JPH06271449A - Wrinkle improver and keratinization improver - Google Patents

Abstract

PURPOSE:To obtain a wrinkle improver and a keratinization improver excellent in action capable of suppressing occurrence of wrinkle and removing wrinkle and suppressing parakeratosis of skin hyperplasia of epidermis and abnormality of lipometabolism and excellent in recovery of normal function and retention of homeostasis. CONSTITUTION:The wrinkle improver and keratinization improver consist of an amine derivative of formula I [R<1> is H or 1-40C straight-chain, branched chain or cyclic hydrocarbon group; R<2> is H or 1-5C hydrocarbon group which may have OH or alkoxy; R IS H or 1-22C hydrocarbon which may have OH or alkoxy; R<4> are H or 1-7C hydrocarbon group which may have OH; R<5> is 2-6C hydrocarbon group which may have OH; X is H, OH or OP(=0) (OH)2; Y is X except OH] or its acid addition salt or quaternary compound, e.g. 1-(2- hydroxyethylamino)-2-octadecanol. This compound has action capable of suppressing DNA synthesis of an epidermic cell, promoting differential induction and suppressing hyperplasia of epidermis. The compound of formula I wherein X is OH and Y is H is obtained by adding an amine of formula 3 to an epoxide of formula 2.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a wrinkle improving agent and a keratinization improving agent, and more specifically, a wrinkle improving agent excellent in preventing and improving wrinkles and a keratinizing improving agent excellent in antidandruff action and sunburn improving action. Regarding

[0002]

2. Description of the Related Art In recent years,
Maintaining healthy and beautiful skin has become a serious concern for people of all ages. However, the skin is subtly affected by temperature and humidity, ultraviolet rays, cosmetics, aging, illness, stress, eating habits, etc. Therefore, various functions of the skin (prevention of loss of water etc. from the living body, constant body temperature) Functions that control maintenance, physical and chemical irritation from the outside world, body protection function from various bacteria, decrease in skin elasticity and function that determines surface morphology, etc., skin aging, etc. Trouble occurs.

Of these, wrinkles, which is one of the problems of the dermis, occur due to aging and aging of the skin due to sunlight. That is, the cells that make up the fibrous tissue of the dermis are smaller and fewer with exposure to sunlight and increasing age,
In particular, collagen fibers are largely lost, and the skin is aged due to degeneration of the dermis, reduction of subcutaneous adipose tissue, etc., which mainly causes wrinkles, relaxation and loss of elasticity. Heretofore, various compositions and methods have been proposed in order to suppress or treat such wrinkles due to the aging effect (Japanese Patent Laid-Open Publication No. 6-58242).
2-185005, JP-A-62-502546, JP-A-2-72157, and JP-A-2-288.
No. 822, etc.).

However, none of them has shown a satisfactory wrinkle improving effect.

On the other hand, dermatitis vulgaris such as dry skin, oily skin, and dandruff in the epidermis causes changes in the external environment (seasonal changes, ultraviolet rays, etc.) and changes in physiological functions (with aging and diseases).
It is caused by functional abnormalities of the skin tissue due to factors inside and outside the body that act on the living body, and skin thickening and parakeratosis induced by these. The main attempts to prevent and improve such skin troubles are to apply a synthetic or natural moisturizing component to prevent the skin from drying out and increase the moisturizing ability of the skin, and to apply a blood circulation promoter to improve blood circulation promotion. Has been done.

However, these methods have various problems in terms of prevention of various skin troubles, improvement effect, persistence thereof, stability and safety of drugs. That is, these methods are generally for the epidermis, especially for replenishing water on the surface of the stratum corneum or for partially supplementing the moisturizing component,
Its efficacy and effects were temporary and no permanent skin improvement could be expected.

Therefore, it has an excellent effect of suppressing the generation of wrinkles and eliminating them, while it also causes parakeratosis of the skin, thickening of the epidermis,
It has been desired to develop a substance having a remarkable inhibitory action against abnormal lipid metabolism.

[0008]

Means for Solving the Problems As a result of intensive studies in view of such circumstances, the present inventors have found that a specific amine derivative described below has a remarkable effect on wrinkle improvement and keratinization improvement. Has been completed.

