WO2017184531A1

WO2017184531A1 - Treatment of movement-related disorders using noribogaine

Info

Publication number: WO2017184531A1
Application number: PCT/US2017/028007
Authority: WO
Inventors: Holger Weis
Original assignee: Demerx, Inc.
Priority date: 2016-04-18
Filing date: 2017-04-17
Publication date: 2017-10-26

Abstract

This invention provides methods and compositions for treating or preventing a neurodegenerative disease or a movement disorder and/or symptoms thereof in a subject. The method comprises administering to the subject in need thereof a therapeutically effective amount of an iboga alkaloid or a pharmaceutically acceptable salt or solvate thereof.

Description

TREATMENT OF MOVEMENT-RELATED DISORDERS USING NORIBOGAINE

RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Patent Application No.

62/324,249, filed on April 18, 2016, entitled "Methods for Treating Movement-Related Disorders Using Noribogaine," the contents of which are all incorporated by reference herein.

FIELD OF THE INVENTION

[0002] This invention relates generally to methods and compositions for the treatment and/or prevention of movement-related disorders and/or symptoms thereof by administering an iboga alkaloid or a pharmaceutically acceptable salt or solvate thereof at a safe and effective dosage. This invention further relates generally to methods and compositions for the treatment and/or prevention of neurodegenerative diseases and/or symptoms thereof by administering an iboga alkaloid or a pharmaceutically acceptable salt or solvate thereof.

BACKGROUND

[0003] Neurodegenerative diseases arise as a result of progressive loss of neuron structure and/or function. Neurodegenerative diseases include, without limitation, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), prion diseases (e.g., Creutzfeldt- Jakob Disease), ataxia, spinocerebellar ataxia, spinal muscular atrophy, Friedreich's ataxia, Lewy body disease, and motor neuron diseases.

Neurodegeneration may also occur as a result of aging or trauma. These diseases have no known cure, and are marked by progressive degeneration and/or death of neurons.

[0004] Movement-related disorders are neurologic disorders that result in excessive or movement (hyperkinetic), or reduced movement (hypokinetic). Several neurodegenerative diseases, including Parkinson's disease, Huntington's disease, and ALS, may also be classified as movement-related disorders. Other movement disorders include, without limitation, bradykinesia, Hallevorden-Spatz disease, progressive supranuclear palsy, multiple system atrophy, dystonia, spasmodic torticollis, essential tremor, other types of tremor, various choreas and diskenesias, tic disorders, Tourette's syndrome, stereotypic movement disorder, paroxysmal nocturnal limb movement, restless leg syndrome, and stiff person syndrome. Movement disorders may interfere with daily functioning and activity. Many movement disorders have no known cure and/or treatment available. [0005] There remains an acute need for effective strategies for treating and preventing movement disorders and neurodegenerative diseases, including symptoms thereof.

SUMMARY

[0006] The current invention is predicated, in part, on the surprising discovery that treatment with a low, narrow dosage range of an iboga alkaloid or pharmaceutically acceptable salt and/or solvate thereof, provides a therapeutic alleviation of at least some symptoms and/or progression of neurodegenerative disease and/or movement disorders. Preferably, the dose provides both therapeutic results and an acceptable QT interval prolongation of less than about 60 milliseconds (ms) in humans, and more preferably less than about 20 ms.

[0007] In one aspect, this invention relates to methods of treating or preventing neurodegenerative disease and/or symptoms and/or progression thereof by administering a therapeutic amount (or prophylactic amount) of an iboga alkaloid or a pharmaceutically acceptable salt or solvate thereof. In a preferred embodiment, the treatment does results in a QT interval prolongation of less than 60 ms, preferably less than 50 ms, more preferably less than 30 ms, even more preferably less than 20 ms.

[0008] In one embodiment, the neurodegenerative disease and/or at least one symptom thereof is prevented. In one embodiment, the neurodegenerative disease and/or at least one symptom thereof is treated. In one embodiment, the iboga alkaloid or pharmaceutically acceptable salt and/or solvate thereof is administered prior to on-set of the disease or symptoms thereof, e.g., to a patient at risk of having the disease (e.g., having a genetic predisposition for the disease, exposed to a substance that may cause the disease or disorder, etc.).

[0009] In one embodiment, the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), a prion disease (e.g., Creutzfeldt- Jakob Disease), spinocerebellar ataxia, spinal muscular atrophy, Friedreich's ataxia, Lewy body disease, and a motor neuron disease. In a preferred embodiment, the neurodegenerative disease is Parkinson's disease. In one embodiment, the neurodegenerative disease is not Alzheimer's disease. In one embodiment, the

neurodegenerative disease is a result of aging or brain trauma (e.g., traumatic brain injury, concussion, stroke). [0010] In one embodiment, the patient is co-administered a therapeutic amount of an agent known to treat the neurodegenerative disease or a symptom(s) thereof in addition to the iboga alkaloid. In one embodiment, both compounds are administered at the same time. In one embodiment, the compounds are administered at different times (e.g., sequentially).

[0011] In another aspect, this invention provides a method for treating or preventing a movement disorder and/or symptoms thereof in a patient in need thereof by administering to the patient a therapeutic amount (or prophylactic amount) of an iboga alkaloid or a pharmaceutically acceptable salt or solvate thereof. In a preferred embodiment, the treatment results in a QT interval prolongation of less than 60 ms, preferably less than 50 ms, more preferably less than 30 ms, even more preferably less than 20 ms.

[0012] In one embodiment, the movement disorder is a hyperkinetic disorder. In one embodiment, the movement disorder is a hypokinetic disorder. In one embodiment, the movement disorder is bradykinesia, Hallevorden-Spatz disease, progressive supranuclear palsy, multiple system atrophy, dystonia, spasmodic torticollis, essential tremor, other types of tremor, various choreas and diskenesias, tic disorders, Tourette's syndrome, stereotypic movement disorder, paroxysmal nocturnal limb movement, restless leg syndrome, or stiff person syndrome.

[0013] In one embodiment, the patient is co-administered a therapeutic amount of an agent known to treat the movement disorder or a symptom(s) thereof in addition to the iboga alkaloid. In one embodiment, both compounds are administered at the same time. In one embodiment, the compounds are administered at different times (e.g., sequentially).

[0014] In one aspect, the therapeutic amount or prophylactic amount of iboga alkaloid is between about 0.1 milligrams (mg) and about 180 mg per day. In one embodiment, the therapeutic amount or prophylactic amount of iboga alkaloid is between about 0.1 mg and about 100 mg per day. In one embodiment, the therapeutic amount or prophylactic amount of iboga alkaloid is between about 1 mg and about 50 mg per day. In one embodiment, the therapeutic amount or prophylactic amount of iboga alkaloid is between about 1 mg and about 30 mg per day. In another embodiment, the therapeutic amount or prophylactic amount of iboga alkaloid is between about 1 mg and about 20 mg per day. [0015] Preferably, the iboga alkaloid is noribogaine, a noribogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof. More preferably, the iboga alkaloid is noribogaine or a pharmaceutically acceptable salt and/or solvate thereof.

[0016] In some embodiments, the therapeutically effective amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is administered once a day, twice a day, or more than twice a day.

[0017] In another aspect, this invention provides a composition for treating and/or preventing a neurodegenerative disease or a movement disorder, which composition contains a therapeutic or prophylactic amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof, at least one agent that is known to treat and/or prevent the diease or disorder, and optionally a pharmaceutically acceptable excipient. Preferably, the iboga alkaloid is noribogaine or a pharmaceutically acceptable salt and/or solvate thereof.

BRIEF DESCRIPTION OF THE FIGURES

[0018] FIG. 1 represents mean noribogaine concentration-time profiles in healthy patients after single oral dosing with 3 mg (·), 10 mg (o), 30 mg (▼) or 60 mg (Δ) doses. Inset: Individual concentration-time profiles from 0-12 h after a 10 mg dose.

[0019] FIG. 2 represents mean plasma noribogaine glucuronide concentration-time profiles in healthy patients after single oral 30 mg (▼) or 60 mg (Δ) doses.

[0020] FIG. 3 illustrates the mean noribogaine concentration-time profile in opioid- addicted patients after a single oral 60 mg (♦), 120 mg (■), or 180 mg (A) dose of noribogaine.

[0021] FIG. 4A illustrates the average change in QT interval (AQTcl) for each cohort (60 mg,■; 120 mg,▲ ; 180 mg,♦; or placebo, ·) over the first 24 hours post administration.

[0022] FIG. 4B illustrates the relationship between noribogaine concentrations and AAQTcI with 90% CI.

[0023] FIG. 4C is a goodness-of-fit plot for observed and predicted relation between noribogaine plasma levels.

[0024] FIG. 5 illustrates the effect of acute noribogaine treatment on cylinder test performance of rats. [0025] FIG. 6A illustrates the effect of L-Dopa/benserazide in combination with noribogaine on cylinder test performance of rats.

[0026] FIG. 6B illustrates the effect of L-Dopa/benserazide in combination with noribogaine on semi-quantitative dyskinesia score in rats.

[0027] FIG. 7 illustrates the effect of sub-chronic, once-daily noribogaine on cylinder test performance of rats.

DETAILED DESCRIPTION

[0028] It is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of this invention will be limited only by the appended claims.

[0029] The detailed description of the invention is divided into various sections only for the reader's convenience and disclosure found in any section may be combined with that in another section. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0030] It must be noted that as used herein and in the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of compounds.

I. Definitions

[0031] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. As used herein the following terms have the following meanings.

[0032] The term "about" when used before a numerical designation, e.g. , temperature, time, amount, concentration, and such other, including a range, indicates approximations which may vary by ( + ) or ( - ) 20%, 10 %, 5 %, 1 %, or any subrange or subvalue there between. Preferably, the term "about" when used with regard to a dose amount means that the dose may vary by +/- 20%. For example, "about 2 mg/kg noribogaine" indicates that a patient may be administered a dose of noribogaine between 1.6 mg/kg and 2.4 mg/kg. In another example, about 120 mg per unit dose of noribogaine indicates that the unit dose may range from 96 mg to 144 mg.

[0033] Where ranges are recited herein, it is to be understood that the amount may be any value or subrange within the recited range, including endpoints.

[0034] "Administration" refers to introducing an agent, such as an iboga alkaloid, into a patient. Typically, an effective amount is administered, which amount can be determined by the treating physician or the like. Any route of administration, such as oral, topical, subcutaneous, peritoneal, intra-arterial, inhalation, vaginal, rectal, nasal, introduction into the cerebrospinal fluid, or instillation into body compartments can be used. The agent, such as an iboga alkaloid, may be administered by direct blood stream delivery, e.g. sublingual, buccal, intranasal, or intrapulmonary administration. Preferably, administration is oral.

[0035] The related terms and phrases "administering" and "administration of, when used in connection with a compound or pharmaceutical composition (and grammatical equivalents) refer both to direct administration, which may be administration to a patient by a medical professional or by self-administration by the patient, and/or to indirect

administration, which may be the act of prescribing a drug. For example, a physician who instructs a patient to self-administer a drug and/or provides a patient with a prescription for a drug is administering the drug to the patient.

[0036] "Periodic administration" or "periodically administering" refers to multiple treatments that occur on a daily, weekly, or monthly basis. Periodic administration may also refer to administration of an agent, such as iboga alkaloid or salt or solvate thereof one, two, three, or more times per day. Administration may be via transdermal patch, gum, lozenge, sublingual tablet, intranasal, intrapulmonary, oral administration, or other administration.

[0037] "Comprising" or "comprises" is intended to mean that the compositions and methods include the recited elements, but not excluding others. "Consisting essentially of when used to define compositions and methods, shall mean excluding other elements of any essential significance to the combination for the stated purpose. Thus, a composition consisting essentially of the elements as defined herein would not exclude other materials or steps that do not materially affect the basic and novel characteristic(s) of the claimed invention. "Consisting of shall mean excluding more than trace elements of other ingredients and substantial method steps. Embodiments defined by each of these transition terms are within the scope of this invention.

[0038] As used herein, the term "alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 12 carbon atoms, 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, and more preferably 1 to 3 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH₃-), ethyl (CH₃CH₂-), ^-propyl (CH₃CH₂CH₂-), isopropyl ((CH₃)₂CH-), w-butyl (CH₃CH₂CH₂CH₂-), isobutyl ((CH₃)₂CHCH₂-), sec-butyl ((CH₃)(CH₃CH₂)CH-), r-butyl ((CH₃)₃C-), w-pentyl

(CH₃CH₂CH₂CH₂CH₂-), and neopentyl ((CH₃)₃CCH₂-). The term "C_x alkyl" refers to an alkyl group having x carbon atoms, wherein x is an integer, for example, C₃ refers to an alkyl group having 3 carbon atoms.

[0039] "Alkenyl" refers to straight or branched hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of vinyl (>C=C<) unsaturation. Such groups are exemplified, for example, by vinyl, allyl, and but-3-en-l-yl. Included within this term are the cis and trans isomers or mixtures of these isomers.

[0040] "Alkynyl" refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of acetylenic (-C≡C-) unsaturation. Examples of such alkynyl groups include acetylenyl (-C≡CH), and propargyl (-CH₂C≡CH).

[0041] "Substituted alkyl" refers to an alkyl group having from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl,

aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.

[0042] "Substituted alkenyl" refers to alkenyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl,

aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy or thiol substitution is not attached to a vinyl (unsaturated) carbon atom.

[0043] "Substituted alkynyl" refers to alkynyl groups having from 1 to 3 substituents, and preferably 1 to 2 substituents, selected from the group consisting of alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl,

aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein and with the proviso that any hydroxy or thiol substitution is not attached to an acetylenic carbon atom.

[0044] "Alkoxy" refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, w-propoxy, isopropoxy, w-butoxy, /-butoxy, seobutoxy, and w-pentoxy.

[0045] "Substituted alkoxy" refers to the group -0-(substituted alkyl) wherein substituted alkyl is defined herein.

[0046] "Acyl" refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclic-C(O)-, and substituted heterocyclic-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Acyl includes the "acetyl" group CH₃C(0)-.

[0047] "Acylamino" refers to the groups -NR ⁸C(0)alkyl, -NR ⁸C(0)substituted alkyl, -NR ⁸C(0)cycloalkyl, -NR ⁸C(0)substituted

cycloalkyl, -NR ⁸C(0)cycloalkenyl, -NR ⁸C(0)substituted

cycloalkenyl, -NR ⁸C(0)alkenyl, -NR ⁸C(0)substituted

alkenyl, -NR ⁸C(0)alkynyl, -NR ⁸C(0)substituted

alkynyl, -NR ⁸C(0)aryl, -NR ⁸C(0)substituted

aryl, -NR ⁸C(0)heteroaryl, -NR ⁸C(0)substituted heteroaryl, -NR ⁸C(0)heterocyclic, and -NR ⁸C(0)substituted heterocyclic wherein R³⁸ is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0048] "Acyloxy" refers to the groups alkyl-C(0)0-, substituted alkyl-C(0)0-, alkenyl-C(0)0-, substituted alkenyl-C(0)O, alkynyl-C(0)O, substituted alkynyl-C(0)O, aryl-C(0)0-, substituted aryl-C(0)0-, cycloalkyl-C(0)0-, substituted cycloalkyl-C(0)0-, cycloalkenyl-C(0)0-, substituted cycloalkenyl-C(0)0-, heteroaryl-C(0)0-, substituted heteroaryl-C(0)0-, heterocyclic-C(0)0-, and substituted heterocyclic-C(0)0- wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0049] "Amino" refers to the group -NH₂.

