Hydroxamic acid derivatives as inhibitors of cytokine production

Details Hydroxamic acid derivatives as inhibitors of cytokine production Hydroxamic acid derivatives as inhibitors of cytokine production

1996-10-28

1998-10-13

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514575, 549 62, 562621, 562623, C07D33334, C07C32360, C07C31744, A61K 3116

Patent

active

058212620

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/GB94/02145 filed Oct. 4, 1994.
This 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 the release of tumour necrosis factor (TNF) from cells, and inhibitors of metalloproteinases involved in tissue degradation.
TNF is a cytokine which is produced initially as a cell-associated 28 kD precursor. It is released as an active, 17 kD form (Jue, D-M et al., (1990) Biochemistry 29:8371-8377), 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 tumours.
Preventing the production or action of TNF is, therefore, predicted to be a potent therapeutic strategy for many inflammatory, infectious, immunological or malignant diseases. These include, but are not restricted to, septic shock, haemodynamic shock and sepsis syndrome (Mathison et al. (1988) J. Clin. Invest. 81:1925-1937; Miethke et al. (1992) J. Exp. Med. 175:91-98), post ischaemic reperfusion injury, malaria (Grau et al., (1989) Immunol. Rev. 112:49-70); mycobacterial infection (Barnes et al. (1992) Infect. Imm. 60:1441-6), meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer, autoimmune disease, inflammatory bowel disease (eg Crohn's disease), rheumatoid arthritis, multiple sclerosis, radiation damage, toxicity following administration of immunosuppressive monoclonal antibodies such as OKT3 or CAMPATH-1 and hyperoxic alveolar injury.
Current clinical anti-TNF strategies involve the use of corticosteroids such as dexamethasone, and the use of cyclosporin-A or FK506, which are non-specific inhibitors of cytokine gene transcription. Phosphodiesterase inhibitors such as pentoxyfilline have been shown to be more specific inhibitors of TNF gene transcription (Endres S et al. (1991) Immunol. 72:56-60, Schandene et al. (1992) Immunol. 76:30-34, Alegre M L, et al. (1991); Transplantation 52:674-679, Bianco et al. (1991) Blood 78:1205-1211). Thalidomide has also been shown to inhibit TNF production by leucocytes (Sampajo et al, (1991) J. Exp. Med. 173:699-703). In experimental settings, anti-TNF monoclonal antibodies, soluble TNF receptors and soluble TNF receptor/immunoadhesins have been shown to specifically inhibit the effects of TNF action (Bagby et al. (1991) J. Infect. Dis. 163:83-88, Charpentier et al. (1991) Presse-med. 20:2009-2011, Silva et al. (1990) J. Infect. Dis. 162:421-427; Franks et al. (1991) Infect. Immun. 59:2609-2614, Tracey et al. (1987) Nature 330:662-664; Fischer et al. (1992) PNAS USA in press, Lesslauer et al. (1991) Eur. J. Immunol. 21:2883-2886, Ashkenazi et al. (1991) PNAS USA 88:10535-10539)
It has recently been shown that the effects of TNF are mediated by two peptides, TNF.alpha. and TNF.beta.. Although these peptides have only 30% homology with each other, they activate the same receptors and are encoded by immediately adjacent genes. As used herein, the term tumour necrosis factor or TNF therefore means tumour necrosis factor .alpha. and peptides having a high degree of sequence homology with, or substantially similar physiological effects to, TNF.alpha., for example TNF.beta..
It is an object of the present invention to provide compounds which substantially inhibit the release of TNF fr

REFERENCES:
patent: 4996358 (1991-02-01), Handa et al.
patent: 5300501 (1994-04-01), Porter et al.
patent: 5300674 (1994-04-01), Crimmin et al.
patent: 5310763 (1994-05-01), Campion et al.

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