Patent NZ-335053-A (NZ)
Title: Beta-sulfonamido hydroxamic acids or ortho-sulfonamido aryl hydroxamic acids as matrix metalloproteinase MMP and TACE (tumour necrosis factor, TNF, alpha converting enzyme) inhibitors
Inventor: LEVIN JEREMY IAN
IPC: A61P25/00
Filed: 1997-10-08
Abstract: Low molecular weight, non-peptide inhibitors of matrix metalloproteinases and TNF- alpha converting enzyme that are useful for the treatment of diseases in which these enzymes are implicated. The TACE and MMP inhibiting ortho-sulfonamido aryl hydroxamic acids are represented by formula (1) where the hydroxamic acid moiety and the sulfonamido moiety are bonded to adjacent carbons on group A where: A is a 5 to 7 membered, monocyclic, non-aromatic heterocyclic ring having from 1 to 2 heteroatoms independently selected from N, O, and S, optionally substituted by R1, R2, R3 and R4, a cycloalkyl containing 0-2 double bonds and optionally substituted with R1, R2, R3 and R4; or -CHR5=CHR6-; and Z, R1, R2, R3 and R4 are independently -H, -COR5, halogen, -C(o)NR5OR6,-CN, -OR5,-C1-C4-perfluoroalkyl, - S (O)xR5 where x is S2, -OPO(OR5)OR6, -PO(OR6)Rs, -OC(O)NR5R6, -COOR5, -CONR5R6, -503H, -NR5R6, -NR5COR6, -NR5COOR6, -S02NR5R6, -N02, -N(R5)So2R6o - NR5CONR5R6, -NR5C(=NR6)NR5R6, -C3-C6-cycloalkyl optionally having 1 or 2 double bonds and optionally substituted with one to three groups each selected independently from R3, 3-6 membered cycloheteroalkyl having one to four heteroatoms independently selected from N, 0, and S, 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, -SO2NHCOR5Or -CONHSO2Rs where R5is not H, -tetrazol-5-yl, -SO2NHCN, -So2NHCONR5R6 or straight chain or branched -C1- C6 alkyl, -C2-C6-alkenyl, or -C2-C6-alkynyl each optionally substituted with -COR5, -CN, -C2-C6 alkenyl, -C2-C6 alkynyl,-OR5, -Cl-C4-perfluoroalkyl, -S(O)XR5 where x is 0-2, -OC(O)NRfR6, -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, -SO2NHCOR5 or-CONHSO2Rf where R5 is not hydrogen, -PO(OR5)OR6, -PO(OR6)R5, -tetrazol-5-yl, -C(O)NR5OR6, -NR5C(=NR6)NR5R6,-S O2NHCONR5R6 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 5-7 membered saturated or unsaturated monocyclic heterocyclic ring, or a 5-6 membered heteroaryl ring, each having from 1 to 2 heteroatoms independently selected from N, 0, and S, wherein said heterocyclic or heteroaryl ring may be optionally substituted by one to four groups each selected independently from R4; or R1 and R2 together with the carbons to which they are attached can form a 5-7 membered saturated or unsaturated carbocyclic ring or an aryl ring wherein said carbocyclic or aryl ring may be optionally substituted by one to four groups each selected independently from R4;  R5 and R6 are independently defined as 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)NR80R9, -C2-C6-alkenyl, -C2-C6-alkynyl, -OR8, -C1-C4-perfluoroalkyl, -S(O)XR8 where x is > 2, -OPO(OR8)0R9, -Po(oR8)R9, -OC(O)NR8R9, -COOR8, -CONR8R9, -SO3H, -NR8R9,-NCOR8R9, -NR8COOR9, -S02NR8R9, -N02, -N(R8)S02R9, -NR8CONR8R9, -C3-C6 cycloalkyl as defined above, -C3-C6- cycloheteroalkyl as defined above, -aryl or heteroaryl as defined above, -SO2NHCOR8 or -CONHSO2R8 where R8 is not hyrdogen, -tetrazol-5-yl, -NR8C(=NR9)NR8R9, -SO2NHCONR8R9, -SO2NHCN;  R7 is hydrogen, straight chain or branched -C1-C6-alkyl, -C--alkenyl, or -C2 C6-alkynyl each optionally substituted with -OH, -COR5, -CN, -C2-C6 alkenyl, -C2-C6-alkynyl, -OR5, -Cl-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) S O2R6, -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)NRsR6, -C(O) N R5OR6, -SO2NHCONR5R6or- S02NHCN; or R7 is phenyl or naphthyl, optionally substituted by Rl, 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 byR',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 with the carbon adjacent to the carbon bearing the sulfonamido group, a non-aromatic fused 7-10 membered heterocyclic ring optionally containing an additional heteroatomselected 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 cycloheteroalkyl as defined above, -C1-C4-perfluoroalkyl, straight chain or branched -C1-C6-alkyl, -C2-C6-alkenyl, or 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; an optical isomer or diastereomer thereof; or a pharmaceutically acceptable salt thereof.