JPH06227958A - External agent for skin - Google Patents

Abstract

PURPOSE:To obtain the subject external agent for skin excellent in the treatment of pigmentation caused by the spots, freckles, sun-burn, etc., stability and safety by compounding a phenylalaninol derivative or a tyrosinol derivative as an effective component. CONSTITUTION:A phenylalaninol derivative or a tyrosinol derivative of formula I (R<1> is H or OH; R<2> and R<3> are H or alkyl; R<4> is H, alkanoyl or benzoyl), e.g. L-tyrosinol is, as an effective component, compounded in an amount of 0.01-50wt.%, preferably 0.1-20wt.%, based on the total composition. The composition is formulated as a cosmetic in a form of lotion, milky lotion, cream, ointment, stick, solution, pack, jell, etc. A compound of formula I is obtained by suspending a phenylalanin derivative or a tyrosin derivative of formula II in alcohol, adding thionyl chloride dropwise under heating and stirring to lead to the ester, adding benzoyl chloride or an alkanoyl chloride dropwise to lead to a compound of formula III and finally subjecting this compound to reduction.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a skin external preparation having an excellent pigmentation improving effect and its phenylalaninol derivative or tyrosinol derivative.

[0002]

2. Description of the Related Art Stain, freckles, and pigmentation on the skin after sunburn are less likely to occur, increase, or disappear with age, which is a problem for middle-aged and older people. Although the pathogenic mechanism of these pigmentation diseases has not been clarified yet,
It is considered that the melanin-synthesizing function in epidermal melanocytes is enhanced by the action of sunlight, especially ultraviolet rays, and melanocyte-stimulating hormone.

It is also considered that the aging-induced keratinization delay of epidermal keratinocytes (keratinocytes) causes an increase in melanin granule density in the epidermis, that is, a clinically symptomatic increase in pigmentation. These pigmented areas are localized and may cause a clear difference with the surrounding normal skin color.

There is a strong demand for the development of a drug capable of restoring such an acquired pigment (ie, melanin) deposit to a normal skin color, and many drugs have been commercialized so far.

For example, in recent years, cosmetics containing a vitamin C (L-ascorbic acid) derivative having an excellent reducing ability have also been used. However, the vitamin C derivative has a problem in stability and almost no effect is observed when used externally.

[0006] On the other hand, in Europe and America, hydroquinone is used as a medicine 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. There is a problem in that it is mixed as a drug from the viewpoint that it sometimes causes Other various melanin inhibitors have been reported, for example, isoflavone derivatives (JP-A-58-2250).
No. 04), p-hydroxycinnamic acid (JP-A-59-1)
96813), p-hydroxycinnamic acid amide derivative (JP-A-62-56459), and the like.

However, at present, there is no known substance which is excellent in both the pigmentation improving effect and the compoundability in the base for external preparations.

[0008]

DISCLOSURE OF THE INVENTION The present invention provides a melanin inhibitor having an excellent pigmentation-improving effect and having excellent performance in terms of compoundability with an external preparation base, and skin cosmetics containing the same. The purpose is to provide fees.

[0009]

In view of such circumstances, the inventors of the present invention have earnestly studied to obtain a substance that reduces or eliminates pigmentation through research on the mechanism of melanin production, and as a result, a specific phenylalaninol derivative or The inventors have found that a tyrosinol derivative has a melanin production inhibitory effect, and completed the present invention.

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

[0011]

[Chemical 3]

(In the formula, R ¹ is a hydrogen atom or a hydroxyl group, and R ^{2 is}
And R ³ each represent a hydrogen atom or an alkyl group, and R ⁴ represents a hydrogen atom, an alkanoyl group or a benzoyl group. And a phenylalaninol derivative or tyrosinol derivative represented by the formula (1) or a salt thereof as an active ingredient.

In the general formula (1), the alkyl group represented by R ² and R ³ is preferably a linear or branched lower alkyl group having 1 to 5 carbon atoms, specifically, a methyl group, an ethyl group or n- Examples thereof include propyl group, isopropyl group, n-butyl group, isobutyl group and the like. The alkanoyl group for R ⁴ is preferably a linear or branched lower alkanoyl group having 2 to 8 carbon atoms, and specific examples thereof include an acetyl group, a propanoyl group, a butyryl group, a pentanoyl group and a hexanoyl group.

As the salt of the phenylalaninol derivative or the tyrosinol derivative (1), inorganic acid salts such as hydrochloride, nitrate and sulfate, or fumaric acid, maleic acid,
Organic acid salts such as tartaric acid, oxalic acid and citric acid can be mentioned.

Preferred specific examples of the phenylalaninol derivative or tyrosinol derivative (1) or a salt thereof used in the present invention include L-tyrosinol, L-tyrosinol hydrochloride, D-tyrosinol, D-tyrosinol hydrochloride and D-tyrosinol. Phenylalaninol, L-phenylalaninol, N-benzoyl-L-tyrosinol, N-acetyl-L-tyrosinol, N-hexanoyl-L-tyrosinol, DL-α-methyltyrosinol, DL-β
-Methylphenylalaninol and the like are mentioned, and among them, L-tyrosinol and L-tyrosinol hydrochloride are particularly preferable.

The phenylalaninol derivative or the tyrosinol derivative (1) can be synthesized by a conventionally known method, and a specific production method thereof includes, for example, the method shown below.

Production Method A According to the following reaction formula, (R ⁵ OH) phenylalanine derivative or tyrosine derivative (2) is suspended in alcohol, and thionyl chloride is added dropwise with stirring under heating to form an ester body (3). Benzoyl chloride or alkanoyl chloride is added dropwise in the presence to form a benzoyl body or an alkanoyl body (4), and this ester body (3) or a benzoyl body or an alkanoyl body (4) is reduced with an appropriate reducing agent such as NaBH _4. Accordingly, in the general formula (1), R ⁴ is a benzoyl group or an alkanoyl group, or a phenylalaninol derivative or a tyrosinol derivative (1
a) is obtained (Michael E. J. et a.
l. , Tetrahedron Lett. , 30, 4
211 (1989)).

[0018]

[Chemical 4]

Production Method B The phenylalanine derivative or tyrosine derivative (5) or its ester form (6) is converted into Li according to the following reaction formula.
A phenylalaninol derivative or a tyrosinol derivative (1) is obtained by reduction with a reducing agent such as AlH ₄ or LiBH ₄ (Saund, AK et a.
l. , (1971), Indian J .; Chem.
9,936, Daniel, V .; S. et al. ，
J. Med. Chem. , 16, 273 (197)
3)).

[0020]

[Chemical 5]

Production Method C According to the following reaction formula, the phenylalanine derivative or the tyrosine derivative (1) is reduced by reducing the phenylalanine derivative or the tyrosine derivative (5) with sodium dihydro-bis- (2-methoxyethoxy) aluminate (SDA). ) Is obtained (Saund, AK e
t al. , Int. J. Pept. Protein
Res. , 5, 7 (1973)).

[0022]

[Chemical 6]

Among the thus obtained phenylalaninol derivative or tyrosinol derivative (1) or a salt thereof, the compound represented by the following general formula (1 ′) and a salt thereof are novel substances not described in the literature.

[0024]

[Chemical 7]

In the external preparation for skin of the present invention, the above-mentioned phenylalaninol derivative or tyrosinol derivative (1) or a salt thereof can be blended alone or in combination of two or more kinds, and the blending amount is the whole composition. 0.01-5 in
0% by weight, particularly 0.1 to 20% by weight is preferred.

The external preparation for skin 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 cosmetics such as

The external preparation for skin of the present invention may contain any component other than the phenylalaninol derivative or the tyrosinol derivative (1) within a range that does not impair the effects of the present invention. Ingredients usually added to skin external preparations, such as purified water, ethanol, oily substances, moisturizers,
Thickeners, preservatives, emulsifiers, medicinal ingredients, powders, fragrances, emulsion stabilizers, pH adjusters and the like can be added.