[0050] "Substituted amino" refers to the group -NR ⁹R⁴⁰ where R³⁹ and R⁴⁰ are

independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -SC^-alkyl, -S0₂-substituted

alkyl, -SC^-alkenyl, -S0₂-substituted alkenyl, -SCh-cycloalkyl, -S0₂-substituted

cylcoalkyl, -SC^-cycloalkenyl, -S0₂-substituted cylcoalkenyl,-S0₂-aryl, -S0₂-substituted aryl, -S0₂-heteroaryl, -S0₂-substituted heteroaryl, -SCh-heterocyclic, and -S0₂-substituted heterocyclic and wherein R³⁹ and R⁴⁰ are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R³⁹ and R⁴⁰ are both not hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. When R³⁹ is hydrogen and R⁴⁰ is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R³⁹ and R⁴⁰ are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it is meant that either R³⁹ or R⁴⁰ is hydrogen but not both. When referring to a disubstituted amino, it is meant that neither R³⁹ nor R⁴⁰ are hydrogen.

[0051] "Aminocarbonyl" refers to the group -C(0)NR⁴¹R⁴² where R⁴¹ and R⁴² are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R⁴¹ and R⁴² are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0052] "Aminothiocarbonyl" refers to the group -C(S)NR⁴¹R⁴² where R⁴¹ and R⁴² are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R⁴¹ and R⁴² are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0053] "Aminocarbonylamino" refers to the group -NR ⁸C(0)NR⁴¹R⁴² where R³⁸ is hydrogen or alkyl and R⁴¹ and R⁴² are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted

cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R⁴¹ and R⁴² are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0054] "Aminothiocarbonylamino" refers to the group -NR ⁸C(S)NR⁴¹R⁴² where R³⁸ is hydrogen or alkyl and R⁴¹ and R⁴² are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted

[0055] "Aminocarbonyloxy" refers to the group -0-C(0)NR⁴¹R⁴² where R⁴¹ and R⁴² are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R⁴¹ and R⁴² are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0056] "Aminosulfonyl" refers to the group -S0₂NR⁴¹R⁴² where R⁴¹ and R⁴² are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R⁴¹ and R⁴² are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0057] "Aminosulfonyloxy" refers to the group -0-S0₂NR⁴¹R⁴² where R⁴¹ and R⁴² are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R⁴¹ and R⁴² are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. [0058] "Aminosulfonylamino" refers to the group -NR ⁸-S0₂NR⁴¹R⁴² where R³⁸ is hydrogen or alkyl and R⁴¹ and R⁴² are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted

[0059] "Amidino" refers to the group -C(=NR⁴ )NR⁴¹R⁴² where R⁴¹, R⁴², and R⁴³ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R⁴¹ and R⁴² are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0060] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of from 6 to 14 carbon atoms having a single ring (e.g. , phenyl) or multiple condensed rings (e.g., naphthyl or anthryl) which condensed rings may or may not be aromatic (e.g. , 2-benzoxazolinone, 2H-l,4-benzoxazin-3(4H)-one-7-yl, and the like) provided that the point of attachment is at an aromatic carbon atom. Preferred aryl groups include phenyl and naphthyl.

[0061] "Substituted aryl" refers to aryl groups which are substituted with 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.

[0062] "Aryloxy" refers to the group -O-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.

[0063] "Substituted aryloxy" refers to the group -0-(substituted aryl) where substituted aryl is as defined herein.

[0064] "Arylthio" refers to the group -S-aryl, where aryl is as defined herein.

[0065] "Substituted arylthio" refers to the group -S -(substituted aryl), where substituted aryl is as defined herein.

[0066] "Carbonyl" refers to the divalent group -C(O)- which is equivalent to -C(=0)-. [0067] "Carboxy" or "carboxyl" refers to -COOH or salts thereof. [0068] "Carboxyl ester" or "carboxy ester" refers to the

groups -C(0)0-alkyl, -C(0)0-substituted alkyl, -C(0)0-alkenyl, -C(0)0-substituted alkenyl, -C(0)0-alkynyl, -C(0)0-substituted alkynyl, -C(0)0-aryl, -C(0)0-substituted aryl, -C(0)0-cycloalkyl, -C(0)0-substituted

cycloalkyl, -C(0)0-cycloalkenyl, -C(0)0-substituted

cycloalkenyl, -C(0)0-heteroaryl, -C(0)0-substituted heteroaryl, -C(0)0-heterocyclic, and -C(0)0-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,

heterocyclic, and substituted heterocyclic are as defined herein.

[0069] "(Carboxyl ester)amino" refers to the

group -NR ⁸-C(0)0-alkyl, -NR ⁸-C(0)0-substituted alkyl, -NR -C(0)0-alkenyl, -NR -C(0)0-substituted

alkenyl, -NR ⁸-C(0)0-alkynyl, -NR ⁸-C(0)0-substituted

alkynyl, -NR ⁸-C(0)0-aryl, -NR ⁸-C(0)0-substituted

aryl, -NR ⁸-C(0)0-cycloalkyl, -NR ⁸-C(0)0-substituted

cycloalkyl, -NR ⁸-C(0)0-cycloalkenyl, -NR ⁸-C(0)0-substituted

cycloalkenyl, -NR ⁸-C(0)0-heteroaryl, -NR ⁸-C(0)0-substituted

heteroaryl, -NR ⁸-C(0)0-heterocyclic, and -NR ⁸-C(0)0-substituted heterocyclic wherein R³⁸ is alkyl or hydrogen, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0070] "(Carboxyl ester)oxy" refers to the group -0-C(0)0-alkyl,

substituted -0-C(0)0-alkyl, -0-C(0)0-alkenyl, -0-C(0)0-substituted

alkenyl, -0-C(0)0-alkynyl, -0-C(0)0-substituted

alkynyl, -0-C(0)0-aryl, -0-C(0)0-substituted

aryl, -0-C(0)0-cycloalkyl, -0-C(0)0-substituted

cycloalkyl, -0-C(0)0-cycloalkenyl, -0-C(0)0-substituted

cycloalkenyl, -0-C(0)0-heteroaryl, -0-C(0)0-substituted

heteroaryl, -0-C(0)0-heterocyclic, and -0-C(0)0-substituted heterocyclic wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0071] "Cyano" refers to the group -CN.

[0072] "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. One or more of the rings can be aryl, heteroaryl, or heterocyclic provided that the point of attachment is through the non-aromatic, non-heterocyclic ring carbocyclic ring. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl. Other examples of cycloalkyl groups include bicycle[2,2,2,]octanyl, norbomyl, and spirobicyclo groups such as spiro[4.5]dec-8-yl. [0073] "Cycloalkenyl" refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings and having at least one >C=C< ring unsaturation and preferably from 1 to 2 sites of >C=C< ring unsaturation.

[0074] "Substituted cycloalkyl" and "substituted cycloalkenyl" refers to a cycloalkyl or cycloalkenyl group having from 1 to 5 or preferably 1 to 3 substituents selected from the group consisting of oxo, thione, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted

cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.

[0075] "Cycloalkyloxy" refers to -O-cycloalkyl.

[0076] "Substituted cycloalkyloxy" refers to -0-(substituted cycloalkyl).

[0077] "Cycloalkylthio" refers to -S-cycloalkyl.

[0078] "Substituted cycloalkylthio" refers to -S-(substituted cycloalkyl).

[0079] "Cycloalkenyloxy" refers to -O-cycloalkenyl.

[0080] "Substituted cycloalkenyloxy" refers to -0-(substituted cycloalkenyl).

[0081] "Cycloalkenylthio" refers to -S-cycloalkenyl.

[0082] "Substituted cycloalkenylthio" refers to -S-(substituted cycloalkenyl).

[0083] "Guanidino" refers to the group -NHC (=NH)NH₂. [0084] "Substituted guanidino" refers to -NR⁴⁴C(=NR⁴⁴)N(R⁴⁴)₂ where each R⁴⁴ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and two R⁴⁴ groups attached to a common guanidino nitrogen atom are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that at least one R⁴⁴ is not hydrogen, and wherein said substituents are as defined herein.

[0085] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.

[0086] "Haloalkyl" refers to alkyl groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkyl and halo are as defined herein.

[0087] "Haloalkoxy" refers to alkoxy groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkoxy and halo are as defined herein.

[0088] "Haloalkylthio" refers to alkylthio groups substituted with 1 to 5, 1 to 3, or 1 to 2 halo groups, wherein alkylthio and halo are as defined herein.

[0089] "Hydroxy" or "hydroxyl" refers to the group -OH.

[0090] "Heteroaryl" refers to an aromatic group of from 1 to 10 carbon atoms and 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur within the ring. Such heteroaryl groups can have a single ring (e.g. , pyridyl, pyridinyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl) wherein the condensed rings may or may not be aromatic and/or contain a heteroatom provided that the point of attachment is through an atom of the aromatic heteroaryl group. In one embodiment, the nitrogen and/or the sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N→0), sulfinyl, and/or sulfonyl moieties. Preferred heteroaryls include pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.

[0091] "Substituted heteroaryl" refers to heteroaryl groups that are substituted with from 1 to 5, preferably 1 to 3, or more preferably 1 to 2 substituents selected from the group consisting of the same group of substituents defined for substituted aryl.

[0092] "Heteroaryloxy" refers to -0-heteroaryl. [0093] "Substituted heteroaryloxy" refers to the group -0-(substituted heteroaryl). [0094] "Heteroarylthio" refers to the group -S-heteroaryl.

[0095] "Substituted heteroarylthio" refers to the group -S-(substituted heteroaryl).

[0096] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a saturated or partially saturated, but not aromatic, group having from 1 to 10 ring carbon atoms and from 1 to 4 ring heteroatoms selected from the group consisting of nitrogen, sulfur, or oxygen. Heterocycle encompasses single ring or multiple condensed rings, including fused bridged and spiro ring systems. In fused ring systems, one or more the rings can be cycloalkyl, aryl, or heteroaryl provided that the point of attachment is through the

non-aromatic heterocyclic ring. In one embodiment, the nitrogen and/or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, sulfinyl, and/or sulfonyl moieties.

[0097] "Substituted heterocyclic" or "substituted heterocycloalkyl" or "substituted heterocyclyl" refers to heterocyclyl groups that are substituted with from 1 to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.

[0098] "Heterocyclyloxy" refers to the group -O-heterocycyl.

[0099] "Substituted heterocyclyloxy" refers to the group -0-(substituted heterocycyl).

[0100] "Heterocyclylthio" refers to the group -S-heterocycyl.

[0101] "Substituted heterocyclylthio" refers to the group -S -(substituted heterocycyl).

[0102] Examples of heterocycle and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as

thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetrahydrofuranyl.

[0103] "Nitro" refers to the group -N0₂. [0104] "Oxo" refers to the atom (=0) or (-0^").

[0105] "Spiro ring systems" refers to bicyclic ring systems that have a single ring carbon atom common to both rings.

[0106] "Sulfonyl" refers to the divalent group -S(0)₂-.

[0107] "Substituted sulfonyl" refers to the group -SC^-alkyl, -S0₂-substituted

cylcoalkyl, -SC^-cycloalkenyl, -S0₂-substituted cylcoalkenyl, -S0₂-aryl, -S0₂-substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl, -SC -heterocyclic, -S02-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. Substituted sulfonyl includes groups such as methyl-SCV, phenyl-SCV, and 4-methylphenyl-S0₂-. The term "alkylsulfonyl" refers to -SCh-alkyl. The term "haloalkylsulfonyl" refers to -SC^-haloalkyl where haloalkyl is defined herein. The term "(substituted sulfonyl)amino" refers to -NH(substituted sulfonyl), and the term

"(substituted sulfonyl)aminocarbonyl" refers to -C(0)NH(substituted sulfonyl), wherein substituted sulfonyl is as defined herein.

[0108] "Sulfonyloxy" refers to the group -OS0₂-alkyl, -OS0₂-substituted

alkyl, -OSC^-alkenyl, -OS0₂-substituted alkenyl, -OSCh-cycloalkyl, -OSCVsubstituted cylcoalkyl, -OS0₂-cycloalkenyl, -OS0₂-substituted

cylcoalkenyl,-OS0₂-aryl, -OS0₂-substituted aryl, -OS0₂-heteroaryl, -OS0₂-substituted heteroaryl, -OS0₂-heterocyclic, -OS0₂-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0109] "Thioacyl" refers to the groups H-C(S)-, alkyl-C(S)-, substituted alkyl-C(S)-, alkenyl-C(S)-, substituted alkenyl-C(S)-, alkynyl-C(S)-, substituted alkynyl-C(S)-, cycloalkyl-C(S)-, substituted cycloalkyl-C(S)-, cycloalkenyl-C(S)-, substituted

cycloalkenyl-C(S)-, aryl-C(S)-, substituted aryl-C(S)-, heteroaryl-C(S)-, substituted heteroaryl-C(S)-, heterocyclic-C(S)-, and substituted heterocyclic-C(S)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0110] "Thiol" refers to the group -SH.

[0111] "Thiocarbonyl" refers to the divalent group -C(S)- which is equivalent to -C(=S)-. [0112] "Thione" refers to the atom (=S).

[0113] "Alkylthio" refers to the group -S-alkyl wherein alkyl is as defined herein.

[0114] "Substituted alkylthio" refers to the group -S -(substituted alkyl) wherein substituted alkyl is as defined herein.

[0115] "Compound" or "compounds" as used herein is meant to include the stereoiosmers and tautomers of the indicated formulas.

[0116] "Stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.

[0117] "Tautomer" refer to alternate forms of a compound that differ in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a ring atom attached to both a ring -NH- moiety and a ring =N- moiety such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles.

[0118] As used herein, the term "phosphate ester" refers to any one of the mono-, di- or triphosphate esters of noribogaine, wherein the mono-, di- or triphosphate ester moiety is bonded to the 12-hydroxy group and/or the indole nitrogen of noribogaine.

[0119] As used herein, the term "phosphate ester" refers to any one of the mono-, di- or triphosphate esters of noribogaine, wherein the mono-, di- or triphosphate ester moiety is bonded to the 12-hydroxy group and/or the indole nitrogen of noribogaine.

[0120] As used herein, the term "monophosphate" refers to the group -P(0)(OH)₂.

[0121] As used herein, the term "diphosphate" refers to the group -P(0)(OH)-OP(0)(OH)₂.

[0122] As used herein, the term "triphosphate" refers to the group -P(0)(OH)- (OP(0)(OH))₂OH. [0123] As used herein, the term "ester" as it refers to esters of the mono-, di- or triphosphate group means esters of the monophosphate can be represented by the formula - P(0)(OR⁴⁵)₂, where each R⁴⁵ is independently hydrogen, C1-C12 alkyl, C3-C10 cycloalkyl, C₆- Ci4 aryl, heteroaryl of 1 to 10 carbon atoms and 1 to 4 optionally oxidized heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur and the like, provided that at least one R⁴⁵ is not hydrogen. Likewise, exemplary esters of the di- or triphosphate can be represented by the formulas -P(0)(OR⁴⁵)-OP(0)(OR⁴⁵)₂

and -P(0)(OR⁴⁵)-(OP(0)(OR⁴⁵))₂OR⁴⁵, where R⁴⁵ is as defined above.

