JP3043582B2 - Flavanonol derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel flavanonol derivative which is useful as a hair restorer and hair restorer.

[0002]

2. Description of the Related Art
Synthetic drugs or natural product extracts having various effects are used in pharmaceuticals or cosmeceuticals for the purpose of hair growth and hair growth, but none of these can provide sufficient effects with the addition of small amounts. On the other hand, when added in a large amount, there is a disadvantage that an uncomfortable irritant feeling is given to the indication site, and dermatitis is caused when used continuously.

[0003] Further, the above-mentioned hair growth and hair growth products do not directly act on the differentiation and proliferation of the hair matrix, but rely on an indirect action through normalization of the condition of the scalp, Enough hair nourishment for human hair
It did not show a hair growth effect.

[0004] Therefore, a novel compound which has an excellent hair-growth / hair-growth effect and a hair loss-preventing effect by directly acting on the differentiation and proliferation of hair mother cells and is useful as a highly safe hair-growth / hair-growth agent. Was desired.

[0005]

Means for Solving the Problems The present inventors have conducted intensive studies in view of the above circumstances, and as a result, the novel flavanonol derivative represented by the following general formula (1) directly acts on the differentiation and proliferation of hair mother cells. The present inventors have found that the present invention has excellent hair-growth and hair-growth effects and is highly safe, and has completed the present invention.

That is, the present invention provides a compound represented by the general formula (1)

[0007]

Embedded image

(Where R ¹ and R ² are R ¹ = H, R ² =
^{_{4'-CH 3; R 1 =}} 8-Cl, R 2 = H; or R ¹ = 7
—CH ₃ , R ² = 4′-CH ₃ ).

In the general formula (1), there are synthesis examples of compounds in which R ¹ and R ² are hydrogen atoms, and compounds in which R ¹ is a hydrogen atom and two methoxy groups are bonded at the 3′- and 4′-positions. Is [D. M. X. Donnelly et al., Tetrahed.
ron Lett. , 1023, 1967; P. C
ullen et al. Chem. Soc. (C), 284
8, 1971], and the hair-growth and hair-growth effects of these compounds are not known at all.

The flavanonol derivative (1) has a plurality of stereoisomers due to the presence of asymmetric carbon atoms at the 2- and 3-positions, and the present invention includes both of these stereoisomers and mixtures thereof. It is. In the present invention, attention is paid to the relationship between the 2-position aromatic ring and the 3-position hydroxyl group, and the trans-form and the cis-form are described.

The flavanonol derivative (1) of the present invention comprises:
For example, it can be produced according to the following reaction formula.

[0012]

Embedded image

(Wherein R ¹ and R ² are the same as described above)

That is, the flavanones (4) are obtained by reacting the benzaldehydes (3) with the o-hydroxyacylbenzenes (2), and then the flavanones (1) are produced by reacting the flavanones with an oxidizing agent. You.

First, the reaction between o-hydroxyacylbenzenes (2) and benzaldehydes (3) proceeds, for example, by heating and stirring with acetic acid and pyrrolidine in alcohol. Further, the mixture may be heated and stirred with a base such as sodium hydroxide in aqueous dimethylformamide.

The reaction between the flavanones (4) and the oxidizing agent is as follows:
It is preferably carried out in a hydrous alcohol in the presence of a base such as, for example, sodium hydroxide. As the oxidizing agent, a peracid such as hydrogen peroxide and perbenzoic acid is preferable.

The flavanol compound (1) thus obtained acts directly on the differentiation and proliferation of hair cells, has the effect of promoting hair shaft elongation, and has a strong hair-growth effect. It can be used as an active ingredient in ingredients.

[0018]

EFFECT OF THE INVENTION Flavanonol derivative (1) of the present invention
Has excellent hair growth, hair growth and hair loss prevention effects.
Useful as a hair restorer.

[0019]

EXAMPLES The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

Example 1 trans-3,4'-dimethylflavanonol: 2'-hydroxypropiophenone (1
5.0 g, 0.10 mol), 4-methylbenzaldehyde (13.2 g, 0.11 mol), piperidine (20.
0 ml, 0.20 mol) and acetic acid (10.0 ml, 0.17 mol)
mol) was stirred in ethanol (100 ml) at reflux for 18 hours. After evaporating the solvent, water (300 ml) was added to obtain crude crystals, which were recrystallized from hexane: ethyl acetate to give trans-3,4'-dimethylflavanone (23.5 g,
93.3 mmol, 93%). Transformer-3,4'-
A mixture of dimethylflavanone (2.52 g, 10.0 mol) and sodium hydroxide (3.20 g, 80.0 mmol) in ethanol (20 ml) -water (60 ml) was mixed with 30% aqueous hydrogen peroxide (6.80 g, 60 mol). 0.0mol) was added dropwise at 40 ° C.
With stirring. After 72 hours, water (100 ml) was added and the mixture was cooled with ice. The precipitate was collected by filtration to obtain a crude crystal. After silica gel column chromatography (SiO2 300 g, hexane: ethyl acetate), recrystallization from hexane: ethyl acetate gave trans-3,4'-dimethylflavanonol (1.61 g,
6.0 mmol, 60%).

