Butyric acid matrix metalloproteinase inhibitors

Details Butyric acid matrix metalloproteinase inhibitors Butyric acid matrix metalloproteinase inhibitors

1998-10-27

2000-02-01

McKane, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

549460, 549461, A61K 3134, C07D30791

Patent

active

060203668

DESCRIPTION:

BRIEF SUMMARY
FIELD OF INVENTION

This invention relates to a group of butyric acid derivatives which inhibit matrix metalloproteinase enzymes and thus are useful for treating diseases resulting from tissue breakdown, such as arthritis and osteoporosis.


BACKGROUND OF THE INVENTION

Matrix metalloproteinases are naturally occurring enzymes found in most mammals and are associated with the breakdown of connective tissues. The class includes gelatinase A and B, stromelysin-1, fibroblast collagenase, neutrophil collagenase, matrilysin, and other forms of collagenase. These enzymes have been implicated with a number of diseases which result from breakdown of connective tissue, such 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 diseases is now recognized to be by inhibiting metalloproteinase enzymes, thereby curtailing and eliminating the breakdown of connective tissues that results in the disease states.
Several inhibitors of metalloproteinases have been identified. Many inhibitors are complex peptides, for instance as described by Chapman, et al., in J. Med. Chem., 1993;36:4293-4301. Small peptide inhibitors are also known, for example as described in U.S. Pat. Nos. 4,599,361 and 5,270,326, as well as nonpeptides as in WO 95/35276.
The need continues for small molecular weight molecules which can be economically prepared and yet are effective inhibitors of metalloproteinases. We have now discovered a group of butyric acid derivatives which have exceptionally good inhibitory activity. An object of this invention is to provide such compounds, their pharmaceutical formulations, and a method for using them to treat diseases mediated by metalloproteinases.


SUMMARY OF THE INVENTION

This invention provides butyric acid derivatives which are inhibitors of matrix metalloproteinases. The invention compounds have Formula I ##STR2## wherein:
X is O, NOR.sub.9, S, OH, SH, or ##STR3##
R.sub.7 and R.sub.7a independently are
R.sub.1 and R.sub.2 independently are
R.sub.6 is hydrogen,
aryl is phenyl or substituted phenyl;
R.sub.3 is hydroxy,
R.sub.4 and R.sub.5 independently are hydrogen,
or one of R.sub.4 and R.sub.5 is hydrogen and the other is: ##STR4## S(O).sub.1 or 2 -C.sub.1 -C.sub.20 alkyl or substituted alkyl, S(O).sub.1 or 2 -aryl
Y is ##STR5##
R.sub.8 and R.sub.9 independently are
W, W.sup.1, Z, and Z.sup.1 independently are CR.sub.1 or N;
the term ##STR6## is a double bond when X is O, S, NOR.sub.9, or
N-NR.sub.7 R.sub.7a, and a single bond when X is OH or SH; and the pharmaceutically acceptable salts, isomers, stereoisomers, and solvates thereof.
Preferred compounds are defined by Formula II ##STR7## wherein R.sub.1, R.sub.2, R.sub.3 R.sub.4, R.sub.5, and X are as defined above.
Further preferred compounds have the formula ##STR8## and especially preferred are those wherein X is O, and R.sub.3 is hydroxy. The most preferred compounds of the invention are in this latter group where R.sub.4 is hydrogen, and R.sub.5 is COR.sub.8, COOR.sub.8, or CONR.sub.8 R.sub.9, where R.sub.8 and R.sub.9 are alkyl or substituted alkyl, aryl or substituted aryl.
A further embodiment of this invention is a pharmaceutical formulation comprising a compound of Formula I admixed with a pharmaceutically acceptable carrier, excipient, or diluent therefor.
The invention additionally provides a method for inhibiting the hydrolytic activity of a matrix metalloproteinase enzyme comprising administering to a mammal an effective amount of a compound of Formula I. In a preferred embodiment, the invention is a method for inhibiting or treating multiple sclerosis, atherosclerotic plaque rupture, aortic aneurysms, heart failure, restenosis, periodontal disease, corneal ulceration, cancer metastasis, tumor angiogenesis, arthritis, and for wound healing.


DETAILED DESCRIPTION OF THE INVENTION

As used herei

REFERENCES:
patent: 4528282 (1985-07-01), Preston et al.
patent: 5665764 (1997-09-01), Hupe et al.
PCT International Search Report, PCT/US97/12389, 1998.
PCT International Preliminary Examination Report, PCT/US97/12389, 1998.

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