HK1150538A - Skin whitening agent and external preparation for the skin - Google Patents

Description

Skin whitening agent and external preparation for skin

RELATED APPLICATIONS

The present application claims the priority of Japanese patent application No. 2008-29106, applied on 8/2/2008, and Japanese patent application No. 2008-199606, applied on 1/8/2008, which are incorporated herein by reference.

Technical Field

The present invention relates to a whitening agent and an external preparation for skin, and particularly to an active ingredient thereof.

Background

Pigmentation of the skin, such as spots and freckles, is caused by abnormal hormones or ultraviolet stimulation, and is caused by increased melanin production in the pigment cells of the epidermis and excessive melanin deposition on the epidermis.

For the purpose of preventing and improving such abnormal deposition of melanin, whitening agents have been incorporated into skin external preparations. At present, vitamin C derivatives, kojic acid, arbutin (4-hydroxyphenyl- β -D-glucopyranoside), resveratrol (Rucinol, ルシノ - ル) (4-n-butylresorcinol), ellagic acid, and the like are known as ingredients to be blended in skin external preparations as whitening agents, and these ingredients have a melanin production inhibitory action.

However, a sufficiently satisfactory substance is not yet obtained in terms of its effect, safety, and the like, and development of a new whitening agent has been desired.

On the other hand, patent document 1 describes a 2-aminothiazole compound having an antibacterial or bactericidal effect.

Patent document 2 describes thiazole compounds having C17 and 20 lyase inhibitory effects.

Patent document 3 describes a thiazoline compound having a pest control effect.

However, these documents do not describe any melanin production inhibitory action or whitening effect.

[ patent document 1 ] patent No. 3033178

[ patent document 2 ] Japanese Kohyo publication No. 2005-532983

[ patent document 3 ] Japanese patent application laid-open No. 6-25197

Disclosure of Invention

The present invention has been made in view of the above problems of the prior art, and an object of the present invention is to provide a compound having an excellent melanin production inhibitory action and useful as a whitening agent, and an external preparation for skin containing the compound.

As a result of intensive studies to solve the above problems, the present inventors have found that a specific heterocyclic compound has an excellent melanin production inhibitory action and very low cytotoxicity, and have completed the present invention.

That is, the whitening agent according to the present invention comprises a heterocyclic compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

(wherein A is C_1-6Alkyl radical, C_5-6Cycloalkyl, benzyl, benzylcarbonyl, benzoyl, or the following group (A1):

X₁is CR₁Or N, R₁Is H, C_1-6Alkyl radical, C_1-6Alkoxy, or OH;

X₂is CR₂Or N, R₂Is H, C_1-6Alkyl radical, C_1-6Alkoxy, or OH;

R₅is C_1-6Alkyl radical, C_1-6Alkoxy, or OH;

p is an integer of 0 to 3, and R is 2 to 3₅May be the same or different;

ra is H, C_1-6Alkyl, or C_2-6An alkenyl group;

represents a single bond or a double bond, n is 2 in the case of a single bond, n is 1 in the case of a double bond, and 2R are present in the case of n being 2₃May be the same or different, 2R₄Or may be the same or different;

y is S or O;

R₃、R₄are each independently H, C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_2-7Acyl, or the above-mentioned group (A1),

or may be one R₃And a R₄Taken together to form a 5-to 6-membered saturated or unsaturated hydrocarbon ring fused with the heterocycle to which they are attached, or

C(R₃)₂Or C (R)₄)₂Each independently is C ═ CH₂；

Wherein the Y-containing heterocycle is a thiazoline ring, R₄＝Ra＝H，X₁＝X₂CH, and p is 0 or R₅Is C_1-6In the case of alkyl, at least one R₃Is C_1-3A group other than an alkyl group. )

In addition, the present invention provides a whitening agent, wherein Y is S.

In addition, the present invention provides a whitening agent, wherein a is a group (a 1).

In addition, the invention also provides a whitening agent, wherein in the whitening agent,is a single bond.

The present invention also provides a whitening agent represented by the following general formula (1-1).

(in the formula, R₃、R₄、R₅And Ra is the same as defined in the above general formula (1). )

In addition, the invention also provides a whitening agent, in the general formula (1-1), R₃Each independently is H or C_1-6An alkyl group.

In addition, the invention also provides a whitening agent, in the general formula (1-1), R₄Each independently is H or C_1-6Alkyl, or C (R)₄)₂Is C ═ CH₂。

The present invention also provides a whitening agent represented by the following general formula (1-2).

(in the formula, R₃、R₄、R₅And Ra is the same as defined in the above general formula (1). )

In addition, the invention also provides a whitening agent, in the general formula (1-2), R₃、R₄Each independently is H or C_1-6An alkyl group.

In addition, the invention also provides a whitening agent, wherein in the whitening agent,is a double bond.

The present invention also provides a whitening agent represented by the following general formula (1-3).

(in the formula, R₃、R₄、R₅And Ra is the same as defined in the above general formula (1). )

The present invention also provides a whitening agent represented by the following general formula (1-4).

(in the formula, R₃、R₄、R₅And Ra is the same as defined in the above general formula (1). )

In addition, the invention also provides a whitening agent, in the general formula (1-3) or (1-4), R₃Is C_1-6Alkyl or a group (A1).

In addition, the invention also provides a whitening agent, in the general formula (1-3) or (1-4), R₄Is H or C_1-6An alkyl group.

In addition, the present invention provides a whitening agent, wherein Ra is H.

In addition, the present invention provides a whitening agent, wherein R is₅Is C_1-6An alkyl group.

In addition, the present invention provides a whitening agent, the active ingredient of which inhibits melanin production.

The present invention also provides a skin preparation for external use and a cosmetic, wherein the heterocyclic compound or a pharmaceutically acceptable salt thereof is contained.

The whitening agent of the present invention has an excellent melanin production-inhibiting effect and very low cytotoxicity, and therefore can be suitably blended as a whitening agent into an external preparation for skin.

Detailed Description

The whitening agent according to the present invention is represented by the following general formula (1).

In the formula, A is C_1-6Alkyl radical, C_5-6Cycloalkyl group, benzyl group, benzylcarbonyl group, benzoyl group, or a group represented by the following general formula (a 1).

In the group (A1), X₁Is CR₁Or N, R₁Is H, C_1-6Alkyl radical, C_1-6Alkoxy, or OH.

X₂Is CR₂Or N, R₂Is H, C_1-6Alkyl radical, C_1-6Alkoxy, or OH.

Thus, comprising X₁、X₂The unsaturated 6-membered ring of (b) is a benzene ring, a pyridine ring, or a pyrimidine ring.

R₅Is C_1-6Alkyl radical, C_1-6Alkoxy, or OH, as R₅A preferred example of (2) is C_1-6An alkyl group.

p is an integer of 0 to 3. When p is 2 to 3, R₅May be the same or different.

Ra is H, C_1-6Alkyl, or C_2-6The preferable example of Ra is H.

Represents a single bond or a double bond, and when the bond is a single bond, n is 2, and when the bond is a double bond, n is 1. When n is 2, 2R₃May be the same or different, 2R₄And may be the same or different.

Y is S or O. Thus, in the general formula (1), the unsaturated 5-membered heterocycle containing Y is thiazole, thiazoline,Oxazole orAn oxazoline.

R₃、R₄May each independently be H, C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_2-7Acyl, or the above group (A1). In addition, one R₃And a R₄Or may be linked together to form a 5-to 6-membered hydrocarbon ring fused with the heterocyclic ring to which they are bonded. Or, C (R)₃)₂Or C (R)₄)₂Or each may independently be C ═ CH₂。

Wherein, in the present invention, the heterocycle containing Y is a thiazoline ring, R₄＝Ra＝H，X₁＝X₂CH, and p is 0 or R₅Is C_1-6In the case of alkyl, at least one R₃Is C_1-3A group other than an alkyl group.

Examples of preferable compounds of the compound represented by the general formula (1) include compounds wherein Y ═ S.

Further, as a preferable example of the compound represented by the general formula (1), a compound in which a is a group (a1) may be mentioned.

As one of preferable examples of the compound wherein A is a group (A1), there may be mentionedA compound which is a single bond. Preferable examples of such a compound include compounds represented by the following general formula (1-1) and general formula (1-2).

(in the general formulae (1-1) and (1-2), R₃、R₄、R₅And Ra is the same as defined in the above general formula (1). )

As one of preferable examples of the compound represented by the general formula (1-1), R may be mentioned₃Each independently is H or C_1-6Alkyl compounds.

Further, one preferable example of the compound represented by the general formula (1-1) is R₄Each independently is H or C_1-6Alkyl, or C (R)₄)₂Is C ═ CH₂The compound of (1).

Further, one preferable example of the compound represented by the general formula (1-2) is R₃、R₄Each independently is H or C_1-6Alkyl compounds.

In addition, in the compound of the general formula (1),the compounds which are single bonds and Ra ═ H are considered to be the following tautomers, and in the present invention, such tautomers are also included in the compounds of the above general formula (1).

Further, one preferable example of the compound wherein A is a group (A1) isA compound which is a double bond. Preferable examples of such a compound include compounds represented by the following general formula (1-3) or general formula (1-4).

(in the general formulae (1-3) and (1-4), R₃、R₄、R₅And Ra is the same as defined in the above general formula (1). )

As one of preferable examples of the compound represented by the general formula (1-3) or (1-4), R may be mentioned₃Is C_1-6Alkyl or a compound of the group (A1).

Further, one preferable example of the compound represented by the general formula (1-3) or (1-4) is R₄Is H or C_1-6Alkyl compounds.

The compound of the general formula (1) can be synthesized by a known method or can be obtained as a commercially available product.

In the case of synthesis, if a functional group exists in a molecule, the functional group inhibits or may inhibit the reaction, it is preferable to efficiently proceed the reaction by using an appropriate protecting group. The use of protecting Groups can be carried out, for example, according to Protective Groups in Organic Synthesis, available from Theodora W.Greene, Peter G.M.Wuts.

When an isomer such as a coordination isomer, a geometric isomer, or an optical isomer exists, a simple isomer or a geometric isomer can be obtained by appropriately selecting a raw material and a reaction condition and performing a separation operation. In the present invention, a single isomer of the compound of the general formula (1) or a mixture thereof is also included.

In the general formula (1)The compound which is a single bond and Ra ═ H can be obtained, for example, by the reaction shown in scheme 1 below.

Scheme 1:

in scheme 1, the reaction of the iso (thio) cyanate compound (2) and the ethanolamine compound (3) can be carried out in an appropriate solvent such as chloroform, if necessary, while heating. The ring-closure reaction of the (thio) urea compound (4) thus obtained can be carried out by heating in the presence of an acid catalyst, for example. The reaction can be carried out, for example, according to the method described in Japanese patent laid-open No. 62-228089.

Further, 2-imino (or 2-amino) thiazoline compounds can be used as described in Japanese patent application laid-open No. 6-25197Oxazoline compounds) with a compound represented by A-X (X is a halogen). The reaction can be usually carried out in an appropriate solvent in the presence of a base such as triethylamine and optionally under heating.

In addition, in the general formula (1)Compounds that are double bonds and Ra ═ H can be obtained, for example, by the reaction shown in scheme 2.

Scheme 2:

in scheme 2, the reaction of the (thio) urea compound (5) with the α haloketone compound (6) can be carried out in an appropriate solvent such as methanol at room temperature or under heating, if necessary, in the presence of a base such as triethylamine. The reaction can be carried out, for example, by the method described in Japanese patent application laid-open No. 2005-532983, patent No. 3023178, and the like.

Further, as described in patent No. 3023178, a 2-aminothiazole compound (or 2-amino group) can be usedAzole compound) with a compound represented by a-X (X is halogen). The reaction can be usually carried out in an appropriate solvent in the presence of a base such as triethylamine and optionally under heating.

The compound of the formula (1) may be converted into an acid addition salt according to a conventional method, if necessary. Examples of the acid addition salt include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and organic acids such as acetic acid, propionic acid, citric acid, lactic acid, oxalic acid, maleic acid, fumaric acid, succinic acid, tartaric acid and methanesulfonic acid.

In addition, there are a number of commercially available products for the compounds of formula (1). For example, they are available from Enamine (Ukraw), Pharmeks (Russian), Labott (Germany), Scientific Exchange (USA), Life Chemicals (Ukraw), Asinex (Russia), Vitas-M Laboratory (Russia), ACB Blocks (Russia), Bionet (USA), Princeton Biomolecular (USA), and various other suppliers.

The compound of the general formula (1) has an excellent melanin production-inhibiting effect and is also very low in cytotoxicity. Therefore, the compound is useful as a whitening agent, and can be suitably blended with various skin external preparations, particularly skin external preparations for the purpose of improving or preventing stains, freckles, dullness, and the like.

When the compound of the general formula (1) is incorporated as a whitening agent into an external preparation for skin, the amount of the external preparation is usually 0.0002 mass% or more, preferably 0.002 mass% or more, based on the total amount of the external preparation. If the amount is too small, the effect cannot be sufficiently exhibited. The upper limit is not particularly limited, and is usually 30% by mass or less, preferably 20% by mass or less, and more preferably 5% by mass or less. Even if the amount is excessively added, a significant effect commensurate with an increase in the amount added may not be obtained, and the design of the preparation and the use thereof may be affected.

The skin preparation for external use of the present invention can be produced by a conventional method, except that the compound of the general formula (1) is blended.

In addition, the external preparation for skin of the present invention may contain, in addition to the compound of the general formula (1), other components used in general external preparations for skin such as cosmetics and medicines, for example, oil components, moisturizers, ultraviolet inhibitors, antioxidants, metal ion blocking agents, surfactants, preservatives, moisturizers, perfumes, water, alcohols, thickeners, powders, colorants, crude drugs, and other various medicinal components, as necessary, within a range that does not impair the effects of the present invention.

In addition, other whitening agents such as vitamin C, magnesium ascorbyl phosphate, ascorbyl glucoside, arbutin, kojic acid, resveratrol, ellagic acid, tranexamic acid, and linoleic acid may be appropriately added.

The skin preparation for external use of the present invention can be widely used in the fields of cosmetics, pharmaceuticals, quasi drugs and the like. The formulation is not particularly limited as long as it can be applied to the skin, and any formulation such as a solution, emulsion, solid, semisolid, powder dispersion, water-oil two-layer separation, water-oil-powder three-layer separation, ointment, gel, aerosol, mousse, and stick can be applied. The form of use is also arbitrary, and examples thereof include facial basic cosmetics such as lotions, milky lotions, creams, pack (パツク), essences, and gels, and makeup cosmetics such as foundation, liquid foundation (makeup base), and concealer.

The present invention will be further described with reference to specific examples, but the present invention is not limited thereto.

Examples

For the compound of the general formula (1), a melanin production inhibition test was performed. The test method is as follows.

Test for inhibition of melanogenesis

(1) Cell inoculation and addition of test substance

Mouse B16 melanoma cells were seeded in 6-well plates at 100,000 cells/well. The next day, the test substance solution (solvent: DMSO) was added.

