JP2699132B2 - Keratinizing agent and external preparation for skin containing same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a keratinizing agent and an external preparation for the skin, and more particularly to a keratinizing agent capable of maintaining the normal function of the skin, having an excellent antidandruff effect and an effect of improving the skin after sunburn. And topical skin preparations.

[0002]

2. Description of the Related Art The skin prevents loss of water and various components from a living body, and controls water evaporation and constant maintenance of body temperature. In addition, it has a barrier function to protect the body from external physical and chemical stimuli (humidity, temperature, ultraviolet rays, etc.) and various bacteria, and its physiological functions are very important in the life activities of living organisms. .

However, changes in the external environment (seasonal changes,
Skin tissue dysfunction often occurs due to factors inside and outside the body that act on the living body, such as ultraviolet rays and fluctuations in physiological functions (associated with aging and disease). Therefore, epidermal thickening and parakeratosis are induced, and as a result, various vulnerable skin troubles such as dry or greasy skin and dandruff occur.

[0004] In order to improve such skin troubles and maintain healthy skin, the skin troubles can be corrected by eliminating or reducing causative substances and events or by adding and applying certain components. Can be considered.
Conventionally, the main methods to prevent and improve skin troubles are to apply a synthetic or natural moisturizing component to prevent skin drying and increase the skin's moisturizing ability, or by applying a blood circulation promoting agent to promote skin blood circulation. Attempts have been made to improve it.

[0005]

However, the above method is effective in preventing and improving various skin problems,
There are various problems in terms of the persistence of the effect, stability and safety of the drug, and the like. That is, since these methods generally replenish moisture on the epidermis, particularly on the surface of the stratum corneum, or supplement some of the moisturizing ingredients, the effect is temporary, so it is permanent. The effect of improving the skin cannot be expected. Therefore, in order to solve the above problems, there has been a demand for the development of biologically-derived components and chemically synthesized analogs that provide permanent physiological action effects and high safety.

[0006]

Means for Solving the Problems In view of such circumstances, the present inventors have intensively studied to improve or reduce the skin function and to maintain the normal function of the skin. Has the effect of suppressing the turnover enhancement of the epidermis (resulting in hyperplasia of the epidermis, parakeratosis and abnormalities of epidermal lipid metabolism) caused by ultraviolet rays and various components and normalizing the keratinization of the epidermis. Thus, the present invention has been completed.

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

[0008]

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(Wherein R ¹ represents a linear, branched, or cyclic saturated or unsaturated hydrocarbon group having 4 to 40 carbon atoms. R ² , R ³ , R ⁴ , R ⁵ , and R ⁶ represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms which may be substituted by one or more hydroxyl groups.) It is.

[0010] The present invention further provides a skin external preparation characterized by further containing the keratinizing agent.

Some of the amine derivatives (1) used in the present invention are known compounds, and have been conventionally used as intermediates for the production of N-acyl amide derivatives (Japanese Patent Application Laid-Open No. Sho 62-228048). JP-A-54-117421 and JP-A-54-13523.
No. 3). However, its effect on the skin, particularly on the epidermal cells, was not known at all.

Specific examples of R ¹ of the amine derivative represented by the general formula (1) include butyl, hexyl, octyl,
Decyl, dodecyl, tetradecyl, pentadecyl, hexadecyl, octadecyl, docosyl, dotriacontyl, methyl-branched isostearyl, 2-ethylhexyl,
2-heptylundecyl, 5,7,7-trimethyl-2
-(1,3,3-trimethylbutyl) -octyl, 9-
And hydrocarbon groups such as octadecenyl, 9,12-octadecadienyl, cyclohexyl, phenyl, benzyl, cholesteryl and the like. Also, R ² , R ³ , R ⁴ , R ⁵ , R
^As specific examples of ⁶ , a hydrogen atom, and methyl, ethyl,
Butyl, hexyl, phenyl, benzyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, 1,2,3-trihydroxypropyl, 1,2,2
3,4-tetrahydroxybutyl, 1,2,3,4,5
-Pentahydroxypentyl and the like.

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, the compound is synthesized by adding an amine derivative (3) to a glycidyl ether derivative (2).

[0014]

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Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶
Has the same meaning as described above). The amine derivative (1) thus obtained may be further subjected to an inorganic acid salt such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or the like, or succinic acid, if necessary, by a conventional method.
Organic acid salts such as fumaric acid, hexadecanoic acid, octadecanoic acid, lactic acid, glycolic acid, citric acid, tartaric acid, and benzoic acid can also be used.

Of these amine derivatives (1), those represented by the following general formulas (1 ') and (1 ") are novel compounds.

