WO2002019975A1

WO2002019975A1 - Hair growth stimulants

Info

Publication number: WO2002019975A1
Application number: PCT/JP2001/007537
Authority: WO
Inventors: Akiko Ikeda; Shigeru Okuyama; Tamotsu Shibasaki; Seiji Kawana; Katsumi Kaneko
Original assignee: Taisho Pharmaceutical Co., Ltd.
Priority date: 2000-09-05
Filing date: 2001-08-31
Publication date: 2002-03-14
Also published as: AU2001284417A1

Abstract

Hair growth stimulants containing a corticotropin release factor (CRF) 1 receptor antagonist as the active ingredient.

Description

Mechanics Hair restorer Technical field

The present invention relates to a hair restorer containing corticotropin releasing factor (CRF) 1 receptor antagonist as an active ingredient, which can be used for the treatment and / or prevention of alopecia. Background art

Hair tissue is one of the skin appendages, and its constituent cells are broadly classified into epithelial cells derived from skin epidermis and dermal mesenchymal cells. The body of the hair is formed by the proliferation and differentiation (keratinization) of epithelial hair follicle keratinocytes. On the other hand, dermal mesenchymal hair papilla cells are thought to regulate hair growth through the transmission of information to epithelial cells. Hair growth has a hair cycle consisting of anagen, catagen and telogen. Hair follicle keratinocytes proliferate actively in the hair follicles that have reached the anagen, forming Z hairs. In the regression phase, the proliferation of hair follicle keratinocytes stops, and the hair follicles contract by apoptosis. The telogen follicle is in a completely atrophied state, but when some signal enters, the hair follicle keratinocytes begin to proliferate again to form a hair follicle, and new hair growth begins. Thus, the hair cycle is repeated through the proliferation, differentiation, and apoptosis of hair follicle keratinocytes, but the molecular mechanisms regulating this cycle are not fully understood.

The active ingredients of conventional hair restorers include vitamin E derivatives, sempuri extract, blood flow enhancers such as potassium chloride, tincture tincture tincture, nicotinic acid amide, pantothenyleethyl ether, and glyceryl pentaglycanate. There are known cell activity enhancers such as glycyrrhetinic acid and anti-inflammatory agents such as allantoin. Hair restorations combining these active ingredients have been developed and used for the treatment of alopecia and for the prevention or prevention of alopecia, but their effects are not satisfactory.

In addition, a hair restorer containing minoxidil as an active ingredient has been shown to have a hair-growing effect in mature alopecia and an effect of preventing progression of hair loss. However, alopecia other than age-related alopecia, For example, the effects on senile alopecia and alopecia areata cannot be said to be sufficient, and the development of new hair restorers is required.

By the way, the expression of the receptor and the receptor has been observed in the hair tissue of the skin on the back of the mouse. CRF is expressed on hair follicle keratinocytes, and CRF receptor is expressed on hair follicle keratinocytes and dermal papilla cells, and their expression levels are higher in anagen hair than in catagen hair or telogen hair. (FAS EB12, 2887-297 (1998)). However, the role of CRF in hair tissue has not been clarified.ぴ〇ぴ〇 1 It is completely unclear how the receptor antagonist affects hair follicle keratinocyte Z hair papilla cells and hair growth. International Patent Application Publications WO95X344563, WO94 / 13643, W094 / 13677, WO94 / 13667, WO95 / 337 5 0, WO 96/3 5 6 8 9, WO 9 7/2 9 10 9, WO 9 7/2 9 1 10, WO 9 8/3 5 1 0, WO 9 8/8 84 6, WO 9 8/8 8 4 7, WO 9 8/2 70 6 6, WO 9 8/2 9 3 9 7, WO 9 8/3 5 9 6 7, WO 9 8/4 2 70 6, WO 9 8 / 4 269 9, WO 9 8/4 7 8 74, WO 9 8/4 7 9 0 3, WO 9 9/1 4 5 4, WO 9/1 0 3 5 0, WO 9 9/3 8 8 6 8, WO 9 9/400 8 9, WO 9 9/4 5 0 7, WO 9 9/5 1 6 0 8, WO 9/5 1 5 9 9, WO 00/1 1 00 3, WO 00/16797 discloses that each of the publications has a CRF receptor antagonist activity, treats a disease promoted or induced by corticotropin releasing factor, or an inflammatory disease such as arthritis, asthma and allergy, anxiety, depression Disease, eating disorder, Alzheimer's disease, schizophrenia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, sickness, psychosomatic disease, senile dementia, panic disorder , Jildeaturette disease, menopause, premenstrual syndrome fatigue syndrome, headache, pain, cancer, Crohn's disease, irritable bowel syndrome including spastic colon and irritable colon, immune dysfunction, human 1, immunodeficiency virus

(HIV), infectious diseases, gastrointestinal disorders, eating disorders such as nervous anorexia, hemorrhagic stress, drug and alcohol dependence, drug addiction, stress-induced psychotic episodes, infertility, head trauma, spinal cord Compounds used as therapeutics for trauma, ischemic neuronal injury, thyroid dysfunction syndrome, epilepsy, seizures, muscle spasms, urinary incontinence, amyotrophic lateral sclerosis, hypoglycemia, etc. In any gazette There is no mention that compounds having CRF receptor antagonist activity can be used for the treatment and / or prevention of alopecia. Disclosure of the invention

An object of the present invention is to provide a hair restorer with a novel mechanism of action. The object of the present invention is achieved by using a CRF 1 receptor antagonist as an active ingredient or a CRF 1 receptor antagonist for producing a hair growth agent. The CRF1 receptor antagonist, which is the active ingredient of the hair restorer of the present invention, has the formula (I)

A-I (I)

[In the above formula,

A is wherein CHI ^ R ² (wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom, d-i al Kinore group, C ₃ -. 8 Shikuroarukinore group, C ₃ -. ₈ Shikuroarukinore d-i Anorekinore group , D- ₆ alkoxy, which represents an a / realkyl group),

A group represented by the formula NI ^ R ² , wherein R ¹ and R ² are as defined above,

