Selective High Affinity Alpha3Beta4 Nicotinic Acetycholine Receptor Antagonists

Abstract

Provided herein are novel and selective high affinity α3β4 nicotinic acetycholine receptor ligands and pharmaceutical compositions thereof. In other embodiments, provided herein are methods of treatment, prevention, or amelioration of a variety of medical disorders such as, for example, drug addiction or pain using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of selectively antagonizing receptors such as, for example, the α3β4 nicotinic acetycholine receptor using the compounds and compositions disclosed herein.

What is claimed is: 
     
         1 . A method of treating or preventing opiate addiction in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I) or a pharmaceutical composition thereof: 
       
         
           
           
               
               
           
         
         or salts, hydrates or solvates thereof wherein: 
         R 1  is hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl; 
         Y is —NR 3 ; 
         R 3  is hydrogen, alkyl, substituted alkyl, arylalkyl, substituted arylalkyl, heteroarylalkyl or substituted heteroarylalkyl; and 
         X is aryl, substituted aryl, heteroaryl or substituted heteroaryl; 
         provided that when R 1  is methyl and Y is —NH— that X is not phenyl and that when R 1  is H and Y is —NH— that X is not 3-chlorophenyl and that the compound of Formula (I) does not include N-(9-methyl-9-azabicyclo[13.3.1.]non-3-yl)-1H indazole-5-amine. 
       
     
     
         2 . The method of  claim 1 , wherein X is o-substituted phenyl. 
     
     
         3 . The method of  claim 1 , wherein R 1  is hydrogen, alkyl or substituted alkyl. 
     
     
         4 . The method of  claim 1 , wherein R 1  is hydrogen, methyl, ethyl, 
       
         
           
           
               
               
           
         
       
     
     
         5 . The method of  claim 1 , wherein X is phenyl or substituted phenyl. 
     
     
         6 . The method of  claim 1 , wherein X is 
       
         
           
           
               
               
           
         
       
       R 4  is —Cl, —Br, —F, —I, —CH 3  —CF 3 , —OCF 3 , —OH, —CO 2 t-Bu, —NO 2 , —NH 2 , —COCH 3  or —CN. 
     
     
         7 . The method of  claim 1 , wherein Y is —NH— or —NCH 3 —. 
     
     
         8 . The method of  claim 1 , wherein R 1  is hydrogen, methyl, ethyl, 
       
         
           
           
               
               
           
         
       
       X is aryl, heteroaryl, phenyl, substituted phenyl, o-substituted phenyl, and Y is —NH— or —NCH 3 —. 
     
     
         9 . The method of  claim 1 , wherein R 1  is hydrogen, alkyl or substituted alkyl, X is 
       
         
           
           
               
               
           
         
       
       R 4  is —Cl, —Br, —F, —I, —CH 3  —CF 3 , —OCF 3 , —OH, —CO 2 t-Bu, —NO 2 , —NH 2 , —COCH 3  or —CN and Y is —NH— or —NCH 3 —. 
     
     
         10 . The method of  claim 1 , wherein R 1  is arylalkyl or substituted arylalkyl, X is 
       
         
           
           
               
               
           
         
       
       R 4  is —Cl, —Br, —F, —I, —CH 3  —CF 3 , —OCF 3 , —OH, —CO 2 t-Bu, —NO 2 , —NH 2 , —COCH 3  or —CN and Y is —NH— or —NCH 3 —. 
     
     
         11 . The method of  claim 1 , wherein R 1  is hydrogen, methyl, ethyl, 
       
         
           
           
               
               
           
         
       
       X is 
       
         
           
           
               
               
           
         
       
       R 4  is —Cl, —Br, —F, —I, —CH 3  —CF 3 , —OCF 3 , —OH, —CO 2 t-Bu, —NO 2 , —NH 2 , —COCH 3  or —CN and Y is —NH— or —NCH 3 —. 
     
     
         12 . The method of  claim 1 , wherein R 1  is methyl, Y is —NH—, X is 
       
         
           
           
               
               
           
         
       
       and R 4  is —Cl, —Br, —F, —I, —CH 3  —CF 3 , —OCF 3 , —OH, —CO 2 t-Bu, —NO 2 , —NH 2 , —COCH 3  or —CN. 
     
     
         13 . The method of  claim 1 , wherein R 1  is methyl, Y is —NH—, X is 
       
         
           
           
               
               
           
         
       
       and R 4  is —Cl, —Br, —F, —I, —CF 3 , —OCF 3 , —NO 2  or —CN. 
     
     
         14 . The method of  claim 1 , wherein R 1  is methyl, Y is —NCH 3 — and X is 
       
         
           
           
               
               
           
         
       
       wherein R 4  is —Br. 
     
     
         15 . The method of  claim 1 , wherein R 1  is hydrogen, Y is —NH— and X is 
       
         
           
           
               
               
           
         
       
       wherein R 4  is —NO 2 . 
     
     
         16 . The method of  claim 1 , wherein R 1  is methyl, Y is —NH— and Xis 2-pyridyl or 2-pyridyl substituted at the 5 position with —Br or —NO 2 . 
     
     
         17 . The method of  claim 1 , wherein R 1  is ethyl, 
       
         
           
           
               
               
           
         
       
       Y is —NH— and X is 
       
         
           
           
               
               
           
         
       
       wherein R 4  is —Br. 
     
     
         18 . The method of  claim 1 , wherein R 1  is hydrogen, Y is —NH— and X is 
       
         
           
           
               
               
           
         
       
       wherein R 4  is —Br. 
     
     
         19 . The method of  claim 1 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       X is 
       
         
           
           
               
               
           
         
       
       wherein R 4  is —Cl, —Br, —F, —I, —CH 3  —CF 3 , —OCF 3 , —OH, —CO 2 t-Bu, —NO 2 , —NH 2 , —COCH 3  or —CN and Y is —NH— or —NCH 3 —. 
     
     
         20 . The method of  claim 1 , wherein R 1  is 
       
         
           
           
               
               
           
         
       
       X is 
       
         
           
           
               
               
           
         
       
       is wherein R 4  is —Cl, —Br, —F, —I, —CH 3  —CF 3 , —OCF 3 , —OH, —CO 2 t-Bu, —NO 2 , —NH 2 , —COCH 3  or —CN and Y is —NH— or —NCH 3 —.