JPH11209319A - Substituted benzyl alcohol derivatives - Google Patents

Abstract

(57) [Summary] (with correction) [PROBLEMS] To provide a skin external preparation that is safe, reduces skin irritation, and gives a warm sensation during use. SOLUTION: The following general formula (1) (Wherein, R ^{1 to} R ³ represent an alkoxy group α- having 1 to 4 carbon atoms)
N R ^{4 s} , such as a methylenedioxy group, are the same or different and n is an integer of 1 to 3, and R ⁵ is an alkyl group having 1 to 6 carbon atoms, such as —CH ₂ CH ₂ O—. A) a benzyl alcohol derivative represented by the formula (1) and an external preparation for skin containing the same as an active ingredient.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel substituted benzyl alcohol derivative and an external preparation containing the same as an active ingredient, which can give a warm feeling when applied to the skin.

[0002]

2. Description of the Related Art Conventionally, polyhydric alcohols, pepper powder, pepper tincture, pepper extract, capsaicin, nonanoic acid vanilamide, ginger solution, for the purpose of giving a warm feeling during use,
Menthol, camphor, methyl salicylate and the like are blended in the external preparation for skin. It is also known that a vanillyl alcohol derivative gives a special stimulus to the skin irritating sensation, and a substance diluted with a solvent gives a warm sensation (JP-A-57-9729). Furthermore, it is known that by adding a vanillyl alcohol derivative, a water-soluble surfactant and water, when applied to the skin, the unpleasant skin irritation to the human body can be reduced and the skin can be quickly warmed. (JP-A-62-205007).

[0003]

However, polyhydric alcohols, pepper powders and the like have problems such as a peculiar irritating odor, a strong skin irritating feeling, and an insufficient warming effect. The technology disclosed in Japanese Patent Application Laid-Open No. 57-9729 is
Although it has a warming effect, it also has a strong unpleasant skin irritation at the same time, and if the amount used is reduced to reduce this irritation, there is a problem in that the duration becomes shorter. Further, the technique disclosed in Japanese Patent Application Laid-Open No. 62-200507 can reduce skin irritation, but the effect is not always satisfactory and the duration of warm feeling is also shortened.

Accordingly, the present invention provides a compound capable of reducing undesired side effects and skin irritation to the human body, giving a warm feeling promptly at the time of use and maintaining a proper warm feeling for a long time, and using such a compound as an active ingredient. It is intended to provide a skin external preparation.

[0005]

Means for Solving the Problems In view of such circumstances, the present inventors have conducted intensive studies in order to achieve the above object.
Surprisingly, a specific substituted benzyl alcohol derivative has a strong warming effect on the skin, and the effect lasts for a relatively long time, and furthermore, almost no undesirable skin irritation is caused to the human body. The present inventors have found that they have characteristics that cannot be realized with a warming sensate, and have completed the present invention.

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

[0007]

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(Where R¹, R^TwoAnd R^ThreeAre the same or different
Becomes a hydrogen atom, a hydroxyl group, or a carbon number 1
4 represents a linear or branched alkoxy group, or
R¹, R^TwoAnd R^ThreeTwo of them together form an α-meth
A dioxy group may be formed. Where R¹, R^Two,
And R^ThreeAre not simultaneously hydrogen atoms. n R
^FourAre the same or different and_TwoCH_TwoO-, -CH_TwoCH
(CH_Three) O- or -CH (CH_Three) CH_TwoO-
And n represents an integer of 1 to 3. R^FiveIs a straight chain having 1 to 6 carbon atoms
Shows a chain or branched alkyl group. )
Benzyl alcohol derivatives and such substituted benzyl alcohols
Also provides a skin external preparation containing a col derivative as an active ingredient.
It is.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the general formula (1), R ^{1 to} R ³ are 2
It binds to any one of carbon atoms at positions 6 to 6.
Examples of R ^{1 to} R ³ include a hydrogen atom, a hydroxyl group, a methoxy group, an ethoxy group, an n-propoxy group, and an n-butoxy group. It is preferred that one of R ^{1 to} R ³ is a hydrogen atom and the other two are an alkoxy group or a hydroxyl group. Furthermore, it is particularly preferred that the other two are methoxy, ethoxy or hydroxyl groups, and it is most preferred that one of the other two is a methoxy group and the other one is a methoxy or hydroxyl group. The alkoxy and hydroxyl groups are preferably attached to the 3-, 4- or 5-position carbon.
It is particularly preferred that they are bonded at the position.

