JP2002371039A - New hinokitiol derivative and skin care preparation containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To utilize various actions of hinokitiol such as antibacterial action, antifungal action, beautifying action and antioxidation action while suppressing the short points of the compound such as the sublimation property, corrosiveness to metals and light instability, especially to utilize the compound as a skin care preparation. SOLUTION: Hinokitiol is esterified with cinnamic acid or its derivative to obtain an ester expressed by formula (I) or (II) (R1 , R2 and R3 are each independently H, hydrox, an alkoxy, a fluoroalkoxy or an alkylcarbonyloxy) and a proper amount of the ester is used as an active component of a skin care preparation having the form of a solution, emulsion, paste or solid.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an ester of hinokitiol with cinnamic acid or a derivative thereof, and the use of the ester in a cosmetic or pharmaceutical external preparation for skin.

[0002]

2. Description of the Related Art Hinokitiol is a compound having the following structure, which has antibacterial, antifungal, antiseptic, whitening, hair growth promotion,
It is known to have many effects such as anti-dandruff, freshness preservation, insect pests, plant growth promotion and antioxidation. Therefore, it is currently used for cosmetics, pharmaceuticals, agricultural chemicals, food additives, everyday goods and the like.

[0003]

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It is known that hinokitiol has the following structure as a tautomeric isomer.

[0005]

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On the other hand, esters containing cinnamic acid or a derivative thereof as a constituent include ascorbic acid (Japanese Patent No. 2719).
No. 895), kojic acid (Japanese Patent No. 2648581), tocopherol (JP-A-10-120542) and the like are known, and it is introduced that these esters are extremely useful for cosmetics and the like.

Hinokitiol has sublimability and photodegradability, and is easily volatilized or decomposed. for that reason,
Although hinokitiol itself has an excellent action, it lacks preservability and stability, and has a problem that handling is troublesome.

[0008] Hinokitiol also has a strong corrosive property to metals, and easily binds to various metal ions to produce organometallic compounds such as colored hinokitiol salts and complexes. This is because it has a keto-enol structure in a resonance structure as a substituent of a 7-membered ring serving as a mother nucleus of hinokitiol. The coloring due to the bonding with the metal ion has limited the use of hinokitiol and has another problem that there is a restriction on the compounding target.

As one measure to solve such a problem, hinokitiol is included in cyclodextrin (JP-A-11-222455) and glucosylation (JP-A-7-222).
17993), alkylation (JP-A-56-26842)
And so on. However, such denaturation lowers the activity inherent to hinokitiol, or rather impairs stability, and lowers the production yield, so that hinokitiol has not been used industrially.

[0010] The inventors of the present invention have conducted studies with the intention of solving the above-mentioned problems, and as a result, it has been found that an ester of hinokitiol with cinnamic acid or a derivative thereof has sublimability, coloring due to chelate formation, and corrosion to metal. It has been found that there is no problem of light stability and that the light stability is remarkably improved. Further, they have found that this ester has tyrosinase activity inhibitory activity and is effective as a whitening agent.

Further studies have shown that this compound has an antioxidant effect, and that the compound having a hydroxyl group has a particularly strong antioxidant activity, especially the free radical scavenging activity is much stronger than that of hinokitiol. It was also found that lipid oxidation of the skin and pigmentation could be prevented. When this compound is applied to the epidermis or scalp, it is lipophilic and easily penetrates the stratum corneum, and is hydrolyzed in the presence of hydrolases such as esterases in the epidermis to release hinokitiol I also confirmed that.

[0012]

SUMMARY OF THE INVENTION Accordingly, an object of the present invention is to provide a novel and useful group of compounds by utilizing the above wide-ranging knowledge obtained by the inventors, and to provide at least one of these compounds. It is an object of the present invention to provide a composition for external use on the skin which contains a seed as an active ingredient and exhibits various medicinal effects.

[0013]

Means for Solving the Problems The ester of the present invention is an ester of hinokitiol and cinnamic acid or a derivative thereof represented by the following general formula (I) or (II).

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Embedded image (Wherein R ₁ , R ₂ and R ₃ are the same or different, and represent a hydrogen atom, a hydroxy group, an alkoxy group,
Represents a fluoroalkoxy group or an alkylcarbonyloxy group. )

The composition for external use on the skin of the present invention is a composition characterized by containing at least one ester of hinokitiol and cinnamic acid or a derivative thereof as an active ingredient.

[0015]

In the above formula, as the alkoxy group for R ₁ , R ₂ and R ₃ , at least one selected from the group consisting of a methoxy group, an ethoxy group and a butoxy group is suitable. As the alkylcarbonyloxy group, at least one selected from the group consisting of an acetoxy group, a propionyloxy group and a butyryloxy group is suitable. The fluoroalkoxy group is preferably a trifluoromethoxy group.

Specific examples of the ester of the present invention include hinokyl cinnamate, hinokyl ferulate, hinokyl caffeate, hinokyl-p-coumarate, hinokyl synapate, hinokyl-4'-methoxycinnamate and hinokyl-4. '-Acetoxyferulate.

Hinokitiol has a keto-enol structure and exhibits tautomerism, so that the hinokitiol derivative, which is the compound of the present invention, also has two types of structures, but both have the same action.

The compound of the present invention may further comprise an acid or an alkali,
Alternatively, the ester bond between hinokitiol and the acid component can be decomposed by the action of a hydrolase to release hinokitiol. The rate of this decomposition can be adjusted by selecting the type and amount of the decomposing agent to be acted and the conditions under which the decomposition reaction proceeds, and a desired sustained-release preparation can be obtained. The released hinokitiol exhibits an antibacterial and antifungal action, a whitening action by inhibiting tyrosinase activity, and a hair growth promoting action on the scalp.

Further, the ester of the present invention has an ultraviolet absorbing effect which is considered to be derived mainly from cinnamic acid or a derivative thereof, and also has a function of protecting the skin from ultraviolet rays. This effect can be expected even after the release of hinokitiol.

The compound of the present invention can be produced by reacting cinnamic acid or a derivative thereof with hinokitiol or a salt thereof to form an ester bond. Specifically, first, cinnamic acid represented by the following general formula (V) or a derivative thereof is used as a raw material.

Embedded image (In the above formula, R ₁ , R ₂ and R ₃ have the meanings described above.) When at least one of the substituents R ₁ , R ₂ and R _{3 on} the aromatic ring is a hydroxyl group, To protect the hydroxyl group. Acetylation can be accomplished by conventional means by reacting acetic anhydride in the presence of a base such as pyridine.

Next, cinnamic acid or a derivative thereof (the one having a hydroxyl group is protected with the hydroxyl group as described above) is mixed with thionyl chloride in an organic solvent such as toluene at 50 to 120 ° C. An acid chloride is prepared by reacting at a temperature. The prepared acid chloride is reacted with hinokitiol or a salt thereof in an organic solvent such as toluene in the presence of a base such as N, N-dimethylaminopyridine to obtain a cinnamic acid ester derivative of hinokitiol.

In the synthesis, a protecting group such as an acetyl group protecting the hydroxyl group of an aromatic ring can be easily removed by, for example, adding 0.1 to 3N hydrochloric acid in acetone and stirring. Both the compound with and without the protecting group are the compounds of the present invention. The protection of the hydroxyl group of the aromatic ring may be performed by a group other than the acetyl group. The esterification reaction may be performed without protection. The esterification reaction can also be performed using another method such as using an acid catalyst or an ion exchange resin.

The composition for external use on the skin of the present invention is a cosmetic or pharmaceutical, which comprises an ester or a salt thereof of the cinnamic acid or a derivative thereof represented by the above formula (I) or (II) with hinokitiol. 0.00 based on the total weight of the product
In an amount ranging from 01 to 10%, preferably 0.001 to 5
%. This composition can of course be used in combination with other known antioxidants and whitening agents.

