JPH06271443A - Skin external preparation - Google Patents

Abstract

PURPOSE:To obtain a skin external preparation 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 the recovery of normal function and retention of homeostasis. CONSTITUTION:The skin external preparation contains a compound of formula I (R<1> is 7-40C hydrocarbon group having a ring structure and containing a hetero atom; R<2> to R<6> are 1-10C hydrocarbon group whose hydrogen may be substituted with OH) or its acid addition salt, e.g. 1-(2-hydroxyethylamino)-3- tocopheryloxy-2-propanol. This compound has action capable of suppressing DNA synthesis of an epidermic cell and promoting differential induction and suppressing hyperplasia of epidermis and is blended in the skin external preparation in an amount of 0.0001-5wt.% in the case of emulsion system or 0.0001-10wt.% in the case of an oil system using a liquid hydrocarbon such as squalane as a base. The compound of formula I is obtained by adding an amine derivative of formula 3 to a glycidyl ether derivative of formula 2.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external preparation for skin, more specifically, it has excellent effects of preventing and improving wrinkles,
The present invention relates to a skin external preparation containing an amine derivative, which enables the normal maintenance of the skin function and is excellent in the antidandruff effect and the effect of improving after sunburn.

[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, dry skin of the epidermis, oily skin, and dermatitis vulgaris such as dandruff are caused by changes in the external environment (seasonal changes, ultraviolet rays, etc.) and physiological changes (accompanying aging and diseases). It is caused by functional abnormalities of the skin tissue due to acting factors inside and outside the body, and skin thickening and parakeratosis induced by these. As a main attempt to prevent and improve such skin troubles, a method of preventing the skin from drying by increasing the moisturizing ability of the skin by applying a synthetic or natural moisturizing component,
A method of improving blood circulation promotion by applying a blood circulation promoter has been made.

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, since these methods are generally for replenishing water on the epidermis, especially for the surface of the stratum corneum or for supplementing a part of the moisturizing components, their efficacy and effect are temporary and permanent. No improvement in skin was expected.

Therefore, it is excellent in the 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 2]

(In the formula, R ¹ represents a hydrocarbon group having a ring structure and containing a hetero atom and having 7 to 40 carbon atoms,
R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ are the same or different,
The present invention provides a skin external preparation containing an amine derivative represented by a hydrogen atom or a hydrocarbon group which may be substituted with a hydroxyl group having 1 to 10 carbon atoms) or an acid addition salt thereof.

Among the compounds represented by the above general formula (1), the amine derivative (1 ') in which R ¹ is a tocopheryl group or a 9,10- (isopropylidenedioxy) octadecyl group is a novel compound, and the present invention Also provides the compound.

The hetero atom contained in R ¹ of the amine derivative represented by the general formula (1) includes O, S, N and Si.
Etc.

The hydrocarbon group having a ring structure represented by R ¹ may be a group consisting of only a ring structure or a group partially having a ring structure. The ring structure may be an alicyclic ring, an aromatic ring or a heterocyclic ring, and examples thereof include benzene, pyran, tetrahydropyran, furan, tetrahydrofuran, dioxolane and dioxane.

In the general formula (1), specific examples of R ¹ are:
Tocopheryl, 4-dodecyloxyphenyl, 4- (9-
Hydroxynonyloxy) phenyl, 9- (4-butoxyphenyloxy) nonyl, 4- (dodecylaminocarbonyl) phenyl, 11- (cyclohexanecarbonylamino) -undecyl, 11- (phenyldimethylsilyl) undecyl, 9,10- ( And groups such as isopropylidenedioxy) octadecyl.

In the general formula (1), R ² , R ³ , R ⁴ ,
Specific examples of R ⁵ and R ⁶ include a hydrogen atom, methyl, ethyl, butyl, hexyl, phenyl, benzyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, 1,2,3-trihydroxypropyl, 1 , 2,
3,4-tetrahydroxybutyl, 1,2,3,4,5
Examples include hydrocarbon groups such as pentapentahydroxypentyl.

The amine derivative represented by the general formula (1) used in the present invention is synthesized by various known methods. For example, as represented by the following reaction formula, it is synthesized by adding an amine derivative (3) to a glycidyl ether derivative (2).

