Polymorphs of cddo ethyl ester and uses thereof

Abstract

The present invention relates to polymorphic forms of the compound of Formula I (i.e., ethyl 2-cyano-3,12-dioxokana-1,9(11)-dien-28-oate (CDDO ethyl ester)) and methods of using them for treating a variety of disease states such as cancer and conditions associated with inflammation.

1 - 44 . (canceled) 
     
     
         45 . A method of treating a physical disorder or condition associated with inflammation in a subject, comprising administering to the subject a polymorph of a compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein the polymorph is a glassy solid form which has a Tg of about 52° C.±10° C. 
       
     
     
         46 . The method of  claim 45 , where the polymorph is a crystalline Form I, wherein the crystalline Form I has an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angles 2θ of approximately 10.3°, 14.1° and 14.6. 
     
     
         47 . The method of  claim 46 , wherein the X-ray powder diffraction pattern comprises characteristic peaks at diffraction angles 2θ of approximately 10.3°, 14.1°, 14.6°, 15.7°, and 16.6°. 
     
     
         48 . The method of  claim 47 , wherein the X-ray powder diffraction pattern comprises additional characteristic peaks at diffraction angles 2θ of approximately 9.3° and 19.6°. 
     
     
         49 . The method of  claim 45 , wherein the X-ray powder diffraction pattern comprises characteristic peaks at diffraction angles 2θ of approximately 10.3°, 14.1°, 14.6°, 15.8°, 16.6° and 19.6°. 
     
     
         50 . The method of  claim 46 , wherein the crystalline Form I has the X-ray powder diffraction pattern comprising characteristic peaks, expressed in terms of the interplanar distance, at 8.6 Å, 6.3 Å and 6.1 Å. 
     
     
         51 . The method of  claim 50 , wherein the X-ray powder diffraction pattern comprises characteristic peaks, expressed in terms of the interplanar distance, at 8.6 Å, 6.3 Å, 6.1 Å, 5.6 Å, 5.3 Å and 4.5 Å. 
     
     
         52 . The method of  claim 45 , wherein the polymorph has a melting point of 174° C.-177° C. 
     
     
         53 . The method of  claim 45 , wherein the polymorph is of crystalline Form II, which has an X-ray powder diffraction pattern comprising characteristic peaks at diffraction angles 2θ of approximately 10.4°, 12.1° and 13.4°. 
     
     
         54 . The method of  claim 53 , wherein the X-ray powder diffraction pattern comprises additional characteristic peaks at diffraction angles 2θ of approximately 15.4°, 17.8° and 18.8°. 
     
     
         55 . The method of  claim 53 , wherein the X-ray powder diffraction pattern comprises characteristic peaks, when expressed in terms of the interplanar distance, at 8.5 Å, 7.3 Å and 6.6 Å. 
     
     
         56 . The method of  claim 55 , wherein the X-ray powder diffraction pattern comprises additional characteristic peaks, when expressed in terms of the interplanar distance, at 5.7 Å, 5.0 Å and 4.7 Å. 
     
     
         57 . The polymorph of  claim 53 , wherein the polymorph has a melting point of 209° C.-212° C. 
     
     
         58 . The method of  claim 45 , wherein the polymorph has a purity of ≧85%. 
     
     
         59 . The method of  claim 45 , wherein the physical disorder or condition associated with inflammation comprises lupus or rheumatoid arthritis, Crohn's disease or ulcerative colitis, a cardiovascular disease, diabetes, or a condition associated with diabetes. 
     
     
         60 . The method of  claim 45 , wherein the physical disorder or condition associated with inflammation is cancer. 
     
     
         61 . The method of  claim 58 , wherein the condition associated with diabetes comprises obesity, hypertension, atherosclerosis, coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, myonecrosis, retinopathy, metabolic syndrome (syndrome X), or a combination thereof. 
     
     
         62 . The method of  claim 45 , wherein the physical disorder or condition associated with inflammation is caused by nitric oxide induced by IFN-γ in a macrophage.