Patent NZ-335029-A (NZ)
Title: Ortho-sulfonamido heteroaryl hydroxamic acids as matrix metalloproteinase (MMP) and TACE (tumor necrosis factor, TNF, alpha converting enzyme) inhibitors
Inventor: LEVIN JEREMY IAN
IPC: C07D213/81
Filed: 1997-10-08
Abstract: The compounds of the formula above are low molecular weight, non-peptide inhibitors of matrix metalloproteinases (e.g. gelatinases, stromelysins and collagenases) and TNF- alpha converting enzyme (TACE, tumor necrosis factor- alpha converting enzyme).  They are useful for the treatment of diseases in which these enzymes are implicated, such as arthritis, tumor growth and metastasis, angiogenesis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, graft rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel diseases, HIV infection, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization.  In the formula above;  the hydroxamic acid moiety and the sulfonamido moiety are bonded to adjacent carbons of group A, where A is a 5-6 membered heteroaryl having from 1 to 3 heteroatoms independently selected from N, O, and S and optionally substituted by R1, R2, R3 and R4;  Z is phenyl, naphthyl, phenyl fused to a heteroaryl or heteroaryl fused to another heteroaryl, optionally substituted by R1, R2, R3 and R4, wherein heteroaryl is as defined above;  R1, R2, R3 and R4 are independently defined as H, COR5, F, Br, Cl, I, C(O)NR5OR6, CN, OR5, C1-C4-perfluoroalkyl, S(O)xR5 (where x is 0-2), OPO(OR5)OR6, PO(OR6)R5, OC(O)NR5R6, COOR5, CONR5R6, SO3H, NR5R6, NR5COR6, NR5COOR6, S02NR5R6, N02, N(R5)SOR6, NR5CONR5R6, NR5C(=NR6)NR5R6, optionally substituted 3-6 membered cycloheteroalkyl having 1-3 heteroatoms independently selected from N, 0, and S, optionally having 1 or 2 double bonds;  R7 is hydrogen, straight chain or branched C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkynyl each optionally substituted with OH, COR5, CN, C2-C6-alkenyl, C2-C6-alkynyl, OR5, C1-C4-perfluoroalkyl, S(O)xR5 (where x is 0-2), OPO(OR5)OR6, PO(OR5)R6, OC(O)NR5R6, COOR5, CONR5R6, SO3H, NR5R6, NR5COR6, NR5COOR6, S02NR5R6, N02, N(R5)SO2R6, NR5CONR5R6, C3-C6-cycloalkyl as defined above, C3-C6-cycloheteroalkyl as defined above, aryl or heteroaryl as defined above, SO2NHCOR5 or CONHSO2R5, where R5 is not hydrogen, tetrazol-5-yl, NR5C(=NR6)NR5R6, C(O)NR5OR6, SO2NHCONR5R6 or S02NHCN; or R7 is phenyl or naphthyl, optionally substituted by R1, R2, R3 and R4 or a 5 to 6 membered heteroaryl group having 1 to 3 heteroatoms selected independently from N, O, and S and optionally substituted by R1, R2, R3 and R4; or R7 is C3-C6 cycloalkyl or 3-6 membered cycloheteroalkyl as defined above; or R7-CH2-N-A-, where A is as defined above, can form a 7-10 membered 1,2-heteroaryl fused to a non-aromatic heterocyclic ring optionally containing an additional heteroatom selected from 0, S and N wherein said heterocyclic ring may be optionally fused to another benzene ring; and  R5, R6, R8 and R9 are defined in the specification.