JP5374058B2 - Glutamic acid derivative, keratinization inhibitor, pore reducing agent, rough skin prevention / improving agent, and composition for external use on skin - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide compounds having excellent effects such as of suppressing parakeratosis, shrinking pores, and preventing and ameliorating skin roughness, and being useful as highly safe parakeratosis-suppressing agents, pore shrinking agents, rough skin preventing and ameliorating agents; and to provide compositions for external preparation for skin in which the compounds are added. <P>SOLUTION: Disclosed is a glutamic acid derivative represented by general formula (1) or a salt thereof. In formula (1), A represents a single bond, an oxycarbonyl group, a carbonyl group, or a sulfonyl group. <P>COPYRIGHT: (C)2009,JPO&amp;INPIT

Description

  The present invention provides a novel glutamic acid derivative, in particular, a keratinization inhibitor that suppresses keratinization caused by sebum, suppresses keratinization due to stimulating components in sebum around pores, and normalizes skin around pores. A glutamic acid derivative that is useful as a pore-reducing agent that prevents and improves rough skin caused by unsaturated fatty acids, and that is useful as an agent for preventing and improving rough skin caused by unsaturated fatty acids. Related to things.

  In recent years, especially for young women, there are increasing concerns about the conspicuous pores, and an external preparation for skin that improves the conspicuousness has been demanded. However, the mechanism by which the conspicuousness of the pores develops is not clear enough, and the countermeasure by removing the astringent lotion and the square plug is common. Or they often improve the appearance with a foundation. However, for example, astringent lotion is intended to tighten the skin, and is due to the action of temporarily lowering the skin surface temperature with alcohol or coagulating proteins with organic acid or the like. For this reason, the load on the skin is large, and it is not a fundamental solution to the conspicuous pores, and the effect is not sufficient.

Although there are reports that glycolic acid and ascorbic acid derivatives have a pore-reducing effect (see, for example, Non-Patent Document 1), there are many unclear points such as the mechanism of action and the degree of effect.
Further, the removal of horn plugs is a method of physically removing horn plugs clogged in pores. In this method, the physical force may damage the skin, and side effects on the skin may be a problem. In addition, the effect is temporary, and the plug may be immediately regenerated, and if removed, the pores may become larger, and the effect is not always sufficient.

  In normal skin, `` nucleation '' disappears during the final differentiation process from the granular layer to the stratum corneum, but if this `` nucleation '' does not occur for some reason, Epidermal keratinocytes are generated. Such a state is called “keratosis”.

  As a result of examining the conspicuous mechanism of the pores, the present inventors have recognized that a concave portion in the shape of a mortar around the pore portion is recognized as a pore, and that this portion is conspicuous, and that the stratum corneum of this mortar-shaped portion is not visible. It was clarified that the keratinized state (nuclei that should have disappeared remain). Therefore, the suppression of keratinization acts on the pore part, and if the keratinization of the cornified layer around the pore part is suppressed, the area recognized as pores decreases and functions as a pore reducing agent. I found out. In addition, it was clarified that people with conspicuous pores have a large amount of sebum, especially a high ratio of unsaturated fatty acids, and that these unsaturated fatty acids cause keratinization. From this, it was found that there is a high possibility that the conspicuous pores are caused by unsaturated fatty acids in sebum (see Non-Patent Documents 2 and 3).

From the above, the present inventors have recognized that the mechanism of conspicuous pores is due to the keratinization caused by sebum, which is recognized as a pore by improving the keratinization in the pore part. It was clarified that the area to be reduced is reduced and the conspicuousness of pores is improved. Based on these findings, a novel keratinization inhibitor and pore reducing agent were discovered, and a patent application was filed as the first report (see Patent Document 1). A reducing agent and an agent for preventing and improving rough skin were found (see Patent Document 2 and Patent Document 3).
In addition, γ-aminobutyric acid (GABA) is known to have an effect of inhibiting keratinization and reducing pores (see Patent Document 4). There is a need for an inhibitor of keratinization and a pore reducing agent.

JP 2004-2289 A JP 2005-179342 A JP 2005-179343 A JP 2003-342195 A Yazawa et al., Fragrance Journal, 2002, Volume 30, Issue 2, p54-58 Iida et al., 102nd Annual Meeting of the Japanese Dermatological Association, Abstract, 2003, 103, p846 Katsuta et al. , Cosmetics & Toiletries magazine, 2004, 119, 10, p59-64.

  The present invention has been made in view of the above circumstances, and its purpose is to have an excellent effect in suppressing keratinization, reducing pores, preventing and improving rough skin, and there is no safety problem such as sensory stimulation. An object of the present invention is to provide a highly safe keratinization inhibitor, a pore-reducing agent, and a rough skin prevention / improving agent.

  In order to solve the above-mentioned problems, the present inventors have searched for a compound that is highly effective in suppressing keratinization, reducing pores and preventing and improving rough skin, and has a high safety and easy formulation without problems such as sensory stimulation. As a result of intensive studies, it was found that the specific glutamic acid derivatives and their salts have an excellent effect of suppressing keratinization, reducing pores, and preventing and improving rough skin, and the above problems are solved. It came to be completed.

That is, the external composition for skin according to the present invention is characterized by containing one or more compounds selected from the group consisting of a glutamic acid derivative represented by the following general formula (1) or a salt thereof .

(In general formula (1), A represents a single bond, an oxycarbonyl group, a carbonyl group or a sulfonyl group, Z represents the following general formula (2), and R _{1 to} R ₄ are each independently a hydrogen atom. , An alkyl group having 1 to 3 carbon atoms, an allyl group, a cycloalkyl group having 3 to 7 carbon atoms or a cycloalkenyl group, a phenyl group, or a benzyl group, or R ₁ and R ₂ and / or R ₃ R ₄ and each nitrogen atom to which they are bonded independently form a heterocyclic ring having a total carbon number of 6 or less, and the heterocyclic ring may contain an oxygen atom, and R ₁ In R ₄ , the alkyl group having 1 to 3 carbon atoms, the allyl group, the cycloalkyl group having 3 to 7 carbon atoms and the cycloalkenyl group, the phenyl group, the benzyl group, and the heterocyclic ring have a hydroxyl group and 1 to 3 carbon atoms. Alkyloxy group of Or an allyloxy group as a substituent, and the cycloalkyl group having 3 to 7 carbon atoms and the cycloalkenyl group, phenyl group, benzyl group, or heterocyclic ring is alkyl having 1 to 3 carbon atoms. May have a group as a substituent.)
(In General Formula (2), X ₁ , X ₂ and X ₃ are each independently an alkyl group having 1 to 3 carbon atoms, an alkyloxy group having 1 to 3 carbon atoms, an allyloxy group, a hydroxyl group, a fluorine atom, or Represents a trifluoromethyl group, n, m and p each independently represents an integer of 0 to 3, and k represents 0 or 1)
In the present invention, _one of R ₁ and R ₂ is a hydrogen atom and the other is an alkyl group having 1 to 3 carbon atoms, and one of R ₃ and R ₄ is a hydrogen atom and the other is an alkyl group having 1 to 3 carbon atoms. A group is preferred.
In the present invention, R ₁ and R ₂ and / or R ₃ and R ₄ independently form a heterocycle having a total carbon number of 6 or less together with the nitrogen atom to which they are bonded. Is preferred.
In the present invention, the -AZ group is preferably a benzoyl group.

  In the present invention, N-benzoyl-N ′, N ″ -dimethyl-L-glutamic acid-1,5-diamide, N-benzoyl-N ′, N ″ -diethyl-L-glutamic acid-1,5- Diamide, N-benzoyl-N ′, N ″ -di n-propyl-L-glutamic acid-1,5-diamide, N-benzoyl-L-glutamic acid bis-1,5-morpholinamide, N-benzoyl-L- Glutamic acid bis-1,5-piperidineamide is preferred.

The glutamic acid derivative or salt thereof according to the present invention is
N-benzoyl-N ′, N ″ -dimethyl-L-glutamic acid-1,5-diamide,
N-benzoyl-N ′, N ″ -diethyl-L-glutamic acid-1,5-diamide,
N-benzoyl-N ′, N ″ -di n-propyl-L-glutamic acid-1,5-diamide,
N-benzoyl-L-glutamic acid bis-1,5-morpholinamide, or
N-benzoyl-L-glutamic acid bis-1,5-piperidineamide
A glutamic acid derivative or a salt thereof,
Further, the keratinization inhibitor, pore reducing agent, or rough skin prevention / improving agent according to the present invention comprises one or more compounds selected from the group consisting of the glutamic acid derivatives and salts thereof as described above as active ingredients. .

  According to the present invention, there is provided a novel and safe glutamic acid derivative and a salt thereof that have an excellent effect of suppressing keratinization, a pore reducing effect and a skin roughening prevention / improving effect, and that do not cause sensory stimulation. Is useful as a keratinization inhibitor, a pore-reducing agent, and a rough skin prevention / improving agent. Further, by blending this, an external composition for skin having functions of inhibiting keratinization, reducing pores, preventing and improving rough skin can be obtained.

The glutamic acid derivative according to the present invention is represented by the following general formula (1).

(In general formula (1), A represents a single bond, an oxycarbonyl group, a carbonyl group or a sulfonyl group, Z represents the following general formula (2), and R _{1 to} R ₄ are each independently a hydrogen atom. , An alkyl group having 1 to 3 carbon atoms, an allyl group, a cycloalkyl group having 3 to 7 carbon atoms or a cycloalkenyl group, a phenyl group, or a benzyl group, or R ₁ and R ₂ and / or R ₃ R ₄ and each nitrogen atom to which they are bonded independently form a heterocyclic ring having a total carbon number of 6 or less, and the heterocyclic ring may contain an oxygen atom, and R ₁ In R ₄ , the alkyl group having 1 to 3 carbon atoms, the allyl group, the cycloalkyl group having 3 to 7 carbon atoms and the cycloalkenyl group, the phenyl group, the benzyl group, and the heterocyclic ring have a hydroxyl group and 1 to 3 carbon atoms. Alkyloxy group of Or an allyloxy group as a substituent, and the cycloalkyl group having 3 to 7 carbon atoms and the cycloalkenyl group, phenyl group, benzyl group, or heterocyclic ring is alkyl having 1 to 3 carbon atoms. May have a group as a substituent.)

(In General Formula (2), X ₁ , X ₂ and X ₃ are each independently an alkyl group having 1 to 3 carbon atoms, an alkyloxy group having 1 to 3 carbon atoms, an allyloxy group, a hydroxyl group, a fluorine atom, or Represents a trifluoromethyl group, n, m and p each independently represents an integer of 0 to 3, and k represents 0 or 1)

In the glutamic acid derivative of the present invention, glutamic acid serving as a mother nucleus may be any of D-form, L-form and DL-form, and the mixing ratio of DL-form may be any.
The glutamic acid derivative (I) according to the present invention has a structure in which the amino group of glutamic acid is substituted with an -AZ group.
In general formula (1), A represents a single bond, an oxycarbonyl group, a carbonyl group, or a sulfonyl group, and Z represents a group represented by the general formula (2).

