Vanadium compounds for treating cancer

Abstract

The invention provides methods for treating cancer and compounds that are useful for the treatment of tumors, as well as pharmaceutical compositions comprising the compounds, and synthetic methods and intermediates useful for preparing the compounds.

1 . A compound of formula V:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 7  and R 9  are each independently H, (C1-C3)alkyl, (C1-C3)alkoxy, or halo(C 1 -C3)alkyl;  
 R 8  is H, (C1-C3)alkyl, halo, (C1-C3)alkoxy, or halo(C1-C3)alkyl;  
 Y and Y 1  are each independently a monodentate or bidentate ligand; and  
 n is 0 or 1;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A compound of formula VII:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  and R 2  are each independently a cyclopentadienyl ring, wherein any cyclopentadienyl ring may optionally be substituted with one or more (C1-C3)alkyl; and  
 R 10 -R 13  are each independently H, halo, or (C1-C6)alkyl;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         3 . A compound which is [VO(Bipym)(H 2 O) 2 ](SO 4 ), [VO(SO 4 )(Bipym) 2 ] or [VO(Br,OH-acph) 2 ].  
     
     
         4 . A method for treating cancer in a mammal comprising administering to the mammal in need of such treatment an effective amount of a vanadium (IV) compound; or a parmaceutically acceptable salt thereof; with the proviso that the vanadium (IV) compound is not VCp 2 Cl 2  or [VO(Phen)(H 2 O) 2 ](SO 4 ).  
     
     
         5 . The method of  claim 4  wherein the vanadium (IV) compound is a compound of formula I:  
       
         
           
           
               
               
           
         
       
       wherein, 
 R 1 -R 2  are each independently halo, OH 2 , O 3 SCF 3 , N 3 , CN, OCN, SCN, or SeCN; and  
 R 3 -R 4  are each independently a cyclopentadienyl ring, wherein each cyclopentadienyl ring is optionally substituted with one or more (C1-C3)alkyl.  
 
     
     
         6 . The method of  claim 4  wherein the vanadium (IV) compound is a compound of formula II:  
       
         
           
           
               
               
           
         
       
       wherein 
 R and R 1  are each independently H, (C1-C3)alkyl, halogen, (C1-C3)alkoxy, halo(C1-C3)alkyl, cyano, (C 2 -C 6 )alkanoyloxy or nitro;  
 X and X 1  are each independently monodentate or bidentate ligands, or no ligand is present on X 1 ; and  
 Y is a monodentate ligand.  
 
     
     
         7 . The method of  claim 4  wherein the vanadium (IV) compound is a compound of formula III:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 2  and R 3  are each independently H, (C1-C3)alkyl, halogen, (C1-C3)alkoxy, halo(C1-C3)alkyl, cyano, (C 2 -C 6 )alkanoyloxy or nitro;  
 X 2  and X 3  are each independently monodentate or bidentate ligands;  
 or no ligand is present on X 3 ; and  
 Z is selected from O, CH 2 , CH 2 —CH 2  and CH═CH.  
 
     
     
         8 . The method of  claim 4  wherein the vanadium (IV) compound is a compound of formula IV:  
       
         
           
           
               
               
           
         
       
       wherein 
 R 4 , R 5  and R 6  are each independently H, (C1-C3)alkyl, halogen, (C1-C3)alkoxy, halo(C1-C3)alkyl, cyano, (C 2 -C 6 )alkanoyloxy or nitro; and  
 X 4  and X 5  are each independently a monodentate or bidentate ligand, or no ligand is present on X 5 ; and Y is a monodentate ligand.  
 
     
     
         9 . The method of  claim 5  wherein the compound of formula I is VCp 2 Cl 2 , VCp 2 Br 2 , VCp 2 I 2 , VCp 2 X 2 , VCp 2 (N 3 ) 2 , VCp 2 (CN) 2 , VCp 2 (NCO) 2 , VCp 2 (NCO)Cl, VCp 2 (NCS) 2 .0.5H 2 O, VCp 2 (NCSe) 2 , VCp 2 Cl (CH 3  CN)(FeCl 4 ), VCp 2 (O 3 SCF 3 ) 2 , V(MeCP) 2 Cl 2 .0.5 H 2 O, V(Me 5 CP) 2 Cl 2 , VCp 2 (acac), VCp 2 (hf-acac), VCp 2 (bpy), VCp 2 (cat), VCp 2 (dtc), VCp 2 PH, VCp 2 H, [VO(Bpy)(H 2 O) 2 ](SO 4 ), [VO(SO 4 )(Bpy) 2 ], [VO(Me 2 -bpy)(H 2 O) 2 ](SO 4 ), [VO(SO 4 )(Me 2 -bpy) 2 ], [VO(Bpy)(H 2 O) 2 ](SO 4 ), [VO(SO 4 )(Bpy) 2 ], [VO(Me 2 -bpy)(H 2 O) 2 ](SO 4 ), [VO(SO 4 )(Me 2 -bpy) 2 ], [VO(Phen)(H 2 O) 2 ](SO 4 ), [VO(SO 4 )(Phen) 2 ], [VO(Me 2 -Phen)(H 2 O) 2 ](SO 4 ), [VO(SO 4 )(Me 2 -Phen) 2 ], [VO(Cl-Phen)(H 2 O) 2 ](SO 4 ), [VO(SO 4 )(Cl-Phen) 2 ], [VO(N 2 -Phen)(H 2 O) 2 ](SO 4 ), [VO(SO 4 )(NO 2 -Phen) 2 ], [VO(Bpy)(H 2 O) 2 ](SO 4 ), [VO(SO 4 )(BPY) 2 ], [VO(Me 2 -bpy)(H 2 O) 2 ](SO 4 ), [VO(SO 4 )(Me 2 -bpy) 2 ], [VO(Phen)(H 2 O) 2 ](SO 4 ), [VO(SO 4 )(Phen) 2 ], [VO(Me 2 -Phen)(H 2 O) 2 ](SO 4 ), or [VO(SO 4 )(Me 2 -Phen) 2 ].  
     
     
         10 . The method of  claim 4  wherein the cancer is testicular cancer, Hodgkin's lymphoma, multiple myeloma, or non-Hodgkin's lymphoma.  
     
     
         11 . A method for treating a mammal inflicted with cancer comprising administering to the mammal in need of such treatment an effective amount of an oxovanadium compound; or a pharmaceutically acceptable salt thereof; with the proviso that the cancer is not pharyngonasal cancer.  
     
     
         12 . A method for treating a mammal inflicted with cancer comprising administering to the mammal in need of such treatment an effective amount of a vanadocene compound; or a pharmaeutically acceptable salt thereof; with the proviso that the vanadocene compound is not VCp 2 Cl 2 .