Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-05-04
1998-01-06
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142245, 514366, 514375, 514393, 514411, 540547, 540558, 540586, 544 32, 544 89, 544252, 546 94, 548217, 548150, 5483024, 548428, C07D21380, C07D40112, C07D49804, A61K 31395
Patent
active
057054983
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 antagonism 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 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.
Accordingly, the present invention provides 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): ##STR3## wherein L is N or CR.sub.S wherein R.sub.S is hydrogen, C.sub.1-6 alkoxy, halogen, C.sub.1-4 alkyl or cyano; wherein X.sub.1 is O or S; X.sub.2 is O, S, NR or NRCO wherein R is hydrogen or C.sub.1-6 alkyl; and alkyl or cyano; 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; ##STR4## wherein --(CH.sub.2).sub.n.sup.1 is attached at carbon; and atoms terminally substituted by R.sub.7 wherein and R.sub.7 is 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, or R.sub.7 is C.sub.2-7 alkoxycarbonyl or secondary or tertiary hydroxy substituted 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 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.
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: ##STR5## 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 is other than carbon; U represents nitrogen or carbon.
Suitable examples of bioisosteres are as described for X, Y and Z in EP-A-328200 (Merck Sharp & Dohme Ltd.), such as an oxadiazole moie
REFERENCES:
Faye et al., Medicinal Chemistry 4th ed., Williams & Wilkins (1995), pp. 156-157.
Gaster Laramie Mary
Wyman Paul Adrian
Kifle Bruck
Kinzig Charles M.
Lentz Edward T.
Shah Mukund J.
SmithKline Beecham plc.
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