Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-09-18
2002-07-23
Higel, Floyd D. (Department: 1613)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S326000, C514S341000, C514S397000, C514S398000, C514S399000, C514S400000, C544S139000, C546S210000, C546S274100, 53, 53
Reexamination Certificate
active
06423712
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to imidazolidine derivatives of the formula I,
in which B, E, W, Z, R, R
0
, R
2
, R
3
, e, and h have the meanings indicated below. The compounds of the formula I are valuable pharmaceutically active compounds, which are suitable, for example, for the therapy and prophylaxis of inflammatory disorders, for example, of rheumatoid arthritis, or of allergic disorders. The compounds of the formula I are inhibitors of the adhesion and migration of leucocytes and/or are antagonists of the integrin adhesion receptor VLA-4. They are generally suitable for the therapy or prophylaxis of illnesses which are caused by or associated with an undesired extent of leucocyte adhesion and/or leucocyte migration, or in illnesses in which cell-cell or cell-matrix interactions which are based on VLA-4 receptor/ligand interactions. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use in the therapy and prophylaxis of the disease states mentioned, and pharmaceutical preparations which contain compounds of the formula I.
2. Description of Related Art
The integrins are a group of adhesion receptors which play an important part in cell—cell-binding and cell-extracellular matrix-binding processes. They have an &agr;&bgr;-heterodimeric structure and exhibit a wide cellular distribution and are highly conserved in evolution. The integrins include, for example, the fibrinogen receptor on platelets, which interacts especially with the RGD sequence of fibrinogen, or the vitronectin receptor on osteoclasts, which interacts especially with the RGD sequence of vitronectin or of osteopontin. The integrins are divided into three major groups, the &bgr;2 subfamily with the representatives LFA-1, Mac-1 and p150/95, which are responsible in particular for cell—cell interactions of the immune system, and the subfamilies &bgr;1 and &bgr;3, whose representatives mainly mediate cell adhesion to components of the extracellular matrix (Ruoslahti, Annu. Rev. Biochem. 1988, 57, 375). The integrins of the &bgr;1 subfamily, also called VLA proteins (very late (activation) antigen), include at least six receptors which interact specifically with fibronectin, collagen and/or laminin as ligands. Within the VLA family, the integrin VLA-4 (&agr;4&bgr;1) is atypical, insofar as it is mainly restricted to lymphoid and myeloid cells where it is responsible for cell—cell interactions with a large number of other cells. For example, VLA-4 mediates the interaction of T and B lymphocytes with the heparin II-binding fragment of human plasma fibronectin (FN). The binding of VLA-4 with the heparin II-binding fragment of plasma fibronectin is especially based on an interaction with an LDVP sequence. In contrast to the fibrinogen or vitronectin receptor, VLA-4 is not a typical RGD-binding integrin (Kilger and Holzmann, J. Mol. Meth. 1995, 73, 347).
The leucocytes circulating in the blood normally exhibit only a low affinity for the vascular endothelial cells which line the blood vessels. Cytokines which are released from inflamed tissue cause the activation of endothelial cells and thus the expression of a large number of cell surface antigens. These include, for example, the adhesion molecules ELAM-1 (endothelial cell adhesion molecule-1; also designated as E-selectin), which, inter alia, binds neutrophils, ICAM-1 (intercellular adhesion molecule-1), which interacts with LFA-1 (leucocyte function-associated antigen 1) on leucocytes, and VCAM-1 (vascular cell adhesion molecule-1), which binds various leucocytes, inter alia lymphocytes (Osborn et al., Cell 1989, 59, 1203). VCAM-1, like ICAM-1, is a member of the immunoglobulin gene superfamily. VCAM-1 (first known as INCAM-110) was identified as an adhesion molecule which is induced on endothelial cells by inflammatory cytokines such as TNF and IL-1 and lipopolysaccharides (LPS). Elices et al. (Cell 1990, 60, 577) showed that VLA-4 and VCAM-1 form a receptor-ligand pair which mediates the adhesion of lymphocytes to activated endothelium. The binding of VCAM-1 to VLA-4 does not take place via an interaction of VLA-4 with an RGD sequence; this sequence is not contained in VCAM-1 (Bergelson et al., Current Biology 1995, 5, 615). VLA-4, however, also occurs on other leucocytes, and the adhesion of leucocytes other than lymphocytes is also mediated via the VCAM-1/VLA-4 adhesion mechanism. VLA-4 thus represents an individual example of a &bgr;1 integrin receptor which, via the ligands VCAM-1 and fibronectin, plays an important part both in cell—cell interactions and in cell-extracellular matrix interactions.
The cytokine-induced adhesion molecules play an important part in the recruitment of leucocytes into extravascular tissue regions. Leucocytes are recruited into inflammatory tissue regions by cell adhesion molecules which are expressed on the surface of endothelial cells and serve as ligands for leucocyte cell surface proteins or protein complexes (receptors) (the terms ligand and receptor can be considered interchangeable here.) Leucocytes from the blood must first adhere to endothelial cells before they can migrate into the synovium. Since VCAM-1 binds to cells which carry the integrin VLA-4 (&agr;4&bgr;1), such as eosinophils, T and B lymphocytes, monocytes or neutrophils, the VCAM-1/VLA-4 mechanism has the function of recruiting cells of this type from the blood stream into areas of infection and inflammatory foci (Elices et al., Cell 1990, 60, 577; Osborn, Cell 1990, 62, 3; Issekutz et al., J. Exp. Med. 1996, 183, 2175).
The VCAM-1/VLA-4 adhesion mechanism has been connected with a number of physiological and pathological processes. Apart from cytokine-activated endothelium, VCAM-1 is additionally expressed, inter alia, by the following cells: myoblasts, lymphoid dendritic cells and tissue macrophages, rheumatoid synovium, cytokine-stimulated neural cells, parietal epithelial cells of the Bowman's capsule, the renal tubular epithelium, inflamed tissue during heart and kidney transplant rejection and by intestinal tissue in graft-versus-host disease. VCAM-1 is also expressed on those tissue areas of the arterial endothelium which correspond to early arteriosclerotic plaques of a rabbit model. Additionally, VCAM-1 is expressed on follicular dendritic cells of human lymph nodes and is found on stroma cells of the bone marrow, for example in the mouse. The latter finding points to a function of VCAM-1 in B-cell development. Apart from cells of hematopoietic origin, VLA-4 is also found, for example, on melanoma cell lines, and the VCAM-1/VLA-4 adhesion mechanism is connected with the metastasis of such tumors (Rice et al., Science 1989, 246, 1303).
The main form in which VCAM-1 occurs in vivo on endothelial cells and which is the dominant form in vivo is designated as VCAM-7D and carries seven immunoglobulin domains. The domains 4, 5 and 6 are similar in their amino acid sequences to the domains 1, 2 and 3. The fourth domain is removed in a further form, consisting of six domains, designated here as VCAM-6D, by alternative splicing. VCAM-6D can also bind VLA-4-expressing cells.
Further details on VLA-4, VCAM-1, integrins and adhesion proteins are found, for example, in the articles by Kilger and Holzmann, J. Mol. Meth. 1995, 73, 347; Elices, Cell Adhesion in Human Disease, Wiley, Chichester 1995, p. 79; and Kuijpers, Springer Semin. Immunopathol. 1995, 16, 379.
On account of the role of the VCAM-1/VLA-4 mechanism in cell adhesion processes, which are important, for example, in infections, inflammations or atherosclerosis, attempts have been made to intervene in these adhesion processes to control illnesses, in particular, for example, in inflammation (Osborn et al., Cell 1989, 59,1203). A method of doing this is the use of monoclonal antibodies which are directed against VLA-4. Monoclonal antibodies (mAB) of this type, which act as VLA-4 antagonists to block the interaction between VCAM-1 and VLA-4, are known. Thus, for example, the anti-VLA-4 mAB H
Schmidt Wolfgang
Seiffge Dirk
Stilz Hans Ulrich
Wehner Volkmar
Aventis Pharma Deutschland GmbH
Heller Ehrman White and McAuliffe LLP
Higel Floyd D.
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