KR20210077156A - Nicotinamide Riboside Derivatives Conjugated with Fatty Amine - Google Patents
Nicotinamide Riboside Derivatives Conjugated with Fatty Amine Download PDFInfo
- Publication number
- KR20210077156A KR20210077156A KR1020190168485A KR20190168485A KR20210077156A KR 20210077156 A KR20210077156 A KR 20210077156A KR 1020190168485 A KR1020190168485 A KR 1020190168485A KR 20190168485 A KR20190168485 A KR 20190168485A KR 20210077156 A KR20210077156 A KR 20210077156A
- Authority
- KR
- South Korea
- Prior art keywords
- nicotinamide riboside
- formula
- whitening
- present
- group
- Prior art date
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- JLEBZPBDRKPWTD-TURQNECASA-O N-ribosylnicotinamide Chemical class NC(=O)C1=CC=C[N+]([C@H]2[C@@H]([C@H](O)[C@@H](CO)O2)O)=C1 JLEBZPBDRKPWTD-TURQNECASA-O 0.000 title claims abstract description 71
- 150000001412 amines Chemical class 0.000 title abstract description 33
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- A61Q7/00—Preparations for affecting hair growth
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/318—Foods, ingredients or supplements having a functional effect on health having an effect on skin health and hair or coat
Abstract
Description
본 발명은 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체에 관한 것으로, 더욱 상세하게는 안정성 및 생체 흡수가 증가되고, 체내에서 가수분해되어 니코틴아미드 아데닌 다이뉴클레오티드(NAD)의 전구체인 니코틴아미드 리보사이드(NR)를 공급할 수 있는 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체 및 그를 포함하는 주름개선, 미백, 세포재생, 탈모 치료 또는 항염용 조성물에 관한 것이다.The present invention relates to a fatty amine-conjugated nicotinamide riboside derivative, and more particularly, to nicotinamide riboside (nicotinamide riboside) that is a precursor of nicotinamide adenine dinucleotide (NAD) through increased stability and bioabsorption and hydrolysis in the body ( It relates to a fatty amine-conjugated nicotinamide riboside derivative capable of supplying NR) and a composition for wrinkle improvement, whitening, cell regeneration, hair loss treatment or anti-inflammatory composition comprising the same.
사람의 피부는 나이를 먹으면서 노화 현상이 일어나고, 햇빛, 스트레스, 식생활 등 여러 가지 복합적인 요인에 의해 노화되는 속도가 영향을 받을 수 있다. 피부를 포함한 신체의 노화에 대한 메커니즘 중 하나로, 노화는 세포의 핵과 미토콘드리아 사이의 신호전달이 원활하지 못할 때 발생할 수 있다. 니코틴아미드 아데닌 다이뉴클레오티드(Nicotinamide adenine dinucleotide, NAD)는 이러한 핵과 미토콘드리아 사이의 활동을 조절하는 핵심분자로 신호를 전달할 수 있도록 하는 화학물질이다. NAD는 체내 반응에 따라 NADH와 NAD+의 형태로 존재할 수 있으며, 이때 NADH는 NAD의 환원형태이고 NAD+는 NAD의 산화형태이다. NAD는 세포 호흡에 필수적인 화합물이며 에너지를 발생시키는 핵심적인 분자이고, 몸 전체에서 건강한 대사를 촉진하는 것으로 알려진 SIRT1 단백질을 활성화시킨다.Human skin aging occurs with age, and the rate of aging can be affected by various complex factors such as sunlight, stress, and diet. As one of the mechanisms for aging of the body including the skin, aging can occur when the signal transduction between the cell nucleus and mitochondria is not smooth. Nicotinamide adenine dinucleotide (NAD) is a key molecule that regulates the activity between the nucleus and mitochondria, and is a chemical substance that allows signals to be transmitted. NAD may exist in the form of NADH and NAD + depending on the reaction in the body, where NADH is the reduced form of NAD and NAD + is the oxidized form of NAD. NAD is an essential compound for cellular respiration, a key molecule that generates energy, and activates the SIRT1 protein, which is known to promote healthy metabolism throughout the body.
최근 노화에 의해 세포 내 NAD의 양이 감소할 수 있으며, NAD의 양적 증가가 노화를 방지할 수 있음이 보고된 바 있다. 하지만, 세포 외부에 존재하는 NAD가 세포막이나 미토콘드리아 막을 통과하는 것은 어렵고, 독성을 유발할 수 있어 NAD를 직접 사용하는 것은 제약이 많았다. 또한, NAD를 직접 사용할 경우 세포 내 NAD가 정상범위를 초과할 수 있어 항상성 유지가 어려울 수 있다.Recently, it has been reported that the amount of NAD in cells can be decreased by aging, and that the quantitative increase of NAD can prevent aging. However, it is difficult for NAD existing outside the cell to pass through the cell membrane or the mitochondrial membrane, and it may cause toxicity, so the direct use of NAD has many limitations. In addition, when NAD is directly used, intracellular NAD may exceed the normal range, making it difficult to maintain homeostasis.
이에, NAD를 직접 사용하지 않고 니코틴아미드 리보사이드(Nicotinamide Riboside, NR)와 같은 NAD의 전구체를 사용하여 부작용이 없으며, 세포 내에 적절한 양의 NAD의 생성을 유도함으로써 노화의 증상 및 징후 또는 피부 주름을 개선하고자 하는 방안들이 제시된 바 있다. 예를 들어, 대한민국 공개특허 제10-2016-0047914호에서는 NAD의 전구체를 포함하는 노화 방지용 화장료 조성물을 개시하고 있으며, 대한민국 공개특허 제10-2016-0067195호에서는 NR 또는 그 염을 국소적으로 투여하여 피부의 UV-매개 DNA 손상을 치료 또는 예방하기 위한 방법을 개시하고 있다.Therefore, there is no side effect by using a precursor of NAD such as nicotinamide riboside (NR) without using NAD directly, and by inducing the generation of an appropriate amount of NAD in cells, the symptoms and signs of aging or skin wrinkles Suggestions for improvement have been suggested. For example, Korean Patent Application Laid-Open No. 10-2016-0047914 discloses a cosmetic composition for anti-aging containing a precursor of NAD, and Korean Patent Publication No. 10-2016-0067195 discloses topical administration of NR or a salt thereof. Thus, a method for treating or preventing UV-mediated DNA damage of the skin is disclosed.
하지만, NR과 같은 NAD의 전구체는 안정성이 많이 떨어진다. 특히, NR은 불안정한 글리코시드 결합을 함유하여, 수용액에서 자발적으로 니코틴아미드 및 리보스 분해 생성물을 산출한다. 이 분해반응은 주위 조건에 따라 수시간 또는 수일에 걸쳐 발생한다. 이에 따라, NR은 안정성을 담보하면서 제품에 적용하기가 곤란하다. 따라서, 안정성이 증가된 NR 유도체에 대한 개발이 절실히 요구되고 있다.However, precursors of NAD such as NR have very poor stability. In particular, NRs contain labile glycosidic bonds, yielding nicotinamide and ribose degradation products spontaneously in aqueous solution. This decomposition reaction takes place over hours or days, depending on the ambient conditions. Accordingly, it is difficult to apply NR to products while ensuring stability. Therefore, there is an urgent need for development of NR derivatives with increased stability.
또한, NAD 전구체를 주름개선 등의 기능성 소재로 적용하기 위하여는 생체 흡수율의 개선이 필요하다.In addition, in order to apply the NAD precursor as a functional material such as wrinkle improvement, it is necessary to improve the bioabsorption rate.
본 발명자들은 상기한 NAD의 전구체인 니코틴아미드 리보사이드의 안정성 및 생체 흡수성 문제를 개선하기 위해 예의 연구 검토한 결과, 니코틴아미드 리보사이드를 지방아민과 컨쥬게이션시킴으로써 장기 보관에도 안정성을 유지하고, 생체 흡수율이 크게 향상됨을 발견하고 본 발명을 완성하게 되었다.As a result of intensive research and review to improve the stability and bioabsorption problems of nicotinamide riboside, a precursor of NAD, the present inventors conjugated nicotinamide riboside with fatty amines to maintain stability even in long-term storage and bioabsorption rate It was found that this greatly improved, and the present invention was completed.
따라서, 본 발명의 목적은 안정성 및 생체 흡수율이 증가된 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체를 제공하는 것이다. Accordingly, it is an object of the present invention to provide a fatty amine-conjugated nicotinamide riboside derivative with increased stability and bioabsorption.