Specific examples of the oily component include 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. As the moisturizer, sorbitol, xylitol, glycerin, maltitol, propylene glycol, 1,3-butylene glycol, 1,4-butylene glycol, sodium pyrrolidonecarboxylate, lactic acid, sodium lactate, polyoxypropylene fatty acid ester, polyethylene glycol, etc. Examples of the thickener include carboxyvinyl polymer, carboxymethyl cellulose, polyvinyl alcohol, carrageenan, water-soluble polymers such as gelatin, sodium chloride, potassium chloride. Electrolytes and the like, preservatives include urea, methylparaben, ethylparaben, propylparaben, butylparaben, sodium benzoate, and the like, and emulsifiers include polyoxyethylene alkyl ether, polyoxyethylene fatty acid ester, polyoxyethylene. Nonionic surfactants such as 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, and the like, powder as talc, Sericite, mica, kaolin, silica, bentonite, vermiculite, zinc white, mica, titanium mica, titanium oxide, magnesium oxide, zirconium oxide, barium sulfate, benga , Iron oxide, include ultramarine blue, as a pH adjusting agent lactate - sodium lactate, citric acid - include buffering agents such as sodium citrate. Also, as various active ingredients, allantoin, vitamin E derivative, glycyrrhizin, ascorbic acid derivative, kojic acid, arbutin, pantethenic acid derivative, placenta extract, anti-inflammatory agent, yoquinin, various plant extracts, etc. are added to suppress melanin. The effect can be improved. Furthermore, by adding various ultraviolet absorbing substances, a skin external preparation having both a sunburn preventive effect and a therapeutic effect can be obtained.

The external preparation for skin of the present invention is applied to the affected area such as inflammation of the skin due to ultraviolet rays, stains, freckles, and pigmented areas after sunburn to treat / improve the area and normal skin. Can be returned to color. Generally, the dose is, for example, in the case of a cream or ointment type preparation,
It is preferably 1 to 20 mg per cm ^{2 of the} skin surface, and 1 to 10 mg in the case of a liquid preparation, but it is not limited to this.

[0030]

EXAMPLES The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto.

Synthesis Example 1 Synthesis of L-tyrosinol hydrochloride (1) L-tyrosine ethyl ester

[0032]

[Chemical 8]

Under a nitrogen atmosphere, 19 g (104.9 mmol) of L-tyrosine was added to 190 ml of absolute ethanol and the mixture was stirred. Thionyl chloride 11.5 ml (1
(57.7 mmol) was added dropwise, and the mixture was reacted at 95 ° C. for 4 hours and 30 minutes. The reaction system was concentrated under reduced pressure to give a white solid. The organic layer was extracted with water (pH 8) / ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to L
-Tyrosine ethyl ester yield 21.1 g, yield 9
Obtained at 6.17%. Molecular formula C ₁₁ H ₁₅ NO ₃ , molecular weight 209.25, white solid ¹ H-NMR (200MHz, CD ₃ OD): δ = 1.30 (t, 3H, J = 7.2Hz), 3.15 (m,
2H), 4.23 (m, 1H), 4.30 (q, 2H, J = 7.2Hz), 6.82 (d, 2H, J = 8.5H
z), 7.11 (d, 2H, J = 8.5Hz) IR (KBr): 3356,2904,1736,1616,1594,1514,1490,1440,12
74,1242,1218,840cm ^-1

(2) L-tyrosinol hydrochloride

[0035]

[Chemical 9]

LiAlH ₄ 0.496 under nitrogen atmosphere
25 ml of anhydrous THF was added to 8 g (13.1 mmol) and stirred. At room temperature, 0.6522 g (3.12 mmol) of L-tyrosine ethyl ester was added little by little to this suspension, and then the mixture was reacted for 50 minutes. 30 ml of water was added to the reaction system, pH was adjusted to 7 with 1N hydrochloric acid, and liquid separation extraction was performed with n-butanol. The organic layer was concentrated under reduced pressure and azeotropically distilled with ethanol to obtain an extract with a yield of 0.5658 g. 0.23 of this extract
20 g of the resin was dissolved in a small amount of water, and 2030 g of resin HP was charged into a column (inner diameter 3 cm) equilibrated with water and eluted with water. The target fraction was azeotroped under reduced pressure with n-butanol and then with ethanol to obtain 0.1408 g of L-tyrosine hydrochloride (estimated yield 0.3138).
g, estimated yield 49.19%). Molecular formula C ₉ H ₁₃ NO ₂ .HCl, molecular weight 204.67, white solid ¹ H-NMR (200 MHz, CD ₃ OD): δ = 2.85 (d, 2 H, J = 7.4 Hz), 3.53 (d.
d., 1H, J = 11.5,6.3Hz), 3.71 (dd, 1H, J = 11.5,3.6Hz), 6.7
8 (d, 2H, J = 8.5Hz), 7.09 (d, 2H, J = 8.5Hz) IR (KBr): 3700 ~ 2300,1614,1588,1492,1438,1260,1216,1
066,820 cm ^-1

