JPH072698B2 - Amide derivative and external preparation for skin containing the same - Google Patents

Description

The present invention relates to a novel amide derivative, and a skin external preparation containing the same, and in particular, the barrier function of the stratum corneum is essentially improved (of normal barrier function). The present invention relates to a skin external preparation capable of maintaining and recovering a damaged barrier function).

[Conventional technology]

The stratum corneum is located on the outermost surface of the skin and covers the entire body surface, plays a role of preventing irritation from the outside of the body and invasion of foreign substances, and preventing evaporation of water from the body.

However, if the barrier function of the stratum corneum is weakened for some reason, problems such as easy inflammation of the skin and easy occurrence of rough skin occur.

It is also known that when essential fatty acids are deficient or deficient in the body by continuing to eat foods that do not contain essential fatty acids such as arachidonic acid and linoleic acid, and essential fatty acid deficiency occurs, the barrier function of the stratum corneum is impaired. Has been.

It has been clarified from the results of analysis of intercellular lipids that lipids between corneal cells, particularly O-acylceramide, play an extremely important role in maintaining the barrier function of the corneal layer. .

In addition, it is said that a part of the barrier function of the stratum corneum is supplemented by the lipid secreted from the sebaceous glands forming the sebaceous membrane on the skin surface. Conventionally, skin external preparations containing vaseline etc. It is used for the purpose of forming a film on the surface and supplementing the barrier function of the stratum corneum.

[Problems to be Solved by the Invention]

However, conventional external preparations for skin and the like merely form a film on the skin surface temporarily to replenish the barrier function, and do not essentially improve the barrier function of the stratum corneum.

Therefore, the object of the present invention is to maintain the normal barrier function of the stratum corneum and to restore the damaged barrier function, that is, the external barrier agent of the stratum corneum. It is intended to provide an external preparation for the skin which can be improved and which makes it less likely to cause inflammation, rough skin and the like.

[Means for Solving the Problems]

As a result of earnest studies to achieve the above-mentioned object, the present inventors have found that an external preparation for skin containing a novel amide derivative represented by the following general formula (I) can essentially improve the barrier function of the stratum corneum. The present invention has been completed.

(In the formula, R ¹ represents a linear or branched saturated or unsaturated hydrocarbon group having 10 to 40 carbon atoms, and R ² represents 3 to 39 carbon atoms.
Is a straight chain or branched chain hydrocarbon group, and R ³ is a hydrogen atom or a straight chain or branched chain saturated or unsaturated hydrocarbon group having 10 to 40 carbon atoms or an acyl group. That is, the present invention provides an amide derivative represented by the general formula (I) and a skin external preparation containing the amide derivative.

Hereinafter, the amide derivative of the present invention will be described first.

The production method of the amide derivative of the present invention represented by the general formula (I) is not particularly limited, and can be produced, for example, by the following methods (1) to (3).

(1) Method for producing an amide derivative (IA) in which R ³ is a hydrogen atom in the general formula (I): The amide derivative (IA) is a known method [for example,
The method described in JP-A-63-216852]. That is, a hydroxy fatty acid lower alkyl ester (III-A) or hydroxy fatty acid lactone (IV) was added to an amine derivative (II) obtained from glycidyl ether and ethanolamine according to the reaction formula shown below in the presence of a base catalyst. It can be produced by causing the reaction to occur while distilling off the produced lower alcohol.

(In the formula, R ¹ and R ² have the same meanings as in the case of the general formula (I), and R ⁴ represents an alkyl group having 1 to 5 carbon atoms.) (2) In the general formula (I), R 4 Method for producing amide derivative (IB) in which ³ is a linear or branched saturated or unsaturated hydrocarbon group having 10 to 40 carbon atoms: The above amide derivative (IB) is a reaction shown by the following. According to the formula, an etherified fatty acid ester (III-B) is obtained by reacting a hydroxy fatty acid (III) or hydroxy fatty acid ester (III-A) with an alkyl halide (V) or a sulfonic acid alkyl ester (VI) in the presence of a base. ) Is obtained, and this is reacted with the amine derivative (II) obtained by the above method (1) in the presence of a base catalyst, and the produced alcohol is reacted while distilling off.

(In the formula, R ¹ , R ² and R ⁴ have the same meanings as in the reaction formula (1), and R ³ is a straight or branched chain saturated or unsaturated hydrocarbon having 10 to 40 carbon atoms. Represents a group, R ⁵
Represents a methyl group, a phenyl group or a p-toluyl group. X represents Cl, Br or I. (3) A method for producing an amide derivative (IC) in which R ³ in the general formula (I) is a linear or branched saturated or unsaturated acyl group having 10 to 40 carbon atoms: I-C) is prepared by reacting a hydroxy fatty acid ester (III-A) and a fatty acid (VII) with a suitable dehydrating agent [eg, according to the reaction formula shown below. And P (C ₆ H ₅ ) ₃ ] in the presence of an acyl fatty acid ester (III-C), and the amine derivative (II) obtained by the method (1) above in the presence of a base catalyst. It can be produced by reacting it while allowing it to act and distill off the produced alcohol.

