Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-01-18
1998-05-19
Morris, Patricia L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
5142352, 544128, 546126, A61K 3146, C07D45106, C07D45104
Patent
active
057536732
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a quinolinecarboxylic acid derivative. More particularly, the present invention relates to a novel quinolinecarboxylic acid derivative, which has an action for stimulating a serotonin 4 receptor. The present invention also relates to a pharmaceutical use of such a quinolinecarboxylic acid derivative and an intermediate thereof.
BACKGROUND ART
Serotonin is a neurotransmitter which is widely distributed in human and has a remarkable variety of physiological effects. It is hitherto known that serotonin receptors include three subtypes of serotonin 1 receptor, serotonin 2 receptor and serotonin 3 receptor. In addition to these receptors, the existence of serotonin 4 receptor was reported by DUMUIS, A., et al., see Molecular Pharmacology, 34, 880, 1988.
The Serotonin 4 receptor forms a conjugate with a G(Gs) protein to accelerate an adenylate cyclase activity, cf., DUMUIS, A., et al., supra. It is suggested that the receptor is located prejunctionally and promotes the release of acetylcholine through cyclic AMP-dependent block of K channel see RIZZI, C. A. et al., J. Pharmacol. Exp. Ther., 1992, 412-419 (1992).
In the central nervous system, a localization of the serotonin 4 receptor is observed on a high level in the striatum, hippocampus, substantia nigra, olfactory tubercle, etc. but with low concentrations in the cerebral cortex, see GROSSMAN, C. J. et al., Br. J. Pharmacol., 109, 618-624 (1993). There are some reports on smooth muscle relaxation (REEVES, K. Y. et al., Br. J. Pharmacol., 103, 1067-1072 (1991)) and on the cardiovascular effects in both human and pig (BOM, A. H. et al., Br. J. Pharmacol., 93, 663-671 (1988); VILLALON, C. M., et al., ibid., 100, 665-667 (1990); and EGLEN, R. M. et al., ibid., 101, 513-520 (1990)).
In the gut, it is reported that the various actions through the serotonin 4 receptors are observed to show cholinergic nerve-mediating contraction in the guinea pig ileum and in the proximal colon (KAUMANN, A. J. et al., Br. J. Pharmacol., 100, 879-885 (1990) and ELSWOOD, C. L. et al., Eur. J. Pharmacol., 196, 149-155 (1991)), a potentiation of electrical field stimulation in the guinea pig ileum (CRAIG, D. A. et al., Br. J. Pharmacol. Exp. Ther., 252, 1378-1386 (1990)), an induction of chloride secretion in rat distal colon (BUNCE, K. T. et al., Br. J. Pharmacol., 102, 811-816 (1991).
These results suggest that the serotonin 4 receptor present in the gut would take a part in the induction and maintenance of gastrointestinal motility and serotonin 4 receptor stimulants would activate the gastrointestinal motor function to exhibit the action of treating and improving the gastrointestinal dysfunctions or conditions accompanied by motility failure. In fact, cisapride and renzapride, which are effective for stimulating the serotonin 4 receptor, are reported to accelerate the gastrointestinal motor function and improve the gastrointestinal conditions such as heartburn, anorexia, bowel pain, abdominal distension, etc., accompanied by chronic gastritis, diabetes mellitus or postoperative gastroparesis, and are thus effective for the treatment of gastro-esophagal reflux, intestinal pseudo-obstruction and constipation, see TALLEY, N. J., Alimentary Pharmacology and Therapeutics, 6, 273 (1992).
As heterocyclic compounds which possess an activity of antagonizing or stimulating serotonin receptors, Japanese Patent Application Laid-Open No. 4-226980 (European Patent No. 0458636Al) discloses quinoline derivatives which antagonize serotonin 3 receptor. Serotonin 3 receptor antagonists are used to prevent nausea or vomiting induced by antitumor agents or upon radiotherapy. In addition, these antagonists suppress the gastrointestinal motility in the descending gut and are thus considered to be effective for diarrhea-predominant irritable bowel syndrome.
On the other hand, Japanese Patent Application Laid-Open No. 3-197462 (U.S. Pat. No. 5,106,851) discloses quinazolinecarboxylic acid derivatives as heterocyclic compounds that are effective for the
Asanuma Hajime
Hatayama Katsuo
Ohuchi Yutaka
Suzuki Masaji
Yokomori Sadakazu
Morris Patricia L.
Taisho Pharmaceutical Co. Ltd.
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