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Biaryl urea carboxylic acid derivative or salt as well as preparation method and application thereof

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

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 carboxylic acid derivative or salt as well as preparation method and application thereof
  • Biaryl urea carboxylic acid derivative or salt as well as preparation method and application thereof
  • Biaryl urea carboxylic acid derivative or salt as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0098] Example 1: 4-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)benzene formic acid

[0099] (4-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)benzoic acid)

[0100]

[0101] Step 1: 4-((3-(2,6-Dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)benzoic acid methyl ester

[0102] Add 2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-amine (100mg, 0.31mmol), DCM (5mL) to a 25mL single-necked bottle, DIEA (120mg, 0.93mmol) was stirred in an ice bath for 5 minutes, then triphosgene (33mg, 0.11mmol) was added, and the ice bath reaction was continued for 30 minutes, then methyl 4-aminomethylbenzoate (56mg, 0.34mmol) was added to continue the reaction on ice Bath for 30 minutes, then react overnight at room temperature. Join H 2 O (10mL), extracted with dichloromethane (10mLx3), combined the organic layers, washed with saturated sodium chloride (10mL), dried over anhydrous sodium sulfate, filtered, a...

Embodiment 2

[0105] Example 2: 2-(4-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methanol base) phenyl) acetic acid

[0106] (2-(4-((3-(2,6-dichloro-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)phenyl)acetic acid)

[0107]

[0108] Step 1: 2-Bromo-1,3-dichloro-5-nitrobenzene

[0109]Add 2,6-dichloro-4-nitroaniline (5g, 24mmol), copper bromide (16g, 72mmol) and acetonitrile (50mL) into a single-necked bottle, add tert-butyl nitrite dropwise under stirring in an ice bath ( 7.46g, 72mmol), then stirred and reacted at room temperature 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, concentrated under pressure to obtain orange 6.3 g of solid, 97% yield.

[0110] Step 2: 4-Bromo-3,5-dichloroaniline

[0111] At room temperature, add 2-bromo-1,3-dichloro-5-nitrobenzene (1g, 4mmol), ethanol (6mL), tetrahydrofuran (1mL), con...

Embodiment 3

[0118] Example 3: 2-(4-((3-(2-chloro-6-cyano-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido )methyl)phenyl)acetic acid

[0119] (2-(4-((3-(2-chloro-6-cyano-2'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)ureido)methyl)phenyl)acetic acid)

[0120]

[0121] Step 1: 3-Chloro-5-cyano-2-bromobenzene

[0122] Add 2-amino-3-chloro-5-nitrobenzonitrile (3g, 15mmol), copper bromide (4g, 18mmol), acetonitrile (50mL) into a 25mL single-necked bottle, stir in an ice bath for 5 minutes, and weigh Amyl nitrite (6.76g, 57.8mmol) in acetonitrile (20mL) was added dropwise to the reaction solution under ice-cooling, and then continued to react in ice-bath for 30 minutes, then naturally warmed to room temperature, and reacted overnight. Add water (100mL), extract with ethyl acetate (100mLx3), wash with water (100mL), wash with saturated sodium chloride (100mL), dry over anhydrous sodium sulfate, and spin to dry the solvent. The crude product is separated on a silica gel column to obtain a yell...

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Abstract

The invention belongs to the technical field of chemical medicines and relates to a biaryl urea carboxylic acid derivative or a salt of the compound of formula I, as well as a preparation method, a medicinal composition and application of the compound in preparing medicines for treating diseases related to RORgamma t. Study results show that the compound 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 invention belongs to the technical field of chemical medicine, relates to a biaryl urea carboxylic acid derivative with general formula I and a RORγt inhibitory activity and a preparation method thereof, and also relates to the use of the biaryl urea carboxylic acid compound in the preparation of therapeutic Use of a drug for a disease associated with RORyt. 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 repor...

Claims

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Application Information

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IPC IPC(8): C07C275/32A61K31/17A61P25/00A61P19/02A61P29/00A61P17/06A61P1/00A61P11/06A61P35/00
CPCC07C275/32
Inventor 王永辉黄亚飞唐婷余发志
Owner FUDAN UNIV
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