Synthesis Example 2 Synthesis of N-benzoyl-L-tyrosinol (1) N-benzoyl-L-tyrosine ethyl ester

[0038]

[Chemical 10]

L-Tyrosine ethyl ester / hydrochloride 1.
After dissolving 17 g (4.76 mmol) in 15 ml of water with stirring, 0
Cooled to 0 ° C., 0.57 g (14.25 mmol) NaOH
/ 10 ml aqueous solution, followed by benzoyl chloride 0.64 ml
(0.77 g) (5.47 mmol) / 5 ml chloroform solution was added dropwise. After reacting for 1 hour, the mixture was extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Flash silica gel column (Silica
70 g of gel 60 (230-400 mesh), equilibrated with hexane / ethyl acetate = 3/1), N
Yield of -benzoyl-L-tyrosine ethyl ester
52 g, yield 34.90%. N as a by-product
The amount of O-dibenzoyl-L-tyrosine ethyl ester obtained was 0.26 g (13.08%).

(2) N-benzoyl-L-tyrosinol

[0041]

[Chemical 11]

Under a nitrogen atmosphere, LiCl 0.1113 g
(2.63 mmol), 0.099 g of NaBH ₄ (2.6
2 mmol) and 10 ml of anhydrous THF are mixed with stirring, and N-benzoyl-L-tyrosine ethyl ester 0.3657 g
(1.17 mmol) / 10 ml anhydrous THF solution was added dropwise.
The reaction was carried out at room temperature for 1 hour and 40 minutes and at 85 ° C. for 4 hours, but the raw materials were not consumed, so LiCl 0.0493 was added.
g (1.16 mmol) and 0.0442 g NaBH ₄
(1.17 mmol) was added and the mixture was reacted at 85 ° C. for 1 hour, but the raw material did not disappear. The reaction system was added little by little to crush the unreacted borohydride compound, extracted with ether, the organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification was carried out using a flash silica gel column (70 g, equilibrated with hexane / ethyl acetate = 5/1). Raw material N-
Benzoyl-L-tyrosine ethyl ester 0.164
6 g (recovery rate 45.01%) was recovered. Yield 0.1590 g of N-benzoyl-L-tyrosinol, yield 5
Obtained at 0.19%. Molecular formula C ₁₆ H ₁₇ O ₃ N, molecular weight 271.32, white solid ¹ H-NMR (200MHz, CD ₃ OD): δ = 2.97 to 2.74 (m, 2H), 3.65 (d, 2)
H, J = 5.2Hz), 4.34 to 4.22 (m, 1H), 6.72 (d, 2H, J = 8.3Hz), 7.1
0 (d, 2H, J = 8.4Hz), 7.51〜7.34 (m, 3H), 7.73 (d, 2H, J = 8.1H
z) IR (KBr): 3464,3316,1628,1602,1518,1450,1422,1238,10
26 cm ^-1

Example 3 Synthesis of N-acetyl-L-tyrosinol (1) N, O-diacetyl-L-tyrosine ethyl ester

[0044]

[Chemical 12]

2.26 g of L-tyrosine ethyl ester
(10.8 mmol), 20 ml of acetic anhydride and the amount of pyridine catalyst were mixed with stirring at 0 ° C. and reacted for 2 hours and 30 minutes. 20 ml of ethanol was added to the reaction system, acetic anhydride was crushed, and the mixture was concentrated under reduced pressure to obtain 3.17 g of N, O-diacetyl-L-tyrosine ethyl ester in a crude yield of 100%. This was used for the next reaction as it was. Molecular formula C ₁₅ H ₁₉ O ₅ N, molecular weight 293.32, white solid ¹ H-NMR (200MHz, CDCl ₃ ): δ = 1.23 (t, 3H, J = 7.1Hz), 1.98 (s,
3H), 2.28 (s, 3H), 3.10 (d, 2H, J = 6.0Hz), 4.16 (q, 2H, 7.1H
z), 4.84 (dd, 1H, J = 13.7,6.0Hz), 6.22 (bd, 1H), 7.00 (d, 2
H, J = 8.5Hz), 7.13 (d, 2H, J = 8.5Hz) IR (KBr): 3344,1742,1642,1514,1370,1220,1022cm ^-1

