Boron-containing small molecules for inhibiting activity of a receptor-like protein tyrosine phosphatase

Abstract

Ar-2, R1, R2, R3 and R4 are defined within. A pharmaceutical composition containing a useful diaryl boron compound is also disclosed, as are particularly preferred diaryl boron compounds.

1 .- 7 . (canceled) 
     
     
         8 . The method according to  claim 17 , wherein one or both of R 1  and R 2  is a halogen. 
     
     
         9 . The method according to  claim 8 , wherein both of R 1  and R 2  are fluoro or chloro. 
     
     
         10 . The method according to  claim 17 , wherein R 2  is phenyl. 
     
     
         11 . The method according to  claim 17 , wherein both of R 1  and R 2  are bonded in the para position. 
     
     
         12 .- 13 . (canceled) 
     
     
         14 . The method according to  claim 17 , wherein said RPTP is a type IIa RPTP and is one or more of leukocyte common antigen- 
     
     
         15 . The method according to  claim 17 , wherein the sum of Hammett sigma functions for para and/or meta substituents, as appropriate, of the depicted R 1  and R 2  groups is greater than about +0.1. 
     
     
         16 . The method according to  claim 17 , wherein contacting said RPTP is carried out RPTP in vivo. 
     
     
         17 . A method of inhibiting a transmembrane receptor-like protein tyrosine phosphatase (RPTP) that comprises the steps of contacting said RPTP with an effective amount of a boron-containing compound of Formula IIb, and maintaining said contact for as long a time period as desired to inhibit said phosphatase activity, 
       
         
           
           
               
               
           
         
       
       wherein in Formula IIb, R 1  and R 2  are the same or different substituents that are selected from one or more of the group consisting of hydrogen, halogen, C 1 -C 6 -hydrocarbyl, trifluoromethyl, cyano, nitro, phenyl, optionally substituted phenyl, benzoyl, optionally substituted benzoyl, C 1 -C 6 -hydrocarbyl-oxycarbonyl, carbamoyl, mono- and di-C 1 -C 6 -hydrocarbyl carbamoyl, sulfamoyl, mono- and di-C 1 -C 6 -hydrocarbyl sulfamoyl, wherein said optional substituent is selected from said R 1  and R 2  substituents other than hydrogen, phenyl and benzoyl, and with the proviso that the sum of Hammett sigma functions for para and/or meta substituents, as appropriate, of the depicted R 1  and R 2  groups is greater than about zero, and
 M +  is a pharmaceutically acceptable cation. 
 
     
     
         18 . The method according to  claim 17 , wherein said R 1  and R 2  are hydrogen, halogen or phenyl. 
     
     
         19 . (canceled) 
     
     
         20 . The method according to  claim 17 , wherein said boron-containing compound of Formula IIb has a structural formula selected from the group consisting of and 
       
         
           
           
               
               
           
         
       
     
     
         21 .- 23 . (canceled) 
     
     
         24 . A pharmaceutical composition comprising a pharmaceutically acceptable diluent in which is dissolved or dispersed an effective transmembrane receptor-like protein tyrosine phosphatase (RPTP) activity-inhibiting amount of a compound of Formula IIb 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  and R 2  are the same or different substituents the sum of whose Hammett sigma functions for para and/or meta substituents, as appropriate, is greater than about zero, 
 the depicted boron atom has a negative charge (B − ) and a charge-balancing pharmaceutically acceptable cation (M + ) is present. 
 
     
     
         25 . (canceled) 
     
     
         26 . The pharmaceutical composition according to  claim 24 , wherein R 1  and R 2  are the same or different substituents selected from one or more of the group consisting of hydrogen, halogen, C 1 -C 6 -hydrocarbyl, trifluoromethyl, cyano, nitro, phenyl, N-morpholinyl, N-piperidinyl, 4-cyanophenoxy, benzoyl, C 1 -C 6 -hydrocarboyl, C 1 -C 6 -hydrocarbyl-oxycarbonyl, carbamoyl, mono- and di-C 1 -C 6 -hydrocarbyl carbamoyl, sulfamoyl, mono- and di-C 1 -C 6 -hydrocarbyl sulfamoyl, and optionally substituted phenyl and benzoyl, wherein said optional substituent is selected from said R 1  and R 2  substituents other than hydrogen, phenyl and benzoyl, with the proviso that the sum of Hammett sigma functions for para and/or meta substituents, as appropriate, of the depicted R 1  and R 2  groups is greater than about zero. 
     
     
         27 .- 35 . (canceled) 
     
     
         36 . A compound of Formula IIb in which M +  is a pharmaceutically acceptable cation and R 1  and R 2  are different substituents, wherein one of the R 1  and R 2  substituents is phenyl 
       
         
           
           
               
               
           
         
       
       are selected from one or more of the group consisting of hydrogen, halogen, C 1 -C 6 -hydrocarbyl, trifluoromethyl, cyano, nitro, optionally substituted phenyl, benzoyl, optionally substituted benzoyl, C 1 -C 6 -hydrocarbyloxycarbonyl, carbamoyl, mono- and di-C 1 -C 6 -hydrocarbyl carbamoyl, sulfamoyl, mono- and di-C 1 -C 6 -hydrocarbyl sulfamoyl,
 wherein an optional phenyl or benzoyl substituent is selected from the R 1  and R 2  substituents other than hydrogen, phenyl and benzoyl, and 
 wherein the sum of Hammett sigma function values for para and/or meta substituents of the R 1  and R 2  substituents as appropriate is greater than about zero. 
 
     
     
         37 . (canceled) 
     
     
         38 . The compound according to  claim 36 , wherein one of the R 1  and R 2  substituents is halogen. 
     
     
         39 . (canceled) 
     
     
         40 . The compound according to  claim 36 , wherein said compound has a structural formula shown below, where M +  is defined above 
       
         
           
           
               
               
           
         
       
     
     
         41 .- 42 . (canceled)