IP Library › Granted Patent US 9,815,827
Granted Patent B2
US 9,815,827 · App. 14/471,919 · Granted Nov 14, 2017

Agent for treatment of schizophrenia

Inventors: Mitsutaka Nakamura (Kawanishi, JP); Masaaki Ogasa (Tokyo, JP); Shunsuke Sami (Kawasaki, JP)
Assignee: Sumitomo Dainippon Pharma Co., Ltd.
C07D417/12A61K31/496
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Quick Facts
Patent No.
US 9,815,827
App. No.
14/471,919
Granted
Nov 14, 2017
Kind
B2
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 (86)

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.

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.

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.

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.

Assignments (1)
CHANGE OF NAME Recorded Nov 21, 2022
From: SUMITOMO DAINIPPON PHARMA CO., LTD.
To: SUMITOMO PHARMA CO., LTD.
Reel/Frame 061972/0730 →
Continuity (3)
Continuation 10525021
Provisional Application 60404927 · Aug 22, 2002
Related Publication 20140371236A1 · Dec 18, 2014