US 5,929,097 A · Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase and tace inhibitors

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 the formula ##STR1## where the hydroxamic acid moiety and the sulfonamido moiety are bonded to adjacent carbons on group A.

A compound having the formula ##STR28## where the hydroxanic acid moiety and the sulfonamido moiety are bonded to adjacent carbons on the phenyl or naphthyl ring of group A where:

A is phenyl or naphthyl, optionally substituted by R.sup.1, R.sup.2, R.sup.3 and R.sup.4 ;
Z is aryl, heteroaryl, orheteroaryl fused to a phenyl,
where aryl is phenyl or naphthyl optionally substituted by R.sup.1, R.sup.2, R.sup.3 and R.sup.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.sup.1, R.sup.2, R.sup.3 and R.sup.4 ;
and when heteroaryl is fused to phenyl, either or both of the rings can be optionally substituted by R.sup.1, R.sup.2, R.sup.3 and R.sup.4 ;
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are independently --H, --COR.sup.5, --F, --Br, --Cl, --I, --C(O)NR.sup.5 OR.sup.6,--CN, --OR.sup.5, -C.sub.1 -C.sub.4 -perfluoroalkyl, --S(O).sub.x R.sup.5 where x is 0-2, --OPO(OR.sup.5)OR.sup.6, --PO(OR.sub.6)R.sub.5, --OC(O)NR.sup.5 R.sup.6, --COOR.sup.5, --CONR.sup.5 R.sup.6, --SO.sub.3 H, --NR.sup.5 R.sup.6, --NR.sup.5 COR.sup.6, --NR.sup.5 COOR.sup.6, --SO.sub.2 NR.sup.5 R.sup.6, --NO.sub.2, --N(R.sup.5)SO.sub.2 R.sup.6, --NR.sup.5 CONR.sup.5 R.sup.6, --NR.sup.5 C(.dbd.NR.sup.6)NR.sup.5 R.sup.6, 3-6 membered cycloheteroalkyl having one to three heteroatoms independently selected from N, O, and S and optionally having 1 or 2 double bonds and optionally substituted by one to three groups each selected independently from R.sup.5 ;
-aryl or heterorryl as defined above, biphenyl optionally substituted by one to four groups each selected independently from R.sup.4, --SO.sub.2 NHCOR.sup.5 or CONHSO.sub.2 R.sup.5 where R.sup.5 is not H, -tetrazol-5-yl, --SO.sub.2 NHCN, --SO.sub.2 NHCONR.sup.5 R.sup.6 or straight chain or branched -C.sub.1 -C.sub.6 alkyl, -C.sub.2 -C.sub.6 -alkenyl, or -C.sub.2 -C.sub.6 -alkynyl, or -C.sub.3 -C.sub.6 -cycloalkyl optionally having 1 or 2 double bonds each optionally substituted with --COR.sup.5, --CN, -C.sub.2 -C.sub.6 alkenyl, -C.sub.2 -C.sub.6 alkynyl, --OR.sup.5, -C.sub.1 -C.sub.4 -perfluoroalkyl, --S(O).sub.x R.sup.5 where x is 0-2, --OC(O)NR.sup.5 R.sup.6, --COOR.sup.5, --CONR.sup.5 R.sup.6, --SO.sub.3 H, --NR.sup.5 R.sup.6, --NR.sup.5 COR.sup.6, --NR.sup.5 COOR.sup.6, --SO.sub.2 NR.sup.5 R.sup.6, --NO.sub.2, --N(R.sup.5)SO.sub.2 R.sup.6, --NR.sup.5 CONR.sup.5 R.sup.6, -C.sub.3 -C.sub.6 cycloalllyl as defined above, 3-6 membered cycloheteIoalkyl as defined above, aryl or heteroaryl as defined above, biphenyl, --SO.sub.2 NHCOR.sup.5 or --CONHSO.sub.2 R.sup.5 where R.sup.5 is not hydrogen;
--PO(OR.sup.5)OR.sup.6, --PO(OR.sup.6)R.sup.5, -tetrazol-5-yl, C(O)NR.sup.5 OR.sup.6, --NR.sup.5 C(.dbd.NR.sup.6)NR.sup.5 R.sup.6, --SO.sub.2 NHCONR.sup.5 R.sup.6 or SO.sub.2 NHCN;
with the proviso that when R.sup.1 and R.sup.2 are on adjacent carbons of A, R.sup.1 and R.sup.2 together with the carbons to which they are attached can form a 5 to 7 membered saturated or unsaturated heterocyclic ring or a 5-6 membered heteroaryl ring, each having 1 to 3 heteroatoms independently selected from O, S, or N, and each optionally substituted by one to four groups each selected independently from R.sup.4 ;
or a 5 to 7 membered saturated or unsaturated carbocyclic ring optionally substituted by one to four groups each selected independently from R.sup.4 ;