[0124] As used herein, the term "hydrolyzable group" refers to a group that can be hydrolyzed to release the free hydroxy group under hydrolysis conditions. Examples of hydrolysable group include, but are not limited to those defined for R above. Preferred hydrolysable groups include carboxyl esters, phosphates and phosphate esters. The hydrolysis may be done by chemical reactions conditions such as base hydrolysis or acid hydrolysis or may be done in vivo by biological processes, such as those catalyzed by a phosphate hydrolysis enzyme. Nonlimiting examples of hydrolysable group include groups linked with an ester-based linker (-C(O)O- or -OC(O)-), an amide-based linker (-C(O)NR⁴⁶- or -NR⁴⁶C(0)-), or a phosphate-linker (-P(0)(OR⁴⁶)-0-, -0-P(S)(OR⁴⁶)-0-, -0-P(S)(SR⁴⁶)- 0-, -S-P(0)(OR⁴⁶)-0-, -0-P(0)(OR⁴⁶)-S-, -S-P(0)(OR⁴⁶)-S-, -0-P(S)(OR⁴⁶)-S-, -S- P(S)(OR⁴⁶)-0-, -0-P(0)(R⁴⁶)-0-, -0-P(S)(R⁴⁶)-0-, -S-P(0)(R⁴⁶)-0-, -S-P(S)(R⁴⁶)-0-, -S- P(0)(R⁴⁶)-S-, or -0-P(S)(R⁴⁶)-S-) where R⁴⁶ can be hydrogen or alkyl.

[0125] Substituted groups of this invention, as set forth above, do not include polymers obtained by an infinite chain of substituted groups. At most, any substituted group can be substituted up to five times.

[0126] "Ibogaine" refers to the compound:

as well as ibogaine derivatives, pharmaceutically acceptable salts, and pharmaceutically acceptable solvates thereof. It should be understood that where "ibogaine" is mentioned herein, one or more polymorphs of ibogaine can be utilized and are contemplated. Ibogaine is isolated from Tabernanth iboga, a shrub of West Africa. Ibogaine can also be synthesized using known methods. See, e.g., Buchi, et al. (1966), J. Am. Chem Society, 88(13), 3099- 3109. Non-limiting examples of ibogaine derivatives encompassed by this invention are given in more detail in the "Compositions of the Invention" section below.

[0127] "Noribogaine" refers to the compound:

as well as noribogaine derivatives, pharmaceutically acceptable salts thereof, or solvates of each thereof. Noribogaine can be prepared by demethylation of naturally occurring ibogaine. Demethylation may be accomplished by conventional techniques such as by reaction with boron tribromide/methylene chloride at room temperature followed by conventional purification. See, for example, Huffman, et al, J. Org. Chem. 50: 1460 (1985), which incorporated herein by reference in its entirety. Noribogaine can be synthesized as described, for example in U.S. Patent Pub. Nos. 2013/0165647, 2013/0303756, and 2012/0253037, PCT Patent Publication No. WO 2013/040471 (includes description of making noribogaine polymorphs), and U.S. PatentNo. 9,617,274, each of which is incorporated herein by reference in its entirety.

[0128] "Noribogaine derivatives" refer to, without limitation, esters or O-carbamates of noribogaine, or solvates of each thereof, or pharmaceutically acceptable salts of each thereof. Also encompassed within this invention are derivatives of noribogaine that act as prodrug forms of noribogaine. A prodrug is a pharmacological substance administered in an inactive (or significantly less active) form. Once administered, the prodrug is metabolized in vivo into an active metabolite. Noribogaine derivatives include, without limitation, those compounds set forth in US Patent Nos. 6,348,456, 8,362,007, and 8,741,891; as well as in US Patent Application Publication Nos. US2013/0131046; US2013/0165647; US2013/0165425; and US2013/0165414; all of which are incorporated herein by reference in their entireties. Non- limiting examples of noribogaine derivatives encompassed by this invention are given in more detail in the "Compositions" section below.

[0129] In some embodiments, the methods of the present disclosure entail the

administration of a prodrug of noribogaine that provides the desired maximum serum concentrations and efficacious average noribogaine serum levels. A prodrug of noribogaine refers to a compound that metabolizes, in vivo, to noribogaine. In some embodiments, the prodrug is selected to be readily cleavable either by a cleavable linking arm or by cleavage of the prodrug entity that binds to noribogaine such that noribogaine is generated in vivo. In one preferred embodiment, the prodrug moiety is selected to facilitate binding to the μ and/or κ receptors in the brain either by facilitating passage across the blood brain barrier or by targeting brain receptors other than the μ and/or κ receptors. Examples of prodrugs of noribogaine are provided in United States Patent No. 8,741,891, the entire content of which is incorporated herein by reference.

[0130] This invention is not limited to any particular chemical form of iboga alkaloid, and the drug may be given to patients either as a free base or as a pharmaceutically acceptable acid addition salt. In the latter case, the hydrochloride salt is generally preferred, but other salts derived from organic or inorganic acids may also be used. Examples of such acids include, without limitation, those described below as "pharmaceutically acceptable salts" and the like. As discussed above, noribogaine itself may be formed from the O-demethylation of ibogaine which, in turn, may be synthesized by methods known in the art (see e.g., Huffman, et al, J. Org. Chem. 50: 1460 (1985)).

[0131] "Pharmaceutically acceptable composition" refers to a composition that is suitable for administration to a mammal, particularly, a human. Such compositions include various excipients, diluents, carriers, and such other inactive agents well known to the skilled artisan.

[0132] "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts, including pharmaceutically acceptable partial salts, of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methane sulfonic acid, phosphorous acid, nitric acid, perchloric acid, acetic acid, tartaric acid, lactic acid, succinic acid, citric acid, malic acid, maleic acid, aconitic acid, salicylic acid, thalic acid, embonic acid, enanthic acid, oxalic acid and the like, and when the molecule contains an acidic functionality, include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like.

[0133] A "pharmaceutically acceptable solvate" or "hydrate" of a compound of the invention means a solvate or hydrate complex that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound, and includes, but is not limited to, complexes of a compound of the invention with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.

[0134] As used herein the term "solvate" is taken to mean that a solid-form of a compound that crystallizes with one or more molecules of solvent trapped inside. A few examples of solvents that can be used to create solvates, such as pharmaceutically acceptable solvates, include, but are certainly not limited to, water, methanol, ethanol, isopropanol, butanol, C1-C6 alcohols in general (and optionally substituted), tetrahydrofuran, acetone, ethylene glycol, propylene glycol, acetic acid, formic acid, water, and solvent mixtures thereof. Other such biocompatible solvents which may aid in making a pharmaceutically acceptable solvate are well known in the art and applicable to the present invention. Additionally, various organic and inorganic acids and bases can be added or even used alone as the solvent to create a desired solvate. Such acids and bases are known in the art. When the solvent is water, the solvate can be referred to as a hydrate. Further, by being left in the atmosphere or recrystallized, the compounds of the present invention may absorb moisture, may include one or more molecules of water in the formed crystal, and thus become a hydrate. Even when such hydrates are formed, they are included in the term "solvate". Solvate also is meant to include such compositions where another compound or complex co-crystallizes with the compound of interest. The term "solvate" as used herein refers to complexes with solvents in which the iboga alkaloid (e.g., noribogaine) is reacted or from which the iboga alkaloid is precipitated or crystallized. For example, a complex with water is known as a "hydrate". Solvates of the iboga alkaloid are within the scope of the invention. It will be appreciated by those skilled in organic chemistry that many organic compounds can exist in more than one crystalline form. For example, crystalline form may vary based on the solvate used. Thus, all crystalline forms of the iboga alkaloid or the pharmaceutically acceptable salts or solvates thereof are within the scope of the present invention.

[0135] "Therapeutically effective amount" or "therapeutic amount" refers to an amount of a drug or an agent that, when administered to a patient suffering from a condition, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of the condition in the patient. The therapeutically effective amount will vary depending upon the patient and the condition being treated, the weight and age of the subject, the severity of the condition, the salt, solvate, or derivative of the active drug portion chosen, the particular composition or excipient chosen, the dosing regimen to be followed, timing of administration, the manner of administration and the like, all of which can be determined readily by one of ordinary skill in the art. The full therapeutic effect does not necessarily occur by administration of one dose, and may occur only after administration of a series of doses. Thus, a therapeutically effective amount may be administered in one or more administrations. For example, and without limitation, a therapeutically effective amount of an agent, in the context of treating a neurodegenerative disease or a movement disorder and/or symptoms thereof, refers to an amount of the agent that attenuates the disease or disorder; attenuates, reverses, or reduces the severity of a symptom or symptoms thereof; and/or prevents, delays, or reduces the severity of progression of the disease or disorder.

[0136] The therapeutically effective amount of the compound may be higher or lower, depending on the route of administration used. For example, when direct blood

administration (e.g., sublingual, pulmonary and intranasal delivery) is used, a lower dose of the compound may be administered. In one aspect, a therapeutically effective amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is from about 50 ng to less than 100 μg per day. Where other routes of administration are used (e.g., oral), a higher dose of the compound may be administered. In one embodiment, the therapeutically effective amount of the compound is from about 0.1 mg to about 180 mg per day. In one embodiment, the therapeutically effective amount of the compound is from about 0.1 mg to about 100 mg per day.

[0137] A "therapeutic level" of a drug is an amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof that is sufficient to treat or prevent the disease or disorder and/or symptoms thereof, but not high enough to pose any significant risk to the patient. Therapeutic levels of drugs can be determined by tests that measure the actual concentration of the compound in the blood of the patient. This concentration is referred to as the "serum concentration."

[0138] As defined herein, a "prophylactically effective amount" of a drug is an amount, typically less than the therapeutically effective amount, that provides prevention of the disease or disorder and/or symptoms thereof in a patient. The prophylactically effective amount of the compound maybe less than the therapeutically effective amount because the level of inhibition may not need to be as high in a patient who is not currently experiencing the disease or disorder. For example, a prophylactically effective amount is preferably 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a therapeutically effective amount. In some embodiments, the prophylactically effective amount of the compound is the same as the therapeutically effective amount.

[0139] "Treatment", "treating", and "treat" are defined as acting upon a disease, disorder, or condition with an agent, such as iboga alkaloid or pharmaceutically acceptable salt or solvate thereof, to reduce or ameliorate harmful or any other undesired effects of the disease, disorder, or condition and/or its symptoms. "Treatment," as used herein, covers the treatment of a human patient, and includes: (a) reducing the risk of occurrence of the condition in a patient determined to be predisposed to the condition but not yet diagnosed as having the condition, (b) impeding the development of the condition, and/or (c) relieving the condition, i.e. , causing regression of the condition and/or relieving one or more symptoms of the condition. "Treating" or "treatment of a condition or patient refers to taking steps to obtain beneficial or desired results, including clinical results such as the reduction of symptoms. For purposes of this invention, beneficial or desired clinical results include, but are not limited to: treating or preventing the neurodegenerative disease or movement disorder; treating or preventing a symptom or symptoms thereof; treating, preventing, or reversing progression of the disease or disorder; and the like.

[0140] As used herein, the term "patient" refers to mammals and includes humans and non-human mammals. Preferably, the patient is a human.

[0141] As used herein, the term "QT interval" refers to the measure of the time between the start of the Q wave and the end of the T wave in the electrical cycle of the heart. Prolongation of the QT interval refers to an increase in the QT interval.

[0142] The term "dose" refers to a range of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof that provides a therapeutic serum level of the iboga alkaloid or pharmaceutically acceptable salt or solvate thereof when given to a patient in need thereof. The dose is recited in a range, for example from about 20 mg to about 120 mg, and can be expressed either as milligrams or as mg/kg body weight. The attending clinician will select an appropriate dose from the range based on the patient's weight, age, degree of addiction, health, and other relevant factors, all of which are well within the skill of the art.

[0143] The term "unit dose" refers to a dose of drug that is given to the patient to provide therapeutic results, independent of the weight of the patient. In such an instance, the unit dose is sold in a standard form (e.g., 10 mg or 20 mg tablet). The unit dose may be administered as a single dose or a series of subdoses. In some embodiments, the unit dose provides a standardized level of drug to the patient, independent of weight of patient. Many medications are sold based on a dose that is therapeutic to all patients based on a therapeutic window. In such cases, it is not necessary to titrate the dosage amount based on the weight of the patient.

II. Compositions

[0144] As will be apparent to the skilled artisan upon reading this disclosure, this invention provides compositions for treating or preventing a neurodegenerative disease and/or symptoms and/or progression thereof in a subject, comprising iboga alkaloid or

pharmaceutically acceptable salt or solvate thereof. In a preferred embodiment, the composition further comprises at least one agent known to treat or prevent the

neurodegenerative disease and/or symptoms and/or progression thereof. This invention further provides compositions for treating or preventing a movement disorder and/or symptoms and/or progression thereof in a subject, comprising iboga alkaloid or

pharmaceutically acceptable salt or solvate thereof. In a preferred embodiment, the composition further comprises at least one agent known to treat or prevent the movement disorder and/or symptoms and/or progression thereof.

[0145] In one embodiment, the iboga alkaloid is ibogaine, noribogaine, an ibogaine derivative, noribogaine derivative, or prodrug, salt or solvate thereof.

[0146] In one embodiment, the noribogaine derivative is represented by Formula I:

I

or a pharmaceutically acceptable salt and/or solvate thereof,

wherein R is hydrogen or a hydrolyzable group such as hydrolyzable esters of from about 1 to 12 carbons.

[0147] Generally, in the above formula, R is hydrogen or a group of the formula:

wherein X is a Cr-C₁₂ group, which is unsubstituted or substituted. For example, X may be a linear alkyl group such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n- octyl, n-nonyl, n -decyl, n-undecyl or n-dodecyl, or a branched alkyl group, such as i-propyl or sec-butyl. Also, X may be a phenyl group or benzyl group, either of which may be substituted with lower alkyl groups or lower alkoxy groups. Generally, the lower alkyl and/or alkoxy groups have from 1 to about 6 carbons. For example, the group R may be acetyl, propionyl or benzoyl. However, these groups are only exemplary.

[0148] Generally, for all groups X, they may either be unsubstituted or substituted with lower alkyl or lower alkoxy groups. For example, substituted X may be o-, m- or p-methyl or methoxy benzyl groups.

[0149] C1-C12 groups include C1-C12 alkyl, C3-C12 cycloalkyl, C6-C12 aryl, C7-C12 arylalkyl, wherein C_x indicates that the group contains x carbon atoms. Lower alkyl refers to C1-C4 alkyl and lower alkoxy refers to C1-C4 alkoxy.

