KR20130025768A - New kojic acid derivatives as skin whitening agent - Google Patents

Abstract

PURPOSE: A novel kojic acid derivative with a skin whitening effect is provided to suppress pigmentation. CONSTITUTION: A novel kojic acid derivative with a skin whitening effect contains a kojic acid derivative of chemical formula 1 or an isomer, a pharmaceutically acceptable salt, a prodrug, a hydrate, or a solvate thereof. In chemical formula 1, R1 is -CH2- or -CH2CH2-; R2 is -CH2OC(O)- or -CH2OC(O)CH=CH-; and n is 1, 2, or 3.

Description

New kojic acid derivatives as skin whitening agent}

The present invention relates to a novel kojic acid derivative exhibiting a skin lightening effect.

Melanin protects skin organs under the dermis by blocking UV rays in the epidermal layer and protects the skin by absorbing free radicals. In addition, melanin is a major factor in determining the color of the skin, and when present in excess, it is also a cause of skin pigmentation such as spots, freckles and spots.

Melanin is made from melanocytes present in the basal layer of the skin, and it is known that the production is promoted by stimulation such as ultraviolet rays or inflammation. Therefore, the production of melanin may be reduced by reducing external stimuli and blocking signal transduction, or inhibiting the synthesis or activity of melanin-producing enzyme tyrosinase.

Kojic acid is known to exert a skin whitening effect by promoting the degradation of tyrosinase or regulating melanin by regulating glycation. However, there is a need for a material having better skin whitening effect, human safety, and formulation stability, and research on a new material having skin whitening effect based on kojic acid continues.

Rho et al., Bull. Korean Chem. Soc. 2007, 28, 471. Kang et al., Chem. Pharm. Bull. 2003, 51, 1085.

The present invention seeks to provide kojic acid derivatives, isomers thereof, pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates thereof or solvates thereof.

The present invention aims to provide a composition for skin whitening comprising the kojic acid derivative, isomer thereof, pharmaceutically acceptable salt thereof, prodrug thereof, hydrate thereof or solvate thereof as an active ingredient.

The present invention also provides a method for preparing the kojic acid derivatives, isomers thereof, pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates thereof or solvates thereof.

One aspect of the present invention provides a kojic acid derivative of Formula 1 below, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof.

In Formula 1, R ₁ is -CH ₂ -or -CH ₂ CH _2- , R ₂ is -CH ₂ OC (O)-or -CH ₂ OC (O) CH = CH-, n is 1, 2 Or an integer of 3.

Another aspect of the present invention provides a composition for skin whitening comprising the kojic acid derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof as an active ingredient.

Another aspect of the present invention is halogenated kojic acid in which the hydroxy group of the hydroxy methyl group of the kojic acid 2-position is substituted with a halogen element; And a method for preparing the kojic acid derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof, comprising reacting a benzoate or cinnamic acid salt.

Kojic acid derivatives, isomers thereof, pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates thereof or solvates thereof according to an aspect of the present invention have excellent skin lightening effect by inhibiting pigmentation.

The present inventors completed the present invention by synthesizing kojic acid derivatives and finding that the kojic acid derivatives can inhibit pigmentation.

As used herein, the term "skin" refers to a tissue covering the body surface of an animal, and is a concept of the broadest notion including a scalp and hair as well as a tissue covering a body surface such as a face or a body.

As used herein, “isomers” in particular are not only optical isomers (eg, essentially pure enantiomers, essentially pure diastereomers or mixtures thereof), but also form isomers ( conformation isomers (ie, isomers that differ only by their angles of one or more chemical bonds), position isomers (especially tautomers) or geometric isomers (eg, cis-trans isomers) do.

As used herein, "essentially pure" means at least about 90%, preferably at least about 95%, of a specific compound, for example enantiomers or diastereomers, when used in connection with an enantiomer or diastereomer. More preferably at least about 97% or at least about 98%, even more preferably at least about 99%, even more preferably at least about 99.5% (w / w).

As used herein, "pharmaceutically acceptable" means the approval of a government or equivalent regulatory body to use in animals, more specifically in humans, by avoiding significant toxic effects when used in conventional medicinal dosages. Received, approved, or listed in a pharmacopoeia or recognized as another general pharmacopeia.

