JP5558728B2 - Skin external composition - Google Patents

Description

  The present invention provides a keratinization inhibitor that suppresses keratinization caused by sebum, suppresses keratinization due to a stimulating component in sebum around pores, keeps the skin around pores normal, and a mortar-like structure of pores The present invention relates to a pore-reducing agent that suppresses the conspicuousness of the skin, an agent for preventing and improving rough skin that prevents and improves rough skin caused by unsaturated fatty acids, and an external composition for skin having these effects.

  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 studying 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 inconspicuous. It was clarified that the keratinized state (nuclei that should have disappeared remain). Therefore, if the inhibitor of keratinization acts on the pore part, and if the keratinization of the horny layer around the pore part is suppressed, the area recognized as pores decreases, and as a pore reducing agent I found it to work. 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).

  As described above, the inventors of the present invention have contributed to the keratinization caused by sebum as a cause for the conspicuous mechanism of the pores. It was clarified that the area perceived as reduced and pore conspicuousness was 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.
Further, as derivatives of glutamic acid having the effects of the present invention, Patent Document 2 describes benzoyl-L-glutamic acid, benzenesulfonyl-L-glutamic acid, acetyl-L-glutamic acid, and the like, but compounds having further excellent effects Development of was desired.

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, a rough skin prevention / improving agent, and a composition for external use on the skin.

  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 specific glutamic acid derivatives and their salts have excellent effects and the above-mentioned problems can be solved, and the present invention has been completed.

  That is, the external composition for skin according to the present invention contains at least one compound selected from the group consisting of glutamic acid derivatives represented by the following general formula (1) or the following general formula (2) and salts thereof. Features. Moreover, the keratinization inhibitor, pore reducing agent or rough skin preventing / improving agent according to the present invention is selected from the group consisting of a glutamic acid derivative represented by the following general formula (1) or the following general formula (2) and a salt thereof. One or more compounds are used as active ingredients.

（一般式（１）中、Ａはカルバモイル基、ベンジルオキシカルボニル基、炭素数１〜３のアルキル基又はアリル基を表す。）

(In General Formula (1), A represents a carbamoyl group, a benzyloxycarbonyl group, an alkyl group having 1 to 3 carbon atoms, or an allyl group.)

(In the general formula (2), Z represents an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a benzyloxy group, or a group represented by the following general formula (3) or the following general formula (4). Y represents a hydroxyl group, an alkyloxy group having 1 to 3 carbon atoms, an allyloxy group, or NR ₃ R ₄ , provided that Z represents the general formula (4) and Y represents NR ₃ 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, or a cyclohexane having 3 to 7 carbon atoms. An alkenyl group, a phenyl group, or a benzyl group, or R ₁ and R ₂ and R ₃ and R ₄ each independently have a total number of carbon atoms of 6 or less together with the nitrogen atom to which they are bonded. Forming a heterocycle, which includes an oxygen atom 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 having 3 to 7 carbon atoms, the phenyl group, and the benzyl group. Or the heterocyclic ring may have a hydroxyl group, an alkyloxy group having 1 to 3 carbon atoms, or an allyloxy group as a substituent, and the cycloalkyl group having 3 to 7 carbon atoms or 3 to 7 carbon atoms. The cycloalkenyl group, phenyl group, benzyl group or heterocyclic ring may have an alkyl group having 1 to 3 carbon atoms as a substituent.

（一般式（３）中、Ｘ_１、Ｘ_２及びＸ_３は、それぞれ独立して炭素数１〜４のアルキル基又は炭素数１〜４のアルケニル基、炭素数１〜４のアルキルオキシ基、炭素数２〜４のアルケニルオキシ基、水酸基、アミノ基、炭素数１〜４のアルキルアミノ基、フッ素原子、又はトリフルオロメチル基を表す。ｎ、ｍ及びｐはそれぞれ独立に０〜３の整数を表し、ｋ及びｑはそれぞれ独立に０〜２の整数を表す。）

(In General Formula (3), X ₁ , X ₂ and X ₃ are each independently an alkyl group having 1 to 4 carbon atoms or an alkenyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms, Represents an alkenyloxy group having 2 to 4 carbon atoms, a hydroxyl group, an amino group, an alkylamino group having 1 to 4 carbon atoms, a fluorine atom or a trifluoromethyl group, wherein n, m and p are each independently an integer of 0 to 3; And k and q each independently represents an integer of 0 to 2.)

（一般式（４）中、Ｘ_１、Ｘ_２、Ｘ_３、ｋ、ｎ、ｍ、ｐは前記一般式（３）に同じ。）

(In the general formula (4), X ₁ , X ₂ , X _3, k, n, m, and p are the same as those in the general formula (3).)

  In the glutamic acid derivative represented by the general formula (1), N-carbamoylglutamic acid, N-benzyloxycarbonylglutamic acid, and N-methylglutamic acid are preferable.

In the glutamic acid derivative represented by the general formula (2), it is preferable that Z is a methyl group or a phenyl group.
Y is preferably a hydroxyl group or NR ₃ R ₄ .
It is also preferred that Y is the same as NR ₁ R ₂ .
In addition, at least one of R ₁ and R ₂ and / or at least one of R ₃ and R ₄ is each independently a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or A benzyl group is preferred.
Moreover, it is preferable that at least one of R ₁ and R ₂ and / or at least one of R ₃ and R ₄ is independently a hydrogen atom, a methyl group, or an ethyl 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. is there.

  N-acetyl-N′-methylglutamic acid-1-amide, N-acetyl-N′-ethylglutamic acid-1-amide, N-acetyl-N′-n-propylglutamic acid-1-amide, N-acetyl- N′-benzylglutamic acid-1-amide, N-acetyl-N′-cyclohexylglutamic acid-1-amide, N-acetyl-N′-cyclopentylglutamic acid-1-amide, N-acetylglutamic acid 1-pyrrolidineamide, N-acetyl Glutamic acid 1-piperidineamide, N-acetylglutamic acid 1-morpholinamide, N-benzoyl-N′-methylglutamic acid-1-amide, N-benzoyl-N′-ethylglutamic acid-1-amide, N-benzoyl-N′- n-Propylglutamic acid-1-amide, N-benzoyl Rutamic acid 1-morpholinamide, N-acetyl-N ′, N ″ -dimethylglutamic acid-1,5-diamide, N-acetyl-N ′, N ″ -diethylglutamic acid-1,5-diamide, N-acetyl —N ′, N ′, N ″, N ″ -tetramethylglutamic acid-1,5-diamide, N-acetyl-N ′, N ′, N ″, N ″ -tetraethylglutamic acid-1,5- Diamide, N-acetylglutamic acid bis-1,5-morpholinamide, and N-acetylglutamic acid bis-1,5-piperidineamide are preferred.

  According to the present invention, a glutamate derivative having a specific structure or a salt thereof has an excellent effect, does not cause sensory irritation, etc., and is a highly safe novel parakeratosis inhibitor, pore reducing agent, skin roughness prevention / improvement An agent is provided. Further, by adding such a glutamic acid derivative or a salt thereof, an external composition for skin having functions such as suppression of keratinization, reduction of pores, prevention and improvement of rough skin can be obtained.

It is the result of measuring the amount of cytokine (IL-1α) in a human normal keratinocyte culture system in which ethanol was added, oleic acid was added, or oleic acid and N-carbamoyl-L-glutamic acid were added, respectively.

  The keratinization inhibitor, pore reducing agent, rough skin prevention / improving agent, and external composition for skin according to the present invention comprise a glutamic acid derivative represented by the following general formula (1) or general formula (2) and a salt thereof. One or more compounds selected from the group are used as active ingredients.

（一般式（１）中、Ａはカルバモイル基、ベンジルオキシカルボニル基、炭素数１〜３のアルキル基又はアリル基を表す。）

(In General Formula (1), A represents a carbamoyl group, a benzyloxycarbonyl group, an alkyl group having 1 to 3 carbon atoms, or an allyl group.)

(In the general formula (2), Z represents an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a benzyloxy group, or a group represented by the following general formula (3) or the following general formula (4). Y represents a hydroxyl group, an alkyloxy group having 1 to 3 carbon atoms, an allyloxy group, or NR ₃ R ₄ , provided that Z represents the general formula (4) and Y represents NR ₃ 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, or a cyclohexane having 3 to 7 carbon atoms. An alkenyl group, a phenyl group, or a benzyl group, or R ₁ and R ₂ and R ₃ and R ₄ each independently have a total number of carbon atoms of 6 or less together with the nitrogen atom to which they are bonded. Forming a heterocycle, which includes an oxygen atom 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 having 3 to 7 carbon atoms, the phenyl group, and the benzyl group. Or the heterocyclic ring may have a hydroxyl group, an alkyloxy group having 1 to 3 carbon atoms, or an allyloxy group as a substituent, and the cycloalkyl group having 3 to 7 carbon atoms or 3 to 7 carbon atoms. The cycloalkenyl group, phenyl group, benzyl group or heterocyclic ring may have an alkyl group having 1 to 3 carbon atoms as a substituent.

