Diamide Compounds Having Muscarinic Receptor Antagonist and Beta2 Adrenergic Receptor Agonist Activity

Abstract

or a pharmaceutically acceptable salt thereof, wherein the pulmonary disorder is asthma or chronic obstructive pulmonary disorder.

1 . A method of treating a pulmonary disorder in a patient, comprising administering a pharmaceutical composition comprising an isotonic aqueous solution comprising a compound of formula I: 
       
         
           
           
               
               
           
         
         wherein 
         Y is a group of formula (a):
   Ar 1  n CH 2  p XCH 2  q    (a)
 
 
         and Y is attached at the 3- or 4-position of the phenylene ring relative to the —CH 2 —(CR 5 R 6 ) e — group; 
         X is selected from —C(O)NH— and —NHC(O)—; 
         Ar 1  is selected from phen-1,3-ylene and phen-1,4-ylene, wherein the phenylene group is unsubstituted or substituted with 1 to 3 substituents selected independently from C 1-3  alkyl, —O—(C 1-3  alkyl) and halo; 
         each R 1  is selected independently from C 1-3  alkyl, —O—(C 1-3  alkyl), hydroxyl and halo; 
         each R 2  is selected independently from C 1-3  alkyl, —O—(C 1-3  alkyl) and halo; 
         each R 3  is selected independently from C 1-3  alkyl; or two R 3  groups are joined to form C 1-3  alkylene, C 2-3  alkenylene or oxiran-2,3-diyl; 
         each R 4  is selected independently from C 1-3  alkyl, —O—(C 1-3  alkyl) and halo; 
         R 5  is selected from hydrogen, methyl and ethyl; 
         R 6  is selected from hydrogen, methyl and ethyl; 
         a is 0, 1, 2 or 3; 
         b is 0, 1, 2 or 3; 
         c is 0, 1, 2, 3 or 4; 
         d is 0, 1, 2 or 3; 
         e is 0 or 1; 
         n is 0 or 1; 
         p is 0, 1, 2, 3, 4, 5 or 6; provided that when n is 0, p is 1, 2, 3, 4, 5 or 6; 
         q is 0, 1, 2, 3, 4, 5 or 6; 
         or a pharmaceutically acceptable salt thereof, 
         wherein the pulmonary disorder is asthma or chronic obstructive pulmonary disorder. 
       
     
     
         2 . The method of  claim 1 , wherein Y is —(CH 2 ) p —X—. 
     
     
         3 . The method of  claim 1 , wherein Y is —(CH 2 ) p —X—(CH 2 ) q —. 
     
     
         4 . The method of  claim 1 , wherein Y is —Ar 1 —(CH 2 ) p —X—(CH 2 ) q —. 
     
     
         5 . The method of  claim 1 , wherein Y is —Ar 1 —X—. 
     
     
         6 . The method of  claim 1 , wherein R 5  is hydrogen or methyl; and R 6  is hydrogen. 
     
     
         7 . The method of  claim 1 , wherein R a  is methyl. 
     
     
         8 . The method of  claim 1 , wherein each R 4  is independently selected from methyl, methoxy, chloro and fluoro. 
     
     
         9 . The method of  claim 1 , wherein a, b and c are 0. 
     
     
         10 . The method of  claim 1 , wherein the compound has formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         11 . The method of  claim 10 , wherein each R 4  is selected independently from methyl, methoxy, chloro and fluoro;
 R a  is methyl;   d is 0, 1 or 2; and   p is 3 or 4.   
     
     
         12 . The method of  claim 10 , wherein each R 4  is selected independently from methyl, methoxy, chloro and fluoro;
 R a  is methyl;   d is 0, 1 or 2; and   p is 4.   
     
     
         13 . The method of  claim 1 , wherein the compound has formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         14 . The method of  claim 13 , wherein
 R 5  is methyl;   R a  is methyl;   p is 3 or 4; and   q is 1.   
     
     
         15 . The method of  claim 1 , wherein the compound has formula IV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         16 . The method of  claim 15 , wherein
 R 4  is selected from methyl, methoxy, and fluoro;   R 5  is hydrogen or methyl;   R a  is methyl;   d is 0 or 1;   p is 1; and   q is 1 or 2.   
     
     
         17 . The method of  claim 1 , wherein the compound has formula V: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         18 . The method of  claim 17 , wherein each R 4  is selected independently from methyl, methoxy, chloro and fluoro;
 R 5  is hydrogen or methyl;   R a  is methyl; and   d is 0, 1 or 2.   
     
     
         19 . The method of  claim 1 , wherein the compound is biphenyl-2-ylcarbamic acid 1-[2-({3-[2-(3-{(S)-2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]propyl}phenyl)acetylamino]-propyl}methylcarbamoyl)-ethyl]piperidin-4-yl ester or a pharmaceutically acceptable salt thereof. 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein the compound is biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-{[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]methyl}-2,5-dimethylphenylcarbamoyl)butyl]methylcarbamoyl}ethyl)-piperidin-4-yl ester or a pharmaceutically acceptable salt thereof. 
     
     
         22 . The method of  claim 1 , wherein the compound is biphenyl-2-ylcarbamic acid 1-(2-{[3-(4-{2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]ethyl}phenylcarbamoyl)phenyl]methylcarbamoyl}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The method of  claim 1 , wherein the compound is biphenyl-2-ylcarbamic acid 1-{2-[(4-{[2-(3-{(R)-2-[(R)-2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethylamino]propyl}phenyl)ethylcarbamoyl]methyl}phenyl)-methylcarbamoyl]ethyl}piperidin-4-yl ester or a pharmaceutically acceptable salt thereof. 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 1 , wherein the composition comprises a further therapeutic agent. 
     
     
         26 . The pharmaceutical composition of  claim 1 , wherein the therapeutic agent is a steroidal anti-inflammatory agent or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         27 . The pharmaceutical composition of  claim 1 , wherein the steroidal anti-inflammatory agent is a corticosteroid or a pharmaceutically acceptable salt or solvate thereof. 
     
     
         28 - 35 . (canceled)