WO2010030000A1 - Skin-whitening agent and external skin preparation for whitening of skin - Google Patents

Abstract

Disclosed are a skin-whitening agent and an external skin preparation for whitening the skin, each of which comprises at least one member selected from a terpene glycoside, a sucrose fatty acid ester and an iridoid glycoside as a skin-whitening active ingredient for inhibiting the production of melanin.  The skin-whitening agent and the external skin preparation can exhibit an excellent skin-whitening effect and are highly safe.

Description

Whitening agent and skin external preparation for whitening

The present invention relates to a whitening agent and a whitening skin external preparation for acting on tyrosinase that produces melanin that causes spots, freckles, and sunburn to suppress the production of melanin. *

In whitening agents conventionally used as whitening cosmetics, β-arbutin, kojic acid, vitamin C derivatives, lucinol, tranexamic acid and the like are frequently used as whitening active ingredients. These whitening active ingredients are known to exert a whitening effect by acting directly or indirectly on an enzyme called tyrosinase, which is important for the production of melanin, and suppressing the production of melanin in the skin.

Recently, whitening agents containing various whitening active ingredients have been developed for the purpose of further improving the whitening effect. For example, the following Patent Documents 1 and 2 describe that α-arbutin composed of hydroquinone-α-D-glucopyranoside has an excellent skin beautifying effect.
In addition, the following Patent Document 3 describes the separation / separation from leaves and fruits, rhizomes, bark, etc. of Gentianaceae plants, Vibrioaceae plants, Rubiaceae plants, Euphorbiaceae plants, Ominaeaceae plants, Honeysuckle family plants, Oleaceae plants Extracted cornuside, loganin, sweroside and moloniside pentaacetate are described as having excellent whitening effects.

JP 2001-316268 A JP 2001-342110 A JP 2006-327988 A

However, whitening active ingredients such as β-arbutin, kojic acid, and vitamin C derivatives that are currently approved as whitening cosmetic ingredients have been confirmed to be safe to some extent, but the whitening effect is not so high.
Therefore, the present invention has been made to eliminate such inconveniences, and its object is to provide a novel whitening agent and a skin whitening external preparation for whitening that have both excellent whitening effect and high safety. Objective.

In order to solve the above problems, the first invention
A whitening agent comprising one or more of terpene glycosides, sugar fatty acid esters and iridoid glycosides as a whitening active ingredient for inhibiting melanin production.
In addition, the second invention,
1st invention WHEREIN: The said terpene glycoside, sugar fatty-acid ester, and iridoid glycoside are whitening agents characterized by being an extract of noni fruit.

In addition, the third invention,
In the first or second invention, the terpene glycoside is (1) a 3-methyl-3-butenyl primeveroside of (1) a hemiterpene glycoside, or (2) A whitening agent characterized by being one or more compounds of 3-methyl-3-butenyl geniobioside of hemiterpene glycoside.

In addition, the fourth invention is
In the first or second invention, the sugar fatty acid ester is (3) 2-O- (β-D glucopyranosyl) -1-O-hexanoyl-β-D-glucopyranose (2-O- (β-D -Glucopyranosyl) -1-O-hexanoyl-β-D-glucopyranose) or (4) 6-O- (β-D-glucopyranosyl) -1-O-hexanoyl-β-D-glucopyranose (6-O -(Β-D-glucopyranosyl) -1-O-hexanoyl-β-D-glucopyrose) or (5) 2,6-di-O- (β-D-glucopyranosyl) -1-O-hexanoyl β- D-glucopyranose (2,6-di-O- (β-D-glucopyranosyl) -1-O-hexanoyl-β-D- lucopyranose), or (6) 6-O- (β-D-glucopyranosyl) -1-O-octanoyl-β-D-glucopyranose (6-O- (β-D-glucopyranosyl) -1-O-octanoyl -Β-D-glucopyranose) or (7) 2,6-di-O- (β-D-glucopyranosyl) -1-O-octanoyl-β-D-glucopyranose (2,6di-O- (β -D-glucopyranosyl) -1-O-octanoyl-β-D-glucopyranose), or a whitening agent.

In addition, the fifth invention,
In the first or second invention, the iridoid glycoside is (8) 9-epi-6-methoxygeniposidic acid of an iridoid type monoterpene glycoside, or (9) Asperuloside acid (Asperulosic acid) or (10) Deacetylyl asperulosic acid of iridoid type monoterpene glycoside (Deacetyl asperulosic acid) or (11) Scand of iridoid type monoterpene glycoside It is a whitening agent characterized by being one or more compounds of sidomethyl ester (Scandoside methyl ester).

In addition, the sixth invention,
It is a skin whitening external preparation characterized by containing any one or more of terpene glycosides, sugar fatty acid esters and iridoid glycosides as a whitening active ingredient for suppressing melanin production in the skin.
In addition, the seventh invention,
In a sixth aspect of the invention, the terpene glycoside, sugar fatty acid ester and iridoid glycoside are a noni fruit extract, which is a skin whitening external preparation.

Since the whitening agent of the present invention contains any one or more of terpene glycoside, sugar fatty acid ester and iridoid glycoside as a whitening active ingredient, as demonstrated in the examples below, Excellent whitening effect compared to whitening agents that use whitening active ingredients such as β-arbutin that has been approved.
In addition, as for safety, it can exhibit excellent safety equivalent to or better than that of active whitening ingredients such as β-arbutin currently approved as a whitening agent.

Moreover, since the skin external preparation for whitening of this invention contains any one or more among terpene glycoside, sugar fatty acid ester, and iridoid glycoside as a whitening active ingredient for skin melanin production suppression. If this skin whitening preparation for skin whitening is applied to the skin, it can act on tyrosinase that produces melanin that causes spots, freckles, and sunburn, thereby effectively suppressing the production of melanin in the skin.

FIG. 2 is a process diagram (first stage) showing the fractionation of noni fruit extract and the isolation process of each compound (1) to (11) according to the present invention. FIG. 2 is a process chart (second stage) showing the fractionation of noni fruit extract and the isolation process of each compound (1) to (11) according to the present invention. FIG. 6 is a graph showing measurement results of melanin production inhibition rates of each compound (1) to (11) and a reference compound (arbutin). FIG. 6 is a graph showing the measurement results of cell viability of each compound (1) to (11) and a reference compound (arbutin).

Hereinafter, embodiments of the present invention will be described with reference to the accompanying drawings.
The whitening agent and the whitening skin external preparation according to the present invention contain any one or more of terpene glycosides, sugar fatty acid esters and iridoid glycosides as whitening active ingredients for inhibiting melanin production.
That is, these terpene glycosides, sugar fatty acid esters, and iridoid glycosides may be contained singly or in full, or in appropriate combinations.

Here, as the terpene glycoside that can be used in the present invention, a 3-methyl-3-butenylprimeveroside (3-Methyl-3) of a hemiterpene glycoside having a chemical structure represented by the following chemical formula 1 in particular is used. -Butenyl primeveroside) (1) (hereinafter, this compound is referred to as compound (1) as appropriate), or hemiterpene glycoside 3-methyl-3-butenyl gentithiobioside (3- Any one or more of the two types of compounds (1) and (2) such as methyl-3-butenediol (2) (hereinafter, this compound is referred to as compound (2) as appropriate) is suitable.
Among these, the compound (1) is a novel compound discovered from the noni fruit extract by the present inventor as shown in the following examples. The two types of compounds (1) and (2) can be used alone or in combination.

As the sugar fatty acid ester, 2-O- (β-D-glucopyranosyl) -1-O-hexanoyl-β-D-glucopyranose (2-O- (β -D-glucopyranyl) -1-O-hexanoyl-β-D-glucopyrose) (3) (hereinafter, this compound is referred to as compound (3) as appropriate), or 6-O having the chemical structure represented by the following chemical formula 4 -(Β-D-glucopyranosyl) -1-O-hexanoyl-β-D-glucopyranose (6-O- (β-D-glucopyranosyl) -1-O-hexanoyl-β-D-glucopyranose) (4) ( Hereinafter, this compound is referred to as compound (4) as appropriate, or 2,6-d having a chemical structure represented by the following chemical formula 5 i-O- (β-D-glucopyranosyl) -1-O-hexanoyl-β-D-glucopyranose (2,6-di-O- (β-D-glucopyranosyl) -1-O-hexanoyl-β-D -Glucopyrose) (5) (hereinafter this compound is referred to as compound (5) as appropriate), or 6-O- (β-D-glucopyranosyl) -1-O-octanoyl- having the chemical structure shown by the following chemical formula 6 β-D-glucopyranose (6-O- (β-D-glucopyranosyl) -1-O-octanoyl-β-D-glucopyranose) (6) (hereinafter, this compound is referred to as compound (6) as appropriate), or 2,6-di-O- (β-D-glucopyranosyl) -1-O-octanoyl-β- having the chemical structure represented by the following chemical formula 7 -Glucopyranose (2,6-di-O- (β-D-glucopyranosyl) -1-O-octanoyl-β-D-glucopyranose) (7) (hereinafter this compound is referred to as compound (7) as appropriate) Any one or more of the types of compounds (3) to (7) are suitable. These five kinds of compounds (3) to (7) may be contained singly or in all, or may be contained in appropriate combination.

In addition, as the iridoid glycoside, 9-epi-6-methoxygeniposidic acid (8-epi-6-methoxygeniposidic acid) (8) is an iridoid monoterpene glycoside having a chemical structure represented by the following chemical formula 8. (Hereinafter, this compound is appropriately referred to as compound (8)), or asperuloside acid (9) (hereinafter, this compound is appropriately referred to as compound (9)) having the chemical structure represented by chemical formula 9 below, Alternatively, an iridoid-type monoterpene glycoside deacetylasperuloside acid having a chemical structure represented by the following chemical formula 10 (Deacetyl asperulosic acid) (10) (hereinafter, this compound is appropriately referred to as compound (10)), or The chemical structure represented by the following chemical formula 11 Four types of compounds (8) to (11), such as scandoside methyl ester (11) (hereinafter, this compound is referred to as compound (11) as appropriate) of iridoid-type monoterpene glycoside having Any one or more compounds are suitable. These four types of compounds (8) to (11) may be contained alone or in whole, or may be contained in appropriate combination.