(2) N-acetyl-L-tyrosinol

[0047]

[Chemical 13]

After cooling to 0 ° C. under a nitrogen atmosphere, N, O-diacetyl-L-tyrosine ethyl ester (1.5 g, 5.1)
1 mmol) and 30 ml of anhydrous ether are mixed by stirring, and 2M
After adding 7.7 ml (15.4 mmol) of LiBH ₄ THF solution dropwise, the mixture was reacted at room temperature for 30 minutes. 2M LiBH ₄
A THF solution (3.4 ml, 6.8 mmol) was added dropwise and the mixture was reacted for 3 hours and 30 minutes and then at 40 ° C. for 1 hour. Furthermore, 3.4 ml (6.8 mmol) of a 2M LiBH ₄ THF solution was added.
Was added and reacted at 50 ° C. for 1 hour to confirm disappearance of the raw materials. Water was added little by little to the reaction system to crush unreacted LiBH ₄ , followed by liquid separation extraction with ethyl acetate and butanol,
The organic layer was concentrated under reduced pressure. Flash silica gel column (Silica gel 60 (230-400 mes
h) 70 g, equilibrated with hexane / ethyl acetate = 1/1,
Hexane / ethyl acetate = 1/1 2.2 liters, ethyl acetate 9 liters, ethyl acetate / methanol = 100 /
11 liters, ethyl acetate / methanol = 50/11
Elution in liters) and purified with N-acetyl-
Yield 0.81 g of L-tyrosinol, 75.70% yield
Got with. Molecular formula C ₁₁ H ₁₅ O ₃ N, molecular weight 209.24, white solid ¹ H-NMR (200MHz, DMSO-d ₆ ): δ = 1.79 (s, 3H), 2.57 to 2.46 (m,
1H), 2.75 to 2.65 (m, 1H), 3.33 (m, 2H), 3.9 to 3.7 (m, 1H), 4.6
3 (m, 1H), 6.65 (d, 2H, J = 8.3Hz), 6.98 (d, 2H, J = 8.3Hz), 7.61
(bd, 1H), 9.03 (bd, 1H) IR (KBr): 3600 ~ 2500,1632,1515,1446,1377,1236,1038cm
^-1

Example 4 Synthesis of N-hexanoyl-L-tyrosinol (1) N-hexanoyl-L-tyrosine ethyl ester

[0050]

[Chemical 14]

2.0 g of L-tyrosine ethyl ester
(9.56 mmol) and 20 ml of pyridine were dissolved with stirring,
After cooling to 19 ° C., CH ₃ (CH ₂ ) ₄ COCl 1.35 m
1 (9.83 mmol) was added dropwise. After reaction for 50 minutes -8 ° C
The temperature was raised to. After 3 ml of ethanol was added dropwise to the reaction system, the mixture was concentrated under reduced pressure. Liquid separation extraction was performed with water (pH 2) / ethyl acetate, the organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. Flash silica gel column (Silica gel 6)
0 (230-400 mesh) 70 g, equilibrated with hexane / ethyl acetate = 2/1) to give N-hexanoyl-L-tyrosine ethyl ester in a yield of 2.93.
g, yield 99.66%. Molecular formula C ₁₇ H ₂₅ O ₄ N, molecular weight 307.39, colorless and transparent ¹ H-NMR (200 MHz, CDCl ₃ ): δ = 2.3 to 0.7 (m, 14H), 3.15 to 2.85
(m, 2H), 4.19 (q, 2H, J = 7.2Hz), 4.9 ~ 4.7 (m, 1H), 6.09 (bd, 1
H), 6.73 (d, 2H, 8.2Hz), 6.94 (d, 2H, J = 8.2Hz), 7.42 (s, 1H) IR (NaCl): 3600 ~ 3100,3050 ~ 2850,1730,1648,1516, 1216
cm ^-1

(2) N-hexanoyl-L-tyrosinol

[0053]

[Chemical 15]

