Matrix metalloproteinase inhibitors

Details Matrix metalloproteinase inhibitors Matrix metalloproteinase inhibitors

2000-09-05

2001-08-21

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S562000, C514S563000, C514S575000, C548S507000, C562S426000, C562S507000, C562S556000, C562S621000

Reexamination Certificate

active

06277876

ABSTRACT:

This invention comprises new matrix metalloproteinase inhibitors, which are succinamide based hydroxamic acid or carboxylic acid thioamides. The invention further comprises processes for their preparation, pharmaceutical compositions containing them, and the use of such compounds in medicine. In particular, the compounds are inhibitors of matrix metalloproteinases involved in tissue degradation. Some of the compounds of the invention are, in addition, inhibitors of the release of tumour necrosis factor-&agr; (TNF-&agr;) from cells.
BACKGROUND OF THE INVENTION
Matrix metalloproteinases (MMPs) are a family of zinc endopeptides, which exhibit proteolytic activity towards most if not all of the constituents of the extra-cellular matrix, such as the interstitial and basement membrane collagens, fibro-nectin, and laminin. They play a key role in both physiological and pathological tissue degradation.
At least 16 different and yet highly homologous MMP-species have been characterised. They share a catalytic domain with the HisGluXaaGlyHis motif responsible for ligating zinc, which is essential for the catalytic function. MMP family members differ from each other structurally by the presence or absence of additional domains that contribute to activities, such as substrate specificity, inhibitor binding, matrix binding and cell-surface localisation. [H. Birkedal-Hansen; W. G. Moore, M. K. Bodden: C. J. Windsor; B. Birkedal-Hansen; A. DeCarlo:
Crit. Rev. Oral Biol. Med.
(1993) 4, 197-250 and A. F. Chambers; L. M. Matristan:
J. Natl. Cancer Inst.
(1997) 89(17), 1260-1270]. There are three major groups of MMPs. identified by their substrate preferences: collagenases degrade fibrillar collagen, stromelysins prefer proteoglycans and glycoproteins as substrates and gelatinases are particularly potent in degradation of nonfibrillar and denatured collagens (gelatine).
Compounds which have the property of inhibiting the action of matrix metalloproteinases are thought to be potentially useful for the treatment or prophylaxis of conditions involving tissue breakdown and inflammation, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis, invasion and growth. MSP inhibitors are also of potential value in the treatment of neuro-inflammatory 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. However, the relative contributions of individual MMPs in any of the above disease states is not yet fully understood.
TNF-&agr; is a cytokine which is produced as a 28-kDa precursor and released in an active 17-kDa form. This active form can mediate a large number of deleterious effects in vivo, including inflammation, fever, cardiovascular effects, haemorrhage, coagulation and acute phase responses, similar to those seen during acute infections and shock states. Chronic administration of TNF-&agr; can cause cachexia and anorexia; accumulation of excess TNF-&agr; can be fatal.
Compounds which inhibit the production or action of TNF-&agr; are therefore thought to be potentially useful for the treatment or prophylaxis of many inflammatory, infectious, immunological and malignant diseases. These include, but are not limited to, septic shock, haemodynamic shock and sepsis syndrome, post ischameic reperfusion injury, malaria, Crohn's disease, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer, autoimmune disease, rheumatoid arthritis, multiple sclerosis, radiation damage, toxicity following administration of immunosuppressive mono-clonal antibodies and hyperoxic alveolar injury.
TNF-&agr; convertase is a metalloprotease involved in the biosynthesis of TNF-&agr;. Inhibition of TNF-&agr; convertase inhibits production of TNF-&agr;. Since excessive TNF-&agr; production has been noted in several disease conditions characterised by MMP-mediated tissue degradation, including multiple sclerosis, arthritis and cancer, compounds which inhibit both MMPs and TNF-&agr; production may have particular advantages in the treatment or prophylaxis of diseases or conditions in which both mechanisms are involved.
Many known MMP inhibitors are peptide derivatives, based on naturally occurring amino acids, and are analogues of the cleavage sites in the natural substrates of the MMPs. Other known MMP inhibitors are less peptidic in structure, and may be viewed as pseudopeptides or peptidomimetics. Such compounds usually have a zinc binding group, which most often is a hydroxamic acid, carboxylic acid, sulphhydryl, and oxygenated phosphorous (e.g. phosphinic acid and phosphonamides including aminophosphonic acid) groups.
Two known classes of pseudopeptide or peptidomnimetic MMP inhibitors have a hydroxamic acid group and a carboxylic acid group, respectively, as their zinc binding groups. With few exceptions, such known inhibitors may be represented by the structural formula (A)
in which X is the zinc binding hydroxamic acid (—CONHOH) or carboxylic acid (—COOH) group and the groups R
1
to R
5
are variable in accordance with the specific prior art disclosures of such compounds.
In such compounds, it is generally understood in the art that the variation of the zinc binding group and the substituents R
1
, R
2
and R
3
can have an appreciable effect on the relative inhibition of the MMPs. The group X is thought to interact with MMPs by binding to a Zn(II) ion in the active site. Generally the hydroxamic acid is preferred over the carboxylic acid in terms of inhibitory activity against the various MMPs. However, the carboxylic acid moiety in combination with other substituents can provide selective inhibition of gelatinase (EP489,577-A). The R
1
, R
2
and R
3
groups are believed to occupy, respectively, the P1, P1
1
and P2
1
amino acid side chain binding sites for the natural enzyme substrates. There is evidence that a larger R
1
substituent can enhance activity against stromelysin, and that a (C
1
-C
6
)alkyl group (such as isobutyl) at R
2
may be preferred for activity against collagenase whilst a phenylalkyl group (such as phenylpropyl) at R
2
may provide selectivity for gelatinase over the other MMPs.
Although numerous MBP inhibitors with potent in vitro activities are known, many have not been suitable for further development as medicines, since they have lacked any useful activity when administered orally at pharmaceutically acceptably doses. Although it is known that a number of factors influence oral bioavailability, the design of enzyme inhibitors with high oral bioavailability is far from straightforward. Finding a combination of R
1
, R
2
, R
3
R
4
, or R
5
substituents that permits a good balance of intrinsic level of activity, water solubility, oral absorption, and pharmakokinetic properties is a continuing problem in the art, since those properties can vary in an unpredictable way as the substituents R
1
-R
5
are varied. Identifying hydroxamic acid and carboxylic acid based MMP inhibitors having such properties remains a much sought after goal in the art.
Now we have found novel potent hydroxamic acid and carboxylic acid thioamide derivatives that have advantageously good oral bioavailability, and after oral administration have advantageously longer duration of action and a pharmacokinetically better profile than their structurally closely related analogues.
This invention thus relates to a hitherto unknown class of compounds of formula (I) below wherein X is a hydroxamic acid or a carboxylic acid group characterised primarily in that one or both Y and Z groups are the atom S.
The present invention provides compounds of general formula (I)
wherein
X is a —CO
2
H or —CONHOH group;
Y and Z are independently sulphur or oxygen, at

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