As for-(R ⁴ ) _n -,-(CH ₂ CH)
_{2 O) -, - (CH} 2 CH 2 O) 2 -, and - (CH ₂ CH
(CH ₃₎ O) - it is particularly preferred.

R ⁵ is preferably a methyl group, an ethyl group, an n-propyl group, an n-butyl group or an i-butyl group.

The substituted benzyl alcohol derivative of the present invention can be synthesized by various known methods. For example, according to the Williamson ether synthesis method, the following general formula (2)

[0013]

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(Wherein R ¹ , R ² and R ³ are the same as above, and X is a halogen atom) and the following general formula (3)

[0015]

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(Wherein, R ⁴ , R ⁵ and n are the same as those described above). The compound can be synthesized by reacting the compound without a solvent or in a solvent. Or the following general formula (4)

[0017]

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(Wherein, R ⁴ , R ⁵ , n and X are the same as described above) and the following general formula (5)

[0019]

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(Wherein, R ¹ , R ² and R ³ are the same as described above). The compound can be synthesized by reacting in the absence or in the presence of a solvent.

Alternatively, for example, it can be synthesized by the following method. That is, the compound represented by the general formula (3) is mixed with a strong acid such as concentrated hydrochloric acid or concentrated sulfuric acid and heated, and the compound represented by the general formula (5) is added thereto and reacted. The desired product can be obtained. Here, the strong acid is preferably added in an amount of about 0.1 to 30 mol% of the compound represented by the general formula (3). The heating temperature is preferably about 20 to 90 ° C. Further, the compound represented by the general formula (3) is preferably used in a molar ratio of about 2 to 20 times the compound represented by the general formula (5). After mixing the compound represented by the general formula (3) and the compound represented by the general formula (5), a strong acid may be mixed.

The external preparation for skin of the present invention contains the above substituted benzyl alcohol derivative as an active ingredient.
One or a mixture of two or more substituted benzyl alcohol derivatives can be used. Alternatively, the stimulation can be further reduced without impairing the warming effect by using other warming compounds such as pepper powder and polyhydric alcohol in combination. There is no particular limitation on the form of the external preparation for skin of the present invention. For example, lotion, emulsion, lotion, dentifrice, liquid soap, solid soap, creamy hair conditioner, cataplasm, cream, body shampoo, hand cream, Gels, ointments and the like can be mentioned. In order to prepare such a formulation, an excipient, a bulking agent, if necessary,
A binder, a wetting agent, a disintegrant, an oily substance, a surfactant, a lubricant, a dispersant, a buffer, a preservative, a preservative, a coloring agent, a fragrance, and the like can be appropriately compounded.

[0023] The content of the substituted benzyl alcohol derivative of the present invention in the external preparation for skin is preferably 0.001 to 10% by weight, particularly preferably 0.01 to 5% by weight. When the content is 0.001 to 10% by weight, the effect of giving a warm feeling to the skin is large, and the undesirable skin irritation is hardly given.

The external preparation for skin of the present invention can be obtained, for example, by mixing the above-mentioned substituted benzyl alcohol derivative and other additives and stirring appropriately.

[0025]

Next, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples.

Example 1 Synthesis of 2-methoxyethyl vanillyl ether (compound (1)) 98.9 g of 2-methoxyethyl alcohol (1.10 g) was placed in a 100 mL two-neck flask equipped with a porcelain stirrer and a reflux condenser.
3 mol) and 4.95 g of concentrated hydrochloric acid, and the mixture was heated to 70 ° C. and stirred. To this, 20.0 g of vanillyl alcohol (0.
13 mol) and reacted for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, and a saturated sodium hydrogen carbonate solution was added to neutralize hydrochloric acid. Then, the mixture was extracted with diethyl ether. The extracted oil layer was sufficiently washed with saturated saline and dried over anhydrous magnesium sulfate, and then the solvent was distilled off to obtain a yellow oil. The yellow oil was purified by column chromatography (silica gel, CHCl ₃ ) to obtain 2.0 g of 2-methoxyethyl vanillyl ether (compound (1)) (7.3% based on vanillyl alcohol). The physical properties of the obtained compound are as follows.

¹ H-NMR (CDCl ₃ , δ): 3.39 (s, 3H), 3.57
(s, 4H), 3.89 (s, 3H), 4.49 (s, 2H), 5.62 (s, 1H), 6.79-6.
90 (m, 3H)

Example 2 Synthesis of 2-n-butoxyethyl vanillyl ether (compound (2)) 1182 g of 2-n-butoxyethyl alcohol was placed in a 2000 mL two-necked flask equipped with a porcelain stirrer and a reflux condenser.
(10 mol) and 154.2 g of vanillyl alcohol
(1.0 mol), and the mixture was heated to 70 ° C. and stirred. 30.4 g of concentrated hydrochloric acid was added thereto and reacted for 5 minutes. Example 1
The same post-treatment as described above was performed to obtain a yellow oily substance. The yellow oil was purified by distillation (100 ° C./0.02 torr) to give 2-n-butoxyethyl vanillyl ether.
0 g (71.6% based on vanillyl alcohol) were obtained. The physical properties of the obtained compound are as follows.

¹ H-NMR (CDCl ₃ , δ): 0.91 (t, 3H, J = 7.2H)
z), 1.27-1.64 (m, 2H), 3.47 (t, 2H, J = 6.6Hz), 3.60 (s, 4
H), 3.89 (s, 3H), 4.49 (s, 2H), 5.61 (s, 1H), 6.79-6.91
(m, 3H)

Example 3 Synthesis of 2- (2-n-butoxyethoxy) ethyl vanillyl ether (compound (3)) 2-n-butoxy was placed in a 100 mL two-necked flask equipped with a porcelain stirrer and a reflux condenser. Ethoxyethyl alcohol 21
0.9 g (1.3 mol) and 10.5 g of concentrated hydrochloric acid were added,
The mixture was heated to 70 ° C. and stirred. And vanillyl alcohol 2
0.0 g (0.13 mol) was added and reacted for 2 hours.
The same post-treatment as in Example 1 was performed to obtain a yellow oily substance. The yellow oil was purified by column chromatography (silica gel, CHCl ₃ ) to obtain 5.5 g of 2- (2-n-butoxyethoxy) ethyl vanillyl ether (14.0% based on vanillyl alcohol). . The physical properties of the obtained compound are as follows.

¹ H-NMR (CDCl ₃ , δ): 0.90 (t, 3H, J = 7.2H)
z), 1.25-1.63 (m, 4H), 3.45 (t, 2H, J = 6.4Hz), 3.55-3.70
(m, 8H), 3.89 (s, 3H), 4.48 (s, 2H), 5.63 (s, 1H), 6.78-
6.89 (m, 3H)

Example 4 Synthesis of 2-n-butoxyethyl veratryl ether (compound (4)) 175.7 g of 2-butoxyethyl alcohol in a 300 mL two-necked flask equipped with a porcelain stirrer and a reflux condenser.
(1.48 mol) and veratryl alcohol 25.0 g
(0.149 mol), and the mixture was heated to 70 ° C. and stirred.
6.78 g of concentrated hydrochloric acid was added thereto and reacted for 30 minutes.
The same post-treatment as in Example 1 was performed to obtain a yellow oily substance. The yellow oil was purified by distillation (150 ° C./0.1 torr), and 2-n-butoxyethyl veratryl ether 1
2.5 g (30.8% based on veratryl alcohol)
I got The physical properties of the obtained compound are as follows.

¹ H-NMR (CDCl ₃ , δ): 0.92 (t, 3H, J = 7.2H)
z), 1.28-1.65 (m, 4H), 3.47 (t, 2H, J = 6.6Hz), 3.60 (s, 4
H), 3.88-3.89 (m, 6H), 4.52 (s, 2H), 6.80-6.92 (m, 3H)

Example 5 Synthesis of 2-ethoxy-1-methylethyl vanillyl ether (compound (5)) 1-ethoxy-2-propanol 20 was placed in a 100 mL two-necked flask equipped with a porcelain stirrer and a reflux condenser. .8g
(0.2 mol) and 3.1 g of vanillyl alcohol (0.
02 mol) and heated to 70 ° C. with stirring. 98 mg of concentrated sulfuric acid was added thereto and reacted for 10 minutes. The same post-treatment as in Example 1 was performed to obtain a yellow oily substance. The yellow oil was purified by column chromatography (silica gel, hexane / ethyl acetate = 2/1) to give 2-ethoxy-1.
-Methylethyl vanillyl ether (compound (5)) 3.
05 g (63.4% based on vanillyl alcohol) were obtained. The physical properties of the obtained compound are as follows.

¹ H-NMR (CDCl ₃ , δ): 1.14-1.24 (m, 6H),
3.34-3.74 (m, 5H), 3.89 (s, 3H), 4.53 (s, 2H), 5.61 (s, 1
H), 6.83-6.92 (m, 3H)

Test Example 1 Test solutions were prepared at the ratios shown in Table 1.

[0037]

[Table 1]

10 μL of each test solution was applied to the flexion side of the forearm of 10 healthy men, and the warmth and skin irritation immediately after, 30 minutes, and 1 hour after the application were examined. Table 2 shows the number of persons who responded that even a slight feeling of warmth or skin irritation was felt.

[0039]

[Table 2]

From Table 2, it was confirmed that the compound of the present invention has an excellent effect that a sufficient warm feeling lasts for a relatively long time and skin irritation is weak. It was also confirmed that such an effect was inferior to that of a conventional warming agent.

Example 6 A lotion was prepared according to a conventional method in the proportions shown in Table 3.

[0042]

Table 3 Ingredients Weight% Glycerin 15.0 Polyethylene glycol (PEG 1500) 2.0 Hyaluronic acid 0.05 Dipropylene glycol 5.0 Compound (1) 0.5 Purified water Balance

[0043]

The external preparation for skin of the present invention, which contains the substituted benzyl alcohol derivative of the present invention as an active ingredient, gives a strong warm feeling to the skin, and its effect lasts for a relatively long time. Furthermore, it exhibits excellent characteristics that hardly causes unpleasant skin irritation to the human body.

 ──────────────────────────────────────────────────の Continuing on the front page (72) Akira Yamamuro, Inventor 2606, Kabane-cho, Akaga-cho, Haga-gun, Tochigi Prefecture (72) Inventor Yoshiaki Fujikura 2606, Akabane, Kaiga-cho, Haga-gun, Tochigi Prefecture, Kao Corporation

Claims (2)

[Claims] 1. The following general formula (1):(Where R¹, R^TwoAnd R^ThreeAre the same or different
A straight chain having 1 to 4 carbon atoms
Or a branched chain alkoxy group, or R¹, R^TwoPassing
And R^ThreeTwo of which together form α-methylenedioxy
Groups may be formed. Where R¹, R^Two, And R^ThreeIs the same
Sometimes it does not become a hydrogen atom. n R ^FourAre the same or
Differently -CH_TwoCH_TwoO-, -CH_TwoCH (CH_Three) O
-Or -CH (CH_Three) CH_TwoO-, n is 1-3
Indicates an integer. R^FiveIs a straight or branched chain having 1 to 6 carbon atoms
Shows an alkyl group. Substituted benzyl alcohol represented by)
Derivatives. 2. An external preparation for skin containing the substituted benzyl alcohol derivative according to claim 1 as an active ingredient.