METHODS FOR TREATMENT OF OPIOID DEPENDENCY AND

WITHDRAWAL USING NORIBOGAINE

FIELD OF THE INVENTION

[0001] This disclosure is directed to a method of treating dependency on an opioid drug, including acute and post-acute withdrawal symptoms, comprising treating an opioid- dependent patient with noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof.

STATE OF THE ART

[0002] Substance abuse is a serious public health problem throughout the world. Heroin and other opioids, including prescription painkillers, are widely abused and account for a large percentage of illicit drug use. Opioid abuse is also linked to approximately 50% of violent crimes in the United States and costs the U.S. economy billions of dollars per year.

[0003] Opioid-dependent patients exhibit withdrawal symptoms soon after cessation of opioids, with the worst symptoms generally occurring 48 to 72 hours after the last opioid dose. Due to the severity and duration of withdrawal symptoms, opioid-dependent patients have a high rate of relapse.

[0004] Acute withdrawal from drug dependence is characterized by dramatic and traumatic symptoms, including sweating, racing heart, palpitations, muscle tension, tightness in the chest, difficulty breathing, tremor, nausea, vomiting, diarrhea, grand mal seizures, heart attacks, strokes, hallucinations and delirium tremens (DTs). Once acute withdrawal symptoms have subsided, post-acute withdrawal syndrome can last for months or years. Post-acute withdrawal symptoms include fatigue, depression, lack of motivation, and increased pain sensitivity.

[0005] Numerous treatments have been developed in attempts to ameliorate acute and post-acute withdrawal symptoms. However, in most cases, treatment of withdrawal requires use of other addictive substances (e.g., morphine, buprenorphine or methadone). Treatment may require that the opioid-dependent patient attend a clinic daily for an extended amount of time. [0006] There is a significant need for an effective, non-addictive treatment for opioid depdency that addresses acute and post-acute opioid withdrawal symptoms, as well as the underlying dependency, including cravings.

SUMMARY OF THE INVENTION

[0007] While the prior art suggests that ibogaine at higher doses is useful as a treatment for opioid dependency, use of ibogaine is associated with hallucinations and other negative side effects, including death. In the United States, ibogaine is classified as a Schedule I controlled substance.

[0008] Noribogaine is a metabolite of ibogaine found in human, dog, rat, and monkey. Noribogaine compounds have been suggested to have a greater and longer lasting activity in humans than ibogaine for reducing craving for addictive substances and treating chemical dependency. U.S. Patent No. 6,348,456, incorporated by reference herein in its entirety, discloses highly purified noribogaine and teaches that it should be provided at dosages from about 0.01 to about 100 mg per kg body weight per day to treat dependency.

[0009] Recent studies have shown that noribogaine reduces opioid-associated withdrawal in dependent patients at a serum level of between 50 nanograms per milliliter (ng/mL) and 180 ng/mL. Although an increase in QT interval has been observed with noribogaine treatment, the increase is concentration-dependent and mean QT interval prolongation of less than about 30 milliseconds (ms) is observed at therapeutic noribogaine plasma levels. See, for example, U.S. Patent Publication Nos. 2015/0231145, 2015/0231146, and 2015/0231147, each of which is incorporated herein by reference in its entirety.

[0010] This invention is predicated on the surprising discovery that administration to a patient of an aggregate amount of up to about 200 mg of noribogaine or pharmaceutically acceptable salt or solvate thereof per day results in a dramatic reduction of withdrawal symptoms, thereby allowing the patient to abstain from opioid abuse for a period of time. This amount, when provided as two or more doses, is sufficient to reduce withdrawal symptoms while maintaining the patient's QT interval at less than about 500 ms. This amount, when provided as two or more doses, is also sufficient to reduce withdrawal symptoms without prolonging the patient's QT interval by more than about 60 ms (compared to baseline, e.g., prior to administration of noribogaine or noribogaine derivative). In one embodiment, the patient is treated with an aggregate amount of up to about 200 mg of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof per day for between 2 and 14 days.

[0011] In one embodiment, such methods are achieved by administration of a loading (initial) dose of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof, followed by periodic administration during the day of one or more therapeutic maintenance doses. Such therapeutic maintenance doses can be continued for several days or longer until the patient is deemed suitable for discontinuation of treatment by the attending clinician.

[0012] In one embodiment, the loading dose of noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is below that dose which was found to be most efficacious as a single bolus dose in methadone-dependent patients (i.e., 120 mg). Without being bound by theory, it is believed that the loading dose provides an increase in serum concentration that is low enough to avoid unacceptable QT interval prolongation, while the therapeutic maintenance doses are sufficient to maintain an efficacious serum concentration without inducing an unacceptable QT interval prolongation.

[0013] In one embodiment, noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is administered to the patient at an aggregate dose that provides therapeutic results, a maximum QT interval prolongation of less than about 50 milliseconds (ms), and a maximum QT interval of less than 500 ms. In a preferred embodiment, the aggregate dose range is between about 50 mg and about 200 mg per day.

[0014] Without being bound by theory, it is also contemplated that, for at least a subset of opioid-dependent patients, noribogaine serum concentration is less predictive of efficacy (e.g., reduced withdrawal symptoms) than opioid metabolism. That is, patients with similar noribogaine serum concentrations may nonetheless have very different scores on one or more opiate withdrawal scales, depending on each patient's abilty to metabolize opioid(s) and eliminate them, e.g. remove the opioid(s) from the brain and/or circulatory system. [0015] Opioid metabolism varies by patient and is dependent on factors including genetics, age, ethnicity, disease (e.g., hepatic impairment, renal impairment), and sex. See, Howard S. Smith, "Opioid Metabolism," Mayo Clin. Proc. 84(7): 613-624, which is incorporated herein by reference in its entirety. For example, patients having allelic variability, mutations, or the like in one or more enzymes that are involved in the metabolic pathway for a given opioid may have altered metabolic processing of that opioid.

[0016] In one aspect, this disclosure relates to a method for treating an opioid-dependent patient being treated according to a noribogaine, or noribogaine derivative, treatment protocol, wherein said patient inefficiently, insufficiently or slowly metabolizes opioids, said method comprising selecting and/or identifying a patient that inefficiently, insufficiently or slowly metabolizes opioid, and altering the treatment protocol to include a revised treatment protocol. In one embodiment, the revised treatment protocol can be or include one or more of increasing an amount of noribogaine or noribogaine derivative administered, increasing a duration of noribogaine or noribogaine derivative

administration, co-administering an opioid antagonist or partial opioid antagonist, and combinations thereof. It should be understood that the identifying or selecting can be done in response to a clinician (e.g., a nurse, a physician's assistant, a physician, a medical provider for dependent patients, and the like) determining that the patient is a slow or inefficient metabolizer and/or that the patient continues to have high levels of opioid in the brain or body (e.g., high enough to at least partially counteract an effect of noribogaine or noribogaine derivative). Those high opioid levels can result in a more challenging experience while receiving the noribogaine treatment. Furthermore, the identifying can include the use of urine, blood or other assays to determine quantities or levels of opioid in the system of the patient.

[0017] In one embodiment, the opioid antagonist is naloxone. In one embodiment, the opioid antagonist is naltrexone. In one embodiment, the opioid antagonist is nalmefene. In one embodiment, the opioid antagonist is nalorphine. In one embodiment, the opioid antagonist is naloxone, levallorphan, cyprodime, naltrindole, or norbinaltorphimine

[0018] In one aspect is provided a method for treating opioid drug abuse in an opioid- dependent human patient, the method comprising administering to the patient a therapeutic dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the therapeutic dosage is between about 60 mg and about 200 mg per day, wherein the therapeutic dosage is administered as at least two subdoses, thereby inhibiting or ameliorating said abuse while maintaining a QT interval in the patient of less than about 500 ms during said treatment.

[0019] In some embodiments, the method comprises:

a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose is between about 50 mg and about 120 mg; and

b) administering at least one therapeutic maintenance dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the at least one therapeutic maintenance dose is between about 5 mg and about 50 mg.

[0020] In some embodiments, the method further comprises administering an effective amount of an opioid antagonist or partial antagonist. In one embodiment, the opioid antagonist or partial antagonist is administered concurrently with noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof. In one embodiment, the opioid antagonist or partial antagonist is administered after administration of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof. In one embodiment, the opioid antagonist or partial antagonist is naloxone, nalmefene, naltrexone, nalorphine, levallorphan, cyprodime, naltrindole, or norbinaltorphimine.

[0021] In some aspects is provided a method for treating an opioid-dependent patient being treated according to a noribogaine or noribogaine derivative treatment protocol, wherein the patient insufficiently metabolizes opioid, said method comprising identifying the patient that insufficiently metabolizes opioid, and altering the treatment protocol to include a revised protocol. In some embodiments, the noribogaine or noribogaine derivative is in salt and/or solvate form. In some embodiments, the revised protocol includes increasing the amount of noribogaine or noribogaine derivative administered. In some embodiments, the revised protocol includes increasing the amount of time of noribogaine or noribogaine derivative administration. In some embodiments, the revised protocol includes co-administering an opioid antagonist or partial opioid antagonist with the noribogaine or noribogaine derivative. In some embodiments, the revised protocol includes a combination of these revisions.

[0022] In some embodiments, insufficient metabolism refers to a decrease in opioid level by less than 90% over 1 to 2 days.

[0023] In some embodiments, the opioid antagonist is naloxone, nalmefene, naltrexone, nalorphine, levallorphan, cyprodime, naltrindole, or norbinaltorphimine. In a preferred embodiment, the opioid antagonist is naloxone.

[0024] In some embodiments, the noribogaine or noribogaine derivative treatment protocol comprises administering to the patient a therapeutic dosage of noribogaine, noribogaine, noribogaine derivative or pharmaceutically acceptable salt or solvate thereof, such that the therapeutic dosage is between about 60 mg and about 200 mg per day.

[0025] In some embodiments, the patient has an acceptable risk level for QT interval prolongation.

[0026] In some embodiments, the average serum concentration of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is maintained between about 30 ng/mL and about 180 ng/mL during the treatment period.

[0027] In preferred embodiments, the patient does not exhibit QT interval prolongation of more than 60 ms.

[0028] In some embodiments, at least one withdrawal symptom is attenuated.

[0029] In some aspects is provided a method for treating an opioid-dependent patient being treated according to a noribogaine or noribogaine derivative treatment protocol, the method comprising:

periodically administering to the patient a unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof;

monitoring an initial opioid level and one or more subsequent periodic opioid levels of the patient; and

modifying the treatment protocol. In some embodiments, the protocol is modified by increasing the amount of noribogaine or noribogaine derivative, prolonging the noribogaine or noribogaine derivative treatment, adding naloxone, and/or reducing the amount of the periodic unit dose when a subsequent opioid level falls below at least about 10% of the initial opioid level.

[0030] In one embodiment, the modified protocol is performed until the patient is substantially free of opioids. In one embodiment, the treatment protocol is modified by reducing the amount of the periodic unit dose when the opioid level falls below at least about 10% of the initial opioid level or where the patient is substantially free of opioid in his or her system.

[0031] In some embodiments, the method further comprises monitoring at least one indicator of withdrawal and modifying the treatment protocol based on the at least one indicator, such that noribogaine or noribogaine derivative treatment is modified by reducing the amount of the periodic unit dose when the indicator indicates substantially no withdrawal.

[0032] In one aspect is provided a method for treating an opioid-dependent patient being treated according to a noribogaine or noribogaine derivative treatment protocol, wherein said patient has insufficient metabolization of opioid, said method comprising selecting a patient that has insufficient metabolization of opioid and altering the treatment protocol to include co-administration of an opioid antagonist, such as naloxone. In one embodiment, insufficient metabolism refers to a decrease in opioid level in the brain by less than 90% over 1 to 2 days. In one embodiment, insufficient metabolism refers to the patient not having beeing substantially free of opioid or to the patient not having had a majority of opioid released from his/her system. In one embodiment, the substantial freedom from opioid or the opioid in the system can be determined by assessing the amount of opioid released into plasma or urine, or as otherwise determined by a clinician.

