JP2003201264A - Hinokitiol derivative and skin care preparation and hair cosmetic containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an odorless hinokitiol derivative having low volatility and extremely high stability, formable to various preparations and giving little stimulation to the skin and mucosa, a method for producing the derivative and a skin care preparation and a hair cosmetic containing the hinokitiol derivative. <P>SOLUTION: The hinokitiol derivative is expressed by general formula (I) or general formula (II) (R is a 1-6C straight chain or branched alkyl or hydroxyalkyl). <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a hinokitiol derivative, a skin external preparation and a cosmetic for hair containing the hinokitiol derivative, more specifically, a novel hinokitiol derivative and a method for producing the same, and the use of the hinokitiol derivative, The present invention relates to a pharmaceutical external preparation for skin and a cosmetic composition for hair, which is excellent in usability and stability.

[0002]

2. Description of the Related Art Hinokitiol has a structure represented by the following general formula.

[0003]

[Chemical 3]

[0004] It is a compound having, and is a natural tropolone compound contained in the essential oil component of trees such as Taiwan cypress and Aomori Hiba. In addition, hinokitiol is antibacterial,
It is known to have many action effects such as antifungal, antiseptic, whitening, hair growth promoting, antidandruff, freshness keeping, harmful insects, plant growth promoting and antioxidant. As a tautomeric isomer of hinokitiol, a structure represented by the following general formula

[0005]

[Chemical 4]

Compounds having are known.

However, since hinokitiol has sublimability and photodegradability, it is easily volatilized or decomposed,
There is a problem that it is lacking in storability, handleability or stability. In addition, it has strong corrosiveness to metals, and easily binds to various metal ions to form an organometallic compound such as a colored hinokitiol salt or complex. This is because it has a keto-enol structure in the resonance structure as a substituent of the 7-membered ring serving as a mother nucleus. Then, there is a problem that the application and the formulation are limited due to the coloring due to the binding with the metal ion.

As a solution to these problems, a cyclodextrin clathrate of hinokitiol (JP-A-11-222)
455), glycosides (JP-A-7-17993), fatty acid esters (JP-A-56-26842), and the like.

[0009]

However, the above-mentioned cyclodextrin clathrate requires a large amount of cyclodextrin in comparison with the amount of hinokitiol, and coloring by metal ions is not improved. In addition, the above-mentioned glycosides and fatty acid esters are easily hydrolyzed during the preparation, and their industrial use is hindered due to problems such as their stability.

The present invention has been made in view of the above problems of the prior art, and the object thereof is to have low volatility, no odor, and extremely stable, and various dosage forms. A further object of the present invention is to provide a hinokitiol derivative which can be produced and has less irritation to the skin and mucous membranes, a method for producing the hinokitiol derivative, and a skin external preparation and hair cosmetic containing the hinokitiol derivative.

[0011]

As a result of intensive studies to solve the above problems, the present inventors have found that the above problems can be solved by ether-bonding an alkyl group or a hydroxyalkyl group to hinokitiol. The present invention has been completed.

That is, the hinokitiol derivative of the present invention is
The following general formula (I)

[0013]

[Chemical 5]

Or the following general formula (II)

[0015]

[Chemical 6]

(R in the formulas (I) and (II) represents a linear or branched alkyl group having 1 to 6 carbon atoms or a hydroxyalkyl group). .

In a preferred form of the hinokitiol derivative of the present invention, the alkyl group is a methyl group, an ethyl group or an n-group.
-Propyl group, isopropyl group, n-butyl group, s-butyl group or t-butyl group, wherein the hydroxyalkyl group is a methanol group, ethanol group, propanol group, propanediol group, butanol group, butanediol group , A sorbitol group or a mannitol group.

Further, the external preparation for skin or cosmetic for hair of the present invention is characterized by containing the above-mentioned hinokitiol derivative.

