Selective inhibitors of aggrecanase in osteoarthritis treatment

摘要

This invention relates to a method of treatment for osteoarthritis involving inhibitors of aggrecanase that demonstrate IC50s of less than 20 nM and demonstrate differential potency against matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs or reprolysins). This invention also relates to compounds, methods of treatment and composition of Formula I: <CHEM> or a therapeutically acceptable salt thereof, wherein X is carbon or nitrogen; R<1> and R<2> are independently selected from the group consisting of hydrogen, hydroxy, and methyl, wherein at least one of R<1> and R<2> is methyl; R<3> and R<4> are independently selected from the group consisting of hydrogen, hydroxy, and methyl, or R<3> and R<4> may be taken together to form a carbonyl group; and R<5> and R<6> are independent substituents in the ortho, meta, or para positions and are independently selected from the group consisting of hydrogen, halogen, cyano, methyl, and ethyl; with the provisos: when X is carbon, then R<7> and R<8> are both hydrogen and at least one of R<1>, R<2>, R<3>, and R<4> is hydroxy; when X is carbon and R<5> is para-halo, then at least one of R<6>, R<3>, and R<4> is not hydrogen; when X is nitrogen, then R<8> is not present and R<7> is hydrogen or a group of the formula: <CHEM> wherein, Y is -CH2-NH2 or -NH-CH3; and when X is nitrogen and R<7> is H, then R<3> and R<4> are taken together to form a carbonyl group.