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1. WO2007146073 - METHOD FOR ENHANCING COGNITIVE FUNCTION

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CLATMS
What is claimed is:

1. A method for treating a cognitive disorder in a patient in need thereof, the method comprising administering to the patient synergistically effective amounts of a compound that is a 5-HT\/± antagonist and a cognitive enhancer.

2. The method of claim 1 , wherein the cognitive disorder is dementia, Parkinson's disease, Huntington's disease, Alzheimer's disease, cognitive deficits associated with Alzheimer's disease, mild cognitive impairment, or schizophrenia.

3. The method of claim 1 , wherein the 5-HTχ A antagonist compound is
(R)-4-cyano-N-{2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]propyl}-N-pyridin-2-yl-benzamide or a pharmaceutically acceptable acid addition salt thereof,
N-[2-[4-(2-methoxyphenyl)- 1 -piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide or a pharmaceutically acceptable acid addition salt thereof,
(R)-N-(2-methyl-(4-indolyl- 1 -piperazinyl)etnyl)-N-(2-pyridinyl)
cyclohexanecarboxamide or a pharmaceutically acceptable acid addition salt thereof,
5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin- 1 -yl)piperidin-l -yl)quinoline or a pharmaceutically acceptable acid addition salt thereof, or 5-fluoro-4-methoxy-8-(4-(4-(6-methoxyqυinolin-8-yl)piperazin- 1 -yl)piρeridin- 1 -yl)-2-(trifluoromethyl)quinoline or a pharmaceutically acceptable acid addition salt thereof.

4. The method of claim 3, wherein the 5-HTi A antagonist compound is
(R)-4-cyano-N- {2-[4-(2,3-dihydro-benzo[ 1 ,4]dioxin-5-yl)-piperazin- 1 -yl]propyl}-N-pyridin-2-yl-benzamide and pharmaceutically acceptable acid addition salts thereof,
N- [2- [4-(2~methoxyphenyl)- 1 -piperazinyl] ethyl] -N-(2-pyridinyl)cyclohexanecarboxarnide and pharmaceutically acceptable acid addition salts thereof,
(R)-N-(2-methyl-(4-indolyl- 1 -piperazinyl)ethyl)-N-(2-pyridinyl)
cyclohexanecarboxamide and pharmaceutically acceptable acid addition salts thereof,
5-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidin-l-yl)quinoline or a pharmaceutically acceptable acid addition salt thereof,
5-fluoro-4-methoxy-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin-l-yl)piperidin-l-yl)-2-(trifiuoromethyl)quinoline and pharmaceutically acceptable acid addition salts thereof,
6-methoxy-8~[4-(l -quinolin-8-yl-piperidin-4-yl)-piperazin-l -yl]-quinoline and pharmaceutically acceptable acid addition salts thereof,
6-fiuoro-8-[4-(l -quinolin-8-yI-piperidin-4-yl)-piperazin- 1 -yl]-quinoline and pharmaceutically acceptable acid addition salts thereof, 8-{4-[4-(lH-indole-4-yl)-piρerazin-l-yl]-piρeridin-l-yl}-quinoline and pharmaceutically acceptable acid addition salts thereof,
5-fluoro-8- {4-[4-(5-fluoro-benzofuran-3-yl)-piperazin-l-yl]- piperidin-1 -yl}-quinoline and pharmaceutically acceptable acid addition salts thereof,
7-fluoro-8-(4-(4-(6-methoxyquinolin-8-yl)piperazin- 1 -yl)piperidin- 1 -yl)quinoline and pharmaceutically acceptable acid addition salts thereof,
6-methoxy-8-(4-( 1 -(quinolm-8-ylmethyl)piperidin-4-yl)piperazin-l -yl)quinoline and pharmaceutically acceptable acid addition salts thereof,
8-[4-(l-quinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-5-trifluoromethyl-quinoline and pharmaceutically acceptable acid addition salts thereof,
5~methoxy-8-[4-(l -quinolin-8-yl-piperidin-4-yl)-piperazin-l -yl]-quinoline and pharmaceutically acceptable acid addition salts thereof,
5-fluoro-8-[4-(4-quinolin-8-yl-piperazin-l-yl)-piperidin-l-yl]-quinoline and pharmaceutically acceptable acid addition salts thereof, or
8-[4-(4-benzofuran-3-yl-piperazin- 1 -yl)-piperidin- 1 -yl]-6-chloro-quinoline and pharmaceutically acceptable acid addition salts thereof.
5. The method of any one of claims 3 or 4, wherein the 5-HTj /^ antagonist

compound is
(R)-4-cyano-N- {2-[4-(2,3-dihydro-benzo[ 1 ,4]dioxin-5-yl)-piperazin- 1 -yl]proρyl}-N-pyridin-2-yl-benzamide and pharmaceutically acceptable acid addition salts thereof,
N-[2-[4-(2-methoxyphenyl)-l-piperazinyl]ethyl]-N-(2~
pyridinyl)cyclohexanecarboxamide and pharmaceutically acceptable acid addition salts thereof, (R)-N-(2-methyl-(4-indolyl-l-piperazinyl)ethyl)-N-(2-pyridinyl)
cyclohexanecarboxamide and pharmaceutically acceptable acid addition salts thereof,
6-methoxy-8- [4-( 1 -quinolin-8-yl-piperidin-4-yl)-piperazin- 1 -yl]-quinoline and pharmaceutically acceptable acid addition salts thereof, or
6-fluoro-8-[4-(l -quinolin-8-yl-piperidin-4-yl)-piperazin-l -yl]-quinoline and pharmaceutically acceptable acid addition salts thereof.

6. The method of any one of claims 3 to 5, wherein the 5-HTj/^ antagonist

compound is
(R)-4-cyano-N-{2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]propyl}-N-pyridin-2-yl-benzamide and pharmaceutically acceptable acid addition salts thereof,
N-[2-[4-(2-fnethoxyphenyl)-l-ρiperazinyl]ethyl]-N-(2-pyridinyl)cyclohexane carboxamide and pharmaceutically acceptable acid addition salts thereof,
(R)-N-(2-methy]-(4-indolyl-l-piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide and pharmaceutically acceptable acid addition salts thereof, or
6-methoxy-8-[4-(l -quinolin-8-yl-piperidin-4-yl)-piperazin-l -yl]-quinoline and pharmaceutically acceptable acid addition salts thereof.

7. The method of any one of claims 3 to 6, wherein the 5-HTi A antagonist compound is
(R)-4-cyano-N- {2-[4-(2,3-dihydro-benzo[ 1 ,4]dioxin-5-yl)-piperazin- 1 -yl]propyl}-N-pyridin-2-yl-benzamide and pharmaceutically acceptable acid addition salts thereof, or
(R)-N-(2-methyl-(4-indolyl- 1 -piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide and pharmaceutically acceptable acid addition salts thereof.

8. The method of any one of claims 3 to 7, wherein the 5-HTJA antagonist compound is
(R)-N -(2-methyl-(4-indolyl- 1 -piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide and pharmaceutically acceptable acid addition salts thereof.

9. The method of any one of claims 1 to 8, wherein the cognitive enhancer is a cholinesterase inhibitor.

10. The method of claim 9, wherein the cholinesterase inhibitor is tacrine, donepezil, rivastigmine, or galantamine.

11. The method of any one of claims 1 to 8, wherein the cognitive enhancer is an NMDA antagonist or an NMDA agonist.

12. The method of any one of claims 1 to 8, wherein the cognitive enhancer is an ampakine class compound.

13. The method of any one of claims 1 to 8, wherein the cognitive enhancer is a BZD/GABA receptor complex modulator.

14. The method of any one of claims 1 to 8, wherein the cognitive enhancer is a serotonin antagonist.

15. The method of any one of claims 1 to 8, wherein the cognitive enhancer is a nicotinic class compound.

16. The method of any one of claims 1 to 8, wherein the cognitive enhancer is a muscarinic class compound.

17. The method of any one of claims 1 to 8, wherein the cognitive enhancer is a MAO-B inhibitor.

18. The method of any one of claims 1 to 8, wherein the cognitive enhancer is a PDE inhibitor.

19. The method of any one of claims 1 to 8, wherein the cognitive enhancer is a G protein class compound.

20. The method of any one of claims 1 to 8, wherein the cognitive enhancer is a channel modulator.

21. The method of any one of claims 1 to 8, wherein the cognitive enhancer is an immunotherapeutic class compound.

22. The method of any one of claims 1 to 8, wherein the cognitive enhancer is an anti-amyloid or amyloid lowering agent.

23. The method of any one of claims 1 to 8, wherein the cognitive enhancer is a statin or a PPARS modulator.

24. The method of any one of claims 1 to 23, wherein the method comprises oral delivery of the compound that is a 5-HTχ A antagonist.

