Novel annelated benzamides

Abstract

The present invention relates to compounds of formula (I) wherein R 1 , R 2 , and Z − have one of the meanings as indicated in the specification or a pharmaceutically acceptable salt thereof, to the use of compounds of formula (I) as a medicament, to pharmaceutical composition comprising at least one compound of formula (I), as well as to medicament combinations containing one or more compounds of formula (I).

1 . A method for the treatment of a disease selected from among respiratory diseases or complaints, allergic diseases of the airways and dry eyes comprising administering a therapeutically effective amount of a compound of formula (I), 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  and R 2  are independently selected from hydrogen and C 1 -C 6 -alkyl, wherein C 1 -C 6 -alkyl may carry 1 to 5 substituents selected from hydroxyl, amino, C 1 -C 4 -alkylamino, di-C 1 -C 4 -alkylamino, morpholin-4-yl and dimethylphosphinoylmethoxy, provided that at least one of R 1  and R 2  is different from hydrogen, unsubstituted C 1 -C 6 -alkyl and C 1 -C 6 -alkyl carrying 1 hydroxyl substituent; or 
 R 1  and R 2  together with the nitrogen atom they are attached to form a heterocyclic moiety selected from piperidine, piperazine and 1,4-diazepane, wherein the heterocyclic moiety may carry 1 or 2 substituents selected from C 1 -C 4 -alkyl, dimethylphosphinoyl-C 1 -C 4 -alkyl and NR a R b , wherein R a  and R b  are independently selected from hydrogen, C 1 -C 4 -alkyl and —C(O)CH 2 NR c R d , wherein R c  and R d  are independently selected from hydrogen and C 1 -C 4 -alkyl; and 
 Z −  is selected from chloride, bromide, iodide, hydroxide, hydrogensulfate, sulfate, nitrate, phosphate, formate, acetate, trifluoroacetate, fumarate, citrate, tartrate, oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The method according to  claim 1 , wherein R 1  and R 2  are independently selected from hydrogen, methyl, isobutyl, 2-aminoethyl, 3-aminopropyl, 2-(methylamino)ethyl, 2-(dimethylamino)ethyl, 3-(methylamino)propyl, 3-(dimethylamino)propyl, 2-(morpholin-4-yl)ethyl, 2-(dimethylphosphinoylmethoxy)ethyl and 2,3,4,5,6-pentahydroxyhex-1-yl;
 or a pharmaceutically acceptable salt thereof.   
     
     
         3 . The method according to  claim 1 , wherein R 1  and R 2  together with the nitrogen atom they are attached to form a moiety selected from 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof 
     
     
         4 . The method according to  claim 1 , wherein Z −  is selected from formate, chloride and trifluoroacetate;
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         5 . The method according to  claim 1 , wherein the compound of formula 1 is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The method according to  claim 1 , wherein the disease is selected from among chronic bronchitis, acute bronchitis, bronchitis caused by bacterial or viral infection or fungi or helminths, allergic bronchitis, toxic bronchitis, chronic obstructive pulmonary disease (COPD), asthma, paediatric asthma, bronchiectasis, allergic alveolitis, allergic or non-allergic rhinitis, chronic sinusitis, idiopathic pulmonary fibrosis, cystic fibrosis or mucoviscidosis, alpha-1-antitrypsin deficiency, cough, pulmonary emphysema, interstitial lung diseases, alveolitis, hyperreactive airways, nasal polyps, pulmonary oedema and pneumonitis of different origins, and dry eyes. 
     
     
         7 . The method according to  claim 1 , further comprising administering the compound of formula (I) with a pharmaceutically acceptable carrier. 
     
     
         8 . The method according to  claim 7 , further comprising administering a therapeutically effective amount of another further active substance selected from among the categories of further ENaC inhibitors, betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine agonists, H1-antihistamines, PAF-antagonists, MAP-kinase inhibitors, MPR4-Inhibitors, iNOS-Inhibitors, SYK-Inhibitors, correctors of the cystic fibrosis transmembrane regulator (CFTR) and CFTR potentiators. 
     
     
         9 . The method according to  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         10 . The method according to  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         11 . The method according to  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         12 . The method according to  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         13 . The method according to  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         14 . The method according to  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         15 . The method according to  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         16 . The method according to  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         17 . The method according to  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         18 . The method according to  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.