[0033] In some embodiments, the opioid antagonist is administered after at least a first dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered. In some embodiments, the opioid antagonist is administered concurrently with at least one dose of noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof. In some embodiments, the opioid antagonist is administered at a sub-therapeutic dose. [0034] In some embodiments, at least one indicator of withdrawal symptoms and/or mood state is measured prior to and at least one time during treatment with noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof. In some embodiments, at least one indicator of withdrawal symptoms is selected from the group consisting of Clinical Opiate Withdrawal Scale (COWS), Subjective Opiate Withdrawal Scale (SOWS), Objective Opiate Withdrawal Scale (OOWS), and Profile of Mood States (POMS). In one embodiment, the patient reports no urge to use the opioid for at least one day after cessation of treatment with noribogaine, noribogaine derivative, or

pharmaceutically acceptable salt or solvate thereof.

[0035] In some embodiments, the opioid is buprenorphine. In a preferred embodiment, the patient has not used buprenorphine for at least 5 days prior to treatment with noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof.

[0036] In especially preferred embodiments, the patient has no history of methadone use within the previous 10 days to about 3 weeks. In other preferred embodiments, the patient has no history of buprenorphine use within the previous 10 days to about 3 weeks.

[0037] In one aspect is provided a method for pretreating an opioid-dependent patient scheduled for treatment with an opioid antagonist, which method comprises administering noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof to said patient in an amount sufficient to attenuate withdrawal symptoms and to allow the patient to be opioid-free for a period of time prior to initiation of opioid antagonist administration. In a preferred embodiment, the patient is opioid-free for at least 7 days prior to initiation of opioid antagonist administration.

[0038] In some embodiments, the method comprises:

a) administering an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the initial dose is between about 50 mg and about 120 mg; and

b) administering at least one therapeutic maintenance dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the at least one therapeutic maintenance dose is between about 5 mg and about 50 mg. [0039] In some embodiments, the at least one therapeutic maintenance dose is administered from about 6 hours to about 24 hours after the initial dose.

[0040] In some embodiments, the opioid antagonist is selected from the group consisting of nalmefene, naltrexone, nalorphine, levallorphan, cyprodime, naltrindole, and norbinaltorphimine.

[0041] In preferred embodiments, the amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof administered is between about 60 mg and about 200 mg per day.

[0042] In especially preferred embodiments, a QT interval of less than about 500 ms is maintained in the patient during said treatment. In preferred embodiments, administration of noribogaine or noribogaine derivative does not result in a maximum QT interval prolongation of more than about 60 ms. More preferably, administration of noribogaine or noribogaine derivative does not result in a maximum QT interval prolongation of more than about 50 ms.

[0043] In some embodiments, the average serum concentration of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is maintained between about 20 ng/mL and about 180 ng/mL during the treatment period.

[0044] In some embodiments, at least two therapeutic maintenance doses are administered, and further wherein the therapeutic maintenance doses are administered from about 6 hours to about 24 hours after the previous dose.

[0045] In some embodiments, at least one withdrawal symptom is attenuated. In some embodiments, the at least one withdrawal symptom is a symptom of acute withdrawal.

[0046] In some aspects is provided a method for treating an opioid-dependent patient with an opioid antagonist which method comprises: identifying and/or selecting an opioid- dependent patient who has been pretreated with noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof so as to be opioid-free for at least 7 days, and then administering the opioid antagonist in a sufficient amount to inhibit a pharmacological effect of opioids in the patient. In some embodiments, the opioid antagonist is nalmefene, naltrexone, nalorphine, levallorphan, cyprodime, naltrindole, or norbinaltorphimine. In some embodiments, the opioid antagonist is in a controlled-release formulation.

[0047] In some embodiments, the opioid antagonist is orally administered. In some embodiments, the opioid antagonist is administered by injection.

[0048] In some embodiments, relapse of opioid use by the patient is inhibited.

[0049] In some embodiments, the method further comprises checking for opioid detoxification in the patient by naloxone challenge and/or a urine test prior to

administration of the opioid antagonist.

[0050] In some aspects is provided a method for opioid detoxification of an opioid- dependent patient prior to treatment with an opioid antagonist, which method comprises administering noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof to said patient for a time sufficient for the patient not to have opioids in his/her body prior to initiation of opioid antagonist administration.

[0051] In some aspects is provided a kit of parts comprising a plurality of unit doses of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, and at least one unit dose of an opioid antagonist or partial antagonist.

[0052] In some embodiments, the opioid antagonist is naloxone. In some embodiments, the unit dose of naloxone is formulated for intravenous, subcutaneous, and/or

intramuscular injection.

[0053] In some embodiments, the opioid antagonist is nalmefene, naltrexone, nalorphine, levallorphan, cyprodime, naltrindole, or norbinaltorphimine.

[0054] In some aspects is provided a pharmaceutical formulation comprising a dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof and an effective amount of an opioid antagonist. In some embodiments, the opioid antagonist is naloxone, nalmefene, naltrexone, nalorphine, levallorphan, cyprodime, naltrindole, or norbinaltorphimine. In some embodiments, the dose of noribogaine is between about 5 mg and about 100 mg. BRIEF DESCRIPTION OF THE DRAWINGS

[0055] FIG. 1 shows noribogaine plasma concentrations over time for each patient in a clinical study.

[0056] FIG. 2A shows the change in Subjective Opioid Withdrawal Scale (SOWS) (area under the curve, AUC) versus noribogaine plasma concentration (AUC) at 3 hours after initial noribogaine administration.

[0057] FIG. IB shows the change in SOWS (AUC) versus noribogaine plasma concentration (AUC) at 36 hours after initial noribogaine administration.

[0058] FIG. 2C shows the change in SOWS (AUC) versus noribogaine plasma concentration (AUC) at 60 hours after initial noribogaine administration.

[0059] FIGs. 3A-3I show total SOWS over time compared to urine opioid levels for each patient.

[0060] FIG. 4 shows the correlation between urine opioid levels and plasma opioid levels.

[0061] FIG. 5 shows mean SOWS score over time. Noribogaine treatment lasted up to 120 hours, followed by 48 hours of observation after the last dose.

[0062] FIG. 6 shows mean scores for SOWS question #16: "I feel like using now."

[0063] FIG. 7 shows mean Profile of Mood States (POMS) Total Mood Disturbance Scores for the first 7 subjects.

DETAILED DESCRIPTION OF THE INVENTION

[0064] 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. [0065] 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.

[0066] 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

[0067] 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.

[0068] 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 ( - ) 10 %, 5 % or 1 %.

[0069] "Administration" refers to introducing an agent 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 may be administered by direct blood stream delivery, e.g. sublingual, intranasal, or intrapulmonary administration.

[0070] 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 administered 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. Administration may be via transdermal patch, gum, lozenge, sublingual tablet, intranasal, intrapulmonary, oral administration, or other administration.

[0071] "Periodic administration" or "periodically administering" refers to administration of noribogaine, noribogaine derivative, or salt or solvate thereof one, two, three, or more times per day. Periodic administration may also refer to multiple treatments that occur on a daily, weekly, or monthly basis.

[0072] "Therapeutic maintenance dose" is the dose of drug that is administered on a periodic basis so as to maintain therapeutic serum concentrations of the drug in the patient.

[0073] "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.

[0074] 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 (CH ₃ -), ethyl

(CH ₃ CH ₂ -), ^-propyl (CH ₃ CH ₂ CH ₂ -), isopropyl ((CH ₃ ) ₂ CH-), w-butyl (CH ₃ CH ₂ CH ₂ CH ₂ -), isobutyl ((CH ₃ ) ₂ CHCH ₂ -), sec-butyl ((CH ₃ )(CH ₃ CH ₂ )CH-), r-butyl ((CH ₃ ) ₃ C-), w-pentyl (CH ₃ CH2CH ₂ CH ₂ CH2-), and neopentyl ((CH ₃ ) ₃ CCH ₂ -). The term "C _x alkyl" refers to an alkyl group having x carbon atoms, wherein x is an integer, for example, C ₃ refers to an alkyl group having 3 carbon atoms.

[0075] "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.

[0076] "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 (-CH ₂ C≡CH).

[0077] "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, SO ₃ H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.

[0078] "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, S0 ₃ H, 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.

[0079] "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, SO ₃ H, 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.

[0080] "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.

[0081] "Substituted alkoxy" refers to the group -0-(substituted alkyl) wherein substituted alkyl is defined herein.

[0082] "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 CH ₃ C(0)-.

[0083] "Acylamino" refers to the groups -NR ⁸ C(0)alkyl, -NR ⁸ C(0)substituted alkyl, -NR ⁸ C(0)cycloalkyl, -NR ⁸ C(0)substituted

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

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

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

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

aryl, -NR ⁸ C(0)heteroaryl, -NR ⁸ C(0)substituted heteroaryl, -NR ⁸ C(0)heterocyclic, and -NR ⁸ C(0)substituted heterocyclic wherein R ³⁸ 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.

[0084] "Acyloxy" refers to the groups alkyl-C(0)0-, substituted alkyl-C(0)0-, alkenyl-C(0)O, substituted alkenyl-C(0)0-, alkynyl-C(0)0-, 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.

[0085] "Amino" refers to the group -NH ₂ .

[0086] "Substituted amino" refers to the group -NR ⁹ R ⁴⁰ where R ³⁹ and R ⁴⁰ 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, -SCh-alkyl, -S0 ₂ -substituted

alkyl, -S0 ₂ -alkenyl, -S0 ₂ -substituted alkenyl, -S0 ₂ -cycloalkyl, -S0 ₂ -substituted cylcoalkyl, -S0 ₂ -cycloalkenyl, -S0 ₂ -substituted cylcoalkenyl,-S0 ₂ -aryl, -S0 ₂ -substituted aryl, -SC -heteroaryl, -S02-substituted heteroaryl, -S02-heterocyclic, and -S02-substituted heterocyclic and wherein R ³⁹ and R ⁴⁰ are optionally joined, together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, provided that R ³⁹ and R ⁴⁰ 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 R ³⁹ is hydrogen and R ⁴⁰ is alkyl, the substituted amino group is sometimes referred to herein as alkylamino. When R ³⁹ and R ⁴⁰ are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino. When referring to a monosubstituted amino, it is meant that either R ³⁹ or R ⁴⁰ is hydrogen but not both. When referring to a disubstituted amino, it is meant that neither R ³⁹ nor R ⁴⁰ are hydrogen.

[0087] "Aminocarbonyl" refers to the group -C(0)NR ⁴¹ R ⁴² where R ⁴¹ and R ⁴² 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 R ⁴¹ and R ⁴² 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.

[0088] "Aminothiocarbonyl" refers to the group -C(S)NR ⁴¹ R ⁴² where R ⁴¹ and R ⁴² 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 R ⁴¹ and R ⁴² 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.

[0089] "Aminocarbonylamino" refers to the group -NR ⁸ C(0)NR ⁴¹ R ⁴² where R ³⁸ is hydrogen or alkyl and R ⁴¹ and R ⁴² 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 R ⁴¹ and R ⁴² 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.

[0090] "Aminothiocarbonylamino" refers to the group -NR ⁸ C(S)NR ⁴¹ R ⁴² where R ³⁸ is hydrogen or alkyl and R ⁴¹ and R ⁴² 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 R ⁴¹ and R ⁴² 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.

[0091] "Aminocarbonyloxy" refers to the group -0-C(0)NR ⁴¹ R ⁴² where R ⁴¹ and R ⁴² 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 R ⁴¹ and R ⁴² 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.

[0092] "Aminosulfonyl" refers to the group -S0 ₂ NR ⁴¹ R ⁴² where R ⁴¹ and R ⁴² 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 R ⁴¹ and R ⁴² 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.

[0093] "Aminosulfonyloxy" refers to the group -0-S0 ₂ NR ⁴¹ R ⁴² where R ⁴¹ and R ⁴² 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 R ⁴¹ and R ⁴² 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.

[0094] "Aminosulfonylamino" refers to the group -NR ⁸ -S0 ₂ NR ⁴¹ R ⁴² where R ³⁸ is hydrogen or alkyl and R ⁴¹ and R ⁴² 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 R ⁴¹ and R ⁴² 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.

[0095] "Amidino" refers to the group -C(=NR ⁴ )NR ⁴¹ R ⁴² where R ⁴¹ , R ⁴² , and R ⁴³ 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 R ⁴¹ and R ⁴² 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.

[0096] "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.

[0097] "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, SO ₃ H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.

[0098] "Aryloxy" refers to the group -0-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.

[0099] "Substituted aryloxy" refers to the group -0-(substituted aryl) where substituted aryl is as defined herein.

[0100] "Arylthio" refers to the group -S-aryl, where aryl is as defined herein.

[0101] "Substituted arylthio" refers to the group -S -(substituted aryl), where substituted aryl is as defined herein.

[0102] "Carbonyl" refers to the divalent group -C(O)- which is equivalent to -C(=0)-. [0103] "Carboxy" or "carboxyl" refers to -COOH or salts thereof. [0104] "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.

[0105] "(Carboxyl ester)amino" refers to the

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

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

heteroaryl, -NR ⁸ -C(0)0-heterocyclic, and -NR ⁸ -C(0)0-substituted heterocyclic wherein R ³⁸ 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.

[0106] "(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.

[0107] "Cyano" refers to the group -CN.

[0108] "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, norbornyl, and spirobicyclo groups such as spiro[4.5]dec-8-yl.

[0109] "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. [0110] "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, SO ₃ H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.

[0111] "Cycloalkyloxy" refers to -O-cycloalkyl.

[0112] "Substituted cycloalkyloxy" refers to -0-(substituted cycloalkyl).

[0113] "Cycloalkylthio" refers to -S-cycloalkyl.

[0114] "Substituted cycloalkylthio" refers to -S-(substituted cycloalkyl).

[0115] "Cycloalkenyloxy" refers to -O-cycloalkenyl.

[0116] "Substituted cycloalkenyloxy" refers to -0-(substituted cycloalkenyl).

[0117] "Cycloalkenylthio" refers to -S-cycloalkenyl.

[0118] "Substituted cycloalkenylthio" refers to -S -(substituted cycloalkenyl).

[0119] "Guanidino" refers to the group -NHC(=NH)NH ₂ .

[0120] "Substituted guanidino" refers to -NR ⁴⁴ C(=NR ⁴⁴ )N(R ⁴⁴ ) ₂ where each R ⁴⁴ is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and two R ⁴⁴ 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 R ⁴⁴ is not hydrogen, and wherein said substituents are as defined herein.

[0121] "Halo" or "halogen" refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.

[0122] "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.

[0123] "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.

[0124] "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.

[0125] "Hydroxy" or "hydroxyl" refers to the group -OH.

[0126] "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.

[0127] "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.

[0128] "Heteroaryloxy" refers to -O-heteroaryl.

[0129] "Substituted heteroaryloxy" refers to the group -0-(substituted heteroaryl). [0130] "Heteroarylthio" refers to the group -S-heteroaryl.

[0131] "Substituted heteroarylthio" refers to the group -S-(substituted heteroaryl).

[0132] "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.

[0133] "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.

[0134] "Heterocyclyloxy" refers to the group -O-heterocycyl.

[0135] "Substituted heterocyclyloxy" refers to the group -0-(substituted heterocycyl).

[0136] "Heterocyclylthio" refers to the group -S-heterocycyl.

[0137] "Substituted heterocyclylthio" refers to the group -S-(substituted heterocycyl).

[0138] 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-tetrahy droisoquinoline, 4,5,6,7-tetrahy drobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, and tetr ahy drofurany 1. [0139] "Nitro" refers to the group -N0 ₂ .

[0140] "Oxo" refers to the atom (=0) or (-0 ^" ).

[0141] "Spiro ring systems" refers to bicyclic ring systems that have a single ring carbon atom common to both rings.

[0142] "Sulfonyl" refers to the divalent group -S(0) ₂ -.

[0143] "Substituted sulfonyl" refers to the group -SC^-alkyl, -S0 ₂ -substituted alkyl, -S0 ₂ -alkenyl, -SC^-substituted alkenyl, -SCVcycloalkyl, -S0 ₂ -substituted cylcoalkyl, -SC^-cycloalkenyl, -S0 ₂ -substituted cylcoalkenyl, -SCh-aryl, -S0 ₂ -substituted aryl, -S0 ₂ -heteroaryl, -S0 ₂ -substituted heteroaryl, -S0 ₂ -heterocyclic, -S0 ₂ -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-S0 ₂ -, phenyl-SCV, and 4-methylphenyl-S02-. The term "alkylsulfonyl" refers to -S0 ₂ -alkyl. The term "haloalkylsulfonyl" refers to -SCh-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.

[0144] "Sulfonyloxy" refers to the group -OS0 ₂ -alkyl, -OS0 ₂ -substituted

alkyl, -OSC^-alkenyl, -OS0 ₂ -substituted alkenyl, -OS0 ₂ -cycloalkyl, -OS0 ₂ -substituted cylcoalkyl, -OS0 ₂ -cycloalkenyl, -OS0 ₂ -substituted

cylcoalkenyl,-OS0 ₂ -aryl, -OS0 ₂ -substituted aryl, -OS0 ₂ -heteroaryl, -OS0 ₂ -substituted heteroaryl, -OSCh-heterocyclic, -OS0 ₂ -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.

[0145] "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.

[0146] "Thiol" refers to the group -SH.

[0147] "Thiocarbonyl" refers to the divalent group -C(S)- which is equivalent to -C(=S)-.

[0148] "Thione" refers to the atom (=S).

[0149] "Alkylthio" refers to the group -S-alkyl wherein alkyl is as defined herein.

[0150] "Substituted alkylthio" refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein.

[0151] "Compound" or "compounds" as used herein is meant to include the stereoiosmers and tautomers of the indicated formulas.

[0152] "Stereoisomer" or "stereoisomers" refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.

[0153] "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.

[0154] 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.

[0155] 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.

[0156] As used herein, the term "monophosphate" refers to the group -P(0)(OH) ₂ . [0157] As used herein, the term "diphosphate" refers to the group -P(0)(OH)- OP(0)(OH) ₂ .

[0158] As used herein, the term "triphosphate" refers to the group -P(0)(OH)- (OP(0)(OH)) ₂ OH.

[0159] 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)(OR ⁴⁵ )2, where each R ⁴⁵ is independently hydrogen, C1-C12 alkyl, C3-C10 cycloalkyl, C6-C14 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 R ⁴⁵ is not hydrogen. Likewise, exemplary esters of the di- or triphosphate can be represented by the formulas -P(0)(OR ⁴⁵ )-OP(0)(OR ⁴⁵ ) ₂

and -P(0)(OR ⁴⁵ )-(OP(0)(OR ⁴⁵ )) ₂ OR ⁴⁵ , where R ⁴⁵ is as defined above.

[0160] 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(0)NR ⁴⁶ - or -NR ⁴⁶ C(0)-), or a phosphate-linker (-P(0)(OR ⁴⁶ )-0-, -0-P(S)(OR ⁴⁶ )-0-, - 0-P(S)(SR ⁴⁶ )-0-, -S-P(0)(OR ⁴⁶ )-0-, -0-P(0)(OR ⁴⁶ )-S-, -S-P(0)(OR ⁴⁶ )-S- , -0-P(S)(OR ⁴⁶ )-S-, -S-P(S)(OR ⁴⁶ )-0-, -0-P(0)(R ⁴⁶ )-0-, -0-P(S)(R ⁴⁶ )-0- , -S-P(0)(R ⁴⁶ )-0-, -S-P(S)(R ⁴⁶ )-0-, -S-P(0)(R ⁴⁶ )-S-, or -0-P(S)(R ⁴⁶ )-S-) where R ⁴⁶ can be hydrogen or alkyl.

[0161] 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.

[0162] "Noribogaine" refers to the compound: as well as noribogaine derivatives or pharmaceutically acceptable salts and

pharmaceutically acceptable solvates thereof. It should be understood that where

"noribogaine" is mentioned herein, one more polymorphs of noribogaine can be utilized and are contemplated. In some embodiments, noribogaine is noribogaine glucuronide. In some embodiments, noribogaine does not refer to noribogaine derivatives, although in such embodiments noribogaine may still refer to solvates and/or salts of noribogaine.

[0163] Noribogaine can be prepared by demethylation of naturally occurring ibogaine:

which is isolated from Tabernanthe iboga, a shrub of West Africa. 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, and PCT Patent Publication No. WO 2013/040471 (includes description of making noribogaine polymorphs), each of which is incorporated herein by reference in its entirety.

[0164] "Noribogaine derivatives" refer to esters or O-carbamates of noribogaine, or pharmaceutically acceptable salts and/or solvates 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 U.S. Patent Nos. 6,348,456; 8,362,007; and 8,741,891 ; as well as in U.S. Patent Application Publication Nos. US2015/0231146; US2014/0315891; US2013/0131046; US2013/0165647; US2013/0165425; and US2013/0165414; each of which is incorporated herein by reference in its entirety.

[0165] In some embodiments, the methods of the present disclosure entail the administration of a prodrug of noribogaine. 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 K 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.

[0166] This invention is not limited to any particular chemical form of noribogaine, and the drug may be given to patients either as a free base, solvate, 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.

[0167] "Pharmaceutically acceptable composition" refers to a composition that is suitable for administration to a human. Such compositions include various excipients, diluents, carriers, and such other inactive agents well known to the skilled artisan.

[0168] "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. [0169] "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 or solvate 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 noribogaine or noribogaine derivative, in the context of treating opioid drug dependency, refers to an amount of noribogaine or noribogaine derivative that attenuates the physical dependency and/or symptoms of acute withdrawal for at least about 2 hours beyond control (placebo), at least about 5 hours beyond control, preferably at least about 10 hours beyond control, and more preferably at least about 15 hours beyond control. In an especially preferred embodiment, a therapeutically effective amount of noribogaine or noribogaine derivative attenuates the physical dependency and/or symptoms of acute withdrawal for at least about 24 hours or at least about 48 hours. In one embodiment, a therapeutically effective amount of noribogaine or noribogaine derivative, in the context of treating opioid drug dependency, refers to an amount of noribogaine or noribogaine derivative that reduces withdrawal symptoms (e.g., as determined by evaluation on an opioid withdrawal scale) for at least about 2 hours, 5 hours, 10 hours, 24 hours, or 48 hours. In one embodiment, a

therapeutically effective amount of noribogaine or noribogaine derivative, in the context of treating opioid drug dependency, refers to an amount of noribogaine or noribogaine derivative that reduces cravings for the opioid of dependency for at least about 2 hours, 5 hours, 10 hours, 24 hours, or 48 hours. In one embodiment, a therapeutically effective amount of noribogaine or noribogaine derivative, in the context of treating opioid drug dependency, refers to an amount of noribogaine or noribogaine derivative that improves mood of the patient for at least about 2 hours, 5 hours, 10 hours, 24 hours, or 48 hours. [0170] A "therapeutic level" of a drug is an amount of noribogaine, noribogaine derivative, or pharmaceutical salt or solvate thereof that is sufficient to treat opioid drug dependency or to treat, prevent, or attenuate acute withdrawal symptoms, 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. " Where the serum concentration of noribogaine is mentioned, it is to be understood that the term "noribogaine" encompasses any form of noribogaine, including derivatives thereof.

[0171] The term "noribogaine treatment protocol" refers to a treatment protocol for administration of noribogaine or derivative that provides a therapeutic aggregate dose of noribogaine (or derivative, or salt or solvate thereof) such that the patient's QT interval is expected to remain below about 500 ms, and preferably below about 470 ms. An alternate protocol is the treatment protocol that is changed based on the factors described herein (e.g., inefficient/insufficient opioid metabolism, clearance of opioid from the body, etc.).

[0172] The term "dose" refers to a range of noribogaine, noribogaine derivative, or pharmaceutical salt or solvate thereof that provides a therapeutic serum level of noribogaine or noribogaine derivative 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 dependency, health, and other relevant factors, all of which are well within the skill of the art.

[0173] The term "aggregate dosage" refers to a combined dosage, for example the total amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof administered over a 24-hour period, where smaller amounts are administered more than once per day.

[0174] 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 the 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.

[0175] "Treatment," "treating," and "treat" are defined as acting upon a disease, disorder, or condition with an agent 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 opioid drug dependency; treating, preventing, eliminating, and/or attenuating acute withdrawal symptoms; treating, preventing, and/or attenuating long-term (post-acute) withdrawal symptoms; treating, preventing, eliminating, and/or attenuating cravings; and preventing relapse of opioid drug use.

[0176] As used herein, the term "patient" refers to humans.

[0177] As used herein, the term "opiate" refers to naturally-occurring alkaloids found in the opium poppy. These include codeine, morphine, oripavine, pseudomorphine, and thebaine. Also included are opium, opium poppy, poppy straw, and extracts and concentrates thereof.

[0178] As used herein, the term "opioid" refers to naturally-occurring opiates and synthetic or semi-synthetic opioids that have psychoactive effects. Non-limiting examples include acetyl-alpha-methylphentanyl, acetylmethadol, alfentanil, allylprodine, alphacetylmethadol, alphamethadol, alpha-methylfentanyl, alpha-methylthiofentanyl, alphaprodine, anileridine, benzylmorphine, benzethidine, betacetylmethadol, beta- hydroxyfentanyl, beta-hydroxy-3-methylfentanyl, betameprodine, betacetylmethadol, beta-hydroxyfentanyl, beta-hydroxy-3-methylfentanyl, betameprodine, betamethadol, betaprodine, bezitramide, buprenorphine, butorphanol, carfentanil, clonitazene, codeine, desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide, diamorphone, diethylthiambutene, dihydrocodeine, dihydroetorphine, dihydromorphine, dimenoxadol, dimepheptanol, dimethyl- thiambutene, dioxaphetyl butyrate, diphenoxylate, difenoxin, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine, etoxeridine, fentanyl, furethidine, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levo- alphacetylmethadol, levomethorphan, levorphanol, levophenacylmorphan, levomoramide, lofentanil, loperamide, laudanum, meperidine, meptazinol, metazocine, methadone, 3- methylfentanyl, 3-methylthiofentanyl, metopon, morphine, morpheridine, MPPP (1- methyl-4-phenyl-4-propionoxypiperidine), myrophine, narceine, nicomorphine, noracymethadol, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, para-fluorofentanyl, paregoric, PEPAP (l-(-2-phenethyl)-4-phenyl-4-acetoxypiperidine), pentazocine, phenadoxone, phenampromide, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene,

racemoramide, racemetho han, racemorphan, remifentanil, sufentanil, tapentadol, thiofentanyl, tilidine, tramadol, trimeperidine, mixtures of any of the foregoing, salts of any of the foregoing, derivatives of any of the foregoing, and the like. The term opioids also encompasses opioid intermediates, including 4-cyano-2-dimethylamino-4,4-diphenyl butane, 2-methyl-3-mo holino-l,l-diphenylpropane-carboxylic acid, 4-cyano-l-methyl- 4-phenylpiperidine, ethyl-4-phenylpiperidine-4-carboxylate, and l-methyl-4- phenylpiperidine-4-carboxylic acid. Many opioids are Schedule I or Schedule II drugs in the US. In some embodiments, one or more of the above-listed opioids can be specifically excluded.

[0179] 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.

[0180] As used herein, a "patient who has been evaluated for acceptable QT interval prolongation", "patient at low risk for QT interval prolongation" and the like refers to a patient who has been pre-screened by a clinician and determined to have an acceptably low risk for QT interval prolongation. Exemplary criteria for pre-screening are described herein, including history of using drugs that are known to prolong QT interval in at least a subset of patients (e.g., cocaine, methadone, and a number of prescription drugs), personal or familial history of cardiac conditions (including long QT syndrome), and a longer-than- average QT interval. A continuously updated list of medications that are known to cause a prolongation of the QT interval is maintained at www.crediblemeds.org. In one embodiment, the patient is prescreened by treatment with a low dose of noribogaine, noribogaine derivative, or salt or solvate thereof and the patient's QT interval is evaluated for a period of time to determine whether a therapeutic amount of the drug would result in an unacceptable QT interval in that patient. In one embodiment, a patient who previously exhibited unacceptable QT interval prolongation upon treatment with ibogaine, noribogaine, noribogaine derivative, or salt or solvate thereof is deemed to have an unacceptable risk of QT interval prolongation.

[0181] As used herein, the terms "addiction" and "dependence" are used interchangeably to refer to the patient's inability to stop using the opioid, even when it would be in his/her best interest to stop. The DSM-5 criteria for opioid dependency include:

A problematic partem of opioid use leading to clinically significant

impairment or distress, as manifested by at least two of the

following, occurring within a 12-month period:

• Opioids are often taken in larger amounts or over a longer period than was intended.

• There is a persistent desire or unsuccessful efforts to cut down or control opioid use.

• A great deal of time is spent in activities necessary to obtain the opioid, use the opioid, or recover from its effects.

• Craving, or a strong desire or urge to use opioids.

• Recurrent opioid use resulting in a failure to fulfill major role obligations at work, school, or home.

• Continued opioid use despite having persistent or recurrent social or

interpersonal problems caused or exacerbated by the effects of opioids.

• Important social, occupational, or recreational activities are given up or

reduced because of opioid use.

• Recurrent opioid use in situations in which it is physically hazardous. • Continued opioid use despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance.

• Tolerance, as defined by either of the following:

o A need for markedly increased amounts of opioids to achieve intoxication or desired effect.

o A markedly diminished effect with continued use of the same amount of an opioid.

• Withdrawal, as manifested by either of the following:

o The characteristic opioid withdrawal syndrome (refer to Criteria A and B of the criteria set for opioid withdrawal),

o Opioids (or a closely related substance) are taken to relieve or avoid

withdrawal symptoms.

[0182] The term "solvate" as used herein refers to complexes with solvents in which noribogaine, or noribogaine derivative, is reacted or from which noribogaine, or noribogaine derivative, is precipitated or crystallized. For example, a complex with water is known as a "hydrate". Solvates of noribogaine and noribogaine derivatives 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 noribogaine, noribogaine derivative, or the pharmaceutically acceptable solvates thereof are within the scope of the present invention.

II. Compositions of the Invention

[0183] As will be apparent to the skilled artisan upon reading this disclosure, this invention provides compositions for treating substance abuse in a subject, comprising noribogaine, noribogaine derivatives, prodrugs of noribogaine, pharmaceutically acceptable salts and/or solvates of each thereof. This invention further provides compositions for treating, attenuating, or preventing withdrawal symptoms in a drug- dependent subject, comprising noribogaine, noribogaine derivatives, prodrugs of noribogaine, pharmaceutically acceptable salts and/or solvates of each thereof. [0184] In some embodiments, the composition comprises a noribogaine derivative. Noribogaine derivatives include, without limitation, those compounds set forth in U.S. Patent Nos. 6,348,456; 8,362,007; and 8,741,891 ; as well as in U.S. Patent Application Publication Nos. US2014/0315891; US2013/0131046; US2013/0165647;

US2013/0165425; and US2013/0165414; each of which is incorporated herein by reference in its entirety.

[0185] In some embodiments, the composition is formulated for oral, transdermal, internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial,

intramuscular, intraperitoneal, intracutaneous or subcutaneous delivery.

[0186] In one embodiment, the noribogaine derivative is represented by Formula 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.

[0187] Generally, in the above formula, R is hydrogen or a group of the formula:

O

II wherein X is a C1-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. [0188] 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 0-, m- or p-methyl or methoxy benzyl groups.

[0189] C1-C12 groups include C1-C12 alkyl, C3-C12 cycloalkyl, C ₆ -Ci ₂ 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.

[0190] 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;

R ¹ is halo, OR ² , or C1-C12 alkyl optionally substituted with 1 to 5 R ;

R ² 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 R ¹⁰ , and each R ^y is independently selected from the group consisting of hydrogen, C1-C6 alkyl optionally substituted with 1 to 5 R ¹⁰ , C6-C14 aryl optionally substituted with 1 to 5 R ¹⁰ , C3-C1 ₀ cycloalkyl optionally substituted with 1 to 5 R ¹⁰ , Ci-Cio heteroaryl having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R ¹⁰ , C1-C1 ₀ heterocyclic having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R ¹⁰ , 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 R ¹⁰ or a C1-C6 heteroaryl having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R ¹⁰ ; R ³ is selected from the group consisting of hydrogen, C1-C12 alkyl optionally substituted with 1 to 5 R ¹⁰ , aryl optionally substituted with 1 to 5 R ¹⁰ , - C(0)R ⁶ , -C(0)NR ⁶ R ⁶ and -C(0)OR ⁶ ;

R ⁴ is selected from the group consisting of hydrogen, -(CH ₂ ) _m OR ⁸ , -

CR ⁷ (OH)R ⁸ , -(CH ₂ ) _m CN, -(CH ₂ ) _m COR ⁸ , -(CH ₂ ) _m C0 ₂ R ⁸ , -(CH ₂ ) _m C(0)NR ⁷ R ⁸ , -(CH ₂ ) _m C(0)NR ⁷ NR ⁸ R ⁸ , -(CH ₂ ) _m C(0)NR ⁷ NR ⁸ C(0)R ⁹ ,

and -(CH ₂ ) _m NR ⁷ R ⁸ ;

m is 0, 1, or 2;

L is a bond or Ci-Ci ₂ alkylene;

R ⁵ is selected from the group consisting of hydrogen, Ci-Ci ₂ alkyl substituted with 1 to 5 R ¹⁰ , Ci-Ci ₂ alkenyl substituted with 1 to 5 R ¹⁰ , -X ^x -R ⁷ , -(X^Y X ¹ - R ⁷ , -S0 ₂ NR ⁷ R ⁸ , -0-C(0)R ⁹ , -C(0)OR ⁸ , -C(0)NR ⁷ R ⁸ , -NR ⁷ R ⁸ , - NHC(0)R ⁹ , and -NR ⁷ C(0)R ⁹ ;

each R ⁶ is independently selected from the group consisting of hydrogen, Ci-Ci ₂ alkyl, C ₂ -Ci ₂ alkenyl, C ₂ -Ci ₂ 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 R ¹⁰ ;

X ¹ is selected from the group consisting of O and S;

Y is C1-C4 alkylene or C6-C1 ₀ arylene, or a combination thereof;

n is 1, 2, or 3;

R ⁷ and R ⁸ are each independently selected from the group consisting of hydrogen, Ci-Ci ₂ alkyl optionally substituted with 1 to 5 R ¹⁰ , C1-C6 heterocycle having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R ¹⁰ , C3-Cio cycloalkyl optionally substituted with 1 to 5 R ¹⁰ , C6-Cio aryl optionally substituted with 1 to 5 R ¹⁰ and C1-C6 heteroaryl having 1 to 4 heteroatoms optionally substituted with 1 to 5 R ¹⁰ ;

R ⁹ is selected from the group consisting of Ci-Ci ₂ alkyl optionally substituted with 1 to 5 R ¹⁰ , C1-C6 heterocycle having 1 to 4 heteroatoms optionally substituted with 1 to 5 R ¹⁰ , C3-Cio cycloalkyl optionally substituted with 1 to 5 R ¹⁰ , C6-C1 ₀ aryl optionally substituted with 1 to 5 R ¹⁰ and C1-C6 heteroaryl having 1 to 4 heteroatoms optionally substituted with 1 to 5 R ¹⁰ ; R ¹⁰ is selected from the group consisting of C1-C4 alkyl, phenyl, halo, -OR ¹¹ , -

CN, -COR ¹¹ , -CO2R ¹¹ , -C(0)NHR ⁿ , -NR ⁿ R ⁿ , -C(0)NR ⁿ R ⁿ , -C(0)NHN HR ¹¹ , -C(0)NR ⁿ NHR ⁿ , -C^NR ¹¹ ^ ¹¹ ^ ¹ , -C(0)NHNR ⁿ C(0)R ⁿ , -C( 0)NHNHC(0)R ⁿ , -SC^NR ¹¹ !* ¹¹ , -C(0) R ¹¹ R ¹¹ C(0)R ¹¹ , and -C(0)NR ⁿ NHC(0)R ⁿ ; and

R ¹¹ is independently hydrogen or C1-C12 alkyl;

provided that:

when L is a bond, then R ⁵ is not hydrogen;

when is a double bond, R ¹ is an ester hydrolyzable group, R ³ and R ⁴ are both hydrogen, then -L-R ⁵ is not ethyl;

when is a double bond, R ¹ is -OH, halo or C1-C12 alkyl optionally

substituted with 1 to 5 R ¹⁰ , then R ⁴ is hydrogen; and

when is a double bond, R ¹ is OR ² , R ⁴ is hydrogen, -L-R ⁵ is ethyl, then R ² is not a hydrolyzable group selected from the group consisting of an ester, amide, carbonate and carbamate.

