JP3137762B2 - Tranexamic acid dimer and salts thereof, and external preparation for skin containing these - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to tranexamic acid dimers
And a skin external preparation containing at least one or more of its salts as an active ingredient and having excellent skin whitening effect, skin roughness prevention and improvement effects.

[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 made intensive studies and as a result, have found that the novel dimer of tranexamic acid and its salt exhibit a whitening effect more than hydroquinone, and furthermore, prevent and improve skin roughness. The present invention was found to have an effect, and the present invention was completed.

[0005]

That is, the present invention provides a truck.
Nexamic acid dimer and at least one or more of its salts
It is a skin external preparation characterized by containing .

Hereinafter, the configuration of the present invention will be described in detail. The tranexamic acid dimer according to the present invention is, in chemical name, trans-4- (trans-4-aminomethylcyclohexanecarbonyl) aminomethylcyclohexanecarboxylic acid.

The dimer of tranexamic acid according to the present invention and
And salts thereof can be synthesized by the following method.

That is, tranexamic acid or a carboxyl group of tranexamic acid is added to a reactive derivative of a protected tranexamic acid in which the amino group of tranexamic acid or tranexamic acid is protected by an appropriate protecting group, for example, a benzyloxycarbonyl group. For example, by reacting a protected tranexamic acid protected by a benzyl group or the like, a tranexamic acid dimer is produced. When a protected tranexamic acid is used, the protective group is eliminated by catalytic reduction or the like after dimer formation. Reactive derivatives include acid chlorides, acid halides such as acid bromide,
Mixed acid anhydrides and active esters are preferred. The reaction is preferably carried out in a solvent that does not participate in the reaction, for example, an organic solvent such as dichloromethane, dichloroethane, chloroform, acetonitrile, benzene or the like for 1 to 24 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.

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 acid salts such as methanesulfonic acid and p-toluenesulfonic acid, or inorganic salts such as sodium salt, potassium salt, ammonium salt, magnesium salt and calcium salt, or monoethanolamine and diethanol
And organic salts such as ruamine and triethanolamine.

The external preparation for skin of the present invention contains at least one or more of the thus obtained tranexamic acid dimer and a salt thereof.
It is 1 to 20% by weight, preferably 0.01 to 7% by weight. 0.00
If the amount is less than 1% by weight, the skin whitening effect and the effect of preventing and improving skin roughness are poor, and if the amount is more than 20% by weight, the effect cannot be expected to increase.

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. .

[0012]

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 the tranexamic acid dimer and 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

Synthesis Example 2 Benzyl protected form of tranexamic acid (benzyl ester of trans-4-aminomethylcyclohexanecarboxylic acid hydrochloride) Tranexamic acid (10.0 g, 63 mmol) was converted to thionyl chloride (40 m
After stirring at room temperature for 1 hour, ethyl ether (60 ml) was added to the system. The precipitated crystals were collected by filtration, added to a solution of benzyl alcohol in dry dioxane [benzyl alcohol (7.5 ml, 70 mmol) dissolved in dry dioxane (40 ml)], and reacted at 80 ° C. for 1 hour. After cooling, the precipitated crystals were collected by filtration. Recrystallization from ethanol gave a benzyl protected form of tranexamic acid (13.8 g, yield 76%) as a hydrochloride. Melting point 154 ~ 155 ℃

Synthesis Example 3 Protected form of tranexamic acid dimer (trans-4- (trans-4-benzyloxycarbonylaminomethylcyclohexanecarbonyl) aminomethylcyclohexanecarboxylic acid benzyl ester) trans-4-benzyloxycarbonylaminomethyl Cyclohexanecarboxylic acid (5.00 g, 17 mmol) was added to thionyl chloride (5 ml) and reacted at 40 ° C. for 30 minutes. Petroleum ether (50 ml) was added to the reaction system, and the precipitated white crystals were collected by filtration. . Dry benzene solution of this white crystal (50ml)
Under stirring at room temperature, benzyl ester of trans-4-aminomethylcyclohexanecarboxylic acid hydrochloride (4.87 g, 17 mmol)
And triethylamine (3.80 g, 37 mmol) were dissolved in a dry benzene solution (200 ml), and the mixture was further stirred for 20 hours. The white crystals precipitated in the reaction system were collected by filtration and separated and purified by a silica gel column to obtain a protected tranexamic acid dimer (3.28 g, yield 36%). 174-175 ° C