Colorless fine crystals mp. 104.9-10
5.4 ° C IR (KBr, cm ^-1 ) 3492, 2996, 1694, 1612, 1468,
1310, 1274, 1178, 1014, 966, 770. 1H-NMR (CDCl ₃ , δ ppm) 1.19 (s, 3H), 2.39 (s, 3H), 3.72 (s, 1H), 5.26 (s, 1H), 7.10 (d) , 2H, J = 8.1 Hz), 7.12 to 7.22 (m, 2H), 7.48 (d, 2H, J = 8.1 Hz), 7.53 to 7.61 (m, 1H) , 7.94 (dd, 1H, J = 8.1, 1.6 Hz).

The same reaction as in Example 1 was carried out using the corresponding raw materials to obtain the compounds of Examples 2 and 3.

Example 2 trans-8-chloro-3-methylflavanonol: colorless fine crystals mp. 86.7-87.9 ° C IR (KBr, cm ^-1 ) 3464, 1704, 1602, 1472, 1446,
1248, 1136, 1022. 1H-NMR (CDCl ₃ , δ ppm) 1.18 (m, 3H), 3.75 (s, 1H), 5.37 (s, 1H), 7.03 to 7.11 (m, 1)
H), 7.40-7.50 (m, 3H), 7.62-7.68.
(M, 3H), 7.86 (dd, 1H, J = 7.9, 1.6 Hz).

Example 3 trans-3,7,4'-trimethylflavanonol: yellow oil IR (neat, cm ^-1 ) 3496, 3016, 2988, 2928, 2872,
1690, 1620, 1456, 1238, 1186, 1154
1040, 818, 752. 1H-NMR (CDCl ₃ , δ ppm) 1.17 (s, 3H), 2.39 (s, 3H), 2.40 (s, 3H), 3.74 (s, 1H), 5.23 (s) , 1H), 6.91 to 6.95 (m, 2
H), 7.24 (d, 2H, J = 8.1 Hz), 7.47 (d, 2H, J = 8.1 Hz), 7.82 (d, 1H, J = 8.4 Hz).

Test Example 1 A hair follicle organ of a newborn SD rat was surgically removed. A phosphate buffer solution for maintaining humidity was put on the outer periphery of an organ culture dish (Falcon 3037), and the obtained hair follicles (5 pieces / dish) were arranged on a triangular grit placed on an inner dish. Flavanonol derivative (1) was added to the medium (RPMI 1640) to a final concentration of 0.1 nM,
The cells were cultured at 31 ° C. in a gas phase of 0% O ₂ and 5% CO ₂ , and daily hair growth was observed. Table 1 shows the results. The degree of hair elongation in Table 1 is a relative value on the third day of culture when the culture solution alone (no addition group) was set to 100. As is clear from Table 1, the remarkable hair shaft elongation-promoting effect was observed in the flavanonol derivative (1) of the present invention.

[0026]

[Table 1]

Test Example 2 The back hair of a 7-week-old C3H mouse (♂) in the resting period was shaved over 2 × 4 cm ² using an electric clipper and an electric razor so as not to damage the skin. These mice were grouped into 20 mice, and the shaved site was coated with the flavanonol derivative (1) (0.05%) dissolved in 70% ethanol once a day at 20 μl / day. In order to observe the state of hair regeneration, a photograph of the shaved site was taken at a fixed magnification, and the ratio of the regenerated hair area (regenerated hair area / shaved area) was calculated using an image analyzer to determine the hair growth activity. . In addition, the case where only the solvent (70% ethanol) was applied was used as a control product. Table 2 shows the hair growth activity (%) on day 20 after the start of sample application. As is clear from the results shown in Table 2 below, superior and remarkable promotion of hair growth was observed in the group to which the present flavanonol derivative (1) was applied compared to the group to which the control product was applied. In addition, the mice to which the flavanol compound of the present invention was applied were all healthy and had no effect on the skin.

[0028]

[Table 2]

──────────────────────────────────────────────────続 き Continuing on the front page (72) Inventor Mitsuyuki Hotta 3167-2 Ujiie-cho, Shioya-gun, Tochigi Prefecture Global Ujiie 201 (72) Inventor Hitoshi Sakaguchi 2606-6, Akabane, Kaimachi-cho, Haga-gun, Tochigi (56) Reference References Tetrahedron Letters, 1967 (11), 1023-7 (1967). Chem. Soc. C, 1971 (7), 2848-55 (1971) (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 311/32 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula (1) (Wherein R ¹ and R ² are R ¹ = H, R ² = 4′-CH ₃ ;
R ¹ = 8-Cl, R ² = H; or R ¹ = 7-CH ₃ , R ²
Flavanonol derivative represented by = 4'-CH is _3).