[0191] 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;

R ¹² is halo, -OH, -SH, -NH ₂ , -S(0) ₂ N(R ¹⁷ ) ₂ , -R ^z -L ^x -R ¹⁸ , -R ^z -L ^x -R ¹⁹ , -R'-I^-R ²⁰ or - R'-L^CHR^R ¹⁹ , where R ^z is O, S or NR ¹⁷ ;

L ¹ is alkylene, arylene, -C(0)-alkylene, -C(0)-arylene, -C(0)0-arylene, -C(0)0- alkylene, -C(O)NR ²⁰ -alkylene, -C(O)NR ²⁰ -arylene, -C(NR ²⁰ )NR ²⁰ -alkylene or -C(NR ²⁰ )NR ²⁰ -arylene, wherein L ¹ is configured such that -O-I^-R ¹⁸ is - OC(0)-alkylene-R ¹⁸ , -OC(0)0-arylene-R ¹⁸ , -OC(0)0-alkylene-R ¹⁸ , - OC(0)-arylene-R ¹⁸ , -OC(O)NR ²⁰ -alkylene-R ¹⁸ , -OC(O)NR ²⁰ -arylene-R ¹⁸ , - OC(NR ^2U )NR -alkylene-R ¹⁸ or -OC(NR ^2U )NR -arylene-R , and wherein the alkylene and arylene are optionally substituted with 1 to 2 R ¹⁶ ;

R ¹³ is hydrogen, -S(0) ₂ OR ² °, -S(0) ₂ R ² °, -C(0)R ¹⁵ , -C(0)NR ¹⁵ R ¹⁵ , -C(0)OR ¹⁵ , d- Ci2 alkyl optionally substituted with 1 to 5 R ¹⁶ , Ci-C 12 alkenyl optionally substituted with 1 to 5 R ¹⁶ , or aryl optionally substituted with 1 to 5 R ¹⁶ ;

R ¹⁴ is hydrogen, halo, -OR ¹⁷ , -CN, C1-C12 alkyl, C1-C12 alkoxy, aryl or aryloxy, where the alkyl, alkoxy, aryl, and aryloxy are optionally substituted with 1 to 5 R ¹⁶ ;

each R ¹⁵ 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 R ¹⁶ ;

R ¹⁶ is selected from the group consisting of phenyl, halo, -OR ¹⁷ , -

CN, -COR ¹⁷ , -CO2R ¹⁷ , -NR ¹⁷ R ¹⁷ , -NR ¹⁷ C(0)R ¹⁷ , -NR ¹⁷ S0 ₂ R ¹⁷ , -C(0)NR ¹⁷ R ¹⁷ , -C(0)NR ¹⁷ NR ¹⁷ R ¹⁷ , -S0 ₂ NR ¹⁷ R ¹⁷ and -C(0)NR ¹⁷ NR ¹⁷ C(0)R ¹⁷ ;

each R ¹⁷ is independently hydrogen or C1-C12 alkyl optionally substituted with from 1 to 3 halo;

R ¹⁸ is hydrogen, -C(0)R ²⁰ , -C(0)OR ²⁰ , -C(O)N(R ²⁰ ) ₂ or -N(R ²⁰ )C(O)R ²⁰ ;

R ¹⁹ is hydrogen, -

N(R ²⁰ ) ₂ , -C(O)N(R ²⁰ ) ₂ , -C(NR ²⁰ )N(R ²⁰ ) ₂ , -C(NSO ₂ R ²⁰ )N(R ²⁰ ) ₂ , -NR ²⁰ C(O) N(R ²⁰ ) ₂ , -NR ²⁰ C(S)N(R ²⁰ ) ₂ , -NR ²⁰ C(NR ²⁰ )N(R ²⁰ ) ₂ , -NR ²⁰ C(NSO ₂ R ²⁰ )N(R ² °) ₂ or tetrazole; and

each R ²⁰ is independently selected from the group consisting of hydrogen, C1-C12 alkyl and aryl;

provided that:

when is a double bond and R ¹³ and R ¹⁴ are hydrogen, then R ¹² is not

hydroxy;

when r rz i _{s a} double bond, R ¹⁴ is hydrogen, R ¹² is -O-I^-R ¹⁸ , -0-L ^x -R ¹⁹ , -O-L ¹ - R ²⁰ , and L ¹ is alkylene, then -O-I^-R ¹⁸ , -0-L ^x -R ¹⁹ , -O-I^-R ²⁰ are not methoxy;

when is a double bond, R ¹⁴ is hydrogen, R ^z is O, L ¹ is -C(O)- alkylene, -C(0)-arylene, -C(0)0-arylene, -C(0)0-alkylene, -C(0)NR ²⁰ - alkylene, or -C(0)NR 20 -arylene, then none of R 18 , R 19 or R 20 are hydrogen. [0192] In one embodiment, the noribogaine derivative is represented by Formula IV:

or a pharmaceutically acceptable salt and/or solvate thereof,

wherein

R ²¹ is selected from the group consisting of hydrogen, a hydrolysable group selected from the group consisting of -C(0)R ²³ , -C(0)NR ²⁴ R ²⁵ and -C(0)OR ²⁶ , where R ²³ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl, R ²⁴ and R ²⁵ 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, R ²⁶ 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 R ²¹ is not a saccharide or an oligosaccharide;

L ² is selected from the group consisting of a covalent bond and a cleavable linker group;

R ²² 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 L ² is a covalent bond and R ²² is hydrogen, then R ²¹ is selected from the group consisting of -C(0)NR ²⁴ R ²⁵ and -C(0)OR ²⁶ ; and

further provided that when R ²¹ is hydrogen or -C(0)R ²³ and L ² is a covalent bond, then R ²² is not hydrogen.

[0193] 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;

R ²⁷ is hydrogen or S0 ₂ OR ²⁹ ;

R ²⁸ is hydrogen or S0 ₂ OR ²⁹ ;

R ²⁹ is hydrogen or Ci - Ce alkyl;

provided that at least one of R ²⁷ and R ²⁸ is not hydrogen.

[0194] 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;

R ³⁰ is hydrogen, a monophosphate, a diphosphate or a triphosphate; and

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

provided that both R ³⁰ and R ³¹ are not hydrogen;

wherein one or more of the monophosphate, diphosphate and triphosphate groups of R ³⁰ and R ³¹ are optionally esterified with one or more C1-C6 alkyl esters.

[0195] In some embodiments, the unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is from about 10 mg to about 120 mg. In one embodiment, the unit dose is about 10 mg. In one embodiment, the unit dose is about 20 mg. In one embodiment, the unit dose is about 30 mg. In one embodiment, the unit dose is about 40 mg. In one embodiment, the unit dose is about 50 mg. In one embodiment, the unit dose is about 60 mg. In one embodiment, the unit dose is about 70 mg. In one embodiment, the unit dose is about 80 mg. In one embodiment, the unit dose is about 90 mg. In one embodiment, the unit dose is about 100 mg. In one embodiment, the unit dose is about 1 10 mg. In one embodiment, the unit dose is about 120 mg.

[0196] In some embodiments, the formulation is designed for periodic administration, such as once, twice, three time, four times or five time daily with noribogaine, noribogaine derivative, or a 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, QT interval (before and/or during treatment), without limitation. Determination of dosage and frequency suitable for the present technology can be readily made a qualified clinician.

[0197] 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 and transdermal 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).

[0198] In a preferred embodiment, the formulation is designed for oral administration, which may conveniently be provided in tablet, caplet, sublingual, liquid or capsule form. In certain embodiments, the noribogaine is 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. [0199] The opioid antagonist (or partial antagonist) may be any agent that blocks opioid interaction with a receptor, e.g. an opioid receptor, so as to block the effects of the opioid in a mammal. In some embodiments, the opioid antagonist (or partial antagonist) blocks subjective effects. "Subjective effects" include the feeling of being "high" that is normally associated with opioid drug use. In one embodiment, the amount of opioid antagonist (or partial antagonist) administered is sufficient to reduce or eliminate opioid cravings in the patient. Where the term "opioid antagonist" is used herein, it is to be understood that a partial opioid antagonist may be substituted.

[0200] Any formulation of the opioid antagonist may be used in the methods described herein. In some embodiments, the opioid antagonist is formulated for oral, transdermal, internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial,

intramuscular, intraperitoneal, intracutaneous or subcutaneous delivery. In one embodiment, the opioid antagonist is formulated for oral administration. In a preferred embodiment, the opioid antagonist is formulated for injection. In a particularly preferred embodiment, the opioid antagonist is in an extended-release formulation.

III. Methods of the Invention

[0201] As will be apparent to the skilled artisan upon reading this disclosure, embodiments of the present invention provide a method for treating opioid abuse, including acute and post-acute withdrawal symptoms, in an opioid-dependent patient. In some embodiments, the patient is evaluated for acceptable QT interval prolongation prior to administration of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof.

[0202] In some aspects, this invention further relates to treatment of the patient with an opioid antagonist or partial antagonist.

[0203] In some aspects, the patient insufficiently metabolizes the opioid(s) and the method comprises administering to the patient noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof according to an altered treatment protocol. That is, the patient having insufficient opioid metabolism is administered noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof for a longer duration, at a higher dose, and/or in combination with a drug that facilitates metabolism of the opioid.

[0204] Embodiments of the present invention further provide a method for treating an opioid-dependent patient comprising periodically administering noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof to the patient, monitoring the patient's opioid level over time, and reducing the amount of the periodic dose when the opioid level falls below a desired threshold. Without being bound by theory, it is believed that a low serum concentration of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof (e.g., as low as 20 ng/mL to 100 ng/mL) will be effective at reducing withdrawal symptoms in a patient having little or no opioid remaining in the brain and/or body. In one embodiment, the amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof administered to the patient is reduced about 24 to about 72 hours after administration of the first dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof.

Patient Pre-screening and Monitoring

[0205] Without being bound by theory, it is believed that patients who are predisposed to QT interval prolongation are more likely to experience dangerous or life-threatening QT interval prolongation upon treatment with noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof. Accordingly, this invention is directed to minimizing the risk of an adverse QT interval prolongation in a patient during noribogaine treatment by excluding from treatment any patient having an increased risk factor for an unacceptable QT interval prolongation during the treatment. In one aspect, this invention is further directed to pre-screening a patient for a risk factor for an unacceptable QT interval prolongation.

