Dinucleotides useful for the treatment of lung disease

Abstract

A pharmaceutical formulation comprises, in an amount effective to hydrate lung mucous secretions, a compound of Formula (I): wherein n is from 1 to 6; X is —OH or —SH; A and B are each independently selected from the group consisting of:  wherein R is H or Br; or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier. A method of hydrating mucous secretions in the lungs of a subject in need of such treatment, comprising administering to the lungs of the subject a compound of Formula I as given above, is also disclosed.

That which is claimed is:  
     
         1 . A pharmaceutical formulation comprising, in an amount effective to hydrate lung mucous secretions, and in a pharmaceutically acceptable carrier, a compound of Formula (I):  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is from 1 to 6;  
 X is —OH or —SH;  
 and A and B are each independently selected from the group consisting of:  
                     
  wherein R is H or Br;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         2 . A pharmaceutical formulation according to    claim 1   , further comprising a compound selected from the group consisting of amiloride, benzamil and phenamil, or a pharmaceutically acceptable salt thereof.  
     
     
         3 . A pharmaceutical formulation according to    claim 1   , wherein said carrier is a liquid carrier.  
     
     
         4 . A pharmaceutical formulation according to    claim 1   , wherein said carrier is a solid particulate carrier.  
     
     
         5 . A method of hydrating mucous secretions in the lungs of a subject in need of such treatment, comprising administering to the lungs of the subject a compound of Formula I below, or a pharmaceutically acceptable salt thereof, in an amount effective to hydrate lung mucous secretions:  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is from 1 to 6;  
 X is —OH or —SH;  
 and A and B are each independently selected from the group consisting of:  
                     
  wherein R is H or Br.  
 
     
     
         6 . A method according to    claim 5   , wherein said compound is delivered by administering an aerosol suspension of respirable particles comprised of said compound to the lungs of said subject.  
     
     
         7 . A method according to    claim 6   , wherein said particles are selected from the group consisting of solid particles and liquid particles.  
     
     
         8 . A method according to    claim 5   , further comprising concurrently administering a compound selected from the group consisting of amiloride, benzamil and phenamil to said subject in an amount effective to inhibit the reabsorption of water from lung mucous secretions.  
     
     
         9 . A method of treating cystic fibrosis in a human subject in need of such treatment, comprising administering by inhalation an aerosol suspension of respirable particles to the respiratory system of said subject, said particles comprised of a compound of Formula I below, or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 n is from 1 to 6;  
 X is —OH or —SH;  
 and A and B are each independently selected from the group consisting of:  
                     
  wherein R is H or Br;  
 in an amount effective to hydrate retained lung mucous secretions in the lungs of said subject, whereby the retained mucous secretions are more easily transported from the lungs via mucociliary action.  
 
     
     
         10 . A method according to    claim 9   , wherein said compound is delivered by administering an aerosol suspension of respirable particles comprised of said compound to the lungs of said subject.  
     
     
         11 . A method according to    claim 9   , wherein said particles are selected from the group consisting of solid particles and liquid particles.  
     
     
         12 . A method according to    claim 9   , further comprising concurrently administering a compound selected from the group consisting of amiloride, benzamil and phenamil to said subject in an amount effective to inhibit the reabsorption of water from lung mucous secretions.  
     
     
         13 . A method of hydrating mucous secretions in the lungs of a subject in need of such treatment, comprising administering to the lungs of the subject a compound of Formula I below, or a pharmaceutically acceptable salt thereof, in an amount effective to hydrate lung mucous secretions:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A and B are each  
                     
 n is 4;  
 X is —OH; and  
 R is H.  
 
     
     
         14 . A method according to    claim 13   , wherein said compound is delivered by administering an aerosol suspension of respirable particles comprised of said compound to the lungs of said subject.  
     
     
         15 . A method according to    claim 13   , wherein said particles are selected from the group consisting of solid particles and liquid particles.  
     
     
         16 . A method according to    claim 13   , further comprising concurrently administering a compound selected from the group consisting of amiloride, benzamil and phenamil to said subject in an amount effective to inhibit the reabsorption of water from lung mucous secretions.  
     
     
         17 . A method of treating cystic fibrosis in a human subject in need of such treatment, comprising administering by inhalation an aerosol suspension of respirable particles to the respiratory system of said subject, said particles comprised of a compound of Formula I below, or a pharmaceutically acceptable salt thereof:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A and B are each  
                     
 n is 4;  
 X is —OH; and  
 R is H.  
 
     
     
         18 . A method according to    claim 17   , wherein said compound is delivered by administering an aerosol suspension of respirable particles comprised of said compound to the lungs of said subject.  
     
     
         19 . A method according to    claim 18   , wherein said particles are selected from the group consisting of solid particles and liquid particles.  
     
     
         20 . A method according to    claim 17   , further comprising concurrently administering a compound selected from the group consisting of amiloride, benzamil and phenamil to said subject in an amount effective to inhibit the reabsorption of water from lung mucous secretions.