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Diaryl hydantoin derivative, as well as preparation method, medicine composition and application thereof

A technology of hydantoin and diaryl group, applied in the field of medicinal chemistry, can solve problems such as weak antagonistic activity

Inactive Publication Date: 2015-02-11
SHANGAI PHARMA GRP CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to increased expression of AR and mutation of AR, the existing anti-prostate cancer drugs have only weak antagonistic activity.

Method used

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  • Diaryl hydantoin derivative, as well as preparation method, medicine composition and application thereof
  • Diaryl hydantoin derivative, as well as preparation method, medicine composition and application thereof
  • Diaryl hydantoin derivative, as well as preparation method, medicine composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] 4-[4,4-Dimethyl-3-(1-methyl-1H-indazol-5-yl)-5-oxo-2-thio-imidazolin-1-yl]-2-tri Preparation of fluoromethyl-benzonitrile (compound I-1)

[0112]

[0113] The first step: the preparation of 2-methyl-2-(1-methyl-1H-indazol-5-ylamino)-propionitrile

[0114] Dissolve 5-amino-1 methylindazole (280mg, 1.9mmol) in acetone (10mL), add trimethylsilyl cyanide (725uL, 5.7mmol) and a few drops of acetic acid, place in a sealed tube, and heat to 90 °C and kept stirring at constant temperature overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, diluted with water, extracted with ethyl acetate (50mL×3), the ethyl acetate layer was washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered, concentrated to obtain the crude product, and flash column chromatography Analysis and separation (petroleum ether: ethyl acetate = 1:1) gave 2-methyl-2-(1-methyl-1H-indazol-5-ylamino)-propionitrile. MS m...

Embodiment 2～ Embodiment 5

[0118] According to the same method as in Example 1, the compounds of Examples 2 to 5 were prepared, and the specific chemical structure identification data are shown in Table 1.

[0119] Table 1 Chemical structure identification data table of compound I-2~compound I-5

[0120]

Embodiment 6

[0122] 4-[3-(1-Ethyl-1H-indazol-5-yl)-4,4-dimethyl-5-oxo-2-thio-imidazolin-1-yl]-2-tri Preparation of fluoromethyl-benzonitrile (compound I-6)

[0123]

[0124] The first step: the preparation of 1-ethyl-1H-indazol-5-ylamine

[0125] Dissolve 1-ethyl-5-nitro-1H-indazole (5g, 26.2mmol) in ethanol (50mL), add water (50mL), heat to 90°C, add solid ammonium chloride (6g, 112mmol) and reduced iron powder (6g, 107mmol), the resulting solution was stirred for 1 hour. After hot filtration, the filtrate was concentrated and flash column chromatographed (petroleum ether: ethyl acetate = 3:1) to obtain 1-ethyl-1H-indazol-5-ylamine (3 g, pink solid). 1 H NMR (400MHz, CDCl 3 ):δ7.80(s,1H),7.27(m,1H),6.96(s,1H),6.90(m,1H),4.39(q,2H,J=7.2Hz),1.51(t,3H, J = 7.2 Hz). MS m / z (ESI): 162.1 [M+H].

[0126] The second step: the preparation of 2-(1-ethyl-1H-indazol-5-ylamino)-2-methyl-propionitrile

[0127] Dissolve 5-amino-1-ethylindazole (1.5g, 9.3mmol) in acetone (15mL), add trimethylsi...

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Abstract

The present invention discloses a diarylhydantoin derivative, and preparation method, pharmaceutical composition, and application thereof. The present invention provides a diarylhydantoin derivative as represented by formula I, a pharmaceutically acceptable salt, solvate, metabolite, stereoisomer, tautomer, polymorph, or prodrug thereof; the diarylhydantoin derivative of the present invention has good performance in treatment of diseases related to androgen receptors, in particular, castration-resistant prostate cancer.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to diarylhydantoin derivatives, their preparation methods, pharmaceutical compositions and applications. Background technique [0002] The androgen receptor (AR) is a 110,000 Dalton (110 KDa) protein and a member of the steroid receptor. Like other steroid receptors, AR contains three domains: an N-terminal domain, a centrally located DNA-binding site and a domain containing the nuclear transfer signal, and a C-terminal domain containing the ligand-binding site. The N-terminal domain contains a transcriptional functional site called activation function 1, which itself can activate the transcription of the target gene without the need for other structural regions. The C-terminus contains a transcription site called activation function 2, which can activate the transcription of its target gene under the activation of its ligand. AR without ligand binding is mainly distributed in t...

Claims

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Application Information

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IPC IPC(8): C07D403/04C07D401/04C07D405/14C07D471/04C07D417/04C07D401/14A61K31/5377A61K31/4439A61K31/4725A61K31/444A61K31/517A61K31/4178A61K31/549A61K31/437A61K31/4184A61P35/00A61P13/08A61P17/14A61P17/00A61P21/00A61P15/08A61P19/10A61P3/06A61P3/04A61P7/06A61P25/24
CPCC07D401/04C07D401/14C07D403/04C07D405/14C07D417/04C07D471/04A61P3/04A61P3/06A61P7/06A61P13/08A61P15/08A61P15/10A61P17/00A61P17/10A61P17/14A61P19/10A61P21/00A61P25/24A61P35/00
Inventor 万惠新夏广新沈竞康许志勇许振民石辰马珂段文虎林逸鹏姚珊燕
Owner SHANGAI PHARMA GRP CO LTD
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