Beta-glucuronide-linker drug conjugates

Abstract

Ligand Drug conjugate compounds comprising a β-glucuronide-based linker and methods of using such compounds are provided.

1 - 6 . (canceled) 
     
     
         7 . A method of preparing a Linker Unit precursor comprising the step of contacting a bi-functional Stretcher Unit having an activated carboxylic acid functional group and another functional group capable of forming a bond to a functional group of another Stretcher Unit, or to a functional group of a Ligand Unit, wherein the bond from said contact is an amide bond to the amino group of a suitably protected compound of formula 5, 
       
         
           
           
               
               
           
         
         wherein the Linker Unit precursor so prepared substantially retains the suitable protection of that protected compound. 
       
     
     
         8 . The method of  claim 7  wherein the prepared Linker Unit precursor has the structure of formula 7: 
       
         
           
           
               
               
           
         
       
     
     
         9 . A method of preparing a drug-linker conjugate compound intermediate comprising
 (a) converting the benzylic hydroxyl group of the Linker Unit precursor of  claim 7  to an activated carbonate functional group;   (b) contacting the product of step (al with a drug having an amino functional group to form a carbamate functional group so as to provide a drug-linker conjugate compound intermediate that substantially retains the suitable protection of the Linker Unit precursor and   (c) optionally deprotecting the protected drug-linker conjugate compound intermediate of step (b).   
     
     
         10 . The method of  claim 9  wherein the prepared drug-linker conjugate compound intermediate has the structure of: 
       
         
           
           
               
               
           
         
         wherein D is a Drug Unit from said contacting of the drug with the Ligand Unit precursor. 
       
     
     
         11 . The method of  claim 10 , wherein D is a minor groove binder or antitubulin agent. 
     
     
         12 . The method of  claim 10 , wherein D is an auristatin. 
     
     
         13 . The method of  claim 12 , wherein D has the structure of: 
       
         
           
           
               
               
           
         
         wherein the wavy line indicates the point of covalent attachment to the remainder of the prepared drug-linker conjugate compound intermediate structure. 
       
     
     
         14 . A method of preparing a drug-linker conjugate compound intermediate comprising
 (a) reacting an —OH group of a Linker Unit precursor with diphosgene and an oxazoline carbamate with a silyl protecting group;   (b) removing the silyl protecting group with fluoride and oxidizing the product to generate an aldehyde group;   (c) performing a reductive alkylation reaction with a drug to provide the drug-linker conjugate compound intermediate,   wherein the drug-linker conjugate compound intermediate has the structure of:   
       
         
           
           
               
               
           
         
         wherein D is a Drug Unit from resulting from said drug of step (c). 
       
     
     
         15 . The method of  claim 14 , wherein D is a doxorubicin moiety. 
     
     
         16 . A method of treating an autoimmune disease, comprising administering to a patient in need thereof a therapeutically effective amount of a ligand drug conjugate compound have the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein 
         L- is a Ligand unit; 
         -A a -W w —Y y — is a Linker unit (LU); 
         -A- is an optional Stretcher unit; 
         a is 0, 1 or 2; 
         each —W— is independently a Glucuronide unit having one of the formulae: 
       
       
         
           
           
               
               
           
         
         Su is a Sugar moiety; 
         each R is independently hydrogen, a halogen, —CN, or —NO 2 ; 
         w is an integer ranging from 1 to 2; 
         —Y— is an optional self-immolative spacer unit; 
         y is 0, 1 or 2; 
         p ranges from 1 to 20; and 
         -D is a Drug unit, wherein the wavy lines indicate covalent attachment within the rest of the compound. 
       
     
     
         17 . The method of  claim 16 , wherein the ligand drug conjugate compound has the structure of: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         18 . A method of treating an infectious disease, comprising administering to a patient in need thereof a therapeutically effective amount of a ligand drug conjugate compound have the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein 
         L- is a Ligand unit; 
         -A a -W w —Y y — is a Linker unit (LU); 
         -A- is an optional Stretcher unit; 
         a is 0, 1 or 2; 
         each —W— is independently a Glucuronide unit having one of the formulae: 
       
       
         
           
           
               
               
           
         
         Su is a Sugar moiety; 
         each R is independently hydrogen, a halogen, —CN, or —NO 2 ; 
         w is an integer ranging from 1 to 2; 
         —Y— is an optional self-immolative spacer unit; 
         y is 0, 1 or 2; 
         p ranges from 1 to 20; and 
       
       -D is a Drug unit, wherein the wavy lines indicate covalent attachment within the rest of the compound. 
     
     
         19 . The method of  claim 18 , wherein the ligand drug conjugate compound has the structure of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The method of  claim 18 , wherein D is an antibiotic moiety.