(In the formula, R ¹ , R ² and R ⁴ have the same meaning as in the reaction formula of the above (1), and R ⁶ is a linear or branched saturated or unsaturated hydrocarbon having 9 to 39 carbon atoms. Further, the above amide derivative (IC) can also be produced according to the reaction formula shown below using an appropriate protecting group.

(In the formula, R ¹ , R ² , R ⁴ and R ⁶ have the same meanings as in the above reaction formula, and R ⁷ is a group. Or And R ⁸ represents an acetyl group or a tert-butyldiphenylsilyl group. ) That is, after protecting the hydroxy group of the hydroxy fatty acid ester (III-A) with an ether protecting group R ⁷ such as tetrahydropyranyl group and ethoxyethyl group, the amine derivative (II)
With a base catalyst to give an amide derivative (IX), and then two hydroxy groups of the amide derivative (IX) are protected with an acetyl group or a tert-butyldiphenylsilyl group (R ⁸ ), followed by a protecting group R ⁷ is deprotected by reacting alcohol with an alcohol in the presence of an acid catalyst to give an amide derivative (XI), and then a suitable dehydrating agent [eg, And P (C ₆ H ₅ ) ₃ ] in the presence of a fatty acid (VII) or in the presence of a base, a fatty acid chloride (XII) to act as an amide derivative (XIII), and finally, protection. Group R ⁸
Deprotection [when R ⁸ is an acetyl group, K _{2 in} a lower alcohol
With CO _3, Na ₂ CO ₃ or the like of the base, and when R ⁸ is tert- butyldiphenylsilyl group, using a fluoride ion such as tetrabutylammonium fluoride] to give the amide derivative (I-C) .

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

The amount of the amide derivative of the present invention used when used as 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, 0.001 to 50% by weight of the total composition (hereinafter, simply referred to as% In the case of oily external preparation for skin based on liquid hydrocarbon such as squalane, 0.01 to
50% is preferred.

The skin external preparation of the present invention comprises a conventional skin external preparation base and an amide derivative represented by the general formula (I). Broadly divided.

Examples of the external medicated skin agent include various ointments containing medicinal components. The ointment may be either an oil-based base, an oil / water, or a water / oil-type emulsion base. The oily base is not particularly limited, for example, vegetable oil,
Examples thereof include 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, alcohols, chelating agents, pH adjusters that are commonly used as cosmetic ingredients. , An antiseptic, a thickener, a dye, a fragrance and the like can be arbitrarily combined and blended.

As cosmetics, various forms, for example, water / oil, oil / water emulsion cosmetics, creams, lotions, lotions, oily cosmetics, lipsticks, foundations, skin cleansers, hairnics, hairdressing agents, hair nourishing agents , And a skin cosmetic such as a hair restorer.

[Action]

Although the details of the mechanism of action of the external preparation for skin containing the amide derivative of the present invention represented by the general formula (I) has not been completely elucidated, keratinocytes can be obtained by applying it to the skin as an external preparation for skin. It is presumed that it strengthens the intervening lipid membrane and improves the barrier function of the stratum corneum.

〔Example〕

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

Example 1 N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-12-hydroxyoctadecane amide [in the general formula (I), R ¹ = C ₁₆ H ₃₃
-as well as Of amide derivative] (I-Aa): Synthesis of N- (2-hydroxy-3-hexadecyloxypropyl) ethanolamine (IIa): Stirrer, dropping funnel, thermometer and reflux condenser 20
61.1 g (1.0 mol) of ethanolamine in a 0 ml 4-necked flask
Was added, and while heating and stirring at 60 to 70 ° C., 24.3 g (0.082 mol) of hexadecyl glycidyl ether was added dropwise to this over 45 minutes. After completion of dropping, the mixture was further heated and stirred under the same conditions for 2 hours, and unreacted ethanolamine was distilled off under reduced pressure (79 to 81
C / 20 Torr). The residue was purified by silica gel flash column chromatography to obtain 18.4 g of the title compound (IIa) (yield 63%). The ¹ H-NMR measurement results of the obtained compound are as follows. ¹ H-NMR (δ, CDCl ₃ ): 0.85 (t, 3H), 1.23 (bs, 28H), 2.6 to 2.8 (m, 4H), 3.
1 ~ 3.9 (m, 10H) Synthesis of amide derivative (I-Aa): 10 equipped with stirrer, dropping funnel, thermometer and distiller
In a 0 ml flask, 17.3 g (48 m) of the compound (IIa) obtained above
mol) and KOH 0.14 g (2.5 mmol) were charged, and 80 ℃ / 20Torr
While heating and stirring under reduced pressure at 15.1, 15.2 g (48 mmol) of methyl 12-hydroxyoctadecanoate was added dropwise over 1 hour.
After completion of the dropwise addition, the mixture was further stirred for 1 hour under the same conditions, and the obtained crude product was purified by silica gel flash column chromatography to obtain 23.0 g of the title compound (I-Aa) (yield 74%). . The melting point of the obtained compound, 1R and ¹ HN
The MR measurement results were as follows.

^{Mp: 70.8~71.3 ℃ IR: 3352,2926,2854,1617,1473,1122,1077cm -1 1} H-NMR (δ, CDCl 3): 0.88 (t, J = 6.3Hz, 6H), 1.12~1.82 ( m, 56H), 2.24 ~
2.51 (m, 2H), 3.23 to 4.30 (m, 15H) Example 2 N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-16-hydroxyhexadecanamide [the above general formula ( In I) R ¹ = C
₁₆ H ₃₃ , R ³ OR ² = HO (CH ₂ ) ₁₅ -is an amide derivative] (IA
Synthesis of b): The amine (IIa) obtained in Example 1 was reacted with methyl 16-hydroxyhexadecanoate in the same manner as in Example 1 to obtain the target compound (I-Ab) as a colorless powder ( Yield 75
%). The melting point, IR and ¹ H-NMR measurement results of the obtained compound are as follows.

Melting point: 80.6-81.5 ° C IR: 3370, 2920, 2854, 1626, 1596, 1473, 1131, 106
^{2,723cm -1 1 H-NMR (δ} , CDCl 3): 0.88 (t, J = 6.6Hz, 3H), 0.96~1.80 (m, 54H), 2.30~
2.48 (m, 2H), 3.24-4.17 (m, 15H) Example 3 N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-16- (9Z, 12Z-octadecadi Enoxy) hexadecanamide [in the general formula (I), R ¹ ═C ₁₆ H ₃₃ and Is an amide derivative] (I-Ba): Synthesis of methyl 16- (9Z, 12Z-octadecadienyloxy) hexadecanoate (III-Ba): Stirrer, dropping funnel, thermometer and reflux condenser Prepared
In a 300 ml 4-necked flask, 16-hydroxyhexadecanoic acid
2.72 g (10 mmol), anhydrous tetrahydrofuran 50 ml, anhydrous hexamethylphosphoryltriamide 5 ml and sodium hydride 0.24 g (10 mmol) were added, and the mixture was stirred at room temperature for 30 minutes under N ₂ gas flow. The mixture was then cooled to -70 ° C,
After adding 6.25 ml (10 mmol) of 1.6N butyllithium hexane solution, the mixture was heated to room temperature over 30 minutes, 0.24 g (10 mmol) of sodium hydride was added thereto, and the mixture was further stirred at room temperature for 30 minutes. Next, p-toluenesulfonic acid 9Z, 12Z-
9.25 g (22 mmol) of octadecadienyl ester was added dropwise, and the mixture was heated and stirred at 65 ° C for 18 hours, 150 ml of anhydrous methanol was added to the reaction mixture, and the mixture was further stirred at 65 ° C for 1 hour. After cooling the reaction mixture to room temperature, excess alkali was neutralized with an aqueous solution of ammonium chloride, the reaction mixture was extracted with toluene, the solvent was evaporated under reduced pressure, and the residue was purified by flash column chromatography to give the title compound ( III-Ba) 0.72 g was obtained (yield 13.5%).

Synthesis of amide derivative (I-Ba): The compound (III-Ba) obtained above and the amine (IIa) obtained in Example 1 were reacted in the same manner as in Example 1 to give the target compound as a colorless powder. (I-Ba) was obtained (yield 71
%). The melting point, IR and ¹ H-NMR measurement results of the obtained compound are as follows.

