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Salts of aminoquinazoline derivatives and uses thereof

A kind of use and drug technology, applied in the direction of medical preparations containing active ingredients, drug combinations, cardiovascular system diseases, etc., can solve problems such as hindering the combination of EGFR and its inhibitors, increasing the affinity of EGFR and ATP

Active Publication Date: 2021-09-28
SUNSHINE LAKE PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The T790M mutation is a point mutation in exon 20 of EGFR, and it is one of the more recognized drug resistance mechanisms at present. , leading to changes in the structure of EGFR, hindering the combination of EGFR and its inhibitors or greatly increasing the affinity of EGFR and ATP, so that the ATP affinity is restored to the wild level of EGFR, thus leading to drug resistance

Method used

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  • Salts of aminoquinazoline derivatives and uses thereof
  • Salts of aminoquinazoline derivatives and uses thereof
  • Salts of aminoquinazoline derivatives and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0129] The succinate crystal form A of the compound shown in embodiment 1 formula (I)

[0130] 1. Preparation of title succinate crystal form A

[0131] The free base (0.259g, 0.501mmol) was added to a mixed solution of methanol (2.0mL) and isopropyl acetate (4.0mL), the temperature was raised to 70°C, and acetic acid of succinic acid (0.142g, 1.20mmol) was added dropwise Isopropyl ester solution (1.0 mL), after dropping, the reaction was naturally cooled to room temperature overnight, filtered with suction, the filter cake was washed with a small amount of isopropyl acetate, and dried under vacuum at room temperature to obtain an off-white solid (0.179 g, 56.26%).

[0132] 2. Identification of the title succinate crystal form A

[0133] (1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): using Cu-Kα radiation, it has the following characteristic peaks expressed in angle 2θ: 5.52°, 10.70°, 11.11°, 13.24°, 14.51°, 15.44°, 16.04 °,16.54°,17.11°,17....

Embodiment 2

[0135] Embodiment 2 The succinate crystal form B of the compound represented by the formula (I)

[0136] 1. Preparation of title succinate crystal form B

[0137] Add free base (0.516g, 0.998mmol) to ethanol (30.0mL), heat to reflux, filter while hot, continue to reflux the filtrate and add succinic acid (0.248g, 2.10mmol), keep warm for 2.5 hours, and cool the reaction naturally to room temperature, then cooled and crystallized at -15°C, suction filtered, and the filter cake was vacuum-dried at room temperature to obtain a light yellow solid (0.17g, 26.82%).

[0138] 2. Identification of the title succinate crystal form B

[0139] (1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): using Cu-Kα radiation, it has the following characteristic peaks expressed in angle 2θ: 5.01°, 7.01°, 9.89°, 10.28°, 11.11°, 13.09°, 13.36 °,13.99°,14.52°,15.11°,15.70°,17.07°,18.58°,18.89°,19.16°,20.20°,20.57°,22.80°,23.29°,23.72°,24.40°,24.52°,25.34°, 26.38°,27.07°...

Embodiment 3

[0141] The succinate amorphous of the compound shown in embodiment 3 formula (I)

[0142] 1. Preparation of the title succinate amorphous

[0143] Add the free base (5.17g, 10.0mmol) to absolute ethanol (180.0mL), heat to reflux to dissolve, filter with suction, continue to reflux the filtrate, and add succinic acid (1.18g, 10.0mmol) in ethanol dropwise to the filtrate The solution (20.0 mL) was incubated for 4 hours, and the above reaction solution was placed in the injection port of a spray dryer, and spray-dried to obtain an off-white solid (3.086 g, 48.6%).

[0144] 2. Identification of the title succinate amorphous

[0145] Through Empyrean X-ray powder diffraction (XRPD) analysis and identification: its X-ray powder diffraction is basically as follows image 3 shown.

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Abstract

The present invention relates to a salt of aminoquinazoline derivatives and use thereof, wherein the salt of the compound can be in the form of crystal, partial crystal, polymorph, amorphous, hydrate or solvate. The present invention also relates to a pharmaceutical composition comprising said salt or a combination thereof, and the use of said salt or said pharmaceutical composition in the preparation of a medicament for preventing or treating proliferative diseases, atherosclerosis or pulmonary fibrosis use.

Description

technical field [0001] The invention belongs to the field of medicines, and relates to salts of aminoquinazoline derivatives and uses thereof, in particular to (E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-(methyl Oxy-D 3 )-quinazolin-6-yl)-4-((4aR,7aS)-tetrahydro-2H-[1,4]dioxalo[2,3-c]pyrrol-6(3H)-yl) The salt of but-2-enamide (compound represented by formula (I)) and its use further relate to a pharmaceutical composition comprising said salt. Said salt or said pharmaceutical composition is used for preventing or treating proliferative diseases, atherosclerosis or pulmonary fibrosis. The salts of the compounds of the present invention may be in crystalline, partially crystalline, polymorphic, amorphous, hydrate or solvate form. Background technique [0002] Protein kinases (PKs) represent a large class of proteins that play an important role in the control of cellular functions and the regulation of various cellular lesions, and can be divided into two categories: protein ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D491/056A61K31/517A61P35/00A61P35/04A61P9/10A61P11/00
CPCC07B2200/13C07D491/056
Inventor 陈亮章维红皇甫德胜李成蹊刘兵张英俊聂飚许娟吴族平劳锦花余天喜
Owner SUNSHINE LAKE PHARM CO LTD
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