US 2003/0191317 A1 · Sulfonyl aryl or heteroaryl hydroxamic acid compounds

Abstract

A sulfonyl aromatic or heteroaromatic ring hydroxamic acid compound that inter alia inhibits matrix metalloprotease activity is disclosed as are a treatment process that comprises administering a contemplated sulfonyl aromatic or heteroaromatic ring hydroxamic acid compound in a MMP enzyme-inhibiting effective amount to a host having a condition associated with pathological matrix metalloprotease activity.

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Claims119

Dependent claims

A compound corresponding to Formula A, or a pharmaceutically acceptable salt thereof:

1884
wherein
y and z are each zero or one and the sum of z+y is zero or one;
the ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring;
X is —CH2— or —NR9—, wherein R9 is selected from the group consisting of a hydrido, aryl, alkyl and arylalkyl substituent;
R1 is (i) a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO2-group and having a length greater than about that of a hexyl group and less than about that of an eicosyl group, said R1 defining a three-dimensional volume, when rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO2-bonded 1-position and the center of 3,4-bond of a 5-membered ring radical, whose widest dimension in a direction transverse to the axis of rotation is about that of one furanyl ring to about that of two phenyl rings, or (ii) an —NR7R8 group in which R7 and R8 are independently selected from the group consisting of hydrido, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and subsituted arylhydrocarbyl;
R2 and R3 are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, hydroxyalkyl, Raoxyalkyl, hydroxyl, thiol, Rathioalkyl, haloalkyl, amino, RbRcamino, RbRcaminoalkyl, RdReaminoalkanoyl(Rb)aminoalkyl, RbRcaminoalkyloxy, RbRcaminoalkyloxyalkyl, heterocyclo, heterocycloalkyl, heterocyclooxy, heterocyclothio, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylthio, or
R2 and R3 together with the depicted carbon atom to which they are bonded form a 4- to 8-membered carbocyclic or heterocyclic ring, that is preferably a 5- or 6-membered ring, in which the heteroatom is oxygen, sulfur or nitrogen, said heteroatom being optionally substituted with one or two oxygens when sulfur and being optionally substituted with a moiety selected from the group consisting of a C1-C4 hydrocarbyl, C3-C6 cyclohydrocarbyl, C1-C4 hydrocarbylcarbonyl, and sulfonyl C1-C4 hydrocarbyl group when nitrogen;
R5 and R6 are independently selected from the group consisting of a hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, a RbRcaminoalkyl substituent, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy and a RbRcaminoalkyloxy substituent;
or R5 and R6 together with the atoms to which they are bonded form a further aliphatic or aromatic carbocyclic or heterocyclic ring having 5- to 7-members;
and
R20 is (a) —O—R21, where R21 is selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, (b) —NR13—O—R22 wherein R22 is a selectively removable protecting group and R13 is a hydrido, C1-C6-alkyl or benzyl group, (c) —NR13—O—R14, where R13 is as before and R14 is hydrido, a pharmaceutically acceptable cation or C(V)R15 where V is O or S and R15 is selected from the group consisting of an 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 group wherein the amino C1-C6-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an 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 radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) —NR23R24, where R23 and R24 are independently selected from the group consisting of a hydrido, C1-C6-alkyl, amino C1-C6-alkyl, hydroxy C1-C6-alkyl, aryl, and an ar-C1-C6-alkyl group, or R23 and R24 together with the depicted nitrogen atom form a 5- to 8-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur;
wherein:
Ra is selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, RbRcaminoalkanoyl, haloalkanoyl, RbRcaminoalkyl, alkoxyalkyl, haloalkyl and an arylalkyloxy group;
Rb and Rc are independently selected from the group consisting of a hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, aminosulfonyl wherein the amino nitrogen is (i) unsubstituted or (ii) independently substituted with one or two Rd radicals, or the substituents on the amino group taken together with the amino nitrogen form a saturated or partially unsaturated heterocyclo group optionally substituted with one, two or three groups independently selected from Rd substituents or a heteroaryl group optionally substituted with one, two or three groups independently selected from Rf substituents;
Rd and Re are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, alkoxycarbonyl and an arylalkyloxycarbonyl group;
and
Rf is selected from the group consisting of a nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and a RdReamino group.

15 more elements

A compound corresponding to Formula I, or a pharmaceutically acceptable salt thereof:

1888
wherein
y and z are each zero or one and the sum of z+y is one;
the ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring;
X is —CH2— or —NR9—, wherein R9 is selected from the group consisting of a hydrido, aryl, alkyl and arylalkyl substituent;
R1 is a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO2-group and having a length greater than about that of a hexyl group and less than about that of an eicosyl group, said R1 defining a three-dimensional volume, when rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO2-bonded 1-position and the center of 3,4-bond of a 5-membered ring radical, whose widest dimension in a direction transverse to the axis of rotation is about that of one furanyl ring to about that of two phenyl rings;
and
R2 and R3 are independently hydrido, C1-C4 hydrocarbyl, hydroxyl or amino, or R2 and R3 together with the depicted carbon atom to which they are bonded form a 5- or 6-membered heterocyclic ring in which the heteroatom is oxygen, sulfur or nitrogen, said heteroatom being optionally substituted with one or two oxygens when sulfur and being optionally substituted with a moiety selected from the group consisting of a C1-C4 hydrocarbyl, C3-C6 cyclohydrocarbyl, C1-C4 hydrocarbylcarbonyl, and sulfonyl C1-C4 hydrocarbyl group when nitrogen;
and
R5 and R6 are independently selected from the group consisting of a hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, a RbRcaminoalkyl substituent, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy and a RbRcaminoalkyloxy substituent;
or R5 and R6 together with the atoms to which they are bonded form a further aliphatic or aromatic carbocyclic or heterocyclic ring having 5- to 7-members.

8 more elements

A compound corresponding to Formula II-1 or III-1, or a pharmaceutically acceptable salt thereof:

1889
wherein
the ring structure W is a 5- or 6-membered aromatic or heteroaromatic;
R1 is (i) a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO2-group and having a length greater than about that of a hexyl group and less than about that of an eicosyl group, said R1 defining a three-dimensional volume, when rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO2-bonded 1-position and the center of 3,4-bond of a 5-membered ring radical, whose widest dimension in a direction transverse to the axis of rotation is about that of one furanyl ring to about that of two phenyl rings, or (ii) an —NR7R8 group in which R7 and R8 are independently selected from the group consisting of hydrido, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and subsituted arylhydrocarbyl;
R2 and R3 are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, hydroxyalkyl, Raoxyalkyl, hydroxyl, thiol, Rathioalkyl, haloalkyl, amino, RbRcamino, RbRcaminoalkyl, RdReaminoalkanoyl(Rb)aminoalkyl, RbRcaminoalkyloxy, RbRcaminoalkyloxyalkyl, heterocyclo, heterocycloalkyl, heterocyclooxy, heterocyclothio, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylthio, or
R2 and R3 together with the depicted carbon atom to which they are bonded form a 4- to 8-membered carbocyclic or heterocyclic ring, that is preferably a 5- or 6-membered ring, in which the heteroatom is oxygen, sulfur or nitrogen, said heteroatom being optionally substituted with one or two oxygens when sulfur and being optionally substituted with a moiety selected from the group consisting of a C1-C4 hydrocarbyl, C3-C6 cyclohydrocarbyl, C1-C4 hydrocarbylcarbonyl, and sulfonyl C1-C4 hydrocarbyl group when nitrogen;
R5 and R6 are independently selected from the group consisting of a hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, a RbRcaminoalkyl substituent, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy and a RbRcaminoalkyloxy substituent;
and
or R5 and R6 together with the atoms to which they are bonded form a further aliphatic or aromatic carbocyclic or heterocyclic ring having 5- to 7-members;
wherein:
Ra is selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, RbRcaminoalkanoyl, haloalkanoyl, RbRcaminoalkyl, alkoxyalkyl, haloalkyl and an arylalkyloxy group;
Rb and Rc are independently selected from the group consisting of a hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, aminosulfonyl wherein the amino nitrogen is (i) unsubstituted or (ii) independently substituted with one or two Rd radicals, or the substituents on the amino group taken together with the amino nitrogen form a saturated or partially unsaturated heterocyclo group optionally substituted with one, two or three groups independently selected from Rd substituents or a heteroaryl group optionally substituted with one, two or three groups independently selected from Rf substituents;
Rd and Re are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, alkoxycarbonyl and an arylalkyloxycarbonyl group;
and
Rf is selected from the group consisting of a nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and a RdReamino group.