Melting point: 63.0-64.3 ° C IR: 3304, 2920, 2854, 1614, 1467, 1116, 1062, 720cm
^{-1 1} H-NMR (δ, CDCl ₃ ): 0.80 to 0.95 (m, 6H), 0.95 to 1.70 (m, 72H), 1.95 to 2.1
2 (m, 4H), 2.39 (t, J = 7.7Hz, 2H), 2.77 (bt, J = 5.7H
z, 2H), 3.39 (t, J = 6.6Hz, 4H), 3.23 to 4.23 (m, 13
H), 5.24 to 5.44 (m, 4H) Example 4 N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-16- (9Z, 12Z-octadecadienoyloxy) hexadecane Amide [in the general formula (I), R ¹ = C ₁₆ H ₃₃ -and Synthesis of amide derivative] (I-Ca): Synthesis of methyl 16- (9Z, 12Z-octadecadienoyloxy) hexadecanoate (III-Ca): 300 ml flask equipped with stirrer, dropping funnel and thermometer In addition, 4.30 g of methyl 16-hydroxyhexadecanoate (15 m
mol), 8.41 g (13 mmol) of linoleic acid, 7.87 g (30 mmol) of triphenylphosphine and 100 ml of tetrahydrofuran, and diethyl azodicarboxylate 5.22 with stirring at room temperature.
g (30 mmol) was added dropwise over 1 hour. 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 (III-Ca) (yield 8
2%).

Synthesis of amide derivative (I-Ca): 50 equipped with stirrer, dropping funnel, thermometer and distillation device
2.74 g (5%) of the compound (III-Ca) obtained above in a ml flask.
mmol), 1.80 g (5 mmo of amine (IIa) obtained in Example 1)
l) and potassium tert-butoxide 0.028 g (0.25 mmol)
Was charged, and the mixture was heated and stirred for 30 minutes under reduced pressure of 80 ° C./20 Torr. The obtained crude product was purified by silica gel column chromatography and gel chromatography to obtain 1.65 g of the title compound (I-Ca) (yield 38%). The measurement results of melting point, IR, ¹ H-NMR and MS of the obtained compound were as follows.

Melting point: 58.2-58.9 ° C IR: 3304, 2920, 2856, 1734, 1612, 1464, 1440, 121
^{6,1166,1108,756,720cm -1 1 H-NMR (δ} , CDCl 3): 0.80~1.00 (m, 6H), 1.00~1.73 (m, 70H), 1.95~2.1
6 (m, 4H), 2.28 (t, J = 7.5Hz, 2H), 2.39 (bt, J = 7.7H
z, 2H), 2.77 (bt, J = 5.9Hz, 2H), 3.23-4.25 (m, 13
H), 4.05 (t, J = 6.6Hz, 2H), 5.26 to 5.47 (m, 4H) MS (FAB, POS): 877 (M + 1), 859, 634, 596, 360 (FAB, NEG): 875 ( M-1), 873, 831, 613, 534, 359, 305, 279 Example 5 N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-16- (9Z-octade Cenoyloxy) hexadecanamide [in the general formula (I), R ¹ ═C ₁₆ H ₃₃ − and Is an amide derivative] (I-Cb): N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-16- (2-tetrahydropyranyloxy) hexadecanamide (IX- Synthesis of b): In one flask equipped with a stirrer and a dropping funnel, 16-
Methyl hydroxyhexadecanoate 100.26g (0.35mol),
0.60 g (3.5 mmol) of p-toluenesulfonic acid and 350 ml of dichloromethane were charged, and 32.39 g (0.385 mol) of dihydropyran was added dropwise with stirring at 0 ° C. After completion of dropping, 1
The reaction was completed by stirring at room temperature for hours. Next, 0.59 g (7 mmol) of NaHCO ₃ was added to the reaction mixture for neutralization, filtration and evaporation of the solvent to give 16- (2-tetrahydropyranyloxy).
A crude product of methyl hexadecanoate was obtained.

Next, in one flask equipped with a stirrer, a dropping funnel, a thermometer and a distillation device, the N- (2 obtained in Example 1 was obtained.
-Hydroxy-3-hexadecyloxypropyl) ethanolamine (IIa) 125.9 g (0.35 mol) and KOH 0.98 g (1
(7.5 mmol) was charged, and the methyl 16- (2-tetrahydropyranyloxy) hexadecanoate crude product obtained above was added dropwise over 2 hours while stirring under heating at 80 ° C./20 Torr under reduced pressure to generate. The methanol was distilled off. After the dropping is completed,
The mixture was further stirred under the same conditions for 2 hours, and the obtained crude product was recrystallized from methanol to give compound (IX-b) 212.
3 g was obtained (yield 86.9%).

N- (2- (tert-butyldiphenylsilyloxy)
-3-Hexadecyloxypropyl) -N-2- (tert-
Synthesis of butyldiphenylsilyloxy) ethyl-16-hydroxyhexadecanamide (XI-b): In one flask equipped with a stirrer and a dropping funnel, 34.91 g (0.05 mol) of compound (IX-b) obtained above, imidazole 13.62g (0.2mol) and dimethylformamide 350ml
Was charged, 30.24 g (0.11 mol) of tert-butyldiphenylchlorosilane was added dropwise with stirring at room temperature, and the mixture was heated to 50 ° C. and stirred for 14 hours. After completion of the reaction, the reaction mixture was extracted with diethyl ether, washed with brine, and the solvent was evaporated under reduced pressure.

