JP2000007631A - Skin lotion - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new amido derivative having an excellent improving effect on a trouble caused by dyskeratosis of the skin. SOLUTION: This amido derivative is shown by formula I [R1 is a (substituted) 4-20C alkyl; R2 is a 1-7C alkyl; R3 is H or 2,3-dihydroxypropyl; R4 is a 2-4C alkylene] such as a compound of formula II. The compound of formula I is, for example, obtained by reacting an alcohol with epichlorohydrin in the presence of a phase transfer catalyst such as a quaternary ammonium salt or the like (e.g. tetrabutyl ammonium bromide or the like) and a base at preferably 20-80 deg.C for 1-12 hrs to form glycidyl ether, reacting the glycidyl ether with an amine derivative of formula H2N-R4 OCH3 at preferably 20-150 deg.C for 2-8 hrs to form an intermediate of formula III and reacting the resulting intermediate of formula III with an ester such as methyl propionate at preferably 15-100 deg.C for 2-8 hrs. Preferably, an external preparation contains 0.01-10 wt.% the above compound.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel amide derivative which is excellent in improving troubles caused by abnormal keratinization of the skin (such as a keratinizing effect, a pigmentation preventing / improving effect, and an acne preventing / improving effect). The present invention relates to this production intermediate and an external preparation for skin containing the same.

[0002]

2. Description of the Related Art The epidermis is impaired in the balance between cell proliferation and keratinization due to factors inside and outside the body, such as ultraviolet rays, age-related skin aging and diseases. May be Therefore, epidermal thickening and parakeratosis are induced, and various vulnerable skin troubles such as dry or greasy skin and dandruff are caused. Further, it is considered that various skin troubles such as pigmentation and the like occur due to onset of acne due to keratin plug formation and delay in melanin metabolism.

Hitherto, as a main method for preventing and improving skin troubles, application of a moisturizing agent or a blood circulation promoting agent has been performed. In order to recover pigmentation, for example, a vitamin C (L-ascorbic acid) derivative, an isoflavone derivative (JP-A-58-225004), a p-hydroxycinnamic acid derivative (JP-A-59-196813)
Attempts have been made to improve the situation.

However, since moisturizers and blood circulation enhancers generally replenish water on the epidermis, particularly on the surface of the keratin, or supplement a part of moisturizing components, they are used for permanent and fundamental improvement of skin. Could not be expected. At present, there is no known substance which has a substantial effect of preventing or improving pigmentation. In addition, retinoic acid is the only substance that has a substantial preventive and ameliorating effect on acne, but it has safety issues (such as teratogenicity) and is generally not used. It is not possible at present.

Accordingly, an object of the present invention is to improve keratinization,
An object of the present invention is to provide a compound excellent in the action of preventing and improving pigmentation and the action of preventing and improving acne, and an external preparation for skin containing the same.

[0006]

Means for Solving the Problems The present inventors have found that the amide derivative represented by the following general formula is excellent in the effect of improving skin troubles caused by abnormal keratinization as described above, and completed the present invention.

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

[0008]

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(Wherein, R ¹ represents a linear or branched alkyl group having 4 to 20 carbon atoms substituted by an alkoxy group having 1 to 12 carbon atoms, and R ² represents an alkyl group having 1 to 7 carbon atoms.) R ³ represents a hydrogen atom or a 2,3-dihydroxypropyl group, and R ⁴ represents an alkylene group having 2 to ⁴ carbon atoms.) And an external preparation for skin containing the same. To provide. The present invention also provides the following general formula (2):

[0010]

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(Wherein R ¹ and R ⁴ are the same as described above).

