JP5886121B2 - Melanin production inhibitor - Google Patents

Description

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

  Blots and freckles are those in which the balance between production and excretion of melanin is lost and melanin is excessively accumulated in epidermal cells. These causes are various, such as inflammation, hormonal balance, genetic factors, etc., but are promoted by the influence of ultraviolet rays. A whitening agent relieves increased pigmentation. Among these, kojic acid, ascorbic acid derivatives, and the like are known as those applied to whitening cosmetics for preventing skin darkening, spots, freckles, and maintaining original white skin. However, these still have problems in terms of the degree of whitening effect and stability in the preparation, and the whitening agents proposed so far have not always been satisfactory. On the other hand, a compound having a phenolic hydroxyl group is known to inhibit the activity of tyrosinase, which is a rate-limiting enzyme for melanin production, and several compounds having this structure have been proposed as whitening agents (Patent Document 1). ~ 3). However, the tyrosinase inhibitory activity of these compounds is not sufficient, and there is a current situation that remains a problem in terms of effects.

  As a compound in which the hydrogen atom at the 3-position of the 3-hydroxybutyl group of 4- (3-hydroxybutyl) phenol is substituted with a hydrocarbon group, the following formula (2), 2-propenyl wherein the hydrocarbon group is a methyl group: Only the compound represented by the following formula (3), which is a group, is applied to pharmaceutical intermediates and resins for peptide synthesis (Patent Documents 4 and 5), and several examples of knowledge used in verification experiments on organic synthesis reactions ( There are only non-patent documents 1 to 3), the physiological activity of the present compound itself is unknown, and no application to a skin external preparation has been proposed.

JP-A-6-107539 JP 63-8314 A Japanese Patent No. 3340935 JP 2001-525399 A JP-A-3-290406

Journal of The American Chemical Society, 1958, 80 (12), pp. 3073-3076 Tetrahedron Letters, 1992, 32 (3), pp. 4639-4642 Organometallics, 1995, 14 (1), pp. 4697-4709

  The subject of this invention is providing the melanin production inhibitor which has the effect outstanding compared with the existing whitening agent, and was excellent also in safety | security.

  As a result of intensive studies to solve the above-mentioned circumstances, the present inventors have found that the compound represented by the following general formula (1) is superior to the existing whitening agent having a phenolic hydroxyl group as an active site, and suppresses melanin production. It has an effect and a whitening effect and has high safety, and has completed the present invention.

  That is, this invention provides the melanin production inhibitor which uses the compound represented by following General formula (1) as an active ingredient.

(In the formula, R represents a linear or branched hydrocarbon group having 1 to 8 carbon atoms.)

Moreover, this invention provides the skin external preparation containing the compound represented by the said General formula (1).
Moreover, this invention provides the compound represented by the said General formula (1) for melanin production suppression.
Moreover, this invention provides use of the compound represented by the said General formula (1) for melanin production suppression.
Moreover, this invention provides use of the compound represented by the said General formula (1) for melanin production inhibitor manufacture.
Moreover, this invention provides the melanin production | generation suppression method characterized by applying the compound represented by the said General formula (1) to skin.
Moreover, this invention provides the whitening agent which uses the compound represented by the said General formula (1) as an active ingredient.
Moreover, this invention provides the compound represented by the said General formula (1) for whitening.
Moreover, this invention provides use of the compound represented by the said General formula (1) for whitening.
Moreover, this invention provides use of the compound represented by the said General formula (1) for whitening agent manufacture.
Moreover, this invention provides the whitening method characterized by applying the compound represented by the said General formula (1) to skin.

  The compound (1) used in the present invention has an excellent whitening action, is useful as a melanin production inhibitor, is excellent in safety, and provides a skin external preparation having a good whitening action. Is possible.

  Hereinafter, embodiments of the present invention will be described in detail.

