# US 5,708,174 A · Heterocyclic-esters or -amides used as 5-HT.sub.4 receptor antagonists

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- Number: US 5,708,174 A
- Document ID: US5708174A
- Status: Granted
- Kind: A
- Application number: 08/416,773
- Filed: 1995-04-11
- Granted: 1998-01-13
- Earliest claimed: 1992-03-12
- Assignees: SmithKline Beecham Corporation
- Inventors: Francis David King; Laramie Mary Gaster; Graham Francis Joiner; Keith Raymond Mulholland; Shirley Katherine Rahman
- Web page: https://patentgrep.com/patent/US5708174A

## CPC

- C07D 401/12: linked by a chain containing hetero atoms as chain links
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 405/12: linked by a chain containing hetero atoms as chain links
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- C07D 455/02: containing not further condensed quinolizine ring systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## 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.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

A compound according to claim 1 wherein:
in formula (I-2): R.sub.1 is hydrogen or amino, R.sub.2 is hydrogen or halo, R.sub.3 is hydrogen or halo, R.sub.4 is hydrogen;
in formula (I-3): R.sub.1 is hydrogen or amino, R.sub.2 is hydrogen or halo, R.sub.3 is hydrogen or halo, R.sub.4 is hydrogen or methyl;
in formula (I-4): R.sub.1 is hydrogen or amino, R.sub.2 is hydrogen or halo, R.sub.3 is hydrogen or halo, R.sub.4 is hydrogen.

### Claim 3 (depends on 1)

A compound according to claim 1 wherein Z is of sub-formula (a) and (CH.sub.2).sub.n 1 is attached at a carbon atom of the azacycle.

### Claim 4 (depends on 3)

A compound according to claim 3 wherein Z is N-substituted 4-piperidylmethyl.

### Claim 5 (depends on 4)

A compound according to claim 4 wherein Z is 4-piperidylmethyl and R.sup.5 is C.sub.2 or greater alkyl, or optionally substituted benzyl.

### Claim 6

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.

### Claim 7

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.

### Claim 8

A compound selected from:
8-(1-Butyl-4-piperidinylmethyl)-1, 2-dihydro-1-methylquinolinecarboxylate, and pharmaceutically acceptable salts thereof.

### Claim 9 (depends on 1, 2, 3, 4, 5, 6, 7, 8)

A pharmaceutical composition comprising a compound according to any one of claims 1 to 8, and a pharmaceutically acceptable carrier.

### Claim 10 (depends on 1)

A compound according to claim 1 wherein Y-Z is ##STR13##

### Claim 11 (depends on 1)

A method of treatment of gastrointestinal disorders, cardiovascular disorders and CNS disorders which comprises administration of a compound according to claim 1.