 색소 과다침착 질환의 예방 또는 치료용 약제학적 조성물, 또는 피부 미백용 화장료 조성물을 제공할 수 있다. The present invention relates to a novel glutamic acid derivative exhibiting an excellent antioxidant effect or an antioxidant composition comprising the same, and by using the composition of the present invention, a cosmetic composition for antioxidant, a functional food composition for antioxidant, prevention or A pharmaceutical composition for treatment or a cosmetic composition for skin whitening may be provided.
Description
본 발명은 글루탐산 유도체 또는 이를 포함하는 항산화 조성물에 관한 것이다.The present invention relates to a glutamic acid derivative or an antioxidant composition comprising the same.
몸은 외부 환경과 밀접하게 접하고 있고, 자외선이나 환경 오염, 화학 물질, 세제, 꽃가루 등의 노출로 인해 쉽게 민감화된다. 외부 환경에 노출된 피부는 활성 산소종에 쉽게 노출되고, 활성 산소종은 정상적인 세포 조직이나 세포막을 공격하게 되어 피부는 결국 염증을 유발한다. 염증화된 조직은 피부에 단백질이나 유전자 물질 등을 파괴하여 주름 등을 형성하는 등 피부 노화가 일어난다.The body is in close contact with the external environment, and it is easily sensitized by exposure to ultraviolet rays, environmental pollution, chemicals, detergents, pollen, etc. The skin exposed to the external environment is easily exposed to reactive oxygen species, and the reactive oxygen species attacks normal cell tissues or cell membranes, causing the skin to eventually become inflamed. Inflamed tissue destroys proteins or genetic materials in the skin to form wrinkles, etc., and skin aging occurs.
일반적으로 피부노화를 설명하는 이론은 여러 가지가 있으나 그 중에서도 체내외의 여러 가지 원인에 의하여 발생되는 자유 라디칼에 의하여 피부가 노화된다는 자유 라디칼 이론이 가장 타당성 있는 이론으로 받아 들여지고 있다. 자유 라디칼은 화학적으로 반응성이 매우 큰 화학물질로 피부가 자외선에 조사되었을 때나 피부내 세포의 호흡 과정에서도 발생된다. 피부의 노화와 관련이 있는 자유 라디칼의 대부분은 활성 산소종(Reactive Oxygen Species, ROS)으로 그 종류로는 수퍼 옥사이드 라디칼(Superoxide Radical), 과산화수소 (H2O2), 하이드록시 라디칼(Hydroxy Radical), 일중항 산소(Single Oxygen) 등이 있다.In general, there are various theories to explain skin aging, but among them, the free radical theory that the skin ages by free radicals generated by various causes outside the body is accepted as the most valid theory. Free radicals are highly chemically reactive chemicals that are generated when the skin is irradiated with ultraviolet rays or in the process of respiration of cells in the skin. Most of the free radicals related to skin aging are Reactive Oxygen Species (ROS) . , and singlet oxygen.
이러한 활성 산소종들은 자외선 조사시 혹은 호흡과정에서 발생되어 다단계의 연쇄 반응을 통하여 세포막의 구성 성분인 지질의 과산화를 유발한다. 지질의 과산화는 라디칼, 과산화물, 알데하이드(Aldehyde), 에폭사이드(Epoxide) 등의 다양한 활성종을 발생시키고 DNA, RNA, 단백질, 세포막 및 세포구조에 손상을 입힌다. 이러한 활성 산소종들의 독성은 암, 조직손상, 노화 등의 주원인으로 여겨지고 있다(문헌 [Black HS, Photochem photobiol, 46(2), 213,1987]).These reactive oxygen species are generated during UV irradiation or respiration and cause peroxidation of lipids, a component of the cell membrane, through a multi-step chain reaction. Lipid peroxidation generates various active species such as radicals, peroxides, aldehydes, and epoxides, and damages DNA, RNA, proteins, cell membranes and cell structures. The toxicity of these reactive oxygen species is considered to be the main cause of cancer, tissue damage, aging, etc. (Black HS, Photochem photobiol, 46(2), 213,1987).
이러한 활성 산소종의 중화를 목적으로 토코페롤, 폴리페놀류, 코엔자임(Coenzyme) Q10, BHT(butylated hydroxy toluene), BHA(butylated hydroxy anisol) 등의 항산화제가 폭넓게 이용되고 있으나 더욱 우수한 항산화제의 개발이 여전히 필요하다Antioxidants such as tocopherol, polyphenols, coenzyme Q10, BHT (butylated hydroxy toluene), and BHA (butylated hydroxy anisol) are widely used for the purpose of neutralizing these reactive oxygen species, but the development of better antioxidants is still needed. Do
본 명세서 전체에 걸쳐 다수의 논문 및 특허문헌이 참조되고 그 인용이 표시되어 있다. 인용된 논문 및 특허문헌의 개시 내용은 그 전체로서 본 명세서에 참조로 삽입되어 본 발명이 속하는 기술 분야의 수준 및 본 발명의 내용이 보다 명확하게 설명된다.Numerous papers and patent documents are referenced throughout this specification and their citations are indicated. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to more clearly describe the level of the technical field to which the present invention pertains and the content of the present invention.
본 발명자들은 항산화활성을 갖는 신규 화합물들을 발굴하고자 예의 연구 노력하였다. 그 결과 소정의 글루탐산 유도체 화합물들이 뛰어난 항산화활성을 가짐을 규명함으로써, 본 발명을 완성하게 되었다. The present inventors made intensive research efforts to discover novel compounds having antioxidant activity. As a result, by identifying that certain glutamic acid derivative compounds have excellent antioxidant activity, the present invention was completed.
따라서, 본 발명의 목적은 글루탐산 유도체 화합물 또는 이의 약제학적으로 허용가능한 염을 제공하는 데 있다.Accordingly, an object of the present invention is to provide a glutamic acid derivative compound or a pharmaceutically acceptable salt thereof.
본 발명의 다른 목적은 항산화용 화장료 조성물을 제공하는 데 있다.Another object of the present invention is to provide a cosmetic composition for antioxidant.
본 발명의 또 다른 목적은 항산화용 기능성 식품 조성물을 제공하는 데 있다.Another object of the present invention is to provide a functional food composition for antioxidants.
본 발명의 또 다른 목적은 멜라닌 색소 과다침착 질환의 예방 또는 치료용 약제학적 조성물을 제공하는 데 있다. Another object of the present invention is to provide a pharmaceutical composition for preventing or treating melanin hyperpigmentation disease.
본 발명의 또 다른 목적은 피부 미백용 화장료 조성물을 제공하는 데 있다.Another object of the present invention is to provide a cosmetic composition for skin whitening.
본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명, 청구범위 및 도면에 의해 보다 명확하게 된다.Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.
본 발명의 일 양태에 따르면, 본 발명은 하기 화학식 1의 화합물 또는 이의 약제학적으로 허용가능한 염을 제공한다:According to one aspect of the present invention, the present invention provides a compound of Formula 1 or a pharmaceutically acceptable salt thereof:
화학식 1Formula 1
상기 화학식 1에서, In Formula 1,
R1은 히드록실 또는 벤질옥시이고;R 1 is hydroxyl or benzyloxy;
R2는 수소 또는 벤질옥시카보닐이며;R 2 is hydrogen or benzyloxycarbonyl;
R3은 히드록실, C1-4 알킬, 할로, 시아노 및 메틸설포닐로 구성된 군으로부터 선택되는 1 내지 3개의 치환기로 치환된 페닐이다. R 3 is phenyl substituted with 1 to 3 substituents selected from the group consisting of hydroxyl, C 1-4 alkyl, halo, cyano and methylsulfonyl.
본 발명자들은 항산화활성을 갖는 신규 화합물들을 발굴하고자 예의 연구 노력하였다. 그 결과 소정의 글루탐산 유도체 화합물들이 뛰어난 항산화활성을 가짐을 규명하였다.The present inventors made intensive research efforts to discover novel compounds having antioxidant activity. As a result, it was identified that certain glutamic acid derivative compounds have excellent antioxidant activity.
본 발명의 용어 "약제학적으로 허용가능한 염"은, 본원에 정의된 바와 같이 약제학적으로 허용되고 모 화합물의 목적하는 약리학적 활성을 보유한 염을 의미한다.As used herein, the term “pharmaceutically acceptable salt” refers to a salt that is pharmaceutically acceptable and retains the desired pharmacological activity of the parent compound, as defined herein.
본 발명의 용어 "히드록실"은 -OH 치환기를 의미한다. The term "hydroxyl" in the present invention refers to a -OH substituent.
