JPH0770030A - Amide derivative and skin external preparation - Google Patents

Abstract

PURPOSE:To obtain a new amide derivative useful as a skin external preparation having effects to improve the barrier function of the stratum corneum, e.g. retention, restoration, reinforcement of such function. CONSTITUTION:An amide derivative of formula I [R<1> is a 10-40C hydrocarbon; R<2> is a 1-39C hydrocarbon; R<3> is H or a 1-6C hydrocarbon; R<4> is an (H- or O-contg.) 1-40C hydrocarbon (may be of cyclic structure)]. The compound of formula I can be obtained by the following method: an amine of formula II is prepared from an ethanolamine and a glycidyl ether; while an aminocarboxylic acid of formula III (R<8> is H or a lower alkyl) or its ester is reacted with a carboxylic acid of formula IV (R<9> is the same as R<8>) or an ester or an acid chloride thereof of formula V to form an amidocarboxylic acid of formula VI or an ester thereof; subsequently, the amine of formula II is reacted with the compound of formula VI in the presence of a base or a dehydrating agent.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel amide derivative,
And a skin external preparation containing the same, particularly a skin external preparation capable of fundamentally improving the barrier function of the stratum corneum (maintaining a normal barrier function, recovering a decrease in the barrier function and reinforcing the same).

[0002]

2. Description of the Related Art Epidermis,
In particular, the stratum corneum is a component derived from an ultrathin epidermis that exists in the outermost layer of the body, and not only protects against various irritation and invasion from outside the body, but also prevents loss of components and water in the body, evaporation, etc. Has a function. The protective effect of the stratum corneum, that is, the barrier function is important for controlling the homeostasis of the epidermal physiological function.

For example, when the barrier function of the stratum corneum is lowered due to various internal and external causes, various skin troubles such as inflammation of the skin, promotion of rough skin and aging are brought about. Therefore, it goes without saying that maintaining / reinforcing the barrier function of the stratum corneum is very important not only for the skin but also for the healthy daily life of the individual.

Therefore, in order to prevent or ameliorate the occurrence of such skin troubles, an external preparation for the skin containing various naturally derived ingredients or chemically synthesized ingredients has been used. Mostly, it is intended to expect the effect of supplementing the skin's moisturizing and barrier functions by forming a film on the skin surface, and these are only a temporary barrier for the skin by forming a film on the skin surface. The effect of merely improving the function of the barrier (maintenance / reinforcement) only by supplementing the function could not be expected sufficiently.

Therefore, the present applicant previously proposed a skin external preparation containing an amide derivative represented by the following [Chemical Formula 2] as a skin external preparation having an effect of essentially improving the barrier function of the skin. (JP-A-2-306952). Scott et al. Have also proposed a cosmetic composition containing an amide derivative having a similar structure (JP-A-4-225907). These amide derivatives are
It acts on the stratum corneum and has the effect of essentially improving the barrier function of the skin, but when it is incorporated into a skin external preparation, it has solubility in base, stability in oxidation, stability against hydrolysis, etc. However, some problems still remained.

[0006]

[Chemical 2]

Therefore, the object of the present invention is to have an effect of essentially improving (maintaining / reinforcing) the barrier function of the stratum corneum, and when it is incorporated into an external preparation for skin, its solubility in a base and oxidation stability. A compound that has good properties and can be easily and stably compounded in a base, and by applying it to the skin, it can improve the barrier function of the stratum corneum, and can prevent rough skin, inflammation and even aging. It is intended to provide an external preparation for skin containing the.

[0008]

Means for Solving the Problems As a result of intensive studies, the present inventors have found that the following general formula (I) ([Chemical formula 1]
The present invention has been completed by finding that the novel amide derivative represented by the general formula (I) and the external preparation for skin containing the amide derivative achieve the above object.

[0009]

[Chemical 3]

That is, the present invention provides an amide derivative represented by the general formula (I) of the above [Chemical formula 3] and a skin external preparation containing the amide derivative.

First, the amide derivative of the present invention will be described in detail below.

In the amide derivative of the present invention represented by the general formula (I) of the above [formula 3], R ¹ in the general formula (I) is
Represents a linear or branched hydrocarbon group having 10 to 40 carbon atoms, and specific examples of the hydrocarbon group include decyl, dodecyl, tetradecyl, hexadecyl, octadecyl,
Docosyl, dotriacontyl, methyl-branched isostearyl, 2-ethylhexyl, 2-heptylundecyl, 9
And hydrocarbon groups such as octadecenyl. Of these, R ¹ is particularly preferably a linear hydrocarbon group having 12 to 18 carbon atoms, and specifically, a tetradecyl, hexadecyl or octadecyl group is preferable.

R ² represents a linear or branched hydrocarbon group having 1 to 39 carbon atoms, and specific examples of the hydrocarbon group include methylene, dimethylene, trimethylene, tetramethylene, pentamethylene and octam. Methylene, decamethylene, undecamethylene, tetradecamethylene, pentadecamethylene, nonacosamethylene, heptadecane-
Hydrocarbon groups such as 1,11-diyl, 8-heptadecene-1,11-diyl and the like can be mentioned. Of these, R ² is particularly preferably a linear hydrocarbon group having 5 to 15 carbon atoms, and specifically, a decamethylene or undecamethylene group is preferred.

R ³ is a hydrogen atom or has 1 to 6 carbon atoms.
And a hydrogen atom is preferable as R ³ . Specific examples of the hydrocarbon group represented by R ³ include hydrocarbon groups such as methyl, ethyl, propyl, butyl, hexyl and allyl.

R ⁴ represents a hydrogen atom or a hydrocarbon group having a carbon number of 1 to 40, which may contain an oxygen atom, and which has a linear, branched or cyclic structure. Specific examples include methyl, propyl, pentyl, heptyl, nonyl, undecyl, tridecyl, pentadecyl,
Heptadecyl, Hentriacontyl, methyl-branched isoheptadecyl, 3-heptyl, 8-heptadecyl, 8-heptadecenyl, 8,11-heptadecadienyl, 8,1
1,14-Heptadecatrienyl, Cholesteryl, 8-
Hydroxyoctyl, 11-hydroxyundecyl, 1
4-hydroxytetradecyl, 15-hydroxypentadecyl, 11-hydroxyheptadecyl, 11-hydroxy-8-heptadecenyl, 8,9-dihydroxyheptadecyl, 11,12-dihydroxy-8-heptadecenyl, 11-methoxyheptadecyl, 11-ethoxyheptadecyl, 11-methoxy-8-heptadecenyl,
9,10- (isopropylidenedioxy) decyl, 8,
9- (isopropylidenedioxy) heptadecyl, 8,
9: 11,12-bis (isopropylidenedioxy) heptadecyl, 8,9: 11,12: 14,15-tris (isopropylidenedioxy) heptadecyl, 11,1
2- (isopropylidenedioxy) -8-heptadecenyl, 8- (6-hydroxyhexyloxy) octyl, 8
-[2- (hexyloxy) ethoxy] octyl, 10-
[2- (hexyloxy) ethoxy] decyl, 10- [2
-(Butoxy) ethoxy] decyl, 14- [2- (hexyloxy) ethoxy] tetradecyl, 14- [2- (2
-Hydroxyethoxy) ethoxy] tetradecyl, 14
-[2- (Butoxy) ethoxy] tetradecyl, 14-
[Polyoxypropylene (5)] tetradecyl, 8-
[6- (2-hydroxyethoxy) hexyloxy] octyl, 11- [2- (2-hydroxyethoxy) ethoxycarbonyl] undecyl, 11- [2- (hexyloxy) ethoxycarbonyl] undecyl, 11-acetoxy-8-heptadecenyl, etc. The hydrocarbon group of is mentioned.
Of these, R ⁴ is preferably a group having a structure represented by the following [Chemical formula 4], and more preferably 8-heptadecenyl, 8,11-heptadecadienyl, 8,1
1,14-heptadecatrienyl, 11-hydroxyundecyl, 14-hydroxytetradecyl, 15-hydroxypentadecyl, 11-hydroxyheptadecyl,
11-hydroxy-8-heptadecenyl, 8,9-dihydroxyheptadecyl, 11,12-dihydroxy-8
-Heptadecenyl, 11-methoxyheptadecyl, 11
-Ethoxyheptadecyl, 11-methoxy-8-heptadecenyl, 8,9- (isopropylidenedioxy) heptadecyl, 8,9: 11,12-bis (isopropylidenedioxy) heptadecyl, 8,9: 11,12: 1
4,15-Tris (isopropylidenedioxy) heptadecyl, 11,12- (isopropylidenedioxy)-
8-heptadecenyl, 8- (6-hydroxyhexyloxy) octyl, 8- [2- (hexyloxy) ethoxy]
Octyl, 10- [2- (hexyloxy) ethoxy] decyl, 10- [2- (butoxy) ethoxy] decyl, 1
4- [2- (hexyloxy) ethoxy] tetradecyl,
14- [2- (2-hydroxyethoxy) ethoxy] tetradecyl, 8- [6- (2-hydroxyethoxy) hexyloxy] octyl, 14- [2- (butoxy) ethoxy] tetradecyl, 14- [polyoxypropylene (5 )] Tetradecyl and the like groups.

