KR101648739B1 - Composition for skin whitening comprising (4aS,5S,6R,8aS)-5-((R)-3-((((E)-3-(3,4-dihydroxyphenyl)acryloyl)oxy)methyl)-5-hydroxypentyl)-5,6,8a-trimethyl-3,4,4a,5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid as effective component and uses thereof - Google Patents

Abstract

(4aS, 5S, 6R, 8aS) -5 - ((R) -3 - (((E) -3- Dihydroxyphenyl) acryloyloxyl) methyl) -5-hydroxypentyl) -5,6,8a-trimethyl-3,4,4a, 5,6,7,8,8a-octa Since the hydro naphthalene-1-carboxylic acid compound has little cytotoxicity, it can be effectively used as an active ingredient of cosmetic compositions for skin whitening, health food compositions and pharmaceutical compositions.

Description

(R) -3 - (((E) -3- (3,4-dihydroxyphenyl) acryloyloxyl) methyl) -5- Hydroxybutyl) -5,6,8a-trimethyl-3,4,4a, 5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid compound as an active ingredient and a composition for skin whitening (4S, 5S, 6R, 8aS) -5 - ((R) -3 - (((E) -3- (3,4- dihydroxyphenyl) acryloyl) oxy) methyl) -5 -hydroxypentyl) -5,6,8a-trimethyl-3,4,4a, 5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid as effective component and uses thereof.

More particularly, the present invention relates to a composition for skin whitening, and more particularly to a composition for skin whitening, (Dihydroxyphenyl) acryloyloxyl) methyl) -5-hydroxypentyl) -5,6,8a-trimethyl-3,4,4a, 5,6,7,8,8a-octahydronaphthalene- A cosmetic composition for skin whitening, a health food composition and a pharmaceutical composition containing 1-carboxylylic acid compound as an active ingredient.

The skin color of a person is determined by various factors such as the activity of the melanocyte which forms the melanin pigment, the distribution of blood vessels, the thickness of the skin, and the presence or absence of pigment in and out of the body such as carotenoid and bilirubin. Among them, melanin, which is formed in melanocyte, is considered to be the most important factor for skin color formation. Melanin is converted to tyrosine by tyrosinase through 3,4-dihydroxyphenylalanine, dopaquinone, leucodopachrome, dopachrome, 5,6-dihydroxyindole and indole-5,6-quinone and finally to melanin It is the end product of the oxidation process being converted. That is, tyrosine and tyrosinase act as proteins which are very important in the production of melanin.

Melanin biosynthesis is a very complex process, and the exact mechanism by which melanin synthesis is induced is not yet elucidated. Melanin provides a natural defense against harmful ultraviolet rays, but when melanin is overproduced, it induces hyperpigmentation such as spots and freckles. In addition, excessive production of melanin due to excessive UV exposure may cause skin cancer. Therefore, the necessity of development of a melanin biosynthesis inhibitor is increasing, and studies related to whitening are actively performed.

Active substances such as arbutin, deoxy arbutin, octadecendioic acid, conjugated linoleic acid, niacinamide, hydroquinone, kojic acid, glutathione, and azelaic acid are known as substances exhibiting a whitening effect by inhibiting pigmentation of skin. Such materials are known to have tyrosinase inhibitory activity and have in fact been used in whitening products. However, the above-mentioned active ingredients are limited in their use due to insufficient whitening effect, safety to skin, difficulty in formulation and stability, and the like. Accordingly, the present inventors intend to provide a cosmetic composition which has excellent whitening effect and high skin safety.

Korean Patent No. 1050484 discloses a composition for skin whitening comprising a lactone compound as an active ingredient and Korean Patent Publication No. 2001-0107962 discloses a skin whitening composition containing an ascorbic acid compound (E) -3- (3,4-dihydroxyphenyl) acryloyl) -5 - ((R) -3 - (( Oxyl) methyl) -5-hydroxypentyl) -5,6,8a-trimethyl-3,4,4a, 5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid compound as an active ingredient A composition for skin whitening that contains a surfactant has not been disclosed.

SUMMARY OF THE INVENTION The present invention has been made in view of the above-mentioned needs, and it is an object of the present invention to provide a melanocyte melanocyte which comprises (4aS, 5S, ) -3- (3,4-dihydroxyphenyl) acryloyloxyl) methyl) -5-hydroxypentyl) -5,6,8a-trimethyl-3,4,4a, The present inventors have completed the present invention by confirming that when 8,8a-octahydronaphthalene-1-carboxylic acid compound is treated, an excellent melanin production inhibitory effect is obtained and cytotoxicity does not occur even at a concentration of 5 μM or more.

In order to solve the above problems, the present invention provides a process for producing (4aS, 5S, 6R, 8aS) -5 - ((R) -3 - Oxyl) methyl) -5-hydroxypentyl) -5,6,8a-trimethyl-3,4,4a, 5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid compound A cosmetic composition for skin whitening, a health food composition and a pharmaceutical composition.

According to the present invention there is provided a process for the preparation of (4aS, 5S, 6R, 8aS) -5 - ((R) -3 - (((E) -3- (3,4- dihydroxyphenyl) acryloyl) ) -5-hydroxypentyl) -5,6,8a-trimethyl-3,4,4a, 5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid compound exhibits excellent melanin production inhibitory effect And has almost no cytotoxicity. Therefore, it can be usefully used as an effective ingredient of a composition for skin whitening.

FIG. 1 is a graph comparing the inhibitory activities of HMG-CoA reductase with 22 selected candidate substances (natural products).
C: no treatment, P: positive control (pravastatin)
FIG. 2 is a graph comparing melanin production rate (% Melanin) versus cell viability (% Viability) versus non-treatment control.
Control: non-treatment, PTU: positive control
3 is a graph showing the inhibitory activity of HMG-CoA reductase of the compound # 21.
Control: no treatment, Pravastatin: positive control (pravastatin)
4 is a graph comparing the melanin production rate (% Melanin) and the cell viability (% Viability) relative to control of # 21 compound.
Control: non-treatment, PTU: positive control

In order to achieve the object of the present invention, the present invention provides a cosmetic composition for skin whitening comprising a compound represented by the following general formula (1) as an active ingredient.

The compound represented by the above formula (1) is a compound represented by the general formula (1): (4aS, 5S, 6R, 8aS) -5 - ((R) -3 - Oxyl) -5-hydroxypentyl) -5,6,8a-trimethyl-3,4,4a, 5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid ((4aS, 5S (R) -3 - (((E) -3- (3,4-dihydroxyphenyl) acryloyl) oxy) methyl) -5-hydroxypentyl) -5,6,8a-trimethyl -3,4,4a, 5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid).

In order to exert an excellent whitening effect when a whitening component is applied to actual skin, it exhibits a highly effective skin whitening effect at a low concentration, has excellent ability to be permeated and absorbed through the skin, Is low, the active ingredient remains stable on the composition or on the skin, is easy to be formulated into medicines or cosmetics, and is safe for the skin. However, among known whitening ingredients, whitening ingredients that satisfy all of the above characteristics are not common. For example, some whitening agents have excellent whitening activity even at low concentrations in vitro, but they are difficult to apply to real skin because of their ability to permeate through the skin. Other whitening ingredients have low hydrophilicity and are difficult to formulate into cosmetics or pharmaceuticals. In addition, some whitening ingredients may be degraded or transformed into other compounds when exposed to heat, light, or oxygen, and the whitening effect may disappear prior to application to the skin. However, the compound of formula (I) of the present invention exhibits excellent melanin production inhibitory effect, and shows no cytotoxicity even at a concentration of 5 μM or more.

In the present invention, 'whitening' refers to inhibiting, inhibiting or alleviating hyperpigmentation of the skin. Hyperpigmentation of the skin includes freckles, stains, hyperpigmentation after exposure to ultraviolet light, hyperpigmentation after inflammation, aging black spots, brown spots or black spots.

In the cosmetic composition according to an embodiment of the present invention, the skin whitening cosmetic composition may contain the compound of Formula 1 in an amount of 0.0001 to 90 parts by weight based on the total weight of the composition, Including, but not limited to, an effective amount.

In the present invention, "effective amount" means the amount of a compound capable of inhibiting, inhibiting or alleviating hyperpigmentation of the skin. The effective amount of the compound contained in the composition for skin whitening of the present invention will vary depending on the form in which the composition for skin whitening is commercialized, the method in which the compound is applied to the skin, and the time on the skin. For example, when the composition for skin whitening is commercialized as a medicament for dermatological treatment due to hyperpigmentation of the skin, the composition of the present invention may contain a compound of the above formula 1 at a higher concentration than a cosmetic product that is routinely applied to skin You can do it. In the case of a wash-off type cosmetic such as a make-up remover, a detergent and the like, in which the active ingredient remains on the skin in a short period of time even when it is commercialized as a cosmetic product, it may contain a relatively high concentration of the compound. On the other hand, in the case of leave-on type cosmetics such as lotion, cream, essence and the like in which the active ingredient remains on the skin for a long period of time, the compound may be contained at a lower concentration than the wash-off type cosmetics will be.

