Treating neurological disorders using selective antagonists of persistent sodium current

1. A method of treating an epileptic condition in a mammal, comprising administering to said mammal an effective amount of a selective persistent sodium channel antagonist, wherein said antagonist has at least 20-fold selectivity for a persistent sodium current relative to a transient sodium current, and wherein said antagonist is a compound included in formula 3, or a pharmaceutically acceptable salt, ester, amide, stereoisomer or racemic mixture thereof:

wherein,

Ar 7 is phenyl or a substituted phenyl;

X is O;

R 17 and R 18 are independently selected from the group consisting of hydrogen, hydroxy, and a C 1 to C 8 alkyl;

R 19 and R 20 are independently selected from the group consisting of hydrogen, hydroxy, and a C 1 to C 8 alkyl;

R 21 is selected from the group consisting of hydrogen, hydroxy, and a C 1 to C 8 alkyl;

R is

a is 0 or 1; and

m is 0, 1, 2, or 3.

2. The method of claim 1 , wherein said persistent sodium current is Na v 1.1 persistent current.

3. The method of claim 1 , wherein said persistent sodium current is Na v 1.2 persistent current.

4. The method of claim 1 , wherein said persistent sodium current is Na v 1.3 persistent current.

5. The method of claim 1 , wherein said persistent sodium current is Na v 1.5 persistent current.

6. The method of claim 1 , wherein said persistent sodium current is Na v 1.6 persistent current.

7. The method of claim 1 , wherein said persistent sodium current is Na v 1.7 persistent current.

8. The method of claim 1 , wherein said persistent sodium current is Na v 1.8 persistent current.

9. The method of claim 1 , wherein said persistent sodium current is Na v 1.9 persistent current.

10. The method of claim 1 , wherein said mammal is a human.

11. The method of claim 1 , wherein said antagonist has at least 50-fold selectivity for said persistent sodium current relative to said transient sodium current.

12. The method of claim 1 , wherein said antagonist has at least 200-fold selectivity for said persistent sodium current relative to said transient sodium current.

13. The method of claim 1 , wherein said antagonist has at least 400-fold selectivity for said persistent sodium current relative to said transient sodium current.

14. The method of claim 1 , wherein said antagonist has at least 600-fold selectivity for said persistent sodium current relative to said transient sodium current.

15. The method of claim 1 , wherein said antagonist has at least 1000-fold selectivity for said persistent sodium current relative to said transient sodium current.

16. The method of claim 1 , wherein said antagonist is administered peripherally.

17. The method of claim 1 , wherein said antagonist is administered systemically.

18. The method of claim 1 , wherein said antagonist is administered orally.

19. The method of claim 1 , wherein said antagonist is administered in a sustained release formula.

20. The method of claim 1 , wherein said antagonist is administered in a bioerodible delivery system.

21. The method of claim 1 , wherein said antagonist is administered in a non-bioerodible delivery system.

22. The method of claim 1 , wherein said Ar 7 is phenyl.

23. The method of claim 1 , wherein said Ar 7 is a substituted phenyl.

24. The method of claim 23 , wherein said substituted phenyl is substituted with one or more of halogen, a C 1 to C 8 alkyl, NO 2 , CF 3 , OCF 3 , OCF 2 H, CN, or (CR 5 R 6 ) c N(R 7 ) 2 , wherein,

R 5 and R 6 are independently selected from the group consisting of hydrogen, hydroxy, fluoro, and a C 1 to C 8 alkyl;

R 7 is selected from the group consisting of hydrogen, and a C 1 to C 8 alkyl; and

c is 0, 1, 2, 3, 4, or 5.

25. The method of claim 1 , wherein said R 17 is hydrogen, methyl, ethyl, propyl, or isopropyl.

26. The method of claim 1 , wherein said R 18 is hydrogen, methyl, ethyl, propyl, or isopropyl.

27. The method of claim 1 , wherein said R 19 is hydrogen, methyl, ethyl, propyl, or isopropyl.

28. The method of claim 1 , wherein said R 20 is hydrogen, methyl, ethyl, propyl, or isopropyl.

29. The method of claim 1 , wherein said R 21 is hydrogen, methyl, ethyl, propyl, or isopropyl.

30. The method of claim 1 , wherein said R 22 is hydrogen, methyl, ethyl, propyl, or isopropyl.

31. The method of claim 1 , wherein said R 23 is hydrogen, methyl, ethyl, propyl, or isopropyl.

32. The method of claim 23 , wherein said antagonist is 6-Isopropyl-3-methyl-2-{4-[(4-propoxy-benzylidene)-amino]-benzylidene}-cyclohexanone.

33. The method of claim 23 , wherein said antagonist is

34. The method of claim 1 , wherein said epileptic condition is a partial-onset seizure.

35. The method of claim 34 , wherein said partial-onset seizure is selected from the group consisting of a simple partial seizure, a complex partial seizure and a secondarily generalized tonic-clonic seizure.

36. The method of claim 1 , wherein said epileptic condition is a generalized-onset seizure.

37. The method of claim 36 , wherein said generalized-onset seizure is selected from the group consisting of an absence seizure, a tonic seizure, a clonic seizure, a myoclonic seizure, a primary generalized tonic-clonic seizure, and an atonic seizure.

38. The method of claim 1 , wherein said epileptic condition is an unclassified seizure.

39. The method of claim 1 , wherein said epileptic condition is a localization-related syndrome.

40. The method of claim 1 , wherein said epileptic condition is a generalized-onset syndrome.

41. The method of claim 1 , wherein said epileptic condition is an inherited epileptic condition.

42. The method of claim 41 , wherein said inherited epileptic condition is selected from the group consisting of an idiopathic epilepsy, a Severe Myoclonic Epilepsy in Infancy (SMEI), a Borderline SMEI (SMEB), and a Generalized Epilepsy with Febrile Seizures Plus (GEFS+).

43. The method of claim 1 , wherein said effective amount reduces the symptoms of an epileptic condition by at least 30%.

44. The method of claim 1 , wherein said effective amount reduces the symptoms of an epileptic condition by at least 50%.

45. The method of claim 1 , wherein said effective amount reduces the symptoms of an epileptic condition by at least 70%.

46. The method of claim 1 , wherein said effective amount reduces the symptoms of an epileptic condition by at least 90%.