[0017]

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(Wherein R ¹ ′ represents an odd-numbered straight-chain alkyl or alkenyl group having 5 to 39 carbon atoms, cholesteryl group or dihydrophytyl group. R ¹ , R ² , R ³ , R
⁴ , R ⁵ and R ⁶ have the same meaning as described above)

These amine derivatives (1) or acid addition salts thereof are used in vivo (in-
In both of vivo and in vitro, it has an excellent effect of suppressing epidermal cell DNA synthesis, promoting differentiation induction, and suppressing epidermal hyperplasia. Therefore, it has an effect of normalizing abnormal keratinization of skin epidermal cells, and can be used as a keratinizing agent.

The keratinizing agent of the present invention can be administered orally, externally, or by any other method.

The keratinizing agent of the present invention is blended in a skin external preparation. The external preparation for skin can take various forms of use, such as external preparation for medicated skin, external preparation for cosmetics, and cosmetics.

Examples of the medicated skin external preparation and the cosmetic skin external preparation include various ointments containing a medicinal 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, synthetic oil, fatty acid, and natural or synthetic glyceride.
The medicinal component is not particularly limited, and for example, an analgesic anti-inflammatory, an analgesic, a bactericidal disinfectant, an astringent, an emollient, a hormonal agent, a vitamin, and the like can be used as needed. .

When used as cosmetics, oils, humectants, ultraviolet absorbers, alcohols, chelating agents, pH adjusters, preservatives, thickeners, pigments generally used as cosmetic ingredients are used. Flavors and the like can be arbitrarily combined and blended. As cosmetics, various uses and forms, for example, water / oil, oil / water emulsified cosmetics, creams,
It can be used as a cosmetic emulsion, lotion, oily cosmetic, lipstick, foundation, skin cleanser, hair tonic, hair styling agent, hair restorer, and hair restorer. The external preparation for skin of the present invention can be prepared into the above various forms by a conventional method.

The amount of the amine derivative or an acid addition salt thereof to be added to the external preparation for skin is not particularly limited. However, in the case of an external preparation for skin which is usually emulsified, 0.0001 to 0.
1% by weight (hereinafter indicated by%) is preferred.

[0025]

EFFECT OF THE INVENTION The keratinizing agent and the external preparation for skin of the present invention are:
It has a remarkable inhibitory effect on parakeratosis, epidermal hyperplasia, abnormal lipid metabolism, etc. due to the effects of ultraviolet rays and various other factors, thereby restoring the normal function of the skin and contributing to the maintenance of homeostasis. And has an especially excellent antidandruff effect and an effect of improving skin after sunburn.

[0026]

EXAMPLES The present invention will be specifically described below with reference to examples, but it goes without saying that the present invention is not limited to these examples.

Synthesis Example 1 1- (2-hydroxyethylamino) -3-tetradecyloxy-2-propanol [In the general formula (1), R ¹ ＣC
₁₄ H ₂₉ —, R ² ＲR ³ ＲR ⁴ ＲR ⁵ ＲR ⁶ ＨH compound]: In a three- and five-necked flask equipped with a stirrer, a dropping funnel, a thermometer, an N ₂ inlet tube and a distillation apparatus. , Ethanolamine 916.2 g (15 mol) and ethanol 183 g were charged and heated and stirred at 80 ° C. under an N ₂ atmosphere, and tetradecyl glycidyl ether 270.5 g (1 mol) was added thereto.
l) was added dropwise over 3 hours. After completion of the dropwise addition, ethanol and excess ethanolamine were distilled off under reduced pressure, and the residue was recrystallized from methanol to obtain 295.7 g of the target compound (1a) as a colorless powder (yield: 89.2).
%).

[0028]

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Synthesis Example 2 The same amine derivative (1b) shown below was synthesized in the same manner as in Synthesis Example 1.
To (1f) were synthesized.

[0030]

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Synthesis Example 3 1- (2-hydroxyethylamino) -3-methyl-branched isostearyloxy-2-propanol [In the general formula (1), R ¹ = methyl-branched isostearyl, R ² = R
³ = Synthesis of ^R 4 ⁼ compound of R 5 ^{= F} 6 = H]: stirrer, a dropping funnel, a thermometer, a 315-neck flask equipped with a _{N 2} inlet tube and a distillation equipment, ethanolamine 91
6.2 g (15 mol) and 183 g of ethanol were charged, and the mixture was heated and stirred at 80 ° C. under a N ₂ atmosphere while adding methyl-branched isostearyloxyglycidyl ether 32 to the mixture.
6.6 g (1 mol) was added dropwise over 3 hours. After completion of the dropwise addition, ethanol and excess ethanolamine were distilled off under reduced pressure, and the residue was purified by flash chromatography on silica gel to obtain 320.5 g of the target compound (1 g) as a pale yellow paste (yield). 82.7
%).

[0032]

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Synthesis Example 4 Synthesis of 1- (2-hydroxyethylamino) -3-methyl-branched isostearyloxy-2-propanol hydrochloride: 13.2 amine derivative (1 g) obtained in Synthesis Example 3.
To a solution of g (34 mmol) in 100 ml of ethanol, 2.83 ml (34 mmol) of 12N hydrochloric acid was added, and then the solvent was distilled off under reduced pressure to give a pale yellow gel of the desired amine derivative (1 g) hydrochloride (1 g '). 14.4 g were obtained.

Synthesis Example 5 In the same manner as in Synthesis Example 3, 1- (2-hydroxyethylamino) -3- (9-octadecenyloxy) -2-propanol (1h) was synthesized.

[0035]

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Synthesis Example 6 1- (2-hydroxyethylamino) -3-phenyloxy-2-propanol [In the general formula (1), R ¹ = phenyl, R ² = R ³ = R ⁴ = R ⁵ = R ⁶ = compound of H synthesis of: stirrer, a dropping funnel, a thermometer, a 500ml4-necked flask equipped with a N ₂ inlet tube and a distillation apparatus was charged with ethanolamine 91.6 g (1.5 mol) and ethanol 20 g, N _While heating and stirring at 80 ° C. under _two atmospheres, 15.0 g of phenylglycidyl ether was added dropwise thereto over 2 hours. After completion of the dropwise addition, ethanol and excess ethanolamine were distilled off under reduced pressure, and the residue was distilled under reduced pressure (175).
-180 ° C / 0.5 Torr) to obtain 18.5 g of the target compound (1i) as a colorless solid (yield: 87.6).
%).

[0037]

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Synthesis Example 7 1- [bis (2-hydroxyethyl) amino] -3-tetradecyloxy-2-propanol [in the general formula (2)
^{_{R 1 = C 14 H 29,}} R 2 = -CH 2 CH 2 OH, R 3 = R 4 = R
⁵ = R ⁶ ＨH compound]: stirrer, dropping funnel,
In a 11-neck flask equipped with a thermometer and an N ₂ inlet tube,
105.1 g (1 mol) of diethanolamine and 100 g of ethanol were charged, and the mixture was heated and stirred at 80 ° C. under a N ₂ atmosphere while adding tetradecyl glycidyl ether 27 thereto.
0.5 g (1 mol) was added dropwise over 30 minutes. After the completion of the dropwise addition, the mixture was further stirred at 80 ° C. for 6 hours, and the obtained reaction mixture was purified by silica gel flash chromatography to give the target compound (1j) 232.
0 g was obtained (61.8% yield).

[0039]

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Synthesis Example 8 In the same manner as in Synthesis Example 7, the following amine derivative (1
k) to (1o) were synthesized.

[0041]

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Synthesis Example 9 1- (2,3-dihydroxypropylamino) -3-tetradecyloxy-2-propanol (1p) [In the general formula (1), R ¹ = C ₁₄ H ₂₉ , R ² = R ^{3 = R 4 = R 6 =} H,
Synthesis of R ⁵ = —CH ₂ OH compound]: 25 g of 3-amino-1,2-propanediol in a 21-neck flask equipped with a stirrer, a dropping funnel, a thermometer, and an N ₂ introduction tube.
(0.27 mol) were charged ethanol 100 g, N ₂
While heating and stirring at 80 ° C. in an atmosphere, 9.9 g (0.037 mol) of tetradecyl glycidyl ether was added to the mixture.
It was dropped over time. After the completion of the dropwise addition, the mixture was further stirred at 80 ° C. for 1 hour, 1 liter of water was added to the obtained reaction mixture, and the generated solid was filtered. Then, the obtained solid was recrystallized from methanol to obtain 10.3 g of the target compound (1p) as a colorless powder (yield: 77.8%).

[0043]

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Synthesis Example 10 In the same manner as in Synthesis Example 9, the following amine derivative (1
q) to (1s) were synthesized.

[0045]

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Synthesis Example 11 The following amine derivative (1t) was prepared in the same manner as in Synthesis Example 1.
~ (1x) was synthesized.

[0047]

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Synthesis Example 12 In the same manner as in Synthesis Example 3, the following amine derivative (1y)
To (1z) were synthesized.

[0049]

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Synthesis Example 13 In the same manner as in Synthesis Example 7, the following amine derivative (1a
a) to (1ac) were synthesized.

[0051]

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Synthesis Example 14 In the same manner as in Synthesis Example 9, the following amine derivative (1a
d) to (1af) were synthesized.

[0053]

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The above (1a) to (1af)
Each substituent R of each amine derivative ¹~ R⁶Table 1 below
The results are shown in Tables 2 and 3.

[0055]

[Table 1]

[0056]

[Table 2]

[0057]

[Table 3]

The obtained amine derivatives (1a) to (1a)
Data on the shape (melting point), IR, and NMR of f) are shown below. (1a) Colorless powder (melting point 69.1-69.5 ° C) IR (KBr, cm ^-1 ) 3448,2920,2852,1464,1374,1330,1120,10
^{90,1054. 1 H-NMR (CDCl} 3, δ) 0.67~1.87 (m, 27H), 2.53~2.90 (m, 4
H), 2.93-3.20 (br, 3H), 3.30-4.07 (m, 7H).

