Method for the treatment of cognitive dysfunction

Abstract

The present invention provides a method for the treatment of a cognitive disorder such as Alzheimer's disease in a patient in need thereof which comprises providing to said patient a therapeutically effective amount of a combination of an acetylcholinesterase inhibitor and a 5-hydroxytryptamine-6 antagonist.

Description

DESCRIPTION OF DRAWINGS

FIG. 1. FIG. 1 is a schematic representation of the effect of a combination of ineffective doses of an acetylcholinesterase inhibitor and a 5-HT6 antagonist on memory retention (Aricept plus Test Compound A), as determined in vivo by a novel object recognition assay.

FIG. 2. FIG. 2 is a schematic representation of the effect of a combination of an ineffective dose of an acetylcholinesterase inhibitor and an effective dose of a 5-HT6 antagonist on memory retention (Aricept plus Test Compound A), as determined in vivo by a novel object recognition assay.

FIG. 3. FIG. 3 is a schematic representation of the enhanced effect of a combination of an effective dose of an acetylcholinesterase inhibitor and an effective dose of a 5-HT6 antagonist on memory retention (Aricept plus Test Compound A), as determined in vivo by a novel object recognition assay.

FIG. 4. FIG. 4 is a schematic representation of the effect of a combination of ineffective doses of an acetylcholinesterase inhibitor and a 5-HT6 antagonist on memory retention (Aricept plus Test Compound B), as determined in vivo by a novel object recognition assay.

FIG. 5. FIG. 5 is a schematic representation of the effect of a combination of ineffective doses of an acetylcholinesterase inhibitor and a 5-HT6 antagonist on memory retention (Razadyne plus Test Compound B), as determined in vivo by a novel object recognition assay.

FIG. 6. FIG. 6 is a graphic representation of the effect of a combination of an acetylcholinesterase inhibitor and a 5-HT6 antagonist on acetylcholine release (Aricept plus Test Compound B) in rat dorsal hippocampus using microdialysis analysis.

Claims

1. A method for the treatment of a cognitive disorder in a patient in need thereof which comprises providing to said patient a therapeutically effective amount of a combination of an acetylcholinesterase inhibitor and a 5-hydroxytryptamine-6 antagonist.

2. The method according to claim 1 wherein the acetylcholinesterase inhibitor is selected from the group consisting essentially of: donepezil; galanthamine; rivastigmine; and a pharmaceutically acceptable salt thereof.

3. The method according to claim 1 wherein the 5-hydroxytryptamine-6 antagonist is a compound of formula I

4. The method according to claim 3 having the formula I compound wherein R1 is O(CH2)3NH2, O(CH2)3N(CH3)2 or piperazinyl; and R18 is an optionally substituted aryl group.

5. The method according to claim 3 having the formula I compound wherein R2 and R3 are H; R4 is SO2R18 and R18 is naphthyl.

6. The method according to claim 3 having the formula I compound wherein R2 and R4 are H; R3 is SO2R18 and R18 is phenyl.

7. The method according to claim 1 wherein the 5-HT6 antagonist is selected from the group consisting essentially of:

8. The method according to claim 2 having a formula I compound selected from the group consisting essentially of:

9. The method according to claim 8 wherein said disorder is Alzheimer's disease.

10. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a combination of an acetylcholinesterase inhibitor and a 5-hydroxytryptamine-6 antagonist.

11. The composition according to claim 10 wherein the acetylcholinesterase inhibitor is selected from the group consisting essentially of: donepezil; galanthamine; rivastigmine; and a pharmaceutically acceptable salt thereof.

12. The composition according to claim 10 wherein said 5-HT6 antagonist is a compound of formula I

13. The composition according to claim 12 having the formula I compound wherein R1 is O(CH2)3NH2, O(CH2)3N(CH3)2 or piperazinyl; and R18 is an optionally substituted aryl group.

14. The composition according to claim 13 having the formula I compound wherein R2 and R3 are H; R4 is SO2R18 and R18 is naphthyl.

15. The method according to claim 13 having the formula I compound wherein R2 and R4 are H; R3 is SO2R18 and R18 is phenyl.

16. The composition according to claim 10 wherein the 5-HT6 antagonist is selected from the group consisting essentially of:

17. The composition according to claim 11 wherein the 5-HT6 antagonist is selected from the group consisting essentially of:

18. The composition according to claim 17 wherein the 5-HT6 antagonist is 3-(1-naphthylsulfonyl)-5-piperazin-1-yl-1H-indazole or a pharmaceutically acceptable salt thereof.

19. The composition according to claim 17 wherein the 5-HT6 antagonist is N,N-dimethyl-3-{[3-(1-naphthylsulfonyl)-1H-indazol-5-yl]oxy}propan-1-amine or a pharmaceutically acceptable salt thereof.

20. The composition according to claim 17 wherein the 5-HT6 antagonist is 1-(phenylsulfonyl)-4-(1-piperazinyl)-1H-indazole or a pharmaceutically acceptable salt thereof.