As used herein, "pharmaceutically acceptable salt" means a salt according to one aspect of the present invention which is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound. The salt is formed from (1) an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or the like; Or acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4-hydroxybenzoyl) Benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2,2,2] -oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tert Acid addition salts formed with organic acids such as butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid; Or (2) salts formed when the acidic proton present in the parent compound is substituted.

As used herein, the term "prodrug" refers to a drug that modulates physical and chemical properties by chemically changing a drug, and itself does not exhibit physiological activity, but is originally produced by the action of a chemical or enzyme in the body after administration. The drug can be turned into a drug.

As used herein, “hydrate” refers to a compound to which water is bound, and is a broad concept including an inclusion compound having no chemical bonding force between water and the compound.

As used herein, "solvate" means a higher order compound produced between molecules or ions of a solute and molecules or ions of a solvent.

In an aspect of the present invention, in Chemical Formula 1, R ₁ is -CH ₂ -or -CH ₂ CH _2- , and R ₂ is -CH ₂ OC (O)-or -CH ₂ OC (O) CH = CH-. , n is an integer of 1, 2 or 3 to provide a kojic acid derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof. In another aspect of the present invention, in Chemical Formula 1, R ₁ is -CH _2- , R ₂ is -CH ₂ OC (O) CH = CH-, n is 1, a kojic acid derivative, an isomer thereof, and a pharmaceutical thereof. To an acceptable salt, prodrug thereof, hydrate thereof or solvate thereof.

One aspect of the present invention provides a composition for skin whitening comprising the kojic acid derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof as an active ingredient. Since the kojic acid derivatives, isomers thereof, pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates thereof or solvates thereof have excellent effects of inhibiting pigmentation, the composition may have an excellent skin lightening effect.

The composition according to one aspect of the present invention is 0.001% to 20% by weight, specifically 0.01% to 10% by weight, more specifically 0.1% to 5% by weight of the kojic acid derivative, based on the total weight of the composition Isomers, pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates thereof, or solvates thereof. When included in the above range is not only suitable for showing the intended effect of the present invention, it can satisfy both the stability and safety of the composition, it may be appropriate to include in the above range in terms of cost-effectiveness. Specifically, when the kojic acid derivatives, isomers thereof, pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates thereof or solvates thereof are less than 0.001% by weight, sufficient skin lightening effects may not be obtained, and more than 20% by weight. Safety and formulation stability can be lowered.

One aspect of the present invention provides a cosmetic composition for skin whitening comprising the kojic acid derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof as an active ingredient. The composition may exhibit an excellent skin whitening effect, and specifically may prevent or improve skin pigmentation such as spots, freckles, and spots.

Cosmetic compositions according to the invention may be provided in all formulations suitable for topical application. For example, it may be provided in the form of a solution, an emulsion obtained by dispersing an oil phase in an aqueous phase, an emulsion obtained by dispersing an aqueous phase in an oil phase, a suspension, a solid, a gel, a powder, a paste, a foam, or an aerosol composition. Compositions of such formulations may be prepared according to conventional methods in the art.

The cosmetic composition according to the present invention may include other ingredients in addition to the above-mentioned substances within the range not impairing the main effect, preferably giving a synergistic effect to the main effect. Specifically, arbutin and ascorbic acid derivatives may further include a skin whitening effect of the cosmetic composition according to the present invention. In addition, the cosmetic composition according to the present invention may further include a moisturizer, an emulsifier, a surfactant, a ultraviolet absorber, a preservative, a fungicide, an antioxidant, a pH adjuster, an organic and an inorganic pigment, a flavoring agent, a cooling agent or a restriction agent. have. The blending amount of the above components can be easily selected by those skilled in the art within the range that does not impair the object and effect of the present invention, the blending amount may be 0.01 to 5% by weight, specifically 0.01 to 3% by weight based on the total weight of the composition. have.

Another aspect of the present invention provides a pharmaceutical composition comprising the kojic acid derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof as an active ingredient. The pharmaceutical composition may exhibit an excellent skin whitening effect, and specifically may improve or treat blemishes, freckles, moles, and skin pigmentation.

