JP2551471B2 - Glyceryl ether derivative and skin external preparation containing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] The present invention relates to a glyceryl ether derivative and an external preparation for skin containing the same, more specifically to enhance the water-retaining power of the stratum corneum.
The present invention relates to a skin external preparation capable of improving rough skin.

[Conventional technology]

BACKGROUND ART Conventionally, it is known that the moisture of the stratum corneum is important for providing moisture to the skin and making the skin soft. And
Retention of the water is the water-soluble component contained in the stratum corneum,
That is, it is said to be caused by free amino acids, organic acids, urea or inorganic ions, and these substances are used alone or in combination in a medicated external preparation for skin or cosmetics for the purpose of improving or preventing skin roughness. There is.

In addition to this, many moisturizing substances having high affinity with water have been developed and used for the same purpose.

[Problems to be Solved by the Invention] However, when these moisturizing substances are applied to the skin, the action is to supply water to the horny layer on the stratum corneum of the skin, and its effect is temporary. However, it does not fundamentally improve the water retention capacity of the stratum corneum and essentially prevent or cure the rough skin.

[Means for solving the problem]

Under such circumstances, the inventors of the present invention have conducted diligent research to solve the above-mentioned problems. As a result, the following general formula (I) synthesized by the present inventors for the first time has been shown. (In the formula, R ¹ is R ² represents a hydrogen atom, a linear or branched saturated or unsaturated hydrocarbon group having 1 to 26 carbon atoms or a group —CH ₂ C
H (OH) CH ₂ OH) has the effect of fundamentally improving the water-retaining capacity of the stratum corneum, and the combined use of a surfactant with this glyceryl ether derivative further enhances the effect. The inventors have found that they can be increased and have completed the present invention.

That is, the present invention provides a glyceryl ether derivative represented by the above formula (I), a skin external preparation containing one or two or more kinds thereof, and an interface with one or more glyceryl ether derivatives represented by the above formula (I). The present invention provides an external preparation for skin containing an active agent.

The glyceryl ether derivative represented by the general formula (I) of the present invention can be prepared by a known method (for example, JP-A-56-133281).
No. 59-175445, No. 59-93022, No. 56-81456, etc.).

That is, a glyceryl ether derivative (Ia) in which R ² is a hydrogen atom in the general formula (I) can be obtained by reacting epichlorohydrin on an abiethyl alcohol (II) in the presence of a chlorine group according to the following reaction formula. The ether derivative (III) is converted to a dioxolane derivative (IV) by using acetone in the presence of a Lewis acid catalyst and then hydrolyzed in the presence of an acid catalyst, or acetic anhydride is added in the presence of a tertiary amine. It is produced by reacting it to form the diacetate derivative (V) and then hydrolyzing it in the presence of a base.

(Here, R ¹ represents the above-mentioned meaning) Further, in the general formula (I), R ² is a glyceryl ether derivative in which R ² is a linear or branched saturated or unsaturated hydrocarbon group having 1 to 26 carbon atoms ( Ib) is produced, for example, by reacting the glycidyl ethereal derivative (III) obtained by the above method with an alcohol (VI) in the presence of a base catalyst according to the following reaction formula.

(Here, R ¹ has the above-mentioned meaning, and R ² ′ has 1 carbon atom.
~ 26 represents a straight chain or branched chain saturated or unsaturated hydrocarbon group) Further, in the general formula (I), R ² is a group —CH ₂ CH (OH) CH ₂ OH. ) Is a dioxolane derivative (VII) obtained by reacting glycidyl ether derivative (III) obtained by the above-mentioned method with 1,2-di-O-impropylideneglycerin in the presence of a base according to the following reaction formula. ) And then hydrolyzing in the presence of an acid catalyst.

(Here, R ¹ represents the above-mentioned meaning.) In the above production method, the raw material abiethyl alcohol (II) is rosin (pine resin) or abietic acid obtained by purifying it. Known methods (for example, U.S. Pat.Nos. 2,146,897 and 2,358,235, Journal of Organism Chemistry (J.
Org. Chem.) Vol. 34, p. 3464 (1969), Mokuzai Gakkaishi No. 2
7 p. 649 (1981), etc.].

Any of the glyceryl ether derivative (I) of the present invention can be used as an active ingredient of a skin external preparation.

The amount of the glyceryl ethereal derivative (I) to be added to the skin external preparation of the present invention is not particularly limited, but in the case of an emulsified skin external preparation, it is usually 0.001 to 50% by weight (hereinafter simply indicated as%) of the total composition. In particular, 0.1 to 20% is preferable, and 1 to 50%, particularly 5 to 25% is preferable in the case of oily external preparation for skin based on liquid hydrocarbon such as squalane.

Further, the external preparation for skin of the present invention may contain a surfactant for enhancing its effect. As the surfactant used in the present invention, any of a nonionic surfactant, an anionic surfactant and an amphoteric surfactant can be used, and among them, a nonionic surfactant is particularly preferable.

As the nonionic surfactant, for example, polyoxyethylene alkyl ether, polyoxyethylene alkyl phenyl ether, polyoxyethylene fatty acid ester,
Examples thereof include sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, fatty acid monoglyceride and glyceryl ether. Among them, the pair of general formula (VIII) (In the formula, R represents an alkyl group having 8 to 24 carbon atoms), wherein R is the following formula (IX) (In the formula, p represents an integer of 4 to 10, q represents an integer of 5 to 11,
(p + q = 11 to 17 and a distribution having p = 7 and q = 8 as vertices) is particularly preferable.

The content of the surfactant is 0.01 to 20% of the total composition, and especially 0.
1-5% is preferable.

The external preparation for skin of the present invention is roughly classified into a medicated external preparation for skin and a cosmetic in its use form.

Examples of the medicated skin external preparation include various ointments containing a pharmaceutically active ingredient. The ointment may be any of those based on an oily base and those based on an oil / water or water / oil type emulsified base. The oily base is not particularly limited, and examples thereof include vegetable oil, animal oil, synthetic oil, fatty acid, natural or synthetic glyceride, and the like. The medicinal component is not particularly limited,
For example, an analgesic anti-inflammatory agent, an antipruritic agent, a bactericidal disinfectant, 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 essential ingredients, oils, moisturizers, which are generally used as cosmetic ingredients,
UV absorbers, alcohols, chelating agents, pH adjusters,
A corrosive agent, a thickener, a pigment, a fragrance and the like can be arbitrarily combined and blended.

As cosmetics, various forms such as water / oil, oil / water type emulsified cosmetics, creams, emulsions, lotions, oily cosmetics, lipsticks, foundations, skin cleansers, hair nicks, hair styling agents, It can be used as a skin cosmetic such as a hair restorer and a hair restorer.

[Action]

Although the details of the mechanism of action of the glyceryl ether derivative represented by the formula (I) in the external preparation for skin of the present invention have not been completely elucidated, this reconstructs a lipid membrane between corneocytes to improve the water retention function of the stratum corneum. It is considered to be effective.

〔The invention's effect〕

Since the external preparation for skin of the present invention contains the glyceryl ether derivative (I) having such an action,
It is possible to exert excellent improvement and preventive effects on the rough skin.

〔Example〕

 Next, examples will be described.

Example 1 Synthesis of 1-O-abiethylglycerin (glyceryl ether dielectric in which R ¹ is a group (B) and R ² is a hydrogen atom in the general formula (I)): (a) Reflux condenser, temperature In a flask equipped with a meter, a dropping funnel, a N ₂ gas introduction tube and a stirring device, 115.4 g (0.4 mol) of abiethyl alcohol, 115.4 g of toluene, 111.0 g (1.2 mol) of epichlorohydrin and tetra-n-hydrogen sulfate.
A 50% by weight aqueous solution of butylammonium 6.79 g (0.02 mol) was charged, and the mixture was heated to 40 ° C. with stirring under N ₂ gas introduction. A 50% aqueous solution of 80 g (2 mol) of sodium hydroxide was added dropwise over 30 minutes with vigorous stirring, then the temperature of the reaction mixture was raised to 50 ° C. and stirring was carried out for 5 hours. The reaction mixture was washed with water in order to remove the sodium chloride produced here, and 92.5 g (0.24 mol) of epichlorohydrin and 1.36 g (0.004 mol) of tetra-n-butylammonium hydrogensulfate were added and the mixture was heated again to 40 ° C. Next, add 80 g (2 mol) of sodium hydroxide to a 50% aqueous solution while stirring vigorously.
The mixture was added dropwise over 0 minutes, the temperature of the reaction mixture was raised to 50 ° C., and the mixture was further stirred for 5 hours. After completion of the reaction, the reaction mixture was washed with water and distilled under reduced pressure to obtain 117.0 g of abiethyl glycidyl ether.
(Yield 84.9%) was obtained.

Boiling point: 148-174 ° C (0.001 Torr.) IR (cm ^-1 ): 2926,1467,1386,1101,918,891,849 NMR (CDCl ₃ , δppm): 0.81 (s, 3H), 0.88 (s, 3H), 1.00
(D, J = 6.6Hz, 3H), 1.01 (d, J = 6.6Hz, 3H), 1.10 to 1.70
(M, 7H), 1.70 to 2.15 (m, 7H), 2.21 (qq, J = 6.6,6.6Hz,
1H), 2.53 to 2.58 (m, 1H), 2.75 (t, J = 4.8Hz, 1H), 2.97
(Dd, J = 18.0,8.8Hz, 1H), 3.04〜3.12 (m, 1H), 3.21 (d
d, J = 18.0,8.8Hz, 1H), 3.28 to 3.37 (m, 1H), 3.65 (dd, J
= 11.7, 2.9Hz, 1H), 5.39 (s, 1H), 5.77 (s, 1H) (b) One flask equipped with a reflux condenser, a thermometer, a N ₂ gas inlet tube, and a stirrer was charged with acetic anhydride 306.3 g (3mol),
12.1 g (0.12 mol) of triethylamine and 103.4 g (0.3 mol) of abiethyl glycidyl ether obtained in the above (a) were charged, and the mixture was heated and stirred at 100 ° C. for 15 hours while introducing N ₂ gas. After cooling, the reaction mixture was added to water, the product was extracted with diethyl ether, and the solvent was evaporated under reduced pressure to give 1-O-abiethyl-2,3-di-O-acetylglycerin crude product.

(C) 1-O-abiethyl-2,3-di-O-acetylglycerin crude product obtained in (b) above, 200 g of ethanol in one flask equipped with a reflux condenser, N ₂ gas introduction tube and stirring device. A 30% by weight aqueous solution of sodium hydroxide (60 g, 1.5 mol) was charged, and the mixture was heated under reflux for 12 hours while introducing N ₂ gas.
After completion of the reaction, the solvent was distilled off under reduced pressure, the residue was dissolved in diethyl ether and washed with saline, and the diethyl ether was distilled off, followed by purification by silica gel column chromatography to obtain the desired 1-O- Abiethyl glycerin 7
8.3 g (72.0% yield from (b)) was obtained as a colorless viscous oil.

IR (cm ^-1 ): 3412,2932,1467,1386,1119,1047,891 NMR (CDCl ₃ , δppm): 0.80 (s.3H), 0.88 (s, 3H), 1.00
(D, J = 7.0Hz, 3H), 1.01 (d, J = 6.6Hz, 3H), 1.10 to 1.67
(M, 7H), 1.70 to 2.12 (m, 7H), 2.21 (qq, J = 7.0,6.6Hz,
1H), 2.92 to 3.01 (m, 1H), 3.08 to 3.27 (m, 3H), 3.42
(D, J = 5.1Hz, 2H), 3.51 to 3.73 (m, 2H), 3.82 (bs, 1
H), 5.38 (s, 1H), 5.76 (s, 1H) Example 2 1-O-tetrahydroabietylglycerin (in the general formula (I), R ¹ is a group (A) and R ² is a hydrogen atom) Synthesis of a certain glyceryl ether derivative: (a) Example 1 except that 117.0 g (0.4 mol) of tetrahydroabietyl alcohol was used in place of 115.4 g (0.4 mol) of abiethyl alcohol in (a) of Example 1.
In the same manner as in (a) above, 99.6 g (yield 71.4%) of tetrahydroabietyl glycidyl ether was obtained.