The whitening agent and the whitening skin external preparation of the present invention contain any one or more of these terpene glycosides, sugar fatty acid esters and iridoid glycosides as whitening active ingredients. As demonstrated in the examples, the whitening effect superior to the whitening agent using the whitening active ingredient such as β-arbutin currently approved can be exhibited.
In addition, as for safety, it can exhibit excellent safety equivalent to or better than that of active whitening ingredients such as β-arbutin currently approved as a whitening agent.

Moreover, since the skin external preparation for whitening of this invention contains any one or more among terpene glycoside, sugar fatty acid ester, and iridoid glycoside as a whitening active ingredient for skin melanin production suppression. If this skin whitening preparation for skin whitening is applied to the skin, it can act on tyrosinase that produces melanin that causes spots, freckles, and sunburn, thereby effectively suppressing the production of melanin in the skin.

The terpene glycoside, sugar fatty acid ester and iridoid glycoside compounds (1) to (11) according to the present invention can also be produced by a known chemical synthesis method. Extraction and separation and purification from natural products containing (1) to (11), particularly noni (Morinda citrifolia) fruit, can be efficiently obtained.

The extraction / separation / purification method of the compounds (1) to (11) from the noni fruit is not particularly limited, and the compounds obtained by known natural product component extraction / separation / purification methods and various chromatographies are used. The extraction / separation / purification method can be used. For example, noni fruits are heated and refluxed with an organic solvent such as methanol to obtain an extract. The extract is distributed with chloroform water or the like, and the water-soluble fraction is extracted with ethyl acetate or the like. The ethyl acetate fraction is fractionated and isolated into each compound by known chromatography and the like. The water fraction after extraction with ethyl acetate is further extracted with butanol to obtain a butanol fraction and a water fraction, and the butanol fraction is further fractionated by various known chromatographic methods, etc. Can be done.

When adjusting the whitening agent using any one or more of the terpene glycoside, sugar fatty acid ester and iridoid glycoside, which are the whitening active ingredients of the present invention, the powdery or fine crystalline In addition to being able to use the compound as a whitening agent as it is, it can also be dissolved or dispersed in water, an organic solvent or a mixture thereof and adjusted to a liquid or pellet form and used as an antioxidant. Furthermore, it can be mixed with an excipient, a thickener, a gelling agent, etc., and adjusted to a granular, gel, or viscous liquid and used as a whitening agent.
The dosage form of the whitening agent of the present invention is arbitrary, ampoules, capsules, powders, granules, pills, tablets, solids, liquids, gels, bubbles, emulsions, creams, ointments , Sheet-like, mousse-like, powder-dispersed, multilayer, aerosol-like pharmaceuticals, quasi-drugs, and cosmetics.

Furthermore, in the case of a skin whitening external preparation using any one or more of terpene glycosides, sugar fatty acid esters and iridoid glycosides, which are whitening active ingredients of the present invention, lotion, emulsion, cream, Basic cosmetics such as ointments, lotions, oils and packs, soaps, cleansing creams, cleansing lotions, skin cleansers such as face wash, shampoos, rinses, treatments, etc., hair creams, hair sprays, hair tonics , Hair gel, hair lotion, hair oil, hair essence, hair water, hair wax, hair foam and other hair styling, hair growth, hair nourishing, 1 part hair dye, 2 part hair dye, hair color etc. Permanent preparations such as permanent wave agents and hair straighteners, hair cosmetics such as wave retention agents, foundations, white powder Makeup cosmetics such as funny, lipstick, blusher, eye shadow, eyeliner, mascara, eyebrows, eyelashes, etc., cosmetics for finishing such as beauty nails, oral compositions such as perfumes, toothpastes, gargles, etc. Cosmetic compositions, topical pharmaceutical preparations, ointments, haptics, bath preparations, medicated toothpastes, medicinal oral compositions such as mouth fresheners, medicinal cosmetics, permanent wave solvents, hair dyes, hair restorers, hair removal inhibitors, removal It can be used in the form of a hair solvent liquid odor / deodorant such as hair agent, quasi-drugs such as sanitary goods, sanitary cotton, wet tissue, and external medicines.

The blending amount of the terpene glycoside, sugar fatty acid ester and iridoid glycoside, which are the whitening active ingredients of the present invention, is slightly different depending on the type and quality of the whitening agent and the skin external preparation for whitening, and the expected degree of action. Therefore, although it is not particularly limited, it is generally used in a concentration range of 0.0001% by mass or more in the total amount of the preparation, preferably 0.01 to 20.0% by mass is effective.

In addition to any one or more of terpene glycosides, sugar fatty acid esters, and iridoid glycosides, which are essential components, the whitening agent and the skin external preparation for whitening of the present invention further suppress pigmentation exemplified below. Agent, tyrosinase activity inhibitor, melanocyte melanin production inhibitor, melanin production promoter, moisturizer, cell activator / metabolic activator, antioxidant, active oxygen scavenger / radical production inhibitor, fat metabolism promoter, ultraviolet light Protective agent / UV absorption enhancer, astringent, anti-inflammatory agent / interleukin production inhibitor / anti-inflammatory agent, antiseborrheic agent, antibacterial agent / antiviral agent, blood flow promoter / vascular stimulator, antiandrogen agent, structure Proteolytic enzymes (elastase, collagenase, keratin protease, serine protease, integrin degrading enzyme, involucrin degrading enzyme, filaggrin content Enzyme, laminin degrading enzyme, fibronectin degrading enzyme, proteoglycan degrading enzyme, etc.) activity inhibitor, structural protein synthesis promoter, mucopolysaccharide (hyaluronic acid, chondroitin sulfate, etc.) degrading enzyme inhibitor, mucopolysaccharide synthesis promoter, intercellular Lipid production promoter / intercellular lipid condition improving agent, keratolytic agent / stratum exfoliation promoter, plasminogen activator antagonist inhibitor, Maillard reaction inhibitor, testosterone 5α reductase activity inhibitor / hair papilla activator / onset Forms active ingredients such as hair promoters, hair matrix cell growth inhibitors / hair growth inhibitors, hair swelling agents / hair protectants, odorant elimination agents, and other cosmetic and food composition forms Ingredients such as extracts and metabolites derived from plant-based materials, animal-based materials, microbial-based materials, and other natural product materials, or various compounds preferred for use above By arbitrarily selecting and using as an additive, various functions can be exhibited.

