JP2008230974A - Hair-growing agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a hair-growing composition which can exhibit an excellent hair-growing effect. <P>SOLUTION: This hair-growing agent includes a compound of formula (wherein, R<SP>1</SP>is H; R<SP>2</SP>is H, an optionally substituted lower alkyl or an optionally substituted lower alkenyl, or R<SP>1</SP>and R<SP>2</SP>may form an optionally substituted unsaturated 5 to 6-membered carbon ring together with carbon atoms bound to R<SP>1</SP>and R<SP>2</SP>; R<SP>3</SP>to R<SP>5</SP>are H or an optionally substituted lower alkyl) or its cosmetically acceptable salt. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention provides a new hair growth material.

  In the modern society, which is called an aging society and a stress society, the hair of the head is exposed to a risk of hair loss due to various causes. Corresponding to this, various attempts have been made to provide a better “hair growth material”.

  Drugs that exhibit hair-growth effects include adenosine, which promotes hair shaft elongation, vitamin E that promotes blood circulation by expanding peripheral blood vessels, carpronium chloride, assembly extract, etc., and anti-inflammatory and antibacterial effects on the scalp Glycyrrhizin derivatives that maintain an improved state, diphenhydramine hydrochloride, hinokitiol, etc., pentadecanoic acid glycerides with cell activation activity, carrot extract, etc., t-flavanone etc. that prolongs the growth period, male pattern alopecia and female alopecia areata Minoxidil and the like which are effective in the past have been known, and some of them have been commercialized and frequently used due to their superior efficacy.

  Currently, in order to further respond to the demands of many people who have worries about thin hair, the development of more effective hair restorers is energetically advanced in various industries including the cosmetics and pharmaceutical industries.

  An object of the present invention is to provide a new hair growth material.

  The present inventor screened a huge number of drugs to find a drug exhibiting hair-growth activity using a mouse whose hair cycle is in a resting state, and found that a drug having a predetermined chemical structure exhibits hair-growth activity. The headline and the present invention have been completed.

（式中、Ｒ¹は水素であり、
Ｒ²は水素、任意的に置換された低級アルキル又は任意的に置換された低級アルケニルであるか、又は
Ｒ¹及びＲ²はそれらが結合している炭素原子と一緒になって任意的に置換された不飽和の５〜６員環を形成してよく；
Ｒ³は水素又は任意的に置換された低級アルキルであり；
Ｒ⁴は任意的に置換された低級アルキルであり；
Ｒ⁵は任意的に置換された低級アルキルであり；
Ｘは水素又はハロゲン原子であり；
Ａは任意的に置換又は任意的に置換されたベンゼン環が挿入された炭素数が２〜６の直鎖状アルキレン基である）
又はその化粧品学的に許容される塩を含んで成る、育毛料。
（２）前記化合物が
Ｎ⁴−（７−クロロ−２−［（Ｅ）−２−（２−クロロフェニル）ビニル］−４−キノリニル）−Ｎ¹，Ｎ¹−ジエチル−１，４−ペンタンジアミン（ＸＩＢ４０３５）、
Ｎ⁴−（７−クロロ−４−キノリニル）−Ｎ¹，Ｎ¹−ジエチル−１，４−ペンタンジアミン（クロロキン）、
２−［［４−［（７−クロロ−４−キノリニル）アミノ］ペンチル］エチルアミノ］エタノール（ヒドロキシクロロキン）、
Ｎ⁴−（６−クロロ−２−メトキシ−９−アクリジニル）−Ｎ¹，Ｎ¹−ジエチル−１，４−ペンタンジアミン（キナクリン）及び
４−［（７−クロロ−４−キノリニル）アミノ］−２−［（ジエチルアミノ）メチル］フェノール（アモジアキン）
から成る群から選ばれる１又は複数種の化合物である、（１）の育毛料。
（３）上記式（１）の化合物又はその化粧品学的に許容される塩を配合した育毛量を頭皮に塗布することを含む、育毛方法。
（４）育毛料の製造ための、上記式（１）の化合物又はその化粧品学的に許容される塩の使用。 Specifically, this application includes the following inventions.
(1) Compound of the following formula (1)

