JP5623901B2 - Antioxidant - Google Patents

Description

  The present invention relates to an antioxidant.

  In recent years, there has been a strong interest in the damage of biomolecules, membranes and tissues caused by free radicals and active oxygen, and various diseases derived therefrom. Examples of reactive oxygen species include superoxide, hydroxy radical, hydrogen peroxide, and singlet oxygen. Among them, superoxide and hydroxy radical are radical species, and hydroxy radical is particularly known as a highly reactive free radical. ing. It has been found that these reactive oxygen species are closely involved in various skin diseases such as inflammation, skin darkening, DNA damage, aging such as spots and wrinkles (Non-patent Document 1).

  As antioxidants that eliminate reactive oxygen species, for example, ascorbic acid, carotenoids, uric acid, vitamin E, flavonoids, etc. are known. Although sulfoxide (DMSO), thiourea, mannitol, sorbitol, xylitol and the like are known (Patent Documents 1 and 2 and Non-Patent Document 2), they cannot always be said to have sufficient effects.

JP 61-502821 gazette JP 2008-266203 A

Miyaki Yoshiki, “Fragrance Journal, Vol. 11,” published by Fragrance Journal, November 15, 1993, p. 12-17 Tetsuo Nagano, “Pharmacia Vol. 27, No. 3”, published by the Japanese Pharmaceutical Association, February 10, 1991, p. 231-233

  The subject of this invention is providing the more superior antioxidant.

  As a result of intensive investigations in view of the above circumstances, the present inventors have found that the alkyl acetal derivative of mannitol has excellent antioxidant ability, and is useful as an antioxidant for external skin preparations and food and beverage compositions, The present invention has been completed.

  That is, the present invention provides an antioxidant containing an alkyl acetal derivative of mannitol as an active ingredient.

  Moreover, this invention provides the skin external preparation and food-drinks composition containing the alkylacetal derivative of mannitol.

  The alkyl acetal derivative of mannitol of the present invention is an antioxidant having excellent hydroxy radical scavenging ability and excellent safety and stability. Therefore, an external preparation for skin and a food / drink composition containing the same can be expected to prevent and suppress inflammation, skin darkening, DNA damage, aging such as spots and wrinkles.

The active ingredient of the antioxidant of the present invention is an alkyl acetal derivative of mannitol.
Mannitol is a sugar alcohol widely distributed in the plant kingdom, such as seaweed, lichen, and fungi. It is the main component of manna, which is a secretion from the wounds of stems and leaves of plants, and crystals are extracted from the alcohol extract. can get. It is used in a wide range of applications such as pharmaceuticals, analytical reagents, food industry, synthetic raw materials, and cosmetic raw materials. In the field of organic synthesis, it is used as a starting material in the synthesis of compounds having asymmetric points, taking advantage of its inexpensiveness and ease of various conversions. Sufficient studies have not been made on its use in the environment and its antioxidant effect.

The alkyl acetal derivative of mannitol according to the present invention is a compound having an acetal structure obtained by reacting mannitol with an alkyl ketone compound represented by R ¹ —C (═O) —R ² . Here, R ¹ and R ² each represent an alkyl group having 1 to 3 carbon atoms, and R ¹ and R ² may be different from each other.
More specifically, in the alkyl acetal derivative of mannitol according to the present invention, two adjacent hydroxyl groups of mannitol or two hydroxyl groups capable of taking a three-dimensional acetal structure are R ¹ (R ² ) —C═ groups. It is a compound having 1 to 3 acetalized structures. The two hydroxyl groups that can be acetalized in mannitol are 1, 2, 3, 4, 5, 6, 1, 3, and 4, 6. Moreover, as an alkyl group shown by said R < ¹ > and R < ² >, a C1-C3 alkyl group is more preferable. Specific examples include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group, a methyl group, an ethyl group, and an n-propyl group are more preferable, and a methyl group and an ethyl group are particularly preferable.

  Specific examples of the alkyl acetal derivative of mannitol include 1,2-isopropylidenemannitol, 1,3-isopropylidenemannitol, 3,4-isopropylidenemannitol, 3,4- (1-ethylpropylidene) mannitol, , 2; 5,6-diisopropylidenemannitol, 1,3; 4,6-diisopropylidenemannitol, 1,2; 5,6-di (1-ethylpropylidene) mannitol, 1,2; 3,4 5,6-triisopropylidenemannitol, 1,2; 3,4; 5,6-tri (1-ethylpropylidene) mannitol and the like. These can be synthesized from mannitol and a corresponding alkyl ketone compound, or those commercially available from Aldrich or Tokyo Chemical Industry Co., Ltd. can be used.

  The alkyl acetal derivative of mannitol according to the present invention has excellent antioxidant ability, particularly excellent hydroxy radical scavenging ability, as shown in Examples below. The antioxidant ability is remarkably superior to mannitol, erythritol, threitol and the like. Therefore, the alkyl acetal derivative of mannitol can be mix | blended with the skin external preparation and food-drinks composition as an antioxidant.

  The alkyl acetal derivative of mannitol of the present invention can be used as it is as an antioxidant. Furthermore, it can also be used in combination with known antioxidant components such as ascorbic acid, vitamin E, and polyphenol compounds within a range not impairing the effects of the present invention.

  The alkyl acetal derivative of mannitol of the present invention can be used as an antioxidant added to an external preparation for skin such as pharmaceuticals, quasi drugs and cosmetics. The cosmetic is not particularly limited, and examples thereof include skin cosmetics, foundations, makeup cosmetics such as lipsticks, and bathing agents. Moreover, it does not restrict | limit especially as a dosage form, For example, it can be set as an ointment, a lotion, an emulsion, a cream, a pack, a granule, a cataplasm etc.

  The content of the alkyl acetal derivative of mannitol in the external preparation for skin is preferably 0.001 to 10% by mass (hereinafter simply referred to as%), more preferably 0.01 based on the total amount of the external preparation for skin. -5%, more preferably 0.1-4%. If it is in these ranges, the alkyl acetal derivative of mannitol can be blended stably and a high antioxidant effect can be exhibited.

  In addition, in addition to the above, coloring agents, perfumes, preservatives, surfactants, pigments, and the like can be appropriately added to the external preparation for skin of the present invention within a range in which the object of the present invention is achieved.

  In addition, the alkyl acetal derivative of mannitol of the present invention can be used as an antioxidant by adding it to ordinary food and beverage compositions including pharmaceuticals, quasi drugs and health foods. The dosage form of the food / beverage composition is not particularly limited and can be various. Specifically, tablets, pills, sugar-coated tablets, powder, granules, fine granules, tea, tea packs, Hard capsules, soft capsules, drinks and the like can be used.

  The content of the alkyl acetal derivative of mannitol in the food / beverage composition is preferably 0.001 to 10%, more preferably 0.01 to 5%, based on the total amount of the food / beverage composition. Preferably it is 0.1 to 4%. If it is in these ranges, the alkyl acetal derivative of mannitol can be blended stably and a high antioxidant effect can be exhibited.

  In addition to the above, excipients and the like are appropriately added to the food / beverage product composition of the present invention, and it can be made into dosage forms such as powder, fine granules and granules according to known techniques.

  EXAMPLES Hereinafter, although this invention is explained in full detail based on an Example and a comparative example, the technical scope of this invention is not restrict | limited by them.

Example 1 (Synthesis of 1,3; 4,6-diisopropylidenemannitol)
10 g of mannitol was suspended in 100 mL of dimethyl sulfoxide, 0.5 mL of sulfuric acid and 10 mL of acetone were added, and the mixture was heated at 50 ° C. After reacting for a whole day and night, 1 g of potassium carbonate was added for neutralization, and excess acetone was removed by about 50% under reduced pressure. Ethyl acetate and saturated brine were added to separate the organic layer. Dehydration was performed using magnesium sulfate, and the solvent was removed under reduced pressure to obtain 5.2 g of 1,3; 4,6-diisopropylidenemannitol as white crystals.

The results of ¹³ C NMR of 1,3; 4,6-diisopropylidenemannitol are shown.
¹³ C NMR [δ: 25.0, 26.3, 26.7, 26.7, 63.8, 68.0, 72.1, 76.4, 80.7, 110.0]

Example 2 (Synthesis of 1,2; 5,6-di (1-ethylpropylidene) mannitol)
5 g of mannitol was suspended in 100 mL of toluene, 0.1 g of paratoluenesulfonic acid was added, 10 mL of 3,3-dimethoxypentane was added, and the mixture was heated to reflux. After reacting for a whole day and night, 1 g of potassium carbonate was added for neutralization, water and ethyl acetate were added, and the organic layer was separated. Dehydration was performed using magnesium sulfate, and the solvent was removed under reduced pressure to obtain 1.3 g of 1,2; 5,6-di (1-ethylpropylidene) mannitol as white crystals.

The results of ¹ H NMR of 1,2; 5,6-di (1-ethylpropylidene) mannitol are shown.
¹ H NMR (400 MHz, CDCl ₃ ) [δ: 0.86-0.95 (m, 12H), 1.58-1.73 (m, 8H), 3.46-3.51 (m, 2H) 3.96-4.01 (m, 2H), 4.12 (t, J = 6.2 Hz, 1H), 4.43 (q, J = 6.8 Hz, 1H), 4.72-4. 79 (m, 2H)]

Example 3 (Synthesis of 3,4- (1-ethylpropylidene) mannitol)
10 g of mannitol was suspended in 100 mL of dimethylformamide, 10 mL of 3,3-dimethoxypentane and 0.5 mL of sulfuric acid were added, and the mixture was heated to 90 ° C. After reacting for a whole day and night, 1 g of potassium carbonate was added to neutralize, water was added, and the mixture was extracted with ethyl acetate to obtain 1,2; 3,4; 5,6-tri (1-ethylpropylidene) mannitol. It was. This was dissolved in 100 mL of methanol, 0.1 mL of 1N hydrochloric acid was added, and the mixture was stirred at 40 ° C. for 3 hours. After completion of the reaction, the mixture was neutralized with 1N sodium hydroxide solution, saturated aqueous sodium chloride solution / ethyl acetate was added, and the organic layer was separated. Dehydration was performed using magnesium sulfate, and the solvent was removed under reduced pressure to obtain 2.2 g of 3,4-pentylidenedenmannitol as a white solid.

The result of ¹³ C NMR of 3,4- (1-ethylpropylidene) mannitol is shown.
¹³ C NMR [δ: 8.34, 31.1, 64.9, 74.7, 81.3, 114.7]

Example 4 (Evaluation of antioxidant power)
According to the following method, 1, 2; 5,6-diisopropylidene mannitol (manufactured by Tokyo Chemical Industry Co., Ltd.) and 1,3; 4, 6-diisopropylidene mannitol synthesized in Example 1, It was measured as hydroxy radical scavenging ability. In addition, mannitol, erythritol, and threitol were used as comparative compounds.
(1) KH ₂ PO ₄ aqueous solution (50 mmol / L) 0.4 mL, test compound 0.1 mL, EDTA aqueous solution (1.04 mmol / L) 0.1 mL, iron chloride aqueous solution (1 mmol / L), ascorbic acid aqueous solution (1 mmol / L) 0.1 mL, deoxyribose aqueous solution (28 mmol / L) 0.1 mL, and hydrogen peroxide (10 mmol / L) 0.1 mL were mixed and kept at 37 ° C. for 1 hour.
(2) After 1 hour, 1 mL of a 20% trichloroacetic acid aqueous solution and 0.5 mL of a 0.67% thiobarbituric acid aqueous solution were added and held in a boiling water bath for 10 minutes.
(3) After 10 minutes, the mixture was allowed to cool, and the absorbance (532 nm) was measured. The measurement results are shown in Table 1.

Hydroxy radical scavenging rate (%) = [[(CD)-(AB)] / (CD)] × 100
A: Absorbance when test compound is added B: Absorbance when hydrogen peroxide is changed to water C: Absorbance when test compound is changed to water D: Absorbance when test compound and hydrogen peroxide are changed to water

  From Table 1, 1,2; 5,6-diisopropylidenemannitol and 1,3; 4,6-diisopropylidenemannitol have significantly superior hydroxyl radical scavenging ability than mannitol, erythritol and threitol. I understand.

  Skin external preparations and food / beverage product compositions containing the antioxidant of the present invention having the following compositions were produced by conventional methods (Examples 5 to 11). In any case, no problem was found in the blending characteristics. In addition, all compounding quantities are the mass%.

Example 5 (milky lotion)
(Blending ingredients) (Blending amount)
3,4-Isopropylidenemannitol 5.0
(Manufactured by Tokyo Chemical Industry Co., Ltd.)
Bentonite 0.5
Glyceryl monostearate 1.0
Stearic acid 0.5
Behenyl alcohol 0.3
Cholesterol 0.3
Vaseline 0.5
Liquid paraffin 10.0
Methyl polysiloxane 1.0
Concentrated glycerin 10.0
Dipropylene glycol 10.0
N-stearoyl-sodium L-glutamate 0.2
Xanthan gum 0.3
Ascorbic acid 2-glucoside 2.0
Dipotassium glycyrrhizinate 0.2
Nicotinamide 1.0
N-acetylglucosamine 0.1
N-methyl-L-serine 0.1
Oat extract 0.2
Kyonin extract 0.1
Yeast extract 0.1
1,2-octanediol 0.2
Phenoxyethanol 0.1
Purified water residue

Example 6 (skin lotion)
(Blending ingredients) (Blending amount)
1,2,5,6-diisopropylidenemannitol 0.5
(Manufactured by Tokyo Chemical Industry Co., Ltd.)
Glycerin 10.0
1,3-butylene glycol 6.0
Ethanol 8.0
Polyoxyethylene hydrogenated castor oil (60 EO) 0.5
Ascorbic acid 1.0
Citric acid 0.1
Sodium citrate 0.3
Purified water residue

Example 7 (cream)
(Blending ingredients) (Blending amount)
1,2; 5,6-diisopropylidenemannitol 0.2
(Manufactured by Tokyo Chemical Industry Co., Ltd.)
1,2; 5,6-di (1-ethylpropylidene) 1.0
Mannitol (Example 2)
Stearic acid 5.0
Stearyl alcohol 5.0
Glyceryl tri-2-ethylhexanoate 10.0
Macadamia nut oil fatty acid cholesteryl 4.0
Dl-α-tocopherol acetate 0.2
Glyceryl monostearate 3.0
Dipropylene glycol 10.0
1,2-hexanediol 1.0
Potassium hydroxide 0.2
Phenoxyethanol 0.3
Methylparaben 0.1
Perfume Appropriate amount of purified water

Example 8 (cream)
(Blending ingredients) (Blending amount)
1,3; 4,6-diisopropylidenemannitol 2.0
Example 1
Olive Squalane 10.0
Palmitic acid 2.0
Hydrogenated palm kernel oil 0.3
Macadamia nut oil 0.2
Medfoam oil 0.2
Jojoba oil 0.1
Apricot kernel oil 0.1
Hydrogenated soybean phospholipid 0.2
Cetanol 3.5
Glyceryl monopalmitate 2.0
Concentrated glycerin 10.0
Phenoxyethanol 0.1
Carboxyvinyl polymer 0.2
Potassium hydroxide 0.2
Purified water residue

Example 9 (sunscreen)
(Blending ingredients) (Blending amount)
1,2-isopropylidenemannitol 0.5
1,2; 5,6-diisopropylidenemannitol 3.0
(Manufactured by Tokyo Chemical Industry Co., Ltd.)
Methyl polysiloxane (1.5 mm ² / s) 1.0
Methyl polysiloxane (2.0 mm ² / s) 2.0
Methyl polysiloxane (6.0 mm ² / s) 1.0
Methylphenylpolysiloxane 2.0
Methylcyclopolysiloxane 4.0
Tris (trimethylsiloxy) methylsilane 4.0
Polyoxyethylene / methylpolysiloxane copolymer 2.0
Isododecane 1.0
Isohexadecane 2.0
Liquid isoparaffin 2.0
Isononyl isononanoate 5.0
Squalane 1.0
2-Ethylhexyl paramethoxycinnamate 5.0
Dimethyl distearyl ammonium hectorite 1.0
Zinc oxide 10.0
Titanium oxide 5.0
1,2-butanediol 1.0
Phenoxyethanol 0.3
Pure water residue

Example 10 (fruit juice drink)
(Blending ingredients) (Blending amount)
3,4-Isopropylidenemannitol 2.0
(Manufactured by Tokyo Chemical Industry Co., Ltd.)
Sorbitol 1.0
Xylitol 1.0
Fragrance 1.0
Apple juice remaining

Example 11 (tablets)
(Blending ingredients) (Blending amount)
3,4- (1-ethylpropylidene) mannitol 1.0
Example 3
Vitamin C 20.0
Fragrance 1.2
Guam gum 0.06
Sucrose fatty acid ester 1.5
Crystalline cellulose 1.0
Powdered sugar residue

  Antioxidants comprising the alkyl acetal derivative of mannitol of the present invention as an active ingredient have an excellent hydroxy radical scavenging ability, are excellent in safety and stability, and are external preparations for skin and food compositions for the purpose of antioxidants It can be stably blended into products.

Claims (4)

1,2-isopropylidenemannitol, 3,4-isopropylidenemannitol, 3,4- (1-ethylpropylidene) mannitol, 1,3; 4,6-diisopropylidenemannitol and 1,2; An antioxidant comprising an alkyl acetal derivative of mannitol selected from di (1-ethylpropylidene) mannitol as an active ingredient. 1,2-isopropylidenemannitol, 3,4-isopropylidenemannitol, 3,4- (1-ethylpropylidene) mannitol, 1,3; 4,6-diisopropylidenemannitol and 1,2; A skin external preparation containing an alkyl acetal derivative of mannitol selected from di (1-ethylpropylidene) mannitol . 1,2-isopropylidenemannitol, 3,4-isopropylidenemannitol, 3,4- (1-ethylpropylidene) mannitol, 1,3; 4,6-diisopropylidenemannitol and 1,2; A cosmetic comprising an alkyl acetal derivative of mannitol selected from di (1-ethylpropylidene) mannitol . 1,2-isopropylidenemannitol, 3,4-isopropylidenemannitol, 3,4- (1-ethylpropylidene) mannitol, 1,3; 4,6-diisopropylidenemannitol and 1,2; A food and beverage composition containing an alkyl acetal derivative of mannitol selected from di (1-ethylpropylidene) mannitol .