JPH06100433A - Tyrosinase activity inhibitor - Google Patents

Abstract

(57) [Summary] (Corrected) [Configuration] The following formula [In the formula, R ₁ , R ₃ and R ₄ are hydrogen atoms or have 1 to 9 carbon atoms.
R ₂ is an alkyl group or an alkenyl group having 2 to 9 carbon atoms. ] The tyrosinase activity inhibitor which has a structure shown by these. [Effect] The above compound is a tyrosinase activity inhibitor that has a high tyrosinase activity inhibitory effect, is chemically stable, and has low toxicity.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a tyrosinase activity inhibitor useful as a skin whitening cosmetic, an antifouling substance for ship bottom paints, and an inhibitor of melanin production by insects and the like.

[0002]

2. Description of the Related Art Several phenolic compounds have been conventionally known as tyrosinase activity inhibitors, and some of them are used for applications such as skin whitening cosmetics. However, many of these have problems in safety, chemical stability, and efficacy for the human body.

At present, hydroquinones and resorcinols having a long-chain alkyl group at the 4-position are known as tyrosinase activity inhibitors.
61-21007, 61-21008, 61-21009, 61-21010
No. 61-21011 and 61-21012 and the like, the tyrosinase activity inhibition mode of hydroquinone is a non-antagonist, from the viewpoint of homeostasis in vivo, there is concern about toxicity to the body. It Further, the resorcinol-type tyrosinase activity inhibitor described in JP-A-3-28462 is 4
Since the alkyl chain at the position is long, it has poor solubility in water,
It cannot be used well in ordinary cosmetics. And
The conventionally used arbutin is toxic. Further, tranexamic acid described in JP-A-4-169515 has a problem that the tyrosinase activity inhibitory effect is low.

[0004]

SUMMARY OF THE INVENTION The present invention is intended to solve the above-mentioned conventional problems, and its object is to:
The object is to obtain a tyrosinase activity inhibitor that has a high tyrosinase activity inhibitory effect, is chemically stable, and has low toxicity.

[0005]

The present invention is based on the formula

[0006]

[Chemical 4]

[In the formula, R ₁ , R ₃ and R ₄ are a hydrogen atom or an alkyl group or alkenyl group having 1 to 9 carbon atoms, and R ₂ is an alkyl group or alkenyl group having 2 to 9 carbon atoms. ] To provide a tyrosinase activity inhibitor having a structure shown by the above, by which the above object is achieved.

[0008] Preferably, the tyrosinase activity inhibitor of the present invention is at least one selected from the group of compounds represented by formula (III), and more preferably:

[0009]

[Chemical 5]

It is a tyrosinase activity inhibitor having a structure represented by:

The method for obtaining the compound having the structure represented by the above formulas (I), (II) and (III) is not particularly limited. These compounds may be synthesized by methods well known to those skilled in the art. For example, they can be synthesized by the following methods.

Method for producing (I) First, 2,4-dihydroxyalkylphenone is obtained by reacting an alkylcarboxylic acid with resorcinol. Next, this is reduced with zinc amalgam obtained from zinc and mercuric chloride to obtain 4-alkylresorcinol.

Method for producing (II) First, by reacting 1,3-dimethoxy-5-benzoyl chloride with alkylmagnesium bromide
1,3-dimethoxy-alkylphenone is obtained. It is then reduced with zinc amalgam obtained from zinc and mercuric chloride. Further, the reaction is promoted by adding 10 to 15 cc of concentrated hydrochloric acid every hour. After completion of the reaction, the mixture is cooled and purified by a known method to give 5-alkylresorcinol.

Method for producing (III) First, 6,3-dimethoxy-5-alkylbenzene, phenoxyacetyl chloride and aluminum chloride are reacted to give 6,6'-dialkyl-2,2 ', 4,4'-tetra. Obtain methoxydiphenylmethane. By hydrolyzing this by a known method, 6,6'-dialkyl-2,2 ', 4,4'-tetrahydroxydiphenylmethane is obtained.