That is, the present invention provides the following general formula (1)

[0010]

[Chemical 3]

A wrinkle improving agent or a keratinization improving agent comprising an amine derivative represented by: or an acid addition salt or quaternary compound thereof.

The present invention also provides the following general formula (1 ')

[0013]

[Chemical 4]

There is also provided an external skin preparation containing less than 1% by weight of an amine derivative represented by: or an acid addition salt or quaternary compound thereof.

A part of the amine derivative (1) used in the present invention has heretofore been an intermediate for producing an amide derivative which is its N-acyl compound (JP-A-63-227514), a surfactant (special feature). KAISHO 63-284295), brain function improving agents, antiallergic agents (JP-A-63-179850), transdermal absorption promoters (JP-A-1-268648), and the like. However, it has not been known at all that these compounds are effective in improving wrinkles and keratinization.

In the general formula (1), the hydrocarbon group represented by R ¹ may be saturated or unsaturated, and specific examples thereof include methyl, ethyl, propyl, butyl, hexyl, octyl, decyl, dodecyl, Tetradecyl, hexadecyl, eicosyl, methyl-branched isopalmityl, 7-hexadecenyl, 4,8,12-trimethyltridecyl, 4
Examples thereof include groups such as -methyl-3-pentenyl, cyclohexyl and phenyl.

Specific examples of the hydrocarbon group represented by R ² in the general formula (1) include methyl, ethyl, butyl, pentyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, Examples include groups such as 5-hydroxypentyl.

Specific examples of the hydrocarbon group represented by R ³ in the general formula (1) include methyl, ethyl, butyl, hexyl, phenyl, benzyl, hydroxymethyl, 2-hydroxyethyl and 1,2-dihydroxyethyl. , 1, 2,
3-trihydroxypropyl, 1,2,3,4-tetrahydroxybutyl, 1,2,3,4,5-pentahydroxypentyl, methoxymethyl, dodecyloxymethyl,
Examples thereof include groups such as tetradecyloxymethyl and methyl-branched isostearyloxymethyl.

In the general formula (1), specific examples of the hydrocarbon group represented by R ⁴ are methyl, ethyl, butyl, hexyl, phenyl, benzyl, hydroxyethyl, 2,3-
Dihydroxypropyl, 2,3,4-trihydroxybutyl, 2,3,4,5-tetrahydroxypentyl,
Examples include groups such as 2,3,4,5,6-pentahydroxyhexyl.

In the general formula (1), specific examples of R ⁵ are:

[0021]

[Chemical 5]

Groups such as X in the general formula (1)
And the phosphoric acid residue which Y may represent may be a salt with a metal or amines.

Amine derivative used in the present invention (1)
Are various known methods, for example, the following reaction formulas I, II or II.
Can be manufactured by I.

[0024]

[Chemical 6]

(In the formula, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meanings as described above.) That is, by adding the amine (3-A) to the epoxide (2) (1- A) [a compound of the general formula (1) where X = OH and Y = H] can be produced.

[0026]

[Chemical 7]

(In the formula, X is H or OH, R ¹ , R ² , R
³ , R ⁴ and R ⁵ are as defined above. )

[0028]

[Chemical 8]

That is, the amide (4) is reduced with LiAlH ₄ or the like to give (1-B) [X in the general formula (1)
H or OH, a compound of Y = H, R ³ = H], or a compound (5) is reacted with an amine (3-A) to give (1-C) [X = H in the general formula (1)]. Or a compound of OH and Y = H] can be produced.

X is --O (O) P (OH) ₂ or Y is-(O) P (OH)
_In the case of ₂ , the amine derivative (1-D) is obtained by converting the amine derivative (1-A) to (1-C) obtained by the method of I to III into H ₃ P.
It can be produced by phosphorylating with a phosphorylating agent such as O ₄ , P ₂ O ₅ , and POCl ₃ .

The amine derivative (1) thus obtained is further subjected, if necessary, to an inorganic acid salt such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or the like, or succinic acid, fumaric acid, hexadecanoic acid, octadecanoic acid by a conventional method. , Lactic acid, glycolic acid,
It is also possible to use organic hydrochloric acid such as citric acid, tartaric acid or benzoic acid. Further, it can also be converted into a quaternary compound by reacting with a lower alkyl halide.

