JPH078844B2 - Amide derivative and external preparation for skin containing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel amide derivative, more specifically, an amide derivative capable of enhancing the water-retaining power of the stratum corneum and improving rough skin, and an amide derivative containing the same. The present invention relates to a skin external preparation.

[Conventional technology]

It has been known that moisture in the stratum corneum is important in order to moisturize and soften the skin. The retention of the water is said to be due to the water-soluble components contained in the stratum corneum, that is, free amino acids, organic acids, urea or inorganic quinone, and these substances are used alone or in combination for the external preparation for medicated skin. Alternatively, it is used in cosmetics for the purpose of improving or preventing skin roughness.

In addition to this, many moisturizing substances having high affinity with water have been developed and used for the same purpose.

[Problems to be solved by the invention]

However, when these moisturizing substances are applied to the skin, the action is to supply water to the stratum corneum on the stratum corneum of the skin, and its effect is temporary,
It does not fundamentally improve the water-retaining ability of the stratum corneum and essentially prevent or cure the rough skin.

[Means for solving problems]

Under such circumstances, the present inventors have conducted diligent research to solve the above-mentioned problems, and the following general formula (I) synthesized by the present inventors for the first time (Wherein, R ¹ is a saturated or unsaturated hydrocarbon group, straight chain or branched chain of 10-26 carbon atoms, R ² is hydrocarbon a saturated or unsaturated linear or branched 9 to 25 carbon atoms A hydrogen group, X and Y represent a hydrogen atom or a linear or branched saturated or unsaturated hydrocarbon group having 1 to 4 carbon atoms, an acyl group, or an aralkyl group, and X and Y are hydrogen atoms at the same time. The amide derivative represented by (1) has the effect of fundamentally improving the water retention capacity of the stratum corneum.
Then, they found that the effect can be further increased by using a surfactant together with this amide derivative, and completed the present invention.

That is, the present invention provides a novel amide derivative represented by the above formula (I), an external skin preparation containing the amide derivative represented by the above formula (I), and an amide derivative represented by the above formula (I). It is intended to provide a skin external preparation containing a surfactant.

The amide derivative represented by the formula (I) used in the present invention is produced, for example, according to the reaction formula shown below.

(In the formula, R ¹ , R ² , X and Y are the same as above.) That is, the compound (II) obtained by selectively acylating the amino group of the compound (II) obtained from the glycidyl ether and the ethanolamine derivative. The amide derivative (I) is produced from this.

The reaction between the glycidyl ether and the ethanolamine derivative is carried out by stirring the glycidyl ether and ethanolamine or 2-methoxyethylamine in an alcohol solvent at 25 to 150 ° C. for several dozen minutes to 5 hours.

To acylate only the amino group of compound (II), for example, long-chain fatty acid methyl ester and compound (II) in the presence of a base such as alkali hydroxide or alkali carbonate can be used at atmospheric pressure to 0.01 Torr.
The reaction is carried out under reduced pressure at 25 to 150 ° C. for several dozen minutes to 5 hours.

Alkylation, acylation or aralkylation of the hydroxyl group of compound (III) is carried out by reacting an alkyl halide, an acyl halide, a carboxylic acid anhydride or an aralkyl halide in the presence of a base catalyst.
Alkyl halides used in this reaction include methyl iodide, ethyl bromide, ethyl iodide, 1-bromopropane, 2-bromopropane, 1-iodopropane, 2-iodopropane, 1-bromobromide. Butane, 2-butane bromide, 1-isobutane bromide, 1-butane iodide, 2-butane iodide,
1-Isobutane iodide, allyl bromide, allyl iodide and the like can be mentioned. Examples of acyl halides include acetyl chloride, propionyl chloride and butyryl chloride. Examples of the carboxylic acid anhydride include acetic anhydride, propionic anhydride, butyric anhydride and the like. Examples of the aralkyl halide include benzyl chloride, benzyl bromide, diphenylmethyl chloride, diphenylmethyl bromide, triphenylmethyl chloride, triphenylmethyl bromide, -p-methoxybenzyl chloride and the like. The base catalyst used in this reaction includes amines such as pyridine and triethylamine; metal hydrides such as sodium hydride;
Metal alkylated products such as butyl lithium; alkali hydroxides such as sodium hydroxide and potassium hydroxide.

