Pegylated drug-linkers for improved ligand-drug conjugate pharmacokinetics

Abstract

The present invention provides Ligand-Drug Conjugates comprising a PEG Unit in a parallel orientation to the Drug Unit. The invention provides inter alia. Ligand-Drug Conjugates (LDCs), methods of preparing and using them, and intermediates thereof. The Ligand-Drug Conjugates are stable in circulation, yet capable of inflicting cell death on targeted cells or inhibiting proliferation of targeted cells once its drug cargo is released in the vicinity or within targeted cells. In principle embodiments, an LDC of the present invention is represented by the structure of Formula I.

1 - 91 . (canceled) 
     
     
         92 . A Linker Compound having the formula VII, VIII or IX: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         PEG is a Polyethylene Glycol Unit; 
         Z′ is a Stretcher Unit capable of forming a covalent attachment to a Ligand Unit; 
         A′ is a Branching Unit capable of forming a covalent attachment to two to four X-D Units, 
         wherein —X-D is a Releasable Assembly Unit (—X—) attached to a Drug Unit (D); 
         A is an optional Branching Unit; 
         AD′ is a Drug Attachment Unit capable of forming a covalent attachment to a —X-D Unit; 
         L P  is a Parallel Connector Unit; 
         L P′  is a Parallel Connector Unit capable of forming a covalent attachment to a —X-D Unit: 
         the subscript t is an integer and is 0 to 8; 
         the subscript m is an integer and is 1 to 4; 
         the subscript s is an integer and is 0 or 1, with the proviso that when s is 0, m is 1 and when s is 1, m is 2 to 4. 
       
     
     
         93 . The Linker Compound of  claim 92 , wherein L P′  is a protected cysteine or penicillamine as shown in the formula below: 
       
         
           
           
               
               
           
         
       
       wherein the wavy line indicates covalent attachment within the Compound and R PR  is a thiol protecting group. 
     
     
         94 . The Linker Compound of  claim 92 , having Formula VIII wherein t is 1 and wherein AD′ is 
       
         
           
           
               
               
           
         
       
       wherein R PR  is a thiol protecting group and the wavy line indicates covalent attachment within the Compound. 
     
     
         95 . The Linker Compound of  claim 92  having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein R PR  is a thiol protecting group. 
       
     
     
         96 . The Linker Compound of  claim 92 , having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein R PR  is a thiol protecting group. 
     
     
         97 - 102 . (canceled) 
     
     
         103 . The Linker Compound of  claim 92 , wherein the compound has the structure of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein 
         R PR  is hydrogen or a protecting group; and 
         n is an integer ranging from 8 to 24. 
       
     
     
         104 . The Linker Compound of  claim 92 , wherein the compound has the structure of: 
       
         
           
           
               
               
           
         
       
     
     
         105 . The Linker Compound of  claim 92 , wherein the compound has the structure of: 
       
         
           
           
               
               
           
         
       
     
     
         106 . The Linker Compound of  claim 92 , wherein the compound has the structure of: 
       
         
           
           
               
               
           
         
       
     
     
         107 . The Linker Compound of  claim 92 , wherein the compound has the structure of: