Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-09-09
2004-12-21
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S253030, C514S277000, C514S336000, C514S349000, C514S351000, C514S357000, C546S001000, C546S304000, C546S339000, C546S329000
Reexamination Certificate
active
06833366
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to pharmaceutical agents (compounds) which are &agr;
v
&bgr;
3
and/or &agr;
v
&bgr;
5
integrin antagonists and as such are useful in pharmaceutical compositions and in methods for treating conditions mediated by &agr;
v
&bgr;
3
and/or &agr;
v
&bgr;
5
integrins.
BACKGROUND OF THE INVENTION
The integrin &agr;
v
&bgr;
3
(also known as vitronectin receptor), is a member of the integrin family of heterodimeric transmembrane glycoprotein complexes that mediate cellular adhesion events and signal transduction processes. Integrin &agr;
v
&bgr;
3
is expressed in number of cell types and has been shown to mediate several biologically relevant processes, including adhesion of osteoclasts to the bone matrix, vascular smooth muscle cell migration and angiogenesis.
The integrin avb3 has been shown to play a role in various conditions or disease states including tumor metastasis, solid tumor growth (neoplasia), osteoporosis (Ross, et al.,
J. Biol, Chem.,
1987, 262, 7703), Paget's disease, humoral hypercalcemia of malignancy (Carron et al.,
Cancer Res.
1998, 58, 1930), osteopenia (Lark et al.,
J Bone Miner Res.
2001, 16, 319), endometriosis (Healy et al.,
Hum. Reproductive Update,
1998, 4, 736), angiogenesis, including tumor angiogenesis (Cheresh,
Cancer Metastasis Rev.,
1991, 10, 3-10 and Brooks, et al.,
Cell,
1994, 79, 1157), retinopathy including macular degeneration (Friedlander et al.,
Proc. Natl. Acad. Sci USA
1996, 93, 9764), arthritis, including rheumatoid arthritis (Badger et al.,
Arthritis Rheum,
2001, 44, 128), periodontal disease, psoriasis and smooth muscle cell migration (e.g. restenosis and artherosclerosis, (Brown et al.,
Cardiovascular Res.,
1994, 28, 1815). The compounds of the present invention are &agr;
v
&bgr;
3
antagonists and can be used, alone or in combination with other therapeutic agents, in the treatment or modulation of various conditions or disease states described above. Additionally, it has been found that such agents would be useful as antivirals, antifungals and antimicrobials
The integrin &agr;
v
&bgr;
5
plays a role in neovascularization. Therefore the compounds of this invention which act as antagonists of the &agr;
v
&bgr;
5
integrin will inhibit neovascularization and will be useful for treating and preventing angiogenesis metastasis, tumor growth, macular degeneration and diabetic retionopathy.
It has been shown that the &agr;
v
&bgr;
3
integrin and other &agr;
v
containing integrins bind to a number of Arg-Gly-Asp (RGD) containing matrix macromolecules. Compounds containing the RGD sequence mimic extracellular matrix ligands so as to bind to cell surface receptors. However, it is also known that RGD peptides in general are non-selective for RGD dependent integrins. For example, most RGD peptides which bind to &agr;
v
&bgr;
3
also bind to &agr;
v
&bgr;
5
, &agr;
v
&bgr;
1
and &agr;
IIb
&bgr;
3
. Antagonism of platelet &agr;
IIb
&bgr;
3
(also known as the fibrinogen receptor) is known to block platelet aggregation in humans. In order to avoid bleeding side-effects when treating the conditions or disease states associated with the integrin &agr;
v
&bgr;
3
, it would be beneficial to develop compounds which are selective antagonists of &agr;
v
⊖
3
as opposed to &agr;
IIb
&bgr;
3
.
