Derivatives of succinamide and their use as metalloproteinase in

Details Derivatives of succinamide and their use as metalloproteinase in Derivatives of succinamide and their use as metalloproteinase in

1997-10-07

1998-11-24

Geist, Gary

Organic compounds -- part of the class 532-570 series

Organic compounds

Fatty compounds having an acid moiety which contains the...

562441, 562623, C07C23100, C07C22900, A61K 3116

Patent

active

058409394

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to therapeutically active hydroxamic acid 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. Some of the compounds of the invention are, in addition, inhibitors of the release of tumour necrosis factor from cells.


BACKGROUND TO THE INVENTION

Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown such as collagenases, stromelysins and/or gelatinases (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.
Metalloproteinases are characterised by the presence in the structure of a zinc(II) ionic site. It is now known that there exists a range of metalloproteinase enzymes that includes human fibroblast collagenase (Type 1), PMN-collagenase, 72 kDa-gelatinase, 92 kDa-gelatinase, stromelysin-1, 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. A paper by Chapman et. al. (J. Med. Chem. 1993, 36, 4293-4301) reports 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.
Two known classes of pseudopeptide or peptide mimetic MMP inhibitors have a hydroxamic acid group and 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) 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 is thought to interact 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 enzyme substrate. There is evidence that a larger R.sub.1 substituent can enhance activity against stromelysin, and that a (C.sub.1 -C.sub.6)alkyl group (

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