(2) Cell proliferation assay

After the addition of the test substance solution for 3 days, the medium was removed by suction filtration, and then 1ml of EMEM medium containing 10% Alamar Blue (アラマブル one) solution was added and allowed to react at 37 ℃. After 30 minutes, 100. mu.l were transferred to a 96-well plate and fluorescence was measured at an excitation wavelength of 544nm and a measurement wavelength of 590 nm. The relative value of the number of cells was used as the value, and the ratio of the number of cells (% number of cells) in the test substance-added group to the test substance-non-added group (only solvent was added) was calculated. Higher% cell number indicates lower cytotoxicity. The cells in% are determined to be non-toxic when the number of cells is 80% or more, and toxic when the number of cells is less than 80%.

(3) Quantification of melanin

After the cell growth test, the cells were washed 3 times with PBS, 200. mu.L of 1M NaOH was added to the cells, and the cells were lysed to measure the absorbance at 475 nm. The ratio (%) of the amount of melanin in the test substance-added group to the amount of melanin in the test substance-non-added group (only solvent was added) was calculated as a relative value of the amount of melanin. The lower the ratio of melanin amount, the higher the melanin production inhibitory effect. The melanin production inhibitory effect was evaluated according to the following criteria, with the minimum test substance final concentration at which the melanin amount ratio (%) reached 80% or less, as the melanin production inhibitory minimum concentration (ppm) in the test substance final concentrations judged to be non-toxic.

Very good: the minimum melanin production inhibition concentration is 1ppm or less.

O: the minimum melanin production inhibition concentration is greater than 1ppm and 10ppm or less.

X: at 10ppm or less, no melanin production-inhibiting effect is exhibited (the melanin content ratio cannot be 80% or less at 10ppm or less).

Tables 1 to 5 show the results of the melanin production inhibition test of the compound of the present invention.

The compounds in tables 1 to 5 were all confirmed to have melanin production-inhibiting effects, and almost all of the compounds exhibited effects at an extremely low concentration of 1ppm or less.

In addition, the symbols in the table refer to the following groups.

Me: methyl group, Et: ethyl, tBu: a tert-butyl group,

Phe: phenyl, Ac: acetyl group

[ TABLE 1 ]

[ TABLE 2 ]

[ TABLE 3 ]

[ TABLE 4 ]

[ TABLE 5 ]

Hereinafter, representative synthetic examples of the heterocyclic compound relating to the whitening agent of the present invention are given. Various heterocyclic compounds can be obtained by carrying out the reaction according to these synthesis examples using the corresponding starting materials.

Synthesis examples 1-14- (5, 5-dimethyl-4, 5-dihydrothiazol-2-ylamino) phenol (formula) Synthesis of Compound 41)

P-anisidine (0.60g, 4.86mmol) and methanol (4.0mL) were placed in a 50mL eggplant-type flask, and methallyl isothiocyanate (0.50g, 4.42mmol) was added dropwise at room temperature. After the completion of the dropwise addition, the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was extracted with ethyl acetate 1 time, and the organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate and hexane to give 0.79g of 1- (4-methoxyphenyl) -3- (2-methylallyl) thiourea (yield 76%).

1- (4-methoxyphenyl) -3- (2-methylallyl) thiourea (0.50g, 2.11mmol and 35% hydrochloric acid (5.0mL) were charged in a pressure-resistant reactor, the tube was sealed, and the mixture was stirred at 140 ℃ for 5 hours, after the completion of the reaction, a 3N aqueous sodium hydroxide solution was added until the pH reached 14, and the mixture was extracted 2 times with ethyl acetate, the organic phase was washed with saturated saline, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate ═ 1: 2) to obtain 0.19g (yield 40%) of 4- (5, 5-dimethyl-4, 5-dihydrothiazol-2-ylamino) phenol (compound 41).

Synthesis example 1-2 Synthesis of (hetero) arylamino thiazolines

(hetero) arylaminothiazolines shown in Table 6 were synthesized in the same manner as in Synthesis example 1-1 except that methoxyaniline was replaced by raw material A.

[ TABLE 6 ]

Synthesis example 24- (pyridin-2-yl) -N-o-toluoylthiazol-2-amine (Compound 2) Synthesis of (2)

To 975mL of methanol were added triethylamine (14.0g, 137mmol), o-toluylthiourea (11.54g, 69.4mmol) and 2- (bromoacetyl) pyridine hydrogen bromide (19.5g, 69.4mmol), and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, 1950mL of water was added, and the precipitated crystals were collected by filtration. Water: the resulting solid was crystallized from a mixed solvent of methanol to give the title compound (14.0g, 76%).

¹H-NMR(DMSO-d₆)：2.30(3H，s)，7.01-7.04(1H，m)，7.22-7.30(3H，m)，7.46(1H，s)，7.82-7.91(2H，m)，7.97(1H，d)，8.56(1H，d)，9.32(1H，s)

Reference example 14 Synthesis of 4, 4-dimethyl-N-phenyl-4, 5-dihydrothiazol-2-amine

2-amino-2-methyl-1-propanol (61.6g, 0.69moL) was dissolved in 500g of chloroform, and a solution of phenylisothiocyanate (81.6g, 0.6moL) in 300g of chloroform was slowly added dropwise over 1 hour while stirring. After the dropwise addition, the mixture was stirred at room temperature for 12 hours, and then the precipitated crystals were dissolved by heating under reflux and recrystallized. The resulting crystals were collected by filtration, washed 3 times with 20mL of diethyl ether, and dried under reduced pressure at room temperature to give 80.1g of N- (1-hydroxy-2-methylpropan-2-yl) -N' -phenylthiourea (yield 60%).

