Method of Treating Cancer

Abstract

This invention is directed to the treatment of cancer, particularly castration-resistant prostate cancer and osteoblastic bone metastases, with a dual inhibitor of MET and VEGF.

1 . A method for treating bone cancer, wherein the bone cancer is osteoblastic bone metastases, prostate cancer, wherein the prostate cancer is castration resistant prostate cancer, or bone cancer associated with prostate cancer, comprising administering a compound that dually modulates MET and VEGF to a patient in need of such treatment, wherein the compound that dually modulates MET and VEGF is the compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is halo; 
 R 2  is halo; 
 R 3  is (C 1 -C 6 )alkyl; 
 R 4  is (C 1 -C 6 )alkyl; and 
 Q is CH or N. 
 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein, the dual MET and VEGF modulator is a compound of Formula Ia 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is halo; 
 R 2  is halo; and 
 Q is CH or N. 
 
     
     
         6 . The method of  claim 1 , wherein the compound of Formula I is Compounds I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         7 . The compound of  claim 6 , which is N-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. 
     
     
         8 . The method of  claim 1 , wherein the compound of Formula (I), Formula I(a) and Compound 1 is the (L)- or (D)-malate salt. 
     
     
         9 . The method of  claim 1 , wherein the compound of Formula (I) is in the crystalline N-1 form of the (L) malate salt and/or the (D) malate salt. 
     
     
         10 . The method of  claim 1  wherein the compound of Formula I, I(a), or Compound 1, or a pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition additionally comprising a pharmaceutically acceptable carrier, excipient, or diluent. 
     
     
         11 . A method for treating osteoblastic bone metastases associated with CRPC, comprising administering a pharmaceutical composition comprising Compound of Formula I or the malate salt of Compound of Formula I or another pharmaceutically acceptable salt of Compound of Formula I, to a patient in need of such treatment. 
     
     
         12 . A method for ameliorating abnormal deposition of unstructured bone accompanied by increased skeletal fractures, spinal cord compression, and severe bone pain of osteoblastic bone metastases, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of Formula I in any of the embodiments disclosed herein. 
     
     
         13 . A method for reducing or stabilizing metastatic bone lesions associated with CRPC, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising Compound of Formula I or the malate salt of Compound of Formula I or another pharmaceutically acceptable salt of Compound of Formula I, to a patient in need of such treatment. 
     
     
         14 . A method for reducing bone pain due to metastatic bone lesions associated with CRPC, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising Compound of Formula I or the malate salt of Compound of Formula I or another pharmaceutically acceptable salt of Compound of Formula I, to a patient in need of such treatment. 
     
     
         15 . A method for treating or minimizing bone pain due to metastatic bone lesions associated with CRPC, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising Compound of Formula I or the malate salt of Compound of Formula I or another pharmaceutically acceptable salt of Compound of Formula I, to a patient in need of such treatment. 
     
     
         16 . A method for preventing osteoblastic bone metastases associated with CRPC, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising Compound of Formula I or the malate salt of Compound of Formula I or another pharmaceutically acceptable salt of Compound of Formula I, to a patient in need of such treatment. 
     
     
         17 . A method for preventing bone metastases in patients with prostate cancer who are castration resistant but have not yet advanced to metastatic disease, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising Compound of Formula I or the malate salt of Compound of Formula I or another pharmaceutically acceptable salt of Compound of Formula I, to a patient in need of such treatment. 
     
     
         18 . A method for extending the overall survival in patients with CRPC, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising Compound of Formula I or the malate salt of Compound of Formula I or another pharmaceutically acceptable salt of Compound of Formula I, to a patient in need of such treatment.