D6Solid oral dosage forms of (E) -tetrabenazine, compounds, and pharmaceutical compositions, preparation and treatment methods thereof

文档序号：1118749 发布日期：2020-10-02 浏览：14次中文

阅读说明：本技术 D6-四苯喹嗪固体口服剂型、化合物、及其药物组合物、制备及治疗方法 (D6Solid oral dosage forms of (E) -tetrabenazine, compounds, and pharmaceutical compositions, preparation and treatment methods thereof ) 是由 A·萨默 C·张 J·卡特 J·阿瑟 M·布雷德伯里 T·甘特 M·沙赫巴兹于 2013-09-18 设计创作，主要内容包括：本发明涉及一种固体口服剂型,所述固体口服制剂包括6毫克的d6-四苯喹嗪和剂型重量的约5％至约30％的聚合物,所述聚合物为聚(环氧乙烷)聚合物、科利当聚合物、羟丙基甲基纤维素聚合物、羟丙基纤维素聚合物、卡波普聚合物或它们的组合,其中如果所述口服剂型以进食状态口服给予人,则其给药结果为：约132hr*ng/mL的血浆中总组合量的氘化二氢四苯喹嗪的AUCinf；或者约15.5ng/mL的血浆中总组合量的氘化二氢四苯喹嗪的Cmax。本发明还涉及有关结晶型体包括该结晶型体的药物组合物,以及施用其的治疗方法。本发明的技术方案使得四苯喹嗪的药代动力学参数表现优异。(The present invention relates to a solid oral dosage form, said solid oral dosage formThe preparation comprises d 6mg 6 -tetrabenazine and from about 5% to about 30% by weight of the dosage form of a polymer which is a poly (ethylene oxide) polymer, a colestyrol polymer, a hydroxypropyl methylcellulose polymer, a hydroxypropyl cellulose polymer, a carbopol polymer, or a combination thereof, wherein if the oral dosage form is administered orally to a human in the fed state, the result of administration is: AUC of total combined amount of deuterated dihydrotetrabenazine in plasma of about 132hr ng/mL inf (ii) a Or about 15.5ng/mL of the total combined amount of deuterated dihydrotetrabenazine C in plasma max . The invention also relates to related crystalline forms, pharmaceutical compositions comprising the crystalline forms, and methods of treatment using the same. The technical scheme of the invention ensures that the pharmacokinetic parameters of the tetrabenazine are excellent.)

1. A solid oral dosage form comprising 6mg of d₆-tetrabenazine and from about 5% to about 30% by weight of the dosage form of a polymer which is a poly (ethylene oxide) polymer, a Kollidon (Kollidon) polymer, a hydroxypropyl methylcellulose (HPMC) polymer, a hydroxypropyl cellulose (HPC) polymer, a Carbopol (Carbopol) polymer, or a combination thereof, wherein if the oral dosage form is administered orally to a human in a fed state, the administration results in:

AUC of total combined amount of deuterated dihydrotetrabenazine in plasma of about 132hr ng/mL_inf(ii) a Or

About 15.5ng/mL of C of deuterated dihydrotetrabenazine in total combined amount in plasma_max。

2. The solid oral dosage form of claim 1, wherein the AUC of the total combined amount of deuterated dihydrotetrabenazine_infIs about 132hr ng/mL; and is

C of deuterated dihydrotetrabenazine in the total combined amount_maxIs about 15.5 ng/mL.

3. The solid oral dosage form of claim 1, wherein the polymer comprises a poly (ethylene oxide) polymer.

4. The solid oral dosage form of claim 3, wherein the poly (ethylene oxide) polymer comprisesN60K polymer.

5. The solid oral dosage form of claim 3, wherein the poly (ethylene oxide) polymer is

6. The solid oral dosage form of claim 1, wherein the polymer comprises a Hydroxypropylmethylcellulose (HPMC) polymer.

7. The solid oral dosage form of claim 5, wherein the polymer comprises an HPMC polymer selected from HPMC K4M, HPMC K100LV, or HPMC E15 LV.

8. The solid oral dosage form of claim 6, wherein the polymer comprises HPMC K4M polymer.

9. The solid oral dosage form of claim 1, wherein the polymer comprises a hydroxypropyl cellulose (HPC) polymer.

10. A solid oral dosage form comprising 12mg d₆-tetrabenazine and from about 5% to about 30% by weight of the dosage form of a polymer which is a poly (ethylene oxide) polymer, a Kollidon (Kollidon) polymer, a hydroxypropyl methylcellulose (HPMC) polymer, a hydroxypropyl cellulose (HPC) polymer, a Carbopol (Carbopol) polymer, or a combination thereof, wherein if the oral dosage form is administered orally to a human in a fed state, the administration results in:

about 289hr ng/mL total combined amount of deuteration in plasmaAUC of dihydrotetrabenazine_inf(ii) a Or

C of deuterated dihydrotetrabenazine in total combined amount in plasma of about 32.1ng/mL_max。

11. The solid oral dosage form of claim 10, wherein

Wherein the AUC of the total combined amount of deuterated dihydrotetrabenazine_infIs about 289hr ng/mL; and is

C of deuterated dihydrotetrabenazine in the total combined amount_maxIs about 32.1 ng/mL.

12. The solid oral dosage form of claim 10, wherein the polymer comprises a poly (ethylene oxide) polymer.

13. The solid oral dosage form of claim 12, wherein the poly (ethylene oxide) polymer comprisesN60K polymer.

14. The solid oral dosage form of claim 12, wherein the poly (ethylene oxide) polymer is

15. The solid oral dosage form of claim 10, wherein the polymer comprises a Hydroxypropylmethylcellulose (HPMC) polymer.

16. The solid oral dosage form of claim 10, wherein the polymer comprises an HPMC polymer selected from HPMC K4M, HPMCK100 LV, or HPMC E15 LV.

17. The solid oral dosage form of claim 13, wherein the polymer comprises HPMC K4M polymer.

18. The solid oral dosage form of claim 1, wherein the polymer comprises a hydroxypropyl cellulose (HPC) polymer.

19. A compound which is crystalline d₆-the tetrabenazine form II, said crystalline d₆-tetrabenazine form II has deuterium enrichment of no less than about 1% at each deuterium position and has an X-ray diffraction pattern comprising three or more peaks at 8.3, 11.6, 13.9, 20.0 or 23.7 in terms of 2 Θ ± 0.2;

or a pharmaceutically acceptable salt or hydrate thereof.

20. The compound of claim 19, having an X-ray diffraction pattern further comprising five or more peaks, in terms of 2 Θ ± 0.2, at 8.3, 9.8, 11.6, 12.0, 13.9, 20.0, 22.0, 23.7, 24.4, 33.5, or 42.3.

21. The compound of claim 19, having an X-ray diffraction pattern further comprising five or more peaks, in terms of 2 Θ ± 0.2, at 7.5, 8.3, 11.6, 12.0, 13.9, 20.0, 20.6, 22.0, 22.9, or 23.7.

22. The compound of claim 19, having an X-ray diffraction pattern comprising peaks, in terms of 2 Θ ± 0.2, at 8.3, 11.6, 13.9, 20.0, and 23.7.

23. The compound of claim 19, further comprising the X-ray diffraction pattern of figure 12.

24. The compound of claim 19, further comprising a differential calorimetry trace of an endotherm between about 120 ℃ and about 140 ℃.

25. The compound of claim 19, further comprising the differential calorimetry trace of figure 11.

26. The compound of claim 19, further comprising a thermogravimetric analysis curve showing about 1.5% weight loss at less than about 160 ℃.

27. The compound of claim 19, further comprising the thermogravimetric analysis curve of figure 10.

28. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and crystal d₆-a tetrabenazine type II or a pharmaceutically acceptable salt or hydrate thereof, said crystalline d₆-tetrabenazine form II has deuterium enrichment of no less than about 90% at each deuterium position and has an X-ray diffraction pattern comprising three or more peaks at 8.3, 11.6, 13.9, 20.0 or 23.7 in terms of 2 Θ ± 0.2.

29. The pharmaceutical composition of claim 28, wherein the crystalline d₆-the tetrabenazine type II has deuterium enrichment of no less than about 98% at each deuterium position.

30. The pharmaceutical composition of claim 28, wherein the crystalline d₆-tetrabenazine form II has an X-ray diffraction pattern further comprising five or more peaks at 8.3, 9.8, 11.6, 12.0, 13.9, 20.0, 22.0, 23.7, 24.4, 33.5 or 42.3 in terms of 2 Θ ± 0.2.

31. The pharmaceutical composition of claim 28, wherein the crystalline d₆-tetrabenazine form II has an X-ray diffraction pattern further comprising five or more in terms of 2 θ ± 0.2 at 7.5, 8.3, 11.6, 12.0, 13.9, 20.0, 20.6, 22.0, 22.9 or 23.7And (4) a peak.

32. The pharmaceutical composition of claim 28, wherein the crystalline d₆The tetrabenazine form II has an X-ray diffraction pattern comprising peaks at 8.3, 11.6, 13.9, 20.0 and 23.7 in terms of 2 theta + -0.2.

33. The pharmaceutical composition of claim 28, wherein the crystalline d₆The tetrabenazine form II further comprises the X-ray diffraction pattern of figure 12.

34. The pharmaceutical composition of claim 28, wherein the crystalline d₆-tetrabenazine type II further comprises an endothermic differential calorimetry trace between about 120 ℃ and about 140 ℃.

35. The pharmaceutical composition of claim 28, wherein the crystalline d₆-tetrabenazine type II further comprises the differential calorimetry trace of figure 11.

36. The pharmaceutical composition of claim 28, wherein the crystalline d₆-tetrabenazine type II further comprises a thermogravimetric analysis curve showing about 1.5% weight loss at less than about 160 ℃.

37. The pharmaceutical composition of claim 28, wherein the crystalline d₆The tetrabenazine type II further comprises the thermogravimetric analysis curve of figure 10.

38. The pharmaceutical composition of claim 28, wherein the pharmaceutically acceptable carrier comprises a polyoxide (polyoxide).

39. The pharmaceutical composition of claim 28, wherein the pharmaceutically acceptable carrier consists of a polyoxide.

40. A method of treating a VMAT 2-mediated disease, the method comprising: administering to a patient in need thereof a compound of claim 19.

41. The method of claim 40, wherein the VMAT 2-mediated disease is hyperkinetic movement disorder.

42. The method of claim 41, wherein the hyperkinetic movement disorder is chronic hyperkinetic movement disorder.

43. The method of claim 42, wherein the chronic hyperkinetic movement disorder is selected from the group consisting of Huntington's disease, tardive dyskinesia, Tourette syndrome, and tic disorders.

44. The method of claim 40, wherein the crystallization d₆-the tetrabenazine type II or a pharmaceutically acceptable salt or hydrate thereof has deuterium enrichment of not less than about 90% at each deuterium position.

45. The method of claim 40, wherein the crystallization d₆-the tetrabenazine type II or a pharmaceutically acceptable salt or hydrate thereof has deuterium enrichment of not less than about 98% at each deuterium position.

46. A method of treating a VMAT 2-mediated disease, the method comprising: administering to a patient in need thereof the pharmaceutical composition of claim 28.

47. The method of claim 46, wherein the VMAT 2-mediated condition is hyperkinetic movement disorder.

48. The method of claim 47, wherein the hyperkinetic movement disorder is chronic hyperkinetic movement disorder.

49. The method of claim 48, wherein the chronic hyperkinetic movement disorder is selected from the group consisting of Huntington's disease, tardive dyskinesia, Tourette's syndrome, and tic disorders.

50. Preparation of crystals d₆Process for the preparation of (E) -the tetrabenazine form II, said crystalline d₆-tetrabenazine form II has deuterium enrichment of no less than about 1% at each deuterium position and has an X-ray diffraction pattern comprising three or more peaks at 8.3, 11.6, 13.9, 20.0 or 23.7 in terms of 2 Θ ± 0.2, said method comprising subjecting d to₆-tetrabenazine is dissolved in methanol and the crystals d are precipitated by slow evaporation₆-the tetrabenazine type II.

51. The method of claim 50, wherein said methanol is substituted with d₆Saturated with-tetrabenazine.

52. The method of claim 50, wherein the crystallization d₆-tetrabenazine type II has deuterium enrichment of no less than about 90% at each deuterium position.

53. The method of claim 50, wherein the crystallization d₆-the tetrabenazine type II has deuterium enrichment of no less than about 98% at each deuterium position.

54. The method of claim 50, wherein the crystallization d₆-tetrabenazine form II further comprises an X-ray diffraction pattern further comprising five or more peaks at 8.3, 9.8, 11.6, 12.0, 13.9, 20.0, 22.0, 23.7, 24.4, 33.5 or 42.3 in terms of 2 Θ ± 0.2.

55. The method of claim 50, wherein the crystallization d₆-the tetrabenazine form II further comprises an X-ray diffraction pattern which also includes 2 θ ± 0.2 at 7.5, 8.3, 11.6, 12.0, 13.9, 20.0, 20.6, 22.0, 22.9, or 23.7.

56. The method of claim 50, wherein the crystallization d₆The tetrabenazine form II has an X-ray diffraction pattern comprising peaks at 8.3, 11.6, 13.9, 20.0 and 23.7 in terms of 2 theta + -0.2.

57. The method of claim 50, wherein the slow evaporation is performed at ambient temperature.

58. The method of claim 50, wherein the slow evaporation is performed at ambient humidity.

59. The method of claim 50, wherein the slow evaporation is performed at ambient temperature and ambient humidity.

60. A process for preparing a pharmaceutical composition, said process comprising reacting₆-crystallization of the tetrabenazine form II, said crystalline d₆-tetrabenazine form II has deuterium enrichment of no less than about 1% at each deuterium position and has an X-ray diffraction pattern comprising three or more peaks at 8.3, 11.6, 13.9, 20.0 or 23.7 in terms of 2 Θ ± 0.2.

61. The method of claim 60, wherein said crystallized d₆-tetrabenazine type II has deuterium enrichment of no less than about 90% at each deuterium position.

62. The method of claim 60, wherein said crystallized d₆-the tetrabenazine type II has deuterium enrichment of no less than about 98% at each deuterium position.

63. The method of claim 60, wherein said crystallized d₆-tetrabenazineForm II further comprises an X-ray diffraction pattern further comprising five or more peaks at 8.3, 9.8, 11.6, 12.0, 13.9, 20.0, 22.0, 23.7, 24.4, 33.5, or 42.3 in terms of 2 θ ± 0.2.

64. The method of claim 60, wherein said crystallized d₆-tetrabenazine form II further comprises an X-ray diffraction pattern further comprising five or more peaks at 7.5, 8.3, 11.6, 12.0, 13.9, 20.0, 20.6, 22.0, 22.9 or 23.7 in terms of 2 Θ ± 0.2.

65. The method of claim 60, wherein said crystallized d₆The tetrabenazine form II has an X-ray diffraction pattern comprising peaks at 8.3, 11.6, 13.9, 20.0 and 23.7 in terms of 2 theta + -0.2.

66. A compound which is crystalline d₆-tetrabenazine form I, said crystalline d₆-tetrabenazine form I has deuterium enrichment of not less than about 1% at each deuterium position and has an X-ray diffraction pattern comprising peaks at 6.5, 12.2, 14.4, 22.4 and 23.4 in terms of 2 Θ ± 0.2;

or a pharmaceutically acceptable salt or hydrate thereof.

67. The compound of claim 66, having an X-ray diffraction pattern comprising peaks, in terms of 2 θ ± 0.2, at 6.5, 10.8, 12.2, 13.0, 14.4, 17.1, 18.0, 21.4, 22.4, and 23.4.

68. The compound of claim 66, having the X-ray diffraction pattern of figure 9.

69. The compound of claim 66, having a differential calorimetry trace of an endotherm between about 115 ℃ and about 135 ℃.

70. The compound of claim 66, having the differential calorimetry trace of FIG. 8.

71. The compound of claim 66, having a thermogravimetric analysis curve showing about 1.5% weight loss at less than about 150 ℃.

72. The compound of claim 66, having the thermogravimetric analysis curve of figure 7.

73. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and crystal d₆-tetrabenazine type I or a pharmaceutically acceptable salt or hydrate thereof, said crystalline d₆-tetrabenazine form I has deuterium enrichment of not less than about 90% and has an X-ray diffraction pattern comprising peaks at 6.5, 12.2, 14.4, 22.4 and 23.4 in terms of 2 Θ ± 0.2.

74. The pharmaceutical composition of claim 73, wherein the crystalline d₆-the tetrabenazine type I has deuterium enrichment of not less than about 98%.

75. The pharmaceutical composition of claim 73, wherein the crystalline d₆The tetrabenazine form I has an X-ray diffraction pattern comprising peaks at 6.5, 10.8, 12.2, 13.0, 14.4, 17.1, 18.0, 21.4, 22.4 and 23.4 in terms of 2 theta + -0.2.

76. The pharmaceutical composition of claim 73, wherein the crystalline d₆The tetrabenazine form I has the X-ray diffraction diagram of figure 9.

77. The pharmaceutical composition of claim 73, wherein the crystalline d₆Differential calorimetry with endotherm between about 115 ℃ and about 135 ℃ for the tetrabenazine type ITrace.

78. The pharmaceutical composition of claim 73, wherein the crystalline d₆The tetrabenazine type I has the differential calorimetry trace of figure 8.

79. The pharmaceutical composition of claim 73, wherein the crystalline d₆-tetrabenazine type I has a thermogravimetric analysis curve showing about 1.5% weight loss at less than about 150 ℃.

80. The pharmaceutical composition of claim 73, wherein the crystalline d₆The tetrabenazine type I has the thermogravimetric analysis curve of figure 7.

81. The pharmaceutical composition of claim 73, wherein the pharmaceutically acceptable carrier comprises a polyoxide.

82. The pharmaceutical composition of claim 73, wherein the pharmaceutically acceptable carrier consists of a polyoxide.

83. A method of treating a VMAT 2-mediated disease, the method comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of claim 66.

84. The method of claim 83, wherein the VMAT 2-mediated disease is hyperkinetic movement disorder.

85. The method of claim 84, wherein the hyperkinetic movement disorder is chronic hyperkinetic movement disorder.

86. The method of claim 85, wherein the chronic hyperkinetic movement disorder is selected from the group consisting of Huntington's disease, tardive dyskinesia, Tourette's syndrome, and tic disorders.

87. The method of claim 83, wherein the crystallization d₆-tetrabenazine type I or a pharmaceutically acceptable salt or hydrate thereof has deuterium enrichment of not less than about 90%.

88. The method of claim 83, wherein the crystallization d₆-tetrabenazine type I or a pharmaceutically acceptable salt or hydrate thereof has deuterium enrichment of not less than about 98%.

89. A method of treating a VMAT 2-mediated disease, the method comprising: administering to a patient in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 73.

90. The method of claim 89, wherein the VMAT 2-mediated disease is hyperkinetic movement disorder.

91. The method of claim 90, wherein the hyperkinetic movement disorder is chronic hyperkinetic movement disorder.

92. The method of claim 91, wherein the chronic hyperkinetic movement disorder is selected from the group consisting of Huntington's disease, tardive dyskinesia, Tourette's syndrome, and tic disorders.

Brief Description of Drawings

FIG. 1: preparation d₆A tetrabenazine extended release formulation and a method of preparing a tetrabenazine extended release formulation.

FIG. 2: gastric retention extends the size of the large release tablet.

FIG. 3: immediate release of d₆Tetrabenzoquinolizine and its metabolite d₆- α -HTBZ and d₆Results of pharmacokinetic studies of- β -HTBZ versus non-deuterated equivalents (tetrabenazine, α -HTBZ, and β -HBZ) along with the corresponding O-demethylated metabolites.

FIG. 4: mean plasma concentrations of total (α + β) -HTBZ in each of TBZ fasted, formulation a fed, formulation B fed, formulation a fasted, and formulation B fasted groups.

FIG. 5: from 3 dose levels d₆Single dose mean plasma concentrations of total (α + β) -HTBZ of-tetrabenazine ER and 1 dose level of tetrabenazine.

FIG. 6: from 3 dose levels d₆Steady state plasma concentrations of total (α + β) -HTBZ of-tetrabenazine ER and 1 dose level of tetrabenazine.

FIG. 7: d₆-tetrabenazine, type I thermogravimetric analysis (TGA) profile.

FIG. 8: d₆Differential Scanning Calorimetry (DSC) curve of form I, tetrabenazine.

FIG. 9: d₆Powder X-ray diffraction (pXRD) profile of tetrabenazine, form I.

FIG. 10: d₆Thermogravimetric analysis (TGA) profile of tetrabenazine, type II.

FIG. 11: d₆Differential Scanning Calorimetry (DSC) curve of form II, tetrabenazine.

FIG. 12: d₆Powder X-ray diffraction (pXRD) profile of tetrabenazine, form II.

In certain embodiments, disclosed herein is a pharmaceutical composition comprising a deuterated analog of tetrabenazine, which, when administered orally to a subject, produces at least one of the following:

at least 50% increase in AUC for the total combined amount of deuterated dihydrotetrabenazine as compared to a pharmaceutical composition comprising an equivalent amount of non-deuterated tetrabenazine; or

At least 50% increase in half-life of deuterated dihydrotetrabenazine as compared to a pharmaceutical composition comprising an equivalent amount of non-deuterated tetrabenazine.

In certain embodiments, the dihydrotetrabenazine is deuterated alpha-dihydrotetrabenazine, deuterated beta-dihydrotetrabenazine, or a combination of deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine.

In certain embodiments, the deuterated analog of tetrabenazine is selected from the group consisting of: (3R,11bR) -1,3,4,6,7,11 b-hexahydro-9, 10-di (methoxy-d)₃) -3- (2-methylpropyl) -2H-benzo [ a]Quinolizin-2-one, (3R,11bS) -1,3,4,6,7,11 b-hexahydro-9, 10-di (methoxy-d)₃) -3- (2-methylpropyl) -2H-benzo [ a]Quinolizin-2-one, (3S,11bR) -1,3,4,6,7,11 b-hexahydro-9, 10-di (methoxy-d)₃) -3- (2-methylpropyl) -2H-benzo [ a]Quinolizin-2-ones and (3S,11bS) -1,3,4,6,7,11 b-hexahydro-9, 10-di (methoxy-d)₃) -3- (2-methylpropyl) -2H-benzo [ a]Quinolizin-2-ones.

In certain embodiments, the deuterated analog of tetrabenazine is d₆-tetrabenazine.

In certain embodiments, the deuterated analog of tetrabenazine is (+/-) -trans-d₆-tetrabenazine.

In certain embodiments, the pharmaceutical composition produces at least a 100% increase in AUC of the total combined amount of deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine as compared to a pharmaceutical formulation comprising an equivalent amount of non-deuterated tetrabenazine; or

At least a 70% increase in half-life of the total combined amount of deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine.

In certain embodiments, the pharmaceutical composition produces at least a 100% increase in the half-life of the total combined amount of deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine as compared to a pharmaceutical composition comprising an equivalent amount of non-deuterated tetrabenazine.

In certain embodiments, the pharmaceutical composition produces a reduced AUC or C of O-demethylated metabolites of deuterated α -dihydrotetrabenazine and deuterated β -dihydrotetrabenazine as compared to a pharmaceutical composition comprising an equivalent amount of non-deuterated tetrabenazine_max。

In certain embodiments, the AUC of the 9-O-demethyl metabolite of deuterated alpha-dihydrotetrabenazine and the 9-O-demethyl metabolite and the 10-O-demethyl metabolite of deuterated beta-dihydrotetrabenazine is reduced by at least 25%.

In certain embodiments, C of O-demethylated metabolites of deuterated α -dihydrotetrabenazine and deuterated β -dihydrotetrabenazine_maxThe reduction is at least 25%.

In certain embodiments, C of O-demethylated metabolites of deuterated α -dihydrotetrabenazine and deuterated β -dihydrotetrabenazine_maxThe reduction is at least 40%.

In certain embodiments, C of O-demethylated metabolites of deuterated α -dihydrotetrabenazine and deuterated β -dihydrotetrabenazine_maxThe reduction is at least 55%.

In certain embodiments, the pharmaceutical composition produces a reduced C of the total combined amount of deuterated α -dihydrotetrabenazine and deuterated β -dihydrotetrabenazine as compared to a pharmaceutical composition comprising non-deuterated tetrabenazine_maxRatio to AUC.

In certain embodiments, the total combined amount of deuterated α -dihydrotetrabenazine and deuterated β -dihydrotetrabenazine-C is compared to a pharmaceutical composition comprising non-deuterated tetrabenazine_maxThe ratio to AUC decreased by at least 20%.

In certain embodiments, the total combined amount of deuterated α -dihydrotetrabenazine and deuterated β -dihydrotetrabenazine has a C of non-deuterated tetrabenazine at a dosage of non-deuterated tetrabenazine that produces an equivalent AUC of total combined α -dihydrotetrabenazine and β -dihydrotetrabenazine and total combined deuterated α -dihydrotetrabenazine and deuterated β -dihydrotetrabenazine_maxSpecific combined amounts of α -dihydrotetrabenazine and β -dihydrotetrabenazine C_maxIs small.

In certain embodiments, the pharmaceutical composition, when orally administered to a population of patients, produces a reduced inter-patient variability in AUC of the total combined amount of alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine, as compared to non-deuterated tetrabenazine.

In certain embodiments, the pharmaceutical composition, when administered orally to a patient population, produces a reduced inter-patient variability in AUC of alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine of the total combined amount between CYP2D6 poor metabolizers and CYP2D6 strong and moderate metabolizers as compared to non-deuterated tetrabenazine.

In certain embodiments, disclosed herein is a compound of formula i₆-an extended release pharmaceutical formulation of tetrabenazine, which allows a reduced dose relative to non-deuterated tetrabenazine, while maintaining at least equivalent AUC of α -dihydrotetrabenazine and β -dihydrotetrabenazine of the total combination.

In certain embodiments, the dose is reduced by at least 30%.

In certain embodiments, the dose is reduced by at least 40%.

In certain embodiments, the extended release pharmaceutical formulation produces at least a 65% increase in the half-life of the total combined deuterated alpha-dihydrotetrabenazine and deuterated beta-dihydrotetrabenazine relative to the half-life of the alpha-dihydrotetrabenazine and beta-dihydrotetrabenazine resulting from administration of an equivalent formulation comprising non-deuterated tetrabenazine.

In certain embodiments, the extended release pharmaceutical formulation produces a total combined C of deuterated α -dihydrotetrabenazine and deuterated β -dihydrotetrabenazine_maxC relative to α -dihydrotetrabenazine and β -dihydrotetrabenazine resulting from administration of an equivalent formulation comprising non-deuterated tetrabenazine_maxAt least 50% reduction.

In certain embodiments, the extended release pharmaceutical formulation produces a total combined C of deuterated α -dihydrotetrabenazine and deuterated β -dihydrotetrabenazine_maxC of α -dihydrotetrabenazine and β -dihydrotetrabenazine achieved upon administration of an immediate release tetrabenazine formulation that results in at least equivalent AUC of α -dihydrotetrabenazine and β -dihydrotetrabenazine combined total_maxA reduction of at least 50%.

In certain embodiments, the total combined C of deuterated α -dihydrotetrabenazine and deuterated β -dihydrotetrabenazine_maxC relative to α -dihydrotetrabenazine and β -dihydrotetrabenazine_maxThe reduction is at least 60%.

In certain embodiments, the total combination of deuterated α -dihydroC of tetrabenazine and deuterated β -dihydrotetrabenazine_maxC relative to α -dihydrotetrabenazine and β -dihydrotetrabenazine_maxThe reduction is at least 70%.

In certain embodiments, disclosed herein is an extended release pharmaceutical formulation comprising between about 100mg and about 1g of the following in a total weight of solid dosage form for oral delivery:

d between about 2% and about 18%₆-tetrabenazine;

between about 70% and about 96% of one or more diluents;

between about 1% and about 10% of a water soluble binder; and

between about 0.5% and about 2% surfactant.

In certain embodiments, the total weight is about 350mg and about 750 mg.

In certain embodiments, the one or more diluents are selected from mannitol, lactose, and microcrystalline cellulose;

the binder is polyvinylpyrrolidone; and is

The surfactant is a polysorbate.

In certain embodiments, the extended release pharmaceutical formulation comprises between about 2.5% and about 11% d₆-tetrabenazine.

In certain embodiments, the extended release pharmaceutical formulation comprises:

between about 60% and about 70% mannitol or lactose;

between about 15% and about 25% microcrystalline cellulose;

about 5% polyvinylpyrrolidone K29/32; and

between about 1% and about 2% tween 80.

In certain embodiments, the extended release pharmaceutical formulation comprises:

d between about 4% and about 9%₆-tetrabenazine;

between about 60% and about 70% mannitol or lactose;

between about 20% and about 25% microcrystalline cellulose;

about 5% polyvinylpyrrolidone K29/32; and

about 1.4% tween 80.

In certain embodiments, the extended release pharmaceutical formulation comprises about 7.5mg of d₆-tetrabenazine.

In certain embodiments, the extended release pharmaceutical formulation comprises about 15mg of d₆-tetrabenazine.

In certain embodiments, the extended release pharmaceutical formulation comprises about 19.5mg of d₆-tetrabenazine.

In certain embodiments, the extended release pharmaceutical formulation comprises between about 100mg and about 1g of the following in a total weight of solid dosage form for oral delivery:

d between about 70% and about 95%₆Granulating substance of tetrabenazine, wherein d₆-tetrabenazine comprises between about 1% and about 15% granulation;

between about 5% and about 15% of one or more diluents;

between about 5% and about 20% of a sustained release polymer; and

between about 0.5% and about 2% of a lubricant.

In certain embodiments, the extended release pharmaceutical formulation comprises:

between about 5% and about 15% of one or more of spray dried mannitol or nozzle dried lactose;

between about 5% and about 20% of a sustained release polymer; and

between about 0.5% and about 2% magnesium stearate.

In certain embodiments, the sustained release polymer is selected from the group consisting of polyvinyl acetate-polyvinylpyrrolidone mixtures and poly (ethylene oxide) polymers.

In certain embodiments, the sustained release polymer is selected fromSR、N60K and

in certain embodiments, the sustained release polymer is

SR。

In certain embodiments, the sustained release polymer isN60K。

In certain embodiments, the sustained release polymer is

In certain embodiments, the total weight is about 350mg and about 700 mg.

In certain embodiments, the extended release pharmaceutical formulation comprises from about 5mg to about 30mg of d₆-tetrabenazine.

In certain embodiments, the extended release pharmaceutical formulation comprises about 6mg of d₆-tetrabenazine.

In certain embodiments, the extended release pharmaceutical formulation comprises about 12mg of d₆-tetrabenazine.

In certain embodiments, the extended release pharmaceutical formulation comprises about 18mg of d₆-tetrabenazine.

In certain embodiments, the extended release pharmaceutical formulation comprises about 7.5mg of d₆-tetrabenazine.

In certain embodiments, the extended release pharmaceutical formulation comprises about 15mg of d₆-tetrabenazine.

In certain embodiments, the extended release pharmaceutical formulation comprises about 22.5mg of d₆-tetrabenazine.

In certain embodiments, disclosed herein is a method of treating a VMAT 2-mediated disease comprising administering a composition comprising 7.5mg d₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 21.37 + -6.78 ng/mL.

In certain embodiments, disclosed herein is a pharmaceutical composition comprising 7.5mg d for use in treating a VMAT 2-mediated disease₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 21.37 + -6.78 ng/mL.

In certain embodiments, disclosed herein comprise 7.5mg d₆Use of an extended release pharmaceutical composition of tetrabenazine in the manufacture of a medicament for the treatment of VMAT 2-mediated diseases, wherein the total combined amount of the C of deuterated dihydrotetrabenazine_maxIs about 21.37 + -6.78 ng/mL.

In certain embodiments, the AUC of the total combined amount of deuterated dihydrotetrabenazine_infIs about 176.2 ± 69.3hr ng/mL.

In certain embodiments, the AUC of the total combined amount of deuterated dihydrotetrabenazine_(0-12)Is about 110.2 ± 32.1hr ng/mL.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine T_maxIs about 3.17 + -0.68 hr.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine T_halfIs about 7.18 + -1.35 hr.

In certain embodiments, disclosed herein is a method of treating a VMAT 2-mediated disease comprising administering a composition comprising 15mg d₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 45.33 + -8.31ng/mL。

In certain embodiments, disclosed herein is a composition comprising 15mg d for use in treating a VMAT 2-mediated disease₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 45.33. + -. 8.31 ng/mL.

In certain embodiments, disclosed herein are compositions comprising 15mg d₆Use of an extended release pharmaceutical composition of tetrabenazine in the manufacture of a medicament for the treatment of VMAT 2-mediated diseases, wherein the total combined amount of the C of deuterated dihydrotetrabenazine_maxIs about 45.33. + -. 8.31 ng/mL.

In certain embodiments, the AUC of the total combined amount of deuterated dihydrotetrabenazine_infIs about 408.3 ± 147.2hr ng/mL.

In certain embodiments, the AUC of the total combined amount of deuterated dihydrotetrabenazine_(0-12)Is about 250.4 ± 64.0hr ng/mL.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine T_maxIs about 3.21 + -0.45 hr.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine T_halfIs about 7.66 + -1.36 hr.

In certain embodiments, disclosed herein is a method of treating a VMAT 2-mediated disease comprising administering a composition comprising 22.5mg d₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 67.49. + -. 16.72 ng/mL.

In certain embodiments, disclosed herein is a composition comprising 22.5mg d for use in treating a VMAT 2-mediated disease₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 67.49. + -. 16.72 ng/mL.

In certain embodiments, disclosed herein comprise 22.5mg d₆Use of an extended release pharmaceutical composition of tetrabenazine in the manufacture of a medicament for the treatment of VMAT 2-mediated diseases, wherein the total combined amount of deuterated dihydrotetrabenazineQuinolizine C_maxIs about 67.49. + -. 16.72 ng/mL.

In certain embodiments, the AUC of the total combined amount of deuterated dihydrotetrabenazine_infIs about 610 ± 291hr ng/mL.

In certain embodiments, the AUC of the total combined amount of deuterated dihydrotetrabenazine_(0-12)Is about 370 ± 123.7hr ng/mL.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine T_maxIs about 3.79 + -0.84 hr.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine T_halfIs about 8.38 + -2.17 hr.

In certain embodiments, disclosed herein is a method of treating a VMAT 2-mediated disease comprising administering with food a composition comprising 6mg d₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 15.5. + -. 3.5 ng/mL.

In certain embodiments, disclosed herein is a composition comprising 6mg d for use in treating a VMAT 2-mediated disease₆-an extended release pharmaceutical composition of tetrabenazine, wherein the pharmaceutical composition is administered with food and the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 15.5. + -. 3.5 ng/mL.

In certain embodiments, disclosed herein are compositions comprising 6mg d₆-use of an extended release pharmaceutical composition of tetrabenazine in the manufacture of a medicament for the treatment of a VMAT 2-mediated disease, wherein the pharmaceutical composition is administered with food and the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 15.5. + -. 3.5 ng/mL.

In certain embodiments, the AUC of the total combined amount of deuterated dihydrotetrabenazine_infIs about 132 ± 47hr ng/mL.

In certain embodiments, the AUC of the total combined amount of deuterated dihydrotetrabenazine_tIs about 122 ± 46hr ng/mL.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine T_maxIs about 3.74 + -0.99 hr.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine T_halfIs about 8.64 + -1.84 hr.

In certain embodiments, disclosed herein is a method of treating a VMAT 2-mediated disease comprising administering with food a composition comprising 12mg d₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 32.1. + -. 8.1 ng/mL.

In certain embodiments, disclosed herein is a composition comprising 12mg d for use in treating a VMAT 2-mediated disease₆-an extended release pharmaceutical composition of tetrabenazine, wherein the pharmaceutical composition is administered with food and the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 32.1. + -. 8.1 ng/mL.

In certain embodiments, disclosed herein are compositions comprising 12mg d₆-use of an extended release pharmaceutical composition of tetrabenazine in the manufacture of a medicament for the treatment of a VMAT 2-mediated disease, wherein the pharmaceutical composition is administered with food and the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 32.1. + -. 8.1 ng/mL.

In certain embodiments, the AUC of the total combined amount of deuterated dihydrotetrabenazine_infIs about 289 ± 115hr ng/mL.

In certain embodiments, the AUC of the total combined amount of deuterated dihydrotetrabenazine_tIs about 279 ± 114hr ng/mL.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine T_maxIs about 3.90 + -1.27 hr.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine T_halfIs about 9.79 + -2.45 hr.

In certain embodiments, disclosed herein is a method of treating a VMAT 2-mediated disease comprising administering with food a composition comprising 18mg d₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 47.8. + -. 12 ng/mL.

In certain embodiments, disclosed herein is a composition comprising 18mg d for use in treating a VMAT 2-mediated disease₆-an extended release pharmaceutical composition of tetrabenazine, wherein the pharmaceutical composition is administered with food and the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 47.8. + -. 12 ng/mL.

In certain embodiments, disclosed herein are compositions comprising 18mg d₆-use of an extended release pharmaceutical composition of tetrabenazine in the manufacture of a medicament for the treatment of a VMAT 2-mediated disease, wherein the pharmaceutical composition is administered with food and the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 47.8. + -. 12 ng/mL.

In certain embodiments, the AUC of the total combined amount of deuterated dihydrotetrabenazine_infIs about 419 ± 165hr ng/mL.

In certain embodiments, the AUC of the total combined amount of deuterated dihydrotetrabenazine_tIs about 407 ± 163hr ng/mL.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine T_maxIs about 3.63 + -0.85 hr.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine T_halfIs about 10.2 + -3.3 hr.

In certain embodiments, disclosed herein is a method of treating a VMAT 2-mediated disease comprising administering with food a composition comprising 24mg d₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 60.9. + -. 13.8 ng/mL.

In certain embodiments, disclosed herein is a pharmaceutical composition comprising 24mg d for use in treating a VMAT 2-mediated disease₆-an extended release pharmaceutical composition of tetrabenazine, wherein the pharmaceutical composition is administered with food and the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 60.9. + -. 13.8 ng/mL.

In certain embodiments, disclosed herein are compositions comprising 24mg d₆-use of an extended release pharmaceutical composition of tetrabenazine in the manufacture of a medicament for the treatment of a VMAT 2-mediated disease, wherein the pharmaceutical composition is administered with food and the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 60.9. + -. 13.8 ng/mL.

In certain embodiments, the AUC of the total combined amount of deuterated dihydrotetrabenazine_infIs about 580 ± 229hr ng/mL.

In certain embodiments, the AUCt of the total combined amount of deuterated dihydrotetrabenazine is about 569 ± 225hr ng/mL.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine T_maxIs about 3.92 + -1.19 hr.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine T_halfIs about 6.00 + -1.60 hr.

In certain embodiments, disclosed herein is a method of treating a VMAT 2-mediated disease comprising administering with a high fat meal a composition comprising 18mg d₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 49.0. + -. 8.1 ng/mL.

In certain embodiments, disclosed herein is a composition comprising 18mg d for use in treating a VMAT 2-mediated disease₆-an extended release pharmaceutical composition of tetrabenazine, wherein the pharmaceutical composition is administered with a high fat meal and the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 49.0. + -. 8.1 ng/mL.

In certain embodiments, disclosed herein are compositions comprising 18mg d₆-use of an extended release pharmaceutical composition of tetrabenazine in the manufacture of a medicament for the treatment of a VMAT 2-mediated disease, wherein the pharmaceutical composition is administered with a high fat meal and the total combined amount of C of deuterated dihydrotetrabenazine_maxIs about 60.9. + -. 13.8 ng/mL.

In certain embodiments, the AUC of the total combined amount of deuterated dihydrotetrabenazine_infIs about 436 ± 129hr ng/mL.

In certain embodimentsAUC of total combined amount of deuterated dihydrotetrabenazine_tIs about 425 ± 127hr ng/mL.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine T_maxIs about 4.09 + -1.25 hr.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine T_halfIs about 10.2 + -2.5 hr.

In certain embodiments, disclosed herein is a method of treating a VMAT 2-mediated disease comprising administering with food a composition comprising 15mg d₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 33.3. + -. 11 ng/mL.

In certain embodiments, disclosed herein is a composition comprising 15mg d for use in treating a VMAT 2-mediated disease₆-an extended release pharmaceutical composition of tetrabenazine, wherein the pharmaceutical composition is administered with food and the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 33.3. + -. 11 ng/mL.

In certain embodiments, disclosed herein are compositions comprising 15mg d₆-use of an extended release pharmaceutical composition of tetrabenazine in the manufacture of a medicament for the treatment of a VMAT 2-mediated disease, wherein the pharmaceutical composition is administered with food and the total combined amount of deuterated dihydrotetrabenazine C_maxIs about 33.3. + -. 11 ng/mL.

In certain embodiments, the AUC of the total combined amount of deuterated dihydrotetrabenazine_infIs about 305 ± 141hr ng/mL.

In certain embodiments, the AUC of the total combined amount of deuterated dihydrotetrabenazine_(0-12)Is about 189 ± 65hr ng/mL.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine T_maxIs about 6.00 hr.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine T_halfIs about 6.00 + -1.60 hr.

In certain embodiments, disclosed herein is a method of treating VMAT2 mediationThe method comprising administering with food a composition comprising d₆-extended release pharmaceutical composition of tetrabenazine, wherein the fed and fasted C of the total combined amount of deuterated dihydrotetrabenazine_maxThe ratio of (A) to (B) is greater than 1.

In certain embodiments, disclosed herein is a composition comprising d for use in treating a VMAT 2-mediated disease₆-an extended release pharmaceutical composition of tetrabenazine, wherein the pharmaceutical composition is administered with food and the fed and fasted C of the total combined amount of deuterated dihydrotetrabenazine_maxThe ratio of (A) to (B) is greater than 1.

In certain embodiments, disclosed herein is a pharmaceutical composition comprising d for use in the manufacture of a medicament for treating a VMAT 2-mediated disease₆-an extended release pharmaceutical composition of tetrabenazine, wherein the pharmaceutical composition is administered with food and the fed and fasted C of the total combined amount of deuterated dihydrotetrabenazine_maxThe ratio of (A) to (B) is greater than 1.

In certain embodiments, fed and fasted C_maxThe ratio of (A) to (B) is greater than about 1.4.

In certain embodiments, fed and fasted C_maxThe ratio of is greater than about 1.9.

In certain embodiments, disclosed herein is a method of treating a VMAT 2-mediated disease comprising administering with food a composition comprising d₆-extended release pharmaceutical compositions of tetrabenazine, wherein the fed and fasted AUC of the total combined amount of deuterated dihydrotetrabenazine_infThe ratio of (A) to (B) is greater than 1.

In certain embodiments, disclosed herein is a composition comprising d for use in treating a VMAT 2-mediated disease₆-an extended release pharmaceutical composition of tetrabenazine, wherein the pharmaceutical composition is administered with food and the fed and fasted AUC of the total combined amount of deuterated dihydrotetrabenazine_infThe ratio of (A) to (B) is greater than 1.

In certain embodiments, disclosed herein is a pharmaceutical composition comprising d for use in the manufacture of a medicament for treating a VMAT 2-mediated disease₆-extended release pharmaceutical compositions of tetrabenazine,wherein the pharmaceutical composition is administered with food and a fed and a fasted AUC of the total combined amount of deuterated dihydrotetrabenazine_infThe ratio of (A) to (B) is greater than 1.

In certain embodiments, fed versus fasted AUC_infThe ratio of (A) to (B) is greater than about 1.1.

In certain embodiments, fed versus fasted AUC_infThe ratio of is greater than about 1.2.

In certain embodiments, disclosed herein is a composition comprising d for use in treating a VMAT 2-mediated disease₆-an extended release pharmaceutical composition of tetrabenazine, wherein the pharmaceutical composition is administered with food and the fed and fasted AUC of the total combined amount of deuterated dihydrotetrabenazine_tThe ratio of (A) to (B) is greater than 1.

In certain embodiments, disclosed herein is a pharmaceutical composition comprising d for use in the manufacture of a medicament for treating a VMAT 2-mediated disease₆-an extended release pharmaceutical composition of tetrabenazine, wherein the pharmaceutical composition is administered with food and the fed and fasted AUC of the total combined amount of deuterated dihydrotetrabenazine_tThe ratio of (A) to (B) is greater than 1.

In certain embodiments, fed versus fasted AUC_tThe ratio of (A) to (B) is greater than about 1.1.

In certain embodiments, fed versus fasted AUC_tThe ratio of is greater than about 1.2.

In certain embodiments, disclosed herein is a method of treating a VMAT 2-mediated disease comprising administering a plurality of doses comprising 7.5mg d₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine is stable state C_maxIs about 31.5. + -. 8.16 ng/mL.

In certain embodiments, disclosed hereinA composition comprising 7.5mg d for use in the treatment of a disease mediated by VMAT2₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine is stable state C_maxIs about 31.5. + -. 8.16 ng/mL.

In certain embodiments, disclosed herein is a pharmaceutical composition for use in the manufacture of a medicament for treating a VMAT 2-mediated disease comprising 7.5mg d₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine is stable state C_maxIs about 31.5. + -. 8.16 ng/mL.

In certain embodiments, the steady state AUC of the total combined amount of deuterated dihydrotetrabenazine_(0-12)Is about 203 ± 69.2hr ng/mL.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine has a steady state T_maxIs about 3.17 + -0.49 hr.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine has a steady state T_halfIs about 8.8 + -1.97 hr.

In certain embodiments, disclosed herein is a method of treating a VMAT 2-mediated disease comprising administering a plurality of doses comprising 15mg d₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine is stable state C_maxIs about 72.0 + -14.5 ng/mL.

In certain embodiments, disclosed herein is a pharmaceutical composition comprising 15mg d for use in the manufacture of a medicament for treating a VMAT 2-mediated disease₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine is stable state C_maxIs about 72.0 + -14.5 ng/mL.

In certain embodiments, theStable state AUC of a combined amount of deuterated dihydrotetrabenazine_(0-12)Is about 443 ± 125.8hr ng/mL.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine has a steady state T_maxIs about 2.78 + -0.41 hr.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine has a steady state T_halfIs about 9.06 + -2.53 hr.

In certain embodiments, disclosed herein is a method of treating a VMAT 2-mediated disease comprising administering a plurality of doses comprising 22.5mg d₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine is stable state C_maxIs about 111.0 + -47.2 ng/mL.

In certain embodiments, disclosed herein is a pharmaceutical composition for use in the manufacture of a medicament for treating a VMAT 2-mediated disease comprising 22.5mg d₆-extended release pharmaceutical compositions of tetrabenazine, wherein the total combined amount of deuterated dihydrotetrabenazine is stable state C_maxIs about 111.0 + -47.2 ng/mL.

In certain embodiments, the steady state AUC of the total combined amount of deuterated dihydrotetrabenazine_(0-12)Is about 769 ± 357hr ng/mL.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine has a steady state T_maxIs about 3.75 + -0.79 hr.

In certain embodiments, the total combined amount of deuterated dihydrotetrabenazine has a steady state T_halfIs about 9.50 + -2.32 hr.

In certain embodiments, the VMAT 2-mediated condition is chronic hyperkinetic movement disorder.

In certain embodiments, the VMAT 2-mediated condition is selected from the group consisting of: huntington's disease, hemiballism (hemiballismus), senile chorea, tic disorders, tardive dyskinesia, dystonia, Tourette's syndrome, depression, cancer, rheumatoid arthritis, psychosis, multiple sclerosis and asthma.

In certain embodiments, the VMAT 2-mediated disorder is huntington's disease.

In certain embodiments, the VMAT 2-mediated disorder is hemiballism.

In certain embodiments, the VMAT 2-mediated condition is senile chorea.

In certain embodiments, the VMAT 2-mediated disorder is a tic disorder.

In certain embodiments, the VMAT 2-mediated condition is tardive dyskinesia.

In certain embodiments, the VMAT 2-mediated condition is a dystonia.

In certain embodiments, the VMAT 2-mediated disorder is tourette's syndrome.

In certain embodiments, the VMAT 2-mediated condition is depression.

In certain embodiments, the VMAT 2-mediated disorder is cancer.

In certain embodiments, the VMAT 2-mediated disorder is rheumatoid arthritis.

In certain embodiments, the VMAT 2-mediated condition is a psychosis.

In certain embodiments, the VMAT 2-mediated condition is multiple sclerosis.

In certain embodiments, the VMAT 2-mediated condition is asthma.

In certain embodiments, disclosed herein is a compound of formula i₆-a tetrabenazine polymorph form I compound.

In certain embodiments, the compounds may be identified by reference to an X-ray diffraction pattern comprising major peaks, in terms of 2 Θ, at about 8.3, about 11.6, about 13.9, about 20.0, and about 23.7.

In certain embodiments, the compounds may be identified by reference to an X-ray diffraction pattern comprising major peaks, in terms of 2 Θ, at about 8.3, about 9.8, about 11.6, about 12.0, about 13.9, about 20.0, about 22.0, about 23.7, about 24.4, about 33.5, and about 42.3.

In certain embodiments, the compounds can be identified by reference to an X-ray powder diffraction pattern substantially as shown in figure 9.

In certain embodiments, the compound has a differential calorimetry trace comprising an endotherm between about 115 ℃ and about 135 ℃.

In certain embodiments, the compound has a differential calorimetry trace substantially as shown in figure 8.

In certain embodiments, the compound has a thermogravimetric analysis curve showing about 1.5% weight loss at less than about 150 ℃.

In certain embodiments, the compound has a thermogravimetric analysis curve substantially as shown in figure 7.

In certain embodiments, disclosed herein is a compound prepared as₆-a process for the preparation of a compound of formula I, wherein the process comprises cooling d₆-a saturated ethanol solution of tetrabenazine.

In certain embodiments, d is₆-tetrabenazine was dissolved in 3 volumes of ethanol and then cooled to room temperature at a rate of 20 ℃/hr.

In certain embodiments, the method further comprises formulating d₆-a tetrabenazine polymorph form I to produce a pharmaceutical composition.

In certain embodiments, disclosed herein is a compound of formula i₆-a tetraphenylquinolizine polymorph form I compound prepared by a process comprising cooling d₆A saturated ethanol solution of tetrabenazine.

In certain embodiments, disclosed herein is a pharmaceutical composition comprising d₆-a tetrabenazine polymorph form I pharmaceutical composition.

In certain embodiments, disclosed herein is a pharmaceutical composition comprising d₆-Tetrabenzoquinolizine polymorph form I, wherein d₆-Tetrabenzoquinolizine polymorph I by including cooling d₆A saturated ethanol solution of tetrabenazine.

In certain embodiments, disclosed herein is a method of treating a VMAT 2-mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of d₆-tetrabenazine polymorphic form I, said d₆-Tetrabenzoquinolizine polymorph I by including cooling d₆A saturated ethanol solution of tetrabenazine.

In certain embodiments, disclosed herein is a compound of formula i for use in treating a VMAT 2-mediated disorder₆-a tetrabenazine polymorph form I compound.

In certain embodiments, disclosed herein is a pharmaceutical composition comprising a compound of formula i d for use in treating a VMAT 2-mediated disorder₆-a tetrabenazine polymorph form I compound.

In certain embodiments, disclosed herein as d₆-use of a tetrabenazine polymorph form I compound in the manufacture of a medicament for the treatment of a VMAT 2-mediated disorder.

In certain embodiments, disclosed herein are compounds comprising a moiety of formula i₆-use of a pharmaceutical composition of a compound of tetrabenazine polymorph form I in the manufacture of a medicament for the treatment of a VMAT 2-mediated disorder.

In certain embodiments, disclosed herein is a compound of formula i₆-a tetrabenazine polymorph form II compound.

In certain embodiments, the compounds can be identified by reference to an X-ray powder diffraction pattern substantially as shown in figure 12.

In certain embodiments, the compound has a differential calorimetry trace comprising an endotherm between about 120 ℃ and about 140 ℃.

In certain embodiments, the compound has a differential calorimetry trace substantially as shown in figure 11.

In certain embodiments, the compound has a thermogravimetric analysis curve showing about 1.5% weight loss at less than about 160 ℃.

In certain embodiments, the compound has a thermogravimetric analysis curve substantially as shown in figure 10.

In certain embodiments, disclosed herein is a compound prepared as₆-a process for preparing a compound of formula II, wherein d is evaporated₆-a saturated methanol solution of tetrabenazine.

In certain embodiments, d₆A methanol solution of tetrabenazine slowly evaporates at ambient temperature and humidity.

In certain embodiments, the method further comprises formulating d₆-a tetrabenazine polymorph form II to produce a pharmaceutical composition.

In certain embodiments, disclosed herein is a compound of formula i₆-a compound of tetrabenazine polymorph form II by a process comprising evaporation of d₆-tetrabenazine in saturated methanol.

In certain embodiments, disclosed herein is a pharmaceutical composition comprising d₆-Tetrabenzoquinolizine polymorphsA pharmaceutical composition of form II.

In certain embodiments, disclosed herein is a pharmaceutical composition comprising d₆-a pharmaceutical composition of tetrabenazine polymorph form II, wherein d₆-tetrabenazine polymorphic form II by processes involving evaporation of d₆-tetrabenazine in saturated methanol.

In certain embodiments, disclosed herein is a method of treating a VMAT 2-mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of d₆-tetrabenazine polymorphic form II, said d₆-tetrabenazine polymorphic form II by processes involving evaporation of d₆-tetrabenazine in saturated methanol.

In certain embodiments, disclosed herein is a compound of formula i for use in treating a VMAT 2-mediated disorder₆-a tetrabenazine polymorph form II compound.

In certain embodiments, disclosed herein as d₆-use of a compound of tetrabenazine polymorph form II in the manufacture of a medicament for the treatment of a VMAT 2-mediated disorder.

In certain embodiments, disclosed herein are compounds comprising a moiety of formula i₆-use of a pharmaceutical composition of a compound of tetrabenazine polymorph form II in the manufacture of a medicament for the treatment of a VMAT 2-mediated disorder.

In certain embodiments of the present invention, the compositions disclosed herein comprise a compound having structural formula I:

or a salt, solvate, or prodrug thereof, wherein:

R₁-R₂₇independently selected from the group consisting of hydrogen and deuterium; and is

R₁-R₂₇Is deuterium.

In certain embodiments of the present invention, the compositions disclosed herein comprise a compound having structural formula II:

or a salt thereof, wherein:

R₁-R₂₈independently selected from the group consisting of hydrogen and deuterium;

R₂₉selected from the group consisting of: hydrogen, deuterium, -C (O) O-alkyl and-C (O) -C_1-6Alkyl, or a group cleavable under physiological conditions, wherein said alkyl or C_1-6Alkyl is optionally selected from the group consisting of-NH-C (NH) NH₂、-CO₂H、-CO₂Alkyl, -SH, -C (O) NH₂、-NH₂Phenyl, -OH, 4-hydroxyphenyl, imidazolyl and indolyl, and any R₂₉The substituents are further optionally substituted with deuterium; and is

R₁-R₂₉Is deuterium or contains deuterium.

In certain embodiments of the present invention, the compositions disclosed herein comprise the following compounds:

in certain embodiments of the present invention, the compositions disclosed herein comprise the following compounds:

in certain embodiments of the present invention, the compositions disclosed herein comprise one or more of the following compounds:

(+)-d₆-α-HTBZ

(-)-d₆-α-HTBZ

(+)-d₆-β-HTBZ

(-)-d₆-β-HTBZ

in certain embodiments of the present invention, the compositions disclosed herein comprise one or more of the following compounds:

(+)-d₃-9-O-demethyl- α -HTBZ

(-)-d₃-9-O-demethyl- α -HTBZ

(+)-d₃-9-O-demethyl- β -HTBZ

(-)-d₃-9-O-demethyl- β -HTBZ

(+)-d₃-10-O-demethyl- β -HTBZ

(-)-d₃-10-O-demethyl- β -HTBZ

In certain embodiments of the present invention, the compositions disclosed herein comprise one or more of the following compounds:

(+)-α-HTBZ

(-)-α-HTBZ

(+)-β-HTBZ

(-)-β-HTBZ

in certain embodiments of the present invention, the compositions disclosed herein comprise one or more of the following compounds:

(+) -9-O-demethyl-alpha-HTBZ

(-) -9-O-demethyl-alpha-HTBZ

(+) -9-O-demethyl-beta-HTBZ

(-) -9-O-demethyl-beta-HTBZ

(+) -10-O-demethyl-beta-HTBZ

(-) -10-O-demethyl-beta-HTBZ

Certain compounds disclosed herein may possess potent VMAT2 inhibitory activity and may be used to treat or prevent conditions in which VMAT2 plays a positive role. Accordingly, certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein and a pharmaceutically acceptable carrier, and methods of making and using the compounds and compositions. Certain embodiments provide methods for inhibiting VMAT 2. Other embodiments provide methods for treating a VMAT 2-mediated disorder in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound or composition according to the invention. Also provided is the use of certain compounds disclosed herein for the manufacture of a medicament for the prevention or treatment of a disorder ameliorated by the inhibition of VMAT 2.

The compounds as disclosed herein may also contain less common isotopes of other elements, including but not limited to carbon¹³C or¹⁴Of C, S³³S、³⁴S or³⁶Of S, N¹⁵Of N and oxygen¹⁷O or¹⁸O。

In certain embodiments, the compounds disclosed herein can expose a patient to a maximum of about 0.000005% D₂O or about 0.00001% DHO, assuming all C-D bonds in the compound as disclosed herein are metabolized and released as D₂O or DHO. In certain embodiments, D is shown to cause toxicity in animals₂The level of O is even much greater than the maximum limit of exposure caused by administration of deuterium enriched compounds as disclosed herein. Thus, in certain embodiments, deuterium-enriched compounds disclosed herein should not form D upon drug metabolism₂O or DHO to cause any additional toxicity.

In certain embodiments, the deuterated compounds disclosed herein maintain the beneficial aspects of the corresponding non-isotopically enriched molecules while substantially increasing the maximum tolerated dose, reducing toxicity, increasing half-life (T) and the like_1/2) Lowering the maximum plasma concentration (C) of the Minimum Effective Dose (MED)_max) Reducing the effective dose and thus reducing non-mechanism related toxicity, and/or reducing the likelihood of drug-drug interactions.

All publications and references cited herein are expressly incorporated herein by reference in their entirety. However, for any similar or identical term found in the incorporated publications or references, as well as terms explicitly set forth or defined in this document, then those term definitions or meanings explicitly set forth in this document shall control in all respects.

As used herein, the following terms have the meanings indicated.

The singular forms "a", "an" and "the" may refer to a plurality of items unless specifically stated otherwise.

As used herein, the term "about" is intended to define the numerical value modified by it, indicating that the value is a variable within the margin of error. When no particular margin of error is recited, such as the standard deviation of the mean values given in a data sheet or table, the term "about" should be understood to mean that the range of values recited is intended to be encompassed, and that ranges encompassed, given the significant figure, by the rounding up or down of that figure.

When disclosing ranges of values and uses "from n₁… to n₂"or" n₁-n₂"(wherein n is₁And n₂Is a number), this notation is intended to include the numbers themselves and ranges therebetween unless otherwise indicated. This range can be an integer or continuous range between and including the endpoints.

Term d₆-tetrabenazine and (+/-) -cis-d₆-tetrabenazine refers to (3R,11bR) -1,3,4,6,7,11 b-hexahydro-9, 10-di (methoxy-d)₃) -3- (2-methylpropyl) -2H-benzo [ a]Quinolizin-2-one and (3S,11bS) -1,3,4,6,7,11 b-hexahydro-9, 10-di (methoxy-d)₃) -3- (2-methylpropyl) -2H-benzo [ a]Racemic mixtures of quinolizin-2-ones having the following structure:

(3R,11bR) -1,3,4,6,7,11 b-hexahydro-9, 10-di (methoxy-d)₃) -3- (2-methylpropyl) -2H-benzo [ a]Quinolizin-2-ones

(3S,11bS) -1,3,4,6,7,11 b-hexahydro-9, 10-di (methoxy-d)₃) -3- (2-methylpropyl) -2H-benzo [ a]Quinolizin-2-ones

The term (+/-) -trans-d₆-tetrabenazine denotes (3R,11bS) -1,3,4,6,7,11 b-hexahydro-9, 10-di (methoxy-d)₃) -3- (2-methylpropyl) -2H-benzo [ a]Quinolizin-2-one and (3S,11bR) -1,3,4,6,7,11 b-hexahydro-9, 10-di (methoxy-d)₃) -3- (2-methylpropyl) -2H-benzo [ a]Racemic mixtures of quinolizin-2-ones having the following structuresStructure:

(3R,11bS) -1,3,4,6,7,11 b-hexahydro-9, 10-di (methoxy-d)₃) -3- (2-methylpropyl) -2H-benzo [ a]Quinolizin-2-ones

(3S,11bR) -1,3,4,6,7,11 b-hexahydro-9, 10-di (methoxy-d)₃) -3- (2-methylpropyl) -2H-benzo [ a]Quinolizin-2-ones

The term "deuterium enrichment" refers to the percentage of deuterium incorporated in place of hydrogen at a given position in a molecule. For example, deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Since the naturally occurring deuterium distribution is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. Deuterium enrichment can be determined using conventional analytical methods known to those of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

The term "is deuterium" when used to describe a given position in a molecule such as R₁-R₂₉When used in reference to a given position in a graphic representation of a molecular structural formula, the symbol "D" indicates that the specified position is enriched in deuterium above the naturally occurring deuterium distribution. In one embodiment, deuterium enrichment at the designated positions is no less than about 1%, in another embodiment no less than about 5%, in another embodiment no less than about 10%, in another embodiment no less than about 20%, in another embodiment no less than about 50%, in another embodiment no less than about 70%, in another embodiment no less than about 80%, in another embodiment no less than about 90%, or in another embodiment no less than about 98% deuterium.

The term "isotopically enriched" refers to the percentage of a less prevalent isotope of an element incorporated at a given position in a molecule that replaces a more prevalent isotope of the element.

The term "non-isotopically enriched" refers to molecules in which the percentage of each isotope is substantially the same as the percentage that is naturally occurring.

Asymmetric centers exist for the compounds disclosed herein. These centers are indicated by the symbol "R" or "S" depending on the configuration of the substituents around the chiral carbon atom. It is to be understood that the present invention encompasses all stereochemically isomeric forms, including diastereomeric, enantiomeric and epimeric forms, as well as the D-and L-isomers and mixtures thereof. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials containing chiral centers, or synthetically by: preparation of a mixture of enantiomeric products, followed by separation, e.g. conversion, into a mixture of diastereomers, followed by separation or recrystallization; chromatographic techniques; separating enantiomers directly on a chiral chromatographic column; or any other suitable method known in the art. Starting compounds having specific stereochemistry are commercially available or may be prepared and isolated by techniques known in the art. In addition, the compounds disclosed herein may exist as geometric isomers. The present invention includes all cis, trans, cis (syns), trans (anti), trans (entgegen) (E) and cis (zusammen) (Z) isomers and suitable mixtures thereof. Furthermore, the compounds may exist as tautomers; the present invention provides all tautomers. In addition, the compounds disclosed herein may exist in unsolvated forms as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to unsolvated forms.

The term "bond" refers to a covalent linkage between two atoms or two moieties (when the atoms linked by the bond are considered to be part of a larger substructure). Unless otherwise indicated, the bonds may be single, double and triple bonds. The dashed line between two atoms in the molecular representation indicates that additional bonds may or may not be present at that position.

As used herein, the term "disorder" is meant to be generally synonymous with, and interchangeable with, the terms "disease," "syndrome," and "condition" (as in medical conditions), in that they each reflect an abnormal condition of the human or animal body or body part that impairs normal function, typically manifested by distinct signs and symptoms.

The terms "treat", "treating" and "treatment" are intended to include alleviating or eliminating a disorder or one or more symptoms associated with a disorder; or to reduce or eradicate the cause of the disorder itself. As used herein, reference to "treatment" of a disorder is intended to include prophylaxis. The terms "preventing", "preventing" and "prevention" refer to a method of delaying or preventing the onset of a disorder and/or its complications, preventing the subject from acquiring a disorder, or reducing the risk of the subject from acquiring a disorder.

The term "therapeutically effective amount" refers to an amount of a compound that, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more symptoms of the disorder being treated. The term "therapeutically effective amount" also refers to an amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or clinician.

The term "subject" refers to an animal, including, but not limited to, primates (e.g., humans, monkeys, chimpanzees, gorillas, etc.), rodents (e.g., rats, mice, gerbils, hamsters, chinchillas, etc.), rabbits, pigs (e.g., pigs, piglets), horses, dogs, cats, etc. The terms "subject" and "patient" are used interchangeably herein when referring to, for example, a mammalian subject, such as a human patient.

The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule containing a fixed ratio of active ingredients, or in multiple, separate capsules of each active ingredient. Furthermore, such administration also encompasses the use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide the beneficial effects of the drug combination in treating the conditions described herein.

The term "chronic hyperkinetic movement disorder" refers to a condition characterized by unintended, repetitive, disorganized motor muscle action variously referred to as "obsessive", "rhythmic", or "stereotyped". In humans, chronic hyperkinetic movement disorders can be psychogenic (e.g., tics), idiopathic (as in, for example, tourette's syndrome and parkinson's disease), hereditary (as in, for example, the characteristics of Chorea such as huntington's disease), infectious (as in, for example, Sydenham's Chorea), or drug-induced as in tardive dyskinesia. Unless otherwise stated, "chronic hyperkinetic movement disorder" refers to and includes all psychiatric, idiopathic, genetic, and drug-induced movement disorders.

The term "stereotypical" refers to a repetitive behavior that varies slightly or often very little as a repetitive appearance of a series of complex movements.

The term "VMAT 2" refers to vesicular monoamine transporter 2, which is an integral membrane protein used to transport monoamines, particularly neurotransmitters such as dopamine, norepinephrine, 5-hydroxytryptamine, and histamine, from the cytosol of a cell to synaptic vesicles.

The term "VMAT 2-mediated disorder" refers to a disorder characterized by aberrant VMAT2 activity. VMAT 2-mediated disorders can be mediated in whole or in part by modulation of VMAT 2. In particular, a VMAT 2-mediated disorder is one in which inhibition of VMAT2 results in some impact on the underlying disorder, e.g., administration of a VMAT2 inhibitor results in some improvement in at least some patients being treated.

The term "VMAT 2 inhibitor", "inhibiting VMAT 2", or "inhibition of VMAT 2" refers to the ability of a compound disclosed herein to alter the function of VMAT 2. The VMAT2 inhibitor can block or reduce the activity of VMAT2 by forming a reversible or irreversible covalent bond between the inhibitor and VMAT2 or by forming a non-covalently bound complex. Such inhibition may be shown only in specific cell types, or may depend on a particular biological event. The terms "VMAT 2 inhibitor", "inhibiting VMAT 2", or "inhibition of VMAT 2" also refer to altering the function of VMAT2 by reducing the likelihood of complex formation between VMAT2 and a natural substrate.

The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, or zwitterionic forms, etc.) that are suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response, immunogenicity, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.

The term "pharmaceutically acceptable carrier", "pharmaceutically acceptable excipient", "physiologically acceptable carrier" or "physiologically acceptable excipient" refers to a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each component must be "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation. They must also be suitable for use in contact with the tissues or organs of humans and animals without undue toxicity, irritation, allergic response, immunogenicity, or other problems or complications commensurate with a reasonable benefit/risk ratio. See Remington, The Science and Practice of Pharmacy, 21 st edition; philadelphia, PA,2005, Lippincott Williams & Wilkins; handbook of Pharmaceutical Excipients, 5 th edition; rowe et al, The Pharmaceutical Press and The American Pharmaceutical Association, 2005; and Handbook of Pharmaceutical Additives, 3 rd edition; ash and Ash, Gower Publishing Company 2007; pharmaceutical preparation and Formulation, Gibson, CRC Press LLC: Boca Raton, FL, 2004).

The terms "active ingredient," "active compound," and "active substance" refer to a compound that is administered to a subject, alone or with one or more pharmaceutically acceptable excipients or carriers, for the treatment, prevention, or amelioration of one or more symptoms of a disorder.

The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a compound or pharmaceutical composition thereof that is administered to a subject for the treatment, prevention, or amelioration of one or more symptoms of a disorder.

The term "release controlling excipient" refers to an excipient whose primary function is to modify the duration or location of release of an active agent from a dosage form as compared to conventional immediate release dosage forms.

The term "non-release controlling excipient" refers to an excipient whose primary function does not include modifying the duration or location of release of the active agent from the dosage form as compared to conventional immediate release dosage forms.

The term "prodrug" refers to a functional derivative of a compound as disclosed herein, and is readily converted in vivo to the parent compound. Prodrugs are often useful because, in some cases, they are easier to administer than the parent compound. For example, they may be bioavailable by oral administration, whereas the parent compound is not. Prodrugs may also have enhanced solubility in pharmaceutical compositions relative to the parent compound. Prodrugs can be converted to the parent drug by a variety of mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962,4, 221-; morozowich et al, "D esign of Biopharmaceutical Properties through drugs and domains," Roche eds., APHA Acad. pharm. Sci.1977; "Bioreversible Carriers in drug Design, Theory and Application," Roche ed., APHA Acad. pharm. Sci.1987; "Design of Prodrugs," Bundgaard, Elsevier, 1985; wang et al, curr. Ph arm. design 1999,5, 265-287; pauletti et al, adv. drug. delivery Rev.1997,27, 235-256; mizen et al, pharm.Biotech.1998,11, 345-; gaignault et al, P ract. Med. chem.1996, 671-696; asghannejad, "Transport Processes in pharmaceutical Systems," Amidon et al, Marcell Dekker, 185-; balan t et al, Eur.J.drug Metab.Pharmacokinet.1990,15,143-53; balimane and Sin ko, adv. drug Delivery Rev.1999,39, 183-209; brown, clin. neuropharma col.1997,20, 1-12; bundgaard, arch, pharm, chem, 1979,86, 1-39; bundg aard, Controlled Drug Delivery 1987,17, 179-96; bundgaard, adv. drug Delivery rev.1992,8, 1-38; fleisher et al, adv. drug Delivery Rev.1996,19, 115-130; fleisher et al, Methods Enzymol.1985,112, 360-381; farquhar et al, J.P harm.Sci.1983,72, 324-325; freeman et al, J.chem.Soc., chem.Commun.1991, 875-877; friis and Bundgaard, eur.j.pharm.sci.1996,4, 49-59; ga ngwar et al, Des.Biopharm.Prop.Prodrugs alloys, 1977, 409-421; nathwani and Wood, Drugs 1993,45, 866-94; sinhababu and Thakker, adv. drug delivery ry Rev.1996,19, 241-; stella et al, Drugs 1985,29, 455-73; tan et al, adv. drug delivery Rev.1999,39, 117-151; taylor, adv. drug Delivery Rev.1996,19, 131-; valentino and Borchardt, Drug Discovery Today 1997,2, 148-155; wiebe and Knaus, adv. drug Delivery rev.1999,39, 63-80; waller et al, Br.J.Clin.Pharmac.1989,28, 497-Buff 507.

The compounds disclosed herein may be present as therapeutically acceptable salts. As used herein, the term "therapeutically acceptable salt" represents a salt or zwitterionic form of a compound disclosed herein, which is therapeutically acceptable (as defined herein). The salts may be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound with the appropriate acid or base. Therapeutically acceptable salts include acid addition salts and base addition salts. For a more complete discussion of salt preparation and selection, reference is made to the Handbook of Pharmaceutical Salts, Properties, and Use, edited by Stah and Wermuth, (Wiley-VCH and VHCA, Zurich,2002) and Berge et al, J.pharm.Sci.1977,66, 1-19.

Suitable acids for use in preparing pharmaceutically acceptable salts include, but are not limited to: acetic acid, 2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+) -camphoric acid, camphorsulfonic acid, (+) - (1S) -camphorsulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1, 2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L-glutamic acid, alpha-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+) -L-lactic acid, (±) -DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-) -L-malic acid, malonic acid, (±) -DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-1, 5-disulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, glucaric acid, salicylic acid, 4-aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+) -L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid.

Suitable bases for use in preparing pharmaceutically acceptable salts include, but are not limited to: inorganic bases such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide or sodium hydroxide; and organic bases, such as primary, secondary, tertiary and quaternary aliphatic and aromatic amines, including L-arginine, benzphetamine, benzathine, choline, danitol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2- (diethylamino) -ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, morpholine, 4- (2-hydroxyethyl) -morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, 1- (2-hydroxyethyl) -pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amine, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2- (hydroxymethyl) -1, 3-propanediol and tromethamine.

Reference to compounds of formula (la) and subgroups thereof includes ionic forms, polymorphs, pseudopolymorphs, amorphous forms and solvates thereof. "crystalline form," "polymorph," and "new form" are used interchangeably herein and are intended to include all crystalline and amorphous forms of the compounds, including, for example, polymorphs, pseudopolymorphs, solvates (including hydrates), co-crystals, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms, and mixtures thereof, unless a particular crystalline form or amorphous form is referred to. In some embodiments, the compounds referred to include polymorphs, solvates, and/or co-crystals thereof. In some embodiments, reference to a compound having formula (la) and subgroups thereof includes polymorphs thereof. Similarly, the term "salt" includes polymorphs of salts of the compounds.

Pharmaceutical preparation

While the compounds of the present invention may be capable of administration as crude chemicals, they may also be provided in the form of pharmaceutical compositions. Thus, provided herein are pharmaceutical compositions comprising one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, prodrugs, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. Suitable formulations depend on the chosen route of administration. Any of the well known techniques, carriers and excipients may be suitably and as understood in the art used; for example in Remington's pharmaceutical sciences. The pharmaceutical compositions disclosed herein can be manufactured in any manner known in the art, for example, by means of conventional mixing, dissolving, granulating, drage-making, levigating, emulsifying, encapsulating, entrapping or compressing processes. The pharmaceutical composition can also be formulated into controlled release dosage forms, including delayed release, extended release, delayed release, sustained release, pulsatile release, controlled release, accelerated and rapid release, targeted release, programmed release; and gastroretentive dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in The art (see Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug delivery Technology, Rathbone et al, Drugs and The Pharmaceutical Science, Marcel Dekker, Inc., New York, NY, 2002; Vol.126).

The compositions include compositions suitable for oral administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Generally, these methods comprise the step of bringing into association a compound of the invention, or a pharmaceutically salt, prodrug or solvate thereof ("active ingredient"), with the carrier which constitutes one or more accessory ingredients. Generally, the composition is prepared by the following method: the active ingredient is uniformly and intimately associated with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, the product is shaped into the desired formulation.

Formulations of the compounds disclosed herein suitable for oral administration may be presented as discrete units such as capsules, cachets, or tablets each containing a predetermined amount of the active ingredient; a powder or granules; solutions or suspensions in aqueous or non-aqueous liquids; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be provided as a bolus (bolus), electuary or paste.

Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin and sealed soft capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be prepared by compression or moulding, optionally together with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, inert diluent, or lubricant, surfactant or dispersant. Molded tablets may be prepared by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored (coded) and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules may contain the active ingredient in admixture with fillers (such as lactose), binders (such as starches) and/or lubricants (such as talc or magnesium stearate) and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyes or pigments may be added to the tablets or dragee coatings to identify or characterize different combinations of active compound doses.

In certain embodiments, the diluent is selected from the group consisting of: mannitol powder, spray-dried mannitol, microcrystalline cellulose, lactose, dicalcium phosphate, tricalcium phosphate, starch, pregelatinized starch, compressible sugar, silicified microcrystalline cellulose, and calcium carbonate.

In certain embodiments, the surfactant is selected from the group consisting of tween 80, sodium lauryl sulfate, and docusate sodium.

In certain embodiments, the binder is selected from the group consisting of: povidone (PVP) K29/32, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), Ethyl Cellulose (EC), corn starch, pregelatinized starch, gelatin, and sugar.

In certain embodiments, the lubricant is selected from the group consisting of: magnesium stearate, stearic acid, sodium stearyl fumarate, calcium stearate, hydrogenated vegetable oil, mineral oil, polyethylene glycol 4000-6000, talc, and glyceryl behenate.

In certain embodiments, the sustained release polymer is selected from the group consisting of:(poly (ethylene oxide)),

N60K grade,SR, HPMC (high viscosity), HPC (high viscosity), and

in certain embodiments, the extended/controlled release coating is selected from the group consisting of ethylcellulose polymers, such as ETHOCEL^TMAndan aqueous dispersion of ethyl cellulose.

In certain embodiments, the antioxidant is selected from the group consisting of Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), sodium ascorbate, and alpha-tocopherol.

In certain embodiments, the tablet coating is selected from the group consisting of:200、

II、fx、

amb、2、

tm、

NS、

preferred unit dosage formulations are those containing an effective dose or an appropriate proportion of the active ingredient as described herein below.

The compounds may be administered orally at a dose of 0.1 to 500mg/kg per day. The dosage range for adults is usually 5mg to 2g per day. Tablets or other finished forms provided in discrete units may conveniently contain an effective amount of one or more compounds at such a dose, or multiples thereof, for example units containing from 5mg to 500mg, typically from about 10mg to 200 mg.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

The precise amount of the compound administered to a patient is the responsibility of the attending physician. The specific dosage level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, body constitution, sex, diet, time of administration, route of administration, rate of excretion, drug combination, the precise condition being treated and the severity of the condition being treated. Likewise, the route of administration may vary depending on the condition and its severity.

Where the condition of the patient is not improved at the discretion of the physician, administration of the compound may be long term, i.e., for a longer period of time, including the entire duration of the patient's life, in order to ameliorate or otherwise control or limit the symptoms of the patient's disorder.

Where the patient's condition does improve, at the discretion of the physician, administration of the compound may be continued or temporarily suspended for a certain length of time (i.e., a "drug holiday").

Once the condition of the patient has improved, a maintenance dose is administered as needed. Subsequently, the dosage or frequency of administration, or both, can be reduced to a level that maintains an improved condition, depending on the symptoms. However, if there is any recurrence of symptoms, the patient may require intermittent treatment for a long period of time.

Indications of

Disclosed herein are methods of treating a VMAT 2-mediated disorder, comprising administering to a subject having or suspected of having such a disorder a therapeutically effective amount of a compound or composition as disclosed herein, or a pharmaceutically acceptable salt, solvate or prodrug thereof.

VMAT 2-mediated disorders include, but are not limited to, chronic hyperkinetic movement disorders, huntington's disease, hemiballism, senile chorea, tic disorders, tardive dyskinesia, dystonia, tourette's syndrome, depression, cancer, rheumatoid arthritis, psychosis, multiple sclerosis, asthma, and/or any disorder that can be alleviated, or prevented by administration of a VMAT2 inhibitor.

In certain embodiments, a method of treating a VMAT 2-mediated disorder comprises administering to a subject a therapeutically effective amount of a compound or composition, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as disclosed herein, such that production is effectedThe following effects: (ii) reduces inter-individual variation in plasma levels of the compound or a metabolite thereof, as compared to a corresponding non-isotopically enriched compound; (2) increasing the mean plasma level of the compound per dosage unit or decreasing the mean plasma level of at least one metabolite per dosage unit compound; (3) reducing at least one cytochrome P in a subject₄₅₀Or inhibition and/or metabolism of monoamine oxidase isoforms; (4) reduction of cytochrome P expression via at least one polymorphism in a subject₄₅₀Metabolism of the isoform; (5) at least one statistically significant improved disorder-control and/or disorder-eradication endpoint; (6) improved clinical efficacy during treatment of the condition; (7) preventing the recurrence of abnormal diet or hepatic parameters or delaying their decline or appearance as a primary clinical benefit, or (8) reducing or eliminating any malignant changes in the diagnostic hepatobiliary function endpoint.

In certain embodiments, the inter-individual variation in plasma levels of a compound as disclosed herein or a metabolite thereof is reduced; an increase in mean plasma levels of a compound as disclosed herein; a decrease in the mean plasma level of a metabolite of a compound as disclosed herein; cytochrome P pairs Compounds as disclosed herein₄₅₀Or reduced inhibition of monoamine oxidase isoforms; or at least one polymorphically expressed cytochrome P₄₅₀Reduced metabolism of a compound as disclosed herein by the isoform; an increase or decrease of greater than about 5%, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, or greater than about 50% as compared to a corresponding non-isotopically enriched compound.

Plasma levels of a compound or metabolite thereof as disclosed herein can be measured using the methods described by: li et al, Rapid Communications in Mass Spectrometry 2005,19, 1943-1950; jendal et al, Journal of Chromatography, Biomedical Applications 1989,493(2), 392-7; schwartz et al, Biochemical Pharmacology 1966,15(5), 645-55; mehvar et al, drug metabolism and displacement 1987,15(2), 250-5; ro berts et al, Journal of chromatography, Biomedical Applications 1981,226(1), 175-82; and any references cited therein or any modifications thereto.

Cytochrome P in mammalian subjects₄₅₀Examples of the isoforms include, but are not limited to, CYP1a1, CYP1a2, CYP1B 2, CYP2a 2, CYP2B 2, CYP2C 2, CYP2D 2, CYP2E 2, CYP2G 2, CYP2J2, CYP2R 2, CYP2S 2, CYP3A5P2, CYP3a 2, CYP4B 2, CYP4F2, CYP4X 2, CYP4Z 2, CYP5a 2, CYP7B 2, CYP8a 2, CYP8B 2, CYP11 a2, CYP 3B 2, CYP3a 2, CYP2B 2, CYP2B 2, CYP2B 2.

Examples of monoamine oxidase isoforms in mammalian subjects include, but are not limited to, MAO_AAnd MAO_B。

Cytochrome P₄₅₀Inhibition of the isoform is measured by the method of Ko et al (British Journal of clinical Pharmacology,2000,49, 343-351). MAO_AInhibition of the isoforms is measured by the method of Weyler et al (J.biol chem.1985,260, 13199-13207). MAO_BInhibition of the isoforms is measured by the method of Uebelhack et al (Pharmacopesylphy, 1998,31, 187-192).

Polymorphically expressed cytochrome P in mammalian subjects₄₅₀Examples of isoforms include, but are not limited to, CYP2C8, CYP2C9, CYP2C19, and CYP2D 6.

Liver microsome and cytochrome P₄₅₀The metabolic activity of isoforms and monoamine oxidase isoforms is measured by the methods described herein.

Examples of improved disorder-control and/or disorder-eradication endpoints, or improved clinical effects include, but are not limited to, changes from baseline in chorea scores of the huntington's disease unified scoring table (UHDRS).

Examples of diagnostic hepatobiliary function endpoints include, but are not limited to, alanine aminotransferase ("ALT"), serum glutamic-pyruvic transaminase ("SGPT"), aspartate aminotransferase ("AST" or "SGOT"), ALT/AST ratio, serum acetalase, alkaline phosphatase ("ALP"), ammonia level, bilirubin, gamma-glutamyl transpeptidase ("GGTP", "gamma-GTP" or "GGT"), leucine aminopeptidase ("LAP"), liver biopsy, liver ultrasonography, liver nuclidescan, 5' -nucleotidase, and blood proteins. Hepatobiliary endpoints were compared to normal levels as set out in the Diagnostic and Laboratory Test Reference, 4 th edition, Mosby, 1999. These measurements are performed by a certification laboratory according to standard protocols.

In addition to use in human therapy, certain compounds and formulations disclosed herein may also be used in veterinary therapy of companion animals, wild animals, and livestock animals (including mammals, rodents, and the like). More preferred animals include horses, dogs, and cats.

Combination therapy

The compounds disclosed herein may also be used in combination with or in conjunction with other agents useful in the treatment of VMAT 2-mediated conditions. Or, by way of example only, the therapeutic effect of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., an adjuvant may itself have little therapeutic benefit, but its combination with another therapeutic agent may enhance the overall therapeutic benefit to the patient).

Such other agents, adjuvants or drugs may be administered by the route and in the amounts it is normally used, either simultaneously or sequentially with a compound as disclosed herein. When a compound as disclosed herein is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound disclosed herein may be utilized, but is not required.

In certain embodiments, the compounds disclosed herein may be used in combination with one or more antipsychotics, including, but not limited to, chlorpromazine, levopromazine, promazine, acepromazine, trifluoropromazine, cyamemazine, chlorpromazine, desipramine, fluphenazine, perphenazine, prochlorperazine, perphenazine acetate, trifluoperazine, acetophenazine, thiopromazine, butapiperazine, mepiquazine, piperazino, thioridazine, mesoridazine, analazine, haloperidol, trifluperidol, meperidol, moperone, amidopiperidone, haloperidol, droperidol, flunixolone, oxyphenpazinol, molindone, sertindole, ziprasidone, flupenthixol, clopenthixol, thiothixene, loxan, loxapine, penoxepidol, flupenthixol, fluxidone, loxapine, clozapine, olanzapine, and clozapine, Quetiapine, tetrabenazine, sulpiride, temapride, amisulpride, verapride, levosulpiride, lithium, prothiocypromide, risperidone, chlorthiapine, moxapamide, zotepine, aripiprazole (pripiprazole), and paliperidone.

In certain embodiments, the compounds disclosed herein may be used in combination with one or more benzodiazepines ("weakly tranquilizers"), including, but not limited to, alprazolam, bromoazepam, carbamazepam, clobazam, clonazepam, chlorthia, clorazolam, diazepam, flurazepam, etizolam, fludiazepam, flunitrazepam, halazepam, kattazolam, lorazepam, medazapam, midazolam, nitrazepam, norazepam, oxazepam, potassium chlordiazepoxide, pinazepam, pramipepam, tofisopam, triazolam, diazepam, and chlordiazepoxide.

In certain embodiments, the compounds disclosed herein may be combined with olanzapine or pimozide.

The compounds disclosed herein may also be administered in combination with other classes of compounds including, but not limited to, antiretrovirals; CYP3A inhibitors; CYP3A inducer; a protease inhibitor; an adrenergic agonist; anticholinergic agents; mast cell stabilizers; xanthine; a leukotriene antagonist; a glucocorticoid therapeutic agent; local or general anesthetics; non-steroidal anti-inflammatory drugs (NSAIDs), such as naproxen; antibacterial agents such as amoxicillin; cholesteryl Ester Transfer Protein (CETP) inhibitors, such as anacetrapib; antifungal agents, such as isoconazole; sepsis therapeutic agents, such as flexuozin-alpha; steroids, such as hydrocortisone; local or general anesthetics, such as ketamine; norepinephrine Reuptake Inhibitors (NRIs), such as atomoxetine; dopamine reuptake inhibitors (DARIs), such as methylphenidate; 5-hydroxytryptamine-norepinephrine reuptake inhibitors (SNRI), such as milnacipran; sedatives such as diazepam (diazepam); norepinephrine-dopamine reuptake inhibitors (NDRI), such as bupropion; 5-hydroxytryptamine-norepinephrine-dopamine reuptake inhibitors (SNDRI), such as venlafaxine; monoamine oxidase inhibitors, such as selegiline; hypothalamic phospholipids; endothelin-converting enzyme (ECE) inhibitors such as phosphoramidon; opioids, such as tramadol; thromboxane receptor antagonists such as ifetroban; a potassium channel opener; thrombin inhibitors, such as hirudin; hypothalamic phospholipids; growth factor inhibitors, such as modulators of PDGF activity; platelet Activating Factor (PAF) antagonists; antiplatelet agents such as GPIIb/IIIa blockers (e.g., abciximab, eptifibatide, tirofiban), P2Y (AC) antagonists (e.g., clopidogrel, ticlopidine, and CS-747), and aspirin; anticoagulants, such as warfarin; low molecular weight heparins, such as enoxaparin; factor VIIa inhibitors and factor Xa inhibitors; a renin inhibitor; neutral Endopeptidase (NEP) inhibitors; vasopeptidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and gemotrilat; HMG-CoA reductase inhibitors such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (also known as itavastatin, nivastatin or niprastatin (nisstatin)) and ZD-4522 (also known as rosuvastatin or atorvastatin (atavastatin) or visstatin (visstatin)); a squalene synthetase inhibitor; a fibrate; bile acid sequestrants, such as boswellia (questran); nicotinic acid; anti-atherosclerotic agents, such as ACAT inhibitors; an MTP inhibitor; calcium channel blockers such as amlodipine besylate; a potassium channel activator; an alpha-muscarinic agent; beta-muscarinic agents such as carvedilol and metoprolol; antiarrhythmic agents; diuretics, such as bischlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichlormethiazide, polythiazide, benzothiazine, ethacrynic acid, tricrynafen, chlorthalidone, flurosendan, moxomimide, bumetanide, triamterene, amiloride and spironolactone; thrombolytic agents, such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and Anisoylated Plasminogen Streptokinase Activator Complex (APSAC); antidiabetic agents such as biguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulin, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiazolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), and PPAR- γ agonists; mineralocorticoid receptor antagonists such as spironolactone and eplerenone; a growth hormone secretagogue; an aP2 inhibitor; phosphodiesterase III inhibitors, such as PDE inhibitors (e.g., cilostazol) and PDEV inhibitors (e.g., sildenafil, tadalafil, vardenafil); protein tyrosine kinase inhibitors; anti-inflammatory agents; antiproliferative agents such as methotrexate, FK506 (tacrolimus, prallel (Prograf), mycophenolate mofetil; chemotherapeutic agents; immunosuppressive agents; anticancer and cytotoxic agents (e.g. alkylating agents such as nitrogen mustards, alkyl sulfonates, nitrosoureas, aziridines and triazenes), antimetabolites such as folic acid antagonists, purine analogues and pyridine analogues, antibiotics such as anthracyclines, bleomycin, mitomycins, actinomycins, plicamycin, enzymes such as L-asparaginase, farnesyl protein transferase inhibitors, hormonal agents such as glucocorticoids (e.g. cortisone), estrogen/antiestrogens, androgen/antiandrogen, progesterone, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; microtubule-disrupting agents such as ecteinascidins; microtubule stabilizers, such as paclitaxel, docetaxel and epothilones a-F; plant-derived products such as vinca alkaloids, epipodophyllotoxins, and taxanes; and a topoisomerase inhibitor; prenyl-protein transferase inhibitors; and cyclosporin; steroids, such as prednisone and dexamethasone; cytotoxic drugs such as azathioprine and cyclophosphamide; TNF- α inhibitors, such as tenidap; anti-TNF antibodies or soluble TNF receptors such as etanercept, rapamycin, and leflunomide; and cyclooxygenase-2 (COX-2) inhibitors such as celecoxib and rofecoxib; and other agents such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes such as cisplatin, satraplatin, and carboplatin.

Thus, in another aspect, certain embodiments provide a method for treating a VMAT 2-mediated disorder in a subject in need of such treatment, the method comprising administering to the subject a compound disclosed herein in combination with at least one additional agent for treating the disorder in an amount effective to reduce or prevent the disorder in the subject. In related aspects, certain embodiments provide therapeutic compositions comprising at least one compound disclosed herein in combination with one or more other agents for treating a VMAT 2-mediated condition.

General synthetic methods for preparing Compounds

The compounds as disclosed herein may be prepared by methods known to those skilled in the art and conventional modifications thereof, and/or by procedures and conventional modifications thereof analogous to those described below and in the references cited therein: US 20100130480 (paragraphs [0093] -0121 ], US 20120003330 (paragraphs [0104] -0162), WO 2005077946; WO 2008/058261; EP 1716145; lee et al, j.med.chem.,1996, (39), 191-196; kilbourn et al, Chirality,1997, (9), 59-62; boldt et al, synth. commun, 2009, (39), 3574-3585; rishel et al, j.org.chem.,2009, (74), 4001-; DaSilva et al, appl.Radiat.Isot.,1993,44(4), 673-; popp et al, J.Pharm.Sci.,1978,67(6), 871-; ivanov et al, Heterocycles 2001,55(8), 1569-1572; US2,830,993; US 3,045,021; WO 2007130365; WO2008058261, the references being incorporated herein in their entirety.

Isotopic hydrogen can be introduced into the compounds as disclosed herein by the following techniques: synthetic techniques employing deuterated reagents whereby the incorporation rate (incorporation rate) is predetermined; and/or by exchange techniques, wherein the rate of incorporation is determined by equilibrium conditions and can be highly variable depending on the reaction conditions. Synthetic techniques, in which tritium or deuterium is inserted directly and specifically by tritiation or deuteration reagents of known isotopic content, can yield high tritium or deuterium abundance, but may be limited by the chemical reactions required. Exchange techniques, on the other hand, can result in lower tritium or deuterium incorporation, where the isotopes are typically distributed over many sites on the molecule.

In certain embodiments, specific examples of compounds of the present invention include compounds selected from the list described in paragraph [0122] of US 20100130480 and paragraph [0163] of US 20120003330, which references are incorporated herein by reference.

Changes in the metabolic properties of certain compounds disclosed herein in vitro compared to their non-isotopically enriched analogues and methods of determining such changes have been described in paragraphs [0125] of US 20100130480 and paragraphs [0165] to [0185] of US 20120003330, which references are incorporated herein by reference.

The invention will be further illustrated by the following examples.

Formulation examples

Examples 1-5 and other examples described herein can be prepared by the method disclosed in fig. 1.

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