In addition, hormones, sequestering agents, pH adjusters, chelating agents, antiseptic / antibacterial agents, refreshing agents, stabilizers, emulsifiers, animal / plant proteins and their degradation products, animal / plant polysaccharides and their Degradation products, animal / plant glycoproteins and their degradation products, anti-inflammatory agents, antiallergic agents, wound treatment agents, foaming agents, thickeners, enzymes, purified water (electronic water, small clusters, etc.), deodorant / A deodorant etc. can be used in combination.

Next, a method for isolating each compound of terpene glycoside, sugar fatty acid ester and iridoid glycoside used as a whitening active ingredient in the whitening agent and skin external preparation for whitening according to the present invention, identification method and structure determination method of the compound And an evaluation of the melanin production inhibitory effect and cytotoxicity of each compound.
As a reference compound, β-arbutin, which is a known whitening active ingredient having a chemical structure represented by the following chemical formula 12, was similarly evaluated for melanin production inhibitory effect and cytotoxicity under the same conditions.

(Method for isolating compounds)
First, as shown in FIG. 1, 1.31 kg of dried noni (Morinda citrifolia) fruit was repeatedly heated and refluxed with methanol (MeOH) three times to obtain 228.2 g of an extract.
The extract was then partitioned between chloroform (CHCl ₃ ) -water (H ₂ O).
Thereafter, the water-soluble fraction (H ₂ O fraction) was extracted with ethyl acetate (EtOAc) to obtain an EtOAc fraction (9.6 g). The EtOAc fraction was subjected to silica gel column chromatography (SiO ₂ CC) and octadecyl silica column chromatography (ODS CC), and then again silica gel column chromatography (SiO ₂ CC). ) And reversed-phase high performance liquid chromatography (RP-HPLC) to obtain three types of compounds (9), (10) and (11) and two types of compounds (6) and (7), respectively.

On the other hand, the water fraction (H ₂ O fraction) after extraction with EtOAc was then extracted with butanol (n-BuOH) to obtain 61.0 g of n-BuOH fraction and 120.8 g of water fraction. (H ₂ O fraction) was obtained.
The n-BuOH fraction was further fractionated by Diaion HP-20 column chromatography (CC), of which 30% MeOH (8.7 g) and 50% MeOH elution fraction ( As shown in FIG. 2, 6.8 g) was further fractionated by various chromatographies as described above, and 11 kinds of compounds (1) to (11) were isolated from the noni fruit MeOH extract.

(Identification and structure determination of compounds)
Next, these 11 kinds of compounds (1) to (11) were identified by comparison with literature values of ¹ H-NMR data and MS data, and as shown below, compounds (2) to (11) were identified. (7) and (9) to (11) were all known compounds, but compounds (1) and (8) were novel compounds.
That is, by the chemical structure analysis method MS method, ¹ H-NMR method, ¹³ C-NMR method and various two-dimensional NMR methods, and by comparison of NMR (magnetic resonance) spectra with known compounds, compound (1) Was revealed to be a novel compound having the structure of 3-methyl-3-butenyl primeveroside, a hemiterpene glycoside.
On the other hand, it has been clarified that the compound (8) is a novel compound having a structure of 9-epi-6-methoxygeniposidic acid (9-epi-6-methoxygeniposidic acid), an iridoid monoterpene glycoside.

<Compound (1)>
Compound (1), which is a novel compound, is 3-methyl-3-butenyl primebioside, which is a hemiterpene glycoside having a chemical structure represented by Chemical Formula 1.
The spectrum data of this compound (1) is shown below.
¹ H-NMR (500 MHz, CD ₃ OD): δ 4.77 (2H, m, H-4), 4.33 (1H, d, J = 8.0 Hz, H-1 ″), 4.28 ( 1H, d, J = 7.4 Hz, H-1 ′), 4.10 (1H, dd, J = 2.3, 11.5 Hz, H-6′a), 4.00 (1H, dt, J = 7.3, 9.7 Hz, H-1a), 3.88 (1H, dd, J = 5.1, 11.5 Hz, H-5 ″ a), 3.76 (1H, dd, J = 5.8, 11.5 Hz, H-6′b), 3.67 (1H, dt, J = 7.2, 9.7 Hz, H-1b), 3.44 (1H, m, H-5 ′ ), 3.37 (1H, m, H-4 ′), 3.50 (1H, ddd, J = 5.3, 8.9, 10.0 Hz, H-4 ″), 3.34 (1H) , M, H-3 ″), 3.32 (1H, m, H-3 ′), 3.2 5 (1H, m, H-2 ″), 3.24 (1H, m, H-5 ″ b), 3.18 (1H, m, H-2 ′), 2.36 (2H, t , J = 7.0 Hz, H-2), 1.73 (3H, s, H-5).
¹³ C-NMR (125 MHz, CD ₃ OD): δ 143.6 (s, C-3), 112.0 (t, C-4), 105.2 (d, C-1 ″), 104.2 (D, C-1 ′), 77.7 (d, C-3 ′), 77.4 (d, C-3 ″), 76.7 (d, C-5 ′), 74.8 ( d, C-2 ′), 74.6 (d, C-2 ″), 71.2 (d, C-4 ′), 70.9 (d, C-4 ″), 69.6 ( t, C-6 '), 69.3 (t, C-1), 66.7 (t, C-5 "), 38.5 (d, C-2), 23.0 (q, C -5)
HR-ESI-MS: m / z 403.1572 [M + Na] ⁺ (calcd. ForC ₁₆ H ₂₈ O ₁₀ Na, m / z 403.1580)

