Agent for treatment of schizophrenia

• US 9,815,827 B2
• Filed: 08/28/2014
• Issued: 11/14/2017
• Est. Priority Date: 08/22/2002
• Status: Expired due to Term

• Current Assignee: Sumitomo Pharmaceuticals Company Limited (Sumitomo Chemical Company Limited)
• Original Assignee: Sumitomo Dainippon Pharma Company Limited (Sumitomo Chemical Company Limited)
• Inventors: Nakamura, Mitsutaka, Ogasa, Masaaki, Sami, Shunsuke
• Primary Examiner(s): Maewall, Snigdha
• Application Number:
  US14/471,919
• Publication Number:
  US 20140371236A1
• Time in Patent Office: 1,174 Days
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• 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: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

The present invention provides a novel method for treatment of schizophrenia which can improve wide-ranging symptoms of schizophrenia, especially positive symptoms and negative symptoms without being accompanied by extrapyramidal symptoms, which comprises orally administering as an active compound (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboxyimide or a pharmaceutically acceptable salt thereof (e.g., hydrochloride) at a daily dose of 5 mg to 120 mg once a day to a patient with schizophrenia, and a therapeutic agent to be used in said method.

Claims

1. A method for treating schizophrenia in a patient without a clinically significant weight gain, comprising:

administering orally to the patient (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide or a pharmaceutically acceptable salt thereof at a dose of from 20 to 120 mg/day such that the patient does not experience a clinically significant weight gain.

2. The method of claim 1, wherein (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride is administered.

3. The method of claim 2, wherein the administering is conducted such that the patient does not experience a clinically significant weight gain after six weeks of administration.

4. The method of claim 3, wherein the administering is conducted without concurrently administering another antipsychotic medication.

5. The method of claim 2, further comprising:

detecting a weight gain after six weeks of administration.

6. The method of claim 1, wherein said patient has a BPRS score of at least 42 and wherein the patient'"'"'s BPRS score is significantly reduced from a baseline measurement prior to the administering.

7. The method of claim 3, wherein the dose is from 40 to 120 mg once daily.

19. The method of claim 3, wherein the dose is 20 mg once daily.

20. The method of claim 3, wherein the dose is 40 mg once daily.

21. The method of claim 3, wherein the dose is 60 mg once daily.

22. The method of claim 3, wherein the dose is 80 mg once daily.

23. The method of claim 3, wherein the dose is 120 mg once daily.

24. The method of claim 2, wherein the dose is 20 mg, 40 mg, 60 mg, 80 mg or 120 mg once daily.

8. A method for treating manic depressive psychosis in a patient without a clinically significant weight gain, comprising:

administering orally to the patient (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide or a pharmaceutically acceptable salt thereof at a dose of from 20 to 120 mg/day such that the patient does not experience a clinically significant weight gain.

9. The method of claim 8, wherein (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride is administered.

10. The method of claim 9, wherein the administering is conducted such that the patient does not experience a clinically significant weight gain after six weeks of administration.

11. The method of claim 9, further comprising:

detecting a weight gain after six weeks of administration.

12. The method of claim 10, wherein the administering is conducted without concurrently administering another antipsychotic medication.

13. The method of claim 10, wherein the dose is 20 mg once daily.

14. The method of claim 10, wherein the dose is 40 mg once daily.

15. The method of claim 10, wherein the dose is 60 mg once daily.

16. The method of claim 10, wherein the dose is 80 mg once daily.

17. The method of claim 10, wherein the dose is 120 mg once daily.

18. The method of claim 9, wherein the dose is 20 mg, 40 mg, 60 mg, 80 mg or 120 mg once daily.

25. A method of treating a patient with an antipsychotic without a clinically significant weight gain in the patient, comprising:

orally administering the antipsychotic to the patient once daily at a dose of from 20 to 120 mg such that the patient does not experience a clinically significant weight gain,

wherein the antipsychotic is (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide or a pharmaceutically acceptable salt thereof.

26. The method of claim 25, wherein the antipsychotic is (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

27. The method of claim 26, wherein the administering is conducted such that the patient does not experience a clinically significant weight gain after six weeks of administration.

28. The method of claim 26, further comprising:

detecting a weight gain after six weeks of administration.

29. The method of claim 27, wherein the method treats schizophrenia in the patient.

30. The method of claim 27, wherein the method treats manic depressive psychosis in the patient.

31. The method of claim 25, wherein the method treats the patient without the patient experiencing a weight gain.

32. The method of claim 29, wherein the administering is conducted without concurrently administering another antipsychotic medication.

33. The method of claim 30, wherein the administering is conducted without concurrently administering another antipsychotic medication.

34. The method of claim 27, wherein the dose is 20 mg.

35. The method of claim 27, wherein the dose is 40 mg.

36. The method of claim 27, wherein the dose is 60 mg.

37. The method of claim 27, wherein the dose is 80 mg.

38. The method of claim 27, wherein the dose is 120 mg.

39. The method of claim 26, wherein the dose is 20 mg, 40 mg, 60 mg, 80 mg or 120 mg.

40. A method of treating a patient with an antipsychotic without a clinically significant weight gain, comprising:

orally administering once daily to the patient a pharmaceutical composition comprising 20 to 120 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide or a pharmaceutically acceptable salt thereof as a sole active ingredient such that the patient does not experience a clinically significant weight gain.

41. The method of claim 40, wherein the sole active ingredient is (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

42. The method of claim 41, wherein the pharmaceutical composition is a tablet.

43. The method of claim 41, wherein the administering is conducted such that the patient does not experience a clinically significant weight gain after six weeks of administration.

44. The method of claim 41, further comprising:

detecting a weight gain after six weeks of administration.

45. The method of claim 43, wherein the method treats schizophrenia in the patient.

46. The method of claim 43, wherein the method treats manic depressive psychosis in the patient.

47. The method of claim 45, wherein the administering is conducted without concurrently administering another antipsychotic medication.

48. The method of claim 46, wherein the administering is conducted without concurrently administering another antipsychotic medication.

49. The method of claim 41, wherein the pharmaceutical composition includes 40 to 120 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

50. The method of claim 41, wherein the pharmaceutical composition includes 20 mg, 40 mg, 60 mg, 80 mg or 120 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

51. The method of claim 41, wherein the pharmaceutical composition includes 20 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

52. The method of claim 41, wherein the pharmaceutical composition includes 40 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

53. The method of claim 41, wherein the pharmaceutical composition includes 60 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

54. The method of claim 41, wherein the pharmaceutical composition includes 80 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

55. The method of claim 41, wherein the pharmaceutical composition includes 120 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

56. A method of treating a patient with an antipsychotic without a weight gain, comprising:

orally administering once daily to the patient a pharmaceutical composition comprising 20 to 120 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide or a pharmaceutically acceptable salt thereof as a sole active ingredient such that the patient does not experience a weight gain.

57. The method of claim 56, wherein the sole active ingredient is (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

58. The method of claim 57, wherein the pharmaceutical composition is a tablet.

59. The method of claim 57, wherein the administering is conducted such that the patient does not experience a weight gain after six weeks of administration.

60. The method of claim 57, further comprising:

detecting a weight gain after six weeks of administration.

61. The method of claim 57, wherein the method treats schizophrenia in the patient.

62. The method of claim 57, wherein the method treats manic depressive psychosis in the patient.

63. The method of claim 61, wherein the administering is conducted without concurrently administering another antipsychotic medication.

64. The method of claim 62, wherein the administering is conducted without concurrently administering another antipsychotic medication.

65. The method of claim 61, wherein the pharmaceutical composition includes 40 to 120 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

66. The method of claim 57, wherein the pharmaceutical composition includes 20 mg, 40 mg, 60 mg, 80 mg or 120 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

67. The method of claim 62, wherein the pharmaceutical composition includes 20 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

68. The method of claim 61, wherein the pharmaceutical composition includes 40 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

69. The method of claim 62, wherein the pharmaceutical composition includes 40 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

70. The method of claim 61 wherein the pharmaceutical composition includes 60 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

71. The method of claim 62 wherein the pharmaceutical composition includes 60 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

72. The method of claim 61, wherein the pharmaceutical composition includes 80 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

73. The method of claim 62, wherein the pharmaceutical composition includes 80 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

74. The method of claim 61, wherein the pharmaceutical composition includes 120 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.

75. The method of claim 62, wherein the pharmaceutical composition includes 120 mg of (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzoisothiazol-3-yl)-1 -piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1]heptanedicarboximide hydrochloride.