Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-04-14
1998-03-10
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546200, A61K 31445, C07D40112
Patent
active
057261873
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB93/02130, Oct. 14, 1993.
This invention relates to novel compounds having pharmacological activity, to a process for their preparation and to their use as pharmaceuticals.
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 WO 93/18036 (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-5), and pharmaceutically acceptable salts thereof, and the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof: ##STR2## wherein X and the carbon atoms to which it is attached represents phenyl, cyclohexyl or cyclohexenyl wherein X is --(CH.sub.2).sub.4 --, and wherein X is optionally substituted by R.sub.3 and R.sub.4 ; C.sub.1-6 alkyl, or C.sub.1-6 alkoxy; ##STR3## wherein X is either --X.sub.1 --(CH.sub.2).sub.x --X.sub.2 -- 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; --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; alkoxy; ##STR4## wherein R.sub.1 and R.sub.2 are hydrogen, halo, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; or --X.sub.2 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.2 is O or S and R.sub.x is hydrogen or C.sub.1-6 alkyl; or two C.sub.1-6 alkyl groups; or 2; ##STR5## wherein - - - represents a single or double bond; alkoxy; or C.sub.1-6 alkylthio; ##STR6## wherein X is O or S; alkoxy; or C.sub.1-6 alkylthio;
In formulae (I-1) to (I-5) inclusive: ##STR7## 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 substituents selected from halo, C.sub.1-6 alkyl and C.sub.1-6 alkoxy.
Halo includes fluoro, chloro, bromo and iodo.
In formula (I-2):
In formula (I-4):
In formula (I-5):
A suitable bioisostere for the amide or ester linkage containing Y in formula (I), is of formula (d): ##STR8## wherein the dotted circle represents one or
REFERENCES:
patent: 5049556 (1991-09-01), King et al.
Drug Actions: Basic Principles and Therapeutic Aspects, Mutschler, E. et al., CRC Press, 1995, pp. 105, 309-12, 173, 325-7, 331, 414, 163, 499, 151 and 142.
Cecil Textbook of Medicine, 19th ed., edited by Wyngaarden, J.B. et al, 1992, pp. 1093-4, 1106-7, 1655-61, 1872-8, 1972-5, 2191-5, 1027-032, 2213-21, 2260 and 127.
Beilstein online data for RN 64057-972.
Clarke et al., Trends in Pharmacological Sciences, 10(10), pp. 385-386 (1989).
Clarke et al., Trends in Pharmacological Sciences, 13(4), pp. 141-145 (1992).
Dumuis et al., European J. Pharmacology, vol. 146, pp. 187-188 (1988).
Dumuis et al., Naunyn-Schmiedeberg's Archives of Pharmacology, vol. 340, pp. 403-410 (1989).
Gaster Laramie Mary
Joiner Graham Francis
Mulholland Keith Raymond
Wyman Paul Adrian
Dahlen Garth M.
Ivy C. Warren
Kinzig Charles M.
Lentz Edward T.
SmithKline Beecham Plc
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