CINNAMIDE COMPOUNDS FOR DEMENTIA

• US 20100130537A1
• Filed: 04/25/2008
• Published: 05/27/2010
• Est. Priority Date: 04/26/2007
• Status: Abandoned Application

• Current Assignee: Eisai R & D Management Company Limited (Eisai Medical Research Incorporated)
• Original Assignee: Eisai R & D Management Company Limited (Eisai Medical Research Incorporated)
• Inventors: Miyagawa, Takehiko
• Application Number:
  US12/594,172
• Publication Number:
  US 20100130537A1
• Time in Patent Office: Days
• US Class Current: 514/295
• 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 31/13 Amines A61K31/04 takes precedence
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• 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 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The invention provides methods for treating, preventing, and delaying the onset of dementia and mild cognitive impairments by administering to a patient in need thereof at least one cinnamide compound and one or more second-line active ingredients, such as cholinesterase inhibitors; AMPA receptor antagonists; NMDA receptor antagonists; and the like. The invention also provides pharmaceutical compositions, combinations, and kits.

Claims

1. A pharmaceutical composition comprising:

(A) a compound of Formula (I) or a pharmaceutically acceptable salt thereof;

wherein R¹ is;

(1) —

X₁—

Ar₁, wherein X₁ is a C_1-6 alkylene group optionally substituted with a C_1-6 alkyl group; and

Ar₁ is a phenyl group optionally substituted with 1 to 3 substituents selected from the group consisting of (i) a halogen atom and (ii) a C_1-6 alkyl group which may optionally be substituted with one to five C_1-6 alkyl groups;

(2) an indenyl group optionally substituted with 1 to 3 halogen atoms;

(3) a tetrahydronaphthyl group optionally substituted with 1 to 3 halogen atoms;

or

(4) a chromanyl group optionally substituted with 1 to 3 halogen atoms;

(B) a cholinesterase inhibitor;

an AMPA receptor antagonist;

an NMDA receptor antagonist;

or a mixture or combination of two or more thereof; and

(C) one or more pharmaceutically acceptable carriers.

2. The pharmaceutical composition of claim 1, wherein R¹ is —

X₁—

Ar₁;

wherein X₁ is a C_1-6 alkylene group optionally substituted with a C_1-6 alkyl group; and

Ar₁ is a phenyl group optionally substituted with 1 to 3 substituents selected from the group consisting of (i) a halogen atom and (ii) a C_1-6 alkyl group which may optionally be substituted with one to five C_1-6 alkyl groups;

3. The pharmaceutical composition of claim 1, wherein R¹ is an indenyl group optionally substituted with 1 to 3 halogen atoms;

a tetrahydronaphthyl group optionally substituted with 1 to 3 halogen atoms;

or a chromanyl group optionally substituted with 1 to 3 halogen atoms.

4. The pharmaceutical composition of claim 1, wherein (A) is at least one compound selected from:

(E)-1-(3,4-difluorobenzyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereat

(E)-1-indan-2-yl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-[(4R)-chroman-4-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereat (E)-1-[(4S)-chroman-4-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-[(1S)-1-(4-fluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereat

(E)-1-(4-tert-butylbenzyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-[(2S)-5-fluoroindan-2-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-[(2R)-5-fluoroindan-2-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-[(4R)-7-fluorochroman-4-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

or (E)-1-[(48)-7-fluorochroman-4-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-[(2R)-1,2,3,4-tetrahydronaphthalen-2-yl]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]piperidin-2-one or a pharmaceutically acceptable salt thereof; and

(E)-1-[(1R)-1-(2,4-difluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

or (E)-1-[(1S)-1-(2,4-difluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition of claim 1, wherein (B) is one or more compounds selected from the group consisting of donepezil or a pharmaceutically acceptable salt thereof, huperzine A or a pharmaceutically acceptable salt thereof, tacrine or a pharmaceutically acceptable salt thereof, rivastigmine or a pharmaceutically acceptable salt thereof, galantamine or a pharmaceutically acceptable salt thereof, pramiracetam or a pharmaceutically acceptable salt thereof, aniracetam or a pharmaceutically acceptable salt thereof, nefiracetam or a pharmaceutically acceptable salt thereof;

