JP3137753B2 - Esters of gentisic acid and tranexamic acid, salts thereof, and external preparation for skin containing these - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel ester of gentisic acid and tranexamic acid or a salt thereof having a skin whitening effect and a skin roughening preventing and improving effect, and a skin whitening effect and a skin roughening prevention containing these compounds as active ingredients. And a skin external preparation having an excellent improvement effect.

[0002]

2. Description of the Related Art Although there are some unclear points about the mechanism of the occurrence of skin spots and the like, melanin pigments are generally formed due to hormonal abnormalities and stimulation of ultraviolet rays from sunlight. It is believed to be abnormally deposited within. Treatment of such spots and bruises includes substances that suppress the production of melanin, such as a method of administering a large amount of vitamin C, a method of injecting glutathione, etc., or kojic acid,
A method of applying cysteine or the like in the form of an ointment, cream, lotion, or the like, and topically applying the composition is employed. In the United States and Europe, hydroquinone preparations are used as pharmaceuticals.

[0003]

However, these compounds, except for hydroquinone, exhibit very slow effects, so that the whitening effect is not sufficient, while hydroquinone has been recognized to be effective. Due to its sensitizing properties, its use is generally restricted.

In view of such circumstances, the present inventors have conducted intensive studies and as a result, have found that a novel ester of gentisic acid and tranexamic acid and a salt thereof exhibit a whitening effect more than hydroquinone, and furthermore, prevent skin roughness. The present invention was found to have an improving effect, and the present invention was completed.

[0005]

That is, the present invention is an external preparation for skin characterized by containing an ester of gentisic acid and tranexamic acid represented by the following general formula (2) or a salt thereof, and containing them.

[0006]

Embedded image

Hereinafter, the configuration of the present invention will be described in detail. Ester of gentisic acid and tranexamic acid according to the present invention
Alternatively, a salt thereof is a novel compound and can be synthesized, for example, by the following method.

That is, gentisic acid is reacted with tranexamic acid or a reactive derivative thereof to produce gentisic acid ester of tranexamic acid. As the reactive derivative of tranexamic acid, acid halides such as acid chloride and acid bromide, mixed acid anhydrides and the like are preferable.
The reaction is a solvent not involved in the reaction, for example, dichloromethane, dichloroethane, chloroform, acetonitrile,
The reaction is preferably performed in an organic solvent such as benzene for 1 to 8 hours at room temperature to the boiling point of the solvent. When tranexamic acid is reacted as it is, it is preferable to coexist a condensing agent such as dicyclohexylcarbodiimide. Alternatively, the amino group of tranexamic acid may be protected with a suitable protecting group, for example, a benzyloxycarbonyl group, and the protecting group may be eliminated by catalytic reduction after esterification. In addition, the carboxyl group and / or one phenolic hydroxyl group of gentisic acid may be protected with a suitable protecting group, for example, a benzyl group, and the protecting group may be eliminated by catalytic reduction or the like after esterification. .

The compound of the present invention produced as described above may optionally contain an inorganic acid salt such as hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid, or acetic acid, lactic acid, maleic acid, fumaric acid, tartaric acid, citric acid, Organic salts such as methanesulfonic acid and p-toluenesulfonic acid, or sodium salts, potassium salts, ammonium salts, magnesium salts, calcium salts and the like can be used.

Specific examples of substance names include 2- (trans-4-aminomethylcyclohexylcarbonyloxy) -5-hydroxybenzoic acid and 5- (trans-4-
Aminomethylcyclohexylcarbonyloxy) -2-
Hydroxybenzoic acid, 2- (trans-4-aminomethylcyclohexylcarbonyloxy) -5-hydroxybenzoic acid, sodium 2- (trans-4-aminomethylcyclohexylcarbonyloxy) -5-hydroxybenzoate, hydrochloric acid 5- ( Trans-4-aminomethylcyclohexylcarbonyloxy) -2-hydroxybenzoic acid; potassium 5- (trans-4-aminomethylcyclohexylcarbonyloxy) -2-hydroxybenzoate;

The external preparation for skin of the present invention contains at least one ester of gentisic acid and tranexamic acid and a salt thereof obtained as described above, and the compounding amount is 0.001 to 20% by weight based on the total amount of the external preparation for skin. %, Preferably 0.01 to 7
% By weight. If the amount is less than 0.001% by weight, the skin whitening effect and the skin roughening prevention and improvement effects are poor.