  When A is a single bond, the glutamic acid derivative of the present invention is an N-phenyl or N-benzyl substituent corresponding to Z. When A is an oxycarbonyl group, the glutamic acid derivative of the present invention is an N-phenyloxycarbonyl substituted or N-benzyloxycarbonyl substituted corresponding to Z. When A is a carbonyl group, the glutamic acid derivative of the present invention is an N-benzoyl substituent or N-phenylacetyl substituent corresponding to Z. When A is a sulfonyl group, the glutamic acid derivative of the present invention is an N-benzenesulfonyl substituent or an N-benzylsulfonyl substituent corresponding to Z.

  In the present invention, any of these may be used, but since it is excellent in thermal stability, A is preferably an N-benzoylglutamic acid derivative or an N-phenylacetylglutamic acid derivative in which a carbonyl group is present. Furthermore, an N-benzoylglutamic acid derivative is particularly desirable from the standpoint of ease of preparation.

The glutamic acid derivative of the present invention is a 1,5-diamide body corresponding to R _{1 to} R ₄ .
R _{1 to} R ₄ are each independently a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an allyl group, a cycloalkyl group having 3 to 7 carbon atoms, a cycloalkenyl group, a phenyl group, or a benzyl group. Can do. Alternatively, R ₁ and R ₂ and / or R ₃ and R ₄ can each independently form a heterocyclic ring having a total carbon number of 6 or less together with the nitrogen atom to which they are bonded. This heterocycle may contain an oxygen atom. Note that in R _{1 to} R ₄ , the alkyl group having 1 to 3 carbon atoms, the allyl group, the cycloalkyl group having 3 to 7 carbon atoms, the cycloalkenyl group, the phenyl group, the benzyl group, and the heterocyclic ring are hydroxyl group, carbon You may have a C1-C3 alkyloxy group or an allyloxy group. Moreover, in R < ₁ > -R < ₄ >, the said C3-C7 cycloalkyl group and cycloalkenyl group, a phenyl group, a benzyl group, and a heterocyclic ring may have a C1-C3 alkyl group. Absent.

In R _{1 to} R ₄ , examples of the alkyl group having 1 to 3 carbon atoms include a methyl group, an ethyl group, an n-propyl group, and an iso-propyl group. In addition, these alkyl groups may have a hydroxyl group, a C1-C3 alkyloxy group, or an allyloxy group.

In the glutamic acid derivative of the present invention, R _{1 to} R ₄ are each preferably a hydrogen atom or an alkyl group having 1 to 3 carbon atoms because of good solubility.
NR ₁ R ₂ and NR ₃ R ₄ corresponding to these include, for example, methylamino group, ethylamino group, n-propylamino group, iso-propylamino group, dimethylamino group, diethylamino group, di-n-propylamino group Group, diiso-propylamino group, methylethylamino group, methyl n-propylamino group, methyliso-propylamino group, ethyl n-propylamino group, ethyliso-propylamino group, n-propyliso-propylamino group , Hydroxyethylamino group, methoxyethylamino group, ethoxyethylamino group and the like.

Among these, since the effect is even better, either one of the combinations of R ₁ and R ₂ and _one of the combinations of R ₃ and R ₄ are each independently a hydrogen atom or a methyl group. It is desirable that one is a hydrogen atom and the other is an alkyl group having 1 to 3 carbon atoms.
Specific examples of the corresponding glutamic acid derivative include N-benzoyl-N ′, N ″ -dimethyl-L-glutamic acid-1,5-diamide, N-benzoyl-N ′, N ″ -diethyl- L-glutamic acid-1,5-diamide, N-benzoyl-N ′, N ″ -di n-propyl-L-glutamic acid-1,5-diamide, N-benzoyl-N ′, N ″ -diiso- Propyl-L-glutamic acid-1,5-diamide, N-benzoyl-N′-ethyl-N ″ -methyl-L-glutamic acid-1,5-diamide, N-benzoyl-N ″ -ethyl-N′- Methyl-L-glutamic acid-1,5-diamide, N-benzoyl-N ″ -methyl-L-glutamic acid-1,5-diamide, N-benzoyl-N′-methyl-L-glutamic acid-1,5-diamide N-benzoyl-N ″- Tyl-L-glutamic acid-1,5-diamide, N-benzoyl-N′-ethyl-L-glutamic acid-1,5-diamide, N-benzoyl-N ″ -n-propyl-L-glutamic acid-1,5 -Diamide, N-benzoyl-N'-n-propyl-L-glutamic acid-1,5-diamide, N-benzoyl-N ''-iso-propyl-L-glutamic acid-1,5-diamide, N-benzoyl- N′-iso-propyl-L-glutamic acid-1,5-diamide, N-benzoyl-N′-ethyl-N ″ -n-propyl-L-glutamic acid-1,5-diamide, N-benzoyl-N ′ '-Ethyl-N'-n-propyl-L-glutamic acid-1,5-diamide, N-benzoyl-N'-ethyl-N''-iso-propyl-L-glutamic acid-1,5-diamide, N- Benzoyl -N "-ethyl-N'-iso-propyl-L-glutamic acid-1,5-diamide, N-benzoyl-N'-methyl-N" -n-propyl-L-glutamic acid-1,5-diamide N-benzoyl-N ″ -methyl-N′-n-propyl-L-glutamic acid-1,5-diamide, N-benzoyl-N′-methyl-N ″ -iso-propyl-L-glutamic acid-1 , 5-diamide, N-benzoyl-N ″ -methyl-N′-iso-propyl-L-glutamic acid-1,5-diamide, N-benzoyl-N′-n-propyl-N ″ -iso-propyl -L-glutamic acid-1,5-diamide, N-benzoyl-N ″ -n-propyl-N′-iso-propyl-L-glutamic acid-1,5-diamide.

In R _{1 to} R ₄ , the cycloalkyl group having 3 to 7 carbon atoms means a saturated hydrocarbon group having 3 to 7 carbon atoms in which at least a part thereof forms a saturated carbocyclic ring.
In R _{1 to} R ₄ , the cycloalkenyl group having 3 to 7 carbon atoms is a total of 3 to 7 carbon atoms in which at least a part forms an unsaturated carbocycle having one or more double bonds. Means an unsaturated hydrocarbon group.

  Examples of the cycloalkyl group having 3 to 7 carbon atoms or the cycloalkenyl group having 3 to 7 carbon atoms include a cyclopropyl group, a cyclopropylmethyl group, a 1-methylcyclopropyl group, a 2-methylcyclopropyl group, and 3-methyl. Cyclopropyl group, 1-cyclopropylethyl group, 2-cyclopropylethyl group, 1,2-dimethylcyclopropyl group, 2,2-dimethylcyclopropyl group, 2,3-dimethylcyclopropyl group, 1-cyclopropylpropyl Group, 2-cyclopropylpropyl group, 3-cyclopropylpropyl group, (2′-methylcyclopropyl) methyl group, (2′-ethylcyclopropyl) methyl group, 1-ethylcyclopropyl group, 2-ethylcyclopropyl Group, 1,2,3-trimethylcyclopropyl group, 2,2,3-trimethylcyclopropyl Group, 1,2,2-trimethylcyclopropyl group, (1 ′, 2′-dimethylcyclopropyl) methyl group, (2 ′, 2′-dimethylcyclopropyl) methyl group, (2 ′, 3′-dimethyl) Cyclopropyl) methyl group, 1- (1′-methylcyclopropyl) ethyl group, 1- (2′-methylcyclopropyl) ethyl group, 2-cyclopropylpropyl group, 2- (2′-methylcyclopropyl) ethyl A group, 1- (1′-methylcyclopropyl) propyl group, 1- (2′-methylcyclopropyl) propyl group, 2-ethyl-1-methylcyclopropyl group, 2-ethyl-2-methylcyclopropyl group, 3-cyclopropylbutyl group, 2-cyclopropylbutyl group, 1-cyclopropylbutyl group, 2-cyclopropyl-1-methylethyl group, 3- (2′-methyl) Cyclopropyl) propyl group, 1- (2′-propylcyclopropyl) methyl group, 3-cyclopropyl-2-methylpropyl group, 3-cyclopropyl-1-methylpropyl group, 3-cyclopropylpentyl group, 3- (2′-ethylcyclopropyl) ethyl group, 1,2-diethylcyclopropyl group, 2,2-diethylcyclopropyl group,

  2-cyclopropyl-1-ethylethyl group, 2- (2 ′, 2′-dimethylcyclopropyl) ethyl group, 2- (2 ′, 3′-dimethylcyclopropyl) ethyl group, 2- (2 ′, 2 ′) -Dimethylcyclopropyl) butyl group, 2- (2 ', 3'-dimethylcyclopropyl) butyl group, 2- (2'-methylcyclopropyl) -1-methylethyl group, 2-cyclopropyl-1-methylbutyl group Tetramethylcyclopropyl group, (2 ', 2', 3'-trimethylcyclopropyl) methyl group, 1- (2 ', 2'-dimethylcyclopropyl) ethyl group, 1- (2', 3'-dimethyl) Cyclopropyl) ethyl group, 1- (2 ′, 2′-dimethylcyclopropyl) -1-methylmethyl group, 1- (2 ′, 3′-dimethylcyclopropyl) -1-methylmethyl group, 1- 3′-methylcyclopropyl) -1-methylethyl group, 1- (2′-methylcyclopropyl) -1-methylethyl group, 1- (2′-ethylcyclopropyl) -1-methylmethyl group, 1- Cyclopropyl-1-methylethyl group, cyclobutyl group, cyclobutylmethyl group, 1-methylcyclobutyl group, 2-methylcyclobutyl group, 3-methylcyclobutyl group, 1,2-dimethylcyclobutyl group, 1,3 -Dimethylcyclobutyl group, 2,2-dimethylcyclobutyl group, 2,3-dimethylcyclobutyl group, 2,4-dimethylcyclobutyl group, 3,3-dimethylcyclobutyl group, 1-ethylcyclobutyl group, 2 -Ethylcyclobutyl group, 3-ethylcyclobutyl group, 1-cyclobutylethyl group, 2-cyclobutylethyl group, 1-cyclobutyl-1-me Rumethyl group, (2 ′, 2′-dimethylcyclobutyl) methyl group, (2 ′, 3′-dimethylcyclobutyl) methyl group, (3 ′, 3′-dimethylcyclobutyl) methyl group, (2 ′, 4 '-Dimethylcyclobutyl) methyl group, 1- (2'-methylcyclobutyl) ethyl group, 1- (3'-methylcyclobutyl) ethyl group,

