JPH05124924A - External preparation with melanin production-inhibitory activity - Google Patents

Abstract

PURPOSE:To provide an odorless, highly stable external preparation giving excellent melanin production-inhibitory activity, effective for inhibiting endogenous as well as exogenous pigmentation, containing, as active ingredient, specific mercaptopyridine or mercaptopyrimidine compound(s) such as 2- mercaptopyridine. CONSTITUTION:The objective external preparation is formulated with pref. 0.01-10wt.% or so of at least one kind selected from a group of compounds of formula I [Q is C or N; X is H, alkali (alkaline earth) metal, ammonium, etc.; R<1>-R<3> are each H, alkyl, cyclohexyl, cyclopentyl, alkenyl, aralkyl, phenyl, halogen, etc.] (e.g. respective compounds of formulae II to VII, etc.). The compound of the formula I gives no side effect at all, also retaining stable quality for a long period of time.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external preparation for suppressing melanin production as a preventive and therapeutic agent for pigmentation, and more specifically, pigmentation such as liver spots caused by external stimuli such as ultraviolet rays. In addition to the prevention and treatment of, it is possible to safely treat pigmentation diseases such as senile lentigines, sunburn lentigines, pigmented spots after inflammation, and endogenous liver spots that are not caused by external stimuli such as sunburn. It relates to drugs that are effectively treated.

[0002]

2. Description of the Related Art Since ancient times, it has been well known that a lot of external preparations such as whitening cosmetics have been proposed without changing women's longing for fair skin.

The cause of blackening of the skin is, for example, pigmentation such as liver spots caused by external stimuli such as ultraviolet rays, senile lentigines, sunburn lentigines, pigmented spots after inflammation, and external irritation. It is known that endogenous melasma, which occurs without it, is caused by an increase in epidermal melanin. Therefore, as a whitening agent for external use, a melanin production-inhibiting substance is mixed in its composition.

As a method for suppressing such melanin production, a method of continuously taking vitamin C, a method of adding a light-scattering substance such as talc, zinc white, titanium oxide or the like and an ultraviolet absorber such as para-aminobenzoic acid to an external preparation. , A method of adding a placenta extract and a liver extract to an external preparation, a method of adding a thiol compound such as cysteine, glutathione, and thiourocanic acid, a method of adding kojic acid or a kojic acid derivative to an external preparation are known. ing.

[0005]

As described above, there are known known whitening cosmetics containing a conventionally known melanin production-inhibiting substance as an active ingredient, and external preparations for skin which are formulated and applied to the skin. However, a substance having an excellent effect of suppressing melanin production is desired.

Therefore, an object of the present invention is to provide an external preparation having an excellent melanin production inhibitory effect.

[0007]

Means for Solving the Problems For the purpose of solving the above problems, the present inventor extensively searched for substances having a melanin production inhibitory effect, and conducted extensive research and studies, and as a result, is represented by the general formula (1). The heterocyclic compound has an excellent melanin production inhibitory action, and moreover, since this compound is odorless and does not cause discoloration or precipitation due to oxidation with the passage of time, it has excellent stability. It has been found that such an external preparation does not impair the commercial value for a long period of time and retains a stable melanin production-inhibiting action even after being stored at 40 ° C. for 6 months.

That is, the greatest technical feature of the present invention is that
Compared to kojic acid, which has been conventionally known as a whitening external preparation, it has an excellent melanin production inhibitory action of 10 to 100 times, is odorless, has excellent stability, and is not only exogenous, It is an object of the present invention to provide a melanin production-inhibiting external preparation that exhibits excellent efficacy against endogenous pigmentation.

[0009]

[Chemical 2]

(In the formula, Q represents a carbon atom or a nitrogen atom,
X represents hydrogen, an alkali metal, an alkaline earth metal, an ammonium group or an organic amine residue, and R ¹ , R ² , R ³
Are the same or different and represent a hydrogen atom, an alkyl group (having 1 to 22 carbon atoms), a cyclohexyl group, a cyclopentyl group, an alkenyl group (having 1 to 22 carbon atoms), an alkynyl group (having 1 to 22 carbon atoms), Substituted or substituted aralkyl groups (benzyl group, phenylethyl group, tolubenzyl group, naphthylmethyl group), unsubstituted or substituted phenyl groups, halogen atoms (chlorine, bromine, fluorine,
_{Iodine), - CF 3, -CH 2} CF 3, -CF 2 C
F ₃ , -COR, -CN, -NRR ', -COOR,-
_{CONRR ', - NHCOR, -NHSO 2} R, -SO
_{2 NRR ', - NO 2,} -OR, -SR, -SOR, -
_{SO 2 R, -SO 3 M,} SiRR'R '', - (CH 2)
_{n-COOR, - (CH 2} ) n-CONRR ', - OC
OR, -OSiRR'R '', -CONHNRR ', -N
_{HCONRR ', - (CH 2)} n-OH, - (OCH 2
_{CH 2) n-OH, -SSR} , -O- pyranose (glucose The pyranose, mannose, galactose), - ', wherein R, R' OPO ₃ RR and R '' is a hydrogen atom, an alkyl group ( 1 to 22 carbon atoms, cyclohexyl group, cyclopentyl group, alkenyl group (1 to 22 carbon atoms), alkynyl group (1 to 22 carbon atoms)
), An unsubstituted or substituted aralkyl group (benzyl group, phenylethyl group, tolubenzyl group, naphthylmethyl group), an unsubstituted or substituted phenyl group or a heterocycle, and M is a hydrogen atom, an alkali metal Represents an ion or an ammonium ion. An external preparation for suppressing melanin production, comprising one or more selected from the group of compounds consisting of

However, in the general formula (1), when X is a hydrogen atom, it is known that the tautomer (2) exists in a certain ratio as shown below, and the compound of the present invention is Means also those containing such tautomers.

[0012]

[Chemical 3]

Next, the compound of the general formula (1) will be described.

In the general formula (1), Q includes a carbon atom and a nitrogen atom.

In the general formula (1), the substituent represented by X is a hydrogen atom, an alkali metal (eg, lithium, sodium, potassium, etc.), an alkaline earth metal (eg, calcium, barium, etc.), ammonium. Examples thereof include groups or organic amine residues (eg, methylamine, ethylamine, n-propylamine, iso-propylamine, n-butylamine, dimethylamine, diethylamine, etc.).

In the general formula (1), R ¹ _, R ² ,
The substituent represented by R ³ is a hydrogen atom, an alkyl group (having 1 to 22 carbon atoms, preferably a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group or an ethyl group). , Propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, etc.), cyclohexyl group, cyclopentyl group, alkenyl group (having 2 to 22 carbon atoms, preferably straight chain). A chain or branched alkenyl group having 2 to 6 carbon atoms, for example, vinyl group, allyl group, 2-butenyl group, isoprenyl group, etc.), alkynyl group (having 2 to 22 carbon atoms, preferably). Is a linear or branched alkynyl group having 2 to 6 carbon atoms, for example, an ethynyl group, 2
Examples include-propynyl group and 4-pentynyl group. ), Unsubstituted or substituted aralkyl group (in the case of benzyl group, for example, benzyl group, 2-methylbenzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 4
-Ethylbenzyl group, 4-hexylbenzyl group, 3-chlorobenzyl group, 4-fluorobenzyl group, 3,5-difluorobenzyl group, 4-nitrobenzyl group, 2-cyanobenzyl group, 4-dimethylaminobenzyl group, 2-acetaminobenzyl group, 4-methoxybenzyl group, 2-
Methoxybenzyl group, 4-trimethylsilyloxybenzyl group, 4-butyldimethylsilyloxybenzyl group, etc.) and phenylethyl group include, for example, phenylethyl group, 2-methylphenylethyl group, 3-methylphenylethyl group, 4-methyl group. Phenylethyl group, 4-ethylphenylethyl group, 4-propylphenylethyl group, 4-
Hexylphenylethyl group, 3-chlorophenylethyl group, 4-fluorophenylethyl group, 3,5-difluorophenylethyl group, 4-nitrophenylethyl group, 2
-Cyanophenylethyl group, 4-dimethylaminophenylethyl group, 2-acetaminophenylethyl group, 4-
Methoxyphenylethyl group, 2-methoxyphenylethyl group, 4-trimethyloxyphenylethyl group, 4-butyldimethylsilyloxyphenylethyl group, etc.) and naphthylmethyl group, for example, 1-naphthylmethyl group,
2-naphthylmethyl group, 2-methyl-1-naphthylmethyl group, 4-methyl-1-naphthylmethyl group, 8-methyl-1-naphthylmethyl group, 4-ethyl-1-naphthylmethyl group, 4-propyl- 1-naphthylmethyl group, 4-chloro-1-naphthylmethyl group, 5-fluoro-1-naphthylmethyl group, 4-dimethylamino-1-naphthylmethyl group, 4-acetamino-1-naphthylmethyl group, 4-
Methoxy-1-naphthylmethyl group, 4-trimethylsilyloxy-1-naphthylmethyl group, etc.), unsubstituted or substituted phenyl group (eg, phenyl group, 2-
Methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 4-ethylphenyl group, 4-isopropylphenyl group, 4-hexylphenyl group, 2,4-dimethylphenyl group, 2,4,6-trimethylphenyl group Base, 4
-Fluorophenyl group, 2,6-difluorophenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 4-dimethylaminophenyl group, 4-acetaminophenyl group, 2-ethoxyphenyl group, 4-ethoxyphenyl group , 4-trimethylsilyloxyphenyl group, 4
-Butyldimethylsilyloxyphenyl group, etc.), halogen atom (eg, chlorine atom, bromine atom, fluorine atom,
Iodine _{atom), - CF 3, -CF 2} CF 3, -CH 2 C
F ₃ , -CN, -NRR '(R and R'are, for example,
R and R ′ may be the same or different, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, and a hexyl group. ), —COR (R is a hydrogen atom, a methyl group,
Alkyl groups such as ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl Group, 4-ethylphenyl group, 4-fluorophenyl group,
2-acetaminophenyl group, 3-methoxyphenyl group, 4-acetoxyphenyl group, 4-isopropylphenyl group, 4-hexylphenyl group, 2,6-difluorophenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group , 4-dimethylaminophenyl group, 4-acetaminophenyl group, 2-ethoxyphenyl group, 4-ethoxyphenyl group, 4-trimethylsilyloxyphenyl group, 4-butyldimethylsilyloxyphenyl group and other phenyl groups, benzyl groups, 2-methylbenzyl group, 3-
Methylbenzyl group, 4-methylbenzyl group, 4-ethylbenzyl group, 4-propylbenzyl group, 4-hexylbenzyl group, 3-chlorobenzyl group, 4-fluorobenzyl group, 3,5-difluorobenzyl group, 4- Nitrobenzyl group, 2-cyanobenzyl group, 4-dimethylaminobenzyl group. Examples thereof include a benzyl group such as a 2-acetaminobenzyl group, a 4-methoxybenzyl group, a 2-methoxybenzyl group and a 4-trimethylsilyloxybenzyl group, and a heterocycle such as a pyridyl group, a quinolyl group and a furyl group. ) -COOR (R is a hydrogen atom, a methyl group,
