JP5994789B2 - Anti-wrinkle cosmetic - Google Patents

Description

  The present invention relates to a cosmetic useful for preventing wrinkles containing a specific cysteine derivative.

  A major cause of wrinkles and sagging associated with skin aging is thought to be related to a decrease in the amount of collagen in the dermis. Collagen amount is an important factor constituting the softness and tension of the skin. In order to increase the amount of collagen in the skin tissue, it is important to inhibit collagenase activity induced by UV irradiation, suppress collagen degradation, and promote collagen production. Although several kinds of substances are commercially available as substances that promote collagen production, they are not always satisfactory in terms of stability, safety and wrinkle prevention effect.

  On the other hand, Patent Document 1 describes that a cysteine derivative obtained by esterifying L-2-methylthiazolidine-2,4-dicarboxylic acid or a salt thereof is useful as a whitening agent or the like. Furthermore, Patent Document 2 describes that 2-methylthiazolidine-2,4-dicarboxylic acid or a derivative thereof has a whitening action. However, these derivatives have not been put into practical use because they are easily decomposed and are not sufficiently stable. The specific cysteine derivative of the present invention is not described, and the wrinkle prevention effect is not described.

JP 2009-227660 A JP 2010-12239 A

An object of the present invention is to provide a cosmetic having high stability and safety and excellent anti-wrinkle effect.
Another object of the present invention is to provide a composition for promoting collagen production (collagen production promoter).

  As a result of intensive research, it was found that a specific cysteine derivative having high stability and safety has an effect of promoting collagen production and thus has an anti-wrinkle effect, and the specific cysteine derivative and a specific collagen production promoting compound The present invention has been completed by finding that the effect is synergistically increased when used in combination.

  That is, the present invention is as follows.

[1] A cysteine derivative represented by the general formula (I) or a salt thereof:
[Where:
X and Y are each independently OR ¹ , NHR ² (wherein R ¹ and R ² each independently represents a hydrogen atom or a C _1-22 alkyl group);
Z represents a hydrogen atom or a C _1-22 alkyl group;
W represents a C _1-22 alkyl group, a C _1-22 alkoxy group or a C _1-22 alkylamino group. ]
Anti-wrinkle cosmetic containing
[2] (A) A cysteine derivative represented by the general formula (I) or a salt thereof:
[Where:
X and Y are each independently OR ¹ , NHR ² (wherein R ¹ and R ² each independently represents a hydrogen atom or a C _1-22 alkyl group);
Z represents a hydrogen atom or a C _1-22 alkyl group;
W represents a C _1-22 alkyl group, a C _1-22 alkoxy group or a C _1-22 alkylamino group. And (B) a cosmetic containing one or more selected from vitamin A or a derivative thereof, vitamin E or a derivative thereof, zinc salt, ubiquinone, peptide, amino acid and nucleic acid.
[3] (A) A cysteine derivative or a salt thereof is N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid, N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid-2-ethyl ester, And the cosmetic according to [1] or [2] above, which is one or more selected from salts thereof.
[4] The above-mentioned [2] or [3], wherein the component (B) is one or more selected from retinoic acid, retinol, vitamin E, pyrrolidone carboxylic acid zinc salt and milk-derived peptide. ] Cosmetics as described in.
[5] (A) The cysteine derivative or a salt thereof is N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid-2-ethyl ester or a salt thereof, and (B) the component is vitamin A or a derivative thereof The cosmetic according to [2] above, wherein
[6] (A) The cysteine derivative or a salt thereof is N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid-2-ethyl ester or a salt thereof, and (B) the component is a pyrrolidone carboxylic acid zinc salt. The cosmetic according to [2] above, wherein
[7] The above, wherein the blending ratio of (A) the cysteine derivative or salt thereof and the component (B) is (A) / (B) = 1/20 to 100000/1 (g / g) The cosmetic according to any one of [2] to [6].
[8] (A) A cysteine derivative represented by the general formula (I) or a salt thereof:
[Where:
X and Y are each independently OR ¹ , NHR ² (wherein R ¹ and R ² each independently represents a hydrogen atom or a C _1-22 alkyl group);
Z represents a hydrogen atom or a C _1-22 alkyl group;
W represents a C _1-22 alkyl group, a C _1-22 alkoxy group or a C _1-22 alkylamino group. ]
Containing collagen production promoter.
[9] (B) Collagen production according to [8] above, further comprising one or more selected from vitamin A or a derivative thereof, vitamin E or a derivative thereof, zinc salt, ubiquinone, peptide, amino acid and nucleic acid Accelerator.
[10] (A) A cysteine derivative or a salt thereof is N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid, N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid-2-ethyl ester, And the collagen production promoter according to [8] or [9] above, which is one or more selected from salts thereof.
[11] The above [9] or [10], wherein the component (B) is one or more selected from retinoic acid, retinol, vitamin E, pyrrolidone carboxylic acid zinc salt and milk-derived peptide. ] The collagen production promoter as described in above.
[12] (A) The cysteine derivative or a salt thereof is N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid-2-ethyl ester or a salt thereof, and (B) the component is vitamin A or a derivative thereof The collagen production promoter according to [9] above, which is characterized in that it exists.
[13] (A) The cysteine derivative or a salt thereof is N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid-2-ethyl ester or a salt thereof, and (B) the component is a pyrrolidone carboxylic acid zinc salt. The collagen production promoter according to [8] above, which is characterized in that it exists.
[14] The above, wherein the blending ratio of (A) cysteine derivative or salt thereof and component (B) is (A) / (B) = 1 / 20-100,000 / 1 (g / g) [9] The collagen production promoter according to any one of [13].
[15] (A) A cysteine derivative represented by the general formula (I) or a salt thereof:
[Where:
X and Y are each independently OR ¹ , NHR ² (wherein R ¹ and R ² each independently represents a hydrogen atom or a C _1-22 alkyl group);
Z represents a hydrogen atom or a C _1-22 alkyl group;
W represents a C _1-22 alkyl group, a C _1-22 alkoxy group or a C _1-22 alkylamino group. ]
A pharmaceutical preparation for external use.
[16] (B) The topical medicine according to the above [15], further comprising one or more selected from vitamin A or a derivative thereof, vitamin E or a derivative thereof, zinc salt, ubiquinone, peptide, amino acid and nucleic acid Agent.
[17] A cysteine derivative represented by the general formula (I) or a salt thereof as an anti-wrinkle cosmetic:
[Where:
X and Y are each independently OR ¹ , NHR ² (wherein R ¹ and R ² each independently represents a hydrogen atom or a C _1-22 alkyl group);
Z represents a hydrogen atom or a C _1-22 alkyl group;
W represents a C _1-22 alkyl group, a C _1-22 alkoxy group or a C _1-22 alkylamino group. ]
Use of.

