JPH05194185A - Cornification-improving agent and external agent for skin containing the same - Google Patents

Abstract

PURPOSE:To provide a cornification-improving agent composed of a specific amine derivative, etc., effective for suppressing the incomplete cornification, acanthosis, lipid metabolism abnormality, etc., having excellent dandruff- preventing effect, sunburnt skin improving effect, stability and safety and useful as cosmetics, etc. CONSTITUTION:The objective cornification-improving agent is composed of an amine derivative expressed by formula [R<1> is 4-40C hydrocarbon group; R<2> to R<6> are H or (OH-substituted) 1-10C hydrocarbon group] or its acid addition salt. An external agent for skin is prepared by compounding 0.0001-1wt.% of the cornification-improving agent.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a keratinization improving agent and a skin external preparation, and more specifically, it is capable of maintaining normal skin function, and has excellent anti-dandruff effect and skin improving effect after sunburn. Agent and external preparation for skin.

[0002]

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

However, changes in the external environment (seasonal changes,
Abnormalities in the skin tissue often occur due to factors inside and outside the body that act on the body, such as ultraviolet rays) and changes in physiological functions (due to aging and diseases). Therefore, epidermal thickening and parakeratosis are induced, and as a result, various skin troubles such as dry or oily skin and dandruff are caused.

In order to improve such skin troubles and maintain healthy skin, normal skin troubles are eliminated by eliminating or reducing causative substances and events, or by adding and applying certain ingredients. The method of making it possible is considered.
Conventionally, the main methods for preventing and improving skin troubles are to apply a synthetic or natural moisturizing component to prevent dryness of the skin to improve the moisturizing ability of the skin and to promote blood circulation of the skin by applying a blood circulation promoter. Attempts have been made to improve it.

[0005]

However, the above method is effective in preventing and improving various skin troubles,
There are various problems in terms of sustainability of effects and stability and safety of drugs. That is, since these methods generally replenish the epidermis, especially the water on the surface of the stratum corneum, or supplement a part of the moisturizing ingredients, their efficacy is temporary and therefore permanent. The skin improving effect cannot be expected. Therefore, in order to solve the above-mentioned problems, it has been desired to develop a biologically derived component or a chemically synthesized analog that brings a permanent physiological effect and high safety.

[0006]

[Means for Solving the Problems] In view of the above situation, the present inventors have made diligent studies to improve the decline or enhancement of skin function and maintain normal skin function, and as a result, the specific amine derivative described below. Found that it has the effect of normalizing the keratinization of the epidermis by suppressing the increase in the turnover of the epidermis (the resulting thickening of the epidermis, parakeratosis and abnormalities of lipid metabolism in the epidermis) caused by ultraviolet rays and various components. The present invention has been completed.

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

[0008]

[Chemical 4]

(In the formula, 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 ^{And 6} each represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms which may be substituted by one or more hydroxyl groups. Is.

The present invention provides an external preparation for the skin, which further comprises the keratinization improving agent.

Among the amine derivatives (1) used in the present invention, some of them are known compounds, and are conventionally intermediates for the production of amide derivatives which are N-acyl compounds thereof (JP-A-62-128048). JP-A-54-117421 and JP-A-54-13523.
No. 3). However, nothing has been known about its action on the skin, particularly on the epidermal cells.

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-heptyl undecyl, 5,7,7-trimethyl-2
-(1,3,3-Trimethylbutyl) -octyl, 9-
Hydrocarbon groups such as octadecenyl, 9,12-octadecadienyl, cyclohexyl, phenyl, benzyl, cholesteryl and the like can be mentioned. In addition, R ² , R ³ , R ⁴ , R ⁵ , R
Specific examples of ⁶ , hydrogen atom, and methyl, ethyl,
Butyl, hexyl, phenyl, benzyl, hydroxymethyl, hydroxyethyl, 1,2-dihydroxyethyl, 1,2,3-trihydroxypropyl, 1,2,
3,4-tetrahydroxybutyl, 1,2,3,4,5
Groups such as -pentahydroxypentyl.

