Psma binding ligand-linker conjugates and methods for using

Abstract

Described herein are prostate specific membrane antigen (PSMA) binding conjugates that are useful for delivering therapeutic, diagnostic and imaging agents. Also described herein are pharmaceutical composition containing them and methods of using the conjugates and compositions. Also described are processes for manufacture of the conjugates and the compositions containing them.

1 - 29 . (canceled) 
     
     
         30 . A method comprising:
 (a) administering a compound of the formula B-L-D, or a salt thereof, to a subject in need thereof, wherein:
 B is a urea of two amino acids; 
 L comprises (i) a divalent alkylenecarbonyl and (ii) at least one nitrogen atom, wherein the divalent alkylenecarbonyl is optionally substituted with one or more substituents X 1  selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, halo, haloalkyl, sulfhydrylalkyl, alkylthioalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, carboxy, carboxyalkyl, and alkyl carboxylate, and wherein L is about 7 to about 9 atoms in length; 
 D comprises a fist radioactive isotope of a metal coordinated to a first chelating group; and 
 wherein the compound or the salt is optionally administered as a pharmaceutical composition comprising a carrier, a diluent, an excipient, or a combination thereof; and 
   (b) administering a compound of the formula B-L′-C, or a salt thereof, to the subject, wherein:
 B is a urea of two amino acids; 
 L′ is a divalent linker of 7 to 20 atoms in length, the divalent linker comprising a divalent alkylene group, a cycloalkylenecarbonyl group and a hydrophobic side chain divalent group comprising an arylalkyl side chain, provided that the divalent linker has a single hydrophobic side chain divalent group; 
 C comprises a second radioactive isotope of a metal coordinated to a second chelating group, and 
 wherein the compound or the salt is optionally administered as a pharmaceutical composition comprising a carrier, a diluent, an excipient, or a combination thereof. 
   
     
     
         31 . The method of  claim 30 , wherein each B is, independently, of the formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen and R 2  is a substituted carboxylic acid, and the substituted carboxylic acid is covalently bound to L. 
       
     
     
         32 . The method of  claim 30 , wherein B is a urea of two amino acids, wherein the two amino acids are independently selected from asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, ornithine, and threonine. 
     
     
         33 . The method of  claim 30 , wherein L and L′ are each, independently, covalently bound to B through an amide bond. 
     
     
         34 . The method of  claim 30 , wherein L is covalently bound to D through an amide bond and L′ is bound to C through an amide bond. 
     
     
         35 . The method of  claim 30 , wherein the first radioactive isotope of a metal is  68 Ga. 
     
     
         36 . The method of  claim 30 , wherein the second radioactive isotope is a therapeutic agent. 
     
     
         37 . The method of  claim 30 , wherein C comprises a chelating group of the formula: 
       
         
           
           
               
               
           
         
         wherein * represents the point of covalent attachment of the chelating group to L′. 
       
     
     
         38 . The method of  claim 30 , further comprising, after (a), (a′) imaging the subject. 
     
     
         39 . The method of  claim 38 , further comprising, after (a′), (a″) diagnosing the subject. 
     
     
         40 . The method of  claim 36 , wherein the subject has prostate cancer. 
     
     
         41 . The method of  claim 38 , wherein the subject has prostate cancer. 
     
     
         42 . The method of  claim 39 , wherein the subject has prostate cancer. 
     
     
         43 . A method for diagnosing and treating prostate cancer comprising:
 (a) administering a compound of the formula B-L-D, or a salt thereof, to a subject in need thereof, wherein:
 B is a urea of two amino acids, wherein the two amino acids are independently selected from asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, ornithine, and threonine; 
 L comprises (i) a divalent alkylenecarbonyl and (ii) at least one nitrogen atom, wherein the divalent alkylenecarbonyl is optionally substituted with one or more substituents X 1  selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, halo, haloalkyl, sulfhydrylalkyl, alkylthioalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, carboxy, carboxyalkyl, and alkyl carboxylate, and wherein L is about 7 to about 9 atoms in length; 
 D comprises a fist radioactive isotope of a metal coordinated to a first chelating group; and 
 wherein the compound or the salt is optionally administered as a pharmaceutical composition comprising a carrier, a diluent, an excipient, or a combination thereof; and 
   (b) administering a compound of the formula B-L′-C, or a salt thereof, to the subject, wherein:
 B is a urea of two amino acids; 
 L′ is a divalent linker of 7 to 20 atoms in length, the divalent linker comprising a divalent alkylene group, a cycloalkylenecarbonyl group and a hydrophobic side chain divalent group comprising an arylalkyl side chain, provided that the divalent linker has a single hydrophobic side chain divalent group; 
 C comprises a second radioactive isotope of a metal coordinated to a second chelating group; and 
 wherein the compound or the salt is optionally administered as a pharmaceutical composition comprising a carrier, a diluent, an excipient, or a combination thereof; and 
   wherein:
 L and L′ are each, independently covalently bound to B through an amide bond; 
 L is covalently bound to D through an amide bond; and 
 L′ is bound to C through an amide bond. 
   
