JP2011241166A5 - - Google Patents

Description

Composition

  The present invention relates to a composition suitable for cosmetics (however, including quasi-drugs). Specifically, 1) a compound represented by the following general formula (1), its isomer and / or their pharmacology It is related with the composition characterized by containing the salt accept | permitted 2) and an anti-wrinkle agent.

(1)
[Wherein R ₁ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₂ represents
Represents a hydrogen atom, an unsubstituted or substituted aromatic group, an unsubstituted or substituted aliphatic group substituted with an aromatic group having 1 to 4 carbon atoms, R ₃ is unsubstituted or substituted Represents an aromatic group having a group, n represents an integer of 1 or 2, and m represents an integer of 0 to 3. ]

Skin aging phenomena such as wrinkles, spots and sagging become apparent with age due to the accumulation of physicochemical stimuli such as exposure to ultraviolet rays and chemical substances over many years, temperature changes, and genetic factors. Such a skin aging phenomenon has a great influence on the appearance of others, so keeping the beauty of the skin beautiful is an important concern for people. In particular, since wrinkles and sagging are a major factor in judging the youthfulness of appearance by others, various methods have been tried to prevent or improve wrinkles and sagging. For such methods, cosmetic methods such as massage treatment and medical methods such as hyaluronic acid injection are known as cosmetic methods, but sufficient effects cannot be obtained. In addition to the above, since the cost is high and there are problems in treatment, it is not necessarily a familiar and effective method for those who expect the effect. On the other hand, although many cosmetics etc. which mix | blended the component which has the prevention or improvement effect of wrinkle formation, and an anti-aging effect | action are marketed, in many cases, the effect may be unclear. For this reason, the technology which strengthens the anti-wrinkle and anti-aging effect which the component which has the prevention or improvement effect with respect to wrinkle formation and the said component has has been desired.

As described above, the attention to prevention or improvement of skin aging phenomenon, especially, wrinkle formation is very high. For this reason, analysis of the mechanism of action of wrinkle formation and development of anti-wrinkle agents based on information on the mechanism of action that has been elucidated have been actively conducted. The mechanism of action of wrinkle formation, apoptosis of cells is enhanced by it and cell damage caused by exposure to ultraviolet rays, fibrous components such as collagen by enhanced expression of matrix metalloprotease (MMP) such as the protease hydrolysis, further Has already been reported, such as disruption of fiber bundles due to enhancement of cytokines. Many anti-wrinkle agents have been developed based on the information obtained by analyzing the mechanism of action. Famous retinoic acid as a component having a prophylactic or improvement effect of wrinkle formation (see, for example, Non-Patent Document 1), wrinkles in the United States, has been approved as a therapeutic medicament for acne, effectiveness is also prove. However, retinoic acid is not approved in Japan because there are major problems in terms of safety, including irritation to the skin. As the component having a pre Bomata improvement effect on wrinkles formed other than retinoic acid, anti-wrinkle agents (e.g., see Patent Document 1), collagen enhancing agent (e.g., see Patent Document 2), hyaluronic acid Production promoters (see, for example, Patent Document 3) are known. Further, triterpene acids, or, Itewa One its benzyl derivative, against wrinkles caused by the collapse of the dermis collagen fiber bundle caused by light irradiation, to rebuild the dermal collagen fiber bundles structure, to exhibit improvement It is known (see, for example, Patent Document 4). However, the above-mentioned anti-wrinkle agent has limitations in formulation such as poor solubility in polar solvents, and there may be cases where sufficient prevention or improvement effect cannot be obtained. For this reason, in addition to the creation of new anti-wrinkle agents, it is desired to develop ingredients and formulation techniques that enhance the effects of existing anti-wrinkle agents.

Moreover, various biological activities are known for 20 types of α-amino acids having different side chains including essential amino acids constituting the living body. Among the aforementioned α-amino acids, methionine, cysteine, and derivatives thereof are expected to have characteristic biological activities different from other α-amino acids due to the presence of a sulfur atom in the chemical structure, Attention has been paid. Actually, an acylated derivative of methionine is known to have an antioxidant effect (see, for example, Patent Document 5), and a dipeptide containing methionine has a whitening effect (see, for example, Patent Document 6). In addition, cysteic acid in which the sulfur atom of cysteine is oxidized and homocysteic acid, which is a derivative thereof, are attracting attention as metabolites in the living body. For example). Furthermore, Itewa One to cysteic acid and homocysteic acid derivative, hydrogen atoms on the nitrogen atom, to derivatives with linear or branched alkyl or alkenyl group, dermabrasion or epidermal renewal action (e.g., see Patent Document 8) Etc. are known. However, regarding the compound represented by the general formula (1), specifically, the compound in which the nitrogen atom of cysteic acid and homocysteic acid is substituted with an aliphatic hydrocarbon group having an aromatic group, the compound itself is Since it is a novel compound, its biological activity was not known at all. Furthermore, the effect which an anti-wrinkle agent has by including the compound represented by the said General formula (1), its isomer, and / or those pharmacologically acceptable salts with an anti-wrinkle agent is included. It was never known to be enhanced.

Japanese Patent Application Laid-Open No. 07-041419 Japanese Patent Laid-Open No. 07-285846 JP 2007-051091 A WO 2007/148474 JP 2006-052152 A Japanese Patent Laid-Open No. 1993-032533 JP 2006-143649 A JP 09-110627 A

Development technology for anti-aging, whitening and moisturizing cosmetics, CM Publishing, supervised by Masato Suzuki

  The present invention has been made under such circumstances, and is a composition for beautifying skin suitable for cosmetics (including quasi-drugs). Specifically, 1) the above general formula ( It is an object of the present invention to provide a composition containing the compound represented by 1), an isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) an anti-wrinkle agent.

In view of such circumstances, the present inventors have intensively sought out a composition for beautifying skin suitable for cosmetics (including quasi-drugs), and 1) the following general formula ( A composition comprising the compound represented by 1), an isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) an anti-wrinkle agent has such properties. And the present invention has been completed. That is, the present invention is as follows.
<1> 1) A composition comprising the compound represented by the following general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) an anti-wrinkle agent. object.

(1)
[Wherein, R ₁ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₂ represents a hydrogen atom, an unsubstituted or substituted aromatic group, an unsubstituted or substituted group. Represents an aliphatic hydrocarbon group having 1 to 4 carbon atoms substituted by an aromatic group having R ₃ , R ₃ represents an unsubstituted or substituted aromatic group, n is an integer of 1 or 2, m Represents an integer of 0 to 3. ]

<2> The composition according to <1>, wherein the compound represented by the general formula (1) is a compound represented by the following general formula (2).

(2)
[Wherein, R ₄ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, R ₅ represents an unsubstituted or substituted aromatic group, and n represents 1 or 2 , M represents an integer of 0 to 3. ]

<3> The compound represented by the general formula (2), characterized in that a compound represented by the following general formula (3) The composition according to <2>.

(3)
[Wherein R ₆ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, R ₇ represents an unsubstituted or substituted aromatic group, and n represents 1 or 2 Represents an integer. ]

<4> The composition according to <3>, wherein the compound represented by the general formula (3) is N- (p-toluyl) homocysteic acid (compound 6).

N- (p-Toluyl) homocysteic acid (Compound 6)

<5> The compound represented by the general formula (3), characterized in that a compound represented by the following general formula (4) The composition according to <3>.

(4)
[Wherein, R ₈ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₉ represents an unsubstituted or substituted aromatic group. ]

< 6 > The compound represented by the general formula ( 4) is N- (o-toluyl) cysteic acid (compound 1), N- (m-toluyl) cysteic acid (compound 2), N- (p-toluyl). ) One or more selected from cysteic acid (compound 3), N- (p-methoxybenzoyl) cysteic acid (compound 4), and N- (biphenylcarbonyl) cysteic acid (compound 5) The composition according to <5> .

N- (o-Toluyl) cysteic acid (Compound 1)

N- (m-Toluyl) cysteic acid (Compound 2)

N- (p-Toluyl) cysteic acid (Compound 3)

N- (p-methoxybenzoyl) cysteic acid (compound 4)

N- (biphenylcarbonyl) cysteic acid (compound 5)

< 7 > The compound represented by the general formula (1), its isomer and / or a pharmacologically acceptable salt thereof is contained in an amount of 0.001% by mass to 20% by mass with respect to the total amount of the composition. The composition according to any one of <1> to < 6 >.
< 8 > The anti-wrinkle agent is vitamin A, a derivative thereof and / or a pharmacologically acceptable salt thereof, triterpenic acid, a derivative thereof and / or a pharmacologically acceptable salt thereof. The composition according to any one of <1> to <7> , which is characterized.
<9> Vitamin A or a derivative of it, and characterized retinol, retinal, retinoic acid, tretinoin, isotretinoin, tocopherol retinoic acid, retinyl palmitate, that is one or more selected from retinol acetate The composition according to <8> .
<10> the triterpenic acids, characterized in that it comprises one of ursolic acid and betulinic acid composition according to <8>.
<11> derivatives of the triterpene acid, characterized by comprising any of the bets Riterupen acid benzyl ester and triterpenic acid phosphate ester composition according to <8>.
< 12 > The composition according to any one of <1> to < 7 >, wherein the anti-wrinkle agent is a plant extract having a dermal collagen fiber bundle restructuring action.
< 13 > The composition according to <12> , wherein the plant extract having a dermis collagen fiber bundle reconstructing action is one or more selected from the following plant extracts. object.
<Plant extract having dermis collagen fiber bundle restructuring action>
A plant extract obtained from the Myrtaceae spp. An extract, a plant extract obtained from the honeysuckle elderberry, a plant extract obtained from the asteraceae cornflower, and a plant extract obtained from the Labiatae rosemary .
< 14 > The composition according to any one of <1> to < 13 >, wherein the anti-wrinkle agent is contained in an amount of 0.00001% by mass to 15% by mass with respect to the total amount of the composition .
< 15> The composition according to any one of <1> to <14>, wherein the composition is for beautifying skin.
<16> The composition according to any one of <1> to <15>, wherein the composition is used for preventing or improving wrinkle formation.
<17> A skin external preparation comprising the composition according to any one of <1> to <16> .
<18> The skin external agent characterized in that it is a water-in-oil emulsifier type external skin preparation according to <17>.
<19> The skin external preparation according to <17> or <18>, wherein the external preparation for skin is a cosmetic (however, including quasi-drugs).

<The compound represented by the general formula (1) of the present invention, its isomer and / or pharmacologically acceptable salt thereof>
The composition of the present invention comprises 1) a compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) an anti-wrinkle agent. And The compound represented by the general formula (1) of the present invention, its isomers and / or pharmacologically acceptable salts thereof, together with the anti-wrinkle agent described below, is contained in the composition, thereby improving skin beautification, In particular, it exerts the effect of enhancing the prevention or improvement action against wrinkle formation. The skin beautifying action of the composition of the present invention means a preventive or ameliorating action against the skin aging phenomenon related to the aesthetic appearance of the skin that becomes apparent with age, in particular, in addition to the improving action to make the wrinkles already formed inconspicuous, It means a preventive or ameliorating action against skin symptoms such as wrinkles and sagging that are formed and become apparent. In addition to the prevention or improvement of wrinkle formation, the component has an overall action of preventing or improving skin conditions such as prevention or improvement of skin symptoms caused by pigmentation such as sunburn, spots and dullness. .

