Substituted triazolo-pyridazine derivatives

Abstract

This invention relates to novel substituted triazolo-pyridazines, their derivatives, and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by administering an α1-GABA-A receptor antagonist and/or a α2, α3 and α5 GABA-A receptor agonist.

1 . A compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is CH 3 , CDH 2 , CD 2 H, or CD 3 ; 
 R 2  is a t-butyl group having 0-9 deuterium atoms; 
 each Y is independently hydrogen or deuterium; and 
 when R 1  is CH 3  and each Y is hydrogen, then R 2  has 1-9 deuterium. 
 
     
     
         2 . The compound of  claim 1 , wherein R 1  is CH 3  or CD 3 . 
     
     
         3 . The compound of  claim 1 , wherein R 2  is —C(CH 3 ) 3  or —C(CD 3 ) 3 . 
     
     
         4 . The compound of an  claim 1 , wherein Y 1a  and Y 1b  are the same. 
     
     
         5 . The compound of  claim 1 , wherein R 2  is —C(CD 3 ) 3 . 
     
     
         6 . The compound of  claim 1 , selected from any one of the compounds set forth in table below: 
       
         
           
                 
                 
                 
                 
                 
                 
                 
               
                     
                     
                 
                     
                   Compound 
                   R 1   
                   R 2   
                   Y 1a   
                   Y 1b   
                   Y 2   
                 
                     
                     
                 
                     
                   101 
                   CD 3   
                   —C(CH 3 ) 3   
                   D 
                   D 
                   H 
                 
                     
                   102 
                   CH 3   
                   —C(CD 3 ) 3   
                   D 
                   D 
                   H 
                 
                     
                   103 
                   CH 3   
                   —C(CD 3 ) 3   
                   H 
                   H 
                   H 
                 
                     
                   104 
                   CD 3   
                   —C(CD 3 ) 3   
                   H 
                   H 
                   H 
                 
                     
                   105 
                   CD 3   
                   —C(CD 3 ) 3   
                   D 
                   D 
                   H 
                 
                     
                   106 
                   CD 3   
                   —C(CH 3 ) 3   
                   H 
                   H 
                   H 
                 
                     
                   107 
                   CH 3   
                   —C(CH 3 ) 3   
                   D 
                   D 
                   H 
                 
                     
                   108 
                   CD 3   
                   —C(CH 3 ) 3   
                   D 
                   D 
                   D 
                 
                     
                   109 
                   CH 3   
                   —C(CD 3 ) 3   
                   D 
                   D 
                   D 
                 
                     
                   110 
                   CH 3   
                   —C(CD 3 ) 3   
                   H 
                   H 
                   D 
                 
                     
                   111 
                   CD 3   
                   —C(CD 3 ) 3   
                   H 
                   H 
                   D 
                 
                     
                   112 
                   CD 3   
                   —C(CD 3 ) 3   
                   D 
                   D 
                   D 
                 
                     
                   113 
                   CD 3   
                   —C(CH 3 ) 3   
                   H 
                   H 
                   D 
                 
                     
                   114 
                   CH 3   
                   —C(CH 3 ) 3   
                   D 
                   D 
                   D 
                 
                     
                     
                 
             
                
                
                
               
               
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         7 . The compound of  claim 1 , wherein any atom not designated as deuterium in any of the embodiments set forth above is present at its natural isotopic abundance. 
     
     
         8 . A pyrogen-free composition comprising a compound of  claim 1 ; and an acceptable carrier. 
     
     
         9 . The composition of  claim 8  formulated for pharmaceutical administration, wherein the carrier is a pharmaceutically acceptable carrier. 
     
     
         10 . The composition of  claim 9  additionally comprising a second therapeutic agent useful in the treatment or prevention of a disease or condition selected from disorders of the central nervous system, neuropathic pain, inflammatory pain, and migraine-associated pain. 
     
     
         11 . A method of:
 a. inhibiting the α-1 subtype of the GABA-A receptor in a cell; or   b. activating one or more of the α2, α3 and α5 subtypes of the GABA-A receptor in a cell,   
       the method comprising contacting the cell with a compound of  claim 1 . 
     
     
         12 . A method of treating a patient suffering from, or susceptible to, a disease or condition selected from disorders of the central nervous system, neuropathic pain, inflammatory pain, and migraine-associated pain, comprising the step of administering to the patient in need thereof a composition of  claim 9 . 
     
     
         13 . The method of  claim 12 , wherein the patient is suffering from or susceptible to anxiety or convulsions. 
     
     
         14 . The method of  claim 12 , comprising the additional step of co-administering to the patient in need thereof a second therapeutic agent useful in the treatment of disorders of the central nervous system, neuropathic pain, inflammatory pain, or migraine-associated pain.