Binding ligand linked drug delivery conjugates of tubulysins

Abstract

Described herein are compounds, pharmaceutical compositions and methods for treating pathogenic cell populations. The compounds described herein include conjugates of tubulysins and vitamin receptor binding ligands. The conjugates also include a releasable bivalent linker.

1 - 36 . (canceled) 
     
     
         37 . A drug delivery conjugate of the formula 
       
         
           
           
               
               
           
         
         wherein D is a tubulysin; or a pharmaceutically acceptable salt thereof. 
       
     
     
         38 . The drug delivery conjugate of  claim 37 , wherein D is of the formula 
       
         
           
           
               
               
           
         
         wherein
 n is an integer from 1 to 3; 
 V is selected from H, OR 2 , and halo, and W is selected from H, OR 2 , and alkyl, wherein R 2  is independently selected from H, alkyl, and C(O)R 3 , wherein R 3  is selected from alkyl, cycloalkyl, alkenyl, aryl, and arylalkyl, providing that R 2  is not H when both V and W are OR 2 ; or V and W are taken together with the attached carbon to form a carbonyl; 
 X is selected from H, C 1-4  alkyl, alkenyl, each of which is optionally substituted, and CH 2 QR 9 ; where Q is selected from —NH—, —O—, and —S—; R 9  is selected from H, C 1-4  alkyl, alkenyl, aryl, and C(O)R 10 ; and R 10  is selected from C 1-6  alkyl, alkenyl, aryl, and heteroaryl; 
 Z is alkyl or C(O)R 4 , where R 4  is selected from alkyl, CF 3 , and aryl; 
 R 1  is H, or R 1  represents 1 to 3 substituents selected from halo, nitro, carboxylate or a derivative thereof, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, phenol protecting groups, prodrug moieties, and OR 6 , where R 6  is selected from alkyl, aryl, COR 7 , P(O)(OR 8 ) 2 , and SO 3 R 8 , wherein R 7  and R 8  are independently selected from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R 8  is a metal cation; and 
 * represents the point of attachment of D to the rest of the conjugate; 
 or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         39 . The drug delivery conjugate of  claim 37 , wherein D is of the formula 
       
         
           
           
               
               
           
         
         wherein
 n is an integer from 1 to 3; 
 V is selected from H, OR 2 , and halo, and W is selected from H, OR 2 , and alkyl, wherein R 2  is independently selected from H, alkyl, and C(O)R 3 , wherein R 3  is selected from alkyl, cycloalkyl, alkenyl, aryl, and arylalkyl, providing that R 2  is not H when both V and W are OR 2 ; or V and W are taken together with the attached carbon to form a carbonyl; 
 X is selected from H, C 1-4  alkyl, alkenyl, each of which is optionally substituted, and CH 2 QR 9 ; where Q is selected from —NH—, —O—, and —S—; R 9  is selected from H, C 1-4  alkyl, alkenyl, aryl, and C(O)R 10 ; and R 10  is selected from C 1-6  alkyl, alkenyl, aryl, and heteroaryl; 
 Z is alkyl or C(O)R 4 , where R 4  is selected from alkyl, CF 3 , and aryl; 
 T is H or OR 6 , wherein R 6  is selected from H, alkyl, aryl, COR 7 , P(O)(OR 8 ) 2 , and SO 3 R 8 , wherein R 7  and R 8  are independently selected from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R 8  is a metal cation; 
 S1 and U are each independently selected from the group consisting of H, halo, nitro, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy; and 
 * represents the point of attachment of D to the rest of the conjugate; 
 or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         40 . The drug delivery conjugate of  claim 37 , wherein D is of the formula 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein
 n is an integer from 1 to 3; 
 V is selected from H, OR 2 , and halo, and W is selected from H, OR 2 , and alkyl, wherein R 2  is independently selected from H, alkyl, and C(O)R 3 , wherein R 3  is selected from alkyl, cycloalkyl, alkenyl, aryl, and arylalkyl, providing that R 2  is not H when both V and W are OR 2 ; or V and W are taken together with the attached carbon to form a carbonyl; 
 Q is selected from —NH—, —O—, and —S—; R 9  is selected from H, C 1-4  alkyl, alkenyl, aryl, and C(O)R 10 ; and R 10  is selected from C 1-6  alkyl, alkenyl, aryl, and heteroaryl; 
 R 12  represents 1 or more substituents selected from alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted; and R 13  is selected from C(O)R 10 , C(O)OR 10 , and CN; 
 Z is alkyl or C(O)R 4 , where R 4  is selected from alkyl, CF 3 , and aryl; 
 T is H or OR 6 , wherein R 6  is selected from H, alkyl, aryl, COR 7 , P(O)(OR 8 ) 2 , and SO 3 R 8 , wherein R 7  and R 8  are independently selected from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R 8  is a metal cation; 
 S1 and U are each independently selected from the group consisting of H, halo, nitro, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy; and 
 * represents the point of attachment of D to the rest of the conjugate; 
 or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         41 . The drug delivery conjugate of  claim 37 , wherein D is of the formula 
       
