Thiol sulfone metalloprotease inhibitors

A matrix metalloprotease inhibitor corresponding to the formula:

• ##STR1176## wherein Ph is phenyl substituted with R.sup.11 at the 4-position;
• R.sup.11 is a substituent selected from the group consisting of C.sub.1 -C.sub.6 alkoxy, C.sub.3 -C.sub.6 alkyl, phenoxy, thiophenoxy, benzamido, phenylazo, and phenyl moieties;
• R.sup.2 is selected from the group consisting of hydrido, a C.sub.1 -C.sub.6 alkyl group, a C.sub.2 -C.sub.3 alkyl cycloamino group having five or six atoms in the ring and zero or one additional heteroatom that is oxygen or nitrogen, a C.sub.1 -C.sub.6 aminocarbonyl group whose amido nitrogen is unsubstituted or mono- or disubstituted with a C.sub.2 -C.sub.3 alkyl or benzyl radical, and a C.sub.1 -C.sub.4 alkylheteroaryl group having a single heteroaryl ring wherein said single heteroaryl ring contains one or two nitrogen atoms, or wherein R.sup.2 and R.sup.6 together with the atoms to which they are bonded form a 5- or 6-membered ring;
• R.sup.6 is a radical selected from the group consisting of an C.sub.1 -C.sub.6 alkyl group, a carboxyl group, a C.sub.1 -C.sub.6 alkoxy carbonyl group, an amino C.sub.1 -C.sub.6 alkanoyl group, a carboxamide group where the amido nitrogen is (i) unsubstituted or (ii) substituted with a C.sub.1 -C.sub.4 alkyl substituted by amino, mono-substituted amino or di-substituted amino, wherein the substituent on the amino nitrogen is selected from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.5 -C.sub.8 cycloalkyl and C.sub.1 -C.sub.6 alkanoyl groups, or wherein two amino nitrogen substituents and the nitrogen to which they are bonded together form a 5- to 8-membered heterocyclic or heteroaryl ring containing zero or one additional hetero atoms that are nitrogen, oxygen or sulfur or (iii) the amido nitrogen is the amine of an amino acid;
• and
• R.sup.10 is C.sub.1 -C.sub.6 alkoxy, or a single-ringed aryl or heteroaryl group,
• with the proviso that only one of R.sup.2 or R.sup.6 is present unless R.sup.2 and R.sup.6 together with the atoms to which they are bonded form a 5- or 6-membered ring.

A process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity that comprises administering a metalloprotease inhibitor in an effective amount to a mammalian host having such a condition, said metalloprotease inhibitor corresponding in structure to formulas I, II or III below ##STR1179## wherein x and y are independently zero, 1 or 2;