Furthermore, the method for producing a hinokitiol derivative of the present invention is a method for producing the above-mentioned hinokitiol derivative, which comprises reacting hinokitiol with an alkyl halide or a halogenohydroalkyl under a basic catalyst. And

[0020]

BEST MODE FOR CARRYING OUT THE INVENTION The hinokitiol derivative of the present invention will be described in detail below. In addition, in this specification, unless otherwise indicated, "%" shall show a mass percentage. Further, the “alkyl group” means an atomic group remaining after removing one hydrogen atom from paraffin hydrocarbon, that is, a general formula C _n H
_A monovalent group represented by _{2n + 1} . Furthermore, the “hydroxyalkyl group” refers to a compound having a structure in which at least one hydroxyl (OH) group is bonded to the carbon atom of the above alkyl group. Furthermore, in the present specification, terms such as "tautomerism" and "keto-enol structure" are used in describing the hydrogen transfer of tropolone compounds.

As described above, the hinokitiol derivative of the present invention has the following general formula (I):

[0022]

[Chemical 7]

Or the following general formula (II)

[0024]

[Chemical 8]

(R in the formulas (I) and (II) represents a linear or branched alkyl group having 1 to 6 carbon atoms or a hydroxyalkyl group). When hinokitiol is used as such an alkyl ether derivative or a hydroxyalkyl ether derivative, it has no sublimation property, coloring property with a chelate, and corrosiveness (solubility) with respect to a metal, and the light stability becomes extremely excellent. It is valid. Further, the hinokitiol derivative of the present invention is
It has a tyrosinase (phenolase) activity inhibitory action and is extremely effective as a whitening agent. Furthermore, it has an antioxidant effect, and is more effective in preventing lipid oxidation and pigmentation of the skin. As shown in the general formulas (I) and (II), the hinokitiol derivative of the present invention has two isomers due to the tautomerism of hinokitiol, but the effects exhibited by both are almost the same.

Here, the alkyl group is preferably a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an s-butyl group or a t-butyl group. In this case, since the alkyl ether derivative exhibits oil solubility, when it is blended in, for example, a cream or the like, it is quickly dissolved in oils and the skin absorbability is likely to be extremely good.

The hydroxyalkyl group is preferably a methanol group, an ethanol group, a propanol group, a propanediol (glycerin) group, a butanol group, a butanediol group, a sorbitol group or a mannitol group. In this case, since the hydroxyalkyl ether derivative exhibits water solubility, the application of hinokitiol can be expanded. That is, in various preparations containing hinokitiol as an active ingredient, the preparation form can be expanded and an aqueous preparation which does not irritate the skin can be obtained.

Further, the hinokitiol derivative of the present invention comprises
When an acid or an alkali is reacted, the ether bond with hinokitiol is decomposed, so that hinokitiol can be released at a desired timing. The decomposition rate at this time can be adjusted by appropriately selecting the type and amount of the decomposition agent to be reacted and the conditions under which the decomposition reaction proceeds, and a desired sustained-release preparation can be obtained. In addition, the released hinokitiol can exhibit antibacterial / antifungal action, whitening action by inhibiting tyrosinase activity, and promoting hair growth on the scalp.

The above-mentioned hinokitiol derivative can be produced by reacting hinokitiol with an alkyl halide or a hydroxyalkyl halide under a basic catalyst. Here, as a particularly desirable specific example, the following general formula (III)

[0030]

[Chemical 9]

And the following general formula (IV)

[0032]

[Chemical 10]

The ethanoyl ether represented by can be mentioned.

These can be obtained, for example, by reacting hinokitiol and haloethanol in an organic solvent together with an alkali compound together with a phase transfer catalyst at about 15 to 150 ° C. for 1 to 48 hours.

Examples of the haloethanol include 2-
Examples thereof include, but are not limited to, iodoethanol, 2-bromoethanol and 2-chloroethanol. Particularly, 2-chloroethanol is desirable in the industrial manufacturing process. Further, as the organic solvent, an inert solvent which does not react with the raw material, the product and the catalyst in the reaction step,
For example, pyridine, dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, dimethoxyethane, acetone and acetonitrile are desirable,
Especially in practical use, it is desirable to use dimethylformamide or acetonitrile. Further, as the basic catalyst, alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, alkali metal alkoxides such as sodium methoxide and potassium t-butoxide, sodium hydride. And alkali metal hydrides such as potassium hydride, and aliphatic or aromatic amines such as triethylamine, pyridine and dimethylaminopyridine, and sodium hydroxide, potassium hydroxide and potassium carbonate are particularly preferable. Furthermore, examples of the phase transfer catalyst include ammonium salts, onium salts such as sulfonium salts and phosphonium salts, and crown ethers, and it is particularly preferable to use 18-crown-6.