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

[0014]

[Chemical 5]

(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 is further, if necessary, an inorganic acid salt such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, or succinic acid, by a conventional method.
It is also possible to use organic acid salts such as fumaric acid, hexadecanoic acid, octadecanoic acid, lactic acid, glycolic acid, citric acid, tartaric acid and benzoic acid.

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

[0017]

[Chemical 6]

(In the formula, R ¹ ′ represents an odd-numbered linear alkyl group or alkenyl group having 5 to 39 carbon atoms, a cholesteryl group or a phytol group. R ¹ , R ² , R ³ , R ⁴ and R
⁵ and R ⁶ have the same meanings as above)

These amine derivatives (1) or their acid addition salts can be prepared in vivo (in
Both in vivo and in vitro, it has excellent actions of suppressing epidermal cell DNA synthesis, promoting differentiation induction, and suppressing epidermal thickening. Therefore, it has an effect of normalizing abnormal keratinization of epidermal cells of the skin and can be used as a keratinization improving agent.

The keratinization-improving agent of the present invention can be administered by any method such as internal administration and external use.

The keratinization-improving agent of the present invention is incorporated into a skin external preparation. The skin external preparation can be used in various forms such as a medicated skin external preparation, a cosmetic skin external preparation, and a cosmetic.

Examples of the external skin agent for medicinal use and the external skin agent for cosmetics include various ointments containing medicinal components. The ointment may be based on an oily base, oil / water, or water / oil type emulsion base. The oily base is not particularly limited, and examples thereof include vegetable oils, animal oils, synthetic oils, fatty acids, and natural or synthetic glycerides.
In addition, the medicinal component is not particularly limited, and for example, an analgesic anti-inflammatory agent, an analgesic agent, a bactericidal disinfectant, an astringent agent, an emollient agent, a hormone agent, vitamins and the like can be appropriately used as necessary. ..

When it is used as a cosmetic, oils, moisturizers, ultraviolet absorbers, alcohols, chelating agents, pH adjusters, preservatives, thickeners, pigments, which are generally used as cosmetic ingredients, Fragrances and the like can be blended in any combination. As the cosmetics, various uses and forms, for example, water / oil, oil / water emulsion cosmetics, creams,
It can be used as a lotion, a lotion, an oily cosmetic, a lipstick, a foundation, a skin cleanser, a hairnic, a hair styling agent, a hair nourishing agent, and a hair restorer. The external preparation for skin of the present invention can be prepared in the above various forms by a conventional method.

The amount of the amine derivative or the acid addition salt thereof to be added to the skin external preparation is not particularly limited, but in the case of an emulsified skin external preparation, it is usually 0.0001-0.
1% by weight (hereinafter referred to as%) is preferable.

[0025]

The keratinization-improving agent and external preparation for skin of the present invention are
It has a remarkable inhibitory effect on parakeratosis, epidermal thickening, lipid metabolism abnormality, etc. due to the influence of ultraviolet rays and various other factors, and eventually contributes to the restoration of normal skin function and maintenance of homeostasis. It has a particularly excellent anti-dandruff effect and an effect of improving the 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 thereto.

Synthesis Example 1 1- (2-Hydroxyethylamino) -3-tetradecyloxy-2-propanol [in the general formula (1), R ¹ = C
₁₄ H ₂₉ -, synthesis of R ² = R ³ = compound of ^{R 4 = R 5 = R 6} = H ]: stirrer, dropping funnel, thermometer, 3l5-necked flask equipped with a N ₂ inlet tube and a distillation equipment , 916.2 g (15 mol) of ethanolamine and 183 g of ethanol were charged, and 270.5 g (1 mol) of tetradecyl glycidyl ether was added thereto while heating and stirring at 80 ° C. under N ₂ atmosphere.
l) was added dropwise over 3 hours. After completion of the dropping, 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]

[Chemical 7]

Synthetic Example 2 The following amine derivative (1b) was prepared in the same manner as in Synthetic Example 1.
~ (1f) were synthesized.

