Benzoimidazol-1,2-yl amides as Kv7 channel activators

Abstract

Optionally substituted benzoimidazol-1,2-yl amides, such as compounds of Formula 1 or Formula 2, can be used to treat disorders associated with a Kv7 potassium channel activator. Compositions, medicaments, and dosage forms related to the treatment are also disclosed herein.

The invention claimed is: 
     
       1. A compound represented by a formula: 
       
         
           
           
               
               
           
         
         wherein: 
         D is cyclobutyl; 
         A is C 1-8  alkyl; 
         X is CF 3 ; 
         Y is H; 
         R 1  is H, Cl, Br, CN, OCH 3 , CF 3 , —CO 2 CH 2 CH 3 , C 1-4  alkyl, or C 1-4  hydroxyalkyl; 
         R 2  is H, F, —CH 2 OH, —CO 2 Me, or —C(CH 3 ) 2 OH; 
         R 3  is H, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br; and 
         R 4  is H, —CH 3 , or —CF 3 . 
       
     
     
       2. A composition comprising a compound of  claim 1 , wherein the composition is pharmaceutically acceptable and further comprises a pharmaceutically acceptable excipient. 
     
     
       3. A method of treating a disease selected from epilepsy, pain, migraine, and tinnitus comprising administering an effective amount of a compound of  claim 1  to a mammal in need thereof. 
     
     
       4. The method of  claim 3 , wherein the pain is selected from neuropathic pain, inflammatory pain, persistent pain, cancer pain and postoperative pain. 
     
     
       5. A compound represented by a formula: 
       
         
           
           
               
               
           
         
         wherein: 
         D is optionally substituted cyclobutyl; 
         A is C 1-8  alkyl; 
         X is CF 3 ; 
         Y is H; 
         R 1  is H, Cl, Br, CN, OCH 3 , CF 3 , —CO 2 CH 2 CH 3 , C 1-4  alkyl, or C 1-4  hydroxyalkyl; 
         R 2  is H, F, —CH 2 OH, —CO 2 Me, or —C(CH 3 ) 2 OH; 
         R 3  is H; and 
         R 4  is H, —CH 3 , or —CF 3 . 
       
     
     
       6. A composition comprising a compound of  claim 5 , wherein the composition is pharmaceutically acceptable and further comprises a pharmaceutically acceptable excipient. 
     
     
       7. A method of treating a disease selected from epilepsy, pain, migraine, and tinnitus comprising administering an effective amount of a compound of  claim 5  to a mammal in need thereof. 
     
     
       8. The method of  claim 7 , wherein the pain is selected from neuropathic pain, inflammatory pain, persistent pain, cancer pain and postoperative pain. 
     
     
       9. A compound represented by a formula: 
       
         
           
           
               
               
           
         
         wherein: 
         D is t-butyl; 
         A is C 1-8  alkyl; 
         X is H; 
         Y is H; 
         R 1  is Cl, Br, CN, OCH 3 , CF 3 , —CO 2 CH 2 CH 3 , C 1-4  alkyl, or C 1-4  hydroxyalkyl; 
         R 2  is H, F, —CH 2 OH, —CO 2 Me, or —C(CH 3 ) 2 OH; 
         R 3  is H, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br; and 
         R 4  is H, —CH 3 , or —CF 3 . 
       
     
     
       10. A composition comprising a compound of  claim 9 , wherein the composition is pharmaceutically acceptable and further comprises a pharmaceutically acceptable excipient. 
     
     
       11. A method of treating a disease selected from epilepsy, pain, migraine, and tinnitus comprising administering an effective amount of a compound of  claim 9  to a mammal in need thereof. 
     
     
       12. The method of  claim 11 , wherein the pain is selected from neuropathic pain, inflammatory pain, persistent pain, cancer pain and postoperative pain. 
     
     
       13. A compound represented by a formula: 
       
         
           
           
               
               
           
         
         wherein: 
         D is t-butyl; 
         A is C 1-8  alkyl; 
         X is CF 3 ; 
         Y is H; 
         R 1  is H, Cl, Br, CN, OCH 3 , CF 3 , —CO 2 CH 2 CH 3 , C 1-4  alkyl, or C 1-4  hydroxyalkyl; 
         R 2  is H, F, —CH 2 OH, —CO 2 Me, or —C(CH 3 ) 2 OH; 
         R 3  is H, F, Cl, Br, I, or a substituent having a molecular weight of 15 Da to 200 Da and consisting of 2 to 5 chemical elements, wherein the chemical elements are independently C, H, O, N, S, F, Cl, or Br; and 
         R 4  is H, —CH 3 , or —CF 3 . 
       
     
     
       14. A composition comprising a compound of  claim 13 , wherein the composition is pharmaceutically acceptable and further comprises a pharmaceutically acceptable excipient. 
     
     
       15. A method of treating a disease selected from epilepsy, pain, migraine, and tinnitus comprising administering an effective amount of a compound of  claim 13  to a mammal in need thereof. 
     
     
       16. The method of  claim 15 , wherein the pain is selected from neuropathic pain, inflammatory pain, persistent pain, cancer pain and postoperative pain.