  According to the present invention, a collagen production promoter having high stability and safety is provided, and as a result, a cosmetic excellent in wrinkle prevention effect and the like can be provided.

  The present invention is a cosmetic containing (A) a specific cysteine derivative or a salt thereof, and optionally (B) a specific collagen production promoting compound. Moreover, this invention is a collagen production promoter containing (A) and optionally (B), and this is applicable as cosmetics (including quasi-drugs), medicines and the like.

[(A) Cysteine derivative]
The cysteine derivative of the present invention is a cysteine derivative represented by the general formula (I) or a salt thereof.

[Where:
X and Y are each independently OR ¹ , NHR ² (wherein R ¹ and R ² each independently represents a hydrogen atom or a C _1-22 alkyl group);
Z represents a hydrogen atom or a C _1-22 alkyl group;
W represents a C _1-22 alkyl group, a C _1-22 alkoxy group or a C _1-22 alkylamino group. ]

The terms used in this specification are defined below.
The “C _1-22 alkyl group” means a linear or branched hydrocarbon group having 1 to 22 carbon atoms, such as a methyl group, an ethyl group, an isopropyl group, a propyl group, a butyl group, Isobutyl group, sec-butyl group, tert-butyl group, pentyl group, sec-pentyl group, tert-pentyl group, isopentyl group, hexyl group, heptyl group, octyl group, 2-ethylhexyl group, tert-octyl group, nonyl group , Isononyl group, decyl group, isodecyl group, undecyl group, dodecyl group, tridecyl group, isotridecyl group, tetradecyl group, pentadecyl group, hexadecyl group, isohexadecyl group, heptadecyl group, octadecyl group, isooctadecyl group, behenyl group, etc. Can be mentioned.
_{Examples of the} “C _1-16 alkyl group” include methyl group, ethyl group, isopropyl group, propyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, sec-pentyl group, tert-pentyl group. Group, isopentyl group, hexyl group, heptyl group, octyl group, 2-ethylhexyl group, tert-octyl group, nonyl group, isononyl group, decyl group, isodecyl group, undecyl group, dodecyl group, tridecyl group, isotridecyl group, tetradecyl group , Pentadecyl group, hexadecyl group, isohexadecyl group and the like.
_{Examples of the} “C _1-6 alkyl group” include methyl group, ethyl group, isopropyl group, propyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, sec-pentyl group, tert-pentyl group. Group, isopentyl group, hexyl group and the like.

The “C _1-22 alkoxy group” means a hydroxyl group substituted with the above “C _1-22 alkyl group”. For example, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, tert-butoxy group, pentyloxy group, hexyloxy group, heptyloxy group, octyloxy group, nonyloxy group, decyloxy group, undecyloxy group, dodecyloxy group, tridecyloxy group, tetradecyloxy group, pentadecyloxy group Hexadecyloxy group, heptadecyloxy group, octadecyloxy group, nonadecyloxy group, eicosyloxy group, heneicosyloxy group, docosyloxy group and the like.
_{Examples of the} “C _1-6 alkoxy group” include methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, tert-butoxy group, pentyloxy group, hexyloxy group and the like.

The “C _1-22 alkylamino group” means an amino group substituted with the above “C _1-22 alkyl group”, and examples thereof include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, and butyl. Amino group, isobutylamino group, tert-butylamino group, pentylamino group, hexylamino group, heptylamino group, octylamino group, nonylamino group, decylamino group, undecylamino group, dodecylamino group, tridecylamino group, tetra Examples include decylamino group, pentadecylamino group, hexadecylamino group, heptadecylamino group, octadecylamino group, nonadecylamino group, eicosylamino group, heneicosylamino group, docosylamino group and the like.
_{Examples of the} “C _1-6 alkylamino group” include methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, tert-butylamino group, pentylamino group, and hexylamino group. Can be mentioned.

  “Halogen atom” includes chlorine atom, bromine atom, fluorine atom and iodine atom.

  Each substituent in the general formula (I) will be described below.

X and Y are each independently OR ¹ and NHR ² (wherein R ¹ and R ² each independently represents a hydrogen atom or a C _1-22 alkyl group).

The “C _1-22 alkyl group” represented by R ¹ or R ² is preferably a C _1-6 alkyl group, more preferably a methyl group, an ethyl group or an isopropyl group, still more preferably an ethyl group. is there.

X is preferably OR ¹ (wherein R ¹ is as defined above); more preferably OR ¹ ′ (wherein R ¹ ′ is a hydrogen atom or a C _1-6 alkyl group (preferably Represents a methyl group, an ethyl group, or an isopropyl group); and more preferably a hydroxyl group, a methoxy group, an ethoxy group, or an isopropoxy group, and even more preferably a hydroxyl group or a methoxy group.

Y is preferably OR ¹ (wherein R ¹ is as defined above), more preferably OR ¹ ′ (wherein R ¹ ′ is as defined above), More preferred is a hydroxyl group, a methoxy group, an ethoxy group or an isopropoxy group, and even more preferred is a hydroxyl group or a methoxy group.

Z represents a hydrogen atom or a C _1-22 alkyl group.
The “C _1-22 alkyl group” represented by Z is preferably a C _1-6 alkyl group, and more preferably a methyl group. Z is preferably a hydrogen atom or a C _1-6 alkyl group, more preferably a hydrogen atom or a methyl group.

W represents a C _1-22 alkyl group, a C _1-22 alkoxy group or a C _1-22 alkylamino group.
The “C _1-22 alkyl group” represented by W is preferably a C _1-16 alkyl group, more preferably a methyl group, a nonyl group, or a pentadecyl group, and still more preferably a methyl group.
The “C _1-22 alkoxy group” represented by W is preferably a C _1-6 alkoxy group, more preferably a tert-butoxy group.
The “C _1-22 alkylamino group” represented by W is preferably a C _1-6 alkylamino group.

W is preferably a C _1-22 alkyl group or a C _1-22 alkoxy group, more preferably a C _1-16 alkyl group or a C _1-6 alkoxy group, still more preferably a methyl group, a nonyl group, A pentadecyl group and a tert-butoxy group are preferable, and a methyl group and a tert-butoxy group are particularly preferable.

  Specific examples of the cysteine derivative represented by the general formula (I) include N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid and N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid. Acid 2-ethyl ester is preferable, and N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid-2-ethyl ester is more preferable.

