Sulfonamido ether substituted imidazoquinolines

Abstract

Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain ether and sulfonamide or sulfamide functionality at the 1-position are useful as immune response modifiers. The compounds and compositions of the invention can induce the biosynthesis of various cytokines and are useful in the treatment of a variety of conditions including viral diseases and neoplastic diseases.

What is claimed is:  
     
         1 . A compound of the formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: X is —CHR 5 —, —CHR 5 -alkyl-, or —CHR 5 -alkenyl-; 
 R 1  is selected from the group consisting of: 
 —R 4 —NR 3 —SO 2 —R 6 -alkyl;  
 —R 4 —NR 3 —SO 2 —R 6 -alkenyl;  
 —R 4 —NR 3 —SO 2 —R 6 -aryl;  
 —R 4 —NR 3 —SO 2 —R 6 -heteroaryl;  
 —R 4 —NR 3 —SO 2 —R 6 -heterocyclyl;  
 —R 4 —NR 3 —SO 2 —R 7 ;  
 —R 4 —NR 3 —SO 2 —NR 5 —R 6 -alkyl;  
 —R 4 —NR 3 —SO 2 —NR 5 —R 6 -alkenyl;  
 —R 4 —NR 3 —SO 2 —NR 5 —R 6 -aryl;  
 —R 4 —NR 3 —SO 2 —NR 5 —R 6 -heteroaryl;  
 —R 4 —NR 3 —SO 2 —NR 5 —R 6 -heterocyclyl; and  
 —R 4 —NR 3 —SO 2 —NH 2 ;  
 
 R 2  is selected from the group consisting of: 
 -hydrogen;  
 -alkyl;  
 -alkenyl;  
 -aryl;  
 -heteroaryl;  
 -heterocyclyl;  
 -alkyl-Y-alkyl;  
 -alkyl-Y- alkenyl;  
 -alkyl-Y-aryl; and  
 -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: 
 —OH;  
 -halogen;  
 —N(R 5 ) 2 ;  
 —CO—N(R 5 ) 2 ;  
 —CO—C 1-10  alkyl;  
 —CO—O—C 1-10  alkyl;  
 —N 3 ;  
 -aryl;  
 -heteroaryl;  
 -heterocyclyl;  
 —CO-aryl; and  
 —CO-heteroaryl;  
 
 
 Y is —O— or —S(O) 0-2 —;  
 R 3  is H, C 1-10  alkyl, or arylalkyl;  
 R 4  is alkyl or alkenyl, which may be interrupted by one or more —O— groups; or R 3  and R 4  can join together to form a ring; each R 5  is independently H, C 1-10  alkyl, or C 2-10  alkenyl;  
 R 6  is a bond, alkyl, or alkenyl, which may be interrupted by one or more —O— groups;  
 R 7  is C 1-10  alkyl; or R 3  and R 7  can join together to form a ring;  
 n is 0to 4; and  
 each R present is independently selected from the group consisting of C 1-10  alkyl, C 1-10  alkoxy, hydroxy, halogen and trifluoromethyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A compound or salt of  claim 1  wherein X is —CH(alkyl)-alkyl-, wherein the alkyl groups can be the same or different.  
     
     
         3 . A compound or salt of  claim 1  wherein X is —CH 2 —CH 2 —.  
     
     
         4 . A compound or salt of  claim 1  wherein X is —CH(C 2 H 5 )—CH 2 —.  
     
     
         5 . A compound or salt of  claim 1  wherein R 2  is H.  
     
     
         6 . A compound or salt of  claim 1  wherein R 2  is alkyl.  
     
     
         7 . A compound or salt of  claim 1  wherein R 2  is -alkyl-O-alkyl.  
     
     
         8 . A compound or salt of  claim 1  wherein R 3  and R 4  join to form a heterocyclic ring.  
     
     
         9 . A compound or salt of  claim 1  wherein R 1  is —R 4 —NR 3 —SO 2 —R 6 -aryl.  
     
     
         10 . A compound or salt of  claim 1  wherein n is o.  
     
     
         11 . A compound selected from the group consisting of: 
 N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide;    N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)methanesulfonamide;    N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmethanesulfonamide;    N-(2-{2-[4-amino-2-(2-methoxyethyl)-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylmethanesulfonamide;    2-butyl-1-{2-[2-(1,1-dioxidoisothiazolidin-2-yl)ethoxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-amine; and    N-[10-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)-4,7-dioxadecyl]-5-dimethylaminonaphthalene-1-sulfonamide;    or a pharmaceutically acceptable salt thereof.    
     
     
         12 . A compound selected from the group consisting of: 
 N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylpropane-2-sulfonamide;    N-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}methanesulfonamide;    N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}methanesulfonamide; and    N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethyl}propane-2-sulfonamide;    or a pharmaceutically acceptable salt thereof.    
     
     
         13 . A compound of the formula (II)  
       
         
           
           
               
               
           
         
       
       wherein: X is —CHR 5 —, —CHR 5 -alkyl-, or —CHR 5 -alkenyl-; 
 R 1  is selected from the group consisting of: 
 —R 4 —NR 3 —SO 2 —R 6 -alkyl;  
 —R 4 —NR 3 —SO 2 —R 6 -alkenyl;  
 —R 4 —NR 3 —SO 2 —R 6 -aryl;  
 —R 4 —NR 3 —SO 2 —R 6 -heteroaryl;  
 —R 4 —NR 3 —SO 2 —R 6 -heter ocyclyl;  
 —R 4 —NR 3 —SO 2 —R 7 ;  
 —R 4 —NR 3 —SO 2 —NR 5 —R 6 -alkyl;  
 —R 4 —NR 3 —SO 2 —NR 5 —R 6 -alkenyl;  
 —R 4 —NR 3 —SO 2 —NR 5 —R 6 -aryl;  
 —R 4 —NR 3 —SO 2 —NR 5 —R 6 -heteroaryl;  
 —R 4 —NR 3 —SO 2 —NR 5 —R 6 -heterocyclyl; and  
 —R 4 —NR 3 —SO 2 —NH 2 ;  
 
 R 2  is selected from the group consisting of: 
 -hydrogen;  
 -alkyl;  
 -alkenyl;  
 -aryl;  
 -heteroaryl;  
 -heterocyclyl;  
 -alkyl-Y-alkyl;  
 -alkyl-Y- alkenyl;  
 -alkyl-Y-aryl; and  
 -alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: 
 —OH;  
 -halogen;  
 —N(R 5 ) 2 ;  
 —CO—N(R 5 ) 2 ;  
 —CO—C 1-10  alkyl;  
 —CO—O—C 1-10  alkyl;  
 —N 3 ;  
 -aryl;  
 -heteroaryl;  
 -heterocyclyl;  
 —CO-aryl; and  
 —CO-heteroaryl;  
 
 
 Y is —O— or —S(O) 0-2 —;  
 R 3  is H, C 1-10  alkyl, or arylalkyl;  
 R 4  is alkyl or alkenyl, which may be interrupted by one or more —O— groups; or R 3  and R 4  can join together to form a ring;  
 each R 5  is independently H, C 1-10  alkyl, or C 2-10  alkenyl;  
 R 6  is a bond, alkyl, or alkenyl, which may be interrupted by one or more —O— groups;  
 R 7  is C 1-10  alkyl; or R 3  and R 7  can join together to form a ring;  
 n is 0 to 4; and  
 each R present is independently selected from the group consisting of C 1-10  alkyl, C 1-10  alkoxy, hydroxy, halogen, and trifluoromethyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         14 . A compound or salt of  claim 13  wherein R 2  is H or alkyl.  
     
     
         15 . A compound or salt of  claim 13  wherein R 2  is -alkyl-O-alkyl.  
     
