JPH0873335A - Melanogenesis inhibitor and skin external preparation - Google Patents

Abstract

PURPOSE: To obtain a skin external preparation having adequate remedying, therapeutic effect on dyspigmentation, also practically satisfying its safety and stability, containing, as active ingredient, a specific compound containing as a partial structure reduced β-ionone ring-contg. pentane. CONSTITUTION: This melanogenesis inhibitor contains, as active ingredient, pref. 0.0001-10wt.% of a compound of formula I (R1 is H or OH; R2 is H or OH; or a total of <=2 double bonds may rest on 1-site, 2-site and/or 3-site) [esp. pref. 3-methyl-3-hydroxy-5-(2,2,6-trimethyl-1-yl-cyclohexane)-1-pentene of formula II, 3-methyl-1-hydroxy-5-(2,2,6-trimethyl-1-yl-cyclohexane)-2-pentene of formula III, 3-methyl-1-hydroxy-5-(2,2,6-triethyl-1-yl-cyclohexane)pentane of formula IV, a compound of formula V, a compound of formula VI or a compound of formula VII].

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a melanin production inhibitor and a skin external preparation, and more specifically, to a skin external preparation excellent in whitening effect, which contains a compound containing a reduced β-ionone ring-containing pentane as a partial structure as an active ingredient. To do.

[0002]

2. Description of the Related Art Pigmentation after freckles and sunburn is a marked increase in melanin production due to the activation of pigment cells in the skin, which is one of the troubles of the middle-aged and old-aged skin. There is. In general, melanin is changed from tyrosine to dopa and dopa to dopaquinone by the action of the enzyme tyrosinase biosynthesized in pigment cells, and then an intermediate such as 5,6-dihydroxyindophenol is formed. It is supposed to be formed through.

Therefore, in order to prevent or improve the color blackness, it is considered to inhibit the melanin production process or to bleach already produced melanin. Based on such an idea, various whitening components have been conventionally proposed. For example, a sulfur compound typified by glutathione is one that inhibits thyrodinase activity and suppresses melanin production. In addition, hydrogen peroxide, hydroquinone, vitamin C, etc. have been used as the ones that lightly bleach the produced melanin.

[0004]

However, these conventional whitening ingredients are extremely poor in stability in the formulation system and cause discoloration or offensive odor due to decomposition, and their effects at the cell or biological level are still insufficient. Met. Further, hydroquinone has a strong lightening effect, but has a problem in safety such as causing irreversible white spots and rashes.

As described above, the conventionally used whitening ingredients are effective, stable and safe.
Not really practically satisfying. The present invention has been made in view of such circumstances, and has a melanin production inhibitor and sufficient skin pigmentation ameliorating and / or treating effect, and the skin that can practically satisfy safety and stability. An object is to provide an external preparation.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the inventors of the present invention include a reduced β-ionone ring-containing pentane represented by the following general formula (I) as a partial structure. Compounds, especially 3-methyl-3-hydroxy-5- (2,2,6-trimethyl-1-yl-cyclohexane) -1-pentene, 3-methyl-1-hydroxy-5- (2,2,6- Trimethyl-1-yl-cyclohexane) -2-pentene, 3-methyl-1-hydroxy-5- (2,2,6-trimethyl-1-yl-
Cyclohexane) pentane, 3-methyl-3-hydroxy-5- (2,2,6-trimethyl-1-yl-cyclohexane) pentane, 3-methyl-5- (2,2,6
-Trimethyl-1-yl-cyclohexane) pentane,
It was found that 3-methyl-1-hydroxy-5- (2,2,6-trimethyl-1-yl-cyclohexane) -3-pentene and the like have a strong inhibitory effect on melanin production of living pigment cells, Further, it was found that when this was blended in a base at a certain concentration or more and used as a skin external preparation, an excellent whitening effect on the skin was exhibited, and the present invention was accomplished.

That is, the present invention provides a melanin production inhibitor comprising a compound represented by the general formula (I) of Chemical formula 2, and 0.00% of the total amount of the melanin production inhibitor as an active ingredient.
The external preparation for skin is characterized by containing 01 to 10% by weight.

[0008]

Embedded image

(In the formula, R ₁ represents hydrogen or a hydroxyl group, and R ₂
Represents hydrogen or a hydroxyl group. Further, there may be two or less double bonds in total at the 1-position, 2-position or 3-position. ) Hereinafter, the present invention will be described in detail. <1> Melanin production inhibitor The melanin production inhibitor of the present invention is a compound represented by the general formula (I).

Examples of such a compound include 3-methyl-3-hydroxy-5- (2,2,6-trimethyl-1-yl-cyclohexane) -1-pentene represented by the following structural formula: 3-methyl-1-hydroxy-5- (2,2,6-trimethyl-1-yl-
Cyclohexane) -2-pentene, 3-methyl-
1-hydroxy-5- (2,2,6-trimethyl-1
-Yl-cyclohexane) pentane, 3-methyl-3-hydroxy-5- (2,2,6-trimethyl-
1-yl-cyclohexane) pentane, 3-methyl-1-hydroxy-5- (2,2,6-trimethyl-1-yl-cyclohexane) -3-pentene of Chemical formula 7, 3-methyl-5-of chemical formula 8 (2,2,6-trimethyl-1-yl-cyclohexane) pentane and the like can be mentioned.

[0011]

[Chemical 3]

[0012]

[Chemical 4]

[0013]

[Chemical 5]

[0014]

[Chemical 6]

[0015]

[Chemical 7]

[0016]

Embedded image

The compound of the general formula (I) can be synthesized from β-ionone, for example, by the synthetic method described below. 1) 3-methyl-3-hydroxy-5- (2,2,6
Synthesis method of -trimethyl-1-yl-cyclohexane) -1-pentene (compound of Chemical formula 3): Tetrahydroionone was dissolved in THF and then reacted with a Grignard reagent at -40 ° C to synthesize a compound of Chemical formula 3.

2) 3-methyl-1-hydroxy-5-
Synthesis method of (2,2,6-trimethyl-1-yl-cyclohexane) -2-pentene (compound of Chemical formula 4): The compound of Chemical formula 3 was used at room temperature in the presence of acetic acid, acetic anhydride and paratoluenesulfonic acid for 10 minutes. After reacting for a minute, an acetate form of the compound of Chemical formula 4 is obtained. This was added with sodium methylate (CH ₃
ONa) was hydrolyzed to synthesize the compound of Chemical formula 4.

3) 3-Methyl-1-hydroxy-5-
Synthesis method of (2,2,6-trimethyl-1-yl-cyclohexane) pentane (compound of Chemical formula 5): The compound of Chemical formula 4 is reacted at room temperature in the presence of palladium carbon and hydrogen to synthesize the compound of Chemical formula 5. did.

4) 3-Methyl-3-hydroxy-5-
Synthesis method of (2,2,6-trimethyl-1-yl-cyclohexane) pentane (compound of Chemical formula 6): The compound of Chemical formula 3 is reacted in methanol at room temperature in the presence of palladium carbon and hydrogen, The compound was synthesized.

Other compounds can also be synthesized from the corresponding raw materials by the same synthetic method as described above. <2> External preparation for skin The external preparation for skin of the present invention is generally 0.0001 based on the total amount of the external preparation containing one or more of the above-mentioned melanin production inhibitors.
Although it is blended in a range of from 10 to 10% by weight, preferably from 0.01 to 10% by weight, more preferably from 0.1 to 5% by weight, among skin external preparations, there are especially spots due to sunburn, freckles, and dark skin. For the purpose of preventing and improving exacerbation, the blending amount is preferably 0.1% by weight or more.

The compounding amount of the compound of the general formula (I) is 0.
If it is less than 0001% by weight, the whitening effect based on the melanin production inhibitory effect is lowered, and even if it is used in an amount exceeding 10% by weight, the effect reaches the ceiling. Therefore, it is preferable to blend in the above range.

In addition to the above-mentioned active ingredients, the external preparation for skin of the present invention contains various components generally used in pharmaceuticals, cosmetics, etc., that is, an aqueous component, an oil component, a powder component, a surfactant (as an emulsifier), and a moisturizing agent. Agents, thickeners, colorants, fragrances, antioxidants, pH adjusters, chelating agents, preservatives, etc., or agents such as external line protective agents, anti-inflammatory agents, etc. can be blended alone or in combination of two or more. .

Examples of the aqueous component include water (purified water),
Examples thereof include lower alcohols (lower alcohols such as ethanol, propanol and isopropanol). Examples of the oily component include higher fatty acids (stearic acid, palmitic acid, myristic acid, lauric acid, and their esters), higher alcohols (cetanol, lanolin alcohol, stearyl alcohol, cetostearyl alcohol, etc.) and waxes ( Solid paraffin, microcrystalline wax, ceresin wax, polyethylene wax, beeswax, wax, carnauba wax, candelilla wax, etc., natural or synthetic oily substances (squalane, liquid paraffin, lanolin or its derivatives, olive oil, camellia oil, cottonseed oil, oleyl) Alcohol, castor oil, petrolatum, adipic acid diethoxyethyl ester,
Silicon oil, fluorine oil, etc.) and the like.