25. The method of any one of claims 1 to 24, wherein the method comprises delivery of a sustained release compound.

26. A method of enhancing cognition in a patient in need thereof, the method comprising administering to the patient synergistically effective amounts of a 5-HTi A antagonist compound and a cognitive enhancer.

27. A pharmaceutical composition for treating a cognitive disorder, the composition comprising a 5-HT]1 /± antagonist compound and a cognitive enhancer.

28. The pharmaceutical composition of claim 27, wherein the 5-HTj A antagonist compound is
(R)-4-cyano-N-{2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]propyl}-N-pyridin-2-yl-benzamide and pharmaceutically acceptable acid addition salts thereof, N-[2-[4-(2-methoxyphenyl)-l-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide and pharmaceutically acceptable acid addition salts thereof,
(R)-N-(2-methyl-(4-indolyl-l-piperazinyl)ethyl)-N-(2-pyridinyl)
cyclohexanecarboxamide and pharmaceutically acceptable acid addition salts thereof,
5-fluoro-8-(4-(4-(6~methoxyquinolin-8-yl)piperazin-l-yl)piperidin-l-yl)quinoline or a pharmaceutically acceptable acid addition salt thereof,
5-fluoro-4-methoxy-8-(4-(4-(6-methoxyquinolin-8-yl)pipera2in-l-yl)piperidin-l-yl)-2-(trifluoromethyl)quinoline and pharmaceutically acceptable acid addition salts thereof,
6-methoxy-8-[4-(l -quinolin-8-yl-piperidin-4-yl)-piperazin- 1 -yl]-quinoline and pharmaceutically acceptable acid addition salts thereof,
6-fluoro-8-[4-(l -quinolin-8-yl-piperidin-4-yl)-piperazin-l -yl]-quinoline and pharmaceutically acceptable acid addition salts thereof,
8-{4-[4-(l//-indole-4-yl)-piperazin-l -yl]-piperidin-l -yl}-quinoline and pharmaceutically acceptable acid addition salts thereof,
5-fluoro-8-{4-[4-(5-fluoro-benzoftiran-3-yl)-ρiperazin-l-yl]- piperidin-l-yl}-quinoline and pharmaceutically acceptable acid addition salts thereof,
7-fluoro-8-(4-(4~(ό-methoxyquinolin-8-yl)piperazin- 1 -yl)piperidin- 1 -yl)quinoline and pharmaceutically acceptable acid addition salts thereof,
6-methoxy-8-(4-(l-(quinolin-8-ylmethyl)piperidin-4-yl)piperazin-l-yl)quinoline and pharmaceutically acceptable acid addition salts thereof,
8-[4-(l-quinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-5-trifluoromethyl-quinoline and pharmaceutically acceptable acid addition salts thereof, 5-methoxy-8-[4-(l -quinolin-8-yl-piperidin-4-yl)-piperazin-l -yl]-quinoline and pharmaceutically acceptable acid addition salts thereof,
5-fluoro-8-[4-(4-quinolin-8-yl-piperazin-l -yl)-piperidin-l -yl]-quinoline and pharmaceutically acceptable acid addition salts thereof, or
8-[4-(4-benzofuran-3-yl-piperazin-l-yl)-piρeridin-l-yl]-6-chloro-quinoline and pharmaceutically acceptable acid addition salts thereof.

29. The pharmaceutical composition of claims 27 or 28, wherein the 5-HTJA

antagonist compound is
(R)-4-cyano-N-{2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]propyl}-N-ρyridin-2-yl-benzamide and pharmaceutically acceptable acid addition salts thereof,
N-[2-[4-(2-methoxyphenyl)-l-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexanecarboxamide and pharmaceutically acceptable acid addition salts thereof,
(R)-N-(2-methyl-(4-indolyl-l-piperazinyl)ethyl)-N-(2-pyridinyl)
cyclohexanecarboxamide and pharmaceutically acceptable acid addition salts thereof,
6-methoxy-8-[4-(l -quinolin-8-yl-piperidin-4-yl)-piperazin- 1 -yl]-quinoline and pharmaceutically acceptable acid addition salts thereof, or
6-fluoro-8-[4-(l -quinolin-8~yl-piperidin-4-yl)-piperazin-l -yl]-quinoline and pharmaceutically acceptable acid addition salts thereof.

30. The pharmaceutical composition of any one of claims 27 to 29, wherein the 5-HTj A antagonist compound is (R)-4-cyano-N- {2-[4-(2,3-dihydro-benzo[ 1 ,4]dioxin-5-yl)-piperazin- 1 -yl]propyl}-N-pyridin-2-yl-benzamide and pharmaceutically acceptable acid addition salts thereof,
N-[2-[4-(2-methoxyρhenyl)-l-piperazinyl]ethyl]-N-(2-pyridinyl)cyclohexane carboxamide and pharmaceutically acceptable acid addition salts thereof,
(R)-N-(2-methyl-(4-indolyl- 1 -piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide and pharmaceutically acceptable acid addition salts thereof, or
6-methoxy-8-[4-(l-quinolin-8-yl-piperidin-4-yl)-piperazin-l-yl]-quinoline and pharmaceutically acceptable acid addition salts thereof.

31. The pharmaceutical composition of any one of claims 27 to 30, wherein the 5-HT]A antagonist compound is
(R)-4-cyano-N-{2-[4-(2,3-dihydro-benzo[l,4]dioxin-5-yl)-piperazin-l-yl]propyl}-N-pyridin-2-yl-benzamide and pharmaceutically acceptable acid addition salts thereof, or
(R)-N-(2-methyl-(4-indolyl- 1 -piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide and pharmaceutically acceptable acid addition salts thereof.

32. The pharmaceutical composition of any of one claims 27 to 31, wherein the 5-HTjA antagonist compound is
(R)-N-(2-methyl-(4-indolyl- 1 -piperazinyl)ethyl)-N-(2-pyridinyl) cyclohexane carboxamide and pharmaceutically acceptable acid addition salts thereof.

33. The pharmaceutical composition of any of one claims 27 to 32, wherein the cognitive enhancer is a cholinesterase inhibitor.

34. The pharmaceutical composition of claim 33, wherein the cholinesterase inhibitor is tacrine, donepezil, rivastigmine, or galantamine.

35. The pharmaceutical composition of any one of claim 27 to 32, wherein the cognitive enhancer is an NMDA antagonist or an NMDA agonist.

36. The pharmaceutical composition of any one of claim 27 to 32, wherein the cognitive enhancer is an ampakine class compound.

37. The pharmaceutical composition of any one of claims 27 to 32, wherein the cognitive enhancer is a BZD/GABA receptor complex modulator.

38. The pharmaceutical composition of any one of claims 27 to 32, wherein the cognitive enhancer is a serotonin antagonist.

39. The pharmaceutical composition of any one of claims 22-27, wherein the cognitive enhancer is a nicotinic class compound.

40. The pharmaceutical composition of any one of claims 27 to 32, wherein the cognitive enhancer is a muscarinic class compound.

41. The pharmaceutical composition of any one of claims 27 to 32, wherein the cognitive enhancer is a MAO-B inhibitor.

42. The pharmaceutical composition of any one of claims 27 to 32, wherein the cognitive enhancer is a PDE inhibitor.

43. The pharmaceutical composition of any one of claims 27 to 32, wherein the cognitive enhancer is a G protein class compound.

44. The pharmaceutical composition of any one of claims 27 to 32, wherein the cognitive enhancer is a channel modulator.

45. The pharmaceutical composition of any one of claims 27 to 32, wherein the cognitive enhancer is an immunotherapeutic class compound.

46. The pharmaceutical composition of any one of claims 27 to 32, wherein the cognitive enhancer is an anti-amyloid or amyloid lowering agent.

47. The pharmaceutical composition of any one of claims 27 to 32, wherein the cognitive enhancer is a statin or a PPARS modulator.

48. The pharmaceutical composition of any one of claims 27 to 47, wherein the pharmaceutical composition comprises a formulation suitable for oral delivery.

49. The pharmaceutical composition of any one of claims 27 to 48, wherein the pharmaceutical composition comprises a formulation suitable for sustained release.

50. The pharmaceutical composition of any one of claims 27 to 49, wherein the 5- . HT]^ antagonist compound and the cognitive enhancer are present in synergistically effective amounts.

51. A package comprising a 5 -HTj j\ antagonist and a cognitive enhancer, wherein the instructions comprise instructions for treating a cognitive disorder.

52. A pharmaceutical product containing a 5-HTi A antagonist and a cognitive enhancer as a combined preparation for simultaneous, separate or sequential use in therapy for treating a cognitive disorder.

53. Use of a 5-HTi A antagonist and a cognitive enhancer in the manufacture of a medicament for treating a cognitive disorder.

54. Use of a cognitive enhancer in the manufacture of a medicament, for use with a 5-HTj A antagonist, for treating a cognitive disorder.

55. Use of a 5-HTi A antagonist in the manufacture of a medicament, for use with a cognitive enhancer, for treating a cognitive disorder.