Treating and/or preventing urinary incontinence using prodrugs of gaba analogs

Abstract

Disclosed herein are methods of using prodrugs of GABA analogs and pharmaceutical compositions thereof to treat and/or prevent urinary incontinence in humans, and pharmaceutical compositions of prodrugs of GABA analogs useful in treating and/or preventing urinary incontinence.

1 . A method of treating or preventing urinary incontinence in a patient in need of such treatment or prevention comprising administering to the patient a therapeutically effective amount of a prodrug of a GABA analog, or a pharmaceutically acceptable salt, hydrate or solvate thereof. 
   
   
       2 . A method of treating or preventing urinary incontinence in a patient in need of such treatment or prevention comprising administering to the patient a pharmaceutical composition comprising a therapeutically effective amount of a prodrug of a GABA analog, or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable carrier. 
   
   
       3 . The method of  claim 1  or  claim 2 , wherein the GABA analog is gabapentin or pregabalin. 
   
   
       4 . The method of  claim 3 , wherein the GABA analog is administered in an amount of between about 10 mg and about 5000 mg per day. 
   
   
       5 . The method of  claim 1  or  claim 2 , wherein the patient is a female patient. 
   
   
       6 . The method of  claim 5 , wherein the female patient is postmenopausal. 
   
   
       7 . The method of  claim 6 , wherein menopause is drug induced or surgically induced. 
   
   
       8 . The method of  claim 1  or  claim 2 , wherein the patient is a male patient. 
   
   
       9 . The method of  claim 1  or  claim 2 , wherein the urinary incontinence is drug-induced. 
   
   
       10 . The method of  claim 1  or  claim 2 , wherein the prodrug is administered orally, parenterally, subcutaneously, intravenously, intramuscularly, intraperitoneally, intranasally, instillationally, intracavitarally or intravesical instillationally, intraocularly, intraarteriall, intralesionally, by implantation or by application to mucous membranes. 
   
   
       11 . The method of  claim 1  or  claim 2 , wherein the prodrug is administered orally. 
   
   
       12 . The method of  claim 1  or  claim 2 , comprising administering the prodrug in a sustained release oral dosage form. 
   
   
       13 . The method of  claim 12 , wherein the dosage form releases the prodrug gradually over a period of at least about 6 hours after swallowing the dosage form, thereby providing a therapeutic concentration of a GABA analog in the plasma of the patient. 
   
   
       14 . The method of  claim 12 , wherein the dosage form is an osmotic dosage form, a prodrug-releasing polymer, a prodrug-releasing lipid, a prodrug-releasing wax, tiny timed-release pills or prodrug releasing beads. 
   
   
       15 . The method of  claim 1  or  claim 2 , wherein the prodrug of a GABA analog has the structure of Formula (I): 
     
       
         
         
             
             
         
       
       or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein: 
       n is 0 or 1; 
       Y is O or S; 
       R 16  is hydrogen, alkyl or substituted alkyl; 
       R 2  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl, substituted acyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, or optionally, R 2  and R 16  together with the atoms to which they are attached form a cycloheteroalkyl or substituted cycloheteroalkyl ring; 
       R 3  and R 6  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; 
       R 4  and R 5  are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl or optionally, R 4  and R 5  together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl or bridged cycloalkyl ring; 
       R 7  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl; 
       R 13  and R 14  are each independently hydrogen, alkyl, substituted alkyl, alkoxycarbonyl, substituted alkoxycarbonyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, carbamoyl, substituted carbamoyl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl or optionally, R 13  and R 14  together with the carbon atom to which they are attached form a cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl ring; and 
       R 25  is selected from the group consisting of acyl, substituted acyl, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl and substituted heteroarylalkyl. 
     
   
   
       16 . The method of  claim 15 , wherein the prodrug of a GABA analog has the structure of Formulae (II) or (III): 
     
       
         
         
             
             
         
       
     
   
   
       17 . The method of  claim 16 , wherein n is 0. 
   
   
       18 . The method of  claim 16 , wherein n is 1, R 16  is hydrogen and R 2  is selected from the group consisting of hydrogen, methyl, 2-propyl, 2-butyl, isobutyl, tert-butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, 4-hydroxybenzyl, 4-imidazolylmethyl, 3-indolylmethyl, —CH 2 OH, —CH(OH)CH 3 , —CH 2 CO 2 H, —CH 2 CH 2 CO 2 H, —CH 2 CONH 2 , —CH 2 CH 2 CONH 2 , —CH 2 CH 2 SCH 3 , —CH 2 SH, —CH 2 (CH 2 ) 3 NH 2  and —CH 2 CH 2 CH 2 NHC(NH)NH 2 . 
   
   
       19 . The method of  claim 17 , wherein R 25  is selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl and sec-butyl, R 13  is methyl and R 14  is hydrogen. 
   
   
       20 . The method of  claim 17 , wherein R 25  is isopropyl, R 13  is methyl and R 14  is hydrogen. 
   
   
       21 . A pharmaceutical composition for treating a patient suffering from urinary incontinence comprising a therapeutically effective amount of a prodrug of a GABA analog or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable vehicle. 
   
   
       22 . A pharmaceutical composition suitable for preventing urinary incontinence in a patient at risk of urinary incontinence comprising a therapeutically effective amount of a prodrug of a GABA analog or a pharmaceutically acceptable salt, hydrate or solvate thereof and a pharmaceutically acceptable vehicle. 
   
   
       23 . The method of  claim 1  or  claim 2 , wherein the urinary incontinence is characterized by symptoms of urge incontinence. 
   
   
       24 . The method of  claim 1  or  claim 2 , wherein the urinary incontinence is characterized by symptoms of stress incontinence.