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WO2002019975A1 - Stimulants de la croissance des cheveux - Google Patents

Stimulants de la croissance des cheveux Download PDF

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Publication number
WO2002019975A1
WO2002019975A1 PCT/JP2001/007537 JP0107537W WO0219975A1 WO 2002019975 A1 WO2002019975 A1 WO 2002019975A1 JP 0107537 W JP0107537 W JP 0107537W WO 0219975 A1 WO0219975 A1 WO 0219975A1
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WO
WIPO (PCT)
Prior art keywords
group
ring
amino
methyl
pyrimidine
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Ceased
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PCT/JP2001/007537
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English (en)
Japanese (ja)
Inventor
Akiko Ikeda
Shigeru Okuyama
Tamotsu Shibasaki
Seiji Kawana
Katsumi Kaneko
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Taisho Pharmaceutical Co Ltd
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Taisho Pharmaceutical Co Ltd
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Priority to AU2001284417A priority Critical patent/AU2001284417A1/en
Publication of WO2002019975A1 publication Critical patent/WO2002019975A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4365—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/69—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing fluorine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth

Definitions

  • 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.
  • CCF corticotropin releasing factor
  • 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.
  • 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.
  • 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.
  • 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.
  • blood flow enhancers such as potassium chloride, tincture tincture tincture, nicotinic acid amide, pantothenyleethyl ether, and glyceryl pentaglycanate.
  • 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.
  • 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.
  • 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.
  • CRF is expressed on hair follicle keratinocytes
  • 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.
  • 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.
  • 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 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),
  • R 3 is a hydrogen atom, d-i.
  • 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
  • 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 ⁇ 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.
  • 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
  • F represents N or C), or a pharmaceutically acceptable salt or hydrate thereof.
  • 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].
  • 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.
  • 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.
  • Ar 1 examples 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.
  • 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 me
  • 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.
  • CRF1 receptor antagonists of the present invention when having at least two asymmetric carbon atoms, 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 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.
  • CRF receptors There are two types of CRF receptors, type 1 and type 2, and type 2 is further classified into ⁇ 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.
  • 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.
  • the hair restorer of the present invention has a great technical feature in that the CRF1 receptor antagonist is used as an active ingredient.
  • the CRF1 receptor antagonist includes all compounds having an antagonistic effect on the CRF1 receptor.
  • CRF is synonymous with corticotropin releasing hormone (CRH), ACTH releasing factor or corticoliverin
  • the CRF receptor antagonist of the present invention also includes CRH receptor antagonist, ACTH releasing factor receptor antagonist and corticoliverin receptor antagonist .
  • 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.
  • examples of the application target include treatment and / or prevention of alopecia areata and male pattern baldness. It is not limited 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.
  • the hair restorer is provided in the form of 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.
  • 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.
  • a pharmaceutically acceptable carrier excipient, binder, disintegrant, flavoring agent, flavoring agent, emulsifier
  • 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.
  • 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 ⁇ g / m 1 at 4 ° C., followed by a reaction with a biotinylated anti-goat IgG antibody.
  • 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.
  • 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 ⁇ g / ml) and on the sample without the CRF1 receptor antagonist. The measurement of the cell number was specifically performed as follows.
  • 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.
  • 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.
  • 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.

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Abstract

Cette invention concerne des stimulants de la croissance des cheveux renfermant comme principe actif un antagoniste du récepteur de la corticolibérine 1 (CRF).
PCT/JP2001/007537 2000-09-05 2001-08-31 Stimulants de la croissance des cheveux Ceased WO2002019975A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001284417A AU2001284417A1 (en) 2000-09-05 2001-08-31 Hair growth stimulants

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JP2000-269291 2000-09-05

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Cited By (27)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6894045B2 (en) 2001-07-12 2005-05-17 Bristol-Myers Squibb Pharma Company Tetrahydropurinones and derivatives thereof as corticotropin releasing factor receptor ligands
WO2005007658A3 (fr) * 2003-07-14 2005-06-16 Arena Pharm Inc Derives aryle et heteroaryle condenses utilises comme modulateurs du metabolisme et prophylaxie et traitement des troubles metaboliques
US6964965B2 (en) 2002-04-26 2005-11-15 Pharmacia & Upjohn Substituted pyrazine derivatives
US7067658B2 (en) 2002-09-30 2006-06-27 Bristol-Myers Squibb Company Pyridino and pyrimidino pyrazinones
US7253284B2 (en) 2001-07-17 2007-08-07 Giaxo Group Limited Chemical compounds
US7427630B2 (en) 2003-04-09 2008-09-23 Sb Pharmaco Puerto Rico Inc. Condensed N-heterocyclic compounds and their use as CRF receptor antagonists
US7470699B2 (en) 2003-07-11 2008-12-30 Arena Pharmaceuticals, Inc. Trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto
US8933083B2 (en) 2003-01-14 2015-01-13 Arena Pharmaceuticals, Inc. 1,2,3-trisubstituted aryl and heteroaryl derivatives as modulators of metabolism and the prophylaxis and treatment of disorders related thereto such as diabetes and hyperglycemia
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