N-hydroxy-2-(alkyl, aryl, or heteroaryl sulfanyl, sulfinyl or sulfonyl)-3-substituted alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors

A compound according to formula I

• wherein:
• R1 is pyridyl, thienyl, imidazolyl or furanyl optionally substituted with C1-C6 alkyl, C1-C6 alkoxy, C6-C10 aryloxy, or heteroaryloxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, C1-C6 alkoxyaryl, C1-C6 alkoxyheteroaryl, halogen, S(O)n—C1-C6 alkyl where n is 0, 1 or 2;
• wherein aryl is phenyl or naphthyl and heteroaryl is a 5-7 membered heteroaromatic group having a heteroatom selected from O, S, or NR7;
• R2 is alkyl of 1 to 12 carbon atoms, alkenyl of 3 to 12 carbon atoms having 1 to 3 double bonds, alkynyl of 3 to 12 carbon atoms having 1 to 3 triple bonds or pyridylalkyl in which the alkyl group has 1 to 6 carbon atoms;
• R3 is alkyl of 1 to 12 carbon atoms;
• alkenyl of 3 to 10 carbon atoms;
• alkadienyl of 4 to 14 carbon atoms;
• alkynyl of 3 to 10 carbon atoms;
• arylalkyl of 7 to 12 carbon atoms;
• biphenylalkyl of 13 to 18 carbon atoms;
• cycloalkylalkyl where the cycloalkyl moiety has 4 to 7 carbon atoms and the alkyl group has 1 to 6 carbon atoms;
• piperidinyl-C1-C6 alkoxyaryl-C1-C6 alkyl, phenoxy-C1-C6 alkyl, di(C1-C6)alkylamino-C1-C6 alkoxyaryl-C1-C6 alkyl, morpholinyl-C1-C6 alkoxyaryl-C1-C6 alkyl, or azepanyl-C1-C6 alkoxyaryl-C1-C6 alkyl, or —C1-C6 alkylamino-C1-C6 alkoxyaryl-C1-C6 alkyl arylalkenyl of 8 to 16 carbon atoms;
• pyridinyl-C1-C6 alkyl or quinolinyl-C1-C6 alkyl;
• and
• R4 is hydrogen or alkyl of 1 to 6 carbon atoms;
• or a pharmaceutically acceptable salt thereof.

A pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of a matrix metalloproteinase or TACE inhibiting compound according to the formula

• wherein:
• R1 is heteroaryl-(CH2)0-6— wherein the heteroaryl group is 5 to 10 membered monocyclic or bicyclic with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R5, with the proviso that R1 is not pyrimidinyl;
• A is —S—, —SO— or SO2—;
• R2 and R3 are independently selected from
• alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
• alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
• arylalkyl of 7 to 16 carbon atoms, where aryl is optionally substituted with one or two groups selected independently from R5;
• biphenylalkyl of 13 to 18 carbon atoms, where biphenyl is optionally substituted with one or two groups selected independently from R5;
• arylalkenyl of 8 to 16 carbon atoms, where aryl is optionally substituted with one or two groups selected independently from R5;
• cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, optionally substituted with one or two groups selected independently from R5;
• R8R9N—C1-C6-alkoxyaryl-C1-C6-alkyl where R8 and R9 are independently selected from C1-C6 alkyl or R8 and R9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;
• or heteroaryl-(CH2)0-6— wherein the heteroaryl group is 5 to 10 membered monocyclic or bicyclic with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R5;
• R4 is hydrogen,
• alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
• alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
• phenyl or naphthyl optionally substituted with one or two groups selected independently from R5;
• C3 to C8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R5;
• saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, optionally substituted with one or two groups selected independently from R5;
• R5 is H, C7-C11 aroyl, C2-C6 alkanoyl, F, Cl, Br, I, CN, CHO, C1 to C12 alkyl, C2 to C12 alkenyl, C2-C12 alkynyl, C1-C6 alkoxy, aryloxy, heteroaryloxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, C1-C6 alkoxyaryl, C1-C6 alkoxyheteroaryl, C1-C6 alkylamino alkoxy, C1-C2 alkylene dioxy, aryloxy-C1-C6alkyl amine, C1-C12 perfluoro alkyl, S(O)n—C1-C6alkyl or S(O)n-aryl where n is 0, 1 or 2;
• OCOOalkyl, OCOOaryl, OCONR6, COOH, COO—C1-C6alkyl, COOaryl, CONR6R6, CONHOH, NR6R6, SO2NR6R6, NR6SO2aryl, NR6CONR6R6, NHSO2CF3, SO2NHheteroaryl, SO2NHCOaryl, CONHSO2—C1-C6alkyl, CONHSO2aryl, SO2NHCOaryl, CONHSO2—C1-C6alkyl, CONHSO2aryl, NH2, OH, aryl, heteroaryl, C3 to C8 cycloalkyl;
• saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7;
• wherein aryl is phenyl or naphthyl optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy and heteroaryl is a 5-7 membered heteroaryl group and contains a heteroatom selected from O, S or NR7;
• R6 is H, C1 to C18 alkyl optionally substituted with OH;
• C3 to C6 alkenyl, C3 to C6 alkynyl, C1 to C6 perfluoroalkyl, S(O)n—C1-C6 alkyl or aryl where n is 0, 1 or 2;
• or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N—C1-C6 alkyl and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
• and R7 is R6 or forms a bond;
• or a pharmaceutically acceptable salt thereof.

A method of treating inhibiting pathological changes mediated by matrix metalloproteinases in mammals which comprises administration to a mammal in need thereof a therapeutically effective amount of a matrix metalloproteinase inhibiting compound of the formula

• wherein:
• R1 is heteroaryl-(CH2)0-6— wherein the heteroaryl group is 5 to 10 membered monocyclic or bicyclic with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R5;
• A is —S—, —SO— or SO2—;
• R2 and R3 are independently selected from
• alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
• alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
• arylalkyl of 7 to 16 carbon atoms, where aryl is optionally substituted with one or two groups selected independently from R5;
• biphenylalkyl of 13 to 18 carbon atoms, where biphenyl is optionally substituted with one or two groups selected independently from R5;
• arylalkenyl of 8 to 16 carbon atoms, where aryl is optionally substituted with one or two groups selected independently from R5;
• cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, optionally substituted with one or two groups selected independently from R5;
• R8R9N—C1-C6-alkoxyaryl-C1-C6-alkyl where R8 and R9 are independently selected from C1-C6 alkyl or R8 and R9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;
• or heteroaryl-(CH2)0-6— wherein the heteroaryl group is 5 to 10 membered monocyclic or bicyclic with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R5;
• R4 is hydrogen,
• alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
• alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
• phenyl or naphthyl optionally substituted with one or two groups selected independently from R5;
• C3 to C8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R5;
• saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, optionally substituted with one or two groups selected independently from R5;
• R5 is H, C7-C11 aroyl, C2-C6 alkanoyl, F, Cl, Br, I, CN, CHO, C1 to C12 alkyl, C2 to C12 alkenyl, C2-C12 alkynyl, C1-C6 alkoxy, aryloxy, heteroaryloxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, C1-C6 alkoxyaryl, C1-C6 alkoxyheteroaryl, C1-C6 alkylamino alkoxy, C1-C2 alkylene dioxy, aryloxy-C1-C6alkyl amine, C1-C12 perfluoro alkyl, S(O)n—C1-C6alkyl or S(O)n-aryl where n is 0, 1 or 2;
• OCOOalkyl, OCOOaryl, OCONR6, COOH, COO—C1-C6alkyl, COOaryl, CONR6R6, CONHOH, NR6R6, SO2NR6R6, NR6SO2aryl, NR6CONR6R6, NHSO2CF3, SO2NHheteroaryl, SO2NHCOaryl, CONHSO2—C1-C6alkyl, CONHSO2aryl, SO2NHCOaryl, CONHSO2—C1-C6alkyl, CONHSO2aryl, NH2, OH, aryl, heteroaryl, C3 to C8 cycloalkyl;
• saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7;
• wherein aryl is phenyl onaphthyl optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy and heteroaryl is a 5-7 membered heteroaryl group and contains a heteroatom selected from O, S or NR7;
• R6 is H, C1 to C18 alkyl optionally substituted with OH;
• C3 to C6 alkenyl, C3 to C6 alkynyl, C1 to C6 perfluoroalkyl, S(O)n—C1-C6 alkyl or aryl where n is 0, 1 or 2;
• or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N—C1-C6 alkyl and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
• and R7 is R6 or forms a bond;
• or a pharmaceutically acceptable salt thereof.

A method of inhibiting pathological changes mediated by TNF-α converting enzyme (TACE) in mammals which comprises administration to a mammal in need thereof a therapeutically effective amount of a TACE inhibiting compound of the formula

• wherein:
• R1 is heteroaryl-(CH2)0-6— wherein the heteroaryl group is 5 to 10 membered monocyclic or bicyclic with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R5;
• A is —S—, —SO— or SO2—;
• R2 and R3 are independently selected from
• alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• alkenyl of 3 to 18 carbon atoms having from 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
• alkynyl of 3 to 18 carbon atoms having from 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
• arylalkyl of 7 to 16 carbon atoms, where aryl is optionally substituted with one or two groups selected independently from R5;
• biphenylalkyl of 13 to 18 carbon atoms, where biphenyl is optionally substituted with one or two groups selected independently from R5;
• arylalkenyl of 8 to 16 carbon atoms, where aryl is optionally substituted with one or two groups selected independently from R5;
• cycloalkylalkyl or bicycloalkylalkyl of 4 to 12 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, optionally substituted with one or two groups selected independently from R5;
• R8R9N—C1-C6-alkoxyaryl-C1-C6-alkyl where R8 and R9 are independently selected from C1-C6 alkyl or R8 and R9 together with the interposed nitrogen forms a 5-7 membered saturated heterocyclic ring optionally containing an oxygen atom, wherein the aryl group is phenyl or naphthyl;
• or heteroaryl-(CH2)0-6— wherein the heteroaryl group is 5 to 10 membered monocyclic or bicyclic with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R5;
• R4 is hydrogen,
• alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R5;
• alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R5;
• alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R5;
• phenyl or naphthyl optionally substituted with one or two groups selected independently from R5;
• C3 to C8 cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R5;
• saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7, optionally substituted with one or two groups selected independently from R5;
• R5 is H, C7-C11 aroyl, C2-C6 alkanoyl, F, Cl, Br, I, CN, CHO, C1 to C12 alkyl, C2 to C12 alkenyl, C2-C12 alkynyl, C1-C6 alkoxy, aryloxy, heteroaryloxy, C3-C6 alkenyloxy, C3-C6 alkynyloxy, C1-C6 alkoxyaryl, C1-C6 alkoxyheteroaryl, C1-C6 alkylamino alkoxy, C1-C2 alkylene dioxy, aryloxy-C1-C6alkyl amine, C1-C12 perfluoro alkyl, S(O)n—C1-C6alkyl or S(O)n-aryl where n is 0, 1 or 2;
• OCOOalkyl, OCOOaryl, OCONR6, COOH, COO—C1-C6alkyl, COOaryl, CONR6R6, CONHOH, NR6R6, SO2NR6R6, NR6SO2aryl, NR6CONR6R6, NHSO2CF3, SO2NHheteroaryl, SO2NHCOaryl, CONHSO2—C1-C6alkyl, CONHSO2aryl, SO2NHCOaryl, CONHSO2—C1-C6alkyl, CONHSO2aryl, NH2, OH, aryl, heteroaryl, C3 to C8 cycloalkyl;
• saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR7;
• wherein aryl is phenyl or naphthyl optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy and heteroaryl is a 5-7 membered heteroaryl group and contains a heteroatom selected from O, S or NR7;
• R6 is H, C1 to C18 alkyl optionally substituted with OH;
• C3 to C6 alkenyl, C3 to C6 alkynyl, C1 to C6 perfluoroalkyl, S(O)n—C1-C6 alkyl or aryl where n is 0, 1 or 2;
• or COheteroaryl, wherein heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or N—C1-C6 alkyl and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C1-C6 alkyl, C1-C6 alkoxy, or hydroxy;
• and R7 is R6 or forms a bond;
• or a pharmaceutically acceptable salt thereof.