본 발명의 다른 목적은 상기 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체를 포함하는 주름개선, 미백, 세포재생, 탈모 치료 또는 항염용 조성물을 제공하는 것이다.Another object of the present invention is to provide a composition for wrinkle improvement, whitening, cell regeneration, hair loss treatment or anti-inflammatory composition comprising the fatty amine-conjugated nicotinamide riboside derivative.
본 발명은 하기 화학식 1의 니코틴아미드 리보사이드 유도체에 관한 것이다.The present invention relates to a nicotinamide riboside derivative represented by the following formula (1).
[화학식 1] [Formula 1]
상기 식에서,In the above formula,
R은 C8-C34의 포화 또는 불포화 지방족 탄화수소기이고,R is a C 8 -C 34 saturated or unsaturated aliphatic hydrocarbon group,
R1, R2 및 R3는 각각 독립적으로 수소 원자 또는 아실기이고, R 1 , R 2 and R 3 are each independently a hydrogen atom or an acyl group,
X는 술포네이트기 또는 할로겐 원자이다.X is a sulfonate group or a halogen atom.
본 명세서에서 사용되는 C8-C34의 포화 또는 불포화 지방족 탄화수소기는 탄소수 8 내지 34개로 구성된 직쇄형 또는 분지형의 포화 또는 불포화 탄화수소기를 의미하며, 예컨대 C8-C34의 알킬기, C8-C34의 알케닐기, C8-C34의 알키닐기일 수 있다. 구체적으로, C8-C34의 포화 또는 불포화 지방족 탄화수소기는 옥틸, 노닐, 데실, 언데실, 도데실, 트리데실, 세틸, 스테아릴, 옥테닐, 노네닐 등이 포함되나 이에 한정되는 것은 아니다.As used herein, the C 8 -C 34 saturated or unsaturated aliphatic hydrocarbon group refers to a linear or branched saturated or unsaturated hydrocarbon group composed of 8 to 34 carbon atoms, for example, a C 8 -C 34 alkyl group, C 8 -C It may be a 34 alkenyl group or a C 8 -C 34 alkynyl group. Specifically, the C 8 -C 34 saturated or unsaturated aliphatic hydrocarbon group includes, but is not limited to, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, cetyl, stearyl, octenyl, nonenyl, and the like.
본 명세서에서 사용되는 아실기는 화학식 -CORa의 기(이때 Ra는 수소, C1-C5의 알킬기 또는 아릴기이다)를 나타내며, 예를 들어 아세틸기, 벤조일기 등이 포함되나 이에 한정되는 것은 아니다.The acyl group as used herein represents a group of the formula -COR a (where R a is hydrogen, a C 1 -C 5 alkyl group, or an aryl group), for example, an acetyl group, a benzoyl group, etc. are included, but are limited thereto it is not
본 명세서에서 사용되는 술포네이트기는 화학식 -OS(=O)2Rb의 기(이때 Rb는 수소, C1-C5의 알킬기, C1-C5의 할로알킬기 또는 아릴기이다)를 나타내며, 예를 들어 메틸술포네이트기, 트리플루오로메틸술포네이트기, 벤젠술포네이트기, 톨루엔술포네이트기 등이 포함되나 이에 한정되는 것은 아니다.A sulfonate group as used herein represents a group of the formula -OS(=O) 2 R b (wherein R b is hydrogen, a C 1 -C 5 alkyl group, a C 1 -C 5 haloalkyl group or an aryl group) , for example, a methylsulfonate group, a trifluoromethylsulfonate group, a benzenesulfonate group, a toluenesulfonate group, etc., but are not limited thereto.
본 발명의 일 실시형태에서, R은 C12-C22의 포화 지방족 탄화수소기일 수 있다.In one embodiment of the present invention, R may be a C 12 -C 22 saturated aliphatic hydrocarbon group.
본 발명의 일 실시형태에서, X는 메틸술포네이트기, 트리플루오로메틸술포네이트기, 클로라이드 또는 브로마이드일 수 있다.In one embodiment of the present invention, X may be a methylsulfonate group, a trifluoromethylsulfonate group, chloride or bromide.
본 발명의 일 실시형태에서, 상기 화학식 1의 니코틴아미드 리보사이드 유도체는 하기 화학식 1-1의 화합물일 수 있다.In one embodiment of the present invention, the nicotinamide riboside derivative of Formula 1 may be a compound of Formula 1-1 below.
[화학식 1-1] [Formula 1-1]
상기 식에서,In the above formula,
X는 술포네이트기 또는 할로겐 원자이고, X is a sulfonate group or a halogen atom,
n은 6 내지 32의 정수이다.n is an integer from 6 to 32;
본 발명의 일 실시형태에서, n은 10 내지 20의 정수일 수 있다.In one embodiment of the present invention, n may be an integer from 10 to 20.
본 발명에 따른 상기 화학식 1의 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체는 하기 반응식 1에 나타낸 방법에 따라 제조될 수 있다. 하기 반응식에 기재된 방법은 본 발명에서 대표적으로 사용된 방법을 예시한 것일 뿐 단위조작의 순서, 반응시약, 반응조건 등은 경우에 따라 얼마든지 변경될 수 있다.The fatty amine-conjugated nicotinamide riboside derivative of Formula 1 according to the present invention may be prepared according to the method shown in Scheme 1 below. The method described in the following scheme is merely an example of the method typically used in the present invention, and the order of unit operations, reaction reagents, reaction conditions, and the like may be changed in any case.
[반응식 1] [Scheme 1]
상기 식에서,In the above formula,
X 및 n은 화학식 1-1에서 정의한 바와 같다.X and n are as defined in Formula 1-1.
상기 화학식 1의 니코틴아미드 리보사이드 유도체는 니코틴산(nicotinic acid)과 지방아민을 축합반응시켜 알킬 니코틴아미드를 수득한 다음, 상기 알킬 니코틴아미드와 테트라아세틸 푸라노즈를 축합반응시킨 후, 탈보호기화 반응시켜 제조할 수 있다.The nicotinamide riboside derivative of Formula 1 is obtained by condensation reaction of nicotinic acid and fatty amine to obtain alkyl nicotinamide, followed by condensation reaction of the alkyl nicotinamide and tetraacetyl furanose, followed by deprotection reaction. can be manufactured.
상기 니코틴산과 지방아민의 축합반응은 용매 중에서 축합제 및 유기아민 촉매의 존재 하에 수행하는 것이 바람직하다. The condensation reaction of nicotinic acid and fatty amine is preferably performed in the presence of a condensing agent and an organic amine catalyst in a solvent.
상기 축합제로는 N,N,N',N'-테트라메틸-(벤조트리아졸-1-일)-우로니움테트라플루오로보레이트(TBTU), N-(3-디메틸아미노프로필)-N'-에틸-카보디이미드(EDC), N,N'-디이소프로필카보디이미드(DIC) 또는 N,N'-디사이클로헥실카보디이미드(DCC)을 사용할 수 있으나, 이에 한정되는 것은 아니다. 상기 축합제는 니코틴산 기준으로 1.0 내지 5.0 당량으로 사용될 수 있다.The condensing agent includes N,N,N',N'-tetramethyl-(benzotriazol-1-yl)-uroniumtetrafluoroborate (TBTU), N-(3-dimethylaminopropyl)-N' -Ethyl-carbodiimide (EDC), N,N'-diisopropylcarbodiimide (DIC), or N,N'-dicyclohexylcarbodiimide (DCC) may be used, but is not limited thereto. The condensing agent may be used in an amount of 1.0 to 5.0 equivalents based on nicotinic acid.
또한, 축합반응을 촉진시키는 유기아민 촉매로는 트리에틸아민(TEA), 디이소프로필에틸아민(DIPEA), 또는 4-디메틸아미노피리딘(DMAP)을 사용할 수 있으나, 이에 한정되는 것은 아니다. 상기 유기아민 촉매는 니코틴산 기준으로 1.0 내지 5.0 당량으로 사용될 수 있다.In addition, the organic amine catalyst for accelerating the condensation reaction may be triethylamine (TEA), diisopropylethylamine (DIPEA), or 4-dimethylaminopyridine (DMAP), but is not limited thereto. The organic amine catalyst may be used in an amount of 1.0 to 5.0 equivalents based on nicotinic acid.
