JPH05105643A - Cinnamic acid derivative and skin-beautifying cosmetic containing the derivative as active component - Google Patents

Abstract

PURPOSE:To provide a safe skin-beautifying cosmetic having excellent pigmentation improving effect and effective for treating and improving the pigmented part such as spots, freckles and sunburnt skin to the normal skin color by topically applying the cosmetic to the pigmented part. CONSTITUTION:A cinnamic acid derivative of formula (R1 is H or lower acyl; R2 is lower alkyl; R3 is H or lower alkyl), preferably 4-hydroxy-2'- methoxycinnamic acid, 4-acetoxy-2-methoxycinnamic acid or their ester, etc., especially 4-acetoxy-2-methoxycinnamic acid ethyl ester is compounded to a skin-beautifying cosmetic as an active component in an amount of preferably 0.01-50wt.%, especially 0.1-20wt.% to obtain the objective skin-beautifying cosmetic having the above effect different from conventional sun-screening agent to prevent the sunburn. The cosmetic is free from irritation to the skin and development of allergy, etc., and has high safety. The preferable amount of the active component per 1cm<2> of the skin is 1-20mg for creamy or ointment preparation and 1-10mg for liquid preparation.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a whitening cosmetic which is safe and has an excellent pigmentation improving effect, and a novel cinnamic acid derivative which is an active ingredient thereof.

[0002]

2. Description of the Related Art Stain, freckles and pigmentation after sunburn are less likely to occur, increase or disappear with ageing, which is a problem for the skin of middle-aged and older people. Although the mechanism of the onset of these pigmentation disorders has not been clarified yet, it is considered that the melanin synthesis function in epidermal melanocytes is enhanced by the action of sunlight, particularly ultraviolet rays, and melanocyte-stimulating hormone. In addition, delayed keratinization with aging of epidermal keratinocytes (keratinocytes) also delays the rate of excretion outside the epidermis, and together with the enhancement of melanin synthesis ability,
It is considered that an increase in melanin granule density in the epidermis, that is, a symptom of clinically increasing pigmentation is manifested. Furthermore, because these pigmented areas are locally present and are clearly different from the surrounding normal skin color, the result is that the mechanism that controls the local melanin synthesis enhancement of melanocytes or the melanin synthesis of melanocytes is modulated. You might also say that.

There is a strong demand for a drug that restores these acquired pigments, that is, the melanin deposits to a normal skin color, and many drugs have been developed and commercialized. For example, in recent years, cosmetics using a vitamin C (L-ascorbic acid) derivative having an excellent reducing ability have been used, but it is difficult to be stable and almost no effect is observed when used externally. Met.

On the other hand, in Europe and America, hydroquinone is used as a drug for treating spots and whitening black skin, but this also has a problem in the safety (irritation and allergenicity) of the substance itself, and vitiligo. In some cases, there is a problem in that it is compounded as a drug. Various other melanin inhibitors have been reported, but as a cinnamic acid derivative, p-hydroxycinnamic acid (Bru
n, J. Soc. Cosmet. Chem., 25, 61 (1974)) and p-hydroxycinnamic acid amide derivative (JP-A-62-56459). However, at present, no substance is known that sufficiently satisfies both the pigmentation improving effect and the safety to the skin.

[0005]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a whitening cosmetic which is safe and has an excellent pigmentation improving effect.

[0006]

[Means for Solving the Problems] As a result of intensive investigations by the present inventors to obtain a substance that reduces or eliminates pigmentation through research on the mechanism of melanin production, a specific cinnamic acid derivative has a melanin production inhibitory action. Furthermore, they have found that no irritation to the skin, no expression of allergies, etc. are found, and the present invention has been completed.

That is, the present invention has the following general formula (1)

[0008]

[Chemical 3]

A whitening agent containing a cinnamic acid derivative represented by the formula (wherein R ₁ is a hydrogen atom or a lower acyl group, R ₂ is a lower alkyl group, and R ₃ is a hydrogen atom or a lower alkyl group) as an active ingredient. It is to provide cosmetics.

