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Pyrazolo-oxo-diaza compound as BTK inhibitor

A compound and pyrazolo technology are applied in the field of pyrazolo oxodiazepine compounds and their preparation, and can solve the problems of affecting drug efficacy and the like

Active Publication Date: 2021-03-23
LUNAN PHARMA GROUP CORPORATION
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In October 2014, Ibrutinib was approved for marketing by the EU EMA; in 2015, it was approved by the Japanese PMDA for the treatment of relapsed or refractory CLL; it has not yet been approved for marketing in China
Due to the limitations of the single-drug effect of BTK inhibitors, studies have found that the combination therapy of BTK inhibitors and certain targeted drugs or chemotherapy drugs may be better than single drugs, but the study found that the combination of ibrutinib and drugs has certain limitations After 6 months of combined treatment of CLL patients with ibrutinib and CD20 monoclonal antibody rituximab, most patients only developed PR; the new study shows that the ITK inhibitory activity of ibrutinib will affect its interaction with CD20 monoclonal antibody The efficacy of drug combination
The existing series of BTK target inhibitors have not completely solved the problems of patients' acquired resistance and drug side effects, so it is still necessary to continuously develop new drugs with BTK inhibitory activity in this field. In order to obtain more efficient and less toxic drugs, further prolong the survival time of patients and improve the quality of life

Method used

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  • Pyrazolo-oxo-diaza compound as BTK inhibitor
  • Pyrazolo-oxo-diaza compound as BTK inhibitor
  • Pyrazolo-oxo-diaza compound as BTK inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0114] Preparation of Compound 2

[0115]

[0116] The ethanol (1500 g) was added to ethanol (3000 mL), stirred at room temperature for 1 h, the reaction mixture was added to propennitrile (1280 g), the temperature control reflow reaction, the reaction was completed, the reaction liquid was lowered to 20 ° C, stirred into crystallization 2h, crystallization After the filtration, the filter cake was dried with 0 ~ 5 ° C ethanol (400 mL), dried at 35 ° C; dried to three bottles, poured into purified water (5000 mL), stirred at room temperature to dissolve, 5 mol / L hydrochloric acid is adjacent to 3 to 4, there is a white solid precipitation, after the washing is complete, filter, filter cake with purified water (500ml), whose white needle crystal, 35 ° C drying to constant weight, Intermediate compound 2, yield 82%, purity 97.2%.

Embodiment 2

[0118] Preparation of Compound 3

[0119]

[0120] Compound 2 (200 g) was added to purified water (500 mL), after stirring, hydrazine (50 mL) was added while stirring, and the reaction temperature reflux reaction was added, the reaction was completed, the reaction liquid was lowered to 0 ° C, analysis. After the crystal is completed, the filter cake is dried down to the constant weight of 35 ° C to constant weight, and the intermediate compound 3, the yield is 86%, and the purity is 98.1%.

Embodiment 3

[0122] Preparation of Compound 4

[0123]

[0124] NaOH (200 g) was added to purified water (500 mL), stirred, and the compound 3 (40 g) was added, and the temperature was refluxed for 10 h, the reaction was completed; the reaction liquid temperature was 0 to 10 ° C, drip 5 mol / L hydrochloric acid to regulate the solution pH Value to 3 ~ 4, there is a white solid precipitation, all precipitation, filtration, filter cakes 35 ° C to constant weight, and the white solid intermediate compound 4, yield 92%, purity 95.2%.

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PUM

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Abstract

The invention provides a pyrazolo-oxo-diaza compound with a remarkable inhibition effect on Bruton's tyrosine protein kinase (BTK) or a hydrate, a solvate, a prodrug, a stereoisomer or a tautomer of pharmaceutically acceptable salt of the pyrazolo-oxo-diaza compound. The invention also provides a process for preparing the compound of the invention and an intermediate compound which can be used inthe process. The compound provided by the invention can be used for preparing medicines for treating diseases related to disorder or imbalance of activity of Bruton's tyrosine kinase (BTK).

Description

Technical field [0001] The present invention belongs to the field of pharmaceutical chemistry, and more particularly to a pyrazole and oximotoxy compound compound of a BTK inhibitor and a preparation method thereof. Background technique [0002] Brundon tyrosine kinase (BTK) is a 75 kDa cytoplasmic prone kinase, which is widely expressed in hematopoietic cells. Immunocytes are generally divided into T cells and B cells, B cells secrete various antibodies to promote human body to resist various foreign invasions, BTK is necessary for B cell receptor signaling and B cell development. Brundon tyrosine kinase (BTK) is mainly expressed in B cells and myeloid cells, distributed in lymphatic systems, hematopoietic and blood systems, but also found lower levels of BTK expression in T cells and slurry cells. BTK is a member of the non-receptor protein tyrosine kinase TEC family, is a key kinase in the B cell antigen receptor (BCR) signaling pathway, and is a signal conduction molecule of ...

Claims

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Application Information

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IPC IPC(8): C07D487/04A61P35/00A61P35/02
CPCC07D487/04A61P35/00A61P35/02Y02P20/55
Inventor 张贵民王友国白文钦
Owner LUNAN PHARMA GROUP CORPORATION
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