Cobalamin conjugates useful as antitumor agents

Abstract

The invention provides cobalamin compounds linked to a neutron capture therapy target (e.g. Boron-10 or Gadolinium-157), and optionally linked to a detectable moiety, as well as pharmaceutical compositions comprising the compounds, and methods for using the compounds in medical diagnosis and therapy.

1 . A compound of formula I: 
     
       
         
         
             
             
         
       
     
     linked to at least two molecules comprising B-10, wherein X is CN, OH, CH 3 , adenosyl, or a molecule comprising B-10; or a pharmaceutically acceptable salt thereof. 
   
   
       2 . The compound of  claim 1 , wherein at least one of the molecules comprising B-10 is directly linked to the 6-position of the compound of formula I or is directly linked to the b-, d-, or e-carboxamide of the compound of formula I. 
   
   
       3 . The compound of  claim 1 , wherein at least one of the molecules comprising B-10 is linked by a linker to the 6-position of the compound of formula I or is linked by a linker to the b-, d-, or e-carboxamide of the compound of formula I. 
   
   
       4 . The compound of  claim 1 , wherein the molecule comprising B-10 contains I to about 20 boron atoms, inclusive. 
   
   
       5 . The compound of  claim 1 , wherein the molecule comprising B-10 is an amino acid, a carbohydrate, a nucleoside, or a carborane. 
   
   
       6 . The compound of  claim 1 , wherein the molecule comprising B-10 is o-carborane, m-carborane, or p-carborane. 
   
   
       7 . The compound of  claim 1 , wherein the molecule comprising B-10 is o-carborane. 
   
   
       8 . The compound of  claim 3 , wherein at least one linker is of the formula W-A-Q wherein A is (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (C 3 -C 8 )cycloalkyl, or (C 6 -C 10 )aryl, wherein W and Q are each independently —N(R)C(═O)—, —C(═O)N(R)—, —OC(═O)—, —C(═O)O—, —O—, —S—, —S(O)—, —S(O) 2 —, —N(R)—, —C(═O)—, or a direct bond; wherein each R is independently H or (C 1 -C 6 )alkyl. 
   
   
       9 . The compound of  claim 8 , wherein W is NH 2  or COOH and Q is NH 2  or COOH. 
   
   
       10 . The compound of  claim 8 , wherein A is (C 1 -C 6 )alkyl. 
   
   
       11 . The compound of  claim 3 , wherein at least one linker comprises a therapeutic radionuclide or a diagnostic radionuclide. 
   
   
       12 . The compound of  claim 11 , wherein the therapeutic radionuclide is a metallic radionuclide. 
   
   
       13 . The compound of  claim 11 , wherein the diagnostic radionuclide is a metallic radionuclide. 
   
   
       14 . The compound of  claim 11 , wherein the diagnostic radionuclide is a non-metallic radionuclide. 
   
   
       15 . The compound of  claim 3 , wherein at least one linker is poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-lysine or poly-L-lysine-L-tyrosine. 
   
   
       16 . The compound of  claim 1 , wherein the compound of formula I is also linked to a linker comprising a detectable radionuclide or a therapeutic radionuclide. 
   
   
       17 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       18 . A method of treating a tumor in a mammal comprising:
 a) administering to the mammal an effective amount of a compound of formula I:   
     
       
         
         
             
             
         
       
        linked to at least two molecules comprising B-10, wherein X is CN, OH, CH 3 , adenosyl, or a molecule comprising B-10; or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable vehicle; and 
       b) administering neutron capture therapy comprising subjecting said mammal to thermal neutron irradiation at the site of said tumor for a time and under conditions effective to treat said tumor. 
     
   
   
       19 . A method of imaging a tumor in a mammal comprising:
 a) administering to the mammal an effective amount of a compound of formula I:   
     
       
         
         
             
             
         
       
        linked to at least two molecules comprising B-10, wherein X is CN, OH, CH 3 , adenosyl, or a molecule comprising B-10; or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable vehicle; and 
       b) detecting the presence of the compound. 
     
   
   
       20 . The method of  claim 19 , further comprising treating the tumor with neutron capture therapy.