In the compound represented by the general formula (1) used in the present invention, R in the formula is a linear or branched hydrocarbon group having 1 to 8 carbon atoms. The hydrocarbon group may be saturated or unsaturated, and may have a substituent such as an amino group or a hydroxyl group. Specific examples of the hydrocarbon group having 1 to 8 carbon atoms include methyl group, ethyl group, vinyl group, n-propyl group, isopropyl group, 1-propenyl group, 2-propenyl group, n-butyl group and sec-butyl. Group, t-butyl group, n-pentyl group, dimethylallyl group, n-hexyl group, n-octyl group, 2-ethylhexyl group, and the like. Within these ranges, the melanin production inhibitory effect is excellent. Among these hydrocarbons, from the viewpoint of melanin production inhibitory effect and safety, a linear or branched alkyl group having 1 to 8 carbon atoms and a linear or branched alkenyl group having 2 to 8 carbon atoms are preferable, and carbon A linear or branched alkyl group having 1 to 6 carbon atoms, a linear or branched alkenyl group having 2 to 6 carbon atoms is more preferable, and a linear or branched alkyl group having 2 to 4 carbon atoms or 2 carbon atoms. -4 linear or branched alkenyl groups are more preferable, and ethyl group, n-propyl group, isopropyl group, n-butyl group, and vinyl group are more preferable.

  The method for producing the compound represented by the general formula (1) used in the present invention is a 4- (4-hydroxyphenyl) such as 4- (4-hydroxyphenyl) -2-butanone or raspberry obtained by a known synthesis method. It can be produced by a known organic synthesis reaction using as a starting material a product separated and purified from a plant extract containing 2-butanone. For example, there is a method of reacting 4- (4-hydroxyphenyl) -2-butanone with a Grignard reagent having a hydrocarbon group having a chain length corresponding to a target compound in a tetrahydrofuran solvent. It can also be obtained by treating a plant extract such as raspberry by an appropriate method and then separating and purifying the target compound.

  The compound of the formula (1) obtained by the above method has an optical isomer, but either the (+) isomer or the (−) isomer can be used alone, or a mixture thereof can be used.

  In the present invention, any one of the compounds represented by the general formula (1) may be used alone, or a mixture of two or more thereof may be used.

  The compound (1) of the present invention has an excellent melanin production inhibitory action as shown in Examples below, and is useful as a melanin production inhibitor and a whitening agent. In addition, since the cytotoxicity is also slight, it can be effectively and safely blended into various preparations as an external preparation for skin, particularly in a whitening cosmetic for the purpose of skin whitening.

  When the compound represented by the general formula (1) of the present invention is used in a skin external preparation, it is usually 0.0001 on the basis of the total amount of the skin external preparation from the viewpoint of the whitening action and safety. It can be made into content in -20 mass%, More preferably, it is 0.01-10 mass%, More preferably, it is 0.1-5 mass%.

  When the compound represented by the general formula (1) of the present invention is blended into a whitening cosmetic composition based on its melanin production inhibitory action, hydroquinone which is already known from the viewpoint of strengthening or assisting its melanin production inhibitory action, Arbutin, ellagic acid, vitamin C or derivatives thereof (for example, ascorbic acid glucoside, ascorbic acid sodium phosphate, ascorbic acid sulfate disodium, ascorbic acid phosphate magnesium, ascorbic acid isopalmitate, ascorbic acid ethyl ester, etc. ), Biphenyl derivatives (for example, dehydrodichloroeo, 2,2′-dihydroxy-5,5′-dipropylbiphenyl, etc.), 4- (4-hydroxyphenyl-)-2-butanone described in Japanese Patent No. 3340935 Or a derivative thereof, 4- ( -Hydroxyphenyl) -2-butanol or a melanin production inhibitor such as derivatives thereof, fire spine extract, geoscorea compositor extract, elderberry extract, rock cabbage extract, chamomile extract, adenosine 5'-1-phosphate or a salt thereof , Linoleic acid derivatives, vitamin B3 or a derivative thereof, tranexamic acid, tranexamic acid salt, tranexamic acid derivatives, and other whitening agents can be used in appropriate combination.

