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 - 25 . (canceled) 
     
     
         26 . A pharmaceutical composition comprising a compound of formula  1 A 
       
         
           
           
               
               
           
         
       
       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 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, and a pharmaceutically acceptable excipient or carrier. 
 
     
     
         27 . The pharmaceutical composition according to  claim 26 , wherein
 R 1  is hydrogen, fluorine, chlorine, methyl, or methoxy; and   R 2  is hydrogen, fluorine, chlorine, methyl, or methoxy.   
     
     
         28 . The pharmaceutical composition according to  claim 26 , wherein:
 R 1  is hydrogen or C 1 -C 4 -alkyl; and   R 2  is hydrogen or C 1 -C 4 -alkyl.   
     
     
         29 . The pharmaceutical composition according to  claim 26 , wherein:
 R 1  is hydrogen, methyl, or ethyl; and   R 2  is hydrogen, methyl, or ethyl.   
     
     
         30 . The pharmaceutical composition according to  claim 26 , wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 
     
     
         31 . A pharmaceutical composition comprising a compound of formula  1 B 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1′  is halogen, C 1 -C 4 -alkyl, or —O—C 1 -C 4 -alkyl; 
 R 2′  is halogen, C 1 l -C 4 -alkyl or —O—C 1 -C 4 -alkyl; 
 R 3′  is C 1 -C 4 -alkyl, halogen, or —O—C 1 -C 4 -alkyl, 
 or an acid addition salt thereof with a pharmacologically acceptable acid, and a pharmaceutically acceptable excipient or carrier. 
 
     
     
         32 . The pharmaceutical composition according to  claim 31 , 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.   
     
     
         33 . The pharmaceutical composition according to  claim 31 , wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 
     
     
         34 . A pharmaceutical composition comprising a compound of formula  1 C 
       
         
           
           
               
               
           
         
       
       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 —COO methyl, —O—CH 2 —COOethyl, —O—CH 2 —CH 2 —COO methyl, —O—CH 2 —CH 2 —COO ethyl, —O—CH 2 —CH 2 —CH 2 COO methyl, —O—CH 2 —CH 2 —CH 2 COO ethyl, or an acid addition salt thereof with a pharmacologically acceptable acid, and a pharmaceutically acceptable excipient or carrier. 
 
     
     
         35 . The pharmaceutical composition according to  claim 34 , 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.   
     
     
         36 . The pharmaceutical composition according to  claim 34 , wherein:
 R 1″  and R 2″  are each hydrogen.   
     
     
         37 . The pharmaceutical composition according to  claim 36 , wherein
 R 3″  is OH, fluorine, chlorine, methoxy, ethoxy or —O—CH 2 —COOH.   
     
     
         38 . The pharmaceutical composition according to  claim 37 , wherein:
 R 3″  is OH, fluorine, chlorine, methoxy or ethoxy.   
     
     
         39 . The pharmaceutical composition according to  claim 34 , wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 
     
     
         40 . A pharmaceutical composition comprising a compound selected from the group consisting of: 
       (1)  R -6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxyphenyl)-1,1-dimethylethylamino]ethyl}4H-benzo[1,4]oxazin-3-one; 
       (2)  R -6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyethylacetate)-1,1-dimethylethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one; 
       (3)  R -6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxyacetic acid)-1,1-dimethylethylamino]- ethyl}-4H-benzo[1,4]oxazin-3-one; 
       (4)  R -8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)ethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (5)  R -6-hydroxy-8-{ 1-hydroxy-2-[2-(4-hydroxyphenyl)-1,1-dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one; 
       (6)  R -6-hydroxy-8-{ 1-hydroxy-2-[2-(4-isopropylphenyl)-1,1dimethylethylamino]ethyl}-4H-benzo[1,4]oxazin-3-one; 
       (7)  R -8-{2-[2-(4-ethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (8)  R -8-{2-[2-(4-fluoro-3-methylphenyl)- 1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4] oxazin-3-one; 
       (9)  R -8-{2-[2-(4-fluoro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl} -6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (10)  R -8-{2-[2-(2,4-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (11)  R -8-{2-[2-(3,5-difluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (12)  R -8-{2-[2-(4-ethoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (13)  R -8-{2-[2-(3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (14)  R -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)  R -8-{2-[2-(3,4-difluorophenyl)-1,1 -dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (16)  R -8-{2-[2-(2-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (17)  R -8-{2-[2-(4-chlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (18)  R -8-{2-[2-(4-bromophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (19)  R -8-{2-[2-(4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (20)  R -8-{2-[2-(4-fluoro-3-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (21)  R -8-{2-[2-(4-fluoro-2,6-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (22)  R -8-{2-[2-(4-chloro-2-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (23)  R -8-{2-[2-(4-chloro-3-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (24)  R -8-{2-[2-(4-chloro-2-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (25)  R -8-{2-[2-(3-chloro-4-fluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (26)  R -8-{2-[2-(2,6-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (27)  R -8-{2-[2-(2,5-difluoro-4-methoxyphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (28)  R -8-{2-[2-(4-fluoro-3,5-dimethylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (29)  R -8-{2-[2-(3,5-dichlorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (30)  R -8-{2-[2-(4-chloro-3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (31)  R -8-{2-[2-(3,4,5-trifluorophenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; 
       (32)  R -8-{2-[2-(3-methylphenyl)-1,1-dimethylethylamino]-1-hydroxyethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one; and 
       (33)  R -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, and a pharmaceutically acceptable excipient or carrier. 
     
     
         41 . The pharmaceutical composition according to  claim 40 , wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 
     
     
         42 . A pharmaceutical composition comprising R-6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one and a pharmaceutically acceptable excipient or carrier. 
     
     
         43 . The pharmaceutical composition according to  claim 42  comprising an acid addition salt of R-6-Hydroxy-8- {1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino ]-ethyl}-4H-benzo[1,4]oxazin-3-one with a pharmacologically acceptable acid, and a pharmaceutically acceptable excipient or carrier. 
     
     
         44 . The pharmaceutical composition according to  claim 42 , wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 
     
     
         45 . The pharmaceutical composition according to  claim 43 , wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 
     
     
         46 . A pharmaceutical composition comprising R-8-{2-[2-(2,4-difluorophenyl)-1,1-dimethyl-ethylamino ]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4] oxazin-3-one and a pharmaceutically acceptable excipient or carrier. 
     
     
         47 . The pharmaceutical composition according to  claim 46  comprising an acid addition salt of R-8-{2-[2-(2,4-difluorophenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one with a pharmacologically acceptable acid, and a pharmaceutically acceptable excipient or carrier. 
     
     
         48 . The pharmaceutical composition according to  claim 46 , wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 
     
     
         49 . The pharmaceutical composition according to  claim 47 , wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 
     
     
         50 . A pharmaceutical composition comprising R-8-{2-[2-(3,5-difluorophenyl)-1,1-dimethyl-ethylamino ]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3 -one and a pharmaceutically acceptable excipient or carrier. 
     
     
         51 . The pharmaceutical composition according to  claim 50  comprising an acid addition salt of the compound of R-8-{2-[2-(3,5-difluorophenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one with a pharmacologically acceptable acid, and a pharmaceutically acceptable excipient or carrier. 
     
     
         52 . The pharmaceutical composition according to  claim 50 , wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 
     
     
         53 . The pharmaceutical composition according to  claim 51 , wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 
     
     
         54 . A pharmaceutical composition comprising R-8-{2-[2-(4-Ethoxy-phenyl)-1,1-dimethyl-ethylamino ]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one and a pharmaceutically acceptable excipient or carrier. 
     
     
         55 . The pharmaceutical composition according to  claim 49  comprising an acid addition salt of the compound of R-8-{2-[2-(4-Ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one with a pharmacologically acceptable acid, and a pharmaceutically acceptable excipient or carrier. 
     
     
         56 . The pharmaceutical composition according to  claim 54 , wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 
     
     
         57 . The pharmaceutical composition according to  claim 55 , wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 
     
     
         58 . A pharmaceutical composition comprising R-8-{2-[2-(4-fluorophenyl)-1,1-dimethyl-ethylamino]-1 -hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one and a pharmaceutically acceptable excipient or carrier. 
     
     
         59 . The pharmaceutical composition according to  claim 58  comprising an acid addition salt of R-8-{2-[2-(4-fluorophenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one with a pharmacologically acceptable acid, and a pharmaceutically acceptable excipient or carrier. 
     
     
         60 . The pharmaceutical composition according to  claim 58 , wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution. 
     
     
         61 . The pharmaceutical composition according to  claim 59 , wherein the pharmaceutical composition is an inhalable powder, propellant-containing metered-dose aerosol, or propellant-free inhalable solution.