Next, the residue obtained above was charged into one flask equipped with a stirrer, and 550 ml of ethanol and 150 ml of methanol were charged therein.
ml and pyridinium paratoluene sulphonate 2.36 g
(9.4 mmol) was added, and the mixture was stirred at room temperature for 28 hours. After the reaction was completed, the reaction mixture was neutralized with NaHCO ₃ , the reaction mixture was extracted with diethyl ether, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash column chromatography to obtain 39.5 g of compound (XI-b). (Yield 72.4%).

Synthesis of amide derivative (I-Cb): In a 200 ml flask equipped with a stirrer and a dropping funnel, 4.25 g (3.9 mmol) of compound (XI-b) obtained above, pyridine
Charge 1.23 g (15.6 mmol) and 50 ml of dichloromethane,
1.41 g (4.7 mmol) of oleoyl chloride was added dropwise with stirring at room temperature. After completion of the dropwise addition, the reaction was completed by stirring at room temperature for 1 hour, the reaction mixture was washed with water, the solvent was distilled off under reduced pressure, and the highly polar by-product was removed by silica gel short column chromatography to obtain a crude product. Obtained.

Next, the crude product obtained above was treated with a stirring device for 200 m.
Into a 1-flask, 50 ml of tetrahydrofuran and 2.46 g (7.8 mmol) of tetrabutylammonium fluoride were added, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was extracted with chloroform, washed with brine, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel flash column chromatography to give the title compound (I-Cb) 2.67.
g was obtained (yield 77.9%). The melting point, IR and ¹ H-NMR measurement results of the obtained compound are as follows.

Melting point: 60.4-61.3 ° C IR: 3304, 2920, 2854, 1737, 1617, 1467, 1443, 119
^{1,1110,1062,723cm -1 1 H-NMR (δ} , CDCl 3): 0.88 (t, J = 6.4Hz, 6H), 1.10~1.85 (m, 76H), 1.85~
2.10 (m, 4H), 2.29 (t, J = 7.5Hz, 2H), 2.39 (bt, J =
7.6Hz, 2H), 3.21 ~ 4.20 (m, 13H), 4.05 (t, J = 6.7Hz,
2H), 5.34 (bt, J = 5.3Hz, 2H) Example 6 N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-16- (methylhepdecanoyloxy) hexadecanamide [In the general formula (I), R ¹ = C ₁₆ H ₃₃ -and (Wherein p represents an integer having a distribution with p = 7 at the apex)] Synthesis of (I-Cc): Methylheptadecanoyl chloride in place of oleoyl chloride in Example 5. The reaction was performed in the same manner as in Example 5 except that was used to obtain the target compound (I-Cc) (yield: 65.5).
%). The melting point, IR and ¹ H-NMR measurement results of the obtained compound are as follows.

Melting point: 60.1-62.0 ° C IR: 3298, 2926, 2380, 1737, 1614, 1467, 1443, 120
^{3,1110,1059,720cm -1 1 H-NMR (δ} , CDCl 3): 0.77~1.00 (m, 9H), 1.03~1.75 (m, 81H), 2.29 (t, J
= 7.5Hz, 2H), 2.40 (bt, J = 7.3Hz, 2H), 3.24 to 4.33
(M, 13H), 4.05 (t, J = 6.6Hz, 2H) Example 7 N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-3- (9Z, 12Z-octa Decadienoyloxy) dotriacontanamide [in the general formula (I), R ¹ ═C ₁₆ H ₃₃ − and Synthesis of amide derivative] (I-Cd) of Example 5; In Example 5, methyl 16-hydroxyhexadecanoate was replaced with methyl 32-hydroxydotriacontanate, and in Example 5, oleoyl chloride was added. Example 5 except that linoleoyl chloride was used instead
A target compound (I-Cd) was obtained by performing a reaction in the same manner as in (24.8% yield). The melting point, IR and ¹ H-NMR measurement results of the obtained compound are as follows.

