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Title:
The preperation and us of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase and tace inhibitors
Document Type and Number:
WIPO Patent Application WO1998016503
Kind Code:
A3
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 system, 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 degeneration, 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 formula (I) where the hydroxamic acid moiety and the sulfonamido moiety are bonded to adjacent carbons on group A where: A is phenyl or naphthyl, optionally substituted by R<1>, R<2>, R<3> and R<4>; Z is aryl, heteroaryl, or heteroaryl fused to a phenyl, where aryl is phenyl or naphthyl optionally substituted by R<1>, R<2>, R<3> and R<4>; heteroaryl is a 5-6 membered heteroaromatic ring having from 1 to 3 heteroatoms independently selected from N, O and S, and optionally substituted by R<1>, R<2>, R<3> and R<4>; and when heteroaryl is fused to phenyl, either or both of the rings can be optionally substituted by R<1>, R<2>, R<3> and R<4>; and R<1>, R<2>, R<3>, R<4>, R<5>, R<6>, R<7>, R<8> and R<9> are described in the specification, and the pharmaceutically acceptable salts thereof and the optical isomers and diastereomers thereof.

Inventors:
LEVIN JEREMY IAN (US)
DU MILA T (US)
VENKATESAN ARANAPAKAM MUDUMBAI (US)
NELSON FRANCES CHRISTY (US)
ZASK ARIE (US)
GU YANSONG (US)
Application Number:
PCT/US1997/018280
Publication Date:
May 28, 1998
Filing Date:
October 08, 1997
Export Citation:
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Assignee:
AMERICAN CYANAMID CO (US)
International Classes:
A61K31/18; A61K31/216; A61K31/381; A61K31/422; A61K31/4406; A61K31/443; A61K31/4433; A61K31/4436; A61K31/495; A61K31/496; A61K31/5377; A61K31/553; A61K31/695; A61P1/02; A61P1/04; A61P9/10; A61P13/02; A61P13/12; A61P17/00; A61P19/04; C07D295/12; A61P25/28; A61P27/02; A61P29/00; A61P31/18; A61P35/04; A61P37/00; A61P43/00; C07C311/21; C07C311/29; C07D213/42; C07D213/68; C07D267/02; C07D267/14; C07D267/20; C07D273/06; C07D333/20; C07D333/24; C07D401/12; C07D405/12; C07D409/04; C07D409/12; C07D413/04; C07D413/12; C07D413/14; C07F7/18; (IPC1-7): C07C311/29; C07D213/40; C07C311/21; C07D409/12; C07D405/12; C07D267/22; C07D267/14; C07D295/12; C07D413/14; C07D295/14; C07D233/61; C07D333/20; C07D309/12; C07D295/08; C07D409/04; C07D213/68; A61K31/18; A61K31/44; A61K31/335; A61K31/38
Domestic Patent References:
WO1995035276A11995-12-28
WO1996000214A11996-01-04
WO1996027583A11996-09-12
Foreign References:
EP0606046A11994-07-13
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