Actinium-225 complexes and conjugates for targeted radiotherapy

Abstract

225 Ac complexes comprising a functionalized polyazamacrocyclic chelant compound of the formula I hereinbelow: G is independently hydrogen or each Q is independently hydrogen, (CHR 5 ) p CO 2 R or (CHR 5 ) p PO 3 R 6 R 7 or Q 1 is hydrogen, (CHR 5 ) w CO 2 R or (CHR 5 ) w PO 3 R 6 R 7 ; each R is independently hydrogen, benzyl or C 1 -C 4 alkyl; R 6 and R 7 are independently H, C 1 -C 6 alkyl or (C 1 -C 2 alkyl)phenyl; each R 5 is independently hydrogen; C 1 -C 4 alkyl or (C 1 -C 2 alkyl)phenyl; with the proviso that at least two of the sum of Q and Q 1 must be other than hydrogen; A is CH, N, C—Br, C—Cl, C—SO 3 H, C—OR 8 , C—OR 9 N + —R 10 X − , or Z and Z 1 independently are CH, N, C—SO 3 H, N + —R 10 X −, C—CH 2 —OR 8 or C—C(O)—R 11 ; R 8 is H, C 1 -C 5 alkyl, benzyl, or benzyl substituted with at least one R 12 ; R 9 is C 1 -C 16 alkylamino; R 10 is C 1 -C 16 alkyl, benzyl, or benzyl substituted with at least one R 12 ; R 11 is —O—(C 1 -C 3 alkyl), OH or NHR 13 ; R 12 is H, NO 2 , NH 2 , isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or carboxyl; R 13 is C 1 -C 5 alkyl; X and Y are each independently hydrogen or may be taken with an adjacent X and Y to form an additional carbon-carbon bond; n is 0 or 1; m is an integer from 0 to 10 inclusive; p is 1 or 2; r is 0 or 1; w is 0 or 1; with the proviso that n is only 1 when X and/or Y form an additional carbon-carbon bond, and the sum of r and w is 0 or 1; L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of one of the carbon atoms to which it is joined, said linker/spacer group being represented by the formula  wherein: s is an integer of 0 or 1; t is an integer of 0 to 20 inclusive; R 1 is H or an electrophilic or nucleophilic moiety which allows for covalent attachment to a biological carrier, or synthetic linker which can be attached to a biological carrier, or precursor thereof; and Cyc represents a cyclic aliphatic moiety, aromatic moiety, aliphatic heterocyclic moiety, or aromatic heterocyclic moiety, each of said moieties optionally substituted with one or more groups which do not interfere with binding to a biological carrier; with the proviso that when R 1 is H, the linkage to the biological carrier is through one of Q or Q 1 ; and with the proviso that when R 1 is other than H, at least one of Q and Q 1 must be (CHR 5 ) p PO 3 R 6 R 7 ; and with further proviso that when Q is (CHR 5 ) p CO 2 R, Q 1 is (CHR 5 ) w CO 2 R, R is H, R 5 is H, and R 1 is H, then the sum of m, n, p, r, s, t, and w is greater than 1; or pharmaceutically acceptable salts thereof; complexed with 225 Ac

What is claimed is:  
     
         1 . An Actinium-225 complex comprising a functionalized polyazamacrocyclic chelant compound of the formula I, hereinbelow:  
       
         
           
           
               
               
           
         
         G is independently hydrogen or  
         
           
             
             
                 
                 
             
           
         
         each Q is independently hydrogen, (CHR 5 ) p CO 2 R or (CHR 5 ) p PO 3 R 6 R 7  or  
         
           
             
             
                 
                 
             
           
         
         Q 1  is hydrogen, (CHR 5 ) w CO 2 R or (CHR 5 ) w PO 3 R 6 R 7 ;  
         each R is independently hydrogen, benzyl or C 1 -C 4  alkyl;  
         R 6  and R 7  are independently H, C 1 -C 6  alkyl or (C 1 -C 2  alkyl)phenyl;  
         each R 5  is independently hydrogen; C 1 -C 4  alkyl or (C 1 -C 2  alkyl) phenyl;  
         with the proviso that at least two of the sum of Q and Q 1  must be other than hydrogen;  
         A is CH, N, C—Br, C—Cl, C—SO 3 H, C—OR 8 , C—OR 9 N + —R 10 X − , or  
         
           
             