본 발명의 용어 "C1-4 알킬"은 1 내지 4 탄소 원자를 포함하는 직쇄 또는 분지쇄(straight or branched chain) 알킬을 나타내고, 예를 들어 메틸, 에틸, n-프로필, 이소프로필, n-부틸, 이소부틸, sec-부틸, tert-부틸 등을 의미한다.The term "C 1-4 alkyl" in the present invention refers to straight or branched chain alkyl containing 1 to 4 carbon atoms, for example, methyl, ethyl, n -propyl, isopropyl, n- butyl, isobutyl, sec -butyl, tert -butyl and the like.
본 발명의 용어 "할로"는 할로겐 치환기를 나타내며, -F, -Cl,-Br 또는 -I 치환기를 나타낸다. The term "halo" in the present invention refers to a halogen substituent and refers to a -F, -Cl, -Br or -I substituent.
본 발명의 용어 "시아노"는 -CN 치환기를 의미한다. The term "cyano" in the present invention refers to a -CN substituent.
본 발명의 용어 "벤질"은 -Bn 치환기를 의미한다. As used herein, the term "benzyl" refers to a -Bn substituent.
본 발명의 용어 "메틸설포닐"은 
본 발명의 일 구현예에 있어서, 본 발명의 C1-4 알킬은 메틸, 에틸, 또는 이소프로필일 수 있다. In one embodiment of the present invention, C 1-4 alkyl of the present invention may be methyl, ethyl, or isopropyl.
본 발명의 일 구현예에 있어서, 본 발명의 R3에서의 할로는 플루오로일 수 있다. In one embodiment of the present invention, halo in R 3 of the present invention may be fluoro.
본 발명의 일 구현예에 있어서, 본 발명의 R3은 4-시아노페닐, 3-시아노페닐, 2,3-디메틸페닐, 2,5-디메틸페닐, 2,4-디히드록시페닐, 3,5-디히드록시페닐, 2-플루오로-4-(메틸설포닐)페닐, 4-이소프로필페닐, 2-에틸페닐, o-톨릴, m-톨릴, p-톨릴 및 3-플루오로페닐로 구성된 군으로부터 선택될 수 있다. In one embodiment of the present invention, R 3 of the present invention is 4-cyanophenyl, 3-cyanophenyl, 2,3-dimethylphenyl, 2,5-dimethylphenyl, 2,4-dihydroxyphenyl, 3,5-dihydroxyphenyl, 2-fluoro-4-(methylsulfonyl)phenyl, 4-isopropylphenyl, 2-ethylphenyl, o -tolyl, m -tolyl, p -tolyl and 3-fluoro It may be selected from the group consisting of phenyl.
본 발명의 일 구현예에 있어서, 본 발명의 R1이 히드록실인 경우 R2는 수소일 수 있고, 상기 R1이 벤질옥시인 경우 R2는 벤질옥시카보닐일 수 있다. In one embodiment of the present invention, when R 1 of the present invention is hydroxyl, R 2 may be hydrogen, and when R 1 is benzyloxy, R 2 may be benzyloxycarbonyl.
본 발명의 일 구현예에 있어서, 본 발명의 화합물은 In one embodiment of the present invention, the compound of the present invention is
(1) N5-((4-시아노페닐)아미노)-L-글루타민;(1) N 5 -((4-cyanophenyl)amino)-L-glutamine;
(2) N5-(p-톨릴아미노)-L-글루타민;(2) N 5 -( p -tolylamino)-L-glutamine;
(3) N5-((2,4-디히드록시페닐)아미노)-L-글루타민;(3) N 5 -((2,4-dihydroxyphenyl)amino)-L-glutamine;
(4) N5-((3,5-디히드록시페닐)아미노)-L-글루타민;(4) N 5 -((3,5-dihydroxyphenyl)amino)-L-glutamine;
(5) N5-((2-플루오로-4-(메틸설포닐)페닐)아미노)-L-글루타민;(5) N 5 -((2-fluoro-4-(methylsulfonyl)phenyl)amino)-L-glutamine;
(6) 벤질 N2-((벤질옥시)카보닐)-N5-((4-시아노페닐)아미노)-D-글루타미네이트;(6) benzyl N 2 -((benzyloxy)carbonyl)-N 5 -((4-cyanophenyl)amino)-D-glutaminate;
(7) N5-((4-시아노페닐)아미노)-D-글루타민;(7) N 5 -((4-cyanophenyl)amino)-D-glutamine;
(8) N5-((3-시아노페닐)아미노)-L-글루타민;(8) N 5 -((3-cyanophenyl)amino)-L-glutamine;
(9) N5-((3-시아노페닐)아미노)-D-글루타민;(9) N 5 -((3-cyanophenyl)amino)-D-glutamine;
(10) N5-((2,4-디히드록시페닐)아미노)-D-글루타민;(10) N 5 -((2,4-dihydroxyphenyl)amino)-D-glutamine;
(11) N5-((3,5-디히드록시페닐)아미노)-D-글루타민;(11) N 5 -((3,5-dihydroxyphenyl)amino)-D-glutamine;
(12) 벤질 N2-((벤질옥시)카보닐)-N5-((4-시아노페닐)아미노)-L-글루타미네이트;(12) benzyl N 2 -((benzyloxy)carbonyl)-N 5 -((4-cyanophenyl)amino)-L-glutaminate;
(13) N5-((2-플루오로-4-(메틸설포닐)페닐)아미노)-D-글루타민;(13) N 5 -((2-fluoro-4-(methylsulfonyl)phenyl)amino)-D-glutamine;
(14) N5-((2,3-디메틸페닐)아미노)-L-글루타민;(14) N 5 -((2,3-dimethylphenyl)amino)-L-glutamine;
(15) N5-((2,3-디메틸페닐)아미노)-D-글루타민;(15) N 5 -((2,3-dimethylphenyl)amino)-D-glutamine;
(16) N5-((2,5-디메틸페닐)아미노)-L-글루타민;(16) N 5 -((2,5-dimethylphenyl)amino)-L-glutamine;
(17) N5-((2,5-디메틸페닐)아미노)-D-글루타민;(17) N 5 -((2,5-dimethylphenyl)amino)-D-glutamine;
(18) N5-((4-이소프로필페닐)아미노)-L-글루타민;(18) N 5 -((4-isopropylphenyl)amino)-L-glutamine;
(19) N5-((4-이소프로필페닐)아미노)-D-글루타민;(19) N 5 -((4-isopropylphenyl)amino)-D-glutamine;
(20) N5-((2-에틸페닐)아미노)-L-글루타민;(20) N 5 -((2-ethylphenyl)amino)-L-glutamine;
(21) N5-((2-에틸페닐)아미노)-D-글루타민;(21) N 5 -((2-ethylphenyl)amino)-D-glutamine;
(22) N5-(o-톨릴아미노)-L-글루타민;(22) N 5 -( o -tolylamino)-L-glutamine;
(23) N5-(o-톨릴아미노)-D-글루타민;(23) N 5 -( o -tolylamino)-D-glutamine;
(24) N5-(m-톨릴아미노)-L-글루타민; (24) N 5 -( m -tolylamino)-L-glutamine;
(25) N5-(m-톨릴아미노)-D-글루타민; (25) N 5 -( m -tolylamino)-D-glutamine;
(26) N5-((3-플루오로페닐)아미노)-L-글루타민;(26) N 5 -((3-fluorophenyl)amino)-L-glutamine;
(27) N5-((4-(메틸설포닐)페닐)아미노)-L-글루타민;(27) N 5 -((4-(methylsulfonyl)phenyl)amino)-L-glutamine;
(28) N5-((2-플루오로페닐)아미노)-L-글루타민;(28) N 5 -((2-fluorophenyl)amino)-L-glutamine;
(29) N5-((3-히드록시페닐)아미노)-L-글루타민;(29) N 5 -((3-hydroxyphenyl)amino)-L-glutamine;
(30) N5-((4- 플루오로페닐)아미노)-L-글루타민; 및(30) N 5 -((4-fluorophenyl)amino)-L-glutamine; and
(31) N5-((2, 4-디메틸페닐)아미노)-L-글루타민(31) N 5 -((2, 4-dimethylphenyl)amino)-L-glutamine
으로 구성된 군으로부터 선택될 수 있다. It can be selected from the group consisting of.