12 more elements

A compound corresponding to Formula VIA, or a pharmaceutically acceptable salt thereof:

1896
wherein:
ring structure W2 including the depicted nitrogen atom is a heterocylic ring that contains 5- or 6-members, and R4 is a substituent bonded at the 4-position relative to that depicted nitrogen atom when W2 is a 6-membered ring and at the 3- or 4-position relative to that depicted nitrogen when W2 is a 5-membered ring;
R4 is a substituent that has a chain length of 3 to about 14 carbon atoms;
R5 and R6 are independently selected from the group consisting of a hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, a RbRcaminoalkyl substituent, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy and a RbRc aminoalkyloxy substituent;
or R5 and R6 together with the atoms to which they are bonded form a further aliphatic or aromatic carbocyclic or heterocyclic ring having 5- to 7-members;
and
R20 is (a) —O—R21, where R21 is selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, (b) —NR13O—R22 wherein R22 is a selectively removable protecting group and R13 is a hydrido, C1-C6-alkyl or benzyl group, (c) —NR13—O—R14, where R13 is as before and R14 is hydrido, a pharmaceutically acceptable cation or C(V)R15 where V is O or S and R15 is selected from the group consisting of an 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 group wherein the amino C1-C6-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an 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 radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) —NR23R24, where R23 and R24 are independently selected from the group consisting of a hydrido, C1-C6-alkyl, amino C1-C6-alkyl, hydroxy C1-C6-alkyl, aryl, and an ar-C1-C6-alkyl group, or R23 and R24 together with the depicted nitrogen atom form a 5- to 8-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur;
Rb and Rc are independently selected from the group consisting of a hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, aminosulfonyl wherein the amino nitrogen is (i) unsubstituted or (ii) independently substituted with one or two Rd radicals, or the substituents on the amino group taken together with the amino nitrogen form a saturated or partially unsaturated heterocyclo group optionally substituted with one, two or three groups independently selected from Rd substituents or a heteroaryl group optionally substituted with one, two or three groups independently selected from Rf substituents;
Rd and Re are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, alkoxycarbonyl and an arylalkyloxycarbonyl group;
and
Rf is selected from the group consisting of a nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and a RdReamino group.

9 more elements

A compound corresponding to Formula VIIC, or a pharmaceutically acceptable salt thereof:

1898
wherein:
ring structure W2 including the depicted nitrogen atom is a heterocylic ring that contains 5- or 6-members, and the substituent —A—R—E—Y is bonded at the 4-position relative to that depicted nitrogen atom when W2 is a 6-membered ring and at the 3- or 4-position relative to that depicted nitrogen when W2 is a 5-membered ring;
in said —A—R—E—Y substituent, A is selected from the group consisting of
(1) —O—;
(2) —S—;
(3) —NRk—;
(4) —CO—N(Rk) or —N(Rk)—CO—;
(5) —CO—O— or —O—CO—;
(6) —O—CO—O—;
(7) —HC═CH—;
(8) —NH—CO—NH—;
(9) —C≡C—;
(10) —N═N—;
(11) —NH—NH—;
(12) —CS—N(Rk)— or —N(Rk)—CS—;
(13) —CH2—;
(14) —O—CH2— or —CH2—O—;
(15) —S—CH2— or —CH2—S—;
(16) —SO—;
and
(17) —SO2—;
or
(18) A is absent and R is directly bonded to ring structure W2;
the moiety R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group;
the group E is selected from the group consisting of
(1) —CORg— or —RgCO—;
(2) —CON(Rk)— or —(Rk)NCO—;
(3) —CO—;
(4) —SO2Rg— or —RgSO2—;
(5) —SO2—;
(6) —N(Rk)—SO2 or —SO2—N(Rk)—;
or
(7) E is absent and R is bonded directly to Y;
and
Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, Raoxyalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group;
wherein
Ra is selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, RbRcaminoalkanoyl, haloalkanoyl, RbRcaminoalkyl, alkoxyalkyl, haloalkyl and an arylalkyloxy group;
Rb and Rc are independently selected from the group consisting of a hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, aminosulfonyl wherein the amino nitrogen is (i) unsubstituted or (ii) independently substituted with one or two Rd radicals, or the substituents on the amino group taken together with the amino nitrogen form a saturated or partially unsaturated heterocyclo group optionally substituted with one, two or three groups independently selected from Rd substituents or a heteroaryl group optionally substituted with one, two or three groups independently selected from Rf substituents;
Rd and Re are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, alkoxycarbonyl and an arylalkyloxycarbonyl group;
Rf is selected from the group consisting of a nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and a RdReamino group;
wherein Rg is selected from the group consisting of a hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen cyano, aldehydo, hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, RhRi-amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, RhRi-aminocarbonyloxy, RhRi-aminocarbonyl, RhRi-aminoalkanoyl, hydroxyaminocarbonyl, RhRi-aminosulfonyl, RhRi-aminocarbonyl(Rh)amino, trifluoromethylsulfonyl (Rh)amino, heteroarylsulfonyl-(Rh)amino, arylsulfonyl(Rh)amino, arylsulfonyl(Rh)-aminocarbonyl, alkylsulfonyl(Rh)amino, arylcarbonyl-(Rh)aminosulfonyl, and an alkylsulfonyl(Rh)-aminocarbonyl substituent;
wherein Rh is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, each of which groups is optionally substituted by one or two groups independently selected from Rj substituents as are the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups;
Ri is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, each of which groups are optionally substituted by one or two Rj substituents;
wherein Rj is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups are selected from the group consisting of an alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl and an alkyloxycarbonyl group;
and
Rk is selected from hydrido, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, RcRdamino carbonyl, RcRdaminosulfonyl, RcRdaminoalkanoyl and RcRdaminoalkysulfonyl.

