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2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof

A technology of polymorphism and forms, applied to 2,2-difluoropropionamide derivatives of bardoxolone methyl, its polymorphic forms and fields of use

Active Publication Date: 2016-02-10
ABBVIE INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008]Given that the bioactivity profiles of the known triterpenoid derivatives vary, and considering the existence of a variety of potent antioxidant and anti-inflammatory The diseases to be treated or prevented by the compounds and the medical needs expressed within such diseases are largely unmet, and it is desirable to synthesize compounds with different biological properties for the treatment or prevention of one or more indications. Activity Profiles of New Compounds

Method used

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  • 2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof
  • 2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof
  • 2,2-difluoropropionamide derivatives of bardoxolone methyl, polymorphic forms and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0389] Example 2: 300 mg RTA408 was dissolved in 1 mL ethyl acetate. To this clear solution was added 2 mL of heptane. Crystallization occurred within 30 minutes. The slurry was stirred overnight and the solid was isolated by vacuum filtration and dried at ambient temperature for 1 hour. The solid was then dried in a vacuum oven at 50°C overnight to give Form A.

Embodiment 2

[0390] A powder X-ray diffraction (PXRD) pattern and a table of peaks with relative intensities are shown in Figure 53 and Table 8. Differential scanning calorimetry (DSC) and thermopycnometric analysis coupled with mass spectrometry (TGA-MS) are shown in Figure 54 and55 middle.

[0391] DSC for Form A indicated an essentially solvent-free form with a melting point of 181.98°C and an enthalpy of fusion of 42.01 J / g. TGA-MS of Form A showed a loss of about 0.5 wt%, with H between 25-200°C (mainly above 160°C) 2 O trace, indicating that RTA408 polymorph Form A may be slightly hygroscopic.

[0392] Table 8: Peak table for RTA408 Form A

[0393] Peak position (°2θ) Relative Strength 10.601 11.0 11.638 7.1 12.121 4.6 13.021 10.9 13.435 100.0 15.418 12.7 15.760 5.9 17.830 19.7 18.753 38.3 19.671 7.5

[0394] RTA408 Polymorph Form B

[0395] Example 3: 1.0g RTA408 was dissolved in 1.5mL acetone. In a scintilla...

Embodiment 3

[0396] Example 4: 2.9g RTA408 was dissolved in 20mL isopropanol under reflux. 20 mL of heptane was added to the solution at reflux. The solution was cooled to room temperature and mixed for 1 hour. A solid slurry formed. The solid was isolated by vacuum filtration and dried under vacuum at ambient temperature to afford Form B.

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Abstract

The present invention relates generally to the compound: N-((4aS,6aR,6bS,8aR,12aS,14aR,14bS)-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,2,3,4,4a,5,6,6a,6b,7,8,8a,9,10,12a,14,1 4a,14b-octadecahydropicen-4a-yl)-2,2-difluoropropanamide, polymorphic forms thereof, methods for preparation and use thereof, pharmaceutical compositions thereof, and kits and articles of manufacture thereof.

Description

Background technique [0001] I.Technical field [0002] The present invention generally relates to compounds: [0003] N -((4a S ,6a R ,6b S ,8a R ,12a S ,14a R ,14b S )-11-cyano-2,2,6a,6b,9,9,12a-heptamethyl-10,14-dioxo-1,2,3,4,4a,5,6,6a,6b ,7,8,8a,9,10,12a,14,14a,14b-octahydroperylene-4a-yl)-2,2-difluoropropionamide, [0004] Also referred to herein as RTA408, 63415 or PP415. The invention also relates to polymorphic forms thereof, methods for their preparation and use, pharmaceutical compositions thereof, and kits and articles of manufacture thereof. [0005] II. Background technology [0006] The anti-inflammatory and anti-proliferative activity of the naturally occurring triterpenoid oleanolic acid has been improved by chemical modification. For example, 2-cyano-3,12-dioxoolean-1,9(11)-dien-28-oic acid (CDDO) and related compounds have been developed. See Honda and others, 1997; Honda and others, 1998; Honda and others, 1999; Honda and others, 2000a;Honda...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J63/00A61K31/565A61P29/00
CPCC07J63/008A61P19/02A61P29/00A61P31/04A61P35/00A61P37/06A61P37/08A61P39/06A61P3/10A61P9/00A61P1/00A61P17/06A61K31/565C07B2200/13
Inventor A.Y.谢赫A.马泰X.C.王
Owner ABBVIE INC