Piperidines

Abstract

Compounds, compositions and methods are provided which are useful in the treatment of diseases through the inhibition of sodium ion flux through voltage-dependent sodium channels. More particularly, the invention provides substituted piperidines, and compositions containing these compounds. Also provided are methods using the compounds of the invention for the treatment of central or peripheral nervous system disorders, particularly pain and chronic pain by blocking sodium channels associated with the onset or recurrance of the indicated conditions. The compounds, compositions and methods of the present invention are of particular use for treating neuropathic or inflammatory pain by the inhibition of ion flux through a channel that includes a PN3 subunit.

1 . A compound having the formula:  
       
         
           
           
               
               
           
         
         in which 
 R 1  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl,  
                     
 R 2  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, alkoxy, —NR 15 R 16    
 wherein 
 R 15  and R 16  are each members independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl and R 15  and R 16  taken together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic ring  
 
 R 3  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and NR 15 R 16 ;  
 R 4  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, and NR 15 R 16 ;  
 R 5  is a member selected from H, nitro, substituted or unsubstituted alkyl, cyano, acyl, and SO 2 R 11    
 wherein 
 R 11  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;  
 
 Y is a member selected from O, C—NO 2  and S;  
 Z is a member selected from:  
                     
 
         in which 
 A, D, E and M are independently selected from CR 12 , N, and N-oxide,  
 wherein 
 R 12  is a member selected from hydrogen, halo, amino, hydroxy, cyano, nitro, acyl, alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, and at least two of A, D, E and M is a selected from CR 12 , and at most one of A, D, E, and M is N-oxide;  
 
 X is a member selected from O, C—NO 2 , S and NR 10 ;  
 R 6 , R 7  and R 8  are members independently selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aminoalkyl, and R 7  and R 8  together with the atom to which they are joined are optionally joined to form a 4- to 8-membered heterocycloalkyl ring.  
 R 9  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted and unsubstituted heterocycloalkyl, OR 20 , and SR 20 ;  
 wherein 
 R 20  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and substituted and unsubstituted heterocycloalkyl;  
 
 R 10  is a member selected from hydrogen cyano, nitro, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted and unsubstituted heteroaryl and SO 2 R 11 ;  
 the dashed bond marked a is either a single or a double bond; and  
 n is and integer selected from 0, 1, and 2.  
 
       
     
     
         2 . The compound according to  claim 1 , wherein 
 R 1  is selected from substituted or unsubstituted alkyl,                          
     
     
         3 . The compound according to  claim 2 , wherein Y is O; and X is O.  
     
     
         4 . The compound according to  claim 3 , wherein R 7  and R 8  are members independently selected from H, substituted or unsubstituted aminoalkyl, and substituted or unsubstituted alkyl.  
     
     
         5 . The compound according to  claim 4 , wherein R 2  is a member selected from substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl; and R 3  is a member selected from substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.  
     
     
         6 . The compound according to  claim 2 , wherein 
 R 3  is substituted or unsubstituted aryl.    
     
     
         7 . The compound according to  claim 6 , wherein Y is O.  
     
     
         8 . The compound according to 6 wherein R 7  and R 8  are members independently selected from H, and substituted or unsubstituted alkyl.  
     
     
         9 . A compound having the formula:  
       
         
           
           
               
               
           
         
       
       in which 
 R 1  is a member selected from  
                     
 R 2  is a member selected from substituted or unsubstituted phenyl, and —NR 15 R 16 ;  
 R 3  is a member selected from NR 15 R 16 , and substituted or unsubstituted phenyl;  
 R 4  is a member selected from NR 15 R 16 ;  
 R 5  is a member selected from hydrogen, nitro, substituted or unsubstituted alkyl, cyano, acyl, and SO 2 R 11    
 wherein 
 R 11  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;  
 Y is a member selected from O and S;  
 Z is a member selected from:  
                     
 
 in which 
 A, D, E and M are independently selected from CR 12 , N, and N-oxide  
 wherein 
 R 12  is a member selected from hydrogen, halo, amino, hydroxy, cyano, nitro, acyl, alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, and  
 
 at least two of A, D, E and M is a selected from CR 12 , and at most one of A, D, E, and M is N-oxide;  
 X is a member selected from O, S, NR 10 , and C—NO 2 ;  
 R 6 , R 7  and R 8  are members independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, and substituted or unsubstituted heterocycloalkyl, and R 7  and R 8  together with the atom to which they are joined are optionally joined to form a 4- to 8-membered heterocycloalkyl ring.  
 R 9  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, and substituted and unsubstituted heterocycloalkyl;  
 R 10  is a member selected from hydrogen, substituted or unsubstituted alkyl, cyano, nitro, acyl, and SO 2 R 11    
 
 the dashed bond marked a is either a single or a double bond; and  
 n is and integer selected from 0, 1, and 2; and 
 R 15  and R 16  are each members independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and R 15  and R 16  taken together with the nitrogen atom to which they are attached to form a 4- to 8-membered heterocyclic ring.  
 
 
     
     
         10 . The compound according to  claim 9 , wherein n is 1.  
     
     
         11 . The compound according to  claim 10 , wherein X is O.  
     
     
         12 . The compound according to  claim 11 , wherein Y is O.  
     
     
         13 . The compound according to 12, wherein 
 Z is a member selected from:                          
     
     
         14 . A method of decreasing ion flow through voltage-dependent sodium channels in a cell, said method comprising contacting said cell with a sodium channel-inhibiting amount of a compound comprising a piperidinyl moiety.  
     
     
         15 . The method according to  claim 14 , wherein said cell is in a human.  
     
     
         16 . A method of decreasing ion flow through voltage-dependent sodium channels in a cell, said method comprising contacting said cell with a sodium channel-inhibiting amount of a compound of the formula:  
       
         
           
           
               
               
           
         
         in which 
 R 1  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl,  
                     
 R 2  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, alkoxy, —NR 15 R 16    
 wherein 
 R 15  and R 16  are each members independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl and R 15  and R 16  taken together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic ring  
 
 R 3  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and NR 15 R 16 ;  
 R 4  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, and NR 15 R 16 ;  
 R 5  is a member selected from H, nitro, substituted or unsubstituted alkyl, cyano, acyl, and SO 2 R 11    
 wherein 
 R 11  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;  
 
 Y is a member selected from O, C—NO 2  and S;  
 Z is a member selected from:  
                     
 
         in which 
 A, D, E and M are independently selected from CR 12 , N, and N-oxide,  
 wherein 
 R 12  is a member selected from hydrogen, halo, amino, hydroxy, cyano, nitro, acyl, alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, and at least two of A, D, E and M is a selected from CR 12 , and at most one of A, D, E, and M is N-oxide;  
 
 X is a member selected from O, C—NO 2 , S and NR 10 ;  
 R 6 , R 7  and R 8  are members independently selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aminoalkyl, and R 7  and R 8  together with the atom to which they are joined are optionally joined to form a 4- to 8-membered heterocycloalkyl ring.  
 R 9  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted and unsubstituted heterocycloalkyl, OR 20 , and SR 20 ;  
 wherein 
 R 20  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and substituted and unsubstituted heterocycloalkyl;  
 
 R 10  is a member selected from hydrogen cyano, nitro, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted and unsubstituted heteroaryl and SO 2 R 11 ;  
 the dashed bond marked a is either a single or a double bond; and 
 n is and integer selected from 0, 1, and 2.  
 
 
       
     
     
         17 . A method of treating a central or peripheral nervous system disorder or condition through inhibition of a voltage-dependent sodium channel, said method comprising administering to a subject in need of such treatment, an effective amount of a compound comprising a piperidinyl moiety.  
     
     
         18 . The method according to  claim 16 , said compound having the formula:  
       
         
           
           
               
               
           
         
         in which 
 R 1  is a member selected from hydrogen, substituted or unsubstituted alkyl substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl,  
                     
 R 2  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, alkoxy, —NR 15 R 16    
 wherein 
 R 15  and R 16  are each members independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl and R 15  and R 16  taken together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic ring  
 
 R 3  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and NR 15 R 16 ;  
 R 4  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, and NR 15 R 16 ;  
 R 5  is a member selected from H, nitro, substituted or unsubstituted alkyl, cyano, acyl, and SO 2 R 11    
 wherein 
 R 11  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;  
 
 Y is a member selected from O, C—NO 2  and S;  
 Z is a member selected from:  
                     
 
         in which 
 A, D, E and M are independently selected from CR 12 , N, and N-oxide,  
 wherein 
 R 12  is a member selected from hydrogen, halo, amino, hydroxy, cyano, nitro, acyl, alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, and at least two of A, D, E and M is a selected from CR 12 , and at most one of A, D, E, and M is N-oxide;  
 
 X is a member selected from O, C—NO 2 , S and NR 10 ;  
 R 6 , R 7  and R 8  are members independently selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aminoalkyl, and R 7  and R 8  together with the atom to which they are joined are optionally joined to form a 4- to 8-membered heterocycloalkyl ring.  
 R 9  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted and unsubstituted heterocycloalkyl, OR 20 , and SR 20 ;  
 wherein 
 R 20  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and substituted and unsubstituted heterocycloalkyl;  
 
 R 10  is a member selected from hydrogen cyano, nitro, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted and unsubstituted heteroaryl and SO 2 R 11 ;  
 the dashed bond marked a is either a single or a double bond; and 
 n is and integer selected from 0, 1, and 2.  
 
 
       
     
     
         19 . The method according to  claim 16 , wherein said disorder is pain selected from inflammatory pain, neuropathic pain and combinations thereof.  
     
     
         20 . A composition comprising a pharmaceutically acceptable excipient and a compound having the formula: 
 in which 
 R 1  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted heteroaryl,  
                     
 R 2  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, alkoxy, —NR 15 R 16    
 wherein 
 R 15  and R 16  are each members independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl and R 15  and R 16  taken together with the nitrogen atom to which they are attached form a 4- to 8-membered heterocyclic ring  
 
 R 3  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl and NR 15 R 16 ;  
 R 4  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroaryl, and NR 15 R 16 ;  
 R 5  is a member selected from H, nitro, substituted or unsubstituted alkyl, cyano, acyl, and SO 2 R 11    
 wherein 
 R 11  is a member selected from substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl;  
 
 Y is a member selected from O, C—NO 2  and S;  
 Z is a member selected from:  
                     
   in which 
 A, D, E and M are independently selected from CR 12 , N, and N-oxide,  
 wherein 
 R 12  is a member selected from hydrogen, halo, amino, hydroxy, cyano, nitro, acyl, alkoxy, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted heteroaryl, and at least two of A, D, E and M is a selected from CR 12 , and at most one of A, D, E, and M is N-oxide;  
 
 X is a member selected from O, C—NO 2 , S and NR 10 ;  
 R 6 , R 7  and R 8  are members independently selected from substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted heteroarylalkyl, substituted or unsubstituted aminoalkyl, and R 7  and R 8  together with the atom to which they are joined are optionally joined to form a 4- to 8-membered heterocycloalkyl ring.  
 R 9  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted and unsubstituted heterocycloalkyl, OR 20 , and SR 20 ;  
 wherein 
 R 20  is a member selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, and substituted and unsubstituted heterocycloalkyl;  
 
 R 10  is a member selected from hydrogen cyano, nitro, acyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heterocycloalkyl, substituted and unsubstituted heteroaryl and SO 2 R 11 ;  
 the dashed bond marked a is either a single or a double bond; and 
 n is and integer selected from 0, 1, and 2.