(1b) Colorless powder (melting point: 52.7-53.8 ° C.) IR (KBr, cm ⁻¹ ) 3452,2920,2852,1466,1432,1380,1358,13
^{32,1120,1050,870. 1 H-NMR (CDCl} 3, δ) 0.63~1.97 (m, 19H), 2.52~3.22 (m, 7
H), 3.25-4.10 (m, 7H).

(1c) Colorless powder (melting point: 60.2-61.5 ° C.) IR (KBr, cm ⁻¹ ) 3452, 2920, 2852, 1464, 1356, 1382, 1120, 10
^{50,958,872. 1 H-NMR (CDCl} 3, δ) 0.63~1.80 (m, 23H), 2.54~2.96 (m, 7
H), 3.26-4.13 (m, 7H).

(1d) Colorless powder (melting point: 70.6 to 71.2 ° C.) IR (KBr, cm ⁻¹ ) 3448, 2920, 2852, 1462, 1124, 1050. ¹ H-NMR (CDCl ₃ , δ) 0.67 to 1.67 (m , 31H), 2.60-2.80 (m, 4
H), 3.10-3.90 (m, 10H).

(1e) Colorless powder (melting point: 77.8-78.3 ° C.) IR (KBr, cm ⁻¹ ) 3452, 2920, 2852, 1464, 1376, 1360, 1330, 11
^{20,1052,868. 1 H-NMR (CDCl} 3, δ) 0.67~1.90 (m, 35H), 2.13~3.11 (m, 7
H), 3.30-4.13 (m, 7H).

(1f) Colorless powder (melting point: 177.6-178.9 ° C.) IR (KBr, cm ⁻¹ ) 3456, 3376, 2936, 2912, 1458, 1368, 1096, 10
^{52,948,860. 1 H-NMR (CDCl} 3, δ) 0.68 (s, 3H), 0.84~1.72 (m, 32H), 1.72
Up to 2.48 (m, 7H), 2.66 to 2.96 (m, 7H), 3.06 to 3.26 (m, 1H), 3.3
6 ~ 3.58 (m, 2H), 3.67 (bt, J = 5.0Hz, 2H), 3.80 ~ 3.96 (m, 1
H), 5.32-5.38 (m, 1H).

[0064] (1 g) pale yellow pasty ^{IR (NaCl, cm -1) 3440,2924,2856,1462,1380,1118,1054} . 1 H-NMR (CDCl 3, δ) 0.65~1.80 (m, 35H) , 2.38-2.92 (m, 4
H), 3.18 to 4.22 (m, 10H).

[0065] (1 g ') light yellow ^{gel:. IR (NaCl, cm -1} ) 3344,2920,2856,1588,1460,1376,1092 1 H-NMR (CDCl 3, δ) 0.62~1.93 (m, 35H), 2.90 to 3.83 (m, 10
H), 3.83-4.67 (m, 5H).

(1h) pale yellow solid (melting point: 36.0-37.2 ° C.) IR (NaCl, cm ⁻¹ ) 3344,2928,2856,1462,1352,1326,1112,1
_{^{058. 1 H-NMR (CDCl 3}} , δ) 0.76~2.33 (m, 33H), 2.60~2.93 (m, 4
H), 3.13 to 4.20 (m, 10H), 5.23 to 5.67 (m, 2H).

(1i) Colorless solid (melting point: 77.0 to 78.4 ° C.) IR (KBr, cm ⁻¹ ) 3308,2872,1596,1496,1440,1244,1062,10
^{44,956,856,754,698. 1 H-NMR (CDCl} 3, δ) 2.70 ~2.90 (m, 4H), 3.44 (bs, 3H), 3.70
(bt, J = 5.0Hz, 2H), 3.94 (d, J = 5.3Hz, 2H), 4.06-4.20 (m, 1
H), 6.85-7.00 (m, 3H), 7.22-7.34 (m, 2H).

(1j) pale yellow oil IR (NaCl, cm ^-1 ) 3364,2924,2856,1460,1376,1118,1076,1
_{^{040. 1 H-NMR (CDCl 3}} , δ) 0.89 (t, J = 6.5Hz, 3H), 1.10~1.75 (m, 24
H), 2.34 to 2.95 (m, 6H), 3.24 to 4.06 (m, 9H), 4.61 (br, 3H).

(1k) pale yellow oil IR (NaCl, cm ^-1 ) 3404,2928,2856,1462,1118,1080,1036,7
_{^{52. 1 H-NMR (CDCl 3}} , δ) 0.88 (t, J = 6.5Hz, 3H), 1.12~1.72 (m, 24
H), 2.30-2.77 (m, 7H), 3.09 (br, 2H), 3.33-3.54 (m, 4H),
3.60 to 3.70 (m, 2H), 3.85 to 4.00 (m, 1H).

(1 l) pale yellow oil IR (NaCl, cm ^-1 ) 3404,2928,2856,1456,1378,1114,1068,7
^{36,698. 1 H-NMR (CDCl} 3, δ) 0.89 (t, J = 6.5Hz, 3H), 1.09~1.70 (m, 27
H), 2.55-3.08 (m, 6H), 3.25-4.04 (m, 9H), 7.18-7.40 (m,
5H).

(1 m) Colorless solid (melting point: 88.9-90.2 ° C.) IR (KBr, cm ⁻¹ ) 3360, 2924, 2852, 1468, 1348, 1244, 1126, 11
00,1084,1042. ¹ H-NMR (CDCl ₃ , δ) 0.88 (t, J = 6.5Hz, 3H), 1.20-1.80 (m, 27
H), 2.27-2.86 (m, 7H), 3.30-4.02 (m, 11H), 4.57 (br, 5H).

(1n) pale yellow oil IR (NaCl, cm ^-1 ) 3388,2920,2856,1470,1110,1074,1036,1
^{026,744,702. 1 H-NMR (CDCl} 3, δ) 0.88 (t, J = 6.5Hz, 3H), 1.16~1.72 (m, 28
H), 2.46 to 2.82 (m, 4H), 3.22 to 4.00 (m, 13H).

(1o) pale yellow oil IR (NaCl, cm ^-1 ) 3352,2928,2856,1458,1118,1088,1054,1
^{042,756,702. 1 H-NMR (CDCl} 3, D 2 O, δ) 0.86 (t, J = 6.5Hz, 3H), 1.08~1.80
(m, 28H), 2.38-2.90 (m, 4H), 3.13-4.13 (m, 13H), 7.14 (b
r, 5H).

[0074] (1p) colorless powder (mp 100.5~102.2 ℃) IR (KBr, cm -1) 3388,2920,2852,1470,1352,1124,1076. 1 H-NMR (CDCl 3, δ) 0.88 (t , J = 6.5Hz, 3H), 1.05-1.67 (m, 24
H), 1.68-2.20 (m, 4H), 2.58-2.94 (m, 4H), 3.31-3.96 (m,
8H).

(1q) Colorless powder (melting point: 98.4-99.5 ° C.) IR (KBr, cm ⁻¹ ) 3440, 2920, 2852, 1468, 1344, 1124, 1096, 10
_{^{64. 1 H-NMR (CDCl 3}} , δ) 0.88 (t, J = 6.5Hz, 3H), 1.13~1.67 (m, 28
H), 2.30-2.97 (m, 8H), 3.30-4.00 (m, 8H).

(1r) Colorless powder (melting point-decomposed, unmeasurable) IR (NaCl, cm ^-1 ) 3352,2928,2856,1470,1458,1118,1088,1
^{054,1042,756,702. 1 H-NMR (CDCl} 3, D 2 O, δ) 0.86 (t, J = 6.5Hz, 3H), 1.08~1.80
(m, 28H), 2.38-2.90 (m, 4H), 3.13-4.13 (m, 13H), 7.14 (b
r, 5H).

[0077] (1s) colorless powder (mp 85.7~87.1 ℃) IR (KBr, cm -1) 3488,2924,2852,1470,1334,1120,1036. 1 H-NMR (MeOH-d 4, δ) 0.67 ~ 1.93 (m, 31H), 2.50 ~ 2.94 (m, 2
H), 3.17 to 3.98 (m, 13H).

(1t) Colorless powder (melting point 50.3-51.2 ° C.) IR (KBr, cm ^-1 ) 3448,2920,2848,1464,1425,1359,1116,10
^{47,957,912,867. 1 H-NMR (CDCl} 3, δ) 1.18~1.75 (m, 14H), 1.95~2.12 (m, 2
H), 2.55-2.84 (m, 4H), 3.02 (brs, 3H), 3.32-3.52 (m, 4H),
3.60 to 3.74 (m, 2H), 3.82 to 3.98 (m, 1H), 4.85 to 5.07 (m, 2
H), 5.68-5.94 (m, 1H).

[0079] (1u) colorless powder (mp 61.2~62.1 ℃) IR (KBr, cm -1) 3448,2920,2852,1466,1120,1052. 1 H-NMR (CDCl 3, δ) 0.80~0.98 (m , 3H), 1.18-1.70 (m, 18
H), 2.54-2.85 (m, 4H), 3.05-4.00 (m, 10H).

(1v) Colorless powder (melting point: 67.4-68.4 ° C.) IR (KBr, cm ^-1 ) 3444, 2920, 2848, 1464, 1358, 1332, 1120, 10
^{90,1050,952,868,722. 1 H-NMR (CDCl} 3, δ) 0.88 (t, J = 6.24Hz, 3H), 1.10~1.70 (m, 2
2H), 2.54-3.20 (m, 7H), 3.30-3.52 (m, 4H), 3.58-3.74
(m, 2H), 3.80 to 3.98 (m, 1H).

(1w) Colorless powder (melting point: 72.2 to 73.4 ° C.) IR (KBr, cm ⁻¹ ) 3448,2920,2852,1464,1378,1328,1122,10
^{52,956,866,720. 1 H-NMR (CDCl} 3, δ) 0.88 (t, J = 6.19Hz, 3H), 1.08~1.70 (m, 2
6H), 2.50-3.20 (m, 7H), 3.28-3.50 (m, 4H), 3.58-3.72
(m, 2H), 3.80 to 3.98 (m, 1H).

(1x) Colorless powder (melting point: 77.4-78.0 ° C) IR (KBr, cm ^-1 ) 3440,3312,2916,2852,1464,1378,1356,13
^{30,1120,1052,954,868,720. 1 H-NMR (CDCl} 3, δ) 0.88 (t, J = 6.24Hz, 3H), 1.10~1.70 (m, 3
0H), 2.50-3.25 (m, 7H), 3.32-3.52 (m, 4H), 3.62-3.72
(m, 2H), 3.82 ~ 3.98 (m, 1H).

[0083] (1y) pale yellow oil ^{IR (NaCl, cm -1) 3388,2926,2856,1461,1377,1110} . 1 H-NMR (CDCl 3, δ) 0.70~0.97 (m, 15H), 0.98 ~ 1.76 (m, 20
H), 2.56 to 2.73 (m, 4H), 3.29 to 3.59 (m, 4H), 3.62 to 4.10 (m,
6H).

(1z) pale yellow oil IR (NaCl, cm ^-1 ) 3296,2924,2856,1458,1374,1118,1052,9
^{40,884. 1 H-NMR (CDCl} 3, δ) 0.70~0.98 (m, 15H), 0.98~1.78 (m, 20
H), 2.56-2.92 (m, 4H), 3.30-3.60 (m, 4H), 3.62-4.10 (m,
6H).

[0085] (1aa) pale yellow oil ^{IR (NaCl, cm -1) 3356,2924,2856,1464,1376,1122,1070} . 1 H-NMR (CDCl 3, δ) 0.78~1.00 (m, 6H) , 1.00 ~ 1.75 (m, 29
H), 2.32 to 2.88 (m, 6H), 3.30 to 4.00 (m, 9H), 4.90 (brs, 3H).

[0086] (1ab) pale yellow oil ^{IR (NaCl, cm -1) 3424,2928,2856,1460,1378,1116,1040} . 1 H-NMR (CDCl 3, δ) 0.72~0.96 (m, 6H) , 1.00 ~ 1.76 (m, 29
H), 2.33 (s, 3H), 2.36 to 2.72 (m, 4H), 3.30 to 3.52 (m, 6H), 3.
57 ~ 3.68 (m, 2H), 3.82 ~ 3.96 (m, 1H).

(1ac) pale yellow oil IR (NaCl, cm ^-1 ) 3388,2924,2856,1454,1370,1118. ¹ H-NMR (CDCl ₃ , δ) 0.63 to 1.92 (m, 35H), 2.40 ~ 4.06 (m, 15
H), 7.18 (brs, 5H).

(1ad) colorless powder (melting point 93.6-94.5 ° C.) IR (KBr, cm ^-1 ) 3404,2924,2852,1470,1350,1120,1102,10
_{^{50. 1 H-NMR (CDCl 3}} , δ) 0.80~1.00 (m, 6H), 1.10~1.68 (m, 24
H), 2.45-2.74 (m, 2H), 3.20-3.64 (m, 12H), 3.78-3.98
(m, 1H).

(1ae) colorless powder (melting point: 84.4 to 85.4 ° C.) IR (KBr, cm ⁻¹ ) 3308, 2924, 2856, 1466, 1378, 1114. ¹ H-NMR (CDCl ₃ , δ) 0.80 to 1.00 (m , 3H), 1.10 to 1.70 (m, 24
H), 2.56 ~ 2.74 (m, 2H), 3.24 ~ 3.74 (m, 15H), 3.88 ~ 4.06
(m, 1H).

(1af) Colorless powder (melting point: 79.5 to 81.2 ° C.) IR (KBr, cm ⁻¹ ) 3424, 3148, 2914, 2848, 1467, 1347, 1110, 10
^{29,969,870. 1 H-NMR (CDCl} 3, δ) 0.88 (t, J = 6.4Hz, 3H), 1.15 (d, J = 6.1Hz,
3H), 1.21 to 1.73 (m, 24H), 2.38 to 2.90 (m, 7H), 3.30 to 3.60
(m, 4H), 3.72-4.01 (m, 2H).

Example 1 Inhibitory Effect of Amine Derivative on DNA Synthesis of Epidermal Keratinocytes (1) Method a) Culture of human keratinocytes Epidermal keratinocytes are human normal keratin cells sold by Kurabo Industries, Ltd. Purified cells (trade name: Epipack) were purchased and used. The cells were maintained and passaged using a medium for human normal keratinocytes (trade name: K-GM) sold by the company. b) Measurement of DNA synthesis (thymidine incorporation measurement) 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 to which no pituitary extract was added was added to replace the medium. Thereafter, the amine derivatives (1a) to (1af) obtained in the above Synthesis Examples were added. further,
Over time, 0.2 μCi / ml [ ³ H] thymidine was added and 4
Incubated for hours. After that, the supernatant was removed by suction and washed three times with PBS (-).
NaOH was added. After incubation at 37 ° C. for 10 minutes, the same amount of 2N HCl was added for neutralization, 4 ml of ice-cooled 10% trichloroacetic acid was added, and the mixture was allowed to stand for 30 minutes. After collecting the precipitate with a glass filter, the precipitate was washed three times with 3 ml of ice-cooled 10% trichloroacetic acid. Ice-cold ethanol 3
After washing the filter once with ml, the glass filter was air-dried and its radioactivity was measured with a liquid scintillation counter to calculate the incorporation of thymidine into the cells.

(2) Results FIGS. 1 and 2 show the relative uptake (%) of [ ³ H] thymidine when the amine derivatives (1a) to (1af) were added at 10 μM (upper) and 100 μM (lower), respectively. Is shown. From the figure, it was clarified that the incorporation of thymidine was significantly reduced by the addition of the amine derivative, that is, the DNA synthesis of human keratinocytes was inhibited.

Example 2 Effect of amine derivative on transglutaminase activity of epidermal keratinocytes (1) Measurement of transglutaminase activity Keratinocytes cultured in a growth state in a 6-well plate 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 amine derivatives (1a) and (1g) were added. Twenty-four hours later, each well was washed three times with PBS (-), and the cells were peeled and collected with a rubber policeman. The obtained cell suspension was centrifuged at 2,500 rpm for 10 minutes to collect a sediment. Buffer solution (a) [10 mM Tri
s-HCl buffer, 10 mM DTT, 0.5 mM EDT
A; pH 7.4], and sonicated twice for 1 minute twice. The resulting suspension was
Ultracentrifugation was performed at 00 rpm for 30 minutes to obtain a supernatant. After dispensing a certain amount of the supernatant, the reaction solution [30
0 mM Tris-HCl buffer, pH 8.1, 60 mM C
aCl ₂ 100 μl, 30 mM DTT 100 μl,
100 μl of distilled water containing 540 μg of dimethyl casein,
A solution obtained by mixing 50 μl of 12 mM putrescine, 50 μl of 2.5 μCl [ ¹⁴ C] putrescine and 100 μl of distilled water] was added, and the mixture was incubated at 37 ° C. for 1 hour. Next, 600 μl of 10% trichloroacetic acid was added, and the mixture was allowed to stand for 30 minutes, and then the precipitate 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.

(2) Results FIG. 3 shows that the amine derivatives (1a) and (1g)
The transglutaminase activity values (cpm) when μM, 10 μM, and 100 μM were added are shown. The activity value increases up to about 2.5 times with respect to the control with the addition amount of the amine derivative. That is, it was revealed that the amine derivative has a keratinocyte differentiation-inducing activity.

Example 3 Inhibitory Effect of Amine Derivative on Epidermal Hyperplasia (1) Method After shaving the pinna of 25 guinea pigs 4 to 6 weeks old, ultraviolet rays (UVB: 2 to 3 MED) were irradiated. Immediately after irradiation, 0.05% amine derivatives (1a) and (1g)
Was applied once a day for one week. One week later, the pinna of the guinea pig was excised, and a section of skin tissue was prepared. Each tissue sample was photographed under a microscope, and the thickness of the epidermis and dermis was measured to examine the inhibitory effect of each evaluation sample on thickening due to ultraviolet (UV) irradiation. (2) Results FIG. 4 shows UVB irradiation, UVB irradiation + amine derivative (1
The results of skin thickness measurement are shown for a) addition and UVB irradiation + amine derivative (1 g) addition. Each sample concentration was 0.05%. From these results, it was clarified that the above-mentioned amine derivative suppresses epidermal hyperplasia.

[0096]

Example 4 Production of W / O cream (% by weight) (1) Amine derivative (1a) 0.01 (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, Chitin Liquid HV) 0.5 (11) Purified water balance

(1) to (7) were dissolved by heating to 80 ° C., and (8) to (11) were added thereto and mixed uniformly.
A / O cream was prepared.

[0098]

Example 5 Production of O / W cream (% by weight) (1) Polyoxyethylene (10) hydrogenated castor oil 1.0 (2) Sorbitan monostearate 0.5 (3) Stearoyl methyl taurine sodium 0 5.5 (4) cetostearyl alcohol 2.0 (5) stearic acid 1.8 (6) amine derivative (1 g) 0.001 (7) cholesterol 1.5 (8) cholesteryl isostearate 1.0 (9) Neopentyl glycol dicaprate 8.0 (10) Methyl polysiloxane 5.0 (11) Glycerin 5.0 (12) Purified water Balance

(1) to (10) were dissolved by heating to 80 ° C., and (11) to (12) were added thereto and mixed uniformly.
An O / W cream was prepared.

[0100]

Example 6 Production of moisturizing sunscreen cream (% by weight) (1) Amine derivative (1 g) 0.0005 (2) Silicon-coated zinc oxide 7.0 (3) 2-Ethylhexyl p-methoxycinnamate 3 0.0 (4) Cholesteryl isostearate 1.0 (5) Polyether-modified silicone 2.0 (6) Methylpolysiloxane 5.0 (7) Cyclic silicone 15.0 (8) Magnesium sulfate 1.0 (9) Glycerin 5.0 (10) Purified water balance

(1) to (7) were heated and dissolved at 80 ° C., and (8) to (10) were added thereto and uniformly mixed to prepare a moisturizing sunscreen cream.

[0102]

Example 7 Production of Packing Agent (% by weight) (1) Amine derivative hydrochloride (1 g ′) 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) Fragrance 0.5 (8) Preservative, oxidizing agent

[0103] (1) to (8) were heated to 70 ° C to dissolve and then cooled to produce a pack.

[0104]

Example 8 Production of ointment (% by weight) (1) Amine derivative (1a) 0.005 (2) White petrolatum balance (3) Cholesteryl isostearate 3.0 (4) Liquid paraffin 10.0 ( 5) Glyceryl ether 1.0 (6) Glycerin 10.0

(1) to (6) were heated to 80 ° C. to dissolve and then cooled to prepare an ointment.

Each of the external preparations containing the keratinizing agent of the present invention prepared in Examples 4 to 8 suppresses parakeratosis, epidermal hyperplasia, abnormal lipid metabolism, and is effective in restoring normal function and maintaining homeostasis. It was something.

[Brief description of the drawings]

FIG. 1 shows amine derivatives (1a) to (1a) in Example 1.
FIG. 2 is a graph showing changes in [ ³ H] thymidine relative uptake by addition of s).

FIG. 2 shows amine derivatives (1t) to (1t) in Example 1.
FIG. 2 is a graph showing changes in the relative uptake of [ ³ H] thymidine by addition of (f).

FIG. 3 is a diagram showing a change in transglutaminase activity value due to addition of an amine derivative in Example 2.

FIG. 4 is a graph showing changes in skin thickness due to UVB irradiation and addition of an amine derivative in Example 3.

──────────────────────────────────────────────────の Continuing on the front page (51) Int.Cl. ⁶ Identification number Agency reference number FI Technical indication A61K 31/13 ADA A61K 31/13 ADA ADN ADN (72) Inventor Yukihiro Yada Ninomiya-cho, Haga-gun, Tochigi 1-115-1 Kusoda Nishi 1-72 (72) Inventor Kazuhiko Higuchi 4594 Hanawa, Kaigamachi, Haga-gun, Tochigi Pref. (JP, A) JP-A-64-9907 (JP, A)

Claims (4)

(57) [Claims] [Claim 1] The following general formula (1) (In the formula, R ¹ .R ² showing a straight, branched, or cyclic hydrocarbon group of saturated or unsaturated 4 to 40 carbon atoms,
R ³ , R ⁴ , R ⁵ , and R ⁶ each represent a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms which may be substituted by one or more hydroxyl groups. A keratinization improver comprising an amine derivative represented by the formula or an acid addition salt thereof. 2. The following general formula (1 ′): (Wherein R ¹ ′ represents an odd-numbered linear alkyl group or alkenyl group having 5 to 39 carbon atoms, a cholesteryl group or a dihydrophytyl group. R ² , R ³ , R ⁴ , R ⁵ and R ⁶ each represent A hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms which may be substituted by one or more hydroxyl groups.) 3. The following general formula (1 ″): (In the formula, R ¹ represents a linear, branched, or cyclic saturated or unsaturated hydrocarbon group having 4 to 40 carbon atoms. R ³ , R ^3
4 , R ⁵ and R ⁶ each represent a hydrogen atom or a carbon atom having 1 or 2 or more hydroxyl groups which may be substituted.
Shows 10 hydrocarbon groups. An amine derivative represented by the formula: 4. The keratinizing agent according to claim 1, wherein the keratinizing agent is 0.000.
An external preparation for skin, characterized by containing 1 to 0.1% by weight.