WO2016134019A1 - Procédés pour le traitement de troubles associés à une activité indésirable de récepteurs nicotiniques neuronaux de l'acétylcholine - Google Patents

Procédés pour le traitement de troubles associés à une activité indésirable de récepteurs nicotiniques neuronaux de l'acétylcholine Download PDF

Info

Publication number
WO2016134019A1
WO2016134019A1 PCT/US2016/018273 US2016018273W WO2016134019A1 WO 2016134019 A1 WO2016134019 A1 WO 2016134019A1 US 2016018273 W US2016018273 W US 2016018273W WO 2016134019 A1 WO2016134019 A1 WO 2016134019A1
Authority
WO
WIPO (PCT)
Prior art keywords
noribogaine
substituted
solvate
group
disorder
Prior art date
Application number
PCT/US2016/018273
Other languages
English (en)
Inventor
Emeline Maillet
Original Assignee
Demerx, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Demerx, Inc. filed Critical Demerx, Inc.
Publication of WO2016134019A1 publication Critical patent/WO2016134019A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/465—Nicotine; Derivatives thereof

Definitions

  • This invention is directed to a method of treating one or more diseases or disorders associated with undesired downstream response(s) of neuronal nicotinic acetylcholine receptor activity, comprising treating a patient with noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof so as to attenuate said undesired effect.
  • This invention is further directed a method of attenuating undesired downstream response(s) of neuronal nicotinic acetylcholine receptor activity in a cell that expresses at least one subtype of neuronal nicotinic acetylcholine receptor.
  • a number of functions and disorders are associated with downstream effect(s) of neuronal nicotinic acetylcholine receptor (nAChR) activity. These include substance abuse and withdrawal; depression; schizophrenia; anxiety-related disorders; regulation of the mood-enhancing effects of antidepressant drugs; baseline affective state; memory and attention (including Alzheimer's disease and attention deficit disorder).
  • nAChR neuronal nicotinic acetylcholine receptor
  • Substance addiction is a serious public health problem throughout the world. Heroin and other drags, including prescription painkillers, are widely abused. Opioid use is also linked to approximately 50% of violent crimes in the United States and costs the U.S. economy billions of dollars per year.
  • psychotic disorders e.g., schizophrenia and bipolar disorder
  • anxiety-related disorders e.g., obsessive-compulsive disorder, panic disorder, social anxiety disorder, and generalized anxiety disorder
  • impulse- control disorders like attention deficit disorder/attention deficit hyperactivity disorder (ADD/ADHD)
  • memory disorders e.g., Alzheimer's disease, dementia
  • This invention is predicated, at least in part, on the surprising discovery that at low concentrations, noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof attenuates the undesired activity of at least a subset of nAChRs.
  • the nAChRs can be activated by a number of ligands, including acetylcholine, nicotine, epibatidine, and choline, and undesired binding of such ligands leads to diseases or mediates the manifestations of diseases including (but not limited to) substance abuse and withdrawal; depression;
  • schizophrenia anxiety-related disorders; and memory and attention disorders (including Alzheimer's disease and attention deficit disorder).
  • noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof attenuate undesirable nAChR activity without itself causing undesirable nAChR activity at these doses.
  • Noribogaine is a well-known member of the ibogaine family of alkaloids and is sometimes referred to as 12-hydroxyibogaine. Noribogaine has been disclosed for treatment of substance addiction, including nicotine, opioids, cocaine and alcohol. See U.S. Patent Application Pub. Nos. 2014/0288056; 2015/0231 147; 2015/0238503;
  • Noribogaine can be depicted by the following formula:
  • a prolonged QT interval is a marker of potential Torsades de Pointes, a serious arrhythmia that can result in death. It has been shown that treatment with noribogaine imparts a dose-dependent prolongation of the treated patient's QT interval, rendering higher dosing of noribogaine unacceptable. Therefore, it is important to administer noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof at a level that is both efficacious and safe.
  • noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof at a dose between about 1 mg/kg body weight and about 4 mg/kg body weight provides a therapeutic reduction in withdrawal symptoms and/or an increase in time to resumption of opioid use in opioid- addicted patients, while also maintaining a QT interval prolongation below about 50 ms.
  • noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof is effective at treating or attenuating the diseases and conditions described herein which are mediated by liAChR activity because noribogaine's direct action to the receptor modulates the downstream effects of this receptor in response to endogenous and exogenous ligand binding.
  • Such lower dosing minimizes the risk of dangerous QT interval prolongation.
  • Nicotinic acetylcholine receptors are ligand-gated ion channels made up of five transmembrane subunits arranged so as to form a central pore. There are two subtypes: muscle-type nAChRs and neuronal-type nAChRs. Neuronal-type nAChRs may be homomeric or heteromeric combinations of a (i.e., a.2- ) and ⁇ (i.e., ⁇ 2 - ⁇ 4 ) subunits.
  • the endogenous agonist for nAChRs is acetylcholine; nicotine, epibatidine, and choline are also known nAChR agonists.
  • this invention relates to a method for attenuating an undesired downstream response as a result of nAChR activity in a cell, the method comprising administering to a cell comprising at least one nAChR an effective amount of noribogaine, noribogaine derivative, or salt or solvate thereof to attenuate the downstream response.
  • the nAChR comprises at least one subunit selected from the group consisting of 3, a5, a7, ⁇ 4, and ⁇ 2.
  • the cell is a neuron.
  • this invention relates to a method for attenuating an undesired downstream response as a result of nAChR activity in a subject having a disorder associated with nAChR activity, the method comprising administering to the subject an effective amount of noribogaine, noribogaine derivative, or salt or solvate thereof to attenuate the undesired response, thereby treating or attenuating the disorder.
  • the disorder is an anxiety-related disorder.
  • the disorder is a depression-related disorder.
  • the disorder is schizophrenia.
  • the disorder is addiction to an addictive substance.
  • the substance is selected from the group consisting of an opioid, cocaine, nicotine, and alcohol.
  • the disorder is a memory or attention disorder.
  • the memory or attention disorder is selected from the group consisting of Alzheimer's disease, dementia, attention deficit hyperactivity disorder, and attention deficit disorder.
  • activity of the nAChR is inhibited by noribogaine, noribogaine derivative, or salt or solvate thereof.
  • desensitization of the nAChR is attenuated.
  • the nAChR is expressed by a neuron of a subject.
  • FIG. 1 shows the dose-dependent inhibition of epibatidine-evoked Ca" ⁇ responses in cx3-(a5, ⁇ 4, ⁇ 2) nACliRs by noribogaine, ibogaine, 18-MC and
  • FIG. 2 shows the modulation of epibatidine-evoked Ca 2+ dose-responses in ⁇ 3-( ⁇ 5, ⁇ 4, ⁇ 2) nAChRs by noribogaine and mecamylamine.
  • FIG. 3 illustrates the alignment of the second transmembrane region T2 of the human a3, a4, a5, a7, ⁇ 2, and ⁇ 4 nACliR subunits.
  • FIG. 4 illustrates the subunit composition of nAChRs occurring in the habenula of mice.
  • FIG. 5 represents mean noribogaine concentration-time profiles in healthy patients after single oral dosing with 3, 10, 30 or 60 mg doses.
  • Inset Individual concentration-time profiles from 0-12 h after a 10 mg dose.
  • FIG. 6 represents mean plasma noribogaine glucuronide concentration- time profiles in healthy patients after single oral 30 or 60 mg doses.
  • the term "about” when used with regard to a dose amount means that the dose may vary by ⁇ l- 20%.
  • "about 2 mg/kg noribogaine” indicates that a patient may be administered a dose of noribogaine between 1.6 mg/kg and 2.4 mg/kg.
  • about 120 mg per unit dose of noribogaine indicates that the unit dose may range from 96 mg to 144 mg.
  • administering refers to introducing an agent, such as noribogaine, into a patient.
  • an effective amount is administered, which amount can be determined by the treating physician or the like. Any route of administration, such as oral, topical, subcutaneous, peritoneal, intra-arterial, inhalation, vaginal, rectal, nasal, introduction into the cerebrospinal fluid, or instillation into body compartments can be used.
  • the agent, such as noribogaine may be administered by direct blood stream delivery, e.g. sublingual, buccal, intranasal, or intrapulmonary administration.
  • administering and “administration of, when used in connection with a compound or pharmaceutical composition (and grammatical equivalents), refer both to direct administration, which may be administration to a patient by a medical professional or by self-administration by the patient, and/or to indirect administration, which may be the act of prescribing a drug.
  • direct administration which may be administration to a patient by a medical professional or by self-administration by the patient
  • indirect administration which may be the act of prescribing a drug.
  • a physician who instructs a patient to self-administer a drag and/or provides a patient wdth a prescription for a drag is administering the drug to the patient.
  • the term "activity", with respect to a nAChR, refers to any activity of the receptor, including (without limitation) activation, inhibition, down-regulation, or desensitization of the receptor.
  • the nAChR activity attenuated by the compound described herein is an activity that is mediated by a ligand (e.g., an endogenous or exogenous ligand of the receptor).
  • a ligand e.g., an endogenous or exogenous ligand of the receptor.
  • the noribogaine, noribogaine derivative, salt or solvate thereof attenuates activation and/or desensitization of the receptor.
  • Periodic administration refers to multiple treatments that occur on a daily, weekly, or monthly basis. Periodic administration may also refer to administration of noribogaine, noribogaine derivative, or salt or solvate thereof one, two, three, or more times per day. Administration may be via transdermal patch, gum, lozenge, sublingual tablet, intranasal, intrapulmonary, oral administration, or other administration.