N- (1-hydroxy-2-methylpropan-2-yl) -N' -phenylthiourea (80.1g, 0.36mol) was dissolved in 2400mL of 35% HCl, and stirred with heating at 90 ℃ for 1.5 hours. After cooling, the reaction mixture was neutralized with NaOH, extracted with ether, washed with saturated brine, and then added with anhydrous sodium sulfate. The organic phase was distilled off under reduced pressure, washed 3 times with hexane, and the resulting crystals were dried under reduced pressure at room temperature. Then, recrystallization from methanol was performed 2 times to obtain 22.4g of the title compound (yield: 18%).

¹H-NMR(CDCl₃)：1.39(6H，s)，3.08(2H，s)，7.01-7.09(3H，m)，7.26-7.30(2H，m)

The following are formulation examples of the external preparation for skin of the present invention. In each formulation example, 1 or 2 or more compounds can be used as the compound of the present invention. The skin external preparations of the following formulation examples all exhibit whitening effects by blending the compound of the present invention.

Formulation example 1 face cream

(formulation)

Stearic acid 5.0% by mass

Stearyl alcohol 4.0

Isopropyl myristate 18.0

Glycerol monostearate 3.0

Propylene glycol 10.0

Compound 0.1 of the invention

0.2 part of potassium hydroxide

Sodium bisulfite 0.05

Proper amount of preservative

Proper amount of perfume

Ion exchange water balance

(preparation method)

Adding propylene glycol and potassium hydroxide into ion exchange water, dissolving, heating, and maintaining at 70 deg.C (water phase). Mixing the other components, heating to melt, and maintaining at 70 deg.C (oil phase). The oil phase is slowly added to the aqueous phase and, after all the addition, is allowed to react by maintaining it at its temperature for a while. Then, the mixture was uniformly emulsified with a homogenizer and cooled to 30 ℃ while sufficiently stirring.

Formulation example 2 face cream

(formulation)

Stearic acid 5.0% by mass

Sorbitan monostearate 2.5

Polyoxyethylene (20 mol) sorbitan monostearate 1.5

Arbutin 7.0

Sodium bisulfite 0.03

Propylene glycol 10.0

Compound 0.05 of the invention

Tricaprylin 10.0

Squalene 5.0

3.0 of octyl p-dimethylaminobenzoate

Ethylenediaminetetraacetic acid disodium salt 0.01

0.3 parts of ethyl p-hydroxybenzoate

Proper amount of perfume

Ion exchange water balance

(preparation method)

Adding propylene glycol and disodium edetate into ion exchange water, dissolving, and maintaining at 70 deg.C (water phase). Mixing other components, heating to dissolve, maintaining at 70 deg.C (oil phase), slowly adding oil phase into water phase, pre-emulsifying at 70 deg.C, homogenizing with homogenizing mixer, and cooling to 30 deg.C while stirring.

Formulation example 3 cream

(formulation)

Solid paraffin 5.0% by mass

Beeswax 10.0

Vaseline 15.0

Liquid paraffin 41.0

Glycerol monostearate 2.0

POE (20) sorbitan monolaurate 2.0

Soap powder 0.1

Borax 0.2

Compound 0.05 of the invention

Sodium bisulfite 0.03

0.3 parts of ethyl p-hydroxybenzoate

Proper amount of perfume

Ion exchange water balance

(preparation method)

Adding soap powder and borax into ion exchange water, heating to dissolve, and maintaining at 70 deg.C (water phase). Mixing the other components, heating to melt, and maintaining at 70 deg.C (oil phase). The oil phase is slowly added into the water phase while stirring, and the reaction is carried out. After the reaction, the mixture was uniformly emulsified in a homogenizer and then cooled to 30 ℃ while being sufficiently stirred.

Formulation example 4 emulsion

(formulation)

Stearic acid 2.5% by mass

Cetyl alcohol 1.5

Vaseline 5.0

Liquid paraffin 10.0

POE (10) monooleate 2.0

Polyethylene glycol 15003.0

Triethanolamine 1.0

Carboxyvinyl Polymer 0.05

Compound 0.01 of the invention

Sodium bisulfite 0.01

0.3 parts of ethyl p-hydroxybenzoate

Proper amount of perfume

Ion exchange water balance

(preparation method)

The carboxyvinyl polymer (phase A) was dissolved in a small amount of ion-exchanged water. Adding polyethylene glycol 1500 and triethanolamine into the rest ion exchange water, heating to dissolve, and maintaining at 70 deg.C (water phase). Mixing the other components, heating to melt, and maintaining at 70 deg.C (oil phase). Adding oil phase into water phase, pre-emulsifying, adding phase A, emulsifying with homogenizing mixer, and cooling to 30 deg.C while stirring.

Formulation example 5 emulsion

(formulation)

Microcrystalline wax 1.0% by mass

Beeswax 2.0

Lanolin 20.0

Liquid paraffin 10.0

Squalane 5.0

Sorbitan sesquioleate 4.0

POE (20) sorbitan monooleate 1.0

Propylene glycol 7.0

Compound 1.0 of the invention

Sodium bisulfite 0.01

0.3 parts of ethyl p-hydroxybenzoate

Proper amount of perfume

Ion exchange water balance

(preparation method)

Propylene glycol was added to the ion-exchanged water, heated, and maintained at 70 deg.C (aqueous phase). Mixing the other components, heating to melt, and maintaining at 70 deg.C (oil phase). The aqueous phase was slowly added thereto while stirring the oil phase, and emulsified uniformly with a homogenizer. After emulsification, the mixture was cooled to 30 ℃ while stirring well.

Formulation example 6 gel

(formulation)

95% ethanol 10.0% by mass

Dipropylene glycol 15.0

POE (50) oleyl ether 2.0

Carboxyvinyl Polymer 1.0

0.15 part of sodium hydroxide

L-arginine 0.1

Compound 5.0 of the invention

Sodium 2-hydroxy-4-methoxybenzophenone sulfonate 0.05

Ethylenediaminetetraacetic acid 3 sodium 2 Water 0.05

0.2 parts of methyl p-hydroxybenzoate

Proper amount of perfume

Ion exchange water balance

(preparation method)

The carboxyvinyl polymer was uniformly dissolved in ion-exchanged water, and the compound of the present invention and POE (50) oleyl ether were dissolved in 95% ethanol and added to the aqueous phase. Then, after adding other components, the mixture was neutralized with sodium hydroxide and L-arginine to increase viscosity.

Formulation example 7 cosmetic liquid

(formulation)

(A phase)

Ethanol (95%) 10.0% by mass

POE (20) octyldodecanol 1.0

Panthenol ethyl ether (パントテニ - ルエチルエ - テル)0.1

Compound 2.0 of the invention

0.15 parts of methyl p-hydroxybenzoate

(phase B)

0.1 part of potassium hydroxide

(C phase)

Glycerol 5.0

Dipropylene glycol 10.0

Sodium bisulfite 0.03

Carboxyvinyl Polymer 0.2

Purified water balance

(preparation method)

Dissolving phase A and phase C uniformly, and adding phase A into phase C for dissolving and liquefying. Then, after adding phase B, filling is performed.

Formulation example 8 Soft film

(formulation)

(A phase)

Dipropylene glycol 5.0% by mass

POE (60) hardened Castor oil 5.0

(phase B)

Compound 0.05 of the invention

Olive oil 5.0

Tocopheryl acetate 0.2

0.2 parts of ethyl p-hydroxybenzoate

Fragrance 0.2

(C phase)

Sodium bisulfite 0.03

Polyvinyl alcohol 13.0

(degree of saponification: 90, degree of polymerization: 2,000)

Ethanol 7.0

Purified water balance

(preparation method)

Respectively and uniformly dissolving the phase A, the phase B and the phase C, adding the phase B into the phase A, and dissolving. Then, after adding it to the C phase, filling is performed.

Formulation example 9 solid foundation

(formulation)

Talc 43.1% by mass

Kaolin 15.0

Sericite 10.0

Zinc oxide 7.0

Titanium dioxide 3.8

Iron oxide yellow 2.9

Iron oxide black 0.2

Squalane 8.0

Isostearic acid 4.0

POE sorbitan monooleate 3.0

Isocetyl octanoate 2.0

Compound 0.5 of the invention

Proper amount of preservative

Proper amount of perfume

(preparation method)

The powdery components of talc to black iron oxide were thoroughly mixed by a mixer, and the oily component of squalane to isocetyl octanoate, the compound of the present invention, a preservative and a perfume were added thereto, and after thorough mixing, the mixture was filled in a container and molded.

Formulation example 10 emulsion type Foundation make-up (face cream type)

(formulation)

(powder portion)

Titanium dioxide 10.3% by mass

Sericite 5.4

Kaolin 3.0

Iron oxide yellow 0.8

Iron oxide Red 0.3

Iron oxide black 0.2

(oil phase)

Decamethylcyclopentasiloxane 11.5

Liquid paraffin 4.5

Polyoxyethylene modified dimethyl polysiloxane 4.0

Compound 0.5 of the invention

(aqueous phase)

Purified water 50.0

1, 3-butanediol 4.5

Sorbitan sesquioleate 3.0

Proper amount of preservative

Proper amount of perfume

(preparation method)

The aqueous phase was heated and stirred, and the well-mixed and pulverized powder fraction was added and treated with a homogenizer. Adding the oil phase, treating with homogenizing mixer, adding perfume under stirring, and cooling to room temperature.

Formulation example 11 toner

(1) 0.05% by mass of the Compound of the present invention

(2) Aspartic acid 1.0

(3) Tocopheryl acetate 0.01

(4) Glycerol 4.0

(5)1, 3-butanediol 4.0

(6) Ethanol 8.0

(7) POE (60) hardened Castor oil 0.5

(8) 0.2 parts of methyl p-hydroxybenzoate

(9) Citric acid 0.05

(10) Sodium citrate 0.1

(11) Perfume 0.05

(12) Purified water balance

(preparation method)

Dissolving (2), (4), (5), (9) and (10) in (12) to prepare a purified aqueous solution. Further, (1), (3), (7), (8) and (11) are dissolved in (6), and the resulting solution is added to the purified aqueous solution, solubilized and filtered to obtain a cosmetic lotion.