[0016]

[Chemical 4]

In the amide derivative of the present invention, the most preferable compound is R ¹ in the general formula (I) of the above [Chemical formula 3],
It is a compound in which R ² , R ³ and R ⁴ are each a group in the above particularly preferable range.

The method for producing the amide derivative of the present invention is not particularly limited, and can be synthesized, for example, by the method represented by the following reaction formula [Chemical formula 5].

[0019]

[Chemical 5]

That is, the amine (II) obtained from glycidyl ether and ethanolamine and the carboxylic acid or its ester (IV) according to the reaction formula [Chem.
Alternatively, an amide carboxylic acid or its ester obtained by condensing an acid chloride (V) with an aminocarboxylic acid or its ester (III) in the absence of a catalyst or a catalyst such as an acid / base or a dehydrating agent such as dicyclohexylcarbodiimide ( The amide derivative (I) of the present invention can be obtained by reacting with VI) in the presence of a base catalyst or a dehydrating agent such as dicyclohexylcarbodiimide.

Next, the skin external preparation of the present invention containing the above-described amide derivative of the present invention will be described.

The external preparation for skin of the present invention comprises the base of a conventional external preparation for skin containing the amide derivative of the present invention represented by the general formula (I) of the above [Chemical Formula 3]. Are roughly classified into medicated skin external preparations and cosmetics.

Examples of the external medicated skin agent include various ointments containing medicinal components. The ointment may be either one based on an oily base or one based on an oil-in-water type or water-in-oil type emulsified base. The oily base is not particularly limited, and examples thereof include vegetable oils, animal oils, synthetic oils, fatty acids, and natural or synthetic glycerides. In addition, the medicinal component is not particularly limited, and for example, an analgesic / anti-inflammatory agent, an antipruritic agent, a bactericidal / antiseptic agent, an astringent agent, an emollient agent, a hormone agent and the like can be appropriately used as necessary.

When used as a cosmetic, in addition to the amide derivative of the present invention, which is an essential component, oils, moisturizers, UV absorbers, whitening agents, alcohols, which are generally used as cosmetic ingredients, Chelating agent, pH adjusting agent,
Preservatives, thickeners, pigments, fragrances and the like can be combined in any combination.

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

The compounding amount of the amide derivative of the present invention in the external preparation for skin of the present invention is not particularly limited, but in the case of an emulsion type external preparation for skin, it is usually 0.001 to 50 of the total composition.
Weight% (hereinafter, simply expressed as%) is preferable, and in the case of oily external preparation for skin based on liquid hydrocarbon such as squalane, 0.01 to 50% of the total composition is preferable.

[0027]

Although the detailed mechanism of action of the external preparation for skin of the present invention containing the amide derivative of the present invention represented by the general formula (I) of the above [Chemical Formula 3] has not been clarified, it is applied to the skin as an external preparation for skin. It is presumed that, by doing so, the amide derivative of the present invention penetrates into the lipid membrane between the cornea and improves (maintains / reinforces) the barrier function of the cornea.

[0028]

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

Example 1 Amide derivative (Ia) [the general formula (I) of the above [formula 3]
In the above, synthesis of an amide derivative in which R ¹ , R ² , R ³ and R ⁴ are the following [Chemical Formula 6]:

[0030]

[Chemical 6]

1- (2-hydroxyethylamino)-
Synthesis of 3-hexadecyloxy-2-propanol (II-a): Ethanolamine 916.2 g (15 mol) in a 3-liter 5-necked flask equipped with a stirrer, a dropping funnel, a thermometer, a N ₂ introduction tube and a distillation apparatus. ) And ethanol 1
83 g was charged, and hexadecyl glycidyl ether 298.6 was added thereto while heating and stirring at 80 ° C. under N ₂ atmosphere.
g (1 mol) was added dropwise over 3 hours. After the dropping is completed,
Ethanol and excess ethanolamine were distilled off under reduced pressure, and the residue was recrystallized from methanol to obtain 331.0 g of the title compound (II-a) as a colorless powder (yield 92.0%).

