WO2017026660A1 - Cosmetic composition or external use skin preparation composition, both containing compound inhibiting activity of 11β-hydroxysteroid dehydrogenase type 1 - Google Patents

Cosmetic composition or external use skin preparation composition, both containing compound inhibiting activity of 11β-hydroxysteroid dehydrogenase type 1 Download PDF

Info

Publication number
WO2017026660A1
WO2017026660A1 PCT/KR2016/007288 KR2016007288W WO2017026660A1 WO 2017026660 A1 WO2017026660 A1 WO 2017026660A1 KR 2016007288 W KR2016007288 W KR 2016007288W WO 2017026660 A1 WO2017026660 A1 WO 2017026660A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
skin
lotion
cosmetic composition
skin aging
Prior art date
Application number
PCT/KR2016/007288
Other languages
French (fr)
Korean (ko)
Inventor
남진주
노윤화
박지은
강승현
김연준
이지영
Original Assignee
코스맥스 주식회사
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 코스맥스 주식회사 filed Critical 코스맥스 주식회사
Publication of WO2017026660A1 publication Critical patent/WO2017026660A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations

Definitions

  • the present invention is made by the task number HN12C0061 under the support of the Ministry of Health and Welfare, the research management professional agency of the task is a global cosmetic research and development project group,
  • the present invention relates to a cosmetic composition
  • a cosmetic composition comprising a compound that inhibits the activity of 11 ⁇ -hydroxysteroid dehydrogenase type 1, and more particularly to preventing skin aging containing a compound that inhibits the activity of ⁇ -hydroxysteroid dehydrogenase type 1 as an active ingredient. It relates to a cosmetic composition for improvement or an external composition for skin.
  • the main areas of interest in functional cosmetics technology can be defined as products that retard skin aging to help improve wrinkles on the skin, products that protect the skin from UV rays and the widow environment, and products that help to whiten the skin.
  • wrinkles and decreased skin elasticity, sagging and dryness of aging skin are mostly due to changes in substrate proteins present in the dermis.
  • the dermis plays a role in determining the strength and shape of the skin within the skin. Morphological changes in this area during aging play a decisive role in wrinkle formation and skin sagging. As enzymes that break down these substrate proteins
  • MMPs Matr ix metal loproteinases
  • ⁇ -HSDl 11 ⁇ -hydroxys ter i i dehydrogease type 1
  • ⁇ ⁇ -HSDl is an enzyme that converts inactive stress hormones into active stress hormones. Its activity and expression are increased by various mental stresses as internal factors and ultraviolet rays, pollutants, and chemicals as external factors. In particular, the increase in activity and expression of ⁇ -HSi by ultraviolet rays is attracting attention as a new target for inhibiting skin aging because it is closely related to skin aging.
  • Pharamcophore based in Si l ico High-Throughput Screening (in Si l ico HTS) analyzes protein-material interactions and expresses them as chemical properties.
  • Pharmacophore is an arrangement of three-dimensional coordinates of chemical conditions that a material must have in order to exhibit efficacy.
  • the definition of an active skeleton is very important and can be defined through known experimental data or sufficient structural analysis.
  • Protein-material interactions can be defined through the formation of hydrogen bonding and hydrophobic (Lipophi 1 ici ty) environments, which are the chemical conditions that make up the active skeleton. Hydrogen bonds are divided into hydrogen bond donors (HBA) and hydrogen bond acceptors (HBD) to express their properties, and the hydrophobic environment is represented by a kind of feature called (Lipo). It is defined in the form of a map.
  • HBA hydrogen bond donors
  • HBD hydrogen bond acceptors
  • the compound having the structural formula of Formula 1 selected as in si ico confirmed the possibility of preventing or improving skin aging by inhibiting photoaging through increased expression of ⁇ -HSDl and MMPs, thereby completing the present invention.
  • the basic object of the present invention is to provide a cosmetic composition or external skin composition comprising a compound that inhibits the activity of 11 ⁇ -hydroxysteroid dehydrogenase type 1 as an active ingredient.
  • Another object of the present invention is a compound that inhibits the activity of the 11 ⁇ -hydroxysteroid dehydrogenase type 1 and physiologically acceptable It is to provide a skin anti-aging cosmetic composition or a topical skin composition comprising a cosmetic base.
  • the present invention provides a cosmetic composition for preventing skin aging comprising a compound that inhibits the activity of 11 ⁇ -hydroxysteroid dehydrogenase type 1 as an active ingredient. .
  • the 11 ⁇ -hydroxysteroid dehydrogenase type 1 (11 ⁇ -hydroxysteroid dehydrogenase type 1) using the three-dimensional structure through the drug discovery through 11 ⁇ -hydroxysteroid dehydrogenase type 1 (11 ⁇ - Compounds that inhibit the activity of hydroxysteroid dehydrogenase type 1) were selected.
  • the compound is 1- [1- (1-adamantylacetyl) pyridin-3-yl] -3, 5-dimethyl-1H-pyrazole (1- [1- (1- adamantyl acetyl) pyrrolidin -3-yl] -3, 5-dimethyl-lH-pyrazole) 3 ⁇ 4l ' and that provides skin anti-aging cosmetic composition, characterized in:
  • the compound of Formula 1 effectively prevents or improves skin aging by effectively inhibiting the expression of 11 ⁇ -hydroxysteroid dehydrogenase type 1 ( ⁇ -HSDl) and MMPs and restoring collagen production. .
  • compounds that can bind to the active site of 11 ⁇ -HSD1 were selected in the virtual drug search for ⁇ -HSDl (FIG. 1), all of which are active sites of the ⁇ -HSm. competitively with the site) Since it can inhibit the activity of ⁇ -HSDl, it can exhibit the same effect as Compound 1 in the experimental example.
  • the compound is characterized in that it contains 0.01 to 10% by weight based on the total weight of the composition. If the amount is less than 0.01 weight 3 ⁇ 4 in the above range, there is a possibility that the effect of inhibiting photoaging may be weak, and conversely, exceeding 10% by weight may not be desirable in terms of economics.
  • the compound is characterized in that it exhibits an inhibitory effect of ⁇ -hydroxysteroid dehydrogenase type 1 ( ⁇ -HSDl) expression.
  • the compound inhibits 11 ⁇ -HSD1 overexpressed by ultraviolet rays, and inhibits the production of the stress hormone cortisol.
  • the compound of Formula 1 of the present invention means that by effectively inhibiting the expression of ⁇ -HSDl can reduce or reduce the body's stress hormones to prevent or improve skin aging.
  • the compound is characterized by restoring the collagen production by inhibiting the expression of Mat ix metal loproteinases (MMPs).
  • MMPs Mat ix metal loproteinases
  • the compound of the present invention can prevent or improve skin aging by effectively inhibiting MMPs expression and restoring type I procol lagen production.
  • the compound is characterized by having a skin damaging effect.
  • the compound can prevent or improve skin aging by significantly recovering a decrease in epidermal thickness caused by ultraviolet irradiation.
  • the skin aging preferably provides a cosmetic composition for preventing skin aging, characterized in that the photo-aging.
  • the term 'photoaging' of the present invention is a phenomenon caused by external environmental factors, and the most representative factor is ultraviolet rays.
  • Ultraviolet rays cause damage to biological components such as protease activation, substrate cleavage and abnormal crosslinking, and the repetition of this mechanism leads to apparent skin aging. That is, in the present invention Unlike the endogenous aging caused by genetic factors irrespective of the external environment, the present invention relates to a cosmetic composition for preventing or improving skin aging caused by photoaging caused by ultraviolet rays, or a composition for external application of skin.
