Methods for treating vascular malformations

Abstract

The present disclosure relates to methods for inhibiting TIE2 kinase useful in the treatment of growth of venous malformations. Specifically, the disclosure relates to methods of using a compound of Formula I and salts thereof

1 . A method for treating TIE2 kinase-mediated vascular anomalies or TIE2 kinase mutant-mediated vascular anomalies, in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the pharmaceutically acceptable salt is tosylate. 
     
     
         3 . The method of  claim 1 , wherein the TIE2 kinase-mediated vascular anomalies or TIE2 kinase mutant-mediated vascular anomalies are slow-flow malformations. 
     
     
         4 . The method of  claim 3 , wherein the slow-flow malformations are selected from capillary malformations, lymphatic malformations, or venous malformations. 
     
     
         5 . The method of  claim 4 , wherein the slow-flow malformations are venous malformations. 
     
     
         6 . The method of  claim 1 , comprising administering to the patient the compound of Formula I once daily, intermittent non-daily, every other day, every third day, every other week, twice daily, once weekly, or twice weekly. 
     
     
         7 . The method of  claim 1 , comprising administering to the patient about 57 mg to about 1200 mg of the compound of Formula I daily. 
     
     
         8 . The method of  claim 1 , comprising administering to the patient about 100 mg of the compound of Formula I daily. 
     
     
         9 . The method of  claim 1 , comprising administering to the patient about 150, 200, or 300 mg of the compound of Formula I once or twice daily. 
     
     
         10 . A method for treating vascular anomalies, in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; 
         wherein the vascular anomalies are mediated by TIE2 kinase or by TIE2 kinase mutant-mediated. 
       
     
     
         11 . The method of  claim 1  or  10 , further comprising administering a second therapeutic agent to the patient. 
     
     
         12 . The method of  claim 11 , wherein the second therapeutic agent is a VEGF inhibitor. 
     
     
         13 . The method of  claim 12 , wherein the VEGF inhibitor is selected from pazopanib, bevacizumab, cabozantinib, sunitinib, sorafenib, axitinib, regorafenib, ponatinib, cabozantinib, vandetanib, ramucirumab, lenvatinib, bevacizumab, and ziv-aflibercept. 
     
     
         14 . The method of  claim 11 , wherein the second therapeutic agent is an Akt inhibitor. 
     
     
         15 . The method of  claim 14 , wherein the Akt inhibitor is selected from AZD5363, miltefosine, perifosine, VQD-002, MK-2206, GSK690693, GDC-0068, triciribine, CCT128930, PHT-427, and honokiol. 
     
     
         16 . The method of  claim 11 , wherein the second therapeutic agent is a mTOR inhibitor. 
     
     
         17 . The method of  claim 16 , wherein the mTOR inhibitor is selected from sirolimus, temsirolimus, everolimus, AP23841, AZD8055, BEZ235, BGT226, deferolimus (AP23573/MK-8669), EM101/LY303511, EX2044, EX3855, EX7518, GDC0980, INK-128, KU-0063794, NV-128, OSI-027, PF-4691502, rapalogs, rapamycin, ridaforolimus, SAR543, SF1126, WYE-125132, XL765, zotarolimus (ABT578), torin 1, GSK2126458, AZD2014, GDC-0349, and XL388. 
     
     
         18 . The method of  claim 11 , wherein the second therapeutic agent is a PI3K inhibitor. 
     
     
         19 . The method of  claim 18 , wherein the PI3K inhibitor is selected from idelalisib, copanlisib, duvelisib, alpelisib, NVP-BEZ235, BKM-120, GDC-0941, GDC-0980, SF1126, PX-866, PF-04691502, XL-765, XL-147, GSK2126458, and ZSTK474. 
     
     
         20 - 37 . (canceled) 
     
     
         38 . A method for treating venous malformations in a patient in need thereof, comprising administering to the patient about 100 to about 200 mg, once or twice daily, of the compound of Formula I: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         39 . A compound of Formula I, or a pharmaceutically acceptable salt thereof 
       
         
           
           
               
               
           
         
         for use in the treatment of venous malformations in a patient in need thereof, comprising administering to the patient about 100 mg to about 200 mg, once or twice daily, of the compound of Formula I, or a pharmaceutically acceptable salt thereof.