（一般式（３）中、Ｘ_１、Ｘ_２及びＸ_３は、それぞれ独立して炭素数１〜４のアルキル基又は炭素数１〜４のアルケニル基、炭素数１〜４のアルキルオキシ基、炭素数２〜４のアルケニルオキシ基、水酸基、アミノ基、炭素数１〜４のアルキルアミノ基、フッ素原子、又はトリフルオロメチル基を表す。ｎ、ｍ及びｐはそれぞれ独立に０〜３の整数を表し、ｋ及びｑはそれぞれ独立に０〜２の整数を表す。）

(In General Formula (3), X ₁ , X ₂ and X ₃ are each independently an alkyl group having 1 to 4 carbon atoms or an alkenyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms, Represents an alkenyloxy group having 2 to 4 carbon atoms, a hydroxyl group, an amino group, an alkylamino group having 1 to 4 carbon atoms, a fluorine atom or a trifluoromethyl group, wherein n, m and p are each independently an integer of 0 to 3; And k and q each independently represents an integer of 0 to 2.)

（一般式（４）中、Ｘ_１、Ｘ_２、Ｘ_３、ｋ、ｎ、ｍ、ｐは前記一般式（３）に同じ。）

(In the general formula (4), X ₁ , X ₂ , X _3, k, n, m, and p are the same as those in the general formula (3).)

  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. In any case, the effect of the present invention is good, but the L-form is preferred in that the glutamic acid derivative of the present invention can be easily obtained.

First, the glutamic acid derivative represented by the general formula (1) will be described.
In the general formula (1), A represents any of a carbamoyl group, a benzyloxycarbonyl group, an alkyl group having 1 to 3 carbon atoms, or an allyl group.
Specific 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.

  As the glutamic acid derivative of the general formula (1), N-carbamoyl-L-glutamic acid, N-benzyloxycarbonyl-L-glutamic acid, N-methyl-L-glutamic acid, N-ethyl-L-glutamic acid, Nn-propyl- L-glutamic acid, N-iso-propyl-L-glutamic acid, N-allyl-L-glutamic acid, N-carbamoyl-DL-glutamic acid, N-benzyloxycarbonyl-DL-glutamic acid, N-methyl-DL-glutamic acid, N- Ethyl-DL-glutamic acid, Nn-propyl-DL-glutamic acid, N-iso-propyl-DL-glutamic acid, N-allyl-DL-glutamic acid, N-carbamoyl-D-glutamic acid, N-benzyloxycarbonyl-D- Glutamic acid, N-methyl-D-glutamic acid N- ethyl -D- glutamate, N-n-propyl -D- glutamate, N-an iso-propyl -D- glutamate, N- allyl -D- glutamic acid.

  Of the glutamic acid derivatives represented by the general formula (1), the most preferable ones are N-carbamoyl-L-glutamic acid, N-benzyloxycarbonyl-L-glutamic acid, N-methyl-L-glutamic acid, and salts thereof. Can be mentioned. Among the glutamic acid derivatives of the general formula (1), they have the best effects of suppressing keratinization, reducing pores, preventing and improving rough skin, having good solubility in preparations, high safety, and the resulting skin The composition for external use is also excellent in those effects, and is the best in solving the object of the present invention.

Next, the glutamic acid derivative represented by the general formula (2) will be described.
In the general formula (2), Z represents an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a benzyloxy group, or a group represented by the general formula (3) or the general formula (4). Represent. The glutamic acid derivative of the present invention represented by the general formula (2) is an acyl glutamic acid derivative having a Z portion.

In Z, the alkyl group having 1 to 4 carbon atoms can be linear, branched or cyclic.
The alkenyl group having 2 to 4 carbon atoms can be linear, branched or cyclic and has one or more double bonds at any position.

When Z is an alkyl group having 1 to 4 carbon atoms or an alkenyl group having 2 to 4 carbon atoms, examples of the acyl group represented by -CO-Z include an acetyl group, a propanoyl group, a propenoyl group, a butanoyl group, and 2 -Butenoyl group, 3-butenoyl group, 2-methylpropanoyl group, 2-methyl-3-propenoyl group, pentanoyl group, 2-methylbutanoyl group, 2-methyl-2-butenoyl group, 2-methyl-3- Butenoyl group, 2-ethylpropenoyl group, 3-methylbutanoyl group, 3-methyl-2-butenoyl group, 3-methyl-3-butenoyl group, 2,2-dimethylpropanoyl group, 2-pentenoyl group, 3 -Pentenoyl group, 4-pentenoyl group, 2,4-pentadienoyl group, cyclopropanecarbonyl group, cyclobutanecarbonyl group, cyclopropyl Cetyl group, 1′-cyclopropenecarbonyl group, 2′-cyclopropenecarbonyl group, 1′-cyclobutenecarbonyl group, 2′-cyclobutenecarbonyl group, 1 ′, 3′-cyclobutadienecarbonyl group, 1′-cyclo A propeneacetyl group, 2'- cyclopropeneacetyl group is mentioned.
Of these, an acetyl group is preferred because the effects of the present invention are good and the solubility is good.

  When Z is a benzyloxy group, the glutamic acid derivative of the general formula (2) is a benzyloxycarbonyl glutamic acid derivative.

In General Formula (3), X ₁ , X ₂ and X ₃ are each an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms, or 2 to 4 carbon atoms. An alkenyloxy group, a hydroxyl group, an amino group, an alkylamino group having 1 to 4 carbon atoms, a fluorine atom, or a trifluoromethyl group. n, m and p each independently represents an integer of 0 to 3, and k and q each independently represents an integer of 0 to 2. However, in the general formula (3), the total sum of n + m + p is 6 at the maximum depending on q.

In X ₁ , X ₂ and X ₃ , the alkyl group having 1 to 4 carbon atoms is a linear or branched alkyl group such as methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl. Group, iso-butyl group, tert-butyl group, 1-methylpropyl group.
Moreover, the alkenyl of a C1-C4 alkenyl group can be linear or branched, and has one or more double bonds. Moreover, you may have a double bond between the cycloalkyl part of General formula (3).
Moreover, a C1-C4 alkyloxy group is a linear or branched alkyloxy group, for example, a methoxy group, an ethoxy group, n-propyloxy group, iso-propyloxy group, n-butoxy group, iso-butoxy group. , Tert-butoxy group, 2-methylpropyloxy group and the like.
Further, the alkenyl of the alkenyloxy group having 2 to 4 carbon atoms can be linear or branched and has one or more double bonds.

In X ₁ , X ₂ and X ₃ , the alkylamino group having 1 to 4 carbon atoms is a mono- or dialkylamino group having one or two linear or branched alkyl groups. For example, N-methylamino group, N-ethylamino group, Nn-propylamino group, N-iso-propylamino group, Nn-butylamino group, N-iso-butylamino group, N-tert- Butylamino group, N- (1-methylpropyl) amino group, N, N-dimethylamino group, N-ethyl-N-methylamino group, N-methyl-Nn-propylamino group, N-methyl-N -Iso-propylamino group, Nn-butyl-N-methylamino group, N-iso-butyl-N-methylamino group, N-tert-butyl-N-methylamino group, N- (1-methylpropyl) ) -N-methylamino group, N-ethyl-N-methylamino group, N, N-diethylamino group, N-ethyl-Nn-propylamino group, N-ethyl-N-iso-propylamino group, N n-butyl-N-ethylamino group, N-iso-butyl-N-ethylamino group, N-tert-butyl-N-ethylamino group, N-ethyl-N- (1-methylpropyl) amino group, N -Methyl-Nn-propylamino group, N-ethyl-Nn-propylamino group, N, N-di (n-propyl) amino group, Nn-propyl-N-iso-propylamino group, Nn-butyl-Nn-propylamino group, N-iso-butyl-Nn-propylamino group, N-tert-butyl-Nn-propylamino group, N- (1-methylpropyl) -N-n-propylamino group,

