JPH0322848B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a melanin suppressant, and more particularly to a melanin suppressant containing a specific cinnamic acid derivative as an active ingredient. Age spots, freckles, melasma, and pigmentation after sunburn occur, increase, or disappear less easily with age, and have become one of the skin concerns of middle-aged and elderly people. The onset mechanism of these pigmentation disorders is
Although it is not clear yet, it is thought that this is due to the increased melanin synthesis function of melanocytes due to the effects of ultraviolet rays and melanocyte-stimulating hormone (MSH). In addition, the age-related tendency of delayed keratinization of epidermal keratinocytes (keratinocytes) delays the rate of melanin excretion outside the epidermis, and together with the enhanced melanin-containing ability, the density of melanin granules in the epidermis increases. This is considered to be a symptom of clinically enhanced pigmentation. Furthermore, these pigmented areas exist locally and are clearly different from the surrounding normal skin color.
It is also thought to be the result of modulating the mechanism that controls melanin synthesis in melanocytes. There is a strong demand for drugs that can restore these acquired pigments, ie, melanin deposits, to their normal skin color, and many drugs have been developed and commercialized to date. For example, peroxides are said to have the effect of bleaching melanin, and attempts have been made to use hydrogen peroxide, zinc peroxide, sodium peroxide, etc., but these are extremely unstable compounds. In addition, almost no effect of reducing pigmentation that could be used practically was observed. In recent years, cosmetics using vitamin C (L-ascorbic acid), which has excellent reducing ability, have also been used, but these also have stability problems and are currently hardly effective when applied externally. It was hot. On the other hand, in Europe and the United States, hydroquinone and various catechols are used as drugs to treat age spots and whiten the skin of black people, but these substances also have safety issues (irritation, allergy). In addition, there are problems in compounding it as a drug because it may cause vitiligo in some cases.
In addition, various melanin suppressants (or whitening agents) have been reported, but at present there are almost no substances that have a substantial melanin suppressing effect. Through many years of research into the melanin production mechanism, the present inventors have conducted an intensive search to obtain substances that reduce or eliminate pigmentation. As a result, they have discovered that certain cinnamic acid derivatives have a melanin-suppressing effect and are irritating to the skin. The present invention was completed based on the discovery that no allergic reaction or allergy was observed. That is, the present invention is based on the following general formula () (In the formula, R' represents an acyl group having 2 to 8 carbon atoms,
R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group, or an alkenyl group. The cinnamic acid derivative represented by the formula () used in the present invention is preferably one in which R' is an acyl group having 2 to 6 carbon atoms, and R is an alkyl group, cycloalkyl group, or alkylene group having 1 to 6 carbon atoms. Preferred examples include p-acetyloxycinnamic acid methyl ester, p-acetyloxycinnamic acid ethyl ester, p-acetyloxycinnamic acid n-propyl ester, p-acetyloxycinnamic acid i-propyl ester, and p-acetyloxycinnamic acid cyclohexyl ester. , p-propionyloxycinnamic acid methyl ester, p-propionyloxycinnamic acid ethyl ester, p-propionyloxycinnamic acid n-propyl ester, p-propionyloxycinnamic acid iso-
Propyl ester, p-propionyloxycinnamic acid cyclohexyl ester, p-butyryloxycinnamic acid methyl ester, p-butyryloxycinnamic acid ethyl ester, p-valeryloxycinnamic acid methyl ester, p-hexanoyloxycinnamic acid methyl ester, p-acetyloxycinnamic acid , p-propionyloxycinnamic acid, p-isopropionyloxycinnamic acid,
Examples include p-butyryloxycinnamic acid, p-isobutyryloxycinnamic acid, p-valeryloxycinnamic acid, p-hexanoyloxycinnamic acid, and the like. Is the cinnamic acid derivative of the present invention a known compound?
Alternatively, it can be manufactured by a method known per se. For example, p-hydroxycinnamic acid and alcohol are esterified in the presence of an acid catalyst (sulfuric acid, p-toluenesulfonic acid, etc.) to form p-hydroxycinnamic acid ester, which is then acylated by a known method. be synthesized. In addition, the intermediate p-
Hydroxycinnamic acid esters can also be synthesized by condensing p-hydroxybenzaldehyde and malonic acid monoester. The melanin suppressant of the present invention contains p-acyloxycinnamic acid ester in an amount of 0.01 to 50% of the nonvolatile components in the composition.
It is manufactured by blending in a proportion by weight, preferably 1 to 20 weight%. The melanin suppressant of the present invention can be in various forms, but generally it is in the form of a lotion, emulsion, cream, ointment, stick, solution in an organic solvent, pack, gel, etc. is preferred. In addition, other optional ingredients include ingredients commonly used in cosmetics (e.g., oily substances, humectants, thickeners, preservatives, emulsifiers,
Medicinal ingredients, fragrances, emulsion stabilizers, etc. can be used. In addition, various active ingredients include allantoin, vitamin E acetate, glycyrrhizin,
By adding Yokuinin, various plant extracts, etc., it is possible to improve the melanin suppressing effect. Furthermore, by adding various ultraviolet absorbing substances, it is possible to obtain a melanin suppressant that has both preventive and therapeutic effects on sunburn. The melanin suppressant of the present invention thus obtained is applied topically to affected areas such as spots, freckles, and pigmented areas after sunburn. In addition, in general, the dosage for cream and ointment preparations is as follows:
The amount is preferably 1 to 20 mg per cm ² of the skin surface, and in the case of a liquid preparation, the amount is preferably 1 to 10 mg, but the amount is not limited thereto. As mentioned above, the melanin suppressant of the present invention can be applied topically to the skin's dark spots, freckles, and pigmented areas after sunburn to treat and improve the areas and restore normal skin color. It is completely new and different from conventional sunscreens that prevent sunburn. Furthermore, the cinnamic acid derivative () used in the present invention is
For example, compared to other compounds such as p-hydroxycinnamic acid, it has excellent compatibility with various carriers and the like, so it is possible to obtain a melanin inhibitor that can be stably stored for a long period of time. Next, the present invention will be further explained by giving test examples, examples, and reference examples. Test Example 1 Effect on guinea pigs' ultraviolet pigment spots: Using experimental animals with acquired pigment spots, the pigmentation reducing effect was investigated. The results are shown in Table 1. [Test method] Yellow guinea pigs were used as experimental animals (guinea pigs whose skin color is similar to that of yellow people, and like humans, pigment spots begin to appear about 4 days after irradiation with ultraviolet rays, and turn darkest at about 8 days). The hair on the back of the guinea pig was clipped using clippers, and the hair was further shaved using an electric razor. 2.5 pieces on the back of this guinea pig in 6 places.
Cover with aluminum foil with a 2cm rectangular hole.
UV-B (6 SE lamps, 3.0 mW/cm ² irradiated once a day for 5 minutes for 3 consecutive days. From the 14th day after irradiation, the compound () was applied to pigmentation in 6 areas caused by irradiation. A 10% ethanol solution was applied twice a day for 25 consecutive days.The degree of darkening of the skin color was judged with the naked eye according to the criteria shown below, and the evaluation scores were averaged to measure the effect.Criteria Evaluation Point Findings -: 0: No pigmentation observed. ±: 1: Slight pigmentation observed only with unclear boundaries. +: 2: Moderate pigmentation observed with clear boundaries.: 3: Intensity with clear boundaries. Pigmentation was observed. [Results]

[Table] Test Example 2 Effect on human ultraviolet pigment spots: The pigmentation reducing effect of the compound of the present invention () was investigated on humans. First of all, the measurement method is Healthy Boy 15
A black rubber plate with three 1cm diameter holes was fixed on the back of the name, and a UV-B (4 SE lamps)
2.1 mW) was irradiated once a day for 1 to 3 minutes for 3 consecutive days. The intensity of this UV-B was determined by measuring the MED of each subject, and was set at an intensity of approximately 1.5 MED. Next, from day 14, when pigmentation occurred after irradiation and the skin color became the darkest, a cream containing 5% of the compound (prescription is the same as in Example 5) was applied once a day at a dose of approximately 15 mg/80 mm ² did. Six weeks after the start of application, comparison was made with the area to which the base cream (not containing only compound ()) was applied. The results are shown in Table 2.

【table】

[Table]
Note that no irritation or allergic reactions were observed in the areas where these creams were applied. Test Example 3 Effect on human pigment spots (spots): For human pigment spots (spots), cream containing 5% of compound () (from Example 5) was applied once a day at a dose of approximately 15 mg/80 mm ² The pigment was applied for 6 weeks, and the intensity of pigment spots was determined after 8 weeks. This result is the third
Shown in the table.

〔Judgment criteria〕

○: Completely transparent. △: Slightly cloudy. x: Cloudiness or precipitation occurs.

