Spirocyclic ligands for sigma receptors, and libraries and methods of use thereof

Abstract

One aspect of the present invention relates to spirocyclic compounds. Another aspect of the present invention relates to the use of the spirocyclic compounds as ligands for mammalian G-protein-coupled receptors or sigma receptors. The present invention also relates to methods of modulating the activity of a G-protein-coupled receptor or a sigma receptor in a mammal using the spirocyclic compounds of the present invention. The present invention also relates to methods of treating various diseases in a mammal using the spirocyclic compounds of the present invention.

1 . A compound represented by structure 1:  
     
       
         
         
             
             
         
       
     
     wherein 
 R represents independently for each occurrence hydrogen, alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl; 
 R 1  is absent, or present between 1 and 4 times;  
 
 R 1  represents independently for each occurrence halogen, alkyl, alkenyl, alkynyl, hydroxyl, alkoxyl, silyloxy, amino, nitro, sulfhydryl, alkylthio, imine, amide, phosphoryl, phosphonate, phosphine, carbonyl, carboxyl, carboxamide, anhydride, silyl, thioalkyl, alkylsulfonyl, arylsulfonyl, selenoalkyl, ketone, aldehyde, ester, heteroalkyl, nitrile, guanidine, amidine, acetal, ketal, amine oxide, aryl, heteroaryl, aralkyl, heteroaralkyl, azide, aziridine, carbamate, epoxide, hydroxamic acid, imide, oxime, sulfonamide, thioamide, thiocarbamate, urea, thiourea, or —(CH 2 ) m —R 8 ;  
 R 2  and R 3  represent independently for each occurrence hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, OR, N(R) 2 , CO 2 R, C(O)N(R) 2 , OC(O)R, or N(R)C(O)R; or two geminal instances of R 2  and R 3  taken together may represent O or C(R) 2 ; 
 R 6  represents hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, C(O)OR, C(O)N(R) 2 , or SO 2 R;  
 R 7  represents hydrogen, alkyl, alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, acyl, C(O)OR, C(O)N(R) 2 , or SO 2 R;  
 R 80  represents an aryl, cycloalkyl, cycloalkenyl, heterocyclyl, or polycyclyl group;  
 m is an integer in the range 0 to 8 inclusive; and  
 n is 1, 2, or 3;  
 
 provided that when n is 3 and a pair of geminal instances of R 2  and R 3  taken together represent O, R 7  is not acetyl;  
 further provided that when n is 2, R 2  and R 3  are not both methyl; or when n is 2, R 6  and R 7  are not both acetyl.  
 
   
   
       2 . The compound of  claim 1 , wherein R 1  represents independently for each occurrence OR, N(R) 2 , halogen, CO 2 R, CON(R) 2 , OCF 3 , CN, or CF 3 .  
   
   
       3 . The compound of  claim 1 , wherein R 1  represents independently for each occurrence OR, halogen, or CF 3 .  
   
   
       4 . The compound of  claim 1 , wherein R 2  and R 3  represent independently for each occurrence H, OR, or N(R) 2 .  
   
   
       5 . The compound of  claim 1 , wherein at least one pair of geminal instances of R 2  and R 3  taken together represent O.  
   
   
       6 . The compound of  claim 1 , wherein R 6  represents H, alkyl or acyl.  
   
   
       7 . The compound of  claim 1 , wherein R 7  represents H, alkyl or aralkyl.  
   
   
       8 . The compound of  claim 1 , wherein R 1  represents independently for each occurrence OR, N(R) 2 , halogen, CO 2 R, CON(R) 2 , OCF 3 , CN, or CF 3 ; and R 2  and R 3  represent independently for each occurrence H, OR, or N(R) 2 .  
   
   
       9 . The compound of  claim 1 , wherein R 1  represents independently for each occurrence OR, N(R) 2 , halogen, CO 2 R, CON(R) 2 , OCF 3 , CN, or CF 3 ; and at least one pair of geminal instances of R 2  and R 3  taken together represent O.  
   
   
       10 . The compound of  claim 1 , wherein R 1  represents independently for each occurrence OR, N(R) 2 , halogen, CO 2 R, CON(R) 2 , OCF 3 , CN, or CF 3 ; R 2  and R 3  represent independently for each occurrence H, OR, or N(R) 2 ; and R 6  represents H, alkyl or acyl.  
   
   
       11 . The compound of  claim 1 , wherein R 1  represents independently for each occurrence OR, N(R) 2 , halogen, CO 2 R, CON(R) 2 , OCF 3 , CN, or CF 3 ; at least one pair of geminal instances of R 2  and R 3  taken together represent O; and R 6  represents H, alkyl or acyl.  
   
   
       12 . The compound of  claim 1 , wherein R 1  represents independently for each occurrence OR, halogen, or CF 3 ; and R 2  and R 3  represent independently for each occurrence H, OR, or N(R) 2 .  
   
   
       13 . The compound of  claim 1 , wherein R 1  represents independently for each occurrence OR, halogen, or CF 3 ; and at least one pair of geminal instances of R 2  and R 3  taken together represent O.  
   
   
       14 . The compound of  claim 1 , wherein R 1  represents independently for each occurrence OR, halogen, or CF 3 ; R 2  and R 3  represent independently for each occurrence H, OR, or N(R) 2 ; and R 6  represents H, alkyl or acyl.  
   
   
       15 . The compound of  claim 1 , wherein R 1  represents independently for each occurrence OR, halogen, or CF 3 ; at least one pair of geminal instances of R 2  and R 3  taken together represent O; and R 6  represents H, alkyl or acyl.