Patent ID: 6750228
Filing Date: 2004-06-15
Classification: A61P,C07D

Abstract:
A process for treating osteoarthritis in a mammal, wherein:the process comprises administering a compound or a pharmaceutically acceptable salt thereof in an effective amount to the mammal; the compound or salt is characterizeable in that the compound or salt exhibits inhibitory activity against one or more of MMP-2, MMP-9 and MMP-13, while exhibiting substantially less inhibitory activity against MMP-1; the compound corresponds in structure to formula B-1: R20 is â€”NHâ€”Oâ€”R14; R14 is selected from the group consisting of hydrido, a pharmaceutically acceptable cation, and C(W)R25; W is selected from the group consisting of O and S; R25 is selected from the group consisting of C1-C6-alkyl, aryl, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, ar-C1-C6-alkoxy, ar-C1-C6-alkyl, heteroaryl, and amino C1-C6-alkyl, wherein: the amino C1-C6-alkyl nitrogen is optionally substituted with: up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl, ar-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, ar-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl, or two substituents such that the two substituents and amino nitrogen form a 5- to 8-membered heterocyclo or heteroaryl ring; m is selected from the group consisting of zero, 1 and 2; n is selected from the group consisting of zero, 1 and 2; p is selected from the group consisting of zero, 1 and 2; the sum of m+n+p is 2; Z is NR6, and X and Y are CR8R9 and CR10R11; R6 is selected from the group consisting of hydrido, formyl, sulfonic-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, C1-C6-alkylcarbonyl-C1-C6-alkyl, R8R9-aminocarbonyl-C1-C6-alkyl, C1-C6-alkoxycarbonyl-C1-C6-alkylcarbonyl, hydroxycarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkylcarbonyl-C1-C6-alkylcarbonyl, C1-C6-alkoxycarbonylcarbonyl, hydroxycarbonylcarbonyl, C1-C6-alkylcarbonylcarbonyl, R8R9-aminocarbonylcarbonyl, C1-C6-alkanoyl, aryl-C1-C6-alkyl, aroyl, bis(C1-C6-alkoxy-C1-C6-alkyl)-C1-C6-alkyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-perfluoroalkyl, C1-C6-trifluoromethylalkyl, C1-C6-perfluoroalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, C3-C6-cycloalkyl, heteroarycarbonyl, heterocyclocarbonyl, C3-C8-heterocycloalkyl, C3-C8-heterocycloalkylcarbonyl, aryl, C5-C6-heterocyclo, C5-C6-heteroaryl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, arylsulfonyl, C1-C6-alkylsulfonyl, C5-C6-heteroarylsulfonyl, carboxy-C1-C6-alkyl, C1-C4-alkoxycaxbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyl(R8N)iminocarbonyl, aryl(R8N)iminocarbonyl, C5-C6-heterocyclo(R8N)iminocarbonyl, arylthio-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C3-C6-alkenyl, C1-C4-alkylthio-C3-C6-alkenyl, C5-C6-heteroaryl-C1-C6-alkyl, halo-C1-C6-alkanoyl, hydroxy-C1-C6-alkanoyl, thiol-C1-C6-alkanoyl, C3-C6-alkenyl, C3-C6-alkynyl, C1-C4-alkoxy-C1-C4-alkyl, C1-C5-alkoxycarbonyl, aryloxycarbonyl, NR8R9â€”(R8)iminomethyl, NR8R9â€”C1-C5-alkoxycarboyl, hydroxy-C1-C5-alkyl, R8R9-aminocarbonyl, R8R9-aminocarbonyl-C1-C6-alkylcarbonyl, hydroxyaminocarbonyl, R8R9-aminosulfonyl, R8R9-aminosulfon-C1-C6-alkyl, R8R9-amino-C1-C6-alkylsulfonyl, and R8R9-amino-C1-C6-alkyl; as to R8: R8 is selected from the group consisting of hydrido, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroar-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide of any of the thio substituents, the sulfone of any of the thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, or R8 and R9 and the carbon to which they are bonded form carbonyl, or R8 and R9 or R8 and R10 and the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to R9: R9 is selected from the group consisting of hydrido, hydroxy, C1-C6-alkyl C1-C6-alkanoyl, aroyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroar-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, hetoroarylthio-C1-C6-alkyl, the sulfoxide of any of the thio substituents, the sulfone of any of the thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, or R8 and R9 and the carbon to which they are bonded form carbonyl, or R8 and R9 and the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5 to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to R10: R10 is selected from the group consisting of hydrido, hydroxy, C1-C6-alkyl, C1-6-alkanoyl, aroyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroar-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide of any of the thio substituents, the sulfone of any of the thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarboylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, or R10 and R11 and the carbon to which they are bonded form carbonyl, or R10 and R11 or R8 and R10 and the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to R11: R11 is selected from the group consisting of hydrido, hydroxy, C1-C6-alkyl, C1-C6-alkanoyl, aroyl, aryl, ar-C1-C6-alkyl, heteroaryl, heteroar-C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, C1-C6-alkythio-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aralkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylar-C1-C6-alkyl, aminocarbonyl-C1-C6-alkyl, aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl the sulfoxide of any of the thio substituents, the sulfone of any of the thio substituents, perfluoro-C1-C6-alkyl, trifluoromethyl-C1-C6-alkyl, halo-C1-C6-alkyl, alkoxycarbonylamino-C1-C6-alkyl, and amino-C1-C6-alkyl, wherein: the aminoalkyl nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, ar-C1-C6-alkyl, cycloalkyl, and C1-C6-alkonoyl, or R10 and R11 and the carbon to which they are bonded form carbonyl or R10 and R11 and the atoms to which they are bonded form a 5- to 8-membered carbocyclic ring, or a 5- to 8-membered heterocyclic or heteroaryl ring containing one or two heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; only one of R8 and R9 or R10 and R11 may be hydroxy, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl; R is other than alkyl or alkoxyalkyl when A is â€”Oâ€” or â€”Sâ€”; R is other than methyl or phenyl when A is a bond; E is selected from the group consisting of: (1) â€”CO(R19)â€”; (2) â€”(R19)COâ€”; (3) â€”CONHâ€”; (4) â€”HNCOâ€”; (5) â€”COâ€”; (6) â€”SO2â€”R19â€”; (7) â€”R19â€”SO2â€”; (8) â€”SO2â€”; (9) â€”NHâ€”SO2â€”; (10) â€”SO2â€”NHâ€”; (11) â€”Sâ€”; (12) â€”NHâ€”COâ€”Oâ€”; (13) â€”Oâ€”COâ€”NHâ€”; and (14) a bond; R19 is selected from the group consisting of heterocycloalkyl and cycloalkyl; and Y2 is selected from the group consisting of hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein: the aryl, heteroaryl, aralkyl, or heterocycloalkyl is optionally substituted with up to two substituents independently selected from the group consisting of alkyl, alkanoyl, halo, nitro, aralkyl, aryl, alkoxy, trifluoroalkyl, trifluoroalkoxy, and amino, wherein: the amino nitrogen is optionally substituted with up to two substituents independently selected from the group consisting of alkyl and aralkyl.