Stated where it had One compound represented by the general formula (1), wherein, R ₁ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, R ₂ is hydrogen An atom, an unsubstituted or substituted aromatic group, an unsubstituted or substituted aromatic group substituted by an aromatic group having 1 to 4 carbon atoms, R ₃ represents an unsubstituted or substituted group N represents an integer of 1 or 2, and m represents an integer of 0 to 3. R ₁ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms. Specific examples include a hydrogen atom, a methyl group, an ethyl group, A propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group and the like can be preferably exemplified, and more preferably, a hydrogen atom, a methyl group and an ethyl group can be suitably exemplified. R ₂ represents a hydrogen atom, an unsubstituted or substituted aromatic group, an unsubstituted or substituted aromatic group substituted with an aromatic group having 1 to 4 carbon atoms, and specific examples For example, hydrogen atom, phenyl group, methylphenyl group, ethylphenyl group, propylphenyl group, butylphenyl group, methoxyphenyl group, ethoxyphenyl group, propyloxyphenyl group, butyloxyphenyl group, hydroxyphenyl group, aminophenyl group N-methylphenyl group, N-ethylphenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl group, chlorophenyl group, bromophenyl group, fluorophenyl group, trifluoromethylphenyl group, pyridyl group, Naphthyl group, biphenyl group, benzyl group, methylbenzyl group, ethylbenzyl group, metho Cibenzyl group, ethoxybenzyl group, hydroxybenzyl group, aminobenzyl group, N-methylaminobenzyl group, N-ethylaminobenzyl group, chlorobenzyl group, fluorobenzyl group, trifluoromethylbenzyl group, naphthylmethyl group, biphenylmethyl group A phenylethyl group, a naphthylethyl group, a biphenylethyl group, a phenylpropyl group, a naphthylpropyl group, a biphenylpropyl group, a phenylbutyl group, a naphthylbutyl group, a biphenylbutyl group, and the like, more preferably a hydrogen atom, Preferred examples include a phenyl group and a benzyl group. R ₃ represents an unsubstituted or substituted aromatic group. Specific examples include a phenyl group, a methylphenyl group, an ethylphenyl group, a propylphenyl group, a butylphenyl group, a methoxyphenyl group, and an ethoxyphenyl group. Propyloxyphenyl group, butyloxyphenyl group, hydroxyphenyl group, aminophenyl group, N-methylphenyl group, N-ethylphenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl group, chlorophenyl group , A bromophenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a pyridyl group, a naphthyl group, a biphenyl group and the like can be suitably exemplified, and more preferably, a phenyl group, a methylphenyl group, a methoxyphenyl group, a naphthyl group, a biphenyl group Can be suitably exemplified. The n represents an integer of 1 or 2, and more preferably, n = 1 can be suitably exemplified. The m represents an integer of 0 to 3, particularly preferably m = 0. Among the compounds represented by the general formula (1), preferred are the compounds represented by the general formula (2), isomers thereof and / or pharmacologically acceptable salts thereof. More preferably, a compound represented by the general formula (3), an isomer thereof and / or a pharmacologically acceptable salt thereof can be preferably exemplified, and more preferably, the general formula (4) is exemplified. ), Its isomers and / or their pharmacologically acceptable salts. Specific examples of preferable compounds among the compounds represented by the general formula (1) include N-benzoylcysteic acid, N- (o-toluyl) cysteic acid (compound 1), N- (m -Toluyl) cysteic acid (compound 2), N- (p-toluyl) cysteic acid (compound 3), N- (p-methoxybenzoyl) cysteic acid (compound 4), N- (biphenylcarbonyl) cysteic acid (compound 5) ), N- (p-toluyl) homocysteic acid (Compound 6), its isomers and / or their pharmacologically acceptable salts. Such a compound, when contained in the composition together with the anti-wrinkle agent described later, has an effect of enhancing an excellent skin beautifying effect, especially, preventing or improving wrinkle formation. In addition, such a compound is excellent in solubility in a hydrophilic or lipophilic medium, and can be easily formulated into a composition for use in a topical skin preparation, and can be formulated into a topical skin preparation. It is excellent in the effect of enhancing the effect of preventing or improving wrinkle formation. In addition, the skin beautifying action possessed by the compound represented by the general formula (1), its isomers and / or pharmacologically acceptable salts thereof is in addition to the additive or synergistic effect with the anti-wrinkle agent described later. , it is believed to be due to wrinkle action, such as Kola progestogen production promoting action as described in PCT / JP2009 / 069261.

Stated where it had One to said compound represented by the general formula (2), wherein, R ₄ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, R ₅ is no Represents a substituted or substituted aromatic group, n represents an integer of 1 or 2, and m represents an integer of 0 to 3. R ₄ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms. Specific examples include a hydrogen atom, a methyl group, an ethyl group, and propyl. A group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, and the like can be preferably exemplified, and a hydrogen atom, a methyl group, and an ethyl group can be suitably exemplified. R ₅ represents an unsubstituted or substituted aromatic group, and specific examples include phenyl group, methylphenyl group, ethylphenyl group, propylphenyl group, butylphenyl group, methoxyphenyl group, ethoxyphenyl group, Propyloxyphenyl group, butyloxyphenyl group, hydroxyphenyl group, aminophenyl group, N-methylphenyl group, N-ethylphenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl group, chlorophenyl group, A bromophenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a pyridyl group, a naphthyl group, a biphenyl group and the like can be preferably exemplified, and a hydrogen atom, a phenyl group and a benzyl group can be suitably exemplified. R ₅ represents an unsubstituted or substituted aromatic group. Specific examples include a phenyl group, a methylphenyl group, an ethylphenyl group, a propylphenyl group, a butylphenyl group, a methoxyphenyl group, and an ethoxyphenyl group. Propyloxyphenyl group, butyloxyphenyl group, hydroxyphenyl group, aminophenyl group, N-methylphenyl group, N-ethylphenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl group, chlorophenyl group , A bromophenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a pyridyl group, a naphthyl group, a biphenyl group, etc. Can be suitably exemplified. The n represents an integer of 1 or 2, and more preferably, n = 1 can be suitably exemplified. The m represents an integer of 0 to 3, particularly preferably m = 0. Specific examples of the compound represented by the general formula (2) that are not included in the compound represented by the general formula (3) or (4) include N- (benzylcarbonyl) cysteic acid. N- (methylbenzylcarbonyl) cysteic acid, N- (ethylbenzylcarbonyl) cysteic acid, N- (propylbenzylcarbonyl) cysteic acid, N- (butylbenzylcarbonyl) cysteic acid, N- (methoxybenzylcarbonyl) cysteic acid N- (ethoxybenzylcarbonyl) cysteic acid, N- (propyloxybezylcarbonyl) cysteic acid, N- (butyloxybenzylcarbonyl) cysteic acid, N- (hydroxybenzylcarbonyl) cysteic acid, N- (aminobenzylcarbonyl) ) Cysteinic acid, N- (N'-methylaminobenzylcarbonyl) Cysteic acid, N- (N′-ethylaminobenzylcarbonyl) cysteic acid, N- (N ′, N′-dimethylaminobenzylcarbonyl) cysteic acid, N- (N ′, N′-diethylaminobenzylcarbonyl) cysteic acid, N- (chlorobenzylcarbonyl) cysteic acid, N- (fluorobenzylcarbonyl) cysteic acid, N- (difluorobenzylcarbonyl) cysteic acid, N- (trifluoromethylbenzylcarbonyl) cysteic acid, N- (benzylcarbonyl) cysteic acid Ethyl ester, N- (methylbenzylcarbonyl) cysteic acid ethyl ester, N- (ethylbenzylcarbonyl) cysteic acid ethyl ester, N- (propylbenzylcarbonyl) cysteic acid ethyl ester, N- (butylbenzylcarbonyl) cysteic acid ethyl ester Ter, N- (methoxybenzylcarbonyl) cysteic acid ethyl ester, N- (ethoxybenzylcarbonyl) cysteic acid ethyl ester, N- (propyloxybezylcarbonyl) cysteic acid ethyl ester, N- (butyloxybenzylcarbonyl) cysteic acid Ethyl ester, N- (hydroxybenzylcarbonyl) cysteic acid ethyl ester, N- (aminobenzylcarbonyl) cysteic acid ethyl ester, N- (N′-methylaminobenzylcarbonyl) cysteic acid ethyl ester, N- (N′-ethyl) Aminobenzylcarbonyl) cysteic acid ethyl ester, N- (N ′, N′-dimethylaminobenzylcarbonyl) cysteic acid ethyl ester, N- (N ′, N′-diethylaminobenzylcarbonyl) cysteic acid ethyl ester, N- ( Rolobenzylcarbonyl) cysteic acid ethyl ester, N- (fluorobenzylcarbonyl) cysteic acid ethyl ester, N- (difluorobenzylcarbonyl) cysteic acid ethyl ester, N- (trifluoromethylbenzylcarbonyl) cysteic acid ethyl ester, N- ( Benzylcarbonyl) homocysteic acid, N- (methylbenzylcarbonyl) homocysteic acid, N- (ethylbenzylcarbonyl) homocysteic acid, N- (propylbenzylcarbonyl) homocysteic acid, N- (butylbenzylcarbonyl) homocysteic acid N- (methoxybenzylcarbonyl) homocysteic acid, N- (ethoxybenzylcarbonyl) homocysteic acid, N- (propyloxybezylcarbonyl) homocysteic acid, N- (butyloxybenzene) Carbonyl) homocysteic acid, N- (hydroxybenzylcarbonyl) homocysteic acid, N- (aminobenzylcarbonyl) homocysteic acid, N- (N′-methylaminobenzylcarbonyl) homocysteic acid, N- (N′-ethyl) Aminobenzylcarbonyl) homocysteic acid, N- (N ′, N′-dimethylaminobenzylcarbonyl) homocysteic acid, N- (N ′, N′-diethylaminobenzylcarbonyl) homocysteic acid, N- (chlorobenzylcarbonyl) Homocysteic acid, N- (fluorobenzylcarbonyl) homocysteic acid, N- (difluorobenzylcarbonyl) homocysteic acid, N- (trifluoromethylbenzylcarbonyl) homocysteic acid, N- (benzylcarbonyl) homocysteic acid ethyl ester N- (Methylbenzyl cal Bonyl) homocysteic acid ethyl ester, N- (ethylbenzylcarbonyl) homocysteine acid ethyl ester, N- (propylbenzylcarbonyl) homocysteine acid ethyl ester, N- (butylbenzylcarbonyl) homocysteine acid ethyl ester, N- ( Methoxybenzylcarbonyl) homocysteine acid ethyl ester, N- (ethoxybenzylcarbonyl) homocysteine acid ethyl ester, N- (propyloxybezylcarbonyl) homocysteine acid ethyl ester, N- (butyloxybenzylcarbonyl) homocysteine acid ethyl Ester, N- (hydroxybenzylcarbonyl) homocysteine acid ethyl ester, N- (aminobenzylcarbonyl) homocysteine acid ethyl ester, N- (N′-methylaminobenzylcarbonyl) Mocysteine acid ethyl ester, N- (N′-ethylaminobenzylcarbonyl) homocysteine acid ethyl ester, N- (N ′, N′-dimethylaminobenzylcarbonyl) homocysteine acid ethyl ester, N- (N ′, N '-Diethylaminobenzylcarbonyl) homocysteine acid ethyl ester, N- (chlorobenzylcarbonyl) homocysteine acid ethyl ester, N- (fluorobenzylcarbonyl) homocysteine acid ethyl ester, N- (difluorobenzylcarbonyl) homocysteine acid ethyl ester N- (trifluoromethylbenzylcarbonyl) homocysteic acid ethyl ester, its isomers and / or their pharmacologically acceptable salts. Among the compounds represented by the general formula (2), preferred are N-benzoylcysteic acid, N- (o-toluyl) cysteic acid (compound 1), N- (m-toluyl) cysteic acid (compound 2), N- (p-toluyl) cysteic acid (compound 3), N- (p-methoxybenzoyl) cysteic acid (compound 4), N- (biphenylcarbonyl) cysteic acid (compound 5), N- (p- Toluyl) homocysteic acid (compound 6), isomers thereof and / or pharmacologically acceptable salts thereof can be suitably exemplified. Such a compound, when contained in the composition together with the anti-wrinkle agent described later, has an effect of enhancing an excellent skin beautifying effect, especially, preventing or improving wrinkle formation. In addition, such a compound is excellent in solubility in a hydrophilic or lipophilic medium, and can be easily formulated into a composition for use in a topical skin preparation, and can be formulated into a topical skin preparation. It is excellent in the effect of enhancing the effect of preventing or improving wrinkle formation.