Melting point: 72.4-73.0 ° C IR: 3304, 2920, 2852, 1738, 1614, 1466, 1442, 116
^{8,1112,1062,760,722cm -1 1 H-NMR (δ} , CDCl 3): 0.81~1.01 (m, 6H), 1.10~1.72 (m, 92H), 1.95~2.1
5 (m, 4H), 2.29 (t, J = 7.5Hz, 2H), 2.39 (bt, J = 7.6H
z, 2H), 2.77 (bt, J = 5.7Hz, 2H), 3.18-4.20 (m, 13
H), 4.05 (t, J = 6.7 Hz, 2H), 5.23 to 5.46 (m, 4H) Example 8 N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-16- (12-Hydroxyoctadecanoyloxy) hexadecanamide [in the above general formula (I), R ¹ = C ₁₆ H ₃₃ -and Synthesis of 12- (tert-butyldimethylsilyloxy) octadecanoic acid; In a 100 ml flask equipped with a stirrer and a dropping funnel, 12- (tert-butyldimethylsilyloxy) octadecanoic acid was added.
-Ethyl hydroxyoctadecanoate 3.28 g (10 mmol),
1.36 g (20 mmol) of imidazole and 50 ml of dimethylformamide were charged, and 1.66 g (11 mmol) of tert-butyldimethylchlorosilane was added dropwise while stirring at room temperature. After completion of the dropwise addition, the reaction mixture was stirred at 50 ° C. for 18 hours to terminate the reaction. Then, the reaction mixture was extracted with ether, washed with brine, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel flash chromatography to obtain ethyl 12- (tert-butyldimethylsilyloxy) octadecanoate. .

Next, 100 ml of the ethyl 12- (tert-butyldimethylsilyloxy) octadecanoate obtained above was equipped with a stirrer.
Place in a flask and add 20 ml of ethanol and 50% KO here.
2.24 g (20 mmol) of H aqueous solution was added, and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the obtained reaction mixture was neutralized with hydrochloric acid,
Chloroform extracted, the solvent was distilled off under reduced pressure, and 12- (te
rt-Butyldimethylsilyloxy) octadecanoic acid 4.0 g
Was obtained (yield 96.4%).

Synthesis of amide derivative (I-Ce): In a 100 ml flask equipped with a stirrer, a dropping funnel and a thermometer, 12.87 g (4.5 mmol) of 12- (tert-butyldimethylsilyloxy) octadecanoic acid obtained above, Example 5.27 g (3 mmol) of the compound (XI-b) obtained in 5 above, 1.18 g (4.5 mmol) of triphenylphosphine and 10
Charge ml and stir at room temperature with stirring with diethyl azodicarboxylate.
A solution of 0.71 g (4.05 mmol) in 5 ml of tetrahydrofuran was added dropwise over 5 minutes. After the dropwise addition was completed, 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 column chromatography.

Next, 100 ml of the intermediate obtained above was equipped with a stirrer.
The mixture was placed in a flask, tetrahydrofuran (60 ml) and tetrabutylammonium fluoride (3.24 g, 10.3 mmol) were added thereto, and the mixture was heated with stirring at 60 ° C for 24 hours. Then, the obtained reaction mixture was extracted with chloroform, washed with brine, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel flash column chromatography to obtain 0.63 g of the title compound (I-Ce). (Yield 23.4%). The melting point, IR and ¹ H-NMR measurement results of the obtained compound are as follows.

Melting point: 71.7-73.7 ° C IR: 3336, 2920, 2852, 1740, 1620, 1470, 1180, 111
^{6,1060,722cm -1 1 H-NMR (δ} , CDCl 3): 0.89 (bt, J = 6.2Hz, 6H), 1.07~2.00 (m, 82H), 2.30
(T, J = 7.5Hz, 2H), 2.40 (bt, J = 7.6Hz, 2H), 3.22 ~
4.21 (m, 15H), 4.06 (t, J = 6.6Hz, 2) Example 9 N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-16- (9,10, 12-trihydroxyoctadecanoyloxy) hexadecanamide [in the general formula (I), R ¹ = C ₁₆ H ₃₃ -and Synthesis of amide derivative] (I-Cf): Reaction similar to that in Example 8 except that ethyl 9,10,12-trihydroxyoctadecanoate was used in place of ethyl 12-hydroxyoctadecanoate in Example 8. Was carried out to obtain the target compound (I-Cf) (yield 32.7%). The melting point, IR and ¹ H-NMR measurement results of the obtained compound are as follows.

Melting point: 75.8-79.2 ° C IR: 3300, 2924, 2856, 1728, 1620, 1470, 1178, 112
^{0,1070,722cm -1 1 H-NMR (δ} , CDCl 3): 0.82~1.02 (m, 6H), 1.15~2.30 (m, 78H), 2.30 (t, J
= 7.4Hz, 2H), 2.41 (bt, J = 7.6Hz, 2H), 3.22 to 4.26
(M, 19H), 4.07 (t, J = 6.6Hz, 2H) Example 10 N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-12- (9Z, 12Z-octa Decadienoyloxy) dodecanamide [in the general formula (I), R ¹ ═C ₁₆ H ₃₃ − and Of amide derivative] (I-Cg): N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-12- (2-tetrahydropyranyloxy) dodecane amide (IX- Synthesis of g): In the same manner as in Example 5 except that methyl 12-hydroxydodecanoate was used in place of methyl 16-hydroxyhexadecanoate in Example 5, the target compound (IX-
g) was obtained (yield 67.8%).