<Compound (2)>
The compound (2) is a hemiterpene glycoside 3-methyl-3-butenyl gentiobioside having a chemical structure represented by the chemical formula 2 (3-Methyl-3-butenyl geniobioside).
The spectral data of this compound (2) is shown below.
¹ H-NMR (400 MHz, CD ₃ OD): δ 4.72 (2H, m, H-4), 4.37 (1H, d, J = 7.8 Hz, H-1 ″), 4.27 ( 1H, d, J = 7.8 Hz, H-1 ′), 4.14 (1H, dd, J = 1.6, 11.5 Hz, H-6′a), 3.97 (1H, dt, J = 7.3, 9.5 Hz, H-1a), 3.82 (1H, dd, J = 1.7, 11.5 Hz, H-6 ″ a), 3.78 (1H, dd, J = 5.5, 11.6 Hz, H-6′b), 3.64 (2H, m, H-1b, H-6 ″ b), 3.44 (1H, m, H-5 ′), 3 .40-3.14 (7H, m, H-2 ′, H-3 ′, H-4 ′, H-2 ″, H-3 ″, H-4 ″, H-5 ″) 2.35 (2H, t, J = 7.1 Hz, H-2), 1.75 (3H, s, H-5)
ESI-MS: m / z 433 [M + Na] ⁺ (C ₁₇ H ₃₀ O ₁₁ Na)

<Compound (3)>
Compound (3) is a sugar fatty acid ester 2-O- (β-D-glucopyranosyl) -1-O-hexanoyl-β-D-glucopyranose (2-O- (β -D-glucopyranyl) -1-O-hexanoyl-β-D-glucopyranose).
The spectral data of this compound (3) is shown below.
¹ H-NMR (600 MHz, CD ₃ OD): δ 5.61 (1H, d, J = 7.9 Hz, H-1 ′), 4.56 (1H, d, J = 7.9 Hz, H-1 ′) '), 3.83 (2H, dt, J = 2.1, 12.1 Hz, H-6'a, H-6''a), 3.68 (2H, dd, J = 4.8, 12 .1 Hz, H-6′b, H-6 ″ b), 3.63 (1H, dd, J = 8.2, 9.3 Hz, H-3 ′), 3.59 (1H, dd, J = 7.9, 9.3 Hz, H-2 ′), 3.40 (1H, m, H-5 ′), 3.38 (1H, dd, J = 7.6, 9.3 Hz, H-4) '), 3.36 (1H, dd, J = 8.6, 9.3 Hz, H-3 ″), 3.30 (1H, dd, J = 8.2, 9.3 Hz, H-4 ′) '), 3.28 (1H, m, H-5 "), 3.19 (1H, dd, J = 7.9, 9 3 Hz, H-2 ″), 42.47 (1H, dt, J = 7.6, 16.5 Hz, H-2a), 2.38 (1H, dt, J = 7.6, 16.5 Hz) , H-2b), 1.63 (2H, quint, J = 7.3 Hz, H-3), 1.34 (4H, m, H-4, H-5), 0.92 (3H, t, J = 7.0Hz, H-6)
ESI-MS: m / z 463 [M + Na] ⁺ (C ₁₈ H ₃₂ O ₁₂ Na)

<Compound (4)>
Compound (4) is a sugar fatty acid ester 6-O- (β-D-glucopyranosyl) -1-O-hexanoyl-β-D-glucopyranose (6-O- (β -D-glucopyranyl) -1-O-hexanoyl-β-D-glucopyranose).
The spectral data of this compound (4) is shown below.
¹ H-NMR (400 MHz, CD ₃ OD): δ 5.45 (1H, d, J = 8.0 Hz, H-1 ′), 4.31 (1H, d, J = 7.8 Hz, H-1 ′) '), 4.14 (1H, dd, J = 2.0, 9.2 Hz, H-6'a), 3.85 (1H, dd, J = 2.0, 10.0 Hz, H-6''a), 3.76 (1H, dd, J = 5.1, 11.5 Hz, H6′b), 3.65 (1H, dd, J = 5.0, 12.0 Hz, H-6 ″) b), 3.53 (1H, m, H-5 '), 3.45-3.26 (6H, m, H-2', H-3 ', H4', H-3 '', H- 4 ″, H−5 ″), 3.20 (1H, dd, J = 7.8, 9.0 Hz, H−2 ″), 2.34 (2H, m, H−2), 1 .63 (1H, quint, J = 7.3 Hz, H-3), 1.32 (4H, m, H-4, -5), 0.91 (3H, t, J = 7.1Hz, H-6)
ESI-MS: m / z 463 [M + Na] ⁺ (C ₁₈ H ₃₂ O ₁₂ Na)

