6,7-Dimethoxyquinazolines and therapeutic use thereof

Abstract

Quinazoline compounds and methods for the treatment of cancer and for the treatment of allergic reactions.

We claim:  
     
         1 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R a  is iodo, (C 1 -C 4 )hydroxyalkyl, methylenedioxy, ethylenedioxy, benzyloxy, OCF 3 . SCF 3 SO 3 H, SO 2 F, SO 2 NR 2 R 3  where R 2  is hydrogen or (C 1 -C 4 )alkyl and R 3  is hydrogen, (C 1- C 4 )alkyl, or phenyl, NR 2 R 4  where R 2  is hydrogen or (C 1 -C 4 )alkyl and R 4  is phenyl; or a group of the formula  
                     
 wherein R 5  and R 6  are each independently, hydrogen, (C 1 -C 4 )alkyl, or (C 1 -C 4 ) perfluoroalkyl, and R 7  is hydrogen, halo, hydroxy, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )hydroxyalkyl, or N(R 2 ) 2 , where R 2  is hydrogen or (C 1 -C 4 )alkyl;  
 n is an integer of 1-4;  
 R b  is each, independently, hydrogen, halo, hydroxy, mercapto, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )thioalkyl, (C 1 -C 4 )hydroxyalkyl, nitro, cyano, methylenedioxy, ethylenedioxy, COCH 3,  CF 3,  OCF 3,  SCF 3,  COOH, SO 3 H, SO 2 F, phenyl, or phenyl substituted by a group selected from halo, hydroxy, mercapto, (C 1 -C 4 )alkyl, (C 1 -C 4 ) alkoxy, (C 1 -C 4 )thioalkyl, (C 1 -C 4 )hydroxyalkyl, amino, nitro, cyano, CF 3 , COOH, SO 3 H, SO 2 NR 2 R 3 , SO 2 F where R 2  is H or (C 1 -C 4 )alkyl and R 3  is H, (C 1 -C 4 )alkyl, phenyl, or phenyl substituted by a group as defined above; benzyloxy or benzyloxy substituted on the phenyl portion by a group defined above; NR 2 R 3  where R 2  is H or (C 1 -C 4 )alkyl and R 3  is H, (C 1 -C 4 )alkyl, phenyl, or phenyl substituted by a group as defined above; and  
 R 1  is (C 1 -C 4 )alkyl or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . The compound of  claim 1  wherein the pharmaceutically acceptable salt is an acid addition salt.  
     
     
         3 . The compound of  claim 1 , wherein R 1  is methyl.  
     
     
         4 . The compound of  claim 3 , wherein R a  is a member selected from the group consisting of I, NHC 6 H 5 , —OCH 2 CH 2 O—, —OCH 2 O—, OCF 3 , SCF 3 , CH 2 OH, C 2 H 4 OH, SO 3 H, SO 2 NH 2 , and SO 2 F.  
     
     
         5 . The compound of  claim 4 , wherein R a  is I, OCF 3,  or SO 2 F.  
     
     
         6 . The compound of  claim 5 , wherein R a  is I.  
     
     
         7 . The compound of  claim 5  wherein R a  is OCF 3 .  
     
     
         8 . The compound of  claim 3 , wherein n is I and R a  is a group of the formula  
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 8 , wherein R 5  and R 6  are each, independently, H, CH 3,  or CF 3 .  
     
     
         10 . The compound of  claim 9 , wherein R 5  and R 6  are CF 3  and R 7  is NH 2 .  
     
     
         11 . The compound of  claim 3 , wherein R b  is at least one member selected from the group consisting of F, Cl, Br, I, OH, NH 2 , NO 2 , CN, COOH, CH 3  and CF 3 .  
     
     
         12 . The compound of  claim 11 , wherein R b  is at least one member selected from the group consisting of F, Cl, Br, OH and CF 3 .  
     
     
         13 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier or diluent.  
     
     
         14 . A method of treating tumors in a subject comprising administering to said subject an anti-tumor effective amount of a compound of  claim 1 .  
     
     
         15 . A method of treating leukemia in a subject comprising administering to said subject a compound of  claim 1  in an amount effective for inducing apoptosis of leukemia cells.  
     
