JP2686172B2 - 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 on the outermost surface of the skin and covers the entire body surface,
It plays a role in preventing irritation from outside the body and invasion of foreign matter, and also 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.

Then, it has been clarified from the results of the analysis of lipids between fats that lipids between corneal cells, particularly O-acylceramide, play an extremely important role in maintaining the barrier function of the stratum corneum. .

Further, it is said that a part of the barrier function of the stratum corneum is supplemented by forming a sebaceous membrane on the skin surface with lipids secreted from the sebaceous line, and conventional skin external preparations containing vaseline etc. It is used for the purpose of forming a film on the skin surface to supplement 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 problem]

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 amide derivative (IA) in which R ³ is a hydrogen atom in the general formula (I): The amide derivative (IA) is a known method [eg, JP-A-63-216852]. The method described in Japanese Patent Publication No. 1994-242242). That is, a hydroxy fatty acid lower alkyl ester (III-A) or hydroxy fatty acid lactone (IV) is 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 (V1) 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 C1, 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 ], to give an acyl fatty acid ester (III-C), which is condensed with an amine derivative (II) obtained by the method (1) 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 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, it is reacted with an amine derivative (II) in the presence of a base catalyst, Amide derivative (I
X), and then the two hydroxy groups of the amide derivative (IX) are protected with an acetyl group or a tert-butyldiphenylsilyl group (R ⁸ ), and the protecting group R ⁷ is treated with an alcohol in the presence of an acid catalyst. Deprotection by 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 protected. Basis
When the R ⁸ Deprotection [R ⁸ is an acetyl group, a lower alcohol
A base such as K ₂ CO ₃ or Na ₂ CO ₃ is used, and when R ⁸ is a tert-butyldiphenylsilyl group, a fluoride ion such as tetrabutylammonium fluoride is used] to prepare an amide derivative (IC ) Get.

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 to be used as the external preparation for skin of the present invention is not particularly limited, but usually 0.001 to 50% by weight of the total composition in the case of an emulsion type external preparation for skin.
(Hereinafter, simply indicated by%) is preferable, and 0 in the case of oily external preparation for skin based on liquid hydrocarbon such as squalane.
01 to 50% is preferable.

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. As an ointment,
It may be based on an oily base, oil / water, or a water / oil type emulsion base. The oily base is not particularly limited and includes, for example, vegetable oil, animal oil, synthetic oil, fatty acid, and natural or synthetic glyceride. 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. , Preservatives, thickeners, pigments,
Fragrances and the like can be blended in any combination.

As cosmetics, various forms such as water / oil, oil /
It can be a skin cosmetic such as a water-based emulsified cosmetic, a cream, a cosmetic emulsion, a lotion, an oily cosmetic, a lipstick, a foundation, a skin cleanser, a hairnic, a hair styling agent, a hair nourishing agent and 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 clarified, keratinocyte 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
-And Of amide derivative] (I-Aa): Synthesis of N- (2-hydroxy-3-hexadecyloxypropyl) ethanolamine (IIa): equipped with stirrer, dropping funnel, thermometer and reflux condenser
61.1 g of ethanolamine (1.0mo
1) 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
〜81 ℃ 〜20Torr). 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 were 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): equipped with stirrer, dropping funnel, thermometer and distillation device
In a 100 ml flask, the compound (IIa) obtained above (17.3 g (4
8m mol) and KOH 0.14g (2.5m mol) were charged, 80 ℃ / 20T
With heating and stirring under reduced pressure at orr, 15.1 g (48 mmol) of methyl 12-hydroxyoctadecanoate was added dropwise over 1 hour. After completion of the dropping, the mixture was further stirred under the same conditions for 1 hour, and the obtained crude product was purified by silica gel flash column chromatography to give the title compound (I-Aa) 2
3.0 g was obtained (74% yield). The melting point, IR and ¹ H-NMR measurement results of the obtained compound were as follows.

