Protein tyrosine kinase modulators salt, crystallographic forms, and uses thereof

A technology of crystal form and use, applied in the field of composition, can solve problems such as infeasibility

Inactive Publication Date: 2019-02-05
BETTA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0024] Despite considerable technological progress, the main limitation of this technique remains the possibility to obtain the crystalline form to be analyzed with a suitable size and with a limited number of defects, which is not always easy or even infeasible

Method used

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  • Protein tyrosine kinase modulators salt, crystallographic forms, and uses thereof
  • Protein tyrosine kinase modulators salt, crystallographic forms, and uses thereof
  • Protein tyrosine kinase modulators salt, crystallographic forms, and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0147] The preparation of embodiment 1 crystal form A

[0148] The free base was prepared by the method described in Example 74 of WO2015 / 003658.

[0149] 350 mg of free base and 70.1 mg of succinic acid were added to a 20 ml glass vial, then 10 ml of EtOAc was added to the glass vial. The mixture was stirred at RT for about 24 hours, then the wet cake was filtered and dried at 50 °C under reduced pressure to afford 314 mg of Form A. MS: m / z 710.3, mp: about 142.0°C. .

[0150] 1 H NMR (400MHz,DMSO)δ=11.36(s,1H),9.03(s,1H),8.83(s,1H),8.63(s,1H),8.26(s,1H),8.08(s,1H) ,7.63(d,J=6.7,1H),7.52(d,J=8.2,1H),7.15(t,J=7.5,1H),6.88(s,1H),6.61(dd,J=17.0,10.2 ,1H),6.17(d,J=17.0,1H),5.71(d,J=10.9,1H),3.78(s,4H),3.01(s,4H),2.90(s,8H),2.61(s ,4H), 2.41(s,5H), 2.30(s,3H), 0.85(d,J=6.6,0H).

Embodiment 2

[0151] The preparation of embodiment 2 crystal form A

[0152] The free base was prepared by the method described in Example 74 of WO2015 / 003658.

[0153] 350 mg free base and 70.1 mg succinic acid were added to a 100 ml glass vial, then 20 ml EtOAc was added to the glass vial. The mixture was stirred at RT for about 96 hours, then the wet cake was filtered and dried at 50 °C under reduced pressure to yield 317 mg of Form A. MS: m / z 710.3, mp: about 141.0°C-143.0°C.

Embodiment 3

[0154] The preparation of embodiment 3 crystal form A

[0155] The free base was prepared by the method described in Example 74 of WO2015 / 003658.

[0156] About 340.1 g of free base and 71.1 g of succinic acid were charged to the reactor, and then 27.2 L of acetone was added to the reactor. The mixture was stirred at 50°C for about 8 hours, cooled to room temperature, then the wet cake was filtered and dried under reduced pressure at 50°C to obtain 285.6 g of Form A. MS: m / z 710.3, mp: about 141.0°C-143.0°C.

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Abstract

The invention relates to N-(5-(5-chloro-4-(2-(2-(dimethylamino)-2-oxoacetyl)phenylamino) pyrimidin-2-ylamino)-4-methoxy-2-(4-methylpiperazin-1-yl)phenyl) acrylamide succinate (the compound of FormulaI) and new crystalline forms thereof, processes for their preparation, their uses in therapy and the pharmaceutical compositions containing them.

Description

technical field [0001] The present invention relates to N-(5-(5-chloro-4-(2-(2-(dimethylamino)-2-oxoacetyl)phenylamino)pyrimidin-2-ylamino)-4-methoxy Base-2-(4-methylpiperazin-1-yl)phenyl)acrylamide succinate and new crystal form thereof, compound, preparation method of new crystal form and pharmaceutical composition thereof, compound for regulating kinase , novel crystal forms and pharmaceutical compositions, in particular modulating the activity of mutant-selective epidermal growth factor receptor (EGFR) kinase. Background technique [0002] Epidermal growth factor receptor (EGFR, Erb-Bl) is a family of proteins involved in the proliferation of normal and malignant cells (Artega, C.L.J. Clin Oncol 19, 2001, 32-40). Overexpression of epidermal growth factor receptor (EGFR) exists in at least 70% of human cancers (Seymour, L.K., Curr Drug Targets 2, 2001, 117-133), such as non-small cell lung cancer (NSCLC), breast cancer, glia Mass tumor, head and neck squamous cell carci...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D401/12C07D401/14A61K31/506A61P37/00A61P29/00
CPCA61P29/00A61K31/506A61P37/00C07B2200/13C07C55/10C07D239/48A61K2300/00
Inventor 胡邵京龙伟刘湘永李俊明李宗权
Owner BETTA PHARM CO LTD
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