JPS62228048A - Amide derivative and dermatic external drug containing same - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is 10-26C hydrocarbon group; R<2> is 9-25C hydrocarbon group). EXAMPLE:N-(2-hydroxy-3-hexadecyloxypropyl)-N-2-hydroxyethylhexadecanam ide. USE:A dermatic drug for external use. Useful for the remedy and prevention of chapped skin. It is effective in improving the moisture-retainability of cuticle and the effect can be further improved by the combined use of a surfactant. PREPARATION:The compound of formula I can be produced by reacting the compound of formula II with the compound of formula R<2>COCl in pyridine and selectively hydrolyzing the ester group of the resultant compound of formula III with potassium carbonate in a mixture of water and methanol.

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention relates to an amide derivative and a skin external preparation containing the same, and more specifically, to an amide derivative and a skin preparation containing the same. Concerning a series of external skin applications.

[Conventional technology]

It has been known that moisture in the stratum corneum is important for moisturizing the skin and making it soft and supple. The retention of moisture is said to be due to water-soluble components contained in the stratum corneum, such as free amino acids, acid, urea, or inorganic ions. It is used in external preparations or cosmetics to improve or prevent rough skin.

Apart from this, many moisturizing substances that have a high affinity for water have been developed and are used for similar purposes.

[Problem that the invention seeks to solve]

However, when these moisturizing substances are applied to the skin, their action is to supply moisture to the stratum corneum on the skin, but their effect is temporary and fundamentally affects the stratum corneum. It does not mean that it improves the moisture retention ability of the skin and essentially prevents or causes rough skin.
won.

[Means for solving the interval tq points]

In the present situation, the present inventors conducted intensive research to solve the above problems, and the following general formula (1) % formula % (in the formula 1 (1 is a straight chain or branched saturated group having 10 to 26 carbon atoms L < is an unsaturated hydrocarbon group, R2 is a straight chain or branched saturated group having 9 to 25 carbon atoms, and R2 is an unsaturated hydrocarbon group) We have discovered that an amide derivative represented by (representing a group) has the effect of fundamentally improving the water retention ability of the stratum corneum, and that when this amide derivative is used in combination with a surfactant, its effectiveness can be further increased. , completed the invention.

That is, the present invention provides an amide derivative represented by the formula ([) and a skin external preparation containing all of them, as well as an amide derivative represented by the formula (1)
) A skin external preparation containing an amide derivative and a surfactant represented by the following formula: All+M IJ.

The amide derivative represented by formula (1) used in the present invention can be obtained by a known method [for example, Holish Journal of Chemistry (Po1. , 1283 (197
8); JP-A-54-117421, JP-A No. 54-1443
No. 08, No. 54-147937]. That is, the compound (It) obtained from glycine ether and conitanolamine can be produced by acylating 1-1 and then selectively hydrolyzing the ester group according to the reaction formula shown below.

CH2C Toki0H R2COCeRIOCH, K, Co.

? CH,, CH20COR" (I) (In the formula, R+ and R2 are the same as above) The amide derivative represented by formula (1) can be directly reacted with fatty acid methyl ester without isolating the compound obtained above. It can also be manufactured by

The amount of amide derivative (I) to be incorporated into the skin external preparation of the present invention is as follows:
Although not particularly limited, in the case of an emulsified skin preparation for external use, it is preferably 0.001 to 50% by weight (hereinafter simply referred to as ``H'') of the total composition, particularly 0.1 to 20% by weight, and a liquid such as diluted squalene. In the case of oily skin external preparations based on hydrocarbons, it is preferably 1 to 50%, particularly 5 to 25%.

As the surfactant, nonionic surfactants, anionic surfactants, and amphoteric surfactants can also be used, but nonionic surfactants are particularly preferred.

Examples of nonionic surfactants include polyoxyethylene alkyl ether, holoxyethylene alkyl phenyl ether, polyoxyethylene utt fatty acid ester, sorbitan fatty acid-c SF#, polyoxyethylene norbitan fatty acid ester, fatty acid monoglyceride, glyceryl Examples include ether. Among them,
A glyceryl ether represented by the following general formula (IV) (in the formula, R represents an alkyl group having 8 to 24 carbon atoms), in which R is the following formula % formula % () (in the formula, p is 4 to 10 and q is an integer of 5 to 11, and p+q=1.1 to 17, with a distribution having p=-=7 and q==3 as vertices.

The amount of the surfactant to be blended is preferably 0.01 to 20 percent of the total composition, particularly 0.1 to 5 percent.

The skin external preparations of the present invention are broadly classified into medicated skin external preparations and cosmetics in terms of their usage forms.

Examples of medicated skin external preparations include various ointments containing medicinal ingredients. The ointment may be one based on an oily base, or one based on an oil/water or water/oil type emulsion base. There are no particular restrictions on the oily base, such as vegetable oil, animal oil,
Examples include synthetic oils, fatty acids, natural or synthetic chryselite, and the like.

There are no particular limitations on the medicinal ingredients, and for example, analgesic and anti-inflammatory agents, antipruritic agents, sterilizing disinfectants, astringents, emollients, hormonal agents, and the like can be used as appropriate.

When used as a cosmetic, in addition to the essential ingredients, oils, moisturizers, ultraviolet absorbers, alcohols, chelating agents, pH adjusters, etc. that are commonly used as cosmetic ingredients,
Preservatives, thickeners, pigments, fragrances, etc. can be optionally added (a total of 11 can be added).

Cosmetics can be used in various forms, such as water/oil, oil/water emulsified cosmetics, cosmetic emulsions, lotions, oil-based cosmetics, [1 Beni, Nountation, skin cleansers, It can be used as skin cosmetics such as hair tonics, hair conditioners, hair tonics, and hair shearing agents.

[Effect]

Although the detailed mechanism of action of the amide derivative represented by formula CI) in the topical skin preparation of the present invention has not been completely elucidated, it rebuilds the lipid membrane between corneocytes and exerts the water retention function of the stratum corneum. It is considered that

〔Effect of the invention〕

Since the skin external preparation of the present invention contains the amide derivative 1 having such an effect, it can exhibit excellent improvement and preventive effects against rough skin.

〔Example〕

Next, an example will be given and explained.

Example I N-(2-hydroxy-3-hexadecyloxyprobyl)-N-2-hydroxyethylhexadecanamide
In 1), R12C,, H3,, R22C,,)i,
Synthesis of (Ta): fl) Synthesis of N-(2-hydroxy-3-hexadecyloxyprobyl)ethanolamine CIl&): 200 mA4 equipped with stirrer, addition funnel, thermometer, reflux condenser
Ethanolamine '1.1' in a Tulo flask! (
1,0rnol) and heated to 60-70°C (while stirring) add 24.
3Sl' (0,082 mol) was added dropwise over 45 minutes. After the dropwise addition was completed, the mixture was further heated and stirred for 2 hours under the same conditions.
Unreacted ethanolamine was distilled off under reduced pressure (79-81
°C/20'1. 'orr) l,ta. residue'e
Shi! By purifying with J Kagel flash column chromatography, 18.4 L of the title compound (la) was obtained.
t was obtained (yield: 63 t).

'H-NMRa CL)Cp, : 0.85(3H,t), 1.23(28H,br,
s), 2.6-2.8 (4H, m),: 3.1-3.
9 (10H,m)+11)N-(2-hexadecanoyloxy3-hexadecylocibrovir)-N-2-
Hexadecano (1, (1) Synthesis of yloxyhexadecanamide (lua): Compound C11a obtained in (1)) 15.2 'i (0,042
mol) f, (fgN+ in 200 ml of chloroform
H-J&NlO,0? (0,126rnol)
Add. Chloride under water cooling #34.6 y
-(0,126 mol) i was added dropwise over 30 minutes, and after the addition was completed, the mixture was stirred at room temperature for 2 hours. The reaction product was washed with water to remove the pyridine hydrochloride, and the solvent was distilled off to obtain 45.1 ff of crude product of the title compound (lla).

+1-l-1-N δCDC,e3: 0.86 (12H,t), 1. ．． 25 (106H,
br, s), 2.2-2.4 (6H, m), 3.
3~: 3.6 (8B, m), 4゜0~4.3 (
2H.

m), 5.1 to 5.2 (IH, m) (Il+)
The crude product 451z of the obtained compound (Illa) was mixed with water-methanol (
1:1) Suspended in 450 t of mixed solvent, 5 t of potassium carbonate
．． 87 (0,0Ft4 m01) 'e was added and heated under reflux for 3 hours. Compound (Ia) 1 as a colorless powder was extracted from the reaction product by extracting chloroform-soluble chlorine and purified by silica gel flash column chromatography.
5.0't was obtained (yield 60t, but from Il&). It is clear from the physical take shown below that this has the desired structure.