  In addition to the above, the external preparation for skin of the present invention includes moisturizers such as hyaluronic acid, polyhydric alcohols, sugar alcohols, tar pigments, colored pigments such as iron oxide, preservatives such as parabens, fatty acid soap, alkyl sulfate Non-ionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene polyhydric alcohol fatty acid ester, polyoxyethylene hydrogenated castor oil, polyhydric alcohol fatty acid ester, polyglycerin fatty acid ester Ionic surfactant, cationic surfactant such as tetraalkylammonium salt, betaine type, sulfobetaine type, sulfoamino acid type, amphoteric surfactant such as sodium N-stearoyl-L-glutamate, lecithin, lyso Gelati, a natural surfactant such as phosphatidylcholine Natural polymers such as casein, starch, gum arabic, karaya gum, guar gum, locust bean gum, tragacanth gum, quince seed, pectin, carrageenan, sodium alginate, etc. Synthetic polymers, polyvinyl alcohol, polyvinyl methyl ether, copolymers thereof, polyvinyl pyrrolidone, sodium polyacrylate, carboxyvinyl polymer, polyethylene oxide polymer and other synthetic polymers, xanthene gum and other thickeners, titanium oxide and other pigments, dibutyl An antioxidant such as hydroxytoluene can be appropriately blended within a range not impairing the object of the present invention.

  The dosage form of the external preparation for skin of the present invention is not particularly limited as long as the compound of the present invention can be stably blended. Examples of the dosage form include granules and powders using a suitable sentence. The emulsified product may be any of water-in-oil type, oil-in-water type, and multi-emulsion. It can also be used as a bath agent.

Specific examples of the present invention and preferred embodiments of the present invention are shown below.
<1> A melanin production inhibitor containing a compound represented by the following general formula (1) as an active ingredient.

(In the formula, R represents a linear or branched hydrocarbon group having 1 to 8 carbon atoms.)
<2> A compound represented by the above general formula (1) for suppressing melanin production.
<3> Use of the compound represented by the above general formula (1) for suppressing melanin production.
<4> Use of the compound represented by the general formula (1) for the production of a melanin production inhibitor.
<5> A method for inhibiting melanin production, comprising applying the compound represented by the general formula (1) to the skin.
<6> A whitening agent comprising the compound represented by the general formula (1) as an active ingredient.
<7> A compound represented by the above general formula (1) for whitening.
<8> Use of the compound represented by the general formula (1) for whitening.
<9> Use of a compound represented by the above general formula (1) for producing a whitening agent.
<10> A whitening method comprising applying the compound represented by the general formula (1) to the skin.
<11> A skin external preparation containing the compound represented by the general formula (1).
<12> R in the general formula (1) is a linear or branched alkyl group having 1 to 8 carbon atoms, or a linear or branched alkenyl group having 2 to 8 carbon atoms, preferably 1 to 1 carbon atoms. 6 linear or branched alkyl groups, or linear or branched alkenyl groups having 2 to 6 carbon atoms, more preferably linear or branched alkyl groups having 2 to 4 carbon atoms, or 2 to 2 carbon atoms. The melanin production | generation in any one of <1>-<11> which is 4 linear or branched alkenyl groups, More preferably, they are an ethyl group, n-propyl group, isopropyl group, n-butyl group, or a vinyl group. Inhibitors, compounds, uses, methods, etc.
<13> The content of the compound represented by the general formula (1) is 0.0001 to 20% by mass, preferably 0.01 to 10% by mass, more preferably 0.8%, based on the total amount of the external preparation for skin. The skin external preparation as described in <11> or <12> which is 1-5 mass%.
The skin external preparation in any one of <11>-<13> which is <14> whitening cosmetics.
<15> In addition, hydroquinone, arbutin, ellagic acid, vitamin C or a derivative thereof (for example, ascorbic acid glucoside, ascorbic acid sodium phosphate ester, ascorbic acid sulfate disodium salt, ascorbic acid phosphate magnesium, ascorbic acid isopalmitic acid Esters, ascorbic acid ethyl ester, etc.), biphenyl derivatives (for example, dehydrodicreole, 2,2′-dihydroxy-5,5′-dipropylbiphenyl, etc.), 4- (4-hydroxy described in Japanese Patent No. 3340935 Phenyl-)-2-butanone or a derivative thereof, melanin production inhibitor such as 4- (4-hydroxyphenyl) -2-butanol or a derivative thereof, fire spine extract, geoscorea compositor extract, elderberry extract, rock cabbage extract, Mosquito <11> to <14> containing a whitening agent such as mitre extract, adenosine 5′-1-phosphate or a salt thereof, linoleic acid derivative, vitamin B3 or a derivative thereof, tranexamic acid, tranexamic acid salt, tranexamic acid derivative The external preparation for skin according to any one of the above.