The pharmaceutical composition according to one aspect of the present invention may be administered orally, parenterally, rectally, topically, transdermally, intravenously, intramuscularly, intraperitoneally, subcutaneously, and the like. Formulations for oral administration may be tablets, pills, soft and hard capsules, granules, powders, granules, solutions, emulsions or pellets, but are not limited thereto. It is not. Formulations for parenteral administration may be, but are not limited to, solutions, suspensions, emulsions, gels, injections, drops, suppositories, patches or spray formers. The formulations may be readily prepared according to conventional methods in the art and may be prepared by conventional means including, but not limited to, surfactants, excipients, wetting agents, emulsifying accelerators, suspending agents, salts or buffers for controlling osmotic pressure, colorants, spices, stabilizers, preservatives, Other commonly used adjuvants may be used.

The active ingredient of the pharmaceutical composition according to one aspect of the present invention will vary depending on the age, sex, weight, pathology and severity of the subject to be administered, the route of administration or the judgment of the prescriber. Dosage determination based on these factors is within the level of one skilled in the art and its daily dosage may be, for example, from 0.1 mg / kg / day to 100 mg / kg / day, more specifically from 5 mg / kg / day to 50 mg / kg. May be, but is not limited to.

One aspect of the present invention is a halogenated kojic acid in which the hydroxy group of the hydroxy methyl group of the kojic acid 2-position is substituted with a halogen element; And it provides a method for producing the kojic acid derivatives, isomers thereof, pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates or solvates thereof comprising the step of reacting benzoate or cinnamic acid salt.

In one aspect of the invention, the halogen of the halogenated kojic acid includes at least one selected from the group consisting of fluorine, bromine, chlorine and iodine.

In one aspect of the invention, the benzoate or cinnamic acid salts include derivatives of benzoates or cinnamic acid salts, specifically salts of 3,4- (methylenedioxy) -benzoic acid, 3,4- (ethylenedioxy) At least one selected from the group consisting of a salt of benzoic acid, a salt of 3,4- (methylenedioxy) -cinnamic acid and a salt of 3,4- (ethylenedioxy) -cinnamic acid. In another aspect of the present invention, the salt of benzoate or cinnamic acid salt includes a metal salt, and specifically includes one or more selected from the group consisting of potassium, sodium, lithium and cesium.

Hereinafter, the configuration and effects of the present invention will be described in more detail with reference to Examples and Experimental Examples. However, these are provided only for the purpose of illustration to help the understanding of the present invention, but the scope and scope of the present invention is not limited thereto.

EXAMPLES Preparation of Kojic Acid Derivatives

Halogenated kojic acid and cinnamic acid metal salts, specifically, kojyl chloride and potassium salts of 3,4- (methylenedioxy) -cinnamic acid (3,4- (methylenedioxy) -cinnamic acid) are reacted according to the present invention. Kojic acid derivatives were prepared. Specific mechanism and reaction scheme is as follows.

First, a proton exchange takes place between the cozyl chloride (1) and the potassium salt of cinnamic acid (2). Then, nucleophilic addition occurs from the potassium salt of cinnamon to the potassium salt of cosyl chloride (3). Compound (4) produced through such a reaction again undergoes a nucleophilic addition reaction with cosyl chloride to produce a kojic acid derivative (5) according to the present invention.

[Reaction Scheme 1]

NMR data of the obtained compound 5 is as follows.

¹ H NMR (300MHz, DMSO-d ₆ ): d 9.21 (s, 1H), 8.34 (s, 1H), 8.09 (s, 1H), 7.68 (d, 1H, J = 15.9 Hz), 7.44 (s, 1H), 7.25 (d, 1H, J = 8.0 Hz), 6.97 (d, 1H, J = 7.9 Hz), 6.62 (d, 1H, J = 15.9 Hz), 6.55 (s, 1H), 6.51 (s, 1H), 6.08 (s, 2H), 5.08 (s, 2H), 4.88 (s, 2H). ¹³ C-NMR (125 MHz, DMSO-d ₆ ): δ 173.5, 172.7, 165.6, 162.1, 161.4, 149.5, 148.0. 146.1, 145.9, 145.7, 143.3, 139.9, 128.2, 125.3, 114.5, 114.1, 112.8, 108.4, 106.7, 101.5, 67.0, 61.0.

Experimental Example Evaluation of Pigmentation Inhibition Effect

For kojic acid and kojic acid derivatives of compound 5 obtained in the above examples, the pigmentation inhibitory effect was evaluated using conventional methods in the art with B16 melanoma cell lines. The results are shown in the table below.

sample Pigmentation IC ₅₀ Kojic acid 1.80 mM Compound 5 45.23 μM

As can be seen from the above results, the inhibitory effect of pigmentation of kojic acid derivatives according to the present invention is very excellent, which is also an excellent effect compared to kojic acid known to have a conventional skin whitening effect. Therefore, it can be seen that the kojic acid derivative according to the present invention has an excellent skin whitening effect.