Examples of the salt of the cysteine derivative of the present invention include a salt with an inorganic base and a salt with an organic base.
Examples of the salt with an inorganic base include sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt, zinc salt, silver salt and the like.
As a salt with an organic base, for example, methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris (hydroxymethyl) methylamine, dicyclohexylamine, N, N′-dibenzylethylenediamine, guanidine , Pyridine, picoline, choline, cinchonine, meglumine, salts with amino acids (eg, arginine, lysine, etc.) and the like.
According to a method known per se, each salt can be obtained by reacting the cysteine derivative of the present invention with an inorganic base or an organic base.

  Since the cysteine derivative and the salt thereof of the present invention have a collagen production promoting effect, they themselves have a wrinkle preventing effect and can be used as a collagen production promoting agent, a wrinkle preventing agent and an anti-aging agent. The anti-wrinkle agent referred to in the present invention is a concept including an anti-wrinkle agent and a therapeutic agent. Moreover, since the cysteine derivative and the salt thereof of the present invention have a collagen production promoting effect, when applied to hair and eyelashes, the hair can be given firmness by promoting the collagen production of the hair, It can be used as a hair nourishing agent, hair restoring agent, hair quality improving agent.

  In the present invention, the lower limit when the cysteine derivative or a salt thereof is blended in a cosmetic is not particularly limited as long as the effect is exhibited, but 0.0001% by weight is preferably the lower limit. From the viewpoint that an effective effect can be exhibited, 0.001% by weight is more preferable, 0.01% by weight is further preferable, 0.1% by weight is still more preferable, 0.5% by weight is even more preferable, and 1% by weight. % Is particularly preferred. When a salt of a cysteine derivative is used, the weight of the cysteine derivative portion (free body) is in the above range.

  In the present invention, the upper limit in the case of blending the cysteine derivative or a salt thereof into a cosmetic is not particularly limited as long as the effect is exhibited, but 20% by weight is preferably the upper limit. 18% by weight is more preferred, 16% by weight is still more preferred, 12% by weight is even more preferred, 10% by weight is particularly preferred, and 5% by weight is particularly preferred. When a salt of a cysteine derivative is used, the weight of the cysteine derivative portion (free body) is in the above range.

  The method for producing the cysteine derivative represented by the general formula (I) (hereinafter sometimes abbreviated as cysteine derivative (I)) is not particularly limited, and is produced by combining known methods. be able to. Specifically, it can be synthesized by the following method, but is not limited thereto.

  Compound (IV), which is a precursor of cysteine derivative (I), can be synthesized by the following step 1, and then cysteine derivative (I) can be synthesized by step 2. Compound (IV) may or may not be purified as necessary.

Step 1
Cysteine or a compound represented by general formula (II) obtained by esterification or amidation of cysteine in advance (hereinafter abbreviated as compound (II) and the same applies to compounds represented by other formulas). ) To form a ring by reacting with compound (III) to obtain compound (IV)

(In the formula, each symbol is as defined above.)
Compound (IV) can be obtained by reacting compound (II) with compound (III) in water or an alcohol such as methanol or ethanol for 5 to 24 hours. Of compound (II), cysteine ethyl ester can be obtained, for example, by reacting cysteine in ethyl alcohol in the presence of hydrochloric acid or thionyl chloride at room temperature for about 5 to 24 hours. Among the compounds (II), cysteine amide is a protected cysteine and an amine in the presence of a dehydrating condensing agent such as EDCI.HCl (1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride), methylene chloride, The compound obtained by reacting in a solvent such as N, N-dimethylformamide (DMF) at room temperature for 5 to 24 hours can be obtained by deprotection.

Step 2

(In the formula, A represents a halogen atom, and other symbols are as defined above.)
Cysteine derivative (I) can be synthesized by reacting compound (IV) with compound (V) or compound (V ′) in the presence or absence of a solvent and in the presence or absence of a base. Examples of the solvent include THF (tetrahydrofuran), ethyl acetate, isopropyl acetate, acetonitrile, acetone, ethanol, methanol, dichloromethane, water, or a mixture thereof, preferably THF, ethyl acetate, isopropyl acetate, acetonitrile, acetone, Dichloromethane, water, or a mixture thereof. Examples of the base include organic bases such as triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, and inorganic bases such as lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium acetate, and potassium acetate. Preferably triethylamine, diisopropylethylamine, pyridine, N-methylmorpholine, potassium carbonate, sodium carbonate.
The amount of compound (V) or compound (V ′) to be used is 1.0 to 5.0 mol, preferably 1.2 to 3.0 mol, per 1 mol of compound (IV). When using a base, the usage-amount of a base is 1.0-5.0 mol with respect to 1 mol of compound (IV), Preferably it is 1.2-4.0 mol. The reaction temperature is −10 to 100 ° C., preferably 0 to 90 ° C. The reaction time is 1 hour to 48 hours, preferably 3 hours to 20 hours.
Further, this may be converted to other cysteine derivatives (I) by esterification, amidation, hydrolysis or acid anhydride.

