3-(ethoxydifluoromethyl)-6-(5-fluoro-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)-[1,2,4]triazolo[4,3-a]pyridine as an ion channel modulator
The present invention is directed to 3-(ethoxydifluoromethyl)-6-(5-fluoro-6-(2,2,2-trofluoroethoxy)pyridine-3-yl)-[1,2,4]triazolo[4,3-a]pyridine, or a pharmaceutically acceptable salt thereof, or a composition thereof, which is useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including neurological disorders (e.g., Dravet syndrome, epilepsy), pain, and neuromuscular disorders are also provided herein.
1. A method for modulating sodium ion channel activity in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of the compound:
or a pharmaceutically acceptable salt thereof.
2. The method of claim 1 , wherein the subject has a condition relating to aberrant function of a sodium channel selected from the group consisting of a neurological disorder and a psychiatric disorder.
3. The method of claim 2 , wherein the neurological disorder or psychiatric disorder is selected from the group consisting of epilepsy, an epilepsy syndrome, and Rasmussen encephalitis.
4. The method of claim 3 , wherein the epilepsy is autosomal dominant nocturnal frontal lobe epilepsy or sudden unexpected death in epilepsy (SUDEP).
5. The method of claim 3 , wherein the epilepsy is genetic epilepsy or pediatric epilepsy.
6. The method of claim 5 , wherein the pediatric epilepsy is selected from the group consisting of a benign familial neonatal-infantile seizure, cryptogenic pediatric partial epilepsy with a SCN3A mutation, generalized epilepsy with a febrile seizure, intractable childhood epilepsy with a generalized tonic-clonic seizure, and a malignant migrating partial seizure of infancy.
7. The method of claim 3 , wherein the epilepsy is focal epilepsy.
8. The method of claim 7 , wherein the focal epilepsy is focal epilepsy with a SCN3A mutation.
9. The method of claim 3 , wherein the epilepsy syndrome is a genetic epilepsy syndrome or a pediatric epilepsy syndrome.
10. The method of claim 3 , wherein the epilepsy syndrome is an epileptic encephalopathy.
11. The method of claim 10 , wherein the epileptic encephalopathy is selected from the group consisting of an epileptic encephalopathy with a SCN1A mutation, an epileptic encephalopathy with a SCN2A mutation, an epileptic encephalopathy with a SCN8A mutation, early infantile epileptic encephalopathy, KCNQ2 epileptic encephalopathy, KCNT1 epileptic encephalopathy, SCN2A epileptic encephalopathy, and SCN8A epileptic encephalopathy.
12. The method of claim 10 , wherein the epileptic encephalopathy is selected from the group consisting of Dravet syndrome, an infantile spasm, and Lennox-Gastaut syndrome.
13. The method of claim 12 , wherein the epileptic encephalopathy is Dravet syndrome.
14. The method of claim 13 , wherein the Dravet syndrome is Dravet syndrome with a SCN1A mutation.
15. The method of claim 1 , wherein the subject is a human.
16. A method for modulating sodium ion channel activity in a subject in need thereof, wherein the method comprises administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound:
or a pharmaceutically acceptable salt thereof.
17. The method of claim 16 , wherein the subject has a condition relating to aberrant function of a sodium channel selected from the group consisting of a neurological disorder and a psychiatric disorder.
18. The method of claim 17 , wherein the neurological disorder or psychiatric disorder is selected from the group consisting of epilepsy, an epilepsy syndrome, and Rasmussen encephalitis.
19. The method of claim 18 , wherein the epilepsy is autosomal dominant nocturnal frontal lobe epilepsy or sudden unexpected death in epilepsy (SUDEP).
20. The method of claim 18 , wherein the epilepsy is genetic epilepsy or pediatric epilepsy.
21. The method of claim 20 , wherein the pediatric epilepsy is selected from the group consisting of a benign familial neonatal-infantile seizure, cryptogenic pediatric partial epilepsy with a SCN3A mutation, generalized epilepsy with a febrile seizure, intractable childhood epilepsy with a generalized tonic-clonic seizure, and a malignant migrating partial seizure of infancy.
22. The method of claim 18 , wherein the epilepsy is focal epilepsy.
23. The method of claim 22 , wherein the focal epilepsy is focal epilepsy with a SCN3A mutation.
24. The method of claim 18 , wherein the epilepsy syndrome is a genetic epilepsy syndrome or a pediatric epilepsy syndrome.
25. The method of claim 18 , wherein the epilepsy syndrome is an epileptic encephalopathy.
26. The method of claim 25 , wherein the epileptic encephalopathy is selected from the group consisting of an epileptic encephalopathy with a SCN1A mutation, an epileptic encephalopathy with a SCN2A mutation, an epileptic encephalopathy with a SCN8A mutation, early infantile epileptic encephalopathy, KCNQ2 epileptic encephalopathy, KCNT1 epileptic encephalopathy, SCN2A epileptic encephalopathy, and SCN8A epileptic encephalopathy.
27. The method of claim 25 , wherein the epileptic encephalopathy is selected from the group consisting of Dravet syndrome, an infantile spasm, and Lennox-Gastaut syndrome.
28. The method of claim 27 , wherein the epileptic encephalopathy is Dravet syndrome.
29. The method of claim 28 , wherein the Dravet syndrome is Dravet syndrome with a SCN1A mutation.
30. The method of claim 16 , wherein the subject is a human.