[0150] In one embodiment, the noribogaine derivative is represented by Formula II:

or a pharmaceutically acceptable salt and/or solvate thereof,

wherein

is a single or double bond;

R¹ is halo, OR², or C1-C12 alkyl optionally substituted with 1 to 5 R ;

R² is hydrogen or a hydrolysable group selected from the group consisting of -

C(0)R^x, -C(0)OR^x and -C(0)N(R^y)₂ where each R^x is selected from the group consisting of C1-C6 alkyl optionally substituted with 1 to 5 R¹⁰, and each R^y is independently selected from the group consisting of hydrogen, C1-C6 alkyl optionally substituted with 1 to 5 R¹⁰, C6-C14 aryl optionally substituted with 1 to 5 R¹⁰, C3-C10 cycloalkyl optionally substituted with 1 to 5 R¹⁰, C1-C10 heteroaryl having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R¹⁰, C1-C1₀ heterocyclic having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R , and where each R^y, together with the nitrogen atom bound thereto form a C1-C6 heterocyclic having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R¹⁰ or a C1-C6 heteroaryl having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R¹⁰;

R³ is selected from the group consisting of hydrogen, C1-C12 alkyl optionally

substituted with 1 to 5 R¹⁰, aryl optionally substituted with 1 to 5 R¹⁰, - C(0)R⁶, -C(0)NR⁶R⁶ and -C(0)OR⁶;

R⁴ is selected from the group consisting of hydrogen, -(CH₂)_mOR⁸, -

CR⁷(OH)R⁸, -(CH₂)_mCN, -(CH₂)_mCOR⁸, -(CH₂)_mC0₂R⁸, -(CH₂)_mC(0)NR⁷R⁸, -(CH₂)_mC(0)NR⁷NR⁸R⁸, -(CH₂)_mC(0)NR⁷NR⁸C(0)R⁹, and -(CH₂)_mNR⁷R⁸; m is 0, 1, or 2;

L is a bond or Ci-Ci₂ alkylene;

R⁵ is selected from the group consisting of hydrogen, Ci-Ci₂ alkyl substituted with 1 to 5 R¹⁰, Ci-Ci₂ alkenyl substituted with 1 to 5 R¹⁰, -X^x-R⁷, -(X'-YVX¹- R⁷, -S0₂NR⁷R⁸, -0-C(0)R⁹, -C(0)OR⁸, -C(0)NR⁷R⁸, -NR⁷R⁸, -NHC(0)R⁹, and -NR⁷C(0)R⁹;

each R⁶ is independently selected from the group consisting of hydrogen, Ci-Ci₂ alkyl, C₂-Ci₂ alkenyl, C₂-Ci₂ alkynyl, C6-Cio aryl, C1-C6 heteroaryl having 1 to 4 heteroatoms, and C1-C6 heterocycle having 1 to 4 heteroatoms, and wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle are optionally substituted with 1 to 5 R¹⁰;

X¹ is selected from the group consisting of O and S;

Y is C1-C4 alkylene or C6-C1₀ arylene, or a combination thereof;

n is 1, 2, or 3;

R⁷ and R⁸ are each independently selected from the group consisting of hydrogen,

Ci-Ci₂ alkyl optionally substituted with 1 to 5 R¹⁰, C1-C6 heterocycle having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R¹⁰, C3-C1₀ cycloalkyl optionally substituted with 1 to 5 R¹⁰, C6-Cio aryl optionally substituted with 1 to 5 R¹⁰ and C1-C6 heteroaryl having 1 to 4 heteroatoms optionally substituted with 1 to 5 R¹⁰;

R⁹ is selected from the group consisting of Ci-Ci₂ alkyl optionally substituted with 1 to 5 R¹⁰, C1-C6 heterocycle having 1 to 4 heteroatoms optionally substituted with 1 to 5 R¹⁰, C3-C10 cycloalkyl optionally substituted with 1 to 5 R¹⁰, C6-C10 aryl optionally substituted with 1 to 5 R and Ci-Ce heteroaryl having 1 to 4 heteroatoms optionally substituted with 1 to 5 R¹⁰;

R¹⁰ is selected from the group consisting of C1-C4 alkyl, phenyl, halo, -OR¹¹, -

CN, -COR¹¹, -CO2R¹¹, -C(0)NHRⁿ, -NRⁿRⁿ, -C(0)NRⁿRⁿ, -C(0)NHNHR n, -C(0)NRⁿNHRⁿ, -C(0)NR¹¹NR¹¹R¹¹, -C(0)NHNRⁿC(0)Rⁿ, -C(0)NHN

HC(0)Rⁿ, -SOzNR¹¹^¹, -C^N^NR¹¹^)^¹,

and -C(0)NRⁿNHC(0)Rⁿ; and

R¹¹ is independently hydrogen or C1-C12 alkyl;

provided that:

when L is a bond, then R⁵ is not hydrogen;

when is a double bond, R¹ is an ester hydrolyzable group, R³ and R⁴ are both hydrogen, then -L-R⁵ is not ethyl;

when is a double bond, R¹ is -OH, halo or C1-C12 alkyl optionally substituted with 1 to 5 R¹⁰, then R⁴ is hydrogen; and

when is a double bond, R¹ is OR², R⁴ is hydrogen, -L-R⁵ is ethyl, then R² is not a hydrolyzable group selected from the group consisting of an ester, amide, carbonate and carbamate.

[0151] In one embodiment, the noribogaine derivative is represented by Formula III:

III

or a pharmaceutically acceptable salt and/or solvate thereof,

wherein

is a single or double bond;

R¹² is halo, -OH, -SH, -NH₂, -S(0)₂N(R¹⁷)₂, -R^z-L^x-R¹⁸, -R^z-L^x-R¹⁹, -R'-I^-R²⁰ or -R^z- I^-CHR^R¹⁹, where R^z is O, S or NR¹⁷;

L¹ is alkylene, arylene, -C(0)-alkylene, -C(0)-arylene, -C(0)0-arylene, -C(0)0- alkylene, -C(O)NR²⁰-alkylene, -C(O)NR²⁰-arylene, -C(NR²⁰)NR²⁰-alkylene or -C(NR²⁰)NR²⁰-arylene, wherein L¹ is configured such that -O-I^-R¹⁸ is - OC(0)-alkylene-R¹⁸, -OC(0)0-arylene-R¹⁸, -OC(0)0-alkylene-R¹⁸, -OC(O)- arylene-R , -OC(0)NR^2U-alkylene-R , -OC(0)NR^2U-arylene-R , - OC(NR²⁰)NR²⁰-alkylene-R¹⁸ or -OC(NR²⁰)NR²⁰-arylene-R¹⁸, and wherein the alkylene and arylene are optionally substituted with 1 to 2 R¹⁶;

R¹³ is hydrogen, -S(0)₂OR²°, -S(0)₂R²°, -C(0)R¹⁵, -C(0)NR¹⁵R¹⁵, -C(0)OR¹⁵, C₁-C₁₂ alkyl optionally substituted with 1 to 5 R¹⁶, C₁-C₁₂ alkenyl optionally substituted with 1 to 5 R¹⁶, or aryl optionally substituted with 1 to 5 R¹⁶;

R¹⁴ is hydrogen, halo, -OR¹⁷, -CN, C ₁-C₁₂ alkyl, Ci-C^ alkoxy, aryl or aryloxy, where the alkyl, alkoxy, aryl, and aryloxy are optionally substituted with 1 to 5 R¹⁶; each R¹⁵ is independently selected from the group consisting of hydrogen, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, aryl, heteroaryl, and heterocycle, and wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle are optionally substituted with 1 to 5 R¹⁶;

R¹⁶ is selected from the group consisting of phenyl, halo, -OR¹⁷, -

CN, -COR¹⁷, -CO₂R¹⁷, -NR¹⁷R¹⁷, -NR¹⁷C(0)R¹⁷, -NR¹⁷S0₂R¹⁷, -C(0)NR¹⁷R¹⁷ , -C(0)NR¹⁷NR¹⁷R¹⁷, -S0₂NR¹⁷R¹⁷ and -C(0)NR¹⁷NR¹⁷C(0)R¹⁷;

each R¹⁷ is independently hydrogen or C₁-C₁₂ alkyl optionally substituted with from 1 to 3 halo;

R¹⁸ is hydrogen, -C(0)R²⁰, -C(0)OR²⁰, -C(O)N(R²⁰)₂ or -N(R²⁰)C(O)R²⁰;

R¹⁹ is hydrogen, -

N(R²⁰)₂, -C(O)N(R²⁰)₂, -C(NR²⁰)N(R²⁰)₂, -C(NSO₂R²⁰)N(R²⁰)₂, -NR²⁰C(O)N( R²⁰)₂, -NR²⁰C(S)N(R²⁰)₂, -NR²⁰C(NR²⁰)N(R²⁰)₂, -NR²⁰C(NSO2R²⁰)N(R²⁰)₂ or tetrazole; and

each R²⁰ is independently selected from the group consisting of hydrogen, C₁-C₁₂ alkyl and aryl;

provided that:

when is a double bond and R¹³ and R¹⁴ are hydrogen, then R¹² is not hydroxy; when = i_{s a} double bond, R¹⁴ is hydrogen, R¹² is -O-I^-R¹⁸, -0-L^x-R¹⁹, -O-L¹-

R²⁰, and L¹ is alkylene, then -O-I^-R¹⁸, -0-L^x-R¹⁹, -O-I^-R²⁰ are not methoxy; when is a double bond, R¹⁴ is hydrogen, R^z is O, L¹ is -C(0)-alkylene, -C(O)- arylene, -C(0)0-arylene, -C(0)0-alkylene, -C(O)NR²⁰-alkylene, or - C(O)NR²⁰-arylene, then none of R¹⁸, R¹⁹ or R²⁰ are hydrogen.

In one embodiment, the noribogaine derivative is represented by Formula IV:

IV

or a pharmaceutically acceptable salt and/or solvate thereof,

wherein

R²¹ is selected from the group consisting of hydrogen, a hydrolysable group selected from the group consisting of -C(0)R²³, -C(0)NR²⁴R²⁵ and -C(0)OR²⁶, where R²³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl, R²⁴ and R²⁵ are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, R²⁶ is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, provided that R²¹ is not a saccharide or an oligosaccharide;

L² is selected from the group consisting of a covalent bond and a cleavable linker group;

R²² is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, provided that R is not a saccharide or an oligosaccharide;

provided that when L² is a covalent bond and R²² is hydrogen, then R²¹ is selected from the group consisting of -C(0)NR²⁴R²⁵ and -C(0)OR²⁶; and

further provided that when R²¹ is hydrogen or -C(0)R²³ and L² is a covalent bond, then R²² is not hydrogen.

[0153] In one embodiment, the noribogaine derivative is represented by Formula V:

V

or a pharmaceutically acceptable salt and/or solvate thereof,

wherein:

refers to a single or a double bond provided that when is a single bond, Formula V refers to the corresponding dihydro compound;

R²⁷ is hydrogen or S0₂OR²⁹;

R²⁸ is hydrogen or S0₂OR²⁹;

R²⁹ is hydrogen or C i - Ce alkyl;

provided that at least one of R²⁷ and R²⁸ is not hydrogen.

[0154] In one embodiment, the noribogaine derivative is represented by Formula VI:

VI

or a pharmaceutically acceptable salt and/or solvate thereof,

wherein:

^ refers to a single or a double bond provided that when ^ is a single bond, Formula VI refers to the corresponding vicinal dihydro compound;

R³⁰ is hydrogen, a monophosphate, a diphosphate or a triphosphate; and

R ¹ is hydrogen, a monophosphate, a diphosphate or a triphosphate;

provided that both R³⁰ and R ¹ are not hydrogen;

wherein one or more of the monophosphate, diphosphate and triphosphate groups of R³⁰ and R³¹ are optionally esterified with one or more C1-C6 alkyl esters.

[0155] In some embodiments, the ibogaine or ibogaine derivative is represented by Formula

VII:

VII

or a pharmaceutically acceptable salt and/or solvate thereof, wherein

R¹⁰⁰ is H, halo, C1-C3 alkyl, substituted C1-C3 alkyl, OR¹¹⁰, NH₂, NHR¹¹⁰, NR¹¹⁰R^{i n},

NHC(0)R¹¹⁰, or NR¹¹⁰C(O)R^{i n};

R¹⁰¹ is H, C1-C3 alkyl, substituted C1-C3 alkyl, C1-C3 alkoxy, CH₂-X-CH₃, or

(CH₂)_mR¹⁰³;

R¹⁰² is H, COOH, COOR¹⁰⁴, (CH₂)_nOH, CH(OH)R¹⁰⁵, CH₂OR¹⁰⁵, C(0)NH₂,

C(0)NHR¹⁰⁵, C(O)NR¹⁰⁵R¹⁰⁶, C(0)NHNH₂, C(0)NHNHR¹⁰⁵, C(O)NHNR¹⁰⁵R¹⁰⁶, C(O)NR¹⁰⁵NH₂, C(O)NR¹⁰⁵NHR¹⁰⁶, C(O)NR¹⁰⁵NR¹⁰⁶R¹⁰⁷, C(0)NHNH(C(0)R¹⁰⁵), C(O)NHNR¹⁰⁵(C(O)R¹⁰⁶), C(O)NR¹⁰⁵NH(C(O)R¹⁰⁶), C(O)NR¹⁰⁵NR¹⁰⁶(C(O)R¹⁰⁷), CN, or C(0)R¹⁰⁵;

R¹⁰³ is C1-C3 alkyl, benzyl, substituted C1-C3 alkyl, YH, YR¹⁰⁸, YC(0)R¹⁰⁸,

C(0)YR¹⁰⁸, C(0)NH₂, C(0)NHR¹⁰⁸, C(O)NR¹⁰⁸R¹⁰⁹, NH₂, NHR¹⁰⁸, N_Rio8_Rio9 _NHC(0)Rio8 o(CH₂)_pO(CH₂)_qO(CH₂)_rCH₃ or NR¹⁰⁸C(O)R¹⁰⁹;

R¹⁰⁴ is Ci-C₆ alkyl or (CH₂CH₂0)_nCH₃;

R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, R¹⁰⁸, R¹⁰⁹, R¹¹⁰, and R¹¹¹ are independently alkyl or substituted alkyl;

R¹¹² is H, alkyl, or substituted alkyl;

R¹¹³ is H, OR¹¹⁰, alkyl, or substituted alkyl;

X is O or NH;

Y is O or S;

m is an integer selected from 0-8;

each of n, p and q is 1, 2 or 3; and

r is 0, 1 or 2.

[0156] In some embodiments, the ibogaine or ibogaine derivative is represented by Formula VIII:

VIII

or a pharmaceutically acceptable salt and/or solvate thereof,

wherein

R¹⁰⁰ is hydrogen or C1-C3 alkoxy,

R¹⁰¹ is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, (CH₂)_mOC(0)alkyl, (CH₂)_mOH, (CH₂)_mOalkyl, (CH₂)_mO(CH₂)_pO(CH₂)_qO(CH₂)_rCH₃ or CH₂-Y-CH₃ where each of m, p and q is 1, 2 or 3; and r is 0, 1 or 2,Y is O or NH, and

R¹⁰² is H, (CH₂)_nOH, COOH, or COOR¹⁰⁴, where R¹⁰⁴ is Ci-C₆ alkyl or

(CH₂CH₂0)nCH₃, where n is 1, 2, or 3.

[0157] In one embodiment, R¹⁰⁰ is methoxy. In one embodiment, R¹⁰¹ is ethyl. In one embodiment, R¹⁰¹ is methoxy. In one embodiment, R¹⁰¹ is CH₂-Y-CH₃ where Y is O. In one embodiment, R¹⁰¹ is CH₂-Y-CH₃ where Y is NH. In one embodiment, R¹⁰² is hydrogen. In one embodiment, In one embodiment, R¹⁰² is COOR¹⁰⁴ and R¹⁰⁴ is methyl. In one embodiment, n = 1. In a preferred embodiment, R¹⁰⁰, R¹⁰¹ and R¹⁰² are all not hydrogen. In one embodiment, when R¹⁰⁰ is methoxy and R¹⁰¹ is hydrogen, then R¹⁰² is COOH or COOR¹⁰⁴. In another embodiment, when R¹⁰⁰ is methoxy and R¹⁰¹ is hydrogen, then X is COOR¹⁰⁴ where R¹⁰⁴ is (CH₂CH₂0)CH₃.

[0158] In one embodiment, R¹⁰² is hydrogen.

