阅读说明：本技术 用于运动机能亢进性运动障碍的治疗的vmat2抑制剂 (VMAT2 inhibitors for the treatment of hyperkinetic movement disorders ) 是由 克里斯托弗·F·奥布赖恩 于 2015-05-06 设计创作，主要内容包括：提供治疗运动机能亢进性疾病和病症,如迟发性运动障碍的方法。在某一实施方案中,将有效的VMAT2抑制剂(+)α-3-异丁基-9,10-二甲氧基-1,3,4,6,7,11b-六氢-2H-吡啶并[2,1-a]异喹啉-2-醇((+)α-HTBZ)用于本文所述的方法,以对需要治疗的患者进行治疗。(Methods for treating hyperkinetic diseases and disorders, such as tardive dyskinesia, are provided. In a certain embodiment, the potent VMAT2 inhibitor (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) α -HTBZ) is used in the methods described herein for the treatment of a patient in need thereof.)

1. Use of a pharmaceutical composition comprising a VMAT2 inhibitor selected from: (a) tetrabenazine (TBZ); (b) (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2, 1-a)]Isoquinolin-2-yl esters; (c) deuterated TBZ; (d) deuterated (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2, 1-a)]Isoquinolin-2-yl esters; (e) (+) -alpha-3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] as a stabilizer]Isoquinolin-2-ol ((+) α -HTBZ); and (f) deuterated (+) α -HTBZ, wherein the Cmax of about 15ng to about 60ng (+) α -HTBZ per mL of plasma is provided over a period of 8 hours_maxAnd a Cmax of at least 15ng (+) alpha-HTBZ per mL of plasma_minIn an amount to administer the drug.

2. The use of claim 1, wherein said C is_maxAbout 15ng per mL of plasmaAbout 20ng, about 25ng, about 30ng, about 35ng, about 40ng, about 45ng, about 55ng, or about 60ng (+) α -HTBZ.

3. The use of claim 1 or 2, wherein C is_minAt least 20ng, at least 25ng, at least 30ng, or at least 35ng (+) α -HTBZ per mL of plasma.

4. The use of claim 1 or 2, wherein C is_minFrom about 15ng to about 35ng (+) α -HTBZ per mL of plasma.

5. The use of any one of claims 1-4, wherein said C is over a period of 12 hours, 16 hours, 20 hours, or 24 hours_minAt least 15ng (+) α -HTBZ per mL of plasma.

6. Use of a pharmaceutical composition comprising a VMAT2 inhibitor selected from: (a) tetrabenazine (TBZ); (b) (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester; (c) deuterated TBZ; (d) deuterated (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester; (e) (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) α -HTBZ); and (f) deuterated (+) α -HTBZ, wherein the following are provided over a period of time sufficient to be from about 8 hours to about 24 hours: (i) a therapeutic concentration range of about 15ng to about 60ng (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) α -HTBZ) per mL of plasma; and (ii) at least 15ng (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) α -HTBZ) per mL of plasma.

7. The use of claim 6, wherein the therapeutic concentration of (+) α -HTBZ ranges from about 15ng/mL to about 35 ng/mL.

8. The use of claim 6, wherein the therapeutic concentration of (+) α -HTBZ is about 15ng/mL to about 40 ng/mL.

9. The use of claim 6, wherein the therapeutic concentration of (+) α -HTBZ is about 15ng/mL to about 45 ng/mL.

10. The use of claim 6, wherein the therapeutic concentration of (+) α -HTBZ is about 15ng/mL to about 50 ng/mL.

11. The use of claim 6, wherein the therapeutic concentration of (+) α -HTBZ is about 15ng/mL to about 55 ng/mL.

12. The use of any one of claims 6 to 11, wherein the threshold concentration of (+) α -HTBZ is about 15 ng/mL.

13. The use of any one of claims 6 to 11, wherein the threshold concentration of (+) α -HTBZ is about 20 ng/mL.

14. The use of any one of claims 6-13, wherein the threshold concentration of (+) α -HTBZ is maintained over a period of about 8 hours.

15. The use of any one of claims 6-13, wherein the threshold concentration of (+) α -HTBZ is maintained for a period of about 12 hours.

16. The use of any one of claims 6-13, wherein the threshold concentration of (+) α -HTBZ is maintained for a period of about 16 hours.

17. The use of any one of claims 6-13, wherein the threshold concentration of (+) α -HTBZ is maintained for a period of about 20 hours.

18. The use of any one of claims 6-13, wherein the threshold concentration of (+) α -HTBZ is maintained for a period of about 24 hours.

19. The use of any one of claims 1-18, wherein the hyperkinetic movement disorder is tardive dyskinesia.

20. The use of any one of claims 1-18, wherein the hyperkinetic movement disorder is tourette's syndrome.

21. The use of any one of claims 1-18, wherein the hyperkinetic movement disorder is not huntington's disease.

22. The use of claim 1, wherein the sufficient amount of the VMAT2 inhibitor provides (+) α -HTBZ at a concentration of at least 50% of Cmax for at least 12 hours per day.

23. The use of any one of claims 1-22, wherein the pharmaceutical composition comprises a sustained release formulation of the VMAT2 inhibitor.

24. The use of any one of claims 1-23, wherein the VMAT2 inhibitor is (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester.

25. The use of claim 24, wherein (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester is administered in a daily dose of about 40mg to about 80 mg.

26. The use of claim 25, wherein (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester is administered in a daily dose of about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, or about 80 mg.

27. The use of any one of claims 1-23, wherein the VMAT2 inhibitor is TBZ.

28. The use of any one of claims 1-23, wherein the VMAT2 inhibitor is (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) α -HTBZ).

29. The use of any one of claims 1-28, wherein the VMAT2 inhibitor is deuterated.

30. The use of claim 29, wherein the (+) α -HTBZ provided in the subject's plasma is deuterated.

31. A pharmaceutical composition for the treatment of hyperkinetic movement disorders comprising (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester or a pharmaceutically acceptable salt thereof, wherein said pharmaceutical composition comprises an amount of (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2 ], (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester or a pharmaceutically acceptable salt thereof, in an amount of the free base of the 1-a ] isoquinolin-2-yl ester.

32. The pharmaceutical composition of claim 31, wherein the pharmaceutically acceptable salt is a salt of xylenesulfonate.

33. The pharmaceutical composition of claim 31 or 32, wherein the pharmaceutical composition comprises an amount equivalent to about 40mg, (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester or a pharmaceutically acceptable salt thereof in an amount of the free base of (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester.

34. The pharmaceutical composition of any one of claims 31-33, wherein the hyperkinetic movement disorder is tardive dyskinesia, chorea associated with huntington's disease, or tourette's syndrome.

Technical Field

Provided herein are methods of obtaining optimal treatment of hyperkinetic movement disorders in a subject, wherein an effective plasma concentration of (+) alpha-3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) alpha-HTBZ) is achieved.

Description of the Related Art

Dysregulation of the dopaminergic system is essential for several Central Nervous System (CNS) disorders and conditions, including hyperkinetic dyskinesias (e.g., Tardive Dyskinesia (TD)), such as schizophrenia and bipolar disorder. Transporter vesicle monoamine transporter 2(VMAT2) plays an important role in presynaptic dopamine release, regulating the uptake of monoamines from the cytoplasm to synaptic vesicles for storage and release. Differential expression of VMAT2 in The human brain versus endocrine tissues provides an opportunity for The use of well-tolerated agents that selectively target VMAT2 that may be useful in The treatment of CNS disorders (see, e.g., Weihe and Eiden, The FASEB Journal 2000,14: 2345-2449).

Tardive Dyskinesia (TD) is a neurological condition characterized by involuntary movements of the orofacial regions (i.e., tongue, lips, jaw, face) and choreoathetosis-like movements of the extremities and trunk. Mild symptoms of TD are not usually treated. Patients with mild TD are generally unaware of involuntary movements and they do not seek treatment. As symptoms increase in severity, hyperkinetic movements begin to disturb normal speech, chewing, breathing, facial expression, limb movements, walking, and balance. At this point, the potential benefit of drug treatment outweighs the potential risk of treatment-related side effects. In the most severe cases, TD may cause self-injury, bruising, laceration, inability to dress, eat or drink. For a recent overview of late onset syndromes, see Bhidayasiri and Boonyawairoj, Postgrad Med J2011, 87(1024): 132-141.

TD occurs as a result of prolonged use of neuroleptic drugs and usually persists after discontinuation of problematic drug therapy. A small fraction of patients treated with dopamine receptor blocking drugs develop TD; most of these patients commonly suffer from schizophrenia. Although the pathophysiology of TD is not fully understood, hypersensitivity of postsynaptic dopamine in the striatum is its most prominent feature. TD is distinct from acute signs or symptoms of dopamine blockade, such as akathisia or parkinsonism. These acute exposure symptoms are often described as "extrapyramidal side effects" or EPSEs, rather than delayed or delayed responses. Although there are cases reporting of TD alone after short-term exposure, most TDs typically occur after months to years of long-term treatment. In addition to the duration and amount of neuro-suppressive exposure, other risk factors for TD appear to include higher age, schizophrenia, and cognitive dysfunction (Margolese et al, Can J Psychiatry 2005,50(9): 541-47).

Recent literature on TD suggests that the prevalence of TD in psychotic patients is about 15% and quite low in other non-psychotic populations (see, e.g., Tarsy and Baldesarini, motion Disorders 2006,21(5): 589-98). This accumulation of TD in schizophrenic patients may reflect: TD usually occurs in the context of chronic exposure. Conversely, short-term use of dopamine antagonists is rarely associated with TD. Most reviews of TD describe exposure to these agents for an average of over five years. DSM-IV and clinical research standards for TD (e.g., Schooler-Kane Standard 1982) record such requirements: the exposure was recorded for more than three months to confirm the diagnosis. Recent evaluations have shown that the incidence of late hyperkinetic movement in patients receiving chronic neuroleptic drug therapy is about 1-5% per year of exposure (see, e.g., Tenback et al, J Psychopharmacol 2010,24: 1031; Woods et al, J Clin Psychiatry 2010,71(4): 463-74). Relief was reported in 30-60% of patients who no longer ingested the problematic agent for years.

It is expected that the incidence of TD will be greatly reduced after atypical or so-called second generation antipsychotic treatments. However, the reduction in incidence is only partially documented in the literature. Short-term trials of 12 months or less reported little TD, while longer non-industry sponsored trials suggested prevalence closer to 4-6% (see, e.g., Correll and Schenk, Curr Opin Psychiatry 2008,21(2): 151-6). Patients with Bipolar Disorder (BD) are also prescribed antipsychotic medication, particularly if the first-line medication is refractory. Second generation atypical antipsychotics are generally prescribed for the treatment of BD. Replacement therapy for BD is available (e.g., lithium, valproate, etc.); thus, patients presenting with signs of TD are often able to discontinue exposure to the problematic agent and continue their standard treatment, which may lead to TD remission.

TD may develop in patients with non-psychotic disorders who receive limited duration and, or, longer duration exposure to dopamine receptor antagonists (e.g., for gastroparesis)[ metoclopramide)]) The treatment of (1). Albeit toThe awareness of the associated side effects has increased and has been the focus of collective litigation, metoclopramide-induced TD seems to be in fact<Occurs in 1% of patients exposed to the drug (see, e.g., Rao et al, Aliment Pharmacol Ther 2010,31(1): 11).

For the treatment of TD, neither standard treatment protocols nor approved drugs are available. The first step in treating the condition is typically to stop or minimize the use of neuroinhibitory drugs suspected of causing the condition. The replacement of the problem-causing medication with an alternative antipsychotic medication (e.g., clozapine) may help some patients. For severe cases, some experimental work has been performed with more aggressive interventions (such as deep brain stimulation). Furthermore, vesicular monoamine transporter 2(VMAT2) inhibitors have been shown to be effective in the treatment of various movement disorders, including tardive dyskinesia (see, e.g., Ondo et al, Am J Psychiatry 1999,156(8): 1279-. Well-tolerated oral medications may provide an important treatment option for patients with moderate or severe TD. Thus, there is a need in the art for therapies that can be used to treat TD.

Summary of The Invention

The following embodiments are provided herein.

Embodiment 1. a method of treating hyperkinetic movement disorders in a subject, the method comprising administering to the subject an amount of a composition comprisingA pharmaceutical composition of a VMAT2 inhibitor selected from: (a) tetrabenazine (TBZ); (b) (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2, 1-a)]Isoquinolin-2-yl esters; (c) deuterated TBZ; (d) deuterated (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2, 1-a)]Isoquinolin-2-yl esters; (e) (+) -alpha-3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] as a stabilizer]Isoquinolin-2-ol ((+) α -HTBZ); and (f) deuterated (+) α -HTBZ in an amount sufficient to provide a Cmax of about 15ng to about 60ng (+) α -HTBZ per mL of plasma over a 8 hour period_maxAnd a Cmax of at least 15ng (+) alpha-HTBZ per mL of plasma_min。

Embodiment 2. the method of embodiment 1, wherein C_maxAbout 15ng, about 20ng, about 25ng, about 30ng, about 35ng, about 40ng, about 45ng, about 55ng, or about 60ng (+) α -HTBZ per mL of plasma.

