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Biaryl urea derivative as well as salt, preparation method and application thereof

A technology of biaryl urea and derivatives is applied in the field of biaryl urea derivatives and their preparation, and can solve the problems of reduced differentiation ability and the like

Active Publication Date: 2017-12-29
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Thp cells isolated from RORγt-deficient mice have significantly reduced ability to differentiate into Th17 cell lines

Method used

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  • Biaryl urea derivative as well as salt, preparation method and application thereof
  • Biaryl urea derivative as well as salt, preparation method and application thereof
  • Biaryl urea derivative as well as salt, preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0108] Example 1: 1-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-3-(4-(ethylsulfonyl) ) benzyl) urea

[0109] (1-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-3-(4-(ethylsulfonyl)benzyl)urea)

[0110]

[0111] Synthetic Intermediate 1: 2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-amine

[0112] Step 1: 2-Bromo-1,3-dichloro-5-nitrobenzene

[0113] Add 2,6-dichloro-4-nitroaniline (5g, 24mmol), copper bromide (16g, 72mmol) and acetonitrile (50mL) into the single-necked bottle, and add tert-butyl nitrite (7.46mL) dropwise under stirring in an ice bath. g, 72mmol), then stirred at room temperature and reacted for 6 hours. After the reaction was completed, water (100ml) was added, extracted with ethyl acetate (100mLx2), saturated sodium chloride (100mL), dried over anhydrous sodium sulfate, and concentrated under pressure to obtain an orange solid 6.3 grams, yield 97%;

[0114] Step 2: 4-Bromo-3,5-dichloroaniline

[0115] At room temperature, a...

Embodiment 2

[0125] Example 2: 1-([1,1'-biphenyl]-4-yl)-3-(4-(ethylsulfonyl)benzyl)urea

[0126] (1-([1,1'-biphenyl]-4-yl)-3-(4-(ethylsulfonyl)benzyl)urea)

[0127]

[0128] Add (4-(ethylsulfonyl)phenyl)methanamine (50mg, 0.30mmol), DCM (2mL), and DIEA (77.4mg, 0.6mmol) to a 25mL single-necked bottle and stir in an ice bath for 5 minutes, then add triphosgene ( 26mg, 0.10mmol, add 4-benzidine (60mg, 0.30mmol) after continuing the ice-bath reaction for 30 minutes, continue the ice-bath for 30 minutes, then react overnight at room temperature. Add H 2 O (10mL), extracted with dichloromethane (10mLx3), combined the organic layers, washed the organic layer with saturated sodium chloride (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried under reduced pressure to obtain a crude product, which was prepared with plate (petroleum ether: ethyl acetate = 1:1) to give white solid 1-([1,1'-biphenyl]-4-yl)-3-(4-(ethylsulfonyl)benzyl)urea 16 mg, yield 22.8%. 1 ...

Embodiment 3

[0129] Example 3: 1-(2-chloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-3-(4-(ethylsulfonyl)benzyl ) urea

[0130] (1-(2-chloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)-3-(4-(ethylsulfonyl)benzyl)urea)

[0131]

[0132] Step 1: 2-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-amine

[0133] Add 4-chloro-3-bromoaniline (500mg, 2.43mmol), 2-trifluoromethoxyphenylboronic acid (649mg, 3.15mmol), Pd 2 (dppf)Cl 2 (69mg, 0.12mmol), potassium carbonate (1.01g, 7.29mmol), acetonitrile / water (4ml / 1ml). Nitrogen gas was bubbled for 5 minutes, and then microwaved at 100°C for 2 hours. Wash with saturated ammonium chloride (20ml). Silica gel column separation (eluent petroleum ether: ethyl acetate = 10:1-5:1) to obtain yellow oil 2-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl Base]-4-amine 610mg, yield 88.5%. 1 H NMR (400MHz, CDCl 3 )δ7.42–7.35(m,1H),7.36–7.28(m,3H),7.06-7.04(d,J=8.2Hz,1H),6.81-6.80(d,J=1.9Hz,1H),6.64 -6.62(d,J=8.2Hz,1H),3.57(s,2H).MS(ESII)m / z:288.0(MH+)...

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Abstract

The invention belongs to the technical field of chemical medicines and relates to a biaryl urea derivative of formula I with RORgamma t inhibition activity, a preparation method of the derivative, and application of the derivative in preparing medicines for treating diseases related to RORgamma t. Tests show that the biaryl urea derivative can effectively inhibit RORgamma t protein receptors, so that differentiation of Th17 cells can be regulated and controlled, generation of IL-17 can be inhibited, treatment medicines for inflammation related diseases mediated by RORgamma t can be further prepared, and inflammation related diseases such as disseminated sclerosis, rheumatoid arthritis, collagen-induced arthritis, psoriasis, inflammatory bowel diseases, encephalomyelitis, clone diseases, asthma and cancer can be treated. The formula I is as shown in the specification.

Description

technical field [0001] The present invention belongs to the technical field of chemistry and medicine, and relates to a biaryl urea derivative having general formula I and a RORγt inhibitory activity and a preparation method thereof, and also relates to the use of the biaryl urea derivative compound in preparing and treating diseases related to RORγt. Use in medicine for disease. Background technique [0002] Retinoic acid receptor-related orphan receptors (retinoic acid receptor-related orphan receptors, RORs), also known as NF1R, is a member of the nuclear receptor superfamily of ligand-dependent transcription factors. The RORs subfamily mainly includes three members: RORα, RORβ and RORγ. There are two different subtypes of RORγ: RORγ1 and RORγt (also known as RORγ2), in which RORγ1 is distributed in skeletal muscle, thymus, testis, pancreas, prostate, heart and liver, etc., while RORγt is only expressed in certain immune cells . [0003] Littman et al. first reported R...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C317/32C07C311/47C07C311/51C07C311/08C07C381/10C07D213/71A61K31/44A61K31/17A61K31/18A61P19/02A61P29/00A61P17/06A61P1/00A61P11/06A61P35/00A61P25/00A61P43/00
CPCC07C311/08C07C311/47C07C311/51C07C317/32C07C381/10C07D213/71
Inventor 王永辉黄亚飞余发志唐婷
Owner FUDAN UNIV
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