US 6,541,489 B1 · Aromatic sulfone hydroxamic acid metalloprotease inhibitor

Abstract

A treatment process is disclosed that comprises administering an effective amount of an aromatic sulfone hydroxamic acid that exhibits excellent inhibitory activity of one or more matrix metalloprotease (MMP) enzymes, such as MMP-2, MMP-9, and MMP-13, while exhibiting substantially less inhibition at least of MMP-1 to a host having a condition associated with pathological matrix metalloprotease activity. The administered enzyme inhibitor corresponds in structure to formula (I), below, or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are both hydrido or R1 and R2 together with the atoms to which they are bonded form a 5- to 8-membered ring containing one, two, or three heteroatoms in the ring that are oxygen, sulfur, or nitrogen. R3 in formula (I) is an optionally substituted aryl or optionally substituted heteroaryl radical. Also disclosed are metalloprotease inhibitor compounds having those selective activities, processes for manufacture of such compounds and pharmaceutical compositions using an inhibitor.

A process for treating a host mammal having a condition associated with pathological matrix metalloprotease (MMP) activity, wherein:

the process comprises administering a metalloprotease inhibitor compound or a pharmaceutically acceptable salt thereof in an effective amount to a mammalian host having such a condition;
said 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 MMP-1;
said compound corresponds in structure to formula (II) below:
R14is selected from the group consisting ofhydrogen 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, C1-C6-alkoxy, heteroaryl-C1-C6-alkyl, C3-C8-cycloalkyl-C1-C6-alkyl, aryloxy, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, heteroaryl, and amino-C1-C6-alkyl, wherein:
the aminoalkyl nitrogen optionally is substituted with up to two 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 optionally is substituted with two substituents such that the aminoalkyl nitrogen and the two substituents together 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 selected from the group consisting of 1, 2, 3, and 4;
as to X, Y, and Z:
(a) one of X, Y, and Z is selected from the group consisting of NR6, O, S, S(O), S(O)2, and NS(O)2R7, and the remaining two of X, Y, and Z are CR8R9 and CR10R11, or
(b) X and Z or Z and Y together constitute a moiety that is selected from the group consisting of NR6C(O), NR6S(O), NR6S(O)2, NR6S, NR6O, SS, NR6NR6, and OC(O), with the remaining one of X and Y being CR8R9, or
(c) n is zero and X, Y, and Z together constitute a moiety selected from the group consisting of:
wherein
the wavy lines are bonds to the atoms of the depicted ring;
each R6 and R6′ is independently selected from the group consisting of hydrogen, C1-C6-alkanoyl, C6-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, C3-C8-heterocycloalkyl, C3-C8-heterocycloalkylcarbonyl, C6-aryl, C5-C6-heterocyclo, C5-C6-heteroaryl, C3-C8-cycloalkyl-C1-C6-alkyl, C6-aryloxy-C1-C6-alkyl, heteroaryloxy-C1-C6-alkyl, heteroaryl-C1-C6-alkoxy-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, C6-arylsulfonyl, C1-C6-alkylsulfonyl, C5-C6-heteroarylsulfonyl, carboxy-C1-C6-alkyl, C1-C4-alkoxycarbonyl-C1-C6-alkyl, aminocarbonyl, C1-C6-alkyliminocarbonyl, C6-aryliminocarbonyl, C5-C6-heterocycloiminocarbonyl, C6-arylthio-C1-C6-alkyl, C1-C6-alkylthio-C1-C6-alkyl, C6-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, NR8R9—C1-C5-alkylcarbonyl, hydroxy-C1-C5-alkyl, aminocarbonyl, hydroxyaminocarbonyl, aminosulfonyl, amino-C1-C6-alkylsulfonyl, and amino-C1-C6-alkyl, wherein:
the aminocarbonyl, aminosulfonyl, aminoalkylsulfonyl, or aminoalkyl nitrogen optionally is substituted with up to two substituents independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, C3-C8-cycloalkyl, and C1-C6-alkanoyl;
R7 is selected from the group consisting of arylalkyl, aryl, heteroaryl, heterocyclo, C1-C6-alkyl, C3-C6-alkynyl, C3-C6-alkenyl, C1-C6-carboxyalkyl, and C1-C6-hydroxyalkyl;
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 said thio substituents, the sulfone of any said 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 optionally is substituted with up to two 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 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 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—, 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 said thio substituents, the sulfone of any said 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 optionally is substituted with up to two 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 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 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-C6alkyl, 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 said thio substituents, the sulfone of any said 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 optionally is substituted with up to two 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 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 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 said thio substituents, the sulfone of any said 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 optionally is substituted with up to two 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 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 is hydroxy;
R12 and R12′ are independently selected from the group consisting of hydrogen, C1-C6-alkyl, aryl, aryl-C1-C6-alkyl, heteroaryl, heteroarylalkyl, C2-C6-alkynyl, C2-C6-alkenyl, thiol-C1-C6-alkyl, cycloalkyl, cycloalkyl-C1-C6-alkyl, heterocycloalkyl-C1-C6-alkyl, C1-C6-alkoxy-C1-C6-alkyl, aryloxy-C1-C6-alkyl, amino-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, C1-C6-alkylthio-C1-C6-alkyl, arylthio-C1-C6-alkyl, heteroarylthio-C1-C6-alkyl, the sulfoxide of any said thio substituents, the sulfone of any said 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 optionally is substituted with up to two radicals independently selected from the group consisting of C1-C6-alkyl, aryl-C1-C6-alkyl, cycloalkyl, and C1-C6-alkanoyl;
R13 is selected from the group consisting of hydrogen, benzyl, phenyl, C1-C6-alkyl, C2-C6-alkynyl, C2-C6-alkenyl, and C1-C6-hydroxyalkyl;
G—A—R—E—Y2 is a substituent that has a length greater than that of a pentyl group but less than that of an icosyl group, wherein:
G is selected from the group consisting of aryl and heteroaryl;
A is selected from the group consisting of:
(1) —O—,
(2) —S—,
(3) —NR17,
(4) —CO—N(R17),
(5) —N(R17)—CO—,
(6) —CO—O—,
(7) —O—CO—,
(8) —O—CO—O—,
(9) —HC═CH—,
(10) —NH—CO—NH—,
(11) —C≡C—,
(12) —NH—CO—O—,
(13) —O—CO—NH—,
(14) —N═N—,
(15) —NH—NH—,
(16) —CS—N(R18),
(17) —N(R18)—CS—, 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 alkyl, alkoxyalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, cycloalkylalkyl, cycloalkoxyalkyl, heterocycloalkoxyalkyl, aryloxyalkyl, heteroaryloxyalkyl, arylthioalkyl, heteroarylthioalkyl, cycloalkylthioalkyl, and heterocycloalkylthioalkyl, wherein:
the aryl, heteroaryl, cycloalkyl, or heterocycloalkyl optionally is substituted with up to two radicals 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, and
R is other than alkyl or alkoxyalkyl when A is —O—or —S—;
E is selected from the group consisting of:
(1) —CO(R19)—,
(2) —(R19)CO—,
(4) —HNCO—,
(5) —CO—,
(6) —SO2—R19—,
(7) —R19—SO2—,
(8) —SO2—,
(9) —NH—SO2—,
(10) —SO2—NH—, 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 two radicals 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 two groups independently selected from the group consisting of hydrogen, alkyl, and arylalkyl.

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Aromatic sulfone hydroxamic acid metalloprotease inhibitor

Life of this patent

Aromatic sulfone hydroxamic acid metalloprotease inhibitor

Life of this patent

Abstract

Claims19