JPH05222015A - Thiazole-analogous compound and skin external agent - Google Patents

Abstract

PURPOSE:To provide a new thiazole-analogous compound used as a tyrosinase activity-inhibiting agent giving a large effect to the biosynthesis of melanine or as an active ingredient for skin external agents, especially beautifully whitening cosmetics. CONSTITUTION:A thiazole-analogous compound of formula I (the ring X is not substituted or is substituted with a group of formula V or VI; R1, R2 are H, halogen, lower alkyl, lower alkoxy; Y is amino residue, group of formula VII; n is an integer of 0-5; A is O, S, NH; R3 is OH, group of formula VIII; R4, R5 are H, lower alkyl), e.g. 2-8beta-methylpropionyl)aminothiazole. The compound of formula I-a (B is lower alkyl having a SH) among the compound can be produced by reacting a compound of formula II and a compound of formula III (R7 is the protecting group of the SH; B1 is the SH-removed residue from B) with a coupling reagent in an inert solvent and subsequently removing the protecting group from the obtained compound of formula IV. An skin external agent containing the compound as an active ingredient has actions to prevent and improve the blacking of skin, the generation of stains or freckles in the skin and is useful as a beautifully whitening agent.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel thiazole analog compound. Further, it relates to a tyrosinase activity inhibitor and a skin external preparation as a whitening cosmetic.

[0002]

2. Description of the Related Art There is a great interest in substances having a whitening effect on the skin and external preparations for skin prepared by blending them, and kojic acid (Japanese Patent Publication No. 61-10447) has hitherto been known. Kojic acid derivatives (JP-A-56-7710), hydrogen peroxide, ascorbic acid, glutathione, colloidal sulfur and the like are known as active ingredients, and they are commonly used as external skin preparations for the purpose of whitening effect. ..
However, no research has been conducted on the whitening effect of the thiazole-related compounds provided by the present invention.

[0003]

Melanin present in human skin originally plays an important role of protecting the body from the harmful effects of ultraviolet rays, and is a very important factor both medically and cosmetically. Theoretically, the biosynthesis of melanin is changed into dopa and then dopaquinone by the action of tyrosinase in pigment cells in skin tissue,
It is supposed to be carried out via 5,6-dihydroxyindole or the like. Excessive amount of melanin biosynthesized in such a process is called dark black, and its uneven distribution is called spots or freckles, both of which are said to be cosmetic defects. .. Therefore, the present invention aims to provide a synthesis of an inhibitor against tyrosinase, which has a great influence on the biosynthesis of melanin, that is, a synthesis of thiazole analog compounds, and an external preparation for skin as a whitening cosmetic containing these compounds as active ingredients. And

[0004]

The present invention has the following general formula (I):

[Chemical 1] [Wherein, ring X is unsubstituted, or

[Chemical 2] (In the formula, R ₁ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group.), Or

[Chemical 3] (Wherein R ₂ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom), Y is an amino residue, or

[Chemical 4] (In the formula, n is an integer of 0 to 5, A is O, S or NH,
R ₃ is OH or

[Chemical 5] (Wherein, R ₄ represents a hydrogen atom or a lower alkyl group, R ₅
Means a hydrogen atom or a lower alkyl group. ] To a novel thiazole-related compound and a skin external preparation as a whitening cosmetic containing them.