Formulation example 12 toner

A: alcohol phase

Ethanol 5.0% by mass

POE oleyl ether 2.0

2-ethylhexyl-p-dimethylaminobenzoate 0.18

Compound 0.1 of the invention

Perfume 0.05

B: aqueous phase

1, 3-butanediol 9.5

2-O-Ethyl ascorbic acid 0.5

Pyrrolidone carboxylic acid sodium 0.5

Whey extractive solution 5.0

Nicotinamide 0.3

Glycerol 5.0

Hydroxypropyl-beta-cyclodextrin 1.0

Ethylenediaminehydroxyethyl 3 acetic acid 3Na 1.0

Lysine 0.05

Tranexamic acid 1.0

Purified water balance

(preparation method)

Adding the alcohol phase of A into the water phase of B, and dissolving to obtain cosmetic water.

Formulation example 13 cream (whitening)

Hydrochloric acid trans-4- (trans-aminomethylcyclohexane carbonyl)

1.0% by mass of Aminomethylcyclohexanecarboxylic acid

4-Methoxysalicylic acid potassium salt 1.0

3-O-Ethyl ascorbic acid 1.0

Linoleic acid 0.3

Sodium lipoate 1.0

Compound 3.0 of the invention

Coenzyme Q10(CoQ10) 0.03

Vaseline 2.0

Dimethylpolysiloxane 2.0

Ethanol 5.0

Behenyl alcohol 0.5

Batyl alcohol 0.2

Glycerol 7.0

1, 3-butanediol 5.0

Polyethylene glycol 200000.5

Jojoba oil 3.0

Squalane 2.0

Hydroxystearic acid phytosterol ester 0.5

Pentaerythritol tetra-2-ethylhexanoate 1.0

Polyoxyethylene hardened castor oil 1.0

0.1 part of potassium hydroxide

Sodium metabisulfite 0.01

Sodium hexametaphosphate 0.05

Glycyrrhetinic acid stearyl alcohol ester 0.1

Panthenol ethyl ether (パントテニ ルエチルエ - テル)0.1

Arbutin 7.0

Tranexamic acid 2.0

Tocopheryl acetate 0.1

Sodium hyaluronate 0.05

Proper amount of p-hydroxybenzoate

Ethylenediaminetetraacetic acid trisodium 0.05

4-tert-butyl-4' -methoxydibenzoylmethane 0.1

Di-p-methoxy cinnamic acid mono-2-ethyl hexanoic acid glyceride 0.1

Proper amount of iron oxide yellow

Xanthan gum 0.1

Carboxyvinyl Polymer 0.2

Purified water balance

Formulation example 14 double-layer cream (sunscreen cream)

Tranexamic acid 2.0% by mass

4-Methoxysalicylic acid potassium salt 1.0

Compound 0.03 of the invention

Dimethylpolysiloxane 5.0

Decamethylcyclopentasiloxane 25.0

Trimethylsiloxysilicates 5.0

Polyoxyethylene-methylpolysiloxane copolymer 2.0

Dipropylene glycol 5.0

Trachyalose palmitate coated particulate zinc oxide (60nm) 15.0

Dipotassium glycyrrhizinate 0.02

Glutathione 1.0

Thiotaurine 0.05

Radix Sophorae Flavescentis extract (クララエキス) 1.0

Proper amount of p-hydroxybenzoate

Proper amount of phenoxyethanol

Proper amount of trisodium ethylenediamine tetraacetate

2-ethylhexyl p-methoxycinnamate 7.5

Disteardimonium hectorite 0.5

Spherical polyalkylacrylate powder 5.0

Butyl ethyl propylene glycol 0.5

Purified water balance

Proper amount of perfume

Formulation example 15 gel (whitening)

4-Methoxysalicylic acid potassium 0.1% by mass

Resveratrol 0.3

Dihydrolipoic acid 1.0

Wild sesame seed 0.1

Dimethylpolysiloxane 5.0

Glycerol 2.0

1, 3-butanediol 5.0

Polyethylene glycol 15003.0

Polyethylene glycol 200003.0

Cetyl octanoate 3.0

Citric acid 0.01

Sodium citrate 0.1

Sodium hexametaphosphate 0.1

Compound 1.0 of the invention

Dipotassium glycyrrhizinate 0.1

Ascorbyl glucoside 2.0

Tocopheryl acetate 0.1

Scutellariae radix extract 0.1

Herba Saxifragae extract 0.1

Ethylenediaminetetraacetic acid trisodium 0.1

Xanthan gum 0.3

Acrylic acid/methacrylic acid alkyl ester copolymer

(ペミユレンTR-2) 0.05

Agar powder 1.5

Proper amount of phenoxyethanol

Appropriate amount of dibutylhydroxytoluene

Purified water balance

Formulation example 16 Soft film (moisture)

trans-4-Aminomethylcyclohexanecarboxylic acid formamide hydrochloride 10.0% by mass

