JPH0672855A - Suppressor of melanogenesis and skin external preparation - Google Patents

Abstract

PURPOSE:To obtain the subject suppressor, composed of a specific compound such as nerolidol, excellent in safety, stability, improving and therapeutic effects on skin pigmentation and useful as a skin external preparation, etc. CONSTITUTION:The objective suppressor is composed of a compound expressed by formula I or II [R1 is H, 1-27C alkyl, alkenyl, etc.; R2 and R3 are H or 1-4C alkyl; (n) is 0-2; R4 is methylene or CH3(OH); R5 and R6 are H, methyl or carboxyl; R7 is H or methyl] such as nerolidol, isophytol, geranyllinalool, geranylnerolidol, 3-hydroxy-3-methyl-1-undecene, manool, 13-epi-manool, scraleol or 13-epi-scraleol. Furthermore, the objective skin external preparation is obtained by including 0.0001-10wt.% at least one resultant suppressor therein.

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 having an effective whitening effect, containing a compound containing 1-ene-3-ol as a partial structure as an active ingredient. The agent is provided.

[0002]

BACKGROUND OF THE INVENTION Pigmentation after freckles, freckles and sunburn is a result of markedly increased melanin production due to activation of pigment cells present in the skin, and is one of the troubles of the middle-aged and old-aged skin. Has become. In general, melanin changes 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-dihydroxyindole is formed. It is believed to be generated through.

Therefore, in order to prevent or improve the darkness of the skin, 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, sulfur compounds typified by glutathione and hydroquinone are examples of compounds that inhibit tyrosinase activity and suppress melanin production.
Further, as a light-color bleaching of the generated melanin,
Hydrogen peroxide, vitamin C, etc. have been used.

[0004]

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

As described above, the conventionally used components are not truly practically satisfactory in terms of effect, efficacy, stability and safety. The present invention has been made in view of such circumstances, the melanin production inhibitory action,
It is another object of the present invention to provide a skin external preparation having a sufficient effect of improving and treating skin pigmentation, and having stability and safety.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that compounds represented by the following general formula (I), particularly nerolidol, isophytol, geranyllinalool , Geranyl nerolidol,
3-hydroxy-3-methyl-1-undecene, and further compounds represented by the following general formula (II), especially manure, 13-epi-manure, sclareol, 13-
It was found that epi-sclareol and the like have a strong inhibitory effect on melanin production of living pigment cells, and when this compound is added to a base at a certain concentration or more, an excellent whitening effect on the skin is obtained. The inventors have found that they are expressed and have reached the present invention.

That is, the present invention is a melanin production inhibitor which is a compound represented by the following general formula (I) and a melanin production inhibitor which is a compound represented by the following general formula (II). Furthermore, the present invention comprises one or more of these melanin production inhibitors, preferably 0.00
The external preparation for skin is characterized by containing 0.1 to 10% by weight.

[0008]

[Chemical 3] In formula (I), R ₁ is hydrogen, a linear or branched alkyl group or alkenyl group having 1 to 27 carbon atoms, the number of double bonds is 0 to 6, and the position thereof is arbitrary. And the number of hydrogen atoms in the alkyl group or alkenyl group is 0 to
It may be substituted with a carboxyl group and / or a hydroxyl group within the range of 6, and the position thereof is arbitrary,
R ₂ and R ₃ represent hydrogen or an alkyl group having 1 to 4 carbon atoms.

[0009]

[Chemical 4] In the formula (II), n represents an integer of 0 to 2, R ₂ and R ₃ represent hydrogen or an alkyl group having 1 to 4 carbon atoms, R ₄ represents a methylene group or —CH ₃ (OH) group, and R ₅ , R ₆ is hydrogen, methyl group,
Either of the carboxyl groups and R ₇ represents hydrogen or a methyl group. 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) or (II), and is 1-ene represented by the following formula (III). It is a compound having -3-ol as a partial structure. The names of these compounds, which are usually used, vary depending on the presence state of various functional groups in the overall structure, but in the present invention, they have the above partial structure and are represented by the formula (I) or (II). 1-en
It will be referred to as an e-3-ol derivative. Such compounds are often found in terpene series and the like, extracted from various natural products, and used or disclosed as synthetic precursors for drugs, fragrances, and active pharmaceutical ingredients.

[0011]

[Chemical 5]

As the compound represented by the above formula (I),
For example, nerolidol (chemical formula 6) represented by the following structural formula,
Examples include isophytol (chemical formula 7), geranyl linalool (chemical formula 8), geranyl nerolidol (chemical formula 9), 3-hydroxy-3-methyl-1-undecene (chemical formula 10), and the like.

[0013]

[Chemical 6]

[0014]

[Chemical 7]

[0015]

[Chemical 8]

[0016]

[Chemical 9]

[0017]

[Chemical 10]

Examples of the compound represented by the above formula (II) include manur (Chemical formula 11), 13-epi-manur, sclareol (Chemical formula 12) and 13-epi-sclareol.

[0019]

[Chemical 11]

[0020]

[Chemical 12]

Among the above compounds, nerolidol,
Isophytol, geranyl linalool, geranyl nerolidol, manur and sclareol are commercially available and may be used. Also, 3-hydroxy-3
-Methyl-1-undecene can be synthesized, for example, using vinyl bromide and a ketone body as follows. That is, 14.7 mmol of vinylmagnesium bromide (solution dissolved in THF (tetrahydrofuran) so as to be 1 M) was added to 3.8 mM 2-decanone (solution dissolved in 23 ml of THF),
Stir at -10 ° C for about 3 minutes, then at 10 ° C for about 10 minutes. This mixture is developed using a silica gel column with a developing solvent of hexane: ethyl acetate = 9: 1, and the eluted fraction is identified by NMR or the like.

<2> External preparation for skin The external preparation for skin of the present invention includes 1 of the above-mentioned melanin production inhibitors.
Or two or more, preferably 0.0 based on the total amount of the external preparation.
001 to 10% by weight, more preferably 0.01 to 10%
Blend in the range of wt%. Among the external preparations for skin, the compounding amount is preferably 0.01% by weight or more, especially for those for the purpose of preventing and improving stains, freckles, and aggravation due to sunburn.

If the blending amount is less than 0.0001% by weight, the effect based on the melanin production inhibitory effect is lowered, and even if the amount is more than 10% by weight, the effect reaches the ceiling, so the content is in the above range. It is preferable. In the external preparation for skin of the present invention, in addition to the above-mentioned active ingredients, various components generally used in pharmaceuticals, cosmetics, etc., that is, an aqueous component,
Compounding agents such as oily ingredients, powder ingredients, surfactants, moisturizers, thickeners, colorants, fragrances, antioxidants, pH adjusters, chelating agents, preservatives, or UV protectants and anti-inflammatory agents I can do things.

A whitening agent other than the 1-ene-3-ol derivative may be blended, for example, pantetheine-s-sulfonic acid, isoferulic acid, ascorbic acid, magnesium phosphate ascorbic acid salt, arbutin,
Examples thereof include koji acid, linoleic acid and methyl linoleate. 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., for example, ointment, cream, emulsion, lotion, pack, bath agent, etc. The dosage form of

[0025]

The following is 1-ene-3-ol used in the present invention.
The action of the derivative will be described based on experimental examples. Among the compounds used below, commercially available compounds were used for nerolidol, isophytol, geranyllinalool, geranylnerolidol, manur, sclareol, phytol and geraniol. 3-Hydroxy-3-methyl-1-undecene was synthesized from vinylmagnesium bromide and 2-decanone in the same manner as above.

(1) Inhibitory Effect of Melanin Production on Pigment Cells 5 × 10 ⁴ B-16 melanoma cells were seeded in a plastic culture flask (75 cm ² ) and an Eagle MEM medium containing 10% serum was used. 37% in the presence of 5% carbon dioxide
Cultured at ° C. Two days later, the test samples shown in Table 1 were added so that the concentration in the medium was 10 ⁻⁵ , 10 ⁻⁴ , 10 ⁻³ , 10 ⁻² %, and the ^cells were further cultured for 4 days.

After completion of the culture, the medium was removed, washed with phosphate buffered saline (PBS), the cells were detached from the flask using a medium containing trypsin and EDTA, and the cells were separated from the cell suspension by centrifugation. Recovered. The obtained cells were washed twice with PBS, and the whiteness of the precipitate was visually observed. The results are shown in Table 1 according to the following criteria.

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

[0029]

[Table 1] Thereafter, 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 at 400 nm of the obtained supernatant was measured, and the amount of melanin was determined from a calibration curve prepared in advance using synthetic melanin. The melanin amount was calculated as the amount per 10 ⁴ cells. The results are shown in Table 2.

The inhibition rate in the table was calculated by the following formula.

Inhibition rate (%) = (melanin amount of control product−melanin amount of test sample added product) × 100 / (melanin amount of control product)

[0032]

[Table 2] As is clear from these results, 3-hydroxy-
3-methyl-1-undecene, nerolidol, isophytol, geranyllinalool, geranylnerolidol, manur, and sclareol were shown to have a remarkable inhibitory effect on melanin production in pigment cells as compared with the solvent control. Was done.

(2) Inhibition of pigmentation by UV rays The back skin of brown guinea pigs (7 animals) was shaved and shaved with an electric hair clipper and a shaver, and this site was cut at 1.5 x 1.5c.
A black cloth with a total of 6 left and right irradiation windows is covered, and the FL20S / E30 lamp is used as a light source for 1m from the top of this cloth.
Ultraviolet rays of W / cm ² / sec were irradiated for 4 minutes and 20 seconds.

This operation was performed once a day for 3 consecutive days. From the day after the end of irradiation, 20 μl of a sample solution in which a predetermined amount of sample was dissolved using ethanol as a solvent was continuously applied once a day. 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 in the treated area was visually determined according to the following criteria. The results are shown in Table 3 as an average value.

0: no pigmentation 0.5: weak pigmentation with unclear boundary 1: weak pigmentation with clear boundary 2: moderate pigmentation with clear boundary 3: intense pigmentation with clear boundary

[0036]

[Table 3] As shown in Table 3, nerolidol, isophytol,
Geranyl linalool, manur and sclareol clearly inhibited UV-induced melanin production at 0.5% concentration when applied to the skin.

As described above, 1-used in the present invention
The ene-3-ol derivative has an action of suppressing melanin production and an action of suppressing pigment deposition. As a result, the ones containing this in a certain proportion or more in the skin external preparation base,
Brings markedly excellent whitening effect to the skin, stains,
It can be used for the improvement and treatment of local pigmentation diseases such as freckles and sunburn, and systemic pigmentation diseases such as Addison's disease. Moreover, it has excellent safety and can be used for a long period of time.

[0038]

EXAMPLES Examples of the present invention will be described below. In addition, the compounding amount in the following examples is parts by weight.

[0039]

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) The components shown in Tables 4A and 4B are mixed and heated to 80 ° C. These are added and stirred to emulsify, and then cooled.

[0041]

[Table 4]

(Actual Use Test of Pigmentation Improvement Effect) The creams obtained above and the cream of the comparative product (the cream of the example in which manure was replaced by water) were statistically equivalent to 40 persons. The effect of improving pigmentation was evaluated by continuously applying it to a female group suffering from dark-black, spots and freckles for 3 months.
The results are shown in Table 5.

[0043]

[Table 5] As is clear from this result, it was shown that the product of the present invention containing manool had a markedly effective pigmentation-improving effect as compared with the comparative product containing no manure. No unfavorable reaction on the skin was observed at the site to which the product of the present invention was applied.

