Monomethylvaline compounds capable of conjugation to ligands

Abstract

Auristatin peptides, including MeVal-Val-Dil-Dap-Norephedrine (MMAE) and MeVal-Val-Dil-Dap-Phe (MMAF), were prepared and attached to Ligands through various linkers, including maleimidocaproyl-val-cit-PAB. The resulting ligand drug conjugates were active in vitro and in vivo.

What is claimed is: 
     
         1 . A method for treating cancer comprising administering to a patient in need thereof an effective amount of an antibody-drug conjugate having Formula Ia′:
   A b A a -W w —Y y -D) p   Ia′
 
 or a pharmaceutically acceptable salt thereof, wherein: 
 Ab is an antibody that specifically binds to an antigen expressed by the cancer, 
 A is a Stretcher unit, 
 a is 1, 
 each W is independently an Amino Acid unit, 
 w is an integer ranging from 2 to 12, 
 Y is a Spacer unit, and 
 y is 1 or 2, 
 p ranges from 1 to about 20, and 
 D is a drug moiety of Formula D F : 
 
       
         
           
           
               
               
           
         
         wherein the wavy line of D F  indicates the covalent attachment site to Y: 
         R 2  is selected from H and C 1 -C 8  alkyl; 
         R 3  is selected from H, C 1 -C 8  alkyl, C 3 -C 8  carbocycle, aryl, C 1 -C 8  alkyl-aryl, C 1 -C 8  alkyl-(C 3 -C 8  carbocycle), C 3 -C 8  heterocycle and C 1 -C 8  alkyl-(C 3 -C 8  heterocycle); 
         R 4  is selected from H, C 1 -C 8  alkyl, C 3 -C 8  carbocycle, aryl, C 1 -C 8  alkyl-aryl, C 1 -C 8  alkyl-(C 3 -C 8  carbocycle), C 3 -C 8  heterocycle and C 1 -C 8  alkyl-(C 3 -C 8  heterocycle); 
         R 5  is selected from H and methyl; 
         or R 4  and R 5  jointly form a carbocyclic ring and have the formula —(CR a R b ) n — wherein R a  and R b  are independently selected from H, C 1 -C 8  alkyl and C 3 -C 8  carbocycle and n is selected from 2, 3, 4, 5 and 6; 
         R 6  is selected from H and C 1 -C 8  alkyl; 
         R 7  is selected from H, C 1 -C 8  alkyl, C 3 -C 8  carbocycle, aryl, C 1 -C 8  alkyl-aryl, C 1 -C 8  alkyl-(C 3 -C 8  carbocycle), C 3 -C 8  heterocycle and C 1 -C 8  alkyl-(C 3 -C 8  heterocycle); 
         each R 8  is independently selected from H, OH, C 1 -C 8  alkyl, C 3 -C 8  carbocycle and O—(C 1 -C 8  alkyl); 
         R 9  is selected from H and C 1 -C 8  alkyl; 
         R 10  is selected from aryl or C 3 -C 8  heterocycle; 
         Z is O, S, NH, or NR 12 , wherein R 12  is C 1 -C 8  alkyl; 
         R 11  is selected from H, C 1 -C 20  alkyl, aryl, C 3 -C 8  heterocycle, —(R 13 O) m —R 14 , or —(R 13 O) m —CH(R 15 ) 2 ; 
         m is an integer ranging from 1-1000; 
         R 13  is C 2 -C 8  alkyl; 
         R 14  is H or C 1 -C 8  alkyl; 
         each occurrence of R 15  is independently H, COOH, —(CH 2 ) n —N(R 16 ) 2 , —(CH 2 ) n —SO 3 H, or —(CH 2 ) n —SO 3 —C 1 -C 8  alkyl; 
         each occurrence of R 16  is independently H, C 1 -C 8  alkyl, or —(CH 2 ), —COOH; and 
         n is an integer ranging from 0 to 6. 
       
     
     
         2 . The method of  claim 1 , wherein the antibody-drug conjugate has the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein R 17  is C 1 -C 10  alkylene-, —C 3 -C 8  carbocyclo-, —O—(C 1 -C 8  alkyl)-, -arylene-, —C 1 -C 10  alkylene-arylene-, -arylene-C 1 -C 10  alkylene-, —C 1 -C 10  alkylene-(C 3 -C 8  carbocyclo)-, —(C 3 -C 8  carbocyclo)-C 1 -C 10 alkylene-, —C 3 -C 8  heterocyclo-, —C 1 -C 10  alkylene-(C 3 -C 8  heterocyclo)-, —(C 3 -C 8  heterocyclo)-C 1 -C 10  alkylene-, —(CH 2 CH 2 O) r —, and —(CH 2 CH 2 O) r —CH 2 —; and r is an integer ranging from 1-10. 
       
     
     
         3 . The method of  claim 1 , wherein the antibody-drug conjugate has the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         4 . The method of  claim 3 , wherein the antibody-drug conjugate has the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         5 . The method of  claim 1 , wherein D has the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         6 . The method of  claim 1 , wherein Z is —O— and R 11  is —H, methyl or t-butyl 
     
     
         7 . The method of  claim 6 , wherein R 11  is —H. 
     
     
         8 . The method of  claim 1 , wherein R 2  and R 6  are each methyl, and R 9  is —H. 
     
     
         9 . The method of  claim 1 , wherein the antibody-drug conjugate has the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof; wherein Val is valine, and Cit is citrulline. 
       
     
     
         10 . The method of  claim 9 , wherein the antibody is a monoclonal antibody.