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JAK inhibitor crystal forms, preparation methods and applications thereof

A technology of inhibitor and crystal form, applied in the field of medicine, can solve problems such as unfavorable industrial production and dosage form development

Inactive Publication Date: 2015-11-18
CHARM PHARMATECH NANJING
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0007] There is nothing in the prior art about (N-(5-(4-(1,1-dioxothiomorpholinyl)methyl)phenyl)-[1,2,4]triazolo[1,5-a ]pyridin-2-yl)cyclopropanecarboxamide polymorphism and research on the properties of different crystal forms and specific applications, which is very unfavorable for the industrial production and formulation development of this product

Method used

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  • JAK inhibitor crystal forms, preparation methods and applications thereof
  • JAK inhibitor crystal forms, preparation methods and applications thereof
  • JAK inhibitor crystal forms, preparation methods and applications thereof

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preparation example Construction

[0038] In the preparation methods of all four crystal forms of the present invention, products prepared according to methods reported in existing literature (such as CN104262337A) are used; other solvents and reagents are commercially available chemically pure or analytically pure products.

[0039] The crystal samples obtained by the crystallization method disclosed in the present invention are characterized by methods such as X-ray powder diffraction (pXRD), differential scanning calorimetry-thermogravimetric (DSC-TGA) analysis and the like.

[0040] The X-ray powder diffractometer used in the embodiment of the present invention is X'pertPRO X-ray powder diffractometer of PANalytical Company. Using Cu-Kα rays, the test power is 40kV×250mA, the scanning speed is 5° / min, and the scanning range is 4-80° (2θ) continuous scanning of θ-2θ. In the X-ray powder diffraction diagram obtained in the embodiment of the present invention, the horizontal axis represents the 2θ position of ...

Embodiment 1

[0042] Example 1 Preparation and characterization of crystal form H1.

[0043] 0.5 g of N-(5-(4-(1,1-dioxothiomorpholinyl)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine- 2-yl) cyclopropanecarboxamide and 0.1 g of water are added to 5 ml of 1,4-dioxane solvent, and the mixture is heated to 85±2°C and stirred to completely dissolve the solid, followed by a speed of 1 to 3°C / min Slowly cool to room temperature and stand at room temperature for 48 hours, and the precipitated white powdery crystals are taken out by filtration, which is the crystal form H1.

[0044] Powder X-ray diffraction analysis of the crystal form H1 obtained in Example 1:

[0045] The crystal form H1 obtained in Example 1 was further ground, and subjected to powder X-ray diffraction analysis. The results are shown in the attached figure 1 shown. attached figure 1 The X-ray diffraction data of the corresponding crystal form H1 are shown in Table 1.

[0046] Table 1 Powder X-ray Diffraction Analysis of Form ...

Embodiment 2

[0052] Example 2 Preparation of Form H1.

[0053] 0.5 g of N-(5-(4-(1,1-dioxothiomorpholinyl)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine- 2-yl) cyclopropanecarboxamide and 0.5 g of water are added to 10 ml of 1,4-dioxane solvent, and the mixture is heated to 80±2°C and stirred to completely dissolve the solid, followed by a speed of 1 to 3°C / min After slowly cooling to room temperature and standing at room temperature for 96 hours, the precipitated white powdery crystals were taken out by filtration. It was analyzed by powder X-ray diffraction and confirmed to be the crystal form H1.

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Abstract

The present invention discloses four crystal forms of a JAK inhibitor N-(5-(4-(1,1-dioxothiomorpholinyl)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl)cyclopropanecarboxamide, and methods for preparing the four crystal forms, wherein the four crystal forms respectively are a crystal form H1, a crystal form H2, a crystal form H3 and a crystal form H4, the crystal form H1 has the characteristic absorption peaks when the diffraction angle 2[theta] is 8.3 DEG, 11.2 DEG, 16.0 DEG, 17.5 DEG, 18.5 DEG, 19.3 DEG, 19.7 DEG, 20.0 DEG, 20.7 DEG, 22.0 DEG and the like, the crystal form H2 has the characteristic absorption peaks when the diffraction angle 2[theta] is 9.3 DEG, 12.8 DEG, 14.0 DEG, 16.4 DEG, 18.7 DEG, 20.5 DEG, 23.5 DEG, 29.4 DEG, 33.1 DEG, 33.4 DEG and the like, the crystal form H3 has the characteristic absorption peaks when the diffraction angle 2[theta] is 9.6 DEG, 9.8 DEG, 10.7 DEG, 15.1 DEG, 15.3 DEG, 16.8 DEG, 16.9 DEG, 19.8 DEG, 20.0 DEG, 24.9 DEG and the like, and the crystal form H1 has the characteristic absorption peaks when the diffraction angle 2[theta] is 8.6 DEG C, 9.6 DEG, 10.5 DEG, 12.9 DEG, 15.1 DEG, 17.2 DEG, 18.9 DEG, 19.9 DEG, 20.7 DEG, 23.8 DEG and the like. According to the present invention, the four crystal forms have advantages of excellent physical and chemical properties, good stability, simple preparation operation and the like, are suitable for pharmaceutical formulation applications.

Description

technical field [0001] The invention belongs to the technical field of medicine, and more specifically relates to a crystal form of a JAK inhibitor, a preparation method thereof and its application in medicine research and development and production. Background technique [0002] (N-(5-(4-(1,1-dioxothiomorpholinyl)methyl)phenyl)-[1,2,4]triazolo[1,5-a]pyridine-2- Base) Cyclopropanecarboxamide is a new type of JAK inhibitor, its general name is Filgotinib (also known as GLPG0634), and its chemical formula is C 21 h 23 N 5 o 3 S, the molecular weight is 425.50, the CAS number is 1206161-97-8, and the chemical structure formula is as follows: [0003] [0004] Filgotinib is a novel JAK inhibitor developed by Galápagos NV in Belgium. The preparation method and application of the compound are disclosed in the patent CN104262337A. [0005] JAK, also known as Janus kinase, is a non-receptor tyrosine protein kinase, which is widely involved in many important biological proces...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/541A61P19/02A61P29/00A61P1/00
CPCC07B2200/13C07D471/04
Inventor 胡咏波
Owner CHARM PHARMATECH NANJING
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