Synthesis of 9,10: 12,13-bis (isopropylidenedioxy) octadecanoic acid (IV-a):
A 2 liter flask equipped with a stirrer was charged with 147.2 g (0.5 mol) of methyl linoleate, 203.2 g (1.18 mol) of metachloroperbenzoic acid and 500 ml of dichloromethane, and stirred at room temperature for 18 hours. After completion of the reaction, the precipitated metachlorobenzoic acid was 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, in a 2 liter flask equipped with a stirrer and a dropping funnel, 1162 g (2
0 mol) and boron trifluoride / ether complex 3.55
g (25 mmol) was charged, and the methyl 9,10: 12,13-diepoxyoctadecanoate obtained above was added dropwise over 3 hours while stirring at room temperature. After completion of the dropping, the reaction was completed by further stirring for 1 hour. Then, NaHCO ₃ was added to the reaction mixture for neutralization, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to give 9,10: 12,13-bis (isopropylidenedioxy) octadecanoic acid. Methyl 201.2
g was obtained (yield 90.9%). Then, in a 2 liter flask equipped with a stirrer, the 9,10: 1 obtained above
141.6 g (0.32 mol) of methyl 2,13-bis (isopropylidenedioxy) octadecanoate and 400 ml of ethanol were charged, and here, 35.8 g of KOH was added.
A solution of 40 ml of water (0.64 mol) and 400 ml of ethanol was added, and the mixture was stirred at 50 ° C. for 1 hour. Then, the reaction mixture was neutralized with hydrochloric acid, extracted with chloroform, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography to obtain 132.0 g of the title compound (IV-a) ( Yield 96.3%).

Methyl 11-aminoundecanoate (III
Synthesis of a): In a 3 liter flask equipped with a stirrer, 201.3 g of 11-aminoundecanoic acid (1 mo)
1), 1600 g of methanol and 294 g of phosphoric acid (3 m
was charged and the mixture was stirred at 60 ° C. for 18 hours. The reaction mixture was allowed to cool, neutralized with an aqueous solution of NaOH and an aqueous solution of NaHCO ₃ , and extracted with chloroform. After the solvent was distilled off under reduced pressure, the title compound (III-a) 20 was purified by alumina short column chromatography.
0.2 g was obtained (yield 93.0%).

Synthesis of methyl 11- [9,10: 12,13-bis (isopropylidenedioxy) octadecanoylamino] undecanoate (VI-a): Obtained above in a 1 liter flask equipped with a stirrer. Compound (IV
-A) 34.3 g (80 mmol), compound (III-a) 21.5 g (100 mmol) obtained above, 1-hydroxybenzotriazole 18.4 g (120 mmo).
1) and 500 ml of chloroform were charged, and N, N'-dicyclohexylcarbodiimide 3 was added while stirring at room temperature.
3.0 g was added, and the mixture was further stirred for 24 hours at room temperature. After completion of the reaction, the precipitated white solid was filtered off, concentrated under reduced pressure and the residue was purified by silica gel chromatography to obtain 31.1 g of the title compound (VI-a) (yield 62.1%. ).

Synthesis of amide derivative (Ia): In a 100 ml flask equipped with a stirrer, a dropping funnel and a distillation device, 9.0 g (25.1) of the compound (II-a) obtained above was obtained.
mmol) and the compound (VI-a) 10.5 obtained above.
g (16.7 mmol) was charged and the temperature was 80 ° C. under N ₂ atmosphere
While stirring at 0.32 g (1.67 mmol) of sodium methoxide 28% methanol solution was added dropwise. After completion of the dropping, the mixture was stirred at 80 ° C. for 1 hour and further under reduced pressure (10 To
rr) The reaction was completed by stirring at 80 ° C. for 1 hour. After cooling the reaction mixture, the target amide derivative (Ia) 1 was purified by silica gel column chromatography.
3.3 g was obtained (yield 83.5%).

