Antagonist for mutated androgen receptor

A technology of resistance and castration resistance, which can be used in anti-tumor drugs, endocrine system diseases, urinary system diseases, etc., and can solve problems such as no disclosure or revelation, and ineffective AR antagonists.

Inactive Publication Date: 2013-06-26
ASTELLAS PHARMA INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] (3) exhibit resistance to an AR antagonist (usually bicalutamide), which becomes ineffective
[0010] (5) Also showed resistance to docetaxel and became ineffective
[0032] Various compounds are disclosed in Patent Document 1 and Patent Documents 4 to 8 as compounds effective against mutant AR. However, there is neither disclosure nor suggestion regarding the problem that AR antagonists effective against wild-type AR In the case that the drug is ineffective due to certain specific AR mutations, how to change the chemical structure of the ineffective AR antagonist so as to obtain a compound that has an effective anticancer effect on the specific mutant AR, that is, a mutant AR antagonist

Method used

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  • Antagonist for mutated androgen receptor
  • Antagonist for mutated androgen receptor
  • Antagonist for mutated androgen receptor

Examples

Experimental program
Comparison scheme
Effect test

preparation example 1

[0183] To a mixture of potassium tert-butoxide (505 mg) and THF (5 ml) was added dropwise ethanol (0.264 ml) under ice-cooling, followed by stirring at room temperature for 30 minutes. The reaction solution was ice-cooled, a mixture of 4-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-2-fluorobenzonitrile (350mg) and THF (3ml) was added dropwise, and Stir at room temperature for 16 hours. Ethyl acetate (20 ml) and water (10 ml) were added to the reaction solution for liquid separation, and the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform / methanol=100 / 0-96 / 4) to obtain 4-[(2S,5R)-2,5-dimethylpiperazin-1-yl]-2- Ethoxybenzonitrile 315mg (81%). ESI+: 260

preparation example 2

[0185] To a mixture of piperazin-2-one (5.06g) and DMF (50ml) was added triethylamine (8ml) and 2-chloro-4-fluorobenzonitrile (8.1g) and stirred at 80°C for 1 day . Water was added to the reaction solution, and the precipitated solid was filtered, and washed with water and diisopropyl ether to obtain 11.2 g (94%) of 2-chloro-4-(3-oxopiperazin-1-yl)benzonitrile. EI+: 235

preparation example 3

[0187] To a mixture of 2-chloro-4-(3-oxopiperazin-1-yl)benzonitrile (11.2g) and DMF (160ml) was added sodium hydride (2.2g, 55% liquid paraffin dispersion), in After stirring at room temperature for 10 minutes, benzyl bromide (6 ml) was added and stirred at room temperature for 1 hour. Add water to the reaction solution, filter the precipitated solid, then wash with water and diisopropyl ether to obtain 12.74 g of 4-(4-benzyl-3-oxopiperazin-1-yl)-2-chlorobenzonitrile (82%). EI+: 325

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Abstract

To provide a novel anticancer drug which is useful for treating prostatic cancer associated with an androgen receptor mutation. [Solution] As the results of intensive studies on mutated androgen-associated diseases for which the conventional anti-androgen drugs are inefficacious, the present inventors found that a compound, said compound being the active ingredient of a medicinal composition according to the present invention, exhibits an effect of inhibiting the transcriptional activation in a human mutated androgen receptor (AR) and has an excellent antitumor effect on a mouse carrying human prostatic cancer cells, thereby completing the present invention. The compound that is the active ingredient of the medicinal composition according to the present invention is useful for treating diseases such as prostatic cancer in which a series of androgen receptors participate.

Description

technical field [0001] The present invention relates to a pharmaceutical composition, and in particular to an anticancer agent useful for the treatment of prostate cancer accompanied by androgen receptor mutation (AR mutation). Background technique [0002] The prostate is an organ unique to men, and among prostate diseases, prostate cancer has become a major social problem. Prostate cancer is one of the most frequent malignant tumors among male malignant tumors in Europe, America and other countries, accounting for about 20% of male cancer deaths. In addition, the incidence of prostate cancer increases with age, so increasing age is an important risk factor. Prostate cancer research is considered to be of great significance to an aging society in the future. [0003] Since most prostate cancers (approximately more than 80%) show androgen-dependent proliferation, GnRH (Gonadotropin releasing hormone) analogues or androgen receptor ( Androgen receptor, hereinafter referred...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12A61K31/496A61K31/506A61P5/26A61P35/00C07D403/12
CPCA61K31/496A61K31/506C07D401/12C07D403/12A61P13/08A61P35/00A61P5/26C07D401/02C07D401/14C07D403/02
Inventor 出山行孝黑光贞夫古谷崇武田正敬小长井智史山田知广谷口伸明近藤裕平野祐明渡边和志菅根隆史挂札昭夫
Owner ASTELLAS PHARMA INC
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