Diaryl and arylheteroaryl urea derivatives as modulators of the 5-HT2A serotonin receptor useful for the prophylaxis and treatment of REM sleep behavior disorder

• US 10,022,355 B2
• Filed: 06/10/2016
• Issued: 07/17/2018
• Est. Priority Date: 06/12/2015
• Status: Active Grant

• Current Assignee: Axovant Sciences Ltd.
• Original Assignee: Axovant Sciences Ltd.
• Inventors: Friedhoff, Lawrence Tim, Ramaswamy, Shankar, Wen, Yandong
• Primary Examiner(s): CHU, YONG LIANG
• Application Number:
  US15/179,926
• Publication Number:
  US 20160361296A1
• Time in Patent Office: 767 Days
• Field of Search: None
• CPC Class Codes: A61K 31/135 having aromatic rings , e.g. ketamine, nortriptyline methadone A61K31/137
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/27 of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
• CPC Class Codes: A61K 31/4045 Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/445 Non condensed piperidines, e.g. piperocaine
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/5513 1,4-Benzodiazepines, e.g. diazepam or clozapine
• CPC Class Codes: A61K 31/554 having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system

Abstract

The present invention relates to certain pyrazole derivatives of Formula (I) and pharmaceutical compositions thereof that modulate the activity of the 5-HT_2A serotonin receptor and their uses for the treatment of REM sleep behavior disorder.

Claims

1. A method for the prophylaxis and/or treatment of REM sleep behavior disorder, idiopathic REM sleep behavior disorder, or a combination thereof, in a subject in need thereof comprising administering to said subject a therapeutically effective amount of a 5-HT_2A inverse agonist.

2. The method of claim 1, wherein the 5-HT_2A inverse agonist is selected from nelotanserin, pimavanserin, pruvanserin, eplivanserin, volinanserin, glemanserin, ketanserin, ritanserin, clozapine, or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

3. The method of claim 2, wherein the 5-HT_2A inverse agonist is nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

4. The method of claim 3, wherein the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is from 10 mg to about 160 mg.

5. The method of claim 3, wherein the therapeutically effective amount of nelotanserin or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof is about 10 mg, 20 mg, about 40 mg, 80 mg, or about 160 mg.

6. The method of claim 3, wherein the therapeutically effective amount of nelotanserin is about 10 mg, 20 mg, about 40 mg, 80 mg, or about 160 mg.

7. The method of claim 3, wherein the therapeutically effective amount of nelotanserin is about 10 mg.

8. The method of claim 3, wherein the therapeutically effective amount of nelotanserin is about 20 mg.

9. The method of claim 3, wherein the therapeutically effective amount of nelotanserin is about 40 mg.

10. The method of claim 3, wherein the therapeutically effective amount of nelotanserin is about 80 mg.

11. The method of claim 3, wherein the therapeutically effective amount of nelotanserin is about 160 mg.

12. The method of claim 1, wherein the therapeutically effective amount of the 5-HT_2A inverse agonist is administered once a day, twice a day, three times a day, or four times a day.

13. The method of claim 1, wherein the 5-HT_2A inverse agonist is configured for immediate release, for extended release, for delayed release, or any combination thereof.

14. The method of claim 1, wherein the 5-HT_2A inverse agonist is in a pharmaceutical composition, and wherein the pharmaceutical composition is formulated for oral administration.

15. The method of claim 1, wherein the therapeutically effective amount of the 5-HT_2A inverse agonist is administered about once daily in the morning, twice daily or once daily about 1 hour prior to the subject'"'"'s bedtime.

16. The method of claim 1, wherein the subject is a human.

17. The method of claim 16, wherein the human is an adult with a diagnosis of a condition selected from Lewy Body dementia, probable Dementia with Lewy Bodies, Dementia with Lewy Bodies, Parkinson'"'"'s disease dementia, Parkinson'"'"'s disease, multiple system atrophy, Alzheimer'"'"'s disease, vascular dementia, dementia, mild cognitive impairment, Parkinson'"'"'s disease psychosis, Alzheimer'"'"'s disease psychosis, a sleep disturbance, insomnia and any combination thereof.

18. The method of claim 16, wherein the human has a concurrent diagnosis of REM Sleep Behavior disorder, idiopathic REM Sleep Behavior disorder, or a combination thereof, and a condition selected from Lewy Body dementia, probable Dementia with Lewy Bodies, Dementia with Lewy Bodies, Parkinson'"'"'s disease dementia, Parkinson'"'"'s disease, multiple system atrophy, Alzheimer'"'"'s disease, vascular dementia, dementia, mild cognitive impairment, Parkinson'"'"'s disease psychosis, Alzheimer'"'"'s disease psychosis, a sleep disturbance, insomnia and a combination thereof.

19. The method of claim 16, wherein the human has a Mini Mental State Examination score of greater than, or equal to, about 18.

