JPH08157436A - Benzoic acid amide derivative - Google Patents

Abstract

(57) [Summary] [Structure] Formula (1) [R ¹ is a C ₈ -C ₂₄ hydroxyalkyl group or 3,7,11-trimethyl-2,6,10-
Dodecatrienyl group, R ² and R ³ are H or a C ₁ -C ₃ alkyl group which may have a hydroxyl group], or a benzoamide derivative or salt thereof. Embedded image [Effect] This compound promotes collagen synthesis of fibroblasts existing in the dermis of human skin, and as a result, improves wrinkles caused by aging and ultraviolet irradiation, and is therefore useful as a skin external preparation.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a benzoic acid amide derivative or a salt thereof having a collagen synthesis promoting action and a wrinkle improving action in the skin and useful as a component of skin cosmetics.

[0002]

2. Description of the Related Art The skin is divided into epidermis, dermis and subcutaneous tissue. Among them, the dermis plays an important role as a connective tissue in supporting the skin and maintaining homeostasis. In the dermis, fibroblasts mainly produce fibrous proteins such as collagen, elastin and fibronectin and glycosaminoglucans such as hyaluronic acid, which form a three-dimensional structure and maintain connective tissue.

On the other hand, as the morphological changes of the skin caused by aging due to aging and photoaging due to ultraviolet rays, there are firstly a decrease in skin thickness and atrophy. Then, the elastic recovery decreases, and eventually wrinkles and sagging are formed, which are the most characteristic changes as seen in the skin of the aged (M
arks R.A. , Biochemistry and P
hyology of the Skin, Oxford
ord Univ. Press, 1983).

When these events are observed biochemically, the greatest biochemical change that accompanies aging of the dermis is found in collagen, which is the main component of connective tissue. 35% of the amount of collagen in the skin is lost between the ages of 20 and 80, and the thickness of the dermis is reduced (Shuste
r S. , British Journal of De
rmatology, 93 , 639 (1975)). In addition, since the metabolism of collagen is also reduced, a disordered intermolecular crosslinked structure (AM Kligma) is present in collagen fibers.
n, aging and skin, p. 221 (1986)), saccharification, etc., and insoluble collagen increases (Legr
aed Y. , Pathological Biolo
gy, 17 , 991 (1969)). It is considered that such biochemical changes are accumulated, the connective tissue hardens, loses flexibility and extensibility, and leads to wrinkles of the skin.

According to the results of these studies, cosmetics containing collagen have been put on the market to supply collagen to the skin, but the collagen applied to the skin surface does not reach the dermal tissue in a sufficient amount, and wrinkle improving effect is obtained. Has not come to get. By the way, if it is possible to specifically enhance the collagen synthesis of dermal fibroblasts, the decreased dermal collagen is increased by the new collagen, and further, the turnover of collagen is also activated, and the new soluble collagen is generated. It is further considered that as a result, the softness and extensibility of connective tissue can be improved, and the morphological changes of skin aging represented by wrinkles can be improved.

[0006] Retinoic acid is a drug attracting attention as a wrinkle-improving agent, but it is known that there is a correlation between the wrinkle-improving action and the collagen synthesis promoting action of the retinoic acid (E. Schwartz et al.
J. Invest. Derm. 96 , 975 (199
1); Bryce et al, Photoder
matol. , 190 , 352 (1990); Ma
rks et al, British Journal
of Dermatology, 122 , 91 (19
90)). However, retinoic acid has side effects such as strong skin irritation, skin thickening, and teratogenicity, and therefore cannot be incorporated into general medicines, quasi drugs, cosmetics and the like.

[0007] As substances that promote collagen synthesis, vitamin Cs, 1α, 25-dihydroxyvitamin D ₃ , Danshen root extract, milk whey from mammals (J. Dob).
aket al, J .; Dermatological
Science, 8 , 18 (1984); Japanese Patent Laid-Open No. 2-2
No. 9080, JP-A-3-20206) and the like are known, but they are not yet sufficiently satisfactory in terms of transdermal absorbability, stability, effect and the like.