Melting point 774.9-75.3°G IRνKBr (cm-1): 3320br, 2924.2852.1616.14
68°1442, 1378.1, 112.1062.7
221H-NMit δCDC,g: 0.86 (611,t), 1.0-1.6 (54H
, m), 2.2-2.5 (2H, m), 3.1-4.
1 (13H, m) Elemental analysis calculated value (chi) C74,31N12.64 N2.
34 actual measurement value excellent) C74, 12812, 70N2.2
3 Example 2 N-(2-hydroxy-3-hexatesiloxyprobyl)-N-2-hydroxyethylhexadecanamide [Formula (
1), 1 likelihood' = C,, HI13. R2==C
,,H,.

Synthesis of (fa): Stirrer, dropping funnel, thermometer, reflux condenser and N, 4
Ethanolamine 1 in a 544 flask equipped with an immigration tube
637 P (26,8 mol) and ethanol 32
7i (7,11 mol) f at 80℃ under N2 atmosphere
While heating and stirring, add Hecateshig +) Sigil x
--r400? (1.34 mol) was added dropwise over 3 hours. After the dropwise addition was completed, the mixture was further heated and stirred for 30 minutes under the same conditions, and then a distillation device was attached and ethanol and unreacted ethanolamine were distilled off under reduced pressure (79-81°C/
201'orr) l,ta. Potassium hydroxide 3.76? (0,067rnol) was added, heated and stirred at 80°C/20 T'orr, and 362.3% of methyl hexadecanoate was added thereto. (1,34 mol
) was added dropwise over 3 hours. After the completion of dripping, continue under the same conditions 1
By heating and stirring for hours, pale yellow crude product 801z
I got it. By recrystallizing this once from total hexane and twice from ethanol, the target compound CI&)6 was obtained as a colorless powder.
491i1f was obtained (yield: 81 h).

Melting point near 4-76°C IR (crn'): 3320 (br), 2924.2852.1616.
146B.

1112.1062 +14-NMR.

0.86 (61i, t), 1.0-1.6 (5
4H,m), 2.2-2.5(2)1. m), :3.
2-4.1 (13H, m) Elemental analysis calculation value book) C74,31) 1t2.64N2.34
Actual value Excellent I C74, 12N12.70 N2.2
3 Example 3 N-(2-hydroxy-3-desyloxyprobyl) -
N-2-Hydroxyethyldecanamide [Formula %Formula % (): By the same method as shown in Example 2 using tethyl glycidyl ether and methyl decanoate, the target compound (Ib) as a colorless powder was obtained. (Yield: 71 cm).

Melting point: 46-49°O IR (Crn-'): 3316 (br), 2920.2860.1620.
1470° 1107, 1085 IH-NMR: 0.86 (6H, t), 1.0-1.6 (30H, r
n), 2.2-2.5 (2H, m), 3.1. -4.
．． 1 (13H,rn) Elemental Analysis II Calculation II (%) C69,88Hl 1.9
6 N3.26 actual value (%) C70,25H
ll, 95 N3.16 Example 4 N-(2-hydroxy-3-tesiloxyprobyl)-N
-R in 2-hydroxyethyl docosanamide
I-C,. Horse, R2-C711 (of 43) (IC
Synthesis of the compound: The desired compound (IC) 14 was obtained as a colorless powder using the same procedure as in Example 2 using tesyl cricidyl ether and methyl tocosanoate (yield: 80%).

Melting point: 65-68°C IR (cm-'): 3310 (br), 2920.2854.161.7
11-1-NMl7 20.87 (6H, t), 1.1~1.7 (54k(,
m), 2.1-2.6 (2H, m), 3.2-4.2
(13H, m) Elemental analysis calculation 1st shift (%l C74,311 (12,64N2
．． 34 actual value (%) C74,33Hl2.65
N2.35 Example 5 N-(2-hydroxy-3-octatesyloxybrobyl)-N-2-hydroxyethyldecanamide [R1-C, H87, R2-C, Hl in formula (1)] thing〕(
Synthesis of rd): The target compound (Id) as a colorless powder was obtained in the same manner as shown in Example 2 (yield 78%) using ophtateryl glycidyl ether and methyl decanoate.

Melting point: 59-61°C IR (.-I): 3298 (br), 2926.2854.1617.
1470°1104, 1010 62II-N.

0.86 (6H, t), 1.0-1.7 (46H, m
), 2.2 to 2.5 (21, m),; U2 to 4.1
(13Td, m) Elemental analysis calculated value (H) C73,14Hl2.46 N2.
58 Actual value (ch) C73,31) 112.49
N2.54 Example 6 N-(2-human white xy-3-tetradecyloxyfur) -N-2-hydroxyethyloleinamide [
In formula (1), R1-C,4H,. , RL=cis
-9-C,,H,.

[Synthesis of (e); Synthesized by the same method as shown in Example 2 using tetratecyl glycidyl ether and methyl oleate, and purified by silica gel column chromatography to obtain the desired product in the form of a colorless paste. Compound (Ie) was obtained (
yield 85%).

Melting point = 35-40°C IR (crn-'): 3400 (br), 2926.2854.1626.
1470°1110, 1010 8011-1-N: 0.87 (6H, t), 1.1~1.7 (46H,
m), 1.8-2.2 (4H, rn), 2.2-2.
5 (2H, m), 3.3-4.2 (13H.

m), 5.2-5.5 (2H, m) Elemental analysis calculated value (punishment C74,57Hl2.35 N2.35
Actual measurement value (C74, 69Hl2.34 N2.
32 Example 7 N-(2-hydroxy-3-methyl-branched octadecylocibrovir)-N-2-hydroxyethylmethyl-branched octadecanamide [methyl-branched octadecyl glycidyl ether and methyl-branched methyl octadecanoate in formula (I)] A colorless liquid target compound (If) was obtained using the same method as shown in Example 6 (yield 84%).
.

Melting point: 17-30°C IR (cm'): 3400 (br), 2926.2854.1626.
1470°'I-l-1-N.

0.86 (1214,t), 1.0~1.7 (5
6t(,m), 2.2-2.5(21(,m), 3.
2-4.2 (13H, m) Elemental analysis calculated value part) C75,28N12.79 N2.1
4 actual measurement value book) C75, 22N12.71 N2.
19 Example 8 Vaseline/compound □a-f) -3/1 (weight ratio)
Using a mixture of (invention product 1) and petrolatum, skin conductance and skin roughness were evaluated by the following method.

All results are shown in Table 1.

(Test Method) Ten women between the ages of 20 and 50 who suffer from rough skin on their cheeks during winter were used as subjects, and different external skin preparations were applied to the left and right cheeks for a total of 2 weeks. On the day after the application of the 2-okagaki was completed, a trial fitting was performed for the following items.

( ] + Skin conductance After washing your face with warm water of 37℃, resting in a room with a temperature of 20℃ and a humidity of 40℃ for 20 minutes, measure the water content of the stratum corneum using a total skin contactance meter (■BS Corporation) K. I wanted to measure it.

The smaller the contactance value, the rougher the skin;
Below, you can see the rough skin. On the other hand, this li & is 2()
If it is more than that, it is hardly noticeable on the skin.

(2) Skin roughness score Skin roughness was observed with the naked eye and judged according to the following criteria. The score was expressed as the average Hanato standard deviation.

Table 1 Example 9 Using the compounds of the present invention (la-f) obtained in Example 1, the following F
External skin preparations (emulsified cosmetics) having the compositions shown in Table 2 were prepared, and their effects on improving rough skin were evaluated in the same manner as in Example 8. The results are shown in Table 3.

Margin below 1'" (＊＊＊)・υ3 Notes → Number of persons affected @ 10 Å or more (23 6, Amendment to procedure subject to amendment (voluntary) November 1985 2711 1 Indication of case 1988 Special Permit Application No. 251485 2, Name of the invention: Amide derivatives and skin external preparations containing the same 3 Relationship with the case of the person making the amendment Applicant Address Name (091) Kao Corporation 4 Column 7 of "Detailed Description", contents of amendment (1) In the specification, page 6, line 3 below the formula, "isolate the compound" is corrected to "isolate the compound DI)" .

(2) Same, page 11, line 1 "Iroxyhexadecanamide" There is a certain "Iroxyethyl hexadecanamide" I am corrected.

Claims (1)

[Claims] 1. General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R^1 is a straight chain or branched chain having 10 to 26 carbon atoms, saturated or unsaturated. (R^2 represents a straight chain or branched chain saturated or unsaturated hydrocarbon group having 9 to 25 carbon atoms). 2. General formula (I) ▲Mathematical formula, chemical formula, table, etc.▼(I) (In the formula, R^1 is a straight chain or branched chain saturated or unsaturated hydrocarbon group having 10 to 26 carbon atoms, R ^2 represents a straight chain or branched chain saturated or unsaturated hydrocarbon group having 9 to 25 carbon atoms) An external preparation for skin containing an amide derivative represented by: 3. General formula (I) ▲Mathematical formula, chemical formula, table, etc.▼(I) (In the formula, R^1 is a straight chain or branched chain saturated or unsaturated hydrocarbon group having 10 to 26 carbon atoms, R ^2 represents a linear or branched saturated or unsaturated hydrocarbon group having 9 to 25 carbon atoms) An external skin preparation containing an amide derivative represented by the following and a surfactant.