[(B) Collagen production promoting compound]
When a collagen production promoting compound is combined as the component (B) with the cysteine derivative or salt thereof as the component (A), the wrinkle prevention effect is synergistically increased. As component (B), vitamin A such as retinoic acid, retinol, tretinoin, retinol acetate, retinol palmitate, retinol propionate, hydrogenated retinol, tocopheryl retinoic acid and hydroxypinacolone retinoic acid; tocopherol, tocotrienol, linol Vitamin E or its derivatives such as tocopherol acid, tocopherol oleate, tocopherol succinate, tocopherol nicotinate, tocopherol phosphate and tocopherol acetate; pyrrolidone carboxylate zinc salt, gluconate zinc salt, zinc phenolsulfonate, zinc lactate salt, various Amino acid zinc salts, acylamino acid zinc salts, zinc salts such as zinc sulfate, zinc chloride and zinc oxide; ubiquinones such as coenzyme Q10; milk-derived peptides ( In the specification, peptides such as peptides derived from cow's milk, horse milk, goat milk and sheep milk and having a molecular weight of 5 to 30 kDa; amino acids such as glutamine, arginine, glycine, proline and lysine; And nucleic acids such as AMP (adenosine monophosphate). One or more selected from vitamin A or a derivative thereof, vitamin E or a derivative thereof, a zinc salt and a peptide are preferable in that the effect of preventing wrinkles can be obtained synergistically, and retinoic acid, retinol, vitamin E, One or more selected from pyrrolidone carboxylic acid zinc salts and milk-derived peptides are more preferred.
The collagen production promoting compound (B) may be used as a mixture of two or more.

  The lower limit when the component (B) is blended into the cosmetic is not particularly limited as long as the effect is exhibited, but 0.0001% by weight is preferably the lower limit. From the viewpoint that an effective effect can be exhibited, 0.001% by weight is more preferable, 0.01% by weight is further preferable, 0.1% by weight is still more preferable, 0.5% by weight is even more preferable, and 1% by weight. % Is particularly preferred.

  The upper limit when the component (B) is blended into the cosmetic is not particularly limited as long as the effect is exhibited, but it is preferable to set the upper limit to 20% by weight. 18% by weight is more preferred, 16% by weight is still more preferred, 12% by weight is even more preferred, 10% by weight is particularly preferred, and 5% by weight is particularly preferred.

  (A) The compounding ratio of the cysteine derivative or salt thereof and the component (B) is not particularly limited as long as the effect is exhibited, but (A) / (B) = 1/20 to 100,000 / 1 (g / G), preferably 1/10 to 10,000 / 1 (g / g), more preferably 1/2 to 5000/1 (g / g), and even more preferably 3/1 to 5000/1 (g / g). When a salt of a cysteine derivative is used, the above ratio is calculated based on the weight of the cysteine derivative portion (free body).

  There is no restriction | limiting in particular as a form as cosmetics of this invention, Arbitrary forms, such as liquid form, paste form, gel form, solid form, and powder form, can be taken. Specifically, lotion, lotion, cream, milky lotion, serum, shampoo, hair rinse, hair conditioner, hair mousse, hair gel, hair wax, enamel, foundation, eyeliner, eyebrow pencil, mascara, eye shadow, teak, lipstick, Lipstick, funny, powder, pack, pack mask, perfume, cologne, facial cleansing foam, cleansing foam, cleansing oil, cleansing gel, cleansing milk, toothpaste, soap, aerosol, bath preparation, hair nourishing agent, sunscreen.

  In the case of cosmetics (including quasi-drugs) or pharmaceutical external preparations, in addition to the cysteine derivative of the present invention, various ingredients that can be used in normal cosmetics (including quasi-drugs) and pharmaceutical external preparations are You may mix | blend in the range which does not inhibit the effect of invention. For example, oil components, surfactants, amino acid derivatives, lower alcohols, higher alcohols, polyhydric alcohols, sugar alcohols and alkylene oxide adducts thereof, water-soluble polymers, gelling agents, whitening agents, bactericides and antibacterial agents, Anti-inflammatory agent, analgesic agent, antifungal agent, keratin softener, skin colorant, hormone agent, UV absorber, hair restorer, antiperspirant and astringent active ingredient, sweat deodorant, vasodilator, herbal medicine, pH adjustment Agents, sequestering agents, viscosity modifiers, pearlizing agents, natural fragrances, synthetic fragrances, dyes, pigments, preservatives, emulsifiers, fats and waxes, silicone compounds, perfume oils and the like.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

[Synthesis of Component A]
[Synthesis Example 1]
N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid-2-ethyl ester (in this specification, this may be abbreviated as N-Ac-CP2Et)

L-cysteine hydrochloride monohydrate (100 g, 569 mmol) was dissolved in water (200 ml), and then a 6N aqueous sodium hydroxide solution was added to adjust the pH to 5.03. The reaction mixture was heated to 40 ° C., pyruvic acid ethyl ester (76 ml, 684 mmol) was added slowly, stirred at 40 ° C. for 3.5 hours, and 2-methylthiazolidine-2,4-dicarboxylic acid-2-ethyl ester. An ester was obtained (when the area ratio of the product in the reaction solution on the HPLC chart was confirmed, the ratio of trans isomer: cis isomer was about 55:45). After completion of the reaction, the mixture was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. Triethylamine (159 ml, 1141 mmol) was added to the obtained ethyl acetate solution under argon, acetyl chloride (61 ml, 858 mmol) was slowly added dropwise, and the reaction mixture was heated to reflux for 4 hours, and N-acetyl-2-methylthiazolidine was added. -2,4-Dicarboxylic acid-2-ethyl ester was obtained (when the area ratio of the product in the reaction solution on the HPLC chart was confirmed, the ratio of trans isomer: cis isomer was about 95: 5). After completion of the reaction, water (300 ml) was added and the pH was adjusted to 1.0 with HCl. After separating the aqueous layer, the organic layer was washed with water (300 ml), washed with saturated brine, and dried over anhydrous magnesium sulfate. The obtained ethyl acetate solution is concentrated to about 500 g, recrystallized by adding heptane, washed with heptane / ethyl acetate = 2/1, dried at 50 ° C. under reduced pressure, and N-acetyl-2-methylthiazolidine. Crystals of trans isomer of -2,4-dicarboxylic acid-2-ethyl ester (when the area ratio in the HPLC chart was confirmed, the trans isomer ratio was about 99%) were obtained (81 g, yield 55%). ).
NMR: ¹ H-NMR (CDCl ₃ ): δ; 1.27 (3H, t, J = 7.12 Hz), 1.94 (3H, s), 2.18 (3H, s), 3.40 ( 1H, d, J = 11.6 Hz), 3.56 (1H, dd, J = 5.5, 11.0 Hz), 4.20 (2H, t, J = 7.08 Hz), 5.00 (1H , D, J = 5.9 Hz), 9.10 (1H, brs).

[HPLC analysis conditions]
Detector: UV spectrophotometer (measurement wavelength: 210 nm)
Column: YMC-Pack ODS-A (particle diameter 5 μm, pore diameter 12 mm, inner diameter 6.0 mm, length 150 mm)
Eluent: 50 mM NaH ₂ PO ₄ (adjusted to pH 2 with 85% H ₃ PO ₄ ): MeOH = 60: 40
Flow rate; 1.0 mL / min column temperature; 40 ° C
Injection volume: 10 μL
Retention time (min); 2-methylthiazolidine-2,4-dicarboxylic acid-2-ethyl ester (cis isomer): 9.0, (trans isomer): 8.6, N-Ac-CP2Et (cis isomer): 7.5, (trans form): 9.2

[Synthesis Example 2]
N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid (N-acetyl-cysteinylpyruvic acid; hereinafter sometimes abbreviated as N-Ac-CP)

N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid-2-ethyl ester obtained by the same operation as in Synthesis Example 1 was dissolved in a mixed solvent of methanol (120 ml) and water (120 ml), and 2N NaOH. (182.4 ml) was added. The reaction was heated with stirring at 100 ° C. for 4 hours and at 80 ° C. overnight under an argon atmosphere. After allowing the reaction liquid to cool to room temperature, AMBERLITE IR120B H AG (about 250 g) was added to adjust the pH of the solution to be 1-2. AMBERLITE was removed by filtration, the filtrate was concentrated under reduced pressure, ethyl acetate (200 ml) was added, and after stirring for 1 hour, white crystals were collected by filtration to give N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid. Obtained (15.99 g, 75%).
NMR: ¹ H-NMR (DMSO-d ₆ ): δ; 1.73 (3H, s), 2.01 (3H, s), 3.36 (2H, d, J = 3.6 Hz), 5. 26 (1H, t, J = 3.6 Hz).
MS spectrum m / z; [M + H] + = 234.0, [M−H] − = 232.0.

[Test Example 1] Measurement of collagen production rate Normal human dermal fibroblasts were seeded in a 24-well plate with DMEM (Dulbecco's modified Eagle medium, containing 10% FBS). The cells were cultured for 24 hours in an incubator at 37 ° C. under 5% CO ₂ and saturated steam. After 24 hours, the medium of the 24-well plate was changed using DMEM (containing 10% FBS and containing 100 μM ascorbic acid) containing a sample of the evaluation concentration (Table 1). Those not dissolved in the medium were dissolved in dimethyl sulfoxide and added to the medium (dimethyl sulfoxide in the medium was 0.1%). After further culturing for 3 days, the medium was collected, and the amount of water-soluble collagen in the medium was quantified by ELISA. The ELISA used was TAKARA, Procollagen Type I-C-peptide (PIP) EIA Kit. When the calculated value of the control (without sample addition) was defined as 100%, the calculated value 3 days after the addition of each sample at a predetermined concentration was defined as relative%, and the water-soluble collagen production rate of each sample was calculated. A sample containing 0.1% dimethyl sulfoxide dissolved and added in dimethyl sulfoxide was used as a control (no sample added). The microplate reader used in this collagen production rate measurement test is MULTISKAN FC, manufactured by Thermo Fisher Scientific.

[Evaluation]
<Collagen production effect>
The collagen production rate of each sample was measured and evaluated according to the following criteria.

OO: Collagen production rate is 130% or more.
◯: Collagen production rate is 120% or more and less than 130%.
○: Collagen production rate is 110% or more and less than 120%.
Δ: Collagen production rate is 100% or more and less than 110%.
X: Collagen production rate is less than 100%.

<Combination effect>
For each sample, the collagen production rate when used alone and when used in combination was measured, and the combined effect was evaluated according to the following criteria using theoretical values.
The theoretical value was collagen production rate (%) when the component (A) was used alone + collagen production rate (%) − 100 when the component (B) was used alone.

OO: Theoretical value-measured value is 10% or more.
◯: Theoretical value-measured value is 5% or more and less than 10%.
A: Theoretical value-actual value is 0% or more and less than 5%.
Δ: Theoretical value-measured value is -5% or more and less than 0%.
X: Theoretical value-actual value is less than -5%.

The evaluated samples were obtained as follows.
Retinoic acid: manufactured by Sigma, R2625-50MG
Retinol: Sigma, 95144-250MG
Pyrrolidonecarboxylic acid zinc salt: AJIDEW ZN-100, manufactured by Ajinomoto Co., Inc.
Milk-derived peptide (hereinafter referred to as MPC or milk peptide): manufactured by Kotobuki Chemical Co., Ltd., milk peptide complex vitamin E (tocopherol): manufactured by Nacalai Tesque, 34114-54

  From Table 1-1 and 1-2, it became clear that (A) cysteine derivative shows the outstanding collagen production effect. In addition, it is found that the collagen production effect is improved by combining zinc salt (pyrrolidonecarboxylic acid zinc salt), peptide (milk-derived peptide), vitamin A derivative (retinoic acid, retinol), or vitamin E as component (B). It was.

  Also, from Table 2, when (A) cysteine derivative and (B) component are combined with zinc salt (pyrrolidonecarboxylic acid zinc salt), peptide (milk-derived peptide), vitamin A derivative (retinoic acid, retinol), or vitamin E The collagen production rate was higher than the theoretical value, and it was found that the collagen production effect was synergistically improved. Furthermore, retinoic acid, retinol, or vitamin E showed a collagen production rate significantly exceeding the theoretical value.

  Below, the cosmetics of this invention are illustrated. All of these cosmetics have high stability and safety, and are excellent in the effect of preventing wrinkles or imparting firmness and firmness to hair.

* 1: Any of the extracts 1 to 59 in Tables 10-1 and 10-2 can be used. * 2: Any of the mixtures 1 to 5 in Table 11 can be used.

