Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-08-03
2000-10-03
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514310, 514320, 514329, 546112, 546143, 546195, 546202, A01N 4342, A01N 4340, C07D22102, C07D21106
Patent
active
061273791
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the use of compounds as 5-HT.sub.4 receptor antagonists in the treatment of gastrointestinal disorders, CNS disorders including migraine and/or cardiovascular disorders, and to certain novel compounds having 5-HT.sub.4 receptor antagonist activity.
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.
Some 5-HT.sub.3 receptor antagonists have been disclosed as of potential use in the treatment of certain aspects of irritable bowel syndrome [EP-A-189002 (Sandoz Limited) and EP-A-201165 (Beecham Group p.l.c)].
5-HT.sub.3 receptor interactions which are of potential use in the treatment of IBS are those associated either with the visceral pain and abnormal perception of sensation aspects of this disease, or they are related to the ability of some 5-HT.sub.3 receptor antagonists to cause constipation in volunteers.
Some 5-HT.sub.3 receptor antagonists have been disclosed as of potential use in the treatment of gastrointestinal disorders associated with upper gut motility [EP-A-226266 (Glaxo Group Ltd.) and EP-A-189002 (Sandoz Limited)]. 5-HT.sub.3 receptor antagonists are also well known antiemetics, such as ondansetron, granisetron and tropisetron [Drugs of the Future 1989, 14 (9) p.875 --F. D. King and G. J. Sanger].
EP-A-234872 (Adria), US 4859683 (Rorer) and EP-A-307172 (Lilly) describe 5-HT.sub.3 receptor antagonists derived from a benzoic acid nucleus, 2,3-disubstituted by alkyleneoxy.
It has now been discovered that certain of the compounds embraced by the general formulae disclosed therein, and related compounds, have 5-HT.sub.4 receptor antagonist properties, and are therefore of potential use in the treatment of IBS or atrial arrhythmias and stroke.
The compounds of the present invention also have a potential use in the treatment of CNS disorders such as anxiety and/or migraine, in the treatment of upper gut motility disorders and as antiemetics.
Accordingly, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof: ##STR3## 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 alkoxy; or C.sub.1-6 alkylthio; ##STR4## wherein n.sup.1 is 1, 2, 3 or 4; n.sup.2 is 1 or 2; n.sup.3 is 2, 3, 4 or 5; aralkyl; or selected from cyano, hydroxyl, C.sub.1-6 alkoxy, phenoxy, C(O)C.sub.1-6 alkyl, COC.sub.6 H.sub.5, --CR.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; 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.
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,.
A suitable bioisostere for the amide or ester linkage containing Y in formula (I), is of formula (d) ##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
REFERENCES:
patent: 4859683 (1989-08-01), Youssetyeh et al.
patent: 5374637 (1994-12-01), Van Daele et al.
Thominet et al, Chemical Abstract vol. 89 No. 6329, "Pham. sub. 2,3-(alkylene dioxy) benzamides" (1978).
Van Daele et al, Chemical Abstract, vol. 114 No. 164012, "Prep. N-(3-methoxy-4-piperidinyl) . . . endocrin gastrointestinal motility" 1990 .
Gaster Laramie Mary
Joiner Graham Francis
King Francis David
Covington Raymond
King William T.
Kinzig Charles M.
Rotman Alan L.
Simon Soma G.
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