JPH10168047A - Amido derivative and amido derivative-containing composition for external application - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an amido derivative that improves a barrier function of the corneal layer of skin, is useful for preventing or curing the skin from chapping, inflaming, or aging and has excellent formulation stability when formulated for external application. SOLUTION: This amido derivative of formula I [R<1> is a 1-40C hydrocarbon; R<2> is a 1-6C alkylene; R<3> is H or a 1-12C alkoxyl; R<4> is a divalent 1-39C hydrocarbon; R<24> is a 1-22C hydrocarbon; R<5> is formula II (R<6> is H or a 1-6C hydrocarbon; R<7> is a 1-40C hydrocarbon), etc.], for example, a glyceryl ether derivative, is obtained by making a glycidyl ether react with an amine to form an amino alcohol derivative, making an aminocarboxylic derivative react with an acid chloride, etc., to form an amidocarboxylic acid derivative, making the amino alcohol derivative with the amidocarboxylic acid derivative in the presence of a dehydrating agent, etc., in vacuum at temperature in the range of room temperature to 150 deg.C to form a compound of formula III, making the compound of formula III react with a halogenated alkyl derivative to form a compound of formula IV, furthermore making a compound of formula III react with a halogenated epoxide at temperature in the range of room temperature to 150 deg.C and then with an alcohol in the presence of an acid, etc., to form a compound of formula V, and producing an amido derivative from the compound of formula IV and the compound of formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention has the effect of fundamentally improving the barrier function of the stratum corneum (maintaining a normal barrier function and recovering and reinforcing the decrease in the barrier function), and has a stable formulation. The present invention relates to a novel amide derivative having excellent properties and an external preparation composition containing the same.

[0002]

2. Description of the Related Art The epidermis, especially the stratum corneum, is an extremely thin component derived from the epidermis present in the outermost layer of the body, and not only protects various stimuli and invasion from outside the body but also protects components and water in the body. It has the function of preventing loss and transpiration. Such a protective effect of the stratum corneum, ie, a barrier function, is important for controlling homeostasis of epidermal physiological functions.

[0003] If the barrier function is reduced by various internal causes or various external causes such as ultraviolet rays, various skin troubles such as inflammation of the skin and promotion of rough skin and aging may occur. Become. Therefore, it is needless to say that the maintenance and reinforcement of the barrier function of the stratum corneum is very important for healthy daily life.

[0004] In order to prevent or improve the occurrence of such skin problems, external preparations containing various natural components and chemically synthesized components have been developed. The main purpose is to obtain the effect of moisturizing the skin and to supplement the barrier function by forming a film on the skin surface.These are those that form the film on the skin surface only temporarily. However, the effect of essentially improving (maintaining / reinforcing) the barrier function could not be sufficiently expected.

Accordingly, the present applicant has firstly proposed a skin external preparation having an effect of essentially improving the barrier function of the skin as represented by the following general formula (3):

[0006]

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Wherein R ¹² represents a linear or branched saturated or unsaturated hydrocarbon group having 10 to 40 carbon atoms, and R ¹³ represents a linear or branched divalent hydrocarbon group having 3 to 39 carbon atoms. And R ¹⁴ represents a hydrogen atom, a linear or branched saturated or unsaturated hydrocarbon group or an acyl group having 10 to 40 carbon atoms, or an amide derivative represented by the formula: (JP-A-2-306952) and the following general formula (4)

[0008]

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(Wherein, R ¹⁵ represents a linear or branched hydrocarbon group having 10 to 40 carbon atoms, and R ¹⁶ represents a linear or branched divalent hydrocarbon group having 1 to 39 carbon atoms.) R ¹⁷ represents a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms, and R ¹⁸ has a hydrogen atom or a linear, branched or cyclic structure having 1 to 40 carbon atoms which may contain an oxygen atom. A skin external preparation (JP-A-7-70030) containing an amide derivative represented by the following formula: Scott et al. Have also proposed a cosmetic composition containing an amide derivative having a similar structure (Japanese Patent Application Laid-Open No. 4-22590).
No. 7 and JP-A-4-342553).

[0010]

However, these amide derivatives have the effect of acting on the stratum corneum and essentially improving the barrier function of the skin. It was not always satisfactory in terms of compoundability such as solubility in a base and compounding stability.

Accordingly, an object of the present invention is to substantially improve (maintain and maintain) the barrier function of the stratum corneum by applying it to the skin.
Reinforcement) and when combined with an external preparation for the skin, can prevent and treat rough skin and inflammation, and can also prevent skin aging, and have a low melting point, low crystallinity, or solubility in bases It is an object of the present invention to provide an amide derivative having improved compoundability, compounding stability, and the like, and a skin external preparation containing the amide derivative, which is improved by the improvement of the compound.

[0012]

Means for Solving the Problems In view of such circumstances, the present inventors have conducted intensive studies and as a result, a novel amide derivative represented by the following general formula (1) and an external preparation composition containing the same have been obtained. And accomplished the present invention.

That is, the present invention provides the following general formula (1)

[0014]

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[0015] (In the formula, R ¹ represents a linear or branched hydrocarbon group having 1 to 40 carbon atoms, R ² represents a linear or branched alkylene group having 1 to 6 carbon atoms, R ³ Represents a hydrogen atom or a linear or branched alkoxyl group having 1 to 12 carbon atoms, R ⁴ represents a linear or branched divalent hydrocarbon group having 1 to 39 carbon atoms, and R ²⁴ represents a hydroxyl group. Or a linear or branched hydrocarbon group having 1 to 22 carbon atoms which may be substituted with an alkoxyl group,

[0016]

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(Where R ⁶ is a hydrogen atom or a carbon atom having 1 to
6 represents a hydrocarbon group, R ⁷ represents a hydrocarbon group having a linear, branched or cyclic structure of 1 to 40 carbon atoms which may contain an oxygen atom, and R ⁸ and R ⁹ are the same or Differently
1 carbon atom which may contain a hydrogen atom or an oxygen atom
Represents a hydrocarbon group having a linear, branched or cyclic structure of from 40 to 40, or a divalent hydrocarbon having from 1 to 40 carbon atoms, wherein R ⁸ and R ⁹ may together contain an oxygen atom R ¹⁰ may represent a carbonyl group or a methylene group, and R ¹¹ may have from 1 to 4 carbon atoms which may contain an oxygen atom.
0 represents a hydrocarbon group or hydrogen atom having a linear, branched or cyclic structure. )

An amide derivative represented by the formula: The present invention also provides an external preparation composition containing the amide derivative.

The amide derivative of the present invention has an effect of essentially improving (maintaining and reinforcing) the barrier function of the stratum corneum, and has a low melting point and low crystallinity when incorporated into an external preparation composition. It has good solubility and stability with respect to the agent, and can be stably and easily incorporated into the base. Therefore, the external preparation composition containing the amide derivative of the present invention, when applied to the skin, essentially improves the barrier function of the stratum corneum, and provides the effect of improving and preventing skin inflammation and rough skin. is there.

[0020]

BEST MODE FOR CARRYING OUT THE INVENTION The amide derivative of the present invention is represented by the above general formula (1), wherein a linear or branched hydrocarbon group having 1 to 40 carbon atoms represented by R ¹ is represented by the formula: May be saturated or unsaturated; specifically, methyl, ethyl, n
-Propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl, n-tetradecyl, n-pentadecyl N-hexadecyl, n-heptadecyl, n-octadecyl, n-nonadecyl, n-icosyl, n-henicosyl, n-docosyl, n-tricosyl, n-tetracosyl, n-pentacosyl, n-hexacosyl, n-heptacosyl, n -Octakosyl, n-nonakosyl, n-triacontyl, n-
Hentria contyl, n-dotriacontyl, n-tritriacontyl, n-tetratriacontyl, n-pentatriacontyl, n-hexatriacontyl, n-heptatriacontyl, n-octatriacontyl, n −
Nonatriacontyl, n-tetracontyl, ethenyl,
Propenyl, butenyl, pentenyl, hexenyl, octenyl, nonenyl, decenyl, undecenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecenyl, octadecenyl, nonadecenyl,
Icocenyl, henicocenyl, tococenyl, tricosenyl, tetracosenyl, pentacosenyl, hexacosenyl, heptacosenyl, octacosenyl, nonacosenyl,
Triacontenyl, Hentriacontenyl, Dotriacontenyl, Tritriacontenyl, Tetratriacontenyl, Pentatriacontenyl, Hexatriacontenyl, Heptatriacontenyl, Octatriacontenyl, Nonatriacontenyl, Tetracontenyl , Isostearyl, 2-ethylhexyl, 2-heptylundecyl, and 9,12-octadecadienyl groups.

R ¹ is preferably a linear or branched hydrocarbon group having 1 to 26 carbon atoms, and preferably has 4 to 2 carbon atoms.
6 straight-chain or branched-chain hydrocarbon groups are more preferable; straight-chain or branched-chain saturated hydrocarbon groups having 4 to 22 carbon atoms are particularly preferable; straight-chain or branched-chain saturated hydrocarbon groups having 4 to 18 carbon atoms Groups are particularly preferred; specifically, butyl, hexyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, methyl-branched isostearyl and docosanyl groups are more particularly preferred. Here, when a methyl-branched isostearyl group is used as R ^1, it is preferable to use an isostearyl group derived from isostearyl alcohol produced by reducing isostearic acid which is a by-product during the production of dimer acid.

Examples of the linear or branched alkylene group having 1 to 6 carbon atoms represented by R ² include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, 1-methylethylene, and 1-methyltrimethylene. , 2-methyltrimethylene, 1,1-dimethylethylene, 1-ethylethylene, 1-methyltetramethylene,
And a 2-ethyltrimethylene group. R ² is preferably a straight-chain alkylene group having 1 to 6 carbon atoms; methylene, ethylene and trimethylene are particularly preferred.

R ³ is a hydrogen atom or a carbon atom having 1 to 12 carbon atoms.
And a specific example of the alkoxy group is methoxy, ethoxy, propoxy, butoxy, hexyloxy, octyloxy, decyloxy, 1-methylethoxy, 2-ethylhexyloxy, 2-hydroxy Ethyloxy and 2,3-dihydroxypropyloxy groups are exemplified. Of these, R
^{As 3} , a hydrogen atom, an alkoxy group having 1 to 8 carbon atoms,
2-hydroxyethyloxy and 2,3-dihydroxypropyloxy are preferred; hydrogen, methoxy, ethoxy, butoxy, 1-methylethoxy, 2-ethylhexyloxy, 2-hydroxyethyloxy,
A 2,3-dihydroxypropyloxy group is particularly preferred.

Examples of the linear or branched divalent hydrocarbon group having 1 to 39 carbon atoms for R ⁴ include a methylene group, a dimethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, Octamethylene group, nonamethylene group, decamethylene group, undecamethylene group,
Dodecamethylene group, tridecamethylene group, tetradecamethylene group, pentadecamethylene group, hexadecamethylene group, heptadecamethylene group, octadecamethylene group, nonadecamethylene group, icosamethylene group, henicosamethylene group, docosamethylene group, trichomethylene group Samethylene group, Tetracosamethylene group, Pentacosamethylene group, Hexacosamethylene group, Heptacosamethylene group, Octacosamethylene group, Nonacosamethylene group, Heptadecane-1,11-diyl group, 8-Heptadecene-1,11 -Diyl group and the like. Among them, R ⁴ is preferably a linear and saturated divalent hydrocarbon group, particularly those having 5 to 31 carbon atoms, specifically, a nonamethylene group, a decamethylene group,
An undecamethylene group, a tetradecamethylene group, a pentadecamethylene group, and a hentriacontamethylene group are particularly preferred.

[0025]

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Here, R ⁶ represents a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms. Specific examples of the hydrocarbon group include a methyl group, an ethyl group, a linear or branched propyl,
Butyl, pentyl, hexyl, vinyl, allyl,
Butenyl, pentenyl and hexynyl. R ⁶ is preferably a hydrogen atom. Examples of the hydrocarbon group having a linear, branched or cyclic structure having 1 to 40 carbon atoms which may contain an oxygen atom represented by R ⁷ include an ether bond (-O-), a ketone (-C (= O)-), carboxyl group (-COOH) and carbochelate bond (-
And a hydrocarbon group which may have one or more of COO-). Specific examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl groups. , N-undecyl group,
n-dodecyl group, n-tridecyl group, n-tetradecyl group, n-pentadecyl group, n-hexadecyl group, n-heptadecyl group, n-octadecyl group, n-nonadecyl group, n-icosyl group, n-hexicosyl group, n-docosyl group, n-tricosyl group, n-tetracosyl group, n-pentacosyl group, n-hexacosyl group, n-heptacosyl group, n-octacosyl group, n-nonacosyl group, n-triacontyl group, n-hentriacontyl Group, n-dotriacontyl group, n-tritriacontyl group, n-tetratriacontyl group, n-pentatriacontyl group, n-
Hexatriacontyl group, n-heptatriacontyl group, n-octatriacontyl group, n-nonatriacontyl group, n-tetracontyl group, 3-heptyl group, 2,
4,4-trimethylpentyl group, 8-heptadecyl group,
Isoheptadecyl group, methyl-branched isoheptadecyl group,
12-pentacosyl group, cyclohexylethyl group, 8-
Heptadecenyl group, 8,11-heptadecadienyl group,
8,11,14-heptadecatrienyl group, cholesteryl group, 11-methoxyheptadecyl group, 11-ethoxyheptadecyl group, 11-benzyloxyheptadecyl group, 11-methoxy-8-heptadecenyl group, 11-ethoxy- 8-heptadecenyl group, 11-benzyloxy-8-heptadecenyl group, 9,10- (isopropylidenedioxy) decyl group, 8,9- (isopropylidenedioxy) heptadecyl group, 8,9: 11,12-bis (Isopropylidenedioxy) heptadecyl group, 8,
9: 11,12: 14,15-Tris (isopropylidenedioxy) heptadecyl group, 11,12- (isopropylidenedioxy) -8-heptadecenyl group, 8- (6
-Hydroxyhexyloxy) octyl group, 8- [2-
(Hexyloxy) ethoxy] octyl group, 10- [2-
(Hexyloxy) ethoxy] decyl group, 10- [2-
(Butoxy) ethoxy] decyl group, 14- [2- (hexyloxy) ethoxy] tetradecyl group, 14- [2-
(2-hydroxyethoxy) ethoxy] tetradecyl group, 14- [2- (butoxy) ethoxy] tetradecyl group, 14- [polyoxypropylene (5)] tetradecyl group, 11- [2- (hexyloxy) ethoxycarbonyl] undecyl group , 11-acetoxy-8-heptadecenyl group and the like. Among them, R ⁷ is a saturated hydrocarbon group having a branched or cyclic structure having 7 to 25 carbon atoms, or the following formula:

[0027]

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[Wherein R ⁷ ′ is one having one or more carbon atoms having 6 to 1 carbon atoms selected from a double bond and an ether bond]
5 represents a hydrocarbon group, and n represents an integer of 7 to 15], and is particularly preferably a methyl-branched isoheptadecyl group, an 8-heptadecyl group, an 8-heptadecenyl group,
8,11-heptadecadienyl group, 8,11,14-heptadecatrienyl group, 11-methoxyheptadecyl group, 11-ethoxyheptadecyl group, 11-benzyloxyheptadecyl group, 11-methoxy-8- Heptadecenyl group, 11-benzyloxy-8-heptadecenyl group, 8,9- (isopropylidenedioxy) heptadecyl group, 8,9: 11,12-bis (isopropylidenedioxy) heptadecyl group, 8,9: 11, 12:14
15-tris (isopropylidenedioxy) heptadecyl group, 11,12- (isopropylidenedioxy) -8
-Heptadecenyl group, 8- [2- (hexyloxy) ethoxy] octyl group, 10- [2- (hexyloxy) ethoxy] decyl group, 10- [2- (butoxy) ethoxy]
Decyl group, 14- [2- (hexyloxy) ethoxy] tetradecyl group, 14- [2- (butoxy) ethoxy] tetradecyl group, 14- [polyoxypropylene (5)]
A group such as a tetradecyl group is preferred. Here, R ¹
When a methyl-branched isoheptadecyl group is used as the above, it is preferable to use an isoheptadecyl group derived from isoheptadecyl alcohol produced by reducing isoheptadecyl acid which is a by-product at the time of producing dimer acid.

R ⁸ and R ⁹ are the same or different and each represent a hydrogen atom or a hydrocarbon group having a linear, branched or cyclic structure having 1 to 40 carbon atoms which may contain an oxygen atom;
R ⁸ and R ⁹ may together form a divalent hydrocarbon group having 1 to 40 carbon atoms which may contain an oxygen atom. Good carbon number 1
The hydrocarbon group having a linear, branched or cyclic structure of from 40 to 40 may be saturated or unsaturated, and may be an alkoxy group, an alkenyloxy group, a hydroxyalkenyloxy group, an aralkyloxy group, an alkylidenedioxy group, a polyoxyalkylene. And a hydrocarbon group which may be substituted by a group, an acyl group, an acyloxy group and the like. Specific examples of the hydrocarbon group include methyl, ethyl, propyl, isopropyl,
Butyl, hexyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, icosyl, dotriacontyl, isostearyl, 2-ethylhexyl, 9-octadecenyl, 9,12-octadecadienyl, 9,12,16-octadecatrienyl Cholesteryl, 2-methoxyethyl, 3-methoxypropyl, 1
2-methoxyoctadecyl, 12-ethoxyoctadecyl, 12-benzyloxyotadecyl, 12-methoxy-
9-octadecenyl, 12-benzyloxy-9-octadecenyl, 9,10- (isopropylidenedioxy) octadecyl, 15- [polyoxypropylene (5)] pentadecyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl group and the like. Can be Among them, those having 1 to 21 carbon atoms are more preferable.

On the other hand, the divalent hydrocarbon group having 1 to 40 carbon atoms which may contain an oxygen atom and is formed by R ⁸ and R ⁹ together may be saturated or unsaturated, and may be an alkoxy group. , An alkenyloxy group, an aralkyloxy group, an alkylidenedioxy group, a polyoxyalkylene group, an acyl group, and a divalent hydrocarbon group which may be substituted with an azioxy group. -O-alkylene group or alkenylene-
An O-alkenylene group is more preferred, and specific examples include:
Examples include a tetramethylene, pentamethylene, and 3-oxopentamethylene group. Among them, those having 1 to 8 carbon atoms are more preferable.

More preferred examples of R ⁸ or R ⁹ include a hydrogen atom, methyl, ethyl, propyl, isopropyl, butyl, hexyl, octyl, decyl, dodecyl,
Tetradecyl, hexadecyl, octadecyl, methyl-branched isostearyl, 2-ethylhexyl, 9-octadecenyl, 9,12-octadecadienyl, 9,12,1
6-octadecatrienyl, 2-methoxyethyl, 3-
Methoxypropyl, 12-methoxyoctadecyl, 12
-Ethoxyotadecyl, 12-benzyloxyoctadecyl, 12-methoxy-9-octadecenyl, 12-benzyloxy-9-octadecenyl, 9,10- (isopropylidenedioxy) octadecyl, 15- [polyoxypropylene (5)] pentadecyl , 9- (6-hydroxyhexyloxy) nonyl, 3-hexadecyloxy-2-
Hydroxypropyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, benzyl groups.

R ¹⁰ is a carbonyl group or a methylene group. Examples of the hydrocarbon group having a linear, branched or cyclic structure having 1 to 40 carbon atoms which may contain an oxygen atom and represented by R ¹¹ include an ether bond (-O-), a ketone (-C (=
O)-), a carboxyl group (-COOH) and a hydrocarbon group which may have one or more of a carboxylate bond (-COO-). Specific examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl groups. , N
-Undecyl group, n-dodecyl group, n-tridecyl group,
n-tetradecyl group, n-pentadecyl group, n-hexadecyl group, n-heptadecyl group, n-octadecyl group,
n-nonadecyl group, n-icosyl group, n-henicosyl group, n-docosyl group, n-tricosyl group, n-tetracosyl group, n-pentacosyl group, n-hexacosyl group, n
-Heptacosyl group, n-octakosyl group, n-nonakosyl group, n-triacontyl group, n-hentriacontyl group, n-dotriacontyl group, n-tritriacontyl group, n-tetratriacontyl group, n-pentatria Contyl group, n-hexatriacontyl group, n-heptatriacontyl group, n-octatriacontyl group, n-nonatriacontyl group, n-tetracontyl group, 3-heptyl group, 2,4,4 -Trimethylpentyl group, 8-heptadecyl group, isoheptadecyl group, methyl branched isoheptadecyl group, 12-pentacosyl group, cyclohexylethyl group, 8-heptadecenyl group, 8,11-heptadecadienyl group, 8,11,14-heptadeca Trienyl group, cholesteryl group, 11-methoxyheptadecyl group,
11-ethoxyheptadecyl group, 11-benzyloxyheptadecyl group, 11-methoxy-8-heptadecenyl group, 11-ethoxy-8-heptadecenyl group, 11-benzyloxy-8-heptadecenyl group, 9,10- (isopropylidene Dendoxy) decyl group, 8,9- (isopropylidenedioxy) heptadecyl group, 8,9: 11,
12-bis (isopropylidenedioxy) heptadecyl group, 8,9: 11,12: 14,15-tris (isopropylidenedioxy) heptadecyl group, 11,12-
(Isopropylidenedioxy) -8-heptadecenyl group, 8- [2- (hexyloxy) ethoxy] octyl group, 10- [2- (hexyloxy) ethoxy] decyl group, 10- [2- (butoxy) ethoxy] decyl group , 1
4- [2- (hexyloxy) ethoxy] tetradecyl group, 14- [2- (butoxy) ethoxy] tetradecyl group, 14- [polyoxypropylene (5)] tetradecyl group, 11- [2- (hexyloxy) ethoxycarbonyl] And hydrocarbon groups such as undecyl group and 11-acetoxy-8-heptadecenyl group. Among them, R ¹¹ is a saturated hydrocarbon group having a branched or cyclic structure having 7 to 25 carbon atoms, or the following formula:

[0033]

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(Wherein R ¹¹ ′ is one having one or two or more carbon atoms having 6 to 1 carbon atoms selected from a double bond and an ether bond)
5 represents a hydrocarbon group, and m represents an integer of 7 to 15), and is particularly preferably a methyl-branched isoheptadecyl group, an 8-heptadecyl group, an 8-heptadecenyl group,
8,11-heptadecadienyl group, 8,11,14-heptadecatrienyl group, 11-methoxyheptadecyl group, 11-ethoxyheptadecyl group, 11-benzyloxyheptadecyl group, 11-methoxy-8- Heptadecenyl group, 11-benzyloxy-8-heptadecenyl group, 8,9- (isopropylidenedioxy) heptadecyl group, 8,9: 11,12-bis (isopropylidenedioxy) heptadecyl group, 8,9: 11, 12:14
15-tris (isopropylidenedioxy) heptadecyl group, 11,12- (isopropylidenedioxy) -8
-Heptadecenyl group, 8- [2- (hexyloxy) ethoxy] octyl group, 10- [2- (hexyloxy) ethoxy] decyl group, 10- [2- (butoxy) ethoxy]
Decyl group, 14- [2- (hexyloxy) ethoxy] tetradecyl group, 14- [2- (2-hydroxyethoxy) ethoxy] tetradecyl group, 8- [6- (2-hydroxyethoxy) hexyloxy] octyl group, 14-
[2- (butoxy) ethoxy] tetradecyl group, 14-
[Polyoxypropylene (5)] A group such as a tetradecyl group is preferred.

R ²⁴ represents a linear or branched hydrocarbon group having 1 to 22 carbon atoms which may be substituted by a hydroxyl group or an alkoxyl group.
Ethyl, propyl, butyl, pentyl, hexyl, octyl, decyl, dodecyl, tetradecyl, hexadecyl, octadecyl, eicosyl, docosyl, 1-methylethyl, 2-ethylhexyl, 2-hydroxyethyl,
3-methoxypropyl, 2-ethoxybutyl and the general formula (2)

[0036]

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In the formula, one of R ²⁵ and R ²⁶ is a hydrogen atom, and the other is a hydrogen atom or a linear or branched alkyl group having 1 to 12 carbon atoms. Among these, one of R ²⁵ and R ²⁶ is a hydrogen atom, and the other is a hydrogen atom or a group having 1 to 1 carbon atoms.
2 represents a straight-chain or branched-chain alkyl group], and particularly preferably 2,3-dihydroxypropyl, 2-hydroxy-3-methoxypropyl,
2-hydroxy-3-ethoxypropyl group.

