JP3458041B2 - Anti-aging agent and skin cosmetic - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a photoaging agent and a skin cosmetic, and more specifically, a photoaging agent comprising a triterpenoid aromatic compound derivative and / or a salt thereof, and a triterpenoid aromatic compound derivative and /
Alternatively, the present invention relates to a skin cosmetic containing a salt thereof and having an excellent skin beautiful effect for preventing and improving wrinkles and the like.

[0002]

2. Description of the Related Art Generally, skin aging is a physiological phenomenon caused by the mutual effects of aging-related physiological aging and photoaging due to sun exposure (ultraviolet rays). The relationship between aging and wrinkles, rough skin, and spots is drawing attention. That is, it is known that if it is exposed to the sun (ultraviolet rays) for a long period of time, it will increase deep wrinkles on the face and neck, and further cause dryness of the skin and pigmentation such as rough skin, spots and freckles. The trouble has come to be seen as a problem.

Conventionally, in order to prevent the skin from being damaged by these ultraviolet rays, cosmetics containing various kinds of ultraviolet absorbing, scattering and shielding substances such as titanium oxide, zinc oxide, paramethoxycinnamic acid ester, paraaminobenzoic acid ester and the like. (Sunscreen, Sunprotect cosmetics) have been developed and are in use. However, even if these cosmetics are used, it is difficult to protect the skin from overwhelming sun exposure. It is widely known that external application of all-trans retinoic acid is effective as a method for improving the photoaging (Methods in Enz).
ymology, 1990, Volume 190, 352-3
Due to safety problems, there is a strong demand for the development of a photoaging improver and a skin cosmetic which are highly effective and safe, because of safety concerns.

In order to meet the above-mentioned demands, plant-derived triterpenoids such as ursolic acid and oleanolic acid and their derivatives such as esters have hitherto been used in photoaging-improving agents, cosmetics, skin external preparations and the like. Came to be. However, the content of triterpenes, which are the raw materials of these substances, in the plant is extremely low, and there is a problem that it becomes expensive if a sufficient effect is added to cosmetics and external preparations, and there is also a problem in terms of supply. There was a problem that it was difficult to secure a large amount. Therefore, it has been desired to develop a triterpenoid compound that is highly safe, has an action of preventing and improving photoaging, and has an excellent skin-beautifying effect, and that can sufficiently exert the effect even when used in a small amount.

[0005]

The present invention has been made from the above viewpoints, and provides a photoaging inhibitor comprising a triterpenoid compound which is highly safe and has an excellent photoaging inhibiting effect, and further, An object of the present invention is to provide a skin cosmetic having an excellent skin-beautifying effect of preventing and improving wrinkles and the like.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that the hydrogen atom and / or the hydrogen atom of the carboxyl group at the 28-position of ursolic acid, oleanolic acid or betulinic acid and / or 3 Among the triterpenoid derivatives in which the hydrogen atom of the hydroxyl group bonded to the carbon atom at the position is substituted with a functional group, a triterpenoid derivative in which at least one of the hydrogen atoms is substituted with a functional group having an aromatic ring (hereinafter, referred to as "aromatic triterpenoid Group compound derivatives "
(Also sometimes referred to as) and salts thereof, compared to conventionally reported triterpenoids such as ursolic acid, oleanolic acid, betulinic acid and their aliphatic acyl derivatives, aliphatic ester derivatives, prevent photoaging of the skin, In the improving effect, the physiological activity is increased 10 times or more, and further, the skin cosmetic containing the aromatic compound derivative of triterpenoid and / or its salt prevents wrinkles and the like,
The inventors have found that the skin-beautifying effect to be improved is excellent and have completed the present invention.

That is, the present invention is a triterpenoid derivative in which the hydrogen atom of the carboxyl group at the 28-position of ursolic acid, oleanolic acid or betulinic acid and / or the hydrogen atom of the hydroxyl group bonded to the carbon atom at the 3-position is substituted with a functional group. There is provided a photoaging inhibitor comprising one or two or more of a triterpenoid derivative and a salt thereof in which at least one of the functional groups has an aromatic ring.

As the compound which becomes the photoaging inhibitor of the present invention, specifically, the functional group having an aromatic ring is 2
The functional group for substituting the hydrogen atom of the 8-position carboxyl group is a group represented by the following general formula (I), and the functional group for substituting the hydrogen atom of the hydroxyl group bonded to the 3-position carbon atom Examples thereof include triterpenoid derivatives, which are groups represented by the following general formula (I) or (II), and salts thereof.

[0009]

[Chemical 5]

However, in the formula (I), R ₁ represents an optionally substituted aromatic ring, and R ₂ represents a hydrogen atom or an optionally substituted aromatic ring.

[0011]

[Chemical 6]

However, in the formula (II), R ₃ represents an optionally substituted aromatic ring, and n represents an integer of 0 to 2. Further, as a more specific compound, R of the general formula (I) is
₁ represents a phenyl group, a methoxyphenyl group, an ethoxyphenyl group, a butoxyphenyl group, a nitrophenyl group, a diphenyl group or a naphthyl group, R ₂ represents a hydrogen atom or a phenyl group, and R _{3 in the} general formula (II) represents phenyl. Examples thereof include triterpenoid derivatives and salts thereof representing a group, a methoxyphenyl group, an ethoxyphenyl group, a butoxyphenyl group, a nitrophenyl group, a diphenyl group or a naphthyl group.

