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Diarylhydantoin compounds

A technology of compounds and mixtures, applied in the field of diarylhydantoin compounds, can solve problems such as time-consuming

Active Publication Date: 2008-07-16
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, for each compound prepared, time-consuming methods for determining the antagonistic and agonistic properties of the compound must be determined
That is, there is no method to accurately predict the properties of the relevant therapeutic prostate cancer from the chemical structure of the compound alone

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] 4-isothiocyanato-2-trifluoromethylbenzonitrile, (1a)

[0130] 4-Amino-2-trifluoromethylbenzonitrile (2.23 g, 12 mmol) was added dropwise to a well stirred solution of thiophosgene (1 ml, 13 mmol) in water (22 ml) over 15 minutes at room temperature. in a homogeneous mixture. Stir for an additional 1 hour. The reaction mixture was extracted with chloroform (3 x 15ml). The combined organic phases were dried over magnesium sulfate and evaporated to dryness under reduced pressure to give the desired product, 4-isothiocyanato-2-trifluoromethylbenzonitrile, (1a), as a brown solid , which was used directly in the next step (2.72 g, 11.9 mmol, 99%).

Embodiment 2

[0132] 2-1).(4-Aminophenyl)carbamate tert-butyl ester, (2a)

[0133] An aqueous solution of potassium carbonate (1.52 g, 11 mmol in 5 ml water) was added to a solution of 1,4-phenylenediamine (3.24 g, 30 mmol) in THF (30 ml) and DMF (10 ml). To this mixture was added dropwise di-tert-butyl dicarbonate (Boc 2 O) (2.18 g, 10 mmol), added dropwise over 0.5 h. The reaction mixture was stirred at room temperature for 4 hours. The mixture was then poured into cold water (40ml) and extracted with chloroform (3 x 50ml). The combined organic phases were dried over magnesium sulfate and concentrated to give a brown residue, which was purified by flash chromatography (dichloromethane / acetone, 4:1) to give tert-butyl (4-aminophenyl)carbamate, (2a ), as a yellow solid (1.98g, 9.5mmol, 95%) (based on Boc 2 O yield).

[0134] 2-2). Tert-butyl {4-[(1-cyano-1-methylethyl)amino]phenyl}carbamate, 2b

[0135] 2a (0.83g, 4mmol), acetone cyanohydrin (acetone cyanohydrin, 2-methyl-2-hydroxypro...

Embodiment 3

[0147] 3-1).2-(4-hydroxyphenylamino)-2-methylpropionitrile, 3a

[0148] 4-Aminophenol (1.09g, 10mmol), acetone cyanohydrin (10ml) and MgSO4 (2g) were heated to 80°C and stirred for 4 hours. After concentrating the mixture under vacuum, compound 3a was crystallized from water (20ml). The solid was filtered off and dried to give 2-(4-hydroxyphenylamino)-2-methylpropionitrile, 3a (1.69 g, 9.6 mmol, 96%).

[0149] 3-2).4-[3-(4-Hydroxyphenyl)-5-imino-4,4-dimethyl-2-thioimidazolidin-1-yl]-2-trifluoromethyl Benzonitrile, 3b

[0150] Triethylamine (0.101 g, 1 mmol) was added to a solution of 1a (0.456 g, 2 mmol) and 3a (0.352 g, 2 mmol) in dry THF (5 ml). The reaction mixture was stirred at 0 °C for 48 hours, then concentrated to give a black residue, which was purified by flash chromatography (dichloromethane / acetone, 85:15) to give 4-[3-(4-hydroxyphenyl )-5-imino-4,4-dimethyl-2-thioimidazolidin-1-yl]-2-trifluoromethylbenzonitrile, 3b (0.274 g, 0.68 mmol, 34%).

[0151] 3-3).4-[...

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Abstract

The present invention relates to diaryl hydantoin compounds, including diaryl thiohydantoins, as well as methods for their synthesis and use in the treatment of hormone-refractory prostate cancer.

Description

technical field [0001] The present invention relates to diarylthiohydantoins, including diarylthiohydantoins, methods of synthesizing them and their use in the treatment of hormone refractory prostate cancer. This application claims priority to US Provisional Application Serial Nos. 60 / 756,552, 60 / 750,351 and 60 / 680,835, which are hereby incorporated by reference. Background of the invention [0002] Prostate cancer is the most common cancer among Western men and the second leading cause of cancer death. When the cancer is localized, the disease can be cured with surgery or radiation. However, 30% of these cancers recur with distant metabolic disease and other conditions that are diagnostically serious. Severe disease is treated with castration and / or administration of antiandrogen substances, known as androgen deprivation therapy. Castration reduces circulating levels of androgens and decreases androgen receptor (AR) activity. Administration of antiandrogens blocks AR f...

Claims

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Application Information

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IPC IPC(8): A61K31/4184C07D235/02A61K31/4166C07D233/86
CPCC07C255/46C07C255/58C07C317/36C07C331/28C07D233/84C07D233/86C07D233/88C07D235/02C07D295/26C07D471/10C07D233/72A61P13/08A61P15/00A61P35/00A61P43/00A61P5/26A61P5/28A61K31/4184A61K31/4166A61K31/4164A61K31/4178C07D403/10
Inventor 查尔斯·L·索耶斯迈克尔·E·琼查利·D·陈萨梅迪·奥克德里克·韦尔斯比克里斯·特兰约翰·旺格维帕特刘东沅
Owner RGT UNIV OF CALIFORNIA
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