Among the amide derivatives of the present invention, the most preferred compounds are the aforementioned R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
It is a compound in which R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ²⁴ , R ²⁵ and R ²⁶ are each a group in the above particularly preferred range.

The method for producing the amide derivative (1) of the present invention is not particularly limited, but it can be synthesized, for example, by the steps shown in the following reaction formula.

[0040]

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[Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁶ and R ⁷ are the same as those described above, R ¹⁹ and R ²⁰ are a hydrogen atom or a lower alkyl group, and R ^24a is In R ²⁴ , one of R ²⁵ and R ²⁶ is a hydrogen atom, and the other is a hydrogen atom or a linear or branched alkyl group having 1 to 12, preferably 1 to 6, carbon atoms. Is shown. R ²⁷ represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms. R ²⁸ represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms. That is, the glycidyl ether (5) is reacted with the amine (6) to obtain the amino alcohol derivative (7) (Step 1). On the other hand, the aminocarboxylic acid derivative (8) is reacted with the carboxylic acid derivative (9) or the acid chloride (10) to obtain the amidecarboxylic acid derivative (11) (Step 2).
Next, the compound (7) and the compound (11) are reacted in the presence of a dehydrating agent or a base catalyst to obtain a compound (12) (Step 3). By reacting the compound (12) thus obtained with an alkyl halide derivative in the presence of a base, an amide derivative (1-A1) which is a part of the target amide derivative (1) is obtained ( Step 4). Further, the compound (12) is reacted with a halogenated epoxide (13) by a phase transfer catalyst method to obtain a compound (14) (Step 5).
By reacting the compound (14) with the alcohol (15) in the presence of an acid or a base, an amide derivative (1-A2) which is a part of the target amide derivative (1) is obtained (step 6). . The combination of the amide derivative (1-A1) and (1-A2) is the amide derivative (1-A) according to the present invention.

The reaction in each step is as follows.

Step 1) Amino alcohol derivative (7)
Can be obtained by reacting glycidyl ether (5) and amine (6) without solvent, or with water or a lower alcohol such as methanol, ethanol or isopropanol, tetrahydrofuran,
It can be obtained by reacting at room temperature to 150 ° C. in an ether solvent such as dioxane and ethylene glycol dimethyl ether, a hydrocarbon solvent such as hexane, benzene, toluene and xylene, or an arbitrary mixed solvent thereof.

Step 2) On the other hand, the amide carboxylic acid derivative (11) is prepared by converting the amino carboxylic acid derivative (8) and the carboxylic acid derivative (9) or the acid chloride (10) without solvent or using chloroform, methylene chloride, -Halogenated hydrocarbon solvents such as dichloroethane, ether solvents such as tetrahydrofuran, dioxane and ethylene glycol dimethyl ether, hexane, benzene, toluene,
It can be obtained by reacting in a hydrocarbon solvent such as xylene, or an arbitrary mixed solvent thereof.

Step 3) The amino alcohol derivative (7) and amide carboxylic acid derivative (1) produced as described above
1) in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, or an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide, an alkaline earth metal hydroxide such as calcium hydroxide, potassium carbonate, etc. In the presence of a basic catalyst such as an alkali metal carbonate, an alkaline earth metal carbonate such as calcium carbonate, an alkali metal alcoholate such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, at normal pressure to 0.0
The amide derivative (12) can be produced by reacting at room temperature to 150 ° C. under a reduced pressure of 1 mmHg. At this time, the amount of the basic catalyst to be used is preferably 0.01 to 0.2 equivalent relative to the amino alcohol derivative (7), and the reaction proceeds rapidly when the alcohol produced by the reaction is removed outside the system. It is preferred.

Step 4) Next, the amide derivative (12) is reacted with an alkyl halide derivative in the presence of a base such as sodium hydroxide to give an amide derivative (1-A1) which is a part of the amide derivative of the present invention. ) Can be obtained. At this time, R ^24a is preferably primary, and tertiary is not preferred because it causes a dehydrohalogenation reaction.

Step 5) To synthesize the amide derivative represented by (1-A2) which is a part of the amide derivative (1) of the present invention, for example, 1 to 20 equivalents of the epoxide (13) is added to the amide derivative (12). ), Preferably epichlorohydrin without solvent or in water or an ether solvent such as tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, a hydrocarbon solvent such as hexane, benzene, toluene, xylene, or any mixed solvent thereof; 1 to 10 equivalents of an alkali metal hydroxide such as potassium hydroxide and sodium hydroxide, an alkaline earth metal hydroxide such as calcium hydroxide, an alkali metal carbonate such as potassium carbonate, and an alkaline earth metal such as calcium carbonate Amide induction by reaction at room temperature to 150 ° C in the presence of carbonate To produce (13). At this time, quaternary ammonium salts such as tetrabutylammonium bromide, tetrabutylammonium chloride, hexadecyltrimethylammonium chloride, hexadecyltrimethylammonium bromide, stearyltrimethylammonium chloride, bistetraoxyethylenestearylmethylammonium chloride, and lauryl dimethyl carbodi It is preferable to carry out the reaction in the presence of a phase transfer catalyst such as betaine such as ammonium betaine from the viewpoint of yield.

Step 6) Next, the amide derivative (14) is converted into an alkali metal hydroxide such as potassium hydroxide or sodium hydroxide, an alkaline earth metal hydroxide such as calcium hydroxide, or an alkali metal carbonate such as potassium carbonate. Salts, basic conditions such as alkaline earth metal carbonates such as calcium carbonate, or mineral acids such as sulfuric acid and hydrochloric acid, Lewis acids such as boron trifluoride and tin tetrachloride, and carboxylic acids such as acetic acid, tetradecanoic acid, and hexadecanoic acid. Acid, acidic conditions such as sulfonic acids such as p-toluenesulfonic acid, or base-acid mixed conditions, at room temperature to
At 300 ° C., the compound represented by the general formula R ²⁸ OH [wherein R ²⁸ represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms. (I.e., by hydration or alcohol addition) to produce (1-A2) which is a part of the amide derivative (1) of the present invention.

[0049]

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Wherein R ^{1 to} R ⁴ , R ⁸ , R ⁹ ,
R ^24a , R ²⁵ , R ²⁶ , R ²⁷ and R ²⁸ are the same as described above, and R ²¹ represents a hydrogen atom or a lower alkyl group. That is, an amine (16) and a dicarboxylic acid derivative (17)
And carboxylic acid derivative (1) in the presence of a dehydrating agent.
8) is obtained (step 7). The amide derivative (19) can be obtained by reacting the compound (7) obtained by the above reaction with the compound (18) in the presence of a dehydrating agent or a base catalyst (step 8).

The reaction in each step is as follows.

Step 7) The carboxylic acid derivative (18) can be obtained by reacting the amine (16) with the dicarboxylic acid derivative (17) without solvent or a halogenated hydrocarbon solvent such as chloroform, methylene chloride, 1,2-dichloroethane, tetrahydrofuran. The presence of a base such as a tertiary amine such as pyridine or triethylamine in an ether-based solvent such as hexane, dioxane or ethylene glycol dimethyl ether, a hydrocarbon-based solvent such as hexane, benzene, toluene, or xylene, or an arbitrary mixed solvent thereof. It can be obtained by reacting in the presence or absence of a dehydrating agent such as dicyclohexylcarbodiimide in the presence or absence.

Step 8) The amino alcohol derivative (7) produced as described above and the carboxylic acid derivative (18) are reacted in the presence of a dehydrating agent such as dicyclohexylcarbodiimide, or are reacted with potassium hydroxide or sodium hydroxide. Such as alkali metal hydroxides, alkaline earth metal hydroxides such as calcium hydroxide, alkali metal carbonates such as potassium carbonate, alkaline earth metal carbonates such as calcium carbonate,
By reacting at room temperature to 150 ° C. under a reduced pressure of normal pressure to 0.01 mmHg in the presence of a basic catalyst such as an alkali metal alcoholate such as sodium methoxide, sodium ethoxide and potassium tert-butoxide, the amide derivative ( 19) can be manufactured. At this time, the amount of the basic catalyst to be used is preferably 0.01 to 0.2 equivalent relative to the amino alcohol derivative (7), and the reaction proceeds rapidly when the alcohol produced by the reaction is removed outside the system. It is preferred.

The amino alcohol derivative (7) may be substituted with dicarboxylic acid di-lower alkyl ester (R ²¹ OCO-R ⁴ -COO
By reacting R ²¹ ), R ⁸ is R ³ -R ^2- ,
Compounds wherein R ⁹ is R ¹ O—CH ₂ CH (OH) CH ₂ — can be prepared. This reaction may be performed according to a general amidation reaction.

Steps 9, 10, and 11 are the same as steps 4, 5, and 6, respectively.

[0056]

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(Wherein R ¹ , R ² , R ³ , R ⁴ , R ¹¹ ,
^{R 24a, R 25, R 26} , R 27 and R ²⁸ have the same meanings as defined above, R ²² represents an alkyl group having 1 to 5 carbon atoms, R ²³
Represents a methyl group, a phenyl group or a p-toluyl group;
Represents a chlorine atom, a bromine atom or an iodine atom. )

That is, by reacting a hydroxy fatty acid (21) or a hydroxy fatty acid ester (21-1) with an alkyl halide (22) or a sulfonic acid alkyl ester (23) in the presence of a base, the etherified fatty acid ester (24) is reacted. ), And the amine derivative (7) is allowed to act in the presence of a base catalyst, and the resulting alcohol is reacted while distilling off the produced alcohol, whereby the amide derivative (25) can be produced.

Steps 14, 15, and 16 are the same as steps 4, 5, and 6, respectively.

[0060]

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(Where R¹, R^Two, R^Three, R^Four, R¹¹,
R^{twenty two}, R^24a, R^{twenty five}, R²⁶, R²⁷, R ²⁸Is the same as above)

That is, the hydroxy fatty acid ester (2
1-1) and a fatty acid (27) with a suitable dehydrating agent [for example,

[0063]

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To give an acyl fatty acid ester (29) or a hydroxy fatty acid ester (2
1-1) is reacted with a carboxylic acid chloride (28) to form an acyl fatty acid ester (29). The acyl fatty acid ester (29) is reacted with the amine derivative (7) obtained in the above-mentioned manner in the presence of a base catalyst to produce an alcohol. The amide derivative (30) can be produced by reacting while distilling off.

Steps 19, 20, and 21 are the same as steps 4, 5, and 6, respectively.

The amide derivative (1) of the present invention thus obtained has an effect of permeating the lipid membrane between the stratum corneum and improving (maintaining and reinforcing) the barrier function of the stratum corneum.

The amide derivative (1) of the present invention can be purified by a known method. When the amide derivative (1) is blended in the external preparation composition, it may be a purified product purified to a purity of 100%, or a mixture having a purity of 70 to 100% containing an intermediate or a reaction by-product without purification. Excellent effect and performance, and no problem in safety. The compounds of the present invention also include solvates represented by hydrates.

The external preparation composition of the present invention comprises the amide derivative (1) of the present invention contained in a base (carrier) usually used for external preparations. It is roughly divided into cosmetics.

Examples of the medicated skin external preparation include various ointments containing a pharmaceutically active ingredient. The ointment may be any of those based on an oily base and those based on an oil-in-water or water-in-oil emulsion base. The oil base is not particularly limited, and includes, for example, vegetable oil, animal oil, synthetic oil, fatty acid, and natural or synthetic glyceride. The medicinal component is not particularly limited, and includes, for example, an analgesic anti-inflammatory, an antipruritic, a bactericidal disinfectant,
Astringents, emollients, hormonal agents and the like can be used as needed.

When used as a cosmetic, in addition to the amide derivative (1) of the present invention, which is an essential component, oils, surfactants, humectants, and ultraviolet absorbers generally used as cosmetic components , Whitening agents, alcohols, chelating agents, pH adjusters, preservatives, thickeners, pigments, fragrances and the like can be arbitrarily combined.

As cosmetics, various forms, for example, water-in-oil type or oil-in-water type emulsified cosmetics, creams, emulsions, lotions, oily cosmetics, lipsticks, foundations, skin cleansers, hair tonics, It can be used as a cosmetic such as a hair styling agent, a hair rinse, a hair treatment, a hair restorer, and a hair restorer.

The compounding amount of the amide derivative (1) in the external preparation for skin of the present invention is not particularly limited. However, in the case of an emulsified external preparation for skin, it is usually 0.001 to 50% by weight (hereinafter referred to as the total composition). , Simply expressed as%). In the case of an oily skin external preparation based on a liquid hydrocarbon such as squalane, it is preferably 0.01 to 50% of the total composition, and in each case, particularly preferably 0%. 0.5-20%.

[0073]

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

Example 1 In the general formula (1), R ⁵ is

[0075]

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Production of the amide derivative (1-a) wherein the groups represented by R ^{1 to} R ⁷ and R ²⁴ are as follows:

[0077]

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(1) N- (3-hexadecyloxy-2-
Preparation of (hydroxypropyl) -N-3-methoxypropylamine (7-a): 3-methoxypropylamine (6-a) 743 was placed in a 2-liter flask equipped with a stirrer, a dropping funnel, a nitrogen inlet tube, and a distillation apparatus. 0.2 g (8.3
4 mol) and 150 ml of ethanol, and 165.9 g (0.56 mol) of hexadecylglycidyl ether (5-a) was added thereto while heating and stirring at 80 ° C. under a nitrogen atmosphere.
l) was added dropwise over 3 hours. After dropping, further 80 ° C
, And ethanol and excess 3-methoxypropylamine were distilled off by heating under reduced pressure, and the residue was purified by silica gel column chromatography.
196.5 g of the title compound (7-a) were obtained as a white solid (yield 91% vs. hexadecylglycidyl ether).

(2) Methyl 12-aminododecanoate (8
Production of -a): In a 3 liter flask equipped with a stirrer, 200.0 g of 12-aminododecanoic acid (0.93 mol
l), methanol 600g and sulfuric acid 100g (1.0mo
l) and stirred at 60 ° C. for 5 hours. After allowing the reaction mixture to cool, it was diluted with methylene chloride and neutralized with an aqueous sodium carbonate solution. After distilling off the solvent under reduced pressure, by purifying with alumina short column chromatography,
201.7 g of the title compound (8-a) was obtained (yield: 95).
%).

(3) Production of methyl-branched methyl isostearoylaminododecanoate (11-a): The compound obtained in the above (2) was placed in a 3 liter 4-neck flask equipped with a stirrer, a nitrogen inlet tube and a dropping funnel. 8-a) 135.3 g
(0.590 mol), 83.7 g of triethylamine
(0.827 mol) and 1.25 l of methylene chloride were charged, and 183 g (0.604 mol) of methyl-branched isostearic acid chloride was added dropwise over 2 hours while stirring at room temperature. After the completion of the dropwise addition, the mixture was further stirred for one hour to complete the reaction. The obtained reaction mixture was washed with saturated saline and concentrated under reduced pressure to give 288 g of the title compound (11-a) (yield: 99).
%).

(4) Preparation of amide derivative (12-a):
In a 2 liter 4-neck flask equipped with a stirrer, a dropping funnel and a distillation apparatus, the compound (7-
a) 196 g (0.506 mol) and 250 g (0.504 mol) of the compound (11-a) obtained in the above (3) were charged, and stirred at 80 ° C. in a nitrogen atmosphere at 28 ° C. for 28% methanol solution of sodium methoxide. 96 g (5.1 mol
%) Was added dropwise. After completion of dropping, the mixture was stirred at 80 ° C. for 1 hour,
The mixture was further stirred under reduced pressure (10 torr) at 80 ° C. for 10 hours to complete the reaction, thereby obtaining 423 g of the title compound (12-a) (yield: 99%).

(5) Glycidyl ether derivative (14-
Production of a): 503 g (0.591 mol) of the amide derivative (12-a) obtained in (4) above was placed in a 2-liter 5-neck flask equipped with a stirrer, a nitrogen inlet tube, and a distillation apparatus.
9.53 g of tetrabutylammonium bromide (0.
0296 mol), epichlorohydrin (13-a) 11
0 g (1.19 mol), 252 g of toluene and 298 g (3.58 mol) of a 48% aqueous sodium hydroxide solution were charged, and the mixture was stirred at 45 ° C. for 10 hours under a nitrogen atmosphere. After the obtained reaction mixture was washed with water at 60 ° C. six times, toluene and excess epichlorohydrin were distilled off by heating under reduced pressure, and 425 g of glycidyl ether derivative (14-a) (yield 79).
%).

(6) Production of amide derivative (1-a): In a 100 ml autoclave equipped with a stirrer,
50.2 g of the compound (14-a) obtained in (5) (5
5.3 mmol), 6.0 g (332 mmol) of water, 0.20 g (4.8 mmol) of sodium hydroxide and 0.1 g of myristic acid.
51 g (2.21 mmol) were charged, and the temperature was 160 ° C. in a closed system.
For 8 hours. After cooling the reaction mixture,
After washing with sodium chloride solution three times, dehydrated under reduced pressure to obtain 43 g of the desired glyceryl ether derivative (1-a) (yield 84
%).

The physical properties of the obtained amide derivative (1-a) are as follows.

Colorless crystals IR (Kbr, cm ^-1 ); 3320, 2930, 2860, 1640, 1540, 1470,
1380, 1260, 1220, 1130 ¹ H-NMR (CDCl ₃ , δ); 0.68-0.96 (m, 9H), 1.00-1.70 (m, 49
H), 1.70-1.92 (m, 2H), 2.12 (t, J = 7.6Hz, 2H), 2.31 (t, J = 7.
6Hz, 2H), 3.05-3.88 (m, 21H), 5.32-5.57 (m, 1H)

Example 2 In the general formula (1), R ⁵ is

[0087]

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Production of the amide derivative (1-b) wherein the groups represented by R ^{1 to} R ⁷ and R ²⁴ are as follows:

[0089]

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(1) Production of amide derivative (1-b): 50 g of the compound (14-a) obtained in (5) of Example 1 was placed in a 300 ml three-necked flask equipped with a stirrer.
(55.1 mmol) and 50 g of methanol at 40 ° C.
Heated. Here, a 10% methanol solution of sodium hydroxide was added dropwise over 1 hour. Then concentrated sulfuric acid 3.24
g was added dropwise to neutralize. 50 g of toluene was added and the layers were separated. After washing twice with 25 g of water, toluene was distilled off under reduced pressure to obtain 46 g of the desired amide derivative (1-b) (yield: 8).
8%).

The physical properties of the obtained amide derivative (1-b) are as follows.

Colorless crystals IR (Kbr, cm ^-1 ); 3310, 2930, 2850, 1640, 1540, 1470,
1390, 1260, 1210, 1130 ¹ H-NMR (CDCl ₃ , δ); 0.68-0.96 (m, 9H), 1.00-1.70 (m, 74
H), 1.70-1.92 (m, 2H), 2.12 (t, J = 7.6Hz, 2H), 2.31 (t, J = 7.
6Hz, 2H), 3.05-3.88 (m, 23H), 5.32-5.57 (m, 1H)

Example 3 In the general formula (1), R ⁵ is

[0094]

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Production of an amide derivative (1-c) wherein the groups represented by R ^{1 to} R ⁷ and R ²⁴ are as follows:

[0096]

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(1) Production of amide derivative (1-c): 50 g of the compound (14-a) obtained in (5) of Example 1 was placed in a 300 ml three-necked flask equipped with a stirrer.
(55.1 mmol) and 50 g of ethanol at 40 ° C.
Heated. Here, a 10% ethanol solution of potassium hydroxide was added dropwise over 1 hour. Then 3.24 g of concentrated sulfuric acid
Was added dropwise to neutralize. 50 g of toluene was added and the layers were separated. After washing twice with 25 g of water, toluene was distilled off under reduced pressure to obtain 47.3 g (yield 90%) of the target amide derivative (1-c).

The physical properties of the obtained amide derivative (1-c) are as follows.

Colorless crystal IR (Kbr, cm ^-1 ); 3320, 2930, 2860, 1640, 1540, 1470,
1390, 1250, 1210, 1130 ¹ H-NMR (CDCl ₃ , δ); 0.69-0.97 (m, 12H), 1.01-1.70 (m, 74
H), 1.69-1.92 (m, 2H), 2.11 (t, J = 7.6Hz, 2H), 2.30 (t, J = 7.
6Hz, 2H), 3.05-3.88 (m, 22H), 5.33-5.58 (m, 1H)

The following is a reference example.

Reference Example 1 Production of amide derivative (12-d) in which the groups represented by R ^{1 to} R ⁷ in amide derivative (12) are as follows:

[0102]

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(1) Production of 9,10: 12,13-bis (isopropylidenedioxy) octadecanoic acid (9-d): In a 2 liter flask equipped with a stirrer, 147.2 g of methyl linoleate (0. 5 mol), 203.2 g (1.18 mol) of metachloroperbenzoic acid and 500 ml of dichloromethane were charged and stirred at room temperature for 18 hours. After the reaction is completed, the precipitated metachlorobenzoic acid is filtered off,
After washing with an aqueous sodium thiosulfate solution, the solvent was distilled off under reduced pressure, and the residue was purified by alumina short column chromatography to obtain methyl 9,10: 12,13-diepoxyoctadecanoate.

Next, a second apparatus equipped with a stirrer and a dropping funnel was used.
In a liter flask, 1162 g (20 mol) of acetone
And 3.55 g of boron trifluoride-ether complex (25 mm
ol) and stirring at room temperature with 9,9 obtained above.
Methyl 10,12,13-diepoxyoctadecanoate was added dropwise over 3 hours. After the completion of the dropwise addition, stirring was further performed for 1 hour to complete the reaction. Next, sodium bicarbonate was added to the reaction mixture to neutralize it, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 9,10: 12,13-bis (isopropylidenedioxy) octadecanoic acid. 201.2 g of methyl was obtained (yield: 91%).

Next, the methyl 9,10: 12,13-bis (isopropylidenedioxy) octadecanoate 14 obtained above was placed in a 2 liter flask equipped with a stirrer.
1.6 g (0.32 mol) and 400 ml of ethanol were charged, and 35.8 g (0.64 mol) of potassium hydroxide was added thereto.
A solution consisting of 40 ml of water in which l) was dissolved and 400 ml of ethanol was added, followed by stirring at 50 ° C. for 1 hour. Then, the reaction mixture was neutralized with hydrochloric acid, extracted with chloroform, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (9-d) 1.
32.0 g was obtained (96% yield).

(2) Production of methyl 12- [9,10: 12,13-bis (isopropylidenedioxy) octadecanoylamino] dodecanoate (11-d): In a 1-liter flask equipped with a stirrer, 34.3 g (80 mmol) of the compound (9-d) obtained in the above (1), (2) in Example 1
22.9 g (100 mmol) of the compound (8-a) obtained in
18.4 g of hydroxybenzotriazole (120 mm
ol) and 500 ml of chloroform and stirring at room temperature while stirring N, N'-dicyclohexylcarbodiimide 3
3.0 g was added, and the mixture was further stirred at room temperature for 24 hours. After completion of the reaction, the precipitated white solid was separated by filtration, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 33.1 g of the title compound (11-d) (yield: 68%). .

(3) Production of amide derivative (12-d):
Compound (7-a) 1 obtained in (1) of Example 1 was placed in a 100 ml flask equipped with a stirrer, a dropping funnel and a distillation apparatus.
1.6 g (30 mmol) and the compound (1
1-d) 20.1 g (33 mmol) was charged, and 0.58 g (3 mmol) of a 28% methanol solution of sodium methoxide was added dropwise while stirring at 80 ° C. under a N ₂ atmosphere. After completion of the dropwise addition, the mixture is stirred at 80 ° C. for 1 hour, and further under reduced pressure (10 Torr).
The mixture was stirred at 80 ° C. for 6 hours to complete the reaction. After cooling the reaction mixture, the mixture was purified by silica gel column chromatography to obtain 25.6 g of the amide derivative (12-d).
Was obtained (88% yield). The resulting amide derivative (12-
The physical properties of d) are as follows.

Melting point: 46-48 ° C IR (KBr, cm ^-1 ); 3350, 2940, 2880, 1615, 1540, 1465,
1380, 1215, 1110, 720 ¹ H-NMR (CDCl ₃ , δ); 0.88 (br t, J = 6.4 Hz, 6H), 1.10-2.05
(m, 82H), 2.15 (t, J = 7.5Hz, 2H), 2.38 (t, J = 7.5Hz, 2H), 3.1
5-4.20 (m, 18H), 3.33 (s, 3H), 5.35-5.50 (m, 1H)

The amide derivative (12-d) obtained above
Can be used to produce an amide derivative (1-d) in which the groups represented by R ^{1 to} R ⁷ and R ²⁴ in the amide derivative (1) are as follows.

[0110]

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Reference Example 2 Production of amide derivative (12-e) in which the groups represented by R ^{1 to} R ⁷ in amide derivative (12) are as follows:

[0112]

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(1) N- (3-hexadecyloxy-2-
Production of (hydroxypropyl) -N-2-methoxyethylamine (7-e): In (1) of Example 1, 2-methoxyethylamine (6-e) was used instead of 3-methoxypropylamine (6-a). Except for using, the production was carried out in the same manner as in Example 1, (1) to obtain the title compound (7-e).

(2) Production of methyl 12-linoleoylaminododecanoate (11-e): The compound obtained in (2) of Example 1 in a 1-liter flask equipped with a stirrer, a dropping funnel and a nitrogen inlet tube. (8-a) 45.9 g (200 mmo
l), 30.4 g (300 mmol) of triethylamine and 300 g of methylene chloride were charged and stirred at room temperature.
Linoleic acid chloride (10-e) 65.8 g (220 mm
ol) was added dropwise over 1 hour. After the completion of the dropwise addition, the mixture was further stirred at room temperature for 1 hour to complete the reaction.

The obtained reaction mixture was washed with saturated saline, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (11-e).
88.3 g were obtained (yield 90%).

(3) Production of amide derivative (12-e):
In (3) of Reference Example 1, the compound (7-e) obtained in the above (1) is used instead of the compound (7-a), and the compound (7-e) obtained in the above (2) is used instead of the compound (11-d). Compound (1
Except that 1-e) was used, the production was carried out in the same manner as in (3) of Reference Example 1 to obtain an amide derivative (12-e). The physical properties of the obtained amide derivative (1-b) are as follows.

Melting point: 56-58 ° C IR (KBr, cm ^-1 ); 3320, 2925, 2860, 1640, 1615, 1545,
1470, 1210, 1110, 1060, 720 ¹ H-NMR (CDCl ₃ , δ); 0.80-1.00 (m, 6H), 1.10-1.80 (m, 62
H), 1.95-2.15 (m, 4H), 2.15 (t, J = 7.5Hz, 2H), 2.30-2.50
(m, 2H), 2.70-2.90 (m, 2H), 3.15-4.05 (m, 17H), 2.50-5.5
0 (m, 5H)

The amide derivative (12-e) obtained above
Can be used to produce an amide derivative (1-e) in which the groups represented by R ^{1 to} R ⁷ and R ²⁴ in the amide derivative (1) are as follows.

[0119]

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Reference Example 3 Production of an amide derivative (12-f) in which the groups represented by R ^{1 to} R ⁷ in the amide derivative (12) are as follows:

[0121]

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(1) Production of 12-methoxy-9-octadecenoic acid (9-f): In a 1-liter flask equipped with a stirrer, a dropping funnel and a condenser, 24 g (0.6 mol) of 60% sodium hydride and Dimethylformamide 50
Then, a solution of 163.3 g (0.5 mol) of ethyl ricinoleate in 142 g (1.0 mol) of methyl iodide was added dropwise over 1 hour while stirring at 40 ° C. under an N ₂ atmosphere. Stirred at 40 ° C. for 6 hours. Hexane was added to the obtained reaction mixture, washed with an aqueous ammonium chloride solution and an aqueous sodium thiosulfate solution, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 155.8 g of ethyl 12-methoxy-9-octadecenoate. Was obtained (92% yield).

Next, 68.1 g (0.2 mol) of ethyl 12-methoxy-9-octadecenoate obtained above and 600 ml of ethanol were placed in a 1-liter flask equipped with a stirrer.
And 45 g of 50% aqueous potassium hydroxide solution.
Stirred at C for 4 hours. Hexane was added to the obtained reaction mixture, and the mixture was neutralized with 3N hydrochloric acid and washed with saturated saline. After concentration under reduced pressure, the residue was purified by silica gel column chromatography to give 58.3 g of the title compound (9-f).
Was obtained (93% yield).

(2) Preparation of amide derivative (12-f):
In Reference Examples 1 (2) and (3), compound (9-d)
Was performed in the same manner as in (2) to (3) of Reference Example 1 except that the compound (9-f) obtained in the above (1) was used instead of to obtain an amide derivative (12-f). The physical properties of the obtained amide derivative (12-f) are as follows.

Melting point: 56-58 ° C IR (KBr, cm ^-1 ); 3310, 2900, 1610, 1545, 1470, 1110,
950, 720 ¹ H-NMR (CDCl ₃ , δ); 0.88 (br t, J = 6.4 Hz, 6H), 1.10-1.78
(m, 66H) 1.83 (t, J = 6.0Hz, 2H), 1.95-2.10 (m, 2H), 2.15 (t,
J = 7.6Hz, 2H), 2.18-2.30 (m, 2H), 2.36 (t, J = 7.5Hz, 2H),
3.10-3.60 (m, 14H), 3.33 (s, 3H), 3.34 (s, 3H), 3.85-4.05
(m, 1H), 5.30-5.60 (m, 3H)

The amide derivative (12-f) obtained above
Can be used to produce an amide derivative (1-f) in which the groups represented by R ^{1 to} R ⁷ and R ²⁴ in the amide derivative (1) are as follows.

[0127]

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Reference Example 4 Production of an amide derivative (12-g) in which the groups represented by R ^{1 to} R ⁷ in the amide derivative (12) are as follows:

[0129]

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The compound (1-d) produced in Reference Example 3 was placed in a 1-liter flask equipped with a stirrer and a hydrogen inlet tube.
9.1 g (10.3 mmol), 1.5 g of 5% palladium carbon and 370 ml of ethanol were charged, and the mixture was stirred at room temperature for 22 hours under a hydrogen atmosphere. The obtained reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 9.06 g of an amide derivative (12-g) (yield: 99%). The physical properties of the obtained amide derivative (12-g) are as follows.

Melting point: 58-60 ° C IR (KBr, cm ^-1 ); 3330, 2920, 1630, 1550, 1470, 1205,
1110, 720 ¹ H-NMR (CDCl ₃ , δ); 0.88 (br t, J = 6.2 Hz, 6H), 1.05-1.80
(m, 74H), 1.83 (t, J = 5.9Hz, 2H), 2.15 (t, J = 7.6Hz, 2H), 2.3
6 (t, J = 7.5Hz, 2H), 3.05-3.60 (m, 14H), 3.31 (s, 3H), 3.33
(s, 3H), 3.85-4.00 (m, 1H), 5.35-5.50 (m, 1H)

The amide derivative (12-g) obtained above
Can be used to produce an amide derivative (1-g) in which the groups represented by R ^{1 to} R ⁷ and R ²⁴ in the amide derivative (1) are as follows.

[0133]

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Reference Example 5 Production of an amide derivative (12-h) in which the groups represented by R ^{1 to} R ⁷ in the amide derivative (12) are as follows:

[0135]

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(1) Production of 12-benzyloxy-9-octadecenoic acid (9-h): The procedure of Reference Example 3 was repeated except that benzyl bromide was used instead of methyl iodide in (1) of Reference Example 3. Production was carried out in the same manner as in (1) to obtain the title compound (9-h).

(2) Preparation of amide derivative (12-h):
In Reference Examples 1 (2) and (3), compound (9-d)
Was carried out in the same manner as in (2) to (3) of Reference Example 1 except that the compound (9-h) obtained in the above (1) was used instead of to obtain an amide derivative (12-h). The physical properties of the obtained amide derivative (12-h) are as follows.

Melting point: 56-58 ° C IR (KBr, cm ^-1 ); 3335, 2900, 1625, 1550, 1470, 1105,
720 ¹ H-NMR (CDCl ₃ , δ); 0.88 (br t, J = 6.4 Hz, 6H), 1.10-1.75
(m, 66H), 1.83 (t, J = 5.9Hz, 2H), 1.95-2.10 (m, 2H), 2.14
(t, J = 7.6Hz, 2H), 2.25-2.45 (m, 2H), 2.37 (t, J = 7.6Hz, 2
H), 3.15-3.60 (m, 14H), 3.33 (s, 3H), 3.85-4.00 (m, 1H),
4.53 (dd, J = 11.7Hz, 20.0Hz, 2H), 5.30-5.55 (m, 3H), 7.20-
7.45 (m, 5H)

The amide derivative (12-h) obtained above
Can be used to produce an amide derivative (1-h) in which the groups represented by R ^{1 to} R ⁷ and R ²⁴ in the amide derivative (1) are as follows.

[0140]

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Reference Example 6 Production of an amide derivative (12-i) in which the groups represented by R ^{1 to} R ⁷ in the amide derivative (12) are as follows:

[0142]

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(1) Production of 12-benzyloxy-octadecanoic acid (9-i): In (1) of Reference Example 3, methyl 12-hydroxyoctadecanoate was used in place of ethyl ricinoleate, and methyl iodide was used. Production was carried out in the same manner as in (1) of Reference Example 3 except that benzyl bromide was used instead, to obtain the title compound (9-i).

(2) Production of amide derivative (12-i):
In Reference Examples 1 (2) and (3), compound (9-d)
Was performed in the same manner as in (2) to (3) of Example 1 except that the compound (9-i) obtained in the above (1) was used instead of to obtain an amide derivative (12-i). The physical properties of the obtained amide derivative (12-i) are as follows.

Melting point: 59-61 ° C IR (KBr, cm ^-1 ); 3320, 2900, 1615, 1545, 1470, 1110,
720 ¹ H-NMR (CDCl ₃ , δ); 0.88 (br t, J = 6.5 Hz, 6H), 1.00-1.95
(m, 76H), 2.15 (t, J = 7.5Hz, 2H), 2.36 (t, J = 7.5Hz, 2H), 3.1
5-3.60 (m, 14H), 3.33 (s, 3H), 3.85-4.00 (m, 1H), 4.50 (s,
2H), 5.35-5.50 (m, 1H), 7.20-7.45 (m, 5H)

The amide derivative (12-i) obtained above
Can be used to produce an amide derivative (1-i) in which the groups represented by R ^{1 to} R ⁷ and R ²⁴ in the amide derivative (1) are as follows.

[0147]

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Reference Example 7 Production of amide derivative (12-k) in which groups represented by R ^{1 to} R ⁷ in amide derivative (12) are as follows:

[0149]

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(1) Production of N- (3-methyl-branched isostearoxy-2-hydroxypropyl) -N-ethylamine (7-k): In Example 1, (1), 3-methoxypropylamine (6 Example 1 except that ethylamine (6-k) was used instead of -d) and methyl-branched isostearylglycidylether (5-k) was used instead of hexadecylglycidylether (5-d).
Production was carried out in the same manner as in (1) to obtain the title compound (7-k).

(2) Preparation of amide derivative (12-k):
In (3) of Reference Example 1, the compound (7-k) obtained in the above (1) is used instead of the compound (7-d), and (3) of Example 1 is used instead of the compound (11-d). )), Except that the compound (11-a) obtained in (1) was used, to produce an amide derivative (12-k) in the same manner as in (5) of Reference Example 1. The physical properties of the obtained amide derivative (12-k) are as follows.

Melting point: 61-64 ° C IR (KBr, cm ^-1 ); 3400, 2930, 2865, 1625, 1540, 1470, white solid
1380, 1230, 1210, 1110, 720 ¹ H-NMR (CDCl ₃ , δ); 0.75-1.00 (m, 12H), 1.00-1.85 (m, 77
H), 2.15 (t, J = 7.6Hz, 2H), 2.35 (t, J = 7.6Hz, 2H), 3.15-3.6
0 (m, 11H), 3.80-4.00 (m, 1H), 5.35-5.50 (m, 1H)

The amide derivative (12-k) obtained above
Can be used to produce an amide derivative (1-k) in which the groups represented by R ^{1 to} R ⁷ and R ²⁴ in the amide derivative (1) are as follows.

[0154]

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Reference Example 8 Production of an amide derivative (12-1) in which the groups represented by R ^{1 to} R ⁷ in the amide derivative (12) are as follows:

[0156]

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(1) Production of methyl octadecanoylaminodecanoate (11-1): In (2) of Reference Example 2,
The title compound (11-l) was obtained in the same manner as in (2) of Reference Example 2, except that octadecanoic acid chloride (10-l) was used instead of linoleic acid chloride (10-e).

(2) Preparation of amide derivative (12-1):
Production was carried out in the same manner as in (3) of Reference Example 1, except that the compound (11-l) obtained in the above (1) was used in place of the compound (11-d) in (3) of Reference Example 1. The amide derivative (12-1) was obtained. The resulting amide derivative (12-
The physical properties of 1) are as follows.

Melting point; 63-64 ° C IR (KBr, cm ^-1 ); 3335, 2925, 1650, 1620, 1550, 1470,
1215, 1010, 720 ¹ H-NMR (CDCl ₃ , δ); 0.88 (br t, J = 6.4 Hz, 6H), 1.05-1.75
(m, 76H), 1.83 (t, J = 5.8Hz, 2H), 2.15 (t, J = 7.5Hz, 2H), 2.3
6 (t, J = 7.5Hz, 2H), 3.15-3.60 (m, 13H), 3.33 (s, 3H), 3.85
-4.00 (m, 1H), 5.30-5.60 (m, 1H)

The amide derivative (12-1) obtained above
Can be used to produce an amide derivative (1-1) in which the groups represented by R ^{1 to} R ⁷ and R ²⁴ in the amide derivative (1) are as follows.

[0161]

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Reference Example 9 Production of an amide derivative (12-m) in which the groups represented by R ^{1 to} R ⁷ in the amide derivative (12) are as follows:

[0163]

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(1) N- (3-butyroxy-2-hydroxypropyl) -N-3-methoxypropylamine (7
Preparation of -m): In the same manner as in (1) of Example 1, except that butyl glycidyl ether (5-m) is used instead of hexadecyl glycidyl ether (5-a) in (1) of Example 1. The production was performed to obtain the title compound (7-m).

(2) Preparation of amide derivative (12-m):
In (3) of Reference Example 1, the compound (7-m) obtained in the above (1) is used instead of the compound (7-a), and (3) of Example 1 is used instead of the compound (11-d). ) Was performed in the same manner as in (3) of Reference Example 1 except that the compound (11-a) obtained in (1) was used to obtain an amide derivative (12-m). The physical properties of the obtained amide derivative (12-m) are as follows.

Colorless oil IR (NaCl, cm ^-1 ); 3320, 2930, 2860, 1630, 1550, 146
0, 1380, 1220, 1120, 750 ¹ H-NMR (CDCl ₃ , δ); 0.70-0.95 (m, 9H), 1.10-1.71 (m, 49
H), 1.72-1.94 (m, 2H), 2.12 (t, J = 7.6Hz, 2H), 2.33 (t, J = 7.
6Hz, 2H), 3.14-3.60 (m, 13H), 3.79-4.00 (m, 1H), 5.34-5.
56 (m, 1H)

The amide derivative (12-m) obtained above
Can be used to produce an amide derivative (1-m) in which the groups represented by R ^{1 to} R ⁷ and R ²⁴ in the amide derivative (1) are as follows.

[0168]

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Reference Example 10 Production of amide derivative (12-n) in which groups represented by R ^{1 to} R ⁷ in amide derivative (12) are as follows:

[0170]

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(1) Production of N- (3-octyloxy-2-hydroxypropyl) -N-3-methoxypropylamine (7-n): In Example 1, (1), hexadecylglycidyl ether (5- Except that octyl glycidyl ether (5-n) is used instead of a), the production was carried out in the same manner as in Example 1, (1), and the title compound (7-
n) was obtained.

(2) Production of amide derivative (12-n):
In (3) of Reference Example 1, the compound (7-n) obtained in the above (1) was used instead of the compound (7-a), and (3) of Example 1 was used instead of the compound (11-n). ), Except that the compound (11-a) obtained in (1) was used, to produce an amide derivative (12-n) in the same manner as in (3) of Reference Example 1. The physical properties of the obtained amide derivative (12-n) are as follows.

White solid IR (KBr, cm ^-1 ); 3320, 2930, 2860, 1630, 1550, 1470,
1380, 1260, 1210, 1120, 720 ¹ H-NMR (CDCl ₃ , δ); 0.72-0.99 (m, 9H), 0.99-1.95 (m, 57
H), 1.83 (t, J = 7.6Hz, 2H), 2.16 (t, J = 7.6Hz, 2H), 2.39 (t, J
= 7.6Hz, 2H), 3.10-3.62 (m, 13H), 3.33 (s, 3H), 3.82-4.02
(m, 1H), 5.35-5.58 (m, 1H)

The amide derivative (12-n) obtained above
Can be used to produce an amide derivative (1-n) in which the groups represented by R ^{1 to} R ⁷ and R ²⁴ in the amide derivative (1) are as follows.

[0175]

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Reference Example 11 Production of an amide derivative (12-o) in which the groups represented by R ^{1 to} R ⁷ in the amide derivative (12) are as follows:

[0177]

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(1) Production of N- (3-dodecyloxy-2-hydroxypropyl) -N-3-methoxypropylamine (7-o): In Example 1, (1), hexadecylglycidyl ether (5- Except that dodecylglycidyl ether (5-o) is used instead of a), the production was carried out in the same manner as in (1) of Reference Example 1, and the title compound (7-
o) was obtained.

(2) Preparation of amide derivative (12-o):
In (3) of Reference Example 1, the compound (7-o) obtained in the above (1) was used instead of the compound (7-a), and (3) of Example 1 was used instead of the compound (11-d). )) Was performed in the same manner as in (3) of Reference Example 1 except that the compound (11-a) obtained in (1) was used to obtain an amide derivative (12-o). The physical properties of the obtained amide derivative (12-o) are as follows.

White solid IR (KBr, cm ^-1 ); 3330, 2930, 1650, 1560, 1470, 1380,
1260, 1215, 1100,750 ¹ H-NMR (CDCl ₃ , δ); 0.72-1.00 (m, 9H), 1.00-1.95 (m, 65
H), 1.83 (t, J = 7.6Hz, 2H), 2.16 (t, J = 7.6Hz, 2H), 2.38 (t, J
= 7.6Hz, 2H), 3.10-3.58 (m, 13H), 3.33 (s, 3H), 3.80-4.00
(m, 1H), 5.35-5.60 (m, 1H)

The amide derivative (12-o) obtained above
Can be used to produce an amide derivative (1-o) in which the groups represented by R ^{1 to} R ⁷ and R ²⁴ in the amide derivative (1) are as follows.

[0182]

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Reference Example 12 Production of an amide derivative (12-p) in which the groups represented by R ^{1 to} R ⁷ in the amide derivative (12) are as follows:

[0184]

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(1) N- (3-octadecyloxy-2-
Production of (hydroxypropyl) -N-3-methoxypropylamine (7-p): In Example (1), octadecyl glycidyl ether (5-p) is used instead of hexadecyl glycidyl ether (5-a). Except for this, the production was carried out in the same manner as (1) of Example 1 to obtain the title compound (7-p).

(2) Production of amide derivative (12-p):
In (3) of Reference Example 1, the compound (7-p) obtained in the above (1) was used instead of the compound (7-a), and (3) of Example 1 was used instead of the compound (11-d). ) Was performed in the same manner as in (3) of Reference Example 1 except that the compound (11-a) obtained in (1) was used to obtain an amide derivative (12-p). The physical properties of the obtained amide derivative (12-p) are as follows.

White solid Melting point: 66.5 to 69 ° C IR (KBr, cm ^-1 ); 3400, 2930, 2860, 1640, 1550, 1470,
1380, 1260, 1210, 1110, 720 ¹ H-NMR (CDCl ₃ , δ); 0.72-0.98 (m, 9H), 1.05-1.80 (m, 77
H), 1.81-1.94 (m, 2H), 2.13 (t, J = 7.6Hz, 2H), 2.35 (t, J =
7.6Hz, 2H), 3.15-3.60 (m, 13H), 3.40 (s, 3H), 3.79-4.00
(m, 1H), 5.35-5.52 (m, 1H)

The amide derivative (12-p) obtained above
Can be used to produce an amide derivative (1-p) in which the groups represented by R ^{1 to} R ⁷ and R ²⁴ in the amide derivative (1) are as follows.

[0189]

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Reference Example 13 Production of an amide derivative (1-r) in which the groups represented by R ^{1 to} R ⁷ in the amide derivative (12) are as follows:

[0191]

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(1) Production of N- (3-methyl-branched isostearyloxy-2-hydroxypropyl) -N-3-methoxypropylamine (7-q): In Example 1, (1), hexadecylglycidyl was used. Production was carried out in the same manner as (1) of Example 1 except that methyl-branched isostearylglycidyl ether (5-k) was used instead of ether (5-a), to obtain the title compound (7-q).

(2) Preparation of amide derivative (1-q): The compound (7-q) obtained in the above (1) was used in place of the compound (7-a) in (3) of Reference Example 1, Further, except that the compound (11-a) obtained in (3) of Example 1 was used instead of the compound (11-d), the production was carried out in the same manner as (3) of Reference Example 1, and the amide derivative (12 -Q) was obtained. The physical properties of the obtained amide derivative (12-q) are as follows.

White viscous solid IR (KBr, cm ^-1 ); 3320, 2930, 2860, 1640, 1550, 1470,
1380, 1220, 1110,750 ¹ H-NMR (CDCl ₃ , δ); 0.70-1.00 (m, 12H), 1.02-1.82 (m, 74
H), 1.82-1.97 (m, 4H), 2.14 (t, J = 7.6Hz, 2H), 2.34 (t, J =
7.6Hz, 2H), 3.14-3.60 (m, 13H), 3.38 (s, 3H), 3.80-4.00
(m, 1H), 5.34-5.50 (m, 1H)

The amide derivative (12-q) obtained above
Can be used to produce an amide derivative (1-q) in which the groups represented by R ^{1 to} R ⁷ and R ²⁴ in the amide derivative (1) are as follows.

[0196]

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Reference Example 14 Production of amide derivative (12-r) in which the groups represented by R ^{1 to} R ⁷ in amide derivative (12) are as follows:

[0198]

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(1) Production of N- (3-docosanoloxy-2-hydroxypropyl) -N-3-methoxypropylamine (7-r): In Example 1, (1), hexadecylglycidyl ether (5- Except that docosanyl glycidyl ether (5-r) is used instead of a), the production was carried out in the same manner as (1) of Example 1, and the title compound (7-
r) was obtained.

(2) Preparation of amide derivative (12-r):
In (3) of Reference Example 1, the compound (7-r) obtained in the above (1) was used instead of the compound (7-a), and (3) of Example 1 was used instead of the compound (11-d). ) Was performed in the same manner as in (3) of Reference Example 1 except that the compound (12-j) obtained in (1) was used to obtain an amide derivative (12-r). The physical properties of the obtained amide derivative (12-r) are as follows.

White solid Melting point: 69.5-71.0 ° C IR (KBr, cm ^-1 ); 3400, 2930, 2860, 1640, 1620, 1550,
1470, 1380, 1260, 1210, 1110, 720 ¹ H-NMR (CDCl ₃ , δ); 0.71-1.00 (m, 9H), 1.02-1.80 (m, 85
H), 1.81-1.97 (m, 2H), 2.15 (t, J = 7.6Hz, 2H), 2.34 (t, J =
7.6Hz, 2H), 3.14-3.60 (m, 13H), 3.38 (s, 3H), 3.78-4.00
(m, 1H), 5.34-5.52 (m, 1H)

The amide derivative (12-r) obtained above
Can be used to produce an amide derivative (1-r) in which the groups represented by R ^{1 to} R ⁷ and R ²⁴ in the amide derivative (1) are as follows.

[0203]

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Reference Example 15 Production of an amide derivative (19-s) in which the groups represented by R ^{1 to} R ⁵ , R ⁸ and R ⁹ in the amide derivative (19) are as follows:

[0205]

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(1) Production of 9,12-octadecadienylamine (16-s): In a 1-liter flask equipped with a stirrer, a dropping funnel and a nitrogen inlet tube, 50 ml of tetrahydrofuran and 5.69 g of lithium aluminum hydride were placed.
(0.15 mol), and 14.0 g (0.05 mol) of linoleamide was added thereto while stirring at room temperature under a nitrogen atmosphere.
l) was added dropwise over 30 minutes. After dropping is completed, another 60
After stirring at 12 ° C. for 12 hours, sodium sulfate decahydrate 1
6 g (0.05 mol) was added to decompose excess lithium aluminum hydride. After the solid content in the system was removed by filtration and the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography to obtain 9.05 g of the title compound (16-s) as a white solid ( Yield 68
% Vs. linoleic acid amide).

(2) Monomethyl dodecane diacid (17-
Production of s): 69.1 g of dodecane diacid (0.3 mol) was placed in a 2 liter flask equipped with a stirrer and a nitrogen inlet tube.
l), methanol 500 ml and sulfuric acid 1.47 g (0.0
15 mol) and stirred under heating at 60 ° C. for 24 hours under a nitrogen atmosphere. This was washed with 1 liter of water, the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (17-
s) 36.3 g were obtained (50% yield vs. dodecane diacid).

(3) Methyl 11- (N- (9,12-octadecadienyl) carbamoyl) undecanoate (18)
-S) production: 500 equipped with stirrer and nitrogen inlet tube
In a ml flask, monomethyl dodecane diacid (17-s)
4.40 g (18 mmol), 2.33 g (18 mmol) of 9,12-octadecadienylamine (16-s), 3.04 g of 1-hydroxybenzotriazole (22.5 mmol)
l), 4.64 g of dicyclohexylcarbodiimide (2
2.5 mmol) and 150 ml of chloroform, and the mixture was stirred at room temperature for 24 hours. The resulting precipitate was removed by filtration, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 5.12 g of the title compound (18-s) as a white solid (yield). 80% vs. monomethyl dodecane diacid (17-s)).

(4) Production of amide derivative (19-s):
1.72 g of the compound (7-e) obtained in (1) of Reference Example 2 was placed in a 50 ml flask equipped with a stirrer and a nitrogen inlet tube.
(4.8 mmol), the compound (18-s) obtained in the above (3)
1.42 g (4.0 mmol) and 0.077 g (0.4 mmol) of a 28% sodium methoxide / methanol solution were charged, and heated and stirred at 80 ° C./10 Torr under reduced pressure for 12 hours. The obtained crude product was purified by silica gel column chromatography to give 2.92 g of the title compound (19-s) as a white solid (80% yield versus compound (18-s)). The physical properties of the obtained amide derivative (19-s) are as follows.

Melting point: 57-59 ° C IR (NaCl, cm ^-1 ); 3324, 2920, 2854, 1620, 1540, 1458,
1426, 1366, 1264, 1102 ¹ H-NMR (CDCl ₃ , δ); 0.86-0.89 (m, 6H), 1.10-1.70 (m, 62
H), 2.00-2.18 (m, 6H), 2.39 (t, J = 7.5Hz, 2H), 2.77 (t, J =
5.7Hz, 2H), 3.18-4.24 (m, 17H), 5.26-5.42 (m, 5H)

The amide derivative (19-s) obtained above
And R ^{1 to} R ⁵ , R in the amide derivative (1)
^An amide derivative (1-s) in which the groups represented by ⁸ , R ⁹ and R ²⁴ are as follows can be produced.

[0212]

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Reference Example 16 Production of an amide derivative (19-t) in which the groups represented by R ^{1 to} R ⁵ , R ⁸ and R ⁹ in the amide derivative (19) are as follows:

[0214]

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(1) Isostearylamine (16-t)
Production of: In Reference Example 15 (1), except that isostearamide was used instead of linoleamide,
Production was carried out in the same manner as in (1) of Reference Example 15, to obtain the title compound (16-t).

(2) Production of methyl 11- (N-isostearylcarbamoyl) undecanoate (18-t): In (3) of Reference Example 15, obtained in the above (1) instead of (16-s) in (3). Except for using the compound (16-t), the production was carried out in the same manner as in (3) of Reference Example 15, and the title compound (18
-T) was obtained.

(3) Production of amide derivative (19-t):
In (4) of Reference Example 15, the compound (7-a) obtained in Example 1 (1) is substituted for the compound (7-e), and the compound (18-s) is replaced with the compound (18-s). Except that the obtained compound (18-t) was used, the production was carried out in the same manner as in (4) of Reference Example 15 to obtain the desired amide derivative (19-t). The physical properties of the obtained amide derivative (19-t) are as follows.

White solid Melting point; 61-64 ° C IR (NaCl, cm ^-1 ); 3416, 3328, 2924, 2854, 1644, 1616,
1548, 1470, 1378,1214, 1112, 952, 722 1 H-NMR (CDCl 3, δ); 0.82-0.91 (m, 9H), 1.05-1.76 (m, 74
H), 1.83 (m, 2H), 2.15 (t, J = 7.6Hz, 2H), 2.37 (t, J = 7.5Hz,
2H), 3.18-3.59 (m, 16H), 3.90 (m, 1H), 5.41 (br, 1H)

The amide derivative (19-t) obtained above
And R ^{1 to} R ⁵ , R
^An amide derivative (1-t) in which the groups represented by ⁸ , R ⁹ and R ²⁴ are as follows can be produced.

[0220]

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Reference Example 17 Production of an amide derivative (19-u) in which the groups represented by R ^{1 to} R ⁵ , R ⁸ and R ⁹ in the amide derivative (19) are as follows:

[0222]

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(1) N- (3-hexadecyloxy-2-
Production of (hydroxypropyl) -N-ethylamine (7-u): A 2-liter flask equipped with a stirrer, a dropping funnel, a nitrogen inlet tube and a distillation device was charged with 500 ml (about 6 mol) of a 70% aqueous solution of ethylamine, and the mixture was stirred at room temperature under nitrogen. While stirring under an atmosphere, a solution of 119 g (0.4 mol) of hexadecylglycidyl ether dissolved in 500 ml of ethanol was added dropwise thereto over 1 hour. After completion of the dropwise addition, the mixture was further stirred at room temperature for 5 hours, and then ethanol, water and excess ethylamine were distilled off by heating under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (7-u) as a white solid. 133 g (96% yield vs. hexadecyl glycidyl ether).

(2) Production of methyl 11- (4-morpholinecarbonyl) undecanoate (18-u): Reference Example 1
In (3) of 5, except that morpholine (16-u) was used instead of (16-s), the production was carried out in the same manner as (3) of Reference Example 15 to obtain the title compound (18-u). .

(3) Production of amide derivative (19-u):
In Reference Example 15 (4), the production was carried out in the same manner as in Reference Example 15 (4), except that the compound (18-u) obtained in the above (2) was used instead of the compound (18-s). An amide derivative (19-u) was obtained. The resulting amide derivative (1
Physical properties of 9-u) are as follows.

Colorless oil IR (NaCl, cm ^-1 ); 2924, 2854, 1620, 1540, 1470, 1384,
1224, 1120, 768 ¹ H-NMR (CDCl ₃ , δ); 0.88 (t, J = 6.3 Hz, 6H), 1.07-1.75 (m,
47H), 2.28-2.41 (m, J = 7.5Hz, 4H), 3.29-4.10 (m, 18H)

The amide derivative (19-u) obtained above
And R ^{1 to} R ⁵ , R in the amide derivative (1)
^8, R ⁹ and groups represented by R ²⁴ are those shown below amide derivative (1-u) can be produced.

[0228]

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Reference Example 18 In the amide derivative (25), the groups represented by R ^{1 to} R ⁵ and R ¹¹ are the following:
Production of v):

[0230]

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(1) Production of methyl 16- (9Z, 12Z-octadecadieniloxy) hexadecanoate (24-v): In a 300 ml four-necked flask equipped with a stirrer, a dropping funnel, a thermometer and a reflux condenser. , 16-hydroxyhexadecanoic acid (2.72 g, 10 mmol), anhydrous tetrahydrofuran (50 ml), anhydrous hexamethylphosphoryltriamide (5 ml) and sodium hydride (0.24 g, 10 mmol), and the mixture was stirred at room temperature for 30 minutes under a nitrogen stream. Next, the mixture was cooled to -70 ° C, and 6.25 ml (10 mmol) of a 1.6N butyllithium hexane solution was added.
The mixture was warmed to room temperature over 0 minutes, and thereto was added 0.24 g (10 mmol) of sodium hydride, and the mixture was further stirred at room temperature for 30 minutes. Next, p-toluenesulfonic acid 9Z, 1
2Z-Octadecadienyl ester (17-γ) 9.2
5 g (22 mmol) was added dropwise, and the mixture was stirred with heating at 65 ° C. for 18 hours. Then, 150 ml of anhydrous methanol was added to the reaction mixture, and further stirred at 65 ° C. for 1 hour. After cooling the reaction mixture to room temperature, the excess alkali was neutralized with an aqueous ammonium chloride solution, the reaction mixture was extracted with toluene, the solvent was distilled off under reduced pressure, and the residue was purified by flash column chromatography to give the title compound ( 21-v) 0.72
g was obtained (13.5% yield).

(2) Preparation of amide derivative (25-v):
Compound (7-a) 1 obtained in Example 1 (1) was placed in a 100 ml flask equipped with a stirrer, a dropping funnel and a distillation apparatus.
1.6 g (30 mmol) and the compound (2) obtained in the above (1)
4-v) 9.0 g (33 mmol) was charged, and 0.58 g (3 mmol) of a 28% methanol solution of sodium methoxide was added dropwise while stirring at 80 ° C under a nitrogen atmosphere. After the completion of the dropwise addition, the mixture was stirred at 80 ° C. for 1 hour and further reduced under reduced pressure (10 Torr).
The mixture was stirred at 0 ° C. for 10 hours to complete the reaction. After cooling the reaction mixture, the mixture was purified by silica gel column chromatography to obtain 15.7 g of the amide derivative (25-v).
Was obtained (83% yield). The obtained amide derivative (25-
The physical properties of v) are as follows.

Melting point: 51-52 ° C IR (KBr, cm ^-1 ); 3300, 2910, 2850, 1615, 1465, 1100, 7
20 ¹ H-NMR (CDCl ₃ , δ); 0.80-0.95 (m, 6H), 0.95-1.95 (m, 74
H), 1.95-2.15 (m, 4H), 2.25-2.50 (m, 2H), 2.65-2.90 (m, 2
H), 3.33 (s, 3H), 3.20-4.25 (m, 16H), 5.20-5.45 (m, 4H)

The amide derivative (25-v) obtained above
And R ^{1 to} R ⁵ , R in the amide derivative (1)
^10, R ¹¹ and it is possible to produce the amide derivative (1-v) in which group the following represented by R ^24.

[0235]

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Reference Example 19 In the amide derivative (30), the groups represented by R ^{1 to} R ⁵ and R ¹¹ are the following:
Production of w):

[0237]

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(1) Methyl 16- (9Z, 12Z-octadecadienoyloxy) hexadecanoate (29-w)
Production: 30 with stirrer, dropping funnel and thermometer
In a 0 ml flask, 4.30 g (15 mmol) of methyl 16-hydroxyhexadecanoate, 8.41 g (13 mmol) of the compound (9-f) obtained in (1) of Reference Example 3, 7.87 g (30 mmol) of triphenylphosphine And 100 ml of tetrahydrofuran, 5.22 g (30 mmol) of diethyl azodicarboxylate was added dropwise over 1 hour with stirring at room temperature. After completion of the dropwise addition, the mixture was further stirred at room temperature for 4 hours.
The solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash chromatography to obtain 6.76 g of the title compound (29-w) (yield: 82%).

(2) Preparation of amide derivative (30-w):
In Reference Example 18 (2), the production was performed in the same manner as in Reference Example 18 (2), except that the compound obtained in the above (1) was used instead of the compound (24-v), and the amide derivative (30
-W) was obtained. Physical properties of obtained amide derivative (30-w) are as follows.

White solid Melting point: 48 to 50 ° C. IR (KBr, cm ⁻¹ ); 3310, 2900, 2870, 1610, 1550, 1465, 1
105, 720 ¹ H-NMR (CDCl ₃ , δ); 0.88 (br t, J = 6.4 Hz, 6H), 1.10-1.95
(m, 76H), 1.95-2.10 (m, 2H), 2.10-2.55 (m, 6H), 3.10-3.70
(m, 12H), 3.33 (s, 3H), 3.34 (s, 3H), 3.80-4.05 (m, 1H),
4.05 (t, J = 6.6Hz, 2H), 5.30-5.60 (2H)

The amide derivative (30-w) obtained above
And R ^{1 to} R ⁵ , R in the amide derivative (1)
^10, R ¹¹ and it is possible to produce the amide derivative (1-w) in which group the following represented by R ^24.

[0242]

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Reference Example 20 Production of an amide derivative (1-x) in which the groups represented by R ^{1 to} R ⁵ , R ¹⁰ and R ¹¹ in the amide derivative (30) are as follows:

[0244]

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In a 1 liter flask equipped with a stirrer and a hydrogen inlet tube, the compound (30-
w) 10.2 g (11.3 mmol), 1.5 g of 5% palladium carbon and 300 ml of ethanol were charged, and the mixture was stirred at room temperature under a hydrogen atmosphere for 26 hours. The obtained reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 9.3 g of an amide derivative (30-x) (yield: 95%). The physical properties of the obtained amide derivative (30-x) are as follows.

Melting point: 52-53 ° C IR (KBr, cm ^-1 ); 3330, 2930, 1625, 1550, 1210, 1110, 7
20 ¹ H-NMR (CDCl ₃ , δ); 0.88 (br t, J = 6.4 Hz), 1.10-1.95 (m, 8
4H), 2.29 (t, J = 7.5Hz, 2H), 7.39 (t, J = 7.5Hz, 2H), 3.00-3.
70 (m, 12H), 3.32 (s, 3H), 3.33 (s, 3H), 3.80-4.00 (m, 1H),
4.05 (t, J = 6.6Hz, 2H)

The amide derivative (30-x) obtained above
And R ^{1 to} R ⁵ , R in the amide derivative (1)
^10, R ¹¹ and it is possible to produce the amide derivative (1-x) in which group the following represented by R ^24.

[0248]

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Reference Example 21 Production of an amide derivative (30-y) in which the groups represented by R ^{1 to} R ⁵ , R ¹⁰ and R ¹¹ in the amide derivative (30) are as follows:

[0250]

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(1) Production of (methyl-branched isostearoylyloxy) methyl hexadecanoate: In Example (1) of Reference Example 19, the compound (9-f) obtained in (1) of Reference Example 3 was replaced with methyl Except for using branched isostearic acid, production was carried out in the same manner as in Reference Example 19 (1).
The title compound was obtained.

(2) Preparation of amide derivative (30-y):
Reference Example 1 is the same as Reference Example 18 (2) except that the compound obtained in the above (1) is used instead of the compound (24-v).
The amide derivative (30-
y) was obtained. The physical properties of the obtained amide derivative (30-y) are as follows.

White solid Melting point: 55-57 ° C IR (KBr, cm ^-1 ); 3335, 2930, 1630, 1550, 1465, 1110, 7
20 ¹ H-NMR (CDCl ₃ , δ); 0.75-1.00 (m, 9H), 1.00-1.95 (m, 83
H), 2.29 (t, J = 7.5Hz, 2H), 2.40 (t, J = 7.5Hz, 2H), 3.15-4.0
0 (m, 12H), 3.33 (s, 3H), 4.05 (t, J = 6.6Hz, 2H)

The amide derivative (30-y) obtained above
And R ^{1 to} R ⁵ , R in the amide derivative (1)
^10, R ¹¹ and it is possible to produce the amide derivative (1-y) in which group the following represented by R ^24.

[0255]

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Reference Example 22 Production of an amide derivative (30-z) in which the groups represented by R ^{1 to} R ⁵ , R ¹⁰ and R ¹¹ in the amide derivative (30) are as follows:

[0257]

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(1) Production of amide derivative (30-z):
In (2) of Reference Example 18, the compound (7-k) obtained in Reference Example 7 (1) is used instead of the compound (7-a), and the compound of Reference Example 21 is used instead of the compound (24-v). Except that the compound obtained in (1) was used, the production was carried out in the same manner as in (2) of Reference Example 18, to obtain the desired amide derivative (30-z). Physical properties of obtained compound (30-z) are as follows.

White solid Melting point: 54-57 ° C IR (KBr, cm ^-1 ); 3380, 2930, 1625, 1550, 1470, 1380, 1
210, 1100, 720 ¹ H-NMR (CDCl ₃ , δ); 0.75-1.00 (m, 12H), 1.00-1.85 (m, 85
H), 2.29 (t, J = 7.5Hz, 2H), 2.40 (t, J = 7.5Hz), 3.15-4.00
(m, 10H), 4.05 (t, J = 6.6Hz, 2H)

The amide derivative (30-z) obtained above
And R ^{1 to} R ⁵ , R in the amide derivative (1)
^10, R ¹¹ and it is possible to produce the amide derivative (1-z) in which group the following represented by R ^24.

[0261]

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The amide derivatives of the present invention shown in the above Examples are compounds represented by the general formula (2) previously proposed in JP-A-2-306952 and JP-A-7-700.
Compared with the compound represented by the general formula (3) proposed in Japanese Patent Publication No. 30, the melting point is lower, the solubility in the base is excellent, and the stability is improved. It was excellent.

Test Example 1 An external preparation composition of the present invention (product of the present invention) comprising 10% of the amide derivative of the present invention and 90% of squalane shown in Table 1 below
Were prepared, and the transdermal water loss and transdermal absorption of these external preparations were measured and evaluated by the following test methods. As a comparison, the same test and evaluation were also performed for an external preparation composed of squalane alone (comparative product). The results are shown in Table 1 below.

(Test Method) Male Wistar rats were bred only with a diet containing no essential fatty acid, and rats having essential fatty acid deficiency were used in this test.
After carefully shaving the back of these essential fatty acid deficiency rats, an external preparation for evaluation was applied once a day for 3 weeks. In addition, for each external preparation for evaluation, 5 animals per group were subjected to this test. Three weeks later, the following items were tested.

(1) Transepidermal water loss The back of the test rat was washed with warm water and allowed to stand for 1 hour (at room temperature 2).
(3 ° C., 45% humidity), and the amount of water evaporated from the skin was measured with an evaporator. In rats with normal barrier function, the value of transdermal water loss is usually 10 or less,
Rats with essential fatty acid deficiency show high values of 20 to 30 or more. This is considered to be because the transdermal water loss increased due to a decrease in the barrier function of the stratum corneum.
In other words, it indicates that the higher the value of the transepidermal water loss, the lower the barrier function of the stratum corneum and the more rough the skin. Therefore, the effect of the product of the present invention as an external preparation can be examined by measuring the transepidermal water loss. In addition, the measured value was shown by the average value.

(2) Percutaneous absorption The back skin of the rat was washed with warm water at 37 ° C., and the back skin was cut off.
And fix it in the transdermal absorption chamber with the epidermis side up.
Was. Fill the lower receiver with phosphate buffered saline and place it on the epidermis
The part of 37KBq¹⁴Phosphate buffer containing C-salicylic acid
1 ml of a salt solution was added and left still. Two hours later, from the lower receiver
1 ml of phosphate buffered saline solution was withdrawn and permeated¹⁴C
-Assessed by measuring the amount of salicylic acid radioactivity
Was. In addition, healthy lanes that maintain a normal barrier function
In the experiment time (2 hours) ¹⁴C-salicylic acid is
Essential oil that hardly penetrates but has impaired barrier function
Significantly in fatty acid deficient rats¹⁴Permeation amount of C-salicylic acid
Increase. The measured values were shown as average values.

[0267]

[Table 1]

As is evident from the results shown in Table 1 above, all of the products of the present invention containing the amide derivative of the present invention showed lower transepidermal water loss and transdermal absorption than the comparative product containing only squalane. It is excellent in suppressing effect.

[0269]

The amide derivative of the present invention has the effect of essentially improving (maintaining and reinforcing) the barrier function of the stratum corneum,
In addition, when blended in an external preparation for skin, it has a low melting point and low crystallinity, has good solubility and stability in a base, and can be stably and easily blended in a base. Therefore, the external preparation for skin of the present invention containing the amide derivative of the present invention, when applied to the skin, essentially improves the barrier function of the stratum corneum, and can be expected to have the effect of improving and preventing skin inflammation and rough skin. Things.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/165 A61K 31/165 31/215 31/215 31/23 31/23 31/535 31/535 C07C 235/08 C07C 235 / 08 237/22 237/22 C07D 295/18 C07D 295/18 Z A (72) Inventor Yoichi Arai 2606 Kabanecho, Akabane-cho, Haga-gun, Tochigi Kao Corporation Research Institute (72) Inventor Shinichi Meguro Haga-gun, Tochigi 2606 Ikaga-cho, Akabane, Kao Corporation Research Institute (72) Inventor Ichiro Tokitsu 2606, Kaiga-cho, Akabane, Haga-gun, Tochigi Prefecture Kao Corporation Research Institute

Claims (6)

[Claims] 1. The following general formula (1): (Wherein, R ¹ represents a linear or branched hydrocarbon group having 1 to 40 carbon atoms, R ² represents a linear or branched alkylene group having 1 to 6 carbon atoms, and R ³ represents a hydrogen atom Or 1 to 1 carbon atoms
2 represents a linear or branched alkoxyl group, R ⁴
Represents a linear or branched divalent hydrocarbon group having 1 to 39 carbon atoms, and R ²⁴ represents a linear or branched carbon group having 1 to 22 carbon atoms which may be substituted by a hydroxyl group or an alkoxyl group. Represents a hydrogen group, (Here, R ⁶ represents a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms, and R ⁷ has a linear, branched or cyclic structure having 1 to 40 carbon atoms which may contain an oxygen atom. A hydrocarbon group, and R ⁸ and R ⁹ are the same or different and each represent a hydrogen atom, or a hydrocarbon group having a linear, branched or cyclic structure having 1 to 40 carbon atoms which may contain an oxygen atom; Show or
R ⁸ and R ⁹ may together form a divalent hydrocarbon group having 1 to 40 carbon atoms which may contain an oxygen atom, and R ¹⁰ represents a carbonyl group or a methylene group; Reference numeral ¹¹ denotes a hydrocarbon group or a hydrogen atom having a linear, branched or cyclic structure having 1 to 40 carbon atoms which may contain an oxygen atom. An amide derivative represented by the formula: 2. In the general formula (1), R ²⁴ represents the following general formula (2): The amide according to claim 1, wherein one of R ²⁵ and R ²⁶ is a hydrogen atom, and the other is a hydrogen atom or a linear or branched alkyl group having 1 to 12 carbon atoms. Derivatives. Wherein R ¹ is a straight-chain or branched hydrocarbon group having 4 to 26 carbon atoms; R ² is an alkylene group of a straight-chain or branched-chain having 1 to 6 carbon atoms; R ³ is hydrogen An atom or a linear or branched alkoxy group having 1 to 12 carbon atoms;
R ⁴ is a straight-chain saturated divalent hydrocarbon group having 5 to 31 carbon atoms; (Where R ⁶ is a hydrogen atom or a hydrocarbon group having 1 to 6 carbon atoms; R ⁷ may have one or more selected from an ether bond, a ketone, a carboxyl group and a carboxylate bond) A hydrocarbon group having a linear, branched or cyclic structure having 7 to 25 carbon atoms, wherein R ⁸ and R ⁹ are the same or different and are selected from a hydrogen atom or an ether bond, a ketone, a carboxyl group and a carboxylate bond Or a hydrocarbon group having a linear, branched or cyclic structure having 7 to 25 carbon atoms which may have 2 or more, or an alkylene having 1 to 40 carbon atoms in which R ⁸ and R ⁹ are taken together. , alkenylene, may form an alkylene -O- alkylene or alkenylene -O- alkenylene, R ¹⁰ is located at the carbonyl group or methylene group; R ¹¹ is an ether bond, ketone, carboxyl group Fine carboxylate bond 1 or carbon atoms which may have two or more selected from 7-25
Is a hydrocarbon group or hydrogen atom having a linear, branched or cyclic structure. The compound according to claim 1 or 2, wherein 4. The compound according to claim 1, wherein R ¹ is a linear or branched saturated hydrocarbon group having 4 to 22 carbon atoms. 5. An external preparation composition comprising the compound according to any one of claims 1 to 4. 6. The composition according to claim 5, which is used as a medicine or cosmetic.