[0206] An "acceptable risk level" in this context indicates that the patient is at low risk of developing QT interval prolongation of greater than 60 milliseconds upon

administration of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof. That is, the patient does not have one or more risk factors associated with increased QT interval prolongation. Risk factors associated with increased QT interval prolongation include, without limitation: genetic factors (e.g., pre-disposition to prolonged QT interval); pre-existing condition (e.g., cardiac condition or other condition that makes the patient susceptible to QT interval prolongation and/or causes QT interval prolongation); current or previous use of drugs (prescription or illicit) that are known to have a risk of QT interval prolongation; and previous unacceptable QT response (i.e., greater than 60 milliseconds (ms) prolongation or QT interval over 500 ms) to ibogaine, noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof.

[0207] In one embodiment, patients deemed suitable for such treatment have been evaluated for one or more of the following: genetic/familial risk factors, preexisting conditions, history of using drugs (e.g., prescription or illicit) that are known to have a risk of QT interval prolongation, and/or previous unacceptable QT response to ibogaine, noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof. Preferably, all of such risk factors are included in the evaluation, as well as others deemed appropriate by the attending or pre-screening clinician.

[0208] Pre-screening of patients before treatment with noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof and/or monitoring of patients during noribogaine treatment may be performed 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. For example, pre-screening and/or monitoring may be necessary at high levels of noribogaine treatment. Pre-screening may be done by the clinician administering noribogaine or by any other qualified professional.

[0209] In one embodiment, a patient receiving noribogaine, noribogaine derivative, or a 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. In one embodiment, the patient is monitored after administration of the initial dose. In one embodiment, the patient is further monitored after administration of at least one therapeutic maintenance dose. In one embodiment, the patient is monitored for a subset of the treatment, e.g., one day, two days, three days, four days, one week. In one embodiment, a patient receiving noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof is not monitored in a clinical setting.

[0210] In one aspect, this invention is directed to a method for pre-screening an opioid- dependent patient prior to administration of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof in order to determine whether the patient has an acceptable risk of QT interval prolongation. In one embodiment, one or more of the following risk factors is evaluated: genetic/familial risk factors, preexisting conditions, history of using drugs (e.g., prescription or illicit) that are known to have a risk of QT interval prolongation, and/or previous unacceptable QT response to ibogaine, noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof. In one embodiment, the risk associated with a history of using a drug that is known to have a risk of QT interval prolongation is based on the half-life of the drug, the amount of drug consumed by the patient, and the last time the patient used the drug. In a preferred embodiment, the patient is deemed to have an acceptable risk of QT interval prolongation if the patient has none of the risk factors. In one embodiment, the patient is deemed to have an acceptable risk of QT interval prolongation if the patient has one or more of the risk factors and is determined to nonetheless be acceptable for noribogaine administration by a clinician or pre-screening individual. For example, a clinician may determine that a familial risk factor is not sufficient to disqualify the patient from noribogaine treatment. In one embodiment, a patient who is deemed to have an acceptable risk of QT interval prolongation is administered noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof.

[0211] In one aspect, this invention relates to a method for prescreening an opioid- dependent patient for tolerance of noribogaine, noribogaine derivative, or a

pharmaceutically acceptable salt or solvate thereof. In one embodiment, prescreening of the patient comprises ascertaining that noribogaine treatment will not result in a maximum QT interval over about 500 ms. In one embodiment, prescreening of the patient comprises ascertaining that noribogaine treatment will not result in a maximum QT interval over about 470 ms. In one embodiment, prescreening comprises ascertaining that noribogaine treatment will not result in a maximum QT interval over about 450 ms. In one

embodiment, prescreening comprises ascertaining that noribogaine treatment will not result in a maximum QT interval over about 420 ms. [0212] 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, familial history of cardiac conditions, current drug (prescription and/or illicit) use, age, sex, general health, and the like. The following are examples of selection criteria for disallowing noribogaine treatment or restricting dose of noribogaine 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 noribogaine to a patient that lacks one more of such criteria. In a preferred embodiment, the patient is not currently taking any medications or illicit drugs that are known to have a risk of QT interval prolongation. In an especially preferred embodiment, the patient has not taken a medication or illicit drug that is known to have a risk of QT interval prolongation for a period of time sufficient for the residual serum concentration of the drug in the patient is so low as to have no significant effect on QT interval prolongation upon administration with noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof. One of skill in the art would understand that the required period of time between the last time the medication or illicit drug was taken and the administration of noribogaine treatment may vary depending, for example, on the half-life of the medication or illicit drug.

[0213] 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 noribogaine. In one embodiment, a patient at risk for prolongation of the QT interval beyond a safe level is administered noribogaine at a limited dosage. In one embodiment, a patient with an acceptable risk of QT interval prolongation is administered noribogaine, noribogaine derivative, or salt or solvate thereof.

[0214] In one embodiment, this invention relates to monitoring a patient who is administered a therapeutic dose of noribogaine, noribogaine derivative, or salt or solvate thereof. In one embodiment, the dose of noribogaine is reduced if the patient has serious adverse side effects. In one embodiment, the noribogaine 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.

Noribogaine Administration

[0215] In one aspect, this invention relates to treatment and/or attenuation of opioid drug use in a dependent patient comprising administering a therapeutically effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof under an altered treatment protocol. In one embodiment, the patient has insufficient metabolism of the opioid. In one embodiment, the patient is pre-screened for acceptable QT interval (or acceptable expected prolongation of the QT interval) prior to treatment.

[0216] In one embodiment, the method further comprises administering an opioid antagonist or partial antagonist to the patient, as described herein.

[0217] In one embodiment, the amount of noribogaine or noribogaine derivative administered at a given time is dependent on the patient's current QT interval. In one embodiment, the amount of noribogaine or noribogaine derivative administered at a given time is dependent on the patient's expected QT interval. That is, the QT interval (or prolongation thereof) that is expected to result in the patient upon administration of a given amount of noribogaine is determined (e.g., based n the patient's current QT interval and the desired dose). If the expected QT interval is greater than 500 ms, and preferably if greater than 480 ms, then the dose of noribogaine is not administered or a lower dose is administered. Expected QT interval (or prolongation) can be determined, for example, based on the average QT prolongation for a given dose (see, e.g., U.S. Pub. No.

2015/0231147, which is incorporated herein by reference in its entirety).

[0218] In one aspect, this invention relates to treatment and/or attenuation of opioid drug abuse in a dependent patient comprising administering a therapeutically effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the amount of noribogaine, noribogaine derivative, or salt or solvate thereof administered to the patient is reduced once the patient's opioid levels fall below a desired threshold. [0219] In one embodiment, this invention further relates to a method for attenuating (reducing) withdrawal symptoms in a human patient susceptible to such symptoms due to opioid drug dependency. In one embodiment, the withdrawal symptoms are symptoms of acute withdrawal. In one embodiment, the withdrawal symptoms are symptoms of post- acute withdrawal.

[0220] In a preferred embodiment, the patient is administered an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, followed by one or more therapeutic maintenance doses. In one embodiment, the one or more therapeutic maintenance doses are administered periodically.

[0221] In one aspect, a QT interval of less than about 500 ms is maintained during noribogaine or noribogaine derivative treatment. In one embodiment, a QT interval of less than about 470 ms is maintained during treatment. Preferably, a QT interval of less than about 450 ms is maintained during treatment. In one embodiment, a QT interval of less than about 420 ms is maintained during treatment. Treatment includes the initial dose and subsequent therapeutic maintenance dose(s).

[0222] In one embodiment, the QT interval is not prolonged more than about 60 ms during noribogaine or noribogaine derivative treatment. In a preferred embodiment, the QT interval is not prolonged more than about 50 ms during noribogaine or noribogaine derivative treatment. In one embodiment, the QT interval is not prolonged more than about 40 ms. In a preferred embodiment, the QT interval is not prolonged more than about 30 ms. In one embodiment, the QT interval is not prolonged more than about 20 ms.

[0223] In one embodiment, the method of treatment with noribogaine or noribogaine derivative maintains an average serum concentration of noribogaine or noribogaine derivative between about 20 ng/mL and about 200 ng/mL. In one embodiment, the method of treatment with noribogaine or noribogaine derivative maintains an average serum concentration of noribogaine or noribogaine derivative between about 20 ng/mL and about 180 ng/mL, or about 40 ng/mL and about 180 ng/mL. In one embodiment, the average serum concentration of noribogaine or noribogaine derivative is maintained between about 20 ng/mL and about 150 ng/mL, or about 40 ng/mL and about 150 ng/mL. In one embodiment, the average serum concentration of noribogaine or noribogaine derivative is maintained between about 20 ng/mL and about 100 ng/mL, or about 40 ng/mL and about 100 ng/mL. In one embodiment, the average serum concentration of noribogaine or noribogaine derivative is maintained between about 50 ng/mL and about 180 ng/mL. In one embodiment, the average serum concentration of noribogaine or noribogaine derivative is maintained between about 50 ng/mL and about 150 ng/mL. In one embodiment, the average serum concentration of noribogaine or noribogaine derivative is maintained between about 50 ng/mL and about 100 ng/mL. The ranges include both extremes as well as any subranges between.

[0224] In one embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a maximum serum

concentration (C _max ) of less than about 250 ng/mL. In one embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax between about 20 ng/mL and about 200 ng/mL. In a preferred embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a C _max between about 40 ng/mL and about 180 ng/mL. In one embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax between about 60 ng/mL and about 180 ng/mL. In one embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a maximum serum concentration (Cmax) of less than about 200 ng/mL. In one embodiment, the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a maximum serum concentration (Cmax) of less than about 120 ng/mL.

[0225] In one embodiment, the aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 40 mg and about 250 mg per day, and preferably about 60 mg to about 200 mg per day. In some embodiments, the initial dose of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 20 mg to about 120 mg, and preferably between about 60 mg and about 100 mg. In one embodiment, the one or more therapeutic maintenance doses are from about 5 mg to about 50 mg, and preferably between about 10 mg and about 30 mg. In one embodiment, each of the one or more therapeutic maintenance doses may or may not comprise the same amount of noribogaine, noribogaine derivative, or salt or solvate thereof. For example, the clinician may adjust the dose up or down depending on factors including the patient's expected or actual QT interval (or prolongation thereof), expected or actual noribogaine or noribogaine derivative plasma concentration, and/or how well the dose is working (e.g. to attenuate withdrawal symptoms).

[0226] In one embodiment, the altered treatment protocol comprises increasing the amount of noribogaine, noribogaine derivative, salt, or solvate thereof that is administered to the patient. In one embodiment, the increase is an increase in one or more unit doses of noribogaine or noribogaine derivative and/or an increase in the aggregate daily amount administered to the patient. When the amount of noribogaine or noribogaine derivative administered is increased, the patient may be evaluated for QT interval prolongation.

[0227] In one embodiment, the one or more therapeutic maintenance doses are administered periodically. In one embodiment, the one or more therapeutic maintenance doses are administered about every 4 hours to about every 48 hours, and preferably about every 6 hours to about every 12 hours.

[0228] In one embodiment, the one or more therapeutic maintenance doses are provided as sustained release formulations of noribogaine, noribogaine derivative, or salt or solvate thereof. As would be apparent to one of skill in the art, the total dosage in the sustained release formulation may be higher than the desired dose at the time administered, because the noribogaine, noribogaine derivative, or salt or solvate thereof is released slowly over time. As will also be apparent to one of skill in the art, sustained formulations may be administered less frequently than non-sustained release formulations to achieve the same results (e.g., maintenance of a desired serum drug level while maintaining a maximum QT interval of less than 500 ms and a QT interval prolongation of less than 60 ms).

[0229] In some embodiments, the patient is administered periodically, such as once, twice, three times, four times, five times, or six times daily with noribogaine, noribogaine derivative, or a 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, dosage, age and body weight of the patient, condition of the patient, and risk of QT prolongation, without limitation.