(Wherein R ¹ is hydrogen,
R ² is hydrogen, optionally substituted lower alkyl or optionally substituted lower alkenyl, or R ¹ and R ² are optionally substituted together with the carbon atom to which they are attached. Formed unsaturated 5-6 membered rings;
R ³ is hydrogen or optionally substituted lower alkyl;
R ⁴ is an optionally substituted lower alkyl;
R ⁵ is an optionally substituted lower alkyl;
X is a hydrogen or halogen atom;
A is a linear alkylene group having 2 to 6 carbon atoms into which an optionally substituted or optionally substituted benzene ring is inserted)
Or a hair restorer comprising a cosmetically acceptable salt thereof.
(2) the compound is N ⁴ - (7- chloro -2 - [(E) -2- ( 2- chlorophenyl) vinyl] -4-quinolinyl) -N ^1, N ¹ - diethyl-1,4-pentanediamine (XIB4035),
N ⁴ - (7- chloro-4-quinolinyl) -N ^1, N ¹ - diethyl-1,4-pentanediamine (chloroquine),
2-[[4-[(7-chloro-4-quinolinyl) amino] pentyl] ethylamino] ethanol (hydroxychloroquine),
N ⁴ - (6- chloro-2-methoxy-9-acridinyl) -N ^1, N ¹ - diethyl-1,4-pentanediamine (quinacrine) and 4 - [(7-chloro-4-quinolinyl) amino] - 2-[(Diethylamino) methyl] phenol (amodiaquine)
The hair restorer according to (1), which is one or more compounds selected from the group consisting of:
(3) A hair-growth method comprising applying to the scalp a hair-growth amount containing a compound of the above formula (1) or a cosmetically acceptable salt thereof.
(4) Use of the compound of the above formula (1) or a cosmetically acceptable salt thereof for the production of a hair restoration.

  The present invention provides a novel hair-growth composition that can exhibit an excellent hair-growth effect.

  In understanding the contents of the present invention, the following definitions of terms will be helpful.

Definition of Terms “Lower alkyl” means a linear or branched alkyl having, for example, 1 to 8, preferably 1 to 5, and generally 1 to 4 carbon atoms. Specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl and the like.
“Lower alkenyl” means a straight or branched alkenyl having, for example, 2 to 8, preferably 2 to 5, and generally 2 to 4 carbon atoms. Specific examples include ethenyl, allyl, 2-methylallyl, propenyl, butenyl and the like.
Unsaturated 5- to 6-membered rings formed by R ¹ and R ² together with the carbon atom to which they are attached in the compound of formula (1) include, but are not limited to, cyclopentyl, cyclohexyl, aryl It may be. These rings may be substituted with one or several substituents, and examples of such substituents include hydroxy, oxo, amide, cyano, halogen, lower alkyl, and lower alkenyl.
Optional substituents for lower alkyl, lower alkenyl or lower alkylene include, but are not limited to, halogen, cyano, C _1-6 alkyl, C _1-6 alkenyl, C _1-6 alkynyl, C _1-6 alkoxy, C _{1 ~ 6} alkyl carbonyl, C _{1 ~ 6} alkoxycarbonyl, C _{1 ~ 6} haloalkoxy, C _{1 ~ 6} alkylthio, tri (C _{1 ~ 4)} alkylsilyl, C _{1 ~ 6} alkyl amino, C _{1 ~ 6} dialkylamino Etc.
“Halogen” includes fluoro, chloro, bromo, iodo and generally means fluoro or chloro.

  Although it does not specifically limit as a salt of the compound represented by General formula (1), For example, hydrochloride, sulfate, phosphate, hydrobromide, sodium salt, potassium salt, magnesium salt as an inorganic salt, A calcium salt, an ammonium salt, etc. are mentioned. Organic salts include acetate, lactate, maleate, fumarate, tartrate, citrate, methanesulfonate, p-toluenesulfonate, triethanolamine salt, diethanolamine salt, amino acid salt, etc. Can be mentioned.

XIB4035 and its structurally related compounds XIB4035, which has been found to have a hair-growth effect according to the present invention, is commercially available from AISNEX. However, there are no reports suggesting a relationship between XIB4035 and hair growth. Similarly to XIB4035, chloroquine, quinacrine and amodiaquine, which are found to have a hair-growth effect and are closely related in structure to XIB4035, are compounds known as antimalarial drugs. Similar to XIB4035, there is no report suggesting a relationship with hair growth.

The structure and physicochemical properties of the above compounds are shown below.

  The hair growth material according to the present invention comprises the compound of formula (1) in an amount of preferably 0.1 mM to 500 mM, more preferably 1 mM to 100 mM, and even more preferably 10 mM to 50 mM. If the compounding amount of the compound of formula (1) is too small, the desired effect cannot be obtained, and if the compounding amount is too large, the effect reaches a peak, which is uneconomical.

  As the dosage form that can be taken by the hair restorer of the present invention, a dosage form of an external preparation that can be applied to the outer skin, for example, a liquid form, an emulsion form, a cream form, an aerosol form, or the like can be selected. Moreover, the form of the hair restorer of this invention is also arbitrary, For example, forms, such as a tonic, a hair cream, a mousse, a shampoo, rinse, a milky lotion, a lotion, a pack, an aerosol agent, can be taken. It is particularly preferable to apply the hair growth material of the present invention to the outer skin. The application method is not particularly limited. For example, it is preferably applied to the scalp at least once a day, for example, 1 to 3 times a day, depending on the skin area to be applied, for example, 1 to 5 ml.

  In the hair restorer of the present invention, in addition to the compound of the above formula (1), which is an essential component, cosmetics, quasi-drugs, pharmaceuticals, etc., if necessary and unless the desired effects of the present invention are impaired. Various oily or aqueous components, humectants, thickeners, preservatives, antioxidants, fragrances, colorants, various chemicals and the like that are generally used in can be used.

  For example, higher fatty acids, solid paraffin, liquid paraffin, silicone oil, squalane, glyceryl monooleate, olive oil, isopropyl myristate, higher alcohol, etc .; glycerin, hyaluronic acid, propylene glycol, maltitol, atelocollagen, sodium lactate, etc. Moisturizer; thickener such as quince mucilage, carboxyvinyl polymer, xanthan gum; vasodilator such as nicotinamide, benzyl nicotinate, vitamin E acetate, assembly extract, carpronium chloride, acetylcholine derivative; serine, methionine, arginine Amino acids such as vitamin B6, vitamin E, biotin, pantothenic acids and the like; nicotinic acid esters such as nicotinic acid, methyl nicotinate and tocopherol nicotinate; Skin function enhancers such as faranthin; female hormone agents such as estradiol; anti-inflammatory agents such as glycyrrhizic acid, glycyrrhetinic acid, and azulene; antibacterial agents such as hinokitiol; refreshing agents such as menthol; salicylic acid, zincs, lactic acids, etc .; citric acid Organic acids such as these can be blended.

  Further, by adding a known hair-growth component other than the compound of formula (1) according to the present invention, for example, minoxidil, cyclo (registered trademark) sporin, adenosine, etc., a more effective hair-growth effect Can be expected in the hair restorer of the present invention. The specific prescription of the hair restorer of the present invention will be described later.

  EXAMPLES Hereinafter, although an Example demonstrates this invention further more concretely, the technical scope of this invention should not be limitedly interpreted by this Example. In addition, in the following examples etc., the numerical value showing a compounding quantity is represented by the mass% with respect to the whole object mix | blended unless there is particular notice.

以下の表に発毛効果を示す薬剤の試験結果を示す。

Screening for drugs with hair-growth effect Mouse hair growth test Using C3H / HeSlc mice (Japan SLC, Inc.) in the resting period of the hair cycle, Ogawa et al.'S method “Normal and Abnormal Epidermal Differ Ren and Renation (Normal and Abnormal Epidermal Differentiation), edited by M. Seiji and IABernstein, pp. 159-170, 1982, The University of Tokyo Press).
Specifically, the back hair of the mouse is shaved to a size of about 2 × 4 cm, and the test drug is applied every day from the next day by 0.1 ml every day, and the appearance change of the area where hair regeneration has started is evaluated. The hair regeneration was examined. Each test agent was tested at a concentration of 50 mM and 100 mM using 70 w / w% ethanol as a solvent. Each sample had 4 mice per group, and the extent of hair regeneration area was evaluated. The results of hair regeneration after 30 days were evaluated in four stages. The four levels are shown in the table below. In addition, as a comparative control, the same operation / evaluation was carried out for the unmixed drug.

The following table shows the test results of drugs showing hair growth effect.

Formulation Example 1 Preparation of emulsion type hair nourishing agent (phase A)
Compounding component amount (% by mass)
Adenosine 5'-disodium phosphate 1.0
Hardened castor oil ethylene oxide (60 mol) adduct 2.0
Glycerin 10.0
Dipropylene glycol 10.0
1,3-butylene glycol 5.0
Polyethylene glycol 1500 5.0

(Phase B)
Compounding component amount (% by mass)
Cetyl isooctanoate 10.0
Squalane 5.0
Vaseline 2.0
Propylparaben 2.0

(Phase C)
Compounding component amount (% by mass)
Carboxyvinyl polymer 1% aqueous solution 30.0
Sodium hexametaphosphate 0.03
Ion exchange water 8.35

(Phase D)
Compounding component amount (% by mass)
Ion exchange water 4.5

(Phase E)
Compounding component amount (% by mass)
Potassium hydroxide 0.12
Ion exchange water 5.0

<Manufacturing method>
The A phase and the B phase were heated and dissolved at 60 ° C., mixed and treated with a homomixer to form a gel. Phase D was gradually added thereto and dispersed with a homomixer.
Next, dissolved C phase was added to this, and finally dissolved E phase was added and emulsified with a homomixer to obtain an O / W emulsion type hair nourishing agent.

Formulation Example 2 Preparation of creamy hair nourishing agent (phase A)
Compounding component amount (% by mass)
Liquid paraffin 5.0
Cetostearyl alcohol 5.5
Glyceryl monostearate 3.0
EO (20 mol) -2-octyldodecyl ether 3.0
Propylparaben 0.3
Fragrance 0.1

(Phase B)
Compounding component amount (% by mass)
Adenosine 5.0
Glycerin 8.0
Dipropylene glycol 20.0
Polyethylene glycol 4000 5.0
Sodium dodecyl sulfate 0.1
Sodium hexametaphosphate 0.005
Ion exchange water balance

<Manufacturing method>
A phase and B phase were dissolved by heating and mixed, and emulsified with a homomixer to obtain a creamy hair nourishing agent.

Formulation Example 3 Preparation of liquid hair nourishment (1)
Compounding component amount (% by mass)
Adenosine 5′-potassium phosphate 0.5
Stearyl dimethylamine oxide 0.5
Hardened castor oil ethylene oxide (40 mol) adduct 1.0
95% ethanol 54.0
Ion exchange water balance

<Manufacturing method>
Add ion-exchanged water to 95% ethanol, add hydrogenated castor oil ethylene oxide (40 mol) adduct and stearyldimethylamine oxide, add adenosine 5'-potassium phosphate, dissolve with stirring, and dissolve in liquid form. Hair was obtained.

Formulation Example 4 Preparation of liquid hair nourishing agent (2)
Compounding component amount (% by mass)
N-coconut lauryl-β-aminopropionic acid sodium salt 0.2
Adenosine 5′-phosphate disodium hydrate 1.0
Sodium dodecylbenzenesulfonate 0.5
Hardened castor oil ethylene oxide (40 mol) adduct 1.0
95% ethanol 54.0
Ion exchange water balance

<Manufacturing method>
After adding ion-exchanged water to 95% ethanol, and adding hydrogenated castor oil ethylene oxide (40 mol) adduct, sodium dodecylbenzenesulfonate and sodium N-cocolauryl-β-aminopropionate, adenosine 5′-phosphate Disodium hydrate was added and dissolved by stirring to obtain a liquid hair nourishing agent.

Formulation Example 5 Preparation of lotion (1)
Compounding component amount (% by mass)
95% ethanol 55.0
Adenosine 0.02
Glycyrrhetinic acid 0.001
Octopirox 0.2
1,3-butylene glycol 2.0
Polyoxyethylene (60 mol) hydrogenated castor oil 1.0
Succinic acid Appropriate fragrances and pigments Appropriate ionic water balance

<Manufacturing method>
Adenosine was dissolved in 95% ethanol, and glycyrrhetinic acid, octopirox, 1,3-butylene glycol, polyoxyethylene (60 mol) hydrogenated castor oil and flavor were dissolved (ethanol part). Next, succinic acid and a pigment | dye were dissolved in purified water, and this was added to the said ethanol part, Then, it stirred and the transparent liquid lotion was obtained.

Formulation Example 6 Preparation of Lotion (2)
Compounding component amount (% by mass)
95% ethanol 75.0
Adenosine 5′-phosphate 0.0001
Dipotassium glycyrrhizinate 5.0
Allantoin 0.2
Salicylic acid 0.01
Dipropylene glycol 1.0
Polyoxyethylene (24 mol), polyoxypropylene (13 mol) 0.5
Decyl tetradecyl ether
Lactic acid Appropriate amount Sodium lactate Appropriate amount of perfume and color

<Manufacturing method>
Adenosine 5'-phosphate is dissolved in 95% ethanol, and dipotassium glycyrrhizinate, allantoin, salicylic acid, dipropylene glycol, polyoxyethylene (24 mol), polyoxypropylene (13 mol) decyltetradecyl ether and flavor Was dissolved (ethanol part). Next, lactic acid, sodium lactate and a pigment were dissolved in purified water, added to the ethanol part, and then stirred to obtain a transparent liquid lotion.

Formulation Example 7 Preparation of lotion (3)
Compounding component amount (% by mass)
95% ethanol 60.0
Adenosine 5′-phosphate disodium or 1.0
Adenosine 5'-dipotassium phosphate
Button pi extract 0.2
Menthol 0.5
Zinc oxide 0.1
Benzalkonium chloride 0.2
Serine 0.05
Polyethylene glycol 400 1.0
Polyoxyethylene (20 mol) hydrogenated castor oil 1.0
Phosphoric acid
Perfume and pigment
Purified water remaining

<Manufacturing method>
In 95% ethanol, adenosine 5'-disodium phosphate or adenosine 5'-dipotassium phosphate is dissolved, and menthol, button pi extract, serine, polyethylene glycol 400, polyoxyethylene (20 mol) hydrogenated castor oil and The fragrance was dissolved (ethanol part). Next, zinc oxide was dispersed in purified water, and further benzalkonium chloride, phosphoric acid and a dye were dissolved, and this was added to the ethanol portion, followed by stirring to obtain a two-layer lotion. .

  The present invention provides a novel hair-growth material having an excellent hair-growth effect.

Claims (2)

Compound of the following formula (1)

(Wherein R ¹ is hydrogen,
R ² is hydrogen, optionally substituted lower alkyl or optionally substituted lower alkenyl, or R ¹ and R ² are optionally substituted together with the carbon atom to which they are attached. Formed unsaturated 5-6 membered carbocycles;
R ³ is hydrogen or optionally substituted lower alkyl;
R ⁴ is an optionally substituted lower alkyl;
R ⁵ is an optionally substituted lower alkyl;
X is a hydrogen or halogen atom;
A is a linear alkylene group having 2 to 6 carbon atoms into which an optionally substituted or optionally substituted benzene ring is inserted)
Or a hair restorer comprising a cosmetically acceptable salt thereof. Wherein said compound is N ⁴ - (7- chloro -2 - [(E) -2- ( 2- chlorophenyl) vinyl] -4-quinolinyl) -N ^1, N ¹ - diethyl-1,4-pentanediamine (XIB4035) ,
N ⁴ - (7- chloro-4-quinolinyl) -N ^1, N ¹ - diethyl-1,4-pentanediamine (chloroquine),
2-[[4-[(7-chloro-4-quinolinyl) amino] pentyl] ethylamino] ethanol (hydroxychloroquine),
N ⁴ - (6- chloro-2-methoxy-9-acridinyl) -N ^1, N ¹ - diethyl-1,4-pentanediamine (quinacrine) and 4 - [(7-chloro-4-quinolinyl) amino] - 2-[(Diethylamino) methyl] phenol (amodiaquine)
The hair restorer according to claim 1, which is one or more compounds selected from the group consisting of: