Matrix metalloproteinase inhibitors

Details Matrix metalloproteinase inhibitors Matrix metalloproteinase inhibitors

1999-03-10

2002-11-19

O'Sullivan, Peter (Department: 1621)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S210010, C514S238200, C514S252110, C514S255010, C514S255050, C514S320000, C514S616000, C544S336000, C544S357000, C544S360000, C544S376000, C544S164000, C546S207000, C546S224000, C548S953000, C564S155000, C564S156000, C564S157000, C564S159000

Reexamination Certificate

active

06482827

ABSTRACT:

The present invention relates to new inhibitors of matrix metalloproteinases (hereinafter MMPs), to a process for their preparation, to pharmaceutical compositions containing them, and to the use of such compounds in the prevention, control and treatment of diseases in which the proteolytic action of MMPs is involved.
Certain disease states are characterised by an imbalance of active MMPs and their natural inhibitors, the tissue inhibitors of metalloproteinases (hereinafter TIMPs). When TIMP levels are insufficient, a progressive slow degradation of the extracellular matrix occurs, for example cartilage matrix loss in rheumatoid arthritis (L. A. Walakovits et al., Arthritis Rheum, 35:35-42, 1992) and osteoarthritis (D. D. Dean et al., J. Clin. Invest., 84:678-685, 1989), and bone matrix degradation in osteoporosis (p. A. Hill et al., Biochem. J., 308:167-175, 1995). In other situations, such as congestive heart failure, rapid degradation of the heart's extracellular matrix occurs (P. W. Armstrong et al., Canadian J. Cardiol. 10:214-220, 1994). Cancer cells use MMPs, either expressed by themselves or by the surrounding tissues, to achieve rapid remodelling of the extracellular matrix. There is considerable evidence that MMPs are involved in at least 3 aspects of the growth and spread of tumors (e.g., see A. H. Davidson et al., Chemistry & Industry, 258-261, 1997, and references therein). In the process of tumor metastasis, MMPs are used to break down the extracellular matrix, allowing primary tumor cancer cells to invade neighbouring blood vessels where they are transported to different organs and establish secondary tumors. The invasive growth at these secondary sites also needs MMPs to help break down tissue. In addition, MMP activity contributes to the invasive in-growth of new blood vessels (angiogenesis) which is required for tumors to grow above a certain size.
Low molecular weight compounds able to inhibit one or more of the matrix metalloproteinases, in particular stromelysin-1 (M-3; EC 3.4.24.17), gelatinase A (MMP-2; EC 3.4.24.24), gelatinase B (MM-9; EC 3.4.24.35), neutrophil collagenase or collagenase-2 (MMP-8; EC 3.4.24.34), interstitial collagenase or collagenase-1 (MMP-1; EC 3.4.27.7), matrilysin (MMP-7; EC 3.4.24.23), collagenase-3 (MMP-13), and the membrane-type metalloproteinase (MT-MMPs: MMP-14, MNP-15, MMP-16, MMP-17) are currently considered as promising therapeutic agents in degenerative, tumoral and autoimmune pathologies (e.g., P. D. Brown: “Matrix metalloproteinase inhibitors: A new class of anticancer agent”, Curr. Opin. Invest. Drugs, 2:617-626, 1993; A. Krantz: “Proteinases in Inflammation”, Annu. Rep. Med. Chem. 28:187-195, 1993). Many of such compounds described hitherto are peptide derivatives or pseudopeptides, bearing analogies to recognized peptide substrates of these enzymes, and characterized in addition by a functional group capable of binding the Zn (II) atom present in the catalytic site of said enzymes. Known classes of MMP inhibitors include those in which the Zn binding group is a hydroxamic acid, and the skeleton, as represented in the general formula (A), mimicks the amino acid sequence of collagen at the site cleaved by collagenase:
wherein R
a
, R
b
, R
c
, and R
d
are hydrogen atoms or appropriate substituents (e.g., N. R. A. Beeley et al., “Inhibitors of matrix metalloproteinases (MMP's)”, Curr. Opin. Ther. Patents 4:7-16, 1994; J. R. Porter et al., “Recent developments in matrix metalloproteinase inhibitors”, Exp. Opin. Ther. Patents 5:1287-1296, 1995; J. R. Morphy et al., “Matrix metalloproteinase inhibitors: Current status”, Curr. Med. Chem. 2:743-762, 1995; R. P. Beckett et al., “Recent advances in matrix metalloproteinase research”, DDT 1:16-26, 1996). Said MMP inhibitors of the prior art can be described as “peptide-based hydroxamates” or “substrate-based” inhibitors (e.g., A. H. Davidson et al., “The inhibition of matrix metalloproteinase enzymes”, Chemistry & Industry, 258-261, 1997).
