Natural amino acid derivatives as metalloproteinase inhibitors

Details Natural amino acid derivatives as metalloproteinase inhibitors Natural amino acid derivatives as metalloproteinase inhibitors

1995-01-23

1997-07-01

Carr, Deborah D.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

562623, A01N 3728

Patent

active

056439644

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB93/01556 filed Jul. 23, 1993.
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.
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 metalioproteinases", 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 turnour metastasis, invasion and growth.
Tumour necrosis factor (herein referred to as "TNF") is a cytokine which is produced initially as a cell-associated 28 kD precursor. It is released as an active, 17 kD form, which can mediate a large number of deleterious effects in vivo. When administered to animals or humans it causes inflammation, fever, cardiovascular effects, haemorrhage, coagulation and acute phase responses. similar to those seen during acute infections and shock states. Chronic administration can also cause cachexia and anorexia. Accumulation of excessive TNF can be lethal.
There is considerable evidence from animal model studies that blocking the effects of TNF with specific antibodies can be beneficial in acute infections, shock states, graft versus host reactions and autoimmune disease. TNF is also an autocrine growth factor for some myelomas and lymphomas and can act to inhibit normal haematopoiesis in patients with these turnours.
Compounds which inhibit the production or action of TNF are therefore thought to be potentially useful for the treatment or prophyiaxis of many inflammatory, infectious, immunological or malignant diseases. These include, but are not restrictecd to, septic shock, haemodynamic shock and sepsis syndrome, post ischaemic reperfusion injury, malaria, Crohn's disease, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer, autoimmune disease, rneumatoid arthritis, multiple sclerosis, radiation damage, toxicity following administration of immunosuppressive monoclonal antibodies such as OKT3 or CAMPATH-1 and hyperoxic alveolar injury.
Since excessive TNF production has been noted in several diseases or conditions also characterised by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may have particular advantages in the treatment or prophylaxis of diseases or conditions in which both mechanisms are involved.
Several classes of MMP inhibitors have been proposed, including derivatives of hydroxamic acid. The following patent publications disclose hydroxamic acid-based MMP inhibitors:
U.S. Pat. No. 4,599,361 (Searle)
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)
EP-A-0489577 (Celltech)
EP-A-0489579 (Celltech)
EP-A-0497192 (Roche)
WO 92/13831 (British Bio-tecnnology)
WO 92/22523 (Research Corporation Technologies)
WO 93/09090 (Yamanouchi) hydroxamic derivatives disclosed in the above publications against particular MMPs can be high. For example. many have a coliagenase IC.sub.50 by the in vitro test method of Cawston and Barrett, (Anal. Blochem., 99, 340-345, 1979) of less than 50 nM. Unfortunately. bowever, the physiochemical and/or pharmacokinetic properties of the specific compounds dislosed in those publications have generally been disappointing. Identifying hydroxamic acid-based MMP inhibitors having a good balance of high intrinsic activity against the target MMPs, and good physicochemical and/or p

REFERENCES:
patent: 3468936 (1969-09-01), van der Burg
patent: 4996358 (1991-02-01), Handa et al.
patent: 5183900 (1993-02-01), Galardy et al.
patent: 5300674 (1994-04-01), Crimmin et al.

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