Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-11-02
1996-05-28
Cintins, Marianne M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514254, 514312, A61K 31495, A61K 3147
Patent
active
055211852
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP94/00326, filed Feb. 28, 1994.
TECHNICAL FIELD
This invention relates to a graft rejection inhibitor and an IL-1 production inhibitor, each comprising a defined carbostyril derivative as an active ingredient.
BACKGROUND ART
The organ transplantation performed these days encompasses a broad spectrum of tissues, including cardiac, pulmonary, hepatic, pancreatic, small intestinal, renal, corneal, dermal, combined heart-lung and bone marrow transplants. Meanwhile, as drugs essential to such organ transplantations, immunosuppressants such as cyclosporine, azathioprine, mizoribine, OKT3 which is a monoclonal antibody, steroids, antilymphocyte globulins, etc. are in use for prophylactic or therapeutic immunosuppression in such organ transplantations. The advent of these drugs resulted in a marked enhancement of the success rate of transplantation but the massive and prolonged administration of the drugs met with not only severe myelosuppression and the consequent side effects such as leukopenia, thrombopenia, anemia and renal failure due to nephrotoxicity but also the risk of dangerous complications such as increased susceptibility to infection, anemia, bleeding tendency and so on. Therefore, the dosage of such drugs has to be restricted in many cases.
In recent years, for further enhancement of the success rate of transplantation and for the purpose of alleviating side effects, research and development efforts are being made on FK506, RS61443, 15-deoxyspergualin; DSG), adhesion molecule antibodies, etc., but antibody preparations have the disadvantage of being unsuited for maintenance therapy requiring long-term administration because heterologous proteins are injected. Moreover, although combination therapies using the above-mentioned drugs are practiced in GVHD (graft-versus-host disease), a unique disease complicating a homoplastic marrow transplantation, the therapeutic effects have not necessarily been satisfactory. Therefore, the industry needs research and development for a new drug which may be termed a graft rejection inhibitor and can be used in a long-term-maintenance therapy for positive suppression of both acute and chronic rejections with a reduced risk of side effects in cases of the organ transplantations mentioned above.
Meanwhile, a large number of cytokines has been discovered as proteineous factors which inhibit the expression of various physiologic functions such as immune response, inflammatory reaction and hematopoiesis in the host and with the progressive elucidation of their structures and actions, it has become increasing clear that the actions of these cytokines are not only confined to the immune system but extend to various biologic functions, thus being closely associated with the genesis, differentiation, homeostasis and pathophysiology of the body.
Among said cytokines, IL-1 is a proteinaceous factor produced chiefly from monocytes and macrophages and is a polypeptide with a molecular weight of about 12000-18000 [S. B. Mizel et. al., Immunol. Rev., 63, 51-71, 1982]. This IL-1 acts on various kinds of cells, exhibits various biological activities and, hence, plays an important role in nearly all the vital reactions, such as immunity, inflammation, hematopoiesis, endocrine system and cerebral nervous system. IL-1 occurs in two distinct molecular forms as classified by isoelectric point, viz. pI5 and pI7, and whereas the former is known as IL-1.alpha., the latter is known as IL-i1.beta. Oppenheim, J. J., et al., Immunol. Today, 7, 45, 1986: Dinarello, C. A., Adv. Immuno., 44, 153, 1988]. The homology of the amino acid sequence of the respective molecular forms is as high as 60-70% even among different animal species but the two molecular forms show only a low homology of 25% even in the same species. Moreover, both IL-1.alpha. and IL-1.beta. reportedly bind to the same receptor on the cell membrane [Lowenthal, K., et al., J. Exp. Med., 164, 1060, 1986]. It has also been reported that IL-1 exerts direct growth inhibiting and cytocidal actions o
REFERENCES:
patent: 4415572 (1983-11-01), Tominaga et al.
Busch et al, "The Inhibitory Effects of a Positive Inotropic Quinolinone Derivative, 3,4-dihydro-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-2-(1H)-Quinolinone( OPC-8212), on Bone-Marrow Progenitor Cells and Peripheral Lymphocytes", Eur. J. Clin. Pharmacol., 42:629-634 (1992).
JPA 57-77676 (Otsuka Pharmaceutical Co., Ltd.) May 15, 1982--Derwent Abstract.
JPA 58-83677 (Otsuka Pharmaceutical Co., Ltd.) May 19, 1983--Derwent Abstract.
JPA 62-135423 (Otsuka Pharmaceutical Co., Ltd.) Jun. 18, 1987-Derwent Abstract.
Cintins Marianne M.
Matsumori Akira
Otsuka Pharmaceutical Co. Ltd.
Weddington Kevin E.
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