<Compound (5)>
The compound (5) is a sugar fatty acid ester 2,6-di-O- (β-D-glucopyranosyl) -1-O-hexanoyl-β-D-glucopyranose (2, 6-di-O- (β-D-glucopyranosyl) -1-O-hexanoyl-β-D-glucopyranose).
The spectral data of this compound (5) is shown below.
¹ H-NMR (400 MHz, CD ₃ OD): δ5.59 (1H, d, J = 7.6 Hz, H-1 ′), 4.56 (1H, d, J = 7.6 Hz, H-1 ′) '), 4.32 (1H, d, J = 7.6 Hz, H-1'''), 4.15 (1H, dd, J = 1.8, 11.3 Hz, H-6'a), 3.85 (1H, m, H-6 ″ a), 3.83 (1H, m, H6 ′ ″ a), 3.76 (1H, dd, J = 4.9, 11.5 Hz, H −6′b), 3.70-3.16 (14H, m, H-2 ′, H-3 ′, H-4 ′, H-5 ′, H-2 ″, H-3 ″, H-4 ″, H-5 ″, H-6 ″ b, H-2 ′ ″, H-3 ′ ″, H-4 ′ ″, H-5 ′ ″, H-6 '''b), 2.42 (2H, m, H-2), 1.63 (2H, quint, J = 7.4 Hz, H-3), 1.34 (4H, m, H-4) , H-5), .92 (3H, t, J = 6.9Hz, H-6)
ESI-MS: m / z 625 [M + Na] ⁺ (C ₂₄ H ₄₂ O ₁₇ Na)

<Compound (6)>
The compound (6) is a sugar fatty acid ester 6-O- (β-D-glucopyranosyl) -1-O-octanoyl-β-D-glucopyranose (6-O- (β -D-glucopyranosyl) -1-O-octanoyl-β-D-glucopyranose).
The spectral data of this compound (6) is shown below.
¹ H-NMR (400 MHz, CD ₃ OD): δ 5.45 (1H, d, J = 8.0 Hz, H-1 ′), 4.31 (1H, d, J = 7.8 Hz, H-1 ′) '), 4.14 (1H, dd, J = 2.0, 11.2 Hz, H-6'a), 3.85 (1H, dd, J = 2.0, 12.0, H-6''a), 3.78 (1H, dd, J = 5.1, 11.5 Hz, H-6'b), 3.66 (1H, dd, 5.4, 12.0 Hz, H-6'' b), 3.52 (1H, m, H-5 ′), 3.44-3.24 (6H, m, H-2 ′, H-3 ′, H-4 ′, H-3 ″, H-4 ″, H-5 ″), 3.20 (1H, dd, J = 7.8, 8.8 Hz, H-2 ″), 2.40 (2H, m, H-2) , 1.64 (2H, quint, J = 7.2 Hz, H-3), 1.32 (8H, m, H-4, H- , H-6, H-7), 0.90 (3H, t, J = 6.8Hz, H-8)
APCI-MS: m / z 467 [M−H] ⁻ (C ₂₀ H ₃₅ O ₁₂ )

<Compound (7)>
Compound (7) is a sugar fatty acid ester of 2,6-di-O- (β-D-glucopyranosyl) -1-O-octanoyl-β-D-glucopyranose (2, 6-di-O- (β-D-glucopyranosyl) -1-O-octanoyl-β-D-glucopyranose).
The spectral data of this compound (7) is shown below.
¹ H-NMR (400 MHz, CD ₃ OD): δ5.59 (1H, d, J = 7.6 Hz, H-1 ′), 4.56 (1H, d, J = 7.8 Hz, H-1 ′) '), 4.31 (1H, d, J = 7.8 Hz, H-1'''), 4.14 (1H, dd, J = 1.7, 11.5 Hz, H-6'a), 3.83 (2H, m, H-6 ″ a, H-6 ′ ″ a), 3.76 (1H, dd, J = 5.0, 11.3 Hz, H-6′b), 3 69-3.16 (14H, m, H-2 ′, H-3 ′, H-4 ′, H-5 ′, H-2 ″, H-3 ″, H-4 ″, H −5 ″, H-6 ″ b, H-2 ′ ″, H-3 ′ ″, H-4 ′ ″, H-5 ′ ″, H-6 ′ ″ b), 52 .42 (2H, m, H-2), 1.63 (2H, quint, J = 7.0 Hz, H-3), 1.31 (8H, m, H-4, H-5, H-6) , H-7), 0 91 (1H, t, J = 6.8Hz, H-8)
FAB-MS: m / z 629 [MH] ⁻ (C ₂₆ H ₄₅ O ₁₇ )