Embodiment 3. the method of embodiment 1 or 2, wherein C_minAt least 20ng, at least 25ng, at least 30ng, or at least 35ng (+) α -HTBZ per mL of plasma.

Embodiment 4. the method of embodiment or 2, wherein C_minFrom about 15ng to about 35ng (+) α -HTBZ per mL of plasma.

Embodiment 5. the method of any one of embodiments 1-4, wherein the C is over a period of 12 hours, 16 hours, 20 hours, or 24 hours_minAt least 15ng (+) α -HTBZ per mL of plasma.

Embodiment 6. a method of treating hyperkinetic movement disorders in a subject, the method comprising administering to the subject a pharmaceutical composition comprising a VMAT2 inhibitor selected from: (a) tetrabenazine (TBZ); (b) (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester; (c) deuterated TBZ; (d) deuterated (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester; (e) (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) α -HTBZ); and (f) deuterated (+) α -HTBZ, in an amount sufficient to provide, over a period of about 8 hours to about 24 hours: (i) a therapeutic concentration range of about 15ng to about 60ng (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) α -HTBZ) per mL of plasma; and (ii) a threshold concentration of at least 15ng (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) α -HTBZ) per mL of plasma.

Embodiment 7. the method of embodiment 6, wherein the therapeutic concentration of (+) α -HTBZ ranges from about 15ng/mL to about 35 ng/mL.

Embodiment 8 the method of embodiment 6, wherein the therapeutic concentration of (+) α -HTBZ is about 15ng/mL to about 40 ng/mL.

Embodiment 9. the method of embodiment 6, wherein the therapeutic concentration of (+) α -HTBZ is about 15ng/mL to about 45 ng/mL.

Embodiment 10 the method of embodiment 6, wherein the therapeutic concentration of (+) α -HTBZ is about 15ng/mL to about 50 ng/mL.

Embodiment 11 the method of embodiment 6, wherein the therapeutic concentration of (+) α -HTBZ is about 15ng/mL to about 55 ng/mL.

Embodiment 12 the method of any one of embodiments 6 to 11, wherein the threshold concentration of (+) α -HTBZ is about 15 ng/mL.

Embodiment 13 the method of any one of embodiments 6 to 11, wherein the threshold concentration of (+) α -HTBZ is about 20 ng/mL.

Embodiment 14 the method of any one of embodiments 6-13, wherein the threshold concentration of (+) α -HTBZ is maintained over a period of about 8 hours.

Embodiment 15 the method of any one of embodiments 6-13, wherein the threshold concentration of (+) α -HTBZ is maintained over a period of about 12 hours.

Embodiment 16 the method of any one of embodiments 6-13, wherein the threshold concentration of (+) α -HTBZ is maintained over a period of about 16 hours.

Embodiment 17 the method of any one of embodiments 6-13, wherein the threshold concentration of (+) α -HTBZ is maintained over a period of about 20 hours.

Embodiment 18 the method of any one of embodiments 6-13, wherein the threshold concentration of (+) α -HTBZ is maintained over a period of about 24 hours.

Embodiment 19. the method of any one of embodiments 1-18, wherein the hyperkinetic movement disorder is tardive dyskinesia.

Embodiment 20 the method of any one of embodiments 1-18, wherein the hyperkinetic movement disorder is tourette's syndrome.

Embodiment 21 the method of any one of embodiments 1-18, wherein the hyperkinetic movement disorder is not huntington's disease.

Embodiment 22 the method of any one of embodiments 1-21, wherein the sufficient amount of the VMAT2 inhibitor provides a (+) α -HTBZ at a concentration of at least 50% of Cmax for at least 12 hours per day.

Embodiment 23 the method of any one of embodiments 1-22, wherein the pharmaceutical composition comprises a sustained release formulation of the VMAT2 inhibitor.

Embodiment 24. the method of any one of embodiments 1-23, wherein the VMAT2 inhibitor is (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester.

Embodiment 25 the method of embodiment 24, wherein (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester is administered in a daily dose of about 40mg to about 80 mg.

Embodiment 26 the method of embodiment 25, wherein (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester is administered in a daily dose of about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg, or about 80 mg.

Embodiment 27 the method of any one of embodiments 1-23, wherein the VMAT2 inhibitor is TBZ.

Embodiment 28. the method of any one of embodiments 1-23, wherein the VMAT2 inhibitor is (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) α -HTBZ).

Embodiment 29 the method of any one of embodiments 1-28, wherein the VMAT2 inhibitor is deuterated.

Embodiment 30 the method of embodiment 29, wherein the (+) α -HTBZ provided in the subject's plasma is deuterated.

These and other embodiments will be apparent by reference to the following detailed description. To this end, various references are set forth herein that describe in more detail certain background information, procedures, compounds, and compositions, and are each incorporated herein by reference in their entirety.

Terms not explicitly defined herein shall have the meaning given to them by those skilled in the art in light of the disclosure and context. However, as used in the specification, unless specified to the contrary, the terms have the meanings indicated.

Reference throughout this specification to "one embodiment" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" appearing in various places throughout the specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

In addition, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to "a non-human animal" can refer to one or more non-human animals, or a plurality of such animals, and reference to "a cell" or "the cell" includes reference to one or more cells and equivalents thereof (e.g., cells) known to those skilled in the art, and so forth. When steps of a method are described or claimed, and they are described as occurring in a particular order, the description that a first step occurs "before" (i.e., precedes) a second step has the same meaning as if rewritten to state that a second step occurs "after" (or is implemented) a first step. The term "about" when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variation (or within statistical experimental error), and thus the number or numerical range may vary from 1% to 15% of the number or numerical range. It should also be noted that the term "or" is generally employed in its sense including "and/or" unless the content clearly dictates otherwise. The term "at least one", for example when referring to at least one compound or to at least one composition, has the same meaning and understanding as the term "one or more".

Brief description of the drawings

Figure 1 shows the mean plasma concentration data (linear scale) of the active metabolite (+) α -HTBZ for patients in the NBI-98854 multi-dose group study at day 8, at the scheduled post-dose time.

Detailed Description

Provided herein are methods of optimizing the clinical benefit of treating hyperkinetic movement disorders (e.g., TD) by administering to a subject a dose of the compound tetrabenazine (3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-one, TBZ), or an analog thereof, that achieves or maintains an optimal concentration of at least one active metabolite of TBZ in the subject, such that the concentration of the active metabolite (e.g., (+) α -HTBZ) is achieved or maintained over a specified period of time. Prior to the disclosure herein, the dose of TBZ or an analog thereof that results in the best clinical benefit for the subject appears to vary for the subject individual being treated.

TetrabenzoquinolizineIs an approved agent having VMAT2 inhibitory activity, which is a dopamine-depleting agent approved in 2008 for the treatment of chorea associated with huntington's disease. However, XENAZINEs are not approved for TD and tetrabenazine has a strict risk assessment and reduction strategy (REMS) program, limiting its allocation to huntington's patients only. Clinical benefit with tetrabenazine is described when used in the treatment of TD and various hyperkinetic dyskinesias at the physician IND (see, e.g., Ondo et al, Am J Psychiatry 1999,156(8): 1279-. The beneficial pharmacological effects of tetrabenazine on targeted hyperkinetic involuntary movements, as well as adverse effects associated with excessive monoamine consumption, such as sedation, depression, akathisia and parkinsonism, were recorded. The occurrence of these adverse effects with tetrabenazine has led to a need for personalized dosing, dose adjustment and management of treatment-related side effects in the restrictive REMS procedure.

The need for dose modulation in the clinic for tetrabenazine may be due to its extensive and variable metabolism. TBZ contains two chiral centers and is a racemic mixture of two stereoisomers that is rapidly and extensively metabolized in vivo to its reduced form, 3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, also known as dihydrotetrabenazine (HTBZ). HTBZ is believed to exist as four separate isomers: (±) α -HTBZ and (+/-) β -HTBZ. (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol or (+) α -HTBZ is considered the absolute configuration of the most active metabolite (see, e.g., Kilbourn Chirality 19979: 59-62). Because of its rapid Metabolism and because of the extremely low exposures observed with oral administration of tetrabenazine, the therapeutic effects of tetrabenazine appear to be primarily due to the action of the metabolites (+) α -HTBZ and (+) β -HTBZ (see, e.g., Kilbourn et al, Eur J Pharmacol 1995,278: 249-. The Metabolism of tetrabenazine to (. + -.) alpha-HTBZ and (. + -.) beta-HTBZ is highly variable in patients (see, e.g., Mehvar et al, Drug Metabolism and Disposition 1987,15(2): 250-. In addition, these stereoisomers of HTBZ exhibit distinct pharmacology (i.e., binding to off-target protein receptors) (see, e.g., Kilbourn et al, Eur J Pharmacol 1995,278: 249-252). This provides a source of increased risk to the patient and a source of complexity to the physician in terms of actively managing the patient's dosing regimen.

Described herein are methods of treating a subject suffering from hyperkinetic movement disorder with a sufficient amount of [ + ] α -dihydrotetrabenazine or a precursor thereof to achieve a suitable concentration of [ + ] α -dihydrotetrabenazine in plasma for a specified period of time.

In one embodiment, an ester of [ + ] α -dihydrotetrabenazine is administered. In one embodiment, the ester is valine ester and the compound is (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester (NBI-98854). In a more specific embodiment, (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester or salt thereof is deuterated.

In another embodiment, tetrabenazine, or a pharmaceutically acceptable salt thereof, is administered. Tetrabenazine may be administered by a variety of methods, including the formulations disclosed in PCT publications WO 2010/018408, WO 2011/019956, and WO 2014/047167.

In another embodiment, d disclosed in U.S. Pat. No. 8,524,733 is administered₆Tetraphenyl quinolizine, responsible for the (+) alpha-3-iso-metabolite in plasma over a specific period of timeButyl-9, 10-d₆-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ]]Suitable concentrations of isoquinolin-2-ol (deuterated (+) α -HTBZ) or deuterated (+) β -HTBZ. D can be administered by a variety of methods₆Tetrabenazine, including formulations as disclosed in PCT publication WO 2014/047167.

In one embodiment, the TBZ compound used in the methods described herein is a substituted 3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol compound and pharmaceutically acceptable salts thereof. In another embodiment, the compound is 3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol, also known as dihydrotetrabenazine (HTBZ), and includes its individual isomers (±) α -HTBZ and (±) β -HTBZ), and pharmaceutically acceptable salts thereof. In another specific embodiment, the HTBZ is deuterated.

In one aspect, provided herein is a method of treating hyperkinetic movement disorders, the method comprising administering to a subject in need thereof an amount of a pharmaceutical composition comprising a VMAT2 inhibitor described herein sufficient to achieve about 15ng to about 60ng of (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] per mL of plasma over a period of 8 hours]Maximum plasma concentration (C) of isoquinolin-2-ol ((+) alpha-HTBZ)_max) And at least 15ng of (+) alpha-3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] per mL of plasma]Minimum plasma concentration (C) of isoquinolin-2-ol ((+) alpha-HTBZ)_min)。

In certain embodiments, the VMAT2 inhibitor is Tetrabenazine (TBZ); (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester; deuterated TBZ; deuterated (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester; (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) α -HTBZ); or deuterated (+) alpha-HTBZ.

Reference to plasma concentrations of (+) α -HTBZ in the methods described herein includes both deuterated (+) α -HTBZ and non-deuterated (+) α -HTBZ. It will be apparent to those skilled in the art that if a deuterated VMAT2 inhibitor (e.g., deuterated TBZ, deuterated (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester, or deuterated (+) α -HTBZ) as described herein is administered to a subject, deuterated (+) α -HTBZ will appear in the plasma of the subject and measured. If a non-deuterated VMAT2 inhibitor (e.g., TBZ, (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester, (+) α -HTBZ) as described herein is administered to a subject, a non-deuterated (+) α -HTBZ will appear in the plasma of the subject and is measured. If a combination of deuterated and non-deuterated VMAT2 inhibitors as described herein is administered to a subject, both deuterated and non-deuterated (+) α -HTBZ will appear in the plasma of the subject and be measured.

In certain embodiments, the C of (+) - α -HTBZ_maxAbout 15ng/mL plasma, about 20ng/mL plasma, about 25ng/mL plasma, about 30ng/mL plasma, about 35ng/mL plasma, about 40ng/mL plasma, about 45ng/mL plasma, about 50ng/mL plasma, about 55ng/mL plasma, or about 60ng/mL plasma. In certain embodiments, the C of the (+) α -HTBZ is within a period of 8 hours, 12 hours, 16 hours, 20 hours, 24 hours, 28 hours, or 32 hours_minIs at least 15ng/mL plasma, at least 20ng/mL plasma, at least 25ng/mL plasma, at least 30ng/mL plasma, or at least 35ng/mL plasma. In certain embodiments, the C of (+) - α -HTBZ_minFrom about 15ng/mL to about 35 ng/mL.

In certain embodiments, provided herein are methods of treating hyperkinetic movement disorders, comprising administering to a subject in need thereof an amount of a pharmaceutical composition comprising a VMAT2 inhibitor described herein sufficient to achieve between about 15ng and about 60ng of (+) β -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] per mL of plasma over a period of 8 hours]Maximum plasma concentration of isoquinolin-2-ol ((+) beta-HTBZ)(C_max) And at least 15ng of (+) beta-3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] per mL of plasma]Minimum plasma concentration (C) of isoquinolin-2-ol ((+) beta-HTBZ)_min)。

In certain embodiments, the C of (+) beta-HTBZ_maxAbout 15ng/mL plasma, about 20ng/mL plasma, about 25ng/mL plasma, about 30ng/mL plasma, about 35ng/mL plasma, about 40ng/mL plasma, about 45ng/mL plasma, about 50ng/mL plasma, about 55ng/mL plasma, or about 60ng/mL plasma. In certain embodiments, the C of the (+) β -HTBZ is within a period of 8 hours, 12 hours, 16 hours, 20 hours, 24 hours, 28 hours, or 32 hours_minIs at least 15ng/mL plasma, at least 20ng/mL plasma, at least 25ng/mL plasma, at least 30ng/mL plasma, or at least 35ng/mL plasma. In certain embodiments, the C of (+) beta-HTBZ_minFrom about 15ng/mL to about 35 ng/mL.

In certain embodiments, the VMAT2 inhibitor is administered in an amount sufficient to: i) achieving a Cc of (+) alpha-HTBZ of about 15ng to about 60ng per mL of plasma over a period of 8 hours_maxAnd a Cmax of (+) alpha-HTBZ of at least 15ng per mL of plasma_min(ii) a And/or ii) a Cmax of about 15ng to about 60ng (+) beta-HTBZ per mL of plasma over an 8 hour period_maxAnd a Cmax of (+) beta-HTBZ of at least 15ng per mL of plasma_min。

In one embodiment, the pharmaceutical composition is administered in an amount sufficient to provide (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] from about 15ng/mL plasma to about 60ng/mL plasma over a 24 hour period]C of isoquinolin-2-ol ((+) alpha-HTBZ)_maxAnd is about C_maxAt least 33% of C_min. In another embodiment, the pharmaceutical composition is administered in an amount sufficient to provide (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] from about 15ng/mL plasma to about 60ng/mL plasma over a 24 hour period]C of isoquinolin-2-ol ((+) alpha-HTBZ)_maxAnd is about C_maxAt least 50% of C_min. In certain embodiments, the pharmaceutical composition is administered in an amount sufficient to be 24 hoursProviding (+) alpha-3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] from about 15ng/mL plasma to about 60ng/mL plasma over a period of time]C of isoquinolin-2-ol ((+) alpha-HTBZ)_maxAnd is about C_maxAbout at least 33% -50% of C_min。

In other particular embodiments, the pharmaceutical composition is administered in an amount sufficient to provide (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] from about 15ng/mL plasma to about 60ng/mL plasma over a 12 hour period]C of isoquinolin-2-ol ((+) alpha-HTBZ)_maxAnd is about C_maxAt least 33% of C_min. In another specific embodiment, the pharmaceutical composition is administered in an amount sufficient to provide (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] from about 15ng/mL plasma to about 60ng/mL plasma over a 12 hour period]C of isoquinolin-2-ol ((+) alpha-HTBZ)_maxAnd is about C_maxAt least 50% of C_min. In certain embodiments, the pharmaceutical composition is administered in an amount sufficient to provide (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] from about 15ng/mL plasma to about 60ng/mL plasma over a 12 hour period]C of isoquinolin-2-ol ((+) alpha-HTBZ)_maxAnd is about C_maxAbout at least 33% -50% of C_min。

In another embodiment, a pharmaceutical composition is administered to a subject in need thereof in an amount that provides (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] from about 15ng/mL plasma to about 60ng/mL plasma over a 24 hour period]C of isoquinolin-2-ol ((+) alpha-HTBZ)_maxAnd Cc from about 5ng/mL plasma to about 30ng/mL plasma_min. In another embodiment, a pharmaceutical composition is administered to a subject in need thereof in an amount that provides (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] from about 15ng/mL plasma to about 60ng/mL plasma over a 24 hour period]C of isoquinolin-2-ol ((+) alpha-HTBZ)_maxAnd Cc from about 7.5ng/mL plasma to about 30ng/mL plasma_min。

In another aspect, provided herein is a method of treating hyperkinetic movement disorders, the method comprising administering to a subject in need thereof an amount of a pharmaceutical composition comprising a VMAT2 inhibitor described herein sufficient to provide, over a period of about 8 hours to about 24 hours: (i) a therapeutic concentration range of about 15ng to about 60ng (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) α -HTBZ) per mL of plasma; and (ii) a threshold concentration of at least 15ng (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) α -HTBZ) per mL of plasma.

In certain embodiments, the VMAT2 inhibitor is Tetrabenazine (TBZ); (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester; deuterated TBZ; deuterated (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester; (+) - α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) α -HTBZ); or deuterated (+) alpha-HTBZ.

In certain embodiments, the therapeutic concentration ranges from about 15ng to about 35ng, to about 40ng, to about 45ng, to about 50ng, or to about 55ng (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) α -HTBZ) per mL of plasma.

In certain embodiments, the threshold concentration of (+) α -HTBZ is about 15ng/mL plasma, about 20ng/mL plasma, about 25ng/mL plasma, about 30ng/mL plasma, about 35ng/mL plasma, about 40ng/mL plasma, about 45ng/mL plasma, about 50ng/mL plasma, about 55ng/mL plasma, or about 60ng/mL plasma over a period of about 8 hours, about 12 hours, about 16 hours, about 20 hours, about 24 hours, about 28 hours, or about 32 hours. In a specific embodiment, the threshold concentration of (+) α -HTBZ is about 15ng/mL to about 35ng/mL for a period of about 8 hours to about 24 hours.

In another aspect, provided herein is a method of treating hyperkinetic movement disorders, the method comprising administering to a subject in need thereof an amount of a pharmaceutical composition comprising a VMAT2 inhibitor described herein sufficient to provide, over a period of about 8 hours to about 24 hours: (i) a therapeutic concentration range of about 15ng to about 60ng (+) beta-3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) beta-HTBZ) per mL of plasma; and (ii) a threshold concentration of at least 15ng (+) beta-3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) beta-HTBZ) per mL of plasma.

In certain embodiments, the therapeutic concentration ranges from about 15ng to about 35ng, about 40ng, about 45ng, about 50ng, or about 55ng (+) beta-3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) beta-HTBZ) per mL of plasma.

In certain embodiments, the threshold concentration of (+) β -HTBZ is about 15ng/mL plasma, about 20ng/mL plasma, about 25ng/mL plasma, about 30ng/mL plasma, about 35ng/mL plasma, about 40ng/mL plasma, about 45ng/mL plasma, about 50ng/mL plasma, about 55ng/mL plasma, or about 60ng/mL plasma over a period of about 8 hours, about 12 hours, about 16 hours, about 20 hours, or about 24 hours.

In certain embodiments, a VMAT2 inhibitor described herein is administered in an amount sufficient to provide: A) over a period of about 8 hours to about 24 hours, (i) a therapeutic concentration range of about 15ng to about 60ng (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) α -HTBZ) per mL of plasma; and (ii) a threshold concentration of at least 15ng (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) α -HTBZ) per mL of plasma; and/or B) over a period of about 8 hours to about 24 hours, (i) a therapeutic concentration range of about 15ng to about 60ng (+) beta-3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7, 11B-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) beta-HTBZ) per mL of plasma; and (ii) a threshold (or minimum) concentration of at least 15ng (+) beta-3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) beta-HTBZ) per mL of plasma.

In a specific embodiment, the pharmaceutical composition for use in the methods described herein comprises (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester. In a more specific embodiment, the compound is a dihydrochloride or a xylenesulfonate.

In a specific embodiment, in the methods described herein, a daily dose of about 40mg to about 80mg of (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester (which may be deuterated or non-deuterated) is administered to the subject. In a more specific embodiment, a daily dose of (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester of about 40mg, about 45mg, about 50mg, about 55mg, about 60mg, about 65mg, about 70mg, about 75mg or about 80mg is administered to the subject.

In another embodiment, the pharmaceutical composition for use in the methods described herein comprises (+) α -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-ol ((+) α -HTBZ), which is administered to a subject in multiple doses throughout the day and/or as a sustained release formulation.

In another embodiment, the pharmaceutical composition for use in the methods described herein comprises Tetrabenazine (TBZ) which is administered to a subject in multiple doses throughout the day and/or as a sustained release formulation.

In another embodiment, the pharmaceutical composition for use in the methods described herein comprises d₆-Tetrabenazine (TBZ) for administration to a subject in multiple doses throughout the day and/or as a sustained release formulation.

792-801; mehvar et al, Drug Metabolism and Distribution 198715 (2):250-55, and plasma concentrations of (+) α -HTBZ, (+) β -HTBZ and the compounds disclosed herein are typically measured by tandem mass spectrometry.

As discussed herein, the compounds and salts described herein may reduce monoamine supply in the central nervous system by inhibiting the human monoamine transporter isoform 2(VMAT 2). As such, these compounds and their salts may have utility in a wide range of therapeutic applications and may be useful in the treatment of a variety of conditions caused by or associated with the inhibition of the human monoamine transporter isoform 2. These disorders include hyperkinetic disorders. In one embodiment, conditions that may be treated with the compounds described herein include, but are not limited to, hyperkinetic disorders such as huntington's disease, tardive dyskinesia, tourette's syndrome, dystonia, hemitoseisis, chorea, and tics. In certain embodiments, the hyperkinetic disorder treated by the compounds described herein does not include huntington's disease, according to the methods described herein.

The compounds described herein can be synthesized according to known organic synthesis techniques described in the art. See, for example, U.S. patent No. 8,039,627 (referred to as 2-1 in U.S. patent No. 8,039,627) which describes a general synthetic scheme and method for the synthesis of specific compounds including (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester.

The compounds described herein can generally be used as the free acid or as the free base. Alternatively, the compounds may be used in the form of acid addition salts or base addition salts. Acid addition salts of the free amino compounds can be prepared by methods well known in the art and can be formed from organic and inorganic acids. Suitable organic acids include: maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, methanesulfonic acid, acetic acid, trifluoroacetic acid, oxalic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, lactic acid, mandelic acid, cinnamic acid, aspartic acid, stearic acid, palmitic acid, glycolic acid, glutamic acid, and benzenesulfonic acid. Suitable inorganic acids include: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and nitric acid. Base addition salts include those formed from carboxylic acid anions and include salts formed from organic and inorganic cations such as those selected from alkali and alkaline earth metals (e.g., lithium, sodium, potassium, magnesium, barium, and calcium), as well as ammonium ions and substituted derivatives thereof (e.g., dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, and the like). Thus, the term "pharmaceutically acceptable salt" of a compound described herein is intended to encompass any and all acceptable salt forms.

With respect to stereoisomers, the compounds described herein may have chiral centers and may occur as racemates, racemic mixtures and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof. Furthermore, it is contemplated herein that some crystal forms of the compounds may exist in the form of polymorphs. In addition, some compounds may also form solvates with water or other organic solvents. Such solvates are also included within the scope of the compounds described herein.

One skilled in the art will appreciate that any of the foregoing compounds may incorporate a radioisotope. Thus, isotopically-labeled compounds are also contemplated for use, which are identical to those recited herein, in that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into these compounds include isotopes of each of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to²H、³H、¹³C、¹⁴C、¹⁵N、¹⁸O、¹⁷O、³¹P、³²P、³⁵S、¹⁸F and³⁶and (4) Cl. Certain isotopically-labeled compounds, e.g. in which a radioactive isotope is incorporated (e.g.³H and¹⁴C) those compounds of (a) can also be used in drug or substrate tissue distribution assays. Deuterated hydrogen (A) is particularly preferred³H) And carbon 14 (C)¹⁴C) Isotopes because they are easy to prepare and detect. With heavier isotopes (e.g. deuterium: (²H) A) may provide certain therapeutic advantages resulting from higher metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. Isotopically labeled compounds can generally be prepared by carrying out conventional procedures practiced in the art.

Tetrabenazine, when administered according to current protocols, predominantly causes CNS reactions (e.g., lethargy, vertigo, inability to sit quietly (pacing quietly), lethargy, fatigue, nervousness, insomnia, anxiety, parkinson's syndrome, and depression) resulting from monoamine consumption of neurons. The effect of tetrabenazine is reversible and thus temporary. In humans, tetrabenazine is rapidly metabolized to its active metabolite HTBZ, so that systemic exposure to tetrabenazine is virtually negligible. The reduction of tetrabenazine to HTBZ is catalyzed by carbonyl reductases and is highly variable, and HTBZ has a short half-life. This has led to the need for personalized dosing regimens (12.5 to 225 mg/day, given 1-3 times per day). As described herein, HTBZ formed from tetrabenazine is a mixture of four stereoisomers leading to different pharmacologies by binding to off-target receptors (see, e.g., kilbrourn et al, 1995 supra). However, the practical limit is 100 mg/kg/day, since the FDA requires CYP2D6 testing (see XENAZINE Package Insert, Biovail Laboratories International,2009) on doses exceeding 50 mg.

NBI-98854((S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester) and pharmaceutically acceptable salts thereof is an orally active valine ester of a vesicular monoamine transporter 2(VMAT2) inhibitor ((+) α -HTBZ), and it is designed to deliver [ + ] α -HTBZ in a controlled manner, with reduced peak plasma concentrations and Pharmacokinetic (PK) variability intended to limit off-target binding and allow for improved safety profiles in human subjects.

The selective targeting of VMAT2 and the pharmacokinetic profile of the active metabolite [ + ] alpha-HTBZ appear to provide preferred and dose-related modulation of dopamine release without evidence of significant serotonin, norepinephrine, or histamine depletion. This should be possible when administered in combination with the patient's existing antipsychotic medication or independently in patients where antipsychotic medication has been discontinued.

As understood by those skilled in the Medical arts, the terms "treatment" and "treatment" refer to the Medical management of a disease, disorder or condition of a subject (i.e., patient) (see, e.g., Stedman's Medical Dictionary). The terms "treatment" and "treating" encompass prophylactic (i.e. prophylactic) treatment or therapeutic, i.e. curative, treatment and/or palliative treatment. The terms "treatment" and "treating" thus include therapeutic treatment of a patient who has developed a condition, particularly in a significant manner. Therapeutic treatment may be symptomatic treatment to alleviate the symptoms of a particular indication or causal treatment to reverse or partially reverse the condition of an indication or to halt or slow the progression of the disease. Thus, the compositions and methods described herein can be used, for example, as therapeutic treatments over a period of time, as well as for chronic therapies. Furthermore, the terms "treatment" and "treating" include prophylactic treatment, i.e. treatment of a patient at risk of developing the above-mentioned conditions, thereby reducing the risk.

Subjects in need of the compositions and methods described herein include subjects that have been diagnosed as having a hyperkinetic disorder (e.g., tardive dyskinesia) by one of skill in the medical and psychiatric arts. The subject (or patient) to be treated may be a mammal, including a human or non-human primate. The mammal may be a domestic animal such as a cat or dog.

Therapeutic and/or prophylactic benefits include, for example, improved clinical outcomes in therapeutic treatment and prophylactic (preventative) or preventative (preventative) measures, wherein the goal is to prevent or slow down or delay (lessen) an undesired physiological change or disorder or to prevent or slow down or delay (lessen) the development or severity of such a disorder. Prophylactic administration of the compositions herein may begin with a first treatment with a dopamine receptor blocking drug, such as a neuroleptic. As discussed herein, beneficial or desired clinical results from treatment of a subject include, but are not limited to: reducing, alleviating or alleviating symptoms caused by or associated with the disease, condition or disorder to be treated; reduced occurrence of symptoms; improved quality of life; a longer disease-free state (i.e., a decreased likelihood or propensity that a subject will exhibit symptoms, based on which a diagnosis of the disease is made); reducing the extent of disease; stable (i.e., not worsening) disease state; delay or slow disease progression; ameliorating or alleviating a disease state; and detectable or undetectable mitigation (whether in part or in whole); and/or overall survival. "treatment" may also mean increasing survival compared to the expected survival if the subject did not receive treatment. Subjects in need of treatment include those already having a condition or disorder, as well as those prone to have, or at risk of developing, a disease, condition, or disorder (e.g., TD or other condition or disorder described herein), and those in whom a disease, condition, or disorder is to be prevented (i.e., the likelihood of the disease, disorder, or condition occurring is reduced). A therapeutically effective amount of any of the compounds described herein is an amount of the compound that provides a statistically or clinically significant therapeutic and/or prophylactic benefit to the treated subject.

Methods of determining the effectiveness of therapeutic agents for treating hyperkinetic disorders are routinely used by those skilled in the medical and clinical arts. By way of illustration, subjects with hyperkinetic disorders can be diagnosed, monitored and evaluated by the Abnormal Involuntary Movement Scale (AIMS). AIMS is a structured neurological examination developed in 1976 and has been widely used for the evaluation of motility disorders. It consists of seven different regions scoring a range of zero to four values with zero being scored as none and four being scored as severe.

Pharmaceutical composition

The present disclosure also provides pharmaceutical compositions comprising any of the VMAT2 inhibitor compounds described herein, and a pharmaceutically acceptable excipient, for use in methods of treating hyperkinetic disorders. Pharmaceutically acceptable excipients are physiologically and pharmaceutically suitable non-toxic and inactive materials or ingredients which do not interfere with the activity of the active ingredient; excipients may also be referred to as carriers. The formulation methods and excipients described herein are exemplary andand are in no way limiting. Pharmaceutically acceptable Excipients are well known in the Pharmaceutical art and are described, for example, in Rowe et al, Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety,5^thEd, 2006 and Remington The Science and Practice of Pharmacy (Gennaro, 21)^stMac k pub. co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline at physiological pH and phosphate buffered saline. Preservatives, stabilizers, dyes, buffers and the like may be provided in the pharmaceutical compositions. In addition, antioxidants and suspending agents may also be used.

For compositions formulated as liquid solutions, acceptable carriers and/or diluents include saline and sterile water, and may optionally include antioxidants, buffers, bacteriostats and other common additives. The compositions may also be formulated as pills, capsules, granules, or tablets that contain diluents, dispersants and surfactants, binders, and lubricants in addition to the VMAT2 inhibitor. One skilled in the art may also formulate VMAT2 inhibitors in a suitable manner and according to accepted practice such as those disclosed in Remington above.

In another embodiment, a method of treating a disorder of the central or peripheral nervous system is provided. Such methods comprise administering to a warm-blooded animal an amount of a compound of the present invention sufficient to treat the condition. In this context, "treating" includes prophylactic administration. Such methods include systemic administration of the VMAT2 inhibitors described herein, preferably in the form of a pharmaceutical composition as discussed above. As used herein, systemic administration includes oral and parenteral methods of administration. For oral administration, suitable pharmaceutical compositions include powders, granules, pills, tablets and capsules as well as liquids, syrups, suspensions and emulsions. These compositions may also contain flavoring agents, preservatives, suspending agents, thickening and emulsifying agents, and other pharmaceutically acceptable additives. For parenteral administration, the compounds of the present invention may be prepared as aqueous injection solutions which may contain, in addition to the VMAT2 inhibitor, buffers, antioxidants, bacteriostats, and other additives commonly used in such solutions.

As described herein, the optimal dosage is typically determined by using experimental models and/or clinical trials. The optimal dosage may depend on the weight (body mass), weight, blood volume or other individual characteristics of the subject. For example, the person skilled in the medical field may consider the condition of the subject, i.e. the stage of the disease, the severity of the symptoms caused by the disease, the overall health status as well as age, sex and weight, as well as other factors that will be apparent to the person skilled in the medical field. Generally, the amount of a compound described herein is present in a dosage range of about 0.1mg to about 2mg per kg of body weight of the subject. In certain embodiments, the daily dose is about 10-150 mg. The use of the lowest dose sufficient to provide effective treatment is generally preferred. The effectiveness of a subject's treatment can generally be monitored by clinical assessment as well as using analysis of conditions appropriate for being treated or prevented, methods of assessment and analysis (e.g., AIMS assessment) being familiar to those skilled in the art and described herein. The concentration of the compound administered to the subject can be monitored by determining the concentration of the compound in a biological fluid, such as blood, blood fractions (e.g., plasma, serum), and/or urine and/or other biological samples from the subject. The concentration of the compound during the treatment regimen can be measured using any method practiced in the art for detecting the compound.

Tetrabenazine and d₆Sustained release formulations of-tetrabenazine are known in the art. Sustained release pharmaceutical compositions are described in PCT publications WO 2010/018408, WO 2011/019956, and WO 2014/047167.

The pharmaceutical compositions described herein comprising at least one of the VMAT2 inhibitor compounds described herein can be administered to a subject in need thereof by any of several routes effective to deliver an effective amount of the composition. Such routes of administration include, for example, oral administration, parenteral administration, enteral administration, rectal administration, intranasal administration, buccal administration, sublingual administration, intramuscular administration, and transdermal administration.

Examples

Example 1

Human clinical trial-NBI-98854

Clinical data from TD subjects administered repeated doses of (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] isoquinolin-2-yl ester from 12.5 mg/day to 100 mg/day show that the drug is generally well tolerated. Efficacy correlates with the concentration of the active metabolite [ + ] alpha-dihydrotetrabenazine. Exposure-response analysis showed that a concentration of 30ng/mL in plasma was a suitable target. Exposure above 60ng/mL in plasma provided a small increase in benefit, but increased risk of adverse events, reflecting the expansion of VMAT2 pharmacology. Exposure below 15ng/mL is suboptimal in the general TD population.

The (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] source]Observed exposure of video ratings of phase 2 clinical studies of isoquinolin-2-yl esters and the Abnormal Involuntary Movement Scale (AIMS) were used for the development of exposure-response relationships. A total of 96 patients were randomized to placebo (N ═ 41) and (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] as placebo]Isoquinolin-2-yl ester group (25mg, 50mg or 75mg, N ═ 45). 38 of the three receptors (S) -2-amino-3-methyl-butyric acid (2R,3R,11bR) -3-isobutyl-9, 10-dimethoxy-1, 3,4,6,7,11 b-hexahydro-2H-pyrido [2,1-a ] S]The patient of isoquinolin-2-yl ester has utility for the metabolite [ +]PK data for α -dihydrotetrabenazine. Thus, data from a total of 79 patients (41 placebo patients and 38 drug-exposed patients) were used for exposure-AIMS analysis. AIMS derived from baseline and week 6 video ratings of each patient can be obtained. The percent change from baseline at week 6 was used as a response metric. Each patient was obtained at about T at week 6_maxThen sample is extracted [ +]Alpha-dihydrotetrabenazine, and C_maxThe steady state (ss) is used as an exposure metric.

Based on week 6C_maxss, will have quantifiable [ +]Patients with alpha-dihydrotetrabenazine concentrations were divided into four groups. Calculate average C for each group_maxss and mean AIMS decrease from baseline. As shown in the following tableThese groups were compared to placebo patients.

As can be seen, the AIMS at week 6 time point for placebo patients was substantially similar to the baseline reading. Group 1 patients (those who showed the lowest [ + ] α -HTBZ Cmax ss at the 6 week time point regardless of the NBI-98854 dose administered) showed a mean Cmax ss of [ + ] α -HTBZ of about 15ng/mL and a moderate decrease in AIMS of about 33%. The next group of patients showed a mean Cmax ss of [ + ] α -HTBZ and a maximum decrease of about 70% of AIMS from baseline readings of about 29 ng/mL. Patients who reached the highest [ + ] alpha-HTBZ concentration in the lower 2 group did not achieve any greater reduction in TD symptoms as measured by a decrease in mean AIMS score relative to patients in group 2.

Example 2

Maintenance of threshold plasma concentrations of [ + ] alpha-HTBZ in NBI-98854 treated patients

Patients in the multi-dose group (n-13 for the 50mg dose group; n-4 for the 100mg dose group) were orally administered NBI-98854 in 50mg or 100mg doses once daily for 8 days. On day 8, (+) -HTBZ plasma concentration data were collected for individual subjects at predetermined post-dose times (0hr, 2hr, 4hr, 6hr, 8hr, 12hr, 16hr, 24hr, 48hr, 96hr and 120hr) and expressed as mean plasma concentration data (linear scale) (see fig. 1). On day 8, T of (+) -alpha-HTBZ for both doses_maxThe median time of (a) was all about 4.0 hours. At the maximum concentration (C)_max) Thereafter, a drop in plasma concentration of (+) - α -HTBZ occurred and showed apparent t-values of about 21 hours (50mg dose) and about 19 hours (100mg dose)_1/2. As shown in figure 1, NBI-98854 at a 50mg dose was shown to maintain the desired therapeutic concentration range of about 15ng to about 60ng (+) α -HTBZ per mL of plasma over a period of about 8 hours to about 24 hours, which is above the threshold concentration of about 15 ng/mL.

According to 35 u.s.c. § 119(e), the present application claims benefit of U.S. provisional application No. 61/989,240 filed 5/6 2014, which is incorporated herein by reference in its entirety.

The various embodiments described above can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications referred to in this specification and/or listed in the application data sheet, are incorporated herein by reference, in their entirety. Aspects of the embodiments can be modified, if necessary, to employ concepts in different patents, applications, and publications to provide yet further embodiments.

These and other changes can be made to the embodiments in light of the above detailed description. In general, in the following claims, the terms used should not be construed to limit the claims to the specific embodiments disclosed in the specification and the claims, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled. Accordingly, the claims are not limited by the disclosure.