Under a nitrogen atmosphere, 1.01 g (3.28 mmol) of N-hexanoyl-L-tyrosine ethyl ester and 30 ml of anhydrous ether were stirred and mixed, and 2M LiBH ₄ T was added.
After dropwise adding 7.31 ml (14.62 mmol) of HF solution, 50
The reaction was carried out at 0 ° C for 1 hour. Water was added little by little to crush unreacted LiBH _4, and the mixture was extracted with ether and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Flash silica gel column (Silica
40 g of gel 60 (230-400 mesh, equilibrated with hexane / ethyl acetate = 1/4) to give N-hexanoyl-L-tyrosinol in a yield of 0.5.
5 g, yield 63.22%. Molecular formula C ₁₅ H ₂₃ O ₃ N, molecular weight 265.35, white solid ¹ H-NMR (200MHz, CD ₃ OD): δ = 1.7 to 0.7 (m, 9H), 2.12 (t, 2H, J
= 7.4Hz), 2.60 (dd, 1H, J = 13.9,8.4Hz), 2.82 (dd, 1H, J =
13.9,6.2Hz), 3.51 (d, 2H, J = 5.3Hz), 4.2〜3.9 (m, 1H), 6.70
(d, 2H, J = 8.5Hz), 7.04 (d, 2H, J = 8.5Hz) IR (KBr): 3600 ~ 3000,2952,2928,2860,1642,1616,1536,1
516,1454,1242,1032cm ^-1

Example 5 Synthesis of DL-α-methyltyrosinol

[0056]

[Chemical 16]

LiAlH ₄ 0.324 under nitrogen atmosphere
7 g (8.56 mmol) and 25 ml of THF were mixed with stirring,
DL-α-methyltyrosine methyl ester 0.5000
g (2.03 mmol) was added to the reaction system in small portions. After reacting for 1 hour, water was added little by little to the reaction system in order to crush unreacted LiAlH ₄ , and the mixture was filtered and the filtrate was concentrated under reduced pressure. The concentrate was charged on a column (inner diameter 2.4 cm) equilibrated with 30 g of resin HP20 and eluted with water. Fractions of the target compound are collected, concentrated under reduced pressure, separated and extracted with water (pH 8) / butanol system, the organic layer is concentrated under reduced pressure, and DL
The amount of -α-methyltyrosinol obtained was 0.2061 g, and the yield was 45.59%. Molecular formula C ₁₀ H ₁₅ O ₂ N, molecular weight 181.23, white solid ¹ H-NMR (200 MHz, CD ₃ OD): δ = 1.20 (s, 3H), 2.77 (d, 1H, J = 13.
5Hz), 2.95 (d, 1H, J = 13.5Hz), 3.44 (d, 1H, J = 11.4Hz), 3.53
(d, 1H, J = 11.4Hz), 6.79 (d, 2H, J = 8.2Hz), 7.08 (d, 2H, J = 8.2
Hz) IR (KBr): 3600-3100,3100-2800,1614,1593,1494,1263,
1206,1044cm ^-1

Example 6 Synthesis of DL-β-methylphenylalaninol (1) DL-β-methylphenylalanine ethyl ester hydrochloride

[0059]

[Chemical 17]

Under a nitrogen atmosphere, 1.0 g (4.62 mmol) of DL-β-methylphenylalanine was added to absolute ethanol 2
Dissolve in 0 ml with stirring, and under ice cooling, thionyl chloride 0.51 ml
(6.99 mmol) was added dropwise, and the mixture was reacted at 80 ° C. for 3 hours and 30 minutes. Further, 0.2 ml (2.74 mmol) of thionyl chloride was added, and the mixture was reacted at 80 ° C for 2 hours. The reaction system was concentrated under reduced pressure and recrystallized from an ethanol / ether system to give DL-
β-methylphenylalanine ethyl ester · hydrochloride was obtained as a secondary crystal in an amount of 0.446 g and a yield of 39.47%. Molecular formula C ₁₂ H ₁₇ O ₂ N.HCl, molecular weight 244.73,
White solid ¹ H-NMR (200MHz, DMSO-d ₆ ): δ = 1.18 (d, 3H, J = 7.1Hz), 1.32
(d, 3H, J = 7.2Hz), 4.23 to 4.11 (m, 3H), 7.32 (s, 5H), 8.49 (b
d, 2H) IR (KBr): 2974,2926,1737,1596,1494,1224cm ^-1

