Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-10-12
2002-12-17
Chang, Celia (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S210030, C514S212010, C514S314000, C514S316000, C514S320000, C514S321000, C514S326000, C514S331000, C514S332000, C514S336000, C514S357000, C514S422000, C514S428000, C540S355000, C540S596000, C540S597000, C540S602000, C540S603000, C540S609000, C546S173000, C546S174000, C546S175000, C546S191000, C546S193000, C546S196000, C546S197000, C546S205000, C546S207000, C546S256000, C546S264000, C546S268100, C546S279700, C546S280100, C546S281700, C546S282100, C546S284100, C546S339000, C548S567000
Reexamination Certificate
active
06495568
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 may be a component of a number of diseases and pathological conditions, including atherosclerotic plaque rupture, heart failure, restenosis, periodontal disease, tissue ulceration, wound repair, 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;
collagenase
gelatins
MMP-2
gelatinase A; 72kDa gelatinase
gelatins; collagens IV, V,
VII, X; 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 gelatinase
gelatins; collagens IV, V;
elastin
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 compounds of the present invention inhibit both MMP-3 and MMP-13 and thus may be of utility in treating these diseases.
The over-expression of MMP-3 is also thought to be responsible for much of the tissue damage and chronicity of chronic wounds, such as venous ulcers, diabetic ulcers and pressure sores: see Brit. J. Dermatology, 1996, 135, 52.
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 may also 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).
Finally, rupture of atherosclerotic plaques by MMP-3 may lead to cardiac or cerebral infarction: see Circulation, 1997, 96, 396. Thus, MMP-3 inhibitors may find utility in the prevention of heart attack and stroke.
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). Certain compounds of the present invention inhibit MMP-2 and therefore may be useful in the treatment of cancer metastasis and tumour angiogenesis.
Various series of MMP inhibitors have appeared in the patent literature. 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 are inhibitors of some of the members of the MMP family. In particular, they are potent inhibitors of MMP-3 and MMP-13, with certain compounds exhibiting varying degrees of selectivity over other MMPs, such as MMP-1, MMP-2 and MMP-9. Certain of the compounds are potent MMP-2 inhibitors.
Thus, according to the present invention, there is provided a compound of formula (I):
or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate (including hydrate) of either entity,
wherein
the broken line represents an optional bond;
A is C or CH;
B is CH
2
, O or absent;
R
1
and R
2
are each independently selected from hydrogen, C
1
to C
6
alkyl optionally substituted with C
1
to C
4
alkoxy or phenyl, and C
1
to C
6
alkenyl; or, together with the carbon atom to which they are attached, form a C
3
to C
6
cycloalkyl group which optionally incorporates a heteroatom linkage selected from O, SO, SO
2
and
NR
6
or which is optionally benzo-fused;
R
3
is hydrogen, halo, R
7
or OR
7
;
R
4
is hydrogen, C
1
to C
4
alkyl, C
1
to C
4
alkoxy, trifluoromethyl or halo;
R
6
is hydrogen or C
1
to C
4
alkyl;
R
7
is a monocyclic or bicyclic ring system selected from phenyl, thienyl, furyl, pyridinyl, pyrimidinyl, naphthyl, indanyl, benzothienyl, benzofuranyl, 2,3-dihydrobenzofuranyl, indolyl, quinolinyl, isoquinolinyl, benzodioxolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl and benzodioxanyl, any of which ring systems is optionally substituted with one or two substituents selected from C
1
to C
4
alkyl optionally substituted with C
1
to C
4
alkoxy or hydroxy, C
1
-C
4
alkoxy optionally substituted with C
1
to C
4
alkoxy or hydroxy, C
1
to C
4
alkylthio, trifluoromethyl, trifluoromethoxy, halo and cyano;
m is 1or 2; and
n is 0, 1 or 2;
with the proviso that B is not O when A is C.
In the above definition, unless otherwise indicated, alkyl, alkoxy, alkylthio and alkenyl groups having three or more carbon atoms may be straight chain or branched chain. Halo means fluoro, chloro, bromo or iodo.
The compounds of formula (I) may contain one or more chiral centres and therefore can exist as stereoisomers, i.e. as enantiomers or diastereoisomers, as well as mixtures thereof. The invention includes both the individual stereoisomers of the compounds of formula (I) and any mixture thereof. Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation or chromatography (including HPLC) of a diastereoisomeric mixture of a compound of formula (I) or a suitable salt or derivative thereof. An individual enantiomer of a compound of formula (I) may be prepared from a corresponding optically pure intermediate or by resolution, either by HPLC of the racemate using a suitable chiral support or, where appropriate, by fractional crystallisation of the diastereoisomeric salts formed by reaction of the racemate with a suitable optically active base or acid.
Furthermore, compound of formula (I) which contain alkenyl groups can exist as cis-stereoisomers or trans-stereoisomers. Again, the invention includes both the separated individual stereoisomers as well as mixtures thereof.
Also included in the invention are radiolabelled derivatives of compounds of formula (I) which are suitable for biological studies.
Compounds of formulae (I) may provide pharmaceutica
Dack Kevin Neil
Whitlock Gavin Alistair
Ashbrook Charles W.
Chang Celia
Warner-Lambert & Company
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