Alkyl groups such as ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl Group, 4-ethylphenyl group, 4-fluorophenyl group,
2-acetaminophenyl group, 3-methoxyphenyl group, 4-acetoxyphenyl group, 4-isopropylphenyl group, 4-hexylphenyl group, 2,6-difluorophenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group , 4-dimethylaminophenyl group, 4-acetaminophenyl group, 2-ethoxyphenyl group, 4-ethoxyphenyl group, 4-trimethylsilyloxyphenyl group, 4-butyldimethylsilyloxyphenyl group and other phenyl groups, benzyl groups, 2-methylbenzyl group, 3-
Methylbenzyl group, 4-methylbenzyl group, 4-ethylbenzyl group, 4-propylbenzyl group, 4-hexylbenzyl group, 3-chlorobenzyl group, 4-fluorobenzyl group, 3,5-difluorobenzyl group, 4- Nitrobenzyl group, 2-cyanobenzyl group, 4-dimethylaminobenzyl group. Examples thereof include a benzyl group such as a 2-acetaminobenzyl group, a 4-methoxybenzyl group, a 2-methoxybenzyl group and a 4-trimethylsilyloxybenzyl group, and a heterocycle such as a pyridyl group, a quinolyl group and a furyl group. ) —CONRR ′ (R and R ′ are, for example, hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, and other alkyl groups, Phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4
-Methylphenyl group, 4-ethylphenyl group, 4-isopropylphenyl group, 4-hexylphenyl group, 2,4
-Dimethylphenyl group, 2,4,6-trimethylphenyl group, 4-fluorophenyl group, 2,6-difluorophenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 4-dimethylaminophenyl group, 4- Phenyl groups such as acetaminophenyl group, 2-ethoxyphenyl group, 4-ethoxyphenyl group, 4-trimethylsilyloxyphenyl group, 4-butyldimethylsilyloxyphenyl group, benzyl group, 2-methylbenzyl group, 3-
Methylbenzyl group, 4-methylbenzyl group, 4-ethylbenzyl group, 4-propylbenzyl group, 4-hexylbenzyl group, 3-chlorobenzyl group, 4-fluorobenzyl group, 3,5-difluorobenzyl group, 4- Benzyl groups such as nitrobenzyl group, 2-cyanobenzyl group, 4-dimethylaminobenzyl group, 2-acetaminobenzyl group, 4-methoxybenzyl group, 2-methoxybenzyl group, 4-trimethylsilyloxybenzyl group, and the like,
R and R'may be the same or different. ), -NH
COR (R is, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, ter
alkyl groups such as t-butyl group, pentyl group and hexyl group, phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 4-ethylphenyl group, 4-isopropylphenyl group, 4 -Hexylphenyl group, 2,4-dimethylphenyl group, 2,4,6-trimethylphenyl group, 4-fluorophenyl group, 2,6
-Difluorophenyl group, 2-methoxyphenyl group, 4
-Methylphenyl group, 4-dimethylaminophenyl group, 4-acetaminophenyl group, 2-ethoxyphenyl group, 4-ethoxyphenyl group, 4-trimethylsilyloxyphenyl group, 4-butyldimethylsilyloxyphenyl group and other phenyl groups And benzyl group, 2-methylbenzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 4-ethylbenzyl group, 4-propylbenzyl group,
4-hexylbenzyl group, 3-chlorobenzyl group, 4-
Fluorobenzyl group, 3,5-difluorobenzyl group,
Benzyl groups such as 4-nitrobenzyl group, 2-cyanobenzyl group, 4-dimethylaminobenzyl group, 2-acetaminobenzyl group, 4-methoxybenzyl group, 2-methoxybenzyl group, 4-trimethylsilyloxybenzyl group and pyridyl Heterocycles such as groups, quinolyl groups, and furyl groups. ), —NHSO ₂ R (R is, for example, an alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group or a hexyl group, a phenyl group, 2 -Methylphenyl group, 3-methylphenyl group, 4
-Methylphenyl group, 4-ethylphenyl group, 4-isopropylphenyl group, 4-hexylphenyl group, 2,4
-Dimethylphenyl group, 2,4,6-trimethylphenyl group, 4-fluorophenyl group, 2,6-difluorophenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 4-dimethylaminophenyl group, 4- Phenyl groups such as acetaminophenyl group, 2-ethoxyphenyl group, 4-ethoxyphenyl group, 4-trimethylsilyloxyphenyl group, 4-butyldimethylsilyloxyphenyl group, benzyl group, 2-methylbenzyl group, 3-
Methylbenzyl group, 4-methylbenzyl group, 4-ethylbenzyl group, 4-propylbenzyl group, 4-hexylbenzyl group, 3-chlorobenzyl group, 4-fluorobenzyl group, 3,5-difluorobenzyl group, 4- Examples of the benzyl group include a nitrobenzyl group, a 2-cyanobenzyl group, a 4-dimethylaminobenzyl group, a 2-acetaminobenzyl group, a 4-methoxybenzyl group, a 2-methoxybenzyl group and a 4-trimethylsilyloxybenzyl group. ), —SO ₂ NRR ′ (R and R ′ are, for example, hydrogen atom, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group,
Alkyl group such as pentyl group and hexyl group, phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4
-Methylphenyl group, 4-ethylphenyl group, 4-isopropylphenyl group, 4-hexylphenyl group, 2,4