Stated where it had One compound represented by the general formula (3), wherein, R ₆ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, R ₇ is unsubstituted Represents a substituted or substituted aromatic group, and n represents an integer of 1 or 2. R ₆ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms. Specific examples include a hydrogen atom, a methyl group, an ethyl group, and propyl. A group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, and the like can be preferably exemplified, and a hydrogen atom, a methyl group, and an ethyl group can be suitably exemplified. R ₇ represents an unsubstituted or substituted aromatic group, and specific examples include phenyl group, methylphenyl group, ethylphenyl group, propylphenyl group, butylphenyl group, methoxyphenyl group, ethoxyphenyl group, Propyloxyphenyl group, butyloxyphenyl group, hydroxyphenyl group, aminophenyl group, N-methylphenyl group, N-ethylphenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl group, chlorophenyl group, A bromophenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a pyridyl group, a naphthyl group, a biphenyl group and the like can be preferably exemplified, and a hydrogen atom, a phenyl group and a benzyl group can be suitably exemplified. R ₈ represents an unsubstituted or substituted aromatic group, and specific examples include a phenyl group, a methylphenyl group, an ethylphenyl group, a propylphenyl group, a butylphenyl group, a methoxyphenyl group, and an ethoxyphenyl group. Propyloxyphenyl group, butyloxyphenyl group, hydroxyphenyl group, aminophenyl group, N-methylphenyl group, N-ethylphenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl group, chlorophenyl group , A bromophenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a pyridyl group, a naphthyl group, a biphenyl group, etc. Can be suitably exemplified. The n represents an integer of 1 or 2, and more preferably, n = 1 can be suitably exemplified. Of the compounds represented by the general formula (3), specific examples of compounds not included in the compound represented by the general formula (4) include N- (benzoyl) homocysteic acid, N- (methyl Benzoyl) homocysteic acid, N- (ethylbenzoyl) homocysteic acid, N- (propylbenzoyl) homocysteic acid, N- (butylbenzoyl) homocysteic acid, N- (methoxybenzoyl) homocysteic acid, N- (ethoxy Benzoyl) homocysteic acid, N- (propyloxybenzoyl) homocysteic acid, N- (butyloxybenzoyl) homocysteic acid, N- (hydroxybenzoyl) homocysteic acid, N- (aminobenzoyl) homocysteic acid, N- (N'-methylaminobenzoyl) homocysteic acid, N- (N'-ethylaminobenzoyl) homosystem Acid, N- (N ′, N′-dimethylaminobenzoyl) homocysteic acid, N- (N ′, N′-diethylaminobenzoyl) homocysteic acid, N- (chlorobenzoyl) homocysteic acid, N- (fluoro Benzoyl) homocysteic acid, N- (difluorobezoyl) homocysteic acid, N- (trifluoromethylbenzoyl) homocysteic acid, N- (naphthylcarbonyl) homocysteic acid, N- (biphenylcarbonyl) homocysteic acid, N -(Benzoyl) homocysteic acid methyl ester, N- (methylbenzoyl) homocysteic acid methyl ester, N- (ethylbenzoyl) homocysteic acid methyl ester, N- (propylbenzoyl) homocysteic acid methyl ester, N- (butyl Benzoyl) homocysteine acid methyl ester, N- (methoxy Nzoiru) homocysteine acid methyl ester, N- (ethoxy-benzoyl) homocysteic acid methyl ester, N-
(Propyloxybenzoyl) homocysteic acid methyl ester, N- (butyloxybenzoyl) homocysteic acid methyl ester, N- (hydroxybenzoyl) homocysteic acid methyl ester, N- (aminobenzoyl) homocysteic acid methyl ester, N- (N'-methylaminobenzoyl) homocysteine acid methyl ester, N- (N'-ethylaminobenzoyl) homocysteine acid methyl ester, N- (N ', N'-dimethylaminobenzoyl) homocysteine acid methyl ester, N -(N ', N'-diethylaminobenzoyl) homocysteic acid methyl ester, N- (chlorobenzoyl) homocysteic acid methyl ester, N- (fluorobenzoyl) homocysteic acid methyl ester, N- (difluorobezoyl) homocysteine Acid methyl ester N- (trifluoromethylbenzoyl) homocysteine acid methyl ester, N- (naphthylcarbonyl) homocysteine acid methyl ester, N- (biphenylcarbonyl) homocysteine acid methyl ester, N- (benzoyl) homocysteine acid ethyl ester, N- (methylbenzoyl) homocysteine acid ethyl ester, N- (ethylbenzoyl) homocysteine acid ethyl ester, N- (propylbenzoyl) homocysteine acid ethyl ester, N- (butylbenzoyl) homocysteine acid ethyl ester, N- (Methoxybenzoyl) homocysteic acid ethyl ester, N- (ethoxybenzoyl) homocysteine acid ethyl ester, N- (propyloxybenzoyl) homocysteine acid ethyl ester, N- (butyloxybenzoyl) homosis Inic acid ethyl ester, N- (hydroxybenzoyl) homocysteine acid ethyl ester, N- (aminobenzoyl) homocysteine acid ethyl ester, N- (N′-methylaminobenzoyl) homocysteine acid ethyl ester, N- (N ′ -Ethylaminobenzoyl) homocysteine acid ethyl ester, N- (N ', N'-dimethylaminobenzoyl) homocysteine acid ethyl ester, N- (N', N'-diethylaminobenzoyl) homocysteine acid ethyl ester, N- (Chlorobenzoyl) homocysteine acid ethyl ester, N- (fluorobenzoyl) homocysteine acid ethyl ester, N- (difluorobezoyl) homocysteine acid ethyl ester, N- (trifluoromethylbenzoyl) homocysteine acid ethyl ester, N -(Naphthylcarbonyl) homo Preferred examples include cysteic acid ethyl ester, N- (biphenylcarbonyl) homocysteic acid ethyl ester, isomers thereof and / or pharmacologically acceptable salts thereof. Among the compounds represented by the general formula (3), N-benzoylcysteic acid, N- (o-toluyl) cysteic acid (compound 1), N- (m-toluyl) cysteic acid (compounds) are preferable. 2), N- (p-toluyl) cysteic acid (compound 3), N- (p-methoxybenzoyl) cysteic acid (compound 4), N- (biphenylcarbonyl) cysteic acid (compound 5), N- (p- Toluyl) homocysteic acid (compound 6), isomers thereof and / or pharmacologically acceptable salts thereof can be suitably exemplified. Such a compound, when contained in the composition together with the anti-wrinkle agent described later, has an effect of enhancing an excellent skin beautifying effect, especially, preventing or improving wrinkle formation. In addition, such a compound is excellent in solubility in a hydrophilic or lipophilic medium, and can be easily formulated into a composition for use in a topical skin preparation, and can be formulated into a topical skin preparation. It is excellent in the effect of enhancing the effect of preventing or improving wrinkle formation.

Stated where it had One compound represented by the general formula (4), wherein, R ₈ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, R ₉ is free A substituted or substituted aromatic group is represented. R ₈ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms. Specific examples include a hydrogen atom, a methyl group, an ethyl group, and propyl. A group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, and the like can be preferably exemplified, and a hydrogen atom, a methyl group, and an ethyl group can be suitably exemplified. R ₉ represents an unsubstituted or substituted aromatic group, and specific examples include a phenyl group, a methylphenyl group, an ethylphenyl group, a propylphenyl group, a butylphenyl group, a methoxyphenyl group, and an ethoxyphenyl group. Propyloxyphenyl group, butyloxyphenyl group, hydroxyphenyl group, aminophenyl group, N-methylphenyl group, N-ethylphenyl group, N, N-dimethylaminophenyl group, N, N-diethylaminophenyl group, chlorophenyl group , A bromophenyl group, a fluorophenyl group, a trifluoromethylphenyl group, a pyridyl group, a naphthyl group, a biphenyl group, and the like can be preferably exemplified, and a hydrogen atom, a phenyl group, and a benzyl group can be suitably exemplified. Specific examples of preferable compounds among the compounds represented by the general formula (4) include N- (benzoyl) cysteic acid, N- (methylbenzoyl) cysteic acid, N- (ethylbenzoyl) cysteic acid, N- (propylbenzoyl) cysteic acid, N- (butylbenzoyl) cysteic acid, N- (methoxybenzoyl) cysteic acid, N- (ethoxybenzoyl) cysteic acid, N- (propyloxybenzoyl) cysteic acid, N- (butyl Oxybenzoyl) cysteic acid, N- (hydroxybenzoyl) cysteic acid, N- (aminobenzoyl) cysteic acid, N- (N′-methylaminobenzoyl) cysteic acid, N- (N′-ethylaminobenzoyl) cysteic acid, N- (N ′, N′-dimethylaminobenzoyl) cysteic acid, N- (N ′, N′-diethylaminoben) Yl) cysteic acid, N- (chlorobenzoyl) cysteic acid, N- (fluorobenzoyl) cysteic acid, N- (difluorobezoyl) cysteic acid, N- (trifluoromethylbenzoyl) cysteic acid, N- (naphthylcarbonyl) Cysteine acid, N- (biphenylcarbonyl) cysteic acid, N- (benzoyl) cysteic acid methyl ester, N- (methylbenzoyl) cysteic acid methyl ester, N- (ethylbenzoyl) cysteic acid methyl ester, N- (propylbenzoyl) Cysteinic acid methyl ester, N- (butylbenzoyl) cysteic acid methyl ester, N- (methoxybenzoyl) cysteic acid methyl ester, N- (ethoxybenzoyl) cysteic acid methyl ester, N- (propyloxybenzoyl) cysteic acid methyl ester Ester, N- (Butyloxybenzoyl) cysteic acid methyl ester, N- (hydroxybenzoyl) cysteic acid methyl ester, N- (aminobenzoyl) cysteic acid methyl ester, N- (N′-methylaminobenzoyl) cysteic acid methyl ester N- (N′-ethylaminobenzoyl) cysteic acid methyl ester, N- (N ′, N′-dimethylaminobenzoyl) cysteic acid methyl ester, N- (N ′, N′-diethylaminobenzoyl) cysteic acid methyl ester N- (chlorobenzoyl) cysteic acid methyl ester, N- (fluorobenzoyl) cysteic acid methyl ester, N- (difluorobezoyl) cysteic acid methyl ester, N- (trifluoromethylbenzoyl) cysteic acid methyl ester, N- (Naphthylcarbonyl) Stearic acid methyl ester, N- (biphenylcarbonyl) cysteic acid methyl ester, N- (benzoyl) cysteic acid ethyl ester, N- (methylbenzoyl) cysteic acid ethyl ester, N- (ethylbenzoyl) cysteic acid ethyl ester, N- (Propylbenzoyl) cysteic acid ethyl ester, N- (butylbenzoyl) cysteic acid ethyl ester, N- (methoxybenzoyl) cysteic acid ethyl ester, N- (ethoxybenzoyl) cysteic acid ethyl ester, N- (propyloxybenzoyl) cysteine Acid ethyl ester, N- (butyloxybenzoyl) cysteic acid ethyl ester, N- (hydroxybenzoyl) cysteic acid ethyl ester, N- (aminobenzoyl) cysteic acid ethyl ester, N- (N′- Tylaminobenzoyl) cysteic acid ethyl ester, N- (N′-ethylaminobenzoyl) cysteic acid ethyl ester, N- (N ′, N′-dimethylaminobenzoyl) cysteic acid ethyl ester, N- (N ′, N ′ -Diethylaminobenzoyl) cysteic acid ethyl ester, N- (chlorobenzoyl) cysteic acid ethyl ester, N- (fluorobenzoyl) cysteic acid ethyl ester, N- (difluorobezoyl) cysteic acid ethyl ester, N- (trifluoromethylbenzoyl) Preferred examples include cysteic acid ethyl ester, N- (naphthylcarbonyl) cysteic acid ethyl ester, N- (biphenylcarbonyl) cysteic acid ethyl ester, isomers thereof and / or pharmacologically acceptable salts thereof. Among the compounds represented by the general formula (4), preferred are N-benzoylcysteic acid, N- (o-toluyl) cysteic acid (compound 1), N- (m-toluyl) cysteic acid (compound 2), N- (p-toluyl) cysteic acid (compound 3), N- (p-methoxybenzoyl) cysteic acid (compound 4), N- (biphenylcarbonyl) cysteic acid (compound 5), its isomers and / or Alternatively, pharmacologically acceptable salts thereof can be preferably exemplified. Such a compound, when contained in the composition together with the anti-wrinkle agent described later, has an effect of enhancing an excellent skin beautifying effect, especially, preventing or improving wrinkle formation. In addition, such a compound is excellent in solubility in a hydrophilic or lipophilic medium, and can be easily formulated into a composition for use in a topical skin preparation, and can be formulated into a topical skin preparation. It is excellent in the effect of enhancing the effect of preventing or improving wrinkle formation.

In addition, the compound represented by the general formula (1), its isomers and / or pharmacologically acceptable salts thereof, together with the anti-wrinkle agent described later, is contained in the composition, thereby providing an excellent skin beautifying effect. In particular, it has an excellent enhancing effect in preventing or improving wrinkle formation. Such an enhancement effect of the skin beautifying effect is an additive or synergistic effect in combination with an anti-wrinkle agent possessed by the compound represented by the general formula (1), its isomer and / or a pharmacologically acceptable salt. In addition to the skin-beautifying action of the compound represented by the general formula (1), in particular, the prevention or improvement action against wrinkle formation such as collagen production promotion action, and further the stain prevention, dullness prevention, etc. Due to improvement. Further, the compound represented by the general formula (1), isomers thereof and / or pharmacologically acceptable salts thereof have high solubility in polar solvents in addition to the biological action described above. Therefore, it is easy to make a highly stable preparation, and it is excellent in the action on the drug guiding state such as improving the delivery efficiency of the anti-wrinkle agent to the target site. In addition to the racemic compound (DL form), the compounds represented by the general formulas (1) to (4) include D and L isomers. The compositions containing these isomers all exhibit excellent skin beautifying effects and preventive or ameliorating effects on wrinkle formation, but the L isomer can be preferably exemplified by the safety to the living body and the stability in the preparation.

The compounds represented by the general formulas (1) to (4), isomers thereof and / or pharmacologically acceptable salts thereof are commercially available cysteic acid, homocysteic acid, and derivatives thereof. Can be produced by carrying out deprotection, coupling, and introduction of a protecting group according to the method described in “Basics and Experiments of Peptide Synthesis (Maruzen)”, etc. It can also be produced by a method. Such a compound can be used in the composition as it is with an anti-wrinkle agent, which will be described later, so that it can be used to enhance the effect of skin beautification, prevention of wrinkle formation or improvement, but it is a pharmaceutically acceptable acid or base. It is also possible to treat it together with it and convert it into a salt form and use it as a salt. For example, mineral salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, para toluenesulfonate, organic acid salts such as benzenesulfonate, sodium salt, alkali metal, calcium salts, alkaline earth metals such as magnesium salt metal, triethylamine salt or potassium salt, triethanolamine salt, an ammonium salt, monoethanolamine Preferred examples include organic amine salts such as amine salts and piperidine salts, and basic amino acid salts such as lysine salts and arginine salts .

The compound represented by the general formula (1) of the present invention, isomers thereof and / or pharmacologically acceptable salts thereof work together with the anti-wrinkle agent described later, skin beautifying action, especially, prevention against wrinkle formation. Alternatively, in order to exert the effect of enhancing the improving action, the total amount is 0.001% by mass to 20% by mass, more preferably 0.01% by mass to 10% by mass, and still more preferably 0%. It is preferable to contain 1 mass%-5 mass%. This resides may not exhibited the effect is too small or too large, the effect becomes plateau is because resides may impair the flexibility of the system.

N- (o-Toluyl) -L-cysteic acid (L isomer of Compound 1)

<Production Example 1: Synthesis of L isomer of Compound 1>
3 g ( 17.7 mmol) of L-cysteic acid (Tokyo Chemical Industry Co., Ltd.), 18 mL of tetrahydrofuran ( Wako Pure Chemical Industries, Ltd.), and 8 mL of water were placed in a 100 mL eggplant-shaped flask and cooled in an ice bath. did. After sufficiently cooling, 4.40 g ( 31.6 mmol) of potassium carbonate (Wako Pure Chemical Industries, Ltd.) was added. o-Toluyl chloride 3.2 8 g ( Tokyo Chemical Industry Co., Ltd.) was sequentially added so that the liquid temperature did not rise. After the addition, the ice bath was removed and the mixture was stirred at room temperature. After confirming the progress of the reaction by thin layer chromatography , tetrahydrofuran was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate, and the pH was adjusted to 2 or less with hydrochloric acid. The filtrate was concentrated and water (20 ml) was added. The precipitated crystals were collected by filtration, and the crystals were washed with acetone. The crystal collected by filtration was dried at 60 ° C. to obtain 0.78 g ( 2,72 mmol) of the L isomer of Compound 1 having the above structure. Shown below are the values of the indications.
¹ H-NMR (D ₂ O): δ 2.31 (3H, s), 3.42 (2H, m), 4.86 (1
H, m), 7.24 (2H, m), 7.35 (2H, m).
FAB-MS (negative ion mode): M / z = 286 ([M−H] ⁻ )

N- (m-Toluyl) -L-cysteic acid (L isomer of compound 2)

<Production Example 2: Synthesis of L isomer of Compound 2>
3 g ( 17.7 mmol) of L-cysteic acid (Tokyo Chemical Industry Co., Ltd.), 18 mL of tetrahydrofuran ( Wako Pure Chemical Industries, Ltd.), and 18 mL of water were placed in a 100 mL eggplant-shaped flask, and then placed in an ice bath. And cooled. After cooling sufficiently, potassium carbonate 4.40 g ( 31.6 mmol) (Wako Pure Chemical Industries, Ltd.) and m-toluyl chloride 2.19 g ( Tokyo Chemical Industry Co., Ltd.) were sequentially added so that the liquid temperature would not rise. Added. After reacting for 1 hour in an ice bath, m-toluyl chloride 1.09 g ( Tokyo Chemical Industry Co., Ltd.) was added again. After the addition, the ice bath was removed and the mixture was stirred at room temperature. After confirming the progress of the reaction by thin layer chromatography , tetrahydrofuran was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate, and the pH was adjusted to 2 or less with hydrochloric acid. The filtrate was concentrated and water (18 mL) was added. After aging at 4 ° C., the precipitated crystals were separated by filtration. The obtained crystals were washed with acetone and collected by filtration. The crystals collected by filtration were dried at 60 ° C. to obtain 1.65 g ( 5.74 mmol) of the L isomer of compound 2 having the above structure. Shown below are the values of the indications.
¹ H-NMR (DMSO-d ₆ ): δ 2.36 (3H, s), 2.94 (2H, m), 4.41 (1H, m), 7.36 (2H, d), 7. 58 (2H, t), 8.84 (1H, d), 12.5 (1H, bs).
FAB-MS (negative ion mode): M / z = 286 ([M−H] ⁻ )

N- (p-Toluyl) -L-cysteic acid (L isomer of compound 3)

<Production Example 3: Synthesis of L isomer of Compound 3>
L- cysteic acid monohydrate 5 g (26.7 mmol) (Sigma-Aldrich), 1,4-dioxane 2 0 mL (Wako Pure Chemical Industries, Ltd.), and were placed water 1 0 mL to 10 0 mL eggplant type flask Then, it was cooled in an ice bath. After sufficient cooling, 8N aqueous sodium hydroxide solution 10. 7 mL, p-toluyl chloride 3.3 6 mL ( Sigma Aldrich) was sequentially added dropwise so that the liquid temperature did not increase. After completion of dropping, the ice bath was removed and the mixture was stirred at room temperature. After confirming the progress of the reaction by thin layer chromatography , 1,4-dioxane was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate, and the pH was adjusted to 2 or less with hydrochloric acid. The obtained aqueous solution was freeze-dried and the target product was extracted with methanol . Methanol was distilled off under reduced pressure, then crystallized and filtered. The crystal collected by filtration was dried to obtain 9 g ( 20.2 mmol) of the L isomer of compound 3 having the above structure. Indicative values are shown below.
¹ H-NMR (D ₂ O): δ 2.32 (3H, s), 3.46 (2H, m), 4.87 (1H, m), 7.25 (2H, d), 7.64 (2H, d).
FAB-MS (negative ion mode): M / z = 286 ([M−H] ⁻ ), 308 ([M + Na−H] ⁻ )

N- (p-methoxybenzoyl) -L-cysteic acid (L isomer of compound 4)

<Production Example 4: Synthesis of L isomer of compound 4>
2 g ( 11.8 mmol) of L-cysteic acid (Tokyo Chemical Industry Co., Ltd.), 12 mL of tetrahydrofuran ( Wako Pure Chemical Industries, Ltd.) and 12 mL of water were placed in a 100 mL eggplant type flask and then placed in an ice bath. And cooled. After sufficiently cooling, the liquid temperature of potassium carbonate 2.9 4 g ( 21.3 mmol) (Wako Pure Chemical Industries, Ltd.) and 4-methoxybenzoyl chloride 1.6 1 g ( Tokyo Chemical Industry Co., Ltd.) is prevented from rising. Sequentially added. After reacting for 1 hour in an ice bath, 4-methoxybenzoyl chloride 0.8 1 g ( Tokyo Chemical Industry Co., Ltd.) was added again. After the addition, the ice bath was removed and the mixture was stirred at room temperature. After confirming the progress of the reaction by thin layer chromatography , tetrahydrofuran was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate, and the pH was adjusted to 2 or less with hydrochloric acid. The precipitated crystals were filtered and washed with water. The filtrate was concentrated and the precipitated crystals were filtered again. The obtained crystals were combined and then washed with acetone. After filtering the crystals, the collected crystals were dried at 60 ° C. to obtain 2.47 g ( 8.14 mmol) of L isomer of compound 4 having the above structure. Indicative values are shown below.
¹ H-NMR (D ₂ O): δ 3.45 (2H, m), 3.81 (3H, s), 4.85 (1H, m), 7.00 (2H, d), 7.72 (2H, d).
FAB-MS (negative ion mode): M / z = 302 ([M−H] ⁻ )

N- (biphenylcarbonyl) -L-cysteic acid (L isomer of compound 5)

<Production Example 5: Synthesis of L isomer of compound 5>
2 g ( 11.8 mmol) of L-cysteic acid (Tokyo Chemical Industry Co., Ltd.), 12 mL of tetrahydrofuran ( Wako Pure Chemical Industries, Ltd.) and 12 mL of water were placed in a 100 mL eggplant type flask and then placed in an ice bath. And cooled. After sufficiently cooling, the liquid temperature of potassium carbonate 2.9 4 g ( 21.3 mmol) (Wako Pure Chemical Industries, Ltd.) and 4-phenylbenzoyl chloride 2.0 5 g ( Tokyo Chemical Industry Co., Ltd.) is prevented from rising. Sequentially added. After reacting in an ice bath for 1.5 hours, 1.02 g of 4-phenylbenzoyl chloride ( Tokyo Chemical Industry Co., Ltd.) was added again. After the addition, the ice bath was removed and the mixture was stirred at room temperature. After confirming the progress of the reaction by thin layer chromatography , tetrahydrofuran was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate, and the pH was adjusted to 2 or less with hydrochloric acid. The precipitated crystals were filtered and washed with water. The obtained crystals were washed with acetone and then filtered. The crystals collected by filtration were dried at 60 ° C. to obtain 2.37 g ( 6.78 mmol) of the L isomer of compound 5 having the above structure. Indicative values are shown below.
¹ H-NMR (DMSO-d ₆ ): δ 2.96 (2H, m), 4.54 (1H, q), 7.42 (1H, m), 7.51 (2H, m), 7. 74 (2H, d), 7.80 (2H, d), 7.90 (2H, d), 8.94 (1H, d).
FAB-MS (negative ion mode): M / z = 348 ([M−H] ⁻ )

N- (p-Toluyl) homocysteic acid (Compound 6)

<Production Example 6: Synthesis of Compound 6>
DL-homocysteic acid 2 g ( 10.9 mmol) (Sigma Aldrich), tetrahydrofuran 12 mL ( Wako Pure Chemical Industries, Ltd.) and water 12 mL were placed in a 100 mL eggplant-shaped flask and then in an ice bath. Cooled down. After cooling sufficiently, 1 g ( 19.6 mmol) of potassium carbonate 2.7 (Wako Pure Chemical Industries, Ltd.) was added. 1. 9 g of p-toluyl chloride ( Sigma Aldrich) was sequentially added so that the liquid temperature did not increase. After reacting for 1 hour in an ice bath, 0.76 g of p-toluyl chloride ( Sigma Aldrich) was added again. After the addition, the ice bath was removed and the mixture was stirred at room temperature. After confirming the progress of the reaction by thin layer chromatography , tetrahydrofuran was distilled off under reduced pressure. The obtained residue was washed with ethyl acetate, and the pH was adjusted to 2 or less with hydrochloric acid. After filtration of the solution, the filtrate was concentrated and methanol was added. The precipitated crystals were separated by filtration and washed with water. The crystals were filtered, and the collected crystals were dried at 60 ° C. to obtain 51.9 g ( 6.47 mmol) of compound 61.9 having the above structure. Indicative values are shown below.
¹ H-NMR (DMSO-d ₆ ): δ 2.12 (2H, m), 2.35 (3H, s), 2.57 (2H, t), 4.37 (1H, m), 7. 26 (2H, d), 7.79 (2H, d),
9.02 (1H, d).
FAB-MS (negative ion mode): M / z = 300 ([M−H] ⁻ )

<Anti-wrinkle agent of the present invention>
The composition of the present invention contains 1) a compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) an anti-wrinkle agent. Features. The anti-wrinkle agent of the present invention can be applied without particular limitation as long as it is an anti-wrinkle agent having a preventive or ameliorating action against wrinkle formation. Preferable examples include physically acceptable salts, triterpenic acid or triterpenic acid derivatives and / or pharmacologically acceptable salts thereof, and plant extracts having a dermis collagen fiber bundle remodeling action. The preventive or ameliorating action for wrinkle formation possessed by the anti-wrinkle agent of the present invention includes a preventive or ameliorating action for wrinkles formed from wrinkles that are formed or wrinkles that are in the process of forming, in addition to the improving action for wrinkles that have already been formed Is included. Further, the action mechanism of the anti-wrinkle agent of the present invention is assumed to be an action mechanism through hyaluronic acid production promoting action, collagen production promoting action, matrix metalloproteinase inhibitory action, dermal collagen fiber bundle remodeling action, etc. Is done. The compound represented by the general formula (1), isomers thereof and / or pharmacologically acceptable salts thereof are combined with an anti-wrinkle agent in a skin external preparation to form wrinkles of the anti-wrinkle agent. Has the effect of enhancing the preventive or ameliorating action against Can have One to any of the anti-wrinkle agent having prophylactic or improvement effect on the wrinkle formation, it can be included in the compositions of the present invention, from the viewpoint of enhancing the effect, as particularly preferred, dermal collagen An anti-wrinkle agent having an action of preventing or improving the disruption of the fiber bundle or the disorder of the structure, specifically, triterpenic acid or a triterpenic acid derivative and / or a pharmacologically acceptable salt thereof, dermal collagen fiber bundle reactivation A plant extract having a construction action can be suitably exemplified.

In addition, the anti-wrinkle agent of the present invention can be preferably exemplified by forms such as simple chemical substances or plant-derived extracts containing the compound. Here, the extract derived from a plant, plant extracts themselves, fractionated plant extracts, purified fractions, also plant extracts fractionation means generic name for solvent removal of purified product. In addition, when the anti-wrinkle agent is contained in the composition together with the compound represented by the general formula (1), its isomer and / or a pharmacologically acceptable salt thereof, the anti-wrinkle agent described above is used. Can contain only 1 type, and can also contain 2 or more types in combination.

Regarding the anti-wrinkle agent of the present invention, vitamin A, its derivatives and / or their pharmacologically acceptable salts, triterpenic acid, their acid derivatives and / or their pharmacologically acceptable ones are particularly preferred. Preferred examples include salts and plant extracts having an action of reconstructing dermal collagen fiber bundles. Among the vitamin A, derivatives thereof and / or pharmacologically acceptable salts thereof, preferred are retinol , derivatives thereof and / or pharmacologically acceptable salts thereof, retinal , derivatives thereof and / or or acceptable salts in their pharmacological, retinoic acid, a derivative thereof and / or a pharmaceutically acceptable salt thereof pharmacologically can be preferably exemplified, if specifically mentioned as further preferred, retinol, salts acceptable derivative thereof and / or their pharmacologically, retinol, retinol acetate, retinol propionate, butyrate retinol, octylate retinol, lauric acid retinol, retinol palmitate, retinol stearic acid, myristic acid retinol, retinol oleic acid, linoleic acid retinol, Reno - such as Le retinyl Retinol retinol fatty acid esters and / or pharmacologically acceptable salts thereof can be preferably exemplified, and as retinal , derivatives thereof and / or pharmacologically acceptable salts thereof, retinal and / or drugs thereof Physiologically acceptable salts can be preferably exemplified, and retinoic acid, its derivatives and / or pharmacologically acceptable salts thereof include retinoic acid, tretinoin ( all-trans retinoic acid ), isotretinoin (13- Cis-retinoic acid), methyl retinoic acid, ethyl retinoic acid, retinol retinoic acid, tocopheryl retinoic acid (the tocopheryl residue may have any chemical structure of α, β, γ, δ) and / or their pharmacologically acceptable salts can be preferably exemplified, and more preferably, retinol, retinal Retinoic acid, tretinoin, isotretinoin, tocopheryl retinoic acid, retinol palmitate, retinol acetate and / or a pharmaceutically acceptable salt thereof pharmacologically can be preferably exemplified, among these, as further preferred, retinol acetate Preferred examples include retinol , tocopheryl retinoic acid and / or pharmacologically acceptable salts thereof. Moreover, the vitamin A derivative and / or pharmacologically acceptable salt thereof used in the present invention can be purchased and used from a reagent vendor such as Sigma-Aldrich.

Furthermore, the above-mentioned triterpenic acid, its derivative and / or pharmacologically acceptable salt thereof can be applied without particular limitation as long as it is used in the field of cosmetics, etc. Specific examples of triterpenic acid include ursolic acid , oleanolic acid , and betulinic acid , and ursolic acid is particularly preferable. Further, as the triterpenic acid derivative, an aliphatic hydrocarbon ester having 1 to 20 carbon atoms of triterpenic acid, a hydrocarbon ester having 1 to 4 carbon atoms substituted by an aromatic group of triterpenic acid, a phosphate ester of triterpenic acid And / or pharmacologically acceptable salts thereof can be preferably exemplified. Examples of the aliphatic hydrocarbon ester having 1 to 20 carbon atoms include methyl ester, ethyl ester, hexyl ester, cyclohexyl ester, octyl ester, isooctyl ester, lauryl ester, cetyl ester, stearyl ester, isostearyl ester, oleyl ester and the like. The aliphatic ester is preferably exemplified. Moreover, as a C1-C4 hydrocarbon ester substituted by the said aromatic group, benzyl ester, phenylethyl ester, phenylpropyl ester, phenylbutyl ester etc. can be illustrated suitably, and benzyl ester is especially preferable. Of the aforementioned anti-wrinkle agents, particularly preferred are ursolic acid and / or a pharmacologically acceptable salt thereof, benzylursolic acid and / or a pharmacologically acceptable salt thereof (for example, JP-A 2000 -302659), ursolic acid phosphate and / or a pharmacologically acceptable salt thereof. The above-described anti-wrinkle agent of the present invention contains a compound represented by the general formula (1), its isomer and / or a pharmacologically acceptable salt thereof in a composition, thereby improving skin beautification, In particular, the effect of preventing or improving wrinkle formation is enhanced.

Benzyl ursolate

Ursolic acid phosphate

The anti-wrinkle agent can be synthesized by the following method, or can be purchased as a commercially available reagent. Among the above-mentioned anti-wrinkle agents, C1-C20 aliphatic hydrocarbon esters of triterpenic acid and C1-C4 hydrocarbon esters substituted with an aromatic group of triterpenic acid include the corresponding triterpenic acid. It can be obtained by treating with sodium hydride to obtain a sodium salt, and then adding a halogenated hydrocarbon to this to react. The reaction temperature and time, at room temperature or under reflux conditions, may be performed 1 to 12 hours. Also, One in phosphoric acid ester of the triterpene acids information, for example, according to the process described in Re Table 2006-132033 discloses, can be derived from the triterpenic acids. Specifically, triterpenic acid phosphate ester, commercially available triterpene acids tetrazole - presence Le, 1-3 equivalents of dimethyl -N, N-diethyl phosphoramidite de - treated with bets, t- butyl hydroperoxide It can be synthesized by reacting a peroxide to obtain methyl phosphate of triterpenic acid and then further reacting with trimethylsilyl bromide.

The above-mentioned anti-wrinkle agent can be used as an anti-wrinkle agent as it is, but it can also be treated with a pharmacologically acceptable acid or base, converted into a salt form, and used as a salt. For example, mineral salts such as hydrochloride, sulfate, nitrate, phosphate, carbonate, maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, para toluenesulfonate, organic acid salts such as benzenesulfonate, sodium salt, alkali metal, calcium salts, alkaline earth metals such as magnesium salt metal, triethylamine salt or potassium salt, triethanolamine salt, an ammonium salt, monoethanolamine Preferred examples include organic amine salts such as amine salts and piperidine salts, and basic amino acid salts such as lysine salts and arginine salts.

Among the anti-wrinkle agent of the present invention will be described with have One to plant extracts having dermal collagen fiber bundles reconstruction action. The component having the action of reconstructing the dermal collagen fiber bundle according to the present invention includes a plant extract obtained from the Myrtaceae spp., A plant extract obtained from Hypericaceae, a plant extract obtained from Hypericum perforatum, Plant extract obtained from Aceraceae, a plant extract obtained from Amaranthaceae, a plant extract obtained from Giraffaceae, a plant extract obtained from Ominaceae, a plant extract obtained from Viraceae Biwa, a rose A plant extract obtained from a family peach, a plant extract obtained from a buckthorn jujube, a plant extract obtained from a honeysuckle family elderberry, a plant extract obtained from a asteraceae cornflower, a plant extract obtained from a Lamiaceae thyme, Labiatae Plant extracts obtained from Zumari, Shisokase - plant extracts obtained from di, plant extracts obtained from Shisoka perilla plant extract obtained from the Labiatae family dead nettle, plant extract obtained from Shisoka peppermint Can be suitably exemplified, and among these, more preferred are plant extracts obtained from Myrtaceae spp. plant extract obtained from hypericaceae Himeotogiri, plant extract obtained from hypericaceae Tomoesou, plant extract obtained from Caprifoliaceae Sambucus nigra, plant extract obtained from Asteraceae cornflower, plant obtained from the Labiatae rosemary extract Good examples can be illustrated The component having the action of reconstructing the dermal collagen fiber bundle is contained in the composition together with the compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof. This enhances the effect of preventing or improving the skin beautifying action, especially the wrinkle formation.

Plant extracts with dermal collagen fiber bundles reconstruction operation of the present invention, if a plant extract having dermal collagen fiber bundles restructuring action, can be adapted without particular limitation. The plant extract in the present invention, the plant itself, drying plants, minced, workpieces processed like grinding, plant or solvent extract extracted by adding a solvent to the workpiece, from the extract It means a general term for a solvent-removed product of an extract from which a solvent has been removed and a purified product obtained by purifying such a product by column chromatography or liquid-liquid extraction . As the plant part used for the preparation of the plant extract of the present invention, any part of the plant body can be used, but a particularly preferable one is a dried whole plant. This is because the site contains many components for reconstructing the dermal collagen fiber bundle. In addition, as the plant extract of the present invention, a polar solvent extract or a solvent-removed product thereof can be particularly preferably exemplified. Examples of the polar solvent include alcohols such as ethanol and methanol , esters such as ethyl acetate and methyl formate, and acetone. ketones and methyl ethyl ketone, ethers such as diethyl ether or tetrahydrofuran, halogenated hydrocarbons such as chloroform and methylene chloride, one selected from water and the like or two or more can be preferably exemplified. Of these, particularly preferred it is one selected from water and alcohols or are two or more. Such extracts or solvent removal thereof is 1 to 10 times the amount of solvent added to the plant or its workpiece, several days if room temperature, if the temperature near the boiling point, is immersed for several hours That's fine. The solvent can be removed by evaporation to dryness, concentration under reduced pressure, or lyophilization. Most preferred are vacuum concentration and lyophilization.

The anti-wrinkle agent of the composition of the present invention can contain only one species or two or more species. Moreover, as preferable content in the composition of this invention, it is 0.00001-15 mass %, More preferably, it is 0.0001 mass%-10 mass %, More preferably, it is 0.001 mass%-5 mass%. , more preferably preferably it contains to 3 wt% 0.01 wt%. This is because if the amount is too small, the effect may not be exhibited, and if the amount is too large, the effect reaches a peak and the degree of freedom of prescription may be impaired.

<Manufacture example 7 : The manufacturing method of the plant extract obtained from Myrtaceae cinnamon>
5 L of methanol was added to 500 g of dried florets of Dendrobaceae, submerged at room temperature for 1 week, filtered, and concentrated under reduced pressure to obtain 3 g of plant extract 3 obtained from Dioscoreaceae of the present invention. .

<Production Example 8 : Method for producing plant extract obtained from Hypericum perforaceae>
A dried plant of Hypericum perforatum Hypericum added to 500 g of 5 L of methanol , soaked at room temperature for 1 week, filtered and concentrated under reduced pressure to obtain 22 g of plant extract obtained from Hypericum perforatum of the present invention. . According to the same procedure, a plant extract obtained from Hypericum perforaceae, a plant extract obtained from Hypericum pertussis, and a plant extract obtained from Hypericum perforatum were obtained.

<Manufacture example 9 : The manufacturing method of the plant extract obtained from the honeysuckle family elderberry>
Add 10 L of ethanol to 1 kg of honeysuckle family elderflower, reflux for 2 hours, filter and remove the filtrate, add it to 3 liters of water at once, and collect the deposited precipitate by filtration. 9 g of plant extract 1 was obtained.

<Production Example 10 : Method for producing plant extract obtained from asteraceae cornflower>
Plants obtained from Asteraceae cornflower of the present invention by adding 10 L of ethanol to 1 kg of Asteraceae cornflower and refluxing for 2 hours, filtering and taking a filtrate, adding this to 3 L of water at once, and collecting the deposited precipitate by filtration. Extract 12g was obtained.

<Production Example 11 : Method for producing plant extract obtained from Lamiaceae rosemary >
10 kg of rosemary was added with 10 L of ethanol , refluxed for 2 hours, filtered, and the filtrate was collected. The filtrate was concentrated under reduced pressure to obtain 3 g of crude extract 1 100 g of the crude extract 1 was dissolved in 600 mL of ethanol , this was added to 200 mL of water all at once, and the deposited precipitate was collected by filtration to obtain 42 g of a crude extract 2. 100 g of the crude extract 2 was dissolved in 500 mL of normal butanol , and 500 mL of water was added for liquid-liquid extraction to obtain a butanol phase. This operation was repeated three times, and the butanol phases were combined and concentrated under reduced pressure to obtain 27 g of a plant extract obtained from the Labiatae rosemary of the present invention.

<Composition of the present invention>
The composition of the present invention comprises 1) a compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) an anti-wrinkle agent. And The compound represented by the general formula (1) of the present invention, isomers thereof and / or pharmacologically acceptable salts thereof, together with the anti-wrinkle agent described above, contains a skin beautifying effect, In particular, the effect of preventing or improving wrinkle formation is shown. The skin beautifying effect in the present invention means a preventive or ameliorating effect on the skin aging phenomenon related to the aesthetic appearance of the skin that becomes apparent with age, and in particular, in addition to the improving action that makes the wrinkles already formed inconspicuous, etc. It means preventive or ameliorating action against skin symptoms such as wrinkles and sagging. Of the skin beautifying effects of the composition of the present invention, specific examples of preferable skin wrinkles will improve wrinkle improvement over the comparative composition (skin external preparation) in the “wrinkle improving action evaluation of the present invention” described below. The component which shows an effect | action can illustrate suitably. In addition, the composition of the present invention has a preventive or ameliorating action against skin formation caused by pigmentation such as sunburn, spots and dullness in addition to a preventive or ameliorating action against wrinkle formation. Prevention or improvement can be expected.

A composition comprising 1) a compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) an anti-wrinkle agent. In formulating, it can contain arbitrary components used in formulating normal foods, pharmaceuticals, cosmetics and the like. Examples of such optional ingredients, if oral dosage composition, for example, excipients such as lactose, white sugar, starch, cellulose, gum arabic, binders such as hydroxypropylcellulose, carboxymethyl cellulose sodium, carboxymethyl cellulose Disintegrants such as calcium, surfactants such as soybean lecithin and sucrose fatty acid esters, sweeteners such as maltitol and sorbitol , sour agents such as citric acid, buffering agents such as phosphate, and film formation such as shellac and zein Agents, lubricants such as talc, waxes, glidants such as light anhydrous silicic acid, dry aluminum hydroxide gel, diluents such as physiological saline and aqueous glucose solution, flavoring agents, coloring agents, bactericides, antiseptics Suitable examples include agents and fragrances.

As the composition of the present invention, pharmaceuticals, cosmetics, foods, beverages and the like can be suitably exemplified, and since they can be taken on a daily basis, it is preferable to adapt to foods, cosmetics and the like. The administration route can be either oral administration or transdermal administration. For the purpose of detoxification (detox), oral administration with high efficiency in reaching the relevant organ is adopted, and forms of oral administration compositions such as foods Is preferably adopted. Moreover, when such a component is continuously administered, and further considering safety, it is preferably administered transdermally . The external skin preparation of the present invention can be used without particular limitation as long as it is applied externally to the skin, for example, cosmetics, skin external medicine, skin external goods and the like can be suitably exemplified, It is particularly preferable to apply to cosmetics. This is because the external preparation for skin of the present invention has an unparalleled feeling of use and is particularly suitable for cosmetics where the feeling of use is important. The cosmetics, as long as it can apply a water-in-oil emulsifier type, no particular limitation, for example, essences, milks, basic cosmetics such as creams, under Mae
Up, foundation, Ji - Kukara, mascara, make-up cosmetics such as eyeliner, such as hair cosmetics such as hair cream can be preferably exemplified.

The external preparation for skin of the present invention can contain, in addition to such components, optional components that are usually used in external preparations for skin. Examples of such optional ingredients include macadamia nut oil, avocado oil , corn oil, olive oil , rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, coconut oil, palm oil , liquid lanolin, and hardened coconut oil. Oils such as hardened oil, mole, castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba wax, waxes , liquid paraffin, squalane, pristane, ozokerite, paraffin, ceresin, petrolatum , hydrocarbons such as microcrystalline wax, oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, higher fatty acids such as undecylenic acid, cetyl alcohol, stearyl alcohol, Isosuteari Alcohol, behenyl alcohol, octyl dodecanoate - le, myristyl alcohol, higher alcohols such as cetostearyl alcohol, cetyl isooctanoate, isopropyl myristate, isostearate hexyl decyl, diisopropyl adipate, sebacic di-2-ethylhexyl, cetyl lactate , Diisostearyl malate, ethylene glycol di-2-ethylhexanoate, neopentyl glycol dicaprate, glycerin di-2-heptylundecanoate, glycerin tri-2-ethylhexanoate, trimethylolpropane tri-2-ethylhexanoate triisostearate trimethylol - trimethylolpropane, synthetic ester oils such as tetra-2-ethylhexanoate pentane pentaerythritol, dimethyl polysiloxane, methylphenyl Rokisan, linear polysiloxanes such as diphenyl polysiloxane, octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, cyclic polysiloxanes such as dodeca methylcyclohexane siloxane, amino-modified polysiloxane, polyether-modified polysiloxane, alkyl-modified polysiloxanes, oil such silicone oils of modified polysiloxanes and fluorine-modified polysiloxane, fatty acid soap (sodium laurate, sodium palmitate), potassium lauryl sulfate, an anionic surfactant such as alkyl sulfate, triethanolamine ether, chloride Cationic surfactants such as stearyltrimethylammonium, benzalkonium chloride, laurylamine oxide , imidazoline-based amphoteric surfactants (2-cocoyl-2-imida Zolinium hydroxide-1-carboxyethyloxy disodium salt, etc.), betaine surfactants (alkyl betaine, amide betaine, sulfobetaine, etc.), amphoteric surfactants such as acylmethyltaurine , sorbitan fatty acid esters (sorbitan) Monostearate, sorbitan sesquioleate, etc.), glycerin fatty acids (glyceryl monostearate, etc.), propylene glycol fatty acid esters (propylene glycol monostearate, etc.), hardened castor oil derivatives, glycerin alkyl ether , POE sorbitan fatty acid esters (POE sorbitan monooleate, monostearate polyoxyethylated sorbitan, etc.), POE sorbitol fatty acid esters (POE- sorbitol monolaurate), POE glycerin fatty et Ethers (POE- glyceryl monoisostearate, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE Jisuteare - DOO etc.), POE alkyl ethers (POE2- octyldodecyl et - ether, etc.), POE alkyl phenyl et - Tells (POE nonylphenyl ether, etc.), Pluronic types, POE / POP alkyl ethers (POE / POP2-decyltetradecyl ether, etc.), Tetronics, POE castor oil / hardened castor oil derivatives (POE castor oil, POE) hardened castor oil, etc.), sucrose fatty acid esters, nonionic surfactants such as alkyl glucosides, sodium pyrrolidone carboxylic acid, lactic acid, moisturizing ingredients, such as sodium lactate, may be surface treated, mica, talc, Kaolin, synthetic mica, Calcium, magnesium carbonate, silicate (silica) anhydrous aluminum oxide powder such as barium sulfate, may be processed to the front surface, red iron oxide, yellow iron oxide, black iron oxide, cobalt oxide, ultramarine, iron blue , titanium oxide, inorganic pigments zinc oxide may be surface treated mica titanium, Sakanarinhaku, pearl agent such as bismuth oxychloride, good red No. 202 be laked red No. 228 , Red No. 226, Yellow No. 4, Blue No. 404, Yellow No. 5, Red No. 505, Red No. 230, Red No. 223, Orange No. 201, Red No. 213, Yellow No. 204, Yellow No. 203, Blue No. 1, Green Organic dyes such as 201, purple 201 and red 204 , polyethylene powder, polymethyl methacrylate, nylon powder, organopolysiloxane elastomer and other organic powders , Raamino benzoic acid UV absorbers, anthranilic acid UV absorbers, salicylic acid ultraviolet absorbers, Katsura peel acid UV absorbers, Baie benzophenone-based ultraviolet absorbents, sugar-based ultraviolet absorber, 2- (2'-hydroxy - UV absorbers such as 5′-t-octylphenyl) benzotriazole and 4-methoxy-4′-t-butyldibenzoylmethane, lower alcohols such as ethanol and isopropanol , vitamin A or its derivatives, vitamin B ₆ hydrochloric acid Salt, vitamin B ₆ tripalmitate , vitamin B ₆ dioctanoate , vitamin B ₂ or a derivative thereof, vitamin B ₁₂ such as vitamin B ₁₂ , vitamin B ₁₅ or a derivative thereof , α- tocopherol , β- tocopherol , γ- tocopherol , vitamin Vitamin E such as E-acetate, Vitamin D, Vitamin H, Pantothen , Pantethine, vitamins pyrroloquinoline quinone such like, antibacterial agents such as phenoxy ethanol, hectorite, organic modified clay minerals such as dimethyl distearyl ammonium modified hectorite may be preferably exemplified.

Among such optional components, organically modified clay minerals are particularly preferable. Here, the organic modified, some covalent bond or an organic compound as a part of the clay mineral caused strong also in loose coupling via an ionic bond, clay No part or of the nature of the organic compound This means that it is imparted to minerals. Examples of such modifications include a method of binding a quaternary amine group and an anion portion of a clay mineral, and a method of binding a carboxyl group and a cation portion of a clay mineral. A method of combining the group and the anion portion of the clay mineral is particularly preferable. Although it does not necessarily limit as a compound which has a quaternary amino group which modifies a clay mineral, The compound called quaternium is illustrated. Quotanium is a low molecular weight substituted quaternary ammonium salt, and is preferably a cosmetic raw material registered in International Standard Cosmetic Ingredients (INCI). Furthermore, the compound having a quaternary amino group that modifies the clay mineral is preferably a quaternium compound contained in a conventional external skin preparation among quaternium compounds. Preferred examples of the quaternium compound used in conventional external preparations for skin include stearyl trimethyl ammonium chloride and dimethyl distearyl ammonium chloride. Among them, dimethyl distearyl ammonium chloride is particularly preferable. This is because two long-chain alkyl groups are contained in one molecule, so that it is easy to make a structure that sterically holds the oil phase. Stearyl trimethyl ammonium chloride, dimethyl distearyl ammonium chloride, and the like are preferable because they can form a stable aqueous oil-in-water component emulsion structure together with clay minerals. In particular, when the aqueous component is an oil-in-water emulsion, an emulsion having a continuous phase as an oil phase can be formed without significantly affecting the oil-in-water emulsion. preferable. On the other hand, as a clay mineral (unmodified clay mineral) modified with a compound having a quaternary amino group, any clay mineral contained in a conventional external preparation for skin can be used without particular limitation. Preferred clay minerals contained in conventional skin external preparations include smectite-type hectorite, bentonite, montmorillonite , kaolinite , illite , marine clay mineral (sea mud) , desert rose clay mineral , and pascalite. Among these, bentonite, hectorite, montmorillonite or kaolinite which can stabilize the water-in-oil emulsion structure is preferably exemplified. Among them, hectorite and montmorillonite are particularly preferable because they have a firm layer structure in minerals and can easily orient cation molecules. An example of a method for producing a clay mineral modified with a compound having a quaternary amino group contained in the external preparation for skin of the present invention will be described below. The unmodified clay mineral is dispersed in a dispersion medium. The dispersant is preferably an aqueous solvent, and may be water. A compound having a quaternary amino group is further added to the dispersion containing the dispersed unmodified clay mineral and stirred well. The compound having a quaternary amino group may be added after being dissolved in water. The amount of the compound having a quaternary amino group added is preferably 0.1 to 20% by mass with respect to the amount of the dispersed unmodified clay mineral,
More preferably, it is 0.5-15 mass%. This is because by taking such a configuration, a preferable feeling of use is exhibited in the emulsification system. After stirring, the dispersoid is filtered, dehydrated and dried to obtain the modified clay mineral in the present invention. Or the modified clay mineral in this invention can also be obtained by removing a dispersing agent by concentrating under reduced pressure without filtering a dispersoid, and making it dry. The obtained modified clay mineral is preferably pulverized to a desired size (preferably having a particle size of 1 to 1000 μm) and contained in the skin external preparation of the present invention. The modified clay mineral in the present invention can be prepared and used as described above, but a commercially available one can also be used. Some modified clay minerals on the market are used as external preparations for skin such as cosmetics. Preferable examples of commercially available modified clay minerals include dimethyl distearyl ammonium modified hectorite sold under the name “Benton 38V” by Elementis. In the skin external preparation of this invention, this component is contained preferably 0.5 mass%-10 mass%, More preferably, 1 mass%-5 mass% are contained. In such a range, the compound represented by the general formula (1) or the anti-wrinkle solution can be stabilized and formulated into a water-in-oil emulsifier form. Here, the water-in-oil emulsifier form described in the present invention is a general term for an emulsifier form in which an oil phase is present in the outermost phase, a form in which water phase drops are dispersed in the oil phase, and an oil-in-water emulsified drop in the oil phase. Any form in which the is dispersed can be employed. In addition, when employ | adopting such a water-in-oil emulsifier form, it is preferable to contain 0.1-5 mass% of polyether modified methyl polysiloxane as an auxiliary | assistant surfactant. Such polyether- modified methylpolysiloxanes are commercially available, and such commercial products can be purchased and used. Preferred commercially available products, manufactured by Shin-Etsu Chemical Co., Ltd. of "Silicone KF6017" can be suitably exemplified.

When diglycerin monooleate and / or triglycerin diisostearate is contained as an emulsifier, it is preferable to contain 0.5 to 2 times the mass of the emulsifier together with a polyhydric alcohol such as maltitol or sorbitol . . The diglycerol monooleate - as a raw material for preparative cosmetics, to be mentioned "Nikkol DGMO-C" (manufactured by Nihon Surfactant Co., Ltd.) is preferred, as a raw material for cosmetics of triglycerol diisostearate is “Emerest 2452” (manufactured by Emery Co., Ltd.) can be preferably exemplified. The preferable content of this component is 1 to 10% by mass, more preferably 2 to 7% by mass, based on the total amount of the external preparation for skin. This is because if the amount is out of this range, emulsification may not be possible or the stability of the solution may be impaired.

Since the external preparation for skin of the present invention takes the form of a water-in-oil emulsifier, silicone , particularly preferably, cyclomethicone and / or a viscosity of 1 mPa -It is preferable to contain the dimethicone below s, and as content of this silicone , it is preferable to contain 10-50 mass% with respect to cosmetics whole quantity, More preferably, it is 20-40 mass% The sum of the contents of cyclomethicone and dimethicone having a viscosity of 1 mPa · s or less is preferably 50% by mass or more, more preferably 55% by mass or more based on the total amount of the oil phase.

When the organically modified clay mineral is used as an emulsifier, a preferable optional component other than the above components is exemplified by a polyhydric alcohol that can stabilize the emulsified state. Particularly preferred are glycerin, diglycerin and dipropylene glycol . Such a component may contain only one species or may contain two or more species in combination. A preferable content is 5-30 mass% with respect to the total amount of skin external preparations in total, More preferably, it is 10-25 mass%. In addition, 1,2-pentanediol, the one or selected from 1,2-hexanediol and 1,2-octanediol also contain two or more kinds 3-7 wt%, improved antiseptic From the viewpoint of making it.

The external preparation for skin of the present invention can be produced by treating the above-mentioned optional components and essential components according to a conventional method.

  Hereinafter, the present invention will be described in more detail with reference to examples.

<The manufacturing method 1 of the skin external preparation of this invention>
According to the formulations described in Tables 1 and 2, water-in-oil emulsifier type cosmetics ( creams ) were prepared. That is, each of the components (a), (b), and (c) is heated to 80 ° C., and (d) is added and dissolved in (b), kneaded to form a gel, and added to (b), diluted, and gradually stirred. The mixture was emulsified with water, stirred and cooled to prepare water-in-oil emulsifier type cosmetics 1 to 10, which are external preparations for skin of the present invention. However, the concentration of the “anti-wrinkle agent of the present invention” in the components of the cosmetics 8 and 9 shown in Tables 1 and 2 is different from the concentrations of the other “wrinkle agents of the present invention” and A cosmetic was prepared at a concentration of 1% by mass, and the mass% reduction caused by the concentration reduction of such compounds was adjusted by the mass% of water. In the same manner, Comparative Example 1 in which “the compound represented by the general formula (1) of the present invention” was replaced with “water” in the formulation component of Cosmetic 1, “ Anti- wrinkle agent of the present invention” was “ Comparative Example 2 in which “water” was substituted, and Comparative Example 3 in which “the compound represented by the general formula (1) of the present invention” and “anti-wrinkle agent of the present invention” were both replaced with “water” were prepared.

< Evaluation 1 of wrinkle improvement effect of the present invention>
Using cosmetics 1 to 10 and Comparative Examples 1 to 3 prepared according to the method described in Production Method 1 , the wrinkle improving effect was examined according to the following method. That is, 104 panelists (women, age group 40-60 years old) worried about the wrinkles of the corners of the eyes are divided into 13 groups of 8 persons, and cosmetics 1 to 10 and Comparative Examples 1 to 3 are given to each group, The wrinkle-improving effect was examined by comparing the eye corner replicas before and after the test. The replica is a white one that does not transmit light, and the surface shape of the skin is transferred to this, and this replica is fixed to the sample stage of the stereomicroscope, irradiated with light at an angle of 45 degrees, and the replica is rotated, A shadow image (1 × 1 cm ² ) in the direction in which the shadow of the skin groove is strongly observed was taken into the image analysis apparatus. According to the wrinkles, the image has low brightness at deep wrinkles and high brightness at no wrinkles, forming a shadow. The luminance distribution in the shadow image is obtained, and with the median value of the luminance as a boundary, the bright spot with the luminance higher than the median value is converted to the maximum luminance, and the bright spot with the luminance less than the median value is converted to the luminance 0, and binarization is performed. The area ratio of the shaded portion (the portion with 0 luminance) was obtained. The wrinkle improvement rate (%) was determined by (area ratio of shadow before test−area ratio of shadow after test) / (area ratio of shadow before test) × 100. The results are shown in Table 3 as the average value ± standard deviation of 8 people in each group. From the result of Table 3, it turns out that the cosmetics 1-10 of this invention have the outstanding wrinkle improvement effect.

< Method 2 for producing external preparation for skin of the present invention>
Regarding the cosmetic 3 described in the production method 1 , “a compound represented by the general formula (1) of the present invention (L isomer of compound 3)” and “a wrinkle improving agent of the present invention ( ursolic acid phosphate ester)” The cosmetics 11 to 14 were prepared with the concentrations changed to those shown in Table 4.

< Wrinkle improving action evaluation 2 of the present invention>
Cosmetics 11-14 two have to have the ingredients described in Preparation Method 2, it was evaluated wrinkle improvement effect according to the evaluation method described in Evaluation 1. The results are shown in Table 5. From the result of Table 5, it turns out that the cosmetics 11-14 of this invention have the outstanding wrinkle improvement effect.

< Method 3 for producing external preparation for skin of the present invention>
During ingredients of the cosmetic 3 according to the production method 1, "Benton 38V" cosmetic 15 was replaced with "Silicone KF6017" a cosmetic obtained by replacing "1,2-pentanediol," the "poly ethylene glycol 400" 16 and the wrinkle improving action was evaluated according to the method described in Evaluation 1 , the wrinkle improving degree of the cosmetic 15 was 3.2 ± 1.5, and the wrinkle improving degree of the cosmetic 16 was 3.5. the ± 1.3 was shown.

< Production of health food of the present invention>
According to the prescription shown in Table 6 and Table 7, health foods (health foods 1 to 10) were prepared. However, the concentration of the “anti-wrinkle agent of the present invention” in the components of the health food 8 and the health food 9 described in Tables 6 and 7 is different from the concentration of the other “anti-wrinkle agent of the present invention” and is 0 A health food was prepared at a concentration of 1 part by weight, and the reduction in parts by weight resulting from a decrease in the concentration of such compounds was adjusted by the weight parts of crystalline cellulose . That is, the formulation components rolling phase granulated with 10 parts by weight of water (manufactured by Fuji Paudal Co., Ltd., "New Marumerizer") to obtain a tablet-shaped health food and then pressed into tablets. In addition, the unit of the numerical value in a table | surface represents a weight part. This health food had an excellent wrinkle improving action.

  The composition of the present invention can be applied to wrinkle-improving cosmetics, foods, and the like.

Claims (19)

1. A composition comprising 1) a compound represented by the following general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, and 2) an anti-wrinkle agent.
(1)
[Wherein, R ₁ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₂ represents a hydrogen atom, an unsubstituted or substituted aromatic group, an unsubstituted or substituted group. Represents an aliphatic hydrocarbon group having 1 to 4 carbon atoms substituted by an aromatic group having R ₃ , R ₃ represents an unsubstituted or substituted aromatic group, n is an integer of 1 or 2, m Represents an integer of 0 to 3. ] The compound represented the general formula (1), characterized in that a compound represented by the following general formula (2), A composition according to claim 1.
(2)
[Wherein, R ₄ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, R ₅ represents an unsubstituted or substituted aromatic group, and n represents 1 or 2 , M represents an integer of 0 to 3. ] The compound represented by the general formula (2), characterized in that a compound represented by the following general formula (3) A composition according to claim 2.
(3)
[Wherein R ₆ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, R ₇ represents an unsubstituted or substituted aromatic group, and n represents 1 or 2 Represents an integer. ] 4. The composition according to claim 3, wherein the compound represented by the general formula (3) is N- (p-toluyl) homocysteic acid (compound 6).
N- (p-Toluyl) homocysteic acid (Compound 6) The compound represented by the general formula (3), characterized in that a compound represented by the following general formula (4) The composition of claim 3.
(4)
[Wherein, R ₈ represents a hydrogen atom, a linear or branched alkyl group having 1 to 8 carbon atoms, and R ₉ represents an unsubstituted or substituted aromatic group. ] The compound represented by the general formula ( 4) is N- (o-toluyl) cysteic acid (compound 1), N- (m-toluyl) cysteic acid (compound 2), N- (p-toluyl) cysteic acid. (compound 3), N- (p-methoxybenzoyl) cysteic acid (compound 4), characterized in that it is N- (biphenylcarbonyl) one or more members selected from cysteine acid (compound 5), The composition according to claim 5 .
N- (o-Toluyl) cysteic acid (Compound 1)
N- (m-Toluyl) cysteic acid (Compound 2)
N- (p-Toluyl) cysteic acid (Compound 3)
N- (p-methoxybenzoyl) cysteic acid (compound 4)
N- (biphenylcarbonyl) cysteic acid (compound 5) 0.001% by mass to 20% by mass of the compound represented by the general formula (1), isomers thereof and / or pharmacologically acceptable salts thereof with respect to the total amount of the composition. The composition according to any one of claims 1 to 6 . The anti-wrinkle agent is vitamin A, a derivative thereof and / or a pharmacologically acceptable salt thereof, triterpenic acid, a derivative thereof and / or a pharmacologically acceptable salt thereof, The composition according to any one of claims 1 to 7 . Vitamin A or a derivative of said, characterized retinol, retinal, retinoic acid, tretinoin, isotretinoin, tocopherol retinoic acid, retinyl palmitate, that is one or more selected from retinol acetate, wherein Item 9. The composition according to Item 8 . The composition according to claim 8 , wherein the triterpenic acid contains either ursolic acid or betulinic acid . Derivative of the triterpenic acid, characterized by comprising any of the bets Riterupen acid benzyl ester and triterpenic acid phosphate ester composition of claim 8. The composition according to any one of claims 1 to 7 , wherein the anti-wrinkle agent is a plant extract having a dermal collagen fiber bundle restructuring action. The composition according to claim 12 , wherein the plant extract having a dermis collagen fiber bundle restructuring action is one or more selected from the following plant extracts.
<Plant extract having dermis collagen fiber bundle restructuring action>
A plant extract obtained from the Myrtaceae spp. An extract, a plant extract obtained from the honeysuckle elderberry, a plant extract obtained from the asteraceae cornflower, and a plant extract obtained from the Labiatae rosemary . The composition according to any one of claims 1 to 13 , wherein the anti-wrinkle agent is contained in an amount of 0.00001 to 15% by mass based on the total amount of the composition. The composition according to claim 1 , wherein the composition is for beautifying skin. The composition according to claim 1 , wherein the composition is used for prevention or improvement against wrinkle formation. A skin external preparation comprising the composition according to any one of claims 1 to 16 . The skin external preparation according to claim 17 , wherein the skin external preparation is in the form of a water- in- oil emulsifier. The external preparation for skin according to claim 17 or 18, wherein the external preparation for skin is a cosmetic (however, including quasi-drugs).