The composition for external use on the skin of the present invention can be in the form of various drugs usually used for topical application, and in particular, aqueous solutions, water-alcohol solutions, oil solutions,
Of polymer nanoparticles such as oil-in-water or water-in-oil emulsions, multiple emulsions, aqueous or oily gels, liquid, pasty or solid anhydrous products, ionic and nonionic lipid vesicles, or nanospheres and nanocapsules It is provided in a form and can be used.

The topical skin composition may be relatively fluid and may be in the form of a white or colored cream, ointment, emulsion, lotion, sealant, paste, or foam. It may be in solid form, for example in stick form. They can be used for skin care, hair care, cosmetic or makeup removal, sunscreen, bath oil.

The compositions according to the invention can contain the usual ingredients in the customary concentrations in the cosmetic or pharmaceutical dermatological field. Its components are in particular selected from fatty substances, preservatives, vitamins, gelling agents, fragrances, surfactants, water, antioxidants, fillers, UV-screening agents, wetting agents, and mixtures thereof. . Fatty substances that can be used in the present invention include:
Animal or vegetable oils, mineral oils, synthetic oils, silicone oils,
And fluorinated oil. Fatty alcohols, fatty acids, and waxes can also be used. Suitable surfactants used in the composition of the present invention include fatty acid esters such as sodium stearate and the like, and fatty acid esters of polyethylene glycol such as polyethylene glycol stearate.

[0027]

EXAMPLES Examples of preparation of the compounds, test examples and preparation examples of the compositions are shown below. [Production Example 1] Production of hinokityl cinnamate 1.64 g (10 mmol) of hinokitiol and 1.22 g (10 mmol) of N, N-dimethylaminopyridine were dissolved in 100 ml of toluene and, with stirring, the silica was dissolved in 50 ml of toluene. 1.22 g (10 mmol) of acid chloride were added dropwise. After stirring at room temperature for 2 hours, 1N hydrochloric acid and then 1N
After washing with N sodium hydrogencarbonate and thoroughly washing with water, dehydrating over anhydrous sodium sulfate and filtering the precipitate, distilling off the solvent under reduced pressure and recrystallizing from methanol to give white crystals, hinokityl cinnamate 1.38 g were obtained.

Melting point: 86 ° C. FT-IR (KBr pellet method): 1730, 163
3,1604,1579,1125 mm- ^{1 13} C-NMR (CDCl ₃ ; 75 MHz): 164.
1, 147.3, 134.1, 130.7, 1
28.9, 128.3, 116.6, 38.3,
22.8, ppm

[Production Example 2] Production of hinoxytyl-4'-acetoxyferrate (1) Production of 4-acetoxyferulate To 13.7 g (71 mmol) of ferulic acid, 55 ml of acetic anhydride and 0.6 ml of pyridine were added. Stir for 5 hours. The reaction solution was poured into water and stirred for 8 hours. The product was filtered, washed several times with water and dried to give 16.5 g of 4-acetoxyferulate as a white powder.

(2) Production of 4-acetoxyferulic acid chloride 4.25 g (18 mmol) of 4-acetoxyferulic acid was added to 85 ml of toluene, and thionyl chloride 1 was added with stirring.
After dropping 0.7 g (90 mmol), the solvent was refluxed under reflux conditions.
Heated and stirred for hours. Next, the solvent was distilled off under reduced pressure to obtain a pale yellow solid. Recrystallized from toluene,
3.74 g of 4-acetoxyferulic chloride were obtained as pale yellow needles.

(3) Preparation of hinokityl-4'-acetoxyferulate 2.46 g (15 mmol) of hinokitiol and 2.20 g (18 mmol) of N, N-dimethylaminopyridine were dissolved in 150 ml of toluene, 100 ml of toluene in which 4.57 g (18 mmol) of acetoxyferulic chloride were dissolved was added dropwise. After stirring overnight at room temperature, the solvent was distilled off under reduced pressure, and the solution extracted with ethyl acetate was washed with 1N hydrochloric acid and 1N sodium hydrogen carbonate, and finally with water. After the organic layer was dehydrated with anhydrous sodium sulfate and the precipitate was filtered, the filtrate was concentrated under reduced pressure, and ethanol was added to perform recrystallization. White crystals, hinoktyl-4 '
3.06 g of acetoxyferulate were obtained.

Melting point: 123 ° C. FT-IR (KBr pellet method): 1765, 172
5,1635,1607,1585,1210,115
1,1124 mm ^{−1 13} C-NMR (CDCl ₃ ; 75 MHz): 168.
7, 163.9, 151.4, 146.5, 1
41.8, 133.1, 123.3, 121.6,
116.8, 111.4, 55.9, 38.3,
22.8, 20.6ppm

[Production Example 3] Production of Hinokyl Ferulate 1.15 g (3 mmol) of the hinoxytyl-4'-acetoxyferulate produced in Production Example 2 was added to 10 ml of acetonitrile.
And 3 ml of 3N hydrochloric acid was added to the solution, followed by stirring for one day. After neutralizing the reaction solution, the mixture was extracted with ethyl acetate, and the extract was washed with 1N sodium bicarbonate and then with water. .

Melting point: 140 ° C. FT-IR (KBr pellet method): 1,724,164
_{^{0,1606,1588,1174,1129mm -1 13 C-NMR (CDCl}} 3; 75MHz): 170.
8, 167.0, 164.8, 153.5, 1
45.9, 135.4, 123.7, 121.8,
119.2, 116.2, 113.4, 55.
5, 38.3, 23.1 ppm

[Test of action] The action of the compound of the present invention obtained as described above is shown. The whitening action is tyrosinase activity inhibitory activity, the antioxidant action is DPPH radical scavenging activity and linoleic acid autoxidation inhibitory activity. Revealed by measurement. The test method and results are shown below.

(Tyrosinase activity inhibitory activity) Using a 0.1 M phosphate buffer (pH 7.0), a 2 mM solution of L-DOPA was used as a substrate solution, and mushroom-derived tyrosinase (6,680 units / mg) 0.02m
A g / ml solution was prepared. 1 ml of a sample solution dissolved in 5% DMSO is mixed with 1 ml of a substrate solution, and the enzyme solution is added to 0.1 ml of the enzyme solution.
2 ml was added and reacted for 10 minutes at room temperature. The absorbance at 475 nm before and after the reaction was measured to determine the tyrosinase activity inhibition rate. [Reference: HSMason & EWPeters
on, Biochim. Biophys. Acta., 111, 134-140 (1965)]

The tyrosinase activity inhibition rate at a sample concentration of 100 μM is shown below together with those of substances known to have a whitening effect. Kojic acid 51.3% Ascorbic acid 6.2% Hinokitiol 93.4% Hinokyl cinnamate 57.5% Hinokyl-4'-acetoxyferulate 73.9% Hinokyl ferulate 78.2%

(DPPH radical scavenging activity) 1 ml of a 0.15 mM DPPH methanol solution was added to 1 ml of a 2 mM methanol solution of the sample, and after 30 minutes, the absorbance at 520 nm was measured to determine the DPPH radical scavenging rate. [References: T. Yamaguchi, H. Takamura, T. Matoba & J. Terao, B
iosci. Biotechnol. Biochem., 62, 1201-1204 (1998)]

The DPPH radical scavenging rate at a sample concentration of 1 mM is shown below. dl-α-tocopherol 90.4% ascorbic acid 95.9% hinokitiol 6.6% hinoxytyl cinnamate 1.6% hinoxytyl-4′-acetoxyferulate 2.6% hinoxytyl ferulate 92.6%

