Fused cycloheptane and fused azacycloheptane compounds and...

Details Fused cycloheptane and fused azacycloheptane compounds and... Fused cycloheptane and fused azacycloheptane compounds and...

2000-09-26

2003-02-04

Kifle, Bruck (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S212070, C514S213010, C540S521000, C540S522000, C540S523000, C540S593000

Reexamination Certificate

active

06514964

ABSTRACT:

BACKGROUND OF THE INVENTION
The present invention comprises a new class of compounds useful in treating diseases, such as diseases, conditions or disorders mediated by integrin receptors, such as vitronectin and fibronectin receptors. In particular, the compounds of the invention and pharmaceutical compositions thereof are useful for the prophylaxis and treatment of diseases, conditions or disorders involving atherosclerosis, restenosis, inflammation, cancer, osteoporosis and the like. This invention also relates to intermediates and processes useful in the preparation of such compounds.
Integrins are heteromeric cell surface receptors many of which have extracellular domains that bind to an Arg-Gly-Asp tripeptide (RDG) found in extracellular (plasma and matrix) proteins, such as fibronectin, vitronectin, fibrinogen and osteopontin. The fibrinogen receptor, gpIIb/IIIa integrin, is a platelet surface receptor that is thought to mediate platelet aggregation and the formation of hemostatic clot at bleeding wound sites (Blood. 71:831, 1988).
Vitronectin receptors, &agr;
v
&bgr;
3
and &agr;
v
&bgr;
5
integrin, are expressed by a number of cells, such as endothelial, smooth muscle, osteoclast, bone resorbing, tumor and epithelial cells. Integrin &agr;
v
&bgr;
3
has been reported to be involved in bone resorption (Endocrinology 137:2347-54, 1996; J. Endocrinol. 154(Suppl.):S47-S56, 1997), in cell attachment, spreading and migration (Int. J. Biochem. Cell Biol. 31:539-544, 1999; Carreitas et al., Int. J. Cancer 80:285-294, 1999), in signal transduction, cell to cell interactions and is upregulated in response to vascular damage (Int. J. Biochem. Cell Biol. 29:721-725, 1997), in tumor cell invasion, angiogenesis, wound healing, phagocytosis of apototic cells and inflammation (J. Cell Biol. 144:767-775, 1999; Drug News Perspect. 10:456-461, 1997; Am. J. Pathol. 148:1407-1421, 1996), in tumor growth and hypercalcemia of malignancy (Cancer Res. 58:1930-1935, 1998), in tumorigenicity of human melanoma cells (Natali et al., Cancer Res. 57:1554-60, 1997), in melanoma metastasis (Cancer Metastasis Rev. 14:241-245, 1995; Cancer Metastasis Rev. 10:3-10, 1991), in the chondrocyte synthesis of matrix metalloproteinases (such as stromelysin, collagenase and gelatinase) which are involved in diseases such as rheumatoid arthritis and osteoarthritis (Arthritis Rheum. 38:1304-1314, 1995), in the progression of the renal injury in Fabry disease (Clin. Chim. Acta 279:55-68, 1999), and in viral infections (J. Virol. 72:3587-3594, 1998; Virology 203:357-65, 1994). Keenan et al. (J. Med. Chem. 40:2289-92, 1997) disclose examples of &agr;
v
&bgr;
3
inhibitors which are selective for &agr;
v
&bgr;
3
over platelet fibrinogen receptor (&agr;
IIb
&bgr;
3
).
Integrin &agr;
v
&bgr;
5
(Smith et al., J. Biol. Chem. 265:11008-13, 1990) is thought to be involved in endocytosis and degredation of vitronectin (J. Biol. Chem. 268:11492-5, 1993), cellular locomotion of human keratinocytes (J. Biol. Chem. 269:26926-32, 1994), tumor cell metastasis (J. Clin. Invest. 99:1390-1398, 1997), differentiation of neuroblastoma metastasis (Am. J. Pathol. 150:1631-1646, 1997), and viral infections (Nat. Med. (N.Y.) 5:78-82, 1999; J. Cell Biol. 127:257-64, 1994).
Integrin &agr;
v
&bgr;
6
is an RGD, tenascin and fibronectin binding protein (J. Biol. Chem. 267:5790-6, 1992) which is expressed by a number of cells, such as carcinoma and epithelial cells, and is thought to be involved in carcinoma cell proliferation (J. Cell Biol. 127:547-56, 1994), in wound healing and cell attachment (J. Invest. Dermatol. 106:42-8, 1996), in epithelial inflammation, such as asthma (J. Cell Biol. 133:921-928, 1996), in inducing gelatinase B secretion, activation of the protein kinase-C pathway, tumor cell spreading and proliferation in colon cancer cells (Biochem. Biophys. Res. Commun. 249:287-291, 1998; Int. J. Cancer 81:90-97, 1999), in regulation of pulmonary inflammation and fibrosis and binding and activating transforming growth factor &bgr;1 (Munger et al., Cell (Cambridge, Mass.) 96:319-328, 1999), and in viral infections (Virology 239:71-77, 1997).
Antagonists of vitronectin receptors &agr;
v
&bgr;
3
, &agr;
v
&bgr;
5
and/or &agr;
v
&bgr;
6
have been reported to be useful in the treatment and prevention of atherosclerosis, restenosis, inflammation, wound healing, cancer (e.g., tumor regression by inducing apoptosis), metastasis, bone resorption related diseases (e.g., osteoporosis), diabetic retinopathy, macular degeneration, angiogenesis and viral disease (e.g., WO 99/30713; WO 99/30709).
WO 99/05107 discloses benzocycloheptenylacetic acid compounds useful as vitronectin receptor antagonists.
WO 98/14192 discloses benzazepin-3-on-4-ylacetic acid compounds as vitronectin receptor antagonists.
WO 96/26190 discloses benzodiazepine-3-one and benzazepin-3-one compounds as integrin receptor inhibitors.
WO 99/11626 discloses compounds of the formula
wherein m, A, E, X
1
, X
2
, R
2
, R
3
, R
4
, R
6
and R
7
are as defined therein, are useful as integrin receptor inhibitors, in particular fibrinogen (&agr;
IIb
&bgr;
3
) or vitronectin (&agr;
v
&bgr;
3
) receptor inhibitors.
WO 97/01540 discloses compounds of the formula
wherein A
1
, E, X
1
, X
2
, X
3
, R
2
, R
3
, R
4
, R
6
and R
7
are as defined therein, are useful as integrin receptor inhibitors, in particular fibrinogen (&agr;
IIb
&bgr;
3
) or vitronectin (&agr;
v
&bgr;
3
) receptor inhibitors.
U.S. Pat. No. 5,565,449 discloses compounds of the formula
wherein A, D, G, T, U, W and X are as defined therein, are useful as integrin inhibitors of fibrinogen GPII
b
III
a
.
U.S. Pat. No. 5,705,890 discloses tricyclic benzodiazepine compounds useful as platelet aggregation (fibrinogen binding) inhibitors.
U.S. Pat. No. 5,674,865 discloses benzodiazepinedione compounds useful as platelet aggregation (fibrinogen binding) inhibitors.
WO 99/15178 and WO 99/15170 disclose benzazepineacetic acid compounds useful as vitronectin receptor antagonists.
WO 99/11626 and WO 99/06049 disclose tricyclic benzazepine, benzodiazepineacetate and benzazepineacetate compounds useful as fibrinogen and vitronectin receptor antagonists.
WO 99/15508 discloses dibenzo[a,d]cycloheptene-10-acetic acid compounds useful as vitronectin receptor antagonists.
WO 99/15506 and WO 99/15507 disclose iminobenzazulene compounds useful as vitronectin receptor antagonists.
WO 98/18461 discloses 4-10 membered mono- or polycyclic aromatic or nonaromatic ring system (containing 0-4 oxygen, sulfur and/or nitrogen heteroatoms) compounds useful as integrin receptor antagonists.
WO 97/01540 discloses dibenzocycloheptene compounds useful as integrin receptor antagonists.
WO 96/26190 discloses benzodiazepine-3-one and benzazepin-3-one compounds as integrin receptor inhibitors.
SUMMARY OF THE INVENTION
The present invention comprises a new class of compounds useful in the prophylaxis and treatment of diseases, such as integrin receptors mediated diseases. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions mediated by integrin receptors, such as &agr;
v
&bgr;
3
, &agr;
v
&bgr;
5
, &agr;
v
&bgr;
6
and the like. Accordingly, the invention also comprises pharmaceutical compositions comprising the compounds, methods for the prophylaxis and treatment of integrin receptors mediated diseases, such as cancer, tumor growth, metastasis, diabetic retinopathy, macular degeneration, angiogenesis, restenosis, bone resorption, atherosclerosis, inflammation, viral infection, wound healing and the like, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention.
The compounds of the invention are represented by the following general structure:
E—B—(Alk)
p
—Q—(Alk)
q
—A—G
wherein E, B, Alk, Q, A, G, p and q are defined below.
The foregoing merely summarizes certain aspects of the invention and is not intended, nor should it be construed, as limiting the invention in any way. All patents and oth

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