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Polymorphs of phenylaminopyrimidine compounds or salts thereof

A technology of polymorphs and compounds, applied in the field of medicine, can solve problems affecting the clinical efficacy and safety of drugs, affecting dissolution, absorption, and the impact of crystal forms

Active Publication Date: 2019-06-25
SUZHOU ZELGEN BIOPHARML
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Since different crystal forms and salt forms of drugs may affect their dissolution and absorption in the body, which may affect the clinical efficacy and safety of drugs to a certain extent, especially for some insoluble oral solid or semi-solid preparations, the crystal form the impact will be greater
At present, there is no research on the polymorphic form of the compound of formula I, and no polymorphic form of the compound of formula I has been developed

Method used

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  • Polymorphs of phenylaminopyrimidine compounds or salts thereof
  • Polymorphs of phenylaminopyrimidine compounds or salts thereof
  • Polymorphs of phenylaminopyrimidine compounds or salts thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0186] Example 1 Preparation of N-(cyanomethyl)-4-(2-(4-(2',2',6',6'-d 4 Polymorph I of -morpholine) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride

[0187]Take 500mg N-(cyanomethyl))-4-(2-(4-(2',2',6',6'-d 4 -morpholine) phenylamino) pyrimidin-4-yl) benzamide, add 5.0ml of absolute ethanol, suspend and stir at room temperature. At room temperature, 2.3ml of newly prepared hydrochloric acid ethanol solution (the concentration of hydrogen chloride is 40mg / ml) was added dropwise, and the suspended mixture was continuously stirred at room temperature for 2.5h after the drop was completed. Filter, wash with absolute ethanol, and dry the solid under high vacuum at 40±5°C for 6 hours to obtain a yellow solid.

[0188] Sampling via 1 H NMR, X-ray powder diffraction, DSC and other tests proved to be the title crystal compound, weighing 512 mg, yield: 87%.

[0189] 1 H NMR (400MHz, DMSO-d 6 )δ10.15(s,1H),9.59(t,J=4.0Hz,1H),8.66(d,J=4.0Hz,1H),8.30(d,J=8.0Hz,2H),8.09(d, J=...

Embodiment 2

[0195] Example 2 Preparation of N-(cyanomethyl)-4-(2-(4-(2',2',6',6'-d 4 Polymorph I of -morpholine) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride

[0196] Take 1.0g N-(cyanomethyl))-4-(2-(4-(2',2',6',6'-d 4 -morpholine) phenylamino) pyrimidin-4-yl) benzamide, add 4.0ml glacial acetic acid, stir at room temperature until dissolving clear, room temperature drips the newly prepared hydrochloric acid ethanol solution 5.2ml (hydrogen chloride concentration is 40mg / ml), Stirring was continued for 2 hours after dropping, the solid was precipitated, filtered, washed with absolute ethanol, and the solid was dried under high vacuum at 55±5°C for 6 hours to obtain a yellow solid which was the title crystalline compound, weighing 1.1 g, yield: 94%. Its X-ray powder diffraction pattern and Figure 1a same.

Embodiment 3

[0197] Example 3 N-(cyanomethyl)-4-(2-(4-(2',2',6',6'-d 4 Polymorph I of -morpholine) phenylamino) pyrimidin-4-yl) benzamide dihydrochloride

[0198] Take 1.0g N-(cyanomethyl))-4-(2-(4-(2',2',6',6'-d 4 -morpholine) phenylamino) pyrimidin-4-yl) benzamide, add 40ml absolute methanol, stir at room temperature, drop into newly prepared hydrochloric acid ethanol solution 4.8ml (hydrogen chloride concentration is 40mg / ml), after dropping, Filtrate, continue to stir the filtrate at room temperature for 2h, precipitate a solid, filter, rinse with anhydrous methanol, and dry the solid under high vacuum at 55±5°C for 6h to obtain a yellow solid, which is the title crystalline compound, weighing 0.88g, yield: 85.5 %. Its X-ray powder diffraction pattern and Figure 1a same.

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Abstract

The present invention relates to polymorphs of phenylaminopyrimidine compounds or salts thereof, specifically, N-(cyanomethyl)-4-(2-(4-(2',2',6',6' -d 4 -morpholine) phenylamino) pyrimidin-4-yl) benzamide, or a pharmaceutically acceptable salt thereof, or a polymorphic form of a solvate thereof, that is, a compound shown in formula I or a salt thereof, or Polymorphs of solvates. The polymorphic form is suitable for the preparation of pharmaceutical compositions for inhibiting non-receptor tyrosine kinases (such as JAK kinases).

Description

technical field [0001] The present invention belongs to the field of medicine, in particular to a polymorphic form of a phenylaminopyrimidine compound or a salt thereof, in particular to N-(cyanomethyl)-4-(2-(4-(2 ',2',6',6'-d 4 -morpholine) phenylamino) pyrimidin-4-yl) benzamide, or a polymorphic form of a pharmaceutically acceptable salt thereof. Background technique [0002] N-(cyanomethyl)-4-(2-(4-(2',2',6',6'-d 4 -morpholine)phenylamino)pyrimidin-4-yl)benzamide (N-(cyanomethyl)-4-(2-((4-(2',2',6',6'-d 4 -morpholino)phenyl)amino)pyrimidin-4-yl)benzamide), the structure is as shown in formula I: [0003] [0004] Formula I [0005] The molecular formula of the compound of formula I is C 23 h 18 D. 4 N 6 o 2 , with a molecular weight of 418.49, the compound is an inhibitor of a class of non-receptor tyrosine kinases such as JAK kinases, and is suitable for preparing medicines for treating / preventing cancer, myeloproliferative diseases, inflammation and other re...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/42A61K31/5377A61P35/00A61P29/00
CPCC07D239/42C07B2200/13A61K31/5377C07D265/30A61P29/00A61P35/00A61P43/00C07D413/12C07D413/14
Inventor 吕彬华李成伟肖丹
Owner SUZHOU ZELGEN BIOPHARML