Fused Amino Pyridines for the Treatment of Lung Cancer

Abstract

The present invention relates to the use of compounds with fused amino pyridine core for the treatment of malignancies associated with brain and lung. The oral administration of compounds of the instant application results in effective brain penetration and provides for non-intrusive treatment of brain and lung tumors.

What is claimed is: 
     
         1 . A method of treating lung cancer comprising the oral administration of a compound of formula I: 
       
         
           
           
               
               
           
         
         or its pharmaceutically acceptable salts thereof, wherein; 
         n is 1 or 2; 
         R 1  and R 2  are independently H, C 1 -C 8  alkyl, or C 1 -C 8  substituted alkyl; 
         R 3  and R 4  are independently H, C 1 -C 8  alkyl, or C 1 -C 8  substituted alkyl; 
         R 5  is halogen, —SR 6  or —NR 6 R 7  wherein R 6  and R 7  are independently H, C 1 -C 8  alkyl, C 1 -C 8  substituted alkyl, C 2 -C 8  alkenyl, C 2 -C 8  substituted alkenyl, C 2 -C 8  alkynyl, C 2 -C 8  substituted alkynyl or C 3 -C 8  cycloalkyl; and, 
         Y is C 1 -C 8  alkyl, C 1 -C 8  substituted alkyl, C 2 -C 8  alkenyl, C 2 -C 8  substituted alkenyl, C 2 -C 8  alkynyl, C 2 -C 8  substituted alkynyl, C 3 -C 8  cycloalkyl or C 3 -C 8  substituted cycloalkyl. 
       
     
     
         2 . The method of  claim 1 , wherein the lung cancer is small cell lung cancer. 
     
     
         3 . The method of  claim 1 , wherein the lung cancer is non-small cell lung cancer. 
     
     
         4 . The method of  claim 1 , wherein said non-small cell lung cancer is selected from adenocarcinoma, squamous cell lung carcinoma and large cell lung carcinoma. 
     
     
         5 . A method according to  claim 1 , wherein said compound of formula I has a c Log P value of more than 3.70. 
     
     
         6 . A method according to  claim 5 , wherein said c Log P value is more than about 4.00. 
     
     
         7 . A method according to  claim 6 , wherein said c Log P value is more than about 4.20. 
     
     
         8 . A method of treating lung cancer in a patient that fails to respond to treatment by an inhibitor of epidermal growth factor (EGFR) selected from gefitinib, erlotinib, vandetanib, AEE-788, PKI-166, PTK787/ZK222584, lapatinib, cetuximab, nimotuzumab, matuzumab, panitumumab, trastuzumab and pertuzumab by administration of a compound of formula I. 
     
     
         9 . The method of  claim 8 , wherein said patient harbors a mutation to the EGFR gene. 
     
     
         10 . The method of  claim 8 , wherein said patient has acquired resistance to EGFR inhibitors. 
     
     
         11 . The method of  claim 10 , wherein said acquired resistance results from a T790M mutation of the EGFR gene. 
     
     
         12 . The method of  claim 10 , wherein said acquired resistance results from D761Y mutation of the EGFR gene. 
     
     
         13 . The method of  claim 10 , wherein said acquired resistance results from L858R mutation of the EGFR gene. 
     
     
         14 . The method of  claim 8 , wherein said patient harbors a mutation to K-Ras gene. 
     
     
         15 . The method of  claim 14 , wherein said mutation renders the patient resistant to treatment by erlotinib and/or lapatinib. 
     
     
         16 . A method according to  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salts thereof. 
       
     
     
         17 . A method of regulating the level of HSP70 in the brain tissue of patient by the oral administration of a compound of formula I to a patient in need thereof. 
     
     
         18 . The method according to  claim 17 , wherein said level of HSP70 is increased.