Method of treating lower urinary tract disorders

• US 20040248979A1
• Filed: 06/03/2004
• Published: 12/09/2004
• Est. Priority Date: 06/03/2003
• Status: Abandoned Application

• Current Assignee: Dynogen Pharmaceuticals, Inc. (Edusa Pharmaceuticals, Inc.)
• Original Assignee: Dynogen Pharmaceuticals, Inc. (Edusa Pharmaceuticals, Inc.)
• Inventors: Landau, Steven B., Brettman, Lee R., Fraser, Matthew O.
• Application Number:
  US10/859,922
• Publication Number:
  US 20040248979A1
• Time in Patent Office: Days
• US Class Current: 514/561
• 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 31/137 Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
• CPC Class Codes: A61K 31/195 having an amino group

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 comprising coadministering to said subject a first amount of an α₂δ subunit calcium channel ligand and a second amount of a substituted aminomethyl-phenyl-cyclohexane derivative, wherein the first and second amounts together comprise a therapeutically effective amount. The coadministration of a first amount of an α₂δ subunit calcium channel ligand and a second amount of a substituted aminomethyl-phenyl-cyclohexane derivative can result in an enhanced or synergistic therapeutic effect, wherein the combined effect is greater than the additive effect resulting from separate administration of the first amount of the α₂δ subunit calcium channel ligand and the second amount of the substituted aminomethyl-phenyl-cyclohexane derivative.

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, urinary urge incontinence, nocturia and enuresis, comprising administering to said subject:

a) a first amount of an α

₂δ

subunit calcium channel ligand; and

b) a second amount of a substituted aminomethyl-phenyl-cyclohexane derivative,

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

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 the α

₂δ

subunit calcium channel ligand is a GABA analog.

7. The method of claim 6, wherein the GABA analog is selected from the group consisting of gabapentin, pregabalin, cis-(1S,3R)-(1-(aminomethyl)-3-methylcyclohexane)acetic acid, cis-(1R,3S)-(1-(aminomethyl)-3-methylcyclohexane)acetic acid, 1α

,3α

,5α

-(1-aminomethyl)-(3,5-dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1]non-9-yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and combinations thereof.

8. The method of claim 7, wherein the GABA analog is gabapentin, pregabalin or a combination thereof.

9. The method of claim 1, wherein the substituted aminomethyl-phenyl-cyclohexane derivative is represented by structural Formula I:

10. The method of claim 9, wherein R₂ is —

OH.

11. The method of claim 10, wherein R₁′

is H and R₁ is —

OCH₃.

12. The method of claim 11, wherein, —

OCH₃ is substituted at the meta position of the phenyl ring.

13. The method of claim 9, wherein the α

₂δ

subunit calcium channel ligand is a GABA analog.

14. The method claim 13, wherein the GABA analog is selected from the group consisting of gabapentin, pregabalin, cis-(1S,3R)-(1-(aminomethyl)-3-methylcyclohexane)acetic acid, cis-(1R,3S)-(1-(aminomethyl)-3-methylcyclohexane)acetic acid, 1α

,3α

,5α

-(1-aminomethyl)-(3,5-dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1]non-9-yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof.

15. The method of claim 14, wherein the GABA analog is gabapentin, pregabalin or a combination thereof.

16. The method of claim 1, wherein the substituted aminomethyl-phenyl-cyclohexane derivative is represented by structural Formula II:

17. The method of claim 16, wherein the compound of Formula II is a mixture of the following enantiomers:

18. The method of claim 17, wherein the mixture is a racemic mixture.

19. The method of claim 17, wherein the compound of Formula II is the (+)cis enantiomer.

20. The method of claim 16, wherein the α

₂δ

subunit calcium channel ligand is a GABA analog.

21. The method claim 20, wherein the GABA analog is selected from the group consisting of gabapentin, pregabalin, cis-(1S,3R)-(1-(aminomethyl)-3-methylcyclohexane)acetic acid, cis-(1R,3S)-(1-(aminomethyl)-3-methylcyclohexane)acetic acid, 1α

,3α

,5α

-(1-aminomethyl)-(3,5-dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1]non-9-yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof.

22. The method of claim 21, wherein the GABA analog is gabapentin, pregabalin or a combination thereof.

49. The method of claim 1, wherein the substituted aminomethyl-phenyl-cyclohexane derivative is represented by structural Formula V:

50. The method of claim 49, wherein for the compound of Formula V, R₁₁ is —

OH, R₁₂ is H and R₁₃ is;

51. The method of claim 50, wherein R₁₉ is —

O-alkyl.

52. The method of claim 51, wherein R₁₉ is —

OCH₃.

53. The method of claim 50, wherein R₁₉ is an alkyl group.

54. The method of claim 53, wherein the R₁₉ is a substituted alkyl group.

55. The method of claim 54, wherein the substituted alkyl group is —

CF₃.

56. The method of claim 49, wherein the α

₂δ

subunit calcium channel ligand is a GABA analog.

57. The method claim 56, wherein the GABA analog is selected from the group consisting of gabapentin, pregabalin, cis-(1S,3R)-(1-(aminomethyl)-3-methylcyclohexane)acetic acid, cis-(1R,3S)-(1-(aminomethyl)-3-methylcyclohexane)acetic acid, 1α

,3α

,5α

-(1-aminomethyl)-(3,5-dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1]non-9-yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof.

58. The method of claim 57, wherein the GABA analog is gabapentin, pregabalin or a combination thereof.

23. 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 administering to said subject:

a) a first amount of a GABA analog selected from the group consisting of;

gabapentin, pregabalin or a combination thereof; and

b) a second amount of tramadol hydrochloride,

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

24. The method of claim 23, wherein the lower urinary tract disorder is selected from the group consisting of overactive bladder, interstitial cystitis, prostatitis, prostadynia and benign prostatic hyperplasia.

25. The method of claim 24, wherein the lower urinary tract disorder is overactive bladder.

26. The method of claim 24, wherein the lower urinary tract disorder is interstitial cystitis.

27. The method of claim 23, wherein the subject is a human.

28. The method of claim 23, wherein the GABA analog is gabapentin.

29. The method of claim 28 wherein the therapeutically effective amount provides a synergistic effect.

30. 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 administering to said subject:

a) a first amount of an α

₂δ

subunit calcium channel ligand; and

b) a second amount of a substituted aminomethyl-phenyl-cyclohexane derivative represented by structural Formula III and enantiomers and mixtures thereof;

or pharmaceutically acceptable salts, solvates and hydrates thereof, wherein the first and second amounts together comprise a therapeutically effective amount.

31. The method of claim 30, wherein the compound of Formula III is a mixture of the following enantiomers:

32. The method of claim 31, wherein the mixture is a racemic mixture.

33. The method of claim 31, wherein the compound of Formula III is the (+)cis enantiomer.

34. The method of claim 30, wherein the lower urinary tract disorder is selected from the group consisting of overactive bladder, interstitial cystitis, prostatitis, prostadynia and benign prostatic hyperplasia.

35. The method of claim 34, wherein the lower urinary tract disorder is overactive bladder.

36. The method of claim 34, wherein the lower urinary tract disorder is interstitial cystitis.

37. The method of claim 30, wherein the subject is a human.

38. The method of claim 30, wherein the α

₂δ

subunit calcium channel ligand is a GABA analog.

39. The method of claim 38, wherein the GABA analog is selected from the group consisting of gabapentin, pregabalin, cis-(1S,3R)-(1-(aminomethyl)-3-methylcyclohexane)acetic acid, cis-(1R,3S)-(1-(aminomethyl)-3-methylcyclohexane)acetic acid, 1α

,3α

,5α

-(1-aminomethyl)-(3,5-dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1]non-9-yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof.

40. The method of claim 39, wherein the GABA analog is gabapentin, pregabalin or a combination thereof.

41. 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 administering to said subject:

a) a first amount of an α

₂δ

subunit calcium channel ligand; and

b) a second amount of a substituted aminomethyl-phenyl-cyclohexane derivative selected from the group consisting of (+/−

)O-desmethyltramadol, (+)O-desmethyltramadol, (−

)O-desmethyltramadol, (+/−

)O-desmethyl-N-mono-desmethyl-tramadol, (+)O-desmethyl-N-mono-desmethyl-tramadol, (−

) O-desmethyl-N-mono-desmethyl-tramadol and a combination thereof.

42. The method of claim 41, wherein the lower urinary tract disorder is selected from the group consisting of overactive bladder, interstitial cystitis, prostatitis, prostadynia and benign prostatic hyperplasia.

43. The method of claim 42, wherein the lower urinary tract disorder is overactive bladder.

44. The method of claim 42, wherein the lower urinary tract disorder is interstitial cystitis.

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

46. The method of claim 41, wherein the α

₂δ

subunit calcium channel ligand is a GABA analog.

47. The method of claim 46, wherein the GABA analog is selected from the group consisting of gabapentin, pregabalin, cis-(1S,3R)-(1-(aminomethyl)-3-methylcyclohexane)acetic acid, cis-(1R,3S)-(1-(aminomethyl)-3-methylcyclohexane)acetic acid, 1α

,3α

,5α

-(1-aminomethyl)-(3,5-dimethylcyclohexane)acetic acid, (9-(aminomethyl)bicyclo[3.3.1]non-9-yl)acetic acid, (7-(aminomethyl)bicyclo[2.2.1]hept-7-yl)acetic acid and a combination thereof.

48. The method of claim 47, wherein the GABA analog is gabapentin, pregabalin or a combination thereof.

59. A kit comprising a sub-therapeutic dose of a compound which is an α

₂δ

subunit calcium channel ligand, instructions for use with a compound which is a substituted aminomethyl-phenyl-cyclohexane derivative and optionally a device for administering the compounds.

60. A kit comprising a sub-therapeutic dose of a compound which is a substituted aminomethyl-phenyl-cyclohexane derivative, instructions for use with a compound which is an α

₂δ

subunit calcium channel ligand and optionally a device for administering the compounds.

61. A kit comprising a first compound which is an α

₂δ

subunit calcium channel ligand, a second compound which is a substituted aminomethyl-phenyl-cyclohexane derivative and instructions for administering the first and second compounds and optionally a device for administering the compounds, wherein at least one of said first or second compound is present in a sub-therapeutic dose.