Heterobifunctional pan-selectin inhibitors

Abstract

Compounds and methods are provided for modulating in vitro and in vivo processes mediated by selectin binding. More specifically, selectin modulators and their use are described, wherein the selectin modulators that modulate (e.g., inhibit or enhance) a selectin-mediated function comprise particular glycomimetics alone or linked to a member of a class of compounds termed BASAs (Benzyl Amino Sulfonic Acids) or a member of a class of compounds termed BACAs (Benzyl Amino Carboxylic Acids).

1 - 25 . (canceled) 
     
     
         26 . A method of inhibiting rejection of a transplanted tissue in a patient wherein said patient is a recipient of the transplanted tissue, comprising administering to the patient a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a physiologically acceptable salt thereof, wherein: 
       
       
         
           
           
               
               
           
         
         where n=0-2, and each occurrence of R 8  is independently selected where n=2: 
         R 2 =H, —C(═O)OX where X is C 1 -C 8  alkanyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl or C 6 -C 14  aryl; 
         —C(═O)NH(CH 2 ) n NH 2 , —[C(═O)NH(CH 2 ) n NHC(═O)] m (L) m Z, where n=0-30, m=0-1, L is a linker, and Z is a benzyl amino carboxylic acid or a polyethylene glycol; 
       
       
         
           
           
               
               
           
         
         —O—C(═O)—X, —NH 2 , —NH—C(═O)—NHX, or —NH—C(═O)—X where n=0-2 and X is independently selected from C 1 -C 8  alkanyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, 
       
       
         
           
           
               
               
           
         
       
       where n=0-10,
 and any of the above ring compounds may be substituted with one to three independently selected of Cl, F, C 1 -C 8  alkanyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 6 -C 14  aryl, or OY where Y is H, C 1 -C 8  alkanyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, or C 6 -C 14  aryl; 
 
       
         
           
           
               
               
           
         
         6′sulfated GlcNAc, 6′carboxylated GlcNAc, 6′sulfated GalNAc, 6′sulfated galactose, or 6′carboxylated galactose; 
         R 5 =H; 
         R 6 =H, fucose, mannose, arabinose, galactose or polyols; 
         R 7 =H, C 1 -C 8  alkanyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl or 
       
       
         
           
           
               
               
           
         
       
       and
 R 8 =H, C 1 -C 8  alkanyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, 
 
       
         
           
           
               
               
           
         
         where n=0-3 and X is independently selected from H, OH, Cl, F, N 3 , NH 2 , C 1 -C 8  alkanyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 6 -C 14  aryl, OC 1 -C 8  alkanyl, OC 2 -C 8  alkenyl, OC 2 -C 8  alkynyl, and OC 6 -C 14  aryl, and any of the above ring compounds may be substituted with one to three independently selected of Cl, F, C 1 -C 8  alkanyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 6 -C 14  aryl or OY where Y is H, C 1 -C 8  alkanyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, or C 6 -C 14  aryl. 
       
     
     
         27 . A method of targeting an agent to a selectin-expressing cell, comprising contacting said selectin-expressing cell with a compound of formula (I): 
       
         
           
           
               
               
           
         
         or a physiologically acceptable salt thereof, wherein: 
       
       
         
           
           
               
               
           
         
         where n=0-2, and each occurrence of R 8  is independently selected where n=2; 
         R 2 =H, —C(═O)OX where X is C 1 -C 8  alkanyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl or C 6 -C 14  aryl; —C(═O)NH(CH 2 )—NH 2 , —[C(═O)NH(CH 2 )—NHC(═O)] m (L) m Z, where n=0-30, m=0-1, L is a linker, and Z is a benzyl amino carboxylic acid or a polyethylene glycol; 
       
       
         
           
           
               
               
           
         
         —O—C(═O)—X, —NH 2 , —NH—C(═O)—NHX, or —NH—C(═O)—X where n=0-2 and X is independently selected from C 1 -C 8  alkanyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, 
       
       
         
           
           
               
               
           
         
       
       where n=0-10,
 and any of the above ring compounds may be substituted with one to three independently selected of C1, F, C 1 -C 8  alkanyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 6 -C 14  aryl, or OY where Y is H, C 1 -C 8  alkanyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, or C 6 -C 14  aryl; 
 
       
         
           
           
               
               
           
         
         6′sulfated GlcNAc, 6′carboxylated GlcNAc, 6′sulfated GalNAc, 6′sulfated galactose, or 6′carboxylated galactose; 
         R 5 =H; 
         R 6 =H, fucose, mannose, arabinose, galactose or polyols; 
         R 7 =H, C 1 -C 8  alkanyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl or 
       
       
         
           
           
               
               
           
         
       
       and
 R 8 =H, C 1 -C 8  alkanyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, 
 
       
         
           
           
               
               
           
         
         where n=0-3 and X is independently selected from H, OH, Cl, F, N 3 , NH 2 , C 1 -C 8  alkanyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 6 -C 14  aryl, OC 1 -C 8  alkanyl, OC 2 -C 8  alkenyl, OC 2 -C 8  alkynyl, and OC 6 -C 14  aryl, and any of the above ring compounds may be substituted with one to three independently selected of Cl, F, C 1 -C 8  alkanyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, C 6 -C 14  aryl or OY where Y is H, C 1 -C 8  alkanyl, C 2 -C 8  alkenyl, C 2 -C 8  alkynyl, or C 5 -C 14  aryl; wherein said compound further comprises a diagnostic or therapeutic agent. 
       
     
     
         28 . The method according to  claim 26  or  27 , wherein R 6  is fucose. 
     
     
         29 . The method according to  claim 26  or  27 , wherein R 7  is H. 
     
     
         30 . The method according to  claim 26  or  27 , wherein R 4  is 
       
         
           
           
               
               
           
         
       
     
     
         31 . The method according to  claim 26  or  27 , wherein R 6  is galactose. 
     
     
         32 . The method according to  claim 26  or  27 , wherein R 2  is —[C(═O)NH(CH 2 ) n NHC(═O)] m (L) m Z, where n, m, L and Z are defined according to  claim 26  or  27 . 
     
     
         33 . The method according to  claim 26  or  27 , wherein L is 
       
         
           
           
               
               
           
         
       
       and wherein the terminal carbonyl group of said L is attached to Z. 
     
     
         34 . The method according to  claim 26  or  27 , wherein R 3  is —O—C(═O)—X or —NH—C(═O)—X, where X is defined according to  claim 26  or  27 . 
     
     
         35 . The method according to  claim 34 , wherein X is 
       
         
           
           
               
               
           
         
       
     
     
         36 . The method according to  claim 26  or  27 , wherein R 8  is: 
       
         
           
           
               
               
           
         
       
     
     
         37 . The method according to  claim 26  or  27 , wherein said physiologically acceptable salt is a sodium salt or a potassium salt. 
     
     
         38 . The method according to  claim 26  or  27 , wherein the compound is administered in combination with a pharmaceutically acceptable carrier or diluent. 
     
     
         39 . The method according to  claim 26  or  27 , wherein the compound is attached to a diagnostic or therapeutic agent.