-Dimethylphenyl group, 2,4,6-trimethylphenyl group, 4-fluorophenyl group, 2,6-difluorophenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 4-dimethylaminophenyl group, 4- Phenyl groups such as acetaminophenyl group, 2-ethoxyphenyl group, 4-ethoxyphenyl group, 4-trimethylsilyloxyphenyl group, 4-butyldimethylsilyloxyphenyl group, benzyl group, 2-methylbenzyl group, 3-
Methylbenzyl group, 4-methylbenzyl group, 4-ethylbenzyl group, 4-propylbenzyl group, 4-hexylbenzyl group, 3-chlorobenzyl group, 4-fluorobenzyl group, 3,5-difluorobenzyl group, 4- Benzyl groups such as nitrobenzyl group, 2-cyanobenzyl group, 4-dimethylaminobenzyl group, 2-acetaminobenzyl group, 4-methoxybenzyl group, 2-methoxybenzyl group, 4-trimethylsilyloxybenzyl group, and the like,
R and R'may be the same or different. ),-NO
_2- OR (R represents, for example, an alkyl group such as a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, a phenyl group, 2 -Methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 4
-Ethylphenyl group, 4-isopropylphenyl group, 4
-Hexylphenyl group, 2,4-dimethylphenyl group,
4-fluorophenyl group, 2-methoxyphenyl group, 3
-Methoxyphenyl group, 4-methoxyphenyl group, 2-
Phenyl groups such as ethoxyphenyl group, 4-ethoxyphenyl group, 4-trimethylsilyloxyphenyl group, 4-butyldimethylsilyloxyphenyl group, 4-nitrophenyl, benzyl group, 2-methylbenzyl group, 3-
Methylbenzyl group, 4-methylbenzyl group, 4-ethylbenzyl group, 4-propylbenzyl group, 4-hexylbenzyl group, 3-chlorobenzyl group, 4-fluorobenzyl group, 3,5-difluorobenzyl group, 4- Benzyl groups such as nitrobenzyl group, 2-cyanobenzyl group, 4-dimethylaminobenzyl group, 2-acetaminobenzyl group, 4-methoxybenzyl group, 2-methoxybenzyl group, 4-trimethylsilyloxybenzyl group and pyridyl group And heterocycles such as quinolyl group and furyl group. ), -SR (R is, for example, a hydrogen atom, a methyl group,
Alkyl groups such as ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl Group, 4-ethylphenyl group, 4-isopropylphenyl group, 4-hexylphenyl group, 2,4-dimethylphenyl group, 4-fluorophenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 3-methoxyphenyl group Group, 4-dimethylaminophenyl group, 4-acetaminophenyl group, 2-ethoxyphenyl group, 4-ethoxyphenyl group, 4-trimethylsilyloxyphenyl group, 4
-Butyldimethylsilyloxyphenyl group, phenyl group such as 4-nitrophenyl, benzyl group, 2-methylbenzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 4-ethylbenzyl group, 4-propylbenzyl group,
4-hexylbenzyl group, 4-nitrobenzyl group, 2-
Cyanobenzyl group, 4-dimethylaminobenzyl group, 2
-Acetaminobenzyl group, 4-methoxybenzyl group,
Examples thereof include benzyl groups such as 2-methoxybenzyl group and 4-trimethylsilyloxybenzyl group, and heterocycles such as pyridyl group, quinolyl group and furyl group. ), -SO
R (R is, for example, a methyl group, an ethyl group, a propyl group,
Isopropyl group, butyl group, isobutyl group, tert-
Alkyl groups such as butyl group, pentyl group, hexyl group, phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 4-ethylphenyl group, 4-isopropylphenyl group, 4-hexyl group Phenyl group, 2,4-dimethylphenyl group, 4-fluorophenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 3-methoxyphenyl group, 4-dimethylaminophenyl group, 4-acetaminophenyl group, 2 Phenyl groups such as -ethoxyphenyl group, 4-ethoxyphenyl group, 4-trimethylsilyloxyphenyl group, 4-butyldimethylsilyloxyphenyl group, 4-nitrophenyl group, benzyl group, 2-methylbenzyl group, 3-methyl Benzyl group, 4-methylbenzyl group, 4-ethylbenzyl group, 4-propyl Njiru group, 4-hexyl benzyl, 3-chlorobenzyl group, 4-fluorobenzyl group,
Examples of the benzyl group include a 4-dimethylaminobenzyl group, a 2-acetaminobenzyl group, a 4-methoxybenzyl group, a 2-methoxybenzyl group, and a 4-trimethylsilyloxybenzyl group. ), —SO ₂ R (R is, for example, an alkyl group such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group or a hexyl group, a phenyl group, 2 -Methylphenyl group, 3-methylphenyl group, 4
-Methylphenyl group, 4-ethylphenyl group, 4-isopropylphenyl group, 4-hexylphenyl group, 2,4
-Dimethylphenyl group, 4-fluorophenyl group, 2-
Methoxyphenyl group, 4-methoxyphenyl group, 3-methoxyphenyl group, 4-dimethylaminophenyl group, 4
-Acetaminophenyl group, 2-ethoxyphenyl group,
Phenyl groups such as 4-ethoxyphenyl group, 4-trimethylsilyloxyphenyl group, 4-butyldimethylsilyloxyphenyl group, 4-nitrophenyl group, benzyl group, 2-methylbenzyl group, 3-methylbenzyl group,
4-methylbenzyl group, 4-ethylbenzyl group, 4-propylbenzyl group, 4-hexylbenzyl group, 3-chlorobenzyl group, 4-fluorobenzyl group, 3,5-difluorobenzyl group, 4-nitrobenzyl group, Examples thereof include benzyl groups such as 2-cyanobenzyl group, 4-dimethylaminobenzyl group, 2-acetaminobenzyl group, 4-methoxybenzyl group, 2-methoxybenzyl group, and 4-trimethylsilyloxybenzyl group. ), -SO ₃ M
(M includes a hydrogen atom, an alkali metal ion such as lithium, sodium and potassium, or an ammonium ion.), —SiRR′R ″ (R, R ′ and R ″ are, for example, a methyl group or an ethyl group. , Propyl group, isopropyl group, butyl group, isobutyl group, pentyl group,
Hexyl group and the like can be mentioned, and R, R ′ and R ″ may be the same or different. _{), - (CH 2) n} -COOR
(R is, for example, a hydrogen atom, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group or a hexyl group, and n is preferably 1
Showing a _{~10), - (CH 2)} n-CONRR '(R and R', for example, a hydrogen atom, a methyl group, an ethyl group,
Alkyl groups such as propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, phenyl group, 2-methylphenyl group,
3-methylphenyl group, 4-methylphenyl group, 4-ethylphenyl group, 4-isopropylphenyl group, 4-hexylphenyl group, 2,4-dimethylphenyl group, 2,
4,6-trimethylphenyl group, 4-fluorophenyl group, 2,6-difluorophenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 4-dimethylaminophenyl group, 4-acetaminophenyl group, 2- Phenyl groups such as ethoxyphenyl group, 4-ethoxyphenyl group, 4-trimethylsilyloxyphenyl group, 4-butyldimethylsilyloxyphenyl group, benzyl group, 2-
Methylbenzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 4-ethylbenzyl group, 4-propylbenzyl group, 4-hexylbenzyl group, 3-chlorobenzyl group, 4-fluorobenzyl group, 3,5- Difluorobenzyl group, 4-nitrobenzyl group, 2-cyanobenzyl group, 4-dimethylaminobenzyl group, 2-acetaminobenzyl group, 4-methoxybenzyl group, 2-methoxybenzyl group, 4-trimethylsilyloxybenzyl group, etc. Examples thereof include a benzyl group, R and R ′ may be the same or different, and n preferably represents 1 to 10. ), −
OCOR (R is, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, te
alkyl groups such as rt-butyl group, pentyl group, hexyl group, phenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 4-ethylphenyl group, 4-isopropylphenyl group, 4 -Hexylphenyl group, 2,4-dimethylphenyl group, 2,4,6-
Trimethylphenyl group, 4-fluorophenyl group, 2,
6-difluorophenyl group, 2-methoxyphenyl group,
Phenyl such as 4-methoxyphenyl group, 4-dimethylaminophenyl group, 4-acetaminophenyl group, 2-ethoxyphenyl group, 4-ethoxyphenyl group, 4-trimethylsilyloxyphenyl group, 4-butyldimethylsilyloxyphenyl group Group, benzyl group, 2-methylbenzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 4-ethylbenzyl group, 4-propylbenzyl group,
4-hexylbenzyl group, 3-chlorobenzyl group, 4-
Fluorobenzyl group, 3,5-difluorobenzyl group,
Benzyl groups such as 4-nitrobenzyl group, 2-cyanobenzyl group, 4-dimethylaminobenzyl group, 2-acetaminobenzyl group, 4-methoxybenzyl group, 2-methoxybenzyl group, 4-trimethylsilyloxybenzyl group and pyridyl Heterocycles such as groups, quinolyl groups, and furyl groups. ), -OSiRR'R '' (R,
Examples of R ′ and R ″ include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group and a hexyl group, and R, R ′ and R ″ are the same or different. May be. ), -CONHNR
R '(R and R'are, for example, a hydrogen atom, a methyl group,
Examples thereof include an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group, a hexyl group, a phenyl group and a benzyl group, and R and R'may be the same or different. ), -NHCONRR '(R and R'
Are, for example, alkyl groups such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, phenyl group, 2-methylphenyl group, 3-methyl group. Phenyl group, 4-methylphenyl group, 4-ethylphenyl group, 4
-Isopropylphenyl group, 4-hexylphenyl group,
2,4-dimethylphenyl group, 2,4,6-trimethylphenyl group, 4-fluorophenyl group, 2,6-difluorophenyl group, 2-methoxyphenyl group, 4-methoxyphenyl group, 4-dimethylaminophenyl group , 4-acetaminophenyl group, 2-ethoxyphenyl group, 4-
Phenyl group such as ethoxyphenyl group, 4-trimethylsilyloxyphenyl group, 4-butyldimethylsilyloxyphenyl group, benzyl group, 2-methylbenzyl group,
3-methylbenzyl group, 4-methylbenzyl group, 4-ethylbenzyl group, 4-propylbenzyl group, 4-hexylbenzyl group, 3-chlorobenzyl group, 4-fluorobenzyl group, 3,5-difluorobenzyl group, Examples of the benzyl group include 4-nitrobenzyl group, 2-cyanobenzyl group, 4-dimethylaminobenzyl group, 2-acetaminobenzyl group, 4-methoxybenzyl group, 2-methoxybenzyl group, 4-trimethylsilyloxybenzyl group. R and R ′ may be the same or different. ), −
(CH ₂ ) n-OH (n preferably represents 1 to 22),-(OCH ₂ CH ₂ ) n-OH (n preferably represents ₂ to 22), -SSR (R represents, for example. , Methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, pentyl group, hexyl group, etc.), —O-pyranose (pyranose,
For example, glucose, mannose, galactose, etc. are mentioned. ), —OPO ₃ RR ′ (R and R ′ are
For example, hydrogen atom, lithium, sodium, potassium,
Examples thereof include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a pentyl group and a hexyl group, and R and R ′ may be the same or different. ) Hereinafter, specific examples of the compound of the general formula (1) are represented by structural formulas.

[0017]

[Chemical 4]

[0018]

[Chemical 5]

Targeted diseases The diseases targeted by the drug of the present invention include prevention and treatment of pigmentation such as liver spots caused by external stimuli such as ultraviolet rays,
And senile lentigans associated with skin aging and sunburn lentigans resulting from exposure to excessive sunlight, hormonal abnormalities, internal diseases, and endogenous melasma caused by taking various therapeutic agents.

Production Method The compound represented by the general formula (1) can be obtained, for example, by Mitsuo Kotake, edited by Dai Organic Chemistry (published by Asakura Shoten, 1971 edition) or by A Weissberger, The Chemistry of Heterocyclic Compounds (A. Weis
sberger: The Chemistry of
Heterocyclic Compounds N.M.
Y. Interscience, 1950-1964
It can be easily synthesized according to a known method described in the literature such as (years) or similar methods.

Dosage form In addition to the above-mentioned active ingredients, the external preparation for skin of the present invention may optionally contain various ingredients generally used in cosmetics and pharmaceuticals, such as alcohol, oily ingredients, powder ingredients, and surfactants. , Moisturizers, thickeners, antiseptics, ultraviolet absorbers, ultraviolet scattering agents, colorants, fragrances, cyclodextrins, etc. can be added. The dosage form of the external preparation for skin of the present invention is arbitrary, and as a specific dosage form, it is used as a skin cosmetic such as lotion, cream, emulsion, pack, gel or an external preparation such as ointment, poultice, aerosol and the like. To be done.

Compounding amount The compounding amount is 0.001 to 20% by weight, preferably 0.01 to 10% by weight, based on the total amount of the external preparation. As described above, the compound of the present invention can be used as an external preparation having an excellent melanin production inhibitory action with an extremely small amount of the compound,
The excellent melanin production inhibitory effect will be understood.

[Test Examples] The present invention is described in more detail below with reference to test examples, but the present invention is not limited to these test examples.

Test Example 1: Whitening effect of B16 cells An evaluation sample was added to Eagle's MEM medium containing fetal bovine serum to a predetermined concentration. 1 × 10 ⁵ B16 cells were seeded in this culture solution. After 3 days, the culture medium was exchanged. After 5 days, a cell pellet was prepared and the whiteness of the cells was visually observed.

The control cells to which the evaluation sample was not added show a black color, but in the case of a substance having an effect of suppressing melanin production, the cells become white. The cell whiteness is 3+ in Table 1.
(Gray) was shown.

As shown in Table 1, the compounds of the present invention showed a whitening effect 10 to 100 times that of kojic acid. Therefore, in comparison with kojic acid, the compounds of the present invention
A remarkable melanin production suppressing effect was recognized.

[0027]

[Table 1]

Test Example 2: Clinical Test The results of clinical tests on the therapeutic effect on the endogenous liver spots, senile lentis, and pigment spots after inflammation of the present invention are shown.

Samples to be Tested The cream obtained by removing Samples 1-2 from Example 2 was used as a base. Samples 1-1 to 1-14 of 14 are added to this cream base.
A mixture containing 1% of each compound was used as a test sample. As a control, a cream containing a cream base and 1% kojic acid was used.

Target Patients: Patients who visited a university hospital, the breakdown of which was 280 patients with endogenous melasma,
120 people with senile pigment spots and 90 people with post-inflammatory pigment spots Test method Twice a day (morning, before bedtime), thoroughly apply 0.5 g each of the test sample to the left side of the facial trunk without applying the right side. Tested as a control. The test was conducted for 3 months.

Judgment After treatment, the left side (treatment side) and the right side (non-treatment side) were compared with each other over time, and the treatment state was visually judged.

The criteria for judgment are as follows.

Significant effect: Pigment spots are almost diminished.

Effective: Those judged to be considerably effective.

Slightly effective: Pigmentation slightly disappeared.

Invalid: Pigmentation did not disappear at all.

Side Effects: Presence or absence of skin abnormalities such as redness of the face and papules after 3 months by the above-mentioned application method. Results are shown in Tables 2, 3 and 4 below.

As described above, the substance of the present invention was found to have a significantly excellent therapeutic effect as compared with the comparative example.

[0039]

[Table 2]

[0040]

[Table 3]

[0041]

[Table 4]

[0042]

EXAMPLES Examples of the external preparation for suppressing melanin production of the present invention will be given.

Example 1 Ointment (wt%) Sample 1-10 1.0 Polyoxyethylenesorbitan monostearate (60EO) 1.0 Polyoxyethylenesorbit tetraoleate (60EO) 1.5 Self Emulsified glycerin monostearate 1.5 Salix beeswax 2.0 Paraffin 2.0 Stearic acid 3.0 Behenyl alcohol 3.0 Liquid paraffin 5.0 1,3-Butylene glycol 5.0 Citric acid 0.3 Preservatives Perfume Trace amount of purified water to 100 Each component is uniformly mixed with heating and cooled to obtain an ointment.

Example 2 Cream A (wt%) Sample 1-2 1.0 Polyoxyethylene oleyl ether 1.6 Glycerin monostearate 3.0 Salix beeswax 2.8 Cetanol 3.0 Stearic acid 1.75 Liquid paraffin 7.1 Squalane 2.5 Preservative A suitable amount Fragrance A trace amount B Glycerin 2.5 Carboxyvinyl polymer 0.08 Disodium edetate 0.01 Purified water-100 A A component belonging to A is heated and dissolved. Separately, the components belonging to B are melted by heating. Add B to A to emulsify and cool to make a cream.

Example 3 Emulsion (% by weight) Sample 1-3 0.5 Polyoxyethylene glycol monostearate (60 EO) 2.0 Self-emulsifying glyceryl monostearate 5.0 Stearic acid 5.0 Behenyl alcohol 1 0.0 liquid paraffin 1.0 glyceryl trioctanoate 10.0 1,3-butylene glycol 5.0 preservative proper amount perfume trace amount purified water to 100 While heating each component, uniformly mix and cool to obtain an emulsion.

Example 4 Liquid formulation (% by weight) Sample 1-1 0.2 Glycerin 5.0 Sorbitol 4.0 Polyoxyl stearate 40 1.55 Ethanol 10.0 Disodium edetate 0.02 Sodium glutamate 0.5 Preservative Agent Appropriate amount Perfume Trace amount Purified water to 100 Mix and stir each component and dissolve them to obtain a liquid formulation.

Example 5 Lotion (wt%) Sample 1-11 0.1 Polyoxyethylene hydrogenated castor oil (60 EO) 1.0 Ethanol 15.0 Citric acid 0.1 Sodium citrate 0.3 1, 3-Butylene glycol 4.0 Preservative A suitable amount Fragrance Trace amount Purified water-100 It mixes and stirs each component, and dissolves these and it is set as a lotion.

Example 6 Lotion (% by weight) Sample 1-13 0.05 Citric acid 0.4 Calcium carbonate 0.2 Ethanol 6.0 Propylene glycol 9.0 Preservative Suitable amount Perfume Trace amount Purified water -100 Mix and stir to dissolve them to make a lotion.

Example 7 Packing agent (% by weight) Sample 1-5 2.0 Veegum 5.0 Squalane 2.0 Propylene glycol 5.0 Zinc oxide 10.0 Ethanol 5.0 Antiseptic proper amount Perfume Trace amount purified water to 100 The components are mixed uniformly while heating and cooled to form a pack.

Example 8 Pap agent A (% by weight) Sample 1-8 2.5 Polyacrylic acid 30.0 Sorbitan monooleate 1.0 Purified water 38.2 B Sodium polyacrylate 7.0 Aluminum chloride 0. 3 Concentrated glycerin 20.0 Titanium oxide 1.0 A component belonging to A is heated and dissolved. Separately, the components belonging to B are melted by heating. B is added to A, and the mixture is stirred and mixed to obtain a poultice.

Example 9 Aerosol (wt%) Sample 1-4 0.5 Cetanol 1.2 Propylene glycol 4.0 Stearic acid 8.0 Freon 123 / 141b (57:43) 7.0 Purified water to 100 each The components are mixed and dissolved and placed in an aerosol container to prepare an aerosol agent.

Example 10 Gel (% by weight) Sample 1-14 1.0 Carboxyvinyl polymer 1.0 Concentrated glycerin 5.0 Ethanol 30.0 Diisopropanolamine 1.0 Purified water ~ 100 Mixing and stirring each component, These are dissolved to form a gel.

[0053]

INDUSTRIAL APPLICABILITY According to the present invention, not only liver spots caused by external stimuli such as ultraviolet rays, but also endogenous liver spots and senile mollusks, which are diseases that are difficult to treat conventionally and cause serious symptoms due to deterioration. , It is possible to provide a drug that effectively cures pigmentation diseases such as sunburn lentigo, post-inflammatory pigment spots, etc., even when used in an extremely small amount, and this compound has no side effects at all and is stable for a long period of time. The quality can be maintained.

Claims (1)

[Claims] 1. A compound represented by the general formula (1): (In the formula, Q represents a carbon atom or a nitrogen atom, X represents hydrogen, an alkali metal, an alkaline earth metal, an ammonium group or an organic amine residue, and R ¹ , R ² and R ³ are the same or different. , Hydrogen atom, alkyl group (having 1 to 22 carbon atoms
), Cyclohexyl group, cyclopentyl group, alkenyl group (having 1 to 22 carbon atoms), alkynyl group (having 1 to 12 carbon atoms)
22), unsubstituted or substituted aralkyl group (benzyl group, phenylethyl group, tolubenzyl group, naphthylmethyl group), unsubstituted or substituted phenyl group, halogen atom (chlorine, bromine, fluorine, iodine) ，
_{-CF 3, -CH 2 CF 3,} -CF 2 CF 3, -CO
R, -CN, -NRR ', -COOR, -CONR
_{R ', - NHCOR, -NHSO 2} R, -SO 2 NR
_{R ', - NO 2, -OR} , -SR, -SOR, -SO 2
_{R, -SO 3 M, -SiRR'R '} ', - (CH 2) n-
_{COOR, - (CH 2) n} -CONRR ', - OCO
R, -OSiRR'R '', -CONHNRR ', -NH
_{CONRR ', - (CH 2)} n-OH, - (OCH 2 C
_{H 2) n-OH, -SSR} , -O- pyranose (glucose The pyranose, mannose, galactose), - ', wherein R, R' OPO ₃ RR and R '' is a hydrogen atom, an alkyl group ( 1 to 22 carbon atoms, cyclohexyl group, cyclopentyl group, alkenyl group (1 to 22 carbon atoms), alkynyl group (1 to 22 carbon atoms)
), An unsubstituted or substituted aralkyl group (benzyl group, phenylethyl group, tolubenzyl group, naphthylmethyl group), an unsubstituted or substituted phenyl group or a heterocycle, and M is a hydrogen atom, an alkali metal Represents an ion or an ammonium ion. An external preparation for suppressing melanin production, comprising one or more selected from the group of compounds consisting of