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Polymorphs of morpholine phenylaminopyrimidine compounds or salts thereof

A technology for polymorphic forms and compounds, applied in the field of medicine, can solve the problems of affecting the clinical efficacy and safety of drugs, lack of research on polymorphic forms of compounds of formula I, and the influence of crystal forms.

Active Publication Date: 2021-06-08
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 morpholine phenylaminopyrimidine compounds or salts thereof
  • Polymorphs of morpholine phenylaminopyrimidine compounds or salts thereof
  • Polymorphs of morpholine phenylaminopyrimidine compounds or salts thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0165] Example 1 Preparation of Polymorph I of N-(cyanomethyl)-4-(2-(4-(morpholine)phenylamino)pyrimidin-4-yl)benzamide dihydrochloride

[0166] Take 1.0g of N-(cyanomethyl)-4-(2-(4-(morpholine)phenylamino)pyrimidin-4-yl)benzamide, add 40ml of anhydrous methanol, stir at room temperature, Add 4.8ml of newly prepared hydrochloric acid ethanol solution (the concentration of hydrogen chloride is 40mg / ml), after dripping, filter, continue to stir the filtrate at room temperature for 2h, precipitate solid, filter, rinse with anhydrous methanol, solid 55±5℃ under high vacuum After drying for 6h, a yellow solid was obtained.

[0167] Sampling via 1 H NMR, X-ray powder diffraction, DSC and other tests proved to be the title crystal compound, weighing 870 mg, yield: 74%.

[0168] 1 H NMR (400MHz, DMSO-d 6 )δ10.12(s,1H),9.56(t,J=4.0Hz,1H),8.65(d,J=4.0Hz,1H),8.30(d,J=8.0Hz,2H),8.09(d, J=8.0Hz, 2H), 7.98(d, J=8.0Hz, 2H), 7.81(d, J=8.0Hz, 2H), 7.58(d, J=8.0Hz, 1H), 4.36(d, J= 4.0Hz, ...

Embodiment 2

[0174] Example 2 Preparation of Polymorph I of N-(cyanomethyl)-4-(2-(4-(morpholine)phenylamino)pyrimidin-4-yl)benzamide dihydrochloride

[0175] Take 500mg of N-(cyanomethyl)-4-(2-(4-(morpholine)phenylamino)pyrimidin-4-yl)benzamide, add 10ml of anhydrous methanol, stir at room temperature, drop new Prepare 2.6ml of methanolic hydrochloric acid solution (the concentration of hydrogen chloride is 40mg / ml). After dropping, add polymorph I seed crystals, stir overnight, filter, wash with anhydrous methanol, and dry the solid under high vacuum at 55±5°C for 6h to obtain The yellow solid is the title crystalline compound, weighing 488 mg, yield: 81%. Its X-ray powder diffraction pattern and Figure 1a same.

Embodiment 3

[0176] Example 3 Preparation of Polymorph I of N-(cyanomethyl)-4-(2-(4-(morpholine)phenylamino)pyrimidin-4-yl)benzamide dihydrochloride

[0177] Take 1.0g of N-(cyanomethyl)-4-(2-(4-(morpholine)phenylamino)pyrimidin-4-yl)benzamide, add 10ml of absolute ethanol, stir at room temperature, drop in 4.8ml of newly prepared hydrochloric acid ethanol solution (the concentration of hydrogen chloride is 40mg / ml), after dripping, continue to stir for 2h, filter, wash with absolute ethanol, and dry the solid under high vacuum at 55±5°C for 6h to obtain a yellow solid which is the title crystal form Compound, weighing 1.11g, yield: 91%. Its X-ray powder diffraction pattern and Figure 1a same.

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Abstract

The present invention relates to a polymorphic form of a morpholine phenylaminopyrimidine compound or a salt thereof, more particularly, to N-(cyanomethyl)-4-(2-(4-(morpholine phenylamino)pyrimidine- 4-yl) benzamide, or a pharmaceutically acceptable salt thereof, or a polymorphic form of a solvate thereof. The polymorphic form is suitable for the preparation of an inhibitory non-receptor tyrosine kinase (such as JAK kinase ) pharmaceutical composition.

Description

technical field [0001] The invention belongs to the field of medicine, in particular to a polymorphic form of a morpholine phenylaminopyrimidine compound or a salt thereof, in particular to N-(cyanomethyl)-4-(2-(4- A polymorph of (morpholinephenylamino)pyrimidin-4-yl)benzamide, or a pharmaceutically acceptable salt thereof. Background technique [0002] N-(cyanomethyl)-4-(2-(4-(morpholinophenylamino)pyrimidin-4-yl)benzamide (N-(cyanomethyl)-4-(2-((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 22 N 6 o 2 , with a molecular weight of 414.46, 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 related diseases. [0006] Since different crystal forms and salt for...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/42A61K31/5377A61P35/00A61P29/00
CPCC07B2200/13C07D239/42
Inventor 吕彬华李成伟
Owner SUZHOU ZELGEN BIOPHARML