[0159] In one embodiment, R¹⁰¹ is H. In one embodiment, R¹⁰¹ is C1-C3 alkyl, such as ethyl. In one embodiment, R¹⁰¹ is CH₂CH₂OH. In one embodiment, R¹⁰¹ is CH₂CH₂OCH₃. In one embodiment, R¹⁰¹ is CH₂CH₂OCH₂Ph. In one embodiment, R¹⁰¹ is

CH₂CH₂OC(0)alkyl. In one embodiment, R¹⁰¹ is CH₂CH₂0(CH₂)_pO(CH₂)_qO(CH₂)_rCH₃.

[0160] In one embodiment, R¹⁰² is CH₂OH and CH(OH)R¹⁰⁵. In one embodiment, R¹⁰² is CH₂OR¹⁰⁵. In one embodiment, R¹⁰² is C0₂R¹⁰⁵. In one embodiment, R¹⁰² is C(0)NH₂, C(0)NHR¹⁰⁵, or C(O)NR¹⁰⁵R¹⁰⁶. In one embodiment, R¹⁰² is C(0)NHNH₂, C(O)NHNHR¹⁰⁵ _i C(O)NR¹⁰⁵NH₂, C(O)NHNR¹⁰⁵R¹⁰⁶ C(O)NHR¹⁰⁵NHR¹⁰⁶, or C(O)NR¹⁰⁵NR¹⁰⁶R¹⁰⁷. In one embodiment, R¹⁰² is C(0)NHNH(C(0)R¹⁰⁵), C(O)NHNR¹⁰⁵(C(O)R¹⁰⁶),

C(O)NR¹⁰⁵NH(C(O)R¹⁰⁶), or C(O)NR¹⁰⁵NR¹⁰⁶(C(O)R¹⁰⁷). In one embodiment, R¹⁰² is C(0)R¹⁰⁵.

[0161] In some embodiments, the ibogaine or ibogaine derivative is selected from:

and pharmaceutically acceptable salts and/or solvates thereof. In one embodiment, the iboga alkaloid is not ibogaine. [0162] In one embodiment, the ibogaine derivative is:

naridine),

amine),

(voacangine),

(18-methoxy coronaridine, 18-MC),

(2-Methoxyethyl-18-methoxycoronaridinate, ME- 18-MC), or

(18-Methylaminocoronaridine, 18-MAC).

[0163] Any of the compounds listed herein may be expressly excluded from the methods or compositions of the present invention.

[0164] Agents known to treat and/or prevent neurodegenerative diseases and/or movement disorders and/or symptoms and/or progression thereof include, without limitation, an anti- epilectic drug (e.g., ethosuximide, carbamazepine, valproate), an anti-seizure medication (e.g., primidone, gabapentin), a beta-blocker (e.g., propranolol), levo-3,4- dihydroxyphenylalanine (1-DOPA) or other dopamine agonist (e.g., pramipexole, ropinirole, rotigotine, apomorphine, bromocriptine, pergolide) or dopamine precursor (e.g., levodopa with or without carbidopa), a cholinesterase inhibitor, choline, an anticholinergic (e.g., benztropine or trihexyphenidyl), an anti-inflammatory, a cannabinoid, a cannabis extract, glutathione or a glutathione analog, an antioxidant, a monoamine oxidase B (MAO-B) inhibitor (e.g., selegiline or rasagiline), a catechol-O-methyltransferase (COMT) inhibitor (e.g., entacapone or tolcapone), amantadine, tetrabenazine, an antipsychotic drug (e.g., haloperidol, chlorpromazine, risperidone, or quetiapine), levetiracetam, clonazepam, riluzole, baclofen, branched-chain amino acids, phenytoin, cell-derived neurotrophic factor, a carbonic anhydrase inhibitor, and a tranquilizer (e.g., a benzodiazepine, for example diazepam or clonazepam). Dosing for these agents is well-known in the art and/or can be determined by a skilled clinician. Any of the agents listed herein may be expressly excluded from the methods or compositions of the present invention.

[0165] In one aspect, the invention provides a pharmaceutical composition comprising a therapeutically or prophylactically effective amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof, a therapeutically or prophylactically effective amount of an agent known to treat or prevent a neurodegenerative disease or movement disorder, and a pharmaceutically acceptable excipient, wherein the therapeutically or prophylactically effective amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is an amount that delivers an aggregate amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof of about 0.1 mg to about 180 mg per day. In some aspects, the therapeutically or prophylactically effective amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is an amount that delivers an aggregate amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof of about 1 mg to about 100 mg per day. In some aspects, the therapeutically or prophylactically effective amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is an amount that delivers an aggregate amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof of about 1 mg to about 50 mg per day.

[0166] In some aspects, the composition is formulated for administration once per day. In some aspects, the composition is formulated for administration two or more times per day.

[0167] In some embodiments, the composition is formulated for oral, sublingual, intranasal, buccal, or intrapulmonary delivery. In some embodiments, the composition is formulated for oral, transdermal, internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial, intramuscular, intraperitoneal, intracutaneous or subcutaneous delivery. Routes of administration are discussed in further detail below in the subsection titled "Dosages and Routes of Administration."

[0168] In one embodiment, the therapeutically effective amount of the compound is about 0.01 to about 4 mg/kg body weight per day. In one embodiment, the therapeutically effective amount of the compound is about 3 mg/kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.7 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.5 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 1.2 mg per kg body weight per day. In another embodiment, the therapeutically effective amount of the compound is about 0.1 to about 1 mg per kg body weight per day.

III. Methods of the Invention

[0169] As will be apparent to the skilled artisan upon reading this disclosure, this invention, in one aspect, provides a method for treating or preventing a neurodegenerative disease and/or symptoms and/or progression thereof in a subject, comprising administering to the patient in need thereof a therapeutically effective amount of an iboga alkaloid or

pharmaceutically acceptable salt or solvate thereof. In one embodiment, the method further comprises administering at least one agent known to treat or prevent the neurodegenerative disease and/or symptoms and/or progression thereof.

[0170] In one embodiment, the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), a prion disease (e.g., Creutzfeldt- Jakob Disease), spinocerebellar ataxia, spinal muscular atrophy, Friedreich's ataxia, Lewy body disease, and a motor neuron disease. In a preferred embodiment, the neurodegenerative disease is Parkinson's disease. In one embodiment, the neurodegenerative disease is not Alzheimer's disease. In one embodiment, the

neurodegenerative disease is a result of aging or brain trauma. [0171] There are currently no known cures for neurodegenerative diseases. Current treatments include treatment of one or more symptoms of the disease by medication, surgery, deep brain stimulation, botulism toxin injections, etc.

[0172] Parkinson's disease is a progressive disorder caused by degeneration of nerve cells in the substantia nigra, which controls movement. Nerve cell degeneration results in a reduction in dopamine production, which causes tremor; muscle rigidity or stiffness of the limbs; gradual loss of spontaneous movement, including decreased mental skill or reaction time, voice changes or decreased facial expression; gradual loss of automatic movement, including decreased blinking, decreased frequency of swallowing, and drooling; a stooped, flexed posture, with bending at the elbows, knees and hips; an unsteady walk or balance; and depression or dementia. Treatments for Parkinson's disease include, without limitation, dopamine precursors, dopamine agonists, and anticholinergics.

[0173] Ataxia refers to lack of voluntary coordination of muscle movements that implies dysfuntion of parts of the nervous system that coordinate movement, e.g., the cerebellum. It may be caused by a number of factors, including disfunction of the cerebellum or vestibular system, lesions of the central nervous system (e.g. from stroke, brain tumor, or multiple sclerosis), some drugs, radiation poisoning, hypothyroidism, vitamin B12 deficiency, and hereditary disorders (e.g., spinocerebellar ataxia, episodic ataxia, dentatorubropallidoluysian atrophy, Friedreich's ataxia, Niemann Pick disease, ataxia-telangiectasia, and

abetalipoproteinaemia). Some drug treatments that have been used to control ataxia include, without limitation, 5-hydroxytryptophan (5-HTP), idebenone, amantadine, physostigmine, L- carnitine or derivatives, trimethoprimsulfamethoxazole, vigabatrin, phosphatidylcholine, acetazolamide, 4-aminopyridine, buspirone, and a combination of coenzyme Q10 and vitamin E.

[0174] Huntington's disease is an inherited disease that causes movement, cognitive and psychiatric disorders. Treatments for Huntington's disease include, withut limitation, tetrabenazine, antipsychotic drugs, amantadine, levetiracetam, and clonazepam, as well as anti-depressants and mood stabilizers. Patients with this disease also frequently undergo speech, physical, and/or occupational therapy to improve some symptoms.

[0175] ALS (also known as Lou Gehrig's disease) is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord which affects muscle movement and control. Voluntary muscle action worsens progressively and may result in total paralysis. ALS is inherited in only about 10% of cases (familial ALS). Treatment for ALS includes riluzole, baclofen, diazepam, trihexyphenidyl or amitriptyline, as well as other medications that address one or more symptoms of the disease.

[0176] Prion diseases are caused by misfolded proteins (prions) in the brain. Human prion diseases include Creutzfeldt- Jakob Disease (CJD) and its variant (vCJD), Gerstmann- Straussler-Scheinker syndrome, Fatal Familial Insomnia, kuru, and multiple system atrophy. Prions cause neurodegenerative disease via extracellular aggregation within the central nervous system to form amyloid plaques, which disrupt the normal tissue structure.

Neurodegenerative symptoms can include convulsions, dementia, ataxia (balance and coordination dysfunction), and behavioural or personality changes. There are no known cures or treatments for prion diseases.

[0177] In one aspect, provides a method for treating or preventing a movement disorder and/or symptoms and/or progression thereof in a subject, comprising administering to the patient in need thereof a therapeutically effective amount of an iboga alkaloid or

pharmaceutically acceptable salt or solvate thereof. In one embodiment, the method further comprises administering at least one agent known to treat or prevent the disorder and/or symptoms and/or progression thereof.

[0178] In one embodiment, the movement disorder is a hyperkinetic disorder. In one embodiment, the movement disorder is a hypokinetic disorder. In one embodiment, the movement disorder is selected from the group consisting of bradykinesia, Hallevorden-Spatz disease, progressive supranuclear palsy, multiple system atrophy, dystonia, spasmodic torticollis, essential tremor, other types of tremor, various choreas and diskenesias, tic disorders, Tourette's syndrome, stereotypic movement disorder, paroxysmal nocturnal limb movement, restless leg syndrome, and stiff person syndrome.

[0179] Where an agent known to treat and/or prevent a particular disease or disorder is discussed throughout the specification, it is to be understood that such an agent may optionally be administered in conjunction with (e.g., before, after, or concurrently with) the iboga alkaloid or pharmaceutically acceptable salt or solvate thereof.

[0180] In one embodiment, treatment with iboga alkaloid or pharmaceutically acceptable salt or solvate thereof results in a QT interval prolongation of less than about 60 ms. In one embodiment, treatment with iboga alkaloid or pharmaceutically acceptable salt or solvate thereof results in a QT interval prolongation of less than about 50 ms. In one embodiment, treatment with iboga alkaloid or pharmaceutically acceptable salt or solvate thereof results in a QT interval prolongation of less than about 40 ms. In a preferred embodiment, treatment with iboga alkaloid or pharmaceutically acceptable salt or solvate thereof results in a QT interval prolongation of less than about 30 ms. In an especially preferred embodiment, treatment with iboga alkaloid or pharmaceutically acceptable salt or solvate thereof results in a QT interval prolongation of less than about 20 ms. In one embodiment, treatment with iboga alkaloid or pharmaceutically acceptable salt or solvate thereof results in a QT interval prolongation of less than about 10 ms.

[0181] In one aspect, the patient is administered a dosage of iboga alkaloid or

pharmaceutically acceptable salt or solvate thereof that provides an average serum concentration of less than about 180 ng/mL, said concentration being sufficient to treat said disease or disorder and/or symptoms and/or progression thereof while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the concentration is sufficient to treat the patient while maintaining a QT interval of less than about 470 ms during treatment. Preferably, the concentration is sufficient to treat the patient while maintaining a QT interval of less than about 450 ms during treatment. In one embodiment, the concentration is sufficient to treat the patient while maintaining a QT interval of less than about 420 ms during treatment.

[0182] In one embodiment, the dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between less than about 6000 ng hr/mL (area under the curve for 24 hours, AUC/24 h). In one embodiment, the dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between less than about 5000 ng hr/mL (area under the curve for 24 hours, AUC/24 h). In one embodiment, the dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between less than about 4000 ng hr/mL (area under the curve for 24 hours, AUC/24 h). In one embodiment, the dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between less than about 3000 ng hr/mL (area under the curve for 24 hours, AUC/24 h). In one embodiment, the dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between less than about 2000 ng hr/mL (area under the curve for 24 hours, AUC/24 h). In one embodiment, the dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between less than about 1000 ng hr/mL (area under the curve for 24 hours, AUC/24 h). In one embodiment, the dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between about 200 ng hr/mL and about 5800 ng hr/mL (AUC/24 h). In one embodiment, the dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof provides a serum concentration of between about 500 ng hr/mL and about 5500 ng hr/mL (AUC/24 h). The ranges include both extremes as well as any subranges between.

[0183] In one embodiment, the dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof provides a maximum serum concentration (Cmax) of less than about 250 ng/mL. In one embodiment, the dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof provides a Cmax between about 10 ng/mL and about 250 ng/mL. In a preferred embodiment, the dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof provides a Cmax less than about 200 ng/mL. In one embodiment, the dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof provides a Cmax less than about 180 ng/mL. The Cmax may include endpoints of the recited ranges, as well as any values or subranges between.

[0184] In one embodiment, the dosage or aggregate dosage of iboga alkaloid or

pharmaceutically acceptable salt or solvate thereof is from about 0.1 mg to about 100 mg per day. The aggregate dosage is the combined dosage, for example the total amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof administered over a 24-hour period where smaller amounts are administered more than once per day. In one embodiment, the dosage or aggregate dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is from about 1 mg to about 90 mg per day. In one embodiment, the dosage or aggregate dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is from about 1 mg to about 80 mg per day. In one embodiment, the dosage or aggregate dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is from about 1 mg to about 70 mg per day. In one embodiment, the dosage or aggregate dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is from about 1 mg to about 60 mg per day. In one embodiment, the dosage or aggregate dosage of iboga alkaloid or

pharmaceutically acceptable salt or solvate thereof is from about 1 mg to about 50 mg per day. In one embodiment, the dosage or aggregate dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is from about 1 mg to about 40 mg per day. In one embodiment, the dosage or aggregate dosage of iboga alkaloid or

pharmaceutically acceptable salt or solvate thereof is from about 1 mg to about 30 mg per day. In one embodiment, the dosage or aggregate dosage of iboga alkaloid or

pharmaceutically acceptable salt or solvate thereof is from about 1 mg to about 20 mg per day. In one embodiment, the dosage or aggregate dosage of iboga alkaloid or

pharmaceutically acceptable salt or solvate thereof is from about 1 mg to about 10 mg per day. The therapeutically effective amount of the compound may be any amount or subrange within any of these ranges, including endpoints.

[0185] In some embodiments, the therapeutically effective amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is administered once a day. In some embodiments, the therapeutically effective amount is administered twice per day. In some embodiments, the therapeutically effective amount is administered more than two times per day.

[0186] Where the therapeutically effective amount is administered more than one time per day, a portion of the total therapeutically effective amount is administered at each time. For example, a patient taking 30 mg iboga alkaloid or pharmaceutically acceptable salt or solvate thereof per day would take 30 mg once a day, 15 mg twice a day, or 10 mg three times a day, etc.

