Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-03-10
1997-04-15
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, C07D40512
Patent
active
056209924
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB93/01895 filed Sep. 7, 1993.
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.
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).
WO 91/16045 (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. WO 93/05038 (SmithKline Beecham p.l.c.) describes 5-HT.sub.4 receptor antagonists derived from a benzoic acid nucleus.
EP-A-501322 (Glaxo Group Limited) describes indole derivatives having 5-HT.sub.4 antagonist activity.
It has now been discovered that certain novel compounds have 5-HT.sub.4 receptor antagonist properties;
When used herein, `treatment` includes prophylaxis as appropriate.
Accordingly, the present invention provides a compound of formula (I) and pharmaceutically acceptable salts thereof, and 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 wherein: alkoxy; or C.sub.1-6 alkylthio; ##STR3## wherein --(CH.sub.2).sub.n.sup.1 is attached at carbon; and is selected from cyano, hydroxyl, C.sub.1-6 alkoxy, phenoxy, C(O)C.sub.1-6 alkyl, COC.sub.6 H.sub.5, --CONR.sub.8 R.sub.9, NR.sub.8 COR.sub.9, SO.sub.2 NR.sub.8 R.sub.9 or NR.sub.8 SO.sub.2 R.sub.9 wherein R.sub.8 and R.sub.9 are hydrogen or C.sub.1-6 alkyl; 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.
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: ##STR4## wherein the dotted circle represents one or two double bonds in any position in the 5-membered ring; H, J and I independently represent oxygen, sulphur, nitrogen or carbon, provided that at least one of H, J and I i
REFERENCES:
patent: 4186135 (1980-01-01), Thominet et al.
patent: 4268512 (1981-05-01), Thominet et al.
patent: 5374637 (1994-12-01), Van Daele et al.
Gaster Laramie M.
King Francis D.
Mulholland Keith R.
Chang Ceila
Kinzig Charles M.
Lentz Edward T.
SmithKline Beecham Plc
Venetianer Stephen
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