Furthermore, the present invention is a triterpenoid derivative in which the hydrogen atom of the carboxyl group at the 28-position of ursolic acid, oleanolic acid or betulinic acid and / or the hydrogen atom of the hydroxyl group bonded to the carbon atom at the 3-position is substituted with a functional group. There is provided a skin cosmetic containing one or more triterpenoid derivatives and a salt thereof, in which at least one of the functional groups is a functional group having an aromatic ring. Specific examples of the aromatic compound derivatives of triterpenoids and / or salts thereof to be blended in the skin cosmetics include compounds similar to the aromatic compound derivatives of triterpenoids and / or salts thereof constituting the photoaging inhibitor. be able to. In addition, a specific example of the content of the aromatic compound derivative of triterpenoid and / or the salt thereof in the skin cosmetic of the present invention is 0.00 relative to the total amount of the cosmetic.
It is about 01 to 10% by weight.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be described in detail below.
First, the photoaging inhibitor of the present invention will be described. <1> Photoaging Agent of the Present Invention The photoaging agent of the present invention is a hydrogen atom of a hydroxyl group bonded to the hydrogen atom of the 28-position carboxyl group and / or the 3-position carbon atom of ursolic acid, oleanolic acid or betulinic acid. A triterpenoid derivative having an atom substituted with a functional group, wherein at least one of the functional groups is a functional group having an aromatic ring, and the triterpenoid derivative and one or more salts thereof.

Ursolic acid (Chemical Formula 7) as a starting material of the triterpenoid derivative used in the photoaging inhibitor of the present invention
The compound shown in 1), oleanolic acid (the compound shown in Chemical formula 8), and betulinic acid (the compound shown in Chemical formula 9) all belong to triterpenoids and are substances widely distributed in the plant kingdom.

[0016]

[Chemical 7]

[0017]

[Chemical 8]

[0018]

[Chemical 9]

These three kinds of triterpenoids can be easily extracted from plants using general organic solvents, for example, alcohols such as methanol and ethanol. Ursolic acid, oleanolic acid, and
Betulinic acid is not limited to the plant from which it originates, and is not limited to the method by which it is extracted from the plant. Further, these triterpenoids can be produced by chemical synthesis in addition to the method of taking them out from the plant body, and the use of the triterpenoids obtained thereby in the present invention is not limited at all. Therefore, as the method for producing the triterpenoid used as the starting material of the photoaging inhibitor of the present invention, an appropriate method can be appropriately selected in consideration of economical efficiency and safety. Alternatively, for example, ursolic acid is available from Tokyo Kasei Co., Ltd., oleanolic acid is available from Wako Pure Chemical Industries, Ltd., and betulinic acid is available from Aldrich Co.
It is also possible to use such a commercially available product as a starting material for the photoaging inhibitor of the present invention.

The triterpenoid derivative used in the present invention has a structure in which the hydrogen atom of the carboxyl group at the 28-position and / or the hydrogen atom of the hydroxyl group bonded to the carbon atom at the 3-position of the above-mentioned three types of triterpenoids are substituted with a functional group. Which is a triterpenoid derivative in which at least one of the hydrogen atoms is substituted with a functional group having an aromatic ring, and specifically, a hydrogen atom of a carboxyl group at the 28-position of ursolic acid, oleanolic acid or betulinic acid. And / or a triterpenoid derivative in which a hydrogen atom of a hydroxyl group bonded to a carbon atom at the 3-position is substituted with a functional group having an aromatic ring;
A triterpenoid in which the hydrogen atom of the carboxyl group at the 28-position of ursolic acid, oleanolic acid or betulinic acid is substituted with an aliphatic functional group and the hydrogen atom of the hydroxyl group bonded to the carbon atom at the 3-position is substituted with a functional group having an aromatic ring. Derivatives: ursolic acid, oleanolic acid or betulinic acid 3
A triterpenoid derivative in which a hydrogen atom of a hydroxyl group bonded to a carbon atom at position 28 is replaced with an aliphatic functional group and a hydrogen atom of a carboxyl group at position 28 is replaced with a functional group having an aromatic ring can be given.

Such a triterpenoid derivative is used in the present invention, and among these triterpenoid derivatives, a triterpenoid derivative having a structure in which at least the hydrogen atom of the carboxyl group at position 28 is substituted with a functional group having an aromatic ring. In this case, it is preferable that the functional group substituting the hydrogen atom of the carboxyl group at the 28-position is a group represented by the above general formula (I), and hydrogen of the hydroxyl group bonded to at least the carbon atom at the 3-position. In a triterpenoid derivative having a structure in which an atom is substituted with a functional group having an aromatic ring, the functional group substituting the hydrogen atom of the hydroxyl group bonded to the carbon atom at the 3-position is represented by the above general formula (I) or (I
The group represented by I) is preferable. In addition, 28
The hydrogen atom of the carboxyl group at position has not been replaced,
Alternatively, in the case of a triterpenoid derivative having a structure in which a hydrogen atom of a hydroxyl group which is substituted with an aliphatic functional group and is bonded to a carbon atom at the 3-position is substituted with a functional group having an aromatic ring, the carbon at the 3-position is The functional group substituting the hydrogen atom of the hydroxyl group bonded to the atom is preferably a group represented by the above general formula (II). It can be said that these triterpenoid derivatives are excellent in the action of preventing and improving photoaging of the skin.

In the general formula (I), R ₁ represents an aromatic ring which may be substituted, and R ₂ represents a hydrogen atom or an aromatic ring which may be substituted. When the group represented by I) is used in the triterpenoid derivative as the above-mentioned substituent, the group connecting the triterpenoid residue and the aromatic ring is a methylene group or a methine group, which is an alkylene having 2 or more carbon atoms. If it is a group or an alkenyl group, a sufficient anti-aging effect may not be obtained. Furthermore, in the present invention, preferably, the compound represented by the general formula (I)
R ₁ is a phenyl group, a methoxyphenyl group, an ethoxyphenyl group, a butoxyphenyl group, a nitrophenyl group,
It represents a diphenyl group or a naphthyl group, and R ₂ represents a hydrogen atom or a phenyl group.