Boiling point: 155 ~ 165 ℃ (0.001 Torr.) IR (cm ^-1 ): 2932, 2868, 1456, 1386, 1104, 848 NMR (CDCl ₃ , δppm): 0.55 ~ 2.10 (m, 33H), 2.58 (dd, J
= 5.1,2.9Hz, 1H), 2.75, (dd, J = 5.1,4.4Hz, 1H), 2.96
(Dd, J = 14.7,8.8Hz, 1H), 3.04〜3.13 (m, 1H), 3.22 (d
d, J = 14.7,8.8Hz, 1H), 3.29 to 3.42 (m, 1H), 3.60 to 3.71
(M, 1H) (b) In a 500 ml flask equipped with a reflux condenser, a thermometer, a dropping funnel, a N ₂ gas introducing tube and a stirring device, acetone 174
g (3 mol) and boron trifluoride ether complex 1.42 g (0.01
mol) was charged and the mixture was stirred under introduction of N ₂ gas. Then, a solution of 69.7 g (0.2 mol) of tetrahydroabiethyl glycidyl ether obtained in (a) above in 58 g (1 mol) of acetone was added dropwise with stirring over 30 minutes, and the stirring was continued for another 1 hour. After the reaction was completed, sodium hydrogen carbonate, 1.68 g (0.02mo
l) and stirred for another 30 minutes to neutralize the reaction mixture,
Acetone was distilled off under reduced pressure. Then, the residue was dissolved in diethyl ether, washed with water, and the solvent was distilled off under reduced pressure to give 2,2-dimethyl-4- (tetrahydroabiethyloxymethyl).
A crude 1,3-dioxolane was obtained.

(C) In a 500 ml flask equipped with a reflux condenser, a thermometer, a N ₂ gas introduction tube and a stirring device, 2,2-dimethyl-4- (tetrahydroabietyloxymethyl) obtained in (b) above was added.
-1,3-dioxolane crude product, methanol 63g, sulfuric acid 1.57
g (0.016 mol) and 157 g of water were charged, and the mixture was heated under reflux for 4 hours while introducing N ₂ gas. After completion of the reaction, the reaction mixture was extracted with diethyl ether, the organic layer was washed with water, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the desired 1-O-tetrahydroabietylglycerin. 44.6 g (60.8% yield from (b)) was obtained as a colorless viscous oil.

IR (cm ^-1 ): 3406,2950,1458,1386,1113,1050 NMR (CDCl ₃ , δppm): 0.55 to 2.05 (m, 33H), 2.49 (bs, 1
H), 2.74 (t, J = 5.1Hz, 1H), 2.94 (dd, J = 8.8, 4.0Hz, 1
H), 3.15 to 3.25 (m, 1H), 3.40 to 3.55 (m, 2H), 3.59 to 3.
78 (m, 2H), 3.80 to 3.91 (m, 1H) Example 3 1-O-dehydroabietylglycerin (in the general formula (I), R ¹ is a group (C) and R ² is a hydrogen atom) Synthesis of (glyceryl ether derivative): (a) Example 1 (a) except that 114.6 g (0.4 mol) of dehydroabietyl alcohol was used instead of 115.4 g (0.4 mol) of abiethyl alcohol. In the same manner as in (a), 84.4 g (yield 61.6%) of thehydrohydrobiethyl glycidyl ether was obtained.