             
                 
                 
             
           
         
         Z and Z 1  independently are CH, N, C—SO 3 H, N + —R 10 X—, C—CH 2 —OR 8  or C—C(O)—R 11 ;  
         R 8  is H, C 1 -C 5  alkyl, benzyl, or benzyl substituted with at least one R 12 ;  
         R 9  is C 1 -C 16  alkylamino;  
         R 10  is C 1 -C 16  alkyl, benzyl, or benzyl substituted with at least one R 12 ;  
         R 11  is —O—(C 1 -C 3  alkyl), OH or NHR 13 ;  
         R 12  is H, NO 2 , NH 2 , isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or carboxyl;  
         R 13  is C 1 -C 5  alkyl;  
         X and Y are each independently hydrogen or may be taken with an adjacent X and Y to form an additional carbon-carbon bond;  
         n is 0 or 1;  
         m is an integer from 0 to 10 inclusive;  
         p is l or 2;  
         r is O or 1;  
         w is O or 1;  
         with the proviso that n is only 1 when X and/or Y form an additional carbon-carbon bond, and the sum of r and w is 0 or 1;  
         L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of one of the carbon atoms to which it is joined, said linker/spacer group being represented by the formula  
         
           
             
             
                 
                 
             
           
         
          wherein:  
         s is an integer of 0 or 1;  
         t is an integer of 0 to 20 inclusive;  
         R 1  is H or an electrophilic or nucleophilic moiety which allows for covalent attachment to a biological carrier, or synthetic linker which can be attached to a biological carrier, or precursor thereof; and  
         Cyc represents a cyclic aliphatic moiety, aromatic moiety, aliphatic heterocyclic moiety, or aromatic heterocyclic moiety, each of said moieties optionally substituted with one or more groups which do not interfere with binding to a biological carrier;  
         with the proviso that when R 1  is H, the linkage to the biological carrier is through one of Q or Q 1 ; and with the proviso that when R 1  is other than H, at least one of Q and Q 1  must be (CHR 5 ) p PO 3 R 6 R 7 ; and with further proviso that when Q is (CHR 5 ) p CO 2 R, Q 1  is (CHR 5 ) w CO 2 R, R is H, R 5  is H, and R 1  is H, then the sum of m, n, p, r, s, t, and w is greater than 1;  
         or pharmaceutically acceptable salt thereof; complexed with  225 Ac  
       
     
     
         2 . A conjugate comprising the complex of  claim 1  covalently attached to a biological carrier.  
     
     
         3 . The conjugate according to  claim 2  wherein the biological carrier is a protein, antibody, antibody fragment, hormone, peptide, growth factor, antigen or hapten.  
     
     
         4 . The complex of  claim 1  wherein R 1  is H, NO 2 , NH 2 , isothiocyanato, semicarbazido, thiosemicarbazido, maleimido, bromoacetamido or carboxyl.  
     
     
         5 . The complex according to  claim 1  wherein the functionalized chelant is a compound of formula II  
       
         
           
           
               
               
           
         
          wherein:  
         each Q is independently hydrogen, (CHR 5 ) p CO 2 R or (CHR 5 ) p PO 3 R 6 R 7  or  
         
           
             
             
                 
                 
             
           
         
         Q 1  is hydrogen, (CHR 5 ) w CO 2 R or (CHR 5 ) w PO 3 R 6 R 7 ;  
         each R is independently hydrogen, benzyl or C 1 -C 4  alkyl;  
         R 6  and R 7  are independently H, C 1 -C 6  alkyl or (C 1 -C 2  alkyl) phenyl;  
         each R 5  is independently hydrogen; C 1 -C 4  alkyl or (C 1 -C 2  alkyl)phenyl;  
         with the proviso that at least two of the sum of Q and Q 1  must be other than hydrogen;  
         X and Y are each independently hydrogen or may be taken with an adjacent X and Y to form an additional carbon-carbon bond;  
         n is 0 or 1;  
         m is an integer from 0 to 10 inclusive;  
         p is l or 2;  
         r is O or 1;  
         w is O or 1;  
         with the proviso that n is only 1 when X and/or Y form an additional carbon-carbon bond, and the sum of r and w is 0 or 1;  
         L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of one of the carbon atoms to which it is joined, said linker/spacer group being represented by the formula  
         
           
             
             
                 
                 
             
           
         
          wherein:  
         s is an integer of 0 or 1;  
         t is an integer of 0 to 20 inclusive;  
         R 1  is H or an electrophilic or nucleophilic moiety which allows for covalent attachment to a biological carrier, or synthetic linker which can be attached to a biological carrier, or precursor thereof; and  
         Cyc represents a cyclic aliphatic moiety, aromatic moiety, aliphatic heterocyclic moiety, or aromatic heterocyclic moiety, each of said moieties optionally substituted with one or more groups which do not interfere with binding to a biological carrier;  
         with the proviso that when R 1  is H, the linkage to the biological carrier is through one of Q or Q 1 ; and with the proviso that when R 1  is other than H, at least one of Q and Q 1  must be (CHR 5 ) p PO 3 R 6 R 7 ; and with further proviso that when Q is (CHR 5 ) p CO 2 R, Q 1  is (CHR 5 ) w CO 2 R, R is H, R 5  is H, and R 1  is H, then the sum of m, n, p, r, s, t, and w is greater than 1;  
         or pharmaceutically acceptable salt thereof.  
       
     
     
         6 . The complex according to  claim 1  wherein the functionalized chelant is a compound of formula III  
       
         
           
           
               
               
           
         
          wherein:  
         each Q is independently hydrogen, (CHR 5 ) p CO 2 R or (CHR 5 ) p PO 3 R 6 R 7  or  
         
           
             
             
                 
                 
             
           
         
         Q 1  is hydrogen, (CHR 5 ) w CO 2 R or (CHR 5 ) w PO 3 R 6 R 7 ;  
         each R is independently hydrogen, benzyl or C 1 -C 4  alkyl;  
         R 6  and R 7  are independently H, C 1 -C 6  alkyl or (C 1 -C 2  alkyl) phenyl;  
         each R 5  is independently hydrogen; C 1 -C 4  alkyl or (C 1 -C 2  alkyl)phenyl;  
         with the proviso that at least two of the sum of Q and Q 1  must be other than hydrogen;  
         X and Y are each independently hydrogen or may be taken with an adjacent X and Y to form an additional carbon-carbon bond;  
         n is 0 or 1;  
         m is an integer from 0 to 10 inclusive;  
         p is l or 2;  
         r is O or 1;  
         w is O or 1;  
         with the proviso that n is only 1 when X and/or Y form an additional carbon-carbon bond, and the sum of r and  
         w is 0 or 1;  
         L is a linker/spacer group covalently bonded to, and replaces one hydrogen atom of one of the carbon atoms to which it is joined, said linker/spacer group being represented by the formula  
         
           
             
             
                 
                 
             
           
         
          wherein:  
         s is an integer of 0 or 1;  
         t is an integer of 0 to 20 inclusive;  
         R 1  is H or an electrophilic or nucleophilic moiety which allows for covalent attachment to a biological carrier, or synthetic linker which can be attached to a biological carrier, or precursor thereof; and  
         Cyc represents a cyclic aliphatic moiety, aromatic moiety, aliphatic heterocyclic moiety, or aromatic heterocyclic moiety, each of said moieties optionally substituted with one or more groups which do not interfere with binding to a biological carrier;  
         with the proviso that when R 1  is H, the linkage to the biological carrier is through one of Q or Q 1 ; and with the proviso that when R 1  is other than H, at least one of Q and Q 1  must be (CHR 5 ) p PO 3 R 6 R 7 ; and with further proviso that when Q is (CHR 5 ) p CO 2 R, Q 1  is (CHR 5 ) w CO 2 R, R is H, R 5  is H, and R 1  is H, then the sum of m, n, p, r, s, t, and w is greater than 1;  
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         7 . A conjugate according to  claim 2  comprising the  225 Ac complex of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) covalently attached via amide linkage to a biological carrier.  
     
     
         8 . A conjugate according to  claim 2  comprising the  225 Ac complex of 2-(p-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid covalently attached to a biological carrier.  
     
     
         9 . A pharmaceutical formulation comprising the  225 Ac conjugate of  claim 2  and a pharmaceutically acceptable carrier.  
     
     
         10 . The formulation of  claim 9  wherein the pharmaceutically acceptable carrier is a liquid.  
     
     
         11 . A method of therapeutic treatment of a mammal having cancer which comprises administering to said mammal a therapeutically effective amount of the formulation of  claim 9.