Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-12-16
2002-01-01
Kifle, Bruck (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S217040, C514S217050, C514S217060, C514S217080, C514S217090, C514S217100, C514S217110, C540S596000, C540S604000
Reexamination Certificate
active
06335329
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to metalloproteinase inhibitors and, more particularly, relates to novel compounds, compositions and methods for prophylaxis and treatment of inflammation, tissue degradation and the like. This invention, in particular, relates to novel carboxylic acid substituted heterocyclic compounds, compositions containing such compounds and methods of use of such compounds. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.
Metalloproteinase enzymes, such as collagenases, stromelysins and gelatinases, may contribute to the onset or etiology of, or exacerbate disease states which are related to, connective tissue degradation and the like. For example, matrix metalloproteinases, such as collagenases, stromelysins and gelatinases, are thought to be involved in the tissue breakdown observed in rheumatoid arthritis; osteoarthritis; osteopenias (e.g., osteoporosis); periodontitis; gingivitis; corneal, epidermal and gastric ulceration; and tumour metastasis, invasion and growth; in neuroinflammatory disorders, such as myelin degradation (e.g., multiple sclerosis); and in angiogenesis dependent diseases, such as arthritic conditions; cancer; solid tumor growth; psoriasis; proliferative retinopathies; neovascular glaucoma; ocular tumours; angiofibromas; hemangiomas; nephritis; pulmonary inflammation; and restenosis.
WO 96/33172 discloses N-arylsulfonyl and N-heteroarylsulfonyl substituted 6 membered ring heterocycle hydroxamic acid derivatives, such as N-arylsulfonyl- and N-heteroarylsulfonyl-piperidinyl-2-hydroxamic acid compounds, and their preparation and use as inhibitors of matrix metalloproteinases and TNF production.
EP 606046 discloses N-arylsulfonyl and N-heteroarylsulfonyl substituted 5-6 membered ring heterocycle hydroxamic acid derivatives, such as N-arylsulfonyl- and N-heteroarylsulfonyl-piperidinyl-2-hydroxamic acid compounds and N-arylsulfonyl- and N-heteroarylsulfonyl-1,2,3,4-tetrahydroisoquinolinyl-2-hydroxamic acid compounds, preparation and use as inhibitors of matrix metalloproteinases.
WO 97/18194 discloses certain cyclic and heterocyclic N-substituted &agr;-substituted iminohydroxamic a and carboxylic acids, and their preparation and use as inhibitors of matrix metalloproteinases.
EP 803505 discloses optionally substituted aryl fused N-heterocycles and their preparation and use as inhibitors of metalloproteinases.
BRIEF DESCRIPTION OF THE INVENTION
The present invention relates to selected metalloproteinase inhibitory compounds, analogs and pharmaceutically acceptable salts and prodrugs thereof. The subject compounds are characterized as carboxylic acid substituted heterocyclic compounds. The compounds are useful in the prophylaxis and treatment of inflammation, tissue degradation and related diseases. Therefore, this invention also encompasses pharmaceutical compositions and methods for prophylaxis and treatment of inflamation, tissue degradation and related diseases. The subject invention also relates to processes for making such compounds, as well as to intermediates useful in such processes.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there is provided a compound of the Formula I below:
or a pharmacutically acceptable salt thereof, wherein
m is 1 or 2; and n is 0, 1 or 2;
R
1
is (1) an alkyl, alkenyl, alkynyl, cycloalkyl or heterocyclyl radical optionally substituted by 1-3 radicals of —OH, —OR
3
, —SR
3
, —S(O)R
3
, —S(O)
2
R
3
, —C(O)R
3
, —NR
3
R
4
, aryl, heteroaryl, cycloalkyl or heterocyclyl; or (2) an aryl radical optionally substituted by an optionally substituted monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; or (3) a heteroaryl radical optionally substituted by an optionally substituted phenyl or a monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionally substituted by 1-3 radicals of hydroxy, —OR
3
, —SR
3
, —S(O)R
3
, —S(O)
2
R
3
, —C(O)R
3
, —NR
3
R
4
, amino, alkanoylamino, alkylsulfonylamino, alkoxycarbonylamino, alkoxycarbonyl, cyano, halo, azido, alkyl or haloalkyl;
preferably, R
1
is (1) an C
1
-C
12
alkyl, C
2
-C
12
alkenyl, C
2
-C
12
alkynyl, cycloalkyl or heterocyclyl radical optionally substituted by 1-3 radicals of —OH, —OR
3
, —SR
3
, —S(O)R
3
, —S(O)
2
R
3
, —C(O)R
3
, —NR
3
R
4
, aryl, heteroaryl, cycloalkyl or heterocyclyl; or ((2) an aryl radical optionally substituted by an optionally substituted monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; or (3) a heteroaryl radical optionally substituted by an optionally substituted phenyl or a monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionally substituted by 1-3 radicals of hydroxy, —OR
3
, —SR
3
, —S(O)R
3
, —S(O)
2
R
3
, —C(O)R
3
, —NR
3
R
4
, amino, C
1
-C
8
alkanoylamino, C
1
-C
8
alkylsulfonylamino, C
1
-C
8
alkoxycarbonylamino, C
1
-C
8
alkoxycarbonyl, cyano, halo, azido, C
1
-C
8
alkyl or C
1
-C
8
haloalkyl of 1-3 halo radicals;
more preferably, R
1
is (1) a C
1
-C
12
alkyl, C
2
-C
12
alkenyl, C
2
-C
12
alkynyl, cycloalkyl or heterocyclyl radical optionally substituted by 1-3 radicals of —OH, —OR
3
, —SR
3
, —S(O)R
3
, —S(O)
2
R
3
, —C(O)R
3
, —NR
3
R
4
, aryl, heteroaryl, cycloalkyl or heterocyclyl; or (2) an aryl radical optionally substituted by an optionally substituted monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; or (3) a heteroaryl radical optionally substituted by an optionally substituted phenyl or a monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionally substituted by 1-3 radicals of hydroxy, —OR
3
, —SR
3
, —S(O)R
3
, —S(O)
2
R
3
, —C(O)R
3
, —NR
3
R
4
, amino, C
1
-C
4
alkanoylamino, C
1
-C
4
alkylsulfonylamino, C
1
-C
4
alkoxycarbonylamino, C
1
-C
4
alkoxycarbonyl, cyano, halo, azido, C
1
-C
6
alkyl or C
1
-C
4
haloalkyl of 1-3 halo radicals;
more preferably, R
1
is (1) a C
1
-C
12
alkyl radical optionally substituted by 1-3 radicals of —OH, —OR
3
, —SR
3
, —S(O)R
3
, —S(O)
2
R
3
, —C(O)R
3
, —NR
3
R
4
, aryl, heteroaryl, cycloalkyl or heterocyclyl; or (2) an aryl radical optionally substituted by an optionally substituted monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; or (3) a heteroaryl radical optionally substituted by an optionally substituted phenyl or a monocyclic heteroaryl or heterocyclyl radical of 5-6 ring members which is optionally substituted by a phenyl radical or monocyclic heteroaryl radical of 5-6 ring members; wherein the phenyl, aryl, heteroaryl, cycloalkyl and heterocyclyl radicals of (1), (2) and (3) are optionally substituted by 1-3 radicals of hydroxy, —OR
3
, —SR
3
, —S(O)R
3
, —S(O)
2
R
3
, —C(O)R
3
, —NR
3
R
4
, amino, acetylamino, methylsulfonylamino, C
1
-C
4
alkoxycarbonylamino, C
1
-C
4
alkoxycarbonyl, cyano, halo, C
1
-C
6
alkyl or —CF
3
radicals; more preferably, R
1
is (1) an C
1
-C
12
alkyl radical optionally substituted by 1-3 radicals of —OH, —OR
3
, —SR
3
, —S(O)
2
R , —NR
3
R
4
, aryl, h
Josey John A.
Koch Kevin
Termin Andreas
Amgen Inc.
Kifle Bruck
Odre Steven M.
Ungemach Frank
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