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

Patent metadata

Field	Value
Publication number	US-9701709-B2
Application number	US-201514625829-A
Country	US
Kind code	B2
Filing date	Feb 19, 2015
Priority date	Apr 27, 2012
Publication date	Jul 11, 2017
Grant date	Jul 11, 2017

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,14,14a,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.

First claim

What is claimed is:

1. A polymorphic form of a compound of the formula:

wherein the polymorphic form has an X-ray powder diffraction pattern (CuKα) comprising a halo peak at about 14° 2θ, further having a T g of about 153° C.

2. A polymorphic form of a compound of the formula:

wherein the polymorphic form is a solvate having an X-ray powder diffraction pattern (CuKα) comprising peaks at about 5.6, 10.6, and 14.6° 2θ.

3. A polymorphic form of a compound of the formula:

wherein the polymorphic form is a solvate having an X-ray powder diffraction pattern (CuKα) comprising peaks at about 7.0, 7.8, 11.9, 13.9 (double peak), and 16.0° 2θ.

4. A polymorphic form of a compound of the formula:

wherein the polymorphic form is an acetonitrile hemisolvate having an X-ray powder diffraction pattern (CuKα) comprising peaks at about 7.5, 15.6, and 16.6° 2θ.

5. A polymorphic form of a compound of the formula:

wherein the polymorphic form is a solvate having an X-ray powder diffraction pattern (CuKα) comprising peaks at about 9.3, 9.5, 10.5, 13.6, and 15.6° 2θ.

6. A pharmaceutical composition comprising:
an active ingredient consisting of a polymorphic form of claim 1 , and
a pharmaceutically acceptable carrier.

7. The pharmaceutical composition according to claim 6 , wherein the pharmaceutical composition is formulated for administration: orally, intraadiposally, intraarterially, intraarticularly, intracranially, intradermally, intralesionally, intramuscularly, intranasally, intraocularly, intrapericardially, intraperitoneally, intrapleurally, intraprostatically, intrarectally, intrathecally, intratracheally, intratumorally, intraumbilically, intravaginally, intravenously, intravesicularlly, intravitreally, liposomally, locally, mucosally, parenterally, rectally, subconjunctival, subcutaneously, sublingually, topically, transbuccally, transdermally, vaginally, in crèmes, in lipid compositions, via a catheter, via a lavage, via continuous infusion, via infusion, via inhalation, via injection, via local delivery, or via localized perfusion.

8. The pharmaceutical composition of claim 7 , wherein the pharmaceutical composition is formulated for oral, intraarterial, intravenous or topical administration.

9. The pharmaceutical composition of claim 7 , wherein the pharmaceutical composition is formulated for oral administration.

10. The pharmaceutical composition of claim 6 , wherein the pharmaceutical composition is formulated as a hard or soft capsule, a tablet, a syrup, a suspension, an emulsion, a solution, a solid dispersion, a wafer, or an elixir.

11. The pharmaceutical composition of claim 6 , wherein the pharmaceutical composition is formulated for topical administration.

12. The pharmaceutical composition of claim 11 , wherein pharmaceutical composition is formulated as a lotion, a cream, a gel, an oil, an ointment, a salve, an emulsion, a solution, or a suspension.

13. The pharmaceutical composition of claim 6 , wherein the amount of the active ingredient is from about 0.01% to about 5% by weight.

14. A method of treating a condition associated with inflammation or oxidative stress, selected from the group consisting of prostate cancer, dermatitis, sepsis, pulmonary inflammation, pulmonary fibrosis, COPD, asthma, mucositis, and ocular inflammation, in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the polymorphic form of claim 1 .

15. The method of claim 14 , wherein the condition is dermatitis.

Assignees

• Reata Pharmaceuticals Inc

Inventors

• Anderson Eric
• Liu Xiaofeng
• Decker Andrea

Classifications

• A61P39/06

  Free radical scavengers or antioxidants · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title