[0030]

[Chemical 8]

Synthesis Example 3 1- (2-hydroxyethylamino) -3-methyl branch
Isostearyloxy-2-propanol [general formula (1)
And R¹= Methyl-branched isostearyl, R²= R ³= R^Four=
R^Five= R⁶= H compound]: Stirrer, dropping
G, thermometer, N₂3l5 port with inlet tube and distillation device
In a flask, 916.2 g of ethanolamine (15 mo
l) and 183 g of ethanol were charged, and N₂8 under the atmosphere
While heating and stirring at 0 ℃, add methyl-branched isostearium to it.
Roxy glycidyl ether 326.6 g (1 mol) 3
It dripped over time. After the dropping, ethanol and excess
Ethanolamine was distilled off under reduced pressure, and the residue was treated with silica gel.
Purification by flash chromatography
The target compound (1 g) of a pale yellow paste 320.
5 g was obtained (yield 82.7%).

[0032]

[Chemical 9]

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

[Chemical 10]

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 = H compound]: 91.6 g (1.5 mol) of ethanolamine and 20 g of ethanol were charged into a 500 ml four-necked flask equipped with a stirrer, a dropping funnel, a thermometer, an N ₂ introducing tube and a distillation device, and N 25.0 g of phenyl glycidyl ether was dripped at this over 2 hours, heating and stirring at 80 degreeC under ₂ atmosphere. After completion of the dropping, 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]

[Chemical 11]

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 = H compound]: Stirrer, dropping funnel,
In a 1l 5-neck flask equipped with a thermometer and a N ₂ introduction tube,
Diethanolamine 105.1 g (1 mol) and ethanol 100 g were charged, and tetradecyl glycidyl ether 27 was added thereto while heating and stirring at 80 ° C. under N ₂ atmosphere.
0.5 g (1 mol) was added dropwise over 30 minutes. After completion of the dropwise addition, the mixture was stirred at 80 ° C. for further 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 (yield 61.8%).

[0039]

[Chemical 12]

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

[0041]

[Chemical 13]

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,
R ⁵ = —CH ₂ OH compound]: 25 g of 3-amino-1,2-propanediol was added to a 21-four-necked flask equipped with a stirrer, a dropping funnel, a thermometer, and an N ₂ inlet tube.
(0.27 mol) and 100 g of ethanol were charged, and N ₂ was added.
While heating and stirring at 80 ° C. under an atmosphere, 3 g of tetradecyl glycidyl ether (9.9 g, 0.037 mol) was added.
It dripped over time. After completion of dropping, the mixture was further stirred at 80 ° C. for 1 hour, 1 l of water was added to the obtained reaction mixture, and the produced 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]

[Chemical 14]

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

[0045]

[Chemical 15]

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

[0047]

[Chemical 16]

Synthesis Example 12 The following amine derivative (1y) was prepared in the same manner as in Synthesis Example 3.
~ (1z) were synthesized.

[0049]

[Chemical 17]

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

[0051]

[Chemical 18]

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

[0053]

[Chemical 19]

The items represented by the above (1a) to (1af)
Each substituent R of each amine derivative ¹~ R⁶The following Table 1,
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
The data regarding the shape (melting point) of f), IR, and NMR are shown below. (1a) Colorless powder (melting point 69.1-69.5 ℃) 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 to 3.20 (br, 3H), 3.30 to 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).

[0061] (1d) colorless powder (mp 70.6~71.2 ℃) IR (KBr, cm -1) 3448,2920,2852,1462,1124,1050. 1 H-NMR (CDCl 3, δ) 0.67~1.67 (m , 31H), 2.60-2.80 (m, 4
H), 3.10 to 3.90 (m, 10H).