  1,2,2-trimethylcyclobutyl group, 1,2,3-trimethylcyclobutyl group, 1,3,3-trimethylcyclobutyl group, 1,2,4-trimethylcyclobutyl group, 2,2,3- Trimethylcyclobutyl group, 2,3,3-trimethylcyclobutyl group, 2,3,4-trimethylcyclobutyl group, (2′-ethylcyclobutyl) methyl group, (3′-ethylcyclobutyl) methyl group, 1 -Cyclobutylpropyl group, 2-cyclobutylpropyl group, 3-cyclobutylpropyl group, 1-propylcyclobutyl group, 2-propylcyclobutyl group, 1-ethyl-2-methylcyclobutyl group, 2-ethyl-2 -Methylcyclobutyl group, 1-ethyl-3-methylcyclobutyl group, 3-ethyl-3-methylcyclobutyl group, 2-ethyl-3-methylcyclobutyl Group, 3-ethyl-2-methylcyclobutyl group, 2-ethyl-1-methylcyclobutyl group, 3-ethyl-1-methylcyclobutyl group, 2-ethyl-4-methylcyclobutyl group, 4-ethyl- 2-methylcyclobutyl group, 2-cyclobutyl-1-methylethyl group, 2- (2′-methylcyclobutyl) ethyl group, 2- (3′-methylcyclobutyl) ethyl group, cyclopentyl group, 1-methyl- 2-propylcyclobutyl group, 1-methyl-3-propylcyclobutyl group, 2-methyl-2-propylcyclobutyl group, 3-methyl-3-propylcyclobutyl group, 2-methyl-3-propylcyclobutyl group 2-methyl-1-propylcyclobutyl group, 3-methyl-1-propylcyclobutyl group, 2-methyl-4-propylcyclobutyl group, cyclopen Group, cyclopentylmethyl group, (2′-methylcyclopentyl) methyl group, (3′-methylcyclopentyl) methyl group, 1-cyclopentylethyl group, 2-cyclopentylethyl group, 1,2-dimethylcyclopentyl group, 2,2 -Dimethylcyclopentyl group, 2,3-dimethylcyclopentyl group,

  3,3-dimethylcyclopentyl group, 1,3-dimethylcyclopentyl group, 2,5-dimethylcyclopentyl group, 2,4-dimethylcyclopentyl group, 3,5-dimethylcyclopentyl group, 3,4-dimethylcyclopentyl group, 1- Cyclopentyl-1-methylmethyl group, cyclohexyl group, cyclohexylmethyl group, 1-methylcyclohexyl group, 2-methylcyclohexyl group, 3-methylcyclohexyl group, cycloheptyl group, cyclopropylenyl group, cyclopropylenylmethyl group, Cyclobutenyl group, cyclobutadienyl group, 1-cyclopentenyl group, 2-cyclopentenyl group, 3-cyclopentenyl group, cyclopentadienyl group, 2-methylcyclopentadienyl group, 3-methylcyclopentadienyl group 2,2-dimethyl-1-silane Lopentenyl group, 2,3-dimethyl-1-cyclopentenyl group, 2,4-dimethyl-1-cyclopentenyl group, 2,5-dimethyl-1-cyclopentenyl group, 3,3-dimethyl-1-cyclopentenyl group 3,4-dimethyl-1-cyclopentenyl group, 3,5-dimethyl-1-cyclopentenyl group, 4,4-dimethyl-1-cyclopentenyl group, 4,5-dimethyl-1-cyclopentenyl group, 5 , 5-dimethyl-1-cyclopentenyl group, 1,2-dimethyl-2-cyclopentenyl group, 1,3-dimethyl-2-cyclopentenyl group, 1,4-dimethyl-2-cyclopentenyl group, 1,5 -Dimethyl-2-cyclopentenyl group, 2,3-dimethyl-2-cyclopentenyl group, 2,4-dimethyl-2-cyclopentenyl group, 2,5-dimethyl- -Cyclopentenyl group, dimethylcyclopentadienyl group, 3,4-dimethyl-2-cyclopentenyl group, 3,5-dimethyl-2-cyclopentenyl group, 4,4-dimethyl-2-cyclopentenyl group, 4, 5-dimethyl-2-cyclopentenyl group, 5,5-dimethyl-2-cyclopentenyl group,

  Cyclopentenylmethyl group, 1,2-dimethyl-3-cyclopentenyl group, 1,3-dimethyl-3-cyclopentenyl group, 2,2-dimethyl-3-cyclopentenyl group, 2,3-dimethyl-3-cyclo Pentenyl group, 2,4-dimethyl-3-cyclopentenyl group, 2,5-dimethyl-3-cyclopentenyl group, 3,4-dimethyl-3-cyclopentenyl group, 3,5-dimethyl-3-cyclopentenyl group 1- (1′-cyclopentenyl) ethyl group, 1- (2′-cyclopentenyl) ethyl group, 1- (3′-cyclopentenyl) ethyl group, 2- (1′-cyclopentenyl) ethyl group, 2 -(2'-cyclopentenyl) ethyl group, 2- (3'-cyclopentenyl) ethyl group, 1-cyclohexenyl group, 2-cyclohexenyl group, 3-cyclohexene Group, 1,3-cyclohexadienyl group, 1,4-cyclohexadienyl group, 1,5-cyclohexadienyl group, 2,4-cyclohexadienyl group, 2,5-cyclohexadienyl group, 2- Methyl-1-cyclohexenyl group, 3-methyl-1-cyclohexenyl group, 4-methyl-1-cyclohexenyl group,

  5-methyl-1-cyclohexenyl group, 6-methyl-1-cyclohexenyl group, 1-methyl-2-cyclohexenyl group, 2-methyl-2-cyclohexenyl group, 3-methyl-2-cyclohexenyl group, 4-methyl-2-cyclohexenyl group, 5-methyl-2-cyclohexenyl group, 6-methyl-2-cyclohexenyl group, 1-methyl-3-cyclohexenyl group, 2-methyl-3-cyclohexenyl group, 3-methyl-3-cyclohexenyl group, 4-methyl-3-cyclohexenyl group, 5-methyl-3-cyclohexenyl group, 6-methyl-3-cyclohexenyl group, 1-cycloheptenyl group, 2-cycloheptenyl group, 3-cycloheptenyl group, 4-cycloheptenyl group, (1′-cyclohexenyl) methyl group, (2′-cyclohexenyl) methyl Group, (3′-cyclohexenyl) methyl group, (1 ′, 3′-cyclohexadienyl) methyl group, (1 ′, 4′-cyclohexadienyl) methyl group, (1 ′, 5′-cyclohexadienyl) ) Methyl group, (2 ′, 4′-cyclohexadienyl) methyl group, (2 ′, 5′-cyclohexadienyl) methyl group and the like.

  These cycloalkyl groups having 3 to 7 carbon atoms or cycloalkenyl groups having 3 to 7 carbon atoms are, as described above, a hydroxyl group, an alkyloxy group having 1 to 3 carbon atoms, an allyloxy group, and an alkyl group having 1 to 3 carbon atoms. Any of these may be substituted.

In R _{1 to} R ₄ , as described above, the phenyl group or benzyl group is a substituent selected from a hydroxyl group, an alkyloxy group having 1 to 3 carbon atoms, an allyloxy group, and an alkyl group having 1 to 3 carbon atoms. You may have as.
Specific examples include 4-methoxyphenyl group, 3-methoxyphenyl group, 2-methoxyphenyl group, 4-ethoxyphenyl group, 3-ethoxyphenyl group, 2-ethoxyphenyl group, 4-propoxyphenyl group, 3-propoxy group. Phenyl group, 2-propoxyphenyl group, 4-allyloxyphenyl group, 3-allyloxyphenyl group, 2-allyloxyphenyl group, 2,4-dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 3,4, 5-trimethoxyphenyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2,4-dihydroxyphenyl group, 3,4-dihydroxyphenyl group, 3,4,5-trihydroxyphenyl Group, 2-hydroxy-4-methoxyphenyl group, 3-hydroxy-4-methoxy Phenyl group, 4-hydroxy-3-methoxyphenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-ethylphenyl group, 3-ethylphenyl group, 4-ethylphenyl group, 2 -Propylphenyl group, 3-propylphenyl group, 4-propylphenyl group,

  4-methoxybenzyl group, 3-methoxybenzyl group, 2-methoxybenzyl group, 4-ethoxybenzyl group, 3-ethoxybenzyl group, 2-ethoxybenzyl group, 4-propoxybenzyl group, 3-propoxybenzyl group, 2- Propoxybenzyl group, 4-allyloxybenzyl group, 3-allyloxybenzyl group, 2-allyloxybenzyl group, 2,4-dimethoxybenzyl group, 3,4-dimethoxybenzyl group, 3,4,5-trimethoxybenzyl Group, 2-hydroxybenzyl group, 3-hydroxybenzyl group, 4-hydroxybenzyl group, 2,4-dihydroxybenzyl group, 3,4-dihydroxybenzyl group, 3,4,5-trihydroxybenzyl group, 2-hydroxy -4-methoxybenzyl group, 3-hydroxy-4-methoxybenzyl group, 4- Droxy-3-methoxybenzyl group, 2-methylbenzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 2-ethylbenzyl group, 3-ethylbenzyl group, 4-ethylbenzyl group, 2-propylbenzyl group, Examples include 3-propylbenzyl group and 4-propylbenzyl group.

In addition, it is preferable that R ₁ and R ₂ and / or R ₃ and R ₄ independently form a heterocyclic ring having a total carbon number of 6 or less together with the nitrogen atom to which they are bonded. The heterocyclic ring may have an unsaturated bond. The heterocyclic ring may contain an oxygen atom.
Specific examples of such NR ₁ R ₂ and NR ₃ R ₄ include piperidine, pyrrolidine, pyrrole, morpholine and the like.

