JP4849213B2 - Hair restorer - Google Patents

Description

  The present invention relates to a hair-growth active ingredient that promotes hair growth in mammals, and a hair-growth nourishing agent comprising this hair-growth active ingredient, and more specifically, it is excellent in hair-growth and hair-growth and has a long-lasting effect. The present invention relates to a hair-growth active ingredient and a hair-growth nourishing agent that are safe enough to withstand use.

  Although hair greatly affects its appearance and occupies a very important position in cosmetics, alopecia still has no precise treatment and is a source of deep trouble. There are congenital and acquired alopecia, and there are many unclear points although many studies have been conducted on the cause and mechanism of the onset. Therefore, the present condition is that the remarkably effective hair-growth active ingredient which can solve the deep trouble of the alopecia patient has not been found yet.

  Conventionally, hair growth nourishing cosmetics and pharmaceuticals containing various drugs have been proposed. For example, a composition comprising a compound such as vitamin E, pyridine N-oxide, adenosine 3 ′, 5′-cyclic-phosphate, or a testosterone-5-α-reductase inhibitor (Patent Document 1: JP-A 64-56608), a composition comprising a herbal extract such as ginkgo biloba and jaundice (Patent Document 2: JP-A-2-48512, Patent Document 3: JP-A-8-73325) (See the publication). In addition, vitamin E having a blood circulation improvement effect, assembly extract, cysteine / methionine as an amino acid serving as a nutritional supplement, and female hormones such as estradiol / ethynyl estradiol are blended in the hair restoration agent.

  In recent years, two drugs (minoxidil and finasteride) have been proposed for the treatment of male pattern baldness. However, due to safety concerns and large individual differences, the search for effective hair-growth active ingredients is ongoing.

  On the other hand, thyroid hormone (3,3 ′, 5-triiodo-L-thyronine; T3) can be cited as one of the in vivo substances that promote hair growth (Patent Document 4: JP 2002-543104 A, Patent Document 5). : Refer to Japanese translations of PCT publication No. 2002-543105). However, since these effects are not necessarily high, it has been desired to provide a hair-growth active ingredient having a further excellent hair-growth effect.

JP-A 64-56608 JP-A-2-48512 JP-A-8-73325 Special Table 2002-543104 Special Table 2002-543105 gazette

  The present invention has been made in view of the above circumstances, and an object thereof is to provide a hair-growth active ingredient having an excellent hair-growth effect and a hair-growth nourishing agent comprising this hair-growth active ingredient.

  As a result of intensive studies to achieve the above object, the present inventor has found that a specific compound exhibits an excellent hair growth promoting action and a hair restoration effect, and has reached the present invention.

[２]．下記化合物３、４又は５を有効成分として配合してなる育毛養毛剤。

Accordingly, the present invention provides the following inventions.
[1]. A hair restorer comprising the following compound 1 or 2 as an active ingredient.

[2]. A hair restorer comprising the following compound 3, 4 or 5 as an active ingredient.

  The compound of the present invention has an excellent hair-restoring effect, and a hair-restoring active ingredient composed of this compound and a hair-restoring agent containing this active ingredient are useful for hair-restoring and hair-restoration.

［式中、Ｒ¹は下記構造式（２）

（式中、Ａは独立にＣＨ₂、Ｃ（＝Ｏ）、Ｏ又はＮＨを示し、Ｒ²はアルキレン基、シクロアルキレン基又はアリーレン基を示す。Ｒ³は独立に水素原子、又は炭素数１〜６のアルキル基もしくはアルコキシ基を示す。ｍは独立に０又は１、ｎは０又は１を示す。）
で表される基である。］ The first compound of the present invention is represented by the following general formula (1).

[Wherein R ¹ represents the following structural formula (2)

(In the formula, A independently represents CH ₂ , C (═O), O, or NH, R ² represents an alkylene group, a cycloalkylene group, or an arylene group. R ³ independently represents a hydrogen atom or 1 carbon atom. -6 represents an alkyl group or an alkoxy group, m is independently 0 or 1, and n is 0 or 1.
It is group represented by these. ]

R ² represents an alkylene group, a cycloalkylene group or an arylene group, specifically, an alkylene group having 1 to 5 carbon atoms such as a methylene group, an ethylene group, a propylene group or a butylene group, a cyclopentylene group, or a cyclohexylene. Groups, cycloalkylene groups having 5 to 8 carbon atoms such as cyclooctylene groups, arylene groups having 6 to 14 carbon atoms such as phenylene groups, tolylene groups, xylylene groups, naphthylene groups and biphenylene groups. Among these, a cycloalkylene group and a phenylene group are preferable.