Examples of the powder component include aluminum powder, titanium oxide powder, zinc oxide powder, iron oxide powder, acrylic powder, silica beads, talc and sericite.

Examples of the surfactant include polyoxyethylene monooleate, polyoxyethylene cetyl ether, aluminum stearate, octyldodecanol, lipophilic glycerin monostearate, propylene glycol monostearate and the like.

Examples of moisturizing agents include glycerin, propylene glycol, 1,3-butylene glycol, dipropylene glycol, ethylene glycol, 1,4-butylene glycol, diglycerin, triglycerin, sorbit and its derivatives, polyethylene glycol and the like. Polyhydric alcohols: glucose, maltose, maltitol, sucrose, fructose, threitol, erythritol, sorbit, starch-degrading sugar, hyaluronic acid, chondroitin sulfate, hydrolyzed collagen, carboxymethyl chitin and the like.

Examples of the thickener include carboxyvinyl polymer, CP jelly, sodium alginate, bentonite, veegum, synthetic hectorite and the like.
Examples of the antioxidant include dibutylated hydroxytoluene (BHT) and butylated hydroxyanisole (BH).
A), tocopherol sodium pyrosulfite, acetone sodium bisulfate, tocopherol acetate, vitamin E, rosemary extract and the like.

Examples of the pH adjusting agent include citric acid, lactic acid, tartaric acid, phosphoric acid and the like. Examples of the chelating agent include EDTA (ethylenediaminetetraacetic acid),
Examples thereof include thioglycolic acid, thiolactic acid, and thioglycerin.

Examples of preservatives include methyl, ethyl, propyl and butyl esters of p-oxybenzoic acid (referred to as methylparaben, ethylparaban, propylparaben and butylparaben, respectively), o-phenylphenol, dehydroacetic acid and the like. Salt, p-cresol,
Examples thereof include m-cresol and o-chloro-m-xylenol.

Examples of the ultraviolet protective agent include ascorbic acid or its derivative, isoferulic acid or its salt, glutathione or its derivative, oxybenzone or its derivative, p-aminobenzoic acid or its derivative, urocanic acid or its derivative, kojic acid, Examples thereof include dibenzoylmethane or its derivative, p-methoxycinnamic acid or its derivative, fine particle titanium oxide, fine particle zinc oxide, and fine particle iron oxide.

Examples of the anti-inflammatory agent include glycyrrhetinic acid or its derivative, glycyrrhizic acid or its derivative, bisabolol, geraniin, horse chestnut extract, aloe extract and the like.

Each of these components or agents can be used alone or in admixture of two or more. The external preparation for skin of the present invention may contain one or more kinds of other whitening components (or whitening agents) other than the compound represented by the general formula (I). Other whitening ingredients include, for example, pantetheine-s-sulfonic acid, isoferulic acid, ascorbic acid and its magnesium phosphate salts, arbutin, cordic acid, linoleic acid, esculin, tranexamic acid and the like.

The dosage form of the external preparation for skin of the present invention is not particularly limited, and it is usually used for medicines, quasi drugs, cosmetics, etc., such as ointments, creams, emulsions, lotions,
The dosage forms include packs and bath agents.

[0035]

The following is the general formula (I) used in the present invention.
The action of the compound group represented by will be described based on experimental examples. (1) Inhibition of melanin production on pigment cells 5 × 10 ⁴ B-16 melanoma cells were seeded in a plastic culture flask (75 cm ² ) and 5% carbon dioxide was added to Eagle MEM medium containing 10% serum. In the presence of
Culture was carried out at the temperature of. After 2 days, the test sample was added so that the concentration in the medium was 5, 10, 15, 20 μM, and the cells were further cultured for 4 days.

After the culture is completed, the medium is removed and washed with a phosphate buffered saline solution (hereinafter referred to as PBS), and then the cells are detached from the flask using trypsin and EDTA-containing medium and centrifuged from the cell suspension. The cells were collected by. The obtained cells were washed twice with PBS, and then the whiteness of the precipitate was visually observed. The results were evaluated according to the following criteria.
The results are shown in Table 1. The number of cells (%) in the table represents the number of cells (%) when the number of cells when a solvent is used instead of the test sample (solvent control) is 100.