In this case, a preferable combination of NR ₁ R ₂ and NR ₃ R ₄ is easy to synthesize, so that NR ₁ R ₂ and NR ₃ R ₄ are desirably the same. Moreover, since solubility is favorable, it is desirable that either NR ₁ R ₂ or NR ₃ R ₄ is composed of a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.
Corresponding glutamic acid derivatives include, for example, N-benzoyl-L-glutamic acid bis-1,5-piperidineamide, N-benzoyl-L-glutamic acid bis-1,5-pyrrolidinamide, N-benzoyl-L-glutamic acid. Bis-1,5-pyrrolamide, N-benzoyl-L-glutamic acid Bis-1,5-morpholinamide, N-benzoyl-1-piperidine-L-glutamic acid-1,5-diamide, N-benzoyl-5-methyl Amine-1-piperidine-L-glutamic acid-1,5-diamide, N-benzoyl-5-ethylamine-1-piperidine-L-glutamic acid-1,5-diamide, N-benzoyl-1-piperidine-5-n- Propylamine-L-glutamic acid-1,5-diamide, N-benzoyl-1-piperidi -5-iso-propylamine-L-glutamic acid-1,5-diamide, N-benzoyl-5-piperidine L-glutamic acid-1,5-diamide, N-benzoyl-1-methylamine-5-piperidi-L -Glutamic acid-1,5-diamide, N-benzoyl-1-ethylamine-5-piperidine-L-glutamic acid-1,5-diamide, N-benzoyl-5-piperidine-1-n-propylamine-1,5- Diamide, N-benzoyl-5-piperidine-1-iso-propylamine-L-glutamic acid-1,5-diamide, N-benzoyl-1-pyrrolidine-L-glutamic acid-1,5-diamide, N-benzoyl-5 -Methylamine-1-pyrrolidine-L-glutamic acid-1,5-diamide, N-benzoyl-5-ethylamine-1- Loridine-L-glutamic acid-1,5-diamide, N-benzoyl-1-pyrrolidine-5-n-propylamine-1,5-diamide, N-benzoyl-1-pyrrolidine-5-iso-propylamine-1, 5-diamide, N-benzoyl-5-pyrrolidine-L-glutamic acid-1,5-diamide, N-benzoyl-1-methylamine-5-pyrrolidine-L-glutamic acid-1,5-diamide, N-benzoyl-1 -Ethylamine-5-pyrrolidine-L-glutamic acid-1,5-diamide, N-benzoyl-5-pyrrolidine-1-n-propylamine-L-glutamic acid-1,5-diamide, N-benzoyl-5-pyrrolidine- 1-iso-propylamine-L-glutamic acid-1,5-diamide, N-benzoyl-1-pyrrole-L-glu Minic acid-1,5-diamide, N-benzoyl-5-methylamine-1-pyrrole-L-glutamic acid-1,5-diamide, N-benzoyl-5-ethylamine-1-pyrrole-L-glutamic acid-1, 5-diamide, N-benzoyl-1-pyrrole-5-n-propylamine-L-glutamic acid-1,5-diamide, N-benzoyl-1-pyrrole-5-iso-propylamine-L-glutamic acid-1, 5-Diamide, N-benzoyl-5-pyrrole-L-glutamic acid-1,5-diamide, N-benzoyl-1-methylamine-5-pyrrole-L-glutamic acid-1,5-diamide, N-benzoyl-1 -Ethylamine-5-pyrrole-L-glutamic acid-1,5-diamide, N-benzoyl-5-pyrrole-1-n-propylamine- L-glutamic acid-1,5-diamide, N-benzoyl-5-pyrrol-1-iso-propylamine-L-glutamic acid-1,5-diamide, N-benzoyl-1-morpholine-L-glutamic acid-1,5 -Diamide, N-benzoyl-5-methylamine-1-morpholine-L-glutamic acid-1,5-diamide, N-benzoyl-5-ethylamine-1-morpholine-L-glutamic acid-1,5-diamide, N- Benzoyl-1-morpholine-5-n-propylamine-L-glutamic acid-1,5-diamide, N-benzoyl-1-morpholine-5-iso-propylamine-L-glutamic acid-1,5-diamide, N- Benzoyl-5-morpholine-L-glutamic acid-1,5-diamide, N-benzoyl-1-methylamine-5-molybdenum Holin-L-glutamic acid-1,5-diamide, N-benzoyl-1-ethylamine-5-morpholine-L-glutamic acid-1,5-diamide, N-benzoyl-5-morpholine-1-n-propylamine-L -Glutamic acid-1,5-diamide, N-benzoyl-5-morpholine-1-iso-propylamine-L-glutamic acid-1,5-diamide.
In addition, the heterocyclic ring may have a hydroxyl group, an alkyloxy group having 1 to 3 carbon atoms, an allyloxy group, or an alkyl group having 1 to 3 carbon atoms as a substituent.

  In the present invention, particularly preferred glutamic acid derivatives are N-benzoyl-N ′, N ″ -dimethyl-L-glutamic acid-1,5-diamide, N-benzoyl-N ′, N ″ -diethyl-L-glutamic acid— 1,5-diamide, N-benzoyl-N ′, N ″ -din-propyl-L-glutamic acid-1,5-diamide, N-benzoyl-L-glutamic acid bis-1,5-morpholinamide, and N -Benzoyl-L-glutamic acid bis-1,5-piperidineamide. These have the best effects of inhibiting keratinization, reducing pores, preventing and improving rough skin, having good solubility in preparations, high safety, and being most excellent in solving the object of the present invention.

The glutamic acid derivative according to the present invention can be synthesized by a known method. For example, R.A. B. It can be synthesized by the method by Angiers et al., 1950, vol. 75, p74-.
Although the typical synthesis example is given to the following, it is not limited to these.

(Synthesis example)
(1) N-benzoyl-N ′, N ″ -dimethyl-L-glutamic acid-1,5-diamide To 10 g of benzoyl-L-glutamic acid, 100 mL of methanol and 100 mL of hydrochloric acid-methanol solution were added and heated to reflux. After air cooling, 20 mL of 40% methylamine methanol solution was added to the concentrated residue and stirred. The reaction solution was concentrated, dried and solidified, and recrystallized from methanol to obtain 8.9 g of the desired product.
The obtained object was confirmed by NMR (EPC-400 manufactured by JASCO, DMSO-d ₆ , 40 ° C.).
¹ H-NMR (δ: PPM): 8.50 (1H), 7.92-7.75 (4H), 7.56-7.45 (3H), 4.35 (1H), 2.60- 2.50 (6H), 2.16 (2H), 2.03-1.91 (2H).
¹³ C-NMR (δ: PPM): 172.1, 171.8, 166.2, 134.0, 131.2, 128.1, 127.5, 53.4, 31.9, 27.4, 25.6, 25.4.

(2) N-benzoyl-N ′, N ″ -diethyl-L-glutamic acid-1,5-diamide To 10 g of benzoyl-L-glutamic acid, 100 mL of methanol and 100 mL of hydrochloric acid-methanol solution were added and heated to reflux. After air cooling, 100 mL of methanol and 15 mL of 70% aqueous ethylamine were added to the concentrated residue and stirred. The reaction solution was concentrated, dried and solidified, and recrystallized from methanol to obtain 8.1 g of the desired product.
The obtained object was confirmed by NMR (EPC-400 manufactured by JASCO, DMSO-d ₆ , 40 ° C.).
¹ H-NMR (δ: PPM): 8.45 (1H), 7.91-7.81 (4H), 7.54-7.45 (3H), 4.35 (1H), 3.29 ( 4H), 2.15 (2H), 2.01-1.91 (2H), 1.0 (6H).
¹³ C-NMR (δ: PPM): 171.3, 171.0, 166.1, 134.1, 131.2, 128.1, 127.4, 53.4, 33.4, 33.3, 32.0, 27.6, 14.7, 14.6.

(3) Benzoyl-L-glutamic acid N ′, N ′, N ″, N ″ -tetramethyl-1,5-diamide 100 g of methanol and 100 mL of hydrochloric acid-methanol solution are added to 10 g of benzoyl-L-glutamic acid and heated to reflux. Went. After air cooling, 100 mL of methanol and 7 g of dimethylamine were added to the concentrated residue and stirred. The reaction solution was concentrated to obtain 10.2 g of the desired product.

(4) Benzoyl-L-glutamic acid N ′, N ″ -diphenyl-1,5-diamide To 10 g of benzoyl-L-glutamic acid, 100 mL of methanol and 100 mL of hydrochloric acid-methanol solution were added and heated to reflux. After air cooling, 100 mL of methanol and 10.8 g of aniline were added to the concentrated residue and stirred. The reaction solution was concentrated and dried and solidified to obtain 8.7 g of the desired product.

(5) N-benzoyl-L-glutamic acid bis-1,5-morpholinamide 100 g of methanol and 100 mL of hydrochloric acid-methanol solution were added to 10 g of benzoyl-L-glutamic acid and heated to reflux. After air cooling, 100 mL of methanol and 12 g of morpholine were added to the concentrated residue and stirred. The reaction solution was concentrated and dried to obtain 12.1 g of the desired product.

(6) N-benzoyl-L-glutamic acid bis-1,5-piperidinamide To 10 g of benzoyl-L-glutamic acid, 100 mL of methanol and 100 mL of hydrochloric acid-methanol solution were added and heated to reflux. After air cooling, 100 mL of methanol and 12 g of piperidine were added to the concentrated residue and stirred. The reaction solution was concentrated, dried and solidified, and recrystallized from methanol to obtain 11.8 g of the desired product.
(7) N-benzoyl-L-glutamic acid N′-ethyl-1,5-diamide 5.5 g of sodium hydroxide was dissolved in water, 10 g of L-glutamine was added, and 9.6 g of benzoyl chloride was added under ice-cooling and stirring. added. After stirring for 30 minutes, the mixture was stirred overnight at room temperature. After the reaction, the pH was adjusted to 1 or less with hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. To the obtained residue, 100 mL of methanol and 100 mL of hydrochloric acid-methanol solution were added and heated to reflux. After air cooling, 100 mL of methanol and 30% methylamine methanol solution were added to the concentrated residue and stirred. The reaction solution was concentrated and dried and solidified to obtain 10.2 g of the desired product.
(8) N-benzoyl-L-glutamic acid N′-methyl-N ″ -ethyl-1,5-diamide 4.6 g of sodium hydroxide was dissolved in water to give L-glutamic acid-5-N-ethylamide (theanine) 10 g was added, and 8.7 g of benzoyl chloride was added with stirring under ice cooling. After stirring for 30 minutes, the mixture was stirred overnight at room temperature. After the reaction, the pH was adjusted to 1 or less with hydrochloric acid, extracted with ethyl acetate, dried over magnesium sulfate, and concentrated under reduced pressure. To the obtained residue, 100 mL of methanol and 100 mL of hydrochloric acid-methanol solution were added, and the mixture was heated to reflux. After air cooling, 100 mL of methanol and 23.8 g of 30% methylamine methanol solution were added to the concentrated residue and stirred. The reaction solution was concentrated and dried and solidified to obtain 9.2 g of the desired product.

  Moreover, the glutamic acid derivative of the present invention is not necessarily required, but can also be used as a salt. The salt is not particularly limited. Examples of the inorganic salt include sodium salt, potassium salt, calcium salt, zinc salt, magnesium salt, ammonium salt, hydrochloride, sulfate, phosphate, hydrobromide, and the like. Can be mentioned. Organic salts include methylamine, pyridine, trimethylamine, triethanolamine, methyl sulfate, p-toluenesulfonate, acetate, lactate, maleate, fumarate, oxalate, succinate Acid salts, tartrate salts, citrate salts, betaine salts, glycine salts, serine salts, taurine salts and the like can be mentioned, but the present invention is not limited thereto. The salt can be obtained by a known method.

In the process of skin metabolism, keratinocytes that have migrated to the outermost layer (skin surface) of the skin eventually become scummed and peeled off, but the keratinocyte nucleus in this state usually disappears. However, for some reason, the differentiation and proliferation of skin cells is disturbed, and the rate of keratinization is abnormally increased, so that epidermal keratinocytes may exist in the keratin in an immature state with nuclei in the cells. Yes, this is called keratinization. In the present invention, the keratinization of the epidermal keratinocytes is also simply referred to as “keratosis”, and the term simply “keratosis” means the keratinization of the epidermal keratinocytes.
Moreover, the pore which the pore became conspicuous has become a mortar shape, and the stratum corneum of the mortar portion around the pore portion of the pore is in a keratinized state. Therefore, when the keratinization occurs in the stratum corneum around the pores (outlet part of the hair) of the pores, mortarization around the pores occurs, and the pores are conspicuous due to the mortar-like structure in which the pores are widened. .

The glutamic acid derivatives and salts thereof according to the present invention (hereinafter sometimes referred to as glutamic acid derivatives) have excellent keratinization suppressing effect, pore reducing effect, and rough skin preventing / improving effect as will be proved later. . Accordingly, one or more compounds selected from the group consisting of glutamic acid derivatives according to the present invention are useful as a keratinization inhibitor, a pore-reducing agent, and a rough skin prevention / improving agent.
The glutamic acid derivative according to the present invention has not been known so far, and the present inventors have also found for the first time an inhibitory effect on keratinization, an effect of reducing pores, and an effect of preventing and improving rough skin.