[0008]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide a novel compound having a collagen synthesis promoting action, a wrinkle improving action, and good transdermal absorbability and chemical stability. .

[0009]

Therefore, the present inventors synthesized various compounds and screened the human skin fibroblasts for their collagen synthesis promoting action and wrinkle improving action. The following general formula (1) It was found that the benzoic acid amide derivative represented by the following formula has an excellent effect of promoting collagen synthesis and an effect of improving wrinkles, and has completed the present invention.

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

[0011]

Embedded image

[Wherein R ¹ is a hydroxyalkyl group having 8 to 24 carbon atoms or 3,7,11-trimethyl-2,6,
A 10-dodecatrienyl group is shown, and R ² and R ³ each have 1 carbon atom which may be replaced by a hydrogen atom or a hydroxyl group.
A benzoamide derivative or a salt thereof represented by

In the general formula (1), the hydroxyalkyl group having 8 to 24 carbon atoms represented by R ¹ includes a linear, branched or cyclic hydroxyalkyl group.

Specific examples of the hydroxyalkyl group represented by R ¹ include 8-hydroxyoctyl group and 10
-Hydroxydecyl group, 11-hydroxyundecyl group, 12-hydroxydodecyl group, 12-hydroxyoctadecyl group and the like can be mentioned.

The alkyl group having 1 to 3 carbon atoms which may be substituted by the hydroxyl group represented by R ² and R ³ includes methyl group, ethyl group, n-propyl group, isopropyl group, hydroxymethyl group, 2- Examples thereof include hydroxyethyl group and 3-hydroxypropyl group.

In the general formula (1), the group represented by -O-R ¹ may be substituted at any position of 2-, 3- or 4-position on the benzene ring, but it may be at 2-position or 4-position. Substitution at the -position is preferable, and substitution at the 4-position is particularly preferable.

The salt of the benzoic acid amide derivative (1) is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include alkali metal salts such as sodium and potassium, and alkaline earth metal salts such as calcium and magnesium. , Ammonium salts, mono-, di- or tri-alkanolamine salts, basic amino acid salts such as lysine and arginine, and the like. Although the benzoic acid amide derivative (1) may have stereoisomers, any stereoisomer or a mixture thereof can be used in the present invention.

Preferred examples of the benzoic acid amide derivative represented by the general formula (1) include 4-[(2E,
6E) -3,7,11-trimethyl-2,6,10-dodecatrienyloxy] benzamide, 4- (12-hydroxydodecyloxy) benzamide, 4- (12-
Hydroxyoctadecyloxy) benzamide, 4-
(11-hydroxyundecyloxy) benzamide,
4- (10-hydroxydecyloxy) benzamide,
N- (2-hydroxyethyl) -4-[(2E, 6E)
-3,7,11-Trimethyl-2,6,10-dodecatrienyloxy] benzamide, N, N-dimethyl-4
-[(2E, 6E) -3,7,11-trimethyl-2,
6,10-dodecatrienyloxy] benzamide and the like can be mentioned.

The benzoic acid amide derivative (1) or a salt thereof can be produced, for example, according to the following reaction scheme 1 or 2.

[0020]

Embedded image

[In the formula, Y represents a leaving group such as a halogen atom, p-toluenesulfonyl group, methanesulfonyl group,
R ¹ , R ² and R ³ are the same as above]

That is, the benzoic acid amide derivative (1) is produced by reacting the compound (2) with the compound (3).

In this reaction, 0.5 to 3.0 mol of the compound (3) is used per 1 mol of the compound (2), and usually 0 to
It is preferably carried out by stirring at a temperature of 150 ° C., preferably 20 to 100 ° C. for several hours. This reaction is preferably carried out in the presence of a base, and any base can be used as long as it does not adversely affect the reaction. For example, sodium hydride, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium carbonate. Etc. are preferably used.

