Tricyclic biphenyl sulfonamide matrix metalloproteinase...

Details Tricyclic biphenyl sulfonamide matrix metalloproteinase... Tricyclic biphenyl sulfonamide matrix metalloproteinase...

2002-02-13

2003-04-29

Rao, Deepak (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S211010, C514S365000, C540S544000, C544S060000, C548S200000, C548S201000

Reexamination Certificate

active

06555535

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a group of tricyclic sulfonamide compounds and derivatives which inhibit matrix metalloproteinase enzymes and thus are useful for treating diseases resulting from tissue breakdown, such as heart disease, multiple sclerosis, arthritis, atherosclerosis, and osteoporosis.
BACKGROUND OF THE INVENTION
Matrix metalloproteinases (sometimes referred to as MMPs) are naturally-occurring enzymes found in most mammals. Over-expression and activation of MMPs or an imbalance between MMPs and inhibitors of MMPs have been suggested as factors in the pathogenesis of diseases characterized by the breakdown of extracellular matrix or connective tissues.
Stromelysin-1 and gelatinase A are members of the matrix metalloproteinases (MMP) family. Other members include fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8), gelatinase B (92 kDa gelatinase) (MMP-9), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), matrilysin (MMP-7), collagenase 3 (MMP-13), TNF-alpha converting enzyme (TACE), and other newly discovered membrane-associated matrix metalloproteinases (Sato H., Takino T., Okada Y., Cao J., Shinagawa A., Yamamoto E., and Seiki M.,
Nature,
1994;370:61-65). These enzymes have been implicated with a number of diseases which result from breakdown of connective tissue, including such diseases as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation which leads to restenosis and ischemic heart failure, and tumor metastasis. A method for preventing and treating these and other diseases is now recognized to be by inhibiting metalloproteinase enzymes, thereby curtailing and/or eliminating the breakdown of connective tissues that results in the disease states.
The catalytic zinc in matrix metalloproteinases is typically the focal point for inhibitor design. The modification of substrates by introducing zinc chelating groups has generated potent inhibitors such as peptide hydroxamates and thiol-containing peptides. Peptide hydroxamates and the natural endogenous inhibitors of MMPs (TIPs) have been used successfully to treat animal models of cancer and inflammation. MMP inhibitors have also been used to prevent and treat congestive heart failure and other cardiovascular diseases, U.S. Pat. No. 5,948,780.
There is a need to discover new low molecular weight compounds that are potent inhibitors of MMP enzymes without causing undesired side effects in animals. McClure recently described a series of arylsulfonyl hydroxamic acid derivatives that are said to be useful as broad spectrum MMP inhibitors (see WO 98/34918). We now have discovered a series of tricyclic sulfonamides that are especially potent MMP inhibitors with little or no toxic effects.
SUMMARY OF THE INVENTION
This invention provides a group of tricyclic sulfonamide compounds that are inhibitors of matrix metalloproteinase enzymes, and especially MMP-13. The invention is more particularly directed to compounds defined by Formula I
or a pharmaceutically acceptable salt thereof,
wherein:
the sulfur atom bearing (O)
q
is bonded to the benzo ring at position a or position b;
R
1
and R
2
independently are hydrogen, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl, or (CH
2
)
t
aryl;
R
3
is NHOH or OR
4
;
R
4
is H, C
1
-C
6
alkyl, or (CH
2
)
t
aryl;
X is O or S(O)
n
;
each n and q independently are 0, 1, or 2;
m is 0, 1, or 2;
p is 0,1,2, or 3;
each t is an integer from 0 to 6; and
— is absent or is a bond.
Another invention embodiment is a compound of Formula II
or a pharmaceutically acceptable salt thereof,
wherein R
1
and R
2
independently are H or C
1
-C
6
alkyl;
R
3
is NHOH or OH;
the sulfonyl diradical is bonded to the benzo ring at position a or position b;
n is 0,1,or 2;
p is 1 or 2; and
— is absent or is a bond.
Another invention embodiment is a compound of Formula III
or a pharmaceutically acceptable salt thereof,
wherein R
1
and R
2
independently are H or C
1
-C
6
alkyl;
R
3
is NHOH or OH;
the sulfonyl diradical is bonded to the benzo ring at position b;
n is 0, 1, or 2;
p is 1 or 2; and
— is absent or is a bond.
Another invention embodiment is a compound of Formulas II or III wherein R
3
is OH.
Another invention embodiment is a compound of Formulas II or III wherein R
3
is NHOH.
Another invention embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, selected from:
(S)-2,2-Dimethyl-4-(6,7,8,9-tetrahydro-dibenzofuran-3-sulfonyl)-thiomorpholine-3-carboxylic acid 1,1-dimethyl ester;
(S)-2,2-Dimethyl-4-(6,7,8,9-tetrahydro-dibenzofuran-3-sulfonyl)-thiomorpholine-3-carboxylic acid;
(S)-2,2-Dimethyl-4-(6,7,8,9-tetrahydro-dibenzofuran-3-sulfonyl)-thiomorpholine-3-carboxylic hydroxamide;
4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]indene-6-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
2,2-Dimethyl-4-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulene-2-sulfonyl)thiomorpholine-3-carboxylic acid hydroxyamide;
4-(5,6,7,8,9,10-Hexahydro-11-oxa-cycloocta[a]indene-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-2,2-Dimethyl-1,1-dioxo-4-(6,7,8,9-tetrahydro-dibenzofuran-3-sulfonyl)-1l
6
-thiomorpholine-3-carboxylic acid hydroxyamide;
4-(2,3-Dihydro-1H-8-oxa-cyclopenta[a]indene-6-sulfonyl)-2,2-dimethyl-1,1-dioxo-1l
6
-thiomorpholine-3-carboxylic acid hydroxyamide;
2,2-Dimethyl-1,1-dioxo-4-(6,7,8,9-tetrahydro-5H-10-oxa-benzo[a]azulene-2-sulfonyl)-1l
6
-thiomorpholine-3-carboxylic acid hydroxyamide; and
4-(5,6,7,8,9,10-Hexahydro-11-oxa-cycloocta[a]indene-2-sulfonyl)-2,2-dimethyl-1,1-dioxo-1l
6
-thiomorpholine-3-carboxylic acid hydroxyamide.
A further embodiment of this invention is a pharmaceutical composition, comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable carrier, excipient, or diluent.
Another invention embodiment is a pharmaceutical composition, comprising a compound of Formula II, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable carrier, excipient, or diluent.
Another invention embodiment is a pharmaceutical composition, comprising a compound of Formula III, or a pharmaceutically acceptable salt thereof, admixed with a pharmaceutically acceptable carrier, excipient, or diluent.
Another embodiment of this invention is a method for inhibiting an MMP enzyme in an animal, comprising administering to the animal an MMP enzyme inhibiting amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
A further embodiment is a method for treating a disease mediated by an MMP enzyme, comprising administering to a patient suffering from such disease an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a method for treating a cancer, comprising administering to a patient suffering from such a disease an anticancer effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a method for treating breast carcinoma, comprising administering to a patient suffering from such a disease an anticancer effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a method for treating a rheumatoid arthritis, comprising administering to a patient suffering from such a disease an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a method for treating a osteoarthritis, comprising administering to a patient suffering from such a disease an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof.
Another invention embodiment is a method for treating a heart failure, comprising administering to a patient suffering from such a disease an effective amount of a compound of Formula I, or a

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