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Biaryl hydantoin derivate and preparation method, medicine composition and application thereof

A technology of compounds and prodrugs, applied in the field of medicinal chemistry, can solve problems such as weak antagonistic activity

Active Publication Date: 2014-05-21
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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  • Biaryl hydantoin derivate and preparation method, medicine composition and application thereof
  • Biaryl hydantoin derivate and preparation method, medicine composition and application thereof
  • Biaryl hydantoin derivate and preparation method, medicine composition and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 14

[0112] Example 14-Isothiocyanato-2-trifluoromethylbenzonitrile (Intermediate 2)

[0113]

[0114]4-Amino-2-trifluoromethylbenzonitrile (10.0 g, 53.8 mmol) was added to n-hexane (22.5 mL) and water (25.0 mL), and the mixture was stirred at room temperature for 8 minutes after the addition. Under an ice bath, thiophosgene (4.5 mL, 58.5 mmol) was added dropwise to the above mixed system, and after the addition was completed, it was placed at room temperature and stirred overnight. Filter, wash the solid with n-hexane (2×25.0 mL), discard the solid, evaporate the filtrate to one-fifth of the original volume under reduced pressure, and place it in a refrigerator at 4°C overnight. After filtration, the solid was dried under high vacuum to obtain 11.0 g of white solid with a yield of 81%. 1 H NMR (CDCl 3 ,300MHz)δ(ppm)7.84(d,J=8.4Hz,1H),7.59(d,J=1.8Hz,1H),7.49(dd,J 1 =8.4Hz,J 2 =1.8Hz,1H).

Embodiment 2

[0115] Example 22-methyl-4-nitrobenzoic acid methyl ester

[0116]

[0117] In an ice bath, SOCl 2 (4.8mL, 66.2mmoL) was added dropwise into anhydrous methanol (100mL). Then, a solution of 2-methyl-4-nitrobenzoic acid (10.0 g, 55.2 mmol) in anhydrous methanol (70 mL) was added dropwise, and the addition was completed in 1 hour. The mixed system was reacted in an oil bath at 70°C for 7 hours, and the reaction was complete as detected by TLC. After cooling, the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL), saturated sodium bicarbonate (100 mL) was added, the layers were separated, and the aqueous phase was extracted once with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, the solvent was evaporated under reduced pressure, and dried under high vacuum to obtain 10.5 g of a white solid with a yield of 98%. 1 H NMR (CDCl 3 ,300MHz)δ(ppm)8.10-8.01(m,3H),3.95(s,3H)...

Embodiment 3

[0118] Example 32-(bromomethyl)-4-nitrobenzoic acid methyl ester

[0119]

[0120] Add 2-methyl-4-nitrobenzoic acid methyl ester (200mg, 1.0mmoL), benzoyl peroxide (48.5mg, 0.2mmoL), N-bromosuccinimide (213mg, 1.2mmoL) to CCl 4 (15mL), under the protection of Ar gas, heated and refluxed for 7 hours, cooled, washed with saturated sodium bicarbonate (3×20mL) and saturated brine (20mL) successively, evaporated the solvent under reduced pressure, and the residue was washed with a flash column Chromatographic separation, the eluent was PE:EA=20:1, and 124 mg of white solid was obtained with a yield of 44%. 1 H NMR (CDCl 3 ,300MHz)δ(ppm)8.34-8.01(m,3H),4.97(s,2H),4.00(s,3H).

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Abstract

The invention provides a compound as shown in a Formula I or salts, solvent compounds, pre-drugs, stereoisomers, tautomers, polymorphic forms or metabolites thereof that are acceptable pharmaceutically, a medicine composition containing the same and an application thereof in preparation of medicines for treating male hormone receptor relevant diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a class of diarylhydantoin derivatives, a preparation method, a pharmaceutical composition and a medical application thereof. Background technique [0002] Androgen receptor (androgen recepror, AR) is a 110,000 Dalton (110KDa) protein and a member of the steroid receptor (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...

Claims

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Application Information

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IPC IPC(8): C07D403/04C07D491/107C07D471/04C07D401/04A61K31/4178A61K31/4184A61K31/496A61K31/4709A61K31/437A61P35/00A61P19/10A61P13/08A61P17/00A61P17/10A61P17/14A61P15/10A61P15/00A61P25/24
CPCC07D401/04C07D403/04C07D471/04C07D491/107A61P5/28A61P13/08A61P15/00A61P15/10A61P17/00A61P17/10A61P17/14A61P19/10A61P25/24A61P35/00
Inventor 段文虎万惠新夏广新梅德盛林逸鹏刘学军沈竞康
Owner SHANGAI PHARMA GRP CO LTD
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