Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1996-03-29
1997-10-14
Higel, Floyd D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514396, 5483047, 5483051, 5483054, 5483057, 5483061, A61K 31415, C07D40306
Patent
active
056773269
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE ART
The present invention relates to indoline compound which is useful as drug, and specifically as 5-HT.sub.3 receptor antagonist.
BACKGROUND OF THE ART
The 5-HT.sub.3 receptor, which is one of the 5-hydroxytryptamine (5-HT, generic name: serotonin) receptors, is widely distributed throughout the sensory nervous system, the autonomic nervous system and the central nervous system, and the action of 5-HT on their receptors is said to cause gastrointestinal motor disturbances, irritant moods, vomiting, algesia, bradycardia, and to have nervous activity affecting feelings, appetite, memory, etc. Consequently, drug agents with 5-HT.sub.3 receptor antagonism are reported to be effective for the treatment and prevention of the irritant mood, vomiting, accompanying cancer chemotherapy, migraine, arrhythmia, and nervous disorders including schizophrenia, mania, etc., as well as diarrhea, irritable bowel syndrome, increased urinary frequency and dysuria.
Among such drug agents with 5-HT.sub.3 receptor antagonism, there are used name: "Metoclopramide"), methyl!-4H-carbazol-4-one-hydrochloride dihydrate (GR38032F, generic name: indol-3-ylcarboxylate (ICS 205-930, generic name: "Tropisetron"), N-(endo-9-methyl-9-azabicyclo name: "Granisetron"), etc., which are used to treat vomiting elicited by antitumor agents such as cisplatin and the like, while other compounds carbonyl!-4,5,6,7-tetrahydrobenzimidazole hydrochloride (YM-060) are currently receiving much attention.
However, a number of subtypes of the 5-HT.sub.3 receptor are reported to exist. As a result of research on a 5-HT.sub.3 receptor in the intestine, it is believed that this intestinal 5-HT.sub.3 receptor plays a role in various forms of diarrhea, for example stress-related diarrhea and secretory diarrhea caused by cholera and other bacteria, and thus compounds with strong antagonism for the intestinal 5-HT3 receptor are expected to work as antidiarrheal drugs. It has in fact been reported that the above mentioned 5-HT.sub.3 receptor antagonists Ondansetron, Granisetron, YM-060, etc. suppress stress-related diarrhea in animal models, with the effect of YM-060 being the strongest (The Journal of Pharmacology and Experimental Therapeutics, Vol.261, No. 1, 297 (1992)). It is also believed that abdominal pain accompanying digestive system diseases such as diarrhea, irritable bowel syndrome, constipation, etc. is heightened by dilative stimulation of the intestinal tract, and indications are that 5-HT.sub.3 antagonists may possibly lower sensitivity to such dilative stimulation (British Journal of Pharmacology, 100, 497 (1990) and British Journal of Pharmacology, 112 (Proceedings Supplement), 101P (1994). However, despite the abundant research on 5-HT.sub.3 receptor antagonists as antiemetics, there has been a little research on 5-HT.sub.3 receptor antagonists as antidiarrheal drugs, and as yet the characteristics of the intestinal 5-HT3 receptor has not been sufficiently studied.
On the other hand, since it is also known that gastric emptying is hindered by administration of antitumor agents such as cisplatin, 5-HT3 receptor antagonists are also expected to suppress these as well.
Incidentally, compounds which are structurally similar to the compounds of the present application are described in Japanese laid-open patent publication No. Hei-3-223278, but as will be explained later, these and other such compounds have low antagonism for the intestinal 5-HT.sub.3 receptor and provide little alleviation of abdominal pain, while they have also proven to be inadequate in terms of duration of action and promotion of gastric emptying.
In view of the above, the present inventors have sought to develop a 5-HT.sub.3 receptor antagonist which not only has the conventional use as an antiemetic but is also useful as an antidiarrheal drug, and as a result of diligent research on compounds exhibiting particularly high antagonism for the intestinal 5-HT.sub.3 receptor, we have discovered indoline compounds which, compared to known compounds with similar structu
REFERENCES:
patent: 3401173 (1968-09-01), Chow et al.
patent: 3772315 (1973-11-01), Regel et al.
patent: 4820757 (1989-04-01), Spang et al.
patent: 5344927 (1994-09-01), Ohta et al.
The Journal of Pharmacology and Experimental Therapeutics vol. 261, No. 1, 297 (1992) Keiji Miyata et al.
British Journal of Pharmacology, 100, 497 (1990) Helen E. Moss & Gareth J. Sanger.
British Journal of Pharmacology, 112 (Proceedings Supplement), 101P, (1994). "Effects of Dexamethasone on Endothelin-1 Release and Growth of Rat Aortic Smooth Muscle Cells".
Croatica Chemica Act 45, 297-312 (1973) I. Butula.
Fukuzaki Atsushi
Kazama Koichi
Tsuchiya Shinji
Yasuda Nobuyuki
Higel Floyd D.
Tokyo Tanabe Company Limited
LandOfFree
Indoline compound and 5-HT.sub.3 receptor antagonist containing does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Indoline compound and 5-HT.sub.3 receptor antagonist containing , we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Indoline compound and 5-HT.sub.3 receptor antagonist containing will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1555635