The amount of the thus-obtained amide derivative (I) in the external preparation for skin of the present invention is not particularly limited, but in the case of an emulsified external preparation for skin, 0.001 to 50% by weight (hereinafter simply referred to as% )), Particularly 0.1 to 20% is preferable, and 1 to 50%, particularly 5 to 25% is preferable in the case of oily external preparation for skin based on liquid hydrocarbon such as squalene.

As the surfactant to be added to the skin external preparation of the present invention, any of a nonionic surfactant, an anionic surfactant, and an amphoteric surfactant can be used, among which a nonionic surfactant is particularly preferable. is there.

Examples of the nonionic surfactant include polyoxyethylene alkyl ether, polyoxyethylene alkylphenyl ether, polyoxyethylene fatty acid ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, fatty acid monoglyceride, glyceryl ether and the like. Among them, the following general formula (IV) (In the formula, R represents an alkyl group having 8 to 24 carbon atoms), wherein R is the following formula (V): (In the formula, p represents an integer of 4 to 10, q represents an integer of 5 to 11,
and a distribution represented by p + q = 11 to 17 with p = 7 and q = 8 at the vertices) is particularly preferable.

The content of the surfactant is 0.01 to 20% of the total composition, especially 0.1%.
-5% is preferable.

The external preparation for skin of the present invention is roughly classified into a medicated external preparation for skin and a cosmetic in its use form.

Examples of the external medicated skin preparation include various ointments containing medicinal components. The ointment may be either one based on an oily base, one based on oil / water, or one based on an emulsion base of water / oil type. The oily base is not particularly limited, for example, vegetable oil, animal oil,
Examples include synthetic oils, fatty acids, and natural or synthetic glycerides. The medicinal component is not particularly limited,
For example, an analgesic anti-inflammatory agent, an antipruritic agent, a bactericidal disinfectant, 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 above essential ingredients, oils, moisturizers, UV absorbers, alcohols, chelating agents, pH adjusters, preservatives, thickeners that are commonly used as cosmetic ingredients. , Dyes, fragrances and the like can be combined in any combination.

As the cosmetics, various forms such as water / oil, oil / water emulsion cosmetics, creams, lotions, lotions, oily cosmetics, lipsticks, foundations, skin cleansers, hair nicks, hair styling agents, It can be used as a skin cosmetic such as a hair nourishing agent or a hair restorer.

[Action]

Although the details of the mechanism of action of the amide derivative represented by the formula (I) in the external preparation for skin of the present invention have not been completely elucidated,
It is considered that this reconstructs the lipid membrane between the corneocytes and exerts the water retaining function of the stratum corneum.

[Effects of the Invention] Since the external preparation for skin of the present invention contains the amide derivative (I) having such an action, it can exert excellent effects of improving and preventing skin roughness.

〔Example〕

 Next, examples will be described.

Example 1 N- (3-hexadecyloxy-2-hydroxypropyl) -N-2-methoxyethylhexadecanamide (R ¹ =
^{_{C 16 H 33, R 2 =}} C 15 H 31, X = H, Y = CH 3) Synthesis of (Ia): stirrer, a dropping funnel, a thermometer, a reflux condenser 200m
l In a four-necked flask, 24.5 g of 2-methoxyethylamine
(0.592 mol) and 50 ml of ethanol were mixed, and 15.9 g (0.06 mol) of hexadecyl glycidyl ether was added dropwise at room temperature over 2 hours. After distilling off the solvent and unreacted 2-methoxyethylamine under reduced pressure, 0.14 g of potassium hydroxide was added to the residue.
(2.5 mmol) was added and the mixture was stirred at 80 ° C., 6.75 g (25 mmol) of methyl hexadecanoate was added dropwise thereto over 1 hour,
After completion of dropping, heating and stirring were continued for another 0.5 hours. The obtained crude product was purified by medium pressure liquid chromatography to obtain 11.38 g (yield 31.0%) of the target compound (Ia) as colorless crystals.

