Preparation of (r,r)-fenoterol and (r,r)-or (r,s)-fenoterol analogues and their use in treating congestive heart failure

Abstract

This disclosure concerns the discovery of (R,R)- and (R,S)-fenoterol analogues which are highly effective at binding β2-adrenergic receptors. Exemplary chemical structures for these analogues are provided. Also provided are pharmaceutical compositions including the disclosed (R,R)-fenoterol and fenoterol analogues, and methods of using such compounds and compositions for the treatment of cardiac disorders such as congestive heart failure and pulmonary disorders such as asthma or chronic obstructive pulmonary disease.

1 . A compound having the formula: 
     
       
         
         
             
             
         
       
       wherein R 1 -R 3  independently are hydrogen, acyl, alkoxy carbonyl or a combination thereof; 
       R 4  is H or lower alkyl; 
       R 5  is lower alkyl, 
     
     
       
         
         
             
             
         
       
       wherein Y 1 , Y 2  and Y 3  independently are hydrogen, lower —OR 6  and —NR 7 R 8 ; 
       wherein X and Y independently are selected from H, —OR 6  and —NR 7 R 8 ; 
       R 6  is H or lower alkyl; 
       R 7  and R 8  independently are hydrogen, lower alkyl, alkoxy carbonyl, acyl or amino carbonyl; and 
       wherein the compound is optically active. 
     
   
   
       2 . The compound of  claim 1 , wherein R 4  is lower alkyl and R 5  is 
     
       
         
         
             
             
         
       
       wherein X is H, —OR 6  or —NR 7 R 8 ; 
       R 6  is lower alkyl; and 
       R 7  and R 8  independently are hydrogen or lower alkyl. 
     
   
   
       3 . The compound of  claim 2 , wherein R 4  is selected from methyl, ethyl, n-propyl, and isopropyl. 
   
   
       4 . The compound of  claim 3 , wherein R 4  is methyl. 
   
   
       5 . The compound of  claim 4 , wherein R 5  has the formula 
     
       
         
         
             
             
         
       
       wherein X is H, —OR 6  or —NR 7 R 8 . 
     
   
   
       6 . The compound of  claim 5 , wherein R 6  is methyl. 
   
   
       7 . The compound of  claim 6 , wherein the compound is a (R,R)-compound. 
   
   
       8 . The compound of  claim 1 , wherein R 5  is one of 
     
       
         
         
             
             
         
       
     
   
   
       9 . The compound of  claim 1  wherein R 5  is 
     
       
         
         
             
             
         
       
     
   
   
       10 . The compound of  claim 1 , wherein R 7  and R 8  are hydrogen. 
   
   
       11 . The compound of  claim 4 , wherein R 5  has the formula 
     
       
         
         
             
             
         
       
     
   
   
       12 . The compound of  claim 11 , wherein R 1 -R 3  are hydrogen. 
   
   
       13 . The compound of  claim 11 , wherein the compound is a (R,R)-compound. 
   
   
       14 . The compound of  claim 1 , wherein the compound is a (R,S)-compound. 
   
   
       15 . A pharmaceutical composition comprising the compound of  claim 1  or  claim 2  and at least one pharmaceutically acceptable carrier. 
   
   
       16 . The pharmaceutical composition of  claim 15 , wherein R 4  is methyl. 
   
   
       17 . The pharmaceutical composition of  claim 16 , wherein R 1 -R 3  are hydrogen. 
   
   
       18 . The pharmaceutical composition of  claim 16 , wherein R 5  has the formula 
     
       
         
         
             
             
         
       
       wherein X is H, —OR 6  or —NR 7 R 8 . 
     
   
   
       19 . The pharmaceutical composition of  claim 18 , wherein R 6  is methyl. 
   
   
       20 . The pharmaceutical composition of  claim 19 , wherein the compound is a (R,R)-compound. 
   
   
       21 . The pharmaceutical composition of  claim 18 , wherein R 7  and R 8  are hydrogen. 
   
   
       22 . The pharmaceutical composition of  claim 17 , wherein R 5  has the formula 
     
       
         
         
             
             
         
       
     
   
   
       23 . The pharmaceutical composition of  claim 22 , wherein the compound is a (R,R)-compound. 
   
   
       24 . A pharmaceutical composition, comprising a compound of  claim 1 , wherein the compound is a (R,S) compound. 
   
