Metalloproteinase inhibitors

Details Metalloproteinase inhibitors Metalloproteinase inhibitors

1998-05-22

2000-10-03

Rotman, Alan L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Nitrogen containing compound doai

514740, 514741, 562621, 562622, 548545, A61K 3104, A61K 3102, C07D20740

Patent

active

061274275

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to therapeutically active hydroxamic acid. N-formyl-N-hydroxyamino and carboxylic acid derivatives, to processes for their preparation, to pharmaceutical compositions containing them, and to the use of such compounds in medicine. In particular, the compounds are inhibitors of metalloproteinases involved in tissue degradation, and in addition are inhibitors of the release of tumour necrosis factor from cells.


BACKGROUND OF THE INVENTION

Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown such as collagenase, stromelysin and gelatinase (known as "matrix metalloproteinases", and herein referred to as MMPs) are thought to be potentially useful for the treatment or prophylaxis of conditions involving such tissue breakdown, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis, invasion and growth. MMP inhibitors are also of potential value in the treatment of neuroinflammatory disorders, including those involving myelin degradation, for example multiple sclerosis, as well as in the management of angiogenesis dependent diseases, which include arthritic conditions and solid tumour growth as well as psoriasis, proliferative retinopathies, neovascular glaucoma, ocular tumours, angiofibromas and hemangiomas. However, the relative contributions of individual MMPs in any of the above disease states is not yet fully understood.
Metalloproteinases are characterised by the presence in the structure of a zinc(II) ionic site at the active site. It is now known that there exists a range of metalloproteinase enzymes that includes fibroblast collagenase (Type 1), PMN-collagenase, 72 kDa-gelatinase, 92 kDa-gelatinase, stromelysin, stromelysin-2 and PUMP-1 (J. F. Woessner, FASEB J, 1991, 5, 2145-2154). Many known MMP inhibitors are peptide derivatives, based on naturally occuring amino acids, and are analogues of the cleavage site in the collagen molecule. Chapman et al. (J. Med. Chem. 1993, 36, 4293-4301) report some general structure/activity findings in a series of N-carboxyalkyl peptides. Other known MMP inhibitors are less peptidic in structure, and may more properly be viewed as pseudopeptides or peptide mimetics. Such compounds usually have a functional group capable of binding to the zinc (II) site in the MMP, and known classes include those in which the zinc binding group is a hydroxamic acid, carboxylic acid, sulphydryl, and oxygenated phosphorus (eg phosphinic acid and phosphonamidate including aminophosphonic acid) groups.
Three known classes of pseudopeptide or peptide mimetic MMP inhibitors have a hydroxamic acid group, N-formyl-N-hydroxyamino or a carboxylic group respectively as their zinc binding groups. With a few exceptions, such known MMPs may be represented by the structural formula (I) ##STR2## in which X is the zinc binding hydroxamic acid (--CONHOH), N-formyl-N-hydroxyamino (--NH(OH)CHO) or carboxylic acid (--COOH) group and the groups R.sub.1 to R.sub.5 are variable in accordance with the specific prior art disclosures of such compounds. Examples of patent publications disclosing such structures are given below.
In such compounds, it is generally understood in the art that variation of the zinc binding group and the substituents R.sub.1, R.sub.2 and R.sub.3 can have an appreciable effect on the relative inhibition of the metalloproteinase enzymes. The group X interacts with metalloproteinase enzymes by binding to a zinc(II) ion in the active site. Generally the hydroxamic acid group is preferred over the carboxylic acid group in terms of inhibitory activity against the various metalloproteinase enzymes. However, the carboxylic acid group in combination with other substituents can provide selective inhibition of gelatinase (EP-489,577-A). The R.sub.1, R.sub.2 and R.sub.3 groups are believed to occupy respectively the P1, P1' and P2' amino acid side chain binding sites for the natural en

REFERENCES:
patent: 4599361 (1986-07-01), Dickens et al.
patent: 5691382 (1997-11-01), Crimmin et al.

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