Any solvent can be used in the above reaction as long as it is inert to the reaction. For example, N, N-dimethylformamide, dimethylsulfoxide, tetrahydrofuran, ethanol, methanol, acetone. Etc. are suitable. After completion of the reaction, the solvent is distilled off, and the benzoic acid amide derivative (1) can be isolated by purification by means such as chromatography and recrystallization.

[0025]

[Chemical 4]

[Wherein R ¹ , R ² and R ³ are the same as above]

That is, the benzoic acid amide derivative (1) can be produced by treating the compound (4) with an acid halogenating agent such as thionyl chloride and then reacting it with an amine in the presence of a base.

The reaction between the compound (4) and the acid halogenating agent is carried out by adding the acid halogenating agent to the compound (4) in a solvent such as tetrahydrofuran, diethyl ether, methyl chloride, N, N-dimethylformamide, dimethylsulfoxide and the like. And stirring at a temperature of 0 to 100 ° C. The reaction between the acid halide thus obtained and the amines is carried out in the presence of a base such as sodium hydroxide, potassium hydroxide or sodium carbonate at −20 to 1
It is carried out by stirring at a temperature of 00 ° C.

The obtained benzoic acid amide derivative (1) is
It can be converted into the above-mentioned salt according to a conventional method.

The thus-obtained benzoic acid amide derivative (1) or a salt thereof has an action of significantly promoting collagen synthesis of fibroblasts of human skin and an action of improving wrinkles, and therefore skin makeup It can be used as an active ingredient of external preparations for skin such as cosmetics.

[0031]

The present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Example 1 In a 100 ml Nuff flask equipped with a 10 ml dropping funnel,
4-hydroxybenzamide 2.00 g (14.6 mmo
l), potassium carbonate 2.42 g (17.5 mmol), N,
Add 15 ml of N-dimethylformamide, and stir at room temperature while stirring farnesyl chloride 7.03 g (29.2 mm).
ol) was added dropwise over 10 minutes. After dropping, the mixture was heated to 80 ° C. and stirred for 3 hours. It was poured into 300 ml of diluted hydrochloric acid and extracted with ethyl acetate. The extract was washed with 100 ml of water and 200 ml of saturated saline and then dried over anhydrous sodium sulfate. After filtration, the crude product obtained by concentration under reduced pressure is purified by silica gel chromatography to give 4-[(2E, 6E) -3,7,1.
3.09 g (yield 62%) of 1-trimethyl-2,6,10-dodecatrienyl] benzamide was obtained. The analysis results are shown below.

Form: colorless solid Melting point: 76.5 to 77.7 ° C. ¹ H-NMR (CDCl ₃ , ppm) 1.60 to 1.75 (m, 12H), 2.00 to 2.1
6 (m, 8H), 4.59 (d, 2H, J = 6.5H
z), 4.98 to 5.22 (m, 2H), 5.48
(T, 1H, J = 6.3 Hz), 5.79 (brs, 2
H), 6.94 (d, 2H, J = 8.8 Hz), 7.7
7 (d, 2H, J = 8.8 Hz). IR (KBr, cm ^-1 ) 3404, 3176, 2924, 1648, 1620,
1426, 1398, 1254.

Example 2 In Example 1, 1 was used instead of farnesyl chloride.
4- (12-Hydroxydodecyloxy) benzamide was synthesized using 2-bromododecanol.

Form: colorless solid Melting point: 141.4 to 142.1 ° C. ¹ H-NMR (CD ₃ OD, ppm) 1.66 to 1.90 (m, 20H), 3.52 (t, 2)
H, J = 6.5 Hz), 4.02 (t, 2H, J = 6.
4 Hz), 6.81 (d, 2H, J = 8.9 Hz),
7.82 (d, 2H, J = 8.9 Hz). IR (KBr, cm ^-1 ) 3436, 3316, 3204, 2924, 2856,
1648, 1620, 1424, 1400, 1256.