Determination of dosage and frequency suitable for the present technology can be readily made a qualified clinician. [0230] In some embodiments, the altered treatment protocol comprises increasing the frequency of administration of noribogaine or noribogaine derivative. For example, where the noribogaine treatment protocol includes administering a unit dose of noribogaine or noribogaine derivative every 6 hours, the altered protocol may include administering a unit dose every 1, 2, 3, 4, or 5 hours, or an increment thereof. In one embodiment, the increased frequency of administration is coupled with an increase in the aggregate amount of noribogaine or noribogaine derivative administered to the patient. In one embodiment, the frequency of noribogaine or noribogaine derivative administration is increased for a portion of the protocol (e.g., for 0.5, 1, 2, 3, 4 or more days).

[0231] In one embodiment, the altered treatment protocol comprises increasing the duration of time that noribogaine, noribogaine derivative, or salt, or solvate thereof is administered to the patient. For example, a standard noribogaine treatment protocol may provide periodic administration of noribogaine or noribogaine derivative for between two and seven days, and a patient having insufficient metabolism of the opioid may be administered noribogaine or noribogaine derivative for three to ten days. Such

determination is within the ability of a skilled clinician, based on factors including the patient's age, gender, health, and the speed at which the opioid is metabolized (e.g., as determined by serum and/or urine analysis).

[0232] The patient may suffer from dependency upon any opioid or opiate. In a preferred embodiment, the opioid is selected from the group consisting of heroin, opiate, morphine, codeine, oxycodone, and hydrocodone. In one embodiment, the opioid is heroin. In one embodiment, the opioid is morphine. In a preferred embodiment, the patient is not currently using methadone. In one embodiment, the patient has not used methadone for at least 5 days prior to noribogaine or noribogaine derivative treatment. In one embodiment, the patient has not used methadone for at least one week, two weeks, three weeks, four weeks, or more prior to noribogaine or noribogaine derivative treatment. In a preferred embodiment, the patient is not currently using buprenorphine. In one embodiment, the patient has not used buprenorphine for at least 5 days prior to noribogaine or noribogaine derivative treatment. In one embodiment, the patient has not used buprenorphine for at least one week, two weeks, three weeks, four weeks, or more prior to noribogaine or noribogaine derivative treatment. Administration of Opioid Antagonist Co-administration of Opioid Antagonist

[0233] In one aspect, a patient having insufficient metabolism of opioid is administered an opioid antagonist or partial opioid antaonist in combination with noribogaine or noribogaine derivative. Without being bound by theory, it is believed that the antagonist can bypass or reduce the need for the patient to metabolize the opioid in order for noribogaine or noribogaine derivative to have its full effect on reduction of withdrawal symptoms and/or treatment of opioid dependency.

[0234] In one embodiment, the opioid antagonist can be one or more of naloxone, naltrexone, nalorphine, nalmefene, levallorphan, cyprodime, naltrindole, and

norbinaltorphimine. In one embodiment, the opioid antagonist is administered at a dose that is sub-therapeutic, i.e., below the dose generally used for other indications. In some embodiments, the opioid antagonist is administered intravenously. In one embodiment, the dose of the opioid antagonist is titrated. In some embodiments, one or more of the listed opioid antagonists can be specifically excluded from the methods and kits and of the technology.

[0235] In one embodiment, the opioid antagonist is administered after at least one dose of noribogaine or noribogaine derivative. In one embodiment, the opioid antagonist is administered at the same time as at least one dose of noribogaine or noribogaine derivative. In one embodiment, the opioid antagonist is administered periodically or continuously for a period of time. Determination of the amount of time for administration of the opioid antagonist is within the ability of a skilled clinician, for example for a period of time sufficient for the patient's withdrawal symptoms to be alleviated by noribogaine or noribogaine derivative.

[0236] In one embodiment, the opioid antagonist is administered without regard for the opioid metabolism of the patient.

[0237] In one embodiment, the opioid antagonist is naloxone. Naloxone is used to counteract side effects of opioid analgesia, to reverse opioid overdose, and in opioid formulations to deter abuse of the opioid (e.g., Suboxone). In one embodiment, about 0.1 to about 4 mg of naloxone is administered. In one embodiment, about 0.1 to about 2 mg of naloxone is administered. In one embodiment, about 0.1 to about 1 mg of naloxone is administered. In one embodiment, about 0.1 to about 0.5 mg of naloxone is administered. In one embodiment, the naloxone is administered periodically (e.g., every 2-30 minutes or every 1-5 hours) or continuously until the desired response is achieved. In one

embodiment, the naloxone is administered by intravenous, subcutaneous, and/or intramuscular injection.

[0238] In one embodiment, the opioid antagonist is naloxone, nalmefene, naltrexone, nalorphine, levallorphan, cyprodime, naltrindole, or norbinaltorphimine.

Opioid Antagonist Following Noribogaine Treatment

[0239] Opioid antagonist (or partial antagonist) therapy may be used to prevent relapse to opioid abuse. Opioid antagonists attenuate or block the physiological effects (e.g., the subjective pleasurable effects) of opioids. For example, naltrexone is an opioid antagonist that is approved for use in treating opioid dependence and alcohol dependence. A drawback of opioid antagonists such as naltrexone for opioid dependence is that, heretofor, a period of opioid abstinence to reduce or completely eliminate opioid in the body is required before the opioid antagonist can be administered. This detoxification period is generally 7-14 days or longer, depending on the opioid being used. Few opioid- dependent patients can meet this requirement.

[0240] In one aspect, this invention is predicated on the surprising discovery that administration of noribogaine to an opioid-dependent patient, for example on a periodic basis, results in a reduction in opioid withdrawal symptoms during the treatment period as well as for a time afterward, such that the patient is opioid-free for at least 7 days. After the noribogaine treatment and opioid abstinence for the required period of time, the patient optionally can be administered an opioid antagonist. In a preferred embodiment, the opioid antagonist is naltrexone. In an especially preferred embodiment, the opioid antagonist such as naltrexone is administered in a controlled-release formulation. Thus, some

embodiments relate to methods of using noribogaine treatment as a pre-treatment or as a detoxification treatment prior to treatment with an opioid antagonist such as naltrexone. Other embodiments relate to methods of treating opioid dependency using an opioid antagonist such as naltrexone by selecting a patient that been pre-treated with noribogaine or that has gone through detoxification to eliminate opioid from the body prior to receiving the naltrexone treatment, and administering the opioid antagonist to the patient.

[0241] This invention is further predicated on the surprising discovery that

administration to a patient of an aggregate amount of up to about 200 mg of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof per day results in a dramatic reduction of withdrawal symptoms, thereby allowing the patient to abstain from opioid abuse for a period of time. In one embodiment, the patient is treated with an aggregate amount of up to about 200 mg of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof per day for between 2 and 14 days, as described herein.

[0242] As will be apparent to the skilled artisan upon reading this disclosure, the present invention provides a method for treating opioid abuse, including acute and post-acute withdrawal symptoms, in an opioid-dependent patient, comprising administering to a patient scheduled to receive opioid antagonist therapy a therapeutic dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof such that the patient is opioid-free for a period of time (e.g., for at least 5 days) prior to initiation of opioid antagonist therapy.

[0243] The present invention further provides a method for treating an opioid-dependent patient who has been pretreated with noribogaine or noribogaine derivative so as to be opioid-free (e.g., for at least 5 days), comprising administering to the patient an opioid antagonist in a sufficient amount to block at least one physiological effect of an opioid.

[0244] In one aspect, this invention relates to treatment and/or attenuation of opioid drug use in a dependent patient comprising administering a therapeutically effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, such that the patient is opioid free for at least about 5 days. In one embodiment, a patient who has been pre-treated with noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is administered an opioid antagonist. In one embodiment, this invention further relates to a method for attenuating withdrawal symptoms in a human patient susceptible to such symptoms due to opioid drug dependency. In one embodiment, the withdrawal symptoms are symptoms of acute withdrawal. In one embodiment, the withdrawal symptoms are symptoms of post-acute withdrawal. [0245] In a preferred embodiment, the patient is administered an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, followed by one or more therapeutic maintenance doses. In one embodiment, the one or more therapeutic maintenance doses are administered periodically.

[0246] In one embodiment, this invention relates to a method for pretreating an opioid- dependent patient scheduled for treatment with an opioid antagonist, which method comprises administering noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof to said patient in an amount sufficient to attenuate withdrawal symptoms and to allow the patient to be opioid-free for at least 7 days prior to initiation of opioid antagonist administration.

[0247] In one embodiment, this invention relates to a method for treating an opioid- dependent patient with an opioid antagonist which method comprises: identifying an opioid-dependent patient who has been pretreated with noribogaine or noribogaine derivative so as to be opioid-free for at least 7 days, and then administering the opioid antagonist in a sufficient amount to inhibit a pharmacological effect of opioids in the patient.

[0248] The opioid antagonist is preferably administered to a patient having residual noribogaine or noribogaine derivative in the patient's serum so as to reduce the risk of relapse during the time between cessation of noribogaine treatment and commencement of opioid antagonist treatment.

[0249] The dosage and administration of opioid antagonist (e.g. naltrexone) to be used can be determined by a skilled clinician. For example, the number of days of opioid abstinence required before the patient can be administered opioid antagonist depends upon factors including the opioid of dependency, the amount of opioid used by the patient, the opioid antagonist being administered, and the availability of medical support (e.g. inpatient facility) in the case of sudden onset of withdrawal. Generally, a patient will abstain from opioid use for between at least about 5 days and about 14 days prior to opioid antagonist administration, and preferably at least about 7 days to about 14 days.

[0250] In one embodiment, the opioid antagonist is naloxone, nalmefene, naltrexone, nalorphine, levallorphan, cyprodime, naltrindole, or norbinaltorphimine. Evaluation of Patient Opioid Metabolism

[0251] In one aspect, this disclosure relates to methods for screening a patient population for rate (or expected rate) of opioid metabolism. In one embodiment, a patient is screened for rate (or expected rate) of opioid metabolism. The patient may be screened prior to intial noribogaine or noribogaine derivative administration, during treatment with noribogaine or noribogaine derivative, or both.

[0252] In one aspect, this disclosure relates to methods for screening a patient population or a patient for opioid levels (e.g., serum and/or urine). In one embodiment, administration of noribogaine or noribogaine derivative (amount, duration, and/or co-administration of opioid antagonist or partial antagonist) is determined based on the opioid levels of the patient as described herein.

[0253] In one embodiment, this disclosure relates to selection of a patient having a desired rate of opioid metabolism and/or a desired level of opioid and determining the noribogaine or noribogaine derivative treatment protocol or altering a protocol based on the rate or level.

[0254] In one embodiment is provided a method for screening a patient for rate (or expected rate) of opioid metabolism, the method comprising evaluating the amount of time required for the patient's opioid levels (e.g., serum and/or urine) to fall below a desired level. In one embodiment, the desired level is an amount of opioid(s) below which noribogaine or noribogaine derivative is capable of reducing withdrawal symptoms. In one embodiment, a patient who does not exhibit an opioid level below the desired level within a predetermined period of time (e.g., 1 to 2 days) has insufficient opioid metabolism.

[0255] In one embodiment, the desired level is less than about 3,000 ng/mL total detectable opioid in urine, or equivalent (e.g., serum equivalent). In one embodiment, the desired level is less than about 2,000 ng/mL in urine, or equivalent. In a preferred embodiment, the desired level is less than about 1,500 ng/mL in urine, or equivalent. In one embodiment, the desired level is less than about 1,000 ng/mL in urine, or equivalent. In one embodiment, the desired level is less than about 900 ng/mL in urine, or equivalent. In one embodiment, the desired level is less than about 800 ng/mL in urine, or equivalent. In one embodiment, the desired level is less than about 700 ng/mL in urine, or equivalent. In one embodiment, the desired level is less than about 600 ng/mL in urine, or equivalent. In one embodiment, the desired level is less than about 500 ng/mL in urine, or equivalent. In one embodiment, the desired level is less than about 400 ng/mL in urine, or equivalent. In one embodiment, the desired level is less than about 300 ng/mL in urine, or equivalent.