[0044]

[Embodiment 2] Next, an embodiment of the emulsion will be described. Dissolve the ingredients of Tables 6A and B 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.

[0045]

[Table 6]

[0046]

[Embodiment 3] Another embodiment of the emulsion will be described. An emulsion is prepared in the same manner as in Example 2, using the components shown in Table 7.

[0047]

[Table 7]

[0048]

Example 4 As an example of the present invention, the components of Table 8A for explaining the lotion are combined and dissolved at room temperature. On the other hand, B
Each component of (3) also dissolves at room temperature, and this is added to the component of A and solubilized.

[0049]

[Table 8]

[0050]

[Fifth Embodiment] Further, an embodiment of the pack charge will be described. Disperse and dissolve the ingredients of Table 9A at room temperature. The component B is added to this and uniformly dissolved.

[0051]

[Table 9]

[0052]

Sixth Embodiment Another embodiment of the oil-in-water cream will be described. (Production method) The components shown in Tables 10A and 10B are mixed and heated to 80 ° C. These are added and stirred to emulsify, and then cooled.

[0053]

[Table 10]

[0054]

According to the present invention, the whitening effect is excellent, and
It is possible to provide a melanin production inhibitor and a skin external preparation having high stability and safety. The external preparation for skin of the present invention can be used for the prevention, amelioration, and treatment of local pigmentation diseases such as spots, freckles, and dark skin due to sunburn, and systemic pigmentation diseases such as Addison's disease.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Koji Yokoyama, 560 Pola Chemical, Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Prefecture Totsuka Research Institute Co., Ltd. (72) Keiko Onuki, 560, Kashio-cho, Totsuka-ku, Yokohama, Yokohama Seiko Kogyo Co., Ltd. Totsuka Research Laboratory (72) Inventor Tomomi Kato 560 Kashio-cho, Totsuka-ku, Yokohama, Kanagawa

Claims (7)

[Claims] 1. A melanin production inhibitor which is a compound represented by the following general formula (I). [Chemical 1] In formula (I), R ₁ is hydrogen, a linear or branched alkyl group or alkenyl group having 1 to 27 carbon atoms, the number of double bonds is 0 to 6, and the position thereof is arbitrary. And the number of hydrogen atoms in the alkyl group or alkenyl group is 0 to
It may be substituted with a carboxyl group and / or a hydroxyl group within the range of 6, and the position thereof is arbitrary,
R ₂ and R ₃ represent hydrogen or an alkyl group having 1 to 4 carbon atoms. 2. The R _{1 as} defined in claim 1, which is a branched alkyl group or alkenyl group, and further has a methyl group of 1
A melanin production inhibitor, characterized in that it comprises from 6 to 6, and the location thereof is arbitrary. 3. A melanin production inhibitor which is a compound represented by the following general formula (II). [Chemical 2] In the formula (II), n represents an integer of 0 to 2, R ₂ and R ₃ represent hydrogen or an alkyl group having 1 to 4 carbon atoms, R ₄ represents a methylene group or —CH ₃ (OH) group, and R ₅ , R ₆ is hydrogen, methyl group,
Either of the carboxyl groups and R ₇ represents hydrogen or a methyl group. 4. The compound represented by the formula (I) is nerolidol, isophytol, geranyllinalool, geranylnerolidol, 3-hydroxy-3-methyl-1-.
The melanin production inhibitor according to claim 1 or 2, which is selected from undecene. 5. The compound represented by the formula (II) is manure, 13-epi-manur, sclareol, 13
The melanin production inhibitor according to claim 3, which is selected from -epi-sclareol. 6. Skin comprising one or more melanin production inhibitors according to any one of claims 1 to 5 in an amount of 0.0001 to 10% by weight based on the total amount. Topical agent. 7. Skin comprising one or more melanin production inhibitors according to any one of claims 1 to 5 in an amount of 0.01 to 10% by weight based on the total amount. Topical agent.