     
         16 . A method of inhibiting cancer cell growth in a subject comprising administering to said subject a cytotoxic effective amount of a compound of  claim 1 .  
     
     
         17 . A method of treating leukemia in a subject comprising administering to said subject a compound selected from the group consisting of: 
 4-(3′,5′-dibromo-4′-methylphenyl)amino-6,7-dimethoxyquinazoline,    4-(2′,4′,6′-tribromophenyl)amino-6,7-dimethoxyquinazoline,    4-(2′,3′,5′,6′-tetrafluoro-4′-bromophenyl)amino-6,7-dimethoxyquinazoline,    4-(4′-fluorophenyl)amino-6,7-dimethoxyquinazoline,    4-(3′-fluorophenyl)amino-6,7-dimethoxyquinazoline,    4-(2′-fluorophenyl)amino-6,7-dimethoxyquinazoline,    4-(4′-trifluoromethylphenyl)amino-6,7-dimethoxyquinazoline,    4-(2′-trifluoromethylphenyl)amino-6,7-dimethoxyquinazoline,    4-(3′,5′-bis-trifluoromethylphenyl)amino-6,7-dimethoxyquinazoline,    and pharmaceutically acceptable acid addition salts thereof.    
     
     
         18 . A method of treating breast tumors in a subject comprising administering to said subject a compound selected from the group consisting of 
 4-(3′-bromophenyl)amino-6,7-dimethoxyquinazoline,    4-(3′,5′-dibromo-4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,    4-(3′-chloro-4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline,    4-(3′,5′-bis-trifluoromethylphenyl)amino-6,7-dimethoxyquinazoline,    4-(2′,3′,5′,6′-tetrafluoro-4′-bromophenyl)amino-6,7-dimethoxyquinazoline,    4-(4′-fluorophenyl)amino-6,7-dimethoxyquinazoline,    4-(3′-fluorophenyl)amino-6,7-dimethoxyquinazoline,    4-(2′-fluorophenyl)amino-6,7-dimethoxyquinazoline, and    pharmaceutically acceptable acid addition salts thereof.    
     
     
         19 . A method of treating multi-drug resistant leukemia in a subject comprising administering to said subject 4-(4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline or a pharmaceutically acceptable salt thereof, in an amount effective for inducing apoptosis of multi-drug resistant leukemia cells.  
     
     
         20 . A method of treating multi-drug resistant leukemia in a subject comprising administering to said subject 4-(3′-bromo-4′-hydroxyphenyl)amino-6,7-dimethoxyquinazoline or a pharmaceutically acceptable acid addition salt thereof, in an amount effective for inducing apoptosis of multi-drug resistant leukemia cells.  
     
     
         21 . The compound 4-(3′,5′-dibromo-4′-methylphenyl)amino-6,7-dimethoxyquinazoline or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         22 . The compound 4-2′,4′,6′-tribromophenyl)amino6,7-dimethoxyquinazoline or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         23 . The compound 4-(2′,3′,5′,6′-tetrafluoro-5′-bromophenyl)amino-6,7-dimethoxyquinazoline or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         24 . The compound 4-(4′-fluorophenyl)amino-6,7-dimethoxyquinazoline or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         25 . The compound 4-(4′-trifluoromethylphenyl)amino-6,7-dimethoxyquinazoline or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         26 . The compound 4-(3′,5′-bis-trifluoromethylphenyl)amino-6,7-dimethoxy-quinazoline or a pharmaceutically acceptable acid addition salt thereof.  
     
     
         27 . A pharmaceutical composition comprising an effective amount of a compound selected from the group consisting of: 
 4-(3,5-bis-trifluoromethylphenyl)amino-6,7-dimethoxyquinazoline,    4-(2′,4′,6′-tribromophenyl)amino-6,7-dimethoxyquinazoline,    4-(2′,3′,5′,6′-tetrafluoro-4′-bromophenyl)amino-6,7-dimethoxyquinazoline,    4-(3′,5′-dibromo-4′-methylphenyl)amino-6,7-dimethoxyquinazoline,    4-(4′-fluorophenyl)amino-6,7-dimethoxyquinazoline,    4-(4′-tifluoromethylphenyl)amino-6,7-dimethoxyquinazoline, and    pharmaceutically acceptable acid addition salts thereof; and    a pharmaceutically acceptable carrier or diluent.