Formulation examples of compositions according to one aspect of the present invention are described below, but may be applied to various other formulations, which are not intended to be limiting but merely illustrative of the invention.

[Formulation Example 1] Lotion

The lotion is prepared according to a conventional method with the composition described in the table below.

ingredient Content (% by weight) Example 2.0 glycerin 3.0 Butylene glycol 2.0 Propylene glycol 2.0 Carboxyvinyl polymer 0.1 PEG 12 nonyl phenyl ether 0.2 Polysorbate 80 0.4 ethanol 10.0 Triethanolamine 0.1 Preservative, coloring, fragrance Suitable amount Purified water Balance

Formulation Example 2 Cream

A cream is prepared according to a conventional method with the composition described in the table below.

ingredient Content (% by weight) Example 2.0 Polysorbate 60 1.5 Sorbitan sesquioleate 0.5 PEG 60 hardened castor oil 2.0 Liquid paraffin 10.0 Squalane 5.0 Caprylic / caproic triglyceride 5.0 glycerin 5.0 Butylene glycol 3.0 Propylene glycol 3.0 Triethanolamine 0.2 Preservative, coloring, fragrance Suitable amount Purified water Balance

Formulation Example 3 Gel

The gel is prepared according to a conventional method with the composition shown in the following table.

ingredient Content (% by weight) Example 0.5 Ethylenediamine sodium acetate 0.05 glycerin 5.0 Carboxyvinyl polymer 0.3 ethanol 5.0 PEG 60 hardened castor oil 0.5 Triethanolamine 0.3 Preservative, coloring, fragrance Suitable amount Purified water Balance

Formulation Example 4 Ointment

Ointments are prepared by conventional methods in the compositions described in the table below.

ingredient Content (% by weight) Example 0.1 glycerin 8.0 Butylene glycol 4.0 Liquid paraffin 15.0 Beta Glucan 7.0 Carbomer 0.1 Caprylic / Capric Triglycerides 3.0 Squalane 1.0 Cetearyl Glucoside 1.5 Sorbitan stearate 0.4 Cetearyl Alcohol 1.0 Wax 4.0 Preservative, coloring, fragrance Suitable amount Purified water Balance

Claims (10)

Kojic acid derivatives of Formula 1, isomers thereof, pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates thereof or solvates thereof:
[Formula 1]

In Formula 1, R ₁ is -CH ₂ -or -CH ₂ CH _2- , R ₂ is -CH ₂ OC (O)-or -CH ₂ OC (O) CH = CH-, n is 1, 2 Or an integer of 3.
The method of claim 1,
R ₁ in formula 1 is —CH ₂ —, R ₂ is —CH ₂ OC (O) CH═CH—, n is 1, an isomer thereof, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof , Hydrates thereof or solvates thereof.
A composition for skin whitening comprising the kojic acid derivative according to claim 1, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof or a solvate thereof as an active ingredient.
The method of claim 3, wherein
The composition comprises a kojic acid derivative, an isomer thereof, a pharmaceutically acceptable salt thereof, a prodrug thereof, a hydrate thereof, or a solvate thereof in an amount of 0.001 to 20% by weight based on the total weight of the composition.
The method of claim 3, wherein
The composition is a composition for skin whitening that inhibits pigmentation.
The method of claim 3, wherein
The composition is a cosmetic composition for skin whitening.
The method of claim 3, wherein
The composition is a pharmaceutical composition for skin whitening.
Halogenated kojic acid in which the hydroxy group of the hydroxy methyl group in the kojic acid 2-position is substituted with a halogen element; And
A process for preparing the kojic acid derivative according to claim 1 or 2, isomers thereof, pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates thereof or solvates thereof, comprising reacting a benzoate or cinnamate.
The method of claim 8,
Halogen of halogenated kojic acid comprises at least one selected from the group consisting of fluorine, bromine, chlorine and iodine.
The method of claim 8,
Salt of benzoate or cinnamate salt comprises at least one selected from the group consisting of potassium, sodium, lithium and cesium.