(1e) Colorless powder (melting point 77.8 to 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 to 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
~ 2.48 (m, 7H), 2.66 ~ 2.96 (m, 7H), 3.06 ~ 3.26 (m, 1H), 3.3
6 to 3.58 (m, 2H), 3.67 (bt, J = 5.0Hz, 2H), 3.80 to 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) Light 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 to 2.33 (m, 33H), 2.60 to 2.93 (m, 4
H), 3.13 to 4.20 (m, 10H), 5.23 to 5.67 (m, 2H).

(1i) Colorless solid (melting point 77.0-78.4 ° 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) Light 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 ~ 3.70 (m, 2H), 3.85 ~ 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 ~ 2.82 (m, 4H), 3.22 ~ 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 to 2.90 (m, 4H), 3.13 to 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 to 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-decomposition, 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 to 2.90 (m, 4H), 3.13 to 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 ~ 3.74 (m, 2H), 3.82 ~ 3.98 (m, 1H), 4.85 ~ 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 to 1.70 (m, 18
H), 2.54 to 2.85 (m, 4H), 3.05 to 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 to 3.20 (m, 7H), 3.30 to 3.52 (m, 4H), 3.58 to 3.74
(m, 2H), 3.80 to 3.98 (m, 1H).

(1w) colorless powder (melting point 72.2-73.4 ° 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 to 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).

(1y) Light yellow oil IR (NaCl, cm ^-1 ) 3388, 2926, 2856, 1461, 1377, 1110. ¹ H-NMR (CDCl ₃ , δ) 0.70 to 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 to 2.92 (m, 4H), 3.30 to 3.60 (m, 4H), 3.62 to 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 to 1.75 (m, 29
H), 2.32 ~ 2.88 (m, 6H), 3.30 ~ 4.00 (m, 9H), 4.90 (brs, 3H).

(1ab) pale yellow oil IR (NaCl, cm ^-1 ) 3424,2928,2856,1460,1378,1116,1040. ¹ H-NMR (CDCl ₃ , δ) 0.72 to 0.96 (m, 6H) , 1.00 to 1.76 (m, 29
H), 2.33 (s, 3H), 2.36 ~ 2.72 (m, 4H), 3.30 ~ 3.52 (m, 6H), 3.
57 to 3.68 (m, 2H), 3.82 to 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 84.4-85.4 ° C.) IR (KBr, cm ⁻¹ ) 3308,2924,2856,1466,1378,11114. ¹ H-NMR (CDCl ₃ , δ) 0.80-1.00 (m , 3H), 1.10 to 1.70 (m, 24
H), 2.56 to 2.74 (m, 2H), 3.24 to 3.74 (m, 15H), 3.88 to 4.06
(m, 1H).

(1af) Colorless powder (melting point: 79.5-81.2 ° 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 ~ 1.73 (m, 24H), 2.38 ~ 2.90 (m, 7H), 3.30 ~ 3.60
(m, 4H), 3.72-4.01 (m, 2H).

Example 1 Inhibitory Effect of Amine Derivatives on DNA Synthesis of Epidermal Keratinocytes (1) Method a) Culture of Human Epidermal Keratinocytes The epidermal keratinocytes are human normal horns sold by Kurabo Industries, Ltd. Activated cells (trade name: Epipack) were purchased and used. For the maintenance and passage of cells, a medium for human normal keratinized cells (trade name: K-GM) sold by the same company was used. b) Measurement of DNA synthesis (measurement of thymidine incorporation) 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 containing no pituitary extract was added to exchange the medium. After that, the amine derivatives (1a) to (1af) obtained in the above Synthesis Example were added. further,
Add 0.2 μCi / ml [ ³ H] thymidine over time and add 4
Incubated for hours. After that, the supernatant was removed by suction, washed 3 times with PBS (-), and then 500 μl of 2N
NaOH was added. After incubating at 37 ° C. for 10 minutes, the same amount of 2N HCl was added to neutralize, 4 ml of ice-cooled 10% trichloroacetic acid was added, and the mixture was allowed to stand for 30 minutes. The precipitate was collected with a glass filter and then washed 3 times with 3 ml of ice-cold 10% trichloroacetic acid. Further ice-cold ethanol 3
After washing the filter once with ml, the glass filter was air-dried, and its radioactivity was measured by a liquid scintillation counter to calculate thymidine incorporation into cells.

(2) Results Relative incorporation amount (%) of [ ³ H] thymidine when amine derivatives (1a) to (1af) were added at 10 μM (top) and 100 μM (bottom) in FIGS. 1 and 2, respectively. Indicates. From the figure, it was revealed that the incorporation of thymidine was significantly reduced by the addition of the amine derivative, that is, the DNA synthesis of human epidermal 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 containing no pituitary extract was added to exchange the medium.
After that, amine derivatives (1a) and (1g) were added. After 24 hours, each well was washed 3 times with PBS (-), and the cells were detached and collected with a rubber policeman. The obtained cell suspension was centrifuged at 2,500 rpm for 10 minutes and the precipitate was collected. Buffer solution (a) [10 mM Tri on the sediment]
s-HCl buffer, 10 mM DTT, 0.5 mM EDT
A; pH 7.4] (200 μl) was added, and the mixture was sonicated twice for 1 minute. 25,0 of the resulting suspension
Ultracentrifugation was performed at 00 rpm for 30 minutes to obtain a supernatant. After dividing this supernatant into aliquots, the reaction mixture [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 dimethylcasein,
50 μl of 12 mM putrescine, 50 μl of 2.5 μCl [ ¹⁴ C] putrescine, and 100 μl of distilled water were 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 this membrane with 15 ml of ice-cold trichloroacetic acid (containing 1% putrescine) having a concentration of 5%, the radioactivity on the membrane was calculated by a liquid scintillation counter.

(2) Results In FIG. 3, 1 each of the amine derivatives (1a) and (1g) was added.
The transglutaminase activity value (cpm) at the time of adding μM, 10 μM, and 100 μM is shown. The activity value increases up to about 2.5 times as much as 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 Derivatives on Epidermal Hyperplasia (1) Method After shaving the auricles of 25 white guinea pigs 4 to 6 weeks old, they were irradiated with ultraviolet rays (UVB: 2 to 3 MED). Immediately after irradiation, 0.05% amine derivatives (1a) and (1g)
The squalane solution containing each of these was applied once a day for 1 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 the thickening due to ultraviolet (UVB) irradiation. (2) Results 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. The concentration of each sample was 0.05%. From this result, it became clear that the amine derivative suppresses the epidermal thickening.

[0096]

Table 4 Example 4 Production of W / O cream (wt%) (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) Methylphenyl Polysiloxane 2.0 (7) Methyl Polysiloxane 2.0 (8) Magnesium Sulfate 0.5 (9) 55% Ethanol 5.0 ( 10) Carboxymethyl chitin (Ichimaru Falcos Co., Ltd., Chitin Liquid HV) 0.5 (11) Purified water balance

(1) to (7) were heated to 80 ° C. to dissolve them, and (8) to (11) were added thereto and mixed homogeneously.
/ O cream was prepared.

[0098]

Table 5 Example 5 Production of O / W cream (wt%) (1) Polyoxyethylene (10) hydrogenated castor oil 1.0 (2) sorbitan monostearate 0.5 (3) stearoylmethyl taurine sodium 0 .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 heated to 80 ° C. to dissolve them, and (11) to (12) were added thereto and mixed uniformly.
An O / W cream was prepared.

[0100]

Table 6 Example 6 Production of Moisturizing Sunscreen Cream (wt%) (1) Amine derivative (1 g) 0.0005 (2) Silicon-coated zinc oxide 7.0 (3) 2-ethylhexyl p-methoxycinnamate 3 .0 (4) Cholesteryl isostearate 1.0 (5) Polyether modified silicone 2.0 (6) Methyl polysiloxane 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 to 80 ° C. and dissolved, and (8) to (10) were added thereto and uniformly mixed to prepare a moisturizing sunscreen cream.