  In the above formulation examples, BG represents 1,3-butylene glycol, PG represents propylene glycol, DPG represents dipropylene glycol, and PEG represents polyethylene glycol.

  The cysteine derivative or salt thereof of the present invention has high stability and safety, and has an excellent anti-wrinkle effect. As a result, it has become possible to provide a cosmetic that is more effective than conventional wrinkle-preventing cosmetics and is less likely to cause skin problems. Moreover, the collagen production promoter of the present invention promotes collagen production and is effective, for example, for preventing wrinkles and preventing and treating wrinkles.

  This application is based on Japanese Patent Application No. 2011-262163 for which it applied in Japan, The content is altogether included in this specification.

Claims (14)

A cysteine derivative represented by the general formula or a salt thereof:

[Where:
X and Y are each independently OR ¹ , NHR ² (wherein R ¹ and R ² each independently represents a hydrogen atom or a C _1-22 alkyl group);
Z represents a hydrogen atom or a C _1-22 alkyl group;
W represents a C _1-22 alkyl group, a C _1-22 alkoxy group or a C _1-22 alkylamino group. ]
Anti-wrinkle cosmetic containing (A) A cysteine derivative represented by the general formula or a salt thereof:

[Where:
X and Y are each independently OR ¹ , NHR ² (wherein R ¹ and R ² each independently represents a hydrogen atom or a C _1-22 alkyl group);
Z represents a hydrogen atom or a C _1-22 alkyl group;
W represents a C _1-22 alkyl group, a C _1-22 alkoxy group or a C _1-22 alkylamino group. And (B) a cosmetic containing one or more selected from vitamin A or a derivative thereof, vitamin E or a derivative thereof, zinc salt, ubiquinone, peptide, amino acid and nucleic acid.   (A) a cysteine derivative or a salt thereof is N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid, N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid-2-ethyl ester, and their The cosmetic according to claim 1 or 2, wherein the cosmetic is one or more selected from salts.   The cosmetic according to claim 2 or 3, wherein the component (B) is one or more selected from retinoic acid, retinol, vitamin E, pyrrolidone carboxylic acid zinc salt and milk-derived peptide. Fee.   (A) The cysteine derivative or a salt thereof is N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid-2-ethyl ester or a salt thereof, and (B) the component is vitamin A or a derivative thereof. The cosmetic according to claim 2, characterized in that:   (A) The cysteine derivative or a salt thereof is N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid-2-ethyl ester or a salt thereof, and (B) the component is a pyrrolidonecarboxylic acid zinc salt. The cosmetic according to claim 2, characterized in that:   The blending ratio of (A) a cysteine derivative or a salt thereof and the component (B) is (A) / (B) = 1/20 to 100000/1 (g / g). 6. Cosmetics of any one of 6. (A) A cysteine derivative represented by the general formula or a salt thereof:

[Where:
X and Y are each independently OR ¹ , NHR ² (wherein R ¹ and R ² each independently represents a hydrogen atom or a C _1-22 alkyl group);
Z represents a hydrogen atom or a C _1-22 alkyl group;
W represents a C _1-22 alkyl group, a C _1-22 alkoxy group or a C _1-22 alkylamino group. ]
Containing collagen production promoter.   (B) The collagen production promoter according to claim 8, further comprising one or more selected from vitamin A or a derivative thereof, vitamin E or a derivative thereof, zinc salt, ubiquinone, peptide, amino acid and nucleic acid.   (A) a cysteine derivative or a salt thereof is N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid, N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid-2-ethyl ester, and their The collagen production promoter according to claim 8 or 9, which is one or more selected from salts.   The collagen according to claim 9 or 10, wherein the component (B) is one or more selected from retinoic acid, retinol, vitamin E, pyrrolidone carboxylic acid zinc salt and milk-derived peptide. Production promoter.   (A) The cysteine derivative or a salt thereof is N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid-2-ethyl ester or a salt thereof, and (B) the component is vitamin A or a derivative thereof. The collagen production promoter according to claim 9,   (A) The cysteine derivative or a salt thereof is N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid-2-ethyl ester or a salt thereof, and (B) the component is a pyrrolidonecarboxylic acid zinc salt. The collagen production promoter according to claim 9,   The blending ratio of (A) a cysteine derivative or a salt thereof and the component (B) is (A) / (B) = 1/20 to 100,000 / 1 (g / g). 14. The collagen production promoter according to any one of items 13.