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Pyridine N-oxidation derivative as well as preparation method and application thereof

A technology of derivatives and compounds, used in drug combination, organic chemistry, digestive system, etc.

Active Publication Date: 2019-07-23
SHANGHAI HANSOH BIOMEDICAL +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] BRD4 inhibitors have good application prospects as drugs in the pharmaceutical industry. There are no drugs on the market. In order to achieve better therapeutic effects and meet market demand, we hope to develop a new generation of selective BRD4 with high efficiency and low toxicity. Inhibitor

Method used

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  • Pyridine N-oxidation derivative as well as preparation method and application thereof
  • Pyridine N-oxidation derivative as well as preparation method and application thereof
  • Pyridine N-oxidation derivative as well as preparation method and application thereof

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Experimental program
Comparison scheme
Effect test

Embodiment

[0216] Compound structures were determined by nuclear magnetic resonance (NMR) or mass spectroscopy (MS). The mensuration of NMR is to use BrukerAVANCE-400 nuclear magnetic instrument, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), the internal standard is tetramethylsilane (TMS), and the chemical shift is 10 -6 (ppm) is given as a unit.

[0217] MS was determined with a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQadvantage MAX).

[0218] The determination of HPLC uses Agilent 1200DAD high pressure liquid chromatography (Sunfire C18 150×4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150×4.6mm chromatographic column).

[0219] Kinase average inhibition rate and IC 50 Values ​​were measured with a NovoStar microplate reader (BMG, Germany).

[0220] Use Yantai Huanghai HSGF254 or Qingdao GF254 silica gel...

Embodiment 1

[0302] 4-(2-(2,4-difluorophenoxy)-5-(ethylsulfonylamino)phenyl)-2,6-lutidine 1-oxidation

[0303]

[0304] The first step: the preparation of 2,6-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine

[0305]

[0306] 4-bromo-2,6-lutidine (1.0g, 5.38mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'- Bi(1,3,2-dioxaborolane) (1.6g, 6.45mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (393mg, 0.54mmol) , Potassium acetate (1.6g, 16.12mmol) was dissolved in 1,4-dioxane (15mL), replaced with nitrogen, heated to 85°C and stirred overnight. LC / MS detected that the reaction was complete. Water (50 mL) was added to the reaction solution, extracted with ethyl acetate (60 mL), the organic phase was washed with saturated brine (50 mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain 2,6-dimethyl- 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.2 g, 95.3% yield).

[0307] MS m / z(ESI):234.1[M+H] + .

[0308] The second st...

Embodiment 2

[0330] Preparation of 4-(5-(ethylsulfonylamino)-2-((4-fluorophenyl)amino)phenyl)-2,6-lutidine by 1-oxidation

[0331]

[0332] Using 4-(2-fluoro-5-nitrophenyl)-2,6-lutidine as the starting material, replacing 2,4-difluorophenol with 4-fluoroaniline, the preparation steps refer to Example 1, 4-(5-(ethylsulfonylamino)-2-((4-fluorophenyl)amino)phenyl)-2,6-lutidine 1-oxidation (20.0mg, yield 24.5%) .

[0333] 1 H NMR (400MHz, CDCl 3 )δ:7.28(s,2H),7.38(m,3H),7.00(d,J=6.4Hz,4H),6.42(s,1H),5.52(s,1H),3.13(q,J=7.2 Hz, 2H), 2.55(s, 6H), 1.41(t, J=7.2Hz, 3H).

[0334] MS m / z(ESI):416.1[M+H] + .

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Abstract

The invention relates to a pyridine N-oxidation derivative as well as a preparation method and an application thereof, in particular to a compound shown in a general formula (I), a preparation methodof the compound, pharmaceutical composition containing the compound and an application of the compound as a BRD4 inhibitor in treating related diseases such as cancer, inflammation, chronic liver diseases, diabetes, cardiovascular diseases, AIDS and the like, wherein in the general formula (I), all substituent groups are the same as definitions in the description.

Description

technical field [0001] The invention belongs to the field of medicine, and relates to a BRD4 inhibitor, its preparation method and the application of its pharmaceutical composition in medical research. The invention discloses that it is used as a BRD4 inhibitor in the treatment of cancer, inflammation, chronic liver disease, diabetes, cardiovascular disease and AIDS and other related diseases. Background technique [0002] Tumor is one of the major diseases that seriously endanger human life, and more than half of it occurs in developing countries. The incidence of malignant tumors in my country is generally on the rise, and the incidence rate is increasing at an average annual rate of 3% to 5%. It is estimated that by 2020, 4 million people in my country will develop cancer and 3 million people will die of cancer. The main reasons are: Aging, urbanization, industrialization and changes in living habits. In the Chinese hospital drug market, the sales scale of antineoplastic...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/89C07D401/12C07D405/04C07D498/04C07D471/04C07D401/10C07D487/04A61K31/4425A61K31/4439A61K31/444A61K31/4427A61K31/4545A61K31/5365A61K31/437A61K31/519A61P35/00A61P29/00A61P1/16A61P3/10A61P9/00A61P25/28A61P35/02A61P31/04A61P11/00A61P43/00
CPCC07D213/89C07D401/12C07D405/04C07D498/04C07D471/04C07D401/10C07D487/04A61P35/00A61P29/00A61P1/16A61P3/10A61P9/00A61P25/28A61P35/02A61P31/04A61P11/00A61P43/00
Inventor 野国中刘磊包如迪吴盛华邓海宁
Owner SHANGHAI HANSOH BIOMEDICAL
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