상기 축합반응의 용매로는 무수 유기용매, 예를 들어 디클로로메탄, 클로로포름, 벤젠, 톨루엔, 테트라하이드로푸란 및 디에틸에테르 중에서 선택된 1종 이상을 사용할 수 있으나, 이에 한정되는 것은 아니다. As the solvent for the condensation reaction, an anhydrous organic solvent, for example, one or more selected from dichloromethane, chloroform, benzene, toluene, tetrahydrofuran and diethyl ether may be used, but is not limited thereto.
상기 축합반응은 실온 내지 가온된 상태에서 진행될 수 있다.The condensation reaction may be carried out at room temperature or in a heated state.
상기 글리코사이드의 축합반응은 축합제로서 실릴화합물, 예컨대 트리메틸실릴트리플루오로메탄술포네이트, 트리메틸실릴메탄술포네이트, 트리메틸실릴톨루엔술포네이트 등을 사용할 수 있으나 이에 한정되는 것은 아니다. 상기 축합제는 알킬 니코틴에이트 기준으로 1.0 내지 5.0 당량으로 사용될 수 있다.In the condensation reaction of the glycoside, a silyl compound such as trimethylsilyltrifluoromethanesulfonate, trimethylsilylmethanesulfonate, trimethylsilyltoluenesulfonate, etc. may be used as a condensation agent, but is not limited thereto. The condensing agent may be used in an amount of 1.0 to 5.0 equivalents based on the alkyl nicotinate.
상기 축합반응의 용매로는 디클로로메탄, 테트라하이드로푸란 및 아세토니트릴 중에서 선택된 1종 이상을 사용할 수 있으나, 이에 한정되는 것은 아니다. As a solvent for the condensation reaction, at least one selected from dichloromethane, tetrahydrofuran, and acetonitrile may be used, but is not limited thereto.
상기 축합반응은 냉각 내지 가온된 상태에서 진행될 수 있다.The condensation reaction may proceed in a cooled or heated state.
상기 탈보호기화 반응은 염기의 존재 하에 수행하는 것이 바람직하다. 상기 염기로는 소듐에톡사이드(NaOEt), 소듐메톡사이드(NaOMe), 암모니아 등을 사용할 수 있으나 이에 한정되는 것은 아니다. 상기 염기는 1.0 내지 10.0 당량으로 사용될 수 있다.The deprotection reaction is preferably performed in the presence of a base. As the base, sodium ethoxide (NaOEt), sodium methoxide (NaOMe), ammonia, or the like may be used, but is not limited thereto. The base may be used in an amount of 1.0 to 10.0 equivalents.
상기 탈보호기화 반응의 용매로는 에탄올 및 메탄올 중에서 선택된 1종 이상을 사용할 수 있으나, 이에 한정되는 것은 아니다. At least one selected from ethanol and methanol may be used as a solvent for the deprotection reaction, but is not limited thereto.
상기 탈보호기화 반응은 냉각 내지 실온 상태에서 진행될 수 있다.The deprotection vaporization reaction may be carried out in a cooling to room temperature state.
본 발명에 따른 상기 화학식 1 의 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체는 니코틴아미드 리보사이드와 비교하여 안정성이 현저하게 개선되었으며, 생체 흡수율이 증가되었다(도 1 내지 도 3).The fatty amine-conjugated nicotinamide riboside derivative of Formula 1 according to the present invention has significantly improved stability and increased bioabsorption compared to nicotinamide riboside ( FIGS. 1 to 3 ).
따라서, 본 발명에 따른 상기 화학식 1의 니코틴아미드 리보사이드 유도체는 체내에서 가수분해되어 니코틴아미드 아데닌 다이뉴클레오티드(NAD)의 전구체인 니코틴아미드 리보사이드(NR)를 공급할 수 있는 NAD 전구체의 공급원으로서, 주름개선, 미백, 세포재생, 탈모 치료 또는 항염용 화장료 조성물, 약제학적 조성물 및 건강기능식품에 효과적으로 사용될 수 있다.Therefore, the nicotinamide riboside derivative of Formula 1 according to the present invention is hydrolyzed in the body to supply nicotinamide riboside (NR), a precursor of nicotinamide adenine dinucleotide (NAD), as a source of NAD precursor, and wrinkles It can be effectively used in cosmetic compositions, pharmaceutical compositions and health functional foods for improvement, whitening, cell regeneration, hair loss treatment or anti-inflammatory.
본 발명의 일 실시형태는 상기 화학식 1의 니코틴아미드 리보사이드 유도체를 포함하는 주름개선, 미백, 세포재생, 탈모 치료 또는 항염용 화장료 조성물에 관한 것이다.One embodiment of the present invention relates to a cosmetic composition for wrinkle improvement, whitening, cell regeneration, hair loss treatment or anti-inflammatory treatment comprising the nicotinamide riboside derivative of Formula 1 above.
본 발명에 따른 화장료 조성물은 상기 화학식 1의 니코틴아미드 리보사이드 유도체를 유효성분으로서 약 0.001 내지 10 중량%, 바람직하게는 0.01 내지 5 중량%로 포함한다. 유효성분의 함량은 그의 사용 목적에 따라 적절하게 결정될 수 있다.The cosmetic composition according to the present invention contains the nicotinamide riboside derivative of Formula 1 as an active ingredient in an amount of about 0.001 to 10% by weight, preferably 0.01 to 5% by weight. The content of the active ingredient may be appropriately determined according to the purpose of its use.
본 발명의 화장료 조성물은 유효성분으로서 상기 화학식 1의 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체 이외에 투과촉진제를 추가로 포함할 수 있다. 상기 화학식 1의 니코틴아미드 리보사이드 유도체와 투과촉진제를 병용하는 경우, 생체 흡수율이 더욱 향상될 수 있어 유리하다.The cosmetic composition of the present invention may further include a penetration enhancer in addition to the fatty amine-conjugated nicotinamide riboside derivative of Formula 1 as an active ingredient. When the nicotinamide riboside derivative of Formula 1 and the permeation promoter are used together, the bioabsorption rate can be further improved, which is advantageous.
상기 투과촉진제로는 당해 기술분야에 공지된 다양한 계면활성제를 제한 없이 사용할 수 있다. 구체적으로, 상기 투과촉진제로는 포화 또는 불포화 지방산 및 그의 유도체, 포화 또는 불포화 지방 알코올 및 그의 유도체 등을 사용할 수 있으며, 예를 들어 지방산 솔비탄에스테르, 폴리옥시에틸렌알킬에테르 등을 사용할 수 있다. 이들의 시판 제품으로는 Span 60, Span 65, Span 80, Tween 20, Tween 60, Tween 80, Brij 30, Brij 35, Brij 58, Brij 78, Brij 93, Brij 98, Brij 700, Triton X-100 등이 있다. 이들은 단독으로 또는 2종 이상 조합하여 사용할 수 있다.As the permeation enhancer, various surfactants known in the art may be used without limitation. Specifically, as the permeation enhancer, saturated or unsaturated fatty acids and derivatives thereof, saturated or unsaturated fatty alcohols and derivatives thereof, etc. may be used, for example, fatty acid sorbitan esters, polyoxyethylene alkyl ethers, etc. These commercially available products include
상기 투과촉진제는 화장료 조성물 전체 100 중량%에 대하여 0.01 내지 20 중량%의 양으로 포함될 수 있다. 상기 투과촉진제가 상기 범위로 포함되면 피부투과뿐만 아니라 제형의 안정화에도 유리하다.The penetration enhancer may be included in an amount of 0.01 to 20% by weight based on 100% by weight of the total cosmetic composition. When the penetration enhancer is included in the above range, it is advantageous not only for skin penetration but also for stabilization of the formulation.
본 발명의 화장료 조성물은 상기한 성분들 이외에 화장료 조성물에 통상적으로 사용되는 성분들, 예를 들어 항산화제, 안정화제, 용해화제, 비타민, 안료 및 향료와 같은 통상적인 보조제, 그리고 담체를 포함한다.The cosmetic composition of the present invention includes components commonly used in cosmetic compositions in addition to the above components, for example, conventional adjuvants such as antioxidants, stabilizers, solubilizers, vitamins, pigments and fragrances, and carriers.
본 발명의 화장료 조성물은 당업계에서 통상적으로 사용되는 어떠한 제형으로도 제조될 수 있으며, 예를 들어, 용액, 현탁액, 유탁액, 페이스트, 겔, 크림, 파우더, 스프레이 등으로 제형화될 수 있다. The cosmetic composition of the present invention may be prepared in any formulation commonly used in the art, for example, it may be formulated as a solution, suspension, emulsion, paste, gel, cream, powder, spray, and the like.
본 발명의 제형이 페이스트, 크림 또는 겔인 경우에는 담체 성분으로서 동물성유, 식물성유, 왁스, 파라핀, 전분, 트라칸트, 셀룰로오스 유도체, 폴리에틸렌 글리콜, 실리콘, 벤토나이트, 실리카, 탈크, 산화아연 등이 이용될 수 있다.When the formulation of the present invention is a paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tracanth, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, zinc oxide, etc. may be used as a carrier component. can
본 발명의 제형이 파우더 또는 스프레이인 경우에는 담체 성분으로서 락토스, 탈크, 실리카, 알루미늄 히드록시드, 칼슘 실리케이트, 폴리아미드 파우더 등이 이용될 수 있고, 특히 스프레이인 경우에는 추가적으로 클로로플루오로히드로카본, 프로판/부탄 또는 디메틸에테르와 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, polyamide powder, etc. may be used as a carrier component. In particular, in the case of a spray, additional chlorofluorohydrocarbon, It may contain propellants such as propane/butane or dimethyl ether.
본 발명의 제형이 용액 또는 유탁액인 경우에는 담체 성분으로서 용매, 용해화제 또는 유탁화제, 예를 들어 물, 에탄올, 이소프로판올, 에틸 카보네이트, 에틸 아세테이트, 벤질 알코올, 벤질 벤조에이트, 프로필렌 글리콜, 1,3-부틸글리콜 오일, 글리세롤 지방산 에스테르, 폴리에틸렌 글리콜, 소르비탄의 지방산 에스테르 등이 이용될 수 있다.When the formulation of the present invention is a solution or emulsion, as a carrier component a solvent, solubilizer or emulsifier, for example, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylglycol oil, glycerol fatty acid ester, polyethylene glycol, fatty acid ester of sorbitan, etc. may be used.
본 발명의 제형이 현탁액인 경우에는 담체 성분으로서 물, 에탄올 또는 프로필렌 글리콜과 같은 액상의 희석제, 에톡실화 이소스테아릴 알코올, 폴리옥시에틸렌 소르비톨 에스테르 또는 폴리옥시에틸렌 소르비탄 에스테르와 같은 현탁제, 미소결정성 셀룰로오스, 알루미늄 메타히드록시드, 벤토나이트, 아가, 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 or polyoxyethylene sorbitan ester, microcrystals Adult cellulose, aluminum metahydroxide, bentonite, agar, tracanth and the like can be used.
본 발명의 화장료 조성물은 스킨, 로션, 크림, 에센스, 팩, 파운데이션, 색조화장품, 선크림, 투웨이케이크, 페이스파우더, 콤팩트, 메이크업베이스, 스킨커버, 아이쉐도우, 립스틱, 립글로스, 립픽스, 아이브로우 펜슬 등의 화장품에 적용될 수 있다. The cosmetic composition of the present invention includes skin, lotion, cream, essence, pack, foundation, color cosmetics, sun cream, two-way cake, face powder, compact, makeup base, skin cover, eye shadow, lipstick, lip gloss, lip fix, eyebrow pencil It can be applied to cosmetics such as
본 발명의 다른 실시형태는 상기 화학식 1의 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체를 포함하는 주름개선, 미백, 세포재생, 탈모 치료 또는 항염용 약제학적 조성물에 관한 것이다.Another embodiment of the present invention relates to a wrinkle improvement, whitening, cell regeneration, hair loss treatment or anti-inflammatory pharmaceutical composition comprising the fatty amine-conjugated nicotinamide riboside derivative of Formula 1 above.
본 발명에 따른 약제학적 조성물은 경구적으로(예를 들면, 복용 또는 흡입) 또는 비경구적으로(예를 들면, 주사, 경피흡수, 직장투여) 투여될 수 있으며, 주사는 예를 들면, 정맥주사, 피하주사, 근육내 주사 또는 복강내 주사일 수 있다. 본 발명에 따른 약제학적 조성물은 투여 경로에 따라, 정제, 캡슐제, 과립제, 파인 서브틸래(fine subtilae), 분제, 설하 정제, 좌약, 연고, 주사제, 유탁액제, 현탁액제, 시럽제, 분무제 등으로 제형화될 수 있다. 상기 여러 가지 형태의 본 발명에 따른 약제학적 조성물은 각 제형에 통상적으로 사용되는 약제학적으로 허용되는 담체(carrier)를 사용하여 공지기술에 의해 제조될 수 있다. 약제학적으로 허용되는 담체의 예는 부형제, 결합제, 붕해제(disintegrating agent), 윤활제, 방부제, 항산화제, 등장제(isotonic agent), 완충제, 피막제, 감미제, 용해제, 기제(base), 분산제, 습윤제, 현탁화제, 안정제, 착색제 등을 포함한다. The pharmaceutical composition according to the present invention may be administered orally (eg, taking or inhalation) or parenterally (eg, injection, transdermal absorption, rectal administration), and injection is, for example, intravenous injection , subcutaneous injection, intramuscular injection or intraperitoneal injection. The pharmaceutical composition according to the present invention may be administered as a tablet, capsule, granule, fine subtilae, powder, sublingual tablet, suppository, ointment, injection, emulsion, suspension, syrup, spray, etc., depending on the route of administration. can be formulated. The various types of the pharmaceutical composition according to the present invention can be prepared by known techniques using a pharmaceutically acceptable carrier commonly used for each formulation. Examples of pharmaceutically acceptable carriers include excipients, binders, disintegrating agents, lubricants, preservatives, antioxidants, isotonic agents, buffers, coating agents, sweetening agents, solubilizing agents, bases, dispersing agents, wetting agents , suspending agents, stabilizing agents, coloring agents, and the like.
본 발명에 따른 약제학적 조성물은 약제의 형태에 따라 다르지만, 상기 화학식 1의 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체를 약 0.001 내지 10 중량%, 바람직하게는 0.01 내지 2 중량%로 포함한다. The pharmaceutical composition according to the present invention varies depending on the form of the drug, but contains about 0.001 to 10% by weight, preferably 0.01 to 2% by weight of the fatty amine-conjugated nicotinamide riboside derivative of Formula 1 above.
본 발명의 약제학적 조성물의 구체적인 투여량은 치료되는 사람을 포함한 포유동물의 종류, 체중, 성별, 질환의 정도, 의사의 판단 등에 따라 다를 수 있다. 바람직하게는, 경구투여의 경우에는 하루에 체중 1 kg 당 활성성분 10 내지 200 mg이 투여된다. 상기 총 일일 투여량은 질환의 정도, 의사의 판단 등에 따라 한번에 또는 수회로 나누어 투여될 수 있다. The specific dosage of the pharmaceutical composition of the present invention may vary depending on the type of mammal, including the person to be treated, body weight, sex, degree of disease, judgment of a doctor, and the like. Preferably, in the case of oral administration, 10 to 200 mg of the active ingredient per 1 kg of body weight is administered per day. The total daily dose may be administered at one time or divided into several doses depending on the severity of the disease, the judgment of the doctor, and the like.
본 발명의 약제학적 조성물이 경피흡수 형태로 제형화 되는 경우, 본 발명의 약제학적 조성물은 유효성분으로서 상기 화학식 1의 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체 이외에 투과촉진제를 추가로 포함할 수 있다. 상기 화학식 1의 니코틴아미드 리보사이드 유도체와 투과촉진제를 병용하는 경우, 생체 흡수율이 더욱 향상될 수 있어 유리하다.When the pharmaceutical composition of the present invention is formulated for transdermal absorption, the pharmaceutical composition of the present invention may further include a permeation enhancer in addition to the fatty amine-conjugated nicotinamide riboside derivative of Formula 1 as an active ingredient. . When the nicotinamide riboside derivative of Formula 1 and the permeation promoter are used together, the bioabsorption rate can be further improved, which is advantageous.
상기 투과촉진제의 종류 및 함량은 상기 화장료 조성물에서 설명한 바와 동일하다.The type and content of the permeation promoter are the same as those described in the cosmetic composition.
본 발명의 또 다른 실시형태는 상기 화학식 1의 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체를 포함하는 주름개선, 미백, 세포재생, 탈모 치료 또는 항염용 건강기능식품에 관한 것이다.Another embodiment of the present invention relates to a health functional food for wrinkle improvement, whitening, cell regeneration, hair loss treatment, or anti-inflammatory, comprising the fatty amine-conjugated nicotinamide riboside derivative of Formula 1 above.
본 발명에 따른 건강기능식품의 종류에는 특별한 제한이 없으며, 산제, 과립제, 정제, 캡슐제, 현탁액제, 에멀젼, 시럽제 등의 경구형 제제 형태이거나, 캔디, 과자, 껌, 아이스크림, 면류, 빵, 음료 등 일반적인 식품에 첨가될 수 있다. The type of health functional food according to the present invention is not particularly limited, and is in the form of oral preparations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, or candies, confectionery, gum, ice cream, noodles, bread, It can be added to general foods such as beverages.
본 발명의 건강기능식품은 형태에 따라 통상적인 방법으로 충진제, 증량제, 결합제, 습윤제, 붕해제, 감미제, 방향제, 보존제, 계면활성제, 윤활제, 부형제 등 식품학적으로 허용되는 담체를 적절히 사용하여 제조될 수 있다. The health functional food of the present invention can be prepared by appropriately using a food-logically acceptable carrier such as a filler, an extender, a binder, a wetting agent, a disintegrant, a sweetener, a fragrance, a preservative, a surfactant, a lubricant, and an excipient in a conventional manner depending on the form. can
상기 건강기능식품의 제조에 있어서 상기 화학식 1의 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체의 함량은 건강기능식품의 형태에 따라 다르지만, 약 0.001 내지 10 중량%, 바람직하게는 0.1 내지 5 중량%이다.In the production of the health functional food, the content of the fatty amine-conjugated nicotinamide riboside derivative of Formula 1 varies depending on the type of health functional food, but is about 0.001 to 10% by weight, preferably 0.1 to 5% by weight. .
본 발명에 따른 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체는 유기용매에 대한 용해도가 증가하고, 안정성이 개선되고, 독성감소 및 생체 흡수력 향상 효과를 가진다. The fatty amine-conjugated nicotinamide riboside derivative according to the present invention has the effects of increasing solubility in organic solvents, improving stability, reducing toxicity and improving bioabsorption.
아울러, 본 발명에 따른 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체는 생체 내 pH 조건에서 가수분해되어 니코틴아미드 아데닌 다이뉴클레오티드(NAD)의 전구체를 서서히 방출할 수 있어 주름개선 등의 생리활성을 지속적으로 나타낼 수 있다.In addition, the fatty amine-conjugated nicotinamide riboside derivative according to the present invention is hydrolyzed under in vivo pH conditions to gradually release the precursor of nicotinamide adenine dinucleotide (NAD), thereby continuously improving physiological activities such as wrinkle improvement. can indicate
따라서, 본 발명에 따른 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체는 우수한 NAD 전구체의 공급원으로서, 주름개선, 미백, 세포재생, 탈모 치료 또는 항염용 화장료 조성물, 약제학적 조성물, 건강기능식품 등에 효과적으로 사용될 수 있다.Therefore, the fatty amine-conjugated nicotinamide riboside derivative according to the present invention is an excellent source of NAD precursor, and can be effectively used for wrinkle improvement, whitening, cell regeneration, hair loss treatment or anti-inflammatory cosmetic composition, pharmaceutical composition, health functional food, etc. can
도 1은 본 발명에 따른 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체의 안정성 시험 결과를 나타낸 그래프이다.
도 2는 본 발명에 따른 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체의 피부흡수 시험결과를 나타낸 그래프이다.
도 3은 본 발명에 따른 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체를 투과촉진제와 함께 사용한 경우의 피부흡수 시험결과를 나타낸 그래프이다.1 is a graph showing the stability test results of a fatty amine-conjugated nicotinamide riboside derivative according to the present invention.
2 is a graph showing the skin absorption test results of the fatty amine-conjugated nicotinamide riboside derivative according to the present invention.
3 is a graph showing the skin absorption test results when the fatty amine-conjugated nicotinamide riboside derivative according to the present invention is used together with a permeation enhancer.
이하, 실시예에 의해 본 발명을 보다 구체적으로 설명하고자 한다. 이들 실시예는 오직 본 발명을 설명하기 위한 것으로, 본 발명의 범위가 이들 실시예에 국한되지 않는다는 것은 당업자에게 있어서 자명하다.Hereinafter, the present invention will be described in more detail by way of Examples. These examples are for illustrative purposes only, and it is apparent to those skilled in the art that the scope of the present invention is not limited to these examples.
실시예 1: 세틸 니코틴아미드(cetyl nicotinamide)의 제조Example 1: Preparation of cetyl nicotinamide
니코틴산 16.8 g(136.7 mmol)을 디클로로메탄 250 mL에 넣은 혼합물에, 4-디메틸아미노피리딘 18.27 g(149.1 mmol)을 넣고 교반하여 용해시키고, 완전히 용해된 용액에 세틸아민 30.0 g(124.2 mmol)을 첨가하였다. 이 용액에 EDC 35.7 g(186.4 mmol)을 디클로로메탄 100 mL에 용해한 용액을 첨가하고 4시간 동안 교반하였다. 상기 용액에 디클로로메탄 150 mL를 첨가하고, 3.5% HCl 수용액 500 mL로 세척한 후, 유기층을 회수한 다음 포화 소듐클로라이드 수용액 500 mL로 세척하였다. 유기층을 회수한 후 무수 황산마그네슘 45 g을 넣어 탈수하고, 여과하였다. 여액을 감압농축하고 진공건조시켜 세틸 니코틴아미드 42 g을 얻었다.To a mixture of 16.8 g (136.7 mmol) of nicotinic acid in 250 mL of dichloromethane, 18.27 g (149.1 mmol) of 4-dimethylaminopyridine was added and stirred to dissolve, and 30.0 g (124.2 mmol) of cetylamine was added to the completely dissolved solution. did. To this solution, a solution of 35.7 g (186.4 mmol) of EDC in 100 mL of dichloromethane was added and stirred for 4 hours. After adding 150 mL of dichloromethane to the solution, and washing with 500 mL of a 3.5% aqueous HCl solution, the organic layer was recovered and then washed with 500 mL of a saturated aqueous sodium chloride solution. After recovering the organic layer, 45 g of anhydrous magnesium sulfate was added thereto, dehydrated, and filtered. The filtrate was concentrated under reduced pressure and dried under vacuum to obtain 42 g of cetyl nicotinamide.
1H NMR 400 MHz(CDCl3) δ 9.37(s, 1H), 9.06(d, 1H), 8.95(d, 1H), 8.25(m, 1H), 8.07(t, 1H), 1.63(m, 2H), 1.30(m, 2H), 1.25(s, 26H), 0.88(t, 3H) 1
실시예 2: 세틸 2,3,5-트리아세틸 니코틴아미드 리보사이드 (cetyl 2,3,5-triacetyl nicotinamide riboside)의 제조Example 2: Preparation of cetyl 2,3,5-triacetyl nicotinamide riboside (cetyl 2,3,5-triacetyl nicotinamide riboside)
세틸 니코틴아미드 20.0 g(57.68 mmol)을 아세토니트릴 200 mL에 넣은 혼합물에, 트리메틸실릴 트리플루오로메탄술포네이트 18.8 mL(104.0 mmol)을 넣고 교반하여 용해시켰다. 이 용액에 1,2,3,5-테트라아세틸 리보푸라노즈 15.6 g(49.2 mmol)을 첨가하고 30분 동안 교반하였다. 1.2M 탄산수소나트륨 수용액 0.8 mL을 첨가한 후 탄산수소나트륨 5.2 g(60.8 mmol)을 첨가하였다. 감압 농축하여 용매를 제거하고, 메탄올 5 mL을 첨가한 다음, 디클로로메탄 200 mL을 첨가한 후 침전물을 여과하여 제거하였다. 여액을 농축하고 디클로로메탄에 침전물이 없을 때까지 여과 및 농축을 반복하였다. 얻어진 농축물을 진공건조하여 세틸 2,3,5-트리아세틸 니코틴아미드 리보사이드 23.9 g을 얻었다.To a mixture of 20.0 g (57.68 mmol) of cetyl nicotinamide in 200 mL of acetonitrile, 18.8 mL (104.0 mmol) of trimethylsilyl trifluoromethanesulfonate was added and stirred to dissolve. To this solution, 15.6 g (49.2 mmol) of 1,2,3,5-tetraacetyl ribofuranose was added and stirred for 30 minutes. 0.8 mL of a 1.2M aqueous sodium hydrogen carbonate solution was added, and then 5.2 g (60.8 mmol) of sodium hydrogen carbonate was added. The solvent was removed by concentration under reduced pressure,
1H NMR 400 MHz(CDCl3) δ 9.52(s, 1H), 9.20(d, 1H), 9.06(d, 1H), 8.25(m, 1H), 8.07(t, 1H), 6.51(d, 1H), 5.50(t, 1H), 5.34(m, 2H), 4.73(t, 1H), 4.61(dd, 1H), 4.55(d, 1H), 1.63(m, 2H), 1.30(m, 2H), 1.25(s, 26H), 0.88(t, 3H) 1
실시예 3: 세틸 니코틴아미드 리보사이드(cetyl nicotinamide riboside)의 제조 Example 3: Preparation of cetyl nicotinamide riboside
세틸 2,3,5-트리아세틸 니코틴아미드 리보사이드 10.0 g(16.5 mmol)을 메탄올 200 mL에 용해하고, 온도를 영하 10℃ 이하로 맞추고, 5M 소듐메톡사이드 5.7 mL을 천천히 첨가한 후 30분 동안 교반하였다. 아세트산으로 pH 3.0으로 맞추고, 유기용매는 감압하여 제거하였다. 잔류 수용액 층을 시클로헥산으로 세척한 후 농축한 다음 FPLC로 정제하고, 분획물을 동결 건조하여 세틸 니코틴아미드 리보사이드 5.4 g을 얻었다.Dissolve 10.0 g (16.5 mmol) of cetyl 2,3,5-triacetyl nicotinamide riboside in 200 mL of methanol, adjust the temperature to -10°C or less, and slowly add 5.7 mL of 5M sodium methoxide for 30 minutes stirred. The pH was adjusted to 3.0 with acetic acid, and the organic solvent was removed under reduced pressure. The residual aqueous layer was washed with cyclohexane, concentrated, purified by FPLC, and the fraction was freeze-dried to obtain 5.4 g of cetyl nicotinamide riboside.
1H NMR 400 MHz(CDCl3) δ 9.66(s, 1H), 9.41(d, 1H), 8.99(d, 1H), 8.28(t, 1H), 6.18(bs, 1H), 4.44(s, 2H), 4.31(d, 1H), 4.03(d, 1H), 3.87(d, 1H), 1.68(t, 2H), 1.41(m, 2H), 1.31(s, 26H), 0.92(t, 3H) 1
실시예 4: 라우릴 니코틴아미드(lauryl nicotinamide)의 제조Example 4: Preparation of lauryl nicotinamide
니코틴산 10.0 g(82.2 mmol)을 디클로로메탄 150 mL에 넣은 혼합물에, 4-디메틸아미노피리딘 10.9 g(89.5 mmol)을 넣고 교반하여 용해시키고, 완전히 용해된 용액에 라우릴아민 13.6 g(73.1 mmol)을 첨가하였다. 이 용액에 EDC 21.2 g(110.5 mmol)을 디클로로메탄 70 mL에 용해한 용액을 첨가하고 4시간 동안 교반하였다. 상기 용액에 디클로로메탄 80 mL를 첨가하고, 3.5% HCl 수용액 300 mL로 세척한 후, 유기층을 회수한 다음 포화 소듐클로라이드 수용액 300 mL로 세척하였다. 유기층을 회수한 후 무수 황산마그네슘 30 g을 넣어 탈수하고, 여과하였다. 여액을 감압농축하고 진공건조시켜 라우릴 니코틴아미드 23 g을 얻었다.To a mixture of 10.0 g (82.2 mmol) of nicotinic acid in 150 mL of dichloromethane, 10.9 g (89.5 mmol) of 4-dimethylaminopyridine was added and stirred to dissolve, and 13.6 g (73.1 mmol) of laurylamine was added to the completely dissolved solution. added. A solution of 21.2 g (110.5 mmol) of EDC in 70 mL of dichloromethane was added to this solution and stirred for 4 hours. 80 mL of dichloromethane was added to the solution, and after washing with 300 mL of a 3.5% aqueous HCl solution, the organic layer was recovered and then washed with 300 mL of a saturated aqueous sodium chloride solution. After the organic layer was recovered, 30 g of anhydrous magnesium sulfate was added thereto, dehydrated, and filtered. The filtrate was concentrated under reduced pressure and dried under vacuum to obtain 23 g of lauryl nicotinamide.
1H NMR 400 MHz(CDCl3) δ 9.36(s, 1H), 9.04(d, 1H), 8.93(d, 1H), 8.24(m, 1H), 8.08(t, 1H), 1.64(m, 2H), 1.31(m, 2H), 1.25(s, 18H), 0.87(t, 3H) 1
실시예 5: 라우릴 2,3,5-트리아세틸 니코틴아미드 리보사이드 (lauryl 2,3,5-triacetyl nicotinamide riboside)의 제조Example 5: Preparation of lauryl 2,3,5-triacetyl nicotinamide riboside (lauryl 2,3,5-triacetyl nicotinamide riboside)
라우릴 니코틴아미드 10.0 g(34.4 mmol)을 아세토니트릴 120 mL에 넣은 혼합물에, 트리메틸실릴 트리플루오로메탄술포네이트 11.2 mL(34.4)을 넣고 교반하여 용해시켰다. 이 용액에 1,2,3,5-테트라아세틸 리보푸라노즈 15.6 g(52.9 mmol)을 첨가하고 30분 동안 교반하였다. 1.2M 탄산수소나트륨 수용액 0.3 mL을 첨가한 후 탄산수소나트륨 5.2 g(36.0 mmol)을 첨가하였다. 감압 농축하여 용매를 제거하고, 메탄올 2 mL을 첨가한 다음, 디클로로메탄 100 mL을 첨가한 후 침전물을 여과하여 제거하였다. 여액을 농축하고 디클로로메탄에 침전물이 없을 때까지 여과 및 농축을 반복하였다. 얻어진 농축물을 진공건조하여 라우릴 2,3,5-트리아세틸 니코틴아미드 리보사이드 12.6 g을 얻었다.To a mixture of 10.0 g (34.4 mmol) of lauryl nicotinamide in 120 mL of acetonitrile, 11.2 mL (34.4) of trimethylsilyl trifluoromethanesulfonate was added and stirred to dissolve. To this solution, 15.6 g (52.9 mmol) of 1,2,3,5-tetraacetyl ribofuranose was added and stirred for 30 minutes. After adding 0.3 mL of a 1.2M aqueous sodium hydrogen carbonate solution, 5.2 g (36.0 mmol) of sodium hydrogen carbonate was added. The solvent was removed by concentration under reduced pressure, 2 mL of methanol was added, and then 100 mL of dichloromethane was added, and the precipitate was removed by filtration. The filtrate was concentrated and filtration and concentration were repeated until there was no precipitate in dichloromethane. The obtained concentrate was vacuum-dried to obtain 12.6 g of lauryl 2,3,5-triacetyl nicotinamide riboside.
1H NMR 400 MHz(CDCl3) δ 9.54(s, 1H), 9.21(d, 1H), 9.07(d, 1H), 8.24(m, 1H), 8.08(t, 1H), 6.53(d, 1H), 5.51(t, 1H), 5.35(m, 2H), 4.74(t, 1H), 4.63(dd, 1H), 4.57(d, 1H), 1.62(m, 2H), 1.30(m, 2H), 1.25(s, 18H), 0.87(t, 3H) 1
실시예 6: 라우릴 니코틴아미드 리보사이드(lauryl nicotinamide riboside)의 제조 Example 6: Preparation of lauryl nicotinamide riboside
라우릴 2,3,5-트리아세틸 니코틴아미드 리보사이드 5.0 g(7.16 mmol)을 메탄올 100 mL에 용해하고, 온도를 영하 10℃ 이하로 맞추고, 5M 소듐메톡사이드 2.5 mL을 천천히 첨가한 후 30분 동안 교반하였다. 아세트산으로 pH 3.0으로 맞추고, 유기용매는 감압하여 제거하였다. 잔류 수용액 층을 시클로헥산으로 세척한 후 농축한 다음 FPLC로 정제하고, 분획물을 동결 건조하여 라우릴 니코틴아미드 리보사이드 2.1 g을 얻었다.Dissolve 5.0 g (7.16 mmol) of lauryl 2,3,5-triacetyl nicotinamide riboside in 100 mL of methanol, adjust the temperature to -10°C or less, and slowly add 2.5 mL of 5M sodium methoxide for 30 minutes stirred for a while. The pH was adjusted to 3.0 with acetic acid, and the organic solvent was removed under reduced pressure. The residual aqueous layer was washed with cyclohexane, concentrated, purified by FPLC, and the fraction was freeze-dried to obtain 2.1 g of lauryl nicotinamide riboside.
1H NMR 400 MHz(CDCl3) δ 9.67(s, 1H), 9.43(d, 1H), 8.98(d, 1H), 8.27(t, 1H), 6.16(bs, 1H), 4.41(s, 2H), 4.29(d, 1H), 4.03(d, 1H), 3.88(d, 1H), 1.67(t, 2H), 1.40(m, 2H), 1.31(s, 18H), 0.91(t, 3H) 1
실험예 1: 콜라겐 합성능 평가Experimental Example 1: Collagen synthesis ability evaluation
본 발명에 따른 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체의 콜라겐 합성능을 평가하였다.The collagen synthesis ability of the fatty amine-conjugated nicotinamide riboside derivative according to the present invention was evaluated.
사람피부섬유아세포를 1x104/well의 농도로 배양하였다. 상기 세포에 각각의 시료를 처리하고 콜라겐 합성량을 측정하여 콜라겐 합성능을 평가하였다. 양성대조군으로서 아데노신은 50 ppm 농도로, 나머지 시료들은 10 ppm 농도로 처리하였다. 콜라겐 정량은 타입 1 프로콜라겐 C-펩타이드 EIA 키트(Type I Procollagen C-Peptide EIA kit)(Takara, Japan)를 사용하였다. 시료를 처리하지 않은 경우를 대조군(CON)으로 하였다. 그 결과를 하기 표 1에 나타내었다.Human skin fibroblasts were cultured at a concentration of 1x10 4 /well. Each sample was treated in the cells, and collagen synthesis ability was evaluated by measuring the amount of collagen synthesis. As a positive control, adenosine was treated at a concentration of 50 ppm, and the remaining samples were treated at a concentration of 10 ppm. Collagen quantification was performed using a Type I Procollagen C-Peptide EIA kit (Takara, Japan). A case in which the sample was not treated was used as a control (CON). The results are shown in Table 1 below.
(% of control)Type 1 procollagen gene expression
(% of control)
상기 표 1을 통해, 본 발명에 따른 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체는 대조군(CON) 대비 콜라겐 합성 증가를 보였다. 특히, 본 발명에 따른 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체는 10 ppm 농도에서 양성대조군인 아데노신을 50 ppm 농도로 처리한 경우와 동등한 수준으로 콜라겐 합성 증가를 나타내었다.Through Table 1, the fatty amine-conjugated nicotinamide riboside derivative according to the present invention showed an increase in collagen synthesis compared to the control (CON). In particular, the fatty amine-conjugated nicotinamide riboside derivative according to the present invention exhibited an increase in collagen synthesis at the same level as when adenosine, a positive control, was treated at a concentration of 50 ppm at a concentration of 10 ppm.
실험예 2: 미백 효능 평가Experimental Example 2: Evaluation of whitening efficacy
본 발명에 따른 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체의 미백 효능을 평가하였다.The whitening efficacy of the fatty amine-conjugated nicotinamide riboside derivative according to the present invention was evaluated.
에펜 튜브에 0.1M 인산염 버퍼 (pH 6.8) 200 μL를 첨가한 후 농도별로 희석한 시료액을 20 μL씩 넣었다. 여기에 머쉬룸 티로시나제(mushroom tyrosinase) (2,000 unit/μL) 20 μL를 첨가한 후, 0.3% 티로신 200 μL를 순서대로 넣은 다음 37 ℃에서 10분 동안 반응시켰다. 이 액을 96 웰 플레이트에 200 μL 옮긴 후, ELISA 판독기를 이용하여 490 nm에서 흡광도를 측정하였다. 양성대조군으로 알부틴을 사용하였다. 그 결과를 하기 표 2에 나타내었다.After adding 200 μL of 0.1M phosphate buffer (pH 6.8) to the Eppen tube, 20 μL of each diluted sample solution was added. Here, after adding 20 μL of mushroom tyrosinase (2,000 unit/μL), 200 μL of 0.3% tyrosine was added in order, and then reacted at 37° C. for 10 minutes. After 200 μL of this solution was transferred to a 96-well plate, absorbance was measured at 490 nm using an ELISA reader. Arbutin was used as a positive control. The results are shown in Table 2 below.
시험관내 (in vitro) 티로시나제 활성평가 결과, 실시예 3의 화합물은 10 ppm 및 100 ppm 농도에서 각각 21.7% 및 41.6%의 티로시나제 활성 억제 효과를 보였으며, 알부틴 대비 우수한 미백 효과를 가지는 것으로 나타났다.As a result of in vitro tyrosinase activity evaluation, the compound of Example 3 showed tyrosinase activity inhibitory effects of 21.7% and 41.6% at concentrations of 10 ppm and 100 ppm, respectively, and showed superior whitening effect compared to arbutin.
실험예 3:Experimental Example 3: 세포재생 효과Cell regeneration effect
본 발명에 따른 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체의 세포재생 효과를 평가하였다.The cell regeneration effect of the fatty amine-conjugated nicotinamide riboside derivative according to the present invention was evaluated.
사람피부섬유아세포(Human Dermal Fibroblast, HDF)를 1X104/Well 농도로 96 웰 플레이트에 넣고 5% CO2, 37℃ 조건 하에서 24 시간 동안 배양하였다. 배양된 HDF 세포에서 배양배지를 제거하고, 상피세포 성장인자(Epidermal Growth Factor, EGF) 및 섬유아세포 성장인자(fibroblast growth factor, FGF) 무함유 무혈청 배지를 넣고, 시료를 농도별로 처리한 후 5% CO2, 37℃ 조건 하에서 72 시간 동안 배양하였다. 배양 후 CCK-8 어세이 키트를 사용하여 450 nm에서 세포 생존율 분석(cell viability assay)을 수행하였다. 양성대조군으로 EGF를 사용하였다. 그 결과를 하기 표 3에 나타내었다.Human Dermal Fibroblasts (HDF) were placed in a 96-well plate at a concentration of 1X10 4 /Well and cultured for 24 hours under 5% CO 2 , 37°C conditions. After removing the culture medium from the cultured HDF cells, adding a serum-free medium containing no epidermal growth factor (EGF) and fibroblast growth factor (FGF), and processing the samples by
상기 표 3을 통해, 본 발명에 따른 지방아민 컨쥬게이션된 니코틴아미드 리보사이드 유도체가 대조군 대비 10 ppm 농도에서 16.0%의 세포 증식 효능을 보임을 확인하였다. From Table 3, it was confirmed that the fatty amine-conjugated nicotinamide riboside derivative according to the present invention showed a cell proliferation efficacy of 16.0% at a concentration of 10 ppm compared to the control.
실험예 4: 탈모평가Experimental Example 4: Evaluation of hair loss
HDP (Human Hair Follicle Dermal Papilla cell) 세포를 1X104/Well 농도로 96 웰 플레이트에 넣고 5% CO2, 37℃ 조건 하에서 24 시간 동안 배양하였다. 배양된 HDF 세포에서 배양배지를 제거하고, 무혈청 배지를 넣고 시료를 농도별로 처리한 후 5% CO2, 37℃ 조건 하에서 72 시간 동안 배양하였다. 배양 후 CCK-8 어세이 키트를 사용하여 450 nm에서 세포 생존율 분석(cell viability assay)을 수행하였다. 양성대조군으로 미녹시딜(minoxidil)을 100 ppm의 농도로 사용하였다. 그 결과를 하기 표 4에 나타내었다.HDP (Human Hair Follicle Dermal Papilla cell) cells were placed in a 96-well plate at a concentration of 1X10 4 /Well and cultured for 24 hours under 5% CO 2 , 37°C conditions. The culture medium was removed from the cultured HDF cells, a serum-free medium was added, and samples were treated by concentration, followed by 5% CO 2 , and incubated for 72 hours under 37°C conditions. After incubation, cell viability assay was performed at 450 nm using a CCK-8 assay kit. As a positive control, minoxidil was used at a concentration of 100 ppm. The results are shown in Table 4 below.
상기 표 4를 통해, 실시예 3의 화합물은 1 ppm 농도에서 대조군 대비 16.0%, 10 ppm에서 17%의 HDP 세포 증식 효능을 보여 미녹시딜 대비 우수한 탈모 효능을 가지는 것으로 확인되었다.Through Table 4, the compound of Example 3 showed an HDP cell proliferation efficacy of 16.0% compared to the control at a concentration of 1 ppm and 17% at a concentration of 10 ppm, and it was confirmed that it had excellent hair loss efficacy compared to minoxidil.
실험예 5:Experimental Example 5: 항염 효능 평가Anti-inflammatory efficacy evaluation
HaCaT 세포를 12 웰 플레이트에 1X105 cells/well씩 시딩(seeding)하고 24 시간 후 기본배지(basal medium)로 교체하여 6 시간 동안 기아(starvation) 처리시켰다. 그 후 시료를 함유한 기본배지로 교체하고 24 시간 동안 배양하였다. 배지를 제거한 후 UVB로 자극을 주고 기본배지를 넣고 24 시간 동안 배양하였다. 배지를 완전히 제거하고 PBS를 이용하여 2회 세척하였다. TRIsure를 이용하여 세포를 파쇄하여 RNA를 회수한 다음 RT-PCR을 수행하여 TNF-α를 증폭하였다. 아가로스 겔에서 전기영동하고 겔 다큐멘테이션 시스템(Gel Documentation system)을 이용하여 발현율을 측정하였다. 양성대조군으로 200 μM 덱사메타손을 사용하였다. 그 결과를 하기 표 5에 나타내었다.HaCaT cells were seeded in a 12-well plate by 1X10 5 cells/well, and after 24 hours, they were replaced with a basal medium and starvated for 6 hours. After that, it was replaced with the basal medium containing the sample and cultured for 24 hours. After the medium was removed, stimulation with UVB was applied, and the basal medium was added and incubated for 24 hours. The medium was completely removed and washed twice with PBS. Cells were disrupted using TRIsure to recover RNA, and then RT-PCR was performed to amplify TNF-α. Electrophoresis was performed on an agarose gel and the expression rate was measured using the Gel Documentation system. 200 μM dexamethasone was used as a positive control. The results are shown in Table 5 below.
상기 표 5를 통해, 실시예 3의 화합물이 HaCaT 세포에서 염증유전인자인 TNF-α의 발현을 억제하는 것을 확인할 수 있다. 실시예 3의 화합물은 5 ppm의 처리농도에서 TNF-α의 발현을 대조군 대비 35%까지 감소시키는 것으로 나타났다. From Table 5, it can be confirmed that the compound of Example 3 inhibits the expression of TNF-α, an inflammatory gene, in HaCaT cells. The compound of Example 3 was shown to reduce the expression of TNF-α by 35% compared to the control at a treatment concentration of 5 ppm.
실험예 6: 안정성 평가Experimental Example 6: Stability evaluation
실시예 3의 화합물을 정제수에 용해하고 밀폐한 뒤 실온에서 4주 동안 보관하면서 일정 간격으로 취하여 HPLC 분석하여 안정성을 평가하였다.The compound of Example 3 was dissolved in purified water, sealed and stored at room temperature for 4 weeks, taken at regular intervals and analyzed by HPLC to evaluate stability.
그 결과를 도 1에 나타내었다.The results are shown in FIG. 1 .
도 1을 통해, 실시예 3의 화합물이 비교화합물인 니코틴아미드 리보사이드 대비 더욱 우수한 안정성을 나타냄을 확인하였다.1, it was confirmed that the compound of Example 3 exhibited better stability than the comparative compound, nicotinamide riboside.
실험예 7: 피부투과 평가Experimental Example 7: Evaluation of skin penetration
프란츠 확산 셀(Franz diffusion cell)을 이용한 피부투과를 평가하였다. 피부는 시험관내(in vitro) 경피 확산평가를 위한 합성 모델인 Strat-M® 멤브레인을 이용하였다. 매끄러운 부분이 위로 향하도록 도너(donor)와 리셉터 페이스(receptor phase) 사이에 멤브레인을 고정시켰다. 리셉터 페이스(Receptor phase)와 접촉하는 표면의 면적은 1.093cm2이었고, 리셉터 페이스로는 정제수를 사용하였다. 리셉터 페이스는 마그네틱 바를 이용하여 140 rpm 속도로 교반시켰다. 실시예 3의 화합물과 비교화합물로 니코틴아미드 리보사이드를 도너의 멤브레인 표면에 가한 후 24시간까지 일정간격으로 취하여 분석하였다. 실시예 3의 화합물과 니코틴아미드 리보사이드는 각각 리셉터 페이스와 동일한 용매에 10 mg/ml의 농도로 용해하여 사용하였다. 매 회 0.5 mL의 리셉터 페이스를 샘플링 포트를 통해 시린지로 채취하여 HPLC 측정을 하였다.Skin permeation was evaluated using a Franz diffusion cell. The skin used Strat-M® membrane, a synthetic model for in vitro transdermal diffusion evaluation. The membrane was clamped between the donor and receptor phases with the smooth side facing up. The area of the surface in contact with the receptor phase was 1.093 cm 2 , and purified water was used as the receptor phase. The receptor face was stirred at 140 rpm using a magnetic bar. Nicotinamide riboside as a compound of Example 3 and a comparative compound was added to the surface of the donor's membrane, and then taken at regular intervals up to 24 hours and analyzed. The compound of Example 3 and nicotinamide riboside were each dissolved in the same solvent as the receptor face at a concentration of 10 mg/ml and used. Each time 0.5 mL of the receptor face was taken with a syringe through the sampling port, and HPLC measurement was performed.
리셉터 페이스를 정제수로 채우고 니코틴아미드 리보사이드와, 실시예 3의 화합물의 투과실험을 진행하였다. 그 결과를 도 2에 나타내었다.The receptor face was filled with purified water, and a permeation test of nicotinamide riboside and the compound of Example 3 was performed. The results are shown in FIG. 2 .
도 2를 통해, 실시예 3의 화합물이 비교화합물 대비 더욱 우수한 피부 투과를 나타냄을 확인하였다.2, it was confirmed that the compound of Example 3 exhibited better skin permeation than the comparative compound.
투과촉진제 비교실험을 위해 리셉터 페이스를 각각 Brij®98(투과촉진제, 알드리치) 0.5% 농도로 제조한 정제수로 채우고 비교화합물인 니코틴아미드 리보사이드와, 실시예 3의 화합물의 투과실험을 진행하였다. 그 결과를 도 3에 나타내었다.For the permeation enhancer comparison experiment, each receptor face was filled with purified water prepared at a concentration of 0.5% Brij®98 (permeation enhancer, Aldrich), and a permeation experiment of the comparative compound nicotinamide riboside and the compound of Example 3 was performed. The results are shown in FIG. 3 .
도 3을 통해, 비교화합물인 니코틴아미드 리보사이드는 도 2와 비교할 때 첨가제에 무관하게 흡수가 미비하고, 실시예 3의 화합물은 첨가제가 있을 경우 투과가 크게 향상됨을 확인하였다.3, it was confirmed that the comparative compound, nicotinamide riboside, has poor absorption regardless of the additive as compared with FIG.
Claims (9)
[화학식 1]
상기 식에서,
R은 C8-C34의 포화 또는 불포화 지방족 탄화수소기이고,
R1, R2 및 R3는 각각 독립적으로 수소 원자 또는 아실기이고,
X는 술포네이트기 또는 할로겐 원자이다.Nicotinamide riboside derivatives of the formula (1):
[Formula 1]
In the above formula,
R is a C 8 -C 34 saturated or unsaturated aliphatic hydrocarbon group,
R 1 , R 2 and R 3 are each independently a hydrogen atom or an acyl group,
X is a sulfonate group or a halogen atom.
[화학식 1-1]
상기 식에서,
X는 술포네이트기 또는 할로겐 원자이고,
n은 6 내지 32의 정수이다.The nicotinamide riboside derivative according to claim 1, which is a compound of Formula 1-1:
[Formula 1-1]
In the above formula,
X is a sulfonate group or a halogen atom,
n is an integer from 6 to 32;
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| WO2017011788A1 (en) * | 2015-07-15 | 2017-01-19 | Cornell University | Syntheses, activities, and methods of use of dihydronicotinamide riboside derivatives |
| WO2018089830A1 (en) * | 2016-11-11 | 2018-05-17 | The Queen's University Of Belfast | Efficient and scalable syntheses of nicotinoyl ribosides and reduced nicotinoyl ribosides, modified derivatives thereof, phosphorylated analogs thereof, adenylyl dinucleotide conjugates thereof, and novel crystalline forms thereof |
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| KR102315139B1 (en) | 2021-10-20 |
| WO2021125708A1 (en) | 2021-06-24 |
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