# US 5,330,982 A · Pharmaceutical composition containing a 5-HT receptor antagonist and an H.sup.+ K.sup.+ Atpase inhibitor and a method of treating gastrointestingal disorders therewith

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- Number: US 5,330,982 A
- Document ID: US5330982A
- Status: Granted
- Kind: A
- Application number: 07/935,443
- Filed: 1992-08-25
- Granted: 1994-07-19
- Earliest claimed: 1986-12-17
- Assignees: Glaxo Group Limited
- Inventors: Michael B. Tyers
- Web page: https://patentgrep.com/patent/US5330982A

## CPC

- A61K 31/44: Non condensed pyridines; Hydrogenated derivatives thereof
- A61K 31/415: 1,2-Diazoles
- A61K 31/46: 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
- A61K 31/55: having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The invention relates to the use of a compound which is an antagonist of 5-HT at 5-HT.sub.3 receptors and promotes gastric emptying in conjunction with an H.sup.+ K.sup.+ ATPase inhibitor in the treatment of gastrointestinal disorders.

## Claims

### Claim 1

A pharmaceutical composition for use in human or veterinary medicine comprising an effective amount of a compound which is an antagonist of 5-HT at 5-HT.sub.3 receptors and promotes gastric emptying, and an effective amount of a compound which is an H.sup.+ K.sup.+ ATPase inhibitor, with at least one physiologically acceptable carrier or excipient, wherein said compound which is an antagonist of 5-HT at 5-HT.sub.3 receptors is a compound of formula (III): ##STR11## wherein R.sub.8 represents a C.sub.1-6 alkoxy or amino N-substituted by one or two groups selected from C.sub.1-6 alkyl and C.sub.3-8 cycloalkyl, or optionally N-substituted by C.sub.4-5 polymethylene; one of R.sub.9, R.sub.10 and R.sub.11 is hydrogen and the other two are independently selected from hydrogen, chloro, bromo, trifluoromethyl, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, C.sub.1-6 alkyl and amino; one of R.sub.12 and R.sub.13 represents hydrogen, C.sub.1-6 alkyl, phenyl or phenylC.sub.1-3 alkyl, which phenyl moieties may be substituted by C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3 or halogen, and the other of R.sub.12 and R.sub.13 is hydrogen or C.sub.1-6 alkyl; q is zero or an integer from 1 to 4; r is zero, or an integer from 1 to 3; and s is zero, 1 or 2,
or a physiologically acceptable salt or solvate thereof, and said H.sup.+ K.sup.+ ATPase inhibitor is a 2-(pyridylmethylsulphinyl)benzimidazole, or a physiologically acceptable salt thereof.

### Claim 2 (depends on 1)

A pharmaceutical composition according to claim 1 wherein said compound which is an antagonist of 5-HT at 5-HT.sub.3 receptors is (.+-.)-endo-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo)-[3.3.1]-non-4-yl)b enzamide, or a physiologically acceptable salt or solvate thereof.

### Claim 3 (depends on 1)

A pharmaceutical composition according to claim 1 wherein said H.sup.+ K.sup.+ ATPase inhibitor is omeprazole.

### Claim 4 (depends on 1)

A pharmaceutical composition according to claim 1 wherein said compound which is an antagonist of 5-HT at 5-HT.sub.3 receptors is (.+-.)-endo-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo)-[3.3.1]-non-4-yl)b enzamide, or a physiologically acceptable salt or solvate thereof, and wherein said H.sup.+ K.sup.+ ATPase inhibitor is omeprazole.

### Claim 5

A method of treating gastrointestinal disorders which comprises administering to a human or animal subject in need thereof an effective amount of a compound which is an antagonist of 5-HT at 5-HT.sub.3 receptors and promotes gastric emptying in conjunction with an effective amount of a compound which is an H.sup.+ K.sup.+ ATPase inhibitor, wherein said compound which is an antagonist of 5-HT at 5-HT.sub.3 receptors is a compound of formula (III): ##STR12## wherein R.sub.8 represents a C.sub.1-6 alkoxy or amino N-substituted by one or two groups selected from C.sub.1-6 alkyl and C.sub.3-8 cycloalkyl, or optionally N-substituted by C.sub.4-5 polymethylene; one of R.sub.9, R.sub.10 and R.sub.11 is hydrogen and the other two are independently selected from hydrogen, chloro, bromo, trifluoromethyl, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, C.sub.1-6 alkyl and amino; one of R.sub.12 and R.sub.13 represents hydrogen, C.sub.1-6 alkyl, phenyl or phenylC.sub.1-3 alkyl, which phenyl moieties may be substituted by C.sub.1-6 alkyl, C.sub.1-6 alkoxy, CF.sub.3 or halogen, and the other of R.sub.12 and R.sub.13 is hydrogen or C.sub.1-6 alkyl; q is zero or an integer from 1 to 4; r is zero, or an integer from 1 to 3; and s is zero, 1 or 2,
or a physiologically acceptable salt or solvate thereof, and said H.sup.+ K.sup.+ ATPase inhibitor is a 2-(pyridylmethylsulphinyl)benzimidazole, or a physiologically acceptable salt thereof.

### Claim 6 (depends on 5)

A method according to claim 5 wherein said compound which is an antagonist of 5-HT at 5-HT.sub.3 receptors is (.+-.)-endo-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo)-[3.3.1]-non-4-yl)b enzamide, or a physiologically acceptable salt or solvate thereof.

### Claim 7 (depends on 5)

A method according to claim 5 wherein said H.sup.+ K.sup.+ ATPase inhibitor is omeprazole.

### Claim 8 (depends on 5)

A method according to claim 5 wherein said compound which is an antagonist of 5-HT at 5-HT.sub.3 receptors is (.+-.)-endo-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo)-[3.3.1]-non-4-yl)b enzamide, or a physiologically acceptable salt or solvate thereof, and wherein said H.sup.+ K.sup.+ ATPase inhibitor is omeprazole.

### Claim 9 (depends on 5)

A method according to claim 5 wherein the compound which is an antagonist of 5-HT at 5-HT.sub.3 receptors is a compound of formula (III) at a unit dose of 0.1 to 20 mg, which is administered in conjunction with the H.sup.+ K.sup.+ ATPase inhibitor at a unit dose of 5 to 250 mg.

### Claim 10 (depends on 9)

A method according to claim 9 wherein (.+-.)-endo-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo)-[3.3.1]-non-4-yl)b enzamide, or a physiologically acceptable salt or solvate thereof, is administered at a unit dose of 0.1 to 20 mg, and wherein omeprazole is administered at a unit dose of 5 to 250 mg.