Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-11-22
1998-04-21
Gupta, Yogendra N.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514210, 514373, 514379, 514403, 514428, 546201, 548207, 548248, 5483565, 548469, 548470, 548950, 548968, A61K 31445, C07D40106
Patent
active
057418012
DESCRIPTION:
BRIEF SUMMARY
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), WO 93/02677, WO 93/03725, WO 93/05038, WO 93/05040, WO 93/18036, PCT/EP93/03054, PCT/GB93/01895, PCT/GB93/02028, PCT/EP93/02808, PCT/EP93/02775, PCT/EP93/02809, PCT/GB 93/02130, PCT/EP93/003054, PCT/GB94/000172 (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.
Accordingly, the present invention provides a compounds of formula (I) and pharmaceutically acceptable salts thereof, and the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof: (a), (b), (c), (d), (e), (f) or (g): ##STR2## wherein C.sub.1-4 alkyl or cyano; X.sub.1 is O or S; X.sub.2 is O, S, --CH.sub.2 --, NR or NRCO wherein R is hydrogen or C.sub.1-6 alkyl; and halo, C.sub.1-6 alkyl or cyano; R.sub.1.sup.a is hydrogen, C.sub.1-10 alkyl, C.sub.2-6 alkenyl, aralkyl, C.sub.2-6 alkanoyl or C.sub.2-6 alkanoyl C.sub.1-3 alkyl; alkoxy; a C.sub.1-6 alkyl group, halo, hydroxy or C.sub.1-6 alkoxy; amino or C.sub.1-6 alkylthio; and amino; C.sub.1-6 alkoxy; amino or C.sub.1-6 alkylthio; amino; alkyl; alkoxy, C.sub.1-6 alkylthio, C.sub.1-6 alkylsulphonyl, C.sub.1-6 alkylsulphinyl, C.sub.1-7 acyl, cyano, C.sub.1-6 alkoxycarbonyl, C.sub.1-7 acylamino, hydroxy, nitro or amino, aminocarbonyl, or aminosulphonyl, optionally N-substituted by one or two groups selected from C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, and C.sub.3-8 cycloalkyl C.sub.1-4 alkyl or disubstituted by C.sub.4 or C.sub.5 polymethylene; phenyl or phenyl C.sub.1-4 alkyl group optionally substituted in the phenyl ring by one or two of halogen, C.sub.1-6 alkoxy or C.sub.1-6 alkyl groups; alkyl; --CR.sub.3.sup.f R.sub.4.sup.f where C.sub.1-6 alkyl; and/or a bond and/or R.sub.1.sup.f /R.sub.2.sup.f /R.sub.3.sup.f /R.sub.4.sup.f are joined to form C.sub.3-6 polymethylene; alkyl; or C.sub.1-6 alkyl; alkoxy; ##STR3## wherein n.sup.1 is 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; or R.sub.5 is straight or branched chain alkylene of chain length 1-6 carbon atoms terminally substituted by aryl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 5 or 6 membered monocyclic heteroaryl or 9 or 10 membered fused bicyclic heteroaryl linked through carbon, C.sub.2-7 alkoxycarbonyl, or secondary or tertiary hydroxy substituted C.sub.1-6 alkyl; and and
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/so-propyl, n-, iso-, sec- and tert-butyl. Cyclic alkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl optionally substituted by one of more alkyl groups of up to 4 carbon atoms.
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.
Values for monocyclic heteroaryl include pyridyl, pyri
REFERENCES:
patent: 4064255 (1977-12-01), Champseix et al.
Degraa et al, Chemical Abstract vol. 64, No. 17539 (d) (1966).
Gaster Laramie Mary
King Francis David
Mulholland Keith Raymond
Gupta Yogendra N.
Kinzig Charles M.
Lentz Edward T.
Simon Soma G.
SmithKline Beecham Plc
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