Peptidyl compounds

Details Peptidyl compounds Peptidyl compounds

1999-05-20

2001-01-30

Celsa, Bennett (Department: 1627)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

C514S002600, C260S998200, C260S998210, C530S868000, C424S185100

Reexamination Certificate

active

06180611

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to a novel class of peptidyl derivatives, to processes for their preparation, and to their use in medicine.
BACKGROUND TO THE INVENTION
In normal tissues, cellular connective tissue synthesis is offset by extracelluar matrix degradation, the two opposing effects existing in dynamic equilibrium. Degradation of the matrix is brought about by the action of proteinases released from resident connective tissue cells and invading inflammatory cell, and is due, in part, to the activity of at least three groups of metalloproteinases. These are the collagenases (interstitial collagenase, MMP-1; PMN collagenase, MMP-8, collagenase-3, MMP13), the gelatinases (gelatinase A, MMP-2, 72 kDa-gelatinase, Type IV collagenase; gelatinase B, MMP-9, 92 kDa-gelatinase, Type IV collagenase) and the stromelysins (proteoglycanase, MMP-3, stromelysin-1, transin; stromelysin-2, MMP:10; stromelysin-3, MMP:11). Normally these catabolic enzymes are tightly regulated at the level of their synthesis and secretion and also at the level of their extracellular activity, the latter through the action of specific inhibitors, such as TIMP (tissue inhibitors of metalloproteinase), which form inactive complexes with metalloproteinases, and more general proteinase inhibitors such as a
2
-macroglobulins.
The accelerated, uncontrolled breakdown of connective tissues by metalloproteinase catalysed resorption of the extracellular matrix is a feature of many pathological conditions such as rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration; tumour metastasis or invasion; periodontal disease, proteinuria, coronary thrombosis associated with atherosclerotic plaque rupture and bone disease. The inhibitors claimed herein may also be useful in preventing the pathological squaelae following a traumatic injury that could lead to a permanent disability. These compounds may also have utility as a means for birth control by preventing ovulation or implantation. It can be expected that the pathogenesis of such diseases is likely to be modified in a beneficial manner by the administration of metalloproteinase inhibitors and numerous compounds have been suggested for this purpose [for a general review see R C Wahl, et al Ann. Rep, Med. Chem. 25: 175-184, Academic Press Inc., San Diego (1990)].
A number of small peptide like compounds which inhibit metalloproteinases have been described. Perhaps the most notable of these are those relating to angiotensin converting enzyme (ACE) where such agents act to block the conversion of the decapeptide angiotensin I to angiotensin II, a potent pressor substance. Compounds of this type are described in EP-A-0012401. Also, related mercaptoamide peptidyl derivatives have shown ACE inhibitor activity in vitro and in vivo (H N Weller et al (1984), Biochem Biophys. Res. Comm., 125 (1):82-89).
TNF&agr; is a cytokine which is produced initially as a cell-associated 28 kD precursor. It is released as an active, 17 kD form (D-M Jue 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&agr; can be lethal. There is considerable evidence from animal model studies that blocking the effects of TNF&agr; with specific antibodies can be beneficial in acute infections, shock states, graft versus host reactions and autoimmune disease. TNF&agr; is also an autocrine growth factor for some myelomas and lymphomas and can act to inhibit normal heamatopoiesis in patients with these tumours.
Preventing the production or action of TNF&agr; 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 (1998) 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, 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&agr; 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&agr; gene transcription (Endres S. (1991) Immunol. 72:56-60, Schandene et al (1992), Immunol. 76:30-34, Alegre ML, et al (1991); Transplantation 52:674-679, Bianco et al (1991) Blood 78:1205-1221). Thalidomide has also been shown to inhibit TNF&agr; production by leucocytes (Sampajo et al (1991), J. Exp. Med. 173:699-703). In experimental settings, anti-TNF&agr; monoclonal antibodies, soluble TNF receptors and soluble TNF receptor/immunoadhesins have been shown to specifically inhibit the effects of TNF&agr; 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&agr; and TNF&bgr;. 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 &agr; and peptides having a high degrees of sequence homology with, or substantially similar physiological effects to, TNF&agr;, for example TNF&bgr;. One of the objectives of the present invention is to provide compounds which substantially inhibit the release of TNF from cells, and therefore may be used in the treatment of conditions mediated by TNF. Such uses include, but are not limited to, the treatment of inflammation, fever, cardiovascular effects, haemorrhage, coagulation and cute phase response, cachexia and anorexia, acute infections, shock states, graft versus host reactions and autoimmune disease.
Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown such as collagenase, stromelysin and gelatinase have been shown to inhibit the release of TNF both in vitro and in vivo (AJH Gearing et al (1994), Nature, 370:555-557; GM McGeehan et al (1994), Nature, 370:558-561: MJ Crimmin et al, WO 93/20047). All of these reported inhibitors contain a hydroxamic acid zinc binding group.
It is, therefore, a further objective of this invention to provide compounds which, in addition to inhibiting TNF release, also inhibit the action of MMPs, and hence may be used in the treatment of patients who suffer from conditions mediated by TNF and/or MMPs.
As appreciated by those of skill in the art the significant proportion of homology between human fibroblast collagenase, stromelysin and gelatinase leads to the possibility that a compound that inhibits one enzyme may to some degree inhibit all of them.
Compounds that inhibit collagenase, which possess structural portions akin to those of the instant invention include those encompassed by U.S. Pat. No. 4,511,504 issued Apr. 16, 1985; U.S. Pat. No. 4,568,666, issued Feb. 4, 1986.
Compounds of related structure that are claimed

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