  The above-mentioned keratinization-inhibiting agent, pore reducing agent and rough skin preventing / ameliorating agent all have a very wide range of applications, for example, applied to various fields such as cosmetics, pharmaceutics, foods including quasi drugs, and preferably skin. It is blended and used in a composition for external use.

  Therefore, a composition containing one or more compounds selected from the group consisting of the glutamic acid derivatives is useful as a keratinization inhibiting composition, a pore reducing composition, or a rough skin preventing / improving composition, The composition exhibits excellent effects such as an action for inhibiting keratinization, an action for reducing pores, and an action for preventing and improving rough skin.

  Examples of external compositions for skin include facial cleansers, milky lotions, creams, lotions, gels, essences (beauty serums), basic cosmetics such as packs and masks, makeup cosmetics such as foundations and lipsticks, and oral cosmetics such as dentifrices And cosmetics such as aromatic cosmetics, hair cosmetics and body cosmetics, and ointments.

  The external composition for skin according to the present invention improves the conspicuousness of pores such as nose and cheek for facial use, prevents and improves rough skin, and improves the conspicuousness of pores after removal of hair such as feet for body use Prevent and improve rough skin. In addition, it is possible to provide a youthful and fresh skin that suppresses the conspicuousness of the pores by suppressing the keratinization and maintaining and improving the skin state and further reducing the pores. .

  In preparing the composition in the present invention, the content of one or more compounds selected from the group consisting of the glutamic acid derivatives is one or more compounds selected from the group consisting of glutamic acid derivatives. Although it can be prepared alone, it is preferably 0.01 to 3.0% by mass, more preferably 0.05 to 1.0% by mass in the total amount of the composition.

  The composition according to the present invention includes, for example, a solution such as an aqueous solution, an aqueous alcohol solution, an oil solution, an emulsion, cream, gel, gel, suspension, capsule, microcapsule, solid, powder, granule, etc. , Alcohol solutions, oil solutions, etc.), solubilization systems, emulsification systems, gel systems, gel systems, dispersion systems, aerosol systems, water-oil two-layer systems, water-oil-powder three-layer systems, etc. be able to.

  The composition according to the present invention can be produced according to a conventional method, and in addition to one or more compounds selected from the group consisting of glutamic acid derivatives, the composition usually contains a quasi drug. Ingredients used in cosmetics, pharmaceutical compositions, foods, etc., such as oils, surfactants, powders, coloring materials, water, alcohols, thickeners, chelating agents, silicones, antioxidants, UV absorbers, Moisturizers, fragrances, various medicinal ingredients, preservatives, pH adjusters, neutralizers, and the like can be appropriately blended as necessary.

  Of the above-mentioned optional blended components, the oil component includes linear alcohols such as lauryl alcohol, cetyl alcohol, stearyl alcohol, myristyl alcohol, oleyl alcohol, monostearyl glycerin ether, lanolin alcohol, cholesterol, phytosterol, isostearyl alcohol. Higher alcohols such as branched chain alcohols, higher fatty acids such as lauric acid, myristic acid, palmitic acid, stearic acid, waxes such as solid paraffin, bees wax, hydrogenated castor oil, carnauba wax, barico wax, beef tallow, pork fat, sheep Fats, squalane, palm oil, palm oil, palm kernel oil, soybean oil, olive oil, cottonseed oil, jojoba oil, castor oil, lanolin and other animal and vegetable oils, liquid paraffin, petroleum jelly and other mineral oils, trimethylprop Triisostearate, isopropyl myristate, glycerol tri-2-ethyl hexanate, pentaerythritol tetra-2-ethyl hexanate, silicone oil, polyoxyethylene (hereinafter also referred to as POE) polyoxypropylene (hereinafter referred to as POP) And synthetic oils such as pentaerythritol ether.

  Examples of surfactants include soap bases, fatty acid soaps such as sodium laurate and sodium palmitate, higher alkyl sulfates such as sodium lauryl sulfate and potassium lauryl sulfate, POE lauryl sulfate triethanolamine, and POE sodium lauryl sulfate. Alkyl ether sulfates, N-acyl sarcosine salts such as lauroyl sarcosine sodium, higher fatty acid amide sulfonates such as sodium N-myristoyl-N-methyl taurate, coconut oil fatty acid methyl tauride sodium, POE stearyl ether phosphate, etc. Phosphoric acid ester salt, sulfosuccinate such as sodium monolauroyl monoethanolamide POE sulfosuccinate, sodium lauryl polypropylene glycol sulfosuccinate, linear dode Alkyl benzene sulfonates such as sodium rubenzene sulfonate and linear dodecyl benzene sulfonate triethanolamine, N-acyl glutamate such as N-stearoyl glutamate disodium, monosodium N-stearoyl glutamate, hydrogenated coconut oil fatty acid sodium glycerine sulfate, etc. Higher fatty acid ester sulfates, sulfated oils such as funnel oil, POE alkyl ether carboxylic acids, POE alkyl allyl ether carboxylates, higher fatty acid ester sulfonates, secondary alcohol sulfates, higher fatty acid alkylolamide sulfates Anionic surfactants such as ester salts, sodium lauroyl monoethanolamide succinate, sodium caseinate;

  Alkyltrimethylammonium salts such as stearyltrimethylammonium chloride, lauryltrimethylammonium chloride, dialkyldimethylammonium salts such as distearyldimethylammonium chloride, alkylpyridinium salts such as cetylpyridinium chloride, alkylquaternary ammonium salts, alkyldimethylbenzylammonium salts, Cationic surfactants such as alkylisoquinolinium salts, dialkylmorpholinium salts, POE alkylamines, alkylamine salts, polyamine fatty acid derivatives, amyl alcohol fatty acid derivatives, benzalkonium chloride; 2-cocoyl-2-imidazoli Imidazoline amphoteric surfactants such as nium hydroxide-1-carboxyethyloxy disodium salt, and betaine fields such as amide betaine and sulfobetaine Amphoteric surfactants such as activators; sorbitan fatty acid esters such as sorbitan monooleate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, sorbitan trioleate, mono cottonseed oil fatty acid glycerin, glyceryl monostearate, Glycerin polyglycerin fatty acids such as glyceryl sesquioleate and glyceryl monostearate, propylene glycol fatty acid esters such as propylene glycol monostearate, hardened castor oil derivatives, glycerin alkyl ether, POE / methylpolysiloxane copolymer Lipophilic nonionic surfactants such as POE sorbitan monooleate, POE sorbitan fatty acid esters such as POE sorbitan monostearate, POE sorbitmo POE sorbite fatty acid esters such as laurate, POE sorbite monooleate, POE sorbite monostearate, POE glycerin monooleate, POE glycerin fatty acid esters such as POE glycerol distearate, POE monooleate, POE distearate, POE monodiolate, etc. POE fatty acid esters, POE lauryl ether, POE oleyl ether, POE alkyl ethers such as POE cholestanol ester, POE alkyl phenyl ethers such as POE octyl phenyl ether and POE nonyl phenyl ether, pluronic types such as brulon, POE POP / POP Al such as POP monobutyl ether, POE / POP cetyl ether, POE / POP glycerin ether Kill ethers, POE castor oil, POE hardened castor oil, POE hardened castor oil monoisostearate, POE hardened castor oil maleic acid and other POE castor oil hardened castor oil derivatives, POE beeswax and lanolin derivatives such as POE sorbite beeswax, palm Examples include alkanolamides such as oil fatty acid diethanolamide and fatty acid isopropanolamide, hydrophilic nonionic surfactants such as POE propylene glycol fatty acid ester, POE fatty acid amide, POE alkylamine, sucrose fatty acid ester, and alkylethoxydimethylamine oxide. .

  Examples of alcohols include lower alcohols such as ethanol, propanol, and isopropanol.

  Thickeners include arabic gum, tragacanth cam, galactan, carop gum, guar gum, carrageenan, pectin, agar, starch (corn, wheat, potato, rice) and other vegetative polymers, dextran, pullulan and other microbial polymers, Starch polymers such as carboxymethyl starch and methylhydroxypropyl starch, animal polymers such as collagen, casein, gelatin, methylcellulose, nitrocellulose, ethylcellulose, hydroxyethylcellulose, sodium cellulose sulfate, hydroxypropylcellulose, carboxymethylcellulose, crystalline cellulose Cellulose polymers such as sodium alginate, alginic acid polymers such as propylene glycol alginate, polyvinyl methyl ether, Vinyl polymers such as ruxoxyvinyl polymer, POE polymers, POE / POP copolymer polymers, acrylic polymers such as sodium polyacrylate and polyacrylamide, polyethyleneimine, cationic polymers, bentonite, silica And water-soluble polymers such as inorganic water-soluble polymers such as aluminum magnesium oxide, laponite, hectorite, and silicic anhydride.

  Chelating agents include citramalic acid, agaric acid, glyceric acid, shikimic acid, hinokitiol, gallic acid, tannic acid, caffeic acid, ethylenediaminetetraacetic acid, ethyleneglycoldiaminetetraacetic acid, diethylenetriaminepentaacetic acid, phytic acid, polyphosphoric acid, metaphosphoric acid , As well as their analogs and their alkali metal salts and carboxylic acid esters.

  Examples of UV absorbers include benzoic acid UV absorbers such as paraaminobenzoic acid; anthranilic acid UV absorbers such as methyl anthranilate; salicylic acid UV absorbers such as octyl salicylate; isopropyl paramethoxycinnamate and paramethoxysilicate. Examples thereof include cinnamic acid-based ultraviolet absorbers such as octyl cinnamate.

  As the humectant, polyethylene glycol, propylene glycol, dipropylene glycol, 1,3-butylene glycol, glycerin, diglycerin, xylitol, maltitol, maltose, D-mannitol, glucose, fructose, sodium chondroitin sulfate, sodium hyaluronate , Sodium lactate, glucosamine, cyclodextrin and the like.

  Medicinal ingredients include vitamin A oil, retinol, retinol palmitate, pyridoxine hydrochloride, benzyl nicotinate, nicotinamide, nicotinic acid dl-α-tocopherol, magnesium ascorbate phosphate, vitamin D2, dl-α-tocopherol, pantothene Vitamins such as acid and biotin; anti-inflammatory agents such as azulene and glycyrrhizin; whitening agents such as arbutin, potassium 4-methoxysalicylate, 2-O-ethylascorbic acid and ascorbic acid glucoside; hormones such as estradiol; zinc oxide, Astringents such as tannic acid; refreshing agents such as L-menthol and camphor; other lysozyme chloride, pyridoxine hydrochloride, sulfur and the like can be blended. Furthermore, various extracts showing various medicinal effects can be blended. In other words, there are dokudami extract, apricot extract, licorice extract, peony extract, button pi extract, loofah extract, saxifrage extract, eucalyptus extract, clove extract, maronier extract, cornflower extract, seaweed extract, thyme extract and the like.

As preservatives, paraoxybenzoates such as methylparaben, ethylparaben, butylparaben, benzoic acid, salicylic acid, sorbic acid, parachlorometacresol, hexachlorophene, benzalkonium chloride, chlorhexidine hydrochloride, trichlorocarbanilide, photosensitive Element, phenoxyethanol, isomethylthiazolinone and the like.
Examples of the neutralizing agent include 2-amino-2-methyl-1-propanol, 2-amino-2-methyl-1,3-propanediol, potassium hydroxide, triethanolamine, sodium carbonate and the like.

Examples of the pH adjuster include lactic acid, citric acid, glycolic acid, succinic acid, tartaric acid, malic acid, sodium hydrogen carbonate, ammonium hydrogen carbonate and the like.
Examples of the antioxidant include ascorbic acid, α-tocopherol, carotenoid and the like.
The said component is an illustration and is not limited to these. Further, these components can be appropriately combined and blended in accordance with a prescription according to a desired form.

EXAMPLES The present invention will be specifically described with reference to examples, but the technical scope of the present invention is not limited to these examples. The blending amount is mass% unless otherwise specified.
[Test Example 1] Test for inhibiting keratokeratosis As a sample solution, a 3% by mass aqueous solution (including 30% by mass ethanol) of a test compound was mainly prepared. In addition, it adjusted with hydrochloric acid or sodium hydroxide so that pH might be set to 7.0-7.5. Moreover, when the solubility of the test compound was low, a solution was prepared accordingly.

  100 μl of 10% by mass of oleic acid (solvent: ethanol) was applied to the back of a hairless mouse (HR-1; Hoshino experimental animal). Thereafter, 100 μl of the sample solution was applied. This was continued for 3 days. The next day, the skin condition of the back was observed with a CCD camera, and rough skin conditions (stratum exfoliation and erythema) were evaluated. The skin condition of the control (control aqueous solution) application was set to 2.0, the condition without any rough skin was set to 0.0, and the visual evaluation was made at intervals of 0.25 points according to the skin condition. At the same time, the stratum corneum at the back of the hairless mouse is collected with a tape, the nucleus is stained with hematoxylin, the degree of keratinization is observed, and the horny angle in the range of 1.0 to 3.0 (in increments of 0.25). The chemical value was evaluated. In addition, it shows that there are many nucleated stratum corneum cells, ie, the keratinization progresses, so that a value is large. The results are shown in Table 1.

As is apparent from Table 1, N-benzoyl-N ′, N ″ -dimethyl-L-glutamic acid-1,5-diamide, N-benzoyl-N ′, N ″ -diethyl-L-glutamic acid-1, 5-Diamide, N-benzoyl-N ′, N ″ -di n-propyl-L-glutamic acid-1,5-diamide, N-benzoyl-L-glutamic acid bis-1,5-morpholinamide and N-benzoyl- Glutamic acid derivatives according to the present invention, such as L-glutamic acid bis-1,5-piperidineamide, exhibited an effect of suppressing rough skin such as stratum corneum peeling and erythema caused by unsaturated fatty acids.
Moreover, the glutamic acid derivative according to the present invention decreased the keratinization value, and an inhibitory effect on keratinization was observed. Inhibition of parakeratosis is effective for pore reduction.
On the other hand, N-acetyl-L-glutamine as a comparative example did not show these effects.

[Test Example 2] Improvement effect test for rough skin by oleic acid application In order to further investigate the improvement effect on rough skin by oleic acid application, the amount of water transpiration (TEWL value) before and after application was measured, and the difference value was calculated. The effect was examined in comparison with the control (control aqueous solution). The sample preparation and application method followed Test Example 1. TEWL was measured using a TEWA meter TM210 (Courage + Khazaka).

  100 μl of 10% by mass oleic acid (solvent: ethanol) was applied to the back of a hairless mouse (HR-1, 4 mice in each group). Thereafter, 100 μl of the sample solution was applied. This was continued for 3 days. The next day, the TEWL value of the back was measured and the values of 4 animals were averaged. The results are shown in Table 2. The larger the ΔTEWL value, the worse the rough skin.

As is apparent from Table 2, N-benzoyl-N ′, N ″ -dimethyl-L-glutamic acid-1,5-diamide, N-benzoyl-N ′, N ″ -diethyl-L-glutamic acid-1, 5-Diamide, N-benzoyl-N ′, N ″ -di n-propyl-L-glutamic acid-1,5-diamide, N-benzoyl-L-glutamic acid bis-1,5-morpholinamide and N-benzoyl- By applying the glutamic acid derivative according to the present invention such as L-glutamic acid bis-1,5-piperidineamide, the ΔTEWL value was significantly lower than that of the control aqueous solution, and the effect of preventing and improving rough skin was observed.
On the other hand, N-acetyl-L-glutamine as a comparative example was not effective, and N-acetyl-L-glutamic acid was also less effective than the compound of the present invention.

[Test Example 3] Sensory stimulation test 1 ml each of the control aqueous solution and sample aqueous solution prepared in Test Example 1 was applied to one female sensory person (sensitive skin) using a cotton swab on each of the left and right cheeks. Immediately after that, 10 minutes later, the stimulation was evaluated every 30 seconds, and the final evaluation was reported. Evaluation of the feeling of irritation was performed based on the following four-point evaluation point criteria, and the average of the evaluation points was calculated and classified into the following criteria. The results are shown in Table 3.

(Evaluation criteria)
3: Extremely strong irritation such as tingling, burning, tingling, and kayumi, cannot be continued.
2: Strong irritation such as tingling, burning, tingling, kayumi, and unacceptable.
1: Slight tingling, burning, tingling, sensation of sensation, etc., but slightly acceptable.
0: No particular irritation is felt.

(Evaluation criteria)
A: Evaluation point average less than 0.2 B: Evaluation point average 0.2 to less than 1.0 C: Evaluation point average 1.0 to less than 2.0 D: Evaluation point average 2.0 or more

As is apparent from Table 3, N-benzoyl-N ′, N ″ -dimethyl-L-glutamic acid-1,5-diamide, N-benzoyl-N ′, N ″ -diethyl-L-glutamic acid-1, 5-Diamide, N-benzoyl-N ′, N ″ -di n-propyl-L-glutamic acid-1,5-diamide, N-benzoyl-L-glutamic acid bis-1,5-morpholinamide and N-benzoyl- It was confirmed that the glutamic acid derivatives according to the present invention such as L-glutamic acid bis-1,5-piperidineamide have no problem of sensory stimulation and have high safety.
On the other hand, although γ-aminobutyric acid used as a comparative example has been disclosed as a conventional effect substance, γ-aminobutyric acid has a result of having a sensory stimulus for a subject with sensitive skin.

  The skin external preparation is shown below as a formulation example of the composition according to the present invention. In addition, any skin external preparation was manufactured by the conventional method. The blending amounts are all mass%. Further, any of the external preparations for skin had excellent effects such as suppression of keratinization, reduction of pores, prevention and improvement of rough skin.

[Formulation Example 1] Lotion (1) 1,3-butylene glycol 6.0
(2) Glycerin 4.0
(3) Oleyl alcohol 0.1
(4) POE (20) sorbitan monolaurate 0.5
(5) POE (15) lauryl alcohol ester 0.5
(6) Ethanol 10.0
(7) N-benzoyl-N ′, N ″ -dimethyl-L-glutamic acid-1,5-diamide 1.0
(8) Purified water residue

[Formulation Example 2] Lotion (alcohol phase)
(1) Ethanol 10.0
(2) Oleyl alcohol 0.1
(3) POE (20) sorbitan monolaurate 0.5
(4) POE (15) lauryl ether 0.5
(5) Preservative appropriate amount (6) perfume appropriate amount (7) N-benzoyl-N ′, N ″ -diethyl-L-glutamic acid-1,5-diamide 0.7
(Water phase)
(8) 1,3-butylene glycol 6.0
(9) Glycerin 4.0
(10) Ion exchange water remaining

[Formulation Example 3] Lotion ethyl alcohol 5.0
Glycerin 1.0
1,3-butylene glycol 5.0
Polyoxyethylene polyoxypropylene decyl tetradecyl ether 0.2
Sodium hexametaphosphate 0.03
Trimethylglycine 1.0
Sodium polyaspartate 0.1
α-Tocopherol 2-L-ascorbic acid phosphate diester potassium 0.1
Thiotaurine 0.1
N-benzoyl-L-glutamic acid bis-1,5-morpholinamide 1.0
Glycyl glucin 0.5
Green tea extract 0.1
Western mint extract 0.1
Iris root extract 0.1
EDTA3 sodium 0.1
Carboxyvinyl polymer 0.05
Potassium hydroxide 0.02
Phenoxyethanol Appropriate amount Purified water Residual perfume Appropriate amount

[Formulation Example 4] Lotion Glycerin 2.0
1,3-butylene glycol 4.0
Erythritol 1.0
N-benzoyl-L-glutamic acid bis-1,5-piperidineamide 1.0
Polyoxyethylene methyl glucoside 1.0
Polyoxyethylene hydrogenated castor oil 0.5
Citric acid 0.02
Sodium citrate 0.08
Phenoxyethanol appropriate amount N-coconut oil fatty acid acyl L-arginine ethyl DL-pyrrolidone carboxylic acid 0.1
Purified water residue

[Formulation Example 5] Lotion Glycerin 1.0
Dipropylene glycol 12.0
Ethanol 8.0
N-benzoyl-N ′, N ″ -di-n-propyl-L-glutamic acid-1,5-diamide 2.0
POE methyl glucoside 3.0
POE (24) POP (13) decyl tetradecyl ether 0.5
Citric acid 0.02
Sodium citrate 0.08
Hydroxypropyl-β-cyclodextrin 0.5
Thiotaurine 0.1
Adenosine triphosphate-2 sodium 0.1
Sodium hyaluronate 0.01
EDTA3 sodium 0.01
Hydroxyethyl cellulose 0.1
Paraben Appropriate amount Purified water Residual flavoring Appropriate amount

[Formulation Example 6] Cream (1) Stearic acid 5.0
(2) Stearyl alcohol 4.0
(3) Isopropyl myristate 18.0
(4) Glycerol monostearate 3.0
(5) Propylene glycol 10.0
(6) N-benzoyl-N ′, N ″ -dimethyl-L-glutamic acid-1,5-diamide 1.0
(7) Potassium hydroxide 0.2
(8) Sodium bisulfite 0.01
(9) Preservative appropriate amount (10) perfume appropriate amount (11) ion-exchanged water remaining

[Formulation Example 7] Cream stearic acid 6.0
Sorbitan monostearate ester 2.0
POE (20) sorbitan monostearate ester 1.5
Propylene glycol 10.0
Glycerin trioctanoate 10.0
Squalane 5.0
N-benzoyl-N ′, N ″ -diethyl-L-glutamic acid-1,5-diamide
0.1
Glycylglycine 1.0
Dihydrolipoic acid 0.1
Sodium bisulfite 0.01
Ethylparaben 0.3
Perfume Appropriate amount of ion-exchanged water

[Formulation Example 8] Cream liquid paraffin 10.0
Dimethylpolysiloxane 2.0
Glycerin 10.0
1,3-butylene glycol 2.0
Erythritol 1.0
N-benzoyl-L-glutamic acid bis-1,5-morpholinamide 3.0
Polyethylene glycol 1500 5.0
Squalane 15.0
Tetra-2-ethylhexanoic acid pentaerythrit 5.0
Potassium hydroxide 0.1
Sodium hexametaphosphate 0.05
Tocopherol acetate 0.05
P-Hydroxybenzoate appropriate amount hydroxypropyl methylcellulose 0.3
Polyvinyl alcohol 0.1
Carboxyvinyl polymer 0.2
Acrylic acid / alkyl methacrylate copolymer (Pemulene TR-2) 0.1
Purified water residue

[Formulation Example 9] Cream liquid paraffin 8.0
Vaseline 3.0
Dimethylpolysiloxane 2.0
Stearyl alcohol 3.0
Behenyl alcohol 2.0
Glycerin 5.0
Dipropylene glycol 4.0
Trehalose 1.0
Tetra-2-ethylhexanoic acid pentaerythrit 4.0
Polyisoethylene glyceryl monoisostearate 2.0
Polyoxyethylene glycerol monostearate 1.0
Lipophilic glyceryl monostearate 2.0
Citric acid 0.05
Sodium citrate 0.05
Potassium hydroxide 0.015
Oil-soluble licorice extract 0.1
Retinol palmitate (1 million units) 0.25
Tocopherol acetate 0.1
P-Hydroxybenzoate appropriate amount phenoxyethanol appropriate amount dibutylhydroxytoluene appropriate amount edetate trisodium 0.05
4-t-butyl-4′-methoxydibenzoylmethane 0.01
2-Ethylhexyl paramethoxycinnamate 0.1
Benzoyl-L-glutamic acid N ′, N ′, N ″, N ″ -tetramethyl-1,5-diamide 1.0
β-carotene 0.01
Polyvinyl alcohol 0.5
Hydroxyethyl cellulose 0.5
Carboxyvinyl polymer 0.05
Purified water Residual fragrance Appropriate amount

[Formulation Example 10] Cream A. Aqueous ion exchange water Residual polyethylene glycol 400 0.1
Glycerin 12.0
1,3-butylene glycol 5.0
Sodium edetate 0.01
Citric acid 0.01
Sodium citrate 0.04
Methylparaben 0.1
N-benzoyl-N′-ethyl-L-glutamic acid-1,5-diamide 2.0
Sodium N-stearoyl glutamate 0.8
B. Oil phase liquid paraffin 35.0
Meadow Foam Oil 3.0
Octyl methoxycinnamate 3.0
2-Heptylundecanoic acid 0.2
Isostearic acid 0.2
Stearyl glycyrrhetinate 0.02
Fragrance 0.05

[Formulation Example 11] Cream α-olefin oligomer 10.0
Vaseline 1.0
Microcrystalline wax 3.0
Decamethylcyclopentasiloxane 5.0
Glycerin 10.0
Dipropylene glycol 2.0
1,3-butylene glycol 2.0
Erythritol 2.0
Glycylglycine 1.0
N-benzoyl-L-glutamic acid bis-1,5-morpholinamide 3.0
Squalane 1.0
Glycerin fatty acid ester eicosane diacid condensate 0.1
Isostearic acid 1.0
Cetyl 2-ethylhexanoate 5.0
Sodium chloride 0.5
Sodium hexametaphosphate 0.05
Stearyl glycyrrhetinate 0.05
Koubo extract 0.1
ACES 1.0
L-ascorbyl magnesium phosphate 2.0
Tocopherol acetate 0.5
Thiotaurine 0.1
DL-pyrrolidonecarboxylate sodium 1.0
Turmeric extract 0.1
Edetate trisodium 0.1
Dimethyl distearyl ammonium hectorite 2.0
Sodium carboxymethylcellulose 0.1
Camellia seed oil 1.0
Paraben Appropriate amount Purified water Residual flavoring Appropriate amount

[Formulation example 12] Cosmetic liquid (phase A)
(1) Ethyl alcohol (95%) 10.0
(2) POE (20) Octyldodecanol 1.0
(3) Pantothenyl ethyl ether 0.1
(4) Glycylglycine 1.5
(5) Methylparaben 0.15
(Phase B)
(6) Potassium hydroxide 0.1
(Phase C)
(7) Glycerin 5.0
(8) Dipropylene glycol 10.0
(9) N-benzoyl-N ′, N ″ -dimethyl
-L-glutamic acid-1,5-diamide 0.3
(10) Carboxyvinyl polymer 0.2
(11) Purified water residue

[Formulation Example 13] Cosmetic liquid (A phase)
95% ethanol 10.0
POE (20) Octyldodecanol 1.0
Methylparaben 0.15
Pantothenyl ethyl ether 0.1
N-benzoyl-N ′, N ″ -di-n-propyl-L-glutamic acid-1,5-diamide 2.5
(Phase B)
Potassium hydroxide 0.1
(Phase C)
Glycerin 5.0
Dipropylene glycol 10.0
Sodium bisulfite 0.03
Carboxyvinyl polymer 0.2
Ion exchange water

[Formulation Example 14] Emulsion decamethylcyclopentasiloxane 15.0
Trimethylsiloxysilicate 5.0
Polyoxyethylene / methylpolysiloxane copolymer 5.0
Glycerin 5.0
1,3-butylene glycol 5.0
Maltitol solution 2.0
Macadamia nut oil 2.0
Squalane 2.0
Cholesteryl hydroxystearate 0.5
Cetyl 2-ethylhexanoate 2.0
N-benzoyl-N ′, N ″ -diiso-propyl-L-glutamic acid-1,5-diamide 2.0
Distearyldimethylammonium chloride 0.2
L-ascorbic acid sulfate disodium 0.1
α-Tocopherol 2-L-ascorbic acid phosphate diester potassium 0.1
Tocopherol acetate 0.05
Fish collagen 0.4
Sodium chondroitin sulfate 0.001
Sodium hyaluronate 0.1
Edetate trisodium 0.005
Diparamethoxycinnamic acid mono-2-ethylhexanoate glyceryl 0.05
Aluminum magnesium silicate 0.3
Paraben Appropriate amount of purified water Residual

[Formulation Example 15] Emulsion petrolatum 5.0
Dimethylpolysiloxane 2.0
Behenyl alcohol 0.6
Batyl alcohol 0.5
Dipropylene glycol 2.0
1,3-butylene glycol 4.0
Xylit 1.0
N-benzoyl-N ′, N ″ -diethyl-L-glutamic acid-1,5-diamide 2.0
Polyethylene glycol 1500 1.0
Squalane 5.0
Glyceryl tri-2-ethylhexanoate 2.0
Polyoxyethylene hydrogenated castor oil 0.5
Dipotassium glycyrrhizinate 0.1
Yeast extract 0.1
Peonies extract 0.1
EDTA3 sodium 0.05
Xanthan gum 0.1
Carboxyvinyl polymer 0.15
Purified water

[Formulation Example 16] Latex ion-exchanged water Residual dynamite glycerin 7.0
Dipropylene glycol 5.0
1,3-butylene glycol 2.0
Acetylated hyaluronic acid 0.002
Carboxyvinyl polymer 0.3
Xanthan gum 0.1
Potassium hydroxide 0.1
N-stearoyl-L-glutamate sodium 0.1
Tetra-2-ethylhexanoic acid pentaerythrit 2.0
N-benzoyl-N ′, N ″ -dimethyl-N ′, N ″ -di-n-propyl-L-glutamic acid-1,5-diamide 1.0
Squalane 4.5
Dextrin palmitate 2.0
Hydrogenated polyisobutene 1.0
EDTA · 3Na · 2H ₂ O 0.05
Methylparaben 0.15
Ethylparaben 0.1
Antioxidant Appropriate amount Antifoam agent Appropriate amount

[Formulation Example 17] Gel (1) 95% ethanol 10.0
(2) Dipropylene glycol 15.0
(3) POE (15 mol) oleyl alcohol ether 2.0
(4) Sodium bisulfite 0.03
(5) N-benzoyl-N ′, N ″ -dimethyl-N ′, N ″ -diethyl-L-glutamic acid-1,5-diamide 1.2
(6) Carboxyvinyl polymer (Carbopol 941) 1.0
(7) Caustic potash 0.15
(8) L-arginine 0.1
(9) Perfume appropriate amount (10) Preservative appropriate amount (11) Purified water remainder

[Formulation Example 18] Gelglycerin 2.0
1,3-butylene glycol 5.0
Potassium hydroxide 0.1
Fish collagen 20.0
N-benzyloxycarbonyl-N ′, N ″ -diethyl-L-glutamic acid-1,5-diamide 1.0
N-benzenesulfonyl γ-aminobutyric acid 0.5
Edetic acid-3Na 0.05
Carboxyvinyl polymer 0.25
P-Hydroxybenzoate appropriate amount purified water remaining

[Formulation Example 19] Geldimethylpolysiloxane 5.0
Glycerin 2.0
1,3-butylene glycol 5.0
Polyethylene glycol 1500 3.0
Polyethylene glycol 20000 3.0
Cetyl alcohol 3.0
Citric acid 0.01
Sodium citrate 0.1
Sodium hexametaphosphate 0.1
Dipotassium glycyrrhizinate 0.1
Ascorbic acid glucoside 2.0
N-benzenesulfonyl-N ′, N ″ -diethyl-L-glutamic acid-1,5-diamide 1.0
Tocopherol acetate 0.1
Ogon Extract 0.1
Yukinoshita extract 0.1
Edetate trisodium 0.1
Xanthan gum 0.3
Acrylic acid / alkyl methacrylate copolymer (Pemulene TR-2) 0.05
Agar powder 15.0
Phenoxyethanol Appropriate amount Dibutylhydroxytoluene Appropriate amount of purified water Residue

[Formulation Example 20] Packed ethanol 3.0
Glycerin 5.0
1,3-butylene glycol 6.0
Polyethylene glycol 1500 5.0
Polyoxyethylene methyl glucoside 2.0
Glyceryl tri-2-ethylhexanoate 1.0
Sodium hexametaphosphate 0.05
Hydroxypropyl-β-cyclodextrin 0.1
Dipotassium glycyrrhizinate 0.1
Loquat leaf extract 0.1
N-benzyl-N ′, N ″ -dimethyl-L-glutamic acid-1,5-diamide hydrochloride 1.8
Sodium L-glutamate 0.1
Fennel extract 0.1
Hamelis extract 0.1
Oat extract 0.1
Giant extract 0.1
Eucalyptus oil 0.05
Dimorpholinopyridazinone 0.1
Xanthan gum 0.05
Carboxyvinyl polymer 0.5
Acrylic acid / alkyl methacrylate copolymer (Pemulene TR-1) 0.05
Potassium hydroxide 0.05
Phenoxyethanol Suitable amount Purified water Residual

[Formulation Example 21] Peel-off type pack (alcohol phase)
95% ethanol 10.0
POE (15 mol) oleyl alcohol ether 2.0
Preservative Appropriate perfume Appropriate amount N-Benzenesulfonyl-L-glutamic acid bis-1,5-piperidineamide 1.8
(Water phase)
Glutathione 3.0
Arbutin 3.0
Polyvinyl alcohol 12.0
Polyethylene glycol 1500 1.0
Ion exchange water

[Formulation Example 22] Peel-off type packed ethanol 10.0
1,3-butylene glycol 6.0
Polyethylene glycol 4000 2.0
Olive oil 1.0
Macadamia nut oil 1.0
N-benzoyl-L-glutamic acid bis-1,5-pyrrolamide 2.0
Phytosteryl hydroxystearate 0.05
Lactic acid 0.05
Sodium lactate 0.1
L-ascorbic acid sulfate disodium 0.1
α-Tocopherol 2-L-ascorbic acid phosphate diester potassium 0.1
Vitamin E acetate 0.1
Fish collagen 0.1
Chondroitin thorium sulfate 0.1
Sodium carboxymethylcellulose 0.2
Polyvinyl alcohol 12.0
Paraoxybenzoic acid ester Appropriate amount Purified water Residual perfume Appropriate amount

[Formulation Example 23] Powdered pack (alcohol phase)
95% ethanol 2.0
Preservative Appropriate amount of perfume Appropriate amount of colorant Appropriate amount of N-benzoyl-L-glutamic acid bis-1,5-pyrrolidine amide 0.7
(Water phase)
Propylene glycol 7.0
Zinc flower 25.0
Kaolin 20.0
Ion exchange water

[Formulation Example 24] Claypack ethanol 3.0
Stearyl alcohol 1.0
Behenyl alcohol 1.0
Glycerin 10.0
Dipropylene glycol 5.0
1,3-butylene glycol 6.0
Fructose 0.1
Hardened oil 2.0
Isostearic acid 0.06
Self-emulsifying glyceryl monostearate 12.0
Polyoxyethylene glyceryl monostearate 0.8
Lauryldimethylaminoacetic acid betaine 0.1
N-benzoyl-N ″ -ethyl-N′-methyl
-L-glutamic acid-1,5-diamide 1.2
Titanium oxide 15.0
Zinc oxide 2.0
Kaolin 7.0
L-Arginine L-Aspartate 0.1
Vitamin E acetate 0.1
Sodium hyaluronate 0.1
EDTA3 sodium 0.1
Bentonite 3.0
Paraoxybenzoic acid ester Appropriate amount Purified water Residual perfume Appropriate amount

[Formulation Example 25] Solid powder-foundation dimethylpolysiloxane 5.0
Isostearic acid 0.5
Diisostearyl malate 1.0
Tri-2-ethylhexane sanglyceryl 3.0
N-benzoyl-N ′, N ″ -dimethyl-L-glutamic acid-1,5-diamide 3.0
Sorbitan sesquiisostearate 1.0
Spherical PMMA-coated mica 4.0
Fine zinc oxide 1.0
Fine particle titanium oxide 3.0
Synthetic phlogopite 1.0
Metal soap treated talc Residual spherical silica 3.0
Bengala-coated mica titanium 1.0
Silica-coated mica 6.0
DL-α-tocopherol acetate 0.1
D-δ-tocopherol 0.1
Ethyl paraben Appropriate amount Methyl bis (trimethylsiloxy) silylisopentyl trimethoxycinnamate 0.1
2-methoxyhexyl paramethoxycinnamate 3.0
Spherical polyalkyl acrylate powder 2.0
Liquid paraffin-containing polyalkyl acrylate powder 4.0
Methyl hydrogen polysiloxane coated talc 20.0
Methyl hydrogen polysiloxane-coated sericite 15.0
Methyl hydrogen polysiloxane-coated titanium oxide 10.0
Methyl hydrogen polysiloxane coated pigment (colorant) 5.0

[Formulation Example 26] Water-in-oil emulsified foundation dimethylpolysiloxane 15.0
Decamethylcyclopentasiloxane 20.0
Polyoxyethylene / methylpolysiloxane copolymer 5.0
High molecular weight amino-modified silicone 0.1
Glycerin 5.0
N-benzoyl-L-glutamic acid bis-1,5-piperidineamide 5.0
1,3-butylene glycol 10.0
Palmitic acid 0.5
Macadamia nut oil fatty acid cholesteryl 0.1
Distearyldimethylammonium chloride 0.2
Alkyl-modified silicone resin coated yellow iron oxide 2.0
Alkyl modified silicone resin coated bengara 1.0
Alkyl-modified silicone resin coated black iron oxide 0.3
Alkyl-modified silicone resin-coated titanium oxide 10.0
Alkyl modified silicone resin coated talc oxide 15.0
Silicone-coated spindle-shaped titanium oxide 3.0
Sodium L-glutamate 0.5
DL-α-tocopherol acetate 0.1
P-Hydroxybenzoic acid ester Methyl bis (trimethylsiloxy) silylisopentyl trimethoxycinnamate 0.1
Dimethyl distearyl ammonium hectorite 15.0
Spherical nylon powder 1.0
Purified water Residual fragrance Appropriate amount

Claims (8)

An external composition for skin comprising one or more compounds selected from the group consisting of a glutamic acid derivative represented by the following general formula (1) or a salt thereof .
(In general formula (1), A represents a single bond, an oxycarbonyl group, a carbonyl group or a sulfonyl group, Z represents the following general formula (2), and R _{1 to} R ₄ are each independently a hydrogen atom. , An alkyl group having 1 to 3 carbon atoms, an allyl group, a cycloalkyl group having 3 to 7 carbon atoms or a cycloalkenyl group, a phenyl group, or a benzyl group, or R ₁ and R ₂ and / or R ₃ R ₄ and each nitrogen atom to which they are bonded independently form a heterocyclic ring having a total carbon number of 6 or less, and the heterocyclic ring may contain an oxygen atom, and R ₁ In R ₄ , the alkyl group having 1 to 3 carbon atoms, the allyl group, the cycloalkyl group having 3 to 7 carbon atoms and the cycloalkenyl group, the phenyl group, the benzyl group, and the heterocyclic ring have a hydroxyl group and 1 to 3 carbon atoms. Alkyloxy group of Or an allyloxy group as a substituent, and the cycloalkyl group having 3 to 7 carbon atoms and the cycloalkenyl group, phenyl group, benzyl group, or heterocyclic ring is alkyl having 1 to 3 carbon atoms. May have a group as a substituent.)
(In General Formula (2), X ₁ , X ₂ and X ₃ are each independently an alkyl group having 1 to 3 carbon atoms, an alkyloxy group having 1 to 3 carbon atoms, an allyloxy group, a hydroxyl group, a fluorine atom, or Represents a trifluoromethyl group, n, m and p each independently represents an integer of 0 to 3, and k represents 0 or 1) The composition for external use according to claim 1, wherein _one of R ₁ and R ₂ is a hydrogen atom and the other is an alkyl group having 1 to 3 carbon atoms, and one of R ₃ and R ₄ is a hydrogen atom and the other is the other. An external composition for skin, which is an alkyl group having 1 to 3 carbon atoms. The composition for external use according to claim 1, wherein R ₁ and R ₂ and / or R ₃ and R ₄ are each independently a heterocycle having a total number of carbon atoms of 6 or less together with a nitrogen atom to which they are bonded. An external composition for skin , characterized in that In the skin external composition according to any one of claims 1 to 3, the composition for external application to skin wherein the -A-Z group is a benzoyl group. The external composition for skin according to claim 1, wherein the general formula (1) is N-benzoyl-N ', N''-dimethyl-L-glutamic acid-1,5-diamide,
N-benzoyl-N ′, N ″ -diethyl-L-glutamic acid-1,5-diamide,
N-benzoyl-N ′, N ″ -di n-propyl-L-glutamic acid-1,5-diamide,
An external composition for skin, which is N-benzoyl-L-glutamic acid bis-1,5-morpholinamide, or N-benzoyl-L-glutamic acid bis-1,5-piperidineamide. N-benzoyl-N ′, N ″ -dimethyl-L-glutamic acid-1,5-diamide,
N-benzoyl-N ′, N ″ -diethyl-L-glutamic acid-1,5-diamide,
N-benzoyl-N ', N "-di-n-propyl-L-glutamic acid-1,5-diamide,
N-benzoyl-L-glutamic acid bis-1,5-morpholinamide, or
N-benzoyl-L-glutamic acid bis-1,5-piperidineamide
A glutamic acid derivative or a salt thereof, wherein A keratinization inhibitor or pore-reducing agent comprising as an active ingredient at least one compound selected from the group consisting of a glutamic acid derivative represented by the following general formula (1) and a salt thereof.
(In general formula (1), A represents a single bond, an oxycarbonyl group, a carbonyl group or a sulfonyl group, Z represents the following general formula (2), and R _{1 to} R ₄ are each independently a hydrogen atom. , alkyl group having 1 to 3 carbon atoms, an allyl group, a cycloalkyl group or cycloalkenyl group of 3 to 7 carbon atoms, or a phenyl group, or benzyl group, or _{R 1} and _{R 2} and / or _{R 3} R ₄ and each nitrogen atom to which they are bonded independently form a heterocyclic ring having a total carbon number of 6 or less, and the heterocyclic ring may contain an oxygen atom, and R ₁ In R ₄ , the alkyl group having 1 to 3 carbon atoms, the allyl group, the cycloalkyl group having 3 to 7 carbon atoms and the cycloalkenyl group, the phenyl group, the benzyl group, and the heterocyclic ring have a hydroxyl group and 1 to 3 carbon atoms. Alkyloxy group of Or an allyloxy group as a substituent, and the cycloalkyl group having 3 to 7 carbon atoms and the cycloalkenyl group, phenyl group, benzyl group, or heterocyclic ring is alkyl having 1 to 3 carbon atoms. May have a group as a substituent.)
(In General Formula (2), X ₁ , X ₂ and X ₃ are each independently an alkyl group having 1 to 3 carbon atoms, an alkyloxy group having 1 to 3 carbon atoms, an allyloxy group, a hydroxyl group, a fluorine atom, or Represents a trifluoromethyl group, n, m and p each independently represents an integer of 0 to 3, and k represents 0 or 1) An agent for preventing and improving rough skin, comprising as an active ingredient at least one compound selected from the group consisting of a glutamic acid derivative represented by the following general formula (1) and a salt thereof.
(In general formula (1), A represents a single bond, an oxycarbonyl group, a carbonyl group or a sulfonyl group, Z represents the following general formula (2), and R _{1 to} R ₄ are each independently a hydrogen atom. , alkyl group having 1 to 3 carbon atoms, an allyl group, a cycloalkyl group or cycloalkenyl group of 3 to 7 carbon atoms, or a phenyl group, or benzyl group, or _{R 1} and _{R 2} and / or _{R 3} R ₄ and each nitrogen atom to which they are bonded independently form a heterocyclic ring having a total carbon number of 6 or less, and the heterocyclic ring may contain an oxygen atom, and R ₁ In R ₄ , the alkyl group having 1 to 3 carbon atoms, the allyl group, the cycloalkyl group having 3 to 7 carbon atoms and the cycloalkenyl group, the phenyl group, the benzyl group, and the heterocyclic ring have a hydroxyl group and 1 to 3 carbon atoms. Alkyloxy group of Or an allyloxy group as a substituent, and the cycloalkyl group having 3 to 7 carbon atoms and the cycloalkenyl group, phenyl group, benzyl group, or heterocyclic ring is alkyl having 1 to 3 carbon atoms. May have a group as a substituent.)
(In General Formula (2), X ₁ , X ₂ and X ₃ are each independently an alkyl group having 1 to 3 carbon atoms, an alkyloxy group having 1 to 3 carbon atoms, an allyloxy group, a hydroxyl group, a fluorine atom, or Represents a trifluoromethyl group, n, m and p each independently represents an integer of 0 to 3, and k represents 0 or 1)