^{Mp: 70.8~71.3 ℃ IR: 3352,2926,2854,1617,1473,1122,1077cm -1 1} H-NMR (δ, CDC1 3): 0.88 (t, J = 6.3Hz, 6H), 1.12~1.82 ( m, 56H), 2.24
-2.51 (m, 2H), 3.23-4.30 (m, 15H) Example 2 N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-16-hydroxyhexadecane amide [the above general formula In (I) R ¹ = C
_{^{16 H 33, R 3 OR 2}} = HO (CH 2) 15 - a is an amide derivative]
Synthesis of (I-Ab): The amine (IIa) obtained in Example 1 was reacted with methyl 16-hydroxyhexadecanoate in the same manner as in Example 1 to give the target compound (I-Ab) as a colorless powder. Obtained (yield 75%). The melting point, IR and ¹ H-NMR measurement results of the obtained compound were 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-octadeca Dienyloxy) hexadecanamide [in the general formula (I), R ¹ ═C ₁₆ H ₃₃ and Amide derivative] (I-Ba): Synthesis of methyl 16- (9Z, 12Z-octadecadienyloxy) hexadecanoate (III-Ba): Stirrer, dropping funnel, thermometer and reflux condenser In a 300 ml four-necked flask provided, 2.72 g (10 mmol) of 16-hydroxyhexadecanoic acid, 50 ml of anhydrous tetrahydrofuran, 5 ml of anhydrous hexamethylphosphoryltriamide and 0.24 g (10 mmol) of sodium hydride were added, and the mixture was kept at room temperature under N ₂ flow. At 30
Stirred for minutes. The mixture was then cooled to -70 ° C and 6.25 ml of 1.6N butyllithium hexane solution (10 mM
l) was added, the mixture was warmed to room temperature over 30 minutes, 0.24 g (10 mmol) of sodium hydride was added, and the mixture was stirred at room temperature for another 30 minutes. Then, here p-toluenesulfonic acid
9.Z, 12Z-octadecadienyl ester 9.25g (22m mol)
Was added dropwise, and the mixture was heated with stirring 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 ammonium chloride solution, 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 were as follows.

Melting point: 63.0-64.3 ° C IR: 3304, 2920, 2854, 1614, 1467, 1116, 1062, 720
^{cm -1 1 H-NMR (δ} , CDC1 3): 0.80~0.95 (m, 6H), 0.95~1.70 (m, 72H), 1.95~
2.12 (m, 4H), 2.39 (t, J = 7.7Hz, 2H), 2.77 (bt, J =
5.7Hz, 2H), 3.39 (t, J = 6.6Hz, 4H), 3.23 to 4.23 (m, 1
3H), 5.24-5.44 (m, 4H) Example 4 N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-16- (9Z, 12Z-octadecadienoyloxy) hexadecane R ¹ = C ₁₆ H ₃₃ in the amide [the general formulas (I) ^- and 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 (1
5m mol), linoleic acid 8.41g (13m mol), triphenylphosphine 7.87g (30m mol) and tetrahydrofuran 10
0 ml was charged, and 5.22 g (30 mmol) of diethyl azodicarboxylate was added dropwise over 1 hour with stirring at room temperature. After completion of the dropwise addition, the mixture was further stirred at room temperature for 4 hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel flash chromatography to obtain 6.76 g of the title compound (III-Ca) (yield 82%).

Synthesis of amide derivative (I-Ca): equipped with stirrer, dropping funnel, thermometer and distillation device
2.74 g of the compound (III-Ca) obtained above in a 50 ml flask.
(5 mmol), 1.80 g of amine (IIa) obtained in Example 1
(5m mol) and potassium tert-butoxide 0.028g (0.25
(mol mol) 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~
2.16 (m, 4H), 2.28 (t, J = 7.5Hz, 2H), 2.39 (bt, J =
7.7Hz, 2H), 2.77 (bt, J = 5.9Hz, 2H), 3.23 to 4.25 (m,
13H), 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 dropping funnel, 16
-Methyl hydroxyhexadecanoate 100.26g (0.35mo
l), 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, the reaction was completed by stirring at room temperature for 1 hour. Then
The reaction mixture was neutralized by adding 0.59 g (7 mmol) of NaHCO ₃ .
Filtration and evaporation of the solvent gave a crude product of methyl 16- (2-tetrahydropyranyloxy) hexadecanoate.

Next, in one flask equipped with a stirrer, a dropping funnel, a thermometer and a distillation device, the N-obtained in Example 1
(2-Hydroxy-3-hexadecyloxypropyl) ethanolamine (IIa) 125.9 g (0.35 mol) and KOH 0.98 g
(17.5 mmol) was charged, and the crude product of methyl 16- (2-tetrahydropyranyloxy) hexadecanoate obtained above was added dropwise over 2 hours while stirring with heating under reduced pressure of 80 ° C./20 Torr to produce The incoming methanol was distilled off. After completion of dropping, the mixture was further stirred under the same conditions for 2 hours, and the obtained crude product was recrystallized from methanol to give the compound (IX-
b) 212.3 g was obtained (yield 86.9%).