R.sup.5 and R.sup.6 are independently H, aryl and heteroaryl as defined above, -C.sub.3 -C.sub.6 -cycloalkyl as defined above, -C.sub.3 -C.sub.6 -cycloheteroalkyl as defined above, -C.sub.1 -C.sub.4 -perfluoroaikyl, or straight chain or branched -C.sub.1 -C.sub.6 alkyl, -C.sub.2 -C.sub.6 -alkenyl, or -C.sub.2 -C.sub.6 -alkynyl each optionally substituted with --OH, --COR.sup.8, --CN, --C(O)NR.sup.8 OR.sup.9, -C.sub.2 -C.sub.6 -alkenyl, -C.sub.2 -C.sub.6 -alkynyl, --OR.sup.8, -C.sub.1 -C.sub.4 -perfluoroalkyl, --S(O).sub.x R.sup.8 where x is 0-2, --OPO(OR.sup.8)OR.sup.9, --PO(OR.sup.8)R.sup.9, --OC(O)NR.sup.8 R.sup.9, --COOR.sup.8, --CONR.sup.8 R.sup.9, --SO.sub.3 H, --NR.sup.8 R.sup.9,--NCOR.sup.8 R.sup.9, --NR.sup.8 COOR.sup.9, --SO.sub.2 NR.sup.8 R.sup.9, --NO.sub.2, --N(R.sup.8)SO.sub.2 R.sup.9, --NR.sup.8 CONR.sup.8 R.sup.9, -C.sub.3 -C.sub.6 cycloaalyl as defined above, 3-6 membered cycloheteroalkyl as defined above, aryl or heteroaryl as defined above, --SO.sub.2 NHCOR.sup.8 or --CONHSO.sub.2 R.sup.8 where R.sup.8 is not hydrogen, -tetrazol-5-yl, --NR.sup.8 C(.dbd.NR.sup.9)NR.sup.8 R.sup.9, --SO.sub.2 NHCONR.sup.8 R.sup.9, or --SO.sub.2 NHCN;
R.sup.7 is hydrogen, straight chain or branched -C.sub.1 -C.sub.6 -alkyl, -C.sub.2 -C.sub.6 -alkenyl, or -C.sub.2 -C.sub.6 -alkynyl each optionally substituted with --OH, --COR.sup.5, --CN, -C.sub.2 -C.sub.6 -alkenyl, -C.sub.2 -C.sub.6 -alkynyl, --OR.sup.5, -C.sub.1 -C.sub.4 -perfluoroalkyl, --S(O).sub.x R.sup.5 where x is 0-2, --OPO(OR.sup.5)OR.sup.6, --PO(OR.sup.5)R.sup.6, --OC(O)NR.sup.5 R.sup.6, --COOR.sup.5, --CONR.sup.5 R.sup.6, --SO.sub.3 H, --NR.sup.5 R.sup.6, --NR.sup.5 COR.sup.6, --NR.sup.5 COOR.sup.6, --SO.sub.2 NR.sup.5 R.sup.6, --NO.sub.2, --N(R.sup.5)SO.sub.2 R.sup.6, --NR.sup.5 CONR.sup.5 R.sup.6, -C.sub.3 -C.sub.6 cycloalkyl as defined above, -C.sub.3 -C.sub.6 -cycloheteroalkyl as defined above, -aryl or heteroaryl as defined above, --SO.sub.2 NHCOR.sup.5 or --CONHSO.sub.2 R.sup.5 where R.sup.5 is not hydrogen, -tetrazol-5-yl, --NR.sup.5 C(.dbd.NR6)NR.sup.5 R.sup.6, --C(O)NR.sup.5 OR.sup.6, --SO.sub.2 NHCONR.sup.5 R.sup.6 or --SO.sub.2 NHCN;
or R.sup.7 is phenyl or naphthyl, optionally substituted by R.sup.1, R.sup.2, R.sup.3 and R.sup.4 or a 5 to 6 membered heteroaryl group having 1 to 3 heteroatoms selected independendy from N, O, and S and optionally substituted by R.sup.1, R.sup.2, R.sup.3 and R.sup.4 ;
or R.sup.7 is C.sub.3 -C.sub.6 cycloalkyl or 3-6 membered cycloheteroalkyl as defined above;
or R.sup.7 CH.sub.2 --N--A--, where A is as defined above, can form a non-aromatic 1,2-benzo-fused 7-10 membered heterocyclic ring optionally containing an additional heteroatom selected from O, S and N wherein said heterocyclic ring may be optionally fused to another benzene ring;
R.sup.8 and R.sup.9 are independently H, aryl or heteroaryl as defined above, -C.sub.3 -C.sub.7 -cycloalkyl or 3 to 6 membered cycloheteroalkyl as defined above, -C.sub.1 -C.sub.4 -perfluoroalkyl, straight chain or branched -C.sub.1 -C.sub.6 -alkyl, -C.sub.2 -C.sub.6 -alkenyl, or -C.sub.2 -C.sub.6 -alkynyl, each optionally substituted with hydroxy, alkoxy, aryloxy, -C.sub.1 -C.sub.4 -perfluoroalkyl, amino, mono- and di-C.sub.1 -C.sub.6 -alkylanino, carboxylic acid, carboalkoxy and carboaryloxy, nitro, cyano, carboxamido primary, mono- and di-C.sub.1 -C.sub.6 -alkylcarbamoyl;
a pharmaceutically acceptable salt thereof where one may be formed;
and an optical isomer or diastereorner thereof where optical isomers and diastereoeers exist.

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Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase and tace inhibitors

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Preparation and use of ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase and tace inhibitors

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Abstract

Claims11