     
         16 . A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         17 . A method of inducing cytokine biosynthesis in an animal comprising administering a therapeutically effective amount of a compound or salt of  claim 1  to the animal.  
     
     
         18 . The method of  claim 17  wherein the cytokine is IFN-α.  
     
     
         19 . A method of treating a viral disease in an animal comprising administering a therapeutically effective amount of a compound or salt of  claim 1  to the animal.  
     
     
         20 . A method of treating a neoplastic disease in an animal comprising administering a therapeutically effective amount of a compound or salt of  claim 1  to the animal.  
     
     
         21 . A compound of the formula (III):  
       
         
           
           
               
               
           
         
       
       wherein X is —CHR 5 —, —CHR 5 -alkyl-, or —CHR 5 -alkenyl-; 
 R 1  is selected from the group consisting of: 
 —R 4 —NR 3 —SO 2 —R 6 -alkyl;  
 —R 4 —NR 3 —SO 2 —R 6 -alkenyl;  
 —R 4 —NR 3 —SO 2 —R 6 -aryl;  
 —R 4 —NR 3 —SO 2 —R 6 -heteroaryl;  
 —R 4 —NR 3 —SO 2 —R 6 -heterocyclyl;  
 —R 4 —NR 3 —SO 2 —R 7 ;  
 —R 4 —NR 3 —SO 2 —NR 5 —R 6 -alkyl;  
 —R 4 —NR 3 —SO 2 —NR 5 —R 6 -alkenyl;  
 —R 4 —NR 3 —SO 2 —NR 5 —R 6 -aryl;  
 —R 4 —NR 3 —SO 2 —NR 5 —R 6 -heteroaryl;  
 —R 4 —NR 3 —SO 2 —NR 5 —R 6 -heterocyclyl; and  
 —R 4 —NR 3 —SO 2 —NH 2 ;  
 
 R 2  is selected from the group consisting of: 
 -hydrogen;  
 -alkyl;  
 -alkenyl;  
 -aryl;  
 -heteroaryl;  
 -heterocyclyl;  
 -alkyl-Y-alkyl;  
 -alkyl-Y-alkenyl;  
 -alkyl-Y-aryl; and  
 - alkyl or alkenyl substituted by one or more substituents selected from the group consisting of: 
 —OH;  
 -halogen;  
 —N(R 5 ) 2 ;  
 —CO—N(R 5 ) 2 ;  
 —CO—C 1-10  alkyl;  
 —CO—O—C 1-10  alkyl;  
 —N 3 ;  
 -aryl;  
 -heteroaryl;  
 -heterocyclyl;  
 —CO-aryl; and  
 —CO-heteroaryl;  
 
 
 Y is —O— or —S(O) 0-2 —;  
 R 3  is H, C 1-10  alkyl, or arylalkyl;  
 R 4  is alkyl or alkenyl, which may be interrupted by one or more —O— groups; or R 4  and R 3  can join to form a ring;  
 each R 5  is independently H, C 1-10  alkyl, or C 2-10  alkenyl;  
 R 6  is a bond, or is alkyl or alkenyl, which may be interrupted by one or more —O— groups;  
 R 7  is C 1-10  alkyl; or R 3  and R 7  can join together to form a ring;  
 n is 0 to 4; and  
 each R present is independently selected from the group consisting of C 1-10  alkyl, C 1-10  alkoxy, hydroxy, halogen and trifluoromethyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         22 . A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of  claim 13  and a pharmaceutically acceptable carrier.  
     
     
         23 . A method of inducing cytokine biosynthesis in an animal comprising administering a therapeutically effective amount of a compound or salt of  claim 13  to the animal.  
     
     
         24 . The method of  claim 23  wherein the cytokine is IFN-α.  
     
     
         25 . A method of treating a viral disease in an animal comprising administering a therapeutically effective amount of a compound or salt of  claim 13  to the animal.  
     
     
         26 . A method of treating a neoplastic disease in an animal comprising administering a therapeutically effective amount of a compound or salt of  claim 13  to the animal.