Inhibitors of ADP-ribosyl transferases, cyclases, and hydrolases

Abstract

The present invention provides compounds having the formula: wherein A is a nitrogen-, oxygen-, or sulfur-linked aryl, alkyl, cyclic, or heterocyclic group, the group being further substituted with an electron contributing moiety; B is hydrogen, or a halogen, amino, or thiol group; C is hydrogen, or a halogen, amino, or thiol group; and D is a primary alcohol, a hydrogen, or an oxygen, nitrogen, carbon, or sulfur linked to phosphate, a phosphoryl group, a pyrophosphoryl group, or adenosine monophosphate through a phosphodiester or carbon-, nitrogen-, or sulfur-substituted phosphodiester bridge, or to adenosine diphosphate through a phosphodiester or carbon-, nitrogen-, or sulfur-substituted pyrophosphodiester bridge. The present invention also provides pharmaceutical compositions containing the above compounds, methods of using the above compounds as pharmaceuticals, and processes for preparing the above compounds. Also provided are methods for inhibiting an ADP-ribosyl transferase, ADP-ribosyl cyclase, ADP-ribosyl hydrolase, or NAD-dependent deacetylase enzyme, and methods for treating a disease or condition associated with an ADP-ribosyl transferase, ADP-ribosyl cyclase, ADP-ribosyl hydrolase, or NAD-dependent deacetylase enzyme in a subject in need of treatment thereof.

1 . A compound represented by the formula:  
     
       
         
         
             
             
         
       
       wherein A is a nitrogen-, oxygen-, or sulfur-linked six- or five-member heterocyclic group having one, two or three nitrogen(s) in its ring structure, the heterocyclic group being substituted with an electron contributing moiety selected from methyl, ethyl, O-methyl, amino, NMe 2 , hydroxyl, CMe 3 , aryl or C3-C10 alkyl;  
       B is hydrogen, or a halogen, amino, or thiol group;  
       C is hydrogen, or a halogen, amino, or thiol group; and  
       D is a primary alcohol, a hydrogen, or an oxygen, nitrogen, carbon, or sulfur linked to phosphate, a phosphoryl group, a pyrophosphoryl group, or adenosine monophosphate through a phosphodiester or carbon-, nitrogen-, or sulfur-substituted phosphodiester bridge, or to adenosine diphosphate through a phosphodiester or  
       carbon-, nitrogen-, or sulfur-substituted pyrophosphodiester bridge.  
     
   
   
       2 - 4 . (canceled)  
   
   
       5 . The compound of  claim 1 , wherein the electron contributing moiety is selected from the group consisting of methyl, ethyl, O-methyl or amino.  
   
   
       6 . The compound of  claim 1 , wherein the electron contributing moiety is a methyl.  
   
   
       7 . The compound of  claim 1 , wherein A is substituted with a second electron contributing moiety.  
   
   
       8 . (canceled)  
   
   
       9 . The compound of  claim 1 , wherein A is an N-linked aryl or heterocyclic group.  
   
   
       10 . The compound of  claim 1 , wherein A is a substituted nicotinamide, pyrazolo, or imidazolo group.  
   
   
       11 - 14 . (canceled)  
   
   
       15 . The compound of  claim 1 , wherein A is an O-linked aryl or heterocyclic group having the formula —O—Y, wherein Y is an aryl or heterocyclic group.  
   
   
       16 . The compound of  claim 1 , wherein A is an S-linked aryl or heterocyclic group having the formula —S—Y, wherein Y is an aryl or heterocyclic group.  
   
   
       17 . The compound of  claim 1 , wherein both B and C are hydrogen, or either B or C is a halogen, amino, or thiol group and the other of B or C is hydrogen.  
   
   
       18 . The compound of  claim 1 , wherein D is a primary alcohol or hydrogen.  
   
   
       19 - 26 . (canceled)