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

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.

What is claimed is: 
     
         1 . A polymorphic form of a compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein the polymorphic form is crystalline, having an X-ray powder diffraction pattern (CuKα) comprising peaks at about 10.601, 11.638, 12.121, 13.021, 13.435, 15.418, 15.760, 17.830, 18.753, and 19.671° 2θ. 
     
     
         2 . The polymorphic form of  claim 1 , wherein the X-ray powder diffraction pattern (CuKα) is substantially as shown in  FIG. 53 . 
     
     
         3 . The polymorphic form of  claim 1 , wherein the melting point is about 181.98° C. 
     
     
         4 . The polymorphic form of  claim 1 , having a differential scanning calorimetry (DSC) curve substantially as shown in  FIG. 54 . 
     
     
         5 . A polymorphic form of a compound having the formula: 
       
         
           
           
               
               
           
         
       
       wherein the polymorphic form is crystalline, having an X-ray powder diffraction pattern (CuKα) comprising peaks at about 7.552, 10.339, 11.159, 12.107, 14.729, 15.329, 15.857, 16.824, 17.994, 18.344, 19.444, 19.764, 20.801, and 22.414° 2θ. 
     
     
         6 . The polymorphic form of  claim 5 , wherein the X-ray powder diffraction pattern (CuKα) is substantially as shown in  FIG. 56 . 
     
     
         7 . The polymorphic form of  claim 5 , wherein the melting point is about 250.10° C. 
     
     
         8 . The polymorphic form of  claim 5 , having a differential scanning calorimetry (DSC) curve substantially as shown in  FIG. 57 . 
     
     
         9 . A pharmaceutical composition comprising:
 an active ingredient comprising a polymorphic form of a compound according to any one of  claims 1 - 8 , and   a pharmaceutically acceptable carrier.   
     
     
         10 . The pharmaceutical composition according to  claim 9 , 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. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the pharmaceutical composition is formulated for oral, intraarterial, intravenous or topical administration. 
     
     
         12 . The pharmaceutical composition according to either  claim 10  or  11 , wherein the pharmaceutical composition is formulated for oral administration. 
     
     
         13 . The pharmaceutical composition according to any one of  claims 9 - 12 , wherein the pharmaceutical composition is formulated as a hard or soft capsule, a tablet, a syrup, a suspension, a solid dispersion, a wafer, or an elixir. 
     
     
         14 . The pharmaceutical composition according to any one of  claims 9 - 13 , further comprising an agent that enhances solubility and dispersibility. 
     
     
         15 . The pharmaceutical composition according to any one of  claims 9 - 14 , wherein the compound or polymorphic form is suspended in sesame oil. 
     
     
         16 . The pharmaceutical composition according to any one of  claim 9 - 11  or  13 - 15 , wherein the pharmaceutical composition is formulated for topical administration. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein pharmaceutical composition is formulated as a lotion, a cream, a gel, an oil, an ointment, a salve, or a suspension. 
     
     
         18 . The pharmaceutical composition of  claim 17 , wherein the pharmaceutical composition is formulated as a lotion. 
     
     
         19 . The pharmaceutical composition of  claim 17 , wherein the pharmaceutical composition is formulated as a cream. 
     
     
         20 . The pharmaceutical composition of  claim 17 , wherein the pharmaceutical composition is formulated as a gel. 
     
     
         21 . The pharmaceutical composition of  claim 9 , wherein the amount of the active ingredient is from about 0.01% to about 5% by weight. 
     
     
         22 . The pharmaceutical composition of  claim 21 , wherein the amount of the active ingredient is from about 0.01% to about 3% by weight. 
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein the amount of the active ingredient is about 0.01% by weight. 
     
     
         24 . The pharmaceutical composition of  claim 22 , wherein the amount of the active ingredient is about 0.1% by weight. 
     
     
         25 . The pharmaceutical composition of  claim 22 , wherein the amount of the active ingredient is about 1% by weight. 
     
     
         26 . The pharmaceutical composition of  claim 22 , wherein the amount of the active ingredient is about 3% by weight. 
     
     
         27 . A method of treating or preventing a condition associated with inflammation or oxidative stress in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the pharmaceutical composition according to any one of  claims 9  to  26 . 
     
     
         28 . The method of  claim 27 , wherein the condition is associated with inflammation. 
     
     
         29 . The method of  claim 27 , wherein the condition is associated with oxidative stress. 
     
     
         30 . The method according to any one of  claims 27 - 29 , wherein the condition is a skin disease or disorder, sepsis, dermatitis, osteoarthritis, cancer, inflammation, an autoimmune disease, inflammatory bowel disease, a complication from localized or total-body exposure to ionizing radiation, mucositis, acute or chronic organ failure, liver disease, pancreatitis, an eye disorder, a lung disease, or diabetes. 
     
     
         31 . The method of  claim 30 , wherein the condition is a skin disease or disorder. 
     
     
         32 . The method of  claim 31 , wherein the skin disease or disorder is dermatitis, a thermal or chemical burn, a chronic wound, acne, alopecia, other disorders of the hair follicle, epidermolysis bullosa, sunburn, complications of sunburn, a disorder of skin pigmentation, an aging-related skin condition, a post-surgical wound, a scar from a skin injury or burn, psoriasis, a dermatological manifestation of an autoimmune disease or a graft-versus host disease, skin cancer, a disorder involving hyperproliferation of skin cells. 
     
     
         33 . The method of  claim 32 , wherein the skin disease or disorder is dermatitis. 
     
     
         34 . The method of  claim 33 , wherein the dermatitis is allergic dermatitis, atopic dermatitis, dermatitis due to chemical exposure, or radiation-induced dermatitis. 
     
     
         35 . The method of  claim 33 , wherein the skin disease or disorder is a chronic wound. 
     
     
         36 . The method of  claim 35 , wherein the chronic wound is a diabetic ulcer, a pressure sore, or a venous ulcer. 
     
     
         37 . The method of  claim 32 , wherein the skin disease or disorder is alopecia. 
     
     
         38 . The method of  claim 37 , wherein the alopecia is selected from baldness and drug-induced alopecia. 
     
     
         39 . The method of  claim 32 , wherein the skin disease or disorder is a disorder of skin pigmentation. 
     
     
         40 . The method of  claim 39 , wherein the disorder of skin pigmentation is vitiligo. 
     
     
         41 . The method of  claim 32 , wherein the skin disease or disorder is a disorder involving hyperproliferation of skin cells. 
     
     
         42 . The method of  claim 41 , wherein the disorder involving hyperproliferation of skin cells is hyperkeratosis. 
     
     
         43 . The method of  claim 30 , wherein the condition is an autoimmune disease. 
     
     
         44 . The method of  claim 43 , wherein the condition is rheumatoid arthritis, lupus, Crohn's disease, or psoriasis. 
     
     
         45 . The method of  claim 30 , wherein the condition is liver disease. 
     
     
         46 . The method of  claim 45 , wherein the liver disease is fatty liver disease or hepatitis. 
     
     
         47 . The method of  claim 30 , wherein the condition is an eye disorder. 
     
     
         48 . The method of  claim 45 , wherein the eye disorder is uveitis, macular degeneration, glaucoma, diabetic macular edema, blepharitis, diabetic retinopathy, a disease or disorder of the corneal endothelium, post-surgical inflammation, dry eye, allergic conjunctivitis, or a form of conjunctivitis. 
     
     
         49 . The method of  claim 48 , wherein the eye disorder is macular degeneration. 
     
     
         50 . The method of  claim 49 , wherein the macular degeneration is the dry form. 
     
     
         51 . The method of  claim 49 , wherein the macular degeneration is the wet form. 
     
     
         52 . The method of  claim 48 , wherein the disease or disorder of the corneal endothelium is Fuchs endothelial corneal dystrophy. 
     
     
         53 . The method of  claim 30 , wherein the condition is a lung disease. 
     
     
         54 . The method of  claim 53 , wherein the lung disease is pulmonary inflammation, pulmonary fibrosis, COPD, asthma, cystic fibrosis, or idiopathic pulmonary fibrosis. 
     
     
         55 . The method of  claim 54 , wherein the lung disease is pulmonary inflammation. 
     
     
         56 . The method of  claim 54 , wherein the lung disease is pulmonary fibrosis. 
     
     
         57 . The method of  claim 54 , wherein the lung disease is COPD. 
     
     
         58 . The method of  claim 57 , wherein the COPD is induced by cigarette smoke. 
     
     
         59 . The method of  claim 54 , wherein the lung disease is asthma. 
     
     
         60 . The method of  claim 30 , wherein the condition is sepsis. 
     
     
         61 . The method of  claim 30 , wherein the condition is mucositis resulting from radiation therapy or chemotherapy. 
     
     
         62 . The method of  claim 61 , wherein the mucositis presents orally. 
     
     
         63 . The method of  claim 30 , wherein the condition is associated with exposure to radiation. 
     
     
         64 . The method of  claim 63 , wherein the radiation exposure leads to dermatitis. 
     
     
         65 . The method according to any one of  claims 63 - 64 , wherein the radiation exposure is acute. 
     
     
         66 . The method according to any one of  claims 63 - 64 , wherein the radiation exposure is fractionated. 
     
     
         67 . The method according to any one of  claims 27 - 66 , wherein the pharmaceutical composition is administered in a single dose per day. 
     
     
         68 . The method according to any one of  claims 27 - 66 , wherein the pharmaceutical composition is administered in more than one dose per day. 
     
     
         69 . The method according to any one of  claims 27 - 68 , wherein the active ingredient is administered in a dose from about 1 mg/kg to about 2000 mg/kg. 
     
     
         70 . The method of  claim 69 , wherein the dose is from about 3 mg/kg to about 100 mg/kg. 
     
     
         71 . The method of  claim 70 , wherein the dose is about 3 mg/kg. 
     
     
         72 . The method of  claim 70 , wherein the dose is about 10 mg/kg. 
     
     
         73 . The method of  claim 70 , wherein the dose is about 30 mg/kg. 
     
     
         74 . The method of  claim 70 , wherein the dose is about 100 mg/kg. 
     
     
         75 . The method according to any one of  claims 27 - 66 , wherein the pharmaceutical composition is administered topically. 
     
     
         76 . The method of  claim 75 , wherein the topical administration is administered to the skin. 
     
     
         77 . The method of  claim 75 , wherein the topical administration is administered to the eye. 
     
     
         78 . The method according to any one of  claims 27 - 66 , wherein the pharmaceutical composition is administered orally. 
     
     
         79 . The method according to any one of  claims 27 - 66 , wherein the pharmaceutical composition is administered intraocularly. 
     
     
         80 . The method according to any one of  claims 27 - 79 , wherein the patient is a human. 
     
     
         81 . The method according to any one of  claims 27 - 79 , wherein the patient is a non-human animal.