TREATMENT OF PSYCHIATRIC DISORDERS

• US 20080033045A1
• Filed: 07/09/2007
• Published: 02/07/2008
• Est. Priority Date: 07/07/2006
• Status: Abandoned Application

• Current Assignee: Myriad Genetics, Inc.
• Original Assignee: Myriad Genetics, Inc.
• Inventors: Hendrix, Suzanne, Zavitz, Kenton, Laughlin, Mark
• Application Number:
  US11/774,692
• Publication Number:
  US 20080033045A1
• Time in Patent Office: Days
• US Class Current: 514/568
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system

Abstract

The invention relates to the treatment of psychiatric disorders.

Claims

1. A method of treating or delaying the onset of a psychiatric disorder in an individual, comprising administering to said individual a therapeutically effective amount of an Aβ

42 lowering agent, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein said Aβ

42 lowering agent is chosen from 2-methyl-2 (2-fluoro-4′

-trifluoromethylbiphen-4-yl)propionic acid;

2-methyl-2 (2-fluoro-4′

cyclohexylbiphen-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, and pharmaceutically acceptable salts thereof.

3. The method of claim 1, wherein said Aβ

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

-biphenyl-4-yl)-2-methylpropionic acid, and pharmaceutically acceptable salts thereof.

4. The method of claim 1, wherein said Aβ

42 lowering agent is (R)-2-(2-fluoro-4-biphenylyl)propionic acid or a pharmaceutically acceptable salt thereof.

5. The method of claim 4, wherein about 800 mg of (R)-2-(2-fluoro-4-biphenylyl)propionic acid, or a bioequivalent amount of a pharmaceutically acceptable salt thereof, is administered to said individual, twice daily.

6. The method of claim 1, wherein said psychiatric disorder, or symptom thereof, is chosen from abnormal behavior, abnormal dreams, aggression, agitation, anger, anxiety, apathy, confusional state, delusion, depression, hallucination, visual hallucination, insomnia, increased libido, mood alterations, mood swings, nightmare, paranoia, psychotic disorder, and sleep disorder.

7. A method of treating or delaying the onset of a psychiatric disorder in a patient having a neurodegenerative disorder comprising administering to said patient a therapeutically effective amount of an Aβ

42 lowering agent, or a pharmaceutically acceptable salt thereof.

8. The method of claim 7, wherein said Aβ

42 lowering agent is chosen from 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, and pharmaceutically acceptable salts thereof.

9. The method of claim 7, wherein said Aβ

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

-biphenyl-4-yl)-2-methylpropionic acid, and pharmaceutically acceptable salts thereof.

10. The method of claim 7, wherein said Aβ

42 lowering agent is (R)-2-(2-fluoro-4-biphenylyl)propionic acid or a pharmaceutically acceptable salt thereof.

11. The method of claim 10, wherein about 800 mg of (R)-2-(2-fluoro-4-biphenylyl)propionic acid, or a bioequivalent amount of a pharmaceutically acceptable salt thereof, is administered twice daily.

12. The method of claim 7, wherein said psychiatric disorder, or symptom thereof, is chosen from abnormal behavior, abnormal dreams, aggression, agitation, anger, anxiety, apathy, confusional state, delusion, depression, hallucination, visual hallucination, insomnia, increased libido, mood alterations, mood swings, nightmare, paranoia, psychotic disorder, and sleep disorder.

13. A method of treating or delaying the onset of a psychiatric disorder in a patient having Alzheimer'"'"'s disease comprising administering to said patient a therapeutically effective amount of an Aβ

42 lowering agent, or a pharmaceutically acceptable salt thereof.

14. The method of claim 13, wherein said Aβ

42 lowering agent is chosen from 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-propanoic 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, and pharmaceutically acceptable salts thereof.

15. The method of claim 13 wherein said Aβ

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

-biphenyl-4-yl)-2-methylpropionic acid, and pharmaceutically acceptable salts thereof.

16. The method of claim 15, wherein said Aβ

42 lowering agent is (R)-2-(2-fluoro-4-biphenylyl)propionic acid or a pharmaceutically acceptable salt thereof.

17. The method of claim 16, wherein about 800 mg of (R)-2-(2-fluoro-4-biphenylyl)propionic acid, or a bioequivalent amount of a pharmaceutically acceptable salt thereof, is administered twice daily.

18. The method of claim 13, wherein said psychiatric disorder, or symptom thereof, is chosen from abnormal behavior, abnormal dreams, aggression, agitation, anger, anxiety, apathy, confusional state, delusion, depression, hallucination, visual hallucination, insomnia, increased libido, mood alterations, mood swings, nightmare, paranoia, psychotic disorder, and sleep disorder.