(Linoleic acid autoxidation inhibitory activity) concentration 10
A sample was dissolved to a concentration of 0.01% in a solution obtained by mixing 1 ml of a 0 mM linoleic acid ethanol solution, 2 ml of a 50 mM phosphate buffer (pH 7.0), 1 ml of distilled water and 1 ml of ethanol. Autoxidation of linoleic acid was performed. Seven days later, the rate of inhibition of linoleic acid oxidation was determined by the rhododan iron method. [Reference: T. Osawa & M. Namiki, Agric. Biol.
Chem., 45 (3), 735-739 (1981)]

The linoleic acid autoxidation inhibitory activity when the sample concentration is 0.01% is shown below. dl-α-tocopherol 89.9% ascorbic acid 67.9% hinokitiol 98.1% hinoxytyl cinnamate 93.5% hinoxytyl-4′-acetoxyferulate 96.5% hinoxytyl ferulate 97.9%

[Composition Example 1] An oil-in-water emulsion was prepared by mixing the following components. Hinokyl-4'-acetoxyferulate 0.1 part (weight) Polyethylene glycol 3 parts Diglycerol monostearate 3 parts Vaseline oil 24 parts Cetyl alcohol 5 parts Water was added to make 100 parts.

[Composition Example 2] An oil-in-water emulsion was prepared by mixing the following components. Hinokyl ferulate 0.1 part (weight) Octyl palmitate 10 parts Glycerol monoisostearate 4 parts Vaseline oil 24 parts Vitamin E 1 part Glycerol 3 parts Water was added to make 100 parts.

[Composition Example 3] The following components were mixed to produce a creamy composition. Hinokyl cinnamate 0.1 part (weight) Jojoba oil 13 parts Methyl paraben 0.05 part Potassium sorbate 0.3 part Cyclopentadimethylsiloxane 10 parts Stearyl alcohol 1 part Stearic acid 4 parts Polyethylene glycol 3 parts Glycerol 3 parts Water In addition, it was 100 parts.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07C 69/732 C07C 69/732 Z 69/734 69/734 Z // A61K 31/216 A61K 31/216 ( 71) Applicant 502004364 Kazuhisa Takahashi 1-27-302, Okaishi-cho, Akashi-shi, Hyogo Prefecture 468-1-204, Kuwaichi, Japan (72) Inventor Sumio Takahara 3-1-1-201, Shioya, Sumoto-shi, Hyogo F-term (reference) 4C083 AA122 AC012 AC072 AC122 AC242 AC271 AC352 AC422 AC482 AD042 AD172 AD551 AD552 AD642 AD661 AD662 CC05 DD33 EE12 EE16 EE17 4C206 AA01 AA02 AA03 DB20 DB50 MA01 MA04 NA14 ZA89 4H006 AA01 AA03 AB12 BJ20 BJ50 BN30 BP30 BR70

Claims (6)

[Claims] 1. An ester of hinokitiol and cinnamic acid or a derivative thereof represented by the following general formula (I) or (II). Embedded image Embedded image (Wherein R ₁ , R ₂ and R ₃ are the same or different, and represent a hydrogen atom, a hydroxy group, an alkoxy group,
Represents a fluoroalkoxy group or an alkylcarbonyloxy group. ) 2. The ester according to claim 1, wherein the alkoxy group is at least one selected from the group consisting of a methoxy group, an ethoxy group and a butoxy group. 3. The ester according to claim 1, wherein the alkylcarbonyloxy group is at least one selected from the group consisting of an acetoxy group, a propionyloxy group and a butyryloxy group. 4. The ester according to claim 1, wherein the fluoroalkoxy group is a trifluoromethoxy group. 5. The method according to claim 1, wherein the ester is hinoxytyl cinnamate,
Hinokityl ferulate, hinokityl caffeate,
Hinokyl-p-coumarate, hinokyl synapate,
2. The ester of claim 1 which is hinoxytyl-4'-methoxycinnamate or hinoxytyl-4'-acetoxyferulate. 6. A composition for external use on skin, comprising as an active ingredient at least one ester of hinokitiol and cinnamic acid or a derivative thereof according to any one of claims 1 to 5.