Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-03-29
1997-12-09
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
540481, 540582, 540599, 546 89, 514183, 514212, 514214, A61K 3144, C07D491147
Patent
active
056961294
DESCRIPTION:
BRIEF SUMMARY
This application is the national phase of PCT/GB93/02028, filed Sep. 28, 1993.
This invention relates to novel compounds having pharmacological activity, to a process for their preparation and to their use as pharmaceuticals.
EP-A-429984 (Nisshin Flour Milling Co., Ltd.) describes indole derivatives having 5-HT.sub.3 receptor antagonist activity. GB 1555682 (Ciba-Geigy) describes a group of 2-methoxy-3-pyridylamides.
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.
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-501322 (Glaxo Group Limited) describes indole derivatives having 5-HT.sub.4 antagonist activity.
WO 93/02677, WO 93/03725, WO 93/05038, WO 93/05040 and PCT/GB93/00506 (SmithKline Beecham plc) describe compounds having 5-HT.sub.4 receptor antagonist activity.
It has now been discovered that certain novel compounds also have 5-HT.sub.4 receptor antagonist properties.
When used herein, `treatment` includes prophylaxis as appropriate.
Accordingly, the present invention provides compounds of formula (I), wherein formula (I) consists of formulae (I-1) to (I-8), and pharmaceutically acceptable salts thereof, and the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof: ##STR2## wherein R.sub.1 is C.sub.1-6 alkoxy; C.sub.1-6 alkyl group, halo, hydroxy or C.sub.1-6 alkoxy; or C.sub.1-6 alkylthio; and ##STR3## wherein R.sub.1, R.sub.2 and R.sub.3 are independently hydrogen, halo, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; ##STR4## wherein R.sub.I is O(CH.sub.2).sub.s X wherein s is 1 to 3 and X is SOR, COR, CONH.sub.2 or OR wherein R is C.sub.1-6 alkyl; C.sub.1-6 alkyl group, halo, hydroxy or C.sub.1-6 alkoxy; or C.sub.1-6 alkylthio; and ##STR5## wherein one of A.sub.1, A.sub.2 and A.sub.3 is N and the other two are CH; in which X.sub.1 -(CH.sub.2).sub.x -X.sub.2 and the aromatic carbon atoms to which they are attached form a 5-7 membered ring wherein one of X.sub.1 and X.sub.2 is O, S or CH.sub.2 and the other is CH.sub.2 and x is 1, 2 or 3; X.sub.3 -(CH.sub.2).sub.2 --CO or X.sub.3 -(CH.sub.2).sub.2 --CH(OR.sub.x) wherein X.sub.3 is O or S and R.sub.x is hydrogen or C.sub.1-6 alkyl; or two C.sub.1-6 alkyl groups; C.sub.1-6 alkoxy; ##STR6## saturated!polymethylene-X where X is O, S, CH.sub.2, or NR where R is hydrogen or C.sub.1-6 alkyl; alkoxy; ##STR7## wherein one of A.sub.1, A.sub.2 and A.sub.3 is N and the other two are CH; alkoxy or amino and the other is hydrogen, halo, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; ##STR8## wherein X is O, S, SO, SO.sub.2, CH.sub.2, CH, N, or NR wherein R is hydrogen or C.sub.1-6 alkyl; alkyl; ##STR9## wherein A is a saturated polymethylene chain of 2-4 carbon atoms; alkyl;
In formulae (I-1) to (I-8) inclusive: ##STR10## wherein n.sup.1 is 0, 1, 2, 3 or 4; n.sup.2 is 0, 1, 2, 3 or 4; n.sup.3 is 2, 3, 4 or 5; (CH.sub.2).sub.z -R.sub.10 wherein z is 2 or 3 and R.sub.10 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.11 R.sub.12, NR.sub.11 COR.sub.12, SO.sub.2 NR.sub.11 R.sub.12 or NR.sub.11 SO.sub.2 R.sub.12 wherein R.sub.11 and R.sub.12 are hydrogen or C.sub.1-6 alkyl; and and heterocyclic bioisostere; activity.
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 substitu
REFERENCES:
patent: 5189041 (1993-02-01), Berger
patent: 5260303 (1993-11-01), Becker
Bockaert, et al, TiPS Reviews, vol. 13, pp. 141-145 (1992).
Gaster Laramie Mary
Joiner Graham Francis
King Francis David
Wyman Paul Adrian
Huang Evelyn
Ivy C. Warren
Kinzig Charles M.
Lentz Edward T.
Simon Soma G.
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