New Medicaments for the Treatment of Chronic Obstructive Pulmonary Disease

Abstract

A pharmaceutical composition comprising a compound of formula 1 wherein: n is 1 or 2; R 1 is hydrogen, C 1 -C 4 -alkyl, halogen, OH, or —O—C 1 -C 4 -alkyl; R 2 is hydrogen, C 1 -C 4 -alkyl, halogen, OH, or —O—C 1 -C 4 -alkyl; R 3 is hydrogen, C 1 -C 4 -alkyl, OH, halogen, —O—C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkylene-COOH, or —O—C 1 -C 4 -alkylene-CO—O—C 1 -C 4 -alkyl, or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof, and a pharmaceutically acceptable excipient or carrier, and methods for using the pharmaceutical formulation in the treatment of chronic obstructive pulmonary disease (COPD).

1 . A pharmaceutical composition comprising a compound of formula 1 
     
       
         
         
             
             
         
       
     
     wherein: 
 n is 1 or 2;  
 R 1  is hydrogen, C 1 -C 4 -alkyl, halogen, OH, or —O—C 1 -C 4 -alkyl;  
 R 2  is hydrogen, C 1 -C 4 -alkyl, halogen, OH, or —O—C 1 -C 4 -alkyl;  
 R 3  is hydrogen, C 1 -C 4 -alkyl, OH, halogen, —O—C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkylene-COOH, or —O—C 1 -C 4 -alkylene-CO—O—C 1 -C 4 -alkyl, or  
 an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof; and  
 a pharmaceutically acceptable excipient or carrier.  
 
   
   
       2 . The pharmaceutical composition according to  claim 1 , wherein: 
 R 1  is hydrogen, halogen or C 1 -C 4 -alkyl;    R 2  is hydrogen, halogen, or C 1 -C 4 -alkyl; and    R 3  is hydrogen, C 1 -C 4 -alkyl, OH, halogen, —O—C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkylene-COOH, or —O—C 1 -C 4 -alkylene-CO—O—C 1 -C 4 -alkyl.    
   
   
       3 . The pharmaceutical composition according to  claim 1 , wherein: 
 R 1  is hydrogen, fluorine, chlorine, or methyl;    R 2  is hydrogen, fluorine, chlorine, or methyl; and    R 3  is hydrogen, C 1 -C 4 -alkyl, OH, fluorine, chlorine, bromine, —O—C 1 -C 4 -alkyl, —O-C 1 -C 4 -alkylene-COOH, or —O—C 1 -C 4 -alkylene-CO—O—C 1 -C 4 -alkyl.    
   
   
       4 . The pharmaceutical composition according to  claim 1 , wherein: 
 R 1  is hydrogen, methyl, or ethyl;    R 2  is hydrogen, methyl, or ethyl; and    R 3  is hydrogen, methyl, ethyl, OH, methoxy, ethoxy, —O—CH 2 —COOH, —O—CH 2 —CO—O-methyl, or —O—CH 2 —COOethyl.    
   
   
       5 . The pharmaceutical composition according to  claim 1 , wherein: 
 R 1  is hydrogen or methyl;    R 2  is hydrogen or methyl; and    R 3  is hydrogen, methyl, OH, methoxy, —O—CH 2 —COOH, or —O—CH 2 —COOethyl.    
   
   
       6 . A compound of formula 1 
     
       
         
         
             
             
         
       
     
     wherein: 
 n is 1;  
 R 1  is hydrogen, halogen, C 1 -C 4 -alkyl, or —O—C 1 -C 4 -alkyl;  
 R 2  is hydrogen, halogen, C 1 -C 4 -alkyl or —O—C 1 -C 4 -alkyl;  
 R 3  is C 1 -C 4 -alkyl, OH, halogen, —O—C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkylene-COOH, or —O—C 1 -C 4 -alkylene-CO—O—C 1 -C 4 -alkyl,  
 with the proviso that if R 1  and R 2  each represent ortho-methyl, R 3  cannot simultaneously be OH,  
 or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.  
 
   
   
       7 . The compound of formula 1 according to  claim 6 , wherein R 3  is methoxy, ethoxy, —O—CH 2 —COOH, —O—CH 2 —COOmethyl, or —O—CH 2 —COOethyl, or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.  
   
   
       8 . The compound of formula 1 according to  claim 6 , wherein: 
 R 1  is hydrogen, fluorine, chlorine, methyl, or methoxy;    R 2  is hydrogen, fluorine, chlorine, methyl, or methoxy;    R 3  is C 1 -C 4 -alkyl, OH, fluorine, chlorine, bromine, —O—C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkylene-COOH, or —O—C 1 -C 4 -alkylene-CO—O—C 1 -C 4 -alkyl,    or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.    
   
   
       9 . The compound of formula 1 according to  claim 8 , wherein R 3  is methoxy, ethoxy, —O—CH 2 —COOH, —O—CH 2 —COOmethyl, or —O—CH 2 —COOethyl, or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.  
   
   
       10 . The compound of formula 1 according to  claim 6 , wherein: 
 R 1  is hydrogen or C 1 -C 4 -alkyl;    R 2  is hydrogen or C 1 -C 4 -alkyl; and    R 3  is C 1 -C 4 -alkyl, OH, —O—C 1 -C 4 -alkyl, —O—C 1 -C 4 -alkylene-COOH, or —O—C 1 -C 4 -alkylene-CO—O—C 1 -C 4 -alkyl,    or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.    
   
   
       11 . The compound of formula 1 according to  claim 10 , wherein R 3  is methoxy, ethoxy, —O—CH 2 —COOH, —O—CH 2 —COOmethyl, or —O—CH 2 —COOethyl, or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.  
   
   
       12 . The compound of formula 1 according to  claim 6 , wherein: 
 R 1  is hydrogen, methyl, or ethyl;    R 2  is hydrogen, methyl, or ethyl;    R 3  is methyl, ethyl, OH, methoxy, ethoxy, —O—CH 2 —COOH, —O—CH 2 —COOmethyl or —O—CH 2 —COOethyl,    or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.    
   
   
       13 . The compound of formula 1 according to  claim 12 , wherein R 3  is methoxy, ethoxy, —O—CH 2 —COOH, —O—CH 2 —COOmethyl, or —O—CH 2 —COOethyl, or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.  
   
   
       14 . The compound of formula 1 according to  claim 6 , wherein: 
 R 1  is halogen, C 1 -C 4 -alkyl, or —O—C 1 -C 4 -alkyl;    R 2  is halogen, C 1 -C 4 -alkyl, or —O—C 1 -C 4 -alkyl; and    R 3  is halogen, C 1 -C 4 -alkyl, or —O—C 1 -C 4 -alkyl,    or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.    
   
   
       15 . The compound of formula 1 according to  claim 14 , wherein: 
 R 1  is fluorine, chlorine, methyl, or methoxy;    R 2  is fluorine, chlorine, methyl, or methoxy; and    R 3  is fluorine, chlorine, methyl, or methoxy,    or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.    
   
   
       16 . The compound of formula 1 according to  claim 6 , wherein: 
 R 1  is hydrogen;    R 2  is hydrogen, fluorine, chlorine, or methyl; and    R 3  is methyl, ethyl, isopropyl, tert-butyl, OH, fluorine, chlorine, bromine, methoxy, ethoxy, —O—CH 2 —COOH, —O—CH 2 —CH 2 —COOH, —O—CH 2 —CH 2 —CH 2 —COOH, —O—CH 2 —COOmethyl, —O—CH 2 —COOethyl, —O—CH 2 —CH 2 —COOmethyl, —O—CH 2 —CH 2 —COOethyl, —O—CH 2 —CH 2 —CH 2 —COOmethyl, or —O—CH 2 —CH 2 —CH 2 —COOethyl,    or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.    
   
   
       17 . The compound of formula 1 according to  claim 16 , wherein: 
 R 1  is hydrogen;    R 2  is hydrogen, fluorine, chlorine, or methyl; and    R 3  is OH, fluorine, chlorine, methyl, methoxy, ethoxy, or —O—CH 2 —COOH,    or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.    
   
   
       18 . The compound of formula 1 according to  claim 6 , wherein: 
 R 1  and R 2  are each hydrogen; and    R 3  is methyl, ethyl, isopropyl, tert-butyl, OH, fluorine, chlorine, bromine, methoxy, ethoxy, —O—CH 2 —COOH, —O—CH 2 —CH 2 —COOH, —O—CH 2 —CH 2 —CH 2 —COOH, —O—CH 2 —COOmethyl, —O—CH 2 —COOethyl, —O—CH 2 —CH 2 —COOmethyl, —O—CH 2 —CH 2 —COOethyl, —O—CH 2 —CH 2 —CH 2 —COOmethyl, or —O—CH 2 —CH 2 —CH 2 —COOethyl,    or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.    
   
   
       19 . The compound of formula 1 according to  claim 18 , wherein R 3  is OH, fluorine, chlorine, methoxy, ethoxy, —O—CH 2 —COOH, or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.  
   
   
       20 . The compound of formula 1 according to  claim 19 , wherein R 3  is OH, fluorine, chlorine, methoxy, or ethoxy, or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.  
   
   
       21 . The compound of formula 1 according to  claim 6 , wherein: 
 R 1  is hydrogen, halogen, C 1 -C 4 -alkyl, or —O—C 1 -C 4 -alkyl;    R 2  is hydrogen, halogen, C 1 -C 4 -alkyl, or —O—C 1 -C 4 -alkyl; and    R 3  is hydrogen,    or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.    
   
   
       22 . The compound of formula 1 according to  claim 21 , wherein: 
 R 1  is hydrogen, fluorine, chlorine, methyl or methoxy; and    R 2  is hydrogen, fluorine, chlorine, methyl or methoxy,    or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.    
   
   
       23 . A compound of formula 1 selected from: 
 (1) 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one;    (2) 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyethylacetate)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one;    (3) 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyacetic acid)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one;    (4) 8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (5) 6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one;    (6) 6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropylphenyl)-1,1dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one;    (7) 8-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (8) 8-{2-[2-(4-fluoro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (9) 8-{2-[2-(4-fluoro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (10) 8-{2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (11) 8-{2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (12) 8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (13) 8-{2-[2-(3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (14) 4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methylpropyl}phenoxy)butyric acid;    (15) 8-{2-[2-(3,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (16) 8-{2-[2-(2-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (17) 8-{2-[2-(4-chlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (18) 8-{2-[2-(4-bromophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (19) 8-{2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (20) 8-{2-[2-(4-fluoro-3-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (21) 8-{2-[2-(4-fluoro-2,6-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (22) 8-{2-[2-(4-chloro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (23) 8-{2-[2-(4-chloro-3-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (24) 8-{2-[2-(4-chloro-2-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (25) 8-{2-[2-(3-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (26) 8-{2-[2-(2,6-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (27) 8-{2-[2-(2,5-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (28) 8-{2-[2-(4-fluoro-3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (29) 8-{2-[2-(3,5-dichlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (30) 8-{2-[2-(4-chloro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (31) 8-{2-[2-(3,4,5-trifluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one;    (32) 8-{2-[2-(3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; and    (33) 8-{2-[2-(3,4-dichlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one,    or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof.    
   
   
       24 . A pharmaceutical composition comprising a compound of formula 1 according to one of  claims 6  to  23 , or an acid addition salt thereof with a pharmacologically acceptable acid, or a solvate or hydrate thereof, and a pharmaceutically acceptable excipient or carrier.  
   
   
       25 . The pharmaceutical composition according to  claim 24 , wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution.