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).

The invention is claimed: 
     
       1. A compound or salt thereof having the formula: 
       
         
           
           
               
               
           
         
       
       or physiologically acceptable salt thereof. 
     
     
       2. The compound or salt thereof according to claim 1, wherein the physiologically acceptable salt is a sodium salt. 
     
     
       3. A pharmaceutical composition comprising a compound or salt thereof according to claim 1 or 2, and a pharmaceutically acceptable carrier. 
     
     
       4. A selectin modulating compound or physiologically acceptable salt thereof, produced by a process comprising the steps of:
 a) reacting the azide group of a compound of Formula XVI   
       
         
           
           
               
               
           
         
          with triphenylphosphine, and reacting the resulting iminophosphorane with an orotic acid chloride to produce a first intermediate compound; 
         b) deprotecting the first intermediate compound produced in step a) to remove all Bn groups and Bz(1) and Bz(2) groups to produce a second intermediate compound; wherein Bz(1) and Bz(2) are benzoyl groups; 
         c) reacting the CO 2 Me group on the cyclohexyl ring of the second intermediate compound produced in step b) with ethylenediamine to produce a third intermediate compound; and 
         d) reacting the terminal amino group on the ethylenediamine group of the third intermediate compound produced in step c) with 
       
       
         
           
           
               
               
           
         
          or an activated ester thereof to produce said selectin modulating compound or physiologically acceptable salt thereof. 
       
     
     
       5. The compound according to claim 4, wherein deprotection step b) involves two deprotection steps. 
     
     
       6. The compound according to claim 4, wherein the physiologically acceptable salt is a sodium salt. 
     
     
       7. A compound having the formula: 
       
         
           
           
               
               
           
         
       
       a tautomer of the compound, a salt of the compound, a salt of the tautomer of the compound, or a mixture of any of the foregoing. 
     
     
       8. The compound according to claim 7, wherein the salt is a sodium salt. 
     
     
       9. A compound selected from: 
       
         
           
           
               
               
           
         
       
       and salts thereof. 
     
     
       10. The compound according to claim 9, wherein the salts are sodium salts. 
     
     
       11. The compound according to claim 9, wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a salt thereof. 
     
     
       12. The compound according to 11, wherein the salt is a sodium salt. 
     
     
       13. A pharmaceutical composition comprising the compound according to any one of claims 7-12 and a pharmaceutically acceptable carrier. 
     
     
       14. The pharmaceutical composition of claim 13, wherein the pharmaceutically acceptable carrier is a buffer. 
     
     
       15. The pharmaceutical composition of claim 14, wherein the buffer is phosphate buffered saline. 
     
     
       16. The pharmaceutical composition of claim 3, wherein the pharmaceutically acceptable carrier is a buffer. 
     
     
       17. The pharmaceutical composition of claim 16, wherein the buffer is phosphate buffered saline.