N- (2- (tert-butyldiphenylsilyloxy) -3-hexadecyloxypropyl) -N-2- (te
Synthesis of rt-butyldiphenylsilyloxy) ethyl-16-hydroxyhexadecanamide (X1-b): In one flask equipped with a stirrer and a dropping funnel, 34.91 g (0.05 mol) of the compound (IX-b) obtained above was obtained. , Imidazole 13.62g (0.2mol) and dimethylformamide 35
0 ml 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 1 ml of methanol were charged therein.
50 ml and pyridinium paratoluenesulfonate 2.36 g
(9.4 mmol) was added, and the mixture was stirred at room temperature for 28 hours. After completion of the reaction, the reaction mixture was neutralized with NaHCO ₃ , the reaction mixture was extracted with diethyl ether, the solvent was evaporated 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,
4.25g (3.9m mol) of the compound (XI-b) obtained above, 1.23g (15.6m mol) of pyridine and 50ml of dichloromethane were charged, and 1.41g (4.7m) of oleoyl chloride was stirred with stirring at room temperature.
mol) was added dropwise. 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 mixed with a stirrer 20
Charge into a 0 ml flask and add 50 ml of tetrahydrofuran here.
And tetrabutylammonium fluoride 2.46g (7.8m mo
l) was 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 were 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 = 6.7H
z, 2H), 5.34 (bt, J = 5.3Hz, 2H) Example 6 N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-16- (methylpeptadecyloxy) Hexadecanamide [the above general formula (I)
Where R ¹ = C ₁₆ H ₃₃ − and (Wherein p represents an integer having a distribution with p = 7 at the apex)] (I-Cc) Synthesis: In Example 5, methylheptadecyl chloride was used instead of oleoyl chloride. The reaction was performed in the same manner as in Example 5 except that the target compound (I-Cc) was obtained (yield: 65.5).
%). The melting point, IR and ¹ H-NMR measurement results of the obtained compound were 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 ~
4.33 (m, 13H), 4.05 (t, J = 6.6Hz, 2H) Example 7 N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-32- (9Z, 12Z- Octadecadienoyloxy) dotriacontanamide [in the general formula (I), R ¹ ═C ₁₆ H ₃₃ − and Synthesis of amide derivative] (I-Cd); In Example 5, methyl 16-hydroxyhexadecanoate was replaced with methyl 32-hydroxydotriacontanate, and in Example 5, oleoyl chloride The reaction was performed in the same manner as in Example 5 except that linoleoyl chloride was used instead to obtain the target compound (I-Cd) (yield 24.8%). Melting point, IR and ¹ H-NM of the obtained compound
The measurement result of R was 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~
2.15 (m, 4H), 2.29 (t, J = 7.5Hz, 2H), 2.39 (bt, J =
7.6Hz, 2H), 2.77 (bt, J = 5.7Hz, 2H), 3.18-4.20 (m,
13H), 4.05 (t, J = 6.7Hz, 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 amide derivative] (I-Ce): 12- (tert-butyldimethylsilyloxy) octadecanoic acid; 1 ml in a 100 ml flask equipped with a stirrer and a dropping funnel.
Ethyl 2-hydroxyoctadecanoate 3.28 g (10 m mo
l), 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 dropping, the reaction mixture was stirred at 50 ° C. for 18 hours to terminate the reaction. The reaction mixture is then extracted with ether,
After washing with brine, the solvent was evaporated under reduced pressure and the residue was purified by silica gel flash chromatography to give 12- (tert
Ethyl -butyldimethylsilyloxy) octadecanoate was obtained.

