abstract |
This invention relates to a method of treatment of osteoarthritis that involves inhibitors of aggrecanase that has an IC50 of less than 20 nM and that demonstrates a differential potency against matrix metalloproteinases (MMP) and a disintegrate and metalloproteinases (ADAM or reprolysins); This invention also relates to the compounds, methods of treatment and composition of formula I: or a therapeutically acceptable salt thereof, wherein X is carbon or nitrogen; R1 and R2 are independently selected from the group consisting of hydrogen, hydroxy and methyl, wherein at least one of R1 and R2 is methyl; R3 and R4 are independently selected from the group consisting of hydrogen, hydroxy and methyl or R3 and R4 can be linked to form a carbonyl group; and R5 and R6 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 conditions that: when X is carbon, then R7 and R8 are both hydrogen and at least one of R1, R2, R3 and R4 is hydroxy; when X is carbon and R5 is para-halogen, then at least one of R6, R3 and R4 is not hydrogen; when X is nitrogen, then R8 is not present and R7 is hydrogen or a group of formula: where Y is ¦ CH2-NH2 or ¦NH-CH3; and when X is nitrogen and R7 is H, then R3 and R4 are joined forming a carbonyl group. |