Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-07-06
1996-02-20
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514364, 546201, 548131, A61K 31445, A61K 3141
Patent
active
054929199
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB92/01419 filed Jul. 31, 1992.
This invention relates to the use of compounds as 5-HT.sub.4 receptor antagonists in the treatment of gastrointestinal disorders, CNS disorders and/or cardiovascular disorders, and to certain novel compounds having 5-HT.sub.4 receptor antagonist activity.
European Journal of Pharmacology 146 (1988), 187-188, and Naunyn-Schmiedeberg's Arch. Pharmacol. (1989) 340:403-410, describe a non classical 5-hydroxytryptamine receptor, now designated the 5-HT.sub.4 receptor, and that ICS 205-930, which is also a 5-HT.sub.3 receptor antagonist, acts as an antagonist at this receptor.
PCT/GB91/00650 (SmithKline and French Laboratories Limited) describes the use of cardiac 5-HT.sub.4 receptor antagonists in the treatment of atrial arrhythmias and stroke.
Some 5-HT.sub.3 receptor antagonists have been disclosed as of potential use in the treatment of certain aspects of irritable bowel syndrome [see EP-A-189002 (Sandoz Limited) and EP-A-200444 (Beecham Group p.l.c)].
5-HT.sub.3 receptor interactions which are of potential use in the treatment of IBS are those associated either with the visceral pain and abnormal perception of sensation aspects of this disease, or they are related to the ability of some 5-HT.sub.3 receptor antagonists to cause constipation in volunteers.
Some 5-HT.sub.3 receptor antagonists have been disclosed as of potential use in the treatment of gastrointestinal disorders associated with upper gut motility [see EP-A-226266 (Glaxo Group Ltd.) and EP-A-189002 (Sandoz Limited)]. 5-HT.sub.3 receptor antagonists are also well known antiemetics, such as ondansetron, granisetron and tropisetron (see Drugs of the Future 1989, 14 (9) p.875--F. D. King and G. J. Sanger).
EP-A-328200 and U.S. Pat. No. 4952587 (Merck Sharp & Dohme Ltd.) disclose a group of heterocyclic compounds which are described as useful in the treatment of psychotic disorders (e.g. schizophrenia and mania); anxiety; alcohol or drug withdrawal; pain; gastric stasis; gastric dysfunction (such as occurs with dyspepsia, peptic ulcer, reflux oesophagitis and flatulence); migraine; nausea and vomiting and presenile and senile dementia (also known as Alzheimer's disease and senile dementia of the Alzheimer type respectively). Certain of the compounds are described as acting on 5-HT.sub.3 receptors and this is attributed in whole or in part, for the pharmacological activity of these compounds. J. Med. Chem. 1991, 34, 140-51 (Swain et. al.) describes these and other compounds and their properties as 5-HT.sub.3 receptor antagonists. J. Med. Chem. 1990, 33, 2715 describes a related group of 5-HT.sub.3 receptor antagonists.
It has now been discovered that certain of the compounds embraced by the general formulae disclosed therein, and related compounds, have 5-HT.sub.4 receptor antagonist properties, and are therefore of potential use in the treatment of IBS or atrial arrhythmias and stroke.
The compounds of the present invention also have a potential use in the treatment of CNS disorders such as anxiety and/or migraine, in the treatment of upper gut motility disorders and as antiemetics.
When used herein `treatment` includes prophylaxis as appropriate.
The invention therefore provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof: ##STR2## wherein the dotted circle represents one or two double bonds in any position in the 5-membered ting; X, Y and Z independently represent oxygen, sulphur, nitrogen or carbon, provided that at least one of X, Y and Z represents oxygen, sulphur or nitrogen; U represents nitrogen or carbon; ##STR3## in which: R.sup.1 represents hydrogen, hydroxy, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.1-6 alkoxy, hydroxy (C1-6)alkyl, halogen, amino, cyano, --CONR.sup.6 R.sup.7 or --SO.sub.2 NR.sup.6 R.sup.7, in which R.sup.6 and R.sup.7 independently represents hydrogen, C.sub.1-6 alkyl, C.sub.2-6 alkenyl or C.sub.2-6 alkynyl; C.sub.1-6 alkylcarbonyl; ##STR4## in which R.sup.8 represents hydrogen, C.sub.1-6 alkyl, C.su
REFERENCES:
patent: 4110536 (1978-08-01), Havera
patent: 4952587 (1990-08-01), Baker
patent: 5298520 (1994-03-01), Baker
Kelarev. et al "Synthesis of amino derivatives" CA 98: 143342 (1982).
Witaker-Azmitia "The neuropharmacology of Serotonin" N.Y. Aca. Sci. 600 pp. 109-110, 195-196 (1990).
Clark. "Principles of Psychopharmacology" Academic Press, (1970) pp. 166-167.
Gotto et al "The Role of Receptors in Biology and Medicine" Raven Press, (1987) p. 191.
Steadman, C. et al., Selective 5-Hydroxytryptamine Type 3 Receptor Antagonism With Ondansetron as Treatment for Diarrhea-Predominant Irritable Bowel Syndrome: A Pilot Study, Mayo Clin Proc 67:732-738, 1992.
Hedge, S. et al., Evidence for the Involvement of 5-Hydroxytryptamine 4 Receptors in 5-Hydroxytryptophan-Induced Diarrhea in Mice, Journal Pharmacology and Experimental Therapeutics, 271:741-747, 1994.
Banner, S. et al., 5-HT Receptors and 5-Hydroxytryptophan-Evoked Defaecation in Mice, Br. J. Pharmacol., Abstract 135P, 1993.
Journal of Medicinal Chemistry, vol. 34, No. 1, Jan 1991, American Chemical Society, C. J. Swain et al.: "Novel 5-HT3 antagonists. Indole oxadiazoles", pp. 140-151, see the entire document (cited in the application).
J Auton. Pharmacol., vol. 5, No. 2, Jun. 1985, P. R. Saxena et al.: "Excitatory 5-hydroxytryptamine receptors in the cat urinary bladder are of the M-and 5-HT2-type", pp. 101-107, see the entire document.
European Journal of Pharmacology, vol. 183, No. 4, Jul. 1990, Elsevier Science Publisher B.V., M. A. Petty et al.: "Anti arrhythmic activity of the 5-HT3 receptor antagonist MDL 73147 in different species", p. 1159, see the entire document.
Naunyn-Schmiedeberg's Arch. Pharmacol., vol. 342, No. 5, Nov. 1990, A. J. Kaumann: "Piglet sinoatrial 5-HT receptors resemble human atrial 5-HT4-like receptors", pp. 619-622, see the entire document (cited in the application).
Baxter Gordon S.
Gaster Laramie M.
Kaumann Alberto J.
Kennett Guy A.
King Francis D.
Chang Ceila
Kinzig Charles M.
Lentz Edward T.
SmithKline Beecham p.l.c.
Venetianer Stephen
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