The external preparation for skin of the present invention contains, in addition to the above-mentioned essential components, other components usually used in external preparations for skin such as cosmetics and pharmaceuticals, for example, oils, ultraviolet absorbers, antioxidants, and surfactants. , Moisturizers, fragrances, water, alcohols, thickeners, coloring materials, skin nutritional agents (tocopherol acetate, pantothenyl ethyl ether, glycyrrhizinate) and the like can be appropriately compounded as necessary. .

[0013]

Next, the present invention will be described in more detail by way of examples. The present invention is not limited by this. First, a synthesis example of an ester of gentisic acid and tranexamic acid or a salt thereof according to the present invention will be described in detail.

Synthesis Example 1 Protected benzyloxycarbonyl of tranexamic acid (trans-4-benzyloxycarbonylaminomethylcyclohexanecarboxylic acid) To a solution of tranexamic acid (6.3 g, 40 mmol) in 10% aqueous sodium hydroxide (16 ml) was added benzyloxycarbonyl. Chloride
(8.2 g, 48 mmol), 10% aqueous sodium hydroxide solution (20 ml)
Were successively added dropwise with stirring under ice-cooling. After stirring for 1 hour under ice cooling, hydrochloric acid was added to make the reaction system acidic, and the crystals were collected by filtration. Recrystallization from benzene-petroleum ether gave a protected benzyloxycarbonyl of tranexamic acid (10.7 g, yield 92%). 114-116 ° C

Synthetic Example 2 Dibenzyl protected form of gentisic acid (5-benzyloxy-2-hydroxybenzoic acid benzyl ester) Gentisic acid (10 g, 65 mmol) was added to benzyl bromide (20 ml, 130 mmol) in acetone at room temperature in the presence of potassium carbonate. )
And 10 hours, separated and purified on a silica gel column,
A dibenzyl protected form of gentisic acid (14.0 g, yield 83%) was obtained. Melting point 68.5-69.0 ℃

Synthesis Example 3 Protected ester of gentisic acid and tranexamic acid (5-benzyloxy-2- (trans-4-benzyloxycarbonylaminomethylcyclohexylcarbonyloxy) benzoic acid benzyl ester) trans-4-benzyloxy After adding carbonylaminomethylcyclohexanecarboxylic acid (4.4 g, 15 mmol) to thionyl chloride (5 ml) and reacting at 40 ° C. for 30 minutes, petroleum ether (50 ml) was added to the reaction system to precipitate white crystals. I filtered it. A dry benzene solution (60 ml) of 5-benzyloxy-2-hydroxybenzoic acid benzyl ester (3.75 g, 14.5 mmol) and triethylamine (1.63 g, 16 mmol) dissolved in a dry benzene solution (50 ml) of the white crystals was stirred at room temperature. ), And the mixture was further stirred for 4 hours.
After the triethylamine hydrochloride precipitated in the reaction system was removed by filtration, the mixture was separated and purified on a silica gel column to give a protected form of an ester of gentisic acid and tranexamic acid (4.02 g, yield 52%).
%). 118.5-119 ° C

Synthesis Example 4 Ester of gentisic acid and tranexamic acid (2- (trans-4-aminomethylcyclohexylcarbonyloxy) -5-hydroxybenzoic acid) 5-benzyloxy-2- (trans-4-benzyloxycarbonyl) Aminomethylcyclohexylcarbonyloxy) benzoic acid benzyl ester (1.07 g, 2 mmol) was dissolved in acetic acid (100 ml), 10% palladium on carbon (100 mg) was added, and catalytic reduction was performed at room temperature and normal pressure. After the theoretical amount of hydrogen was absorbed, the catalyst was removed by filtration, the reaction solution was concentrated under reduced pressure, and the residue was crystallized from ether to form an ester of gentisic acid and tranexamic acid as white crystals (438 mg, yield 100%). Obtained. Melting point 196-198.5 ℃

Synthesis Example 5 Ester hydrochloride of gentisic acid and tranexamic acid (2- (4-aminomethylcyclohexylcarbonyloxy) -5-hydroxybenzoic acid hydrochloride) 2- (4-aminomethylcyclohexylcarbonyloxy) -5- Hydroxybenzoic acid (500 mg) was crystallized from 9% hydrochloric acid / acetic acid solution-ether and recrystallized from ethanol-ether to give gentisic acid and tranexamic acid ester hydrochloride as white crystals (420 mg, yield 72%). Obtained. Melting point 246.5-248.5 ° C ¹ H-NMR (DMSO-d6 _, TMS, ppm) δ 1.01 to 2.51 (m, 10H, cyclohexane ring) δ 2.66 (d, 2H, J = 6.8 Hz, -C H ₂ NH
₂ ) δ 6.91 (d, 1H, J = 8.5 Hz, benzene ring H
-3) δ 6.98 (dd, 1H, J = 2.9 and 8.5 Hz,
Benzene ring H-4) δ 7.28 (d, 1H, J = 2.9 Hz, benzene ring H)
-6) δ8.05 (bs, 3H, -N H 3 + Cl -) δ9.75 (bs, 1H, -O H) δ12.74 (bs, 1H, -COO H) 13 C-NMR (DMSO- d6 _, TMS, ppm) δ27.6 (cyclohexane ring C-3, C-5) δ28.6 (cyclohexane ring C-2, C-6) δ34.9 (cyclohexane ring C-4) δ42.0 (cyclohexane ring C-1) δ44.1 (- C H 2 NH 2) δ117.0 ( benzene ring C-6) δ120.0 (benzene ring C-4) δ124.4 (benzene ring C-3) δ124.6 ( benzene ring C-1) δ142.0 (benzene ring C-2) δ154.8 (benzene ring C-5) δ165.6 (ester C = O) δ173.7 (- C OOH) elemental analysis C ₁₅ H ₁₉ Calculated value (%) as NO ₅ · HCl C: 54.63 , H: 6.11, N: 4.25,
Cl: 10.75 actual value (%) C: 54.62, H: 6.12, N: 4.22,
Cl: 10.72

Synthesis Examples 6 to 8 The following compounds were synthesized according to the methods of Synthesis Examples 2 to 5.

Synthesis Example 6 2,5-dihydroxy-benzoic acid benzyl ester
101.5 ~ 103.0 ℃

Synthesis Example 7 5- (trans-4-benzyloxycarbonylaminomethylcyclohexylcarbonyloxy) -2-hydroxybenzoic acid benzyl ester Melting point 110-111 ° C.

Synthesis Example 8 5- (4-aminomethylcyclohexylcarbonyloxy) -2-hydroxybenzoic acid hydrochloride Melting point: 181 to 185 ° C. ¹ H-NMR (DMSO-d6 _, TMS, ppm) δ1.02 to 2.55 (M, 10H, cyclohexane ring) δ 2.68 (t, 2H, J = 5.9 Hz, -CH ₂ NH
₂ ) δ 6.98 (d, 1H, J = 8.8 Hz, benzene ring H
-3) δ 7.25 (dd, 1H, J = 2.9 and 8.8 Hz,
Benzene ring H-4) δ7.47 (d, 1H, J = 2.9 Hz, benzene ring H)
-6) δ8.11 (bs, 3H, -N H 3 + Cl - Calculated) Elemental analysis _{C 15 H 19 NO 5 · HCl} (%) C: 54.63, H: 6.11, N: 4.25,
Cl: 10.75 actual value (%) C: 54.64, H: 6.08, N: 4.22,
Cl: 10.78

Next, examples of the skin external preparation will be described in detail. The compounding amount is% by weight. Prior to the examples, the effect test method and the evaluation method of the present invention will be described.