[0187] In some embodiments, iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is administered to a patient periodically, such as once, twice, three time, four times or five time daily. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration may depend on the route of administration, content of composition, age and body weight of the patient, condition of the patient, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made by a qualified clinician.

[0188] In some embodiments, the iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is administered sublingually, intrapulmonary, buccally, or intranasally.

Preferably, the iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is administered orally. These routes of administration are discussed in further detail below in the subsection titled "Dosages and Routes of Administration."

IV. Dosages and Routes of Administration

[0189] The compositions, provided herein or known, suitable for administration in accordance with the methods provided herein, can be suitable for a variety of delivery modes including, without limitation, oral, sublingual, buccal, intrapulmonary, or intranasal delivery. Compositions suitable for internal, rectal, vaginal, lingual, intravenous, intraarterial, intramuscular, intraperitoneal, intracutaneous and subcutaneous routes may also be used. Other dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. Sustained release dosage forms may also be used. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980).

[0190] In one embodiment, an iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is administered orally, which may conveniently be provided in tablet, caplet, sublingual, liquid or capsule form. For example, in certain embodiments, noribogaine is provided as noribogaine HC1, with dosages reported as the amount of free base noribogaine. In some embodiments, the iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is provided in hard gelatin capsules containing only the compound with no excipients.

[0191] The iboga alkaloid or pharmaceutically acceptable salt or solvate thereof can also be used in conjunction with any of the vehicles and excipients commonly employed in pharmaceutical preparations, e.g., talc, gum Arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc.

Coloring and flavoring agents may also be added to preparations, particularly to those for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, poly glycols, dimethylsulfoxide, fatty alcohols, triglycerides, partial esters of glycerine and the like. Parenteral compositions containing iboga alkaloid or pharmaceutically acceptable salt or solvate thereof may be prepared using conventional techniques that may include sterile isotonic saline, water, 1,3-butanediol, ethanol, 1,2-propylene glycol, poly glycols mixed with water, Ringer's solution, etc. [0192] The compositions utilized herein may be formulated for aerosol administration, particularly to the respiratory tract and including intrapulmonary or intranasal administration. The compound will generally have a small particle size, for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization. The active ingredient may be provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC), (for example,

dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane), carbon dioxide or other suitable gases. The aerosol may conveniently also contain a surfactant such as lecithin. The dose of drug may be controlled by a metered valve. Alternatively, the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine. In some embodiments, the powder carrier will form a gel in the nasal cavity. The powder composition may be presented in unit dose form, for example in capsules or cartridges, gelatin or blister packs, from which the powder may be administered by means of an inhaler.

[0193] The compositions utilized herein may be formulated for sublingual administration, for example as sublingual tablets. Sublingual tablets are designed to dissolve very rapidly. The formulations of these tablets contain, in addition to the drug, a limited number of soluble excipients, usually lactose and powdered sucrose, but sometimes dextrose and mannitol.

[0194] It has been discovered that iboga alkaloids have a bitter taste to at least some patients. Accordingly, compositions for oral use (including sublingual, inhaled, and other oral formulations) may be formulated to utilize taste-masking technologies. A number of ways to mask the taste of bitter drugs are known in the art, including addition of sugars, flavors, sweeteners, or coatings; use of lipoproteins, vesicles, and/or liposomes; granulation;

microencapsulation; numbing of taste buds; multiple emulsion; modification of viscosity; prodrug or salt formation; inclusion or molecular complexes; ion exchange resins; and solid dispersion. Any method of masking the bitterness of the compound of the invention may be used.

[0195] In some embodiments, the patient is administered periodically, such as once, twice, three times, four times or five times daily with iboga alkaloid or pharmaceutically acceptable salt or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on the route of administration, content of composition, age and body weight of the patient, condition of the patient, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made by a qualified clinician.

[0196] In another embodiment, there is provided a unit dose of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof which is about 50 mg to about 200 mg per dose. In one embodiment, the unit dose is about 50 to about 120 mg per dose. In one embodiment, the unit dose is about 120 mg per dose. It is to be understood that the term "unit dose" means a dose sufficient to provide therapeutic results whether given all at once or serially over a period of time.

V. Patient Pre-screening and Monitoring

[0197] Pre-screening of patients before treatment with iboga alkaloid or pharmaceutically acceptable salt or solvate thereof and/or monitoring of patients during treatment may be required to ensure that QT interval is not prolonged beyond a certain value. For example, QT interval greater than about 500 ms can be considered dangerous for individual patients. Pre- screening and/or monitoring may be necessary at high levels of iboga alkaloid or

pharmaceutically acceptable salt or solvate thereof.

[0198] In one embodiment, a patient receiving a therapeutic dose of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is monitored in a clinical setting.

Monitoring may be necessary to ensure the QT interval is not prolonged to an unacceptable degree. A "clinical setting" refers to an inpatient setting (e.g., inpatient clinic, hospital, rehabilitation facility) or an outpatient setting with frequent, regular monitoring (e.g., outpatient clinic that is visited daily to receive dose and monitoring). Monitoring includes monitoring of QT interval. Methods for monitoring of QT interval are well-known in the art, for example by ECG.

[0199] In one embodiment, a patient receiving iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is not monitored in a clinical setting. In one embodiment, a patient receiving iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is monitored periodically, for example daily, weekly, monthly, or occasionally.

[0200] In one aspect, this invention relates to a method for treating, preventing, or attenuating a disease or disorder or symptoms of a disease or disorder described herein who is prescreened to evaluate the patient's expected tolerance for prolongation of QT interval, administering to the patient a dosage of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof that is sufficient to inhibit or ameliorate said disease or disorder or symptoms/progression thereof, while maintaining a QT interval of less than about 500 ms during said treatment. In some embodiments, the dosage maintains a QT interval of less than about 470 ms during treatment. Preferably, the co dosage maintains a QT interval of less than about 450 ms during treatment. In one embodiment, the dosage maintains a QT interval of less than about 420 ms during treatment.

[0201] In one embodiment, prescreening of the patient comprises ascertaining that iboga alkaloid or pharmaceutically acceptable salt or solvate thereof treatment will not result in a maximum QT interval over about 500 ms. In one embodiment, prescreening of the patient comprises ascertaining that iboga alkaloid or pharmaceutically acceptable salt or solvate thereof treatment will not result in a maximum QT interval over about 470 ms. In one embodiment, prescreening comprises ascertaining that iboga alkaloid or pharmaceutically acceptable salt or solvate thereof treatment will not result in a maximum QT interval over about 450 ms. In one embodiment, prescreening comprises ascertaining that iboga alkaloid or pharmaceutically acceptable salt or solvate thereof treatment will not result in a maximum QT interval over about 420 ms. In one embodiment, prescreening comprises determining the patient's pre-treatment QT interval.

[0202] As it relates to pre-screening or pre-selection of patients, patients may be selected based on any criteria as determined by the skilled clinician. Such criteria may include, by way of non-limiting example, pre-treatment QT interval, pre-existing cardiac conditions, risk of cardiac conditions, age, sex, general health, and the like. The following are examples of selection criteria for disallowing iboga alkaloid or pharmaceutically acceptable salt or solvate thereof treatment or restricting dose of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof administered to the patient: high QT interval before treatment (e.g., such that there is a risk of the patient's QT interval exceeding about 500 ms during treatment);

congenital long QT syndrome; bradycardia; hypokalemia or hypomagnesemia; recent acute myocardial infarction; uncompensated heart failure; and taking other drugs that increase QT interval. In some embodiments, the methods can include selecting and/or

administering/providing iboga alkaloid or pharmaceutically acceptable salt or solvate thereof to a patient that lacks one more of such criteria.

[0203] In one embodiment, this invention relates to pre-screening a patient to determine if the patient is at risk for prolongation of the QT interval beyond a safe level. In one embodiment, a patient at risk for prolongation of the QT interval beyond a safe level is not administered iboga alkaloid or pharmaceutically acceptable salt or solvate thereof. In one embodiment, a patient at risk for prolongation of the QT interval beyond a safe level is administered iboga alkaloid or pharmaceutically acceptable salt or solvate thereof at a limited dosage.

[0204] In one embodiment, this invention relates to monitoring a patient who is

administered a therapeutic dose of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof. In one embodiment, the dose of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is reduced if the patient has serious adverse side effects. In one embodiment, the iboga alkaloid or pharmaceutically acceptable salt or solvate thereof treatment is discontinued if the patient has serious adverse side effects. In one embodiment, the adverse side effect is a QT interval that is prolonged beyond a safe level. The

determination of a safe level of prolongation is within the skill of a qualified clinician.

VI. Kit of Parts

[0205] One aspect of this invention is directed to a kit of parts for the treatment, prevention, or attenuation of a disease or disorder or symptoms of a disease or disorder described herein, wherein the kit comprises a composition comprising iboga alkaloid or pharmaceutically acceptable salt or solvate thereof and a means for administering the composition to a patient in need thereof. The means for administration to a patient can include, for example, any one or combination of a pharmaceutically acceptable formulation or composition as described herein (e.g., a pill, transdermal patch, injectable, and the like, without limitation) and optionally a means for dispensing and/or administering the formulation (e.g., a syringe, a needle, an IV bag comprising the composition, a vial comprising the composition, an inhaler comprising the composition, etc, without limitation). In one embodiment, the kit of parts further comprises instructions for dosing and/or administration of the composition. In one embodiment, the kit of parts further comprises one or more additional agents known to treat the disease or disorder.

[0206] In some aspects, the invention is directed to a kit of parts for administration of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof and optionally an agent for treatment of the disease or disorder, the kit comprising multiple delivery vehicles, wherein each delivery vehicle contains a discrete amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof and further wherein each delivery vehicle is identified by the amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof and/or agent provided therein; and optionally further comprising a dosing treatment schedule in a readable medium. In some embodiments, the dosing treatment schedule includes the amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof required to achieve each average serum level is provided. In some embodiments, the kit of parts includes a dosing treatment schedule that provides an attending clinician the ability to select a dosing regimen of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof based on the sex of the patient, mass of the patient, and the serum level that the clinician desires to achieve. In some embodiments, the dosing treatment schedule further provides information corresponding to the volume of blood in a patient based upon weight (or mass) and sex of the patient. In an embodiment, the storage medium can include an accompanying pamphlet or similar written information that accompanies the unit dose form in the kit. In an embodiment, the storage medium can include electronic, optical, or other data storage, such as a nonvolatile memory, for example, to store a digitally-encoded machine-readable representation of such information.

[0207] The term "delivery vehicle" as used herein refers to any formulation that can be used for administration of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof and optionally agent to treat the disease or disorder to a patient. Non-limiting, exemplary delivery vehicles include caplets, pills, capsules, tablets, powder, liquid, or any other form by which the drug can be administered. Delivery vehicles may be intended for administration by oral, inhaled, injected, or any other means.

[0208] The term "readable medium" as used herein refers to a representation of data that can be read, for example, by a human or by a machine. Non-limiting examples of human- readable formats include pamphlets, inserts, or other written forms. Non-limiting examples of machine-readable formats include any mechanism that provides (i.e., stores and/or transmits) information in a form readable by a machine (e.g., a computer, tablet, and/or smartphone). For example, a machine-readable medium includes read-only memory (ROM); random access memory (RAM); magnetic disk storage media; optical storage media; and flash memory devices. In one embodiment, the machine-readable medium is a CD-ROM. In one embodiment, the machine-readable medium is a USB drive. In one embodiment, the machine-readable medium is a Quick Response Code (QR Code) or other matrix barcode. [0209] In some aspects, the machine-readable medium comprises software that contains information regarding dosing schedules for the unit dose form of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof and optionally other drug information. In some embodiments, the software may be interactive, such that the attending clinician or other medical professional can enter patient information. In a non-limiting example, the medical professional may enter the weight and sex of the patient to be treated, and the software program provides a recommended dosing regimen based on the information entered. The amount and timing of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof recommended to be delivered will be within the dosages that result in the serum

concentrations as provided herein.

[0210] In some embodiments, the kit of parts comprises multiple delivery vehicles in a variety of dosing options. For example, the kit of parts may comprise pills or tablets in multiple dosages, such as 120 mg, 90 mg, 60 mg, 30 mg, 20 mg, 10 mg, and/or 5 mg of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof per pill. Each pill is labeled such that the medical professional and/or patient can easily distinguish different dosages. Labeling may be based on printing or embossing on the pill, shape of the pill, color of pill, the location of the pill in a separate, labeled compartment within the kit, and/or any other distinguishing features of the pill. In some embodiments, all of the delivery vehicles within a kit are intended for one patient. In some embodiments, the delivery vehicles within a kit are intended for multiple patients.

[0211] In some embodiments, the unit dose of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is from 0.1 mg to 100 mg. In one embodiment, the unit dose is 0.1 mg. In one embodiment, the unit dose is 1 mg. In one embodiment, the unit dose is 2 mg. In one embodiment, the unit dose is 3 mg. In one embodiment, the unit dose is 4 mg. In one embodiment, the unit dose is 5 mg. In one embodiment, the unit dose is 6 mg. In one embodiment, the unit dose is 10 mg. In one embodiment, the unit dose is 20 mg. In one embodiment, the unit dose is 25 mg. In one embodiment, the unit dose is 30 mg. In one embodiment, the unit dose is 40 mg. In one embodiment, the unit dose is 50 mg. In one embodiment, the unit dose is 60 mg. In one embodiment, the unit dose is 70 mg. In one embodiment, the unit dose is 80 mg. In one embodiment, the unit dose is 90 mg. In one embodiment, the unit dose is 100 mg. Unit doses may include any range or subrange between any of these doses, as well as any value therebetween, including endpoints.

[0212] In some embodiments, the unit dose form comprises one or multiple dosages to be administered periodically, such as once, twice, three times, four times or five times daily with iboga alkaloid or pharmaceutically acceptable salt or solvate thereof and optionally the agent to treat the disease or disorder. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on criteria including the route of administration, content of composition, age and body weight of the patient, condition of the patient, sex of the patient, without limitation, as well as by the severity of the addiction. Determination of the unit dose form providing a dosage and frequency suitable for a given patient can readily be made by a qualified clinician.

[0213] In some embodiments, the doses of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof are provided as one or multiple dosages to be administered

periodically, such as once, twice, three times, four times or five times daily with iboga alkaloid or pharmaceutically acceptable salt or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on criteria including the route of administration, content of composition, age and body weight of the patient, condition of the patient, sex of the patient, without limitation, as well as by the severity of the addiction. Determination of the unit dose form providing a dosage and frequency suitable for a given patient can readily be made by a qualified clinician.

[0214] In one aspect, provided herein is a kit of parts comprising two or more doses of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof, wherein the two or more doses comprise an amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof that is sufficient to maintain a serum concentration of less than 180 ng/mL when administered to a patient.

[0215] These dose ranges may be achieved by transdermal, oral, or parenteral

administration of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof in unit dose form. Such unit dose form may conveniently be provided in transdermal patch, tablet, caplet, liquid or capsule form. In certain embodiments, the iboga alkaloid is noribogaine provided as noribogaine HC1, with dosages reported as the amount of free base noribogaine. In some embodiments, the noribogaine HC1 is provided in hard gelatin capsules containing only noribogaine HC1 with no excipients. In some embodiments, iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is provided in saline for intravenous administration. VII. Formulations

[0216] This invention further relates to pharmaceutically acceptable formulations comprising a unit dose of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof and an agent known to treat the neurodegenerative disease or movement disorder or a symptom and/or progression thereof, and optionally a pharmaceutically acceptable excipient.

