Compounds that modulate the activity of PTP-1B and TC-PTP

Abstract

The present invention relates to a new and improved method for treating diabetes and or its associated complications by modulating the activity of protein tryosin phosphatase 1B (“PTP-1B”). The inventive compounds modulate the activity PTP-1B by binding to a novel binding site referred herein as the PTP-1B exosite that is distal to the active site of PTP-1B. The present invention also relates to a new and improved method of treating immune system disorders by modulating the activity of T-cell protein tyrosine phosphatase (“TC-PTP”). The inventive compound modulate the activity of TC-PTP by binding to a novel binding site referred herein as the TC-PTP exosite that is distal to the active site of PTP-1B.

What is claimed is:  
     
         1 . A compound that inhibits PTP-1B and that interacts with at least one of the PTP-1B exosite-forming residues.  
     
     
         2 . A compound that inhibits TC-PTP and that interacts with at least one of the TC-PTP exosite-forming residues.  
     
     
         3 . A compound having the structure having the structure  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 1  is hydrogen, methyl, ethyl, or propyl;  
 R 2  is hydrogen, —S(O 2 )R 3 , —NH(C(═O)R 3 , —NH(C(═O)CH 2 (C═O)OR 3 , —S(O 2 )NR 4 R 5 , or —NR 4 S(O 2 )R 3  where R 3  is C 1 -C 5  alkyl, R 4  is hydrogen, C 1 -C 5  alkyl, unsubstituted cyclic moiety, or substituted cyclic moiety, and R 5  is either hydrogen or R 5  and R 4  together form an unsubstituted cyclic moiety or a substituted cyclic moiety;  
 R 6  is hydrogen or alternatively when R is —NR 4 S(O 2 )NR 3 ; then R 6  and R 4  together form an unsubstituted cyclic moiety or substituted cyclic moiety; and,  
 L is —NHS(O 2 )— or —S(O 2 )NR 7 CH 2 — where R 7  is hydrogen or C 1 -C 5  alkyl.  
 
     
     
         4 . The compound of  claim 3  wherein the one or more substituents on the substituted cyclo group are each independently selected from the group consisting of: C 1 -C 5  alkyl, phenyl, benzyl, F, Cl, I, Br, —OH; —NO 2 ; —CN; —CF 3 ; —CH 2 CF 3 ; —CH 2 Cl; —CH 2 OH; —CH 2 CH 2 OH; —CH 2 NH 2 ; —CH 2 SO 2 CH 3 ; —OR 8 ; —C(O)R 8 ; —COOR 8 ; —C(O)NR 8 R 9 ; —OC(O)R 8 ; —OCOOR 8 ; —OC(O)NR 8 R 9 ; —NR 8 R 9 ; —S(O) 2 R 8 ; and —NR 8 C(O)R 9  where R 8  and R 9  are each independently hydrogen, C 1 -C 5  alkyl, phenyl or benzyl.  
     
     
         5 . The compound of  claim 3  wherein R 2  and R 6  are both hydrogen.  
     
     
         6 . The compound of  claim 3  wherein R 2  is —S(O 2 )NHR 5  where R 5  is an unsubstituted cyclic moiety or substituted cyclic moiety, and R 6  is hydrogen.  
     
     
         7 . The compound of  claim 3  wherein R 2  is —S(O 2 )R 3  where R 3  is methyl, ethyl, or propyl, and R 6  is hydrogen.  
     
     
         8 . The compound of  claim 3  wherein R 2  is —NH(C(═O)R 3  where R 3  is methyl, ethyl, or propyl, and R 6  is hydrogen.  
     
     
         9 . The compound of  claim 3  wherein R 2  is —NH(C(═O)CH 2 (C═O)OR 3  where R 3  is methyl, ethyl, or propyl, and R 6  is hydrogen.  
     
     
         10 . The compound of  claim 3  wherein R 2  is —NR 4 S(O 2 )R 3  wherein R 3  is methyl and R 4  and R 6  together form an unsubstituted heterocyclo or a substituted heterocyclo.  
     
     
         11 . A compound having the structure  
       
         
           
           
               
               
           
         
       
       wherein: 
 R 10  is C 1 -C 5  alkyl or NHR 11  where R 11  is hydrogen, C 1 -C 10  alkyl or aryl; and,  
 L is —NHS(O 2 )— or —S(O 2 )N(CH 2 ) 3 CH 2 —.  
 
     
     
         12 . The compound of  claim 11  wherein R 10  is methyl, ethyl or propyl.  
     
     
         13 . The compound of  claim 11  wherein R 10  is NHR 11  and R 11  is hydrogen.  
     
     
         14 . The compound of  claim 11  wherein R 10  is NHR 11  and R 11  is aryl.  
     
     
         15 . The compound of  claim 19  wherein R 11  is phenyl.  
     
     
         16 . The compound of  claim 19  wherein R 11  is heteroaryl.  
     
     
         17 . An exosite mutant of PTP-1B.  
     
     
         18 . An exosite mutant of TC-PTP.  
     
     
         19 . A pharmaceutical composition comprising an effective amount of a compound of any one of claims  1 - 3 , and  11 , or a prodrug or pharmaceutically acceptable derivative thereof, in admixture with a pharmaceutically acceptable carrier.  
     
     
         20 . A method of identifying an exosite inhibitor of PTP-1B comprising 
 a) contacting a test compound with PTP-1B;    b) contacting the test compound with an exosite mutant of PTP-1B; and    c) comparing the activity of PTP-1B in the presence of the test compound with the activity of the exosite mutant of PTP-1B in the presence of the test compound.    
     
     
         21 . A method of identifying an exosite inhibitor of TC-PTP comprising 
 a) contacting a test compound with TC-PTP;    b) contacting the test compound with an exosite mutant of TC-PTP; and    c) comparing the activity of TC-PTP in the presence of the test compound with the activity of the exosite mutant of TC-PTP in the presence of the test compound.    
     
     
         22 . A method for treating type 2 diabetes, or a pathologic condition associated with type 2 diabetes, comprising administering to a subject in need thereof a therapeutically effective amount of a PTP-1B exosite inhibitor of  claim 1 .  
     
     
         23 . The method of  claim 22  wherein the pathologic condition associated with type 2 diabetes is insulin resistance.  
     
     
         24 . A method for treating inflammation is provided comprising administering to a subject in need thereof a therapeutically effective amount of a TC-PTP exosite inhibitor of  claim 2 .  
     
     
         25 . A method for treating an immune system disorder comprising administering to a subject in need thereof a therapeutically effective amount of a TC-PTP exosite inhibitor of  claim 2 .  
     
     
         26 . A method for treating a hematopoiesis disorder comprising administering to a subject in need thereof a therapeutically effective amount of a TC-PTP exosite inhibitor of  claim 2.