Hereinafter, although this invention is demonstrated in detail based on a manufacture example, a test example, and an Example, this invention is not limited to these. The following 4- (4-hydroxyphenyl) -2-butanone, each Grignard reagent, reaction solvent, and the like were used as general reagents. NMR was measured with JEOL JNM-LA400 manufactured by JEOL Ltd. using CD ₃ OD or CDCl ₃ as a measurement solvent. MS was measured using a GC system equipped with 5975C MSD manufactured by Agilent Technologies.

Production Example: Synthesis of various compounds represented by the general formula (1) The compound of the general formula (1) was synthesized based on the conditions of a general Grignard reaction. That is, 4- (4-hydroxyphenyl) -2-butanone and a hydrocarbon magnesium halide having an appropriate chain length corresponding to the target compound were reacted in a nitrogen atmosphere while cooling with ice, and further at room temperature. Stir for 12-24 hours. The obtained crude product was treated with an aqueous ammonium chloride solution and the like, then extracted with ethyl acetate or diethyl ether, and the concentrate was purified by silica gel column chromatography.

4- (3-hydroxy-3-methylbutyl) phenol: colorless needle crystal
¹³ C-NMR (100 MHz, CD ₃ OD) δ (ppm): 156.2, 134.9, 130.1, 116.1, 71.3, 47.3, 30.9, 29.2
MS (m / z): 180 (M ⁺ )

4- (3-hydroxy-3-methylpentyl) phenol: white amorphous
¹³ C-NMR (100 MHz, CDCl ₃ ) δ (ppm): 153.9, 134.6, 129.4, 115.4, 73.4, 43.3, 33.4, 29.5, 26.4 8.3
MS (m / z): 194 (M ⁺ )

4- (3-hydroxy-3-methylheptyl) phenol: white amorphous
¹³ C-NMR (100 MHz, CDCl ₃ ) δ (ppm): 153.6, 134.7, 129.4, 115.2, 72.8, 43.9, 41.8, 29.4, 26.9 , 26.2, 23.3, 14.1
MS (m / z): 222 (M ^<+> )

4- (3-hydroxy-3,4,4-trimethylpentyl) phenol: white amorphous
¹³ C-NMR (100 MHz, CD ₃ OD) δ (ppm): 156.2, 135.5, 130.2, 116.1, 77.1, 40.1, 39.1, 30.6, 25. 9,20.7
MS (m / z): 222 (M ^<+> )

4- (3-hydroxy-3-methylnonyl) phenol: white amorphous
¹³ C-NMR (100 MHz, CDCl ₃ ) δ (ppm): 153.7, 134.6, 129.3, 115.3, 73.0, 43.8, 42.0, 31.8, 29.9 , 29.4, 26.9, 23.9, 22.6, 14.1
MS (m / z): 250 (M ⁺ )