[Table] Example 1 Lotion type melanin suppressant: (Composition) p-acetyloxycinnamic acid n-propyl ester 5.0% Glycerin 4.0% Polyoxyethylene hydrogenated castor oil 1.5% Ethanol 10.0% Sodium pyrrolidone carboxylate 2.0% Fragrance Trace amount Purified water Remaining amount 100.0% Example 2 Oil essence type melanin suppressant: (Composition) p-acetyloxycinnamic acid methyl ester 5% Mink oil 55% Wheat germ oil 40.0% Example 3 W/O type moisture cream type Melanin inhibitor: (Composition) p-propionyloxycinnamic acid n-propyl ester 5 (%) Vaseline 6.0 (%) Cholesterol 0.6 Cetol 0.5 Sorbitan sesquiolate 2.0 Liquid lanolin 4.0 Isopropyl palmitate 8.0 Squalane 10.0 Solid paraffin 4.0 Butyl paraben 0.1 Methylparaben 0.1 Glycerin 3.0 Fragrance 0.2 Purified water Balance Example 4 O/W Moisture Cream Type Melanin Suppressant: (Composition) p-acetyloxycinnamic acid n-propyl ester
5.0 (%) Stearic acid 2.0 Setanol 4.0 Vaseline 5.0 Squalane 8.0 Hardened palm oil 4.0 Polyoxyethylene sorbitan monostearate (20E.O) 1.4 Lipophilic glycerin monostearate 2.4 Butylparaben 0.1 Methylparaben 0.1 Glycerin 3.0 Dipropylene glycol 3.0 L -Arginine 10.0 (%) Potassium hydroxide 0.2 Fragrance 0.2 Purified water Balance example 5 Emulsion type melanin suppressant: (Composition) p-acetyloxycinnamic acid ethyl ester
5 (%) Stearic acid 1.0 Setanol 2.0 Vaseline 2.5 Squalane 4.0 Hydrogenated palm oil 2.0 Polyoxyethylene sorbitan monostearate (20E.O) 1.4 Lipophilic glyceryl monostearate 1.2 (%) Butylparaben 0.1 Methylparaben 0.1 Glycerin 3.0 Dipropylene Glycol 3.0 Potassium hydroxide 0.2 Carboxyvinyl polymer 0.2 Fragrance 0.2 Purified water Balance example 6 Pack type (paste peel-off type) melanin suppressant: (Composition) p-acetyloxycinnamic acid n-propyl ester
10.0% 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 (EO addition 30
Mol) 0.5 Titanium oxide 8.0 Kaolin 6.0 Fragrance 0.1 Methylparaben 0.1 Purified water Balance example 7 Ointment-type melanin suppressant: (Composition) p-acetyloxycinnamic acid cyclohexyl ester 10 (%) White petrolatum 90 Example 8 Liquid-type melanin suppressant : (Composition) p-acetyloxycinnamic acid ethyl ester
10 (%) Ethanol 90 Reference Example 1 Production of p-acetyloxycinnamic acid n-propyl ester (i) p-hydroxycinnamic acid 19.7g (0.12 mol)
was dissolved in a mixed solvent of n-propyl alcohol (80 ml) and ether (10 ml), and a solution of 25 g (0.12 mol) of dicyclohexylcarbodiimide in ether (20 ml) was added dropwise to this solution over about 15 minutes under ice cooling. After stirring for 1 hour under ice-cooling, the mixture was stirred at room temperature for 5 hours to complete the reaction. After completion, the reaction mixture is poured into a large amount of saturated ammonium chloride aqueous solution, 300 ml of ethyl acetate is added, and the mixture is thoroughly stirred. After separating the crystalline N,N-dicyclohexylurea,
The organic layer and the aqueous layer are separated, and the aqueous layer is further extracted once with ethyl acetate. After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off to obtain a residue. This residue was dissolved in a hexane-ethyl acetate mixed solvent (4:
1), and after separating the insoluble substances again, p-hydroxycinnamic acid n-propyl ester was isolated using high performance liquid chromatography (silica gel: 30 cm, eluent: hexane/ethyl acetate = 4/1). This was further purified by recrystallization from methanol. Yield 80%. Melting point: 72.5-73℃ Elemental analysis (calculated value) as C ₁₂ H ₁₄ O ₃ : C: 69.60 (69.80), H: 6.55 (6.84) IR (KBr, cm ^-1 ): 3260 (OH), 1670 (CO ) NMR (CDCl ₃ , TMS internal standard, δ): 0.98 (3H, t, J = 7.5Hz, CH ₃ -) 1.72 (2H, q, t, J = 7.5Hz, J = 6.5Hz,