  N-methyl-N-iso-propylamino group, N-ethyl-N-iso-propylamino group, N-iso-propyl-Nn-propylamino group, N, N-di (iso-propyl) amino group N-butyl-N-iso-propylamino group, N-iso-butyl-N-iso-propylamino group, N-tert-butyl-N-iso-propylamino group, N- (1-methylpropyl) ) -N-iso-propylamino group, Nn-butyl-N-methylamino group, Nn-butyl-N-ethylamino group, Nn-butyl-Nn-propylamino group, N- n-butyl-N-iso-propylamino group, N, N-di (n-butylamino) group, Nn-butyl-N-iso-butylamino group, Nn-butyl-N-tert-butyl Amino group, N- -Butyl-N- (1-methylpropyl) amino group, N-iso-butyl-N-methylamino group, N-iso-butyl-N-ethylamino group, N-iso-butyl-Nn-propylamino group Group, Nn-butyl-N-iso-propylamino group, N, N-di (iso-butylamino) group, N-iso-butyl-N-ter-butylamino group,

  N-iso-butyl-N-tert-butylamino group, N-iso-butyl-N-1-methylpropylamino group, N-ter-butyl-N-methylamino group, N-ter-butyl-N-ethyl Amino group, N-ter-butyl-Nn-propylamino group, N-ter-butyl-N-iso-propylamino group, N, N-di (ter-butylamino) group, N-ter-butyl- N-iso-butylamino group, Nn-butyl-N-tert-butylamino group, N-ter-butyl-N- (1-methylpropyl) amino group, N-methyl-N- (1-methylpropyl) ) Amino group, N-ethyl-N- (1-methylpropyl) amino group, N- (1-methylpropyl) -Nn-propylamino group, N- (1-methylpropyl) -N-iso-propyla Group, Nn-butyl 1-methylpropylamino group, N-iso-butyl-N- (1-methylpropyl) amino group, N-tert-butyl-N- (1-methylpropyl) amino group, N , N-di (1-methylpropyl) amino group, and the like.

The _X 1 to X ₃ in the general formula (3), since the effect of the present invention is good, alkyl group having 1 to 4 carbon atoms, an alkenyl group having 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms A group or a hydroxyl group is preferred. Furthermore, since solubility is favorable, a methyl group, an ethyl group, a methoxy group, an ethoxy group, or a hydroxyl group is preferable. Moreover, the case where n, m, and p are 0 as a preferable thing from the point of the effect of this invention and solubility is also mentioned.

In the general formula (3), when k is 0, the glutamic acid derivative of the present invention is a cycloalkylcarbonylglutamic acid derivative corresponding to q, and when k is 1, it is a cycloalkylmethylcarbonylglutamic acid derivative corresponding to q. Is a cycloalkylethylcarbonylglutamic acid derivative corresponding to q. Moreover, when q is 0, General formula (3) has a cyclopentyl part, When q is 1, it has a cyclohexyl part, When q is 2, it will have a cycloheptyl part.
Of these, k is preferably 0 and q is preferably 1 because the effects of the present invention are good.

  Therefore, when Z is a group represented by the general formula (3), preferred examples of the —CO—Z group include cyclohexanecarbonyl group, 4-methoxycyclohexanecarbonyl group, 3-methoxycyclohexanecarbonyl group, 2-methoxycyclohexane. Carbonyl group, 4-hydroxycyclohexanecarbonyl group, 3-hydroxycyclohexanecarbonyl group, 2-hydroxycyclohexanecarbonyl group, cyclohexylacetyl group, 4-methoxycyclohexylacetyl group, 3-methoxycyclohexylacetyl group, 2-methoxycyclohexylacetyl group, 4 -Hydroxycyclohexylacetyl group, 3-hydroxycyclohexylacetyl group, 2-hydroxycyclohexylacetyl group, cyclohexylpropionyl group, 4-methoxycyclohexyl Examples include a silpropionyl group, 3-methoxycyclohexylpropionyl group, 2-methoxycyclohexylpropionyl group, 4-hydroxycyclohexylpropionyl group, 3-hydroxycyclohexylpropionyl group, and 2-hydroxycyclohexylpropionyl group, and a cyclohexanecarbonyl group is particularly preferable. .

In the general formula (4), X ₁ , X ₂ , X _3, k, n, m, and p are the same as defined in the general formula (3), and preferable X ₁ , X ₂ , X _3, k, m , P are the same as in the general formula (3). However, in the general formula (4), the sum total of n + m + p is 5 at the maximum.
When Z is a group represented by the general formula (4), the —CO—Z group is a benzoyl group corresponding to X _{1 to} X ₃ when k is 0, or X ₁ to X when k is 1. A phenylacetyl group corresponding to X _3, and when k is 2, a phenylpropionyl group corresponding to X _{1 to} X ₃ . In general formula (4), k is preferably 0 because the effects of the present invention are good.

  When Z is the general formula (4), preferred examples of the —CO—Z group include benzoyl group, p-anisoyl (4-methoxybenzoyl) group, m-anisoyl (3-methoxybenzoyl) group, and o-anisoyl. (2-methoxybenzoyl) group, 4-ethoxybenzoyl group, 3-ethoxybenzoyl group, 2-ethoxybenzoyl group, 4-propoxybenzoyl group, 3-propoxybenzoyl group, 2-propoxybenzoyl group, 2,4-dimethoxybenzoyl Group, 3,4-dimethoxybenzoyl group, 3,4,5-trimethoxybenzoyl group, 2,3,4-trimethoxybenzoyl group, 2-hydroxybenzoyl (salicyl) group, 3-hydroxybenzoyl group, 4-hydroxy Benzoyl group, 2,4-dihydroxybenzoyl group, 3,4-dihydroxybenzo Group, 3,4,5-trihydroxybenzoyl (galloyl) group, 2-hydroxy-4-methoxybenzoyl group, 3-hydroxy-4-methoxybenzoyl group, 4-hydroxy-3-methoxybenzoyl group, 2-methyl Benzoyl (o-toluyl) group, 3-methylbenzoyl (m-toluyl) group, 4-methylbenzoyl (p-toluyl) group, 2-ethylbenzoyl group, 3-ethylbenzoyl group, 4-ethylbenzoyl group, 2- Propylbenzoyl group, 3-propylbenzoyl group, 4-propylbenzoyl group,

  Phenylacetyl group, 4-methoxyphenylacetyl group, 3-methoxyphenylacetyl group, 2-methoxyphenylacetyl group, 4-ethoxyphenylacetyl group, 3-ethoxyphenylacetyl group, 2-ethoxyphenylacetyl group, 4-propoxyphenyl Acetyl group, 3-propoxyphenylacetyl group, 2-propoxyphenylacetyl group, 2,4-dimethoxyphenylacetyl group, 3,4-dimethoxyphenylacetyl group, 3,4,5-trimethoxyphenylacetyl group, 2-hydroxy Phenylacetyl group, 3-hydroxyphenylacetyl group, 4-hydroxyphenylacetyl group, N-2,4-dihydroxyphenylacetyl group, N-3,4-dihydroxyphenylacetyl group, N-3,4,5-trihydroxy Phenylacetate Group, 2-hydroxy-4-methoxyphenylacetyl group, 3-hydroxy-4-methoxyphenylacetyl group, 4-hydroxy-3-methoxyphenylacetyl group, 2-methylphenylacetyl group, 3-methylphenylacetyl group, 4-methylphenylacetyl group, 2-ethylphenylacetyl group, 3-ethylphenylacetyl group, 4-ethylphenylacetyl group, 2-propylphenylacetyl group, 3-propylphenylacetyl group, 4-propylphenylacetyl group,

  Phenylpropionyl group, 4-methoxyphenylpropionyl group, 3-methoxyphenylpropionyl group, 2-methoxyphenylpropionyl group, 4-ethoxyphenylpropionyl group, 3-ethoxyphenylpropionyl group, 2-ethoxyphenylpropionyl group, 4-propoxyphenyl Propionyl group, 3-propoxyphenylpropionyl group, 2-propoxyphenylpropionyl group, 2,4-dimethoxyphenylpropionyl group, 3,4-dimethoxyphenylpropionyl group, 3,4,5-trimethoxyphenylpropionyl group, 2-hydroxy Phenylpropionyl group, 3-hydroxyphenylpropionyl group, 4-hydroxyphenylpropionyl group, N-2,4-dihydroxyphenylpropionyl group, N-3,4-dihydride Xiphenylpropionyl group, N-3,4,5-trihydroxyphenylpropionyl group, 2-hydroxy-4-methoxyphenylpropionyl group, 3-hydroxy-4-methoxyphenylpropionyl group, 4-hydroxy-3-methoxyphenylpropionyl group Group, 2-methylphenylpropionyl group, 3-methylphenylpropionyl group, 4-methylphenylpropionyl group, 2-ethylphenylpropionyl group, 3-ethylphenylpropionyl group, 4-ethylphenylpropionyl group, 2-propylphenylpropionyl group , 3-propylphenylpropionyl group, 4-propylphenylpropionyl group and the like. Of these, a benzoyl group is preferred because the effects of the present invention are the best.