The above general formula (I) will be described more specifically. The lower alkyl groups of R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are methyl, ethyl, n-propyl, iso-propyl and n-. A linear or branched alkyl group such as butyl, iso-butyl, tert-butyl, etc., and a lower alkoxy group for R ₁ , R ₂ and R ₅ is methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy. , Ter
a linear or branched alkoxy group such as t-butoxy,
The halogen atom of R ₁ and R _{2 is} a halogen atom such as fluorine, chlorine, bromine or iodine, and the amino group of Y is methylamino group, ethylamino group, n-propylamino group, iso-
Alkylamino group such as propylamino group, n-butylamino group, iso-butylamino group, cyclopropylamino group, cyclopropylmethylamino group, cyclobutylamino group, cyclobutylmethylamino group, cyclopentylamino group, cyclopentylmethylamino Group, cyclohexylamino group, alicyclic amino group such as cyclohexylmethylamino group, —NH (CH ₂ ) m—R ₆ (where m is 0
An integer of 6 to 6, R ₆ is a lower alkoxy group, a lower alkylamino group, a piperidino group, a pyrrolidino group, a morpholino group,
It means a cyclic amino group such as a piperazino group. ) Substituted alkylamino group, aromatic secondary amines such as N-methylaniline, unsubstituted or substituted pyridylamino group, pyridylmethylamino group, pyridylamino group, heterocyclic amino group such as thiazolylamino group, piperidino group, pyrrolidino Group, morpholino group, N-methylpiperazino group, cyclic amino group such as N-benzylpiperazino group or -NHCO-B
(In the formula, B is mercaptomethyl, α-mercaptoethyl, β-mercaptoethyl, α-mercaptopropyl,
β-mercaptopropyl, γ-mercaptopropyl, α
-A lower alkyl group having a mercapto group such as mercaptobutyl, β-mercaptobutyl, γ-mercaptobutyl and δ-mercaptobutyl. ) Means.
Incidentally, the compound of the present invention is an inorganic salt (for example, hydrochloride, nitrate, sulfate, phosphate, etc.) or organic salt (for example, fumarate, maleate, succinate, lactate, etc.) as necessary.
It is possible to form addition salts such as citrates, lysine salts, etc.).

The thiazole analog compound of the present invention is used as an active ingredient in medicines, quasi drugs, cosmetics and the like, and the formulation of these compounds can be appropriately performed according to well-known or known methods. As the external preparation for skin of the present invention, in addition to the above active ingredients, usual pharmaceuticals, raw materials used for quasi drugs or cosmetics, for example, surfactants, oils, alcohols, humectants, thickeners, preservatives, Antioxidants, chelates, agent pH adjusters, fragrances, dyes, UV absorbers / scatterers, vitamins, amino acids, water and the like can be added.

Specifically, the surfactants include lipophilic glycerin monostearate, self-emulsifying glycerin monostearate, polyglycerin monostearate, sorbitan monooleate, polyethylene glycol monostearate, polyoxyethylene sorbitan. Monooleate, polyoxyethylene cetyl ether, polyoxyethylenated sterol, polyoxyethylenated lanolin,
Polyoxyethylenated beeswax, nonionic surfactant such as polyoxyethylene hydrogenated castor oil, sodium stearate, potassium palmitate, sodium cetyl sulfate, sodium lauryl phosphate, triethanolamine palmitate, sodium polyoxyethylene lauryl phosphate, Examples thereof include anionic surfactants such as sodium N-acylglutamines, cationic surfactants such as stearyldimethylbenzylammonium chloride and stearyltrimethylammonium chloride, and amphoteric surfactants such as alkylaminoethylglycine hydrochloride liquid and lecithin. it can.

As the oil component, castor oil, olive oil, cacao butter, camellia oil, coconut oil, wood wax, jojoba oil, grape seed oil, vegetable oils such as avocado oil, animal oils such as mink oil and egg yolk oil, and beeswax. Wax such as whale wax, lanolin, carnauba wax, candelilla wax, liquid paraffin, squalane, microcrystalline wax, ceresin wax, paraffin wax, hydrocarbons such as petrolatum, lauric acid, myristic acid, stearic acid, oleic acid, Natural and synthetic fatty acids such as isostearic acid and behenic acid, natural and synthetic higher alcohols such as cetanol, stearyl alcohol, hexyldecanol, octyldodecanol and lauryl alcohol, isopropyl myristate, isopropyl palmitate, octyl myristate. Sill, octyldodecyl oleate, can be exemplified esters such as cholesterol oleate.