Dihydrothiooctanoic acid amide 1.0

Rose fruit 0.1

Ethanol 10.0

1, 3-butanediol 6.0

Polyethylene glycol 40002.0

Olive oil 1.0

Macadamia nut oil 1.0

Hydroxystearic acid phytosterol ester 0.05

Lactic acid 0.05

Sodium lactate 0.1

L-ascorbic acid sulfate 2 sodium 0.1

Compound 0.5 of the invention

Alpha-tocopherol 2-L-ascorbic acid potassium phosphate diester 0.1

Vitamin E acetate 0.1

Fish collagen 0.1

Chondroitin sulfate sodium 0.1

Sodium carboxymethylcellulose 0.2

Polyvinyl alcohol 12.0

Proper amount of p-hydroxybenzoate

Purified water balance

Proper amount of perfume

Formulation example 17 astringent (moisture)

Tranexamic acid 1.0% by mass

4-Methoxysalicylic acid potassium salt 1.0

Lipoic acid 10.0

Witch hazel 0.1

Silica coated Zinc oxide 0.1

Hypotaurine 0.1

0.1 part of Sophora flavescens Aiton extract (クララエキス)

Semen Persicae extract 0.1

Beech bud extract 0.1

Retinol 0.1

Compound 0.01 of the invention

Ethanol 5.0

Glycerol 1.0

1, 3-butanediol 5.0

Polyoxyethylene polyoxypropylene decyl tetradecyl ether 0.2

Sodium hexametaphosphate 0.03

Trimethylglycine 1.0

Polyaspartic acid sodium 0.1

Alpha-tocopherol 2-L-ascorbic acid potassium phosphate diester 0.1

Thiotaurine 0.1

Green tea extract 0.1

Peppermint (western ハツカ) extract 0.1

Iris root extract 1.0

EDTA3 sodium 0.1

Carboxyvinyl Polymer 0.05

0.02 part of potassium hydroxide

Proper amount of phenoxyethanol

Purified water balance

Proper amount of perfume

Claims (19)

1. A whitening agent comprising, as an active ingredient, a heterocyclic compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof.

(wherein A is C_1-6Alkyl radical, C_5-6Cycloalkyl, benzyl, benzylcarbonyl, benzoyl, or the following group (A1):

X₁is CR₁Or N, R₁Is H, C_1-6Alkyl radical, C_1-6Alkoxy, or OH;

X₂is CR₂Or N, R₂Is H, C_1-6Alkyl radical, C_1-6Alkoxy, or OH;

R₅is C_1-6Alkyl radical, C_1-6Alkoxy, or OH;

p is an integer of 0 to 3, and R is 2 to 3₅May be the same or different;

ra is H, C_1-6Alkyl, or C_2-6An alkenyl group;

represents a single bond or a double bond, n is 2 in the case of a single bond, n is 1 in the case of a double bond, and 2R are present in the case of n being 2₃May be the same or different, 2R₄Or may be the same or different;

y is S or O;

R₃、R₄are each independently H, C_1-6Alkyl, hydroxy C_1-6Alkyl radical, C_2-7Acyl, or the above-mentioned group (A1),

or may be one R₃And a R₄Taken together to form a 5-to 6-membered saturated or unsaturated hydrocarbon ring fused with the heterocycle to which they are attached, or

C(R₃)₂Or C (R)₄)₂Each independently is C ═ CH₂；

Wherein the Y-containing heterocycle is a thiazoline ring, R₄＝Ra＝H，X₁＝X₂CH, and p is 0 or R₅Is C_1-6In the case of alkyl, at least one R₃Is C_1-3A group other than an alkyl group. )

2. The whitening agent of claim 1, wherein Y is S.

3. The whitening agent according to claim 1 or 2, wherein A is the group (A1).

4. The whitening agent according to any one of claims 1 to 3,is a single bond.

5. The whitening agent according to claim 4, which is represented by the following general formula (1-1).

(in the formula, R₃、R₄、R₅And Ra is the same as defined in the above general formula (1). )

6. The whitening agent of claim 5, wherein R is R₃Each independently is H or C_1-6An alkyl group.

7. The whitening agent of claim 4 or 5, wherein R is₄Each independently is H or C_1-6Alkyl, or C (R)₄)₂Is C ═ CH₂。

8. The whitening agent according to claim 4, which is represented by the following general formula (1-2).

(in the formula, R₃、R₄、R₅And Ra is the same as defined in the above general formula (1). )

9. The whitening agent of claim 8, wherein R is R₃、R₄Each independently is H or C_1-6An alkyl group.

10. The whitening agent according to any one of claims 1 to 3,is a double bond.

11. The whitening agent according to claim 10, which is represented by the following general formula (1-3).

(in the formula, R₃、R₄、R₅And Ra is the same as defined in the above general formula (1). )

12. The whitening agent according to claim 10, which is represented by the following general formula (1-4).

(in the formula, R₃、R₄、R₅And Ra is the same as defined in the above general formula (1). )

13. The whitening agent of claim 11 or 12, wherein R is₃Is C_1-6Alkyl or a group (A1).

14. The whitening agent according to any one of claims 11 to 13, wherein R is R₄Is H or C_1-6An alkyl group.

15. The whitening agent according to any one of claims 1 to 14, wherein Ra is H.

16. The whitening agent according to any one of claims 1 to 15, wherein R is R₅Is C_1-6An alkyl group.

17. The whitening agent according to any one of claims 1 to 16, wherein the active ingredient inhibits melanogenesis.

18. An external preparation for skin, which comprises the heterocyclic compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

19. A cosmetic comprising the heterocyclic compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.