Methods of treating overactive bladder and urinary incontinence

• US 20070015832A1
• Filed: 07/14/2006
• Published: 01/18/2007
• Est. Priority Date: 07/14/2005
• Status: Abandoned Application

• Current Assignee: Myriad Genetics, Inc.
• Original Assignee: Myriad Genetics, Inc.
• Inventors: Laughlin, Mark
• Application Number:
  US11/487,177
• Publication Number:
  US 20070015832A1
• Time in Patent Office: Days
• US Class Current: 514/568
• 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 31/35 having six-membered rings with one oxygen as the only ring hetero atom
• CPC Class Codes: A61K 31/381 having five-membered rings
• CPC Class Codes: A61K 31/41 having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole

Abstract

The invention relates to methods of treating or slowing the onset of overactive bladder or urinary incontinence, or a symptom thereof selected from urinary frequency, urinary urgency, nocturia, or enuresis comprising identifying and administering to a subject in need of treatment a therapeutically effective amount of a compound according to Formulae I-V, as defined herein.

Claims

1. A method of treating or slowing the onset of overactive bladder or urinary incontinence, or a symptom thereof selected from urinary frequency, urinary urgency, nocturia, or enuresis, comprising identifying and administering to a subject in need of treatment a therapeutically effective amount of an Aβ

₄₂ lowering agent.

2. The method of claim 1, wherein the Aβ

₄₂ lowering agent is a compound according to Formulae I-V;

3. The method of claim 1 wherein the 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.

4. The method of claim 1, wherein the Aβ

₄₂ lowering agent is (R)-2-(2-fluoro-4-biphenyl)propionic acid.

5. The method of claim 1, further comprising administering to the subject in need of treatment one or more additional therapeutic agents chosen from:

antimuscarinic agents;

a muscosal surface protectant;

an antihistamine;

an anticonvulsant;

a muscle relaxant;

a bladder antispasmodic;

a tricyclic antidepressant;

a nitric oxide donor;

a β

₃-adrenergic receptor agonist;

a bradykinin receptor antagonist;

a neurokinin receptor antagonist;

a sodium channel modulator, an activity dependent sodium channel modulator, and a Cav2.2 subunit calcium channel modulator.

6. The method of claim 5 wherein the Aβ

₄₂ lowering agent is (R)-2-(2-fluoro-4-biphenyl)propionic acid.

7. The method of claim 1 wherein overactive bladder is treated.

8. The method of claim 1 wherein urinary incontinence is treated.

9. The method of claim 7 wherein the Aβ

₄₂ lowering agent is (R)-2-(2-fluoro-4-biphenyl)propionic acid.

10. The method of claim 8 wherein the Aβ

₄₂ lowering agent is (R)-2-(2-fluoro-4-biphenyl)propionic acid.

11. A method of treating or slowing the onset of overactive bladder or urinary incontinence, or a symptom thereof selected from urinary frequency, urinary urgency, nocturia, or enuresis, comprising identifying and administering to a subject with Alzheimer'"'"'s disease who is in need of such treatment a therapeutically effective amount of an Aβ

₄₂ lowering agent.

12. The method of claim 11, wherein the Aβ

₄₂ lowering agent is a compound according to Formulae I-V;

13. The method of claim 11 wherein the 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.

14. The method of claim 11, wherein the Aβ

₄₂ lowering agent is (R)-2-(2-fluoro-4-biphenyl)propionic acid.

15. The method of claim 11, further comprising administering to the subject in need of treatment one or more additional therapeutic agents chosen from:

antimuscarinic agents;

a muscosal surface protectant;

an antihistamine;

an anticonvulsant;

a muscle relaxant;

a bladder antispasmodic;

a tricyclic antidepressant;

a nitric oxide donor;

a β

₃-adrenergic receptor agonist;

a bradykinin receptor antagonist;

a neurokinin receptor antagonist;

a sodium channel modulator, an activity dependent sodium channel modulator, and a Cav2.2 subunit calcium channel modulator.

16. The method of claim 15 wherein the Aβ

₄₂ lowering agent is (R)-2-(2-fluoro-4-biphenyl)propionic acid.

17. The method of claim 11 wherein overactive bladder is treated.

18. The method of claim 11 wherein urinary incontinence is treated.

19. The method of claim 17 wherein the Aβ

₄₂ lowering agent is (R)-2-(2-fluoro-4-biphenyl)propionic acid.

20. The method of claim 18 wherein the Aβ

₄₂ lowering agent is (R)-2-(2-fluoro-4-biphenyl)propionic acid.

21. The method of claim 11, wherein the subject has mild to moderate Alzheimer'"'"'s disease or mild cognitive impairment.

22. The method of claim 21, wherein the Aβ

₄₂ lowering agent is (R)-2-(2-fluoro-4-biphenyl)propionic acid.

23. The method of claim 22, further comprising administering to the subject in need of treatment one or more additional therapeutic agents chosen from:

antimuscarinic agents;

a muscosal surface protectant;

an antihistamine;

an anticonvulsant;

a muscle relaxant;

a bladder antispasmodic;

a tricyclic antidepressant;

a nitric oxide donor;

a β

₃-adrenergic receptor agonist;

a bradykinin receptor antagonist;

a neurokinin receptor antagonist;

a sodium channel modulator, an activity dependent sodium channel modulator, and a Cav2.2 subunit calcium channel modulator.

24. The method of claim 22, wherein overactive bladder is treated.

25. The method of claim 22 wherein urinary incontinence is treated.