Patent ID: 6750233
Filing Date: 2004-06-15
Classification: A61K,A61P,C07D,Y02A

Abstract:
A process for treating a pathological condition in a mammal, wherein:the pathological condition is treatable by inhibiting matrix metalloprotease activity; the process comprises administering a compound or a pharmaceutically acceptable salt thereof in a therapeutically-effective amount to the mammal; the compound or salt inhibits the activity of one or more of MMP-2, MMP-9, and MMP-13, while exhibiting substantially less inhibiting activity against M-1; the compound corresponds in structure to formula (II) below: R14 is selected from the group consisting of hydrogen and C(W)R15; W is selected from the group consisting of O and S; R15 is selected from the group consisting of C1-C6-alkyl, aryl, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryl-C1-C6-alkyl, heteroaryl, and amino-C1-C6-alkyl, wherein: the aminoalkyl nitrogen optionally is substituted with up to 2 substituents independently selected from the group consisting of C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryl-C1-C6-alkoxycarbonyl, C1-C6-alkoxycarbonyl, and C1-C6-alkanoyl, or the aminoalkyl nitrogen, together with two substituents bonded thereto, optionally form a 5- to 8-member heterocyclo or heteroaryl ring; m is zero, 1, or 2; n is zero, 1, or 2; p is zero, 1, or 2; m+n+p is 2; one of X, Y, and Z is S, S(O), or S(O)2; and the remaining two of X, Y, and Z are CR8R9 and CR10R11; as to R8: R8 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-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, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-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 listed in this group, the sulfone of any of the thio substituents listed in this group, 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 optionally is substituted with up to 2 radicals independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, R8 and R9, together with the carbon to which they are bonded, form a carbonyl group, or R8 and R9 or R8 and R10, together with the atom(s) to which they are bonded, form a 5- to 8-member carbocyclic ring or a 5- to 8-member heterocyclic ring containing up to 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to R9: R9 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-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, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-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 listed in this group, the sulfone of any of the thio substituents listed in this group, 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 optionally is substituted with up to 2 radicals independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, R8 and R9, together with the carbon to which they are bonded, form a carbonyl group, or R8 and R9, together with the carbon to which they are bonded, form a 5- to 8-member carbocyclic ring or a 5- to 8-member heterocyclic ring containing up to 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; as to R10: R10 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-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, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-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 listed in this group, the sulfone of any of the thio substituents listed in this group, 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 optionally is substituted with up to 2 radicals independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, R10 and R11, together with the carbon to which they are bonded, form a carbonyl group, or R8 and R10 or R10 and R11, together with the atom(s) to which they are bonded, form a 5- to 8-member carbocyclic ring, or a 5- to 8-member heterocyclic ring containing up to 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, as to R11: R11 is selected from the group consisting of hydrogen, hydroxy, C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroaryl-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, arylalkoxy-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkoxy-C1-C6-alkyl, hydroxy-C1-C6-alkyl, hydroxycarbonyl-C1-C6-alkyl, hydroxycarbonylaryl-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 listed in this group, the sulfone of any of the thio substituents listed in this group, 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 optionally is substituted with up to 2 radicals independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl, R10 and R11, together with the carbon to which they are bonded, form a carbonyl group, or R10 and R11, together with the carbon to which they are bonded, form a 5- to 8-member carbocyclic ring or a 5- to 8-member heterocyclic ring containing up to 2 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur; only one of R8 and R9 or R10 and R11 is hydroxy; G is selected from the group consisting of aryl and heteroaryl; A is selected from the group consisting of: (1) â€”Oâ€”, (2) â€”Sâ€”, (3) â€”NR17â€”, (4) â€”COâ€”N(R17), (5) â€”N(R17)â€”COâ€”, (6) â€”COâ€”Oâ€”, (7) â€”Oâ€”COâ€”, (8) â€”Oâ€”COâ€”Oâ€”, (9) â€”HC&boxH;CHâ€”, (10) â€”NHâ€”COâ€”NHâ€”, (11) â€”Câ‰¡Câ€”, (12) â€”NHâ€”COâ€”Oâ€”, (13) â€”Oâ€”COâ€”NHâ€”, (14) â€”N&boxH;Nâ€”, (15) â€”NHâ€”NHâ€”, (16) â€”CSâ€”N(R18)â€”, (17) â€”N(R18)â€”CSâ€”, and (18) a bond; R17 is selected from the group consisting of hydrogen, C1-C4-alkyl, and phenyl; R18 is selected from the group consisting of hydrogen C1-C4-alkyl, and phenyl; R is selected from the group consisting of aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl, wherein: â€ƒany member of such group optionally is substituted with one or more substituents independently selected from the group consisting of halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylene-dioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and alkoxycarbonyl; 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€”, and (11) a bond; R19 is selected from the group consisting of heterocycloalkyl and cycloalkyl; and Y2 is selected from the group consisting of hydrogen, alkyl, alkoxy, haloalkyl, aryl, arylalkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and aminoalkyl, wherein: the aryl, heteroaryl, or heterocycloalkyl optionally is substituted with up to 2 substituents independently selected from the group consisting of alkanoyl, halo, nitro, arylalkyl, aryl, alkoxy, and amino, wherein: the amino nitrogen optionally is substituted with up to 2 groups independently selected from the group consisting of hydrogen, alkyl, and arylalkyl.