Melting point: 51-52 ° C IR (ν _KBr , cm ^-1 ): 3418,2920,2854,1620,1470,1110,72
3 Elemental analysis Calculated value: C74.57%, H12.68%, N2.29% Actual value: C74.70%, H12.75%, N2.25% Example 2 N- (3-hexadecyloxy-2- hydroxypropyl) -N-2-triphenylmethyl-methoxyethyl hexadecanol cyanamide ^{_{(R 1 = C 16 H 33}} , R 2 = C 15 H 31, X = H, Y = Ph
₃ C) (Ib) synthesis: N- (3-hexadecyloxy-2-hydroxypropyl) -N- in a 500 ml four-necked flask equipped with a stirrer, dropping funnel, reflux condenser and nitrogen inlet tube. 59.81 g (0.1 mol) of 2-hydroxyethylhexadecanamide, 28.73 g (0.101 mol) of triphenylmethyl chloride and 300 ml of anhydrous dichloromethane were stirred and mixed under a nitrogen stream. To this, a solution of 8.70 g (0.11 mol) of pyridine in 50 ml of anhydrous dichloromethane was added dropwise over about 5 minutes, and the mixture was heated under reflux at 40 ° C. for 6 hours. After completion of the reaction, the mixture was allowed to cool, the precipitated pyridine hydrochloride was filtered off, the filtrate was washed 4 times with 100 ml of water, dried over anhydrous sodium sulfate, and the solvent was distilled off to give a colorless wax-like crude product 77.11. g
Got This was purified by silica gel flash column chromatography (silica gel; 230 to 400 mesh, 1 kg, developing solvent; dichloromethane / ethyl acetate = 19/1) to obtain 59.37 g of the target compound (Ib) as a colorless wax-like solid ( Yield 70.7%) was obtained.

Melting point: 46-47 ° C IR (ν _KBr , cm ^-1 ): 3412,3058,3028,2926,2854,1653,1626,1473,1452,1083,
705 ¹ H-NMR (CDCl ₃ , δ): 1.86 (6H, t), 1.0 to 1.6 (54H, m), 2.2 to 2.5 (2H, m) 3.2
-4.1 (12H, m), 7.2-7.5 (15H, m) Example 3 N- (3-hexadecyloxy-2-methoxypropyl)
-N-2-hydroxyethylhexadecanamide ((R ¹ =
Synthesis of C ₁₆ H ₃₃ , R ² = C ₁₅ H ₃₁ , X = CH ₃ , Y = H) (Ic): 500 m equipped with stirrer, dropping funnel, thermometer, reflux condenser
l 100m anhydrous N, N-dimethylformamide in a four-necked flask
l, Sodium hydride (60% in mineral oil) 1.8g (0.045mol)
Were mixed at room temperature, and N- (3-hexadecyloxy-2-hydroxypropyl) -N-2-triphenylmethoxyethylhexadecanamide (Ib) 25.2 obtained in Example 2 was mixed therein.
A solution of g (0.03 mol) in anhydrous N, N-dimethylformamide in 100 ml was added. After the effervescence subsided, 8.5 g of methyl iodide (0.
06 mol) was added and stirred for 1 hour. Water was carefully added to the reaction product to decompose sodium hydride and then extracted with dichloromethane. After distilling off the solvent and water, the residue was dissolved in 50 ml of anhydrous dichloromethane to give boron trifluoride ether 11.07 g.
(0.078 mol) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate and extracted with chloroform. The chloroform extraction portion was dried, the solvent was distilled off, and the residue was purified by silica gel flash column chromatography to obtain 7.0 g (yield 38.1%) of the target compound (Ic) in the form of a colorless wax.

Melting point: 38-41 ° C IR (ν _KBr , cm ^-1 ): 3412,2920,2854,1644,1473,1425,1377,1188,1119,1083,
723 Elemental analysis Calculated value: C74.57%, H12.68%, N2.29% Measured value: C74.60%, H12.71%, N2.24% Example 4 N- (2-benzyloxy-3-hexadede siloxy propyl) -N-2-hydroxyethyl-hexadecanol cyanamide _{^{((R 1 = C 16 H}} 33, R 2 = C 15 H 31, X = PhCH 2, Y = H) (I
Synthesis of d): A 200 ml four-necked flask equipped with a stirrer, a dropping funnel, a reflux condenser, a thermometer and a nitrogen introducing tube was placed in the N- (3-hexadecyloxy-2-) obtained in Example 2. 58.82 g (0.07 mol) of (hydroxypropyl) -N-2-triphenylmethoxyethylhexadecanamide and 100 ml of anhydrous N, N-dimethylformamide were added and dissolved under stirring in a nitrogen stream. 5.6g (0.14% of sodium hydride (60% in mineral oil))
mol) was added and the mixture was stirred at room temperature for 3 hours. After the effervescence subsides, heat to 60 ° C and take benzyl chloride 17.90g (0.14mol)
Was added dropwise over 20 minutes, and the mixture was heated with stirring for 1.5 hours after completion of the addition. After completion of the reaction, water was dropped under a nitrogen stream to decompose excess sodium hydroxide, and then the mixture was poured into 500 ml of water. This was extracted with hexane, the hexane layer was washed twice with water and once with saturated saline, and then dried over anhydrous sodium sulfate,
Silica gel flash column chromatography (silica gel; 230-400 mesh, 1 kg, developing solvent: hexane /
Purified with ethyl acetate = 9/1) to give a pale yellow oily N-
(2-benzyloxy-3-hexadecyloxypropyl)
59.5 g of -N-2-triphenylmethoxyethylhexadecanamide was obtained.

This compound 55.83g (0.06mol), concentrated hydrochloric acid 6ml (0.072mol)
And 100 ml of dioxane were stirred at room temperature under a nitrogen stream for 9 hours. After the reaction was completed, dioxane was distilled off, 100 ml of dichloromethane was added, and the mixture was neutralized with aqueous sodium hydrogen carbonate. The dichloromethane layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give a pale yellow oily crude product 5
8.02 g was obtained. This was purified by silica gel flash column chromatography and medium-pressure liquid chromatography to obtain 14.17 g of the target compound (Id) as a colorless wax-like solid.
(Yield 31.4%) was obtained.