         
           
           
               
               
           
         
         wherein
 n is an integer from 1 to 3; 
 V is selected from H, OR 2 , and halo, and W is selected from H, OR 2 , and alkyl, wherein R 2  is independently selected from H, alkyl, and C(O)R 3 , wherein R 3  is selected from alkyl, cycloalkyl, alkenyl, aryl, and arylalkyl, providing that R 2  is not H when both V and W are OR 2 ; or V and W are taken together with the attached carbon to form a carbonyl; 
 X 3  is selected from halogen, OS(O) 2 R 10 , OP(O)(OR 10a )R 10  and OP(O)(OR 10a ) 2 ; where R 10  and R 10a  are each independently selected from the group consisting of H, alkyl, alkenyl, cycloalkyl, aryl, and arylalkyl, each of which is optionally substituted, or R 10a  is a metal cation; 
 Z is alkyl or C(O)R 4 , where R 4  is selected from alkyl, CF 3 , and aryl; 
 T is H or OR 6 , wherein R 6  is selected from H, alkyl, aryl, COR 7 , P(O)(OR 8 ) 2 , and SO 3 R 8 , wherein R 7  and R 8  are independently selected from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R 8  is a metal cation; 
 S1 and U are each independently selected from the group consisting of H, halo, nitro, cyano, alkyl, haloalkyl, alkoxy, and haloalkoxy; and 
 * represents the point of attachment of D to the rest of the conjugate; 
 or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         42 . The drug delivery conjugate of  claim 37 , wherein D is a naturally occurring tubulysin, or an analog or derivative thereof; or a pharmaceutically acceptable salt thereof. 
     
     
         43 . The drug delivery conjugate of  claim 37 , wherein D is of the formula 
       
         
           
           
               
               
           
         
         wherein
 R 10  is selected from C 1-6  alkyl, alkenyl, aryl, and heteroaryl; 
 R 1  is H, or R 1  represents 1 to 3 substituents selected from halo, nitro, carboxylate or a derivative thereof, cyano, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, phenol protecting groups, prodrug moieties, and OR 6 , where R 6  is selected from alkyl, aryl, COR 7 , P(O)(OR 8 ) 2 , and SO 3 R 8 , wherein R 7  and R 8  are independently selected from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted, or R 8  is a metal cation; and 
 * represents the point of attachment of D to the rest of the conjugate; 
 or a pharmaceutically acceptable salt thereof. 
 
       
     
     
         44 . The drug delivery conjugate of  claim 38 , wherein Z is methyl; or a pharmaceutically acceptable salt thereof. 
     
     
         45 . The drug delivery conjugate of  claim 38 , wherein R 1  is H; or a pharmaceutically acceptable salt thereof. 
     
     
         46 . The drug delivery conjugate of  claim 38 , wherein R 1  is OR 6 , where R 6  is selected from H, alkyl, and COR 7 ; wherein R 7  is selected from H, alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl, and arylalkyl, each of which is optionally substituted; or a pharmaceutically acceptable salt thereof. 
     
     
         47 . The drug delivery conjugate of  claim 38 , wherein V is H, and W is OC(O)R 3 , wherein R 3  is selected from alkyl, cycloalkyl, alkenyl, aryl, and arylalkyl; or a pharmaceutically acceptable salt thereof. 
     
     
         48 . The drug delivery conjugate of  claim 38 , wherein X is CH 2 OC(O)R 10  and R 10  is selected from C 1-6  alkyl, alkenyl, aryl, and heteroaryl; or a pharmaceutically acceptable salt thereof. 
     
     
         49 . A pharmaceutical composition comprising a therapeutically effective amount of the drug delivery conjugate  claim 37  or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient therefore, or a combination thereof. 
     
     
         50 . A method of eliminating a population of pathogenic cells in a host animal harboring the population of pathogenic cells wherein the members of the pathogenic cell population have an accessible binding site for a vitamin, or a vitamin receptor binding analog or a derivative thereof, and wherein the binding site is uniquely expressed, overexpressed, or preferentially expressed by the pathogenic cells, said method comprising the step of administering to the host a therapeutically effective amount of the drug delivery conjugate of  claim 37  or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.