JPH11209322A - Isovanillyl alcohol derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: 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 represents a linear or branched alkyl group having 3 to 6 carbon atoms) 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 isovanillyl 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, undesired 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 technology disclosed in Japanese Patent Laid-Open No.
Although the skin irritation feeling can be reduced, 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 isovanillyl alcohol derivative has a strong warming effect on the skin, the effect lasts for a relatively long time, and furthermore, almost no undesirable skin irritation occurs on the human body. The present inventors have found that they have characteristics that cannot be realized with a warming agent, and have completed the present invention.

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

[0007]

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(Wherein R represents a straight-chain or branched-chain alkyl group having 3 to 6 carbon atoms), and an external preparation for skin containing the isovanillyl alcohol derivative as an active ingredient Is provided.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION As the isovanillyl alcohol derivative of the present invention, R in the general formula (1) is
It is preferably an i-propyl group, an n-butyl group, an i-butyl group, or an n-pentyl group.

The isovanilyl alcohol derivative of the present invention can be synthesized by various known methods. For example, the compound can be synthesized by reacting 3-hydroxy-4-methoxybenzyl halide with an alkoxide or isovanillyl alkoxide and an alkyl halide without a solvent or in a solvent according to Williamson's ether synthesis method.

Alternatively, for example, it can be synthesized by the following method. That is, a strong acid such as concentrated hydrochloric acid or concentrated sulfuric acid is mixed with the corresponding alcohol, and isovanillyl alcohol is added thereto and reacted to obtain an intended product. Here, the strong acid is preferably added in an amount of about 0.1 to 30 mol% of the alkyl alcohol. The heating temperature is preferably about 20 to 90 ° C. Further, the alkyl alcohol is preferably used in a molar ratio of about 2 to 20 times that of the isovanyl alcohol.

The topical skin preparation of the present invention contains the above-mentioned isovanillyl alcohol derivative as an active ingredient.
One or a mixture of two or more of the above isovanyl alcohol derivatives can be used. Or pepper powder,
The combined use of other warming compounds such as polyhydric alcohols can further enhance the warming effect without increasing skin irritation. The form of the external preparation for skin of the present invention is not particularly limited, for example, lotion, emulsion,
Examples include lotion, dentifrice, liquid soap, solid soap, creamy hair conditioner, poultice, cream, body shampoo, hand cream, gel, ointment and the like. In order to prepare such a preparation, if necessary, excipients, extenders, binders, wetting agents, disintegrants, oily substances, surfactants, lubricants, dispersants, buffers, preservatives, preservatives , A coloring agent, a fragrance and the like can be appropriately compounded.

The content of the isovanillyl alcohol derivative of the present invention in the external preparation for skin is preferably from 0.001 to 10% by weight, particularly preferably from 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 great, and the undesirable skin irritation is hardly given.

The external preparation for skin of the present invention can be obtained, for example, by mixing an isovanillyl alcohol derivative and other additives and stirring the mixture as appropriate.

[0015]

EXAMPLES 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 Compound (1) Isovanilyl n
Synthesis of n-propyl alcohol 23.4 g (389 mmol) in a 100 mL two-necked flask equipped with a porcelain stirrer and a reflux condenser.
l) and 0.18 mL of concentrated hydrochloric acid were added, and the mixture was heated to 70 ° C. and stirred. 6.00 g of isovanilyl alcohol (3
8.9 mmol) and reacted for 30 minutes. 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 ethyl acetate. 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 distilled under reduced pressure (150-160 ° C / 0.1 mmH
g) to give 3.28 g (43.0% of isovanillyl alcohol) of the title compound isovanillyl n-propyl ether (1-1). The physical properties of the obtained compound (1) are as follows.