In the general formula (II), R ₃ represents an aromatic ring which may be substituted, but in the present invention, R ₃ is preferably phenyl group, methoxyphenyl group, ethoxyphenyl group, butoxyphenyl group. Group, nitrophenyl group,
It represents a diphenyl group or a naphthyl group. The preferred specific examples of the groups having an aromatic ring represented by the general formula (I) or the general formula (II) have been described above. Thus, in the present invention, these aromatic rings have a ring number of 1 or less. Alternatively, it is preferably 2 aromatic rings.

Among the triterpenoid derivatives used in the present invention, the hydrogen atom of the hydroxyl group bonded to the 3-position carbon atom of ursolic acid, oleanolic acid or betulinic acid is a functional group having an aromatic ring, and the 28-position carboxyl group. In the triterpenoid derivative in which the hydrogen atoms of the group are each substituted with an aliphatic functional group, examples of the aliphatic functional group include an alkyl group, an alkenyl group, and an alkylene group. As the triterpenoid derivative used in the present invention, the aliphatic functional group is preferably an alkyl group, and the alkyl group having 1 to 20 carbon atoms, particularly 8 to 20 carbon atoms has stability and handling properties. It is more preferable in terms of ease of operation. The alkyl group may be linear, branched, or cyclic.

In addition, the hydrogen atom of the carboxyl group at the 28-position of ursolic acid, oleanolic acid or betulinic acid is a functional group having an aromatic ring, and the hydrogen atom of the hydroxyl group bonded to the carbon atom at the 3-position is aliphatic. In the triterpenoid derivative substituted with a functional group, examples of the aliphatic functional group include an alkyl group, an alkenyl group, an alkylene group, and an aliphatic acyl group.
In the triterpenoid derivative used in the present invention, the aliphatic functional group is preferably an alkyl group or an alkylacyl group, and the alkyl moiety has 1 to 20 carbon atoms, particularly 8 to 20 carbon atoms. , As above. The alkyl moiety may be linear, branched, or cyclic.

The triterpenoid derivative used in the present invention can be prepared by a conventional method, for example, using ursolic acid, oleanolic acid or betulinic acid as a starting material, or the hydrogen atom of the carboxyl group at the 28-position of ursolic acid, oleanolic acid or betulinic acid. Starting from a triterpenoid derivative obtained by substituting a hydrogen atom of a hydroxyl group bonded to the 3-position carbon atom with an aliphatic functional group, a hydroxyl group bonded to the hydrogen atom of the 28-position carboxyl group and / or the 3-position carbon atom A method of reacting these starting materials with an aromatic compound by a synthetic reaction that contributes to the reaction, specifically, by coupling the 28-position carboxyl group with a halogenated aromatic compound to a 3-position carbon atom. The hydroxyl groups to be etherified with aromatic alcohols or with aromatic carboxylic acids It can be prepared by methods such as for esterification.

A triterpenoid derivative in which the hydrogen atom of the carboxyl group at the 28-position of ursolic acid, oleanolic acid or betulinic acid or the hydrogen atom of the hydroxyl group bonded to the carbon atom at the 3-position of ursolic acid, oleanolic acid or betulinic acid, is substituted with an aliphatic functional group. The carboxylic acid at the 28-position of ursolic acid, oleanolic acid or betulinic acid is esterified with an aliphatic compound, or the hydroxyl group bonded to the carbon atom at the 3-position is etherified or esterified with an aliphatic compound. And the like. These etherifications and esterifications can be carried out in the same manner as usual methods. For example, the esterification carried out via the carboxyl group at the 28-position is carried out in the same manner as in the usual esterification reaction of a carboxylic acid, for example, the above-mentioned triterpenoid in a suitable solvent such as chloroform in the presence of a base such as triethylamine, A chlorinating agent such as thionyl chloride is caused to act to generate a chloride of a triterpenoid, and a desired aliphatic alcohol such as methanol, ethanol, isopropyl alcohol, butanol, 2-ethylhexyl alcohol, oleyl alcohol, cetanol, stearyl alcohol is added to triethylamine, etc. It can be carried out by reacting in the presence of a base.

More specifically, the method for producing the triterpenoid derivative used in the present invention will be described. For example, as a starting material, ursolic acid, oleanolic acid, betulinic acid, or a hydrogen atom of a hydroxyl group bonded to the carbon atom at the 3-position thereof is used as a fatty acid. Using a triterpenoid derivative substituted with a group functional group,
In the case of producing a triterpenoid derivative having a structure in which at least the hydrogen atom of the carboxyl group at the 28-position thereof is substituted with the group represented by the general formula (I), the starting material is an aromatic compound such as acetone in a polar solvent. A preferred method is to react a desired reagent obtained by adding bromine or chlorine to a ring-bonded methylene group or methine group.

Further, ursolic acid, oleanolic acid, betulinic acid, or a triterpenoid derivative obtained by substituting the hydrogen atom of the carboxyl group at the 28-position with an aliphatic functional group is used as a starting material and bonded to at least the carbon atom at the 3-position. In the case of producing a triterpenoid derivative having a structure in which a hydrogen atom of the hydroxyl group is substituted with a group represented by the general formula (II), a structure in which a carboxyl group is bonded to an aromatic ring via an alkylene group having 0 to 2 carbon atoms Preferred is a method of reacting a reagent obtained by brominated or chlorinated a carboxyl group of an aromatic carboxylic acid having a, in the presence of a nonpolar solvent such as tetrahydrofuran as the starting material in the presence of a base such as triethylamine. .

Further, among the triterpenoid derivatives used in the present invention, the hydrogen atom of the carboxyl group at the 28-position of ursolic acid, oleanolic acid or betulinic acid is a functional group having an aromatic ring and a hydroxyl group bonded to the carbon atom at the 3-position. Or a triterpenoid derivative having a structure in which each hydrogen atom is substituted with an aliphatic functional group, or a hydrogen atom of a hydroxyl group bonded to a carbon atom at the 3-position of these is a functional group having an aromatic ring and a carboxyl group at the 28-position of In a triterpenoid derivative having a structure in which a hydrogen atom is substituted with an aliphatic functional group, ursolic acid, oleanolic acid or betulinic acid is substituted with an aromatic functional group, and then a production method of performing aliphatic functional group substitution is performed. It is also possible to collect.

As the photoaging inhibitor of the present invention, the triterpenoid derivative produced in this manner is used, but it is also possible to use salts of the above triterpenoid derivative. Examples of salts of triterpenoid derivatives include ammonium salts, alkali metal salts and organic amine salts obtained by reacting the above triterpenoid derivatives with an inorganic or organic base.

The hydrogen atom of the carboxylic acid at the 28-position of ursolic acid, oleanolic acid or betulinic acid applied to the photoaging agent of the present invention and / or the hydrogen atom of the hydroxyl group bonded to the carbon atom at the 3-position is functional. A triterpenoid derivative substituted with a group, wherein at least one of the functional groups is a functional group having an aromatic ring, the triterpenoid derivative and salts thereof are extremely stable, and discoloration, odor and decomposition even when formulated. Since it does not change with time such as deactivation, it can be stably and easily compounded in various dosage forms.

Next, the skin cosmetic of the present invention will be described. <2> Skin cosmetic of the present invention The skin cosmetic of the present invention has a hydrogen atom of a hydroxyl group bonded to the carboxylic acid at the 28-position of ursolic acid, oleanolic acid or betulinic acid and / or a carbon atom at the 3-position. A triterpenoid derivative substituted with a functional group, comprising:
At least one of the functional groups contains one or more triterpenoid derivatives and salts thereof, which are functional groups having an aromatic ring.

The hydrogen atom of the carboxyl group at the 28-position and / or the hydrogen atom of the hydroxyl group bonded to the carbon atom at the 3-position of ursolic acid, oleanolic acid or betulinic acid to be incorporated in the skin cosmetic of the present invention is substituted with a functional group. The triterpenoid derivative wherein at least one of the hydrogen atoms is substituted with a functional group having an aromatic ring and salts thereof (hereinafter referred to as triterpenoid compound) are as described in <1>. A triterpenoid compound similar to this is used in the skin cosmetic of the present invention.

The blending amount of the triterpenoid compound in the skin cosmetic of the present invention is preferably 0.0001 to 10% by weight, more preferably, the total amount of the cosmetic.
It is 0.001 to 1% by weight. The above triterpenoid compound is contained in the skin cosmetic in an amount of 0.0001% by weight.
If the amount is smaller, the skin-improving effect for improving the skin condition such as wrinkles may not be sufficiently obtained, and even if the amount exceeds 10% by weight, the effect commensurate with the increase cannot be expected. Sometimes.

The dosage form of the cosmetic composition of the present invention is not particularly limited, and examples thereof include creams, emulsions, oils, lotions, packs, aqueous gels, oil gels and ointments. From the viewpoint, cream, milky lotion, oil and the like are more preferable dosage forms. These skin cosmetics can be produced by the same method as that for ordinary skin cosmetics, except that the above triterpenoid compound is appropriately selected and blended according to the dosage form.

In addition to the above-mentioned triterpenoid compounds, the skin cosmetics of the present invention include hydrocarbons such as liquid paraffin, petrolatum and squalane which are generally applied to skin cosmetics, isopropyl myristate (IPM) and synthetic compounds. Esters such as gay wax, jojoba oil, carnauba wax, animal and vegetable oils such as olive oil and beef tallow, higher alcohols such as cetanol and stearyl alcohol, higher fatty acids such as stearic acid and oleic acid, sodium lauryl sulfate, alkyl sulfosuccinate ester Anionic surfactant such as quaternary alkylamine salt, cationic surfactant such as quaternary alkylamine salt, fatty acid monoglyceride, nonionic surfactant such as pooxyethylene hydrogenated castor oil, and amphoteric surfactant such as alkylbetaine Such as glycerin and propylene glycol Polyhydric alcohols include ethanol, lower alcohols propanol, parabens and preservatives such as chlorhexidine gluconate, p-aminobenzoic acid derivatives, ultraviolet absorbers such as benzophenone derivatives, antioxidants such as vitamin E or butylhydroxytoluene,
Thickeners such as gum arabic and carboxyvinyl polymer,
Moisturizers such as polyethylene glycol, pH adjusting agents such as citrate and acetate, powders such as titanium oxide, silica gel and talc, perfumes and pigments, hyaluronic acid, placenta extract,
Medicinal ingredients such as ginseng extract, vitamins, sterol glycosides and the like are appropriately selected and mixed according to various purposes.

[0038]

EXAMPLES Examples of the present invention will be described below. First,
A production example of the triterpenoid compound used in the present invention will be described.

[0039]

[Production Example 1] To a solution of benzyl ursolic acid and benzyl betulinic acid 1 g of ursolic acid dissolved in 50 ml of acetone, 5 ml of benzyl bromide and 5 g of potassium carbonate were added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. It was filtered off. After distilling off the solvent from the filtrate, the residue was purified by a silica gel column to give a benzyl derivative of ursolic acid 1.2.
g (yield 97%) was obtained. The obtained benzyl derivative of ursolic acid was measured by NMR (nuclear magnetic resonance) and IR (infrared spectroscopy). The results are shown in FIG. 1 for ¹ H-NMR, FIG. 2 for ¹³ C-NMR, and FIG. 3 for IR. From this, it was confirmed that the benzyl derivative of ursolic acid obtained above was a benzyl ursolic acid having a structure in which the hydrogen atom of the carboxyl group at the 28-position of ursolic acid was replaced with a benzyl group.

