Melanogenesis inhibitor

Abstract

Provided are: a novel compound having low cytotoxicity and a strong melanogenesis-inhibiting activity; and a topical preparation for skin, which contains this melanogenesis inhibitor.　This melanogenesis inhibitor contains (4aR,8aS)-4a-methyl-8-methylene-octahydronaphthalen-2(1H)-one as an active ingredient.

Description

Melanin production inhibitor

[0001] The present invention relates to a melanin production inhibitor and an external skin preparation containing the same.

[0002] Age spots and freckles are caused by an imbalance between melanin production and excretion, resulting in excessive accumulation of melanin in epidermal cells. These are caused by a variety of factors, including inflammation, hormonal imbalance, and genetic factors, but are exacerbated by the effects of ultraviolet rays. Whitening agents inhibit melanin production and alleviate increased pigmentation. Among these, bitter melon extract (Patent Document 1), kojic acid (Patent Document 2), ascorbic acid derivatives (Patent Document 3), and the like are known to be used in whitening cosmetics to prevent skin darkening, age spots, and freckles and maintain the skin's natural whiteness. However, these agents have issues with the level of whitening effect and stability in formulations, and the whitening agents proposed to date have not necessarily been satisfactory.

[0003] The compound represented by the following formula (1), (4aR,8aS)-4a-methyl-8-methyleneoctahydronaphthalen-2(1H)-one, is a bicyclic sesquiterpene compound, and is only described in Non-Patent Document 1 as an intermediate product in a synthetic reaction, and no proposal is made regarding the physiological activity of this compound itself or its application to topical skin preparations.

[0004] Japanese Patent Publication No. 2007-530606 Japanese Patent Application Laid-open No. 1983-143313 Publication No. 182412-1999

[0005] Agric. Biol. Chem., 52(8), 2043-2048, 1988Tetrahedron: Asymmetry, (1993), 4(6), 1295-1306J. Org. Chem., (1991), 56(26), 7232-7236Helv. Chim. Acta, (1972), 55(7), 2371-2382J. Org. Chem., (1978), 43(4), 755-757J. Org. Chem., (1980), 45(25), 5079-5081Tetrahedron Lett., (1965), 35, 3107-3114J. Org. Chem., (1966), 31(9), 2933-2941

[0006] There is a continuing search for new natural or synthetic compounds that have potent melanin production inhibitory activity without cytotoxicity. An object of the present invention is to provide a melanin production inhibitor that has superior efficacy and safety compared to existing skin whitening agents.

[0007] The present inventors have conducted extensive research to solve the above-mentioned problems, and as a result have found that a compound represented by the following formula (1) has superior melanin production inhibitory effects and whitening effects to existing whitening agents such as kojic acid and ascorbic acid derivatives, and is also highly safe, thereby completing the present invention.

[0008]

[0009] Furthermore, we synthesized various compounds similar to this bicyclic compound structure and confirmed that the following four compounds have the effect of inhibiting melanin production.

[0010]

[0011]

[0012]

[0013]

[0014] That is, the present invention provides a compound represented by formula (1) [(4aR,8aS)-4a-methyl-8-methyleneoctahydronaphthalen-2(1H)-one] (hereinafter, sometimes referred to as "compound (1)"), a compound represented by formula (2) [(4aR,8aR)-4a-methyloctahydronaphthalene-1,7-dione] (hereinafter, sometimes referred to as "compound (2)"), and a compound represented by formula (3) [(4aR,8aS)-4a,8-dimethyloctahydronaphthalen-2(1H)-one]. (hereinafter, may be referred to as "compound (3)"), a compound represented by formula (4) [(4aR)-4a,8-dimethyl-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one] (hereinafter, may be referred to as "compound (4)"), or a compound represented by formula (5) [(4aR,8aS)-4a-methyl-8-methylenedecahydronaphthalen-2-ol] (hereinafter, may be referred to as "compound (5)") as an active ingredient.

[0015] Furthermore, compounds (1) to (5) themselves have a fragrance and are excellent in harmonization with other fragrance raw materials. Harmonization refers to the process of incorporating any of compounds (1) to (5) as one of the constituent elements of a fragrance composition to transform the fragrance of the composition into a more pleasant fragrance or to impart desirable properties (such as a luxurious feel or a natural feel) without changing the original fragrance characteristics or intensity.

[0016] That is, the present invention includes the following configurations. [1] A melanin production inhibitor comprising one or more compounds represented by compounds (1) to (5) as an active ingredient. [2] A skin whitening agent comprising one or more compounds represented by compounds (1) to (5) as an active ingredient. [3] A topical skin preparation comprising one or more compounds represented by compounds (1) to (5) as an active ingredient. [4] A fragrance composition for topical skin preparation comprising one or more compounds represented by compounds (1) to (5) as an active ingredient. [5] A skin whitening method comprising the step of administering to an individual a cosmetic composition comprising one or more compounds represented by compounds (1) to (5) as an active ingredient. [6] A fragrance composition containing a compound represented by compounds (1) to (5). [7] An oral composition containing the fragrance composition of the above [6]. [8] A cosmetic product (excluding topical skin preparations) containing the fragrance composition of the above [6].

[0017] The compounds (1) to (5) used in the present invention have an excellent whitening effect, are useful as melanin production inhibitors, and are also excellent in safety, making it possible to provide an external skin preparation having a good whitening effect.

[0018] 1 is a graph showing the melanin production inhibitory effect of using compound (1) and the cell viability rate of using compound (1).

[0019] Regarding the mass units for the melanin production inhibitor of the present invention, % means % by mass, and ppm means ppm by mass, unless otherwise specified.

[0020] The compounds (1) to (5) of the present invention can be produced by known methods described in the above-mentioned Patent Documents 2 to 8, etc.

[0021] The compounds (1) to (5) obtained by the above-mentioned methods and the like have isomers, and in the present invention, any one of them may be used alone, or two or more of them may be used as a mixture.

[0022] As shown in the Examples below, the compounds (1) to (5) of the present invention have excellent melanin production inhibitory activity and are useful as melanin production inhibitors and skin whitening agents. Furthermore, because they are non-cytotoxic, they can be effectively and safely incorporated into various skin topical preparations, particularly skin whitening cosmetics.

[0023] Furthermore, since compound (1) itself has an indole-like animalic and floral scent, compound (1) is also suitable as a fragrance material.

[0024] Compound (1) has the effect of enhancing the natural feel of a fragrance when used in combination with the fragrance. Therefore, simply adding compound (1) to cosmetics or topical skin preparations as a melanin production inhibitor can dramatically improve the commercial value of cosmetics and the like.

[0025] Therefore, by adding compound (1) to a fragrance composition having a flavor and aroma reminiscent of a specific natural material, the flavor and aroma of the component in the fragrance composition having the flavor and aroma reminiscent of the natural material can be enhanced, and the scent of the flavor and aroma component can be improved to a complex, rich scent unique to natural materials that differs from synthetic fragrances (imparting a natural feel). Therefore, compound (1) can also be suitably used as a fragrance material itself. Hereinafter, unless otherwise specified, the effect of enhancing the natural feel of a fragrance and the effect of imparting a natural feel to a fragrance will be collectively referred to as the "natural feel enhancing effect."

[0026] Furthermore, compounds (2) to (5) themselves have a fragrance and can bring about harmonization in fragrance compositions. The natural feeling enhancing effect is also one example of harmonization.

[0027] Inhibition of melanogenesis can occur through inhibition of melanin-producing enzymes, suppression of melanin-producing enzyme production, enhanced enzyme degradation, inhibition of structural scaffolding involved in melanogenesis or melanosome biosynthesis, or inhibition of melanogenesis itself through inhibition of melanosome transport. Compounds covered by the present application exert their melanin production inhibitory effect through one or more of these mechanisms.

[0028] The compounds (1) to (5) of the present invention may be administered orally, by injection, inhalant, transdermal, topical, or other means depending on the condition of the individual, but are preferably used as external skin preparations. Depending on the route of administration, they may be formulated into an appropriate dosage unit containing pharmaceutically acceptable carriers, additives, and vehicles.

[0029] In the present invention, the term "individual" refers to a subject that produces melanin, and more specifically, may be a mammal such as a human or non-human primate, mouse, rat, dog, cat, horse, or cow, but is not limited thereto.

[0030] In the present invention, "administration" means providing a predetermined compound (1) to (5) of the present invention to an individual by any suitable method.

[0031] Examples of topical skin preparations (including cosmetics, pharmaceuticals, and quasi-drugs) in the present invention include emulsions, soaps, facial cleansers, bath additives, creams, emulsions, lotions, colognes, shaving creams, shaving lotions, cosmetic oils, sunscreen lotions, face powders, foundations, perfumes, packs, nail creams, enamel, enamel removers, eyebrow pencils, blushers, eye creams, eye shadows, mascara, eyeliners, lipsticks, lip balms, shampoos, conditioners, hair dyes, dispersions, cleansers, and the like, but are not limited to these.

[0032] When compounds (1) to (5) are used in topical skin preparations, the content of compounds (1) to (5) in the topical skin preparation is not particularly limited as long as the desired effect of each embodiment is achieved, but the total amount of compounds (1) to (5) is usually 0.00001 to 15% by mass, preferably 0.0001 to 10% by mass, and more preferably 0.0003 to 5% by mass.

[0033] When the compounds (1) to (5) are used as a fragrance composition for a topical skin preparation, the content of the compounds (1) to (5) relative to the topical skin preparation is not particularly limited as long as the desired effect of each embodiment is achieved, but the total amount of the compounds (1) to (5) is usually 0.00001 to 15% by mass, preferably 0.0001 to 10% by mass, and more preferably 0.0003 to 5% by mass.

[0034] The topical skin preparation of the present invention can suppress melanin production and therefore can prevent or improve skin blemishes, freckles, dullness, melasma, senile pigmentation, darkening due to physical irritation, etc., and is therefore suitable for use as a topical composition for whitening.

[0035] The contents of compounds (1) to (5) in the fragrance composition according to the present invention are not particularly limited. From the viewpoint of obtaining a sufficient fragrance-imparting effect, the contents of compounds (1) to (5) in the fragrance composition according to the present invention are preferably 0.000001 (0.01 ppm) to 40 mass%, more preferably 0.00001 (0.1 ppm) to 10.0 mass%, and even more preferably 0.0001 (1 ppm) to 2.0 mass%, relative to the total amount (mass) of the fragrance composition. If the content of compounds (1) to (5) in the fragrance composition is less than 0.01 ppm, a sufficient effect may not be obtained, whereas if it exceeds 40 mass%, the flavor of compounds (1) to (5) themselves may be perceived as unpleasant.

[0036] The flavor of an oral composition can be enhanced by adding the flavor composition of the present invention to the oral composition. Compounds (1) to (5) or the flavor composition of the present invention can be added to the oral composition in the same manner as other food flavors.

[0037] Oral compositions to which the compounds (1) to (5) or the flavor composition according to the present invention are applied are products to be taken orally or used in the oral cavity, and include foods and beverages, quasi-drugs, pharmaceuticals, oral hygiene agents, etc. Specifically, examples of foods and beverages include: (a) beverages such as tea beverages (e.g., green tea, black tea, oolong tea), fruit beverages, fruit-flavored beverages (including non-fruit juice beverages), vegetable beverages, sports drinks, energy drinks, dairy beverages, carbonated beverages, coffee, cocoa, and alcoholic beverages; (b) frozen desserts (e.g., ice cream, sorbet, and popsicles); (c) fermented dairy products (e.g., yogurt, cheese, and the like); (d) luxury items (e.g., Japanese and Western confectioneries, baked goods, jams, chewing gum, bread, and cigarettes); (e) desserts (e.g., puddings, jellies, bavarois, and mousses); (f) soups (e.g., Japanese-style soups, Western-style soups, and instant food soups and stocks); (g) flavor seasonings (e.g., dressings, sauces, dipping sauces, mayonnaise, furikake, ochazuke (rice toppings), pickles, rice ball mixes, and sushi mixes); and (h) ready-to-eat foods (e.g., various instant foods, snack foods, and frozen prepared foods). Examples of pharmaceuticals include mouthwashes, etc. Examples of oral hygiene agents include toothpaste, mouthwashes, mouth fresheners, and breath fresheners.

[0038] The amount of the compounds (1) to (5) or the flavor composition according to the present invention added to the oral composition is not particularly limited, and can be appropriately adjusted so that the oral composition has a desired natural feel. In general, the compounds (1) to (5) are added so that the content (mass) of each compound relative to the total amount (mass) of the oral composition is in the range of 0.001 ppb to 2% by mass, and more preferably in the range of 0.1 ppb to 200 ppm.

[0039] By incorporating the flavor composition of the present invention into an oral composition, the flavor of the oral composition can be enhanced. In other words, by applying the flavor composition of the present invention or the compounds (1) to (5) to a cosmetic product, the commercial value of the cosmetic product can be further increased.

[0040] The compounds (1) to (5) or the fragrance composition according to the present invention can be widely used in general cosmetics. For example, examples of cosmetics to which the compounds (1) to (5) or the fragrance composition according to the present invention can be applied include (a) health and hygiene materials such as tissue paper, toilet paper, and sanitary products, and (b) fragrance and deodorizing products such as room air fresheners, car air fresheners, fabric mists, and deodorizers.

[0041] The amount of compounds (1) to (5) or the fragrance composition of the present invention added to a cosmetic product is not particularly limited, and can be appropriately adjusted so that the natural feel of the cosmetic product has the desired strength. Generally, the content (mass) of compounds (1) to (5) relative to the total amount (mass) of the cosmetic product is usually 0.0001 ppb to 15% by mass, preferably 0.001 ppb to 10% by mass, and more preferably 0.1 ppb to 5% by mass.

[0042] Example 1 (Method of Synthesizing Compound 1) Compound (1) [(4aR,8aS)-4a-methyl-8-methyleneoctahydronaphthalen-2(1H)-one] was synthesized according to the method described in Non-Patent Document 1.

[0043] <Data for Compound (1)> 13C NMR (100 MHz, CDCl3, δ ppm) 15.4, 23.0, 35.6, 35.9, 37.9, 40.3, 40.6, 40.9, 49.1, 106.5, 148.7, 212.2 1H NMR (400 MHz, CDCl3, δ ppm) 0.92 (s, 3H), 1.29 (ddd, 1H), 1.53-1.69 (m, 4H), 1.77 (ddd, 1H), 1.91-2.1 (m, 1H), 2.11-2.17 (m, 1H), 2.25-2.37 (m, 4H), 2.39-2.52 (m, 1H), 4.40 (m, 1H), 4.80 (m, 1H) Boiling point: 80℃ / 79Pa

[0044] [Example 2] (Method for synthesizing compound 2) Compound (2) [(4aR,8aR)-4a-methyloctahydronaphthalene-1,7-dione] was obtained by obtaining a mixture with (4aR,8aS)-4a-methyloctahydronaphthalene-1,7-dione according to the method described in Non-Patent Document 2, and then separating the mixture according to the method described in Non-Patent Document 3. The 1H NMR spectrum showed good agreement with the values ​​described in Non-Patent Document 3.

[0045] [Example 3] (Method for synthesizing compound 3) Compound (3) [(4aR,8aS)-4a,8-dimethyloctahydronaphthalen-2(1H)-one] was synthesized according to the method described in Non-Patent Document 4. The 13C NMR spectrum showed good agreement with the values ​​described in Non-Patent Document 5.

[0046] [Example 4] (Method for synthesizing compound 4) Compound (4) [(4aR)-4a,8-dimethyl-4,4a,5,6,7,8-hexahydronaphthalen-2(3H)-one] was obtained from compound (1) by applying the double bond isomerization conditions (5% sulfuric acid in acetic acid) described in Non-Patent Document 6. The 1H NMR and 13C NMR spectra showed good agreement with the values ​​described in Non-Patent Documents 4 and 5.

[0047] [Example 5] (Method for synthesizing compound 5) Compound (5) [(4aR,8aS)-4a-methyl-8-methylenedecahydronaphthalen-2-ol] was obtained by reducing compound (1) according to the method described in Non-Patent Document 7. The 1H NMR spectrum showed good agreement with the values ​​described in Non-Patent Document 8.

[0048] Example 6 (Melanin production inhibition test using a three-dimensional cultured skin model) Compound (1) obtained in the above Production Example was subjected to the following melanin production inhibition test. As comparative controls, kojic acid (manufactured by Nacalai Tesque) and an ascorbic acid derivative (L-ascorbic acid 2-glucoside, manufactured by Chem-Impex Int'l. Inc.), which are known to have whitening effects, were used.

[0049] (Test Method) <Cell Culture> A three-dimensional cultured skin model (MEL-300, Black Doner, manufactured by Kurabo Industries, Ltd.) was used. The culture cup was immersed in 5 ml of long-term maintenance medium (EPI-100LLBB) and cultured at 37°C in the presence of 5% carbon dioxide for 24 hours. Next, 50 μL of various concentrations of Compound 1 solution diluted in liquid paraffin, kojic acid diluted in water, and ascorbic acid derivative (L-ascorbic acid 2-glucoside) solution (these are referred to as samples) were added to the culture cup, and the cells were cultured at 37°C in the presence of 5% carbon dioxide for 26 days. The culture cup was washed with PBS every 2 to 3 days, and the sample and medium were replaced.

[0050] After the culture was completed, the cell survival rate and melanin production were measured as follows.

[0051] <Measurement of cell viability> After completion of the culture, the skin models were washed with PBS and immersed in 400 μL of a 10% AlamarBlue (Molecular Probes) solution diluted with EPI-100LLBB. After 2 hours of culture at 37°C in the presence of 5% carbon dioxide, 200 μL of each supernatant was transferred to a 96-well plate, and cell viability was measured by fluorescence measurement (Excitation: 544 nm, Emission: 590 nm) using a microplate reader. Cell viability was measured from the fluorescence intensity ratio between liquid paraffin (a control) and various concentrations of Compound 1.

[0052] <Measurement of melanin production amount> After measuring cell viability, the melanin production amount in each skin model was measured. After washing the skin model with PBS, 300 μL of 1% sodium bicarbonate aqueous solution was added, and 30 minutes later, the 1% sodium bicarbonate aqueous solution was removed. The cells were detached from the culture cup and transferred to a 1.5 mL tube. 500 μL of Solvable (PerkinElmer) was added and heated at 95°C overnight. 300 μL of each supernatant was transferred to a 96-well plate, and the melanin production amount was determined by colorimetric measurement (490 nm) using a microplate reader.

[0053] The amount of melanin production measured using this method with the addition of various concentrations of compound (1) is shown in Figure 1. The control is the result when compound (1) was not added. Table 1 also shows the results of calculating the IC50 value for melanin production inhibition. Furthermore, the production inhibitory strength is shown when the IC50 value of compound (1) is set to 1. The IC50 value refers to the concentration that inhibits melanin production by 50%, and is a value that indicates the effectiveness of the melanin production inhibitory effect of each test substance. Therefore, a lower IC50 value means that the test substance exerts the effect of inhibiting melanin production at a lower concentration than other test substances, that is, the inhibitory effect is stronger.

[0054]

[0055] From the results in Table 1, it was confirmed that compound (1) of the present invention has a strong melanin production inhibitory effect, and that the melanin production inhibitory effect is 100 times stronger than that of ascorbic acid derivatives and about 2 times stronger than that of kojic acid, which are known to have the melanin production inhibitory effect, compared to kojic acid and ascorbic acid derivatives.

[0056] The cell viability was measured by varying the concentration of compound (1) used, and the results are shown in Figure 2. As shown in Figure 2, even when compound (1) was added at a concentration of 4000 ppm, which suppresses melanin production to less than 20%, there was no effect on cell viability. Therefore, it was confirmed that compound (1) has no or extremely low cytotoxicity.

[0057] Example 7 (Test for inhibiting melanin production by bicyclic compounds) Compounds (1) to (5) were tested for inhibiting melanin production by the following method.

[0058] (Test Method) <Cell Culture> A three-dimensional cultured skin model (MEL-300, Black Doner, manufactured by Kurabo Industries, Ltd.) was used. The culture cup was immersed in 5 ml of long-term maintenance medium (EPI-100LLBB) and cultured at 37°C in the presence of 5% carbon dioxide for 24 hours. Next, 50 μL of a solution of compounds (1) to (5) previously diluted to 0.4% with liquid paraffin (referred to as "sample") was added to each culture cup, and the culture was continued at 37°C in the presence of 5% carbon dioxide for 26 days. The culture cup was washed with PBS every 2 to 3 days, and the sample and medium were replaced.

[0059] After the culture was completed, the amount of melanin produced was measured by the method described in Example 6. The amount of melanin produced is shown in the table below, assuming that the amount of melanin produced in the culture cup to which only the liquid paraffin solution was added is 100.

[0060]

[0061] The results in Table 2 confirm that compounds (1) to (5) of the present invention have a strong melanin production inhibitory effect. Furthermore, since γ-selinene (CAS No. 515-17-3), which has a bicyclic compound structure shown below, does not have a melanin production effect, it was also confirmed that not all compounds having a bicyclic compound structure have a melanin production effect.