Test Example 1 Collagen synthesis promoting effect Human skin fibroblasts (denatured Dulbecco's essential medium containing 5% FCS (fetal calf serum): abbreviated as DMEM hereinafter) 0.5% F were cultured to confluence.
The test compound was replaced with CS-containing DMEM and 1 μM to
It was added so as to have a concentration of 10 µM and cultured at 37 ° C for 24 hours. Then triline-labeled proline (
³ H-proline) was added (5 μCi / ml medium), and then 2
The culture was continued at 7 ° C. to incorporate ³ H-proline.
After 24 hours, the medium was collected, and the amount of ³ H-labeled collagen contained in the medium was quantified by purifying collagen (DF Webster, W. Harvey., An.
analytical. Biochem. 96 , 220 (1
979)). The results are shown in Table 1. As a result, it was found that the benzoic acid amide derivative (1) significantly promotes collagen synthesis in human skin fibroblasts.

[0037]

[Table 1]

Compound 1: 4-{(2E, 6E) -3,
7,11-Trimethyl-2,6,10-dodecatrienyloxy} benzamide Compound 2: 4- (12-hydroxydodecyloxy) benzamide

Test Example 2 Action of Benzoic Acid Amide Derivative (1) on Wrinkles Produced in Hairless Mice by UVB Irradiation: (a) Hairless mice (HR / ICR, 9 weeks old at the start of experiment) U using 6 lamps 20SE
VB light was irradiated 3 times a week. The amount of energy is TOKYO
UV-Radiometer U made by OPTICAL
It measured using VR-305 / 365D. The irradiation amount per irradiation was 1 MED or less, and the energy amount was 0.28 mW / cm ² and was 65 mJ. The irradiation period was 20 weeks, and after confirming that a wrinkle was formed on the back of the hairless mouse, each group was divided into 8 mice, and 80 μl of a 0.005% concentration benzoic acid amide derivative (1) ethanol solution was added 5 times a week. One application was continued for 6 weeks. Only ethanol as a control 8
Each 0 μl was applied in the same manner as the sample. After the application, the degree of wrinkles was evaluated with the naked eye according to the following criteria (wrinkle index). The results are shown in Table 3.

[0040]

[Table 2] (Wrinkle index) 1: Wrinkles disappear completely 2: Do not know if there are wrinkles 3: Wrinkles are a little 4: Wrinkles are very

(B) Furthermore, in order to analyze the details of wrinkles,
At 0 week (application day) and 6 weeks after application of the test compound, a replica of skin was collected from 3 sites with a diameter of 1 cm ² on each mouse using Hydrophilic Exaflex hydrophilic vinyl silicone impression material. . This replica was placed in a horizontal state and irradiated with light from the direction of 30 degrees, and the ratio of shadows formed by wrinkles was obtained as an area ratio (%) using an image analyzer. Next, the wrinkle improvement rate at 6 weeks with respect to 0 weeks after application was determined by the following formula.

[0042]

[Equation 1]

The results are shown in Table 3. As a result, it was found that the wrinkles formed on the back of the hairless mouse can be eliminated / improved by applying the benzoic acid amide derivative (1).

[0044]

[Table 3]

[0045]

EFFECTS OF THE INVENTION The benzoic acid amide derivative (1) or a salt thereof promotes collagen synthesis of fibroblasts existing in the dermis of human skin, and as a result, improves wrinkles caused by aging and UV irradiation. It is useful as an agent.

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

[Procedure amendment]

[Submission date] December 12, 1994

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0025

[Correction method] Change

[Correction content]

[0025]

[Chemical 4]

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Tsutomu Fujimura 2166 Kamigamo, Kamimikawa-cho, Kawachi-gun, Tochigi Prefecture (166) Inventor Yoshinori Takema 5-26-6 Gion Minamikochi-cho, Kawachi-gun, Tochigi Prefecture

Claims (1)

[Claims] 1. A compound represented by the general formula (1): [In the formula, R ¹ represents a hydroxyalkyl group having 8 to 24 carbon atoms or a 3,7,11-trimethyl-2,6,10-dodecatrienyl group, and R ² and R ³ each represent a hydrogen atom or a hydroxyl group. Represents an optionally substituted alkyl group having 1 to 3 carbon atoms] or a salt thereof.