Dipeptide-based prodrug linkers for aromatic amine-containing drugs

Abstract

The present invention relates to a prodrug or a pharmaceutically acceptable salt thereof, comprising a drug linker conjugate D-L, wherein D being a biologically active moiety containing an aromatic amine group is conjugated to one or more polymeric carriers via dipeptide-containing linkers. Such carrier-linked prodrugs achieve drug releases with therapeutically useful half-lives. The invention also relates to pharmaceutical compositions comprising said prodrugs and their use as medicaments.

1 : A prodrug or a pharmaceutically acceptable salt thereof comprising:
 a drug linker conjugate D-L;   wherein D is a biologically active moiety containing an aromatic amine group; and   wherein L is a non-biologically active linker containing:
 i) a moiety L 1  represented by formula (I); 
   
       
         
           
           
               
               
           
         
         
           
             wherein the dashed line indicates the attachment of L 1  to an aromatic amine group of D by forming an amide bond; 
             wherein R 1 , R 1a , R 2 , R 3 , R 3a , R 4  and R 4a  are independently selected from H and C 1-4  alkyl; 
             wherein, optionally, any two of R 1 , R 1a , R 2 , R 3 , R 3a , R 4  and R 4a  a may independently form one or more cyclic fragments selected from C 3-7  cycloalkyl, 4 to 7 membered heterocyclyl, phenyl, naphthyl, indenyl, indanyl, tetralinyl, and 9 to 11 membered heterobicyclyl; and 
             wherein, optionally, R 1 , R 1a , R 2 , R 3 , R 3a , R 4  and R 4a  are further substituted; 
           
           ii) a moiety L 2 , which is a chemical bond or a spacer, and L 2  is bound to a carrier group Z; 
           wherein L 1  is substituted with one to four L 2  moieties; 
           wherein Z is PEG or a hydrogel; 
         
         wherein, optionally, L is further substituted. 
       
     
     
         2 . The prodrug according to  claim 1 ;
 wherein L 2  is a chemical bond.   
     
     
         3 . The prodrug according to  claim 1 ;
 wherein the carrier group Z is a polymer with a molecular weight ≧500 g/mol.   
     
     
         4 . The prodrug according to  claim 1 ;
 wherein the carrier group Z is a hydrogel.   
     
     
         5 . The prodrug of  claim 4 ;
 wherein the hydrogel is composed of backbone moieties interconnected by hydrolytically degradable bonds.   
     
     
         6 . The prodrug of  claim 5 ;
 wherein the backbone moieties have a molecular weight in the range of from 1 kDa to 20 kDa.   
     
     
         7 . The prodrug of  claim 5 ;
 wherein backbone moieties are linked together through crosslinker moieties, each crosslinker moiety being terminated by at least two of the hydrolytically degradable bonds.   
     
     
         8 . The prodrug of  claim 7 ;
 wherein the crosslinker moieties have a molecular weight in the range of from 0.5 kDa to 5 kDa.   
     
     
         9 . A pharmaceutical composition comprising:
 a prodrug of  claim 1  or a pharmaceutically acceptable salt thereof; and   a pharmaceutically acceptable excipient.   
     
     
         10 . The pharmaceutical composition according to  claim 9 ;
 wherein the pharmaceutical composition is dry.   
     
     
         11 . The pharmaceutical composition according to  claim 9 ;
 wherein the prodrug is sufficiently dosed in the composition to provide a therapeutically effective amount of biologically active agent for at least 12 hours in one application.   
     
     
         12 . A kit of parts comprising:
 a needle; and   a container containing:
 reconstitution solution; and 
 the dry composition according to  claim 11  configured for use with the needle. 
   
     
     
         13 . The kit of parts according to  claim 12 ;
 wherein the container is a dual-chamber syringe; and   wherein one of the two-chambers of the dual-chamber syringe contains the dry pharmaceutical composition and the second chamber of said dual-chamber syringe contains the reconstitution solution.   
     
     
         14 . The prodrug according to any of  claim 1 ;
 wherein the prodrug is configured for use as pharmaceutical.   
     
     
         15 . A method for the synthesis of a prodrug or a pharmaceutically acceptable salt thereof according to  claim 1 , comprising:
 a step of reacting a prodrug precursor L-Y or L 1 -Y with a biologically active drug D-H, to obtain the drug linker conjugate D-L or a drug linker intermediate D-L 1  by forming an amide bond;   wherein Y is a leaving group.   
     
     
         16 . The prodrug according to any of  claim 1 ;
 wherein the carrier group Z is a PEG based hydrogel.   
     
     
         17 . The prodrug according to any of  claim 1 ;
 wherein the carrier group Z is a biodegradable polyethylene glycol based water-insoluble hydrogel.