In the cosmetic composition according to one embodiment of the present invention, the cosmetic composition for skin whitening may be at least one selected from the group consisting of ointment for external use, cream, softening agent, nutritional lotion, pack, essence, hair tonic, shampoo, rinse, hair conditioner, , Skin lotion, skin softener, skin toner, astringent, lotion, milk lotion, moisturizing lotion, nutrition lotion, massage cream, nutritional cream, moisturizing cream, hand cream, foundation, nutrition essence, sunscreen, soap, cleansing foam, cleansing lotion , A cleansing cream, a body lotion, and a body cleanser. The composition of each of these formulations may contain various kinds of bases and additives necessary for formulation of the formulation, and the kinds and amounts of these ingredients can be easily selected by those skilled in the art.

The composition of the present invention may further contain at least one skin whitening active ingredient which exhibits the same or similar function to the compound of the present invention. Skin whitening active ingredients include kojic acid and its derivatives, arbutin, ascorbic acid and its derivatives, hydroquinone and its derivatives, resorcinol, cycloalkanone, methylenedioxyphenylalkanol, 2,7-dinitroindazole or Plant extracts such as mandarin orange extract, rice extract, licorice extract, and the like, but are not limited thereto.

When the formulation of the present invention is a paste, cream or gel, animal fiber, plant fiber, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc or zinc oxide may be used as the carrier component .

When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. In the case of a spray, in particular, / Propane or dimethyl ether.

In the case of the solution or emulsion of the present invention, a solvent, a solvent or an emulsifier is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, , 3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid esters.

When the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.

When the formulation of the present invention is an interfacial active agent-containing cleansing, the carrier component is selected from aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, linolenic derivatives or ethoxylated glycerol fatty acid esters.

The formulation of the present invention may further contain an excipient including a fluorescent substance, a fungicide, a hygroscopic substance, a humidifier, a fragrance, a fragrance carrier, a protein, a solubilizing agent, a sugar derivative, a sunscreen, a vitamin, .

When the cosmetic composition for skin whitening as described above is formulated into pharmaceuticals or cosmetics, it may contain known excipients applicable to the skin acting as a carrier for the active ingredient. When formulating into pharmaceuticals, reference is made to the disclosure of [Remington ' s Pharmaceutical Science, Mack Publishing Company, Easton PA], and in formulation into cosmetics, International cosmetic ingredient dictionary, 6th ed., The cosmetic, Toiletry and Fragrance Association, Inc., Washington, 1995). Which are incorporated herein by reference.

The present invention also provides a health food composition for skin whitening comprising a compound represented by the following formula (1) as an active ingredient.

[Chemical Formula 1]

When a composition containing the compound of Formula 1 of the present invention as an active ingredient is used as a food additive, the composition may be added as it is or may be used together with other food or food ingredients, and may be suitably used according to a conventional method . The amount of the active ingredient to be mixed can be suitably determined according to its intended use (prevention, health or therapeutic treatment). Generally, the composition of the present invention is added in an amount of not more than 15 parts by weight, preferably not more than 10 parts by weight, based on the raw material, when the food or beverage is produced. However, in the case of long-term consumption intended for health and hygiene purposes or for health control purposes, the amount may be less than the above range, and since there is no problem in terms of safety, the active ingredient may be used in an amount exceeding the above range .

There is no particular limitation on the kind of the food. Examples of foods to which the above substances can be added include dairy products including meats, sausages, breads, chocolates, candies, snacks, confectionery, pizza, ramen noodles, gums, ice cream, soups, drinks, tea, Alcoholic beverages, and vitamin complexes, all of which include healthy foods in a conventional sense.

The health beverage composition of the present invention may contain various flavors or natural carbohydrates as an additional ingredient such as ordinary beverages. Such natural carbohydrates are monosaccharides such as glucose and fructose, disaccharides such as maltose and sucrose, and polysaccharides such as dextrin and cyclodextrin, and sugar alcohols such as xylitol, sorbitol and erythritol. Examples of sweeteners include natural sweeteners such as tau martin and stevia extract, synthetic sweeteners such as saccharin and aspartame, and the like.

