Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-04-11
1998-01-13
Ivy, C. Warren
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
546168, 546169, 546166, 546170, 546138, 514312, 514306, 514211, 514311, 514314, 540593, C07D215227, C07D21506, A61K 3147
Patent
active
057081743
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) describes indole derivatives having 5-HT.sub.4 antagonist activity.
WO 93/02677, WO 93/03725, WO 93/05038, WO 93/05040 and PCT/GB93/00506 (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-4), and pharmaceutically acceptable salts thereof, and the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof: ##STR1## wherein X is O or S; CH(OR.sub.x)--(CH.sub.2).sub.2 wherein R.sub.x is hydrogen or C.sub.1-6 alkyl; alkoxy; or C.sub.1-6 alkylthio; ##STR2## wherein X is --N.dbd.CH--CH.dbd.CH-- or --NR.sub.4 --(CH.sub.2).sub.3 --; alkoxy; or C.sub.1-6 alkylthio; ##STR3## wherein X is O or NR.sub.4, where R.sub.4 is hydrogen or C.sub.1-6 alkyl; alkoxy; or C.sub.1-6 alkylthio; ##STR4## wherein X is --NR.sub.4 --CH.sub.2 CH--CH--; alkoxy; or C.sub.1-6 alkylthio; ##STR5## 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.
A suitable bioisostere for the amide or ester linkage containing Y in formula (I), is of formula (d): ##STR6## 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 (d) are as described for X, Y and Z in EP-A-328200 (Merck Sharp & Dohme Ltd.), such as an oxadiazole moiety.
Y is preferably O or NH.
When Z is of sub-formula (a), n.sup.1 is preferably 2, 3 or 4 when the azacycle is attached at the nitrogen atom and n.sup.1 is preferably 1 when the azacycle is attached at a carbon atom, such as the 4-position when q is 2.
When Z is of sub-formula (b), n.sup.2 is preferably such that the number of carbon atoms between the ester or amide linkage is from 2 to 4 carbon atoms.
Suitable values for p and m include p=m=1; p=0, m=1, p=1, m=2, p=2, m=1.
When Z is of sub-formula (c), n.sup.3 is preferably 2, 3 or 4.
R.sub.8 and R.sub.9 are preferably both alkyl, especially one of R.sub.8 and R.sub.9 is C.sub.4 or larger alkyl.
Specific values of Z of particular inter
REFERENCES:
patent: 5620992 (1997-04-01), King
King, F.D. and Sanger, G.J; "5-HT.sub.3 Receptor Antagonists"; Drugs of the Future vol. 14, No. 9, 1989; pp. 875-889.
Evans S.M., Galdes, A., Gall, M.; "Molecular Modeling of 5-HT.sub.3 Receptor Ligands"; Pharmacology Biochemistry & Behavior, vol. 40, 1991; pp. 1033-1040.
Gaster Laramie Mary
Joiner Graham Francis
King Francis David
Mulholland Keith Raymond
Rahman Shirley Katherine
Ivy C. Warren
Kinzig Charles M.
Lentz Edward T.
M. Mach D. Margaret
Simon Soma G.
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