Azetidinyl diamines useful as ligands of the nociceptin receptor ORL-1

Abstract

Disclosed are nociceptin ORL-1 receptor agonists of the formula wherein: (a) R 1 is optionally substituted alkyl, fluorenyl, pyrimidinyl or optionally substituted piperidinyl; R 2 is H; and R 3 is —C(H)(R)—NR 7 R 8 ; R is H, optionally substituted aryl or arylalkyl, or heteroaryl; R 7 is —(CH 2 ) x R 9 , optionally substituted tetrahydronaphthyl, or cycloalkyl; and R 8 is H; or R 7 and R 8 together form a substituted piperidinyl or piperazinyl ring; x is 0-10; and R 9 is H, alkoxy, optionally substituted phenyl, naphthyl, heteroaryl, pyrrolidinyl, pyrrolidonyl, optionally substituted piperidinyl or diphenylmethyl; or (b) R 2 is —NHR 7 or and R 3 is H; pharmaceutical compositions; and methods of using the compounds to treat cough and pain.

What is claimed is:  
     
         1 . A compound represented by the formula  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, or a diastereomer or enantiomer thereof, wherein:  
         (a) R 1  is —(CH 2 ) n CHR 4 R 5 , fluorenyl, pyrimidinyl or  
         
           
             
             
                 
                 
             
           
         
         n is 0, 1, 2 or 3;  
         R 2  is H; and R 3  is —C(H)(R)—NR 7 R 8 ;  
         R is H, aryl, R 6 -aryl, aryl(CH 2 ) 1-2 , R 6 -aryl(CH 2 ) 1-2  or heteroaryl;  
         R 4  is H, aryl, R 6 -aryl, heteroaryl, C 1-6 alkyl, C 3-6  cycloalkyl or C 2-6  alkenyl;  
         R 5  is aryl, R 6 -aryl, heteroaryl, C 1-6  alkyl, C 3-6  cycloalkyl, C 2-6  alkenyl or fluorenyl, provided that when R 4  and R 5  are each phenyl, R is not phenyl or R 6 -phenyl;  
         or R 4  is H and R 5  is tetrahydronaphthyl or tetrahydronaphthyl substituted with 1 or 2 substituents selected from the group consisting of halogen, C 1-6  alkoxy, hydroxy, C 1-6  alkyl and trihalo(C 1-6 )alkyl;  
         R 6  is 1 or 2 substituents independently selected from the group consisting of halogen, C 1-6  alkoxy, hydroxy, phenyl, phenoxy, C 1-6  alkyl, trihalo(C 1-6 )alkyl, amino, amido, —NO 2 , naphthyl, benzoyl and benzyloxy, or 2 adjacent ring carbon atoms can be substituted by methylenedioxy;  
         R 7  is —(CH 2 ) x R 9 , tetrahydronaphthyl, tetrahydronaphthyl substituted with 1 or 2 R 10  groups, or C 5 -C 7  cycloalkyl; and R 8  is H;  
         or R 7  and R 8  together form a ring of the formula  
         
           
             
             
                 
                 
             
           
         
         x is 0to 10;  
         R 9  is H, C 1 -C 6  alkoxy, phenyl, phenyl substituted with 1 or 2 R 10  groups, naphthyl, pyridyl, imidazolyl, furanyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, N—(C 1 -C 6  alkyl)-piperidinyl, N-aryl(C 1 -C 6  alkyl)piperidinyl or diphenylmethyl;  
         R 10  is independently selected from the group consisting of halogen, C 1 -C 6  alkoxy, C 1 -C 6  alkyl, —OCF 3  and methylenedioxy;  
         R 11  is aryl(C 1 -C 6 )alkyl, di-aryl(C 1 -C 6 )alkyl or piperidinyl; and  
         R 17  is H, C 1 -C 6  alkyl or benzyl;  
         or  
         (b) R 2 is —NHR 7  or  
         
           
             
             
                 
                 
             
           
         
         and R 3  is H; and  
         R 1  and R 7  are as defined in (a).  
       
     
     
         2 . The compound of  claim 1  wherein R 1  is —(CH 2 ) n CHR 4 R 5  and n is 0 or 1.  
     
     
         3 . The compound of  claim 2  wherein R 4  is aryl, R 6 -aryl or heteroaryl and R 5  is aryl or C 1 -C 6  alkyl.  
     
     
         4 . The compound of  claim 3  wherein n is 0, R 4  is phenyl, R 6 -phenyl or pyridyl and R 5  is phenyl, R 6 -phenyl or C 2 -C 5  alkyl.  
     
     
         5 . The compound of  claim 4  wherein R 6  is halogen.  
     
     
         6 . The compound of  claim 1  wherein R 2  is H and R 3  is —C(H)(R)—NR 7 R 8 .  
     
     
         7 . The compound of  claim 6  wherein R is R 6 -phenyl, benzyl or R 6 -benzyl.  
     
     
         8 . The compound of  claim 7  wherein R 6  is 1 or 2 substituents independently selected from the group consisting of —CF 3 , halogen, benzyloxy and —CH 3 .  
     
     
         9 . The compound of  claim 7  wherein R 7  and R 8  are each H.  
     
     
         10 . The compound of  claim 1  selected from the group consisting of  
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         11 . A pharmaceutical composition comprising a therapeutically effective amount of at least one compound of  claim 1  in combination with a pharmaceutically acceptable carrier.  
     
     
         12 . A pharmaceutical composition comprising: a therapeutically effective amount of at least one compound of  claim 1;  a therapeutically effective amount of one or more additional agents selected from the group consisting of: antihistamines, 5-lipoxy-genase inhibitors, leukotriene inhibitors, H 3  inhibitors, β-adrenergic receptor agonists, xanthine derivatives, α-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NK 1 , NK 2  and NK 3  tachykinin receptor antagonists, and GABA B  agonists; and a pharmaceutically acceptable carrier.  
     
     
         13 . A method of treating cough, pain, anxiety, asthma, depression or alcohol abuse comprising administering an effective amount of at least one compound of  claim 1  to a mammal in need of such treatment.  
     
     
         14 . The method of  claim 13 , wherein in addition to at least one compound of claim I, an effective amount of one or more additional agents for treating cough, allergy or asthma symptoms selected from the group consisting of: antihistamines, 5-lipoxy-genase inhibitors, leukotriene inhibitors, H 3  inhibitors, β-adrenergic receptor agonists, xanthine derivatives, α-adrenergic receptor agonists, mast cell stabilizers, anti-tussives, expectorants, NK 1 , NK 2  and NK 3  tachykinin receptor antagonists, and GABA B  agonists is administered.