   
       25 . A method for treating a pulmonary or cardiovascular disorder in a subject, comprising:
 administering a therapeutically effective amount of the compound of  claim 2  to the subject with the pulmonary or cardiovascular disorder.   
   
   
       26 . The method of  claim 25 , wherein the disorder is a cardiovascular disorder. 
   
   
       27 . The method of  claim 26 , wherein the cardiovascular disorder is congestive heart failure. 
   
   
       28 . The method of  claim 25 , wherein the disorder is a pulmonary disorder. 
   
   
       29 . The method of  claim 28 , wherein the pulmonary disorder is at least one of asthma or chronic pulmonary obstructive disease. 
   
   
       30 . A method for treating a pulmonary or cardiovascular disorder in a subject, comprising:
 administering a therapeutically effective amount of the compound of  claim 11  to the subject with the pulmonary or cardiovascular disorder.   
   
   
       31 . The method of  claim 30 , wherein the disorder is a cardiovascular disorder. 
   
   
       32 . The method of  claim 30 , wherein the cardiovascular disorder is congestive heart failure. 
   
   
       33 . The method of  claim 30 , wherein the disorder is a pulmonary disorder. 
   
   
       34 . The method of  claim 33 , wherein the pulmonary disorder is at least one of asthma or chronic pulmonary obstructive disease. 
   
   
       35 . A method for treating a pulmonary or cardiovascular disorder in a subject, comprising:
 administering a therapeutically effective amount of the compound of  claim 12  to the subject with the pulmonary or cardiovascular disorder.   
   
   
       36 . The method of  claim 36 , wherein the disorder is a cardiovascular disorder. 
   
   
       37 . The method of  claim 36 , wherein the cardiovascular disorder is congestive heart failure. 
   
   
       38 . The method of  claim 35 , wherein the disorder is a pulmonary disorder. 
   
   
       39 . The method of  claim 38 , wherein the pulmonary disorder is at least one of asthma or chronic pulmonary obstructive disease. 
   
   
       40 . A method for treating a pulmonary or cardiovascular disorder in a subject, comprising:
 administering a therapeutically effective amount of the pharmaceutical composition of  claim 15  to the subject with the pulmonary or cardiovascular disorder.   
   
   
       41 . The method of  claim 40 , wherein the disorder is a cardiovascular disorder. 
   
   
       42 . The method of  claim 41 , wherein the cardiovascular disorder is congestive heart failure. 
   
   
       43 . The method of  claim 40 , wherein the disorder is a pulmonary disorder. 
   
   
       44 . The method of  claim 43 , wherein the pulmonary disorder is at least one of asthma or chronic pulmonary obstructive disease. 
   
   
       45 . A method for treating a pulmonary or cardiovascular disorder in a subject, comprising:
 administering a therapeutically effective amount of the pharmaceutical composition of  claim 20  to the subject with the pulmonary or cardiovascular disorder.   
   
   
       46 . The method of  claim 45 , wherein the disorder is a cardiovascular disorder. 
   
   
       47 . The method of  claim 44 , wherein the cardiovascular disorder is congestive heart failure. 
   
   
       48 . The method of  claim 45 , wherein the disorder is a pulmonary disorder. 
   
   
       49 . The method of  claim 48 , wherein the pulmonary disorder is at least one of asthma or chronic pulmonary obstructive disease. 
   
   
       50 . A method for treating a pulmonary or cardiovascular disorder in a subject, comprising:
 administering a therapeutically effective amount of the pharmaceutical composition of  claim 21  to the subject with the pulmonary or cardiovascular disorder.   
   
   
       51 . The method of  claim 50 , wherein the disorder is a cardiovascular disorder. 
   
   
       52 . The method of  claim 51 , wherein the cardiovascular disorder is congestive heart failure. 
   
   
       53 . The method of  claim 50 , wherein the disorder is a pulmonary disorder. 
   
   
       54 . The method of  claim 53 , wherein the pulmonary disorder is at least one of asthma or chronic pulmonary obstructive disease. 
   
   
       55 . A method for treating a cardiovascular disorder in a subject, comprising:
 administering an effective amount of a substantially optically pure (R,R)-fenoterol to the subject with the cardiovascular disorder.   
   
   
       56 . The method of  claim 55 , wherein the cardiovascular disorder is congestive heart failure.