R ³ independently represents a hydrogen atom, or an alkyl group or alkoxy group having 1 to 6 carbon atoms. Examples of the alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, and a hexyl group. Examples of the group include a methoxy group, an ethoxy group, a propoxy group, and a butoxy group. R ³ is preferably a hydrogen atom, a methoxy group, or an ethoxy group. Examples of R ¹ include a group represented by the following formula.

［式中、Ｒ⁴は下記構造式（４）

（式中、Ｒ⁵は炭素数１〜８の直鎖又は分岐鎖のアルキレン基又はアルケニレン基を示す。Ｒ⁶は独立に水素原子、又は炭素数１〜６のアルキル基もしくはアルコキシ基を示す。）
で表される基である。］ The second compound of the present invention is represented by the following general formula (3).

[Wherein R ⁴ represents the following structural formula (4)

(In the formula, R ⁵ represents a linear or branched alkylene group or alkenylene group having 1 to 8 carbon atoms. R ⁶ independently represents a hydrogen atom, or an alkyl group or alkoxy group having 1 to 6 carbon atoms. )
It is group represented by these. ]

R ⁵ is a linear or branched alkylene group or alkenylene group having 1 to 8 carbon atoms, preferably a methylene group, an ethylene group, a propylene group, a butylene group, or an isobrene group. R ⁶ independently represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms or an alkoxy group. Examples of the alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, and a hexyl group. Examples of the group include a methoxy group, an ethoxy group, a propoxy group, and a butoxy group. R ⁶ is preferably a hydrogen atom, a methoxy group, or an ethoxy group. Examples of R ⁴ include a group represented by the following formula.

（式中、Ｒ⁷、Ｒ⁸、Ｒ⁹及びＲ¹⁰は独立に、水素原子又はヨウ素原子であり、Ｒ⁷、Ｒ⁸、Ｒ⁹及びＲ¹⁰の中で一つはヨウ素原子である。Ｒ¹¹は炭素数１〜５の直鎖又は分岐鎖のアルキレン基である。） The third compound of the present invention is represented by the following general formula (3).
A hair growth active ingredient comprising the compound represented by the following general formula (5) or formula (6) or (7).

(In the formula, R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are independently a hydrogen atom or an iodine atom, and one of R ⁷ , R ⁸ , R ⁹ and R ¹⁰ is an iodine atom. ¹¹ is a linear or branched alkylene group having 1 to 5 carbon atoms.

In the general formula (5), R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are hydrogen atoms or iodine atoms, and one of R ⁷ , R ⁸ , R ⁹ and R ¹⁰ may be an iodine atom, R ⁷ , R ⁸ , R ⁹ and R ¹⁰ may all be iodine atoms. In particular, R ⁹ and R ¹⁰ are preferably iodine atoms. R ¹¹ is a linear or branched alkylene group having 1 to 5 carbon atoms, and examples thereof include a methylene group, an ethylene group, a propylene group, and a butylene group, and a methylene group and an ethylene group are preferable.

  The first compound and the second compound can be obtained from Lead Quest (registered trademark), which is a compound library of Tripos, and the third compound can be obtained from Sigma.

  Since the hair-growth active ingredient of the present invention has an excellent hair-growth effect, the hair-growth active ingredient can be used as it is or diluted in alcohol, water, etc. It can be used as a hair restorer. The above-mentioned hair-growth active ingredient can be used alone or in combination of two or more kinds for the hair-growth agent.

The compounding amount of the hair-growth active ingredient is appropriately selected according to the use, dosage form, etc. of the hair-growth, but is preferably 10 ⁻⁹ M (mol / L) to 10 ⁻² M (mol / L), more It is preferably 10 ⁻⁷ M (mol / L) to 10 ⁻⁴ M (mol / L). Within this range, the hair-restoring effect can be particularly exerted, and if it exceeds 10 ⁻² M (mol / L), there is a risk that problems such as worsening the feeling of use of the hair-restoring agent will occur.

  The hair growth agent may be used in combination with other hair growth components. For example, pentadecanoic acid glyceride, Coleus extract, 6-benzylaminopurine, tocotrienol, minoxidil, finasteride, flavanol derivative and the like can be mentioned. Among these, pentadecanoic acid glyceride and 6-benzylaminopurine are preferable from the viewpoint of hair growth effect.

  Other plant extracts and drugs can be appropriately blended with the hair growth agent. For example, capsicum, yatei, aloe, wolfberry, mugwort, mustard, rice, mangeshi, mannenrou, kosaiho, licorice, gentian, tanjin, loofah, kyoto, pine, kuzin, safflower, barberry, betel roe, eucalyptus, kagosou, moktsu, gohitsu, Psycho, Cha, Shiny, Wasabi, Jotesi, Dutch Sennichi, Gardenia, Usba Saishin, Garlic, Hakka, Yokuinin, Giraffe, Coconut, Burdock, Licorice, Hop, Chrysanthemum, Raccho, Leek, Leek, Onion, Senega, Amanazuru, Mannentake, Giant , Monoammonium glycyrrhizinate, glycyrrhetinic acid, glycyrrhizin, sesame, nematode, cashew and the like.

  The hair growth agent of the present invention can be used in various preparations such as cosmetics for external and internal use, pharmaceuticals, quasi drugs and the like. Specifically, capsules, powders, granules, solids, liquids, gels, creams, aerosols, ointments, or foams 1) pharmaceuticals, 2) quasi drugs, 3) topical or Skin cosmetics for the whole body, 4) medicinal and / or cosmetic preparations applied to the scalp and hair (eg shampoos, rinses, treatments, permanent agents, hair dyes, hair styling agents, hair styling agents, hair growth agents) -Hair nourishing etc.). Moreover, it can utilize also as a tablet, a drink agent, etc. as various foodstuffs including the nutrition functional food which has the hair growth effect. Of these, shampoos, rinse agents, treatment agents, permanent agents, hair dyes, hair styling agents, hair styling agents, hair growth and hair nourishing agents and the like are preferable.

  The hair growth agent of the present invention can be prepared by a conventional method by adding known ingredients according to the type and dosage form of the hair growth agent. The blending components can be appropriately selected within a range not impairing the effects of the present invention. For example, surfactants, oils, alcohols, moisturizers, thickeners, preservatives, chelating agents, pH adjusters, fragrances, dyes, UV absorbers / scatterers, vitamins, alcohols, polyvalents Alcohol, water, and the like can be appropriately blended as necessary. In addition to the above active ingredients, generally used deodorants, preservatives, antioxidants and the like can be blended.

  When the hair growth composition of the present invention is in the form of an aerosol, in addition to the above components, lower alcohols such as n-propyl alcohol or isopropyl alcohol, butane, propane, isobutane, liquefied petroleum gas, dimethyl ether, etc. Compressed gases such as gas, nitrogen gas, oxygen gas, carbon dioxide gas, and nitrous oxide gas can be blended.

  EXAMPLES Hereinafter, although a test example and a formulation example are shown and this invention is demonstrated concretely, this invention is not restrict | limited to the following Example. In the following examples, unless otherwise specified, “%” in the composition represents mass%.

[Test Example 1]
Thyroid hormone receptor (TR) activation test using human scalp-derived dermal papilla cells Thyroid hormone binds to a receptor (TR) in the nucleus and activates TR to regulate the expression of various genes. Thyroid hormone originally has a function of maintaining the homeostasis of a living body, and thyroid hormone is known to have a hair-restoring effect. The hair growth effect was evaluated by measuring thyroid hormone receptor (TR) activation.
Human scalp-derived dermal papilla cells (manufactured by TOYOBO) were seeded at 20,000 cells / well in a 24-well multiwell plate (Sumilon; manufactured by Sumitomo Bakelite) and cultured at 37 ° C. in a 5% carbon dioxide atmosphere for 1 day. As the medium, 10% FBS-containing DMEM (FBS; manufactured by Biowest, DMEM; manufactured by Sigma) was used. There, three plasmids of pTR (obtained by cloning), pTRE-TA-SEAP (BD Bioscience), and pRL-CMV (for internal standard, Promega) were transferred for 24 hours using FuGENE6 (Roche). Erected. The culture supernatant was removed by aspiration, control (medium only), T3 (3,3 ′, 5-triiodo-L-thyronine: positive control 10 ⁻⁷ M (mol / L)) and 8 compounds (test compounds 1 to 1). 10. Control compounds 1 to 3) were added at the concentrations shown in the table and cultured for 1 day. The activity of SEAP (Secreted alkaline phosphatase) secreted into the culture supernatant upon TR activation was measured using BD Great EscAPeTM SEAP Chemiluminescence Detection Kit (BD Bioscience). In addition, the transfection efficiency into the cells was determined by measuring the Luc (Luciferase) activity in the cells using Renilla Luciferase Assay System (Promega).
Test compounds 1 to 5 were obtained from Lead Quest (registered trademark), which is a compound library of Tripos, and test compounds 6 to 10 were obtained from Sigma.

The TR activation rate was calculated by the following formula (1) and formula (2). Table 1 shows the TR activation rate (%) of each compound obtained.
TR activity = (SEAP activity value) / (Luc activity value) (1)

ＴＲ活性_Sample:化合物添加細胞のＴＲ活性値
ＴＲ活性_Control:コントロール細胞のＴＲ活性値
ＴＲ活性_T3:Ｔ３添加細胞のＴＲ活性値

TR activity _Sample : TR activity value of compound-added cells
TR activity _Control : TR activity value of control cells
TR activity _T3 : TR activity value of T3-added cells

  As in the results shown in Table 1 above, it was revealed that TR was activated by 20% or more in the cells to which test compounds 1 to 10 were added, compared to the control. Among them, test compounds 1, 3, and 6 to 10 showed TR activation rates exceeding 50%.

[Test Example 2] Mouse hair growth test Male C57BL / 6 mice (7 weeks old) were used and the method of Ogawa et al. (See Fragrance Journal, Vol. 17, No. 5, p20-29, 1989.) was referred to. The experiment was conducted.
The back hair of the mouse was removed to a size of about 2 to 4 cm with an electric clipper and an electric shaver to induce the hair growth period. After depilation, 30 mg of dihydrotestosterone (DHT), an active male hormone, was administered subcutaneously. Apply the sample once a day from the next day 100 μL 5 times a week for 40 days, find the change of the area ratio of the hair regeneration part to the hair removal part, and the speed of hair regeneration by the following 10-step evaluation A comparison was made. The sample amount was 1 × 10 ⁻⁴ M (mol / L)) and the positive control T3 (1 × 10 ⁻⁴ M (mol / L)). Further, a 50% ethanol aqueous solution as a solvent was applied to the control group. Each group was subjected to the experiment as 6 animals per group. Table 2 shows the number of days required until the hair growth score reached 5 after depilation and subcutaneous administration.

[Hair growth score]
Ratio of the area of the part where hair regeneration has started to the total area of the part where hair has been removed 1 point: 0 to 10%
2 points: 10-20%
3 points: 20-30%
4 points: 30-40%
5 points: 40-50%
6 points: 50-60%
7 points: 60-70%
8 points: 70-80%
9 points: 80-90%
10 points: 90-100%

  As shown in Table 2 above, it was revealed that when test compounds 1 to 10 were applied, hair regeneration on the back of the mouse was accelerated compared to 50% ethanol aqueous solution. In particular, it was suggested that test compounds 1, 3, 6 and 8 promote hair regeneration at the same level as T3.

[Prescription Examples 1 to 18]
Hereinafter, the formulation example which mix | blended the compound of this invention is shown. All of the following examples were excellent in the hair growth effect. In addition, the fragrance | flavor described in the composition was suitably selected from the fragrance | flavors AE described in Unexamined-Japanese-Patent No. 2003-267841.

Claims (2)

A hair restorer comprising the following compound 1 or 2 as an active ingredient.

A hair restorer comprising the following compound 3, 4 or 5 as an active ingredient.