<Compound (8)>
Compound (8), which is a novel compound, is 9-epi-6-methoxygeniposidic acid, an iridoid-type monoterpene glycoside having the chemical structure represented by Chemical Formula 8.
The spectral data of this compound (8) is shown below.
¹ H-NMR (600 MHz, CD ₃ OD): δ 7.38 (1H, s, H-3), 5.84 (1H, brs, H-7), 5.61 (1H, d, J = 3. 1 Hz, H-1), 4.60 (1H, d, J = 7.9 Hz, H-1 ′), 4.28 (1H, d, J = 15.3 Hz, H-10a), 4.23 ( 1H, brs, H-6), 4.19 (1H, d, J = 15.3 Hz, H-10b), 3.89 (1H, dd, J = 1.8, 11.7 Hz, H-6 ′ a), 3.66 (1H, dd, J = 5.5, 11.7 Hz, H-6′b), 3.44 (1H, s, OMe), 3.36 (1H, t, J = 9) .0Hz, H-3 '), 3.29 (1H, m, H-5'), 3.28 (1H, m, H-4 '), 3.27 (1H, m, H-9), 3.23 (1H, m, H-5), 3.2 (1H, dd, J = 7.9,8.9Hz, H-2 ')
¹³ C NMR (150 MHz, CD ₃ OD): δ 172.0 (s, COOH), 152.9 (d, C-3), 149.6 (s, C-4), 127.3 (d, C— 7), 110.8 (s, C-8), 100.0 (d, C-1 ′), 95.0 (d, C-1), 89.9 (d, C-6), 78. 2 (d, C-5 ′), 77.8 (d, C-3 ′), 74.6 (d, C-2 ′), 71.5 (d, C-4 ′), 62.7 ( t, C-6 '), 60.4 (t, C-10), 57.0 (d, OMe), 47.4 (t, C-9), 39.2 (t, C-5)
HR-ESI-MS: m / z 427.1217 [M + Na] ⁺ (calcd. ForC ₁₇ H ₂₄ O ₁₁ Na m / z 427.1216)

<Compound (9)>
Compound (9) is an iridoid-type monoterpene glycoside having a chemical structure represented by the chemical formula 9 (Asperulosic acid).
The spectral data of this compound (9) is shown below.
¹ H-NMR (400 MHz, CD ₃ OD): δ 7.65 (1H, s, H-3), 6.02 (1H, s, H-7), 5.06 (1H, d, J = 9. 0 Hz, H-1), 4.29 (1H, m, H-10a), 4.88 (1H, s, H-6), 4.83 (1H, m, H10b), 4.72 (1H, d, J = 7.8 Hz, H-1 ′), 3.86 (1H, dd, J = 1.6, 12.0 Hz, H-6′a), 3.63 (1H, dd, J = 6) 0.0, 12.0 Hz, H-6′b), 3.40-3.22 (4H, m, H-2 ′, H-3 ′, H-4 ′, H-5 ′), 3.02 (1H, t, J = 6.3 Hz, H-5), 2.63 (1H, t, J = 8.3 Hz, H-9), 2.09 (3H, s, OCOMe)
ESI-MS: m / z 455 [M + Na] ⁺ (C ₁₈ H ₂₄ O ₁₂ Na)

<Compound (10)>
Compound (10) is an iridoid-type monoterpene glycoside having a chemical structure represented by Chemical Formula 10 (deacetylasperulosic acid).
The spectral data of this compound (10) is shown below.
¹ H-NMR (600 MHz, C ₅ D ₅ N): δ 8.15 (1H, s, H-3), 6.58 (1H, s, H-7), 5.90 (1H, d, J = 8.6 Hz, H-1), 5.50 (1H, d, J = 5.9 Hz, H-6), 5.32 (1H, d, J = 7.9 Hz, H-1 ′), 5. 10 (1H, d, J = 15.8 Hz, H-10a), 4.64 (1H, d, J = 15.9 Hz, H-10b), 4.28 (1H, dd, J = 3.0, 11.8 Hz, H-6′a), 4.24-4.19 (3H, m, H-3 ′, H-4 ′, H-6b), 4.07 (1H, t, J = 8. 3Hz, H-2 ′), 3.78 (1H, m, H-5 ′), 3.48 (1H, t, J = 6.0 Hz, H-5), 2.85 (1H, t, J = 7.9Hz, H9)
ESI-MS: m / z 413 [M + Na] ⁺ (C ₁₆ H ₂₂ O ₁₁ Na)

<Compound (11)>
Compound (11) is a scandoside methyl ester of an iridoid-type monoterpene glycoside having the chemical structure represented by Chemical Formula 11.
The spectral data of this compound (11) is shown below.
¹ H-NMR (400 MHz, C ₅ D ₅ N): δ 8.05 (1H, s, H-3), 6.54 (1H, d, J = 1.9 Hz, H-7), 5.65 ( 1H, d, J = 8.8 Hz, H−1), 5.30 (1H, d, J = 7.8 Hz, H−1 ′), 5.09 (1H, d, J = 16.1 Hz, H-10a), 4.73 (1H, d, J = 6.8 Hz, H-6), 4.57 (1H, d, 16.3 Hz, H-10b), 4.32 (1H, dd, J = 2.7, 11.7 Hz, H-6'a), 4.25-4.18 (3H, m, H-3 ', H-4', H6'b), 4.06 (1H, t , J = 7.3 Hz, H-2 ′), 3.80 (1H, m, H-5 ′), 3.43 (1H, t, J = 6.5 Hz, H-5), 3.21 ( 3H, s, OMe), 2.73 (1H, t, J = 7.9H , H-9)
ESI-MS: m / z 427 [M + Na] ⁺ (C ₁₇ H ₂₄ O ₁₁ Na)