  • 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.
  • Treatment of addiction includes amelioration of at least one symptom of acute withdrawal or post-acute withdrawal, and/or preventing or reducing the risk of relapse to substance abuse.
  • Any substance of addiction is contemplated, including, without limitation, nicotine, caffeine, alcohol, opioids, cocaine, barbituates, and other narcotics or prescription drugs.
  • 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 (CH3CH 2 -), "-propyl (CH 3 CH 2 CH 2 -), isopropyl ((CH 3 ) 2 CH-), n-butyl (CH3CH 2 CH 2 CH 2 -), isobutyl ((CH 3 ) 2 CHC3 ⁇ 4-), sec-butyl ((CH3)(CH 3 CH 2 )CH-), /-butyl ((CH 3 ) 3 C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH aCCIt-).
  • 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.
  • 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.
  • alkynyl groups include acetylenyl (-C ⁇ CH), and propargyl (-CH 2 C ⁇ CH).
  • 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, ammocarbonyloxy, 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, cycloalkyloxy
  • heterocyclylthio nitro, SO 3 H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio, wherein said substituents are defined herein.
  • 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, cycloalkyloxy,
  • heterocyclylthio nitro, SO3H, substituted sulfonyl, sulfonyloxy, thioacyl, thiol, alkyithio, and substituted alkyithio, 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.
  • 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, cycloalkyloxy
  • Alkoxy refers to the group -O-alkyl wherein alkyl is defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, w-butoxy, r-butoxy, sec-butoxy, and w-pentoxy.
  • Substituted alkoxy refers to the group -0-(substituted alkyl) wherein substituted alkyl is defined herein.
  • 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, substituted
  • Acylamino refers to the groups -NR 38 C(0)alkyl, -NR 38 C(0)substituted alkyl, -NR 8 C(0)cycloalkyl, -NR 38 C(0)substituted
  • 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, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic are as defined herein.
  • Acyloxy refers to the groups alkyl-C(0)O, substituted alkyl-C(0)0-, alkenyl-C(0)0-, substituted alkenyl-C(0)0-, alkynyl-C(0)0-, substituted
  • 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.
  • Amino refers to the group -NH 2 .
  • Substituted amino refers to the group -NR 39 R 40 where R 39 and R 40 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alicenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic, -S0 2 -alkyl, -SOi-substituted
  • alkyl -SC alkenyl, -SOi-substituted alkenyl, -S0 2 -cycloalkyl, -S0 2 -substituted cylcoalkyl, -S02-cycloalkenyl, -SC ⁇ -substituted cylcoalkenyl,-S02-aryl, -S02-substituted aryl, -S02-heteroaryl, -SCb-substituted heteroaryl, -SCb-heterocyclic, and -S0 2 -substituted heterocyclic and wherein R SJ and R 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, cyclo
  • R “ 9 is hydrogen and R 40 is alkyl
  • the substituted amino group is sometimes referred to herein as alkylamino.
  • R 39 and R 40 are alkyl
  • the substituted amino group is sometimes referred to herein as dialkylamino.
  • a monosubstituted amino it is meant that either R j9 or R 40 is hydrogen but not both.
  • R j9 or R 40 is hydrogen but not both.
  • a disubstituted amino it is meant that neither R 39 nor R 40 are hydrogen.
  • 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 alicenyl, 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
  • 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
  • Aminocarbonylamino refers to the group -NR 38 C(0)NR 41 R 42 where R jS is hydrogen or alkyl and R 41 and R 4 " 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 4 !
  • 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.
  • Aminothiocarbonylamino refers to the group -NR ' C(S)NR R where R ' 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,
  • Aminocarbonyloxy ' refers to the group -0-C(0)NR 4i 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, alicenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, substituted cyclo
  • Aminosulfony l refers to the group -S0 2 NR 4i R 42 where R 4! and R 42 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alicenyl, 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, substituted
  • Aminosulfonyloxy refers to the group -0-S0 2 NR , 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, substituted cycl
  • Aminosulfonylamino refers to the group -NR 38 -S0 2 NR 4, R 42 where R 3S is hydrogen or alkyl and R 41 and R 42 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aikenyl, substituted aikenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R 4!
  • R 42 are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, aikenyl, substituted allcenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.
  • 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.,
  • Preferred aryl groups include phenyl and naphthyl.
  • 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, aikenyl, substituted aikenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aiyl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)
  • Aryloxy refers to the group -0-aryl, where aryl is as defined herein, that includes, by way of example, phenoxy and naphthoxy.
  • Substituted aryloxy refers to the group -0-(substituted aryl) where substituted aryl is as defined herein.
  • Arylthio refers to the group -S-aryl, where aryl is as defined herein.
  • Substituted arylthio refers to the group -S-(substituted aryl), where substituted aryl is as defined herein.
  • Carboxy or “carboxyl” refers to -COOH or salts thereof.
  • Carboxyl ester or “carboxy ester” refers to the
  • 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, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic are as defined herein.
  • (Carboxyl ester)oxy refers to the group -0-C(0)0-alkyl
  • heteroaiyl -0-C(0)0-heterocyclic, and -0-C(0)0-substituted heterocyclic
  • alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryi, substituted heteroaryi, heterocyclic, and substituted heterocyclic are as defined herein.
  • Cyano refers to the group -CN.
  • 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, heteroaiyl, or heterocyclic provided that the point of attachment is through the non-aromatic, non-heterocyclic ring carbocyclic ring.
  • suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, and cyclooctyl.
  • Other examples of cycloalkyl groups include
  • 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,
  • Cycloalkyloxy refers to -O-cycloalkyl.
  • Substituted cycloalkyloxy refers to -0-(substituted cycloalkyl).
  • Cycloalkylthio refers to -S-cycloalkyl.
  • Substituted cycloalkylthio refers to -S-(substituted cycloalkyl).
  • Cycloalkenyloxy refers to -O-cycloalkenyl.
  • Substituted cycloalkenyloxy refers to -0-(substituted cycloalkenyl).
  • Cycloalkenylthio refers to -S-cycloalkenyl.
  • Substituted cycloalkenylthio refers to -S-(substituted cycloalkenyl).
  • Halo or "halogen” refers to fluoro, chloro, bromo and iodo and preferably is fluoro or chloro.
  • 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.
  • 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.
  • 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.
  • Heteroaiyl 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 heteroaiyl groups can have a single ring (e.g., pyridyl, pyridinyl or fuiyl) 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 heteroaiy l group.
  • the nitrogen and/or the sulfur ring atom(s) of the heteroaiyl 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.
  • 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.
  • Heteroaryloxy refers to -0-heteroaryl.
  • Substituted heteroaryloxy refers to the group -0-(substituted heteroaryl).
  • Heteroarylthio refers to the group -S-heteroaryl.
  • Substituted heteroarylthio refers to the group -S-(substituted heteroaryl).
  • 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 cvcloalkyl, 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.
  • Substituted heterocyclic or “substituted heterocycloalkyl” or “substituted heterocyclyl” refers to heterocyclyl groups that are substituted with from I to 5 or preferably 1 to 3 of the same substituents as defined for substituted cycloalkyl.
  • Heterocyclyloxy refers to the group -O-heterocycyl.
  • Substituted heterocyclyloxy refers to the group -0-(substituted heterocycyl).
  • Heterocyclylthio refers to the group -S-heterocycyl.
  • Substituted heterocyclylthio refers to the group -S-(substituted heterocycyl).
  • heterocycle and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline,
  • Neitro refers to the group -N0 2 .
  • Spiro ring systems refers to bicyclic ring systems that have a single ring carbon atom common to both rings.
  • Substituted sulfonyl refers to the group -SC -alkyl, -S0 2 -substituted alkyl, -S0 2 -alkenyl, -SC -substituted alkenyl, -SCh-cycloalkyl, -S0 2 -substituted cylcoalkyl, -S0 2 -cycloalkenyl, -S0 2 -substituted cylcoalkenyl, -S0 2 -aryl, -SC substituted aryl, -S02-heteroaryl, -S02-substituted heteroaryl, -S Vheterocyclic, -S02-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl
  • Substituted sulfonyl includes groups such as methyl-S02-, phenyl-S , and 4-methylphenyl-SC>2-.
  • alkylsulfonyl refers to -S0 2 -alkyl.
  • haloalkylsulfonyl refers to -SOi-haloalkyl where haloalkyl is defined herein.
  • (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.
  • alkyl -OS0 2 -alkenyl, -OS0 2 -substituted alkenyl, -OS0 2 -cycloalkyl, -OS0 2 -substituted cylcoalkyl, -OS0 2 -cycloalkenyl, -OS0 2 -substituted
  • 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, substituted
  • Thiol refers to the group -SH.
  • Alkylthio refers to the group -S-alkyl wherein alkyl is as defined herein.
  • Substituted alkylthio refers to the group -S-(substituted alkyl) wherein substituted alkyl is as defined herein.
  • Stereoisomer or “stereoisomers” refer to compounds that differ in the chirality of one or more stereocenters. Stereoisomers include enantiomers and diastereomers.
  • 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.
  • 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.
  • diphosphate refers to the group -P(0)(OH)- ⁇ ( ⁇ )( ⁇ ) 2 .
  • triphosphate refers to the group -P(0)(OH)- (OP(0)(OH)) 2 OH.
  • esters of the mono-, di- or triphosphate group means esters of the monophosphate can be represented by the formula -P(0)(OR 4, ) 2 , where each R 45 is independently hydrogen, Ci-Ci? alkyl, C3-C 10 cycloalkyl, C -Ci4 aryl, heteroaryl of 1 to 10 carbon atoms and 1 to 4 optionally oxidized heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur and the like, provided that at least one R 45 is not hydrogen.