The amine derivative (1) or its acid addition salt or quaternary compound has a function of suppressing the generation of wrinkles and eliminating wrinkles, and therefore can be used as a wrinkle improving agent. The wrinkle-improving agent of the present invention can be administered by any method such as internal use and external use, and as an active ingredient, an anti-wrinkle agent usually used in addition to the amine derivative (1) or its acid addition salt or quaternary compound. Inflammatory agents, vitamins and the like can be appropriately added as needed.

On the other hand, the amine derivative (1) or an acid addition salt or quaternary compound thereof has an action of suppressing epidermal cell DNA synthesis, promoting differentiation induction, and suppressing epidermal thickening. That is, it has an effect of normalizing abnormal keratinization of epidermal cells of the skin, and can be used as a keratinization improving agent. The keratinization-improving agent of the present invention, like the above-mentioned wrinkle-improving agent, can be administered by any method such as internal use and external use, and as the active ingredient, the amine derivative (1) or an acid addition salt or quaternary compound thereof. In addition to these, commonly used anti-inflammatory agents, vitamins and the like can be appropriately added as needed.

The amine derivative (1) of the present invention or its acid addition salt or quaternary compound is incorporated into a skin external preparation. As the external skin preparation, various external forms such as a medicated skin external preparation, a cosmetic external skin preparation, and a cosmetic can be used.

Examples of the external skin preparation for medicinal use and the external skin preparation for cosmetic use include various ointments containing a medicinal component.

The ointment may be one based on an oily base, one based on an oil / water or water / oil type emulsion base. The oily base is not particularly limited, and examples thereof include vegetable oils, animal oils, synthetic oils, fatty acids, and natural or synthetic glycerides. Further, the medicinal component is not particularly limited, for example,
An analgesic anti-inflammatory agent, an analgesic, a bactericidal disinfectant, an astringent, an emollient, a hormone, vitamins and the like can be appropriately used as necessary.

When used as a cosmetic, oils, moisturizers, ultraviolet absorbers, alcohols, chelating agents, pH adjusters, preservatives, thickeners, pigments, etc. which are generally used as cosmetic ingredients are used. Fragrances and the like can be blended in any combination. As the cosmetics, various uses and forms, for example, water / oil or oil / water type emulsified cosmetics, creams, lotions, lotions, oily cosmetics, lipsticks, foundations, skin cleansers, hairnics, hair styling It can be used as an agent, a hair restorer, and a hair restorer. The external preparation for skin of the present invention can be prepared in the above various forms by a conventional method.

The amount of the amine derivative (1) or its acid addition salt or quaternary compound to be added to the skin external preparation is 0.0001 or more and less than 1% by weight of the total composition in the case of an emulsified skin external preparation. (Hereinafter referred to as “%”), and particularly 0.
0001 to 0.1% is preferable. Further, in the case of an oily external preparation for skin, which is based on liquid hydrocarbon such as squalane, it is 0.0001 to 10% of the total composition amount, and particularly preferably 0.0001 to 0.1%.

[0039]

The wrinkle improving agent of the present invention has an excellent effect of remarkably suppressing the generation of wrinkles and eliminating wrinkles. On the other hand, the keratinization-improving agent of the present invention has a remarkable inhibitory effect on parakeratosis due to the influence of ultraviolet rays and various other factors, epidermal thickening, lipid metabolism abnormality, and the like, and has a normal function of the skin. It restores and contributes to the maintenance of homeostasis, and has a particularly excellent anti-dandruff effect and an effect of improving the skin after sunburn.

[0040]

EXAMPLES The present invention will be described in detail below with reference to examples, but the present invention is not limited thereto.

Production Example 1 Production of 1- (2-hydroxyethylamino) -2-octadecanol (1a)

[0042]

[Chemical 9]

In a 300 ml flask equipped with a stirrer and a dropping funnel, 45.8 g (0.75 mol) of ethanolamine was added.
), 9 g of ethanol was charged and stirred at 80 ° C.,
1,2-epoxy octadecane 13.4 g (50 mmol)
Was added dropwise over 2 hours. Water was added to the reaction mixture, and white crystals that formed were filtered, washed with water, and recrystallized from methanol to give 12.3 g of the title compound (1a).
(Yield 74.6%) was obtained.

Colorless solid Melting point: 84.5-86.0 ° C. IR (KBr, cm ^-1 ): 3400, 2920, 285
2,1472,1126,1076. ¹ H-NMR (CDCl ₃ , δ): 0.82-0.96
(M, 3H), 1.14-1.51 (m, 31H),
2.42-2.88 (m, 7H), 3.69 (t, J =
4.8 Hz, 2H).

Production Example 2 Production of 1- [N- (2-hydroxyethyl) -N-methylamino) -2-octadecanol (1b)

[0046]

[Chemical 10]

In a 100 ml flask equipped with a stirrer,
26.85 g of 2-epoxy octadecane (0.1 mol
), N-methylethanolamine 7.51 g (0.1 m
ol) and 50 ml of ethanol were charged and the mixture was stirred at 80 ° C. for 18 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (1b) (23.0 g, yield 67%).

Colorless solid Melting point: 39.0-40.6 ° C. IR (NaCl, cm ⁻¹ ): 3392, 2920, 285
2,1660, 1466, 1300, 1080, 104
2,874. ¹ H-NMR (CDCl ₃ , δ): 0.82-0.96
(M, 3H), 1.12 to 1.55 (m, 30H),
2.33 (s, 3H), 2.34-2.77 (m, 6
H), 3.55-3.84 (m, 3H).

Production Example 3 2- (2-hydroxyethylamino) -3,7,11,
Production of 15-tetramethyl-1,3-hexadecanediol (1c)

[0050]

[Chemical 11]

In a 100 ml two-necked flask equipped with a stirrer and a dropping funnel, 8.79 g (0.1
4 mol) and 20.0 g of ethanol were added and 2,3-epoxy-3, while stirring with heating at 80 ° C. under a nitrogen atmosphere.
7,11,15-Tetramethyl-1,3-hexadecanediol (phytyl oxide) 3.01 g (9.6 mmo)
l) was added dropwise over 1 hour. After heating and stirring for additional 2 hours, the residue obtained by concentration under reduced pressure is purified by silica gel column chromatography to give 3.02 g of the title compound.
(Yield 84%) was obtained.

Yellow solid Melting point: 49.1-50.2 ° C. IR (KBr, cm ⁻¹ ): 3388, 3276, 292
0,2852,1464,1380,1058,103
4. ¹ H-NMR (CDCl ₃ , δ): 0.80-0.95
(M, 15H), 0.98-1.68 (m, 21H),
2.44 (t, J = 4.3 Hz, 1H), 2.72-
3.08 (m, 6H), 3.58-3.66 (m, 4
H).

Preparation Example 4 Preparation of 3- (2-hydroxyethylamino) -4-tetradecyloxy-2-methyl-2-butanol (1d)

[0054]

[Chemical 12]

In a 100 ml two-necked flask equipped with a stirrer and a dropping funnel, 15.3 g (16.
7 mmol) and 5.0 g of ethanol were added, and under a nitrogen atmosphere 8
1-tetradecyloxy-3-, with heating and stirring at 0 ° C.
Methyl-2-butene oxide 5.00g (16.7mmo
The ethanol solution of l) was added dropwise over 3 hours. 1 more
After heating and stirring for 6 hours, the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography to obtain 3.47 g (yield 58%) of the title compound (1d).

Pale yellow oil IR (NaCl, cm ^-1 ): 3384, 2924, 285
2,1462, 1374, 1114, 1060. ¹ H-NMR (CDCl ₃ , δ): 0.88 (t, J =
6.4 Hz, 3H), 1.06-1.72 (m, 30
H), 2.55 (dd, J = 4.1 Hz, 6.4 Hz,
1H), 2.63-3.05 (m, 5H), 3.30-
3.80 (m, 6H).

Production Example 5 In Production Example 4, 1-tetradecyloxy-3-methyl-
The reaction was performed using 1-tetradecyloxy-2-butene oxide instead of 2-butene oxide to obtain the following amine derivative (1e).

[0058]

[Chemical 13]

Light yellow solid Melting point: 54.4-55.4 ° C. IR (KBr, cm ⁻¹ ): 3280, 2920, 285
2, 1468, 1374, 1116, 1060. ¹ H-NMR (CDCl ₃ , δ): 0.88 (t, J =
6.4 Hz, 3H), 1.08-1.68 (m, 27
H), 2.41 (brs, 3H), 2.65 (ddd,
J = 6.2Hz, 4.1Hz, 4.1Hz, 1H),
2.83 (t, J = 2.3 Hz, 2H), 3.30-
3.78 (m, 6H), 3.90 (dq, J = 3.9H
z, 6.2 Hz, 1H).

Production Example 6 Production of 2- (9-octadecenylamino) -1-ethanol (1f)

[0061]

[Chemical 14]

L in a 100 ml eggplant flask equipped with a stirrer
1.40 g (37.2 mmol) of iAlH ₄ and 30 ml of tetrahydrofuran were charged, and a solution of N- (9-octadecenoyl) ethanolamine (1.67 g, 5.12 mmol) in tetrahydrofuran was stirred at 10 at room temperature under N ₂ atmosphere. Dropped in minutes. The temperature was raised to 60 ° C, the mixture was stirred for 16 hours, then cooled to room temperature, and 14 g of 5% KOH aqueous solution
Was added. The precipitated salt was filtered off and concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography to obtain 0.96 g of the title compound (yield 65%).

Yellow oil IR (NaCl, cm ^-1 ): 3328, 2920, 285
2, 1458, 1376, 1118, 1060. ¹ H-NMR (CDCl ₃ , δ): 0.88 (t, J =
6.6 Hz, 3 H), 1.15 to 1.65 (m, 24
H), 1.88-2.15 (m, 4H), 2.35 (b
rs, 2H), 2.61 (t, J = 7.3 Hz, 2
H), 2.76 (t, J = 5.3 Hz, 2H), 3.6
4 (t, J = 5.3 Hz, 2H), 5.22-5.48
(M, 2H).

Production Examples 7 to 8 The same reaction as in Production Example 6 was carried out using N-octadecanoylethanolamine and N-methyl branched isostearoylethanolamine instead of N- (9-octadecenoyl) ethanolamine. The following amine derivatives (1g) and (1i) were synthesized.

[0065]

[Chemical 15]

(1 g) Colorless solid Melting point: 57.3-58.2 ° C. IR (KBr, cm ^-1 ): 3370, 2914, 284
8, 1467, 1035. ¹ H-NMR (CDCl ₃ , δ): 0.88 (t, J =
6.7 Hz, 3 H), 1.04-1.75 (m, 32
H), 2.42 (brs, 2H), 2.61 (t, J =
7.3 Hz, 2 H), 2.77 (t, J = 5.1 Hz,
2H), 3.65 (t, J = 5.1Hz, 2H).

(1h) Colorless oil IR (NaCl, cm ^-1 ): 3196, 2924, 285
6, 1460, 1376, 1122, 1062. ¹ H-NMR (CDCl ₃ , δ): 0.77-1.00
(M, 6H), 1.14-1.78 (m, 29H),
2.24-2.56 (m, 2H), 2.62 (t, J =
7.3 Hz, 2 H), 2.77 (t, J = 5.1 Hz,
2H). 3.65 (t, J = 5.1 Hz, 2H).

Production Example 9 Phosphoric acid 2- [N- (2-hydroxyoctadecyl) -N
-Methylamino] ethyl monosodium salt [(1h) monosodium salt]

[0069]

[Chemical 16]

In a 200 ml flask equipped with a stirrer, 5.10 g (14.8) of the amine derivative (1b) obtained in Preparation Example 2 was obtained.
mmol), tetrahydrofuran 50 ml, 85% phosphoric acid 1.
95 g (16.9 mmol) was charged, and the mixture was stirred at room temperature for 20 minutes. Then 3.54 g (30.7 mmol) of P ₂ O ₅ was added,
The mixture was stirred at 65 ° C. for 7 hours, allowed to cool, 0.56 g of water was added, and the mixture was stirred for 30 minutes. Next, 2.38 g of NaOH and 3 g of water were added thereto, stirred for 30 minutes, and concentrated under reduced pressure. The obtained residue was extracted with ethanol using a Soxhlet extractor, the solvent was evaporated, and the residue was purified by column chromatography to give 0.75 g of the title compound (yield 11
%) Was obtained.

Colorless solid IR (KBr, cm ^-1 ): 3296, 2920, 285
2, 1470, 1148, 1074, 938. ¹ H-NMR (CD ₃ OD, δ): 0.78-0.98
(M, 3H), 1.04-1.87 (m, 30H),
2.82-3.68 (m, 7H), 3.75-4.32.
(M, 3H).