−CH ₂ −) 4.17 (2H, O, J=6.5Hz, −CH ₂ −) 6.26 (dJ=16.0Hz, C=C−H) 7.67 (d, J=16.0Hz, C=C−H) 6.92 (2H, d-m, J=9.0Hz, Ar-H) 7.41 (2H, d-m, J=9.0Hz, Ar-H) (ii) p-hydroxycinnamic acid n obtained in (i) above −
9.7 g (0.0471 mol) of propyl ester and 4.5 g (0.0565 mol) of pyridine in 50 ml of anhydrous benzene
Dissolve 4.4 g (0.0565 mol) of acetyl chloride in benzene (20 ml) while stirring under ice-cooling.
Add the solution dropwise over 15 minutes. After continuing stirring under ice-cooling for 1 hour, the temperature was raised to room temperature, and stirring was continued for an additional 4 hours to complete the reaction. After completion, the reaction mixture is poured into a large amount of saturated aqueous sodium bicarbonate solution and stirred for 1 hour. This is extracted with ether, and the ether layer is washed with 1N HCl and then with a saturated aqueous sodium bicarbonate solution. After drying the obtained ether layer over anhydrous sodium sulfate, the solvent was distilled off to obtain a residue. This residue was subjected to high performance liquid chromatography (silica gel, eluent: hexane/ethyl acetate = 5/1).
The desired p-acetyloxycinnamic acid n-
The propyl ester was isolated. Yield 96%. Melting point: 66.0-67.0℃ Elemental analysis (calculated value) as C ₁₄ H ₁₆ O ₄ : C: 68.00 (67.73), H: 6.76 (6.50) IR
(KBr, cm ^-1 ): 1700 (CO), 1740 (CO) NMR (CDCl ₃ , TMS internal standard, δ) 0.98 (3H, t, J = 7.0Hz, -CH ₃ -) 1.72 (2H, q, t, J=7.02Hz, J=6.5
Hz, -CH ₂ -) 2.27 (3H, s, CH ₃ CO) 4.17 (2H, t, J=6.5Hz, -CH ₂ -) 6.40 (1H, C=C-H) 7.71 (1H, C=C -H) 7.12 (2H, Ar-H) 7.56 (2H, Ar-H) Reference Example 2 Production of p-propionyloxycinnamic acid i-propyl ester (i) In (i) of Reference Example 1, n- The reaction was carried out under the same conditions except that i-propyl alcohol was used instead of propyl alcohol. After similar work-up, p-hydroxycinnamic acid i-propyl ester was obtained. Yield 92%. Melting point: 70-71℃ Elemental analysis (calculated value), as C ₁₂ H ₁₄ O ₃ : C: 70.16 (69.89), H: 7.01 (6.84) IR (KBr, cm ^-1 ): 3375 (OH), 1670 ( CO) NMR (CDCl ₃ , TMS internal standard, δ) 1.33 (6H, d, J=6.5Hz, CH ₃ −) 5.17 (1H, sep, J=6.5Hz, CH−) 6.27 (1H, d, J= 16.0Hz, C=C-H) 7.68 (1H, d, J=16.0Hz, C=C-H) 6.90 (2H, d-m, J=9.0Hz, Ar-H) 7.42 (2H, d-m , J=9.0Hz, Ar-H) (ii) p-hydroxycinnamic acid i- obtained in (i) above
9.7 g (0.0471 mol) of propyl ester, 5.2 g (0.0565 mol) of propionyl chloride,
The reaction was carried out in the same manner as in (ii) of Reference Example 1. After similar work-up, p-propionyloxycinnamic acid i-propyl ester was obtained. Yield 95%. Melting point: 33.5-34.0℃ Elemental analysis (calculated value) C ₁₅ H ₁₈ O ₄ : C: 68.65 (68.69), H: 6.98 (6.92) IR (KBr, cm ^-1 ): 1705 (CO), 1755 (CO) NMR (CDCl ₃ , TMS internal standard, δ): 1.24 (3H, t, J = 7.0Hz CH - ₃ CH ₂ -) 1.32 (6H, d, J = 6.5Hz

[Formula]) 2.58 (2H, q, J = 7.0Hz CH ₃ - CH ₂ -) 5.35 (1H, sep, J = 6.5Hz CH ₂ -) 6.37 (1H, C = C - H) 7.70 (1H, C = C-H) 7.13 (2H, Ar-H) 7.56 (2H, Ar-H) Reference Example 3 The compounds shown in Table 4 were obtained in the same manner as in Reference Example 1 or 2.

【table】

Claims (1)

[Claims] 1 General formula () (In the formula, R' represents an acyl group having 2 to 8 carbon atoms,
A melanin suppressant containing as an active ingredient a cinnamic acid derivative represented by R represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group, or an alkenyl group. 2. The melanin inhibitor according to claim 1, which contains 0.01 to 50% by weight of a cinnamic acid derivative ().