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Bridged ring piperazine derivatives or salts thereof, preparation method and use thereof

A derivative, piperazine technology, applied in the field of chemical medicine, can solve the problem of reduced ability of strain differentiation and the like

Active Publication Date: 2021-03-19
FUDAN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Littman et al. reported the role of RORγt in naive CD4 + It is necessary for T cells to differentiate into Th17 cells; during the differentiation of Thp cells stimulated by antigens to Th17 cells, the expression of RORγt is induced under the action of cytokines such as IL-6, IL-21 and TGF-β; from RORγt-deficient mice The ability of the isolated Thp cells to differentiate into Th17 cell lines is significantly reduced

Method used

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  • Bridged ring piperazine derivatives or salts thereof, preparation method and use thereof
  • Bridged ring piperazine derivatives or salts thereof, preparation method and use thereof
  • Bridged ring piperazine derivatives or salts thereof, preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0075] Example 1: N-(5-chloro-3-((8-(cyclopentanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)methyl Base)-2-methoxyphenyl)-6-methylnicotinamide

[0076] N-(5-chloro-3-((8-(cyclopentanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-2-methylphenyl)-6-methylnicotinamide

[0077]

[0078] Step 1: Preparation of 5-chloro-2-methyl-3-nitrobenzoic acid

[0079] At 0°C, 5-chloro-2-methylbenzoic acid (10g, 58.8mmol) was dissolved in concentrated sulfuric acid (98%, 150mL), the mixture was stirred at 0°C for 10 minutes, until the solid was dissolved, nitric acid (65%, 20mL) It was added dropwise into the solution, and after the dropwise addition was completed, the mixture was naturally warmed to room temperature and stirred for 5 hours. The reaction solution was poured into an ice-water mixture (500 mL), filtered, and the filter cake was washed with water (100 mL) to obtain 12.0 g of a light yellow solid with a yield of 95.2%. 1 H-NMR (400MHz, CDCl 3 )δ: 8.17 (s, 1H), 8.01 (s, ...

Embodiment 2

[0094] Example 2: N-(5-chloro-3-((8-(cyclopentanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)methyl Base)-2-methylphenyl)-3-aminobenzamide

[0095] N-(5-chloro-3-((8-(cyclopentanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-2-methylphenyl)-3-cyanobenzamide

[0096]

[0097] At 0°C, to a dichloromethane solution (5 mL) containing 6-methylnicotinic acid (88.2 mg, 0.6 mmol), 2 drops of a catalytic amount of DMF, and oxalyl chloride (152.4 mg, 1.2 mmol) were added dropwise. dichloromethane solution. After the dropwise addition was completed, it was raised to room temperature to react for 3 hours, and the solvent was evaporated to dryness under reduced pressure; at 0°C, the residue was dissolved in dichloromethane, and the solution containing (3-(3-amino-5-chloro-2-methyl Benzyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)(cyclopentyl)methanone (150mg, 0.4mmol) and dichlorotriethylamine (121.2mg, 1.2mmol) In methane solution (5 mL), the dropwise addition was completed, raised to ...

Embodiment 3

[0098] Example 3: N-(5-chloro-3-((8-(cyclopentanecarbonyl)-3,8-diazabicyclo[3.2.1]oct-3-yl)methyl Base)-2-methoxyphenyl)-2-methylpyrimidine-5-carboxamide

[0099] N-(5-chloro-3-((8-(cyclopentanecarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)methyl)-2-methylphenyl)-2-methylpyrimidine-5-carboxamide

[0100]

[0101] At 0°C, in a dichloromethane solution (5 mL) containing 2-methyl-5-pyrimidinecarboxylic acid (82.8 mg, 0.6 mmol), 2 drops of a catalytic amount of DMF, and oxalyl chloride (152.4 mg, 1.2 mmol) in dichloromethane solution; after the dropwise addition, rise to room temperature and react for 3 hours, evaporate the solvent to dryness under reduced pressure; at 0°C, after dissolving the residue with dichloromethane, add dropwise 5-Chloro-2-methylbenzyl)-3,8-diazabicyclo[3.2.1]oct-8-yl)(cyclopentyl)methanone (150mg, 0.4mmol) and triethylamine (121.2 mg, 1.2mmol) in dichloromethane solution (5mL), the dropwise addition was completed, and it was raised to room temperatur...

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Abstract

The invention belongs to the technical field of chemical medicines, and relates to a bridge ring piperazine derivative or salt thereof, a preparing method of the derivative and application of the bridge ring piperazine derivative or salt thereof in preparing medicines for treating ROR gamma t related diseases. Through experiments, the result shows that the bridge ring piperazine derivative can effectively restrain ROR gamma t protein receptors, adjust the differentiation of Th17 cells and restrain the generation of IL-17, can further be used as the treatment medicines for treating the ROR gamma t mediated inflammation related diseases and is particularly suitable for treating the inflammation related diseases such as disseminated sclerosis, rheumatoid arthritis, collagen induced arthritis,psoriasis, inflammatory bowel disease, encephalomyelitis, cloning diseases, asthma and cancers. The chemical formula can be seen in the description.

Description

technical field [0001] The invention belongs to the technical field of chemistry and medicine, and relates to a bridged piperazine derivative or a salt thereof and a preparation method thereof, and the use of the bridged piperazine derivative or a salt thereof in the preparation of a medicine for treating diseases related to RORγt . Background technique [0002] Currently known, 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 It mainly includes three members, RORα, RORβ and RORγ; there are two different subtypes of RORγ: RORγ1 and RORγt (also known as RORγ2), wherein 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. reported the role of RORγt in naive CD4 + It i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/08A61K31/4995A61P17/00A61P19/02A61P17/06A61P1/00A61P25/00A61P35/00A61P11/06
CPCC07D487/08
Inventor 王永辉田金龙郁明诚
Owner FUDAN UNIV
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