JPH08295689A - Kojic acid-tranexamic acid ester and dermal preparation for external use - Google Patents

Abstract

PURPOSE: To obtain the subject new stable compound, comprising an ester of kojic acid with tranexamic acid or an N-protected tranexamic acid, having high suppressing actions on tyrosinase activities, excellent in beautifying and whitening effects without coloring, etc., and useful as a dermal preparation for external use, etc. CONSTITUTION: This new ester of kojic acid with tranexamic acid of formula I (X is H or an amino-protecting group) comprises the ester derivative (salt) of the kojic acid with the tranexamic acid or an N-protected tranexamic acid, has high suppressing actions on tyrosinase activities and is excellent in stability without coloring change, etc., with time and useful as a dermal preparation for external use, etc. The compound is obtained by dispersing N- acetyltranexamic acid, etc., in tetrahydrofuran, adding triethylamine and ethyl chlorocarbonate thereto while stirring the dispersion under chilling with ice, then adding kojic acid of formula II and N,N-dimethylaminopyridine to the dispersion, stirring the resultant mixture at ambient temperature for 20 hr, subsequently neutralizing the mixture with hydrochloric acid and collecting the formed crystal by filtration.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention provides a novel esterification product of kojic acid and tranexamic acid or N-protected tranexamic acid having a skin lightening effect and salts thereof, and a skin lightening effect containing these compounds as active ingredients. Skin external preparation.

[0002]

BACKGROUND OF THE INVENTION Blotches and bruises result from the deposition of a black-brown or black pigment called melanin on the body surface. It is considered that this melanin is mainly produced from the following production pathway starting from tyrosine.

[0003]

Embedded image

In the melanin production pathway, tyrosinase (o-diphenol oxidase) catalyzes the oxidation of tyrosine to dopa and the oxidation of dopa to dopaquinone. Therefore, inhibiting the activity of tyrosinase suppresses the production of melanin. Therefore, substances (medicines) that inhibit tyrosinase activity are used for the treatment and prevention of spots and bruises.

[0005] Kojic acid and certain kojic acid derivatives are known to be excellent in skin whitening effect because they have a large inhibitory effect on this tyrosinase activity, and have been attracting attention in recent years. For example, as a treatment method for spots and bruises, a treatment such as topically applying kojic acid in the form of an ointment, a cream, a lotion or the like is taken.

Examples of the kojic acid derivative include hydroxyl groups of hydroxymethyl groups of kojic acid represented by the following formula, fatty acids (see JP-A-4-95009 and JP-A-4-352708), amino acids or peptides (special characteristics). Kaihei 4-187618) and the like, and derivatives produced by ester reaction, and glycosides in which a saccharide is introduced into the hydroxy group of the hydroxymethyl group (JP-A-4-46191, JP-A-4-145095).
(See Japanese Patent Laid-Open No. 4-145096 and Japanese Patent Laid-Open No. 4-198115), and aromaltol obtained by converting the hydroxymethyl group to a chloromethyl group and then converting the methyl group by a reduction reaction ( Japanese Patent Laid-Open No. 4-36217) has been proposed so far.

[0007]

[Chemical 4]

[0008]

However, kojic acid has a very high chemical reactivity and is apt to undergo a chemical change by heat or light. Therefore, in the case of incorporating kojic acid into cosmetics, pharmaceuticals, etc., there is an inconvenience that coloring due to kojic acid occurs over time during storage and distribution. Many of the currently known kojic acid derivatives have similar problems. On the other hand, a chemically relatively stable kojic acid derivative has a reduced whitening effect and needs to be used in combination with another component having a whitening effect.

In view of such circumstances, an object of the present invention is to provide a novel kojic acid derivative which is chemically stable and has an excellent whitening effect. Further, it is a further object of the present invention to provide a skin external preparation containing the kojic acid derivative and having an excellent whitening effect.

[0010]

As a result of intensive studies, the present inventors have found that a novel compound, an ester of kojic acid and tranexamic acid or an N-protected tranexamic acid, and a salt thereof are chemically reacted. They have found that they are stable and have a whitening effect superior to that of kojic acid, and have completed the present invention.

That is, the present invention has the formula

Embedded image The present invention provides an ester of kojic acid represented by the formula (wherein X represents a hydrogen atom or an amino-protecting group) and tranexamic acid or N-protected tranexamic acid, and salts thereof.

Furthermore, the present invention provides a skin external preparation containing these compounds as an active ingredient and having an excellent skin whitening effect.

[0013]

Action: Tranexamic acid has an action of reducing the activity of plasmin or fibrinolytic enzyme (antiplasmin action), and is expected to have some anti-allergic, anti-edema and anti-inflammatory effects. Therefore, clinically, oral administration with the aim of suppressing erythema, swelling, itchiness of the skin and mucous membranes,
It is administered as an intravenous or intramuscular injection.

However, tranexamic acid does not have an action of suppressing tyrosinase activity.

The ester form of kojic acid represented by the following formula and tranexamic acid or N-protected tranexamic acid and salts thereof are novel substances found by the present invention.

[0016]

[Chemical 6]

(In the formula, X represents a hydrogen atom or an amino protecting group)

The compound is chemically stable and does not change its color with time. Further, the present compound has a much higher tyrosinase activity inhibitory action than kojic acid and conventional kojic acid derivatives, and is excellent in the skin whitening effect.

[0019]

Preferred Embodiment The compound can be produced, for example, by an esterification reaction of a reactive derivative of N-protected tranexamic acid with kojic acid. The amino groups must be protected beforehand to prevent the tranexamic acids from forming amide bonds with each other. As the N-protecting group,
All known amino protecting groups apply. Examples thereof include amino protecting groups such as acetyl group, benzyloxycarbonyl group and t-butoxycarbonyl group, but are not limited thereto.

The reactive derivative of N-protected tranexamic acid is preferably a mixed acid anhydride of N-protected tranexamic acid and ethyl chloroformate, ethyl chlorocarbonate or the like. This mixed anhydride is prepared by dispersing the N-protected tranexamic acid in an inert polar solvent such as tetrahydrofuran and mixing it with the above halogenated acid ester in the presence of a basic catalyst such as a tertiary amine. It is obtained by Preferably, within the range of about -10 to 10 ° C,
React for about 5 to 30 minutes.

The reactive derivative of N-protected tranexamic acid thus obtained is used for esterification reaction with kojic acid by a general method. For example, in an inert polar solvent such as tetrahydrofuran, the both may be stirred and mixed in the presence of a basic catalyst such as a tertiary amine to react. Preferably, within the range of about −5 to 30 ° C., 8 to 2
React for about 4 hours.

Since the above reaction passes through an acid anhydride as an intermediate, it is necessary to use a sufficiently dehydrated solvent and carry out the reaction in the presence of an inert gas. When the amino protecting group is removed from the produced ester form of kojic acid and N-protected tranexamic acid, a known treatment method such as catalytic reduction can be applied.

Examples of the salt of the compound of the present invention produced as described above include sodium salt, potassium salt, ammonium salt, magnesium salt, calcium salt and the like. Furthermore, phosphate, hydrobromide, hydrochloride, sulfate, or acetate, lactate, maleate, fumarate, tartrate, citrate, methanesulfonate, p-
Also included are acid addition salts such as toluene sulfonate.

The external preparation for skin of the present invention is, for example, at least one compound selected from the ester form of kojic acid and tranexamic acid or N-protected tranexamic acid obtained by the above-mentioned production method and salts thereof. It has an excellent whitening effect. The amount thereof is preferably about 0.001 to 30% by weight, more preferably about 0.0.
It is 5 to 10% by weight. If it is less than 0.001% by weight, the whitening effect due to the addition of the compound of the present invention is not conspicuous, which is not desirable. On the contrary, if it exceeds 30% by weight, the enhancement of the effect cannot be expected and it is excessive. It's just that, so it's still not good.

The dosage form of the external preparation for skin of the present invention is not particularly limited, and examples thereof include cream, emulsion, lotion,
Examples thereof include jelly, ointment, powder and the like, which can be arbitrarily selected from the dosage forms generally adopted as pharmaceuticals, quasi drugs, cosmetics and the like.

The external preparation for skin of the present invention can be used in pharmaceuticals such as fragrances, pigments, preservatives, antioxidants, ultraviolet absorbers, skin nutrients, thickeners and surfactants, quasi drugs, cosmetics and the like. Other components that are generally added can be appropriately added within the range where the present invention is achieved. In addition, other currently used whitening agents such as ascorbic acid may be used in combination.

