# US 5,705,509 A · Tricyclic heterocyclic compounds as 5-HT.sub.4 receptor antagonists

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- Number: US 5,705,509 A
- Document ID: US5705509A
- Status: Granted
- Kind: A
- Application number: 08/495,538
- Filed: 1995-07-28
- Granted: 1998-01-06
- Earliest claimed: 1993-01-28
- Assignees: SmithKline Beecham Corporation
- Inventors: Laramie Mary Gaster; Paul Adrian Wyman
- Web page: https://patentgrep.com/patent/US5705509A

## CPC

- C07D 491/04: Ortho-condensed systems
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 9/08: Vasodilators for multiple indications
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Compounds of formula (I) or a pharmaceutically acceptable salt thereof, wherein X.sub.1 --(CH.sub.2).sub.x --X.sub.2 and the aromatic carbon atoms to which they are attached form 5-7 membered ring wherein X.sub.1 is O or S; X.sub.2 is O, S, NR.sub.5 or NR.sub.6 CO wherein R.sub.5 is hydrogen or C.sub.1-6 alkyl; or one of X.sub.1 and X.sub.2 is O, S or CH.sub.2 and the other is CH.sub.2 ; x is 1, 2 or 3; R.sub.1 and R.sub.2 together are Q--CH.sub.2 --CH.sub.2, Q--CH.dbd.CH, or Q--CH.dbd.N where Q is linked either to the R.sub.1 or the R.sub.2 substitution position and Q is O, S or NR.sub.t wherein R.sub.t is hydrogen or C.sub.1-6 alkyl; R.sub.3 is hydrogen halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or amino; R.sub.4.sup.1 and R.sub.4.sup.2 are independently hydrogen or C.sub.1-6 alkyl; Y is O or NH; Z is of sub-formula (a), (b) or (c) and their use as pharmaceuticals in the treatment of gastrointestinal disorders, cardiovascular disorders and CNS disorders. ##STR1##

## Claims

### Claim 1

Compounds of formula (I), or pharmaceutically acceptable salts thereof: ##STR6## wherein 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
X.sub.1 is O or S; X.sub.2 is O or S; or one of
X.sub.1 and X.sub.2 is O, S or CH.sub.2 and the other is CH.sub.2 ;
x is 1 or 2;
R.sub.1 and R.sub.2 together are Q--CH.sub.2 --CH.sub.2, Q--CH.dbd.CH, or Q--CH.dbd.N where Q is linked either to the R.sub.1 or the R.sub.2 substitution position and Q is O, S or NR.sub.t wherein R.sub.t is hydrogen or C.sub.1-6 alkyl;
R.sub.3 is hydrogen, halo, C.sub.1-6 alkyl, C.sub.1-6 alkoxy or amino;
R.sub.4.sup.1 and R.sub.4.sup.2 are independently hydrogen or C.sub.1-6 alkyl;
Y is O or NH;
Z is of sub-formula (a): ##STR7## wherein n.sup.1 is 1, 2, 3 or 4;
q is 0, 1, 2 or 3;
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; or R.sub.5 is straight or branched chain alkylene of chain length 1-6 carbon atoms terminally substituted by aryl, 3 to 8 membered cycloalkyl, 3 to 8 membered heterocyclyl, 5 or 6 membered monocyclic heteroaryl or 9 or 10 membered fused bicyclic heteroaryl linked through carbon, 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 R.sub.1 and R.sub.2 are joined to form --NH--CH.dbd.N--.

### Claim 3 (depends on 1)

A compound according to claim 1 wherein the moiety attached to CO--Y--Z in formula (I) is wherein:
R.sub.1 --R.sub.2 are together --NH--CH.dbd.N--, R.sub.3 is H, R.sub.4.sup.1 and R.sub.4.sup.2 are H, X.sub.1 and X.sub.2 are O, and x is 2;
R.sub.1 --R.sub.2 are together --NH--CH.dbd.CH--, R.sub.3 is H, R.sub.4.sup.1 and R.sub.4.sup.2 are H, X.sub.1 and X.sub.2 are O, and x is 2; or
R.sub.1 --R.sub.2 are together --C.dbd.CH--NH--, R.sub.3 is H, R.sub.4.sup.1 and R.sub.4.sup.2 are H, X.sub.1 is O, X.sub.2 is CH.sub.2, and x is 2.

### Claim 4 (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 5 (depends on 4)

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

### Claim 6 (depends on 5)

A compound according to claim 5 wherein the N-substituent is C.sub.2 or greater alkyl, or optionally substituted benzyl.

### Claim 7 (depends on 1)

A compound according to claim 1 wherein Y is NH.

### Claim 8

(1-Butyl-4-piperidinyl)methyl 1 H-7,8-dihydro-›1,4!-dioxino›2,3-g!benzimidazole-5-carboxylate.

### Claim 9 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1, and a pharmaceutically acceptable carrier.

### Claim 10 (depends on 1)

A method of treating gastrointestinal disorders or cardiovascular disorders which comprises administering an effective amount of a compound according to claim 1.

### Claim 11 (depends on 1)

A method of treating migraine, anxiety, schizophrenia, Parkinson's disease and Huntington's chorea which comprises the administering an effective amount of a compound according to claim 1.

### Claim 12 (depends on 1)

A method of treating atrial arrhythmia or stroke which comprises administering an effective amount of a compound according to claim 1.

### Claim 13 (depends on 1)

A method of treating urinary incontinence which comprises administering an effective amount of a compound according to claim 1.

### Claim 14 (depends on 1)

A method of treating irritable bowel syndrome which comprises administering an effective amount of a compound according to claim 1.