JPH07300412A - Active oxygen remover and composition containing the same - Google Patents

Abstract

PURPOSE:To obtain an active oxygen remover containing a specific compound such as 2,6-dimethoxyphenol and its salt as an active ingredients and applicable for cosmetics, medicines or foods, etc. CONSTITUTION:This active oxygen remover contains a compound expressed by the formula (R<1> and R<2> each is H, OH or a short-chain length alkoxyl; R<3> is H, carboxyl, a short-chain length alkoxycarbonyl, formyl, a short-chain length acyl, etc.) and/or its physiologlically permissible salt as an active ingredient. Especially, 2,6-dimethoxyphenol, syringic acid, gallic acid, caffeic acid, pyrogallol, guaiacol, methyl sinapate, syringaaldehyde, methyl gallate, protocatechinic acid, acetosyringo, ferulic acid or coniferyl alcohol is preferably used as the compound of formula I. The remover has action capable of removing active oxygen generated in organisms sufficiently and further, has high safety.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an active oxygen scavenger and cosmetics, pharmaceutical compositions and edible compositions containing the same.

[0002]

2. Description of the Related Art Generally, the effects of active oxygen on the living body include cross-linking of collagen fibers, partial cleavage of DNA helix, and tissue damage due to generation of chained radicals, resulting in skin wrinkles. Aging of the body such as loss of elasticity and loss of hair, induction of allergic reactions such as bronchial asthma and inflammation due to histamine release, damage of smooth muscle in ischemic myocardial infarction, deterioration of diseases such as liver damage, and brain It is known that tissue destruction causes dementia and the like. Furthermore, although the detailed cause is unknown, it is said that active oxygen is involved in the onset of rheumatism.

Therefore, suppressing the generation of active oxygen in the living body is very important in treating or preventing these diseases, and therefore, the active oxygen generated in the living body is eliminated from the conventional case. The search for substances that have the action to do so has been widely conducted.

[0004] For example, as a drug having such an action, conventionally used are those derived from natural products such as fat-soluble tocopherol (vitamin E),
Examples include water-soluble ascorbic acid (vitamin C), and synthetic compounds include BHT (butylhydroxytoluene),
BHA (butylhydroxyanisole) etc. are mentioned. However, these agents have insufficient active oxygen scavenging action, and in synthetic compounds, both BHT and BHA are suspected to be carcinogenic, and it was difficult to say that any of them was practical as an active oxygen scavenger.

In recent years, many attempts have been made to obtain a substance having an active oxygen scavenging action from a crude drug extract in search of sufficient medicinal effect and safety, for example, JP-A-60-224629. , JP-A-61-24522,
JP-A-2-193930, JP-A-2-243632
No. 2, JP-A-2-264727, JP-A-3-15362
No. 9, JP-A-3-221587, JP-A-4-6934.
3, JP-A-4-202138, and JP-A-4-2470.
The inventions described in the respective publications of No. 10 each utilize a substance having an active oxygen scavenging action derived from a crude drug. However, although these crude drug extracts have no safety problems, they have not been sufficiently obtained in terms of active oxygen scavenging action.

Further, attempts have been made to eliminate active oxygen generated in the living body by administering superoxide desmutase (SOD), one of the enzymes in the living body, but since SOD is a protein, Not only is it difficult to obtain, but it is digested, so oral administration is not possible, and even when administered by injection,
The blood half-life was short and it was not satisfactory.

On the other hand, it has not been known at all that the compound represented by the general formula (I) or a salt thereof has a function of eliminating active oxygen. Furthermore, there has been no attempt to use it for the prevention or treatment of various diseases mentioned above, prevention of aging, or improvement by incorporating it into cosmetics, pharmaceuticals, foods, or the like.

[0008]

SUMMARY OF THE INVENTION The present invention has been made from the above viewpoints, and has an active oxygen scavenger having a sufficient effect of scavenging active oxygen generated in the living body and having high safety. An object of the present invention is to provide a composition such as a cosmetic, a drug, a food containing the same.

[0009]

In order to solve the above problems, the present inventors extensively screened various compounds using the active oxygen scavenging action as an index, and as a result, the compound represented by the general formula (I) was excellent. They have found that they have an active oxygen scavenging action, and have completed the present invention.

That is, the present invention provides an active oxygen scavenger comprising a compound represented by the following general formula (I) and / or a physiologically acceptable salt thereof, and a cosmetic, pharmaceutical composition or edible composition containing the active oxygen scavenger. It is a thing.

[0011]

[Chemical 15]

However, in Chemical formula 15, R ₁ and R ₂ each independently represent a hydrogen atom, a hydroxyl group or a short chain length alkoxyl group, and R ₃ is a hydrogen atom, a carboxyl group, a short chain length alkoxycarbonyl group, A formyl group, a short chain length acyl group, a short chain length carboxyalkenyl group, a short chain length alkoxycarbonylalkenyl group, a short chain length alkenyl group or a short chain length hydroxyalkenyl group is shown.

The present invention will be described in detail below.

<1> Active Oxygen Scavenger of the Present Invention The active oxygen scavenger of the present invention comprises a compound represented by the above general formula (I) and / or a physiologically acceptable salt thereof.

Here, in the compound represented by the general formula (I), R ₁ and R ₂ represent a hydrogen atom or a short chain length alkoxyl group, and R ₃ represents a hydrogen atom, a carboxyl group or a short chain length. An alkoxycarbonyl group, a formyl group, a short chain length acyl group, a short chain length carboxyalkenyl group, a short chain length alkoxycarbonylalkenyl group, a short chain length alkenyl group or a short chain length hydroxyalkenyl group, among them, an alkoxyl group, The number of carbon atoms in the alkyl moiety of the alkoxycarbonyl group, the acyl group and the alkoxycarbonylalkenyl group is preferably 1 to 10, more preferably 1 to 6, and further preferably 1 to 4. Also,
The alkenyl portion of the carboxyalkenyl group, the alkoxycarbonylalkenyl group, the alkenyl group, and the hydroxyalkenyl group preferably has 2 to 10 carbon atoms, more preferably 2 to 6 carbon atoms, and further preferably 2 to 4 carbon atoms.

The alkoxyl group includes, for example, a methoxyl group, an ethoxyl group, a propoxyl group, etc., the alkoxycarbonyl group includes, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, etc., and the acyl group includes: For example, an acetyl group, a propionyl group, a butyryl group, and the like, an alkoxycarbonylalkenyl group, for example, a methoxycarbonylvinyl group, an ethoxycarbonylallyl group, a propoxycarbonylbutenyl group, and the like, and a carboxyalkenyl group, for example, carboxyvinyl. Groups, carboxyallyl groups, carboxybutenyl groups, etc., alkenyl groups, for example, vinyl groups, allyl groups, butenyl groups, etc., and hydroxyalkenyl groups, for example, hydroxyvinyl groups, hydroxyarites. Group, and preferably a hydroxy butenyl group.

The compound represented by the general formula (I) used in the present invention is preferably 2,6-dimethoxyphenol represented by the chemical formula 16, sialic acid represented by the chemical formula 17, Gallic acid represented by 18, caffeic acid represented by Chemical formula 19, pyrogallol represented by Chemical formula 20,
Guaiacol represented by Chemical Formula 21, methyl synapate represented by Chemical Formula 22, syringaldehyde represented by Chemical Formula 23,
Examples include methyl gallate represented by Chemical formula 24, protocatechinic acid represented by Chemical formula 25, acetosyringo apple represented by Chemical formula 26, ferulic acid represented by Chemical formula 27, and coniferyl alcohol represented by Chemical formula 28.

[0018]

[Chemical 16]

[0019]

[Chemical 17]

[0020]

[Chemical 18]

[0021]

[Chemical 19]

[0022]

[Chemical 20]

[0023]

[Chemical 21]

[0024]

[Chemical formula 22]

[0025]

[Chemical formula 23]

[0026]

[Chemical formula 24]

[0027]

[Chemical 25]

[0028]

[Chemical formula 26]

[0029]

[Chemical 27]

[0030]

[Chemical 28]

All the above compounds are known substances and can be obtained by a general production method. In addition, since most of these compounds are commercially available as synthetic products, these commercially available products can be used in the present invention.

For the active oxygen scavenger of the present invention, in addition to the compound represented by the general formula (I), a physiologically acceptable salt of this compound can be used. In this case, one kind of the compound represented by the general formula (I) and a salt thereof may be used alone, or two or more kinds may be mixed and used.

There are no particular restrictions on such salts as long as they are physiologically acceptable. For example, salts with alkali metals such as sodium and potassium, alkaline earth metals such as calcium and magnesium, etc. And salts with amines such as ammonia, triethylamine and triethanolamine, and salts with basic amino acids such as arginine and lysine.

<2> Composition Containing Active Oxygen Scavenger of the Present Invention The composition of the present invention is prepared by blending one or more active oxygen scavengers described above by a conventional method. Examples include cosmetics, pharmaceuticals, foods, and the like.

(1) Cosmetics The cosmetics of the present invention contain the above active oxygen scavenger for the purpose of preventing and improving wrinkles, hair loss and the like, and preventing the generation of undesirable odors such as body odor. .

The content of the active oxygen scavenger of the present invention in the above cosmetics is not particularly limited, but it is preferably in the range of 0.01 to 10% by weight with respect to the total amount of the cosmetics. More preferably, it is blended in the range of 1 to 1% by weight. When the content of the active oxygen scavenger is less than 0.01%, it improves wrinkles and hair loss of the active oxygen scavenger.
In some cases, the effect of improving body odor may not be sufficiently obtained.
Even if it is blended in excess of weight%, the effect will reach the ceiling and it is often uneconomical.

The dosage form of the cosmetics to which the present invention is applied is not particularly limited. For example, basic cosmetics such as lotion, emulsion, cream, foundation makeup, make-up cosmetics such as white powder, Hair tonic,
Hair cosmetics such as hair liquid, shampoo, and conditioner can be used. These cosmetics can be produced by the same method as that for ordinary cosmetics except that the active oxygen scavenger is added.

In the cosmetic of the present invention, in addition to the active oxygen scavenger, various components generally used in cosmetics, for example, hydrocarbons such as petrolatum and liquid paraffin, jojoba oil, carnauba wax, etc. Esters, olive oil,
Triglycerides such as beef tallow, stearyl alcohol,
Higher alcohols such as behenyl alcohol, stearic acid, fatty acids such as behenic acid, glyceryl monostearate, polyoxyethylene stearic acid, polyoxyethylene hydrogenated castor oil, nonionic surfactants such as polyoxyethylene stearyl ether, soap, sulfuric acid Anionic surfactants such as esters, cationic surfactants such as stearylamine, amphoteric surfactants such as alkyl betaines, polyhydric alcohols such as glycerin and propylene glycol,
Various powder components, moisturizers, thickeners, colorants, fragrances, antioxidants, pH adjusters, chelating agents, preservatives, UV protectants, anti-inflammatory agents, whitening agents and the like can be added.

Further, the cosmetic of the present invention contains the compound represented by the general formula (I) which is the active oxygen scavenger of the present invention, and / or
Alternatively, in addition to a physiologically acceptable salt thereof, a substance having an active oxygen scavenging action such as SOD may be blended.

(2) Pharmaceutical When the active oxygen scavenger of the present invention is formulated as a pharmaceutical, the dosage form is not particularly limited, but for example, injections, powders, granules, tablets, capsules, liquids, etc. are usually used. Each of the various preparations described above can be made into a dosage form according to a usual method. In addition, in formulating the dosage form, in addition to the above active oxygen scavenger, any optional ingredient commonly used in pharmaceuticals such as an excipient, a binder, a disintegrating agent, a lubricant, a flavoring agent, a bulking agent, and a coating agent is optional. Can also be used.

Regarding the dose of the above-mentioned pharmaceuticals, it depends on the type of disease, symptoms, age of patient, weight, etc.
As an amount of active oxygen scavenger per person per day, 10 mg to 1
It is suitable to administer 000 mg orally in one or several divided doses or to administer 5 mg to 500 mg by injection. Examples of the administration method of the injection include intravenous administration, intraarterial administration, portal vein administration, intraperitoneal administration, intramuscular administration, subcutaneous administration and the like.

(3) Food When the active oxygen scavenger of the present invention is added to food, it can be added to various foods together with optional components usually used in foods. Examples thereof include confectionery such as candy, gummy candy, jelly, drinks such as juice, and staple food such as bread. The blending amount varies depending on the type of food, but is preferably 0.01 to 10% by weight, which can expect a sufficient active oxygen scavenging effect without impairing the taste of the food.
It is more preferably 0.1 to 1% by weight.

[0043]

The compound represented by the general formula (I), which is used as the active oxygen scavenger of the present invention, is 2,6-dimethoxyphenol, sialic acid, gallic acid, caffeic acid, pyrogallol, guaiacol, methyl synapate, schilling. Using aldehyde, methyl gallate, protocatechuic acid, acetosyringo, ferulic acid and coniferyl alcohol, a test for safety and active oxygen scavenging action was conducted.

All the above compounds used in the test were manufactured by Aldrich.

(1) Acute toxicity test (intraperitoneal administration) 13 groups of 5 ICR male mice (body weight 25-30)
In each group of g), each compound was dissolved in physiological saline to prepare 1
Each was intraperitoneally administered at a rate of 000 mg / kg. Life or death was determined 14 days after administration, but no death was observed in any of the groups. From this, it is understood that the LD ₅₀ value by intraperitoneal administration of the active oxygen scavenger of the present invention is larger than 1000 mg / kg, which is excellent in safety.

(2) Acute toxicity test (oral administration) 13 groups of 6 ICR male mice (body weight 25-30)
In each group of g), each compound was dissolved in physiological saline to prepare 1
Each was orally administered at a rate of 000 mg / kg. Live or dead was determined 14 days after administration, but no death was observed in any of the groups. From this, it is understood that the LD ₅₀ value by oral administration of the active oxygen scavenger of the present invention is larger than 1000 mg / kg, and the safety is excellent.

[0047] (3) based on the reaction formula shown in the measurement of 29 of active oxygen scavenging action, xanthine - superoxide anions which is one of active oxygen by xanthine oxidase (XOD) system (O ₂ ^-) to generate, generating The production rate of O ₂ ⁻ was measured by the nitrous acid method, and this value was corrected with the xanthine oxidase inhibition rate value to obtain the active oxygen elimination action value.

[0048]

[Chemical 29]

0.1 mL of an active oxygen scavenger aqueous solution containing each of the above compounds at various molar concentrations was added to 65 mM potassium dihydrogen phosphate, 35 mM sodium borate, 0.5 mM ED.
TA2 sodium aqueous solution (hereinafter referred to as buffer solution A)
2 mL, 0.5 mM xanthine solution 0.2 mL, 10 m
It was added to a mixed solution of 0.1 mL of an aqueous solution of M hydroxylamine hydrochloride and 0.2 mL of pure water and well stirred to prepare a test solution. Similarly, instead of the active oxygen scavenger, pure water 0.1
A control solution using mL was prepared.

To the test solution and control solution, 0.2 mL of buffer solution A containing xanthine oxidase at a concentration of 1 μL / mL was added and stirred, and then incubated at 37 ° C. for 30 minutes. As a blank, 0.2 mL of xanthine oxidase-free buffer solution A was added to the test solution and control solution prepared in the same manner as above, and a solution treated in the same manner as above was prepared.

To each of the solutions thus obtained, 2 mL of a mixed solution of 30 μM N-1-naphthylethylenediamine hydrochloride, 3 mM sulfanilic acid and 25% glacial acetic acid was added.
And leave it for 30 minutes at room temperature.
The generation amount of active oxygen was measured at the absorbance of 50 nm, and the generation amount of uric acid was measured at the absorbance of 295 nm.

Using the values obtained, based on the following equation,
The active oxygen scavenging activity value was calculated.

[0053]

[ _Formula 1] Active oxygen generation rate = [(A _550-3 −A _550-4 ) /
(A _550-1 -A _550-2 )] x 100 Urea production rate = [(A _295-3 -A _295-4 ) / (A _295-1 -A
_295-2 )] × 100 Active oxygen scavenging activity = 100− (active oxygen generation rate / uric acid production rate) × 100 However, the symbols in the formula are the absorbance values of the respective solutions adjusted under the conditions shown in Table 1. To do.

[0054]

[Table 1]

Further, the active oxygen scavenging activity value obtained by the above method was applied to a non-linear least squares program to calculate an IC ₅₀ value (M). The results are shown in Table 2.

[0056]

[Table 2]

As is apparent from these results, all of the above 13 kinds of compounds used as the active oxygen scavenger of the present invention have extremely low IC ₅₀ values and have excellent active oxygen scavenging activity even at low concentration. I understand.

The active oxygen scavenger of the present invention and the composition of cosmetics, pharmaceuticals, foods, etc., containing the active oxygen scavenger, are the active ingredient of the compound represented by the general formula (I) and / or physiologically acceptable thereof. Due to the excellent active oxygen scavenging effect of the salt
It is said that active oxygen as described above is involved,
For the treatment of various diseases such as wrinkle formation, generation of body odor, hair loss, inflammation, senile dementia, myocardial infarction, or allergic diseases, liver disorders, rheumatism, and improvement of aging of the body such as skin It works effectively.

The active oxygen scavenger of the present invention and the composition of cosmetics, pharmaceuticals, foods and the like containing the same can be effectively used for the prevention of the above-mentioned diseases and biological aging. This is because the active oxygen generated in the living body can be quickly eliminated and detoxified by allowing the component having the active oxygen scavenging effect to exist in the living body in advance.

[0060]

EXAMPLES Examples of the composition of the present invention, such as foods, pharmaceuticals, cosmetics, etc., containing the compound represented by the general formula (I) as an active oxygen scavenger will be described below. The amounts used below are all parts by weight unless otherwise specified.

In addition, 2,6-dimethoxyphenol, sialic acid, gallic acid, caffeic acid, pyrogallol, guaiacol, methylsynapate, syringaldehyde, methylgallate and coniferyl which have been added to the examples of the present invention as active oxygen scavengers. All alcohol was from Aldrich.

[0062]

Example 1 Candy A component of Table 3 was melted by heating at 150 ° C., cooled to 120 ° C., and then B component was added and stirred to homogenize. After molding this, it was cooled to obtain a candy.

[0063]

[Table 3]

[0064]

Example 2 Gummies A component of Table 4 was heated and dissolved at 110 ° C., separately swollen B component was added, and further C component was added and poured into a mold,
After leaving it for a whole day and night, I removed it from the mold and got a gummy.

[0065]

[Table 4]

[0066]

Examples 3 to 6 Juice The components in Table 5 were well solubilized by stirring, sterilized, aseptically filled, and sealed to produce juice.

[0067]

[Table 5]

[0068]

Example 7 Hot Cake A hot cake was prepared by thoroughly mixing the ingredients shown in Table 6 and baking them in an oiled frying pan.

[0069]

[Table 6]

[0070]

Example 8 Granules Component A in Table 7 was mixed well and 100 mL of 20%
The B component dissolved in an ethanol aqueous solution was gradually added while kneading and granulated. This was blow-dried at 40 ° C. for 2 days, sieved and sized to obtain granules.

[0071]

[Table 7]

[0072]

Example 9 Injectable Solution The components shown in Table 8 were dissolved, filtered, sterilized, and aseptically filled into an ampoule and sealed to obtain an injectable solution.

[0073]

[Table 8]

[0074]

Examples 10 and 11 Lotion A lotion was obtained by solubilizing the components of Table 9 at room temperature with stirring.

[0075]

[Table 9]

[0076]

Examples 12 and 13 Emulsions The components A, B and C shown in Table 10 were heated and dissolved at 80 ° C., the components B were added to the components A, the components C were further added to obtain a coarse emulsion, and the mixture was homogenized with a homogenizer. Then, it was cooled to obtain an emulsion.

[0077]

[Table 10]

[0078]

Example 14 Cream Ingredients A, B, and C in Table 11 were dissolved by heating at 80 ° C., and ingredient B was added to ingredient A, followed by addition of ingredient C.
It was emulsified and cooled to obtain a cream.

[0079]

[Table 11]

[0080]

The active oxygen scavenger of the present invention is excellent in the active oxygen scavenging action and has high safety. Therefore, a composition such as a cosmetic, a drug, a food, or a beverage containing the same can be effectively used for a long period of time for the prevention and treatment of diseases associated with active oxygen.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI technical display location A61K 7/48 31/085 AGZ 9455-4C 31/09 9455-4C 31/11 9455-4C 31 / 12 9455-4C 31/19 ADS 9455-4C 31/215 ADD 9455-4C 31/235 9455-4C

Claims (5)

[Claims] 1. An active oxygen scavenger comprising a compound represented by the following general formula (I) and / or a physiologically acceptable salt thereof. [Chemical 1] However, in Chemical formula ₁ , R ₁ and R ₂ each independently represent a hydrogen atom, a hydroxyl group or a short chain length alkoxyl group, and R ₃ is
Hydrogen atom, carboxyl group, short chain length alkoxycarbonyl group, formyl group, short chain length acyl group, short chain length carboxyalkenyl group, short chain length alkoxycarbonylalkenyl group, short chain length alkenyl group or short chain length hydroxyalkenyl group. Show. 2. The compound represented by the general formula (I) is
2,6-dimethoxyphenol represented by Chemical formula 2, sialic acid represented by Chemical formula 3, gallic acid represented by Chemical formula 4, caffeic acid represented by Chemical formula 5, pyrogallol represented by Chemical formula 6, Guaiacol represented by the formula, methyl synapate represented by the chemical formula 8, syringaldehyde represented by the chemical formula 9, methyl gallate represented by the chemical formula 10, protocatechuic acid represented by the chemical formula 11, represented by the chemical formula 12. The active oxygen scavenger according to claim 1, wherein the active oxygen scavenger is selected from acetosyringo, ferulic acid represented by Chemical formula 13, and coniferyl alcohol represented by Chemical formula 14. [Chemical 2] [Chemical 3] [Chemical 4] [Chemical 5] [Chemical 6] [Chemical 7] [Chemical 8] [Chemical 9] [Chemical 10] [Chemical 11] [Chemical 12] [Chemical 13] [Chemical 14] 3. A cosmetic containing the active oxygen scavenger according to claim 1. 4. A pharmaceutical composition containing the active oxygen scavenger according to claim 1 or 2. 5. An edible composition containing the active oxygen scavenger according to claim 1.