Amido ether substituted imidazoquinolines

Abstract

Imidazoquinoline and tetrahydroimidazoquinoline compounds that contain ether and amide 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 —CR 3 —Z—R 6 -alkyl;  
 —R 4 —CR 3 —Z—R 6 -alkenyl;  
 —R 4 —CR 3 —Z—R 6 -aryl;  
 —R 4 —CR 3 —Z—R 6 -heteroaryl;  
 —R 4 —CR 3 —Z—R 6 -heterocyclyl;  
 —R 4 —CR 3 —Z—H;  
 —R 4 —NR 7 —CR 3 —R 6 -alkyl;  
 —R 4 —NR 7 —CR 3 —R 6 -alkenyl;  
 —R 4 —NR 7 —CR 3 —R 6 -aryl;  
 —R 4 —NR 7 CR 3 —R 6 -heteroaryl;  
 —R 4 —NR 7 —CR 3 —R 6 -heterocyclyl; and  
 —R 4 —NR 7 —CR 3 —R 8 ;  
 
 Z is —NR 5 —, —O—, or —S—;  
 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—Cl 1-10  alkyl;  
 —CO—O—Cl 1-10  alkyl;  
 —N 3 ;  
 -aryl;  
 -heteroaryl;  
 -heterocyclyl;  
 —CO-aryl; and  
 —CO-heteroaryl;  
 
 
 R 3  is ═O or ═S;  
 R 4  is alkyl or alkenyl, which may be interrupted by one or more —O— groups;  
 each R 5  is independently H or C 1-10  alkyl;  
 R 6  is a bond, alkyl, or alkenyl, which may be interrupted by one or more —O— groups;  
 R 7  is H, C 1-10  alkyl, or arylalkyl; or R 4  and R 7  can join together to form a ring;  
 R 8  is H or C 1-10  alkyl; or R 7  and R 8  can join together to form a ring;  
 Y is —O— or —S(O) 0-2 —;  
 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.  
 
     
     
         2 . A compound or salt of  claim 1  wherein the heteroaryl is selected from the group consisting of 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-thiazolyl, and 4-pyrazolyl.  
     
     
         3 . A compound or salt of  claim 1  wherein X is —CH(alkyl)-alkyl- wherein the alkyl groups can be the same or different.  
     
     
         4 . A compound or salt of  claim 1  wherein X is —CH 2 —CH 2 —.  
     
     
         5 . A compound or salt of  claim 1  wherein X is —CH(C 2 H 5 )—CH 2 —.  
     
     
         6 . A compound or salt of  claim 1  wherein R 2  is H.  
     
     
         7 . A compound or salt of  claim 1  wherein R 2  is alkyl.  
     
     
         8 . A compound or salt of  claim 1  wherein R 2  is -alkyl-O-alkyl.  
     
     
         9 . A compound or salt of  claim 1  wherein n is o.  
     
     
         10 . A compound selected from the group consisting of: 
 N-{2-[2-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)thoxy]ethyl}benzamide;    N-{2-[2-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)thoxy]ethyl}benzamide;    N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N-methylcyclohexanecarboxamide; and    N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl-N methylcyclohexanecarboxamide,    or a pharmaceutically acceptable salt thereof.    
     
     
         11 . 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 —CR 3 —Z—R 6 -alkyl;  
 —R 4 —CR 3 —Z—R 6 -alkenyl;  
 —R 4 —CR 3 —Z—R 6 -aryl;  
 —R 4 —CR 3 —Z—R 6 -heteroaryl;  
 —R 4 —CR 3 —Z—R 6 -heterocyclyl;  
 —R 4 —CR 3 —Z—H;  
 —R 4 —NR 7 —CR 3 —R 6 -alkyl;  
 —R 4 —NR 7 —CR 3 —R 6 -alkenyl;  
 —R 4 —NR 7 —CR 3 —R 6 -aryl;  
 —R 4 —NR 7 —CR 3 —R 6 -heteroaryl;  
 —R 4 —NR 7 —CR 3 —R 6 -heterocyclyl; and  
 —R 4 —NR 7 —CR 3 —R 8 ;  
 
 Z is —NR 5 —, —O—, or —S—;  
 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;  
 
 
 R 3  is ═O or ═S;  
 R 4  is alkyl or alkenyl, which may be interrupted by one or more —O— groups;  
 each R 5  is independently H or C 1-10  alkyl;  
 R 6  is a bond, alkyl, or alkenyl, which may be interrupted by one or more —O— groups;  
 R 7  is H, C 1-10  alkyl, arylalkyl; or R 4  and R 7  can join together to form a ring;  
 R 8  is H or C 1-10  alkyl; or R 7  and R 8  can join together to form a ring;  
 Y is —O— or —S(O) 0-2 —;  
 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.  
 
     
     
         12 . A compound or salt of  claim 11  wherein R 2  is H or alkyl.  
     
     
         13 . A compound or salt of  claim 11  wherein R 2  is -alkyl-O-alkyl.  
     
     
         14 . A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         15 . 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.  
     
     
         16 . The method of  claim 15  wherein the cytokine is IFN-α.  
     
     
         17 . 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.  
     
     
         18 . 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.  
     
     
         19 . 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 —CR 3 —Z—R 6 -alkyl;  
 —R 4 —CR 3 —Z—R 6 -alkenyl;  
 —R 4 —CR 3 —Z—R 6 -aryl;  
 —R 4 —CR 3 —Z—R 6 -heteroaryl;  
 —R 4 —CR 3 —Z—R 6 -heterocyclyl;  
 —R 4 —CR 3 —Z—H;  
 —R 4 —NR 7 —CR 3 —R 6 -alkyl;  
 —R 4 —NR 7 —CR 3 —R 6 -alkenyl;  
 —R 4 —NR 7 —CR 3 —R 6 -aryl;  
 —R 4 —NR 7 —CR 3 —R 6 -heteroaryl;  
 —R 4 —NR 7 —CR 3 —R 6 -heterocyclyl; and  
 —R 4 —NR 7 —CR 3 —R 8 ;  
 
 Z is —NR 5 —, —O—, or —S—;  
 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;  
 
 
 R 3  is ═O or ═S;  
 R 4  is alkyl or alkenyl, which may be interrupted by one or more —O— groups;  
 each R 5  is independently H or C 1-10  alkyl;  
 R 6  is a bond, or is alkyl, or alkenyl, which may be interrupted by one or more —O— groups;  
 R 7  is H, C 1-10  alkyl, or arylalkyl; or R 4  and R 7  can join to form a ring;  
 R 8  is H or C 1-10  alkyl; or R 7  and R 8  can join to form a  
 Y is —O— or —S(O) 0-2 —;  
 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.  
 
     
     
         20 . A compound of the formula (IV):  
       
         
           
           
               
               
           
         
       
       wherein 
 X is —CHR 5 —, —CHR 5 -alkyl-, or —CHR 5 -alkenyl-;  
 R 1  is selected from the group consisting of: 
 —R 4 —CR 3 —Q—R 6 -alkyl;  
 —R 4 —CR 3 —Q—R 6 -alkenyl;  
 —R 4 —CR 3 —Q—R 6 -aryl;  
 —R 4 —CR 3 —Q—R 6 -heteroaryl;  
 —R 4 —CR 3 —Q—R 6 -heterocyclyl;  
 —R 4 —CR 3 —Q—H;  
 —R 4 —NR 5 —CR 3 —R 6 -alkyl;  
 —R 4 —NR 5 —CR 3 —R 6 -alkenyl;  
 —R 4 —NR 7 —CR 3 —R 6 -aryl;  
 —R 4 —NR 7 —CR 3 —R 6 -heteroaryl;  
 —R 4 —NR 7 —CR 3 —R 6 -heterocyclyl; and  
 —R 4 —NR 7 —CR 3 —R 8 ;  
 
 Q is —NR 5 — or —O—:  
 R 3  is ═O or ═S;  
 R 4  is alkyl or alkenyl, which may be interrupted by one or more —O— groups;  
 each R 5  is independently H or C 1-10  alkyl;  
 R 6  is a bond, alkyl, or alkenyl, which may be interrupted by one or more —O— groups;  
 R 7  is H, C 1-10  alkyl, or arylalkyl; or R 4  and R 7  can join to form a ring;  
 R 8  is H or C 1-10  alkyl; or R 7  and R 8  can join 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, halogen and trifluoromethyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         21 . A pharmaceutical composition comprising a therapeutically effective amount of a compound or salt of  claim 11  and a pharmaceutically acceptable carrier.  
     
     
         22 . A method of inducing cytokine biosynthesis in an animal comprising administering a therapeutically effective amount of a compound or salt of  claim 11  to the animal.  
     
     
         23 . The method of  claim 22  wherein the cytokine is IFN-α.  
     
     
         24 . A method of treating a viral disease in an animal comprising administering a therapeutically effective amount of a compound or salt of  claim 11  to the animal.  
     
     
         25 . A method of treating a neoplastic disease in an animal comprising administering a therapeutically effective amount of a compound or salt of  claim 11  to the animal.  
     
     
         26 . A compound of the formula (V):  
       
         
           
           
               
               
           
         
       
       wherein: 
 X is —CHR 5 —, —CHR 5 -alkyl-, or —CHR 5 -alkenyl-;  
 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;  
 
 
 R 4  is alkyl or alkenyl, which may be interrupted by one or more —O— groups;  
 each R 5  is independently H or C 1-10  alkyl;  
 R 7  is H, C 1-10  alkyl, or arylalkyl; or R 4  and R 7  can join to form a ring;  
 Y is —O— or —S(O) 0-2 —;  
 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.  
 
     
     
         27 . A compound selected from the group consisting of: 
 1-[2-(2-aminoethoxy)ethyl]-2-methyl-1H-imidazo [4,5-c]quinolin-4-amine;    1-[2-(2-aminoethoxy)ethyl]-2-ethyl-1H-imidazo [4,5-c]quinolin-4-amine;    1-[2-(2-aminoethoxy)ethyl]-2-ethoxymethyl-1H-imidazo [4,5-c]quinolin-4-amine;    and pharmaceutically acceptable salts thereof.