Hydroxamic acid derivatives as metalloproteinase inhibitors

Details Hydroxamic acid derivatives as metalloproteinase inhibitors Hydroxamic acid derivatives as metalloproteinase inhibitors

1995-12-01

1997-07-29

Conrad, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Ester doai

562623, 560158, 549 76, 548131, A61K 31215, C07C26900, C07D27106, C07D33322

Patent

active

056522622

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 are in addition inhibitors of the release of tumour necrosis factor from cells.


BACKGROUND TO THE INVENTION

There is evidence that 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 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.
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 (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 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 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, sulphydril, and oxygenated phosphorus (eg phosphinic acid and phosphonic acid) groups.
The following patent publications published prior to the first claimed priority date of this application disclose hydroxamic acid-based MMP inhibitors:


______________________________________ US 4599361 (Searle) EP-A-0231081 (ICI) EP-A-0236872 (Roche) EP-A-0274453 (Bellon) WO 90/05716 (British Bio-technology Ltd ("BBL")) WO 90/05719 (BBL) WO 91/02716 (BBL) WO 92/09563 (Glycomed) EP-A-0497192 (Roche) WO 92/13831 (BBL) EP-A-0489577 (Celltech) EP-A-0489579 (Celltech) WO 92/22523 (Research Corporation Technologies) ______________________________________
The following patent publications published after the first claimed priority date of this application, but before its filing date, also relate to hydroxamic acid-based MMP inhibitors:


______________________________________ US 6256657 (Sterling Winthrop) WO 93/09090 (Yamanouchi) WO 93/09097 (Sankyo) WO 93/20047 (BBL) WO 93/21942 (BBL) WO 93/24449 (Celltech) WO 93/24475 (Celltech) EP-A-0574758 (Roche) WO 94/02446 (BBL) WO 94/02447 (BBL) ______________________________________
The intrinsic potency of compounds within the broad structural groups of 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. Unfortunately, however, the pharmacokinetic properties of the specific compounds disclosed in those publications have generally been disappointing. Identifying hydroxamic acid-based MMP inhibitors having a good balance of high intrinsic activity and good pharmacokinetic properties, for example prolonged effective plasma concentrations following oral dosing such that the compounds have high in vivo activity in target diseases or conditions such as rheumatoid or osteoarthritis, or cancer, remains a much sought after goal in the art.
With a few exceptions, the hydroxamic acid derivatives disclosed in the above pub

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