Novel annelated phenoxyacetamides

Abstract

The present invention relates to compounds of formula (I) wherein R 1 , R 2 , R 3 , 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 compositions comprising at least one compound of formula (I), as well as to medicament combinations containing one or more compounds of formula (I).

1 . A compound of formula (I), 
       
         
           
           
               
               
           
         
         wherein 
         R 1  and R 2  are independently selected from ethyl, 2-hydroxyethyl, 2-tetrahydrofuranylmethyl and 4-tetrahydropyranylmethyl; 
         R 3  is selected from a moiety NR a R b , wherein R a  and R b  are independently selected from hydrogen, C 1 -C 4 -alkyl and 1-(2-ethoxyethyl)piperidin-4-yl, wherein C 1 -C 4 -alkyl may carry 1 or 2 substituents selected from hydroxyl, amino, C 1 -C 4 -alkylamino, di-C 1 -C 4 -alkylamino, (dimethylphosphinoyl)methoxy, 4-(dimethylphosphinoyl)phenyl, 6-methyl-3-hydroxy-pyridin-2-yl and the oxyanion of 6-methyl-3-hydroxy-pyridin-2-yl, provided that at least one of R a  and R b  is different from hydrogen, 
         or wherein R a  and R b  together with the nitrogen they are attached to form a heterocyclic moiety selected from piperidine and 1-oxothiomorpholinyl, wherein the heterocyclic moiety may carry 1 or 2 substituents selected from NH 2 ; 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 Z −  may be absent if R a  or R b  is C1-C 4 -alkyl and carries the oxyanion of 6-methyl-3-hydroxy-pyridin-2-yl; 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein at least one of R 1  and R 2  is ethyl;
 or a pharmaceutically acceptable salt thereof.   
     
     
         3 . The compound according to  claim 2 , wherein both of R 1  and R 2  are ethyl;
 or a pharmaceutically acceptable salt thereof.   
     
     
         4 . The compound according to  claim 1 , wherein Z −  is selected from chloride, formate, and trifluoroacetate;
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         5 . The compound according to  claim 1 , wherein R 3  is selected from 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         6 . The compound according to  claim 1 , selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . A method for the treatment of a disease selected from among respiratory diseases or complaints and allergic diseases of the airways, or dry eyes comprising administering a therapeutically effective amount of a compound according to  claim 1  to a patient in need thereof. 
     
     
         8 . The method according to  claim 7 , 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 bronchitis (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, pneumonitis of different origins, and dry eyes. 
     
     
         9 . A pharmaceutical composition comprising at least one compound according to  claim 1  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 
     
     
         10 . The pharmaceutical composition according to  claim 9 , wherein the composition further comprises as further active substances, one or more compounds 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.