Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-07-28
1996-12-03
Chang, Ceila
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514306, 546138, 546197, A61K 31445, A61K 3144, C07D40512, C07D45502
Patent
active
055808859
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB92/01649 filed Sep. 9, 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, antagonises at this receptor.
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-201165 (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).
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.
EP-A-36269 (Beecham Group p.l.c.) describes a group of compounds of potential use in the treatment of gastrointestinal motility disorders.
WO 92/10494 (Beecham Group p.l.c.) describes 5-HT.sub.3 receptor antagonists derived from a benzoic acid nucleus 2,3 disubstituted by alkylenedioxy.
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.
Accordingly, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof: ##STR2## in which X.sub.1 --(CH.sub.2).sub.x --X.sub.2 forms a 5-7 membered ring alkoxy; or C.sub.1-6 alkylthio; ##STR3## wherein --(CH.sub.2).sub.n.sup.1 is attached at carbon or nitrogen and aralkyl; and heterocyclic bioisostere; antagonist.
Examples of alkyl or alkyl containing groups include C.sub.1, C.sub.2, C.sub.3, C.sub.4, C.sub.5, C.sub.6, C.sub.7, C.sub.8, C.sub.9, C.sub.10, C.sub.11 or C.sub.12 branched, straight chained or cyclic alkyl, as appropriate. C.sub.1-4 alkyl groups include methyl, ethyl n- and iso-propyl, n-, iso-, sec- and tert-butyl. Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
Aryl includes phenyl and naphthyl optionally substituted by one or more substituents selected from halo, C.sub.1-6 alkyl and C.sub.1-6 alkoxy, a suitable value for R.sub.a aralkyl, being benzyl.
Halo includes fluoro, chloro, bromo and iodo, preferably chloro.
A suitable bioisostere for the amide or ester linkage containing Y in formula (I), is of formula (d) ##STR4## wherein the dotted circle represents one or two double bonds in any position in the 5-membered ring; provided that at least one of H, J and I is other than carbon;
Suitable examples of (d) are as described for X, Y and Z in EP-A-328200 (Merck Sharp & Dohme Ltd.), such as an oxadiazole moiety.
Suitable examples of the X.sub.1 --(CH.sub.2).su
REFERENCES:
patent: 4186135 (1980-01-01), Thominet
patent: 4268512 (1981-05-01), Thominet
patent: 4499099 (1985-02-01), Watts
patent: 4772459 (1988-09-01), Sun
patent: 5185335 (1993-02-01), Van Daele
Witaker-Azmitia et al. "The neuropharmacology of Serotonin" N.Y. Academy of Science, 600 p. 195-196 (1990).
Clark et al. "Principles of Psychopharmacology" Academic Press, p. 166-167 (1970).
Baxter Gordon S.
Gaster Laramie M.
Kauman Alberto J.
Kennett Guy A.
King Francis D.
Chang Ceila
Kinzig Charles M.
Lentz Edward T.
SmithKline Beecham p.l.c.
Venetianer Stephen
LandOfFree
5-HT.sub.4 receptor antagonists does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 5-HT.sub.4 receptor antagonists, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 5-HT.sub.4 receptor antagonists will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-785913