Betulinic acid 1 instead of ursolic acid
1.2 g of benzyl betulinate having a structure in which the hydrogen atom of the carboxyl group at the 28-position of betulinic acid was replaced with a benzyl group by the same synthetic method as described above.
%) Was obtained.

[0041]

[Production Example 2] Methoxybenzyl oleanolate 1 g of oleanolic acid dissolved in 50 ml of acetone was added with 5 ml of methoxybenzyl bromide and 5 g of potassium carbonate, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere, and then the insoluble matter was filtered off. did. After distilling off the solvent from the filtrate, the residue was purified by a silica gel column, and 1.1 g of methoxybenzyl oleanolate having a structure in which the hydrogen atom of the carboxyl group at the 28-position of oleanolic acid was replaced with a methoxybenzyl group.
(Yield 84%) was obtained.

[0042]

Production Example 3 Nitrobenzyl betulinate, nitrobenzyl ursolic acid 1 g of betulinic acid was dissolved in 50 ml of acetone,
Add 5 ml of nitrobenzyl bromide and 5 g of potassium carbonate,
The mixture was stirred at room temperature under a nitrogen atmosphere for 24 hours, and then the insoluble matter was filtered off. After the solvent was distilled off from the filtrate, the residue was purified by a silica gel column, and 1.1 g of nitrobenzyl betulinate having a structure in which the hydrogen atom of the 28-position carboxyl group of betulinic acid was replaced with a nitrobenzyl group (yield 83 %) Was obtained.

Ursolic acid 1 instead of betulinic acid
Nitrobenzyl ursolic acid having a structure in which the hydrogen atom of the carboxyl group at the 28-position of ursolic acid is replaced with a nitrobenzyl group by the same synthetic method as described above using 1.
05 g (yield 79%) was obtained.

[0044]

[Production Example 4] To a solution of naphthylmethyl ursolic acid and 1 g of naphthylmethyl betulinic acid ursolic acid dissolved in 50 ml of acetone, 5 g of naphthylmethyl bromide and 5 g of potassium carbonate were added, and the mixture was stirred at room temperature under a nitrogen atmosphere for one day. The insoluble material was filtered off. After distilling off the solvent from the filtrate, the residue was purified by a silica gel column to obtain 0.95 g of naphthylmethyl ursolic acid having a structure in which the hydrogen atom of the carboxyl group at the 28-position of ursolic acid was replaced with a naphthylmethyl group (yield 72
%) Was obtained.

Betulinic acid 1 instead of ursolic acid
naphthylmethyl betulinate 0.96 having a structure in which the hydrogen atom of the carboxyl group at the 28-position of betulinic acid is replaced with a naphthylmethyl group by the same synthetic method as described above using g.
g (yield 73%) was obtained.

[0046]

Production Example 5 5 g of diphenylmethane bromide and 5 g of potassium carbonate were added to a solution prepared by dissolving 1 g of diphenylmethyloleanolic acid oleanolate in 50 ml of acetone, and the mixture was stirred under nitrogen atmosphere at room temperature for 24 hours, and then the insoluble matter was filtered off. . After removing the solvent from the filtrate, the residue was purified by a silica gel column, and diphenylmethyl oleanolate having a structure in which the hydrogen atom of the carboxyl group at the 28-position of oleanolic acid was replaced with a diphenylmethyl group 1.05 g
(Yield 77%) was obtained.

[0047]

[Production Example 6] Phenylbenzyl betulinate, phenylbenzyl oleanolate 1 g of betulinic acid was dissolved in 50 ml of acetone,
Add 5 g of methyl biphenyl bromide and 5 g of potassium carbonate,
Under nitrogen atmosphere, the mixture was stirred at room temperature for 24 hours, and then insoluble matter was filtered off. After removing the solvent from the filtrate, the residue was purified by a silica gel column, and 1.1 g of phenylbenzyl betulinate having a structure in which the hydrogen atom of the carboxyl group at the 28-position of betulinic acid was replaced with a phenylbenzyl group (yield 80%. ) Got.

By using 1 g of oleanolic acid instead of betulinic acid, phenylbenzyl oleanolate having a structure in which the hydrogen atom of the carboxyl group at the 28-position of oleanolic acid was replaced with a phenylbenzyl group by the same synthetic method as described above. 1 g (yield 80%) was obtained.

[0049]

[Production Example 7] Benzoyl oleanolic acid 1 g of oleanolic acid was dissolved in 50 ml of tetrahydrofuran, and 1 g of benzoyl chloride was added dropwise and stirred in a nitrogen atmosphere under ice cooling to a mixed solution containing 3 g of triethylamine, and then the mixture was stirred at room temperature for 2 hours. Stir for hours. Then, the reaction product was extracted with ethyl acetate, and the obtained extract was treated with a 2% aqueous hydrochloric acid solution, saturated aqueous sodium carbonate solution and sodium sulfate, and filtered to obtain a crudely purified product. This was purified using a silica gel column to obtain 1.02 g of white crystals of benzoyloleanolic acid (a compound in which the hydrogen atom of the hydroxyl group bonded to the carbon atom at the 3-position of oleanolic acid was substituted with a benzoyl group). The yield was 80.5%.

[0050]

[Production Example 8] Methoxybenzoylbetulinic acid 1 g of betulinic acid was dissolved in 50 ml of tetrahydrofuran, and 3 g of triethylamine was added to the solution to prepare a mixed solution.
1 g of methoxybenzoyl chloride was dropped and stirred in a nitrogen atmosphere under ice cooling, and then stirred at room temperature for 2 hours. afterwards,
The reaction product was extracted with ethyl acetate, and the resulting extract was 2%
A crude purified product was obtained by treating with an aqueous hydrochloric acid solution, saturated aqueous sodium carbonate and sodium sulfate, and filtering. This was purified using a silica gel column to obtain 1 g of methoxybenzoyl betulinic acid having a structure in which the hydrogen atom of the hydroxyl group bonded to the carbon atom at the 3-position of betulinic acid was replaced with a methoxybenzoyl group. The yield was 76%.

[0051]

[Production Example 9] Phenylpropionyl ursolic acid 1 g of ursolic acid was dissolved in 50 ml of tetrahydrofuran, and 3 g of triethylamine was added to the solution to prepare a mixed solution.
1 g of phenylpropionyl chloride was added dropwise and stirred in a nitrogen atmosphere under ice cooling, and then stirred at room temperature for 2 hours. Then, the reaction product was extracted with ethyl acetate, and the obtained extract was treated with a 2% aqueous hydrochloric acid solution, saturated aqueous sodium carbonate solution and sodium sulfate, and filtered to obtain a crudely purified product. This was purified using a silica gel column to obtain 1.05 g of white crystals of phenylpropionyl ursolic acid (a compound in which the hydrogen atom of the hydroxyl group bonded to the carbon atom at the 3-position of ursolic acid was replaced with a phenylpropionyl group). The yield was 78.1%.

[0052]

[Production Example 10] 2-ethylhexyl betulinic acid-2-ethylhexyl betulinic acid 45.7 g and triethylamine 10.1 g dissolved in 100 ml of benzene in a mixed solution, and 11.9 g of newly distilled thione chloride dissolved in 30 ml of benzene. Was allowed to react with stirring for 1 hour while being added dropwise under ice cooling. Without removing the betulinic acid chloride formed from the reaction solution, 12 g of 2-ethylhexyl alcohol and 10.1 g of triethylamine were added to benzene 3
The mixed solution dissolved in 0 ml was further added dropwise under ice cooling, and the mixture was reacted for 3 hours. Then, the produced triethylamine hydrochloride was filtered off, and the solvent was distilled off at 40 ° C. or lower to remove betulinic acid-
2-Ethylhexyl was obtained. Obtained betulinic acid-2-
Ethylhexyl was dissolved in 200 ml of benzene, and a mixture of 32 g of triethylamine was added thereto, and 30 ml of benzyl bromide was added dropwise under ice-cooling to react with stirring for 1 hour. Then, the mixture was stirred at room temperature for 2 hours, and at the boiling temperature of benzene. Reflux for 1 hour. After the reaction was stopped, unreacted triethylamine was treated with 2% hydrochloric acid, the reaction product was extracted with ethyl acetate, and the extraction solvent was distilled off from the extract to obtain a crude product. Purification was carried out by using a column and eluting with a hexane / ether (9/1) solvent to give 2-ethylhexyl benzyl betulinate (a hydroxyl group bonded to the carbon atom at the 3-position of 2-ethylhexyl betulinate). A compound in which the hydrogen atom of is substituted with a benzyl group)
32 g was obtained. The yield was 50%.

<Evaluation of Photoaging Agent of the Present Invention> The triterpenoid compounds obtained in each of the above Production Examples were tested for safety and photoaging effect on skin by the following method. It was evaluated.

(1) Safety test (1) -1. Skin irritation test Benzyl ursolic acid, methoxybenzyl oleanolate, nitrobenzyl betulinate, naphthyl methyl ursolic acid, diphenylmethyl oleanolate, benzoyl oleanolic acid, methoxybenzoyl betulinic acid, phenylpropionyl ursolic acid obtained in each of the above production examples The skin irritation test was conducted using Hartley guinea pigs (300 to 500 g, female) as experimental animals.

After removing and shaving the backs of 6 guinea pigs per group, the white parts containing the triterpenoid aromatic compound derivative obtained in each of the above Production Examples at a concentration of 10% by weight in the removed and shaving parts. A cloth patch having a diameter of 15 mm was impregnated with 50 mg of petrolatum and attached to a plastic bandage, and the patch was attached and a closed patch for 24 hours was performed.
After completion of the closed patch, the skin reaction immediately after the plastic bandage was removed (0 hour later) and 24 hours later was evaluated according to the following criteria, and an average evaluation score of 6 animals was calculated for each test group.

(Criteria) 0: No skin reaction 1: Weak or indistinct border erythema 2: Clear erythema 3: Reaction with edema 4: Reactions such as ulcer and necrosis

As a control, the same tests and evaluations were performed using only white petrolatum. The results are shown in Table 1.

[0058]

[Table 1]

(1) -2. Allergenicity test The allergenicity test for benzyl ursolic acid, methoxybenzyl oleanolate, phenylbenzyl betulinate, benzoyloleanolic acid, methoxybenzoylbetulinic acid, phenylpropionyl ursolic acid obtained in each of the above-mentioned production examples was conducted as a test animal. It was carried out using a system guinea pig (300 to 500 g, female).

Maximize the triterpenoid aromatic compound derivative with olive oil at a concentration of 3 w / v%, the triterpenoid aromatic compound derivative with olive oil at a concentration of 0.3 w / v%, and olive oil to 6 guinea pigs per group. (Maximization) method was used to induce sensitization.

Then, after a grace period of 10 days from the last sensitization day in order to induce a sufficient immune response, the back skin of each group of guinea pigs was treated with olive oil at a concentration of 3 w / v%, 0.3 w / v. % Of triterpenoid aromatic compound derivative and olive oil only, 100% each
Was applied and attached to a patch plate having a diameter of 1.5 cm, and 24 hours later, the patch plate was removed. After removing the patch board 24
The skin reaction over time was evaluated according to the following criteria, and the average score was calculated for each test group. The results are shown in Table 2.

(Judgment criteria) 0: No skin reaction 1: Weak or indistinct border erythema 2: Clear erythema 3: Reaction with edema 4: Reactions such as ulcer and necrosis

[0063]

[Table 2]

As is clear from these results, none of the triterpenoid compounds obtained in the above Production Examples showed almost any skin irritation and allergenicity,
Therefore, it can be said that the photoaging inhibitor of the present invention is excellent in safety.

(2) UV Wrinkle Model Improvement Test UV of benzyl ursolic acid, methoxybenzyl oleanolate, phenylbenzyl betulinate, benzoyloleanolic acid, methoxybenzoylbetulinic acid, and phenylpropionyl ursolic acid obtained in each of the above production examples. The wrinkle model improvement test was carried out using hairless mice (5 weeks old, female) as experimental animals. UVB (60 mJ / cm) on the back skin of 10 hairless mice per group
² ) was irradiated once a day at a rate of 5 days a week, and after 8 weeks, wrinkle formation due to photoaging was confirmed on the back skin. Thereafter, 100 μl of an ethanol solution containing the aromatic compound derivative of triterpenoid obtained in each of the above Production Examples at a concentration shown in Table 3 was applied once a day at a rate of 5 days a week. After 9 weeks from the start of application, the degree of improvement of skin wrinkles due to photoaging was visually evaluated according to the following criteria.

(Judgment criteria) −: No wrinkle improvement effect ±: Slightly improved wrinkle ＋: Wrinkle reduction effect is recognized

For comparison, palmitoyl oleanolic acid and 2-ethylhexanoyl ursolic acid, which have been conventionally used as agents having an action of preventing photoaging,
A solution in which 2-ethylhexyl was dissolved in ethanol at a concentration of 1% and ethanol alone as a control were applied to hairless mice after UVB irradiation in the same manner as above, and the degree of improvement in wrinkles was evaluated. The results are shown in Table 3.

[0068]

[Table 3]

From these results, the aromatic compound derivatives of triterpenoids obtained in the above-mentioned production examples were prepared from the conventional ones such as palmitoyl oleanolic acid and 2-ethylhexanoyl ursolic acid-2-ethylhexyl.
Compared to triterpenoid derivatives obtained by acylating a hydroxyl group bonded to the 3-position carbon atom of a triterpenoid such as ursolic acid, oleanolic acid and betulinic acid with an aliphatic compound and / or esterifying a carboxyl group at the 28-position with an aliphatic compound , Extremely low concentration (1/20 to 1
It is clear that the administration of a concentration of about / 200) sufficiently exerts the skin wrinkle improving effect due to photoaging, and therefore it can be said that the photoaging inhibitor of the present invention has an excellent photoaging preventing action.

Next, examples of the skin cosmetic of the present invention containing the aromatic compound derivative of the triterpenoid obtained in each of the above Production Examples will be described. In addition, all compounding amounts used below are parts by weight.

[0071]

Example 1 Toner lotion The component A shown in Table 4 was dissolved at room temperature, and the component B separately dissolved at room temperature was added thereto to solubilize it, and the lotion was obtained in the above Production Example 1. A lotion containing benzyl ursolate was prepared. Further, in the same manner, a lotion of a comparative example was prepared in which a conventionally used triterpenoid derivative (octanoyl ursolic acid) was mixed instead of benzyl ursolic acid.

[0072]

[Table 4]

[0073]

Example 2 Emulsion Table 5 Component A was heated and mixed to 70 ° C.
The component A was added to the component B which was heated and mixed at 0 ° C., and the component C was added while emulsifying and cooling to prepare the emulsion containing methoxybenzyl oleanolate obtained in the above Production Example 2.
Similarly, a lotion of Comparative Example was prepared in which a conventionally used triterpenoid derivative (ethyl palmitoyl oleanolate) was added instead of methoxybenzyl oleanolate.

[0074]

[Table 5]

[0075]

Example 3 Cream A component of Table 6 was heated and mixed to 70 ° C., to which B component heated and mixed at 70 ° C. was added and emulsified 35
The mixture was cooled to 0 ° C., and the component C was further added thereto to produce the cream containing naphthylmethyl betulinate obtained in Production Example 4 above.

[0076]

[Table 6]

[0077]

Example 4 Cream A component of Table 7 was heated to 80 ° C., to which B component heated to 80 ° C. was added, and the mixture was stirred and emulsified.
After cooling to 0 ° C., the cream containing benzyl betulinate obtained in Production Example 1 above was produced.

[0078]

[Table 7]

[0079]

Example 5 Emulsion The components A and B of Table 8 were dissolved at 70 ° C. with stirring, respectively, and then the component A was added to the component B for preliminary emulsification. Next, this was uniformly emulsified with a homomixer and then cooled to 30 ° C. with stirring to produce the emulsion containing phenylbenzyl oleanolate obtained in Production Example 6 above.

[0080]

[Table 8]

[0081]

Example 6 Toner Lotion The A component shown in Table 9 was dissolved at room temperature, and the B component separately dissolved at room temperature was added to the solution to solubilize it. A lotion containing nitrobenzyl ursolic acid was prepared.

[0082]

[Table 9]

<Evaluation of Skin Cosmetics of the Present Invention> Using the skin cosmetics obtained in the above Examples 1 and 2 and Comparative Examples 1 and 2, an actual use test was conducted, and the skin cosmetic effect of the skin cosmetics of the present invention was evaluated. Was evaluated.

20 Japanese men with clear wrinkles around the corners of the eyes were divided into 2 groups of 10 each as panelists to participate in the experiment (half-face test). Before the experiment, we took pictures of the faces of all the panelists. After that, the lotion of Example 1 was applied to one of the outer corners of the face of the panelists in the A group, the lotion of Comparative Example 1 was applied to the other outer corner of the face, and the lotion of the face of the panelists in the B group was applied to one of the outer corners of the face. The emulsion of Example 2 and the emulsion of Comparative Example 2 were used on the other outer corner of the eye in the usual manner twice a day for 6 weeks continuously. Six weeks after the start of use, the state of improvement of wrinkles and the state of spontaneous deterioration were compared in each group using the above-mentioned photograph, and the state before use and the state 6 weeks after use were compared and evaluated according to the following evaluation criteria. . The results are shown in Table 10.

