Pharmaceutical Composition And Method For Treating Neurodegenerative Disorders

• US 20070232589A1
• Filed: 02/12/2007
• Published: 10/04/2007
• Est. Priority Date: 08/11/2004
• Status: Abandoned Application

• Current Assignee: Myriad Genetics
• Original Assignee: Myriad Genetics
• Inventors: Hobden, Adrian
• Application Number:
  US11/674,032
• Publication Number:
  US 20070232589A1
• 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 31/192 having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid cannabinoids A61K31/658
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca

Abstract

The invention provides compositions and methods for treating neurodegenerative disorders. The method of the invention involves administering to an individual in need of treatment a composition an acetylcholine esterase inhibitor in combination with another therapeutic agent. The methods and compositions of the invention are useful for treating and preventing neurodegenerative disorders like Alzheimer'"'"'s disease, dementia, and mild cognitive impairment.

Claims

1. A unit dosage form comprising a combination of (R)-2-(2-fluoro-4-biphenylyl)propionic acid or a pharmaceutically acceptable salt or ester thereof and an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt or ester thereof.

2. The unit dosage form of claim 1 wherein said acetylcholine esterase inhibitor is galantamine.

3. The unit dosage form of claim 1 wherein (R)-2-(2-fluoro-4-biphenylyl)propionic acid or a pharmaceutically acceptable salt or ester thereof is present in an amount from 100 mg to 1000 mg.

4. The unit dosage form of claim 2 wherein galantamine or a pharmaceutically acceptable salt or ester thereof is present in an amount from 1 to 40 mg.

5. The unit dosage form of claim 1 wherein (R)-2-(2-fluoro-4-biphenylyl)propionic acid or a pharmaceutically acceptable salt or ester thereof is present in an amount from 200 mg to 800 mg.

6. The unit dosage form of claim 2 wherein galantamine or a pharmaceutically acceptable salt or ester thereof is present in an amount from 2 mg to 30 mg.

7. The unit dosage form of claim 1 wherein (R)-2-(2-fluoro-4-biphenylyl)propionic acid or a pharmaceutically acceptable salt or ester thereof is present in an amount from 300 mg to 500 mg.

8. The unit dosage form of claim 2 wherein galantamine or a pharmaceutically acceptable salt or ester thereof is present in an amount from 2 mg to 20 mg.

9. The unit dosage form according to claims 1, wherein said unit dosage form is chosen from a tablet, a capsule, and a caplet.

10. The unit dosage form of claim 1, further comprising microcrystalline cellulose.

11. A method of treating mild Alzheimer'"'"'s disease in an individual comprising identifying an individual having mild Alzheimer'"'"'s disease and administering to the individual an Alzheimer'"'"'s disease treating effective amount of (R)-2-(2-fluoro-4-biphenylyl)propionic acid or a pharmaceutically acceptable salt or ester thereof and an acetylcholine esterase inhibitor or a pharmaceutically acceptable salt or ester thereof.

12. The method of claim 11 wherein the acetylcholine esterase inhibitor is a galantamine.

14. The method of claim 12 wherein galantamine and (R)-2-(2-fluoro-4-biphenylyl)propionic acid are co-administered.

15. The method of claim 12 wherein said individual is titrated to a stable dose of galantamine prior to treatment with (R)-2-(2-fluoro-4-biphenylyl)propionic acid.

16. The method of claim 12 wherein 1 mg to 40 mg of galantamine, or a pharmaceutically acceptable salt or ester, thereof is administered per day.

17. The method of claim 12 wherein 32 mg of galantamine, or a pharmaceutically acceptable salt or ester thereof, is administered per day.

18. The method of claim 12 wherein 24 mg of galantamine, or a pharmaceutically acceptable salt or ester thereof, is administered per day.

19. The method of claim 12 wherein 400 or more mg of (R)-2-(2-fluoro-4-biphenylyl)propionic acid, or a pharmaceutically acceptable salt or ester thereof, is administered per day.

20. The method of claim 12 wherein 600 or more mg of (R)-2-(2-fluoro-4-biphenylyl)propionic acid, or a pharmaceutically acceptable salt or ester thereof, is administered per day.

21. The method of claim 12 wherein 800 or more mg of (R)-2-(2-fluoro-4-biphenylyl)propionic acid, or a pharmaceutically acceptable salt or ester thereof, is administered per day.

22. The method of claim 12 wherein 1600 or more mg of (R)-2-(2-fluoro-4-biphenylyl)propionic acid, or a pharmaceutically acceptable salt or ester thereof, is administered per day.

13. The method of 12 wherein galantamine and (R)-2-(2-fluoro-4-biphenylyl)propionic acid are co-formulated.

23. A co-formulation comprising a first compound which is galantamine or a pharmaceutically acceptable salt or ester thereof and a second compound which is an Aβ

42 lowering agent or a pharmaceutically acceptable salt or ester thereof.

