Macrocyclic complexes of alpha-emitting radionuclides and their use in targeted radiotherapy of cancer

Abstract

The present technology provides compounds as well as compositions including such compounds useful for the treatment of cancers where the compounds are represented by the following formula or a pharmaceutically acceptable salt thereof, wherein M is an alpha-emitting radionuclide.

1 .- 29 . (canceled) 
     
     
         30 . A compound of the formula 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 R 2  and R 7  are each independently —C(O)OH; 
 R 9  is —NH 2 , —C(O)R′, —C(S)R′, —OCN, —SCN, —NCO, —NCS, —NR′—NR′R′, —N 3 , —N═C═N—R′, —SO 2 Cl, —C(O)Cl, or an epoxide group; 
 R 3 , R 4 , R 5 , R 8 , and R 10  are each independently H; 
 R′ is independently at each occurrence H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 5 -C 6  cycloalkenyl, C 2 -C 6  alkynyl, C 5 -C 6  aryl, heterocyclyl, or heteroaryl, 
 
         L 1  and L 2  are each —(CH 2 ) p —, where p is a value of 1; 
         r is 1; and 
         s is 1. 
       
     
     
         31 . The compound of  claim 30 , wherein R 9  is —NH 2  or —NCS. 
     
     
         32 . A composition of Formula I-b 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 M is an alpha-emitting radionuclide; 
 R 2  and R 7  are each independently —C(O)OH; 
 R 9  is —NH 2 , —C(O)R′, —C(S)R′, —OCN, —SCN, —NCO, —NCS, —NR′—NR′R′, —N 3 , —N═C═N—R′, —SO 2 Cl, —C(O)Cl, or an epoxide group; 
 R 3 , R 4 , R 5 , R 8 , and R 10  are each independently H; 
 R′ is independently at each occurrence H, C 1 -C 6  alkyl, C 3 -C 6  cycloalkyl, C 2 -C 6  alkenyl, C 5 -C 6  cycloalkenyl, C 2 -C 6  alkynyl, C 5 -C 6  aryl, heterocyclyl, or heteroaryl, 
 L 1  and L 2  are each —(CH 2 ) p —, where p is a value of 1; 
 r is 1; and 
 s is 1. 
 
       
     
     
         33 . The composition of  claim 32 , wherein M is selected from actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+  and/or  212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium-226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), and uranium-230. 
     
     
         34 . The composition of  claim 32 , wherein R 9  is —NH 2  or —NCS. 
     
     
         35 . The composition of  claim 34 , wherein M is selected from actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+  and/or  212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 225 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium-226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), and uranium-230. 
     
     
         36 . A composition useful in targeted radiotherapy of cancer, wherein the composition is of Formula II-b 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 M is an alpha-emitting radionuclide; 
 R 2  and R 7  are each independently —C(O)OH; 
 R 9  is a selective cancer cell targeting group linked to the carbon atom to which it is attached by a —NH—, —C(O)—, —OC(O)—, —C(O)O—, —C(S)O—, —C(O)NH—, —C(S)NH—, —NHC(O)—, —NHC(S)—, —NHC(O)N—, —NHC(S)N—, —S(O)—, —SO 2 —, —S(O) 2 O—, or —SO 2 NH—; 
 R 3 , R 4 , R 5 , R 8 , and R 10  are each independently H; 
 L 1  and L 2  are each —(CH 2 ) p —, where p is a value of 1; 
 r is 1; and 
 s is 1. 
 
       
     
     
         37 . The composition of  claim 36 , wherein M is selected from actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+  and/or  212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium-226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), and uranium-230. 
     
     
         38 . The composition of  claim 36 , wherein R 9  is a selective cancer cell targeting group linked to the carbon atom to which it is attached by a —NH 2  or —NHC(S)—. 
     
     
         39 . The composition of  claim 38 , wherein M is selected from actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+  and/or  212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium-226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), and uranium-230. 
     
     
         40 . The composition of  claim 36 , wherein said selective cancer cell targeting group contains amino acids linked by peptide bonds. 
     
     
         41 . The composition of  claim 40 , wherein said selective cancer cell targeting group is a cancer-targeting antibody or antibody fragment. 
     
     
         42 . The composition of  claim 40 , wherein said selective cancer cell targeting group is an oligopeptide containing up to 50 amino acids. 
     
     
         43 . A method of treating cancer in a subject, the method comprising administering to a subject having cancer an effective amount of a composition of Formula II-b 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein
 M is an alpha-emitting radionuclide; 
 R 2  and R 7  are each independently —C(O)OH; 
 R 9  is a selective cancer cell targeting group linked to the carbon atom to which it is attached by a —NH—, —C(O)—, —OC(O)—, —C(O)O—, —C(S)O—, —C(O)NH—, —C(S)NH—, —NHC(O)—, —NHC(S)—, —NHC(O)N—, —NHC(S)N—, —S(O)—, —SO 2 —, —S(O) 2 O—, or —SO 2 NH—;
 R 3 , R 4 , R 5 , R 8 , and R 10  are each independently H; 
 L 1  and L 2  are each —(CH 2 ) p —, where p is a value of 1; 
 r is 1; and 
 s is 1. 
 
 
       
     
     
         44 . The method of  claim 43 , wherein M is selected from actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+  and/or  212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium-226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), and uranium-230. 
     
     
         45 . The method of  claim 43 , wherein R 9  is a selective cancer cell targeting group linked to the carbon atom to which it is attached by a —NH 2  or —NHC(S)—. 
     
     
         46 . The method of  claim 45 , wherein M is selected from actinium-225 ( 225 Ac 3+ ), radium-223 ( 233 Ra 2+ ), bismuth-213 ( 213 Bi 3+ ), lead-212 ( 212 Pb 2+  and/or  212 Pb 4+ ), terbium-149 ( 149 Tb 3+ ), fermium-255 ( 255 Fm 3+ ), thorium-227 ( 227 Th 4+ ), thorium-226 ( 226 Th 4+ ), astatine-211 ( 211 At + ), astatine-217 ( 217 At + ), and uranium-230. 
     
     
         47 . The method of  claim 43 , wherein said selective cancer cell targeting group contains amino acids linked by peptide bonds. 
     
     
         48 . The method of  claim 47 , wherein said selective cancer cell targeting group is a cancer-targeting antibody or antibody fragment. 
     
     
         49 . The method of  claim 47 , wherein said selective cancer cell targeting group is an oligopeptide containing up to 50 amino acids.