(Evaluation criteria) ++: Significant improvement ++: Significantly improved ＋: Slight improvement -: No change −−: Natural deterioration

[0086]

[Table 10]

As is clear from these results, the skin cosmetics of Examples containing the aromatic compound derivative of triterpenoid had good evaluation contents regarding the effect of improving wrinkles, and also octanoyl ursolic acid and ethyl palmitoyl oleanolate. The skin cosmetics of Comparative Examples and the skin cosmetics of the present invention containing the conventionally used triterpenoid derivatives at a concentration 10 times or more that of the triterpenoid aromatic compound derivative in the skin cosmetics of the present invention are equivalent to the skin cosmetics of the present invention. It was confirmed that the effect of improving wrinkles was exhibited.
It was also confirmed at the same time that the skin cosmetic of the present invention has almost no tactile adverse effects such as stickiness during use.

[0088]

EFFECT OF THE INVENTION Since the photoaging inhibitor of the present invention is highly safe and has an excellent photoaging-preventing action as compared with conventional triterpenoid compounds, a small amount of photoaging is sufficient when blending the composition. It is possible to exert a preventive action.
Further, the skin cosmetic of the present invention has an excellent skin-beautifying effect of preventing and improving wrinkles and the like, and can be safely used without any harmful effect on the skin.

[Brief description of drawings]

FIG. 1 shows benzyl ursolic acid obtained in Production Example 1.
^The figure which shows the ¹ H-NMR measurement result.

FIG. 2 shows benzyl ursolic acid obtained in Production Example 1.
^The figure which shows the measurement result of ¹³ C-NMR.

FIG. 3 is a graph showing IR measurement results of benzyl ursolic acid obtained in Production Example 1.

─────────────────────────────────────────────────── ─── Continued Front Page (51) Int.Cl. ⁷ Identification FI A61P 17/16 A61P 17/16 // C07J 61/00 C07J 61/00 (72) Inventor Yasutomo Nishimori Kashio Totsuka-ku, Yokohama, Kanagawa 560 Pola Chemical Industry Co., Ltd. Totsuka Research Laboratory (72) Inventor Yukiko Yokoyama 560 Pola Chemical Industry Co., Ltd. Totsuka Research Laboratory (56) Reference JP-A-58-57307 (JP, A) (58) Fields surveyed (Int.Cl. ⁷ , DB name) A61K ^7/ 00-7/50 A61K 31/56 REGISTRY (STN) CA (STN)

Claims (5)

(57) [Claims] 1. A triterpenoid derivative in which a hydrogen atom of a carboxyl group at the 28-position of ursolic acid, oleanolic acid or betulinic acid and / or a hydrogen atom of a hydroxyl group bonded to a carbon atom at the 3-position is substituted with a functional group, The sensuality
Group that replaces the hydrogen atom of the carboxyl group at position 28
The functional group is a group represented by the following general formula (I),
Substitute the hydrogen atom of the hydroxyl group bonded to the 3rd carbon atom
The functional group is represented by the following general formula (I) or (II)
A photo-aging agent comprising one or more of a triterpenoid derivative which is a group to be treated and salts thereof. [Chemical 1] However, in the formula (I), R ₁ represents an optionally substituted aromatic ring, and R ₂ represents a hydrogen atom or an optionally substituted aromatic ring. [Chemical 2] However, in the formula (II), R ₃ represents an optionally substituted aromatic ring, and n represents an integer of 0 to 2. 2. R _{1 in the} general formula (I) represents a phenyl group, a methoxyphenyl group, an ethoxyphenyl group, a butoxyphenyl group, a nitrophenyl group, a diphenyl group or a naphthyl group, and R ₂ represents a hydrogen atom or a phenyl group. The photoaging inhibitor according to claim 1 , wherein R ₃ in the general formula (II) represents a phenyl group, a methoxyphenyl group, an ethoxyphenyl group, a butoxyphenyl group, a nitrophenyl group, a diphenyl group, or a naphthyl group. 3. A triterpenoid derivative in which the hydrogen atom of the carboxyl group at the 28-position and / or the hydrogen atom of the hydroxyl group bonded to the carbon atom at the 3-position of ursolic acid, oleanolic acid or betulinic acid is substituted with a functional group, The sensuality
Government group, replacing a hydrogen atom of 28-position of the mosquito carboxyl group
The functional group is a group represented by the following general formula (I),
Substitute the hydrogen atom of the hydroxyl group bonded to the 3rd carbon atom
The functional group is represented by the following general formula (I) or (II)
A skin cosmetic containing one or two or more of a triterpenoid derivative and a salt thereof as a group . [Chemical 3] However, in the formula (I), R ₁ represents an optionally substituted aromatic ring, and R ₂ represents a hydrogen atom or an optionally substituted aromatic ring. [Chemical 4] However, in the formula (II), R ₃ represents an optionally substituted aromatic ring, and n represents an integer of 0 to 2. 4. R ₁ of the general formula (I) represents a phenyl group, a methoxyphenyl group, an ethoxyphenyl group, a butoxyphenyl group, a nitrophenyl group, a diphenyl group, or a naphthyl group, and R ₂ represents a hydrogen atom or a phenyl group. And R _{3 of} the general formula (II) is a phenyl group, a methoxyphenyl group,
Ethoxyphenyl group, butoxyphenyl group, nitrophenyl group, claim 3 representing a diphenyl group, or a naphthyl group
The skin cosmetics described in. 5. One or two of the above derivatives and salts thereof.
The above content is 0.0001 to 1 with respect to the total amount of the cosmetic.
The skin cosmetic according to claim 3 or 4 , which is 0% by weight.