Tyrosine alkoxyguanidines as integrin inhibitors

Details Tyrosine alkoxyguanidines as integrin inhibitors Tyrosine alkoxyguanidines as integrin inhibitors

2000-02-11

2002-02-05

Gerstl, Robert (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

C514S538000, C560S034000, C562S434000

Reexamination Certificate

active

06344484

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel tyrosine alkoxyguanidine compounds that are inhibitors of alpha V (&agr;v) integrins, for example &agr;v&bgr;3 and &agr;v&bgr;5 integrins, their pharmaceutically acceptable salts, and pharmaceutical compositions thereof.
BACKGROUND OF THE INVENTION
Integrins are cell surface glycoprotein receptors which bind extracellular matrix proteins and mediate cell-cell and cell-extracellular matrix interactions (generally referred to as cell adhesion events) (Hynes, R. O.,
Cell
69:11-25 (1992)). These receptors are composed of noncovalently associated alpha (&agr;) and beta (&bgr;) chains which combine to give a variety of heterodimeric proteins with distinct cellular and adhesive specificities (Albeda, S. M.,
Lab. Invest.
68:4-14 (1993)). Recent studies have implicated integrins in the regulation of cellular adhesion, migration, invasion, proliferation, apoptosis and gene expression (Albeda, S. M.,
Lab. Invest.
68:4-14 (1993); Juliano, R.,
Cancer Met. Rev.
13:25-30 (1994); Ruoslahti, E. and Reed, J. C.,
Cell
77:477-478 (1994); and Ruoslahti, E. and Giancotti, F. G.,
Cancer Cells
1:119-126 (1989)).
One member of the integrin family which has been shown to play a significant role in a number of pathological conditions is the integrin &agr;v&bgr;3, or vitronectin receptor (Brooks, P. C.,
DN&P
10(8):456-461 (1997)). This integrin binds a variety of extracellular matrix components and other ligands, including fibrin, fibrinogen, fibronectin, vitronectin, laminin, thrombospondin, and proteolyzed or denatured collagen (Cheresh, D. A.,
Cancer Met. Rev.
10:3-10 (1991) and Shattil, S. J.,
Thromb. Haemost.
74:149-155 (1995)). The two related &agr;v integrins, &agr;v&bgr;5 and &agr;v&bgr;1 (also vitronectin receptors), are more specific and bind vitronectin (&agr;v&bgr;5) or fibronectin and vitronectin (&agr;v&bgr;1) exclusively (Horton, M.,
Int. J. Exp. Pathol.
71:741-759 (1990)). &agr;v&bgr;3 and the other integrins recognize and bind to their ligands through the tripeptide sequence Arg-Gly-Asp (“RGD”) (Cheresh, D. A.,
Cancer Met. Rev.
10:3-10 (1991) and Shattil, S. J.,
Thromb. Haemost.
74:149-155 (1995)) found within all the ligands mentioned above.
The &agr;v&bgr;3 integrin has been implicated in a number of pathological processes and conditions, including metastasis and tumor growth, pathological angiogenesis, and restenosis. For example, several studies have clearly implicated &agr;v&bgr;3 in the metastatic cascade (Cheresh, D. A.,
Cancer Met. Rev.
10:3-10 (1991); Nip, J. et al.,
J. Clin. Invest.
95:2096-2103 (1995); and Yun, Z., et al.,
Cancer Res.
56:3101-3111 (1996)). Vertically invasive lesions in melanomas are also commonly associated with high levels of &agr;v&bgr;3, whereas horizontally growing noninvasive lesions have little if any &agr;v&bgr;3 (Albeda, S. M., et al.,
Cancer Res.
50:6757-6764 (1990)). Moreover, Brooks et al. (in
Cell
79:1157-1164 (1994)) have demonstrated that systemic administration of &agr;v&bgr;3 antagonists disrupts ongoing angiogenesis on chick chorioallantoic membrane (“CAM”), leading to the rapid regression of histologically distinct human tumors transplanted onto the CAM. These results indicate that antagonists of &agr;v&bgr;3 may provide a therapeutic approach for the treatment of neoplasia (solid tumor growth).
&agr;v&bgr;3 has also been implicated in angiogenesis, which is the development of new vessels from preexisting vessels, a process that plays a significant role in a variety of normal and pathological biological events. It has been demonstrated that &agr;v&bgr;3 is up-regulated in actively proliferating blood vessels undergoing angiogenesis during wound healing as well as in solid tumor growth. Also, antagonists of &agr;v&bgr;3 have been shown to significantly inhibit angiogenesis induced by cytokines and solid tumor fragments (Brooks, P. C., et al.,
Science
264:569-571 (1994); Enenstein, J. and Kramer, R. H.,
J. Invest. Dermatol.
103:381-386 (1994); Gladson, C. L.,
J. Neuropathol. Exp. Neurol
55:1143-1149 (1996); Okada, Y., et al.,
Amer. J. Pathol.
149:37-44 (1996); and Brooks, P. C., et al.,
J. Clin. Invest.
96:1815-1822 (1995)). Such &agr;v&bgr;3 antagonists would be useful for treating conditions that are associated with pathological angiogenesis, such as rheumatoid arthritis, diabetic retinopathy, macular degeneration, and psoriasis (Nicosia, R. F. and Madri, J. A.,
Amer. J. Pathol.
128:78-90 (1987); Boudreau, N. and Rabinovitch, M.,
Lab. Invest.
64:187-99 (1991); and Brooks, P. C.,
Cancer Met. Rev.
15:187-194 (1996)).
There is also evidence that &agr;v&bgr;3 plays a role in neointimal hyperplasia after angioplasty and restenosis. For example, peptide antagonists and monoclonal antibodies directed to both &agr;v&bgr;3 and the platelet receptor IIb&bgr;3 have been shown to inhibit neointimal hyperplasia in vivo (Choi, E. T., et al.,
J. Vasc. Surg.
19:125-134 (1994); and Topol, E. J., et al., Lancet 343:881-886 (1994)), and recent clinical trials with a monoclonal antibody directed to both IIb&bgr;3 and &agr;v&bgr;3 have resulted in significant reduction in restenosis, providing clinical evidence of the therapeutic utility of &bgr;3 antagonists (Topol, E. J., et al.,
Lancet
343:881-886 (1994)).
It has also been reported that &agr;v&bgr;3 is the major integrin on osteoclasts responsible for attachment to bone. Osteoclasts cause bone resorption. When bone resorbing activity exceeds bone forming activity, the result is osteoporosis, a condition which leads to an increased number of bone fractures, incapacitation and increased mortality. Antagonists of &agr;v&bgr;3 have been shown to be potent inhibitors of osteoclastic activity both in vitro (Sato, M., et al.,
J. Cell Biol.
111:1713-1723 (1990)) and in vivo (Fisher, J. E., et al.,
Endocrinology
132:1411-1413 (1993)).
Lastly, White (in
Current Biology
3(9):596-599 (1993)) has reported that adenovirus uses &agr;v&bgr;3 for entering host cells. The &agr;v&bgr;3 integrin appears to be required for endocytosis of the virus particle and may be required for penetration of the viral genome into the host cell cytoplasm. Thus compounds which inhibit &agr;v&bgr;3 could be useful as antiviral agents.
The &agr;v&bgr;5 integrin has been implicated in pathological processes as well. Friedlander et al. have demonstrated that a monoclonal antibody for &agr;v&bgr;5 can inhibit VEGF-induced angiogenesis in rabbit cornea and chick chorioalloantoic membrane, indicating that the &agr;v&bgr;5 integrin plays a role in mediating growth factor-induced angiogenesis (Friedlander, M. C., et al.,
Science
270:1500-1502 (1995)). Compounds that act as &agr;v&bgr;5 antagonists could be used to inhibit pathological angiogenesis in tissues of the body, including ocular tissue undergoing neovascularization, inflamed tissue, solid tumors, metastases, or tissues undergoing restenosis.
Discovery of the involvement of &agr;v&bgr;3 and &agr;v&bgr;5 in such processes and pathological conditions has led to an interest in these integrins as potential therapeutic targets, as suggested in the preceding paragraphs. A number of specific antagonists of &agr;v&bgr;3 and &agr;v&bgr;5 that can block the activity of these integrins have been developed. One major group of such antagonists includes nonpeptide mimetics and organic-type compounds. For example, a number of organic non-peptidic mimetics have been developed that appear to inhibit tumor cell adhesion to a number of &agr;v&bgr;3 ligands, including vitronectin, fibronectin, and fibrinogen (Greenspoon, N., et al.,
Biochemistry
32:1001-1008 (1993); Ku, T. W., et al.,
J. Amer. Chem. Soc.
115:8861-8862 (1993); Hershkoviz, R., et al.,
Clin. Exp. Immunol.
95:270-276 (1994); and Hardan, L., et al.,
Int. J. Cancer
55:1023-1028 (1993)).
Additional organic compounds developed specifically as &agr;v&bgr;3 or &agr;v&bgr;5 integrin antagonists or as compounds useful in the treatment of &agr;v-mediated conditions have been described in several recent publications.
For example, U.

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