EGb 761 or a pharmaceutically acceptable salt thereof;

rosiglitazone or a pharmaceutically acceptable salt thereof, rasagiline or a pharmaceutically acceptable salt thereof;

levacecarnine or a pharmaceutically acceptable salt thereof, celecoxib or a pharmaceutically acceptable salt thereof, 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one, a pharmaceutically acceptable salt thereof or a hydrate thereof;

talampanel or a pharmaceutically acceptable salt thereof;

becampanel or a pharmaceutically acceptable salt thereof;

memantine or a pharmaceutically acceptable salt thereof, neramexane or a pharmaceutically acceptable salt thereof;

xaliproden or a pharmaceutically acceptable salt thereof;

tarenflurbil or a pharmaceutically acceptable salt thereof;

tramiprosate or a pharmaceutically acceptable salt thereof; and

leuprorelin-D or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition of claim 1, wherein (B) is one or more compounds selected from the group consisting of donepezil or a pharmaceutically acceptable salt thereof;

3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one, a pharmaceutically acceptable salt thereof or a hydrate thereof and memantine or a pharmaceutically acceptable salt thereof.

7. The pharmaceutical composition of claim 1, wherein (B) is donepezil or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition of claim 1, wherein the composition is used for:

treating dementia or one or more mild cognitive impairments;

the prophylaxis of dementia or one or more mild cognitive impairments;

or delaying the onset of dementia or one or more mild cognitive impairments.

27. A kit comprising the pharmaceutical composition of claim 1.

28. A method for treating dementia or one or more mild cognitive impairments;

for the prophylaxis of dementia or one or more mild cognitive impairments;

or

delaying the onset of dementia or one or more mild cognitive impairments comprising administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 1.

9. A combination comprising:

(A) a compound of Formula (I) or a pharmaceutically acceptable salt thereof;

wherein R¹ is;

(1) —

X₁—

Ar₁, wherein X_t is a C_1-6 alkylene group optionally substituted with a C_1-6 alkyl group; and

Ar₁ is a phenyl group optionally substituted with 1 to 3 substituents selected from the group consisting of (i) a halogen atom and (ii) a C_1-6 alkyl group which may optionally be substituted with one to five C_1-6 alkyl groups;

(2) an indenyl group optionally substituted with 1 to 3 halogen atoms;

(3) a tetrahydronaphthyl group optionally substituted with 1 to 3 halogen atoms;

or

(4) a chromanyl group optionally substituted with 1 to 3 halogen atoms; and

(B) a cholinesterase inhibitor;

an AMPA receptor antagonist;

an NMDA receptor antagonist;

or a mixture or combination of two or more thereof.

10. The combination of claim 9, wherein R¹ is —

X₁—

Ar₁;

wherein X₁ is a C_1-6 alkylene group optionally substituted with a C_1-6 alkyl group; and

Ar₁ is a phenyl group optionally substituted with 1 to 3 substituents selected from the group consisting of (i) a halogen atom and (ii) a C_1-6 alkyl group which may optionally be substituted with one to five C_1-6 alkyl groups;

11. The combination of claim 9, wherein R¹ is an indenyl group optionally substituted with 1 to 3 halogen atoms;

a tetrahydronaphthyl group optionally substituted with 1 to 3 halogen atoms;

or a chromanyl group optionally substituted with 1 to 3 halogen atoms.

12. The combination of claim 9, wherein (A) is at least one compound selected from:

(E)-1-(3,4-difluorobenzyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-indan-2-yl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-[(4R)-chroman-4-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-[(4S)-chroman-4-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-[(1S)-1-(4-fluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-(4-tert-butylbenzyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-[(2S)-5-fluoroindan-2-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-[(2R)-5-fluoroindan-2-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-[(4R)-7-fluorochroman-4-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

or (E)-1-[(4S)-7-fluorochroman-4-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-[(2R)-1,2,3,4-tetrahydronaphthalen-2-yl]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]piperidin-2-one or a pharmaceutically acceptable salt thereof; and

(E)-1-[(1R)-1-(2,4-difluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

or (E)-1-[(1S)-1-(2,4-difluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof

13. The combination of claim 9, wherein (B) is one or more compounds selected from the group consisting of donepezil or a pharmaceutically acceptable salt thereof, huperzine A or a pharmaceutically acceptable salt thereof, tacrine or a pharmaceutically acceptable salt thereof, rivastigmine or a pharmaceutically acceptable salt thereof, galantamine or a pharmaceutically acceptable salt thereof, pramiracetam or a pharmaceutically acceptable salt thereof, aniracetam or a pharmaceutically acceptable salt thereof, nefiracetam or a pharmaceutically acceptable salt thereof, EGb 761 or a pharmaceutically acceptable salt thereof, rosiglitazone or a pharmaceutically acceptable salt thereof, rasagiline or a pharmaceutically acceptable salt thereof, levacecarnine or a pharmaceutically acceptable salt thereof, celecoxib or a pharmaceutically acceptable salt thereof, 3-(2-cyanophenyl)-5(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one, a pharmaceutically acceptable salt thereof or a hydrate thereof, talampanel or a pharmaceutically acceptable salt thereof, becampanel or a pharmaceutically acceptable salt thereof;

memantine or a pharmaceutically acceptable salt thereof, neramexane or a pharmaceutically acceptable salt thereof, xaliproden or a pharmaceutically acceptable salt thereof, tarenflurbil or a pharmaceutically acceptable salt thereof, tramiprosate or a pharmaceutically acceptable salt thereof, and leuprorelin-D or a pharmaceutically acceptable salt thereof.

14. The combination of claim 9, wherein (B) is one or more compounds selected from the group consisting of donepezil or a pharmaceutically acceptable salt thereof, 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one, a pharmaceutically acceptable salt thereof or a hydrate thereof and memantine or a pharmaceutically acceptable salt thereof.

15. The combination of claim 9, wherein (B) is donepezil or a pharmaceutically acceptable salt thereof.

16. The combination of claim 9, wherein (A) and (B) are administered separately to a patient or are administered to a patient in the form of a pharmaceutical composition.

17. The combination of claim 9, wherein the combination is used for treating dementia or one or more mild cognitive impairments;

for the prophylaxis of dementia or one or more mild cognitive impairments;

or delaying the onset of dementia or one or more mild cognitive impairments.

29. A kit comprising the combination of claim 9.

30. A method for treating dementia or one or more mild cognitive impairments;

for the prophylaxis of dementia or one or more mild cognitive impairments;

or delaying the onset of dementia or one or more mild cognitive impairments comprising administering to a patient in need thereof a therapeutically effective amount of the combination of claim 9.

18. A method for producing a pharmaceutical composition comprising compounds (A) and (B) in the treatment of dementia or one or more mild cognitive impairments;

for the prophylaxis of dementia or one or more mild cognitive impairments;

or delaying the onset of dementia or one or more mild cognitive impairments, wherein (A) and (B) are;

(A) a compound of Formula (I) or a pharmaceutically acceptable salt thereof;

wherein R¹ is;

(1) —

X₁—

Ar₁, wherein X₁ is a C_1-6 alkylene group optionally substituted with a C_1-6 alkyl group; and

Ar₁ is a phenyl group optionally substituted with 1 to 3 substituents selected from the group consisting of (i) a halogen atom and (ii) a C_1-6 alkyl group which may optionally be substituted with one to five C_1-6 alkyl groups;

(2) an indenyl group optionally substituted with 1 to 3 halogen atoms;

(3) a tetrahydronaphthyl group optionally substituted with 1 to 3 halogen atoms;

or

(4) a chromanyl group optionally substituted with 1 to 3 halogen atoms; and

(B) a cholinesterase inhibitor;

an AMPA receptor antagonist;

an NMDA receptor antagonist;

or a mixture or combination of two or more thereof.

19. The method of claim 18, wherein R¹ is —

X₁—

Ar₁;

wherein X₁ is a C_1-6 alkylene group optionally substituted with a C_1-6 alkyl group; and

Ar₁ is a phenyl group optionally substituted with 1 to 3 substituents selected from the group consisting of (i) a halogen atom and (ii) a C_1-6 alkyl group which may optionally be substituted with one to five C_1-6 alkyl groups;

20. The method of claim 18, wherein R¹ is an indenyl group optionally substituted with 1 to 3 halogen atoms;

a tetrahydronaphthyl group optionally substituted with 1 to 3 halogen atoms;

or a chromanyl group optionally substituted with 1 to 3 halogen atoms.

21. The method of claim 18, wherein (A) is at least one compound selected from:

(E)-1-(3,4-difluorobenzyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-indan-2-yl-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-[(4R)-chroman-4-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-[(4S)-chroman-4-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-[(1S)-1-(4-fluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-(4-tert-butylbenzyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-[(2S)-5-fluoroindan-2-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-[(2R)-5-fluoroindan-2-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-1-[(4R)-7-fluoro chroman-4-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

or (E)-1-[(4S)-7-fluorochroman-4-yl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-[(2R)-1,2,3,4-tetrahydronaphthalen-2-yl]piperidin-2-one or a pharmaceutically acceptable salt thereof;

(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-1-[(2S)-1,2,3,4-tetrahydronaphthalen-2-yl]piperidin-2-one or a pharmaceutically acceptable salt thereof; and

(E)-1-[(1R)-1-(2,4-difluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof;

or (E)-1-[(1S)-1-(2,4-difluorophenyl)ethyl]-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]piperidin-2-one or a pharmaceutically acceptable salt thereof.

22. The method of claim 18, wherein (B) is one or more compounds selected from the group consisting of donepezil or a pharmaceutically acceptable salt thereof, huperzine A or a pharmaceutically acceptable salt thereof, tacrine or a pharmaceutically acceptable salt thereof, rivastigmine or a pharmaceutically acceptable salt thereof;

galantamine or a pharmaceutically acceptable salt thereof;

pramiracetam or a pharmaceutically acceptable salt thereof, aniracetam or a pharmaceutically acceptable salt thereof;

nefiracetam or a pharmaceutically acceptable salt thereof;

EGb 761 or a pharmaceutically acceptable salt thereof;

rosiglitazone or a pharmaceutically acceptable salt thereof, rasagiline or a pharmaceutically acceptable salt thereof;

levacecarnine or a pharmaceutically acceptable salt thereof;

celecoxib or a pharmaceutically acceptable salt thereof, 3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one, a pharmaceutically acceptable salt thereof or a hydrate thereof, talampanel or a pharmaceutically acceptable salt thereof, becampanel or a pharmaceutically acceptable salt thereof;

memantine or a pharmaceutically acceptable salt thereof, neramexane or a pharmaceutically acceptable salt thereof, xaliproden or a pharmaceutically acceptable salt thereof, tarenflurbil or a pharmaceutically acceptable salt thereof;

tramiprosate or a pharmaceutically acceptable salt thereof, and leuprorelin-D or a pharmaceutically acceptable salt thereof.

23. The method of claim 18, wherein (B) is one or more compounds selected from the group consisting of donepezil or a pharmaceutically acceptable salt thereof;

3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one, a pharmaceutically acceptable salt thereof or a hydrate thereof and memantine or a pharmaceutically acceptable salt thereof.

24. The method of claim 18, wherein (B) is donepezil or a pharmaceutically acceptable salt thereof.

25. The method of claim 18, wherein (A) and (B) are to be administered separately to a patient or are administered to a patient in the form of a pharmaceutical composition.

26. A method for the treatment of dementia or one or more mild cognitive impairments;

for the prophylaxis of dementia or one or more mild cognitive impairments;

or delaying the onset of dementia or one or more mild cognitive impairments, by administering compounds (A) and (B), wherein (A) and (B) are;

(A) a compound of Formula (I) or a pharmaceutically acceptable salt thereof;

wherein R¹ is;

(1) —

X₁—

Ar₁, wherein X₁ is a C_1-6 alkylene group optionally substituted with a C_1-6 alkyl group; and

Ar₁ is a phenyl group optionally substituted with 1 to 3 substituents selected from the group consisting of (i) a halogen atom and (ii) a C_1-6 alkyl group which may optionally be substituted with one to five C_1-6 alkyl groups;

(2) an indenyl group optionally substituted with 1 to 3 halogen atoms;

(3) a tetrahydronaphthyl group optionally substituted with 1 to 3 halogen atoms;

or

(4) a chromanyl group optionally substituted with 1 to 3 halogen atoms; and

(B) a cholinesterase inhibitor;

an AMPA receptor antagonist;

an NMDA receptor antagonist;

or a mixture or combination of two or more thereof.