(2) DL-β-methylphenylalaninol

[0062]

[Chemical 18]

LiAlH ₄ 0.157 under nitrogen atmosphere
1 g (4.14 mmol) and 10 ml of THF were mixed with stirring,
0.2017 g (0.824 mmol) of DL-β-methylphenylalanine ethyl ester · hydrochloride was added little by little and reacted for 1 hour and 30 minutes. In order to crush unreacted LiAlH ₄ , water was added little by little to the reaction system, then filtered, the filtrate was extracted with ethyl acetate and dried over anhydrous sodium sulfate,
The organic layer was concentrated under reduced pressure. Concentrate the resin HP20
25 g of the column (inside diameter 2.2 cm) equilibrated with water was charged and eluted with water to obtain DL-β-methylphenylalaninol in an amount of 0.1157 g and a yield of 85.70%. Molecular formula C ₁₀ H ₁₅ ON, molecular weight 165.23, white solid ¹ H-NMR (200 MHz, CD ₃ OD): δ = 1.35 (d, 3 H, J = 6.9 Hz), 3.2 to 2.
9 (m, 1H), 4.0 to 3.7 (m, 2H), 7.35 (s, 5H) IR (KBr): 3468,2980,1584,1500,1044cm ^-1

Test Example 1 Evaluation of guinea pig dorsal skin hair follicle organ culture system by tyrosinase activity Test method: 8 to 1 after birth, which is actively performing melanin synthesis
One day brown guinea pig dorsal follicles were cultured for 3-4 days. The evaluation sample was added to the culture medium during culturing so that the final concentration was 5 mM, and the activity of the enzyme responsible for melanin synthesis, tyrosinase, was measured by the amount of free tritium ( ³ HOH) from 3,5- ³ H-tyrosine. It was evaluated by comparing with a control according to a standard. The results are shown in Table 1. No suppressive effect 0 0 to 5% ± 5 to 35% + 35% to ++ Result:

[0065]

[Table 1]

Example 1 Pigmentation improving cream

[Table 2] (Components) (% by weight) (1) Decaglyceryl stearate 1.8 (2) Polyoxyethylene cetyl ether 1.2 (3) Squalane 12.0 (4) Cetanol 6.0 (5) Palmitin Cetyl acid 3.0 (6) 1,3-butylene glycol 6.0 (7) Glycerin 3.0 (8) L-tyrosinol 1.0 (9) Purified water remaining amount (10) Perfume trace amount (production method) Oil phase Ingredients (1) to (6) were heated and mixed at 80 ° C, and heated to 80 ° C with stirring.
0) is added and emulsified, and then cooled to room temperature with stirring.

Example 2 Emulsion for improving pigmentation

[Table 3] (Components) (wt%) (1) Polyoxyethylene sorbitan stearate 1.0 (2) Glycerol oleate 1.0 (3) Glyceryl monostearate 0.5 (4) Squalane 6.0 ( 5) Glyceryl trioctanoate 2.0 (6) Cetyl octanoate 2.0 (7) Stearyl alcohol 2.0 (8) 1,3-Butylene glycol 5.0 (9) Glycerin 3.0 (10) L-tyrosinol Hydrochloride 0.05 (11) Purified water Remaining amount (12) Perfume Trace amount (manufacturing method) The oil phase components (1) to (7) are heated and mixed at 80 ° C., and the aqueous phase component (80) is heated under stirring ( 8) ~ (1
After 2) is added and emulsified, it is cooled to room temperature with stirring.

Example 3 Pigmentation improving lotion

[Table 4] (Components) (wt%) (1) 1,3-butylene glycol 8.0 (2) glycerin 4.0 (3) sodium hyaluronate 0.1 (4) ethanol 3.0 (5) poly Oxyethylene polyoxypropylene decyl tetradecyl ether 0.3 (6) N-hexanoyl-L-tyrosinol 0.1 (7) Purified water remaining amount (8) Fragrance A slight amount (production method) (1) to (3) and (6) After dispersing the component (4), 60% of the component (7) is added thereto to obtain A. On the other hand, after stirring and dissolving the components (4), (5) and (8), the remaining amount of the component (7) is added and designated as B. While stirring A, add B and mix.

Example 4 Serum for improving pigmentation

[Table 5] (Components) (wt%) (1) 1,3-butylene glycol 8.0 (2) glycerin 4.0 (3) xanthan gum 0.3 (4) sodium chondroitin sulfate 0.1 (5) hyalurone Sodium acid 0.05 (6) Ethanol 3.0 (7) Polyoxyethylene polyoxypropylene decyl tetradecyl ether 0.3 (8) DL-β-methylphenylalaninol 2.0 (9) Purified water balance ( 10) Fragrance A small amount (manufacturing method) After stirring and dispersing the components (1) to (5) and (8), 65% of the component (9) is added thereto to obtain A.
On the other hand, after stirring and dissolving the components (6), (7) and (10), the remaining amount of the component (9) is added and designated as B. While stirring A, add B and mix.

[0070]

EFFECT OF THE INVENTION Phenylalaninol derivative or tyrosinol derivative (1) contained in the external preparation for skin of the present invention.
Strongly suppresses the activity of tyrosinase, which is an enzyme required for melanin synthesis, and also suppresses the production of melanin in artificially formed pigment spots. Moreover, it has an excellent effect of improving melanin deposition with almost no side effects.

Therefore, the external preparation for skin of the present invention is excellent in the effect of improving pigmentation on the skin such as spots, freckles, and after sunburn, and is stable and highly safe.

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[Procedure amendment]

[Submission date] March 16, 1993

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0017

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Production Method A According to the following reaction formula, a phenylalanine derivative or a tyrosine derivative (2) is suspended in an alcohol (R ⁵ OH), and thionyl chloride is added dropwise with stirring under heating to form an ester body (3). Benzoyl chloride or alkanoyl chloride is added dropwise in the presence to give a benzoyl body or an alkanoyl body (4), and this ester body (3) or benzoyl body or alkanoyl body (4) is converted into LiAl.
A phenylalaninol derivative or a tyrosinol derivative (1) can be obtained by reduction with an appropriate reducing agent such as H ₄ , LiBH ₄ , NaBH ₄ (Michael
E. J. et al. , Tetrahedron Let
t. , 30, 4211 (1989); Saund, A .;
K. et al. , (1971), Indian J .;
Chem. 9, 936; Daniel, V .; S. et
al. J. Med. Chem. , 16, 273 (1
973)).

[Procedure Amendment 2]

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[Correction target item name] 0018

[Correction method] Change

[Correction content]

[0018]

[Chemical 4]

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0019

[Correction method] Delete

[Procedure amendment 4]

[Document name to be amended] Statement

[Correction target item name] 0020

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[Procedure Amendment 5]

[Document name to be amended] Statement

[Correction target item name] 0021

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[Correction content]

Production Method B By reacting sodium phenylalanine derivative or tyrosine derivative (5) with sodium dihydro-bis- (2-methoxyethoxy) aluminate (SDA) according to the following reaction formula, without esterifying the carboxyl group. It can be reduced to obtain a phenylalaninol derivative or a tyrosinol derivative (1) (Saund,
A. K. et al. , Int. J. Pept. Pro
tainRes. , 5, 7 (1973)).

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI Technical indication location A61K 31/165 9283-4C (72) Inventor Yukihiro Yada 1-chome Kushitada-nishi 115, Ninomiya-cho, Haga-gun, Tochigi Prefecture − 1 (72) Inventor Genji Imokawa 1022-89 Himurocho, Utsunomiya City, Tochigi Prefecture

Claims (2)

[Claims] 1. A compound represented by the general formula (1): (Wherein R ¹ represents a hydrogen atom or a hydroxyl group, R ² and R ³ represent a hydrogen atom or an alkyl group, respectively, and R ⁴ represents a hydrogen atom, an alkanoyl group or a benzoyl group). A skin external preparation containing a tyrosinol derivative or a salt thereof as an active ingredient. 2. The general formula (1 ′): (In the formula, R ¹ represents a hydrogen atom or a hydroxyl group, R ² and R ³ represent a hydrogen atom or an alkyl group, and R ⁴ ′ represents a hydrogen atom or an alkanoyl group, provided that R ³ and R ⁴ ′ are simultaneously a hydrogen atom. The phenylalaninol derivative or the tyrosinol derivative represented by the formula) or a salt thereof.