[0018]

[Chemical 3]

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ ,
R ⁶ has the same meaning as defined above. )

As the acid addition salt of the amine derivative (1) used in the present invention, inorganic hydrochloric acid such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, or succinic acid, fumaric acid, hexadecanoic acid, octadecanoic acid, lactic acid. , Glycolic acid, citric acid,
Examples thereof include organic acid salts such as tartaric acid and benzoic acid. These may be obtained by reacting the amine derivative (1) with each of the above acids by a conventional method.

The amine derivative (1) or an acid addition salt thereof has a function of suppressing the generation of wrinkles and eliminating wrinkles, and therefore can be used as a wrinkle improving agent. As a wrinkle improving agent, it is usually used externally, but it can also be administered orally, and as an active ingredient, an anti-inflammatory agent and vitamins which are usually used in addition to the amine derivative (1) or its acid addition salt. Etc. can be appropriately blended as necessary.

On the other hand, the amine derivative (1) or an acid addition salt 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. As the keratinization improving agent, it is used externally like the above-mentioned wrinkle improving agent, but it can also be administered orally and is usually used as an active ingredient in addition to the amine derivative (1) or its acid addition salt. Anti-inflammatory agents, vitamins and the like can be appropriately added as needed.

The skin external preparation of the present invention is a medicated skin external preparation,
It can be used in various forms such as a skin external preparation for cosmetics and cosmetics.

Examples of the external skin preparation for medicinal use and the external preparation for skin use for cosmetics 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, and examples thereof include vegetable oils, 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 analgesic agent, a bactericidal disinfectant, an astringent agent, an emollient agent, a hormone agent, vitamins and the like can be appropriately used as necessary. .

When used as a cosmetic, oils, moisturizers, whitening agents, UV absorbers, alcohols, chelating agents, pH adjusters, preservatives, thickeners commonly used as cosmetic ingredients. , Dyes, fragrances and the like may be combined in any combination. As the cosmetics, various uses and forms, for example, water / oil or oil / water emulsion cosmetics,
Creams, lotions, lotions, oily cosmetics, lipsticks, foundations, skin cleansing agents, hair nicks, hair styling agents,
It can be used as a hair restorer and 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 to be added to the skin external preparation is not particularly limited, but in the case of an emulsified skin external preparation, it is usually 0.0% of the total composition.
001 to 5% by weight (hereinafter referred to as "%"), and 0.0001 to 0.1% is particularly preferable. Further, in the case of an oily external preparation for skin based on liquid hydrocarbon such as squalane, it is 0.0001 to 10% of the total composition amount, respectively.
In particular, 0.0001 to 0.1% is preferable.

[0027]

The external preparation for skin of the present invention is excellent in the effects of remarkably suppressing the generation of wrinkles and eliminating wrinkles. Furthermore, the external preparation for skin of the present invention has a marked inhibitory effect on parakeratosis due to the influence of ultraviolet rays and various other factors, epidermal thickening, abnormal lipid metabolism, and the like, and restores the normal function of the skin. It also contributes to the maintenance of homeostasis, and has a particularly excellent anti-dandruff effect and an effect of improving the skin after sunburn.

[0028]

EXAMPLES The present invention will be described below in greater detail by giving Examples, but the present invention is not limited thereto.

Production Example 1 Production of 1- (2-hydroxyethylamino) -3-tocopheryloxy-2-propanol (1'a)

[0030]

[Chemical 4]

In a 500 ml flask equipped with a reflux condenser, a dropping funnel and a stirrer, 61.1 g of ethanolamine (1
mol) and 100 g of ethanol, and under a nitrogen atmosphere 80
A solution of 24.3 g (0.05 mol) of tocopheryl glycidyl ether in 25 ml of ethanol was added dropwise to the mixture over 2 hours while heating and stirring at 0 ° C. After heating and stirring for further 18 hours, excess ethanol was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 23.8 g (yield 86.9%) of the title compound (1'a).

Pale yellow oil IR (NaCl, cm ^-1 ): 3312, 2936, 145
6,1414,1378,1252,1088,106
2,916,746. ¹ H-NMR (CDCl _3, δ): 0.79-0.90
(M, 12H), 0.94-1.62 (m, 24H),
1.68-1.87 (m, 2H), 2.07 (s, 3
H), 2.13 (s, 3H), 2.17 (s, 3H),
2.56 (br, 5H), 2.80-2.89 (m, 4
H), 3.63-3.75 (m, 4H), 4.07-
4.21 (m, 1H).

Production Example 2 1- (2-hydroxyethylamino) -3- [9,10
-(Isopropylidenedioxy) octadecyloxy]-
Production of 2-propanol (1'b)

[0034]

[Chemical 5]

In a 200 ml flask equipped with a stirrer, 9,
Methyl 10-dihydroxyoctadecanoate 33.05g
(100 mmol), 52 g of 2,2-dimethoxypropane
(500 mmol) and p-toluenesulfonic acid 0.86 g
(5 mmol) was charged and stirred at room temperature for 18 hours, then NaHC
After neutralizing with O ₃ , the solvent was distilled off under reduced pressure. Next, in a 500 ml flask equipped with a stirrer and a dropping funnel, 3.8 g of LiAlH _{4 was} added.
(100 mmol) and 200 ml of tetrahydrofuran were charged, and the intermediate obtained in the above reaction was stirred at room temperature for 2
The mixture was added in 0 minutes and further stirred for 1 hour at room temperature. 5% KO
12 g of H aqueous solution was added dropwise to decompose excess LiAlH ₄ , and the precipitated salt was filtered off, and the solvent was distilled off under reduced pressure. Then, the above residue was transferred to a 300 ml flask equipped with a stirrer and a reflux condenser, to which 27.8 g of epichlorohydrin (3
00 mmol), tetrabutylammonium bromide 1.6
Charge 1 g (5 mmol) and stir at 40 ° C for 48%
33.3 g (400 mmol) of an aqueous NaOH solution was added dropwise over 3 hours. After further stirring for 2 hours at 40 ° C., washing with water, concentration under reduced pressure, and purification of the residue by silica gel column chromatography, 23.9 g of 9,10- (isopropylidenedioxy) octadecyl glycidyl ether (yield 60.0% ) Was obtained as an intermediate. Next, in a 200 ml flask equipped with a stirrer, a reflux condenser and a dropping funnel, 30.9 g (506 mmol) of ethanolamine and 6.5 g of ethanol were charged, and the mixture was stirred at 80 ° C. for 9,10-
13.1 g (32.9 mmol) of (isopropylidenedioxy) octadecyl glycidyl ether was added dropwise over 2 hours. After further stirring for 1 hour, the mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 12.9 g (yield 85%) of the title compound (1'b).

Pale yellow oil IR (NaCl, cm ^-1 ): 3316, 2924, 285
6,1464,1370,1240,1216,111
8,864,748. ¹ H-NMR (CDCl _3, δ): 0.88 (t, J =
6.25Hz, 3H), 1.10-1.70 (m, 34
H), 2.50-2.88 (m, 4H), 3.00-
3.52 (m, 7H), 3.58-3.78 (m, 2
H), 3.82-4.10 (m, 3H).

Example 1 Action of amine derivative on wrinkles formed in hairless mouse by UVB irradiation: Hairless mouse (HR / ICR, 9 weeks old at the start of the experiment) was supplied with Toshiba Health Line Lamp 20SE 6
The book was used and irradiated with UVB light three times a week. The amount of energy is UV-Radiom made by TOKYO OPTICAL.
It was measured using an eter UVR-305 / 365D. 0.28mW / cm2, less than 1MED per dose
The energy amount of ² was set to 65 mJ. The irradiation period was 20 weeks, and after confirming that wrinkles were formed on the back of the hairless mouse, the hairless mice were divided into groups of 8 mice each, and 0.025% concentration of the amine derivatives (1'a) and (1'b) was added. 80 μl of each ethanol solution was applied 5 times a week for 6 weeks. As a control, 80 μl of ethanol alone was applied in the same manner as the sample. After the application, the degree of wrinkles was evaluated with the naked eye according to the following criteria (wrinkle index). 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.

[0039]

[Table 1]

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

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 shown in Table 2.

[0042]

[Table 2]

As is clear from the results of Table 2, the wrinkles formed on the back of the hairless mouse can be eliminated by applying the amine derivative (1'a).

Example 2 Inhibitory Effect of Amine Derivatives on DNA Synthesis of Epidermal Keratinocytes (1) Method a) Culture of Human Epidermal Keratinocytes The epidermal keratinocytes are human normal horns sold by Kurabo Industries, Ltd. Activated cells (trade name: Epipack) 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 (1'a) and (1'b) obtained by the above-mentioned synthesis example were added, respectively.
Furthermore, 0.2 μCi / ml [ ³ H] thymidine was added over time, and the mixture was incubated for 4 hours. Then, the supernatant was removed by suction, and the wells were washed 3 times with PBS (-), and then 500 μl of 2N
NaOH was added. After incubating at 37 ° C. for 10 minutes, the same amount of 2N HCl was added to neutralize, and the mixture was cooled on ice.
4 ml of% trichloroacetic acid was added and the mixture was left standing 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.

[0045]

[Table 3]

From Table 3, it can be seen that the incorporation of thymidine is significantly reduced by the addition of the amine derivative,
It was revealed that DNA synthesis of human epidermal keratinocytes was inhibited. 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.

[0048]

Table 4 (Composition) (wt%) (1) Amine derivative (1'a) 0.1 (2) Cholesterol 0.5 (3) Cholesterol isostearate 1.0 (4) Polyether-modified silicone 1. 5 (5) Cyclic Silicone 20.0 (6) Methylphenylpolysiloxane 2.0 (7) Methylpolysiloxane 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) are heated to 80 ° C. and dissolved, and (8) to (11) are added thereto and uniformly mixed to prepare a W / O cream.

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

[0051]

[Table 5] (Composition) (wt%) (1) Polyoxyethylene (10) hydrogenated castor oil 1.0 (2) sorbitan monostearate 0.5 (3) stearoylmethyl taurine sodium 0.5 (4) set Stearyl alcohol 2.0 (5) Stearic acid 1.8 (6) Amine derivative (1'a) 0.001 (7) Cholesterol 1.5 (8) Cholesteryl isostearate 1.0 (9) Neopentyl dicaprate Glycol 8.0 (10) Methyl polysiloxane 5.0 (11) Glycerin 5.0 (12) Purified water balance

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

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

[0054]

(Table 6) (Composition) (wt%) (1) Amine derivative (1'b) 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) Methyl polysiloxane 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) are heated to 80 ° C. and dissolved, and (8) to (10) are 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.

[0057]

[Table 7] (Composition) (wt%) (1) Amine derivative (1'a) hydrochloride 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) are 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.

[0060]

(Table 8) (Composition) (wt%) (1) Amine derivative (1'b) 0.2 (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) are heated to 80 ° C. to dissolve and then cooled to prepare an ointment.

The external preparations for skin containing the amine derivatives (1'a) and (1'b) of the present invention prepared in Examples 3 to 7 were excellent in the effect of suppressing the generation and elimination of wrinkles as well as in the skin. It suppressed keratinization, epidermal thickening, and abnormal lipid metabolism, and was excellent in restoring normal function and maintaining homeostasis.

Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical indication location C07D 311/72 101 9360-4C 319/06 (72) Inventor Higuchi Kazuhiko 4954 (72) Hanawa-cho, Haga-gun, Tochigi Prefecture ) Inventor Yoshinori Takema 2606-6 Akabane, Kaicho, Haga-gun, Tochigi Prefecture (72) Inventor Hiroyuki Osu 2606-6 Akabane, Kai-cho, Haga-gun, Tochigi Prefecture 7272-89, Genji Imogawa, Utsunomiya City, Tochigi Prefecture

Claims (2)

[Claims] 1. The following general formula (1): (In the formula, R ¹ represents a hydrocarbon group having a ring structure and having a hetero atom and having 7 to 40 carbon atoms, and R ² , R ³ ,
R ⁴ , R ⁵ , and R ⁶ are the same or different and each represents a hydrogen atom or a hydrocarbon group which may be substituted with a hydroxyl group having 1 to 10 carbon atoms), or an amine derivative or an acid addition salt thereof. An external preparation for skin characterized by: 2. An amine derivative (1 ′) in which R ¹ is a tocopheryl group or a 9,10- (isopropylidenedioxy) octadecyl group in the general formula (1) according to claim 1.
Or an acid addition salt thereof.