3,5-diamino-6-chloro-n-(n-(4-phenylbutyl)carbamimidoyl) pyrazine-2- carboxamide compounds

Abstract

or pharmaceutically acceptable salts thereof, useful as sodium channel blockers, as well as compositions containing the same, processes for the preparation of the same, and therapeutic methods of use therefore in promoting hydration of mucosal surfaces and the treatment of diseases including cystic fibrosis, chronic obstructive pulmonary disease, asthma, bronchiectasis, acute and chronic bronchitis, emphysema, and pneumonia.

1 - 16 . (canceled) 
     
     
         17 . A method for treating reversible or irreversible airway obstruction, chronic obstructive pulmonary disease (COPD), asthma, bronchiectasis, including bronchiectasis due to conditions other than cystic fibrosis, acute bronchitis, chronic bronchitis, post-viral cough, cystic fibrosis, emphysema, pneumonia, panbronchiolitis, transplant-associate bronchiolitis, or ventilator-associated tracheobronchitis in a subject in need thereof, or for preventing ventilator-associated pneumonia in a subject in need thereof, the method comprising administering to the subject a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Ar is a moiety selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         X is selected from —CH 2 —, —O—, and —S—; 
         R 1  and R 2  are independently selected from H and C 1 -C 6  alkyl; or R 1  and R 2  together with the nitrogen atom to which they are bound form a 5-membered or 6-membered heterocyclic ring optionally containing one additional ring heteroatom selected from N and 0; 
         R 3  is an alkyl group having from 3 to 8 carbon atoms or a polyhydroxylated alkyl group having from 3 to 8 carbon atoms; 
         R 4  is a polyhydroxylated alkyl group having from 3 to 8 carbon atoms; and 
         R 5  is selected from H and C 1 -C 3  alkyl; 
       
       or comprising administering to the subject a compound of one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The method of  claim 17 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         19 . The method of  claim 17 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         20 . The method of  claim 18 , wherein the compound is of one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         21 . The method of  claim 18 , wherein the compound is of one of the following formulae: 
       
         
           
           
               
               
           
         
       
       or pharmaceutically acceptable salt thereof. 
     
     
         22 . The method of  claim 17 , wherein the compound is of one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The method of  claim 17 , wherein the compound is of one of the following formulae: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         24 . The method of  claim 17 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         25 . A method for treating dry mouth (xerostomia), dry skin, vaginal dryness, sinusitis, rhinosinusitis, nasal dehydration, including nasal dehydration brought on by administering dry oxygen, dry eye, Sjogren's disease, otitis media, primary ciliary dyskinesia, distal intestinal obstruction syndrome, esophagitis, constipation, or chronic diverticulitis in a subject in need thereof, or for promoting ocular or corneal hydration in a subject in need thereof, the method comprising administering to the subject a compound of the following formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Ar is a moiety selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         X is selected from —CH 2 —, —O—, and —S—; 
         R 1  and R 2  are independently selected from H and C 1 -C 6  alkyl; or R 1  and R 2  together with the nitrogen atom to which they are bound form a 5-membered or 6-membered heterocyclic ring optionally containing one additional ring heteroatom selected from N and 0; 
         R 3  is an alkyl group having from 3 to 8 carbon atoms or a polyhydroxylated alkyl group having from 3 to 8 carbon atoms; 
         R 4  is a polyhydroxylated alkyl group having from 3 to 8 carbon atoms; and 
         R 5  is selected from H and C 1 -C 3  alkyl; 
       
       or comprising administering to the subject a compound of one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         26 . The method of  claim 25 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         27 . The method of  claim 25 , wherein the compound is of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         28 . The method of  claim 26 , wherein the compound is of one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         29 . The method of  claim 26 , wherein the compound is of one of the following formulae: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         30 . The method of  claim 25 , wherein the compound is of one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         31 . The method of  claim 26 , wherein the compound is of one of the following formulae: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         32 . The method of  claim 25 , wherein the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         33 . A method for promoting hydration of mucosal surfaces, improving mucociliary clearance, or restoring mucosal defense in a subject comprising administering to the subject a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Ar is a moiety selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         X is selected from —CH 2 —, —O—, and —S—; 
         R 1  and R 2  are independently selected from H and C 1 -C 6  alkyl; or R 1  and R 2  together with the nitrogen atom to which they are bound form a 5-membered or 6-membered heterocyclic ring optionally containing one additional ring heteroatom selected from N and 0; 
         R 3  is an alkyl group having from 3 to 8 carbon atoms or a polyhydroxylated alkyl group having from 3 to 8 carbon atoms; 
         R 4  is a polyhydroxylated alkyl group having from 3 to 8 carbon atoms; and 
         R 5  is selected from H and C 1 -C 3  alkyl; 
       
       or comprising administering to the subject a compound of one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         34 . A method for preventing, mitigating, and/or treating deterministic health effects to the respiratory tract and/or other bodily organs caused by respirable aerosols containing radionuclides in a human in need thereof, said method comprising administering to the human a compound of the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Ar is a moiety selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         X is selected from —CH 2 —, —O—, and —S—; 
         R 1  and R 2  are independently selected from H and C 1 -C 6  alkyl; or R 1  and R 2  together with the nitrogen atom to which they are bound form a 5-membered or 6-membered heterocyclic ring optionally containing one additional ring heteroatom selected from N and 0; 
         R 3  is an alkyl group having from 3 to 8 carbon atoms or a polyhydroxylated alkyl group having from 3 to 8 carbon atoms; 
         R 4  is a polyhydroxylated alkyl group having from 3 to 8 carbon atoms; and 
         R 5  is selected from H and C 1 -C 3  alkyl; 
       
       or comprising administering to the human a compound of one of the following formulae: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         35 . The method of  claim 17 , wherein the compound or pharmaceutically acceptable salt thereof is administered via inhalation. 
     
     
         36 . The method of  claim 33 , wherein the compound or pharmaceutically acceptable salt thereof is administered via inhalation.