JAK-3 inhibitors for treating allergic disorders

Abstract

Inhibitors of JAK3 kinase for the treatment of allergy, and others are described.

1 . A method for inhibiting JAK-3 tyrosine kinase activity comprising contacting 
 JAK-3 tyrosine kinase with a compound of formula:                          wherein    X is HN, R 11 N, S, O, CH 2 , or R 11 CH;    R 11  is (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkanoyl; 
 R 1 —R 8  are each independently hydrogen, hydroxy, mercapto, amino, nitro, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, or halo;  
 R 9 —R 10  are each independently hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkanoyl or halo; or R 9  and R 10  together are methylenedioxy; or a pharmaceutically acceptable salt thereof;  
 wherein two adjacent groups of R 1 —R 5  together with the phenyl ring to which they are attached may optionally form a fused ring; and  
 wherein the ring formed by the two adjacent groups of R 1 —R 5  may optionally each be independently hydroxy, mercapto, amino, nitro, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, or halo.  
   
     
     
         2 . The method according to  claim 1  wherein the compound is 4-(3′-5′-dibromo-4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline, or pharmaceutically acceptable salts thereof.  
     
     
         3 . A method for treating asthma comprising administering to a patient a therapeutically effective amount of a compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 X is HN, R 11 N, S, O, CH 2 , or R 11 CH;  
 R 11  is (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkanoyl; 
 R 1 —R 8  are each independently hydrogen, hydroxy, mercapto, amino, nitro, (C 1 -C 4 )alkyl, (C 1 -C 4 )ailoxy, (C 1 -C 4 )alkylthio, or halo;  
 R 9 —R 10  are each independently hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkanoyl or halo; or R 9  and R 10  together are methylenedioxy; or a pharmaceutically acceptable salt thereof;  
 wherein two adjacent groups of R 1 —R 5  together with the phenyl ring to which they are attached may optionally form a fused ring; and  
 
 wherein the ring formed by the two adjacent groups of R 1 —R 5  may optionally be substituted with hydroxy, mercapto, amino, nitro, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, or halo.  
 
     
     
         4 . The method according to  claim 3  wherein the compound is 4-(3′-5′-dibromo-4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline, or pharmaceutically acceptable salts thereof.  
     
     
         5 . The method according to  claim 3  wherein the JAK-3 inhibitor comprises 4-(4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline; or a pharmaceutically acceptable salt thereof.  
     
     
         6 . The method according to  claim 3  wherein the JAK-3 inhibitor comprises 4-(3′-bromo-4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline; or a pharmaceutically acceptable salt thereof.  
     
     
         7 . A method for treating allergic reaction comprising administering to a patient a therapeutically effective amount of a compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 X is HN, R 11 N, S, O, CH 2 , or R 11 CH;  
 R 11  is (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkanoyl; 
 R 1 —R 8  are each independently hydrogen, hydroxy, mercapto, amino, nitro, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, or halo;  
 R 9 —R 10  are each independently hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkanoyl or halo; or R 9  and R 10  together are methylenedioxy; or a pharmaceutically acceptable salt thereof;  
 wherein two adjacent groups of R 1 —R 5  together with the phenyl ring to which they are attached may optionally form a fused ring; and  
 wherein the ring formed by the two adjacent groups of R 1 —R 5  may optionally be substituted with hydroxy, mercapto, amino, nitro, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, or halo.  
 
 
     
     
         8 . The method according to  claim 7 , wherein the compound is 4-(3′-5′-dibromo-4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline, or pharmaceutically acceptable salts thereof.  
     
     
         9 . The method according to  claim 7  wherein the JAK-3 inhibitor comprises 4-(4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline; or a pharmaceutically acceptable salt thereof.  
     
     
         10 . The method according to  claim 7 , wherein the JAK-3 inhibitor comprises 4-(3′-bromo-4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline; or a pharmaceutically acceptable salt thereof.  
     
     
         11 . A method for inhibiting proinflamatory mediator release comprising administering to a patient a therapeutically effective amount of a compound of formula:  
       
         
           
           
               
               
           
         
       
       wherein 
 X is HN, R 11 N, S, O, CH 2 , or R 11 CH;  
 R 11  is (C 1 -C 4 )alkyl, or (C 1 -C 4 )alkanoyl; 
 R 1 —R 8  are each independently hydrogen, hydroxy, mercapto, amino, nitro, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, or halo;  
 R 9 —R 10  are each independently hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkanoyl or halo; or R 9  and R 10  together are methylenedioxy; or a pharmaceutically acceptable salt thereof;  
 wherein two adjacent groups of R 1 —R 5  together with the phenyl ring to which they are attached may optionally form a fused ring; and  
 wherein the ring formed by the two adjacent groups of R 1 —R 5  may optionally be substituted with hydroxy, mercapto, amino, nitro, (C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkylthio, or halo.  
 
 
     
     
         12 . The method according to  claim 11 , wherein the compound is 4-(3′-5′-dibromo-4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline, or pharmaceutically acceptable salts thereof.  
     
     
         13 . The method according to  claim 11 , wherein the JAK-3 inhibitor comprises 4-(4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline; or a pharmaceutically acceptable salt thereof.  
     
     
         14 . The method according to  claim 11 , wherein the JAK-3 inhibitor comprises 4-(3′-bromo-4′-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline; or a pharmaceutically acceptable salt thereof.  
     
     
         15 . The method according to  claim 11 , wherein the proinflamatory mediator comprises a proinflamatory cytokine TNFa.