Synthesis Example 4 Dimer of tranexamic acid (trans-4- (trans-4-aminomethylcyclohexanecarbonyl) aminomethylcyclohexanecarboxylic acid) trans-4- (trans-4-benzyloxycarbonylaminomethylcyclohexanecarbonyl) ) Aminomethylcyclohexanecarboxylic acid benzyl ester (5.12
g, 9.83 mmol) was dissolved in acetic acid (150 ml), 10% palladium on carbon (600 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, the residue was crystallized from 10% hydrochloric acid-acetic acid solution-ether, and the obtained crystal was recrystallized from ethanol-ether, Tranexamic acid dimer (2.82 g, 86 yield)
%) As the hydrochloride salt. Melting point 290 ° C (decomposition) ¹ H-NMR (DMSO-d _6, TMS, ppm) δ 0.82 to 2.15 (m, 20H, cyclohexane ring) δ 2.62 (d, 2H, J = 6.8 Hz, − CH ₂ NH
_{^{3 + Cl -) δ2.88 (t}} , 2H, J = 6.2Hz, -C H 2 NH
-) δ7.55 (bs, 1H, -CH 2 N H -) δ8.03 (bs, 3H, -N H 3 + Cl -) δ11.74 (bs, 1H, -COO H) 13 C-NMR ( DMSO-d _6, TMS, ppm) δ28.2 (cyclohexane ring) δ28.4 (cyclohexane ring) δ29.0 (cyclohexane ring) δ29.3 (cyclohexane ring) δ34.9 (cyclohexane ring) δ36.9 (cyclohexane ring) ) δ42.4 (cyclohexane ring) δ43.5 (cyclohexane ring) δ44.2, δ44.3 (- C H 2 NH 3 + Cl - and - C H ₂ NH-) δ174.7 (amide C = O) δ176 .4 (- C OOH) elemental analysis _{C 16 H 28 N 2 O 3} · HCl calculated (%) C: 57.73, H : 8.78, N: 8.42,
Cl: 10.65 actual value (%) C: 57.62, H: 8.85, N: 8.22,
Cl: 10.81

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 for whitening effect The test was performed on the inner skin of the upper arm of 50 subjects exposed to sunlight in the 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 4 groups, and the test was performed according to the following formulation.

Samples of Examples 1 and 2 and Comparative Examples 1 and 2 (alcohol phase) 95% by weight of ethyl alcohol 25.0 Polyoxyethylene (25 mol) hydrogenated castor oil ether 2.0 Antioxidant / preservatives Appropriate amount Perfume Appropriate 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

[0021]

[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 Twice in the morning and evening, after washing the face, an appropriate amount of the cosmetic of Examples 1 and 2 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 20 female panels into 10 groups, each group comprising 2 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

[0024]

[Table 2]

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

Example 3 Cream% by weight Stearic acid 5.0 Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerin monostearate 3.0 Propylene glycol 10.0 Trans-4- (trans-4-aminomethylcyclohexane carbonyl) aminomethylcyclohexanecarboxylic acid hydrochloride 20.0 Caustic potash 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 4 Cream weight% stearic acid 6.0 sorbitan monostearate 2.0 polyoxyethylene (20 mol) sorbitan monostearate 1.5 propylene glycol 10.0 trans-4- (trans-4-aminomethylcyclohexanecarbonyl) aminomethyl Cyclohexanecarboxylic acid 7.0 Glycerin trioctanoate 10.0 Squalene 5.0 Sodium bisulfite 0.01 Ethylparaben 0.3 Perfume Appropriate amount Ion-exchanged water Residue (Preparation method) Add propylene glycol to ion-exchanged water, heat to maintain 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 5 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 trans-hydrochloride 4- (trans-4-aminomethylcyclohexanecarbonyl) aminomethylcyclohexanecarboxylic acid 0.005 Fragrance Appropriate amount Sodium bisulfite 0.03 Ethylparaben 0.3 Ion-exchanged water Residue (Preparation method) Add propylene glycol to ion-exchanged water, heat to 70 ° C Keep (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, and uniformly emulsified by a homomixer.

Example 6 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 Trans-4-Hydrochloride 4-Aminomethylcyclohexane carbonyl) aminomethylcyclohexanecarboxylic acid 10.0 Sodium bisulfite 0.01 Ethylparaben 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 7 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 trans-4- (trans-4-aminomethylcyclohexanecarbonyl) aminomethylcyclohexanecarboxylic acid 1.0 trans-4- (trans-4-aminomethylcyclohexanecarbonyl) aminomethylcyclohexanecarboxylic acid 1.0 perfume (Aqueous 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 That. 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 8 Jelly wt% 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 trans-4- (trans-4-aminomethyl Cyclohexane carbonyl) aminomethylcyclohexanecarboxylic acid 2.0 Methyl paraben 0.2 Perfume Appropriate amount Ion-exchanged water Residue (Preparation method) Carboxyvinyl polymer is uniformly dissolved in ion-exchanged water, while trans-4-one in 95% ethanol
(Trans-4-aminomethylcyclohexanecarbonyl) aminomethylcyclohexanecarboxylic acid and polyoxyethylene (50 mol) oleyl alcohol ether are dissolved and added to the aqueous phase. Then, after adding other components, the mixture is neutralized with caustic soda and L-arginine to increase the viscosity.

Example 9 Serum Weight% (A phase) Ethanol (95%) 10.0 Polyoxyethylene (20 mol) Octyldodecanol 1.0 Methyl paraben 0.15 Pantothenyl ethyl ether 0.1 Trans-4- (Trans-4-aminomethylcyclohexane Carbonyl) aminomethylcyclohexanecarboxylic 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) Dissolve A phase and C phase uniformly A to C phase
Add phases and solubilize. Next, after the phase B is added, filling is performed.

Example 10 pack weight% (phase A) dipropylene glycol 5.0 polyoxyethylene (60 mol) hydrogenated castor oil 5.0 (phase B) trans-4- (trans-4-aminomethylcyclohexane carbonyl) aminomethylcyclohexane hydrochloride Carboxylic acid 1.0 Olive oil 5.0 Tocophenol acetate 0.2 Ethyl paraben 0.2 Perfume 0.2 (C phase) Sodium bisulfite 0.03 Polyvinyl alcohol (degree of saponification, degree of polymerization 2000) 13.0 Ethanol 7.0 Purified water Residue (Preparation method) A phase, B phase, C Dissolve each phase uniformly, A
Add phase B to phase and solubilize. Then, after adding this to phase C, filling is performed.

Each of the skin external preparations obtained in the present invention was subjected to the whitening effect test and the prevention of rough skin conducted in Examples 1 and 2,
The effect was recognized in the improvement effect test.

[0035]

According to the present invention, the tranexamic acid dimer and
And a skin external preparation containing at least one or more of its salts are new skin external preparations having both skin whitening effect and skin roughening prevention and improvement effects.

Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/195 A61K 31/195 A61P 17/00 A61P 17/00 (72) Inventor Yuki Yamase 1050 Nippa-cho, Kohoku-ku, Yokohama-shi, Kanagawa Shiseido Research Center No. 1 (72) Inventor Naoe Akiyama 1050 Nippa-cho, Kohoku-ku, Yokohama, Kanagawa Prefecture Shiseido Research Center No. 1 (72) Kenshi Kitamura 1050 Nippa-cho, Kohoku-ku, Yokohama, Kanagawa Koji Ito, Examiner, Shiseido Research Center No. 1 (56) References JP-A-57-59847 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 7/00 A61K 7 / 42 A61K 7/48 A61K 31/195 A61P 17/00 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. An external preparation for skin, comprising at least one or more of a tranexamic acid dimer and a salt thereof.