[0012]

BEST MODE FOR CARRYING OUT THE INVENTION In the general formulas (1) and (2), R ¹
As the alkoxy group having 1 to 12 carbon atoms which is a substituent of the above, an alkoxy group having 1 to 8 carbon atoms is preferable, and a methoxy group,
A 2-methylhexyloxy group is particularly preferred. Carbon number 4
As the linear or branched alkyl group having 20 to 20 carbon atoms, those having 6 to 20 carbon atoms are preferable, and a nonyl group and an octadecyl group are particularly preferable. The number of substituted alkoxy groups may be two or more, but is preferably one. The substitution position of the alkyl group may be any position on the alkyl group, and may be at the terminal or intermediate position such as the 9-position of the nonyl group and the 12-position of the octadecyl group. R ² is preferably an alkyl group having 1 to 4 carbon atoms, and particularly preferably a methyl group and an ethyl group. Further, R ⁴ is preferably a linear alkylene group having 2 to 4 carbon atoms, particularly a trimethylene group.

The amide derivative represented by the general formula (1) is
For example, it can be manufactured by the following manufacturing method disclosed in JP-A-8-319263.

[0014]

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(Wherein R ¹ , R ² and R ³ are the same as described above. R ⁵ is a linear or branched alkyl group having 1 to ⁵ carbon atoms, preferably a methyl group.) .)

(Step 1) Phase transfer catalyst 0.01 to 0.05 such as 1 to 3 moles of epichlorohydrin (4) and quaternary ammonium salt such as tetrabutylammonium bromide per mole of alcohol (3) The reaction is carried out using 1 mol of a base such as sodium hydroxide and potassium hydroxide. The reaction temperature is 20-80 ° C, and the reaction time is 1-12.
Time is preferred. In addition, it is preferable to use no solvent or a solvent inert to the reaction, such as toluene, tetrahydrofuran, or n-hexane.

(Step 2) 1 mol of glycidyl ether (5) is reacted with 1 to 20 mol of amine derivative (6). The reaction temperature is 20 to 150 ° C, and the reaction time is 2 to
8 hours is preferred. In addition, it is preferable to use no solvent or a solvent inert to the reaction, such as methanol, ethanol, or tetrahydrofuran.

(Step 3) The same base as in Step 1 (0.01 to 0.1 mol) and the ester (7) such as methyl acetate and methyl propionate (1 to 2 mol) are used per 1 mol of the amine derivative (2). To react. The reaction temperature is preferably 15 to 100 ° C, and the reaction time is preferably 2 to 8 hours. In addition, it is preferable to use no solvent or a solvent inert to the reaction, such as toluene, tetrahydrofuran, or n-hexane.

(Step 4) 1 mol of the amine derivative (2) is reacted with 1 to 3 mol of the acid anhydride (8). The reaction temperature is preferably 15 to 100 ° C, and the reaction time is preferably 2 to 8 hours. In addition, it is preferable to use no solvent or a solvent inert to the reaction, such as toluene or tetrahydrofuran.

(Step 5) It is preferable to carry out the reaction under the same conditions using the amide derivative (1-1) in place of the alcohol (3) in step 1.

(Step 6) Based on 1 mol of the amide derivative (9), 0.01 to 0.1 mol of the same base as in Step 1, a mineral acid such as sulfuric acid or an organic acid such as decanoic acid / lauric acid. 01
The reaction is carried out using 0.1 mol. Reaction temperature is 20-2
00 ° C is preferred. In addition, it is preferable to use no solvent or a solvent inert to the reaction, such as toluene or tetrahydrofuran.

The amide derivative (1-1) or (1-2) of the present invention thus obtained can be purified by a known method. When these are blended in an external preparation for skin, even if they are purified to a purity of 100%, the purity including intermediates and reaction by-products is 70 to 10 without particular purification.
It may be a 0% mixture.

The content of the amide derivative represented by the general formula (1) in the external preparation for skin of the present invention is, for example, 0.01 to 10%.
% By weight, especially 0.1 to 5% by weight.

The skin external preparation of the present invention can be used as a medicated skin external preparation or a cosmetic in the form of use.
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 includes, for example, vegetable oil, animal oil,
Examples include synthetic oils, fatty acids and natural or synthetic glycerides. Also as other medicinal ingredients, for example, analgesic anti-inflammatory,
Antipruritic agents, disinfectants, astringents, emollients, hormonal agents, and the like can be appropriately added as necessary. It is preferable to add a surfactant.

When used as a cosmetic, in addition to the essential components, oils, surfactants, humectants, ultraviolet absorbers, alcohols, chelating agents, pH adjusters generally used as cosmetic components, Preservatives, thickeners, pigments, fragrances and the like can be arbitrarily combined and blended. The cosmetic can be in various forms, for example, skin cosmetics such as water / oil, oil / water emulsified cosmetics, creams, emulsions, lotions, oily cosmetics, foundations, and skin cleansers. The external preparation for skin of the present invention has an effect of improving skin trouble caused by abnormal keratinization (an effect of improving keratinization, preventing pigmentation,
Improvement, acne prevention / improvement, etc.)
Further, it is also effective in preventing skin aging such as wrinkle improvement, and is particularly useful as an acne preventive / ameliorating agent.

[0026]

【Example】

Example 1 N- [3- (9- (2-methylhexyloxy) nonyloxy) -2- (2,3-dihydroxypropyloxy) propyl] -N- (3-methoxypropyl) acetamide (1- Production method of b) (1) Production of 9- (2-methylhexyloxy) -1-nonanol (3-1)

[0028]

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In a 500 ml five-necked flask equipped with a stirrer, a dropping funnel, a nitrogen inlet tube and a distillation apparatus, 71.4 g (0.44 mol) of 1,9-nonanediol and 12.5 g (0.21 mol) of potassium hydroxide were placed. The mixture was heated and stirred at 140 ° C. in a nitrogen atmosphere, and depressurized to 20 Torr for 2 hours to perform dehydration. After returning to normal pressure, 20.2 g (0.15 mol) of 2-methylhexyl chloride was added dropwise over 1 hour, and the mixture was further stirred for 5 hours under the same conditions. After cooling, water was added, extraction was performed with n-hexane, the obtained organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. 16.3 g (yield 54%) of compound (3-1) was obtained. The physical properties of the obtained compound are as follows.

¹ H-NMR (CDCl ₃ , δ) 0.80-0.96 (m, 6H), 0.96-1.80 (m, 22H), 3.05-3.55 (m, 4
H), 3.64 (t, 2H , J = 6.7Hz). 13 C-NMR (CDCl 3, δ) 14.1, 17.3, 23.2, 25.9, 26.3, 29.3-29.9, 33.0, 33.
6, 63.2, 71.1, 76.4.

(2) 9- (2-methylhexyloxy)
Production of nonyl glycidyl ether (5-1)

[0032]

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200 ml equipped with a stirrer and a nitrogen inlet tube
In a two-necked flask, 9- (2-methylhexyloxy)-
15.7 g (0.06 mol) of 1-nonanol, 11.5 g (0.12 mol) of epichlorohydrin, 0.97 g (0.003 mol) of tetrabutylammonium bromide
And 15 g of n-hexane, and heated and stirred at 44 ° C. under a nitrogen atmosphere, and 4.84 g of sodium hydroxide (0.12 g) was added.
mol) was added over 30 minutes. Further, after stirring for 2.5 hours under the same conditions, water was added and extraction was performed with n-hexane. After washing with a saturated saline solution, the obtained organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified on a silica gel column to give the title compound (5-
1) 14.8 g (78% yield) was obtained. The physical properties of the obtained compound are as follows.

¹ H-NMR (CDCl ₃ , δ) 0.80-0.98 (m, 6H), 1.00-1.80 (m, 21H), 2.60 (dd, 1H, J = 2.
7,5.0Hz), 2.79 (dd, 1H, J = 4.5,5.0Hz), 3.06-3.58 (m, 8H),
3.70 (dd, 1H, J = 3.1,11.4Hz). IR (NaCl, cm ^-1 ) 2932, 2860, 1464, 1112.

(3) Production of 1- (3-methoxypropylamino) -3- (9- (2-methylhexyloxy) nonyloxy) -2-propanol (2-1)

[0036]

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200 ml equipped with a stirrer and a nitrogen inlet tube
In a two-neck flask, 26.0 g of methoxypropylamine was added.
(0.29 mol) and 5.2 g of ethanol, and heated and stirred at 80 ° C. under a nitrogen atmosphere, and 6.0 g of 9- (2-methylhexyloxy) nonyl glycidyl ether (19)
mmol) was added dropwise over 1 hour. After further stirring for 2 hours under the same conditions, the crude product obtained by concentration under reduced pressure was purified by distillation using a glass tube oven (195 ° C./5.0×).
10 ^-3 torr) to obtain 6.5 g (yield: 85%) of the title compound (2-1). The physical properties of the obtained compound are as follows.

¹ H-NMR (CDCl ₃ , δ) 0.80-0.98 (m, 6H), 1.00-1.94 (m, 25H), 2.55-2.81 (m, 4
H), 3.08-3.55 (m, 13H), 3.75-3.94 (m, 1H) .IR (NaCl, cm ^-1 ) 3323, 2932, 2860, 1466, 1114.

(4) N- [3- (9- (2-methylhexyloxy) nonyloxy) -2-hydroxypropyl] -N- (3-methoxypropyl) acetamide (1
Production of -a)

[0040]

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20 ml 2 equipped with a stirrer and a nitrogen inlet tube
1- (3-methoxypropylamino)-
6.50 g (16.1 mmol) of 3- (9- (2-methylhexyloxy) nonyloxy) -2-propanol and 13 ml of tetrahydrofuran were added, and 1.82 ml (19.4 mmol, 19.4 mmol) of acetic anhydride was added at room temperature under a nitrogen atmosphere. .2eq)
Was added dropwise over 10 minutes. After stirring for 3 hours under the same conditions, the mixture was poured into an aqueous sodium hydroxide solution and extracted with n-hexane. The obtained organic layer was washed with a saturated saline solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was purified with a silica gel column to give 5.59 g of the title compound (1-b). (78% yield). The physical properties of the obtained compound are as follows.

¹ H-NMR (CDCl ₃ , δ) 0.82-0.98 (m, 6H), 1.00-1.95 (m, 24H), 2.14 (s, 3H), 3.0
6-3.62 (m, 17H), 3.84-4.02 (m, 1H). IR (NaCl, cm ^-1 ) 3416, 2936, 2860, 1630, 1464, 1116.

(5) N- [3- (9- (2-methylhexyloxy) nonyloxy) -2- (2,3-dihydroxypropyloxy) propyl] -N- (3-methoxypropyl) acetamide (1- b) Manufacturing

[0044]

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50 ml 2 equipped with a stirrer and a nitrogen inlet tube
5.0 g of the compound obtained above (11.2 mm
ol), 0.18 g of tetrabutylammonium bromide
(0.5 mmol), 2.12 g of epichlorohydrin (2
2.9 mmol), 0.92 g (23 mmol) of sodium hydroxide
l) and 5 ml of toluene, and put them in a nitrogen atmosphere at 42 to 4
The mixture was stirred at 8 ° C for 10 hours. Water was added and extracted with toluene. The obtained organic layer is dried with magnesium sulfate,
Filtration and concentration under reduced pressure gave a crude product. After removing a low-polar substance produced as a by-product in a silica gel column, the mixture was transferred to a pressure-resistant flask equipped with a stirrer.
mg (0.2 mmol) and 90 mg (0.4 mmol) of lauric acid were added and stirred at 160 ° C. for 6 hours in a closed system. After cooling,
After washing with brine, drying over magnesium sulfate, filtration,
The crude product obtained by concentration under reduced pressure was formed on a silica gel column to give 3.1 g of the title compound (1-a) (yield 53%).
I got The physical properties of the obtained compound are as follows.

¹ H-NMR (CDCl ₃ , δ) 0.80-0.98 (m, 6H), 1.00-1.95 (m, 25H), 2.16 (s, 3H), 2.9
5-4.10 (m, 23H). IR (NaCl, cm ^-1 ) 3440, 2930, 2860, 1630, 1465, 1120.

Example 2 N- [3- (12-methoxyoctadecyloxy) -2
Production of -hydroxypropyl] -N- (3-methoxypropyl) acetamide (1-c) (1) 1- (3-methoxypropylamino) -3- (1
Production of 2-methoxyoctadecyloxy) -2-propanol (2-2)

[0048]

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200 ml equipped with a stirrer and a nitrogen inlet tube
In a two-necked flask, 23.5 g of methoxypropylamine
(0.26 mol) and 4.7 g of ethanol were added, heated and stirred at 80 ° C. under a nitrogen atmosphere, and 6.0 g (18 mmol) of 12-methoxyoctadecylglycidyl ether was added dropwise over 1 hour. Further, after stirring for 2 hours under the same conditions, the crude product obtained by concentration under reduced pressure was purified by distillation (210 ° C./5.0×10 ⁻³ torr) using a glass tube oven.
6.1 g (yield 81%) of the title compound (2-2) was obtained.
The physical properties of the obtained compound are as follows.

¹ H-NMR (CDCl ₃ , δ) 0.88 (t, 3H, J = 6.5 Hz), 1.14-2.04 (m, 34H), 2.57-2.72 (m,
4H), 3.02-3.21 (m, 1H), 3.32 (s, 3H), 3.35 (s, 3H), 3.38-
3.54 (m, 6H), 3.75-3.95 (m, 1H).

(2) N- [3- (12-methoxyoctadecyloxy) -2-hydroxypropyl] -N- (3
Production of (-methoxypropyl) acetamide (1-c)

[0052]

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In (4) of Example 1, 1- (3-methoxypropylamino) -3- (9- (2-methylhexyloxy) nonyloxy) -2-propanol is used instead of 1- (3-methoxypropyl). Amino) -3- (12
The reaction was carried out in the same manner as (4) of Example 1 except that -methoxyoctadecyloxy) -2-propanol was used to obtain the title compound (1-c). The physical properties of the obtained compound are as follows.

¹ H-NMR (CDCl ₃ , δ) 0.88 (t, 3H, J = 6.8 Hz), 1.08-1.93 (m, 34H), 2.14 (s, 3H),
3.03-3.17 (m, 2H), 3.20-3.61 (m, 14H), 3.82-4.02 (m, 1H) .IR (NaCl, cm ^-1 ) 3384, 2932, 2860, 1630, 1464, 1120.

Test Example 1: Amide derivatives (1-a) to (1-a) for transglutaminase activity of keratinocytes
Effect of c) The activity was measured as follows in the same manner as in the method described in JP-A-5-194185. Keratinocytes cultured in a proliferating state in a 10 cm Petri dish were used. The medium in each well was removed by suction, and 2 ml of K-GM to which no pituitary extract was added was added to replace the medium. Thereafter, the amide derivatives (1-a) to (1-c) obtained above were added. Twenty-four hours later, each well was washed three times with PBS (-), and the cells were peeled and collected using a rubber policeman. The obtained cell suspension was centrifuged at 2,500 rpm for 10 minutes to collect a sediment. Buffer (a) was added to the sediment [10 mM Tris-HCl buffer, 10 mM, DTT, 0.5 mM EDTA; pH 7.4]
200 μl was added and sonicated twice for 1 minute twice. The resulting suspension was subjected to 25,000 rpm, 30
After ultracentrifugation for minutes, the supernatant was obtained. After dispensing a certain amount of this supernatant, each reaction solution [300 mM Tris-HC
buffer, pH 8.1, 100 mM 60 mM CaCl ₂ ,
100 μl of 30 mM DTT, 540 dimethyl casein
100 μl of distilled water containing μg, 50 μm of 12 mM putrescine
2.5 μCi [ ¹⁴ C] Putrescine mixed with 50 μl of distilled water and 100 μl of distilled water], and incubated at 37 ° C. for 1 hour. Then add 10% trichloroacetic acid,
After allowing to stand for 30 minutes, a 200 μl sediment was collected using a 0.45 μm nitrocellulose membrane. After washing the membrane with 15 ml of 5% ice-cold trichloroacetic acid (containing 1% putrescine), the radioactivity on the membrane was calculated by a liquid scintillation counter.

FIG. 1 shows amide derivatives (1-a) to (1-a).
The transglutaminase activity when 10 μl of c) was added was shown as a ratio with the control being 100%. As is clear from these results, the amide derivative (1) of the present invention
-A) to (1-c) were confirmed to have transglutaminase activating action.

Test Example 2: Effect of amide derivatives (1-a) to (1-c) on experimental comedone formation by tetradecane New Zealand white rabbit (male, body weight 2.0-)
2.5 kg) of the inner pinna skin was used. 0.3 ml of 50% tetradecane containing 50% tetradecane (squalane solution) and 0.01% amide derivatives (1-a) to (1-c) was applied once a day for two weeks. Two weeks later, the effect of the amide derivative on experimental comedone formation was examined by measuring the area of the pore-matched rash (experimental comedone) using a surface microscope.

Tetradecane (control), tetradecane / amide derivative (1-a), tetradecane / amide derivative (1-b), tetradecane / amide derivative (1-a)
FIG. 2 shows the results of measuring the areas of the crust and the eruptions (experimental comedones) in the uncoated group and c). The concentration of each amide derivative was 0.01%. From the above results, it was confirmed that the amide derivatives (1-a) to (1-c) suppressed the formation of experimental comedones.

Formulation Example 1 Using the amide derivatives (1-a) to (1-c) of the present invention, a skin external preparation (emulsion cosmetic) was prepared according to the formulation shown in Table 1.

[0060]

[Table 1]

The amide derivatives (1-a) to (1-a) of the present invention
The external preparation for skin containing c) is a treatment for acne,
Excellent effect on prevention. Furthermore, the amide derivative of the present invention was also effective for improving pigmentation and wrinkles.

[0062]

EFFECTS OF THE INVENTION The external preparation for skin containing the amide derivative of the present invention has an effect of improving skin trouble caused by abnormal keratinization (an effect of improving keratinization, preventing / improving pigmentation, an effect of preventing / improving acne) and improving wrinkles. It is effective in preventing skin aging.

[Brief description of the drawings]

FIG. 1 shows the transglutaminase activity of an amide derivative on keratinocytes of the epidermis.

FIG. 2 shows the effect of amide derivatives on experimental comedone formation by tetradecane.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) C07C 217/28 C07C 217/28 (72) Inventor Yoshiaki Fujikura 2606 Kabane-cho, Akaba, Kaga, Haga-gun, Tochigi Kao Corporation Within the research institute (72) Kazuhiko Higuchi 2606 Akabane, Kaigamachi, Haga-gun, Tochigi Prefecture Inside the Kao Corporation Research Laboratory (72) Inventor Kimihiko Hori 2606 Akabane, Akabane-cho, Haga-gun, Tochigi Prefecture Kao Corporation Research Institute (72) Inventor Imokawa Genji 2606 Akabane, Kaiga-cho, Haga-gun, Tochigi Pref.

Claims (3)

[Claims] 1. The following general formula (1): (Wherein, R ¹ represents a C 4-20 linear or branched alkyl group substituted by a C 1-12 alkoxy group, and R ² represents a C 1-7 alkyl group. , R ³ represents a hydrogen atom or a 2,3-dihydroxypropyl group,
R ⁴ represents an alkylene group having 2 to ⁴ carbon atoms. An amide derivative represented by the formula: 2. The following general formula (2): (In the formula, R ¹ represents a linear or branched alkyl group having 4 to 20 carbon atoms substituted by an alkoxyl group having 1 to 12 carbon atoms, and R ⁴ represents an alkylene group having 2 to ⁴ carbon atoms. .)
An amine derivative represented by the formula: 3. An external preparation for skin containing the amide derivative according to claim 1.