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Pyrimidine derivative, preparation method and applications thereof

A technology of pyrimidine derivatives and pharmaceutical preparations, applied in the field of medicine, can solve problems such as the decrease in the number of red blood cells and white blood cells, and the increase in cholesterol levels

Active Publication Date: 2016-03-16
SHENZHEN CHIPSCREEN BIOSCIENCES CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, Xeljanz has side effects including a decrease in the number of red blood cells and white blood cells and an increase in cholesterol levels, which may be related to its high JAK2 inhibitory activity (ZakM., etal.2012, J.Med.Chem., 55:6176-6193)

Method used

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  • Pyrimidine derivative, preparation method and applications thereof
  • Pyrimidine derivative, preparation method and applications thereof
  • Pyrimidine derivative, preparation method and applications thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0079] Preparation of embodiment 12-fluoro-N-methyl-5-nitroaniline

[0080]

[0081] 2-Fluoro-5-nitroaniline (20.0g, 128.2mmol) and paraformaldehyde (16.0g, 533.3mmol) were dissolved in 500mL methanol and stirred at room temperature, then a methanol solution of NaOMe (3.4g, 63mmol) was added dropwise 100mL, the reaction solution was stirred at room temperature for 16 hours and then added NaBH 4 (9.7g, 255.2mmol), stirred for 15 minutes, followed by LCMS. After the reaction, it was poured into 1M KOH aqueous solution, the solid was precipitated by stirring, and the yellow solid 2-fluoro-N-methyl-5-nitroaniline (19.0 g, 87% yield) was obtained by filtration. LC-MS (m / z) 171 (M+1).

Embodiment 2

[0082] The preparation of embodiment 2N-(2-fluoro-5-nitrophenyl)-N-methacrylamide

[0083]

[0084] 2-Fluoro-N-methyl-5-nitroaniline (11.0g, 64.7mmol) and DIPEA (23mL, 129.4mmol) were dissolved in 100mL THF and stirred at room temperature, then acryloyl chloride (11mL, 129.4mmol) was added dropwise, The reaction solution was stirred at room temperature for 1 hour, and most of the solvent was evaporated, diluted with 100 mL of ethyl acetate, washed with saturated brine, dried, filtered, and distilled under reduced pressure to obtain N-(2-fluoro-5-nitro Phenyl)-N-methacrylamide (12.0 g, 83% yield). LC-MS (m / z) 225 (M+1).

Embodiment 3

[0085] The preparation of embodiment 3N-(5-amino-2-fluorophenyl)-N-methacrylamide

[0086]

[0087] Iron powder (20.0g, 357mmol) and NH 4 Cl (20.0g, 374mmol) was dissolved in 200mL water and heated to 80°C and stirred for half an hour, then N-(2-fluoro-5-nitrophenyl)-N-methacrylamide (12g, 53.6mmol) was added in acetic acid Ethyl ester solution 20mL. The reaction solution was stirred at 80°C for 1 hour and then NaHCO was added 3 The aqueous solution was adjusted to alkali, the iron sludge was filtered, the filtrate was extracted with ethyl acetate, and the combined organic phases were distilled under reduced pressure to obtain a brown oily substance N-(5-amino-2-fluorophenyl)-N-methacrylamide (5.6g, 54 %yield). LC-MS (m / z) 195 (M+1).

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PUM

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Abstract

The present invention provides a pyrimidine derivative represented by a formula (I) or a pharmaceutically acceptable salt thereof, a preparation method and applications thereof, wherein the pyrimidine derivative represented by a formula (I), or pharmaceutically acceptable salt thereof has JAK kinase inhibition activity, particularly provides selective and high inhibition activity on JAK3 kinase, can be used for preparation of a JAK3 kinase inhibitor, and can be used for preparation of drugs for prevention or treatment of diseases associated with abnormal JAK3 kinase activity so as to prevent or treat diseases associated with abnormal JAK3 kinase activity. The formula (I) is defined in the specification.

Description

technical field [0001] The invention relates to the technical field of medicines, in particular to a pyrimidine derivative, its preparation method and its application. Background technique [0002] In 2002, Manning et al. determined that the human kinome includes 518 protein kinase genes, of which 218 enzyme genes are closely related to the occurrence and development of human diseases (Manning G., et al. 2002, Science, 298:1912-1934). Among the drugs discovered so far, the drugs targeting enzymes account for as much as 20%, especially those targeting protein kinases have special value in clinical application. [0003] Protein kinases are a class of intracellular messenger-dependent enzymes that catalyze the phosphorylation of specific proteins and complete the signal transmission process, mainly including tyrosine protein kinases, such as JAKs, Src, Abl, EGFR, FGFR, PDGFR, etc.; serine / threonine Acid protein kinases, such as PKC, MAPK, Rho kinase, etc.; dual-specificity pro...

Claims

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Application Information

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IPC IPC(8): C07D239/48C07D401/12A61K31/505A61K31/506A61P37/00A61P29/00A61P35/00A61P19/08A61P37/06A61P19/02A61P25/00A61P3/10A61P17/06A61P37/08A61P11/06A61P11/00A61P35/02
Inventor 鲁先平余金迪杨千姣李志斌潘德思山松朱江飞王祥辉刘湘衡宁志强
Owner SHENZHEN CHIPSCREEN BIOSCIENCES CO LTD
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