As another particularly preferable specific example, the following general formula (V)

[0037]

[Chemical 11]

And the following general formula (VI)

[0039]

[Chemical 12]

The glyceryl ether represented by can be mentioned.

These are obtained, for example, by reacting hinokitiol and epihalohydrin (or 1,3-dihalo-2-propanol) in an organic solvent under a basic catalyst at about 15 to 150 ° C. for 1 to 48 hours.

Examples of the above epihalohydrin include epichlorohydrin, epibromohydrin, epiiodohydrin, 1,3-dichloropropanol, 1,3-dibromo-2-propanol, and 1,3-diiodo-2-.
Examples include, but are not limited to, propanol and the like. Of these, 1,3-dihalo-2-propanol requires 2 equivalents or more of a basic catalyst to produce hinokitiol glycidyl ether, whereas
Epihalohydrin has the advantage that it can be produced with approximately equal amounts of catalyst, and it is particularly desirable to use epichlorohydrin. Further, as the organic solvent, an inert solvent which does not react with the raw material, the product and the catalyst in the reaction step, such as pyridine, dimethylformamide, dimethylsulfoxide, dioxane, tetrahydrofuran, dimethoxyethane and acetone is desirable, and particularly practically used. , Dioxane and dimethoxyethane are more preferred. Further, examples of the basic catalyst include alkali hydroxides such as sodium hydroxide and potassium hydroxide, alkali carbonates such as sodium carbonate and potassium carbonate, sodium methoxide and potassium-t.
-Alkali metal alkoxides such as butoxide, alkali metal hydrides such as sodium hydride and potassium hydride,
Aliphatic and aromatic amines such as triethylamine, pyridine and dimethylaminopyridine can be mentioned, but sodium hydroxide, potassium hydroxide and sodium methoxide are particularly preferable.

Other alkyl derivatives and hydroxyalkyl derivatives can also be produced by almost the same operations as in the above production method.

Next, the external preparation for skin and the cosmetic for hair of the present invention will be described in detail. Such an external preparation for skin and a cosmetic composition for hair contain the above-mentioned hinokitiol derivative (formula (I) or formula (II)). in this case,
The hinokitiol derivative described above serves as an active ingredient for whitening or antioxidant. It can also be used in combination with other known whitening agents and antioxidants. Furthermore, the above-mentioned external preparation for skin and cosmetic for hair can be commercialized in various drug forms that are usually adopted for topical application, and in particular, an aqueous solution, a water-alcohol solution, an oil solution,
Polymer nanoparticles such as oil-in-water or water-in-oil emulsions, multiple emulsions, aqueous gels, oily gels, liquids, pasty or solid anhydrous products, ionic and nonionic lipid vesicles, or nanospheres and nanocapsules It can be provided in the form of. Furthermore, relatively fluid states such as white or colored creams,
It may have the appearance of an ointment, emulsion, lotion, sealant, paste or foam, or it may be solid, eg in stick form. These can be used for skin care, makeup or makeup remover, sunscreen, bath oil and the like.

The above-mentioned external preparation for skin and cosmetic for hair can contain the above-mentioned hinokitiol derivative in a proportion of 0.001 to 10% with respect to the total amount of the external preparation for skin and cosmetic for hair. . More preferably 0.01-5%
It is preferable that the hinokitiol derivative is blended in the ratio.

Further, the above-mentioned external preparation for skin and cosmetic for hair can contain various components usually used in the field of pharmaceutical skin products or cosmetics in a usual concentration. Typically, fatty substances, preservatives, vitamins, gelling agents, fragrances, surfactants, water, antioxidants, fillers, UV-screening or wetting agents, and mixtures of any of these, as appropriate. Can be included. Examples of the fatty substances include oils derived from animals or plants, mineral oils, synthetic oils, silicone oils, and fluorinated oils, as well as fatty alcohols, fatty acids, and waxes. Examples of the surfactant include fatty acid esters such as sodium stearate and polyethylene glycol fatty acid esters such as polyethylene glycol stearate.

[0047]

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

Example 1 Hinokitiol ethanoyl ether (the above general formula (I
II) and (IV)) Synthesis 2.46 g of hinokitiol and 2-iodoethanol 3.
5 ml, potassium carbonate 2.07 g and 18-crown-
6 (400 mg) was dissolved in 150 ml of acetonitrile and stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure, ethyl acetate was added for extraction, the extract was washed with saturated brine, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The viscous oil obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to obtain 2.6 g (yield 85%) of a pale yellow viscous oil of hinokitiol ethanoyl ether. Furthermore, the compound of general formula (III) was isolated and purified using high performance liquid chromatography (HPLC). The physical properties of this compound were as follows.

UV λ _max nm: 243.4, 3
^{29.1 · FAB-MS m / z} : 209 [M + H] + · 1 H-NMR (C 5 D 5 N) δ: 7.19 (d, J
= 1.5 Hz, 3-H), 6.59 (dd, J = 11.1.
0, 1.5 Hz, 5-H), 6.85 (dd, J = 1)
1.0, 9.5 Hz, 6-H), 6.71 (d, J =
9.5 Hz, 7-H), 4.12 to 4.18 (m, 11
and12-H), 2.52 (m, 8-H), 0.96.
(6H, d, J = 6.8 Hz, 9 and 10-H) ¹³ C-NMR (C ₅ D ₅ N) δ: 22.2, 3
7.7, 59.8, 71.2, 112.4, 128.
3, 131.5, 133.8, 156.2, 164.
4,179.5

Experimental Example 2 Synthesis of hinokitiol glyceryl ether (general formulas (V) and (VI) above) 6.6 g of hinokitiol and epichlorohydrin 18.6
g was dissolved in 60 ml of 1,4-dioxane, stirred under heating under reflux, 10 ml of 20% aqueous sodium hydroxide solution was added over 4 hours after the initiation of reflux, and the mixture was further stirred for 4 hours. After completion of the reaction, the solvent was distilled off under reduced pressure, ethyl acetate and water were added for extraction, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The viscous oil obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to obtain 6.2 g (yield 65%) of a pale yellow viscous oil of hinokitiol glyceryl ether. Further, the compound of general formula (V) was isolated and purified by high performance liquid chromatography. The physical properties of this compound were as follows.

UV λ _max nm: 243.4, 3
^{33.9 · FAB-MS m / z} : 239 [M + H] + · 1 H-NMR (C 5 D 5 N) δ: 7.19 (d, J
= 1.5 Hz, 3-H), 6.64 (dd, J = 11.1.
0, 1.5 Hz, 5-H), 6.90 (dd, J = 1)
1.0, 10.0 Hz, 6-H), 6.77 (d, J =
10.0 Hz, 7-H), 4.56 (m, 12-H),
4.33 (dd, J = 10.0, 6.5 Hz, 11-
H), 4.17 (2H, d, J = 5.0 Hz, 13-
H), 2.54 (m, 8-H), 0.99 (6H, d,
J = 7.0 Hz, 9 and 10-H) ¹³ C-NMR (C ₅ D ₅ N) δ: 22.4, 3
7.8, 63.6, 70.4, 71.7, 112.8,
128.6, 131.9, 133.8, 156.8, 1
64.4, 179.7

(Example 3) Synthesis of hinokitiol methyl ether 1.64 g of hinokitiol, 2.84 g of methyl iodide,
1.38 g of potassium carbonate and 18-Crown-6 (3
(00 mg) was dissolved in 70 ml of dimethylformamide,
The mixture was stirred at room temperature for 48 hours. After confirming the completion of the reaction by TLC, the solvent was evaporated under reduced pressure, ethyl acetate and water were added for extraction, and the ethyl acetate layer was dried over anhydrous sodium sulfate. The viscous oil obtained by distilling off the solvent under reduced pressure was purified by silica gel column chromatography to give 1.5 g of a pale yellow viscous oil of hinokitiol methyl ether.
(Yield 84%) was obtained. The obtained compound was isolated and purified by high performance liquid chromatography, and NMR and MS analyzes were performed to determine the structure.

(Evaluation test) The effect of the compounds obtained in Examples 1 to 3 was clarified by measuring the tyrosinase activity inhibitory activity for whitening activity and the DPPH radical scavenging activity for antioxidant activity. Specific test methods and results are shown below.

<Test Example 1> The tyrosinase activity inhibitory activity was measured as follows. 0.1M phosphate buffer (pH 7.
0), L-DOPA was adjusted to 2 mM in the substrate solution, and mushroom-derived tyrosinase (6,68) was used in the enzyme solution.
0 units / mg) was adjusted to 0.02 mg / ml. 1 ml of the sample solution dissolved in 5% DMSO and 1 ml of the substrate solution were mixed, and 0.2 ml of the enzyme solution was added to this, and 1
The reaction was carried out for 0 minutes at room temperature. The absorbance at 475 nm before and after the reaction was measured to determine the tyrosinase activity inhibition rate (reference: HS Mason & EW Pet.
erson, Biochim. Biophys. Act
a. , 111, 134-140 (1965). ). The tyrosinase activity inhibition rate at a sample concentration of 10 mM is shown below.

-Tyrosinase activity inhibition rate Arbutin ... 32.7% Hinokitiol: 94.4% Hinokitiol methyl ether ... 85.3% Hinokitiol ethanoyl ether ... 63.9% Hinokitiol propanoyl ether ... 49.4% Hinokitiol glyceryl ether ... 48.8%

<Test Example 2> The DPPH radical scavenging activity was measured as follows. Sample 2mM methanol solution 1m
1 ml of 0.15 mM DPPH methanol solution was added to 1, and the absorbance at 520 nm was measured after 30 minutes to obtain DPPH.
Radical scavenging rate was determined (reference: T. Yamagu
chi, H .; Takamura, T .; Matoba &
J. Terao, Biosci. Biotechno
l. Biochem. , 62, 1201-1204 (1
998). ). The DPPH radical scavenging rate at a sample concentration of 1 mM is shown below.

Radical scavenging rate dl-α-tocopherol ... 90.4% Ascorbic acid: 95.9% Hinokitiol: 6.6% Hinokitiol ethanoyl ether ... 15.0% Hinokitiol propanoyl ether ... 8.9% Hinokitiol glyceryl ether ... 12.0%

From the above results, the hinokitiol alkyl derivative and the hinokitiol hydroxyalkyl derivative obtained in the examples have tyrosinase inhibitory activity and are superior in radical scavenging activity to hinokitiol simple substance, and are suitable as a whitening agent and an antioxidant. It can be used for.

Next, typical formulation examples 1 to 4 of the external preparation for skin and cosmetic for hair of the present invention will be shown.

(Prescription example 1) O / W in the following prescription example
Type emollient cream was produced. Stearic acid: 7.5% Cetostearyl alcohol: 1.5% Liquid paraffin: 10.0% Glycerin triisooctanoate: 12.0% Lanolin: 3.0% Cetyl palmitate: 4.0% Polyethylene glycol monostearate 2.0% Glycerin monostearate 5.0% Hinokitiol ethanoyl ether 0.5% Purified water added 100.0%

(Formulation Example 2) A lotion for skin in the following formulation example was produced. Polyoxyethylene (20) sorbitan monolaurate 1.0% 1,3-butylene glycol 3.0% Sorbitol 70% 2.0% Sodium pyrrolidonecarboxylate solution 3.0% Hinokitiol glyceryl ether 0 .5% ethanol ... 10.0% Add purified water ... 100.0%

