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Benzidine compound and application thereof

A compound, benzidine technology, applied in the field of chemical medicine, can solve problems such as no good effect, few structural types of RORγ inhibitors, unpublished druggability data, etc.

Active Publication Date: 2019-06-14
GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] The research on RORγ has received extensive attention at home and abroad in recent years, but the structure types of RORγ inhibitors in the prior art are generally less
Although some compounds have entered the clinic, the specific druggability data has not yet been published
In addition, most of these small molecule inhibitors are effective in treating inflammation but not effective in treating cancers such as prostate cancer

Method used

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  • Benzidine compound and application thereof
  • Benzidine compound and application thereof
  • Benzidine compound and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] This example provides a benzidine compound: N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1 , 1'-biphenyl]-4-base)-2-(4-(methylsulfonyl)phenyl)acetamide, its preparation method comprises the steps:

[0056] (1) Preparation of 2-(4-amino-3-fluorophenyl)-1,1,1,3,3,3-hexafluoro-2-propanol with the following structure:

[0057]

[0058] Take difluoroaniline (6.0 g, 54 mmol), hexafluoroacetone trihydrate (12.5 g, 56.7 mmol) and p-toluenesulfonic acid (0.85 g, 5.4 mmol) in a pressure vessel. After vacuuming, heat to 90°C with argon protection and react overnight. Cool to room temperature, wash once with saturated sodium bicarbonate, and extract three times with ethyl acetate (3×50 mL). The organic layers were combined, washed once with saturated sodium chloride, dried over anhydrous sodium sulfate, and the organic phase was spin-dried in vacuo. The crude product was separated through a silica gel column (PE:EA=10:1) to obtain 4.45 g of a white solid (90...

Embodiment 2

[0074] This example provides a benzidine compound: 2-(4-(ethylsulfonyl)phenyl)-N-(2'-fluoro-4'-(1,1,1,3,3,3- Hexafluoro-2-hydroxypropane-2-yl)-[1,11,1'-biphenyl]-4-yl)acetamide, its preparation method comprises the steps:

[0075] Steps (1)-(4) are consistent with Example 1, and then step (5) is performed.

[0076] (5) Prepare 2-(4-(ethylsulfonyl)phenyl)-N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro- 2-Hydroxypropan-2-yl)-[1,11,1'-biphenyl]-4-yl)acetamide:

[0077]

[0078] Compound 2-(4-(ethylsulfonyl)phenyl)acetic acid (70.7 mg, 0.31 mmol), diisopropylethylamine (0.5 mL) and HATU (646.4 mg, 1.70 mmol) were dissolved in 20 mL of DCM. The reaction mixture was stirred at room temperature for 5 minutes, then the compound 2-(4'-amino-2-fluoro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3 , 3-hexafluoro-2-propanol (100mg, 0.28mmol), and the resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC. After the reaction was completed, water was added, extrac...

Embodiment 3

[0082] This example provides a benzidine compound: N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1 , 1'-biphenyl]-4-base)-2-(4-nitrophenyl)acetamide, its preparation method comprises the steps:

[0083] Steps (1)-(4) are consistent with Example 1, and then step (5) is performed.

[0084] (5) Preparation of N-(2'-fluoro-4'-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)-[1,1' -biphenyl]-4-yl)-2-(4-nitrophenyl)acetamide:

[0085]

[0086] Compound 2-(4-nitrophenyl)acetic acid (56.2 mg, 0.31 mmol), diisopropylethylamine (0.5 mL) and HATU (646.4 mg, 1.70 mmol) were dissolved in 20 mL of DCM. The reaction mixture was stirred at room temperature for 5 minutes, then the compound 2-(4'-amino-2-fluoro-[1,1'-biphenyl]-4-yl)-1,1,1,3,3 , 3-hexafluoro-2-propanol (100mg, 0.28mmol), and the resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC. After the reaction was completed, water was added, extracted with ethyl acetate (3×5...

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Abstract

The invention relates to a benzidine compound and application thereof. The benzidine compound has a structure disclosed in the following formula I. The invention also provides the pharmaceutically acceptable salt, the isomer, the raceme, the pro-drug cocrystallization compound, the hydrate and the solvate of the compound, and the application thereof for preparing medicines for treating or preventing ROR (Retinoid-related Orphan nuclear Receptor) gamma regulation and control relevant diseases. More importantly, the class of compound can be used for treating medicines used for treating inflammation, immunological diseases, cancers and neurological diseases.

Description

technical field [0001] The invention belongs to the technical field of chemistry and medicine, and in particular relates to a benzidine compound and an application thereof. Background technique [0002] Retinoic acid receptor-related orphan receptor (ROR) is an important class of orphan receptors in the nuclear receptor family. This receptor family includes 3 subtypes, RORα, RORβ and RORγ. RORα is widely expressed in liver, skeletal muscle, skin, lung, adipocyte tissue, kidney, thymus and brain. The RORβ expression site is very limited, only expressed in the central nervous system. RORγ is expressed in liver, skeletal muscle, and adipocyte tissues, especially in key cells in the immune system. [0003] In the past few years, RORα and RORγ have attracted extensive attention because of their important roles in the differentiation and development of T helper 17 (TH17) cells. Studies have found that TH17 cells are key regulators of immunopathology, thus modulating TH17 cell ...

Claims

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Application Information

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IPC IPC(8): C07C315/04C07C231/02C07C317/44C07C233/29C07C237/20C07C233/25A61P29/00A61P37/02A61P35/00A61P35/02A61P25/00A61P19/02A61P17/06A61P11/06A61P15/00A61P13/02A61P17/16A61P11/02A61P11/00A61P9/00A61P13/12A61P1/16A61P1/00A61P17/00A61P1/02A61P1/18A61P37/08A61P1/04A61P37/06A61P17/14A61P7/06A61P7/00A61P9/10A61P25/16A61P25/28A61P3/10A61P31/00A61P21/04A61P31/22A61P31/20A61P31/14A61K31/167
CPCA61K31/167A61P1/00A61P1/02A61P1/04A61P1/16A61P1/18A61P3/10A61P7/00A61P7/06A61P9/00A61P9/10A61P11/00A61P11/02A61P11/06A61P13/02A61P13/12A61P15/00A61P17/00A61P17/06A61P17/14A61P17/16A61P19/02A61P21/04A61P25/00A61P25/16A61P25/28A61P29/00A61P31/00A61P31/14A61P31/20A61P31/22A61P35/00A61P35/02A61P37/02A61P37/06A61P37/08C07C233/25C07C233/29C07C237/20C07C317/44
Inventor 许永张岩吴锡山薛晓纤罗小雨师语聃王蕊
Owner GUANGZHOU INST OF BIOMEDICINE & HEALTH CHINESE ACAD OF SCI
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