Among the active ingredients, the general formula (2)

[0011]

[Chemical 4]

A cinnamic acid derivative represented by the formula ( _{1) wherein} R ₁ ′ is a lower acyl group and R ₂ and R ₃ have the same meanings as described above is also provided.

Cinnamic acid derivatives used in the present invention
Preferred examples of (1) include 4-hydroxy-2-methoxycinnamic acid or its ester and 4-acetoxy-2-methoxycinnamic acid or its ester. As a particularly suitable compound, 4-acetoxy-2-methoxycinnamic acid ethyl ester can be mentioned.

The cinnamic acid derivative (1) of the present invention can be synthesized according to the method described in the literature or in accordance therewith, and, for example, a 4-hydroxy-2-methoxybenzaldehyde compound and malonic acid or its ester are combined with a base such as pyridine. Condensation in the presence of, and optionally hydrolysis and / or conversion to derivatives by conventional methods, such as 4-hydroxy-2-methoxybenzaldehyde compounds and (carbetoxymethylene) triphenylphosphorane with Wittig It can be easily obtained by, for example, condensing a reagent, and if necessary, by hydrolysis and / or converting it into a derivative by a conventional method.

In the whitening cosmetic composition of the present invention, the cinnamic acid derivative (1) can be blended alone or in combination of two or more, and the blending amount is 0.01 to 50% by weight in the composition. %, Preferably 0.1 to 20% by weight.

The whitening cosmetic composition of the present invention can be made into various forms, but in general, it is generally a lotion, an emulsion, a cream, an ointment, a stick, a solution with an organic solvent, a pack, or a gel. It is preferable to use such cosmetics.

The whitening cosmetic composition of the present invention may contain any component other than the cinnamic acid derivative (1) within a range that does not impair the effects of the present invention. Ingredients such as purified water, ethanol, oily substance,
Moisturizers, thickeners, preservatives, emulsifiers, medicinal ingredients, powders, fragrances, emulsion stabilizers, pH adjusters and the like can be added.
Specifically, as the oil component, liquid paraffin, petrolatum, paraffin wax, squalane, beeswax, carnauba wax, olive oil, lanolin, higher alcohols,
Fatty acids, synthetic ester oils of higher alcohols and fatty acids, silicone oils and the like can be mentioned. Moisturizing agents include sorbitol, xylitol, glycerin, maltitol, propylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, pyrrolidone carboxylic acid. Sodium acid, lactic acid, sodium lactate, polyoxypropylene fatty acid ester, polyethylene glycol and the like can be mentioned. As the thickener, carboxyvinyl polymer, carboxymethyl cellulose, polyvinyl alcohol, carrageenan, water-soluble polymer such as gelatin, sodium chloride, chloride and the like. Examples include electrolytes such as potassium, and examples of preservatives include urea, methylparaben, ethylparaben, propylparaben, butylparaben, sodium benzoate, and the like. Nonionics such as alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene sorbitan fatty acid ester, glycerin fatty acid ester, polyglycerin fatty acid ester, polyoxyethylene glycerin fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitol fatty acid ester Surfactants can be mentioned, and powders include talc, sericite, mica, kaolin, silica, bentonite, vermiculite, zinc white, mica, titanium mica,
Examples include titanium oxide, magnesium oxide, zirconium oxide, barium sulfate, red iron oxide, iron oxide, ultramarine blue, and the like.
Examples of the adjusting agent include buffers such as lactic acid-sodium lactate and citric acid-sodium citrate. Also, as various active ingredients, allantoin, vitamin E acetate,
By adding glycyrrhizin, yoquinin, various plant extracts and the like, the melanin suppressing effect can be improved. Further, by adding various ultraviolet absorbing substances, it is possible to obtain a cosmetic having both a sunburn preventing effect and a sunburn preventing effect.

