Organic compounds -- part of the class 532-570 series – Organic compounds – Hydroxamic acids – chalcogen analogs or salts thereof
Patent
1997-12-19
1999-06-29
Burn, Brian M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Hydroxamic acids, chalcogen analogs or salts thereof
562621, 514575, A01N 3728
Patent
active
059170905
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to therapeutically active hydroxamic 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 TO 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.
Metalloproteinases are characterised by the presence in the structure of a zinc(ll) ion 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 (L. M. Matrisian, Trends in Genetics, 1990, 6, 121-125).
Many known MMP inhibitors are peptide derivatives, based on naturally occurring amino acids, and are analogues of the cleavage site in the collagen molecule. 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 active site zinc(ll) 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.
A known class of pseudopeptide or peptide mimetic MMP inhibitors have a hydroxamic acid group as their zinc binding group. 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) 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-231081 (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 (Glycomed)
WO 92/17460 (SmithKline Beecham)
EP-A-0489577 (Celltech)
EP-A-0489579 (Celltech)
EP-A-0497192 (Roche)
US 5256657 (Sterling Winthrop)
WO 92/13831 (British Bio-technology)
WO 92/22523 (Research Corporation Technologies)
WO 93/09090 (Yamanouchi)
WO 93/09097 (Sankyo)
WO 93/20047 (British Bio-technology)
WO 93/24449 (Celltech)
WO 93/24475 (Celltech)
EP-A-0574758 (Roche)
WO 94/02447 (British Biotech)
WO 94/02446 (British Biotech)
______________________________________
hydroxamic derivatives disclosed in the above publications against
particular MMPs can be high. For example, many have a collagenase
IC.sub.50 by the in vitro test method of Cawston and Barrett, (Anal.
Biochem., 99, 340-345, 1979) of less than 50 nM. Also, compounds are known
which have high broad spectum intrinsic activities against the main MMP
groups, namely the collagenases, gelatinases, stromelysins and PUMP.
Unfortunately howev
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Huxley Philip
Martin Fionna Mitchell
Miller Andrew
Spavold Zoe Marie
British Biotech Pharmaceuticals Ltd.
Burn Brian M.
Davis Brian J.
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