  • the composition is a skin lotion (skin lotion), skin softener, skin toner, astringent, Rossin, milk lotion, moisturizing lotion, nutrition lotion, massage cream, nutrition cream, moisture cream, hand cream, foundation, essence, nutrition It is characterized in that the formulation is selected from the group consisting of essence, pack, soap, cleansing products, cleansing lotion, cleansing cream, body lotion and body cleanser.
  • the present invention provides the compound of the following formula (1) in which ⁇ - [ ⁇ - ( ⁇ -adamantylacetyl) pyridin-3-yl] -3,5-dimethyl-1H-pyrazole (1- [1- (1-adamanty lacetyl) pyrrol idi ⁇ —3—y 1] 3, 5—d imethyl- ⁇ -pyr azole) is provided as an active ingredient for external skin preparations for preventing or improving skin aging:
  • Skin external preparation composition for the prevention or improvement of skin aging containing LH-pyrazole as an active ingredient is 1- [1- (1- (adamantylacetyl) pyridin-3-yl] -3, 5 of Formula 1 above. -As described in the cosmetic composition for preventing or improving skin aging containing dimethyl -1H-pyrazole as an active ingredient.
  • the external composition for skin may be prepared in any formulation commonly prepared in the art, for example, emulsion, cream, lotion, pack, foundation, lotion, essence, hair cosmetics and the like. .
  • the composition of the present invention may include other auxiliaries in addition to the carrier, and may include, for example, preservatives, antioxidants, stabilizers, solubilizers, vitamins, pigments and flavorings.
  • the composition can be used in the form of powder, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and other external preparations and sterile injectable solutions, respectively, according to a conventional method, preferably May have a cream, gel patch, spray, ointment, warning, lotion, liniment, pasta or cataplasma formulation.
  • Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, oligosaccharides, sorbbi, manny, xylly, erythris, malty, starch, acacia rubber, alginate, gelatin, Calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyridone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, water, and the like Prepared by mixing sucrose or lactose, gelatin and the like.
  • lubricants such as magnesium styrate talc are also used.
  • Oral liquid preparations include suspensions, solvents, emulsions, syrups, etc.
  • liquid paraffin which is a commonly used simple diluent
  • various excipients for example, wetting agents, sweeteners, fragrances, and preservatives may be included.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations and suppositories.
  • non-aqueous solvent and suspending agent propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used.
  • wi tepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.
  • the compound of Chemical Formula 1 of the present invention can prevent, prevent or improve skin aging by not only inhibiting the expression of ⁇ -HSDl and MMPs overexpressed by ultraviolet rays but also restoring collagen production and skin damage.
  • 1 is a three-dimensional structure of ⁇ -HSDl.
  • Figure 2 is a map of the two active skeleton binding to ⁇ -HSDl.
  • Figure 3 is the result of Experiment 1 measuring the effect on the cell proliferation when the formula 1 treatment on human fibroblasts.
  • Figure 4 is the result of Experimental Example 1 measuring the effect on the cell thinning damaged by UVB when the above formula 1 treatment on human fibroblasts.
  • Figure 7 is the result of Experiment 3 measuring the effect on the expression of MMP-1 messenger RNA when the formula 1 treatment in human fibroblasts.
  • Virtual drug search for ⁇ -HSDl determines the active site to which the material binds in the known three-dimensional structure of 11 ⁇ -HSD1, and selects the surrounding 5A to determine the active skeletal map for this region.
  • One map was defined to include 5-6 elements, and finally two active skeleton maps were completed (FIG. 2).
  • the compound library was searched using this active skeletal map, and the potential material was selected as 11 ⁇ _ HSD1 inhibitory effect material.
  • the compound library searched for multiple conformmat ions of three-dimensional structure to include all chemically possible conformers.
  • a focused library including about 300 kinds of compounds was constructed in consideration of the characteristics of the cosmetic material to meet the purpose of the present invention.
  • Table 1 is a value of the inhibition of the ⁇ -HSDl activity of the compounds of Formula 1 to Formula 11. As a result, it was confirmed that the compound of Formula 1 inhibits the activity of ⁇ -HSDl significantly better than other compounds. [Table 1]
  • Compound 1 of Formula 1 (hereinafter referred to as Compound 1) selected in Example 1 was purchased from Chembridge (USA) and dissolved in dimethyl sul foxide (DMSO) and used as a reagent.
  • DMSO dimethyl sul foxide
  • human fibroblasts were seeded in a 96 wel l cell culture dish at a density of 4 ⁇ 10 4 and then cultured in a 37 ° C. 5% CO 2 incubator for 24 hours.
  • UVB was irradiated with 15mJ, and then the compound 1 was added and cultured for 24 hours, and the cells were rarely crystallized with 0.5% solution of MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazol ium bromide). After dissolved in DMS0 absorbance was measured.
  • Human fibroblasts were cultured in 6 wel l cell culture dishes to determine the effect of UVB-induced ⁇ -HSDl on messenger RNA expression in human fibroblasts. After inoculation at a density of 4 ⁇ 10 5, the cells were incubated for 24 hours in a 37C, 5% CO 2 incubator. After irradiating with UVB at 15 mJ, Compound 1 was added to incubate for 24 hours, and the cells were recovered, and trizol (RNA iso, DAKARA, Japan) 1 ⁇ was added to separate RNA. After quantifying RNA at 260ran using an ultraviolet detector, cDNA was synthesized (Reverse Transcriptase Mix, ELPIS biotech, Korea).
  • RT-PCR was carried out using a PCR machine (Step One Plus, Applied Biosystems, USA) and assayed by adding Cyberlin (SYBRGreen supermix, Ap lied Biosystems, USA) with ⁇ -HSDl primer and cDNA.
  • the primers and reaction conditions were as shown in Table 2 below, and the expression level of the gene of ⁇ -HSDl was corrected for the ⁇ -actin gene.
  • human fibroblasts were inoculated at a density of 4 X 10 5 in a 6 well cell culture dish to confirm the effect of inhibiting the expression of UVB-induced MMP-1 protein of Compound 1 in human fibroblasts at 37 ° C, 5 Incubated for 24 hours in a% C0 2 incubator. After irradiating 15mJ of UVB, Compound 1 was added at a concentration (1, 10 / g /), incubated for 72 hours, and cells were recovered. 100 m lysis buffer was added to the cells, and the proteins were extracted and quantified at 595 nm by a Bradford assay.
  • Electrophoresis using SDS-PAGE Sod i umdodecy 1 su 1 f at e-po 1 yacry 1 am i de gel electrophoresis
  • transfer protein bands to PVDF Polyvinyl idene fluoride, Bio-rad, USA
  • Enhanced chemi luminescence, ThermoScientific, USA was confirmed the amount of protein expression.
  • the epidermal damage repair effect of the compound 1 was confirmed using a three-dimensional artificial skin tissue in order to evaluate in vivo model.
  • Compound 1 was added to the medium after E idermal t ssue (Skin Ethics, Nikoderm Research Inc., France) was stabilized in growth medium for 24 hours. UVB 40mJ was irradiated three times every four hours, and then cultured for 72 hours, and epidermal tissues were collected and subjected to H & E staining.
  • the toner agent containing the compound 1 was prepared in a conventional manner according to the composition components and the composition ratios shown in Table 4 below.
  • Component content (% by weight)
  • the lotion agent containing the compound 1 was prepared by a conventional method according to the composition components and composition ratios shown in Table 5 below.
  • the cream agent containing the compound 1 was prepared according to a conventional method according to the composition components and composition ratios shown in Table 6 below.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Dermatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Birds (AREA)
  • Gerontology & Geriatric Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Cosmetics (AREA)

Abstract

The present invention relates to a skin antiaging cosmetic composition or an external use skin preparation composition, both containing a compound inhibiting the activity of 11β-hydroxysteroid dehydrogenase type 1 and, more specifically, the present invention relates to a skin antiaging cosmetic composition or an external use skin preparation composition, both containing a 3,5-dimethylpyrazole derivative compound of the following chemical formula 1.

Description

【명세서】  【Specification】
【발명의 명칭】 [Name of invention]
11β -hydroxysteroid dehydrogenase type 1의 활성을 저해하는 화합물을 포함하는 화장료 조성물 또는 피부 외용제 조성물  Cosmetic composition or external composition for skin containing a compound that inhibits the activity of 11β-hydroxysteroid dehydrogenase type 1
【기술분야】 Technical Field
본 발명은 대한민국 보건복지부 지원하에 과제번호 HN12C0061에 의해 이루어진 것으로서， 상기 과제의 연구관리전문기관은 글로벌코스메틱연구개발사업단， 연구사업명은 The present invention is made by the task number HN12C0061 under the support of the Ministry of Health and Welfare, the research management professional agency of the task is a global cosmetic research and development project group,
"글로벌화장품신소재.신기술연구개발지원" , 연구과제명은 "피부세포 핵수용체 조절 천연물 허브 구축을 통한 한류 화장품 개발" ， 주관기관은 코스맥스(주)， 연구기간은 2014.11.01 ~ 2015.10.31이다. "Global Cosmetics New Materials.New Technology R & D Support," the research title is "Development of Korean Wave Cosmetics by Establishing Skin Cell Nuclear Receptor-regulated Natural Herbs", Host Organization is Cosmax Co., Ltd. and research period is 2014.11.01 ~ 2015.10.31.
본 발명은 11 β -hydroxysteroid dehydrogenase type 1의 활성을 저해하는 화합물을 포함하는 화장료 조성물에 관한 것으로， 더욱 구체적으로 ιΐβ - hydroxysteroid dehydrogenase type 1의 활성을 저해하는 화합물을 유효성분으로함유하는 피부노화 예방 또는 개선용 화장료 조성물 또는 피부 외용제 조성물에 관한 것이다.  The present invention relates to a cosmetic composition comprising a compound that inhibits the activity of 11 β-hydroxysteroid dehydrogenase type 1, and more particularly to preventing skin aging containing a compound that inhibits the activity of ιΐβ-hydroxysteroid dehydrogenase type 1 as an active ingredient. It relates to a cosmetic composition for improvement or an external composition for skin.
【배경기술】 Background Art
기능성 화장품 기술에서의 주된 관심분야는 피부노화를 지연시켜 피부의 주름개선에 도움을 주는 제품， 자외선 및 와부환경으로부터 피부를 보호하는 제품， 피부의 미백에 도움을 주는 제품으로 정의될 수 있다.  The main areas of interest in functional cosmetics technology can be defined as products that retard skin aging to help improve wrinkles on the skin, products that protect the skin from UV rays and the widow environment, and products that help to whiten the skin.
이 중 피부노화를 지연시키기 위한 주름개선 화장품의 개발하기 위해서 피부 내에서 생리적으로 효능을 나타낼 수 있는 기능성 원료의 개발이 선행되어야 한다.  Among these, in order to develop wrinkle improvement cosmetics for delaying skin aging, development of functional raw materials that can exhibit physiological efficacy in the skin should be preceded.
일반적으로 노화된 피부에서 나타나는 주름살과 피부의 탄력 감소， 피부 쳐짐 및 건조 현상 등은 대부분 진피에 존재하는 기질단백질의 변화 때문이다. 진피는 피부 내에서 피부의 강도와 형태를 지자하는 역할을 하고 있기 때문에 노화가 진행될 때 이 부분에 형태적인 변화가 일어나게 되면 주름 생성 및 피부 쳐짐에 결정적인 역할을 하게 된다. 이러한 기질단백질을 분해하는 효소로In general, wrinkles and decreased skin elasticity, sagging and dryness of aging skin are mostly due to changes in substrate proteins present in the dermis. The dermis plays a role in determining the strength and shape of the skin within the skin. Morphological changes in this area during aging play a decisive role in wrinkle formation and skin sagging. As enzymes that break down these substrate proteins
Matr ix metal loproteinases (MMPs)가 대표적이며 한 번의 자외선 조사에도 피부 내의 MMPs 활성이 증가되고， 피부 내의 콜라겐 및 기타 기질단백질을 현저하게 분해시켜 피부 노화를 촉진하는데 주요한 요인으로 작용한다. Matr ix metal loproteinases (MMPs) are typical, and MUVs activity in the skin is increased in a single UV irradiation, and it is a major factor in promoting skin aging by remarkably degrading collagen and other matrix proteins in the skin.
최근 정신적인 내부 스트레스나 외부 유해환경에 노출이 잦아지면서 피부 노화가 가속화되는 도시형 노화 방지에 대한 중요성이 요구되고 있다. 시간의 흐름에 따라 발생하는 자연 노화나， 태양광선에 의한 광노화뿐만 아니라 외부적 스트레스에 의해 일어나는 인체 내 생리학적 변화가 피부 노화를 악화시킬 수 있다는 연구가 진행되어 왔다.  Recently, the importance of preventing urban aging, which accelerates skin aging due to frequent exposure to internal mental stress or external harmful environment, is required. Natural aging that occurs over time, photoaging due to sunlight, as well as physiological changes in the human body caused by external stress have been aggravated skin aging.
Tiganescu 등에 따르면, 11 β -hydroxys t er o i d dehydrogease type 1 (이하 ΙΙβ -HSDl)라는 스트레스 호르몬 생성 조절 효소가 피부 노화에 있어서 상당한 역할을 하고 있음을 밝혔다. 즉， 피부 노화가 진행됨에 따라 ΙΙ β -HSDl의 활성 및 발현이 증가하고 (Tiganescu A et al， 2011；131 , 30-36) , 특히 자외선에 의해 ΙΙ β -HSDl의 활성 및 발현이 현저히 증가함을 밝혔다 (Tiganescu A et al , 2013； 123(7)：3051?3060) . 또한， ΙΙ β -HSDl의 억제제를 도포하거나， ΙΙβ -HSDl 유전자를 소실한 노화 마우스를 만들었을 때， 피부 상처 회복이 촉진되고 진피에서의 노화 변화가 거의 나타나지 않음도 확인하였다 (Tiganescu A et al , 2013； 123(7)： 305173060) . 따라서， ΙΙ β—HSDl을 조절함으로써 피부 노화를 억제하거나 개선할 수 있음을 제안하였다. ΙΙ β -HSDl 효소는 비활성 스트레스 호르몬을 활성 스트레스 호르몬으로 전환하는 효소로서 내부 요인으로는 다양한 정신적 스트레스, 외부 요인으로는 자외선， 오염 물질， 화학 물질 등에 의해 활성 및 발현이 증가된다. 특히， 자외선에 의한 ιΐβ -HSi 의 활성 및 발현 증가는 피부 노화와 밀접한 관련이 있기 때문에 피부 노화 억제를 위한 새로운 타겟으로 주목되고 있다.  According to Tiganescu et al., A stress hormone production regulating enzyme, 11 β-hydroxys ter i i dehydrogease type 1 (hereinafter, ΙΙβ -HSDl), plays a significant role in skin aging. That is, as the skin ages, the activity and expression of ΙΙ β -HSDl increases (Tiganescu A et al, 2011; 131, 30-36), and the activity and expression of ΙΙ β -HSDl increases significantly, especially by ultraviolet rays. (Tiganescu A et al, 2013; 123 (7): 3051-3060). In addition, the application of an inhibitor of ΙΙ β -HSDl or the development of an aging mouse that lost the ΙΙβ -HSDl gene promoted the recovery of skin wounds and showed little change in aging in the dermis (Tiganescu A et al, 123 (7): 305173060). Therefore, it was suggested that the control of Ιβ—HSDl could inhibit or improve skin aging. Ιβ β-HSDl is an enzyme that converts inactive stress hormones into active stress hormones. Its activity and expression are increased by various mental stresses as internal factors and ultraviolet rays, pollutants, and chemicals as external factors. In particular, the increase in activity and expression of ιΐβ -HSi by ultraviolet rays is attracting attention as a new target for inhibiting skin aging because it is closely related to skin aging.
한편， ΙΙ β -HSDl의 발현 및 활성 저해는 피부 상처 치료， 항당뇨 등의 대사 질환 치료 등 다양한 생리학적 효과가 보고되고 있다. 그러나 피부에서의 광노화 억제 효과에 대해서는 연구결과가 아직 미미한 실정이다.  On the other hand, various physiological effects, such as treatment of skin wounds and the treatment of metabolic diseases such as anti-diabetic, have been reported for the inhibition of expression and activity of Ιβ β-HSDl. However, research on the effect of inhibiting photoaging in the skin is still insignificant.
이에, 본 발명자들은 상기 종래기술들의 문제점들을 극복하기 위하여 예의 연구 노력한 결과， 자외선에 의해 활성된 ΙΙβ -HSDl의 역할아 광노화에 관련이 있음을 인지하고 이를 개선하는 물질을 발굴하고자， ιΐβ-Hsm의 활성을 효과적으로 저해하는 화합물을 in si l ico로써 선별하였다. Accordingly, the present inventors have diligence to overcome the problems of the prior art. As a result of the research efforts, in order to recognize the role of ΙΙβ -HSDl activated by UV light and to find a substance to improve it, a compound which effectively inhibits the activity of ιΐβ-Hsm was selected as in Si l ico.
단백질 -기반 활성골격을 이용한 초고속 가상신약탐색 (Receptor-Oriented Pharamcophore based in si l ico High-Throughput Screening, in Si l ico HTS)은 단백질과 소재의 상호작용을 분석하고 이들을 화학적 특성으로 표현하여 기능은 유사하나 새로운 화학적 구조를 가진 신규한 소재 개발을 위한 계산화학 (Computat ional Chemi stry) 방법 중의 하나이다. 활성골격 (Pharmacophore)은 소재가 효능을 나타내기 위해 필수적으로 가져야 할 화학적 조건을 3차원 좌표를 이용하여 배열한 것이다. 특히, 하나의 소재가 단백질과 잘 결합하여 그 단백질의 활성을 조절하기 위해서는 활성골격의 정의가 매우 중요하며 이는 알려진 실험 데이터나 충분한 구조 분석 등을 통해 정의할 수 있다. 단백질 -소재 사이의 상호작용은 수소결합 (Hydrogen bonding)과 소수성 (Lipophi 1 ici ty) 환경 형성위치를 통해 정의할 수 있으며 이들이 활성골격을 이루는 화학적 조건이 된다. 수소결합은 수소결합 주개 (HBA) , 수소결합 받개 (HBD)로 나누어 그 성질을 표현하고 소수성 환경은 (Lipo)라는 일종의 요소 (feature)로 나타내며 이들을 적절하게 조합하여 3차원 좌표로 표현되는 하나의 지도 (map) 형태로 정의된다.  Receptor-Oriented Pharamcophore based in Si l ico High-Throughput Screening (in Si l ico HTS) analyzes protein-material interactions and expresses them as chemical properties. One of the computat ional chemistry methods for the development of new materials with similar but novel chemical structures. Pharmacophore is an arrangement of three-dimensional coordinates of chemical conditions that a material must have in order to exhibit efficacy. In particular, in order for one material to bind well with a protein and regulate its activity, the definition of an active skeleton is very important and can be defined through known experimental data or sufficient structural analysis. Protein-material interactions can be defined through the formation of hydrogen bonding and hydrophobic (Lipophi 1 ici ty) environments, which are the chemical conditions that make up the active skeleton. Hydrogen bonds are divided into hydrogen bond donors (HBA) and hydrogen bond acceptors (HBD) to express their properties, and the hydrophobic environment is represented by a kind of feature called (Lipo). It is defined in the form of a map.
본 발명에서는 in si l ico로 선별된 화학식 1의 구조식을 갖는 화합물이 ΙΙβ -HSDl와 MMPs 발현 증가를 통한 광노화를 억제함으로써 피부노화 예방 또는 개선 가능성을 확인하고， 본 발명을 완성하게 되었다.  In the present invention, the compound having the structural formula of Formula 1 selected as in si ico confirmed the possibility of preventing or improving skin aging by inhibiting photoaging through increased expression of Ιβ-HSDl and MMPs, thereby completing the present invention.
【발명의 상세한 설명】 [Detailed Description of the Invention]
【기술적 과제】  [Technical problem]
본 발명의 기본적인 목적은 11β -히드록시스테로이드 디하이드로게나제 타입 1의 활성을 저해하는 화합물을 유효성분으로 포함하는 화장료 조성물 또는 피부 외용제 조성물을 제공하는데 있다.  The basic object of the present invention is to provide a cosmetic composition or external skin composition comprising a compound that inhibits the activity of 11β-hydroxysteroid dehydrogenase type 1 as an active ingredient.
본 발명의 또 다른 목적은 상기 11 β -히드록시스테로이드 디하이드로게나제 타입 1의 활성을 저해하는 화합물 및 생리학적으로 허용되는 화장품 기제를 포함하는 피부 노화 방지용 화장료 조성물 또는 피부 외용제 조성물을 제공하는 것이다. Another object of the present invention is a compound that inhibits the activity of the 11 β-hydroxysteroid dehydrogenase type 1 and physiologically acceptable It is to provide a skin anti-aging cosmetic composition or a topical skin composition comprising a cosmetic base.
【기술적 해결방법】 Technical Solution
본 발명의 한 양태에 따르면， 본 발명은 11β-히드록시스테로이드 디하이드로게나제 타입 1(11β -hydroxysteroid dehydrogenase type 1)의 활성을 저해하는 화합물을 유효성분으로 포함하는 피부노화 방지용 화장료 조성물을 제공한다.  According to an aspect of the present invention, the present invention provides a cosmetic composition for preventing skin aging comprising a compound that inhibits the activity of 11β-hydroxysteroid dehydrogenase type 1 as an active ingredient. .
본 발명에서는, 11 β-히드록시스테로이드 디하이드로게나제 타입 1(11β- hydroxysteroid dehydrogenase type 1)의 3차원 구조를 이용하여 가상신약 탐색을 통해 11β-히드록시스테로이드 디하이드로게나제 타입 1(11β- hydroxysteroid dehydrogenase type 1)의 활성을 저해하는 화합물들을 선정하였다.  In the present invention, the 11β-hydroxysteroid dehydrogenase type 1 (11β-hydroxysteroid dehydrogenase type 1) using the three-dimensional structure through the drug discovery through 11β-hydroxysteroid dehydrogenase type 1 (11β- Compounds that inhibit the activity of hydroxysteroid dehydrogenase type 1) were selected.
본 발명에 있어서, 바람직하게는 상기 화합물은 하기 화학식 1의 1- [1- ( 1-아다만틸아세틸)피를리딘 -3-일 ] -3 , 5-디메틸 -1H-피라졸 (1-[1-(1- adamantyl acetyl )pyrrolidin-3-yl ]-3, 5-dimethyl-lH-pyrazole)¾l '것을 특징으로 하는 피부노화 방지용 화장료 조성물을 제공한다: In the present invention, preferably, the compound is 1- [1- (1-adamantylacetyl) pyridin-3-yl] -3, 5-dimethyl-1H-pyrazole (1- [1- (1- adamantyl acetyl) pyrrolidin -3-yl] -3, 5-dimethyl-lH-pyrazole) ¾l ' and that provides skin anti-aging cosmetic composition, characterized in:
[화학식 1]  [Formula 1]
Figure imgf000006_0001
Figure imgf000006_0001
본 발명의 실험예에서는， 상기 화학식 1의 화합물이 11 β -hydroxysteroid dehydrogenase type 1 (ΙΙβ-HSDl) 발현 및 MMPs 발현을 효과적으로 억제하고 콜라겐 생상을 회복시킴으로써 피부노화를 예방 또는 개선할 수 있음을 증명하였다.  In the experimental example of the present invention, it was proved that the compound of Formula 1 effectively prevents or improves skin aging by effectively inhibiting the expression of 11 β-hydroxysteroid dehydrogenase type 1 (ΙΙβ-HSDl) and MMPs and restoring collagen production. .
본 발명의 실시예에서는 ΙΙβ-HSDl (도 1)에 대한 가상신약탐색에서 11β- HSD1의 활성자리 (active site)에 결합할 수 있는 화합물들을 선별하였으며， 이들은 모두 상기 ΙΙβ-HSm의 활성자리 (active site)에 경쟁적으로 ¾합하여 ΙΙβ -HSDl의 활성을 저해할 수 있으므로， 실험예에서 화합물 1과 동등한 효과를 나타낼 수 있다. In an embodiment of the present invention, compounds that can bind to the active site of 11β-HSD1 were selected in the virtual drug search for ΙΙβ-HSDl (FIG. 1), all of which are active sites of the ΙΙβ-HSm. competitively with the site) Since it can inhibit the activity of ΙΙβ -HSDl, it can exhibit the same effect as Compound 1 in the experimental example.
본 발명에 있어서， 상기 화합물은 조성물 총 중량 대비 0.01 내지 10 중량 ¾» 함유하는 것을 특징으로 한다. 상기 범위에서 0.01 중량 ¾ 미만일 경우 광노화 억제 효과가 미약하게 될 우려가 있어 바람직하지 못하며， 역으로 10중량 %를 초과하는 것은 경제성 측면에서 바람직하지 못할수 있다.  In the present invention, the compound is characterized in that it contains 0.01 to 10% by weight based on the total weight of the composition. If the amount is less than 0.01 weight ¾ in the above range, there is a possibility that the effect of inhibiting photoaging may be weak, and conversely, exceeding 10% by weight may not be desirable in terms of economics.
본 발명에 있어서， 상기 화합물은 Ιΐβ -hydroxysteroid dehydrogenase type 1 (ΙΙβ -HSDl) 발현 억제 효과를 나타내는 것을 특징으로 한다.  In the present invention, the compound is characterized in that it exhibits an inhibitory effect of Ιΐβ -hydroxysteroid dehydrogenase type 1 (ΙΙβ -HSDl) expression.
본 발명의 실험예에 따르면， 상기 화합물은 자외선에 의해 과발현된 11 β - HSD1를 억제하는 것을 확인할 수 있었으며， 스트레스 호르몬인 코르티졸의 생성을 억제하는 것을 확인할 수 있었다. 이러한 결과로 볼 때， 본원발명의 상기 화학식 1의 화합물은 ΙΙβ -HSDl 발현을 효과적으로 억제함으로써 체내 스트레스 호르몬을 감소시켜 피부노화를 예방또는 개선할수 있음을 의미한다.  According to the experimental example of the present invention, it was confirmed that the compound inhibits 11 β-HSD1 overexpressed by ultraviolet rays, and inhibits the production of the stress hormone cortisol. In view of these results, the compound of Formula 1 of the present invention means that by effectively inhibiting the expression of ΙΙβ -HSDl can reduce or reduce the body's stress hormones to prevent or improve skin aging.
본 발명에 있어서， 상기 화합물은 Matr ix metal loproteinases (MMPs) 발현을 억제하여 콜라겐 생성을 회복시키는 것을 특징으로 한다.  In the present invention, the compound is characterized by restoring the collagen production by inhibiting the expression of Mat ix metal loproteinases (MMPs).
본 발명의 실험예에 따르면， 본원발명의 상기 화합물은 MMPs 발현을 효과적으로 억제하고 type I procol lagen 생성을 회복시킴으로써 피부노화를 예방또는 개선할 수 있다.  According to the experimental example of the present invention, the compound of the present invention can prevent or improve skin aging by effectively inhibiting MMPs expression and restoring type I procol lagen production.
본 발명에 있어서， 상기 화합물은 피부 손상 희복 효능을 갖는 것을 특징으로 한다.  In the present invention, the compound is characterized by having a skin damaging effect.
본 발명의 실험예에 따르면， 상기 화합물은 자외선 조사에 의한 표피 두께의 감소를 유의하게 회복시킴으로써 피부노화를 예방 또는 개선할 수 있다. 본 발명에 있어서， 바람직하게는 상기 피부노화는 광노화인 것을 특징으로 하는 피부노화 방지용 화장료 조성물을 제공한다.  According to the experimental example of the present invention, the compound can prevent or improve skin aging by significantly recovering a decrease in epidermal thickness caused by ultraviolet irradiation. In the present invention, the skin aging preferably provides a cosmetic composition for preventing skin aging, characterized in that the photo-aging.
본 발명의 상기 용어 '광노화 (Photoaging)' 는 외부 환경적인 요인에 의해 유발되는 현상으로, 가장 대표적인 인자로는 자외선이 있다. 자외선은 단백질 분해효소의 활성화와 기질단백질의 사슬절단 및 비정상적인 교차결합 등의 생체 구성 성분들의 손상을 가져오고， 이러한 메커니즘의 반복은 외관상으로도 확연한 피부노화를 초래하게 된다. 즉， 본 발명에서는 외부환경과는 무관하게 유전적 요소에 의해 발생하는 내인성 노화와는 달리， 상기와 같이 자외선에 의한 광노화로 인해 발생하는 피부노화의 예방 또는 개선을 위한 화장료조성물， 또는피부 외용제 조성물에 관한 것이다. The term 'photoaging' of the present invention is a phenomenon caused by external environmental factors, and the most representative factor is ultraviolet rays. Ultraviolet rays cause damage to biological components such as protease activation, substrate cleavage and abnormal crosslinking, and the repetition of this mechanism leads to apparent skin aging. That is, in the present invention Unlike the endogenous aging caused by genetic factors irrespective of the external environment, the present invention relates to a cosmetic composition for preventing or improving skin aging caused by photoaging caused by ultraviolet rays, or a composition for external application of skin.
본 발명에 있어서, 상기 조성물은 화장수 (스킨로션)， 스킨소프너， 스킨토너， 아스트린젠트， 로셨， 밀크로션， 모이스쳐 로션， 영양 로션， 마사지 크림, 영양 크림， 모이스쳐 크림， 핸드크림, 파운데이션， 에센스， 영양 에센스, 팩， 비누， 클렌징품， 클렌징로션, 클렌징크림， 바디로션 및 바디클렌저로 구성된 군에서 선택된 제형인 것을 특징으로 한다.  In the present invention, the composition is a skin lotion (skin lotion), skin softener, skin toner, astringent, Rossin, milk lotion, moisturizing lotion, nutrition lotion, massage cream, nutrition cream, moisture cream, hand cream, foundation, essence, nutrition It is characterized in that the formulation is selected from the group consisting of essence, pack, soap, cleansing products, cleansing lotion, cleansing cream, body lotion and body cleanser.
본 발명의 다른 양태에 따르면， 본 발명은 하기 화학식 1의 ι-[ι-(ι- 아다만틸아세틸)피를리딘 -3-일] -3， 5-디메틸 -1H-피라졸 ( 1- [ 1-( 1- adamanty lacetyl ) pyr rol idi η—3—y 1 ] 3， 5— d imethyl- ΙΗ-pyr azole)을 유효성분으로 포함하는 피부노화 예방또는 개선용 피부외용제 조성물을 제공한다:  According to another embodiment of the present invention, the present invention provides the compound of the following formula (1) in which ι- [ι- (ι-adamantylacetyl) pyridin-3-yl] -3,5-dimethyl-1H-pyrazole (1- [1- (1-adamanty lacetyl) pyrrol idi η—3—y 1] 3, 5—d imethyl- ΙΗ-pyr azole) is provided as an active ingredient for external skin preparations for preventing or improving skin aging:
[화학식 1]  [Formula 1]
Figure imgf000008_0001
Figure imgf000008_0001
상기 화학식 1의 i-^-Q-아다만틸아세틸)피를리딘 -3-일 ]-3，5-디메틸-; LH- 피라졸을 유효성분으로 함유하는 피부노화 예방 또는 개선용 피부 외용제 조성물은 앞서 상기 화학식 1의 1-[ 1-( 1-아다만틸아세틸)피를리딘 -3-일] -3 , 5- 디메틸 -1H-피라졸을 유효성분으로 함유하는 피부노화 예방 또는 개선용 화장료 조성물에서 설명한 바와 같다. Of Formula 1 i - ^ - Q- adamantyl acetyl) avoid naphthyridin-3-yl] - 3, 5 - dimethyl -; Skin external preparation composition for the prevention or improvement of skin aging containing LH-pyrazole as an active ingredient is 1- [1- (1- (adamantylacetyl) pyridin-3-yl] -3, 5 of Formula 1 above. -As described in the cosmetic composition for preventing or improving skin aging containing dimethyl -1H-pyrazole as an active ingredient.
본 발명에 있어서， 상기 피부 외용제 조성물은 당업계에서 통상적으로 제조되는 어떠한 제형으로도 제조될 수 있으며， 예를 들어 유액， 크림， 화장수， 팩， 파운데이션， 로션， 미용액， 모발화장료 등을 들 수 있다. 구체적으로는， 스킨로션， 스킨소프너， 스킨토너， 아스트린젠트， 로션， 밀크로션， 모이스처로션， 영양로션， 맛사지크림, 영양크림， 모이스처크림， 핸드크림， 파운데이션， 에센스， 영양 에센스， 팩, 비누， 클렌징 품， 클렌징로션， 클렌징크림, 바디로션 및 바디클렌저의 제형을 포함한다. 본 발명의 조성물은 담체 이외에 다른 보조제를 포함할 수 있는데, 예를 들면 보존제， 항산화제， 안정화제， 용해화제， 비타민 , 안료 및 향료 등을 포함할 수 있다. In the present invention, the external composition for skin may be prepared in any formulation commonly prepared in the art, for example, emulsion, cream, lotion, pack, foundation, lotion, essence, hair cosmetics and the like. . Specifically, Skin Lotion, Skin Softener, Skin Toner, Astringent, Lotion, Milk Lotion, Moisture Lotion, Nutrition Lotion, Massage Cream, Nutrition Cream, Moisture Cream, Hand Cream, Foundation, Essence, Nutrition Essence, Pack, Soap, Cleansing Product, cleansing lotion, cleansing cream, body lotion and body cleanser. The composition of the present invention may include other auxiliaries in addition to the carrier, and may include, for example, preservatives, antioxidants, stabilizers, solubilizers, vitamins, pigments and flavorings.
본 발명에 있어서, 상기 조성물은 각각 통상의 방법에 따라산제， 과립제， 정제， 캡슐제， 현탁액, 에멀견， 시럽， 에어로졸 등의 외용제 및 멸균 주사 용액의 형태로 제형화하여 사용될 수 있으며， 바람직하게는 크림， 젤ᅳ 패취ᅳ 분무제， 연고제， 경고제， 로션제， 리니멘트제， 파스타제 또는 카타플라스마제 제형을 가질 수 있다.  In the present invention, the composition can be used in the form of powder, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols and other external preparations and sterile injectable solutions, respectively, according to a conventional method, preferably May have a cream, gel patch, spray, ointment, warning, lotion, liniment, pasta or cataplasma formulation.
상기 조성물에 포함될 수 있는 담체， 부형제 및 희석제로는 락토즈， 덱스트로즈， 수크로스， 올리고당， 솔비를， 만니를， 자일리를, 에리스리를， 말티를， 전분， 아카시아 고무， 알지네이트， 젤라틴， 칼슘 포스페이트， 칼슘 실리케이트, 셀를로즈, 메틸 셀를로즈， 미정질 셀를로스， 폴리비닐 피를리돈, 물, 메틸히드록시벤조에이트， 프로필히드록시벤조에이트， 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 제제화할 경우에는 보통사용하는 층진제, 증량제， 결합제， 습윤제， 붕해제, 계면활성제 등의 회석제 또는 부형제를 사용하여 조제된다. 경구투여를 위한 고형제제에는 정제， 환제, 산제， 과립제, 캡슐제 등이 포함되며， 이러한 고형제제는 상기 화학식 1의 화합물에 적어도 하나 이상의 부형제 예를 들면， 전분, 칼슘카보네이트 (calcium carbonate) , 수크로스 (sucrose) 또는 락토오스 ( lactose)， 젤라틴 등을 섞어 조제된다. 또한 단순한 부형제 이외에 마그네슘 스티레이트 탈크 같은 윤활제들도 사용된다. 경구를 위한 액상제제로는 현탁제， 내용액제， 유제， 시럽제 등이 해당되는데 흔히 사용되는 단순회석제인 물, 리퀴드 파라핀 이외에 여러가지 부형제， 예를 들면 습윤제, 감미제， 방향제， 보존제 등이 포함될 수 있다. 비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제， 현탁제, 유제， 동결건조제제ᅳ 좌제가 포함된다. 비수성용제， 현탁제로는 프로필렌글리콜 (propylene glycol ) , 폴리에틸렌 글리콜， 올리브 오일과 같은 식물성 기름， 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔 (wi tepsol ) , 마크로골, 트윈 (tween) 61 , 카카오지， 라우린지， 글리세로제라틴 등이 사용될 수 있다. 【유리한 효과】 Carriers, excipients and diluents that may be included in the composition include lactose, dextrose, sucrose, oligosaccharides, sorbbi, manny, xylly, erythris, malty, starch, acacia rubber, alginate, gelatin, Calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyridone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. In the case of formulation, it is prepared by using a diluent or excipient such as commonly used layering agents, extenders, binders, wetting agents, disintegrating agents and surfactants. Solid preparations for oral administration include tablets, pills, powders, granules, capsules, and the like, and such solid preparations include at least one excipient such as starch, calcium carbonate, water, and the like Prepared by mixing sucrose or lactose, gelatin and the like. In addition to simple excipients, lubricants such as magnesium styrate talc are also used. Oral liquid preparations include suspensions, solvents, emulsions, syrups, etc. In addition to water, liquid paraffin, which is a commonly used simple diluent, various excipients, for example, wetting agents, sweeteners, fragrances, and preservatives may be included. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used. As the base of the suppository, wi tepsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used. Advantageous Effects
이상 설명한 바와 같이， 본원발명의 상기 화학식 1의 화합물은 자외선에 의해 과발현된 ΙΙβ -HSDl 및 MMPs 발현을 억제할 뿐만 아니라 콜라겐 생성 및 피부 손상을 회복시킴으로써 피부노화를 방지하거나 예방또는 개선할 수 있다.  As described above, the compound of Chemical Formula 1 of the present invention can prevent, prevent or improve skin aging by not only inhibiting the expression of Ιβ-HSDl and MMPs overexpressed by ultraviolet rays but also restoring collagen production and skin damage.
【도면의 간단한 설명】 [Brief Description of Drawings]
도 1은 ΙΙβ -HSDl의 3차원 구조이다.  1 is a three-dimensional structure of ΙΙβ -HSDl.
도 2는 ΙΙβ -HSDl와 결합하는 2가지의 활성골격 지도이다.  Figure 2 is a map of the two active skeleton binding to ΙΙβ -HSDl.
도 3은 사람 섬유아세포에 상기 화학식 1 처리 시 세포증식에 미치는 영향을 측정한 실험예 1의 결과이다.  Figure 3 is the result of Experiment 1 measuring the effect on the cell proliferation when the formula 1 treatment on human fibroblasts.
도 4는 사람 섬유아세포에 상기 화학식 1 처리 시 UVB에 의해 손상된 세포희복에 미치는 영향을 측정한실험예 1의 결과이다.  Figure 4 is the result of Experimental Example 1 measuring the effect on the cell thinning damaged by UVB when the above formula 1 treatment on human fibroblasts.
도 5는 사람 섬유아세포에 상기 화학식 1 처리 시 ΙΙβ -HSDl 발현에 미치는 영향을 측정한 실험예 2의 결과이다.  5 is a result of Experimental Example 2 measuring the effect on the ΙΙβ -HSDl expression when the formula 1 treatment in human fibroblasts.
