BIFUNCTIONAL do2pa DERIVATIVES, CHELATES WITH METALLIC CATIONS AND USE THEREOF

Abstract

Disclosed are chelates resulting from the complexation of bifunctional do2pa derivatives ligands of formula (I), wherein the substituents R 1 , R 1′ , R 2 , R 2′ , R 3 , R 3′ , L 1 , L 1′ , L 2 and L 2′ are defined as in the claims, with metallic cations, especially Pb(II) and Bi(III). Also disclosed are bifunctional do2pa derivatives ligands of formula (I), as well as the use of chelates in nuclear medicine and the use of ligands in cations detection or epuration of effluents.

1 - 14 . (canceled) 
     
     
         15 . A chelate resulting from the complexation of a ligand of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1 , R 1′ , R 2  and R 2′  each independently represents:
 a hydrogen atom; 
 a coupling function, wherein the coupling function is selected from the group consisting of amine; isothiocyanate; isocyanate; activated ester; carboxylic acid; activated carboxylic acid; alcohol; alkyne; halide; azide; siloxy; phosphonic acid; thiol; tetrazine; norbornen; oxoamine; aminooxy; thioether; haloacetamide; glutamate; glutaric anhydride, succinic anhydride, maleic anhydride; aldehyde; ketone; hydrazide; chloroformate; and maleimide; or 
 a bioactive group, wherein the bioactive group is selected from the group consisting of antibody; hapten; peptide; protein; polysaccharide; fatty acid; liposome; lipid; polyamine; solid support; fluorophore; chromophore; macrocyclic chelate; and combinations thereof; 
 
         L 1 , L 1′ , L 2  and L 2′  each independently represents:
 a single bond; or 
 a linker selected from the group consisting of alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, alkenyl, and alkynyl; wherein alkyl moieties are optionally interrupted by one or more heteroatoms selected from the group consisting of O, N, and S; optionally additionally comprising a residue of a coupling function through which R 1 , R 1′ , R 2  and R 2′  are bounded to L 1 , L 1′ , L 2  and L 2′  respectively; 
 
         R 3  and R 3′  each independently represents:
 a hydrogen atom; 
 an activating function, wherein the activating function is selected from the group consisting of N-hydroxysuccinimide, N-hydroxyglutarimide, maleimide, halide, and —OCOR 4 , wherein R 4  is selected from the group consisting of alkyl and aryl; or 
 a bioactive group, wherein the bioactive group is selected from the group consisting of antibody; hapten; peptide; protein; polysaccharide; fatty acid; liposome; lipid; polyamine; solid support; fluorophore; chromophore; macrocyclic chelate; and combinations thereof; 
 
         provided that at least one of -L 1 -R 1 , -L 1′ -R 1′ , -L 2 -R 2  and -L 2′ -R 2′  represents a linker with a coupling function or a linker with a bioactive group; 
         with a metallic cation selected from the group consisting of bismuth (III), lead (II), copper (II), copper (I), gallium (III), zirconium (IV), technetium (III), indium (III), rhenium (VI), astatine (III), yttrium (III), samarium (III), actinium (III), lutetium (III), terbium (III), holmium (III), gadolinium (III), and europium(III). 
       
     
     
         16 . The chelate according to  claim 15 , wherein, in the coupling function, the activated ester is selected from the group consisting of N-hydroxysuccinimide ester, N-hydroxyglutarimide ester, and maleimide ester; the activated carboxylic acid is selected from the group consisting of anhydride and acid halide; and the haloacetamide is selected from the group consisting of chloroacetamide, bromoacetamide, and iodoacetamide. 
     
     
         17 . The chelate according to  claim 15 , wherein, in the bioactive group, the antibody is selected from the group consisting of polyclonal antibody, monoclonal antibody, hybrid antibody, chimeric antibody, single-domain antibody, dimeric antibody fragment construct, trimeric antibody fragment construct, and minibody; the chelate is spermine; and the solid support is selected from the group consisting of nanoparticle and polymeric microparticle. 
     
     
         18 . The chelate according to  claim 15 , wherein the ligand is of formula (Ia) 
       
         
           
           
               
               
           
         
         wherein R 1 , R 1′ , L 1  and L 1′  are as defined in  claim 15 . 
       
     
     
         19 . The chelate according to  claim 15 , wherein the metallic cation is a radioisotope. 
     
     
         20 . The chelate according to  claim 15 , wherein the metallic cation is a radioisotope selected from the group consisting of  212 Bi ( 212 Pb),  213 Bi (III),  64 Cu (II),  67 Cu (II),  68 Ga (III),  89 Zr (IV),  99m TC (III),  111 In (III),  186 Re (VI),  188 Re (VI),  211 At (III),  225 Ac(III),  90 Y(III),  177 Lu(III),  153 Sm(III),  149 Tb(III), and  166 Ho(III). 
     
     
         21 . The chelate according to  claim 15 , wherein the metallic cation is a radioisotope selected from the group consisting of  212 Bi( 212 Pb) and  213 Bi(III). 
     
     
         22 . A pharmaceutical composition comprising the chelate according to  claim 15 , in association with at least one pharmaceutically acceptable excipient. 
     
     
         23 . A ligand of formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1 , R 1′ , R 2  and R 2′  each independently represents:
 a hydrogen atom; 
 a coupling function, wherein the coupling function is selected from the group consisting of amine; isothiocyanate; isocyanate; activated ester; carboxylic acid; activated carboxylic acid; alcohol; alkyne; halide; azide; siloxy; phosphonic acid; thiol; tetrazine; norbornen; oxoamine; aminooxy; thioether; haloacetamide; glutamate; glutaric anhydride, succinic anhydride, maleic anhydride; aldehyde; ketone; hydrazide; chloroformate, and maleimide; or 
 a bioactive group, wherein the bioactive group is selected from the group consisting of antibody; hapten; peptide; protein; polysaccharide; fatty acid; liposome; lipid; polyamine; solid support; fluorophore; chromophore; macrocyclic chelate; and combinations thereof; 
 
         L 1 , L 1′ , L 2  and L 2′  each independently represents:
 a single bond; or 
 a linker selected from the group consisting of alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, alkenyl, and alkynyl; wherein alkyl moieties are optionally interrupted by one or more heteroatoms selected from the group consisting of O, N, and S; optionally additionally comprising a residue of a coupling function through which R 1 , R 1′ , R 2  and R 2′  are bounded to L 1 , L 1′ , L 2  and L 2′  respectively; 
 
         R 3  and R 3′  each independently represents:
 a hydrogen atom; 
 an activating function, wherein the activating function is selected from the group consisting of N-hydroxysuccinimide, N-hydroxyglutarimide, maleimide, halide, and —OCOR 4 , wherein R 4  is selected from the group consisting of alkyl and aryl; or 
 a bioactive group, wherein the bioactive group is selected from the group consisting of antibody; hapten; peptide; protein; polysaccharide; fatty acid; liposome; lipid; polyamine; solid support; fluorophore; chromophore; macrocyclic chelate; and combinations thereof; 
 
         provided that at least one of -L 1 -R 1 , -L 1′ -R 1′ , -L 2 -R 2  and -L 2′ -R 2′  represents a linker with a coupling function or a linker with a bioactive group. 
       
     
     
         24 . The ligand according to  claim 23 , wherein, in the coupling function, the activated ester is selected from the group consisting of N-hydroxysuccinimide ester, N-hydroxyglutarimide ester, and maleimide ester; the activated carboxylic acid is selected from the group consisting of anhydride and acid halide; and the haloacetamide is selected from the group consisting of chloroacetamide, bromoacetamide, and iodoacetamide. 
     
     
         25 . The ligand according to  claim 23 , wherein, in the bioactive group, the antibody is selected from the group consisting of polyclonal antibody, monoclonal antibody, hybrid antibody, chimeric antibody, single-domain antibody, dimeric antibody fragment construct, trimeric antibody fragment construct, and minibody; the chelate is spermine; and the solid support is selected from the group consisting of nanoparticle and polymeric microparticle. 
     
     
         26 . The ligand according to  claim 23 , wherein at least one of -L 1 -R 1 , -L 1′ -R 1′ , -L 2 -R 2  and -L 2′ -R 2′  is selected from formulae (a) and (b): 
       
         
           
           
               
               
           
         
         wherein n and m represent each independently an integer ranging from 1 to 10. 
       
     
     
         27 . The ligand according to  claim 23 , wherein at least one of -L 1 -R 1 , -L 1′ -R 1′ , -L 2 -R 2  and -L 2′ -R 2′  is selected from formulae (a) and (b): 
       
         
           
           
               
               
           
         
         wherein n and m represent each independently 1, 2, 3, or 4. 
       
     
     
         28 . The ligand according to  claim 23 , of formula (Ia) 
       
         
           
           
               
               
           
         
         wherein R 1 , R 1′ , L 1  and L 1′  are as defined in  claim 23 . 
       
     
     
         29 . The ligand according to  claim 23 , selected from the group consisting of:
 6,6′-((4-(4-isothiocyanatobenzyl)-10-methyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))dipicolinic acid;   6,6′-((4-(3-aminopropyl)-10-methyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))dipicolinic acid; and   6, 6′-((4-(4-(3-(4-(6-((aminooxy) carbonyl)-2-(16-((aminooxy)carbonyl)-1-(1H-imidazol-4-yl)-4,7,10,18-tetraoxo-3,8,11,17-tetraazanonadecan-19-yl)-21-(1H-imidazol-4-yl)-4,12,15,18-tetraoxo-2,5,11,14,19-pentaazahenicosyl)phenyl)thioureido)benzyl)-10-methyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)bis(methylene))dipicolinate.   
     
     
         30 . A process for manufacturing a ligand according to  claim 23 , comprising starting from cyclen glyoxal: 
       
         
           
           
               
               
           
         
         and performing the following steps: 
         (a1) reacting with compound M 1 -L 1 -X 1  wherein 
         L 1  is as defined in formula (I); 
         X 1  represents a halogen atom; 
         M 1  represents R 1 , wherein R 1  is as defined in formula (I); or M 1  represents a precursor of a coupling function; 
         (a1′) reacting with compound M 1′ -L 1′ -X 1′  wherein 
         L 1′  is as defined in formula (I); 
         X 1′  represents a halogen atom; 
         M 1′  represents R 1′ , wherein R 1′  is as defined in formula (I); or M 1′  represents a precursor of a coupling function; 
         (b1) reacting with compound of formula (i) 
       
       
         
           
           
               
               
           
         
         wherein 
         L 2  is as defined in formula (I); 
         X represents a halogen atom; 
         M 2  represents R 2 , wherein R 2  is as defined in formula (I); or M 2  represents a precursor of a coupling function; 
         M 3  represents 
         a protecting group selected from alkyl group; or 
         R 3 , wherein R 3  is as defined in formula (I), provided that it does not represents a hydrogen atom; 
         (b1′) reacting with compound of formula (i′) 
       
       
         
           
           
               
               
           
         
         wherein 
         L 2′  is as defined in formula (I); 
         X represents a halogen atom; 
         M 2′  represents R 2′,  wherein R 2′  is as defined in formula (I); or M 2′  represents a precursor of a coupling function; 
         M 3′  represents 
         a protecting group selected from alkyl group; or 
         R 3′ , wherein R 3′  is as defined in formula (I), provided that it does not represents a hydrogen atom; 
         (c) performing glyoxal bridge deprotection; 
         said steps being performed in the following order: (a1), (a1′), (c), (b1) and (b1′); or alternatively (b1), (b1′), (c), (a1) and (a1′); 
         to afford intermediate compound (ii) 
       
       
         
           
           
               
               
