Method for inhibiting detrusor muscle overactivity

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-HT 3 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-HT 3 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.

1 - 70 . (canceled)  
   
   
       71 . A method of inhibiting detrusor muscle overactivity comprising administering a compound of formula I:  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof to a human subject in need thereof, wherein R 1  and R 2  independently represent hydrogen, halogen or a C 1 -C 6  alkyl group; or R 1  and R 2  together with the carbon atom to which they are attached form a cycloalkylene group having 5 to 6 carbon atoms;  
       R 3  and R 4  independently represent hydrogen or a C 1 -C 6  alkyl group;  
       R 5  is hydrogen, C 1 -C 6  alkyl,  
       
         
           
           
               
               
           
         
       
       or —C(O)—NH—R 6  
 wherein m is an integer from about 1 to about 3, X is halogen and R 6  is a C 1 -C 6  alkyl group; and  
 
       Ar is a substituted or unsubstituted phenyl, 2-thienyl or 3-thienyl group; and n is 2 or 3.  
     
   
   
       72 . The method of  claim 71 , wherein said administering is oral.  
   
   
       73 . The method of  claim 71 , wherein said administering is on an as-needed basis.  
   
   
       74 . The method of  claim 71 , wherein said therapeutically effective amount is from about 0.001 to about 1000 mg per day.  
   
   
       75 . The method of  claim 71 , wherein said therapeutically effective amount is from about 0.05 to about 500 mg per day.  
   
   
       76 . The method of  claim 71 , wherein said therapeutically effective amount is from about 0.03 to about 300 mg per day.  
   
   
       77 . The method of  claim 71 , wherein said therapeutically effective amount is from about 0.02 to about 200 mg per day.  
   
   
       78 . The method of  claim 71 , wherein said therapeutically effective amount is from about 0.1 to about 50 mg per day.  
   
   
       79 . The method of  claim 71 , wherein said detrusor muscle overactivity is associated with stroke, Parkinson's disease, diabetes, multiple sclerosis, peripheral neuropathy, a spinal cord lesion, bladder stones, muscle disease, an urinary tract infection or a drug side effect.  
   
   
       80 . A method of inhibiting detrusor muscle overactivity comprising administering a compound of formula II:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof to a human subject in need thereof.  
   
   
       81 . The method of  claim 80 , wherein said administering is oral.  
   
   
       82 . The method of  claim 80 , wherein said administering is on an as-needed basis.  
   
   
       83 . The method of  claim 80 , wherein said therapeutically effective amount is from about 0.001 to about 1000 mg per day.  
   
   
       84 . The method of  claim 80 , wherein said therapeutically effective amount is from about 0.05 to about 500 mg per day.  
   
   
       85 . The method of  claim 80 , wherein said therapeutically effective amount is from about 0.03 to about 300 mg per day.  
   
   
       86 . The method of  claim 80 , wherein said therapeutically effective amount is from about 0.02 to about 200 mg per day.  
   
   
       87 . The method of  claim 80 , wherein said therapeutically effective amount is from about 0.1 to about 50 mg per day.  
   
   
       88 . The method of  claim 80 , wherein said detrusor muscle overactivity is associated with stroke, Parkinson's disease, diabetes, multiple sclerosis, peripheral neuropathy, a spinal cord lesion, bladder stones, muscle disease, an urinary tract infection or a drug side effect.  
   
   
       89 . A method of promoting detrusor muscle stability comprising administering a compound of formula I:  
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt thereof to a human subject in need thereof, wherein R 1  and R 2  independently represent hydrogen, halogen or a C 1 -C 6  alkyl group; or R 1  and R 2  together with the carbon atom to which they are attached form a cycloalkylene group having 5 to 6 carbon atoms;  
       R 3  and R 4  independently represent hydrogen or a C 1 -C 6  alkyl group;  
       R 5  is hydrogen, C 1 -C 6  alkyl,  
       
         
           
           
               
               
           
         
       
       or —C(O)—NH—R 6  
 wherein m is an integer from about 1 to about 3, X is halogen and R 6  is a C 1 -C 6  alkyl group; and  
 
       Ar is a substituted or unsubstituted phenyl, 2-thienyl or 3-thienyl group; and n is 2 or 3.  
     
   
   
       90 . The method of  claim 89 , wherein said administering is oral.  
   
   
       91 . The method of  claim 89 , wherein said administering is on an as-needed basis.  
   
   
       92 . The method of  claim 89 , wherein said therapeutically effective amount is from about 0.001 to about 1000 mg per day.  
   
   
       93 . The method of  claim 89 , wherein said therapeutically effective amount is from about 0.05 to about 500 mg per day.  
   
   
       94 . The method of  claim 89 , wherein said therapeutically effective amount is from about 0.03 to about 300 mg per day.  
   
   
       95 . The method of  claim 89 , wherein said therapeutically effective amount is from about 0.02 to about 200 mg per day.  
   
   
       96 . The method of  claim 89 , wherein said therapeutically effective amount is from about 0.1 to about 50 mg per day.  
   
   
       97 . The method of  claim 89 , wherein said detrusor muscle stability is desired in a subject with bladder stones, muscle disease, an urinary tract infection or a drug side effect.  
   
   
       98 . A method of promoting detrusor muscle stability comprising administering a compound of formula II:  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof to a human subject in need thereof.  
   
   
       99 . The method of  claim 98 , wherein said administering is oral.  
   
   
       100 . The method of  claim 98 , wherein said administering is on an as-needed basis.  
   
   
       101 . The method of  claim 98 , wherein said therapeutically effective amount is from about 0.001 to about 1000 mg per day.  
   
   
       102 . The method of  claim 98 , wherein said therapeutically effective amount is from about 0.05 to about 500 mg per day.  
   
   
       103 . The method of  claim 98 , wherein said therapeutically effective amount is from about 0.03 to about 300 mg per day.  
   
   
       104 . The method of  claim 98 , wherein said therapeutically effective amount is from about 0.02 to about 200 mg per day.  
   
   
       105 . The method of  claim 98 , wherein said therapeutically effective amount is from about 0.1 to about 50 mg per day.  
   
   
       106 . The method of  claim 98 , wherein said detrusor muscle stability is desired in a subject with bladder stones, muscle disease, an urinary tract infection or a drug side effect.