Examples of moisturizers include polyhydric alcohols such as glycerin, propylene glycol, 1,3-butylene glycol, sorbitol, polyglycerin, polyethylene glycol and dipropylene glycol, and amino acids such as sodium lactate and sodium pyrrolidonecarboxylate.
Examples thereof include water-soluble polymer substances such as MF component, hyaluronic acid, collagen, mucopolysaccharide, and chondroitin sulfate.

As the thickener, sodium alginate,
Natural polymer substances such as xanthan gum, aluminum silicate, quince seed extract, tragacanth gum, starch, etc., semi-synthetic polymer substances such as methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, soluble starch, cationized cellulose, carboxyvinyl polymer, polyvinyl alcohol, etc. The synthetic polymer substance and the like can be exemplified. Preservatives include benzoate, salicylate, sorbate, dehydroacetate, paraoxybenzoate, 2,4,4'-trichloro-2 '.
-Hydroxydiphenyl ether, 3,4,4'-trichlorocarbanilide, benzalkonium chloride, hinokitiol, resorcin, ethanol and the like can be exemplified.

Antioxidants include dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate, and ascorbic acid, and chelating agents include disodium edetate, ethylenediaminetetraacetate, pyrophosphate, hexametaphosphate, and citrate. Acid, tartaric acid, gluconic acid, etc., sodium hydroxide,
Examples thereof include triethanolamine, citric acid, sodium citrate, boric acid, borax, potassium hydrogen phosphate and the like.

Examples of the ultraviolet absorbing / scattering agent include 2-hydroxy-4-methoxybenzophenone, octyldimethylparaaminobenzoate, ethylhexylparamethoxycinnamate, titanium oxide, kaolin, talc and the like. As vitamins, vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, vitamin F, vitamin K, vitamin P, vitamin U, carnitine, ferulic acid, γ-oryzanol, α-
Examples thereof include lipoic acid, orotic acid and derivatives thereof.

The amino acids include glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan,
Examples thereof include cystine, cysteine, methionine, broline, hydroxybroline, aspartic acid, glutamic acid, arginine, histidine, lysine and their derivatives. The optional components are not limited to these. Various product forms such as lotion, cream, lotion, skin milk, emulsion, pack, ointment, gel, gel cream, pap, stick, spray, powder or soap can be prepared by appropriately blending the above active ingredients and optional ingredients. Can be used as

Next, a method for producing the compound according to the present invention will be described. The compound of the present invention can be produced according to the following methods, but these production methods are merely examples, and naturally, they can be produced by other appropriate similar methods. Manufacturing method 1

[Chemical 6] (In the formula, B has the same meaning as described above, B ₁ means a lower hydrocarbon obtained by removing the mercapto group from B, and R ₇ means a protecting group for the mercapto group.)

The production method 1 will be described in detail. The 2-aminothiazole of the general formula (II) and the general formula (II)
I) (in the formula, R ₇ represents a mercapto-protecting group such as a benzoyl group or a benzyl group, and B ₁ represents a methylene group, an ethylene group, a propylene group, a trimethylene group, etc. obtained by removing the mercapto group from B.) In an inert solvent (for example, chloroform, dichloromethane, tetrahydrofuran, dioxane, dimethylformamide, etc.), an S-protected carboxylic acid derivative represented by
A coupling reagent such as 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline and -50 to 50
The N-alkanoylaminothiazole derivative represented by the general formula (IV) is obtained by reacting at 1 ° C (preferably -20 to 10 ° C) for 1 to 24 hours. The formation of disulfide bonds is suppressed as much as possible, and the deprotection reaction is performed according to a known method.