[0027]

The present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.
Unless otherwise specified,% means% by weight.

First, production examples of the ester form of kojic acid and tranexamic acid or N-protected tranexamic acid and salts thereof according to the present invention will be described.

Production Example 1 Ester Form of Kojic Acid and N-Acetyltranexamic Acid 10 g (50.2 mmol) of N-acetyl tranexamic acid was dispersed in tetrahydrofuran, and 6.96 mL (50.2 mmol) of triethylamine was added under stirring with ice cooling. Then, 4.8 mL (50.2 mmol) of ethyl chlorocarbonate was added dropwise. After a few minutes, kojic acid
7.13 g (50.2 mmol) and N, N-dimethylaminopyridine 613 mg (5.02 mmol) were added, and the mixture was stirred at room temperature for 20 hours. After the completion of the reaction, the mixture was neutralized with hydrochloric acid, the crystals were collected by filtration and then recrystallized to obtain 6.5 g of the compound of the present invention (yield 40%). It was confirmed by the following identification method that this compound was an ester of kojic acid and N-acetyltranexamic acid. The melting point of this compound is 191 to 1
It was 93 ° C.

TLC Rf value: 0.5 (CHCl ₃ : M
eOH = 10: 1)

IR (cm ^-1 ): 3320, 1724, 1660, 165
0, 1625, 1560, 1230, 1171

¹ H-NMR (CDCl ₃ , TMS, pp
m): δ 0.8 to 1.8 (m, 9H), 1.95 (s, 3H), 2.
16 (s, H), 3.15 (t, 2H), 4.92 (s, 2H),
5.60 (s, 1H), 6.48 (s, 1H), 8.05 (s, 1
H)

(Production Example 2) Ester of kojic acid and tranexamic acid N-benzyloxycarbonyl tranexamic acid was used as a starting material, and it was converted into a mixed acid anhydride derivative in the same manner as in Production Example 1, and then mixed with kojic acid. The ester reaction was carried out. Then, catalytic reduction was performed to remove the N-benzyloxycarbonyl group to obtain an ester form of kojic acid and tranexamic acid.

Next, examples of the external preparation for skin will be described. Kojic acid and tranexamic acid or N according to the present invention
The following tests were carried out in order to clarify the effect of the ester form with protected tranexamic acid and its salt.

(Tyrosinase activity inhibition test) For kojic acid and the ester form of kojic acid and N-acetyltranexamic acid, the tyrosinase activity inhibition rate at each concentration was measured according to the following method.

Method: 0.9m 0.045% tyrosine solution in a test tube
L and 0.1 M phosphate buffer (pH 6.8-7.2, 1.02 mL) were added, the test solution (1.00 mL) was added, and this was incubated at 37 ° C for 10 minutes. Then, 0.1% tyrosinase solution 0.0
8 mL was added and incubated at 37 ° C. for 15 minutes. 475n
The absorbance at m (maximum absorption wavelength of dopachrome) was measured, and the tyrosinase activity inhibition rate was calculated by the following formula.

[0037]

[Equation 1]

[0038]

[Table 1]

The results are shown in Table 1, and it was confirmed that the ester form of kojic acid and N-acetyltranexamic acid according to the present invention was superior to kojic acid in suppressing the tyrosinase activity.

Example 1 <Oil phase> (1) Polyoxyethylene (15 mol) cetyl ether 0.7% (2) Polyoxyethylene (40 mol) monooleate 0.4% (3) Glycerin Monostearic acid ester 1.0% (4) Cetyl alcohol 3.0% (5) Liquid paraffin 6.0% (6) Glycerin trioctanoic acid ester 4.0% (7) Preservative Suitable amount

<Aqueous phase> (8) 1,3-butylene glycol 7.0% (9) Hydroxyethyl cellulose 0.4% (10) Kojic acid-tranexamic acid ester hydrochloride 2.5% (11) Purified water residue amount

<Production method> A mixed liquid of (1) to (7) (oil phase)
And (8) to (11) mixed liquids (aqueous phase) are heated and kept at 70 ° C., the aqueous phase is added to the oil phase while stirring well, the mixture is uniformly emulsified, and then cooled to 30 ° C.

