Synthetic triterpenoids and methods of use in the treatment of disease

Abstract

The present invention concerns methods for treating and preventing renal/kidney disease, insulin resistance/diabetes, fatty liver disease, and/or endothelial dysfunction/cardiovascular disease using synthetic triterpenoids, optionally in combination with a second treatment or prophylaxis.

1 . A method for treating renal/kidney disease (RKD), insulin resistance, diabetes, endothelial dysfunction, fatty liver disease, or cardiovascular disease (CVD) in a patient comprising, administering to the patient a pharmaceutically effective amount of a compound having the structure: 
       
         
           
           
               
               
           
         
         wherein R 1  is:
 —CN, or 
 C 1 -C 15 -acyl or C 1 -C 15 -alkyl, wherein either of these groups is heteroatom-substituted or heteroatom-unsubstituted; or 
 
         a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the patient is human. 
       
     
     
         2 . The method of  claim 1 , wherein the patient has RKD. 
     
     
         3 . The method of  claim 2 , wherein the RKD is diabetic nephropathy (DN). 
     
     
         4 - 16 . (canceled) 
     
     
         17 . The method of  claim 1 , wherein the patient has insulin resistance. 
     
     
         18 . The method of  claim 1 , wherein the patient has diabetes. 
     
     
         19 - 24 . (canceled) 
     
     
         25 . The method of  claim 1 , wherein the patient has CVD. 
     
     
         26 . (canceled) 
     
     
         27 . The method of  claim 1 , wherein the patient has endothelial dysfunction. 
     
     
         28 - 40 . (canceled) 
     
     
         41 . The method of  claim 1 , wherein the compound is administered orally. 
     
     
         42 . (canceled) 
     
     
         43 . The method of  claim 1 , wherein the compound is formulated as a solid dispersion. 
     
     
         44 - 50 . (canceled) 
     
     
         51 . The method of  claim 1 , wherein the daily dose is from about 10 mg to about 200 mg of the compound. 
     
     
         52 . The method of  claim 51 , wherein the daily dose is about 25 mg of the compound. 
     
     
         53 . (canceled) 
     
     
         54 . (canceled) 
     
     
         55 . The method of  claim 1 , wherein the daily dose is from about 0.1 mg to about 30 mg of the compound. 
     
     
         56 - 58 . (canceled) 
     
     
         59 . The method of  claim 55 , wherein the daily dose is from about 5 mg to about 30 mg of the compound. 
     
     
         60 - 66 . (canceled) 
     
     
         67 . The method of  claim 1 , further comprising a second therapy, wherein the second therapy comprises administering to the patient a pharmaceutically effective amount of a second drug. 
     
     
         68 . (canceled) 
     
     
         69 . The method of  claim 67 , wherein the second drug is a cholesterol lowering drug, an anti-hyperlipidemic, a calcium channel blocker, an anti-hypertensive, or an HMG-CoA reductase inhibitor. 
     
     
         70 . (canceled) 
     
     
         71 . (canceled) 
     
     
         72 . The method of  claim 67 , wherein the second drug is a statin. 
     
     
         73 . The method of  claim 72 , wherein the statin is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin or simvastatin. 
     
     
         74 - 117 . (canceled) 
     
     
         118 . The method of  claim 1 , wherein the compound is further defined as: 
       
         
           
           
               
               
           
         
       
     
     
         119 . The method of  claim 118 , wherein at least a portion of the compound of  claim 118  is present as a polymorphic form, wherein the polymorphic form is a crystalline form having an X-ray diffraction pattern (CuKα) comprising significant diffraction peaks at about 8.8, 12.9, 13.4, 14.2 and 17.4 °2θ. 
     
     
         120 . (canceled) 
     
     
         121 . The method of  claim 118 , wherein at least a portion of the compound of  claim 118  is present as a polymorphic form, wherein the polymorphic form is an amorphous form having an X-ray diffraction pattern (CuKα) with a halo peak at approximately 13.5 °2θ, substantially as shown in  FIG. 12C , and a T g  in the range of about 120° C. to about 135° C. 
     
     
         122 - 131 . (canceled) 
     
     
         132 . The method of  claim 118 , wherein the compound is formulated as a pharmaceutical composition comprising (i) a therapeutically effective amount of the compound and (ii) an excipient is (A) a carbohydrate, carbohydrate derivative, or carbohydrate polymer, (B) a synthetic organic polymer, (C) an organic acid salt, (D) a protein, polypeptide, or peptide, or (E) a high molecular weight polysaccharide. 
     
     
         133 - 136 . (canceled) 
     
     
         137 . The method of  claim 132 , wherein the excipient is a methacrylic acid-ethyl acrylate copolymer. 
     
     
         138 - 157 . (canceled) 
     
     
         158 . The method of  claim 67 , wherein the second drug is an anti-hypertensive. 
     
     
         159 . The method of  claim 158 , wherein the anti-hypertensive is an angiotensin II receptor blocker. 
     
     
         160 . The method of  claim 158 , wherein the anti-hypertensive is an angiotensin-converting enzyme inhibitor.