That is, the target compound represented by the general formula (Ia) can be obtained by debenzoylation with sodium methylate or the like or by catalytic reduction in the presence of palladium carbon or the like. Manufacturing method 2

[Chemical 7] (Wherein R ₁ , R ₃ , n and A have the same meanings as described above, h
al means a halogen atom. The production method 2 will be specifically described. 2-mercaptobenzothiazole represented by the general formula (V) is treated with an alkali metal base (for example, hydroxylation) in an inert solvent (for example, tetrahydrofuran, benzene, acetonitrile, dimethylformamide, etc.). Sodium, sodium hydride, etc.) or an organic base (eg, sodium methylate, butyllithium, 1,8-diazabicyclo [5,4,0] undec-7-ene, etc.) and then treated with a compound of general formula (VI) 30 with compound and 0-150 ℃
The target compound (I-
b) can be obtained.

Manufacturing method 3

[Chemical 8] The 2-aminoindeno [1,2-d] thiazole derivative represented by the general formula (VII) (R ₂ and Y have the same meanings as described above) alone or in a mixed solvent (for example,
Halogenated hydrocarbons such as chloroform and dichloromethane, ethers such as tetrohydrofuran and dioxane,
Polar aprotic solvents such as dimethylformamide and dimethyl sulfoxide, protic solvents such as water, methanol and ethanol, benzene solvents such as benzene, toluene and xylene, mineral acids such as hydrochloric acid, acetic acid, sulfuric acid, nitric acid, ethyl acetate and pyridine. , Acetone, etc.), an oxidizer such as manganese dioxide, potassium permanganate, selenium dioxide, periodate, chromic acid, cobalt oxide, ozone or oxygen is appropriately selected, and the amount is 1 to 50 at 0 to 300 ° C.
By reacting for a time, preferably in the presence of cobalt oxide, in the presence of an air stream, by heating under reflux in dimethylsulfoxide to give a compound of the general formula [Ic] (R ₂ and Y have the same meanings as described above). A 2-aminoindeno [1,2-d] thiazole derivative can be obtained.

[0018]

EXAMPLES The present invention will be described in more detail below with reference to examples, but of course the present invention is not limited to these examples. Example 1 To a solution of 6.3 g of 3-benzoylthiopropionic acid in 100 ml of dichloromethane is added at 0 ° C. a solution of 6.2 g of dicyclohexylcarbodiimide in 20 ml of dichloromethane. Then a solution of 3 g of 2-aminothiazole in 30 ml of dichloromethane is added and stirred for 2 hours. Then, the suspension was filtered, and the filtrate was concentrated and then subjected to column chromatography to obtain 2-[(β
6.8 g of -benzoylthiopropionyl) amino] thiazole were obtained. Melting point 164 to 165 ℃ Elemental analysis value C ₁₃ H ₁₂ N ₂ O ₂ S ₂ 292.37 Theoretical value C: 53.41 H: 4.14 N: 9.58 Calculated value C: 53.40 H: 4.31 N: 9.41 Next, 2-[(β- After adding 6.7 g of benzoylthiopropionyl) amino] thiazole and the equivalent amount of sodium methylate to 200 ml of methanol, the mixture is stirred at room temperature for 2 hours under a nitrogen atmosphere. Then, after adding dilute hydrochloric acid, extraction is performed with dichloromethane. Further, the organic layer was washed with saturated saline and dried with MgSO ₄ , then the solution was concentrated to dryness and recrystallized from dioxane to obtain 2.8 g of colorless 2- (β-mercaptopropionyl) aminothiazole. Melting point 177-180 ° C Elemental analysis C ₆ H ₈ N ₂ OS ₂ 188.26 Theoretical C: 38.28 H: 4.28 N: 14.88 Calculated C: 38.40 H: 4.51 N: 15.01

Example 2 2.5 g of 2-mercaptobenzothiazole was dissolved in 50 ml of dimethylformamide, and then ice-cooled water and 0.72 g of 50% sodium hydride were added. Furthermore, after stirring this mixture at room temperature for 1 hour, p- (4-bromobutoxy)
4.71 g of ethyl phenylacetate was added under ice cooling. The reaction solution was stirred at 80 ° C. for 4 hours, poured into 100 ml of ice water, extracted with 100 ml of ethyl acetate on the second floor and washed with water. The organic layer is dehydrated, the solvent is removed, and then vacuum distillation is performed to
73-178 ° C./0.1 mmHg p- [4- (2-benzothiazolylthio) butoxy] phenyl ethyl acetate 5.3
g (88% yield) was obtained. Here, the vacuum distillation is performed by the glass tube oven GTO manufactured by Shibata Chemical Instrument Co., Ltd.
-250R rotary system is used, and the distillation temperature (boiling point) indicates the column temperature. Next, 0.3 g was added to 5.3 g of the ester compound.
50 ml of aqueous ethanol containing 78 g of potassium hydroxide was added, and the mixture was heated under reflux for 2 hours. After completion of the reaction, the solvent was removed under reduced pressure, 50 ml of water was added and the mixture was washed with 50 ml of ethyl acetate, and then the aqueous layer was acidified. Then, the mixture was extracted with 50 ml of ethyl acetate, washed with water and dried, and the solvent was removed. The residue was recrystallized from ethyl acetate to give p- [4- (2-benzothiazolylthio)
Butoxy] phenylacetic acid (4.1 g, yield 83%) was obtained. Melting point 103.5-104.5 ° C Elemental analysis C ₁₉ H ₁₉ NO ₃ S ₂ 373.48 Theoretical value C: 61.10 H: 5.13 N: 3.75 Calculated value C: 61.24 H: 5.12 N: 3.81

Reference Example 25 g of 2-bromo-6-chloroindanone and 14.7 g of thiocarbamoylpiperidine are added to 500 ml of ethanol and refluxed for 2 hours. The solution is then concentrated under reduced pressure and dichloromethane and Na ₂ CO ₃ aqueous solution are added. Then, the organic layer is separated, dried and the solvent is distilled off to obtain pale purple crystals. This was recrystallized from isopropyl ether to give 23.2 g of 5-chloro-2-piperidino-8H-indeno [1,2-d] thiazole as colorless prism crystals.
was gotten. Melting point 112-113 ° C

Example 3 5-chloro-2-piperidino-8H-indeno [1,2
-D] 20 g of cobalt oxide was added to 250 ml of DMSO solution containing 10 g of thiazole, and the mixture was heated at 140 ° C for 10 hours in an air stream. Then, water and dichloromethane are added to separate the organic layer. The organic layer is washed with saturated saline, concentrated under reduced pressure, and subjected to column chromatography. The fraction eluted from dichloromethane was concentrated and recrystallized from ether to obtain 2.6 g of 5-chloro-2-piperidino-8-oxoindeno [1,2-d] thiazole as red crystals. Melting point 211-215 ° C Elemental analysis C ₁₅ H ₁₃ N ₂ OSCl 304.79 Theoretical C: 59.11 H: 4.30 N: 9.19 Calculated C: 59.40 H: 4.51 N: 9.01

Next, the test method and test data of the compound of the present invention will be shown. Test Example 1 Enzyme Inhibitory Action on Tyrosinase The enzyme inhibiting action of the compound of the present invention was examined using mushroom-derived tyrosinase as an enzyme source. That is, 10
The test compound and enzyme were added to mM dopa and incubated at 37 ° C. After stopping the reaction, the absorbance of the produced reddish purple reaction solution was measured at 490 nm. The results show the inhibition rate from the test compound-free group.

Test Example 1-A Kojic acid 0.1 mM (concentration) 59.8% Compound of Example 1 0.1 mM (concentration) 100%

Test Example 1-B Kojic acid 0.1 mM (concentration) 51.2% Compound of Example 2 0.1 mM (concentration) 100%

Test Example 1-C Kojic acid 0.1 mM (concentration) 49.8% Compound of Example 3 0.1 mM (concentration) 63.0%

Test Example 2 Effect on the amount of melanin in B-16 cells Mouse B-16 melanoma cells were treated with 10% FBS and 90%.
After culturing in Dulbecco's modified Eagle medium containing μg / ml theophylline for 2 days, the test compound was added for 4 days. The day after the final addition, extract melanin by the method of Oikawa et al.
The amount of melanin was measured at 400 nm using an absorptiometer. The results show the inhibition rate per 10 ⁶ cells with the test compound-free group as the control group.

Test Example 2-A Kojic acid 3.0 mM (concentration) 40.0% Compound of Example 1 0.3 mM (concentration) 37.1%

Test Example 2-B Kojic acid 3.0 mM (concentration) 40.0% Compound of Example 2 0.3 mM (concentration) 30.6%

Test Example 2-C Kojic acid 3.0 mM (concentration) 40.0% Compound of Example 3 3.0 mM (concentration) 30.4%

Test Example 3 Safety An acute (single dose) toxicity test in subcutaneous administration in mice was carried out using the up and down method. That is, ddy
After the test substance was subcutaneously administered to the neck of male mice, general symptoms and the presence or absence of death were observed for one week. Compound of Example 1 LD ₅₀ (g / kg)> 1.0 Compound of Example 2 LD ₅₀ (g / kg)> 1.0 Compound of Example 3 LD ₅₀ (g / kg)> 1.0

Next, prescription examples of various preparations containing the compound of the present invention will be shown, but of course the present invention is not limited thereto. Hereinafter, the numerical values shown in the formulation examples are% by weight. Formulation Example 1 (Toilet lotion) Compound of Example 1 (Na salt) 3.0 Carboxyvinyl polymer 0.5 Glycerin 3.5 Ethanol 12.0 Fragrance Trace amount Purified water Remaining amount

Formulation Example 2 (Ointment) Compound of Example 1 1.0 Propylene glycol 10.0 White petrolatum 24.0 Cetanol 26.0 Polyoxyethylene 40 monostearate 5.0 Paraoxybenzoic acid ester 0.1 Disodium edetate 0.01 Purified water balance

Formulation Example 3 (Emulsion) Compound of Example 2 0.5 Stearic acid 1.0 Cetanol 2.0 Squalane 4.0 Vaseline 2.0 Glycerin 2.0 Benzalkonium chloride 0.02 Fragrance Trace amount Purified water Remaining amount

Formulation Example 4 (Toilet lotion) Compound of Example 2 1.0 Glycerin 4.0 Oleyl alcohol 0.1 Propylene glycol 5.0 Polyoxyethylene sorbitan monolaurate 1.0 Polyoxyethylene lauryl ether 0.8 Ethanol 10.0 Paraoxybenzoate 0.1 Perfume Trace purified water Residue amount

Formulation Example 5 (packing agent) Compound of Example 2 0.3 Polyvinyl alcohol 17.0 Sodium carboxymethyl cellulose 5.5 Propylene glycol 3.5 Ethanol 10.0 Dibutylhydroxytoluene 0.01 Paraoxybenzoic acid ester 0.05 Perfume Trace amount of purified water Remaining amount

Formulation Example 6 (Lotion) Compound of Example 1 0.5 1,3-butylene glycol 4.0 Ethanol 13.0 Polyoxyethylene hydrogenated castor oil 8.0 Paraoxybenzoic acid ester 0.1 Wenoic acid 0.1 Sodium citrate 0.3 Disodium edetate 0.01 Purification water
Remaining amount

Formulation Example 7 (Cream) Compound of Example 1 0.5 L-lactic acid 2.0 1,3-butylene glycol 5.0 polyoxyethylene glycol monostearate 2.0 self-emulsifying glyceryl monostearate 4.5 DL-potassium lactate 4.5 behenyl alcohol 1.0 Eicosane tetraenoic acid 2.0 Liquid paraffin 1.0 Glyceryl trioctanoate 10.0 Paraoxybenzoic acid ester 0.2 Perfume Trace amount of purified water Remaining amount

Formulation Example 8 (packing agent) Compound of Example 3 1.0 Polyoxyethylene hydrogenated castor oil 0.5 Glycerin 3.8 Linolenic acid 0.5 Squalane 1.2 L-sodium lactate 5.8 Polyvinyl alcohol 14.0 Ethanol 10.0 Paraoxybenzoic acid ester 0.1 Fragrance Purified water Residue amount

Formulation Example 9 (lotion) Compound of Example 3 0.5 Ethanol 10.0 Polyoxyethylene (20) lauryl ether 0.5 Propylene glycol 1.0 Glycerin 2.0 Perfume Trace amount Purified water Remaining amount

Formulation Example 10 (Cream) Compound of Example 1 2.0 Stearic acid 6.0 Stearyl alcohol 5.0 Stearic acid butyl alcohol ester 7.0 Glycerin monostearate ester 2.0 Propylene glycol 11.0 Glycerin 5.0 Potassium hydroxide 0.2 Disodium edetate 0.01 Fragrance Trace amount Purified water remaining

Formulation Example 11 (gel agent) Compound of Example 2 3.0 Ethanol 10.0 Dipropylene glycol 15.0 Polyoxyethylene (15) oleyl alcohol ether 2.0 Carboxyvinyl polymer 1.0 Sodium hydroxide 0.15 L-Arginine 0.1 UV absorber Trace amount Fragrance Trace Paraoxybenzoic acid ester Trace amount Purified water Remaining amount

Formulation Example 12 (Cream) Compound of Example 3 3.0 Stearic acid 2.5 Cetanol 1.5 Liquid paraffin 12.0 Vaseline 5.0 Polyethylene glycol 1500 3.05 Glycerin 1.0 Disodium edetate 0.02 Fragrance Trace amount Purified water Remaining amount

[0043]

INDUSTRIAL APPLICABILITY The novel thiazole analog compound represented by the general formula (I) of the present invention has been found to remarkably inhibit the tyrosinase activity which has a great influence on melanin biosynthesis, and is expected to be used as a whitening cosmetic composition. It is possible.
That is, by using a thiazole analog compound obtained in the present invention as an external preparation for the skin containing the active ingredient, darkening of the skin due to sunburn, spots, a drug having prevention / improvement of freckles, as a quasi drug or a cosmetic product. Whitening cosmetics are provided. Further, it can be used as a skin aging preventive agent having an excellent skin aging preventive effect.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Koichi Beppu 408 Tadai Daikancho, Tosu City, Saga Prefecture Hisamitsu Pharmaceutical Co., Ltd. (72) Inventor Yuji Shimozono, 408, Tashiro Daikancho, Tosu City, Saga Prefecture Hisamitsu Yaku Co., Ltd. (72) Inventor Mizue Yoke, 408 Tadai Daikanmachi, Tosu City, Saga Prefecture Hisamitsu Pharmaceutical Co., Ltd. (72) Inventor Shigeo Ota, 408 Tashiro Daikancho, Tosu City, Saga Prefecture Hisamitsu Pharmaceutical Co., Ltd.

Claims (4)

[Claims] 1. A thiazole-related compound represented by the following general formula (I). [Wherein, ring X is unsubstituted, or (In the formula, R ₁ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group.), Or (Wherein R ₂ represents a hydrogen atom, a lower alkyl group, a lower alkoxy group or a halogen atom), Y is an amino residue, or (In the formula, n is an integer of 0 to 5, A is O, S or NH,
R ₃ is OH or (Wherein, R ₄ represents a hydrogen atom or a lower alkyl group, R ₅
Means a hydrogen atom or a lower alkyl group. ] 2. A tyrosinase activity inhibitor comprising the thiazole analog compound according to claim 1. 3. A skin external preparation containing the thiazole analog compound according to claim 1. 4. A whitening cosmetic composition comprising the thiazole analog compound according to claim 1.