4- (3-hydroxy-3-methylundecyl) phenol: white amorphous
¹³ C-NMR (100 MHz, CDCl ₃ ) δ (ppm): 153.7, 134.5, 129.3, 115.3, 73.1, 43.8, 42.0, 31.9, 30.2 , 29.6, 29.4, 29.3, 26.9, 24.0, 22.7, 14.1.
MS (m / z): 278 (M ⁺ )

4- (3-hydroxy-3-methyl-4-pentenyl) phenol: white amorphous
¹³ C-NMR (100 MHz, CDCl ₃ ) δ (ppm): 153.7, 144.6, 134.1, 129.3, 115.3, 112.2, 73.7, 44.1, 29.4 , 27.8
MS (m / z): 192 (M ⁺ )

Test Example 1: Inhibition test of melanin production using B16 melanoma cells 4- (3-hydroxy-3-methylpentyl) phenol, 4- (3-hydroxy-3-methylheptyl) phenol obtained in the above production example, 4 The following tests were performed on-(3-hydroxy-3-methylnonyl) phenol and 4- (3-hydroxy-3-methylundecyl) phenol. For comparison, 4- (3-hydroxybutyl) phenol, which is a phenolic compound with a known whitening effect, was used.

(Test method)
B16 melanoma cells were seeded in a 12-well culture plate at a concentration of 1 × 10 ⁴ cells / well in a 10 vol% fetal bovine serum-containing MEM medium, and precultured for 24 hours in a conventional manner. After the preculture, the medium was replaced with a test medium to which each evaluation sample was added at various concentrations, and cultured for 72 hours. As the test medium, a medium obtained by adding theophylline to the above-mentioned pre-culture medium so as to be 2 mmol / L was used. After the culture, the cells were collected and dissolved in a 1 mol / L sodium hydroxide aqueous solution containing 10 vol% dimethyl sulfoxide, and the OD475 value of the dissolved solution was measured as an index of the melanin amount. At the same time, the total protein amount of the lysate was quantified using Coomasie Plus Protein Assay Kit (manufactured by PIERCE), and the melanin amount per protein amount was calculated.

(IC ₅₀ )
Based on the calculated amount of melanin per protein amount, the melanin production inhibition rate was determined for each of various addition concentrations by the following formula.
Melanin production inhibition rate (%) = (A−B) / A × 100
(A: melanin amount per protein amount when no sample is added, B: melanin amount per protein amount when the sample is added)
Next, a graph was prepared by plotting the sample addition concentration on the horizontal axis and the melanin production inhibition rate on the vertical axis, and the concentration (IC ₅₀ ) at which each evaluation sample inhibited melanin production by 50% was determined from this graph.

  The results are shown in Table 1.

  From the results in Table 1, it was shown that each compound of the present invention has an excellent melanin production inhibitory effect. Moreover, it was confirmed that 4- (3-hydroxy-3-methylpentyl) phenol and 4- (3-hydroxy-3-methylheptyl) phenol have low cytotoxicity and are particularly excellent in terms of safety. .

Test Example 2: Melanin production inhibition test using a three-dimensional cultured skin model 4- (3-hydroxy-3-methylpentyl) phenol and 4- (3-hydroxy-3-methylpentenyl) phenol obtained in the above production example The following melanin production inhibition test was conducted. For comparison, 4- (3-hydroxybutyl) phenol, which is a phenolic compound with a known whitening effect, was used.

(Test method)
Test substance solution 0... In a skin model cup of a melanocyte-containing cultured skin model (MEL-300, Asian Doner, Kurashiki Boseki Co., Ltd.). After 2 mL was added and the skin model was cultured for 13 days using the LLMM medium attached to the product, the skin model was washed and measured by fluorescence using an AlamarBlue (Molecular Probe) reagent (Excitation: 560 nm, Emission: 590 nm). After measuring the survival rate, the amount of melanin synthesis in each skin model was measured. The amount of melanin synthesis is a solution obtained by immersing each skin model in PBS, separating the cell layer, washing with PBS and aqueous ethanol, adding 0.2 mL of 2 mol / L NaOH aqueous solution and extracting melanin under conditions of 100 ° C. for 3 hours. Was determined by colorimetric measurement (405 nm).

  The results are shown in Table 2.

  From the results in Table 2, it was shown that the compound of the present invention has a good whitening effect as compared with known phenolic compounds. At the above test concentrations, no significant cytotoxicity was detected for any compound.

Test Example 3: Whitening Practical Test A skin lotion (Example 1) having the composition shown in Table 3 below and blended with 4- (3-hydroxy-3-methylpentyl) phenol obtained in the above production example was prepared according to a conventional method. A whitening practical test was conducted by the following method. As a comparative control, a skin lotion (Comparative Example 1) having the composition shown in Table 3 below and blended with arbutin, which has a known whitening effect, was used.

(Test method)
The left and right forearm flexor skins of 20 subjects were irradiated with ultraviolet rays for 3 hours (1.5 hours per day for 2 consecutive days). After the irradiation, the skin lotion of the example was applied to the subject's left forearm flexion side skin once a day in the morning and evening for 13 consecutive weeks. Moreover, the skin lotion of the comparative example was apply | coated to the right forearm bending side skin on the same conditions. At the end of the final application, the degree of whitening before and after continuous use of the left and right forearm skin was evaluated by a specialist judge. In addition, the evaluation result was shown by the number of the subjects whose whitening effect was confirmed as “having whitening effect”.

  The results are shown in Table 4 below. This result shows that the skin lotion containing 4- (3-methoxypentyl) phenol of the present invention is very excellent as a whitening cosmetic compared with the skin lotion containing arbutin of Comparative Example 1. It was. During the test period, no skin irritation reaction or skin sensitization reaction was observed at the site where the skin lotion of Example 1 was applied, and the product of the present invention may be safe in the form of a solution formulation. confirmed.

Test Example 4: Whitening Practical Test A skin cream (Example 2) having the composition shown in Table 5 below formulated with 4- (3-hydroxy-3-methylpentenyl) phenol obtained in the above Production Example was prepared according to the following production method. Then, a whitening practical test was conducted by the above method. In addition, the skin cream (comparative example 2) of the composition shown in following Table 5 which mix | blended 4- (3-hydroxybutyl) phenol with known whitening effect | action was used as a comparison control.

(Production method)
What mixed the A component of Table 5 was heated and melt | dissolved, the temperature was set to 80 degreeC, and after inject | pouring and emulsifying B component to this, it cooled to 30 degreeC, stirring.

  The results are shown in Table 6 below. From this result, the skin cream containing 4- (3-methoxypentenyl) phenol of the present invention was compared with the skin cream containing 4- (3-hydroxybutyl) phenol of Comparative Example 2 as a whitening cosmetic. It was shown to be very good. During the test period, no skin irritation reaction and skin sensitization reaction were observed at the site where the skin cream of Example 2 was applied, and it was confirmed that the product of the present invention is safe even in the form of an emulsified preparation. It was done.

  The compound of the present invention has an excellent melanin production inhibitory effect and safety, and can be applied to a wide range of dosage forms such as lotions, emulsions, creams, packs, bath preparations and the like. In addition, since it has an excellent whitening effect, it is very useful in terms of skin cosmetics.

Claims (2)

The melanin production inhibitor which uses the compound represented by following General formula (1) as an active ingredient.

(In the formula, R represents a linear or branched hydrocarbon group having 1 to 8 carbon atoms.) The melanin production inhibitor according to claim 1, wherein R in the general formula (1) is a linear or branched alkyl or alkenyl group having 2 to 4 carbon atoms.