Carbostyril derivatives for inhibiting production of interleukin

Details Carbostyril derivatives for inhibiting production of interleukin Carbostyril derivatives for inhibiting production of interleukin

1995-06-07

1997-06-10

Cintins, Marianne M.

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

056375972

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP94/01739 filed Oct. 17, 1994.


FIELD OF THE INDUSTRIAL UTILIZATION

The present invention relates to an agent for inhibiting production of interleukin-8, an agent for inhibiting activation of granulocytes, an agent for curing inflammatory diseases, an agent for curing Behcet disease, an agent for curing stomatitis, an agent for curing nephritis and an agent for curing voice disorders. More particularly, the present invention relates to an agent for inhibiting production of interleukin-8, an agent for inhibiting activation of granulocytes, an agent for curing inflammatory diseases, an agent for curing Behcet disease, an agent for curing stomatitis, an agent for curing nephritis and an agent for curing voice disorders, all comprising, as an effective ingredient, a carbostyril derivative represented by the following general formula (I) ##STR2## [wherein R is a halogen atom (a fluorine atom, a chlorine atom, a bromine atom or an iodine atom); the substitution site of the substituent on the carbostyril skeleton is 3- or 4-position of the carbostyril skeleton; and the carbon-carbon bond between 3- and 4positions in the carbostyril skeleton is a single bond or a double bond] or a salt thereof, preferably 2-(4-chlorobenzoylamino)-3-(2-quinolon-4-yl)propionic acid or a salt thereof.


BACKGROUND ART

The carbostyril derivatives represented by the above general formula (I) and the processes for producting thereof are described in Japanese Patent Publication No. 35623/1988. Further, the usefulness of the carbostyril derivative as an anti-gastric ulcer agent is described in Japanese Patent Application Kokai (Laid-Open) No. 74329/1991.
Also the usefulness of these carbostyril derivatives as an agent for curing diabetes is described in International Publication No. WO 92/21342; their usefulness as an agent for protecting intestinal mucosa from disorders is described in International Publication No. WO 94/12182; and their usefulness as an agent for inhibiting reduction in somatostatin secretion is described in International Publication No. WO 93/24043.
Interleukin-8 (hereinafter abbreviated to IL-8), which is also called a neutrophil leucocytes-activating factor, is a basic heparin binding polypeptide composed of 72 amino acids and is a cytokine produced not only from activated macrophages but also from various types of human cells.
IL-8 has various physiological activities such as the followings. (1) IL-8 is a chemotactic factor to neutrophil leucocytes, T cells and basophil leucocytes; (2) IL-8 activates neutrophil leucocytes, releases a lysosomal enzyme, changes the adhesion of neutrophil leucocytes to the endothelial cells of blood cells, and exasperates the inhibitory effect for propagation of candida species; (3) IL-8, when injected into joints, gives rise to destruction of synovial membrane accompanied with wetting of a large amount of neutrophil leucocytes; (4) IL-8 increases the appearance of adhesion factor on the surface of neutrophil leucocytes; (5) IL-8 controls the release of histamine from basophil leucocytes; and (6) IL-8 activates neutrophil leucocytes in artificial organs. IL-8 is also called as an inflammatory cytokine, and abnormal production of IL-8 and excessive reaction to IL-8 are thought to cause inflammatory diseases.
Behcet disease is a peculiar systemic inflammatory disease which attacks the mucous membrane of oral cavity, eyes, pudenda, skin and nearly all organs. The cause of the disease is said to be connected with infection, immunological abnormality, etc. but is not clarified yet. In curing the disease, there are used steroidal hormones, colchicine, Endoxan, cyclosporins, etc., but they must be used with the greatest possible care in view of their side effects. No useful curing agent has been found yet which is safe and can be administered over a long period.
The aphthous stomatitis caused by diseases such as stomatitis and the like is difficult to clinically distinguish from the aphthous stomatitis caused by Behcet disease and, similarly to Behcet dise

REFERENCES:
Arzneimittel Forschung Drug Research 43 (I), No., 3, Mar. 1993, pp. 363-366.
Research Communications In Chemical Pathology and Pharmacology vol. 78, No. 3, pp. 259-277 (Dec. 1992).
Nippon Rinsho, vol. 51, No. 12, Dec. 1993, pp. 3154-3158.
Patent Abstracts of Japan vol. 15, No. 238 (C-841) [4766] (JP-A-3-74329), 1992.
Database WPI, Derwent Publication/Patent Abstracts of Japan, vol. 12, No. 365 (C-532) [3212] (JP-A-63-119467), 1988.
Patent Abstracts of Japan, vol. 14, No. 453 1990 (C-764) [4396] (JP-A-2-178227).

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