Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-11-08
1996-07-09
McKane, Joseph K.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514284, 514289, 514296, 546 71, 546 72, 546 74, 546 75, 546 76, 546 98, 546 99, 546 79, 5483121, A61K 31395, C07D47112
Patent
active
055345212
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US93/05862 filed Jun. 23, 1993.
BACKGROUND OF THE INVENTION
The present invention relates to pharmaceutical agents (compounds) which act as 5-HT.sub.4 agonists or ##STR2## antagonists and/or 5-HT.sub.3 antagonists in mammals. As 5-HT.sub.4 agonists these agents are useful in the treatment of hypomotility disorders of the gastrointestinal (GI) tract including reflux esophagitis, non-ulcer dyspepsia, gastroparesis, ileus, irritable bowel syndrome (constipation predominant) and constipation. Additionally, 5-HT.sub.4 agonists are useful for the treatment of learning and memory disorders and as cardiovascular inotropic agents. As 5-HT.sub.4 antagonists these compounds are useful in the treatment of motility disorders of the GI tract such as diarrhea and irritable bowel syndrome (diarrhea predominant). As 5-HT.sub.3 antagonists these compounds are useful for treating emesis (caused by cancer chemotherapy or post-operative), anxiety, cognitive disorders, drug abuse (either cravings or withdrawal syndrome) and irritable bowel syndrome (diarrhea predominant).
Serotonin (5-hydroxytryptamine; 5-HT) functions as a neurotransmitter in the mammalian central nervous system (CNS) and in the periphery. Serotonergic neurons regulate a wide variety of sensory, motor and cortical functions. Additionally serotonin regulates enteric reflexes, mediates contraction of the vascular smooth muscle and platelet shape change and aggregation and as such effects such diverse systems as the cardiovascular system and gastrointestinal system, in addition to the central nervous system.
Pharmacological and physiological studies show that the activity of serotonin is mediated by several distinct cell surface receptor subtypes. These receptor subtypes either transduce extracellular signals by activating GTP-binding proteins (G-protein-coupled receptor subtypes) or activate the opening of nonselective cation channels to promote fast, depolarizing responses in neurons (ligand-gated ion channel receptor subtypes). 5-HT.sub.4 belongs to the former category while 5-HT.sub.3 belongs to the latter. Agents which interact with these receptors thereby modulate a variety of ion channels and intracellular messenger signaling pathways thereby extending the flexibility of serotonin's activity and eliciting a multitude of cellular and physiological responses. P. Bonate, Clinical Neuropharmacology, Vol. 14, No. 1, pp. 1-16 (1991).
European Patent application 309,423 discloses azabicyclo substituted benzimidazoline-2-oxo-1-carboxylic acid derivatives which are useful as 5-HT receptor antagonists.
Dumuis et al., Nauyn-Schmiedeberg's Arch Pharmacol, (1991) 343:245-251 disclose azabicycloalkyl benzimidazolone derivatives as potent agonists at the 5-HT.sub.4 receptor.
In Pharmacological Research, Vol. 22, Supplement 2, (1990) Schiantarelli et al. disclose two benzimidazolone compounds useful as 5-HT.sub.3 antagonists and 5-HT.sub.4 agonists.
There is a need in the area of serotonin regulation for agents with broad clinical usefulness. Serotonin is one of the newer neurotransmitters to be recognized for physiological importance and agents which interact with 5-HT receptors are currently the focus of much research. P. Bonate, Clinical Neuropharmacology, Vol. 14, No. 1, pp. 1-16 (1991). Accordingly, it is the object of this invention to produce compounds for use as pharmaceutical agents which will exhibit 5-HT.sub.4 agonist or antagonist activity and/or 5-HT.sub.3 antagonist activity in mammals. The compounds of the present invention meet the need for an agent which has broad clinical usefulness for treating serotonin mediated conditions in mammals by administering a therapeutically effective amount of the compounds to act as 5-HT.sub.4 agonists or antagonists and/or 5-HT.sub.3 antagonists.
SUMMARY OF THE INVENTION
This invention relates to compounds of the Formula I ##STR3## or a pharmaceutically acceptable salt thereof wherein hydrogen, alkoxy, halogen, amino, monoalkylamino, dialkylamino, acylamino and alkylsulfonylamino; ##S
REFERENCES:
patent: 4083985 (1978-04-01), Cohen et al.
patent: 4816453 (1989-03-01), Watts
patent: 5300512 (1994-04-01), Flynn et al.
Schiantarelli et al. "The Prokinetic Properties of New Benzimidazolone Derivatives, etc." Pharmacological Research 22, Supp. 2 453 1990.
Dumuis et al. "Azabicycloalkyl benzimidazolone Derivatives etc." Naunyn-Schmiedeberg's Arch Pharmacol 343 245-251 1991.
Turconi et al. "Synthesis of a New Class of 2,3-Dihydro-2-oxo-1H-benzimidazole-1-carboxylic Acid Derivatives" J. Med. Chem. 33, No. 8 2101-2108 1990.
CA 116:34274w Antiemetic . . . radiation. Sagrada et al., p. 59, 1992.
CA 116:248303d Chronic . . . area. Prisco et al., p. 63, 1992.
CA 117:225688q Pharmacokinetic . . . therapy. Schiantarelli et al., p. 11, 1992.
Becker Daniel P.
Dappen Michael S.
Flynn Daniel L.
Moormann Alan E.
Nosal Roger
G. D. Searle & Co.
Kovacevic Cynthia S.
McKane Joseph K.
Williams Roger A.
LandOfFree
Benzimidazole compounds does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Benzimidazole compounds, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Benzimidazole compounds will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1867427