본 발명의 다른 일 양태에 따르면, 본 발명은 상술한 화합물 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 포함하는 항산화용 화장료 조성물을 제공한다. According to another aspect of the present invention, the present invention provides a cosmetic composition for antioxidant comprising the above-described compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명인 화장료 조성물은 당업계에서 통상적으로 제조되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어, 용액, 현탁액, 유탁액, 페이스트, 겔, 크림, 로션, 파우더, 비누, 계면활성제-함유 클린싱, 오일, 분말 파운데이션, 유탁액 파운데이션, 왁스 파운데이션 및 스프레이 등으로 제형화될 수 있으나, 이에 한정되는 것은 아니다. 보다 상세하게는, 유연 화장수, 영양 화장수, 로션, 영양 크림, 마사지 크림, 에센스, 아이 크림, 클렌징 크림, 클렌징 포옴, 클렌징 워터, 팩, 스프레이 또는 파우더의 제형으로 제조될 수 있다.The cosmetic composition of the present invention may be prepared in any formulation conventionally prepared in the art, for example, a solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing, It may be formulated as an oil, powder foundation, emulsion foundation, wax foundation and spray, but is not limited thereto. More specifically, it may be prepared in the form of a flexible lotion, a nourishing lotion, a lotion, a nourishing cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray, or a powder.
본 발명의 제형이 페이스트, 크림, 로션, 또는 겔인 경우에는 담체 성분으로서 동물성유, 식물성유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크 또는 산화아연 등이 이용될 수 있다.When the formulation of the present invention is a paste, cream, lotion, or gel, animal oil, vegetable oil, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide, etc. as a carrier component This can be used.
본 발명의 제형이 파우더 또는 스프레이인 경우에는 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄 히드록시드, 칼슘 실리케이트 또는 폴리아미드 파우더가 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본, 프로판/부탄 또는 디메틸 에테르와 같은 추진체를 포함할 수 있다.When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. In particular, in the case of a spray, additional chlorofluorohydrocarbon, propane /may contain propellants such as butane or dimethyl ether.
본 발명의 제형이 용액 또는 유탁액인 경우에는 담체 성분으로서 용매, 용해화제 또는 유탁화제가 이용되고, 예컨대 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸글리콜 오일, 글리세롤 지방족 에스테르, 폴리에틸렌 글리콜 또는 소르비탄의 지방산 에스테르가 있다.When the formulation of the present invention is a solution or emulsion, a solvent, solubilizer or emulsifier is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylglycol oil, glycerol fatty esters, fatty acid esters of polyethylene glycol or sorbitan.
본 발명의 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상의 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 및 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가 또는 트라칸트 등이 이용될 수 있다.When the formulation of the present invention is a suspension, as a carrier component, a liquid diluent such as water, ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, microcrystals Adult cellulose, aluminum metahydroxide, bentonite, agar or tracanth may be used.
본 발명의 제형이 계면-활성제 함유 클린징인 경우에는 담체 성분으로서 지방족 알코올 설페이트, 지방족 알코올 에테르 설페이트, 설포숙신산 모노에스테르, 이세티오네이트, 이미다졸리늄 유도체, 메틸타우레이트, 사르코시네이트, 지방산 아미드 에테르 설페이트, 알킬아미도베타인, 지방족 알코올, 지방산 글리세리드, 지방산 디에탄올아미드, 식물성 유, 라놀린 유도체 또는 에톡실화 글리세롤 지방산 에스테르 등이 이용될 수 있다.When the formulation of the present invention is a surfactant-containing cleansing agent, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyl taurate, sarcosinate, fatty acid amide as carrier components Ether sulfate, alkylamidobetaine, fatty alcohol, fatty acid glyceride, fatty acid diethanolamide, vegetable oil, lanolin derivative or ethoxylated glycerol fatty acid ester and the like may be used.
본 발명의 화장료 조성물에 포함되는 성분은 유효 성분과 담체 성분 이외에, 화장품학적 조성물에 통상적으로 이용되는 성분들을 포함하며, 예컨대 항산화제, 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제를 포함할 수 있다.The ingredients included in the cosmetic composition of the present invention include ingredients commonly used in cosmetic compositions in addition to the active ingredient and carrier ingredient, for example, conventional auxiliary agents such as antioxidants, stabilizers, solubilizers, vitamins, pigments and fragrances. may include
본 발명의 또 다른 일 양태에 따르면, 본 발명은 상술한 화합물을 유효성분으로 포함하는 항산화용 기능성 식품 조성물을 제공한다. According to another aspect of the present invention, the present invention provides a functional food composition for antioxidants comprising the above-described compound as an active ingredient.
본 발명의 기능성 식품 조성물은 식품 제조 시에 통상적으로 첨가되는 성분을 포함하며, 예를 들어, 단백질, 탄수화물, 지방, 영양소 및 조미제를 포함한다. 예컨대, 드링크제로 제조되는 경우에는 유효성분 이외에 향미제 또는 천연 탄수화물을 추가 성분으로서 포함시킬 수 있다. 예를 들어, 천연 탄수화물은 모노사카라이드(예컨대, 글루코오스, 프럭토오스 등); 디사카라이드(예컨대, 말토스, 수크로오스 등); 올리고당; 폴리사카라이드(예컨대, 덱스트린, 시클로덱스트린 등); 및 당알코올(예컨대, 자일리톨, 소르비톨, 에리쓰리톨 등)을 포함할 수 있다.The functional food composition of the present invention includes ingredients commonly added during food production, for example, proteins, carbohydrates, fats, nutrients and seasonings. For example, when manufactured as a drink, a flavoring agent or natural carbohydrate may be included as an additional ingredient in addition to the active ingredient. For example, natural carbohydrates include monosaccharides (eg, glucose, fructose, etc.); disaccharides (eg, maltose, sucrose, etc.); oligosaccharide; polysaccharides (eg, dextrins, cyclodextrins, etc.); and sugar alcohols (eg, xylitol, sorbitol, erythritol, etc.).
향미제로서 천연 향미제(예컨대, 타우마틴, 스테비아 추출물 등) 및 합성 향미제(예컨대, 사카린, 아스파르탐 등)을 이용할 수 있다.As the flavoring agent, natural flavoring agents (eg, thaumatin, stevia extract, etc.) and synthetic flavoring agents (eg, saccharin, aspartame, etc.) can be used.
본 발명의 다른 일 양태에 있어서, 본 발명은 상술한 화합물 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 포함하는 멜라닌 색소 과다침착 질환의 예방 또는 치료용 약제학적 조성물을 제공한다. In another aspect of the present invention, the present invention provides a pharmaceutical composition for preventing or treating melanin hyperpigmentation disease comprising the above-mentioned compound or a pharmaceutically acceptable salt thereof as an active ingredient.
본 발명의 "멜라닌 색소 과다침착 질환"은 구체적으로 예를 들면, 기미, 주근깨, 검버섯, 잡티, 밀크커피색 반점(Cafe's aulait macules), 베커 모반(Becker's Nevus), 반문상 모반(Nevus Spilus), 몽고반(Mongolian spot), 오타 모반(Nevus of Ota), 후천성 양측성 오타모반양반(Acquired bilateral nevus of Ota-like macules), 이토 모반(Nevus of Ito), 청색 모반(Blue nevus), 경계 모반(Junctional nevus), 복합 모반(Compound nevus), 진피내 모반(Intradermal nevus), 운륜 모반(Halo nevus), 선천성 멜라닌세포성 모반(Congenital nevocytic nevus), 스피츠 모반(Spitz nevus), 이형성 모반(Dysplastic nevus), 일광흑색증(solar tigines) 및 수족증후군(Handand-Foot syndrome)을 들 수 있지만 이에 제한되는 것은 아니다. The "melanin hyperpigmentation disease" of the present invention is specifically, for example, melasma, freckles, age spots, blemishes, milky coffee-colored spots (Cafe's aulait macules), Becker's Nevus, nevus patellae (Nevus Spilus), Mongolian plaque (Mongolian spot), Nevus of Ota, Acquired bilateral nevus of Ota-like macules, Nevus of Ito, Blue nevus, Junctional nevus ), Compound nevus, Intradermal nevus, Halo nevus, Congenital nevocytic nevus, Spitz nevus, Dysplastic nevus melanosis (solar tigines) and hand-foot syndrome (Hand-Foot syndrome), but are not limited thereto.
본 발명의 약제학적 조성물은 유효성분 이외에 약제학적으로 허용되는 담체를 포함한다. 본 발명의 약제학적 조성물에 포함되는 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. 본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약제학적으로 허용되는 담체 및 제제는 문헌 [Remington's Pharmaceutical Sciences(19th ed., 1995)]에 상세히 기재되어 있다.The pharmaceutical composition of the present invention includes a pharmaceutically acceptable carrier in addition to the active ingredient. Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil; it is not going to be The pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the above components. Suitable pharmaceutically acceptable carriers and agents are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 한편, 본 발명의 약제학적 조성물의 투여량은 바람직하게는 1일 당 0.001-1000 mg/kg(체중)이다.A suitable dosage of the pharmaceutical composition of the present invention is variously prescribed depending on factors such as formulation method, administration method, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and reaction sensitivity of the patient. can be Meanwhile, the dosage of the pharmaceutical composition of the present invention is preferably 0.001-1000 mg/kg (body weight) per day.