Certain compounds of this invention antagonize both the &agr;
v
&bgr;
5
and the &agr;
v
&bgr;
3
receptor and therefore are referred to as “mixed &agr;
v
&bgr;
5
/&agr;
v
&bgr;
3
antagonists” or “dual &agr;
v
&bgr;
3
/&agr;
v
&bgr;
5
antagonists”. Such dual or mixed antagonists are useful for treating or preventing angiogenesis, tumor metastasis, tumor growth, diabetic retinopathy, macular degeneration, atherosclerosis and osteoporosis. The compounds of the present invention further show greater selectivity for the &agr;
v
&bgr;
3
and/or &agr;
v
&bgr;
5
integrin than for the &agr;
v
&bgr;
6
integrin. It has been found that the selective antagonism of the &agr;
v
&bgr;
3
integrin is desirable in that the &agr;
v
&bgr;
6
integrin may play a role in normal physiological processes of tissue repair and cellular turnover that routinely occur in the skin and pulmonary tissue. Therefore, compounds of the present invention which selectively inihibit the &agr;
v
&bgr;
3
integrin as opposed to the &agr;
v
&bgr;
6
integrin have reduced side-effects associated with inhibtion of the &agr;
v
&bgr;
6
integrin.
The compounds of this invention are therefore 1) &agr;
v
&bgr;
3
integrin antagonists; or 2) &agr;
v
&bgr;
5
integrin antagonists; or 3) mixed or dual &agr;
v
&bgr;
3
/&agr;
v
&bgr;
5
antagonists. The present invention includes compounds which inhibit the respective integrins and also includes pharmaceutical compositions comprising such compounds. The present invention further provides for methods for treating or preventing conditions mediated by the &agr;
v
&bgr;
3
and/or &agr;
v
&bgr;
5
receptors in a mammal in need of such treatment comprising administering a therapeutically effective amount of the compounds of the present invention and pharmaceutical compositions of the present invention. Administration of such compounds and compositions of the present invention inhibits angiogenesis, tumor metastasis, tumor growth, osteoporosis, Paget's disease, humoral hypercalcemia of malignancy, retinopathy, macular degeneration, arthritis, periodontal disease, smooth muscle cell migration, including restenosis and artherosclerosis, and viral diseases.
Tumor cell invasion occurs by a three step process: 1) tumor cell attachment to extracellular matrix; 2) proteolytic dissolution of the matrix; and 3) movement of the cells through the dissolved barrier. This process can occur repeatedly and can result in metastases at sites distant from the original tumor.
Seftor et al. (Proc. Natl. Acad. Sci. USA, Vol. 89 (1992) 1557-1561) have shown that the &agr;
v
&bgr;
3
integrin has a biological function in melanoma cell invasion. Montgomery et al., (Proc. Natl. Acad. Sci. USA, Vol. 91 (1994) 8856-60) have demonstrated that the integrin &agr;
v
&bgr;
3
expressed on human melanoma cells promotes a survival signal, protecting the cells from apoptosis. Mediation of the tumor cell metastatic pathway by interference with the &agr;
v
&bgr;
3
integrin cell adhesion receptor to impede tumor metastasis would be beneficial.
Brooks et al. (Cell, Vol. 79 (1994) 1157-1164) have demonstrated that antagonists of &agr;
v
&bgr;
3
provide a therapeutic approach for the treatment of neoplasia (inhibition of solid tumor growth) since systemic administration of &agr;
v
&bgr;
3
antagonists causes dramatic regression of various histologically distinct human tumors.
The compounds of the present invention are useful for the treatment, including prevention of angiogenic disorders. The term angiogenic disorders include conditions involving abnormal neovascularization. The growth of new blood vessels, or angiogenesis, also contributes to pathological conditions such as diabetic retinopathy including macular degeneration (Adamis et al., Amer. J. Ophthal., Vol. 118, (1994) 445-450) and rheumatoid arthritis (Peacock et al., J. Exp. Med., Vol. 175, (1992), 1135-1138). Therefore, &agr;
v
&bgr;
3
antagonists would be useful therapeutic agents for treating such conditions associated with neovascularization (Brooks et al., Science, Vol. 264, (1994), 569-571).
It has been reported that the cell surface receptor &agr;
v
&bgr;
3
is the major integrin on osteoclasts responsible for attachment to bone. Osteoclasts cause bone resorption and when such bone resorbing activity exceeds bone forming activity it 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 et al., J. Cell. Biol., Vol. 111 (1990) 1713-1723] and in vivo [Fisher et al., Endocrinology, Vol. 132 (1993)1411-1413]. Antagonism of &agr;
v
&bgr;
3
leads to decreased bone resorption and therefore re
Khanna Ish Kumar
Lu Hwang-Fun
Malecha James W.
Nagarajan Srinivasan Raj
Penning Thomas
Harness Dickey & Pierce
Patel Sudhaker B.
Pharmacia Corporation
Raymond Richard L.
LandOfFree
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