Patent TW-410220-B (TW)
Title: Ortho-sulfonamido aryl hydroxamic acids, their pharmaceutical composition and their use as matrix metalloproteinase and tace inhibitors
Inventor: LEVIN JEREMY I
IPC: C07D333/20
Filed: 1997-10-15
Granted: 2000-11-01
Abstract: The present invention relates to the discovery of novel, 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) which 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 sytstem, graft rejection, cachexia, anorexia, inflammation, fever, insulin resistance, septic shock, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, HIV infection, age related macular degeneratioon, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis/neovascularization. The TACE and MMP inhibiting ortho-sulfonamido aryl hydroxamic acids of the present invention are represented by the formula I, where the hydroxamic acid moiety and the  sulfonamido moiety are bonded to adjacent carbons on group A where: A is naphthyl; or A is phenyl optionally substituted by one to four substituents selected from halogen, cyano, nitro, trifluoromethyl, C1-C12 alkyl, C2-C12 alkynyl, vinyl, C1-C6 alkoxy, (C1-C6 alkoxy)(C1-C6 alkoxy)(C1-C6 alkoxy), C1-C6 trifluoroalkoxy, C3-C7 aralkoxy, hydroxy(C1-C6 alkoxy), hydroxycarbamoyl, hydroxycarbamoyl(C1-C6 alkyl), hydroxycarbamoyl(aryl), hydroxycarbamoyl(C1-C6 alkoxy), hydroxycarbamoyl(C3-C7 aralkoxy), C1-C6 alkoxy(C1-C6 alkyl), (C2-C12 dialkyl)amino, (C2-C12 dialkyl) amino(C1-C6 alkyl), (C2-C12 dialkyl)carbamoyl, (C2-C12 dialkyl)carbamoyl(C1-C6 alkyl), (C2-C12 dialkyl) carbamoylvinyl, (C1-C6 alkyl)(C1-C6 alkyl)pyridylcarbamoylvinyl, C1-C6 alkyl(phenyl)carbamoylvinyl, hydroxyimino(C3-C6 aryl), phenyl, phenyl substituted with nitro or trifluoromethyl, furyl, pyridyl, pyridyl(C1-C6 alkoxy), thienyl thienyl substituted with halogen, hydroxyimino or C2-C6 alkenyl, morpholinocarbonyl(C2-C6 alkenyl), pyrolidinyl(C1-C6 alkyl), imidazolyl(C1-C6 alkyl), piperazinyl(C1-C6 alkyl), benzothienyl, benzofuryl, benzodioxyl, benzopiperazinyl(C1-C6 alkyl), phenylpiperazinyl (C1-C6 alkyl), (C1-C6 alkyl)piperazinyl(C1-C6 alkyl), (C1-C6 alkyl)furylisoxazolyl, pyrolidin-carboxylic acid (C1-C6 alkyl) ester, tetrahydropyranyloxy(C1-C6 alkyl), biphenyl, biphenyl substituted with C1-C6 alkoxy, biphenyl (C1-C6 alkyl) and biphenyl(C2-C6 alkynyl); Z is phenyl optionally substituted by one to four substituents selected from halogen, C2-C12 alkynyl, C2-C12 alkynyloxy, phenyl(C2-C12 alkynyl)oxy, C1-C6 alkoxy, C3-C7 aralkoxy, phenyloxy, phenyl, phenyl substituted with trifluromethyl or C1-C6 alkoxy, thienyl, pyridinyloxy, benzodioxyl, and benzothienyl; R7 is hydrogen, C1-C8 alkyl, hydroxy(C1-C8 alkyl), (C1-C6 alkyl)carboxylic acid(C2-C7 aralkyl) ester, (C1-C6 alkyl)carboxylic acid (C1-C6 alkyl)ester, (C2-C12 dialkyl)amino(C2-C6 alkynyl), (C1-C6 alkyl)piperazinylcarbonyl, or pyridinyl (C1-C6 alkyl)(C1-C6 alkyl)carbamoyl, or R7 is phenyl optionally substituted by one to four groups selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, piperidinyl(C1-C6 alkoxy), (C2-C12 dialkyl)amino(C1-C6 alkoxy), (C2-C12 dialkyl)amino(C1-C6 alkyl), (C1-C6 alkyl)piperazinyl, and piperadinyl(C1-C6 alkyl)carbamoyl or R7 is pyridyl or thienyl or R7CH2-N-A- is dihydrobenzoxazocine, tetrahydrobenzoxazocine, or tetrahydrobenzoxazepine; or a pharmaceutical salt thereof.