Sulfonamide matrix metalloproteinase inhibitors

Details Sulfonamide matrix metalloproteinase inhibitors Sulfonamide matrix metalloproteinase inhibitors

2002-02-08

2003-05-06

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

06559142

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a group of cyclic sulfonamide compounds and derivatives that 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 gel atinase A are members of the 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., Seiki M.,
Nature,
1994;370:61-65). These enzymes have been implicated in 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 (TIMPs) 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. For example, see U.S. Pat. No. 5,948,780.
The need to find new low-molecular weight compounds that are potent MMP inhibitors, and that have an acceptable therapeutic index of toxicity/potency to make them amenable for clinical use in the prevention and treatment of the associated disease states, continues. An object of this invention is to provide a group of MMP inhibitors characterized as being sulfonamides bearing a tricyclic aromatic or heteroaromatic substituent.
SUMMARY OF THE INVENTION
This invention provides a group of tricyclic substituted sulfonamide compounds that are inhibitors of matrix metalloproteinase enzymes. The invention is more particularly directed to compounds defined by Formula I
or the pharmaceutically acceptable salts thereof wherein:
R
1
and R
2
independently are hydrogen or C
1
-C
6
alkyl;
R
3
and R
4
independently are hydrogen, halo, nitro, NR
5
R
6
, C
1
-C
6
alkyl, C
2
-C
6
alkenyl, C
2
-C
6
alkynyl; (CH
2
)
m
OH, (CH
2
)
m
OR
5
, (CH
2
)
m
cycloalkyl, (CH
2
)
m
aryl, (CH
2
)
m
substituted aryl, (CH
2
)
m
heteroaryl, (CH
2
)
m
substituted heteroaryl, (CH
2
)
m
carbocycle, (CH
2
)
m
heterocycle; (CH
2
)
m
NR
5
R
6
, (CH
2
)
m
COR
5
, (CH
2
)
m
CONR
5
R
6
, or (CH
2
)
m
CO
2
R
5
;
m is an integer from 0 to 6;
R
5
and R
6
independently are hydrogen or C
1
-C
6
alkyl, or taken together with the nitrogen to which they are attached complete a 3- to 7-membered ring;
Z is (CH
2
)
n
;
n is 0, 1, or 2;
Y is S, SO, or SO
2
;
X is OH or NHOH;
V is O, S, SO
2
, NH, NR
5
, or CH
2
.
Another invention embodiment is a compound of Formula II
or a pharmaceutically acceptable salt thereof, wherein R
1
, R
2
, R
3
, V, and X are as defined above.
Another invention embodiment is a compound of Formula II, or a pharmaceutically acceptable salt thereof, wherein R
3
is halo.
Another invention embodiment is a compound of Formulas I or II, or a pharmaceutically acceptable salt thereof, wherein X is OH.
Another invention embodiment is a compound of Formulas I or II, or a pharmaceutically acceptable salt thereof, wherein X is NHOH.
Another invention embodiment is a compound of Formula III
or a pharmaceutically acceptable salt thereof, wherein R
1
, R
2
, R
3
, and X are as defined above.
Another invention embodiment is a compound of Formula IV
or a pharmaceutically acceptable salt thereof, wherein R
1
, R
2
, R
3
, and X have the above defined meanings.
Another invention embodiment is a compound of Formula V
or a pharmaceutically acceptable salt thereof, wherein R
1
, R
2
, R
3
, and X are as defined above.
Another invention embodiment is a compound of Formula VI
or a pharmaceutically acceptable salt thereof, wherein R
1
, R
2
, R
3
, and X are as defined above.
Another invention embodiment is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein Y is SO
2
.
Another invention embodiment is a compound of Formula VII
or a pharmaceutically acceptable salt thereof, wherein V, Z, X, R
1
, and R
2
are as defined above for Formula I.
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 any one of Formulas II through VII, 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 selected from:
(S)-4-(Dibenzofuran-3-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-4-(Dibenzofuran-3-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
R-3-(Dibenzofuran-3-sulfonyl)-5,5-dimethyl-thiazolidine-4-carboxylic acid;
R-3-(Dibenzofuran-3-sulfonyl)-5,5-dimethyl-thiazolidine-4-carboxylic acid hydroxyamide;
(S)-4-(9H-Fluorene-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-4-(9H-Fluorene-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-4-(Dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-4-(Dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-4-(7-Bromo-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-4-(7-Bromo-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-4-(7-Methoxycarbonyl-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-4-(7-Methoxycarbonyl-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-2,2-Dimethyl-4-(7-nitro-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylic acid;
(S)-2,2-Dimethyl-4-(7-nitro-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-4-(Dibenzofuran-2-sulfonyl)-2,2-dimethyl-1,1-dioxo-thiomorpholine-3-carboxylic acid hydroxyamide;
(S)-4-(7-Isobutyrylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-2,2-Dimethyl-4-[7-(3-phenyl-propionylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylic acid;
(S)-2,2-Dimethyl-4-[7-(4-methyl-pentanoylamino)-dibenzofuran-2-sulfonyl]-thiomorpholine-3-carboxylic acid;
(S)-4-(7-Benzoylamino-dibenzofuran-2-sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-2,2-Dimethyl-4-(7-propionylamino-dibenzofuran-2-sulfonyl)-thiomorpholine-3-carboxylic acid;
(S)-4-[7-(3-Ethyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-4-[7-(3-Isopropyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-dimethyl-thiomorpholine-3-carboxylic acid;
(S)-2,2-Dimethyl-4-[7-(3-phenyl-ureido)-dibenzofuran-2-sulfonyl]-2,2-

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