Matrix metalloproteinase inhibitors

Details Matrix metalloproteinase inhibitors Matrix metalloproteinase inhibitors

2001-07-06

2003-02-18

Lambkin, Deborah C. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C558S081000

Reexamination Certificate

active

06521606

ABSTRACT:

The present invention relates to a hitherto unknown class of compounds comprising new matrix metalloproteinase inhibitors, which are 1,3,2-oxazaphos-phacycloalkane based hydroxamic acids, carboxylic acids, phosphonic acids or thiols, to pharmaceutical compositions containing said compounds, to methods of treating patients with said compounds, and to the use of such compounds in the preparation of 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 endopeptidases, 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 17 different and yet highly homologous MMP-species have been characterised. They share a catalytic domain with the VAAHEXGHXXGXXH 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).
MMPs are also believed to be important in the processing, or secretion, of biologically important cell mediators, such as TNF-&agr;, and the post translational proteolysis processing, or shedding, of biologically important membrane proteins, such as the low affinity IgE receptor CD 23 (for a more complete list see N. M. Hooper et al.:
Biochem. J.
(1997) 321, 265-279).
Potential therapeutic indications of MMP inhibitors have been discussed in the literature [e.g. T. H. Vu, Z. Werb. (1998) (In: Matrix Metalloproteinases. 1998. Edited by W. C. Parks and R. P. Mecham. Pp115-148. Academic Press. ISBN 0-12-545090-7); D. E. Mullins et al.:
Biochem. Biophys. Acta
(1983) 695, 117-214; B. Henderson et al.:
Drugs of the Future
(1990) 15, 495-508; R. Reich et al.:
Cancer Res.
(1988) 48, 3307-3312]. Compounds which have the property of inhibiting the action of matrix metalloproteinases are thought to be potentially useful for, but not restricted to, 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, skin ageing and tumour metastasis, tumour invasion and tumour growth. MMP inhibitors are also of potential value in the treatment of neuroinflammatory 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, angio fibromas 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 ischaemic reperfusion injury, Crohn's disease, mycobacterial infection, meningitis, psoriasis, congestive heart failure, cancer, rheumatoid arthritis and multiple sclerosis.
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, e.g. sulfonamides. Such compounds usually have a zinc binding group, which most often is a hydroxamic acid, reverse hydroxamic acid, carboxylic acid, sulphhydryl, and oxygenated phosphorous (e.g. phosphinic acid and phosphonamides including aminophosphonic acid) groups.
Although numerous MMP 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 series of compounds that permits a good balance of intrinsic level of activity, water solubility, oral absorption, and favourable pharmacokinetic properties is a continuing problem in the art, since those properties can vary in an unpredictable way in relation to the structure. Identifying MMP inhibitors having such properties remains a challenge.
Prior art has consisted of simple peptidic compounds as well as linear and cyclic sulfonamide compounds, e.g. EP-A-0489577, WO 96/16931, WO 96/33991, WO 97/44315 and WO 00/09485. Only a single example of a prior art patent publication exists depicting simple linear phosphinamide compounds [WO 98/08853]. These are structurally diverse from the cyclic compounds of general formula (I). Prior art has depicted only 1,3,2-oxazaphosphorocycloalkanes with simple phenyl and alkyl substituents, however they do not contain the requisite hydroxamic acid or other zinc binding groups (e.g. PL 149593, FR 2567129,
Izv. Akad. Nauk., Ser. Khim
(1995) (11), 2241-9). It has now surprisingly been found that the novel 1,3,2-oxazaphoshacycloalkane based compounds of general formula (I) of the present invention are potent MMP inhibitors. Preferred compounds of the present invention display nanomolar to micromolar potency in inhibiting MMPs, such as MMP-13, MMP-9 and MMP-3.
The present invention relates to a novel class of compounds of the general formula I
wherein Y is O or S;
n is 1, 2, 3 or 4;
X represents hydroxamic acid, carboxylic acid, phosphonic acid, acetylthiomethyl group or a mercaptomethyl group;
R1 is
wherein E, when present represents, a bond or optionally substituted methylene or ethylene;
s and t are independently 0, 1, 2 or 3;
A and A′ independently represent a bond, or a saturated or unsaturated, optionally substituted cyclic or heterocyclic hydro

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