Drug delivery conjugates containing unnatural amino acids and methods for using

Abstract

Described herein are drug delivery conjugates for targeted therapy. In particular, described herein are drug delivery conjugates that include polyvalent linkers comprising one or more unnatural amino acids that are useful for treating cancers and inflammatory diseases. The invention described herein pertains to drug delivery conjugates for targeted therapy. In particular, the invention described herein pertains to drug delivery conjugates that include polyvalent linkers comprising one or more unnatural amino acids.

1 .- 46 . (canceled) 
     
     
         47 . A compound of the formula
   B-L(D) x      
       or a salt thereof, wherein
 B is a binding ligand of the formula 
 
       
         
           
           
               
               
           
         
       
       wherein * represents the point of attachment of B to L;
 L is a linker comprising one or more unnatural amino acids, wherein at least one unnatural amino acid has the D-configuration; 
 D is a therapeutic agent; and 
 x is 1. 
 
     
     
         48 . The compound of  claim 47 , or a salt thereof, wherein at least one unnatural amino acid is selected from the group consisting of D-alanine, D-aspartic acid, D-asparagine, D-cysteine, D-glutamic acid, D-phenylalanine, D-histidine, D-isoleucine, D-lysine, D-leucine, D-methionine, D-proline, D-glutamine, D-arginine, D-serine, D-threonine, D-valine, D-tryptophan, D-tyrosine, and D-ornithine. 
     
     
         49 . The compound of  claim 47 , or a salt thereof, wherein L comprises two or more unnatural amino acids. 
     
     
         51 . The compound of  claim 47 , or a salt thereof, wherein L comprises three or more unnatural amino acids. 
     
     
         52 . The compound of  claim 47 , or a salt thereof, wherein L comprises four or more unnatural amino acids. 
     
     
         53 . The compound of  claim 47 , or a salt thereof, wherein L comprises a plurality of spacer linkers selected from the group consisting of the naturally occurring amino acids and stereoisomers thereof. 
     
     
         54 . The compound of  claim 47 , or a salt thereof, wherein L comprises a plurality of spacer linkers selected from the group consisting of the naturally occurring amino acids selected from the group consisting of asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, and ornithine. 
     
     
         55 . The compound of  claim 47 , or a salt thereof, wherein L comprises at least one naturally occurring amino acid. 
     
     
         56 . The compound of  claim 47 , or a salt thereof, wherein L comprises at least one hydrophilic spacer linker. 
     
     
         57 . The compound of  claim 56 , or a salt thereof, wherein the hydrophilic spacer linker includes a plurality of hydroxyl functional groups. 
     
     
         58 . The compound of  claim 47 , or a salt thereof, wherein L comprises one or more of the following fragments: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein
 R is H, alkyl, cycloalkyl, or arylalkyl; 
 m is an integer from 1 to about 3; 
 n is an integer from 1 to about 6; 
 p is an integer from 1 to about 5; 
 r is an integer selected from 1 to about 3; and 
 
       each * represents a covalent bond to B, D, or another linker portion. 
     
     
         59 . The compound of  claim 47 , or a salt thereof, wherein D is a radiotherapeutic agent. 
     
     
         60 . The compound of  claim 59 , or a salt thereof, wherein the therapeutic agent comprises a chelating group sequestering a radionuclide. 
     
     
         61 . The compound of  claim 60 , or a salt thereof, wherein the radionuclide is selected from the group consisting of  157 Gd,  64 Cu,  67 Cu,  186 Re,  188 Re,  90 Y,  111 In, and  177 Lu. 
     
     
         62 . The compound of  claim 61 , or a salt thereof, wherein the chelating group is DOTA or DPTA. 
     
     
         63 . A pharmaceutical composition comprising at least one compound of  claim 47 , or a salt thereof, and at least one pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         64 . A unit dose or unit dosage form composition comprising a therapeutically effective amount of one or more compounds of  claim 47 , optionally in combination with one or more carrier, diluent, or excipient, or a combination thereof. 
     
     
         65 . A method of treating cancer in a patient, comprising administering a therapeutically effective amount of one or more compounds of  claim 47 , or a salt thereof. 
     
     
         66 . A compound of the formula
   B-L(D) x      
       or a salt thereof, wherein
 B is a binding ligand of the formula 
 
       
         
           
           
               
               
           
         
       
       wherein * represents the point of attachment of B to L;
 L is a linker comprising one or more unnatural amino acids, wherein at least one unnatural amino acid has the D-configuration; 
 D is a diagnostic agent; and 
 x is 1. 
 
     
     
         67 . The compound of  claim 66 , or a salt thereof, wherein at least one unnatural amino acid is selected from the group consisting of D-alanine, D-aspartic acid, D-asparagine, D-cysteine, D-glutamic acid, D-phenylalanine, D-histidine, D-isoleucine, D-lysine, D-leucine, D-methionine, D-proline, D-glutamine, D-arginine, D-serine, D-threonine, D-valine, D-tryptophan, D-tyrosine, and D-ornithine. 
     
     
         68 . The compound of  claim 66 , or a salt thereof, wherein L comprises two or more unnatural amino acids. 
     
     
         69 . The compound of  claim 66 , or a salt thereof, wherein L comprises three or more unnatural amino acids. 
     
     
         70 . The compound of  claim 66 , or a salt thereof, wherein L comprises four or more unnatural amino acids. 
     
     
         71 . The compound of  claim 66 , or a salt thereof, wherein L comprises a plurality of spacer linkers selected from the group consisting of the naturally occurring amino acids and stereoisomers thereof. 
     
     
         72 . The compound of  claim 66 , or a salt thereof, wherein L comprises a plurality of spacer linkers selected from the group consisting of the naturally occurring amino acids selected from the group consisting of asparagine, aspartic acid, cysteine, glutamic acid, lysine, glutamine, arginine, serine, and ornithine. 
     
     
         73 . The compound of  claim 66 , or a salt thereof, wherein L comprises at least one naturally occurring amino acid. 
     
     
         74 . The compound of  claim 66 , or a salt thereof, wherein L comprises at least one hydrophilic spacer linker. 
     
     
         75 . The compound of  claim 66 , or a salt thereof, wherein the hydrophilic spacer linker includes a plurality of hydroxyl functional groups. 
     
     
         76 . The compound of  claim 66 , or a salt thereof, wherein L comprises one or more of the following fragments: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein each * represents a covalent bond to B, D, or another linker portion. 
       
     
     
         77 . The compound of  claim 66 , or a salt thereof, wherein the diagnostic agent comprises a chelating agent coordinated to a superparamagnetic metal, a paramagnetic metal, a ferrimagnetic metal, ferromagnetic metal, a radioactive gamma-emitting metal, a positron-emitting or photon-emitting metal, or a radionuclide. 
     
     
         78 . The compound of  claim 77 , or a salt thereof, wherein the metal is selected from the group consisting of Cr(III), Mn(II), Fe(II), Fe(III), and Ni(II). 
     
     
         79 . The compound of  claim 77 , or a salt thereof, wherein the metal is selected from the group consisting of  99m Tc,  51 Cr,  67 Ga,  68 Ga,  103 Ru,  211 Bi,  64 Cu and  111 In. 
     
     
         80 . The compound of  claim 79 , or a salt thereof, wherein the chelating agent is DOTA or DPTA.