도 6은 사람 ^ ^아세포에 상기 화학식 1 처리 시 Cort i sol ^¾에 미치는 영향을 측정한 실험예 2의 결과이다.  6 is a result of Experimental Example 2 measuring the effect on Cort i sol ^ ¾ when the treatment of the formula (1) in human ^ ^ cells.
도 7은 사람 섬유아세포에 상기 화학식 1 처리 시 MMP-1 메신저 RNA 발현에 미치는 영향을 측정한 실험예 3의 결과이다.  Figure 7 is the result of Experiment 3 measuring the effect on the expression of MMP-1 messenger RNA when the formula 1 treatment in human fibroblasts.
도 8은 사람 섬유아세포에 상기 화학식 1 처리 시 MMP-1 단백질 발현에 미치는 영향을 측정한 실험예 3의 결과이다.  8 is a result of Experiment 3 measuring the effect on the expression of MMP-1 protein when the formula 1 treatment on human fibroblasts.
도 9는 사람 섬유아세포에 상기 화학식 1 처리 시 type 1 procol lagen 발현에 미치는 영향을 측정한실험예 3의 결과이다.  9 is a result of Experiment 3 measuring the effect on the expression of type 1 procol lagen when the formula 1 treatment on human fibroblasts.
도 10은 3차원 피부모델에 상기 화학식 1 처리 시 표피층 두께 변화에 미치는 영향을 측정한 실험예 4의 결과이다.  10 is a result of Experiment 4 measuring the effect on the epidermal layer thickness change when the formula 1 treatment on a three-dimensional skin model.
도 11은 3차원 피부모델에 상기 화학식 1 처리 시 표피층 두께 변화에 미치는 영향을 측정한 실험예 4의 결과이다.  11 is a result of Experimental Example 4 measuring the effect on the epidermal layer thickness change during the treatment of Formula 1 in the three-dimensional skin model.
【발명의 실시를 위한 형태】 [Form for implementation of invention]
이하， 실시예를 통하여 본 발명을 더욱 상세히 설명하기로 한다. 이들 실시예는 단지 본 발명을 예시하기 위한 것이므로 본 발명의 범위가 이들 실시예에 의해 제한되는 것으로 해석되지는 않는다. 실시예 1: 일반 화학식 1의 발굴 Hereinafter, the present invention will be described in more detail with reference to Examples. these The examples are only intended to illustrate the invention and are not to be construed as limiting the scope of the invention. Example 1 Excavation of General Formula 1
ΙΙβ-HSDl (도 1)에 대한 가상신약탐색은 알려진 11β— HSD1의 3차원 구조에서 소재가 결합하는 활성자리 (active site)를 결정하고 주변 5 A을 선정하여 이 영역에 대해 활성골격 지도를 결정하였으며 하나의 지도에는 5- 6개의 요소들이 포함 되도록 정의하여 최종적으로 2가지의 활성골격 지도를 완성하였다 (도 2).  Virtual drug search for ΙΙβ-HSDl (FIG. 1) determines the active site to which the material binds in the known three-dimensional structure of 11β-HSD1, and selects the surrounding 5A to determine the active skeletal map for this region. One map was defined to include 5-6 elements, and finally two active skeleton maps were completed (FIG. 2).
이 활성골격 지도를 이용하여 화합물 라이브러리를 검색하였으며 11β_ HSD1 저해효능 소재로 가능성이 있는 물질을 선정하였다. 화합물 라이브러리는 3차원 구조의 multiple conformmat ion을 검색하여 화학적으로 가능한 모든 conformer를 포함할 수 있도록 하였다. 화합물 라이브러리의 경우 본 과제의 목적에 부합하도록 화장품 소재로서의 특징을 고려하여 약 300여 종의 화합물을 포함한 목적형 라이브러리 (Focused Library)를 구축하였다.  The compound library was searched using this active skeletal map, and the potential material was selected as 11β_ HSD1 inhibitory effect material. The compound library searched for multiple conformmat ions of three-dimensional structure to include all chemically possible conformers. In the case of the compound library, a focused library including about 300 kinds of compounds was constructed in consideration of the characteristics of the cosmetic material to meet the purpose of the present invention.
본 발명을 위하여 위의 가상신약탐색 과정을 통해 최종적으로 ΙΙβ-HSDl 활성을 저해할 것으로 예측되는 11종의 화합물을 선정하였다. 실험예 1: 11 -HSD1활성 확인  For the present invention, 11 kinds of compounds predicted to finally inhibit Ιβ-HSDl activity were selected through the virtual drug discovery process. Experimental Example 1 Confirming 11-HSD1 Activity
실시예 1에서 선정된 화학식 1 ~ 화학식 11의 화합물을 Chembridge (미국)로부터 구입하여 DMSCKDimethyl sulfoxide)에 용해시켜 시료로 사용하였다. llp-HSi 가 과발현된 사람 CH0 세포를 96 well 세포 배양 접시에 2.5 X 104의 밀도로 접종한 후 37°C, 5% C02 배양기에서 24시간 배양하였다. 160 nM cortisone과 상기 화합물을 처리하여 3시간 동안 배양하고 HTRF( homogenous timeresolved fluorescence) assay를 시행하였다. Compounds of Formula 1 to Formula 11 selected in Example 1 were purchased from Chembridge (USA) and dissolved in DMSCKDimethyl sulfoxide) to use as samples. Human CH0 cells over-expressing llp-HSi were inoculated at a density of 2.5 × 10 4 in 96 well cell culture dishes and incubated in 37 ° C., 5% CO 2 incubator for 24 hours. 160 nM cortisone and the compound were incubated for 3 hours and subjected to homogenous timeresolved fluorescence (HTRF) assay.
하기 표 1은 화학식 1 내지 화학식 11의 화합물들의 ΙΙβ-HSDl 활성 저해율을 측정한 값이다. 그 결과， 화학식 1의 화합물이 다른 화합물들에 비해 월등히 우수하게 ΙΙβ-HSDl의 활성을 저해시킴을 확인하였다. 【표 1] Table 1 below is a value of the inhibition of the ΙΙβ-HSDl activity of the compounds of Formula 1 to Formula 11. As a result, it was confirmed that the compound of Formula 1 inhibits the activity of ΙΙβ-HSDl significantly better than other compounds. [Table 1]
Figure imgf000012_0001
실험예 2: 상기 화합물 1의 세포 증식 효과 확인
Figure imgf000012_0001
Experimental Example 2: Confirm the cell proliferation effect of the compound 1
실시예 1에서 선별된 화학식 1의 화합물 (이하 화합물 1이라고 함)을 Chembridge (미국)로부터 구입하여 DMSO(Dimethyl sul foxide)에 용해시켜 시^로 사용하였다.  Compound 1 of Formula 1 (hereinafter referred to as Compound 1) selected in Example 1 was purchased from Chembridge (USA) and dissolved in dimethyl sul foxide (DMSO) and used as a reagent.
사람 섬유아세포에서 상기 화합물 1의 세포 증식 효과를 확인하기위해 사람 섬유아세포를 96 wel l 세포 배양 접시에 4 X 104의 밀도로 접종한 후 37°C 5% C02 배양기에서 24시간 배양하였다. UVB를 15mJ 조사한 후 상기 화합물 1를 첨가하여 24 시간 동안 배양하고 세포를 희수하여 MTT (3-(4,5-dimethylthiazol- 2-yl )-2 ,5-diphenyltetrazol ium bromide) 0.5% 용액으로 결정화한 후 DMS0에 녹여 흡광도를 측정하였다. In order to confirm the cell proliferation effect of the compound 1 in human fibroblasts, human fibroblasts were seeded in a 96 wel l cell culture dish at a density of 4 × 10 4 and then cultured in a 37 ° C. 5% CO 2 incubator for 24 hours. UVB was irradiated with 15mJ, and then the compound 1 was added and cultured for 24 hours, and the cells were rarely crystallized with 0.5% solution of MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazol ium bromide). After dissolved in DMS0 absorbance was measured.
그 결과， 도면 4에 나타낸 바와 같이 상기 화합물 1의 농도에 따라 세포 증식 효능을 보였으며 , 도면 5에 나타낸 바와 같이 UVB에 의해 손상받은 세포를 회복시키는 효능을 보였다. 실험예 3: 상기 화합물 1의 스트레스 저해 효능  As a result, as shown in Figure 4 showed the cell proliferation efficacy according to the concentration of the compound 1, and as shown in Figure 5 showed the effect of recovering the cells damaged by UVB. Experimental Example 3: Stress Inhibition Effect of Compound 1
사람 섬유아세포에서 상기 화합물 1의 UVB로 유도된 ΙΙβ -HSDl의 메신저 RNA 발현저해 효과를 확인하기 위해 사람 섬유아세포를 6 wel l 세포 배양 접시에 4 X 105의 밀도로 접종한 후 37C, 5% C02 배양기에서 24시간 배양하였다. UVB를 15mJ 조사한 후 상기 화합물 1을 첨가하여 24 시간 동안 배양하고 세포를 회수하여 트리졸 (RNA iso, DAKARA, 일본) 1 ^을 첨가하여 RNA를 분리하였다. 자외선 검출기를 이용하여 260ran에서 RNA를 정량한 후， cDNA를 합성하였다 (Reverse Transcriptase Mix, ELPIS biotech, 한국). RT-PCR은 PCR 기계 (Step One Plus, Applied Biosystems, 미국)를 이용하였고 사이버그린 (SYBRGreen supermix, Ap lied Biosystems, 미국)을 ΙΙβ-HSDl 프라이머 및 cDNA와 함께 첨가하여 에세이하였다. Human fibroblasts were cultured in 6 wel l cell culture dishes to determine the effect of UVB-induced ΙΙβ -HSDl on messenger RNA expression in human fibroblasts. After inoculation at a density of 4 × 10 5, the cells were incubated for 24 hours in a 37C, 5% CO 2 incubator. After irradiating with UVB at 15 mJ, Compound 1 was added to incubate for 24 hours, and the cells were recovered, and trizol (RNA iso, DAKARA, Japan) 1 ^ was added to separate RNA. After quantifying RNA at 260ran using an ultraviolet detector, cDNA was synthesized (Reverse Transcriptase Mix, ELPIS biotech, Korea). RT-PCR was carried out using a PCR machine (Step One Plus, Applied Biosystems, USA) and assayed by adding Cyberlin (SYBRGreen supermix, Ap lied Biosystems, USA) with ΙΙ-HSDl primer and cDNA.
프라이머와 반응 조건은 하기의 표 2와 같았으며， ΙΙβ-HSDl의 유전자의 발현양은 β-actin유전자에 대해 보정을 하여 나타내었다.  The primers and reaction conditions were as shown in Table 2 below, and the expression level of the gene of ΙΙβ-HSDl was corrected for the β-actin gene.
【표 2】 Table 2
Figure imgf000013_0001
