Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-06-10
1997-11-11
Conrad, Joseph
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 3141
Patent
active
056864795
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/JP92/01619 filed Dec. 10, 1992.
This invention relates to an immunosuppressive drug which comprises a specific thienotriazolodiazepine compound, an immunosuppression method and use thereof.
Organ transplantation has been carried out extensively in recent years, with the use of immunosuppressive drugs such as ciclosporin, azathioprine, steroidal drugs and the like in order to inhibit rejection reactions caused by the transplantation. However, frequent use of these immunosuppressive drugs causes renal toxicity or other serious side effects, thus bringing about problems in the field of medical treatment.
It has been disclosed, for example, in Transplantation Proceedings, vol.20, no.2, supplement 1, pp.313-315 (February, 1988) that a platelet activating factor antagonist (PAF antagonist), which is expected to be used as a drug for the treatment of inflammatory diseases, allergic diseases and the like, is effective in increasing immunosuppression action of ciclosporin, and in Japanese Patent Application Toppyo No. Hei-3-500898 that side effects of ciclosporin are reduced by the combined use of a thienotriazolodiazepine.
Also, it has been revealed that intercellular adhesion molecules are taking an important role in rejection reactions at the time of organ transplantation. It has been reported that rejection reactions accompanying organ transplantation were suppressed with prolonged survival of the grafts when antibodies specific for LFA-1 (leukocyte function-associated antigen-1, a molecule composed of CDlla (.alpha. chain) and CD18 (.beta. chain)) and ICAM-1 (intercellular adhesion molecule-1), both known as intracellular adhesion molecules, were administered to mice which have been subjected to allogenic heart transplantation (Science, vol.225, pp.1125-1127, Feb. 28, 1992). In consequence, it is possible to suppress the organ transplantation-accompanying rejection reactions by the use of specific antibodies to inhibit the cell adhesion caused via the intercellular adhesion molecules LFA-1 and ICAM-1.
In addition, great concern has been directed in recent years toward the development of a method for the treatment of rheumatoid arthritis which is regarded as an considerable autoimmune disease because the disease is chronic by itself and progressive and entails joint function disorder. Though nonsteroidal anti-inflammatory drugs, steroidal drugs, immunomodulators and the like are used in the pharmacotherapy of articular rheumatism, it is necessary to develop more effective therapeutic drugs because nonsteroidal anti-inflammatory drugs are not so effective and steroidal drugs and immunomodulators generate side effects with a high frequency and sometimes result in serious cases. On the other hand, it has been reported that onset of arthritis was inhibited when an antibody specific for the intercellular adhesion molecule ICAM-1 was administered to a rat adjuvant arthritis model (Journal of Immunology, vol.147, pp.4167-4171, Dec. 15, 1991).
However, use of the antibody is limited because of a possibility to induce allergy, anaphylactic shock and the like when it is administered.
In consequence, it has been suggested that a drug which inhibits cell adhesion caused via the intercellular adhesion molecules LFA-1, ICAM-1 and the like, or a drug which inhibits expression of these intercellular adhesion molecules on the cell surface, could be used as an immunosuppressive drug having less side effects, because such a drug would inhibit organ transplantation-induced rejection reactions and would be useful for the treatment of autoimmune diseases.
DISCLOSURE OF THE INVENTION
With the aim of overcoming the aforementioned problems, the inventors of the present invention have conducted intensive studies and found that a thienotriazolo-diazepine compound wherein the 2-position of its diazepine ring is alkylated can increase actions of ciclosporin and the like immunosuppressive drugs, shows an immunosuppression function by itself, has a function to inhibit adhesion of leukocytes to blood vessel
REFERENCES:
patent: 5221671 (1993-06-01), Okano et al.
patent: 5304552 (1994-04-01), Okano
Muino et al, "Prolongation of Rabbit Skin Allograft Survival with Immunosuppression and Specific Antagonist of Platelet-Activating Factor", Transplantation Proceedings, vol. XX, No. 1 (Suppl. 1), pp. 313-315 (Feb. 1988).
Watanabe et al, "Stimulation of Neutrophil Adherence to Vascular Endothelial Cells by Histamine and Thrombin and Its Inhibitors by PAF Antagonist and Dexamethasone", Br. J. Pharmacol., 102:239-245 (1991).
Walser et al, "Thienotriazolodiazepines as Platelet-Activating Factor Antagonists. Steric Limitations for the Substituent in Position 2", J. Med. Chem., 34:1440-1446 (1991).
Aratani Hidekazu
Chiba Kenji
Hoshino Yukio
Komatsu Hirotsugu
Moriwaki Minoru
Conrad Joseph
Yoshitomi Pharmaceutical Industries Ltd.
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