Thiazole derivative

A derivative, thiazole technology, applied in the fields of hair growth agent and hair follicle cell growth promoter, can solve the problems such as no report on the inhibitory effect of activin receptor-like kinase 5, no thiazolyl imidazole compound, etc.

Inactive Publication Date: 2007-05-02
TAISHO PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although WO00 / 61576A, WO01 / 72737A, WO01 / 62756A, WO02 / 40468A, WO03 / 87304A etc. have reported substances that have an inhibitory effect on the type I receptor activin receptor-like kinase 5 (ALK5) of TGF-β, there is no Relating to the thiazolyl imidazole compound described in the present invention
[0008] In addition, although WO99 / 03837A, WO96 / 03387A, WO03 / 62215A, WO01 / 85723A, WO01 / 44203A, JP2001163861A, JP07112975A, US Pat. , the inhibitory effect of these compounds on activin receptor-like kinase 5 (ALK5) has not been reported

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0128]

[0129] Synthesis of compound 217

[0130] To a solution of 2-iodo-4-methylthiazole (2.50g) in acetonitrile (50ml) was added triethylamine (25ml), tetrakis(triphenylphosphine)palladium (642mg) and 5-ethynyl-benzo( 1,3) Dioxole (1.79 g), and the mixture was stirred under reflux for 4 hours. After distilling off the solvent, the resulting residue was purified by flash column chromatography on silica gel using a mixed solvent of ethyl acetate, chloroform and hexane to obtain the title compound (2.38 g).

[0131] 1 H-NMR (300MHz, CDCl 3 )δppm:

[0132]2.49 (3H, d, J = 0.9Hz), 6.01 (2H, s), 6.81 (1H, d, J = 8.1Hz), 6.91 (1H, d, J = 0.9Hz), 7.01 (1H, d, J = 1.6Hz), 7.13 (1H, dd, J = 8.1, 1.6Hz) mp: 111.5-112.0°C

Embodiment 2

[0134] Synthesis of compound 203

[0135]

[0136] To a solution of compound 217 (1.91 g) in dimethylsulfoxide (13 ml) was added palladium (H) chloride (139 mg), and the mixture was stirred at 125°C for 3 hr. The solution was diluted with ethyl acetate and filtered, and the resulting solution was washed successively with water and brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The resulting residue was purified by flash column chromatography on silica gel using a mixed solvent of ethyl acetate and hexane to obtain the title compound (960 mg).

[0137] 1 H-NMR (300MHz, CDCl 3 )δppm:

[0138] 2.52 (3H, d, J = 0.9Hz), 6.09 (2H, s), 6.88 (1H, d, J = 8.7Hz), 7.40 (1H, d, J = 0.9Hz), 7.48-7.54 (2H, m )mp: 131.5-132.5°C

Embodiment 3

[0140] Synthesis of Compound 8

[0141]

[0142] To a solution of compound 203 (893 mg) and 4-cyanobenzaldehyde (510 mg) in acetic acid (40 ml) was added ammonium acetate (1.50 g), and the mixture was stirred under reflux for 4 hr. After distilling off the solvent, the solution was neutralized with aqueous ammonia and extracted twice with chloroform. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off. The obtained residue was recrystallized from methanol and chloroform to obtain the title compound (575 mg).

[0143] 1 H NMR (300MHz, DMSO-d6) δppm:

[0144] 2.36(3H, s), 6.10(2H, s), 7.06(1H, d, J=7.6Hz), 7.20(1H, s), 7.55(1H, bd, J=7.6Hz), 7.73(1H, bs ), 7.97 (2H, d, J = 8.3Hz), 8.26 (2H, d, J = 8.3Hz), 13.05 (1H, brs)

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Abstract

A thiazolylimidazole derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof, and an ALK5 inhibitor, an therapeutic agent for alopecia or a hair growth agent having the above as an active ingredient, wherein: X 1 and X 2 are different from each other and represent a sulfur atom or a carbon atom; R 1 represents a phenyl group; a substituted phenyl group; a phenyl group condensed with a hetero aromatic ring; a pyridyl group; or a pyridyl group condensed with a hetero aromatic ring; R 2 represents a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 1 to 6 carbon atoms substituted with 1 to 5 halogen atoms, an alkoxy group having 1 to 6 carbon atoms, an alkanoyl group having 1 to 5 carbon atoms, or a hydroxyalkyl group having 1 to 6 carbon atoms, A represents a group which is represented by the formula (II). The present invention provides an inhibitory substance against ALK5 which is a TGF- type I receptor and provides a hair growth stimulant or a hair growth agent based on its novel activities.

Description

technical field [0001] The invention relates to a compound capable of inhibiting TGF-beta type I receptor activin receptor-like kinase 5 (ALK5). The present invention also relates to a hair follicle cell growth promoter, a hair growth agent and a hair growth agent, all of which contain an ALK5 function inhibitor as an active ingredient. Background technique [0002] Transforming growth factor-beta (TGF-beta), activin, BMP, etc. are molecules belonging to the TGF-beta superfamily. TGF-β has two distinct signaling receptors (type I and type II), both of which have serine / threonine kinase domains in their respective cells. Once TGF-β binds to the receptor, the type I receptor is phosphorylated by the type II receptor, thereby being activated, thus transmitting the signal to the nucleus through the Smad2 / 3 pathway or the TAB1 / TAK1 pathway. [0003] Obviously, TGF-β has many physiological effects, and it is well known that one of them is that TGF-β has the property of accumulat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D417/04A61K31/426A61K31/427A61K31/428A61K31/4439A61K31/454A61K45/00A61P1/16A61P11/00A61P13/12A61P17/14A61P27/02A61P43/00C07D277/24C07D417/06C07D417/14A61K8/49A61Q7/02
Inventor 佐藤正和松永结子浅沼肇天田英明小网武史高山哲男薮内哲也盐泽史康片贝博典梅宫广树池田明子
Owner TAISHO PHARMACEUTICAL CO LTD
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