-: Equivalent to solvent control +: slightly different from solvent control ++: clearly different from solvent control

[0038]

[Table 1] Then, 1N sodium hydroxide was added to the precipitate to dissolve it by heating, and after cooling, chloroform was added and the mixture was centrifuged again.
The absorbance of the obtained supernatant was measured at 400 nm, and the amount of melanin was determined from a calibration curve prepared in advance using synthetic melanin. The amount of melanin was calculated as the amount per 10 ⁴ cells. The results are shown in Table 2. The suppression rate in the table was calculated by the following formula. Suppression rate (%) = [(amount of melanin in control product)-
(Melanin amount of test sample added product)] × 100 / (Melanin amount of control product)

[0039]

[Table 2]As is clear from these results, 3-methyl-3-ha
Idroxy-5- (2,2,6-trimethyl-1-yl
-Cyclohexane) pentane, 3-methyl-1-hydrate
Roxy-5- (2,2,6-trimethyl-1-yl-oxy
Chlorohexane) pentane, 3-methyl-1-hydroxy
Ci-5- (2,2,6-trimethyl-1-yl-cyclo
Hexane) -3-pentene, 3-methyl-3-hydro
Xy-5- (2,2,6-trimethyl-1-yl-shik
(Rohexane) -1-pentene, 3-methyl-1-hydrate
Roxy-5- (2,2,6-trimethyl-1-yl-oxy
Chlorohexane) -2-pentene and 3-methyl-5-
(2,2,6-trimethyl-1-yl-cyclohexa
N) Pentane was used as a solvent control.
In comparison, it significantly suppresses melanin production in pigment cells
It was found to have (2) Inhibition of pigmentation by ultraviolet rays The back skin of brown guinea pigs (7 animals) was treated with electric clippers
The hair is removed and shaved with a fiber, and this site is cut by 1.5 × 1.
Cover with a black cloth that has a total of 6 5 cm irradiation windows on the left and right sides,
Use the FL20S / E30 lamp as the light source from above this cloth
1 mW / cm ²/ 4 sec UV irradiation for 4 minutes and 20 seconds
did.

This operation was performed once a day for 3 consecutive days. From the day after the end of irradiation, 20 μl of a test solution in which a predetermined amount of sample was dissolved using ethanol as a solvent was added once a day,
It was applied continuously. In addition, the same experiment was conducted using ethanol as a control. On the 21st day from the start of the experiment, the degree of pigmentation of the treated area was evaluated by visual observation according to the following criteria. The results are shown in Table 3 as an average value. Remark) 0: No pigmentation 0.5: Weak pigmentation with indistinct borders 1: Weak pigmentation with clear borders 2: Moderate pigmentation with clear borders 3: Pigment with clear intensity There is deposition

[0041]

[Table 3] As shown in Table 3, 3-methyl-3-hydroxy-
5- (2,2,6-trimethyl-1-yl-cyclohexane) pentane (compound of Chemical formula 6), 3-methyl-1-hydroxy-5- (2,2,6-trimethyl-1-yl-cyclohexane) Pentane (compound of formula 5), 3-methyl-1-hydroxy-5- (2,2,6-trimethyl-1-yl-cyclohexane) -3-pentene (formula 7)
Compound), 3-methyl-3-hydroxy-5-
(2,2,6-Trimethyl-1-yl-cyclohexane) -1-pentene (compound of formula 3), 3-methyl-1
-Hydroxy-5- (2,2,6-trimethyl-1-
Il-cyclohexane) -2-pentene (compound of formula 4) and 3-methyl-5- (2,2,6-trimethyl-
1-yl-cyclohexane) pentane (compound of Chemical formula 8)
When applied to the skin, each of them clearly suppressed the deposition of melanin pigment by ultraviolet rays at a concentration of 0.5%.

As explained above, the reduced β-ionone ring-containing pentane derivative used in the present invention has the action of suppressing melanin production and the action of suppressing pigment deposition. As a result, those formulated in a certain proportion or more in the skin external preparation base material bring about an excellent whitening effect on the skin, and not only local pigmentation diseases such as spots, freckles, and dark skin due to sunburn, It can be used for prevention, improvement and treatment of systemic pigmentation such as Addison's disease. Moreover, since the compound is excellent in safety and stability, it can be used continuously for a long period of time.

[0043]

EXAMPLES Examples of the present invention will be described below.

