Method of treating lower urinary tract disorders

• US 6,846,823 B2
• Filed: 04/02/2004
• Issued: 01/25/2005
• Est. Priority Date: 04/04/2003
• Status: Expired due to Fees

• Current Assignee: Edusa Pharmaceuticals, Inc.
• Original Assignee: Dynogen Pharmaceuticals, Inc. (Edusa Pharmaceuticals, Inc.)
• Inventors: Landau, Steven B., Fraser, Matthew O., Miller, Cheryl L.
• Primary Examiner(s): Killos, Paul J.
• Application Number:
  US10/817,332
• Publication Number:
  US 20040209869A1
• Time in Patent Office: 298 Days
• Field of Search: 514/249
• US Class Current: 514/249
• 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 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/08 of the prostate
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The invention relates to a method of treating at least one symptom of a lower urinary tract disorder in a subject in need of treatment wherein the symptom is selected from the group consisting of urinary frequency, urinary urgency, urinary urge incontinence, nocturia and enuresis. The method comprises administering to a subject in need of treatment a therapeutically effective amount of a compound that has 5-HT₃ receptor antagonist activity and NorAdrenaline Reuptake Inhibitor (NARI) activity. The invention further relates to a method of treating at least one symptom of a lower urinary tract disorder in a subject in need of treatment wherein the symptom is selected from the group consisting of urinary frequency, urinary urgency, urinary urge incontinence, nocturia and enuresis, comprising coadministering to said subject a first amount of a 5-HT₃ antagonist and a second amount of a NARI, wherein the first and second amounts together comprise a therapeutically effective amount or are each present in a therapeutically effective amount.

Claims

1. A method of treating at least one symptom of a lower urinary tract disorder in a subject in need of treatment, wherein the symptom is selected from the group consisting of urinary frequency, urinary urgency, nocturia and enuresis, comprising administering to said subject a therapeutically effective amount of a compound of Formula I:

wherein, R₁ and R₂ independently represent hydrogen, halogen or a C₁-C₆ alkyl group;

or R₁ and R₂ together with the carbon atom to which they are attached form a cycloalkylene group having 5 to 6 carbon atoms;

R₃ and R₄ independently represent hydrogen or a C₁-C₆ alkyl group;

R₅ is hydrogen, C₁-C₆ alkyl,

or —

C(O)—

NH—

R₆

wherein m is an integer from about 1 to about 3, X is halogen and R₆ is a C₁-C₆ alkyl group; and

Ar is a substituted or unsubstituted phenyl, 2-thienyl or 3-thienyl group; and

n is 2 or 3;

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the lower urinary tract disorder is selected from the group consisting of overactive bladder, interstitial cystitis, prostatitis, prostadynia and benign prostatic hyperplasia.

3. The method of claim 2, wherein the lower urinary tract disorder is overactive bladder.

4. The method of claim 2, wherein the lower urinary tract disorder is interstitial cystitis.

5. The method of claim 1, wherein the subject is a human.

6. The method of claim 1, wherein for the compound of Formula I, R₁ is a C₁-C₆ alkyl group and Ar is a substituted phenyl.

7. The method of claim 6, wherein the substituted phenyl group is substituted with a halogen.

8. The method of claim 1, wherein for the compound of Formula I, n is 2, R₁ is a C₁-C₆ alkyl group and Ar is a substituted phenyl.

9. The method of claim 8, wherein the substituted phenyl group is substituted with a halogen and R₁ is a methyl group.

10. The method of claim 1, wherein for the compound of Formula I, R₁ is a C₁-C₆ alkyl group or a halogen and Ar is an unsubstituted phenyl.

11. The method of claim 10, wherein R₂ is hydrogen or a C₁-C₆ alkyl group.

12. The method of claim 1, wherein for the compound of Formula I, n is 2, R₁ is a C₁-C₆ alkyl group and Ar is an unsubstituted phenyl.

13. The method of claim 12, wherein R₂ is hydrogen or a C₁-C₆ alkyl group.

14. The method of claim 1, wherein the compound of Formula I is administered on an as-needed basis.

15. The method of claim 14, wherein the compound of Formula I is administered prior to commencement of an activity wherein suppression of at least one symptom of overactive bladder is desired.

16. The method of claim 14, wherein the compound of Formula I is administered from about 0 minutes to about 10 hours prior to commencement of an activity wherein suppression of at least one symptom of overactive bladder is desired.

17. The method of claim 16, wherein the compound of Formula I is administered from about 0 minutes to about 3 hours prior to commencement of an activity wherein suppression of at least one symptom of overactive bladder is desired.

18. The method of claim 1, wherein the compound of Formula I is administered in a controlled release formulation.

19. The method of claim 18, wherein the compound of Formula I is administered in a delayed release formulation.

20. The method of claim 18, wherein the compound of Formula I is administered in a pulsatile release formulation.

21. The method of claim 18, wherein the compound of Formula I is administered in a sustained release formulation.

22. The method of claim 1, wherein the compound of Formula I is administered orally.

23. The method of claim 22, wherein the compound of Formula I is administered in a dosage form selected from the group consisting of:

a tablet, a capsule, a caplet, a pill, a gel cap, a troche, a lozenge, a magma, a dispersion, a solution, a suspension, a syrup, a granule, a bead, a powder and a pellet.

24. The method of claim 23, wherein the dosage form is a tablet.

25. The method of claim 23, wherein the dosage form is a capsule.

26. The method of claim 1, wherein the compound of Formula I is administered transmucosally.

27. The method of claim 26, wherein the compound of Formula I is administered sublingually.

28. The method of claim 26, wherein the compound of Formula I is administered bucally.

29. The method of claim 26, wherein the compound of Formula I is administered transurethrally.

30. The method of claim 26, wherein the compound of Formula I is administered rectally.

31. The method of claim 1, wherein the compound of Formula I is administered by inhalation.

32. The method of claim 1, wherein the compound of Formula I is administered intravesically.

33. The method of claim 1, wherein the compound of Formula I is administered topically.

34. The method of claim 1, wherein the compound of Formula I is administered transdermally.

35. The method of claim 1, wherein the compound of Formula I is administered parenterally.

36. A method of treating at least one symptom of a lower urinary tract disorder in a subject in need of treatment, wherein the symptom is selected from the group consisting of urinary frequency, urinary urgency, nocturia and enuresis, comprising administering to said subject a therapeutically effective amount of a compound represented by Formula II:

or a pharmaceutically acceptable salt thereof.

37. The method of claim 36, wherein the lower urinary tract disorder is selected from the group consisting of overactive bladder, interstitial cystitis, prostatitis, prostadynia and benign prostatic hyperplasia.

38. The method of claim 37, wherein the lower urinary tract disorder is overactive bladder.

39. The method of claim 37, wherein the lower urinary tract disorder is interstitial cystitis.

40. The method of claim 36, wherein the subject is a human.

41. A method of treating at least one symptom of overactive bladder in a subject in need of treatment, wherein the symptom is selected from the group consisting of urinary frequency, urinary urgency, nocturia and enuresis, comprising administering to said subject a therapeutically effective amount of a compound represented by Formula II:

or a pharmaceutically acceptable salt thereof.

42. The method of claim 41, wherein the subject is a human.

43. A method of treating at least one symptom of interstitial cystitis in a subject in need of treatment, wherein the symptom is selected from the group consisting of urinary frequency, urinary urgency, nocturia and enuresis, comprising administering to said subject a therapeutically effective amount of a compound represented by Formula II:

or a pharmaceutically acceptable salt thereof.

44. The method of claim 43, wherein the subject is a human.

45. A method of treating at least one symptom of a lower urinary tract disorder in a subject in need of treatment, wherein the symptom is selected from the group consisting of urinary frequency, urinary urgency, nocturia and enuresis, comprising administering to said subject:

a) a first amount of a 5-HT₃ receptor antagonist; and

b) a second amount of a noradrenaline reuptake inhibitor

wherein the first and second amounts together comprise a therapeutically effective amount.

46. The method of claim 45, wherein the lower urinary tract disorder is selected from the group consisting of overactive bladder, interstitial cystitis, prostatitis, prostadynia and benign prostatic hyperplasia.

47. The method of claim 46, wherein the lower urinary tract disorder is overactive bladder.

48. The method of claim 46, wherein the lower urinary tract disorder is interstitial cystitis.

49. The method of claim 45, wherein the subject is a human.

50. The method of claim 45, wherein the 5-HT₃ receptor antagonist is selected from the group consisting of indisetron, YM-114 ((R)-2,3-dihydro-1-[(4,5,6,7-tetrahydro-1H-benzimidazol-5-yl-)carbonyl]-1H-indole), granisetron, talipexole, azasetron, bemesetron, tropisetron, ramosetron, ondansetron, palonosetron, lerisetron, alosetron, N-3389, zacopride, cilansetron, E-3620 ([3(S)-endo]-4-amino-5-chloro-N-(8-methyl-8-azabicyclo[3.2.1-]oct-3-yl-2[(1-methyl-2 -butynyl)oxy]benzamide), lintopride, KAE-393, itasetron, zatosetron, dolasetron, (±

)-zacopride, (±

)-renzapride, (−

)-YM-060, DAU-6236, BIMU-8 and GK-128 ([2-[2-methylimidazol-1-yl)methyl]-benzo[f]thiochromen-1-one monohydrochloride hemihydrate]).

51. The method of claim 50, wherein the 5-HT₃ receptor antagonist is selected from the group consisiting of indisetron, granisetron, azasetron, bemesetron, tropisetron, ramosetron, ondansetron, palonosetron, lerisetron, alosetron, cilansetron, itasetron, zatosetron, and dolasetron.

52. The method of claim 45, wherein the noradrenaline reuptake inhibitor is selected from the group consisting of venlafaxine, duloxetine, buproprion, milnacipran, reboxetine, lefepramine, desipramine, nortriptyline, tomoxetine, maprotiline, oxaprotiline, levoprotiline, viloxazine and atomoxetine.

53. The method of claim 52, wherein the noradrenaline reuptake inhibitor is selected from the group consisting of reboxetine, lefepramine, desipramine, nortriptyline, tomoxetine, maprotiline, oxaprotiline, levoprotiline, viloxazine and atomoxetine.

54. A method of treating at least one symptom of a lower urinary tract disorder in a subject in need of treatment, wherein the symptom is selected from the group consisting of urinary frequency, urinary urgency, nocturia and enuresis, comprising administering to said subject:

a) a therapeutically effective amount of a 5-HT₃ receptor antagonist; and

b) a therapeutically effective amount of a noradrenaline reuptake inhibitor.

55. The method of claim 54, wherein the lower urinary tract disorder is selected from the group consisting of overactive bladder, interstitial cystitis, prostatitis, prostadynia and benign prostatic hyperplasia.

56. The method of claim 55, wherein the lower urinary tract disorder is overactive bladder.

57. The method of claim 55, wherein the lower urinary tract disorder is interstitial cystitis.

58. The method of claim 54, wherein the subject is a human.

59. The method of claim 54, wherein the 5-HT₃ receptor antagonist is selected from the group consisting of indisetron, YM-114 ((R)-2,3-dihydro-1-[(4,5,6,7-tetrahydro-1H-benzimidazol-5-yl-)carbonyl]-1H-indole), granisetron, talipexole, azasetron, bemesetron, tropisetron, ramosetron, ondansetron, palonosetron, lerisetron, alosetron, N-3389, zacopride, cilansetron, E-3620 ([3(S)-endo]-4-amino-5-chloro-N-(8-methyl-8-azabicyclo[3.2.1-]oct-3-yl-2[(1-methyl-2-butynyl)oxy]benzamide), lintopride, KAE-393, itasetron, zatosetron, dolasetron, (±

)-zacopride, (±

)-renzapride, (−

)—

YM-060, DAU-6236, BIMU-8 and GK-128 ([2-[2-methylimidazol-1-yl)methyl]-benzo[f]thiochromen-1-one monohydrochloride hemihydrate]).

60. The method of claim 59, wherein the 5-HT₃ receptor antagonist is selected from the group consisiting of indisetron, granisetron, azasetron, bemesetron, tropisetron, ramosetron, ondansetron, palonosetron, lerisetron, alosetron, cilansetron, itasetron, zatosetron, and dolasetron.

61. The method of claim 54, wherein the noradrenaline reuptake inhibitor is selected from the group consisting of venlafaxine, duloxetine, buproprion, milnacipran, reboxetine, lefepramine, desipramine, nortriptyline, tomoxetine, maprotiline, oxaprotiline, levoprotiline, viloxazine and atomoxetine.

62. The method of claim 61, wherein the noradrenaline reuptake inhibitor is selected from the group consisting of reboxetine, lefepramine, desipramine, nortriptyline, tomoxetine, maprotiline, oxaprotiline, levoprotiline, viloxazine and atomoxetine.