• W is oxygen or sulfur;
• a starred R* group, y* or x* is the same or different from an unstarred R, y or x;
• R.sup.10 is selected from the group consisting of alkyl, aryl, alkoxy, cycloalkyl, aryloxy, aralkoxy, aralkyl, aminoalkyl, heteroaryl and N-monosubstituted or N,N-disubstituted aminoalkyl wherein the substituent on the nitrogen is selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and alkanoyl, or wherein the nitrogen and two substituents attached thereto form a 5 to 8 member heterocyclo or heteroaryl ring;
• R.sup.1 is an aryl or heteroaryl substituent selected from the group consisting of aralkyl, heteroaralkyl, aralkoxy, heteroaralkoxy, aralkoxyalkyl, aryloxyalkyl, aralkanoylalkyl, arylcarbonylalkyl, aralkylaryl, aryloxyalkylaryl, aralkoxyaryl, arylazoaryl, arylhydrazinoaryl, alkylthioaryl, arylthioalkyl, alkylthioaralkyl, aralkylthioalkyl, and aralkylthioaryl, the sulfoxide or sulfone of any of said thio substituents, and a fused ring structure comprising two or more 5- or 6-membered rings selected from the group consisting of aryl, heteroaryl, carbocyclic and heterocyclic, said aryl or heteroaryl substituent of which R.sup.1 is comprised being substituted cyano, perfluoroalkyl, trifluoromethylalkyl, hydroxy, with one or more substituents independently selected from among halo, C.sub.2 -C.sub.10 alkyl, C.sub.1 -C.sub.10 alkoxy, nitro, thiol, hydroxycarbonyl, aryloxy, arylthio, arylamino, aralkyl, aryl, heteroaryloxy, heteroarylthio, heteroarylamino, heteroaralkyl, cycloalkyl, heterocyclooxy, heterocyclothio, heterocycloamino, cycloalkyloxy, cycloalkylthio, cycloalkylamino, heteroaralkoxy, heteroaralkylthio, heteroaralkylamino, aralkoxy, aralkylthio, aralkylamino, heterocyclic, heteroaryl, arylazo, hydroxycarbonylalkoxy, alkoxycarbonylalkoxy, alkanoyl, arylcarbonyl, aralkanoyl, alkanoyloxy, aralkanoyloxy, hydroxyalkyl, hydroxyalkoxy, alkylthio, alkoxyalkylthio, alkoxycarbonyl, aryloxyalkoxyaryl, arylthioalkylthioaryl, aryloxyalkylthioaryl, arylthioalkoxyaryl, hydroxycarbonylalkoxy, hydroxycarbonylalkylthio, alkoxycarbonylalkoxy, alkoxycarbonylalkylthio, amino, alkanoylamino, arylcarbonylamino, aralkanoylamino, heteroarylcarbonylamino, heteroaralkanoylamino, and N-monosubstituted or N,N-disubstituted aminoalkyl wherein the substituent on the amino nitrogen are selected from the group consisting of alkyl, aryl, aralkyl, cycloalkyl, aralkoxycarbonyl, alkoxycarbonyl, and alkanoyl, or wherein the nitrogen and two substituents attached thereto form a 5 to 8 member heterocyclo or heteroaryl ring;
• R.sup.2 and R.sup.3 are independently selected from the group consisting of hydrido, an alkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, alkynylalkyl, alkenylalkyl, thioalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl, alkoxyalkyl, aralkoxyalkyl, aminoalkyl, alkoxyalkoxyalkyl, aryloxyalkyl, hydroxyalkyl, hydroxycarbonylalkyl, hydroxycarbonylaralkyl, or N-monosubstituted or N,N-disubstituted aminoalkyl group wherein the substituent on the amino nitrogen are selected from the group consisting of alkyl, aralkyl, cycloalkyl and alkanoyl, or wherein R.sup.3 is hydrido and R.sup.2 and another substituent selected from the group consisting of R.sup.4, R.sup.6 and R.sup.8 together with the atoms to which they are bonded form a 4- to 8-membered ring;
• R.sup.4 and R.sup.5 are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, aryloxyalkyl, aralkoxyalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, hydroxycarbonyl, alkoxycarbonyl, perfluoroalkyl, trifluoromethylalkyl, thioalkyl, alkylthioalkyl, arylthioalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, or a sulfoxide or sulfone of any of said thio substituents, aminocarbonyl, aminocarbonylalkyl and N-monosubstituted or N,N-disubstituted aminocarbonyl or aminocarbonylalkyl wherein the substituent on the amino nitrogen are independently selected from among alkyl, aralkyl, cycloalkyl and alkanoyl, or R.sup.5 is hydrido and R.sup.4 and another substituent selected from the group consisting of R.sup.2, R.sup.6 and R.sup.8 together with the atoms to which they are bonded form a 4- to 8-membered ring;
• R.sup.6 and R.sup.7 are independently selected from the group consisting of hydrido, an C.sub.1 -C.sub.6 alkyl group, a cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, aryloxyalkyl, aralkoxyalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, hydroxycarbonylalkyl, alkoxycarbcnylalkyl, aralkoxycarbonylalkyl, hydroxycarbonyl, alkoxycarbonyl, perfluoroalkyl, trifluoromethylalkyl, thioalkyl, alkylthioalkyl, arylthioalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, or a sulfoxide or sulfone of any of said thio substituents, a carboxyl group, a C.sub.1 -C.sub.6 alkoxy carbonyl group, an amino C.sub.1 -C.sub.6 alkanoyl group, a carboxamide group where the amido nitrogen is (i) unsubstituted or (ii) substituted with a C.sub.1 -C.sub.4 alkyl substituted by amino, mono-substituted amino or di-substituted amino, wherein the substituent on the amino nitrogen is selected from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.5 -C.sub.8 cycloalkyl and C.sub.1 -C.sub.6 alkanoyl groups, or wherein two amino nitrogen substitutents and the nitrogen to which they are bonded together form a 5- to 8-membered heterocyclic or heteroaryl ring containing zero or one additional hetero atoms that are nitrogen, oxygen or sulfur or (iii) the amido nitrogen is the amine of an amino acid, or R.sup.7 is hydrido and R.sup.6 and another substituent selected from the group consisting of R.sup.2, R.sup.4 and R.sup.8 together with the atoms to which they are bonded form a 4- to 8-membered ring;
• R.sup.8 and R.sup.9 are independently selected from the group consisting of hydrido, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, hydroxyalkyl, aryloxyalkyl, aralkoxyalkyl, aralkyl, aryl, heteroaryl, heteroaralkyl, hydroxycarbonylalkyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, hydroxycarbonyl, alkoxycarbonyl, perfluoroalkyl, trifluoromethylalkyl, thioalkyl, alkylthioalkyl, arylthioalkyl, aralkylthioalkyl, heteroaralkylthioalkyl, or a sulfoxide or sulfone of any of said thio substituents, aminocarbonyl, aminocarbonylalkyl and N-monosubstituted or N,N-disubstituted aminocarbonyl or aminocarbonylalkyl wherein the substituent on the anino nitrogen are independently selected from among alkyl, aralkyl, cycloalkyl and alkanoyl, or R.sup.9 is hydrido and R.sup.8 and another substituent selected from the group consisting of R.sup.2, R.sup.4 and R.sup.6 together with the atoms to which they are bonded form a 4- to 8-membered ring;
• provided that no carbon atom is geminally substituted with more than one sulfhydryl group.

A process for treating a host mammal having a condition associated with pathological matrix activity that comprises administering a metalloprotease inhibitor in an effective amount to a mammalian host having such a condition, said metalloprotease inhibitor corresponding in structure to a formula shown below ##STR1180## wherein Ph is phenyl substituted with R.sup.11 at the 4-position;

• R.sup.11 is a substituent selected from the group consisting of C.sub.1 -C.sub.6 alkoxy, C.sub.3 -C.sub.6 alkyl, phenoxy, thiophenoxy, benzamido, phenylazo, and phenyl moieties;
• R.sup.2 is selected from the group consisting of hydrido, a C.sub.1 -C.sub.6 alkyl group, a C.sub.2 -C.sub.3 alkyl cycloamino group having five or six atoms in the ring and zero or one additional heteroatom that is oxygen or nitrogen, a C.sub.1 -C.sub.6 aminocarbonyl group whose amido nitrogen is unsubstituted or mono- or disubstituted with a C.sub.2 -C.sub.3 alkyl or benzyl radical, and a C.sub.1 -C.sub.4 alkylheteroaryl group having a single heteroaryl ring wherein said single heteroaryl ring contains one or two nitrogen atoms, or wherein R.sup.2 and R.sup.6 together with the atoms to which they are bonded form a 5- or 6-membered ring;
• R.sup.6 is a radical selected from the group consisting of an C.sub.1 -C.sub.6 alkyl group, a carboxyl group, a C.sub.1 -C.sub.6 alkoxy carbonyl group, an amino C.sub.1 -C.sub.6 alkanoyl group, a carboxamide group where the amido nitrogen is (i) unsubstituted or (ii) substituted with (a C.sub.1 -C.sub.4 alkyl substituted by amino, mono-substituted amino or di-substituted amino, wherein the substituent on the amino nitrogen is selected from the group consisting of C.sub.1 -C.sub.6 alkyl, C.sub.5 -C.sub.8 cycloalkyl and C.sub.1 -C.sub.6 alkanoyl groups, or wherein two amino nitrogen substitutents and the nitrogen to which they are bonded together form a 5- to 8-membered heterocyclic or heteroaryl ring containing zero or one additional hetero atoms that are nitrogen, oxygen or sulfur or (iii) the amido nitrogen is the amine of an amino acid;
• and
• R.sup.10 is C.sub.1 -C.sub.6 alkoxy, or a single-ringed aryl or heteroaryl group,
• with the proviso that only one of R.sup.2 or R.sup.6 is present unless R.sup.2 and R.sup.6 together with the atoms to which they are bonded form a 5- or 6-membered ring.