¹ H-NMR (CDCl ₃ , δ): 0.93 (t, 3H, J = 7.4 Hz),
1.61 (m, 2H), 3.40 (t, 2H, J = 6.7Hz), 3.88 (s, 3H), 4.40 (s,
2H), 5.63 (s, 1H), 6.82-6.93 (m, 3H) IR (cm ^-1 ): 3436, 2968, 2940, 2864, 1596, 1514, 145
8, 1446, 1370, 1278,1154, 1128, 1092, 1028, 804, 7
60

Example 2 Compound (2) isovanilyl i
Synthesis of so-propyl ether The n-propyl alcohol used in Example 1 above was
Instead of 19.5 g (324 mmol) of propyl alcohol, 4.75 g (30.8 mmo) of isovanillyl alcohol was used.
l) in the same manner as in Example 1 above, and purified by distillation under reduced pressure (160 ° C./0.1 mmHg) to give 2.56 g of the title compound isovanilyl isopropyl ether (2).
(42.3% based on isovanillyl alcohol). The physical properties of the obtained compound (2) are as follows.

¹ H-NMR (CDCl ₃ , δ): 1.20 (d, 6H, J = 6.0 Hz),
3.66 (sept, 1H, J = 6.0Hz), 3.88 (s, 3H), 4.41 (s, 2H), 5.61
(s, 1H), 6.82-6.94 (m, 3H) IR (cm ^-1 ): 3448, 2976, 2940, 2876, 1596, 1516, 144
6, 1382, 1278, 1126,1030, 800, 760

Example 3 Compound (3) Isovanilyl n
Synthesis of -butyl ether The n-propyl alcohol used in Example 1 was replaced with n-butyl alcohol 82.0 g (1.11 mol),
17.0 g of isovanillyl alcohol (110.3 mmo
l), using 0.48 g of concentrated hydrochloric acid in the same manner as in Example 1 above, and purifying under reduced pressure (170 ° C./0.2 mmHg) to obtain 12.19 g of the title compound isovanillyl n-butyl ether (3) (isovanillyl). 52.6% of alcohol). Physical properties of compound (3) obtained are as described below.

¹ H-NMR (CDCl ₃ , δ): 0.91 (t, 3H, J = 7.2 Hz),
1.36-1.62 (m, 4H), 3.44 (t, 2H, J = 8.0Hz), 3.88 (s, 3H), 4.
40 (s, 2H), 5.62 (s, 1H), 6.62-6.93 (m, 3H) IR (cm ^-1 ): 3448, 2964, 2940, 2872, 1596, 1514, 144
6, 1374, 1278, 1128,1094, 1030, 802, 760

Example 4 Compound (4) Isovanillyl i
Synthesis of so-butyl ether The n-propyl alcohol used in Example 1 above was
Butyl alcohol instead of 28.8 g (379 mmol)
The same procedure as in Example 1 was carried out except that vacuum distillation was carried out at 160 to 170 ° C./0.1 mmHg, and 4.23 g of the title compound isovanillyl iso-butyl ether (4) (51.7 g with respect to isovanilyl alcohol). %). Physical properties of compound (4) obtained are as described below.

¹ H-NMR (CDCl ₃ , δ): 0.91 (d, 6H, J = 6.6 Hz),
1.89 (sept, 1H, J = 6.6Hz), 3.20 (d, 2H, J = 6.6Hz), 3.88 (s, 3
H), 4.41 (s, 2H), 5.62 (s, 1H), 6.82-6.93 (m, 3H) IR (cm ^-1 ): 3248, 3036, 3004, 2956, 2876, 1592, 151
4, 1460, 1448, 1370,1280, 1132, 1066, 1026, 756, 6
40

Example 5 Synthesis of Compound (5) Isovanilyl Amyl Ether The n-propyl alcohol used in Example 1 was replaced with 34.3 g (389 mmol) of n-amyl alcohol, and distillation at reduced pressure was carried out at 160-170 ° C. / The procedure was performed in the same manner as in Example 1 except that the procedure was performed at 0.1 mmHg, to obtain 4.38 g of the title compound isovanillyl n-amyl ether (5) (50.2% based on isovanillyl alcohol). Physical properties of compound (5) obtained are as described below.

¹ H-NMR (CDCl ₃ , δ): 0.89 (t, 3H, J = 6.9 Hz),
1.33 (m, 4H), 1.56-1.63 (m, 2H), 3.43 (t, 2H, J = 6.6Hz), 3.
88 (s, 3H), 4.40 (s, 2H), 5.61 (s, 1H), 6.82-6.93 (m, 3H) IR (cm ^-1 ): 3448, 2940, 2864, 1596, 1514, 1460, 136
8, 1276, 1128, 1094,1028, 802, 760

Example 6 Compound (6) isovanilyl i
Synthesis of so-amyl ether The n-propyl alcohol used in Example 1 was
-Instead of 28.6 g (324 mmol) of amyl alcohol,
The same procedure as in Synthesis Example 1 was carried out except that vacuum distillation was carried out at 160 to 170 ° C./0.1 mmHg, and 3.25 g of the title compound isovanylyl iso-amyl ether (6) (44. 7%). Physical properties of compound (6) obtained are as described below.

¹ H-NMR (CDCl ₃ , δ): 0.89 (d, 6H, J = 6.5 Hz),
1.50 (q, 2H, J = 6.8Hz), 1.73 (m, 1H), 3.46 (t, 2H, J = 6.8Hz),
3.88 (s, 3H), 4.40 (s, 2H), 5.60 (s, 1H), 6.82-6.93 (m, 3
H) IR (cm ^-1 ): 3432, 2960, 2872, 1596, 1514, 1464, 144
6, 1372, 1278, 1128,1092, 1028, 802, 760

Example 7 Compound (7) Isovanilyl n
Synthesis of -hexyl ether Example 1 except that n-propyl alcohol used in Example 1 was replaced with 33.0 g (324 mmol) of n-hexyl alcohol and distillation under reduced pressure was performed at 160 to 170 ° C / 0.1 mmHg. In the same manner as in the above, 4.83 g (62.6% based on isovanilyl alcohol) of the title compound isovanillyl n-hexyl ether (7) was obtained. Physical properties of compound (7) obtained are as described below.

¹ H-NMR (CDCl ₃ , δ): 0.88 (t, 3H, J = 6.8 Hz),
1.29-1.63 (m, 8H), 3.43 (t, 2H, J = 6.6Hz), 3.88 (s, 3H), 4.
40 (s, 2H), 5.60 (s, 1H), 6.82-6.93 (m, 3H) IR (cm ^-1 ): 3440, 2936, 2864, 1596, 1514, 1462, 144
6, 1372, 1278, 1128,1096, 1030, 802, 758

Test Example 1 Test solutions were prepared according to the formulations shown in Table 1.

[0031]

[Table 1]

10 μL of each of the test solutions obtained above was applied to the inside 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 answered that even a slight feeling of warmth or skin irritation was felt.

[0033]

[Table 2]

From Table 2, it was confirmed that the test solutions (1) to (5) had an excellent effect that a sufficient warm feeling was maintained for a relatively long time and a skin irritation was weak. It was also confirmed that such an effect could not be obtained from a conventional warming agent.

Example 8 A lotion was prepared according to a conventional method in the proportions shown in Table 3.

[0036]

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

[0037]

The external preparation for skin of the present invention contains the isovanillyl alcohol derivative of the present invention as an active ingredient, so that undesired side effects on the human body are reduced in skin irritation, and the skin is immediately warmed when used. It gives a feeling and can maintain an appropriate warm feeling for a long time.

 ──────────────────────────────────────────────────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): (Wherein, R represents a straight-chain or branched-chain alkyl group having 3 to 6 carbon atoms). 2. An external preparation for skin comprising the isovanillyl alcohol derivative according to claim 1 as an active ingredient.