24. The co-formulation of claim 23 wherein said Aβ

42 lowering agent is chosen from 5[1-(2-Fluoro-biphenyl-4-yl)-1-methyl-ethyl]-2H-tetrazole, 2-(4-isobutyl-phenyl)-2-methyl propionic acid, 2-(2-fluoro-1,1′

-biphenyl-4-yl)-2-methylpropionic acid, 2-methyl-2 (2-fluoro-4′

-trifluoromethylbiphen-4-yl)propionic acid, 2-methyl-2 (2-fluoro-4′

cyclohexyl biphen-4-yl)propionic acid, 1-(2-fluoro-4′

-trifluoromethylbiphenyl-4-yl)cyclopropanecarboxylic acid, 1-(4′

-cyclohexyl-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid, 1-(4′

-benzyloxy-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid, 1-(2-fluoro-4′

-isopropyloxybiphenyl-4-yl)cyclopropanecarboxylic acid, 1-(2-fluoro-3′

-trifluoromethoxybiphenyl-4-yl)cyclopropanecarboxylic acid, 1-(2-fluoro-4′

-trifluoromethoxybiphenyl-4-yl)cyclopropanecarboxylic acid, 1-(2-fluoro-3′

-trifluoromethylbiphenyl-4-yl)cyclopropanecarboxylic acid, 1-(4′

-cyclopentyl-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid, 1-(4′

-cycloheptyl-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid, 1-(2′

-cyclohexyl-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid, 1-(2-fluoro-4′

-hydroxybiphenyl-4-yl)cyclopropanecarboxylic acid, 1-[2-fluoro-4′

-(tetrahydropyran-4-yloxy)biphenyl-4-yl]-cyclopropane-carboxylic acid, 1-(2,3′

,4′

-trifluorobiphenyl-4-yl)cyclopropanecarboxylic acid, 1-(3′

,4′

-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid, 1-(3′

,5′

-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarboxylic acid 1-(3′

-chloro-2,4′

-difluorobiphenyl-4-yl)cyclopropanecarboxylic acid, 1-(4-benzo[b]thiophen-3-yl-3-fluorophenyl)cyclopropanecarboxylic acid, 1-(2-fluoro-4′

-prop-2-inyloxy-biphenyl-4-yl)-cyclopropanecarboxylic acid, 1-(4′

-cyclohexyloxy-2-fluoro-biphenyl-4-yl)-cyclopropanecarboxylic acid, 1-[2-fluoro-4′

-(tetrahydropyran-4-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid, 1-[2-fluoro-4′

-(4-oxo-cyclohexyl)-biphenyl-4-yl]-cyclopropanecarboxylic acid, 2-(2″

-fluoro-4-hydroxy-[1,1′

;

4′

,1″

]tert-phenyl-4″

-yl)-cyclopropanecarboxylic acid, 1-[4′

-(4,4-dimethylcyclohexyl)-2-fluoro[1,1′

-biphenyl]-4-yl]-cyclopropane-carboxylic acid, 1-[2-fluoro-4′

-[[4-(trifluoromethyl)benzoyl]amino][1,1′

-biphenyl]-4-yl]-cyclopropanecarboxylic acid, 1-[2-fluoro-4′

-[[4-(trifluoromethyl)cyclohexyl]oxy][1,1′

-biphenyl]-4-yl]-cyclopropanecarboxylic acid, 1-[2-fluoro-4′

-[(3,3,5,5-tetramethylcyclohexyl)oxy][1,1′

-biphenyl]-4-yl]-cyclopropanecarboxylic acid, 1-[4′

-[(4,4-dimethylcyclohexyl)oxy]-2-fluoro[1,1′

-biphenyl]-4-yl]-cyclopropanecarboxylic acid, 1-(2,3′

,4″

-trifluoro[1,1′

;

4′

,1″

-tert-phenyl]-4-yl)-cyclopropanecarboxylic acid, 1-(2,2′

,4″

-trifluoro[1,1′

;

4′

,1″

-tert-phenyl]-4-yl)-cyclopropanecarboxylic acid, 1-(2,3′

-difluoro-4″

-hydroxy[1,1′

;

4′

,1″

-tert-phenyl]-4-yl)-cyclopropane-carboxylic acid, 1-(2,2′

-difluoro-4″

-hydroxy[1,1′

;

4′

,1″

-tert-phenyl]-4-yl)-cyclopropane-carboxylic acid, 2-(2-fluoro-3′

,5′

-bis(chloro)biphen-4-yl)propionic acid amide, 2-(2-fluoro-4′

-trifluoromethylbiphen-4-yl)propionic acid, 2-(2-fluoro-3′

-trifluoromethylbiphen-4-yl)propionic acid, 2-(2-fluoro-3′

,5′

-bis(trifluoromethyl)biphen-4-yl)propionic acid, 2-(4′

-cyclohexyl-2-fluorobiphen-4-yl)propionic acid, 2-(2-Fluoro-1,1′

-biphenyl-4-yl)-2-methylpropanoic acid, 2-Methyl-2-(3-phenoxy-phenyl)-propionic acid, 2-(4-Isobutyl-phenyl)-2-methyl-propionic acid;

2-(6-Chloro-9H-carbazol-2-yl)-2-methyl-propionic acid, 2-[1-(4-Chloro-benzoyl)-5-methoxy-2-methyl-1H-indol-3-yl]-2-methyl-propionic acid, and 5-[1-(2-Fluoro-biphenyl-4-yl)-1-methyl-ethyl]-2H-tetrazole, or a pharmaceutically acceptable salt or ester thereof.

25. The co-formulation of claim 23 wherein galantamine or a pharmaceutically acceptable salt or ester thereof is present in an amount from 1 mg to 40 mg.