Synthesis of N- (2-acetoxy-3-hexadecyloxypropyl) -N-2-acetoxyethyl-12-hydroxydodecanamide (XI-g): Obtained as above in one flask equipped with stirrer and dropping funnel. Compound (IX-g) 167.0g (0.23mol), pyridine 9
Charge 1.0 g (1.15 mol) and 440 ml of dichloromethane,
45.1 g (0.575 mol) of acetyl chloride was added dropwise over 1.5 hours with stirring at ℃. After the dropping is completed, the reaction is further performed for 1 hour,
The reaction was completed. Then, 7.4 g (0.23 mol) of methanol was added to this reaction mixture to react with excess acetyl chloride, and the obtained mixture was washed with water, 2N-hydrochloric acid and brine, and the solvent was evaporated.

Next, the intermediate obtained above was charged into one flask equipped with a stirrer, and 368 g (0.115 mol) of methanol and 1.16 g (4.6 mmo of pyridinium paratoluenesulfonate were added thereto.
l) was added and the mixture was stirred at 40 ° C. for 5 hours. After completion of the reaction, NaHCO
₃ 0.76 g (9.2 mmol) was added for neutralization, methanol was distilled off, the residue was dissolved in chloroform and washed with brine,
The solvent was distilled off under reduced pressure, the residue was purified by silica gel short column chromatography, and the target compound (XI-g) 118.
3 g was obtained (yield 80.1%).

Synthesis of amide derivative (I-Cg): 73.6 g (0.115 mol) of the compound (XI-g) obtained above, 160 ml of dichloromethane and 21.8 g (0.276 mol) of pyridine were placed in a flask equipped with a stirrer and a dropping funnel. Preparation,
41.2 g (0.138 mol) of linoleoyl chloride was mixed with stirring at 0 ° C.
The solution was added dropwise over 0 minutes, and after the completion of the addition, stirring was continued for 2 hours. Next, 1.6 g (0.05 mol) of methanol was added to this to make excess linoleoyl chloride into methyl linoleate, the reaction mixture was washed with brine, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel short column chromatography. Purified.

Next, the intermediate obtained above was charged into a 3 l flask equipped with a stirrer, and ethanol 1, methanol 0.5 l and
29.4 g (0.213 mol) of K ₂ CO ₃ was added, and the mixture was stirred at 0 to 10 ° C for 1 hour. After the reaction is complete, add water to dissolve the formed salt, extract the reaction mixture with diisopropyl ether, wash with brine, evaporate the solvent under reduced pressure, and purify the residue by silica gel flash column chromatography. This gave 62.0 g of the title compound (I-Cg) (yield 65.7%).
The melting point, IR and ¹ H-NMR measurement results of the obtained compound are as follows.

Melting point: 50.6-52.8 ° C IR: 3304, 2924, 2856, 1734, 1616, 1470, 1176, 110
^{8,1060,720cm -1 1 H-NMR (δ} , CDCl 3): 0.82~0.95 (m, 6H), 1.13~1.74 (m, 62H), 1.96~2.1
3 (m, 4H), 2.29 (t, J = 7.5Hz, 2H), 2.39 (bt, J = 7.6H
z, 2H), 2.77 (bt, J = 5.7Hz, 2H), 3.22 to 4.21 (m, 13
H), 4.05 (t, J = 6.71 Hz, 2H), 5.23 to 5.48 (m, 4H) Example 11 N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-15- (9Z, 12Z-octadecadienoyloxy) pentadecanamide [in the above general formula (I), R ¹ = C ₁₆ H ₃₃ -and Synthesis of amide derivative of (I-Ch): In Example 10, except that methyl 15-hydroxypentadecanoate was used instead of methyl 12-hydroxydodecanoate, a reaction was carried out in the same manner as in Example 10, The target compound (I-Ch) was obtained (yield 42.3%). The melting point, IR and ¹ H-NMR measurement results of the obtained compound are as follows.

Melting point: 64.2-65.7 ° C IR: 3312, 2924, 2856, 1734, 1618, 1466, 1440, 118
^{6,1110,1060,722cm -1 1 H-NMR (δ} , CDCl 3): 0.82~0.97 (m, 6H), 1.15~1.63 (m, 58H), 1.96~2.1
4 (m, 4H), 2.29 (t, J = 7.5Hz, 2H), 2.39 (bt, J = 7.6H
z, 2H), 2.77 (bt, J = 5.7Hz, 2H), 3.21 ~ 4.20 (m, 13
H), 4.05 (t, J = 6.7 Hz, 2H), 5.23 to 5.48 (m, 4H) Example 12 External use for the skin of the present invention consisting of 10% of the amide derivative of the present invention shown in Table 1 below and 90% of squalane. Each of these preparations was manufactured, and the transepidermal water loss and percutaneous absorption of these external preparations for skin were evaluated by the following test methods. Also,
As a comparison, the same test was performed on a skin external preparation (comparative product) consisting of squalane alone. The results are shown in Table 1 below.

(Test method) Wister with only feed that does not contain essential fatty acids
Male male rats are bred, and the external skin preparation is applied to the shaved back skin once a day for 3 weeks to the rats showing symptoms of essential fatty acid deficiency. The test was conducted on the following items the day after the application for 3 weeks was completed.

In addition, three rats were subjected to the test for each external preparation for skin.

(1) Transepidermal water loss After washing the rat's back skin with warm water at 37 ℃, leave it in a room at a temperature of 20 ℃ and a humidity of 45% for 1 hour, and then measure the water loss from the epidermis with an evaporation meter. It was measured at. The larger the value of this water evaporation amount, the lower the barrier function of the stratum corneum, indicating that the skin is roughened.

This value is 10 if the normal barrier function is maintained.
Below, but above 35 in essential fatty acid deficient rats with impaired barrier function. The measured values are shown as the average value ± standard deviation.

(2) Percutaneous absorption amount After washing the back skin of rats with warm water at 37 ° C, the skin is cut off and inserted into the transdermal absorption chamber with the epidermis side facing up. The lower receiver is filled with phosphate buffered balanced salt solution and the epidermal side container is filled with 1 ml of a solvent containing 37 KBq of ¹⁴ C-salicylic acid. After 2 hours, the amount of ¹⁴ C-salicylic acid that has penetrated into the lower receiver is measured. When the normal barrier function is maintained, it hardly penetrates in 2 hours, and the larger the impaired barrier function, the larger the value. The measured values are shown as the average value ± standard deviation.

Example 13 Using the amide derivative of the present invention, a skin external preparation (emulsified cosmetic) of the present invention having the composition shown in Table 2 below was produced, and its skin roughening improving effect was evaluated by the following test methods. Further, for comparison, the same test was performed on an external preparation for skin (comparative product) containing no amide derivative of the present invention.
The results are shown in Table 3 below.

(Test method) Ten females aged 20 to 40 who have rough skin on the cheeks in winter are used as test subjects, and different topical skin preparations are applied to the left and right cheeks once a day for 3 weeks. The test was conducted on the following items the day after the application for 3 weeks was completed.

(1) Transepidermal water loss 30 After washing the face with warm water at 37 ° C, 30 in a room at a temperature of 20 ° C and a humidity of 45%.
After resting for a minute, the amount of water evaporated from the epidermis was measured with an evaporation meter. The larger the value of this water evaporation amount, the lower the barrier function of the stratum corneum, indicating that the skin is roughened. When this value exceeds 40, the skin is severely roughened, and when it is hardly observed, it becomes 10 or less. The measured values are shown as the average value ± standard deviation.

(2) Skin roughness score The skin roughness was visually observed and judged according to the following criteria. The score was shown by the average value +/- standard deviation.

Score Rough skin judgment 0 No rough skin is recognized 1 Slight rough skin is recognized 2 Rough skin is recognized 3 Slightly rough skin is recognized 4 Severe rough skin is recognized [Effects of the Invention] The external preparation for skin containing the amide derivative of the present invention has the effect of essentially improving the barrier function of the stratum corneum, and when applied to the skin, it is less likely to cause inflammation, rough skin, etc. can do.

Claims (2)

[Claims] 1. An amide derivative represented by the following general formula (I). (In the formula, R ¹ represents a linear or branched saturated or unsaturated hydrocarbon group having 10 to 40 carbon atoms, and R ² represents 3 to 39 carbon atoms.
Is a straight chain or branched chain hydrocarbon group, and R ³ is a hydrogen atom or a straight chain or branched chain saturated or unsaturated hydrocarbon group having 10 to 40 carbon atoms or an acyl group. ) 2. A skin external preparation containing an amide derivative represented by the following general formula (I). (In the formula, R ¹ represents a linear or branched saturated or unsaturated hydrocarbon group having 10 to 40 carbon atoms, and R ² represents 3 to 39 carbon atoms.
Is a straight chain or branched chain hydrocarbon group, and R ³ is a hydrogen atom or a straight chain or branched chain saturated or unsaturated hydrocarbon group having 10 to 40 carbon atoms or an acyl group. )