The whitening cosmetic composition of the present invention can be applied to the affected areas such as skin inflammation caused by ultraviolet rays, stains, freckles, and pigmented areas after sunburn to treat / improve the affected areas to obtain normal skin. Can be returned to color. Generally, the dose is, for example, in the case of a cream or ointment type preparation,
1 to ²⁰ mg per cm ^{2 of} skin surface, the same for liquid formulations 1
It is preferably about 10 mg.

[0019]

EXAMPLES Next, the present invention will be described with reference to examples and reference examples.

Reference Example 1 Synthesis of 4-hydroxy-2-methoxycinnamic acid ethyl ester: 0.5 g of 4-hydroxy-2-methoxybenzaldehyde
(3.3 mmol) was dissolved in 23 ml of benzene, and 1.64 g of triphenylphosphorane at room temperature (carbetoxymethylene)
(4.7 mmol) was added over 1 hour, and stirring was continued in that state for 3 hours. After completion of the reaction, benzene was distilled off with an evaporator, and the residue was purified by column chromatography (silica gel) to obtain 0.7 g of a crude product. This was recrystallized from water-ethanol and had a melting point of 143.1 to 146.0 ° C.
As a white needle crystal, 496 mg (2.2 mmol) of 4-hydroxy-2-methoxycinnamic acid ethyl ester was obtained (68% yield). IR (KBr, cm ^-1 ) 3364 (s), 3080, 2980, 2944, 1682 (s), 1610 (s), 1582
(s), 1480, 1436, 1372, 1350, 1312 (s), 1286, 1238, 1
186 (s), 1168, 1112, 1038, 988,960, 860, 800, 672, 6
52, 518, 470 ¹ H-NMR (CDCl ₃ + D ₂ O, TMS, δ) 7.90 (1H, d, J = 16.1Hz), 7.37 (1H, d, J = 9.0Hz), 6.5-6.3 (3
H), 4.25 (2H, q, J = 7.2Hz), 3.85 (3H, s), 1.33 (3H, t, J = 7.2
Hz),

Example 1 Synthesis of 4-acetoxy-2-methoxycinnamic acid ethyl ester: 4-hydroxy-2-methoxycinnamic acid ethyl ester 300
A mixture of mg (1.35 mmol), acetic anhydride 220 mg (2.15 mmol) and pyridine 1.07 g was stirred overnight at room temperature. 10 ml of water to this
Was added thereto, extracted twice with 20 ml of ethyl acetate, and dried over magnesium sulfate. After distilling off the solvent with an evaporator,
The residue was subjected to column chromatography (SiO ₂ , hexane /
The product was purified with ethyl acetate = 5) to obtain 341 mg (1.29 mmol) of 4-acetoxy-2-methoxycinnamic acid ethyl ester as white crystals having a melting point of 56.4 to 57.0 ° C (yield 96%). ¹ H-NMR (CDCl ₃ , TMS, δ) 7.92 (1H, d, J = 16.1Hz), 7.50 (1H, d, J = 8.3Hz), 6.8-6.6 (2
H), 6.49 (1H, d, J = 16.1Hz), 4.26 (1H, q, J = 7.2Hz), 3.87 (3
H, s), 2.31 (3H, s), 1.33 (3H, t, J = 7.2Hz)