In General formula (2), Y represents any of a hydroxyl group, a C1-C3 alkyloxy group, an allyloxy group, or NR < ₃ > R < ₄ >.
When Y is a hydroxyl group, the glutamic acid derivative of the general formula (2) is a 1-amide body corresponding to R ₁ and R ₂ . Therefore, the glutamic acid derivative of the general formula (2) becomes an acyl glutamic acid-1-amide body corresponding to Z, R ₁ and R ₂ .

When Y is an alkyloxy group having 1 to 3 carbon atoms or an allyloxy group, the glutamic acid derivative of the general formula (2) is a 5-ester form. Therefore, the glutamic acid derivative of the general formula (2) is an acyl glutamic acid-1-monoamide-5-ester corresponding to Y, Z, R ₁ and R ₂ . In this case, specific examples of Y include a methoxy group, an ethoxy group, an n-propoxy group, an iso-propoxy group, and an allyloxy group.

When Y is NR ₃ R ₄ , the glutamic acid derivative of the general formula (2) becomes a 1,5-diamide body corresponding to R _{1 to} R ₄ . Therefore, the glutamic acid derivative of the general formula (2) becomes an acyl glutamic acid-1,5-diamide body corresponding to Y, Z, R _{1 to} R ₄ . However, when Z is the general formula (4), Y is not simultaneously NR ₃ R ₄ .

Y in the general formula (2) is preferably a hydroxyl group or NR ₃ R ₄ because of good stability.
In General Formula (2), 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 having 3 to 7 carbon atoms. Group, phenyl group, or benzyl group. Alternatively, R ₁ and R ₂ and / or R ₃ and R ₄ may 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 ring 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 having 3 to 7 carbon atoms, the phenyl group, the benzyl group, and the complex The ring may have a hydroxyl group, an alkyloxy group having 1 to 3 carbon atoms, and an allyloxy group as a substituent.
In R _{1 to} R ₄ , the cycloalkyl group having 3 to 7 carbon atoms, the cycloalkenyl group having 3 to 7 carbon atoms, the phenyl group, the benzyl group, and the heterocyclic ring are alkyl groups having 1 to 3 carbon atoms. You may have as a substituent.

When R ₁ and R ₂ are both hydrogen atoms and Y is a hydroxyl group, the glutamic acid derivative of the present invention is acylglutamic acid-1-amide or acylglutamine amide corresponding to Z.

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 R _{1 to} R ₄ , the alkyl group having 1 to 3 carbon atoms and the allyl group may have a hydroxyl group, an alkyloxy group having 1 to 3 carbon atoms, and an allyloxy group as a substituent. Examples thereof include 2-hydroxyethyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 1-hydroxy-1-methylethyl group, 2-hydroxy-1-methylethyl group, 2,3-dihydroxy. Propyl group, 2,2,3-trihydroxypropyl group, 2,1'-dihydroxy-1-methylethyl group, 2-methoxyethyl group, 2-methoxypropyl group, 3-methoxypropyl group, 1-methoxy-1 -Methylethyl group, 2-methoxy-1-methylethyl group, 2,3-dimethoxypropyl group, 2,2,3-trimethoxypropyl group, 2,1'-dimethoxy-1-methylethyl group, 2-ethoxy Ethyl group, 2-ethoxypropyl group, 3-ethoxypropyl group, 1-ethoxy-1-methylethyl group, 2-ethoxy-1-methylethyl group, , 3-diethoxypropyl group, 2,2,3-triethoxypropyl group, 2,1′-diethoxy-1-methylethyl group, 2-n-propoxyethyl group, 2-n-propoxypropyl group, 3- n-propoxypropyl group, 1-n-propoxy-1-methylethyl group, 2-n-propoxy-1-methylethyl group, 2,3-di-n-propoxypropyl group, 2,2,3-tri-n- Propoxypropyl group, 2,1'-di-n-propoxy-1-methylethyl group, 2-iso-propoxyethyl group, 2-iso-propoxy-iso-propyl group, 3-iso-propoxypropyl group, 1-iso -Propoxy-1-methylethyl group, 2-iso-propoxy-1-methylethyl group, 2,3-diiso-propoxypropyl group, 2,2,3-triiso-propo Cypropyl group, 2,1′-diiso-propoxy-1-methylethyl group, 2-allyloxyethyl group, 2-allyloxy-n-propyl group, 3-allyloxypropyl group, 1-allyloxy-1-methylethyl Group, 2-allyloxy-1-methylethyl group, 2,3-diallyloxypropyl group, 2,2,3-triallyloxypropyl group, 2,1′-diallyloxy-1-methylethyl group, 2-hydroxy Examples include -3-methoxypropyl group and 3-hydroxy-2-methoxypropyl group.

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, an alkyl group having 1 to 3 carbon atoms. Any of these may be substituted. What was mentioned above is mentioned as a C1-C3 alkyloxy group and a C1-C3 alkyl group.
Of these cycloalkyl groups having 3 to 7 carbon atoms or cycloalkenyl groups having 3 to 7 carbon atoms, a cyclohexyl group and a cyclopentyl group are preferable because the effects of the present invention are good.

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. What was mentioned above is mentioned as a C1-C3 alkyloxy group and a C1-C3 alkyl group.
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.
Among these, a phenyl group and a benzyl group are preferable because the effects of the present invention are good and the solubility is good.

As R _{1 to} R ₄ , since the effect of the present invention is good and the solubility is good, at least one of R ₁ and R ₂ and / or at least one of R ₃ and R ₄ is It is preferably each independently a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or a benzyl group, and particularly preferably at least one of R ₁ and R ₂ and / or At least one of R ₃ and R ₄ is independently a hydrogen atom, a methyl group or an ethyl group.

It is also 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. Moreover, an oxygen atom may be included.
Specific examples of such NR ₁ R ₂ or NR ₃ R ₄ include piperidine, pyrrolidine, pyrrole, morpholine and the like. As described above, these heterocyclic rings may have any of 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 as a substituent.

As preferred NR ₁ R ₂ or NR ₃ R ₄ , specifically, methylamino group, ethylamino group, n-propylamino group, iso-propylamino group, hydroxyethylamino group, ethoxyethylamino group, dimethylamino group , Diethylamino group, di-n-propylamino group, methylethylamino group, cyclohexylamino group, cyclopentylamino group, phenylamino group, benzylamino group, piperidino group, pyrrolidino group, pyrrolino group and morpholino group.

In the present invention, NR ₃ R ₄ is preferably the same as NR ₁ R ₂ because synthesis from glutamic acid is easy. However, since the glutamic acid derivative of the present invention in which NR ₃ R ₄ is different from NR ₁ R ₂ can be easily obtained by using glutamine or theanine as a raw material or by an appropriate synthesis method, the present invention Not as long.

  In the present invention, preferred examples of the glutamic acid derivative represented by the general formula (2) include N-acetyl-N′-methyl-L-glutamic acid-1-amide, N-acetyl-N′-ethyl-L-glutamic acid— 1-amide, N-acetyl-N′-n-propyl-L-glutamic acid-1-amide, N-acetyl-N′-benzyl-L-glutamic acid-1-amide, N-acetyl-N′-cyclohexyl-L -Glutamic acid-1-amide, N-acetyl-N'-cyclopentyl-L-glutamic acid-1-amide, N-acetyl-L-glutamic acid 1-pyrrolidineamide, N-acetyl-L-glutamic acid 1-piperidineamide, N- Acetyl-L-glutamic acid 1-morpholinamide, N-benzoyl-N′-methyl-L-glutamic acid-1-amino N-benzoyl-N′-ethyl-L-glutamic acid-1-amide, N-benzoyl-N′-n-propyl-L-glutamic acid-1-amide, N-benzoyl-L-glutamic acid 1-morpholinamide, N -Acetyl-N ', N "-dimethyl-L-glutamic acid-1,5-diamide, N-acetyl-N', N" -diethyl-L-glutamic acid-1,5-diamide, N-acetyl-N ', N', N ″, N ″ -tetramethyl-L-glutamic acid-1,5-diamide, N-acetyl-N ′, N ′, N ″, N ″ -tetraethyl-L-glutamic acid— 1,5-diamide, N-acetyl-L-glutamic acid bis-1,5-morpholinamide, N-acetyl-L-glutamic acid bis-1,5-piperidineamide, N-acetyl-N′-me Ru-DL-glutamic acid-1-amide, N-acetyl-N′-ethyl-DL-glutamic acid-1-amide, N-acetyl-N′-n-propyl-DL-glutamic acid-1-amide, N-acetyl- N′-benzyl-DL-glutamic acid-1-amide, N-acetyl-N′-cyclohexyl-DL-glutamic acid-1-amide, N-acetyl-N′-cyclopentyl-DL-glutamic acid-1-amide, N-acetyl -DL-glutamic acid 1-pyrrolidineamide, N-acetyl-DL-glutamic acid 1-piperidineamide, N-acetyl-DL-glutamic acid 1-morpholinamide, N-benzoyl-N'-methyl-DL-glutamic acid-1-amide, N-benzoyl-N′-ethyl-DL-glutamic acid-1-amide, N-benzoyl- N′-n-propyl-DL-glutamic acid-1-amide, N-benzoyl-DL-glutamic acid 1-morpholinamide, N-acetyl-N ′, N ″ -dimethyl-DL-glutamic acid-1,5-diamide, N-acetyl-N ′, N ″ -diethyl-DL-glutamic acid-1,5-diamide, N-acetyl-N ′, N ′, N ″, N ″ -tetramethyl-DL-glutamic acid-1, 5-diamide, N-acetyl-N ′, N ′, N ″, N ″ -tetraethyl-DL-glutamic acid-1,5-diamide, N-acetyl-DL-glutamic acid bis-1,5-morpholinamide, N-acetyl-DL-glutamic acid bis-1,5-piperidineamide, N-acetyl-N′-methyl-D-glutamic acid-1-amide, N-acetyl-N′-ethyl- -Glutamic acid-1-amide, N-acetyl-N'-n-propyl-D-glutamic acid-1-amide, N-acetyl-N'-benzyl-D-glutamic acid-1-amide, N-acetyl-N'- Cyclohexyl-D-glutamic acid-1-amide, N-acetyl-N′-cyclopentyl-D-glutamic acid-1-amide, N-acetyl-D-glutamic acid 1-pyrrolidineamide, N-acetyl-D-glutamic acid 1-piperidineamide N-acetyl-D-glutamic acid 1-morpholinamide, N-benzoyl-N′-methyl-D-glutamic acid-1-amide, N-benzoyl-N′-ethyl-D-glutamic acid-1-amide, N-benzoyl -N'-n-propyl-D-glutamic acid-1-amide, N-benzoyl-D-glutamic acid 1 Morpholine amide, N-acetyl-N ′, N ″ -dimethyl-D-glutamic acid-1,5-diamide, N-acetyl-N ′, N ″ -diethyl-D-glutamic acid-1,5-diamide, N-acetyl-N ′, N ′, N ″, N ″ -tetramethyl-D-glutamic acid-1,5-diamide, N-acetyl-N ′, N ′, N ″, N ″ -tetraethyl -D-glutamic acid-1,5-diamide, N-acetyl-D-glutamic acid bis-1,5-morpholinamide, N-acetyl-D-glutamic acid bis-1,5-piperidineamide, and a group thereof It is a compound chosen from.

Among these, N-acetyl-N′-methyl-L-glutamic acid-1-amide, N-acetyl-N′-ethyl-L-glutamic acid-1-amide, N-acetyl-N′-n are more preferable. -Propyl-L-glutamic acid-1-amide, N-acetyl-N'-benzyl-L-glutamic acid-1-amide, N-acetyl-N'-cyclohexyl-L-glutamic acid-1-amide, N-acetyl-N '-Cyclopentyl-L-glutamic acid-1-amide, N-acetyl-L-glutamic acid 1-pyrrolidineamide, N-acetyl-L-glutamic acid 1-piperidineamide, N-acetyl-L-glutamic acid 1-morpholinamide, N- Benzoyl-N′-methyl-L-glutamic acid-1-amide, N-benzoyl-N′-ethyl-L-glutamic acid-1-ami , N- benzoyl-N'-n-propyl--L- glutamic acid-1-amide, N- benzoyl -L- glutamic acid 1-morpholine amide, N- acetyl -N '
, N ″ -dimethyl-L-glutamic acid-1,5-diamide, N-acetyl-N ′
, N ″ -diethyl-L-glutamic acid-1,5-diamide, N-acetyl-N ′
, N ′, N ″, N ″ -tetramethyl-L-glutamic acid-1,5-diamide, N-acetyl-N ′
, N ′, N ″, N ″ -tetraethyl-L-glutamic acid-1,5-diamide, N-acetyl-L-glutamic acid bis-1,5-morpholinamide, N-acetyl-L-glutamic acid bis-1 , 5-piperidineamide, and a compound selected from the group consisting of these salts. Among these compounds, the compound having the general formula (2) is most effective in inhibiting keratinization, shrinking pores, preventing and improving rough skin, has good solubility in preparations, and is highly safe. It is the best in solving the purpose.

The glutamic acid derivatives and salts thereof according to the present invention can be obtained by synthesis by a known method, or extraction / purification from animals, plants, microorganisms and the like. Moreover, it can also obtain as a commercial item and N-carbamoyl-L-glutamic acid etc. are marketed, for example from Sigma. N-benzyloxycarbonyl-L-glutamic acid, N-methyl-DL-glutamic acid, and the like are commercially available from, for example, Tokyo Chemical Industry Co., Ltd. N-methyl-L-glutamic acid and the like are commercially available from, for example, Kokusan Chemical.
Although the typical synthesis example is given to the following, it is not limited to these.

(Synthesis example)
(1) N-acetyl-N ′, N ″ -dimethyl-L-glutamic acid-1,5-diamide 50 mL of methanol is added to 5 g of N-acetyl-L-glutamic acid, 10 mL of a 10% hydrochloric acid methanol solution is added, and the mixture is heated to reflux. For 1 hour. After air cooling, 20 mL of 40% methylamine methanol solution was added to the residue obtained by concentration, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, dried and solidified, and recrystallized from methanol to obtain 3.8 g of the desired product.
The structure of the obtained target product was confirmed by NMR (JEOL EX-400, solvent DMSO).
¹ H-NMR (ppm): 8.01 (1H), 7.82 (1H), 7.73 (1H), 4.12 (1H), 2.55 (6H), 2.05 (2H), 1.85 (4H), 1.68 (1H). ¹³ C-NMR (ppm): 171.8, 171.8, 169.2, 62.3, 31.8, 28.1, 25.5, 25.4, 22.5.

(2) N-acetyl-N ′, N ″ -diethyl-L-glutamic acid-1,5-diamide 50 mL of methanol is added to 5 g of N-acetyl-L-glutamic acid, 50 mL of a 10% hydrochloric acid methanol solution is added, and the mixture is heated to reflux. For 1 hour. After air cooling, 20 mL of 70% ethylamine aqueous solution was added to the residue obtained by concentration, and the mixture was stirred at 50 ° C. for 2 hours. The reaction solution was concentrated, dried and solidified, and recrystallized from methanol to obtain 3.7 g of the desired product.

(3) N-acetyl-N ′, N ′, N ″, N ″ -tetramethyl-L-glutamic acid-1,5-diamide 50 g of methanol is added to 5 g of N-acetyl-L-glutamic acid and 10% hydrochloric acid is added. A methanol solution (50 mL) was added and the mixture was heated to reflux for 1 hour. After air cooling, 20 mL of dimethylamine was added to the residue obtained by concentration, and the mixture was stirred at 50 ° C. for 3 hours. The reaction solution was concentrated and dried to obtain 5.8 g of a liquid target product.

(4) N-acetyl-N′-methyl-L-glutamic acid-1-amide 10 g of N-benzyloxycarbonyl-tert-butyl-L-glutamic acid-5-ester was dissolved in 200 mL of methylene chloride, and methylamine hydrochloride at room temperature. Salt g, 4.9 mL of triethylamine, 6.7 g of EDCI, and 5.4 g of HOBt were added and stirred overnight at room temperature. The mixture was diluted with 50 mL of methylene chloride, washed with 50 mL of water, 50 mL of 2M hydrochloric acid, and 50 mL of saturated aqueous sodium hydrogen carbonate, dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 9.1 g of a residue. The obtained residue was dissolved in 200 mL of methanol, 1 g of 5% Pd-C (50% wet) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere, filtered and concentrated to obtain 5.9 g of a residue.

  1.02 g of the obtained residue was dissolved in 30 mL of methylene chloride, 1.4 mL of triethylamine and 525 μL of acetyl chloride were added, and the mixture was stirred overnight at room temperature. 1 mL of methanol was added and stirred for 10 minutes, diluted with 50 mL of methylene chloride, washed with 50 mL of water, 50 mL of 2M hydrochloric acid, 50 mL of saturated sodium bicarbonate, 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. . To the obtained residue, 10 mL of dioxane was added, 10 mL of 4M dioxane hydrochloride solution was added at room temperature, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure to obtain 0.4 g of the desired product.

(5) N-benzoyl-N′-methyl-L-glutamic acid-1-amide 1.02 g of the residue obtained in (4) was dissolved in 30 mL of methylene chloride, and 1.4 mL of triethylamine and 900 μl of benzoyl chloride were added. And stirred at room temperature overnight. Add 1 mL of N, N-dimethylethylenediamine, stir for 10 minutes, dilute with 50 mL of methylene chloride, wash with 50 mL of water, 50 mL of 2M hydrochloric acid, 50 mL of saturated aqueous sodium bicarbonate, 50 mL of saturated brine, dry over anhydrous magnesium sulfate, filter After leaving, it was concentrated. To the obtained residue, 10 mL of dioxane was added, 10 mL of 4M dioxane hydrochloride solution was added at room temperature, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure to obtain 1.4 g of the desired product.

(6) N-acetyl-N′-ethyl-L-glutamic acid-1-amide 10 g of N-benzyloxycarbonyl-L-glutamic acid-tert-butyl-5-ester is dissolved in 200 mL of methylene chloride and ethylamine hydrochloride is used at room temperature. 4.9 mL of triethylamine, 6.7 g of EDCI, and 5.4 g of HOBt were added and stirred overnight at room temperature. The mixture was diluted with 50 mL of methylene chloride, washed with 50 mL of water, 50 mL of 2M hydrochloric acid, and 50 mL of saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and concentrated to obtain 9.4 g of a residue. The obtained residue was dissolved in 200 mL of methanol, 1 g of 5% Pd-C (50% wet) was added, the mixture was stirred overnight at room temperature in a hydrogen atmosphere, filtered and concentrated to obtain 6.2 g of a residue.

  Of the obtained residue, 1.15 g was dissolved in 30 mL of methylene chloride, 1.4 mL of triethylamine and 525 μL of acetyl chloride were added, and the mixture was stirred overnight at room temperature. 1 mL of methanol was added and stirred for 10 minutes, diluted with 50 mL of methylene chloride, washed with 50 mL of water, 50 mL of 2M hydrochloric acid, 50 mL of saturated sodium bicarbonate, 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated. . To the obtained residue, 10 mL of dioxane was added, 10 mL of 4M dioxane hydrochloride solution was added at room temperature, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure to obtain 0.6 g of the desired product.

(7) N-benzoyl-N′-ethyl-L-glutamic acid-1-amide 1.15 g of the residue obtained in (6) was dissolved in 30 mL of methylene chloride, and 1.4 mL of triethylamine and 900 μl of benzoyl chloride were added. And stirred at room temperature overnight. Add 1 mL of N, N-dimethylethylenediamine, stir for 10 minutes, dilute with 50 mL of methylene chloride, wash with 50 mL of water, 50 mL of 2M hydrochloric acid, 50 mL of saturated aqueous sodium bicarbonate, 50 mL of saturated brine, dry over anhydrous magnesium sulfate, filter After leaving, it was concentrated. To the obtained residue, 10 mL of dioxane was added, 10 mL of 4M dioxane hydrochloride solution was added at room temperature, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure to obtain 1.6 g of the desired product.

(8) N-acetyl-N′-benzyl-L-glutamic acid-1-amide 10 g of N-benzyloxycarbonyl-L-glutamic acid-tert-butyl-5-ester was dissolved in 200 mL of methylene chloride, and benzylamine 3 was dissolved at room temperature. .75 g, EDCI 6.7 g, and HOBt 5.4 g were added and stirred overnight at room temperature. Dilute with 50 mL of methylene chloride, wash with 50 mL of water, 50 mL of 2M hydrochloric acid, and 50 mL of saturated aqueous sodium bicarbonate, then dry over anhydrous sodium sulfate, filter, and concentrate. The resulting residue is dissolved in 200 mL of methanol, 5% 1 g of Pd-C (50% wet) was added, and the mixture was stirred overnight at room temperature in a hydrogen atmosphere, filtered and concentrated to obtain 7.8 g of a residue.

  1.46 g of the obtained residue is dissolved in 30 mL of methylene chloride, 1.4 mL of triethylamine and 525 μl of acetyl chloride are added and stirred for 10 minutes, diluted with 50 mL of methylene chloride, 50 mL of water, 50 mL of 2M hydrochloric acid, saturated aqueous sodium bicarbonate solution. The extract was washed with 50 mL and 50 mL of saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. To the obtained residue, 10 mL of dioxane was added, 10 mL of 4M dioxane hydrochloride solution was added at room temperature, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure to obtain 1.3 g of the desired product.

(9) N-benzoyl-N′-benzyl-L-glutamic acid-1-amide 1.46 g of the residue obtained in (8) is dissolved in 30 mL of methylene chloride, and 1.4 mL of triethylamine and 900 μL of benzoyl chloride are added. And stirred at room temperature overnight. Add 1 mL of N, N-dimethylethylenediamine, stir for 10 minutes, dilute with 50 mL of methylene chloride, wash with 50 mL of water, 50 mL of 2M hydrochloric acid, 50 mL of saturated aqueous sodium bicarbonate, 50 mL of saturated brine, dry over anhydrous magnesium sulfate, filter After leaving, it was concentrated. To the obtained residue, 10 mL of dioxane was added, 10 mL of 4M dioxane hydrochloride solution was added at room temperature, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure to obtain 1.3 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 as long as it is a pharmacologically or pharmaceutically acceptable salt. Examples of inorganic salts include sodium salts, potassium salts, calcium salts, zinc salts, magnesium salts, ammonium salts, hydrochloride salts, Examples thereof include sulfates, phosphates, hydrobromides, and the like. 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 the 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, preferably for external use on the skin. Pulmonary and / or glutamic acid derivatives and salts thereof can be suitably used as a composition, in particular, a composition for external skin use for inhibiting keratinization, reducing pores, or preventing or improving rough skin.

All of these uses are new and useful uses based on the discovery of the novel effects of the glutamic acid derivatives according to the present invention.
The glutamic acid derivative represented by the general formula (1) or the general formula (2) according to the present invention and a salt thereof, and a composition for external use containing the skin have an inhibitory effect on keratinization, a pore reducing action, a rough skin prevention It has not been known so far to have an improving action and has been found for the first time by the present inventors.

  The above-mentioned keratinization inhibitor, pore-reducing agent, rough skin prevention / improving agent, and composition for external application to skin are all in a wide range of applications, for example, applied in various fields such as cosmetics, pharmaceuticals, foods including quasi drugs. Is done.

  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 To 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, cypress extract, eucalyptus extract, clove extract, maronier extract, cornflower extract, seaweed extract, thyme extract and the like.

  Preservatives include paraoxybenzoates such as methylparaben, ethylparaben, and 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 Hereinafter, although an Example demonstrates this invention concretely, the technical scope of this invention is not limited by 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.
The evaluation was carried out based on a plan approved by the in-house animal experiment council, in compliance with other relevant laws and regulations.

  As is apparent from Table 1, N-carbamoyl-L-glutamic acid, N-benzyloxycarbonyl-L-glutamic acid, N-methyl-L-glutamic acid, N-methyl-DL-glutamic acid, N-acetyl-N′-methyl -L-glutamic acid-1-amide, N-acetyl-N'-ethyl-L-glutamic acid-1-amide, N-acetyl-N'-n-propyl-L-glutamic acid-1-amide, N-acetyl-N '-Benzyl-L-glutamic acid-1-amide, N-acetyl-N'-cyclohexyl-L-glutamic acid-1-amide, N-acetyl-N'-cyclopentyl-L-glutamic acid-1-amide, N-acetyl- L-glutamic acid 1-pyrrolidineamide, N-acetyl-L-glutamic acid 1-piperidineamide, N-acetyl-L- Glutamic acid 1-morpholinamide, N-benzoyl-N′-methyl-L-glutamic acid-1-amide, N-benzoyl-N′-ethyl-L-glutamic acid-1-amide, N-benzoyl-N′-n-propyl -L-glutamic acid-1-amide, N-benzoyl-L-glutamic acid 1-morpholinamide, N-acetyl-N ′, N ″ -dimethyl-L-glutamic acid-1,5-diamide, N-acetyl-N ′ , N ″ -diethyl-L-glutamic acid-1,5-diamide, N-acetyl-N ′, N ′, N ″, N ″ -tetramethyl-L-glutamic acid-1,5-diamide, N— Acetyl-N ′, N ′, N ″, N ″ -tetraethyl-L-glutamic acid-1,5-diamide, N-acetyl-L-glutamic acid bis-1,5-morpholine Such as de and N- acetyl -L- glutamic acid bis-1,5-piperidine amide, a glutamic acid derivative of the present invention, the effect of suppressing skin irritation, such as desquamating and erythema which is caused by unsaturated fatty acids was observed.

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-acetylglutamine as a comparative example does not have these effects, and the effect of N-acetylglutamic acid is inferior to that of the compound of the present invention.

[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 is TEWA
Measured using a 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-carbamoyl-L-glutamic acid, N-benzyloxycarbonyl-L-glutamic acid, N-methyl-L-glutamic acid, N-methyl-DL-glutamic acid, N-acetyl-N′-methyl -L-glutamic acid-1-amide, N-acetyl-N'-ethyl-L-glutamic acid-1-amide, N-acetyl-N'-n-propyl-L-glutamic acid-1-amide, N-acetyl-N '-Benzyl-L-glutamic acid-1-amide, N-acetyl-N'-cyclohexyl-L-glutamic acid-1-amide, N-acetyl-N'-cyclopentyl-L-glutamic acid-1-amide, N-acetyl- L-glutamic acid 1-pyrrolidineamide, N-acetyl-L-glutamic acid 1-piperidineamide, N-acetyl-L-glutami Acid 1-morpholinamide, N-benzoyl-N′-methyl-L-glutamic acid-1-amide, N-benzoyl-N′-ethyl-L-glutamic acid-1-amide, N-benzoyl-N′-n-propyl -L-glutamic acid-1-amide, N-benzoyl-L-glutamic acid 1-morpholinamide, N-acetyl-N ′, N ″ -dimethyl-L-glutamic acid-1,5-diamide, N-acetyl-N ′ , N ″ -diethyl-L-glutamic acid-1,5-diamide, N-acetyl-N ′, N ′, N ″, N ″ -tetramethyl-L-glutamic acid-1,5-diamide, N— Acetyl-N ′, N ′, N ″, N ″ -tetraethyl-L-glutamic acid-1,5-diamide, N-acetyl-L-glutamic acid bis-1,5-morpholinamide and N-acetyl-L- Glutamic acid Such as scan-1,5-piperidine amide, by applying a glutamic acid derivative of the present invention, DerutaTEWL value is significantly lower than the control solution, rough skin prevention and improvement effect was observed.
On the other hand, N-acetylglutamine as a comparative example did not have such an effect, and the effect of N-acetylglutamic acid was inferior to that of 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 irritation was evaluated every 30 seconds, and the final evaluation was reported (n = 2). 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 or more and less than 1.0 C: Evaluation point average 1.0 or more and less than 2.0 D: Evaluation point average 2.0 or more

As is apparent from Table 3, N-carbamoyl-L-glutamic acid, N-benzyloxycarbonyl-L-glutamic acid, N-methyl-L-glutamic acid, N-methyl-DL-glutamic acid, N-acetyl-N′-methyl -L-glutamic acid-1-amide, N-acetyl-N'-ethyl-L-glutamic acid-1-amide, N-acetyl-N'-n-propyl-L-glutamic acid-1-amide, N-acetyl-N '-Benzyl-L-glutamic acid-1-amide, N-acetyl-N'-cyclohexyl-L-glutamic acid-1-amide, N-acetyl-N'-cyclopentyl-L-glutamic acid-1-amide, N-acetyl- L-glutamic acid 1-pyrrolidineamide, N-acetyl-L-glutamic acid 1-piperidineamide, N-acetyl-L-glutamine 1-morpholinamide, N-benzoyl-N′-methyl-L-glutamic acid-1-amide, N-benzoyl-N′-ethyl-L-glutamic acid-1-amide, N-benzoyl-N′-n-propyl- L-glutamic acid-1-amide, N-benzoyl-L-glutamic acid 1-morpholinamide, N-acetyl-N ′, N ″ -dimethyl-L-glutamic acid-1,5-diamide, N-acetyl-N ′, N ″ -diethyl-L-glutamic acid-1,5-diamide, N-acetyl-N ′, N ′, N ″, N ″ -tetramethyl-L-glutamic acid-1,5-diamide, N-acetyl -N ', N', N ", N" -tetraethyl-L-glutamic acid-1,5-diamide, N-acetyl-L-glutamic acid bis-1,5-morpholinamide and N-acetyl-L-glutamic acid Bi Such as 1,5-piperidine amide, glutamic acid derivatives according to the present invention has no problem in sensory irritation, it was confirmed that 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.

[Test Example 4] Inhibitory effect on inflammatory cytokine production enhancement by oleic acid Human normal keratinocytes purchased from Kurabo Industries (Strain
No. 070413-902) was cultured in KGM medium for 3 days in a 75 cm ² flask. The cells were collected by trypsin treatment by a conventional method, and then seeded in a 24-well plate (Corning) at 40,000 cells / 0.5 ml in KGM medium. After further culturing for 3 days, oleic acid or oleic acid and a test compound were added. Oleic acid and the test compound were added to 2 × 10 ⁻³ % and 0.05%, respectively. As a control, ethanol was added instead of oleic acid. After 8 hours, the culture solution was collected, and the amount of IL-1α was measured with a quantification kit (R & D systems).
As a representative example, the results when N-carbamoyl-L-glutamic acid is used as a test compound are shown in FIG.
As can be seen from FIG. 1, it was clarified that the compound of the present invention suppresses the production increase of IL-1α, which is a kind of inflammatory cytokine, caused by oleic acid.

Table 4 below shows that in the above test, oleic acid (10 mM ethanol solution) and N-acetyl-N ′, N ″ -diethyl-L-glutamic acid-1,5-diamide (50 mM aqueous solution) were each 10 μM (2. 8 × 10 ⁻⁴ %) and 500 μM (0.012%) The results are shown in Table 4. Table 4 also shows the production of IL-1α, a kind of inflammatory cytokine caused by oleic acid. It is understood that the compounds of the present invention significantly suppress the enhancement.

  The composition for external use as a skin is shown below as a formulation example of the composition according to the present invention. In addition, any skin external composition was manufactured by the conventional method. The blending amounts are all mass%. In addition, all of the compositions for external use for skin had excellent effects such as inhibition 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-carbamoyl-L-glutamic acid 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-benzyloxycarbonyl-L-glutamic acid 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-acetyl-L-glutamic acid bis-1,5-piperidineamide 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-methyl-L-glutamic acid 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-acetyl-N ′, N ′, N ″, N ″ -tetraethyl-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 perfume 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-acetyl-L-glutamic acid bis-1,5-morpholinamide
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-acetyl-N′-methyl-L-glutamic acid-1-amide 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-acetyl-N′-ethyl-L-glutamic acid-1-amide 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
N-benzoyl-N′-ethyl-L-glutamic acid-1-amide 1.0
β-carotene 0.01
Polyvinyl alcohol 0.5
Hydroxyethyl cellulose 0.5
Carboxyvinyl polymer 0.05
Purified water Residual fragrance

[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-acetyl-N ′, N ″ -dimethyl-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
N-acetyl-N ′, N ″ -diethyl-L-glutamic acid-1,5-diamide
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
4- (1-Pyrrolidine) butyric acid 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 perfume Appropriate amount

[Formulation Example 12] Cosmetic liquid (A phase)
(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-acetyl-L-glutamic acid 1-morpholinamide 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-acetyl-N′-benzyl-L-glutamic acid-1-amide 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] Latex 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-acetyl-L-glutamic acid 1-piperidineamide 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 Vaseline 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-acetyl-L-glutamic acid 1-pyrrolidinamide 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 Remaining 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-acetyl-N′-ethyl-L-glutamic acid-1-amide 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-acetyl-N′-cyclopentyl-L-glutamic acid-1-amide 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
Glycylglycine 1.0
N-acetyl-N ′, N′-dimethyl-L-glutamic acid-1-amide 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-benzoyl-N′-propyl-L-glutamic acid-1-amide 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-acetyl-N′-cyclopentyl-L-glutamic acid-1-amide 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 amount perfume Appropriate amount N-acetyl-N′-cyclopentyl-L-glutamic acid-1-amide 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-acetyl-L-glutamic acid 1-pyrrolidinamide 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
Sodium chondroitin 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] Pack with powder (alcohol phase)
95% ethanol 2.0
Preservative Appropriate amount of perfume Appropriate amount of colorant Appropriate amount of N-methyl-DL-glutamic acid 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-acetyl-N ′, N ′, N ″, N ″ -tetraethyl-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
Glyceryl tri-2-ethylhexanoate 3.0
N-benzoyl-L-glutamic acid 1-morpholinamide 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-acetyl-N′-n-propyl-L-glutamic acid-1-amide 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

Claims (13)

An external composition for skin, comprising one or more compounds selected from the group consisting of the following general formula (1) and glutamic acid derivatives represented by the following general formula (2) and salts thereof.

(In General Formula (1), A represents a carbamoyl group, a benzyloxycarbonyl group, an alkyl group having 1 to 3 carbon atoms, or an allyl group.)

(In the general formula (2), Z represents an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a benzyloxy group, or a group represented by the following general formula (3) or the following general formula (4). Y represents a hydroxyl group, an alkyloxy group having 1 to 3 carbon atoms, an allyloxy group, or NR ₃ R ₄ , provided that Z represents the general formula (4) and Y represents NR ₃ 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, or a cyclohexane having 3 to 7 carbon atoms. An alkenyl group, a phenyl group, or a benzyl group, or R ₁ and R ₂ and / or R ₃ and R ₄ are each independently taken together with the nitrogen atom to which they are bonded to give a total number of carbon atoms of 6 It forms the following heterocycle, which contains an oxygen atom In R _{1 to} R ₄ , the alkyl group having 1 to 3 carbon atoms, allyl group, cycloalkyl group having 3 to 7 carbon atoms, cycloalkenyl group having 3 to 7 carbon atoms, phenyl group, benzyl The group or the heterocyclic ring may have a hydroxyl group, an alkyloxy group having 1 to 3 carbon atoms, or an allyloxy group as a substituent, and the cycloalkyl group having 3 to 7 carbon atoms or 3 to 3 carbon atoms. 7 cycloalkenyl group, phenyl group, benzyl group, or heterocyclic ring may have an alkyl group having 1 to 3 carbon atoms as a substituent.

(In General Formula (3), X ₁ , X ₂ and X ₃ are each independently an alkyl group having 1 to 4 carbon atoms or an alkenyl group having 1 to 4 carbon atoms, an alkyloxy group having 1 to 4 carbon atoms, Represents an alkenyloxy group having 2 to 4 carbon atoms, a hydroxyl group, an amino group, an alkylamino group having 1 to 4 carbon atoms, a fluorine atom or a trifluoromethyl group, wherein n, m and p are each independently an integer of 0 to 3; And k and q each independently represents an integer of 0 to 2.)

(In the general formula (4), X ₁ , X ₂ , X _3, k, n, m, and p are the same as those in the general formula (3).)   The external composition for skin according to claim 1, comprising at least one compound selected from the group consisting of the glutamic acid derivative represented by the general formula (1) and a salt thereof.   The external composition for skin according to claim 2, comprising at least one compound selected from N-carbamoylglutamic acid, N-benzyloxycarbonylglutamic acid, N-methylglutamic acid and salts thereof. .   The external composition for skin according to claim 1, comprising at least one compound selected from the group consisting of the glutamic acid derivative represented by the general formula (2) and a salt thereof.   The external composition for skin according to claim 4, wherein Z is a methyl group or a phenyl group. According to claim 4 or 5 external composition for skin according dermatological composition, characterized in that Y is a hydroxyl group or NR ₃ R _4. The composition for external skin according to any one of claims 4 to 6, wherein Y is the same as NR ₁ R ₂ . The composition for external skin according to any one of claims 4 to 7, wherein at least one of R ₁ and R ₂ and / or at least one of R ₃ and R ₄ is each independently a hydrogen atom or a carbon number of 1 to 8. A composition for external use on skin, which is an alkyl group having 3 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or a benzyl group. The composition for external skin according to any one of claims 4 to 8, wherein at least one of R ₁ and R ₂ and / or at least one of R ₃ and R ₄ is independently a hydrogen atom, a methyl group or ethyl. A composition for external use on the skin, which is a base. The composition for external skin according to any one of claims 4 to 7, wherein R ₁ and R ₂ and / or R ₃ and R ₄ are each independently a carbon atom together with a nitrogen atom to which they are bonded. A composition for external use on skin, characterized by forming a heterocyclic ring having a total of 6 or less. The external composition for skin according to claim 4, wherein N-acetyl-N'-methylglutamic acid-1-amide, N-acetyl-N'-ethylglutamic acid-1-amide, N-acetyl-N'-n-propylglutamic acid -1-amide, N-acetyl-N′-benzylglutamic acid-1-amide, N-acetyl-N′-cyclohexylglutamic acid-1-amide, N-acetyl-N′-cyclopentylglutamic acid-1-amide, N-acetyl Glutamic acid 1-pyrrolidineamide, N-acetylglutamic acid 1-piperidineamide, N-acetylglutamic acid 1-morpholinamide, N-benzoyl-N′-methylglutamic acid-1-amide, N-benzoyl-N′-ethylglutamic acid-1- Amido, N-benzoyl-N′-n-propylglutamic acid-1-amino , N- benzoyl glutamic acid 1-morpholine amide, N- acetyl -N ', N''- -1,5- dimethyl glutamic acid diamide, N- acetyl -N'
, N ″ -diethylglutamic acid-1,5-diamide, N-acetyl-N ′, N ′, N ″, N ″ -tetramethylglutamic acid-1,5-diamide, N-acetyl-N ′, N ', N ″, N ″ -tetraethylglutamic acid-1,5-diamide, N-acetylglutamic acid bis-1,5-morpholinamide, and N-acetylglutamic acid bis-1,5-piperidineamide, and salts thereof An external composition for skin, comprising one or more compounds selected from the group consisting of: Parakeratosis inhibitor or pore-shrinking agent as an active ingredient, one or more glutamic acid derivatives and compounds selected from the group consisting of salts represented by the following following general formula (1) or down following general formula (2).

(In General Formula (1), A represents a carbamoyl group, a benzyloxycarbonyl group, an alkyl group having 1 to 3 carbon atoms, or an allyl group.)

(In the general formula (2), Z represents an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a benzyloxy group, or a group represented by the following general formula (3) or the following general formula (4). Y represents a hydroxyl group, an alkyloxy group having 1 to 3 carbon atoms, an allyloxy group, or NR ₃ R ₄ , provided that Z represents the general formula (4) and Y represents NR ₃ 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, or a cyclohexane having 3 to 7 carbon atoms. An alkenyl group, a phenyl group, or a benzyl group, or R ₁ and R ₂ and / or R ₃ and R ₄ are each independently taken together with the nitrogen atom to which they are bonded to give a total number of carbon atoms of 6 It forms the following heterocycle, which contains an oxygen atom In R _{1 to} R ₄ , the alkyl group having 1 to 3 carbon atoms, allyl group, cycloalkyl group having 3 to 7 carbon atoms, cycloalkenyl group having 3 to 7 carbon atoms, phenyl group, benzyl The group or the heterocyclic ring may have a hydroxyl group, an alkyloxy group having 1 to 3 carbon atoms, or an allyloxy group as a substituent, and the cycloalkyl group having 3 to 7 carbon atoms or 3 to 3 carbon atoms. 7 cycloalkenyl group, phenyl group, benzyl group, or heterocyclic ring may have an alkyl group having 1 to 3 carbon atoms as a substituent. Rough skin preventing and improving agents containing, as an active ingredient, one or more glutamic acid derivatives and compounds selected from the group consisting of salts represented by the following following general formula (1) or down following general formula (2).

(In General Formula (1), A represents a carbamoyl group, a benzyloxycarbonyl group, an alkyl group having 1 to 3 carbon atoms, or an allyl group.)

(In the general formula (2), Z represents an alkyl group having 1 to 4 carbon atoms, an alkenyl group having 2 to 4 carbon atoms, a benzyloxy group, or a group represented by the following general formula (3) or the following general formula (4). Y represents a hydroxyl group, an alkyloxy group having 1 to 3 carbon atoms, an allyloxy group, or NR ₃ R ₄ , provided that Z represents the general formula (4) and Y represents NR ₃ 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, or a cyclohexane having 3 to 7 carbon atoms. An alkenyl group, a phenyl group, or a benzyl group, or R ₁ and R ₂ and / or R ₃ and R ₄ are each independently taken together with the nitrogen atom to which they are bonded to give a total number of carbon atoms of 6 It forms the following heterocycle, which contains an oxygen atom In R _{1 to} R ₄ , the alkyl group having 1 to 3 carbon atoms, allyl group, cycloalkyl group having 3 to 7 carbon atoms, cycloalkenyl group having 3 to 7 carbon atoms, phenyl group, benzyl The group or the heterocyclic ring may have a hydroxyl group, an alkyloxy group having 1 to 3 carbon atoms, or an allyloxy group as a substituent, and the cycloalkyl group having 3 to 7 carbon atoms or 3 to 3 carbon atoms. 7 cycloalkenyl group, phenyl group, benzyl group, or heterocyclic ring may have an alkyl group having 1 to 3 carbon atoms as a substituent.

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