     
     
         44 . The method of  claim 43 , wherein each B is, independently, of the formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen and R 2  is a substituted carboxylic acid, and the substituted carboxylic acid is covalently bound to L. 
       
     
     
         45 . The method of  claim 43 , wherein B is a urea of two amino acids, wherein the two amino acids are independently selected from asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, ornithine, and threonine. 
     
     
         46 . The method of  claim 43 , wherein L and L′ are each, independently, covalently bound to B through an amide bond. 
     
     
         47 . The method of  claim 43 , wherein L is covalently bound to D through an amide bond and L′ is bound to C through an amide bond. 
     
     
         48 . The method of  claim 43 , wherein the first radioactive isotope of a metal is  68 Ga. 
     
     
         49 . The method of  claim 43 , wherein the second radioactive isotope is a therapeutic agent. 
     
     
         50 . The method of  claim 43 , wherein C comprises a chelating group of the formula: 
       
         
           
           
               
               
           
         
         wherein * represents the point of covalent attachment of the chelating group to L′. 
       
     
     
         51 . The method of  claim 43 , further comprising, after (a), (a′) imaging the subject. 
     
     
         52 . The method of  claim 51 , further comprising, after (a′), (a″) diagnosing the subject. 
     
     
         53 . A kit for diagnosing and treating prostate cancer comprising:
 (a) a compound of the formula B-L-D, or a salt thereof, to a subject in need thereof, wherein:
 B is a urea of two amino acids; 
 L comprises (i) a divalent alkylenecarbonyl and (ii) at least one nitrogen atom, wherein the divalent alkylenecarbonyl is optionally substituted with one or more substituents X 1  selected from the group consisting of alkyl, alkoxy, alkoxyalkyl, hydroxy, hydroxyalkyl, amino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, halo, haloalkyl, sulfhydrylalkyl, alkylthioalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, carboxy, carboxyalkyl, and alkyl carboxylate, and wherein L is about 7 to about 9 atoms in length; 
 D comprises a fist radioactive isotope of a metal coordinated to a first chelating group; and 
 wherein the compound or the salt is optionally administered as a pharmaceutical composition comprising a carrier, a diluent, an excipient, or a combination thereof; 
   (b) a compound of the formula B-L′-C, or a salt thereof, to the subject, wherein:
 B is a urea of two amino acids; 
 L′ is a divalent linker of 7 to 20 atoms in length, the divalent linker comprising a divalent alkylene group, a cycloalkylenecarbonyl group and a hydrophobic side chain divalent group comprising an arylalkyl side chain, provided that the divalent linker has a single hydrophobic side chain divalent group; 
 C comprises a second radioactive isotope of a metal coordinated to a second chelating group; and 
 wherein the compound or the salt is optionally administered as a pharmaceutical composition comprising a carrier, a diluent, an excipient, or a combination thereof; and 
   (c) optionally instructions for using the kit to diagnose and treat prostate cancer.   
     
     
         54 . The kit of  claim 53 , wherein each B is, independently, of the formula: 
       
         
           
           
               
               
           
         
         wherein R 1  is hydrogen and R 2  is a substituted carboxylic acid, and the substituted carboxylic acid is covalently bound to L. 
       
     
     
         55 . The kit of  claim 54 , wherein B is a urea of two amino acids, wherein the two amino acids are independently selected from asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, ornithine, and threonine. 
     
     
         56 . The kit of  claim 54 , wherein L and L′ are each, independently, covalently bound to B through an amide bond. 
     
     
         57 . The kit of  claim 54 , wherein L is covalently bound to D through an amide bond and L′ is bound to C through an amide bond. 
     
     
         58 . The kit of  claim 54 , wherein the first radioactive isotope of a metal is  68 Ga. 
     
     
         59 . The kit of  claim 54 , wherein the second radioactive isotope is a therapeutic agent. 
     
     
         60 . The kit of  claim 54 , wherein C comprises a chelating group of the formula: 
       
         
           
           
               
               
           
         
         wherein * represents the point of covalent attachment of the chelating group to L′.