Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Reexamination Certificate
2000-10-10
2002-07-16
Raymond, Richard L. (Department: 1624)
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
C544S333000, C546S001000, C546S304000, C546S329000, C546S339000, C546S244000, C546S246000, C546S248000, C548S304400, C548S311100, C514S275000, C514S259500, C514S331000, C514S394000, C514S398000
Reexamination Certificate
active
06420558
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to aminopiperidine derivatives having integrin &agr;
v
&bgr;
3
antagonistic activity and pharmaceuticals comprising the same.
2. Background Art
A signal transduction system is very important to organisms from the viewpoint of maintaining life and inheriting the life over to the next generation, specifically from the viewpoints of physiological significance, mechanisms for the regulation of gene expression and the like. It has recently been clarified that integrins, glycoprotein receptors which are involved in cell adhesion and penetrate cell membranes, are related, for example, to wound healing and hemostasis, phagocytosis, biophylaxis, and the construction of cytoskeletons and, in addition, as such are molecules for signal transduction. For this reason, in recent years, organic chemistry associated with integrins has suddenly become drawn attention from the viewpoint of pharmacology, as well as from the viewpoints of molecular biology and cell biology.
It is being elucidated that, while the conformation of integrins undergoes a dynamic and complicate change, integrins binds to various ligands to transmit signal in both intracellular and extracellular directions (Junichi Takagi et al., The 50th Annual Meeting of the Japan Society for Cell Biology, S5-1, 1997). T. A. Springer of Harvard Medical School has recently predicted that a certain activated integrin has a &bgr;-propeller structure and binds to a ligand on the upper face of the &bgr;-propeller (Proc. Natl. Acad. Sci. USA, 94, 65, 1997). This hypothesis was also supported by researchers in our country (Atsushi Irie et al., The 50th Annual Meeting of the Japan Society for Cell Biology, S5-2, 1997), and three-dimensional analysis on a molecular level associated with the activation of integrins, binding between integrins and ligands and the like has been initiated on a full scale.
Among them, integrin &agr;
v
&bgr;
3 binds
binds to various extracellular matrixes, that is, ligands deeply involved, for example, in biodynamics or the crisis of diseases, such as vitronectin, fibrinogen, fibronectin, osteopontin, thrombospondin, von Willebrand factors, and collagen, to form complexes. Accordingly, integrin &agr;
v
&bgr;
3
is of special interest as a potential drug target. In fact, &agr;
v
&bgr;
3
is expressed in a large amount in B cells, macrophages, monocytes, smooth muscle cells, activated endothelial cells and the like. Further, &agr;
v
&bgr;
3
is known not to be strongly expressed in endothelial cells in a resting stage, but to be highly activated in the course of growth and infiltration, that is, in vascularization, wound healing, and inflamed sites. Further, the correlation between the frequency of expression of &agr;
v
&bgr;
3
and the increase in infiltration of cancer has been observed in various cancer cells. On the other hand, a group of researchers at Scripps Research Institute in U.S.A. have clarified by advanced computer-assisted video imaging microscopy that microvascular expression of &agr;
v
&bgr;
3
is observed during experimental middle cerebral artery occlusion and reperfusion in a baboon as a model (Y. Okada et al., Am. J. Pathol., 149, 37, 1996).
As described above, relationship of cell species, which express integrin &agr;
v
&bgr;
3
in vivo, with &agr;
v
&bgr;
3
activation stage, biophylaxis mechanism and the like has led to an expectation of clinical application of molecules having integrin &agr;
v
&bgr;
3
antagonistic activity in various fields. In fact, compounds having integrin &agr;
v
&bgr;
3
antagonistic activity are intended to be used clinically, and the results of animal tests on compounds having &agr;
v
&bgr;
3
antagonistic activity in a wide range of diseases have been reported (S. S. Srivatsa et al., The 69th Annual Meeting of American Heart Association, 0231, 1996 (DuPont-Merck); J. F. Gourvest et al., The 18th Annual Meeting of The American Society for Bone and Mineral Research, p228, 1996 (Roussel-Hoechst); S. B. Rodan et al., The 18th Annual Meeting of The American Society for Bone and Mineral Research, M430, 1996 (Merck); T. L. Yue et al., The 70th Annual Meeting of American Heart Association, 3733, 1997 (SmithKline Beecham); A. L. Racanelli et al., The 70th Annual Meeting of American Heart Association, 3734, 1997 (DuPont-Merck); and W. S. Westlin, Conference of American IBC, Feb. 23, 1998 (Searle & Co.).
