Maytansinoid derivatives

Abstract

Disclosed herein are maytansinoid drug linker derivatives which can be linked to a antigen binding unit (Abu), and maytansinoid drugs linked with an antigen binding unit (Drug-Linker-Antigen binding Unit: D-L-Abu), for targeted delivery to disease tissues. D-L-Abu, D-L-Abu derivatives, and methods relating to the use of such drug conjugates to treat antigen positive cells in cancers and immunological disorders are provided.

1 - 57 . (canceled) 
     
     
         58 . A compound of Formula IV: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, 
       wherein
 X is H or CI; 
 Y is H or methyl; 
 R 7  is hydrogen, C 1 -C 6  alkyl or an amino acid side chain; 
 R 8  is hydrogen or C 1 -C 6 alkyl; and 
 m is an integer of 1 to 20, preferably 1 to 10, more preferably 5 to 10. 
 
     
     
         59 . The compound of  claim 58 , which is a compound of Formula V: 
       
         
           
           
               
               
           
         
       
     
     
         60 . A compound of Formula IVa: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof, 
       wherein
 X is H or CI; 
 Y is H or methyl; 
 R 7  is hydrogen, C 1 -C 6  alkyl or an amino acid side chain; 
 R 8  is hydrogen or C 1 -C 6 alkyl; 
 p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; 
 m is selected from an integer of 1 to 20, preferably 1 to 10, more preferably 5 to 10; and 
 Abu is an antigen binding unit. 
 
     
     
         61 . The compound of  claim 60 , which is a compound of Formula Va: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         62 . The compound of any one of  claim 60  or  61 , wherein Abu is an antigen binding unit with binding specificity to human EGFR. 
     
     
         63 . The compound of any one of  claim 60  or  61 , wherein Abu is an antigen binding unit with binding specificity to human CD20. 
     
     
         64 . The compound of any one of  claim 60  or  61 , wherein Abu is an antigen binding unit with binding specificity to human Her2. 
     
     
         65 . The compound of any one of  claim 60  or  61 , wherein Abu is an antibody comprising SEQ ID NOs: 1 and 2, or SEQ ID NOs: 3 and 4, or SEQ ID NOs: 5 and 6, or SEQ ID NOs: 7 and 8, or SEQ ID NOs: 9 and 10, or SEQ ID NOs: 11 and 12, or SEQ ID NOs: 13 and 14. 
     
     
         66 . The compound of any one of  claim 60  or  61 , wherein Abu is selected from C225, EGF-ABX, EGF-ABX, NIMO, Matu, rituxamab, Cetuximab, trastuzumab and Pertuzumab. 
     
     
         67 . A compound of Formula IVb: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, 
       wherein
 X is H or CI; 
 Y is H or methyl; 
 R 7  is hydrogen, C 1 -C 6  alkyl or an amino acid side chain; 
 R 8  is hydrogen or C 1 -C 6 alkyl; 
 m is selected from an integer of 1 to 20, preferably 1 to 10, more preferably 5 to 10; and 
 AA is an amino acid or thiolated amino acid. 
 
     
     
         68 . The compound of  claim 67 , which is of Formula Vb: 
       
         
           
           
               
               
           
         
       
       or a salt thereof, 
       wherein
 AA is an amino acid or thiolated amino acid. 
 
     
     
         69 . The compound of  claim 68 , wherein AA is, but not limited to 
       
         
           
           
               
               
           
         
       
       wherein   represents point of connection to the rest of the molecule. 
     
     
         70 . A method of treating a proliferative, inflammatory or immunologic disease or condition in a patient in need thereof comprising administering an effective amount of a compound of Formula XIVc, 
       
         
           
           
               
               
           
         
       
       wherein the compound of Formula XIVc is generated as a result of a metabolic chemical reaction following administration of a compound of Formula XIVa, 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, to the patient. 
       wherein
 Abu is antigen binding unit; 
 p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10. 
 
     
     
         71 . A method of preparing a compound of Formula Va: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, comprising contacting an antigen binding unit with a compound of Formula V: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
         72 . The method of  claim 71 , wherein the antigen binding unit is an antibody comprising SEQ ID NOs: 1 and 2, or SEQ ID NOs: 3 and 4, or SEQ ID NOs: 5 and 6, or SEQ ID NOs: 7 and 8, or SEQ ID NOs: 9 and 10, or SEQ ID NOs: 11 and 12, or SEQ ID NOs: 13 and 14.