Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-07-03
1999-03-23
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
A61K 3147
Patent
active
058860100
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to an inhibitor of production or secretion of tumor necrosis factor-.alpha. (TNF-.alpha.), which comprises as an active ingredient a carbostyril compound or a pharmaceutically acceptable salt thereof.
BACKGROUND OF THE INVENTION
There have been found various cytokines which are a protein inhibiting manifectation of biofunctions such as immunoresponse, inflammatory reaction and hemopoietic function in biobody, and the structures and activities thereof have gradually been clarified. With such clarification, it has also been made clear that they are effective not only onto the immune system but also onto various biofunctions and have much relevance to generation of biobody, differentiation, homeostasis, and pathological physiology.
Among the cytokines, TNF has been found as an antitumor cytokine and has been expected to be useful as an antitumor agent. However, later on it was found that it is identical with cachectin which is a cachexy-inducing factor. It is reported that TNF has an activity of stimulating production of other cytokines such as IL-1, etc., proliferative activity of fibroblast, endotoxin shock-inducing activity, an activity of promoting the adhesion of leukocytes to endothelium by increasing intercellular adhesion molecules (ICAM-1, ICAM-2) or endothelial leukocyte adhesion molecule-i (ELAM-1), an activity of bone absorption, and an activity of et al., Nature, 316, 552-554 (1985); Peetre, C., et al., J. Clin. Invest., 78, 1694-1700 (1986); Kurt-Jones, E. A., et al., J. Immunol., 139, 2317-2324 (1987); Bevilacqua, M. P., et al., Science, 241, 1160-1165 (1989); Akatu, K. & Suda, T., Medical Practice, 8 (9), 1393-1396 (1991)!.
Moreover, it is reported that in bacterial or parasitic infectious diseases, TNF is contained in a higher concentration in blood and (1991); and Nakao, M., IGAKU-NO-AYUMI, 159 (8), 471-474 (1991)!. It is also reported that in rheumatoid arthritis, the joint fluid and blood 31, 1041 (1988); Chu, C. Q., et al., Arthritis Rheum., 34, 1125-1132 (1991); Macnaul, K. L., et al., J. Immunol., 145, 4154-4166 (1990); Brennan, F. M., et al., J. Immunol., 22, 1907-1912 (1992); and Brennan, F. M., et al., Bri. J. Rheum., 31, 293-298 (1992)!.
It is further reported that in patients suffered from a severe respiratory diseases: adult respiratory distress syndrome (ARDS), the phlegm of the 73 (1986)!, and that TNF participates also in the severity of virus
It is also reported that the blood concentration of TNF-.alpha. raises in Latini, R., et al., J. Cardiovasc. Pharmacol., 23, 1-6 (1994)!, and it is A. M., et al, Science, 249, 61-64 (1990)!. It is recently reported that Science, 257, 387-389 (1992); and Pagani, D. F., et al., J. Clin. Invest., 90, 389-398 (1992)!.
However, there have never been developed a chemo-therapeutic drug which exhibits satisfactory effects on the above-mentioned various diseases such as rheumatoid arthritis, endotoxin shock, or ARDS, and there have merely been used some steroids, antiinflammatory agents, platelet agglutination inhibitors, antibiotics from the nostropic viewpoint. Since it has been suggested the correlation between these diseases and the raising of concentration and activity of TNF-.alpha., it has recently been tried to employ an antibody of TNF-.alpha. in the treatment of these diseases, but it did not give satisfactory result. Thus, it has been desired to find and develop a new type drug for the treatment of these diseases by a new mechanism to inhibit the accelerated production or secretion of TNF-.alpha.. hereinafter are disclosed in U.S. Pat. No. 5,053,514 as a cardiotonic agent, wherein the processes for the preparation thereof are also disclosed. It is also known that these compounds have myocardial contract increasing activity (i.e. positive inotropic activity), coronary blood flow increasing activity, hypotensive activity, an activity of inhibiting blood vessel contract induced by norepinephrine, and antiinflammatory activity (cf. the above U.S. Patent as well as U.S. Pat. Nos. 5,266,577 an
REFERENCES:
patent: 5053514 (1991-10-01), Fujioka et al.
patent: 5401754 (1995-03-01), Fujioka et al.
Mori Toyoki
Ono Yukihisa
Tominaga Michiaki
Goldberg Jerome D.
Otsuka Pharmaceutical Company Limited
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