[0256] In one embodiment, the predetermined period of time is between 0 and 4 days after administration of noribogaine, noribogaine derivative, or salt and/or solvate thereof. In one embodiment, the predetermined period of time is 0 days after administration of noribogaine or noribogaine derivative. In one embodiment, the predetermined period of time is 1 days after administration of noribogaine or noribogaine derivative. In one embodiment, the predetermined period of time is 2 days after administration of noribogaine or noribogaine derivative. In one embodiment, the predetermined period of time is 3 days after administration of noribogaine or noribogaine derivative. In one embodiment, the predetermined period of time is 4 days after administration of noribogaine or noribogaine derivative.

[0257] In one embodiment, at least one indicator of withdrawal symptoms is measured prior to and at least one time during treatment with noribogaine or noribogaine derivative and/or the opioid antagonist. In one embodiment, at least one indicator of withdrawal symptoms is assessed as may be described in a group of assessments such as Clinical Opiate Withdrawal Scale (COWS), Subjective Opiate Withdrawal Scale (SOWS), Objective Opiate Withdrawal Scale (OOWS), and Profile of Mood States (POMS). In one embodiment, the dose of noribogaine or noribogaine derivative and/or opioid antagonist is adjusted based on the indicator. For example, a patient exhibiting higher levels of withdrawal/withdrawal symptoms may be administered more noribogaine or noribogaine derivative and/or altered dose (more or less) of opioid antagonist. Alternatively, a patient exhibiting lower levels of withdrawal/withdrawal symptoms may be administered less noribogaine or noribogaine derivative and/or altered dose (more or less) of opioid antagonist. In some embodiments, a patient exhibiting high levels of

withdrawal/withdrawal symptoms is administered an additional therapeutic agent to address one or more symptoms. Determination of whether, what, and how much additional therapeutic agent to administer is within the ability of a skilled clinician. In one embodiment, the patient reports no urge to use the opioid for at least one day after cessation of noribogaine or noribogaine derivative treatment. [0258] In one embodiment is provided a method for screening a patient for expected rate of opioid metabolism, the method comprising determining the ability of the patient to metabolize an opioid of interest based on the allelic variant(s) or genetic mutation(s) of at least one enzyme that is involved in metabolism of the opioid of interest. In one embodiment, the enzyme is a cytochrome P450 enzyme. In one embodiment, the enzyme is a glucuronidation enzyme (UGT). In one embodiment, the enzyme is selected from the group consisting of CYP3A4, CYP2D6, CYP2B6, CYP2C8, CYP2C19, CYP2C9, and UGT2B7. Allelic variations of the enzymes that affect metabolism of opioids are known in the art. Methods for determining allelic variant or genetic mutation of a given gene in a patient are well-known in the art.

[0259] In one embodiment is provided a method for screening a patient for expected rate of opioid metabolism, the method comprising evaluating the patient's age, ethnicity, sex, and diseases (e.g., hepatic impairment, renal impairment) to determine whether the patient is expected to have a fast, intermediate (normal) or slow rate of opioid metabolism.

[0260] In one embodiment, the noribogaine or noribogaine derivative treatment protocol for a patient having insufficient opioid metabolism is adjusted as described herein.

[0261] In one embodiment, the amount and/or duration of noribogaine or noribogaine derivative treatment is reduced for a patient having a fast rate of opioid metabolism.

[0262] In one embodiment, the amount and/or duration of noribogaine treatment or noribogaine derivative is reduced once the patient's opioid levels fall below a desired threshold.

IV. Kit of Parts

[0263] In one aspect, this disclosure relates to a kit of parts comprising a composition comprising an opioid antagonist or partial opioid antagonist and a second composition comprising noribogaine, noribogaine derivative, or salt or solvate thereof, and a means for administering the compositions 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 comprising noribogaine, noribogaine derivative, or a

pharmaceutically acceptable salt or solvate thereof and/or the antagonist (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 compositions.

[0264] In some embodiments, the kit of parts further comprises a dosing treatment schedule in a readable medium. In some embodiments, the dosing treatment schedule includes the amount of noribogaine or noribogaine derivative required to achieve a desired 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 noribogaine or noribogaine derivative and/or antagonist, for example based on the sex of the patient, mass of the patient, QT interval (and/or expected prolongation thereof) and the serum level that the clinician desires to achieve. 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 non-volatile memory, for example, to store a digitally-encoded machine-readable representation of such

information.

[0265] 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.

[0266] In some aspects, the machine-readable medium comprises software that contains information regarding dosing schedules for noribogaine or noribogaine derivative and/or antagonist, 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 noribogaine or noribogaine derivative recommended to be delivered will be within the dosages that result in the serum concentrations as provided herein.

V. Formulations

[0267] In one aspect, this disclosure relates to formulations of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof and an effective amount of an opioid antagonist. In some embodiments, the opioid antagonist is naloxone, nalmefene, naltrexone, nalorphine, levallorphan, cyprodime, naltrindole, or

norbinaltorphimine. In some embodiments, the dose of noribogaine or noribogaine derivative is between about 5 mg and about 200 mg. Preferably, the dose of noribogaine or noribogaine derivative is between about 10 mg and about 120 mg.

EXAMPLES

[0268] The following Examples are intended to further illustrate certain embodiments of the disclosure and are not intended to limit its scope.

Example 1. Efficacy of Multi-Dose Noribogaine Treatment in Humans

[0269] A phase IB, open-label, titration study was conducted in a secure in-patient clinical unit. A loading dose of noribogaine 80mg was followed by titrated maintenance dosing (10, 20, 30, or 40mg, q6h) for up to 5 days. Maintenance dosing considered subjective and objective clinical assessments, and change-from-baseline QTc (AQTcF), using a predefined algorithm to avoid pronounced QT prolongation (exclusion with QTcF >500msec or AQTcF >60msec). Standard safety evaluations, PK and PD assessments were conducted. Continuous cardiac monitoring was performed via Holter monitor and telemetry.

[0270] Nine (9) patients (6 males/3 females; mean age, 31.2 years) were enrolled.

Documented opioid use included heroin and prescription opioids. Cumulative noribogaine doses ranged from 80mg to 670mg, with 4 patients administered the maximum 20 doses (mean 653mg, range 640 - 670mg).

[0271] No serious adverse events (AEs) were reported. For treatment-emergent AEs, 97% were mild in severity, 56% were opioid withdrawal related and 10% were headaches. The largest AQTcF by subject ranged between 22 - 51msec (mean 33msec). A

noribogaine concentration-dependent increase in AQTcF was observed, corresponding to a predicted AQTcF of 17msec at the geometric mean of peak concentrations of 89. lng/mL. No QTc changes resulted in discontinuation.

[0272] Noribogaine plasma concentrations showed high inter-subject variability, even between subjects with similar unit/daily/total doses, with Cmax values following multiple dosing ranging from 52 to 252 (mean 102) ng/mL. 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 subjects, 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. Scores on withdrawal, including cravings, and mood scales decreased rapidly and substantially following administration of noribogaine with very positive subjective experiences in the majority of patients. Follow-up results reflect the fragility of this population: 5 subjects relapsed, 3 were lost to follow-up and 1 remained abstinent (15 wks).

[0273] Noribogaine treatment for up to 5 days was well-tolerated. The previously noted QT effect of noribogaine was confirmed and a dosing algorithm with QT criteria was successful in avoiding pronounced QT prolongation: no patient experienced QTcF >500msec or AQTcF >60msec. Clinically significant reductions in withdrawal symptoms and mood assessments were seen following noribogaine administration.

[0274] 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. Demographic information for each patient is provided in Table 1. Table 1: Demographic Data by Patient

[0275] Noribogaine plasma concentrations for each patient are provided in FIG. 1. Surprisingly, although patients 02-004 and 02-005 had among the lowest and the highest noribogaine plasma concentrations, respectively, both patients exhibited few withdrawal symptoms at 24 to 48 hours after administration of the initial noribogaine dose. Other patients with varying noribogaine plasma concentrations exhibited more/more intense withdrawal symptoms. As can be seen in FIGs. 2A-2C, there is little correlation between noribogaine plasma concentration and change in SOWS score.

[0276] Also surprisingly, the patients exhibited an improvement in withdrawal symptoms after their opioid levels (urine) dropped below about 1500 ng/mL, regardless of noribogaine plasma concentration. FIGS. 3A through 31 show the correlation between SOWS and urine opiate levels for each patient. The data used to generate the figures is provided in Tables 2 through 4. Two patients exhibited opioid levels greater than 2000 ng/mL at day 3 (post noribogaine administration), and both of the patients left the study around that time. Table 4 provides SOWS scores by patient over time. Urine opioid levels show strong correlation to plasma levels at the same time points (FIG. 4). Measurement of plasma opioid levels included morphine, hydromorphone, oxycodone, and morphine-6- beta-glucuronide levels.

Table 2: Morphine* levels in urine (ng/mL)

J - Second Day of Observation 20 0 31 0

*Test reported as "morphine" in the urine drug screen represents results of the

MULTIGENT Opiates Assay, which may detect the following substances with varying sensitivity: 6-Monoacetyl morphine, Codeine, Dihydrocodeine, Heroin, Hydrocodone, Hydromorphone, Levorphanol, Morphine, Morphine-3-glucuronide, Morphine-6- glucuronide, Oxycodone, Oxymorphone, or Ranitidine.

Table 3: Oxycodone levels in urine (ng/niL)

Table 4: SOWS Scores

Table 4: SOWS Scores (cont.)

[0277] Average SOWS scores over time are provided in FIG. 5. SOWS scores are interpreted as follows: Mild withdrawal: score of 1-10; Moderate withdrawal: score of 11- 20; Severe withdrawal: score of >21. Mean scores for SOWS question 16 ("I feel like using now") are provided in FIG. 6. Scores dropped almost immediately after first noribogaine administration and generally continued to fall during treatment. Surprisingly, all four of the patients who remained in the study by 96 hours post first noribogaine dose replied "Not at all" in answer to this question. Scoring for SOWS assessment: Patient is asked to score the items "According to how you feel now" on a scale of 0-4 (0: Not at all; 1 : a little; 2: moderately; 3: quite a bit; 4: extremely).

[0278] Mean Profile of Mood States (POMS) Total Mood Disturbance Scores for first seven subjects (001 - 007) is provided in FIG. 7. POMS Total Mood Disturbance Scores also dropped within the first 24 hours after first noribogaine dose. POMS is a self-reported measure to assess changes in positive and negative mood over time. There are six subscales: tension/anxiety, depression/dejection, anger/hostility, vigor, fatigue, confusion/bewilderment. A comprehensive global impairment score, Total Mood Disturbance or TMD, is the sum of all negative mood subscales less the positive mood assessment of vigor. Negative TMD scores indicate that vigor exceeds the sum of negative mood subscales.

[0279] Patients reported various feelings and during the treatment period. Patient 1 overcame extreme sadness, depression experienced on Day 2, and had a change in perspective on Day 3/4 of treatment. Patient 1 completed the full 15 week follow-up period opioid free. Patient 4 also experienced change in perspective on Day 2 coincident with significant reduction in withdrawal symptoms, and called noribogaine "a re-set button pushed in my brain," with no cravings and substantially shortened withdrawal symptoms (2-3 days, versus 2-3 weeks for "cold-turkey").

[0280] Patient 3 also experienced a change in perspective on Day 3/4, including first positive thoughts (in sobriety) since teenage years; "I wanted to be happy and sober at the same time, which I am now, which is something that never happens to me." Patient 3 was opioid-free for Patients 4 and 5 experienced a change in perspective on Day 2, coincident with significant reduction in withdrawal symptoms. Patient 6, despite request of rescue at 60 hours (hydromorphone) to help with sleep (which did not work) had SOWS score of 0 at 24 hours post-discharge and had not resumed opiate consumption. Patient 7, despite early discharge, reported no cravings 24 hours after discharge.

[0281] The results of this multi-dose study indicate that safe multiple dosing is possible with noribogaine, and that exposure response modeling reliably predicts QT prolongation in individual patients. The dosing regimen described herein is a safe way of titrating dosages. Finally, noribogaine is effective at treating both opioid withdrawal and dependency.

[0282] 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.