In addition to the above, the composition of the present invention may further contain various nutrients, vitamins, electrolytes, flavors, colorants, pectic acid and salts thereof, alginic acid and its salts, organic acids, protective colloid thickeners, pH adjusters, stabilizers, preservatives, glycerin, A carbonating agent used in beverages, and the like. In addition, the composition of the present invention may contain flesh for the production of natural fruit juices, fruit juice drinks and vegetable drinks. These components may be used independently or in combination. Although the ratio of these additives is not critical, it is generally selected from the range of 0.01 to 0.1 parts by weight per 100 parts by weight of the composition of the present invention, but the present invention is not limited thereto.

The present invention also provides a pharmaceutical composition for skin whitening comprising a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[Chemical Formula 1]

In the pharmaceutical composition for skin whitening according to the present invention, the compound of Formula 1, which is an effective ingredient, may be used as it is or in the form of a pharmaceutically acceptable salt. The salt is not particularly limited as long as it is pharmaceutically acceptable so long as it is pharmaceutically acceptable and includes, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrofluoric acid, hydrobromic acid, formic acid acetic acid, tartaric acid, lactic acid, citric acid, fumaric acid, , Benzenesulfonic acid, toluenesulfonic acid, and naphthalenesulfonic acid. In addition to acid addition salts, additional base salts such as sodium hydroxide, potassium hydroxide, triethylamine, tertiary-butylamine may also be used.

In the formulation of the pharmaceutical composition according to the present invention, the content of the active ingredient may vary widely depending on the formulations, and is generally according to a conventional method.

The pharmaceutical composition according to the present invention may be formulated by adding various adjuvants such as carriers and other additives such as stabilizers, emollients, emulsifiers and the like, which are used in medicines, if necessary, so long as they do not adversely affect the active ingredients.

In addition, the composition according to the present invention can be administered parenterally or orally. As the route of parenteral administration, transdermal administration is preferable, and local application is most preferable. For example, it may be manufactured in the form of a bandage, but is not limited thereto. The formulations may be any formulations suitable for pharmaceutical preparations including ointments, creams, injections, powders, granules, tablets, and the like.

The preferred dosage of the pharmaceutical composition according to the present invention may be 0.001 to 1000 mg / Kg · day, but is not limited thereto. In addition, the composition according to the present invention may be administered alone, or may be administered together with other medicines in order to aid in the same or another medicament. In addition, in the composition of each formulation, components other than the composition, which is the above-mentioned essential ingredient, can be mixed and selected by a person skilled in the art according to the formulation or purpose of use of the other external preparation. In this case, Can happen.

Hereinafter, the present invention will be described in detail with reference to examples. However, the following examples are illustrative of the present invention, and the present invention is not limited to the following examples.

Materials and Methods

1 cells and reagents

Kit used for HMG-CoA Reductase activity inhibition assay, DMSO used for melanin quantitation test, and MTT reagent added to the cell viability assay were purchased from Sigma Aldrich (USA).

The cells used were murine melanocyte cells (Melan-a), medium containing 0.1% penicillin streptomycin and 10% FBS (fetal bovine serum) in RPMI-1640 medium (GIBCO) , And a thermostat at 37 ° C and 10% CO ₂ was used.

2. Experimental Sample

Experimental samples were dissolved in DMSO.

3. Based on protein structure-based virtual drug discovery Skin whitening  Discovery of natural materials

First, the hot spot region of HMG-CoA reductase was confirmed by literature review. Twenty-two HMG-CoA reductase X-ray crystal structures, which have been published in the Protein Data Bank to date, (homology). The amino acid residues of the protein binding sites interacting with the ligands were analyzed based on the results of the mutation experiments presented in the literature and one core amino acid was selected for hydrophobic interaction with three hydrophilic interacting core amino acids (Table 1) . Based on the interaction with key amino acids in this major binding site, two kinds of active skeletons (Pharmacophore query) were generated. These active skeletons are commonly composed of two hydrogen bonders, one hydrogen bond acceptor, and one hydrophobic segment, the difference being whether or not there is an additional hydrophobic segment.

The key amino acids of the protein binding sites that interact with the ligands Core amino acid Hydrophilic interaction Lysine 735, aspartate (Asp) 690, glutamic acid (Glu) 559 Hydrophobic interaction Leu 562

The library for virtual drug discovery is configured in the form of Accelrys Discovery Studio / CatDB. We have found multiple conformation of the three-dimensional structure of the compound and adjusted its parameters to include all chemically possible conformers. Currently, about 7.9 million natural / synthetic compound libraries have been constructed. Using the 'Search 3D Database' protocol of Discovery Studio and the two active scaffolds created previously, .

