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Diaryl hydantoin compound as androgen receptor antagonist and applications of diaryl hydantoin compound

A technology of compound and solvate, applied in diarylhydantoin compound as androgen receptor antagonist and its application field, can solve the problem of inability to prevent prostate cancer from developing to hormone resistance stage, inability to inhibit, ineffectiveness treatment of prostate cancer and other issues

Inactive Publication Date: 2015-02-11
NANJING HENGJIE BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although it suppresses AR in hormone-sensitive prostate cancer, it fails to suppress AR when the cancer becomes hormone-resistant
Because it cannot prevent prostate cancer from developing from a hormone-sensitive stage to a hormone-resistant stage, nor can it effectively treat hormone-refractory prostate cancer, these two shortcomings are the current bottlenecks in the treatment of anti-androgen substances

Method used

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  • Diaryl hydantoin compound as androgen receptor antagonist and applications of diaryl hydantoin compound
  • Diaryl hydantoin compound as androgen receptor antagonist and applications of diaryl hydantoin compound
  • Diaryl hydantoin compound as androgen receptor antagonist and applications of diaryl hydantoin compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0090] Example 1: N-Methyl-d3 -Synthesis of 2-fluoro-4-nitrobenzamide

[0091]

[0092] Thionyl chloride (0.15g, 1.3mmol) was added slowly to a solution of 2-fluoro-4-nitrobenzoic acid (0.20g, 1.10mmol) in DMF (5ml) cooled at -5°C. The mixture was stirred for another 1 hour at -5°C. An excess of deuterated methylamine (dissociated thermally from its hydrochloride with sodium hydroxide) is added to the reaction medium. This second mixture was stirred for an additional hour. Ethyl acetate (50ml) was added to the mixture which was washed with hydrochloric acid (2 x 50ml). MgSO for organic layer 4 Dry and concentrate to give N-methyl-d 3 -2-Fluoro-4-nitrobenzamide (0.16g, 0.75%).

[0093] 1 H NMR δ 6.31 (dd, 1H, J=13.5 and 2.1), 6.40 (dd, 1H, J=8.6 and 2.1), 7.64 (dd, 1H, J=8.6 and 8.6).

[0094] MS (ESI) m / z: 201.06.

Embodiment 2

[0095] Example 2: N-Methyl-d 3 -Synthesis of 2-fluoro-4-aminobenzamide

[0096]

[0097] N-methyl-d 3 - 2-Fluoro-4-nitrobenzamide (0.18g, 0.91mmol) and iron (0.31g, 5.60mmol) were refluxed in a mixture of ethyl acetate (5ml) and acetic acid (5ml) for 1 hour. Filter out solid particles. The filtrate was washed with water and extracted with ethyl acetate. The organic layer was dried, and column chromatography gave an off-white solid (0.14g, 92%).

[0098] 1 H NMRδ5.50 (br s, 2H), 6.37 (dd, 1H, J=14.7 and 2.1), 6.50 (dd, 1H, J=8.6 and 2.1), 7.06 (br s, 1H), 7.68 (dd, 1H , J=8.8 and 8.8).

[0099] MS (ESI) m / z: 171.09.

Embodiment 3

[0100] Example 3: Synthesis of N-methyl-d3-2-fluoro-4-(1,1-dimethyl-cyanomethyl)-aminobenzamide

[0101]

[0102] N-methyl-d 3 - A mixture of 2-fluoro-4-aminobenzamide (96mg, 0.57mmol), acetone cyanohydrin (0.3ml, 3.14mmol) and magnesium sulfate (50mg) was heated to 80°C and stirred for 12 hours. Ethyl acetate (25 ml) was added to the reaction solution, followed by washing with water. The organic layer was washed with MgSO 4 Dried and concentrated, purified by column chromatography to give N-methyl-d 3 -2-Fluoro-4-(1,1-dimethyl-cyanomethyl)-aminobenzamide (101 mg, 75%) as a white solid.

[0103] 1 H NMRδ1.74 (s, 6H), 6.58 (dd, 1H, J=14.6 and 2.3), 6.63 (dd, 1H, J=8.7 and 2.3), 6.66 (br s, 1H), 7.94 (dd, 1H, J=8.7 and 8.7).

[0104] MS (ESI) m / z: 238.13.

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PUM

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Abstract

The invention relates to diaryl hydantoin compounds of general formula (I), and derivatives, pharmaceutically acceptable salts and solvates of the diaryl hydantoin compounds, as well as applications thereof in treatment of hormone refractory prostate cancer and breast cancer. The structural formula is as shown in the description, wherein R1-R5, G and X are as defined in the description.

Description

technical field [0001] The present invention relates to novel diarylhydantoin compounds, their derivatives, pharmaceutically acceptable salts, hydrates or solvates, and their application in treating hormone-refractory prostate cancer and breast cancer. Background technique [0002] Prostate cancer is a common cancer in elderly men. In Western countries, the mortality rate of prostate cancer is second only to lung cancer. In China, there was little awareness of prostate cancer in the past, and the incidence of prostate cancer in China and even the entire Asian region was relatively low. With the advancement of screening and incidence, this data has been rising consistently. The incidence rate of prostate cancer is extremely low in men before the age of 45, and the incidence rate is high in elderly men. With the improvement of social living standards and medical conditions, the average life expectancy of the population has been significantly extended. The growth of the populat...

Claims

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Application Information

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IPC IPC(8): C07D233/86A61K31/4166A61P35/00
CPCC07D233/86
Inventor 张维威
Owner NANJING HENGJIE BIOTECH
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