Methods Of Coupling Multidentate AZA Ligands To Targeting Molecules

Abstract

Methods of coupling targeting molecules to multidentate aza ligands of general formula (I): in which: R 1 through R 5 and FG are as defined in the specification are presented. The aza ligands and/or the resulting conjugates may be labeled with bi-trivalent ions of the metal elements having atomic number ranging between 20 and 31, 39, 42, 43, 44, 49, and between 57 and 83, and radioisotopes chosen among 203 Pb, 67 Ga, 68 Ga, 72 As, 111 In, 113 In, 90 Y, 97 Ru, 62 Cu, 64 Cu, 52 Fe, 52m Mn, 140 La, 175 Yb, 153 Sm, 166 Ho, 149 Pm, 177 Lu, 142 Pr, 159 Gd, 212 Bi, 47 Sc, 149 Pm, 67 Cu, 111 Ag, 199 Au, 161 Tb, 51 Cr, 167 Tm, 141 Ce, 168 Yb, 88 Y, 165 Dy, 166 Dy, 97 Ru, 103 Ru, 186 Re, 188 Re, 99m Tc, 211 Bi, 212 Bi, 213 Bi, 214 Bi, 105 Rh, 109 Pd, 117m Sn, 177 Sn and 199 Au.

1 - 60 . (canceled) 
     
     
         61 . A method of coupling an Aazta derivative with an amino group or a protected amino group to a targeting moiety containing a carboxylic acid group comprising the following reaction: 
       
         
           
           
               
               
           
         
       
       wherein T-CO 2 H is the targeting moiety containing a carboxylic acid group, Aazta-NH 2  is the Aazta derivative with an amino group or a protected amino group, and Aazta NH—CO-T is the Aazta derivative with an amino group or protected amino group coupled to the targeting moiety containing a carboxylic acid group, with the proviso that if the amino group of the Aazta derivative is protected, it is deprotected before the above reaction proceeds. 
     
     
         62 . A method of coupling an Aazta derivative with an amino group or a protected amino group to a targeting moiety containing an amino group comprising the following reaction: 
       
         
           
           
               
               
           
         
       
       wherein Aazta-NH 2  is the Aazta derivative with an amino group or a protected amino group and T-NH 2  is a targeting moiety containing an amino group, with the proviso that if the amino group of the Aazta derivative is protected, it is deprotected before the above reaction proceeds. 
     
     
         63 . A method of coupling an Aazta derivative with one or more carboxylic acid side chains, wherein one or more of the carboxylic acid side chains can be protected, to a targeting moiety containing an amino group, comprising a reaction selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein Aazta-CO 2 H or 
       
         
           
           
               
               
           
         
       
       is the Aazta derivative with one or more carboxylic acid side chains, wherein one or more of the carboxylic acid side chains can be protected, T-NH 2  is the targeting moiety containing an amino group and Aazta CONH-T or 
       
         
           
           
               
               
           
         
       
       is the Aazta derivative with one or more carboxylic acid side chains, wherein one or more of the carboxylic acid side chains are protected, coupled to the targeting moiety containing an amino group, with the proviso that if one or more of the carboxylic acid side chains of the Aazta derivative are protected, they are deprotected before the reaction proceeds. 
     
     
         64 . (canceled) 
     
     
         65 . The method of any one of  claims 61 - 63  wherein the Aazta derivative is a compound of general formula (I): 
       
         
           
           
               
               
           
         
       
       in which:
 R 1  is hydrogen, C 1 -C 20  alkyl, C 3 -C 10  cycloalkyl, C 4 -C 20  cycloalkylalkyl, aryl, arylalkyl or the two R 1  groups, taken together, form a straight or cyclic C 2 -C 10  alkylene group or an ortho-disubstituted arylene; 
 R 2  is hydrogen, carboxy, or an optionally substituted group selected from C 1 -C 20  alkyl, C 3 -C 10  cycloalkyl, C 4 -C 20  cycloalkylalkyl, aryl, arylalkyl, a group bearing an acidic moiety, and a group bearing an amino moiety, each of which may be further optionally substituted with functional groups which allow conjugation with a suitable molecule able to interact with physiological systems; 
 R 3 , R 4  and R 5 , which are the same or different, are hydrogen, carboxy, or an optionally substituted group selected from C 1 -C 20  alkyl, C 3 -C 10  cycloalkyl, C 4 -C 20  cycloalkylalkyl, aryl, arylalkyl, a group bearing an acidic moiety and a group bearing an amino moiety, each of which may be further optionally substituted with functional groups selected from the group consisting of carboxyl, amino, aldehydes, haloalkyl, maleimidoalkyl, hydroxyl and sulfhydryl groups which allow conjugation with a suitable molecule able to interact with physiological systems; 
 FG, which can be the same or different, are carboxy, —PO 3 H 2  or —RP(O)OH groups, wherein R is hydrogen, or an optionally substituted group selected from C 1 -C 20  alkyl, C 3 -C 10  cycloalkyl, C 4 -C 20  cycloalkylalkyl, aryl, arylalkyl, a group bearing an acidic moiety and a group bearing an amino moiety, each of which may be further optionally substituted with functional groups selected from the group consisting of carboxyl, amino, aldehydes, haloalkyl, maleimidoalkyl, hydroxyl and sulfhydryl groups which allow conjugation with a suitable molecule able to interact with physiological systems; 
 as well as the salts thereof with physiologically compatible bases or acids.