Example 1 A wrinkle pattern generated in a hairless mouse by UVB irradiation
Action of Min Derivatives: (1) Hairless mouse (HR / ICR, experiment start 9 weeks
Age, use 6 Toshiba Health Line lamps 20SE
VB light was irradiated 3 times a week. The amount of energy is TOKYO
UV-Radiometer made by OPTICAL
It was measured using UVR-305 / 365D. 1 time light
Irradiation is less than 1 MED, 0.28 mM / cm ²Energy of
-The amount was set to 65 mJ. Irradiation period is 20 weeks, hairless
After confirming that wrinkles are formed on the back of the mouse,
Divided into groups of 8 each, 0.025% concentration of amine derivative
80 μl each of (1a)-(1h) ethanol solution per week
The application was continued 5 times for 6 weeks. Ethano as control
80 μl of each sample was applied in the same manner as the sample. End of application
After completion, visually check the degree of wrinkles with the following criteria (wrinkle finger
It evaluated by the number. The results are shown in Table 1.

(Wrinkle index evaluation standard) 1: Wrinkles disappear completely. 2: I don't know if there are wrinkles or not. 3: There are some wrinkles. 4: Very wrinkled.

Further, in order to analyze the details of wrinkles, skin replicas of each mouse were collected from three locations with a diameter of 1 cm ² using a Hydrophilic Exaflex hydrophilic vinyl silicone impression material. This replica was placed in a horizontal state and irradiated with light from the direction of 30 degrees, and the ratio of the shadow formed by wrinkles was obtained as an area ratio using an image analyzer. The results are also shown in Table 1.

[0075]

[Table 1]

As is clear from the results shown in Table 1, the wrinkles formed on the back of the hairless mouse can be eliminated by applying the amine derivatives (1a) to (1h).

Example 2 Inhibitory effect of amine derivative on DNA synthesis of epidermal keratinocytes: (1) Method

A) Culture of human epidermal keratinocytes As the epidermal keratinocytes, human normal keratinocytes (trade name: Epipack) sold by Kurabo Co., Ltd. were purchased and used. A medium for human normal keratinized cells (trade name: K-GM) sold by the same company was used for cell maintenance and passage. b) Measurement of DNA synthesis (measurement of thymidine incorporation) Keratinocytes cultured in a proliferating state in a 24-well plate were used. First, the medium in each well was removed by suction, and 450 μl of K-GM containing no pituitary extract was added to exchange the medium. Then, the amine derivatives (1a) to (1h) obtained in the above Production Example were added. Furthermore, 0.2 μCi / ml [ ³ H] thymidine was added over time, and the mixture was incubated for 4 hours. Then, the supernatant is aspirated and removed, and PBS
After washing three times with (-), 500 μl of 2N NaOH was added. After incubating at 37 ° C. for 10 minutes, the same amount of 2N HCl was added for neutralization, 4 ml of ice-cooled 10% trichloroacetic acid was added, and the mixture was allowed to stand for 30 minutes. The precipitate was collected with a glass filter and then washed 3 times with 3 ml of ice-cold 10% trichloroacetic acid. Further, the filter was washed once with 3 ml of ice-cold ethanol, the glass filter was air-dried, and its radioactivity was measured by a liquid scintillation counter to calculate thymidine incorporation into cells. The results are shown in Table 2.

[0079]

[Table 2]

From Table 2, it can be seen that the incorporation of thymidine is significantly reduced by the addition of the above amine derivative, that is,
It was revealed that DNA synthesis of human epidermal keratinocytes was inhibited. Further, when the human epidermal keratinocytes treated under the same conditions were observed on the 4th day, it was found that most of the cells became an insoluble membrane (cornified envelope) and were keratinized. From this, it became clear that this amine derivative has an activity of promoting keratinization of the epidermis.

Example 3 A W / O cream having the following composition was obtained by the following production method.