[0102]

Table 7 Example 7 Production of Packing Agent (wt%) (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) Perfume 0.5 (8) Preservative, oxidizer Suitable amount

Packing agents were manufactured by heating (1) to (8) to 70 ° C. to dissolve and then cooling.

[0104]

Table 8 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.

The external preparations containing the keratinization-improving agent of the present invention prepared in Examples 4 to 8 all suppress parakeratosis, epidermal thickening, abnormal lipid metabolism, and are effective in restoring normal function and maintaining homeostasis. It was something.

[Brief description of drawings]

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

FIG. 2 shows amine derivatives (1t) to (1) in Example 1.
It is a figure which shows [ ³ H] thymidine relative uptake amount change by addition of af).

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

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

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] October 13, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] Claim 2

[Correction method] Change

[Correction content]

[Chemical 2] (In the formula, 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 are respectively An amine derivative represented by a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms which may be substituted with one or two or more hydroxyl groups.).

[Procedure Amendment 2]

[Document name to be amended] Statement

[Correction target item name] 0018

[Correction method] Change

[Correction content]

(In the formula, 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 ¹ , R ² , R ³ and R
⁴ , R ⁵ and R ⁶ have the same meanings as above)

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0031

[Correction method] Change

[Correction content]

Synthesis Example 3 1- (2-hydroxyethylamino) -3-methyl-branched isostearyloxy-2-bropanol [in the general formula (1), R ¹ = methyl-branched isostearyl, R ² = R
³ = R ⁴ = R ⁵ = F ⁶ = H compound]: Ethanolamine 916.2 in a 315-necked flask equipped with a stirrer, a dropping funnel, a thermometer, a N ₂ introduction tube and a distillation apparatus.
g (15 mol) and 183 g of ethanol were charged, and N
Methyl branched isostearyloxyglycidyl ether 326.6 was added to this while heating and stirring at 80 ° C. under ₂ atmospheres.
g (1 mol) was added dropwise over 3 hours. After finishing the dropping
Ethanol and excess ethanolamine were distilled off under reduced pressure, and the residue was purified by silica gel flash chromatography to obtain 320.5 g of the target compound (1 g) as a pale yellow paste (yield 82.7%. ).

Continuation of front page (51) Int.Cl. ⁵ Identification number Reference number in the agency FI Technical indication location A61K 31/13 ADN 8413-4C (72) Inventor Yukihiro Yada 1-1115, Kushita-nishi, Ninomiya-cho, Haga-gun, Tochigi prefecture (72) Inventor Kazuhiko Higuchi 4594 Hanawa-cho, Kaigamachi-shi, Haga-gun, Tochigi Prefecture (72) Genji Imagawa 1022-87 Himuro-cho, Utsunomiya-shi, Tochigi Prefecture

Claims (4)

[Claims] 1. 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 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 with one or two or more hydroxyl groups. ) A keratinization improving agent comprising an amine derivative or an acid addition salt thereof represented by 2. The following general formula (1 ′): (In the formula, R ¹ ′ represents an odd-numbered linear alkyl group or alkenyl group having 5 to 39 carbon atoms, a cholesteryl group or a phytol group. R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each a hydrogen atom. , Or a hydrocarbon group having 1 to 10 carbon atoms, which may be substituted with one or two or more hydroxyl groups.)
An amine derivative represented by. 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
⁴ , R ⁵ , and R ⁶ are each a hydrogen atom, or 1 to 2 carbon atoms which may be substituted by one or more hydroxyl groups.
10 hydrocarbon groups are shown. ) An amine derivative represented by 4. The keratinization improving agent according to claim 1, which is 0.000.
A skin external preparation characterized by being compounded in an amount of 1 to 0.1% by weight.