Patent NZ-335028-A (NZ)
Title: Ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase (MMP) and TACE (TNF-alpha converting enzyme) inhibitors
Inventor: LEVIN JEREMY IAN
IPC: A61K31/216
Filed: 1997-10-08
Abstract: A compound of formula I, pharmaceutically acceptable salts and optical isomers or diastereoisomers wherein the hydroxamic acid moiety and the sulfonamido moiety are bonded to adjacent carbons on the phenyl or naphthyl ring of group A wherein A is phenyl or naphthyl, optionally substituted by R1, R2, R3 and R4, Z is aryl, heteroaryl, or heteroaryl fused to a phenyl, where aryl is phenyl or naphthyl optionally substituted by R1, R2, R3 and R4, heteroaryl is a 5-6 membered heteroaromatic ring having from 1 to 3 heteroatoms independently selected from N, O and S and being optionally substituted by R1, R2, R3 and R4 and when heteroaryl is fused to phenyl, either or both of the rings can be optionally substituted by R1, R2, R3 and R4, R1, R2, R3 and R4 are independently 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, SO2NR5R6, NO2, N(R5)SO2R6, NR5CONR5R6, NR5C(=NR6)NR5R6, 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 R5, aryl or heteroaryl as defined above, biphenyl optionally substituted by one to four groups each selected independently from R4, SO2NHCOR5 or CONHSO2R5 where R5 is not H, tetrazol-5-yl, SO2NHCN, SO2NHCONR5R6 or straight chain or branched C1-C6 alkyl, C2-C6-alkenyl, or C2-C6-alkynyl, or C3-C6-cycloalkyl optionally having 1 or 2 double bonds each optionally substituted with COR5, CN, C2-C6-alkenyl, C2-C6-alkynyl, OR5, C1-C4 perfluoroalkyl, S(O)xR5 where x is 0-2, OC(O)NR5R6, COOR5, CONR5R6, SO3H, NR5R6, NR5COR6, NR5COOR6, SO2NR5R6, NO2, N(R5)SO2R6, NR5CONR5R6, C3-C6-cycloalkyl as defined above, 3-6 membered cycloheteroalkyl as defined above, aryl or heteroaryl as defined above, biphenyl, SO2NHCOR5 or CONHSO2R5 where R5 is not H, PO(OR5)OR6, PO(OR6)R5, tetrazol-5-yl, C(O)NR5OR6, NR5C(=NR6)NR5R6, SO2NHCONR5R6 or  SO2NHCN, with the proviso that when R1 and R2 are on adjacent carbons of A, R1 and R2  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 R4 or a 5 to 7 membered saturated or unsaturated carbocyclic ring optionally substituted by one to four groups each selected independently from R4, R5 and R6 are independently H, aryl and heteroaryl as defined above, C3-C6-cycloalkyl as defined above, C3-C6-cycloheteroalkyl as defined above, C1-C4-perfluoroalkyl, or straight chain or branched C1-C6 alkyl, C2-C6-alkenyl or C2-C6-alkynyl each optionally substituted with OH, COR8, CN, C(O)NR8OR9, C2-C6-alkenyl, C2-C6-alkynyl, OR8, C1-C4-perfluoroalkyl, S(O)xR8 where x is 0-2, OPO(OR8)OR9, PO(OR8)R9, OC(O)NR8R9, COOR8, CONR8R9, SO3H, NR8R9, NR8COR9, NR8COOR9, SO2NR8R9, NO2, N(R8)SO2R9, NR8CONR8R9, C3-C6-cycloalkyl as defined above, 3-6 membered cycloheteroalkyl as defined above, aryl or heteroaryl as defined above, SO2NHCOR8 or CONHSO2R8 where R8 is not hydrogen, tetrazol-5-yl, NR8C(=NR9)NR8R9, SO2NHCONR8R9, or SO2NHCN, R7 is hydrogen, straight chain or branched C1-C6-alkyl, C2-C6-alkenyls 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, SO2NR5R6, NO2, 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, 0 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 R7CH2-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, R8 and R9 are independently H, aryl or heteroaryl as defined above, C3-C7-cycloalkyl or 3-6 membered cycloheteroalkyl as defined above, C1-C4 -perfluoroalkyl, straight chain or branched C1-C6-alkyl, C2-C6-alkenyl, or C2-C6-alkynyl each optionally substituted with hydroxy, alkoxy, aryloxy, C1-C4-perfluoroalkyl, amino, mono and di C1-C6-alkylamino, carboxylic acid, carboalkoxy and carboaryloxy, nitro, cyano, carboxamido primary, mono and di C1-C6-alkylcarbamoyl. Also described is the use of these compounds in the treatment of conditions in which pathological changes are mediated by matrix metalloproteases or TNF-alpha converting enzyme (TACE).