44 more elements

A compound corresponding to Formula VIIB, or a pharmaceutically acceptable salt thereof:

1899
wherein:
G is a N-heterocyclo group;
the substituent A is selected from the group consisting of
(1) —O—;
(2) —S—;
(3) —NRk—;
(4) —CO—N(Rk) or —N(Rk)—CO—;
(5) —CO—O— or —O—CO—;
(6) —O—CO—O—;
(7) —HC═CH—;
(8) —NH—CO—NH—;
(9) —C≡C—;
(10) —N═N—;
(11) —NH—NH—;
(12) —CS—N(Rk)— or —N(Rk)—CS—;
(13) —CH2—;
(14) —O—CH2— or —CH2—O—;
(15) —S—CH2— or —CH2—S—;
(16) —SO—;
and
(17) —SO2—;
or
(18) A is absent and R is directly bonded to the N-heterocyclo group, G;
the moiety R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group;
the moiety E is selected from the group consisting of
(1) —CORg— or —RgCO—;
(2) —CON(Rk)— or —(Rk)NCO—;
(3) —CO—;
(4) —SO2—Rg— or —Rg—SO2—;
(5) —SO2—;
(6) —N(Rk)—SO2— or —SO2—N(Rk)—;
or
(7) E is absent and R is bonded directly to Y;
and
the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl or heteroaryl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, aralkyl, aryl, alkoxy, and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group;
wherein
Ra is selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, RbRcaminoalkanoyl, haloalkanoyl, RbRcaminoalkyl, alkoxyalkyl, haloalkyl and an arylalkyloxy group;
Rb and Rc are independently selected from the group consisting of a hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, aminosulfonyl wherein the amino nitrogen is (i) unsubstituted or (ii) independently substituted with one or two Rd radicals, or the substituents on the amino group taken together with the amino nitrogen form a saturated or partially unsaturated heterocyclo group optionally substituted with one, two or three groups independently selected from Rd substituents or a heteroaryl group optionally substituted with one, two or three groups independently selected from Rf substituents;
Rd and Re are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, alkoxycarbonyl and an arylalkyloxycarbonyl group;
Rf is selected from the group consisting of a nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and a RdReamino group;
wherein Rg is selected from the group consisting of a hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen cyano, aldehydo, hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, RhRi-amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxycarbonyl, arylalkyloxycarbonyl, arylalkyloxycarbonylamino, aryloxycarbonyloxy, carboxy, RhRi-aminocarbonyloxy, RhRi-aminocarbonyl, RhRi-aminoalkanoyl, hydroxyaminocarbonyl, RhRi-aminosulfonyl, RhRi-aminocarbonyl(Rh)amino, trifluoromethylsulfonyl(Rh)amino, heteroarylsulfonyl-(Rh)amino, arylsulfonyl(Rh)amino, arylsulfonyl(Rh)-aminocarbonyl, alkylsulfonyl(Rh)amino, arylcarbonyl-(Rh)aminosulfonyl, and an alkylsulfonyl(Rh)-aminocarbonyl substituent;
wherein Rh is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, each of which groups is optionally substituted by one or two groups independently selected from Rj substituents as are the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups;
Ri is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, each of which groups are optionally substituted by one or two Rj substituents;
wherein Rj is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups are selected from the group consisting of an alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl and an alkyloxycarbonyl group;
and
Rk is selected from hydrido, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, RcRdamino carbonyl, RcRdaminosulfonyl, RcRdaminoalkanoyl and RcRdaminoalkysulfonyl.

44 more elements

A process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity that comprises administering a compound corresponding in structure to Formula A or a pharmaceutically acceptable salt thereof in an MMP enzyme-inhibiting effective amount to a mammalian host having such a condition:

1939
wherein
y and z are each zero or one and the sum of z+y is zero or one;
the ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring;
X is —CH2— or —NR9—, wherein R9 is selected from the group consisting of a hydrido, aryl, alkyl and arylalkyl substituent;
R1 is (i) a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO2-group and having a length greater than about that of a hexyl group and less than about that of an eicosyl group, said R1 defining a three-dimensional volume, when rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO2-bonded 1-position and the center of 3,4-bond of a 5-membered ring radical, whose widest dimension in a direction transverse to the axis of rotation is about that of one furanyl ring to about that of two phenyl rings, or (ii) an —NR7R8 group in which R7 and R8 are independently selected from the group consisting of hydrido, hydrocarbyl, aryl, substituted aryl, arylhydrocarbyl, and subsituted arylhydrocarbyl;
R2 and R3 are independently selected from the group consisting of hydrido, alkyl, alkenyl, alkynyl, hydroxyalkyl, Raoxyalkyl, hydroxyl, thiol, Rathioalkyl, haloalkyl, amino, RbRcamino, RbRcaminoalkyl, RdReaminoalkanoyl(Rb)aminoalkyl, RbRcaminoalkyloxy, RbRcaminoalkyloxyalkyl, heterocyclo, heterocycloalkyl, heterocyclooxy, heterocyclothio, heteroaryl, heteroarylalkyl, heteroaryloxy, heteroarylthio, or
R2 and R3 together with the depicted carbon atom to which they are bonded form a 4- to 8-membered carbocyclic or heterocyclic ring, that is preferably a 5- or 6-membered ring, in which the heteroatom is oxygen, sulfur or nitrogen, said heteroatom being optionally substituted with one or two oxygens when sulfur and being optionally substituted with a moiety selected from the group consisting of a C1-C4 hydrocarbyl, C3-C6 cyclohydrocarbyl, C1-C4 hydrocarbylcarbonyl, and sulfonyl C1-C4 hydrocarbyl group when nitrogen;
R5 and R6 are independently selected from the group consisting of a hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, a RbRcaminoalkyl substituent, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy and a RbRcaminoalkyloxy substituent;
or R5 and R6 together with the atoms to which they are bonded form a further aliphatic or aromatic carbocyclic or heterocyclic ring having 5- to 7-members;
and
R20 is (a) —O—R21, where R21 is selected from the group consisting of a hydrido, C1-C6-alkyl, aryl, ar-C1-C6-alkyl group and a pharmaceutically acceptable cation, (b) —NR13—O—R22 wherein R22 is a selectively removable protecting group and R13 is a hydrido, C1-C6-alkyl or benzyl group, (c) —NR—O—R14, where R13 is as before and R14 is hydrido, a pharmaceutically acceptable cation or C(V)R15 where V is O or S and R15 is selected from the group consisting of an 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 group wherein the amino C1-C6-alkyl nitrogen is (i) unsubstituted or (ii) substituted with one or two substituents independently selected from the group consisting of an 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 radical, or (iii) wherein the amino C1-C6-alkyl nitrogen and two substituents attached thereto form a 5- to 8-membered heterocyclo or heteroaryl ring, or (d) —NR23R24, where R23 and R24 are independently selected from the group consisting of a hydrido, C1-C6-alkyl, amino C1-C6-alkyl, hydroxy C1-C6-alkyl, aryl, and an ar-C1-C6-alkyl group, or R23 and R24 together with the depicted nitrogen atom form a 5- to 8-membered ring containing zero or one additional heteroatom that is oxygen, nitrogen or sulfur;
wherein:
Ra is selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, RbRcaminoalkanoyl, haloalkanoyl, RbRcaminoalkyl, alkoxyalkyl, haloalkyl and an arylalkyloxy group;
Rb and Rc are independently selected from the group consisting of a hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, aminosulfonyl wherein the amino nitrogen is (i) unsubstituted or (ii) independently substituted with one or two Rd radicals, or the substituents on the amino group taken together with the amino nitrogen form a saturated or partially unsaturated heterocyclo group optionally substituted with one, two or three groups independently selected from Rd substituents or a heteroaryl group optionally substituted with one, two or three groups independently selected from Rf substituents;
Rd and Re are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, alkoxycarbonyl and an arylalkyloxycarbonyl group;
and
Rf is selected from the group consisting of a nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and a RdReamino group.

15 more elements

1943
wherein
y and z are each zero or one and the sum of z+y is zero or one;
the ring structure W is a 5- or 6-membered aromatic or heteroaromatic ring;
X is —CH2— or —NR9—, wherein R9 is selected from the group consisting of a hydrido, aryl, alkyl and arylalkyl substituent;
R1 is a substituent containing a 5- or 6-membered cyclohydrocarbyl, heterocyclo, aryl or heteroaryl radical bonded directly to the depicted SO2-group and having a length greater than about that of a hexyl group and less than about that of an eicosyl group, said R1 defining a three-dimensional volume, when rotated about an axis drawn through the SO2-bonded 1-position and the 4-position of a 6-membered ring radical or drawn through the SO2-bonded 1-position and the center of 3,4-bond of a 5-membered ring radical, whose widest dimension in a direction transverse to the axis of rotation is about that of one furanyl ring to about that of two phenyl rings;
and
R2 and R3 are independently hydrido, C1-C4 hydrocarbyl, hydroxyl or amino, or R2 and R3 together with the depicted carbon atom to which they are bonded form a 5- or 6-membered heterocyclic ring in which the heteroatom is oxygen, sulfur or nitrogen, said heteroatom being optionally substituted with one or two oxygens when sulfur and being optionally substituted with a moiety selected from the group consisting of a C1-C4 hydrocarbyl, C3-C6 cyclohydrocarbyl, C1-C4 hydrocarbylcarbonyl, and sulfonyl C1-C4 hydrocarbyl group when nitrogen;
and
R5 and R6 are independently selected from the group consisting of a hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, a RbRcaminoalkyl substituent, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy and a RbRcaminoalkyloxy substituent;
or R5 and R6 together with the atoms to which they are bonded form a further aliphatic or aromatic carbocyclic or heterocyclic ring having 5- to 7-members.

8 more elements

A process for treating a host mammal having a condition associated with pathological matrix metalloprotease activity that comprises administering a compound corresponding in structure to Formula VIB-2 or a pharmaceutically acceptable salt thereof in an MMP enzyme-inhibiting effective amount to a mammalian host having such a condition:

1944
wherein
R5 and R6 are independently selected from the group consisting of a hydrido, alkyl, cycloalkyl, acylalkyl, halo, nitro, hydroxyl, cyano, alkoxy, haloalkyl, haloalkyloxy, hydroxyalkyl, a RbRcaminoalkyl substituent, thiol, alkylthio, arylthio, cycloalkylthio, cycloalkkoxy, alkoxyalkoxy, perfluoroalkyl, haloalkyl, heterocyclooxy and a RbRcaminoalkyloxy substituent;
or R5 and R6 together with the atoms to which they are bonded form a further aliphatic or aromatic carbocyclic or heterocyclic ring having 5- to 7-members;
and
said R7 and R8 are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkynyl, alkoxyalkyl, haloalkyl, Raoxyalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and a heterocyclo substituent, each of which substituent groups is optionally substituted with an —A—R—E—Y substituent;
in said —A—R—E—Y substituent, A is selected from the group consisting of
(1) —O—;
(2) —S—;
(3) —NRk—;
(4) —CO—N(Rk) or —N(Rk)—CO—;
(5) —CO—O— or —O—CO—;
(6) —O—CO—O—;
(7) —HC═CH—;
(8) —NH—CO—NH—;
(9) —C≡C—;
(10) —N═N—;
(11) —NH—NH—;
(12) —CS—N(Rk)— or —N(Rk)—CS—;
(13) —CH2—;
(14) —O—CH2— or —CH2—O—;
(15) —S—CH2— or —CH2—S—;
(16) —SO—;
and
(17) —SO2—;
or
(18) A is absent and R is directly bonded to R7 or R8, or both R7 and R8;
the moiety R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl, heteroaryl, cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group;
the group E is selected from the group consisting of
(1) —CORg— or —RgCO—;
(2) —CON(Rk)— or —(Rk)NCO—;
(3) —CO—;
(4) —SO2Rg— or —RgSO2—;
(5) —SO2—;
(6) —N(Rk)—SO2— or —SO2—N(Rk)—;
or
(7) E is absent and R is bonded directly to Y;
and
Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, nitrile, nitro, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, Raoxyalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl, heteroaryl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, nitrile, haloalkyl, alkyl, aralkyl, aryl, alkoxy, and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group;
or
R7 and R8 taken together with the nitrogen atom to which they are bonded form a group —G—A—R—E—Y wherein
G is a N-heterocyclo group;
the substituent A is selected from the group consisting of
(1) —O—;
(2) —S—;
(3) —NRk—;
(4) —CO—N(Rk) or —N(Rk)—CO—;
(5) —CO—O— or —O—CO—;
(6) —O—CO—O—;
(7) —HC═CH—;
(8) —NH—CO—NH—;
(9) —C≡C—;
(10) —N═N—;
(11) —NH—NH—;
(12) —CS—N(Rk)— or —N(Rk)—CS—;
(13) —CH2—;
(14) —O—CH2— or —CH2—O—;
(15) —S—CH2— or —CH2—S—;
(16) —SO—;
and
(17) —SO2—;
or
(18) A is absent and R is directly bonded to the N-heterocyclo group, G;
the moiety R is selected from the group consisting of alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, aralkyl, heteroaralkyl, heterocycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and a heterocycloalkylthioalkyl group wherein the aryl or heteroaryl or cycloalkyl or heterocycloalkyl substituent is (i) unsubstituted or (ii) substituted with one or two radicals selected from the group consisting of a halo, alkyl, perfluoroalkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, amino, alkoxycarbonylalkyl, alkoxy, C1-C2-alkylenedioxy, hydroxycarbonylalkyl, hydroxycarbonylalkylamino, nitro, hydroxy, hydroxyalkyl, alkanoylamino, and a alkoxycarbonyl group;
the moiety E is selected from the group consisting of
(1) —CORg— or —RgCO—;
(2) —CON(Rk)— or —(Rk)NCO—;
(3) —CO—;
(4) —SO2—Rg— or —Rg—SO2—;
(5) —SO2—;
(6) —N(Rk)—SO2— or —SO2—N(Rk)—;
or
(7) E is absent and R is bonded directly to Y;
and
the moiety Y is absent or is selected from the group consisting of a hydrido, alkyl, alkoxy, haloalkyl, aryl, aralkyl, cycloalkyl, heteroaryl, hydroxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyl, perfluoroalkoxy, perfluoroalkylthio, trifluoromethylalkyl, alkenyl, heterocycloalkyl, cycloalkyl, trifluoromethyl, alkoxycarbonyl, and a aminoalkyl group, wherein the aryl or heteroaryl or heterocycloalkyl group is (i) unsubstituted or (ii) substituted with one or two radicals independently selected from the group consisting of an alkanoyl, halo, nitro, aralkyl, aryl, alkoxy, and an amino group wherein the amino nitrogen is (i) unsubstituted or (ii) substituted with one or two groups independently selected from hydrido, alkyl, and an aralkyl group;
Ra is selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, RbRcaminoalkanoyl, haloalkanoyl, RbRcaminoalkyl, alkoxyalkyl, haloalkyl and an arylalkyloxy group;
Rb and Rc are independently selected from the group consisting of a hydrido, alkanoyl, arylalkyl, aroyl, bisalkoxyalkyl, alkyl, haloalkyl, perfluoroalkyl, trifluoromethylalkyl, perfluoroalkoxyalkyl, alkoxyalkyl, cycloalkyl, heterocycloalkyl, heterocycloalkylcarbonyl, aryl, heterocyclo, heteroaryl, cycloalkylalkyl, aryloxyalkyl, heteroaryloxyalkyl, heteroarylalkoxyalkyl, heteroarylthioalkyl, arylsulfonyl, aralkanoyl, alkylsulfonyl, heteroarylsulfonyl, carboxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, alkyliminocarbonyl, aryliminocarbonyl, heterocycloiminocarbonyl, arylthioalkyl, alkylthioalkyl, arylthioalkenyl, alkylthioalkenyl, heteroarylalkyl, haloalkanoyl, hydroxyalkanoyl, thiolalkanoyl, alkenyl, alkynyl, alkoxyalkyl, alkoxycarbonyl, aryloxycarbonyl, aminoalkylcarbonyl, hydroxyalkyl, aminoalkyl, aminoalkylsulfonyl, aminosulfonyl wherein the amino nitrogen is (i) unsubstituted or (ii) independently substituted with one or two Rd radicals, or the substituents on the amino group taken together with the amino nitrogen form a saturated or partially unsaturated heterocyclo group optionally substituted with one, two or three groups independently selected from Rd substituents or a heteroaryl group optionally substituted with one, two or three groups independently selected from Rf substituents;
Rd and Re are independently selected from the group consisting of a hydrido, alkyl, alkenyl, alkenyl, arylalkyl, aryl, alkanoyl, aroyl, arylalkycarbonyl, alkoxycarbonyl and an arylalkyloxycarbonyl group;
and
Rf is selected from the group consisting of a nitro, hydroxy, alkyl, halogen, aryl, alkoxy, cyano, and a RdReamino group;
Rg is selected from the group consisting of a hydrido, aryl, heteroaryl, heterocyclo, aroyl, alkanoyl, heteroaroyl, halogen cyano, aldehydo, hydroxy, amino, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, alkoxy, aryloxy, heteroaryloxy, alkenyloxy, alkynyloxy, alkoxyaryl, alkoxyheteroaryl, RhRi-amino, alkoxyalkyl, alkylenedioxy, aryloxyalkyl, perfluoroalkyl, trifluoroalkyl, alkylthio, arylthio, alkyloxycarbonyl, alkyloxycarbonyloxy, aryloxy-carbonyl, arylalkyloxycarbonyl, arylalkyloxy-carbonylamino, aryloxycarbonyloxy, carboxy, RhRi-aminocarbonyloxy, RhRi-aminocarbonyl, RhRi-aminoalkanoyl, hydroxyaminocarbonyl, RhRi-aminosulfonyl, RhRi-aminocarbonyl(Rh)amino, trifluoromethylsulfonyl(Rh)amino, heteroarylsulfonyl-(Rh)amino, arylsulfonyl(Rh)amino, arylsulfonyl(Rh)-aminocarbonyl, alkylsulfonyl(Rh)amino, arylcarbonyl-(Rh)aminosulfonyl, and an alkylsulfonyl(Rh)-aminocarbonyl substituent;
Rh is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, each of which groups is optionally substituted by one or two groups independently selected from Rj substituents as are the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups;
Ri is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkylalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, each of which groups are optionally substituted by one or two Rj substituents;
Rj is selected from the group consisting of an arylalkyl, aryl, heteroaryl, heterocyclo, alkyl, alkynyl, alkenyl, alkoxyalkyl, alkoxyalkyl, substituted or unsubstituted aminoalkyl, alkyloxycarbonyl, arylalkyloxycarbonyl, carboxyalkyl, haloalkyl, alkanoyl, aroyl, substituted or unsubstituted aminoalkanoyl, halo alkanoyl and a hydroxyalkyl group, wherein the substituents of the substituted aminoalkyl and substituted aminoalkanoyl groups are selected from the group consisting of an alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl and an alkyloxycarbonyl group;
and
Rk is selected from hydrido, alkyl, alkenyl, alkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, aryloxycarbonyl, alkyloxycarbonyl, RcRdamino carbonyl, RcRdaminosulfonyl, RcRdaminoalkanoyl and RcRdaminoalkysulfonyl.

83 more elements

Dependencies are inferred from the claim text.

Description34,317 words

Summary23,798 words

#This invention is directed to proteinase (protease) inhibitors, and more particularly to sulfonyl aryl or heteroaryl hydroxamic acid compounds that, inter alia, inhibit the activity of matrix metalloproteinases, compositions of those inhibitors, intermediates for the syntheses of those compounds, processes for the preparation of the compounds and processes for treating pathological conditions associated with pathological matrix metalloproteinase activity.

#Connective tissue, extracellular matrix constituents and basement membranes are required components of all mammals. These components are the biological materials that provide rigidity, differentiation, attachments and, in some cases, elasticity to biological systems including human beings and other mammals. Connective tissues components include, for example, collagen, elastin, proteoglycans, fibronectin and laminin. These biochemicals make up, or are components of structures, such as skin, bone, teeth, tendon, cartilage, basement membrane, blood vessels, cornea and vitreous humor.

#Under normal conditions, connective tissue turnover and/or repair processes are controlled and in equilibrium. The loss of this balance for whatever reason leads to a number of disease states. Inhibition of the enzymes responsible for the loss of equilibrium provides a control mechanism for this tissue decomposition and, therefore, a treatment for these diseases.

Detailed description10,519 words

#1863

#Part A: To a solution of phthalide (6.30 g, 47.0 mmol) in DMF (100 mL) was added K2CO3 (10.0 g, 49.4 mmol) and 4-(phenoxy)benzenethiol (9.59 g, 49.4 mmol) and the solution was heated to one hundred degrees Celsius for 2 hours. The solution was diluted with H2O and acidified with 1N HCl to pH=1. The resulting tan solid was collected and washed with H2O. The solid was dissolved into ethyl ether and dried over MgSO4. Concentration in vacuo followed by recrystallization (ethyl ether/hexane) provided the sulfide as a white solid (9.12 g, 58%). MS(CI) MH+ calculated for C20H16O3S: 337, found 337. Analytical calculation for C20H16O3S: C, 71.41; H, 4.79; S, 9.53. Found: C, 71.28; H, 4.67; S, 9.19.

#Part B: To a solution of the sulfide of Part A (3.00 g, 8.92 mmol) in dichloromethane (28 mL) and DMF (1 drop) was added oxalyl chloride (1.08 mL, 12.4 mmol) and the solution was stirred for one hour. After concentration in vacuo, the residue was dissolved into dichloromethane (16 mL) and the solution was cooled to zero degrees Celsius. Tetramethylsilyl hydroxylamine (2.55 mL, 20.8 mmol) was added and the solution was stirred for 1.5 hours. The solution was diluted with dichloromethane and washed with 1 N HCl, H2O and saturated NaCl and dried over MgSO4. Chromatography (on silica, ethyl acetate/hexane/toluene) provide the hydroxylamine as a clear paste (970 mg, 31%).

Sulfonyl aryl or heteroaryl hydroxamic acid compounds

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Sulfonyl aryl or heteroaryl hydroxamic acid compounds

Life of this patent

Life of this patent

Abstract

Drawings

Drawings

Claims119

Description34,317 words

Drawings

Classification25 codes

Life of this patent

Description34,317 words