VMAT2 inhibitor and method of use

JP7879148B2Active Publication Date: 2026-06-23NEUROCRINE BIOSCIENCES INC
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Patent Information

Authority / Receiving Office
JP · JP
Patent Type
Patents
Current Assignee / Owner
NEUROCRINE BIOSCIENCES INC
Filing Date
2022-03-21
Publication Date
2026-06-23

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Abstract

The present disclosure generally relates to VMAT2 inhibitor compounds of formula (I), compositions and methods related thereto.Also provided herein is a method for treating vesicular monoamine transporter-2 (VMAT2) disease or disorder in a subject in need thereof, comprising administering to the subject a compound of formula (I), or a pharmaceutical product comprising a compound of formula (I), or a pharmaceutical salt thereof; or a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutical salt thereof. TIFF2024511053000105.tif2944
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Claims

1. Compound of formula (Ia): 【Chemistry 48】 or a pharmaceutically acceptable salt thereof [in the formula, R １ は、-CH ２ CF ３ 、-CH ２ CF ２ H、-CH ２ CF ２ CH ３ 、 【Chemistry 53】 It is.

2. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-1) The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(2,2,2-trifluoroethoxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-1) The compound according to claim 1.

4. (2R,3R,11bR)-9-(2,2-difluoroethoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-13) The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

5. (2R,3R,11bR)-9-(2,2-difluoroethoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-13) The compound according to claim 1.

6. (2R,3R,11bR)-9-(2,2-difluoropropoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-14) The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

7. (2R,3R,11bR)-9-(2,2-difluoropropoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-14) The compound according to claim 1.

8. (2R,3R,11bR)-9-cyclopropoxy-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-27) The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

9. (2R,3R,11bR)-9-cyclopropoxy-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-27) The compound according to claim 1.

10. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(oxetane-3-yloxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-30) The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

11. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-(oxetane-3-yloxy)-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-30) The compound according to claim 1.

12. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(1-fluorocyclopropyl)methoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-31) The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(1-fluorocyclopropyl)methoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-31) The compound according to claim 1.

14. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-(2-hydroxy-2-methylpropoxy)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-47) The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

15. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-(2-hydroxy-2-methylpropoxy)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-47) The compound according to claim 1.

16. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(2R)-3,3,3-trifluoro-2-hydroxypropoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-49) The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

17. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(2R)-3,3,3-trifluoro-2-hydroxypropoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-49) The compound according to claim 1.

18. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(2S)-3,3,3-trifluoro-2-hydroxypropoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-50) The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

19. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-10-methoxy-9-[(2S)-3,3,3-trifluoro-2-hydroxypropoxy]-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-50) The compound according to claim 1.

20. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, is (2R,3R,11bR)-9-(3,3-difluoro-2-hydroxypropoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-51).

21. The compound according to claim 1, which is (2R,3R,11bR)-9-(3,3-difluoro-2-hydroxypropoxy)-3-(2,2-dimethylpropyl)-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-51).

22. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2R)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-55) The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

23. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2R)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-55) The compound according to claim 1.

24. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2S)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-114) The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

25. (2R,3R,11bR)-3-(2,2-dimethylpropyl)-9-[(2S)-2-hydroxypropoxy]-10-methoxy-1H,2H,3H,4H,6H,7H,11bH-pyrido[2,1-a]isoquinoline-2-ol (compound 4-114) The compound according to claim 1.

26. Pharmaceutical compositions, formulation, Unit dosage form, and A pharmaceutical product selected from the kit, Each is a compound according to any one of claims 1 to 25, or comprising a pharmaceutically acceptable salt as described in any one of claims 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24 Pharmaceutical products.

27. Pharmaceutical compositions, formulation, Unit dosage form, and A pharmaceutical product selected from the kit, Each is a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt according to any one of claims 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24, A compound comprising at least one pharmaceutically acceptable excipient, Pharmaceutical products.

28. A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt according to any one of claims 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22 and 24, A compound comprising at least one pharmaceutically acceptable excipient, Pharmaceutical composition.

29. For subjects requiring treatment of vesicular monoamine transporter-2 (VMAT2) disease or disorder, A composition comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt according to any one of claims 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24. A pharmaceutical product according to claim 26 or 27, or The pharmaceutical composition according to claim 28.

30. For subjects requiring treatment of vesicular monoamine transporter-2 (VMAT2) disease or disorder, A composition comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt according to any one of claims 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24. A pharmaceutical product according to claim 26 or 27, or A pharmaceutical composition according to claim 28, Here, the aforementioned VMAT2 disease or disorder is Compositions, pharmaceutical products, or pharmaceutical compositions selected from ataxia or spinal muscular atrophy; chorea; congenital malformations, deformities or abnormalities; dementia; oral, salivary gland or jawbone disorders; dyskinesia; dystonia; endocrine, nutritional or metabolic disorders; epilepsy; habitual or impulsivity disorders; Huntington's disease or related disorders; mood or psychotic disorders; neurotic, stress-related and somatoform disorders; degenerative disorders of the basal ganglia; extrapyramidal and motor disorders; neurological or psychiatric disorders or disorders; nervous system or motor dysfunction; Parkinson's disease / parkinsonism; childhood-onset behavioral and affective disorders; pervasive developmental disorders; and substance abuse or addiction disorders.

31. For treating neurological or psychiatric disorders in subjects requiring treatment of such disorders, A composition comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt according to any one of claims 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24. A pharmaceutical product according to claim 26 or 27, or The pharmaceutical composition according to claim 28.

32. For treating neurological or psychiatric disorders in subjects requiring treatment of such disorders, A composition comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt according to any one of claims 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24. A pharmaceutical product according to claim 26 or 27, or A pharmaceutical composition according to claim 28, Here, the aforementioned neurological or mental illness or disorder is Hyperactivity disorder, schizophrenia, schizoaffective disorder, mood disorders, treatment-resistant obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor / ataxia syndrome, autism spectrum disorder, Rett syndrome, and acanthocyaninic chorea. A composition, pharmaceutical product, or pharmaceutical composition selected from the group consisting of the following.

33. The aforementioned neurological or mental disorder or disorder is hyperactivity disorder. The composition, pharmaceutical product, or pharmaceutical composition according to claim 32.

34. The aforementioned hyperactive movement disorder is tardive dyskinesia. The composition, pharmaceutical product, or pharmaceutical composition according to claim 33.

35. The aforementioned hyperactive movement disorder is chorea associated with Huntington's disease. The composition, pharmaceutical product, or pharmaceutical composition according to claim 33.

36. The composition, pharmaceutical product, or pharmaceutical composition according to claim 32, wherein the neurological or mental illness or disorder is schizophrenia or schizoaffective disorder.

37. The composition, pharmaceutical product, or pharmaceutical composition according to claim 32, wherein the neurological or mental illness or disorder is schizophrenia.

38. The aforementioned neurological or psychiatric disorder or disorder is treatment-resistant obsessive-compulsive disorder. The composition, pharmaceutical product, or pharmaceutical composition according to claim 32.

39. The aforementioned neurological or mental disorder or disability is autism spectrum disorder. The composition, pharmaceutical product, or pharmaceutical composition according to claim 32.

40. The aforementioned neurological or mental disorder or illness is a mood disorder. The composition, pharmaceutical product, or pharmaceutical composition according to claim 32.

41. The aforementioned neurological or psychiatric disorder or disorder is a mood disorder selected from bipolar disorder, major depressive disorder, mania in mood disorders, or depression in mood disorders. The composition, pharmaceutical product, or pharmaceutical composition according to claim 32.

42. The composition, pharmaceutical product, or pharmaceutical composition according to any one of claims 32 to 41, characterized in that the composition, pharmaceutical product, or pharmaceutical composition is for use in adjunctive therapy for treating neurological or mental disorders or conditions.

43. In the manufacture of pharmaceuticals for treating vesicular monoamine transporter-2 (VMAT2) diseases or disorders, A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt according to any one of claims 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24. A pharmaceutical product according to claim 26 or 27, or Pharmaceutical composition according to claim 28 Use.

44. Ataxia or spinal muscular atrophy; chorea; congenital malformations, deformities or abnormalities; dementia; oral, salivary gland or jawbone disorders; dyskinesia; dystonia; endocrine, nutritional or metabolic disorders; epilepsy; habitual or impulsivity disorders; Huntington's disease or related disorders; mood or psychotic disorders; neurotic, stress-related and somatoform disorders; degenerative disorders of the basal ganglia; extrapyramidal and motor disorders; neurological or psychiatric disorders or disorders; nervous system or motor dysfunction; Parkinson's disease / parkinsonian disorders; childhood-onset behavioral and affective disorders; pervasive developmental disorders; and substance abuse or addiction disorders. Selected from vesicular monoamine transporter-2 (VMAT2) in the manufacture of pharmaceuticals for treating diseases or disorders, A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt according to any one of claims 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24. A pharmaceutical product according to claim 26 or 27, or Pharmaceutical composition according to claim 28 Use.

45. In the manufacture of pharmaceuticals for treating neurological or psychiatric disorders or conditions, A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt according to any one of claims 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24. A pharmaceutical product according to claim 26 or 27, or Pharmaceutical composition according to claim 28 Use.

46. Hyperactivity disorder, schizophrenia, schizoaffective disorder, mood disorders, treatment-resistant obsessive-compulsive disorder, neurological dysfunction associated with Lesch-Nyhan syndrome, agitation associated with Alzheimer's disease, fragile X syndrome or fragile X-associated tremor / ataxia syndrome, autism spectrum disorder, Rett syndrome, and acanthocyaninic chorea. In the manufacture of a pharmaceutical product for treating a neurological or psychiatric disorder or illness selected from the group consisting of, A compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt according to any one of claims 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24. A pharmaceutical product according to claim 26 or 27, or Pharmaceutical composition according to claim 28 Use.

47. The aforementioned neurological or mental disorder or disorder is hyperactivity disorder. The use described in claim 46.

48. The aforementioned hyperactive movement disorder is tardive dyskinesia. The use described in claim 47.

49. The aforementioned hyperactive movement disorder is chorea associated with Huntington's disease. The use described in claim 47.

50. The use according to claim 46, wherein the neurological or mental disorder or disorder is schizophrenia or schizoaffective disorder.

51. The aforementioned neurological or mental illness or disorder is schizophrenia. The use described in claim 46.

52. The aforementioned neurological or psychiatric disorder or disorder is treatment-resistant obsessive-compulsive disorder. The use described in claim 46.

53. The aforementioned neurological or mental disorder or disability is autism spectrum disorder. The use described in claim 46.

54. The aforementioned neurological or mental disorder or illness is a mood disorder. The use described in claim 46.

55. The aforementioned neurological or psychiatric disorder or disorder is a mood disorder selected from bipolar disorder, major depressive disorder, mania in mood disorders, or depression in mood disorders. The use described in claim 46.

56. The use according to any one of claims 46 to 55, characterized in that the pharmacopoeia is for use in adjunctive therapy for treating neurological or mental disorders or conditions.

57. For use in therapeutic methods of treating the body of a human or animal, A composition comprising a compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt according to any one of claims 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24. A pharmaceutical product according to claim 26 or 27, or The pharmaceutical composition according to claim 28.