Although MMPs have been recognized as drug targets for at least 20 years, and potent MMP inhibitors described by formula (A) have been disclosed since 1986 or before (e.g., see J. P. Dickens et al., U.S. Pat. No. 4,599,361), no drug of this type has arrived at the market yet. This is not because of questions about the therapeutic potential of MMP inhibitors, but because of problems of “peptide-based hydroxamates”, such as aqueous solubility, metabolic stability, and other desirable properties, oral bioavailability in particular (e.g., J. R. Porter, reference above; J. Hodgson, “Remodelling MMPIs”, Biotechnology 13:554-557, 1995). For example, it is well known that most “peptide-based hydroxamates” of general formula (A) are rapidly glucuronidated, oxidized to the carboxylic acid, and excreted in the bile (e.g., see J. Singh et al., Bioorg. Med. Chem. Lett. 5:337-342, 1995, and other references above). Finally, another type of problem of the known inhibitors described by general formula (A) may be one of tolerability. This problem is emerging for the most advanced MMP inhibitor in the clinic, marimastat (formula A; R
a
=OH, R
b
=CH
2
CHMe
2
, R
c
=CMe
3
, R
d
=Me), which was reported to give muscoloskeletal problems in humans. We have extended these observations by developing an animal model of tolerability with MMP inhibitors (S. Castellino et al., unpublished), involving intraperitoneal administration of the latter in rats for 10 consecutive days, and histological evaluation of stifle joints at the end of treatment. In this model, peptide-based MMP inhibitors of the prior art, e.g. Roche Ro31-9790 (formula A; R
a
=H, R
b
=CH
2
CHMe
2
, R
c
=CMe
3
, R
d
=Me), at daily doses of 150 mg/kg or less, elicited hypertrophic fibrosis of stifle ligaments, interstitial hypertrophic fibrosis of skeletal muscles, hypertrophic fibroplasia of the periostium and synovium, and chondrosysplasia and decreased endochondrial ossification of the ephyseal plate. Although the precise reasons for these side-effects are not known at present, they support a strong need for better and diversified molecules, especially as far as the properties referred to above are concerned.
The present invention is concerned with novel MMP inhibitors, specifically characterized by the presence of a nitrogen atom as a substituent at the carbon atom next to the zinc-binding group, and with less or no peptidic character, as compared to substrate-based inhibitors of the prior art.
The present invention provides a compound which is an amine derivative of formula (I)
wherein
W is —CONHOH or —COOH;
R
1
and R
2
, which are the same or different, are each hydrogen or
a group G, which is methyl, C
2
-C
10
alkyl, C
2
-C
10
alkenyl, C
3
-C
7
cycloalkyl, cycloalkyl-C
1
-C
10
-alkyl, aryl, aryl-C
1
-C
10
-alkyl, aryl-C
2
-C
10
-alkenyl, heterocyclyl, heterocyclyl-C
1
-C
10
-alkyl or heterocyclyl-C
2
-C
10
-alkenyl, the said methyl, alkyl, alkenyl, cycloalkyl, aryl and heterocyclyl groups being unsubstituted or substituted by one to three substituents; or
—SO
2
—G, wherein G is as defined above; or
—SO—G, wherein G is as defined above; or
—CO—G, wherein G is as defined above; or
—COO—G, wherein G is as defined above; or
—SO
2
—NH
2
, —SO
2
—NHG or —SO
2
—NGG′, wherein G is as defined above and G′, which is the same or different, is as defined above for G, or G and G′, together with the nitrogen atom to which they are attached, form a saturated or unsaturated 3- to 7-membered azaheterocyclic ring, which may be fused to a carbocyclic, heterocyclic, or aromatic ring, and may be substituted at any carbon or additional nitrogen atom, or
a group —CONH
2
, —CONHG or —CO—NGG′ wherein G and G′ are as defined above, or G and G′, together with the nitrogen atom to which they are attached, constitute a saturated or unsaturated 3- to 7-membered azaheterocyclic ring, which may be fused to a carbocyclic, heterocyclic, or aromatic ring, and may be substituted at any carbon or additional nitrogen atom, or
R

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