           
         
         wherein L 1 , L 1′  L 2 , L 2′  are as defined in formula (I) and wherein M 1 , M 1′ , M 2 , M 2′ , M 3  and M 3′ , are as defined above; 
         and where needed, conducting on intermediate compound (ii) one or more subsequent step selected from:
 in the case wherein M 1 , M 1′ , M 2  or M 2′  represents a precursor of a coupling function, converting the precursor to a coupling function to afford compound of formula (I) wherein R 1 , R 1′ , R 2  or R 2′  respectively represents a coupling function; 
 in the case wherein M 1 , M 1′ , M 2  or M 2′  represents a coupling function, introducing a bioactive group to afford compound of formula (I) wherein R 1 , R 1′ , R 2  or R 2′  respectively represents a bioactive group; 
 in the case wherein M 3  or M 3′  represents a protecting group, deprotecting the acidic function, to afford compound of formula (I) wherein R 3  or R 3′  represent a hydrogen atom; and 
 introducing an activating function or a bioactive group on the acidic function to afford compound of formula (I) wherein R 3  or R 3′  represents an activating function or a bioactive group; 
 
         to afford compound of formula (I). 
       
     
     
         31 . The process according to  claim 30 , wherein the alkyl group is selected from the group consisting of methyl, ethyl, and t-butyl. 
     
     
         32 . The process according to  claim 30 , wherein X 1  represents an halogen atom selected from the group consisting of Br and I; X 1′  represents an halogen atom selected from the group consisting of Br and I; and X represents Cl. 
     
     
         33 . A process for manufacturing a chelate according to  claim 15  comprising reacting a ligand of formula (I) with a metallic cation selected from bismuth (III), lead (II), copper (II), copper (I), gallium (III), zirconium (IV), technetium (III), indium (III), rhenium (VI), astatine (III), yttrium (III), samarium (III), actinium (III), lutetium (III), terbium (III), holmium (III), gadolinium (III), and europium(III);
 wherein the ligand of formula (I) is defined as 
 
       
         
           
           
               
               
           
         
         wherein 
         R 1 , R 1′ , R 2  and R 2′  each independently represents:
 a hydrogen atom; 
 a coupling function, wherein the coupling function is selected from the group consisting of amine; isothiocyanate; isocyanate; activated ester; carboxylic acid; activated carboxylic acid; alcohol; alkyne; halide; azide; siloxy; phosphonic acid; thiol; tetrazine; norbornen; oxoamine; aminooxy; thioether; haloacetamide; glutamate; glutaric anhydride, succinic anhydride, maleic anhydride; aldehyde; ketone; hydrazide; chloroformate, and maleimide; or 
 a bioactive group, wherein the bioactive group is selected from the group consisting of antibody; hapten; peptide; protein; polysaccharide; fatty acid; liposome; lipid; polyamine; solid support; fluorophore; chromophore; macrocyclic chelate; and combinations thereof; 
 
         L 1 , L 1′ , L 2  and L 2′  each independently represents:
 a single bond; or 
 a linker selected from the group consisting of alkyl, aryl, arylalkyl, alkylaryl, heteroaryl, heteroarylalkyl, alkylheteroaryl, alkenyl, and alkynyl; wherein alkyl moieties are optionally interrupted by one or more heteroatoms selected from the group consisting of O, N, and S; optionally additionally comprising a residue of a coupling function through which R 1 , R 1′ , R 2  and R 2′  are bounded to L 1 , L 1′ , L 2  and L 2′  respectively; 
 
         R 3  and R 3′  each independently represents:
 a hydrogen atom; 
 an activating function, wherein the activating function is selected from the group consisting of N-hydroxysuccinimide, N-hydroxyglutarimide, maleimide, halide, and —OCOR 4 , wherein R 4  is selected from the group consisting of alkyl and aryl; or 
 a bioactive group, wherein the bioactive group is selected from the group consisting of antibody; hapten; peptide; protein; polysaccharide; fatty acid; liposome; lipid; polyamine; solid support; fluorophore; chromophore; macrocyclic chelate; and combinations thereof; 
 
         provided that at least one of -L 1 -R 1 , -L 1′ -R 1′ , -L 2 -R 2  and -L 2′ -R 2′  represents a linker with a coupling function or a linker with a bioactive group. 
       
     
     
         34 . A pharmaceutical composition comprising the chelate according to  claim 16 , in association with at least one pharmaceutically acceptable excipient.