The followings are physical properties of the amide derivative (Ia) so obtained. Pale yellow solid, melting point; 59.7-61.0 ° C. IR (neat, cm ⁻¹ ); 3312, 2924, 2856,
1638, 1614, 1546, 1464, 1374,
_{^{1214,1168,1106,1060 1 H-NMR (CDCl 3}} , δ); 0.82~1.02
(M, 6H), 1.13 to 1.97 (m, 78H),
2.15 (t, J = 7.5 Hz, 2H), 2.40
(T, J = 7.6 Hz, 2H), 3.18 to 4.23
(M, 19H), 5.49 (br, 1H)

Example 2 Amide derivative (Ib) [the general formula (I) of the above [formula 3]
In the above, synthesis of an amide derivative in which R ¹ , R ² , R ³ and R ⁴ are represented by the following [Chemical formula 7]:

[0038]

[Chemical 7]

The reaction was carried out in the same manner as in Example 1 except that 12-aminododecanoic acid was used instead of 11-aminoundecanoic acid in Example 1 to obtain the desired amide derivative (Ib). .

The followings are physical properties of the amide derivative (Ib) so obtained. Colorless solid, melting point; 73.0 to 73.8 ° C IR (neat, cm ^-1 ); 3320, 2912, 2852,
1610, 1536, 1462, 1440, 1372,
_{^{1238,1214,1166,1100,1060 1 H-NMR (CDCl 3}} , δ); 0.82~0.97
(M, 6H), 1.12 to 1.86 (m, 80H),
2.15 (t, J = 7.5 Hz, 2H), 2.39
(T, J = 7.5 Hz, 2H), 3.17 to 4.19.
(M, 19H), 5.44 (br, 1H)

Example 3 Amide derivative (Ic) [the general formula (I) of the above [formula 3]
In the above, synthesis of an amide derivative in which R ¹ , R ² , R ³ and R ⁴ are represented by the following [Chemical formula 8]:

[0042]

[Chemical 8]

Synthesis of methyl 11-linoleoylaminoundecanoate (VI-c): In a 200 ml flask equipped with a stirrer and a dropping funnel, 5.73 g (25 mmol) of the compound (III-a) obtained in Example 1 was added. , Pyridine 3.95 g (50 mmol) and dichloromethane 100
ml was charged, and 8.22 g (27.5 mmol) of linoleoyl chloride (V-c) was added dropwise over 1 hour while stirring at room temperature. After the completion of dropping, the reaction was further stirred at room temperature for 24 hours to complete the reaction. The obtained reaction mixture was washed with saturated brine, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 9.52 g of the title compound (VI-c) (yield 77.4%). .

Synthesis of amide derivative (Ic): the same as Example 1 except that the compound (VI-c) obtained above is used in place of the compound (VI-a) in Example 1. To give the desired amide derivative (Ic).

The followings are physical properties of the amide derivative (Ic) so obtained. Colorless solid, melting point; 81.4-82.5 ° C. IR (neat, cm ⁻¹ ); 3316, 2924, 2852,
1640, 1612, 1546, 1466, 1434,
1110, 1058 ¹ H-NMR (CDCl ₃ , δ); 0.80 to 1.06
(M, 6H), 1.08 to 1.80 (m, 60H),
1.92 to 2.12 (m, 4H), 2.15 (t, J =
7.6 Hz, 2 H), 2.40 (t, J = 7.5 Hz,
2H), 2.69 to 2.84 (m, 2H), 3.14 to
4.19 (m, 15H), 5.24-5.48 (m, 4
H), 5.58 (br, 1H)

Example 4 Amide derivative (Id) [the general formula (I) of the above [formula 3]
In the above, synthesis of an amide derivative in which R ¹ , R ² , R ³ and R ⁴ are represented by the following [Chemical Formula 9]:

[0047]

[Chemical 9]

In Example 3, methyl 12-aminododecanoate (III-b) synthesized from 12-aminododecanoic acid in the same manner as in Example 1 was used instead of compound (III-a). The reaction was performed in the same manner as in Example 3 to obtain the target amide derivative (Id).

The followings are physical properties of the amide derivative (Id) so obtained. Colorless solid, melting point; 84.7 to 85.9 ° C. IR (neat, cm ⁻¹ ); 3320, 2924, 2852,
1618, 1538, 1464, 1430, 1370,
1298, 1262, 1216, 1168, 1106,
1052 ¹ H-NMR (CDCl ₃ , δ); 0.82 to 1.01
(M, 6H), 1.11 to 1.74 (m, 62H),
1.94 to 2.12 (m, 4H), 2.15 (t, J =
7.6 Hz, 2 H), 2.32 to 2.45 (m, 2
H), 2.72 to 2.83 (m, 2H), 3.18 to
4.18 (m, 15H), 5.23 to 5.52 (m, 5
H)

Example 5 Amide derivative (Ie) [the general formula (I) of the above [formula 3]
Wherein R ¹ , R ² , R ³ and R ⁴ are represented by the following [Chemical Formula 10]
Synthesis of amide derivative]

[0051]

[Chemical 10]

In Example 3, instead of the compound (III-a), methyl 12-aminododecanoate (III-b) was used.
And using oleoyl chloride (V-e) instead of linoleoyl chloride (V-c),
The reaction was performed in the same manner as in Example 3 to obtain the desired amide derivative
-E) was obtained.

The followings are physical properties of the amide derivative (Ie) so obtained. Colorless solid, melting point; 82.4-83.9 ° C. IR (neat, cm ⁻¹ ); 3312, 2920, 2852,
1608, 1540, 1462, 1108, 1056 ¹ H-NMR (CDCl ₃ , δ); 0.80 to 1.02
(M, 6H), 1.12 to 1.87 (m, 68H),
1.90 to 2.11 (m, 4H), 2.15 (t, J =
7.5 Hz, 2 H), 2.40 (t, J = 7.6 Hz,
2H), 3.16 to 4.22 (m, 15H), 5.24.
~ 5.57 (m, 3H)

Example 6 Amide derivative (If) [Formula (I) of the above [Chemical Formula 3]
In the formula, R ¹ , R ² , R ³ and R ⁴ are represented by the following [Chemical formula 11]
Synthesis of amide derivative]

[0055]

[Chemical 11]

In Examples 1 to 3, the compound (IV-
The reaction was performed in the same manner as in Example 1 except that ricinoleic acid was used instead of a), and methyl 12-aminododecanoate (III-b) was used instead of compound (III-a). To obtain the amide derivative (If).

The followings are physical properties of the amide derivative (If) thus obtained. Pale yellow solid melting point; 75.9 to 77.9 ° C. IR (neat, cm ⁻¹ ); 3312, 2912, 2852,
1610, 1542, 1468, 1440, 1374,
1294, 1260, 1220, 1194, 1164,
1108, 1058 ¹ H-NMR (CDCl ₃ , δ); 0.91 to 1.00
(M, 6H), 1.12 to 1.78 (m, 64H),
1.78 to 2.48 (m, 9H), 3.16 to 4.22
(M, 15H), 5.32 to 5.69 (m, 3H)

Example 7 Amide derivative (Ig) [the general formula (I) of the above [formula 3]
In the formula, R ¹ , R ² , R ³ and R ⁴ are represented by the following [formula 12].
Synthesis of amide derivative]

[0059]

[Chemical 12]

Synthesis of 12-methoxy-9-octadecenoic acid (IV-g): In a 1 liter flask equipped with a stirrer, dropping funnel and condenser, 24 g (0.6 mol) of 60% sodium hydride and 50 of dimethylformamide were added.
0 ml was charged, and 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 with stirring under N ₂ atmosphere at 40 ° C. The mixture was stirred at 40 ° C for 6 hours.
Hexane was added to the obtained reaction mixture, and the mixture was washed with an aqueous solution of ammonium chloride and an aqueous solution of sodium thiosulfate, 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 (yield 91.5%). Next, in a 1-liter flask equipped with a stirrer, the 6-ethyl 12-methoxy-9-octadadecenoate obtained above was used.
g (0.2 mol), 600 ml of ethanol and 45 g of 50% aqueous potassium hydroxide solution were charged, and the mixture was stirred at 50 ° 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 obtain 58.3 g of the title compound (IV-g) (yield 93.3%).

Synthesis of amide derivative (Ig): In Example 1 to, the compound (IV-g) obtained above was used in place of the compound (IV-a), and the compound (II) was used.
The reaction was performed in the same manner as in Example 1 except that methyl 12-aminododecanoate (III-b) was used instead of I-a) to obtain the desired amide derivative (I-g).

The followings are physical properties of the amide derivative (Ig) so obtained. Pale yellow solid melting point; 82.4-83.9 ° C. IR (neat, cm ⁻¹ ); 3304, 2896, 2868,
1606, 1542, 1460, 1438, 1102,
1056 ¹ H-NMR (CDCl ₃ , δ); 0.82 to 0.97
(M, 6H), 1.10 to 1.73 (m, 70H),
1.88 to 2.47 (m, 6H), 2.15 (t, J =
7.5 Hz, 2H), 3.12 to 4.18 (m, 19
H), 5.19 to 5.71 (m, 3H)

Example 8 Amide derivative (Ih) [the general formula (I) of the above [formula 3]
Wherein R ¹ , R ² , R ³ and R ⁴ are represented by the following [Chemical Formula 13]
Synthesis of amide derivative]

[0064]

[Chemical 13]

Synthesis of methyl 11- (2-hexyloxyethoxy) undecanoate (IV-h): In a 1 liter flask equipped with a stirrer, dropping funnel and cooling tube, 70.2 g of 2-hexyloxyethanol (0. 48 mol) and 60 ml of dimethylformamide were charged, and 12 g (0.3%) of 60% sodium hydride was added while stirring under N ₂ atmosphere.
0 mol) was added. Then, 31.8 g of 11-bromoundecanoic acid was added to this mixture with heating and stirring at 80 ° C.
A solution of (0.12 mol) in 90 ml of tetrahydrofuran was added dropwise, and after completion of the addition, the mixture was further stirred at 80 ° C. for 4 hours.
After completion of the reaction, the mixture was cooled to room temperature, neutralized with 3N hydrochloric acid, and extracted with isopropyl ether. After the solvent was distilled off under reduced pressure, the residue was distilled under reduced pressure (160 to 170 ° C./0.01 Torr) to obtain 33.0 g of the title compound (IV-h) (yield 83.3%).

Synthesis of amide derivative (I-h): In Example 1 to, instead of the compound (IV-a), the compound (IV-h) obtained above was used, and the compound (II-h) was used.
The reaction was performed in the same manner as in Example 1 except that methyl 12-aminododecanoate (III-b) was used instead of I-a) to obtain the desired amide derivative (I-h).

The followings are physical properties of the amide derivative (Ih) so obtained. Colorless solid, melting point; 82.8 to 84.2 ° C IR (neat, cm ^-1 ); 3304, 2920, 2856,
1606, 1536, 1462, 1374, 1214,
_{^{1102,1054 1 H-NMR (CDCl 3}} , δ); 0.82~1.01
(M, 6H), 1.12 to 1.74 (m, 70H),
2.15 (t, J = 7.6 Hz, 2H), 2.40
(T, J = 7.6 Hz, 2H), 3.16 to 4.20
(M, 19H), 3.58 (s, 4H), 5.43-
5.58 (m, 1H)

Example 9 Amide derivative (Ii) [the general formula (I) of the above [formula 3]
In the formula, R ¹ , R ² , R ³ and R ⁴ are represented by the following [Chemical formula 14]
Synthesis of amide derivative]

[0069]

[Chemical 14]

The reaction was performed in the same manner as in Example 8 except that 2-butoxyethanol was used instead of 2-hexyloxyethanol in Example 8, to obtain the desired amide derivative (Ii).

The followings are physical properties of the amide derivative (Ii) so obtained. Colorless solid, melting point; 82.0 to 84.1 ° C IR (neat, cm ^-1 ); 3304, 2916, 2852,
1610, 1540, 1460, 1106, 1056 ¹ H-NMR (CDCl ₃ , δ); 0.82 to 1.02
(M, 6H), 1.13 to 1.77 (m, 66H),
2.15 (t, J = 7.6 Hz, 2H), 2.40
(T, J = 7.6 Hz, 2H), 3.17 to 4.20
(M, 19H), 3.57 (s, 4H), 5.38-
5.53 (m, 1H)

Example 10 Amide derivative (Ij) [general formula (I) of the above [formula 3]
In the formula, R ¹ , R ² , R ³ and R ⁴ are represented by the following [formula 15].
Synthesis of amide derivative]

[0073]

[Chemical 15]

Compound (IV-j) [in the general formula (IV) in the reaction formula of the above [Chemical formula 5], R ⁴ is the following [Chemical formula 1]
6] Synthesis of compound]

[0075]

[Chemical 16]

In a 200 ml flask equipped with a stirrer, a dropping funnel and a condenser, 10.0 g (33.9 mmol) of isopropyl 15-hydroxypentadecanoate, 25 ml of dimethylformamide and 60% sodium hydride were added.
4 g (10 mmol) was charged, and 19.7 g (339 mmol) of propylene oxide was added thereto, and the temperature was 100 ° C.
It was stirred for 18 hours. After completion of the reaction, 8 g of 50% aqueous sodium hydroxide solution and 80 ml of ethanol were added, and the mixture was stirred at 60 ° C. for 1 hour. After cooling to room temperature, water was added to the reaction mixture and washed with hexane. The mixture was acidified with 3N hydrochloric acid, extracted with isopropyl ether, and concentrated under reduced pressure to give 17.0 g of the crude product (IV-j) of the title compound (crude yield 92%).

Synthesis of amide derivative (I-j): In Example 1 to, the compound (IV-j) obtained above was used in place of the compound (IV-a), and the compound (III) was used.
-A) instead of methyl 12-aminododecanoate (II
The reaction was performed in the same manner as in Example 1 except that I-b) was used to obtain the desired amide derivative (I-j).

The followings are physical properties of the amide derivative (Ij) so obtained. Pale yellow solid melting point; 74.2-80.3 ° C IR (neat, cm ^-1 ); 3320, 2920, 2852,
_{^{1614,1464,1102 1 H-NMR (CDCl 3}} , δ); 0.79~1.00
(M, 3H), 1.00 to 1.24 (m, about 15H),
1.24 to 1.82 (m, 70H), 1.87 to 2.0
4 (m, 2H), 2.15 (t, J = 7.4Hz, 2
H), 2.32 to 2.48 (m, 2H), 3.11 to
4.39 (m, about 31H), 5.56 (bs, 1H)

Example 11 A skin external preparation of the present invention (product of the present invention) consisting of 10% of the amide derivative of the present invention and 90% of squalane shown in the following [Table 1] was prepared. The transepidermal water loss and transdermal absorption were measured and evaluated by the test method. For comparison, the same test evaluation was carried out on a skin external preparation (comparative product) consisting of squalane alone. 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 symptoms of essential fatty acid deficiency were used in this test. The backs of these essential fatty acid deficient rats were shaved carefully, and then the external preparation for evaluation was applied once a day for 3 weeks. In addition, 5 animals per group were subjected to this test for each external preparation for evaluation. After 3 weeks, the following items were tested.

(1) Amount of transepidermal water loss After washing the back of a test rat with warm water, it was allowed to stand for 1 hour (room temperature 2
After 3 ° C. and a humidity of 45%), the amount of water evaporated from the skin was measured with an evaporation meter. In rats with normal barrier function, the value of transepidermal water loss is usually 10 or less,
Rats with essential fatty acid deficiency show high values of 20 to 30 or more. It is considered that this is because the transepidermal water loss increased because the barrier function of the stratum corneum was decreased.
That is, it is shown that the higher the transepidermal water loss, the lower the barrier function of the stratum corneum and the more rough the skin. Therefore, by measuring the value of this transepidermal water loss,
The effect of the product of the present invention as an external preparation for skin can be examined. The measured values are shown as the average value ± standard deviation.

(2) Percutaneous absorption amount After washing the back of a rat with warm water at 37 ° C., the back skin was cut off.
And place it in the transdermal absorption chamber with the epidermis side facing up.
It was Fill the lower receiver with phosphate buffered saline and
Of 37KBq¹⁴Phosphate buffer containing C-salicylic acid
1 ml of salt solution was added and the mixture was left standing. 2 hours later, from the lower receiver
1 ml of phosphate buffered saline solution was withdrawn and penetrated¹⁴C
-Evaluated by measuring the amount of radioactivity of salicylic acid.
It was It should be noted that healthy barriers that maintain a normal barrier function
In this experiment time (2 hours) ¹⁴C-salicylic acid
Essential fat that hardly penetrates but has impaired barrier function
Significantly in fatty acid deficient rats¹⁴Penetration of C-salicylic acid
Will increase. The measured value was shown by the average value +/- standard deviation.

[0083]

[Table 1]

As is clear from the results shown in [Table 1] above, each of the products of the present invention containing the amide derivative of the present invention had a significantly higher transepidermal water loss and a greater transepidermal water loss than the comparative product containing only squalane. The percutaneous absorption was suppressed.

The amide derivative of the present invention has an 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 good solubility and oxidation stability in the base, and can be blended stably and easily in the base. Further, 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 an effect of improving or preventing skin inflammation, rough skin, etc. It is a thing.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location C07D 317/30 (72) Inventor Genji Imagawa 1022-89 Himurocho, Utsunomiya City, Tochigi Prefecture

Claims (2)

[Claims] 1. An amide derivative represented by the following general formula (I) represented by general formula (I). [Chemical 1] 2. A skin external preparation containing the amide derivative according to claim 1.