Bivalent linkers and conjugates thereof

Abstract

Bivalent linkers to be included in or for preparing vitamin, drug, diagnostic agent, and/or imaging agent conjugates are described.

1 . 6 . (canceled) 
     
     
         7 . A compound of the formula I 
       
         
           
           
               
               
           
         
       
       wherein
 V is an aminopterin; 
 1 s  is a bond; 
 R a  and R b  are each independently selected from the group consisting of hydrogen C 1 -C 4  alkyl; 
 Y is hydrogen, nitro, cyano, halo, alkylsulfonyl, or a carboxylic acid, and wherein each hydrogen atom present on the cysteine portion is optionally substituted with an alkyl. 
 
     
     
         8 . The compound of  claim 7 , wherein R a  and R b  are H. 
     
     
         9 . The compound of  claim 7 , wherein Y is nitro. 
     
     
         10 . The compound of  claim 8 , wherein Y is nitro. 
     
     
         11 . A folate conjugate comprising an antifolate prepared from a compound of the formula I 
       
         
           
           
               
               
           
         
       
       wherein
 V is an aminopterin; 
 1 s  is a bond; 
 R a  and R b  are each independently selected from the group consisting of hydrogen C 1 -C 4  alkyl; 
 Y is hydrogen, nitro, cyano, halo, alkylsulfonyl, or a carboxylic acid, and wherein each hydrogen atom present on the cysteine portion is optionally substituted with an alkyl. 
 
     
     
         12 . The folate conjugate of  claim 11 , wherein R a  and R b  are H. 
     
     
         13 . The folate conjugate of  claim 11 , wherein Y is nitro. 
     
     
         14 . The folate conjugate of  claim 12 , wherein Y is nitro. 
     
     
         15 . A process for preparing a folate conjugate comprising an antifolate, comprising,
 contacting a compound of the formula I   
       
         
           
           
               
               
           
         
       
       wherein
 V is an aminopterin; 
 1 s  is a bond; 
 R a  and R b  are each independently selected from the group consisting of hydrogen C 1 -C 4  alkyl; 
 Y is hydrogen, nitro, cyano, halo, alkylsulfonyl, or a carboxylic acid, and wherein each hydrogen atom present on the cysteine portion is optionally substituted with an alkyl with a compound of the formula II 
 
       
         
           
           
               
               
           
         
         wherein 
         R 2  is an amino acid side chain selected from cysteine, β-methyl cysteine, and β,β-dimethyl cysteine; 
         AA is an amino acid or an amino acid derivative; and 
         n is an integer from 0 to 100. 
       
     
     
         16 . The process of  claim 15 , wherein R a  and R b  are H. 
     
     
         17 . The process of  claim 15 , wherein Y is nitro. 
     
     
         18 . The process of  claim 16 , wherein Y is nitro.