  • exemplary esters of the di- or triphosphate can be represented by the formulas -P(0)(OR 45 )-OP(0)(OR 45 ) 2
  • hydrolyzable group refers to a group that can be hydrolyzed to release the free hydroxy group under hydrolysis conditions.
  • 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)(0R 46 )-O, -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(0)(R 46 )-Ck -S-P(0)
  • Substituted groups of this invention do not include polymers obtained by an infinite chain of substituted groups. At most, any substituted group can be substituted up to five times.
  • noribogaine is mentioned herein, one more polymorphs of noribogaine can be utilized and are contemplated. In some embodiments, noribogaine is noribogaine glucuronide.
  • Noribogaine can be prepared by demethylation of naturally occurring ibogaine:
  • Demethylation may be accomplished by conventional techniques such as by reaction with boron
  • Noribogaine can be synthesized as described, for example in U.S. Patent Pub. Nos. 2013/0165647, 2013/0303756, and 2012/0253037, PCT Patent Publication No. WO 2013/040471 (includes description of making noribogaine polymorphs), and U.S. Patent App. No. 13/593,454, each of which is incorporated herein by reference in its entirety.
  • Nonibogaine 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 US Patent Nos. 6,348,456 and 8,362,007; as well as in US Patent Application Serial No. 13/165,626; and US Patent Application Publication Nos.
  • the methods of the present disclosure entail the administration of a prodrug of noribogaine that provides the desired maximum serum concentrations and efficacious average noribogaine serum levels.
  • a prodrug of noribogaine refers to a compound that metabolizes, in vivo, to noribogaine.
  • 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. Examples of prodrugs of noribogaine are provided in United States Patent Application Serial No. 13/165626, the entire content of which is incorporated herein by reference.
  • This invention is not limited to any particular chemical form of noribogaine or noribogaine derivative, and the drug may be given to patients either as a free base, solvate, or as a pharmaceutically acceptable acid addition salt.
  • 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.
  • composition refers to a composition that is suitable for administration to a mammal, preferably a human.
  • Such compositions include various excipients, diluents, carriers, and such other inactive agents well known to the skilled artisan.
  • 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.
  • “Therapeutically effective amount” or “therapeutic amount” refers to an amount of a drug or an agent that, when administered to a patient suffering from a condition, will have the intended therapeutic effect, e.g., alleviation, amelioration, palliation or elimination of one or more manifestations of the condition in the patient.
  • the therapeutically effective amount will vary depending upon the patient and the condition being treated, the weight and age of the subject, the severity of the condition, the salt, solvate, or derivative of the active drag 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.
  • a therapeutically effective amount may be administered in one or more administrations.
  • a therapeutically effective amount of noribogaine in the context of drag dependency, refers to an amount of noribogaine that attenuates the dependency and/or symptoms of acute withdrawal for at least about 2 hours beyond control (placebo), at least about 5 hours beyond control, and preferably at least about 10 hours beyond control.
  • a "therapeutic level" of a drug is an amount of noribogaine, noribogaine derivative, or pharmaceutical salt or solvate thereof that is sufficient to treat the disease or symptoms thereof, but not high enough to pose any significant risk to the patient.
  • Therapeutic levels of drugs can be determined by tests that measure the actual concentration of the compound in the blood of the patient. This concentration is referred to as the " " serum concentration.” 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. [0130]
  • dose refers to a range of noribogaine, noribogaine derivative, or pharmaceutical salt or solvate thereof that provides a therapeutic serum level of noribogaine when given to a patient in need thereof. The dose is recited in a range, for example from about 20 mg to about 120 mg, and can be expressed either as milligrams or as mg/kg body weight. The attending clinician will select an appropriate dose from the range based on the patient's weight, age, degree of addiction, health, and other relevant factors, all of which are well within the skill of the art.
  • 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.
  • the unit dose is sold in a standard form (e.g., 20 mg tablet).
  • the unit dose may be administered as a single dose or a series of subdoses.
  • the unit dose provides a standardized level of drug to the patient, independent of weight of patient.
  • Many medications are sold based on a dose that is therapeutic to all patients based on a therapeutic window. In such cases, it is not necessary to titrate the dosage amount based on the weight of the patient.
  • Treatment 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.
  • the term "patient” refers to mammals and includes humans and non-human mammals.
  • opioid refers to naturally-occurring alkaloids found in the opium poppy.
  • opioid refers to naturally-occurring opiates and synthetic or semi-synthetic opioids that have psychoactive effects.
  • a non-limiting list of opioids can be found in U.S. Application Pub. No. 2015/0231147, which is
  • 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.
  • solvate refers to complexes with solvents in which noribogaine is reacted or from which noribogaine is precipitated or crystallized.
  • a complex with water is known as a "hydrate”.
  • Solvates of noribogaine 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 or the pharmaceutically acceptable solvates thereof are within the scope of the present invention.
  • a " pharmaceutically acceptable solvate” or “hydrate” of a compound of the invention means a solvate or hydrate complex that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound, and includes, but is not limited to, complexes of a compound of the invention with one or more solvent or water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
  • the therapeutically effective amount of the compound may be higher or lower, depending on the route of administration used. For example, when direct blood administration (e.g., sublingual, pulmonary and intranasal delivery) is used, a lower dose of the compound may be administered. In one aspect, a therapeutically effective amount of noribogaine or derivative is from about 50 ng to less than 100 ⁇ g per kg of body weight. Where other routes of administration are used, a higher dose of the compound may be administered.
  • a "sub-therapeutic level" of noribogaine or pharmaceutical salt and/or solvate thereof that is less than the therapeutic level described above.
  • the subtherapeutic level of noribogaine may be e.g., 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a therapeutically effective amount (e.g., 120 mg) of noribogaine, or any subvalue or subrange there between.
  • a prophylactically effective amount of a drug is an amount, typically less than the therapeutically effective amount, that provides attenuation and/or prevention of a disease or disorder or symptoms of a disease or disorder in a patient.
  • the prophylactically effective amount of the compound is expected to be less than the therapeutically effective amount because the level of inhibition does not need to be as high in a patient who no longer has a disease or disorder or symptoms of a disease or disorder (e.g., no longer physically addicted to nicotine).
  • a prophylactically effective amount is preferably 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a therapeutically effective amount.
  • a prophylactically effective amount may be the same as the therapeutically effective amount.
  • the prophylactically effective amount may vary for different a diseases or disorders or symptoms of different diseases or disorders.
  • a "maintenance amount" of a drug or an agent is an amount, typically less than the therapeutically effective amount that provides attenuation and/or prevention of syndrome disease or disorder or symptoms of a disease or disorder in a patient.
  • the maintenance amount of the compound is expected to be less than the therapeutically effective amount because the level of inhibition does not need to be as high in a patient who is no longer physically manifests a disease or disorder or symptoms of a disease or disorder.
  • a maintenance amount is preferably 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10% less than a therapeutically effective amount, or any subvalue or subrange there between.
  • this invention provides compositions for treating diseases associated with undesired downstream effect(s) of nAChR activity 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 a cell expressing at least one nAChR, comprising noribogaine, noribogaine derivatives, prodrugs of noribogaine, pharmaceutically acceptable salts and/or solvates of each thereof.
  • the composition is formulated for oral, transdermal, internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intraarterial,
  • intramuscular, intraperitoneal, intracutaneous or subcutaneous delivery is provided.
  • the noribogaine derivative is represented by Formula I:
  • R is hydrogen or a hydrolyzable group such as hydrolyzable esters of from about 1 to 12 carbons.
  • R is hydrogen or a group of the formula:
  • X is a C1-C12 group, which is unsubstituted or substituted.
  • 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.
  • X may be a phenyl group or benzyl group, either of which may be substituted with lower alkyl groups or lower alkoxy groups.
  • the lower alkyl and/or alkoxy groups have from 1 to about 6 carbons.
  • the group R may be acetyl, propionyl or benzoyl. However, these groups are only exemplary.
  • Ci-Ci 2 groups include C 1 -C 12 alkyl, C3-C 12 cycloalkyl, C6-C 12 aryl, C7-C 12 arylalkyl, wherein C x indicates that the group contains x carbon atoms.
  • Lower alkyl refers to C 1 -C4 alkyl and lower alkoxy refers to C 1 -C4 alkoxy.
  • the noribogaine deriyative is represented by Formula II:
  • R 1 is halo, OR 2 , or C,-C 12 alkyl optionally substituted with 1 to 5 R 10 ;
  • R 2 is hydrogen or a hydrolvsable 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 Q-Ce alkyl optionally substituted with 1 to 5 R 10 , and each R y is independently selected from the group consisting of hydrogen, Ci-Cf, alkyl optionally substituted with 1 to 5 R i0 , Ce-Cu aryl optionally substituted with 1 to 5 R 10 , C3-C 1 0 cycloalkyl optionally substituted with 1 to 5 R i0 , Ci-Cio heteroaryl having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R i0 , G-C 1 0 heterocyclic having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R 10 , and where each R 5 , together with the nitrogen atom bound thereto form a Ci-Ce heterocyclic having
  • R 3 is selected from the group consisting of hydrogen, C 1 -C 12 alkyl optionally
  • R 4 is selected from the group consisting of hydrogen, -(CFL nOR 8 , -
  • n 0, 1, or 2;
  • L is a bond or O-C12 alkylene
  • R 5 is selected from the group consisting of hydrogen, C 1 -C 12 alkyl substituted with 1 to 5 R 10 , C 1 -C 12 alkenyl substituted with 1 to 5 R i0 , -X ⁇ R 7 , -(X'-YVX 1 - R 7 , -S0 2 NR 7 R s , -0-C(0)R 9 , -C(0)OR 8 , -C(0)NR 7 R 8 , -NR 7 R S , - NHC(0)R 9 , and -NR 7 C(0)R 9 ;
  • each R 6 is independently selected from the group consisting of hydrogen, C 1 -C 1 ? alkyl, C2-Q2 alkenyl, C2-C12 alkynyl, Cg-Qo aryl, Q-Ce heteroaryl having 1 to 4 heteroatoms, and Ci-Cg heterocycle having 1 to 4 heteroatoms, and wherein the alkyl, alkenyl, alkynyl, aryl, heteroaryl, and heterocycle are optionally substituted with 1 to 5 R i0 ;
  • X 1 is selected from the group consisting of O and S;
  • Y is C 1-C4 alkylene or C6-Cio rylene, or a combination thereof;
  • n 1, 2, or 3;
  • R 7 and R 8 are each independently selected from the group consisting of hydrogen, C 1 -C 12 alkyl optionally substituted with 1 to 5 R i0 , C 1 -C6 heterocycle having 1 to 4 heteroatoms and which is optionally substituted with 1 to 5 R !0 , C3-Cio cycloalkyl optionally substituted with 1 to 5 R 10 , Ce-Cio aryl optionally substituted with 1 to 5 R 10 and O-Ce heteroaryl having 1 to 4 heteroatoms optionally substituted with 1 to 5 R i0 ;
  • R 9 is selected from the group consisting of C Ci? alkyl optionally substituted with 1 to 5 R 10 , Ci-Ce heterocycle having 1 to 4 heteroatoms optionally substituted with 1 to 5 R 10 , Cs-Cio cycloalkyl optionally substituted with 1 to 5 R 10 , Ce-Cio ar>'l optionally substituted with 1 to 5 R i0 and Ci-C-6 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 , -
  • R 11 is independently hydrogen or Ci-Q? alkyl; provided that:
  • R 5 is not hydrogen
  • R 1 when is a double bond, R 1 is an ester hydrolyzable group, R 1 and R 4 are both hydrogen, then -L-R 5 is not ethyl;
  • R 1 when is a double bond, R 1 is -OH, halo or C Ci? alkyl optionally
  • R 4 is hydrogen
  • R 1 when is a double bond, R 1 is OR 2 , R 4 is hydrogen, -L-R 5 is ethyl, then R 2 not a hydrolyzable group selected from the group consisting of an ester, amide, carbonate and carbamate.
  • the noribogaine derivative is represented by Formula III:
  • R 12 is halo, -OH, -SH, -NH 2 , -S(0) 2 N(R 17 ) 2 , -R'-L'-R 18 , -R Z -L'-R 19 , -R Z -L'-R 20 or - R'-lZ-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 , S , -OC(0)0-arylene-R 18 , -OC(0)0-alkylene-R 18 , - OC(O)-arylene-R 18 , -OC(0)NR 2a -alkylene-R 18 , -OC(O)NR 20 -arylene-R 18 , -OC(NR 20 )NR 20 -alkylene-R 18 or -OC(NR 20 )NR 20 -aiylene-R 18 , and wherein
  • R 13 is hydrogen, -S(0) 2 OR 20 , -S(0) 2 R 20 , -C(0)R 15 , -C(0)NR 15 R 15 , -C(0)OR 15 , C,- Ci 2 alkyl optionally substituted with 1 to 5 R 16 , C 1 -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, Ci-C 12 alkyl, C, -C I 2 alkoxy, aryl or aryloxy, where the alkyl, alkoxy, aryl, and aryloxy are optionally substituted with 1 to 5 R' 6 ;
  • each R 15 is independently selected from the group consisting of hydrogen, C 1 -C 12 alkyl, C- 2 -C 1 ? alkenyl, C 2 -Ci 2 alkynyi, aryl, heteroaryl, and heterocvcle, and wherein the alkyl, alkenyl, alkynyi, aryl, heteroaryl, and heterocycle are optionally substituted with 1 to 5 R 16 ;
  • R lb is selected from the group consisting of phenyl, halo, -OR 1 ' , -
  • each R 17 is independently hydrogen or O-C 12 alkyl optionally substituted with from 1 to 3 halo;
  • R 1 S is hydrogen, -C(0)R 20 , -C(0)OR 2 °, -C(O)N(R 20 ) 2 or -N(R 20 )C(O)R 20 ;
  • R 19 is hydrogen, -
  • each R 20 is independently selected from the group consisting of hydrogen, Q-C 12 alkyl and aryl;
  • R 14 is hydrogen
  • R 12 is -O-I ⁇ -R 1 8 , -0-L ! -R 19 , -O-L 1 - R 20
  • L 1 is alkylene, then -O-L' -R 18 , -O-L'-R 19 , -O-I ⁇ -R 20 are not methoxy;
  • R 14 when is a double bond, R 14 is hydrogen, R Z is O, L' is -C(O)- alkylene, -C(0)-arylene, -C(0)0-arylene, -C(0)0-alkylene, -C(0)NR 20 - alkylene, or -C(O)NR 20 -arylene, then none of R 18 , R 19 or R " ° are hydrogen.
  • the noribogaine derivative is represented by Fonnula IV:
  • 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 23 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaiyl, 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, heteroaiyl, substituted heteroaryl, heterocycl
  • 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, cycioalkyi, substituted cycioalkyi, heteroaiyl, substituted heteroaryl, heterocyclic, and substituted heterocyclic, provided that R is not a saccharide or an oligosaccharide;
  • R 2i is selected from the group consisting of -C(0)NR 24 R 25 and -C(0)OR 26 ;
  • R 21 is hydrogen or -C(0)R 23 ⁇ 4 and V is a covalent bond, then R 22 is not hydrogen.
  • the noribogaine derivative is represented by Formula V:
  • ⁇ ⁇ ' 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 d - C alkyl
  • R 7 and R 28 are provided that at least one of R 7 and R 28 is not hydrogen.
  • the noribogaine derivative is represented by Formula VI:
  • Formula VI refers to the corresponding vicinal dihydro compound
  • R 3 ⁇ is hydrogen, a monophosphate, a diphosphate or a triphosphate
  • R j l is hydrogen, a monophosphate, a diphosphate or a triphosphate
  • R j0 and R 31 are optionally esterified with one or more Ci-Ce alkyl esters.
  • the present invention provides a method for treating a disease associated with an undesired downstream effect of nAChR activity in a patient in need thereof, the method comprising administering to the patient a dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof.
  • the present invention further provides a method for treating a cell expressing at least one nAChR, the method comprising administering to the cell noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof.
  • this invention relates to treatment or attenuation of a disease associated with an undesired downstream effect of nAChR activity, or a symptom of said disease.
  • the disease is associated with activation of one or more nAChR subtypes.
  • the disease is associated with desensitization of one or more nAChR subtypes.
  • the treatment comprises administration of a therapeutically effective amount of noribogaine, noribogaine derivative, or
  • this invention relates to a method for treating a disease associated with an undesired downstream effect of nAChR activity, comprising administering to the patient an effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof to treat said disease.
  • this invention relates to attenuating at least one symptom of a disease associated with an undesired downstream effect of nAChR activity in a sub ject, the method comprising administering to the subject an effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof to attenuate said symptom.
  • this invention is based on the surprising and unexpected discovery that low doses of noribogaine, noribogaine derivative, salt or solvate thereof are effective for attenuating diseases or disorders (or symptoms thereof) that are associated with an undesired downstream response as a result of nicotinic acetylcholine receptor (nAChR) activity.
  • nAChR nicotinic acetylcholine receptor
  • this invention is directed to treatment of a disease or disorder (or symptom thereof) that is associated with an undesired downstream response as a result of nicotinic acetylcholine receptor (nAChR) activity in a patient in need thereof, the method comprising administering to the patient an effective, low dose of noribogaine, noribogaine derivative, salt or solvate thereof.
  • the disease or disorder is a depressive disorder, an anxiety disorder, a memory disorder, or an attention disorder.
  • the disease or disorder is addiction to an addictive substance and/or withdrawal from the addictive substance.
  • the addictive substance is nicotine or caffeine.
  • Depressive disorders or “depression-related disorders” include major depressive disorder and dysthymic disorder (American Psychiatric Association, 1994a; American Psychiatric Association, 1994b).
  • Major depressive disorder is characterized by the occurrence of one or more major depressive episodes without manic or hypomanic episodes.
  • a major depressive episode is defined as a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it can include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation.
  • Dysthymic disorder involves a type of depression that is not severe enough to be called a major depressive episode, but that lasts much longer than major depressive disorder, without high phases.
  • U.S. Patent Application Pub. No. 2015/0258107 relates to treatment of depressive disorders and is incorporated by reference herein in its entirety.
  • panic disorder include panic disorder, agoraphobia with or without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder and generalized anxiety disorder. It is contemplated that the compounds of this invention will be effective in treating these disorders in patients who have been diagnosed as having such disorders.
  • the compounds utilized herein can be effective in treating ADHD or ADD in patients who have the disorder, based upon the diagnostic criteria described in DSM-IV or DSM-5. It is further contemplated that the compounds utilized herein will be effective in reducing symptoms of this disorder, including impulsivity or lack of self-control. It is also contemplated that the compounds described herein will be effective in preventing relapse of ADD or ADHD.
  • U.S. Patent Application Nol4/624,415 (filed 2/17/2015) relates to treatment of anxiety related disorders, schizophrenia, and ADD/ADHD, and is incorporated by reference herein in its entirety.
  • the compounds utilized herein can be effective in treating memory and attention disorders, including dementia and Alzheimer's disease, in patients who have the disorder, based upon standard diagnosis protocols.
  • the effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides an average serum concentration of less than about 60 ng/mL. In one embodiment, the effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides an average serum concentration of less than about 50 ng/mL. In one embodiment, the effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides an average serum concentration of less than about 40 ng/mL. In one embodiment, the effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides an average serum concentration of less than about 30 ng/mL. In one embodiment, the effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides an average serum concentration of less than about 20 ng/mL.
  • the QT interval is not prolonged more than about 20 ms. . In one embodiment, the QT interval is not prolonged more than about 10 ms.
  • the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 70 mg and about 150 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 75 mg and about 150 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 80 mg and about 140 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 90 mg and about 140 mg.
  • the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 90 mg and about 130 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 100 mg and about 130 mg. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 1 10 mg and about 130 mg.
  • the therapeutically effective amount of the compound is from about 50 ng to less than 10 ug per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 5 ⁇ g per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about I ⁇ g per kilogram body weight per day. In another embodiment, the therapeutically effective amount of the compound is from about 50 ng to about 1 ⁇ g per kilogram body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is from about 500 ng to less than 10 ⁇ g per kilogram body weight per day.
  • the therapeuticaUv effective amount of the compound is from about I ⁇ g to less than 10 g per kilogram body weight per day. In yet another embodiment, the therapeutically effective amount of the compound is about 50 ng, about 100 ng, about 150 ng, about 200 ng, about 250 ng, about 300 ng, about 350 ng, about 400 ng, about 450 ng, about 500 ng, about 550 ng, about 600 ng, about 650 ng, about 700 ng, about 750 ng, about 800 ng, about 850 ng, about 900 ng, about 950 ng, about 1 ⁇ g, about 2 ⁇ g, about 3 g, about 3 g, about 4 ⁇ g, about 5 ⁇ g, about 6 ug, about 7 ⁇ g, about 8 ug, about 9 ⁇ g, about 10 g per kilogram body weight per day.
  • the therapeutically effective amount of the compound may be any amount within any of these ranges, including endpoints.
  • this invention is directed to a method for treatment of a disorder or disease (and/or symptom thereof) that is associated with an undesired downstream response as a result of nicotinic acetylcholine receptor (nAChR) activity in a patient in need thereof comprising administering to the patient an effective amount of noribogaine, noribogaine derivative, salt or solvate thereof so as to treat the disease or disorder, or to ameliorate a symptom thereof.
  • the effective amount of noribogaine, noribogaine derivative, salt or solvate thereof is a low dose as described above. In one embodiment, the effective amount is a higher dose.
  • noribogaine, noribogaine derivative, salt or solvate thereof will be acceptable in the treatment of some disorders/symptoms, e.g. addiction to addictive substances,
  • the symptoms associated with such disorders may be severe and/or life-altering. Therefore, an increased risk of QT interval prolongation may be appropriate for patients suffering from these disorders.
  • Sudicidal depression refers to severe depression that is accompanied by suicidal ideation and/or an increased risk of suicide.
  • the disease or disorder is schizophrenia.
  • the disease or disorder is addiction to an addictive substance and/or withdrawal from the addictive substance.
  • the addictive substance is alcohol, an opioid, cocaine, a barbituate, or another narcotic or prescription drug.
  • the compounds utilized herein can be effective in treating schizophrenia in patients who have the disorder, based upon the diagnostic criteria described in DSM-IV or DSM-5. Schizophrenia is characterized by delusions, hallucinations, disorganized speech and behavior, and other symptoms that cause social or occupational dysfunction. It is further contemplated that the compounds utilized herein will be effective in reducing symptoms of this disorder. It is also contemplated that the compounds described herein will be effective in preventing relapse of schizophrenia.
  • the effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides an average serum concentration of less than about 180 ng/niL. In one embodiment, the effective amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides an average serum concentration of between about 50 ng/mL and about I SO ng/mL. [0174] In some embodiments, the serum concentration is sufficient to attenuate said symptoms or treat said disease while maintaining a QT interval of less than about 500 ms during treatment. In some embodiments, 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.
  • the QT interval is not prolonged more than about 50 ms. In one embodiment, the QT interval is not prolonged more than about 40 ms. In one embodiment, the QT interval is not prolonged more than about 30 ms. In one embodiment, the QT interv al is not prolonged more than about 20 ms.
  • the average serum concentration of noribogaine after treatment is less than about 180 ng/mL. In one embodiment, the average serum
  • concentration of noribogaine is less than about 150 ng/mL . In one embodiment, the average serum concentration of noribogaine is less than about 130 ng/mL. In one embodiment, the average serum concentration of noribogaine is less than about 120 ng/mL. In one embodiment, the average serum concentration of noribogaine is less than about 110 ng/mL. In one embodiment, the average serum concentration of noribogaine is less than about 100 ng/mL.
  • the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a maximum serum
  • the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a maximum serum concentration (Cmax) of less than about 150 ng/mL.
  • the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax between about 40 ng/mL and about 250 ng/mL.
  • the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax between about 60 ng/mL and about 200 ng/mL.
  • the dosage of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof provides a Cmax between about 100 ng/mL and about 180 ng/mL.
  • the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 1 mg/kg to about 4 mg/kg body weight per day.
  • the aggregate dosage is the 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.
  • the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 1.3 mg/kg to about 4 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 1.3 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 1.3 mg/kg to about 2 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 1.5 mg/kg to about 3 mg/kg body weight.
  • the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 1.7 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 2 mg/kg to about 4 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 2 mg/kg to about 3 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 2 mg/kg body weight. The ranges include both extremes as well as any subranges there between.
  • the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 4 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 3 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 2 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.9 mg/kg body weight per day.
  • the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.8 mg/kg body- weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.7 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.6 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.5 mg/kg body weight per day.
  • the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.4 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.3 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.2 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1.1 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1 mg/kg body weight per day.
  • the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 0.1 mg/kg to about 1 mg/kg body weight per day.
  • the aggregate dosage is the 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.
  • the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 0.3 mg/kg to about I mg/kg body weight.
  • the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 0.3 mg/kg to about 0.8 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 0.3 mg/kg to about 0.5 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 0.5 mg/kg to about 0.8 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 0.6 mg/kg to about 0.8 mg/kg body weight.
  • the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 0.7 mg/kg to about 1 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is from about 0.7 mg/kg to about 0.8 mg/kg body weight. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 0.5 mg/kg body weight. The ranges include both extremes as well as any subranges there between.
  • the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 1 mg kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 0.9 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 0.8 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 0.7 mg/kg body weight per day.
  • the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 0.6 mg kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 0.5 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 0.4 mg/kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 0.3 mg/kg body weight per day.
  • the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 0.2 mg kg body weight per day. In one embodiment, the dosage or aggregate dosage of noribogaine, noribogaine derivative, or salt or solvate thereof is about 0.1 mg/kg body weight per day.
  • a unit dose of noribogaine, noribogaine derivative, or salt or solvate thereof may be any dose provided herein.
  • the unit dose is about 120 mg. In one embodiment, the unit dose is between about 5 mg and about 120 mg. It being understood that the term "unit dose" means a dose sufficient to provide therapeutic results whether given all at once or serially over a period of time.
  • the patient is administered an initial dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, followed by one or more additional doses.
  • a dosing regimen provides an average serum concentration of noribogaine of less than about 180 ng/mL.
  • the one or more additional doses maintain an average serum concentration of less than about 180 ng/mL over a period of time.
  • the patient is administered periodically, such as once, twice, three time, four times or five time daily with noribogaine, noribogaine derivative, or a pharmaceutically acceptable salt or solvate thereof.
  • 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, without limitation. Determination of dosage and frequency suitable for the present technology can be readily made a qualified clinician.
  • Noribogaine, noribogaine derivative, or a pharmaceutically acceptable solvate or salt thereof, suitable 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.
  • Compositions suitable for internal, pulmonary, rectal, nasal, vaginal, lingual, intravenous, intra-arterial, intramuscular, intraperitoneal, intracutaneous and subcutaneous routes may also be used.
  • Possible dosage forms include tablets, capsules, pills, powders, aerosols, suppositories, parenterals, and oral liquids, including suspensions, solutions and emulsions. Sustained release dosage forms may also be used. All dosage forms may be prepared using methods that are standard in the art (see e.g., Remington's Pharmaceutical Sciences, 16th ed., A. Oslo editor, Easton Pa. 1980).
  • noribogaine noribogaine derivative, or a
  • the noribogaine is provided as noribogaine HC1, with dosages reported as the amount of free base noribogaine.
  • the noribogaine HC1 is provided in hard gelatin capsules containing only noribogaine HC1 with no excipients.
  • a method for attenuating an unwanted downstream effect of nAChR activity in a cell comprising at least one nAChR comprising treating the cell with an effective amount of noribogaine, noribogaine derivative, or salt or solvate thereof.
  • the cell is a neuron.
  • the effective amount of noribogaine, noribogame derivative, or salt or solvate thereof is between about 0.3 ⁇ and about 50 ⁇ . In one embodiment, the effective amount of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 1 ⁇ and about 50 ⁇ . In one embodiment, the effective amount of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 5 ⁇ and about 50 ⁇ . In one embodiment, the effective amount of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 10 ⁇ and about 50 ⁇ .
  • the effective amount of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 15 ⁇ and about 50 ⁇ . In one embodiment, the effective amount of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 20 ⁇ and about 50 ⁇ . In one embodiment, the effective amount of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 25 ⁇ and about 50 ⁇ . In one embodiment, the effective amount of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 30 ⁇ and about 50 ⁇ . In one embodiment, the effective amount of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 40 ⁇ and about 50 ⁇ .
  • the effective amount of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 0.3 ⁇ and about 40 ⁇ . In one embodiment, the effective amount of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 0.3 ⁇ and about 30 ⁇ . In one embodiment, the effective amount of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 0.3 ⁇ and about 20 ⁇ . In one embodiment, the effective amount of noribogaine, noribogaine derivative, or salt or solvate thereof is between about 0.3 ⁇ and about 10 ⁇ .
  • Pre-screening of patients before treatment with noribogaine and/or monitoring of patients during noribogaine treatment may be required to ensure that QT interval is not prolonged beyond a certain value. For example, QT interval greater than about 500 ms can be considered dangerous for individual patients. Pre-screening and/or monitoring may be necessary at high levels of noribogaine treatment.
  • a patient receiving a therapeutic dose of noribogaine 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.
  • a patient receiving a therapeutic dose of noribogaine is not monitored in a clinical setting.
  • a patient receiving a maintenance dose of noribogaine is monitored periodically, for example daily, weekly, monthly, or occasionally. This is particularly relevant where the therapeutic dose of noribogaine administered to the patient is below that known to cause a problematic QT interval prolongation, e.g., when the aggregate dose is below about 120 mg per day.
  • patients may be selected based on any criteria as determined by the skilled clinician.
  • criteria may include, by way of non-limiting example, pre-treatment QT interval, pre-existing cardiac conditions, risk of cardiac conditions, age, sex, general health, and the like.
  • 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.
  • the methods can include selecting and/or administering/providing noribogaine to a patient that lacks one more of such criteria.
  • 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.
  • a patient at risk for prolongation of the QT interval beyond a safe lev el is not administered noribogaine.
  • a patient at risk for prolongation of the QT interval beyond a safe level is administered noribogaine at a limited dosage.
  • this invention relates to monitoring a patient who is administered a therapeutic dose of noribogaine.
  • the dose of noribogaine is reduced if the patient has serious adverse side effects.
  • the noribogaine treatment is discontinued if the patient has serious adverse side effects.
  • 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.
  • This invention further relates to pharmaceutically acceptable formulations comprising a unit dose of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof, wherein the amount of noribogaine is sufficient to provide an average serum concentration of less than about 180 ng/mL when administered to a patient. In a preferred embodiment, the amount of noribogaine is sufficient to provide an average serum concentration of less than about 100 ng/mL when administered to a patient.
  • the formulation may comprise any amount of noribogaine, noribogaine derivative, or pharmaceutically acceptable salt or solvate thereof as described herein.
  • the unit dose of noribogaine is administered in one or more dosings.
  • 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 fonnulations 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).
  • the formulation is designed for oral administration, which may conveniently be provided in tablet, caplet, sublingual, liquid or capsule form.
  • the noribogaine is provided as noribogaine HC1, with dosages reported as the amount of free base noribogaine.
  • the noribogaine HC1 is provided in hard gelatin capsules containing only noribogaine HC1 with no excipients.
  • Blood was obtained for pharmacokinetic assessments pre-dose and then at 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, 14, 18, 24, 30, 36, 48, 60, 72, 96, 120, 168 and 216 hours post-dose. Samples were centrifuged and plasma stored at -70 C C until analyzed. Block 24 hour urine collections were obtained following study drug administration for the 30 and 60 mg cohorts. Aliquots were frozen at -20 °C until analyzed.
  • Pulse oximetry and capnography data were collected continuously using a GE Carescape B650 monitoring system from 2 hours prior to dosing and until six hours after dosing, and thereafter at 12, 24, 48 and 72 hours post-dosing. Additional oximetry data were collected at 120, 168 and 216 hours.
  • Pupillary miosis was assessed by pupillometry. Dark-adapted pupil diameter was measured in triplicate using a Neuroptics PLR-200 pupillometer under standardized light intensity ( ⁇ 5 lux) pre-dose, and at 2, 4, 6, 12, 24, 48, 72, 96, 120, 168 and 216 hours post-dosing.
  • Plasma noribogaine concentrations were determined in the 3 mg and 10 mg dose groups using a validated, sensitive LCMSMS method.
  • Sample preparation involved double extraction of basified plasma samples with tert-butyl methyl ether, drying the samples under a stream of nitrogen and reconstitution of sample with acetonitrile:B.P. water (5:95, v/v) containing 0.1% (v/v) formic acid.
  • the compounds were separated by a 150 x 2.0 mm Luna 5 ⁇ CI 8 column and detected with a triple - quadrupole API 4000 or 5000 mass spectrometer using electrospray ionization in positive mode and multiple reaction monitoring.
  • Noribogaine-d 4 was used as the internal standard.
  • the precursor- product ion transition values for noribogaine were iri/z 297.6 -> 122.3, and for the internal standard noribogaine-d 4 m/z 301.1 -> 122.2.
  • Analyst ® software was used for data acquisition and processing.
  • the ratio of the peak area of noribogaine to the internal standard noribogaine ⁇ was used for calibration and measurement of the unknown concentration of noribogaine.
  • the lower limit of quantification (LLOQ) was 0.025 ng/ml noribogaine.
  • the calibration curve was between 0.025 and 25.600 ng/ml noribogaine.
  • Mobile phase A was acetonitrile:B.P.
  • Plasma noribogaine concentrations were determined in the 30 mg and 60 mg dose groups using a validated, sensitive LCMSMS method.
  • Sample preparation involved deproteinization of plasma samples with acetonitrile and dilution of sample with 0.1% (v/v) formic acid.
  • the compounds were separated by a 150 x 2.0 mm Luna 5um C18 column and detected with a triple - quadrupole API 4000 or 5000 mass spectrometer using electrospray ionization in positive mode and multiple reaction monitoring.
  • Noribogaine-d4 was used as the internal standard.
  • the precursor-product ion transition values for noribogaine were m/z 297.6 -> 122.3, and for the internal standard noribogaine-d4 m/z 301.1 -> 122.2.
  • Analyst* software was used for data acquisition and processing.
  • the ratio of the peak area of noribogaine to the internal standard noribogaine-d.4 was used for calibration and measurement of the unknown concentration of noribogaine.
  • the LLOQ was 0.50 ng/ml noribogaine.
  • the calibration curve was between 0.50 and 256.00 ng/ml noribogaine.
  • Mobile phase was the same as method A, and binary flow was also the same as method A.
  • the within- and between-day assay precision was ⁇ 9%, and the within- and between-day assay accuracy was ⁇ 9%.
  • Plasma noribogaine glucuronide concentrations were determined in the 30 mg and 60 mg dose groups using a validated sensitive LCMSMS method.
  • Sample preparation involved deproteinization of plasma samples with acetonitrile, drying the samples under a stream of nitrogen and reconstitution of sample with acetonitrile: B.P. water (5:95, v/v) containing 0.1% (v/v) formic acid.
  • the compounds were separated by a 150 x 2.0 mm Lima 5 ⁇ CI 8 column and detected with a triple - quadrupole API 4000 or 5000 mass spectrometer using electrospray ionization in positive mode and multiple reaction monitoring. Noribogame-d.4 was used as the internal standard.
  • the precursor-product ion transition values for noribogaine glucuronide were m z 472.8 -> 297.3, and for the internal standard noribogaine-d4 m/z 301.1 -> 122.2.
  • Analyst* software was used for data acquisition and processing.
  • the ratio of the peak area of noribogaine glucuronide to the internal standard noribogaine-d4 was used for calibration and measurement of the unknown concentration of noribogaine glucuronide.
  • the LLOQ was 0.050 ng/ml noribogaine glucuronide.
  • the calibration curve was between 0.050 and 6.400 ng/ml noribogaine glucuronide.
  • Mobile phases was the same as method A.
  • Urine noribogaine and noribogaine glucuronide concentrations were determined in the 30 mg and 60 mg dose groups using a validated sensitive LCMSMS method.
  • Sample preparation involved deproteinization of urine samples with acetonitrile and dilution of the sample with 0.1% (v/v) formic acid.
  • the compounds were separated by a 150 x 2.0 mm Luna 5 ⁇ C18 column and detected with a triple - quadrupole API 5000 mass spectrometer using electrospray ionization in positive mode and multiple reaction monitoring.
  • Noribogame-d.4 was used as the internal standard.
  • the precursor-product ion transition values for noribogaine were m z 297.6 -> 122.3, noribogaine glucuronide m/z 472.8 -> 297.3, and for the internal standard noribogaine-o m/z 301.1 -> 122.2.
  • Analyst* software was used for data acquisition and processing.
  • the ratios of the peak area of noribogaine and noribogaine glucuronide to the internal standard noribogaine-d4 were used for calibration and measurement of the unknown concentration of noribogaine and its glucuronide.
  • Assay LLOQ was 20.0 ng/ml for noribogaine and 2.0 ng/ml for noribogaine glucuronide.
  • the calibration curve was between 20.0 and 5120.0 ng/ml noribogaine, and 2.0 and 512.0 ng/ml noribogaine glucui nide.
  • Mobile phases were as described in method A, and binary flow as in method C.
  • the within- and between-day assay precision was ⁇ 13%, and within- and between-day assay accuracy was ⁇ 12%.
  • Noribogaine and noribogaine glucuronide concentrations above the limit of quantification were used to calculate pharmacokinetic parameters using model- independent methods.
  • the maximum plasma concentration (Cmax) and time to maximum plasma concentration (Tmax) were the observed values.
  • the area under the concentration-time curve (AUC) from time zero to the last determined concentration-time point (tf) in the post distribution phase was calculated using the trapezoidal rule.
  • the concentration used for Ctf was the last determined value above the LLOQ at the time point.
  • the total AUCo- ⁇ was obtained by adding AUC t i and AUC t - .
  • Total urine noribogaine was the sum of both analytes.
  • Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing. Fluctuations in individual distribution-phase concentration-time profiles may suggest the possibility of enterohepatic recirculation (see highlighted individual 4-8 hour profiles in Figure 5, insert). Both Cmax and AUC increased linearly with dose (Table 1 , upper panel). Mean half-life estimates of 28-50 hours were observed across dose groups for noribogaine. Volume of distribution was extensive (1417-3086 L across dose groups).
  • Analgesic effect was assessed based on duration of hand immersion in ice water and on visual analog scale (VAS) pain scores upon hand removal from the water bath.
  • VAS visual analog scale
  • Safety and tolerability of noribogaine were tested in the group of volunteers from Example 1. Cold pressor testing was conducted in 1 °C water according to the method of Mitchell et al. (J Pain 5:233-237, 2004) pre-dose, 6, 24, 48, 72 and 216 hours post-dosing. Safety evaluations included clinical monitoring, recording of adverse events (AEs), safety laboratory tests, vital signs, ECG telemetry from -2h to 6h after dosing, and 12-lead electrocardiograms (ECGs) up to 216 hours post-dosing.
  • AEs adverse events
  • ECG telemetry ECG telemetry from -2h to 6h after dosing
  • ECGs 12-lead electrocardiograms
  • Fluo-2HA high affinity
  • TEFLabs, Inc. (Austin, TX). G418 sulfate, and Minimal Essential Medium was purchased from InVitrogen, (Carlsbad, CA). Mecamylamine, epibatidine, PNU- 120596 and all buffer constituents were purchased from Sigma-Aldrich Corp. (St. Louis, MO). Ibogaine was provided by Dr. Deborah Mash at the University of Miami (Miami, FL). 18-MC was purchased at Orbiter Pharmaceutical. Noribogaine hydrochloride was purchased at Sigma Aldrich Chemie GmbH (Buchs Switzerland). SH-SY5Y human neuroblastoma cells which express endogenous nAChR a3, a5, a7, ⁇ 2, and ⁇ 4 subunit genes were purchased from ATCC (Manassas, VA.).
  • SH-SY5Y cells were cultured in 50% Minimal Essential Medium (MEM) and 50% F12 + Glutamax containing 10% (v/v) fetal bovine serum at 37 °C in a 5% CO? incubator. SH-SY5Y cells were passaged every 4-6 days at 70-80% confluency using standard cell culture methods.
  • MEM Minimal Essential Medium
  • F12 + Glutamax 10% (v/v) fetal bovine serum at 37 °C in a 5% CO? incubator.
  • SH-SY5Y cells were passaged every 4-6 days at 70-80% confluency using standard cell culture methods.
  • HBSS Hank's balanced salt solution
  • HBSS Hank's balanced salt solution
  • VAL/PHE position 12/13 '
  • Van der Waals interactions between the aliphatic ring of ibogaine and the VAL/PHE and LEU rings were described for the outer region, whereas its methoxy moiety was proposed to form hydrogen bonds with several hydroxy! groups at the lower, deeper, serine ring. This is in contrast with the proposed binding of
  • mecamylamine which was shown to interact with the outer ring portion of the pore.
  • test compounds influenced the basal calcium concentration, indicating that none were promoting partial nAChR agonism or artifactual stimulations under these conditions.
  • Epibatidine concentration for inhibition dose-response assays were chosen at ⁇ 5 times its EC 50 to allow sub-maximal stimulation without a large excess of agonist applied (50 nM).
  • Noribogaine inhibited epibatidine-evoked calcium flux at ⁇ 3-( ⁇ 5, ⁇ 4, ⁇ 2) nAChRs with an IC 50 of 488 ⁇ 109 nM ( Figure 1, Table 4).
  • Ibogaine inhibited epibatidine-evoked calcium flux at oc3-(ct5, ⁇ 4, ⁇ 2) with an IC 50 of 38 ⁇ 20 nM ( Figure 1 , Table 4).
  • Mecamylamine inhibited epibatidine-evoked calcium flux at ⁇ 3-( ⁇ 5, ⁇ 4, ⁇ 2) nAChRs with an IC 50 of 88 ⁇ 8 nM ( Figure 1 , Table 4).
  • Ibogaine has been proposed to bind in the pore area of the nicotinic receptors, partially overlapping the PCP binding, deeper than the binding site of the channel blocker mecamylamine.
  • Noribogaine at 0.3 and 1.5 ⁇ decreased by 30 and 70 % the maximal response of epibatidine-evoked calcium flux at ⁇ 3-( ⁇ 5, ⁇ 4, ⁇ 2) without affecting the EC 5 o for epibatidine (from 9 nM to 1 1 , and 22 nM) ( Figure 2).
  • This phenomenon is prototypical of non-competitive inhibitory mode of noribogaine at the a3-containing nAChRs.
  • SER 6' was conserved in all subunits except a7, where the residue was THR.
  • LEU 9 1 was conserved in all subunits except a5 where the residue was VAL.
  • VAL13' was conserved in all subunits except ⁇ 4 where the residue was PF1E.
  • PHE14' was conserved in all subunits. For each subunit, there were no differences noted in between human and rat species for these key amino acids (not shown).
  • noribogaine is a non-competitive inhibitor of several neuronal ionotropic cholinergic receptors species, including heteromeric a3-containing nAChRs, at mid-nanomolar potencies. Ibogaine also displayed low and mid-nanomolar potencies at these targets (Table 1). This is in contrast to reported apparent affinities and potencies of ibogaine (from 100 to 1000 times less potent/affine) at other targets commonly thought to be primordial (e.g. NMDA, SERT) for its effects at impeding addiction-related behaviors.
  • primordial e.g. NMDA, SERT
  • Both noribogaine and ibogaine had high specificity for the receptor populations expressed in the SH-SY5Y cell-line, and this specificity was higher than that observed for rat nAChRs.
  • ibogaine allosterically inhibits (+/-)- epibatidine-induced Ca 2" influx in ⁇ 3 ⁇ 4 nAChR via a site overlapping with the PCP binding site (Arias et al. 2010).
  • Amino acids presumed to govern ibogaine and noribogaine' binding are highly conserved between human and rats, with no differences in either subunit investigated (a3, 4, a5, ⁇ 2, ⁇ 4, a7).
  • the a5 subunit has a VAL in position 5 instead of a LEU as for the ⁇ 3, ⁇ 4, and ⁇ 2 subunits, which constitutes an aliphatic-conserved substitution of smaller size.
  • substitution even if subtle, could result in significant changes in the sensitivity of the a5-containing channels to particular ligands.
  • Bupropion an anti-depressant also prescribed for smoking cessation, blocked norepinephrine and dopamine reuptake, and was later discovered to preferentially antagonized 3 ⁇ 4 nAChRs as well (Slemmer et al. 2000; Arias 2009).
  • 18-MC was an antagonist at 3 ⁇ 4 nAChR receptors mXenopus oocytes (Maisonneuve and Glick 2003), with supplemental activities at opioids receptor sites and batrachotoxin-sensitive sodium channels sites (Glick and Maisonneuve 2000). It is unclear if 18-MC mediates all of its in vivo behavioral effects through blockade of ⁇ 3 ⁇ 4 nAChR uniquely.
  • the habenula receives input from the limbic system and basal ganglia while the fasciculus retroflexus is the primary habenular output to the midbrain.
  • the habenula is a critical crossroad that influences the brain's response to pain, stress, anxiety, sleep, reward and disappointment. Dysfunction of the habenula has been linked to depression, schizophrenia, and the effects of drugs of abuse, a 7 nAChRs are predominantly expressed in the CNS, including the hippocampus, cortex, and ventral tegmental area, and are involved with long term potentiation (LTP), memory, and attention deficits.
  • LTP long term potentiation
  • noribogaine is expected to have beneficial effects in a variety of neurophsychiatric disorders.
  • substance- abuse related disorders e.g. alcohol and nicotine
  • anxiety related disorders notably PTSD
  • co-occurrence particularly prevalent in returning veterans a co-occurrence particularly prevalent in returning veterans
  • Figure 4 represents the subunit composition of nAChRs occurring in the habenula of P18 wild-type mice as originally described in (Scholze et al. 2012).
  • the diagram illustrates a proposed subunit composition and relative expression levels of hetero- oligomeric receptors in this brain region.
  • the SH-SY5Y cell line has been shown to express a3, a5, b2 and b4 subunits, resulting in a heterogeneous population of nicotinic receptors composed of ⁇ 3 ⁇ 4, a3a5b4, a3p4b2, a3a5b4b2 nAChRs (Wang et al. 1996) that represents a useful cellular model of the nAChR population expressed in certain neurons of the habenula.

Abstract

La présente invention concerne un procédé de traitement d'un ou de plusieurs trouble(s) associé(s) à une activité en aval indésirable d'au moins un sous-type du récepteur nicotinique neuronal de l'acétylcholine, comprenant le traitement d'un patient avec de la noribogaïne, un dérivé de noribogaïne, ou un sel ou solvate pharmaceutiquement acceptable de celui-ci pour atténuer ledit effet indésirable.
PCT/US2016/018273 2015-02-19 2016-02-17 Procédés pour le traitement de troubles associés à une activité indésirable de récepteurs nicotiniques neuronaux de l'acétylcholine WO2016134019A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562118397P 2015-02-19 2015-02-19
US62/118,397 2015-02-19

Publications (1)

Publication Number Publication Date
WO2016134019A1 true WO2016134019A1 (fr) 2016-08-25

Family

ID=56692393

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/018273 WO2016134019A1 (fr) 2015-02-19 2016-02-17 Procédés pour le traitement de troubles associés à une activité indésirable de récepteurs nicotiniques neuronaux de l'acétylcholine

Country Status (1)

Country Link
WO (1) WO2016134019A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9549935B2 (en) 2014-07-14 2017-01-24 Demerx, Inc. Methods and compositions for treating migraines using noribogaine
US9561232B2 (en) 2014-02-18 2017-02-07 Demerx, Inc. Low dose noribogaine for treating nicotine addiction and preventing relapse of nicotine use
US9591978B2 (en) 2014-03-13 2017-03-14 Demerx, Inc. Methods and compositions for pre-screening patients for treatment with noribogaine
US9744174B2 (en) 2013-03-15 2017-08-29 Demerx, Inc. Method for noribogaine treatment in patients on methadone
US10660900B2 (en) 2014-11-26 2020-05-26 Demerx, Inc. Methods and compositions for potentiating the action of opioid analgesics using iboga alkaloids

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030194438A1 (en) * 2002-04-11 2003-10-16 Albert Prescott Extended release analgesic for pain control
US20060229293A1 (en) * 2005-04-06 2006-10-12 Addiction Research Institute, Inc. Compositions for the treatment of hepatitis C and methods for using compositions for the treatment of hepatitis C
US20140179685A1 (en) * 2012-12-20 2014-06-26 Deborah C. Mash Substituted noribogaine
US20140288056A1 (en) * 2013-03-15 2014-09-25 Demerx, Inc. Methods for non-toxic treatment for drug withdrawal
US8853201B2 (en) * 2011-12-09 2014-10-07 Demerx, Inc. Sulfate esters of noribogaine

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030194438A1 (en) * 2002-04-11 2003-10-16 Albert Prescott Extended release analgesic for pain control
US20060229293A1 (en) * 2005-04-06 2006-10-12 Addiction Research Institute, Inc. Compositions for the treatment of hepatitis C and methods for using compositions for the treatment of hepatitis C
US8853201B2 (en) * 2011-12-09 2014-10-07 Demerx, Inc. Sulfate esters of noribogaine
US20140179685A1 (en) * 2012-12-20 2014-06-26 Deborah C. Mash Substituted noribogaine
US20140288056A1 (en) * 2013-03-15 2014-09-25 Demerx, Inc. Methods for non-toxic treatment for drug withdrawal

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHANG ET AL.: "Noribogaine reduces nicotine selfadministration in rats", JOURNAL OF PSYCHOPHARMACOLOGY, vol. 29, no. 6, 20 May 2015 (2015-05-20), pages 704 - 711 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9744174B2 (en) 2013-03-15 2017-08-29 Demerx, Inc. Method for noribogaine treatment in patients on methadone
US9561232B2 (en) 2014-02-18 2017-02-07 Demerx, Inc. Low dose noribogaine for treating nicotine addiction and preventing relapse of nicotine use
US9591978B2 (en) 2014-03-13 2017-03-14 Demerx, Inc. Methods and compositions for pre-screening patients for treatment with noribogaine
US9549935B2 (en) 2014-07-14 2017-01-24 Demerx, Inc. Methods and compositions for treating migraines using noribogaine
US10660900B2 (en) 2014-11-26 2020-05-26 Demerx, Inc. Methods and compositions for potentiating the action of opioid analgesics using iboga alkaloids
US11197866B2 (en) 2014-11-26 2021-12-14 Demerx, Inc. Methods and compositions for potentiating the action of opioid analgesics using iboga alkaloids
US11260059B2 (en) 2014-11-26 2022-03-01 Demerx, Inc. Methods and compositions for potentiating the action of opioid analgesics using iboga alkaloids

Similar Documents

Publication Publication Date Title
US11066415B2 (en) Compositions and methods for regulating glucose homeostasis and insulin action
WO2016134019A1 (fr) Procédés pour le traitement de troubles associés à une activité indésirable de récepteurs nicotiniques neuronaux de l'acétylcholine
AU2021202957B2 (en) Methods and compositions for potentiating the action of opioid analgesics using iboga alkaloids
Pasquier Autophagy inhibitors
Highland et al. Hydroxynorketamines: pharmacology and potential therapeutic applications
Novella Romanelli et al. HCN channels modulators: the need for selectivity
JP7360409B2 (ja) 認知症における激越の処置のためのデキストロメトルファン化合物およびキニジンを含む医薬組成物
J Robson et al. Sigma-1 receptors: potential targets for the treatment of substance abuse
US20150258106A1 (en) Methods for acute and long-term treatment of substance abuse
US20150258105A1 (en) Methods for acute and long-term treatment of alcohol dependence
SK10752003A3 (sk) Použitie inverzných agonistov GABAA v kombinácii s parciálnymi agonistami receptora nikotínu, estrogénom, selektívnymi modulátormi estrogénu alebo vitamínom E pri liečení kognitívnych porúch
US20150258108A1 (en) Methods and compositions for reducing tolerance to opioid analgesics
CA2977636C (fr) Methodes therapeutiques faisant intervenir de la noribogaine et des composes apparentes
Yang et al. Neuroprotective effects of Ginkgolide B in focal cerebral ischemia through selective activation of prostaglandin E2 receptor EP4 and the downstream transactivation of epidermal growth factor receptor
CA2750928A1 (fr) Methodes de diagnostic et de traitement de maladies neurodegeneratives
Yang et al. Benidipine, an anti-hypertensive drug, relaxes mouse airway smooth muscle
Hu et al. Involvements of calcium channel and potassium channel in Danshen and Gegen decoction induced vasodilation in porcine coronary LAD artery
DK2744781T3 (en) FENTANYL DERIVATIVES AS PH-DEPENDENT OPIOID RECEPTOR AGONISTS
US20120010264A1 (en) Novel medicament for treating cognitive impairment
Schulte et al. Allosteric modulation and potential therapeutic applications of heteromeric nicotinic acetylcholine receptors
Danyeli et al. Ketamine in Psychiatric Disorders
KR20220054593A (ko) 병용 치료를 위한 화합물
Hu et al. Efficacy of SAL0114, an Oral NMDA Receptor Antagonist with Multimodal Activity, in Major Depressive Disorder
WO2018187606A1 (fr) PROCÉDÉS ET COMPOSITIONS POUR MODULER LES INTERACTIONS β-AMYLOÏDE/α7-NACHR

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 16752980

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 16752980

Country of ref document: EP

Kind code of ref document: A1