[0217] In some embodiments, the formulation is a controlled release formulation. The term "controlled release formulation" includes sustained release and time-release formulations. Controlled release formulations are well-known in the art. These include excipients that allow for sustained, periodic, pulse, or delayed release of the drug. Controlled release formulations include, without limitation, embedding of the drug into a matrix; enteric coatings; microencapsulation; gels and hydrogels; implants; transdermal patches; and any other formulation that allows for controlled release of a drug.

[0218] In some embodiments, the formulation is designed for periodic administration, such as once, twice, three times, four times or five times daily with iboga alkaloid or

pharmaceutically acceptable salt or solvate thereof. In some embodiments, the administration is once daily, or once every second day, once every third day, three times a week, twice a week, or once a week. The dosage and frequency of the administration depends on the route of administration, content of composition, age and body weight of the patient, condition of the patient, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made a qualified clinician.

[0219] In some embodiments, the formulation designed for administration in accordance with the methods provide herein can be suitable for a variety of delivery modes including, without limitation, oral, transdermal, sublingual, buccal, intrapulmonary or intranasal delivery. Formulations suitable for internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intra-arterial, intramuscular, intraperitoneal, intracutaneous and subcutaneous routes may also be used. Possible formulations include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. Sustained release dosage forms may also be used. All formulations may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980).

[0220] In a preferred embodiment, the formulation is designed for oral administration, which may conveniently be provided in tablet, caplet, sublingual, liquid or capsule form. For example, in certain embodiments, the iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is noribogaineprovided as noribogaine HC1, with dosages reported as the amount of free base noribogaine. In some embodiments, the noribogaine HC1 is provided in hard gelatin capsules containing only noribogaine HC1 with no excipients.

EXAMPLES

[0221] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.

Example 1. Safety, tolerability. and efficacy of noribogaine in opioid-addicted humans

[0222] This example is to illustrate that noribogaine can be administered at a therapeutic dosing while maintaining an acceptable QT interval. While the therapy employed is directed to opioid-dependent participants in a randomized, placebo-controlled, double-blind trial, the results show that a therapeutic window can be established for noribogaine. Safety, tolerability and efficacy of noribogaine in healthy humans is provided in U.S. Patent No. 9,345,711, which is incorporated herein by reference in its entirety.

[0223] The efficacy of noribogaine in humans was evaluated in opioid-dependent participants in a randomized, placebo-controlled, double-blind trial. Patients had been receiving methadone treatment as the opioid substitution therapy, but were transferred to morphine treatment prior to noribogaine administration. This was done to avoid negative noribogaine-methadone interactions that are not observed between noribogaine and morphine. See U.S. Application Pub. Nos. 2014/0288056 and 2016/0271139, which are incorporated herein by reference in their entireties.

[0224] Three cohorts of nine (9) subjects (6 administered noribogaine and 3 administered placebo in each cohort) were evaluated for tolerability, pharmacokinetics, and efficacy. Cohort 1 received a single dose of 60 mg noribogaine or placebo. Cohort 2 received a single dose of 120 mg noribogaine or placebo. Cohort 3 received a single dose of 180 mg noribogaine or placebo. Treatment was administered 2 hours after last morphine dose and the time to resumption of morphine (opioid substitution treatment, OST) was determined. Few adverse effects of noribogaine were observed in any of the participants, including no hallucinatory effects. [0225] Figure 3 indicates the average serum noribogaine concentration over time after administration of noribogaine for each cohort (60 mg, diamonds; 120 mg, squares; or 180 mg, triangles).

Results

[0226] Pharmacokinetic results for each cohort are given in Table 1. Maximum serum concentration of noribogaine (Cmax) increased in a dose-dependent manner. Time to Cmax (Tmax) was similar in all three cohorts. Mean half-life of serum noribogaine was similar to that observed in healthy patients.

Table 1: Pharmacokinetic results from the Patients in Phase IB Study

Cohort 1 (60mg) Cohort 2 (120mg) Cohort 3 (180mg)

Data (mean ±SD) Data (mean ±SD) Data (mean ±SD)

PK parameter

[range] [range] [range]

81.64 ±23.77 172.79± 30.73 267.88 ±46.92

Cmax (ng/ml)

[41.29-113.21] [138.84-229.55] [204.85-338.21]

3.59 ±0.92 2.99 ± 1.23 4.41±1.80

Tmax (hours)

[2.50-5.00] [0.98 - 4.02] [3.00-8.00]

AUC(O-T) 2018.01 ± 613.91 3226.38 ± 1544.26 6523.28±2909.80

(ng.hr/ml) [1094.46-2533.44] [1559.37-5638.98] [3716.69- 10353.12]

AUC(o-¥) 2060.31 ± 609.39 3280.50 ± 1581.43 6887.67±3488.91

(ng.hr/ml) [1122.29-2551.63] [1595.84-5768.52] [3734.21 - 12280.91]

29.32 ±7.28 30.45±9.14 23.94±5.54

Half-life (hrs)

[18.26-37.33] [21.85-48.33] [19.32-34.90]

1440.7 ± 854.0 2106.43±1644.54 1032.19±365.30

Vd/F

[619.5-2772.5] [824.24 - 5243.78] [581.18- 1608.98]

32.14± 12.38 44.68 ±21.40 31.47±13.12

Cl/F

[23.51 -53.46] [20.80-75.20] [14.66-48.20]

[0227] Patients receiving a single 120 mg dose of noribogaine exhibited an average time to resumption of opioids of greater than 20 hours. Patients receiving a single 180 mg dose of noribogaine exhibited an average time to resumption of opioids similar to that of placebo. This demonstrates that increasing the dose of noribogaine to 180 mg results in a shorter time to resumption of OST than observed in patients receiving 120 mg noribogaine. Time to resumption of OST after treatment with 180 mg was still longer than untreated patients (7 hours, not shown) or those administered 60 mg noribogaine.

[0228] Patients were evaluated based on the Clinical Opiate Withdrawal Scale (COWS), Subjective Opiate Withdrawal Scale (SOWS), and Objective Opiate Withdrawal Scale (OOWS) scoring systems over the period of time between administration of noribogaine (or placebo) until resumption of OST. These scales are outlined in Guidelines for the

Psychosocially Assisted Pharmacological Treatment of Opioid Dependence, World Health Organization, Geneva (2009), Annex 10, which is incorporated herein by reference in its entirety. The scales measure the intensity of withdrawal symptoms, based on clinical, subjective, and objective indicia.

[0229] The data indicate that withdrawal symptoms get worse over time after cessation of OST, and that patients administered placebo experience generally worse withdrawal symptoms over that period. Patients who received 120 mg noribogaine generally experienced fewer withdrawal symptoms than the other patients, regardless of the scale used. Patients administered placebo generally experienced more withdrawal symptoms than patients who were administered noribogaine.

[0230] Patients' QT intervals were evaluated at regular time points throughout the study. Figure 4A shows the average change in QT interval (AQTcl, i.e., QT interval prolongation) over the first 24 hours post noribogaine (or placebo) administration. Figure 4B shows the relationship between noribogaine concentrations and AAQTcI with 90% CI. There is a dose- dependent increase in QT interval prolongation that is correlated with the serum

concentration of noribogaine. A goodness-of-fit plot for the observed and predicted relation between noribogaine plasma levels and AAQTcI is provided in Figure 4C.

Example 2. Efficacy of Multi-Dose Noribogaine Treatment in Humans

[0231] Seven patients who were addicted to opioids were administered a 80 mg loading dose of noribogaine, followed by therapeutic maintenance doses (20 mg to 40 mg) of noribogaine approximately every 6 hours for up to 5 days. The patients' scores on various Opiate Withdrawal Scales (Clinical, COWS; Subjective, SOWS; Objective, OOWS) and Profile of Mood States (POMS) were evaluated during treatment. QT interval, pupil diameter, noribogaine serum concentration, opioid levels (urine), and adverse events were also monitored and recorded. Scores and additional details regarding the study can be found in PCT Publication No. WO 2016/183244, which is incorporated herein by reference in its entirety.

[0232] The slope of the relationship between noribogaine and AQTcF was 0.086 msec per ng/mL [90% confidence interval (CI): 0.052 to 0.1 19] with a significant intercept of 9.5 msec. The predicted AQTcF effect using this model was 17.1msec (90% CI: 13.57 to 20.71) at the observed geometric mean peak plasma level after dosing with noribogaine; 89.1 ng/mL. There were no adverse events, and no patient exhibited QTcF over 500 msec, or prolonged by more than 60 msec, during the treatment.

[0233] An intercept at this level raises concern in regard to the employed exposure response models and it is therefore prudent to conclude that noribogaine causes QT prolongation, but to be cautious in regard to predictions of the effect using these data. Importantly, within the limitations of a small study, the dosing algorithm worked successfully in terms of ensuring that no subject experienced a clinically concerning QT prolongation (i.e., AQTcF > 60 msec or QTcF > 500 msec).

[0234] After oral administration of noribogaine, plasma concentrations with time were consistent with an open, 2 compartment first-order absorption model. The model-predicted values for the primary PK parameters CL/F and Vl/F were reasonably consistent among the 4 subjects with sufficient data for modeling. Steady-state plasma concentrations were reached between 12 and 24 hours after the 1st dose in 5 subjects and prior to 48 hours for 2 other subjects. Although plasma concentrations vary among subj ects, they are consistent within a subject once steady-state has been reached even when the variation of doses with a subject is taken into account.

[0235] Further examples of the tolerance and efficacy of noribogaine in humans are found, by way of non-limiting example, in U. S. Patent App. Pub. Nos. 2015/0231 147 and

2015/0231146, each of which is incorporated herein by reference in its entirety.

[0236] Further examples of dosing regimens that can be used in the current invention can be found, by way of non-limiting example, in PCT Publication No. WO 2016/183244, which is incorporated herein by reference in its entirety.

[0237] The noribogaine concentration in the plasma and brains of the female rats was also measured after a single (acute) administration of noribogaine (3 mg/kg and 10 mg/kg), as provided in Table 2. Table 2

Example 3 : Acute effect of noribogaine on motor performance in a rat model of

Parkinson's disease

[0238] Female rats were studied using the unilateral 6-hydroxy dopamine (6-OHDA) model. The unilateral 6-OHDA model is the traditional model for testing Parkinson's disease therapies, especially those intended to increase dopamine levels in the striatum. Briefly, the toxin 6-OHDA is injected into the rats unilaterally (i.e., into one hemisphere of the brain), while the opposite hemisphere serves as an intra-animal control. The injection produces dopamine neuron loss on the 6-OHDA-inj ected side while sparing the contralateral dopamine neurons.

[0239] After injection of rats with 6-OHDA, the animals were assessed using the cylinder test (also called the forelimb asymmetry test). The rat was placed in a confined, open-top, clear plastic cylinder and recorded for a period of time. A mirror was placed behind the cylinder to allow capture of all forelimb movement, even when the animal was turned away from the camera. Forelimb activity was assessed by blinded observers reviewing video of the rat's activity in the cylinder. Animals with a lesion in the right stratum are expected to present a significant impairment in the contralateral (left) forepaw use (called use

asymmetry). The number of left and right forepaw contacts with the cylinder were counted. Forelimb contact was defined as the placement of the whole palm on the wall of the cylinder, and indicated its use during supported rearing. The percentage of use of the left paw was calculated. [0240] Six weeks after right medial forebrain bundle (MFB) lesion by 6-OHDA, rats were treated with vehicle (0.9% NaCl for L-Dopa/benserazide; 35% [0.5% TWEEN 80 in 5% dextrose] and 65% [1.5% methylcellulose] for noribogaine); L-dopa (6 mg/kg) and benserazide (15 mg/kg) via intraperitoneal injection 50 minutes prior to test; or noribogaine (10 mg/kg, 30 mg/kg, or 60 mg/kg) via oral administration 120 minutes prior to test. The percentage of left forepaw use was determined and data analyzed using one-way ANOVA followed by Fisher LSD. Figure 5 illustrates the effect of vehicle, L-Dopa and benzerazide, or noribogaine on the percent of left forepaw use.

Example 4: Acute effect of noribogaine in combination with L-dopa on motor

performance in a rat model of Parkinson's disease

[0241] The rats were tested in the cylinder test as described above, 8 weeks after right MFB lesion by 6-OHDA (2 weeks after the cylinder test of Example 5). Rats were treated with vehicle (0.9% NaCl for L-Dopa/benserazide; 35% [0.5% TWEEN 80 in 5% dextrose] and 65% [1.5% methylcellulose] for noribogaine); L-dopa (6 mg/kg) and benserazide (15 mg/kg) via intraperitoneal injection 50 minutes prior to test; or L-dopa (6 mg/kg) and benserazide (15 mg/kg) via intraperitoneal injection 50 minutes prior to test and noribogaine (10 mg/kg, 30 mg/kg, or 60 mg/kg) via oral administration 120 minutes prior to test. Figure 6 A illustrates the effect of vehicle, L-Dopa and benzerazide, or L-Dopa/benzerazide and noribogaine on the percent of left forepaw use. Figure 6B shows a semi-quantitative dyskinesia score, where a score of 0 indicates no dyskinesia behavior; 1 indicates mild dyskinesia behavior; 2 indicates moderate dyskinesia behavior; and 3 indicates severe dyskinesia behavior.

Example 5 : Subchronic effect of noribogaine on motor performance in a rat model of Parkinson's disease

[0242] The rats were treated daily for three weeks with vehicle or noribogaine (10 mg/kg, 30 mg/kg, or 60 mg/kg) via oral administration, followed by vehicle, L-Dopa benserazide, or noribogaine as in Example 5. Figure 7 illustrates the effect of daily noribogaine treatment on the percent of left forepaw use. Both L-Dopa/benserazide and 10 mg/kg noribogaine provided significant improvement in left forepaw use in this model.

[0243] The noribogaine concentration in the plasma of the female rats after three weeks of daily noribogaine dosing was also measured (1 mg/kg, 3 mg/kg, or 10 mg/kg), as provided in Table 3. Table 3

[0244] The rats were administered noribogaine for a total of 11 weeks, and the plasma and brain concentrations determined, as shown in Table 4.

Table 4

Example 6: Effect of noribogaine on Parkinson's disease in humans

[0245] A male patient, age 60, with Parkinson's disease is treated with noribogaine hydrochloride at an initial dose of about 6 mg per day (administered as 3 mg twice per day). Improvement in one or more symptoms is expected. Prolonged (e.g. 6 months or more) administration of between 6 mg and 20 mg per day is expected to delay progression of the disease and/or symptoms thereof.

Claims

What is claimed is:

1. A method for treating a neurodegenerative disease and/or symptoms thereof in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof.

2. The method of claim 1, wherein the therapeutically effective amount is from about 0.1 mg to about 100 mg per day.

3. The method of claim 2, wherein the therapeutically effective amount is from about 1 mg to about 50 mg per day.

4. The method of any one of claims 1-3, wherein the patient's QT interval is not prolonged by more than about 30 ms.

5. The method of any one of claims 1-3, wherein the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), a prion disease, spinocerebellar ataxia, spinal muscular atrophy, Friedreich's ataxia, Lewy body disease, and a motor neuron disease.

6. The method of claim 5, wherein the neurodegenerative disease is Parkinson's disease.

7. The method of claim 6, further comprising administering L-dopa to the patient.

8. The method of any one of claims 1-3, further comprising administering at least one agent known to treat and/or prevent the neurodegenerative disease and/or a symptom or symptoms thereof.

9. A method for preventing a neurodegenerative disease and/or symptoms thereof in a patient in need thereof, comprising administering to the patient a prophylactically effective amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof.

10. The method of claim 9, wherein said prophylactically effective amount is from about 0.1 mg to about 100 mg per day.

11. The method of claim 10, wherein said prophylactically effective amount is from about 1 mg to about 50 mg per day.

12. The method of any one of claims 9-11, wherein the patient's QT interval is not prolonged by more than about 30 ms.

13. The method of any one of claims 9-11, wherein the neurodegenerative disease is selected from the group consisting of Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), a prion disease, spinocerebellar ataxia, spinal muscular atrophy, Friedreich's ataxia, Lewy body disease, and motor neuron disease.

14. The method of any one of claims 9-11, further comprising administering at least one agent known to treat and/or prevent the neurodegenerative disease and/or a symptom or symptoms thereof.

15. A method for treating or preventing a movement disorder and/or symptoms thereof in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof.

16. The method of claim 15, wherein the therapeutically effective amount is from about 0.1 mg to about 100 mg per day.

17. The method of claim 16, wherein the therapeutically effective amount is from about 1 mg to about 50 mg per day.

18. The method of any one of claims 15-17, wherein the patient's QT interval is not prolonged by more than about 30 ms.

19. The method of any one of claims 15-17, wherein the movement disorder is selected from the group consisting of bradykinesia, Hallevorden-Spatz disease, progressive supranuclear palsy, multiple system atrophy, dystonia, spasmodic torticollis, essential tremor, other types of tremor, various choreas and diskenesias, tic disorders, Tourette's syndrome, stereotypic movement disorder, paroxysmal nocturnal limb movement, restless leg syndrome, and stiff person syndrome.

20. The method of any one of claims 1-19, wherein the therapeutically effective amount is administered once a day.

21. The method of any one of claims 1-19, wherein the therapeutically effective amount is administered two or more times per day.

22. A pharmaceutical composition comprising a therapeutically effective amount of an iboga alkaloid or pharmaceutically acceptable salt or solvate thereof, at least one agent for treating or preventing a neurodegenerative disease, and a pharmaceutically acceptable excipient.

23. The pharmaceutical composition of claim 22, wherein the therapeutically effective amount of iboga alkaloid or pharmaceutically acceptable salt or solvate thereof is an amount that delivers an aggregate amount of noribogaine of about 0.1 mg to about 100 mg per day.

24. The pharmaceutical composition of claim 22, wherein the pharmaceutical

composition is formulated for oral, sublingual, intranasal, or intrapulmonary delivery.

25. The pharmaceutical composition of any one of claims 22-24, wherein the at least one agent is selected from the group consisting of an anti-epilectic drug, an anti-seizure medication, a beta-blocker, a dopamine agonist, a dopamine precursor, a cholinesterase inhibitor, choline, an anticholinergic, an anti-inflammatory, a cannabinoid, a cannabis extract, glutathione or a glutathione analog, an antioxidant, a monoamine oxidase B inhibitor, a catechol-O-methyltransferase inhibitor, amantadine, tetrabenazine, an antipsychotic drug, levetiracetam, clonazepam, riluzole, baclofen, branched-chain amino acids, phenytoin, cell- derived neurotrophic factor, a carbonic anhydrase inhibitor, and a tranquilizer.

26. The method of any one of claims 1-21 or the pharmaceutical formulation of any one of claims 22-25, wherein the iboga alkaloid is noribogaine, noribogaine derivative, or pharmaceutically acceptable salt and/or solvate thereof.

27. The method or pharmaceutical formulation of claim 26, wherein the noribogaine derivative is represented by Formula I:

I

or a pharmaceutically acceptable salt thereof,

wherein R is hydrogen or a hydrolyzable group of the formula:

O C X

wherein X is an unsubstituted CVC₁₂ group or a C₁-C₁₂ group substituted by lower alkyl or lower alkoxy groups, wherein the noribogaine having the hydrolyzable group hydrolyzes in vivo to form 12-hydroxy ibogamine.

28. The method or pharmaceutical formulation of claim 26, wherein the noribogaine derivative is represented by Formula II:

or a pharmaceutically acceptable salt thereof,

wherein

is a single or double bond;

R¹ is halo, OR², or C1-C12 alkyl optionally substituted with 1 to 5 R ;

R² is hydrogen or a hydrolysable group selected from the group consisting of -C(O) R^x, -C(0)OR^x and -C(0)N(R^y)₂ where each R^x is selected from the group consisting of C1-C6 alkyl optionally substituted with 1 to 5 R¹⁰, and each R^y is independently selected from the group consisting of hydrogen, C1-C6 alkyl optionally substituted with 1 to 5 R¹⁰, C6-C 14 aryl optionally substituted with 1 to 5 R¹⁰, C3-C1₀ cycloalkyl optionally substituted with 1 to 5 R¹⁰, C1-C1₀ heteroaryl having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R¹⁰, C1-C1₀ heterocyclic having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R¹⁰, and where each R^y, together with the nitrogen atom bound thereto form a C1-C6 heterocyclic having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R¹⁰ or a C1-C6 heteroaryl having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R¹⁰;

R³ is selected from the group consisting of hydrogen, C1-C12 alkyl optionally

R⁴ is selected from the group consisting of hydrogen, -(CH₂)_mOR⁸, -

L is a bond or Ci-Ci₂ alkylene;

each R⁶ is independently selected from the group consisting of hydrogen, Cr-C₁₂ alkyl, C2-C12 alkenyl, C2-Ci2 alkynyl, C6-Cio aryl, C1-C6 heteroaryl having 1 to 4 heteroatoms, and C1-C6 heterocycle having 1 to 4 heteroatoms, and wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle are optionally substituted with 1 to 5 R¹⁰;

X¹ is selected from the group consisting of O and S;

Y is C1-C4 alkylene or C6-C1₀ arylene, or a combination thereof;

n is 1 , 2, or 3;

C1-C12 alkyl optionally substituted with 1 to 5 R¹⁰, Ci-Ce heterocycle having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R¹⁰, C3-C1₀ cycloalkyl optionally substituted with 1 to 5 R¹⁰, C6-Cio aryl optionally substituted with 1 to 5 R¹⁰ and Ci-Ce heteroaryl having 1 to 4 heteroatoms optionally substituted with 1 to 5 R¹⁰;

R⁹ is selected from the group consisting of C1-C12 alkyl optionally substituted with 1 to 5 R¹⁰, C1-C6 heterocycle having 1 to 4 heteroatoms optionally substituted with 1 to 5 R¹⁰, C3-C1₀ cycloalkyl optionally substituted with 1 to 5 R¹⁰, C6-C1₀ aryl optionally substituted with 1 to 5 R¹⁰ and C1-C6 heteroaryl having 1 to 4 heteroatoms optionally substituted with 1 to 5 R¹⁰;

CN, -COR¹¹, -CO2R¹¹, -C(0)NHRⁿ, -NRⁿRⁿ, -C(0)NRⁿRⁿ, -C(0)NHNHR n, -C(0)NRⁿNHRⁿ, -C(0)NR¹¹NR¹¹R¹¹, -C(0)NHNRⁿC(0)Rⁿ, -C(0)NHN HC(0)Rⁿ, -SOzNR¹¹^¹, -C^N^NR¹¹^)^¹,

and -C(0)NRⁿNHC(0)Rⁿ; and

R¹¹ is independently hydrogen or C1-C12 alkyl;

provided that:

when L is a bond, then R⁵ is not hydrogen;

when is a double bond, R¹ is -OH, halo or Cr-C₁₂ alkyl optionally substituted with 1 to 5 R¹⁰, then R⁴ is hydrogen; and when is a double bond, R¹ is OR², R⁴ is hydrogen, -L-R⁵ is ethyl, then R² is not a hydrolyzable group selected from the group consisting of an ester, amide, carbonate and carbamate.

29. The method or pharmaceutical formulation of claim 26, wherein the noribogaine derivative is represented by Formula III:

III

or a pharmaceutically acceptable salt thereof,

wherein

is a single or double bond;

R¹² is halo, -OH, -SH, -NH₂, -S(0)₂N(R¹⁷)₂, -R^z-L^x-R¹⁸, -R^z-L*-R¹⁹, -R'-I^-R²⁰ or -R^z- I^-CHR^R¹⁹, where R^z is O, S or NR¹⁷;

L¹ is alkylene, arylene, -C(0)-alkylene, -C(0)-arylene, -C(0)0-arylene, -C(0)0- alkylene, -C(O)NR²⁰-alkylene, -C(O)NR²⁰-arylene, -C(NR²⁰)NR²⁰-alkylene or -C(NR²⁰)NR²⁰-arylene, wherein L¹ is configured such that -O-I^-R¹⁸ is - OC(0)-alkylene-R¹⁸, -OC(0)0-arylene-R¹⁸, -OC(0)0-alkylene-R¹⁸, -OC(O)- arylene-R¹⁸, -OC(O)NR²⁰-alkylene-R¹⁸, -OC(O)NR²⁰-arylene-R¹⁸, - OC(NR²⁰)NR²⁰-alkylene-R¹⁸ or -OC(NR²⁰)NR²⁰-arylene-R¹⁸, and wherein the alkylene and arylene are optionally substituted with 1 to 2 R¹⁶;

R¹³ is hydrogen, -S(0)₂OR²°, -S(0)₂R²⁰, -C(0)R¹⁵, -C(0)NR¹⁵R¹⁵, -C(0)OR¹⁵, Ci-Ci₂ alkyl optionally substituted with 1 to 5 R¹⁶, Ci-Ci₂ alkenyl optionally substituted with 1 to 5 R¹⁶, or aryl optionally substituted with 1 to 5 R¹⁶;

R¹⁴ is hydrogen, halo, -OR¹⁷, -CN, C i-Ci₂ alkyl, Ci-Ci₂ alkoxy, aryl or aryloxy, where the alkyl, alkoxy, aryl, and aryloxy are optionally substituted with 1 to 5 R¹⁶; each R¹⁵ is independently selected from the group consisting of hydrogen, Ci-Ci₂ alkyl, C₂-Ci₂ alkenyl, C₂-Ci₂ alkynyl, aryl, heteroaryl, and heterocycle, and wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle are optionally substituted with 1 to 5 R¹⁶; R is selected from the group consisting of phenyl, halo, -OR , -

CN, -COR¹⁷, -C0₂R¹⁷, -NR¹⁷R¹⁷, - NR¹⁷C(0)R¹⁷, - NR¹⁷S0₂R¹⁷, -C(0)NR¹⁷R 1¹ , -C(0)NR¹⁷NR¹⁷R¹⁷, -S0₂NR¹⁷R¹⁷ and -C(0)NR¹⁷NR¹⁷C(0)R¹⁷;

each R¹⁷ is independently hydrogen or C1-C12 alkyl optionally substituted with from 1 to 3 halo;

R¹⁹ is hydrogen, -

N(R²⁰)₂, -C(O)N(R²⁰)₂, -C(NR²⁰)N(R²⁰)₂, -C(NSO₂R²⁰)N(R²⁰)₂, -NR²⁰C(O)N( R²⁰)₂, -NR²⁰C(S)N(R²⁰)₂, -NR²⁰C(NR²⁰)N(R²⁰)₂, -NR²⁰C(NSO₂R²⁰)N(R²⁰)₂ or tetrazole; and

each R²⁰ is independently selected from the group consisting of hydrogen,

alkyl and aryl;

provided that:

when is a double bond and R¹³ and R¹⁴ are hydrogen, then R¹² is not hydroxy; when i_{s a} double bond, R¹⁴ is hydrogen, R¹² is -O-I^-R¹⁸, -0-L^x-R¹⁹, -O-L¹-

30. The method or pharmaceutical formulation of claim 26, wherein the noribogaine derivative is represented by Formula IV:

IV

or a pharmaceutically acceptable salt thereof,

wherein

R²¹ is selected from the group consisting of hydrogen, a hydrolysable group selected from the group consisting of -C(0)R²³, -C(0)NR²⁴R²⁵ and -C(0)OR²⁶, where R²³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl, R and R are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, R²⁶ is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic, provided that R²¹ is not a saccharide or an oligosaccharide;

31. The method or pharmaceutical formulation of claim 26, wherein the noribogaine derivative is represented by Formula V:

V

or a pharmaceutically acceptable salt thereof,

wherein:

^ refers to a single or a double bond provided that when

Formula V refers to the corresponding dihydro compound;

R²⁷ is hydrogen or S0₂OR²⁹;

R²⁸ is hydrogen or S0₂OR²⁹;

R²⁹ is hydrogen or Ci - Ce alkyl;

provided that at least one of R²⁷ and R²⁸ is not hydrogen.

32. The method or pharmaceutical formulation of claim 26, wherein the noribogaine derivative is represented by Formula VI:

VI

or a pharmaceutically acceptable salt thereof ,

wherein:

R³⁰ is hydrogen, a monophosphate, a diphosphate or a triphosphate; and

R ¹ is hydrogen, a monophosphate, a diphosphate or a triphosphate;

provided that both R³⁰ and R ¹ are not hydrogen;

33. The method of any one of claims 1-21 or the pharmaceutical formulation of any one of claims 22-25, wherein the iboga alkaloid is noribogaine or a pharmaceutically acceptable salt and/or solvate thereof.

34. The method of any one of claims 1-21 or the pharmaceutical formulation of any one of claims 22-25, wherein the iboga alkaloid is ibogaine, an ibogaine derivative, or a pharmaceutically acceptable salt and/or solvate thereof.

35. The method or pharmaceutical formulation of claim 34, wherein the ibogaine derivative is represented by Formula VIII:

VIII or a pharmaceutically acceptable salt and/or solvate thereof,

wherein R is hydrogen or C1-C3 alkoxy;

R¹⁰¹ is hydrogen, C1-C3 alkyl, C1-C3 alkoxy, (CH₂)_mOC(0)alkyl, (CH₂)_mOH, (CH₂)_mOalkyl, (CH2)_mO(CH2)_pO(CH2)_qO(CH₂)_rCH₃ or CH₂-Y-CH₃ where each of m, p and q is 1, 2 or 3; and r is 0, 1 or 2,Y is O or NH; and

(CH₂CH₂0)_nCH₃, where n is 1, 2, or 3.

36. The method or pharmaceutical formulation of claim 34, wherein the ibogaine derivative is selected from the group consisting of coronaridine, ibogamine, voacangine, 18- methoxy coronaridine, 2-Methoxyethyl-18-methoxycoronaridinate, and 18- Methylaminocoronaridine.

37. The method or pharmaceutical formulation of claim 34, wherein the ibogaine derivative is selected from the group consisting of 16-hydroxymethyl-18-hydroxyibogaline, 16-hydroxymethyl-18-methoxyibogaline, 16-ethoxycarbonyl-18-hydroxyibogaline laurate, and 16-ethoxycarbonyl-18-hydroxyibogaline methoxyethoxymethyl ether.

38. The method or pharmaceutical formulation of claim 34, wherein the ibogaine derivative is represented by Formula VIII:

VIII or a pharmaceutically acceptable salt and/or solvate thereof,

wherei

R¹⁰¹ is CH₂CH₃; and

R¹⁰² is COOR¹⁰⁴, where R¹⁰⁴ is (CH₂CH₂0)_nCH₃, where n is 1.

39. The method or pharmaceutical formulation of claim 34, wherein ibogaine or a pharmaceutically acceptable salt and/or solvate thereof is administered.

40. The method of any one of the above claims, wherein L-dopa is further administered. The composition of any one of the above claims, further comprising L-dopa.