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Azole derivative

一种吡咯烷、化合物的技术，应用在吡咯衍生物领域，能够解决没有公开吡咯结构、抑免蛋白FKBP12键合活性和生发促进活性的关联不清楚等问题

Inactive Publication Date: 2014-01-08
TAISHO PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there is no report on the growth-promoting effect of other derivatives, and the relationship between the binding activity of immunophilin FKBP12 and the growth-promoting activity is unclear.
Moreover, the same pyrrole structure as the present invention is not disclosed in the above compounds bonded to FKBP12

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0264] [chemical formula 18]

[0265]

[0266] (S)-1-(2-(5-((3,4-dimethoxyphenoxy)methyl)isoxazol-3-yl)pyrrolidin-1-yl)-2,2-di Fluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexane)ethanone (compound 1)

Embodiment 1－（1）

[0268] [chemical formula 19]

[0269]

[0270] (S)-5-((3,4-dimethoxyphenoxy)methyl)-3-(pyrrolidin-2-yl)isoxazole

[0271] Under argon atmosphere, add 1,2-dimethoxy-4-(prop-2-yn-1-yloxy)benzene (81.85g) in THF (1000mL) at 60℃~-70℃ Add n-BuLi (147mL, 2.76N hexane solution) dropwise over 55 minutes, and after stirring at the same temperature for 30 minutes, add (S)-tert-butyl 2-(methoxy(methyl)carbamoyl) dropwise ) THF (600 mL) solution of pyrrolidine-1-carboxylate (100.00 g), heated up to room temperature over 2 hours, and stirred at 25° C. for 30 minutes. The reaction solution was added to saturated NH 4 Cl aqueous solution (3L), ice water (2L), hexane (1L) and AcOEt (1L), the organic layer was separated, washed with brine (5L), water (2L), brine (1L) successively, and dried (MgSO 4 ), filtered, concentrated and dissolved the obtained brown oil (161.24g) in EtOH (1000mL), added hydroxyamino hydrochloride (53.79g), heated to reflux for 13 hours, and stirred at room tempe...

Embodiment 1－（2）

[0274] [chemical formula 20]

[0275]

[0276] (S)-1-(2-(5-((3,4-dimethoxyphenoxy)methyl)isoxazol-3-yl)pyrrolidin-1-yl)-2,2-di Fluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexane)ethanone (compound 1)

[0277] 2,2-Difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexane)acetic acid (87.83g) and Et 3 Ethyl chloroformate (30.8 mL) was added to a solution of N (122 mL) in THF (2000 mL), and stirred for 30 minutes. A THF (500 mL) solution of the compound (89.00 g) obtained in Example 1-(1) was added dropwise to the reaction mixture over 1 hour at room temperature, followed by stirring at room temperature for 20 hours. The reaction mixture was concentrated, AcOEt (2 L) and saturated NH 4 Cl aqueous solution (2L), after filtering the insoluble matter, the separated organic layer was washed with saturated aqueous sodium bicarbonate solution (2L), dried (MgSO 4 ), filtered, and concentrated to obtain a crude product (165.0 g). Follow the same method using 2,2-difluoro-2-(1-hydrox...

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PUM

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Abstract

Provided are novel compounds that bind to FKBP12 or pharmaceutically acceptable salts thereof, as well as new therapeutics useful in the prevention or treatment of alopecia which comprise those compounds or pharmaceutically acceptable salts thereof. Specifically, compounds represented by formula (1) [where R1 represents either the following formula (2) or (3)] or pharmaceutically acceptable salts thereof are provided.

Description

technical field [0001] The present invention relates to a novel compound bonded to FKBP12 or a pharmaceutically acceptable salt thereof, and a preventive or therapeutic agent for alopecia containing the same as an active ingredient. Background technique [0002] There are various types of hair loss such as androgenetic alopecia, senile alopecia, circular alopecia, and postmenopausal female alopecia. Most of them are not related to life or death, but they are often accompanied by mental pain due to their appearance problems, and excellent preventive or therapeutic agents for alopecia are expected. [0003] Hair changes through phases of growth, catagen, and telogen (hair cycle). This hair cycle generally takes 2 to 7 years for one cycle, and if this time is shortened due to any abnormality, the hair cannot grow sufficiently and the growth stops. As a result, the density of hair decreases and the thickness per hair decreases with the increase in the number of hairs removed. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04A61K31/4155A61K31/4196A61K31/422A61K31/4245A61K31/433A61K31/4439A61K31/506A61K31/5377A61P17/14C07D413/04C07D413/14C07D417/04
CPCC07D413/04A61K31/433C07D413/14C07D417/04A61K31/4155A61K31/4439C07D403/04A61K31/422A61K31/506A61K31/4245A61K31/5377A61K31/4196A61P17/00A61P17/14A61K31/42
Inventor 小野直哉黑田翔一白崎仁久高山哲男关口喜功牛山文仁冈裕辅
Owner TAISHO PHARMACEUTICAL CO LTD
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