Methods for inhibiting tie-2 kinase useful in the treatment of cancer

Abstract

The present invention relates to methods of inhibiting TIE2 kinase useful in the treatment of tumor growth, invasiveness, intravasation, dissemination, metastasis, and immunosuppression. Specifically, the invention relates to methods of using 1-(3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl)-3-(2-fluoro-4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)urea and salts thereof of Formula I.

1 . A method of blocking primary breast tumor growth and invasiveness comprising administering to a patient in need thereof an effective amount of a composition of Formula I 
       
         
           
           
               
               
           
         
         wherein
 n is an integer from 0 to 7; 
 X is the basic radical of a pharmaceutically acceptable salt; 
 provided that when n is 0, the composition of Formula I is the parent free base; 
 
         in a dosing regimen sufficient to block TIE2 kinase in the tumor microenvironment. 
       
     
     
         2 . The method of  claim 1 , wherein the dosing regimen is administered daily. 
     
     
         3 . The method of  claim 1 , wherein the dosing regimen is intermittent non-daily dosing, alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing. 
     
     
         4 . The method of  claim 1 , wherein the dosing regimen is twice weekly, once weekly, or on an alternately weekly dosing. 
     
     
         5 . The method of  claim 1 , wherein the composition of Formula I is used in combination with one or more agents taken from an anti-tubulin agent. 
     
     
         6 . The method of  claim 1 , wherein the composition of Formula I is used in combination with paclitaxel. 
     
     
         7 . The method of  claim 1 , wherein the composition of Formula I is used in combination with paclitaxel protein-bound particles for injectable suspension. 
     
     
         8 . The method of  claim 1 , wherein the compound of Formula I is used in combination with eribulin. 
     
     
         9 . The method of  claim 1 , wherein the composition of Formula I is used in combination with docetaxel, ixabepilone, or vinorelbine. 
     
     
         10 .- 35 . (canceled) 
     
     
         36 . The method of  claim 1 , wherein the composition of Formula I is the composition having Formula IL 
       
         
           
           
               
               
           
         
         and wherein Formula II is used in combination with one or more agents taken from an anti-tubulin agent comprising paclitaxel, paclitaxel protein-bound particles for injectable suspension, eribulin, ixabepilone, and vinorelbine. 
       
     
     
         37 . (canceled) 
     
     
         38 . A method of blocking breast cancer intravasation, dissemination and metastasis, comprising administering to a patient in need thereof an effective amount of a composition of Formula I 
       
         
           
           
               
               
           
         
         wherein
 n is an integer from 0 to 7; 
 X is the basic radical of a pharmaceutically acceptable salt; 
 provided that when n is 0, the composition of Formula I is the parent free base, 
 
         in a dosing regimen sufficient to block TIE2 kinase in tumor microenvironment TIE2-expressing macrophages. 
       
     
     
         39 . The method of  claim 38 , wherein the dosing regimen of is administered daily. 
     
     
         40 . The method of  claim 38 , wherein the dosing regimen is intermittent non-daily dosing, alternate daily dosing, every third daily dosing, twice weekly dosing, or once weekly dosing. 
     
     
         41 . The method of  claim 38 , wherein the dosing regimen is twice weekly, once weekly, or on an alternately weekly dosing. 
     
     
         42 . The method of  claim 38 , wherein the composition of Formula I is used in combination with one or more agents taken from an anti-tubulin agent. 
     
     
         43 . The method of  claim 38 , wherein the composition of Formula I is used in combination with paclitaxel. 
     
     
         44 . The method of  claim 38 , wherein the composition of Formula I is used in combination with paclitaxel protein-bound particles for injectable suspension. 
     
     
         45 . The method of  claim 38 , wherein the composition of Formula I is used in combination with eribulin. 
     
     
         46 . The method of  claim 38 , wherein the composition of Formula I is used in combination with docetaxel, ixabepilone, or vinorelbine. 
     
     
         47 .- 219 . (canceled)