아울러， 상기 화합물 1의 UVB로 유도된 Cortisol 발현저해 효과를 확인하기 위해 사람 섬유아세포를 6 well 세포 배양 접시에 4 X 105의 밀도로 접종한 후 37°C, 5% C02 배양기에서 24시간 배양하였다. UVB를 15mJ 조사한 후 상기 화합물 1을 첨가하여 24 시간 동안 추가 배양하고 배지를 회수하였다. 회수한 배지는 12,000rpm에서 10분간 원심 분리하여 불순물을 제거하고 Cortisol EL ISA( Enzyme 1 inked immunosorbent assay) kit (R&D system, 미국)를 이용하여 에세이 하였다.
Figure imgf000013_0001
In addition, in order to confirm the inhibitory effect of UVB-induced Cortisol expression of Compound 1, human fibroblasts were inoculated in a 6 well cell culture dish at a density of 4 × 10 5 and then incubated at 37 ° C., 5% CO 2 incubator for 24 hours. Incubated. UVB was irradiated with 15mJ, and then Compound 1 was added to further incubate for 24 hours, and the medium was recovered. The recovered medium was centrifuged at 12,000 rpm for 10 minutes to remove impurities and assayed using the Cortisol ELISA (Enzyme 1 inked immunosorbent assay) kit (R & D system, USA).
그 결과， 도면 6과 7에 나타낸 바와 같이 상기 화합물 1의 농도에 따라 ΙΙβ-HSDl 및 cortis 의 발현이 억제되는 효능을 보였다. 실험예 4: 상기 화합물 1의 콜라겐 분해 억제 효능  As a result, as shown in Figures 6 and 7 showed the effect of suppressing the expression of Ιβ-HSDl and cortis depending on the concentration of the compound 1. Experimental Example 4: Collagen Degradation Inhibitory Effect of Compound 1
사람 섬유아세포에서 상기 화합물 1의 UVB로 유도된 MMP-1의 억제 효과를 확인하기 위해 상기의 실험예 2에 기술한 방법과 동일한 방법으로 사람 섬유아세포를 배양하여 UVB 및 상기 화합물 1을 첨가한 후 24 시간 추가 배양하여 MMP-1의 메신저 RNA 발현양을 확인하였다. 프라이머와 반웅 조건은 하기의 표 3과 같으며， MMP-1 유전자의 발현양은 β-actin유전자에 대해 보정을 하여 나타내었다. In order to confirm the inhibitory effect of the UVB-induced MMP-1 of the compound 1 in human fibroblasts in the same manner as described in Experimental Example 2 Fibroblasts were cultured and UVB and Compound 1 were added, followed by further culture for 24 hours to confirm the amount of messenger RNA expression of MMP-1. The primer and reaction conditions are shown in Table 3 below, and the expression level of the MMP-1 gene was expressed by correcting for the β-actin gene.
【표 3] [Table 3]
Figure imgf000014_0001
또한， 사람 섬유아세포에서 상기 화합물 1의 UVB로 유도된 MMP-1 단백질 발현저해 효과를 확인하기 위해 사람섬유아세포를 6 well 세포 배양 접시에 4 X 105의 밀도로 접종한 후 37 °C, 5% C02 배양기에서 24시간 배양하였다. UVB를 15mJ 조사한 후 상기 화합물 1을 농도 (1， 10/g/ )로 첨가하여 72 시간 동안 배양하고 세포를 회수하였다. 세포에 100 m의 lysis 버퍼를 첨가한 후 단백질을 추출하고 브래드포드 에세이 (Bradford assay)를 통해 595nm에서 단백질을 정량하였다. SDS-PAGE ( Sod i umdodecy 1 su 1 f at e-po 1 yacry 1 am i de gel electrophoresis)를 이용하여 전기영동하고 PVDF (Polyvinyl idene fluoride, Bio-rad, 미국)에 단백질 밴드를 전달하여 ECL (Enhanced chemi luminescence, ThermoScientific, 미국) 용액으로 단백질 발현량을 확인하였다.
Figure imgf000014_0001
In addition, human fibroblasts were inoculated at a density of 4 X 10 5 in a 6 well cell culture dish to confirm the effect of inhibiting the expression of UVB-induced MMP-1 protein of Compound 1 in human fibroblasts at 37 ° C, 5 Incubated for 24 hours in a% C0 2 incubator. After irradiating 15mJ of UVB, Compound 1 was added at a concentration (1, 10 / g /), incubated for 72 hours, and cells were recovered. 100 m lysis buffer was added to the cells, and the proteins were extracted and quantified at 595 nm by a Bradford assay. Electrophoresis using SDS-PAGE (Sod i umdodecy 1 su 1 f at e-po 1 yacry 1 am i de gel electrophoresis) and transfer protein bands to PVDF (Polyvinyl idene fluoride, Bio-rad, USA) Enhanced chemi luminescence, ThermoScientific, USA) solution was confirmed the amount of protein expression.
그 결과， 도면 8과 9에 나타낸 바와 같이 상기 화합물 1에서 농도 의존적으로 MMP-1의 저해 효능을 확인하였다.  As a result, as shown in Figures 8 and 9 confirmed the inhibitory effect of MMP-1 concentration-dependently in the compound 1.
또한， 상기 화합물 1의 UVB로 유도된 type 1 procollagen 생성 회복 효과를 확인하기 위해 사람 섬유아세포를 6 well 세포 배양 접시에 4 X 105의 밀도로 접종한 후 37°C, 5% C02 배양기에서 24시간 배양하였다. UVB를 15mJ 조사한 후 상기 화합물 1을 첨가하여 24 시간 동안 추가 배양하고 배지를 회수하였다. 회수한 배지는 12,000rpm에서 10분간 원심 분리하여 불순물을 제거하고 type 1 procollagen EIA(Enzyme immuno assay) kit (DAKARA, 일본)를 이용하여 에세이 하였다. 그 결과， 도면 10에 나타낸 바와 같이 상기 화합물 1에서 농도 의존적으로 type 1 procol lagen 생성 회복 효능을 확인하였다. 실험예 5: 상기 화합물 1의 삼차원 인공피부손상회복능확인 In addition, in order to confirm the recovery effect of UVB-induced type 1 procollagen production of Compound 1, human fibroblasts were inoculated in a 6 well cell culture dish at a density of 4 X 10 5 and then in a 37 ° C, 5% C0 2 incubator. Incubated for 24 hours. UVB was irradiated with 15mJ, and then Compound 1 was added to further incubate for 24 hours, and the medium was recovered. The recovered medium was centrifuged at 12,000 rpm for 10 minutes to remove impurities and assayed using a type 1 procollagen Enzyme immunoassay kit (DAKARA, Japan). As a result, as shown in Figure 10 was confirmed the recovery efficiency of type 1 procol lagen production concentration-dependently in the compound 1. Experimental Example 5: Confirmation of the three-dimensional artificial skin damage recovery of the compound 1
상기 화합물 1의 표피층 손상 회복 효과를 in vivo 모델에서 평가하기 위해 삼차원 인공피부조직을 이용하여 확인하였다.  The epidermal damage repair effect of the compound 1 was confirmed using a three-dimensional artificial skin tissue in order to evaluate in vivo model.
E idermal t i ssue (Skin Ethics , Nikoderm Research Inc . , 프랑스)를 growth medi a에 24시간 동안 안정화한 후 배지에 상기 화합물 1을 첨가하였다. UVB 40mJ을 4시간 마다 3회 조사한 후 72시간 동안 배양 후 표피 조직을 채취하여 H&E 염색을실시하였다.  Compound 1 was added to the medium after E idermal t ssue (Skin Ethics, Nikoderm Research Inc., France) was stabilized in growth medium for 24 hours. UVB 40mJ was irradiated three times every four hours, and then cultured for 72 hours, and epidermal tissues were collected and subjected to H & E staining.
그 결과， 도 10 및 12와 같이 UVB를 조사한 표피 조직을 UVB를 조사하지 않은 조직과 비교하여 표피 두께의 감소가 두드러짐을 확인하였고, 상기 화합물 1은 이러한표피 두께의 감소를유의하게 회복시키는 것으로나타났다. 제형예 1 : 토너제의 제조  As a result, as shown in Figures 10 and 12, it was confirmed that the reduction in epidermal thickness was noticeable compared to the tissues irradiated with UVB compared with the tissues not irradiated with UVB, and the compound 1 was found to significantly recover the decrease of the epidermal thickness. . Formulation Example 1 Preparation of Toner
상기 화합물 1을 함유하는 토너제를 하기의 표 4에 나타낸 조성 성분 및 조성비에 따라통상적인 방법으로 제조하였다.  The toner agent containing the compound 1 was prepared in a conventional manner according to the composition components and the composition ratios shown in Table 4 below.
【표 4】 Table 4
성 분 함량 (중량 %)  Component content (% by weight)
화합물 1 0.5  Compound 1 0.5
글리세린 3.0  Glycerin 3.0
부릴렌 글리콜 2.0  Burylene Glycol 2.0
플리옥시에칠렌 (60) 경화 피마자듀 0.5  Polyoxyethylene (60) Cured Castor Dew 0.5
풀리솔페비트 80 0.5  Pulley Sol Pebeat 80 0.5
에탄올 1 0.0  Ethanol 1 0.0
방부제 미량  Preservative traces
향료 미량  A small amount of spices
정제수 잔량 제형예 2: 로션제의 제조 Purified water level Formulation Example 2: Preparation of Lotion
상기 화합물 1을 함유하는 로션제를 하기의 표 5에 나타낸 조성 성분 및 조성비에 따라통상적인 방법으로 제조하였다.  The lotion agent containing the compound 1 was prepared by a conventional method according to the composition components and composition ratios shown in Table 5 below.
【표 5] [Table 5]
Figure imgf000016_0001
제형예 3: 크림제의 제조
Figure imgf000016_0001
Formulation Example 3: Preparation of Cream
상기 화합물 1을 함유하는 크림제를 하기의 표 6에 나타낸 조성 성분 및 조성비에 따라통상적인 방법으로 제조하였다.  The cream agent containing the compound 1 was prepared according to a conventional method according to the composition components and composition ratios shown in Table 6 below.
【표 6】 Table 6
성 분 함량 (중량 °/o)  Component Content (Weight ° / o)
화합물 1 0.5 글리세릴스테아례이트 /피이지 -100스테아레이트 2.0 풀리솔베이트 60 0.5 소르비탄 스테아레이트 0.5 피토스쿠알란 5.0 호호바 오일 3.0 카프릴릭 /카프릭트리글리세라이드 10.0 알로에 버터 3.0 밀납 1 .0 스테아릴 알코올 0.5 베헤릴 알코올 0.5 스테아린산 0.5 글리세린 7.0 부릴렌 글리콜 5.0 카르복시 비닐풀리머 0.2 아르기닌 0.3 디메치콘 0.5 방부제 미량 향료 미량 정제수 잔량 Compound 1 0.5 Glyceryl Stearate / Fiji-100 Stearate 2.0 Fully Solate 60 0.5 Sorbitan Stearate 0.5 Phytoscualan 5.0 Jojoba Oil 3.0 Caprylic / Capric Triglyceride 10.0 Aloe Butter 3.0 Beeswax 1.0 Stearyl Alcohol 0.5 Ve Heryl Alcohol 0.5 Stearic Acid 0.5 Glycerine 7.0 Burylene Glycol 5.0 Carboxy Vinyl Puller 0.2 Arginine 0.3 Dimethicone 0.5 Preservative Tracer Trace Trace Trace Purified Water

Claims

【청구의 범위】 [Range of request]
【청구항 1】 [Claim 1]
11 β -히드록시스테로이드 디하이드로게나제 타입 1의 활성을 저해하는 화합물을 유효성분으로 포함하는 피부노화 방지용 화장료 조성물.  A cosmetic composition for preventing skin aging comprising a compound that inhibits the activity of 11 β-hydroxysteroid dehydrogenase type 1 as an active ingredient.
【청구항 2】 [Claim 2]
제 1항에 있어서， 상기 화합물은 하기 화학식 1의 ι-[ι-(ι-아다만틸아세틸) 피를리딘 -3-일] -3， 5-디메틸 -1Η-피라졸 ( 1- [ l-( l-adamantyl acetyl )pyrrol idin-3- yl ]-3 , 5-dimethyl-lH-pyrazole)인 것을 특징으로 하는 피부노화 방지용 화장료 조성물:  The compound according to claim 1, wherein the compound is represented by ι- [ι- (ι-adamantylacetyl) pyridin-3-yl] -3,5-dimethyl-1Η-pyrazole (I- [l] -(l-adamantyl acetyl) pyrrol idin-3- yl] -3, 5-dimethyl-lH-pyrazole) cosmetic composition for preventing skin aging, characterized in that:
[화학식 1]  [Formula 1]
Figure imgf000018_0001
Figure imgf000018_0001
【청구항 3】 [Claim 3]
제 1항에 있어서， 상기 화합물은 조성물 총 중량 대비 0.01 내지 10 증량 % 함유하는 것을 특징으로 하는 피부노화 방지용 화장료 조성물.  The cosmetic composition for preventing skin aging according to claim 1, wherein the compound contains 0.01 to 10% by weight, based on the total weight of the composition.
【청구항 4】 [Claim 4]
제 1항에 있어서， 상기 화합물은 ΙΙβ -HSDl 활성 저해 및 MMP-1 발현 저해 효능을 갖는 것을 특징으로 하는 피부노화 방지용 화장료 조성물.  The cosmetic composition for preventing skin aging according to claim 1, wherein the compound has inhibitory effect on ΙΙβ -HSDl activity and inhibition of MMP-1 expression.
【청구항 5】 [Claim 5]
제 1항에 있어서， 상기 화합물은 콜라겐 생성 회복 및 피부 손상 회복 효능을 갖는 것을 특징으로 하는 피부노화 방지용 화장료 조성물. The cosmetic composition for preventing skin aging according to claim 1, wherein the compound has collagen production recovery and skin damage recovery efficacy.
【청구항 6] [Claim 6]
제 1항에 있어서， 상기 피부노화는 광노화인 것을 특징으로 하는 피부노화방지용 화장료 조성물.  The cosmetic composition for preventing skin aging according to claim 1, wherein the skin aging is photoaging.
[청구항 7】 [Claim 7]
제 1항에 있어서， 상기 조성물은 화장수 (스킨로션)， 스킨소프너 , 스킨토너， 아스트린젠트， 로션， 밀크로션， 모이스쳐 로션， 영양 로션， 마사지 크림， 영양 크림, 모이스쳐 크림， 핸드크림， 파운데이션， 에센스， 영양 에센스， 팩, 비누， 클렌징품， 클렌징로션， 클렌징크림， 바디로션 및 바디클렌저로 구성된 군에서 선택된 제형인 것을 특징으로 하는 피부노화 방지용 화장료 조성물.  According to claim 1, wherein the composition is a lotion (skin lotion), skin softener, skin toner, astringent, lotion, milk lotion, moisturizing lotion, nutrition lotion, massage cream, nutrition cream, moisturizer cream, hand cream, foundation, essence, Skin aging cosmetic composition, characterized in that the formulation selected from the group consisting of nutrient essence, pack, soap, cleansing products, cleansing lotion, cleansing cream, body lotion and body cleanser.
【청구항 8】 [Claim 8]
하기 화학식 1 의 1-[1-(1-아다만틸아세틸)피를리딘 -3-일] -3，5-디메틸 -1H- 피라졸 ( 1- [ 1-( 1-adamanty 1 acetyl )pyrrol i din-3-y 1 ] -3 , 5-dimethy 1-lH- pyrazole)을 유효성분으로 포함하는 피부노화 예방 또는 개선용 피부외용제 조성물:  1- [1- (1-adamantylacetyl) pyridin-3-yl] -3,5-dimethyl-1H-pyrazole (1- [1- (1-adamanty 1 acetyl) pyrrol of formula 1 i din-3-y 1] -3, 5-dimethy 1-lH-pyrazole) as an active ingredient for skin aging prevention or improvement composition:
[화학식 1]  [Formula 1]
Figure imgf000019_0001
Figure imgf000019_0001
PCT/KR2016/007288 2015-08-07 2016-07-06 Cosmetic composition or external use skin preparation composition, both containing compound inhibiting activity of 11β-hydroxysteroid dehydrogenase type 1 WO2017026660A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2015-0111383 2015-08-07
KR1020150111383A KR101759874B1 (en) 2015-08-07 2015-08-07 Skin external composition or Cosmetics composition for anti-wrinkle comprising compound of 11β-hydroxysteroid dehydrogenase type 1 inhibitor

Publications (1)

Publication Number Publication Date
WO2017026660A1 true WO2017026660A1 (en) 2017-02-16

Family

ID=57983998

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2016/007288 WO2017026660A1 (en) 2015-08-07 2016-07-06 Cosmetic composition or external use skin preparation composition, both containing compound inhibiting activity of 11β-hydroxysteroid dehydrogenase type 1

Country Status (2)

Country Link
KR (1) KR101759874B1 (en)
WO (1) WO2017026660A1 (en)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008163014A (en) * 2006-12-06 2008-07-17 Kaneka Corp 11beta-HSD1 INHIBITOR AND ITS USE
US20090023709A1 (en) * 2007-07-17 2009-01-22 Paul Gillespie Inhibitors of 11B-Hyrdoxysteroid Dehydrogenase
KR20110007258A (en) * 2006-03-22 2011-01-21 에프. 호프만-라 로슈 아게 Pyrazoles as 11-beta-hsd-1

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20110007258A (en) * 2006-03-22 2011-01-21 에프. 호프만-라 로슈 아게 Pyrazoles as 11-beta-hsd-1
JP2008163014A (en) * 2006-12-06 2008-07-17 Kaneka Corp 11beta-HSD1 INHIBITOR AND ITS USE
US20090023709A1 (en) * 2007-07-17 2009-01-22 Paul Gillespie Inhibitors of 11B-Hyrdoxysteroid Dehydrogenase

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
NAM, JIN JOO ET AL.: "Inhibitory Effect of Fractionated Trapa Japonica Extracts on UVB-induced Skin Photoaging", JOURNAL OF THE SOCIETY OF COSMETIC SCIENTISTS OF KOREA, vol. 40, no. 4, December 2014 (2014-12-01), pages 321 - 330, XP055363706 *
TIGANESCU, ANA ET AL.: "11 -Hydroxysteroid Dehydrogenase Blockade Prevents Age -induced Skin Structure and Function Defects", THE JOURNAL OF CLINICAL INVESTIGATION, vol. 123, no. 7, pages 3051 - 3060, XP055239268, DOI: doi:10.1172/JCI64162 *

Also Published As

Publication number Publication date
KR101759874B1 (en) 2017-07-21
KR20170018212A (en) 2017-02-16

Similar Documents

Publication Publication Date Title
US7642062B2 (en) Compositions and methods of their use for improving the condition and appearance of skin
TW201206494A (en) Use of Tiliacora triandra in cosmetics and compositions thereof
TW201323005A (en) Modulation of thymosin beta-4 in skin
Naika et al. Molecular docking and dynamic studies of bioactive compounds from Naravelia zeylanica (L.) DC against glycogen synthase kinase-3β protein
Loo et al. Development on potential skin anti-aging agents of Cosmos caudatus Kunth via inhibition of collagenase, MMP-1 and MMP-3 activities
JP5697879B2 (en) Heat shock protein expression inducer
JPWO2006064975A1 (en) Composition and method for promoting production and / or enhancing activity of fibulin-5
JP2000136124A (en) Skin lotion
CA2799083A1 (en) Use of tiliacora triandra in cosmetics and compositions thereof
KR20100059302A (en) Compositions for skin external application containing extracts of hisbiscior cortex
Naika et al. In silico and in vivo wound healing studies of ursolic acid isolated from Clematis gouriana against GSK-3 beta
JP5872805B2 (en) MFAP-4 production promoter
WO2018004901A1 (en) Compositions including bauhinia, methods of making and using the same in skin anti-aging and other skin applications
WO2017026660A1 (en) Cosmetic composition or external use skin preparation composition, both containing compound inhibiting activity of 11β-hydroxysteroid dehydrogenase type 1
JP5224719B2 (en) Hair papilla cell growth promoter, testosterone 5α-reductase inhibitor, androgen receptor binding inhibitor, vascular endothelial growth factor production promoter, bone morphogenetic protein-2 production promoter, insulin-like growth factor-1 production promoter, hair restorer And hair cosmetics
CN112386655A (en) Use of phalaenopsis amabilis extract for preparing composition for resisting saccharification and improving skin appearance
WO2015141926A1 (en) Composition for inhibiting or alleviating skin aging caused by stress stimulation, containing trapa japonica as active ingredient
KR102114682B1 (en) Wrinkle improvement cosmetic containing ginsenoside Rg3, Rg5 and Rk1
JP2013166732A (en) Method for producing endothelin activity inhibitor and method for producing usnea longissima extract
WO2017082534A1 (en) SKIN ANTI-AGING COSMETIC COMPOSITION OR EXTERNAL USE SKIN PREPARATION COMPOSITION, BOTH OF WHICH CONTAIN COMPOUND INHIBITING ACTIVITY OF 11β-HYDROXYSTEROID DEHYDROGENASE TYPE 1
JP6047793B2 (en) Enzyme activity inhibitor
TW202038903A (en) Use of compound essential oil composition for regulating the gene expression level of mmp, mc1r, krt, tert, terc, and/or ogg1
CN116283786B (en) Preparation method of Grifolin derivative in geotrichum Qiliensis and application of Grifolin derivative in anti-aging skin care product
JP2014059210A (en) Screening method of cytostatic agent using inhibition of coupling between nptn and s100a8 as index
CN102552237A (en) Pharmaceutical composition and health food for preventing hepatic fibrosis or liver cirrhosis

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16835301

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16835301

Country of ref document: EP

Kind code of ref document: A1