When the tyrosinase activity inhibitor of the present invention is used in cosmetics, at least one compound represented by the formulas (I), (II) and (III) is selected and mixed, and often used in cosmetics. Bases (for example oils and fats such as olive oil and mink oil, waxes such as lanolin and beeswax,
Hydrocarbons such as petrolatum and squalane, esters such as isopropyl palmitate, higher alcohols such as cetyl alcohol and lauryl alcohol, higher fatty acids such as stearic acid and palmitic acid, sterols such as cholesterol) And various cosmetics dissolved or dispersed in alcohols (for example, ethanol, isopropyl alcohol and propylene glycol) and the like (for example, cream, emulsion, lotion, various basic cosmetics such as packs and face wash,
Widely applicable to various makeup products such as foundations, blushers, blushers and lipsticks, and soaps, shampoos, rinses, perfumes and colognes and other cosmetics. In this case, various cosmetic additives (for example, various surfactants, solvents, dyes, fragrances,
Antiseptics, antioxidants, moisturizers, vitamins and animal and plant extracts and other additives). The various cosmetics can be applied in various shapes such as solution, emulsion, ointment, oil, wax, gel, sol, powder and spray.

The blending amount of the tyrosinase activity inhibitor in various cosmetics can be appropriately selected and changed depending on the usage form. In principle, an effective amount should be present.
Generally from 0.001 to 20 in cosmetic composition (based on total weight)
It is preferable to add the composition in an amount of 0.01% by weight, preferably 0.01-5% by weight.

The tyrosinase activity inhibitor of the present invention has low toxicity and irritation to the skin, high stability to light and heat, and high stability to various cosmetic bases and additives. It can be used in combination with materials and additives.

[0018]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

[0019]

[Synthesis Example 1] Synthesis of 4- ethylresorcinol 151 g of zinc chloride was dissolved in 162 g of butyric acid. Next, 110 g of resorcinol was added and reacted at 150 ° C. for 20 minutes. After reaction 2
After adding 50 ml of concentrated hydrochloric acid and 250 ml of water, cooling and purifying by a conventional method, compound 2,4-dihydroxyethylphenone 100 g
Got Next, add 300 cc of water, 300 cc of concentrated hydrochloric acid and 100 g of zinc amalgam obtained from 400 g of zinc and 20 g of mercuric chloride.
2,4-dihydroxyethylphenone was added and reduced. Further, 10 to 15 cc of concentrated hydrochloric acid was added every hour. After completion of the reaction and cooling, the reaction solution was saturated with sodium chloride and extracted with ether to obtain 88 g of 4-ethylresorcinol.

[0020]

[Synthesis Example 2] Synthesis of 5-methylresorcinol 45% was obtained by adding 35 g of methylmagnesium bromide to 100 g of 1,3-dimethoxy-5-benzoyl chloride.
The yield of 1,3-dimethoxy-methylphenone was obtained. Then 4
To zinc amalgam obtained from 00 g of zinc and 20 g of mercuric chloride, 300 cc of water, 300 cc of concentrated hydrochloric acid and 100 g of 1,3-dimethoxy-methylphenone were added and reduced. An additional 10 to 15c
Concentrated hydrochloric acid from c was added every hour. After completion of the reaction and cooling, the reaction solution was saturated with sodium chloride and extracted with ether to obtain 40 g of 1,3-dimethoxy-5-methylbenzene. Hydrogen iodide was added to the obtained 1,3-dimethoxy-5-methylbenzene and the mixture was stirred under nitrogen substitution at 115 to 125 ° C. for 3 hours, cooled and extracted with methylene chloride to obtain 30 g of 5-methylresorcinol. It was

[0021]

[Synthesis Example 3] 6,6'-di-n-propyl-2,2 ', 4,4'-tetrahydroxydi
Synthesis of Phenylmethane To 70 ml of benzene, 11 g of 1,3-dimethoxy-5-propylbenzene, 11 g of phenoxyacetyl chloride and 9 g of aluminum chloride were added, and the mixture was stirred at 5 ° C for 1.5 hours.
Hydrolyzed with hydrochloric acid under ice cooling, extracted with ether, 6,6'-
0.3 g of di-n-propyl-2,2 ', 3,3'-tetramethoxydiphenylmethane was obtained. The resulting 6,6'-di-n-propyl-2,2 ', 4,
Hydrogen iodide was added to 4'-tetramethoxydiphenylmethane, and the mixture was stirred at 115 to 125 ° C for 3 hours, cooled, extracted with methylene chloride, and 0.3 g of 6,6'-di-n-propyl-2,2 ', 4,4'-Tetrahydroxydiphenylmethane was obtained. The ¹ H-NMR and ¹³ C-NMR charts of the obtained compound are shown in FIGS. 1 and 2, respectively.