(Melanin production inhibition test)
First, as a melanin production inhibition test, B16 melanoma 4A5 cells were used, seeded with 500 μl of 1 × 10 ⁴ cells / ml on a 24 well plate, and cultured for 24 hours. After culturing, the B16 melanoma 4A5 cells are treated with α-MSH (Melanocyte-Stimulating-Hormone), 11 kinds of noni fruit-derived compounds (1) to (11) and β-arbutin (Arbutin) according to the present invention described above. Added as a sample. Thereafter, this was allowed to act for 4 days, and then the supernatant was removed by suction and dissolved in a 2M NaOH solution containing 10% DMSO (dimethyl sulfoxide: hereinafter the same).
And the light absorbency in 405 nm of the lysate was measured, and it was set as the melanin production suppression rate of each sample (suppression rate (%) in sample density | concentration of 100 micromol).

(Cytotoxicity test MTT method)
In parallel with the melanin production inhibition test described above, the same B16 melanoma 4A5 cells were used, seeded in a 24 well plate at 1 × 10 ⁴ cells / ml, and cultured for 24 hours. After the culture, 11 types of noni fruit-derived compounds (1) to (11) and β-arbutin (Arbutin) according to the present invention were added as samples to the B16 melanoma 4A5 cells.
Thereafter, this was allowed to act for 4 days as in the melanin production test, then 0.5% MTT solution was added and allowed to act for 3 hours, and i-PrOH containing 0.08M NaCl was added and dissolved.
Then, the wavelength 570 (top). Absorbance at 630 (bottom) nm was measured to calculate cell viability.

(Evaluation)
As a result of the melanin production inhibition test, as shown in FIG. 3 and Table 2 below, the melanin production inhibition rate of β-arbutin was about 30%, whereas the compounds (1) to (11) showed an excellent melanin production inhibition rate of about 65% or more. In FIG. Shows only the solvent DMSO.
On the other hand, as a result of the cytotoxicity test, as shown in FIG. 4 and the following Table 3, the compounds (1) to (11) according to the present invention all showed an excellent cell survival rate of about 70% or more. This is an excellent cell survival rate equal to or better than that of conventional β-arbutin, which has already been confirmed to be highly safe. In FIG. Shows only the solvent DMSO.

Claims (7)

1. A whitening agent comprising any one or more of terpene glycosides, sugar fatty acid esters and iridoid glycosides as a whitening active ingredient for inhibiting melanin production.
2. The whitening agent according to claim 1,
   The whitening agent, wherein the terpene glycoside, sugar fatty acid ester and iridoid glycoside are extracts of noni fruits.
3. In the whitening agent according to claim 1 or 2,
   The terpene glycoside is
   (1) 3-methyl-3-butenyl primeveroside of hemiterpene glycoside, or
   (2) A whitening agent characterized by being one or more compounds of 3-methyl-3-butenyl geniobioside of hemiterpene glycoside.
4. In the whitening agent according to claim 1 or 2,
   The sugar fatty acid ester is
   (3) 2-O- (β-D-glucopyranosyl) -1-O-hexanoyl-β-D-glucopyranose (2-O- (β-D-glucopyranosyl) -1-O-hexanoyl-β-D- glucocopyrose), or
   (4) 6-O- (β-D-glucopyranosyl) -1-O-hexanoyl-β-D-glucopyranose (6-O- (β-D-glucopyranosyl) -1-O-hexanoyl-β-D- glucocopyrose), or
   (5) 2,6-di-O- (β-D-glucopyranosyl) -1-O-hexanoyl-β-D-glucopyranose (2,6-di-O- (β-D-glucopyranosyl) -1- O-hexanoyl-β-D-glucopyranose), or
   (6) 6-O- (β-D-glucopyranosyl) -1-O-octanoyl-β-D-glucopyranose (6-O- (β-D-glucopyranosyl) -1-O-octanoyl-β-D- glucocopyrose), or
   (7) 2,6-di-O (β-D-glucopyranosyl) -1-O-octanoyl-β-D-glucopyranose (2,6-di-O- (β-D-glucopyranosyl) -1-O -Octanoyl-β-D-glucopyranose), a whitening agent characterized by being one or more compounds.
5. In the whitening agent according to claim 1 or 2,
   The iridoid glycoside is
   (8) 9-epi-6-methoxygeniposidic acid of an iridoid type monoterpene glycoside (9epi-6-methoxygeniposidic acid), or
   (9) Asperulosidic acid, or
   (10) an iridoid-type monoterpene glycoside, deacetylasperulosic acid, or
   (11) A whitening agent characterized by being one or more compounds of scandoside methyl ester of an iridoid type monoterpene glycoside.
6. A skin whitening preparation for whitening comprising one or more of terpene glycoside, sugar fatty acid ester and iridoid glycoside as an active whitening ingredient for suppressing melanin production in the skin.
7. In the skin external preparation for whitening according to claim 6,
   The whitening skin external preparation, wherein the terpene glycoside, sugar fatty acid ester and iridoid glycoside are extracts of noni fruit.

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