Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1996-11-22
2000-02-22
Dees, Jose G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
514613, 514614, 514615, 514620, 514902, 514825, 514925, 514575, 514576, 530331, 530335, 530336, 562400, 562495, 562623, 562543, A61K 3119, A61K 31181, A61K 3116, C07C 5131
Patent
active
060281103
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 gelatinases, which are metalloproteinases involved in tissue degradation.
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. 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 (L. M. Matrisian, Trends in Genetics, 1990, 6, 121-125).
The precise role of each of the various types of MMP in mediating different clinical disease conditions is not understood at present. However, there is some evidence that for some clinical end points individual MMP types may have a greater causative role than others. For the treatment of conditions mediated mainly by one MMP type, clearly it would be desirable to use an MMP inhibitor which selectively inhibited that MMP, or at least was significantly more potent as an inhibitor of that MMP than of other MMP types.
Many known MMP inhibitors are peptide derivatives, based on naturally occurring amino acids, and are analogues of the cleavage site in the collagen molecule. A recent 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 having a functional group capable of binding to the active site zinc (II) ion 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 phosphonic acid) groups.
Three known classes of pseudopeptide or peptide mimetic MMP inhibitors have a hydroxamic acid group, an N-formyl-N-hydroxyamino, and a carboxylic acid group respectively as their zinc binding groups. With a few exceptions, such known MMPs may be represented by the structural formula (IA) ##STR2## in which X is the zinc binding hydroxamic acid (--CONHOH), N-formyl-N-hydroxyamino (--N(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. The following patent publications disclose hydroxamic acid-based MMP inhibitors:
______________________________________ US 4599361 (Searle)
EP-A-2321081 (ICI)
EP-A-0236872 (Roche)
EP-A-0274453 (Bellon)
WO 90/05716 (British Bio-technology)
WO 90/05719 (British Bio-technology)
WO 91/02716 (British Bio-technology)
WO 92/09563 (Glycomed)
US 5183900 (Glycomed)
US 5270326 (Gly
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Beckett Raymond Paul
Martin Fionna Mitchell
Miller Andrew
Whittaker Mark
British Biotech Pharmaceuticals Ltd.
Dees Jos,e G.
Qazi Sabiha N.
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