Neurotherapeutic azole compounds

• US 7,598,279 B2
• Filed: 04/20/2006
• Issued: 10/06/2009
• Est. Priority Date: 04/22/2005
• Status: Active Grant

• Current Assignee: SK Biopharmaceuticals Co., Ltd. (SK Inc.)
• Original Assignee: SKK Holdings Limited
• Inventors: Lee, Hyun-Seok, Kim, Choon-Gil, Choi, Yong Moon, Yi, Han-Ju, Kang, Young-Sun
• Primary Examiner(s): Shameem; Golam M. M.
• Assistant Examiner(s): CHUNG, SUSANNAH LEE
• Application Number:
  US11/407,526
• Publication Number:
  US 20060258718A1
• Time in Patent Office: 1,265 Days
• Field of Search: 514/259, 514/281, 514/283, 548/250, 548/255, 548/262, 548/2
• US Class Current: 514/359
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 25/34 Tobacco-abuse
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 249/04 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
• CPC Class Codes: C07D 257/04 Five-membered rings
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

Azole compounds containing carbamoyl group and pharmaceutically useful salts thereof are described. The compounds are effective anticonvulsants which are used in the treatment of disorders of the central nervous system, especially as anxiety, depression, convulsion, epilepsy, migraine, bipolar disorder, drug abuse, smoking, ADHD, obesity, sleep disorder, neuropathic pain, stroke, cognitive impairment, neurodegeneration, stroke and muscle spasm.

Claims

1. An azole compound of the formula:

2. The azole of claim 1, wherein said compound has the formula:

3. The azole of claim 1, wherein said compound has the formula:

4. The azole of claim 1, wherein said compound has the formula:

5. The azole of claim 1, wherein said compound has the formula:

6. The azole of claim 1, wherein said compound has the formula:

7. The azole of claim 1, wherein said compound has the formula:

8. The azole of claim 7, wherein one of A₃, A₄ and A₅ are CH and the others are N.

9. The azole of claim 8, wherein R₆ and R₇ are independently hydrogen, halogen or perfluoroalkyl.

10. The azole of claim 9, wherein said compound is carbamic acid 1-(2-chloro-phenyl)-2tetrazol-2-yl-ethyl ester.

11. The azole of claim 10, wherein said compound is carbamic acid (R)-(+)-1-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester substantially free of its (S)enantiomer and said (R)-enantiomer is present to the extent of at least about 95%.

12. The azole of claim 10, wherein said compound is carbamic acid (S)-(−

)-1-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester substantially;

free of its (R)-enantiomer and said (S)-enantiomer is present to the extent of at least about 95%.

13. The azole of claim 9, wherein said compound is methyl-carbamic acid-1-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester.

14. The azole of claim 13, wherein said compound is methyl-carbamic acid (R)-1-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester substantially free of its (S)-enantiomer and said (R)-enantiomer is present to the extent of at least about 95%.

15. The azole of claim 13, wherein said compound is methyl-carbamic acid (S)-1-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester substantially free of its (R)-enantiomer and said (S)-enantiomer is present to the extent of at least about 95%.

16. The azole of claim 9, wherein said compound is carbamic acid -1-(2,4-dichloro-phenyl)2-tetrazol-2-yl-ethyl ester.

17. The azole of claim 16, wherein said compound is carbamic acid (R)-1-(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester substantially free of its (S)-enantiomer and said (R)-enantiomer is present to the extent of at least about 95%.

18. The azole of claim 16, wherein said compound is carbamic acid (S)-1-(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester substantially free of its (R)-enantiomer and said (S)-enantiomer is present to the extent of at least about 95%.

19. The azole of claim 9, wherein said compound is carbamic acid 1-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester.

20. The azole of claim 19, wherein said compound is carbamic acid (R)-1-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester substantially free of its (S)-enantiomer and said (R)-enantiomer is present to the extent of at least about 95%.

21. The azole of claim 19, wherein said compound is carbamic acid (S)-1-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester substantially free of its (R)-enantiomer and said (S)-enantiomer is present to the extent of at least about 95%.

22. The azole of claim 9, wherein said compound is carbamic acid-1-(2,6-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester.

23. The azole of claim 9, wherein said compound is carbamic acid 1-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-propyl ester.

24. The azole of claim 7, wherein one of A₃, A₄ and A₅ is N and the others are CH.

25. The azole of claim 24, wherein R₆ and R₇ are independently hydrogen, halogen or perfluoroalkyl.

26. The azole of claim 25, wherein said compound is carbamic acid-1-(2-chloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester.

27. The azole in accordance with claim 26 wherein said compound is Carbamic acid (R)-1-(2-chloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester substantially free of its (S)-enantiomer and said (R)-enantiomer is present to the extent of at least about 95%.

28. The azole in accordance with claim 26 wherein said compound is Carbamic acid (S)-1-(2-chloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester substantially free of its (R)-enantiomer and said (S)-enantiomer is present to the extent of at least about 95%.

29. The azole of claim 25, wherein said compound is carbamic acid-1-(2,4-dichloro-phenyl)-2-[1,2,3]triazol-1-yl-ethyl ester.

30. The azole in accordance with claim 29 wherein said compound is Carbamic acid (R)-1-(2,4-dichloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester substantially free of its (S)-enantiomer and said (R)-enantiomer is present to the extent of at least about 95%.

31. The azole in accordance with claim 29 wherein said compound is Carbamic acid (S)-1-(2,4-dichloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester substantially free of its (R)-enantiomer and said (S)-enantiomer is present to the extent of at least about 95%.

32. The azole of claim 25, wherein said compound is carbamic acid 1-(3,4-dichloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester.

33. The azole in accordance with claim 32 wherein said compound is Carbamic acid (R)-1-(3,4-dichloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester substantially free of its (S)-enantiomer and said (R)-enantiomer is present to the extent of at least about 95%.

34. The azole in accordance with claim 32 wherein said compound is Carbamic acid (S)-1-(3,4-dichloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester substantially free of its (R)-enantiomer and said (S)-enantiomer is present to the extent of at least about 95%.

35. The azole of claim 1 wherein said compound has the formula:

36. The azole of claim 35, wherein R₆ and R₇ are independently hydrogen, halogen or perfluoroalkyl.

37. The azole of claim 36, wherein said compound is carbamic acid 2-(3,4-dichloro-phenoxy)-1-tetrazol-2-ylmethyl-ethyl ester.

38. The azole of claim 36, wherein said compound is carbamic acid 2-(2-chloro-phenoxy)-1-tetrazol-2-ylmethyl-ethyl ester.

39. The azole of claim 35, wherein one of A₃, A₄ and A₅ is N and the others are CH.

40. The azole of claim 39, wherein R₆ and R₇ are independently hydrogen, halogen or perfluoroalkyl.

41. The azole of claim 40, wherein said compound is carbamic acid 2-(2,4-dichloro-phenoxy)-1-[1,2,3]triazol-2-ylmethyl-ethyl ester.

42. The azole of claim 1, wherein said compound is:

43. The azole of claim 42, wherein one of A₃, A₄ and A₅ are CH and the others are N.

44. The azole of claim 43, wherein R₆ and R₇ are independently hydrogen, halogen or perfluoroalkyl.

45. The azole of claim 44, wherein said compound is 4-(3,4-dichloro-benzyl)-piperidine-1-carboxylic acid 1-(2,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester.

46. The azole of claim 44, wherein said compound is 4-(3,4-dichloro-benzyl)-piperidine-1-carboxylic acid 1-(3,4-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester.

47. The azole of claim 44, wherein said compound is 4-(3,5-bis-trifluoromethyl-benzyl)-piperidine-1-carboxylic acid 1-(2-chloro-phenyl)-2-tetrazol-2-yl-ethyl ester.

48. The azole of claim 44, wherein said compound is 3-phenethyl-pyrrolidine-1-carboxylic acid 1-(2,5-dichloro-phenyl)-2-tetrazol-2-yl-ethyl ester.

49. The azole of claim 42, wherein one of A₃, A₄ and A₅ is N and the others are CH.

50. The azole of claim 49, wherein R₆ and R₇ are independently hydrogen, halogen or perfluoroalkyl.

51. The azole of claim 50, wherein said compound is 4-benzyl-piperidine-1-carboxylic acid-1-(2-chloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester.

52. The azole in accordance with claim 51 wherein said compound is 4-benzyl-piperidine-1-carboxylic acid (R)-1-(2-chloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester substantially free of its (S)-enantiomer and said (R)-enantiomer is present to the extent of at least about 95%.

53. The azole in accordance with claim 51 wherein said compound is 4-benzyl- piperidine-1-carboxylic acid (S)-1-(2-chloro-phenyl)-2-[1,2,3]triazol-2-yl-ethyl ester substantially free of its (R)-enantiomer and said (S)-enantiomer is present to the extent of at least about 95%.

54. The compound of claim 1 having the formula:

55. The compound of claim 54 wherein p is 0 and o is 1.

56. The compound of claim 54 wherein o is 0 and p is 1.

57. The compound of claim 1 wherein said compound has the formula:

58. The compound of claim 57 wherein o is 0 and p equals 1.

59. The compound of claim 57 wherein p is 0 and o is 0.

60. An azole compound of the formula: