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Roflumilast N-oxide polymorphs and their preparation methods and pharmaceutical composition

A technology of roflumilast and crystal forms, which is applied in the direction of drug combination, active ingredients of heterocyclic compounds, digestive system, etc., and can solve problems such as no description of crystal forms

Inactive Publication Date: 2013-11-06
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Although the international patent WO0190076 reports the preparation method of roflumilast N-oxide, the related crystal form research has not been described

Method used

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  • Roflumilast N-oxide polymorphs and their preparation methods and pharmaceutical composition
  • Roflumilast N-oxide polymorphs and their preparation methods and pharmaceutical composition
  • Roflumilast N-oxide polymorphs and their preparation methods and pharmaceutical composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Form I of roflumilast N-oxide

[0058] Under stirring at a bath temperature of 30° C., 3.1 g of N-(3,5-dichloro-1-oxo-pyridin-4-yl)-3-cyclopropanemethoxy-4-difluoromethoxyformamide ( Roflumilast N-oxide) solid was dissolved in a mixed solvent of dichloromethane-methanol (80:1, 50mL), and the solvent was spin-dried under reduced pressure at 40°C to precipitate a white solid. The obtained solid was collected and dried under reduced pressure at 55°C to obtain 3.1g of a white solid with a melting point of 179°C to 180°C, which was confirmed to be roflumilast N by X-ray powder diffraction, infrared scanning, DSC scanning, TGA scanning, and elemental analysis. - Form I of the oxide.

Embodiment 2

[0060] Form I of roflumilast N-oxide

[0061] Under stirring at a bath temperature of 85°C, dissolve 500 mg of N-(3,5-dichloro-1-oxo-pyridin-4-yl)-3-cyclopropanemethoxy-4-difluoromethoxyformamide as a solid After cooling to 20°C in ethyl acetate (5 mL) and standing still, a white solid precipitated out of the solution. Suction filtration, the filter cake was collected, and the obtained solid was dried at 40°C under reduced pressure to obtain 290 mg of white solid, melting point: 179°C-180°C, which was confirmed to be the crystal form of roflumilast N-oxide by X-ray powder diffraction Object I.

Embodiment 3

[0063] Form I of roflumilast N-oxide

[0064] Under stirring at a bath temperature of 85°C, dissolve 1 g of N-(3,5-dichloro-1-oxo-pyridin-4-yl)-3-cyclopropanemethoxy-4-difluoromethoxyformamide as a solid After cooling to 20°C in acetonitrile (9 mL) and standing still, a white solid precipitated out of the solution. Suction filtration, the filter cake was collected, and the obtained solid was dried at 40°C under reduced pressure to obtain 680 mg of white solid, melting point: 179°C-180°C, which was confirmed to be the crystal form of roflumilast N-oxide by X-ray powder diffraction Object I.

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Abstract

The invention discloses N-(3,5-dichloro-1-oxo-pyridyl-4-yl)-3-cyclopropylmethoxy-4-difluoromethoxymethylamide (roflumilast N-oxide) and its monohydrate polymorphs I and II. The invention also discloses preparation methods and a pharmaceutical composition of the polymorphs I and II.

Description

technical field [0001] The present invention relates to a polymorphic form of a pharmaceutical compound, in particular to a polymorphic form of roflumilast N-oxide and its monohydrate. In addition, the present invention also relates to a preparation method of the polymorphic form and a pharmaceutical combination thereof things. Background technique [0002] Chemical name of Roflumilast N-oxide: N-(3,5-dichloro-1-oxo-pyridin-4-yl)-3-cyclopropanemethoxy-4-difluoromethoxycarboxamide , which is a metabolite of roflumilast in the body. Roflumilast is a phosphodiesterase 4 (PDE4) inhibitor for the treatment of chronic obstructive pulmonary disease (COPD). Roflumilast N-oxide and roflumilast have comparable levels of PDE4 inhibition. [0003] In organisms, the second messengers cAMP and cGMP are catalyzed by adenylate cyclase and guanylate cyclase, respectively, and regulate glucose and lipid metabolism, cell proliferation and differentiation, secretion, relaxation and inflammat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75A61K31/44A61P1/00A61P3/10A61P9/10A61P11/00A61P11/06A61P25/16A61P25/28A61P37/02
Inventor 孙宏斌向左娟
Owner CHINA PHARM UNIV
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