Example 2 <Oil phase> (1) Polyoxyethylene (15 mol) cetyl ether 0.7% (2) Polyoxyethylene (40 mol) monooleate 0.4% (3) Glycerin Monostearate 1.0% (4) Cetyl alcohol 3.0% (5) Squalane 6.0% (6) Glycerin trioctanoate 4.0% (7) Preservative Suitable amount

<Aqueous phase> (8) 1,3-butylene glycol 5.0% (9) Glycerin 2.0% (10) Hydroxyethyl cellulose 0.4% (11) Kojic acid-tranexamic acid ester hydrochloride 2. 5% (12) Remaining purified water

<Manufacturing Method> Mixture of (1) to (7) (oil phase)
And (8) to (12) mixed liquids (aqueous phase) are heated and maintained at 70 ° C., the aqueous phase is added to the oil phase while stirring well to uniformly emulsify, and then cooled to 30 ° C.

(Example 3) <Oil phase> (1) Stearic acid 10.0% (2) Solid paraffin 3.0% (3) Cetyl alcohol 2.5% (4) Liquid paraffin 3.0% (5 ) Isopropyl myristate 3.0% (6) Sorbitan monostearate 0.5% (7) Polyoxyethylene (20 moles) sorbitan monostearate 2.5% (8) Kojic acid-N-acetyl tranexamic acid ester 3.0% (9) Preservative Suitable amount

<Aqueous phase> (10) Propylene glycol 5.0% (11) Triethanolamine 0.5% (12) Purified water Remaining amount

<Manufacturing Method> Mixture of (1) to (9) (oil phase)
And the mixed liquid (aqueous phase) of (10) to (12) is 80
The mixture is heated to 0 ° C., uniformly dissolved, the aqueous phase is gradually added to the oil phase with thorough stirring to emulsify, and the mixture is cooled to 30 ° C.

(Example 4) <Oil phase> (1) Stearic acid 4.2% (2) Glycerin trioctanoate 10.0% (3) Liquid paraffin 10.0% (4) Polyoxyethylene (40 Mol) monostearate 2.0% (5) glycerin monostearate (self-emulsifying type) 5.0% (6) kojic acid-N-acetyl tranexamic acid ester 5.0% (7) preservative proper amount

<Aqueous phase> (8) Glycerin 5.0% (9) Purified water residual amount <Production method> (1) to (7) mixed liquid (oil phase) and (8) to
Each of the mixed liquids (water phase) of (9) is heated to 80 ° C. to be uniformly dissolved, and the water phase is gradually added to the oil phase while stirring well to emulsify and cooled to 30 ° C.

(Example 5) <Oil phase> (1) Polyoxyethylene (20 moles) sorbitan monostearate 1.5% (2) Sorbitan monostearate 1.5% (3) Polyoxyethylene (30 moles) ) Sorbitol tetrastearate 2.0% (4) Beeswax 5.0% (5) Stearic acid 4.0% (6) Solid paraffin 1.0% (7) Liquid paraffin 40.0% (8) Jojoba oil 10 0.0% (9) Kojic acid-N-acetyl tranexamic acid ester 2.5% (10) Preservative Suitable amount

<Aqueous phase> (11) 1,3-butylene glycol 3.0% (12) Triethanolamine 0.5% (13) Purified water remaining amount

<Manufacturing Method> The mixed liquids (oil phase) of (1) to (10) and the mixed liquids (aqueous phase) of (11) to (13) are respectively heated and uniformly dissolved, and kept at 80 ° C. . The water phase is added to the oil phase with thorough stirring to emulsify and then cooled to 30 ° C.

(Example 6) <Oil phase> (1) Polyoxyethylene (60 mol) castor oil 1.0% (2) Stearic acid 7.0% (3) Glycerin 40.0% (4) Kojic acid -Tranexamic acid ester hydrochloride 2.0% (5) Preservative Suitable amount

<Aqueous phase> (6) Sodium hydroxide 1.4% (7) Purified water 10.0% (8) Remaining amount of ethanol

<Manufacturing Method> Mixture of (1) to (5) (oil phase)
And a mixed solution of (6) to (7) (aqueous phase other than ethanol)
Each is heated to dissolve uniformly and kept at 80 ° C. While stirring well, add an aqueous phase other than ethanol to the oil phase, mix, and cool to 50 ° C. Add ethanol at 50 ° C and cool to 30 ° C.

(Example 7) <Oil phase> (1) Kaolin 30.0% (2) Bentonite 10.0% (3) 1,3-butylene glycol 10.0% (4) Pyrrolidonecarboxylic acid 5.0 % (5) Kojic acid-N-acetyl tranexamic acid ester 2.0%

<Aqueous phase> (6) Polyoxyethylene (4 mol) lauryl ether phosphoric acid 0.5% (7) Ethanol 5.0% (8) Purified water residual amount

<Production Method> (1) to (5) are uniformly mixed and dispersed, to the solution (oil phase), the solution (aqueous phase) in which (6) to (8) is mixed is added and uniformly mixed.

(Example 8) <Oil phase> (1) Polyoxyethylene (20 mol) behenyl ether 1.5% (2) Sorbitan monostearate 1.0% (3) Glycerin trioctanoate 5.0 % (4) Liquid paraffin 10.0% (5) Kojic acid-N-acetyl tranexamic acid ester 4.0% (6) Preservative proper amount

<Aqueous phase> (7) Carboxyvinyl polymer 1.0% (8) Glycerin 5.0% (9) Triethanolamine 1.0% (10) Purified water remaining amount

<Production Method> A mixed liquid of (1) to (6) (oil phase)
And a mixed solution of (7) to (8) and (10) (aqueous phase excluding triethanolamine) are uniformly dissolved while heating, and kept at 80 ° C. While stirring well, add the aqueous phase excluding triethanolamine to the oil phase and uniformly emulsify. When uniform, triethanolamine is added to neutralize and thicken, and then cooled to 30 ° C.

(Example 9) <Oil phase> (1) Polyoxyethylene (40 mol) monostearate 2.0% (2) Glycerin monostearate 5.0% (3) Stearic acid 6.0% ( 4) Liquid paraffin 12.0% (5) Squalane 5.0% (6) Vitamin E 0.1% (7) Kojic acid-N-acetyl tranexamic acid ester 5.0% (8) Preservative proper amount

<Aqueous phase> (9) 1,3-butylene glycol 3.0% (10) Glycerin 3.0% (11) Purified water residual amount

<Manufacturing Method> Mixture of (1) to (8) (oil phase)
And the mixed liquid (aqueous phase) of (9) to (11) is heated to be uniformly dissolved and kept at 80 ° C. The water phase is added to the oil phase with thorough stirring to emulsify and then cooled to 30 ° C.

(Example 10) (1) Sorbitan monooleate 1.0% (2) Octyldodecyl myristate 10.0% (3) Olive oil 10.0% (4) Squalane 10.0% (5) Pyridoxine di Caprylate 0.2% (6) Kojic acid-N-acetyl tranexamic acid ester 3.0% (7) UV absorber proper amount (8) Preservative proper amount (9) Antioxidant proper amount (10) Liquid paraffin remaining amount

<Manufacturing Method> Components other than liquid paraffin are mixed and heated to 80 ° C. to dissolve and homogenize. Liquid paraffin is added to this mixture and cooled to 40 ° C.

[0068]

INDUSTRIAL APPLICABILITY The ester form of kojic acid and tranexamic acid or N-protected tranexamic acid of the present invention or a salt thereof has a high inhibitory effect on tyrosinase activity, an excellent whitening effect, and is chemically stable.

Further, the external preparation for skin containing this compound has an excellent whitening effect, does not cause color change over time, and has excellent stability.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 31/35 AED A61K 31/35 AED C12N 9/99 C12N 9/99

Claims (2)

[Claims] 1. The following formula: An ester of kojic acid and tranexamic acid or N-protected tranexamic acid represented by the formula (wherein X represents a hydrogen atom or an amino-protecting group) or a salt thereof. 2. The following formula: (Wherein, X represents a hydrogen atom or an amino-protecting group), at least selected from an ester of kojic acid and tranexamic acid, an ester of kojic acid and N-protected tranexamic acid, and salts thereof. A skin external preparation containing one or more compounds.