Tricyclic inhibitors of poly(ADP-ribose) polymerases

Abstract

Compounds of the formula below are poly(ADP-ribosyl)transferase (PARP) inhibitors, and are useful as therapeutics in treatment of cancers and the amelioration of the effects of stroke, head trauma, and neurodegenerative disease. As cancer therapeutics, the compounds of the invention may be used, e.g., in combination with cytotoxic agents and/or radiation.

What is claimed is:  
     
         1 . A compound selected from the group consisting of:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof.  
     
     
         2 . A compound, pharmaceutically acceptable salt, prodrug, active metabolite, or solvate according to  claim 1 , having a PARP-inhibiting activity corresponding to a K 1  of 100 μM or less in a PARP enzyme inhibition assay.  
     
     
         3 . A compound, pharmaceutically acceptable salt, prodrug, active metabolite, or solvate according to  claim 1 , having a cytotoxicity potentiation activity corresponding to a PF 50  of at least 1 in a cytotoxicity potentiation assay.  
     
     
         4 . A pharmaceutical composition comprising: 
 (a) an effective amount of a PARP-inhibiting agent that is: 
 (i) a compound selected from the group consisting of:  
                     
 (ii) a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof; and  
   (b) a pharmaceutically acceptable carrier for said PARP-inhibiting agent.    
     
     
         5 . A method of inhibiting PARP activity of an enzyme, comprising contacting the enzyme with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, active metabolite, or solvate according to  claim 1 .  
     
     
         6 . A method according to  claim 5 , wherein the enzyme is poly(ADP-ribose) polymerase or tankyrase.  
     
     
         7 . A method of inhibiting PARP enzyme activity in mammalian tissue by administering to a mammal a therapeutically effective amount of a compound, pharmaceutically acceptable salt, prodrug, active metabolite, or solvate according to  claim 1 .  
     
     
         8 . A method of inhibiting PARP activity of an enzyme, comprising contacting the enzyme with an effective amount of a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is: H;  
 halogen;  
 cyano;  
 an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or  
 —C(O)—R 10 , where R 10  is: H; an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or OR 100  or NR 100 R 110 , where R 100  and R 110  are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group  
 R 2  is H or alkyl;  
 R 3  is H or alkyl;  
 R 4  is H, halogen or alkyl;  
 X is O or S;  
 Y is (CR 5 R 6 )(CR 7 R 8 ) n  or N═C(R 5 ), where: 
 n is 0 or 1;  
 R 5  and R 6  are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; and  
 R 7  and R 8  are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;  
 or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate of the compound.  
 
 
     
     
         9 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is: H;  
 halogen;  
 cyano;  
 an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or  
 —C(O)—R 10 , where R 10  is: H; an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;  2665  or OR 100  or NR 100 R 110 , where R 100  and R 110  are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group  
 R 2  is H or alkyl;  
 R 3  is H or alkyl;  
 R 4  is H, halogen or alkyl;  
 X is O or S;  
 Y is (CR 5 R 6 )(CR 7 R 8 ) n  or N═C(R 5 ), where: 
 n is 0 or 1;  
 R 5  and R 6  are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; and  
 R 7  and R 8  are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group;  
 where when R 1 , R 4 , R 5 , R 6 , and R 7  are each H, R 8  is not unsubstituted phenyl;  
 or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate of the compound.  
 
 
     
     
         10 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 p is 1 or 2;  
 R 11  is H or alkyl;  
 R 12  is halogen or an optionally substituted aryl, alkyl, alkenyl, alkynyl or acyl group —C(O)—R 10  where R 10  is: H; an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; or OR 100  or NR 100 R 110 , where R 100  and R 110  are each independently H or an optionally substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group  
 R 13  is H or alkyl; and  
 R 14  is H or halogen;  
 or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate of the compound.  
 
     
     
         11 . A compound of the formula  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 15  is H, halogen, or an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and alkyl and aryl groups unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, and amino;  
 R 16  is H; halogen; cyano; or an alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, and alkyl and aryl groups unsubstituted or substituted with one or more substituents selected from halogen, hydroxy, nitro, and amino;  
 R 17  is H or alkyl; and  
 R 18  is H, halogen, or alkyl;  
 where R 15 , R 16 , R 17  and R 18  are not all H.  
 
     
     
         12 . A compound selected from the group consisting of  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug, active metabolite or solvate thereof.  
     
     
         13 . A compound, pharmaceutically acceptable salt, prodrug, active metabolite, or solvate according to  claim 9 , having a PARP-inhibiting activity corresponding to a K i  of 100 μM or less in a PARP enzyme inhibition assay.  
     
     
         14 . A compound, pharmaceutically acceptable salt, prodrug, active metabolite, or solvate according to  claim 9 , having a cytotoxicity potentiation activity corresponding to a PF 50  of at least 1 in a cytotoxicity potentiation assay.  
     
     
         15 . A pharmaceutical composition comprising: 
 (a) an effective amount of a PARP-inhibiting agent that is a compound according to  claim 9;  or a pharmaceutically acceptable salt, prodrug, active metabolite, or solvate thereof; and    (b) a pharmaceutically acceptable carrier for said PARP-inhibiting agent.    
     
     
         16 . A method of inhibiting PARP activity of an enzyme, comprising contacting the enzyme with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, active metabolite, or solvate according to  claim 9 .  
     
     
         17 . A method according to  claim 16 , wherein the enzyme is poly(ADP-ribose) polymerase or tankyrase.  
     
     
         18 . A method of inhibiting PARP enzyme activity in mammalian tissue by administering to a mammal a therapeutically effective amount of a compound, pharmaceutically acceptable salt, prodrug, active metabolite, or solvate according to  claim 9 .  
     
     
         19 . A method of inhibiting PARP activity of an enzyme, comprising contacting the enzyme with an effective amount of a compound, pharmaceutically acceptable salt, prodrug, active metabolite, or solvate according to  claim 12.