From the viewpoint of chemical structure, compounds having integrin &agr;
v
&bgr;
3
antagonistic activity can be classified into antibodies, low-molecular peptide and compounds analogous thereto, and small molecules. All the antagonists are structurally related to the sequence of tripeptide RGD (arginine-glycine-aspartic acid) that are considered indispensable for recognition in the attachment of a ligand. Low-molecular peptides having antagonistic activity include disintegrins derived from venom of snakes and, in addition, cyclic peptides. One of them, GpenGRGDSPCA, has been reported to inhibit migration of smooth muscle cells and to block integrin &agr;
v
&bgr;
3
, thereby actually inhibiting neointima formation in rabbits (E. T. Choi et al., J. Vasc. Surg.,19, 125, 1994). On the other hand, the cyclic peptide containing BTD designed by a &bgr;-turn mimic has been proved to strongly binds to &agr;
v
&bgr;
3
receptors (M. Goodman et al., Bioorg. Med. Chem. Lett., 7, 997, 1997).
Several methods are known for designing small molecules through the utilization of the amino acid sequence of interest (RGD being used herein) as a key. For example, a peptide mimetic for constructing a new molecule based on the backbone of a peptide chain is generally known in the art. The concept of a new de novo design focused on the chemical structure and spatial configuration of amino acid side chains has been introduced for the first time early in the 1990s (R. Hirschman et al., J. Am. Chem. Soc., 115, 12550, 1993). An attempt to apply this approach to the design and synthesis of &agr;
v
&bgr;
3
antagonists has already been initiated (K. C. Nicolaou et al., Tetrahedron, 53, 8751, 1997).
Up to now, small molecules having &agr;
v
&bgr;
3
antagonistic activity are disclosedipn WO 9532710, WO 9637492, WO 9701540, WO 9708145, WO 9723451, WO 9723480, WO 9724119, WO 9726250, WO 9733887, WO 9736858, WO 9736859, WO 9736860, WO 9736861, WO 9736862, and EP 0796855. Low-molecular organic compounds having &agr;
v
&bgr;
3
antagonistic activity are also disclosed in U.S. Pat. Nos. 5,843,906 and 5,852,210, WO 9737655, WO 9808840, WO 9818460, WO 981359, WO 9835949, WO 9846220, British Patent Nos. 2326609 and 2327672, WO 9843962, WO 9724336, WO 9830542, WO 9905107, EP 820988, EP 820991, EP 853084, and Bioorganic & Medicinal Chemistry, 6, 1185-1208 (1998), which were published after the priority date of the present application.
SUMMARY OF THE INVENTION
The present inventors have found that a certain group of derivatives have potent integrin &agr;
v
&bgr;
3
antagonistic activity. The present inventors have also found that a certain group of derivatives have potent cell adhesion inhibitory activity. The present inventors have further found that a certain group of derivatives have potent GP IIb/IIIa antagonistic activity and human platelet aggregation inhibitory activity.
Accordingly, an object of the present invention is to provide a compound having integrin &agr;
v
&bgr;
3
antagonistic activity, cell adhesion inhibitory activity, GP IIb/IIIa antagonistic activity, and/or human platelet aggregation inhibitory activity.
Another object of the present invention is to provide a therapeutic agent for treating a disease selected from the group consisting of integrin &agr;
v
&bgr;
3
-mediated diseases, diseases such that the inhibition of cell adhesion is effective for the treatment of said diseases, and diseases such that GP IIb/IIIa antagonistic action and/or platelet aggregation inhibitory action are effective for the treatment of said diseases, and an agent for inhibiting platelet aggregation.
The compounds according to the present
Ajito Keiichi
Hachisu Mitsugu
Ishikawa Minoru
Katano Kiyoaki
Kubota Dai
Meiji Seika Kaisha Ltd.
Patel Sudhaker B.
Raymond Richard L.
Wenderoth , Lind & Ponack, L.L.P.
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