TREATMENT OF COGNITIVE DISORDERS WITH CERTAIN ALPHA-7 NICOTINIC ACID RECEPTORS IN COMBINATION WITH ACETYLCHOLINESTERASE INHIBITORS

• US 20110124631A1
• Filed: 12/27/2010
• Published: 05/26/2011
• Est. Priority Date: 05/11/2009
• Status: Abandoned Application

• Current Assignee: Forum Pharmaceuticals Inc.
• Original Assignee: Forum Pharmaceuticals Inc.
• Inventors: Koenig, Gerhard, Hilt, Dana
• Application Number:
  US12/979,139
• Publication Number:
  US 20110124631A1
• Time in Patent Office: Days
• US Class Current: 514/215
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 31/18 for HIV
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

A method for improving cognition comprising administering to a patient (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof and an acetylcholinesterase inhibitor is described together with related compositions.

Claims

1. A method for improving cognition comprising administering to a patient (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof and an acetylcholinesterase inhibitor.

2. The method of claim 1 wherein the patient has been diagnosed with Alzheimer'"'"'s disease or pre-Alzheimer'"'"'s disease.

3. The method of claim 1 wherein the patient has been diagnosed with mild to moderate Alzheimer'"'"'s disease.

4. The method of claim 1 wherein the patient has been diagnosed with moderate to severe Alzheimer'"'"'s disease.

13. The method of claim 1 wherein one or both of the (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof and the acetylcholinesterase inhibitor is administered at a subclinical dose.

14. The method of claim 13 wherein (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof is orally administered at less than 1.0 mg/day.

15. The method of claim 13 wherein (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof is orally administered at less than 0.5 mg/day.

16. The method of claim 13 wherein (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof is orally administered at less than 0.3 mg/day.

17. The method of claim 13 wherein (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof is orally administered at less than 0.1 mg/day.

18. The method of claim 13 wherein the acetylcholinesterase inhibitor is donepezil and is orally administered at less than 5 mg/day.

19. The method of claim 13 wherein the acetylcholinesterase inhibitor is donepezil and is orally administered 4.5 mg/day or less.

20. The method of claim 13 wherein the acetylcholinesterase inhibitor is donepezil and is orally administered at 4.0 mg/day or less.

21. The method of claim 13 wherein the acetylcholinesterase inhibitor is donepezil and is orally administered at 2.5 mg/day or less.

22. The method of claim 13 wherein the acetylcholinesterase inhibitor is donepezil and is orally administered at 1.5 mg/day or less.

23. The method of claim 13 wherein the acetylcholinesterase inhibitor is donepezil and is orally administered at than 1.0 mg/day or less.

24. The method of claim 1 wherein the acetylcholinesterase inhibitor is administered at a dose that achieves 10-65% steady state red blood cell acetylcholinesterase inhibition.

5. The method of any of the forgoing claims wherein the acetylcholinesterase inhibitor is selected from tacrine, donepezil, rivastigmine and galantamine.

6. The method of claim 5 wherein the acetylcholinesterase inhibitor is selected from donepezil, rivastigmine and galantamine.

7. The method of claim 5 wherein the acetylcholinesterase inhibitor is selected from donepezil and rivastigmine.

8. The method of any of the forgoing claims wherein the patient has been administered an acetylcholinesterase inhibitor for a period of time prior to being administered (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof.

9. The method of claim 8 wherein the prior administration has been for at least one month.

10. The method of claim 9 wherein the prior administration has been for at least three months.

11. The method of claim 10 wherein the prior administration has been for at least six months.

12. The method of any of the forgoing claims wherein the method improves one or more of:

learning, delayed memory, attention, working memory, visual learning, speed of processing, vigilance, verbal learning, visual motor function, social cognition, long term memory or executive function.

25. A pharmaceutical composition comprising (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof and an acetylcholinesterase inhibitor.

26. The pharmaceutical composition of claim 25 wherein the acetylcholinesterase inhibitor is selected from tacrine, donepezil, rivastigmine and galantamine.

27. The pharmaceutical composition of claim 25 wherein the acetylcholinesterase inhibitor is selected from donepezil, rivastigmine and galantamine.

28. The pharmaceutical composition of claim 25 wherein the acetylcholinesterase inhibitor is selected from donepezil and rivastigmine.

29. The pharmaceutical composition of claim 25 wherein the acetylcholinesterase inhibitor is donepezil.

30. A daily unit dosage pharmaceutical composition comprising no more than 1.0 mg of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof, an acetylcholinesterase inhibitor and a pharmaceutically acceptable carrier.

31. The daily unit dosage pharmaceutical composition of claim 30 comprising no more than 0.5 mg of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof.

32. The daily unit dosage pharmaceutical composition of claim 31 comprising no more than 0.3 mg of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof.

33. The daily unit dosage pharmaceutical composition of claim 31 comprising no more than 0.1 mg of (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof.

34. The daily unit dosage pharmaceutical composition of claim 31 comprising no more than 5 mg of donepezil.

35. The daily unit dosage pharmaceutical composition of claim 31 comprising no more than 4 mg of donepezil.

36. The daily unit dosage pharmaceutical composition of claim 31 comprising no more than 2.5 mg of donepezil.

37. The daily unit dosage pharmaceutical composition of claim 31 comprising no more than 1 mg of donepezil.

38. Packaged pharmaceuticals comprising a package containing a first unit dosage pharmaceutical composition comprising (R)-7-chloro-N-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide or a pharmaceutically acceptable salt thereof and a second unit dosage pharmaceutical composition comprising an acetylcholinesterase inhibitor.