[0062] (γ-selinene)

[0063] Formulation examples of the topical skin preparation of the present invention are given below. Formulation Example 1: Lotion

[0064] <Formulation Example 2> Cosmetic cream

[0065] <Formulation Example 3> Emulsion

[0066] The lotions, cosmetic creams, and emulsions containing compounds (1) to (5) of Formulation Examples 1 to 3 were all normal in appearance, properties, and feel when used. In Formulation Examples 1 to 3, a rose-type fragrance was used as the fragrance, and it was confirmed that Formulation Examples 1 to 3 enhanced the natural feel of the rose fragrance (having a natural feel enhancing effect).

[0067] The odor of the synthesized compound (1) was smelled by five well-trained panelists, who commented on the characteristics of the odor. As a result, it was confirmed that the characteristic odor of compound (1) was an indole-like, animalic, floral odor, and that compound (1) is suitable as a fragrance material.

[0068] The scent of the synthesized compound (2) was smelled by five well-trained panelists, who commented on the characteristics of the scent. As a result, the scent of compound (2) was characterized by a faint but distinct camphor-like scent, confirming that compound (2) is suitable as a fragrance material.

[0069] The aroma of the synthesized compound (3) was smelled by five well-trained panelists, who commented on the characteristics of the aroma. As a result, the aroma of compound (3) was characterized by a strong camphor-like, strong, gorgeous, and minty aroma, confirming that compound (3) is suitable as a fragrance material.

[0070] The scent of the synthesized compound (4) was smelled by five well-trained panelists, who commented on the characteristics of the scent. As a result, the scent of compound (4) was characterized by a sweet camphor-like, leathery scent, and it was confirmed that compound (4) is suitable as a fragrance material.

[0071] The aroma of the synthesized compound (5) was smelled by five well-trained panelists, who commented on the characteristics of the aroma. As a result, the aroma of compound (5) was characterized by a camphor-like aroma with a herbal atmosphere, and it was confirmed that compound (5) is suitable as a fragrance material.

[0072] Example 8 Coffee Beverage Commercially available coffee beans (with an L value of 20, indicating the degree of roasting) were ground, and the ground coffee beans were dripped with 10 times the amount of hot water to obtain a coffee extract. The resulting coffee extract was diluted with water to a solids content of 1.2%, and sodium bicarbonate was added to adjust the pH to 6.3. The mixture was filled into a container and retort-sterilized at 121°C for 10 minutes to produce a black coffee beverage. Coffee flavors were prepared according to the formulations in Table 6. 0.01 g of each of compounds (1) to (5) was blended with this coffee flavor, and 0.1% of each coffee flavor was added to the black coffee beverage. The black coffee beverage exhibited an improved authentic coffee flavor, with a deep aroma, a fuller, more authentic coffee flavor, and a lingering aftertaste.

[0073]

[0074] A rose-type fragrance was prepared according to the formulation in Table 7, and a spray-type fragrance was prepared by mixing methylparaben, polyoxyethylene (POE) hydrogenated castor oil, ethanol, and water in that order. The spray-type fragrance maintained its rose-type fragrance even several hours after spraying, and the luxurious scent spread, leaving a lingering aftertaste.

[0075]

[0076] The compounds represented by the following formulas (1) to (5) have excellent melanin production inhibitory effects and are safe, and can be applied to a wide range of formulations, for example, topical skin preparations such as lotions, emulsions, and creams. In addition, they have excellent whitening effects, making them very useful in terms of skin beauty.

Claims

1. A melanin production inhibitor comprising one or more compounds represented by the following formulas (1) to (5) as an active ingredient:

2. A skin whitening agent comprising, as an active ingredient, one or more of the compounds represented by the following formulas (1) to (5):

3. A skin preparation for external use, comprising as an active ingredient one or more of the compounds represented by the following formulas (1) to (5):

4. A fragrance composition for external use on the skin, comprising as an active ingredient one or more of the compounds represented by the following formulas (1) to (5):

5. A method for whitening the skin, comprising the step of administering to an individual a cosmetic composition containing, as an active ingredient, one or more compounds represented by the following formulas (1) to (5):

6. A fragrance composition containing one or more compounds represented by the following formulas (1) to (5):

7. An oral composition containing the flavor composition according to claim 6.

8. A cosmetic product (excluding external skin preparations) containing the fragrance composition according to claim 6.

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