(Formulation Example 3) A hand cream according to the following formulation example was produced. Stearic acid: 8.0% Cetyl palmitate: 2.0% Cetanol: 3.0% Lanolin: 1.0% Liquid paraffin: 15.0% Silicone oil: 1.0% Polyoxyethylene monostearate (20) Sorbitan: 1.0% Triethanolamine: 1.0% Propylene glycol: 5.0% Sorbitol (70%): 2.0% Hinokitiol methyl ether: 0.5% Add purified water: 100.0%

(Formulation Example 4) A hair restorer in the following formulation example was produced. Ethanol: 60.0% Polyoxyethylene (50EO) hydrogenated castor oil: 3.0% Tocopherol acetate: 0.5% Hop: 50% Ethanol extract: 2.0% Propylene glycol: 2.0% Perfume: 0.1 % Hinokitiol propanoyl ether 0.5% Add purified water 100.0%

Although the present invention has been described in detail with reference to the preferred embodiments, the present invention is not limited to these embodiments, and various modifications can be made without departing from the gist of the present invention. For example, it goes without saying that the hinokitiol derivative of the present invention includes isomers having a keto-enol structure, as well as racemates and optically active forms thereof.

[0065]

Industrial Applicability As described above, according to the present invention, since an alkyl group or a hydroxyalkyl group is ether-bonded to hinokitiol, it has low volatility, no odor, and is extremely stable. It is possible to provide a hinokitiol derivative that can be manufactured into a shape and has less irritation to the skin and mucous membranes, a method for producing the hinokitiol derivative, and a skin external preparation and a hair cosmetic containing the hinokitiol derivative.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/122 A61K 31/122 A61P 17/00 A61P 17/00 17/14 17/14 C07C 49/717 C07C 49/717 // C07B 61/00 300 C07B 61/00 300 (71) Applicant 502004364 Kazuhisa Takahashi 1-27-302 (72) 1-chome, Okeishi-cho, Akashi-shi, Hyogo Tsuyoshi Furuya Minami Nerima-ku, Tokyo Oizumi 4-2033 (72) Inventor Yoichi Matsuura 4-152 Korikawa, Yao-shi, Osaka Prefecture (152) Inventor Sumio Takahara 3-1-12-1 Shioya, Sumoto-shi, Hyogo F-term (reference) 4C083 AA112 AC022 AC072 AC102 AC122 AC132 AC242 AC352 AC402 AC422 AC432 AC442 AC542 AC612 AD152 AD512 AD551 AD552 AD662 CC02 CC05 CC37 EE12 EE16 EE22 FF01 4C206 AA01 AA02 CB21 MA01 MA04 MA83 NA14 ZA89 ZA92 4H006 AA02 A C43 BA02 BA29 BA32 4H039 CA61 CD10 CD20 CL25

Claims (7)

[Claims] 1. The following general formula (I): Alternatively, the following general formula (II): (In the formula (I) and the formula (II), R represents a linear or branched alkyl group having 1 to 6 carbon atoms or a hydroxyalkyl group), a hinokitiol derivative. 2. The alkyl group is a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group,
The hinokitiol derivative according to claim 1, which is an s-butyl group or a t-butyl group. 3. The hydroxyalkyl group is a methanol group, an ethanol group, a propanol group, a propanediol group, a butanol group, a butanediol group, a sorbitol group or a mannitol group.
Or the hinokitiol derivative according to item 2. 4. An external preparation for skin, comprising the hinokitiol derivative according to any one of claims 1 to 3. 5. A cosmetic for hair, comprising the hinokitiol derivative according to any one of claims 1 to 3. 6. The external preparation for skin according to claim 4, or the cosmetic for hair according to claim 5, wherein the hinokitiol derivative is contained in a proportion of 0.001 to 10% with respect to the total amount. . 7. A method for producing a hinokitiol derivative according to any one of claims 1 to 3, wherein the hinokitiol is reacted with an alkyl halide or a hydroxyalkyl halide under a basic catalyst. A method for producing a hinokitiol derivative, comprising: