Polymorphs of Pyrrole Substituted 2-Indolinone Protein Kinase Inhibitors

Abstract

The present invention relates to polymorphs of the 3-pyrrole substituted 2-indolinone compound 5-(5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-yl-ethyl)-amide.

1 - 18 . (canceled) 
   
   
       19 . A method for the modulation of the catalytic activity of a protein kinase comprising contacting said protein kinase with a polymorph from of a compound of formula I: 
     
       
         
         
             
             
         
       
     
     wherein the polymorph form is either polymorph form I or polymorph form II. 
   
   
       20 . The method of  claim 19 , wherein said protein kinase is selected from the group consisting of a receptor tyro sine kinase, a non-receptor tyrosine kinase, and a serine-threonine kinase. 
   
   
       21 . A method for treating or preventing a protein kinase related disorder in an organism comprising administering a therapeutically effective amount of a pharmaceutical composition comprising a polymorph form of  claim 19  and a pharmaceutically acceptable carrier or excipient to said organism. 
   
   
       22 . The method of  claim 21  wherein said protein kinase related disorder is selected from the group consisting of a receptor tyrosine kinase related disorder, a non-receptor tyrosine kinase related disorder, and a serine-threonine kinase related disorder. 
   
   
       23 . The method of  claim 21  wherein said protein kinase related disorder is selected from the group consisting of an EGFR related disorder, a PDGFR related disorder, an IGFR related disorder, a c-kit related disorder, and a flk related disorder. 
   
   
       24 . The method of  claim 21  wherein said protein kinase related disorder is a cancer selected from the group consisting of leukemia, brain cancer non-small cell lung cancer, squamous cell carcinoma, astrocytoma, Kaposi's sarcoma, glioblastoma, lung cancer, bladder cancer, head cancer, neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, glioma, mastocytosis, mast cell tumor, colorectal cancer, genitourinary cancer, and gastrointestinal stromal cancer. 
   
   
       25 . The method of  claim 21  wherein said protein kinase related disorder is selected from the group consisting of diabetes, an autoimmune disorder, a hyperproliferation disorder, restenosis, fibrosis, psoriasis, von Heppel-Lindau disease, osteoartlritis, rheumatoid arthritis, angiogenesis, an inflammatory disorder, an immunological disorder and a cardiovascular disorder. 
   
   
       26 . The method of  claim 21 , wherein said organism is a human. 
   
   
       27 . A method of treating cancer in a companion animal comprising administering a pharmaceutical composition, comprising a polymorph form of  claim 19  and a pharmaceutically acceptable carrier or excipient to said animal. 
   
   
       28 . The method of  claim 27 , wherein said companion animal is a cat or a dog. 
   
   
       29 . The method of  claim 19 , wherein polymorph form I has a powder X-ray diffraction spectrum comprising peaks expressed in degrees (±0.1 degree) of two theta angle of 5.0, 16.7, 18.9, 24.8, and 27.3 obtained using CuKα 1  emission (wavelength=1.5406 Angstroms). 
   
   
       30 . The method of  claim 19 , wherein polymorph form II has a powder X-ray diffraction spectrum comprising peaks expressed in degrees (±0.1 degree) of two theta angle of 7.1, 13.9, 16.0, 20.9, and 24.7 obtained using CuKα 1  emission (wavelength=1.5406 Angstroms).