[0082]

[Table 3] (Composition) (% by weight) (1) Amine derivative (1a) 0.01 (2) Cholesterol 0.5 (3) Cholesterol isostearate 1.0 (4) Polyether-modified silicone 1.5 ( 5) Cyclic silicone 20.0 (6) Methylphenyl polysiloxane 2.0 (7) Methyl polysiloxane 2.0 (8) Magnesium sulfate 0.5 (9) 55% ethanol 5.0 (10) Carboxymethyl chitin ( Ichimaru Falcos Co., Ltd., Chitin Liquid HV) 0.5 (11) Purified water balance

(Manufacturing Method) (1) to (7) were heated to 80 ° C. and dissolved, and (8) to (11) were added and mixed uniformly to prepare a W / O cream.

Example 4 An O / W cream having the following composition was obtained by the following production method.

[0085]

[Table 4] (Composition) (wt%) (1) Polyoxyethylene (10) hydrogenated castor oil 1.0 (2) sorbitan monostearate 0.5 (3) sodium stearoylmethyl taurine 0.5 (4) set Stearyl alcohol 2.0 (5) Stearic acid 1.8 (6) Amine derivative (1e) 0.001 (7) Cholesterol 1.5 (8) Cholesteryl isostearate 1.0 (9) Neopentyl glycol dicaprate 8 0.0 (10) Methyl polysiloxane 5.0 (11) Glycerin 5.0 (12) Purified water balance

(Manufacturing Method) (1) to (10) were heated to 80 ° C. and dissolved, and (11) to (12) were added and mixed uniformly to prepare an O / W cream.

Example 5 A moisturizing sunscreen cream having the following composition was obtained by the following production method.

[0088]

[Table 5] (Composition) (wt%) (1) Amine derivative (1d) 0.05 (2) Silicon-coated zinc oxide 7.0 (3) 2-ethylhexyl p-methoxycinnamate 3.0 (4) Cholesteryl Isostearate 1.0 (5) Polyether-modified silicone 2.0 (6) Methylpolysiloxane 5.0 (7) Cyclic silicone 15.0 (8) Magnesium sulfate 1.0 (9) Glycerin 5.0 (10 ) Purified water balance

(Manufacturing Method) (1) to (7) were heated to 80 ° C. and dissolved, and (8) to (10) were added thereto and uniformly mixed to prepare a moisturizing sunscreen cream.

Example 6 A pack agent having the following composition was obtained by the following production method.

[0091]

(Table 6) (Composition) (wt%) (1) Amine derivative (1h) Monosodium salt 0.05 (2) Polyvinyl alcohol 15.0 (3) Sodium carboxymethyl cellulose 5.0 (4) Propylene glycol 3.0 (5) Ethanol 8.0 (6) Purified water balance (7) Perfume 0.5 (8) Preservative, oxidizer Suitable amount

(Manufacturing Method) (1) to (8) were heated to 70 ° C., dissolved and then cooled to manufacture a pack agent.

Example 7 An ointment having the following composition was obtained by the following production method.

[0094]

(Table 7) (Composition) (wt%) (1) Amine derivative (1f) 0.075 (2) White petrolatum balance (3) Cholesteryl isostearate 3.0 (4) Liquid paraffin 10.0 (5) Glyceryl Ether 1.0 (6) Glycerin 10.0

(Manufacturing Method) (1) to (6) were heated to 80 ° C., dissolved and then cooled to prepare an ointment.

The external preparations for skin of the present invention prepared in Examples 3 to 7 have excellent effects of suppressing and eliminating wrinkles, suppress parakeratosis, epidermal thickening, lipid metabolism abnormality, and restore normal function and maintain homeostasis. It was excellent.

Front Page Continuation (72) Inventor Kazuhiko Higuchi 4954, Hanawa-cho, Haga-gun, Tochigi Prefecture Yoshinori Takeuma 2606-6 Inventor Tsutomu Fujimura, Kai-cho, Haga-gun, Tochigi Prefecture Ichikawa 4594 (72) Inventor Genji Imokawa 1022-89 Himurocho, Utsunomiya City, Tochigi Prefecture

Claims (3)

[Claims] 1. The following general formula (1): A wrinkle improving agent comprising an amine derivative represented by or an acid addition salt or quaternary compound thereof. 2. A keratinization improving agent comprising the amine derivative (1) according to claim 1 or an acid addition salt or quaternary compound thereof. 3. The following general formula (1 ′): A skin external preparation containing less than 1% by weight of an amine derivative represented by or an acid addition salt or quaternary compound thereof.