Heterocyclic-esters or -amides used as 5-HT.sub.4 receptor antagonists
AssigneeSmithKline Beecham Corporation
InventorsFrancis David King, Laramie Mary Gaster, Graham Francis Joiner, Keith Raymond Mulholland, Shirley Katherine Rahman
Life of this patent
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Abstract
Compounds of formula (I), wherein formula I consists of formulae (I-1) to (I-4), which are defined in the specification, and pharmaceutically acceptable salts thereof, and the use of a compound of formula I or a pharmaceutically acceptable salt thereof, and their use as pharmaceuticals in the treatment of gastrointestinal disorders, cardiovascular disorders and CNS disorder.
Claims11
Compounds of formula (I), wherein formula (I) consists of formulae (I-2) to (I-4), and pharmaceutically acceptable salts thereof:
- ##STR8## wherein X is --N.dbd.CH--CH.dbd.CH-- or --NR.sub.4 --(CH.sub.2).sub.3 --;
- R.sub.1 is hydrogen, amino, halo, C.sub.1-6 alkyl, hydroxy or C.sub.1-6 alkoxy;
- R.sub.2 is hydrogen, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, nitro, amino or C.sub.1-6 alkylthio;
- R.sub.3 is hydrogen, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or amino;
- R.sub.4 is hydrogen or C.sub.1-6 alkyl;
- ##STR9## wherein X is NR.sub.4, where R.sub.4 is hydrogen or C.sub.1-6 alkyl;
- - - - represents a single or double bond;
- R.sub.1 is hydrogen, amino, halo, C.sub.1-6 alkyl, hydroxy or C.sub.1-6 alkoxy;
- R.sub.2 is hydrogen, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, nitro, amino or C.sub.1-6 alkylthio;
- R.sub.3 is hydrogen, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or amino;
- ##STR10## wherein X is --NR.sub.4 --CH.sub.2 CH.dbd.CH--;
- R.sub.1 is hydrogen, amino, halo, C.sub.1-6 alkyl, hydroxy or C.sub.1-6 alkoxy;
- R.sub.2 is hydrogen, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, nitro, amino or C.sub.1-6 alkylthio;
- R.sub.3 is hydrogen, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or amino;
- R.sub.4 is hydrogen or C.sub.1-6 alkyl;
- wherein in formulae (I-2) to (I-4) inclusive:
- Y is O or NH;
- Z is of sub-formula (a), (b) or (c):
- ##STR11## wherein n.sup.1 is 0, 1, 2, 3 or4;
- n.sup.2 is 0, 1, 2, 3 or4;
- n.sup.3 is 2, 3, 4or5;
- q is 0, 1, 2 or3;
- p is 0,1 or 2;
- m is 0,1 or 2;
- R.sub.5 is hydrogen, C.sub.1-12 alkyl, aralkyl or R.sub.5 is (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
- R.sub.6, R.sub.7 and R.sub.8 are independently hydrogen or C.sub.1-6 alkyl;
- and
- R.sub.9 is hydrogen or C.sub.1-10 alkyl;
- or a compound of formula (I) wherein the CO--Y linkage is replaced by a heterocyclic bioisostere of formula (d):
- ##STR12## 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;
- and U represents nitrogen or carbon.
A compound selected from the group consisting of:
- (1-butyl-4-piperidinylmethyl)quinolinyl-8-carboxylate, and (1-butyl-4-piperidinylmethyl)-1, 2, 3, 4-tetrahydroquinoline-8-carboxylate, and pharmaceutically acceptable salts thereof.
A compound selected from the group consisting of:
- 8-(1-butyl-4-piperidinylmethyl)-1, 2-dihydro-2-oxoquinolinecarboxylate, and 8-(1-butyl-4-piperidinylmethyl)-1, 2, 3, 4-tetrahydro-2-oxoquinolinecarboxylate, and pharmaceutically acceptable salts thereof.
A compound selected from:
- 8-(1-Butyl-4-piperidinylmethyl)-1, 2-dihydro-1-methylquinolinecarboxylate, and pharmaceutically acceptable salts thereof.
Dependencies are inferred from the claim text.