Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2002-02-05
2004-06-15
Berch, Mark L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S210000, C546S215000, C546S216000, C546S223000, C546S235000, C544S332000, C544S335000, C514S269000, C514S275000, C514S326000, C514S327000, C514S331000
Reexamination Certificate
active
06750219
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to novel &ohgr;-amino-&agr;-hydroxycarboxylic acid derivatives having integrin &agr;
v
&bgr;
3
antagonistic activity and a pharmaceutical composition comprising as active ingredient at least one of said derivatives.
2. Description of Related Art
A signal transmission system is very important to organisms from the viewpoints of physiological significance, the regulation of gene expression and the like. It has been clarified that integrins, i.e., 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 signal transfer molecules (Cell, 69, 11, (1992)). 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 Japan (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 as well as binding between integrins and ligands and the like has been initiated in real earnest.
T. A. Springer et al. has recently substantiated a hypothesis regarding the &bgr;-propeller domain by experimentation, and has suggested that the &bgr;-propeller domain in integrin &agr;-subunit has important interaction with integrin &bgr;-subunit (Proc. Natl. Acad. Sci. USA, 95, 4870, 1998).
Among others, integrin &agr;
v
&bgr;
3
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 (DN & P, 10, 456, 1997). In fact, &agr;
v
&bgr;
3
is expressed in a large amount in B cells, macrophages, monocytes, smooth muscle, 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-Merc); 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-Merc); M. Friedlander et al., Conference of American IBC, Sep. 11, 1997 (The Scripps Research Institute); W. S. Westlin, Conference of American IBC, Feb. 23, 1998 (Searle); M. W. Lark et al., The 2nd Joint Conference of The American Society for Bone and Mineral Research and International Bone and Mineral Society, T064, 1998 (SmithKline Beecham); R. K. Keenan et al., Bioorg. Med. Chem. Lett., 8, 3171, 1998 (SmithKline Beecham); C. P. Carron et al., Cancer Res., 58, 1930, 1998 (Searle); and W. H. Miller et al., Bioorg. Med. Chem. Lett., 9, 1807, 1999 (SmithKline Beecham)).
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 low-molecular organic compounds. 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 and to block integrin &agr;
v
&bgr;
3
, thereby to actually inhibit neointima formation in rabbits (E. T. Choi et al., J. Vasc. Surg., 19, 125, 1994). Further, RGD-containing cyclic peptide G4120 inhibited neointima formation in hamsters (Circulation, 90, 2203 (1994)). Further, Scripps Research Institute has recently reported that cyclic peptides having &agr;
v
&bgr;
3
antagonistic activity are promising novel therapeutic agents for rheumatic arthritis (C. M. Storgard et al., J. Clin. Invest., 103, 47 (1999)). On the other hand, cyclic peptides containing BTD designed by a &bgr;-turn mimic have been proved to strongly bind 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 here) as a clue (Gen Ojima et al., Journal of The Society of Synthetic Organic Chemistry, 52, 413 (1994); Toshio Furuya, Shin-Tanpakushitu Oyo Kogaku, Fujitec Corporation). A peptide mimesis 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 disclosed in WO 95/32710 (Merck); WO 96/37492 (Dupont-Merc); WO 97/01540 (SmithKline Beecham); WO 97/08145 (Searle Co.); WO 97/23451 (Merck); WO 97/23480 (Dupont-Merc); WO 97/24119 (SKB); WO 97/26250 (Merck); WO 97/33887 (Dupont-Merc); WO 97/36858 (Searle); WO 97/36859 (Searle); WO 97/36860 (Searle); WO 97/36861 (Searle); WO 97/36862 (Searle); WO 97/24336 (SmithKline Beecham); WO 97/37655 (Merck); WO 98/08840 (Merck); WO 98/18460 (Merck); WO 98/25892 (Lilly); WO 98/30542 (SmithKline Beecham); WO 98/31359 (Merck); WO 98/35949 (Merck); WO 98/43962 (Dupont-Merc); WO
Ajito Keiichi
Fujishima Kazuyuki
Gomi Shuichi
Ishikawa Minoru
Kubota Dai
Berch Mark L.
Habte Kahsay
Meiji Seika Kaisha Ltd.
Wenderoth , Lind & Ponack, L.L.P.
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