Melting point: 39-40 ° C IR (ν _KBr , cm ^-1 ): 3412,2920,2854,1647,1626,1473,1116,1089,1032 ¹ H-NMR (CDCl ₃ , δ): 0.86 (6H, t) , 1.1 ~ 1.5 (54H, br.s), 2.26 (2H, m), 3.3
~ 3.8 (12H, m), 4.51 (1H, d, J = 12.0Hz), 4.64 (1H, dd,
J = 12.0,1.6Hz), 7.31 (5H, br, s) Example 5 N- (2-acetoxy-3-hexadecyloxypropyl) -N-2-hydroxyethylhexadecanamide (R ^{1
_{= C 16 H 33, R 2}} = C 15 H 31, X = CH 3 CO, Y = H) Synthesis of (Ie): stirrer, equipped dropping funnel, reflux condenser, a thermometer and a nitrogen inlet tube 30ml In a four-necked four-necked flask, 500 mg (0.595 mmol) of N- (3-hexadecyloxy-2-hydroxypropyl) -N-2-triphenylmethoxyethylhexadecanamide obtained in Example 2 was added to 10 ml of anhydrous dichloromethane. Dissolved. To this, add 4 ml of pyridine, then 2 ml of acetic anhydride to 30
The mixture was added dropwise over minutes and stirred at room temperature for 8 hours. After completion of the reaction, the product was washed with 2N hydrochloric acid and then with water, dried over sodium sulfate, evaporated to remove the solvent, and purified by silica gel preparative thin layer chromatography to obtain N- (2-acetoxy-3-hexadecyloxypropyl). ) -N-2-triphenylmethoxyethylhexadecanamide 520 mg was obtained. 105 mg of this compound
(0.119 mmol) was dissolved in 2 ml of anhydrous dichloromethane in a 10 ml two-necked flask, and at room temperature and under a nitrogen atmosphere, 0.6 ml (0.595 mmol) of a 17% hexane solution of diethylaluminum chloride was added and stirred for 40 minutes, and 5% aqueous sodium hydrogen carbonate was added. Stopped the reaction. The white insoluble matter formed was filtered off using Celite, washed with water, dried over Glauber's salt, and the solvent was distilled off. The residue was purified by silica gel preparative thin-layer chromatography to obtain 73 mg of the target compound (Ie) as colorless crystals (yield 96 %) Was obtained.

Melting point: 59.5-60.0 ° C IR (ν _KBr , cm ^-1 ): 3514,2920,2854,1713,1641,1473,13
86,1275,1224,1206,1146,1077,1050 ¹ H-NMR (δ, CDCl ₃ ): 0.88 (6H, t), 1.2 to 1.8 (54H,
m), 2.07 (3H, s), 2.38 (2H, m), 3.3 to 3.9 (11H, m), 5.
1 to 5.3 (1H, m) Example 6 N- (2-acetoxy-3-hexadecyloxypropyl) -N-2-acetoxyethylhexadecanamide ((R ¹ = C ₁₆ H ₃₃ , R ² = C ₁₅ H ₃₁ , X = Y = CH ₃ CO) (If)
Synthesis of N- (3-hexadecyloxy-2-hydroxypropyl) -N-2-hydroxyethyl in a 30 ml four-necked flask equipped with a stirrer, a dropping funnel, a reflux condenser, a thermometer and a nitrogen inlet tube. Hexadecanamide (500 mg, 0.838 mmol) was suspended in pyridine (7 ml) and stirred at room temperature. Acetic anhydride 1 ml
Was added dropwise over 30 minutes and stirring was continued for 12 hours. After completion of the reaction, 10 ml of dichloromethane was added, washed with 2N hydrochloric acid and then with water, dried over anhydrous nitric acid, and the solvent was distilled off. The residue was purified by silica gel preparative thin layer chromatography to obtain colorless crystals of the target compound (If ) 570 mg (yield quantitative) was obtained.

Melting point: 58.5-60.6 ° C IR (ν _KBr , cm ^-1 ): 2920, 2854, 1740, 1650, 1467, 1380, 12
78,1257,1221,1206,1071,1053 ¹ H-NMR (δ, CDCl ₃ ): 1.26 (6H, t), 1.2 to 1.8 (54H,
m), 2.06 (6H, s) 2.35 (2H, m), 3.3 to 3.8 (8H, m), 4.20
(2H, m), 5.0-5.2 (1H, m) Example 7 N- (3-hexadecyloxy-2-methoxypropyl)
-N-2-methoxyethylhexadecanamide ((R ¹ = C
^{_{16 H 33, R 2 = C}} 15 H 31, X = Y = CH 3) Synthesis of (Ig): stirrer, dropping funnel, 300ml ml four-necked flask equipped with a nitrogen inlet tube N- (3- hexa Desiloxy-2-hydroxypropyl) -N-2-hydroxyethylhexadecanamide (23.92 g, 40 mmol) was suspended in 200 ml of anhydrous dioxane and stirred at room temperature. In addition to this, sodium hydride (in mineral oil
(60%) 3.52 g (88 mmol) was added and the mixture was stirred for 3 hours, and then methyl iodide 25.0 g (0.176 mol) was added dropwise over 1 hour. After completion of dropping, the mixture was stirred at room temperature for 19 hours. The reaction product was filtered through Celite to remove unreacted sodium hydride, and the solvent was distilled off to obtain 25.2 g of a pale yellow oily product. This was purified by medium-pressure liquid chromatography to give the target compound (Ig) 10.2 as a colorless wax.
7 g (yield 41%) was obtained.

Melting point: 36.3-38.0 ° C IR (ν _KBr , cm ^-1 ): 2920,2854,1644,1473,1422,1185,11
28,1095,717 ¹ H-NMR (δ, CDCl ₃ ): 0.86 (6H, t), 1.27 (54H, m), 2.
38 (2H, m), 3.43 (6H, s) 3.3 to 3.9 (11H, m) Example 8 Using compounds Ia to Ik obtained according to Examples 1 to 7 and the same, petrolatum / compound (Ia to The skin conductance and rough skin of the mixture (Ik) = 3/1 (weight ratio) (invention product 1) and petrolatum (comparative product 1) were evaluated by the following methods. The results are shown in Table 1.

(Test method) Ten women aged 20 to 50 who have rough skin on the cheeks in winter are used as test subjects, and different skin external preparations are applied to the left and right cheeks for 2 weeks. On the day after the application for two weeks was completed, the following items were tested.

(1) Skin conductance After washing the face with warm water of 37 ℃, apply 20 in a room with a temperature of 20 ℃ and a humidity of 40%.
After resting for a minute, the water content of the stratum corneum was measured with a skin conductance meter (IBS). The smaller the conductance value is, the rougher the skin is, and when the conductance value is 5 or less, the skin is severely rough. On the other hand, if this value is 20 or more, almost no skin is recognized.

(2) Rough skin score Rough skin was visually observed and judged according to the following criteria. The score is shown as an average value.

Example 9 An external preparation for skin (emulsified cosmetic) having the composition shown in Table 2 below using the compounds Ia to Ik obtained according to Examples 1 to 7 and the same.
Was produced, and its skin roughening improving effect was evaluated by the same method as in Example 8. The results are shown in Table 3.

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Claims (3)

[Claims] 1. The following general formula (I): (Wherein, R ¹ is a saturated or unsaturated hydrocarbon group, straight chain or branched chain of 10-26 carbon atoms, R ² is hydrocarbon a saturated or unsaturated linear or branched 9 to 25 carbon atoms A hydrogen group, X and Y represent a hydrogen atom or a linear or branched saturated or unsaturated hydrocarbon group having 1 to 4 carbon atoms, an acyl group, or an aralkyl group, and X and Y are hydrogen atoms at the same time. Amide derivative represented by 2. The following general formula (I): (Wherein, R ¹ is a saturated or unsaturated hydrocarbon group, straight chain or branched chain of 10-26 carbon atoms, R ² is hydrocarbon a saturated or unsaturated linear or branched 9 to 25 carbon atoms A hydrogen group, X and Y represent a hydrogen atom or a linear or branched saturated or unsaturated hydrocarbon group having 1 to 4 carbon atoms, an acyl group, or an aralkyl group, and X and Y are hydrogen atoms at the same time. The external preparation for skin is characterized by containing an amide derivative represented by 3. The following general formula (I): (Wherein, R ¹ is a saturated or unsaturated hydrocarbon group, straight chain or branched chain of 10-26 carbon atoms, R ² is hydrocarbon a saturated or unsaturated linear or branched 9 to 25 carbon atoms A hydrogen group, X and Y represent a hydrogen atom or a linear or branched saturated or unsaturated hydrocarbon group having 1 to 4 carbon atoms, an acyl group, or an aralkyl group, and X and Y are hydrogen atoms at the same time. Claim 2 characterized in that it contains an amide derivative represented by
The external preparation for skin according to the item.