[0044]

Example 1 An oil-in-water cream will be described as an example of the external preparation for skin of the present invention. <Manufacturing method> Each of the components A and B in Table 4 is mixed at 80 ° C.
Heat to. These are added and stirred, emulsified, and then cooled.

[0045]

[Table 4] <Actual Use Test of Melanin Suppressing Effect> The cream obtained above and a comparative cream (in the cream of Example 1, 3-methyl-3-hydroxy-5- (2,2,6-
Trimethyl-1-yl-cyclohexane) pentane was replaced with water) and was used for a period of 3 months for a statistically equivalent group of 40 women suffering from dark-black, spots, and freckles,
The melanin suppressing effect by actual use was evaluated. The results are shown in Table 5.

[0046]

[Table 5] As is clear from this table, the product of the present invention containing 3-methyl-3-hydroxy-5- (2,2,6-trimethyl-1-yl-cyclohexane) pentane is remarkably different from the comparative product not containing it. It was confirmed to have an effective melanin suppressing effect. Incidentally, in the application site of the product of the present invention,
No unfavorable reaction on the skin was observed.

[0047]

Example 2 An example of an oil-in-water cream will be further described. The manufacturing method is the same as in Example 1 except that the components shown in Table 6 below are used.

[0048]

[Table 6]

[0049]

[Embodiment 3] Next, an embodiment of the emulsion will be described. <Production Method> Components A and B shown in Table 7 are dissolved at 70 ° C. with stirring. The component A is added to the component B to carry out preliminary emulsification, uniformly emulsify with a homomixer, and after emulsification, cool to 30 ° C. with stirring.

[0050]

[Table 7]

[0051]

[Embodiment 4] Further, an embodiment of the emulsion will be described. The manufacturing method is the same as in Example 3 except that the components shown in Table 8 below are used.

[0052]

[Table 8]

[0053]

[Embodiment 5] A lotion will be described as an embodiment of the present invention. <Manufacturing Method> Components A in Table 9 are mixed and dissolved at room temperature. On the other hand, the component B is also dissolved at room temperature and added to the component A to be solubilized.

[0054]

[Table 9]

[0055]

[Embodiment 6] Still another lotion will be described. The manufacturing method is the same as in Example 5 except that the components shown in Table 10 below are used.

[0056]

[Table 10]

[0057]

[Embodiment 7] Further, an embodiment of the pack charge will be described. <Manufacturing Method> The component A shown in Table 11 is dispersed and dissolved at room temperature.
Component B is added to this and dissolved uniformly.

[0058]

[Table 11] In addition, the actual use test of the melanin suppressing effect was also performed for Examples 2 to 7, and the same results as in Example 1 were obtained.

[0059]

Industrial Applicability According to the present invention, it is possible to provide a melanin production inhibitor and an external preparation for skin which are excellent in whitening effect and are highly stable and safe. The external preparation for skin of the present invention is
It can be used for the prevention, improvement and treatment of not only local pigmentation diseases such as stains, freckles and sunburn, but also systemic pigmentation diseases such as Addison's disease.

Front Page Continuation (72) Inventor Susumu Nozawa 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Pola Chemical Industry Co., Ltd. Totsuka Laboratory

Claims (3)

[Claims] 1. A melanin production inhibitor comprising a compound represented by the following general formula (I). Embedded image (In the formula, R ₁ represents hydrogen or a hydroxyl group, R ₂ represents hydrogen or a hydroxyl group, and there may be two or less double bonds in total at the 1-position, 2-position or 3-position.) 2. The compound represented by the general formula (I) is
3-Methyl-3-hydroxy-5- (2,2,6-trimethyl-1-yl-cyclohexane) pentane, 3-
Methyl-1-hydroxy-5- (2,2,6-trimethyl-1-yl-cyclohexane) pentane, 3-methyl-5- (2,2,6-trimethyl-1-yl-cyclohexane) pentane, 3- Methyl-1-hydroxy-
5- (2,2,6-Trimethyl-1-yl-cyclohexane) -3-pentene, 3-methyl-3-hydroxy-5- (2,2,6-trimethyl-1-yl-cyclohexane) -1- The melanin production inhibitor according to claim 1, which is any one of pentene and 3-methyl-1-hydroxy-5- (2,2,6-trimethyl-1-yl-cyclohexane) -2-pentene. . 3. One or more melanin production inhibitors according to claim 1 or 2 with respect to the total amount of 0.0001 to 1
A skin external preparation characterized by containing 0% by weight.