Boiling point: 198-210 ° C (0.03 Torr.) IR (cm ^-1 ): 2932,2872,1464,1383,1104,826 NMR (CDCl ₃ , δppm): 0.87 (s, 3H), 1.20 (s, 6H) , 1.23
(S, 3H), 1.28 to 1.96 (m, 9H), 2.25 (bd, J = 12.1Hz, 1
H), 2.51 to 2.57 (m, 1H), 2.71 (dd, J = 4.8, 4.4Hz, 1H),
2.73 ~ 2.94 (m, 2H), 2.95 ~ 3.12 (m, 2H), 3.17 ~ 3.40
(M, 2H), 3.58 to 3.71 (m, 1H), 6.87 (bs, 1H), 6.96 (b
d, J = 8.1Hz, 1H), 7.16 (d, J = 8.1Hz, 1H) (b) In (b) to (c) of Example 2, instead of 69.7 g (0.2 mol) of tetrahydroabietyl glycidyl ether 68.5 g of dehydroabietyl glycidyl ether
1-O-dehydroabietylglycerin 5 was prepared in the same manner as in (b) to (c) of Example 2 except that (0.2 mol) was used.
9.9 g (yield 8.31% was obtained.

IR (cm ^-1 ): 3406,2926,2872,1464,1383,1116,1044,822,
738 NMR (CDCl ₃ , δppm): 0.85 (s, 3H), 1.18 (s, 6H), 1.21
(S, 3H), 1.27 to 2.10 (m, 9H), 2.22 (bd, J = 12.1Hz, 1
H), 2.68 ~ 3.03 (m, 3H), 3.08 ~ 3.67 (m, 5H), 3.75 (b
s, 1H), 3.91 (s.1H), 6.85 (s, 1H), 6.94 (d, J = 8.1Hz,
1H), 7.12 (d, J = 8.1 Hz, 1H) Example 4 1-O-tetrahydroabietyl-3-O-methylglycerin (in the general formula (I), R ¹ is a group (A),
Synthesis of glyceryl ether derivative in which R ² is a methyl group: 100 g of methanol (3.13 mol), MeON in a 300 ml flask equipped with a reflux condenser, a dropping funnel, a thermometer and a stirring device.
0.53 g (0.01 mol) of a was added, and the mixture was heated with stirring at 60 ° C. 34.9 g (0.1 mol) of tetrahydroabietyl glycidyl ether obtained in Example 2 (a) was added dropwise over 2 hours with stirring, and after the addition was completed, the mixture was further stirred at 60 ° C. for 8 hours. After completion of the reaction, excess methanol was distilled off under reduced pressure, the residue was neutralized with an aqueous ammonium chloride solution, and extracted with dichloromethane. Then, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain 32.5 g of the desired 1-O-abiethyl-3-O-methylglycerin.
(Yield 85.4%) was obtained as a colorless oil.

IR (cm ^-1 ): 3380,2936,2868,1456,1386,1116,870 NMR (CDCl ₃ , δppm): 0.54 to 2.03 (m, 33H), 2.53 (d, J =
4.0Hz, 1H), 2.93 (dd, J = 8.8,4.4Hz, 1H), 3.13 to 3.22
(M, 1H), 3.32-3.50 (m, 4H), 3.39 (s, 3H), 3.88-3.9
9 (m, 1H) Example 5 1-O-tetrahydroabietyl-3-O-methyl branched isostearyl glycerin (in the general formula (I), R ¹
Is a group (A) and R ² is a methyl-branched isostearyl group) synthesis: a 300-flask equipped with a reflux condenser, a dropping funnel, a thermometer, a N ₂ gas inlet tube and a stirring device. 135.3g (0.5mo) of branched isostearyl alcohol (manufactured by Emery USA)
l) was charged, and 0.81 g of sodium was introduced therein under N ₂ gas introduction.
(0.03 mol) was added and the mixture was stirred at 80 ° C. for 1 hour to completely dissolve sodium. Then, 34.8 g (0.1 mol) of the tetrahydroabietyl glycidyl ether obtained in (a) of Example 2 was used.
l) was added dropwise with stirring at 80 ° C. over 2 hours, and after the completion of dropping, the mixture was further stirred at 80 ° C. for 3 hours. After completion of the reaction, excess alcohol was distilled off under reduced pressure, the residue was neutralized with an aqueous ammonium chloride solution, and extracted with dichloromethane. Then, the solvent was distilled off under reduced pressure and the residue was purified by silica gel chromatography to give the desired 1-O-tetrahydroabiet-3-O-methyl branched isostearyl glycerin 51.2.
g (yield 82.6%) was obtained.

IR (cm ^-1 ): 3464,2928,2860,1466,1386,1116 NMR (CDCl ₃ , δppm): 0.53 to 2.02 (m, 68H), 24.6 (d, J =
4.8Hz, 1H), 2.88 ~ 3.00 (m, 1H), 3.13 ~ 3.26 (m, 1H),
3.34 to 3.53 (m, 6H), 3.91 (dtt, J = 5.1Hz, 1H) Example 6 1-O-tetrahydroabietyl-3-O- (2,3-
Dihydroxypropyl) -glycerin (in the general formula (I), R ¹ is a group (A) and R ² is a group —CH ₂ CH (OH) CH ₂ OH
(A) In Example 5, 132.2 g of 2,2-dimethyl-1,3-dioxolaso-4-methanol (instead of 135.3 g (0.5 mol) of methyl-branched isostearyl alcohol in Example 5) 1mo
4- (3-) is the same as Example 5 except that l) is used.
Tetrahydroabiethyloxy-2-hydroxypropyloxymethyl) -2,2-dimethyl-1,3-dioxolane was obtained.

(B) In (c) of Example 2, 2,2-dimethyl-
4- (tetrahydroabiethyloxymethyl) -1,3-
Instead of crude dioxolane, 4-obtained in (a) above
(3-tetrahydroabiethyloxy-2-hydroxypropyloxymethyl) -2,2-dimethyl-1,3-dioxolane was used in the same manner as in Example 2 (c) except that
35.8 g of 1-0-tetrahydroabiethyl-3-O- (2,3-dihydroxypropyl) -glycerin (81.3% yield from (a)) was obtained.

IR (cm ^-1 ): 3456,2932,2872,1456,1386,1112,972 NMR (CDCl ₃ δppm): 0.54 to 2.05 (m, 33H), 2.92 to 3.15
(M, 2H), 3.12 to 3,26 (m, 1H), 3.33 to 4.08 (m, 11H), 4.
35 (bs, 1H) Example 7 Skin conductance and skin roughness were evaluated by the following methods using a mixture of petrolatum / compound of Examples 1 to 6 = 3/1 (weight ratio) and petrolatum. The results are shown in Table 1.

(Test method) Women aged 20 to 50 who have rough skin on the cheeks in winter 10
The first name is the subject, and different skin external preparations are applied to the left and right cheeks for 2 weeks. On the day after the application for two weeks was completed, the following items were tested.

(1) Skin conductance After washing the face with warm water of 37 ℃, in a room with temperature of 20 ℃ and humidity of 40%
After resting for 20 minutes, the water content of the stratum corneum was measured with a skin conductance meter (IBS). The smaller the conductance value is, the rougher the skin is, and when the conductance value is 5 or less, the skin is severely rough. On the other hand, if this value is 20 or more, skin roughness is hardly recognized.

(2) Rough skin score Rough skin was visually observed and judged according to the following criteria. The score is shown as an average value.

Example 8 A skin external preparation (emulsified cosmetic) having the composition shown in Table 2 below was produced using the compounds obtained in Examples 1 to 6, and the skin roughening improving effect was evaluated by the same method as in Example 7. did. The results are shown in Table 3.

Claims (3)

(57) [Claims] 1. A general formula (I) (In the formula, R ¹ is R ² represents a hydrogen atom, a linear or branched saturated or unsaturated hydrocarbon group having 1 to 26 carbon atoms or a group —CH ₂ C
H (OH) CH ₂ OH) glyceryl ether derivative. 2. A glyceryl ether derivative according to claim 1
External preparation for skin containing one or more kinds. 3. The external preparation for skin according to claim 2, which further contains a surfactant.