BORON-CONTAINING SMALL MOLECULES FOR INHIBITING ACTIVITY OF A RECEPTOR-LIKE PROTEIN TYROSINE PHOSPHATASE
A method is disclosed for altering the redox equilibrium of a transmembrane receptor-like protein tyrosine phosphatase (RPTP), particularly a type IIa RPTP, by chemically modulating the activity through contact of such an enzyme with a diaryl boron compound that preferentially reacts with an RPTP in an oxidized state (CyS-OH). This redox modulation is most readily observed and put to use by assaying the inhibition of the phosphatase activity of the RPTP. Such an assay can be carried out on an enzyme in vitro or by contacting the enzyme in a living organism (in vivo). A useful diaryl boron compound corresponds in structure to Formula I in which Ar-1, Ar-2, R 1 , R 2 , R 3 and R 4 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)