Allosteric modulators of the mu opioid receptor

Abstract

Disclosed herein are compounds, of the class of amine-bearing heterocycles, which act as positive allosteric modulators and silent allosteric modulators of the mu opioid receptor. These compounds are useful for the treatment of pain, drug addiction, and other CNS derived maladies that are controlled directly or indirectly by activation of the mu opioid receptor. Methods for making and using the allosteric modulators disclosed herein are also provided.

1 . A method for making a pharmaceutical composition, the method comprising combining:
 (a) a compound selected from the group consisting of   
       
         
           
           
               
               
           
         
         wherein
 A9 is CH or N and A10 is C or N, 
 R38 is Br, Cl, CF 3  or OCF 3 , 
 R39 is H, Cl or F, 
 R40 is H or F, 
 R41 is H or D (deuterium), 
 R42 is H or F, 
 R43 is H or F when A10 is C, and 
 R43 is null when A10 is N; 
 
       
       
         
           
           
               
               
           
         
         wherein:
 A11 is CH or N, 
 R44 is Cl, Br, F or CF 3 , 
 R45 is H, Cl, F or OCF 3 , 
 R46 is H or F, 
 R47 is H or D (deuterium), 
 R48 is H or F, and 
 R49 is H, ═CH or F; and 
 
       
       
         
           
           
               
               
           
         
         wherein:
 A12 is CH or N, 
 A13 is CH 2  or null, 
 R50 is Cl, Br or CF 3 , 
 R51 is H, F or Cl, 
 R52 is H or F, 
 R53 is H, F or CH 3 , 
 R54 is H or D, 
 R55 is H or F, 
 R56 is H or Cl, 
 R57 is H or Cl, and 
 if A13 is null, R53 is F; and 
 
         (b) a pharmaceutically acceptable carrier or excipient. 
       
     
     
         2 . The method of  claim 1 , wherein the pharmaceutical composition is for treatment of a condition selected from the group consisting of substance abuse, acute pain, chronic pain, inflammatory pain, neuropathic pain, chemotherapy-induced neuropathy, sexual dysfunction, abdominal constriction, inhibited gut transit, constipation, respiratory depression and allodynia. 
     
     
         3 . The method of  claim 1 , wherein the structure is Formula 3 and
 A11 is CH;   R44 is CF 3 ;   R45 is H;   R46 is H;   R47 is H;   R48 is H; and   R49 is H.   
     
     
         4 . The method of  claim 1  further comprising the step of administering the pharmaceutical composition to a subject. 
     
     
         5 . The method of  claim 4 , wherein the subject is a human. 
     
     
         6 . The method of  claim 5 , wherein administration results in positive allosteric modulation of the mu opioid receptor. 
     
     
         7 . The method of  claim 5 , wherein administration results in selective modulation of the activity of the mu opioid receptor, compared to the delta opioid receptor, the kappa opioid receptor, or the ORL1 receptor. 
     
     
         8 . The method of  claim 5 , wherein the composition potentiates the effect of an endogenous opioid. 
     
     
         9 . The method of  claim 8 , wherein the endogenous opioid is endomorphin-1 or endomorphin-2. 
     
     
         10 . The method of  claim 5 , further comprising administering an orthosteric ligand of the mu opioid receptor to the subject. 
     
     
         11 . The method of  claim 10 , wherein the orthosteric ligand of the mu opioid receptor is a synthetic opioid. 
     
     
         12 . The method of  claim 11 , wherein the synthetic opioid is selected from the group consisting of fentanyl, morphine, oxycodone, oxycontin, hydrocodone and codeine. 
     
     
         13 . The method of  claim 12 , wherein a sub-therapeutic dose of the synthetic opioid is administered. 
     
     
         14 . A method for reducing the side effects of an opioid on a subject, the method comprising co-administering, to the subject:
 (a) a sub-therapeutic dose of the opioid; and   (b) a compound selected from the group consisting of:   
       
         
           
           
               
               
           
         
         wherein
 A9 is CH or N and A10 is C or N, 
 R38 is Br, Cl, CF 3  or OCF 3 , 
 R39 is H, Cl or F, 
 R40 is H or F, 
 R41 is H or D (deuterium), 
 R42 is H or F, 
 R43 is H or F when A10 is C, and 
 R43 is null when A10 is N; 
 
       
       
         
           
           
               
               
           
         
         wherein:
 A11 is CH or N, 
 R44 is Cl, Br, F or CF 3 , 
 R45 is H, Cl, F or OCF 3 , 
 R46 is H or F, 
 R47 is H or D (deuterium), 
 R48 is H or F, and 
 R49 is H, ═CH or F; and 
 
       
       
         
           
           
               
               
           
         
         wherein:
 A12 is CH or N, 
 A13 is CH 2  or null, 
 R50 is Cl, Br or CF 3 , 
 R51 is H, F or Cl, 
 R52 is H or F, 
 R53 is H, F or CH 3 , 
 R54 is H or D, 
 R55 is H or F, 
 R56 is H or Cl, 
 R57 is H or Cl, and 
 if A13 is null, R53 is F. 
 
       
     
     
         15 . The method of  claim 14 , wherein the structure is Formula 3 and
 A11 is CH;   R44 is CF 3 ;   R45 is H;   R46 is H;   R47 is H;   R48 is H; and   R49 is H.