Diaminopyrimidine p2x3 and p2x2/3 receptor modulators for use in the treatment of cough

Abstract

Methods for treating cough, chronic cough and urges to cough associated with respiratory diseases with a P2X3 and/or a P2X2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of Formula (I):or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are as defined herein.

1 . A method for treating chronic cough, comprising administering to a patient with chronic cough about 15 mg twice daily of a compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is hydrogen or C 1 -C 6  alkyl; and 
 R 2  is: alkyl; aminosulfonyl; halo; amido; haloalkyl; alkoxy; hydroxy; haloalkoxy; nitro; hydroxyalkyl; alkoxyalkyl; hydroxyalkoxy; alkynylalkoxy; alkylsulfonyl; arylsulfonyl; carboxyalkyl; cyano or alkylcarbonyl; and 
 wherein the method exhibits a reduced taste disturbance relative to a taste disturbance resulting from administering a dose of about 100 mg or greater of the compound of formula (I) or the pharmaceutically acceptable salt thereof twice daily to a patient with chronic cough. 
 
     
     
         2 . The method of  claim 1 , wherein the chronic cough is idiopathic or treatment resistant cough. 
     
     
         3 - 4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the compound of Formula (I), or the pharmaceutically acceptable salt thereof, is administered twice daily for days, weeks, months or years. 
     
     
         6 . The method of  claim 1 , wherein the chronic cough is refractory chronic cough. 
     
     
         7 . The method of  claim 1 , wherein the reduced taste disturbance is relative to a taste disturbance resulting from administering about 100 mg of the compound of Formula (I) or the pharmaceutically acceptable salt thereof twice daily to a patient with chronic cough. 
     
     
         8 . The method of  claim 1 , wherein the chronic cough is daytime cough. 
     
     
         9 - 10 . (canceled) 
     
     
         11 . The method of  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The method of  claim 1 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         13 - 20 . (canceled) 
     
     
         21 . A method for treating chronic cough, comprising administering to a patient with chronic cough about 15 mg twice daily of a pharmaceutically acceptable salt of the following compound: 
       
         
           
           
               
               
           
         
       
       wherein the method exhibits a reduced taste disturbance relative to a taste disturbance resulting from administering a dose of about 100 mg or greater of the pharmaceutically acceptable salt of the compound of formula (I) twice daily to a patient with chronic cough. 
     
     
         22 . The method of  claim 21 , wherein the reduced taste disturbance is relative to a taste disturbance resulting from administering about 100 mg of the pharmaceutically acceptable salt of the compound of formula (I) twice daily to a patient with chronic cough. 
     
     
         23 - 26 . (canceled) 
     
     
         27 . The method of  claim 21 , wherein the reduced taste disturbance is relative to a taste disturbance resulting from administering about 600 mg of the pharmaceutically acceptable salt of the compound of formula (I) twice daily to a patient with chronic cough.