Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-07-28
1998-01-06
Ivy, C. Warren
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514213, 514319, 514320, 514321, 514323, 514324, 514325, 514366, 514375, 514394, 514411, 514422, 514408, 514183, 540450, 540480, 540602, 540603, 540609, 540610, 546197, 546198, 546199, 546200, 546202, 548150, 548151, 548217, 548218, 5483021, 548430, 548429, 548427, 548528, 548525, 548526, 548527, A61K 31445, C07D40114
Patent
active
057055092
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB94/00172, Jan. 28, 1994.
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, and PCT/EP93/03054 (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.
EP-A-234872 (Adria), U.S. Pat. No. 4,859,683 (Rorer) and EP-A-307 172 (Lilly) describe 5-HT.sub.3 receptor antagonists derived from a benzoic acid nucleus, 2,3-disubstituted by alkyleneoxy.
A class of novel, structurally distinct compounds has now been discovered, which compounds are fused tricyclic derivatives incorporating and linking through a core which is a phenyl ring. These compounds have 5-HT.sub.4 receptor antagonist activity.
Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof: ##STR2## wherein 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 is hydrogen or C.sub.1-6 alkyl; or Q--CH.dbd.N where Q is linked either to the R.sub.1 or the R.sub.2 substitution position and Q is O, S or NR.sub.t wherein R.sub.t is hydrogen or C.sub.1-6 alkyl; alkyl; ##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 heterocyclic bioisostere;
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.
Values for monocyclic heteroaryl include pyridyl, pyrimidyl, pyrazinyl, pyrryl, imidazolyl, thienyl, furanyl, oxazole or thiazole (all possible isomers). Bicyclic heteroaryl include benzofuranyl, benzothiophenyl, indolyl and indazolyl, quinolyl and isoquinolyl (all possible isomers).
Values for 3 to 8 membered heterocyclyl, include cyclic polymethylene interrupted by one or two of N, O or S, linked through C or N, for example N-linked piperidinyl or pyrrolidinyl.
Halo includes fluoro, chloro, bromo and iodo.
A suitable bioisostere for the amide or ester linkage containing Y in formula (I), is of formula (d): ##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 oxy
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Gaster Laramie Mary
Wyman Paul Adrian
Dahlen Garth M.
Ivy C. Warren
Kinzig Charles M.
Lentz Edward T.
SmithKline Beecham Plc
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