Substituted triazoles as sodium channel blockers
View Patent ↗Substituted triazole compounds represented by Formula I, II or III, or pharmaceutically acceptable salts thereof. Pharmaceutical compositions comprise an effective amount of the instant compounds, either alone, or in combination with one or more other therapeutically active compounds, and a pharmaceutically acceptable carrier. Methods of treating conditions associated with, or caused by, sodium channel activity, including, for example, acute pain, chronic pain, visceral pain, inflammatory pain, neuropathic pain, migraine, headache pain, migraine headache, epilepsy, irritable bowel syndrome, diabetic neuropathy, multiple sclerosis, manic depression and bipolar disorder, comprise administering an effective amount of the present compounds, either alone, or in combination with one or more other therapeutically active compounds. A method of administering local anesthesia comprises administering an effective amount of a compound of the instant invention, either alone, or in combination with one or more other therapeutically active compounds, and a pharmaceutically acceptable carrier.
1. A compound represented by Formula (I) or (II):
or a pharmaceutically acceptable salt thereof, wherein
R 1 is
(a) H,
(b) C 1 -C 6 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkynyl, any of which is optionally substituted with one or more of the following substituents: NR a R b , COOH, CONR a R b , or
(c) —C(═O)R a , COOR a , CONR a R b ;
R a is:
(a) H,
(b) C 1 -C 6 -alkyl, optionally substituted with one or more of halogen or CF 3 , or
(c) CF 3 ;
R b is
(a) H, or
(b) C 1 -C 6 -alkyl, optionally substituted with one or more of halogen or CF 3 , or
(c) CF 3 ;
R 2 is H or C 1-4 alkyl;
R 3 and R 4 each independently is:
(a) H,
(b) —C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl or —O—C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl,
(c) halogen, or
(d) —C 1 -C 6 alkyl, optionally substituted with one or more of halogen or CF 3 ; and
R 5 , R 6 and R 7 each independently is:
(a) H,
(b) —O—C 1 -C 6 -alkyl, —O—C 1 -C 6 -alkenyl, —O—C 1 -C 6 -alkynyl, any of which is optionally substituted with one or more of halogen or CF 3 ,
(c) —C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl, or —O—C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl,
(d) —O-phenyl, or —O—C 1 -C 4 -alkyl-phenyl, wherein phenyl is optionally substituted with 1-3 substituents selected from i) halogen, ii) —CN, iii) —NO 2 , iv) CF 3 , v) —OR a , vi) —NR a R b , vii) —C 0-4 alkyl-CO—OR a , viii) —(C 0-4 alkyl)-CO—N(R a )(R b ), ix) and x) —C 1-10 alkyl, wherein one or more of the alkyl carbons can be replaced by a —NR a , C(O)—O—, or —N(R a )—C(O)—N(R a )—, or
(e) halogen, —OR a , or phenyl wherein phenyl is optionally substituted with 1-3 substituents selected from i) halogen, ii) —CN, iii) —NO 2 , iv) CF 3 , v) pyrazolyl, vi) —OR a , vii) —NR a R b , viii) —C 0-4 alkyl-CO—OR a , ix) —(C 0-4 alkyl)-CO—N(R a )(R b ), and x) —C 1-10 alkyl, wherein one or more of the alkyl carbons can be replaced by a —NR a , C(O)—O—, or —N(R a )—C(O)—N(R a )—.
2. The compound of claim 1 described by the chemical Formula (I), or a pharmaceutically acceptable salt thereof, wherein
R 5 is other than H and is attached at the ortho position.
3. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 5 is optionally substituted —O—C 1 -C 6 -alkyl.
4. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 5 is optionally substituted phenyl.
5. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 5 is —O—C 1 -C 4 -alkyl-phenyl, wherein phenyl is optionally substituted.
6. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 5 is optionally substituted —O—C 1 -C 6 -alkenyl.
7. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 6 is halogen.
8. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 3 is halogen.
9. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 3 and R 4 are halogen.
10. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 3 , R 4 and R 6 are halogen.
11. The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 3 is —O—C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl.
12. The compound of claim 1 described by the chemical Formula (II), or a pharmaceutically acceptable salt thereof, wherein
R 5 is other than H and is attached at the ortho position.
13. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein
R 5 is optionally substituted —O—C 1 -C 6 -alkyl.
14. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein
R 5 is optionally substituted phenyl.
15. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein
R 5 is —O—C 1 -C 4 -alkyl-phenyl, wherein phenyl is optionally substituted.
16. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein
R 5 is optionally substituted —O—C 1 -C 6 -alkenyl.
17. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein
R 6 is halogen.
18. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein
R 3 is halogen.
19. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein
R 3 and R 4 are halogen.
20. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein
R 3 , R 4 and R 6 are halogen.
21. The compound of claim 12 , or a pharmaceutically acceptable salt thereof, wherein
R 3 is —O—C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl.
22. A compound represented by Formula (III)
or a pharmaceutically acceptable salt thereof, wherein R 1 -R 7 each is as defined in claim 1 .
23. The compound of claim 22 , or a pharmaceutically acceptable salt thereof, wherein
R 5 is other than H and is attached at the ortho position.
24. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein
R 5 is optionally substituted —O—C 1 -C 6 -alkyl.
25. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein
R 5 is optionally substituted phenyl.
26. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein
R 5 is —O—C 1 -C 4 -alkyl-phenyl, wherein phenyl is optionally substituted.
27. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein
R 5 is optionally substituted —O—C 1 -C 6 -alkenyl.
28. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein
R 6 is halogen.
29. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein
R 3 is halogen.
30. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein
R 3 and R 4 are halogen.
31. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein
R 3 , R 4 and R 6 are halogen.
32. The compound of claim 23 , or a pharmaceutically acceptable salt thereof, wherein
R 3 is —O—C 0 -C 4 -alkyl-C 1 -C 4 -perfluoroalkyl.
33. A compound represented by
34. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
35. The pharmaceutical composition according to claim 34 , further comprising a second therapeutic agent selected from the group consisting of: i) opiate agonists, ii) opiate antagonists, iii) calcium channel antagonists, iv) 5HT receptor agonists, v) 5HT receptor antagonists vi) sodium channel antagonists, vii) NMDA receptor agonists, viii) NMDA receptor antagonists, ix) COX-2 selective inhibitors, x) NK1 antagonists, xi) non-steroidal anti-inflammatory drugs , xii) selective serotonin reuptake inhibitors , xiii) selective serotonin and norepinephrine reuptake inhibitors, xiv) tricyclic antidepressant drugs, xv) norepinephrine modulators, xvi) lithium, xvii) valproate, and xviii) neurontin.
36. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 22 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
37. The pharmaceutical composition according to claim 36 , further comprising a second therapeutic agent selected from the group consisting of: i) opiate agonists, ii) opiate antagonists, iii) calcium channel antagonists, iv) 5HT receptor agonists, v) 5HT receptor antagonists vi) sodium channel antagonists, vii) NMDA receptor agonists, viii) NMDA receptor antagonists, ix) COX-2 selective inhibitors, x) NK1 antagonists, xi) non-steroidal anti-inflammatory drugs , xii) selective serotonin reuptake inhibitors , xiii) selective serotonin and norepinephrine reuptake inhibitors, xiv) tricyclic antidepressant drugs, xv) norepinephrine modulators, xvi) lithium, xvii) valproate, and xviii) neurontin.