본 발명의 약제학적 조성물은 경구 또는 비경구로 투여할 수 있고, 비경구로 투여되는 경우, 피부에 국소적으로 도포, 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 경피 투여 등으로 투여할 수 있다. 본 발명의 약제학적 조성물이 멜라닌 색소 과다침착 질환의 치료를 위해 적용되는 점을 감안하면, 투여는 피부에 국소적으로 도포되어 이루어지는 것이 바람직하다.The pharmaceutical composition of the present invention may be administered orally or parenterally, and when administered parenterally, it may be administered by topical application to the skin, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc. . Considering that the pharmaceutical composition of the present invention is applied for the treatment of melanin hyperpigmentation disease, it is preferable that the administration is applied topically to the skin.
본 발명의 약제학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화 함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액 또는 유화액 형태이거나 엑스제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical composition of the present invention is prepared in unit dosage form by formulating using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily carried out by a person of ordinary skill in the art to which the present invention pertains. Or it can be prepared by introducing into a multi-dose container. In this case, the formulation may be in the form of a solution, suspension or emulsion in oil or aqueous medium, or may be in the form of an extract, powder, granule, tablet or capsule, and may additionally include a dispersant or stabilizer.
본 발명의 약제학적 조성물은 피부외용 제형 형태로 제조될 수 있다. 상기 피부 외용 제형은 특별히 한정되지 않으나, 파우더, 젤, 연고, 크림, 액체 또는 에어로졸 제형이 바람직하다.The pharmaceutical composition of the present invention may be prepared in the form of a skin external formulation. The formulation for external application to the skin is not particularly limited, but a powder, gel, ointment, cream, liquid or aerosol formulation is preferred.
본 발명에서 피부외용제형의 겔 기재로는 카보폴(Carbopol), 카르보머(Carbomer), 폴리에틸렌글리콜(Polyethyleneglycol), 폴리프로필렌글리콜(Polypropylene glycol), 폴리아크릴산(Polyacrylic acid), 카르복시메틸셀룰로오스(Carboxymethyl cellulose), 히드록시메틸셀룰로오스(Hydroxymethylcellulose), 폴리비닐피롤리돈 (Polyvinylpyrrolidone), 젤라틴(Gelatine), 알지네이트염(Alginate Salt), 키틴(Chitin) 또는 키토산(Chitosan) 유도체, 하이알우론산(hyaluronic acid), 콜라겐(collagen) 중에서 선택된 1종 또는 2종 이상을 사용할 수 있으나, 이에 한정되지 않는다.In the present invention, as the gel base of the skin external preparation type, Carbopol, Carbomer, Polyethyleneglycol, Polypropylene glycol, Polyacrylic acid, Carboxymethyl cellulose ), hydroxymethylcellulose, polyvinylpyrrolidone, gelatin, alginate salt, chitin or chitosan derivatives, hyaluronic acid, One or two or more types selected from collagen may be used, but the present invention is not limited thereto.
본 발명의 다른 일 양태에 따르면, 본 발명은 상술한 화합물 또는 이의 약제학적으로 허용가능한 염을 유효성분으로 포함하는 피부 미백용 화장료 조성물을 제공한다. 본 발명인 화장료 조성물의 피부 미백 효과는 상술한 본 발명의 다른 일 양태인 항산화용 화장료 조성물에 대하여 설명한 본 발명의 화합물 들의 항산화 효과를 이용하는 것으로서, 화장료 조성물의 제형 및 상기 제형에 따른 담체, 추가적으로 포함되는 보조 성분 등에 대하여는 항산화용 화장료 조성물에 대하여 상술한 내용을 참조할 수 있고, 중복되는 내용에 대하여는 본 명세서 기재의 과도한 복잡성을 피하기 위해 생략하도록 한다. According to another aspect of the present invention, the present invention provides a cosmetic composition for skin whitening comprising the above-described compound or a pharmaceutically acceptable salt thereof as an active ingredient. The skin whitening effect of the cosmetic composition of the present invention utilizes the antioxidant effect of the compounds of the present invention described above with respect to the cosmetic composition for antioxidant, which is another aspect of the present invention, and the formulation of the cosmetic composition, the carrier according to the formulation, and additionally included For auxiliary components and the like, reference may be made to the above-described contents for the cosmetic composition for antioxidants, and overlapping contents will be omitted to avoid excessive complexity of the description of the present specification.
본 발명인 약제학적 조성물은 유효성분 이외에 약제학적으로 허용되는 담체를 포함할 수 있고, 상기 담체에 대하여는 본 발명의 다른 일 양태인 멜라닌 색소 과다침착 질환의 예방 또는 치료용 약제학적 조성물에 대하여 상술한 바와 동일하다. The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient, and the carrier is as described above for the pharmaceutical composition for the prevention or treatment of melanin hyperpigmentation disease, which is another embodiment of the present invention. same.
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 한편, 본 발명의 약제학적 조성물의 투여량은 바람직하게는 1일 당 0.001-1000 mg/kg(체중)이다.A suitable dosage of the pharmaceutical composition of the present invention is variously prescribed depending on factors such as formulation method, administration method, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and reaction sensitivity of the patient. can be Meanwhile, the dosage of the pharmaceutical composition of the present invention is preferably 0.001-1000 mg/kg (body weight) per day.
본 발명의 약제학적 조성물은 경구 또는 비경구로 투여할 수 있고, 비경구로 투여되는 경우, 피부에 국소적으로 도포, 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 경피 투여 등으로 투여할 수 있다. The pharmaceutical composition of the present invention may be administered orally or parenterally, and when administered parenterally, it may be administered by topical application to the skin, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc. .
본 발명인 약제학적 조성물은 유효성분 이외에 약제학적으로 허용되는 담체를 포함할 수 있고, 상기 담체에 대하여는 본 발명의 다른 일 양태인 멜라닌 색소 과다침착 질환의 예방 또는 치료용 약제학적 조성물에 대하여 상술한 바와 동일하다. The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier in addition to the active ingredient, and the carrier is as described above for the pharmaceutical composition for the prevention or treatment of melanin hyperpigmentation disease, which is another embodiment of the present invention. same.
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하게 처방될 수 있다. 한편, 본 발명의 약제학적 조성물의 투여량은 바람직하게는 1일 당 0.001-1000 mg/kg(체중)이다.A suitable dosage of the pharmaceutical composition of the present invention is variously prescribed depending on factors such as formulation method, administration method, age, weight, sex, pathological condition, food, administration time, administration route, excretion rate, and reaction sensitivity of the patient. can be Meanwhile, the dosage of the pharmaceutical composition of the present invention is preferably 0.001-1000 mg/kg (body weight) per day.
본 발명의 약제학적 조성물은 경구 또는 비경구로 투여할 수 있고, 비경구로 투여되는 경우, 피부에 국소적으로 도포, 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 경피 투여, 비강 투여 등으로 투여할 수 있다. The pharmaceutical composition of the present invention can be administered orally or parenterally, and when administered parenterally, it is administered by topical application to the skin, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, nasal administration, etc. can do.
본 발명은 우수한 항산화 효과를 발휘하는 신규한 화합물을 제공하며, 이를 이용하여 항산화용 화장료 조성물, 항산화용 기능성 식품 조성물, 멜라닌 색소 과다침착 질환의 예방 또는 치료용 약제학적 조성물, 또는 피부 미백용 화장료 조성물을 제공한다.The present invention provides a novel compound exhibiting an excellent antioxidant effect, and using the same, a cosmetic composition for antioxidant, a functional food composition for antioxidant, a pharmaceutical composition for the prevention or treatment of melanin hyperpigmentation disease, or a cosmetic composition for skin whitening provides
도 1은 시험예 2의 세포 독성 시험 결과를 나타낸 그래프이다.
도 2는 시험예 3의 NO 분석 결과를 나타낸 그래프이다.
도 3a 및 도 3b는 시험예 5의 인 비보 항염증 활성 시험 결과를 나타낸 사진 및 그래프이다. 1 is a graph showing the cytotoxicity test results of Test Example 2.
2 is a graph showing the NO analysis result of Test Example 3.
3a and 3b are photographs and graphs showing the in vivo anti-inflammatory activity test results of Test Example 5.
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
실시예Example
실시예Example 1: N 1: N 55 -((4--((4- 시아노페닐cyanophenyl )아미노)-L-글루타민의 제조) Preparation of amino)-L-glutamine
10% Pd/C의 촉매량(10 mg)을 100 mL의 메탄올 내의 벤질 N2-((벤질옥시)카보닐)-N5-((4-시아노페닐)아미노)-L-글루타미네이트(100 mg, 0.206 mmol)의 현탁액에 첨가하였다. 수소를 플라스크 상단 상의 벌룬(balloon)으로부터 2시간 동안 교반하여 인가시켰다. 이후, 혼합물을 여과하였고, 여과물을 증발시켰다. 잔사를 메탄올로 연마하였고(triturated), 고체를 여과하여 백색 고체로서 N5-((4-(시아노페닐)아미노)-L-글루타민(41 mg, 수율 76%)을 수득하였다. 수득한 화합물의 NMR 데이터는 아래와 같다.A catalytic amount (10 mg) of 10% Pd/C was dissolved in benzyl N 2 -((benzyloxy)carbonyl)-N 5 -((4-cyanophenyl)amino)-L-glutaminate ( 100 mg, 0.206 mmol). Hydrogen was applied from a balloon on the top of the flask with stirring for 2 hours. Then, the mixture was filtered and the filtrate was evaporated. The residue was triturated with methanol, and the solid was filtered to give N 5 -((4-(cyanophenyl)amino)-L-glutamine (41 mg, yield 76%) as a white solid. The NMR data of
1H NMR (300 MHz, DMSO-d6): δ8.58 (s, 1H), 7.90 (bs, 2H), 7.52 (d, J = 8.11 Hz, 2H), 6.74 (d, J = 8.21 Hz, 2H), 3.32-3.14 (m, 1H), 2.44-2.25 (m, 2H), 2.04 - 1.78 (m, 2H). 1 H NMR (300 MHz, DMSO-d 6 ): δ8.58 (s, 1H), 7.90 (bs, 2H), 7.52 (d, J = 8.11 Hz, 2H), 6.74 (d, J = 8.21 Hz, 2H), 3.32-3.14 (m, 1H), 2.44-2.25 (m, 2H), 2.04 - 1.78 (m, 2H).
실시예Example 2. 2. NN 55 -(p--(p- 톨릴아미노tolylamino )-L-글루타민의 제조)-L-glutamine production
40% Pd/C의 촉매량(40 mg)을 100 mL의 메탄올 내의 벤질 N2-((벤질옥시)카보닐)-N5-((4-시아노페닐)아미노)-L-글루타미네이트(100 mg, 0.206 mmol)의 현탁액(suspension)에 첨가하였다. 수소를 플라스크 상단 상의 벌룬으로부터 6시간 동안 교반하여 인가시켰다. 이후, 혼합물을 여과하였고, 여과물을 증발시켰다. 잔사를 메탄올로 연마하였고, 고체를 여과하여 백색 고체로서 N5-(p-톨릴아미노)-L-글루타민(39 mg, 수율 75%)을 수득하였다. 수득한 화합물의 NMR 데이터는 아래와 같다.A catalytic amount (40 mg) of 40% Pd/C was dissolved in benzyl N 2 -((benzyloxy)carbonyl)-N 5 -((4-cyanophenyl)amino)-L-glutaminate ( 100 mg, 0.206 mmol) was added to the suspension. Hydrogen was applied from a balloon on the top of the flask with stirring for 6 hours. Then, the mixture was filtered and the filtrate was evaporated. The residue was triturated with methanol, and the solid was filtered to obtain N 5 -(p-tolylamino)-L-glutamine (39 mg, yield 75%) as a white solid. The NMR data of the obtained compound are as follows.
1H NMR (300 MHz, DMSO-d6): δ9.80 (s, 1H), 7.67 (bs, 2H), 7.48 (s, 1H), 6.93 (d, J = 8.09 Hz, 2H), 6.60 (d, J = 8.21 Hz, 2H), 3.19 (t, J = 6.30 Hz, 1H), 2.32 (t, J = 6.78 Hz, 2H), 2.16 (s, 3H), 2.01-1.77 (m, 2H). LC-MS (m/z):252.1 (MH+) 1 H NMR (300 MHz, DMSO-d 6 ): δ9.80 (s, 1H), 7.67 (bs, 2H), 7.48 (s, 1H), 6.93 (d, J = 8.09 Hz, 2H), 6.60 ( d, J = 8.21 Hz, 2H), 3.19 (t, J = 6.30 Hz, 1H), 2.32 (t, J = 6.78 Hz, 2H), 2.16 (s, 3H), 2.01-1.77 (m, 2H). LC-MS (m/z): 252.1 (MH + )
실시예Example 3: N 3: N 55 -((2,4--((2,4- 디히드록시페닐dihydroxyphenyl )아미노)-L-글루타민의 제조) Preparation of amino)-L-glutamine
20% Pd/C의 촉매량(60 mg)을 200 mL 메탄올 내의 N2-((벤질옥시)카보닐)-N5-((2,4-비스(벤질옥시)페닐)아미노)-L-글루타미네이트(300 mg, 0.445 mmol)의 현탁액에 첨가하였다. 수소를 플라스크 상단 상의 벌룬으로부터 2시간 동안 교반하여 인가시켰다. 이후, 혼합물을 여과하였고, 여과물을 증발시켰다. 잔사를 메탄올로 연마하였고, 고체를 여과하여 짙은 미황색(dark pale yellow) 고체로서 N5-((2,4-디히드록시페닐)아미노)-L-글루타민(82 mg, 수율 72%)을 수득하였다. 수득한 화합물의 NMR 데이터는 아래와 같다.A catalytic amount (60 mg) of 20% Pd/C was added to N 2 -((benzyloxy)carbonyl)-N 5 -((2,4- bis (benzyloxy)phenyl)amino)-L-glu in 200 mL methanol. To a suspension of taminate (300 mg, 0.445 mmol). Hydrogen was applied from a balloon on the top of the flask with stirring for 2 hours. Then, the mixture was filtered and the filtrate was evaporated. The residue was triturated with methanol, and the solid was filtered to obtain N 5 -((2,4-dihydroxyphenyl)amino)-L-glutamine (82 mg, yield 72%) as a dark pale yellow solid. did The NMR data of the obtained compound are as follows.
1H NMR (300 MHz, DMSO-d6):δ 9.65-8.85 (m, 3H), 7.26-7.10 (m, 1H), 6.28 (s, 1H), 6.16 (d, J = 8.43 Hz, 1H), 3.36 -3.24 (m, 1H), 2.06-1.80 (m, 2H), 1.32-1.12 (m, 2H). 1 H NMR (300 MHz, DMSO-d 6 ): δ 9.65-8.85 (m, 3H), 7.26-7.10 (m, 1H), 6.28 (s, 1H), 6.16 (d, J = 8.43 Hz, 1H) , 3.36 -3.24 (m, 1H), 2.06-1.80 (m, 2H), 1.32-1.12 (m, 2H).
실시예Example 4: N 4: N 55 -((3,5--((3,5- 디히드록시페닐dihydroxyphenyl )아미노-L-글루타민의 제조) Preparation of amino-L-glutamine
20% Pd/c의 촉매량(70 mg)을 250 mL의 메탄올 내의 벤질 N2-((벤질옥시)카보닐)-N5-((3,5-비스(벤질옥시)페닐)아미노)-L-글루타미네이트 (350 mg, 0.519 mmol)의 현탁액에 첨가하였다. 수소를 플라스크 상단 상의 벌룬으로부터 2시간 동안 교반하여 인가시켰다. 이후, 혼합물을 여과하였고, 여과물을 증발시켰다. 잔사를 메탄올로 연마하였고, 고체를 여과하여 짙은 미황색 고체로서 N5-((3,5-디히드록시페닐)아미노)-L-글루타민(86 mg, 수율 61%)을 수득하였다. 수득한 화합물의 NMR 데이터는 아래와 같다.A catalytic amount (70 mg) of 20% Pd/c was dissolved in benzyl N 2 -((benzyloxy)carbonyl)-N 5 -((3,5- bis (benzyloxy)phenyl)amino)-L in 250 mL of methanol. -Added to a suspension of glutaminate (350 mg, 0.519 mmol). Hydrogen was applied from a balloon on the top of the flask with stirring for 2 hours. Then, the mixture was filtered and the filtrate was evaporated. The residue was triturated with methanol, and the solid was filtered to give N 5 -((3,5-dihydroxyphenyl)amino)-L-glutamine (86 mg, yield 61%) as a dark pale yellow solid. The NMR data of the obtained compound are as follows.
1H NMR (300 MHz, DMSO-d6):δ 10.08 (s, 1H), 9.213(s, 1H), 7.74 (bs, 2H), 6.56 (s, 2H), 5.87 (s, 1H), 3.31 - 3.18 (m, 1H), 2.43 (t, J = 7.37 Hz, 2H), 2.02 -1.82 (m, 2H). 1 H NMR (300 MHz, DMSO-d 6 ): δ 10.08 (s, 1H), 9.213 (s, 1H), 7.74 (bs, 2H), 6.56 (s, 2H), 5.87 (s, 1H), 3.31 - 3.18 (m, 1H), 2.43 (t, J = 7.37 Hz, 2H), 2.02 -1.82 (m, 2H).
실시예Example 5: 5: NN 55 -((2--((2- 플루오로fluoro -4-(-4-( 메틸설포닐methylsulfonyl )페닐)아미노)-L-글루타민 (12b)의 제조Preparation of )phenyl)amino)-L-glutamine (12b)
10% Pd/c의 촉매량(25.5 mg)을 100 mL의 메탄올 내의 벤질 N 2-((벤질옥시)카보닐)-N 5-((2-플루오로-4-(메틸설포닐)페닐)아미노)-L-글루타미네이트(255 mg, 0.457 mmol)의 용액에 첨가하고, 수소 벌룬을 사용하여 수득한 혼합물에 수소를 첨가하였다. 반응 완료 후, 촉매를 여과하고 메탄올로 세척하였다. 여과물을 진공 농축하고, 조질 잔사를 메탄올로 연마하였다. 이후, 고체를 여과하고 메탄올로 세척하여 백색 고체로서 N 5-((2-플루오로-4-(메틸설포닐)페닐)아미노)-L-글루타민(130 mg, 수율 85%)을 수득하였다. 수득한 화합물의 NMR 데이터는 아래와 같다.A catalytic amount (25.5 mg) of 10% Pd/c was dissolved in benzyl N 2 -((benzyloxy)carbonyl) -N 5 -((2-fluoro-4-(methylsulfonyl)phenyl)amino in 100 mL of methanol. )-L-glutaminate (255 mg, 0.457 mmol) was added, and hydrogen was added to the resulting mixture using a hydrogen balloon. After completion of the reaction, the catalyst was filtered and washed with methanol. The filtrate was concentrated in vacuo and the crude residue was triturated with methanol. Then, the solid was filtered and washed with methanol to obtain N 5 -((2-fluoro-4-(methylsulfonyl)phenyl)amino)-L-glutamine (130 mg, yield 85%) as a white solid. The NMR data of the obtained compound are as follows.
1H NMR (300MHz, DMSO-d6): δ 8.50 (s, 1H), 7.66-7.46 (m, 2H), 7.41-7.28 (m, 1H), 6.98-6.82 (m, 1H), 3.29-3.19 (m, 1H), 3.14 (s, 3H), 2.40 (t, J=7.28Hz, 2H), 2.12-1.74 (m, 2H). 1 H NMR (300 MHz, DMSO-d 6 ): δ 8.50 (s, 1H), 7.66-7.46 (m, 2H), 7.41-7.28 (m, 1H), 6.98-6.82 (m, 1H), 3.29-3.19 (m, 1H), 3.14 (s, 3H), 2.40 (t, J=7.28 Hz, 2H), 2.12-1.74 (m, 2H).
상기 화합물, 및 상기 절차를 사용하여 제조된 추가 화합물을, NMR 데이터 또는 LC-MS (m/z) 데이터와 함께 하기 표 1에 제시하였다.The above compounds, and additional compounds prepared using the above procedures, along with NMR data or LC-MS (m/z) data are presented in Table 1 below.
비교예comparative example 1. One. 라말린(Ramalin)의of Ramalin 제조 Produce
상기 실시예에 기재된 방법을 사용하여 하기 화학 구조식으로 표시되는 화합물(일반명 라말린(Ramalin))을 제조하였다:Using the method described in the examples above, a compound represented by the following chemical structure (common name Ramalin) was prepared:
시험예 1: DPPH 분석에 의한 항산화 효과 실험Test Example 1: Antioxidant effect experiment by DPPH analysis
상기 실시예에서 제조된 화합물의 항산화 효과를 시험하기 위해 2,2-디페닐피크릴히드라질(DPPH) 분석을 수행하였다. DPPH 분석은 자유 라디칼 소거로 인한 항산화 활성을 평가하기 위해 널리 사용되며, 본원 명세서 시험예 1에서는 문헌 [Brand-Williams, Cuvelier 및 Berset (1995)]에 기재된 절차에 따라 분석을 수행하였다.2,2-diphenylpicrylhydrazyl (DPPH) analysis was performed to test the antioxidant effect of the compound prepared in the above Examples. DPPH analysis is widely used to evaluate antioxidant activity due to free radical scavenging, and in Test Example 1 of the present specification, the analysis was performed according to the procedure described in [Brand-Williams, Cuvelier and Berset (1995)].
DMSO 내에서 실시예에서 제조된 화합물 중 일부 화합물을 10 mg/ml의 농도로 준비하고, 96-웰 마이크로 플레이트에 옮기기 전, 3.1 μg/mL, 6.3 μg/mL, 12.5 μg/mL, 25.0 μg/mL, 50.0 μg/mL, 100.0 μg/mL의 농도로 희석하여 시료 용액으로 하였다. 각 웰은 DPPH (0.2 mM)의 메탄올 용액 100 μL와 시료 용액 100 μL를 함유하였다. 마이크로플레이트를 암실 조건에서 실온으로 30분 동안 방치하고, 마이크로플레이트 판독기(바이오-텍 인스트루먼츠, 위누스키, 버몬트)를 사용하여 540 nm에서 흡광도를 측정 하였다. 블랭크(Blank)는 메탄올 및 DMSO 혼합물 (200 μL)로 제조하였고, 아스코르브산도 양성 대조군으로 측정하였다. DPPH 라디칼 소거 능력은 다음 공식을 사용하여 계산하였고, 그 결과를 하기 표 2에 나타내었다.Some of the compounds prepared in Examples were prepared in DMSO at a concentration of 10 mg/ml, and before transfer to a 96-well microplate, 3.1 μg/mL, 6.3 μg/mL, 12.5 μg/mL, 25.0 μg/ mL, 50.0 µg/mL, and 100.0 µg/mL were diluted to obtain a sample solution. Each well contained 100 μL of a methanol solution of DPPH (0.2 mM) and 100 μL of a sample solution. The microplate was left at room temperature in the dark for 30 minutes, and absorbance was measured at 540 nm using a microplate reader (Bio-Tec Instruments, Winusky, Vermont). A blank was prepared with a mixture of methanol and DMSO (200 μL), and ascorbic acid was also measured as a positive control. The DPPH radical scavenging ability was calculated using the following formula, and the results are shown in Table 2 below.
DPPH 소거 능력 (저해%) = {(AB-AS)/AB)*100}DPPH scavenging ability (% inhibition) = {(A B -A S )/A B )*100}
(식 중, AB는 블랭크 반응의 흡광도이고, AS는 글루탐산 유도체 시료 및 양성 대조군의 존재 하의 흡광도이다. 시험은 3번 반복하여 수행하였고, 그 결과값을 평균내었다. IC50은 시험 시료에 의해 50%의 라디칼이 소거된 수준(level)을 나타낸다.(wherein A B is the absorbance of the blank reaction, AS is the absorbance in the presence of the glutamic acid derivative sample and the positive control. The test was repeated three times, and the results were averaged. IC50 was determined by the test sample. It represents a level at which 50% of the radicals are scavenged.
시험예test example 2: 세포 독성 시험 2: Cytotoxicity test
세포 생존율을 시험하기 위해, ATCC(어메리칸 타입 컬처 콜렉션)으로부터 수득한 쥐의 단핵 세포/대식 세포 세포주 RAW 264.7을, 37 ℃, 5% CO2 하에서 10% FBS와 1% 항생제가 보충된 DMEM으로 75 cm2 조직 배양 플라스크 내에서 배양하였다. 배양된 세포에 실시예 2, 실시예 5, 실시예 22 및 비교예 1에 의해 제조된 화합물 각각 100 μg/mL를 24시간 동안 처리하였다. 이후 상대 생존율을 숙시네이트-테트라졸륨 리덕타아제에 의한 수용성 포르마잔에 대한 테트라졸륨 염의 소거에 기초하여 EZ-사이톡스 세포 생존율 분석 키트(EZ-Cytox Cell Viability Assay Kit)(대일 랩서비스, 한국)에 의해 결정하였다. 10 μL의 EZ-사이톡스를 100 μL/웰의 최종 부피로 배지에 첨가하였다. 세포를 37 ℃에서 1시간 추가 배양하고, 마이크로플레이트 판독기(바이오-텍 인스트루먼츠, 위누스키, 버몬트)를 사용하여 450 nm에서 흡광도를 측정하였다. 그 결과를 도 1에 나타내었다. To test cell viability, the murine mononuclear cell/macrophage cell line RAW 264.7 obtained from ATCC (American Type Culture Collection) was treated with DMEM supplemented with 10% FBS and 1% antibiotics at 37°C under 5% CO 2 75 Cultivated in cm 2 tissue culture flasks. The cultured cells were treated with 100 μg/mL of each of the compounds prepared in Example 2, Example 5, Example 22 and Comparative Example 1 for 24 hours. Thereafter, the relative viability was calculated using EZ-Cytox Cell Viability Assay Kit (EZ-Cytox Cell Viability Assay Kit) based on clearance of tetrazolium salt to water-soluble formazan by succinate-tetrazolium reductase (Dail Lab Service, Korea). was determined by 10 μL of EZ-Cytox was added to the medium to a final volume of 100 μL/well. Cells were further incubated at 37° C. for 1 hour, and absorbance was measured at 450 nm using a microplate reader (Bio-Tec Instruments, Winusky, Vermont). The results are shown in FIG. 1 .
시험예test example 3: NO (Nitric Oxide) 분석 3: NO (Nitric Oxide) analysis
아질산(Nitrite) 이온 축적을 배지의 NO 생산의 지표로 사용하duT고, 그리이스(Griess) 반응으로 측정하였다. 상기 시험예 2와 동일한 방법으로 Raw 264.7 세포를 배양하였다. 실시예 5에 의해 제조된 화합물의 NO 생산 효과를 시험하기 위해 새로운 배지를 사용하여 세포를 96-웰 플레이트(5x104 세포/웰)에 씨딩하였다. 24시간 동안 예비 배양한 후, 글루탐산 유도체의 농축액(3.1 μg/mL, 6.3 μg/mL, 12.5 μg/mL, 25.0 μg/mL, 50.0 μg/mL, 100.0 μg/mL) 존재 또는 부존재 하에서 세포를 LPS(300 ng/mL)로 자극시켰다. 24시간의 배양 시간 동안 생산된 NO의 농도를 측정하기 위해, 96 웰 플레이트의 웰 당 100 μL의 배양 상등액을, 15분 동안 실온에서 50 μL의 그리이스 시약 A (2.5% H3PO4 중 1% 설파닐아마이드) 및 50 μL의 그리이스 시약 B (2.5% H3PO4 중 0.1% 나프틸에틸렌디아민 디히드로클로라이드)와 함께 배양시켰다. 마이크로플레이트 판독기를 사용하여 540 nm에서의 흡광도를 측정하였다(바이오-텍 인스트루먼츠, 위누스키, 버몬트). A540 표준을 비교하여 질산염(Nitrate) 농도를 계산하였다. 데이터는 한 웰에 대해 3번 측정한 값의 평균±표준편차로 나타내었으며, 그 결과를 도 2에 나타내었다. Nitrite ion accumulation was used as an indicator of NO production in the medium and was measured by the Griess reaction. Raw 264.7 cells were cultured in the same manner as in Test Example 2. Cells were seeded in 96-well plates (5×10 4 cells/well) using fresh medium to test the NO production effect of the compound prepared in Example 5. After pre-incubation for 24 h, cells were washed with LPS in the presence or absence of a concentrate of glutamic acid derivatives (3.1 µg/mL, 6.3 µg/mL, 12.5 µg/mL, 25.0 µg/mL, 50.0 µg/mL, 100.0 µg/mL). (300 ng/mL). To determine the concentration of NO produced during a 24-h incubation time, 100 µL of culture supernatant per well of a 96-well plate was transferred to 50 µL of grease reagent A (1% in 2.5% H 3 PO 4 ) at room temperature for 15 min. sulfanylamide) and 50 μL of Grease Reagent B (0.1% naphthylethylenediamine dihydrochloride in 2.5% H 3 PO 4 ). Absorbance at 540 nm was measured using a microplate reader (Bio-Tech Instruments, Winusky, Vermont). A 540 standard was compared to calculate the nitrate concentration. Data were expressed as the mean±standard deviation of the values measured three times for one well, and the results are shown in FIG. 2 .
시험예test example 4. 인 비트로(in vitro) 안정성 시험 4. In vitro stability test
실시예 2, 5, 22 및 27에 의해 제조된 화합물 및 비교예 1에 의해 제조된 화합물을 각각 탈이온수(1 mg/mL)에 용해시키고 45 ℃에서 배양하여 4주 동안 화학적 안정성을 측정하였다. 각 시료를 1주일 마다 분리하고, 역상 HPLC로 측정하였다. 각 시료 10 μL를, 1mL/분으로 30분에 걸쳐 0.1% 포름산 용액 중 95-10% 물의 구배에 의해 용리된 4.6X150 mm 이클립스 XDB-C-18(Eclipse XDB-C18) 컬럼(애질런트)을 포함하는 구배 HPLC 시스템에 주입하였다. 용리액을 UV 흡광도(254 nm)에 대해 모니터링하고, 시작 시점에서의 값을 100%로 하여 상대 안정성을 계산하였다. 그 결과를 하기 표 3에 나타내었다.The compounds prepared by Examples 2, 5, 22 and 27 and the compound prepared by Comparative Example 1 were each dissolved in deionized water (1 mg/mL) and incubated at 45° C. to measure chemical stability for 4 weeks. Each sample was separated weekly and measured by reverse-phase HPLC. 10 µL of each sample contained a 4.6X150 mm Eclipse XDB-C-18 (Agilent) column (Agilent) eluted by a gradient of 95-10% water in 0.1% formic acid solution over 30 min at 1 mL/min. was injected into a gradient HPLC system. The eluent was monitored for UV absorbance (254 nm) and the relative stability was calculated with the value at the starting point being 100%. The results are shown in Table 3 below.
(45℃)1 day
(45℃)
(45℃)7 days
(45℃)
(45℃)14 days
(45℃)
(45℃)21 days
(45℃)
(45℃)28 days
(45℃)
*: 시작(0일)의 HPLC AUC를 100%로 하여 계산함.Condition: compound stability 45 Analyzed after storage at °C; Dissolve 1 mg of each sample in 1 mL distilled water.
*: Calculated by taking the HPLC AUC of the start (day 0) as 100%.
시험예test example 5. 인 비보(in 5. in vivo vivoin vivo ) 항염증 활성 시험) anti-inflammatory activity test
인 비보에서 실시예 5에 의해 제조된 화합물의 항염증 활성을 조사하기 위해 제브라피시(zebrafish) 모델을 사용하였다. Tg(mpx:GFP) 제브라피시 라인은 호중구 특이적인 미엘로페록시다아제(myeloperoxidase) 프로모터의 조절 하에 HFP를 발현하는, 염증 반응의 분석을 위해 사용되는 인 비보 모델이다. 수정 후 3일째에, Tg(mpx:GFP) 유충을 트리카인으로 마취시키고, 꼬리 지느러미를 절단하였다. 꼬리 지느러미를 절단한 후, GFP-발현 호중구가 상처 부위로 이동하였다. 절단 4시간 후, 부상당한 유충을 포함하는 배아 배지를 6 시간 동안 실시예 5에 의해 제조된 화합물로 처리하였다. 실시예 5에 의해 제조된 화합물은 상처 입은 꼬리 지느러미로의 호중구 유입을 감소시켰다. 그러나, 절단되지 않은 유충은 실시예 5에 의해 제조된 화합물 처리에 반응하여 호중구 유입이 일어나지 않았다. 덱사메타손을 양성 대조군으로 사용하였다. 그 결과를 도 3a 및 도 3b에 나타내었다. 이 결과는 실시예 5에 의해 제조된 화합물이 호중구 매개 상처 염증을 억제시킨다는 것을 확인시켜 준다. A zebrafish model was used to investigate the anti-inflammatory activity of the compound prepared in Example 5 in vivo. The Tg(mpx:GFP) zebrafish line is an in vivo model used for the analysis of inflammatory responses, expressing HFP under the control of a neutrophil-specific myeloperoxidase promoter. On day 3 after fertilization, Tg(mpx:GFP) larvae were anesthetized with tricaine and the caudal fin was amputated. After excision of the caudal fin, GFP-expressing neutrophils migrated to the wound site. After 4 hours of amputation, the embryo medium containing the injured larvae was treated with the compound prepared according to Example 5 for 6 hours. The compound prepared by Example 5 reduced the influx of neutrophils into the wounded caudal fin. However, in uncut larvae, neutrophil influx did not occur in response to treatment with the compound prepared in Example 5. Dexamethasone was used as a positive control. The results are shown in FIGS. 3A and 3B. This result confirms that the compound prepared by Example 5 inhibits neutrophil-mediated wound inflammation.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현 예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.As the specific parts of the present invention have been described in detail above, for those of ordinary skill in the art, these specific techniques are only preferred embodiments, and it is clear that the scope of the present invention is not limited thereto. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
Claims (11)
화학식 1
상기 화학식 1에서,
R1은 히드록실 또는 벤질옥시이고;
R2는 수소 또는 벤질옥시카보닐이며;
R3은 4-시아노페닐, 3-시아노페닐, 2,3-디메틸페닐, 2,4-디메틸페닐, 2,5-디메틸페닐, 2,4-디히드록시페닐, 3,5-디히드록시페닐, 4-(메틸설포닐)페닐, 2-플루오로-4-(메틸설포닐)페닐, 4-이소프로필페닐, 2-에틸페닐, 2-플루오로페닐, 3-플루오로페닐 및 4-플루오로페닐로 구성된 군으로부터 선택되는 어느 하나이다.
A compound of Formula 1 or a pharmaceutically acceptable salt thereof:
Formula 1
In Formula 1,
R 1 is hydroxyl or benzyloxy;
R 2 is hydrogen or benzyloxycarbonyl;
R 3 is 4-cyanophenyl, 3-cyanophenyl, 2,3-dimethylphenyl, 2,4-dimethylphenyl, 2,5-dimethylphenyl, 2,4-dihydroxyphenyl, 3,5-di Hydroxyphenyl, 4-(methylsulfonyl)phenyl, 2-fluoro-4-(methylsulfonyl)phenyl, 4-isopropylphenyl, 2-ethylphenyl, 2-fluorophenyl, 3-fluorophenyl and Any one selected from the group consisting of 4-fluorophenyl.
상기 R3은 2-플루오로-4-(메틸설포닐)페닐 또는 4-(메틸설포닐)페닐인 것을 특징으로 하는, 화합물 또는 이의 약제학적으로 허용가능한 염.
The method of claim 1,
Wherein R 3 is 2-fluoro-4-(methylsulfonyl)phenyl or 4-(methylsulfonyl)phenyl, a compound or a pharmaceutically acceptable salt thereof.
상기 R1이 히드록실인 경우 R2는 수소이고, 상기 R1이 벤질옥시인 경우 R2는 벤질옥시카보닐인 것을 특징으로 하는, 화합물 또는 이의 약제학적으로 허용가능한 염.
The method of claim 1,
When R 1 is hydroxyl, R 2 is hydrogen, and when R 1 is benzyloxy, R 2 is benzyloxycarbonyl. A compound or a pharmaceutically acceptable salt thereof.
상기 화합물은
(1) N5-((4-시아노페닐)아미노)-L-글루타민;
(3) N5-((2,4-디히드록시페닐)아미노)-L-글루타민;
(4) N5-((3,5-디히드록시페닐)아미노)-L-글루타민;
(5) N5-((2-플루오로-4-(메틸설포닐)페닐)아미노)-L-글루타민;
(6) 벤질 N2-((벤질옥시)카보닐)-N5-((4-시아노페닐)아미노)-D-글루타미네이트;
(7) N5-((4-시아노페닐)아미노)-D-글루타민;
(8) N5-((3-시아노페닐)아미노)-L-글루타민;
(9) N5-((3-시아노페닐)아미노)-D-글루타민;
(10) N5-((2,4-디히드록시페닐)아미노)-D-글루타민;
(11) N5-((3,5-디히드록시페닐)아미노)-D-글루타민;
(12) 벤질 N2-((벤질옥시)카보닐)-N5-((4-시아노페닐)아미노)-L-글루타미네이트;
(13) N5-((2-플루오로-4-(메틸설포닐)페닐)아미노)-D-글루타민;
(14) N5-((2,3-디메틸페닐)아미노)-L-글루타민;
(15) N5-((2,3-디메틸페닐)아미노)-D-글루타민;
(16) N5-((2,5-디메틸페닐)아미노)-L-글루타민;
(17) N5-((2,5-디메틸페닐)아미노)-D-글루타민;
(18) N5-((4-이소프로필페닐)아미노)-L-글루타민;
(19) N5-((4-이소프로필페닐)아미노)-D-글루타민;
(20) N5-((2-에틸페닐)아미노)-L-글루타민;
(21) N5-((2-에틸페닐)아미노)-D-글루타민;
(26) N5-((3-플루오로페닐)아미노)-L-글루타민;
(27) N5-((4-(메틸설포닐)페닐)아미노)-L-글루타민;
(28) N5-((2-플루오로페닐)아미노)-L-글루타민;
(30) N5-((4- 플루오로페닐)아미노)-L-글루타민; 및
(31) N5-((2, 4-디메틸페닐)아미노)-L-글루타민
으로 구성된 군으로부터 선택되는 것을 특징으로 하는, 화합물 또는 이의 약제학적으로 허용가능한 염.
The method of claim 1,
The compound is
(1) N 5 -((4-cyanophenyl)amino)-L-glutamine;
(3) N 5 -((2,4-dihydroxyphenyl)amino)-L-glutamine;
(4) N 5 -((3,5-dihydroxyphenyl)amino)-L-glutamine;
(5) N 5 -((2-fluoro-4-(methylsulfonyl)phenyl)amino)-L-glutamine;
(6) benzyl N 2 -((benzyloxy)carbonyl)-N 5 -((4-cyanophenyl)amino)-D-glutaminate;
(7) N 5 -((4-cyanophenyl)amino)-D-glutamine;
(8) N 5 -((3-cyanophenyl)amino)-L-glutamine;
(9) N 5 -((3-cyanophenyl)amino)-D-glutamine;
(10) N 5 -((2,4-dihydroxyphenyl)amino)-D-glutamine;
(11) N 5 -((3,5-dihydroxyphenyl)amino)-D-glutamine;
(12) benzyl N 2 -((benzyloxy)carbonyl)-N 5 -((4-cyanophenyl)amino)-L-glutaminate;
(13) N 5 -((2-fluoro-4-(methylsulfonyl)phenyl)amino)-D-glutamine;
(14) N 5 -((2,3-dimethylphenyl)amino)-L-glutamine;
(15) N 5 -((2,3-dimethylphenyl)amino)-D-glutamine;
(16) N 5 -((2,5-dimethylphenyl)amino)-L-glutamine;
(17) N 5 -((2,5-dimethylphenyl)amino)-D-glutamine;
(18) N 5 -((4-isopropylphenyl)amino)-L-glutamine;
(19) N 5 -((4-isopropylphenyl)amino)-D-glutamine;
(20) N 5 -((2-ethylphenyl)amino)-L-glutamine;
(21) N 5 -((2-ethylphenyl)amino)-D-glutamine;
(26) N 5 -((3-fluorophenyl)amino)-L-glutamine;
(27) N 5 -((4-(methylsulfonyl)phenyl)amino)-L-glutamine;
(28) N 5 -((2-fluorophenyl)amino)-L-glutamine;
(30) N 5 -((4-fluorophenyl)amino)-L-glutamine; and
(31) N 5 -((2, 4-dimethylphenyl)amino)-L-glutamine
A compound or a pharmaceutically acceptable salt thereof, characterized in that it is selected from the group consisting of.
A cosmetic composition for antioxidant comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
A functional food composition for antioxidants comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
A pharmaceutical composition for preventing or treating melanin hyperpigmentation disease comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
상기 멜라닌 색소 과다침착 질환은 기미, 주근깨, 검버섯, 잡티, 밀크커피색 반점(Cafe's aulait macules), 베커 모반(Becker's Nevus), 반문상 모반(Nevus Spilus), 몽고반(Mongolian spot), 오타 모반(Nevus of Ota), 후천성 양측성 오타모반양반(Acquired bilateral nevus of Ota-like macules), 이토 모반(Nevus of Ito), 청색 모반(Blue nevus), 경계 모반(Junctional nevus), 복합 모반(Compound nevus), 진피내 모반(Intradermal nevus), 운륜 모반(Halo nevus), 선천성 멜라닌세포성 모반(Congenital nevocytic nevus), 스피츠 모반(Spitz nevus), 이형성 모반(Dysplastic nevus), 일광흑색증(solar tigines) 및 수족증후군(Handand-Foot syndrome)으로 구성된 군으로부터 선택되는 것을 특징으로 하는 조성물.
10. The method of claim 9,
The melanin hyperpigmentation disease is melasma, freckles, age spots, blemishes, milk coffee-colored spots (Cafe's aulait macules), Becker's Nevus, nevus mottled (Nevus Spilus), Mongolian spot, nevus of Ota (Nevus of Ota), Acquired bilateral nevus of Ota-like macules, Nevus of Ito, Blue nevus, Junctional nevus, Compound nevus, dermis Intradermal nevus, Halo nevus, Congenital nevocytic nevus, Spitz nevus, Dysplastic nevus, solar tigines and hand-foot syndrome Handand-Foot syndrome) composition, characterized in that selected from the group consisting of.
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