Metalloprotease inhibitors

Details Metalloprotease inhibitors Metalloprotease inhibitors

2000-06-02

2003-01-28

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S194000, C546S186000, C546S187000, C546S191000, C546S209000, C546S211000, C546S234000, C546S268100, C546S313000, C514S316000, C514S317000, C514S326000

Reexamination Certificate

active

06511993

ABSTRACT:

This invention relates to a series of substituted &agr;-aminosulphonyl-acetohydroxamic acids which are inhibitors of zinc-dependent metalloprotease enzymes. In particular, the compounds are inhibitors of certain members of the matrix metalloprotease (MMP) family.
Matrix metalloproteases (MMPs) constitute a family of structurally similar zinc-containing metalloproteases, which are involved in the remodelling and degradation of extracellular matrix proteins, both as part of normal physiological processes and in pathological conditions. Since they have high destructive potential, MMPs are usually under close regulation and failure to maintain MMP regulation has been implicated as a component of a number of diseases and conditions including pathological conditions, such as atherosclerotic plaque rupture, heart failure, restenosis, periodontal disease, tissue ulceration, cancer metastasis, tumour angiogenesis, age-related macular degeneration, fibrotic disease, rheumatoid arthritis, osteoarthritis and inflammatory diseases dependent on migratory inflammatory cells.
Another important function of certain MMPs is to activate various enzymes, including other MMPs, by cleaving the pro-domains from their protease domains. Thus some MMPs act to regulate the activities of other MMPs, so that over-production of one MMP may lead to excessive proteolysis of extracellular matrix by another. Moreover, MMPs have different substrate preferences (shown in the following Table for selected family members) and different functions within normal and pathological conditions. For recent reviews of MMPs, see Current Pharmaceutical Design, 1996, 2, 624 and Exp. Opin. Ther. Patents, 1996, 6 1305.
TABLE
Enzyme
Other Names
Preferred Substrates
MMP-1
collagenase-1; interstitial
collagens I, II, III, VII, X; gelatins
collagenase
MMP-2
gelatinase A; 72kDa
gelatins; collagens IV, V, VII, X;
gelatinase
elastin; fibronectin; activates pro-
MMP-13
MMP-3
stromelysin-1
proteoglycans; laminin;
fibronectin; gelatins
MMP-8
collagenase-2; neutrophil
collagens I, II, III
collagenase
MMP-9
gelatinase B; 92kDa
gelatins; collagens IV, V; elastin
gelatinase
MMP-13
collagenase-3
collagens I, II, III; gelatins
MMP-14
MT-MMP-1
activates pro-MMP-2 & 13;
gelatins
Excessive production of MMP-3 is thought to be responsible for pathological tissue breakdown which underlies a number of diseases and conditions. For example, MMP-3 has been found in the synovium and cartilage of osteoarthritis and rheumatoid arthritis patients, thus implicating MMP-3 in the joint damage caused by these diseases: see Biochemistry, 1989, 28, 8691 and Biochem. J., 1989, 258, 115. MMP-13 is also thought to play an important role in the pathology of osteoarthritis and rheumatoid arthritis: see Lab. Invest., 1997, 76, 717 and Arthritis Rheum., 1997, 40, 1391.
The over-expression of MMP-3 has also been implicated in the tissue damage and chronicity of chronic wounds, such as venous ulcers, diabetic ulcers and pressure sores: see Brit. J. Dermatology, 1996, 135, 52. Collagenase-3 (MMP-13) has also recently been implicated in the pathology of chronic wounds (
J Invest Dermatol
, 1997, 109, 96-101).
Furthermore, the production of MMP-3 may also cause tissue damage in conditions where there is ulceration of the colon (as in ulcerative colitis and Crohn's disease: see J. Immunol., 1997 158, 1582 and J. Clin. Pathol., 1994, 47, 113) or of the duodenum (see Am. J. Pathol., 1996, 148, 519).
Moreover, MMP-3 is also thought to be involved in skin diseases such as dystrophic epidermolysis bullosa (see Arch. Dermatol. Res., 1995, 287, 428) and dermatitis herpetiformis (see J. Invest. Dermatology, 1995, 105, 184).
Rupture of atherosclerotic plaques by MMP-3 has also been described (see e.g. Circulation, 1997, 96, 396). Thus, MMP-3 inhibitors may find utility in the treatment of conditions caused by or complicated by embolic phenomena such as cardiac or cerebral infarctions.
Studies of human cancers have shown that MMP-2 is activated on the invasive tumour cell surface (see J. Biol. Chem., 1993, 268, 14033) and BB-94, a non-selective peptidic hydroxamate MMP inhibitor, has been reported to decrease the tumour burden and prolong the survival of mice carrying human ovarian carcinoma xenografts (see Cancer Res., 1993, 53, 2087). Various series of MMP inhibitors have appeared in the literature which have a carbonyl moiety (CO) and a sulphone moiety (SO
2
) with a two atom “spacer” interposed between them. For example, &agr;-arylsulphonamido-substituted acetohydroxamic acids are disclosed in EP-A-0606046, WO-A-9627583 and WO-A-9719068, whilst EP-A-0780386 discloses certain related sulphone-substituted hydroxamic acids.
The compounds of the present invention represent a new class of compounds, and are inhibitors of some of the members of the MMP family. In particular, they are inhibitors of MMP-3 and/or MMP-13, with certain compounds exhibiting varying degrees of selectivity over other MMPs, such as MMP-1, MMP-2, MMP-9 and MMP-14. Thus they may be of utility in treating diseases and conditions mediated by MMPs, in particular MMP-3 and/or MMP-13.
A series of substances related to the instant invention were disclosed in International Patent Application number publication no. WO 99/29667, herein incorporated by reference in its entirety.
According to one aspect of the present invention (“A”), there is provided a compound of formula (I):
and pharmaceutically-acceptable salts thereof, and solvates thereof, wherein
the dotted line represents an optional bond,
X is a monocyclic aromatic linker moiety selected from phenylene, pyridinylene, pyrazolylene, thiazolylene, thienylene, furylene, pyrimidinylene, pyrazinylene, pyridazinylene, pyrrolylene, oxazolylene, isoxazolylene, oxadiazolylene, thiadiazolylene, imidazolylene, triazolylene, or tetrazolylene;
R is H, C
1-4
alkyl optionally substituted by C
1-4
alkoxy, NR
4
R
5
or OH, or R is C
1-4
alkoxy optionally substituted by 1 or 2 substituents selected from (C
1-4
alkyl optionally substituted by OH), C
1-4
alkoxy, OH and NR
4
R
5
;
R
1
and R
2
are each independently H, C
1-6
alkyl optionally substituted by OH or C
1-4
alkoxy, or C
2-6
alkenyl;
or R
1
and R
2
are taken together, with the C atom to which they are attached, to form a 3- to 7-membered ring optionally incorporating a hetero-moiety selected from O, S, SO, SO
2
and NR
6
, and which 3- to 7-membered ring is optionally substituted by one or more OH;
R
3
is H, halo, methyl, or methoxy;
R
4
and R
5
are each independently H or C
1
to C
6
alkyl optionally substituted by OH, C
1
to C
4
alkoxy or aryl,
or R
4
and R
5
can be taken together with the N atom to which they are attached, to form a 3- to 7-membered ring, optionally incorporating a further hetero-moiety selected from O, S, SO
2
and NR
7
; and
R
6
and R
7
are each independently H or C
1
to C
4
alkyl.
According to a further aspect of the invention (“B”), there is provided a compound of formula (I):
and pharmaceutically-acceptable salts thereof, and solvates thereof, wherein
the dotted line represents an optional bond;
X is a monocyclic aromatic linker moiety selected from pyrazolylene, thiazolylene, pyrazinylene, pyridazinylene, pyrrolylene, oxazolylene, isoxazolylene, oxadiazolylene, thiadiazolylene, imidazolylene, triazolylene, or tetrazolylene;
R is H, C
1-4
alkyl optionally substituted by C
1-4
alkoxy or NR
4
R
5
or OH, or C
1-4
alkoxy optionally substituted by 1 or 2 substituents selected from (C
1-4
alkyl optionally substituted by OH), C
1-4
alkoxy, OH and NR
4
NR
5
;
R
1
and R
2
are each independently H, C
1-6
alkyl optionally substituted by OH or C
1-4
alkoxy, or C
2-6
alkenyl;
or R
1
and R
2
are taken, together with the C atom to which they are attached, to form a 3- to 7-membered ring optionally incorporating a hetero-moiety selected from O, S, SO, SO
2
and NR
6
, and which 3- to 7-membered ring is optionally substituted by one or more OH;
R
3
is H, halo, methyl, or methoxy;
R
4
and R
5
are each independently H or C
1
to C
6
alkyl optionally substituted by OH, C
1
to

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