Various types of isomers possessed by each compound were mapped to the active skeleton to evaluate whether the set interaction elements and the atom or the substructure of the natural compound molecule were appropriately located. A total of 730 natural compounds were selected as virtual leader materials through a virtual search to measure fitness. Among them, the final 22 kinds of natural compounds based on the structural diversity between molecules, the calculated value of solubility in water, The compounds were selected. All of these were purchased from Analyticon Discovery as an extractable natural compound with a purity of 80% or more, and were used in biological experiments to verify the inhibition of HMG-CoA reductase activity and skin whitening effects.

4. In vitro HMG - CoA  Reductase activity inhibition test ( HMG - CoA Reductase Assay )

In this experiment, an HMG-CoA reductase assay kit from Sigma was used. The experiments were performed according to the instructions attached to the kit. First, the quantitation buffer was placed in all wells (96 wells). And the inhibitor or sample to be used as a control was put into the well. NADPH and HMG-CoA were added to all wells. The sample was stirred so that it could be mixed well. Thereafter, the absorbance was measured with a microplate reader at 37 ° C and 370 nm for 10 minutes every 20 seconds. After 10 minutes, the inhibitory activity of the enzyme relative to the control group was determined using a measured absorbance, and the activity was corrected by blank test.

Enzyme Inhibitory Activity (%) = (1-Enzyme Activity in Treatment / Non-Enzymatic Enzyme Activity) × 100

5. Test for inhibition of melanin formation in cells ( Melanogenesis inhibition assay )

This test method Melan-a (murine melanocyte) cells to 10% of FBS (fetal bovine serum) is containing the inoculated in 6 well plates in DMEM medium well 1 × 10 ⁵ pieces per then 10% CO under _2, 37 ℃ Cells were cultured until approximately 80% of the cells were attached to the well bottom. After removing the culture medium and the sample concentrations were cultured in the predetermined period of time 10% CO _2, 37 ℃ was replaced with the diluted medium to a suitable. Cells from which the medium was removed were washed with PBS (phosphatized buffer saline), and treated with trypsin to recover the cells. The recovered cells were centrifuged at 5,000 to 10,000 rpm for 10 minutes, and then the supernatant was removed to obtain pellets. To this cell pellet, 100 μl of a 1M sodium hydroxide solution containing 10% DMSO was added to obtain intracellular melanin in a thermostat at 80 ° C. The absorbance of this solution was measured at 405 nm with a microplate reader, and the amount of melanin relative to the control group was determined and corrected by blank test.

Melanin production (%) = absorbance of treatment / non-treatment absorbance × 100

6. Cell viability experiments ( MTT Assay )

After removing 10% of the medium from the wells, the MTT solution (0.5% 3- (4,5-dimethylthiazol-2-yl) -2,5 diphenyl -2H-tetrazolium bromide) was added thereto and cultured for 2 hours. After removing the culture solution, 200 μl of DMSO (dimethylsulfoxide) solution was added and shaken for 10 minutes, and the absorbance was measured at 540 nm with an ELISA reader.

Cell survival rate (%) = (absorbance of treated / uncoated absorbance) × 100

Example  1: Melanin synthesis inhibitor compound selection

The HMG-CoA reductase is a rate-limiting enzyme in the Mevalonate pathway, an important pathway for cholesterol biosynthesis. Studies on the induction of cholesterol depletion in the body when inhibiting the activity of the enzyme by binding to HMG-CoA reductase have continued, as in the case of the statin family of conventional hyperlipidemic drugs. Based on previous studies, it was hypothesized that inhibition of HMG-CoA reductase activity could reduce cholesterol synthesis and ultimately be used as a whitening agent to inhibit melanin production.

Development of in silico drug to select natural products that inhibit the activity of HMG-CoA reductase and produce whitening effect) silico drug discovery method. As a result, the final 22 natural compounds were selected (Fig. 1).

The HMG-CoA reductase quantitation kit was used to identify the 22 inhibitor candidates (natural products) selected to inhibit the binding between the HMG-CoA reductase and HMG-CoA and to inhibit the activity. And their efficacy was measured and compared. The candidate groups of 22 candidates were found to have HMG-CoA reductase activity inhibition ability. Among them, HMG-CoA reduction of 6 candidates (# 2, # 5, # 8, # 9, # 21, # 22) And showed excellent results in enzyme inhibition (Fig. 1). Based on the results of the analysis, it was concluded that the six candidate groups were inhibitors of HMG-CoA reductase activity.

FIG. 2 shows the results of experiments to inhibit the activity of HMG-CoA reductase in melanocytes to reduce melanin production and to select samples that are not toxic to cells. HMG-CoA reductase inhibitor, were tested. The candidate group was tested at a concentration of 5 μM, and # 22 was highly toxic at that concentration and was excluded from this experiment. As a result, it was shown that the inhibitors of HMG-CoA reductase were 3 kinds of # 8, # 9 and # 21, which showed melanin inhibitory activity at 5 μM. Of the three natural products, # 8 is a compound having already known whitening effect, and therefore, two natural products of # 9 and # 21 are regarded as natural whitening products.

As a result, as a new whitening target, HMG-CoA reductase was inhibited and a new natural product showing a whitening effect was obtained. (9R) -5 - [[(2R, 3S, 4R, 5R, 6S) -6- [2- (3,4-dihydroxyphenyl) -5,7-dihydroxy-4-oxo-chromen-8-yl] -3,4,5-trihydroxy-tetrahydropyran- -3-hydroxy-3-methyl-5-oxo-pentanoic acid), # 21 ((4aS, 5S, 6R, 8aS) -5 - Oxyl) methyl) -5-hydroxypentyl) -5,6,8a-trimethyl-3,4,4a, 5,6,7,8,8-tetrahydro- 8a-octahydronaphthalene-1-carboxylic acid).

Example  2: In vitro HMG - CoA  Reductase activity inhibition test

This experiment was carried out in the same manner as in Example 1 except that # 21 ((4aS, 5S, 6R, 8aS) -5 - ((R) -3 - (((E) -3- (3,4-dihydroxyphenyl) acryloyloxyl) Methyl-5-hydroxypentyl) -5,6,8a-trimethyl-3,4,4a, 5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid) HMG-CoA reductase To confirm the inhibition of the activity. Pravastatin was used as a positive control (Fig. 3).

50, and 100 μM of # 21 ((4aS, 5S, 6R, 8aS) -5 - ((R) -3 - (((E) -3- (3,4-dihydroxyphenyl) acryloyl ) Oxyl) methyl) -5-hydroxypentyl) -5,6,8a-trimethyl-3,4,4a, 5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid) About 57.9% and 64.6% of HMG-CoA reductase inhibitory activity, respectively.

Example  3: Test for inhibition of melanin formation in cells

This experiment was carried out in the same manner as in Example 1 except that # 21 ((4aS, 5S, 6R, 8aS) -5 - ((R) -3 - (((E) -3- (3,4-dihydroxyphenyl) acryloyloxyl) Methyl) -5-hydroxypentyl) -5,6,8a-trimethyl-3,4,4a, 5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid) And the degree of inhibition of the production. Melan-a (mouse melanocyte) cell lines were used and PTU was treated as a positive control.

1, 5 and 10 μM of # 21 ((4aS, 5S, 6R, 8aS) -5 - ((R) -3 - (((E) -3- (3,4-dihydroxyphenyl) acryloyl Methyl) -5-hydroxypentyl) -5,6,8a-trimethyl-3,4,4a, 5,6,7,8,8a-octahydronaphthalene-1-carboxylic acid) , Melanin production was decreased by 11.6, 40.9, and 72.6%, respectively. Cell viability was maintained at 92.3, 97.9 and 61.8%, respectively (Fig. 4).

Claims (4)

A cosmetic composition for skin whitening comprising a compound represented by the following formula (1) as an active ingredient.
[Chemical Formula 1]

The cosmetic composition according to claim 1, wherein the cosmetic composition is at least one selected from the group consisting of an ointment for external use, a cream, a softening agent, a nutritional lotion, a pack, an essence, a hair tonic, a shampoo, a rinse, a hair conditioner, a hair treatment, a gel, a skin lotion, Lotion, milk lotion, moisturizing lotion, nutrition lotion, massage cream, nutritional cream, moisturizing cream, hand cream, foundation, nutrition essence, sunscreen, soap, cleansing foam, cleansing lotion, cleansing cream, body lotion and body cleanser Wherein the cosmetic composition has a formulation selected from the group consisting of: A health food composition for skin whitening comprising a compound represented by the following formula (1) as an active ingredient.
[Chemical Formula 1]

A pharmaceutical composition for skin whitening comprising a compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[Chemical Formula 1]

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