(1) Test method of whitening effect Test method: The test was conducted on the inner skin of the upper arm of 50 subjects who were exposed to sunlight in summer for 4 hours (2 hours a day for 2 days). After the day, each sample was applied once in the morning and evening for 8 weeks. The panel was divided into 10 groups and divided into 5 groups, and the test was performed according to the following formulation.

Samples of Examples 1 to 3 and Comparative Examples 1 and 2 (alcohol phase) weight% 95% ethyl alcohol 25.0 polyoxyethylene (25 mol) hydrogenated castor oil ether 2.0 antioxidant / preservative proper amount perfume proper amount Table 1) 1.0 (aqueous phase) Glycerin 5.0 Sodium hexametaphosphate Appropriate amount Ion-exchanged water Residue (Preparation method) Prepare aqueous and alcohol phases and solubilize.

(Evaluation Method) The lightening effect after use was determined based on the following criteria. (Judgment) ：: When the ratio of the effective and effective of the subjects is 80% or more ○: The ratio of the effective and effective among the subjects is 50 to 8
0%: △: 30% to 5% of the test subjects showed significant and effective
0%: ×: The proportion of subjects who show excellent and effective is 30% or less

[0027]

[Table 1]

As is evident from Table 1, the effect of the embodiment after exposure to sunlight was less in the example than in the comparative example. Admitted.

(2) Test Method for Preventing and Improving Roughness of Skin After washing the face twice a day in the morning and at night, an appropriate amount of the cosmetics of Examples 1 to 3 was applied to the left side of the face, and an appropriate amount of the cosmetic of Comparative Example 1 was applied to the right side of the face. This was done by applying for two weeks. The test was conducted by dividing the 30 female panels into 10 groups, each group comprising 10 groups. (Evaluation method) The effectiveness of three items (moisture of skin, firmness of skin, moisture of the next morning) was determined based on the following criteria. (Judgment) ：: When the ratio of the effective and effective of the subjects is 80% or more ○: The ratio of the effective and effective among the subjects is 50 to 8
0%: △: 30% to 5% of the test subjects showed significant and effective
0%: ×: The proportion of subjects who show excellent and effective is 30% or less

[0030]

[Table 2]

As is evident from Table 2, the effect of the skin moisture, the skin firmness, and the effect of the moisture in the next morning were better in the example than in the comparative example.

Example 4 Cream% by Weight Stearic Acid 5.0 Stearyl Alcohol 4.0 Isopropyl Myristate 18.0 Glycerin Monostearate 3.0 Propylene Glycol 10.0 2- (Trans-4-aminomethylcyclohexylcarbonyloxy) -5-hydroxybenzoic Acid Hydrochloride 20.0 Caustic Potassium 0.2 Sodium bisulfite 0.01 Preservatives Appropriate amount Fragrance Appropriate amount Ion-exchanged water Residue (Preparation method) Add propylene glycol and caustic potash to ion-exchanged water, heat and maintain at 70 ° C (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is gradually added to the aqueous phase, and after the addition is completed, the temperature is maintained for a while to cause a reaction. Thereafter, the mixture is uniformly emulsified with a homomixer and cooled to 30 ° C. while stirring well.