20. The method of claim 16, wherein the human is an adult with a diagnosis of REM sleep behavior disorder associated with Dementia with Lewy Bodies.

21. The method of claim 16, wherein the human is an adult aged 50-85 inclusive.

22. The method of claim 16, wherein the human has experienced frequent episodes of REM sleep behavior disorder.

23. The method of claim 16, wherein the human has experienced episodes of REM sleep behavior disorder.

24. The method of claim 16, wherein the human has experienced episodes of REM sleep behavior disorder on at least three to four days in a week.

25. The method of claim 1, wherein the subject is concurrently receiving a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of melatonin, quetiapine, clonazepam, levodopa, carbidopa, an antiparkinsonian drug, an acetylcholinesterase inhibitor, NMDA receptor antagonist, and a combination thereof.

26. The method of claim 25, wherein the antiparkinsonian drug is selected from an MAO-B inhibitor, a COMT inhibitor, a dopamine agonist or any combination thereof.

27. The method of claim 25, wherein the acetylcholinesterase inhibitor is selected from the group consisting of donepezil, rivastigmine, galantamine, and pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof.

28. The method of claim 25, wherein the acetylcholinesterase inhibitor is donepezil or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

29. The method of claim 25, wherein the acetylcholinesterase inhibitor is rivastigmine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

30. The method of claim 25, wherein the acetylcholinesterase inhibitor is galantamine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

31. The method of claim 25, wherein NMDA receptor antagonist is selected from the group consisting of memantine, amantadine, ketamine, and pharmaceutically acceptable salts, hydrates, polymorphs, or solvates thereof.

32. The method of claim 31, wherein the NMDA receptor antagonist is memantine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

33. The method of claim 25, wherein the NMDA receptor antagonist is amantadine or a pharmaceutically acceptable salt, hydrate, polymorph, or solvate thereof.

34. The method of claim 1, wherein administration of a therapeutically effective amount of a 5-HT_2A inverse agonist results in treatment, and/or prophylaxis of REM sleep behavior disorder, idiopathic REM sleep behavior disorder, or a combination thereof.

35. The method of claim 1, wherein treating or prophylaxis results in a decrease in the frequency, severity, or a combination thereof of REM sleep behavior disorder episodes.

36. The method of claim 1, wherein treating or prophylaxis results in a decrease in the frequency of abnormal vocalizations and motor behavior per sleep period.

37. The method of claim 1, wherein treatment results in a decrease in the amount of nightmare content per sleep period.

38. The method of claim 1, wherein treating or prophylaxis results in a decrease in the potential for injury or injury to said subject during a sleep period.

39. The method of claim 1, wherein treating or prophylaxis results in an increase in quality of partner sleep.

40. The method of claim 1, wherein treating or prophylaxis results in an improvement in subjective sleep quality, objective sleep measures, or a combination thereof.

41. The method of claim 1, wherein treating or prophylaxis results in an improvement in the clinician assessment of global change pertaining to REM sleep behavior disorder.

42. The method of claim 1, wherein treating or prophylaxis results in a decrease in the frequency of REM sleep behavior disorder behaviors.

43. The method of claim 42, wherein REM sleep behavior disorder behaviors are selected from the group consisting of vocalizations, simple and complex motor behaviors, and any combination thereof.

44. The method of claim 1, wherein treating or prophylaxis results in a decrease in the severity of REM sleep behavior disorder behaviors.

45. The method of claim 1, wherein treating or prophylaxis results in a decrease in the number of nights with injurious behaviors to subject or bed partner per week.

46. The method of claim 45, wherein injurious behaviors are selected from a group consisting of vocalizations, simple and complex motor behaviors, and any combination thereof.

47. The method of claim 1, wherein treating or prophylaxis results in a decrease in the number of nightmares per week.

48. The method of claim 1, wherein treating or prophylaxis results in an improvement in the subject'"'"'s Mini-Mental State Examination score.

63. The method of claim 16, wherein the human is an adult with a diagnosis of REM sleep behavior disorder associated with Dementia with Lewy Bodies.

49. A method for the prophylaxis and/or treatment of REM sleep behavior disorder, idiopathic REM sleep behavior disorder, or a combination thereof, in a subject in need thereof comprising administering to said subject a daily dose of about 40 mg of nelotanserin.

50. The method of claim 49, wherein the daily dose of about 40 mg of nelotanserin is administered once a day, twice a day, three times a day or four times a day.

51. The method of claim 49, wherein the subject has a concurrent diagnosis of REM Sleep Behavior disorder, idiopathic REM Sleep Behavior disorder, or a combination thereof, and a condition selected from Lewy Body dementia, probable Dementia with Lewy Bodies, Dementia with Lewy Bodies, Parkinson'"'"'s disease dementia, Parkinson'"'"'s disease, multiple system atrophy, Alzheimer'"'"'s disease, vascular dementia, dementia, mild cognitive impairment, Parkinson'"'"'s disease psychosis, Alzheimer'"'"'s disease psychosis, a sleep disturbance, insomnia and a combination thereof.

64. The method of claim 49, wherein the subject has a concurrent diagnosis of REM Sleep Behavior disorder, idiopathic REM Sleep Behavior disorder, or a combination thereof, and Lewy Body dementia.

52. A method for the prophylaxis and/or treatment of REM sleep behavior disorder, idiopathic REM sleep behavior disorder, or a combination thereof, in a subject in need thereof comprising administering to said subject a daily oral dose of about 40 mg of nelotanserin.

53. The method of claim 52, wherein the daily dose of about 40 mg of nelotanserin is administered once a day, twice a day, three times a day or four times a day.

54. The method of claim 52, wherein the subject has a concurrent diagnosis of REM Sleep Behavior disorder, idiopathic REM Sleep Behavior disorder, or a combination thereof, and a condition selected from Lewy Body Dementia, probable Dementia with Lewy Bodies, Dementia with Lewy Bodies, Parkinson'"'"'s disease dementia, Parkinson'"'"'s disease, multiple system atrophy, Alzheimer'"'"'s disease, vascular dementia, dementia, mild cognitive impairment, Parkinson'"'"'s disease psychosis, Alzheimer'"'"'s disease psychosis, a sleep disturbance, insomnia and a combination thereof.

65. The method of claim 52, wherein the subject has a concurrent diagnosis of REM Sleep Behavior disorder, idiopathic REM Sleep Behavior disorder, or a combination thereof, and Lewy Body Dementia.

55. A method for the prophylaxis and/or treatment of REM sleep behavior disorder, idiopathic REM sleep behavior disorder, or a combination thereof, in a subject in need thereof comprising administering to said subject a daily dose of about 80 mg of nelotanserin.

56. The method of claim 55, wherein the daily dose of about 80 mg of nelotanserin is administered once a day, twice a day, three times a day or four times a day.

57. The method of claim 55, wherein the subject has a concurrent diagnosis of REM Sleep Behavior disorder, idiopathic REM Sleep Behavior disorder, or a combination thereof, and a condition selected from Lewy Body Dementia, probable Dementia with Lewy Bodies, Dementia with Lewy Bodies, Parkinson'"'"'s disease dementia, Parkinson'"'"'s disease, multiple system atrophy, Alzheimer'"'"'s disease, vascular dementia, dementia, mild cognitive impairment, Parkinson'"'"'s disease psychosis, Alzheimer'"'"'s disease psychosis, a sleep disturbance, insomnia and a combination thereof.

66. The method of claim 55, wherein the subject has a concurrent diagnosis of REM Sleep Behavior disorder, idiopathic REM Sleep Behavior disorder, or a combination thereof, and Lewy Body Dementia.

58. A method for the prophylaxis and/or treatment of REM sleep behavior disorder, idiopathic REM sleep behavior disorder, or a combination thereof, in a subject in need thereof comprising administering to said subject a daily oral dose of about 80 mg of nelotanserin.

59. The method of claim 58, wherein the daily dose of about 80 mg of nelotanserin is administered once a day, twice a day, three times a day or four times a day.

60. The method of claim 58, wherein the subject is a human adult with a diagnosis of a condition selected from Lewy Body Dementia, probable Dementia with Lewy Bodies, Dementia with Lewy Bodies, Parkinson'"'"'s disease dementia, Parkinson'"'"'s disease, multiple system atrophy, Alzheimer'"'"'s disease, vascular dementia, dementia, mild cognitive impairment, Parkinson'"'"'s disease psychosis, Alzheimer'"'"'s disease psychosis, a sleep disturbance, insomnia and any combination thereof.

67. The method of claim 58, wherein the subject is a human adult with a diagnosis of Lewy Body Dementia.

61. A method for the prophylaxis and/or treatment of REM sleep behavior disorder, idiopathic REM sleep behavior disorder, or a combination thereof, in a subject in need thereof comprising administering to said subject a dose of about 40 mg of nelotanserin for a first time period followed by administering to said subject a dose of about 80 mg of nelotanserin for a second time period.

62. The method of claim 61, wherein the subject is a human adult with a diagnosis of a condition selected from Lewy Body Dementia, probable Dementia with Lewy Bodies, Dementia with Lewy Bodies, Parkinson'"'"'s disease dementia, Parkinson'"'"'s disease, multiple system atrophy, Alzheimer'"'"'s disease, vascular dementia, dementia, mild cognitive impairment, Parkinson'"'"'s disease psychosis, Alzheimer'"'"'s disease psychosis, a sleep disturbance, insomnia and any combination thereof.

68. The method of claim 61, wherein the subject is a human adult with Lewy Body Dementia.