Example 2 Synthesis of 4-acetoxy-2-methoxycinnamic acid and 4-hydroxy-2-methoxycinnamic acid: 4-acetoxy-2-methoxybenzaldehyde 0.86 g (4.43 mmol), malonic acid 1.15 g (11.1
mmol), 4 ml of pyridine and 1 drop of piperidine
The mixture was heated and stirred for 1.5 hours. After cooling, 30 ml of water was added and the mixture was stirred for 30 minutes, then the precipitated crystals were collected by filtration. Melting point from the first crystal
295 mg (1.25 mmol) of 4-acetoxy-2-methoxycinnamic acid was obtained as white crystals at 187.1 to 193.4 ° C (yield 28%). ¹ H-NMR (DMSOd ₆ , TMS, δ) 12.34 (1H, brs), 7.78 (1H, d, J = 16.1Hz), 7.72 (1H, d, J = 8.5
Hz), 6.91 (1H, s), 6.77 (1H, d, J = 8.5Hz), 6.50 (1H, d, J = 1
6.1Hz), 3.85 (3H, s), 2.28 (3H, s) From the second crystal, 399 mg of a mixture of 4-acetoxy-2-methoxycinnamic acid and 4-hydroxy-2-methoxycinnamic acid was obtained. .. Then 399 mg of this mixture and sodium methylate 2
A solution of 00 mg (3.70 mmol) in methanol was stirred with heating for 30 minutes. After cooling, the mixture was acidified by adding saturated aqueous ammonium chloride solution, and then extracted with 20 ml of tetrahydrofuran. After distilling off the solvent with an evaporator, it was dissolved in ether,
A saturated aqueous sodium hydrogen carbonate solution was added and the organic layer was separated. After dilute hydrochloric acid was added to the aqueous layer to make it acidic, the precipitated yellow-green crystals were collected by filtration. This was recrystallized from water-acetone to give 4-yellow as a slightly yellow powder with a melting point of 165.5-167.5 ° C (decomposition).
Hydroxy-2-methoxycinnamic acid (114.6 mg, 0.52 mmol) was obtained (yield: 12% based on 4-acetoxy-2-methoxybenzaldehyde). ¹ H-NMR (DMSOd ₆ , TMS, δ) 10.12 (1H, brs), 7.73 (1H, d, J = 16.1Hz), 7.49 (1H, d, J = 8.3
Hz), 6.44 (1H, s), 6.40 (1H, d, J = 8.3Hz), 6.29 (1H, d, J = 1
6.1Hz), 3.80 (3H, s)

[0023] Example 3 lotion cosmetic composition: (composition) 4-acetoxy-2-methoxycinnamic acid ethyl ester 5.0 (wt%) Glycerin 4.0 Polyoxyethylene hardened castor oil 1.5 Ethanol 10.0 sodium pyrrolidone carboxylate 2.0 Perfume trace Purified Total water remaining 100.0

Example 4 Oil Essence Type Cosmetic: (Composition) 4-Acetoxy-2-methoxycinnamic acid ethyl ester 5.0 (wt%) Mink oil 55.0 Wheat germ oil 40.0 Total 100.0

Example 5 W / O type moisture cream type cosmetic composition: (Composition) 4-acetoxy-2-methoxycinnamic acid 5.0 (wt%) Vaseline 6.0 Cholesterol 0.6 Cetanol 0.5 Sorbitan sesquioleate 2.0 Liquid lanolin 4.0 Isopropyl palmitate 8.0 Squalene 10.0 Solid paraffin 4.0 Butylparaben 0.1 Methylparaben 0.1 Glycerin 3.0 Perfume 0.2 Purified water Balance 100.0

Example 6 O / W type moisturizing cream type cosmetic composition: (composition) 4-hydroxy-2-methoxycinnamic acid ethyl ester 5.0 (% by weight) stearic acid 2.0 cetanol 4.0 vaseline 5.0 squalene 8.0 hardened palm oil 4.0 polyoxy Ethylene sorbitan monostearate (20E.O.) 1.4 Lipophilic glyceryl monostearate 2.4 Butylparaben 0.1 Methylparaben 0.1 Glycerin 3.0 Dipropylene glycol 3.0 L-Arginine 10.0 (%) Potassium hydroxide 0.2 Perfume 0.2 Purified water Balance total 100.0

Example 7 Emulsion type cosmetic composition: (Composition) 4-hydroxy-2-methoxycinnamic acid ethyl ester 5.0 (% by weight) Stearic acid 1.0 Cetanol 2.0 Vaseline 2.5 Squalene 4.0 Hardened palm oil 2.0 Polyoxyethylene sorbitan monostearate (20E.O.) 1.4 Lipophilic glycerin monostearate 1.2 Butylparaben 0.1 Methylparaben 0.1 Glycerin 3.0 Dipropylene glycol 3.0 Potassium hydroxide 0.2 Carboxyvinyl polymer 0.2 Perfume 0.2 Purified water Balance 100.0

Example 8 Pack-type cosmetic (paste peel-off type): (Composition) 4-hydroxy-2-methoxycinnamic acid 10.0 (% by weight) Polyvinyl alcohol 12.0 Sodium carboxymethyl cellulose 3.0 Dipropylene glycol 2.0 Glycerin 2.0 Ethanol 5.0 Olive oil 3.0 Polyoxyethylene hydrogenated castor oil (30E.O.) 0.5 Titanium oxide 8.0 Kaolin 6.0 Perfume 0.1 Methylparaben 0.1 Purified water Balance 100.0

Example 9 Ointment Cosmetic: (Composition) 4-Acetoxy-2-methoxycinnamic acid ethyl ester 10.0 (wt%) White petrolatum 90.0 Total 100.0

Example 10 Liquid formulation cosmetics: (Composition) 4-acetoxy-2-methoxycinnamic acid ethyl ester 5.0 (wt%) ethanol 95.0 Total 100.0

Test Example 1 Evaluation of mouse dorsal skin hair follicle organ culture system by tyrosinase activity Test method: 8-11 after birth in which melanin synthesis is actively carried out
The dorsal hair follicles of C57BL mice for 3 days were cultured for 3 to 4 days.
The evaluation sample was added to the culture solution during culturing so that the final concentration was 5 mM, and the enzyme responsible for melanin synthesis, tyrosinase activity, was released from 3,5- ³ H-tyrosine to release tritium ( ³ HOH).
Was evaluated by comparing with the control. The results are shown in Table 1. No suppression effect 0-5% ± 5-35% +35%-++ Result:

[0032]

[Table 1]

Test Example 2 A brown guinea pig having an acquired ability to form melanin pigment spots was used as an experimental animal, and after the formation of pigmentation, the effect of improving fading on pigmentation was examined. Test method: Using a brown guinea pig (a guinea pig whose skin color is similar to that of a human race of yellow color, pigmented spots start to appear about 4 days after irradiation of ultraviolet rays like humans, and turn black most in about 8 days).
The back hair of the guinea pig was shaved with a hair clipper and then shaved with an electric razor. After 8-methoxypsoralen (PUVA) was intraperitoneally administered to this guinea pig, UVA (BLB lamp, 3.1 m
W / cm ² ) was irradiated for 5 minutes. PUV generated from 15 days after irradiation
A sample (4-acetoxy-2-methoxycinnamic acid ethyl ester) 5% solution (ethanol 80
%, Water 20%) was applied twice a day continuously for a total of 30 days. The degree of blackening of the skin color was visually evaluated according to the following criteria, and the evaluation points were averaged to measure the effect. The results are shown in Table 2. Criteria 0: No pigmentation is observed. 1: A slight pigmentation with unclear boundaries is observed. 2: Medium pigmentation with clear boundaries is recognized. 3: Clearly marked strong pigmentation is observed. result:

[0034]

[Table 2]

[0035]

EFFECTS OF THE INVENTION The whitening cosmetic composition of the present invention has an excellent pigmentation improving effect and is different from the conventional sunscreen agents etc. which prevent sunburn in advance, and is locally applied to the spots on the skin, freckles, and the pigmented portion after sunburn. It is possible to treat and improve the area and restore the normal skin color by applying In addition, the cinnamic acid ester derivative (1) of the present invention, which is an active ingredient, has no irritation to the skin, expression of allergies, etc., and thus the whitening cosmetic composition of the present invention is highly safe.

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Claims (2)

[Claims] 1. A general formula (1): A whitening cosmetic composition containing a cinnamic acid derivative represented by the formula (wherein R ₁ represents a hydrogen atom or a lower acyl group, R ₂ represents a lower alkyl group, and R ₃ represents a hydrogen atom or a lower alkyl group) as an active ingredient. 2. A general formula (2): (In the formula, R ₁ ′ is a lower acyl group, R ₂ is a lower alkyl group, and R ₃ is a hydrogen atom or a lower alkyl group).