[0022]

EXAMPLES Tyrosinase activity inhibitors obtained in Synthesis Examples 1 to 3 and
Others shown in Table 2 obtained in the same manner as in Synthesis Examples 1 to 3
Inhibitors (within and outside the claims (control)
Compound) The measurement of tyrosinase activity inhibition rate was performed by the following method. (1) Reaction system reagents The following were used as the reaction system reagents. Substrate: 2mM L-DOPA (Wako Pure Chemicals) Buffer: 0.1M Phosphate-potassium (pH6.8) solution Inhibitor: Compound of formula (I), 4-ethylresorcinol; Formula (II) Compound, 5-methylresorcinol;
A compound represented by the formula (III), 6,6'-di-n-propyl-2,2 ',-
4,4'-Tetrahydroxydiphenylmethane; 1% each solution Enzyme: Tyrosinase (Sigma) 0.5 mg / ml

(2) Measurement of tyrosinase activity inhibition rate Preparation of reaction solution When measuring tyrosinase activity, sample solutions No. 1, No. 2 and No. 3 mixed at the ratios shown in the following Table 1 were spectroscopically analyzed. Prepared in a photometer cell (1 ml).

[Table 1] Add the enzyme solution (0.20 ml) to the measuring cell, and 3 minutes after the addition
Absorbance at 471 nm was measured with a spectrophotometer over time. No.2
Absorbance of No.3 (Ab.2) at the time of maximum value (Ab.2)
b.3) and No. 1 absorbance (Ab.1) were applied to the following formula to calculate the inhibition rate. IC ₅₀ (Tyrosinase activity inhibition rate 50%
Table 2 shows the tyrosinase activity inhibitor concentration at that time. Inhibition rate (%) = {1- (Ab.3-Ab.1 / Ab.2-Ab.1)} × 100

[Table 2]

[0024]

The present invention provides a tyrosinase activity inhibitor which has a high tyrosinase activity inhibitory effect, is chemically stable, and has low toxicity.

[Brief description of drawings]

FIG. 1 is a ¹ H-NMR chart of the compound obtained in Synthesis Example 3.

FIG. 2 is a ¹³ C-NMR chart of the compound obtained in Synthesis Example 3.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location // A23K 1/16 301 B 9123-2B (72) Inventor ▲ Takahashi Kunio Urawa City, Saitama Prefecture Hota 2-23-6 (72) Inventor Kiyotaka Koyama 4-2-24 Chuo-cho, Higashi-Kurume City, Tokyo (72) Inventor Kaoru Kinoshita 1-11-22-201 Gakuen-cho, Higashi-Kurume City, Tokyo

Claims (5)

[Claims] 1. The formula: [In the formula, R ₁ is a hydrogen atom or an alkyl group or an alkenyl group having 1 to 9 carbon atoms. ] The tyrosinase activity inhibitor which has a structure shown by these. 2. The formula: [In the formula, R ₂ is an alkyl group or an alkenyl group having ₂ to 9 carbon atoms. ] The tyrosinase activity inhibitor which has a structure shown by these. 3. The formula: [Wherein, R ₃ and R ₄ are a hydrogen atom or an alkyl group or an alkenyl group having 1 to 9 carbon atoms. ]
A tyrosinase activity inhibitor having the structure shown in. 4. The tyrosinase activity inhibitor according to claim 3, wherein R ₃ and R ₄ are propyl groups. 5. 6,6′-Di-n-propyl-2,2′4,4′-tetrahydrodiphenylmethane.