A group represented by the formula NHCHR ¹ ! ^ ² (wherein R ¹ and R ² are as defined above), a formula OR ³ (where R ³ is a hydrogen atom, d-i. An alkyl group, C ₃ - ₈ cycloalkyl groups, C

₃ — ₈ mouth alkyl C Alkyl group, d-6 alkoxy C i. Which represents an alkyl group),

Piperidino group,

Morpholino group,

Piperazino group, or

The following formula (II)

(In the formula, Ar ¹ represents a halogen atom, a d- ₆ alkyl group, a d- ₆ alkoxy group, Which has 1 to 3 identical or different substituents selected from fluoromethyl groups, or represents an aryl group or a heteroaryl group having no substituents), and

Z is the Byon notation (III)-(VIII)

(In each formula,

R ⁴ and R ⁵ are each a hydrogen atom, d- ₆ alkyl group, C ₃ - ₈ a cycloalkyl group or a C cycloalkyl d- alkyl group shows a) a group represented by;

Ar ² represents a halogen atom, a d-alkyl group, a Ci-alkoxy group, a d-alkyl / retio group, a trifluoromethyl group, a trifluoromethoxy group, and a compound represented by the formula N (R ⁷ ) R ⁸ (where R ⁷ andぴ R ⁸ is the same or different and represents a hydrogen atom or a d- ₆ alkyl group) having 1 to 3 identical or different substituents selected from the group represented by, or a phenyl group having no substituent Shows;

Ring Q1 has ¹ to 3 identical or different substituents selected from a halogen atom, a dalkyl group, an oxo group and a thioxo group, or has no substituent, a benzene ring, a pyridine ring, a pyrimidine ring, and a pyridazine ring. , An isooxazole ring, an isothiazole ring, a pyrazole ring, a furan ring, a thiophene ring, a thiazoline ring, an imidazoline ring, a piperazine ring, a piperidine ring, a triazole ring or a pyrrole ring, and ring Q ² is a halogen atom and d alkyl. A pyrrole ring, an imidazole ring, or a pyrazole ring having a substituent selected from the group or an unsubstituted group; a ring Q ³ is selected from a halogen atom, a d- ₆ alkyl group, an oxo group, and a thioxo group; Villas with 1 to 3 identical or different substituents or no substituents A sol ring or a pyrimidine ring;

E represents N or CH; and

F represents N or C), or a pharmaceutically acceptable salt or hydrate thereof.

Further, the hetero group represented by the formula (III) is

Wherein Ar ² , R ⁴ and R ⁵ are as defined above, and R ⁶ represents a hydrogen atom, d alkyl group, C ₃ -cycloalkyl group or C cycloalkyl d-alkyl group, X represents S or N-R ^5, and, Y may be either a represents O or S].

The heterocyclic group represented by the formula (IV)

[Wherein Ar ² , R ⁴ and R ⁵ are as defined above].

Further, the heterocyclic group represented by the formula (V)

[Wherein Ar ² , R ⁴ and R ⁵ are as defined above].

More specifically, the compound of formula (I)

2-[N- (2-methylthio-1-isopropylphenyl) -N-ethylamino] -4-1 [4- (3-fluorophenyl) _1,2,3,6-tetrahydropyridine-1 6-methylpyrimidine,

2-[N- (2-bromo- 4-isopropinolepheninole) -N-ethylamino] 4-1 [4- (3-Fluorophenyl) -1,2,3,6-tetrahydropyridine-11-yl ] 6-methinolepyrimidine,

2-[N— (2-methinorethiol 4 _isopropinolefeninole) 1 N-ethinoreamino] 1 4— [5-(2-methylphenyl) 1 1,2,3,6-tetrahydropyridine 1 1-isle] One 6-methylpyrimidine,

6- [4- (4-mono-ethylen)-1,2,3,6-tetrahydropyridine 1-inole] 1 2-methyl-9-1 (2-methinolethiol 4-isopropylpheninole) purine,

4-(N-Puchinore-I-N-Echinorenoamino) 1-2,5-Dimethinole 7-(2,4,6

— Trimethylphenol) 1H-pyrro [2,3-d] pyrimidine,

4-(N-butyl-N-ethylamino) _ 2, 5, 6-trimethyl-7- (2,

4, 6-trimethylphenyl) _ 7 H-pyrro [2,3-d] pyrimidine,

7-[bis- (2-methoxethyl) amino] _3- (2-bromo-4-isopropyl-pyrufel) -1-5-methyl-3H- [1,2,3] triazolo [4,5-d] Pyrimidine,

2- (N-cyclopropylmethyl-1-N-propyl) amino-1-41 (2,4,6-trimethylphenyl) amino-6-methyl- [1,3,5] triazine,

4- (N-cyclopropylmethyl-1-N-propyl) amino-6- (2,4,6-trichloromethylphenyl) amino-2,5-dimethylpyrimidine,

5-chloro-1- (N-cyclopropylmethyl-1-N-propyl) amino-6- (2,4,6-trichlorophenyl) amino-2-methylpyrimidine,

2-[N- (2-promo 4,6-dimethoxypheninole) -N-ethyl] amino-4,6-dimethylpyrimidine,

2-N- [N- (2-bromo-4,6-dimethoxyphenyl) -1-N-ethynole] amino 4- (meth) / le 6-morpholinol [1,3,5] triazine

7-(2-promo 4,6-dimethoxyphenol) 1,2,4-dimethino 7H-pyro [2,3-d] pyrimidine,

7-1- (N-cyclopropinolemethyl-N-propynole) amino-2,5-dimethinole 3- (2,4,6-trimethylphenyl) 1-2H-pyrazo [4,3-d] pyrimidine,

4-[N- (1-Ethylpropyl) amino] 12-Methyl-8 _ (2,4,6-trimethylphenyl) quinoline,

4- (N-cyclopropylmethyl-1-N-propylamino) -1-2-methyl-18- (2,4-dichloro-mouth quinolin) quinoline,

5-methyl-7- (N, N-dipropylamino) -3- (2,4,6-trimethyi) Rufiel) Thieno [3, 2-b] pyridine,

7-(1-ethynolepropoxy) _ 5-methinole 3 _ (2,4, 6-trimethinolephenyl) pyrazo mouth [1,5-a] pyrimidine,

7-1- (N-butyl-N-ethylamino) 1,2,5-dimethyl-3- (2,4-dichloromethane feninole) pyrazo [1,5—a] pyrimidine,

7-[N— (2-Methoxyxetyl) -N-propylamino) 1,2,5-dimethyl—3- (2,4-dimethoxyphenyl) pyrazo-mouth [1,5—a] pyrimidine, 7— [N— (1-Ethylpropyl) amino] 1,2,5-dimethyl-3- (2-methyl-14-methoxyphenyl) pyrazo [1,5-a] pyrimidine,

4- (N-cyclopropylmethyl-N-propylamino) _1- (2,4,6-trimethylphenyl) isoquinoline,

3- (2,4-dichlorophenyl) -1-5-methinole 7- (N, N-dipropizoleamino) pyro mouth [1,2-a] pyrimidine,

6 1 (2-chloro-4- methoxyphenyl) 1 9 dicyclopropyl meth / le 8 ethynoleprine,

5-Ethyl-1 3-Methyl-4-1 (1-Methylbutyl) 1-11 (2,4,6-Triclo-Mouth-Fe-Ninole) 1-1,3a, 4,6a-Tetrahydrimidazo [4,5-c ] Pyrazonore,

5-Ethyl-3-Methyl-41- (1-methylbutyl) 1-1- (2-Bromo-4-isopropylphenyl) 1-1,3a, 4,6a-Tetrahydromidazo [4,5-1c] pyrazole,

3-[(R) 1- (1-methoxymethyl) propyl] -5-methyl-7-1 (2, 4,

6—trimethylphenyl) amino-3H— [1,2,3] triazolo [4,5-d] pyrimidine,

3— (1-Propyl) butyl -5-Methyl-7— (2-Bromo-4-isopropyl-6-methoxyphenyl) amino-3H— [1,2,3] triazolo [4,5-1d] pyrimidine ,

1- (1-ethyl) propyl -6-methyl-4- (2-chloro-4,6_dimethylphenyl) amino-1H— [1,2,3] triazolo [4,5-c] pyridine, 1- (1-Echinole) propizole 6-methinole 4- (2,4_dibromopheninole) amino-1 H— [1,2,3] triazolo [4,5-c] pyridine,

1- (1-Methoxymethyl) propyl-1 6-Methyl-4- (2-methyl-4-methoxyphenyl) amino-1H— [1,2,3] triazolo [4,5-c] pyridine,

4-(1-Methoxymethyl-2-methoxethylamino)-2,7-dimethyl

8— (2,4 dichloromouth phenyl) 1-birazolo [1,5—a] [1,3,5] triazine,

5 _Methyl-17- (N, N-dipropylamino) _2-Methyl-3- (2,4-dichlorophenyl) pyrazo-mouth [4,3-b] pyridine,

3- (2-promo-1-4-isopropyle) 2-5-methinole 7-monoreholino 1-thiazolo [4,5-d] pyrimidine-1 2-thione,

9— (2-Promo 4-isopropylphenole) -6- (N-Cyclopropyl / lemethyl-1-N-propylamino) -2,7-Dimethyl 7,9-Dihydropurine 8-one

9- (2-promo 4-isopropinolephenyl / le) -6- (N-cyclopropinolemethyl-1N-propylamino) -1,2,7-dimethyl-1,7,9-dihydropurine 8-thione,

4- (1-ethylpropoxy) -2,6-dimethyl-2- (2,4,6-trimethylphenylenoxy) pyrimidine,

4-piperazininole 3,6-dimethyi / le 1- (2,4,6-trimethinolephenyl) Pyrro [2,3-b] pyridine and

3— (2,4 dichloromouth phenyl) -1-5-methizure 7— (3-pentinole) amino monoisoxazole [4,5-d] pyrimidine

Is preferably selected from the group consisting of:

The definitions of the terms in each chemical formula of the present invention are as follows. In the present invention, “C _n _-m ” means that the group that follows is r! Has ~ m carbon atoms. di. The alkyl group and the d- ₆ alkyl group respectively represent a linear or branched alkyl group having 1 to 10 carbon atoms and] to 6, and include, for example, a methyl group, an ethyl group, Examples include propyl, petit / le, pentyl, hexyl, isopropyl, isobutyl, 1-ethylpropyl, and t-butyl.

C ₃ - and ₈ cycloalkyl group, a cyclic alkyl group having 3-8 carbon atoms, for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group.

C3-8 cycloalkyl C i. The alkyl group is a C 3-8 cycloalkyl group and di. Alkyl groups have a complex form. Similarly, C ₃ - 8 cycloalkyl CI- 6 Al kill groups, C 3- 8 cycloalkyl group and CI- 6 alkyl group that has a structure composed. Examples thereof include a cyclopropylmethyl group, a cyclopropylethyl group, a cyclobutylmethyl group, a cyclopentylmethyl group, a cyclohexylmethyl group and the like.

The C ₆ alkoxy group, points to the linear or branched alkoxy group having 1 to 6 carbon atoms, for example, main butoxy group, an ethoxy group, a propoxy group, Putokishi group, Penchiruo alkoxy group, to Kishiruokishi group, iso Propoxy group, isobutoxy group, 1-ethylpropyloxy group, t-butoxy group and the like.

^ — (; Alkoxy ^-^ anolequinole group is a complex of C! -6 alkoxy group and di.anolequinole group, therefore d-6 alkoxy di. Examples of alkyl groups are methoxymethyl Group, methoxethyl group, methoxypropyl group, ethoxymethyl group, isopropoxyshetyl group, cyclopropoxyshetyl group and the like.

The d-6 alkylthio group refers to a linear or branched alkylthio group having 1 to 6 carbon atoms, such as methylthio, ethylthio, propylthio, butylthio, pentylthio, pentylthio, hexylthio, and isopropylthio. And isobutylthio, 1-ethylpropylthio and _t- butylthio.

The aryl group is a phenyl group, a naphthyl group, or the like, and is preferably a phenyl group. The heteroaryl group is, for example, a phenyl group, a furanyl group or the like.

Specific examples of Ar ¹ include a phenyl group, a 2-phenyl group, a 2-furyl group, a 3-fluorophenyl group, a 4-chlorophenyl group, and a 2-methylphenyl group. Further, specific examples of A r ² is 2-methylthio-one 4 one-isopropyl-phenylene group, 2-bromo-4 one isopropyl phenylalanine group, 2, 4, 6_ Torimechirufue group, 2, 4- Dichlorophenol group, 2,4-dibromophenyl group, 2,4,6-trichlorophenol group, 2-methyl-4-methoxyphenyl group, 4-isopropyl / phenyl group, 2,4 —Dimethoxy-1 6-bromophenole group, 2-meth / phenyl 4-Methoxyphenole group, 2,4-Dimethoxyphenyl group, 2-Bromo-1,6 dimethoxyphenyl group, 2-chloro-4- Examples thereof include a methoxyphenyl group, a 2-bromo-4-isopropinolefeninole group, a 2-chloro-4,6-dimethynolepheninole group, a 2-bromo-4-isopropyl-16-methoxy group, and the like.

In the present invention, the pharmaceutically acceptable salts include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and nitric acid, and salts with organic acids such as acetic acid, maleic acid, citric acid, tartaric acid, and fumaric acid. Can be The category of the CRF1 receptor antagonists of the present invention is as follows. Hydrates of R F 1 receptor antagonists (monohydrate, dihydrate, hemihydrate, trihydrate, etc.) are also included. When the CRF1 receptor antagonist contains an asymmetric atom, it can be used as a racemic mixture or an optically active substance. Further, when having at least two asymmetric carbon atoms, the category of CRF1 receptor antagonists of the present invention also includes the individual diastereomers and Z or a mixture thereof. Furthermore, the category of the CRF1 receptor antagonist of the present invention also includes stereoisomers thereof. Corticotropin releasing factor (CRF) is a neuropeptide derived from the hypothalamus. CRF released from the hypothalamus binds to the pituitary CRF receptor and promotes the release of adrenocorticotropic hormone (ACTH) from the pituitary into the blood. ACTH released from the pituitary gland stimulates the adrenal cortex and stimulates the production and secretion of various corticosteroids.

There are two types of CRF receptors, type 1 and type 2, and type 2 is further classified into α type and type. Expression of the CRF receptor has been observed in addition to the brain and pituitary gland. For example, the CRF type 2 receptor is expressed in cardiac muscle and skeletal muscle. And, as already mentioned, CRF type 1 receptor (CRF 1 receptor) It has been confirmed that it is also expressed in skin hair tissue (FAS EB 12, 287 — 297 (1998)). The role of CRF in hair growth has not yet been clarified.

We believe that CRF receptor antagonists that antagonize the effects of CRF may regulate hair growth through proliferation, differentiation, or apoptosis of skin Z follicle keratinocytes and dermal papilla cells I did my research. As a result, they have found that a CRF 1 receptor antagonist has keratinocyte proliferation promoting activity and is useful as a hair restorer.

That is, the hair restorer of the present invention has a great technical feature in that the CRF1 receptor antagonist is used as an active ingredient. Here, the CRF1 receptor antagonist includes all compounds having an antagonistic effect on the CRF1 receptor. In addition, CRF is synonymous with corticotropin releasing hormone (CRH), ACTH releasing factor or corticoliverin, and the CRF receptor antagonist of the present invention also includes CRH receptor antagonist, ACTH releasing factor receptor antagonist and corticoliverin receptor antagonist .

As used herein, the term "hair restorer" refers to drugs, quasi-drugs, and cosmetics used for the purpose of inducing hair growth, promoting hair growth, preventing hair loss, and the like, but this term is the broadest definition. Must not be interpreted in any way and must not be used in any way in a restrictive manner. When the hair restorer of the present invention is used as a medicine, examples of the application target include treatment and / or prevention of alopecia areata and male pattern baldness. It is not limited to. The amount of CRF 1 receptor antagonist in the hair growth agent of the present invention, of the total formulation 0. 000. 1 to: L 0 wt%, preferably 0.00 1-5 wt ^_0/0, more preferably 0.00 1 ~ 1% by weight. If the amount is less than 0.001% by weight, the hair growth effect is not sufficient, and if it exceeds 10% by weight, it becomes difficult to design the formulation in relation to other ingredients.

The hair restorer of the present invention can be administered externally or orally.

The form of the hair restorer of the present invention is not particularly limited, but when used externally, a CRF 1 receptor antagonist, for example, a compound of the general formula (I) may be used as an active ingredient. Preferably, the hair restorer is provided in the form of a water-soluble composition. In the production of such a water-soluble composition, various additives generally used in the production of pharmaceuticals, quasi-drugs, or cosmetics can be used. The hair restorer of the present invention can be provided, for example, as a hair-modifying composition such as hair tonic, hair oil ^^, hair mousse, gel, a hair-washing composition such as shampoo, rinse, or an ointment.

In addition, when used in the mouth, a CRF 1 receptor antagonist, for example, a compound of the general formula (I), which is a pharmaceutically acceptable carrier (excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifier) Tablets, capsules, granules, powders, syrups, suspensions, and solutions obtained by formulating a pharmaceutical composition obtained by blending with a diluent, a solubilizing agent, etc. according to a conventional method. It is desirable to provide it in such a form. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a photograph of a sample obtained by immunostaining the scalp hair follicle of a rhesus monkey using an anti-CRF receptor antibody.

FIG. 2 is a graph showing that a CRF1 receptor antagonist has keratinocyte proliferation promoting activity. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail with reference to the drawings using experimental examples, but the present invention is not limited thereto. Experimental Example 1: Immunostaining of monkey scalp with anti-CRF receptor antibody

The scalp was collected from the top of the macaque monkey (os) and fixed with 10% neutral formalin at room temperature. Next, make the paraffin section and add 1% 83? 83 was added and left at room temperature for 60 minutes. Then, an anti-CRF receptor antibody CRF-RI (Santa Cruz) was reacted with 1 μg / m 1 at 4 ° C., followed by a reaction with a biotinylated anti-goat IgG antibody. Thereafter, reacted with ABC standardkit (vector one), AEC substarate (Sigma) _c The results obtained by color development using, specific to § force Gezaru scalp hair follicle keratinocytes of the outer root sheath region of the hair tissue Pojite An Eve reaction was observed (Figure 1). Experimental Example 2: Keratinocyte growth-promoting activity of CRF1 receptor antagonist

Normal human epidermal keratinocytes (Kurabo) were cultured using keratinocyte growth medium KGM-2 (Sanko Junyaku).

Epidermal keratinocytes at the second passage were seeded on a 24-well plate at 1.5 × 10 ⁴ ce 11 s / we 11 and cultured overnight in KGM-2. The medium was replaced with a growth medium-free basal medium KBM-2 (Sanko Junyaku) and precultured for another 6 hours. Then, the CRF1 receptor antagonist, 2- [N- (2-methylthio2-4-isopropylphenyl) -1-N-ethylamino] 1-4- [4- (3-fluorophenyl) 1-1,2,3 , 6-Tetrahydropyridine-11-yl] — 6-methylpyrimidine was added to the medium and cultured for 72 hours, and the number of cells at the end of the culture was measured using a Ce11 counting kit (Wako Pure Chemical Industries). . Measurements were performed on two different concentrations of the CRF1 receptor antagonist (0.3 / g / ml, 1 μg / ml) and on the sample without the CRF1 receptor antagonist. The measurement of the cell number was specifically performed as follows. That is, 2 hours before the end of the culture, a WST-1 reagent in an amount of lZl0 of the medium was added to the medium, and at the end of the culture, the absorbance of the medium (OD450nm / 690nm) was measured. Since a positive correlation was observed between the cell number and the absorbance in the range of 0.25 to 8 × 10 ⁴ cellswell, the cell number was calculated using the correlation coefficient.

As a result, the CRF1 receptor antagonist 2- [N- (2-methylthio-14-isopropiggrefenole) -N-ethynoleamino] -4-1- [4- (3-fenoleo mouth fehenore) 1-1 2,2,3,6-Tetrahydropyridine-11-yl] -16-methylpyrimidine was found to have keratinocyte growth-promoting activity (Fig. 2). The values in the figure are the average values of 3 we 11 for each group. Student's t-test was used for comparison between the control group and the group to which the CRF1 receptor antagonist was added.

The above experimental examples showed that the CRF receptor was expressed in primate scalp hair follicle keratinocytes, and that the CRF1 receptor antagonist had keratinocyte proliferation promoting activity. Industrial applicability

A CRF1 receptor antagonist, for example, a compound of the general formula (I) having CRF1 receptor antagonist activity or a pharmaceutically acceptable salt thereof is useful as a hair restorer having a novel mechanism of action. '

Claims

The scope of the claims

Hair restorer _c containing CRF 1 receptor antagonist as active ingredient

2. The CRF 1 receptor antagonist has the formula (I)

A (I)

[In the above formula,

A is wherein Chitr ² (wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom, d-Al kill group, C ₃ _ _s cycloalkyl group, C ₃ -. ₈ cycloalkyl C -! !. alkyl group , C

₆ alkoxy C i-! . Which represents an alkyl group),

A group represented by the formula NRiR ² , wherein R ¹ and R ² are as defined above,

A group represented by the formula NHCHR ¹ ! ^ ² (wherein R ¹ and R ² are as defined above), a formula OR ³ (where R ³ is a hydrogen atom, C!-. An alkyl group, C ₃ -!.. ₈ cycloalkyl group, C consequent opening alkyl C physician alkyl group, d-alkoxy C i group represented by group shows the)

Piperidino group,

Morpholino group,

Piperazino group, or.

The following formula (II)

Ar ¹

(H)

N

(Wherein, A r ¹ represents a halogen atom, _d-6 alkyl group, or having one to three same or different substituents selected from _d-6 alkoxy and triflate Ruoromechiru groups, it is also properly no substituent Represents a aryl group or a heteroaryl group).

And

Z is the following formula (III) to (VIII)

(In each formula,

R ⁴及Pi R ⁵ are respectively a hydrogen atom, _d-6 alkyl group, a group represented by showing a C ₃ _ ₈ cycloalkyl group or a C 3- 8 cycloalkyl d-6 alkyl group);

Ar ² represents a halogen atom, a d- ₆ alkyl group, a d- ₆ alkoxy group, a d- ₆ alkylthio group, a trifluoromethyl group, a trifluoromethoxy group, and a compound represented by the formula N (R ⁷ ) R ⁸ (wherein R ⁷ And R ⁸ are the same or different and each represent a hydrogen atom or a d- ₆ alkyl group) or a phenyl group having 1 to 3 identical or different substituents selected from the groups represented by Shows;

Ring Q ¹ has 1 to 3 identical or different substituents selected from a halogen atom, a d- ₆ alkyl group, an oxo group and a thioxo group, or has no substituent, a benzene ring, a pyridine ring, a pyrimidine ring, A pyridazine ring, an isooxazole ring, an isothiazole ring, a pyrazole ring, a furan ring, a thiophene ring, a thiazoline ring, an imidazoline ring, a piperazine ring, a piperidine ring, a triazole ring or a pyrrole ring, and ring Q ² is a halogen atom and d- ₆ alkyl group: a pyrrole ring, imidazole ring or pyrazole ring having a substituent selected or not having a substituent; ring Q ³ represents a halogen atom, a d- ₆ alkyl group, an oxo group and a thioxo ring; A virazol ring having 1 to 3 identical or different substituents selected from Represents a pyrimidine ring;

E represents N or CH; and

Wherein F is N or C), or a pharmaceutically acceptable salt or hydrate thereof. Hair restorer.

3. When the heterocyclic group represented by the formula (III) is

2

[In each formula, Ar ² , R ⁴ and R ⁵ have the same meanings as described above, and R ⁶ represents a hydrogen atom, a d ₆ alkyl group, a C ₃ -cycloalkyl group or a C-cycloalkyl dalkyl group. ,

X represents S or N—R ⁵ , and Y represents O or S].

4. When the heterocyclic group represented by the formula (IV) is R

3. The hair restorer according to claim 2, wherein in each formula, Ar ² , R ⁴ and R ⁵ have the same meanings as described above.

5. When the heterocyclic group represented by the formula (V) is

6. The compound of formula (I)

2- [N- (2-Methylthio-1-4-isopropylphenyl) -N-ethylamino] —4- [4- (3-Fluorophenyl) 1-1,2,3,6-tetrahydropyridin-1-1- 1] 6-methylpyrimidine,

2-[N- (2-bromo-1- 4-phenylphenyl) 1-N-ethylamino]-4-1 [4- (3-fluorophenyl) 1-1,2,3,6-tetrahydropyridine-11-yl] — 6-methylpyrimidine,

2- [N— (2-Methylthio-1-isopropylpropyl) —N-ethylamino] —4-1—5- (2-Methylphenyl) —1,2,3,6-tetrahydropyridine-1— 6-methylpyrimidine,

6— [4- (4-chlorophen-2-ole) -1 1,2,3,6-tetrahydropyridine-11-yl] — 2-methylinole 9 _ (2-methizlethio-1-4-isopropylphenyl) Pudding,

4- (N-butyl-1-N-ethylamino) _25-dimethyl-17- (2,4,6-trimethylphenyl) -17H-pyro [23-d] pyrimidine,

4- (N-butynole-N-ethynoleamino) 1 25,6-trimethyl-7- (2,4,6-trimethylphenyl) 1 7H-pyro [2,3-d] pyrimidine,

7- [bis (2-methoxhetyl) amino] 1-3- (2-bromo-14-isop orpirufeninole) 1-5-methyl-1 3H— [1,2,3] triazolo [4,5-d ] Pyrimidine,

2- (N-cyclopropylmethyl-N-propyl) amino-4-1 (2,4,6-trimethylphenyl) amino-6-methyl- [1,3,5] triazine, 4- (N-cyclopropylmethyl-N —Propyl) amino-6— (2,4,6—trichlorophenyl) amino-2,5-dimethylpyrimidine,

5- (N-cyclopropylmethyl-N-propyl) amino-6- (2,4,6-trichlorophenyl) amino-2-methylpyrimidine,

2-[N- (2-promo 4,6-dimethoxyphenyl) -N-ethynole] amino-4,6-dimethylpyrimidine,

2- [N- (2-bromo_4,6-dimethoxyphenyl) -N-ethyl / le] amino—4-methyl-6-morpholinol [1,3,5] triazine

7- (2-promo 4,6-dimethoxyphenyl) _2,4-dimethyi / le 7H-birolo [2,3-d] pyrimidine,

7-(N-cyclopropyl propylmethyl-N-propyl) amino 2,5-

3— (2,4,6—trimethylphenyl) 1-2H—pyrazo-mouth [4,3d] pyrimidine,

4- [N_ (1-ethylpropyl) amino] _2-methyl-8- (24,6-trimethylphenyl) quinoline,

4-I- (N-cyclopropylmethyl-N-propylamino) -1-Methyl-8- (2,4-dichlorophenol) quinoline,

5-methyl-7- (N, N-dipropylamino) _3- (2,4,6-trimethylphenyl) thieno [3,2-b] pyridine, 7— (1-Echinolepropoxy) 1—5-Methyl-3— (2,4,6-trimethinorefuel) pyrazo mouth [1, 5—a] pyrimidine,

7- (N-butyl-N-ethylamino) 1, 2,5-V_3— (2,4-dichloro mouth feninole) pyrazo [1, 5-a] pyrimidine,

7- [N- (2-Methoxyxetyl) -N-propylamino) 1-2,5-dimethyl- 3- (2,4-dimethoxyphenyl) pyrazo-mouth [1,5-a] pyrimidine, 7- [N- (1 1-ethylpropyl) amino] 1,2,5-dimethyl-3- (2-methyl-4-methoxyphenyl) pyrazo [1,5_a] pyrimidine,

4- (N-cyclopropylmethyl-N-propylamino) 1- (2,4,6-trimethylphenyl) isoquinoline,

3- (2,4-dichlorophenyl) -1-5-methyl-7- (N, N-dipropylamino) pyro [1,2_a] pyrimidine,

6- (2-Chloro-4-methoxyphenyl) -1-9-dicyclopropylmethyl-8-ethylpurine,

5-Ethyl-3_Methyl-1_4_ (1-Methylbutyl) -1-1 (2,4,6-Tric-mouth Mouth-Feninole) 1-1,3a4,6a-Tetrahydrimidazo [4,5-c ] Pyrazole,

5-Ethynole 3 -Methynole 4 (1-Methylbutyl) _ 11- (2-Bromo-4-Isopropylpheninole)-13a, 4,6a-Tetrahydroimidazo [4,51c] pyrazole,

3-1-[(R) -1- (1-Methoxymethyl) propyl] -1-5-methyl-7- (2,4,6-trimethinolephenyl) amino-3H— [1,2,3] triazolo [4,5-d ] Pyrimidine,

3- (1-monopropyl) butyl-5-methyl-7- (2-bromo-4-isopropyl-6-methoxyphenyl) amino-3H— [1,2,3] triazolo [4,5-1d] pyrimidine,

1-1- (1-ethynole) Propinole 6-methinole 4- (2-chloro-1,4,6-dimethylphenyl) amino-1H— [1,2,3] triazolo [4,5-c] pyridine, 1-1 ( 1-Echinole) Propinole 6-Methinole 4--(2,4-Dibromopheninole) Amino-1H— [1,2,3] triazolo [4,5-c] pyridine,

1- (1-Methoxymethyl) propyl-6-methyl_4- (2-methyl-4-methoxyphenyl) amino-1H—Ll, 2,3] triazolo [4,5_c] pyridine,

4-(1-Methoxymethyl-1- 2-methoxyhexylamino)-2,7-Dimethyl

8— (2,4-dichloro-phenyl) 1-pyrazo [1,5—a] [1,3,5] triazine,

5-Methyl-7- (N, N-dipropylamino) -1-2-Methyl-3- (2,4-dichlorophenyl) pyrazo-mouth [4,3-b] pyridine,

3-(2-Promo 4-Isopropylpheninole) 1-5-Methyl-1 7-Moleholino 1-thiazolo [4,5-d] pyrimidine _ 2-Thion,

9— (2-promo_4_isopropinolefe / re) _6— (N-cyclopropinolemethyl-N-propylamino) -2,7-dimethyl_7,9 dihydropurine

9- (2-promo 4-isopropinolepheninole) 1-6_ (N-cyclopropizolemethyl-N-propylamino) 1,2,7-dimethyl_7,9-dihydropurine 18-thione,

4-(1 -ethylpropoxy) 1, 2,6-dimethyl-1 2 _ (2,4,6-trimethyl phenylenoxy) pyrimidine,

4-piperazinyl-3,6_dimethyl-1- (2,4,6_trimethylphenyl) pyrro [2,3-b] pyridine and

3- (2,4-dichlorophenyl) -1-5-methyl-1 7- (3-pentyl) amino monoisoxazole [4,5-d] pyrimidine

The hair restorer according to claim 2, which is selected from the group consisting of:

7. Use of a CRF 1 receptor antagonist for the manufacture of a hair restorer.

8. The CRF 1 receptor antagonist has the formula (I)

A (I)

[In the above formula,

A is wherein CHR R ² (wherein, R ¹ and R ² are the same or different and each represents a hydrogen atom, d-. Al Kill group, Rei_3-8 cycloalkyl group, C ₃ -8 cycloalkyl d-i. Alkyl group , D-

₆ alkoxy C!-I. Which represents an alkyl group),

A group represented by the formula NR ¹ ! ^ ² (wherein R ¹ and R ² are as defined above),

A group represented by the formula NHCHR'R ² (wherein R ¹ and R ² are as defined above), a formula OR ³ (where R ³ is a hydrogen atom, d—i. An alkyl group, C ₃ — ₈ cycloalkyl group, C

₃ one ₈ Shikuroarukinore C Bok i. An anoalkyl group, d-6 alkoxy C. Which represents an alkyl group),

Piperidino group,

Monoreholino group,

Piperazino group, or

The following formula (II)

(Wherein, A r ¹ represents a halogen atom, _d-6 alkyl group, C -! ₆ alkoxy group and one having three or 1 identical or different substituents selected from triflate Ruoromechiru group, is also properly have a substituent Represents an aryl group or a heteroaryl group, which is not represented by

And

z is the following formula (ιπ)-(νπι)

(In each formula,

R ⁴ and R ⁵ are each a hydrogen atom, _d-6 alkyl group, C ₃ - ₈ cycloalkyl group Or a C ₃ -cycloalkyl d-alkyl group).

Ar ² represents a halogen atom, a d- ₆ alkyl group, a d- ₆ alkoxy group, a d- ₆ alkylthio group, a trifluoromethyl group, a trifluoromethoxy group and a formula N (R ⁷ ) R ⁸ (wherein R ⁷ And R ⁸ are the same or different and each represent a hydrogen atom or a d- ₆ alkyl group) or a group having 1 to 3 identical or different substituents selected from the groups represented by Represents a group;

Ring Q ¹ has 1 to 3 identical or different substituents selected from a halogen atom, a d- ₆ alkyl group, an oxo group and a thioxo group, or has no substituent, a benzene ring, a pyridine ring, a pyrimidine ring, A pyridazine ring, an isooxazole ring, an isothiazole ring, a pyrazole ring, a furan ring, a thiophene ring, a thiazoline ring, an imidazoline ring, a piperazine ring, a piperidine ring, a triazole ring or a pyrrole ring, and ring Q ² is a halogen atom and or having a substituent selected from _d-6 alkyl group, if Ku has no pyrrole ring substituent group, the Imidazoru ring or a pyrazole ring; ring Q ³ are halogen atoms, _d-6 alkyl group, Okiso group and Chiokiso A virazole ring having 1 to 3 identical or different substituents selected from Shows the pyrimidine ring;

E represents N or CH; and

F represents N or C), or a pharmaceutically acceptable salt or hydrate thereof.

9. When the heterocyclic group represented by the formula (III) is

[In the formulas, Ar ^2, R ⁴ and R ⁵ are as defined above, R ⁶ is a hydrogen atom, d- ₆ alkyl le group, C ₃ - 8 consequent opening alkyl or C 3- 8 cycloalkyl d- 6 represents an alkyl group,

X represents S or N-R ^5, and, Y is Use according to claim 8, wherein either represents O or S].

0. The heterocyclic group represented by the formula (IV) is

9. The use according to claim 8, wherein, in each formula, R ² , R ⁴ and R ⁵ are as defined above.

The heterocyclic group represented by the formula (V) is

9. The use according to claim 8, wherein in each formula, Ar ² , R ⁴ and R ⁵ are as defined above.

1 2. The compound of the formula (I) is

2-[N- (2-Methynolethio-1-4-isopropizolephenyl) -N-ethylamino] -4-1- [3- (3-Fluorophenyl)-1,2,3,6-tetrahydropyridine-1-inole ] One 6-methylpyrimidine,

2— [N— (2-promo-1-4-phenylphenol) 1-N-ethylamino] 4_ [4- (3-fluorophenyl) 1-1,2,3,6-tetrahydropyridine-11-yl] _ 6—Methylpyrimidine,

2- [N- (2-Methylthio-14-isopropylphenyl) -N-ethylamino] 1-41- [5- (2-Methylphenyl) 1-1,2,3,6-tetrahydropyridin-1-yl ] One 6-methylpyrimidine,

6- [4- (4-chlorophenol-1) -1,2,3,6-tetrahydropyridine-11-yl] -12-methyl-9-1-1 (2-methylthio-14-isopropylphenyl) Pudding,

4- (N-butynole N-ethylamino) 1,2,5-dimethyl 7- (2,4,6

— Trimethylphenyl) 1H-pyrro [2,3-d] pyrimidine,

1- (N-butynole-N-ethylamino) 1,2,5,6-trimethyl-7- (2,

4, 6_trimethylphenyl) 1H-pyrro [2,3-d] pyrimidine,

7- [bis- (2-methoxethyl) amino] 1-3- (2-bromo-4-isopropylpyrphenyl) -1-methyl-3-H- [1,2,3] triazolo [4,5-d] pyri Midines,

2- (N-cyclopropy / remethinole-N-propizole) amino-4- (2,4,6-trimethylphenyl) amino-6-methyl-1- [1,3,5] triazine,

4- (N-cyclopropinolemethinole N-propynole) amino-6- (2,4,6-trichloromethylphenyl) amino-2,5-dimethylpyrimidine,

5 _ Black mouth 41-1 (N-cyclopropinolemethinole 1-N-propynole) Amino-6- (2,4,6—Triclofenenole) Amino-2-methylpyrimidine,

2— [N— (2-promo 4, 6-dimethoxypheninole) 1N-ethynole] amino 1,4,6-dimethylpyrimidine,

2- [N- (2-promo 4,6-dimethoxyphenole) -1-N-ethyl] amino-1 4-methyl-1 6-monoreholino [1,3,5] triazine

7— (2-promo-4,6-dimethoxyphenolene)-2,4,1-dimethy7-7-1H-pyro [2,3-d] pyrimidine,

7- (N-cyclopropylmethyl-N-propyl) amino-1,2,5-dimethyl

3-(2,4,6-trimethylphenyl) 1 2H-pyrazo [4,3-d] pyrimidine,

4- [N— (1-ethylpropyl) amino] —2-methyl-1-8— (2,4,6-trimethylphenyl) quinoline,

4- (N-cyclopropylmethyl-1-N-propylamino) -1-methyl-8- (2,4-dichlorophenol) quinoline,

5-methyl-7- (N, N-dipropylamino) 1-3- (2,4,6_trimethylphenyl) thieno [3,2-b] pyridine, 7- (1-Ethylpropoxy) -1-5-Methynole 3- (2,4,6-trimethylphenyl) pyrazo-mouth [1,5-a] pyrimidine,

7- (N-petit gray N-ethynoleamino) _2,5-dimethyl-3- (2,4-dichlorophenyl) pyrazo [1,5-a] pyrimidine,

7-[N- (2-Methoxyxetyl) -N-propylamino) _ 2,5-dimethyl- 3- (2,4-dimethoxyphenyl) pyrazo [1,5-a] pyrimidine, 7- [N- ( 1-ethylpropyl) amino] _2,5_dimethyl-3_ (2-methyl-4-methoxyphenyl) pyrazo [1,5-a] pyrimidine,

4- (N-cyclopropylmethyl-N-propylamino) 1- (2,4,6-trimethylphenyl) isoquinoline,

3-(2,4-dichloro mouth fuel) 1 5-Methyl _ 7— (N, N-dipropylamino) Pyro mouth [1, 2—a] pyrimidine,

6- (2-chloro-1-4-methoxyphenyl) _9-dicyclopropinolemethinole_8 8-ethylpurine,

5-ethyl-1-3-methyl-1-4- (1-methylbutyl) 1-1-1 (2,4,6-trichloromethane) 1,1,3a, 4,6a-tetrahydrimidazo [4,5- c] pyrazonore,

5-Ethyl-1-3-methyl-14- (1-methylbutyl) 1-1- (2-Bromo-4_isopropylphenyl) 1-1,3a, 4,6a-Tetrahydrimidazo [4,5—c] pyrazole,

3-[(R)-(1-Methoxymethyl) propyl] 1-5-methyl-7-(2, 4,

6-trimethylphenyl) amino-3H— [1,2,3] triazolo [4,5-d] pyrimidine,

3- (1-propyl) butyl-5-methyl-7- (2-bromo-4-isopropyl-6-methoxyphenyl) amino-3H— [1,2,3] triazolo [4,51-d] pyrimidine,.

1- (1-Echinole) Propinole 6-Methinole 4- (2-Clot_4,6-Dimethylphenyl) Amino-1 H— [1,2,3] Triazolo [4,5-c] pyridine, 1- (1—Echinole) Propinole 6—Methi, Re 41 (2,4-Dibromopheninole) Amino-1H— [1,2,3] triazolo [4,5—c] pyridine,

1- (1-Methoxymethyl) propyl / Ray 6-Methyl-4 (2-Methynole-1-Methoxyphenyl) Amino-1H— [1,2,3] Triazolo [4,5-c]

4- (1-Methoxymethyl-2-methoxythiylamino) 1,2,7-Dimethyl

8— (2,4-dichlorophenyl) 1-birazolo [1,5-a] [1,3,5] triazine,

5-Methyl-1- (N, N-dipropylamino) _2-Methyl-1- (2,4-dichlorophenyl) pyrazo [4,3-b] pyridine,

3— (2-promo 4-isopropylpropene) _5-methinole 7-morpholino monothiazolo [4,5-d] pyrimidine-1-thione,

9-1- (2-bromo-4-isopropylphenyl) -1-6- (N-cyclopropylmethyl-1-N-propylamino) -1,7-dimethyl-7,9-dihydropurine-1-one,

9- (2-Promo 4-isopropylphenyl) -1-6- (N-cyclopropylmethyl-1-N-propylamino) -1,7_dimethyl-7,9-dihydropurine-8-thione,

4- (1-ethylpropoxy) -1,2,6-dimethyl-1-2- (2,4,6-trimethylphenylenoxy) pyrimidine,

4-piperazininole 3,6-dimethinole 1- (2,4,6-trimethy / refenyl) Pyro-mouth [2,3-b] pyridine, and

3- (2,4-dichlorophenyl) -1-5-methyl-1-7- (3-pentyl) amino-isoxazole [4,5-d] pyrimidine

9. The use according to claim 8, wherein the use is selected from the group consisting of: