# US 5,705,498 A · Piperidine derivatives as 5-HT.sub.4 receptor antagonists > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 5,705,498 A - Document ID: US5705498A - Status: Granted - Kind: A - Application number: 08/433,369 - Filed: 1995-05-04 - Granted: 1998-01-06 - Earliest claimed: 1992-11-05 - Assignees: SmithKline Beecham Corporation - Inventors: Laramie Mary Gaster; Paul Adrian Wyman - Web page: https://patentgrep.com/patent/US5705498A ## CPC - C07D 405/12: linked by a chain containing hetero atoms as chain links - A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 - C07D 405/14: containing three or more hetero rings - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract Compounds of formula (I): ##STR1## wherein X.sup.g is O, S, SO, SO.sub.2, CH.sub.2, CH, N or NR wherein R is hydrogen or C.sub.1-6 alkyl; A is a saturated or unsaturated polymethylene chain of 2-4 carbon atoms; R.sub.1.sup.g and R.sub.2.sup.g are hydrogen or C.sub.1-6 alkyl; R.sub.3.sup.g is hydrogen, halo, C.sub.1-6 alkyl, amino, nitro or C.sub.1-6 alkoxy; R.sub.4.sup.g is hydrogen, halo, C.sub.1-6 alkyl or C.sub.1-6 alkoxy, Y is O or NH, or CO--Y together are a heterocyclic bioisostere; Z is of sub-formula: ##STR2## wherein --(CH.sub.2).sub.n.sup.1 is attached at carbon; and n.sup.1 is 0, 1, 2, 3 or 4; q is 0, 1, 2 or 3; R.sub.a is a straight or branched chain alkylene of chain length 1-6 carbon atoms terminally substituted by R.sub.7 wherein R.sub.7 is 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 R.sub.6 is hydrogen or C.sub.1-6 alkyl; are useful as 5HT.sub.4 receptor antagonists. ## Claims ### Claim 1 A compound according to formula (I): ##STR6## wherein X.sup.g is O, S, SO, SO.sub.2, CH.sub.2, CH, N or NR wherein R is hydrogen or C.sub.1-6 alkyl; A is a saturated or unsaturated polymethylene chain of 2-4 carbon atoms; R.sub.1.sup.g and R.sub.2 .sup.g are hydrogen or C.sub.1-6 alkyl; R.sub.3.sup.g is hydrogen, halo, C.sub.1-6 alkyl, amino, nitro or C.sub.1-6 alkoxy; R.sub.4.sup.g is hydrogen, halo, C.sub.1-6 alkyl or C.sub.1-6 alkoxy; Y is O or NH; Z is of sub-formula: ##STR7## wherein --(CH.sub.2).sub.n.sup.1 is attached at carbon; and n.sup.1 is 0, 1, 2, 3 or 4; q is 0, 1, 2 or 3; R.sub.a is a straight or branched chain alkylene of chain length 1-6 carbon atoms terminally substituted by R.sub.7 wherein R.sub.7 is 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 R.sub.6 is hydrogen or C.sub.1-6 alkyl; or a compound of formula (I) wherein the CO--Y linkage is replaced by a heterocyclic bioisostere. ### Claim 2 (depends on 1) A compound according to claim 1 wherein n.sup.1 is 1, q is 2 and the azacycle is attached at a 4-position carbon atom. ### Claim 3 (depends on 1) A compound according to claim 1 wherein A is --CH.sub.2 --(CH.sub.2).sub.r -CH.sub.2 --, wherein r is 0, 1 or 2; --CH.sub.2 --CH.dbd.CH.dbd.; or --C(CH.sub.3).dbd.CH--. ### Claim 4 (depends on 1) A compound according to claim 1 wherein X.sup.g is CH or N, and A is --(CH.sub.2).sub.2 --CH.dbd. or --CH.dbd.CH--CH.dbd.. ### Claim 5 (depends on 1) A compound according to claim 1 wherein Z is 4-piperidinylmethyl, N-substituted by R.sub.a. ### Claim 6 (depends on 1) A compound according to claim 1 wherein Z is 4-pyrrolidinylmethyl, N-substituted by R.sub.a. ### Claim 7 (depends on 1) A compound according to claim 1 wherein R.sub.1g and R.sub.2.sup.g are both hydrogen or are gem-dimethyl. ### Claim 8 (depends on 1) A compound according to claim 1 wherein R.sub.4.sup.g is hydrogen or halo. ### Claim 9 (depends on 1) A compound according to claim 1 wherein R.sub.7 is pyridyl, pyrimidyl, pyrazinyl, pyrryl, imidazolyl, thienyl, furanyl, oxazole, thiazole, benzofuranyl, benzothiophenyl, indolyl, indazolyl, quinolyl and isoquinolyl. ### Claim 10 (depends on 1) A compound according to claim 1 wherein R.sub.7 is piperidinyl or pyrrolidinyl. ### Claim 11 (depends on 1) A compound according to claim 1 which is: N-›(1-(4-pyridylmethyl)-4-piperidinyl)methyl!3,4-dihydro-2H-›1,3!oxazino›3 ,2-a!indole-10-carboxamide or a pharmaceutically acceptable salt thereof. ### Claim 12 (depends on 1) A compound according to claim 1 which is: N-›(1-(2-piperidinyl)ethyl)-4-piperidinyl)methyl!3,4-dihydro-2H-›1,3!oxazi no›3,2-a!indole-10-carboxamide or a pharmaceutically acceptable salt thereof. ### Claim 13 (depends on 1) A compound according to claim 1 which is: N-›(1-(benzofuran-2-ylmethyl)-4-piperidinyl)methyl!3,4-dihydro-2H-›1,3!oxa zino›3,2-a!indole-10-carboxamide or a pharmaceutically acceptable salt thereof. ### Claim 14 (depends on 1) A compound according to claim 1 which is: N-›(1-(quinolin-2-ylmethyl)-4-piperidinyl)methyl!3,4-dihydro-2H-›1,3!oxazi no›3,2-a!indole- 10-carboxamide or a pharmaceutically acceptable salt thereof. ### Claim 15 (depends on 1) A compound according to claim 1 which is: N-›(1-(2-thienylmethyl)-4-piperidinyl)methyl!3,4-dihydro-2H-›1,3!oxazino›3 ,2-a!indole-10-carboxamide or a pharmaceutically acceptable salt thereof. ### Claim 16 (depends on 1) A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier. ### Claim 17 (depends on 1) A method for treating irritable bowel syndrome comprising administering an effective amount of a compound according to claim 1. ### Claim 18 (depends on 1) A method for treating atrial arrhythmia or stroke comprising administering an effective amount of a compound according to claim 1. ### Claim 19 (depends on 1) A method of treating anxiety comprising administering an effective amount of a compound according to claim 1. ### Claim 20 (depends on 1) A method of treating migraine comprising administering an effective amount of a compound according to claim 1. ### Claim 21 (depends on 1) A method of treating dyspepsia comprising administering an effective amount of a compound according to claim 1.