Example 5 Cream wt% stearic acid 6.0 sorbitan monostearate 2.0 polyoxyethylene (20 mol) sorbitan monostearate 1.5 propylene glycol 10.0 5- (trans-4-aminomethylcyclohexylcarbonyloxy) -2 hydrochloride -Hydroxybenzoic acid 7.0 Glycerin trioctanoate 10.0 Squalene 5.0 Sodium bisulfite 0.01 Ethylparaben 0.3 Perfume Appropriate amount Ion-exchanged water Residue (Production method) Add propylene glycol to ion-exchanged water, heat and maintain at 70 ° C (water phase) . The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is added to the water phase, pre-emulsified, homogenized with a homomixer, and cooled to 30 ° C. with good stirring.

Example 6 Cream% by weight stearyl alcohol 7.0 stearic acid 2.0 hydrogenated lanolin 2.0 squalane 5.0 2-octyldodecyl alcohol 6.0 polyoxyethylene (25 mol) cetyl alcohol ether 3.0 glycerin monostearate 2.0 propylene glycol 5.0 2- ( Trans-4-Aminomethylcyclohexylcarbonyl oxy) -5-hydroxybenzoic acid 0.005 Fragrance Appropriate amount Sodium bisulfite 0.03 Ethyl paraben 0.3 Ion-exchanged water Residue (Preparation method) Add propylene glycol to ion-exchanged water, heat and maintain at 70 ° C. (Aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is added to the water phase, pre-emulsified, homogenized with a homomixer, and cooled to 30 ° C. with good stirring.

Example 7 Emulsion Weight% Stearic Acid 2.5 Cetyl Alcohol 1.5 Vaseline 5.0 Liquid Paraffin 10.0 Polyoxyethylene (10 mol) Monooleate 2.0 Polyethylene Glycol 1500 3.0 Triethanolamine 1.0 5- (trans-4-amino) Methylcyclohexylcarbonyl oxy) -2-hydroxybenzoic acid 10.0 Sodium bisulfite 0.01 Ethyl paraben 0.3 Carboxyvinyl polymer 0.05 Perfume Appropriate amount Ion exchange water Residue (Preparation method) Dissolve the carboxyvinyl polymer in a small amount of ion exchange water (A phase). Polyethylene glycol 1500 and triethanolamine are added to the remaining ion-exchanged water, dissolved by heating, and maintained at 70 ° C. (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is added to the water phase, pre-emulsification is performed, phase A is added, and the mixture is uniformly emulsified with a homomixer. After the emulsification, the mixture is cooled to 30 ° C. while stirring well.

Example 8 Emulsion weight% (oil phase part) Stearyl alcohol 1.5 Squalene 2.0 Vaseline 2.5 Deodorized liquid lanolin 1.5 Evening primrose oil 2.0 Isopropyl myristate 5.0 Glycerin monooleate 2.0 Polyoxyethylene (60 mol) hydrogenated castor oil 2.0 Tocopherol acetate 0.05 Ethyl paraben 0.2 butyl paraben 0.1 5- (trans-4-aminomethylcyclohexylcarbonyloxy) -2-hydroxybenzoic acid 1.0 2- (trans-4-aminomethylcyclohexylcarbonyloxy) -5-hydroxybenzoic acid 1.0 Phase) Sodium bisulfite 0.01 Glycerin 5.0 Sodium hyaluronate 0.01 Carboxyvinyl polymer 0.2 Potassium hydroxide 0.2 Purified water Residue (Preparation method) Dissolve the oil phase at 70 ° C. 70 ° C in the aqueous phase
And the oil phase is mixed with the aqueous phase, emulsified by an emulsifier, and then cooled to 30 ° C. by a heat exchanger.

Example 9 Jelly weight% 95% ethyl alcohol 10.0 dipropylene glycol 15.0 polyoxyethylene (50 mol) oleyl alcohol ether 2.0 carboxyvinyl polymer 1.0 caustic soda 0.15 L-arginine 0.1 5- (trans-4-aminomethylcyclohexyl hydrochloride) Carbonyl oxy) -2-hydroxybenzoic acid 1.0 2- (trans-4-aminomethylcyclohexylcarbonyloxy) -5-hydroxybenzoic acid hydrochloride 1.0 Methyl paraben 0.2 Perfume Appropriate amount Ion-exchanged water Residue (Preparation method) Carboxyvinyl polymer in ion-exchanged water Dissolves homogeneously, while 5- (trans-4-aminomethylcyclohexylcarbonyloxy) -2-hydroxybenzoic acid in 95% ethanol, 2- (trans-hydrochloric acid)
4-aminomethylcyclohexylcarbonyloxy)-
Dissolve 5-hydroxybenzoic acid, polyoxyethylene (50 mol) oleyl alcohol ether and add to the aqueous phase. Then, after adding other ingredients, caustic soda,
Neutralize with L-arginine to thicken.

Example 10 Serum Weight% (A phase) Ethanol (95%) 10.0 Polyoxyethylene (20 mol) octyldodecanol 1.0 Methyl paraben 0.15 Pantothenyl ethyl ether 0.1 2- (Trans-4-aminomethylcyclohexylcarbonyloxy) ) -5-Hydroxybenzoic acid 0.05 (B phase) Potassium hydroxide 0.1 (Phase C) Glycerin 5.0 Dipropylene glycol 10.0 Sodium bisulfite 0.03 Carboxyvinyl polymer 0.2 Purified water Residue (Preparation method) A phase and C phase are uniformly dissolved A to C phase
Add phases and solubilize. Next, after the phase B is added, filling is performed.

Example 11 pack weight% (phase A) dipropylene glycol 5.0 polyoxyethylene (60 mol) hydrogenated castor oil 5.0 (phase B) 2- (trans-4-aminomethylcyclohexylcarbonyloxy) -5-hydroxy hydrochloride Benzoic acid 1.0 Hydrochloric acid 5- (trans-4-aminomethylcyclohexylcarbonyloxy) -2-hydroxybenzoic acid 1.0 Olive oil 5.0 Tocophenol acetate 0.2 Ethylparaben 0.2 Perfume 0.2 (Phase C) Sodium hydrogen sulfite 0.03 Polyvinyl alcohol (Saponification degree 90 , Polymerization degree 2000) 13.0 Ethanol 7.0 Purified water Residue (Preparation method)
Add phase B to phase and solubilize. Then, after adding this to phase C, filling is performed.

The skin external preparations obtained in the present invention were all tested in Examples 1 to 3 for their whitening effect and for preventing skin roughness.
The effect was recognized in the improvement effect test.

[0041]

The ester of gentisic acid and tranexamic acid or a salt thereof according to the present invention is a novel compound excellent in skin whitening effect, skin roughness prevention and improvement effects. Further, a skin external preparation containing the same is a novel skin external preparation having both skin whitening effect and skin roughening prevention and improvement effects.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 7/48 A61K 7/48 31/24 31/24 A61P 17/00 A61P 17/00 (72) Inventor Yoshihiro Morikawa Yokohama, Kanagawa 1050 Nishiha-cho, Kohoku-ku, Shiseido 1st Research Center in Shiseido (72) Inventor Yuki Yamase 1050 Nippa-cho, Kohoku-ku, Yokohama, Kanagawa Prefecture 1st Research Center in Shiseido (72) Inventor Naoe Akiyama Kohoku, Yokohama, Kanagawa 1050 No., Nippa-cho, Shiseido 1st Shiseido Research Center (72) Inventor Kenji Kitamura 1050 Nippa-cho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Examiner in Shiseido 1st Research Center Koji Ito (58) Cl. ⁷ , DB name) C07C 229/48 A61K 7/00 A61K 7/42 A61K 7/48 A61K 31/24 A61P 17/00 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. An ester of gentisic acid and tranexamic acid represented by the following general formula 1, or a salt thereof. Embedded image 2. An external preparation for skin, comprising at least one ester of gentisic acid and tranexamic acid according to claim 1 and salts thereof.