Next, ethyl 12- (tert-butyldimethylsilyloxy) octadecanoate obtained above was added to 100 m equipped with a stirrer.
Place in a l-flask and add 20 ml of ethanol and 50% K to it.
2.24 g (20 mmol) of an OH 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, 1.87 g (4.5 mmol) of 12- (tert-butyldimethylsilyloxy) octadecanoic acid obtained above was used. 3.27 g (3 mmol) of the compound (XI-b) obtained in Example 5, 3.18 g (4.5 mmol) of triphenylphosphine and 10 ml of tetrahydrofuran were charged, and 0.71 g (4.05 mmol) of diethyl azodicarboxylate was stirred at room temperature. Tetrahydrofuran 5m
The solution was added dropwise over 5 minutes. After completion of the dropping, 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 m of the intermediate obtained above was equipped with a stirrer.
l Charge to a flask, and add 60 ml of tetrahydrofuran and 3.24 g (10.3 mmol) of tetrabutylammonium fluoride.
Was added and the mixture was heated with stirring at 60 ° C. for 24 hours. Then, the obtained reaction mixture was extracted with chloroform, washed with saline,
The solvent was distilled off 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 were 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), 2.3
0 (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 performed to obtain the target compound (I-Cf) (yield 32.7%). The melting point, IR and ¹ H-NMR measurement results of the obtained compound were 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〜
4.26 (m, 19H), 4.07 (t, J = 6.6Hz, 2H) Example 10 N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-12- (9Z, 12Z- Octadecadienoyloxy) 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. 167.0 g (0.23 mol) of compound (IX-g), 91.0 g (1.15 mol) of pyridine and 440 ml of dichloromethane were charged, and 45.1 g (0.575 mol) of acetyl chloride was added with stirring at 0 ° C.
It was added dropwise over 1.5 hours. After completion of the dropping, the reaction was further continued for 1 hour to complete the reaction. 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 product obtained above was placed in a stirrer 1
Put in a flask, and 368g of methanol (0.115mol)
And 1.16 g of pyridinium paratoluenesulfonate (4.6 m
mol) was added and the mixture was stirred at 40 ° C. for 5 hours. After the reaction, NaH
After neutralizing by adding 0.76g (9.2mmol) of CO ₃ , methanol was distilled off, the residue was dissolved in chloroform, washed with brine, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel short column chromatography. After purification, the target compound (XI-
g) 118.3 g was obtained (yield 80.1%).

Synthesis of amide derivative (I-Cg): In one flask equipped with a stirrer and a dropping funnel, 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 added. Charge and stir at 0 ° C with linoleoyl chloride 41.2g (0.138mo
l) was added dropwise over 30 minutes, and after the addition was completed, the mixture was stirred for 2 hours. Next, 1.6 g (0.05 mol) of methanol was added to this to make excess linoleoyl chloride 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, ethanol 1, methanol 0.5 l and K ₂ CO ₃ 29.4 g (0.213 mol) were added thereto, and the mixture was stirred at 0 to 10 ° C for 1 hour. did. After the reaction was completed, water was added to dissolve the generated salt, and the reaction mixture was extracted with diisopropyl ether,
The extract was washed with brine, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel flash column chromatography to obtain 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 were 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~
2.13 (m, 4H), 2.29 (t, J = 7.5Hz, 2H), 2.39 (bt, J =
7.6Hz, 2H), 2.77 (bt, J = 5.7Hz, 2H), 3.22 to 4.21 (m,
13H), 4.05 (t, J = 6.71Hz, 2H), 5.23 to 5.48 (m, 4H) Example 11 N- (2-hydroxy-3-hexadecyloxypropyl) -N-2-hydroxyethyl-15- (9Z, 12Z-octadecadienoyloxy) pentadecane amide [in the general formula (I), R ¹ ═C ₁₆ H ₃₃ − and Synthesis of amide derivative] (I-Ch): The reaction was performed in the same manner as in Example 10 except that methyl 15-hydroxypentadecanoate was used instead of methyl 12-hydroxydodecanoate 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 were 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~
2.14 (m, 4H), 2.29 (t, J = 7.5Hz, 2H), 2.39 (bt, J =
7.6Hz, 2H), 2.77 (bt, J = 5.7Hz, 2H), 3.21 ~ 4.20 (m,
13H), 4.05 (t, J = 6.7Hz, 2H), 5.23 to 5.48 (m, 4H) Example 12 External skin application 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) Wistar with only feed that does not contain essential fatty acids
r) male rats are bred, and external skin preparations are applied to the shaved back skin once a day for 3 weeks to 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.

If the normal barrier function is maintained, this value is
It is 10 or less, but 35 or more in essential fatty acid deficient rats with impaired barrier function. Measured values are mean ±
The standard deviation is shown.

(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. Fill the lower receiver with phosphate buffered balanced salt solution,
1 ml of solvent containing 37 KBq of ¹⁴ C-salicylic acid in the epidermal container
Insert 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) Women aged 20 to 40 who have rough skin on the cheeks in winter 10
First name is test subject, and different skin external materials on left and right cheeks 1 a day
Apply 3 times a week. The test was conducted on the following items the day after the application for 3 weeks was completed.

(1) Transepidermal water loss After washing the face with warm water at 37 ℃, in a room at a temperature of 20 ℃ and a humidity of 45%
After resting for 30 minutes, 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) Rough skin score The rough skin was observed with the naked eye and measured according to the following criteria. Scores were shown as mean ± 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)

(57) [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. )